CN116554147A - Pyrazole derivative, composition and pharmaceutical application thereof - Google Patents
Pyrazole derivative, composition and pharmaceutical application thereof Download PDFInfo
- Publication number
- CN116554147A CN116554147A CN202210844681.4A CN202210844681A CN116554147A CN 116554147 A CN116554147 A CN 116554147A CN 202210844681 A CN202210844681 A CN 202210844681A CN 116554147 A CN116554147 A CN 116554147A
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- Prior art keywords
- alkyl
- membered
- substituted
- independently selected
- alkoxy
- Prior art date
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- 239000000203 mixture Substances 0.000 title description 7
- 150000003217 pyrazoles Chemical class 0.000 title description 2
- 150000001875 compounds Chemical class 0.000 claims abstract description 72
- 239000013078 crystal Substances 0.000 claims abstract description 39
- 239000000651 prodrug Substances 0.000 claims abstract description 37
- 229940002612 prodrug Drugs 0.000 claims abstract description 37
- 150000003839 salts Chemical class 0.000 claims abstract description 37
- 239000012453 solvate Substances 0.000 claims abstract description 34
- 239000002207 metabolite Substances 0.000 claims abstract description 33
- 125000000217 alkyl group Chemical group 0.000 claims description 291
- -1 benzopyrrolyl Chemical group 0.000 claims description 249
- 229910052739 hydrogen Inorganic materials 0.000 claims description 190
- 229910052731 fluorine Inorganic materials 0.000 claims description 164
- 125000000623 heterocyclic group Chemical group 0.000 claims description 157
- 229910052740 iodine Inorganic materials 0.000 claims description 156
- 229910052760 oxygen Inorganic materials 0.000 claims description 152
- 125000003545 alkoxy group Chemical group 0.000 claims description 129
- 125000005842 heteroatom Chemical group 0.000 claims description 109
- 229910052717 sulfur Inorganic materials 0.000 claims description 107
- 229910052757 nitrogen Inorganic materials 0.000 claims description 96
- 125000001424 substituent group Chemical group 0.000 claims description 92
- 125000001072 heteroaryl group Chemical group 0.000 claims description 87
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 71
- 229910052799 carbon Inorganic materials 0.000 claims description 68
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 68
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 58
- 125000003118 aryl group Chemical group 0.000 claims description 53
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 53
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 49
- 125000002911 monocyclic heterocycle group Chemical group 0.000 claims description 45
- 229910052736 halogen Inorganic materials 0.000 claims description 37
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 36
- 125000006297 carbonyl amino group Chemical group [H]N([*:2])C([*:1])=O 0.000 claims description 34
- 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 claims description 32
- 125000001313 C5-C10 heteroaryl group Chemical group 0.000 claims description 29
- 125000004432 carbon atom Chemical group C* 0.000 claims description 28
- 150000002367 halogens Chemical class 0.000 claims description 27
- 125000002393 azetidinyl group Chemical group 0.000 claims description 25
- 125000004076 pyridyl group Chemical group 0.000 claims description 25
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 claims description 23
- 125000002541 furyl group Chemical group 0.000 claims description 23
- 125000002883 imidazolyl group Chemical group 0.000 claims description 23
- 125000003373 pyrazinyl group Chemical group 0.000 claims description 23
- 125000002098 pyridazinyl group Chemical group 0.000 claims description 23
- 125000001544 thienyl group Chemical group 0.000 claims description 23
- 125000002971 oxazolyl group Chemical group 0.000 claims description 22
- 125000003226 pyrazolyl group Chemical group 0.000 claims description 22
- 125000000168 pyrrolyl group Chemical group 0.000 claims description 22
- 125000000335 thiazolyl group Chemical group 0.000 claims description 22
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 21
- 125000000714 pyrimidinyl group Chemical group 0.000 claims description 21
- 125000002618 bicyclic heterocycle group Chemical group 0.000 claims description 18
- 125000004452 carbocyclyl group Chemical group 0.000 claims description 18
- 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 claims description 18
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 claims description 18
- 125000003342 alkenyl group Chemical group 0.000 claims description 16
- 125000006570 (C5-C6) heteroaryl group Chemical group 0.000 claims description 15
- 125000004414 alkyl thio group Chemical group 0.000 claims description 15
- 125000000304 alkynyl group Chemical group 0.000 claims description 15
- 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 14
- 125000001425 triazolyl group Chemical group 0.000 claims description 14
- 125000005843 halogen group Chemical group 0.000 claims description 13
- 125000001183 hydrocarbyl group Chemical group 0.000 claims description 13
- 125000003253 isopropoxy group Chemical group [H]C([H])([H])C([H])(O*)C([H])([H])[H] 0.000 claims description 13
- 125000000041 C6-C10 aryl group Chemical group 0.000 claims description 11
- 125000000842 isoxazolyl group Chemical group 0.000 claims description 11
- 125000003386 piperidinyl group Chemical group 0.000 claims description 11
- 125000003785 benzimidazolyl group Chemical group N1=C(NC2=C1C=CC=C2)* 0.000 claims description 10
- 125000000592 heterocycloalkyl group Chemical group 0.000 claims description 10
- 125000003453 indazolyl group Chemical group N1N=C(C2=C1C=CC=C2)* 0.000 claims description 10
- 125000005346 substituted cycloalkyl group Chemical group 0.000 claims description 10
- HSFWRNGVRCDJHI-UHFFFAOYSA-N alpha-acetylene Natural products C#C HSFWRNGVRCDJHI-UHFFFAOYSA-N 0.000 claims description 9
- 125000002534 ethynyl group Chemical group [H]C#C* 0.000 claims description 9
- 125000006574 non-aromatic ring group Chemical group 0.000 claims description 9
- 125000004306 triazinyl group Chemical group 0.000 claims description 9
- 125000003566 oxetanyl group Chemical group 0.000 claims description 8
- 125000004193 piperazinyl group Chemical group 0.000 claims description 8
- 125000001164 benzothiazolyl group Chemical group S1C(=NC2=C1C=CC=C2)* 0.000 claims description 7
- 125000004196 benzothienyl group Chemical group S1C(=CC2=C1C=CC=C2)* 0.000 claims description 7
- 125000000160 oxazolidinyl group Chemical group 0.000 claims description 7
- 125000000719 pyrrolidinyl group Chemical group 0.000 claims description 7
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 7
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 claims description 7
- 229920002554 vinyl polymer Polymers 0.000 claims description 7
- 125000006552 (C3-C8) cycloalkyl group Chemical group 0.000 claims description 6
- YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical compound C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 claims description 6
- GLUUGHFHXGJENI-UHFFFAOYSA-N Piperazine Chemical compound C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 claims description 6
- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 claims description 6
- 125000000499 benzofuranyl group Chemical group O1C(=CC2=C1C=CC=C2)* 0.000 claims description 6
- 125000004619 benzopyranyl group Chemical group O1C(C=CC2=C1C=CC=C2)* 0.000 claims description 6
- 125000002183 isoquinolinyl group Chemical group C1(=NC=CC2=CC=CC=C12)* 0.000 claims description 6
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 claims description 6
- 239000012634 fragment Substances 0.000 claims description 5
- 125000000325 methylidene group Chemical group [H]C([H])=* 0.000 claims description 5
- 125000002757 morpholinyl group Chemical group 0.000 claims description 5
- 125000001624 naphthyl group Chemical group 0.000 claims description 5
- 125000002943 quinolinyl group Chemical group N1=C(C=CC2=CC=CC=C12)* 0.000 claims description 5
- KNLOUXALILBKPY-UHFFFAOYSA-N 5,8-diazabicyclo[4.2.0]octane Chemical compound C1CCNC2CNC21 KNLOUXALILBKPY-UHFFFAOYSA-N 0.000 claims description 4
- 125000006700 (C1-C6) alkylthio group Chemical group 0.000 claims description 3
- 125000006714 (C3-C10) heterocyclyl group Chemical group 0.000 claims description 3
- RHRLGFPTYKGJPR-UHFFFAOYSA-N 1-cyclobutylpiperidine Chemical compound C1CCC1N1CCCCC1 RHRLGFPTYKGJPR-UHFFFAOYSA-N 0.000 claims description 3
- KYNSBQPICQTCGU-UHFFFAOYSA-N Benzopyrane Chemical compound C1=CC=C2C=CCOC2=C1 KYNSBQPICQTCGU-UHFFFAOYSA-N 0.000 claims description 3
- 125000004029 hydroxymethyl group Chemical group [H]OC([H])([H])* 0.000 claims description 3
- 125000004857 imidazopyridinyl group Chemical group N1C(=NC2=C1C=CC=N2)* 0.000 claims description 3
- 125000002572 propoxy group Chemical group [*]OC([H])([H])C(C([H])([H])[H])([H])[H] 0.000 claims description 3
- 125000002294 quinazolinyl group Chemical group N1=C(N=CC2=CC=CC=C12)* 0.000 claims description 3
- 125000001567 quinoxalinyl group Chemical group N1=C(C=NC2=CC=CC=C12)* 0.000 claims description 3
- DSSKLTAHHALFRW-UHFFFAOYSA-N N-cyclohexylpiperidine Chemical compound C1CCCCC1N1CCCCC1 DSSKLTAHHALFRW-UHFFFAOYSA-N 0.000 claims description 2
- 125000002178 anthracenyl group Chemical group C1(=CC=CC2=CC3=CC=CC=C3C=C12)* 0.000 claims description 2
- 125000001792 phenanthrenyl group Chemical group C1(=CC=CC=2C3=CC=CC=C3C=CC12)* 0.000 claims description 2
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims 9
- GXPBBJPLXAOLTM-UHFFFAOYSA-N 2,5-diazabicyclo[2.2.0]hexane Chemical compound C1NC2CNC21 GXPBBJPLXAOLTM-UHFFFAOYSA-N 0.000 claims 2
- WYANFTXHKVXPFJ-UHFFFAOYSA-N 1-cyclopentylpiperidine Chemical compound C1CCCC1N1CCCCC1 WYANFTXHKVXPFJ-UHFFFAOYSA-N 0.000 claims 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 abstract description 19
- 201000010099 disease Diseases 0.000 abstract description 17
- 238000003776 cleavage reaction Methods 0.000 abstract description 6
- 230000007017 scission Effects 0.000 abstract description 6
- 206010028980 Neoplasm Diseases 0.000 abstract description 4
- 239000000543 intermediate Substances 0.000 abstract description 4
- 201000011510 cancer Diseases 0.000 abstract description 2
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 39
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 21
- 238000006243 chemical reaction Methods 0.000 description 20
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 18
- 125000004356 hydroxy functional group Chemical group O* 0.000 description 18
- 239000000126 substance Substances 0.000 description 15
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 14
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 12
- 125000004122 cyclic group Chemical group 0.000 description 12
- 238000000034 method Methods 0.000 description 11
- 239000007787 solid Substances 0.000 description 11
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 11
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 10
- 239000008194 pharmaceutical composition Substances 0.000 description 10
- 238000005481 NMR spectroscopy Methods 0.000 description 9
- 102000001307 androgen receptors Human genes 0.000 description 9
- 108010080146 androgen receptors Proteins 0.000 description 9
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 8
- 239000012043 crude product Substances 0.000 description 8
- 239000003814 drug Substances 0.000 description 8
- 150000003254 radicals Chemical class 0.000 description 8
- 125000003003 spiro group Chemical group 0.000 description 8
- VWQKUDGVDYSRCA-AWEZNQCLSA-N (2S)-N-[4-cyano-3-(trifluoromethyl)phenyl]-2-hydroxy-3-(4-iodopyrazol-1-yl)-2-methylpropanamide Chemical compound C[C@](O)(CN1C=C(I)C=N1)C(=O)NC1=CC(=C(C=C1)C#N)C(F)(F)F VWQKUDGVDYSRCA-AWEZNQCLSA-N 0.000 description 7
- 206010060862 Prostate cancer Diseases 0.000 description 7
- 208000000236 Prostatic Neoplasms Diseases 0.000 description 7
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 7
- 125000004429 atom Chemical group 0.000 description 7
- 125000002837 carbocyclic group Chemical group 0.000 description 7
- 239000003208 petroleum Substances 0.000 description 7
- 239000000741 silica gel Substances 0.000 description 7
- 229910002027 silica gel Inorganic materials 0.000 description 7
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 6
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 6
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 6
- 230000002401 inhibitory effect Effects 0.000 description 6
- 238000002360 preparation method Methods 0.000 description 6
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- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 5
- 229940079593 drug Drugs 0.000 description 5
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- 230000005496 eutectics Effects 0.000 description 5
- 230000005764 inhibitory process Effects 0.000 description 5
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 5
- QLNJFJADRCOGBJ-UHFFFAOYSA-N propionamide Chemical compound CCC(N)=O QLNJFJADRCOGBJ-UHFFFAOYSA-N 0.000 description 5
- 125000006413 ring segment Chemical group 0.000 description 5
- JUXAVSAMVBLDKO-UHFFFAOYSA-N 1-(1-azabicyclo[2.2.2]octan-3-yl)-3-[3-(1h-indol-3-yl)-1-oxo-1-spiro[1,2-dihydroindene-3,4'-piperidine]-1'-ylpropan-2-yl]urea Chemical compound C1N(CC2)CCC2C1NC(=O)NC(C(=O)N1CCC2(C3=CC=CC=C3CC2)CC1)CC1=CNC2=CC=CC=C12 JUXAVSAMVBLDKO-UHFFFAOYSA-N 0.000 description 4
- 241000124008 Mammalia Species 0.000 description 4
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- 229940125904 compound 1 Drugs 0.000 description 4
- 229940126214 compound 3 Drugs 0.000 description 4
- VFRSADQPWYCXDG-LEUCUCNGSA-N ethyl (2s,5s)-5-methylpyrrolidine-2-carboxylate;2,2,2-trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F.CCOC(=O)[C@@H]1CC[C@H](C)N1 VFRSADQPWYCXDG-LEUCUCNGSA-N 0.000 description 4
- 239000001257 hydrogen Substances 0.000 description 4
- 125000002950 monocyclic group Chemical group 0.000 description 4
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 4
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- YZCKVEUIGOORGS-OUBTZVSYSA-N Deuterium Chemical compound [2H] YZCKVEUIGOORGS-OUBTZVSYSA-N 0.000 description 3
- 241001465754 Metazoa Species 0.000 description 3
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 description 3
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 3
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- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 3
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- 125000002947 alkylene group Chemical group 0.000 description 3
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- 125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 description 2
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- 239000002253 acid Substances 0.000 description 2
- ORILYTVJVMAKLC-UHFFFAOYSA-N adamantane Chemical compound C1C(C2)CC3CC1CC2C3 ORILYTVJVMAKLC-UHFFFAOYSA-N 0.000 description 2
- 125000002029 aromatic hydrocarbon group Chemical group 0.000 description 2
- 125000004567 azetidin-3-yl group Chemical group N1CC(C1)* 0.000 description 2
- KVVMXWRFYAGASO-UHFFFAOYSA-N azetidine-1-carboxylic acid Chemical compound OC(=O)N1CCC1 KVVMXWRFYAGASO-UHFFFAOYSA-N 0.000 description 2
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- 125000004404 heteroalkyl group Chemical group 0.000 description 2
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- 150000002431 hydrogen Chemical class 0.000 description 2
- 125000000336 imidazol-5-yl group Chemical group [H]N1C([H])=NC([H])=C1[*] 0.000 description 2
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- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 2
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
- C07D403/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing three or more hetero rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
- C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
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Abstract
The present invention relates to a compound of formula (I) or a stereoisomer, deuterate, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal thereof, and intermediates thereof, and use thereof in AR or AR cleavage mutant related diseases such as cancer. B-L-K (I).
Description
Technical Field
The present invention relates to a compound of general formula (I) or stereoisomers, deuterates, solvates, prodrugs, metabolites, pharmaceutically acceptable salts or co-crystals thereof, as well as intermediates and preparation methods thereof, and uses thereof in AR or AR cleavage mutant related diseases such as cancer diseases.
Background
Androgen receptor (Androgen receptor, AR) is a hormone nuclear receptor, structurally divided into an N-terminal activation region (NTD), a DNA binding region (DBD) and a ligand binding region (LTD), capable of modulating gene expression that induces prostate cancer, and therefore, inhibition of androgen receptor is an effective method for treating prostate cancer. Androgen receptor inhibitors such as enzalutamide, bicalutamide and the like which are currently marketed mainly exert an inhibitory effect through the action with a ligand binding domain (LTD) of an androgen receptor, but a drug resistance phenomenon caused by androgen receptor cleavage mutants (Androgen receptor splice variants, AR-Vs) in which LTD fragments are deleted occurs in some patients during the course of treatment. Preclinical studies indicate that androgen receptor cleavage mutants can accelerate the progression of enzalutamide resistant prostate cancer, and how to solve the drug resistance problem becomes a concern of clinical medicine.
PROTAC (proteolysis targeting chimera) is a double-function compound capable of simultaneously combining target protein and E3 ubiquitin ligase, and the compound can be recognized by a proteasome of a cell to cause degradation of the target protein, so that the content of the target protein in the cell can be effectively reduced. By introducing ligands capable of binding different targeting proteins into the PROTAC molecule, the application of the PROTAC technology to the treatment of various diseases has become possible, and this technology has received a great deal of attention in recent years.
Therefore, there is a need to develop novel inhibitors of AR or AR cleavage mutants (Androgen receptor splice variants, AR-Vs) and proto drugs of E3 ubiquitin ligases for the treatment of tumor diseases associated with AR or AR cleavage mutants.
Disclosure of Invention
The invention aims to provide a compound which has novel structure, good drug effect, high bioavailability, safer performance and can inhibit and reduce Jie Xiong hormone receptor shear mutant, and is used for treating diseases related to AR or AR shear mutant such as autoimmune diseases, inflammatory diseases or cancers.
The invention provides a compound or stereoisomer, deuterated compound, solvate, prodrug, metabolite, pharmaceutically acceptable salt or eutectic crystal thereof, wherein the compound is selected from compounds shown in a general formula (I),
B-L-K (I);
In certain embodiments, L is selected from a bond or-C 1-50 Hydrocarbyl-, having from 0 to 20 methylene units in said hydrocarbyl optionally further replaced by-Ak-, -Cy-;
in certain embodiments, L is selected from a bond or-C 1-20 Hydrocarbyl-, having from 0 to 20 methylene units in said hydrocarbyl optionally further replaced by-Ak-, -Cy-;
in certain embodiments, L is selected from a bond or-C 1-10 Hydrocarbyl-, having from 0 to 10 (e.g., 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10) methylene units in the hydrocarbyl group optionally further replaced by-Ak-, -Cy-;
in certain embodiments, each-Ak-is independently selected from Ak1, ak2, ak3, ak4, or Ak5;
in certain embodiments, each-Ak-is independently selected from- (CH) 2 ) q -、-(CH 2 ) q -O-、-O-(CH 2 ) q -、-(CH 2 ) q -NR L -、-NR L -(CH 2 ) q -、-(CH 2 ) q -NR L C(=O)-、-NR L (CH 2 ) q C(=O)-、-(CH 2 ) q -C(=O)NR L -、-C(=O)-、-C(=O)-(CH 2 ) q -NR L -、-(C≡C) q -、-CH=CH-、-Si(R L ) 2 -、-Si(OH)(R L )-、-Si(OH) 2 -、-P(=O)(OR L )-、-P(=O)(R L )-、-S-、-S(=O)-、-S(=O) 2 -or a bond, said-CH 2 Optionally further 0 to 2 (e.g. 0, 1 or 2) are selected from H, halogen, OH, CN, NH 2 、C 1-6 Alkyl, C 1-6 Alkoxy, halogen substituted C 1-6 Alkyl, hydroxy substituted C 1-6 Alkyl-and cyano-substituted C 1-6 Substituted by alkyl;
in certain embodiments, each-Cy-is independently selected from Cy1, cy2, cy3, cy4, or Cy5;
in certain embodiments, each-Cy-is independently selected from the group consisting of a bond, a 4-8 membered heteromonocyclic ring, a 4-10 membered heteroacene, a 5-12 membered heterospiro ring, a 7-10 membered heterobridged ring, a 3-7 membered monocycloalkyl, a 4-10 membered heterocycloalkyl, a 5-12 membered spirocycloalkyl, a 7-10 membered bridged cycloalkyl, a 5-10 membered heteroaryl, or a 6-10 membered aryl, said aryl, heteroaryl, cycloalkyl, heteromonocyclic ring, heteroacene, heterospiro ring, or heterobridged ring optionally further being 0 to 4 (e.g., 0, 1, 2, 3, or 4) selected from H, F, cl, br, I, OH, COOH, CN, NH 2 、=O、C 1-4 Alkyl, halogen substituted C 1-4 Alkyl, hydroxy substituted C 1-4 Alkyl or C 1-4 A substituent of an alkoxy group, said heteroaryl, heteromonocyclic, heterobicyclic, heterospiro, or heterobridged ring containing from 1 to 4 (e.g., 1, 2, 3, or 4) heteroatoms selected from O, S, N, when the heteroatom is selected from S, optionally further substituted with 0, 1, or 2 = O;
in certain embodiments, cy1, cy2, cy3, cy4, or Cy5 are each independently selected from the group consisting of a bond, a 4-7 membered heteromonocyclic ring, a 4-10 membered heteroacene, a 5-12 membered heterospiro ring, a 7-10 membered heterobridged ring, a 3-7 membered monocycloalkyl, a 4-10 membered cycloalkyl, a 5-12 membered spirocycloalkyl, a 7-10 membered bridged cycloalkyl, a 5-10 membered heteroaryl, or a 6-10 membered aryl, said aryl, heteroaryl, cycloalkyl, heteromonocyclic ring, heteroacene, heterospiro ring, or heterobridged ring optionally further being 0 to 4 (e.g., 0, 1, 2, 3, or 4) selected from H, F, cl, br, I, OH, COOH, CN, NH 2 、=O、C 1-4 Alkyl, halogen substituted C 1-4 Alkyl, hydroxy substituted C 1-4 Alkyl or C 1-4 A substituent of an alkoxy group, said heteroaryl, heteromonocyclic, heterobicyclic, heterospiro, or heterobridged ring containing from 1 to 4 (e.g., 1, 2, 3, or 4) heteroatoms selected from O, S, N, when the heteroatom is selected from S, optionally further substituted with 0, 1, or 2 = O;
In some embodiments of the present invention, in some embodiments, L is selected from the group consisting of-Cy 1-Cy2-Ak2-Cy3-Cy4-Ak 4-Cy5-Ak5-, -Cy1-Cy2-Cy3-Cy4-Ak2-Ak3-Ak4-Ak5-, -Cy1-Ak1-Cy2-Ak2-Cy3-Ak3-Cy4-Ak 5-, -Ak1-Cy1-Ak2-Cy2-Ak3-Cy3-Ak4-Cy4-Ak5-, -Cy1-Ak1-Cy2-Ak2-Cy3-Cy4-Ak3-Ak4-Ak5-, -Cy1-Ak 1-2-Ak 2-Ak3-Cy3-Cy4-Ak 5-; -Cy1-Ak1-Ak2-Ak3-Ak4-Ak5-Cy2-Cy3-Cy4-, -Cy1-Cy2-Ak1-Ak2-Ak3-Ak4-Ak5-Cy3-Cy4-, -Cy1-Cy2-Cy3-Ak1-Ak2-Ak3-Ak4-Ak5-Cy 1-Cy2-Cy3-Cy4-Ak1-Ak2-Ak3-Ak4-Ak5-, -Cy1-Ak1-Cy2-Cy3-Cy4-Ak2-Ak3-Ak4-Ak5-, -Cy1-Cy2-Ak1-Cy3-Cy4-Ak2-Ak3-Ak4-Ak5- -Cy1-Cy2-Cy3-Ak1-Cy4-Ak2-Ak3-Ak4-Ak5-, -Cy1-Ak1-Ak2-Cy2-Cy3-Cy4-Ak3-Ak4-Ak5-, -Cy1-Cy2-Ak1-Ak2-Cy3-Cy4-Ak3-Ak4-Ak5-, -Cy1-Cy2-Cy3-Ak 2-Cy4-Ak3-Ak4-Ak5-, -Cy1-Ak1-Ak2-Ak3-Cy 3-Cy4-Ak4-Ak5-, -Cy1-Cy2-Ak1-Ak2-Ak3-Cy 4-Ak4-Ak5-, -1-Cy 2-Cy3-Ak2-Ak 3-Cy4-Ak4-Ak 5-; -Cy1-Ak1-Ak2-Ak3-Ak4-Cy2-Cy3-Cy4-Ak5-, -Cy1-Cy2-Ak1-Ak2-Ak3-Ak4-Cy3-Cy4-Ak5-, -Cy1-Cy2-Cy3-Ak1-Ak2-Ak3-Ak4-Cy4-Ak5-, -Ak1-Ak2-Ak 4-Ak5-Cy1-Cy2-Cy3-Cy 2-Ak3-Ak4-Ak5-, -Ak1-Ak2-Cy1-Cy2-Cy3-Cy4-Ak3-Ak4-Ak5- -Ak1-Ak2-Ak3-Cy1-Cy2-Cy3-Cy4-Ak4-Ak5-, -Ak1-Ak2-Ak3-Ak4-Cy1-Cy2-Cy3-Cy4-Ak5-, -Ak1-Cy1-Ak2-Ak3-Ak4-Ak5-Cy2-Cy3-Cy4-, -Ak1-Cy1-Cy2-Ak2-Ak3-Ak4-Ak5-Cy3-Cy 4-; -Ak1-Cy1-Cy2-Cy3-Ak2-Ak3-Ak4-Ak5-Cy4-, -Ak1-Ak2-Cy1-Ak3-Ak4-Ak5-Cy2-Cy3-Cy4-, -Ak1-Ak2-Cy1-Cy2-Ak3-Ak4-Ak5-Cy3-Cy 4-; -Ak1-Ak2-Cy1-Cy2-Cy3-Ak3-Ak4-Ak5-Cy4-, -Ak1-Ak2-Ak3-Cy1-Ak4-Ak5-Cy2-Cy3-Cy4-, -Ak1-Ak2-Ak3-Cy1-Cy2-Ak4-Ak5-Cy3-Cy4-, -Ak1-Ak2-Ak3-Cy1-Cy 3-Ak4-Ak5-Cy4-, -Ak1-Ak2-Ak3-Ak4-Cy1-Ak5-Cy2-Cy 4-, -Ak1-Ak2-Ak3-Ak4-Cy1-Cy2-Ak5-Cy3-Cy4- Ak1-Ak2-Ak3-Ak4-Cy1-Cy2-Cy3-Ak5-Cy4-;
In some embodiments of the present invention, in some embodiments, L is selected from the group consisting of-Cy 1-, -Cy1-Ak1-Ak2-Ak3-Ak4-, -Cy1-Cy2-, -Cy1-Ak1-Cy2-Ak2-, cy1-Ak1-Ak2-, cy1-Cy2-, cy1-Ak 2-, cy1-Cy2-, cy2-Cy 2, and Cy 1-Cy-Cy 1-Ak1-Cy2-Ak2-Ak3-, -Cy1-Ak1-Cy2-Ak2-Ak3-Ak4-, -Cy1-Cy2-Ak2-Ak3-Ak4-, -Cy1-Ak1-Cy2-Ak2-Ak3-Ak 4-; -Cy1-Ak1-Ak2-Cy3-, -Cy1-Ak1-Ak2-Cy3-Ak3-, -Cy1-Cy2-Cy3-, -Cy1-Ak1-Cy2-Cy3-, -Cy1-Cy2-Ak2-Cy3-, -Cy1-Ak1-Cy2-Cy3-Ak3-, -Cy1-Cy2-Ak 3-, -Cy1-Ak1-Cy2-Ak 3-, -Cy1-Ak 2-Ak3-, -Cy2-Cy3-Ak3-Ak4- -Cy1-Cy2-Cy3-Ak3-Cy4-, -Cy1-Cy2-Cy3-Cy4-, -Cy1-Ak1-Cy2-Cy3-Cy4-, -Cy1-Cy2-Cy3-Cy4-Ak4-, -Cy1-Ak1-Cy2-Ak2-Cy3-Ak3-Cy4-, -Cy1-Ak1-Cy2-Ak2-Cy3-Cy4-, -Ak1-Cy2-Cy3-, -Ak1-Ak2-Cy3-Cy 4-; -Ak1-Cy2-Ak2-Cy3-, -Ak1-Cy2-Cy3-Ak3-Cy4-, -Ak1-Cy2-Cy3-Cy4-Ak4-Cy5-, -Ak1-Cy2-Ak2-, -Ak1-Ak2-Ak 4-, -Ak1-Ak2-Ak3-Ak4-Ak5-, -Cy1-Cy2-Cy3-Ak3-Ak4-Ak5-, -Cy1-Cy2-Ak2-Cy3-Ak3-Ak4-Ak5-, -Cy1-Ak 2-Ak3-Ak4-Ak5- -Cy1-Cy2-Cy3-Cy4-Ak4-Ak5-, -Cy1-Ak1-Ak2-Ak3-Ak4-Ak5-, -Ak1-Cy2-Ak 3-Ak4-Ak5-, -Ak1-Cy2-Ak 3-Ak4-, -Ak1-Cy2-Ak 3-;
In certain embodiments, L is selected from a bond or a group of table a, the left side of the group being attached to B;
in certain embodiments, ak1, ak2, ak3, ak4, ak5 are each independently selected from- (CH) 2 ) q -、-(CH 2 ) q -O-、-O-(CH 2 ) q -、-(CH 2 ) q -NR L -、-NR L -(CH 2 ) q -、-(CH 2 ) q -NR L C(=O)-、-(CH 2 ) q -C(=O)NR L -、-C(=O)-、-C(=O)-(CH 2 ) q -NR L -、-(C≡C) q -or a bond, said-CH 2 Optionally further 0 to 2 (e.g. 0, 1 or 2) are selected from H, halogen, OH, CN, NH 2 、C 1-4 Alkyl, C 1-4 Alkoxy, halogen substituted C 1-4 Alkyl, hydroxy substituted C 1-4 Alkyl-and cyano-substituted C 1-4 Substituted by alkyl;
in certain embodiments, ak1, ak2, ak3, ak4, ak5 are each independently selected from the group consisting of-O-, -OCH 2 -、-CH 2 O-、-OCH 2 CH 2 -、-CH 2 CH 2 O-、-C≡C-、-C(CH 3 ) 2 -、-CH 2 -、-CH 2 CH 2 -、-CH 2 CH 2 CH 2 -、-N(CH 3 )-、-NH-、-CH 2 N(CH 3 )-、-CH 2 NH-、-NHCH 2 -、-CH 2 CH 2 N(CH 3 )-、-CH 2 CH 2 NH-、-NHCH 2 CH 2 -、-C(=O)-、-C(=O)CH 2 NH-、-CH 2 C (=o) NH-, -C (=o) NH-or-NHC (=o) -;
in certain embodiments, R L Each independently selected from H, C 1-6 Alkyl, 3-7 membered heterocyclyl, 3-7 membered cycloalkyl, phenyl or 5-6 membered heteroaryl;
in certain embodiments, R L Each independently selected from H or C 1-6 An alkyl group;
in certain embodiments, R L Each independently selected from H or C 1-4 An alkyl group;
in certain embodiments, R L Each independently from H, methyl or ethyl;
in certain embodiments, cy1, cy2, cy3, cy4, or Cy5 are each independently selected from a bond or one of the following substituted or unsubstituted groups: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, piperidine, morpholine, piperazine, phenyl, cyclopropyl-and-cyclopropyl, cyclopropyl-and-cyclobutyl, cyclopropyl-and-cyclopentyl, cyclopropyl-and-cyclohexyl, cyclobutyl-and-cyclopentyl, cyclobutyl-and-cyclohexyl, cyclopentyl-and-cyclopentyl, cyclopentyl-and-cyclohexyl, cyclohexyl-and-cyclohexyl, cyclopropyl-and-spiropropyl, cyclopropyl-spirocyclobutyl, cyclopropyl-and-spirocyclopentyl, cyclopropyl-and-spirocyclohexyl cyclobutylspirobutyl, cyclobutylspiropentyl, cyclobutylspirohexyl, cyclopentylpspiropentyl, cyclopentylpspirohexyl, cyclohexylspirohexyl, cyclopropylazacyclobutyl, cyclopropylazacyclopentyl, cyclopropylazacyclohexyl, cyclopropylpiperidine, cyclobutylazacyclobutyl, cyclobutylazacyclopentyl, cyclobutylazacyclohexyl, cyclobutylazapiperidine, cyclopentylazacyclobutyl, cyclopentylazacyclopentyl, cyclopentylazacyclohexyl Piperidine, cyclohexylazetidine, cyclohexylpiperidine, azetidine, and the like azetidinoazacyclopentyl, azetidinoazacyclohexyl, azetidinopiperidine, azetidinoazacyclobutyl, azetidinoazacyclopentyl azetidino-azetidinyl, azetidino-piperidine, and azetidino azetidinyl, azetidino-azetidinyl, azetidinyl cyclopentyl spiroazetidinyl, cyclohexyl spiroazetidinyl, azetidinyl spiroazetidinyl, cyclohexyl azetidinyl, and cyclohexyl azetidinyl azetidinyl spiroazetidinyl, azetidinyl-containing, azetidinyl Azacyclopentyl spirocyclohexyl, azacyclohexyl spiroazetidinyl, azacyclohexyl spiroazetidine, cyclobutylspiropiperidine, cyclopentyl spiropiperidine, cyclohexyl spiropiperidine, azacyclobutylspiropiperidine, azacyclopentyl spiropiperidine, azacyclohexyl spiropiperidine, When substituted, optionally further is selected from H, F, cl, br, I, OH, NH by 0 to 4 (e.g., 0, 1, 2, 3 or 4) 2 、COOH、CN、=O、C 1-4 Alkyl, halogen substituted C1-4 alkyl, hydroxy substituted C 1-4 Alkyl or C 1-4 Alkoxy radicalSubstituted by substituents of radicals;
in certain embodiments, cy1, cy2, cy3, cy4, or Cy5 are each independently selected from a bond or one of the following substituted or unsubstituted groups: when substituted, optionally further is selected from H, F, CF by 0 to 4 (e.g., 0, 1, 2, 3 or 4) 3 Methyl, =o, hydroxymethyl, COOH, CN or NH 2 Is substituted by a substituent of (2);
in certain embodiments, K is selected from
In certain embodiments, K is selected from Represents a ring selected from aromatic or non-aromatic rings;
in certain embodiments, K is selected from
In certain embodiments, each Q is independently selected from the group consisting of bond, -O-, -S-, -CH 2 -、-NR q -、-CO-、-NR q CO-、-CONR q -or a 3-12 membered heterocyclyl, said heterocyclyl optionally being further substituted with 0 to 4 (e.g. 0, 1, 2, 3, 4) groups selected from H, F, cl, br, I, OH, = O, NH 2 、CN、COOH、CONH 2 、C 1-4 Alkyl or C 1-4 A substituent of an alkoxy group, the heterocyclic group containing 1 to 4 (e.g., 1, 2, 3, 4) heteroatoms selected from O, S, N;
in certain embodiments, each Q is independently selected from the group consisting of-O-, -S-, -CH 2 -、-NR q -、-CO-、-NR q CO-、-CONR q -or a 4-7 membered heterocyclyl, said heterocyclyl optionally being further substituted with 0 to 4 (e.g. 0, 1,2,3, 4) groups selected from H, F, cl, br, I, OH, = O, NH 2 、CN、COOH、CONH 2 、C 1-4 Alkyl or C 1-4 A substituent of an alkoxy group, the heterocyclic group containing 1 to 4 (e.g., 1,2,3, 4) heteroatoms selected from O, S, N;
in certain embodiments, R q Selected from H or C 1-6 An alkyl group;
in certain embodiments, R q Selected from H or C 1-4 An alkyl group;
in certain embodiments, R q Selected from H, methyl, ethyl;
in certain embodiments, E is each independently selected from C 3-10 Carbocyclyl, C 6-10 Aryl, 3-12 membered heterocyclyl or 5-12 membered heteroaryl, said heterocycle or heteroaryl containing 1 to 4 (e.g. 1,2,3, 4) heteroatoms selected from O, S, N;
in certain embodiments, E is each independently selected from C 3-8 A carbocycle, a benzene ring, a 4-7 membered heterocycle, an 8-12 membered heterocycle, a 7-12 membered heteroaryl or a 5-6 membered heteroaryl, said heterocycle or heteroaryl containing 1 to 4 (e.g. 1,2,3, 4) heteroatoms selected from O, S, N;
in certain embodiments, each E is independently selected from phenyl, pyridyl, pyridazinyl, pyrazinyl, pyrimidinyl, pyrrolyl, pyrazolyl, imidazolyl, thiazolyl, furanyl, thienyl, oxazolyl, indolinyl, isoindolinyl, 1,2,3, 4-tetrahydroquinolinyl, or 1,2,3, 4-tetrahydroisoquinolinyl;
In certain embodiments, each E is independently selected from phenyl, pyridyl, pyridazinyl, pyrazinyl, pyrimidinyl, pyrrolyl, pyrazolyl, imidazolyl, thiazolyl, furanyl, thienyl, or oxazolyl;
in certain embodiments, each E is independently selected from phenyl, pyridinyl, pyridazinyl, pyrazinyl, pyrimidinyl;
in certain embodiments, each E is independently selected from a benzene ring or a pyridine ring;
in certain embodiments, A is selected from C 3-10 Carbocyclyl, C 6-10 Aryl, 3-10 membered heterocyclyl or 5-10 membered heteroaryl, said heterocycle or heteroaryl containing 1 to 4 (e.g. 1, 2, 3 or 4) heteroatoms selected from O, S, N;
in certain embodiments, A, H or H2 are each independently selected from C 3-8 A carbocycle, benzene ring, 4-7 membered heterocycle or 5-6 membered heteroaryl, said heterocycle or heteroaryl containing 1 to 4 (e.g. 1, 2, 3 or 4) heteroatoms selected from O, S, N;
in certain embodiments, A, H or H2 are each independently selected from phenyl, pyridyl, pyridazinyl, pyrazinyl, pyrimidinyl, pyrrolyl, pyrazolyl, imidazolyl, thiazolyl, furanyl, thienyl, or oxazolyl;
in certain embodiments, A, H1 or H2 are each independently selected from phenyl or pyridinyl;
In certain embodiments, F is each independently selected from C 3-20 Carbocyclyl group,C 6-20 Aryl, 3-20 membered heterocyclyl or 5-20 membered heteroaryl, said heterocyclyl or heteroaryl containing 1 to 4 (e.g. 1, 2,3, 4) heteroatoms selected from O, S, N;
in certain embodiments, each F is independently selected from 3-7 membered monocycloalkyl, 4-10 membered cycloalkyl, 5-12 membered spirocycloalkyl, 5-10 membered bridged cycloalkyl, 4-7 membered heteromonocyclic, 4-10 membered heterobicyclic, 5-12 membered heterospirocyclic, 5-10 membered heterobridged ring, C 6-14 Aryl or 5-10 membered heteroaryl, said heteromonocyclic, heterobicyclic, heterospiro, heterobridged, or heteroaryl containing 1 to 4 (e.g., 1, 2,3, 4) heteroatoms selected from O, S, N;
in certain embodiments, each F is independently selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, bicyclo [1.1.1] pentyl, 6, 7-dihydro-5H-cyclopenta [ c ] pyridyl, 2, 3-dihydro-1H-indenyl, phenyl, naphthyl, anthryl, phenanthryl, azetidinyl, azacyclopentyl, piperidinyl, morpholinyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, triazinyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, oxazolyl, furyl, thienyl, thiazolyl, benzimidazolyl, benzopyrazolyl, benzothiazolyl, benzothienyl, benzopyrrolyl, benzopyridyl, benzopyrimidinyl, benzopyridinyl, pyrrolopyrrolyl, pyrrolopyridinyl, pyrrolopyrimidinyl, imidazopyridinyl, imidazopyrazinyl, imidazopyridazinyl, pyrazolopyrimidinyl, pyrazinyl, pyrazolopyrimidinyl, pyridazinyl, or pyridazinyl;
In certain embodiments, R k2 Each independently selected from the group consisting of bond, -CO-, -SO 2 -, -SO-or-C (R) k3 ) 2 -;
In certain embodiments, R k2 Each independently selected from-CO-, -SO 2 -or-C (R) k3 ) 2 -;
In certain embodiments, R k1 Each independently selected from H, F, cl, br, I, OH, = O, NH 2 、CN、COOH、CONH 2 、C 1-6 Alkyl or C 1-6 Alkoxy, said alkyl or alkoxy optionally further being 0 to 4 (e.g. 0, 1, 2, 3, 4) selected from H, F, cl, br, I, OH, = O, NH 2 、CN、COOH、CONH 2 、C 1-4 Alkyl or C 1-4 Substituted with alkoxy;
in certain embodiments, R k3 Each independently selected from H, F, cl, br, I, OH, = O, NH 2 、CN、COOH、CONH 2 、C 1-6 Alkyl, C 1-6 Alkoxy, C 3-8 Cycloalkyl or 3-8 membered heterocyclyl, said alkyl, alkoxy, cycloalkyl or heterocyclyl optionally being further substituted with 0 to 4 (e.g. 0, 1, 2, 3, 4) groups selected from H, F, cl, br, I, OH, = O, NH 2 、CN、COOH、CONH 2 、C 1-4 Alkyl or C 1-4 A substituent of an alkoxy group, the heterocyclic group containing 1 to 4 (e.g., 1, 2, 3, 4) heteroatoms selected from O, S, N;
in certain embodiments, R k1 、R k3 Each independently selected from H, F, cl, br, I, OH, = O, NH 2 、CF 3 、CN、COOH、CONH 2 、C 1-4 Alkyl or C 1-4 Alkoxy, said alkyl or alkoxy optionally being further selected from H, F, cl, br, I, OH, NH by 0 to 4 (e.g. 0, 1, 2, 3 or 4) 2 Is substituted by a substituent of (2);
in certain embodiments, R k1 、R k3 Each independently selected from H, F, cl, br, I, OH, = O, NH 2 、CF 3 、CN、COOH、CONH 2 Methyl, ethyl, isopropyl, methoxy, ethoxy or isopropoxy, optionally further from 0 to 4 (e.g. 0, 1, 2, 3 or 4) being selected from H, F, cl, br, I, OH, NH 2 Is substituted by a substituent of (2);
in some embodiments of the present invention, in some embodiments,two R k3 And the carbon atoms or ring skeletons directly linked to each other form together a 3-8 membered carbocycle or 3-8 membered heterocycle, said carbocycle or heterocycle optionally being further substituted with 0 to 4 (e.g. 0, 1, 2, 3, 4) selected from H, F, cl, br, I, OH, = O, NH 2 、CN、COOH、CONH 2 、C 1-4 Alkyl or C 1-4 A substituent of an alkoxy group, the heterocycle containing 1 to 4 (e.g. 1, 2, 3, 4) heteroatoms selected from O, S, N;
in certain embodiments, two R' s k3 And the carbon atoms or ring skeletons directly linked to each other together form a 3-6 membered carbocycle or 3-7 membered heterocycle, said carbocycle or heterocycle optionally being further substituted with 0 to 4 (e.g. 0, 1, 2, 3, 4) selected from H, F, cl, br, I, OH, = O, NH 2 、CN、COOH、CONH 2 、C 1-4 Alkyl or C 1-4 A substituent of an alkoxy group, the heterocycle containing 1 to 4 (e.g. 1, 2, 3, 4) heteroatoms selected from O, S, N;
In certain embodiments, R k4 Each independently selected from H, OH, NH 2 、CN、CONH 2 、C 1-6 Alkyl, C 3-8 Cycloalkyl or 3-8 membered heterocyclyl, said alkyl, cycloalkyl or heterocyclyl optionally being further substituted with 0 to 4 (e.g. 0, 1, 2, 3, 4) groups selected from H, F, cl, br, I, OH, = O, NH 2 、CN、COOH、CONH 2 、C 1-4 Alkyl or C 1-4 A substituent of an alkoxy group, the heterocyclic group containing 1 to 4 (e.g., 1, 2, 3, 4) heteroatoms selected from O, S, N;
in certain embodiments, R k4 Each independently selected from H, OH, NH 2 、CF 3 、CN、C 1-4 An alkyl group;
in certain embodiments, R k5 Each independently selected from CO, CH 2 、SO 2 Or (b)
In certain embodiments, R k6 Each independently selected from CO, CH, SO, SO 2 、CH 2 Or N;
in certain embodiments, R k7 Each independently selected from CO, CH, N, CH 2 、O、S、N(CH 3 ) Or NH;
in certain embodiments, R k7 Each independently selected from CH 2 、O、N(CH 3 ) Or NH;
in certain embodiments, R k8 Each independently selected from C, N or CH;
in certain embodiments, R k9 Each independently selected from CO, SO 2 Or CH (CH) 2 ;
In certain embodiments, M 1 Selected from the group consisting of bond, -C (=O) NH-, -NHC (=O) -, -CH 2 -C(=O)NH-、-C(=O)CH 2 NH-, 5-6 membered heteroaryl, said heteroaryl optionally being further substituted with 0 to 4 (e.g. 0, 1, 2, 3, 4) selected from H, F, cl, br, I, OH, = O, CF 3 、NH 2 、CN、C 1-4 Alkyl, halogen substituted C 1-4 Alkyl, hydroxy substituted C 1-4 Alkyl, C 1-4 Substituted with an alkoxy substituent, said heteroaryl containing 1 to 4 (e.g., 1, 2, 3, 4) heteroatoms selected from O, S, N;
in certain embodiments, M1 is selected from the group consisting of a bond, -C (=o) NH-, -CH 2 -C(=O)NH-、-C(=O)CH 2 NH-, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, oxazolyl, isoxazolyl, furanyl, thienyl, thiazolyl; in certain embodiments, M 2 Selected from-NHC (=o) -C 1-6 Alkyl, -NHC (=o) -C 3-6 Cycloalkyl or 4-10 membered heterocyclyl, said alkyl, cycloalkyl or heterocyclyl optionally being further substituted with 0 to 4 (e.g. 0, 1, 2, 3, 4) groups selected from H, F, cl, br, I, =o, OH, NH 2 、C 1-4 Alkyl or C 1-4 A substituent of an alkoxy group, the heterocyclic group containing 1 to 4 (e.g., 1, 2, 3, 4) heteroatoms selected from O, S, N;
in certain embodiments, M 2 Selected from-NHC (=o) -C 1-4 Alkyl, -NHC (=o) -C 3-6 Cycloalkyl or 4-10 membered heterocyclyl, said alkyl, cycloalkylThe radical or heterocyclic radical is optionally further substituted with 0 to 4 (e.g. 0, 1, 2, 3, 4) radicals selected from H, F, cl, br, I, =o, OH, NH 2 、C 1-4 Alkyl or C 1-4 A substituent of an alkoxy group, the heterocyclic group containing 1 to 4 (e.g., 1, 2, 3, 4) heteroatoms selected from O, S, N;
In certain embodiments, M 2 Selected from-NHC (=O) -CH 3 -NHC (=o) -cyclopropyl, -NHC (=o) -cyclobutyl, azetidinyl, benzazetidinyl, optionally further substituted with 0 to 4 (e.g. 0, 1, 2, 3, 4) groups selected from H, F, cl, br, I, =o, OH, NH 2 、C 1-4 Alkyl or C 1-4 Substituted with alkoxy;
in certain embodiments, M 3 Selected from-NH-or-O-;
in certain embodiments, R k10 Selected from C 1-6 Alkyl optionally further substituted with 0 to 4 (e.g. 0, 1, 2, 3, 4) alkyl groups selected from H, F, cl, br, I, =o, OH, C 1-6 Alkyl or C 3-6 Substituted cycloalkyl;
in certain embodiments, R k10 Selected from C 1-4 Alkyl optionally further substituted with 0 to 4 groups selected from H, F, cl, br, I, =o, OH, C 1-4 Alkyl or C 3-6 Substituted cycloalkyl;
in certain embodiments, R k10 Selected from methyl, ethyl, isopropyl, propyl, tert-butyl, said methyl, ethyl, isopropyl, propyl, tert-butyl optionally further being 0 to 4 selected from H, F, cl, br, I, =o, OH, C 1-4 Alkyl or C 3-6 Substituted cycloalkyl;
in certain embodiments, G is selected from 6-10 membered aryl or 5-10 membered heteroaryl, optionally further substituted with 0 to 4 (e.g., 0, 1, 2, 3, 4) selected from H, F, cl, br, I, OH, = O, CF 3 、CN、C 1-4 Alkyl, halogen substituted C 1-4 Alkyl, hydroxy substituted C 1-4 Alkyl, C 1-4 Alkoxy or C 3-6 A cycloalkyl group substituted with a substituent, the heteroaryl group containing 1 to 4 (e.g., 1, 2, 3, 4) heteroatoms selected from N, O, S;
in certain embodiments, R k11 Each independently selected from H, F, cl, br, I, = O, OH, SH, C 1-6 Alkyl, C 1-6 Alkoxy or C 1-6 Alkylthio or-O-C (=o) -C 1-6 Alkyl, said alkyl, alkoxy or alkylthio optionally further being selected from H, F, cl, br, I, OH, C by 0 to 4 (e.g. 0, 1, 2, 3, 4) 1-4 Alkyl or C 1-4 Substituted with alkoxy;
in certain embodiments, R k11 Each independently selected from H, F, cl, br, I, = O, OH, SH, C 1-4 Alkyl, C 1-4 Alkoxy or C 1-4 Alkylthio or-O-C (=o) -C 1-4 Alkyl, said alkyl, alkoxy or alkylthio being optionally further substituted with 0 to 4 groups selected from H, F, cl, br, I, OH, C 1-4 Alkyl or C 1-4 Substituted with alkoxy;
In certain embodiments, R k11 Each independently selected from H, F, cl, br, I, =o, OH, SH, methyl, ethyl, isopropyl, propyl, methoxy, ethoxy, propoxy, isopropoxy, methylthio, ethylthio, propylthio or-O-C (=o) -CH 3 Said methyl, ethyl, isopropyl, propyl, methoxy, ethoxy, propoxy, isopropoxy, methylthio, ethylthio, propylthio optionally further being 0 to 4 groups selected from H, F, cl, br, I, OH, C 1-4 Alkyl or C 1-4 Substituted with alkoxy;
in certain embodiments, R k12 、R k13 Each independently selected from H, C 1-6 Alkyl or C 3-6 Cycloalkyl, said alkyl or cycloalkyl optionally being further substituted with 0 to 4 (e.g. 0, 1, 2, 3, 4) groups selected from H, F, cl, br, I, =o, OH, NH 2 、C 1-4 Alkyl or C 1-4 Of alkoxy groupsSubstituted by substituents;
in certain embodiments, R k12 、R k13 Each independently selected from H, C 1-4 Alkyl or C 3-6 Cycloalkyl, said alkyl or cycloalkyl optionally being further substituted with 0 to 4 groups selected from H, F, cl, br, I, =o, OH, NH 2 、C 1-4 Alkyl or C 1-4 Substituted with alkoxy;
in certain embodiments, R k12 、R k13 Each independently selected from H, methyl, ethyl, isopropyl, propyl, cyclopropyl or cyclobutyl, optionally further substituted with 0 to 4 groups selected from H, F, cl, br, I, =o, OH, NH 2 、C 1-4 Alkyl or C 1-4 Substituted with alkoxy;
in certain embodiments, R k14 Selected from 5-6 membered heteroaryl, optionally further substituted with 0 to 4 (e.g. 0, 1, 2, 3, 4) selected from H, F, cl, br, I, OH, = O, CF 3 、CN、C 1-4 Alkyl, halogen substituted C 1-4 Alkyl, hydroxy substituted C 1-4 Alkyl, C 1-4 Alkoxy or C 3-6 A cycloalkyl group substituted with a substituent, the heteroaryl group containing 1 to 4 (e.g., 1, 2, 3, 4) heteroatoms selected from N, O, S;
in certain embodiments, R k14 Selected from the group consisting of pyrrolyl, pyrazolyl, imidazolyl, triazolyl, oxazolyl, isoxazolyl, furanyl, thienyl, thiazolyl, pyridyl, pyridazinyl, pyrazinyl, or pyrimidinyl, said pyrrolyl, pyrazolyl, imidazolyl, triazolyl, oxazolyl, isoxazolyl, furanyl, thienyl, thiazolyl, pyridyl, pyridazinyl, pyrazinyl, or pyrimidinyl optionally further being 0 to 4 selected from H, F, cl, br, I, OH, = O, CF 3 、CN、C 1-4 Alkyl, halogen substituted C 1-4 Alkyl, hydroxy substituted C 1-4 Alkyl, C 1-4 Alkoxy or C 3-6 Substituted cycloalkyl;
in certain embodiments, K is selected from the group of table B, the left side of the group being attached to L;
in certain embodiments, K is selected from one of the following structural fragments:
In certain embodiments, B is selected from
In certain embodiments, B is selected from />
In certain embodiments, Y is selected from S or O;
in certain embodiments, X 1 、X 2 、X 3 、X 4 、X 5 Each independently selected from CR b2 Or N;
in certain embodiments, B 1 Selected from C 6-10 A carbocyclyl or 5-10 membered heterocyclyl, said heterocyclyl containing 1 to 4 heteroatoms selected from O, S, N;
in certain embodiments, B1 is selected from phenyl, 5-6 membered mono-heteroaryl, or 9-10 membered bicyclic heterocyclyl, said heteroaryl or heterocyclyl containing 1 to 4 heteroatoms selected from O, S, N;
in certain embodiments, B 1 Selected from phenyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, triazinyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, oxazolyl, isoxazolyl, furanyl, thienyl, thiazolyl, benzopyrrolyl, benzopyrazolyl, benzofuranyl, benzothienyl, benzothiazolyl, benzimidazolyl, pyridopyrrolyl, quinolinyl, isoquinolinyl, quinazolinyl, quinoxalinyl, benzopiperidinyl, benzopyranyl, or benzopyranyl;
in some casesIn embodiments, B 1 Selected from phenyl, pyridyl, quinolinyl, isoquinolinyl, benzopiperidinyl or benzopyran;
In certain embodiments, ring W is selected from 5 to 10 membered heteroaryl rings containing 1 to 5 heteroatoms selected from O, S, N;
in certain embodiments, ring W is selected from a 5-6 membered monocyclic heteroaryl ring or a 9-10 membered bicyclic heteroaryl ring containing 1 to 5 heteroatoms selected from O, S, N;
in certain embodiments, ring W is selected from pyridinyl, pyrimidinyl, pyridazinyl, pyridazinonyl, pyrazinyl, triazinyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, oxazolyl, isoxazolyl, furanyl, thienyl, thiazolyl, benzopyrrolyl, benzopyrazolyl, benzimidazolyl, pyridopyrrolyl;
in certain embodiments, R b1 、R b2 Each independently selected from H, F, cl, br, I, = O, OH, CN, NO 2 、COOH、C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-4 Alkoxy, C 1-4 Alkylthio, - (CH) 2 ) n -R b21 、-OR b21 、-N(R b21 ) 2 、-C(=O)N(R b21 ) 2 、-C(=O)OR b21 、-C(=O)R b22 、-NR b21 C(=O)R b22 、-NR b21 S(=O) 2 R b22 、C 3-6 Cycloalkyl, C 6-10 Aryl, 5-10 membered heteroaryl or 4-10 membered heterocyclyl, said alkyl, alkenyl, alkynyl, alkoxy, alkylthio, cycloalkyl, heterocyclyl, aryl or heteroaryl optionally being further substituted with 0 to 4 groups selected from H, F, cl, br, I, OH, =o, -N (R b21 ) 2 、CN、COOH、C 1-4 Alkyl, C 1-4 Alkoxy, halogen substituted C 1-4 Alkyl-and cyano-substituted C 1-4 Alkyl, C 3-6 Cycloalkyl, 5-10 membered heteroaryl or 4-10 membered heterocyclyl, said heteroaryl or heterocyclyl containing 1 to 4 heteroatoms selected from O, S, N;
in certain embodiments, R b1 、R b2 Each independently selected from H, F, cl, br, I, =o, OH, NH 2 、CN、NO 2 、CF 3 、CHF 2 、COOH、NHCH 3 、NHCH 2 CH 3 、NHCH(CH 3 ) 2 、N(CH 3 ) 2 、N(CH 2 CH 3 ) 2 、NHC(=O)CH 3 、NHS(=O) 2 CH 3 Methyl, ethyl, isopropyl, vinyl, ethynyl, methoxy, ethoxy, propoxy, isopropoxy, morpholinyl, piperazinyl, pyrrolidinyl, piperidinyl or oxazolidinyl, said methyl, ethyl, vinyl, isopropyl, ethynyl, methoxy, ethoxy, propoxy, isopropoxy, morpholinyl, piperazinyl, pyrrolidinyl, piperidinyl or oxazolidinyl optionally further being 0 to 4 groups selected from H, F, cl, br, I, OH, CN, CF 3 、NH 2 Is substituted by a substituent of (2);
in certain embodiments, R b1 Each independently selected from H, F, cl, br, I, OH, CN, NO 2 、CF 3 、CHF 2 、CH 2 F. Methyl, ethyl, isopropyl, said methyl, ethyl, isopropyl optionally further being 0 to 4 selected from H, F, cl, br, I, OH, CN, CF 3 、NH 2 Is substituted by a substituent of (2);
in certain embodiments, R b2 Each independently selected from H, F, cl, br, I, OH, NH 2 、CN、NO 2 、CF 3 、CHF 2 、COOH、NHCH 3 、N(CH 3 ) 2 Methyl, ethyl, isopropyl, methoxy, ethoxy, propoxy or isopropoxy, said methyl, ethyl, isopropyl, methoxy, ethoxy, propoxy or isopropoxy optionally further being 0 to 4 selected from H, F, cl, br, I, OH, CN, CF 3 、NH 2 Is substituted by a substituent of (2);
in certain embodiments, R b3 Selected from H, C 1-4 Alkyl optionally further substituted with 0 to 4 groups selected from H, F, cl, br, I, OH, = O, NH 2 、CN、CF 3 、COOH、C 1-4 Alkyl, C 3-6 Cycloalkyl, C 1-4 Substituted with alkoxy;
in certain embodiments, R b3 Selected from H, methyl, ethyl, propyl or isopropyl, said methyl, ethyl, propyl or isopropyl optionally being further substituted with 0 to 4 members selected from H, F, cl, br, I, OH, CN, CF 3 、NH 2 Is substituted by a substituent of (2);
in certain embodiments, R b4 Selected from H, OH, -OR b21 、-N(R b21 ) 2 、-OC(=O)R b22 、-NR b21 C(=O)R b22 Or C 1-4 Alkyl optionally further substituted with 0 to 4 groups selected from H, F, cl, br, I, OH, = O, NH 2 、CN、CF 3 、COOH、C 1-4 Alkyl, C 3-6 Cycloalkyl, C 1-4 Substituted with alkoxy;
in certain embodiments, R b4 Selected from H, OH, NH 2 、NHCH 3 、NHCH 2 CH 3 、NHCH(CH 3 ) 2 、N(CH 3 ) 2 、N(CH 2 CH 3 ) 2 、NHC(=O)CH 3 Methyl, ethyl, isopropyl, methoxy, ethoxy, propoxy or isopropoxy, said methyl, ethyl, isopropyl, methoxy, ethoxy, propoxy or isopropoxy optionally further being 0 to 4 selected from H, F, cl, br, I, OH, CN, CF 3 、NH 2 Is substituted by a substituent of (2);
in certain embodiments, R b21 Each independently selected from H, C 1-4 Alkyl, C 3-6 Cycloalkyl, C 6-10 Aryl, 5-10 membered heteroaryl or 4-10 membered heterocyclyl, said alkyl, cycloalkyl, aryl, heteroaryl or heterocyclyl optionally being further substituted with 0 to 4 substituents selected from H, F, cl, br, I, OH, = O, NH 2 、CN、CF 3 、COOH、C 1-4 Alkyl, C 3-6 Cycloalkyl, C 1-4 An alkoxy substituent, said heteroaryl or heterocyclyl containing 1 to 4 heteroatoms selected from O, S, N;
in some casesIn embodiments, R b22 Each independently selected from H, C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-4 Alkoxy, C 3-6 Cycloalkyl, said alkyl, alkoxy, cycloalkyl, alkenyl, alkynyl optionally being further substituted with 0 to 4 groups selected from H, F, cl, br, I, OH, = O, NH 2 、CN、CF 3 、COOH、C 1-4 Alkyl, C 3-6 Cycloalkyl, C 1-4 Substituted with alkoxy;
in certain embodiments, R b3 、R b4 Together with the carbon atoms to which they are attached form C 3-6 Cycloalkyl or 3 to 8 heteromonocyclic rings, said cycloalkyl or heteromonocyclic ring optionally being further substituted with 0 to 4 substituents selected from H, F, cl, br, I, OH, NH 2 、=O、C 1-4 Alkyl or C 1-4 An alkoxy substituent, said heteromonocyclic ring containing 1 to 4 heteroatoms selected from O, S, N;
in certain embodiments, R b3 、R b4 The carbon atoms to which they are attached together form cyclopropyl, cyclobutyl, cyclopentyl, azetidinyl, oxetanyl, the cyclopropyl, cyclobutyl, cyclopentyl, azetidinyl, oxetanyl are optionally further substituted with 0 to 4 members selected from H, F, cl, br, I, OH, NH 2 A substituent of =o, methyl, ethyl, isopropyl, methoxy, ethoxy or propoxy;
in certain embodiments, B is selected from/>
In certain embodiments, B is selected from
In certain embodiments, m1, m2 are each independently selected from 0, 1, 2, 3, 4, or 5;
in certain embodiments, m1, m2 are each independently selected from 0, 1, 2;
in certain embodiments, q is each independently selected from 0, 1, 2, 3, 4, 5, or 6;
in certain embodiments, q is each independently selected from 0, 1, 2, 3, or 4;
in certain embodiments, q is each independently selected from 0, 1, or 2;
in certain embodiments, n1, n2, n3 are each independently selected from 0, 1, 2, or 3;
in certain embodiments, p1 or p2 are each independently selected from 0, 1, 2, 3, 4, or 5;
in certain embodiments, p1 or p2 are each independently selected from 0, 1, or 2.
As a first embodiment of the present invention, the compound represented by the above general formula (I) or a stereoisomer, deuterated, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal thereof,
B-L-K (I);
l is selected from a bond or-C 1-50 Hydrocarbyl-, having from 0 to 20 methylene units in said hydrocarbyl optionally further replaced by-Ak-, -Cy-;
each-Ak-is independently selected from- (CH) 2 ) q -、-(CH 2 ) q -O-、-O-(CH 2 ) q -、-(CH 2 ) q -NR L -、-NR L -(CH 2 ) q -、-(CH 2 ) q -NR L C(=O)-、-NR L (CH 2 ) q C(=O)-、-(CH 2 ) q -C(=O)NR L -、-C(=O)-、-C(=O)-(CH 2 ) q -NR L -、-(C≡C) q -、-CH=CH-、-Si(R L ) 2 -、-Si(OH)(R L )-、-Si(OH) 2 -、-P(=O)(OR L )-、-P(=O)(R L )-、-S-、-S(=O)-、-S(=O) 2 -or a bond, said-CH 2 Optionally further 0 to 2 are selected from H, halogen, OH, CN, NH 2 、C 1-6 Alkyl, C 1-6 Alkoxy, halogen substituted C 1-6 Alkyl, hydroxy substituted C 1-6 Alkyl-and cyano-substituted C 1-6 Substituted by alkyl;
q is each independently selected from 0, 1, 2, 3, 4, 5 or 6;
R L each independently selected from H, C 1-6 Alkyl, 3-7 membered heterocyclyl, 3-7 membered cycloalkyl, phenyl or 5-6 membered heteroaryl;
each-Cy-is independently selected from the group consisting of a bond, 4-8 membered heteromonocyclic ring, 4-10 membered heterobicyclic ring, 5-12 membered heterospiro ring, 7-10 membered heterobridged ring, 3-7 membered monocycloalkyl, 4-10 membered heterocycloalkyl, 5-12 membered spirocycloalkyl, 7-10 membered bridged cycloalkyl, 5-10 membered heteroaryl, or 6-10 membered aryl, said aryl, heteroaryl, cycloalkyl, heteromonocyclic ring, heterofused ring, heterospiro ring, or heterobridged ring optionally further being 0 to 4 selected from H, F, cl, br, I, OH, COOH, CN, NH 2 、=O、C 1-4 Alkyl, halogen substituted C 1-4 Alkyl, hydroxy substituted C 1-4 Alkyl or C 1-4 A substituent of an alkoxy group, said heteroaryl, heteromonocyclic, heterobicyclic, heterospiro, or heterobridged ring containing from 1 to 4 heteroatoms selected from O, S, N, optionally further substituted with 0, 1, or 2 = O when the heteroatom is selected from S;
B is selected from
Y is selected from S or O;
m1, m2 are each independently selected from 0, 1, 2, 3, 4 or 5;
B 1 selected from C 6-10 A carbocyclyl or 5-10 membered heterocyclyl, said heterocyclyl containing 1 to 4 heteroatoms selected from O, S, N;
ring W is selected from 5 to 10 membered heteroaryl rings containing 1 to 5 heteroatoms selected from O, S, N;
R b1 、R b2 each independently selected from H, F, cl, br, I, = O, OH, CN, NO 2 、COOH、C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-4 Alkoxy, C 1-4 Alkylthio, - (CH) 2 ) n -R b21 、-OR b21 、-N(R b21 ) 2 、-C(=O)N(R b21 ) 2 、-C(=O)OR b21 、-C(=O)R b22 、-NR b21 C(=O)R b22 、-NR b21 S(=O) 2 R b22 、C 3-6 Cycloalkyl, C 6-10 Aryl, 5-10 membered heteroaryl or 4-10 membered heterocyclyl, said alkyl, alkenyl, alkynyl, alkoxy, alkylthio, cycloalkyl, heterocyclyl, aryl or heteroaryl optionally being further substituted with 0 to 4 groups selected from H, F, cl, br, I, OH, =o, -N (R b21 ) 2 、CN、COOH、C 1-4 Alkyl, C 1-4 Alkoxy, halogen substituted C 1-4 Alkyl-and cyano-substituted C 1-4 Alkyl, C 3-6 Cycloalkyl, 5-10 membered heteroaryl or 4-10 membered heterocyclyl, said heteroaryl or heterocyclyl containing 1 to 4 heteroatoms selected from O, S, N;
R b21 each independently selected from H, C 1-4 Alkyl, C 3-6 Cycloalkyl, C 6-10 Aryl, 5-10 membered heteroaryl or 4-10 membered heterocyclyl, said alkyl, cycloalkyl, aryl, heteroaryl or heterocyclyl optionally being further substituted with 0 to 4 substituents selected from H, F, cl, br, I, OH, = O, NH 2 、CN、CF 3 、COOH、C 1-4 Alkyl, C 3-6 Cycloalkyl, C 1-4 An alkoxy substituent, said heteroaryl or heterocyclyl containing 1 to 4 heteroatoms selected from O, S, N;
R b22 each independently selected from H, C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-4 Alkoxy, C 3-6 Cycloalkyl, said alkyl, alkoxy, cycloalkyl, alkenyl, alkynyl optionally being further substituted with 0 to 4 groups selected from H, F, cl, br, I, OH, = O, NH 2 、CN、CF 3 、COOH、C 1-4 Alkyl, C 3-6 Cycloalkyl, C 1-4 Substituted with alkoxy;
R b3 selected from H, C 1-4 Alkyl optionally further substituted with 0 to 4 groups selected from H, F, cl, br, I, OH, = O, NH 2 、CN、CF 3 、COOH、C 1-4 Alkyl, C 3-6 Cycloalkyl, C 1-4 Substituted with alkoxy;
R b4 selected from H, OH, -OR b21 、-N(R b21 ) 2 、-OC(=O)R b22 、-NR b21 C(=O)R b22 Or C 1-4 Alkyl optionally further substituted with 0 to 4 groups selected from H, F, cl, br, I, OH, = O, NH 2 、CN、CF 3 、COOH、C 1-4 Alkyl, C 3-6 Cycloalkyl, C 1-4 Substituted with alkoxy;
or R is b3 、R b4 Together with the carbon atoms to which they are attached form C 3-6 Cycloalkyl or 3 to 8 heteromonocyclic rings, said cycloalkyl or heteromonocyclic ring optionally being further substituted with 0 to 4 substituents selected from H, F, cl, br, I, OH, NH 2 、=O、C 1-4 Alkyl or C 1-4 An alkoxy substituent, said heteromonocyclic ring containing 1 to 4 heteroatoms selected from O, S, N;
k is selected from />
Q is each independently selected from the group consisting of bond, -O-, -S-, -CH 2 -、-NR q -、-CO-、-NR q CO-、-CONR q -or a 3-12 membered heterocyclyl, said heterocyclyl optionally being further substituted with 0 to 4 substituents selected from H, F, cl, br, I, OH, = O, NH 2 、CN、COOH、CONH 2 、C 1-4 Alkyl orC 1-4 A substituent of an alkoxy group, the heterocyclic group containing 1 to 4 heteroatoms selected from O, S, N;
R q selected from H or C 1-6 An alkyl group;
a is selected from C 3-10 Carbocyclyl, C 6-10 Aryl, 3-10 membered heterocyclyl or 5-10 membered heteroaryl, said heterocycle or heteroaryl containing 1 to 4 heteroatoms selected from O, S, N;
f are each independently selected from C 3-20 Carbocyclyl, C 6-20 Aryl, 3-20 membered heterocyclyl or 5-20 membered heteroaryl, said heterocyclyl or heteroaryl containing 1 to 4 heteroatoms selected from O, S, N;
R k2 each independently selected from the group consisting of bond, -CO-, -SO 2 -, -SO-or-C (R) k3 ) 2 -;
R k1 Each independently selected from H, F, cl, br, I, OH, = O, NH 2 、CN、COOH、CONH 2 、C 1-6 Alkyl or C 1-6 Alkoxy, said alkyl or alkoxy optionally being further substituted with 0 to 4 groups selected from H, F, cl, br, I, OH, = O, NH 2 、CN、COOH、CONH 2 、C 1-4 Alkyl or C 1-4 Substituted with alkoxy;
R k3 each independently selected from H, F, cl, br, I, OH, = O, NH 2 、CN、COOH、CONH 2 、C 1-6 Alkyl, C 1-6 Alkoxy, C 3-8 Cycloalkyl or 3-8 membered heterocyclyl, said alkyl, alkoxy, cycloalkyl or heterocyclyl optionally being further substituted with 0 to 4 substituents selected from H, F, cl, br, I, OH, = O, NH 2 、CN、COOH、CONH 2 、C 1-4 Alkyl or C 1-4 A substituent of an alkoxy group, the heterocyclic group containing 1 to 4 heteroatoms selected from O, S, N;
or two R k3 And the carbon atoms or ring skeletons directly linked to each other together form a 3-8 membered carbocycle or 3-8 membered heterocycle, said carbocycle or heterocycle optionally being further substituted with 0 to 4 groups selected from H, F, cl, br, I, OH, = O, NH 2 、CN、COOH、CONH 2 、C 1-4 Alkyl or C 1-4 Alkoxy radicalA substituent of a group, the heterocyclic ring containing 1 to 4 heteroatoms selected from O, S, N;
R k4 each independently selected from H, OH, NH 2 、CN、CONH 2 、C 1-6 Alkyl, C 3-8 Cycloalkyl or 3-8 membered heterocyclyl, said alkyl, cycloalkyl or heterocyclyl optionally being further substituted with 0 to 4 substituents selected from H, F, cl, br, I, OH, = O, NH 2 、CN、COOH、CONH 2 、C 1-4 Alkyl or C 1-4 A substituent of an alkoxy group, the heterocyclic group containing 1 to 4 heteroatoms selected from O, S, N;
M 1 selected from the group consisting of bond, -C (=O) NH-, -NHC (=O) -, -CH 2 -C(=O)NH-、-C(=O)CH 2 NH-, 5-6 membered heteroaryl, said heteroaryl optionally being further substituted with 0 to 4 substituents selected from H, F, cl, br, I, OH, = O, CF 3 、NH 2 、CN、C 1-4 Alkyl, halogen substituted C 1-4 Alkyl, hydroxy substituted C 1-4 Alkyl, C 1-4 Substituted with an alkoxy substituent, said heteroaryl containing 1 to 4 heteroatoms selected from O, S, N;
M 2 selected from-NHC (=o) -C 1-6 Alkyl, -NHC (=o) -C 3-6 Cycloalkyl or 4-10 membered heterocyclyl, said alkyl, cycloalkyl or heterocyclyl optionally being further substituted with 0 to 4 substituents selected from H, F, cl, br, I, =o, OH, NH 2 、C 1-4 Alkyl or C 1-4 A substituent of an alkoxy group, the heterocyclic group containing 1 to 4 heteroatoms selected from O, S, N;
M 3 selected from-NH-or-O-;
R k10 selected from C 1-6 Alkyl optionally further substituted with 0 to 4 groups selected from H, F, cl, br, I, =o, OH, C 1-6 Alkyl or C 3-6 Substituted cycloalkyl;
R k11 each independently selected from H, F, cl, br, I, = O, OH, SH, C 1-6 Alkyl, C 1-6 Alkoxy or C 1-6 Alkylthio or-O-C (=o) -C 1-6 Alkyl, said alkyl, alkoxy or alkylthio being optionally further substituted with 0 to4 are selected from H, F, cl, br, I, OH, C 1-4 Alkyl or C 1-4 Substituted with alkoxy;
R k12 、R k13 each independently selected from H, C 1-6 Alkyl or C 3-6 Cycloalkyl, said alkyl or cycloalkyl optionally being further substituted with 0 to 4 groups selected from H, F, cl, br, I, =o, OH, NH 2 、C 1-4 Alkyl or C 1-4 Substituted with alkoxy;
R k14 selected from 5-6 membered heteroaryl, optionally further substituted with 0 to 4 groups selected from H, F, cl, br, I, OH, = O, CF 3 、CN、C 1-4 Alkyl, halogen substituted C 1-4 Alkyl, hydroxy substituted C 1-4 Alkyl, C 1-4 Alkoxy or C 3-6 A cycloalkyl substituent, said heteroaryl containing 1 to 4 heteroatoms selected from N, O, S;
g is selected from 6-10 membered aryl or 5-10 membered heteroaryl, said aryl or heteroaryl optionally further being 0 to 4 selected from H, F, cl, br, I, OH, = O, CF 3 、CN、C 1-4 Alkyl, halogen substituted C 1-4 Alkyl, hydroxy substituted C 1-4 Alkyl, C 1-4 Alkoxy or C 3-6 A cycloalkyl substituent, said heteroaryl containing 1 to 4 heteroatoms selected from N, O, S;
n1, n2, n3 are each independently selected from 0, 1, 2 or 3;
p1 or p2 are each independently selected from 0, 1, 2, 3, 4 or 5.
As a second embodiment of the present invention, the compound represented by the above general formula (I) or a stereoisomer, deuterated, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal thereof,
l is selected from the group consisting of-Cy 1-Cy2-Ak2-Cy3-Cy4-Ak 4-Cy5-Ak5-, -Cy1-Cy2-Cy3-Cy4-Ak2-Ak3-Ak4-Ak5-, -Cy1-Ak1-Cy2-Ak2-Cy3-Ak3-Cy4-Ak 5-, -Ak1-Cy1-Ak2-Cy2-Ak3-Cy3-Ak4-Cy4-Ak5-, -Cy1-Ak1-Cy2-Ak2-Cy3-Cy4-Ak3-Ak4-Ak5-, -Cy1-Ak 1-2-Ak 2-Ak3-Cy3-Cy4-Ak 5-; -Cy1-Ak1-Ak2-Ak3-Ak4-Ak5-Cy2-Cy3-Cy4-, -Cy1-Cy2-Ak1-Ak2-Ak3-Ak4-Ak5-Cy3-Cy4-, -Cy1-Cy2-Cy3-Ak1-Ak2-Ak3-Ak4-Ak5-Cy4-, -Cy1-Cy2-Cy3-Cy4-Ak1-Ak2-Ak3-Ak4-Ak 5-; -Cy1-Ak1-Cy2-Cy3-Cy4-Ak2-Ak3-Ak4-Ak5-, -Cy1-Cy2-Ak1-Cy3-Cy4-Ak2-Ak3-Ak4-Ak5-, -Cy1-Cy2-Cy3-Ak1-Cy4-Ak2-Ak3-Ak4-Ak5- -Cy1-Ak1-Ak2-Cy2-Cy3-Cy4-Ak3-Ak4-Ak5-, -Cy1-Cy2-Ak1-Ak2-Cy3-Cy4-Ak3-Ak 5-, -Cy1-Cy2-Cy3-Ak1-Ak2-Cy4-Ak3-Ak 5-, -Cy1-Ak1-Ak2-Ak3-Cy2-Cy3-Cy4-Ak4-Ak5-, -Cy1-Ak2-Ak 3-Cy3-Cy4-Ak4-Ak5-, -Cy1-Cy2-Cy3-Ak1-Ak2-Ak3-Cy4-Ak4-Ak5-, -1-Ak 2-Ak3-Ak4-Ak 2-Cy3-Cy4-Ak 5-; -Cy1-Cy2-Ak1-Ak2-Ak3-Ak4-Cy3-Cy4-Ak5-, -Cy1-Cy2-Cy3-Ak1-Ak2-Ak3-Ak4-Cy4-Ak5-, -Ak1-Ak2-Ak3-Ak 2-Cy 5-Cy1-Cy 2-Ak3-Ak4-Ak5-, -Ak1-Ak2-Cy1-Cy2-Cy3-Cy4-Ak3-Ak4-Ak5-, -Ak1-Ak2-Ak3-Cy1-Cy2-Cy3-Cy4-Ak4-Ak5- -Ak1-Ak2-Ak3-Ak4-Cy1-Cy2-Cy3-Cy4-Ak5-, -Ak1-Cy1-Ak2-Ak3-Ak4-Ak5-Cy2-Cy3-Cy4-, -Ak1-Cy1-Cy2-Ak2-Ak3-Ak4-Ak5-Cy3-Cy4-, -Ak1-Cy1-Cy2-Cy3-Ak2-Ak3-Ak4-Ak5-Cy4-, -Ak1-Ak2-Cy1-Ak3-Ak4-Ak5-Cy2-Cy3-Cy4-, -Ak1-Ak2-Cy 2-Ak3-Ak4-Ak5-Cy3-Cy 4-; -Ak1-Ak2-Cy1-Cy2-Cy3-Ak3-Ak4-Ak5-Cy4-, -Ak1-Ak2-Ak3-Cy1-Ak4-Ak5-Cy2-Cy3-Cy4-, -Ak1-Ak2-Ak3-Cy1-Cy2-Ak4-Ak5-Cy3-Cy4-, -Ak1-Ak2-Ak3-Cy1-Cy 3-Ak4-Ak5-Cy4-, -Ak1-Ak2-Ak3-Ak4-Cy1-Ak5-Cy2-Cy 4-, -Ak1-Ak2-Ak3-Ak4-Cy1-Cy2-Ak5-Cy3-Cy4- Ak1-Ak2-Ak3-Ak4-Cy1-Cy2-Cy3-Ak5-Cy4-;
Ak1, ak2, ak3, ak4, ak5 are each independently selected from- (CH) 2 ) q -、-(CH 2 ) q -O-、-O-(CH 2 ) q -、-(CH 2 ) q -NR L -、-NR L -(CH 2 ) q -、-(CH 2 )q-NR L C(=O)-、-(CH 2 ) q -C(=O)NR L -、-C(=O)-、-C(=O)-(CH 2 ) q -NR L -、-(C≡C) q -or a bond, said-CH 2 Optionally further 0 to 2 are selected from H, halogen, OH, CN, NH 2 、C 1-4 Alkyl, C 1-4 Alkoxy, halogen substituted C 1-4 Alkyl, hydroxy substituted C 1-4 Alkyl-and cyano-substituted C 1-4 Substituted by alkyl;
Cy1、cy2, cy3, cy4 or Cy5 are each independently selected from the group consisting of a bond, 4-7 membered heteromonocyclic ring, 4-10 membered heteroacene, 5-12 membered heterospiro ring, 7-10 membered heterobridged ring, 3-7 membered monocycloalkyl, 4-10 membered heterocycloalkyl, 5-12 membered spirocycloalkyl, 7-10 membered bridged cycloalkyl, 5-10 membered heteroaryl or 6-10 membered aryl, said aryl, heteroaryl, cycloalkyl, heteromonocyclic ring, heteroacene, heterospiro ring or heterobridged ring optionally further being selected from 0 to 4 from H, F, cl, br, I, OH, COOH, CN, NH 2 、=O、C 1-4 Alkyl, halogen substituted C 1-4 Alkyl, hydroxy substituted C 1-4 Alkyl or C 1-4 A substituent of an alkoxy group, said heteroaryl, heteromonocyclic, heterobicyclic, heterospiro, or heterobridged ring containing from 1 to 4 heteroatoms selected from O, S, N, optionally further substituted with 0, 1, or 2 = O when the heteroatom is selected from S;
q is each independently selected from 0, 1, 2, 3 or 4;
R L each independently selected from H or C 1-6 An alkyl group;
B 1 selected from phenyl, 5-6 membered mono heteroaryl or 9-10 membered fused ring heterocyclyl, said heteroaryl or heterocyclyl containing 1 to 4 heteroatoms selected from O, S, N;
Ring W is selected from a 5-6 membered monocyclic heteroaryl ring or a 9-10 membered fused ring heteroaryl ring containing 1 to 5 heteroatoms selected from O, S, N;
the remaining groups are as defined in the first embodiment of the invention.
As a third embodiment of the present invention, the compound represented by the above general formula (I) or stereoisomers, deuterates, solvates, prodrugs, metabolites, pharmaceutically acceptable salts or co-crystals thereof,
cy1, cy2, cy3, cy4 or Cy5 are each independently selected from the group consisting of a bond, a 4-7 membered nitrogen containing heteromonocyclic ring, a 4-10 membered nitrogen containing heteromonocyclic ring, a 5-12 membered nitrogen containing heterospiro ring, a 7-10 membered nitrogen containing heterobridged ring, a 3-7 membered monocycloalkyl, a 4-10 membered cycloalkyl, a 5-12 membered spirocycloalkyl, a 7-10 membered bridged cycloalkyl, a 5-10 membered heteroaryl or a 6-10 membered aryl, said heteromonocyclic ring, heterofused ring, heterobridged ring, heterospiro ring, cycloalkyl, aryl or heteroaryl optionally being further substituted with 0 to 4 members selected from H, F, cl, br, I, OH, COOH,CN、NH 2 、=O、C 1-4 Alkyl, halogen substituted C 1-4 Alkyl, hydroxy substituted C 1-4 Alkyl or C 1-4 A substituent of an alkoxy group, said heteromonocyclic, heterobicyclic, heterobridged, heterospiro or heteroaryl group containing from 1 to 4 heteroatoms selected from O, S, N, optionally further substituted with 0, 1 or 2 = O when the heteroatoms are selected from S;
R L Each independently selected from H or C 1-4 An alkyl group;
B 1 selected from phenyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, triazinyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, oxazolyl, isoxazolyl, furanyl, thienyl, thiazolyl, benzopyrrolyl, benzopyrazolyl, benzofuranyl, benzothienyl, benzothiazolyl, benzimidazolyl, pyridopyrrolyl, quinolinyl, isoquinolinyl, quinazolinyl, quinoxalinyl, benzopiperidinyl, benzopyranyl, or benzopyranyl;
ring W is selected from pyridinyl, pyrimidinyl, pyridazinyl, pyridazinonyl, pyrazinyl, triazinyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, oxazolyl, isoxazolyl, furanyl, thienyl, thiazolyl, benzopyrrolyl, benzopyrazolyl, benzimidazolyl, pyridopyrrolyl;
R b1 、R b2 each independently selected from H, F, cl, br, I, =o, OH, NH 2 、CN、NO 2 、CF 3 、CHF 2 、COOH、NHCH 3 、NHCH 2 CH 3 、NHCH(CH 3 ) 2 、N(CH 3 ) 2 、N(CH 2 CH 3 ) 2 、NHC(=O)CH 3 、NHS(=O) 2 CH 3 Methyl, ethyl, isopropyl, vinyl, ethynyl, methoxy, ethoxy, propoxy, isopropoxy, morpholinyl, piperazinyl, pyrrolidinyl, piperidinyl or oxazolidinyl, said methyl, ethyl, vinyl, isopropyl, ethynyl, methoxy, ethoxy, propoxy, isopropoxy, morpholinyl, piperazinyl, pyrrolidinyl, piperidinyl or oxazolidinyl optionally being further substituted with 0 Up to 4 are selected from H, F, cl, br, I, OH, CN, CF 3 、NH 2 Is substituted by a substituent of (2);
R b3 selected from H, methyl, ethyl, propyl or isopropyl, said methyl, ethyl, propyl or isopropyl optionally being further substituted with 0 to 4 members selected from H, F, cl, br, I, OH, CN, CF 3 、NH 2 Is substituted by a substituent of (2);
R b4 selected from H, OH, NH 2 、NHCH 3 、NHCH 2 CH 3 、NHCH(CH 3 ) 2 、N(CH 3 ) 2 、N(CH 2 CH 3 ) 2 、NHC(=O)CH 3 Methyl, ethyl, isopropyl, methoxy, ethoxy, propoxy or isopropoxy, said methyl, ethyl, isopropyl, methoxy, ethoxy, propoxy or isopropoxy optionally further being 0 to 4 selected from H, F, cl, br, I, OH, CN, CF 3 、NH 2 Is substituted by a substituent of (2);
or R is b3 、R b4 The carbon atoms to which they are attached together form cyclopropyl, cyclobutyl, cyclopentyl, azetidinyl, oxetanyl, the cyclopropyl, cyclobutyl, cyclopentyl, azetidinyl, oxetanyl are optionally further substituted with 0 to 4 members selected from H, F, cl, br, I, OH, NH 2 A substituent of =o, methyl, ethyl, isopropyl, methoxy, ethoxy or propoxy;
K is selected from
Represents a ring selected from aromatic or non-aromatic rings;
M 2 selected from-NHC (=o) -C 1-4 Alkyl, -NHC (=o) -C 3-6 Cycloalkyl or 4-10 membered heterocyclyl, said alkyl, cycloalkyl or heterocyclyl optionally being further substituted with 0 to 4 substituents selected from H, F, cl, br, I, =o, OH, NH 2 、C 1-4 Alkyl or C 1-4 A substituent of an alkoxy group, the heterocyclic group containing 1 to 4 heteroatoms selected from O, S, N;
R k10 selected from C 1-4 Alkyl optionally further substituted with 0 to 4 groups selected from H, F, cl, br, I, =o, OH, C 1-4 Alkyl or C 3-6 Substituted cycloalkyl;
R k11 each independently selected from H, F, cl, br, I, = O, OH, SH, C 1-4 Alkyl, C 1-4 Alkoxy or C 1-4 Alkylthio or-O-C (=o) -C 1-4 Alkyl, said alkyl, alkoxy or alkylthio being optionally further substituted with 0 to 4 groups selected from H, F, cl, br, I, OH, C 1-4 Alkyl or C 1-4 Substituted with alkoxy;
R k12 、R k13 each independently selected from H, C 1-4 Alkyl or C 3-6 Cycloalkyl, said alkyl or cycloalkyl optionally being further substituted with 0 to 4 groups selected from H, F, cl, br, I, =o, OH, NH 2 、C 1-4 Alkyl or C 1-4 Substituted with alkoxy;
q is each independently selected from-O-, -S-, -CH 2 -、-NR q -、-CO-、-NR q CO-、-CONR q -or a 4-7 membered heterocyclyl, said heterocyclyl optionally being further substituted with 0 to 4 substituents selected from H, F, cl, br, I, OH, = O, NH 2 、CN、COOH、CONH 2 、C 1-4 Alkyl or C 1-4 A substituent of an alkoxy group, the heterocyclic group containing 1 to 4 heteroatoms selected from O, S, N;
R q selected from H or C 1-4 An alkyl group;
R k1 、R k3 each independently selected from H, F, cl, br, I, OH, = O, NH 2 、CF 3 、CN、COOH、CONH 2 、C 1-4 Alkyl or C 1-4 Alkoxy, said alkyl or alkoxy optionally being further substituted with 0 to 4 groups selected from H, F, cl, br, I, OH, NH 2 Is substituted by a substituent of (2);
or two R k3 And the carbon atoms or ring skeletons directly linked to each other together form a 3-6 membered carbocycle or a 3-7 membered heterocycle, said carbocycle or heterocycle optionally being further substituted with 0 to 4 groups selected from H, F, cl, br, I, OH, = O, NH 2 、CN、COOH、CONH 2 、C 1-4 Alkyl or C 1-4 A substituent of an alkoxy group, said heterocycle containing 1 to 4 heteroatoms selected from O, S, N;
R k4 each independently selected from H, OH, NH 2 、CF 3 、CN、C 1-4 An alkyl group;
R k5 each independently selected from CO, CH 2 、SO 2 Or (b)
R k6 Each independently selected from CO, CH, SO, SO 2 、CH 2 Or N;
R k7 each independently selected from CO, CH, N, CH 2 、O、S、N(CH 3 ) Or NH;
R k8 each independently selected from C, N or CH;
R k9 each independently selected from CO, CH 2 Or SO 2 ;
A. H1 or H2 are each independently selected from C 3-8 A carbocycle, benzene ring, 4-7 membered heterocycle or 5-6 membered heteroaryl, said heterocycle or heteroaryl containing 1 to 4 heteroatoms selected from O, S, N;
e is each independently selected from C 3-8 A carbocycle, a benzene ring, a 4-7 membered heterocycle, an 8-12 membered heterocyclyl, a 7-12 membered heteroaryl or a 5-6 membered heteroaryl, said heterocycle or heteroaryl containing 1 to 4 heteroatoms selected from O, S, N;
f is each independently selected from 3-7 membered monocycloalkyl, 4-10 membered cycloalkyl, 5-12 membered spirocycloalkyl, 5-10 membered bridged cycloalkyl, 4-7 membered heteromonocyclic, 4-10 membered heteroacene, 5-12 membered heteroaceneSpiro, 5-10 membered hetero-bridged ring, C 6-14 An aryl or 5-10 membered heteroaryl group, said heteromonocyclic, heterobicyclic, heterospiro, heterobridged, or heteroaryl group containing 1 to 4 heteroatoms selected from O, S, N;
the remaining groups are as defined in either of the first and second embodiments of the invention.
As a fourth embodiment of the present invention, the compound represented by the above general formula (I) or stereoisomers, deuterates, solvates, prodrugs, metabolites, pharmaceutically acceptable salts or co-crystals thereof,
R L selected from H, methyl or ethyl;
q is each independently selected from 0, 1 or 2;
cy1, cy2, cy3, cy4 or Cy5 are each independently selected from a bond or one of the following substituted or unsubstituted groups: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, piperidine, morpholine, piperazine, phenyl, cyclopropyl-and-cyclopropyl, cyclopropyl-and-cyclobutyl, cyclopropyl-and-cyclopentyl, cyclopropyl-and-cyclohexyl, cyclobutyl-and-cyclobutyl, cyclobutyl-and-cyclopentyl, cyclobutyl-and-cyclohexyl cyclopentyl, cyclopentyl cyclohexyl, cyclohexyl, cyclopropyl spiropropyl, cyclopropyl spirobutyl, cyclopropyl spiropentyl, cyclopropyl spirohexyl, cyclobutylspirobutyl, cyclobutylspiropentyl, cyclobutylspirohexyl, cyclopentyl spiropentyl, cyclopentyl spirohexyl, cyclohexyl spirohexyl, cyclopropyl spirohexyl cyclopropyl azetidinyl, cyclopropyl piperidine, cyclobutyl azetidinyl, cyclopropyl azetidinyl cyclobutyl-azetidinyl, cyclobutyl-piperidine, cyclopentyl-azetidinyl, cyclohexyl-amino-substituted-amino-cyclobutyl-azetidinyl, cyclobutyl-piperidine, cyclopentyl-azetidinyl cyclopentyl-azacyclopentyl, cyclopentyl-azacyclohexyl Pentyl-azacyclopentyl-azacyclohexyl-azacyclopentyl-azapiperidine-azacyclohexyl-azacyclobutyl-azacyclopentyl-azacyclohexyl-azacyclobutyl-azacyclohexyl-azaon-on-a-on Azacyclohexanoazacyclopentyl, azacyclohexanoazacyclohexyl, azacyclohexanopiperidine, cyclobutylspiroazetidinyl Azacyclohexanoazacyclopentyl, azacyclohexanoazacyclohexyl Azacyclohexylpiperidine, cyclobutylspiroazetidine, azetidinyl spiroazetidinyl, azetidinyl an azacyclopentyl spiroazacyclopentyl group, an azacyclopentyl spiroazacyclohexyl group, an azacyclohexyl spiroazacyclobutyl group Azacyclohexaspiro-azacyclopentyl, azacyclohexaspiro-azacyclohexyl, cyclobutyl spiro-piperidine, cyclopentyl spiro-piperidine, cyclohexyl spiro-piperidine, azetidine spiro-piperidine, azacyclopentyl spiro-piperidine, azacyclohexyl spiro-piperidine, cyclohexyl spiro-piperidine, When substituted, optionally further substituted with 0 to 4 members selected from H, F, cl, br, I, OH, NH 2 、COOH、CN、=O、C 1-4 Alkyl, halogen substituted C 1-4 Alkyl, hydroxy substituted C 1-4 Alkyl or C 1-4 Substituted with alkoxy;
b is selected from
m1 and m2 are respectively and independently selected from 0, 1 and 2;
y is independently selected from S or O;
X 1 、X 2 、X 3 、X 4 、X 5 each independently selected from CR b2 Or N;
B 1 selected from phenyl, pyridyl and quinolylA pinyl, isoquinolinyl, benzopiperidinyl or benzopyran;
k is selected from />
/>
M1 is selected from the group consisting of bond, -C (=O) NH-, -CH 2 -C(=O)NH-、-C(=O)CH 2 NH-, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, oxazolyl, isoxazolyl, furanyl, thienyl, thiazolyl;
M 2 selected from-NHC (=O) -CH 3 -NHC (=o) -cyclopropyl, -NHC (=o) -cyclobutyl, azetidinyl, benzazetidinyl, said cyclopropyl, cyclobutyl, azetidinyl, benzazetidinyl or benzazetidinyl optionally being further substituted with 0 to 4 groups selected from H, F, cl, br, I, =o, OH, NH 2 、C 1-4 Alkyl or C 1-4 Substituted with alkoxy;
R k10 selected from methyl, ethyl, isopropyl, propyl, tert-butyl, said methyl, ethyl, isopropyl, propyl, tert-butyl optionally further being 0 to 4 selected from H, F, cl, br, I, =o, OH, C 1-4 Alkyl or C 3-6 Substituted cycloalkyl;
R k11 each independently selected from H, F, cl, br, I, =o, OH, SH, methyl, ethyl, isopropyl, propyl, methoxy, ethoxy, propoxy, isopropoxy, methylthio, ethylthio, propylthio or-O-C (=o) -CH 3 The armor is provided withOptionally further 0 to 4 radicals selected from H, F, cl, br, I, OH, C, ethyl, isopropyl, propyl, methoxy, ethoxy, propoxy, isopropoxy, methylthio, ethylthio, propylthio 1-4 Alkyl or C 1-4 Substituted with alkoxy;
R k12 、R k13 each independently selected from H, methyl, ethyl, isopropyl, propyl, cyclopropyl or cyclobutyl, optionally further substituted with 0 to 4 groups selected from H, F, cl, br, I, =o, OH, NH 2 、C 1-4 Alkyl or C 1-4 Substituted with alkoxy;
e is each independently selected from phenyl, pyridyl, pyridazinyl, pyrazinyl, pyrimidinyl, pyrrolyl, pyrazolyl, imidazolyl, thiazolyl, furanyl, thienyl or oxazolyl;
each a is independently selected from phenyl, pyridyl, pyridazinyl, pyrazinyl, pyrimidinyl, pyrrolyl, pyrazolyl, imidazolyl, thiazolyl, furanyl, thienyl or oxazolyl;
F is each independently selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, bicyclo [1.1.1] pentyl, 6, 7-dihydro-5H-cyclopenta [ c ] pyridinyl, 2, 3-dihydro-1H-indenyl, phenyl, naphthyl, anthracenyl, phenanthrenyl, azetidinyl, azacyclopentyl, piperidinyl, morpholinyl, pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl, triazinyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, oxazolyl, furanyl, thienyl, thiazolyl, benzimidazolyl, benzopyrazolyl, benzothiazolyl, benzothienyl, benzofuranyl, benzopyrrolyl, benzopyridyl benzopyrazinyl, benzopyrimidinyl, benzopyridazinyl, pyrrolopyrrolyl, pyrrolopyridinyl, pyrrolopyridazinyl, pyrrolopyrazinyl, imidazopyrimidinyl, imidazopyridinyl, imidazopyrazinyl, imidazopyridazinyl, pyrazolopyridinyl, pyrazolopyrimidinyl, pyrazolopyrazinyl, pyrimidopyridinyl, pyrimidopyrazinyl, pyrimidopyridazinyl, pyrimidopyrimidinyl, pyridopyridinyl, pyridopyrazinyl, pyridopyridazinyl, pyridazinopyrazinyl or pyrazinopyrazinyl;
R k7 Each independently selected from CH 2 、O、N(CH 3 ) Or NH;
p1 or p2 are each independently selected from 0, 1 or 2;
the remaining groups are as defined in any of the first, second and third embodiments of the invention.
As a fifth embodiment of the present invention, the compound represented by the above general formula (I) or stereoisomers, deuterates, solvates, prodrugs, metabolites, pharmaceutically acceptable salts or co-crystals thereof,
cy1, cy2, cy3, cy4 or Cy5 are each independently selected from a bond or one of the following substituted or unsubstituted groups:/> when substituted, optionally further substituted with 0 to 4 members selected from H, F, CF 3 Methyl, =o, hydroxymethyl, COOH, CN or NH 2 Is substituted by a substituent of (2);
R b1 each independently selected from H, F, cl, br, I, OH, CN, NO 2 、CF 3 、CHF 2 、CH 2 F. Methyl, ethyl, isopropyl, said methyl, ethyl, isopropyl optionally further being 0 to 4 selected from H, F, cl, br, I, OH, CN, CF 3 、NH 2 Is substituted by a substituent of (2);
R b2 each independently selected from H, F, cl, br, I, OH, NH 2 、CN、NO 2 、CF 3 、CHF 2 、COOH、NHCH 3 、N(CH 3 ) 2 Methyl, ethyl, isopropyl, methoxy, ethoxy, propoxy or isopropoxy, said methyl, ethyl, isopropyl, methoxy,Optionally further 0 to 4 ethoxy, propoxy or isopropoxy groups selected from H, F, cl, br, I, OH, CN, CF 3 、NH 2 Is substituted by a substituent of (2);
k is selected from the group B, and the left side of the group is connected with L;
the remaining groups are as defined in any of the first, second, third or fourth embodiments of the invention.
As a sixth embodiment of the present invention, the compound represented by the above general formula (I) or stereoisomers, deuterates, solvates, prodrugs, metabolites, pharmaceutically acceptable salts or co-crystals thereof,
l is selected from the group consisting of-Cy 1-, -Cy1-Ak1-Ak2-Ak3-Ak 4-; -Cy1-Cy2-, -Cy1-Ak1-Cy2-, -Cy1-Cy2-Ak2-, -Cy1-Ak1-Cy2-Ak2-, -Cy1-Ak1-Cy2-Ak2-Ak3-, -Cy1-Ak1-Cy2-Ak2-Ak3-Ak4-, -Cy1-Cy2-Ak2-Ak3-Ak4-, -Cy1-Ak1-Cy2-Ak2-Ak3-Ak 4-; -Cy1-Ak1-Ak2-Cy3-, -Cy1-Ak1-Ak2-Cy3-Ak3-, -Cy1-Cy2-Cy3-, -Cy1-Ak1-Cy2-Cy3-, -Cy1-Cy2-Ak2-Cy3-, -Cy1-Ak1-Cy2-Cy3-Ak3-, -Cy1-Cy2-Ak 3-, -Cy1-Ak1-Cy2-Ak 3-, -Cy1-Ak 2-Ak3-, -Cy2-Cy3-Ak3-Ak4- -Cy1-Cy2-Cy3-Ak3-Cy4-, -Cy1-Cy2-Cy3-Cy4-, -Cy1-Ak1-Cy2-Cy3-Cy4-, -Cy1-Cy2-Cy3-Cy4-Ak4-, -Cy1-Ak1-Cy2-Ak2-Cy3-Ak3-Cy4-, -Cy1-Ak1-Cy2-Ak2-Cy3-Cy4-, -Ak1-Cy2-Cy3-, -Ak1-Ak2-Cy3-Cy 4-; -Ak1-Cy2-Ak2-Cy3-, -Ak1-Cy2-Cy3-Ak3-Cy4-, -Ak1-Cy2-Cy3-Cy4-Ak4-Cy5-, -Ak1-Cy2-Ak2-, -Ak1-Ak2-Ak 4-, -Ak1-Ak2-Ak3-Ak4-Ak5-, -Cy1-Cy2-Cy3-Ak3-Ak4-Ak5-, -Cy1-Cy2-Ak2-Cy3-Ak3-Ak4-Ak5-, -Cy1-Ak 2-Ak3-Ak4-Ak5- -Cy1-Cy2-Cy3-Cy4-Ak4-Ak5-, -Cy1-Ak1-Ak2-Ak3-Ak4-Ak5-, -Ak1-Cy2-Ak 3-Ak4-Ak5-, -Ak1-Cy2-Ak 3-Ak4-, -Ak1-Cy2-Ak 3-;
Ak1, ak2, ak3, ak4, ak5 are each independently selected from the group consisting of-O-, -OCH 2 -、-CH 2 O-、-OCH 2 CH 2 -、-CH 2 CH 2 O-、-C≡C-、-C(CH 3 ) 2 -、-CH 2 -、-CH 2 CH 2 -、-CH 2 CH 2 CH 2 -、-N(CH 3 )-、-NH-、-CH 2 N(CH 3 )-、-CH 2 NH-、-NHCH 2 -、-CH 2 CH 2 N(CH 3 )-、-CH 2 CH 2 NH-、-NHCH 2 CH 2 -、-C(=O)-、-C(=O)CH 2 NH-、-CH 2 C (=o) NH-, -C (=o) NH-or-NHC (=o) -;
the remaining groups are as defined in any of the first, second, third, fourth or fifth embodiments of the invention. As a seventh embodiment of the present invention, the compound represented by the above general formula (I) or a stereoisomer, a deuterate, a solvate, a prodrug, a metabolite, a pharmaceutically acceptable salt or a co-crystal thereof,
l is selected from a bond or a group in Table A, wherein the left side of the group is attached to B;
the remaining groups are as defined in any of the first, second, third, fourth, fifth or sixth embodiments of the invention.
As an eighth embodiment of the present invention, the compound represented by the above general formula (I) or a stereoisomer, deuterated, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal thereof,
b is selected from one of the following structural fragments:
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or B is selected from
K is selected from one of the following structural fragments:
the remaining groups are as defined in any of the first, second, third, fourth, fifth, sixth or seventh embodiments of the invention.
The present invention relates to a compound or a stereoisomer, deuterate, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal thereof, wherein the compound is selected from one of the following structures:
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Table A L group
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Table B K group
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The present invention relates to a pharmaceutical composition comprising a compound of the invention described above or a stereoisomer, deuterated, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal thereof, and a pharmaceutically acceptable carrier.
The present invention relates to a pharmaceutical composition comprising a therapeutically effective amount of a compound of the invention described above or a stereoisomer, deuterate, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal thereof, and a pharmaceutically acceptable carrier.
The present invention relates to a pharmaceutical composition or pharmaceutical formulation comprising a therapeutically effective amount of a compound of the invention or a stereoisomer, deuterate, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal thereof, and a pharmaceutically acceptable excipient. The pharmaceutical composition may be in unit dosage form (the amount of the main drug in a unit dosage form is also referred to as "formulation specification").
As used herein, an "effective amount" or "therapeutically effective amount" refers to the administration of a sufficient amount of a compound disclosed herein that will alleviate one or more symptoms of the disease or disorder being treated (e.g., kidney disease). In some embodiments, the result is a reduction and/or alleviation of the signs, symptoms, or causes of a disease, or any other desired alteration of a biological system. For example, an "effective amount" for therapeutic use is the amount of a composition comprising a compound disclosed herein that is required to provide clinically significant reduction in disease symptoms. Examples of therapeutically effective amounts include, but are not limited to, 1-1500mg, 1-1200mg, 1-1000mg, 1-900mg, 1-800mg, 1-700mg, 1-600mg, 2-600mg, 3-600mg, 4-600mg, 5-600mg, 6-600mg, 10-600mg, 20-600mg, 25-600mg, 30-600mg, 40-600mg, 50-600mg, 60-600mg, 70-600mg, 75-600mg, 80-600mg, 90-600mg, 100-600mg, 200-600mg, 1-500mg, 2-500mg, 3-500mg, 4-500mg, 5-500mg, 6-500mg, 10-500mg, 20-500mg, 25-500mg, 30-500mg, 40-500mg, 50-500mg, 60-500mg, 70-500mg, 75-500mg, 80-500mg 90-500mg, 100-500mg, 125-500mg, 150-500mg, 200-500mg, 250-500mg, 300-500mg, 400-500mg, 5-400mg, 10-400mg, 20-400mg, 25-400mg, 30-400mg, 40-400mg, 50-400mg, 60-400mg, 70-400mg, 75-400mg, 80-400mg, 90-400mg, 100-400mg, 125-400mg, 150-400mg, 200-400mg, 250-400mg, 300-400mg, 1-300mg, 2-300mg, 5-300mg, 10-300mg, 20-300mg, 25-300mg, 30-300mg, 40-300mg, 50-300mg, 60-300mg, 70-300mg, 75-300mg, 80-300mg, 90-300mg, 100-300mg, 125-300mg, 150-300mg, 200-300mg, 250-300mg, 1-200mg, 2-200mg, 5-200mg, 10-200mg, 20-200mg, 25-200mg, 30-200mg, 40-200mg, 50-200mg, 60-200mg, 70-200mg, 75-200mg, 80-200mg, 90-200mg, 100-200mg, 125-200mg, 150-200mg, 80-1000mg, 80-800mg.
In some embodiments, the pharmaceutical composition includes, but is not limited to, 1-1000mg, 20-800mg, 40-400mg, 25-200mg, 1mg, 5mg, 10mg, 15mg, 20mg, 25mg, 30mg, 35mg, 40mg, 45mg, 50mg, 55mg, 65mg, 70mg, 75mg, 80mg, 85mg, 90mg, 95mg, 100mg, 110mg, 120mg, 125mg, 130mg, 140mg, 150mg, 160mg, 170mg, 180mg, 190mg, 200mg, 210mg, 220mg, 230mg, 240mg, 250mg, 300mg, 320mg, 400mg, 480mg, 500mg, 600mg, 640mg, 840mg of a compound of the invention or a stereoisomer, deuterate, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal thereof.
A method for treating a disease in a mammal, said method comprising administering to a subject a therapeutically effective amount of a compound of the invention, or a stereoisomer, deuterate, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal thereof, preferably 1-1500mg, said disease preferably inhibiting or degrading AR or an AR-shear mutant related disease (e.g., prostate cancer).
A method for treating a disease in a mammal comprising administering a pharmaceutical compound of the invention or a stereoisomer, deuterated, solvate, prodrug, metabolite, pharmaceutically acceptable salt, or co-crystal thereof to a subject at a daily dose of 1-1000 mg/day, which may be a single dose or divided doses, and in some embodiments, the daily dose includes, but is not limited to, 10-1500 mg/day, 10-1000 mg/day, 10-800 mg/day, 25-800 mg/day, 50-800 mg/day, 100-800 mg/day, 200-800 mg/day, 25-400 mg/day, 50-400 mg/day, 100-400 mg/day, 200-400 mg/day, in some embodiments, daily doses include, but are not limited to, 10 mg/day, 20 mg/day, 25 mg/day, 50 mg/day, 80 mg/day, 100 mg/day, 125 mg/day, 150 mg/day, 160 mg/day, 200 mg/day, 300 mg/day, 320 mg/day, 400 mg/day, 600 mg/day, 1000 mg/day.
The present invention relates to a kit comprising a single or multiple dose form of a composition comprising a compound of the invention or a stereoisomer, deuterate, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal thereof, in an amount equivalent to the amount of the compound of the invention or a stereoisomer, deuterate, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal thereof.
The present invention relates to a method for treating a disease in a mammal, said method comprising administering to a subject a therapeutically effective amount of a compound of the invention or a stereoisomer, deuterate, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal thereof, preferably 1-1500mg, said disease preferably inhibiting or degrading an AR or AR splice variant related disease (such as prostate cancer).
The invention relates to application of the compound or stereoisomer, deuterated compound, solvate, prodrug, metabolite, pharmaceutically acceptable salt or eutectic or the pharmaceutical composition in preparing medicaments for treating diseases related to activity or expression quantity of AR or AR shear mutant.
The invention relates to application of the compound or stereoisomer, deuterated compound, solvate, prodrug, metabolite, pharmaceutically acceptable salt or eutectic crystal of the compound or the stereoisomer, the solvate, the metabolite, the pharmaceutically acceptable salt or eutectic crystal of the compound or the prodrug in preparation of medicines for treating and inhibiting or degrading diseases related to AR or AR shear mutants.
The invention relates to the application of the compound or stereoisomer, deuterated compound, solvate, prodrug, metabolite, pharmaceutically acceptable salt or eutectic crystal or the pharmaceutical composition of the invention, and is characterized in that the disease is selected from prostate cancer.
The amount of a compound of the invention or a stereoisomer, deuterate, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal thereof in the present invention is in each case converted in the form of the free base.
Unless stated to the contrary, the terms used in the specification and claims have the following meanings.
The carbon, hydrogen, oxygen, sulfur, nitrogen or F, cl, br, I referred to in the groups and compounds of the invention each include their isotopic condition, and the carbon, hydrogen, oxygen, sulfur or nitrogen referred to in the groups and compounds of the invention are optionally further replaced by one or more of their corresponding isotopes, where the isotopes of carbon include 12 C、 13 C and C 14 Isotopes of C, hydrogen include protium (H), deuterium (D, also known as heavy hydrogen), tritium (T, also known as super heavy hydrogen), isotopes of oxygen include 16 O、 17 O and 18 isotopes of O, sulfur include 32 S、 33 S、 34 S and 36 isotopes of S, nitrogen include 14 N and 15 isotopes of N, fluorine include 17 F and F 19 Isotopes of F, chlorine include 35 Cl and Cl 37 Isotopes of Cl, bromine include 79 Br and 81 Br。
"halogen" means F, cl, br or I.
"halo substituted" means F, cl, br or I substituted, including but not limited to 1 to 10 substituents selected from F, cl, br or I, 1 to 6 substituents selected from F, cl, br or I, 1 to 4 substituents selected from F, cl, br or I. "halo substituted" is simply referred to as "halo".
"alkyl" refers to a substituted or unsubstituted straight or branched chain saturated aliphatic hydrocarbon group including, but not limited to, alkyl groups of 1 to 20 carbon atoms, alkyl groups of 1 to 8 carbon atoms, alkyl groups of 1 to 6 carbon atoms, alkyl groups of 1 to 4 carbon atoms. Non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, neobutyl, tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl and various branched isomers thereof; alkyl groups appearing herein are defined in accordance with the present definition. The alkyl group may be monovalent, divalent, trivalent, or tetravalent.
"heteroalkyl" refers to a substituted or unsubstituted alkyl in which 1 or more (including but not limited to 2, 3, 4, 5, or 6) carbon atoms are replaced with a heteroatom (including but not limited to N, O or S). Non-limiting examples include-X (CH 2 )v-X(CH 2 )v-X(CH 2 ) v-H (v is an integer from 1 to 5, X are each independently selected from bonds or heteroatoms including, but not limited to N, O or S, and at least 1X is selected from heteroatoms, and N or S in the heteroatoms may be oxidized to various oxidation states). The heteroalkyl group may be monovalent, divalent, trivalent, or tetravalent.
"alkylene" meansSubstituted or unsubstituted straight-chain and branched divalent saturated hydrocarbon groups comprising- (CH) 2 ) v - (v is an integer of 1 to 10), alkylene examples include, but are not limited to, methylene, ethylene, propylene, butylene and the like.
"heteroalkylene" means a substituted or unsubstituted alkylene in which 1 or more (including but not limited to 2, 3, 4, 5, or 6) carbon atoms are replaced with a heteroatom (including but not limited to N, O or S). Non-limiting examples include-X (CH 2 )v-X(CH 2 )v-X(CH 2 ) v-, v is an integer from 1 to 5, X is each independently selected from a bond, N, O or S, and at least 1X is selected from N, O or S.
"cycloalkyl" refers to a substituted or unsubstituted saturated carbocyclic hydrocarbon group, typically having 3 to 10 carbon atoms, non-limiting examples of which include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and the like. Cycloalkyl groups as herein presented are defined as described above. Cycloalkyl groups may be monovalent, divalent, trivalent, or tetravalent.
"heterocycloalkyl" refers to a substituted or unsubstituted saturated heteroatom-containing cyclic hydrocarbon group including, but not limited to, 3 to 10 atoms, 3 to 8 atoms, containing 1 to 3 heteroatoms selected from N, O or S, optionally substituted N, S in the ring of the heterocycloalkyl group being oxidizable to various oxidation states. Heterocycloalkyl groups can be attached to heteroatoms or carbon atoms, heterocycloalkyl groups can be attached to aromatic or non-aromatic rings, and heterocycloalkyl groups can be attached to bridged or spiro rings, non-limiting examples include oxiranyl, aziridinyl, oxetanyl, azetidinyl, tetrahydrofuranyl, tetrahydro-2H- [ pyranyl, dioxolanyl, dioxane, pyrrolidinyl, piperidinyl, imidazolidinyl, oxazolidinyl, oxazinidinyl, morpholinyl, hexahydropyrimidinyl, piperazinyl. Heterocyclylalkyl can be monovalent, divalent, trivalent, or tetravalent
"alkenyl" refers to substituted or unsubstituted straight and branched unsaturated hydrocarbyl groups having at least 1, typically 1, 2 or 3 carbon-carbon double bonds, the backbone including but not limited to 2 to 10, 2 to 6 or 2 to 4 carbon atoms, alkenyl examples 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-3-butenyl, 1-hexenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, 5-hexenyl, 1-methyl-1-pentenyl, 2-methyl-1-pentenyl, 1-heptenyl, 2-heptenyl, 3-heptenyl, 1-octenyl, 3-octenyl, 1-nonenyl, 3-nonenyl, 1-decenyl, 4-decenyl, 1, 3-pentadienyl, 1, 4-pentadienyl and the like; alkenyl groups appear herein, the definition of which is consistent with the definition. Alkenyl groups may be monovalent, divalent, trivalent, or tetravalent.
"alkynyl" refers to substituted or unsubstituted straight and branched monovalent unsaturated hydrocarbon radicals having at least 1, typically 1, 2 or 3 carbon-carbon triple bonds, including but not limited to 2 to 10 carbon atoms, 2 to 6 carbon atoms, 2 to 4 carbon atoms in the backbone, alkynyl embodiments including but not limited to ethynyl, propargyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, 3-butynyl, 1-pentynyl, 2-pentynyl, 3-pentynyl, 4-pentynyl, 1-methyl-1-butynyl, 2-methyl-3-butynyl, 1-hexynyl, 2-hexynyl, 3-hexynyl, 4-hexynyl, 5-hexynyl, 1-methyl-1-pentynyl, 2-methyl-1-pentynyl, 1-heptynyl, 2-heptynyl, 3-heptynyl, 4-heptynyl, 1-octynyl, 3-octynyl, 1-nonynyl, 3-decynyl, 4-decynyl, and the like; alkynyl groups may be monovalent, divalent, trivalent or tetravalent.
"alkoxy" refers to a substituted or unsubstituted-O-alkyl group. Non-limiting examples include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, sec-butoxy, tert-butoxy, n-pentoxy, n-hexoxy, cyclopropoxy and cyclobutoxy.
"carbocyclyl" or "carbocycle" refers to a substituted or unsubstituted saturated or unsaturated aromatic or non-aromatic ring which may be a 3 to 8 membered monocyclic ring, a 4 to 12 membered bicyclic ring, or a 10 to 15 membered tricyclic ring system, and carbocyclyl may be attached to the aromatic ring orOn the non-aromatic ring, the aromatic ring or the non-aromatic ring is optionally a single ring, a bridged ring or a spiro ring. Non-limiting examples include cyclopropane, cyclobutane, cyclopentane, cyclohexane, cycloheptane, 1-cyclopentyl-1-enyl, 1-cyclopentyl-2-enyl, 1-cyclopentyl-3-enyl, cyclohexyl, 1-cyclohexyl-2-enyl, 1-cyclohexyl-3-enyl, cyclohexenyl, benzene ring, naphthalene ring, "carbocyclyl" or "carbocycle" may be monovalent, divalent, trivalent, or tetravalent.
"heterocyclyl" or "heterocycle" refers to a substituted or unsubstituted saturated or unsaturated aromatic or non-aromatic ring that may be a 3-to 8-membered monocyclic, 4-to 12-membered bicyclic, or 10-to 15-membered tricyclic ring system and that contains 1 or more (including but not limited to 2, 3, 4, or 5) heteroatoms selected from N, O or S, and N, S optionally substituted in the ring of the heterocyclyl can be oxidized to various oxidation states. The heterocyclic group may be attached to a heteroatom or carbon atom, the heterocyclic group may be attached to an aromatic or non-aromatic ring, the heterocyclic group may be attached to a bridged or spiro ring, non-limiting examples include an oxiranyl, aziridinyl, oxetanyl, azetidinyl, 1, 3-dioxolanyl, 1, 4-dioxolanyl, 1, 3-dioxanyl, azepanyl, pyridyl, furyl, thienyl, pyranyl, N-alkylpyrrolyl, pyrimidinyl, pyrazinyl, pyridazinyl, imidazolyl, piperidinyl, morpholinyl, thiomorpholinyl, 1, 3-dithianyl, dihydrofuranyl, dihydropyranyl, dithianyl, tetrahydrofuranyl, tetrahydropyrrolyl, tetrahydroimidazolyl, tetrahydrothiazolyl, tetrahydropyranyl, benzimidazolyl, benzopyridyl, pyrrolopyridinyl, benzodihydropyranyl, pyrrolyl, pyrazolyl, thiazolyl, oxazolyl, pyrazinyl, indazolyl, benzothienyl, benzofuranyl, benzopyrrolyl, benzothiazolyl, benzopyrimidinyl, benzoxazolyl, benzopyrimidinyl, Benzopyrazinyl, piperazinyl and azabicyclo [3.2.1]Octyl and azabicyclo [5.2.0]Nonylalkyl oxatricyclo [5.3.1.1 ]]Dodecyl, azaadamantyl, oxaspiro [3.3 ]]Heptyl radical, "heterocyclyl" or "heterocycle" may be monovalent, divalent, trivalent, or tetravalent.
"Spiro" or "spirocyclic group" refers to a polycyclic group having one atom (referred to as a spiro atom) shared between substituted or unsubstituted monocyclic rings, the number of ring atoms in the spirocyclic ring system including, but not limited to, 5 to 20, 6 to 14, 6 to 12, 6 to 10, wherein one or more of the rings may contain 0 or more (including, but not limited to, 1, 2, 3, or 4) double bonds, and optionally may contain 0 to 5 members selected from N, O or S (=O) n Is a heteroatom of (2).
"Spiro" or "spirocyclic group" may be monovalent, divalent, trivalent, or tetravalent.
"fused ring" or "fused ring group" refers to a polycyclic group wherein each ring in the system shares an adjacent pair of atoms with the other rings in the system, wherein one or more of the rings may contain 0 or more (including but not limited to 1, 2, 3, or 4) double bonds, and may be substituted or unsubstituted, and each ring in the ring system may contain 0 to 5 heteroatoms or heteroatom-containing groups (including but not limited to those selected from N, S (=o) n Or O, n is 0, 1 or 2). The number of ring atoms in the fused ring system includes, but is not limited to, 5 to 20, 5 to 14, 5 to 12, 5 to 10. Non-limiting examples include:
"fused" or "fused-ring" groups may be monovalent, divalent, trivalent, or tetravalent.
"bridged ring" or "bridged ring radical" refers to a substituted or unsubstituted polycyclic group containing any two atoms not directly attached, which may contain 0 or more double bonds, and any ring in the ring system may contain 0 to 5 groups selected from heteroatoms or containing heteroatoms (including but not limited to N, S (=o) n Or O, where n is 0, 1, 2). The number of ring atoms includes, but is not limited to, 5 to 20, 5 to 14, 5 to 12, or 5 to 10. Non-limiting examples include Cubane and adamantane. "bridged ring" or "bridged ring radical" can be monovalent, divalent, trivalent, or tetravalent.
"carbospiro", "spirocarbocyclyl" or "carbospirocyclyl" refers to a "spiro" ring system consisting of only carbon atoms. "carbospiro", "spirocarbocyclyl" or "carbospirocyclyl" as referred to herein are defined in accordance with spirocyclic rings.
"carbon-fused", "fused carbocyclyl" or "carbon-fused cyclic" refers to a "fused ring" in which the ring system has only carbon atoms. "carbo-cyclic", "carbocyclyl" or "carbo-cyclic" as used herein is defined as consistent with a carbo-cyclic group.
"carbon bridged ring", "bridged carbocyclyl" or "carbon bridged cyclyl" refers to a "bridged ring" in which the ring system has only carbon atoms. "carbobridged ring", "bridged ring carbocyclyl", "bridged carbocyclyl" or "carbobridged ring radical" as used herein is defined as being identical to a bridged ring.
"heteromonocyclic", "monocyclic heterocyclyl" or "heteromonocyclic" refers to a "heterocyclyl" or "heterocycle" of a monocyclic system, and the heterocyclic groups, "monocyclic heterocyclyl" or "heteromonocyclic" appearing herein are defined as identical to heterocycles.
"heterobicyclic", "heterobicyclic radical", "fused-to-heterocyclic radical" or "heterobicyclic radical" refers to a "fused ring" containing a heteroatom. The "heteroacene", "heteroacenyl", "fused-ring heterocyclyl" or "heteroacenyl" as presented herein are defined in accordance with the fused ring.
"Heterospiro", "spirocyclic heterocyclyl" or "Heterospiro" refers to a "spiro" containing heteroatoms. As used herein, a heterospiro, "spiroheterocyclyl," or "heterospiro" is defined as a spiro.
"heterobridged", "bridged heterocyclyl" or "heterobridged heterocyclyl" refers to a "bridged ring" that contains a heteroatom. The term "heterobridged ring," as used herein, refers to a bridged ring, or a bridged ring.
"aryl" or "aromatic ring" refers to a substituted or unsubstituted aromatic hydrocarbon group having a single ring or a fused ring, the number of ring atoms in the aromatic ring including, but not limited to, 6 to 18, 6 to 12, or 6 to 10 carbon atoms. The aryl ring may be fused to a saturated or unsaturated carbocyclic or heterocyclic ring in which the ring attached to the parent structure is an aryl ring, non-limiting examples of which include benzene rings, naphthalene rings,The "aryl" or "aromatic ring" may be monovalent, divalent, trivalent, or tetravalent. When divalent, trivalent or tetravalent, the attachment site is located on the aryl ring.
"heteroaryl" or "heteroaryl ring" refers to a substituted or unsubstituted aromatic hydrocarbon group and contains 1 to 5 optional heteroatoms or heteroatom-containing groups (including but not limited to N, O or S (=o) n N is 0, 1, 2), the number of ring atoms in the heteroaromatic ring including, but not limited to, 5 to 15, 5 to 10, or 5 to 6. Non-heteroaryl groupsNon-limiting examples include, but are not limited to, furyl, thienyl, pyridyl, pyranyl, N-alkylpyrrolyl, pyrimidinyl, pyrazinyl, pyridazinyl, imidazolyl, benzopyrazole, benzimidazole, benzopyridine, pyrrolopyridine, and the like. The heteroaryl ring may be fused to a saturated or unsaturated carbocyclic or heterocyclic ring in which the ring attached to the parent structure is a heteroaryl ring, non-limiting examples of which include Heteroaryl groups as herein appear, the definition of which is consistent with the definition. Heteroaryl groups may be monovalent, divalent, trivalent, or tetravalent. When divalent, trivalent or tetravalent, the attachment sites are located on the heteroaryl ring.
"5 membered ring and 5 membered heteroaryl ring" refers to a fused heteroaryl ring of 5 and 5 members, at least 1 of the 2 rings containing more than 1 heteroatom (including but not limited to O, S or N), the entire group having aromaticity, non-limiting examples including pyrrolopyrrole rings, pyrazolopyrrole rings, pyrazolopyrazole rings, pyrrolofuran rings, pyrazolofuran rings, pyrrolothiene rings, pyrazolothiophene rings.
"5-and 6-membered heteroaryl ring" refers to a fused 5-and 6-membered heteroaryl ring, at least 1 of the 2 fused rings containing more than 1 heteroatom (including but not limited to O, S or N), the entire group having aromaticity, non-limiting examples including benzo 5-membered heteroaryl, 6-membered heteroaryl and 5-membered heteroaryl rings.
"substituted" or "substituted" means substituted with 1 or more (including but not limited to 2, 3, 4, or 5) substituents including but not limited to H, F, cl, br, I, alkyl, cycloalkyl, alkoxy, haloalkyl, thiol, hydroxy, nitro, mercapto, amino, cyano, isocyano, aryl, heteroaryl, heterocyclyl, bridged ring, spirocyclic, and cyclic, hydroxyalkyl, =o, carbonyl, aldehyde, carboxylic acid, formate, - (CH) 2 ) m -C(=O)-R a 、-O-(CH 2 ) m -C(=O)-R a 、-(CH 2 ) m -C(=O)-NR b R c 、-(CH 2 ) m S(=O) n R a 、-(CH 2 ) m -alkenyl-R a 、OR d Or- (CH) 2 ) m -alkynyl-R a (wherein m, n is 0, 1 or 2), arylthio, thiocarbonyl, silane or-NR b R c Etc., wherein R is b And R is R c Independently selected from the group consisting of H, hydroxy, amino, carbonyl, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, sulfonyl, trifluoromethanesulfonyl, and optionally R b And R is R c Five-or six-membered cycloalkyl or heterocyclyl groups may be formed.
"containing 1 to 5 heteroatoms selected from O, S, N" means containing 1, 2, 3, 4 or 5 heteroatoms selected from O, S, N.
"0 to X is substituted with a substituent" means substituted with 0, 1, 2, 3. As "0 to 4 selected..substituents" means substituted with 0, 1, 2, 3 or 4 selected..substituents. As "0 to 5 selected..substituents" means substituted with 0, 1, 2, 3, 4, or 5 selected..substituents. By "the hetero-bridge ring is optionally further substituted with 0 to 4 substituents selected from H or F" is meant that the hetero-bridge ring is optionally further substituted with 0, 1, 2, 3 or 4 substituents selected from H or F.
The X-Y membered ring (X is selected from integers less than Y and greater than 3 and Y is selected from any integer between 4 and 12) includes x+1, x+2, x+3, x+4. The ring includes heterocyclic, carbocyclic, aromatic, aryl, heteroaryl, cycloalkyl, heteromonocyclic, heterobicyclic, heterospiro, or heterobridged rings. For example, "4-7 membered heteromonocyclic ring" means 4-, 5-, 6-or 7-membered heteromonocyclic ring, and "5-10 membered heteromonocyclic ring" means 5-, 6-, 7-, 8-, 9-or 10-membered heteromonocyclic ring.
"optional" or "optionally" means that the subsequently described event or circumstance may but need not occur, and that the description includes instances where the event or circumstance occurs or does not. Such as: "alkyl optionally substituted with F" means that the alkyl may be, but is not necessarily, substituted with F, and is intended to include both cases where the alkyl is substituted with F and cases where the alkyl is not substituted with F.
By "pharmaceutically acceptable salt" or "pharmaceutically acceptable salt thereof" is meant a salt of a compound of the invention that retains the biological effectiveness and properties of the free acid or free base, and the free acid is obtained by reaction with a non-toxic inorganic or organic base.
"pharmaceutical composition" refers to one or more compounds of the present invention, or stereoisomers, tautomers, deuterides, solvates, prodrugs, metabolites, pharmaceutically acceptable salts or co-crystals thereof, and mixtures of other chemical components, wherein "other chemical components" refers to pharmaceutically acceptable carriers, excipients, and/or one or more other therapeutic agents.
By "carrier" is meant a material that does not cause significant irritation to the organism and does not abrogate the biological activity and properties of the administered compound.
"excipient" refers to an inert substance that is added to a pharmaceutical composition to facilitate administration of a compound. Non-limiting examples include calcium carbonate, calcium phosphate, sugars, starches, cellulose derivatives (including microcrystalline cellulose), gelatin, vegetable oils, polyethylene glycols, diluents, granulating agents, lubricants, binders, and disintegrating agents.
"prodrug" means a compound of the invention which is converted into a biologically active form by in vivo metabolism. Prodrugs of the invention are prepared by modifying amino or carboxyl groups in the compounds of the invention, which modifications may be removed by conventional procedures or in vivo to give the parent compound. When the prodrugs of the invention are administered to a mammalian subject, the prodrugs are cleaved to form the free amino or carboxyl groups.
"co-crystals" refers to crystals of Active Pharmaceutical Ingredient (API) and co-crystal former (CCF) that are bound by hydrogen bonds or other non-covalent bonds, wherein the pure states of the API and CCF are both solid at room temperature and there is a fixed stoichiometric ratio between the components. A co-crystal is a multi-component crystal that includes both binary co-crystals formed between two neutral solids and multi-component co-crystals formed between a neutral solid and a salt or solvate.
"animal" is meant to include mammals, such as humans, companion animals, zoo animals and livestock, preferably humans, horses or dogs.
"stereoisomers" refers to isomers arising from the spatial arrangement of atoms in a molecule, and include cis-trans isomers, enantiomers and conformational isomers.
"tautomer" refers to a functional group isomer produced by rapid movement of an atom in a molecule at two positions, such as keto-enol isomers and amide-imine alcohol isomers.
"optional" or "optionally" means that the subsequently described event or circumstance may but need not occur, and that the description includes instances where the event or circumstance occurs and instances where it does not. For example, "a heterocyclic group optionally substituted with an alkyl group" means that the alkyl group may be, but is not necessarily, present, and the description includes cases where the heterocyclic group is substituted with an alkyl group, and cases where the heterocyclic group is not substituted with an alkyl group.
“IC 50 "is the concentration of drug or inhibitor required to inhibit half of a given biological process (or a component of the process such as an enzyme, receptor, cell, etc.).
Detailed Description
For the purpose of the present invention, starting from commercially available chemicals and/or compounds described in the chemical literature, the compounds "commercially available chemicals" used in the reactions described herein are prepared from standard commercial sources, including Shanghai Allatin Biotechnology Co., ltd, shanghai Michelin Biochemical Co., sigma-Aldrich, alfa Elisa (China) chemical Co., ltd, boschiza (Shanghai) chemical industry development Co., an Naiji chemical, shanghai Tetan technology Co., kelong chemical, bailingwei Co., etc., according to organic synthesis techniques known to those skilled in the art.
The following examples illustrate the technical aspects of the present invention in detail, but the scope of the present invention is not limited thereto.
The compounds used in the reactions described herein are prepared according to organic synthesis techniques known to those skilled in the art starting from commercially available chemicals and/or compounds described in the chemical literature. "commercially available chemicals" are obtained from regular commercial sources and include: taitan technology, an Naiji chemistry, shanghai de moer, chengdu Kelong chemical, shaoguan chemical technology, nanjing medical stone, ming Kangde and Budweiser technologies.
The structure of the compounds is determined by Nuclear Magnetic Resonance (NMR) or (sum) Mass Spectrometry (MS). NMR shift (. Delta.) of 10 -6 Units of (ppm) are given. NMR was performed using a (Bruker Avance III and Bruker Avance 300) magnetonuclear apparatus with deuterated dimethyl sulfoxide (DMSO-d) 6 ) Deuterated chloroform (CDCl) 3 ) Deuterated methanol (CD) 3 OD), internal standard Tetramethylsilane (TMS);
MS measurement (Agilent 6120B (ESI) and Agilent 6120B (APCI));
HPLC was performed using an Agilent 1260DAD high pressure liquid chromatograph (Zorbax SB-C18X14.6mm, 3.5. Mu.M);
the thin layer chromatography silica gel plate uses a smoke table yellow sea HSGF254 or Qingdao GF254 silica gel plate, the specification of the silica gel plate used by the Thin Layer Chromatography (TLC) is 0.15mm-0.20mm, and the specification of the thin layer chromatography separation and purification product is 0.4mm-0.5mm;
column chromatography generally uses tobacco stage yellow sea silica gel 200-300 mesh silica gel as carrier.
SEM:THP:/>Boc: a tert-butoxycarbonyl group; ms: />TBS:/>MTBE: methyl tertiary butyl ether; bn: />DIPEA: n, N-diisopropylethylamine; DMAc: n, N-dimethylacetamide; DMSO: dimethyl sulfoxide; DCM: dichloromethane; cbz: />NMP: n-methylpyrrolidone.
Example 1:
trifluoroacetate salt of (2S) -N- (4-cyano-3- (trifluoromethyl) phenyl) -3- (4- ((1- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-5-yl) azetidin-3-yl) ethynyl) -1H-pyrazol-1-yl) -2-hydroxy-2-methylpropanamide (compound 1)
(2S)-N-(4-cyano-3-(trifluoromethyl)phenyl)-3-(4-((1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)azetidin-3-yl)ethynyl)-1H-pyrazol-1-yl)-2-hydroxy-2-methylpropanamide trifluoroacetate
The first step: (S) -N- (4-cyano-3- (trifluoromethyl) phenyl) -2-hydroxy-3- (4-iodo-1H-pyrazol-1-yl) -2-methylpropanamide (1 b)
(S)-N-(4-cyano-3-(trifluoromethyl)phenyl)-2-hydroxy-3-(4-iodo-1H-pyrazol-1-yl)-2-methylpropanamide
(R) -3-bromo-N- (4-cyano-3- (trifluoromethyl) phenyl) -2-hydroxy-2-methylpropanamide (1 a) (see J.Med. Chem.,2020, 63, 12642-12665) (3.7 g,10.54 mmol) was dissolved in 30mL of acetonitrile, solid potassium carbonate (4.37 g,31.62 mmol) was added, the temperature was raised to 70℃for 3h, then 4-iodopyrazole (2.25 g,11.60 mmol) was added at the same temperature, and the reaction was continued at 95℃for 2h. The reaction solution was cooled to room temperature, and the residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate (v/v) =2:1) to give (S) -N- (4-cyano-3- (trifluoromethyl) phenyl) -2-hydroxy-3- (4-iodo-1H-pyrazol-1-yl) -2-methylpropanamide (1 b) (2.0 g, yield: 41%).
1 H NMR(400MHz,DMSO-d 6 )δ10.34(s,1H),8.44(d,1H),8.22(dd,1H),8.08(d,1H),7.78(s,1H),7.45(s,1H),6.28(s,1H),4.47(d,1H),4.30(d,1H),1.35(s,3H).
LCMS m/z=465.0[M+1] +
And a second step of: (S) -3- ((1- (3- ((4-cyano-3- (trifluoromethyl) phenyl) amino) -2-hydroxy-2-methyl-3-oxopropyl) -1H-pyrazol-4-yl) ethynyl) azetidine-1-carboxylic acid tert-butyl ester (1 c)
tert-butyl(S)-3-((1-(3-((4-cyano-3-(trifluoromethyl)phenyl)amino)-2-hydroxy-2-methyl-3-oxopropyl)-1H-pyrazol-4-yl)ethynyl)azetidine-1-carboxylate
(S) -N- (4-cyano-3- (trifluoromethyl) phenyl) -2-hydroxy-3- (4-iodo-1H-pyrazol-1-yl) -2-methylpropanamide (1 b) (200 mg,0.43 mmol) was dissolved in 2mL of methylene chloride, triethylamine (130 mg,1.28 mmol) was added, pdCl2 (PPh 3) 2 (45 mg,0.064 mmol) and cuprous iodide (12 mg,0.063 mmol) were sequentially added under nitrogen protection, and a solution of tert-butyl 3-ethynyl azetidine-1-carboxylate (120 mg,0.66 mmol) in methylene chloride (1 mL) was slowly added dropwise thereto and reacted at room temperature for 1.5 hours. To the reaction solution were added 15mL of water and 10mL of methylene chloride, the organic layer was separated, washed with 5mL of saturated sodium chloride solution, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was purified by column chromatography on silica gel (petroleum ether/ethyl acetate (v/v) =2:1) to give (S) -3- ((1- (3- ((4-cyano-3- (trifluoromethyl) phenyl) amino) -2-hydroxy-2-methyl-3-oxopropyl) -1H-pyrazol-4-yl) ethynyl) azetidine-1-carboxylic acid tert-butyl ester (1 c) (240 mg, yield: > 99%).
And a third step of: trifluoroacetate salt of (2S) -N- (4-cyano-3- (trifluoromethyl) phenyl) -3- (4- ((1- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-5-yl) azetidin-3-yl) ethynyl) -1H-pyrazol-1-yl) -2-hydroxy-2-methylpropanamide (compound 1)
(2S)-N-(4-cyano-3-(trifluoromethyl)phenyl)-3-(4-((1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)azetidin-3-yl)ethynyl)-1H-pyrazol-1-yl)-2-hydroxy-2-methylpropanamide trifluoroacetate
(S) -3- ((tert-butyl 1- (3- ((4-cyano-3- (trifluoromethyl) phenyl) amino) -2-hydroxy-2-methyl-3-oxopropyl) -1H-pyrazol-4-yl) ethynyl) azetidine-1-carboxylate (1 c) (98 mg,0.19 mmol) was dissolved in 2mL DCM, 2mL trifluoroacetic acid was added and stirred at room temperature for 1H. The reaction was concentrated under reduced pressure, the residue was dissolved in 10mL of 4mol/L aqueous NaOH solution, extracted with DCM (20 mL. Times.3), the organic phase was washed with 50mL of water, dried over anhydrous sodium sulfate and concentrated under reduced pressure to give an oil. The oil was dissolved in 5mL of DMSO, 0.16mL of DIPEA and 2- (2, 6-dioxopiperidin-3-yl) -5-fluoroisoindoline-1, 3-dione (see WO 2017197056) (52 mg,0.19 mmol) were added and the reaction was stirred at 80℃for 4h. The reaction solution was cooled to room temperature, 30mL of water was added, filtration was performed, the solid was collected, washed with 20mL of water, the solid was dissolved with 50mL of methylene chloride, dried over anhydrous sodium sulfate, and after concentration under reduced pressure, the crude product was subjected to Pre-HPLC (instrument and preparative column: preparation of liquid phase using Glison GX-281, preparative column model is Sunfire C18,5 μm, inner diameter×length=30 mm×150 mm). The preparation method comprises the following steps: the crude product was dissolved in methanol and dimethylsulfoxide and filtered through a 0.45 μm filter to prepare a sample solution. Mobile phase system: acetonitrile/water (with 0.1% tfa). The gradient elution method comprises the following steps: acetonitrile was eluted from a 5% gradient 60% (elution time 15 min), and lyophilized to give the trifluoroacetate salt (48 mg) of (2S) -N- (4-cyano-3- (trifluoromethyl) phenyl) -3- (4- ((1- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-5-yl) azetidin-3-yl) ethynyl) -1H-pyrazol-1-yl) -2-hydroxy-2-methylpropanamide (compound 1).
1 H NMR(400MHz,DMSO-d 6 )δ11.05(s,1H),10.35(s,1H),8.44(d,1H),8.21(dd,1H),8.08(d,1H),7.86(s,1H),7.67(d,1H),7.53(s,1H),6.85(d,1H),6.70(dd,1H),6.29(s,1H),5.06(dd,1H),4.43(d,1H),4.36(t,2H),4.27(d,1H),3.99(t,2H),3.91-3.80(m,1H),2.94-2.82(m,1H),2.63-2.51(m,2H),2.08-1.96(m,1H),1.34(s,3H).
LCMS m/z=674.2[M+1] +
Example 2:
(2S) -N- (4-cyano-3- (trifluoromethyl) phenyl) -3- (4- ((1- ((1- (2, 6-dioxopiperidin-3-yl) -3-methyl-2-oxo-2, 3-dihydro-1H-benzo [ d ] imidazol-5-yl) methyl) azetidin-3-yl) ethynyl) -1H-pyrazol-1-yl) -2-hydroxy-2-methylpropanamide (Compound 2)
(2S)-N-(4-cyano-3-(trifluoromethyl)phenyl)-3-(4-((1-((1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)methyl)azetidin-3-yl)ethynyl)-1H-pyrazol-1-yl)-2-hydroxy-2-methylpropanamide
(S) -3- ((tert-butyl 1- (3- ((4-cyano-3- (trifluoromethyl) phenyl) amino) -2-hydroxy-2-methyl-3-oxopropyl) -1H-pyrazol-4-yl) ethynyl) azetidine-1-carboxylate (1 c) (98 mg,0.19 mmol) was dissolved in 2mL DCM, 2mL trifluoroacetic acid was added and stirred at room temperature for 1H. The reaction system was concentrated under reduced pressure, 10mL of tetrahydrofuran and solid sodium hydrogencarbonate (64 mg,0.76 mmol) were added to the residue, and after stirring at room temperature for 0.5H, 1- (2, 6-dioxopiperidin-3-yl) -3-methyl-2-oxo-2, 3-dihydro-1H-benzo [ d ] imidazole-5-carbaldehyde (see WO 2020113233) (55 mg,0.19 mmol) was added, and after stirring at room temperature for 0.5H, sodium triacetoxyborohydride (100 mg,0.47 mmol) was further added and reacted at room temperature for 16H. To the reaction solution was slowly added 50mL of saturated sodium bicarbonate solution, extracted with 100mL of dichloromethane, and the organic phase was washed with 50mL of saturated sodium chloride solution, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the crude product was purified by column chromatography on silica gel (dichloromethane/methanol (v/v) =1:0-9:1) to give (2S) -N- (4-cyano-3- (trifluoromethyl) phenyl) -3- (4- ((1- ((1- (2, 6-dioxopiperidin-3-yl) -3-methyl-2-oxo-2, 3-dihydro-1H-benzo [ d ] imidazol-5-yl) methyl) azetidin-3-yl) ethynyl) -1H-pyrazol-1-yl) -2-hydroxy-2-methylpropanamide (compound 2) (20 mg, yield: 15%).
1 H NMR(400MHz,DMSO-d 6 )δ11.07(s,1H),10.35(s,1H),8.44(d,1H),8.21(dd,1H),8.08(d,1H),7.81(s,1H),7.48(s,1H),7.08(s,1H),7.03(d,1H),6.94(d,1H),6.28(s,1H),5.34(dd,1H),4.42(d,1H),4.27(d,1H),3.57(s,2H),3.52(t,2H),3.41-3.31(m,4H),3.02(t,2H),2.96-2.82(m,1H),2.77-2.57(m,2H),2.06-1.96(m,1H),1.34(s,3H).
LCMS m/z=689.2[M+1] +
Example 3: preparation of Compound 3
The first step: (R) -3-bromo-N- (2-chloro-4- (trifluoromethyl) phenyl) -2-hydroxy-2-methylpropanamide (3 b)
(R)-3-bromo-N-(2-chloro-4-(trifluoromethyl)phenyl)-2-hydroxy-2-methylpropanamide
(R) -3-bromo-2-hydroxy-2-methylpropanoic acid (2.0 g,10.93 mmol) was dissolved in 50mL of methylene chloride, cooled to 0℃and thionyl chloride (1.5 g,12.61 mmol) was added thereto, followed by reaction at room temperature for 1 hour, and then 3a (1.95 g,10.0 mmol) was added thereto, followed by reaction at room temperature for 16 hours. The reaction system was concentrated under reduced pressure, and the crude product was purified by silica gel chromatography (petroleum ether: ethyl acetate (v/v) =4:1) to give 3b (3.1 g, yield: 86%).
And a second step of: (S) -N- (2-chloro-5- (trifluoromethyl) phenyl) -2-hydroxy-3- (4-iodo-1H-pyrazol-1-yl) -2-methylpropanamide (3 c)
(S)-N-(2-chloro-4-(trifluoromethyl)phenyl)-2-hydroxy-3-(4-iodo-1H-pyrazol-1-yl)-2-methylpropanamide
3b (3.1 g,8.6 mmol) was dissolved in 30mL of acetonitrile, potassium carbonate (2.35 g,17 mmol) was added, and after 3h reaction at 70℃4-iodopyrazole (1.93 g,10 mmol) was added and reacted at 70℃for 2h reaction at 95 ℃. The reaction solution was cooled to room temperature, concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (petroleum ether/ethyl acetate (v/v) =2:1) to give 3c (3.0 g, yield: 74%).
And a third step of: (2S) -N- (2-chloro-5- (trifluoromethyl) phenyl) -3- (4- ((1- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-5-yl) azetidin-3-yl) ethynyl) -1H-pyrazol-1-yl) -2-hydroxy-2-methylpropanamide (Compound 3)
(2S)-N-(2-chloro-4-(trifluoromethyl)phenyl)-3-(4-((1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)azetidin-3-yl)ethynyl)-1H-pyrazol-1-yl)-2-hydroxy-2-methylpropanamide
3c (0.1 g,0.2 mmol) was dissolved in 5mL of LDMF and crude intermediate 1 (0.09 g), TEA (0.1 g,0.99 mmol), cuprous iodide (4 mg,0.021 mmol) and PdCl were added sequentially 2 (PPh 3 ) 2 (14 mg,0.02 mmol), nitrogen was replaced three times and reacted at 55℃for 1 hour. The reaction solution was cooled to room temperature, 50mL of water was added to precipitate a solid, the solid was filtered, a cake was collected, the cake was washed with 10mL of water, the cake was dissolved with 50mL of water, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the crude product was purified by silica gel chromatography (petroleum ether/ethyl acetate (v/v) =1:3) to give compound 3 (0.08 g, yield: 59%).
1 H NMR(400MHz,CDCl 3 )δ9.40(s,1H),8.44-8.36(m,1H),8.08-7.90(m,1H),7.68-7.38(m,5H),6.76-6.68(m,1H),6.46(dd,1H),4.91-4.81(m,1H),4.60-4.52(m,1H),4.34-4.11(m,3H),4.03-3.90(m,2H),3.78-3.63(m,1H),2.88-2.57(m,3H),2.13-2.00(m,1H),1.42(s,3H).
LCMS m/z=683.4[M+1] +
Example 4: preparation of Compound 4
The first step: n- (2-chloro-4- (trifluoromethyl) phenyl) -3- (4-iodo-1H-pyrazol-1-yl) propanamide (4 b)
N-(2-chloro-4-(trifluoromethyl)phenyl)-3-(4-iodo-1H-pyrazol-1-yl)propenamide
4a (2.2 g,8.3 mmol) (Journal of the Chemical Society C: organic,1966, 1179-1183) was dissolved in 50mL of dichloromethane, TCFH (CAS: 94790-35-9) (3.4 g,12.1 mmol) and 2-chloro-4- (trifluoromethyl) aniline (1.95 g,9.97 mmol) were added, cooled to 0℃and N-methylimidazole (2.5 g,30.45 mmol) was added dropwise and reacted at room temperature for 5h. The reaction solution was concentrated under reduced pressure, and the crude product was purified by silica gel chromatography (petroleum ether: ethyl acetate (v/v) =4:1) to give 4b (2.4 g, yield: 65%).
LCMS m/z=444.3[M+1] +
And a second step of: n- (2-chloro-4- (trifluoromethyl) phenyl) -3- (4- ((1- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-5-yl) azetidin-3-yl) ethynyl) -1H-pyrazol-1-yl) propanamide (Compound 4)
N-(2-chloro-4-(trifluoromethyl)phenyl)-3-(4-((1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)azetidin-3-yl)ethynyl)-1H-pyrazol-1-yl)propanamide
4b (0.1 g,0.23 mmol) was dissolved in 5mL DMF and crude intermediate 1 (0.09 g), TEA (0.1 g,0.99 mmol), cuI (4 mg,0.021 mmol) and PdCl were added sequentially 2 (PPh 3 ) 2 (14 mg,0.02 mmol), nitrogen was replaced three times and reacted at 55℃for 1 hour. The reaction solution was cooled to room temperature, 50mL of water was added to precipitate a solid, the solid was filtered, a cake was collected, the cake was washed with 10mL of water, the cake was dissolved with 50mL of water, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the crude product was purified by silica gel chromatography (petroleum ether/ethyl acetate (v/v) =1:3) to give compound 4 (0.06 g, yield: 40%).
1 H NMR(400MHz,CDCl 3 )δ8.41(d,1H),8.27(s,1H),8.00(s,1H),7.64-7.38(m,5H),6.78-6.66(m,1H),6.46(dd,1H),4.92-4.81(m,1H),4.43(t,2H),4.34-4.17(m,2H),4.04-3.90(m,2H),3.79-3.63(m,1H),3.01(t,2H),2.92-2.55(m,3H),2.14-1.99(m,1H).
Biological test example:
1. inhibition of 22RV1 cell proliferation assay
Prostate cancer cells 22RV1 were purchased from ATCC and cultured in RPMI 1640+10% FBS at 37deg.C in 5% CO 2 In the incubator. Cells in exponential growth phase were collected on the first day, cell suspensions were adjusted to the corresponding concentrations with 1% css-FBS phenol red free medium, plated, cells were 2000 cells/well, and incubated overnight. The next day, different concentrations of the compound were added and placed in incubator for further incubation for 7 days. After the incubation, 50. Mu.L of CellTiter-Glo reagent, which had been melted and equilibrated to room temperature in advance, was added to each well according to the protocol of CellTiter-Glo kit (Promega, G7573), and the mixture was homogenized for 2 minutes with a microplate shaker, and after 10 minutes of standing at room temperature, the fluorescence signal value was measured with a microplate reader (PHER Astar FSX). Results the inhibition of each concentration of the compound was calculated by the treatment of formula (1) and IC with 50% inhibition of the compound was calculated using the origin9.2 software using the DoseResp function 50 Values. Wherein RLU is provided with compound For drug treatment group readings, RLU control Mean value of DMSO solvent control group.
Inhibition%=[1-RLU compound /RLU control ]X 100% type (1)
IC for inhibiting 22RV1 cell proliferation 50 The results are shown in Table 1.
TABLE 1 Compounds of the invention inhibit 22RV1 cell IC 50 Value of
Sequence number | Numbering of compounds | IC 50 (μM) |
1 | Trifluoroacetate salt of Compound 1 | <5 |
2 | Compound 2 | <5 |
3 | Compound 3 | <5 |
Conclusion: the compounds of the present invention have an inhibitory effect on prostate cell 22RV 1.
Claims (6)
1. A compound or a stereoisomer, a deuterate, a solvate, a prodrug, a metabolite, a pharmaceutically acceptable salt or a co-crystal thereof, wherein the compound is selected from compounds shown in a general formula (I),
B-L-K(I);
l is selected fromBond or-C 1-50 Hydrocarbyl-, having from 0 to 20 methylene units in said hydrocarbyl optionally further replaced by-Ak-, -Cy-;
each-Ak-is independently selected from- (CH) 2 ) q -、-(CH 2 ) q -O-、-O-(CH 2 ) q -、-(CH 2 ) q -NR L -、-NR L -(CH 2 ) q -、-(CH 2 ) q -NR L C(=O)-、-NR L (CH 2 ) q C(=O)-、-(CH 2 ) q -C(=O)NR L -、-C(=O)-、-C(=O)-(CH 2 ) q -NR L -、-(C≡C) q -、-CH=CH-、-Si(R L ) 2 -、-Si(OH)(R L )-、-Si(OH) 2 -、-P(=O)(OR L )-、-P(=O)(R L )-、-S-、-S(=O)-、-S(=O) 2 -or a bond, said-CH 2 Optionally further 0 to 2 are selected from H, halogen, OH, CN, NH 2 、C 1-6 Alkyl, C 1-6 Alkoxy, halogen substituted C 1-6 Alkyl, hydroxy substituted C 1-6 Alkyl-and cyano-substituted C 1-6 Substituted by alkyl;
q is each independently selected from 0, 1, 2, 3, 4, 5 or 6;
R L each independently selected from H, C 1-6 Alkyl, 3-7 membered heterocyclyl, 3-7 membered cycloalkyl, phenyl or 5-6 membered heteroaryl;
each-Cy-is independently selected from the group consisting of a bond, 4-8 membered heteromonocyclic ring, 4-10 membered heterobicyclic ring, 5-12 membered heterospiro ring, 7-10 membered heterobridged ring, 3-7 membered monocycloalkyl, 4-10 membered heterocycloalkyl, 5-12 membered spirocycloalkyl, 7-10 membered bridged cycloalkyl, 5-10 membered heteroaryl, or 6-10 membered aryl, said aryl, heteroaryl, cycloalkyl, heteromonocyclic ring, heterofused ring, heterospiro ring, or heterobridged ring optionally further being 0 to 4 selected from H, F, cl, br, I, OH, COOH, CN, NH 2 、=O、C 1-4 Alkyl, halogen substituted C 1-4 Alkyl, hydroxy substituted C 1-4 Alkyl or C 1-4 Substituted by alkoxy, said heteroaryl, heteromonocyclic, heterobicyclic, heterospiro or bridged ring containing 1 to 4 substituents selected from O,S, N, when the heteroatom is selected from S, is optionally further substituted with 0, 1 or 2 = O;
b is selected from
Y is selected from S or O;
m1, m2 are each independently selected from 0, 1, 2, 3, 4 or 5;
B 1 selected from C 6-10 A carbocyclyl or 5-10 membered heterocyclyl, said heterocyclyl containing 1 to 4 heteroatoms selected from O, S, N;
ring W is selected from 5 to 10 membered heteroaryl rings containing 1 to 5 heteroatoms selected from O, S, N;
R b1 、R b2 each independently selected from H, F, cl, br, I, = O, OH, CN, NO 2 、COOH、C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-4 Alkoxy, C 1-4 Alkylthio, - (CH) 2 ) n -R b21 、-OR b21 、-N(R b21 ) 2 、-C(=O)N(R b21 ) 2 、-C(=O)OR b21 、-C(=O)R b22 、-NR b21 C(=O)R b22 、-NR b21 S(=O) 2 R b22 、C 3-6 Cycloalkyl, C 6-10 Aryl, 5-10 membered heteroaryl or 4-10 membered heterocyclyl, said alkyl, alkenyl, alkynyl, alkoxy, alkylthio, cycloalkyl, heterocyclyl, aryl or heteroaryl optionally being further substituted with 0 to 4 groups selected from H, F, cl, br, I, OH, =o, -N (R b21 ) 2 、CN、COOH、C 1-4 Alkyl, C 1-4 Alkoxy, halogen substituted C 1-4 Alkyl-and cyano-substituted C 1-4 Alkyl, C 3-6 Cycloalkyl, 5-10 membered heteroaryl or 4-10 membered heterocyclyl, said heteroaryl or heterocyclyl containing 1 to 4 heteroatoms selected from O, S, N;
R b21 each independently selected from H, C 1-4 Alkyl, C 3-6 Cycloalkyl, C 6-10 Aryl, 5-10 membered heteroaryl or 4-10 membered heterocyclyl, said alkyl,Cycloalkyl, aryl, heteroaryl or heterocyclyl is optionally further substituted with 0 to 4 substituents selected from H, F, cl, br, I, OH, = O, NH 2 、CN、CF 3 、COOH、C 1-4 Alkyl, C 3-6 Cycloalkyl, C 1-4 An alkoxy substituent, said heteroaryl or heterocyclyl containing 1 to 4 heteroatoms selected from O, S, N;
R b22 each independently selected from H, C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-4 Alkoxy, C 3-6 Cycloalkyl, said alkyl, alkoxy, cycloalkyl, alkenyl, alkynyl optionally being further substituted with 0 to 4 groups selected from H, F, cl, br, I, OH, = O, NH 2 、CN、CF 3 、COOH、C 1-4 Alkyl, C 3-6 Cycloalkyl, C 1-4 Substituted with alkoxy;
R b3 selected from H, C 1-4 Alkyl optionally further substituted with 0 to 4 groups selected from H, F, cl, br, I, OH, = O, NH 2 、CN、CF 3 、COOH、C 1-4 Alkyl, C 3-6 Cycloalkyl, C 1-4 Substituted with alkoxy;
R b4 selected from H, OH, -OR b21 、-N(R b21 ) 2 、-OC(=O)R b22 、-NR b21 C(=O)R b22 Or C 1-4 Alkyl optionally further substituted with 0 to 4 groups selected from H, F, cl, br, I, OH, = O, NH 2 、CN、CF 3 、COOH、C 1-4 Alkyl, C 3-6 Cycloalkyl, C 1-4 Substituted with alkoxy;
or R is b3 、R b4 Together with the carbon atoms to which they are attached form C 3-6 Cycloalkyl or 3 to 8 heteromonocyclic rings, said cycloalkyl or heteromonocyclic ring optionally being further substituted with 0 to 4 substituents selected from H, F, cl, br, I, OH, NH 2 、=O、C 1-4 Alkyl or C 1-4 An alkoxy substituent, said heteromonocyclic ring containing 1 to 4 heteroatoms selected from O, S, N;
k is selected from
Q is each independently selected from the group consisting of bond, -O-, -S-, -CH 2 -、-NR q -、-CO-、-NR q CO-、-CONR q -or a 3-12 membered heterocyclyl, said heterocyclyl optionally being further substituted with 0 to 4 substituents selected from H, F, cl, br, I, OH, = O, NH 2 、CN、COOH、CONH 2 、C 1-4 Alkyl or C 1-4 A substituent of an alkoxy group, the heterocyclic group containing 1 to 4 heteroatoms selected from O, S, N;
R q selected from H or C 1-6 An alkyl group;
a is selected from C 3-10 Carbocyclyl, C 6-10 Aryl, 3-10 membered heterocyclyl or 5-10 membered heteroaryl, said heterocycle or heteroaryl containing 1 to 4 heteroatoms selected from O, S, N;
F are each independently selected from C 3-20 Carbocyclyl, C 6-20 Aryl, 3-20 membered heterocyclyl or 5-20 membered heteroaryl, said heterocyclyl or heteroaryl containing 1 to 4 heteroatoms selected from O, S, N;
R k2 each independently selected from the group consisting of bond, -CO-, -SO 2 -, -SO-or-C (R) k3 ) 2 -;
R k1 Each independently selected from H, F, cl, br, I, OH, = O, NH 2 、CN、COOH、CONH 2 、C 1-6 Alkyl or C 1-6 Alkoxy, said alkyl or alkoxy optionally being further substituted with 0 to 4 groups selected from H, F, cl, br, I, OH, = O, NH 2 、CN、COOH、CONH 2 、C 1-4 Alkyl or C 1-4 Substituted with alkoxy;
R k3 each independently selected from H, F, cl, br, I, OH, = O, NH 2 、CN、COOH、CONH 2 、C 1-6 Alkyl, C 1-6 Alkoxy, C 3-8 Cycloalkyl or 3-8 membered heterocyclyl, said alkyl, alkoxy, cycloalkyl or heterocyclyl optionally being further substituted with 0 to 4 substituents selected from H, F, cl, br, I, OH, = O, NH 2 、CN、COOH、CONH 2 、C 1-4 Alkyl or C 1-4 A substituent of an alkoxy group, the heterocyclic group containing 1 to 4 heteroatoms selected from O, S, N;
or two R k3 And the carbon atoms or ring skeletons directly linked to each other together form a 3-8 membered carbocycle or 3-8 membered heterocycle, said carbocycle or heterocycle optionally being further substituted with 0 to 4 groups selected from H, F, cl, br, I, OH, = O, NH 2 、CN、COOH、CONH 2 、C 1-4 Alkyl or C 1-4 A substituent of an alkoxy group, said heterocycle containing 1 to 4 heteroatoms selected from O, S, N;
R k4 Each independently selected from H, OH, NH 2 、CN、CONH 2 、C 1-6 Alkyl, C 3-8 Cycloalkyl or 3-8 membered heterocyclyl, said alkyl, cycloalkyl or heterocyclyl optionally being further substituted with 0 to 4 substituents selected from H, F, cl, br, I, OH, = O, NH 2 、CN、COOH、CONH 2 、C 1-4 Alkyl or C 1-4 A substituent of an alkoxy group, the heterocyclic group containing 1 to 4 heteroatoms selected from O, S, N;
M 1 selected from the group consisting of bond, -C (=O) NH-, -NHC (=O) -, -CH 2 -C(=O)NH-、-C(=O)CH 2 NH-, 5-6 membered heteroaryl, said heteroaryl optionally being further substituted with 0 to 4 substituents selected from H, F, cl, br, I, OH, = O, CF 3 、NH 2 、CN、C 1-4 Alkyl, halogen substituted C 1-4 Alkyl, hydroxy substituted C 1-4 Alkyl, C 1-4 Substituted with an alkoxy substituent, said heteroaryl containing 1 to 4 heteroatoms selected from O, S, N;
M 2 selected from-NHC (=o) -C 1-6 Alkyl, -NHC (=o) -C 3-6 Cycloalkyl or 4-10 membered heterocyclyl, said alkyl, cycloalkyl or heterocyclyl optionally being further substituted with 0 to 4 substituents selected from H, F, cl, br, I, =o, OH, NH 2 、C 1-4 Alkyl or C 1-4 A substituent of an alkoxy group, the heterocyclic group containing 1 to 4 heteroatoms selected from O, S, N;
M 3 selected from-NH-or-O-;
R k10 selected from C 1-6 Alkyl optionally further substituted with 0 to 4 groups selected from H, F, cl, br, I, =o, OH, C 1-6 Alkyl or C 3-6 Substituted cycloalkyl;
R k11 Each independently selected from H, F, cl, br, I, = O, OH, SH, C 1-6 Alkyl, C 1-6 Alkoxy or C 1-6 Alkylthio or-O-C (=o) -C 1-6 Alkyl, said alkyl, alkoxy or alkylthio being optionally further substituted with 0 to 4 groups selected from H, F, cl, br, I, OH, C 1-4 Alkyl or C 1-4 Substituted with alkoxy;
R k12 、R k13 each independently selected from H, C 1-6 Alkyl or C 3-6 Cycloalkyl, said alkyl or cycloalkyl optionally being further substituted with 0 to 4 groups selected from H, F, cl, br, I, =o, OH, NH 2 、C 1-4 Alkyl or C 1-4 Substituted with alkoxy;
R k14 selected from 5-6 membered heteroaryl, optionally further substituted with 0 to 4 groups selected from H, F, cl, br, I, OH, = O, CF 3 、CN、C 1-4 Alkyl, halogen substituted C 1-4 Alkyl, hydroxy substituted C 1-4 Alkyl, C 1-4 Alkoxy or C 3-6 A cycloalkyl substituent, said heteroaryl containing 1 to 4 heteroatoms selected from N, O, S;
g is selected from 6-10 membered aryl or 5-10 membered heteroaryl, said aryl or heteroaryl optionally further being 0 to 4 selected from H, F, cl, br, I, OH, = O, CF 3 、CN、C 1-4 Alkyl, halogen substituted C 1-4 Alkyl, hydroxy substituted C 1-4 Alkyl, C 1-4 Alkoxy or C 3-6 A cycloalkyl substituent, said heteroaryl containing 1 to 4 heteroatoms selected from N, O, S;
n1, n2, n3 are each independently selected from 0, 1, 2 or 3;
p1 or p2 are each independently selected from 0, 1, 2, 3, 4 or 5.
2. The compound of claim 1, or a stereoisomer, deuterate, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal thereof, wherein,
l is selected from the group consisting of-Cy 1-Cy2-Ak2-Cy3-Cy4-Ak 4-Cy5-Ak5-, -Cy1-Cy2-Cy3-Cy4-Ak2-Ak3-Ak4-Ak5-, -Cy1-Ak1-Cy2-Ak2-Cy3-Ak3-Cy4-Ak 5-, -Ak1-Cy1-Ak2-Cy2-Ak3-Cy3-Ak4-Cy4-Ak5-, -Cy1-Ak1-Cy2-Ak2-Cy3-Cy4-Ak3-Ak4-Ak5-, -Cy1-Ak 1-2-Ak 2-Ak3-Cy3-Cy4-Ak 5-; -Cy1-Ak1-Ak2-Ak3-Ak4-Ak5-Cy2-Cy3-Cy4-, -Cy1-Cy2-Ak1-Ak2-Ak3-Ak4-Ak5-Cy3-Cy4-, -Cy1-Cy2-Cy3-Ak1-Ak2-Ak3-Ak4-Ak5-Cy4-, -Cy1-Cy2-Cy3-Cy4-Ak1-Ak2-Ak3-Ak4-Ak 5-; -Cy1-Ak1-Cy2-Cy3-Cy4-Ak2-Ak3-Ak4-Ak5-, -Cy1-Cy2-Ak1-Cy3-Cy4-Ak2-Ak3-Ak4-Ak5-, -Cy1-Cy2-Cy3-Ak1-Cy4-Ak2-Ak3-Ak4-Ak5- -Cy1-Ak1-Ak2-Cy2-Cy3-Cy4-Ak3-Ak4-Ak5-, -Cy1-Cy2-Ak1-Ak2-Cy3-Cy4-Ak3-Ak 5-, -Cy1-Cy2-Cy3-Ak1-Ak2-Cy4-Ak3-Ak 5-, -Cy1-Ak1-Ak2-Ak3-Cy2-Cy3-Cy4-Ak4-Ak5-, -Cy1-Ak2-Ak 3-Cy3-Cy4-Ak4-Ak5-, -Cy1-Cy2-Cy3-Ak1-Ak2-Ak3-Cy4-Ak4-Ak5-, -1-Ak 2-Ak3-Ak4-Ak 2-Cy3-Cy4-Ak 5-; -Cy1-Cy2-Ak1-Ak2-Ak3-Ak4-Cy3-Cy4-Ak5-, -Cy1-Cy2-Cy3-Ak1-Ak2-Ak3-Ak4-Cy4-Ak5-, -Ak1-Ak2-Ak3-Ak 2-Cy 5-Cy1-Cy 2-Ak3-Ak4-Ak5-, -Ak1-Ak2-Cy1-Cy2-Cy3-Cy4-Ak3-Ak4-Ak5-, -Ak1-Ak2-Ak3-Cy1-Cy2-Cy3-Cy4-Ak4-Ak5- -Ak1-Ak2-Ak3-Ak4-Cy1-Cy2-Cy3-Cy4-Ak5-, -Ak1-Cy1-Ak2-Ak3-Ak4-Ak5-Cy2-Cy3-Cy4-, -Ak1-Cy1-Cy2-Ak2-Ak3-Ak4-Ak5-Cy3-Cy4-, -Ak1-Cy1-Cy2-Cy3-Ak2-Ak3-Ak4-Ak5-Cy4-, -Ak1-Ak2-Cy1-Ak3-Ak4-Ak5-Cy2-Cy3-Cy4-, -Ak1-Ak2-Cy 2-Ak3-Ak4-Ak5-Cy3-Cy 4-; -Ak1-Ak2-Cy1-Cy2-Cy3-Ak3-Ak4-Ak5-Cy4-, -Ak1-Ak2-Ak3-Cy1-Ak4-Ak5-Cy2-Cy3-Cy4-, -Ak1-Ak2-Ak3-Cy1-Cy2-Ak4-Ak5-Cy3-Cy4-, -Ak1-Ak2-Ak3-Cy1-Cy 3-Ak4-Ak5-Cy4-, -Ak1-Ak2-Ak3-Ak4-Cy1-Ak5-Cy2-Cy 4-, -Ak1-Ak2-Ak3-Ak4-Cy1-Cy2-Ak5-Cy3-Cy4- Ak1-Ak2-Ak3-Ak4-Cy1-Cy2-Cy3-Ak5-Cy4-;
Ak1, ak2, ak3, ak4, ak5 are each independently selected from- (CH) 2 ) q -、-(CH 2 ) q -O-、-O-(CH 2 ) q -、-(CH 2 ) q -NR L -、-NR L -(CH 2 ) q -、-(CH 2 )q-NR L C(=O)-、-(CH 2 ) q -C(=O)NR L -、-C(=O)-、-C(=O)-(CH 2 ) q -NR L -、-(C≡C) q -or a bond, said-CH 2 Optionally further 0 to 2 are selected from H, halogen, OH, CN, NH 2 、C 1-4 Alkyl, C 1-4 Alkoxy, halogen substituted C 1-4 Alkyl, hydroxy substituted C 1-4 Alkyl-and cyano-substituted C 1-4 Substituted by alkyl;
cy1, cy2, cy3, cy4 or Cy5 are each independently selected from the group consisting of a bond, 4-7 membered heteromonocyclic ring, 4-10 membered heterobicyclic ring, 5-12 membered heterospiro ring, 7-10 membered heterobridged ring, 3-7 membered monocycloalkyl, 4-10 membered heterocycloalkyl, 5-12 membered spirocycloalkyl, 7-10 membered bridged cycloalkyl, 5-10 membered heteroaryl or 6-10 membered aryl, said aryl, heteroaryl, cycloalkyl, heteromonocyclic ring, heterofused ring, heterospiro ring or heterobridged ring optionally further being selected from 0 to 4 from H, F, cl, br, I, OH, COOH, CN, NH 2 、=O、C 1-4 Alkyl, halogen substituted C 1-4 Alkyl, hydroxy substituted C 1-4 Alkyl or C 1-4 A substituent of an alkoxy group, said heteroaryl, heteromonocyclic, heterobicyclic, heterospiro, or heterobridged ring containing from 1 to 4 heteroatoms selected from O, S, N, optionally further substituted with 0, 1, or 2 = O when the heteroatom is selected from S;
q is each independently selected from 0, 1, 2, 3 or 4;
R L each independently selected from H or C 1-6 An alkyl group;
B 1 Selected from phenyl, 5-6 membered mono heteroaryl or 9-10 membered fused ring heterocyclyl, said heteroaryl or heterocyclyl containing 1 to 4 heteroatoms selected from O, S, N;
ring W is selected from a 5-6 membered monocyclic heteroaryl ring or a 9-10 membered fused ring heteroaryl ring containing 1 to 5 heteroatoms selected from O, S, N.
3. The compound of claim 2, or a stereoisomer, deuterate, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal thereof, wherein,
cy1, cy2, cy3, cy4 or Cy5 are each independently selected from the group consisting of a bond, a 4-7 membered nitrogen containing heteromonocyclic ring, a 4-10 membered nitrogen containing heteromonocyclic ring, a 5-12 membered nitrogen containing heterospiro ring, a 7-10 membered nitrogen containing heterobridged ring, a 3-7 membered monocycloalkyl, a 4-10 membered cycloalkyl, a 5-12 membered spirocycloalkyl, a 7-10 membered bridged cycloalkyl, a 5-10 membered heteroaryl or a 6-10 membered aryl, said heteromonocyclic ring, heterofused ring, heterobridged ring, heterospiro ring, cycloalkyl, aryl or heteroaryl optionally being further substituted with 0 to 4 members selected from H, F, cl, br, I, OH, COOH, CN, NH 2 、=O、C 1-4 Alkyl, halogen substituted C 1-4 Alkyl, hydroxy substituted C 1-4 Alkyl or C 1-4 A substituent of an alkoxy group, said heteromonocyclic, heterobicyclic, heterobridged, heterospiro or heteroaryl group containing from 1 to 4 heteroatoms selected from O, S, N, optionally further substituted with 0, 1 or 2 = O when the heteroatoms are selected from S;
R L Each independently selected from H or C 1-4 An alkyl group;
B 1 selected from phenyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, triazinyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, oxazolyl, isoxazolyl, furanyl, thienyl, thiazolyl, benzopyrrolyl, benzopyrazolyl, benzofuranyl, benzothienyl, benzothiazolyl, benzimidazolyl, pyridopyrrolyl, quinolinyl, isoquinolinyl, quinazolinyl, quinoxalinyl, benzopiperidinyl, benzopyranyl, or benzopyranyl;
ring W is selected from pyridinyl, pyrimidinyl, pyridazinyl, pyridazinonyl, pyrazinyl, triazinyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, oxazolyl, isoxazolyl, furanyl, thienyl, thiazolyl, benzopyrrolyl, benzopyrazolyl, benzimidazolyl, pyridopyrrolyl;
R b1 、R b2 each independently selected from H, F, cl, br, I, =o, OH, NH 2 、CN、NO 2 、CF 3 、CHF 2 、COOH、
NHCH 3 、NHCH 2 CH 3 、NHCH(CH 3 ) 2 、N(CH 3 ) 2 、N(CH 2 CH 3 ) 2 、NHC(=O)CH 3 、NHS(=O) 2 CH 3 、
Methyl, ethyl, isopropyl, vinyl, ethynyl, methoxy, ethoxy, propoxy, isopropoxy, morpholinyl, piperazinyl, pyrrolidinyl, piperidinyl or oxazolidinyl, said methyl, ethyl, vinyl, isopropyl, ethynyl, methoxy, ethoxy, propoxy, isopropoxy, morpholinyl, piperazinyl, pyrrolidinyl, piperidinyl or oxazolidinyl optionally being further substituted with 0 to 4 groups selected from H, F, cl, br, I, OH, CN, CF 3 、NH 2 Is substituted by a substituent of (2);
R b3 selected from H, methyl, ethyl, propyl or isopropyl, said methyl, ethyl, propyl or isopropyl optionally being further substituted with 0 to 4 members selected from H, F, cl, br, I, OH, CN, CF 3 、NH 2 Is substituted by a substituent of (2);
R b4 selected from H, OH, NH 2 、NHCH 3 、NHCH 2 CH 3 、NHCH(CH 3 ) 2 、N(CH 3 ) 2 、N(CH 2 CH 3 ) 2 、NHC(=O)
CH 3 Methyl, ethyl, isopropyl, methoxy, ethoxy, propoxy or isopropoxy, said methyl, ethyl, isopropyl, methoxy, ethoxy, propoxy or isopropoxy optionally further being 0 to 4 selected from H, F, cl, br, I, OH, CN, CF 3 、NH 2 Is substituted by a substituent of (2);
or R is b3 、R b4 The carbon atoms to which they are attached together form cyclopropyl, cyclobutyl, cyclopentyl, azetidinyl, oxetanyl, the cyclopropyl, cyclobutyl, cyclopentyl, azetidinyl, oxetanyl, oxepinylThe radicals are optionally further substituted with 0 to 4 radicals selected from H, F, cl, br, I, OH, NH 2 A substituent of =o, methyl, ethyl, isopropyl, methoxy, ethoxy or propoxy;
k is selected from
Represents a ring selected from aromatic or non-aromatic rings;
M 2 Selected from-NHC (=o) -C 1-4 Alkyl, -NHC (=o) -C 3-6 Cycloalkyl or 4-10 membered heterocyclyl, said alkyl, cycloalkyl or heterocyclyl optionally being further substituted with 0 to 4 substituents selected from H, F, cl, br, I, =o, OH, NH 2 、C 1-4 Alkyl or C 1-4 A substituent of an alkoxy group, the heterocyclic group containing 1 to 4 heteroatoms selected from O, S, N;
R k10 selected from C 1-4 Alkyl optionally further substituted with 0 to 4 groups selected from H, F, cl, br, I, =o, OH, C 1-4 Alkyl or C 3-6 Substituted cycloalkyl;
R k11 each independently selected from H, F, cl, br, I, = O, OH, SH, C 1-4 Alkyl, C 1-4 Alkoxy or C 1-4 Alkylthio or-O-C (=o) -C 1-4 Alkyl, said alkyl, alkoxy or alkylthio being optionally further substituted with 0 to 4 groups selected from H, F, cl, br, I, OH, C 1-4 Alkyl or C 1-4 Substituted with alkoxy;
R k12 、R k13 each independently selected from H, C 1-4 Alkyl or C 3-6 A cycloalkyl group,said alkyl or cycloalkyl optionally being further substituted with 0 to 4 groups selected from H, F, cl, br, I, =o, OH, NH 2 、C 1-4 Alkyl or C 1-4 Substituted with alkoxy;
q is each independently selected from-O-, -S-, -CH 2 -、-NR q -、-CO-、-NR q CO-、-CONR q -or a 4-7 membered heterocyclyl, said heterocyclyl optionally being further substituted with 0 to 4 substituents selected from H, F, cl, br, I, OH, = O, NH 2 、CN、COOH、CONH 2 、C 1-4 Alkyl or C 1-4 A substituent of an alkoxy group, the heterocyclic group containing 1 to 4 heteroatoms selected from O, S, N;
R q selected from H or C 1-4 An alkyl group;
R k1 、R k3 each independently selected from H, F, cl, br, I, OH, = O, NH 2 、CF 3 、CN、COOH、CONH 2 、C 1-4 Alkyl or C 1-4 Alkoxy, said alkyl or alkoxy optionally being further substituted with 0 to 4 groups selected from H, F, cl, br, I, OH, NH 2 Is substituted by a substituent of (2);
or two R k3 And the carbon atoms or ring skeletons directly linked to each other together form a 3-6 membered carbocycle or a 3-7 membered heterocycle, said carbocycle or heterocycle optionally being further substituted with 0 to 4 groups selected from H, F, cl, br, I, OH, = O, NH 2 、CN、COOH、CONH 2 、C 1-4 Alkyl or C 1-4 A substituent of an alkoxy group, said heterocycle containing 1 to 4 heteroatoms selected from O, S, N;
R k4 each independently selected from H, OH, NH 2 、CF 3 、CN、C 1-4 An alkyl group;
R k5 each independently selected from CO, CH 2 、SO 2 Or (b)
R k6 Each independently selected from CO, CH, SO, SO 2 、CH 2 Or N;
R k7 each independently selected from CO, CH,N、CH 2 、O、S、N(CH 3 ) Or NH;
R k8 each independently selected from C, N or CH;
R k9 each independently selected from CO, CH 2 Or SO 2 ;
A. H1 or H2 are each independently selected from C 3-8 A carbocycle, benzene ring, 4-7 membered heterocycle or 5-6 membered heteroaryl, said heterocycle or heteroaryl containing 1 to 4 heteroatoms selected from O, S, N;
e is each independently selected from C 3-8 A carbocycle, a benzene ring, a 4-7 membered heterocycle, an 8-12 membered heterocyclyl, a 7-12 membered heteroaryl or a 5-6 membered heteroaryl, said heterocycle or heteroaryl containing 1 to 4 heteroatoms selected from O, S, N;
F is each independently selected from 3-7 membered monocycloalkyl, 4-10 membered cycloalkyl, 5-12 membered spirocycloalkyl, 5-10 membered bridged cycloalkyl, 4-7 membered heteromonocyclic, 4-10 membered heteroacene, 5-12 membered heterospirocyclic, 5-10 membered heterobridged ring, C 6-14 Aryl or 5-10 membered heteroaryl, said heteromonocyclic, heterobicyclic, heterospiro, heterobridged or heteroaryl containing 1 to 4 heteroatoms selected from O, S, N.
4. The compound of claim 3, or a stereoisomer, deuterate, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal thereof, wherein,
R L selected from H, methyl or ethyl;
q is each independently selected from 0, 1 or 2;
cy1, cy2, cy3, cy4 or Cy5 are each independently selected from a bond or one of the following substituted or unsubstituted groups: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, azacyclyl, azacyclohexenyl, piperidine, morpholine, piperazine, phenyl, cyclopropyl-and-cyclopropyl, cyclopropyl-and-cyclobutyl, cyclobutyl-and-cyclopentyl, cyclobutyl-and-cyclohexyl, cyclopentyl-and-cyclopentyl, cyclopentyl-and-cyclohexyl, cyclohexyl-and-cyclohexyl, cyclopropyl-and-spirobutyl, cyclopropyl-and-spirocyclopentyl, cyclopropyl-and-spirocyclohexyl, cyclobutyl-and-spirobutyl, cyclobutyl-and-spiropentyl, cyclobutyl-and-spirocyclohexyl, cyclopentyl-and-spiropentyl, cyclopentyl-and-spirocyclohexyl, cyclohexyl-and-spirocyclohexyl, cyclopropyl-and-azacyclobutyl, cyclobutyl-and-azacyclohexyl, cyclopropyl-and-piperidine, cyclobutyl-and-azacyclopentyl cyclobutyl azetidinyl, cyclobutyl piperidine, cyclopentyl azetidinyl, cyclopentyl piperidine, cyclohexyl azetidinyl, cyclopentyl azeted, cyclopentyl azetidinyl, cyclopentyl azeted, cyclohexyl azeted, cyclohexyl cyclohexyl-azetidinyl, cyclohexyl-piperidine, azetidinyl-yl azetidinopiperidine, azetidinoazetidine, azetidinoazeyl, azetidinopiperidine, azetidinoazetidine, azetidino-azacyclopentyl, azetidino-azacyclohexyl, azetidinopiperidine, cyclobutylspiroazetidine, cyclobutylspiroazetidinyl, cyclopentyl spiroazetidinyl, cyclohexyl spiroazetidinyl, cyclohexyl spiroazetidinyl, azetidinyl spiroazetidinyl, and an azacyclopentyl spiroazacyclopentyl, an azacyclopentyl spiroazacyclohexyl, an azacyclyl spiroazacyclobutyl, an azacyclyl spiroazacyclopentyl, an azacyclyl spiroazacyclyl cyclobutyl spiropiperidine, cyclopentyl spiropiperidine, cyclohexyl spiropiperidine, azetidinyl spiropiperidine, cyclohexyl spiropiperidine,
When substituted, optionally further substituted with 0 to 4 members selected from H, F, cl, br, I, OH, NH 2 、COOH、CN、=O、C 1-4 Alkyl, halogen substituted C 1-4 Alkyl, hydroxy substituted C 1-4 Alkyl or C 1-4 Substituted with alkoxy;
b is selected from
m1 and m2 are respectively and independently selected from 0, 1 and 2;
y is independently selected from S or O;
X 1 、X 2 、X 3 、X 4 、X 5 each independently selected from CR b2 Or N;
B 1 selected from phenyl, pyridyl, quinolinyl, isoquinolinyl, benzopiperidinyl or benzopyran;
k is selected from
M1 is selected from the group consisting of bond, -C (=O) NH-, -CH 2 -C(=O)NH-、-C(=O)CH 2 NH-, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, oxazolyl, isoxazolyl, furanyl, thienyl, thiazolyl;
M 2 selected from-NHC (=O) -CH 3 -NHC (=o) -cyclopropyl, -NHC (=o) -cyclobutyl, azetidinyl, benzazetidinyl, said cyclopropyl, cyclobutyl, azetidinyl, benzazetidinyl or benzazetidinyl optionally being further substituted with 0 to 4 groups selected from H, F, cl, br,I、=O、OH、NH 2 、C 1-4 Alkyl or C 1-4 Substituted with alkoxy;
R k10 selected from methyl, ethyl, isopropyl, propyl, tert-butyl, said methyl, ethyl, isopropyl, propyl, tert-butyl optionally further being 0 to 4 selected from H, F, cl, br, I, =o, OH, C 1-4 Alkyl or C 3-6 Substituted cycloalkyl;
R k11 each independently selected from H, F, cl, br, I, =o, OH, SH, methyl, ethyl, isopropyl, propyl, methoxy, ethoxy, propoxy, isopropoxy, methylthio, ethylthio, propylthio or-O-C (=o) -CH 3 Said methyl, ethyl, isopropyl, propyl, methoxy, ethoxy, propoxy, isopropoxy, methylthio, ethylthio, propylthio optionally further being 0 to 4 groups selected from H, F, cl, br, I, OH, C 1-4 Alkyl or C 1-4 Substituted with alkoxy;
R k12 、R k13 each independently selected from H, methyl, ethyl, isopropyl, propyl, cyclopropyl or cyclobutyl, optionally further substituted with 0 to 4 groups selected from H, F, cl, br, I, =o, OH, NH 2 、C 1-4 Alkyl or C 1-4 Substituted with alkoxy;
e is each independently selected from phenyl, pyridyl, pyridazinyl, pyrazinyl, pyrimidinyl, pyrrolyl, pyrazolyl, imidazolyl, thiazolyl, furanyl, thienyl or oxazolyl;
each a is independently selected from phenyl, pyridyl, pyridazinyl, pyrazinyl, pyrimidinyl, pyrrolyl, pyrazolyl, imidazolyl, thiazolyl, furanyl, thienyl or oxazolyl;
F is each independently selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, bicyclo [1.1.1] pentyl, 6, 7-dihydro-5H-cyclopenta [ c ] pyridinyl, 2, 3-dihydro-1H-indenyl, phenyl, naphthyl, anthracenyl, phenanthrenyl, azetidinyl, azacyclopentyl, piperidinyl, morpholinyl, pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl, triazinyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, oxazolyl, furanyl, thienyl, thiazolyl, benzimidazolyl, benzopyrazolyl, benzothiazolyl, benzothienyl, benzofuranyl, benzopyrrolyl, benzopyridyl benzopyrazinyl, benzopyrimidinyl, benzopyridazinyl, pyrrolopyrrolyl, pyrrolopyridinyl, pyrrolopyridazinyl, pyrrolopyrazinyl, imidazopyrimidinyl, imidazopyridinyl, imidazopyrazinyl, imidazopyridazinyl, pyrazolopyridinyl, pyrazolopyrimidinyl, pyrazolopyrazinyl, pyrimidopyridinyl, pyrimidopyrazinyl, pyrimidopyridazinyl, pyrimidopyrimidinyl, pyridopyridinyl, pyridopyrazinyl, pyridopyridazinyl, pyridazinopyrazinyl or pyrazinopyrazinyl;
R k7 Each independently selected from CH 2 、O、N(CH 3 ) Or NH;
p1 or p2 are each independently selected from 0, 1 or 2.
5. The compound of claim 4, or a stereoisomer, deuterate, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal thereof, wherein,
cy1, cy2, cy3, cy4 or Cy5 are each independently selected from a bond or one of the following substituted or unsubstituted groups:
when substituted, optionally further substituted with 0 to 4 members selected from H, F, CF 3 Methyl, =o, hydroxymethyl, COOH, CN or NH 2 Is substituted by a substituent of (2);
R b1 each independently selected from H, F, cl, br, I, OH, CN, NO 2 、CF 3 、CHF 2 、CH 2 F. Methyl, ethylIsopropyl, said methyl, ethyl, isopropyl optionally further being 0 to 4 selected from H, F, cl, br, I, OH, CN, CF 3 、NH 2 Is substituted by a substituent of (2);
R b2 each independently selected from H, F, cl, br, I, OH, NH 2 、CN、NO 2 、CF 3 、CHF 2 、COOH、NHCH 3 、N(CH 3 ) 2 Methyl, ethyl, isopropyl, methoxy, ethoxy, propoxy or isopropoxy, said methyl, ethyl, isopropyl, methoxy, ethoxy, propoxy or isopropoxy optionally further being 0 to 4 selected from H, F, cl, br, I, OH, CN, CF 3 、NH 2 Is substituted by a substituent of (2);
k is selected from one of the following structural fragments:
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6. The compound of claim 5, or a stereoisomer, deuterate, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal thereof, wherein,
l is selected from the group consisting of-Cy 1-, -Cy1-Ak1-Ak2-Ak3-Ak 4-; -Cy1-Cy2-, -Cy1-Ak1-Cy2-, -Cy1-Cy2-Ak2-, -Cy1-Ak1-Cy2-Ak2-, -Cy1-Ak1-Cy2-Ak2-Ak3-, -Cy1-Ak1-Cy2-Ak2-Ak3-Ak4-, -Cy1-Cy2-Ak2-Ak3-Ak4-, -Cy1-Ak1-Cy2-Ak2-Ak3-Ak 4-; -Cy1-Ak1-Ak2-Cy3-, -Cy1-Ak1-Ak2-Cy3-Ak3-, -Cy1-Cy2-Cy3-, -Cy1-Ak1-Cy2-Cy3-, -Cy1-Cy2-Ak2-Cy3-, -Cy1-Ak1-Cy2-Cy3-Ak3-, -Cy1-Cy2-Ak 3-, -Cy1-Ak1-Cy2-Ak 3-, -Cy1-Ak 2-Ak3-, -Cy2-Cy3-Ak3-Ak4- -Cy1-Cy2-Cy3-Ak3-Cy4-, -Cy1-Cy2-Cy3-Cy4-, -Cy1-Ak1-Cy2-Cy3-Cy4-, -Cy1-Cy2-Cy3-Cy4-Ak4-, -Cy1-Ak1-Cy2-Ak2-Cy3-Ak3-Cy4-, -Cy1-Ak1-Cy2-Ak2-Cy3-Cy4-, -Ak1-Cy2-Cy3-, -Ak1-Ak2-Cy3-Cy 4-; -Ak1-Cy2-Ak2-Cy3-, -Ak1-Cy2-Cy3-Ak3-Cy4-, -Ak1-Cy2-Cy3-Cy4-Ak4-Cy5-, -Ak1-Cy2-Ak2-, -Ak1-Ak2-Ak 4-, -Ak1-Ak2-Ak3-Ak4-Ak5-, -Cy1-Cy2-Cy3-Ak3-Ak4-Ak5-, -Cy1-Cy2-Ak2-Cy3-Ak3-Ak4-Ak5-, -Cy1-Ak 2-Ak3-Ak4-Ak5- -Cy1-Cy2-Cy3-Cy4-Ak4-Ak5-, -Cy1-Ak1-Ak2-Ak3-Ak4-Ak5-, -Ak1-Cy2-Ak 3-Ak4-Ak5-, -Ak1-Cy2-Ak 3-Ak4-, -Ak1-Cy2-Ak 3-;
Ak1, ak2, ak3, ak4, ak5 are each independently selected from the group consisting of-O-, -OCH 2 -、-CH 2 O-、-OCH 2 CH 2 -、-CH 2 CH 2 O-、-C≡C-、-C(CH 3 ) 2 -、-CH 2 -、-CH 2 CH 2 -、-CH 2 CH 2 CH 2 -、-N(CH 3 )-、-NH-、-CH 2 N(CH 3 )-、-CH 2 NH-、-NHCH 2 -、-CH 2 CH 2 N(CH 3 )-、-CH 2 CH 2 NH-、-NHCH 2 CH 2 -、-C(=O)-、-C(=O)CH 2 NH-、-CH 2 C (=o) NH-, -C (=o) NH-, or-NHC (=o) -.
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