WO2022206964A1 - Prmt5抑制剂及其用途 - Google Patents
Prmt5抑制剂及其用途 Download PDFInfo
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- WO2022206964A1 WO2022206964A1 PCT/CN2022/084850 CN2022084850W WO2022206964A1 WO 2022206964 A1 WO2022206964 A1 WO 2022206964A1 CN 2022084850 W CN2022084850 W CN 2022084850W WO 2022206964 A1 WO2022206964 A1 WO 2022206964A1
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- WO
- WIPO (PCT)
- Prior art keywords
- alkyl
- membered
- cycloalkyl
- alkoxy
- deuterium
- Prior art date
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- 229940125897 PRMT5 inhibitor Drugs 0.000 title abstract description 3
- 150000001875 compounds Chemical class 0.000 claims abstract description 277
- 239000013078 crystal Substances 0.000 claims abstract description 51
- 150000003839 salts Chemical class 0.000 claims abstract description 49
- 239000012453 solvate Substances 0.000 claims abstract description 46
- 239000002207 metabolite Substances 0.000 claims abstract description 42
- 239000000651 prodrug Substances 0.000 claims abstract description 42
- 229940002612 prodrug Drugs 0.000 claims abstract description 42
- 238000002360 preparation method Methods 0.000 claims abstract description 12
- 239000003814 drug Substances 0.000 claims abstract description 9
- 201000010099 disease Diseases 0.000 claims abstract description 6
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims abstract description 6
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 6
- 229940079593 drug Drugs 0.000 claims abstract description 5
- 125000000217 alkyl group Chemical group 0.000 claims description 605
- 125000003545 alkoxy group Chemical group 0.000 claims description 356
- 229910052805 deuterium Inorganic materials 0.000 claims description 308
- 125000000592 heterocycloalkyl group Chemical group 0.000 claims description 307
- YZCKVEUIGOORGS-OUBTZVSYSA-N Deuterium Chemical compound [2H] YZCKVEUIGOORGS-OUBTZVSYSA-N 0.000 claims description 306
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 259
- 229910052736 halogen Inorganic materials 0.000 claims description 227
- -1 nitro, cyano, amino, hydroxyl Chemical group 0.000 claims description 222
- 150000002367 halogens Chemical class 0.000 claims description 214
- 125000001072 heteroaryl group Chemical group 0.000 claims description 143
- 229910052739 hydrogen Inorganic materials 0.000 claims description 134
- 125000003118 aryl group Chemical group 0.000 claims description 132
- 239000001257 hydrogen Substances 0.000 claims description 130
- 150000002431 hydrogen Chemical class 0.000 claims description 119
- 238000006467 substitution reaction Methods 0.000 claims description 113
- 229910052799 carbon Inorganic materials 0.000 claims description 90
- 229910052760 oxygen Inorganic materials 0.000 claims description 61
- 125000004432 carbon atom Chemical group C* 0.000 claims description 59
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 55
- 150000001721 carbon Chemical group 0.000 claims description 52
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 51
- 125000005843 halogen group Chemical group 0.000 claims description 49
- 125000000882 C2-C6 alkenyl group Chemical group 0.000 claims description 33
- 125000006580 bicyclic heterocycloalkyl group Chemical group 0.000 claims description 32
- 125000003601 C2-C6 alkynyl group Chemical group 0.000 claims description 29
- 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 claims description 28
- 229910052731 fluorine Inorganic materials 0.000 claims description 28
- 229910052801 chlorine Inorganic materials 0.000 claims description 27
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 27
- 125000006578 monocyclic heterocycloalkyl group Chemical group 0.000 claims description 26
- 239000000126 substance Substances 0.000 claims description 26
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 20
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 20
- 125000006552 (C3-C8) cycloalkyl group Chemical group 0.000 claims description 19
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 18
- 102100034607 Protein arginine N-methyltransferase 5 Human genes 0.000 claims description 17
- 125000004191 (C1-C6) alkoxy group Chemical group 0.000 claims description 15
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 15
- 125000006570 (C5-C6) heteroaryl group Chemical group 0.000 claims description 12
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 12
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims description 11
- 125000006163 5-membered heteroaryl group Chemical group 0.000 claims description 11
- 125000006652 (C3-C12) cycloalkyl group Chemical group 0.000 claims description 10
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 10
- 229910052794 bromium Inorganic materials 0.000 claims description 10
- 125000004890 (C1-C6) alkylamino group Chemical group 0.000 claims description 8
- 125000006619 (C1-C6) dialkylamino group Chemical group 0.000 claims description 8
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 8
- 125000003342 alkenyl group Chemical group 0.000 claims description 8
- 125000000304 alkynyl group Chemical group 0.000 claims description 8
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 8
- 239000000203 mixture Substances 0.000 claims description 8
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 7
- 125000002950 monocyclic group Chemical group 0.000 claims description 6
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 claims description 5
- 125000000623 heterocyclic group Chemical group 0.000 claims description 5
- 230000001404 mediated effect Effects 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 4
- 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 4
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 claims description 4
- 125000003566 oxetanyl group Chemical group 0.000 claims description 4
- 125000006707 (C3-C12) heterocycloalkyl group Chemical group 0.000 claims description 3
- 125000006577 C1-C6 hydroxyalkyl group Chemical group 0.000 claims description 3
- 206010028980 Neoplasm Diseases 0.000 claims description 3
- HONIICLYMWZJFZ-UHFFFAOYSA-N azetidine Chemical compound C1CNC1 HONIICLYMWZJFZ-UHFFFAOYSA-N 0.000 claims description 3
- 239000003937 drug carrier Substances 0.000 claims description 3
- 150000003254 radicals Chemical class 0.000 claims description 3
- 150000001335 aliphatic alkanes Chemical group 0.000 claims description 2
- 125000000325 methylidene group Chemical group [H]C([H])=* 0.000 claims description 2
- 101710084427 Protein arginine N-methyltransferase 5 Proteins 0.000 claims 2
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 195
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 142
- 238000006243 chemical reaction Methods 0.000 description 127
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 113
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 108
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- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 43
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 41
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 39
- 239000012074 organic phase Substances 0.000 description 37
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 28
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 28
- 210000004027 cell Anatomy 0.000 description 28
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 27
- 239000000543 intermediate Substances 0.000 description 26
- 229910052757 nitrogen Inorganic materials 0.000 description 25
- 239000002994 raw material Substances 0.000 description 25
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 24
- 239000012071 phase Substances 0.000 description 24
- 238000012360 testing method Methods 0.000 description 22
- 239000000460 chlorine Substances 0.000 description 21
- 238000003756 stirring Methods 0.000 description 21
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 20
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 20
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 18
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 18
- 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 17
- 229940125797 compound 12 Drugs 0.000 description 17
- 238000000746 purification Methods 0.000 description 16
- 101000924530 Homo sapiens Protein arginine N-methyltransferase 5 Proteins 0.000 description 15
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 15
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 15
- MFRIHAYPQRLWNB-UHFFFAOYSA-N sodium tert-butoxide Chemical compound [Na+].CC(C)(C)[O-] MFRIHAYPQRLWNB-UHFFFAOYSA-N 0.000 description 14
- 238000001308 synthesis method Methods 0.000 description 14
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- 125000005842 heteroatom Chemical group 0.000 description 13
- 238000004809 thin layer chromatography Methods 0.000 description 13
- UWYZHKAOTLEWKK-UHFFFAOYSA-N 1,2,3,4-tetrahydroisoquinoline Chemical compound C1=CC=C2CNCCC2=C1 UWYZHKAOTLEWKK-UHFFFAOYSA-N 0.000 description 12
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 12
- 230000014759 maintenance of location Effects 0.000 description 12
- 125000003367 polycyclic group Chemical group 0.000 description 12
- 239000012312 sodium hydride Substances 0.000 description 12
- 229910000104 sodium hydride Inorganic materials 0.000 description 12
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 12
- AOSZTAHDEDLTLQ-AZKQZHLXSA-N (1S,2S,4R,8S,9S,11S,12R,13S,19S)-6-[(3-chlorophenyl)methyl]-12,19-difluoro-11-hydroxy-8-(2-hydroxyacetyl)-9,13-dimethyl-6-azapentacyclo[10.8.0.02,9.04,8.013,18]icosa-14,17-dien-16-one Chemical compound C([C@@H]1C[C@H]2[C@H]3[C@]([C@]4(C=CC(=O)C=C4[C@@H](F)C3)C)(F)[C@@H](O)C[C@@]2([C@@]1(C1)C(=O)CO)C)N1CC1=CC=CC(Cl)=C1 AOSZTAHDEDLTLQ-AZKQZHLXSA-N 0.000 description 11
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- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 10
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 10
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- JAXFJECJQZDFJS-XHEPKHHKSA-N gtpl8555 Chemical compound OC(=O)C[C@H](N)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](C(C)C)C(=O)N1CCC[C@@H]1C(=O)N[C@H](B1O[C@@]2(C)[C@H]3C[C@H](C3(C)C)C[C@H]2O1)CCC1=CC=C(F)C=C1 JAXFJECJQZDFJS-XHEPKHHKSA-N 0.000 description 10
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- NLHBHVGPMMXWIM-UHFFFAOYSA-N 1-(4-aminopiperidin-1-yl)ethanone Chemical compound CC(=O)N1CCC(N)CC1 NLHBHVGPMMXWIM-UHFFFAOYSA-N 0.000 description 9
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- WWTBZEKOSBFBEM-SPWPXUSOSA-N (2s)-2-[[2-benzyl-3-[hydroxy-[(1r)-2-phenyl-1-(phenylmethoxycarbonylamino)ethyl]phosphoryl]propanoyl]amino]-3-(1h-indol-3-yl)propanoic acid Chemical compound N([C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)O)C(=O)C(CP(O)(=O)[C@H](CC=1C=CC=CC=1)NC(=O)OCC=1C=CC=CC=1)CC1=CC=CC=C1 WWTBZEKOSBFBEM-SPWPXUSOSA-N 0.000 description 5
- UNILWMWFPHPYOR-KXEYIPSPSA-M 1-[6-[2-[3-[3-[3-[2-[2-[3-[[2-[2-[[(2r)-1-[[2-[[(2r)-1-[3-[2-[2-[3-[[2-(2-amino-2-oxoethoxy)acetyl]amino]propoxy]ethoxy]ethoxy]propylamino]-3-hydroxy-1-oxopropan-2-yl]amino]-2-oxoethyl]amino]-3-[(2r)-2,3-di(hexadecanoyloxy)propyl]sulfanyl-1-oxopropan-2-yl Chemical compound O=C1C(SCCC(=O)NCCCOCCOCCOCCCNC(=O)COCC(=O)N[C@@H](CSC[C@@H](COC(=O)CCCCCCCCCCCCCCC)OC(=O)CCCCCCCCCCCCCCC)C(=O)NCC(=O)N[C@H](CO)C(=O)NCCCOCCOCCOCCCNC(=O)COCC(N)=O)CC(=O)N1CCNC(=O)CCCCCN\1C2=CC=C(S([O-])(=O)=O)C=C2CC/1=C/C=C/C=C/C1=[N+](CC)C2=CC=C(S([O-])(=O)=O)C=C2C1 UNILWMWFPHPYOR-KXEYIPSPSA-M 0.000 description 5
- RLLZPXDJYADIEU-UHFFFAOYSA-N 3,4-dihydro-5-methylisoquinolinone Chemical compound O=C1NCCC2=C1C=CC=C2C RLLZPXDJYADIEU-UHFFFAOYSA-N 0.000 description 5
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- HBAQYPYDRFILMT-UHFFFAOYSA-N 8-[3-(1-cyclopropylpyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-methyl-3,8-diazabicyclo[3.2.1]octan-2-one Chemical class C1(CC1)N1N=CC(=C1)C1=NNC2=C1N=C(N=C2)N1C2C(N(CC1CC2)C)=O HBAQYPYDRFILMT-UHFFFAOYSA-N 0.000 description 5
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 5
- FJPYVHVPPOPIEP-UHFFFAOYSA-N CC(C=C(CCN(CC(CN1CC2=CC=CC=C2CC1)O)C1=O)C1=C1)=C1I Chemical compound CC(C=C(CCN(CC(CN1CC2=CC=CC=C2CC1)O)C1=O)C1=C1)=C1I FJPYVHVPPOPIEP-UHFFFAOYSA-N 0.000 description 5
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Classifications
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- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—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
- A61K31/438—The ring being spiro-condensed with carbocyclic or heterocyclic ring systems
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- A—HUMAN NECESSITIES
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- A61K31/33—Heterocyclic compounds
- 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
- A61K31/439—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 the ring forming part of a bridged ring system, e.g. quinuclidine
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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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
- A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
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- A—HUMAN NECESSITIES
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- 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
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- A—HUMAN NECESSITIES
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- A61K31/50—Pyridazines; Hydrogenated pyridazines
- A61K31/501—Pyridazines; Hydrogenated pyridazines not condensed and containing further heterocyclic rings
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- A—HUMAN NECESSITIES
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- A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
- A61K31/5375—1,4-Oxazines, e.g. morpholine
- A61K31/5386—1,4-Oxazines, e.g. morpholine spiro-condensed or forming part of bridged ring systems
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- A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
- A61K31/553—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having at least one nitrogen and one oxygen as ring hetero atoms, e.g. loxapine, staurosporine
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- A—HUMAN NECESSITIES
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- 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
- C07D401/06—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 linked by a carbon chain containing only aliphatic carbon atoms
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
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- 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
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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
- C07D471/08—Bridged systems
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/04—Ortho-condensed systems
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D498/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
- C07D498/08—Bridged systems
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D513/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00
- C07D513/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00 in which the condensed system contains two hetero rings
- C07D513/04—Ortho-condensed systems
Definitions
- the invention belongs to the field of medicine, and in particular relates to a derivative of a protein arginine methyltransferase inhibitor, its stereoisomer, pharmaceutically acceptable salt, solvate, co-crystal or deuterated compound, and preparation thereof Use in a medicament for the treatment of PRMT5-mediated related diseases.
- Protein arginine methyltransferase can methylate a variety of proteins (including histones and non-histone proteins) and affect a variety of biological processes, such as participating in gene transcription, cell signal transduction, protein stability, cell proliferation, differentiation, apoptosis and tumor formation.
- PRMT Protein arginine methyltransferase
- PRMT4, PRMT6, PRMT8 belong to type I, and the catalytic form is monomethyl and non-methylated.
- PEMT5 and PRMT9 belong to type II, and their catalytic form is symmetrical bismethyl
- PRMT7 belongs to type III, which can catalyze monomethyl.
- Protein arginine methyltransferase 5 is ubiquitous in the cytoplasm and nucleus, and can specifically catalyze the symmetrical methylation of many substrates such as histones and non-histone proteins, thereby affecting multiple target genes and multiple Signaling pathways play a variety of biological functions.
- PRMT5 Protein arginine methyltransferase 5
- the expression of PRMT5 is up-regulated, which fully shows that it plays an important role in the formation and development of tumors. effect.
- PRMT5 has been confirmed as a therapeutic target for mantle cell lymphoma, so the research on its small molecule inhibitor has become a hot spot in the development of anti-tumor drugs.
- the purpose of the present invention is to provide a new PRMT5 inhibitor with high activity, small side effects, high bioavailability and high selectivity.
- the compounds provided by the present invention and their stereoisomers, deuterated compounds, solvates, prodrugs, metabolites, pharmaceutically acceptable salts or co-crystals have an inhibitory effect on PRMT5, can inhibit cell proliferation, and have good pharmacokinetics It has kinetic characteristics, high bioavailability, good safety, small toxic and side effects, and has the advantages of oral administration, fast absorption, and high clearance rate.
- the present invention provides a compound represented by formula (I), its stereoisomer, deuterated compound, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal,
- Ring A is selected from phenyl or 5-6 membered heteroaryl
- R 1 , R 2 , R 3 , R 4 are each independently selected from hydrogen, deuterium, hydroxyl, halogen, amino, nitro, cyano, C 1-6 alkyl, C 1-6 alkoxy, C 3- 8 cycloalkyl, C 1-6 alkylamino, di(C 1-6 alkyl) amino, -C(O)C 1-6 alkyl, -C(O)NHC 1-6 alkyl, -C (O)NH 2 , -NHC(O)C 1-6 alkyl, -N(C 1-6 alkyl)C(O)C 1-6 alkyl, the alkyl and alkoxy are optionally 1 to 5 groups selected from halogen, deuterium, hydroxyl, amino, cyano, C 1-6 alkoxy group substitution;
- R 1 , R 2 together with the attached carbon atoms form a 3-6 membered cycloalkyl, 3-6 membered heterocycloalkyl;
- R 3 , R 4 together with the attached carbon atoms form a 3-6 membered cycloalkyl, 3-6 membered heterocycloalkyl;
- R 5 is selected from hydrogen, deuterium, C 1-6 alkyl, C 1-6 alkoxy, -C(O)C 1-6 alkyl, -C(O)NH 2 , -C(O)NHC 1 -6 alkyl, the alkyl and alkoxy are optionally substituted by 1 to 5 groups selected from halogen, deuterium, hydroxyl, amino, cyano, and C 1-6 alkoxy;
- R 8 is selected from hydrogen, deuterium, hydroxyl, halogen, amino, nitro, cyano, C 1-6 alkyl, C 1-6 alkoxy, halogenated C 1-6 alkyl, halogenated C 1-6 alkoxy, deuterated C 1-6 alkyl, deuterated C 1-6 alkoxy;
- R 6a is selected from hydrogen, deuterium, C 1-6 alkyl, C 3-8 cycloalkyl, 3-8 membered heterocycloalkyl, and the alkyl, cycloalkyl, and heterocycloalkyl are optionally selected from 1 to 5 are selected from halogen, deuterium, hydroxyl, amino, cyano, C 1-6 alkoxy;
- X is selected from a bond, -O-, -S-, -S(O)-, -S(O) 2 -, -CR xa R xb - or -NR xa -;
- Y is selected from a bond, -O-, -S-, -S(O)-, -S(O) 2 -, -CR ya R yb -, -NR ya - or -CR ya -;
- Z is selected from a bond, -O-, -S-, -S(O)-, -S(O) 2- , -CR za R zb -, -NR za -, -CR za - or -N-;
- X 1 is selected from -CR x1a - or -N-;
- X 2 is selected from -CR x2a - or -N-;
- X 3 is selected from -CR x3a -or -N-;
- X 7 is selected from -CR x7a - or -N-;
- X 4 is selected from -O-, -S-, -CR x4a R x4b - or -NR x4a -;
- X 5 is selected from -O-, -S-, -CR x5a R x5b - or -NR x5a -;
- X is selected from a bond, -O-, -S-, -CRx6a Rx6b- or -NRx6a- ;
- R x1a , R x2a , R x3a , R x7a are each independently selected from hydrogen, deuterium, halogen, nitro, cyano, amino, hydroxyl, -LR 7 , C 1-6 alkyl, C 1-6 alkoxy, C 2-6 alkenyl, C 2-6 alkynyl, -SF 5 , -(CH 2 ) r -C 3-12 cycloalkyl, -(CH 2 ) r -(3-12 membered heterocycloalkyl) , -OC 3-12 cycloalkyl, -O-(3-12 membered heterocycloalkyl), -NH-C 3-12 cycloalkyl, -NH-(3-12 membered heterocycloalkyl), - SC 3-12 -membered cycloalkyl, -S-(3-12-membered heterocycloalkyl), 5- to 12-membered heteroaryl, 6- to 12-membere
- Rxa , Rxb , Rya , Ryb , Rza, Rzb, Rx4a, Rx4b, Rx5a , Rx5b , Rx6a , Rx6b are each independently selected from hydrogen, deuterium, halogen, nitro, cyano , amino, hydroxyl, C 1-6 alkyl, C 1-6 alkoxy, C 2-6 alkenyl, C 2-6 alkynyl, -SF 5 , -(CH 2 ) r -C 3-12 ring Alkyl, -(CH 2 ) r -(3-12-membered heterocycloalkyl), -OC 3-12 -membered cycloalkyl, -O-(3-12-membered heterocycloalkyl), -NH-C 3- 12 cycloalkyl, -NH-(3-12 membered heterocycloalkyl), -SC 3-12 membered heterocycloalkyl, -S-(
- R xaa and R xab are each independently selected from hydrogen, deuterium, amino, hydroxyl, C 1-6 alkyl, halo-C 1-6 alkyl, deuterated C 1-6 alkyl, C 1-6 alkoxy, Halogenated C 1-6 alkoxy, deuterated C 1-6 alkoxy;
- Rxa and Rxb, Rya and Ryb, Rza and Rzb, Rx4a and Rx4b , Rx5a and Rx5b , or Rx6a and Rx6b attached to the same carbon atom are attached to the same carbon atom.
- the carbon atoms together form O, 3-6 membered cycloalkyl or 3-6 membered heterocycloalkyl;
- Rx4a and Rx6a together form -CH2- or -CH2CH2- ;
- L is selected from bond, -NR La , -C(O)-, -C(O)NR La -, -NR La C(O)-, -NR La C(O)-(CH 2 ) p -O- , -O-(CH 2 ) p -C(O)NR La -, -NR La C(O)-NR La -, -O-, -S-, -S(O) 2 NR La -, -NR La S(O) 2 -;
- R La is selected from hydrogen, deuterium, C 1-6 alkyl, halogenated C 1-6 alkyl, deuterated C 1-6 alkyl;
- R cya and R cyb are each independently selected from C 1-6 alkyl, halogenated C 1-6 alkyl, and deuterated C 1-6 alkyl;
- -LR 7 is selected from hydrogen, deuterium, amino, hydroxyl, halogen, cyano, C 1-6 alkyl , C 1-6 hydroxyalkyl, C 1-6 alkoxy, halogenated C 1-6 Alkyl, deuterated C 1-6 alkyl, halogenated C 1-6 alkoxy, deuterated C 1-6 alkoxy;
- n is selected from 0, 1, 2, 3 or 4;
- p is selected from 0, 1 or 2;
- r is selected from 0, 1, 2 or 3;
- the compound represented by the formula (I) of the present invention has the formula (II), (III), (IV), (V) structures:
- Ring A is selected from phenyl, 5-membered heteroaryl or 6-membered heteroaryl;
- X is selected from a bond, -O-, -S-, -S(O)-, -S(O) 2 -, -CR xa R xb - or -NR xa -;
- Y is selected from a bond, -O-, -S-, -S(O)-, -S(O) 2 -, -CR ya R yb -, -NR ya - or -CR ya -;
- Z is selected from a bond, -O-, -S-, -S(O)-, -S(O) 2- , -CR za R zb -, -NR za -, -CR za - or -N-;
- X 4 is selected from -O-, -S-, -CR x4a R x4b - or -NR x4a -;
- X 5 is selected from -O-, -S-, -CR x5a R x5b - or -NR x5a -;
- X is selected from a bond, -O-, -S-, -CRx6a Rx6b- or -NRx6a- ;
- X 1 is selected from -CR x1a - or -N-;
- X 2 is selected from -CR x2a - or -N-;
- X 3 is selected from -CR x3a -or -N-;
- X 7 is selected from -CR x7a - or -N-;
- R x1a , R x2a , R x3a , R x7a are each independently selected from hydrogen, deuterium, halogen, nitro, cyano, amino, hydroxyl, C 1-4 alkyl, C 1-4 alkoxy, C 2-6 Alkenyl, C 2-6 alkynyl, -SF 5 , the alkyl, alkoxy are optionally further selected from 1 to 3 groups selected from F, Cl, deuterium, nitro, cyano, amino, hydroxyl, C 1 -2 alkyl, C 1-2 alkoxy, halo C 1-2 alkyl, halo C 1-2 alkoxy, deuterated C 1-2 alkyl, deuterated C 1-2 alkoxy group substitution;
- Rxa , Rxb , Rya , Ryb , Rza, Rzb, Rx4a, Rx4b, Rx5a , Rx5b , Rx6a , Rx6b are each independently selected from hydrogen, deuterium, halogen, nitro, cyano , amino, hydroxyl, C 1-4 alkyl, C 1-4 alkoxy, C 2-4 alkenyl, C 2-4 alkynyl, -SF 5 , -(CH 2 ) r -C 3-6 mono Cyclocycloalkyl, -(CH 2 ) r -C 5-10 bicyclic cycloalkyl, -(CH 2 ) r -(3-6 membered monocyclic heterocycloalkyl), -(CH 2 ) r -(5 -10-membered bicyclic heterocycloalkyl), -OC 3-6 monocyclic cycloalkyl, -OC 5-10 bicyclic cycloalkyl
- R xaa and R xab are each independently selected from hydrogen, deuterium, amino, hydroxyl, C 1-4 alkyl, halo-C 1-4 alkyl, deuterated C 1-4 alkyl, C 1-4 alkoxy, Halogenated C 1-4 alkoxy, deuterated C 1-4 alkoxy;
- Rxa and Rxb, Rya and Ryb, Rza and Rzb, Rx4a and Rx4b , Rx5a and Rx5b , or Rx6a and Rx6b attached to the same carbon atom are attached to the same carbon atom.
- Rx4a and Rx6a together form -CH2- or -CH2CH2- ;
- Rx3a is selected from hydrogen
- the compounds of formula (I) and (II) according to the present invention have Structure of formula (II-a), (II-b), (II-c):
- X 1 is selected from -CR x1a - or -N-;
- X 2 is selected from -CR x2a - or -N-;
- X 3 is selected from -CR x3a -or -N-;
- R x1a , R x2a , R x3a are each independently selected from hydrogen, deuterium, halogen, nitro , cyano, amino, hydroxyl, C 1-4 alkyl, C 1-4 alkoxy, said alkyl, alkoxy
- the group is optionally further selected from 1 to 3 groups selected from F, Cl, deuterium, nitro, cyano, amino, hydroxyl, C 1-2 alkyl, C 1-2 alkoxy, halogenated C 1-2 alkyl , halogenated C 1-2 alkoxy, deuterated C 1-2 alkyl, deuterated C 1-2 alkoxy group substitution;
- X is selected from -O- or -CR xa R xb -;
- R xa , R xb are each independently selected from hydrogen, deuterium, halogen, C 1-6 alkyl, and the alkyl is optionally further selected from 1 to 3 groups selected from halogen, deuterium, hydroxyl, C 1-4 alkoxy, Group substitution of halogenated C 1-4 alkyl, halogenated C 1-4 alkoxy, deuterated C 1-4 alkyl, and deuterated C 1-4 alkoxy;
- Rxa and Rxb attached to the same carbon atom together with the attached carbon atom form 3-membered cycloalkyl, 4-membered cycloalkyl, 5-membered cycloalkyl, 3-membered heterocycloalkyl, 4-membered Heterocycloalkyl, 5-membered heterocycloalkyl;
- the compound of the present invention in another technical scheme, its stereoisomer, deuterated compound, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal, wherein
- R 1 , R 2 are each independently selected from hydrogen, deuterium, and optionally, R 1 , R 2 together with the carbon atom to which they are attached form a 3-membered, 4-membered, or 5-membered cycloalkyl; and/or
- R 5 is selected from hydrogen, deuterium, C 1-4 alkyl, halogenated C 1-4 alkyl; and/or
- R x1a , R x2a , R x3a , R x7a are each independently selected from hydrogen, deuterium, halogen, hydroxyl, cyano, C 1-4 alkyl, C 1-4 alkoxy;
- the compound of the present invention in another technical scheme, its stereoisomer, deuterated compound, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal, wherein
- L is selected from bond, -NR La , -C(O)-, -C(O)NR La -, -NR La C(O)-, -O-, -NR La C(O)-CH 2 -O -;
- R La is selected from hydrogen, deuterium, C 1-4 alkyl, haloC 1-4 alkyl, deuterated C 1-4 alkyl; or
- L is selected from bond, -NH-,
- the compound of the present invention in another technical scheme, its stereoisomer, deuterated compound, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal, wherein
- r is selected from 0 or 1;
- R cya , R cyb are each independently selected from C 1-4 alkyl, halogenated C 1-4 alkyl, deuterated C 1-4 alkyl; or
- R 7 is selected from
- the compound of the present invention in another technical scheme, its stereoisomer, deuterated compound, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal, wherein
- R 7 -L- is selected from F, Cl, Br, cyano, C 1-4 alkyl, C 1-4 hydroxyalkyl, C 1-4 alkoxy, halogenated C 1-4 alkyl, deuterated C 1-4 alkyl, halogenated C 1-4 alkoxy, deuterated C 1-4 alkoxy; or
- R 7 -L- is selected from F, Cl, Br, cyano, methyl, ethyl, propyl, isopropyl, hydroxymethyl, hydroxyethyl, hydroxypropyl, methoxy, ethoxy, propyl Oxy, isopropoxy, tert-butoxy, -CH 2 F, -CHF 2 , -CF 3 , -OCH 2 F, -OCHF 2 , -OCF 3 , -CH 2 D, -CHD 2 , -CD 3 , -OCH 2 D, -OCHD 2 , -OCD 3 .
- the compound of the present invention in another technical scheme, its stereoisomer, deuterated compound, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal, wherein
- n 0, 1, 2;
- r is selected from 0 or 1;
- R 6a is selected from hydrogen, deuterium, C 1-2 alkyl group optionally by 1, 2, 3 groups selected from halogen, deuterium, hydroxyl, amino, cyano, C 1-2 alkoxy group group replacement;
- R 6b is selected from hydrogen, deuterium, C 1-4 alkyl, and said alkyl is optionally substituted by 1, 2, 3 selected from halogen, deuterium, hydroxyl, amino, cyano, C 1-2 alkoxy group substitution; or
- n is selected from 0, 1;
- R is selected from deuterium, F, Cl , Br, cyano, methyl, ethyl, propyl, isopropyl, tert-butyl, 2-methylpropyl, cyclopropyl, cyclobutyl, cyclopentyl , cyclohexyl, -CH 2 -cyclopropyl, -CH 2 -cyclobutyl, -CH 2 -cyclopentyl, -CH 2 -cyclohexyl, azetidine, azacyclopentyl, azacycle Hexyl, -CH2 -Azacyclobutyl, -CH2 -Azacyclopentyl, -CH2 -Azacyclohexyl, Oxetanyl, Oxolatyl, Oxanyl, -CH 2 -oxetanyl, -CH 2 -oxolane, -CH 2 -oxane, -C(O)
- a compound represented by formula (I) of the present invention its stereoisomer, deuterated compound, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal,
- Ring A is selected from phenyl or 5-6 membered heteroaryl
- R 1 , R 2 , R 3 , R 4 are each independently selected from hydrogen, deuterium, hydroxyl, halogen, amino, nitro, cyano, C 1-6 alkyl, C 1-6 alkoxy, C 3- 8 cycloalkyl, C 1-6 alkylamino, di(C 1-6 alkyl) amino, -C(O)C 1-6 alkyl, -C(O)NHC 1-6 alkyl, -C (O)NH 2 , -NHC(O)C 1-6 alkyl, -N(C 1-6 alkyl)C(O)C 1-6 alkyl, the alkyl and alkoxy are optionally 1 to 5 groups selected from halogen, deuterium, hydroxyl, amino, cyano, C 1-6 alkoxy group substitution;
- R 1 , R 2 together with the attached carbon atoms form a 3-6 membered cycloalkyl, 3-6 membered heterocycloalkyl;
- R 3 , R 4 together with the attached carbon atoms form a 3-6 membered cycloalkyl, 3-6 membered heterocycloalkyl;
- R 5 is selected from hydrogen, deuterium, C 1-6 alkyl, C 1-6 alkoxy, -C(O)C 1-6 alkyl, -C(O)NH 2 , -C(O)NHC 1 -6 alkyl, the alkyl and alkoxy are optionally substituted by 1 to 5 groups selected from halogen, deuterium, hydroxyl, amino, cyano, and C 1-6 alkoxy;
- R 8 is selected from hydrogen, deuterium, hydroxyl, halogen, amino, nitro, cyano, C 1-6 alkyl, C 1-6 alkoxy, halogenated C 1-6 alkyl, halogenated C 1-6 alkoxy, deuterated C 1-6 alkyl, deuterated C 1-6 alkoxy;
- R 6a is selected from hydrogen, deuterium, C 1-6 alkyl, C 3-8 cycloalkyl, 3-8 membered heterocycloalkyl, and the alkyl, cycloalkyl, and heterocycloalkyl are optionally selected from 1 to 5 groups selected from halogen, deuterium, hydroxyl, amino, cyano, C 1-6 alkoxy group substitution;
- X is selected from a bond, -O-, -S-, -S(O)-, -S(O) 2 -, -CR xa R xb - or -NR xa -;
- Y is selected from a bond, -O-, -S-, -S(O)-, -S(O) 2 -, -CR ya R yb -, -NR ya - or -CR ya -;
- Z is selected from a bond, -O-, -S-, -S(O)-, -S(O) 2- , -CR za R zb -, -NR za -, -CR za - or -N-;
- X 1 is selected from -CR x1a - or -N-;
- X 2 is selected from -CR x2a - or -N-;
- X 3 is selected from -CR x3a -or -N-;
- X 7 is selected from -CR x7a - or -N-;
- X 4 is selected from -O-, -S-, -CR x4a R x4b - or -NR x4a -;
- X 5 is selected from -O-, -S-, -CR x5a R x5b - or -NR x5a -;
- X is selected from a bond, -O-, -S-, -CRx6a Rx6b- or -NRx6a- ;
- R x1a , R x2a , R x3a , R x7a are each independently selected from hydrogen, deuterium, halogen, nitro, cyano, amino, hydroxyl, -LR 7 , C 1-6 alkyl, C 1-6 alkoxy, C 2-6 alkenyl, C 2-6 alkynyl, -SF 5 , -(CH 2 ) r -C 3-12 cycloalkyl, -(CH 2 ) r -(3-12 membered heterocycloalkyl) , -OC 3-12 cycloalkyl, -O-(3-12 membered heterocycloalkyl), -NH-C 3-12 cycloalkyl, -NH-(3-12 membered heterocycloalkyl), - SC 3-12 -membered cycloalkyl, -S-(3-12-membered heterocycloalkyl), 5- to 12-membered heteroaryl, 6- to 12-membere
- Rxa , Rxb , Rya , Ryb , Rza, Rzb, Rx4a, Rx4b, Rx5a , Rx5b , Rx6a , Rx6b are each independently selected from hydrogen, deuterium, halogen, nitro, cyano , amino, hydroxyl, C 1-6 alkyl, C 1-6 alkoxy, C 2-6 alkenyl, C 2-6 alkynyl, -SF 5 , -(CH 2 ) r -C 3-12 ring Alkyl, -(CH 2 ) r -(3-12-membered heterocycloalkyl), -OC 3-12 -membered cycloalkyl, -O-(3-12-membered heterocycloalkyl), -NH-C 3- 12 cycloalkyl, -NH-(3-12 membered heterocycloalkyl), -SC 3-12 membered heterocycloalkyl, -S-(
- R xaa and R xab are each independently selected from hydrogen, deuterium, amino, hydroxyl, C 1-6 alkyl, halo-C 1-6 alkyl, deuterated C 1-6 alkyl, C 1-6 alkoxy, Halogenated C 1-6 alkoxy, deuterated C 1-6 alkoxy;
- Rxa and Rxb, Rya and Ryb, Rza and Rzb, Rx4a and Rx4b , Rx5a and Rx5b , or Rx6a and Rx6b attached to the same carbon atom are attached to the same carbon atom.
- the carbon atoms together form O, 3-6 membered cycloalkyl or 3-6 membered heterocycloalkyl;
- Rxa and Rza attached to adjacent carbon atoms together with the attached carbon atom O, 3-6 membered cycloalkyl or 3-6 membered heterocycloalkyl;
- Rx4a and Rx6a together form -CH2- or -CH2CH2- ;
- L is selected from bond, -NR La , -C(O)-, -C(O)NR La -, -NR La C(O)-, -NR La C(O)-(CH 2 ) p -O- , -O-(CH 2 ) p -C(O)NR La -, -NR La C(O)-NR La -, -O-, -S-, -S(O) 2 NR La -, -NR La S(O) 2 -;
- R La is selected from hydrogen, deuterium, C 1-6 alkyl, halogenated C 1-6 alkyl, deuterated C 1-6 alkyl;
- R cya and R cyb are each independently selected from C 1-6 alkyl, halogenated C 1-6 alkyl, and deuterated C 1-6 alkyl;
- -LR 7 is selected from hydrogen, deuterium, amino, hydroxyl, halogen, cyano, C 1-6 alkyl , C 1-6 hydroxyalkyl, C 1-6 alkoxy, halogenated C 1-6 Alkyl, deuterated C 1-6 alkyl, halogenated C 1-6 alkoxy, deuterated C 1-6 alkoxy;
- n is selected from 0, 1, 2, 3 or 4;
- p is selected from 0, 1 or 2;
- r is selected from 0, 1, 2 or 3;
- the compound represented by the formula (I) of the present invention its stereoisomer, deuterated substance, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal, said Compounds of formula (I) have formulas (II-1), (II-2), (II-3), (II-5), (II-6), (II-7), (II-8), ( II-9), (II-10), (II-11), (II-12), (II-13), (II-14), (II-15) structures:
- Ring A is selected from phenyl, 5-membered heteroaryl or 6-membered heteroaryl;
- Ring B is selected from 5-membered heteroaryl or 6-membered heteroaryl
- E ring is 3-6 membered cycloalkyl or 3-6 membered heterocycloalkyl
- Ring H is 3-6 membered cycloalkyl or 3-6 membered heterocycloalkyl
- R 11 , R 12 , R 13 , R 15 , R 17 , R 18 , R 19 , R 110 , R 111 , R 112 , R 113 , R 114 , R 115 , R 21 , R 22 , R 23 , R 25 , R 27 , R 28 , R 29 , R 210 , R 211 , R 212 , R 213 , R 214 , R 215 , R 31 , R 32 , R 33 , R 35 , R 36 , R 37 , R 38 , R 39 , R 310 , R 311 , R 312 , R 313 , R 314 , R 315 , R 41 , R 42 , R 43 , R 45 , R 46 , R 47 , R 48 , R 49 , R 410 , R 411 , R 412 , R 413 , R 414 , R 415 are each independently selected from hydrogen, deuterium, hydroxyl, hal
- R 51 , R 52 , R 53 , R 55 , R 56 , R 57 , R 58 , R 59 , R 510 , R 511 , R 512 , R 513 , R 514 , R 515 are each independently selected from hydrogen, deuterium, C 1-4 alkyl, the alkyl is optionally substituted by 1 to 3 groups selected from halogen, deuterium, hydroxyl;
- R 81 , R 82 , R 83 , R 85 , R 86 , R 87 , R 88 , R 89 , R 810 , R 811 , R 812 , R 813 , R 814 , R 815 are each independently selected from hydrogen, deuterium, Hydroxyl, halogen;
- R 9a1 and R 9b1 , R 9a2 and R 9b2 together with the attached carbon atom form 3-membered cycloalkyl, 4-membered cycloalkyl, 5-membered cycloalkyl, 6-membered cycloalkyl, 3-membered cycloalkyl membered heterocycloalkyl, 4-membered heterocycloalkyl, 5-membered heterocycloalkyl, or 6-membered heterocycloalkyl; or
- R 9a1 and R 9a2 are linked to form -CH 2 -, -CH 2 CH 2 -;
- R 61 , R 63 , R 65 , R 66 , R 67 , R 68 , R 69 , R 610 , R 611 , R 612 , R 613 , R 614 , R 615 , R 616 , R 617 are each independently selected from deuterium , halogen, cyano, nitro, amino, hydroxyl, C 1-4 alkyl, C 1-4 alkoxy, -(CH 2 ) r -C 3-8 cycloalkyl, -(CH 2 ) r - (3-8 membered heterocycloalkyl), -OC 3-8 cycloalkyl, -O-(3-8 membered heterocycloalkyl), -NH-C 3-8 cycloalkyl, -NH-(3 -8-membered heterocycloalkyl), -SC 3-8 -membered cycloalkyl, -S-(3-8-membered heterocycloalkyl),
- R 6a is selected from hydrogen, deuterium, C 1-6 alkyl, C 3-8 cycloalkyl, 3-8 membered heterocycloalkyl, and the alkyl, cycloalkyl, and heterocycloalkyl are optionally selected from 1 to 5 groups selected from halogen, deuterium, hydroxyl, amino, cyano, C 1-6 alkoxy group substitution;
- X81 , X83 , X86 , X88, X89, X810, X811, X813, X814, X815 are each independently selected from -O- , -S-, -S(O)-, - S(O) 2 -, -CR xa R xb - or -NR xa -;
- X 87 is selected from -O-, -S(O)-, -S(O) 2 -, -CR xa R xb - or -NR xa -;
- X 812 is selected from -O-, -S-, -S(O)-, -S(O) 2 -, -CR xa2 R xb2 - or -NR xa -;
- X 82 is selected from -O-, -S-, -S(O)-, -S(O) 2 -, -CR xa1 R xb1 - or -NR xa -;
- Y 1 , Y 2 , Y 3 , Y 4 , Y 5 , Y 6 are each independently selected from a bond, -CR ya R yb -, -NR ya - or -CR ya -;
- Z 1 , Z 2 , Z 3 , Z 4 , Z 5 , Z 6 are each independently selected from a bond, -CR za R zb -, -NR za -, -CR za - or -N-;
- X 41 , X 42 , X 43 , and X 44 are each independently selected from -CR x4a R x4b - or -NR x4a -;
- X 51 , X 52 , X 53 , and X 54 are each independently selected from -CR x5a R x5b - or -NR x5a -;
- X 61 , X 62 , X 63 , X 64 are each independently selected from a bond, -CR x6a R x6b - or -NR x6a -;
- X 11 , X 12 , X 13 , X 15 , X 16 , X 17 , X 18 , X 19 , X 110 , X 113 , X 114 , X 115 are each independently selected from -CR x1a - or -N-;
- X 21 , X 22 , X 23 , X 25 , X 26 , X 27 , X 28 , X 29 , X 211 , X 213 , X 214 , X 215 are each independently selected from -CR x2a - or -N-;
- X 31 , X 32 , X 33 , X 35 , X 36 , X 37 , X 38 , X 39 , X 310 , X 311 are each independently selected from -CR x3a - or -N-;
- X 710 , X 711 , X 713 , X 714 , X 715 are each independently selected from -CR x7a - or -N-;
- X 112 is selected from -CR x1b -;
- X 212 is selected from -CR x2b -;
- X 712 is selected from -CR x7b -;
- R x1a , R x2a , R x3a , R x7a are each independently selected from hydrogen, deuterium, halogen, nitro, cyano, amino, hydroxyl, C 1-4 alkyl, C 1-4 alkoxy, C 2-6 Alkenyl, C 2-6 alkynyl, -SF 5 , the alkyl, alkoxy are optionally further selected from 1 to 3 groups selected from F, Cl, deuterium, nitro, cyano, amino, hydroxyl, C 1 -2 alkyl, C 1-2 alkoxy, halo C 1-2 alkyl, halo C 1-2 alkoxy, deuterated C 1-2 alkyl, deuterated C 1-2 alkoxy group substitution;
- Rxa , Rxb , Rxa2 , Rxb2 , Rya , Ryb , Rza, Rzb, Rx4a, Rx4b, Rx5a , Rx5b , Rx6a , Rx6b are each independently selected from hydrogen, deuterium, halogen , nitro, cyano, amino, hydroxyl, C 1-4 alkyl, C 1-4 alkoxy, C 2-4 alkenyl, C 2-4 alkynyl, -SF 5 , -(CH 2 ) r -C 3-6 monocyclic cycloalkyl, -(CH 2 ) r -C 5-10 bicyclic cycloalkyl, -(CH 2 ) r -(3-6 membered monocyclic heterocycloalkyl), -(CH 2 ) r -(5-10 membered bicyclic heterocycloalkyl), -OC 3-6 monocyclic cycloalkyl, -OC
- R xaa and R xab are each independently selected from hydrogen, deuterium, amino, hydroxyl, C 1-4 alkyl, halo-C 1-4 alkyl, deuterated C 1-4 alkyl, C 1-4 alkoxy, Halogenated C 1-4 alkoxy, deuterated C 1-4 alkoxy;
- R x1b , R x2b , R x7b are each independently selected from H, deuterium, nitro, cyano, amino, hydroxyl, C 1-4 alkyl, C 1-4 alkoxy, C 2-6 alkenyl, C 2 -6 alkynyl, -SF 5 , the alkyl and alkoxy groups are optionally further selected from 1 to 3 groups selected from F, Cl, deuterium, nitro, cyano, amino, hydroxyl, C 1-2 alkyl, Group substitution of C 1-2 alkoxy, halogenated C 1-2 alkyl, halogenated C 1-2 alkoxy, deuterated C 1-2 alkyl, deuterated C 1-2 alkoxy;
- R x1b , R x2b , and R x7b are not H at the same time
- R x1b , R x2b and R x7b are selected from H at the same time, -L 12 -R 712 is selected from H;
- Rxa and Rxb, Rxa1 and Rxb1, Rya and Ryb, Rza and Rzb, Rx4a and Rx4b , Rx5a and Rx5b , or Rx6a and Rx5b are attached to the same carbon atom.
- R x6b together with the attached carbon atom forms 3-membered cycloalkyl, 4-membered cycloalkyl, 5-membered cycloalkyl, 6-membered cycloalkyl, 3-membered heterocycloalkyl, 4-membered heterocycloalkyl, 5-membered Heterocycloalkyl or 6-membered heterocycloalkyl;
- Rxa and Rza attached to adjacent carbon atoms together with the attached carbon atoms form 3-membered cycloalkyl, 4-membered cycloalkyl, 5-membered cycloalkyl, 6-membered cycloalkyl, 3-membered cycloalkyl Heterocycloalkyl, 4-membered heterocycloalkyl, 5-membered heterocycloalkyl or 6-membered heterocycloalkyl;
- Rx4a and Rx6a together form -CH2- or -CH2CH2- ;
- L 1 is selected from *-C(O)NR La- , *-NR La C(O)-, *-NR La C(O)-(CH 2 ) p -O-, *-O-(CH 2 ) p -C(O)NR La -, -NR La C(O)-NR La -, -S-, *-S(O) 2 NR La -, *-NR La S(O) 2 -, * represents L 1 and R 71 linking site;
- L 2 is selected from -NR La -, -C(O)-, -C(O)NR La -**, -NR La C(O)-(CH 2 ) p -O-**, -O-( CH 2 ) p -C(O)NR La -**, -NR La C(O)-NR La -**, -S-, -S(O) 2 NR La -**, -NR La S( O) 2 -**, ** represents the linking site of L 2 and R 72 ;
- L 3 , L 5 , L 6 are each independently selected from a bond, -NR La , -C(O)-, -C(O)NR La -, -NR La C(O)-, -NR La C(O )-(CH 2 ) p -O-, -O-(CH 2 ) p -C(O)NR La -, -NR La C(O)-NR La -, -O-, -S-, -S (O) 2 NR La -, -NR La S(O) 2 -;
- L 7 , L 8 , L 9 , L 10 , L 11 , L 12 , L 13 , L 14 , L 15 are each independently selected from -NR La , -C(O)-, -C(O)NR La - , -NR La C(O)-, -NR La C(O)-(CH 2 ) p -O-, -O-(CH 2 ) p -C(O)NR La -, -NR La C(O )-NR La -, -O-, -S-, -S(O) 2 NR La -, -NR La S(O) 2 -;
- R La is selected from hydrogen, deuterium, halogenated C 1-4 alkyl, deuterated C 1-4 alkyl;
- L 1 is selected from -NR La -
- R 72 is selected from -(CH 2 ) r -4-12 membered heterocycloalkyl, 6-12 membered aryl or -(CH 2 ) r -C 3-12
- cycloalkyl one of the following conditions is satisfied: m is not 0, or one of X 12 and X 32 is selected from N, or R x2a and R x3a are not H at the same time; or
- L 2 is selected from -NR La C(O)-**
- R 73 , R 75 , R 76 , R 77 , R 78 , R 79 , R 710 , R 711 , R 712 , R 713 , R 714 , R 715 are each independently selected from deuterium, halogen, C 1-6 alkyl , C 1-6 alkoxy, C 2-6 alkenyl, C 2-6 alkynyl, -SF 5 , -(CH 2 ) r -C 3-12 cycloalkyl, -(CH 2 ) r -( 4-12-membered heterocycloalkyl), -(CH 2 ) r -(5-12-membered heteroaryl), -(CH 2 ) r -(6-12-membered aryl), the CH 2 , alkyl , alkoxy, cycloalkyl, heterocycloalkyl, heteroaryl, aryl optionally further substituted with 1 to 5 groups selected from R f ;
- -L 7 -R 77 , -L 13 -R 713 are each independently selected from halogen, 5-12-membered heteroaryl, and the heteroaryl is optionally further selected from 1-5 R f group substitution;
- -L 8 -R 78 , -L 9 -R 79 , -L 10 -R 710 , -L 11 -R 711 are each independently selected from SF 5 , -(CH 2 ) r -C 3-12 ring Alkyl, -(CH 2 ) r -(4-12 membered heterocycloalkyl), -(CH 2 ) r -(5-12 membered heteroaryl), -(CH 2 ) r -(6-12 membered heteroaryl) aryl), said CH2 , cycloalkyl, heterocycloalkyl, heteroaryl, aryl are optionally further substituted with 1 to 5 groups selected from Rf ;
- R cya and R cyb are each independently selected from C 1-6 alkyl, halogenated C 1-6 alkyl, and deuterated C 1-6 alkyl;
- the compound of the present invention its stereoisomer, deuterated compound, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal, wherein,
- R 11 , R 12 , R 13 , R 15 , R 17 , R 18 , R 19 , R 110 , R 111 , R 112 , R 113 , R 114 , R 115 , R 21 , R 22 , R 23 , R 25 , R 27 , R 28 , R 29 , R 210 , R 211 , R 212 , R 213 , R 214 , R 215 , R 31 , R 32 , R 33 , R 35 , R 36 , R 37 , R 38 , R 39 , R 310 , R 311 , R 312 , R 313 , R 314 , R 315 , R 41 , R 42 , R 43 , R 45 , R 46 , R 47 , R 48 , R 49 , R 410 , R 411 , R 412 , R 413 , R 414 , and R 415 are each independently selected from hydrogen, deuterium, C 1-4 alky
- R 51 , R 52 , R 53 , R 55 , R 56 , R 57 , R 58 , R 59 , R 510 , R 511 , R 512 , R 513 , R 514 , R 515 are each independently selected from hydrogen, deuterium, C 1-4 alkyl, the alkyl is optionally substituted by 1 to 3 groups selected from halogen, deuterium;
- R 81 , R 82 , R 83 , R 85 , R 86 , R 87 , R 88 , R 89 , R 810 , R 811 , R 812 , R 813 , R 814 , R 815 are each independently selected from hydrogen, deuterium;
- R 9a1 and R 9b1 , R 9a2 and R 9b2 together with the attached carbon atom form 3-membered cycloalkyl, 4-membered cycloalkyl, 5-membered cycloalkyl, 6-membered cycloalkyl, 4-membered cycloalkyl membered heterocycloalkyl, 5-membered heterocycloalkyl, or 6-membered heterocycloalkyl; or
- R 9a1 and R 9a2 are linked to form -CH 2 -;
- R 6a is selected from hydrogen, deuterium, C 1-4 alkyl, C 3-8 cycloalkyl, 3-8 membered heterocycloalkyl, and the alkyl, cycloalkyl, and heterocycloalkyl are optionally selected from 1 to 3 groups selected from halogen, deuterium, C 1-4 alkoxy group substitution;
- R 6b is selected from hydrogen, deuterium, C 1-4 alkyl, C 1-4 alkoxy, C 3-8 cycloalkyl, 3-8 membered heterocycloalkyl, said alkyl, alkoxy, Cycloalkyl and heterocycloalkyl are optionally substituted with 1 to 3 groups selected from halogen, deuterium, C 1-4 alkyl, and C 1-4 alkoxy;
- X81 , X83 , X86 , X88 , X89 , X810, X811, X813 , X814 , X815 are each independently selected from -O-, -S-, -CRxaRxb -or- NRxa -;
- X 87 is selected from -O-, -CR xa R xb - or -NR xa -;
- X 812 is selected from-O-,-S-,- CRxa2Rxb2 -or - NRxa- ;
- X 82 is selected from -O-, -S-, -CR xa1 R xb1 - or -NR xa -;
- Y 1 , Y 2 , Y 3 , Y 4 , Y 5 , Y 6 are each independently selected from a bond, -CR ya R yb - or -NR ya -;
- Z 1 , Z 2 , Z 3 , Z 4 , Z 5 , Z 6 are each independently selected from a bond, -CR za R zb - or -NR za -;
- X 41 , X 42 , X 43 , and X 44 are each independently selected from -CR x4a R x4b - or -NR x4a -;
- X 51 , X 52 , X 53 , and X 54 are each independently selected from -CR x5a R x5b - or -NR x5a -;
- X 61 , X 62 , X 63 , X 64 are each independently selected from a bond, -CR x6a R x6b - or -NR x6a -;
- X 11 , X 12 , X 13 , X 15 , X 16 , X 17 , X 18 , X 19 , X 110 , X 113 , X 114 , X 115 are each independently selected from -CR x1a - or -N-;
- X 21 , X 22 , X 23 , X 25 , X 26 , X 27 , X 28 , X 29 , X 211 , X 213 , X 214 , X 215 are each independently selected from -CR x2a - or -N-;
- X 31 , X 32 , X 33 , X 35 , X 36 , X 37 , X 38 , X 39 , X 310 , X 311 are each independently selected from -CR x3a - or -N-;
- X 710 , X 711 , X 713 , X 714 , X 715 are each independently selected from -CR x7a - or -N-;
- X 112 is selected from -CR x1b -;
- X 212 is selected from -CR x2b -;
- X 712 is selected from -CR x7b -;
- R x1a , R x2a , R x3a , R x7a are each independently selected from hydrogen, deuterium, halogen, C 1-4 alkyl, C 1-4 alkoxy, and the alkyl and alkoxy are optionally further selected from 1 to 3 groups selected from F, Cl, deuterium, hydroxyl, C 1-2 alkyl, C 1-2 alkoxy group substitution;
- R xa1 and R xb1 are each independently selected from hydrogen, deuterium, C 1-4 alkyl, C 1-4 alkoxy, -(CH 2 ) r -C 3-6 monocyclic cycloalkyl, -(CH 2 ) r -C 5-10 bicyclic cycloalkyl, -(CH 2 ) r -(3-6 membered monocyclic heterocycloalkyl), -(CH 2 ) r -(5-10 membered bicyclic heterocycloalkyl), 5- to 6-membered heteroaryl, phenyl, the CH 2 , alkyl, alkoxy, cycloalkyl, heterocycloalkyl, heteroaryl, aryl optionally further selected from 1 to 3 halogens, Group substitution of deuterium, C 1-4 alkyl, C 1-4 alkoxy;
- R xaa , R xab are each independently selected from hydrogen, deuterium, C 1-4 alkyl;
- R x1b , R x2b , R x7b are each independently selected from H, deuterium, hydroxyl, cyano, C 1-4 alkyl, C 1-4 alkoxy, and the alkyl and alkoxy are optionally further selected from 1 to 3 groups selected from F, Cl, deuterium, hydroxyl, C 1-2 alkyl, C 1-2 alkoxy group substitution;
- R x1b , R x2b , and R x7b are not H at the same time
- R x1b , R x2b and R x7b are selected from H at the same time, -L 12 -R 712 is selected from H;
- Rxa and Rxb, Rxa1 and Rxb1, Rya and Ryb, Rza and Rzb, Rx4a and Rx4b , Rx5a and Rx5b , or Rx6a and Rx5b are attached to the same carbon atom.
- R x6b together with the carbon atom to which it is attached forms a 3-membered cycloalkyl, 4-membered cycloalkyl, 5-membered cycloalkyl, 4-membered heterocycloalkyl, 5-membered heterocycloalkyl or 6-membered heterocycloalkyl;
- Rxa and Rza attached to adjacent carbon atoms together with the attached carbon atoms form 3-membered cycloalkyl, 4-membered cycloalkyl, 5-membered cycloalkyl, 6-membered cycloalkyl, 3-membered cycloalkyl Heterocycloalkyl, 4-membered heterocycloalkyl, 5-membered heterocycloalkyl or 6-membered heterocycloalkyl;
- Rx4a and Rx6a together form -CH2- or -CH2CH2- ;
- the compound of the present invention in another technical solution, the compound of the present invention, its stereoisomer, deuterated compound, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal, the compound has the formula (III-1 ), (III-2), (III-3), (III-5), (III-6), (III-7), (III-8), (III-9) structures:
- Ring E is 3-membered cycloalkyl, 4-membered cycloalkyl, 5-membered cycloalkyl, 6-membered cycloalkyl, 3-membered heterocycloalkyl, 4-membered heterocycloalkyl, 5-membered heterocycloalkyl, or 6-membered Heterocycloalkyl;
- Ring H is 3-membered cycloalkyl, 4-membered cycloalkyl, 5-membered cycloalkyl, 6-membered cycloalkyl, 3-membered heterocycloalkyl, 4-membered heterocycloalkyl, 5-membered heterocycloalkyl, or 6-membered Heterocycloalkyl;
- R 52 is selected from hydrogen, deuterium, C 1-4 alkyl, and the alkyl is optionally substituted by 1 to 3 groups selected from halogen, deuterium;
- R 9a1 and R 9b1 , R 9a2 and R 9b2 together with the attached carbon atom form 3-membered cycloalkyl, 4-membered cycloalkyl, 5-membered cycloalkyl, 4-membered heterocycloalkyl, 5-membered heterocycloalkyl or 6-membered heterocycloalkyl; or
- R 9a1 and R 9a2 are linked to form -CH 2 -;
- R 69 is selected from deuterium, halogen, hydroxyl, C 1-4 alkyl, C 1-4 alkoxy, and the alkyl and alkoxy are optionally further replaced by 1 to 3 groups selected from halogen, deuterium, and hydroxyl group replacement;
- R 6a is selected from hydrogen, deuterium, C 1-4 alkyl optionally substituted by 1 to 3 groups selected from halogen, deuterium;
- R 6b is selected from hydrogen, deuterium, C 1-4 alkyl, and the alkyl is optionally substituted by 1 to 3 groups selected from halogen and deuterium;
- X 81 , X 87 , X 88 , X 89 are each independently selected from -O-, -CR xa R xb - or -NR xa -;
- X 82 is selected from -O-, -CR xa1 R xb1 - or -NR xa -;
- X 12 is selected from -CR x1a - or -N-;
- X 22 is selected from -CR x2a - or -N-;
- X 32 is selected from -CR x3a - or -N-;
- R x1a , R x2a , R x3a are each independently selected from hydrogen, deuterium, halogen, C 1-4 alkyl, C 1-4 alkoxy, and the alkyl and alkoxy are optionally further replaced by 1 to 3 Substituted by groups selected from F, Cl, deuterium;
- R xa , R xb are each independently selected from hydrogen, deuterium, halogen, C 1-4 alkyl, C 1-4 alkoxy, and the alkyl and alkoxy are optionally further selected from F by 1 to 3 , Cl, deuterium group substitution;
- R xa1 and R xb1 are each independently selected from hydrogen, deuterium, C 1-4 alkyl, and C 1-4 alkoxy, and the alkyl and alkoxy are optionally further selected from 1 to 3 groups selected from F, Cl , group substitution of deuterium;
- Rxa and Rxb attached to the same carbon atom together with the attached carbon atom form 3-membered cycloalkyl, 4-membered cycloalkyl, 5-membered cycloalkyl, 3-membered heterocycloalkyl, 4-membered Heterocycloalkyl, 5-membered heterocycloalkyl;
- L 1 is selected from -NR La , *-C(O)NR La -, *-NR La C(O)-, * represents the linking site of L 1 and R 71 ;
- L 2 is selected from -NR La , -C(O)-, -C(O)NR La -**, -NR La C(O)-(CH 2 ) p -O-**, -O-(CH 2 ) p -C(O)NR La -**, ** represents the linking site of L 2 and R 72 ;
- L 3 , L 5 , L 6 are each independently selected from a bond, -NR La , -C(O)-, -C(O)NR La -, -NR La C(O)-;
- L 7 , L 8 , L 9 are each independently selected from -NR La , -C(O)-, -C(O)NR La -, -NR La C(O)-;
- R La is selected from hydrogen, deuterium, C 1-4 alkyl
- R 71 is selected from 5-membered heteroaryl or 6-membered heteroaryl, and the heteroaryl is optionally further substituted by 1 to 3 groups selected from deuterium, halogen, and C 1-4 alkyl;
- R 72 is selected from -(CH 2 ) r -4-12 membered heterocycloalkyl, 6-12 membered aryl or -(CH 2 ) r -C 3-12
- cycloalkyl one of the following conditions is satisfied: m is not 0, or one of X 12 and X 32 is selected from N, or R x2a and R x3a are not H at the same time; or
- L 2 is selected from -NR La C(O)-**
- R 73 , R 75 , R 76 , R 77 , R 78 , R 79 are each independently selected from deuterium, halogen, C 1-4 alkyl, C 1-4 alkoxy, C 3-6 cycloalkyl, 5 -8-membered monocyclic heterocycloalkyl, 6-12-membered bicyclic heterocycloalkyl, 5-8-membered heteroaryl, 6-9-membered aryl, the alkyl, alkoxy, cycloalkyl, heterocycle Alkyl, heteroaryl, aryl are optionally further substituted with 1 to 3 groups selected from Rf ;
- -L 7 -R 77 are each independently selected from halogen, 5-9 membered heteroaryl, and said heteroaryl is optionally further substituted by 1-3 groups selected from R f ;
- -L 8 -R 78 , -L 9 -R 79 are each independently selected from C 3-6 cycloalkyl, 5-8-membered monocyclic heterocycloalkyl, 6-12-membered bicyclic heterocycloalkyl, 5-8-membered heteroaryl, 6-9-membered aryl, the cycloalkyl, heterocycloalkyl, heteroaryl, and aryl are optionally further substituted by 1 to 3 groups selected from R f ;
- R cya and R cyb are each independently selected from C 1-4 alkyl, halogenated C 1-4 alkyl, and deuterated C 1-4 alkyl;
- the compound of the present invention in another technical solution, the compound of the present invention, its stereoisomer, deuterated compound, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal, the compound has the formula (III-1 ), (III-2), (III-3), (III-5), (III-6), (III-7), (III-8), (III-9) structures: wherein
- n is selected from 0, 1 or 2;
- R 62 is selected from deuterium, halogen, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidine, azacyclopentyl, azacyclohexyl, oxetanyl, oxolane , -C(O)NHCH 3 , -NHC(O)CH 3 , -N(CH 3 )C(O)CH 3 , -NHC(O)CH 2 CH 3 , -N(CH 3 ) C(O)CH 2 CH 3 , -NH 2 , -NHCH 3 , -C(O) CH 3 , -C(O) CH 2 CH 3 , the above groups are further selected from 1, 2, and 3 F, the group substitution of deuterium;
- R 69 is selected from deuterium, F, Cl, Br, methyl, ethyl, propyl, methyl, ethyl, propyl are optionally further substituted by 1, 2, 3 groups selected from F, deuterium;
- the compound of the present invention has the formula (IV-1 )structure:
- L 10 is selected from -NR La , -C(O)-, -C(O)NR La -, -NR La C(O)-;
- R La is selected from hydrogen, deuterium
- R 710 is selected from halogen, C 1-4 alkyl, C 1-4 alkoxy, C 3-6 cycloalkyl, 5-8-membered monocyclic heterocycloalkyl, 6-12-membered bicyclic heterocycloalkyl, 5-8-membered heteroaryl, 6-9-membered aryl, the cycloalkyl, heterocycloalkyl, heteroaryl, and aryl are optionally further substituted by 1 to 3 groups selected from R f ;
- -L 10 -R 710 is selected from C 3-6 cycloalkyl, 5-8 membered monocyclic heterocycloalkyl, 6-12 membered bicyclic heterocycloalkyl, 5-8 membered heteroaryl, 6- 9-membered aryl, the cycloalkyl, heterocycloalkyl, heteroaryl, aryl optionally further substituted with 1 to 3 groups selected from R f ;
- the compound of the present invention has the formula (V-1 )structure:
- L 11 is selected from -NR La , -C(O)-, -C(O)NR La -, -NR La C(O)-;
- R La is selected from hydrogen, deuterium
- R cya , R cyb are each independently selected from methyl, ethyl, propyl , butyl, -CH2F , -CH2CH2F , -CHF2 , -CF3 , -CH2CHF2 , -CH2 CHF 3 , -CH 2 D, -CH 2 CH 2 D, -CHD 2 , -CD 3 , -CH 2 CHD 2 , -CH 2 CHD 3 ;
- the compound of the present invention in another technical solution, has formula (VI-1) , (VI-2), (VI-3), (VI-4), (VI-5) structures:
- X 812 is selected from -O-, -CR xa2 R xb2 - or -NR xa -;
- X 813 , X 814 , and X 815 are each independently selected from -O-, -CR xa R xb - or -NR xa -;
- X 112 is selected from -CR x1b -;
- X 212 is selected from -CR x2b -;
- X 712 is selected from -CR x7b -;
- R xa , R xb , R xa2 , R xb2 are each independently selected from hydrogen, deuterium, halogen, C 1-4 alkyl, C 1-4 alkoxy, and the alkyl and alkoxy are optionally further selected from 1 to 3 groups selected from halogen, deuterium are substituted;
- R x1b , R x2b , R x7b are each independently selected from H, deuterium, hydroxyl, cyano, C 1-4 alkyl, C 1-4 alkoxy, and the alkyl and alkoxy are optionally further selected from 1 to 3 groups selected from F, Cl, deuterium, hydroxyl group substitution;
- R x1b , R x2b , R x7b are not selected from H at the same time;
- R x1b , R x2b and R x7b are selected from H at the same time, -L 12 -R 712 is selected from H;
- Rxa and Rxb attached to the same carbon atom together with the attached carbon atom form 3-membered cycloalkyl, 4-membered cycloalkyl, 5-membered cycloalkyl, 4-membered heterocycloalkyl, 5-membered Heterocycloalkyl or 6-membered heterocycloalkyl;
- L 12 , L 13 , L 14 , L 15 are each independently selected from -NR La , -C(O)-, -C(O)NR La -, -NR La C(O)-;
- R La is selected from hydrogen, deuterium
- R 712 , R 713 , R 714 , R 715 are each independently selected from H, deuterium, halogen, C 1-6 alkyl, C 1-6 alkoxy, C 3-6 cycloalkyl, 5-8 unitary unit Cycloheterocycloalkyl, 6-12-membered bicyclic heterocycloalkyl, 5-8-membered heteroaryl, 6-9-membered aryl, the alkyl, alkoxy, cycloalkyl, heterocycloalkyl, hetero Aryl, aryl are optionally further substituted by 1 to 3 groups selected from R f ;
- -L 13 -R 713 is selected from F, Cl, 5-8-membered heteroaryl, and the heteroaryl is optionally further substituted with 1 to 3 groups selected from R f ;
- R cya , R cyb are each independently selected from methyl, ethyl, propyl , butyl, -CH2F , -CH2CH2F , -CHF2 , -CF3 , -CH2CHF2 , -CH2 CHF 3 , -CH 2 D, -CH 2 CH 2 D, -CHD 2 , -CD 3 , -CH 2 CHD 2 , -CH 2 CHD 3 ;
- the compound of the present invention in another technical scheme, its stereoisomer, deuterated compound, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal, wherein
- L 1 is selected from -NH-
- * represents the linking site of L 1 and R 71
- R 71 is selected from
- L 2 is selected from -NH-
- ** represents the linking site of L 2 and R 72
- R 72 is selected from
- the condition is that when L 2 is selected from -NH-, R 72 is selected from , one of the following conditions is satisfied: m is not 0, or one of X 12 and X 32 is selected from N, or R x2a and R x3a are not H at the same time; or
- L 2 is selected from ** represents the linking site of L 2 and R 72
- R 72 is selected from
- -L 2 -R 72 is selected from CN, -C(O)N(CH 3 ) 2 ,
- L 3 , L 5 , L 6 are each independently selected from -NH-, R 73 , R 75 and R 76 are each independently selected from
- L 7 , L 8 , L 9 are each independently selected from -NH-, R 77 , R 78 , R 79 are each independently selected from
- -L 7 -R 77 is selected from F, Br,
- -L 8 -R 78 , -L 9 -R 79 are each independently selected from
- L 11 is each independently selected from -NH-, R 711 from
- L 12 , L 13 , L 14 , L 15 are each independently selected from -NH-, R 712 , R 713 , R 714 , R 715 are each independently selected from
- -L 13 -R 713 is selected from F
- the compound of the present invention its stereoisomer, deuterated compound, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal, wherein the compound is selected from the group having formula (VII-1) , any one of the structures of formula (VII-2),
- X 82 is selected from -CR xa1 R xb1 -, R xa1 , R xb1 are each independently selected from any one of the group consisting of hydrogen, deuterium, halogen, and C 1-4 alkyl group, and optionally the alkyl group is further selected by 1 To 3 groups selected from halogen and deuterium are substituted, R xa1 , R xb1 can form a 3- to 5-membered cycloalkyl together with the carbon atoms to which the two are connected, preferably R xa1 , R xb1 are connected to the two. The carbon atoms form a 3-membered cycloalkyl;
- X 12 is selected from -CR x1a -, and X 32 is selected from -CR x3a -;
- R x1a and R x3a are each independently selected from any one of the group consisting of hydrogen, deuterium, halogen, and C 1-4 alkyl;
- L 2 is -C(O)-
- L 2 is -NH-, -C(O)NR La -**, ** represents the linking site of L 2 and R 72
- L 2 is -NR La C(O)-**, ** represents the linking site of L 2 and R 72
- R cya is selected from C 1 -2 alkyl, halogenated C 1-2 alkyl, deuterated C 1-2 alkyl;
- -L 2 -R 72 is selected from H or CN;
- R x3a is not H
- X 715 is selected from -CR x7a - or -N-, R x7a is selected from hydrogen, deuterium, halogen;
- X 815 is selected from -O- or -CR xa R xb -;
- R xa and R xb are each independently selected from any one of the group consisting of hydrogen, deuterium, halogen, and C 1-4 alkyl group, and the alkyl group is optionally further Substituted by 1 to 3 groups selected from halogen, deuterium, Rxa , Rxb can form 3- to 5-membered cycloalkyl together with the carbon atoms to which they are attached, preferably Rxa , Rxb and both The attached carbon atoms together form a 3-membered cycloalkyl or 4-membered cycloalkyl;
- Z 6 is selected from bond or -CR za R zb -, R za and R zb are each independently selected from hydrogen;
- L 15 is selected from -NR La , -C(O)-, -C(O)NR La -, -NR La C(O)-;
- the compounds of the present invention their stereoisomers, deuterated compounds, solvates, prodrugs, metabolites, pharmaceutically acceptable salts or co-crystals, wherein
- R 72 is -NR cya R cyb , Any one of the group consisting of, wherein R' is selected from any one of the group consisting of hydrogen, deuterium, halogen and C 1-4 alkyl, optionally further alkyl is further selected from 1 to 3 halogens , group substitution of deuterium, as an option, R' is composed of H, deuterium, methyl, ethyl, propyl, butyl, -CH 2 F, -CH 2 CH 2 F, -CHF 2 , -CF 3 Any one of the group; as selection R' is methyl, ethyl, -CH 2 F, -CHF 2 , -CF 3 ; R cya , R cyb are each independently H, deuterium, methyl, ethyl, Propyl , Butyl , -CH2F , -CH2CH2F , -CHF2 , -CF3 , -CHCH
- L2 for * represents the linking site of L 2 and R 72 , and R 72 is
- L2 for * represents the linking site of L 2 and R 72 , and R 72 is
- R xa1 and R xb1 are each independently selected from any one of the group consisting of hydrogen, deuterium, halogen, and C 1-4 alkyl group, and optionally the alkyl group may be further selected from 1 to 3 groups selected from halogen and deuterium Substitute, R xa , R xb can form 3-membered to 5-membered cycloalkyl together with the carbon atoms to which the two are connected, preferably R xa , R xb and the carbon atoms to which the two are connected form a 3-membered cycloalkyl;
- R xa and R xb are each independently selected from the group consisting of hydrogen, deuterium, halogen and C 1-4 alkyl Any one, the alkyl group is optionally further substituted by 1 to 3 groups selected from halogen and deuterium, R xa , R xb can form a 3- to 5-membered cycloalkyl together with the carbon atoms to which the two are connected, preferably R xa , R xb and the carbon atoms to which they are attached together form a 3-membered cycloalkyl group or a 4-membered cycloalkyl group;
- L 15 is selected from -NH-, R 715 is
- the compounds of the present invention their stereoisomers, deuterated compounds, solvates, prodrugs, metabolites, pharmaceutically acceptable salts or co-crystals, wherein
- X 82 is -CH 2 -, C(CH 3 ) 2 or cyclopropyl, X 12 is selected from -CH-, X 32 is selected from -CH-; L 2 is R 72 is N(R cya R cyb ), Any one of the group consisting of, R cya and R cyb are each independently methyl, ethyl, -CH 2 F, -CHF 2 , -CF 3 ;
- L2 for * represents the linking site of L 2 and R 72 , and R 72 is
- L2 for * represents the linking site of L 2 and R 72 , and R 72 is
- the compounds of the present invention their stereoisomers, deuterated compounds, solvates, prodrugs, metabolites, pharmaceutically acceptable salts or co-crystals, wherein
- -X 815 -Z 6 - is -O-CR xa R xb , and R xa and R xb are each independently selected from any one of the group consisting of hydrogen, deuterium and halogen; L 15 is selected from -NH-, R 715 is
- the compounds of the present invention their stereoisomers, deuterated compounds, solvates, prodrugs, metabolites, pharmaceutically acceptable salts or co-crystals, wherein said compounds are selected from compounds having formula (VII- 3), any one of the structures of formula (VII-4)
- X 818 is -CR xa R xb -, and R xa and R xb are each independently selected from any one of the group consisting of hydrogen, deuterium, halogen, and C 1-4 alkyl group, and the alkyl group is optionally further 1 to 3 groups selected from halogen and deuterium are substituted, and the R xa and R xb can form a 3- to 5-membered cycloalkyl group together with the carbon atoms to which they are connected, preferably the R xa , R xb together with the carbon atoms to which the two are attached to form a 3-membered cycloalkyl or a 4-membered cycloalkyl;
- L 18 is selected from -NH-, R 718 is
- L 7 is selected from -NH-, R 77 is Alternatively, L 7 is attached to the meta carbon atom of the five-membered heterocycle of the benzene ring.
- the compound of the present invention its stereoisomer, deuterated compound, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal, wherein the compound is selected from the following structures:
- the compound of the present invention its stereoisomer, deuterated compound, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal, wherein the compound is selected from the following structures:
- the present invention also provides a pharmaceutical composition, characterized in that it contains the compound described in any of the foregoing technical solutions, its stereoisomers, deuterated compounds, solvates, prodrugs, metabolites, pharmaceutically acceptable compounds salts or co-crystals, and pharmaceutically acceptable carriers and/or excipients.
- the present invention also relates to the compound described in any of the foregoing technical solutions, its stereoisomers, deuterated compounds, solvates, prodrugs, metabolites, pharmaceutically acceptable salts or co-crystals, or compositions, in An application in preparing a medicine for treating a disease mediated by PRMT5; the disease mediated by PRMT5 is a tumor.
- references and monographs in the field detail the synthesis of reactants useful in the preparation of the compounds described herein, or provide references for articles describing such preparations. These references and monographs include: “Synthetic Organic Chemistry,” John Wiley & Sons, Inc., New York; S.R. Sandler et al., “Organic Functional Group Preparations,” 2nd Ed., Academic Press, New York, 1983; H.O. House, “Modern Synthetic Reactions", 2nd Ed., W.A. Benjamin, Inc. Menlo Park, Calif. 1972; T.L. Gilchrist, “Heterocyclic Chemistry", 2nd Ed., John Wiley & Sons, New York, 1992; J.
- the carbon, hydrogen, oxygen, sulfur, nitrogen or halogen involved in the groups and compounds of the present invention all include their isotopes, and carbon, hydrogen, oxygen, sulfur, The nitrogen or halogen is optionally further replaced by one or more of their corresponding isotopes, wherein isotopes of carbon include12C, 13C and14C , and isotopes of hydrogen include protium (H), deuterium (deuterium, also known as deuterium) ), tritium (T, also known as super-heavy hydrogen), isotopes of oxygen include 16 O, 17 O and 18 O, isotopes of sulfur include 32 S, 33 S, 34 S and 36 S, and isotopes of nitrogen include 14 N and 15 N, the isotope of fluorine19F, the isotope of chlorine includes35Cl and37Cl , and the isotope of bromine includes79Br and81Br .
- isotopes of carbon include12C, 13C and14C
- C xy group refers to a group containing from x to y carbon atoms, eg "C 1-6 alkyl” refers to an alkyl group containing 1-6 carbon atoms.
- Halogen refers to fluorine (F), chlorine (Cl), bromine (Br), iodine (I) or isotopes thereof.
- Halo or halogen substitution means that a hydrogen atom is replaced by one or more isotopes selected from F, Cl, Br, I or their isotopes, and the upper limit of the number of halogen substituents is equal to the number of hydrogens that can be replaced by the substituted group
- the number of halogen substituents is any integer between 1 and the upper limit, preferably 1-5 halogen substitutions, 1-3 halogen substitutions, 1-2 halogen substitutions, and 1 halogen substitution ; When the number of halogen substituents is greater than 1, the same or different halogens can be substituted.
- HaloC 1-6 alkyl refers to an alkyl group containing 1-6 carbon atoms in which one or more hydrogens are replaced by one or more halogen atoms (eg, fluorine, chlorine, bromine, iodine) , the upper limit of the number of halogen substituents is equal to the sum of the number of hydrogens that can be substituted in the alkyl group, without special limitation, the number of halogen substituents is any integer between 1 and the upper limit, preferably 1-5 halogen substitutions , 1-3 halogen substitution, 1-2 halogen substitution or 1 halogen substitution; when the number of halogen substituents is greater than 1, it can be substituted by the same or different halogens; including but not limited to -CF 3 , -CH 2 Cl , -CH 2 CF 3 , -CCl 2 , CF 3 and the like.
- halogen atoms eg, fluorine, chlorine, bromine, iodine
- Deuterium refers to the isotope deuterium of hydrogen (H).
- Deuterated or “deuterated” means that a hydrogen atom on an alkyl, cycloalkyl, alkylene, aryl, heteroaryl, mercapto, heterocycloalkyl, alkenyl, alkynyl, etc. group is replaced by at least In the case of substitution by one deuterium atom, the upper limit of the number of deuterium is equal to the sum of the number of hydrogens that can be substituted by the substituted group.
- the number of deuterium is any integer between 1 and the upper limit, preferably 1- 20 deuterium atoms substitution, 1-10 deuterium atom substitution, 1-6 deuterium atom substitution, 1-3 deuterium atom substitution, 1-2 deuterium atom substitution, or 1 deuterium atom substitution.
- Alkyl refers to a straight-chain or branched-chain saturated aliphatic hydrocarbon group, unless otherwise specified, an alkyl group of 1 to 20 carbon atoms, preferably an alkyl group of 1 to 8 carbon atoms, more preferably an alkyl group of 1 to 6 carbon atoms
- An alkyl group of 1 to 4 carbon atoms is further preferably an alkyl group of 1 to 4 carbon atoms, and further preferably an alkyl group of 1 to 2 carbon atoms.
- Non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, neobutyl, tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl etc.; the alkyl group can be further substituted by any substituent.
- Hydroalkyl means an alkyl group substituted with hydroxy, as defined above.
- Alkenyl refers to a straight-chain hydrocarbon group or a branched-chain hydrocarbon group containing at least one carbon-carbon double bond (C ⁇ C), unless otherwise specified, the main, including 2 to 18 (such as 2 to 8, further such as 2 to 6, and further such as 2 to 4) carbon atoms, including but not limited to vinyl, allyl, 1-propenyl, 2-propenyl, 1-butenyl, 2-butenyl, 3 -butenyl, 1-pentenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 1-methyl-1-butenyl, 2-methyl-1-butenyl , 2-methyl-3-butenyl, 1-hexenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, 5-hexenyl, 1-methyl-1-pentyl Alkenyl, 2-methyl-1-pentenyl, 1-heptenyl, 2-heptenyl, 3-heptenyl, 4-
- Alkynyl refers to a hydrocarbon group containing at least one carbon-carbon triple bond (C ⁇ C) straight-chain hydrocarbon group, branched-chain hydrocarbon group, and the main chain includes 2 to 18 (such as 2 to 8, further such as 2 to 6, and then Further such as 2 to 4) carbon atoms.
- alkynyl 1-propynyl, 2-propynyl, butynyl, 2-butynyl, 3-butynyl, 1-methyl-2-propynyl, 4-pentynyl, 3- Pentynyl, 1-methyl-2-butynyl, 2-hexynyl, 3-hexynyl, 2-heptynyl, 3-heptynyl, 4-heptynyl, 3-octynyl , 3-nonynyl and 4-decynyl, etc.; the alkynyl group may be optionally further substituted by any substituent.
- Alkoxy refers to -O-alkyl, when not particularly limited, it is -OC 1-8 alkyl, preferably -OC 1-6 alkyl, more preferably -OC 1 -4 alkyl, more preferably -OC 1-2 alkyl.
- Non-limiting examples include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, sec-butoxy, tert-butoxy, n-pentoxy, n-hexyloxy, cyclopropyl Oxy group and cyclobutoxy group, etc.; the alkoxy group can be optionally further substituted by any substituent.
- Haloalkoxy refers to -O-haloalkyl, and when not particularly limited, is -O-haloC 1-8 alkyl, preferably -O-halo C 1-6 alkyl, more preferably -O -halogenated C 1-4 alkyl, more preferably -O-halogenated C 1-2 alkyl; the upper limit of the number of halogen substituents is equal to the sum of the number of hydrogens that can be substituted by the substituted group, unless otherwise specified Under the limit, the number of halogen substituents is any integer between 1 and the upper limit, preferably 1-5 halogen substitutions, 1-3 halogen substitutions, 1-2 halogen substitutions, and 1 halogen substitution; when the number of halogen substituents is greater than 1 can be substituted with the same or different halogens; non-limiting examples include monofluoromethoxy, difluoromethoxy, trifluoromethoxy, difluoroethyloxy, and the like.
- Cycloalkyl refers to a substituted or unsubstituted, saturated, partially unsaturated or fully unsaturated non-aromatic hydrocarbon ring, which may be monocyclic, bicyclic or polycyclic, and bicyclic or polycyclic may be polycyclic, Spiro or bridged ring, unless otherwise specified, usually has 3 to 20 carbon atoms; when it is a monocyclic cycloalkyl, preferably 3-15 carbon atoms, preferably 3-10 carbon atoms, more preferably 3-8 carbon atoms carbon atoms, more preferably 3-6 carbon atoms, further preferably 3-4 carbon atoms; when bicyclic or polycyclic cycloalkyl, preferably 4-12 carbon atoms, preferably 4-11 carbon atoms , more preferably 5-11 carbon atoms, more preferably 6-11 carbon atoms, further preferably 6-10 carbon atoms; non-limiting examples include cyclopropyl, cyclobutyl, cyclopentyl,
- Heterocycloalkyl refers to a substituted or unsubstituted, saturated, partially unsaturated or fully unsaturated non-aromatic ring containing at least one heteroatom.
- the heterocycloalkyl group is 3 to 20 Member ring, when it is a monocyclic heterocycloalkyl, preferably 3 to 15 members, preferably 3-10 members, more preferably 3-8 members, more preferably 3-6 members; when it is a bicyclic or polycyclic ring heterocycloalkyl , preferably 4-12 members, preferably 4-11 members, more preferably 5-11 members, more preferably 6-11 members, further preferably 6-10 members; heterocycloalkyl can be monocyclic, bicyclic or polycyclic , the bicyclic or polycyclic ring can be a bridged ring, a heterocyclic ring and a spirocyclic ring, wherein the heteroatoms are selected from N, S, O, P, Si heteroatoms and their oxidation states
- Aryl refers to a substituted or unsubstituted 5- to 15-membered aromatic carbocyclic ring, including monocyclic aromatic groups and fused-ring aromatic groups.
- a 5- to 10-membered aromatic ring is preferred, and a 5- to 8-membered aromatic ring is further preferred;
- the aryl ring may be fused to a non-aryl ring (such as a heteroaryl, heterocycloalkyl or cycloalkyl ring), wherein aryl
- the ring is the attachment site, non-limiting examples include phenyl, naphthyl, anthracenyl, phenanthryl,
- Said aryl group may be optionally further substituted with any substituent.
- Heteroaromatic ring or “heteroaryl” refers to a substituted or unsubstituted heteroatom or group containing at least one heteroatom or group selected from N, S, O, P, Si heteroatoms and their oxidation states, having aromaticity
- the ring can be monocyclic, bicyclic or polycyclic, and can be bridged, combined, spirocyclic; when bicyclic or polycyclic, it can be heteroaryl and non-heteroaryl rings such as cycloalkyl, heterocyclic Alkyl, aryl fused, or heteroaryl and heteroaryl fused, where the heteroaryl ring is the point of attachment; non-limiting examples include furyl, thienyl, pyrrolyl, oxazolyl , thiazolyl, imidazolyl, pyrazolyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, indolyl, pur
- Spirocycle refers to a 5- to 20-membered polycyclic group with one carbon atom (called a spiro atom) shared between substituted or unsubstituted rings, which may contain 0 to 5 double bonds, and may contain 0 Up to 5 heteroatoms or groups selected from N, O, S, P, Si and their oxidation states.
- the spiro ring can be formed between cycloalkyl and heterocycloalkyl; three-membered ring spiro three-membered ring), trispirotetra, trispiropenta, trispirohexa, tetraspirotetra, tetraspiropenta, tetraspirohexa, pentaspiropenta, or pentaspirohexa; non-limiting examples of rings include
- Said spiro ring may be optionally further substituted with any substituent.
- Parenter refers to a polycyclic group in which the ring shares two adjacent atoms with the ring, wherein one or more rings may contain zero or more double bonds, and may be substituted or unsubstituted, and the rings in the ring system
- Each ring may contain 0 to 5 heteroatoms selected from N, S, O, P, Si and their oxidation states. It is preferably 5 to 20 yuan, more preferably 5 to 14 yuan, more preferably 5 to 12 yuan, and still more preferably 5 to 10 yuan.
- three-membered tetracyclic ring (representing a three-membered ring and a four-membered ring formed by the ring, according to the IUPC naming rules may be a three-membered ring as a basic ring or a four-membered ring as a basic ring, the same ring, the following is the same), Tri-penta-, tri-, tetra-, tetra-, tetra-, tetra-, penta-, penta-, hexa-, non-limiting examples include purine, quinoline, Isoquinoline, benzopyran, benzofuran, benzothiophene, Said paracyclic ring may be optionally further substituted with any substituent.
- “Bridged ring” refers to two non-adjacent atoms shared between two rings, may contain 0 or more double bonds, and may be substituted or unsubstituted, wherein one or more rings may contain 0 to 5 are selected from N, S, O, P, Si heteroatoms and their oxidation states; the ring atoms contain 5 to 20 atoms, preferably 5 to 14 atoms, more preferably 5 to 12, still more preferably 5 to 10 non-limiting examples include adamantane
- heteroatoms described in the present invention are selected from N, O, S, Si, P atoms and their oxidation state forms.
- alkyl optionally substituted by F means that the alkyl group may but not necessarily be substituted by F, and the description includes the case where the alkyl group is substituted by F and the case where the alkyl group is not substituted by F.
- “Pharmaceutically acceptable salt” means that a compound of the present invention retains the biological availability and properties of a free acid or free base that is treated with a non-toxic inorganic or organic base, and the free base is treated with Salts obtained by the reaction of non-toxic inorganic or organic acids.
- “Pharmaceutical composition” means a mixture of one or more of the compounds described herein, or a stereoisomer, solvate, pharmaceutically acceptable salt, co-crystal, deuterated form thereof, and other components, wherein the other components comprise Physiologically/pharmaceutically acceptable carriers and/excipients.
- Carrier means one that does not significantly irritate the organism and does not eliminate the biological activity and properties of the administered compound, and can change the way the drug enters the human body and its distribution in the body, controls the release rate of the drug and removes the drug
- Non-limiting examples of systems for delivery to targeted organs include microcapsules and microspheres, nanoparticles, liposomes, and the like.
- Excipient means: not itself a therapeutic agent, but used as a diluent, adjuvant, binder and/or vehicle for addition to a pharmaceutical composition to improve its handling or storage properties or to allow or facilitate The compound or pharmaceutical composition is formed in unit dosage form for administration.
- pharmaceutical excipients can serve various functions and can be described as wetting agents, buffers, suspending agents, lubricants, emulsifying agents, disintegrating agents, absorbing agents, preservatives , surfactants, colorants, flavors and sweeteners.
- Examples of pharmaceutical excipients include, but are not limited to: (1) sugars such as lactose, glucose and sucrose; (2) starches such as corn starch and potato starch; (3) cellulose and derivatives thereof such as carboxymethyl Sodium cellulose, ethyl cellulose, cellulose acetate, hydroxypropyl methylcellulose, hydroxypropyl cellulose, microcrystalline cellulose and croscarmellose (e.g.
- croscarmellose sodium (4) tragacanth powder; (5) malt; (6) gelatin; (7) talc; (8) excipients such as cocoa butter and suppository wax; (9) oils such as peanut oil, cottonseed oil, red Flower oil, sesame oil, olive oil, corn oil and soybean oil; (10) glycols such as propylene glycol; (11) polyols such as glycerol, sorbitol, mannitol and polyethylene glycol; (12) esters such as oils (13) agar; (14) buffers such as magnesium hydroxide and aluminum hydroxide; (15) alginic acid; (16) pyrogen-free water; (17) isotonic saline; ( 18) Ringer's solution; (19) Ethanol; (20) pH buffer solution; (21) Polyester, polycarbonate and/or polyanhydride; Compatible substances.
- oils such as peanut oil, cottonseed oil, red Flower oil, sesame oil, olive oil, corn oil and soybean oil
- Steps refer to isomers resulting from different arrangements of atoms in a molecule in space, including cis-trans isomers, enantiomers and conformational isomers.
- Solvate refers to a substance formed by a compound of the present invention or a salt thereof and a stoichiometric or non-stoichiometric solvent bound non-covalently by intermolecular forces.
- the solvent is water, it is a hydrate.
- Co-crystal refers to a crystal formed by the combination of an active pharmaceutical ingredient (API) and a co-crystal former (CCF) under the action of hydrogen bonds or other non-covalent bonds, wherein the pure states of API and CCF are both at room temperature solid, and there is a fixed stoichiometric ratio between the components.
- a co-crystal is a multicomponent crystal that includes both binary co-crystals formed between two neutral solids and multi-component co-crystals formed between neutral solids and salts or solvates.
- NMR nuclear magnetic resonance
- MS mass spectrometry
- HPLC HPLC-based high pressure liquid chromatograph
- the thin layer chromatography silica gel plate uses Yantai Huanghai HSGF254 or Qingdao GF254 silica gel plate, the size of the silica gel plate used for thin layer chromatography (TLC) is 0.15mm-0.20mm, and the specification used for TLC separation and purification products is 0.4mm -0.5mm;
- Preparative conditions Instrument: Waters SFC 350, Preparative column: DAICEL CHIRALPAK AD (250mm*50mm, 10 ⁇ m), mobile phase: A for CO 2 and B for IPA+ACN (0.1% NH 3 ⁇ H 2 O), gradient: 80 % Phase B, flow rate: 180mL/min, back pressure: 100bar, column temperature: 35°C, wavelength: 220nm, cycle time: ⁇ 8.2min, sample pretreatment: compound dissolved in methanol dichloromethane system, concentration 40mg/mL, .Injection: 10mL per injection.
- the first step 2-(3-(3,4-dihydroisoquinolin-2(1H)-yl)-2-hydroxypropyl)-1-oxo-1,2,3,4-tetrahydro Isoquinoline-6-carboxylic acid (4A, single isomer)
- the second step 2-(3-(3,4-dihydroisoquinolin-2(1H)-yl)-2-hydroxypropyl)-N,N-dimethyl-1-oxo1,2 ,3,4-Tetrahydroisoquinoline-6-carboxamide (compound 4, single isomer)
- the first step tert-butyl 4-(2-(3-(3-(3,4-dihydroisoquinolin-2(1H)-yl)-2-hydroxypropyl)-1-oxo-1 ,2,3,4-Tetrahydroisoquinoline-6-carbonyl)piperazine-1-carboxylate (6A)
- the second step 2-(3-(3,4-dihydroisoquinolin-2(1H)-yl)-2-hydroxypropyl)-6-(piperazine-1-carbonyl)-3,4- Dihydroisoquinolin-1(2H)-one (compound 6, single isomer)
- the first step 6-amino-2-(3-(3,4-dihydroisoquinoline-2(1H)-yl)-2-hydroxypropyl)-3,4-dihydroisoquinoline-1 (2H)-ketone (10A, single isomer)
- Step 2 1-Acetyl-N-(2-(3-(3,4-dihydroisoquinolin-2(1H)-yl)-2-hydroxypropyl)-1-oxo-1,2 ,3,4-Tetrahydroisoquinolin-6-yl)piperidine-4-carboxamide (Compound 10, single isomer)
- Step 2 7-Bromo-2-(3-(6,7-dihydrothieno[3,2-c]pyridine)-5(4H)-yl)-2-hydroxypropyl)-3,4 -Dihydroisoquinolin-1(2H)-one (11C)
- the reactant 11C (0.5 g, 1.19 mmol), 4-aminopyridazine (0.23 g, 2.38 mmol) were dissolved in 1,4 dioxane (50 mL), and sodium tert-butoxide (0.23 g) was added to it successively. , 2.38mmol), Pd 2 (dba) 3 (0.22g, 0.24mmol), Xantphos (0.28g, 0.48mmol), nitrogen replacement protection, 100 degree reaction 1h.
- Example 12 7'-((1-Acetylpiperidin-4-yl)amino)-2'-(3-(6,7-dihydrothieno[3,2-c]pyridinyl-5( 4H)-yl)-2-hydroxypropyl)-2',3'-dihydro-1'H-spiro[cyclopropane-1,4'-isoquinolin]-1'-one (Compound 12)
- Step 2 7'-((1-Acetylpiperidin-4-yl)amino)-2'-(3-(6,7-dihydrothieno[3,2-c]pyridinyl-5( 4H)-yl)-2-hydroxypropyl)-2',3'-dihydro-1'H-spiro[cyclopropane-1,4'-isoquinolin]-1'-one (Compound 12)
- 12B (synthesized with reference to patent WO2020259478) (0.2 g, 0.64 mmol) was added to the DMF (10 mL) suspension of sodium hydrogen (23 mg, 0.96 mmol) in batches. After the reaction for 0.5 h, a solution of 12A (0.12 g, 0.64 mmol) in DMF (2 mL) was added dropwise. After the dropwise addition was complete, the solution was raised to room temperature and reacted overnight.
- Example 14 2-(3-(3,4-Dihydroisoquinolin-2(1H)-yl)-2-hydroxypropyl)-6-(2-methoxy-7-azaspiro[ 3.5] Nonane-7-carbonyl)-3,4-dihydroisoquinolin-1(2H)-one (compound 14, single isomer)
- Example 15 7-(2-(3-(3,4-Dihydroisoquinolin-2(1H)-yl)-2-hydroxypropyl)-1-oxo-1,2,3,4 - Tetrahydroisoquinoline-6-carbonyl)-7-azaspiro[3.5]nonane-2-carbonitrile (compound 15, single isomer)
- Example 16 7'-((1-Acetylpiperidin-4-yl)amino)-2'-(2-hydroxy-3-(isoindolin-2-yl)propyl)-2',3 '-Dihydro-1'H-spiro[cyclopropane-1,4'-isoquinolin]-1'-one (Compound 16)
- Example 17 6-((1-Acetylpiperidin-4-yl)amino)-2-(3-(3,4-dihydroisoquinolin-2(1H)-yl)-2-hydroxypropane yl)-7-fluoro-3,4-dihydroisoquinolin-1(2H)-one (Compound 17)
- 6-bromo-7-fluoroisoquinoline 17A (2.5 g, 11.06 mmol) was dissolved in glacial acetic acid (55 mL), sodium borohydride (0.46 g, 12.1 mmol) was added in portions, and it was raised to The reaction was stirred at room temperature for 3h.
- the sixth step 6-bromo-7-fluoro-2-(2-hydroxy-3-(1,2,3,4-tetrahydronaphthalene-2-yl)propyl)-3,4-dihydroisoquine Lin-1(2H)-one (17G)
- Step 7 6-((1-Acetylpiperidin-4-yl)amino)-2-(3-(3,4-dihydroisoquinolin-2(1H)-yl)-2-hydroxypropane yl)-7-fluoro-3,4-dihydroisoquinolin-1(2H)-one (Compound 17)
- 17G (0.6 g, 1.39 mmol) was dissolved in dry dioxane (20 mL), 1-acetylpiperidin-4-amine (0.24 g, 1.67 mmol), sodium tert-butoxide (0.4 g, 4.17 mmol) were added successively mmol), 4,5-bisdiphenylphosphine-9,9-dimethylxanthene (0.26g, 0.36mmol), bisdibenzylideneacetone palladium (0.1g, 0.17mmol), nitrogen protection, 100 °C for 3 hours.
- Example 18 6-(4-Acetylpiperazine-1-carbonyl)-2-(3-(3,4-dihydroisoquinolin-2(1H)-yl)-2-hydroxypropyl)-3 ,4-Dihydroisoquinolin-1(2H))-one (Compound 18, single isomer)
- Example 20 7-((1-Acetylpiperidin-4-yl)amino)-2-(3-(3,4-dihydroisoquinolin-2(1H)-yl)-2-hydroxypropyl )-5-methyl-3,4-dihydroisoquinolin-1(2H)-one (Compound 20)
- the third step 7-amino-5-methyl-3,4-dihydroisoquinolin-1(2H)-one (20D)
- Step 5 7-(2,5-Dimethyl-1H-pyrrol-1-yl)-5-methyl-2-(oxiran-2-ylmethyl)-3,4-dihydro Isoquinolin-1(2H)-one (20F)
- Step 6 2-(3-(3,4-Dihydroisoquinolin-2(1H)-yl)-2-hydroxypropyl)-7-(2,5-dimethyl-1H-pyrrole- 1-yl)-5-methyl-3,4-dihydroisoquinolin-1(2H)-one (20G)
- the seventh step 7-amino-2-(3-(3,4-dihydroisoquinolin-2(1H)-yl)-2-hydroxypropyl)-5-methyl-3,4-di Hydroisoquinolin-1(2H)-one (20H)
- Step 8 7-((1-Acetylpiperidin-4-yl)amino)-2-(3-(3,4-dihydroisoquinolin-2(1H)-yl)-2-hydroxypropyl )-5-methyl-3,4-dihydroisoquinolin-1(2H)-one (Compound 20)
- Example 21 7-((1-Acetylpiperidin-4-yl)amino)-2-(3-(3,4-dihydroisoquinolin-2(1H)-yl)-2-hydroxypropyl )-6-methyl-3,4-dihydroisoquinolin-1(2H)-one (Compound 21)
- the third step 7-iodo-6-methyl-2-(oxiran-2-ylmethyl)-3,4-dihydroisoquinolin-1(2H)-one (21C)
- the fourth step 2-(3-(3,4-dihydroisoquinolin-2(1H)-yl)-2-hydroxypropyl)-7-iodo-6-methyl-3,4-dihydro Isoquinolin-1(2H)-one (21D)
- the fifth step 7-((1-acetylpiperidin-4-yl)amino)-2-(3-(3,4-dihydroisoquinolin-2(1H)-yl)-2-hydroxypropyl )-6-methyl-3,4-dihydroisoquinolin-1(2H)-one (Compound 21)
- 21D (0.30 g, 0.63 mmol) was dissolved in dry dioxane (20 mL), 1-acetylpiperidin-4-amine (0.13 g, 0.95 mmol), sodium tert-butoxide (0.18 g, 1.89 mmol), 4,5-bisdiphenylphosphine-9,9-dimethylxanthene (0.29g, 0.50mmol), bisdibenzylideneacetone palladium (0.072g, 0.13mmol), nitrogen protection, 100 °C for 3 hours.
- Apparatus Waters 150mgm, preparative column: DAICEL CHIRALPAK AD (250mm*30mm, 10 ⁇ m), mobile phase: A for CO 2 and B for IPA+ACN (0.1% NH 3 ⁇ H 2 O), gradient: 45% Phase B, Flow rate: 120mL/min, back pressure: 100bar, column temperature: 35°C, wavelength: 220nm, cycle time: ⁇ 8min, sample pretreatment: compound dissolved in ethanol, concentration 5mg/mL, .Injection: 6mL per injection.
- Example 22 7-((1-Acetylpiperidin-4-yl)amino)-2-(3-(6,7-dihydrothieno[3,2-c]pyridin-5(4H)-yl )-2-hydroxypropyl-3,4-dihydroisoquinolin-1(2H)-one (Compound 22)
- compound 22, isomer 2 was obtained with 22B as raw material.
- Example 23 7'-((1-Acetylpiperidin-4-yl)amino)-2'-(3-(6,7-dihydrothieno[3,2-c]pyridinyl-5( 4H)-yl)-2-hydroxypropyl)-2',3'-dihydro-1'H-spiro[cyclopropane-1,4'-isoquinolin]-1'-one (compound 12, isoquinoline) isomer 1 and isomer 2)
- Compound 12 was resolved by chiral HPLC to obtain compound 12, isomer 1 and isomer 2.
- the resolution conditions were as follows: Instrument name: Waters 150Mgm; Chromatographic column: DAICEL CHIRALPAK AD (250mm*30mm, 10 ⁇ m) Mobile phase: A for CO 2 and B for EtOH (0.1% NH 3 ⁇ H 2 O); gradient: 50% phase B isocratic elution; flow rate: 80 mL/min; column pressure: 100 bar; column temperature: 38 °C; absorption wavelength: 220 nm; circulation Time: ⁇ 9.5min). Isomer 1 retention time: 5.891 min; isomer 2 retention time: 9.420 min.
- Example 24 8-(2-(3-(3,4-Dihydroisoquinolin-2(1H)-yl)-2-hydroxypropyl)-1-oxo-1,2,3,4 -Tetrahydroisoquinoline-6-carbonyl)-2,8-diazaspiro[4.5]decan-3-one (compound 24, single isomer)
- Example 27 6-(5-Acetyloctahydropyrrole[3,4-c]pyrrole-2-carbonyl)-2-(3-(3,4-dihydroisoquinolin-2(1H)-yl )-2-hydroxypropyl)-3,4-dihydroisoquinolin-1(2H)-one (Compound 27)
- 2-BOC-octahydropyrrolyl[3,4-C]pyrrole 27A (1.06 g, 5 mmol) was dissolved in dichloromethane (20 mL) and triethylamine (0.76 g, 7.5 mmol) was added , acetyl chloride (0.47 g, 6 mmol) was added dropwise, and the reaction was stirred at room temperature for 1 h.
- reaction solution was slowly added dropwise to saturated aqueous sodium bicarbonate solution (200 mL) to quench the reaction, the aqueous phase was extracted with dichloromethane, the layers were separated, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure Compound 27B (1.2 g, 94.5%) was obtained and used in the next reaction without further purification.
- Dissolve 27B (0.6 g, 1.54 mmol) in dichloromethane (20 mL), add methanolic hydrochloric acid (5 mL), react at room temperature for 3 hours, and concentrate to give the title compound 27C (0.6 g, 99%). It was used directly in the next reaction without purification.
- the third step 6-(5-Acetyl octahydropyrrole[3,4-c]pyrrole-2-carbonyl)-2-(3-(3,4-dihydroisoquinolin-2(1H)-yl )-2-hydroxypropyl)-3,4-dihydroisoquinolin-1(2H)-one (Compound 27)
- Example 28 2-(-3-(3,4-Dihydroisoquinolin-2(1H)-yl)-2-hydroxypropyl)-6-((3aR,5R,6aS)-5-methyl Oxyoctahydrocyclopentadieno[c]pyrrole-2-carbonyl)-3,4-dihydroisoquinolin-1(2H)-one (Compound 28)
- the fourth step 2-(-3-(3,4-dihydroisoquinolin-2(1H)-yl)-2-hydroxypropyl)-6-((3aR,5R,6aS)-5-methyl Oxyoctahydrocyclopentadieno[c]pyrrole-2-carbonyl)-3,4-dihydroisoquinolin-1(2H)-one (Compound 28)
- Dissolve 29A (refer to US20120225857) (1.00g, 3.97mmol) in N,N-dimethylformamide (10mL), add sodium hydride (0.32g, 7.97mmol) at 0°C, add (R) after 30min -(-)-Glycidyl p-nitrobenzenesulfonate (1.54 g, 5.96 mmol), reacted for 1 hour.
- Water 80 mL was added, extracted with ethyl acetate (20 mL x 3), the combined organic phases were dried over anhydrous sodium sulfate, filtered and concentrated to give the title compound 29B (1.0 g, 81.7%).
- Example 31 7-((1-Acetylpiperidin-4-yl)amino)-2-(3-(3,4-dihydroisoquinolin-2(1H)-yl)-2-hydroxypropyl )-5-methyl-3,4-dihydroisoquinolin-1(2H)-one (Compound 20 Isomer 1, Isomer 2, the two are enantiomers of each other)
- Chiral separation conditions instrument: Waters 350mgm, preparative column: DAICEL CHIRALPAK AD (250mm ⁇ 30mm, 10 ⁇ m), mobile phase: A for CO 2 and B for EtOH+ACN (0.1% NH 3 ⁇ H 2 O), gradient: 40% Phase B isocratic elution, flow rate: 180mL/min, back pressure: 100bar, column temperature: 35°C, wavelength: 220nm, cycle time: 3.8min, sample pretreatment: compound dissolved in ethanol, concentration 12mg/mL, injection: 1.5mL per injection.
- 20H-1 was synthesized with reference to the seventh step synthesis method of Example 20.
- 20H-2 was synthesized with reference to the seventh-step synthesis method of Example 20.
- Example 33 7-(2-(3-(3,4-Dihydroisoquinolin-2(1H)-yl)-2-hydroxypropyl)-4,4-dimethyl-1-oxo -1,2,3,4-Tetrahydroisoquinoline-6-carbonyl)-7-azaspiro[3.5]nonane-2-carbonitrile (Compound 33)
- 6-bromo-4,4-dimethyl-3,4-dihydroisoquinolin-1(2H)-one 33A (synthesized with reference to the method described in patent WO2019094312) (0.5 g, 1.97 mmol) ) was dissolved in N,N-dimethylformamide (15 mL), 60% sodium hydride (0.12 g, 3.0 mmol) was added, and the reaction was stirred for 1 h.
- Epibromopropane (0.32 g, 2.36 mmol) was added, and after the addition, the temperature was raised to room temperature and the reaction was stirred for 2 hours.
- Compound 33C was resolved by chiral HPLC to obtain isomer 33C-1 and isomer 33C-2 (enantiomers of each other), and the purification conditions were as follows: (Instrument name: Waters 350; chromatographic column: DAICEL CHIRALCEL AD ( 250mm*30mm, 10 ⁇ m) mobile phase: A for CO 2 and B for IPA (Neu) gradient: 45% phase B isocratic elution; flow rate: 200mL/min; column pressure: 100bar; column temperature: 35°C; absorption wavelength: 220nm ; cycle time: ⁇ 7min). Retention time of isomer 33C-1: 2.265 min; retention time of isomer 33C-2: 2.579 min. The absolute configuration of isomer 33C-1 and isomer 33C-2 is uncertain.
- 33D-2 was synthesized.
- 33E-2 was synthesized.
- TMSCN (6.41 g, 64.62 mmol) was dissolved in dry acetonitrile (200 mL) and tetrabutylammonium fluoride (21.12 g, 80.78 mmol) was added.
- LCMS monitored the completion of the reaction.
- Example 38 7-[(1-Acetylpiperidin-4-yl)amino]-4-[(2R)-2-hydroxy-3-(4H,5H,6H,7H-thiophene[3,2-c ]pyridin-5-yl)propyl]-2,3,4,5-tetrahydro-1,4-azazepin-5-one (Compound 38)
- reaction solution was concentrated to 2 mL, isopropanol (20 mL) was added, concentrated to 2 mL again, isopropanol (100 mL) was added, N,N-diisopropylethylamine (800 mg, 6.21 mmol), 4,5 , 6,7-Tetrahydrothieno[3,2-c]pyridine hydrochloride (580 mg, 4.14 mmol) was replaced with nitrogen, and the temperature was raised to 100° C. to react for 3 hours.
- 1X assay buffer (10 mM Tris, 1 mM DTT, 0.01% BSA, 0.01% Tween-20, pH adjusted to 8.0).
- the test compounds were dissolved in DMSO to prepare a 10 mM stock solution, and then diluted with DMSO to 100-fold final concentration. 100 nL of compound was added to each well of the administration group, and 100 nL of DMSO solution was added to blank wells and negative control wells. Then, 5 ⁇ L of PRMT5/MEP50 (BPS, Cat. 31921) enzyme solution (final concentration 1 nM) was added to the wells of the administration group and the negative control, and 5 ⁇ L of 1 ⁇ test buffer was added to the blank wells, and incubated at room temperature for 15 minutes.
- PRMT5/MEP50 BPS, Cat. 31921
- inhibition rate (%) (maximum negative control -detected signal value)/(maximum negative control -minimum blank control )*100, and IC50 values were fitted using XL-Fit.
- Test results The compounds of the present invention showed inhibitory activity to PRMT5 receptor, and the IC50 values of the compounds of the examples for PRMT5 enzymatic activity were in the range of 0.01-1000 nM. Wherein, the test results of some embodiments are shown in Table 1:
- Compound 24 65 Compound 25 80 Compound 26 54 Compound 27 76 Compound 29 13 Compound 30 16 Compound 20, Isomer 1 90 Compound 20, Isomer 2 30 Compound 32 31 Compound 33, Isomer 1 54 Compound 34, Isomer 1 45 Compound 34, Isomer 2 40 Compound 35 twenty two Compound 36 31 Compound 37 36 Compound 38 7.7
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Abstract
提供了一种式(I)的化合物,其立体异构体、氘代物、溶剂化物、前药、代谢产物、药学上可接受的盐或共晶,或含它们的药物组合物,及其作为PRMT5抑制剂在制备治疗相关疾病的药物中的用途。
Description
本发明属于药物领域,尤其涉及一种蛋白质精氨酸甲基转移酶抑制剂的衍生物,其立体异构体、药学上可接受的盐、溶剂化物、共晶或氘代物,及其在制备治疗PRMT5介导的相关疾病的药物中的用途。
蛋白质精氨酸甲基转移酶(PRMT)能够使多种蛋白(包括组蛋白和非组蛋白)甲基化,并对多种生物学过程进行影响,比如参与基因转录,细胞信号转导,蛋白质稳定性,细胞增殖、分化、凋亡和肿瘤的形成等。目前,已发现了11种PRMT家族的成员,根据催化精氨酸甲基化方式的不同,可分为三类:PRMT1-4、PRMT6、PRMT8属于Ⅰ型,催化的形式为单甲基和不对称双甲基;PEMT5和PRMT9属于Ⅱ型,其催化的形式为对称双甲基;PRMT7属于Ⅲ型,能够单甲基催化。
蛋白精氨酸甲基转移酶5(PRMT5)普遍存在于细胞浆和细胞核内,能够特异性催化组蛋白及非组蛋白等众多底物的对称甲基化,从而影响多个靶基因及多条信号通路途径,发挥着多种生物学功能。在人类的多种恶性肿瘤(肺癌、卵巢癌、结直肠癌、乳腺癌、黑色素瘤、白血病及恶性胶质瘤)中,PRMT5的表达均出现上调,充分说明其在肿瘤的形成发展中有重要的作用。此外,PRMT5已经被确认为是套细胞淋巴癌的治疗靶标,因此其小分子抑制剂的研究成为抗肿瘤药物研发的热点。
发明内容
本发明的目的是提供一种活性高、副作用小、生物利用度高、选择性高的新的PRMT5抑制剂。
本发明提供的化合物及其立体异构体、氘代物、溶剂化物、前药、代谢产物、药学上可接受的盐或共晶,对PRMT5具有抑制作用,能抑制细胞增殖,具有良好的药代动力学特征,高的生物利用度,安全性好,毒副作用小,具有口服给药、吸收快、清除率高等优点。
本发明提供一种式(I)所示的化合物,其立体异构体、氘代物、溶剂化物、前药、代谢产物、药学上可接受的盐或共晶,
其中,
A环选自苯基或者5-6元杂芳基;
R
1、R
2、R
3、R
4各自独立地选自氢、氘、羟基、卤素、氨基、硝基、氰基、C
1-6烷基、C
1-6烷氧基、C
3-8环烷基、C
1-6烷基氨基、二(C
1-6烷基)氨基、-C(O)C
1-6烷基、-C(O)NHC
1-6烷基、-C(O)NH
2、-NHC(O)C
1-6烷基、-N(C
1-6烷基)C(O)C
1-6烷基,所述烷基、烷氧基任选被1至5个选自卤素、氘、羟基、氨基、氰基、C
1-6烷氧基的基团取代;
作为选择,R
1、R
2与连接的碳原子一起形成3-6元环烷基、3-6元杂环烷基;
作为选择,R
3、R
4与连接的碳原子一起形成3-6元环烷基、3-6元杂环烷基;
R
5选自氢、氘、C
1-6烷基、C
1-6烷氧基、-C(O)C
1-6烷基、-C(O)NH
2、-C(O)NHC
1-6烷基,所述烷基、烷氧基任选被1至5个选自卤素、氘、羟基、氨基、氰基、C
1-6烷氧基的基团取代;
R
8选自氢、氘、羟基、卤素、氨基、硝基、氰基、C
1-6烷基、C
1-6烷氧基、卤代C
1-6烷基、卤代C
1-6烷氧基、氘代C
1-6烷基、氘代C
1-6烷氧基;
R
6选自氘、卤素、氰基、硝基、氰基、氨基、羟基、C
1-6烷基、C
1-6烷氧基、C
2-6烯基、C
2-6炔基、-SF
5、-(CH
2)
r-C
3-8环烷基、-(CH
2)
r-(3-8元杂环烷基)、-O-C
3-8环烷基、-O-(3-8元杂环烷基)、-NH-C
3-8环烷基、-NH-(3-8元杂环烷基)、-S-C
3-8环烷基、-S-(3-8元杂环烷基)、5至8元杂芳基、6至8元芳基、-C(=O)NR
6aR
6b、-NR
6aC(=O)-R
6b、-NR
6aR
6b、-C(=O)-R
6a、-S-C
1-6烷基、-S(O)-C
1-6烷基、-S(O)
2-C
1-6烷基,所述CH
2、烷基、烷氧基、环烷基、杂环烷基、杂芳基、芳基任选进一步被1至5个选自卤素、氘、硝基、氰基、氨基、羟基、=O、C
1-6烷基、C
1-6烷氧基、卤代C
1-6烷基、卤代C
1-6烷氧基、氘代C
1-6烷基、氘代C
1-6烷氧基的基团取代;
R
6a选自氢、氘、C
1-6烷基、C
3-8环烷基、3-8元杂环烷基,所述烷基、环烷基、杂环烷基任选被1至5个选自卤素、氘、羟基、氨基、氰基、C
1-6烷氧基;
R
6b选自氢、氘、C
1-6烷基、C
1-6烷氧基、C
3-8环烷基、3-8元杂环烷基、C
1-6烷基氨基、二(C
1-6烷基)氨基、-S(O)
2C
1-6烷基,所述的烷基、烷氧基、环烷基、杂环烷基任选被1至5 个选自卤素、氘、羟基、氨基、氰基、=O、C
1-6烷基、C
1-6烷氧基、卤代C
1-6烷基、卤代C
1-6烷氧基、氘代C
1-6烷基、氘代C
1-6烷氧基的基团取代;
X选自键、-O-、-S-、-S(O)-、-S(O)
2-、-CR
xaR
xb-或者-NR
xa-;
Y选自键、-O-、-S-、-S(O)-、-S(O)
2-、-CR
yaR
yb-、-NR
ya-或者-CR
ya-;
Z选自键、-O-、-S-、-S(O)-、-S(O)
2-、-CR
zaR
zb-、-NR
za-、-CR
za-或者-N-;
条件是,X、Y、Z不同时为键;
X
1选自-CR
x1a-或者-N-;
X
2选自-CR
x2a-或者-N-;
X
3选自-CR
x3a-或者-N-;
X
7选自-CR
x7a-或者-N-;
X
4选自-O-、-S-、-CR
x4aR
x4b-或者-NR
x4a-;
X
5选自-O-、-S-、-CR
x5aR
x5b-或者-NR
x5a-;
X
6选自键、-O-、-S-、-CR
x6aR
x6b-或者-NR
x6a-;
R
x1a、R
x2a、R
x3a、R
x7a各自独立选自氢、氘、卤素、硝基、氰基、氨基、羟基、-L-R
7、C
1-6烷基、C
1-6烷氧基、C
2-6烯基、C
2-6炔基、-SF
5、-(CH
2)
r-C
3-12环烷基、-(CH
2)
r-(3-12元杂环烷基)、-O-C
3-12环烷基、-O-(3-12元杂环烷基)、-NH-C
3-12环烷基、-NH-(3-12元杂环烷基)、-S-C
3-12环烷基、-S-(3-12元杂环烷基)、5至12元杂芳基、6至12元芳基、-C(=O)NR
xaaR
xab、-NR
xaaC(=O)-R
xab、-NR
xaaR
xab、-C(=O)-R
xaa、-S-C
1-6烷基、-S(O)-C
1-6烷基、-S(O)
2-C
1-6烷基,所述CH
2、烷基、烷氧基、环烷基、杂环烷基、杂芳基、芳基任选进一步被1至5个选自卤素、氘、硝基、氰基、氨基、羟基、=O、C
1-6烷基、C
1-6烷氧基、卤代C
1-6烷基、卤代C
1-6烷氧基、氘代C
1-6烷基、氘代C
1-6烷氧基的基团取代;
R
xa、R
xb、R
ya、R
yb、R
za、R
zb、R
x4a、R
x4b、R
x5a、R
x5b、R
x6a、R
x6b各自独立选自氢、氘、卤素、硝基、氰基、氨基、羟基、C
1-6烷基、C
1-6烷氧基、C
2-6烯基、C
2-6炔基、-SF
5、-(CH
2)
r-C
3-12环烷基、-(CH
2)
r-(3-12元杂环烷基)、-O-C
3-12环烷基、-O-(3-12元杂环烷基)、-NH-C
3-12环烷基、-NH-(3-12元杂环烷基)、-S-C
3-12环烷基、-S-(3-12元杂环烷基)、5至12元杂芳基、6至12元芳基、-C(=O)NR
xaaR
xab、-NR
xaaC(=O)-R
xab、-NR
xaaR
xab、-C(=O)-R
xaa、-S-C
1-6烷基、-S(O)-C
1-6烷基、-S(O)
2-C
1-6烷基,所述CH
2、烷基、烷氧基、环烷基、杂环烷基、杂芳基、芳基任选进一步被1至5个选自卤素、氘、硝基、氰基、氨基、羟基、=O、 C
1-6烷基、C
1-6烷氧基、卤代C
1-6烷基、卤代C
1-6烷氧基、氘代C
1-6烷基、氘代C
1-6烷氧基的基团取代;
R
xaa、R
xab各自独立选自氢、氘、氨基、羟基、C
1-6烷基、卤代C
1-6烷基、氘代C
1-6烷基、C
1-6烷氧基、卤代C
1-6烷氧基、氘代C
1-6烷氧基;
作为选择,连接于同一碳原子上的R
xa和R
xb、R
ya和R
yb、R
za和R
zb、R
x4a和R
x4b、R
x5a和R
x5b,或R
x6a和R
x6b与所连接的碳原子一起形成=O、3-6元环烷基或3-6元杂环烷基;
作为选择,R
x4a与R
x6a一起形成-CH
2-或者-CH
2CH
2-;
L选自键、-NR
La、-C(O)-、-C(O)NR
La-、-NR
LaC(O)-、-NR
LaC(O)-(CH
2)
p-O-、-O-(CH
2)
p-C(O)NR
La-、-NR
LaC(O)-NR
La-、-O-、-S-、-S(O)
2NR
La-、-NR
LaS(O)
2-;
R
La选自氢、氘、C
1-6烷基、卤代C
1-6烷基、氘代C
1-6烷基;
R
7选自C
1-6烷基、C
1-6烷氧基、C
2-6烯基、C
2-6炔基、-SF
5、-(CH
2)
r-C
3-12环烷基、-(CH
2)
r-(4-12元杂环烷基)、-(CH
2)
r-(5-12元杂芳基)、-(CH
2)
r-(6-12元芳基),所述CH
2、烷基、烷氧基、环烷基、杂环烷基、杂芳基、芳基任选进一步被1至5个选自氘、卤素、硝基、氰基、氨基、羟基、C
1-6烷基、=O、C
1-6烷氧基、C
2-6烯基、C
2-6炔基、卤代C
1-6烷基、卤代C
1-6烷氧基、氘代C
1-6烷基、氘代C
1-6烷氧基、-SF
5、-(CH
2)
r-C
3-8环烷基、-(CH
2)
r-(3-8元杂环烷基)、-O-C
3-8环烷基、-O-(3-8元杂环烷基)、-NH-C
3-8环烷基、-NH-(3-8元杂环烷基)、-S-C
3-8环烷基、-S-(3-8元杂环烷基)、5至8元杂芳基、6至8元芳基、-C(=O)NR
cyaR
cyb、-NR
cyaC(=O)-R
cyb、-NR
cyaR
cyb、-C(=O)-R
cya、-S-C
1-6烷基、-S(O)-C
1-6烷基、-S(O)
2-C
1-6烷基的基团取代。
R
cya、R
cyb各自独立选自C
1-6烷基、卤代C
1-6烷基、氘代C
1-6烷基;
作为选择,-L-R
7选自氢、氘、氨基、羟基、卤素、氰基、C
1-6烷基、C
1-6羟基烷基、C
1-
6烷氧基、卤代C
1-6烷基、氘代C
1-6烷基、卤代C
1-6烷氧基、氘代C
1-6烷氧基;
m选自0、1、2、3或4;
p选自0、1或2;
r选自0、1、2或者3;
条件是,式(I)化合物不选自如下化合物:
另一技术方案中,本发明所述的式(I)所示的化合物,其立体异构体、氘代物、溶剂化物、前药、代谢产物、药学上可接受的盐或共晶,具有式(II)、(III)、(IV)、(V)结构:
其中,
A环选自苯基、5元杂芳基或者6元杂芳基;
X选自键、-O-、-S-、-S(O)-、-S(O)
2-、-CR
xaR
xb-或者-NR
xa-;
Y选自键、-O-、-S-、-S(O)-、-S(O)
2-、-CR
yaR
yb-、-NR
ya-或者-CR
ya-;
Z选自键、-O-、-S-、-S(O)-、-S(O)
2-、-CR
zaR
zb-、-NR
za-、-CR
za-或者-N-;
条件是,X、Y、Z不同时为键;
X
4选自-O-、-S-、-CR
x4aR
x4b-或者-NR
x4a-;
X
5选自-O-、-S-、-CR
x5aR
x5b-或者-NR
x5a-;
X
6选自键、-O-、-S-、-CR
x6aR
x6b-或者-NR
x6a-;
X
1选自-CR
x1a-或者-N-;
X
2选自-CR
x2a-或者-N-;
X
3选自-CR
x3a-或者-N-;
X
7选自-CR
x7a-或者-N-;
R
x1a、R
x2a、R
x3a、R
x7a各自独立选自氢、氘、卤素、硝基、氰基、氨基、羟基、C
1-4烷基、C
1-4烷氧基、C
2-6烯基、C
2-6炔基、-SF
5,所述烷基、烷氧基任选进一步被1至3个选自F、Cl、氘、硝基、氰基、氨基、羟基、C
1-2烷基、C
1-2烷氧基、卤代C
1-2烷基、卤代C
1-2烷氧基、氘代C
1-2烷基、氘代C
1-2烷氧基的基团取代;
R
xa、R
xb、R
ya、R
yb、R
za、R
zb、R
x4a、R
x4b、R
x5a、R
x5b、R
x6a、R
x6b各自独立选自氢、氘、卤素、硝基、氰基、氨基、羟基、C
1-4烷基、C
1-4烷氧基、C
2-4烯基、C
2-4炔基、-SF
5、-(CH
2)
r-C
3-6单环环烷基、-(CH
2)
r-C
5-10双环环烷基、-(CH
2)
r-(3-6元单环杂环烷基)、-(CH
2)
r-(5-10元双环杂环烷基)、-O-C
3-6单环环烷基、-O-C
5-10双环环烷基、-O-(3-6元单环杂环烷基)、-O-(5-10元双环杂环烷基)、-NH-C
3-6单环环烷基、-NH-C
5-10双环环烷基、-NH-(3-6元单环杂环烷基)、-NH-(5-10元双环杂环烷基)、5至6元杂芳基、苯基、-C(=O)NR
xaaR
xab、-NR
xaaC(=O)-R
xab、-NR
xaaR
xab、-C(=O)-R
xaa,所述CH
2、烷基、烷氧基、环烷基、杂环烷基、杂芳基、芳基任选进一步被1至3个选自卤素、氘、硝基、氰基、氨基、羟基、=O、C
1-4烷基、C
1-4烷氧基、卤代C
1-4烷基、卤代C
1-4烷氧基、氘代C
1-4烷基、氘代C
1-4烷氧基的基团取代;
R
xaa、R
xab各自独立选自氢、氘、氨基、羟基、C
1-4烷基、卤代C
1-4烷基、氘代C
1-4烷基、C
1-4烷氧基、卤代C
1-4烷氧基、氘代C
1-4烷氧基;
作为选择,连接于同一碳原子上的R
xa和R
xb、R
ya和R
yb、R
za和R
zb、R
x4a和R
x4b、R
x5a和R
x5b,或R
x6a和R
x6b与所连接的碳原子一起形成3元环烷基、4元环烷基、5元环烷基、6元环烷基、3元杂环烷基、4元杂环烷基、5元杂环烷基或6元杂环烷基;
作为选择,R
x4a与R
x6a一起形成-CH
2-或者-CH
2CH
2-;
条件是,当-L-R
7为氢时,R
x3a选自氢;
其他基团与前文任一技术方案所述一致。
另一技术方案中,本发明所述的式(I)、(II)化合物,其立体异构体、氘代物、溶剂化物、前药、代谢产物、药学上可接受的盐或共晶,具有式(II-a)、(II-b)、(II-c)结构:
X
1选自-CR
x1a-或者-N-;
X
2选自-CR
x2a-或者-N-;
X
3选自-CR
x3a-或者-N-;
R
x1a、R
x2a、R
x3a各自独立选自氢、氘、卤素、硝基、氰基、氨基、羟基、C
1-4烷基、C
1-
4烷氧基,所述烷基、烷氧基任选进一步被1至3个选自F、Cl、氘、硝基、氰基、氨基、羟基、C
1-2烷基、C
1-2烷氧基、卤代C
1-2烷基、卤代C
1-2烷氧基、氘代C
1-2烷基、氘代C
1-2烷氧基的基团取代;
X选自-O-或-CR
xaR
xb-;
R
xa、R
xb各自独立选自氢、氘、卤素、C
1-6烷基,所述烷基任选进一步被1至3个选自卤素、氘、羟基、C
1-4烷氧基、卤代C
1-4烷基、卤代C
1-4烷氧基、氘代C
1-4烷基、氘代C
1-4烷氧基的基团取代;
作为选择,连接于同一碳原子上的R
xa和R
xb与所连接的碳原子一起形成3元环烷基、4元环烷基、5元环烷基、3元杂环烷基、4元杂环烷基、5元杂环烷基;
其他基团定义与前文任一技术方案一致。
另一技术方案中,本发明所述的化合物,其立体异构体、氘代物、溶剂化物、前药、代谢产物、药学上可接受的盐或共晶,其中
R
1、R
2各自独立选自氢、氘,作为选择,R
1、R
2与连接的碳原子一起形成3元环烷基、4元环烷基或5元环烷基;和/或
R
5选自氢、氘、C
1-4烷基、卤代C
1-4烷基;和/或
R
x1a、R
x2a、R
x3a、R
x7a各自独立选自氢、氘、卤素、羟基、氰基、C
1-4烷基、C
1-4烷氧基;
其他基团定义与前文所述的任一技术方案一致。
另一技术方案中,本发明所述的化合物,其立体异构体、氘代物、溶剂化物、前药、代谢产物、药学上可接受的盐或共晶,其中
L选自键、-NR
La、-C(O)-、-C(O)NR
La-、-NR
LaC(O)-、-O-、-NR
LaC(O)-CH
2-O-;
R
La选自氢、氘、C
1-4烷基、卤代C
1-4烷基、氘代C
1-4烷基;或者
其他基团与前文任一技术方案所述一致。
另一技术方案中,本发明所述的化合物,其立体异构体、氘代物、溶剂化物、前药、代谢产物、药学上可接受的盐或共晶,其中
R
7选自-(CH
2)
r-(5-6元单环杂芳基)、-(CH
2)
r-(4-6元单环杂环烷基)、-(CH
2)
r-(6-10元双环杂环烷基)、-(CH
2)
r-(3-6元单环环烷基)、-(CH
2)
r-(6-10元双环环烷基),所述的Cy任选进一步被1、2、3、4、5个选自氘、卤素、氰基、羟基、C
1-6烷基、C
1-6烷氧基、C
2-6烯基、C
2-6炔基、-SF
5、-(CH
2)
r-C
3-8环烷基、-(CH
2)
r-C
3-8杂环烷基、-C(=O)NR
cyaR
cyb、-NR
cyaC(=O)-R
cyb、-NR
cyaR
cyb、-C(=O)-R
cya,所述CH
2、烷基、烷氧基、环烷基、杂环烷基任选进一步被1、2、3、4、5个选自卤素、氘、硝基、氰基、氨基、羟基、=O、C
1-4烷基、C
1-4烷氧基、卤代C
1-4烷基、卤代C
1-4烷氧基、氘代C
1-4烷基、氘代C
1-4烷氧基的基团取代;
r选自0或1;
R
cya、R
cyb各自独立选自C
1-4烷基、卤代C
1-4烷基、氘代C
1-4烷基;或者
R
7选自
其他基团与前文任一技术方案所述一致。
另一技术方案中,本发明所述的化合物,其立体异构体、氘代物、溶剂化物、前药、代谢产物、药学上可接受的盐或共晶,其中
R
7-L-选自F、Cl、Br、氰基、C
1-4烷基、C
1-4羟基烷基、C
1-4烷氧基、卤代C
1-4烷基、氘代C
1-4烷基、卤代C
1-4烷氧基、氘代C
1-4烷氧基;或者
R
7-L-选自F、Cl、Br、氰基、甲基、乙基、丙基、异丙基、羟基甲基、羟基乙基、羟基丙基、甲氧基、乙氧基、丙氧基、异丙氧基、叔丁氧基、-CH
2F、-CHF
2、-CF
3、-OCH
2F、-OCHF
2、-OCF
3、-CH
2D、-CHD
2、-CD
3、-OCH
2D、-OCHD
2、-OCD
3。
另一技术方案中,本发明所述的化合物,其立体异构体、氘代物、溶剂化物、前药、代谢产物、药学上可接受的盐或共晶,其中
m选自0、1、2;和/或
R
6选自氘、卤素、氰基、C
1-4烷基、-(CH
2)
r-C
3-6环烷基、-(CH
2)
r-C
3-6杂环烷基、-C(=O)NR
6aR
6b、-NR
6aC(=O)-R
6b、-NR
6aR
6b、-C(=O)-R
6a,所述CH
2、烷基、环烷基、杂环烷基任选进一步被1、2、3、4、5个选自卤素、氘、硝基、氰基、氨基、羟基、=O、C
1-4烷基、C
1-4烷氧基、卤代C
1-4烷基、卤代C
1-4烷氧基、氘代C
1-4烷基、氘代C
1-4烷氧基的基团取代;
r选自0或者1;
R
6a选自氢、氘、C
1-2烷基,所述烷基任选被1、2、3个选自卤素、氘、羟基、氨基、氰基、C
1-2烷氧基的基团取代;
R
6b选自氢、氘、C
1-4烷基,所述的烷基任选被1、2、3个选自卤素、氘、羟基、氨基、氰基、C
1-2烷氧基的基团取代;或者
m选自0、1;
R
6选自氘、F、Cl、Br、氰基、甲基、乙基、丙基、异丙基、叔丁基、2-甲基丙基、环丙基、环丁基、环戊基、环己基、-CH
2-环丙基、-CH
2-环丁基、-CH
2-环戊基、-CH
2-环己基、氮杂环丁基、氮杂环戊基、氮杂环己基、-CH
2-氮杂环丁基、-CH
2-氮杂环戊基、-CH
2-氮杂环己基、氧杂环丁基、氧杂环戊基、氧杂环己基、-CH
2-氧杂环丁基、-CH
2-氧杂环戊基、-CH
2-氧杂环己基、-C(O)NHCH
3、-NHC(O)CH
3、-N(CH
3)C(O)CH
3、-NHC(O)CH
2CH
3、-N(CH
3)C(O)CH
2CH
3、-NH
2、-NHCH
3、-C(O)CH3、-C(O)CH
2CH
3,以上基团选进一步被1、2、3个选自F、氘的基团取代;
其他基团与前文任一技术方案所述一致。
本发明一种式(I)所示的化合物,其立体异构体、氘代物、溶剂化物、前药、代谢产物、药学上可接受的盐或共晶,
其中,
A环选自苯基或者5-6元杂芳基;
R
1、R
2、R
3、R
4各自独立地选自氢、氘、羟基、卤素、氨基、硝基、氰基、C
1-6烷基、C
1-6烷氧基、C
3-8环烷基、C
1-6烷基氨基、二(C
1-6烷基)氨基、-C(O)C
1-6烷基、-C(O)NHC
1-6烷基、-C(O)NH
2、-NHC(O)C
1-6烷基、-N(C
1-6烷基)C(O)C
1-6烷基,所述烷基、烷氧基任选被1至5个选自卤素、氘、羟基、氨基、氰基、C
1-6烷氧基的基团取代;
作为选择,R
1、R
2与连接的碳原子一起形成3-6元环烷基、3-6元杂环烷基;
作为选择,R
3、R
4与连接的碳原子一起形成3-6元环烷基、3-6元杂环烷基;
R
5选自氢、氘、C
1-6烷基、C
1-6烷氧基、-C(O)C
1-6烷基、-C(O)NH
2、-C(O)NHC
1-6烷基,所述烷基、烷氧基任选被1至5个选自卤素、氘、羟基、氨基、氰基、C
1-6烷氧基的基团取代;
R
8选自氢、氘、羟基、卤素、氨基、硝基、氰基、C
1-6烷基、C
1-6烷氧基、卤代C
1-6烷基、卤代C
1-6烷氧基、氘代C
1-6烷基、氘代C
1-6烷氧基;
R
6选自氘、卤素、氰基、硝基、氰基、氨基、羟基、C
1-6烷基、C
1-6烷氧基、C
2-6烯基、C
2-6炔基、-SF
5、-(CH
2)
r-C
3-8环烷基、-(CH
2)
r-(3-8元杂环烷基)、-O-C
3-8环烷基、-O-(3-8元杂环烷基)、-NH-C
3-8环烷基、-NH-(3-8元杂环烷基)、-S-C
3-8环烷基、-S-(3-8元杂环烷基)、5至8元杂芳基、6至8元芳基、-C(=O)NR
6aR
6b、-NR
6aC(=O)-R
6b、-NR
6aR
6b、-C(=O)-R
6a、-S-C
1-6烷基、-S(O)-C
1-6烷基、-S(O)
2-C
1-6烷基,所述CH
2、烷基、烷氧基、环烷基、杂环烷基、杂芳基、芳基任选进一步被1至5个选自卤素、氘、硝基、氰基、氨基、羟基、=O、C
1-6烷基、C
1-6烷氧基、卤代C
1-6烷基、卤代C
1-6烷氧基、氘代C
1-6烷基、氘代C
1-6烷氧基的基团取代;
R
6a选自氢、氘、C
1-6烷基、C
3-8环烷基、3-8元杂环烷基,所述烷基、环烷基、杂环烷基任选被1至5个选自卤素、氘、羟基、氨基、氰基、C
1-6烷氧基的基团取代;
R
6b选自氢、氘、C
1-6烷基、C
1-6烷氧基、C
3-8环烷基、3-8元杂环烷基、C
1-6烷基氨基、二(C
1-6烷基)氨基、-S(O)
2C
1-6烷基,所述的烷基、烷氧基、环烷基、杂环烷基任选被1至5 个选自卤素、氘、羟基、氨基、氰基、=O、C
1-6烷基、C
1-6烷氧基、卤代C
1-6烷基、卤代C
1-6烷氧基、氘代C
1-6烷基、氘代C
1-6烷氧基的基团取代;
X选自键、-O-、-S-、-S(O)-、-S(O)
2-、-CR
xaR
xb-或者-NR
xa-;
Y选自键、-O-、-S-、-S(O)-、-S(O)
2-、-CR
yaR
yb-、-NR
ya-或者-CR
ya-;
Z选自键、-O-、-S-、-S(O)-、-S(O)
2-、-CR
zaR
zb-、-NR
za-、-CR
za-或者-N-;
条件是,X、Y、Z不同时为键;
X
1选自-CR
x1a-或者-N-;
X
2选自-CR
x2a-或者-N-;
X
3选自-CR
x3a-或者-N-;
X
7选自-CR
x7a-或者-N-;
X
4选自-O-、-S-、-CR
x4aR
x4b-或者-NR
x4a-;
X
5选自-O-、-S-、-CR
x5aR
x5b-或者-NR
x5a-;
X
6选自键、-O-、-S-、-CR
x6aR
x6b-或者-NR
x6a-;
R
x1a、R
x2a、R
x3a、R
x7a各自独立选自氢、氘、卤素、硝基、氰基、氨基、羟基、-L-R
7、C
1-6烷基、C
1-6烷氧基、C
2-6烯基、C
2-6炔基、-SF
5、-(CH
2)
r-C
3-12环烷基、-(CH
2)
r-(3-12元杂环烷基)、-O-C
3-12环烷基、-O-(3-12元杂环烷基)、-NH-C
3-12环烷基、-NH-(3-12元杂环烷基)、-S-C
3-12环烷基、-S-(3-12元杂环烷基)、5至12元杂芳基、6至12元芳基、-C(=O)NR
xaaR
xab、-NR
xaaC(=O)-R
xab、-NR
xaaR
xab、-C(=O)-R
xaa、-S-C
1-6烷基、-S(O)-C
1-6烷基、-S(O)
2-C
1-6烷基,所述CH
2、烷基、烷氧基、环烷基、杂环烷基、杂芳基、芳基任选进一步被1至5个选自卤素、氘、硝基、氰基、氨基、羟基、=O、C
1-6烷基、C
1-6烷氧基、卤代C
1-6烷基、卤代C
1-6烷氧基、氘代C
1-6烷基、氘代C
1-6烷氧基的基团取代;
R
xa、R
xb、R
ya、R
yb、R
za、R
zb、R
x4a、R
x4b、R
x5a、R
x5b、R
x6a、R
x6b各自独立选自氢、氘、卤素、硝基、氰基、氨基、羟基、C
1-6烷基、C
1-6烷氧基、C
2-6烯基、C
2-6炔基、-SF
5、-(CH
2)
r-C
3-12环烷基、-(CH
2)
r-(3-12元杂环烷基)、-O-C
3-12环烷基、-O-(3-12元杂环烷基)、-NH-C
3-12环烷基、-NH-(3-12元杂环烷基)、-S-C
3-12环烷基、-S-(3-12元杂环烷基)、5至12元杂芳基、6至12元芳基、-C(=O)NR
xaaR
xab、-NR
xaaC(=O)-R
xab、-NR
xaaR
xab、-C(=O)-R
xaa、-S-C
1-6烷基、-S(O)-C
1-6烷基、-S(O)
2-C
1-6烷基,所述CH
2、烷基、烷氧基、环烷基、杂环烷基、杂芳基、芳基任选进一步被1至5个选自卤素、氘、硝基、氰基、氨基、羟基、=O、 C
1-6烷基、C
1-6烷氧基、卤代C
1-6烷基、卤代C
1-6烷氧基、氘代C
1-6烷基、氘代C
1-6烷氧基的基团取代;
R
xaa、R
xab各自独立选自氢、氘、氨基、羟基、C
1-6烷基、卤代C
1-6烷基、氘代C
1-6烷基、C
1-6烷氧基、卤代C
1-6烷氧基、氘代C
1-6烷氧基;
作为选择,连接于同一碳原子上的R
xa和R
xb、R
ya和R
yb、R
za和R
zb、R
x4a和R
x4b、R
x5a和R
x5b,或R
x6a和R
x6b与所连接的碳原子一起形成=O、3-6元环烷基或3-6元杂环烷基;
作为选择,连接于相邻碳原子上的R
xa和R
za与所连接的碳原子一起形成=O、3-6元环烷基或3-6元杂环烷基;
作为选择,R
x4a与R
x6a一起形成-CH
2-或者-CH
2CH
2-;
L选自键、-NR
La、-C(O)-、-C(O)NR
La-、-NR
LaC(O)-、-NR
LaC(O)-(CH
2)
p-O-、-O-(CH
2)
p-C(O)NR
La-、-NR
LaC(O)-NR
La-、-O-、-S-、-S(O)
2NR
La-、-NR
LaS(O)
2-;
R
La选自氢、氘、C
1-6烷基、卤代C
1-6烷基、氘代C
1-6烷基;
R
7选自H、C
1-6烷基、C
1-6烷氧基、C
2-6烯基、C
2-6炔基、-SF
5、-(CH
2)
r-C
3-12环烷基、-(CH
2)
r-(4-12元杂环烷基)、-(CH
2)
r-(5-12元杂芳基)、-(CH
2)
r-(6-12元芳基),所述CH
2、烷基、烷氧基、环烷基、杂环烷基、杂芳基、芳基任选进一步被1至5个选自氘、卤素、硝基、氰基、氨基、羟基、C
1-6烷基、=O、C
1-6烷氧基、C
2-6烯基、C
2-6炔基、卤代C
1-6烷基、卤代C
1-6烷氧基、氘代C
1-6烷基、氘代C
1-6烷氧基、-SF
5、-(CH
2)
r-C
3-8环烷基、-(CH
2)
r-(3-8元杂环烷基)、-O-C
3-8环烷基、-O-(3-8元杂环烷基)、-NH-C
3-8环烷基、-NH-(3-8元杂环烷基)、-S-C
3-8环烷基、-S-(3-8元杂环烷基)、5至8元杂芳基、6至8元芳基、-C(=O)NR
cyaR
cyb、-NR
cyaC(=O)-R
cyb、-NR
cyaR
cyb、-C(=O)-R
cya、-S-C
1-6烷基、-S(O)-C
1-6烷基、-S(O)
2-C
1-6烷基的基团取代;
R
cya、R
cyb各自独立选自C
1-6烷基、卤代C
1-6烷基、氘代C
1-6烷基;
作为选择,-L-R
7选自氢、氘、氨基、羟基、卤素、氰基、C
1-6烷基、C
1-6羟基烷基、C
1-
6烷氧基、卤代C
1-6烷基、氘代C
1-6烷基、卤代C
1-6烷氧基、氘代C
1-6烷氧基;
m选自0、1、2、3或4;
p选自0、1或2;
r选自0、1、2或者3;
条件是,式(I)化合物不选自如下化合物:
另一技术方案中,本发明所述的式(I)所示的化合物,其立体异构体、氘代物、溶剂化物、前药、代谢产物、药学上可接受的盐或共晶,所述式(I)化合物具有式(II-1)、(II-2)、(II-3)、(II-5)、(II-6)、(II-7)、(II-8)、(II-9)、(II-10)、(II-11)、(II-12)、(II-13)、(II-14)、(II-15)结构:
其中,
A环选自苯基、5元杂芳基或者6元杂芳基;
B环选自5元杂芳基或者6元杂芳基;
E环为3-6元环烷基或3-6元杂环烷基;
H环为3-6元环烷基或3-6元杂环烷基;
R
11、R
12、R
13、R
15、R
17、R
18、R
19、R
110、R
111、R
112、R
113、R
114、R
115、R
21、R
22、R
23、R
25、R
27、R
28、R
29、R
210、R
211、R
212、R
213、R
214、R
215、R
31、R
32、R
33、R
35、R
36、R
37、R
38、R
39、R
310、R
311、R
312、R
313、R
314、R
315、R
41、R
42、R
43、R
45、R
46、R
47、R
48、 R
49、R
410、R
411、R
412、R
413、R
414、R
415各自独立地选自氢、氘、羟基、卤素、氰基、C
1-4烷基、C
1-4烷氧基,所述烷基、烷氧基任选被1至3个选自卤素、氘、羟基的基团取代;
作为选择,连接于同一碳原子上的R
11和R
21、R
31和R
41、R
12和R
22、R
32和R
42、R
13和R
23、R
33和R
43、R
15和R
25、R
35和R
45、R
36和R
46、R
17和R
27、R
37和R
47、R
18和R
28、R
38和R
48、R
19和R
29、R
39和R
49、R
110和R
210、R
310和R
410、R
111和R
211、R
311和R
411、R
112和R
212、R
312和R
412、R
112和R
213、R
313和R
413、R
114和R
214、R
314和R
414、R
115和R
215,或者R
315和R
415分别各自独立地与所连接的碳原子一起形成3元环烷基、4元环烷基、5元环烷基、6元环烷基、3元杂环烷基、4元杂环烷基、5元杂环烷基或6元杂环烷基;
R
51、R
52、R
53、R
55、R
56、R
57、R
58、R
59、R
510、R
511、R
512、R
513、R
514、R
515各自独立地选自氢、氘、C
1-4烷基,所述烷基任选被1至3个选自卤素、氘、羟基的基团取代;
R
81、R
82、R
83、R
85、R
86、R
87、R
88、R
89、R
810、R
811、R
812、R
813、R
814、R
815各自独立地选自氢、氘、羟基、卤素;
连接于同一碳原子上R
9a1和R
9b1、R
9a2和R
9b2与所连接的碳原子一起形成3元环烷基、4元环烷基、5元环烷基、6元环烷基、3元杂环烷基、4元杂环烷基、5元杂环烷基或6元杂环烷基;或者
R
9a1和R
9a2相链接形成-CH
2-、-CH
2CH
2-;
R
61、R
63、R
65、R
66、R
67、R
68、R
69、R
610、R
611、R
612、R
613、R
614、R
615、R
616、R
617各自独立地选自氘、卤素、氰基、硝基、氨基、羟基、C
1-4烷基、C
1-4烷氧基、-(CH
2)
r-C
3-8环烷基、-(CH
2)
r-(3-8元杂环烷基)、-O-C
3-8环烷基、-O-(3-8元杂环烷基)、-NH-C
3-8环烷基、-NH-(3-8元杂环烷基)、-S-C
3-8环烷基、-S-(3-8元杂环烷基)、5至8元杂芳基、6至8元芳基、-C(=O)NR
6aR
6b、-NR
6aC(=O)-R
6b、-NR
6aR
6b、-C(=O)-R
6a、-S-C
1-6烷基、-S(O)-C
1-6烷基、-S(O)
2-C
1-6烷基,所述CH
2、烷基、烷氧基、环烷基、杂环烷基、杂芳基、芳基任选进一步被1至5个选自卤素、氘、硝基、氰基、氨基、羟基、=O、C
1-6烷基、C
1-6烷氧基、卤代C
1-6烷基、卤代C
1-6烷氧基、氘代C
1-6烷基、氘代C
1-6烷氧基的基团取代;
R
62为氘、卤素、-(CH
2)
r-C
3-8环烷基、-(CH
2)
r-(3-8元杂环烷基)、-C(=O)NR
6aR
6b、-NR
6aC(=O)-R
6b、-NR
6aR
6b、-C(=O)-R
6a,所述CH
2、环烷基、杂环烷基任选进一步被1至3个选自卤素、氘、氰基、羟基、=O、C
1-4烷基、C
1-4烷氧基、卤代C
1-4烷基、卤代C
1-4烷氧基、氘代C
1-4烷基、氘代C
1-4烷氧基的基团取代;
R
6a选自氢、氘、C
1-6烷基、C
3-8环烷基、3-8元杂环烷基,所述烷基、环烷基、杂环烷基任选被1至5个选自卤素、氘、羟基、氨基、氰基、C
1-6烷氧基的基团取代;
R
6b选自氢、氘、C
1-6烷基、C
1-6烷氧基、C
3-8环烷基、3-8元杂环烷基、C
1-6烷基氨基、二(C
1-6烷基)氨基、-S(O)
2C
1-6烷基,所述的烷基、烷氧基、环烷基、杂环烷基任选被1至5个选自卤素、氘、羟基、氨基、氰基、=O、C
1-6烷基、C
1-6烷氧基、卤代C
1-6烷基、卤代C
1-6烷氧基、氘代C
1-6烷基、氘代C
1-6烷氧基的基团取代;
X
81、X
83、X
86、X
88、X
89、X
810、X
811、X
813、X
814、X
815各自独立地选自-O-、-S-、-S(O)-、-S(O)
2-、-CR
xaR
xb-或者-NR
xa-;
X
87选自-O-、-S(O)-、-S(O)
2-、-CR
xaR
xb-或者-NR
xa-;
X
812选自-O-、-S-、-S(O)-、-S(O)
2-、-CR
xa2R
xb2-或者-NR
xa-;
X
82选自-O-、-S-、-S(O)-、-S(O)
2-、-CR
xa1R
xb1-或者-NR
xa-;
Y
1、Y
2、Y
3、Y
4、Y
5、Y
6各自独立地选自键、-CR
yaR
yb-、-NR
ya-或者-CR
ya-;
Z
1、Z
2、Z
3、Z
4、Z
5、Z
6各自独立地选自键、-CR
zaR
zb-、-NR
za-、-CR
za-或者-N-;
X
41、X
42、X
43、X
44各自独立地选自-CR
x4aR
x4b-或者-NR
x4a-;
X
51、X
52、X
53、X
54各自独立地选自-CR
x5aR
x5b-或者-NR
x5a-;
X
61、X
62、X
63、X
64各自独立地选自键、-CR
x6aR
x6b-或者-NR
x6a-;
X
11、X
12、X
13、X
15、X
16、X
17、X
18、X
19、X
110、X
113、X
114、X
115各自独立地选自-CR
x1a-或者-N-;
X
21、X
22、X
23、X
25、X
26、X
27、X
28、X
29、X
211、X
213、X
214、X
215各自独立地选自-CR
x2a-或者-N-;
X
31、X
32、X
33、X
35、X
36、X
37、X
38、X
39、X
310、X
311各自独立地选自-CR
x3a-或者-N-;
X
710、X
711、X
713、X
714、X
715各自独立地选自-CR
x7a-或者-N-;
X
112选自-CR
x1b-;
X
212选自-CR
x2b-;
X
712选自-CR
x7b-;
R
x1a、R
x2a、R
x3a、R
x7a各自独立选自氢、氘、卤素、硝基、氰基、氨基、羟基、C
1-4烷基、C
1-4烷氧基、C
2-6烯基、C
2-6炔基、-SF
5,所述烷基、烷氧基任选进一步被1至3个选自F、Cl、氘、硝基、氰基、氨基、羟基、C
1-2烷基、C
1-2烷氧基、卤代C
1-2烷基、卤代C
1-2烷氧基、氘代C
1-2烷基、氘代C
1-2烷氧基的基团取代;
R
xa、R
xb、R
xa2、R
xb2、R
ya、R
yb、R
za、R
zb、R
x4a、R
x4b、R
x5a、R
x5b、R
x6a、R
x6b各自独立选自氢、氘、卤素、硝基、氰基、氨基、羟基、C
1-4烷基、C
1-4烷氧基、C
2-4烯基、C
2-4炔基、-SF
5、-(CH
2)
r-C
3-6单环环烷基、-(CH
2)
r-C
5-10双环环烷基、-(CH
2)
r-(3-6元单环杂环烷 基)、-(CH
2)
r-(5-10元双环杂环烷基)、-O-C
3-6单环环烷基、-O-C
5-10双环环烷基、-O-(3-6元单环杂环烷基)、-O-(5-10元双环杂环烷基)、-NH-C
3-6单环环烷基、-NH-C
5-10双环环烷基、-NH-(3-6元单环杂环烷基)、-NH-(5-10元双环杂环烷基)、5至6元杂芳基、苯基、-C(=O)NR
xaaR
xab、-NR
xaaC(=O)-R
xab、-NR
xaaR
xab、-C(=O)-R
xaa,所述CH
2、烷基、烷氧基、环烷基、杂环烷基、杂芳基、芳基任选进一步被1至3个选自卤素、氘、硝基、氰基、氨基、羟基、=O、C
1-4烷基、C
1-4烷氧基、卤代C
1-4烷基、卤代C
1-4烷氧基、氘代C
1-4烷基、氘代C
1-4烷氧基的基团取代;
R
xa1、R
xb1各自独立选自氢、氘、氰基、羟基、C
1-4烷基、C
1-4烷氧基、C
2-4烯基、C
2-4炔基、-SF
5、-(CH
2)
r-C
3-6单环环烷基、-(CH
2)
r-C
5-10双环环烷基、-(CH
2)
r-(3-6元单环杂环烷基)、-(CH
2)
r-(5-10元双环杂环烷基)、5至6元杂芳基、苯基,所述CH
2、烷基、烷氧基、环烷基、杂环烷基、杂芳基、芳基任选进一步被1至3个选自卤素、氘、氰基、羟基、=O、C
1-4烷基、C
1-4烷氧基、卤代C
1-4烷基、卤代C
1-4烷氧基、氘代C
1-4烷基、氘代C
1-4烷氧基的基团取代;
R
xaa、R
xab各自独立选自氢、氘、氨基、羟基、C
1-4烷基、卤代C
1-4烷基、氘代C
1-4烷基、C
1-4烷氧基、卤代C
1-4烷氧基、氘代C
1-4烷氧基;
R
x1b、R
x2b、R
x7b各自独立选自H、氘、硝基、氰基、氨基、羟基、C
1-4烷基、C
1-4烷氧基、C
2-6烯基、C
2-6炔基、-SF
5,所述烷基、烷氧基任选进一步被1至3个选自F、Cl、氘、硝基、氰基、氨基、羟基、C
1-2烷基、C
1-2烷氧基、卤代C
1-2烷基、卤代C
1-2烷氧基、氘代C
1-2烷基、氘代C
1-2烷氧基的基团取代;
条件是,R
x1b、R
x2b、R
x7b不同时为H;
作为选择,当R
x1b、R
x2b、R
x7b同时选自H时,-L
12-R
712选自H;
作为选择,连接于同一碳原子上的R
xa和R
xb、R
xa1和R
xb1、R
ya和R
yb、R
za和R
zb、R
x4a和R
x4b、R
x5a和R
x5b,或R
x6a和R
x6b与所连接的碳原子一起形成3元环烷基、4元环烷基、5元环烷基、6元环烷基、3元杂环烷基、4元杂环烷基、5元杂环烷基或6元杂环烷基;
作为选择,连接于相邻碳原子上的R
xa和R
za与所连接的碳原子一起形成3元环烷基、4元环烷基、5元环烷基、6元环烷基、3元杂环烷基、4元杂环烷基、5元杂环烷基或6元杂环烷基;
作为选择,R
x4a与R
x6a一起形成-CH
2-或者-CH
2CH
2-;
L
1选自*-C(O)NR
La-、*-NR
LaC(O)-、*-NR
LaC(O)-(CH
2)
p-O-、*-O-(CH
2)
p-C(O)NR
La-、-NR
LaC(O)-NR
La-、-S-、*-S(O)
2NR
La-、*-NR
LaS(O)
2-,*代表L
1与R
71链接位点;
L
2选自-NR
La-、-C(O)-、-C(O)NR
La-**、-NR
LaC(O)-(CH
2)
p-O-**、-O-(CH
2)
p-C(O)NR
La-**、-NR
LaC(O)-NR
La-**、-S-、-S(O)
2NR
La-**、-NR
LaS(O)
2-**,**代表L
2与R
72链接位点;
L
3、L
5、L
6各自独立地选自键、-NR
La、-C(O)-、-C(O)NR
La-、-NR
LaC(O)-、-NR
LaC(O)-(CH
2)
p-O-、-O-(CH
2)
p-C(O)NR
La-、-NR
LaC(O)-NR
La-、-O-、-S-、-S(O)
2NR
La-、-NR
LaS(O)
2-;
L
7、L
8、L
9、L
10、L
11、L
12、L
13、L
14、L
15各自独立地选自-NR
La、-C(O)-、-C(O)NR
La-、-NR
LaC(O)-、-NR
LaC(O)-(CH
2)
p-O-、-O-(CH
2)
p-C(O)NR
La-、-NR
LaC(O)-NR
La-、-O-、-S-、-S(O)
2NR
La-、-NR
LaS(O)
2-;
R
La选自氢、氘、卤代C
1-4烷基、氘代C
1-4烷基;
R
71选自-(CH
2)
r-(4-12元杂环烷基)、-(CH
2)
r-C
3-12环烷基、-(CH
2)
r-(5-12元杂芳基)、-(CH
2)
r-(6-12元芳基),所述CH
2、环烷基、杂环烷基、杂芳基、芳基任选进一步被1至3个选自氘、卤素、硝基、氰基、氨基、羟基、C
1-4烷基、=O、C
1-4烷氧基、卤代C
1-4烷基、卤代C
1-4烷氧基、氘代C
1-4烷基、氘代C
1-4烷氧基、-C(=O)NR
cyaR
cyb、-NR
cyaC(=O)-R
cyb、-NR
cyaR
cyb、-C(=O)-R
cya、-S-C
1-4烷基、-S(O)-C
1-4烷基、-S(O)
2-C
1-4烷基的基团取代;或者
L
1选自-NR
La-,R
71选自5-12元杂芳基、-(CH
2)
r-(6-12元芳基),所述CH
2、杂芳基、芳基任选进一步被1至3个选自氘、卤素、硝基、氰基、氨基、羟基、C
1-4烷基、=O、C
1-4烷氧基、卤代C
1-4烷基、卤代C
1-4烷氧基、氘代C
1-4烷基、氘代C
1-4烷氧基、-C(=O)NR
cyaR
cyb、-NR
cyaC(=O)-R
cyb、-NR
cyaR
cyb、-C(=O)-R
cya、-S-C
1-4烷基、-S(O)-C
1-4烷基、-S(O)
2-C
1-4烷基的基团取代;
R
72选自C
2-6烯基、-SF
5、-(CH
2)
r-C
3-12环烷基、-(CH
2)
r-(4-12元杂环烷基)、5-12元杂芳基、6-12元芳基,所述CH
2、环烷基、杂环烷基、杂芳基、芳基任选进一步被1至5个选自氘、卤素、硝基、氰基、氨基、羟基、C
1-6烷基、=O、C
1-6烷氧基、C
2-6烯基、C
2-6炔基、卤代C
1-6烷基、卤代C
1-6烷氧基、氘代C
1-6烷基、氘代C
1-6烷氧基、-(CH
2)
r-C
3-8环烷基、-(CH
2)
r-(3-8元杂环烷基)、-O-C
3-8环烷基、-O-(3-8元杂环烷基)、-NH-C
3-8环烷基、-NH-(3-8元杂环烷基)、-S-C
3-8环烷基、-S-(3-8元杂环烷基)、5至8元杂芳基、6至8元芳基、-C(=O)NR
cyaR
cyb、-NR
cyaC(=O)-R
cyb、-NR
cyaR
cyb、-C(=O)-R
cya、-S-C
1-6烷基、-S(O)-C
1-6烷基、-S(O)
2-C
1-6烷基的基团取代;
条件是,当L
2选自-NH-,R
72选自-(CH
2)
r-4-12元杂环烷基、6-12元芳基或-(CH
2)
r-C
3-12环烷基时,满足以下条件之一:m不为0,或者X
12、X
32之一选自N,或者R
x2a、R
x3a不同时为H;或者
L
2选自-NR
LaC(O)-**,R
72选自C
2-6烯基、-SF
5、-(CH
2)
r-C
3-12环烷基、-(CH
2)
r-(4-12元饱和杂环烷基)、6-12元芳基,所述CH
2、环烷基、杂环烷基、芳基任选进一步被1至5个选自氘、卤素、硝基、氰基、氨基、羟基、C
1-6烷基、=O、C
1-6烷氧基、C
2-6烯基、C
2-6炔基、卤代C
1-6烷基、卤代C
1-6烷氧基、氘代C
1-6烷基、氘代C
1-6烷氧基、-(CH
2)
r-C
3-8环烷基、-(CH
2)
r-(3-8元杂环烷基)、-O-C
3-8环烷基、-O-(3-8元杂环烷基)、-NH-C
3-8环烷基、-NH-(3-8元杂环烷基)、-S-C
3-8环烷基、-S-(3-8元杂环烷基)、5至8元杂芳基、6至8元芳基、-C(=O)NR
cyaR
cyb、-NR
cyaC(=O)-R
cyb、-NR
cyaR
cyb、-C(=O)-R
cya、-S-C
1-6烷基、-S(O)-C
1-6烷基、-S(O)
2-C
1-6烷基的基团取代;
作为选择,-L
2-R
72选自CN、-C(O)N(C
1-4烷基)
2、5元杂芳基、7-12元杂芳基,所述的杂芳基任选进一步被1至3个氘、卤素、羟基、氨基、氰基、C
1-4烷基、=O、C
1-4烷氧基、C
3-6环烷基、4-8元杂环烷基、-C(=O)NR
cyaR
cyb、-NR
cyaC(=O)-R
cyb、-NR
cyaR
cyb、-C(=O)-R
cya的基团取代;
R
73、R
75、R
76、R
77、R
78、R
79、R
710、R
711、R
712、R
713、R
714、R
715各自独立地选自氘、卤素、C
1-6烷基、C
1-6烷氧基、C
2-6烯基、C
2-6炔基、-SF
5、-(CH
2)
r-C
3-12环烷基、-(CH
2)
r-(4-12元杂环烷基)、-(CH
2)
r-(5-12元杂芳基)、-(CH
2)
r-(6-12元芳基),所述CH
2、烷基、烷氧基、环烷基、杂环烷基、杂芳基、芳基任选进一步被1至5个选自R
f的基团取代;
作为选择,-L
7-R
77、-L
13-R
713各自独立地选自卤素、5-12元杂芳基,所述的杂芳基任选进一步被1-5个选自R
f的基团取代;
作为选择,-L
8-R
78、-L
9-R
79、-L
10-R
710、-L
11-R
711各自独立地选自SF
5、-(CH
2)
r-C
3-12环烷基、-(CH
2)
r-(4-12元杂环烷基)、-(CH
2)
r-(5-12元杂芳基)、-(CH
2)
r-(6-12元芳基),所述CH
2、环烷基、杂环烷基、杂芳基、芳基任选进一步被1至5个选自R
f的基团取代;
每个R
f各自独立地选自氘、卤素、硝基、氰基、氨基、羟基、C
1-6烷基、=O、C
1-6烷氧基、C
2-6烯基、C
2-6炔基、卤代C
1-6烷基、卤代C
1-6烷氧基、氘代C
1-6烷基、氘代C
1-6烷氧基、-SF
5、-(CH
2)
r-C
3-8环烷基、-(CH
2)
r-(3-8元杂环烷基)、-O-C
3-8环烷基、-O-(3-8元杂环烷基)、-NH-C
3-8环烷基、-NH-(3-8元杂环烷基)、-S-C
3-8环烷基、-S-(3-8元杂环烷基)、5至8元杂芳基、6至8元芳基、-C(=O)NR
cyaR
cyb、-NR
cyaC(=O)-R
cyb、-NR
cyaR
cyb、-C(=O)-R
cya、-S-C
1-6烷基、-S(O)-C
1-6烷基、-S(O)
2-C
1-6烷基;
R
cya、R
cyb各自独立选自C
1-6烷基、卤代C
1-6烷基、氘代C
1-6烷基;
其他基团与前文任一技术方案所述一致。
另一技术方案中,本发明所述的化合物,其立体异构体、氘代物、溶剂化物、前药、代谢产物、药学上可接受的盐或共晶,其中,
R
11、R
12、R
13、R
15、R
17、R
18、R
19、R
110、R
111、R
112、R
113、R
114、R
115、R
21、R
22、R
23、R
25、R
27、R
28、R
29、R
210、R
211、R
212、R
213、R
214、R
215、R
31、R
32、R
33、R
35、R
36、R
37、R
38、R
39、R
310、R
311、R
312、R
313、R
314、R
315、R
41、R
42、R
43、R
45、R
46、R
47、R
48、R
49、R
410、R
411、R
412、R
413、R
414、R
415各自独立地选自氢、氘、C
1-4烷基,所述烷基任选被1至3个选自卤素、氘的基团取代;
作为选择,连接于同一碳原子上的R
11和R
21、R
31和R
41、R
12和R
22、R
32和R
42、R
13和R
23、R
33和R
43、R
15和R
25、R
35和R
45、R
36和R
46、R
17和R
27、R
37和R
47、R
18和R
28、R
38和R
48、R
19和R
29、R
39和R
49、R
110和R
210、R
310和R
410、R
111和R
211、R
311和R
411、R
112和R
212、R
312和R
412、R
112和R
213、R
313和R
413、R
114和R
214、R
314和R
414、R
115和R
215,或者R
315和R
415分别各自独立地与所连接的碳原子一起形成3元环烷基、4元环烷基、5元环烷基、4元杂环烷基、5元杂环烷基或6元杂环烷基;
R
51、R
52、R
53、R
55、R
56、R
57、R
58、R
59、R
510、R
511、R
512、R
513、R
514、R
515各自独立地选自氢、氘、C
1-4烷基,所述烷基任选被1至3个选自卤素、氘的基团取代;
R
81、R
82、R
83、R
85、R
86、R
87、R
88、R
89、R
810、R
811、R
812、R
813、R
814、R
815各自独立地选自氢、氘;
连接于同一碳原子上R
9a1和R
9b1、R
9a2和R
9b2与所连接的碳原子一起形成3元环烷基、4元环烷基、5元环烷基、6元环烷基、4元杂环烷基、5元杂环烷基或6元杂环烷基;或者
R
9a1和R
9a2相链接形成-CH
2-;
R
61、R
63、R
65、R
66、R
67、R
68、R
69、R
610、R
611、R
612、R
613、R
614、R
615、R
616、R
617各自独立地选自氘、卤素、羟基、C
1-4烷基、C
1-4烷氧基、-(CH
2)
r-C
3-8环烷基、-(CH
2)
r-(3-8元杂环烷基)、5至8元杂芳基、6至8元芳基、-C(=O)NR
6aR
6b、-NR
6aC(=O)-R
6b、-NR
6aR
6b、-C(=O)-R
6a,所述CH
2、烷基、烷氧基、环烷基、杂环烷基、杂芳基、芳基任选进一步被1至3个选自卤素、氘、C
1-4烷基的基团取代;
R
62为氘、卤素、-(CH
2)
r-C
3-8环烷基、-(CH
2)
r-(3-8元杂环烷基)、-C(=O)NR
6aR
6b、-NR
6aC(=O)-R
6b、-NR
6aR
6b、-C(=O)-R
6a,所述CH
2、环烷基、杂环烷基任选进一步被1至3个选自卤素、氘、=O、C
1-4烷基、C
1-4烷氧基的基团取代;
R
6a选自氢、氘、C
1-4烷基、C
3-8环烷基、3-8元杂环烷基,所述烷基、环烷基、杂环烷基任选被1至3个选自卤素、氘、C
1-4烷氧基的基团取代;
R
6b选自氢、氘、C
1-4烷基、C
1-4烷氧基、C
3-8环烷基、3-8元杂环烷基,所述的烷基、烷氧基、环烷基、杂环烷基任选被1至3个选自卤素、氘、C
1-4烷基、C
1-4烷氧基的基团取代;
X
81、X
83、X
86、X
88、X
89、X
810、X
811、X
813、X
814、X
815各自独立地选自-O-、-S-、-CR
xaR
xb-或者-NR
xa-;
X
87选自-O-、-CR
xaR
xb-或者-NR
xa-;
X
812选自-O-、-S-、-CR
xa2R
xb2-或者-NR
xa-;
X
82选自-O-、-S-、-CR
xa1R
xb1-或者-NR
xa-;
Y
1、Y
2、Y
3、Y
4、Y
5、Y
6各自独立地选自键、-CR
yaR
yb-或者-NR
ya-;
Z
1、Z
2、Z
3、Z
4、Z
5、Z
6各自独立地选自键、-CR
zaR
zb-或者-NR
za-;
X
41、X
42、X
43、X
44各自独立地选自-CR
x4aR
x4b-或者-NR
x4a-;
X
51、X
52、X
53、X
54各自独立地选自-CR
x5aR
x5b-或者-NR
x5a-;
X
61、X
62、X
63、X
64各自独立地选自键、-CR
x6aR
x6b-或者-NR
x6a-;
X
11、X
12、X
13、X
15、X
16、X
17、X
18、X
19、X
110、X
113、X
114、X
115各自独立地选自-CR
x1a-或者-N-;
X
21、X
22、X
23、X
25、X
26、X
27、X
28、X
29、X
211、X
213、X
214、X
215各自独立地选自-CR
x2a-或者-N-;
X
31、X
32、X
33、X
35、X
36、X
37、X
38、X
39、X
310、X
311各自独立地选自-CR
x3a-或者-N-;
X
710、X
711、X
713、X
714、X
715各自独立地选自-CR
x7a-或者-N-;
X
112选自-CR
x1b-;
X
212选自-CR
x2b-;
X
712选自-CR
x7b-;
R
x1a、R
x2a、R
x3a、R
x7a各自独立选自氢、氘、卤素、C
1-4烷基、C
1-4烷氧基,所述烷基、烷氧基任选进一步被1至3个选自F、Cl、氘、羟基、C
1-2烷基、C
1-2烷氧基的基团取代;
R
xa、R
xb、R
xa2、R
xb2、R
ya、R
yb、R
za、R
zb、R
x4a、R
x4b、R
x5a、R
x5b、R
x6a、R
x6b各自独立选自氢、氘、卤素、C
1-4烷基、C
1-4烷氧基、-(CH
2)
r-C
3-6单环环烷基、-(CH
2)
r-C
5-10双环环烷基、-(CH
2)
r-(3-6元单环杂环烷基)、-(CH
2)
r-(5-10元双环杂环烷基)、5至6元杂芳基、苯基、-C(=O)NR
xaaR
xab、-NR
xaaC(=O)-R
xab、-NR
xaaR
xab、-C(=O)-R
xaa,所述CH
2、烷基、烷氧基、环烷基、杂环烷基、杂芳基、芳基任选进一步被1至3个选自卤素、氘、C
1-4烷基、C
1-
4烷氧基的基团取代;
R
xa1、R
xb1各自独立选自氢、氘、C
1-4烷基、C
1-4烷氧基、-(CH
2)
r-C
3-6单环环烷基、-(CH
2)
r-C
5-10双环环烷基、-(CH
2)
r-(3-6元单环杂环烷基)、-(CH
2)
r-(5-10元双环杂环烷基)、5至6元杂芳基、苯基,所述CH
2、烷基、烷氧基、环烷基、杂环烷基、杂芳基、芳基任选进一步被1至3个选自卤素、氘、C
1-4烷基、C
1-4烷氧基的基团取代;
R
xaa、R
xab各自独立选自氢、氘、C
1-4烷基;
R
x1b、R
x2b、R
x7b各自独立选自H、氘、羟基、氰基、C
1-4烷基、C
1-4烷氧基,所述烷基、烷氧基任选进一步被1至3个选自F、Cl、氘、羟基、C
1-2烷基、C
1-2烷氧基的基团取代;
条件是,R
x1b、R
x2b、R
x7b不同时为H;
作为选择,当R
x1b、R
x2b、R
x7b同时选自H时,-L
12-R
712选自H;
作为选择,连接于同一碳原子上的R
xa和R
xb、R
xa1和R
xb1、R
ya和R
yb、R
za和R
zb、R
x4a和R
x4b、R
x5a和R
x5b,或R
x6a和R
x6b与所连接的碳原子一起形成3元环烷基、4元环烷基、5元环烷基、4元杂环烷基、5元杂环烷基或6元杂环烷基;
作为选择,连接于相邻碳原子上的R
xa和R
za与所连接的碳原子一起形成3元环烷基、4元环烷基、5元环烷基、6元环烷基、3元杂环烷基、4元杂环烷基、5元杂环烷基或6元杂环烷基;
作为选择,R
x4a与R
x6a一起形成-CH
2-或者-CH
2CH
2-;
其他基团与前文任一技术方案所述一致。
另一技术方案中,本发明所述的化合物,其立体异构体、氘代物、溶剂化物、前药、代谢产物、药学上可接受的盐或共晶,所述化合物具有式(III-1)、(III-2)、(III-3)、(III-5)、(III-6)、(III-7)、(III-8)、(III-9)结构:
E环为3元环烷基、4元环烷基、5元环烷基、6元环烷基、3元杂环烷基、4元杂环烷基、5元杂环烷基或6元杂环烷基;
H环为3元环烷基、4元环烷基、5元环烷基、6元环烷基、3元杂环烷基、4元杂环烷基、5元杂环烷基或6元杂环烷基;
R
52选自氢、氘、C
1-4烷基,所述烷基任选被1至3个选自卤素、氘的基团取代;
连接于同一碳原子上R
9a1和R
9b1、R
9a2和R
9b2与所连接的碳原子一起形成3元环烷基、4元环烷基、5元环烷基、4元杂环烷基、5元杂环烷基或6元杂环烷基;或者
R
9a1和R
9a2相链接形成-CH
2-;
R
69选自氘、卤素、羟基、C
1-4烷基、C
1-4烷氧基,所述烷基、烷氧基任选进一步被1至3个选自卤素、氘、羟基的基团取代;
R
62选自氘、卤素、C
3-6环烷基、3-5元杂环烷基、-C(=O)NR
6aR
6b、-NHC(=O)-R
6b、-NR
6aR
6b、-C(=O)-R
6a,所述环烷基、杂环烷基任选进一步被1至3个选自卤素、氘、=O、C
1-4烷基的基团取代;
R
6a选自氢、氘、C
1-4烷基,所述烷基任选被1至3个选自卤素、氘的基团取代;
R
6b选自氢、氘、C
1-4烷基,所述的烷基任选被1至3个选自卤素、氘的基团取代;
X
81、X
87、X
88、X
89各自独立地选自-O-、-CR
xaR
xb-或者-NR
xa-;
X
82选自-O-、-CR
xa1R
xb1-或者-NR
xa-;
X
12选自-CR
x1a-或者-N-;
X
22选自-CR
x2a-或者-N-;
X
32选自-CR
x3a-或者-N-;
R
x1a、R
x2a、R
x3a各自独立地选自氢、氘、卤素、C
1-4烷基、C
1-4烷氧基,所述烷基、烷氧基任选进一步被1至3个选自F、Cl、氘的基团取代;
R
xa、R
xb各自独立地选自氢、氘、卤素、C
1-4烷基、C
1-4烷氧基,所述烷基、烷氧基任选进一步被1至3个选自F、Cl、氘的基团取代;
R
xa1、R
xb1各自独立地选自氢、氘、C
1-4烷基、C
1-4烷氧基,所述烷基、烷氧基任选进一步被1至3个选自F、Cl、氘的基团取代;
作为选择,连接于同一碳原子上的R
xa和R
xb与所连接的碳原子一起形成3元环烷基、4元环烷基、5元环烷基、3元杂环烷基、4元杂环烷基、5元杂环烷基;
L
1选自-NR
La、*-C(O)NR
La-、*-NR
LaC(O)-,*代表L
1与R
71链接位点;
L
2选自-NR
La、-C(O)-、-C(O)NR
La-**、-NR
LaC(O)-(CH
2)
p-O-**、-O-(CH
2)
p-C(O)NR
La-**,**表示L
2与R
72的连接位点;
L
3、L
5、L
6各自独立地选自键、-NR
La、-C(O)-、-C(O)NR
La-、-NR
LaC(O)-;
L
7、L
8、L
9各自独立地选自-NR
La、-C(O)-、-C(O)NR
La-、-NR
LaC(O)-;
R
La选自氢、氘、C
1-4烷基;
R
71选自5元杂芳基或6元杂芳基,所述杂芳基任选进一步被1至3个选自氘、卤素、C
1-4烷基的基团取代;
R
72选自C
3-6环烷基、5-8元单环杂环烷基、6-12元双环杂环烷基、5-8元杂芳基、6-9元芳基,所述环烷基、杂环烷基、杂芳基、芳基任选进一步被1至3个选自氘、卤素、羟基、氨基、氰基、C
1-4烷基、=O、C
1-4烷氧基、卤代C
1-4烷氧基、C
3-6环烷基、4-8元杂环烷基、-C(=O)NR
cyaR
cyb、-NR
cyaC(=O)-R
cyb、-NR
cyaR
cyb、-C(=O)-R
cya的基团取代;
条件是,当L
2选自-NH-,R
72选自-(CH
2)
r-4-12元杂环烷基、6-12元芳基或-(CH
2)
r-C
3-12环烷基时,满足以下条件之一:m不为0,或者X
12、X
32之一选自N,或者R
x2a、R
x3a不同时为H;或者
L
2选自-NR
LaC(O)-**,R
72选自C
3-6环烷基、5-8元单环杂环烷基、6-12元双环杂环烷基、6-9元芳基,所述环烷基、杂环烷基、芳基任选进一步被1至3个选自氘、卤素、氰基、氨基、羟基、C
1-4烷基、=O、C
1-4烷氧基、C
3-6环烷基、4-8元杂环烷基、-C(=O)-R
cya的基团取代;
作为选择,-L
2-R
72选自CN、-C(O)N(C
1-4烷基)
2、5元杂芳基,所述的杂芳基任选进一步被1至3个氘、卤素、C
1-4烷基、C
3-6环烷基、4-8元杂环烷基、-C(=O)NR
cyaR
cyb、-NR
cyaC(=O)-R
cyb、-NR
cyaR
cyb、-C(=O)-R
cya的基团取代;
R
73、R
75、R
76、R
77、R
78、R
79各自独立地选自氘、卤素、C
1-4烷基、C
1-4烷氧基、C
3-6环烷基、5-8元单环杂环烷基、6-12元双环杂环烷基、5-8元杂芳基、6-9元芳基,所述烷基、烷氧基、环烷基、杂环烷基、杂芳基、芳基任选进一步被1至3个选自R
f的基团取代;
作为选择,-L
7-R
77各自独立地选自卤素、5-9元杂芳基,所述的杂芳基任选进一步被1-3个选自R
f的基团取代;
作为选择,-L
8-R
78、-L
9-R
79各自独立地选自C
3-6环烷基、5-8元单环杂环烷基、6-12元双环杂环烷基、5-8元杂芳基、6-9元芳基,所述环烷基、杂环烷基、杂芳基、芳基任选进一步被1至3个选自R
f的基团取代;
每个R
f各自独立地选自氘、卤素、氰基、氨基、羟基、C
1-4烷基、=O、C
1-4烷氧基、C
3-6环烷基、3-8元杂环烷基、5至8元杂芳基、6至8元芳基、-C(=O)NR
cyaR
cyb、-NR
cyaC(=O)-R
cyb、-NR
cyaR
cyb、-C(=O)-R
cya;
R
cya、R
cyb各自独立选自C
1-4烷基、卤代C
1-4烷基、氘代C
1-4烷基;
其他基团与前文任一技术方案所述一致。
另一技术方案中,本发明所述的化合物,其立体异构体、氘代物、溶剂化物、前药、代谢产物、药学上可接受的盐或共晶,所述化合物具有式(III-1)、(III-2)、(III-3)、(III-5)、(III-6)、(III-7)、(III-8)、(III-9)结构:其中
m选自0、1或2;
R
62选自氘、卤素、环丙基、环丁基、环戊基、环己基、氮杂环丁基、氮杂环戊基、氮杂环己基、氧杂环丁基、氧杂环戊基、氧杂环己基、-C(O)NHCH
3、-NHC(O)CH
3、-N(CH
3)C(O)CH
3、-NHC(O)CH
2CH
3、-N(CH
3)C(O)CH
2CH
3、-NH
2、-NHCH
3、-C(O)CH3、-C(O)CH
2CH
3,以上基团选进一步被1、2、3个选自F、氘的基团取代;
R
69选自氘、F、Cl、Br、甲基、乙基、丙基,甲基、乙基、丙基任选进一步被1、2、3个选自F、氘的基团取代;
其他基团与前文任一技术方案所述一致。
另一技术方案中,本发明所述的化合物,其立体异构体、氘代物、溶剂化物、前药、代谢产物、药学上可接受的盐或共晶,所述化合物具有式(IV-1)结构:
L
10选自-NR
La、-C(O)-、-C(O)NR
La-、-NR
LaC(O)-;
R
La选自氢、氘;
R
710选自卤素、C
1-4烷基、C
1-4烷氧基、C
3-6环烷基、5-8元单环杂环烷基、6-12元双环杂环烷基、5-8元杂芳基、6-9元芳基,所述环烷基、杂环烷基、杂芳基、芳基任选进一步被1至3个选自R
f的基团取代;
作为选择,-L
10-R
710选自C
3-6环烷基、5-8元单环杂环烷基、6-12元双环杂环烷基、5-8元杂芳基、6-9元芳基,所述环烷基、杂环烷基、杂芳基、芳基任选进一步被1至3个选自R
f的基团取代;
每个R
f各自独立地选自氘、卤素、C
1-4烷基、=O的基团取代;
其他基团与前文任一技术方案所述一致。
另一技术方案中,本发明所述的化合物,其立体异构体、氘代物、溶剂化物、前药、代谢产物、药学上可接受的盐或共晶,所述化合物具有式(V-1)结构:
L
11选自-NR
La、-C(O)-、-C(O)NR
La-、-NR
LaC(O)-;
R
La选自氢、氘;
R
711选自卤素、C
1-4烷基、C
1-4烷氧基、C
3-6环烷基、-(CH
2)
0-2-5-8元单环杂环烷基、6-12元双环杂环烷基、5-8元杂芳基、6-9元芳基,所述环烷基、杂环烷基、杂芳基、芳基任选进一步被1至3个选自氘、卤素、C
1-4烷基、=O、-C(=O)NR
cyaR
cyb、-NR
cyaC(=O)-R
cyb、-NR
cyaR
cyb、-C(=O)-R
cya的基团取代;
R
cya、R
cyb各自独立选自甲基、乙基、丙基、丁基、-CH
2F、-CH
2CH
2F、-CHF
2、-CF
3、-CH
2CHF
2、-CH
2CHF
3、-CH
2D、-CH
2CH
2D、-CHD
2、-CD
3、-CH
2CHD
2、-CH
2CHD
3;
其他基团与前文任一技术方案所述一致。
另一技术方案中,本发明所述化合物,其立体异构体、氘代物、溶剂化物、前药、代谢产物、药学上可接受的盐或共晶,所述化合物具有式(VI-1)、(VI-2)、(VI-3)、(VI-4)、(VI-5)结构:
X
812选自-O-、-CR
xa2R
xb2-或者-NR
xa-;
X
813、X
814、X
815各自独立地选自-O-、-CR
xaR
xb-或者-NR
xa-;
X
112选自-CR
x1b-;
X
212选自-CR
x2b-;
X
712选自-CR
x7b-;
R
xa、R
xb、R
xa2、R
xb2各自独立选自氢、氘、卤素、C
1-4烷基、C
1-4烷氧基,所述烷基、烷氧基任选进一步被1至3个选自卤素、氘的基团取代;
R
x1b、R
x2b、R
x7b各自独立选自H、氘、羟基、氰基、C
1-4烷基、C
1-4烷氧基,所述烷基、烷氧基任选进一步被1至3个选自F、Cl、氘、羟基的基团取代;
条件是,R
x1b、R
x2b、R
x7b不同时选自H;
作为选择,当R
x1b、R
x2b、R
x7b同时选自H时,-L
12-R
712选自H;
作为选择,连接于同一碳原子上的R
xa和R
xb与所连接的碳原子一起形成3元环烷基、4元环烷基、5元环烷基、4元杂环烷基、5元杂环烷基或6元杂环烷基;
L
12、L
13、L
14、L
15各自独立地选自-NR
La、-C(O)-、-C(O)NR
La-、-NR
LaC(O)-;
R
La选自氢、氘;
R
712、R
713、R
714、R
715各自独立地选自H、氘、卤素、C
1-6烷基、C
1-6烷氧基、C
3-6环烷基、5-8元单环杂环烷基、6-12元双环杂环烷基、5-8元杂芳基、6-9元芳基,所述烷基、烷氧基、环烷基、杂环烷基、杂芳基、芳基任选进一步被1至3个选自R
f的基团取代;
作为选择,-L
13-R
713选自F、Cl、5-8元杂芳基,所述杂芳基任选进一步被1至3个选自R
f的基团取代;
每个R
f各自独立地选自氘、卤素、羟基、C
1-6烷基、=O、C
1-6烷氧基、C
3-8环烷基、3-8元杂环烷基、-C(=O)NR
cyaR
cyb、-NR
cyaC(=O)-R
cyb、-NR
cyaR
cyb、-C(=O)-R
cya;
R
cya、R
cyb各自独立选自甲基、乙基、丙基、丁基、-CH
2F、-CH
2CH
2F、-CHF
2、-CF
3、-CH
2CHF
2、-CH
2CHF
3、-CH
2D、-CH
2CH
2D、-CHD
2、-CD
3、-CH
2CHD
2、-CH
2CHD
3;
其他基团与前文任一技术方案所述一致。
另一技术方案中,本发明所述的化合物,其立体异构体、氘代物、溶剂化物、前药、代谢产物、药学上可接受的盐或共晶,其中
其他基团与前文任一技术方案所述一致。
在一些技术方案中,本发明的化合物,其立体异构体、氘代物、溶剂化物、前药、代谢产物、药学上可接受的盐或共晶,其中化合物选自具有式(Ⅶ-1)、式(Ⅶ-2)结构中的任意一种,
X
82选自-CR
xa1R
xb1-,R
xa1、R
xb1各自独立选自氢、氘、卤素、C
1-4烷基组成的组中的任意一种,作为选择烷基任选进一步被1至3个选自卤素、氘的基团取代,R
xa1、R
xb1能够与二者所连接的碳原子一起形成3元至5元环烷基,优选地R
xa1、R
xb1与二者所连接的碳原子形成3元环烷基;
X
12选自-CR
x1a-,X
32选自-CR
x3a-;
R
x1a、R
x3a各自独立选自氢、氘、卤素、C
1-4烷基组成的组中的任意一种;
L
2为-C(O)-,R
72选自-NR
cyaR
cyb、4-12元杂环烷基、6-12元芳基,杂环烷基、6-12元芳基任选进一步被1至3个选自卤素、氘、氰基、C
1-4烷氧基、卤代C
1-4烷氧基、氘代C
1-4烷氧基、=O、-C(=O)-R
cya的基团取代,R
cya、R
cyb各自独立选自C
1-2烷基、卤代C
1-2烷基、氘代C
1-2烷基;或者
L
2为-NH-、-C(O)NR
La-**,**代表L
2与R
72链接位点,R
72选自C
3-12环烷基、4-12元杂环烷基、5-12元杂芳基、6-12元芳基,环烷基、杂环烷基、杂芳基、芳基任选进一步被1 至3个选自氘、卤素、硝基、氰基、=O、-C(=O)-R
cya的基团取代,R
cya选自C
1-2烷基、卤代C
1-2烷基、氘代C
1-2烷基;或者
L
2为-NR
LaC(O)-**,**代表L
2与R
72链接位点,R
72选自C
3-12环烷基、4-12元饱和杂环烷基,环烷基、饱和杂环烷基任选进一步被1至3个选自氘、卤素、硝基、氰基、=O、-C(=O)-R
cya的基团取代,R
cya选自C
1-2烷基、卤代C
1-2烷基、氘代C
1-2烷基;
作为选择,-L
2-R
72选自H或者CN;
条件是,当L
2选自-NH-,R
x3a不为H;
X
715选自-CR
x7a-或者-N-,R
x7a选自氢、氘、卤素;
X
815选自-O-或者-CR
xaR
xb-;R
xa、R
xb各自独立选自氢、氘、卤素、C
1-4烷基组成的组中的任意一种,烷基任选进一步被1至3个选自卤素、氘的基团取代,R
xa、R
xb能够与二者所连接的碳原子一起形成3元至5元环烷基,优选地R
xa、R
xb与二者所连接的碳原子一起形成3元环烷基或4元环烷基;
Z
6选自键或者-CR
zaR
zb-,R
za、R
zb各自独立选自氢;
L
15选自-NR
La、-C(O)-、-C(O)NR
La-、-NR
LaC(O)-;
R
715选自4-12元杂环烷基、5-12元杂芳基,杂环烷基、杂芳基任选进一步被1至3个选自C
1-2烷基、=O、C
1-2烷氧基、卤代C
1-2烷基、卤代C
1-2烷氧基、氘代C
1-2烷基、氘代C
1-2烷氧基、-NR
cyaR
cyb、-C(=O)-R
cya的基团取代,R
cya、R
cyb各自独立选自C
1-2烷基、卤代C
1-2烷基、氘代C
1-2烷基。
在一些技术方案中,本发明所述的化合物,其立体异构体、氘代物、溶剂化物、前药、代谢产物、药学上可接受的盐或共晶,其中
L
2为
R
72为-NR
cyaR
cyb、
组成的组中的任意一种,其中R’选自氢、氘、卤素和C
1-4烷基组成的组中的任意一种,作为选择烷基任选进一步被1至3个选自卤素、氘的基团取代,作为选择,R’为H、氘、甲基、乙基、丙基、丁基、-CH
2F、-CH
2CH
2F、-CHF
2、-CF
3组成的组中的任意一种;作为选择R’为甲基、乙基、-CH
2F、-CHF
2、-CF
3;R
cya、R
cyb各自独立地为H、氘、甲基、乙基、丙基、丁基、-CH
2F、-CH
2CH
2F、-CHF
2、-CF
3、-CH
2CHF
2、-CH
2CHF
3、-CH
2D、-CH
2CH
2D、-CHD
2、-CD
3、-CH
2CHD
2、-CH
2CHD
3组成的组中的任意一种,作为选择R
cya、R
cyb各自独立地为甲基、乙基、-CH
2F、-CHF
2、-CF
3;
R
xa1、R
xb1各自独立选自氢、氘、卤素、C
1-4烷基组成的组中的任意一种,作为选择烷基任选进一步被1至3个选自卤素、氘的基团取代,R
xa、R
xb能够与二者所连接的碳原子一起形成3元至5元环烷基,优选地R
xa、R
xb与二者所连接的碳原子形成3元环烷基;
-X
815-Z
6-为-O-CR
xaR
xb-或-CR
xaR
xb-,R
xa、R
xb各自独立选自氢、氘、卤素、C
1-4烷基组成的组中的任意一种,烷基任选进一步被1至3个选自卤素、氘的基团取代,R
xa、R
xb能够与二者所连接的碳原子一起形成3元至5元环烷基,优选地R
xa、R
xb与二者所连接的碳原子一起形成3元环烷基或4元环烷基;
在一些技术方案中,本发明所述的化合物,其立体异构体、氘代物、溶剂化物、前药、代谢产物、药学上可接受的盐或共晶,其中
上述式(VII-1)中,X
82为-CH
2-、C(CH
3)
2或环丙基,X
12选自-CH-,X
32选自-CH-;L
2为
R
72为N(R
cyaR
cyb)、
组成的组中的任意一种,R
cya、R
cyb各自独立地为甲基、乙基、-CH
2F、-CHF
2、-CF
3;
在一些技术方案中,本发明所述的化合物,其立体异构体、氘代物、溶剂化物、前药、代谢产物、药学上可接受的盐或共晶,其中
在一些技术方案中,本发明的化合物,其立体异构体、氘代物、溶剂化物、前药、代谢产物、药学上可接受的盐或共晶,其中所述化合物选自具有式(Ⅶ-3)、式(Ⅶ-4)结构中的任意一种
其中,X
818为-CR
xaR
xb-,R
xa、R
xb各自独立选自氢、氘、卤素、C
1-4烷基组成的组中的任意一种,所述烷基任选进一步被1至3个选自卤素、氘的基团取代,所述R
xa、R
xb能够与二者所连接的碳原子一起形成3元至5元环烷基,优选地所述R
xa、R
xb与二者所连接的碳原子一起形成3元环烷基或4元环烷基;
本发明所述的化合物,其立体异构体、氘代物、溶剂化物、前药、代谢产物、药学上可接受的盐或共晶,其中所述化合物选自以下结构:
本发明所述的化合物,其立体异构体、氘代物、溶剂化物、前药、代谢产物、药学上可接受的盐或共晶,其中所述化合物选自以下结构:
本发明还提供一种药物组合物,其特征在于,含有前文所述的任一技术方案所述的化合物,其立体异构体、氘代物、溶剂化物、前药、代谢产物、药学上可接受的盐或共晶,以及药学上可接受的载体和/或赋形剂。
本发明还涉及前文所述的任一技术方案所述的化合物,其立体异构体、氘代物、溶剂化物、前药、代谢产物、药学上可接受的盐或共晶,或者组合物,在制备治疗PRMT5介导的疾病的药物中的应用;所述PRMT5介导的疾病为肿瘤。
合成路线
本领域技术人员可以结合WO2019173804A1文献以及已知的有机合成技术制备本发明的化合物,其起始原料为市售化学品和(或)化学文献中所述的化合物。“市售化学品”是从正规商业来源获得的,供应商包括:泰坦科技、安耐吉化学、上海德默、成都科龙化工、韶远化学科技、南京药石、药明康德和百灵威科技等公司。
本领域的参考书和专著,详细介绍了可用于制备本文所述化合物的反应物的合成,或提供了描述该制备方法的文章以供参考。这些参考书和专著包括:“Synthetic Organic Chemistry”,John Wiley&Sons,Inc.,New York;S.R.Sandler et al.,“Organic Functional Group Preparations,”2nd Ed.,Academic Press,New York,1983;H.O.House,“Modern Synthetic Reactions”,2nd Ed.,W.A.Benjamin,Inc.Menlo Park,Calif.1972;T.L.Gilchrist,“Heterocyclic Chemistry”,2nd Ed.,John Wiley&Sons,New York,1992;J.March,“Advanced Organic Chemistry:Reactions,Mechanisms and Structure”,4th Ed.,Wiley-Interscience,New York,1992;Fuhrhop,J.and Penzlin G.“Organic Synthesis:Concepts,Methods,Starting Materials”,Second,Revised and Enlarged Edition(1994)John Wiley&Sons ISBN:3-527-29074-5;Hoffman,R.V.“Organic Chemistry,An Intermediate Text”(1996)Oxford University Press,ISBN 0-19-509618-5;Larock,R.C.“Comprehensive Organic Transformations:A Guide to Functional Group Preparations”2nd Edition(1999)Wiley-VCH,ISBN:0-471-19031-4;March,J.“Advanced Organic Chemistry:Reactions,Mechanisms,and Structure”4th Edition(1992)John Wiley&Sons,ISBN:0-471-60180-2;Otera,J.(editor)“Modern Carbonyl Chemistry”(2000)Wiley-VCH,ISBN:3-527-29871-1;Patai,S.“Patai’s 1992Guide to the Chemistry of Functional Groups”(1992)Interscience ISBN:0-471-93022-9;Solomons,T.W.G.“Organic Chemistry”7th Edition(2000)John Wiley&Sons,ISBN:0-471-19095-0;Stowell,J.C.,“Intermediate Organic Chemistry”2nd Edition(1993)Wiley-Interscience,ISBN:0-471-57456-2;“Industrial Organic Chemicals:Starting Materials and Intermediates:An Ullmann’s Encyclopedia”(1999)John Wiley&Sons,ISBN:3-527-29645-X,in 8 volumes;“Organic Reactions”(1942-2000)John Wiley&Sons,in over 55 volumes;and“Chemistry of Functional Groups”John Wiley&Sons,in 73 volumes.
通过美国化学会化学文摘社制备的已知化学物质的索引,可以选择性地识别特定和类似的反应物,这些索引可在大多数公共图书馆和大学图书馆以及在线获得。已知但在目录中不可商购的化学品可选地由定制化学合成工厂制备,其中许多标准化学供应工厂(例如,上面列出的那些)提供定制合成服务。制备和选择本文所述化合物的药用盐的参考文献是P.H.Stahl&C.G.Wermuth“Handbook of Pharmaceutical Salts”,Verlag Helvetica Chimica Acta,Zurich,2002.
术语
在本发明未特殊说明的情况下,本发明的术语具有以下含义:
本发明所述基团和化合物中所涉及的碳、氢、氧、硫、氮或卤素均包括它们的同位素,及本发明所述基团和化合物中所涉及的碳、氢、氧、硫、氮或卤素任选进一步被一个或多个它们对应的同位素所替代,其中碳的同位素包括
12C、
13C和
14C,氢的同位素包括氕(H)、氘(氘,又称为重氢)、氚(T,又称为超重氢),氧的同位素包括
16O、
17O和
18O,硫的同位素包括
32S、
33S、
34S和
36S,氮的同位素包括
14N和
15N,氟的同位素
19F,氯的同位素包括
35Cl和
37Cl,溴的同位素包括
79Br和
81Br。
C
x-y基团的表达是指包含x至y个碳原子的基团,比如“C
1-6烷基”指包含1-6个碳原子的烷基。
“卤素”是指氟(F)、氯(Cl)、溴(Br)、碘(I)或者它们的同位素。
“卤代”或“卤素取代”是指氢原子被一个及以上选自F、Cl、Br、I或者它们的同位素取代,卤素取代基的数量的上限等于被取代基团可被取代的氢数之和,在未作特殊限定下,卤素取代基数量为1至该上限之间的任意整数,优选1-5个卤素取代、1-3卤素取代、1-2个卤素取代、1个卤素取代;当卤素取代基数量大于1时,可以是相同或不同的卤素进行取代。
“卤代C
1-6烷基”是指包含1-6个碳原子的烷基中的一个或多个氢被一个或多个卤素原子(如氟、氯、溴、碘)替代的烷基,卤素取代基的数量的上限等于烷基中可被取代的氢数之和,在未作特殊限定下,卤素取代基数量为1至该上限之间的任意整数,优选1-5个卤素取代、1-3卤素取代、1-2个卤素取代或1个卤素取代;当卤素取代基数量大于1时,可以是相同或不同的卤素进行取代;包括但不限于-CF
3、-CH
2Cl、-CH
2CF
3、-CCl
2、CF
3等。
“氘”是指氢(H)的同位素氘。
“氘代”或“氘代物”是指烷基、环烷基、亚烷基、芳基、杂芳基、巯基、杂环烷基、烯基、炔基等基团上的氢原子被至少一个氘原子取代的情形,氘代的数量上限等于被取代基团可被取代的氢数之和,在未作特殊限定下,氘代数量为1至该上限之间的任意整数,优选1- 20个氘原子取代、1-10个氘原子取代、1-6个氘原子取代、1-3个氘原子取代、1-2个氘原子取代或1个氘原子取代。
“烷基”是指直链或支链的饱和脂肪烃基,无特殊说明时,为1至20个碳原子的烷基,优选为1至8个碳原子的烷基,更优选为1至6个碳原子的烷基,进一步优选为1至4个碳原子的烷基,进一步优选1-2个碳原子的烷基。非限制性实施例包括甲基、乙基、正丙基、异丙基、正丁基、仲丁基、新丁基、叔丁基、正戊基、异戊基、新戊基、正己基等;所述的烷基可以进一步被任意取代基取代。
“羟烷基”是指被羟基取代的烷基,烷基定义如上。
“烯基”是指包含至少一个碳碳双键(C=C)的直链烃基或支链烃基的烃基,无特殊说明时,主,包含2至18个(如2至8个,进一步如2至6个,再进一步如2至4个)碳原子,包括但不限于乙烯基、烯丙基、1-丙烯基、2-丙烯基、1-丁烯基、2-丁烯基、3-丁烯基、1-戊烯基、2-戊烯基、3-戊烯基、4-戊烯基、1-甲基-1-丁烯基、2-甲基-1-丁烯基、2-甲基-3-丁烯基、1-己烯基、2-己烯基、3-己烯基、4-己烯基、5-己烯基、1-甲基-1-戊烯基、2-甲基-1-戊烯基、1-庚烯基、2-庚烯基、3-庚烯基、4-庚烯基、1-辛烯基、3-辛烯基、1-壬烯基、3-壬烯基、1-癸烯基、4-癸烯基、1,3-丁二烯、1,3-戊二烯、1,4-戊二烯和1,4-己二烯等;所述的烯基可以任选进一步被任意基团取代。
“炔基”是指含有至少一个碳碳三键(C≡C)直链烃基、支链烃基的烃基,主链包括2至18个(如2至8个,进一步如2至6个,再进一步如2至4个)碳原子。乙炔基、1-丙炔基、2-丙炔基、丁炔基、2-丁炔基、3-丁炔基、1-甲基-2-丙炔基、4-戊炔基、3-戊炔基、1-甲基-2-丁炔基、2-己炔基、3-己炔基、2-庚炔基、3-庚炔基、4-庚炔基、3-辛炔基、3-壬炔基和4-癸炔基等;所述的炔基可以任选进一步被任意取代基取代。
“烷氧基”或“烷基氧基”是指-O-烷基,未特殊限定时,为-O-C
1-8烷基,优选为-O-C
1-6烷基,更优选为-O-C
1-4烷基,进一步优选为-O-C
1-2烷基。非限制性实施例包括甲氧基、乙氧基、正丙氧基、异丙氧基、正丁氧基、仲丁氧基、叔丁氧基、正戊氧基、正己氧基、环丙氧基和环丁氧基等;所述的烷氧基可以任选进一步被任意取代基取代。
“卤代烷氧基”是指-O-卤代烷基,未特殊限定时,为-O-卤代C
1-8烷基,优选为-O-卤代C
1-6烷基,更优选为-O-卤代C
1-4烷基,进一步优选为-O-卤代C
1-2烷基;卤素取代基的数量的上限等于被取代基团可被取代的氢数之和,在未作特殊限定下,卤素取代基数量为1至该上限之间的任意整数,优选1-5个卤素取代、1-3卤素取代、1-2个卤素取代、1个卤素取 代;当卤素取代基数量大于1时,可以是相同或不同的卤素进行取代;非限制性实施例包括一氟甲氧基、二氟甲氧基、三氟甲氧基、二氟乙基氧基等。
“环烷基”是指取代或未取代的、饱和、部分不饱和或者完全不饱和的非芳香性环的烃环,可以是单环、双环或多环,双环或多环可以是并环、螺环或桥环,无特殊说明时,通常有3至20个碳原子;当为单环环烷基时,优选3-15个碳原子,优选3-10个碳原子,再优选3-8个碳原子,更优选有3-6个碳原子,进一步优选有3-4个碳原子;当为双环或多环环烷基时,优选4-12个碳原子,优选4-11个碳原子,再优选5-11个碳原子,更优选有6-11个碳原子,进一步优选有6-10个碳原子;非限制性实施例包括环丙基、环丁基、环戊基、环己基、环庚基、丁烯基、环戊烯基、环己烯基、
等。
“杂环烷基”是指取代或未取代的、包含至少一个杂原子的饱和、部分不饱和或者完全不饱和的非芳香性环的环,无特殊说明时,杂环烷基为3至20元环,当为单环杂环烷基时,优选3至15元,优选3-10元,再优选3-8元,进一步优选3-6元;当为双环或多环环杂环烷基时,优选4-12元,优选4-11元,再优选5-11元,更优选有6-11元,进一步优选有6-10元;杂环烷基可以是单环、双环或多环,双环或多环可以是桥环、并环和螺环,其中的杂原子选自N、S、O、P、Si杂原子及其氧化态;杂环烷基为双环或多环时,至少其中的一个环中包含至少一个杂原子,可以是含杂原子的环与不含杂原子的环形成的二环或多环;当与其他基团连接时,可以是杂原子或碳原子处作为连接点;非限制性实施例包括氮杂环丁基、吗啉基、哌嗪基、哌啶基、四氢吡喃基、氧杂环丁基、吡喃基、氮杂环戊烯基、氮杂环己烯基、氧杂环戊烯基、氧杂环己烯基等。
“芳基”是指取代的或未取代的5至15元具有芳香性的碳环,包括单环芳香基和稠环芳香基。优选5至10元芳香环,进一步优选5至8元芳香环;芳基环可以稠合于非芳基的环(比如杂芳基、杂环烷基或环烷基环)上,其中芳基环为连接位点,非限制性实施例包含苯基、萘基、蒽基、菲基、
所述的芳基可以任选进一步被任意取代基所取代。
“杂芳环”或“杂芳基”是指取代或未取代的、包含至少一个选自N、S、O、P、Si杂原子及其氧化态的杂原子或基团的、具有芳香性的环,可以是单环、双环或多环,可以是桥环、并环、螺环;当为双环或多环时,可以是杂芳基与非杂芳基环比如环烷基、杂环烷基、芳基稠和,也可以是杂芳基与杂芳基的稠和,其中杂芳基环为连接位点;非限制性实施例包括呋喃基、噻吩基、吡咯基、噁唑基、噻唑基、咪唑基、吡唑基、吡啶基、嘧啶基、哒嗪基、吡嗪基、吲哚基、嘌呤基、
等;所述的杂芳基可以任选进一步被任意取代基所取代。
“羧基”是指-C(=O)-OH。
“螺环”是指取代的或未取代的环与环之间共用一个碳原子(称螺原子)的5至20元多环基团,其可以包含0至5个双键,且可以含有0至5个选自N、O、S、P、Si及其氧化态的杂原子或集团。优选为6至14元,进一步优选为6至12元,更有选6至10元的螺环;螺环可以是环烷基、杂环烷基之间形成的;优选三螺三(表示三元环螺三元环)、三螺四、三螺五、三螺六、四螺四、四螺五、四螺六、五螺五或者五螺六;环其非限定性实例包括
“并环”是指环与环共享毗邻的两个原子的多环基团,其中一个或多个环可以含有0个或多个双键,且可以是取代的或未取代,并环体系中的各个环可以含0至5个选自N、S、O、P、Si的杂原子及其氧化态。优选为5至20元,进一步优选为5至14元,更优选5至12元,再进一步优选5至10元。优选三并四环(表示三元环与四元环形成的并环,根据IUPC命名规则有可能是三元环作为基本环也可能是四元环作为基本环的并环,以下同理)、三并五环、三并六环,四并四环、四并五环、四并六环、五并五环、五并六环、六并六环,非限定性实例包括嘌呤、喹啉、异喹啉、苯并吡喃、苯并呋喃、苯并噻吩、
所述的并环可以任选进一步被任意取代基所取代。
“桥环”是指两个环之间共享两个不相邻的原子,可以含有0个或多个双键,且可以是取代的或未取代的,其中一个或多个环可以含0至5个选自N、S、O、P、Si杂原子及其氧化态;环原子包含5至20个原子,优选为5至14个原子,进一步优选5至12个,再进一步优选5至10个;非限定性实例包括金刚烷
本发明所述的杂原子为选自N、O、S、Si、P原子及其氧化态形式。
“任选”或“任选地”是指随后所描述的事件或环境可以但不必须发生,该说明包括该事件或环境发生或不发生的场合。如:“任选被F取代的烷基”指烷基可以但不必须被F取代,说明包括烷基被F取代的情形和烷基不被F取代的情形。
本文所描述的基团被取代基取代,未特殊说明是指在化学理论允许的位置取代,取代基个数符合化学键规则。
“药学上可接受的盐”是指本发明化合物保持游离酸或者游离碱的生物有效性和特性,且所述的游离酸通过与无毒的无机碱或者有机碱,所述的游离碱通过与无毒的无机酸或者有机酸反应获得的盐。
“药物组合物”表示一种或多种本文所述化合物或其立体异构体、溶剂化物、药学上可接受的盐、共晶、氘代物,与其他组成成分的混合物,其中其他组分包含生理学/药学上可接受的载体和/赋形剂。
“载体”指的是:不会对生物体产生明显刺激且不会消除所给予化合物的生物活性和特性,并能改变药物进入人体的方式和在体内的分布、控制药物的释放速度并将药物输送到靶向器官的体系,非限制性的实例包括微囊与微球、纳米粒、脂质体等。
“赋形剂”指的是:其本身并非治疗剂,用作稀释剂、辅料、粘合剂和/或媒介物,用于添加至药物组合物中以改善其处置或储存性质或允许或促进化合物或药物组合物形成用于给药的单位剂型。如本领域技术人员所已知的,药用赋形剂可提供各种功能且可描述为润湿剂、缓冲剂、助悬剂、润滑剂、乳化剂、崩解剂、吸收剂、防腐剂、表面活性剂、着色剂、矫味剂及甜味剂。药用赋形剂的实例包括但不限于:(1)糖,例如乳糖、葡萄糖及蔗糖;(2) 淀粉,例如玉米淀粉及马铃薯淀粉;(3)纤维素及其衍生物,例如羧甲基纤维素钠、乙基纤维素、乙酸纤维素、羟丙基甲基纤维素、羟丙基纤维素、微晶纤维素及交联羧甲基纤维素(例如交联羧甲基纤维素钠);(4)黄蓍胶粉;(5)麦芽;(6)明胶;(7)滑石;(8)赋形剂,例如可可脂及栓剂蜡;(9)油,例如花生油、棉籽油、红花油、芝麻油、橄榄油、玉米油及大豆油;(10)二醇,例如丙二醇;(11)多元醇,例如甘油、山梨醇、甘露醇及聚乙二醇;(12)酯,例如油酸乙酯及月桂酸乙酯;(13)琼脂;(14)缓冲剂,例如氢氧化镁及氢氧化铝;(15)海藻酸;(16)无热原水;(17)等渗盐水;(18)林格溶液(Ringer’s solution);(19)乙醇;(20)pH缓冲溶液;(21)聚酯、聚碳酸酯和/或聚酐;及(22)其他用于药物制剂中的无毒相容物质。
“立体异构体”是指由分子中原子在空间上排列方式不同所产生的异构体,包括顺反异构体、对映异构体和构象异构体。
“溶剂化物”指本发明化合物或其盐与分子间非共价力结合的化学计量或非化学计量的溶剂形成的物质。当溶剂为水时,则为水合物。
“共晶”是指活性药物成分(API)和共晶形成物(CCF)在氢键或其他非共价键的作用下结合而成的晶体,其中API和CCF的纯态在室温下均为固体,并且各组分间存在固定的化学计量比。共晶是一种多组分晶体,既包含两种中性固体之间形成的二元共晶,也包含中性固体与盐或溶剂化物形成的多元共晶。
以下将通过实施例对本发明的内容进行详细描述。实施例中未注明具体条件的,按照常规条件的实验方法进行。所举实施例是为了更好地对本发明的内容进行说明,但并不能理解为本发明的内容仅限于所举实例。本领域常规技术人员根据上述发明内容对实施方案进行非本质的改进和调整,仍属于本发明的保护范围。
测试方法
化合物的结构是通过核磁共振(NMR)或(和)质谱(MS)来确定的。NMR位移(δ)以10-6(ppm)的单位给出。NMR的测定是用(Bruker Avance III 400和Bruker Avance 300)核磁仪,测定溶剂为氘代二甲基亚砜(DMSO-d6),氘代氯仿(CDCl3),氘代甲醇(CD3OD),内标为四甲基硅烷(TMS);
MS的测定用(Agilent 6120B(ESI)和Agilent 6120B(APCI));
HPLC的测定使用Agilent 1260DAD高压液相色谱仪(Zorbax SB-C18 100×4.6mm,3.5μM);
薄层层析硅胶板使用烟台黄海HSGF254或青岛GF254硅胶板,薄层色谱法(TLC)使用的硅胶板采用的规格是0.15mm-0.20mm,薄层层析分离纯化产品采用的规格是0.4mm-0.5mm;
柱层析一般使用烟台黄海硅胶200-300目硅胶为载体。
中间体1:
6-溴-2-(3-(3,4-二氢异喹啉-2(1H)-基)-2-羟基丙基)-3,4-二氢异喹啉-1(2H)-酮(中间体1)
6-bromo-2-(3-(3,4-dihydroisoquinolin-2(1H)-yl)-2-hydroxypropyl)-3,4-dihydroisoquinolin-1(2H)-one
第一步:
6-溴-2-(环氧乙烷-2-基甲基)-3,4-二氢异喹啉-1(2H)-酮(1b)
6-bromo-2-(oxiran-2-ylmethyl)-3,4-dihydroisoquinolin-1(2H)-one
将1a(2.26g,10mmol)溶于干燥N.N-二甲基甲酰胺(30mL)中,氮气保护下冷却至0℃,分批加入钠氢(0.44g,11mmol,60%wt),加毕,此条加下反应30分钟后,向体系滴加溴甲基环氧乙烷(1.64g,12mmol)。加毕,室温反应1小时。加入水(100mL)淬灭反应,乙酸乙酯萃取(100mL×2),合并有机相,饱和食盐水洗(100mL×1),无水硫酸钠干燥,过滤,滤液减压浓缩残留物经硅胶柱层析分离(石油醚:乙酸乙酯(v/v)=2:1)得到目标化合物6-溴-2-(环氧乙烷-2-基甲基)-3,4-二氢异喹啉-1(2H)-酮(1b)(1.8g,产率64%)。
LCMS m/z=282.0/284.0[M+H]
+.
第二步:
6-溴-2-(3-(3,4-二氢异喹啉-2(1H)-基)-2-羟基丙基)-3,4-二氢异喹啉-1(2H)-酮(中间体1)
6-bromo-2-(3-(3,4-dihydroisoquinolin-2(1H)-yl)-2-hydroxypropyl)-3,4-dihydroisoquinolin-1(2H)-one
将化合物1b(1.8g,6.4mmol)溶于异丙醇(20mL)中,加入1,2,3,4-四氢异喹啉(0.85g,6.4mmol),室温反应过夜。反应结束后,过滤,滤饼用少量异丙醇洗涤,真空干燥得到标题化合物6-溴-2-(3-(3,4-二氢异喹啉-2(1H)-基)-2-羟基丙基)-3,4-二氢异喹啉-1(2H)-酮(中间体1)(1.76g,收率66%)。
LCMS m/z=415.1/417.1[M+H]
+.
1H NMR(400MHz,CDCl
3)δ7.92(d,1H),7.47(dd,1H),7.35(d,1H),7.17-7.07(m,3H),7.03–6.96(m,1H),4.17-4.08(m,1H),3.90–3.58(m,6H),3.43(dd,1H),3.01–2.70(m,5H),2.68-2.62(m,1H),2.58-2.49(m,1H).
中间体1经手性SFC制备得到两个异构体。
中间体1,异构体1:
LCMS m/z=415.1/417.1[M+H]
+.
1H NMR(400MHz,CDCl
3)δ7.92(d,1H),7.47(dd,1H),7.35(d,1H),7.17-7.07(m,3H),7.03–6.96(m,1H),4.17-4.08(m,1H),3.89–3.57(m,6H),3.43(dd,1H),3.01–2.70(m,5H),2.68-2.62(m,1H),2.58-2.48(m,1H).
中间体1,异构体2:
LCMS m/z=415.1/417.1[M+H]
+.
1H NMR(400MHz,CDCl
3)δ7.92(d,1H),7.47(dd,1H),7.35(d,1H),7.17-7.07(m,3H),7.03–6.95(m,1H),4.17-4.08(m,1H),3.90–3.58(m,6H),3.43(dd,1H),3.01–2.71(m,5H),2.68-2.62(m,1H),2.58-2.49(m,1H).
制备条件:仪器:Waters SFC 350,制备柱:DAICEL CHIRALPAK AD(250mm*50mm,10μm),流动相:A for CO
2和B for IPA+ACN(0.1%NH
3·H
2O),梯度:80%Phase B,流速:180mL/min,背压:100bar,柱温:35℃,波长:220nm,循环时间:~8.2min,样品预处理:化合物溶解于甲醇二氯甲烷体系,浓度40mg/mL,.注射:10mL每针。
分析方法:仪器:SHIMADZU LC-30ADsf,柱子:Chiralpak AD-3 50×4.6mm I.D.,3μm,流动相:A for CO
2和B for IPA+ACN(0.05%DEA),梯度:40%Phase B,流速:3mL/min,背压:100bar,柱温:35℃,波长:220nm。保留时间:异构体1:tR=1.02min;异构体2:tR=1.45min。
中间体2:
中间体2的合成方法参照WO2014100719中描述。
实施例1:(R)-5-溴-2-(3-(3,4-二氢异喹啉-2(1H)-基)-2-羟丙基)异吲哚-1-酮(化合物1)
(R)-5-bromo-2-(3-(3,4-dihydroisoquinolin-2(1H)-yl)-2-hydroxypropyl)isoindolin-1-one
(Compound 1)
第一步:4-溴-2-(溴甲基)苯甲酸甲酯(1B)
methyl 4-bromo-2-(bromomethyl)benzoate(1B)
将1A(3g,13.10mmol)溶于四氯化碳(50mL)中,氮气保护下加入N-溴代琥珀酰亚胺(2.45g,13.77mmol)及过氧化二苯甲酰(0.9g,3.72mmol)后,于80℃反应2h。冷却至室温,减压旋蒸除去大部分溶剂,向残留物中加入40mL水,以乙酸乙酯(20mL×3)萃取,合并有机层,以无水硫酸钠干燥,浓缩后残留物用硅胶柱层析分离提纯(石油醚:乙酸乙酯(v/v)=10:1)得到标题化合物1B(3.3g,81%)。
LC-MS(ESI):m/z=308.9[M+H]
+.
第二步:(R)-5-溴-2-(3-(3,4-二氢异喹啉-2(1H)-基)-2-羟丙基)异吲哚-1-酮(化合物1)
(R)-5-bromo-2-(3-(3,4-dihydroisoquinolin-2(1H)-yl)-2-hydroxypropyl)isoindolin-1-one
(Compound 1)
将1B(0.5g,1.62mmol)、中间体2(0.5g,2.43mmol)及N,N-二异丙基乙胺(1.05g,8.10mmol)溶于DMF(20mL)中,氮气保护下,于80℃反应16h。冷却至室温,加入30mL水,以乙酸乙酯(15mL×5)萃取,合并有机层,用无水硫酸钠干燥,浓缩后残留物用硅胶柱层析分离提纯(二氯甲烷:甲醇(v/v)=20:1)得到标题化合物1(0.22g,34%)。
1H NMR(400MHz,CD
3OD)δ7.70(d,J=8.8Hz,1H),7.51–7.44(m,2H),7.21–7.11(m,4H),4.58(d,J=12.0,1H),4.35(d,J=12.0,1H),4.16–4.08(m,1H),3.87–3.73(m,3H),3.58–3.46(m,2H),2.95–2.82(m,3H),2.79–2.62(m,3H).
LC-MS(ESI):m/z=401.1[M+H]
+.
实施例2 2-(3-(3,4-二氢异喹啉-2(1H)-基)-2-羟丙基)-1-氧代-1,2,3,4-四氢异喹啉-6-腈(化合物2,单一异构体)
2-(3-(3,4-dihydroisoquinolin-2(1H)-yl)-2-hydroxypropyl)-1-oxo-1,2,3,4-tetrahydroisoquinoline-6-carbonitrile(Compound 2,single isomer)
将中间体1,异构体2(0.20g,0.48mmol)溶于N,N-二甲基甲酰胺(10mL)中,加入氰化锌(0.11g,0.96mmol)和4-(三苯基膦)钯(0.10g,0.086mmol),加完后100℃反应3小时。冷却至室温,过滤,加入水(80mL),用乙酸乙酯(20mL×3)萃取,合并后的有机相,用无水硫酸钠干燥,过滤,浓缩,残留物用硅胶柱色谱分离提纯(二氯甲烷:甲醇(v/v)=20:1-10:1)得到标题化合物2(0.10g,57.6%)。
LC-MS(ESI):m/z=362.2[M+H]
+.
1H NMR(400MHz,CDCl
3)δ8.17–8.15(m,1H),7.64–7.62(m,1H),7.51(s,1H),7.18–7.10(m,3H),7.01–6.99(m,1H),4.20–4.14(m,1H),3.94–3.65(m,5H),3.46–3.41(m,1H),3.07–2.91(m,5H),2.82–2.68(m,2H),2.60–2.54(m,1H).
实施例3、2-(3-(3,4-二氢异喹啉-2(1H)-基)-2-羟丙基)-3,4-二氢异喹啉-1(2H)-酮(化合物3,单一异构体)
2-(3-(3,4-dihydroisoquinolin-2(1H)-yl)-2-hydroxypropyl)-3,4-dihydroisoquinolin-1(2H)-one
(Compound 3,single isomer)
将中间体1,异构体2(0.20g,0.48mmol)溶于甲醇中(10mL)中,加入钯碳(0.05g,10%),氢气氛围下,室温反应24小时。过滤,浓缩,残留物用硅胶柱色谱分离提纯(二氯甲烷:甲醇(v/v)=20:1-10:1)得到标题化合物3(0.10g,61.9%)。
LC-MS(ESI):m/z=337.2[M+H]
+.
1H NMR(400MHz,CDCl
3)δ8.08–8.06(m,1H),7.44–7.32(m,2H),7.19–7.09(m,4H),7.01–6.99(m,1H),4.19–4.13(m,1H),3.92–3.64(m,5H),3.51–3.46(m,1H),3.02–2.86(m,5H),2.80–2.75(m,1H),2.71–2.67(m,1H),2.61–2.56(m,1H).
实施例4、2-(3-(3,4-二氢异喹啉-2(1H)-基)-2-羟丙基)-N,N-二甲基-1-氧代1,2,3,4-四氢异喹啉-6-羧酰胺(化合物4,单一异构体)
2-(3-(3,4-dihydroisoquinolin-2(1H)-yl)-2-hydroxypropyl)-N,N-dimethyl-1-oxo-1,2,3,4-tetrahydroisoquinoline-6-carboxamide(Compound 4,single isomer)
第一步:2-(3-(3,4-二氢异喹啉-2(1H)-基)-2-羟丙基)-1-氧代-1,2,3,4-四氢异喹啉-6-羧酸(4A,单一异构体)
2-(3-(3,4-dihydroisoquinolin-2(1H)-yl)-2-hydroxypropyl)-1-oxo-1,2,3,4-tetrahydroisoquinoline-6-carboxylic acid(4A,single isomer)
将化合物2(1.7g,4.87mmol)溶于甲醇(10mL)中,加入浓盐酸(20mL),加完后封管中80℃反应16小时。冷却至室温,浓缩,残留物用硅胶柱色谱分离提纯(二氯甲烷:甲醇(v/v)=20:1-10:1)得到标题化合物4A(1.2g,62.5%)。
LC-MS(ESI):m/z=381.2[M+H]
+.
第二步:2-(3-(3,4-二氢异喹啉-2(1H)-基)-2-羟丙基)-N,N-二甲基-1-氧代1,2,3,4-四氢异喹啉-6-羧酰胺(化合物4,单一异构体)
2-(3-(3,4-dihydroisoquinolin-2(1H)-yl)-2-hydroxypropyl)-N,N-dimethyl-1-oxo-1,2,3,4-tetrahydroisoquinoline-6-carboxamide(Compound 4,single isomer)
将4A(0.12g,0.32mmol)溶于二氯甲烷(10mL)中,加入二甲胺(0.055g,0.38mmol),N,N-二异丙基乙胺(0.12g,0.96mmol)和2-(7-氮杂苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯(0.16g,0.42mmol),加完后室温反应1小时。浓缩,残留物用硅胶柱色谱分离提纯(二氯甲烷:甲醇(v/v)=40:1-10:1)得到标题化合物4(0.05g,38.3%)。
LC-MS(ESI):m/z=408.3[M+H]
+.
1H NMR(400MHz,CDCl
3)δ8.09–8.07(m,1H),7.35–7.33(m,1H),7.26(s,1H),7.17–7.09(m,3H),7.02–7.00(m,1H),4.68–4.63(m,1H),4.20–4.14(m,1H),3.92–3.65(m,5H),3.50–3.44(m,1H),3.12–2.91(m,10H),2.81–2.76(m,1H),2.72–2.68(m,1H),2.61–2.55(m,1H).
实施例5、N-(3,3-二氟环丁基)-2-(3-(3,4-二氢异喹啉-2(1H)-基)-2-羟丙基)-1-氧代-1,2,3,4-四氢异喹啉-6-羧酰胺(化合物5,单一异构体)
N-(3,3-difluorocyclobutyl)-2-(3-(3,4-dihydroisoquinolin-2(1H)-yl)-2-hydroxypropyl)-1-oxo-1,2,3,4-tetrahydroisoquinoline-6-carboxamide(Compound 5,single isomer)
以中间体4A和3,3-二氟环丁胺为原料,参考化合物4的合成方法,合成得到化合物5。
LC-MS(ESI):m/z=470.4[M+H]
+.
1H NMR(400MHz,CDCl
3)δ8.07–8.05(m,1H),7.65–7.62(m,2H),7.17–7.09(m,3H),7.01–6.99(m,1H),6.60–6.58(m,1H),4.52–4.42(m,1H),4.19–4.13(m,1H),3.93–3.64(m,5H),3.46–3.41(m,1H),3.16–2.90(m,7H),2.80–2.75(m,1H),2.70–2.54(m,4H).
实施例6、2-(3-(3,4-二氢异喹啉-2(1H)-基)-2-羟丙基)-6-(哌嗪-1-羰基)-3,4-二氢异喹啉-1(2H)-酮(化合物6,单一异构体)
2-(3-(3,4-dihydroisoquinolin-2(1H)-yl)-2-hydroxypropyl)-6-(piperazine-1-carbonyl)-3,4-dihydroisoquinolin-1(2H)-one(Compound 6,single isomer)
第一步:叔丁基4-(2-(3-(3-(3,4-二氢异喹啉-2(1H)-基)-2-羟丙基)-1-氧代-1,2,3,4-四氢异喹啉-6-羰基)哌嗪-1-羧酸酯(6A)
tert-butyl 4-(2-(3-(3,4-dihydroisoquinolin-2(1H)-yl)-2-hydroxypropyl)-1-oxo-1,2,3,4-tetrahydroisoquinoline-6-carbonyl)piperazine-1-carboxylate(6A)
以中间体4A和N-Boc哌嗪为原料,参考化合物4的合成方法,合成得到标题化合物6A。
第二步:2-(3-(3,4-二氢异喹啉-2(1H)-基)-2-羟丙基)-6-(哌嗪-1-羰基)-3,4-二氢异喹啉-1(2H)-酮(化合物6,单一异构体)
(R)-2-(3-(3,4-dihydroisoquinolin-2(1H)-yl)-2-hydroxypropyl)-6-(piperazine-1-carbonyl)-3,4-dihydroisoquinolin-1(2H)-one(Compound 6,single isomer)
将6A(0.20g,0.36mmol)溶于二氯甲烷(10mL)中,加入三氟乙酸(3mL),加完后室温反应3小时。浓缩,残留物用硅胶柱色谱分离提纯(二氯甲烷:甲醇(v/v)=20:1-10:1)得到标题化合物6(0.11g,68.1%)。
LC-MS(ESI):m/z=449.1[M+H]
+.
1H NMR(400MHz,CDCl
3)δ8.10–8.08(m,1H),7.33–7.31(m,1H),7.26(s,1H),7.17–7.09(m,3H),7.01–6.99(m,1H),4.18–4.12(m,1H),3.92–3.63(m,7H),3.49–3.39(m,3H),3.04–2.73(m,10H),2.70–2.65(m,1H),2.59–2.53(m,1H).
实施例7、6-(3-氧杂-8-氮杂双环[3.2.1]辛烷-8-羰基)-2-(3-(3,4-二氢异喹啉-2(1H)-基)-2-羟丙基)-3,4-二氢异喹啉-1(2H)-酮(化合物7,单一异构体)
6-(3-oxa-8-azabicyclo[3.2.1]octane-8-carbonyl)-2-(3-(3,4-dihydroisoquinolin-2(1H)-yl)-2-hydroxypropyl)-3,4-dihydroisoquinolin-1(2H)-one(Compound 7,single isomer)
以中间体4A和3-氧杂-8-氮杂双环[3.2.1]辛烷盐酸盐为原料,参考化合物4的合成方法,合成得到化合物7。
LC-MS(ESI):m/z=476.3[M+H]
+.
1H NMR(400MHz,CDCl
3)δ8.11–8.09(m,1H),7.41–7.39(m,1H),7.36(s,1H),7.17–7.09(m,3H),7.01–6.99(m,1H),4.73(s,1H),4.19–4.13(m,1H),3.93–3.59(m,10H),3.49–3.44(m,1H),3.05–2.90(m,5H),2.80–2.75(m,1H),2.71–2.67(m,1H),2.60–2.55(m,1H),2.06–1.97(m,4H).
实施例8、N-(1-乙酰基哌啶-4-基)-2-(3-(3,4-二氢异喹啉-2(1H)-基)-2-羟丙基)-1-氧代-1,2,3,4-四氢异喹啉-6-羧酰胺(化合物8,单一异构体)
N-(1-acetylpiperidin-4-yl)-2-(3-(3,4-dihydroisoquinolin-2(1H)-yl)-2-hydroxypropyl)-1-oxo-1,2,3,4-tetrahydroisoquinoline-6-carboxamide(Compound 8,single isomer)
以中间体4A和1-乙酰哌啶-4-胺为原料,参考化合物4的合成方法,合成得到化合物8。
LC-MS(ESI):m/z=505.3[M+H]
+.
1H NMR(400MHz,CDCl
3)δ8.10–8.08(m,1H),7.66–7.65(m,2H),7.17–7.09(m,3H),7.01–6.99(m,1H),6.33–6.32(m,1H),4.63–4.59(m,1H),4.25–4.14(m,2H),3.92–3.65(m,6H),3.47–3.41(m,1H),3.26–3.19(m,1H),3.06–2.92(m,5H),2.81–2.67(m,3H),2.60–2.55(m,1H),2.18–2.03(m,5H),1.49–1.39(m,2H).
实施例9、2-(3-(3,4-二氢异喹啉-2(1H)-基)-2-羟丙基)-1-氧代-N-(哒嗪-4-基)-1,2,3,4-四氢异喹啉-6-羧酰胺(化合物9,单一异构体)
2-(3-(3,4-dihydroisoquinolin-2(1H)-yl)-2-hydroxypropyl)-1-oxo-N-(pyridazin-4-yl)-1,2,3,4-tetrahydroisoquinoline-6-carboxamide(Compound 9,single isomer)
以中间体4A和4-氨基哒嗪为原料,参考化合物4的合成方法,合成得到化合物9。
LC-MS(ESI):m/z=458.3[M+H]
+.
1H NMR(400MHz,CDCl
3)δ9.58(s,1H),9.49–9.48(m,1H),9.02–9.00(m,1H),8.29–8.27(m,1H),7.96–7.94(m,1H),7.80–7.78(m,2H),7.18–7.09(m,3H),7.01–6.99(m,1H),4.23–4.17(m,1H),3.91–3.69(m,5H),3.45–3.40(m,1H),3.03–2.83(m,6H),2.74–2.70(m,1H),2.65–2.59(m,1H).
实施例10:1-乙酰基-N-(2-(3-(3,4-二氢异喹啉-2(1H)-基)-2-羟基丙基)-1-氧-1,2,3,4-四氢异喹啉-6-基)哌啶-4-甲酰胺(化合物10,单一异构体)
1-acetyl-N-(2-(3-(3,4-dihydroisoquinolin-2(1H)-yl)-2-hydroxypropyl)-1-oxo-1,2,3,4-tetrahydroisoquinolin-6-yl)piperidine-4-carboxamide(Compound 10,single isomer)
第一步:6-氨基-2-(3-(3,4-二氢异喹啉-2(1H)-基)-2-羟基丙基)-3,4-二氢异喹啉-1(2H)-酮(10A,单一异构体)
6-amino-2-(3-(3,4-dihydroisoquinolin-2(1H)-yl)-2-hydroxypropyl)-3,4-dihydroisoquinolin-1(2H)-one
将中间体1,异构体2(0.41g,1.0mmol),二苯甲酮亚胺(0.27g,1.5mmol),双(2-二苯基磷苯基)醚(54mg,0.1mmol),Pd
2(dba)
3(47mg,0..05mmol)和叔丁醇钠(0.19g,2mmol)混溶于干燥1,4-二氧六环(20mL)中,氮气保护下,105℃下反应2小时。反应结束后冷却至室温,用乙酸乙酯(80mL)稀释,加入饱和NaHCO
3(80mL)分液,水相用乙酸乙酯(80mL)萃取,合并有机相,饱和食盐水洗涤,无水硫酸钠干燥,浓缩后粗品加入到四氢呋喃(20mL)和盐酸(10mL,1N水溶液)中搅拌1小时。饱和碳酸氢钠调节pH至碱性,乙酸乙酯(80mL)萃取。饱和食盐水洗涤,无水硫酸钠干燥,过滤,滤液减压浓缩,硅胶柱层析分离(甲醇:二氯甲烷(v/v)=0:1~1:30)得到目标化合物6-氨基-2-(3-(3,4-二氢异喹啉-2(1H)-基)-2-羟基丙基)-3,4-二氢异喹啉-1(2H)-酮(10A)(0.21g,收率60%)。
LCMS m/z=352.2[M+H]
+.
第二步:1-乙酰基-N-(2-(3-(3,4-二氢异喹啉-2(1H)-基)-2-羟基丙基)-1-氧-1,2,3,4-四氢异喹啉-6-基)哌啶-4-甲酰胺(化合物10,单一异构体)
1-acetyl-N-(2-(3-(3,4-dihydroisoquinolin-2(1H)-yl)-2-hydroxypropyl)-1-oxo-1,2,3,4-tetrahydroisoquinolin-6-yl)piperidine-4-carboxamide
将10A(0.21g,0.6mmol)溶于乙腈(10mL)中,依次加入1-乙酰基-4-哌啶甲酸(0.1g,0.6mmol)和N-甲基咪唑(0.25g,3mmol)。搅拌均匀后加入N,N,N',N'-四甲基氯甲脒六氟 磷酸盐(0.20g,0.72mmol),加完后室温反应1小时。加入水(30mL),用乙酸乙酯(60mL×2)萃取,有机相用饱和氯化钠水溶液(60mL)洗涤,无水硫酸钠干燥,过滤,浓缩,残留物经硅胶柱层析分离(DCM:MeOH(v/v)=10:1)得到化合物10(0.13g,收率43%)。
LCMS m/z=505.3[M+H]
+.
1H NMR(400MHz,CD
3OD)δ7.89(d,1H),7.64(d,1H),7.47(dd,1H),7.17–6.99(m,4H),4.58(d,1H),4.28-4.20m,1H),4.03(d,1H),3.90(dd,1H),3.83–3.68(m,4H),3.44–3.34(m,1H),3.28–3.15(m,1H),3.08–2.99(m,2H),2.99–2.84(m,4H),2.82–2.59(m,4H),2.14(s,3H),1.99–1.88(m,2H),1.84–1.60(m,2H).
实施例11:2-(3-(6,7-二氢噻吩并[3,2-c]吡啶-5(4H)-基)-2-羟丙基)-7-(哒嗪-4-基氨基)-3,4-二氢异喹啉-1(2H)-酮(化合物11)
2-(3-(6,7-dihydrothieno[3,2-c]pyridin-5(4H)-yl)-2-hydroxypropyl)-7-(pyridazin-4-ylamino)-3,4-dihydroisoquinolin-1(2H)-one
第一步:1-氯-3-(6,7-二氢噻吩并[3,2-c]吡啶-5(4H)-基)丙-2-醇(11B)
1-chloro-3-(6,7-dihydrothieno[3,2-c]pyridin-5(4H)-yl)propan-2-ol
室温下将11A(1.4g,10.06mmol)和环氧氯丙烷(0.93g,10.06mmol)溶于异丙醇(20mL)中,室温下搅拌过夜,TLC监测原料反应完全,旋干过柱(PE:EA=2:1),得到化合物11B(1.6g,产率68%)。
LCMS m/z=232.1[M+H]
+.
第二步:7-溴-2-(3-(6,7-二氢噻吩并[3,2-c]吡啶)-5(4H)-基)-2-羟丙基)-3,4-二氢异喹啉-1(2H)-酮(11C)
7-bromo-2-(3-(6,7-dihydrothieno[3,2-c]pyridin-5(4H)-yl)-2-hydroxypropyl)-3,4-dihydroisoquinolin-1(2H)-one
0℃条件下,将7-溴-3,4-二氢-2H-异喹啉-1-酮(1.6g,6.9mmol)分批加入到钠氢的DMF(10mL)悬浮液中,加入完毕后室温反应1h后,滴加11B(1.56g,6.9mmol)的DMF(10mL)溶液,滴加完全后70℃反应5h。加入300mL水,乙酸乙酯萃取两次,合并后的有机相 用饱和食盐水洗两次,无水硫酸钠干燥,过滤,滤液减压浓缩,硅胶柱层析分离(DCM:MeOH=20:1)得到11C(0.8g,收率28%)。
LCMS m/z=421.0/423.0[M+H]
+.
第三步:2-(3-(6,7-二氢噻吩并[3,2-c]吡啶-5(4H)-基)-2-羟丙基)-7-(哒嗪-4-基氨基)-3,4-二氢异喹啉-1(2H)-酮(化合物11)
2-(3-(6,7-dihydrothieno[3,2-c]pyridin-5(4H)-yl)-2-hydroxypropyl)-7-(pyridazin-4-ylamino)-3,4-dihydroisoquinolin-1(2H)-one
将反应物11C(0.5g,1.19mmol),4-氨基哒嗪(0.23g,2.38mmol)溶于1,4二氧六环(50mL)中,再向其中依次加入叔丁醇钠(0.23g,2.38mmol),Pd
2(dba)
3(0.22g,0.24mmol),Xantphos(0.28g,0.48mmol),氮气置换保护,100度反应1h。待反应冷至室温,减压浓缩后,向残余物中加入DCM(10mL),硅藻土过滤,将滤液减压浓缩后柱层析分离(DCM/CH
3OH=0%-20%)得到目标化合物11(0.1g,收率20%)。
LCMS m/z=436.2[M+H]
+.
1H NMR(400MHz,CDCl
3)δ8.89(d,1H),8.65(dd,1H),7.91(d,1H),7.66(s,1H),7.33-7.30(m,1H),7.21-7.19(m,1H),7.09(d,1H),6.97-6.95(m,1H),6.70(d,1H),4.19-4.13(m,1H),3.92–3.71(m,4H),3.61-3.57(m,1H),3.49-3.44(m,1H),3.01-2.97(m,4H),2.90-2.87(m,2H),2.85-2.79(m,1H),2.75-2.70(m,1H),2.61-2.55(m,1H).
实施例12:7'-((1-乙酰基哌啶-4-基)氨基)-2'-(3-(6,7-二氢噻吩并[3,2-c]吡啶基-5(4H)-基)-2-羟丙基)-2',3'-二氢-1'H-螺[环丙烷-1,4'-异喹啉]-1'-酮(化合物12)
7'-((1-acetylpiperidin-4-yl)amino)-2'-(3-(6,7-dihydrothieno[3,2-c]pyridin-5(4H)-yl)-2-hydroxypropyl)-2',3'-dihydro-1'H-spiro[cyclopropane-1,4'-isoquinolin]-1'-one
第一步:5-(环氧乙烷-2-基甲基)-4,5,6,7-四氢噻吩并[3,2-c]吡啶(12A)
5-(oxiran-2-ylmethyl)-4,5,6,7-tetrahydrothieno[3,2-c]pyridine
室温下将11A(0.4g,2.88mmol)和环氧溴丙烷(0.59g,4.32mmol)溶于THF(20mL)中,向其中加入碳酸钾(1.2g,8.64mmol),室温下搅拌过夜,TLC监测原料反应完全,将反应液浓缩后柱层析分离(PE:EA=4:1)得到化合物12A(0.4g,产率71%)。
LCMS m/z=232.1[M+H]
+.
第二步:7'-((1-乙酰基哌啶-4-基)氨基)-2'-(3-(6,7-二氢噻吩并[3,2-c]吡啶基-5(4H)-基)-2-羟丙基)-2',3'-二氢-1'H-螺[环丙烷-1,4'-异喹啉]-1'-酮(化合物12)
7'-((1-acetylpiperidin-4-yl)amino)-2'-(3-(6,7-dihydrothieno[3,2-c]pyridin-5(4H)-yl)-2-hydroxypropyl)-2',3'-dihydro-1'H-spiro[cyclopropane-1,4'-isoquinolin]-1'-one
0℃条件下,将12B(参考专利WO2020259478合成)(0.2g,0.64mmol)分批加入到钠氢(23mg,0.96mmol)的DMF(10mL)悬浮液中,加入完毕后,继续在0℃下反应0.5h,滴加12A(0.12g,0.64mmol)的DMF(2mL)溶液,滴加完全后升至室温反应过夜。加入10mL饱和氯化铵水溶液淬灭反应,残余物用乙酸乙酯萃取两次,合并后的有机相用饱和食盐水洗两次,无水硫酸钠干燥,过滤,将滤液减压浓缩,柱层析分离(DCM:CH
3OH=4:1)得到目标化合物12(20mg,收率6%)。
LCMS m/z=509.3[M+H]
+.
1H NMR(400MHz,CDCl
3)δ7.34-7.33(m,1H),7.15(d,1H),6.73(d,1H),6.67-6.65(m,2H),4.50-4.47(m,1H),4.28-4.27(m,1H),3.80-3.75(m,3H),3.60-3.53(m,5H),3.23-3.17(m,3H),3.04-2.81(m,6H),2.10(s,3H),1.33-1.25(m,5H),0.97-0.91(m,4H).
实施例13:(R)-5-((1-乙酰基哌啶-4-基)胺基)-2-(3-(3,4-二氢异喹啉-2(1H)-基)-2-羟基丙基)异吲哚啉-1-酮(化合物13)
(R)-5-((1-acetylpiperidin-4-yl)amino)-2-(3-(3,4-dihydroisoquinolin-2(1H)-yl)-2-hydroxypropyl)isoindolin-1-one(Compound 13)
将化合物1(0.50g,1.25mmol)溶于干燥二氧六环中(20mL)中,依次加入1-乙酰哌啶-4-胺(0.36g,2.50mmol),叔丁醇钠(0.36g,3.75mmol),4,5-双二苯基膦-9,9-二甲基氧杂蒽(0.58g,1.01mmol),双二亚苄基丙酮钯(0.14g,0.25mmol)。氮气保护,100℃反应3小时后,过滤,浓缩,残留物用硅胶柱色谱分离提纯(二氯甲烷:甲醇(v/v)=10:1)得到标题化合物13(15mg,2.6%)。
LC-MS(ESI):m/z=463.3[M+H]
+.
1H NMR(400MHz,CDCl
3)δ7.63–7.61(m,1H),7.17–7.09(m,3H),7.01–6.99(m,1H),6.64–6.61(m,1H),6.57(s,1H),4.53–4.50(m,3H),4.17–4.10(m,1H),3.97–3.95(m,1H),3.89–3.77(m,3H),3.70–3.66(m,1H),3.60–3.55(m,2H),3.26–3.20(m,1H),3.00–2.90(m,3H),2.87–2.78(s,2H),2.73–2.69(m,1H),2.63–2.57(m,1H),2.16–2.07(m,5H),1.45–1.33(m,2H).
实施例14:2-(3-(3,4-二氢异喹啉-2(1H)-基)-2-羟丙基)-6-(2-甲氧基-7-氮杂螺[3.5]壬烷-7-羰基)-3,4-二氢异喹啉-1(2H)-酮(化合物14,单一异构体)
2-(3-(3,4-dihydroisoquinolin-2(1H)-yl)-2-hydroxypropyl)-6-(2-methoxy-7-azaspiro[3.5]nonane-7-carbonyl)-3,4-dihydroisoquinolin-1(2H)-one(Compound 14)
以4A和2-甲氧基-7-氮杂螺[3.5]壬烷为原料,参考化合物4的合成方法,合成得到化合物14.
LC-MS(ESI):m/z=518.3[M+H]
+.
1H NMR(400MHz,CDCl
3)δ8.08–8.06(m,1H),7.31–7.29(m,1H),7.23(s,1H),7.16–7.09(m,3H),7.01–6.99(m,1H),4.18–4.12(m,1H),3.92–3.63(m,8H),3.49–3.44(m,1H),3.27–3.23(m,5H),3.05–2.89(m,5H),2.82–2.74(m,1H),2.70–2.66(m,1H),2.59–2.54(m,1H),2.23(s,2H),1.75–1.53(m,6H).
实施例15:7-(2-(3-(3,4-二氢异喹啉-2(1H)-基)-2-羟基丙基)-1-氧代-1,2,3,4-四氢异喹啉-6-羰基)-7-氮杂螺[3.5]壬烷-2-腈(化合物15,单一异构体)
7-(2-(3-(3,4-dihydroisoquinolin-2(1H)-yl)-2-hydroxypropyl)-1-oxo-1,2,3,4-tetrahydroisoquinoline-6-carbonyl)-7-azaspiro[3.5]nonane-2-carbonitrile(Compound 15)
以4A和7-氮杂螺[3.5]壬烷-2-腈为原料,参考化合物4的合成方法,合成得到化合物15.
LC-MS(ESI):m/z=513.3[M+H]
+.
1H NMR(400MHz,CDCl
3)δ8.09–8.07(m,1H),7.30–7.28(m,1H),7.23(s,1H),7.18–7.10(m,3H),7.02–7.01(m,1H),4.23–4.18(m,1H),3.93–3.87(m,2H),3.84–3.68(m,5H),3.51–3.46(m,1H),3.29(s,1H),3.14–2.95(m,6H),2.91–2.84(m,1H),2.77–2.73(m,1H),2.67–2.61(m,1H),2.34–2.20(m,5H),1.81–1.66(m,4H).
实施例16:7'-((1-乙酰哌啶-4-基)氨基)-2'-(2-羟基-3-(异吲哚啉-2-基)丙基)-2',3'-二氢-1'H-螺[环丙烷-1,4'-异喹啉]-1'-酮(化合物16)
7'-((1-acetylpiperidin-4-yl)amino)-2'-(2-hydroxy-3-(isoindolin-2-yl)propyl)-2',3'-dihydro-1'H-spiro[cyclopropane-1,4'-isoquinolin]-1'-one(Compound 16)
第一步:7'-硝基-2'-(环氧乙烷-2-基甲基)-2',3'-二氢-1'H-螺[环丙烷-1,4'-异喹啉]-1'-酮(16B)
7'-nitro-2'-(oxiran-2-ylmethyl)-2',3'-dihydro-1'H-spiro[cyclopropane-1,4'-isoquinolin]-1'-one
将16A(参考专利WO2020259478合成)(0.50g,2.29mmol)溶于N,N-二甲基甲酰胺(10mL)中,0℃下加入氢化钠(0.18g,4.58mmol),然后加入溴环氧乙烷(0.62g,4.58mmol),恢复室温反应3小时。加入水淬灭反应,用乙酸乙酯(20mL×3)萃取,合并后的有机相,用无水硫酸钠干燥,过滤,浓缩,残留物用硅胶柱色谱分离提纯(二氯甲烷:甲醇(v/v)=40:1-20:1)得到标题化合物16B(0.3g,47.7%)。
第二步:2'-(2-羟基-3-(异吲哚啉-2-基)丙基)-7'-硝基-2',3'-二氢-1'H-螺[环丙烷-1,4'-异喹啉]-1'-酮(16C)
2'-(2-hydroxy-3-(isoindolin-2-yl)propyl)-7'-nitro-2',3'-dihydro-1'H-spiro[cyclopropane-1,4'-isoquinolin]-1'-one
将16B(0.20g,0.73mmol)溶于异丙醇(10mL)中,加入异吲哚啉(0.17g,1.46mmol),室温反应16小时。浓缩,残留物用硅胶柱色谱分离提纯(二氯甲烷:甲醇(v/v)=20:1-10:1)得到标题化合物16C(0.2g,69.6%)。
LC-MS(ESI):m/z=394.2[M+H]
+.
第三步:7'-氨基-2'-(2-羟基-3-(异吲哚啉-2-基)丙基)-2',3'-二氢-1'H-螺[环丙烷-1,4'-异喹啉]-1'-酮(16D)
7'-amino-2'-(2-hydroxy-3-(isoindolin-2-yl)propyl)-2',3'-dihydro-1'H-spiro[cyclopropane-1,4'-isoquinolin]-1'-one
将16C(0.20g,0.51mmol)溶于甲醇(10mL)中,加入钯碳(0.050g,10%),氢气氛围下室温反应16小时。过滤,浓缩,得到标题化合物16D(0.12g,64.7%)。
LC-MS(ESI):m/z=364.2[M+H]
+.
第四步:7'-((1-乙酰哌啶-4-基)氨基)-2'-(2-羟基-3-(异吲哚啉-2-基)丙基)-2',3'-二氢-1'H-螺[环丙烷-1,4'-异喹啉]-1'-酮(化合物16)
7'-((1-acetylpiperidin-4-yl)amino)-2'-(2-hydroxy-3-(isoindolin-2-yl)propyl)-2',3'-dihydro-1'H-spiro[cyclopropane-1,4'-isoquinolin]-1'-one
将中间体16D(0.12g,0.33mmol)溶于二氯甲烷中(10mL)中,加入1-乙酰哌啶-4-胺(0.14g,0.99mmol),然后加入乙酸(0.0099g,0.17mmol),室温反应8小时,加入三乙酰氧基硼氢化钠(0.21g,0.99mmol),室温反应1小时后,浓缩,残留物用硅胶柱色谱分离提纯(二氯甲烷:甲醇(v/v)=40:1-10:1)得到标题化合物16(0.065g,40.3%)。
LC-MS(ESI):m/z=489.3[M+H]
+.
1H NMR(400MHz,CDCl
3)δ7.37–7.35(m,1H),7.25–7.20(m,4H),6.67–6.66(m,2H),4.50–4.47(m,1H),4.19–4.13(m,3H),4.07–4.04(m,2H),3.84–3.78(m,2H),3.62–3.53(m,4H),3.24–3.17(m,1H),2.99–2.92(m,2H),2.89–2.81(m,1H),2.15–2.05(m,6H),1.38–1.32(m,2H),0.99–0.93(m,3H).
实施例17:6-((1-乙酰基哌啶-4-基)氨基)-2-(3-(3,4-二氢异喹啉-2(1H)-基)-2-羟丙基)-7-氟-3,4-二氢异喹啉-1(2H)-酮(化合物17)
6-((1-acetylpiperidin-4-yl)amino)-2-(3-(3,4-dihydroisoquinolin-2(1H)-yl)-2-hydroxypropyl)-7-fluoro-3,4-dihydroisoquinolin-1(2H)-one(Compound 17)
第一步:6-溴-7-氟-1,2,3,4-四氢异喹啉(17B)
6-bromo-7-fluoro-1,2,3,4-tetrahydroisoquinoline
在0℃下,将6-溴-7-氟异喹啉17A(2.5g,11.06mmol)溶于冰乙酸(55mL)中,分批次加入硼氢化钠(0.46g,12.1mmol),升至室温搅拌反应3h。减压浓缩大部分乙酸,然后将反应液缓慢滴加到饱和碳酸氢钠水溶液(200mL)中淬灭,残余物用二氯甲烷萃取,分层,有机相用饱和食盐水洗涤,无水硫酸钠干燥,过滤,减压浓缩得到化合物17B(2.1g,82.52%),淡黄色油状固体,无需进一步纯化可直接用于下一步反应。
LC-MS(ESI):m/z=230.1[M+H]
+.
第二步:1-(6-溴-7-氟-3,4-二氢异喹啉-2(1H)-基)乙烷-1-酮(17C)
methyl 1-(6-bromo-7-fluoro-3,4-dihydroisoquinolin-2(1H)-yl)ethan-1-one
在0℃下,将化合物17B(1.0g,4.35mmol),三乙胺(0.84g,6.5mmol)溶于二氯甲烷混合溶剂中,缓慢滴加乙酰氯(0.41g,5.22mmol),滴毕,反应液升温至室温搅拌1小时。将反应液倒入水中,分离后的有机相依次用饱和碳酸氢钠水溶液洗,饱和食盐水洗,无水硫酸钠干燥,过滤,滤液经过减压浓缩后得到化合物17C(1.2g,100%),黄棕色固体,无需纯化进一步可直接用于下一步。
LC-MS(ESI):m/z=272.2[M+H]
+.
第三步:2-乙酰基-6-溴-7-氟-3,4-二氢异喹啉-1(2H)-酮(17D)
2-acetyl-6-bromo-7-fluoro-3,4-dihydroisoquinolin-1(2H)-one
将17C(1.08g,3.97mmol)溶于二氯甲烷(20mL)中,依次加入高锰酸钾(1.26g,8.0mmol),苄基三甲基溴化铵(0.18g,0.79mmol),然后室温继续搅拌反应18小时。将反应液逐滴滴加到1N稀盐酸(100mL)中,剧烈搅拌15min,用二氯甲烷(50×3mL)萃取,合并后的有机相用饱和氯化钠洗涤,无水硫酸钠干燥,过滤,浓缩,得到黄色油状粗品,粗品经快速柱层析硅胶柱色谱分离提纯(石油醚:乙酸乙酯(v/v)=5:1-3:1)得到17D(0.5g,44.02%),白色固体。
LC-MS(ESI):m/z=286.1[M+H]
+.
第四步:6-溴-7-氟-3,4-二氢异喹啉-1(2H)-酮(17E)
6-bromo-7-fluoro-3,4-dihydroisoquinolin-1(2H)-one
将17D(0.5g,1.75mmol)溶于甲醇(10mL)中,缓慢加入甲醇钠(0.28g,3.52mmol),室温继续搅拌反应1小时。减压浓缩除去大部分反应溶剂,将残余物加入到50mL水中,用稀盐酸调节pH=7,用二氯甲烷(20×3mL)萃取,合并后的有机相用无水硫酸钠干燥,过滤,浓缩,残留物用硅胶柱色谱分离提纯(二氯甲烷:甲醇(v/v)=100:1-50:1)得到17E(0.4g,93.65%),黄色固体。
LC-MS(ESI):m/z=243.9[M+H]
+.
第五步:6-溴-7-氟-2-(环氧乙烷-2-基甲基)-3,4-二氢异喹啉-1(2H)-酮(17F)
6-bromo-7-fluoro-2-(oxiran-2-ylmethyl)-3,4-dihydroisoquinolin-1(2H)-one
在0℃下,将17E(0.40g,1.64mmol)溶于N,N-二甲基甲酰胺(10mL)中,加入氢化钠(0.13g,3.28mmol),搅拌反应15min,然后加入环氧溴丙烷(0.27g,1.97mmol),恢复室温反应3小时。加入水淬灭反应,用乙酸乙酯(20mL×3)萃取,合并后的有机相,用无水硫酸钠干燥,过滤,浓缩,残留物用硅胶柱色谱分离提纯(二氯甲烷:甲醇(v/v)=60:1-40:1)得到标题17F(0.27g,54.86%),黄色油状。
LC-MS(ESI):m/z=300.0[M+H]
+.
第六步:6-溴-7-氟-2-(2-羟基-3-(1,2,3,4-四氢萘-2-基)丙基)-3,4-二氢异喹啉-1(2H)-酮(17G)
6-bromo-7-fluoro-2-(2-hydroxy-3-(1,2,3,4-tetrahydronaphthalen-2-yl)propyl)-3,4-dihydroisoquinolin-1(2H)-one
在50mL单口瓶中,依次将化合物17F(1.04g,3.47mmol),1,2,3,4-四氢异喹啉(0.46g,3.47mmol)溶于异丙醇(10mL)中,室温继续搅拌反应16小时。将反应液浓缩,残留物用硅胶柱色谱分离提纯(二氯甲烷:甲醇(v/v)=40:1-20:1)得到化合物17G(0.6g,53.33%),白色固体。
LC-MS(ESI):m/z=478.3[M+H]
+.
第七步:6-((1-乙酰基哌啶-4-基)氨基)-2-(3-(3,4-二氢异喹啉-2(1H)-基)-2-羟丙基)-7-氟-3,4-二氢异喹啉-1(2H)-酮(化合物17)
6-((1-acetylpiperidin-4-yl)amino)-2-(3-(3,4-dihydroisoquinolin-2(1H)-yl)-2-hydroxypropyl)-7-fluoro-3,4-dihydroisoquinolin-1(2H)-one(Compound 17)
将17G(0.6g,1.39mmol)溶于干燥二氧六环中(20mL)中,依次加入1-乙酰哌啶-4-胺(0.24g,1.67mmol),叔丁醇钠(0.4g,4.17mmol),4,5-双二苯基膦-9,9-二甲基氧杂蒽(0.26g,0.36mmol),双二亚苄基丙酮钯(0.1g,0.17mmol),氮气保护,100℃反应3小时。待反应冷至室温,过滤,浓缩,残留物用硅胶柱色谱分离提纯(二氯甲烷:甲醇(v/v)=20:1)得到化合物17的消旋体(300mg,43.7%)。
化合物17的消旋体通过手性HPLC拆分得化合物17,异构体1(保留时间:4.117min,72mg,10.5%)和化合物17,异构体2(保留时间:4.260min,76mg,11.07%),手性HPLC分离纯化条件如下:仪器名称:Waters 150Mgm;色谱柱:DAICEL CHIRALPAK AD(250mm*30mm,10μm)流动相:A for CO
2and B for EtOH(0.1%NH
3·H
2O);梯度:30%phase B isocratic elution;流速:130mL/min;柱压:100bar;柱温:35℃;吸收波长:220nm;循环时间:~9.5min)。
化合物17,异构体1:LC-MS(ESI):m/z=495.3[M+H]
+.
1H NMR(400MHz,CDCl
3-d)δ7.66–7.58(m,1H),7.24–7.16(m,2H),7.17–7.11(m,1H),7.06–7.01(m,1H),6.44–6.37(m,1H),4.55–4.44(m,1H),4.33(s,1H),4.23–4.15(m,1H),4.15–4.06(m,1H),3.99–3.95(m,1H),3.88–3.76(m,2H),3.73(t,J=6.6Hz,2H),3.61–3.50(m,2H),3.29–3.17(m,2H),3.14–3.04(m,3H),2.96–2.84(m,5H),2.20–2.04(m,5H),1.53–1.37(m,2H).
化合物17,异构体2:LC-MS(ESI):m/z=495.3[M+H]
+.
1H NMR(400MHz,CDCl
3-d)δ7.64–7.56(m,1H),7.25–7.18(m,2H),7.18–7.13(m,1H),7.08–7.01(m,1H),6.46–6.37(m,1H),4.57–4.47(m,1H),4.44(s,1H),4.28–4.07(m,3H), 3.89–3.80(m,1H),3.80–3.70(m,3H),3.66–3.52(m,2H),3.38–3.19(m,3H),3.15–3.06(m,3H),3.06–2.78(m,5H),2.17–2.03(m,5H),1.50–1.39(m,2H).
实施例18:6-(4-乙酰哌嗪-1-羰基)-2-(3-(3,4-二氢异喹啉-2(1H)-基)-2-羟丙基)-3,4-二氢异喹啉-1(2H))-酮(化合物18,单一异构体)
6-(4-acetylpiperazine-1-carbonyl)-2-(3-(3,4-dihydroisoquinolin-2(1H)-yl)-2-hydroxypropyl)-3,4-dihydroisoquinolin-1(2H)-one
以中间体4A和1-乙酰哌嗪为原料,参考化合物4的合成方法,合成得到化合物18。
1H NMR(400MHz,CDCl
3)δ8.12–8.10(m,1H),7.35–7.32(m,1H),7.27(s,1H),7.16–7.09(m,3H),7.02–7.00(m,1H),4.20–4.14(m,1H),3.93–3.73(m,6H),3.69–3.65(m,2H),3.61–3.53(m,2H),3.49–3.44(m,2H),3.05–3.02(m,2H)3.00–2.91(m,3H),2.81–2.76(m,1H),2.72–2.68(m,1H),2.61–2.55(m,1H),2.13(s,3H),1.95–1.76(m,2H).
LC-MS(ESI):m/z=491.3[M+H]
+.
实施例19:(R)-6-((1-乙酰基哌啶-4-基)胺基)-2-(3-(3,4-二氢异喹啉-2(1H)-基)-2-羟基丙基)异吲哚啉-1-酮(化合物19)
(R)-6-((1-acetylpiperidin-4-yl)amino)-2-(3-(3,4-dihydroisoquinolin-2(1H)-yl)-2-hydroxypropyl)isoindolin-1-one
以2-甲基-5-溴苯甲酸甲酯(19A)为原料,参考化合物1的合成方法得到19C,然后以19C为原料,参考化合物13的合成方法,得到化合物19.
1H NMR(400MHz,CDCl
3)δ7.22–7.11(m,4H),7.02–7.00(m,2H),6.79–6.76(m,1H),4.55–4.52(m,2H),4.26–4.19(m,1H),3.97–3.93(m,1H),3.84–3.76(m,3H),3.65–3.55(m,2H),3.24–3.18(m,1H),3.07–2.92(m,4H),2.87–2.79(m,2H),2.71–2.66(m,1H),2.21–2.08(m,5H),1.37–1.27(m,3H).
LC-MS(ESI):m/z=463.3[M+H]
+.
实施例20:7-((1-乙酰哌啶-4-基)氨基)-2-(3-(3,4-二氢异喹啉-2(1H)-基)-2-羟丙基)-5-甲基-3,4-二氢异喹啉-1(2H)-酮(化合物20)
7-((1-acetylpiperidin-4-yl)amino)-2-(3-(3,4-dihydroisoquinolin-2(1H)-yl)-2-hydroxypropyl)-5-methyl-3,4-dihydroisoquinolin-1(2H)-one
第一步:5-甲基-3,4-二氢异喹啉-1(2H)-酮(20B)
5-methyl-3,4-dihydroisoquinolin-1(2H)-one
将5-溴-3,4-二氢异喹啉-1(2H)-酮(20A)(5.0g,22.1mmol)溶于二氧六环中(100mL)中,依次加入甲基硼酸(3.98g,66.4mmol),碳酸钠(7.04g,66.4mmol),[1,1'-双(二苯基膦基)二茂铁]二氯化钯(4.8g,6.64mmol),水(10mL),100℃反应3小时后,过滤,浓缩,残留物用硅胶柱色谱分离提纯(PE:EA(v/v)=5:1-1:1)得到标题化合物20B(3.1g,88.5%)。
LC-MS(ESI):m/z=162.1[M+H]
+.
第二步:5-甲基-7-硝基-3,4-二氢异喹啉-1(2H)-酮(20C)
5-methyl-7-nitro-3,4-dihydroisoquinolin-1(2H)-one
将20B(3.1g,19.3mmol)溶于浓硫酸(10mL)中,0℃下加入硝酸钾(2.33g,23.1mmol),0℃反应1小时。加入水(30mL),过滤,干燥,得到标题化合物20C(3.2g,80.7%)。
LC-MS(ESI):m/z=207.1[M+H]
+.
第三步:7-胺基-5-甲基-3,4-二氢异喹啉-1(2H)-酮(20D)
7-amino-5-methyl-3,4-dihydroisoquinolin-1(2H)-one
将20C(3.2g,15.5mmol)溶于甲醇中(20mL)中,加入钯碳(0.3g,10%),氢气氛围下,室温反应8小时后,过滤,浓缩,得到标题化合物20D(2.6g,96.2%)。
LC-MS(ESI):m/z=177.2[M+H]
+.
第四步:7-胺基-5-甲基-3,4-二氢异喹啉-1(2H)-酮(20E)
7-amino-5-methyl-3,4-dihydroisoquinolin-1(2H)-one
将20D(0.50g,2.84mmol)溶于DMF中(10mL)中,加入2,5-己二酮(0.65g,5.68mmol)和对甲苯磺酸(0.24g,1.42mmol),100℃反应3小时,加入水(30mL),EA(30×3mL)萃取,合并后的有机相用饱和氯化钠洗,无水硫酸钠干燥,浓缩,残留物用硅胶柱色谱分离提纯(PE:EA(v/v)=5:1-1:1)得到标题化合物20E(0.6g,83.1%)。
LC-MS(ESI):m/z=255.2[M+H]
+.
第五步:7-(2,5-二甲基-1H-吡咯-1-基)-5-甲基-2-(环氧乙烷-2-基甲基)-3,4-二氢异喹啉-1(2H)-酮(20F)
7-(2,5-dimethyl-1H-pyrrol-1-yl)-5-methyl-2-(oxiran-2-ylmethyl)-3,4-dihydroisoquinolin-1(2H)-one
将20E(0.50g,1.97mmol)溶于DMF中(10mL)中,0℃下加入氢化钠(0.16g,3.94mmol),搅拌30分钟后,加入环氧溴丙烷(0.54g,3.94mmol),0℃反应2小时,加入水(30mL),EA(30×3mL)萃取,合并后的有机相用饱和氯化钠洗,无水硫酸钠干燥,浓缩,得到标题化合物20F(0.4g,65.4%)。
LC-MS(ESI):m/z=311.2[M+H]
+.
第六步:2-(3-(3,4-二氢异喹啉-2(1H)-基)-2-羟丙基)-7-(2,5-二甲基-1H-吡咯-1-基)-5-甲基-3,4-二氢异喹啉-1(2H)-酮(20G)
2-(3-(3,4-dihydroisoquinolin-2(1H)-yl)-2-hydroxypropyl)-7-(2,5-dimethyl-1H-pyrrol-1-yl)-5-methyl-3,4-dihydroisoquinolin-1(2H)-one
将20F(0.30g,0.97mmol)溶于异丙醇中(10mL)中,加入1,2,3,4-四氢异喹啉(0.26g,1.94mmol),室温反应16小时,浓缩,残留物用硅胶柱色谱分离提纯(PE:EA(v/v)=5:1-1:1)得到标题化合物20G(0.3g,69.7%)。
LC-MS(ESI):m/z=444.3[M+H]
+.
第七步:7-胺基-2-(3-(3,4-二氢异喹啉-2(1H)-基)-2-羟丙基)-5-甲基-3,4-二氢异喹啉-1(2H)-酮(20H)
7-amino-2-(3-(3,4-dihydroisoquinolin-2(1H)-yl)-2-hydroxypropyl)-5-methyl-3,4-dihydroisoquinolin-1(2H)-one
将20G(0.30g,0.68mmol)溶于乙醇中(15mL)中,加入羟胺(0.22g,6.80mmol)和盐酸羟胺(0.28g,4.08mmol),80℃反应24小时,加入水(30mL),EA(30×3mL)萃取。合并后的有机相用饱和氯化钠洗,无水硫酸钠干燥,浓缩,得到标题化合物20H(0.2g,80.5%)。
LC-MS(ESI):m/z=366.3[M+H]
+.
第八步:7-((1-乙酰哌啶-4-基)氨基)-2-(3-(3,4-二氢异喹啉-2(1H)-基)-2-羟丙基)-5-甲基-3,4-二氢异喹啉-1(2H)-酮(化合物20)
7-((1-acetylpiperidin-4-yl)amino)-2-(3-(3,4-dihydroisoquinolin-2(1H)-yl)-2-hydroxypropyl)-5-methyl-3,4-dihydroisoquinolin-1(2H)-one
将20H(0.20g,0.55mmol)溶于二氯甲烷中(10mL)中,加入1-乙酰哌啶-4-胺(0.23g,1.65mmol),然后加入乙酸(0.017g,0.28mmol),室温反应8小时,加入三乙酰氧基硼氢化钠(0.23g,1.65mmol),室温反应1小时后,浓缩,残留物用硅胶柱色谱分离提纯(二氯甲烷:甲醇(v/v)=40:1-10:1)得到标题化合物20(0.03g,11.1%)。
1H NMR(400MHz,CDCl
3)δ7.21–7.20(m,1H),7.18–7.10(m,3H),7.02–7.00(m,1H),6.57–6.55(m,1H),4.50–4.47(m,1H),4.23–4.14(m,1H),3.90–3.67(m,6H),3.60–3.49(m,2H),3.24–3.17(m,1H),3.02–2.93(m,3H),2.87–2.80(m,4H),2.75–2.61(m,2H),2.22(s,3H),2.15–2.04(m,5H),1.38–1.29(m,2H).
LC-MS(ESI):m/z=491.3[M+H]
+.
实施例21:7-((1-乙酰哌啶-4-基)氨基)-2-(3-(3,4-二氢异喹啉-2(1H)-基)-2-羟丙基)-6-甲基-3,4-二氢异喹啉-1(2H)-酮(化合物21)
7-((1-acetylpiperidin-4-yl)amino)-2-(3-(3,4-dihydroisoquinolin-2(1H)-yl)-2-hydroxypropyl)-6-methyl-3,4-dihydroisoquinolin-1(2H)-one
第一步:6-甲基-3,4-二氢异喹啉-1(2H)-酮(21A)
6-methyl-3,4-dihydroisoquinolin-1(2H)-one
将6-溴-3,4-二氢异喹啉-1(2H)-酮(1a)(5.00g,22.12mmol)溶于二氧六环中(100mL)中,依次加入甲基硼酸(3.98g,66.36mmol),碳酸钠(7.04g,66.36mmol),[1,1'-双(二苯基膦基)二茂铁]二氯化钯(5.42g,6.64mmol),水(10mL),100℃反应3小时后,过滤,浓缩,残留物用硅胶柱色谱分离提纯(PE:EA(v/v)=5:1-1:1)得到标题化合物21A(3.1g,88.5%)。
LC-MS(ESI):m/z=162.2[M+H]
+.
第二步:7-碘-6-甲基-3,4-二氢异喹啉-1(2H)-酮(21B)
7-iodo-6-methyl-3,4-dihydroisoquinolin-1(2H)-one
将21A(3.20g,19.85mmol)溶于三氟乙酸(20mL)中,0℃下加入N-碘代丁二酰亚胺(4.91g,21.84mmol),室温反应24小时后,浓缩,残留物用硅胶柱色谱分离提纯(PE:E A(v/v)=5:1-2:1)得到标题化合物21B(3.5g,61.4%)。
LC-MS(ESI):m/z=288.0[M+H]
+.
第三步:7-碘-6-甲基-2-(环氧乙烷-2-基甲基)-3,4-二氢异喹啉-1(2H)-酮(21C)
7-iodo-6-methyl-2-(oxiran-2-ylmethyl)-3,4-dihydroisoquinolin-1(2H)-one
将21B(3.00g,10.45mmol)溶于DMF中(20mL)中,0℃下加入氢化钠(0.84g,20.90mmol),搅拌30分钟后,加入环氧溴丙烷(2.12g,15.67mmol),0℃反应2小时。加入水(50mL),EA(30×3mL)萃取,合并后的有机相用饱和氯化钠洗,无水硫酸钠干燥,浓缩,得到标题化合物21C(2.3g,64.1%)。
LC-MS(ESI):m/z=344.0[M+H]
+.
第四步:2-(3-(3,4-二氢异喹啉-2(1H)-基)-2-羟丙基)-7-碘-6-甲基-3,4-二氢异喹啉-1(2H)-酮(21D)
2-(3-(3,4-dihydroisoquinolin-2(1H)-yl)-2-hydroxypropyl)-7-iodo-6-methyl-3,4-dihydroisoquinolin-1(2H)-one
将21C(0.50g,1.46mmol)溶于异丙醇中(10mL)中,加入1,2,3,4-四氢异喹啉(0.29g,2.19mmol),室温反应16小时。浓缩,残留物用硅胶柱色谱分离提纯(DCM:MeOH(v/v)=40:1-10:1)得到标题化合物21D(0.45g,64.7%)。
LC-MS(ESI):m/z=477.2[M+H]
+.
第五步:7-((1-乙酰哌啶-4-基)氨基)-2-(3-(3,4-二氢异喹啉-2(1H)-基)-2-羟丙基)-6-甲基-3,4-二氢异喹啉-1(2H)-酮(化合物21)
7-((1-acetylpiperidin-4-yl)amino)-2-(3-(3,4-dihydroisoquinolin-2(1H)-yl)-2-hydroxypropyl)-6-methyl-3,4-dihydroisoquinolin-1(2H)-one
将21D(0.30g,0.63mmol)溶于干燥二氧六环中(20mL)中,依次加入1-乙酰哌啶-4-胺(0.13g,0.95mmol),叔丁醇钠(0.18g,1.89mmol),4,5-双二苯基膦-9,9-二甲基氧杂蒽(0.29g,0.50mmol),双二亚苄基丙酮钯(0.072g,0.13mmol),氮气保护,100℃反应3小时。待反应冷至室温,过滤,浓缩,残留物用硅胶柱色谱分离提纯((二氯甲烷:甲醇(v/v)=10:1)得到标题化合物21(120mg,39.0%)。化合物21经手性SFC制备得到两个异构体。
制备条件:
仪器:Waters 150mgm,制备柱:DAICEL CHIRALPAK AD(250mm*30mm,10μm),流动相:A for CO
2和B for IPA+ACN(0.1%NH
3·H
2O),梯度:45%Phase B,流速:120mL/min,背压:100bar,柱温:35℃,波长:220nm,循环时间:~8min,样品预处理:化合物溶解于乙醇,浓度5mg/mL,.注射:6mL每针。
分析方法:
仪器:SHIMADZU LC-30ADsf,柱子:Chiralpak AD-3 50×4.6mm I.D.,3μm,流动相:A for CO2和B for IPA+ACN(0.05%DEA),梯度:40%Phase B,流速:3mL/min,背压:100bar,柱温:35℃,波长:220nm。保留时间:异构体1:tR=1.237;异构体2:tR=1.485。
化合物21,异构体1:
1H NMR(400MHz,CDCl
3)δ7.28(s,1H),7.24–7.13(m,3H),7.05–7.04(m,1H),6.90(s,1H),4.52–4.49(m,1H),4.42–4.34(m,1H),4.18–4.14(m,1H),4.05–4.01(m,1H),3.85–3.76(m,2H),3.74–3.64(m,3H),3.57–3.51(m,1H),3.27–3.21(m,3H),3.14–3.04(m,2H),2.91–2.83(m,5H),2.21–2.18(m,1H),2.14(s,3H),2.11–2.09(m,4H),1.41–1.33(m,2H).
LCMS m/z=491.3[M+H]
+.
化合物21,异构体2:
1H NMR(400MHz,CDCl
3)δ7.28(s,1H),7.23–7.13(m,3H),7.05–7.04(m,1H),6.90(s,1H),4.53–4.49(m,1H),4.41–4.32(m,1H),4.17–4.13(m,1H),4.05–4.01(m,1H),3.85–3.76(m,2H),3.74–3.63(m,3H),3.56–3.48(m,1H),3.27–3.20(m,3H),3.13–3.03(m,2H),2.99–2.83(m,5H),2.21–2.18(m,1H),2.14(s,3H),2.11–2.09(m,4H),1.41–1.32(m,2H).
LCMS m/z=491.3[M+H]
+.
实施例22:7-((1-乙酰哌啶-4-基)氨基)-2-(3-(6,7-二氢噻吩并[3,2-c]吡啶-5(4H)-基)-2-羟丙基-3,4-二氢异喹啉-1(2H)-酮(化合物22)
7-((1-acetylpiperidin-4-yl)amino)-2-(3-(6,7-dihydrothieno[3,2-c]pyridin-5(4H)-yl)-2-hydroxypropyl)-3,4-dihydroisoquinolin-1(2H)-one
第一步:
11C手性拆分方法:(仪器名称:Waters 150Mgm;色谱柱:DAICEL CHIRALPAK AD(250mm*30mm,10μm)流动相:A for CO
2and B for EtOH(0.1%NH
3·H
2O);梯度:45%phase B isocratic elution;流速:105mL/min;柱压:100bar;柱温:35℃;吸收波长:220nm;循环时间:~4.8min)。化合物22A保留时间:0.918min;化合物22B保留时间:1.127min,化合物22A和22B互为对映异构体。
第二步:
依次将22A(0.5g,1.19mmol),1-乙酰哌啶-4-胺(0.34g,2.38mmol)溶于1,4二氧六环(50mL)中,再向其中依次加入叔丁醇钠(0.23g,2.38mmol),Pd
2(dba)
3(0.22g,0.24mmol),Xantphos(0.28g,0.48mmol)。氮气置换保护,100℃反应1h。TLC与LC-MS显示原料反应完全,浓缩旋干,DCM溶解,硅藻土抽滤,将滤液浓缩,得到的残余物经柱层析分离(DCM/CH
3OH=0%-20%)得到化合物22,异构体1(20mg,收率6%)。
1H NMR(400MHz,CDCl
3)δ7.30(d,1H),7.11(d,1H),6.98(d,1H),6.73-6.65(m,2H),4.51-4.48(m,1H),4.22-4.20(m,1H),3.88-3.70(m,6H),3.57-3.50(m,3H),3.24-3.17(m,1H),3.10-3.08(m,1H),2.97-2.85(m,5H),2.73-2.67(m,1H),2.10(s,3H),1.33-1.25(m,4H).
LCMS m/z=483.6[M+H]
+.
参考上述合成方法,以22B为原料得到化合物22,异构体2。
1H NMR(400MHz,CDCl
3)δ7.29(d,1H),7.11(d,1H),6.98(d,1H),6.74-6.66(m,2H),4.51-4.48(m,1H),4.22-4.20(m,1H),3.88-3.70(m,5H),3.57-3.50(m,3H),3.24-3.17(m,2H),3.10-3.08(m,3H),2.94-2.80(m,6H),2.73-2.67(m,1H),2.10(s,3H),1.33-1.25(m,4H).
LCMS m/z=483.6[M+H]
+.
实施例23:7'-((1-乙酰基哌啶-4-基)氨基)-2'-(3-(6,7-二氢噻吩并[3,2-c]吡啶基-5(4H)-基)-2-羟丙基)-2',3'-二氢-1'H-螺[环丙烷-1,4'-异喹啉]-1'-酮(化合物12,异构体1和异构体2)
7'-((1-acetylpiperidin-4-yl)amino)-2'-(3-(6,7-dihydrothieno[3,2-c]pyridin-5(4H)-yl)-2-hydroxypropyl)-2',3'-dihydro-1'H-spiro[cyclopropane-1,4'-isoquinolin]-1'-one
化合物12通过手性HPLC拆分得化合物12,异构体1和异构体2,拆分条件如下:仪器名称:Waters 150Mgm;色谱柱:DAICEL CHIRALPAK AD(250mm*30mm,10μm)流动相:A for CO
2and B for EtOH(0.1%NH
3·H
2O);梯度:50%phase B isocratic elution;流速:80mL/min;柱压:100bar;柱温:38℃;吸收波长:220nm;循环时间:~9.5min)。异构体1保留时间:5.891min;异构体2保留时间:9.420min。
化合物12,异构体1:
1H NMR(400MHz,CDCl
3)δ7.34(s,1H),7.06(d,1H),6.73(d,1H),6.67(s,2H),4.50-4.47(m,1H),4.28-4.27(m,1H),3.83-3.78(m,2H),3.76-3.74(m,1H),3.66-3.48(m,5H),3.23-3.17(m,5H),3.04-2.81(m,7H),2.10(s,3H),1.33-1.26(m,5H),1.00-0.83(m,4H).
LCMS m/z=509.3[M+H]
+.
化合物12,异构体2:
1H NMR(400MHz,CDCl
3)δ7.35(s,1H),7.10(d,1H),6.73(d,1H),6.67(s,2H),4.50-4.47(m,1H),4.28-4.27(m,1H),3.83-3.78(m,3H),3.66-3.48(m,5H),3.23-3.17(m,3H),3.04-2.81(m,6H),2.10(s,3H),1.33-1.26(m,5H),1.00-0.83(m,4H).
LCMS m/z=509.3[M+H]
+.
实施例24:8-(2-(3-(3,4-二氢异喹啉-2(1H)-基)-2-羟丙基)-1-氧代-1,2,3,4-四氢异喹啉-6-羰基)-2,8-二氮螺环[4.5]癸烷-3-酮(化合物24,单一异构体)
8-(2-(3-(3,4-dihydroisoquinolin-2(1H)-yl)-2-hydroxypropyl)-1-oxo-1,2,3,4-tetrahydroisoquinoline-6-carbonyl)-2,8-diazaspiro[4.5]decan-3-one
将化合物4A(0.1g,0.26mmol)溶于二氯甲烷(10mL)中,加入2,8-二氮螺环[4.5]癸烷-3-酮(0.049g,0.32mmol),N,N-二异丙基乙胺(0.05g,0.4mmol)和2-(7-氮杂苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯(0.12g,0.31mmol),加完后室温继续搅拌反应3小时。将反应倒入50mL水中,用二氯甲烷(40mL×3)萃取,合并后的有机相用无水硫酸钠干燥,过滤,浓缩,残留物用硅胶柱色谱分离提纯(二氯甲烷:甲醇(v/v)=40:1-20:1)得到标题化合物24(0.060g,44.18%)。
1H NMR(400MHz,CDCl
3)δ8.12–8.08(m,1H),7.49–7.47(m,1H),7.38(s,1H),7.20–7.13(m,3H),7.07–7.03(m,1H),4.81-4.75(m,1H),4.51-4.48(m,2H),4.32(s,1H),4.07–4.03(m,1H),3.92–3.84(m,7H),3.82–3.79(m,1H),3.75–3.71(m,1H),3.60–3.53(m,1H),3.16-3.12(m,1H),3.06-3.04(m,5H),2.95-2.88(m,1H),2.83-2.77(m,1H),2.35–1.87(m,5H).
LC-MS(ESI):m/z=517.3[M+H]
+.
实施例25:2-(3-(3,4-二氢异喹啉-2(1H)-基)-2-羟丙基)-6-(5,6,7,8-四氢咪唑[1,2-a]吡嗪-7-羰基)-3,4-二氢异喹啉-1(2H)-酮(化合物25,单一异构体)
2-(3-(3,4-dihydroisoquinolin-2(1H)-yl)-2-hydroxypropyl)-6-(5,6,7,8-tetrahydroimidazo[1,2-a]pyrazine-7-carbonyl)-3,4-dihydroisoquinolin-1(2H)-one
以中间体4A和5,6,7,8-四氢咪唑[1,2-A]吡嗪为起始原料,参考化合物4的合成步骤,按照以上合成路线得到化合物25。
1H NMR(400MHz,CDCl
3)δ8.14–8.12(m,1H),7.41–7.39(m,1H),7.30(s,1H),7.15–7.12(m,3H),7.04–7.00(m,2H),6.89–6.88(m,1H),4.78(s,2H),4.17–4.01(m,4H),3.92–3.65(m,6H),3.52–3.49(m,2H),3.05–2.92(m,5H),2.79–2.77(m,1H),2.72-2.68(m,1H),2.60–2.55(m,1H).
LC-MS(ESI):m/z=486.2[M+H]
+.
实施例26:2-(3-(3,4-二氢异喹啉-2(1H)-基)-2-羟丙基)-6-(2-甲基-2,4,5,6-四氢吡咯[3,4-c]吡唑-5-羰基)-3,4-二氢异喹啉-1(2H)-酮(化合物26,单一异构体)
2-(3-(3,4-dihydroisoquinolin-2(1H)-yl)-2-hydroxypropyl)-6-(2-methyl-2,4,5,6-tetrahydropyrrolo[3,4-c]pyrazole-5-carbonyl)-3,4-dihydroisoquinolin-1(2H)-one
以中间体4A和2-甲基-2,4,5,6-四氢吡咯并[3,4-c]吡唑为起始原料,参考化合物4的合成步骤,按照以上合成路线得到化合物26。
1H NMR(400MHz,CDCl
3)δ8.10–8.08(m,1H),7.33–7.30(m,1H),7.25(s,1H),7.17–7.10(m,3H),7.02–7.00(m,1H),5.71(s,1H),4.24–4.18(m,1H),3.93–3.87(m,2H),3.85–3.71(m,3H),3.51–3.46(m,2H),3.25(s,2H),3.05–3.01(m,3H),2.97–2.94(m,2H),2.88–2.83(m,1H),2.80(s,2H),2.77–2.73(m,1H),2.67–2.62(m,1H),1.76–1.64(m,3H).
LC-MS(ESI):m/z=486.3[M+H]
+.
实施例27:6-(5-乙酰基八氢吡咯[3,4-c]吡咯-2-羰基)-2-(3-(3,4-二氢异喹啉-2(1H)-基)-2-羟丙基)-3,4-二氢异喹啉-1(2H)-酮(化合物27)
(6-(5-acetyloctahydropyrrolo[3,4-c]pyrrole-2-carbonyl)-2-(3-(3,4-dihydroisoquinolin-2(1H)-yl)-2-hydroxypropyl)-3,4-dihydroisoquinolin-1(2H)-one
第一步:5-乙酰基六氢吡咯[3,4-c]吡咯-2(1H)-甲酸叔丁酯(化合物27B)
tert-butyl 5-acetylhexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate
在0℃下,将2-BOC-八氢吡咯基[3,4-C]吡咯27A(1.06g,5mmol)溶于二氯甲烷(20mL)中,加入三乙胺(0.76g,7.5mmol),逐滴滴加乙酰氯(0.47g,6mmol),升至室温搅拌反应1h。将反应液缓慢滴加到饱和碳酸氢钠水溶液(200mL)中淬灭反应,用二氯甲烷萃取水相,分层,有机相用饱和食盐水洗涤,无水硫酸钠干燥,过滤,减压浓缩得到化合物27B(1.2g,94.5%),无需进一步纯化直接用于下一步反应。
LC-MS(ESI):m/z=199.1[M-55]
+.
第二步:1-(六氢吡咯基[3,4-c]吡咯-2(1H)-基)乙烷-1-酮盐酸盐(化合物27C)
1-(hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)ethan-1-one hydrochloride
将27B(0.6g,1.54mmol)溶于二氯甲烷(20mL)中,加入盐酸甲醇溶液(5mL),加完后室温反应3小时,浓缩,得到标题化合物27C(0.6g,99%)。无需纯化直接用于下一步反应。
LC-MS(ESI):m/z=155.2[M+H]
+.
第三步:6-(5-乙酰基八氢吡咯[3,4-c]吡咯-2-羰基)-2-(3-(3,4-二氢异喹啉-2(1H)-基)-2-羟丙基)-3,4-二氢异喹啉-1(2H)-酮(化合物27)
(6-(5-acetyloctahydropyrrolo[3,4-c]pyrrole-2-carbonyl)-2-(3-(3,4-dihydroisoquinolin-2(1H)-yl)-2-hydroxypropyl)-3,4-dihydroisoquinolin-1(2H)-one
将化合物4A(0.1g,0.26mmol)溶于二氯甲烷(10mL)中,加入化合物27C(0.06g,0.32mmol),N,N-二异丙基乙胺(0.1g,0.8mmol)和2-(7-氮杂苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯(0.12g,0.31mmol),加完后室温继续搅拌反应3小时。将反应倒入50mL水中,用二氯甲烷(20mL×3)萃取。合并后的有机相用无水硫酸钠干燥,过滤,浓缩,残留物用硅胶柱色谱分离提纯(二氯甲烷:甲醇(v/v)=40:1-20:1)得到标题化合物27(0.050g,36.8%)。
1H NMR(400MHz,CDCl
3-d)δ8.03–8.01(m,1H),7.42–7.40(m,1H),7.33(s,1H),7.30–7.17(m,3H),7.10–7.08(m,1H),4.66-4.64(m,1H),4.48-4.37(m,2H),3.97-3.91(m,1H),3.85–3.75(m,5H),3.71–3.63(m,5H),3.54–3.43(m,4H),3.33–3.26(m,6H),3.10–2.92(m,5H),2.08–2.05(m,3H),1.57–1.52(m,2H),1.46–1.44(m,2H).
LC-MS(ESI):m/z=517.3[M+H]
+.
实施例28:2-(-3-(3,4-二氢异喹啉-2(1H)-基)-2-羟丙基)-6-((3aR,5R,6aS)-5-甲氧基八氢环戊二烯并[c]吡咯-2-羰基)-3,4-二氢异喹啉-1(2H)-酮(化合物28)
2-(-3-(3,4-dihydroisoquinolin-2(1H)-yl)-2-hydroxypropyl)-6-((3aR,5R,6aS)-5-methoxyoctahydrocyclopenta[c]pyrrole-2-carbonyl)-3,4-dihydroisoquinolin-1(2H)-one
第一步:(3aR,5r,6aS)-5-羟基六氢环戊二烯并[c]吡咯-2(1H)-甲酸叔丁酯(28B)
tert-butyl(3aR,5r,6aS)-5-hydroxyhexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate
在0℃下,将顺式-5-氧代六氢环戊二烯并[C]吡咯-2(1H)-羧酸叔丁酯28A(1.3g,5.77mmol)溶于甲醇(20mL)中,缓慢加入NaBH
4(0.288g,6mmol),升至室温搅拌反应1h。减压浓缩除去大部分甲醇,将反应液倒入水中,用乙酸乙酯(100mL×3)萃取,合并后的有机相用饱和食盐水洗涤,无水硫酸钠干燥,过滤,减压浓缩得到化合物28B(1.3g,99.11%),无需进一步纯化可直接用于下一步反应。
LC-MS(ESI):m/z=172.2[M-55]
+.
第二步:(3aR,5r,6aS)-5-甲氧八氢环戊二烯并[c]吡咯-2(1H)-甲酸叔丁酯(28C)
tert-butyl(3aR,5r,6aS)-5-methoxyhexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate
将28B(1.3g,5.72mmol)溶于N,N-二甲基甲酰胺(20mL)中,在0℃下加入氢化钠(0.28g,7mmol),加完继续搅拌1小时,滴入碘甲烷(1.0g,7mmol),升温至室温反应2小时。将反应液缓慢倒入冰水中,用乙酸乙酯(100mL×3)萃取,合并后的有机相用饱和食盐水洗涤,无水硫酸钠干燥,减压浓缩得到标题化合物28C(1.3g,94.2%)。无需纯化直接用于下一步反应。
LC-MS(ESI):m/z=186.2[M-55]
+.
第三步:(3aR,5r,6aS)-5-甲氧八氢环戊二烯并[c]吡咯盐酸盐(28D)
(3aR,5r,6aS)-5-methoxyoctahydrocyclopenta[c]pyrrole hydrochloride
将28C(1.3g,1.54mmol)溶于二氯甲烷(20mL)中,加入盐酸甲醇溶液(5mL),加完后室温反应3小时,减压浓缩,得到标题化合物28D(0.9g,94%)。无需纯化直接用于下一步反应。
LC-MS(ESI):m/z=142.2[M+H]
+.
第四步:2-(-3-(3,4-二氢异喹啉-2(1H)-基)-2-羟丙基)-6-((3aR,5R,6aS)-5-甲氧基八氢环戊二烯并[c]吡咯-2-羰基)-3,4-二氢异喹啉-1(2H)-酮(化合物28)
2-(-3-(3,4-dihydroisoquinolin-2(1H)-yl)-2-hydroxypropyl)-6-((3aR,5R,6aS)-5-methoxyoctahydrocyclopenta[c]pyrrole-2-carbonyl)-3,4-dihydroisoquinolin-1(2H)-one
将化合物4A(0.1g,0.26mmol)溶于二氯甲烷(10mL)中,加入化合物28D(0.06g,0.33mmol),N,N-二异丙基乙胺(0.1g,0.8mmol)和2-(7-氮杂苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯(0.12g,0.31mmol),加完后室温继续搅拌反应3小时。将反应倒入50mL水中,用二氯甲烷(20mL×3)萃取,合并后的有机相用无水硫酸钠干燥,过滤,浓缩,残留物用硅胶柱色谱分离提纯(二氯甲烷:甲醇(v/v)=40:1-20:1)得到标题化合物28(0.050g,37.7%)。
1H NMR(400MHz,CDCl
3)δ7.94–7.92(m,1H),7.37–7.34(m,1H),7.30(s,1H),7.23–7.14(m,3H),7.08–7.06(m,1H),4.40–4.39(m,1H),4.29–4.09(m,2H),3.87–3.63(m,2H),3.59–3.55(m,3H),3.35–3.29(m,3H),3.27(s,4H),3.16–3.08(m,3H),3.05–3.00(m,3H),2.71–2.61(m,2H),2.15–1.99(m,1H),1.68–1.44(m,5H).
LC-MS(ESI):m/z=504.3[M+H]
+.
实施例29:(R)-2'-(3-(3,4-二氢异喹啉-2(1H)-基)-2-羟丙基)-6'-(2-甲氧基-7-氮杂螺[3.5]壬烷-7-羰基)-2',3'-二氢-1'H-螺[环丙烷-1,4'-异喹啉]-1'-酮(化合物29)
(R)-2'-(3-(3,4-dihydroisoquinolin-2(1H)-yl)-2-hydroxypropyl)-6'-(2-methoxy-7-azaspiro[3.5]nonane-7-carbonyl)-2',3'-dihydro-1'H-spiro[cyclopropane-1,4'-isoquinolin]-1'-one
将29A(参考专利US20120225857)(1.00g,3.97mmol)溶于N,N-二甲基甲酰胺(10mL)中,0℃下加入氢化钠(0.32g,7.97mmol),30min后加入(R)-(-)-对硝基苯磺酸缩水甘油酯(1.54g,5.96mmol),反应1小时。加入水(80mL),用乙酸乙酯(20mL×3)萃取,合并后的有机相,用无水硫酸钠干燥,过滤,浓缩,得到标题化合物29B(1.0g,81.7%)。
LC-MS(ESI):m/z=310.0[M+H]
+.
以29B为原料,参考化合物14的合成方法,得到化合物29.
1H NMR(400MHz,CDCl
3)δ8.11-8.09(m,1H),7.25-7.24(m,1H),7.19-7.11(m,3H),7.03-7.00(m,1H),6.88(s,1H),4.26-4.21(m,1H),3.97-3.87(m,2H),3.86-3.82(m,1H),3.79-3.75(m,1H),3.71-3.50(m,5H),3.31-3.23(m,5H),3.11-2.97(m,4H),2.82-2.67(m,2H),2.28-2.16(m,2H),1.76-1.64(m,4H),1.56-1.46(m,2H),1.12-1.05(m,4H).
LC-MS(ESI):m/z=544.3[M+H]
+.
实施例30:(R)-7-(2'-(3-(3,4-二氢异喹啉-2(1H)-基)-2-羟丙基)-1'-氧代-2',3'-二氢-1'H-螺[环丙烷-1,4'-异喹啉]-6'-羰基)-7-氮杂螺[3.5]壬烷-2-腈(化合物30)
(R)-7-(2'-(3-(3,4-dihydroisoquinolin-2(1H)-yl)-2-hydroxypropyl)-1'-oxo-2',3'-dihydro-1'H-spiro[cyclopropane-1,4'-isoquinolin]-6'-ylcarbonyl)-7-azaspiro[3.5]nonane-2-carbonitrile
以29E和7-氮杂螺[3.5]壬烷-2-腈为原料参考化合物29的合成方法,合成得到化合物30。
1H NMR(400MHz,CDCl
3)δ8.12–8.10(m,1H),7.24–7.23(m,1H),7.18–7.10(m,3H),7.02–7.00(m,1H),6.87(s,1H),4.22–4.17(m,1H),3.93–3.83(m,2H),3.74–3.47(m,6H),3.32–3.19(m,2H),3.13–2.94(m,4H),2.90–2.62(m,4H),2.35–2.18(m,5H),1.71–1.62(m,2H),1.12–1.02(m,4H).
LC-MS(ESI):m/z=539.3[M+H]
+.
实施例31:7-((1-乙酰哌啶-4-基)氨基)-2-(3-(3,4-二氢异喹啉-2(1H)-基)-2-羟丙基)-5-甲基-3,4-二氢异喹啉-1(2H)-酮(化合物20异构体1,异构体2,二者互为对映异构体)
7-((1-acetylpiperidin-4-yl)amino)-2-(3-(3,4-dihydroisoquinolin-2(1H)-yl)-2-hydroxypropyl)-5-methyl-3,4-dihydroisoquinolin-1(2H)-one(R and S enantiomer of Compound 20)
第一步:
将7-胺基-5-溴-3,4-二氢异喹啉-1(2H)-酮31A(参考专利WO2021028806中描述方法合成)(5.00g,20.74mmol)溶于DMF中(50mL)中,加入2,5-己二酮(4.73g,41.49mmol)和对甲苯磺酸(0.36g,2.07mmol),100℃反应3小时。待反应冷至室温,将反应液倒入冰水中,过滤,干燥得到标题化合物31B(6.5g,97.7%)。
LC-MS(ESI):m/z=321.0[M+H]
+.
第二步:
将31B(6.50g,20.37mmol)溶于DMF中(50mL)中,0℃下加入氢化钠(1.63g,40.74mmol),搅拌30分钟后,加入环氧溴丙烷(4.19g,30.56mmol),0℃反应2小时。加入水(150mL)淬灭,EA(50×3mL)萃取,合并后的有机相用饱和氯化钠洗,无水硫酸钠干燥,过滤,浓缩,得到标题化合物31C(7.2g,94.7%)。
LC-MS(ESI):m/z=375.0[M+H]
+.
第三步:
将31C溶于异丙醇(80mL)中,加入四氢异喹啉(7.66g,57.6mmol),室温反应16小时。浓缩,残留物用硅胶柱色谱分离提纯(PE:EA(v/v)=2:1-1:3)得到标题化合物31D(7.8g,82.1%)。
LC-MS(ESI):m/z=508.1[M+H]
+.
第四步:
中间体31D(18.01g,5.96mmol)经手性SFC制备得到两个异构体31E和31F(二者互为对映异构体)。
手性分离条件:仪器:Waters 350mgm,制备柱:DAICEL CHIRALPAK AD(250mm×30mm,10μm),流动相:A for CO
2和B for EtOH+ACN(0.1%NH
3·H
2O),梯度:40%Phase B isocratic elution,流速:180mL/min,背压:100bar,柱温:35℃,波长:220nm,循环时间:3.8min,样品预处理:化合物溶解于乙醇,浓度12mg/mL,注射:1.5mL每针。
分析方法:仪器:SHIMADZU LC-30AD sfc,柱子:Chiralpak AD-3 50×4.6mm I.D.,3μm,流动相:A for CO
2和B for EtOH+ACN(0.05%DEA),梯度:40%Phase B,流速:3mL/min,背压:100bar,柱温:35℃,波长:220nm。保留时间:异构体1(31E):tR=0.92min;异构体2(31F):tR=1.409min。
第五步:
将31E溶于二氧六环中(100mL)中,依次加入甲基硼酸(3.98g,66.4mmol),碳酸钠(7.04g,66.4mmol),[1,1'-双(二苯基膦基)二茂铁]二氯化钯(4.8g,6.64mmol),水(10mL), 100℃反应3小时。待反应冷至室温,过滤,浓缩,残留物用硅胶柱色谱分离提纯(PE:EA(v/v)=5:1-1:1)得到标题化合物20G-1(3.1g,72.1%)。
LC-MS(ESI):m/z=444.3[M+H]
+.
以31F为原料,参考20G-1的合成方法,合成得到20G-2。
LC-MS(ESI):m/z=444.3[M+H]
+.
第六步:
以20G-1为原料,参考实施例20第七步合成方法,合成得到20H-1。
以20G-2为原料,参考实施例20第七步合成方法,合成得到20H-2。
第七步:
以20H-1为原料,参考实施例20第八步的合成方法,得到化合物20,异构体1。
1H NMR(400MHz,CDCl
3)δ7.21-7.20(m,1H),7.17-7.09(m,3H),7.02-7.00(m,1H),6.57-6.55(m,1H),4.50-4.46(m,1H),4.23-4.14(m,1H),3.90-3.67(m,6H),3.60-3.49(m,2H),3.24-3.17(m,1H),3.02-2.93(m,3H),2.87-2.80(m,4H),2.75-2.61(m,2H),2.22(s,3H),2.14-2.04(m,5H),1.35-1.29(m,2H).
LC-MS(ESI):m/z=491.3[M+H]
+.
以20H-2为原料,参考实施例20第八步的合成方法,得到化合物20,异构体2。
1H NMR(400MHz,CDCl
3)δ7.21-7.20(m,1H),7.17-7.10(m,3H),7.02-7.00(m,1H),6.57-6.55(m,1H),4.50-4.47(m,1H),4.23-4.13(m,1H),3.90-3.68(m,6H),3.59-3.49(m,2H),3.24-3.17(m,1H),3.02-2.93(m,3H),2.87-2.80(m,4H),2.75-2.61(m,2H),2.22(s,3H),2.15-2.04(m,5H),1.37-1.29(m,2H).
LC-MS(ESI):m/z=491.3[M+H]
+.
实施例32:(R)-7'-((1-乙酰基吡啶-4-基)氨基)-2'-(3-(6,7-二氢噻吩[3,2-c]吡啶-5(4H)-基)-2-羟丙基)-2',3'-二氢-1'H-螺[环丁烷-1,4'-异喹啉]-1'-酮(化合物32)
(R)-7'-((1-acetylpiperidin-4-yl)amino)-2'-(3-(6,7-dihydrothieno[3,2-c]pyridin-5(4H)-yl)-2-hydroxypropyl)-2',3'-dihydro-1'H-spiro[cyclobutane-1,4'-isoquinolin]-1'-one
第一步:
在0℃下,将7'-硝基-2',3'-二氢-1'H-螺[环丁烷-1,4'-异喹啉]-1'-酮(32A)(参考专利CN112125886中描述方法合成)(0.6g,2.58mmol)溶于N,N-二甲基甲酰胺(10mL)中,加入60%氢化钠(0.15g,3.87mmol)搅拌反应15min,然后加入(R)-(-)-对硝基苯磺酸缩水甘油酯(0.27g,1.97mmol),升温至室温反应3小时。加入水淬灭反应,用乙酸乙酯(20mL×3)萃取,合并后的有机相,用无水硫酸钠干燥,过滤,浓缩,残留物用硅胶柱色谱分离提纯(二氯甲烷:甲醇(v/v)=95:5)得到标题化合物32B(0.31g,41.63%)。
LC-MS(ESI):m/z=289.2[M+H]
+.
第二步:
向50mL单口瓶中,依次将化合物32B(0.31g,1.08mmol),4,5,6,7-四氢噻吩[3,2-c]吡啶(0.15g,1.08mmol)溶于异丙醇(10mL)中,室温继续搅拌反应16小时。将反应液浓缩,残留物用硅胶柱层析分离提纯(二氯甲烷:甲醇(v/v)=96:4)得到化合物32C(0.30g,65.26%)。
LC-MS(ESI):m/z=428.3[M+H]
+.
第三步:
向50mL单口瓶中,依次加入化合物32C(0.30g,0.7mmol),10%钯碳(0.15g),甲醇(20mL),氢气保护,室温下搅拌反应2小时。反应液用硅藻土过滤,减压浓缩得到化合物32D(0.24g,86.03%),无需进一步纯化直接用于下一步反应。
LC-MS(ESI):m/z=398.3[M+H]
+.
第四步:
向50mL单口瓶中,依次加入化合物32D(0.24g,0.6mmol),1-乙酰基哌啶-4-酮(0.12g,0.84mmol),二氯甲烷(3mL),乙酸(5mL),室温下搅拌反应10min,然后加入三乙酰氧基硼氢化钠(0.18g,0.84mmol),继续搅拌反应2小时。减压浓缩反应液得到黄色油状粗品,向粗品中加入二氯甲烷,饱和碳酸氢钠水溶液,萃取,有机相用饱和食盐水洗涤,有机无水硫酸钠干燥,过滤,浓缩,得到黄色油状粗品经硅胶柱层析分离(二氯甲烷:甲醇(v/v)=10:1)得到目标化合物32(0.18g,57.04%)。
1H NMR(400MHz,CDCl
3-d)δ7.30-7.28(m,2H),7.11-7.10(m,1H),6.78-6.75(m,1H),6.73-6.71(m,1H),4.50-4.47(m,1H),4.23-4.18(m,1H),3.97-3.77(m,3H),3.74(s,2H),3.68-3.53(m,4H),3.23-3.18(m,1H),3.09-3.05(m,1H),2.93-2.78(m,5H),2.69-2.53(m,1H),2.30-2.22(m,3H),2.15-1.94(m,11H).
LC-MS(ESI):m/z=523.2[M+H]
+.
实施例33:7-(2-(3-(3,4-二氢异喹啉-2(1H)-基)-2-羟丙基)-4,4-二甲基-1-氧代-1,2,3,4-四氢异喹啉-6-碳酰)-7-氮杂螺[3.5]壬烷-2-腈(化合物33)
7-(2-(3-(3,4-dihydroisoquinolin-2(1H)-yl)-2-hydroxypropyl)-4,4-dimethyl-1-oxo-1,2,3,4-tetrahydroisoquinoline-6-carbonyl)-7-azaspiro[3.5]nonane-2-carbonitrile
第一步:
在0℃下,将6-溴-4,4-二甲基-3,4-二氢异喹啉-1(2H)-酮33A(参照专利WO2019094312中描述方法合成)(0.5g,1.97mmol)溶于N,N-二甲基甲酰胺(15mL)中,加入60%氢化钠(0.12g,3.0mmol),搅拌反应1h。加入环氧溴丙烷(0.32g,2.36mmol),加完后升温至室温搅拌反应2小时。将反应液倒入100mL水中,乙酸乙酯萃取水相三次,合并后的有机相,用饱和食盐水洗涤,无水硫酸钠干燥,浓缩,残留物用硅胶柱色谱分离提纯(石油醚:乙酸乙酯(v/v)=3:1-1:1)得到标题化合物33B(0.3g,49.16%)。
LC-MS(ESI):m/z=310.1[M+H]
+.
第二步:
向50mL单口瓶中,依次将化合物33B(0.3g,0.97mmol),1,2,3,4-四氢异喹啉(0.14g,1.06mmol)于异丙醇(10mL)中,室温继续搅拌反应16小时。将反应液浓缩,残留物用硅胶柱色谱分离提纯(二氯甲烷:甲醇(v/v)=40:1-20:1)得到化合物33C(0.35g,81.62%)。
LC-MS(ESI):m/z=443.3[M+H]
+.
第三步:
化合物33C通过手性HPLC拆分得异构体33C-1和异构体33C-2(互为对映异构体),纯化条件如下:(仪器名称:Waters 350;色谱柱:DAICEL CHIRALCEL AD(250mm*30mm,10μm)流动相:A for CO
2and B for IPA(Neu)梯度:45%phase B isocratic elution;流速:200mL/min;柱压: 100bar;柱温:35℃;吸收波长:220nm;循环时间:~7min)。异构体33C-1保留时间:2.265min;异构体33C-2保留时间:2.579min。异构体33C-1和异构体33C-2绝对构型不确定。
第四步:
将化合物33C-1(0.42g,0.95mmol),[1,1'-双(二苯基膦)二茂铁]二氯化钯二氯甲烷络合物(80mg)和三乙胺(424m g,4.2mmol)加入甲醇(20mL)和二氯甲烷(20mL)的混合溶剂中,在一氧化碳(20MPa)氛围下,110℃反应3小时。待反应液冷至室温,过滤,滤液减压浓缩后柱层析得到化合物33D-1(0.34g,85%)。
LC-MS(ESI):m/z=423.2[M+H]
+.
以33C-2为原料,参考上述合成方法,合成得到33D-2。
第五步:
将化合物33D-1(0.34g,0.8mmol)溶于甲醇(3mL),四氢呋喃(3mL)和水(6mL)中,加入一水合氢氧化锂(0.17g,4.02mmol),然后室温下搅拌反应2小时。加入稀盐酸调pH至5-6,加入水(50mL)和二氯甲烷(20×3mL)萃取,合并后的有机相用饱和氯化钠洗涤,无水硫酸钠干燥,过滤,浓缩,得到标题化合物33E-1(0.26g,79.1%),无需纯化直接用于下一步反应。
LC-MS(ESI):m/z=409.1[M+H]
+.
以33D-2为原料,参考上述合成方法,合成得到33E-2。
第六步:
将化合物33E-1(0.08g,0.20mmol)溶于二氯甲烷(10mL)中,加入7-氮杂螺[3.5]壬烷-2-腈盐酸盐(0.048g,0.24mmol),N,N-二异丙基乙胺(0.12g,0.96mmol)和2-(7-氮杂苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯(0.09g,0.24mmol),加完后室温反应1小时。浓缩,残留物用硅胶柱色谱分离提纯(二氯甲烷:甲醇(v/v)=40:1-10:1)得到化合物33,异构体1(0.04g,38.7%)。
1H NMR(400MHz,CDCl
3)δ8.10-8.08(m,1H),7.33-7.32(m,1H),7.30-7.28(m,1H),7.19-7.11(m,3H),7.03-7.00(m,1H),4.23-4.21(m,1H),3.93-3.87(m,2H),3.76-3.70(m,4H),3.60-3.47(m,3H),3.31-3.24(m,2H),3.10-2.64(m,10H),2.31-2.24(m,5H),1.35(m,6H).
LC-MS(ESI):m/z=541.3[M+H]
+.
以33E-2为原料,参考上述合成方法,合成得到化合物33,异构体2。
1H NMR(400MHz,CDCl
3)δ8.09-8.08(m,1H),7.33-7.31(m,1H),7.30-7.27(m,1H),7.19-7.12(m,3H),7.05-7.00(m,1H),4.23-4.21(m,1H),3.93-3.85(m,2H),3.76-3.71(m,4H),3.60-3.47(m,3H),3.31-3.24(m,2H),3.10-2.64(m,10H),2.32-2.24(m,5H),1.35(m,6H).
LC-MS(ESI):m/z=541.2[M+H]
+.
实施例34:2-(3-(3,4-二氢异喹啉-2(1H)-基)-2-羟丙基)-6-(2-甲氧基-7-氮杂螺[3.5]壬烷-7-碳酰)-4,4-二甲基-3,4-二氢异喹啉-1(2H)-酮(化合物34)
2-(3-(3,4-dihydroisoquinolin-2(1H)-yl)-2-hydroxypropyl)-6-(2-methoxy-7-azaspiro[3.5]nonane-7-carbonyl)-4,4-dimethyl-3,4-dihydroisoquinolin-1(2H)-one
将33E-1(0.08g,0.19mmol)溶于二氯甲烷(8mL)中,加入化合物34A(参考专利WO2021088992中描述方法合成)(0.045g,0.24mmol),N,N-二异丙基乙胺(0.06g,0.48mmol)和2-(7-氮杂苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯(0.09g,0.24mmol),加完后室温反应1小时。浓缩,残留物用硅胶柱色谱分离提纯(二氯甲烷:甲醇(v/v)=40:1-10:1)得到标题化合物化合物34,异构体1(16mg,15%)。
1H NMR(400MHz,CDCl
3)δ8.08-8.06(m,1H),7.33-7.32(m,1H),7.31-7.28(m,1H),7.20-7.13(m,3H),7.04-7.02(m,1H),4.35-4.33(m,1H),4.09-4.05(m,1H),3.93-3.84(m,3H),3.69-3.60(m,2H),3.59-3.52(m,3H),3.23-3.18(m,6H),3.05-2.80(m,6H),2.25-2.22(m,2H),1.75-1.68(m,6H),1.35(s,6H).
LC-MS(ESI):m/z=546.3[M+H]
+.
以33E-2为原料,参考上述合成方法,合成得到化合物34,异构体2。
1H NMR(400MHz,CDCl
3)δ
1H NMR(400MHz,CDCl
3)δ8.08-8.05(m,1H),7.33-7.32(m,1H),7.32-7.28(m,1H),7.20-7.13(m,3H),7.04-7.02(m,1H),4.35-4.33(m,1H),4.09-4.06(m,1H),3.93-3.84(m,3H),3.70-3.61(m,2H),3.59-3.52(m,3H),3.23-3.18(m,6H),3.05-2.82(m,6H),2.26-2.22(m,2H),1.76-1.68(m,6H),1.35(s,6H).
LC-MS(ESI):m/z=546.3[M+H]
+.
实施例35:2-(3-(3,4-二氢异喹啉-2(1H)-基)-2-羟丙基)-6-(2-(三氟甲氧基)-7-氮杂螺[3.5]壬烷-7-碳酰)-3,4-二氢异喹啉-1(2H)-酮(化合物35)
2-(3-(3,4-dihydroisoquinolin-2(1H)-yl)-2-hydroxypropyl)-6-(2-(trifluoromethoxy)-7-azaspiro[3.5]nonane-7-carbonyl)-3,4-dihydroisoquinolin-1(2H)-one
将化合物4A(0.1g,0.26mmol)溶于二氯甲烷(10mL)中,加入化合物35A(按照文献WO2017001660的方法合成)(0.066g,0.32mmol),N,N-二异丙基乙胺(0.1g,0.8mmol)和2-(7-氮杂苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯(0.12g,0.31mmol),加完后室温继续搅拌反应3小时。将反应倒入50mL水中,用二氯甲烷(20mL×3)萃取,合并后的有机相用无水硫酸钠干燥,过滤,浓缩,残留物用硅胶柱色谱分离提纯(二氯甲烷:甲醇(v/v)=40:1-20:1)得到标题化合物35(0.030g,20%)。
1H NMR(400MHz,CDCl
3)δ8.07-8.05(m,1H),7.31-7.28(m,1H),7.23(s,1H),7.19-7.12(m,2H),7.04-7.02(m,1H),4.76-4.74(m,1H),4.29-4.27(m,1H),4.07-3.95(m,1H),3.89-3.75(m,3H),3.74-3.68(m,2H),3.55-3.50(m,1H),3.33-3.30(m,2H),3.09-2.97(m,6H),2.86-2.72(m,3H),2.39-2.32(m,2H),2.08-2.05(m,2H),1.69-1.59(m,6H).
LC-MS(ESI):m/z=572.3[M+H]
+.
实施例36:(R)-7-((1-乙酰哌啶-4-基)氨基)-2-(3-(6,7-二氢噻吩[3,2-c]吡啶-5(4H)-基)-2-羟丙基)-4,4-二甲基-3,4-二氢异喹啉-1(2H)-酮(化合物36)
(R)-7-((1-acetylpiperidin-4-yl)amino)-2-(3-(6,7-dihydrothieno[3,2-c]pyridin-5(4H)-yl)-2-hydroxypropyl)-4,4-dimethyl-3,4-dihydroisoquinolin-1(2H)-one
第一步:
将化合物36A(5.00g,28.54mmol)溶于二甲亚砜(100mL)溶液中,氮气保护下加入碳酸铯(27.9g,85.62mmol),室温搅拌30min。缓慢滴加碘甲烷(8.91g,62.79mmol),室温搅拌过夜。TLC反应完成后,加入300mL水,用乙酸乙酯(300mL×3)萃取,合并后的有机相,用无水硫酸钠干燥,过滤,浓缩后得到化合物36B(5.60g,96.58%)。
LC-MS(ESI):m/z=204.1[M+H]
+.
第二步:
将化合物36B(5.6g,27.55mmol)溶于甲醇100(mL)溶液中,氮气保护下加入二氯化钴(14.31g,110.2mmol),降温至0-10℃,搅拌30min,分批次缓慢加入硼氢化钠(6.25g,165.3mmol),然后升至室温搅拌,TLC监测反应。反应完全后,过滤,滤饼溶少量的甲醇洗涤。将滤液减压浓缩后,向残余物中加入水(200mL),并用乙酸乙酯(300mL×3)萃取,合并后的有机相,用无水硫酸钠干燥,过滤,浓缩后得到的残余物经硅胶柱层析分离提纯(石油醚:乙酸乙酯(v/v)=50:1-10:1)得到化合物36C(3.8g,78.71%)。
LC-MS(ESI):m/z=176.2[M+H]
+.
第三步:
将化合物36C(3.6g,20.54mmol)溶于浓硫酸(30mL)中。冰浴、氮气氛围下搅拌30min,温度控制在0-10℃,缓慢滴加浓硝酸(6mL),滴加完毕后继续搅拌30min,TLC监测反应。反应完全后,将反应液缓慢倾倒至冰水(100mL)中,并用乙酸乙酯(300mL×3)萃取,合并后的有机相用无水硫酸钠干燥,过滤,浓缩后得到化合物36D(2.6g,57.48%)。
LC-MS(ESI):m/z=221.1[M+H]
+.
第四步:
将化合物36D(1.00g,4.50mmol)溶于DMF(20mL)溶液中。0℃、氮气氛围下,加入氢化钠(0.16g,6.75mmol),继续搅拌30min。滴加(R)-(-)-对硝基苯磺酸缩水甘油酯(1.17g,4.50mmol)的DMF(20mL)溶液,滴加完毕后,TLC监测反应。反应完成后,加入水50mL,用乙酸乙酯(50mL×3)萃取,合并后的有机相用无水硫酸钠干燥,过滤,浓缩后得到化合物36E(0.60g,48.26%)。
LC-MS(ESI):m/z=277.1[M+H]
+.
第五步:
将化合物36E(1.24g,4.46mmol)溶于异丙醇(60mL)中,氮气保护下加入N,N-二异丙基乙胺(1.73g,13.38mmol),搅拌30min后,加入4,5,6,7-四氢噻吩[3,2-c]吡啶盐酸盐(0.86g,4.91mmol),升温至100℃反应3小时。待反应冷至室温后,浓缩,残余物经硅胶柱层析纯化(二氯甲烷:甲醇(v/v)=99:1-10:1)得化合物36F(1.1g,59.07%)。
LC-MS(ESI):m/z=416.2[M-H]
-.
第六步:
将铁粉(0.96g,17.22mmol)和氯化铵(0.92g,17.22mmol)固体加入到80mL乙醇和水(1:1),60℃下搅拌30min,加入化合物36F(1.10g,2.65mmol),升温至80℃反应1小时。待反应冷至室温后,浓缩,残余物经硅胶柱层析纯化(二氯甲烷:甲醇(v/v)=99:1-10:1)得化合物36G(0.75g,73.41%)。
LC-MS(ESI):m/z=386.2[M+H]
+.
第七步:
将化合物36G(300mg,0.77mmol)溶于20mL乙酸中,氮气保护下加入1-乙酰哌啶-4-酮(0.13g,0.92mmol)和三乙酰氧基硼氢化钠(0.33g,1.54mmol),室温搅拌3小时。LC-MS监测反应完全,反应液直接浓缩,得到的残余物经反相硅胶柱色谱分离提纯(水:乙腈(v/v)=99:1-65:35)得化合物36(220mg,55.73%)。
1H NMR(400MHz,DMSO-d6)δ7.25(d,1H),7.18-7.03(m,2H),6.83-6.69(m,2H),5.59(d,1H),4.17(dd,3H),4.00-3.70(m,5H),3.48-3.39(m,2H),3.31(d,1H),3.25-3.14(m,2H),2.78(s,4H),2.00(s,3H),1.85(s,6H),1.20(d,6H).
LC-MS(ESI):m/z=511.3[M+H]
+.
实施例37:(R)-7'-((1-乙酰哌啶-4-基)氨基)-2'-(3-(6,7-二氢噻吩并[3,2-c]吡啶-5(4H)-基)-2-羟丙基)-2',3'-二氢-1H-螺[环丙烷-1,4'-[2,6]萘啶]-1'-酮(化合物37)
(R)-7'-((1-acetylpiperidin-4-yl)amino)-2'-(3-(6,7-dihydrothieno[3,2-c]pyridin-5(4H)-yl)-2-hydroxypropyl)-2',3'-dihydro-1'H-spiro[cyclopropane-1,4'-[2,6]naphthyridin]-1'-one
第一步:
将37A(10g,42.29mmol)溶于100mL二氯甲烷中,冷却到0℃,加入草酰氯(5.90g,46.52mmol)和一滴DMF,反应升至室温搅拌过夜。加入20mL乙醇,反应半小时,浓缩后经硅胶柱层析分离(石油醚:乙酸乙酯(v/v)=5:1)得到化合物37B(10g,收率:94.40%)。
LCMS m/z=265.3[M+H]
+
第二步:
将化合物37B(22.00g,83.18mmol),甲基硼酸(7.47g,124.77mmol),磷酸钾(61.80g,291.13mmol)和三环已基磷(4.67g,16.68mmol)溶于200mL甲苯和10mL水中,氮气保护,加入醋酸钯(1.87g,8.32mmol),100℃反应16小时。LC-MS显示反应完全,冷却,过 滤,滤饼用乙酸乙酯洗两次,将滤液浓缩后得到的粗产品经硅胶柱层析分离(石油醚:乙酸乙酯(v/v)=5:1)得到化合物37C(9.7g,收率:58.42%)。
LCMS m/z=200.1[M+H]
+
第三步:
将化合物37C(5.14g,27.69mmol)溶于四氯化碳(50mL)中,加入NBS(4.93g,27.7mmol),过氧化苯甲酰(1g,4.13mmol),80℃下搅拌反应过夜。LCMS监测反应完全,冷却,减压浓缩除去反应溶剂后,加入水和乙酸乙酯萃取,有机相用饱和氯化钠洗2次,无水硫酸钠干燥,过滤,浓缩后经硅胶柱层析分离(石油醚:乙酸乙酯(v/v)=5:1)得到化合物37D(3.8g,收率:53.15%)。
LCMS m/z=279.3[M+H]
+
第四步:
将TMSCN(6.41g,64.62mmol)溶于无水乙腈(200mL)中,加入四丁基氟化铵(21.12g,80.78mmol)。向反应液中缓慢滴加化合物37D(15.00g,53.85mmol)的乙腈(10mL)溶液,滴加完毕后反应3小时。LCMS监测反应完全,反应液用硅藻土抽滤后,向滤液中加水,用乙酸乙酯萃取,有机相用饱和氯化钠洗2次,无水硫酸钠干燥,有机相浓缩后经硅胶柱层析分离(石油醚:乙酸乙酯(v/v)=4:1)得到化合物37E(10.3g,收率:85.15%)。
LCMS m/z=225.4[M+H]
+
第五步:
将2-氯-5-(氰基甲基)异烟酸乙酯(37E)(1.6g,7.12mmol)溶于无水DMF(25mL)中,依次加入1,2-二溴乙烷(2.0g,10.65mmol),碳酸铯(4.64g,14.24mmol)。室温,氮气氛围下搅拌16个小时。LCMS监测反应完全后,加水,用乙酸乙酯萃取,有机相用饱和氯化钠洗2次,无水硫酸钠干燥,过滤,浓缩,柱层析分离(石油醚:乙酸乙酯(v/v)=3:1)得到化合物37F(1.3g,收率:73.03%)。
LCMS m/z=251.1[M+H]
+
第六步:
将化合物37F(0.011g,0.042mmol)溶于无水1,4-二氧六环(3mL)中,加入1-乙酰基哌啶-4-胺(0.006g,0.042mmol),碳酸铯(0.041g,0.13mmol),(2-二环己基膦基-2′,4′,6′-三异丙基-1,1′-联苯基)[2-(2-氨乙基)苯基)]氯化钯(II)(0.0033g,0.0042mmol),氮气氛围,90℃下反应过夜。LCMS监测反应完全,冷却,浓缩后柱层析分离(二氯甲烷:甲醇(v/v)=10:1)得到化合物37G(10mg,收率:66.80%)。
LCMS m/z=357.2[M+H]
+
第七步:
将化合物37G(0.2g,0.56mmol)溶于10mL氨的甲醇溶液,加入1g雷尼镍,氢气氛围反应2小时。TLC显示反应完全,过滤,滤饼用10mL二氯甲烷/甲醇(10:1)洗三次,将滤液浓缩后得到37H(0.17g,收率:95.00%)。
第八步:
将化合物37H(0.22g,0.7mmol)溶于10mL无水N,N-二甲基甲酰胺中,加入氢化钠(0.042g,1.05mmol),搅拌半小时。加入(R)-(-)-4-硝基苯磺酸缩水甘油酯(0.22g,0.84mmol),反应半小时,TLC显示反应完全,浓缩,再加入DCM洗三次,浓缩得到37I(0.12g,46.28%)。
第九步:
将4,5,6,7-四氢噻吩并[3,2-c]吡啶盐酸盐(0.084g,0.48mmol),DIPEA(0.12g,0.96mmol)溶于5mL异丙醇中。反应半小时,加入化合物37I(60mg,0.16mmol),升温至110℃搅拌1小时。冷却,浓缩后,残余物经反相制备柱纯化(乙腈:水(v/v)=35:65)得到目标化合物37(5mg,收率:6.10%)。
LCMS m/z=510.3[M+H]
+
实施例38:7-[(1-乙酰哌啶-4-基)氨基]-4-[(2R)-2-羟基-3-(4H,5H,6H,7H-噻吩[3,2-c]吡啶-5-基)丙基]-2,3,4,5-四氢-1,4-并氮杂卓-5-酮(化合物38)
7-[(1-acetylpiperidin-4-yl)amino]-4-[(2R)-2-hydroxy-3-(4H,5H,6H,7H-thieno[3,2-c]pyridin-5-yl)propyl]-2,3,4,5-tetrahydro-1,4-benzoxazepin-5-one
第一步:
将3,4-二氢-1,4-苯并氧氮杂卓-5(2H)-酮(2.00g,12.25mmol)置于乙酸(20mL)中。加入液溴(2.15g,13.48mmol),升温至60℃反应6小时。反应完全后,冷至室温,浓缩反应液,所得残余物经硅胶柱纯化(乙酸乙酯:石油醚=0-100%)得化合物38B(1.08g,收率36.42%)
LC-MS(ESI):m/z=242.1[M+H]
+
第二步:
将化合物38B(500mg,2.07mmol)置于N,N-二甲基甲酰胺(40mL)中。氮气氛围,0-10℃下,加入氢化钠(99mg,4.14mmol)。搅拌30分钟后,将(R)-(-)-4-硝基苯磺酸缩水甘油酯(590mg,2.28mmol)的N,N-二甲基甲酰胺(10mL)溶液缓慢加入反应液中,反应升至室温搅拌30分钟。浓缩反应液至2mL,加入异丙醇(20mL),再次浓缩至2mL后,加入异丙醇(100mL),依次加入N,N-二异丙基乙胺(800mg,6.21mmol)、4,5,6,7-四氢噻吩并[3,2-c]吡啶盐酸盐(580mg,4.14mmol),氮气置换后升温至100℃反应3小时。待反应完全后,冷至室温,将反应液过滤浓缩至干,残余物经硅胶柱纯化(甲醇:二氯甲烷=0-10%),得化合物38C(720mg,收率79.53%)。
LC-MS(ESI):m/z=437.0[M+H]
+
第三步:
将化合物38C(200mg,0.46mmol)、1-乙酰哌啶-4-胺(78mg,0.55mmol)、1,1'-联萘-2,2'-双二苯膦(43mg,0.069mmol)、叔丁醇钠(88mg,0.92mmol)依次加入到甲苯(10mL)中。氮气置换3次后,加入三(二亚苄基丙酮)二钯(51mg,0.055mmol),再次氮气置换3次后,升温至80℃反应过夜。待反应完全后,冷至室温,过滤,将滤液旋干后得到的残余物用液相制备柱分离提纯(液相制备条件:C18反相制备柱,流动相为含0.1%氨水的去离子水(A),乙腈(B),梯度洗脱,B含量=5%~50%,洗脱时间15min,流速12mL/min,柱温:30℃);得到化合物38(10mg,收率4.36%,保留时间约为4.47min)。
LC-MS(ESI):m/z=499.3[M+H]
+
1H NMR(400MHz,DMSO-d
6)δ9.87(s,1H),7.50(d,1H),6.99-6.69(m,4H),5.86(s,1H),4.54(s,1H),4.38-4.15(m,8H),3.78(m,6H),3.18(m,4H),2.80(s,1H),2.00(s,5H),1.41-1.11(m,2H).
生物测试:
1、PRMT5酶活测试方法
配制1×测试缓冲液(10mM Tris,1mM DTT,0.01%BSA,0.01%Tween-20,调整PH至8.0)。测试化合物用DMSO溶解配成10mM母液,后用DMSO稀释至100倍终浓度,给药组每孔加入100nL化合物,空白孔和阴性对照孔加入100nL DMSO溶液。然后,给药组与阴性对照孔加入5μL PRMT5/MEP50(BPS,Cat.31921)酶溶液(终浓度为1nM),空白孔加入5μL 1×测试缓冲液,室温孵育15分钟。每孔加入5μL H4(1-21)S1ac(0.05μM;GL Biochem, customized)与SAM(1μM;Sigma,Cat.A7007)混合液后室温孵育1小时。配制1×Epigenetics buffer(PerkinElmer,Cat.AL008F)用于稀释受体微珠与供体微珠。加入15μL受体微珠(终浓度为10μg/mL;PerkinElmer,Cat.AL150C)与供体微珠(终浓度为10μg/mL;PerkinElmer,Cat.AS106M)避光室温孵育1小时后,使用Enspire酶标仪中Alpha模块检测。所得数据在Excel中计算抑制率:抑制率(%)=(最大值
阴性对照-检测信号值)/(最大值
阴性对照-最小值
空白对照)*100,使用XL-Fit拟合IC
50值。
测试结果:本发明化合物对PRMT5受体显示有抑制活性,实施例化合物对PRMT5酶活的IC50值在0.01-1000nM范围内。其中,部分实施例的测试结果如表1所示:
表1化合物PRMT5酶活
化合物编号 | IC50(nM) |
化合物1 | 95 |
化合物2 | 38 |
化合物3 | 51 |
化合物5 | 53 |
化合物6 | 72 |
化合物7 | 69 |
化合物8 | 53 |
化合物9 | 31 |
化合物10 | 24 |
化合物11 | 18 |
化合物12 | 23 |
化合物13 | 26 |
化合物14 | 27 |
化合物15 | 24 |
化合物16 | 13 |
化合物17,异构体2 | 17 |
化合物18 | 85 |
化合物19 | 27 |
化合物20 | 39 |
化合物22,异构体1 | 18 |
化合物22,异构体2 | 61 |
化合物12,异构体1 | 15 |
化合物12,异构体2 | 15 |
化合物24 | 65 |
化合物25 | 80 |
化合物26 | 54 |
化合物27 | 76 |
化合物29 | 13 |
化合物30 | 16 |
化合物20,异构体1 | 90 |
化合物20,异构体2 | 30 |
化合物32 | 31 |
化合物33,异构体1 | 54 |
化合物34,异构体1 | 45 |
化合物34,异构体2 | 40 |
化合物35 | 22 |
化合物36 | 31 |
化合物37 | 36 |
化合物38 | 7.7 |
结论:本发明专利的化合物对PRMT5有抑制作用。
2、SW620细胞增殖抑制实验
SW620细胞用DMEM培养基(ATCC,Cat#30-2002,添加10%FBS与1%双抗)培养至汇合度达到85%左右时进行细胞铺板。弃培养基,用1×PBS润洗后加入胰酶(Gibco,Cat#15400-054)消化,待细胞变圆并开始脱落时加入培养基终止消化,将细胞吹打下来并转移至无菌离心管中,1000rpm离心3分钟,离心完毕取出,弃上清液。离心管加入培养基重悬细胞,计数。根据计数结果将细胞悬液调整到适当浓度后倒入加样槽中,加入第一块96孔细胞板(Corning,Cat#3903)中,同时铺10个Day0孔于第二块96孔细胞板中,并在两块96孔细胞板上标注好细胞信息及铺板日期。用DMSO将化合物溶解至10mM保存备用,实验时将化合物母液依次进行5倍稀释。铺板24小时后在第一块96孔细胞板上加入稀释好的化合物,共9个浓度,每个浓度3复孔,同时设置DMSO溶媒对照组,在37℃、5%CO
2条件下继续培养6天。第二块96孔细胞板于铺板24小时后每孔加入CELL VIABILITY试剂(Promega,Cat#G7573),第一块96孔细胞板于给药后第6天每孔加入CELL VIABILITY试剂,室温孵育30分钟,孵育结束后轻轻振摇5次,然后用酶标仪检测化学发光读数。细胞增殖抑制率按照以下公式计算:[1-(T
测试-T
0/T
对照-T
0)]×100式,再使用Origin9.2软件,采用DoseResp函数计算化合物抑制细胞增殖的GI
50值。
测试结果:本发明化合物对PRMT5受体显示有抑制活性,实施例化合物对SW620细胞的IC50值小于100μM。化合物A(专利WO2015198229中描述的Compound A),化合物B(专利WO2019173804中描述的24a),其中,部分实施例的测试结果如表2所示:
表2细胞增殖活性
化合物编号 | IC50(μM) |
化合物12 | 0.5 |
化合物14 | 0.21 |
化合物15 | 0.25 |
化合物16 | 0.73 |
化合物12,异构体2 | 0.036 |
化合物A | 0.33 |
化合物B | 0.11 |
结论:本发明专利的化合物对SW620细胞有增殖抑制作用。
3、MDA-MB-231细胞增殖抑制实验
MDA-MB-231细胞用DMEM培养基(添加10%FBS与1%双抗)培养至汇合度达到85%左右时进行细胞铺板。弃培养基,用1×PBS润洗后加入胰酶(Gibco,Cat#15400-054)消化,待细胞变圆并开始脱落时加入培养基终止消化,将细胞吹打下来并转移至无菌离心管中,1000rpm离心3分钟,离心完毕取出,弃上清液。离心管加入培养基重悬细胞,计数。根据计数结果将细胞悬液调整到适当浓度后倒入加样槽中,加入第一块96孔细胞板(Corning,Cat#3903)中,同时铺10个Day0孔于第二块96孔细胞板中,并在两块96孔细胞板上标注好细胞信息及铺板日期。用DMSO将化合物溶解至10mM保存备用,实验时将化合物母液依次进行5倍稀释。铺板24小时后在第一块96孔细胞板上加入稀释好的化合物,共9个浓度,每个浓度3复孔,同时设置DMSO溶媒对照组,在37℃、5%CO
2条件下继续培养6天。第二块96孔细胞板于铺板24小时后每孔加入CELL VIABILITY试剂(Promega,Cat#G7573),第一块96孔细胞板于给药后第6天每孔加入CELL VIABILITY试剂,室温孵育30分钟,孵育结束后轻轻振摇5次,然后用酶标仪检测化学发光读数。细胞增殖抑制率按照以下公式计算:[1-(T
测试-T
0/T
对照-T
0)]×100式,再使用Origin9.2软件,采用DoseResp函数计算化合物抑制细胞增殖的GI
50值。
表3细胞增殖活性
化合物编号 | IC50(μM) |
化合物14 | 0.078 |
化合物15 | 0.063 |
化合物12,异构体2 | 0.043 |
化合物29 | 0.029 |
化合物30 | 0.134 |
化合物32 | 0.115 |
化合物34,异构体1 | 0.4 |
化合物35 | 0.137 |
化合物37 | 0.47 |
化合物A | 0.21 |
化合物B | 0.15 |
结论:本发明专利的化合物对MDA-MB-231细胞有增殖抑制作用。
4、小鼠药代动力学测试
实验目的:通过单剂量静脉和灌胃给予受试物于BALB/c小鼠,测定小鼠血浆中受试物的浓度,评价受试物在小鼠体内药代特征和生物利用度。
实验对象:本发明实施例化合物12,异构体2。
试验动物:雄性BALB/c小鼠,20~25g左右,6~8周龄,18只/化合物。购于湖南斯莱克景达实验动物有限公司。
试验方法:试验当天,18只BALB/c小鼠按体重随机分组。给药前1天禁食不禁水12~14h,给药后4h给食。按照表4给药。
表4给药信息
静脉给药溶媒:5%DMA+5%Solutol+90%Saline;灌胃给药溶媒:0.5%MC
于给药前及给药后异氟烷麻醉经眼眶取血0.08mL,置于EDTAK2离心管中。5000rpm,4℃离心10min,收集血浆。静脉组采血时间点:0,5,15,30min,1,2,4,6,8,24h;灌胃组采血时间点:0,5,15,30min,1,2,4,6,8,24h。分析检测前,所有样品存于-80℃。
表5化合物在小鼠体内的药代动力学参数
结论:化合物12,异构体2小鼠药代动力学上生物利用度优异。
5、食蟹猴药代动力学测试
实验目的:通过单剂量静脉和灌胃给予受试物于食蟹猴,测定食蟹猴血浆中受试物的浓度,评价受试物在食蟹猴体内药代特征和生物利用度。
实验对象:本发明实施例化合物。
试验动物:雄性食蟹猴,3~5kg左右,6只/化合物,购于苏州西山中科实验动物有限公司。
试验方法:试验当天,6只食蟹猴按体重随机分组。给药前1天禁食不禁水12~14h,给药后4h给食。按照表6给药。
表6给药信息
静脉给药溶媒:5%DMA+5%Solutol+90%Saline;灌胃给药溶媒:0.5%MC
于给药前及给药后异氟烷麻醉经眼眶取血1ml,置于EDTAK2离心管中。5000rpm,4℃离心10min,收集血浆。静脉组采血时间点:0,5,15,30min,1,2,4,6,8,10,12,24h;灌胃组采血时间点:0,5,15,30min,1,2,4,6,8,10,12,24h。分析检测前,所有样品存于-80℃。
表7化合物在食蟹猴体内的药代动力学参数
结论:化合物12,异构体2猴药代动力学上生物利用度优异。
Claims (15)
- 一种式(I)所示的化合物,其立体异构体、氘代物、溶剂化物、前药、代谢产物、药学上可接受的盐或共晶,其中,A环选自苯基或者5-6元杂芳基;R 1、R 2、R 3、R 4各自独立地选自氢、氘、羟基、卤素、氨基、硝基、氰基、C 1-6烷基、C 1-6烷氧基、C 3-8环烷基、C 1-6烷基氨基、二(C 1-6烷基)氨基、-C(O)C 1-6烷基、-C(O)NHC 1-6烷基、-C(O)NH 2、-NHC(O)C 1-6烷基、-N(C 1-6烷基)C(O)C 1-6烷基,所述烷基、烷氧基任选被1至5个选自卤素、氘、羟基、氨基、氰基、C 1-6烷氧基的基团取代;作为选择,R 1、R 2与连接的碳原子一起形成3-6元环烷基、3-6元杂环烷基;作为选择,R 3、R 4与连接的碳原子一起形成3-6元环烷基、3-6元杂环烷基;R 5选自氢、氘、C 1-6烷基、C 1-6烷氧基、-C(O)C 1-6烷基、-C(O)NH 2、-C(O)NHC 1-6烷基,所述烷基、烷氧基任选被1至5个选自卤素、氘、羟基、氨基、氰基、C 1-6烷氧基的基团取代;R 8选自氢、氘、羟基、卤素、氨基、硝基、氰基、C 1-6烷基、C 1-6烷氧基、卤代C 1-6烷基、卤代C 1-6烷氧基、氘代C 1-6烷基、氘代C 1-6烷氧基;R 6选自氘、卤素、氰基、硝基、氰基、氨基、羟基、C 1-6烷基、C 1-6烷氧基、C 2-6烯基、C 2-6炔基、-SF 5、-(CH 2) r-C 3-8环烷基、-(CH 2) r-(3-8元杂环烷基)、-O-C 3-8环烷基、-O-(3-8元杂环烷基)、-NH-C 3-8环烷基、-NH-(3-8元杂环烷基)、-S-C 3-8环烷基、-S-(3-8元杂环烷基)、5至8元杂芳基、6至8元芳基、-C(=O)NR 6aR 6b、-NR 6aC(=O)-R 6b、-NR 6aR 6b、-C(=O)-R 6a、-S-C 1-6烷基、-S(O)-C 1-6烷基、-S(O) 2-C 1-6烷基,所述CH 2、烷基、烷氧基、环烷基、杂环烷基、杂芳基、芳基任选进一步被1至5个选自卤素、氘、硝基、氰基、氨基、羟基、=O、C 1-6烷基、C 1-6烷氧基、卤代C 1-6烷基、卤代C 1-6烷氧基、氘代C 1-6烷基、氘代C 1-6烷氧基的基团取代;R 6a选自氢、氘、C 1-6烷基、C 3-8环烷基、3-8元杂环烷基,所述烷基、环烷基、杂环烷基任选被1至5个选自卤素、氘、羟基、氨基、氰基、C 1-6烷氧基的基团取代;R 6b选自氢、氘、C 1-6烷基、C 1-6烷氧基、C 3-8环烷基、3-8元杂环烷基、C 1-6烷基氨基、二(C 1-6烷基)氨基、-S(O) 2C 1-6烷基,所述的烷基、烷氧基、环烷基、杂环烷基任选被1至5个选自卤素、氘、羟基、氨基、氰基、=O、C 1-6烷基、C 1-6烷氧基、卤代C 1-6烷基、卤代C 1-6烷氧基、氘代C 1-6烷基、氘代C 1-6烷氧基的基团取代;X选自键、-O-、-S-、-S(O)-、-S(O) 2-、-CR xaR xb-或者-NR xa-;Y选自键、-O-、-S-、-S(O)-、-S(O) 2-、-CR yaR yb-、-NR ya-或者-CR ya-;Z选自键、-O-、-S-、-S(O)-、-S(O) 2-、-CR zaR zb-、-NR za-、-CR za-或者-N-;条件是,X、Y、Z不同时为键;X 1选自-CR x1a-或者-N-;X 2选自-CR x2a-或者-N-;X 3选自-CR x3a-或者-N-;X 7选自-CR x7a-或者-N-;X 4选自-O-、-S-、-CR x4aR x4b-或者-NR x4a-;X 5选自-O-、-S-、-CR x5aR x5b-或者-NR x5a-;X 6选自键、-O-、-S-、-CR x6aR x6b-或者-NR x6a-;R x1a、R x2a、R x3a、R x7a各自独立选自氢、氘、卤素、硝基、氰基、氨基、羟基、-L-R 7、C 1-6烷基、C 1-6烷氧基、C 2-6烯基、C 2-6炔基、-SF 5、-(CH 2) r-C 3-12环烷基、-(CH 2) r-(3-12元杂环烷基)、-O-C 3-12环烷基、-O-(3-12元杂环烷基)、-NH-C 3-12环烷基、-NH-(3-12元杂环烷基)、-S-C 3-12环烷基、-S-(3-12元杂环烷基)、5至12元杂芳基、6至12元芳基、-C(=O)NR xaaR xab、-NR xaaC(=O)-R xab、-NR xaaR xab、-C(=O)-R xaa、-S-C 1-6烷基、-S(O)-C 1-6烷基、-S(O) 2-C 1-6烷基,所述CH 2、烷基、烷氧基、环烷基、杂环烷基、杂芳基、芳基任选进一步被1至5个选自卤素、氘、硝基、氰基、氨基、羟基、=O、C 1-6烷基、C 1-6烷氧基、卤代C 1-6烷基、卤代C 1-6烷氧基、氘代C 1-6烷基、氘代C 1-6烷氧基的基团取代;R xa、R xb、R ya、R yb、R za、R zb、R x4a、R x4b、R x5a、R x5b、R x6a、R x6b各自独立选自氢、氘、卤素、硝基、氰基、氨基、羟基、C 1-6烷基、C 1-6烷氧基、C 2-6烯基、C 2-6炔基、-SF 5、-(CH 2) r-C 3-12环烷基、-(CH 2) r-(3-12元杂环烷基)、-O-C 3-12环烷基、-O-(3-12元杂环烷基)、-NH-C 3-12环烷基、-NH-(3-12元杂环烷基)、-S-C 3-12环烷基、-S-(3-12元杂环烷基)、5至12 元杂芳基、6至12元芳基、-C(=O)NR xaaR xab、-NR xaaC(=O)-R xab、-NR xaaR xab、-C(=O)-R xaa、-S-C 1-6烷基、-S(O)-C 1-6烷基、-S(O) 2-C 1-6烷基,所述CH 2、烷基、烷氧基、环烷基、杂环烷基、杂芳基、芳基任选进一步被1至5个选自卤素、氘、硝基、氰基、氨基、羟基、=O、C 1-6烷基、C 1-6烷氧基、卤代C 1-6烷基、卤代C 1-6烷氧基、氘代C 1-6烷基、氘代C 1-6烷氧基的基团取代;R xaa、R xab各自独立选自氢、氘、氨基、羟基、C 1-6烷基、卤代C 1-6烷基、氘代C 1-6烷基、C 1-6烷氧基、卤代C 1-6烷氧基、氘代C 1-6烷氧基;作为选择,连接于同一碳原子上的R xa和R xb、R ya和R yb、R za和R zb、R x4a和R x4b、R x5a和R x5b,或R x6a和R x6b与所连接的碳原子一起形成=O、3-6元环烷基或3-6元杂环烷基;作为选择,连接于相邻碳原子上的R xa和R za与所连接的碳原子一起形成=O、3-6元环烷基或3-6元杂环烷基;作为选择,R x4a与R x6a一起形成-CH 2-或者-CH 2CH 2-;L选自键、-NR La、-C(O)-、-C(O)NR La-、-NR LaC(O)-、-NR LaC(O)-(CH 2) p-O-、-O-(CH 2) p-C(O)NR La-、-NR LaC(O)-NR La-、-O-、-S-、-S(O) 2NR La-、-NR LaS(O) 2-;R La选自氢、氘、C 1-6烷基、卤代C 1-6烷基、氘代C 1-6烷基;R 7选自H、C 1-6烷基、C 1-6烷氧基、C 2-6烯基、C 2-6炔基、-SF 5、-(CH 2) r-C 3-12环烷基、-(CH 2) r-(4-12元杂环烷基)、-(CH 2) r-(5-12元杂芳基)、-(CH 2) r-(6-12元芳基),所述CH 2、烷基、烷氧基、环烷基、杂环烷基、杂芳基、芳基任选进一步被1至5个选自氘、卤素、硝基、氰基、氨基、羟基、C 1-6烷基、=O、C 1-6烷氧基、C 2-6烯基、C 2-6炔基、卤代C 1-6烷基、卤代C 1-6烷氧基、氘代C 1-6烷基、氘代C 1-6烷氧基、-SF 5、-(CH 2) r-C 3-8环烷基、-(CH 2) r-(3-8元杂环烷基)、-O-C 3-8环烷基、-O-(3-8元杂环烷基)、-NH-C 3-8环烷基、-NH-(3-8元杂环烷基)、-S-C 3-8环烷基、-S-(3-8元杂环烷基)、5至8元杂芳基、6至8元芳基、-C(=O)NR cyaR cyb、-NR cyaC(=O)-R cyb、-NR cyaR cyb、-C(=O)-R cya、-S-C 1-6烷基、-S(O)-C 1-6烷基、-S(O) 2-C 1-6烷基的基团取代;R cya、R cyb各自独立选自C 1-6烷基、卤代C 1-6烷基、氘代C 1-6烷基;作为选择,-L-R 7选自氢、氘、氨基、羟基、卤素、氰基、C 1-6烷基、C 1-6羟基烷基、C 1- 6烷氧基、卤代C 1-6烷基、氘代C 1-6烷基、卤代C 1-6烷氧基、氘代C 1-6烷氧基;m选自0、1、2、3或4;p选自0、1或2;r选自0、1、2或者3;条件是,式(I)化合物不选自如下化合物:
- 根据权利要求1所述的式(I)所示的化合物,其立体异构体、氘代物、溶剂化物、前药、代谢产物、药学上可接受的盐或共晶,所述式(I)化合物具有式(II-1)、(II-2)、(II-3)、(II-5)、(II-6)、(II-7)、(II-8)、(II-9)、(II-10)、(II-11)、(II-12)、(II-13)、(II-14)、(II-15)结构:其中,A环选自苯基、5元杂芳基或者6元杂芳基;B环选自5元杂芳基或者6元杂芳基;E环为3-6元环烷基或3-6元杂环烷基;H环为3-6元环烷基或3-6元杂环烷基;R 11、R 12、R 13、R 15、R 17、R 18、R 19、R 110、R 111、R 112、R 113、R 114、R 115、R 21、R 22、R 23、R 25、R 27、R 28、R 29、R 210、R 211、R 212、R 213、R 214、R 215、R 31、R 32、R 33、R 35、R 36、R 37、R 38、R 39、R 310、R 311、R 312、R 313、R 314、R 315、R 41、R 42、R 43、R 45、R 46、R 47、R 48、R 49、R 410、R 411、R 412、R 413、R 414、R 415各自独立地选自氢、氘、羟基、卤素、氰基、C 1-4烷基、C 1-4烷氧基,所述烷基、烷氧基任选被1至3个选自卤素、氘、羟基的基团取代;作为选择,连接于同一碳原子上的R 11和R 21、R 31和R 41、R 12和R 22、R 32和R 42、R 13和R 23、R 33和R 43、R 15和R 25、R 35和R 45、R 36和R 46、R 17和R 27、R 37和R 47、R 18和R 28、R 38和R 48、R 19和R 29、R 39和R 49、R 110和R 210、R 310和R 410、R 111和R 211、R 311和R 411、R 112和R 212、R 312和R 412、R 112和R 213、R 313和R 413、R 114和R 214、R 314和R 414、R 115和R 215,或者R 315和R 415分别各自独立地与所连接的碳原子一起形成3元环烷基、4元环烷基、5元环烷基、6元环烷基、3元杂环烷基、4元杂环烷基、5元杂环烷基或6元杂环烷基;R 51、R 52、R 53、R 55、R 56、R 57、R 58、R 59、R 510、R 511、R 512、R 513、R 514、R 515各自独立地选自氢、氘、C 1-4烷基,所述烷基任选被1至3个选自卤素、氘、羟基的基团取代;R 81、R 82、R 83、R 85、R 86、R 87、R 88、R 89、R 810、R 811、R 812、R 813、R 814、R 815各自独立地选自氢、氘、羟基、卤素;连接于同一碳原子上R 9a1和R 9b1、R 9a2和R 9b2与所连接的碳原子一起形成3元环烷基、4元环烷基、5元环烷基、6元环烷基、3元杂环烷基、4元杂环烷基、5元杂环烷基或6元杂环烷基;或者R 9a1和R 9a2相链接形成-CH 2-、-CH 2CH 2-;R 61、R 63、R 65、R 66、R 67、R 68、R 69、R 610、R 611、R 612、R 613、R 614、R 615、R 616、R 617各自独立地选自氘、卤素、氰基、硝基、氨基、羟基、C 1-4烷基、C 1-4烷氧基、-(CH 2) r-C 3-8环烷基、-(CH 2) r-(3-8元杂环烷基)、-O-C 3-8环烷基、-O-(3-8元杂环烷基)、-NH-C 3-8环烷基、-NH-(3-8元杂环烷基)、-S-C 3-8环烷基、-S-(3-8元杂环烷基)、5至8元杂芳基、6至8元芳基、-C(=O)NR 6aR 6b、-NR 6aC(=O)-R 6b、-NR 6aR 6b、-C(=O)-R 6a、-S-C 1-6烷基、-S(O)-C 1-6烷基、-S(O) 2-C 1-6烷基,所述CH 2、烷基、烷氧基、环烷基、杂环烷基、杂芳基、芳基任选进一步被1至5个选自卤素、氘、硝基、氰基、氨基、羟基、=O、C 1-6烷基、C 1-6烷氧基、卤代C 1-6烷基、卤代C 1-6烷氧基、氘代C 1-6烷基、氘代C 1-6烷氧基的基团取代;R 62为氘、卤素、-(CH 2) r-C 3-8环烷基、-(CH 2) r-(3-8元杂环烷基)、-C(=O)NR 6aR 6b、-NR 6aC(=O)-R 6b、-NR 6aR 6b、-C(=O)-R 6a,所述CH 2、环烷基、杂环烷基任选进一步被1至3 个选自卤素、氘、氰基、羟基、=O、C 1-4烷基、C 1-4烷氧基、卤代C 1-4烷基、卤代C 1-4烷氧基、氘代C 1-4烷基、氘代C 1-4烷氧基的基团取代;R 6a选自氢、氘、C 1-6烷基、C 3-8环烷基、3-8元杂环烷基,所述烷基、环烷基、杂环烷基任选被1至5个选自卤素、氘、羟基、氨基、氰基、C 1-6烷氧基的基团取代;R 6b选自氢、氘、C 1-6烷基、C 1-6烷氧基、C 3-8环烷基、3-8元杂环烷基、C 1-6烷基氨基、二(C 1-6烷基)氨基、-S(O) 2C 1-6烷基,所述的烷基、烷氧基、环烷基、杂环烷基任选被1至5个选自卤素、氘、羟基、氨基、氰基、=O、C 1-6烷基、C 1-6烷氧基、卤代C 1-6烷基、卤代C 1-6烷氧基、氘代C 1-6烷基、氘代C 1-6烷氧基的基团取代;X 81、X 83、X 86、X 88、X 89、X 810、X 811、X 813、X 814、X 815各自独立地选自-O-、-S-、-S(O)-、-S(O) 2-、-CR xaR xb-或者-NR xa-;X 87选自-O-、-S(O)-、-S(O) 2-、-CR xaR xb-或者-NR xa-;X 812选自-O-、-S-、-S(O)-、-S(O) 2-、-CR xa2R xb2-或者-NR xa-;X 82选自-O-、-S-、-S(O)-、-S(O) 2-、-CR xa1R xb1-或者-NR xa-;Y 1、Y 2、Y 3、Y 4、Y 5、Y 6各自独立地选自键、-CR yaR yb-、-NR ya-或者-CR ya-;Z 1、Z 2、Z 3、Z 4、Z 5、Z 6各自独立地选自键、-CR zaR zb-、-NR za-、-CR za-或者-N-;X 41、X 42、X 43、X 44各自独立地选自-CR x4aR x4b-或者-NR x4a-;X 51、X 52、X 53、X 54各自独立地选自-CR x5aR x5b-或者-NR x5a-;X 61、X 62、X 63、X 64各自独立地选自键、-CR x6aR x6b-或者-NR x6a-;X 11、X 12、X 13、X 15、X 16、X 17、X 18、X 19、X 110、X 113、X 114、X 115各自独立地选自-CR x1a-或者-N-;X 21、X 22、X 23、X 25、X 26、X 27、X 28、X 29、X 211、X 213、X 214、X 215各自独立地选自-CR x2a-或者-N-;X 31、X 32、X 33、X 35、X 36、X 37、X 38、X 39、X 310、X 311各自独立地选自-CR x3a-或者-N-;X 710、X 711、X 713、X 714、X 715各自独立地选自-CR x7a-或者-N-;X 112选自-CR x1b-;X 212选自-CR x2b-;X 712选自-CR x7b-;R x1a、R x2a、R x3a、R x7a各自独立选自氢、氘、卤素、硝基、氰基、氨基、羟基、C 1-4烷基、C 1-4烷氧基、C 2-6烯基、C 2-6炔基、-SF 5,所述烷基、烷氧基任选进一步被1至3个选自 F、Cl、氘、硝基、氰基、氨基、羟基、C 1-2烷基、C 1-2烷氧基、卤代C 1-2烷基、卤代C 1-2烷氧基、氘代C 1-2烷基、氘代C 1-2烷氧基的基团取代;R xa、R xb、R xa2、R xb2、R ya、R yb、R za、R zb、R x4a、R x4b、R x5a、R x5b、R x6a、R x6b各自独立选自氢、氘、卤素、硝基、氰基、氨基、羟基、C 1-4烷基、C 1-4烷氧基、C 2-4烯基、C 2-4炔基、-SF 5、-(CH 2) r-C 3-6单环环烷基、-(CH 2) r-C 5-10双环环烷基、-(CH 2) r-(3-6元单环杂环烷基)、-(CH 2) r-(5-10元双环杂环烷基)、-O-C 3-6单环环烷基、-O-C 5-10双环环烷基、-O-(3-6元单环杂环烷基)、-O-(5-10元双环杂环烷基)、-NH-C 3-6单环环烷基、-NH-C 5-10双环环烷基、-NH-(3-6元单环杂环烷基)、-NH-(5-10元双环杂环烷基)、5至6元杂芳基、苯基、-C(=O)NR xaaR xab、-NR xaaC(=O)-R xab、-NR xaaR xab、-C(=O)-R xaa,所述CH 2、烷基、烷氧基、环烷基、杂环烷基、杂芳基、芳基任选进一步被1至3个选自卤素、氘、硝基、氰基、氨基、羟基、=O、C 1-4烷基、C 1-4烷氧基、卤代C 1-4烷基、卤代C 1-4烷氧基、氘代C 1-4烷基、氘代C 1-4烷氧基的基团取代;R xa1、R xb1各自独立选自氢、氘、氰基、羟基、C 1-4烷基、C 1-4烷氧基、C 2-4烯基、C 2-4炔基、-SF 5、-(CH 2) r-C 3-6单环环烷基、-(CH 2) r-C 5-10双环环烷基、-(CH 2) r-(3-6元单环杂环烷基)、-(CH 2) r-(5-10元双环杂环烷基)、5至6元杂芳基、苯基,所述CH 2、烷基、烷氧基、环烷基、杂环烷基、杂芳基、芳基任选进一步被1至3个选自卤素、氘、氰基、羟基、=O、C 1-4烷基、C 1-4烷氧基、卤代C 1-4烷基、卤代C 1-4烷氧基、氘代C 1-4烷基、氘代C 1-4烷氧基的基团取代;R xaa、R xab各自独立选自氢、氘、氨基、羟基、C 1-4烷基、卤代C 1-4烷基、氘代C 1-4烷基、C 1-4烷氧基、卤代C 1-4烷氧基、氘代C 1-4烷氧基;R x1b、R x2b、R x7b各自独立选自H、氘、硝基、氰基、氨基、羟基、C 1-4烷基、C 1-4烷氧基、C 2-6烯基、C 2-6炔基、-SF 5,所述烷基、烷氧基任选进一步被1至3个选自F、Cl、氘、硝基、氰基、氨基、羟基、C 1-2烷基、C 1-2烷氧基、卤代C 1-2烷基、卤代C 1-2烷氧基、氘代C 1-2烷基、氘代C 1-2烷氧基的基团取代;条件是,R x1b、R x2b、R x7b不同时为H;作为选择,当R x1b、R x2b、R x7b同时选自H时,-L 12-R 712选自H;作为选择,连接于同一碳原子上的R xa和R xb、R xa1和R xb1、R ya和R yb、R za和R zb、R x4a和R x4b、R x5a和R x5b,或R x6a和R x6b与所连接的碳原子一起形成3元环烷基、4元环烷基、5元环烷基、6元环烷基、3元杂环烷基、4元杂环烷基、5元杂环烷基或6元杂环烷基;作为选择,连接于相邻碳原子上的R xa和R za与所连接的碳原子一起形成3元环烷基、4元环烷基、5元环烷基、6元环烷基、3元杂环烷基、4元杂环烷基、5元杂环烷基或6元杂环烷基;作为选择,R x4a与R x6a一起形成-CH 2-或者-CH 2CH 2-;L 1选自*-C(O)NR La-、*-NR LaC(O)-、*-NR LaC(O)-(CH 2) p-O-、*-O-(CH 2) p-C(O)NR La-、-NR LaC(O)-NR La-、-S-、*-S(O) 2NR La-、*-NR LaS(O) 2-,*代表L 1与R 71链接位点;L 2选自-NR La-、-C(O)-、-C(O)NR La-**、-NR LaC(O)-(CH 2) p-O-**、-O-(CH 2) p-C(O)NR La-**、-NR LaC(O)-NR La-**、-S-、-S(O) 2NR La-**、-NR LaS(O) 2-**,**代表L 2与R 72链接位点;L 3、L 5、L 6各自独立地选自键、-NR La、-C(O)-、-C(O)NR La-、-NR LaC(O)-、-NR LaC(O)-(CH 2) p-O-、-O-(CH 2) p-C(O)NR La-、-NR LaC(O)-NR La-、-O-、-S-、-S(O) 2NR La-、-NR LaS(O) 2-;L 7、L 8、L 9、L 10、L 11、L 12、L 13、L 14、L 15各自独立地选自-NR La、-C(O)-、-C(O)NR La-、-NR LaC(O)-、-NR LaC(O)-(CH 2) p-O-、-O-(CH 2) p-C(O)NR La-、-NR LaC(O)-NR La-、-O-、-S-、-S(O) 2NR La-、-NR LaS(O) 2-;R La选自氢、氘、卤代C 1-4烷基、氘代C 1-4烷基;R 71选自-(CH 2) r-(4-12元杂环烷基)、-(CH 2) r-C 3-12环烷基、-(CH 2) r-(5-12元杂芳基)、-(CH 2) r-(6-12元芳基),所述CH 2、环烷基、杂环烷基、杂芳基、芳基任选进一步被1至3个选自氘、卤素、硝基、氰基、氨基、羟基、C 1-4烷基、=O、C 1-4烷氧基、卤代C 1-4烷基、卤代C 1-4烷氧基、氘代C 1-4烷基、氘代C 1-4烷氧基、-C(=O)NR cyaR cyb、-NR cyaC(=O)-R cyb、-NR cyaR cyb、-C(=O)-R cya、-S-C 1-4烷基、-S(O)-C 1-4烷基、-S(O) 2-C 1-4烷基的基团取代;或者L 1选自-NR La-,R 71选自5-12元杂芳基、-(CH 2) r-(6-12元芳基),所述CH 2、杂芳基、芳基任选进一步被1至3个选自氘、卤素、硝基、氰基、氨基、羟基、C 1-4烷基、=O、C 1-4烷氧基、卤代C 1-4烷基、卤代C 1-4烷氧基、氘代C 1-4烷基、氘代C 1-4烷氧基、-C(=O)NR cyaR cyb、-NR cyaC(=O)-R cyb、-NR cyaR cyb、-C(=O)-R cya、-S-C 1-4烷基、-S(O)-C 1-4烷基、-S(O) 2-C 1-4烷基的基团取代;R 72选自C 2-6烯基、-SF 5、-(CH 2) r-C 3-12环烷基、-(CH 2) r-(4-12元杂环烷基)、5-12元杂芳基、6-12元芳基,所述CH 2、环烷基、杂环烷基、杂芳基、芳基任选进一步被1至5个选自氘、卤素、硝基、氰基、氨基、羟基、C 1-6烷基、=O、C 1-6烷氧基、C 2-6烯基、C 2-6炔基、卤代C 1-6烷基、卤代C 1-6烷氧基、氘代C 1-6烷基、氘代C 1-6烷氧基、-(CH 2) r-C 3-8环烷基、-(CH 2) r-(3-8元杂环烷基)、-O-C 3-8环烷基、-O-(3-8元杂环烷基)、-NH-C 3-8环烷基、-NH-(3-8元杂环烷基)、-S-C 3-8环烷基、-S-(3-8元杂环烷基)、5至8元杂芳基、6至8元芳基、- C(=O)NR cyaR cyb、-NR cyaC(=O)-R cyb、-NR cyaR cyb、-C(=O)-R cya、-S-C 1-6烷基、-S(O)-C 1-6烷基、-S(O) 2-C 1-6烷基的基团取代;条件是,当L 2选自-NH-,R 72选自-(CH 2) r-4-12元杂环烷基、6-12元芳基或-(CH 2) r-C 3-12环烷基时,满足以下条件之一:m不为0,或者X 12、X 32之一选自N,或者R x2a、R x3a不同时为H;或者L 2选自-NR LaC(O)-**,R 72选自C 2-6烯基、-SF 5、-(CH 2) r-C 3-12环烷基、-(CH 2) r-(4-12元饱和杂环烷基)、6-12元芳基,所述CH 2、环烷基、杂环烷基、芳基任选进一步被1至5个选自氘、卤素、硝基、氰基、氨基、羟基、C 1-6烷基、=O、C 1-6烷氧基、C 2-6烯基、C 2-6炔基、卤代C 1-6烷基、卤代C 1-6烷氧基、氘代C 1-6烷基、氘代C 1-6烷氧基、-(CH 2) r-C 3-8环烷基、-(CH 2) r-(3-8元杂环烷基)、-O-C 3-8环烷基、-O-(3-8元杂环烷基)、-NH-C 3-8环烷基、-NH-(3-8元杂环烷基)、-S-C 3-8环烷基、-S-(3-8元杂环烷基)、5至8元杂芳基、6至8元芳基、-C(=O)NR cyaR cyb、-NR cyaC(=O)-R cyb、-NR cyaR cyb、-C(=O)-R cya、-S-C 1-6烷基、-S(O)-C 1-6烷基、-S(O) 2-C 1-6烷基的基团取代;作为选择,-L 2-R 72选自CN、-C(O)N(C 1-4烷基) 2、5元杂芳基、7-12元杂芳基,所述的杂芳基任选进一步被1至3个氘、卤素、羟基、氨基、氰基、C 1-4烷基、=O、C 1-4烷氧基、C 3-6环烷基、4-8元杂环烷基、-C(=O)NR cyaR cyb、-NR cyaC(=O)-R cyb、-NR cyaR cyb、-C(=O)-R cya的基团取代;R 73、R 75、R 76、R 77、R 78、R 79、R 710、R 711、R 712、R 713、R 714、R 715各自独立地选自氘、卤素、C 1-6烷基、C 1-6烷氧基、C 2-6烯基、C 2-6炔基、-SF 5、-(CH 2) r-C 3-12环烷基、-(CH 2) r-(4-12元杂环烷基)、-(CH 2) r-(5-12元杂芳基)、-(CH 2) r-(6-12元芳基),所述CH 2、烷基、烷氧基、环烷基、杂环烷基、杂芳基、芳基任选进一步被1至5个选自R f的基团取代;作为选择,-L 7-R 77、-L 13-R 713各自独立地选自卤素、5-12元杂芳基,所述的杂芳基任选进一步被1-5个选自R f的基团取代;作为选择,-L 8-R 78、-L 9-R 79、-L 10-R 710、-L 11-R 711各自独立地选自SF 5、-(CH 2) r-C 3-12环烷基、-(CH 2) r-(4-12元杂环烷基)、-(CH 2) r-(5-12元杂芳基)、-(CH 2) r-(6-12元芳基),所述CH 2、环烷基、杂环烷基、杂芳基、芳基任选进一步被1至5个选自R f的基团取代;每个R f各自独立地选自氘、卤素、硝基、氰基、氨基、羟基、C 1-6烷基、=O、C 1-6烷氧基、C 2-6烯基、C 2-6炔基、卤代C 1-6烷基、卤代C 1-6烷氧基、氘代C 1-6烷基、氘代C 1-6烷氧基、-SF 5、-(CH 2) r-C 3-8环烷基、-(CH 2) r-(3-8元杂环烷基)、-O-C 3-8环烷基、-O-(3-8元杂环烷 基)、-NH-C 3-8环烷基、-NH-(3-8元杂环烷基)、-S-C 3-8环烷基、-S-(3-8元杂环烷基)、5至8元杂芳基、6至8元芳基、-C(=O)NR cyaR cyb、-NR cyaC(=O)-R cyb、-NR cyaR cyb、-C(=O)-R cya、-S-C 1-6烷基、-S(O)-C 1-6烷基、-S(O) 2-C 1-6烷基;R cya、R cyb各自独立选自C 1-6烷基、卤代C 1-6烷基、氘代C 1-6烷基。
- 根据权利要求2所述的化合物,其立体异构体、氘代物、溶剂化物、前药、代谢产物、药学上可接受的盐或共晶,其中,R 11、R 12、R 13、R 15、R 17、R 18、R 19、R 110、R 111、R 112、R 113、R 114、R 115、R 21、R 22、R 23、R 25、R 27、R 28、R 29、R 210、R 211、R 212、R 213、R 214、R 215、R 31、R 32、R 33、R 35、R 36、R 37、R 38、R 39、R 310、R 311、R 312、R 313、R 314、R 315、R 41、R 42、R 43、R 45、R 46、R 47、R 48、R 49、R 410、R 411、R 412、R 413、R 414、R 415各自独立地选自氢、氘、C 1-4烷基,所述烷基任选被1至3个选自卤素、氘的基团取代;作为选择,连接于同一碳原子上的R 11和R 21、R 31和R 41、R 12和R 22、R 32和R 42、R 13和R 23、R 33和R 43、R 15和R 25、R 35和R 45、R 36和R 46、R 17和R 27、R 37和R 47、R 18和R 28、R 38和R 48、R 19和R 29、R 39和R 49、R 110和R 210、R 310和R 410、R 111和R 211、R 311和R 411、R 112和R 212、R 312和R 412、R 112和R 213、R 313和R 413、R 114和R 214、R 314和R 414、R 115和R 215,或者R 315和R 415分别各自独立地与所连接的碳原子一起形成3元环烷基、4元环烷基、5元环烷基、4元杂环烷基、5元杂环烷基或6元杂环烷基;R 51、R 52、R 53、R 55、R 56、R 57、R 58、R 59、R 510、R 511、R 512、R 513、R 514、R 515各自独立地选自氢、氘、C 1-4烷基,所述烷基任选被1至3个选自卤素、氘的基团取代;R 81、R 82、R 83、R 85、R 86、R 87、R 88、R 89、R 810、R 811、R 812、R 813、R 814、R 815各自独立地选自氢、氘;连接于同一碳原子上R 9a1和R 9b1、R 9a2和R 9b2与所连接的碳原子一起形成3元环烷基、4元环烷基、5元环烷基、6元环烷基、4元杂环烷基、5元杂环烷基或6元杂环烷基;或者R 9a1和R 9a2相链接形成-CH 2-;R 61、R 63、R 65、R 66、R 67、R 68、R 69、R 610、R 611、R 612、R 613、R 614、R 615、R 616、R 617各自独立地选自氘、卤素、羟基、C 1-4烷基、C 1-4烷氧基、-(CH 2) r-C 3-8环烷基、-(CH 2) r-(3-8元杂环烷基)、5至8元杂芳基、6至8元芳基、-C(=O)NR 6aR 6b、-NR 6aC(=O)-R 6b、-NR 6aR 6b、-C(=O)-R 6a,所述CH 2、烷基、烷氧基、环烷基、杂环烷基、杂芳基、芳基任选进一步被1至3个选自卤素、氘、C 1-4烷基的基团取代;R 62为氘、卤素、-(CH 2) r-C 3-8环烷基、-(CH 2) r-(3-8元杂环烷基)、-C(=O)NR 6aR 6b、-NR 6aC(=O)-R 6b、-NR 6aR 6b、-C(=O)-R 6a,所述CH 2、环烷基、杂环烷基任选进一步被1至3个选自卤素、氘、=O、C 1-4烷基、C 1-4烷氧基的基团取代;R 6a选自氢、氘、C 1-4烷基、C 3-8环烷基、3-8元杂环烷基,所述烷基、环烷基、杂环烷基任选被1至3个选自卤素、氘、C 1-4烷氧基的基团取代;R 6b选自氢、氘、C 1-4烷基、C 1-4烷氧基、C 3-8环烷基、3-8元杂环烷基,所述的烷基、烷氧基、环烷基、杂环烷基任选被1至3个选自卤素、氘、C 1-4烷基、C 1-4烷氧基的基团取代;X 81、X 83、X 86、X 88、X 89、X 810、X 811、X 813、X 814、X 815各自独立地选自-O-、-S-、-CR xaR xb-或者-NR xa-;X 87选自-O-、-CR xaR xb-或者-NR xa-;X 812选自-O-、-S-、-CR xa2R xb2-或者-NR xa-;X 82选自-O-、-S-、-CR xa1R xb1-或者-NR xa-;Y 1、Y 2、Y 3、Y 4、Y 5、Y 6各自独立地选自键、-CR yaR yb-或者-NR ya-;Z 1、Z 2、Z 3、Z 4、Z 5、Z 6各自独立地选自键、-CR zaR zb-或者-NR za-;X 41、X 42、X 43、X 44各自独立地选自-CR x4aR x4b-或者-NR x4a-;X 51、X 52、X 53、X 54各自独立地选自-CR x5aR x5b-或者-NR x5a-;X 61、X 62、X 63、X 64各自独立地选自键、-CR x6aR x6b-或者-NR x6a-;X 11、X 12、X 13、X 15、X 16、X 17、X 18、X 19、X 110、X 113、X 114、X 115各自独立地选自-CR x1a-或者-N-;X 21、X 22、X 23、X 25、X 26、X 27、X 28、X 29、X 211、X 213、X 214、X 215各自独立地选自-CR x2a-或者-N-;X 31、X 32、X 33、X 35、X 36、X 37、X 38、X 39、X 310、X 311各自独立地选自-CR x3a-或者-N-;X 710、X 711、X 713、X 714、X 715各自独立地选自-CR x7a-或者-N-;X 112选自-CR x1b-;X 212选自-CR x2b-;X 712选自-CR x7b-;R x1a、R x2a、R x3a、R x7a各自独立选自氢、氘、卤素、C 1-4烷基、C 1-4烷氧基,所述烷基、烷氧基任选进一步被1至3个选自F、Cl、氘、羟基、C 1-2烷基、C 1-2烷氧基的基团取代;R xa、R xb、R xa2、R xb2、R ya、R yb、R za、R zb、R x4a、R x4b、R x5a、R x5b、R x6a、R x6b各自独立选自氢、氘、卤素、C 1-4烷基、C 1-4烷氧基、-(CH 2) r-C 3-6单环环烷基、-(CH 2) r-C 5-10双环环烷基、-(CH 2) r-(3-6元单环杂环烷基)、-(CH 2) r-(5-10元双环杂环烷基)、5至6元杂芳基、苯基、-C(=O)NR xaaR xab、-NR xaaC(=O)-R xab、-NR xaaR xab、-C(=O)-R xaa,所述CH 2、烷基、烷氧基、环烷基、杂环烷基、杂芳基、芳基任选进一步被1至3个选自卤素、氘、C 1-4烷基、C 1- 4烷氧基的基团取代;R xa1、R xb1各自独立选自氢、氘、C 1-4烷基、C 1-4烷氧基、-(CH 2) r-C 3-6单环环烷基、-(CH 2) r-C 5-10双环环烷基、-(CH 2) r-(3-6元单环杂环烷基)、-(CH 2) r-(5-10元双环杂环烷基)、5至6元杂芳基、苯基,所述CH 2、烷基、烷氧基、环烷基、杂环烷基、杂芳基、芳基任选进一步被1至3个选自卤素、氘、C 1-4烷基、C 1-4烷氧基的基团取代;R xaa、R xab各自独立选自氢、氘、C 1-4烷基的基团取代;R x1b、R x2b、R x7b各自独立选自H、氘、羟基、氰基、C 1-4烷基、C 1-4烷氧基,所述烷基、烷氧基任选进一步被1至3个选自F、Cl、氘、羟基、C 1-2烷基、C 1-2烷氧基的基团取代;条件是,R x1b、R x2b、R x7b不同时为H;作为选择,当R x1b、R x2b、R x7b同时选自H时,-L 12-R 712选自H;作为选择,连接于同一碳原子上的R xa和R xb、R xa1和R xb1、R ya和R yb、R za和R zb、R x4a和R x4b、R x5a和R x5b,或R x6a和R x6b与所连接的碳原子一起形成3元环烷基、4元环烷基、5元环烷基、4元杂环烷基、5元杂环烷基或6元杂环烷基;作为选择,连接于相邻碳原子上的R xa和R za与所连接的碳原子一起形成3元环烷基、4元环烷基、5元环烷基、6元环烷基、3元杂环烷基、4元杂环烷基、5元杂环烷基或6元杂环烷基;作为选择,R x4a与R x6a一起形成-CH 2-或者-CH 2CH 2-。
- 根据权利要求2或3所述的化合物,其立体异构体、氘代物、溶剂化物、前药、代谢产物、药学上可接受的盐或共晶,所述化合物具有式(III-1)、(III-2)、(III-3)、(III-5)、(III-6)、(III-7)、(III-8)、(III-9)结构:E环为3元环烷基、4元环烷基、5元环烷基、6元环烷基、3元杂环烷基、4元杂环烷基、5元杂环烷基或6元杂环烷基;H环为3元环烷基、4元环烷基、5元环烷基、6元环烷基、3元杂环烷基、4元杂环烷基、5元杂环烷基或6元杂环烷基;R 52选自氢、氘、C 1-4烷基,所述烷基任选被1至3个选自卤素、氘的基团取代;连接于同一碳原子上R 9a1和R 9b1、R 9a2和R 9b2与所连接的碳原子一起形成3元环烷基、4元环烷基、5元环烷基、4元杂环烷基、5元杂环烷基或6元杂环烷基;或者R 9a1和R 9a2相链接形成-CH 2-;R 69选自氘、卤素、羟基、C 1-4烷基、C 1-4烷氧基,所述烷基、烷氧基任选进一步被1至3个选自卤素、氘、羟基的基团取代;R 62选自氘、卤素、C 3-6环烷基、3-5元杂环烷基、-C(=O)NR 6aR 6b、-NHC(=O)-R 6b、-NR 6aR 6b、-C(=O)-R 6a,所述环烷基、杂环烷基任选进一步被1至3个选自卤素、氘、=O、C 1-4烷基的基团取代;R 6a选自氢、氘、C 1-4烷基,所述烷基任选被1至3个选自卤素、氘的基团取代;R 6b选自氢、氘、C 1-4烷基,所述的烷基任选被1至3个选自卤素、氘的基团取代;X 81、X 87、X 88、X 89各自独立地选自-O-、-CR xaR xb-或者-NR xa-;X 82选自-O-、-CR xa1R xb1-或者-NR xa-;X 12选自-CR x1a-或者-N-;X 22选自-CR x2a-或者-N-;X 32选自-CR x3a-或者-N-;R x1a、R x2a、R x3a各自独立地选自氢、氘、卤素、C 1-4烷基、C 1-4烷氧基,所述烷基、烷氧基任选进一步被1至3个选自F、Cl、氘的基团取代;R xa、R xb各自独立地选自氢、氘、卤素、C 1-4烷基、C 1-4烷氧基,所述烷基、烷氧基任选进一步被1至3个选自F、Cl、氘的基团取代;R xa1、R xb1各自独立地选自氢、氘、C 1-4烷基、C 1-4烷氧基,所述烷基、烷氧基任选进一步被1至3个选自F、Cl、氘的基团取代;作为选择,连接于同一碳原子上的R xa和R xb与所连接的碳原子一起形成3元环烷基、4元环烷基、5元环烷基、3元杂环烷基、4元杂环烷基、5元杂环烷基;L 1选自-NR La、*-C(O)NR La-、*-NR LaC(O)-,*代表L 1与R 71链接位点;L 2选自-NR La、-C(O)-、-C(O)NR La-**、-NR LaC(O)-(CH 2) p-O-**、-O-(CH 2) p-C(O)NR La-**,**表示L 2与R 72的连接位点;L 3、L 5、L 6各自独立地选自键、-NR La、-C(O)-、-C(O)NR La-、-NR LaC(O)-;L 7、L 8、L 9各自独立地选自-NR La、-C(O)-、-C(O)NR La-、-NR LaC(O)-;R La选自氢、氘、C 1-4烷基;R 71选自5元杂芳基或6元杂芳基,所述杂芳基任选进一步被1至3个选自氘、卤素、C 1-4烷基的基团取代;R 72选自C 3-6环烷基、5-8元单环杂环烷基、6-12元双环杂环烷基、5-8元杂芳基、6-9元芳基,所述环烷基、杂环烷基、杂芳基、芳基任选进一步被1至3个选自氘、卤素、羟基、氨基、氰基、C 1-4烷基、=O、C 1-4烷氧基、卤代C 1-4烷氧基、C 3-6环烷基、4-8元杂环烷基、-C(=O)NR cyaR cyb、-NR cyaC(=O)-R cyb、-NR cyaR cyb、-C(=O)-R cya的基团取代;条件是,当L 2选自-NH-,R 72选自-(CH 2) r-4-12元杂环烷基、6-12元芳基或-(CH 2) r-C 3-12环烷基时,满足以下条件之一:m不为0,或者X 12、X 32之一选自N,或者R x2a、R x3a不同时为H;或者L 2选自-NR LaC(O)-**,R 72选自C 3-6环烷基、5-8元单环杂环烷基、6-12元双环杂环烷基、6-9元芳基,所述环烷基、杂环烷基、芳基任选进一步被1至3个选自氘、卤素、氰基、氨基、羟基、C 1-4烷基、=O、C 1-4烷氧基、C 3-6环烷基、4-8元杂环烷基、-C(=O)-R cya的基团取代;作为选择,-L 2-R 72选自CN、-C(O)N(C 1-4烷基) 2、5元杂芳基,所述的杂芳基任选进一步被1至3个氘、卤素、C 1-4烷基、C 3-6环烷基、4-8元杂环烷基、-C(=O)NR cyaR cyb、-NR cyaC(=O)-R cyb、-NR cyaR cyb、-C(=O)-R cya的基团取代;R 73、R 75、R 76、R 77、R 78、R 79各自独立地选自氘、卤素、C 1-4烷基、C 1-4烷氧基、C 3-6环烷基、5-8元单环杂环烷基、6-12元双环杂环烷基、5-8元杂芳基、6-9元芳基,所述烷基、烷氧基、环烷基、杂环烷基、杂芳基、芳基任选进一步被1至3个选自R f的基团取代;作为选择,-L 7-R 77选自卤素、5-9元杂芳基,所述的杂芳基任选进一步被1-3个选自R f的基团取代;作为选择,-L 8-R 78、-L 9-R 79各自独立地选自C 3-6环烷基、5-8元单环杂环烷基、6-12元双环杂环烷基、5-8元杂芳基、6-9元芳基,所述环烷基、杂环烷基、杂芳基、芳基任选进一步被1至3个选自R f的基团取代;每个R f各自独立地选自氘、卤素、氰基、氨基、羟基、C 1-4烷基、=O、C 1-4烷氧基、C 3-6环烷基、3-8元杂环烷基、5至8元杂芳基、6至8元芳基、-C(=O)NR cyaR cyb、-NR cyaC(=O)-R cyb、-NR cyaR cyb、-C(=O)-R cya;R cya、R cyb各自独立选自C 1-4烷基、卤代C 1-4烷基、氘代C 1-4烷基。
- 根据权利要求4所述的化合物,其立体异构体、氘代物、溶剂化物、前药、代谢产物、药学上可接受的盐或共晶,其中m选自0、1或2;R 62选自氘、卤素、环丙基、环丁基、环戊基、环己基、氮杂环丁基、氮杂环戊基、氮杂环己基、氧杂环丁基、氧杂环戊基、氧杂环己基、-C(O)NHCH 3、-NHC(O)CH 3、-N(CH 3)C(O)CH 3、-NHC(O)CH 2CH 3、-N(CH 3)C(O)CH 2CH 3、-NH 2、-NHCH 3、-C(O)CH3、-C(O)CH 2CH 3,以上基团选进一步被1、2、3个选自F、氘的基团取代;R 69选自氘、F、Cl、Br、甲基、乙基、丙基,甲基、乙基、丙基,以上基团任选进一步被1、2、3个选自F、氘的基团取代。
- 根据权利要求2或3所述的化合物,其立体异构体、氘代物、溶剂化物、前药、代谢产物、药学上可接受的盐或共晶,所述化合物具有式(IV-1)、(V-1)结构:L 10、L 11各自独立地选自-NR La、-C(O)-、-C(O)NR La-、-NR LaC(O)-;R La选自氢、氘;R 710选自卤素、C 1-4烷基、C 1-4烷氧基、C 3-6环烷基、5-8元单环杂环烷基、6-12元双环杂环烷基、5-8元杂芳基、6-9元芳基,所述环烷基、杂环烷基、杂芳基、芳基任选进一步被1至3个选自R f的基团取代;作为选择,-L 10-R 710选自C 3-6环烷基、5-8元单环杂环烷基、6-12元双环杂环烷基、5-8元杂芳基、6-9元芳基,所述环烷基、杂环烷基、杂芳基、芳基任选进一步被1至3个选自R f的基团取代;R f各自独立地选自氘、卤素、C 1-4烷基、=O的基团取代;R 711选自卤素、C 1-4烷基、C 1-4烷氧基、C 3-6环烷基、-(CH 2) 0-2-5-8元单环杂环烷基、6-12元双环杂环烷基、5-8元杂芳基、6-9元芳基,所述环烷基、杂环烷基、杂芳基、芳基任选进一步被1至3个选自氘、卤素、C 1-4烷基、=O、-C(=O)NR cyaR cyb、-NR cyaC(=O)-R cyb、-NR cyaR cyb、-C(=O)-R cya的基团取代;R cya、R cyb各自独立选自甲基、乙基、丙基、丁基、-CH 2F、-CH 2CH 2F、-CHF 2、-CF 3、-CH 2CHF 2、-CH 2CHF 3、-CH 2D、-CH 2CH 2D、-CHD 2、-CD 3、-CH 2CHD 2、-CH 2CHD 3。
- 根据权利要求2或3所述化合物,其立体异构体、氘代物、溶剂化物、前药、代谢产物、药学上可接受的盐或共晶,所述化合物具有式(VI-1)、(VI-2)、(VI-3)、(VI-4)、(VI-5)结构:X 812选自-O-、-CR xa2R xb2-或者-NR xa-;X 813、X 814、X 815各自独立地选自-O-、-CR xaR xb-或者-NR xa-;X 112选自-CR x1b-;X 212选自-CR x2b-;X 712选自-CR x7b-;R xa、R xb、R xa2、R xb2各自独立选自氢、氘、卤素、C 1-4烷基、C 1-4烷氧基,所述烷基、烷氧基任选进一步被1至3个选自卤素、氘的基团取代;R x1b、R x2b、R x7b各自独立选自H、氘、羟基、氰基、C 1-4烷基、C 1-4烷氧基,所述烷基、烷氧基任选进一步被1至3个选自F、Cl、氘、羟基的基团取代;条件是,R x1b、R x2b、R x7b不同时选自H;作为选择,当R x1b、R x2b、R x7b同时选自H时,-L 12-R 712选自H;作为选择,连接于同一碳原子上的R xa和R xb与所连接的碳原子一起形成3元环烷基、4元环烷基、5元环烷基、4元杂环烷基、5元杂环烷基或6元杂环烷基;L 12、L 13、L 14、L 15各自独立地选自-NR La、-C(O)-、-C(O)NR La-、-NR LaC(O)-;R La选自氢、氘;R 712、R 713、R 714、R 715各自独立地选自H、氘、卤素、C 1-6烷基、C 1-6烷氧基、C 3-6环烷基、5-8元单环杂环烷基、6-12元双环杂环烷基、5-8元杂芳基、6-9元芳基,所述烷基、烷氧基、环烷基、杂环烷基、杂芳基、芳基任选进一步被1至3个选自R f的基团取代;作为选择,-L 13-R 713选自F、Cl、5-8元杂芳基,所述杂芳基任选进一步被1至3个选自R f的基团取代;每个R f各自独立地选自氘、卤素、羟基、C 1-6烷基、=O、C 1-6烷氧基、C 3-8环烷基、3-8元杂环烷基、-C(=O)NR cyaR cyb、-NR cyaC(=O)-R cyb、-NR cyaR cyb、-C(=O)-R cya;R cya、R cyb各自独立选自甲基、乙基、丙基、丁基、-CH 2F、-CH 2CH 2F、-CHF 2、-CF 3、-CH 2CHF 2、-CH 2CHF 3、-CH 2D、-CH 2CH 2D、-CHD 2、-CD 3、-CH 2CHD 2、-CH 2CHD 3。
- 根据权利要求2至7任意一项所述的化合物,其立体异构体、氘代物、溶剂化物、前药、代谢产物、药学上可接受的盐或共晶,其中
- 根据权利要求1所述的化合物,其立体异构体、氘代物、溶剂化物、前药、代谢产物、药学上可接受的盐或共晶,其中所述化合物选自具有式(Ⅶ-1)、式(Ⅶ-2)结构中的任意一种,X 82选自-CR xa1R xb1-,R xa1、R xb1各自独立选自氢、氘、卤素、C 1-4烷基组成的组中的任意一种,作为选择所述烷基任选进一步被1至3个选自卤素、氘的基团取代,所述R xa1、R xb1能够与二者所连接的碳原子一起形成3元至5元环烷基,优选地所述R xa1、R xb1与二者所连接的碳原子形成3元环烷基;X 12选自-CR x1a-,X 32选自-CR x3a-;R x1a、R x3a各自独立选自氢、氘、卤素、C 1-4烷基组成的组中的任意一种;L 2为-C(O)-,R 72选自-NR cyaR cyb、4-12元杂环烷基、6-12元芳基,所述杂环烷基、6-12元芳基任选进一步被1至3个选自卤素、氘、氰基、C 1-4烷氧基、卤代C 1-4烷氧基、氘代C 1-4烷氧基、=O、-C(=O)-R cya的基团取代,R cya、R cyb各自独立选自C 1-2烷基、卤代C 1-2烷基、氘代C 1-2烷基;或者L 2为-NH-、-C(O)NR La-**,**代表L 2与R 72链接位点,R 72选自C 3-12环烷基、4-12元杂环烷基、5-12元杂芳基、6-12元芳基,所述环烷基、杂环烷基、杂芳基、芳基任选进一步被1至3个选自氘、卤素、硝基、氰基、=O、-C(=O)-R cya的基团取代,R cya选自C 1-2烷基、卤代C 1-2烷基、氘代C 1-2烷基;或者L 2为-NR LaC(O)-**,**代表L 2与R 72链接位点,R 72选自C 3-12环烷基、4-12元饱和杂环烷基,所述环烷基、饱和杂环烷基任选进一步被1至3个选自氘、卤素、硝基、氰基、=O、-C(=O)-R cya的基团取代,R cya选自C 1-2烷基、卤代C 1-2烷基、氘代C 1-2烷基;作为选择,-L 2-R 72选自H或者CN;条件是,当L 2选自-NH-,R x3a不为H;X 715选自-CR x7a-或者-N-,R x7a选自氢、氘、卤素;X 815选自-O-或者-CR xaR xb-;R xa、R xb各自独立选自氢、氘、卤素、C 1-4烷基组成的组中的任意一种,所述烷基任选进一步被1至3个选自卤素、氘的基团取代,所述R xa、R xb能够与二者所连接的碳原子一起形成3元至5元环烷基,优选地所述R xa、R xb与二者所连接的碳原子一起形成3元环烷基或4元环烷基;Z 6选自键或者-CR zaR zb-,R za、R zb各自独立选自氢;L 15选自-NR La、-C(O)-、-C(O)NR La-、-NR LaC(O)-;R 715选自4-12元杂环烷基、5-12元杂芳基,所述杂环烷基、杂芳基任选进一步被1至3个选自C 1-2烷基、=O、C 1-2烷氧基、卤代C 1-2烷基、卤代C 1-2烷氧基、氘代C 1-2烷基、氘代C 1-2烷氧基、-NR cyaR cyb、-C(=O)-R cya的基团取代,R cya、R cyb各自独立选自C 1-2烷基、卤代C 1-2烷基、氘代C 1-2烷基。
- 根据权利要求9所述的化合物,其立体异构体、氘代物、溶剂化物、前药、代谢产物、药学上可接受的盐或共晶,其中L 2为 R 72为-NR cyaR cyb、 组成的组中的任意一种,其中R’选自氢、氘、卤素和C 1-4烷基组成的组中的任意一种,作为选择所述烷基任选进一步被1至3个选自卤素、氘的基团取代,作为选择,所述R’为H、氘、甲基、乙基、丙基、丁基、-CH 2F、-CH 2CH 2F、-CHF 2、-CF 3组成的组中的任意一种;作为选择所述R’为甲基、乙基、-CH 2F、-CHF 2、-CF 3;R cya、R cyb各自独立地为H、氘、甲基、乙基、丙基、丁基、-CH 2F、-CH 2CH 2F、-CHF 2、-CF 3、-CH 2CHF 2、-CH 2CHF 3、-CH 2D、-CH 2CH 2D、-CHD 2、-CD 3、-CH 2CHD 2、-CH 2CHD 3组成的组中的任意一种,作为选择R cya、R cyb各自独立地为甲基、乙基、-CH 2F、-CHF 2、-CF 3;R xa1、R xb1各自独立选自氢、氘、卤素、C 1-4烷基组成的组中的任意一种,作为选择所述烷基任选进一步被1至3个选自卤素、氘的基团取代,所述R xa、R xb能够与二者所连接的碳原子一起形成3元至5元环烷基,优选地所述R xa、R xb与二者所连接的碳原子形成3元环烷基;-X 815-Z 6-为-O-CR xaR xb-或-CR xaR xb-,R xa、R xb各自独立选自氢、氘、卤素、C 1-4烷基组成的组中的任意一种,所述烷基任选进一步被1至3个选自卤素、氘的基团取代,所述R xa、R xb能够与二者所连接的碳原子一起形成3元至5元环烷基,优选地所述R xa、R xb与二者所连接的碳原子一起形成3元环烷基或4元环烷基;
- 一种药物组合物,其特征在于,含有权利要求1-12任意一项所述的化合物,其立体异构体、氘代物、溶剂化物、前药、代谢产物、药学上可接受的盐或共晶,以及药学上可接受的载体和/或赋形剂。
- 权利要求1-12任意一项所述的化合物,其立体异构体、氘代物、溶剂化物、前药、代谢产物、药学上可接受的盐或共晶,或者权利要求13所述的组合物,在制备治疗PRMT5介导的疾病的药物中的应用。
- 根据权利要求14所述的应用,其特征在于,所述PRMT5介导的疾病为肿瘤。
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CN112125886A (zh) * | 2019-06-24 | 2020-12-25 | 南京圣和药物研发有限公司 | 作为prmt5抑制剂的三环类化合物及其应用 |
WO2021066578A1 (ko) * | 2019-10-02 | 2021-04-08 | 에스케이바이오팜 주식회사 | 바이사이클릭 화합물 및 이의 용도 |
KR20210039666A (ko) * | 2019-10-02 | 2021-04-12 | 에스케이바이오팜 주식회사 | 바이사이클릭 화합물 및 이의 용도 |
CN112645946A (zh) * | 2019-10-12 | 2021-04-13 | 南京圣和药业股份有限公司 | 作为prmt5抑制剂的取代三环类化合物及其应用 |
WO2021080359A1 (ko) * | 2019-10-23 | 2021-04-29 | 에스케이바이오팜 주식회사 | 바이사이클릭 화합물 및 이의 용도 |
KR20210048654A (ko) * | 2019-10-23 | 2021-05-04 | 에스케이바이오팜 주식회사 | 바이사이클릭 화합물 및 이의 용도 |
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- 2022-04-01 CN CN202280013815.6A patent/CN117242073A/zh active Pending
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WO2019173804A1 (en) * | 2018-03-09 | 2019-09-12 | Pharmablock Sciences (Nanjing), Inc. | Inhibitors of protein arginine methyltransferase 5 (prmt5), pharmaceutical products thereof, and methods thereof |
CN111825656A (zh) * | 2019-04-15 | 2020-10-27 | 南京药石科技股份有限公司 | 蛋白质精氨酸甲基转移酶5(prmt5)的抑制剂、其药学产品及其方法 |
CN112125886A (zh) * | 2019-06-24 | 2020-12-25 | 南京圣和药物研发有限公司 | 作为prmt5抑制剂的三环类化合物及其应用 |
WO2021066578A1 (ko) * | 2019-10-02 | 2021-04-08 | 에스케이바이오팜 주식회사 | 바이사이클릭 화합물 및 이의 용도 |
KR20210039666A (ko) * | 2019-10-02 | 2021-04-12 | 에스케이바이오팜 주식회사 | 바이사이클릭 화합물 및 이의 용도 |
CN112645946A (zh) * | 2019-10-12 | 2021-04-13 | 南京圣和药业股份有限公司 | 作为prmt5抑制剂的取代三环类化合物及其应用 |
WO2021080359A1 (ko) * | 2019-10-23 | 2021-04-29 | 에스케이바이오팜 주식회사 | 바이사이클릭 화합물 및 이의 용도 |
KR20210048654A (ko) * | 2019-10-23 | 2021-05-04 | 에스케이바이오팜 주식회사 | 바이사이클릭 화합물 및 이의 용도 |
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