CN103804358A - Biaryl hydantoin derivate and preparation method, medicine composition and application thereof - Google Patents
Biaryl hydantoin derivate and preparation method, medicine composition and application thereof Download PDFInfo
- Publication number
- CN103804358A CN103804358A CN201310567203.4A CN201310567203A CN103804358A CN 103804358 A CN103804358 A CN 103804358A CN 201310567203 A CN201310567203 A CN 201310567203A CN 103804358 A CN103804358 A CN 103804358A
- Authority
- CN
- China
- Prior art keywords
- alkyl
- compound
- tautomer
- prodrug
- solvate
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
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- 239000003814 drug Substances 0.000 title claims abstract description 12
- -1 Biaryl hydantoin Chemical compound 0.000 title claims description 97
- 238000002360 preparation method Methods 0.000 title abstract description 37
- 239000000203 mixture Substances 0.000 title abstract description 36
- 229940091173 hydantoin Drugs 0.000 title 1
- 150000001875 compounds Chemical class 0.000 claims abstract description 126
- 150000003839 salts Chemical class 0.000 claims abstract description 58
- 239000002207 metabolite Substances 0.000 claims abstract description 50
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims abstract description 15
- 201000010099 disease Diseases 0.000 claims abstract description 14
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims description 69
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 54
- 239000000651 prodrug Substances 0.000 claims description 49
- 229940002612 prodrug Drugs 0.000 claims description 49
- 239000012453 solvate Substances 0.000 claims description 49
- 108010080146 androgen receptors Proteins 0.000 claims description 36
- 102000001307 androgen receptors Human genes 0.000 claims description 36
- 229910052736 halogen Inorganic materials 0.000 claims description 31
- 150000002367 halogens Chemical class 0.000 claims description 31
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 30
- 229910052757 nitrogen Inorganic materials 0.000 claims description 28
- 125000004432 carbon atom Chemical group C* 0.000 claims description 26
- 125000000217 alkyl group Chemical group 0.000 claims description 25
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 25
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 24
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 22
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 21
- 206010060862 Prostate cancer Diseases 0.000 claims description 18
- 208000000236 Prostatic Neoplasms Diseases 0.000 claims description 18
- 125000000229 (C1-C4)alkoxy group Chemical group 0.000 claims description 17
- 239000008194 pharmaceutical composition Substances 0.000 claims description 16
- 125000003118 aryl group Chemical group 0.000 claims description 15
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 15
- 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 claims description 15
- 125000004186 cyclopropylmethyl group Chemical group [H]C([H])(*)C1([H])C([H])([H])C1([H])[H] 0.000 claims description 15
- 229910052731 fluorine Inorganic materials 0.000 claims description 15
- 125000003341 7 membered heterocyclic group Chemical group 0.000 claims description 14
- 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 claims description 13
- 125000004850 cyclobutylmethyl group Chemical group C1(CCC1)C* 0.000 claims description 12
- 125000005843 halogen group Chemical group 0.000 claims description 12
- 125000001072 heteroaryl group Chemical group 0.000 claims description 12
- 229910052739 hydrogen Inorganic materials 0.000 claims description 12
- 229910052760 oxygen Inorganic materials 0.000 claims description 12
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 claims description 11
- 229910052805 deuterium Inorganic materials 0.000 claims description 11
- 229910052717 sulfur Inorganic materials 0.000 claims description 10
- 125000004191 (C1-C6) alkoxy group Chemical group 0.000 claims description 9
- 125000004429 atom Chemical group 0.000 claims description 9
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 claims description 9
- 125000000623 heterocyclic group Chemical group 0.000 claims description 9
- 125000003566 oxetanyl group Chemical group 0.000 claims description 9
- 229910052801 chlorine Inorganic materials 0.000 claims description 8
- 125000004431 deuterium atom Chemical group 0.000 claims description 8
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 8
- 229910052794 bromium Inorganic materials 0.000 claims description 7
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 7
- 125000006273 (C1-C3) alkyl group Chemical group 0.000 claims description 6
- 125000004070 6 membered heterocyclic group Chemical group 0.000 claims description 6
- 125000002393 azetidinyl group Chemical group 0.000 claims description 6
- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 claims description 6
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 6
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 6
- 206010006187 Breast cancer Diseases 0.000 claims description 5
- 208000026310 Breast neoplasm Diseases 0.000 claims description 5
- 125000000051 benzyloxy group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])O* 0.000 claims description 5
- 208000002874 Acne Vulgaris Diseases 0.000 claims description 4
- 201000004384 Alopecia Diseases 0.000 claims description 4
- 206010000496 acne Diseases 0.000 claims description 4
- 238000004519 manufacturing process Methods 0.000 claims description 4
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 4
- 206010020112 Hirsutism Diseases 0.000 claims description 3
- 208000035150 Hypercholesterolemia Diseases 0.000 claims description 3
- 206010024419 Libido decreased Diseases 0.000 claims description 3
- 208000007466 Male Infertility Diseases 0.000 claims description 3
- 206010057672 Male sexual dysfunction Diseases 0.000 claims description 3
- 208000008589 Obesity Diseases 0.000 claims description 3
- 208000001132 Osteoporosis Diseases 0.000 claims description 3
- 125000003277 amino group Chemical group 0.000 claims description 3
- 208000007502 anemia Diseases 0.000 claims description 3
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 3
- 230000002710 gonadal effect Effects 0.000 claims description 3
- 125000004970 halomethyl group Chemical group 0.000 claims description 3
- 210000003205 muscle Anatomy 0.000 claims description 3
- 235000020824 obesity Nutrition 0.000 claims description 3
- 125000004430 oxygen atom Chemical group O* 0.000 claims description 3
- 229940124531 pharmaceutical excipient Drugs 0.000 claims description 3
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims description 2
- 239000011737 fluorine Substances 0.000 claims description 2
- 125000001153 fluoro group Chemical group F* 0.000 claims description 2
- 206010020718 hyperplasia Diseases 0.000 claims description 2
- 230000003676 hair loss Effects 0.000 claims 1
- 210000002307 prostate Anatomy 0.000 claims 1
- LMBFAGIMSUYTBN-MPZNNTNKSA-N teixobactin Chemical compound C([C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H](CCC(N)=O)C(=O)N[C@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H]1C(N[C@@H](C)C(=O)N[C@@H](C[C@@H]2NC(=N)NC2)C(=O)N[C@H](C(=O)O[C@H]1C)[C@@H](C)CC)=O)NC)C1=CC=CC=C1 LMBFAGIMSUYTBN-MPZNNTNKSA-N 0.000 claims 1
- 239000002904 solvent Chemical class 0.000 abstract description 53
- 229940079593 drug Drugs 0.000 abstract description 5
- 108091008039 hormone receptors Proteins 0.000 abstract 1
- 239000000543 intermediate Substances 0.000 description 247
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 207
- 239000007787 solid Substances 0.000 description 106
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 104
- 238000005160 1H NMR spectroscopy Methods 0.000 description 96
- 238000006243 chemical reaction Methods 0.000 description 71
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 50
- 230000002829 reductive effect Effects 0.000 description 49
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 45
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 42
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 39
- 239000000243 solution Substances 0.000 description 37
- OKKJLVBELUTLKV-MZCSYVLQSA-N Deuterated methanol Chemical compound [2H]OC([2H])([2H])[2H] OKKJLVBELUTLKV-MZCSYVLQSA-N 0.000 description 30
- 238000003818 flash chromatography Methods 0.000 description 29
- 239000003921 oil Substances 0.000 description 27
- 238000004809 thin layer chromatography Methods 0.000 description 27
- 239000003208 petroleum Substances 0.000 description 26
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 25
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 22
- 238000001816 cooling Methods 0.000 description 21
- 238000000034 method Methods 0.000 description 20
- 238000003756 stirring Methods 0.000 description 19
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 16
- 210000004027 cell Anatomy 0.000 description 16
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 16
- CSCPPACGZOOCGX-MICDWDOJSA-N 1-deuteriopropan-2-one Chemical compound [2H]CC(C)=O CSCPPACGZOOCGX-MICDWDOJSA-N 0.000 description 14
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 14
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 14
- 229940125904 compound 1 Drugs 0.000 description 14
- 238000001704 evaporation Methods 0.000 description 14
- 239000012074 organic phase Substances 0.000 description 14
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 13
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 12
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 12
- 239000010410 layer Substances 0.000 description 11
- 239000003480 eluent Substances 0.000 description 10
- 230000005764 inhibitory process Effects 0.000 description 10
- 239000011734 sodium Substances 0.000 description 10
- TYXKOMAQTWRDCR-UHFFFAOYSA-N 4-isothiocyanato-2-(trifluoromethyl)benzonitrile Chemical compound FC(F)(F)C1=CC(N=C=S)=CC=C1C#N TYXKOMAQTWRDCR-UHFFFAOYSA-N 0.000 description 9
- 238000005406 washing Methods 0.000 description 9
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 8
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 8
- 230000004913 activation Effects 0.000 description 8
- 239000007864 aqueous solution Substances 0.000 description 8
- 230000000694 effects Effects 0.000 description 8
- WXCXUHSOUPDCQV-UHFFFAOYSA-N enzalutamide Chemical compound C1=C(F)C(C(=O)NC)=CC=C1N1C(C)(C)C(=O)N(C=2C=C(C(C#N)=CC=2)C(F)(F)F)C1=S WXCXUHSOUPDCQV-UHFFFAOYSA-N 0.000 description 8
- 239000005457 ice water Substances 0.000 description 8
- 125000002950 monocyclic group Chemical group 0.000 description 8
- 238000013518 transcription Methods 0.000 description 8
- 230000035897 transcription Effects 0.000 description 8
- XEEYBQQBJWHFJM-UHFFFAOYSA-N Iron Chemical compound [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 description 7
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 description 7
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 7
- 239000003098 androgen Substances 0.000 description 7
- 239000000460 chlorine Substances 0.000 description 7
- 239000012043 crude product Substances 0.000 description 7
- 150000001975 deuterium Chemical group 0.000 description 7
- 229960004671 enzalutamide Drugs 0.000 description 7
- 238000000605 extraction Methods 0.000 description 7
- 125000005842 heteroatom Chemical group 0.000 description 7
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical class [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 7
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 6
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 6
- 229960000583 acetic acid Drugs 0.000 description 6
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical group [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 6
- 125000002619 bicyclic group Chemical group 0.000 description 6
- 239000012091 fetal bovine serum Substances 0.000 description 6
- 238000001914 filtration Methods 0.000 description 6
- INQOMBQAUSQDDS-UHFFFAOYSA-N iodomethane Chemical compound IC INQOMBQAUSQDDS-UHFFFAOYSA-N 0.000 description 6
- BHIWKHZACMWKOJ-UHFFFAOYSA-N methyl isobutyrate Chemical compound COC(=O)C(C)C BHIWKHZACMWKOJ-UHFFFAOYSA-N 0.000 description 6
- 239000011259 mixed solution Substances 0.000 description 6
- IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Substances N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 6
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 description 6
- 239000001301 oxygen Chemical group 0.000 description 6
- 108090000623 proteins and genes Proteins 0.000 description 6
- 238000010992 reflux Methods 0.000 description 6
- 229910000104 sodium hydride Inorganic materials 0.000 description 6
- 238000012360 testing method Methods 0.000 description 6
- UNILWMWFPHPYOR-KXEYIPSPSA-M 1-[6-[2-[3-[3-[3-[2-[2-[3-[[2-[2-[[(2r)-1-[[2-[[(2r)-1-[3-[2-[2-[3-[[2-(2-amino-2-oxoethoxy)acetyl]amino]propoxy]ethoxy]ethoxy]propylamino]-3-hydroxy-1-oxopropan-2-yl]amino]-2-oxoethyl]amino]-3-[(2r)-2,3-di(hexadecanoyloxy)propyl]sulfanyl-1-oxopropan-2-yl Chemical compound O=C1C(SCCC(=O)NCCCOCCOCCOCCCNC(=O)COCC(=O)N[C@@H](CSC[C@@H](COC(=O)CCCCCCCCCCCCCCC)OC(=O)CCCCCCCCCCCCCCC)C(=O)NCC(=O)N[C@H](CO)C(=O)NCCCOCCOCCOCCCNC(=O)COCC(N)=O)CC(=O)N1CCNC(=O)CCCCCN\1C2=CC=C(S([O-])(=O)=O)C=C2CC/1=C/C=C/C=C/C1=[N+](CC)C2=CC=C(S([O-])(=O)=O)C=C2C1 UNILWMWFPHPYOR-KXEYIPSPSA-M 0.000 description 5
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 5
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 5
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 description 5
- 239000012980 RPMI-1640 medium Substances 0.000 description 5
- NPXOKRUENSOPAO-UHFFFAOYSA-N Raney nickel Chemical compound [Al].[Ni] NPXOKRUENSOPAO-UHFFFAOYSA-N 0.000 description 5
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 5
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 5
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical class OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 5
- 239000002253 acid Substances 0.000 description 5
- 239000005557 antagonist Substances 0.000 description 5
- 239000003054 catalyst Substances 0.000 description 5
- 238000001514 detection method Methods 0.000 description 5
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- 230000002401 inhibitory effect Effects 0.000 description 5
- 239000012044 organic layer Substances 0.000 description 5
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- 238000012746 preparative thin layer chromatography Methods 0.000 description 5
- 239000012312 sodium hydride Substances 0.000 description 5
- 125000001424 substituent group Chemical group 0.000 description 5
- RGJCJWXNNDARPQ-UHFFFAOYSA-N 5-amino-2,3-dihydroisoindol-1-one Chemical compound NC1=CC=C2C(=O)NCC2=C1 RGJCJWXNNDARPQ-UHFFFAOYSA-N 0.000 description 4
- PCLIMKBDDGJMGD-UHFFFAOYSA-N N-bromosuccinimide Chemical compound BrN1C(=O)CCC1=O PCLIMKBDDGJMGD-UHFFFAOYSA-N 0.000 description 4
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical group [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 4
- MUMGGOZAMZWBJJ-DYKIIFRCSA-N Testostosterone Chemical compound O=C1CC[C@]2(C)[C@H]3CC[C@](C)([C@H](CC4)O)[C@@H]4[C@@H]3CCC2=C1 MUMGGOZAMZWBJJ-DYKIIFRCSA-N 0.000 description 4
- 229910052786 argon Inorganic materials 0.000 description 4
- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 description 4
- 229910000024 caesium carbonate Inorganic materials 0.000 description 4
- 229910052799 carbon Inorganic materials 0.000 description 4
- 125000004122 cyclic group Chemical group 0.000 description 4
- 239000012065 filter cake Substances 0.000 description 4
- 239000001257 hydrogen Substances 0.000 description 4
- 239000003446 ligand Substances 0.000 description 4
- 238000002156 mixing Methods 0.000 description 4
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 4
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- 238000007747 plating Methods 0.000 description 4
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- 239000011593 sulfur Chemical group 0.000 description 4
- 239000006228 supernatant Substances 0.000 description 4
- 238000002560 therapeutic procedure Methods 0.000 description 4
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 4
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical class [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 3
- 206010004446 Benign prostatic hyperplasia Diseases 0.000 description 3
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 3
- 108060001084 Luciferase Proteins 0.000 description 3
- 239000005089 Luciferase Substances 0.000 description 3
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 description 3
- 206010028980 Neoplasm Diseases 0.000 description 3
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 3
- 208000004403 Prostatic Hyperplasia Diseases 0.000 description 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
- 230000009471 action Effects 0.000 description 3
- 125000003545 alkoxy group Chemical group 0.000 description 3
- 231100000360 alopecia Toxicity 0.000 description 3
- 229910021529 ammonia Inorganic materials 0.000 description 3
- 230000002280 anti-androgenic effect Effects 0.000 description 3
- 239000000051 antiandrogen Substances 0.000 description 3
- HJBWBFZLDZWPHF-UHFFFAOYSA-N apalutamide Chemical compound C1=C(F)C(C(=O)NC)=CC=C1N1C2(CCC2)C(=O)N(C=2C=C(C(C#N)=NC=2)C(F)(F)F)C1=S HJBWBFZLDZWPHF-UHFFFAOYSA-N 0.000 description 3
- JFDZBHWFFUWGJE-UHFFFAOYSA-N benzonitrile Chemical compound N#CC1=CC=CC=C1 JFDZBHWFFUWGJE-UHFFFAOYSA-N 0.000 description 3
- 230000027455 binding Effects 0.000 description 3
- 230000004071 biological effect Effects 0.000 description 3
- 230000036983 biotransformation Effects 0.000 description 3
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 3
- SHQSVMDWKBRBGB-UHFFFAOYSA-N cyclobutanone Chemical compound O=C1CCC1 SHQSVMDWKBRBGB-UHFFFAOYSA-N 0.000 description 3
- 125000000532 dioxanyl group Chemical group 0.000 description 3
- 239000002552 dosage form Substances 0.000 description 3
- 238000001035 drying Methods 0.000 description 3
- SRCZQMGIVIYBBJ-UHFFFAOYSA-N ethoxyethane;ethyl acetate Chemical compound CCOCC.CCOC(C)=O SRCZQMGIVIYBBJ-UHFFFAOYSA-N 0.000 description 3
- 238000002474 experimental method Methods 0.000 description 3
- 239000007788 liquid Substances 0.000 description 3
- PGNKFDOPHHNVNF-UHFFFAOYSA-N methyl 2-(bromomethyl)-4-nitrobenzoate Chemical compound COC(=O)C1=CC=C([N+]([O-])=O)C=C1CBr PGNKFDOPHHNVNF-UHFFFAOYSA-N 0.000 description 3
- 239000013642 negative control Substances 0.000 description 3
- 230000007935 neutral effect Effects 0.000 description 3
- 239000006186 oral dosage form Substances 0.000 description 3
- 125000003386 piperidinyl group Chemical group 0.000 description 3
- 229910000027 potassium carbonate Inorganic materials 0.000 description 3
- 230000008569 process Effects 0.000 description 3
- 239000000047 product Substances 0.000 description 3
- 125000006239 protecting group Chemical group 0.000 description 3
- 125000000719 pyrrolidinyl group Chemical group 0.000 description 3
- 125000002943 quinolinyl group Chemical group N1=C(C=CC2=CC=CC=C12)* 0.000 description 3
- 239000002994 raw material Substances 0.000 description 3
- 102000005962 receptors Human genes 0.000 description 3
- 108020003175 receptors Proteins 0.000 description 3
- 239000007858 starting material Substances 0.000 description 3
- 239000000126 substance Substances 0.000 description 3
- 239000000725 suspension Substances 0.000 description 3
- VZGDMQKNWNREIO-UHFFFAOYSA-N tetrachloromethane Chemical compound ClC(Cl)(Cl)Cl VZGDMQKNWNREIO-UHFFFAOYSA-N 0.000 description 3
- 125000003718 tetrahydrofuranyl group Chemical group 0.000 description 3
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- A—HUMAN NECESSITIES
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P19/00—Drugs for skeletal disorders
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Abstract
The invention provides a compound as shown in a Formula I or salts, solvent compounds, pre-drugs, stereoisomers, tautomers, polymorphic forms or metabolites thereof that are acceptable pharmaceutically, a medicine composition containing the same and an application thereof in preparation of medicines for treating male hormone receptor relevant diseases.
Description
Technical Field
The invention belongs to the field of medical chemistry, and particularly relates to diarylhydantoin derivatives, a preparation method thereof, a pharmaceutical composition and application thereof in medicine.
Background
The Androgen Receptor (AR) is an 11 kilodalton (110 KDa) protein that is a member of the steroid receptor (sterod receptor). Similar to other steroid receptors, AR contains three domains: an N-terminal domain, a centrally located DNA binding site and a domain comprising a nuclear transfer signal, and a C-terminal domain containing a ligand binding site. The N-terminal domain contains a transcription functional site called activation activity 1 (activation function 1), and no other structural region is needed, and the transcription of the target gene can be activated by the transcription site. The C-terminus contains a transcription site called activation activity 2 (activation function 2) which, upon activation of its ligand, activates transcription of its target gene. The ligand-free AR is distributed mainly in the cytoplasm and forms a complex with heat shock proteins. When combined with androgens (such as testosterone and dihydrotestosterone), AR is released from the complex formed by heat shock proteins, undergoes phosphorylation reactions, forms dimers, and is transferred into the nucleus where it binds to its associated DNA fragment, thereby stimulating transcription of its target gene. The transcriptional activity of androgen receptors activated by ligand binding is thought to be coordinated by a group of proteins called co-activators (coactivators) such as SRC-1, TIF-2 and AIB-1. The co-activators modify the nuclear chromosome structure and help to attract and stabilize transcripts for transcription onto target genes. When bound to inhibitors, co-repressors (corepressors), such as NCoR SMRT, are attracted, resulting in the inhibition of transcription.
The primary effects of selective AR antagonists are to directly prevent testosterone or dihydrotestosterone from binding to the androgen receptor, blocking the action of androgens on cells, causing "starvation" of cells, and ultimately promoting apoptosis. It can be used for: 1) preventing and treating Prostate Cancer (PC), breast cancer, ovarian cancer, cervical cancer, bladder cancer, etc.; 2) treating benign prostatic hyperplasia, acne, alopecia and hair hyperplasia; 3) male contraception; 4) treating a range of disorders associated with male hormones such as hypersomnia and libido disorders; 5) preventing symptoms associated with androgen decline such as post-castration fever; 6) is especially used for preventing or inhibiting muscle growth in women during the course of sexual transfer therapy.
Treatment of PC is one of the most important clinical applications of AR antagonists. PC is highly prevalent in male malignancies-first mortality second-186320 new cases of PC in the united states alone in 2008-and 26660 deaths. Although the incidence of the disease in China is lower than that in the Western world, the PC tends to increase with the increase of the life rhythm, the life level and the diagnosis level. This cancer is a rapidly progressing malignancy, with an average survival of only 3-5 years from the onset of symptoms if no early diagnosis is available. Early PC can be effectively controlled by surgery or chemotherapy. However, for advanced stage PC, the general therapeutic strategy is an anti-androgen therapy based on androgen and its receptor (AR), i.e. surgical castration therapy (such as bilateral orchiectomy, etc.) and anti-androgen drug therapy. However, most patients treated with this therapy experience a worsening of disease and Castration-Resistant Prostate Cancer (CRPC) at 18-24 weeks. At this time, the currently clinically used antiandrogen drugs no longer have an inhibitory effect on CRPC, but some drugs such as flutamide and bicalutamide have an agonistic effect on CRPC, and 80% of patients die due to CRPC. Further studies have shown that androgen and its bound ligand are essential for the growth of CRPC, suggesting that androgen receptor remains an important target for this disease. However, the existing anti-prostate cancer drugs have only weak antagonistic activity due to increased expression of AR, mutation of AR and the like. Therefore, there is a need to develop AR antagonists with higher antagonistic activity to treat CRPC.
In recent years, a milestone-like progression has been made in the study of diarylhydantoin AR antagonists, such as MDV3100 (IC)50=40nM, LNCaP cell), ARN-509, and the like. MDV3100, among others, was co-developed by Medivation and astler, and was approved by the FDA in the united states for the treatment of CRPC in month 8 of 2012. 1199 previously received docetaxel in a randomized, double-blind, placebo-controlled studyCRPC for the chemotherapy regimen was randomly divided into MDV3100 treatment group and placebo group. The results show that the median overall survival of patients in the MDV3100 treatment group was significantly increased compared to the placebo group (18.4 vs13.6 months, P < 0.0001) and the risk of mortality was reduced by 37% compared to the placebo group. MDV3100 is also currently in phase I clinical use for the treatment of breast cancer. ARN-509 was developed by the Ann corporation for the treatment of CRPC and is now in phase I/II clinical use. Research progress in MDV3100 and ARN-509 suggests that diarylhydantoin AR antagonists have very good prospects for development.
Disclosure of Invention
The invention provides diarylhydantoin derivatives, pharmaceutically acceptable salts, solvates, prodrugs, stereoisomers, tautomers, polymorphs or metabolites thereof, which are completely different from the prior art, as well as preparation methods and intermediates thereof, pharmaceutical compositions containing the diarylhydantoin derivatives, the pharmaceutically acceptable salts, solvates, prodrugs, stereoisomers, tautomers, polymorphs or metabolites thereof, and application of the diarylhydantoin derivatives in preparation of drugs for treating androgen receptor related diseases, particularly prostate cancer. The diaryl hydantoin derivative prepared by the invention has better inhibitory activity to androgen receptors.
In one aspect, the invention provides a compound of formula I or a pharmaceutically acceptable salt, solvate, prodrug, stereoisomer, tautomer, polymorph or metabolite thereof,
wherein,
the ring A is a 6-to 10-membered aromatic ring; preferably 6-10 membered aromatic ring; further preferred is a benzene ring or a naphthalene ring; more preferably a benzene ring;
ring B is a benzene ring or a 6-membered heteroaromatic ring; preferably a benzene ring or a pyridine ring; further preferred is a benzene ring or a 2,3, 5-trisubstituted pyridine ring; more preferably a benzene ring;
R1is H, C1-C4 alkyl or phenyl, the C1-C4 alkyl is optionally substituted by one or more groups selected from C3-C6 cycloalkyl, C1-C6 alkoxy, -NH2Mono (C1-C6 alkyl) amino, di (C1-C6 alkyl) amino, deuterium atom, phenyl and-C (O) R8Wherein R is substituted by the group of8Is selected from-NH2Mono (C1-C6 alkyl) amino, di (C1-C6 alkyl) amino or a 5-to 7-membered heterocyclic group containing at least 1 nitrogen atom, the 5-to 7-membered heterocyclic group containing at least 1 nitrogen atom being optionally substituted with C1-C4 alkyl; preferably H, C1-C4 alkyl or phenyl, said C1-C4 alkyl being optionally substituted by 1 or more groups selected from C3-C6 cycloalkyl, C1-C4 alkoxy, di (C1-C4 alkyl) amino, deuterium atom, phenyl and-C (O) R8Wherein R is substituted by the group of8Is selected from-NH2Or a 5-to 7-membered heterocyclic group containing at least 1 nitrogen atom, said 5-to 7-membered heterocyclic group containing at least 1 nitrogen atom being optionally substituted with a C1-C4 alkyl group; further preferred is H, C1-C4 alkyl group or phenyl group, said C1-C4 alkyl group being optionally substituted with 1 or more groups selected from C3-C6 cycloalkyl group, C1-C4 alkoxy group, di (C1-C4 alkyl) amino group, deuterium atom, phenyl group and-C (O) R8Wherein R is substituted by the group of8Is selected from-NH2Or a 6-membered heterocyclic group containing at least 1 nitrogen atom, said 6-membered heterocyclic group containing at least 1 nitrogen atom being optionally substituted with a C1-C4 alkyl group; further preferred is H, C1-C4 alkyl group or phenyl group, said C1-C4 alkyl group being optionally substituted by one or more groups selected from the group consisting of cyclopropyl group, cyclobutyl group, methoxy group, deuterium atom, phenyl group and-C (O) R8Wherein R is substituted by the group of8Selected from amino or N-methylpiperazinyl; more preferably H, methyl, ethyl, cyclopropylmethyl, cyclobutylmethyl, phenyl, benzyl, 2- (methoxy) ethyl, -CH2C(O)NH2Or
R2Is H, halogen or C1-C4 alkyl, said C1-C4 alkyl being optionally substituted by one or more halogen atoms; preferably H, F, Cl, Br or C1-C3 alkyl; further preferred is H or halogen; more preferably H or F;
R3and R4Each independently is-CH2-R6Wherein R is6H, OH, carboxyl, benzyloxy, C1-C4 alkoxy or halogenated C1-C2 alkyl; preferably R3And R4Each independently is-CH2-R6Wherein R is6Is H, C1-C4 alkoxy or halogenated C1-C2 alkyl; more preferably R3And R4Each independently is-CH2-R6Wherein R is6Is H, -OCH3or-CH2Cl;
Or R3、R4And the carbon atoms connected with the compounds form 3-6 membered cycloalkyl or 4-6 membered heterocyclic group; preferably R3、R4And the carbon atoms connected with the above-mentioned groups together form a 3-6 membered cycloalkyl group or a 4-6 membered heterocyclic group containing 1 oxygen atom; wherein the 3-6 membered cycloalkyl is preferably cyclopropyl, cyclobutyl or cyclopentyl, further preferably cyclopropyl, cyclobutyl or cyclopentyl, and more preferably cyclobutyl or cyclopentyl; the 4-to 6-membered heterocyclic group is preferably an oxetanyl group, an azetidinyl group, a tetrahydrofuryl group, an oxacyclohexyl group, a pyrrolidinyl group, a dioxanyl group, a piperidinyl group or an N-methylpiperidinyl group, more preferably an oxetanyl group, an azetidinyl group or an oxacyclohexyl group, and still more preferably an oxetanyl group or an oxacyclohexyl group; more preferably R3、R4And the carbon atoms to which they are attached together form a cyclobutyl, cyclopentyl or oxacyclohexyl group;
R5cyano, halogen, C1-C4 alkyl or C1-C4 alkoxy, said C1-C4 alkyl being optionally substituted by one or more halogen atoms; preferably R5Is halogen, methyl, halomethyl or-OCH3(ii) a More preferably R5Is halogen, -CH3、-CF3or-OCH3;
R7Is H or halogen, preferably H or F, more preferably H;
x is S or O, preferably S;
y is- (CH)2)n-, O or a direct bond, wherein- (CH)2)n-optionally substituted by one or more deuterium atoms or methyl groups, n is 1 or 2; preferably Y is- (CH)2)nOr a direct bond, wherein- (CH2)n-optionally substituted with one or more methyl groups, n is 1 or 2; more preferably Y is- (CH)2) 2-or-CH (CH)3)-。
In one embodiment, in formula I,
the ring A is a 6-to 10-membered aromatic ring; preferably a benzene ring;
ring B is a benzene ring or a 6-membered heteroaromatic ring; preferably a benzene ring;
R1is H or C1-C4 alkyl, the C1-C4 alkyl is optionally substituted by one or more groups selected from C3-C6 cycloalkyl, C1-C6 alkoxy, -NH2Mono (C1-C6 alkyl) amino, di (C1-C6 alkyl) amino, -CONH2Mono (C1-C6 alkyl) carbamoyl, di (C1-C6 alkyl) carbamoyl and deuterium atom; preferably H or C1-C3 alkyl, said C1-C3 alkyl optionally substituted by one or more groups selected from C3-C6 cycloalkyl, C1-C4 alkoxy, di (C1-C4 alkyl) amino, -CONH2And deuterium atom; further preferred is H or C1-C2 alkyl, said C1-C2 alkyl optionally substituted with one or more groups selected from cyclopropyl, methoxy, diethylamino, -CONH2And deuterium atom; further preferred are H, methyl, ethyl, cyclopropylmethyl, 2- (methoxy) ethyl, 2- (diethylamino) ethyl, -CH2CONH2or-CD3(ii) a More preferably H, methyl or ethyl;
R2is H, halogen or C1 ℃C4 alkyl, said C1 to C4 alkyl being optionally substituted by one or more halogen atoms; preferably H, F, Cl, Br or C1-C3 alkyl; further preferred is H or halogen; more preferably H or F;
R3and R4Each independently is-CH2-R6Wherein R is6H, OH, carboxyl, benzyloxy or C1-C4 alkoxy; preferably H, OH or C1-C4 alkoxy; preferably, R3And R4At least 1 of which is methyl; more preferably, R3And R4Are both methyl;
or R3、R4And the carbon atoms connected with the 3-6 membered cycloalkyl or the 4-6 membered heterocyclic group are formed together, wherein the 3-6 membered cycloalkyl is preferably cyclopropyl, cyclobutyl or cyclopentyl, is further preferably cyclopropyl or cyclobutyl, and is more preferably cyclobutyl; the 4-6 membered heterocyclic group is preferably an oxetanyl group, an azetidinyl group, a tetrahydrofuryl group, a pyrrolidinyl group, a dioxane group, a piperidinyl group or an N-methylpiperidinyl group, more preferably an oxetanyl group or an azetidinyl group, and even more preferably an oxetanyl group;
R5is cyano, halogen or C1-C4 alkyl, said C1-C4 alkyl being optionally substituted by one or more halogen atoms; preferably cyano, F, Cl, Br or C1 to C4 alkyl, said C1 to C4 alkyl being optionally substituted by one or more atoms selected from F, Cl and Br; further preferred is cyano, F, Cl or C1 to C2 alkyl, said C1 to C2 alkyl being optionally substituted by one or more F atoms; still more preferably cyano, F, Cl or-CF3(ii) a More preferably-CF3;
X is S or O, and X is S or O,
y is- (CH)2)n-, O or a direct bond, wherein- (CH)2)n-optionally substituted by one or more deuterium atoms, n is 1 or 2; preferably Y is-CH2-;
R7Is H.
In yet another embodiment of the present invention, the compound of formula I is preferably a compound represented by formula II,
wherein,
R1is H, C1-C4 alkyl or phenyl, said C1-C4 alkyl being optionally substituted by one or more groups selected from C3-C6 cycloalkyl, C1-C6 alkoxy, phenyl and-C (O) R8Wherein R is substituted by the group of8Selected from amino, mono (C1-C6 alkyl) amino, di (C1-C6 alkyl) amino or a 5-to 7-membered heterocyclic group containing at least 1 nitrogen atom, said 5-to 7-membered heterocyclic group containing at least 1 nitrogen atom being optionally substituted with C1-C4 alkyl; preferably R1Is H, C1-C4 alkyl or phenyl, said C1-C4 alkyl being optionally substituted by one or more groups selected from C3-C6 cycloalkyl, C1-C6 alkoxy, phenyl and-C (O) R8Wherein R is substituted by the group of8Selected from amino or a 5-to 7-membered heterocyclic group containing at least 1 nitrogen atom, said 5-to 7-membered heterocyclic group containing at least 1 nitrogen atom being optionally substituted with a C1-C4 alkyl group; further preferred is R1Is H, C1-C4 alkyl or phenyl, said C1-C4 alkyl being optionally substituted by one or more groups selected from C3-C6 cycloalkyl, C1-C6 alkoxy, phenyl and-C (O) R8Wherein R is substituted by the group of8Selected from amino or a 6-membered heterocyclic group containing at least 1 nitrogen atom, said 6-membered heterocyclic group containing at least 1 nitrogen atom being optionally substituted with a C1-C4 alkyl group; further preferred is R1Is H, C1-C4 alkyl or phenyl, said C1-C4 alkyl optionally substituted with one or more groups selected from cyclopropyl, cyclobutyl, methoxy, phenyl and-C (O) R8Wherein R is substituted by the group of8Selected from amino or N-methylpiperazinyl; more preferably R1Is H, methyl, ethyl, phenyl, cyclopropylmethyl, cyclobutylmethyl, 2- (methoxy) ethyl, benzyl, -CH2C(O)NH2Or
R2Is H, halogen or C1-C4 alkyl, said C1-C4 alkyl being optionally substituted by one or more halogen atoms; preferably R2Is H or halogen; more preferably R2Is H or F;
R3and R4Each independently is-CH2-R6Wherein R is6Is H, C1-C4 alkoxy or halogenated C1-C2 alkyl; preferably R3And R4Each independently is-CH2-R6Wherein R is6Is H, -OCH3or-CH2Cl;
Or R3、R4And the carbon atoms connected with the compounds form 3-6 membered cycloalkyl or 4-6 membered heterocyclic group; preferably R3、R4And the carbon atoms connected with the above-mentioned groups together form a 3-6 membered cycloalkyl group or a 4-6 membered heterocyclic group containing 1 oxygen atom; more preferably R3、R4And the carbon atoms to which they are attached together form a cyclobutyl, cyclopentyl or oxacyclohexyl group;
R5is halogen, C1-C4 alkyl or C1-C4 alkoxy, said C1-C4 alkyl being optionally substituted by one or more halogen atoms; preferably R5Is halogen, methyl, halomethyl or-OCH3(ii) a More preferably R5Is halogen, -CH3、-CF3or-OCH3;
R7Is H or halogen; preferably H;
y is- (CH)2)n- (CH)2)n-optionally substituted by one or more C1 to C4 alkyl groups, n is 1 or 2; preferably Y is- (CH)2)n- (CH)2)n-optionally substituted with one or more methyl groups, n is 1 or 2; more preferably Y is- (CH)2)2-or-CH (CH)3)-。
In still another preferred embodiment of the present inventionIn the formula, when Y is- (CH)2)2When is, R2Is H.
In a preferred embodiment of the present invention there is provided a compound of formula I or II as described above or a pharmaceutically acceptable salt, solvate, prodrug, stereoisomer, tautomer, polymorph or metabolite thereof, wherein ring a is a phenyl ring or a quinoline ring and ring B is a phenyl ring, and the other substituents in formula I or II are as defined and preferred above.
In a further preferred embodiment of the present invention, there is provided a compound represented by formula I or II above or a pharmaceutically acceptable salt, solvate, prodrug, stereoisomer, tautomer, polymorph or metabolite thereof, wherein ring a is a benzene ring or a quinoline ring, cyano group, R attached to ring a, and R is a cyano group, R attached to ring a5、R7Andare all located on the benzene ring in the A ring, and cyano groups andsubstituted para to each other, ring B is a phenyl ring, and the other substituents in formula I or II are as defined and preferred above.
In a further preferred embodiment of the present invention, there is provided a compound represented by formula I or II above or a pharmaceutically acceptable salt, solvate, prodrug, stereoisomer, tautomer, polymorph or metabolite thereof, wherein ring a is a benzene ring, and cyano group attached to ring a are bonded to ring aSubstituted in para position to each other on ring A, R5Is trifluoromethyl or halogen, R7Is H or halogen, ring B is a phenyl ring, and the other substituents in formula I or II are as defined and preferred above.
In a still further preferred embodiment of the present invention, there is provided a compound represented by formula I or II aboveOr a pharmaceutically acceptable salt, solvate, prodrug, stereoisomer, tautomer, polymorph or metabolite thereof, wherein ring A is a phenyl ring, and the cyano group attached to ring A are linked to ring ASubstituted in para position to each other on ring A, R5Is trifluoromethyl, R7Is H, ring B is a phenyl ring and the other substituents in formula I or II are as defined and preferred above.
In a more preferred embodiment of the present invention, there is provided a compound represented by formula I or II above, or a pharmaceutically acceptable salt, solvate, prodrug, stereoisomer, tautomer, polymorph or metabolite thereof, wherein ring a is a phenyl ring and R is a phenyl ring5Is trifluoromethyl, R7Is H, cyano attached to ring A andcyano radicals attached to ring A and R, substituted in para position to each other on ring A5Substituted in ortho position to each other on ring A, ring B is a phenyl ring, and the other substituents in formula I or II are as defined and preferred above.
In a preferred embodiment of the invention, when R is2When it is halogen, R2Andare ortho-substituted to each other on the B ring.
In a further preferred embodiment of the invention, when R is2When is F, R2Andare ortho-substituted to each other on the B ring.
In a further preferred embodiment of the present invention, the compounds of formula I or II according to the present invention are preferably selected from the following compounds:
in another aspect, the invention provides a process for the preparation of said compounds of formula I. The compound of formula I according to the invention can be prepared by the following method:
method 1 the target compound I is prepared by the cyclization reaction of I-1 and I-2
Wherein each group is as defined above.
Specifically, I-1 and I-2 are added into a first polar solvent, the mixture is heated (by microwave or oil bath heating, the temperature is 30-150 ℃) until the TLC detection reaction is completed, then an aqueous solution of acid A and a second polar solvent (which is the same as or different from the first solvent) are added into the reaction mixed solution, the mixture is heated and refluxed until the TLC detection reaction is completed, and the target compound I is obtained by separating and purifying the mixture. Wherein the first polar solvent comprises DMF, DMA, DMSO, NMP, etc., preferably DMF; the second polar solvent comprises methanol, ethanol, isopropanol, n-propanol, n-butanol, DMF, etc., preferably methanol; the acid A includes hydrochloric acid, sulfuric acid, phosphoric acid, etc., and hydrochloric acid and sulfuric acid are preferable.
Wherein, the intermediate I-2 can be prepared by the reaction of the intermediate I-5 and the raw material I-6, or by the reaction of the intermediate I-5, the raw material I-7 and metal cyanide (NaCN, KCN and the like) or trialkyl cyanogen silane.
The reaction conditions and the operating steps can be carried out as disclosed in International patent application WO2006/124118 and journal articles J.Med.chem.2010,53,2779-.
Method 2 target compound I is prepared by reacting intermediate I-3 and intermediate I-4
Wherein, in I-3, X is O or S; in I-4R1Is as defined for formula I except that it is not H; in the target compound I produced in this reaction, X is O, and the other groups are as defined above.
Dissolving I-3 in a polar aprotic solvent (preferably DMF and DMSO) at the temperature of-80-0 ℃, adding an alkali metal hydride (preferably sodium hydride), continuously stirring at the temperature for 10-100 minutes, then heating to 20-30 ℃, adding halogenated alkane I-4, completing TLC detection reaction, and separating and purifying from a reaction mixture to obtain a target compound I.
Wherein, the intermediate I-3 can be composed of I-1 and I-2 (wherein R is1Is H) reaction. The reaction conditions and the operation steps were the same as those of I-1 and I-2 in Process 1.
Method 3 the target compound I is prepared by converting I-8 under strong alkaline condition
Wherein each group is as defined above. Dissolving I-8 in a polar aprotic solvent (preferably DMF and DMSO) at the temperature of-80-0 ℃, adding an alkali metal hydride (preferably sodium hydride), continuously stirring at the temperature, detecting by TLC to complete the reaction, and separating and purifying from the reaction mixture to obtain the target compound I.
It is to be understood that for the compounds of formula I or II according to the present invention, one skilled in the art can prepare them by a combination of various methods well known to those skilled in the art of organic synthesis or pharmaceutical chemistry in light of the above methods, and the compounds of the present invention can be synthesized by combining the methods described above with synthetic methods known in the art or variations thereon as would be understood by those skilled in the art, without being limited to the above methods.
The compounds of formula I or II according to the present invention can be prepared from readily available starting materials using the following general methods and procedures. It is to be understood that typical or preferred process conditions (i.e., reaction temperatures, times, mole ratios of reactants, solvents, pressures, methods or sequences of addition, etc.) are given herein, and that other process conditions may be used unless otherwise specified. Optimum reaction conditions may vary with the particular starting materials, intermediates, reagents, catalysts or solvents used, but such conditions can be determined by one skilled in the art by routine optimization procedures.
The compounds of formula I or II of the present invention may be prepared by any suitable method known in the art for monitoring the manufacturing process or for identifying the chemical structure. Such as thin layer chromatography, liquid chromatography, gas chromatography, mass spectrometry, LC-MS, nuclear magnetic resonance, infrared spectroscopy, ultraviolet spectroscopy, and the like.
The preparation of compounds may involve the protection and deprotection of multiple chemical groups. The need for protection and deprotection, and the choice of an appropriate protecting group, can be readily determined by those skilled in the art, and the chemistry of the protecting group is found, for example, in Protective Groups in Organic Synthesis (second edition, Wiley & Sons, 1991), by Greene et al, which is incorporated herein by reference in its entirety.
In another aspect, the present invention also provides a pharmaceutical composition comprising a therapeutically effective amount of a compound represented by formula I or II, or a pharmaceutically acceptable salt, solvate, prodrug, stereoisomer, tautomer, polymorph or metabolite thereof, and at least one pharmaceutical excipient. The pharmaceutical composition comprises an oral dosage form, a parenteral dosage form, an external dosage form and a rectal dosage form. In some embodiments, the pharmaceutical composition is in oral dosage forms including tablets, capsules, pills, powders, sustained-release preparations, solutions, suspensions and the like, in parenteral dosage forms including sterile solutions, suspensions or emulsions, in topical dosage forms including ointments, oils, emulsions, gels, suspensions, solutions, lotions or creams, and in rectal dosage forms including suppositories, drops. The choice of pharmaceutical excipients varies with the route of administration and the nature of action and may generally be fillers, diluents, binders, wetting agents, disintegrants, lubricants, emulsifiers or suspending agents and the like. In other embodiments, the pharmaceutical composition further comprises at least one additional therapeutic agent. Preferably, the pharmaceutical composition provided by the invention is an oral dosage form.
In another aspect, the present invention provides a method of modulating the activity of an androgen receptor, comprising contacting the compound of formula I or II, or a pharmaceutically acceptable salt, solvate, prodrug, stereoisomer, tautomer, polymorph or metabolite thereof, or a pharmaceutical composition comprising the same, with the androgen receptor. Preferably, the androgen receptor modulating activity of the present invention is androgen receptor inhibiting activity.
In yet another aspect, the present invention also provides a use of the compound of formula I or II, or a pharmaceutically acceptable salt, solvate, prodrug, stereoisomer, tautomer, polymorph or metabolite thereof, or a pharmaceutical composition comprising the same, for the manufacture of a medicament for the treatment of androgen receptor related diseases. According to one embodiment of the present invention, the androgen receptor-associated diseases include prostate cancer, breast cancer, prostatic hyperplasia, hirsutism, acne, alopecia, muscle failure, gonadal failure, osteoporosis, hypercholesterolemia, male infertility, male sexual dysfunction, anemia obesity, hyposexuality, and depression. According to a preferred embodiment of the present invention, the androgen receptor associated disease is castration-resistant prostate cancer.
In a further aspect, the present invention also provides a method of using a compound of formula I or II, or a pharmaceutically acceptable salt, solvate, prodrug, stereoisomer, tautomer, polymorph or metabolite thereof, or a pharmaceutical composition comprising same, for the treatment of an androgen receptor associated disease, said method of treatment comprising contacting said active substance with a mammal. According to one embodiment of the present invention, the androgen receptor-associated diseases include prostate cancer, breast cancer, prostatic hyperplasia, hirsutism, acne, alopecia, muscle failure, gonadal failure, osteoporosis, hypercholesterolemia, male infertility, male sexual dysfunction, anemia obesity, hyposexuality, and depression. According to a preferred embodiment of the present invention, the androgen receptor associated disease is castration-resistant prostate cancer.
Certain chemical or pharmaceutical terms
Unless otherwise specifically indicated, chemical and pharmaceutical terms in the claims and specification of the present application have the meanings as described below.
"halogen" means fluorine, chlorine, bromine or iodine.
"cyano" means-CN.
"isocyano" means-N = C = O.
"isothiocyanato" means-N = C = S.
"hydroxy" means-OH.
"carboxyl" means-COOH.
"benzyloxy" refers to the group-OCH2C6H5。
The abbreviation "DMA" refers to N, N-dimethylacetamide.
The abbreviation "NMP" refers to N-methylpyrrolidone.
"C1-C4" means that the number of carbon atoms in the group defined by it (e.g., alkyl, alkoxy, cycloalkyl, etc.) is 1,2,3, or 4. Other terms described in a similar manner, such as "C1-C6", "C3-C6", etc., are hereby inferred.
The term "6-to 10-membered" means that the number of atoms constituting the skeleton of the closed ring itself in the defined closed ring group (e.g., aryl, heteroaryl, heterocyclic group, etc.) is 6,7, 8, 9, or 10, and the number may be different depending on the number of rings, the degree of saturation, the nature of the atoms constituting the ring, and the like. It is to be understood that other terms described in a similar manner, such as "3-6 member", "4-6 member", etc., may be used.
"alkyl" means a straight or branched hydrocarbon chain group consisting only of carbon and hydrogen atoms, free of unsaturation, having, for example, from 1 to 12 carbon atoms, and attached to the rest of the molecule by a single bond. Generally, examples of alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, 2-methylbutyl, 2-dimethylpropyl, n-hexyl, heptyl, 2-methylhexyl, 3-methylhexyl, octyl, nonyl, and decyl, and the like.
"alkoxy" refers to a group of formula-OR, wherein R is alkyl as defined above. Generally, examples of alkoxy groups include, but are not limited to, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy, and the like.
"Mono (C1-C6 alkyl) amino" refers to a group of the formula-NHR, wherein R is an alkyl group having 1 to 6 carbon atoms as defined above.
"Di (C1-C6 alkyl) amino" refers to the formula-NRaRbGroup, wherein Ra、RbEach independently an alkyl group having 1 to 6 carbon atoms as defined above.
"Mono (C1-C6 alkyl) carbamoyl" refers to a group of formula-CONHR wherein R is an alkyl group having 1 to 6 carbon atoms as defined above.
"Di (C1-C6 alkyl) carbamoyl" means a compound of the formula-CONRaRbGroup, wherein Ra、RbEach independently an alkyl group having 1 to 6 carbon atoms as defined above.
"cycloalkyl" refers to a stable non-aromatic monocyclic or polycyclic hydrocarbon group consisting of only carbon and hydrogen atoms, and may include fused, bridged or spiro ring systems, typically having from 3 to 15 carbon atoms. It may be attached to the rest of the molecule by a single bond via any suitable carbon atom on the ring. Generally, examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, and the like. For the purposes of the present invention, preference is given to cycloalkyl groups having a monocyclic ring system of 3 to 6 carbon atoms, more preferably cycloalkyl groups having a monocyclic ring system of 3 to 5 carbon atoms.
"heterocyclyl" refers to a stable 3-to 20-membered non-aromatic cyclic group consisting of 2 to 14 carbon atoms and 1 to 6 heteroatoms selected from nitrogen, oxygen, and sulfur, which may be a monocyclic, bicyclic, tricyclic, or higher ring system, and may also include fused, bridged, or spiro ring systems. It may be attached to the rest of the molecule by a single bond via any suitable carbon or heteroatom in the ring. Wherein the nitrogen atom may be optionally further substituted with other groups to form tertiary or quaternary amine structures. In general, examples of heterocyclyl groups include, but are not limited to, aziridinyl, azetidinyl, oxetanyl, pyrrolidinyl, imidazolinyl, pyrazolidinyl, imidazolidinyl, thiazolidinyl, isothiazolidinyl, isoxazolidinyl, tetrahydrofuryl, dioxolanyl, oxocyclohexyl, morpholinyl, piperazinyl, N-substituted piperazinyl, homopiperazinyl, N-substituted homopiperazinyl, piperidinyl, N-substituted piperidinyl, dioxanyl, indolinyl, tetrahydroisoquinolinyl, decahydroisoquinolinyl, and the like. For the purpose of the present invention, a heterocyclic group of a 3-to 7-membered monocyclic system containing at least 1 heteroatom selected from nitrogen, oxygen, or sulfur is preferable, a heterocyclic group of a 4-to 6-membered monocyclic system containing at least 1 heteroatom selected from nitrogen or oxygen is more preferable, and a heterocyclic group of a 4-to 6-membered monocyclic system containing at least 1 to 2 heteroatoms selected from nitrogen or oxygen is even more preferable.
"aryl" or "aromatic ring" refers to a group of conjugated aromatic hydrocarbon ring systems having 6 to 18 carbon atoms, which may be monocyclic, bicyclic, tricyclic, or higher ring systems. It may be attached to the rest of the molecule by single bonds via atoms on the aromatic ring. In general, examples of aryl groups include, but are not limited to, phenyl, naphthyl, anthracenyl, phenanthrenyl, fluorenyl, and the like. For the purposes of the present invention, preference is given to aryl or aromatic rings of monocyclic or bicyclic systems having from 6 to 10 carbon atoms.
"heteroaryl" or "heteroaromatic ring" refers to a 5-to 16-membered conjugated aromatic ring system group consisting of 1 to 15 carbon atoms and 1 to 6 heteroatoms selected from nitrogen, oxygen and sulfur, and may be a monocyclic, bicyclic, tricyclic or higher ring system, which may be attached to the remainder of the molecule by single bonds via atoms on the aromatic ring. Generally, examples of heteroaryl groups include, but are not limited to, pyrrolyl, furanyl, thienyl, imidazolyl, pyrazolyl, thiazolyl, oxazolyl, oxadiazolyl, isoxazolyl, triazolyl, tetrazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, indolyl, isoindolyl, indazolyl, benzimidazolyl, benzotriazolyl, quinolinyl, isoquinolinyl, benzothiazolyl, benzopyridazinyl, quinazolinyl, quinoxalinyl, and the like. For the purpose of the present invention, a heteroaryl or heteroaryl ring of a monocyclic or bicyclic system, which is 6 to 10-membered and contains at least 1 heteroatom selected from nitrogen, oxygen or sulfur, is preferred, and a heteroaryl or heteroaryl ring of a bicyclic system, which is obtained by fusing a 5 to 6-membered heteroaryl ring containing at least 1 nitrogen atom with a benzene ring, is more preferred.
"pharmaceutically acceptable acid addition salts" refers to salts with inorganic or organic acids which retain the biological effectiveness of the free base without other side effects. Inorganic acid salts include, but are not limited to, hydrochloride, hydrobromide, sulfate, nitrate, phosphate, and the like; organic acid salts include, but are not limited to, formates, acetates, 2-dichloroacetates, trifluoroacetates, propionates, caproates, caprylates, caprates, undecylenates, glycolates, gluconates, lactates, sebacates, adipates, glutarates, malonates, oxalates, maleates, succinates, fumarates, tartrates, citrates, palmitates, stearates, oleates, cinnamates, laurates, malates, glutamates, pyroglutamates, aspartates, benzoates, methanesulfonates, benzenesulfonates, p-toluenesulfonates, alginates, ascorbates, salicylates, 4-aminosalicylates, napadisylates, and the like. "pharmaceutically acceptable base addition salts" refers to salts with inorganic or organic bases which maintain the biological effectiveness of the free acid without other side effects. Salts derived from inorganic bases include, but are not limited to, sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum, and the like. Preferred inorganic salts are ammonium, sodium, potassium, calcium and magnesium salts. Salts derived from organic bases include, but are not limited to, the following: primary, secondary and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines and basic ion exchange resins, such as ammonia, isopropylamine, trimethylamine, diethylamine, ethylenediamine, triethylamine, tripropylamine, ethanolamine, diethanolamine, triethanolamine, dimethylethanolamine, 2-dimethylaminoethanol, 2-diethylaminoethanol, dicyclohexylamine, lysine, arginine, histidine, glucosamine and the like. These salts can be prepared by methods known in the art.
"solvate" refers to an aggregate formed by the association of molecules of certain compounds of the present invention with one or more solvent molecules during crystallization. The solvent molecules may be water or other organic solvents (e.g., methanol, ethanol, acetone, etc.).
By "prodrug" is meant a pharmaceutically acceptable metabolic precursor of some of the compounds of the invention which is generally inactive, but which can be converted under physiological conditions in vivo to the parent compound of the invention which is biologically active. The properties of the parent compound in terms of solubility, histocompatibility or pharmacokinetics may generally be improved.
"stereoisomers" refers to compounds that consist of the same atoms, are bonded by the same bonds, but have different three-dimensional structures. The compounds of formula I or II according to the invention encompass the various possible optical isomers, cis-trans isomers and mixtures thereof.
"tautomer" refers to an isomer formed by the transfer of a proton from one atom of a molecule to another atom of the same molecule. The compounds of formula I or II described herein encompass a variety of possible tautomers and mixtures thereof.
"polymorph" refers to different solid crystalline phases of certain compounds of the present invention in the solid state due to the presence of two or more different molecular arrangements. The compounds of formula I or II described herein encompass a variety of possible crystalline forms and mixtures thereof.
"metabolite" refers to a compound produced by in vivo biotransformation, such as functionalization reactions (I-phase biotransformation reactions, including oxidation, reduction, hydrolysis, etc.) and conjugation reactions (II-phase biotransformation reactions), under the action of enzymes after some of the compounds of the present invention are absorbed by the body.
"pharmaceutical composition" refers to a pharmaceutical formulation comprised of a compound of the present invention and optionally a vehicle generally accepted in the art for delivery of biologically active compounds to a mammal (e.g., a human). The medium includes a pharmaceutically acceptable carrier. The purpose of the pharmaceutical composition is to facilitate administration to an organism, facilitate absorption of active ingredients and exert biological activity. Wherein "pharmaceutically acceptable carrier" includes, but is not limited to, any adjuvant, carrier, excipient, glidant, sweetener, diluent, preservative, dye/colorant, flavoring agent, surfactant, wetting agent, dispersant, suspending agent, stabilizer, isotonic agent, solvent, emulsifier, etc., which is approved by the relevant governmental regulatory agency for use in humans or livestock, is relatively nontoxic and does not cause adverse physiological reactions in humans or livestock.
Detailed Description
The invention will now be further illustrated, but is not limited, by the following specific examples.
In the following preparation examples, the following examples were conducted,1H-NMR was measured using a Varian Mercury AMX300 model apparatus. MS was determined with VG ZAB-HS or VG-7070 type and Esquire3000 plus-01005.
Examples of preparation of Compounds
Example 14-isothiocyanato-2-trifluoromethylbenzonitrile (intermediate 2)
4-amino-2-trifluoromethylbenzonitrile (10.0 g,53.8 mmoL) was added to n-hexane (22.5 mL) and water (25.0 mL), and the mixture was stirred at room temperature for 8 minutes. Thiophosgene (4.5 mL, 58.5 mmoL) was added dropwise to the above mixed system while cooling on ice, and the mixture was left to stir at room temperature overnight after the addition. Filtration, washing of the solid with n-hexane (2X 25.0 mL), discarding the solid, pressure-reduced evaporation of the filtrate to one fifth of the original volume, and placing in a refrigerator at 4 ℃ overnight. Filtration and drying of the solid under high vacuum gave 11.0g of a white solid with a yield of 81%.1H NMR(CDCl3,300MHz)δ(ppm)7.84(d,J=8.4Hz,1H),7.59(d,J=1.8Hz,1H),7.49(dd,J1=8.4Hz,J2=1.8Hz,1H).
Example 22 methyl-4-nitrobenzoate
In ice bath, SOCl is added2(4.8 mL, 66.2 mmoL) was added dropwise to dry methanol (100 mL). Then, a solution of 2-methyl-4-nitrobenzoic acid (10.0 g,55.2 mmoL) in anhydrous methanol (70 mL) was added dropwise over 1 hour. The mixed system is placed in an oil bath at 70 ℃ for reaction for 7 hours, and the reaction is completely detected by TLC. Cooling, and evaporating the solvent under reduced pressure. The residue was dissolved in ethyl acetate (100mL), saturated sodium bicarbonate (100mL) was added, the solution was separated, and the aqueous phase was extracted once with ethyl acetate (50 mL). The combined organic phases were dried over anhydrous magnesium sulfate, filtered, the solvent was evaporated under reduced pressure and dried under high vacuum to give 10.5g of a white solid with a yield of 98%.1H NMR(CDCl3,300MHz)δ(ppm)8.10-8.01(m,3H),3.95(s,3H),2.69(s,3H).
Example 32- (bromomethyl) -4-nitrobenzoic acid methyl ester
Methyl 2-methyl-4-nitrobenzoate (200mg, 1.0 mmoL), benzoyl peroxide (48.5 mg,0.2 mmoL), N-bromosuccinimide (213 mg,1.2 mmoL) were added to CCl4(15mL) was reacted under reflux for 7 hours under Ar gas, the reaction mixture was cooled, washed with saturated sodium bicarbonate (3X 20mL) and saturated brine (20mL) in this order, the solvent was evaporated under reduced pressure, and the residue was separated by flash column chromatography using PE: EA =20:1 as an eluent to give 124mg of a white solid with a yield of 44%.1H NMR(CDCl3,300MHz)δ(ppm)8.34-8.01(m,3H),4.97(s,2H),4.00(s,3H).
Example 45-Nitro-1-isoindolinone
Methyl 2- (bromomethyl) -4-nitrobenzoate (250 mg,0.92 mmoL) was added to ammonia (NH)3) Was stirred at room temperature for 2 hours in a saturated methanol solution (5mL), and the reaction was completed by TLC. The solvent was evaporated under reduced pressure and the residue was added to ethyl acetate (7 mL), sonicated for 3 minutes, placed in a-20 ℃ freezer for 3 minutes to give a large amount of solid, filtered and dried under high vacuum to give 150mg of a pale yellow solid with a yield of 92%.1H NMR(CDCl3,300MHz)δ(ppm)9.01(s,1H),8.47(d,J=0.9Hz,1H),8.30(dd,J1=8.1Hz,J2=0.9Hz,1H),7.89(d,J=8.1,1H).
Example 55-amino-1-isoindolinone (intermediate 8a)
5-Nitro-1-isoindolone (100 mg,0.56 mmoL) and reduced iron powder (314 mg,5.6 mmoL) were added to ethanol (2.0 mL) and concentrated hydrochloric acid (0.5 mL), and the mixture was refluxed for 2 hours to complete the reaction by TLC. Cooling with ammonia (NH)3) The acid was neutralized with a saturated methanol solution, filtered through celite, washed with methanol, and the solvent was distilled off under reduced pressure to give 70.0mg of a white solid with a yield of 84%.1H NMR(CD3OD,300MHz)δ(ppm)7.48-7.46(d,J=6.6Hz,1H),6.73-6.71(m,2H),4.30(s,2H).
Example 62-methyl-2- (1-oxoisoindolin-5-ylamino) propionitrile (intermediate 9a)
5-amino-1-isoindolinone (intermediate 8a,2.1g,14.2 mmoL), acetone (3.5 mL,47.6 mm)oL) and sodium cyanide (2.1 g,46.8 mmoL) were added to 90% acetic acid (45 mL). After the addition was complete, the mixture was stirred at room temperature for 48 hours. To the reaction mixture were added water (50 mL) and ethyl acetate (100mL), the mixture was separated, the organic phase was washed successively with water (3X 50 mL), saturated sodium bicarbonate (50 mL), and water (50 mL), dried over anhydrous magnesium sulfate, filtered, the solvent was evaporated under reduced pressure, and the residue was separated by flash column chromatography with an eluent of PE: EA =1:1 to give 2.7g of a white solid with a yield of 88%.1H NMR(CDCl3,300MHz)δ(ppm)8.10(s,1H),7.48-7.44(d,J=8.4Hz,1H),6.92-6.89(m,2H),6.68(s,1H),4.28(s,1H),1.68(s,6H).
Example 74- [4, 4-dimethyl-5-oxo-3- (1-oxoisoindolin-5-yl) -2-thioimidazolidin-1-yl ] -2- (trifluoromethyl) benzonitrile (Compound 1)
4-isothiocyanato-2-trifluoromethylbenzonitrile (intermediate 9a,209mg,0.92 mmoL), 2-methyl-2- (1-oxoisoindolin-5-ylamino) propionitrile (100 mg,0.46 mmoL) was added to anhydrous DMF (5.0 mL), reacted at 50 ℃ with microwave for 6 hours, and TLC checked for completion. Added to 2N HCl (4.0 mL) and methanol (4.0 mL) and heated at reflux for 1 hour. Cooling, and evaporating the solvent under reduced pressure. The residue was added to ethyl acetate, the pH was adjusted to neutral with saturated sodium bicarbonate, and the layers were separated. The organic phase was evaporated under reduced pressure and the residue was separated by flash column chromatography eluting with dichloromethane acetone =20:1 to give 55mg of a white solid with a yield of 30%.1H NMR(DMDO-d6,300MHz)δ(ppm)8.05(t,1H),8.01-7.97(m,2H),7.86-7.84(m,1H),7.44-7.42(m,1H),6.45(s,1H),4.56(s,2H),1.63(s,6H).
Example 82-bromo-6-fluoro-3-nitrobenzoic acid (intermediate 4b)
Fuming nitric acid (1.0mL, 11.4 mmoL) was added dropwise to a mixed solution of 2-bromo-6-fluorobenzoic acid (2.5 g,11.4 mmoL) and concentrated sulfuric acid (7.5 mL) while cooling on ice. After the addition, the system was left to stir at room temperature for 2 hours. Poured into ice water (40.0 mL) to give a large amount of solid, filtered, the solid washed with water and dried under high vacuum to give 2.5g of a white solid in 83% yield. Directly used for the next reaction.
Example 92-bromo-6-fluoro-3-nitrobenzoic acid methyl ester (intermediate 5b)
2-bromo-6-fluoro-3-nitrobenzoic acid (intermediate 4b,2.5g,9.5 mmoL) was added to thionyl chloride (11.0 mL) and heated at reflux for 1 h. Volatile materials were distilled off under reduced pressure, and the residue was added to anhydrous methanol (30mL) and heated under reflux for 1 hour. The solvent was evaporated under reduced pressure and dried under high vacuum to give 2.5g of a white solid with a yield of 96%. Directly used for the next reaction.
Example 102 methyl bromo-6-fluoro-3-aminobenzoate (intermediate 6b)
Methyl 2-bromo-6-fluoro-3-nitrobenzoate (intermediate 5b,2.5g,9.0 mmoL) and reduced iron powder (1.0g, 17.8 mmoL) were added to glacial acetic acid (13.0 mL), heated under reflux for 2 hours, and the reaction was complete by TLC. The mixture was filtered through celite, washed with ethyl acetate, and the solvent was evaporated under reduced pressure. The residue was added to ethyl acetate (30mL) and water (10mL), liquid-separated, the solvent was evaporated under reduced pressure, and the residue was separated by flash column chromatography with petroleum ether/ethyl acetate =10/1 as an eluent, to give 1.7g of a colorless liquid with a yield of 70%.1H NMR(DMDO-d6,300MHz)δ(ppm)8.05(t,1H),7.05(t,1H),6.92-6.90(m,1H),5.44(s,2H),3.86.(s,3H).
Example 113-amine-2-nitrile-6-fluorobenzoic acid methyl ester (intermediate 7b)
Methyl 2-bromo-6-fluoro-3-aminobenzoate (intermediate 6b,1.7g,6.9 mmoL), cuprous cyanide (6.5 g,73.1 mmoL) were added to anhydrous DMF (50 mL) and reacted at 160 ℃ in an oil bath for 15 minutes, and the reaction was complete by TLC. Cooling, filtering with diatomite, washing with ethyl acetate, and evaporating the solvent under reduced pressure. The residue was taken up in ethyl acetate and washed with water. The solvent was evaporated under reduced pressure and the residue was subjected to flash column chromatography with petroleum ether/ethyl acetate =3/1 as eluent to give 530mg of a white solid with a yield of 40%.1H NMR(CDCl3,300MHz)δ(ppm)7.16(t,1H),6.90-6.85(dd,J1=9.0Hz,J2=3.9Hz,1H),4.53(br,2H),3.99(s,3H).
Example 124-amino-7-fluoroisoindolin-1-one (intermediate 8b)
Methyl 3-amine-2-cyano-6-fluorobenzoate (intermediate 7b,275mg,1.4 mmoL) and raney nickel (30 mg) were added to a mixed solution of methanol (19 mL) and water (6 mL), hydrogenated under pressure at 50 ℃ under 3 kg for 7 hours, filtered through celite, the solvent was evaporated under reduced pressure, and dried under high vacuum to give 210mg of a white solid with a yield of 89%. Directly used for the next reaction.1H NMR (acetone-d6, 300MHz) delta (ppm)7.45(br,1H),6.92-6.82(M,2H),4.78(br,2H),4.29(s,2H). MS (ESI): M/z =189.0(M + Na)+.
Example 132- (7-fluoro-1-oxoisoindolin-4-ylamino) -2-methylpropanenitrile (intermediate 9b)
Intermediate 9b was prepared as intermediate 9a in 51% yield as a white solid, except intermediate 8b was used instead of intermediate 8 a.1H NMR (acetone-d 6,300MHz) delta (ppm)7.55(br,1H),7.29(dd, J)1=6.6Hz,J2=2.7Hz,1H),7.13(t,1H),5.03(s,1H),4.37(s,2H),1.78(s,6H).
Example 144- [3- (7-fluoro-1-oxoisoindolin-4-yl) -4, 4-dimethyl-5-oxo-2-thioimidazolidin-1-yl ] -2- (trifluoromethyl) benzonitrile (Compound 2)
Compound 2 was prepared as compound 1 in a white solid with a yield of 35% except intermediate 9b was used instead of intermediate 9 a.1HNMR(CDCl3,300MHz)δ(ppm)7.98(dd,J1=19.2Hz,J2=2.4Hz,1H),7.84(dd,J1=8.4Hz,J2=2.1Hz,1H),7.46(dd,J1=8.7Hz,J2=3.9Hz,1H),7.31(t,1H),7.10(s,1H),4.50(q,2H),1.75(s,3H),1.53(s,3H).
Example 152-bromo-3-fluoro-6-nitrobenzoic acid (intermediate 4c) and 2-bromo-3-fluoro-5-nitrobenzoic acid (intermediate 4e)
Fuming nitric acid (2mL, 22.83 mmoL) was added dropwise to a mixed solution of 2-bromo-3-fluoro-benzoic acid (5 g,22.8 mmoL) and concentrated sulfuric acid (15mL) while cooling on ice. After the completion of the dropwise addition, the mixture was stirred at room temperature for 2 hours. Pour into ice water, appear a lot of solid, filter, wash solid with water, dry under high vacuum, 5.3g of white solid, a mixture of intermediates 4c and 4e (4 c/4e = 2/1) with 88% yield. Most of the mixture was used directly in the next reaction, and a small amount was isolated by column chromatography and identified as follows:
the intermediate 4c is a mixture of two or more,1H NMR(CDCl3,300MHz)δ(ppm)8.26(dd,J1=6.9,J2=3.3Hz,1H),7.48(dd,J1=6.9Hz,J2=5.7Hz,1H)。
the intermediate 4e is a mixture of two or more,1H NMR(CD3OD,400MHz)δ(ppm)8.39(dd,J1=1.8Hz,J2=1.2Hz,1H),8.18(dd,J1=6.0Hz,J2=1.8Hz,1H).
example 162-bromo-3-fluoro-6-nitrobenzoic acid methyl ester (intermediate 5c) and 2-bromo-3-fluoro-5-nitrobenzoic acid methyl ester (intermediate 5 e).
The preparation of a mixture of intermediate 5c and intermediate 5e as intermediate 5b gave the desired product in a reddish brown color with a yield of 100% and was used directly in the next step, except that intermediate 4c and intermediate 4e were used instead of intermediate 4 b.
Example 176-amino-2-bromo-3-fluorobenzoic acid methyl ester (intermediate 6c) and 5-amino-2-bromo-3-fluorobenzoic acid methyl ester (intermediate 6e)
A mixture of intermediate 6c and intermediate 6e was prepared as intermediate 6b except intermediate 5b was replaced with a mixture of intermediate 5c and intermediate 5 e. And performing column chromatography separation on the product to obtain a pure intermediate 6c and an intermediate 6 e.
Intermediate 6c, a white solid, in 53% yield.TLC: rf =0.66 (developing solvent: petroleum ether/ethyl acetate = 6: 1).1H NMR(CDCl3,300MHz)δ(ppm)6.99(dd,J1=9.0Hz,J2=7.8Hz,1H),6.60(dd,J1=9.0Hz,J2=4.2Hz,1H),4.58(br,2H),3.94(s,3H).
Intermediate 6e, a white solid, in 27% yield. TLC: rf =0.33 (developing solvent: petroleum ether/ethyl acetate = 6: 1).1H NMR(CDCl3,300MHz)δ(ppm)6.88(dd,J1=2.7Hz,J2=1.2Hz,1H),6.56(dd,J1=9.9Hz,J2=2.7Hz,1H),3.97(s,5H).
Example 186-amino-2-cyano-3-fluorobenzoic acid methyl ester (intermediate 7c)
Intermediate 7c was prepared as intermediate 7b in a white solid with a yield of 30% except intermediate 6c was used instead of intermediate 6 b. Directly used for the next reaction.
Example 197-amino-4-fluoroisoindolin-1-one (intermediate 8c)
Intermediate 8c was prepared as intermediate 8b in a white solid with a yield of 58% except intermediate 7c was used instead of intermediate 7 b.1HNMR (acetone-d 6,300MHz) delta (ppm)7.41(br,1H),7.00(t,3H),6.30(dd, J)1=9.0Hz,J2=3.6Hz,1H),5.72(br,2H),4.39(s,3H).
Example 202- (7-fluoro-3-oxoisoindolin-4-ylamino) -2-methylpropanenitrile (intermediate 9c)
Intermediate 9c was prepared as intermediate 9a in 62% yield as a white solid, except intermediate 8c was used instead of intermediate 8 a.1H NMR (acetone-d 6,300MHz) delta (ppm)7.66(br,1H),7.23(dd, J)1=17.7Hz,J2=8.7Hz,1H),7.02(br,1H),6.98(dd,J1=8.4Hz,J2=5.7Hz,1H),4.46(s,2H),1.78(s,6H).
EXAMPLE 214- [3- (7-fluoro-3-oxoisoindolin-4-yl) -4, 4-dimethyl-5-oxo-2-thioimidazolidin-1-yl ] -2- (trifluoromethyl) benzonitrile (Compound 3)
Compound 3 was prepared as compound 1, a white solid, in 36% yield, except intermediate 9c was used instead of intermediate 9 a.1H NMR(CDCl3,300MHz)δ(ppm)7.98-7.95(m,1H),7.90-7.87(m,1H),7.45-7.36(m,1H),7.35-7.26(m,1H),6.42(br,1H),4.52(s,2H),1.73(s,3H),1.51(s,3H).
Example 222-bromo-4-fluoro-5-benzoic acid (intermediate 4d)
Intermediate 4d was synthesized as intermediate 4b in a white solid with a yield of 91% except that 2-bromo-4-fluorobenzoic acid was used instead of 2-bromo-6-fluorobenzoic acid.1H NMR(CDCl3,300MHz)δ(ppm)8.59(d,J=7.8Hz,1H),7.88(d,J=5.7Hz,1H).
Example 232-bromo-4-fluoro-5-benzoic acid methyl ester (intermediate 5d)
Thionyl chloride (4.1mL,56.0 mmoL) was added dropwise to anhydrous methanol (244 mL) while cooling on ice, and stirring was continued under these conditions for 30 minutes. 2-bromo-4-fluoro-5-benzoic acid (13.4 g,50.8 mmoL) was added thereto, and the mixture was heated at 60 ℃ for reaction for 18 hours. The solvent was evaporated under reduced pressure, ethyl acetate was added, washed with saturated sodium carbonate, the solvent was evaporated under reduced pressure and dried under high vacuum to give 14g of a pale yellow solid with a yield of 99%. Directly used for the next reaction.1H NMR(CDCl3,300MHz)δ(ppm)8.62(d,J=7.8Hz,1H),7.69(d,J=9.3Hz,1H),3.99(s,3H).
Example 245-amino-2-bromo-4-fluorobenzoic acid methyl ester (intermediate 6d)
Methyl 2-bromo-4-fluoro-5-benzoate (14.0 g,50.3 mmoL) and reduced iron powder (14.1 g,252.0 mmoL) were added to a mixed solution of ethanol (396.0 mL), water (96.0 mL) and glacial acetic acid (19.3 mL), and the mixture was heated at 110 ℃ for 1 hour to complete the reaction as checked by TLC. After cooling, the solvent was evaporated under reduced pressure, and ethyl acetate and saturated sodium bicarbonate were added to the residue. The organic phase was dried over anhydrous magnesium sulfate, filtered, and the solvent was evaporated under reduced pressure and dried under high vacuum to give 10.0g of a yellow solid with a yield of 80%.1H NMR(CDCl3,300MHz)δ(ppm)7.30-7.18(m,2H),3.92(s,3H).
Example 255-amino-2-cyano-4-fluorobenzoic acid methyl ester (intermediate 7d)
Preparation of intermediate 7d is the same intermediate except intermediate 6d is used instead of intermediate 6b7b, white solid, 18% yield.1H NMR(CDCl3,300MHz)δ(ppm)8.62(d,J=8.7Hz,1H),7.69(d,J=10.5Hz,1H),3.95(s,3H).
Example 266-amino-5-fluoroisoindolin-1-one (intermediate 8d)
Intermediate 8d was prepared as intermediate 8b in a white solid with 85% yield, except intermediate 7d was used instead of intermediate 7 b.1H NMR(DMSO-d6,300MHz)δ(ppm)8.34(s,1H),7.19(d,J=10.8Hz,1H),7.01(d,J=8.1Hz,1H),5.32(s,2H),4.17(s,2H).
Example 272- (6-fluoro-3-oxoisoindolin-5-ylamino) -2-methylpropanenitrile (intermediate 9d)
Intermediate 9d was prepared as intermediate 9a in a white solid with 73% yield, except intermediate 8d was used instead of intermediate 8 a.1H NMR(DMSO-d6,300MHz)δ(ppm)8.51(s,1H),7.39(d,J=11.1Hz,1H),7.26(d,J=7.8Hz,1H),5.92(s,1H),4.25(s,2H),1.67(s,6H).
Example 284- [3- (6-fluoro-3-oxoisoindolin-5-yl) -4, 4-dimethyl-5-oxo-2-thioimidazolidin-1-yl ] -2- (trifluoromethyl) benzonitrile (Compound 4);
compound 4 was prepared as compound 1 in 18% yield as a white solid, except intermediate 9d was used instead of intermediate 9 a.1H NMR(CDCl3,300MHz)δ(ppm)8.00-7.98(m,2H),7.89-7.82(m,2H),7.46-7.43(d,J=9.0Hz,1H),6.78(s,1H),4.55(s,2H),1.70(s,3H),1.54(s,3H).MS(ESI):m/z=461.0(M-H)-.
Example 295-amino-2-cyano-3-fluorobenzoic acid methyl ester (intermediate 7e)
Intermediate 7e was prepared as intermediate 7b in a white solid with a yield of 38% except intermediate 6e was used instead of intermediate 6 b.1H NMR(DMSO-d6,300MHz)δ(ppm)7.09(d,J=2.4Hz,1H),6.81(s,2H),6.63(dd,J1=12.6Hz,J2=2.4Hz,1H),3.84(s,3H).
Example 306-amino-4-fluoroisoindolin-1-one (intermediate 8e)
Intermediate 8e was prepared as intermediate 8b in a white solid with a yield of 68% except intermediate 7e was used instead of intermediate 7 b.1H NMR(DMSO-d6,300MHz)δ(ppm)8.47(s,1H),6.66(d,J=1.5Hz,1H),6.52(dd,J1=11.4Hz,J2=1.8Hz,1H),5.58(s,2H),4.21(s,2H).
Example 312- (7-fluoro-3-oxoisoindolin-5-ylamino) -2-methylpropanenitrile (intermediate 9e)
Intermediate 9e was prepared as intermediate 7a in 61% yield as a white solid, except intermediate 8e was used instead of intermediate 8 a.1H NMR(DMSO-d6,300MHz)δ(ppm)8.65(s,1H),6.92(s,1H),6.79(d,J=12.3Hz,1H),6.62(s,1H),4.30(s,2H),1.65(s,6H).
Example 324- [3- (7-fluoro-3-oxoisoindolin-5-yl) -4, 4-dimethyl-5-oxo-2-thioimidazolidin-1-yl ] -2- (trifluoromethyl) benzonitrile (Compound 5)
Compound 5 was prepared as compound 1 in a white solid with a yield of 37% except intermediate 9e was used instead of intermediate 9 a.1H NMR(CD3OD,300MHz)δ(ppm)8.20-8.15(m,2H),8.03-7.99(m,2H),7.67(d,J=1.2Hz,1H),7.51(dd,J1=9.0Hz,J2=1.2Hz,1H),4.61(s,2H),1.61(s,6H).
Example 332-bromo-6-fluoro-4-nitrobenzoic acid (intermediate 4f)
2-fluoro-1-methyl-4-nitrobenzene (20.0 g,129 mmoL) and iron powder (0.87 g,15.5 mmoL) were added to liquid bromine (45.6 g,284 mmoL) and reacted in a sealed tube in an oil bath at 100 ℃ for 100 hours. Cooled, poured into ice water and excess bromine treated with sodium sulfite. Extraction with ether, combination of organic phases, washing with saturated brine and separation of liquids. The solvent was evaporated under reduced pressure and the residue was separated by flash column chromatography using petroleum ether as eluent to give 1-bromo-3-fluoro-2-methyl-5-nitrobenzene as a white solid in 7.5g, 25% yield.1H NMR(CDCl3,300MHz)δ(ppm)2.41(d,J=3.0Hz,1H),8.26(s,1H),7.86(d,J=8.4Hz,1H).MS(ESI):m/z=232.0(M-H)-.
1-bromo-3-fluoro-2-methyl-5-nitrobenzene (6.0 g,25.8 mmoL), potassium permanganate (16.3 g,103.0 mmoL), potassium hydroxide (11.5 g,206 mmoL) were added to water (60.0 mL), heated in an oil bath at 70 ℃ for 8 hours, and checked by TLCThe reaction was determined to be complete. The hot diatomaceous earth was filtered and washed with hot water. Cooling, adjusting pH to neutral with concentrated hydrochloric acid, extracting with ether, evaporating the solvent under reduced pressure, separating the residue by flash column chromatography with ethyl acetate/methanol =9/1 as eluent to obtain 1.7g of white solid with a yield of 25%.1H NMR(DMSO-d6,300MHz)δ(ppm)8.10(dd,J1=2.4Hz,J2=1.2Hz,1H),7.96(dd,J1=8.1Hz,J2=2.4Hz,1H).MS(ESI):m/z=262.0(M-H)-.
Example 342-bromo-6-fluoro-4-nitrobenzoic acid methyl ester (intermediate 5f)
Intermediate 5f was prepared as intermediate 5b in a white solid with 93% yield, except intermediate 4f was used instead of intermediate 4 b. Directly used for the next reaction.
Example 354-amino-2-cyano-6-fluorobenzoic acid methyl ester (intermediate 6f)
Intermediate 6f was prepared as intermediate 6b in a white solid with 93% yield, except intermediate 5f was used instead of intermediate 5 b. Directly used for the next reaction.
Example 362-nitrile-6-fluoro-4-nitrobenzoic acid methyl ester (intermediate 7f)
Intermediate 7f was prepared as intermediate 7b in 43% yield as a white solid, except intermediate 6f was used instead of intermediate 6 b.1H NMR(DMSO-d6,300MHz)δ(ppm)6.84(d,J=2.1Hz,1H),6.69(s,2H),6.57(d,J=14.1Hz,1H),3.78(s,3H).MS(ESI):m/z=193.0(M-H)-.
Example 375-amino-7-fluoroisoindolin-1-one (intermediate 8f)
Intermediate 8f was prepared as intermediate 8b in a white solid with a yield of 58% except intermediate 7f was used instead of intermediate 7 b.1H NMR(DMSO-d6,300MHz)δ(ppm)7.88(s,1H),6.41(d,J=1.2Hz,1H),6.27(dd,J1=12.3Hz,J2=1.5Hz,1H),6.02(s,2H),4.18(s,2H).MS(ESI):m/z=189.0(M+Na)+.
Example 382- (7-fluoro-1-oxoisoindolin-5-ylamino) -2-methylpropanenitrile (intermediate 9f)
Intermediate 9f was prepared as intermediate 9a in a white solid with a 56% yield, except intermediate 8f was used instead of intermediate 8 a.1H NMR(DMSO-d6,300MHz)δ(ppm)8.10(s,1H),6.97(s,1H),6.73(s,1H),6.53(d,J=12.3Hz,1H),4.29(d,2H),1.68(s,6H).MS(ESI):m/z=256.0(M+Na)+.
Example 394- [3- (7-fluoro-1-oxoisoindolin-5-yl) -4, 4-dimethyl-5-oxo-2-thioimidazolidin-1-yl ] -2- (trifluoromethyl) benzonitrile (Compound 6)
Preparation of Compound 6 with the exception of intermediate 9f instead of intermediate 9aMaterial 1, white solid, 37% yield.1H NMR(CD3OD,300MHz)δ(ppm)8.18-8.16(m,2H),8.01-7.99(m,1H),7.48(s,1H),7.33(d,J=7.2Hz,1H),4.56(s,2H),1.61(s,6H).MS(ESI):m/z=463.0(M+H)+.
EXAMPLE 404- [3- (6-fluoro-2-methyl-3-oxoisoindolin-5-yl) -4, 4-dimethyl-2, 5-dioxoimidazolidin-1-yl ] -2- (trifluoromethyl) benzonitrile (Compound 7)
60% sodium hydride (3.5 mg,0.087mmoL) was added to compound 4(30.0mg,0.067 mmoL) in dry DMF (3.0 mL) while cooling on ice. After the addition was complete, stirring was continued for 30 minutes in an ice bath. The ice bath was removed and methyl iodide (21. mu.L, 0.33mmoL) was added at room temperature. Stirring was continued at room temperature for 3 hours and the reaction was complete by TLC. Ethyl acetate was added and washed with water. The solvent was evaporated under reduced pressure and flash column chromatography was performed with petroleum ether/ethyl acetate =1/2 as eluent to give 25.0mg of a white solid with a yield of 81%.1H NMR(CD3OD,300MHz)δ(ppm)8.19(s,1H),8.05(d,J=8.4Hz,1H),7.94(d,J=8.4Hz,1H),7.80(d,J=6.6Hz,1H),7.38(d,J=8.7Hz,1H),4.45(s,2H),3.22(s,3H),1.58(s,6H).MS(ESI):m/z=461.0(M+H)+.
EXAMPLE 414- [3- (6-fluoro-3-oxoisoindolin-5-yl) -4, 4-dimethyl-2, 5-dioxoimidazolidin-1-yl ] -2- (trifluoromethyl) benzonitrile (Compound 8)
60% sodium hydride (3.5 mg,0.087mmoL) was added to compound 4(30.0mg,0.067 mmoL) in dry DMF (3.0 mL) while cooling on ice. After the addition was complete, stirring was continued for 30 minutes in an ice bath. Remove ice bath, stir at room temperature for 3hWhen the reaction was complete, the TLC checked. Add ethyl acetate and wash with water (3 ×). The solvent was evaporated under reduced pressure and flash column chromatography was performed with petroleum ether/ethyl acetate =1/2 as eluent to give 21.0mg of a white solid with a yield of 70%.1H NMR(CD3OD,300MHz)δ(ppm)8.19(s,1H),8.07(d,J=12.0Hz,1H),7.96(d,J=8.4Hz,1H),7.84(d,J=6.6Hz,1H),7.42(d,J=8.7Hz,1H),6.50(s,1H),4.54(s,2H),1.59(s,6H).MS(ESI):m/z=447.0(M+H)+.
EXAMPLE 424- [3- (2-Ethyl-6-fluoro-3-oxoisoindolin-5-yl) -4, 4-dimethyl-2, 5-dioxoimidazolidin-1-yl ] -2- (trifluoromethyl) benzonitrile (Compound 9)
Compound 9 was prepared as compound 7 in a white solid with a yield of 62% except that iodoethane was used instead of iodomethane.1H NMR(CD3OD,300MHz)δ(ppm)8.22(s,1H),8.08(dd,J1=8.7Hz,J2=1.8Hz,1H),8.00(d,J=8.4Hz,1H),7.83(d,J=6.6Hz,1H),7.43(d,J=8.7Hz,1H),4.49(s,2H),3.73(q,2H),1.61(s,6H),1.33(t,J=7.2Hz,3H).MS(ESI):m/z=475.0(M+H)+.
Example 431- (7-fluoro-3-oxoisoindolin-5-ylamino) cyclobutylcarbonitrile (intermediate 9g)
Intermediate 8e (180 mg,0.92 mmoL) and trimethylnitrilosilane (2.0 mL) were added to cyclobutanone (7.0 mL), the reaction was heated overnight at 70 ℃ in an oil bath for hours, and the reaction was complete by TLC. Saturated potassium carbonate (2.0 mL) was added, extraction was performed with ethyl acetate, the solvent was evaporated under reduced pressure, and the residue was separated by flash column chromatography with methanol/dichloromethane =1/20 as an eluent, to give 220.0mg of a pale yellow solid with a yield of 98%. Directly used for the next reaction.
Example 444- [ [5- (7-fluoro-3-oxoisoindolin-5-yl) -8-oxo-6-thioxo-5, 7-diazaspiro [3.4] octan-7-yl ] ] -2- (trifluoromethyl) benzonitrile (Compound 10)
Compound 10 was prepared as compound 1, a white solid, 41% yield, except intermediate 9g was used instead of intermediate 9 a.1H NMR (acetone-d 6,300MHz) δ (ppm)8.27(d, J =7.2Hz,1H),8.17(s,1H),8.07(d, J =6.3Hz,1H),8.00-7.90(m1H),7.65(d, J =1.5Hz,1H),7.53(dd, J =1.5Hz,1H)1=9.3Hz,J2=1.5Hz,1H),4.66(s,2H),2.76-2.62(m,4H),2.14-2.07(m,1H),1.68-1.64(m,1H).MS(ESI):m/z=475.0(M+H)+.
EXAMPLE 455- [ bis (tert-butoxycarbonyl) amino ] -2-cyano-4-fluorobenzoic acid methyl ester (intermediate 10a)
Intermediate 8d (1.9 g,9.9 mmoL), Boc anhydride (5.7 g,21.7 mmoL), N-dimethylaminopyridine (122 mg,1.0 mmoL) were added to anhydrous THF under ice bath, naturally warmed, and stirred overnight. The solvent was evaporated under reduced pressure and the residue was separated by flash column chromatography eluting with petroleum ether to give 2.2g of a white solid with a yield of 56%.1H NMR(CDCl3,300MHz)δ(ppm)8.01(d,J=7.5Hz,1H),7.54(d,J=9.0Hz,1H),3.99(s,3H),1.44(s,18H).MS(ESI):m/z=417.0(M+Na)+.
Example 466- [ bis (tert-Butoxycarbonyl) amino ] -5-fluoroisoindolin-1-one (intermediate 11a)
Intermediate 11a was prepared as intermediate 8b in 63% yield as a white solid, except intermediate 10a was used instead of intermediate 7 b.1H NMR (acetone-d 6,300MHz) δ (ppm)7.65(d, J =6.9Hz,1H),7.49(d, J =9.6Hz,1H),4.51(s,2H),1.44(s,18H) ms (esi): M/z =389.0(M + Na)+.
Example 476- [ bis (tert-butyloxycarbonyl) amino ] -5-fluoroisoindolin-1-one (intermediate 12a)
Intermediate 11a (1.2 g,3.28 mmoL), cesium carbonate (3.24 g,10.0 mmoL) and methyl iodide (1.1 mL,16.0 mmoL) were added to anhydrous DMF (10.0 mL) and stirred at room temperature overnight. The mixed system was added to ethyl acetate, washed with water, the solvent was evaporated under reduced pressure, and the residue was separated by flash column chromatography with petroleum ether/ethyl acetate =5/1 as eluent, to give 720.0mg of a white solid with a yield of 58%.1H NMR (acetone-d 6,300MHz) δ (ppm)7.61(d, J =6.9Hz,1H),7.48(d, J =9.6Hz,1H),4.50(s,2H),3.11(s,3H),1.43(s,18H) ms (esi) M/z =403.0(M + Na)+.
Example 486-amino-5-fluoro-2-methylisoindoline-1-one (intermediate 13a)
Trifluoroacetic acid (14.4 mL) was added dropwise to intermediate 12a (720 mg,1.9 mmoL) in dichloromethane (28.8 mL) while cooling on ice. The mixture was allowed to warm to room temperature and stirred overnight. The solvent was evaporated under reduced pressure, the residue was taken up in ethyl acetate, washed successively with saturated sodium bicarbonate and water, the solvent was evaporated under reduced pressure and dried under high vacuum to give 310mg of a white solid with a yield of 91%.1H NMR(CDCl3,300MHz)δ(ppm)7.21(d,J=6.3Hz,1H),7.03(d,J=7.8Hz,1H),4.24(s,2H),3.90(br,2H),3.15(s,3H).MS(ESI):m/z=203.0(M+Na)+.
EXAMPLE 492- (6-fluoro-2-methyl-3-oxoisoindolin-5-ylamino) -2-methylpropanenitrile (intermediate 14a)
Intermediate 14a was prepared as intermediate 9a in 62% yield as a white solid, except intermediate 13a was used instead of intermediate 8 a.1H NMR (acetone-d 6,300MHz) δ (ppm)7.45(d, J =6.0Hz,1H),7.30(d, J =8.6Hz,1H),5.25(s,1H),4.34(s,2H),3.08(s,3H),1.79(s,6H) ms (esi) M/z =270.0(M + Na)+.
EXAMPLE 504- [3- (6-fluoro-2-methyl-3-oxoisoindolin-5-yl) -4, 4-dimethyl-5-oxo-2-thioimidazolidin-1-yl ] -2- (trifluoromethyl) benzonitrile (Compound 11)
Preparation of compound 11 with compound 1 except intermediate 14a was used instead of intermediate 9a gave a white solid with a yield of 32%.1H NMR(CDCl3,300MHz)δ(ppm)8.00-7.96(m,2H),7.86(dd,J1=8.4Hz,J2=2.4Hz,1H),7.79(d,J=6.6Hz,1H),7.40(d,J=8.4Hz,1H),4.47(s,2H),3.22(s,3H),1.69(s,3H),1.53(s,3H).MS-EI:m/z=476.0(M)+.
Example 511- (6-fluoro-2-methyl-3-oxoisoindolin-5-amino) cyclobutyronitrile (intermediate 14b)
Intermediate 14b was prepared as in 9a except that cyclobutanone was used instead of acetone and 6-amino-5-fluoro-2-methylisoindoline-1-one (intermediate 13a) was used instead of 5-amino-1-isoindolinone (intermediate 8a) to give a white solid in 55% yield.1H NMR (acetone-d 6,300MHz) δ (ppm)7.31(d, J =10.8Hz,1H),6.99(d, J =7.8Hz,1H),5.97(s,1H),4.34(s,2H),3.09(s,3H),2.83-2.81(M,2H),2.63-2.54(M,2H),2.23-2.18(M,2H). ms (esi): M/z =260.0(M + H)+.
Example 524- [ [5- (6-fluoro-2-methyl-3-oxoisoindolin-5-yl) -8-oxo-6-thioxo-5, 7-diazaspiro [3.4] octan-7-yl ] ] -2- (trifluoromethyl) benzonitrile (Compound 12)
Preparation of compound 12 with the exception of using 1- (6-fluoro-2-methyl-3-oxoisoindolin-5-amino) cyclobutyronitrile (intermediate 14b) instead of 2-methyl-2- (1-oxoisoindolin-5-ylamino) propionitrile (intermediate 9a), gave compound 1 as a white solid in 26% yield.1H NMR(CDCl3,300MHz)δ(ppm)8.00-7.97(m,2H),7.89-7.83(m,2H),7.44(d,J=8.1Hz,1H),4.49(s,2H),3.22(s,3H),2.75-2.57(m,2H),2.43-2.22(m,2H),1.69-1.59(m,2H).MS(ESI):m/z=489.0(M+H)+.
Example 531- (7-fluoro-1-oxoisoindolin-5-ylamino) cyclobutyronitrile
Preparation of intermediate 1- (7-fluoro-1-oxoisoindolin-5-ylamino) cyclobutyronitrile with 2-methyl-2- (1-oxoisoindolin-5-ylamino) propionitrile (intermediate 9a) as a white solid, except that cyclobutanone was used instead of acetone, the yield was 78%。1H NMR(CDCl3,400MHz)δ(ppm)6.84(s,1H),6.42(s,1H),6.34(dd,J=10.9,1.4Hz,1H),4.72(s,1H),4.38(s,2H),2.85(ddd,J=12.3,8.8,5.6Hz,2H),2.42(dd,J=12.1,8.3Hz,2H),2.35–2.12(m,2H).
EXAMPLE 544- [5- (7-fluoro-1-oxoisoindolin-5-yl) -8-oxo-6-thioxo-5, 7-diazaspiro [3,4] oct-7-yl ] -2- (trifluoromethyl) benzonitrile (Compound 13)
Compound 13 was prepared as compound 1, a light yellow solid in 75% yield, except intermediate 1- (7-fluoro-1-oxoisoindolin-5-amino) cyclobutyronitrile was used in place of 2-methyl-2- (1-oxoisoindolin-5-ylamino) propionitrile (intermediate 9 a).1H NMR(CDCl3,300MHz)δ(ppm)7.99(d,J=8.4Hz,1H),7.97(s,1H),7.89(s,1H),7.85(dd,J=8.2,1.9Hz,1H),7.28(s,1H),7.14(d,J=8.9Hz,1H),4.60(s,2H),2.73(m,2H),2.65–2.47(m,2H),2.28(m,1H),1.72(m,1H).EI-MS474.08[M]+.
Example 556-bromo-5-fluoroisoindolin-1-one
6-amino-5-fluoroisoindolin-1-one (intermediate 8d) (3.0g,18.1mmoL) was added to a mixed solution of water (110 mL) and concentrated sulfuric acid (40 mL), cooled to 0 deg.C, and NaNO was slowly added dropwise2(1.9 g) in water (30 mL). After the addition was complete, stirring was continued at this temperature for 1 hour. A48% hydrobromic acid solution (300 mL) of CuBr (3.9 g) was added dropwise to the above system, and the reaction was heated in an oil bath at 60 ℃ to complete the addition, and the completion of the reaction was checked by TLC. Diluting with water, and extracting with ethyl acetate. Concentrating organic phase under reduced pressure, separating residue by flash column chromatography, and eluting with dichloromethaneAlkane methanol =50:1, giving 3.6g of a grey solid with a yield of 88%.1H NMR(DMSO-d6,300MHz)δ(ppm)8.73(brs,1H),7.92(d,J=6.3Hz,1H),7.64(d,J=8.4Hz,1H),4.35(s,2H).EI-MS229.0[M]+.
Example 566-bromo-2- (cyclopropylmethyl) -5-fluoroisoindolin-1-one
NaH (60%,5.1mg,0.127mmoL) was added to a solution of 6-bromo-5-fluoroisoindolin-1-one (20.0 mg,0.087mmoL) in anhydrous DMF (0.87mL) while cooling on ice. After the addition was complete, the mixture was stirred for 5 minutes. Bromomethylcyclopropane (13.0 μ L,0.127mmoL) and tetrabutylammonium iodide (9.5 mg,0.024mmoL) were added. Stirring was continued for 2 hours under ice bath and completion of the reaction was checked by TLC. The reaction is extracted by water and extracted by ethyl acetate. The organic phase was concentrated under reduced pressure and the residue was separated by preparative thin layer chromatography using petroleum ether: ethyl acetate =2:1 as developing solvent to give 8.0mg of a white solid with a yield of 32%.1H NMR (acetone-d 6,300MHz) δ (ppm)7.91(d, J =4.8Hz,1H),7.56(d, J =6.6Hz,1H),4.60(s,2H),3.42(d, J =8.1Hz,2H),1.07(m,1H),0.56(m,2H),0.33(m,1H).
Example 572- [2- (cyclopropylmethyl) -6-fluoro-3-isoindolin-5-amino ] -2-methylpropionic acid
Mixing 6-bromo-2- (cyclobutylmethyl) -5-5-fluoroisoindolin-1-one (95.0 mg,0.33mmoL), aminoisobutyric acid (52.0 mg,0.50mmoL), K2CO3(117.0mg,0.84mmoL), CuCl (6.24mg,0.063mmoL), 2-acetylcyclohexanone (9.0. mu.L) and water (14.0. mu.L) were added to DMF (0.45mL) and reacted under argon in an oil bath at 105 ℃ overnight. The solvent was evaporated under reduced pressure, water was added to the residue, and the pH was adjusted to neutral with 1N hydrochloric acid. Removing water and residue under reduced pressureThe residue was separated by flash column chromatography eluting with dichloromethane methanol =10:1 to give 40mg of a light red oil in 40% yield.1H NMR(CD3OD,300MHz)δ(ppm)7.22(brs,1H),7.04(br,1H),4.47(brs,2H),3.42(d,J=6.9Hz,1H),1.98(s,1H),1.59(s,6H),1.06(m,1H),0.56(m,2H),0.32(m,1H).
Example 582- [2- (cyclopropylmethyl) -6-fluoro-3-isoindolin-5-amino ] -2-methylpropanoic acid methyl ester
Reacting 2- [2- (cyclopropylmethyl) -6-fluoro-3-isoindoline-5-amino]-2-methylpropionic acid (40.0 mg,0.13mmoL), K2CO3(22.0mg), methyl iodide (10. mu.L) was added to anhydrous DMF (0.23 mL) and stirred at room temperature overnight. The solvent was evaporated under reduced pressure. The residue was separated by preparative thin layer chromatography using petroleum ether-ethyl acetate =1:1 as a developing solvent to give 21mg of a yellow oil with a yield of 50%.1H NMR(CDCl3,300MHz)δ(ppm)7.06(d,J=10.5Hz,1H),6.97(d,J=7.8Hz,1H),4.48(brs,1H),4.34(s,2H),3.74(s,3H),3.41(d,J=7.2Hz,2H),1.61(s,6H),1.00(m,1H),0.56(m,2H),0.29(m,1H).
Example 594- [ [3- [2- (cyclopropylmethyl) -6-fluoro-3-isoindolin-5-amino ] -4, 4-dimethyl-5-oxo-2-thioxoimidazolidin-1-yl ] ] -2- (trifluoromethyl) benzonitrile (Compound 14)
4-isothiocyanato-2-trifluoromethylbenzonitrile (intermediate 2) (34 mg,0.15mmoL) and 2- [2- (cyclopropylmethyl) -6-fluoro-3-isoindolin-5-amine]Methyl-2-methylpropionate (21 mg,0.066mmoL) was added to anhydrous DMF (0.40mL) and reacted at microwave 50 ℃ for 6 hours. Evaporating the solvent under reduced pressure, separating the residue by thin layer chromatography, and developing with developing agentAcetone =20:1 as dichloromethane, giving 17mg of a white solid with a yield of 50%.1H NMR(CDCl3,300MHz)δ(ppm)8.00(m,2H),7.87(dd,J=8.4,1.5Hz,1H),7.79(d,J=6.9Hz,1H),7.42(d,J=8.7Hz,1H),4.59(s,2H),3.50(m,2H),1.69(s,3H),1.53(s,3H),1.07(m,1H),0.62(m,2H),0.30(m,1H).
EXAMPLE 604- [3- (6-fluoro-2-acetylamino-3-oxoisoindolin-5-yl) -4, 4-dimethyl-2-thioxo-5-oxoimidazolidin-1-yl ] -2- (trifluoromethyl) benzonitrile (Compound 15)
Compound 4 (46.0 mg,0.10 mmoL), 2-bromoacetamide (68.6 mg,0.50mmoL) and anhydrous potassium carbonate (137.5 mg,1.0 mmoL) were added to anhydrous DMF (1.0mL) and reacted at 50 ℃ for 24 hours. The solvent was evaporated under reduced pressure and the residue was isolated by preparative thin layer chromatography using DCM: MeOH =20:1 as developing solvent to give 6.0mg of white solid in 18% yield.1H NMR(CD3OD,400MHz)δ(ppm)8.22-8.10(m,2H),8.01(dd,J=8.3,1.3Hz,1H),7.86(d,J=6.6Hz,1H),7.61(d,J=9.1Hz,1H),4.66(s,2H),4.40-4.24(m,2H),1.66(s,3H),1.52(s,3H).EI-MS519.10[M]+.
EXAMPLE 614- {3- [ 6-fluoro-2- (2- (4-methylpiperazin-1-yl) -2-oxoethyl) -3-oxoisoindolin-5-yl ] -4, 4-dimethyl-2-thioxo-5-oxoimidazolidin-1-yl } -2- (trifluoromethyl) benzonitrile (Compound 16)
Compound 4(30.0mg,0.06 mmoL), cesium carbonate (105.7 mg,0.32 mmoL) was added to anhydrous DMF (1.0mL), followed by addition of N-methylchloroacylpiperazine (27.7 mg,0.13mmoL) and reaction at 50 ℃ for 24 hours. Evaporating the solvent under reduced pressure, separating the residue by thin layer chromatography with developing solvent DCM: MeOH =10:1, giving 2.33mg of white solid in 12% yield.1H NMR(CDCl3,300MHz)δ(ppm)8.01(d,J=8.1Hz,2H),7.88(d,J=8.3Hz,1H),7.82(d,J=6.5Hz,1H),7.43(d,J=8.7Hz,1H),4.71(dd,J=28.1,15.3Hz,2H),4.41(dd,J=74.3,22.4Hz,2H),3.66(d,J=18.8Hz,4H),2.52(d,J=18.9Hz,4H),2.38(s,3H),1.71(s,3H),1.55(s,3H).EI-MS602.17[M]+.
EXAMPLE 624- [3- (6-fluoro-2-tert-Butoxycarbonyl-3-oxoisoindolin-5-yl) -4, 4-dimethyl-2-thioxo-5-oxoimidazolidin-1-yl ] -2- (trifluoromethyl) benzonitrile
Compounds No. 4 (150.0 mg,0.32 mmoL), DMAP (7.93 mg,0.06 mmoL) and (Boc)2O (106.2 mg,0.49 mmol) was added to anhydrous THF (5.0 mL) and reacted at room temperature for 2 hours. The solvent was evaporated under reduced pressure and the residue was separated by preparative thin layer chromatography using dichloromethane: acetone =20:1 as a developing solvent to give 146.0mg of a white solid with a yield of 80.0%.1H NMR(CDCl3,400MHz)δ(ppm)7.98(dd,J=10.0,5.0Hz,2H),7.91-7.81(m,2H),7.43(d,J=8.5Hz,1H),4.84(d,J=2.6Hz,2H),1.68(s,3H),1.59(s,9H),1.52(s,3H).
EXAMPLE 634- [3- (6-fluoro-1, 2-dimethyl-3-oxoisoindolin-5-yl) -4, 4-dimethyl-2-thioxo-5-oxoimidazolidin-1-yl ] -2- (trifluoromethyl) benzonitrile (Compound 17) and 4- [3- (6-fluoro-1-methyl-3-oxoisoindolin-5-yl) -4, 4-dimethyl-2-thioxo-5-oxoimidazolidin-1-yl ] -2- (trifluoromethyl) benzonitrile (Compound 18)
Compound 4 (146.0 mg,0.26 mmoL), cesium carbonate (169.1 mg,0.52 mmoL) were added to anhydrous DMF (5.0 mL), and iodomethane (184.2 mg,1.30 mmoL) was added and reacted at room temperature overnight. Saturated ammonium chloride was added to dilute the solution, followed by extraction with ethyl acetate 3 times, and the organic phases were combined, and DCM (3.0 ml) and trifluoroacetic acid (2.0 ml) were added to react at room temperature overnight. The solvent was evaporated under reduced pressure and the residue was separated by preparative thin layer chromatography using dichloromethane acetone =20:1 as the developing solvent.
Compound 17 was a white solid, 4.0mg, 3% yield.1H NMR(CDCl3,400MHz)δ(ppm)7.98(dd,J=15.2,5.0Hz,2H),7.86(dd,J=8.3,1.9Hz,1H),7.83-7.75(m,2H),3.95(d,J=15.8Hz,1H),3.23(s,3H),1.71(s,3H),1.56(s,6H).EI-MS490.11[M]+.
Compound 18 was a white solid, 15.0mg, 13% yield.1H NMR(CD3OD,400MHz)δ(ppm)8.22-8.11(m,2H),8.02(dd,J=8.3,1.7Hz,1H),7.82(d,J=6.6Hz,1H),7.62(d,J=9.0Hz,1H),4.80(m,1H),1.67(d,J=3.8Hz,3H),1.52(t,J=6.2Hz,6H).EI-MS476.09[M]+.
Example 641- (6-fluoro-3-oxoisoindoline-5-amino) cyclopentylcarboxonitrile
The compound 1- (6-fluoro-3-oxoisoindolin-5-amino) cyclopentanecarbonitrile was prepared in the same manner as 2-methyl-2- (1-oxoisoindolin-5-ylamino) propionitrile (intermediate 9a) except that cyclopentanone was used instead of acetone to give a white solid in 26% yield. 1H NMR (CDCl)3,300MHz)δ(ppm)8.00-7.97(m,2H),7.89-7.83(m,2H),7.44(d,J=8.1Hz,1H),4.49(s,2H),3.22(s,3H),2.75-2.57(m,2H),2.43-2.22(m,2H),1.69-1.59(m,2H).MS-ESI:489.0[M+H]+.
Example 654- [1- (6-fluoro-3-oxoisoindolin-5-yl) -4-oxo-2-thioxo-1, 3-diaza [4.4] nonan-spiro-3-yl ] -2- (trifluoromethyl) benzonitrile (Compound 19)
Compound 19 was prepared as compound 1, 41mg of a white solid, 27% yield, except that intermediate 1- (6-fluoro-3-oxoisoindolin-5-amino) cyclopentylcyanecarbonitrile was used instead of intermediate 2-methyl-2- (1-oxoisoindolin-5-ylamino) propionitrile (intermediate 9 a).1H NMR(CDCl3,400MHz)δ(ppm)8.00-7.99(m,2H),7.90-7.86(m,2H),7.46(d,J=8.8Hz,1H),7.09(s,1H),4.57(s,2H),2.42-2.29(m,4H),2.04-1.89(m,4H).MS-ESI489[M+H]+.
Example 662- (6-fluoro-3-oxoisoindolin-5-amino) -3-methoxy-2-methylpropanenitrile
The same 2- (6-fluoro-3-oxoisoindolin-5-ylamino) -3-methoxy-2-methylpropanenitrile (intermediate 9d) was prepared as 2- (6-fluoro-3-oxoisoindolin-5-ylamino) -2-methylpropanenitrile (intermediate 325 mg) as a white solid in 51% yield, except that 1-methoxyacetone was used instead of acetone.1H NMR(CDCl3,400MHz)δ(ppm)7.57(d,J=8.0Hz,1H),7.51(brs,1H),7.19(d,J=10.0Hz,1H),4.77(d,J=3.6Hz,1H),4.39(s,2H),3.73(d,J=9.2Hz,1H),3.67(d,J=9.2Hz,1H),3.53(s,3H),1.73(s,3H).
EXAMPLE 674- [3- (6-fluoro-3-oxoisoindolin-5-yl) -4-methoxymethyl-4-methyl-5-oxo-2-thioimidazolidin-1-yl ] -2- (trifluoromethyl) benzonitrile (Compound 20)
Except that 2- (6-fluoro-3-oxoisoindolin-5-amino) -3-methoxy-2-methylpropanenitrile is used instead of 2Compound 20 was prepared in the form of compound 1, a white solid with a yield of 20%, except for-methyl-2- (1-oxoisoindolin-5-ylamino) propionitrile (intermediate 9 a).1H NMR(CDCl3,300MHz)δ(ppm)8.00-7.82(m,4H),7.45(d,J=8.7Hz,1H),7.11(brs,1H),4.55(s,2H),3.76(d,J=9.9Hz,1H),3.52(d,J=9.9Hz,1H),3.50(s,3H),1.45(m,3H).LRMS(ESI)m/z[M+H]+493.
EXAMPLE 682-chloro-4- [5- (6-fluoro-3-oxoisoindolin-5-yl) -8-oxo-6-thioxo-5, 7-diazaspiro [3.4] -2-octan-7-yl ] -2- (trifluoromethyl) benzonitrile (Compound 21)
Compound 21 was prepared as compound 13 in a white solid with a yield of 29% except that 4-isothiocyanato-2-chlorobenzonitrile was used instead of 4-isothiocyanato-2-trifluoromethylbenzonitrile (intermediate 2).1H NMR(DMSO-d6,300MHz,)δ(ppm)8.83(s,1H),8.19(d,J=8.2Hz,1H),8.02(s,1H),7.78(dd,J=21.5,9.7Hz,2H),4.50(s,2H),2.63(m,2H),2.30(m,2H),2.00-1.59(m,2H).MS-EI440.05[M]+.
Example 694- [5- (6-fluoro-3-oxoisoindolin-5-yl) -8-oxo-6-thioxo-5, 7-diazaspiro [3,4] octan-7-yl ] -2-bromobenzonitrile (Compound 22)
Compound 22 was prepared as compound 13 in 33% yield as a white solid, except that 4-isothiocyanato-2-bromobenzonitrile was used instead of 4-isothiocyanato-2-trifluoromethylbenzonitrile (intermediate 2).1H NMR(DMSO-d6,300MHz)δ(ppm)8.83(s,1H),8.15(d,J=8.4Hz,2H),7.84-7.74(m,2H),4.49(s,2H),2.63(m,2H),2.33(m,2H),1.97-1.59(m,2H).MS-EI485.0[M+H]+.
Example 704- [5- (6-fluoro-3-oxoisoindolin-5-yl) -8-oxo-6-thioxo-5, 7-diazaspiro [3,4] octan-7-yl ] -2-methylbenzonitrile (Compound 23)
Compound 23 was prepared as compound 13 in a yellow solid with a yield of 38% except that 4-isothiocyanato-2-methylbenzonitrile was used in place of 4-isothiocyanato-2-trifluoromethylbenzonitrile (intermediate 2).1H NMR(CDCl3,300MHz,)δ(ppm)7.89(d,J=6.7Hz,1H),7.75(d,J=8.2Hz,1H),7.43(dd,J=14.1,8.2Hz,3H),6.33(s,1H),4.57(s,2H),2.67(m,2H),2.43–2.16(m,2H),1.67–1.51(m,2H).MS-EI420.11[M]+.
Example 714- [5- (6-fluoro-3-oxoisoindolin-5-yl) -8-oxo-6-thioxo-5, 7-diazaspiro [3,4] octan-7-yl ] -3-methoxybenzonitrile (Compound 24)
Compound 24 was prepared in 42% yield as a yellow solid with the exception of using 4-isothiocyanato-3-methoxybenzonitrile instead of 4-isothiocyanato-2-trifluoromethylbenzonitrile (intermediate 2).1H NMR(CDCl3,300MHz)δ(ppm)7.89(d,J=6.7Hz,1H),7.70(d,J=8.1Hz,1H),7.46(d,J=8.5Hz,1H),7.17-7.07(m,2H),6.34(s,1H),4.57(s,2H),3.98(s,3H),2.80-2.57(m,2H),2.44-2.19(m,2H),1.66(m,2H).MS-EI436.10[M]+.
Example 726-bromo-2- (cyclobutylmethyl) -5-fluoroisoindolin-1-one
6-bromo-2- (cyclobutylmethyl) -5-5-fluoroisoindolin-1-one was prepared as a yellow solid in 30% yield from 6-bromo-2- (cyclopropylmethyl) -5-5-fluoroisoindolin-1-one, except that bromomethylcyclobutane was used instead of bromomethylcyclopropane.1H NMR(CDCl3,300MHz)δ(ppm)8.02(d,J=6.3Hz,1H),7.19(d,J=7.8Hz,1H),4.29(s,2H),3.62(d,J=7.8Hz,2H),2.70-2.60(m,1H),2.13-1.80(m,6H).
Example 732- [2- (cyclobutylmethyl) -6-fluoro-3-isoindolin-5-amino ] -2-methylpropanoic acid
2- [2- (cyclobutylmethyl) -6-fluoro-3-isoindolin-5-amino ] -2-methylpropanoic acid was prepared as a yellow oil in 42% yield from 2- [2- (cyclopropylmethyl) -6-fluoro-3-isoindolin-5-amino ] -2-methylpropanoic acid, except that 6-bromo-2- (cyclobutylmethyl) -5-fluoroisoindolin-1-one was used instead of 6-bromo-2- (cyclopropylmethyl) -5-fluoroisoindolin-1-one. Directly used for the next reaction.
Example 742- [2- (cyclobutylmethyl) -6-fluoro-3-isoindolin-5-amino ] -2-methylpropanoic acid methyl ester
Except using 2- [2- (cyclobutylmethyl) -6-fluoro-3-isoindolin-5-amine]-2-Methylpropanoic acid instead of 2- [2- (cyclopropylmethyl) -6-fluoro-3-isoindolin-5-amine]2- [2- (cyclobutylmethyl) -6-fluoro-3-isoindolin-5-amine-2-methylpropanoic acid]Preparation of methyl (E) -2-methylpropionate the same as 2- [2- (cyclopropylmethyl) -6-fluoro-3-isoindolin-5-amine]Methyl 2-methylpropionate in the form of a yellow oil, yield 38%.1H NMR(CDCl3,300MHz)δ(ppm)7.04(d,J=10.8Hz,1H),6.95(d,J=7.8Hz,1H),4.48(brs,1H),4.18(s,2H),3.75(s,3H),3.58(d,J=7.8Hz,2H),2.66-2.61(m,1H),2.66-1.67(m,6H),1.62(s,6H).
Example 754- [ [3- [2- (cyclobutylmethyl) -6-fluoro-3-isoindolin-5-amino ] -4, 4-dimethyl-5-oxo-2-thioxoimidazolidin-1-yl ] ] -2- (trifluoromethyl) benzonitrile (Compound 25)
Except using 2- [2- (cyclobutylmethyl) -6-fluoro-3-isoindolin-5-amine]-methyl 2-methylpropionate instead of 2- [2- (cyclopropylmethyl) -6-fluoro-3-isoindolin-5-amine]Production of compound 25 was carried out in the same manner as compound 14 in the form of a white solid with a yield of 54% except for methyl-2-methylpropionate.1H NMR (acetone-d 6,300MHz) δ (ppm)8.31-8.26(M,2H),8.15-8.04(M,1H),7.75(d, J =6.6Hz,1H),7.62(d, J =9.3Hz,1H),4.58(s,2H),3.63(d, J =7.5Hz,2H),2.82-2.75(M,1H),2.12-2.04(M,6H),1.85(s,3H),1.75(s,3H) MS-ESI531.0[ M + H531.0 ], (M + H, 3H)]+.
EXAMPLE 764- [3- (6-fluoro-3-oxo-2-phenylisoindolin-5-yl) -4, 4-dimethyl-5-oxo-2-thioimidazolidin-1-yl ] -2- (trifluoromethyl) benzonitrile (Compound 26)
Mixing compound 4 (50.0 mg,0.108mmoL), iodobenzene (14 μ L,0.13mmoL), CuI (2.1mg,0.0108moL), K3PO4(41.0mg,0.216mmoL) and N, N' -dimethylethylenediamine (3.0. mu.L, 0.216mmoL) were added to anhydrous toluene (1.0mL) and reacted in an oil bath under argon atmosphere at 120 ℃ overnight. Water was added thereto, and the mixture was extracted with ethyl acetate. The organic phase was concentrated under reduced pressure and the residue was separated by flash column chromatography eluting with petroleum ether ethyl acetate =2:1 to give 24.0mg of a white solid with a yield of 42%.1H NMR (acetone-d 6,300MHz)δ(ppm)8.32-8.28(m,2H),8.14(dd,J=6.0,1.5Hz,1H),7.98(dd,J=6.6,0.9Hz,2H),7.88(d,J=5.1Hz,1H),7.75(d,J=6.9Hz,1H),7.48-7.44(m,2H),7.23-7.19(m,1H),5.15(d,J=4.8Hz,2H),1.78(s,3H),1.61(s,3H).MS-ESI539.0[M+H]+.
EXAMPLE 774- [3- (2-benzyl-6-fluoro-3-oxoisoindolin-5-yl) -4, 4-dimethyl-2-thioxo-5-oxoimidazolidin-1-yl ] -2-trifluoromethylbenzonitrile (Compound 27)
Compound 4 (46.2 mg,0.1 mmoL), benzyl bromide (17.1 mg,0.1 mmoL) and cesium carbonate were added to anhydrous dimethylsulfoxide (5.0 mL) and reacted under argon in an oil bath at 50 ℃ for 6 hours. Adding ethyl acetate, and washing with water to remove dimethyl sulfoxide. The organic phase was concentrated and the residue was separated by flash column chromatography eluting with petroleum ether ethyl acetate =2:1 to give 3.0mg of a white solid with a yield of 5.5%.1H NMR (acetone-d 6,300mhz) δ (ppm)8.31-8.26(M,2H),8.11(d, J =9.1Hz,1H),7.80(d, J =6.5Hz1H),7.65(d, J =3.2Hz,1H),7.38(M,5H),4.78(d, J =14.2Hz,2H),4.50(d, J =3.2Hz,2H),1.75(s,3H),1.58(s,1H) MS-ESI551.0[ M-H551.0 (M-H, 1H) ]]-.
Example 784- (6-fluoro-3-oxoisoindolin-5-ylamino) tetrahydro-2H-pyran-4-carbonitrile
The same preparation of 4- (6-fluoro-3-oxoisoindolin-5-ylamino) tetrahydro-2H-pyran-4-carbonitrile as 2- (6-fluoro-3-oxoisoindolin-5-ylamino) -2-methylpropanenitrile (intermediate 9d) was carried out in the form of a white solid with the exception of using 4-oxocyclohexanone instead of acetone, and the yield was 91.0%. Directly used for the next reaction.
Example 794- [1- (6-fluoro-3-oxoisoindolin-5-yl) -4-oxo-2-thioxo-1, 3-diazaspiro [4,5] decan-3-yl ] -2-trifluoromethylbenzonitrile (Compound 28)
Compound 28 was prepared as a yellow solid in 60% yield with the exception of intermediate 4- (6-fluoro-3-oxoisoindolin-5-ylamino) tetrahydro-2H-pyran-4-carbonitrile instead of 2-methyl-2- (1-oxoisoindolin-5-ylamino) propionitrile (intermediate 9 a).1H NMR(CD3OD,300MHz)δ(ppm)8.18(m,2H),8.04(d,J=6.2Hz,2H),7.81(d,J=6.6Hz,1H),7.62(d,J=9.0Hz,1H),4.58(s,2H),4.12(q,2H),3.86(m,2H),2.33(m,2H),2.15(m,1H),1.88(m,1H).MS-EI504.0[M]+.
Example 804-chloro-2- (6-fluoro-3-oxoisoindolin-5-ylamino) -2-methylbutyronitrile
The same procedure for the preparation of 4-chloro-2- (6-fluoro-3-oxoisoindolin-5-ylamino) -2-methylbutanenitrile as 2- (6-fluoro-3-oxoisoindolin-5-ylamino) -2-methylpropanenitrile (intermediate 9d) was followed, except that 4-chloro-2-butanone was used instead of acetone, in 76% yield. Directly used for the next reaction.
Example 814- [4- (2-chloromethyl) -3- (6-fluoro-2-acetylamino-3-oxoisoindolin-5-yl) -4-methyl-2-thioxo-5-oxoimidazolidin-1-yl ] -2-trifluoromethylbenzonitrile (Compound 29)
Except using the intermediate 4-chloro-2- (6-fluoro-3-oxoisoindoline-5-ylamino) -2-methylbutyronitrile instead of intermediate 2-methyl-2- (1-oxoisoindolin-5-ylamino) propionitrile (intermediate 9a), compound 29 was prepared as compound 1 in the form of a pale yellow solid with a yield of 19%.1H NMR (acetone-d 6,300mhz) δ (ppm)8.40-8.33(M,2H),8.25-8.22(d, J =8.9Hz,1H),7.88(s,1H),7.5(brs,1H),7.38(s,1H),4.67(t, J =7.8Hz,2H),4.46(s,2H),3.18(t, J =6.9Hz,2H),2.15(s,3H), MS-EI510.0[ M, 3H ] [ M, M ] s, M ] M]+.
Example 822-methyl-2- (6-methyl-5-oxo-6, 7-dihydro-5H-pyrrolo [3,4-b ] pyridin-3-ylamino) propionitrile
The intermediate 2-methyl-2- (6-methyl-5-oxo-6, 7-dihydro-5H-pyrrolo [3,4-b ] pyridin-3-ylamino) propionitrile was prepared as for 2-methyl-2- (1-oxoisoindolin-5-ylamino) propionitrile (intermediate 9a), except that 3-amino-6-methyl-6, 7-dihydro-5H-pyrrolo [3,4-b ] pyridin-5-one was used instead of intermediate 5-amino-1-isoindolinone (intermediate 8 a). White solid, yield 60%. Directly used for the next reaction.
Example 834- (3- (6-methyl-5-oxo-6, 7-dihydro-5H-pyrrolo [3,4-b ] pyrid-in-3-yl) -4, 4-dimethyl-5-oxo-2-thioimidazolidin-1-yl) -2-trifluoromethylbenzonitrile (Compound 30)
Except using the intermediate 2-methyl-2- (6-methyl-5-oxo-6, 7-dihydro-5H-pyrrolo [3,4-b ]]The preparation of compound 30 is also the same as compound 1 except that the 3-ylamino bipyridyl) propionitrile replaces intermediate 2-methyl-2- (1-oxoisoindolin-5-ylamino) propionitrile (intermediate 9 a). Light yellow solid, yield 7%.1H NMR(CD3OD,300MHz)δ(ppm)8.77(d,J=5.4Hz,1H),8.20(m,3H),8.05(d,J=8.4Hz,1H),4.65(s,2H),3.25(s,3H),1.61(s,6H).MS-EI459.1[M]+.
Example 842 methyl-4-nitrobenzoate
2-methyl-4-nitrobenzoic acid (5.0 g, 27.60 mmol) was dissolved in methanol (60mL) and concentrated sulfuric acid (1.5mL) was added dropwise with stirring. After the addition was complete, the mixture was heated to reflux for 22 hours. Cooling, concentrating, adding water, extracting with dichloromethane, combining organic phases, and washing with saturated brine. The organic phase was dried over anhydrous sodium sulfate, filtered, and the solvent was evaporated under reduced pressure to give 5.26g of a yellow solid with a yield of 98%. Directly used for the next reaction.1H NMR(CDCl3,300MHz)δ(ppm)8.11-8.05(m,3H),3.95(s,3H),2.69(s,3H).
Example 852- (bromomethyl) -4-nitrobenzoic acid methyl ester
Methyl 2-methyl-4-nitrobenzoate (5.0 g, 25.62 mmoL) was added to CCl4To (30mL) was added, with stirring, N-bromosuccinimide (6.84 g, 38.43 mmoL) and azobisisobutyronitrile (421 mg, 2.56 mmoL). Heated to 70 ℃ under argon protection and stirred for 2 hours. Cooling, evaporating the solvent under reduced pressure, and separating the residue by flash column chromatography to obtain 3.49g of white solid with a yield of 50%.1H NMR(CDCl3,300MHz)δ(ppm)8.34(d,J=2.1Hz,1H),8.21(d,J=8.7,2.1Hz,1H),8.12(d,J=8.4Hz,1H),4.98(s,2H),4.01(s,3H).
Example 862- (nitrilomethyl) -4-nitrobenzoic acid methyl ester
Methyl 2- (bromomethyl) -4-nitrobenzoate (3.4 g, 12.41 mmoL), sodium cyanide (608 mg, 12.41 mmoL) were added to a mixed system of dioxane (15mL) and water (20mL), heated to 80 ℃ and stirred for 4 hours. Cooled, added with water and extracted with ethyl acetate. The solvent was evaporated under reduced pressure and the residue was separated by flash column chromatography to give 1.11g of a white solid with a yield of 41%.1H NMR(CDCl3,300MHz)δ(ppm)8.44(m,1H),8.28-8.27(m,2H),4.31(s,2H),4.01(s,3H).
Example 874 amino-2- (nitrilomethyl) benzoic acid methyl ester
Methyl 2- (cyanomethyl) -4-nitrobenzoate (1.13 g, 5.06 mmoL), methanol (10mL), tetrahydrofuran (10mL) and ammonium chloride (2.7 g,50.55 mmoL) were added to a mixed system of water (20mL) and iron powder (1.42 g, 25.28 mmoL), heated to 80 deg.C, and stirred for 3 hours. Cooling, adding water, extracting with ethyl acetate, mixing organic phases, washing with saturated sodium chloride, drying with anhydrous sodium sulfate, and evaporating the solvent under reduced pressure to obtain yellow solid 962mg with a yield of 100%. Directly used for the next reaction.1H NMR(DMSO-d6,300MHz)δ(ppm)7.72(d,J=8.7Hz,1H),6.66(d,J=2.4Hz,1H),6.53(dd,J=8.7,2.1Hz,1H),6.19(s,2H),4.16(s,2H),3.74(s,3H).
Example 886-amino-3, 4-dihydroisoquinolin-1 (2H) -one
The preparation of 6-amino-3, 4-dihydroisoquinolin-1 (2H) -one was the same as that of 3-amine-2-cyano-6-fluorobenzoic acid methyl ester except that 4-amino-2- (cyanomethyl) benzoic acid methyl ester was used instead of methyl 3-amine-2-cyano-6-fluorobenzoate4-amino-7-fluoroisoindolin-1-one (intermediate 8 b). White solid, yield 85%.1H NMR(DMSO-d6,300MHz)δ(ppm)7.50(d,J=8.4Hz,1H),7.36(s,1H),6.44(dd,J=8.4,1.6Hz,1H),6.33(s,1H),5.69(s,2H),3.29-3.25(m,2H),2.70(t,J=6.4Hz,2H).
Example 892-methyl-2- (1-oxo-1, 2,3, 4-tetrahydroisoquinolin-6-ylamino) propionitrile
The intermediate 2-methyl-2- (1-oxo-1, 2,3, 4-tetrahydroisoquinolin-6-ylamino) propionitrile was prepared as described for 2-methyl-2- (1-oxoisoindolin-5-ylamino) propionitrile (intermediate 9a), except that 6-amino-3, 4-dihydroisoquinolin-1 (2H) -one was used instead of 5-amino-1-isoindolinone (intermediate 8 a). 191mg of a white solid, 67% yield.1H NM(DMSO-d6,300MHz)δ(ppm)7.66(d,J=8.4Hz,1H),7.56(s,1H),6.74(dd,J=8.4,2.4Hz,1H),6.69(s,1H),6.63(d,J=2.0Hz,1H),3.30-3.34(m,2H),2.81(t,J=6.4Hz,2H),1.67(s,6H).
EXAMPLE 904- [4, 4-dimethyl-5-oxo-3- (1-oxo-1, 2,3, 4-tetrahydroquinolin-6-yl) -2-t-thioimidazolidin-1-yl) -2-trifluoromethylbenzonitrile (Compound 31)
Compound 1 was prepared except that 2-methyl-2- (1-oxo-1, 2,3, 4-tetrahydroisoquinolin-6-ylamino) propionitrile, an intermediate, was used in place of 2-methyl-2- (1-oxoisoindolin-5-ylamino) propionitrile (intermediate 9 a). White solid, yield 30%.1H NMR (acetone-d 6,300mhz) δ (ppm)8.29(d, J =8.7Hz,1H),8.22(m,1H),8.12-8.09(m,2H),7.42-7.40(m,2H),7.18(brs,1H),3.57-3.63(m,2H),3.09(t, J =6.6Hz,2H),1.64(s,6H), MS-EI m/z458M+.
EXAMPLE 917-Nitro-3, 4-dihydro-2H-isoquinolin-1-one preparation (intermediate 15)
The starting material, 3, 4-dihydro-2H-isoquinolin-1-one (1.47g,9.99mmoL), was dissolved in sulfuric acid (20ml) and fuming nitric acid (2ml) was added dropwise with cooling in an ice bath. After stirring at room temperature for 45 minutes, the reaction solution was poured into a large amount of ice water. The aqueous solution was extracted with ethyl acetate, and the ethyl acetate layer was washed with water, saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated to dryness to give a yellow oil, which was subjected to flash column chromatography (petroleum ether: ethyl acetate = 3: 1) to give intermediate 15 (800 mg). LC-MS: C9H8N2O3[M+H]+Calculated 193.05, found 192.9.
EXAMPLE 927-amino-3, 4-dihydro-2H-isoquinolin-1-one preparation (intermediate 16)
The intermediate 15(500mg) was dissolved in 30ml of methanol, 1g of Raney-Ni catalyst was added, and the mixture was stirred overnight under hydrogen, the reaction solution was filtered, the filter cake was washed with 200ml of methanol, and the filtrates were combined and concentrated to dryness to give a white solid. This solid was isolated by flash column chromatography (petroleum ether: ethyl acetate =1: 1) to give intermediate 16(400 mg).1H NMR(DMSO-d6,400MHz)δ(ppm)8.55(d,1H,J=2Hz),8.32(dd,1H,J=2,8.4Hz),7.64(d,1H,J=8.4Hz),3.44(m,2H),3.07(m,2H).LC-MS:C9H10N2O[M+H]+Calculated 163.08, found 164.0.
EXAMPLE 932-methyl-2- [ (1-oxo-3, 4-dihydro-2H-isoquinolin-7-yl) amino ] propionitrile (intermediate 17)
Intermediate 16(400mg) was dissolved in 10ml of acetone, trimethylsilylcyanide (2ml) and 2ml of acetic acid were added, the tube sealed and heated to 60 ℃ overnight. The reaction solution was cooled to room temperature, concentrated under reduced pressure, then added with water, the aqueous solution was extracted with ethyl acetate (100ml × 3), the ethyl acetate layer was washed with water, washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated to dryness to give a yellow oil, which was subjected to flash column chromatography (petroleum ether: ethyl acetate =2: 1) to give intermediate 17(460 mg). (DMSO-d6, 400MHz) δ (ppm)7.40(d,1H, J =3.2Hz),7.13(d,1H, J =8.0Hz),6.95(dd,1H, J =2.8,8.0Hz),6.15(s,1H),3.33(t,2H, J =),2.77(t,2H),1.63(s,6H). LC-MS: C13H15N3O[M+H]+Calculated 230.1, found 230.0.
EXAMPLE 944- (4, 4-dimethyl-5-oxo-3- (1-oxo-1, 2,3, 4-tetrahydroisoquinolin-7-yl) -2-thioimidazolidin-1-yl) -2- (trifluoromethyl) benzonitrile preparation (Compound 32)
Intermediate 17(460mg,2.006mmoL), 4-isothiocyanato-2- (trifluoromethyl) benzonitrile (480mg,2.1mmoL) and a catalytic amount of triethylamine were dissolved in anhydrous tetrahydrofuran, the tube was sealed, heated to 50 ℃, and stirred overnight. The reaction solution was cooled to room temperature and concentrated to dryness under reduced pressure. The resulting crude product was dissolved in 10ml of methanol, 3ml of 2N hydrochloric acid solution was added, refluxed for 1 hour, cooled to room temperature, concentrated to distill off methanol, extracted with ethyl acetate, the organic layer was dried over anhydrous magnesium sulfate, filtered, concentrated to dryness, and the resulting oily product was subjected to flash column chromatography (dichloromethane: acetone =10:1) to obtain the objective compound. (CD)3OD,400MHz)δ(ppm)8.11-8.21(m,2H),8.03(d,1H,J=8.0Hz),7.95(d,1H,J=2.0Hz),7.53-7.55(m,2H),3.59(t,2H,J=6.8Hz),3.11(t,2H,J=6.4Hz),1.60(s,6H).LC-MS:C22H17F3N4O2S[M+H]+Calculated 459.1, found 458.8.
Example 955-Fluoroisoindolin-1-one preparation (intermediate 18)
Methyl 2-cyano-4-fluorobenzoate (1.5g,8.4mmoL) was dissolved in 30ml of methanol, 1g of Raney-Ni catalyst was added, and the mixture was stirred under hydrogen overnight. The reaction solution was filtered, the filter cake was washed with ethyl acetate (200 ml), the filtrates were combined and concentrated to dryness to give a crude product. Flash column chromatography (petroleum ether: ethyl acetate = 5:1) gave intermediate 18 (1.2 g, white solid)8H6FNO[M+H]+Calculated 152.0 and found 152.0.
Example 965-fluoro-2- (2-methoxyethyl) isoindolin-1-one preparation (intermediate 19)
The starting intermediate 18(700mg,4.6315mmoL) was dissolved in 10ml DMF and sodium hydrogen (65%, 342 mg) was added portionwise with ice bath cooling. The resulting mixture was stirred for 30 minutes, then 1-bromo-2-methoxyethane (800mg) was added, and the resulting black solution was heated to 60 ℃ and stirred for 5 hours. The reaction solution is cooled to room temperature, LC-MS detection shows that the reaction is complete, and the reaction solution is poured into ice water. The aqueous solution was extracted with ethyl acetate (100ml × 3), the ethyl acetate layer was washed with water, washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated to dryness to give a yellow oil, which was subjected to flash column chromatography (petroleum ether: ethyl acetate =1: 1) to give intermediate 19(800 mg).1H NMR(CDCl3,400MHz)δ(ppm)7.83-7.80(m,1H),7.16-7.12(m,1H),4.52(s,2H),3.79(t,2H,J=4.8Hz),3.64(t,2H,J=4.8Hz),3.33(s,3H).LC-MS:C11H12FNO2[M+H]+Calculated value 210.1, trueMeasure 210.0.
EXAMPLE 975-fluoro-2- (2-methoxyethyl) -6-nitro-isoindolin-1-one preparation (intermediate 20)
Intermediate 19(800mg) was dissolved in sulfuric acid (20ml), fuming nitric acid (2ml) was added dropwise under ice-bath cooling, and the mixture was stirred at room temperature for 3 hours, and then poured into a large amount of ice water. The aqueous solution was extracted with ethyl acetate, the ethyl acetate layer was washed with water, washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated to dryness to give a yellow oil, which was separated by flash column chromatography (petroleum ether: ethyl acetate =10:1) to give intermediate 20 (yellow solid, 800 mg). LC-MS: C11H11FN2O4Calculated value [ M + H]+255.1, found 254.9.
EXAMPLE 986-amino-5-fluoro-2- (2-methoxyethyl) isoindolin-1-one preparation (intermediate 21)
Intermediate 20(800mg) was dissolved in 30ml of methanol, 1g of Raney-Ni catalyst was added, and the mixture was stirred overnight under hydrogen. The reaction solution was filtered, the filter cake was washed with ethyl acetate (200 ml), and the filtrates were combined and concentrated to dryness to give intermediate 21 (700 mg).1H NMR(CD3OD,400MHz)δ(ppm)7.20-7.17(m,2H),4.44(s,2H),3.76(t,2H,J=5.2Hz),3.64(t,2H,J=5.2Hz),3.37(s,3H).LC-MS:C11H13FN2O2[M+H]+Calcd for 225.1, found 225.0.
Example 992- [ [ 6-fluoro-2- (2-methoxy) -3-oxo-isoindolin-5-yl ] amino ] -2-methylpropanenitrile preparation (intermediate 22)
The intermediate 21(400mg) was dissolved in 30ml of acetone, trimethylsilylcyanide (1 ml) and a few drops of acetic acid were added, the tube was sealed, heated to 50 ℃ and stirred continuously at constant temperature for 48 hours. The reaction solution was cooled to room temperature, concentrated under reduced pressure, then added with water, the aqueous solution was extracted with ethyl acetate (100ml × 3), the ethyl acetate layer was washed with water, washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated to dryness to give a yellow oil, which was subjected to flash column chromatography (petroleum ether: ethyl acetate =1: 2) to give intermediate 22(400 mg).1H NMR(CD3OD,400MHz)δ(ppm)7.55(d,1H,J=8.0Hz),7.30(d,1H,J=6.8Hz),4.88(s,3H),4.50(s,2H),3.79(t,2H,J=4.8Hz),3.65(t,2H,J=4.8Hz),1.78(s,6H).LC-MS:C15H18FN3O2[M+H]+Calculated 292.1, found 291.9.
EXAMPLE 1004- (3- (6-fluoro-2- (2-methoxyethyl) -3-oxoindolin-5-yl) -4, 4-dimethyl-5-oxo-2-thioimidazolidin-1-yl) -2- (trifluoromethyl) benzonitrile preparation (Compound 33)
4-isothiocyanato-2- (trifluoromethyl) benzonitrile (160mg) and intermediate 22(200mg) were dissolved in anhydrous DMF, sealed, heated to 80 ℃ and stirred overnight. The reaction solution was cooled to room temperature, and the resulting crude product was added to 10ml of methanol, followed by addition of 3ml of a 2N hydrochloric acid solution, stirring at room temperature for 3 hours, concentration to remove methanol by evaporation, and extraction with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated to dryness, and the resulting oil was subjected to thin layer chromatography (dichloromethane: acetone =10:1) to obtain compound 33.1H NMR(DMSO-d6,400MHz)δ(ppm)8.42-8.40(m,1H),8.34(s,1H),8.14-8.11(m,1H),7.80-7.77(m,1H),4.62(s,2H),3.73-3.64(m,4H),3.28(s,3H),1.60(s,3H),1.51(s,3H).LC-MS:C24H20F4N4O3S[M+H]+Calcd for 521.1, found 520.8.
EXAMPLE 1012-methyl-3, 4-dihydroisoquinolin-1 (2H) one preparation (intermediate 23)
The raw material 3, 4-dihydroisoquinoline-1 (2H) one (8 g, 54.36 mmoL) was dissolved in DMF (100ml), cooled in ice bath, sodium hydride (60%, 3.0g) was added in portions, and the resulting mixture was stirred for further 30 minutes, followed by addition of methyl iodide (15 g, 105.68 mmoL). The reaction solution was stirred overnight at room temperature, poured into ice water, extracted with ethyl acetate (500 ml × 3), the ethyl acetate layer was washed with water, washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated to dryness to give a yellow oil, and flash column chromatography (petroleum ether: ethyl acetate =1: 1) to give intermediate 23 (7.5 g, yellow oil).1H NMR(CDCl3,400MHz)δ(ppm)8.10(dd,1H,J=1.6,7.6Hz),7.42(t,1H,J=5.6Hz),7.35(t,1H,J=7.6Hz),7.17(dd,1H,J=0.4,7.6Hz),3.58(t,2H,J=6.8Hz),3.17(s,3H),3.02(t,2H,J=6.8Hz).LC-MS:C10H11Calculated value of NO [ M + H]+162.1, found 162.0.
EXAMPLE 1022-methyl-7-nitro-3, 4-dihydroisoquinolin-1 (2H) one preparation (intermediate 24)
Intermediate 23 (7.5 g) was dissolved in sulfuric acid (100ml), fuming nitric acid (20ml) was added dropwise under ice-bath cooling, and the mixture was stirred at room temperature overnight, and the reaction solution was poured into a large amount of ice water. The aqueous solution was extracted with ethyl acetate, the ethyl acetate layer was washed with water, washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated to dryness to give a yellow solid, petroleum ether: ethyl acetate =10:1 washing and filtering to obtain intermediate 24 as yellow solid8.5 g.1H NMR(CDCl3,400MHz)δ(ppm)8.93(dd,1H,J=2.4Hz),8.28(dd,1H,J=2.4,8.0Hz),7.39(d,1H,J=8.4Hz),3.66(t,2H,J=6.8Hz),3.22(s,3H),3.15(t,2H,J=6.4Hz).
EXAMPLE 1037-amino-2-methyl-3, 4-dihydroisoquinolin-1 (2H) one preparation (intermediate 25)
Intermediate 24 (8.5 g) was dissolved in 250ml of methanol, 1g of Raney-Ni catalyst was added and stirred under hydrogen overnight the reaction solution was filtered and the filter cake was washed with methanol (200 ml), the filtrates were combined and concentrated to dryness to give intermediate 25.1H NMR(CD3OD,400MHz)δ(ppm)7.30(dd,1H,J=2.4Hz),7.00(d,1H,J=8.0Hz),6.84(dd,1H,J=2.4,8.0Hz),3.57(t,2H,J=6.8Hz),3.13(s,3H),2.89(t,2H,J=6.8Hz).
EXAMPLE 1042-methyl-2- (2-methyl-1-oxo-1, 2,3, 4-tetrahydroisoquinoline-7-amino) propionitrile (intermediate 26)
Intermediate 25 (3.3 g) was dissolved in 10ml of acetone, trimethylsilylcyanide (5ml) and a few drops of acetic acid were added, the tube sealed, heated to 90 ℃ and stirred continuously at constant temperature for 48 hours. The reaction solution was cooled to room temperature, concentrated under reduced pressure, then water was added, the aqueous solution was extracted with ethyl acetate (100ml × 3), the ethyl acetate layer was washed with water, washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated to dryness to give a yellow oil, and flash column chromatography (dichloromethane: methanol = 5:1) to give intermediate 26(3.0 g).1H NMR(CDCl3,400MHz)δ(ppm)7.58(s,1H),7.13-7.09(m,2H),3.75(brs,1H),3.55(t,2H,9.6Hz),3.17(s,1H),2.93(t,2H,J=9.6Hz),1.73(s,6H).
EXAMPLE 1054- (4, 4-dimethyl-3- (2-methyl-1-oxo-1, 2,3, 4-tetrahydroisoquinolin-7-yl) -5-oxo-2-thioxoimidazolidin-1-yl) -2- (trifluoromethyl) benzonitrile preparation (Compound 34)
Intermediate 26 (160mg) and 4-isothiocyanato-2- (trifluoromethyl) benzonitrile (160mg) were dissolved in anhydrous DMF, sealed, heated to 80 ℃ and stirred overnight. The reaction solution was cooled to room temperature, and the resulting crude product was added to 10ml of methanol, followed by addition of 3ml of a 2N hydrochloric acid solution, stirring overnight at room temperature, concentration to remove methanol by evaporation, and extraction with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated to dryness, and the resulting oil was prepared by thin layer chromatography (petroleum ether: ethyl acetate =1: 2) to give compound 34 (180 mg, yellow solid).1H NMR(CDCl3,400MHz)δ(ppm)8.05-7.99(m,3H),7.88-7.86(m,1H),7.9(s,1H),3.67(t,2H,J=6.8Hz),3.21(s,3H),3.13(t,2H,J=6.8Hz),1.59(s,6H).LC-MS:C23H19F3N4O2S[M+H]+Calculated 473.1, found 473.1.
EXAMPLE 1062-chloro-4- (4, 4-dimethyl-3- (2-methyl-1-oxo-1, 2,3, 4-tetrahydroisoquinolin-7-yl) -5-oxo-2-thioimidazolidin-1-yl) benzonitrile preparation (Compound 35)
Intermediate 26 (120mg) and 2-chloro-4-isothiocyanatobenzonitrile (110mg) were dissolved in anhydrous DMF, the tube was sealed, and the mixture was heated to 80 ℃ and stirred overnight. The reaction solution was cooled to room temperature, and the resulting crude product was added to 10ml of methanol, followed by addition of 3ml of a 2N hydrochloric acid solution, stirring overnight at room temperature, concentration to remove methanol by evaporation, and extraction with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated to dryness, and the resulting oil was subjected to thin layer chromatography (petroleum ether: ethyl acetate =1:2) the title compound (34 mg, yellow solid) was obtained.1H NMR(DMSO-d6,400MHz)δ(ppm)8.19(d,1H,J=8.4Hz),8.04(d,1H,J=1.6Hz),7.86(s,1H),7.75(m,1H),7.49-7.46(m,2H),3.61(t,2H,J=6.4Hz),3.09(t,2H,J=6.4Hz),3.05(s,3H),1.50(s,6H).LC-MS:C22H19ClN4O2S[M+H]+Calculated 439.1, found 439.1.
Example 1074-amino-2, 6-difluoro-phenylacetonitrile preparation (intermediate 27)
4-bromo-3, 5-difluoroaniline (1.0g) and zinc cyanide (5.6g), Pd (PPh)3)4(320mg) were mixed in NMP (5ml) solvent, the system was exchanged with argon and heated to 100 ℃ to react with stirring overnight. TLC monitored that the reaction had ended. Diluting with ethyl acetate and water, filtering, separating layers, washing the organic phase with water, washing with saturated brine, drying, filtering, evaporating to obtain a crude product, and separating by flash column chromatography (petroleum ether: ethyl acetate =15:1) to obtain intermediate 27 as a yellow solid (320 mg).1H NMR(CDCl3,400MHz)δ(ppm)6.23(d,2H),4.62(brs,2H).LC-MS:C7H4F2N2[M+H]+Calculated 155.0 and found 155.0.
Example 1082, 6-difluoro-4-isothiocyanatobenzonitrile preparation (intermediate 28)
Intermediate 27(300mg) was suspended in dichloromethane and water (20 ml: 20ml), and 1g of solid sodium bicarbonate was added. The resulting reaction was added dropwise to a solution of thiophosgene (400mg) in methylene chloride, and stirred at room temperature overnight. TLC showed the reaction was complete, the dichloromethane layer was separated, dried over anhydrous sodium sulfate, filtered, and concentrated to give intermediate 28, which was used directly in the next reaction.
Example 1094- (4, 4-dimethyl-3- (2-methyl-1-oxo-1, 2,3, 4-tetrahydroisoquinolin-7-yl) -5-oxo-2-thioimidazolidin-1-yl) -2, 6-difluorobenzonitrile (Compound 36)
Intermediate 26 (120mg) and intermediate 28(120mg) were dissolved in anhydrous DMF, the tube was sealed, heated to 80 ℃ and stirred overnight. The reaction solution was cooled to room temperature, and the resulting crude product was added to 10ml of methanol, followed by addition of 3ml of a 2N hydrochloric acid solution, stirring overnight at room temperature, concentration to remove methanol by evaporation, and extraction with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated to dryness, and the resulting oil was prepared by thin layer chromatography (petroleum ether: ethyl acetate =1: 1) to give compound 36 (18 mg, yellow solid).1H NMR(CDCl3,400MHz)δ(ppm)8.03(d,1H,J=2.0Hz),7.38-7.30(m,4H),3.67(t,2H,J=6.8Hz),3.20(s,3H),3.12(t,2H,J=6.8Hz),1.60(s,6H).LC-MS:C22H18F2N4O2S[M+H]+Calculated 441.0, found 441.1.
Biological Activity test example 1Androgen receptor activation assay by inhibiting androgen DHT with compound
The purpose is as follows: the cellular level of the test compound was examined for the inhibition of the activation of androgen receptor by DHT.
Test cells: androgen receptor positive cells LNCaP, overexpressing androgen receptor and stably transferring into luciferase (luciferase) plasmid regulated and expressed by androgen receptor; hereinafter referred to as L1AR cells.
The experimental method comprises the following steps: intracellular Luciferase activity was detected using the Luciferase assay system kit (PROMEGA; E1501).
The experimental steps are as follows:
1. culturing L1AR cells (RPMI-1640 medium containing 10% FBS), changing the culture solution to RPMI-1640 culture solution containing 10% Charcol strippod FBS (activated carbon-treated fetal bovine serum) after digestion, and plating in 96-well plate at 2000 cell density per well;
2. after 3 days of plating, dosing: setting cell control group, DHT control group (adding DHT with final concentration of 1 nM), compound test group (containing DHT with final concentration of 1nM, compound initial concentration of 1800nM, 3-fold dilution of 1800, 600, 200, 66.67, 22.22, 7.41, 2.47, 0.82 nM)
3. After 3 days of compound treatment, the supernatant was discarded, 20. mu.l of cell lysate equilibrated at room temperature was added to each well, and the cells were lysed thoroughly by shaking in a shaker.
4. Transferring the liquid after cell lysis into a 96-well opaque white plate, adding 100 mu l of Luciferase assay detection reagent into each well, mixing uniformly, and immediately using PerkinEmlerenvisionTMThe instrument measures the fluorescence intensity over the full wavelength range (Relative LightUnit, RLU).
5. Calculation of AR activation inhibition by compound:
inhibition rate (%) = (drug test well-DHT control)/(cell control-DHT control) × 100
6. Log (inhibition) vs. stress-Variable slope (fourparameters) curve fitting was performed on the data using Graphpad prism5.0, and the corresponding IC was calculated50。
And (3) testing results:
compound (I) | IC50(nM) |
1 | 24.2 |
2 | 120 |
3 | 92.3 |
4 | 41.6 |
5 | 50.9 |
7 | 21.6 |
14 | 24.1 |
15 | 86.2 |
19 | 60.0 |
21 | 12.8 |
22 | 6.0 |
23 | 38.8 |
24 | 23.7 |
25 | 31.2 |
26 | 27.2 |
27 | 74.9 |
28 | 153 |
32 | 66.7 |
34 | 36.7 |
35 | 30.2 |
36 | 68.4 |
Biological Activity test example 2Inhibition effect of compound on PSA protein secretion of prostate cancer LNCaP cells induced by DHT
The experimental method comprises the following steps: the PSA content in the cell supernatant was measured using a PSA (Total) EIA assay kit manufactured by ALPCO.
The experimental steps are as follows:
1. normally culturing LNCaP cells (RPMI 1640 culture medium containing 10% FBS), changing the culture solution after digestion to RPMI1640 culture solution containing 10% CS-FBS (charcoal adsorption-treated serum), plating in 96-well plate with cell density of 2 × 104Per ml, about 2000 per well;
2. after 3 days from plating, RPMI1640 medium containing 10% CS-FBS (charcoal adsorption-treated serum) containing 1nM DHT was renewed. Adding medicine: set 1 well as a negative control well (1 nM DHT added, no compound added), positive compound MDV3100 and the example compound starting concentration 10000nM, sequentially 5-fold diluted 2000, 400, 80, 16, 3.2, 0.64, 0.128 nM.
3. After the compound treatment for 3 days, 50. mu.l of the supernatant was collected and the PSA content in the cell supernatant was measured using a PSA (Total) EIA assay kit (ALPCO). FlexStation3 measured optical density values (OD) at a wavelength of 450 nm.
Data processing and results:
1. at the end of the experiment, the compounds have no obvious inhibition effect on cell growth under microscope observation, the cell growth inhibition rate of each compound is determined to be lower than 30 percent for the first time, and the cytotoxic effect is eliminated.
2. Calculation of inhibition rate of PSA protein secretion: inhibition (%) = [1- (drug test well-negative control well)/negative control well ] × 100
3. IC was calculated from inhibition at each concentration using GraphPad Prism50The results are shown in the following table:
compound (I) | IC50(nM) |
1 | 31.6 |
4 | 19.8 |
5 | 17.5 |
6 | 168 |
7 | 56.0 |
9 | 26.5 |
10 | 33.0 |
11 | 15.7 |
12 | 24.1 |
Claims (38)
1. A compound of formula I or a pharmaceutically acceptable salt, solvate, prodrug, stereoisomer, tautomer, polymorph or metabolite thereof,
wherein,
the ring A is a 6-to 10-membered aromatic ring;
ring B is a benzene ring or a 6-membered heteroaromatic ring;
R1is H, C1-C4 alkyl or phenyl, the C1-C4 alkyl is optionally substituted by one or more groups selected from C3-C6 cycloalkyl, C1-C6 alkoxy, -NH2Mono (C1-C6 alkyl) amino, di (C1-C6 alkyl) amino, deuterium atom, phenyl and-C (O) R8Wherein R is substituted by the group of8Is selected from-NH2Mono (C1-C6 alkyl) amino, di (C1-C6 alkyl) amino or a 5-to 7-membered heterocyclic group containing at least 1 nitrogen atom, the 5-to 7-membered heterocyclic group containing at least 1 nitrogen atom being optionally substituted with C1-C4 alkyl;
R2is H, halogen or C1-C4 alkyl, said C1-C4 alkyl being optionally substituted by one or more halogen atoms;
R3and R4Each independently is-CH2-R6Wherein R is6H, OH, carboxyl, benzyloxy, C1-C4 alkoxy or halogenated C1-C2 alkyl;
or R3、R4And the carbon atoms connected with the compounds form 3-6 membered cycloalkyl or 4-6 membered heterocyclic group;
R5cyano, halogen, C1-C4 alkyl or C1-C4 alkoxy, said C1-C4 alkyl being optionally substituted by one or more halogen atoms;
R7is H or halogen;
x is S or O;
y is- (CH)2)n-, O or a direct bond, wherein- (CH)2)nOptionally substituted by one or more deuterium atoms or methyl groups, n being 1 or 2.
2. The compound of claim 1, or a pharmaceutically acceptable salt, solvate, prodrug, stereoisomer, tautomer, polymorph, or metabolite thereof, wherein:
the ring A is a 6-to 10-membered aromatic ring;
ring B is a benzene ring or a 6-membered heteroaromatic ring;
R1is H or C1-C4 alkyl, the C1-C4 alkyl is optionally substituted by one or more C3-C6 cycloalkaneRadical, C1-C6 alkoxy, -NH2Mono (C1-C6 alkyl) amino, di (C1-C6 alkyl) amino, -CONH2Mono (C1-C6 alkyl) carbamoyl, di (C1-C6 alkyl) carbamoyl and deuterium atom;
R2is H, halogen or C1-C4 alkyl, said C1-C4 alkyl being optionally substituted by one or more halogen atoms;
R3and R4Each independently is-CH2-R6Wherein R is6H, OH, carboxyl, benzyloxy or C1-C4 alkoxy;
or R3、R4And the carbon atoms connected with the compounds form 3-6 membered cycloalkyl or 4-6 membered heterocyclic group;
R5is cyano, halogen or C1-C4 alkyl, said C1-C4 alkyl being optionally substituted by one or more halogen atoms;
x is S or O;
y is- (CH)2)n-, O or a direct bond, wherein- (CH)2)n-optionally substituted by one or more deuterium atoms, n is 1 or 2;
R7is H.
3. The compound of claim 2, or a pharmaceutically acceptable salt, solvate, prodrug, stereoisomer, tautomer, polymorph, or metabolite thereof, wherein ring a is a phenyl ring and ring B is a phenyl ring.
5. The compound of claim 2 or a pharmaceutical thereofA pharmaceutically acceptable salt, solvate, prodrug, stereoisomer, tautomer, polymorph or metabolite thereof, wherein R is1Is H or C1-C3 alkyl, the C1-C3 alkyl is optionally substituted by one or more groups selected from C3-C6 cycloalkyl, C1-C4 alkoxy, di (C1-C4 alkyl) amino, -CONH2And deuterium atom.
6. The compound of claim 5, or a pharmaceutically acceptable salt, solvate, prodrug, stereoisomer, tautomer, polymorph, or metabolite thereof, wherein R is1Is H or C1-C2 alkyl, said C1-C2 alkyl being optionally substituted by one or more groups selected from cyclopropyl, methoxy, diethylamino, -CONH2And deuterium atom.
7. The compound of claim 6, or a pharmaceutically acceptable salt, solvate, prodrug, stereoisomer, tautomer, polymorph, or metabolite thereof, wherein R is1Is H, methyl, ethyl, cyclopropylmethyl, 2- (methoxy) ethyl, 2- (diethylamino) ethyl, -CH2CONH2or-CD3。
8. The compound of claim 7, or a pharmaceutically acceptable salt, solvate, prodrug, stereoisomer, tautomer, polymorph, or metabolite thereof, wherein R is1Is H, methyl or ethyl.
9. The compound of claim 2, or a pharmaceutically acceptable salt, solvate, prodrug, stereoisomer, tautomer, polymorph, or metabolite thereof, wherein R is2Is H or halogen.
10. The compound of claim 9, or a pharmaceutically acceptable salt, solvate, prodrug thereofA compound, stereoisomer, tautomer, polymorph or metabolite, wherein R2Is H or F.
11. The compound of claim 2, or a pharmaceutically acceptable salt, solvate, prodrug, stereoisomer, tautomer, polymorph, or metabolite thereof, wherein when R is3And R4Each independently is-CH2-R6When R is6Is H.
12. The compound of claim 2, or a pharmaceutically acceptable salt, solvate, prodrug, stereoisomer, tautomer, polymorph, or metabolite thereof, wherein when R is3、R4And carbon atoms connected with the 3-6 membered cycloalkyl or 4-6 membered heterocyclic group are formed together, wherein the 3-6 membered cycloalkyl is cyclopropyl, cyclobutyl or cyclopentyl, and the 4-6 membered heterocyclic group is oxetanyl or azetidinyl.
13. The compound of claim 12, or a pharmaceutically acceptable salt, solvate, prodrug, stereoisomer, tautomer, polymorph or metabolite thereof, wherein the 3-6 membered cycloalkyl is cyclobutyl and the 4-6 membered heterocyclyl is oxetanyl.
14. The compound of claim 2, or a pharmaceutically acceptable salt, solvate, prodrug, stereoisomer, tautomer, polymorph, or metabolite thereof, wherein R is5Is cyano or C1-C4 alkyl, said C1-C4 alkyl being optionally substituted by one or more atoms selected from F, Cl and Br.
15. The compound of claim 14, or a pharmaceutically acceptable salt, solvate, prodrug, stereoisomer, tautomer, polymorph, or metabolite thereof, wherein R is5Is C1-C2 alkyl, said C1-C2 alkyl being optionally substituted by one or more F atoms.
16. The compound of claim 15, or a pharmaceutically acceptable salt, solvate, prodrug, stereoisomer, tautomer, polymorph, or metabolite thereof, wherein R is5is-CF3。
17. The compound of claim 2, or a pharmaceutically acceptable salt, solvate, prodrug, stereoisomer, tautomer, polymorph, or metabolite thereof, wherein Y is-CH2-。
18. The compound of claim 1, or a pharmaceutically acceptable salt, solvate, prodrug, stereoisomer, tautomer, polymorph, or metabolite thereof, wherein the compound of formula I is a compound of formula II:
wherein,
R1is H, C1-C4 alkyl or phenyl, said C1-C4 alkyl being optionally substituted by one or more groups selected from C3-C6 cycloalkyl, C1-C6 alkoxy, phenyl and-C (O) R8Wherein R is substituted by the group of8Selected from amino, mono (C1-C6 alkyl) amino, di (C1-C6 alkyl) amino or a 5-to 7-membered heterocyclic group containing at least 1 nitrogen atom, said 5-to 7-membered heterocyclic group containing at least 1 nitrogen atom being optionally substituted with C1-C4 alkyl;
R2is H, halogen or C1-C4 alkyl, said C1-C4 alkyl being optionally substituted by one or more halogen atoms;
R3and R4Each independently is-CH2-R6Wherein R is6Is H, C1-C4 alkoxy or halogenated C1-C2 alkyl;
or R3、R4And the carbon atoms connected with the compounds form 3-6 membered cycloalkyl or 4-6 membered heterocyclic group;
R5is halogen, C1-C4 alkyl or C1-C4 alkoxy, said C1-C4 alkyl being optionally substituted by one or more halogen atoms;
R7is H or halogen;
y is- (CH)2)n- (CH)2)nOptionally substituted by one or more C1-C4 alkyl groups, n is 1 or 2.
19. The compound of claim 18, or a pharmaceutically acceptable salt, solvate, prodrug, stereoisomer, tautomer, polymorph, or metabolite thereof, wherein R is1Is H, C1-C4 alkyl or phenyl, said C1-C4 alkyl being optionally substituted by one or more groups selected from C3-C6 cycloalkyl, C1-C6 alkoxy, phenyl and-C (O) R8Wherein R is substituted by the group of8Selected from amino or a 5-to 7-membered heterocyclic group containing at least 1 nitrogen atom, said 5-to 7-membered heterocyclic group containing at least 1 nitrogen atom being optionally substituted with a C1-C4 alkyl group;
20. the compound of claim 19, or a pharmaceutically acceptable salt, solvate, prodrug, stereoisomer, tautomer, polymorph, or metabolite thereof, wherein R is1Is H, C1-C4 alkyl or phenyl, said C1-C4 alkyl being optionally substituted by one or more groups selected from C3-C6 cycloalkyl, C1-C4 alkoxy, phenyl and-C (O) R8Wherein R is substituted by the group of8Selected from amino groups or 6-membered heterocyclic groups containing at least 1 nitrogen atom, said 6-membered heterocyclic group containing at least 1 nitrogen atom being optionally substituted by C1-C4 alkyl.
21. The compound of claim 20, or a pharmaceutically acceptable salt, solvate, prodrug, stereoisomer, tautomer thereofPolymorphs or metabolites of, wherein R1Is H, C1-C4 alkyl or phenyl, said C1-C4 alkyl optionally substituted with one or more groups selected from cyclopropyl, cyclobutyl, methoxy, phenyl and-C (O) R8Wherein R is substituted by the group of8Selected from amino or N-methylpiperazinyl.
22. The compound of claim 21, or a pharmaceutically acceptable salt, solvate, prodrug, stereoisomer, tautomer, polymorph, or metabolite thereof, wherein R is1Is H, methyl, ethyl, phenyl, cyclopropylmethyl, cyclobutylmethyl, 2- (methoxy) ethyl, benzyl, -CH2C(O)NH2Or
23. The compound of claim 18, or a pharmaceutically acceptable salt, solvate, prodrug, stereoisomer, tautomer, polymorph, or metabolite thereof, wherein R is2Is H or halogen.
24. The compound of claim 23, or a pharmaceutically acceptable salt, solvate, prodrug, stereoisomer, tautomer, polymorph, or metabolite thereof, wherein R is2Is H or F.
25. The compound of claim 18, or a pharmaceutically acceptable salt, solvate, prodrug, stereoisomer, tautomer, polymorph, or metabolite thereof, wherein, when R is3And R4Each independently is-CH2-R6When R is6Is H, -OCH3or-CH2Cl。
26. The compound of claim 18 or a pharmaceutically acceptable salt thereofOr a salt, solvate, prodrug, stereoisomer, tautomer, polymorph or metabolite thereof, wherein, when R is3、R4And carbon atoms connected with the heterocyclic group and the heterocyclic group form 3-6 membered cycloalkyl or 4-6 membered heterocyclic group together, wherein the 4-6 membered heterocyclic group is 4-6 membered heterocyclic group containing 1 oxygen atom.
27. The compound of claim 26, or a pharmaceutically acceptable salt, solvate, prodrug, stereoisomer, tautomer, polymorph, or metabolite thereof, wherein, when R is3、R4And carbon atoms connected with the above-mentioned groups together form a 3-6 membered cycloalkyl group or a 4-6 membered heterocyclic group, the 3-6 membered cycloalkyl group is a cyclobutyl group or a cyclopentyl group, and the 4-6 membered heterocyclic group is an oxacyclohexyl group.
28. The compound of claim 18, or a pharmaceutically acceptable salt, solvate, prodrug, stereoisomer, tautomer, polymorph, or metabolite thereof, wherein R is5Is halogen, methyl, halomethyl or-OCH3。
29. The compound of claim 28, or a pharmaceutically acceptable salt, solvate, prodrug, stereoisomer, tautomer, polymorph, or metabolite thereof, wherein R is5Is halogen, methyl, -CF3or-OCH3。
30. The compound of claim 18, or a pharmaceutically acceptable salt, solvate, prodrug, stereoisomer, tautomer, polymorph, or metabolite thereof, wherein R is7Is H or fluorine.
31. The compound of claim 18, or a pharmaceutically acceptable salt, solvate, prodrug, stereoisomer, tautomer, polymorph, or metabolite thereof, wherein Y isIs- (CH)2)n- (CH)2)nOptionally substituted by one or more methyl groups, n being 1 or 2.
32. The compound of claim 31, or a pharmaceutically acceptable salt, solvate, prodrug, stereoisomer, tautomer, polymorph, or metabolite thereof, wherein Y is- (CH)2)2-or-CH (CH)3)-。
33. The compound of claim 32, or a pharmaceutically acceptable salt, solvate, prodrug, stereoisomer, tautomer, polymorph, or metabolite thereof, wherein, when Y is- (CH)2)2When is, R2Is H.
35. a pharmaceutical composition comprising a therapeutically effective amount of one or more selected from the group consisting of a compound according to any one of claims 1 to 34, a pharmaceutically acceptable salt, solvate, prodrug, stereoisomer, tautomer, polymorph and metabolite thereof, and optionally one or more pharmaceutical excipients.
36. Use of a compound of any one of claims 1 to 34, a pharmaceutically acceptable salt, solvate, prodrug, stereoisomer, tautomer, polymorph or metabolite thereof, or a pharmaceutical composition of claim 35, for the manufacture of a medicament for the treatment of androgen receptor associated diseases.
37. The use according to claim 36, wherein the androgen receptor-associated disease is prostate cancer, breast cancer, prostate hyperplasia, hirsutism, acne, baldness, muscle failure, gonadal failure, osteoporosis, hypercholesterolemia, male infertility, male sexual dysfunction, anemic obesity, hyposexuality, or depression.
38. The use according to claim 36, wherein the androgen receptor-associated disease is castration-resistant prostate cancer.
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Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2011103202A2 (en) * | 2010-02-16 | 2011-08-25 | Aragon Pharmaceuticals, Inc. | Androgen receptor modulators and uses thereof |
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Patent Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2011103202A2 (en) * | 2010-02-16 | 2011-08-25 | Aragon Pharmaceuticals, Inc. | Androgen receptor modulators and uses thereof |
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