CN106573932A - 吲唑类 - Google Patents
吲唑类 Download PDFInfo
- Publication number
- CN106573932A CN106573932A CN201580045223.2A CN201580045223A CN106573932A CN 106573932 A CN106573932 A CN 106573932A CN 201580045223 A CN201580045223 A CN 201580045223A CN 106573932 A CN106573932 A CN 106573932A
- Authority
- CN
- China
- Prior art keywords
- bases
- ketone
- phenyl
- pyrrolidin
- pyrazolos
- 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
Links
- 150000002473 indoazoles Chemical class 0.000 title description 2
- 206010028980 Neoplasm Diseases 0.000 claims abstract description 22
- 201000011510 cancer Diseases 0.000 claims abstract description 19
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims abstract description 19
- 201000010099 disease Diseases 0.000 claims abstract description 17
- 208000015122 neurodegenerative disease Diseases 0.000 claims abstract description 6
- 208000027866 inflammatory disease Diseases 0.000 claims abstract description 5
- 238000004519 manufacturing process Methods 0.000 claims abstract description 5
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 270
- 239000000203 mixture Substances 0.000 claims description 144
- 150000001875 compounds Chemical class 0.000 claims description 140
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 133
- 125000000068 chlorophenyl group Chemical group 0.000 claims description 88
- -1 n-pro-pyl Chemical group 0.000 claims description 87
- RWRDLPDLKQPQOW-UHFFFAOYSA-N tetrahydropyrrole Substances C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 claims description 77
- 238000000034 method Methods 0.000 claims description 70
- AYDQIZKZTQHYIY-UHFFFAOYSA-N OC(=O)C1(C)CC(C(O)=O)=CC=C1 Chemical compound OC(=O)C1(C)CC(C(O)=O)=CC=C1 AYDQIZKZTQHYIY-UHFFFAOYSA-N 0.000 claims description 53
- 150000003839 salts Chemical class 0.000 claims description 36
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 33
- 229910052801 chlorine Inorganic materials 0.000 claims description 31
- 125000004429 atom Chemical group 0.000 claims description 29
- YDTDKKULPWTHRV-UHFFFAOYSA-N 1H-indazol-3-amine Chemical compound C1=CC=C2C(N)=NNC2=C1 YDTDKKULPWTHRV-UHFFFAOYSA-N 0.000 claims description 26
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 26
- 150000002576 ketones Chemical class 0.000 claims description 25
- 229910052794 bromium Inorganic materials 0.000 claims description 23
- 125000004799 bromophenyl group Chemical group 0.000 claims description 23
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 23
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 21
- BFJMHTOBRRZELQ-UHFFFAOYSA-N 3-iodo-2h-pyrazolo[3,4-c]pyridine Chemical compound N1=CC=C2C(I)=NNC2=C1 BFJMHTOBRRZELQ-UHFFFAOYSA-N 0.000 claims description 18
- 229910052731 fluorine Inorganic materials 0.000 claims description 18
- 125000004432 carbon atom Chemical group C* 0.000 claims description 16
- 239000003814 drug Substances 0.000 claims description 16
- 125000001255 4-fluorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1F 0.000 claims description 15
- 210000004027 cell Anatomy 0.000 claims description 14
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 claims description 13
- 229910052760 oxygen Inorganic materials 0.000 claims description 13
- MDFFNEOEWAXZRQ-UHFFFAOYSA-N aminyl Chemical compound [NH2] MDFFNEOEWAXZRQ-UHFFFAOYSA-N 0.000 claims description 12
- 125000002837 carbocyclic group Chemical group 0.000 claims description 12
- 229910052799 carbon Inorganic materials 0.000 claims description 12
- 125000000623 heterocyclic group Chemical group 0.000 claims description 12
- 229910052739 hydrogen Inorganic materials 0.000 claims description 12
- BAXOFTOLAUCFNW-UHFFFAOYSA-N 1H-indazole Chemical compound C1=CC=C2C=NNC2=C1 BAXOFTOLAUCFNW-UHFFFAOYSA-N 0.000 claims description 11
- SZYAGROZFVYBJG-UHFFFAOYSA-N 2-fluoro-1-methylcyclohexa-3,5-diene-1,3-dicarboxylic acid Chemical class FC1C(C(=O)O)=CC=CC1(C(=O)O)C SZYAGROZFVYBJG-UHFFFAOYSA-N 0.000 claims description 11
- 239000008194 pharmaceutical composition Substances 0.000 claims description 11
- 210000003734 kidney Anatomy 0.000 claims description 9
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 8
- 201000001441 melanoma Diseases 0.000 claims description 8
- 230000002062 proliferating effect Effects 0.000 claims description 8
- 125000000217 alkyl group Chemical group 0.000 claims description 7
- 229940079593 drug Drugs 0.000 claims description 7
- 229910052740 iodine Inorganic materials 0.000 claims description 7
- 125000001316 cycloalkyl alkyl group Chemical group 0.000 claims description 6
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 6
- 210000003128 head Anatomy 0.000 claims description 6
- 125000004430 oxygen atom Chemical group O* 0.000 claims description 6
- 150000003222 pyridines Chemical class 0.000 claims description 6
- BXBFDGASRUACBL-UHFFFAOYSA-N 1-fluoroindazole Chemical class C1=CC=C2N(F)N=CC2=C1 BXBFDGASRUACBL-UHFFFAOYSA-N 0.000 claims description 5
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 5
- 239000012190 activator Substances 0.000 claims description 5
- 210000001072 colon Anatomy 0.000 claims description 5
- 239000003937 drug carrier Substances 0.000 claims description 5
- 210000004072 lung Anatomy 0.000 claims description 5
- 210000002784 stomach Anatomy 0.000 claims description 5
- 208000031261 Acute myeloid leukaemia Diseases 0.000 claims description 4
- 208000010839 B-cell chronic lymphocytic leukemia Diseases 0.000 claims description 4
- 208000007766 Kaposi sarcoma Diseases 0.000 claims description 4
- 208000031422 Lymphocytic Chronic B-Cell Leukemia Diseases 0.000 claims description 4
- 208000034578 Multiple myelomas Diseases 0.000 claims description 4
- 208000033776 Myeloid Acute Leukemia Diseases 0.000 claims description 4
- 206010035226 Plasma cell myeloma Diseases 0.000 claims description 4
- 150000001335 aliphatic alkanes Chemical class 0.000 claims description 4
- 125000001931 aliphatic group Chemical group 0.000 claims description 4
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 4
- 210000004556 brain Anatomy 0.000 claims description 4
- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 claims description 4
- 125000006297 carbonyl amino group Chemical group [H]N([*:2])C([*:1])=O 0.000 claims description 4
- 208000032852 chronic lymphocytic leukemia Diseases 0.000 claims description 4
- 210000003238 esophagus Anatomy 0.000 claims description 4
- 210000004185 liver Anatomy 0.000 claims description 4
- 210000005075 mammary gland Anatomy 0.000 claims description 4
- 210000001672 ovary Anatomy 0.000 claims description 4
- 210000000496 pancreas Anatomy 0.000 claims description 4
- 210000002307 prostate Anatomy 0.000 claims description 4
- 239000000126 substance Substances 0.000 claims description 4
- 125000004434 sulfur atom Chemical group 0.000 claims description 4
- 238000003419 tautomerization reaction Methods 0.000 claims description 4
- 210000001550 testis Anatomy 0.000 claims description 4
- 210000003932 urinary bladder Anatomy 0.000 claims description 4
- 210000004291 uterus Anatomy 0.000 claims description 4
- JGLMVXWAHNTPRF-CMDGGOBGSA-N CCN1N=C(C)C=C1C(=O)NC1=NC2=CC(=CC(OC)=C2N1C\C=C\CN1C(NC(=O)C2=CC(C)=NN2CC)=NC2=CC(=CC(OCCCN3CCOCC3)=C12)C(N)=O)C(N)=O Chemical compound CCN1N=C(C)C=C1C(=O)NC1=NC2=CC(=CC(OC)=C2N1C\C=C\CN1C(NC(=O)C2=CC(C)=NN2CC)=NC2=CC(=CC(OCCCN3CCOCC3)=C12)C(N)=O)C(N)=O JGLMVXWAHNTPRF-CMDGGOBGSA-N 0.000 claims description 3
- 125000000954 2-hydroxyethyl group Chemical group [H]C([*])([H])C([H])([H])O[H] 0.000 claims description 2
- 206010011224 Cough Diseases 0.000 claims description 2
- 208000024770 Thyroid neoplasm Diseases 0.000 claims description 2
- 125000000738 acetamido group Chemical group [H]C([H])([H])C(=O)N([H])[*] 0.000 claims description 2
- 125000006367 bivalent amino carbonyl group Chemical group [H]N([*:1])C([*:2])=O 0.000 claims description 2
- 125000000250 methylamino group Chemical group [H]N(*)C([H])([H])[H] 0.000 claims description 2
- 125000004170 methylsulfonyl group Chemical group [H]C([H])([H])S(*)(=O)=O 0.000 claims description 2
- 238000004806 packaging method and process Methods 0.000 claims description 2
- 238000012360 testing method Methods 0.000 claims description 2
- 201000002510 thyroid cancer Diseases 0.000 claims description 2
- 125000004199 4-trifluoromethylphenyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1*)C(F)(F)F 0.000 claims 8
- 125000004861 4-isopropyl phenyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1*)C([H])(C([H])([H])[H])C([H])([H])[H] 0.000 claims 4
- UYQLRQAPVVHBFN-UHFFFAOYSA-N 1-chloroindazole Chemical class C1=CC=C2N(Cl)N=CC2=C1 UYQLRQAPVVHBFN-UHFFFAOYSA-N 0.000 claims 3
- 239000008280 blood Substances 0.000 claims 3
- 210000004369 blood Anatomy 0.000 claims 3
- 210000003887 myelocyte Anatomy 0.000 claims 3
- 210000004907 gland Anatomy 0.000 claims 2
- 206010061218 Inflammation Diseases 0.000 claims 1
- 230000004054 inflammatory process Effects 0.000 claims 1
- 238000011282 treatment Methods 0.000 abstract description 13
- 230000002757 inflammatory effect Effects 0.000 abstract description 6
- 230000003463 hyperproliferative effect Effects 0.000 abstract description 3
- 125000003453 indazolyl group Chemical class N1N=C(C2=C1C=CC=C2)* 0.000 abstract 1
- 239000002585 base Substances 0.000 description 157
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 151
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 129
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 116
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 98
- 239000000243 solution Substances 0.000 description 97
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 81
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 74
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 69
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 62
- 239000007787 solid Substances 0.000 description 61
- 238000000746 purification Methods 0.000 description 60
- 235000019439 ethyl acetate Nutrition 0.000 description 51
- 235000019253 formic acid Nutrition 0.000 description 37
- 238000004128 high performance liquid chromatography Methods 0.000 description 37
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 36
- 235000019441 ethanol Nutrition 0.000 description 34
- 239000000376 reactant Substances 0.000 description 32
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 30
- RTZKZFJDLAIYFH-UHFFFAOYSA-N ether Substances CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 30
- 101000980937 Homo sapiens Cyclin-dependent kinase 8 Proteins 0.000 description 28
- 102100024456 Cyclin-dependent kinase 8 Human genes 0.000 description 27
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 27
- 239000012044 organic layer Substances 0.000 description 27
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 26
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 26
- 239000002904 solvent Substances 0.000 description 26
- 235000002639 sodium chloride Nutrition 0.000 description 25
- 239000000460 chlorine Substances 0.000 description 23
- 238000005160 1H NMR spectroscopy Methods 0.000 description 22
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 22
- 239000013078 crystal Substances 0.000 description 20
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 20
- PVNIIMVLHYAWGP-UHFFFAOYSA-N Niacin Chemical compound OC(=O)C1=CC=CN=C1 PVNIIMVLHYAWGP-UHFFFAOYSA-N 0.000 description 19
- 239000012043 crude product Substances 0.000 description 19
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 18
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 18
- 229960001866 silicon dioxide Drugs 0.000 description 18
- IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Substances N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 17
- 239000003921 oil Substances 0.000 description 17
- 235000019198 oils Nutrition 0.000 description 17
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 16
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 16
- 229910052757 nitrogen Inorganic materials 0.000 description 16
- 239000000741 silica gel Substances 0.000 description 16
- 229910002027 silica gel Inorganic materials 0.000 description 16
- 238000003756 stirring Methods 0.000 description 16
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 15
- 239000002253 acid Substances 0.000 description 15
- 150000001412 amines Chemical class 0.000 description 14
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 14
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- BQFCCCIRTOLPEF-UHFFFAOYSA-N chembl1976978 Chemical compound CC1=CC=CC=C1N=NC1=C(O)C=CC2=CC=CC=C12 BQFCCCIRTOLPEF-UHFFFAOYSA-N 0.000 description 13
- 150000002118 epoxides Chemical class 0.000 description 13
- 239000007788 liquid Substances 0.000 description 13
- 239000000463 material Substances 0.000 description 13
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 13
- DTQVDTLACAAQTR-UHFFFAOYSA-N trifluoroacetic acid Substances OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 13
- 125000004214 1-pyrrolidinyl group Chemical group [H]C1([H])N(*)C([H])([H])C([H])([H])C1([H])[H] 0.000 description 12
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 12
- 230000015572 biosynthetic process Effects 0.000 description 12
- 238000002360 preparation method Methods 0.000 description 12
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- 238000004364 calculation method Methods 0.000 description 11
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- 239000012453 solvate Substances 0.000 description 11
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 description 10
- 241000124008 Mammalia Species 0.000 description 10
- 229940060038 chlorine Drugs 0.000 description 10
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- 239000000047 product Substances 0.000 description 10
- CUYKNJBYIJFRCU-UHFFFAOYSA-N 3-aminopyridine Chemical compound NC1=CC=CN=C1 CUYKNJBYIJFRCU-UHFFFAOYSA-N 0.000 description 9
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- 238000001035 drying Methods 0.000 description 9
- 238000001556 precipitation Methods 0.000 description 9
- 239000000377 silicon dioxide Substances 0.000 description 9
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 8
- OKKJLVBELUTLKV-MZCSYVLQSA-N Deuterated methanol Chemical compound [2H]OC([2H])([2H])[2H] OKKJLVBELUTLKV-MZCSYVLQSA-N 0.000 description 8
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- SJRJJKPEHAURKC-UHFFFAOYSA-N N-Methylmorpholine Chemical class CN1CCOCC1 SJRJJKPEHAURKC-UHFFFAOYSA-N 0.000 description 8
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- 239000012317 TBTU Substances 0.000 description 8
- CLZISMQKJZCZDN-UHFFFAOYSA-N [benzotriazol-1-yloxy(dimethylamino)methylidene]-dimethylazanium Chemical compound C1=CC=C2N(OC(N(C)C)=[N+](C)C)N=NC2=C1 CLZISMQKJZCZDN-UHFFFAOYSA-N 0.000 description 8
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- QRUDEWIWKLJBPS-UHFFFAOYSA-N benzotriazole Chemical compound C1=CC=C2N[N][N]C2=C1 QRUDEWIWKLJBPS-UHFFFAOYSA-N 0.000 description 7
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- 108090000623 proteins and genes Proteins 0.000 description 7
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- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 6
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- 150000003851 azoles Chemical class 0.000 description 5
- 150000001721 carbon Chemical group 0.000 description 5
- 230000008859 change Effects 0.000 description 5
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- 239000003480 eluent Substances 0.000 description 5
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- 230000014509 gene expression Effects 0.000 description 5
- IKDUDTNKRLTJSI-UHFFFAOYSA-N hydrazine hydrate Chemical compound O.NN IKDUDTNKRLTJSI-UHFFFAOYSA-N 0.000 description 5
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- 238000002156 mixing Methods 0.000 description 5
- 239000011734 sodium Substances 0.000 description 5
- 235000011152 sodium sulphate Nutrition 0.000 description 5
- 238000003786 synthesis reaction Methods 0.000 description 5
- 239000003826 tablet Substances 0.000 description 5
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 4
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 4
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 4
- YCKRFDGAMUMZLT-UHFFFAOYSA-N Fluorine atom Chemical compound [F] YCKRFDGAMUMZLT-UHFFFAOYSA-N 0.000 description 4
- OAKJQQAXSVQMHS-UHFFFAOYSA-N Hydrazine Chemical compound NN OAKJQQAXSVQMHS-UHFFFAOYSA-N 0.000 description 4
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 4
- 102000013814 Wnt Human genes 0.000 description 4
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Classifications
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- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
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- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
- A61K31/444—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring heteroatom, e.g. amrinone
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- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/445—Non condensed piperidines, e.g. piperocaine
- A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
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- A61K31/5375—1,4-Oxazines, e.g. morpholine
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Abstract
本发明提供式(I)的新型取代的吲唑化合物,其制备及其用于治疗过度增殖性疾病例如癌症、炎性或退行性疾病的用途。
Description
发明领域
本发明涉及在治疗哺乳动物中的过度增殖性疾病(例如癌症)以及炎性或退行性疾病中有用的一系列新型取代的吲唑化合物。本发明还包括这样的化合物在治疗哺乳动物中、特别是人类中的过度增殖性、炎性或退行性疾病中的用途,以及含有这样的化合物的药物组合物。
相关技术总结
CDK8及其密切相关的同种型CDK19是致癌转录调节激酶。与CDK家族的更为公知的成员(例如CDK1,CDK2和CDK4/6)相反,CDK8在细胞周期进程中没有直接作用。因为其在多能干细胞表型中的重要作用,胚胎干细胞中的CDK8敲除防止胚胎发育,但CDK8耗竭不抑制正常细胞的生长。
CDK8在癌症中的作用是由于其作为涉及癌发生的几种转录程序的调节子的独特功能。CDK8已经被鉴定为黑素瘤和结肠癌中的致癌基因,CDK8基因在约50%的后者癌症中被扩增。CDK8的较高表达与结肠癌、乳腺癌和卵巢癌中较差的预后相关。CDK8的已知癌症相关活性包括Wnt/β-连环蛋白通路、生长因子诱导的转录和TGFα信号传导的正调节。还显示CDK8维持胚胎干细胞的多能表型并且已经与癌症干细胞表型相关。DNA损伤性化疗药在内皮细胞和其它癌症相关基质元件中诱导TNFα,一种转录因子NFκB的激活剂。基质来源的TNFα作用于肿瘤细胞,在此其诱导NFκB介导的相关肿瘤促进细胞因子CXCL1和CXCL2的产生。CXCL1/2通过结合骨髓细胞表面上的CXCR2受体而将骨髓细胞吸引到肿瘤。骨髓细胞然后分泌与慢性炎症和癌症相关的小钙结合蛋白5100A8和A9。5100A8/9作用于肿瘤细胞,促进其转移和化疗存活两者。
CDK8是细胞周期蛋白依赖性激酶,其在转录中作为介体复合物的一部分而具有保守的功能。Taatjes,D.J.,Trends Biochem Sci 35,315-322(2010);Conaway,R.C.和Conaway,J.W.,Curr Opin Genet Dev 21,225-230(2011)。最近,已经报道CDK8在结肠癌(Firestein R.等人,Nature 455:547-51(2008);Morris EJ等人,Nature 455:552-6(2008);Starr TK等人,Science 323:1747-50(2009))和黑素瘤(Kapoor A.等人,Nature468:1105-9(2010))中是致癌基因。CDK8在人结肠肿瘤的亚组中被上调和扩增。CDK8转化永生化细胞并且是体外结肠癌增殖所必需的(Firestein,R.等人,Nature 455,547-551(2008))。还发现CDK8在黑素瘤中过表达并且是黑素瘤增殖所必需的(Kapoor,A.等人,Nature 468,1105-1109(2010))。已经显示CDK8调节作为ES多能性和癌症两者的关键调节剂的几种信号通路。CDK8通过促进β-连环蛋白靶基因的表达(Firestein,R.等,Nature455,547-551(2008))或通过抑制E2F1(一种β-连环蛋白转录活性的有效抑制剂)(Morris,E.J.等人,Nature 455,552-556(2008))来激活Wnt通路。CDK8通过使Notch胞内结构域磷酸化,在靶基因激活Notch增强子复合物来促进Notch靶基因表达(Fryer C.J.等人,Mol Cell16:509-20(2004))。最后,SMAD蛋白的CDK8磷酸化导致TGFβ/BMP靶基因的活化,随后降解SMAD蛋白以限制靶基因表达(Alarcon,C.等人,Cell 139,757-769(2009))。
靶向Wnt通路的其它化合物公开于,例如,WO2010/041054,WO2013/110433,WO2014/063778或WO2014/086453。
然而,由于针对Wnt通路,特别是CDK8/19的治疗剂尚未商业化,仍然存在显著未满足的医疗需求,使得必须鉴定和开发进一步有希望的Wnt通路抑制剂。
发明内容
因此,本发明的目的在于,提供在治疗哺乳动物中的炎性或过度增殖性疾病(例如癌症)中有用的新型CDK8/19抑制剂,其在它们的活性以及它们的溶解性、代谢清除率和生物利用度特性方面具有优异的药理特性。
因此,本发明提供新型的取代的吲唑化合物、或者它们的立体异构体或互变异构体、或者药学上可接受的盐,其为CDK8/19抑制剂,并且特别是在上文和下文中提及的疾病的治疗中用作药物。
化合物由式(I)所定义:
其中:
X、Y独立地为CH或N,
Z为CH,C(Hal)或N,
R1为H,LA,CA,NH2,NH(LA)或(LA)NH(LA),Hal,-S(LA),-SO2(LA),O(LA),
Cyc为3,4,5,6或7元脂族杂环,其具有1或2个N原子,或1个N原子和1个O原子,
R2为-LA-Ar或Ar,其相对于Cyc的环N原子位于2-或3-位,
R3为H,OH,NH2,COO(LA),CONH2,CONH(LA),NHCO(LA),(LA)OH,NH(LA)或LA,其位于Cyc的任何位置,
Ar为单核或双核,脂族或芳族3,4,5,6,7,8,9或10元碳环或杂环,具有0,1,2,3或4个N,O和/或S原子,其可以是未被取代的,或被Hal,OH,CN,LA,O(LA),S(LA)单取代或独立二取代,
LA为非支链或支链烷基,具有1,2,3,4或5个碳原子,其可以是饱和的或部分未饱和的,其中1,2或3个H原子可被Hal替代,
CA为环烷基,具有3,4,5或6个碳原子;或环烷基烷基,具有3,4,5或6个环碳原子和1或2非环碳原子,
Hal为F,Cl,Br或I。
通常而言,所有出现多于一次的残基可以相同或者不同,即彼此独立。上文和下文中,残基和参数具有针对式(I)所说明的含义,除非明确地另有说明。
因此,本发明特别涉及式(I)的化合物,其中,至少一个所述残基具有下文所述的优选含义之一。
Hal表示氟、氯、溴或碘,特别是氟或氯,并且优选为氯。
“LA”表示例如甲基、乙基、三氟甲基、二氟甲基、1,1,1-三氟乙基、丙基、异丙基、丁基、异丁基、仲丁基或叔丁基、异丙烯基、乙烯基、乙炔基或丙-1-炔基。
“CA”表示例如环丙基、(环丙基)甲基、环丁基或(环戊基)乙基。
“Cyc”表示例如氮丙啶基,氮杂环丁烷基,吡咯烷基,哌啶基,氮杂环庚烷基,优选氮丙啶-1-基,氮杂环丁烷-1-基,吡咯烷-1-基,哌啶-1-基,氮杂环庚烷-1-基。
“Ar”表示例如苯基,2-或3-呋喃基,2-或3-噻吩基,1-,2-或3-吡咯基,1-,2,4-或5-咪唑基,1-,3-,4-或5-吡唑基,2-,4-或5-噁唑基,3-,4-或5-异噁唑基,2-,4-或5-噻唑基,3-,4-或5-异噻唑基,2-,3-或4-吡啶基,2-,4-,5-或6-嘧啶基,2-,3-,5-,或6-吡嗪-1-或4-基,此外优选1,2,3-三唑-1-,-4-或-5-基,1,2,4-三唑-1-,-3-或5-基,1-或5-四唑基,1,2,3-噁二唑-4-或-5-基,1,2,4-噁二唑-3-或-5-基,1,3,4-噁二唑-2-基,1,3,4-噻二唑-2-或-5-基,1,2,4-噻二唑-3-或-5-基,1,2,3-噻二唑-4-或-5-基,3-或4-哒嗪基,1-,2-,3-,4-,5-,6-或7-吲哚基,2-,3-,4-或5-异吲哚基,2-,6,-或8-嘌呤基,1-,2-,4-或5-苯并咪唑基,1-,3-,4-,5-,6-或7-苯并吡唑基,2-,4-,5-,6-或7-苯并噁唑基,3-,4-,5-,6-或7-苯并异噁唑基,2-,4-,5-,6-或7-苯并噻唑基,2-,4-,5-,6-或7-苯并异噻唑基,4-,5-,6-或7-苯并-2,1,3-噁二唑基,1-,3-,4-,5-,6-,7-或8-异喹啉基,3-,4-,5-,6-,7-或8-喹啉基,2-,4-,5-,6-,7-或8-喹唑啉基,喹噁啉-2-,3-,4-或5-基,4-,5-,或6-酞嗪基,2-,3-,5-,6-,7-或8-2H-苯并-1,4-噁嗪基。
优选“Ar”表示2-,3-或-4-吡啶基,苯基,2-,4-,5-或6-嘧啶基,2-或3-吡嗪基。
“LA-Ar”表示例如,2-,3-或4-苯基甲基,2-,3-或4-苯基乙基,2-,3-或4-吡啶基甲基,2-,3-或4-吡啶基乙基。
在优选的实施方案中,本发明化合物符合上文所示的式(I),其中:
X,Y,Z独立地为CH或N,
R1为H,LA,CA,NH2,NH(LA)或(LA)NH(LA),
Cyc为3,4,5,6或7元脂族杂环,具有1个N原子,
R2为-LA-Ar或Ar,其相对于Cyc的环N原子位于2-,或3-位,
R3为H,OH,NH2,COO(LA),CONH2,CONH(LA)或LA,其位于Cyc的任何位置,
Ar为单核或双核,脂族或芳族3,4,5,6,7,8,9或10元碳环或杂环,具有0,1,2,3或4个N,O和/或S原子,其可以是未被取代的,或被Hal,OH,CN,LA,O(LA),S(LA)单取代或独立二取代,
LA为非支链或支链烷基,具有1,2,3,4或5个碳原子,其可以是饱和的或部分未饱和的,其中1,2或3个H原子可被Hal替代,
CA为环烷基,具有3,4,5或6个碳原子,或环烷基烷基,具有3,4,5或6个环碳原子和1或2个非环碳原子,
Hal为F,Cl,Br或I。
在另一优选实施方案中,本发明化合物符合上文所示的式(I),其中:
X,Y独立地为CH或N,
Z为CH,
R1为H,LA,CA,NH2,NH(LA)或(LA)NH(LA),
Cyc为3,4,5,6或7元脂族杂环,具有1个N原子,
R2为-LA-Ar或Ar,其相对于Cyc的环N原子位于2-,或3-位,
R3为H,NH2或LA,其位于Cyc的任何位置,
Ar为单核,芳族,6元碳环或杂环,具有0,1或2个N原子,其可以是未被取代的,或被Hal,OH,CN,LA,O(LA),S(LA)单取代或独立二取代,
LA为非支链或支链烷基,具有1,2,3,4或5个碳原子,其可以是饱和的或部分未饱和的,其中1,2或3个H原子可被Hal替代,
CA为环烷基,具有3,4,5或6个碳原子,或环烷基烷基,具有3,4,5或6个环碳原子和1或2个非环碳原子,
Hal为F,Cl,Br或I。
在更优选的实施方案中,本发明化合物符合式(IIa)或(IIb),
其中所有取代基具有对于式(I)所指出的含义。
在另一优选实施方案中,本发明化合物符合式(I)(IIa)或(IIb)的子式1-26,其中
在子式1中
Ar为单核,芳族,6元碳环或杂环,具有0,1或2个N原子,其为未被取代的,或被Hal,LA或O(LA)单取代,
在子式2中
X为N,
在子式3中
X为CH,
在子式4中
Y为CH,
在子式5中
Y为N,
在子式6中
Z为CH,
在子式7中
X为CH,
Y为N,
Z为CH,
在子式8中
X为N,
Y为CH,
Z为CH,
在子式9中
Ar为单核,芳族,6元碳环或杂环,具有0,1或2个N原子,其可以是未被取代的,或被Hal,OH,CN,LA,O(LA),S(LA)单取代或独立二取代,
X为CH,
Y为N,
Z为CH,
在子式10中
Ar为单核,芳族,6元碳环或杂环,具有0,1或2个N原子,其可以是未被取代的,或被Hal,OH,CN,LA,O(LA),S(LA)单取代或独立二取代,
X为N,
Y为CH,
Z为CH,
在子式11中
R1为LA或NH2,NHLA
在子式12中
Cyc具有4,5或6个环原子,
在子式13中
R3为H,OH,NH2或甲基,
在子式14中
R3为H,
在子式15中
R2为苄基,
R3为H,NH2或甲基,
Cyc具有6个环原子,
在子式16中
Cyc具有5或6个环原子,
R2为苯基,其为未被取代的,或被Hal或LA单取代或独立二取代,
在子式17中
Z为CH,
R2为苄基或苯基,所述苯基为未被取代的,或被Hal或LA单取代或独立二取代,
在子式18中
X为N或CH,
Y为CH,
Z为CH,
R1为甲基,正丙基,异丙基,环丙基,NH2,NHLA
在子式19中
Z为CH,
Cyc具有5个环原子,
在子式20中
Z为CH,
R2为苯基,其为未被取代的或被Br,Cl,甲基或CF3单取代,
R3为H,
在子式21中
Z为CH,
R2为苯基,其为未被取代的或被Br,Cl,甲基或CF3单取代,
R3为H,
在子式22中
Z为CH,
R2为苯基,其为未被取代的或被Br,Cl,甲基或CF3对位取代,
R3为H,
在子式23中
Y为CH,
Z为CH,
R1为甲基,正丙基,异丙基,环丙基或NH2,
在子式24中
X为N或CH,
Y为CH,
Z为CH,
R1为甲基,正丙基,异丙基,环丙基或NH2,
Cyc具有4,5或6个环原子,
在子式25中
X为N或CH,
Y为CH,
Z为CH,
R1为甲基,正丙基,异丙基,环丙基或NH2,
Cyc具有4,5或6个环原子,
R2为苯基,其为未被取代的或被Br,Cl,甲基或CF3对位取代,
R3为H,
在子式26中
X为N或CH,
Y为CH,
Z为CH,
R1为甲基,正丙基,异丙基,环丙基或NH2,
Cyc具有5个环原子,
R2为苯基,其为未被取代的或被Br,Cl,甲基或CF3对位取代,
R3为H,
在子式27中
R1为甲基,正丙基,异丙基,环丙基,甲基硫基,甲磺酰基,甲氧基,F或NH2,
在子式28中
R3为H,OH,NH2,甲基,乙酰胺基,2-羟基乙基或甲基氨基,
在子式29中
Z为CH或C(Hal),
Cyc具有4,5或6个环原子,其中1个原子为N和其它原子为C,
R2为苯基,其为未被取代的或被Br,Cl,F,甲基,甲氧基,异丙基或CF3对位取代,或被Cl和F独立间位/对位二取代,
R3为H,
在子式30中
Z为CH或C(Hal),
Cyc具有4或5个环原子,其中1个原子为N和其它原子为C,
R2为苯基,其为未被取代的或被Br,Cl,F,甲基,甲氧基,异丙基或CF3对位取代,或被F间位取代和被Cl对位取代,
R3为H,
并且,剩余残基具有针对式(I)所说明的含义。
式(I)的化合物可以具有一个或多个手性中心。因此它们可以多种对映异构体形式存在,并且呈外消旋或者光学活性的形式。本发明因此还涉及这些化合物的光学活性形式、对映异构体、外消旋体、非对映异构体,总称为立体异构体。
由于根据本发明所述的化合物的外消旋体或立体异构体的药物活性可能会不同,因此可能需要使用对映异构体。在这些情况中,可以通过本领域技术人员已知的化学或物理手段将终产物或者甚至中间体分离成对映异构化合物,或者甚至在合成中原样使用。
在外消旋胺的情况中,通过与光学活性的拆分剂反应从而由混合物形成非对映异构体。适合的拆分剂的实例是光学活性的酸,例如R和S形式的酒石酸、二乙酰基酒石酸、二苯甲酰基酒石酸、扁桃酸、苹果酸、乳酸、适合地N-保护的氨基酸(例如N-苯甲酰基脯氨酸或N-苯磺酰基脯氨酸)、或者多种光学活性的樟脑磺酸。还有利的是借助光学活性的拆分剂(例如,固定化在硅胶上的二硝基苯甲酰基苯基甘氨酸、纤维素三乙酸酯或其它碳水化合物的衍生物、或者手性衍生的甲基丙烯酸酯聚合物)的色谱对映异构体拆分。为该目的而适合的洗脱液是水性或者醇性溶剂混合物,例如己烷/异丙醇/乙腈,其例如为82:15:3的比率。
一种用于拆分含有酯基团(例如乙酰酯)的外消旋体的简洁方法是使用酶,特别是酯酶。
公知的是,原子可以具有不同于通常天然存在的原子的原子量或质量数的原子量或质量数。容易商业可得且可以通过公知的方法而并入本发明的化合物中的同位素的实例包括氢、碳、氮、氧、磷、氟和氯的同位素,例如分别为2H、3H、13C、14C、15N、18O、17O、31P、32P、35S、18F和36Cl。将较重的同位素、特别是氘(2H)并入本发明的化合物中具有治疗优点,这归因于该同位素标记的化合物的较高的代谢稳定性。较高的代谢稳定性直接转换为提高的体内半衰期或更低的剂量。因此,这些同位素被包括在如在本发明的化合物中使用的原子H、C、N等的定义中。
本发明的化合物可以呈前药化合物的形式。“前药化合物”意指在活体中的生理条件下例如通过氧化、还原、水解等(其每一种以酶促的方式或者不需要酶介入的方式进行)而被转化为根据本发明所述的生物活性化合物的衍生物。前药的实例是下述化合物,其中本发明的化合物中的氨基基团被酰基化、烷基化或磷酸化,例如为二十碳酰基氨基、丙氨酰基氨基、新戊酰氧基甲基氨基;或者其中羟基基团被酰基化、烷基化、磷酸化或者被转化为硼酸酯,例如乙酰氧基、棕榈酰氧基、新戊酰氧基、丁二酰氧基、富马酰氧基、丙氨酰氧基;或者其中羧基基团被酯化或者酰胺化;或者其中巯基基团与将药物选择性地递送至靶点和/或递送至细胞的胞液的载体分子、例如肽形成二硫键。这些化合物可以根据公知的方法由本发明的化合物生产。前药的其它实例是下述化合物,其中,本发明的化合物中的羧酸酯被转化为例如烷基-、芳基-、胆碱-、氨基、酰氧基甲酯、亚麻酰基(linolenoyl)-酯。
在可能存在本发明的化合物或它们前药的互变异构、例如酮-烯醇互变异构时,以单独的方式和作为以任意比率的混合物一起的方式要求保护单个形式,例如酮或烯醇形式。这同样适用于立体异构体,例如对映异构体、顺式/反式异构体、构象异构体等等。
如果需要的话,异构体可以通过本领域公知的方法、例如通过液相色谱法分离。这同样适用于对映异构体,例如通过使用手性固定相。此外,对映异构体可以通过以下方法分离:将它们转化为非对映异构体,即与对映异构体纯辅助化合物偶联,随后分离所得非对映异构体并裂解(cleavage)辅助残基。替代地,本发明的化合物的任意对映异构体可以使用光学纯起始材料由立体选择性合成而获得。
本发明的化合物可以呈药学上可接受的盐、药学上可接受的溶剂合物、或药学上可接受的盐的药学上可接受的溶剂合物的形式。
术语“药学上可接受的盐”是指由药学上可接受的碱或酸,包括无机碱或酸以及有机碱或酸制备的盐。在其中本发明的化合物含有一个或多个酸性或碱性基团的情况下,本发明还包含它们相应的药学上可接受的盐。因此,含有酸性基团的本发明的化合物可以以盐形式存在,并且可以根据本发明例如以碱金属盐、碱土金属盐的形式或者以铵盐的形式使用。这样的盐的更准确的实例包括钠盐、钾盐、钙盐、镁盐或与氨、或有机胺(例如乙胺、乙醇胺、三乙醇胺)、或氨基酸的盐。含有一个或多个碱性基团(可以被质子化的基团)的本发明的化合物可以以盐的形式存在,并且可以根据本发明以它们与无机或有机酸的加成盐的形式使用。合适的酸的实例包括盐酸、氢溴酸、磷酸、硫酸、硝酸、甲磺酸、对甲苯磺酸、萘二磺酸、草酸、乙酸、酒石酸、乳酸、水杨酸、苯甲酸、甲酸、丙酸、新戊酸、二乙基乙酸、丙二酸、丁二酸、庚二酸、富马酸、马来酸、苹果酸、氨基磺酸、苯基丙酸、葡糖酸、抗坏血酸、异烟酸、柠檬酸、己二酸和本领域技术人员已知的其它酸。如果本发明的化合物在分子中同时含有酸性和碱性基团,除了所提到的盐形式外,本发明还包括内盐或内铵盐(betaines)(两性离子)。各种盐可以通过本领域技术人员已知的惯用的方法获得,例如通过使这些与有机或无机的酸或碱在溶剂或分散剂中接触、或通过与其它盐的阴离子交换或阳离子交换来获得。本发明还包括本发明的化合物的所有盐,其因低生理相容性而不直接适用于药物,但是其可以例如作为用于化学反应或用于制备药学上可接受的盐的中间体而使用。
术语“药学上可接受的溶剂合物”意指与药学上可接受的溶剂的加成形式,所述加成形式含有化学计量或非化学计量的量的溶剂。一些化合物具有在结晶固态中捕获固定摩尔比的溶剂分子从而形成溶剂合物的倾向。如果该溶剂是水,则形成的溶剂合物是水合物,例如单水合物或二水合物。如果该溶剂是醇,则形成的溶剂合物是醇合物,例如甲醇合物或乙醇合物。如果该溶剂是醚,则形成的溶剂合物是醚合物,例如乙醚合物。
因此,下列项目也符合本发明:
a)所述化合物的所有立体异构体或互变异构体,包括其以所有比率的混合物;
b)所述化合物的前药,或者这些前药的立体异构体或互变异构体;
c)所述化合物和(a)与(b)中提及的项目的药学上可接受的盐;
d)所述化合物和(a)、(b)与(c)中提及的项目的药学上可接受的溶剂合物。
应当理解的是,上下文中所有对化合物的提及意指包括这些项目,特别是所述化合物的药学上可接受的溶剂合物或其药学上可接受的盐的药学上可接受的溶剂合物。
此外,本发明涉及药物组合物,其包含本发明的化合物、或者其立体异构体或互变异构体、或者前述每种的药学上可接受的盐、包括其所有比率的混合物作为活性成分;以及药学上可接受的载体。
“药物组合物”是指一种或多种活性成分、和一种或多种构成载体的惰性成分;以及任何直接或间接地来自于任意两种或更多种成分的组合、复合或聚集的产物;或者来自一种或多种成分的分解的产物;或者来自一种或多种成分的其它类型反应或相互作用的产物。相应地,本发明的药物组合物涵盖通过掺混本发明的化合物与药学上可接受的载体而制成的任意组合物。
本发明的药物组合物可以额外地包含一种或多种其它化合物作为活性成分,例如一种或多种额外的本发明的化合物、或者其它Wnt通路抑制剂。
药物组合物包括适于口服、直肠、局部、肠胃外(包括皮下、肌肉内和静脉内)、眼部(眼睛)、肺部(鼻腔或口腔吸入)或鼻内给药的组合物,尽管在任何给定情况下最合适的路径将取决于所治疗的病症的性质和严重程度、以及该活性成分的性质。它们可以方便地以单位剂量形式呈现,并且通过药学领域公知的任何方法制备。
在一个实施方案中,所述化合物和药物组合物用于治疗癌症,例如脑、肺、结肠、表皮样、鳞状细胞、膀胱、胃、胰腺、乳腺、头部和颈部、肾区(renal)、肾脏(kidney)、肝、卵巢、前列腺、子宫、食管、睾丸、妇科、甲状腺的癌症、黑素瘤,以及恶性血液病,例如急性骨髓性白血病、多发性骨髓瘤、慢性骨髓性白血病、髓细胞白血病、卡波西肉瘤或任何其它类型的实体或液体肿瘤。优选地,待治疗的癌症选自结肠癌、肺癌、乳腺癌和血液肿瘤类型。
此外,所述化合物和药物组合物用于治疗炎性疾病,例如多发性硬化症、类风湿性关节炎、系统性红斑狼疮;炎性肠疾病;或者退行性疾病,例如骨关节炎和阿尔茨海默病。
上文和下文所定义的抗癌治疗可以被应用为单药治疗,或者可以在本文中公开的式(I)的化合物之外还涉及常规的手术或放射疗法或药物疗法。这样的药物疗法(例如化疗或靶向疗法)可以包括一种或多种(但优选一种)下述抗肿瘤剂:
-烷基化剂,例如六甲蜜胺、苯达莫司汀、白消安、卡莫司汀、苯丁酸氮芥、盐酸氮芥、环磷酰胺、氮烯唑胺、异环磷酰胺、英丙舒凡甲苯磺酸盐、洛莫司汀、美法仑、二溴甘露醇、二溴卫矛醇、尼莫司汀、雷莫司汀、替莫唑胺、噻替派、曲奥舒凡、二氯甲基二乙胺(mechloirtamine)、卡波醌、阿帕齐醌、福莫司汀、葡磷酰胺、帕利伐米、哌泊溴烷、曲磷胺、尿嘧啶氮芥;
-铂化合物,例如卡铂、顺铂、依铂、米铂水合物、奥沙利铂、洛铂、奈达铂、吡铂、沙铂;
-DNA改变剂,例如氨柔比星、比生群、地西他滨、米托蒽醌、甲苄肼、曲贝替定、氯法拉滨、安吖啶(amsacrin)、溴他里辛(brostallicin)、匹克生琼、laromustine;
-拓扑异构酶抑制剂,例如依托泊苷、依立替康、雷佐生、索布佐生、替尼泊苷、托泊替康、氨萘非特、贝洛替康、依利醋铵、伏利拉辛(voreloxin);
-微管调节剂,例如卡巴他赛、多西他赛、艾日布林、伊沙匹隆、紫杉醇、长春碱、长春新碱、长春瑞滨、长春地辛、长春氟宁、康普瑞汀A4前药(fosbretabulin)、替司他赛;
-抗代谢物,例如天冬酰胺酶、阿扎胞苷、左亚叶酸钙、卡培他滨、克拉屈滨、阿糖胞苷、依诺他滨、氟尿苷、氟达拉滨、氟尿嘧啶、吉西他滨、巯嘌呤、甲氨蝶呤、奈拉滨、培美曲塞、普拉曲沙、硫唑嘌呤、硫鸟嘌呤、卡莫氟、去氧氟尿苷、艾西拉滨、雷替曲塞、沙帕他滨、替加氟、曲麦克特;
-抗癌抗生素,例如博来霉素、更生霉素、多柔比星、表柔比星、伊达比星、左旋咪唑、米替福新、丝裂霉素C、罗米地辛、链佐星、戊柔比星、净司他丁、佐柔比星、道诺霉素、光神霉素、阿柔比星、培来霉素、吡柔比星;
-激素/拮抗剂,例如阿巴瑞克、阿比特龙、比卡鲁胺、布舍瑞林、卡鲁睾酮、氯烯雌醚、地加瑞克、地塞米松、雌二醇、氟可龙、氟甲睾酮、氟他胺、氟维司群、戈舍瑞林、组氨瑞林、亮丙瑞林、甲地孕酮、米托坦、那法瑞林、诺龙、尼鲁米特、奥曲肽、泼尼松龙、雷洛昔芬、他莫昔芬、促甲状腺激素α、托瑞米芬、曲洛司坦、曲普瑞林、己烯雌酚、阿考比芬、达那唑、德舍瑞林、环硫雄醇、orteronel、恩杂鲁胺;
-芳香化酶抑制剂,例如氨鲁米特、阿那曲唑、依西美坦、法倔唑、来曲唑、睾内脂、福美坦;
-小分子激酶抑制剂,例如克唑替尼、达沙替尼、厄洛替尼、伊马替尼、拉帕替尼、尼洛替尼、帕唑帕尼、瑞格非尼、鲁索利替尼、索拉非尼、舒尼替尼、凡德他尼、维罗非尼、博舒替尼、吉非替尼、阿西替尼、阿法替尼、alisertib、达拉菲尼、达可替尼、dinaciclib、多韦替尼、恩扎妥林、尼达尼布、乐伐替尼、利尼伐尼、linsitinib、马赛替尼、米哚妥林、莫特塞尼、来那替尼、orantinib、哌立福辛、普纳替尼、拉多替尼、rigosertib、替吡法尼、tivantinib、tivozanib、曲美替尼、pimasertib、丙氨酸布立尼布、西地尼布、阿帕替尼、卡波替尼S-苹果酸盐、卡非佐米、依鲁替尼、埃克替尼;
-光敏剂,例如甲氧沙林、卟吩姆钠、他拉泊芬、替莫泊芬;
-抗体,例如阿仑单抗、贝西索单抗、贝伦妥单抗-维多汀、西妥昔单抗、地诺单抗、易普利单抗、奥法木单抗、帕尼单抗、利妥昔单抗、托西莫单抗、曲妥珠单抗、贝伐单抗、卡妥索单抗、elotuzumab、依帕珠单抗、farletuzumab、mogamulizumab、necitumumab、尼妥珠单抗、奥奴珠单抗、ocaratuzumab、奥戈伏单抗、雷莫芦单抗、利妥木单抗、司妥昔单抗、托珠单抗、扎鲁木单抗、扎木单抗、马妥珠单抗、达妥珠单抗、onartuzumab、帕妥珠单抗、雷妥莫单抗、tabalumab;
-细胞因子,例如阿地白介素、干扰素α、干扰素α2a、干扰素α2b、他索纳明、替西白介素、奥普瑞白介素;
-药物共轭物,例如地尼白介素、替伊莫单抗、碘苄胍I123、松龙苯芥、曲妥珠单抗-emtansine、雌莫司汀、吉妥珠单抗奥唑米星、阿柏西普、cintredekin besudotox、依多曲肽、奥英妥珠单抗、那莫单抗、莫奥珠单抗、锝(99mTc)阿西莫单抗、vintafolide;
-疫苗,例如前列腺癌疫苗(sipuleucel)、维特斯朋、emepepimut-S、结肠癌疫苗(oncoVAX)、rindopepimut、troVax、stimuvax;
-其它药剂,例如阿利维A酸、贝沙罗汀、硼替佐米、依维莫司、伊班膦酸、咪喹莫特、来那度胺、蘑菇多糖、甲酪氨酸、米伐木肽、帕米磷酸、培加帕酶、喷司他丁、sipuleucel、西佐糖、他米巴罗汀、替西莫司、沙利度胺、维A酸、维莫德吉、唑来膦酸、沙利度胺、伏立诺他、塞来考昔、西仑吉肽、恩替诺特、依他硝唑、ganetespib、idronoxil、iniparib、ixazomib、氯尼达明、尼莫唑、帕比司他、培瑞维A酸、plitidepsin、泊马度胺、procodazol、ridaforolimus、他喹莫德、telotristat、胸腺法新、替拉扎明、托多司他、trabedersen、乌苯美司、伐司朴达多、今又生(gendicine)、溶链菌、reolysin、盐酸瑞他霉素、trebananib、维鲁利秦。
特别地,本发明涉及用于抑制哺乳动物中的异常细胞生长或者治疗过度增殖性病症的方法,其包括对哺乳动物以组合放射疗法的方式给药一定量的本发明的化合物或药物组合物,其中,化合物或药物组合物的量在与放射疗法组合的情况下对于抑制哺乳动物中的异常细胞生长或者治疗过度增殖性病症而言是有效的。用于给药放射疗法的技术是本领域公知的,并且这些技术可以被用于本文中所述的组合疗法。可以如本文中所描述地确定该组合疗法中的本发明的化合物或药物组合物的给药。据信,本发明的化合物可以使得异常细胞对以杀死和/或抑制这样的细胞的生长为目的的采用辐射的治疗更加敏感。
相应地,本发明进一步涉及用于使哺乳动物中的异常细胞对采用辐射的治疗敏感的方法,其包括对哺乳动物给药一定量的本发明的化合物或药物组合物,其量对于使异常细胞对采用辐射的治疗敏感而言是有效的。该方法中的化合物的量可以根据在本文中描述的用于确定这样的化合物的有效量的手段来确定。
在实际使用中,可以根据常规的药学配混技术,将本发明的化合物作为活性成分与药物载体组合成紧密掺混物。载体可以采取广泛的形式,这取决于给药、例如口服或肠胃外(包括静脉内)给药所需的制剂形式。在制备用于口服剂型的组合物时,可以使用任何常用的药物介质,例如水、二醇、油、醇、调味剂、防腐剂、着色剂等。在口服液体制剂的情况中,可以使用任何常用的药物介质,例如混悬剂、酏剂和溶液;或者载体,例如淀粉、糖、微晶纤维素、稀释剂、造粒剂、润滑剂、粘合剂、崩解剂等。在口服固体制剂的情况中,组合物可以采取例如粉末、硬胶囊和软胶囊、以及片剂的形式,固体口服制剂比液体制剂更优选。
由于其易于给药,因此片剂和胶囊代表最有利的口服单位剂型,在该情况中,显然使用固体药物载体。如果需要的话,片剂可以通过标准的水性或非水性技术包衣。这样的组合物和制剂应当含有至少0.1%的活性化合物。这些组合物中活性化合物的百分比当然可以变化,并且可以方便地为单位重量的约2%至约60%之间。这样的治疗可用组合物中的活性化合物的量使得将获得有效的剂量。活性化合物还可以以例如液滴或喷雾的形式进行鼻内给药。
片剂、丸剂、胶囊等还可以含有粘合剂,例如黄蓍胶、阿拉伯树胶、玉米淀粉或明胶;赋形剂,例如磷酸二钙;崩解剂,例如玉米淀粉、马铃薯淀粉、藻酸;润滑剂,例如硬脂酸镁;以及甜味剂,例如蔗糖、乳糖或糖精。当单位剂型为胶囊时,除了上述类型的材料之外,其还可以含有液体载体,例如脂肪油。
各种其它材料可以作为包衣存在,或用以改变剂量单位的物理形式而存在。例如,可以用虫胶、糖或这两者对片剂包衣。糖浆或酏剂可以在活性成分之外还含有作为甜味剂的蔗糖、作为防腐剂的对羟基苯甲酸甲酯和对羟基苯甲酸丙酯、染料、以及调味剂(例如樱桃或橘子调味剂)。
本发明的化合物还可以肠胃外给药。可以在适当地混有表面活性剂(例如羟丙基纤维素)的水中制备这些活性化合物的溶液或悬浮液。还可以在丙三醇、液体聚乙二醇和其在油中的混合物中来制备分散液。在平常的储存与使用条件下,这些制剂含有用以防止微生物生长的防腐剂。
适合于注射用途的药物形式包括无菌水溶液或分散液和用于临时制备无菌注射溶液或分散液的无菌粉末。在所有情况下,该形式必须是无菌的,并且必须是存在易于注射性的程度的流体。其必须在制造和储存条件下稳定,并且必须防腐以免受微生物、例如细菌和真菌的污染作用。该载体可以是包括例如水、乙醇、多元醇(例如丙三醇、丙二醇和液体聚乙二醇)、其合适的混合物、以及植物油的溶剂或分散介质。
可以使用任何合适的给药途径以用于对哺乳动物、特别是人提供有效剂量的本发明的化合物。例如,可以使用口服、直肠、局部、肠胃外、眼、肺、鼻腔等途径。剂型包括片剂、锭剂、分散剂、混悬剂、溶液、胶囊、乳膏剂、软膏剂、气雾剂等。优选本发明的化合物是口服给药的。
所使用的活性成分有效剂量可以根据所使用的特定化合物、给药模式、所治疗的病况和所治疗的病况的严重程度而改变。这样的剂量可以容易地由本领域技术人员确定。
当治疗本发明的化合物所适用的炎性、退行性或过度增殖性疾病时,当以每千克体重约0.01毫克至约100毫克的日剂量(优选作为每日一次的剂量给予)给药本发明的化合物时,通常获得令人满意的结果。对于大多数大型哺乳动物而言,总的日剂量为约0.1毫克至约1000毫克,优选为约0.2毫克至约50毫克。在70kg的成年人的情况中,总的日剂量将通常为约0.2毫克至约200毫克。可以调节该给药方案以提供最佳的治疗反应。
本发明还涉及套装(set)(试剂盒(kit)),其由以下物质的独立包装组成:
a)有效量的根据本发明的化合物、或者其立体异构体或互变异构体、或前述中的每种的药学上可接受的盐、包括其所有比率的混合物,和
b)有效量的其它药物活性成分。
该套装包括合适的容器,例如盒、单独的瓶、袋或安瓿。
例如,该套装可以包括独立的安瓿,其每一个含有呈溶解或冻干形式的有效量的根据本发明的化合物和有效量的其它药物活性成分。
实验部分
在本申请中可能出现的一些缩写如下所述:
缩写
可以使用适当的材料根据下列方案和实施例的程序来制备本发明的化合物,并且通过下述具体实施例进一步例示。
此外,通过利用本文中所述的程序,结合本领域的普通技术,可以容易地制备本文中要求保护的其它本发明的化合物。但是,实施例中举例说明的化合物不应被解释为形成视为本发明的唯一属类。实施例进一步举例说明了制备本发明的化合物的细节。本领域技术人员将容易理解的是下述制备程序的条件与工艺的已知变化可以用于制备这些化合物。
本化合物通常被分离成其药学上可接受的盐的形式,例如上文所述的那些。可以通过下述方式生成对应于所分离的盐的胺游离碱(amine-free base):用合适的碱(例如碳酸氢钠、碳酸钠、氢氧化钠和氢氧化钾水溶液)中和,并将所释放的胺游离碱萃取到有机溶剂中,接着进行蒸发。以该方式分离的胺游离碱可以通过下述方式来进一步转化为另一种药学上可接受的盐:将其溶解在有机溶剂中,接着添加适当的酸,并接着进行蒸发、沉淀或结晶。
将通过参照在下述实施例中描述的具体实施方案来举例说明本发明,但不受它们的限制。除非在方案中另有说明,变量具有与上述说明相同的含义。
除非另有规定,所有起始材料都获自商业供应商,并且在没有进一步纯化的情况下使用。除非另有规定,所有温度以℃表示,并且所有反应在室温下进行。化合物通过硅胶色谱或制备型HPLC纯化。
本发明还涉及用于制造式(I)的化合物的方法,其中,在任选存在激活剂时,使式(IV)的化合物
与式(III)的化合物
反应从而生成式(I)的化合物。
本领域技术人员知道许多通常用于肽合成以加快反应的激活剂,例如碳二亚胺和三唑。这些激活剂的具体实例为DCC,DIC,HBTU,HATU,HCTU,TBTU,DAPECI,PyBOP,HOBt或HOAt。
实施例
下文所示的工作实施例意图为举例说明本发明的特别优选的实施方案,并且不意图以任何方式限制说明书或权利要求书的范围。
HPLC方法
方法A(HPLC/MS方法,极性)
溶剂A:水+0,05%甲酸
溶剂B:乙腈+0,04%甲酸
流速:2.4mL/min,波长:220nm
梯度:0,00min 5%B
2,80min 100%B
3,30min 100%B
3,40min 5%B
柱:Speed ROD RP18e 50-4.6mm
方法B(HPLC/MS方法)
溶剂A:水+0,1%TFA
溶剂B:乙腈+0,1%TFA
流速:2mL/min,波长:220nm
梯度:0,00min 1%B
0,20min 1%B
3,80min 100%B
4,20min 100%B
4,30min 1%B
柱:Performance RP18e 100-3mm
方法C(HPLC/MS方法)
溶剂A:水+0,1%甲酸
溶剂B:乙腈+0,08%甲酸
流速:0.9mL/min,波长:220nm
梯度:0,00min 5%B
1,00min 100%B
1,2min 100%B
1,40min 5%B
柱:ACQUITYBEH C18 1.7μm
方法D(HPLC/MS方法)
溶剂A:水+0,05%甲酸
溶剂B:乙腈+0,05%甲酸
流速:2,5mL/min,波长:220nm
梯度:0,00min 0%B
1,40min 100%B
2,00min 100%B
2,20min 0%B
柱:Performance RP18e 100-3mm方法E(HPLC/MS方法)
溶剂A:水+5mM NH4HCO3
溶剂B:乙腈
流速:1.5mL/min,波长:190-400nm
梯度:0,01min 10%B
4,20min 70%B
5,20min 70%B
5,30min 10%B
5,60min,停止
柱:XBridge BEH C18 3.5μM 50-4.6mm
柱温:40℃
方法F(HPLC/MS方法)
溶剂A:水+0,05%TFA
溶剂B:乙腈+0,05%TFA
流速:1mL/min,波长:220nm
梯度:0,01min 5%B
3,00min 50%B
5,00min 50%B
5,20min 5%B
5,60min,停止
柱:Shim-pack VP-ODS 50-3mm
柱温:40℃
方法G(HPLC/MS方法)
溶剂A:水+0,05%TFA
溶剂B:乙腈+0,05%TFA
流速:1mL/min,波长:220nm
梯度:0,01min 5%B
2,20min 100%B
3,20min 100%B
3,30min 5%B
3,60min,停止
柱:Shim-pack VP-ODS 50-3mm
柱温:40℃
方法H(HPLC/MS方法)
溶剂A:水+5mM NH4HCO3
溶剂B:乙腈
流速:1.5mL/min,波长:190-400nm
梯度:0,01min 5%B
2,20min 95%B
3,20min 95%B
3,30min 5%B
3,60min,停止
柱:XBridge BEH C18 3.5μM 50-4.6mm柱温:40℃
方法I(HPLC/MS方法)
溶剂A:水+0,05%TFA
溶剂B:乙腈+0,05%TFA
流速:1mL/min,波长:220nm
梯度:0,01min 5%B
4,20min 100%B
5,20min 100%B
5,30min 5%B
5,60min,停止
柱:Shim-pack VP-ODS 50-3mm
柱温:40℃
方法J(HPLC/MS方法)
溶剂A:水+0,1%TFA
溶剂B:乙腈+0,1%TFA
流速:1,5mL/min,波长:220nm
梯度:0,01min 10%B
2,00min 95%B
2,60min 95%B
2,70min 10%B
3,00min,停止
柱:ACE UltraCore 2.5Super C18,50-3mm
柱温:40℃
LCMS方法K:
分析型分离在40℃在Merck Purospher STAR柱(RP-18e,30x 4mm)上进行,采用3mL/min流速,以2分钟梯度洗脱,在254nm检测。流动相为甲醇(溶剂A)和水(溶剂B)的混合物,均含有0.1%甲酸。梯度洗脱如下进行:经1.25min 1:9(A/B)至9:1(A/B),9:1(A/B)持续0.5min,然后经0.15min返回至1:9(A/B),最后1:9(A/B)持续0.1min。
LCMS方法L:
分析型分离在30℃在Merck Purospher STAR柱(RP-18e,30x 4mm)上进行,采用1.5mL/min流速,以4分钟梯度洗脱,在254nm检测。流动相为甲醇(溶剂A)和水(溶剂B)的混合物,均含有0.1%甲酸。梯度洗脱如下进行:经2.5min 1:9(A/B)至9:1(A/B),9:1(A/B)持续1min,然后经0.3min返回至1:9(A/B),最后1:9(A/B)持续0.2min。
LCMS方法M:
分析型分离在30℃在Phenomenex Kinetex XB-C18柱(30x 2.1mm,1.7u,100A)上进行,采用0.5mL/min流速,以2分钟梯度洗脱,在254nm检测。流动相为甲醇(溶剂A)和含0.1%甲酸的水(溶剂B)的混合物。梯度洗脱如下进行:经1.25min 1:9(A/B)至9:1(A/B),9:1(A/B)持续0.5min,然后经0.15min返回至1:9(A/B),最后1:9(A/B)持续0.1min。
化学合成
在本部分中,为根据式(I)的多个实施例化合物和它们的合成中间体提供实验细节。
1.[(S)-2-(4-溴-苯基)-吡咯烷-1-基]-(3-丙基-1H-吲唑-5-基)-甲酮5和[(R)-2-(4-溴-苯基)-吡咯烷-1-基]-(3-丙基-1H-吲唑-5-基)-甲酮6
1.1[2-(4-溴-苯基)-吡咯烷-1-基]-(3-丙基-1H-吲唑-5-基)-甲酮4
向3-丙基-1H-吲唑-5-甲酸(50.0mg,0.24mmol),2-(4-溴-苯基)-吡咯烷,97%(110mg,0.47mmol)和4-甲基吗啉(0.064mL,0.58mmol)的N,N-二甲基-甲酰胺(2mL)的溶液中,加入2-(1H-苯并三唑-1-基)-1,1,3,3-四甲基铵四氟硼酸盐(TBTU,83.0mg,0.26mmol)和1-羟基苯并三唑水合物(9.00mg,0.068mmol)和在室温搅拌过夜。加入水和滤出形成的沉淀和在真空干燥。粗产物通过快速色谱纯化(二氯甲烷/甲醇),得到52.0mg(52%)标题化合物,为黄色晶体。
备选合成:
在螺旋瓶盖玻璃瓶中,将3-丙基-1H-吲唑-5-甲酸(50.0mg,0.24mmol),2-(4-溴-苯基)-吡咯烷,97%(72.0mg,0.31mmol)溶于二氯甲烷(5mL),接着溶于N,N-二异丙基乙基胺(0.12mL,0.73mmol)和1-丙基膦酸环酐(50%/乙酸乙酯,0.28mL,0.47mmol)。将溶液在室温搅拌过夜。将溶液用乙酸乙酯研磨,用水,NaHCO3溶液和盐水洗涤。有机层经硫酸钠干燥,过滤和蒸发至干。粗产物通过快速色谱纯化(环己烷/乙酸乙酯/甲醇),得到7.30mg(8%)标题化合物,为黄色晶体。
1.2.[(S)-2-(4-溴-苯基)-吡咯烷-1-基]-(3-丙基-1H-吲唑-5-基)-甲酮5和[(R)-2-(4-溴-苯基)-吡咯烷-1-基]-(3-丙基-1H-吲唑-5-基)-甲酮6
将52.0mg(0.13mmol)溶于甲醇(1mL)的外消旋混合物通过手性HPLC,以25μL/运行部分,分离到所含的对映体纯物质中,得到19.9mg(38%)浅黄色晶体5和19.4mg(37%)浅黄色晶体6。HPLC/MS(手性):Rt 2.40min(以下方法,5),Rt 3.32min(以下方法,6)。
仪器:SFC Berger Minigram,柱:ChiralPak AD-H,洗脱液:CO2/甲醇+0.5%二乙基胺60:40,等度,流速:5mL/min,检测:220nm.
根据这些程序,合成化合物8,9,11和12。
2.(S)-2-(4-氯-苯基)-吡咯烷-1-基]-(3-甲基-1H-吡唑并[3,4-b]吡啶-5-基)-甲酮13和[(R)-2-(4-氯-苯基)-吡咯烷-1-基]-(3-甲基-1H-吡唑并[3,4-b]吡啶-5-基)-甲酮14
2.1. 3-甲基-1H-吡唑并[3,4-b]吡啶-5-甲酸
将3-甲基-1H-吡唑并[3,4-b]吡啶-5-甲酸甲酯(500mg,2.54mmol)溶于四氢呋喃(100mL)。加入溶于水(50mL)的氢氧化锂(180mg,7.60mmol)和在室温搅拌过夜。使用1N HCl将反应混合物酸化至pH 5和滤出沉淀,用甲基叔-丁基醚洗涤和在真空干燥,得到377mg(83%)标题化合物,为白色晶体,HPLC:(纯度)99%.HPLC MS:室温1.21min(方法A)。
2.2.[2-(4-氯-苯基)-吡咯烷-1-基]-(3-甲基-1H-吡唑并[3,4-b]吡啶-5-基)-甲酮10
在室温向3-甲基-1H-吡唑并[3,4-b]吡啶-5-甲酸(510mg,2.74mmol),2-(4-氯-苯基)-吡咯烷盐酸盐(1.00g,4.56mmol)和4-甲基吗啉(0.064mL,0.58mmol)的N,N-二甲基甲酰胺(2mL)溶液中加入2-(1H-苯并三唑-1-基)-1,1,3,3-四甲基铵四氟硼酸盐(TBTU,83.0mg,0.26mmol)和1-羟基苯并三唑水合物(9.00mg,0.068mmol)。将其在室温搅拌过夜。将水加入混合物,和水层用乙酸乙酯萃取。产物存在于水相。将其蒸发至干和粗产物通过快速色谱纯化(二氯甲烷/甲醇),得到667mg(71%)标题化合物,为黄色晶体。
2.3.(S)-2-(4-氯-苯基)-吡咯烷-1-基]-(3-甲基-1H-吡唑并[3,4-b]吡啶-5-基)-甲酮13和[(R)-2-(4-氯-苯基)-吡咯烷-1-基]-(3-甲基-1H-吡唑并[3,4-b]吡啶-5-基)-甲酮14
将100mg(0.56mmol)溶于甲醇(1mL)的外消旋混合物通过手性HPLC,以60μL/运行部分,分离到所含的对映体纯物质中,得到39.1mg(39%)浅黄色晶体13和40.2mg(40%)浅黄色晶体14。HPLC/MS(手性):Rt 3.84min(以下方法,13),Rt 5.96min(以下方法,14)。
仪器:SFC Berger Minigram,柱:ChiralPak AD-H,洗脱液:CO2/甲醇+0.5%二乙基胺60:40,等度,流速:5mL/min,检测:220nm.
根据这些程序,合成化合物1-3,7,15-30,32-34,36-41和43-46,55-69,94-95,121-123,125,127,129,130,136-139,141-146,149-150,157-160,162和170。
3.[(S)-2-(4-氯-苯基)-吡咯烷-1-基]-(3-异丁基-1H-吲唑-5-基)-甲酮35和[(R)-2-(4-氯-苯基)-吡咯烷-1-基]-(3-异丁基-1H-吲唑-5-基)-甲酮31
3.1. 3-碘代-1H-吲唑-5-甲酸
向25-mL圆底烧瓶中放入1H-吲唑-5-甲酸(200mg,1.23mmol),N,N-二甲基甲酰胺(3mL),氢氧化钾(138mg,2.46mmol)和碘(470mg,1.85mmol)。将溶液在25℃搅拌3h。通过添加10mL Na2S2O3淬灭反应。用氯化氢溶液(10%)将溶液的pH值调整至6。通过过滤收集固体。这得到300mg(84%)3-碘代-1H-吲唑-5-甲酸,为白色固体。
3.2. 3-(2-甲基丙-1-烯-1-基)-1H-吲唑-5-甲酸
向用惰性氮气气氛吹扫和保持的250mL圆底烧瓶中放入3-碘代-1H-吲唑-5-甲酸(2.00g,6.94mmol),4,4,5,5-四甲基-2-(2-甲基丙-1-烯-1-基)-1,3,2-二氧杂硼杂环戊烷(1.90g,10.4mmol),Pd(PPh3)4(800mg,0.69mmol),碳酸钾(2.86g,20.7mmol),二氧杂环己烷(40mL)和水(10mL)。将溶液在90℃搅拌3h。用氯化氢溶液(10%)将溶液的pH值调整至6。通过过滤收集固体。这得到1.30g(87%)3-(2-甲基丙-1-烯-1-基)-1H-吲唑-5-甲酸,为黄色固体。
3.3 3-(2-甲基丙基)-1H-吲唑-5-甲酸
向2000mL密封管中放入3-(2-甲基丙-1-烯-1-基)-1H-吲唑-5-甲酸(1.20g,5.55mmol)和披钯碳(2.00g,18.8mmol)。这接着添加甲醇(800mL)。向上述混合物引入氢气和加入氯化氢溶液(4mL,10%)。将溶液在60℃搅拌4h。滤出固体。混合物在真空浓缩。这得到1.00g(83%)3-(2-甲基丙基)-1H-吲唑-5-甲酸,为黄色固体。
3.4.[(S)-2-(4-氯-苯基)-吡咯烷-1-基]-(3-异丁基-1H-吲唑-5-基)-甲酮35和[(R)-2-(4-氯-苯基)-吡咯烷-1-基]-(3-异丁基-1H-吲唑-5-基)-甲酮31
向25-mL圆底烧瓶中放入3-(2-甲基丙基)-1H-吲唑-5-甲酸(120mg,0.55mmol),2-(4-氯苯基)吡咯烷(150mg,0.83mmol),1-[双(二甲基氨基)亚甲基]-1H-1,2,3-三唑并[4,5-b]吡啶鎓3-氧化物六氟磷酸盐(HATU,208mg,0.55mmol),N,N-二异丙基乙基胺(212mg,1.64mmol)和N,N-二甲基甲酰胺(2mL)。将溶液在室温搅拌1h。将混合物在真空浓缩。剩余部分通过制备型-HPLC纯化,得到80mg(38%)外消旋物质。外消旋混合物通过手性-制备型-HPLC纯化(柱:ChiralPak IC,2*25cm,5μm,流动相:己烷/异丙醇(在25min内保持50%异丙醇),检测器:UV 254/220nm)。得到20mg(10%)白色固体的5-[[(2S)-2-(4-氯苯基)吡咯烷-1-基]羰基]-3-(2-甲基丙基)-1H-吲唑35,和20mg(10%)白色固体的5-[[(2R)-2-(4-氯苯基)吡咯烷-1-基]羰基]-3-(2-甲基丙基)-1H-吲唑31。
根据这些通用程序合成化合物42。
4.(3-氨基-1H-吲唑-5-基)-[2-(4-氯-苯基)-吡咯烷-1-基]-甲酮78
4.1. 3-氨基-1H-吲唑-5-甲酸
将3-氰基-4-氟-苯甲酸(2.00g,12.1mmol)和氢氧化肼(0.60mL,12.1mmol)溶于1-丁醇(40mL)和在110℃搅拌过夜。将冷却至室温后形成的晶体滤出,用甲基叔-丁基醚洗涤和在40℃在真空干燥,得到1.16g(66%)标题化合物,为米色晶体。LC/MS:Rt 0.99min(方法A)。
4.2(3-氨基-1H-吲唑-5-基)-[2-(4-氯-苯基)-吡咯烷-1-基]-甲酮
向3-氨基-1H-吲唑-5-甲酸(50.0mg,0.28mmol),2-(4-氯-苯基)-吡咯烷盐酸盐(123mg,0.56mmol)和4-甲基吗啉(0.064mL,0.58mmol)在N,N-二甲基-甲酰胺(2mL)的溶液中加入2-(1H-苯并三唑-1-基)-1,1,3,3-四甲基铵四氟硼酸盐(TBTU,83.0mg,0.26mmol)和1-羟基苯并三唑水合物(9.00mg,0.068mmol)和在室温搅拌过夜。将水加入至混合物,和滤出沉淀和在真空干燥。粗产物通过制备型HPLC纯化,得到48.0mg(50%)标题化合物,为灰白色固体。
4.3.(3-氨基-1H-吲唑-5-基)-[(S)-2-(4-氯-苯基)-吡咯烷-1-基]-甲酮79和(3-氨基-1H-吲唑-5-基)-[(R)-2-(4-氯-苯基)-吡咯烷-1-基]-甲酮80
将45.0mg(0.13mmol)溶于甲醇(1mL)的外消旋混合物通过手性HPLC,以90μL/运行部分,分离到所含的对映体纯物质中,得到22.1mg(49%)浅黄色晶体79和20.0mg(44%)浅黄色晶体80。HPLC/MS(手性):Rt 3.47min(以下方法,79),Rt 6.45min(以下方法,80).
仪器:SFC Berger Minigram,柱:ChiralPak AD-H,洗脱液:CO2/甲醇+0.5%二乙基胺60:40,等度,流速:5mL/min,UV检测:220nm.
根据这些通用程序合成化合物74-77,81-93,104-118,120,124,131-135,147,148和167。
5.[2-(4-氯-苯基)-吡咯烷-1-基]-(3-环丙基-1H-吡唑并[3,4-b]吡啶-5-基)-甲酮70
5.1. 1-(3-环丙基-1H-吲唑-5-羰基)-1,3-二甲基-脲
将3-氨基-5-环丙基-1H-吡唑(250mg,2.03mmol)和1,3-二甲基-2,4-二氧代-1,2,3,4-四氢嘧啶-5-甲醛(360mg,2.03mmol)在冰乙酸(20mL)中的混合物回流6h。在冷却后,将溶剂在减压下蒸发。将残余物溶于甲醇和将溶液放置过夜。混合物用乙醚稀释,滤出形成的晶体和在真空干燥,得到246mg(44%)标题化合物,为浅米色晶体。
5.2. 3-环丙基-1H-吲唑-5-甲酸
将1-(3-环丙基-1H-吡唑并[3,4-b]吡啶-5-羰基)-1,3-二甲基-脲(246mg,0.89mmol)和氢氧化钠溶液,10%(8mL)混合物加热和在60℃搅拌2h。冷却后,将反应混合物过滤,和滤液用稀HCl酸化。混合物用二氯甲烷萃取。让有机相静置过夜,形成悬浮液。将晶体滤出,用水洗涤和在真空干燥,得到133mg(74%)标题化合物,为白色晶体。
5.3.[2-(4-氯-苯基)-吡咯烷-1-基]-(3-环丙基-1H-吡唑并[3,4-b]吡啶-5-基)-甲酮70
向3-环丙基-1H-吡唑并[3,4-b]吡啶-5-甲酸(100mg,0.49mmol),2-(4-氯-苯基)-吡咯烷(152mg,0.84mmol)和4-甲基吗啉(0.064mL,0.58mmol)的N,N-二甲基-甲酰胺(2mL)溶液中加入O-(1H-苯并三唑-1-基)-N,N,N',N'-四甲基脲鎓四氟硼酸盐(TBTU,83.0mg,0.26mmol)和1-羟基苯并三唑水合物(9.00mg,0.07mmol)和在室温搅拌过夜。将水加入混合物中,用乙酸乙酯萃取两次和将合并有机相用Na2SO4干燥,过滤和蒸发至干。粗产物通过制备型HPLC纯化(乙腈/水)。用1N NaOH使合并级分成碱性,用二氯甲烷萃取两次,合并有机相经Na2SO4干燥,过滤和蒸发至干,得到92.3mg标题化合物,为白色晶体。
根据这些通用程序合成化合物71-73,152-153和168-169。
6.(S)-2-(4-氯-苯基)-吡咯烷-1-基]-(3-甲基-1H-吡唑并[3,4-b]吡啶-5-基)-甲酮155和[(R)-2-(4-氯-苯基)-吡咯烷-1-基]-(3-甲基-1H-吡唑并[3,4-b]吡啶-5-基)-甲酮156
6.1.[2-(4-溴-苯基)-吡咯烷-1-基]-(1H-吡唑并[3,4-b]吡啶-5-基)-甲酮154
在室温向1H-吲唑-5-甲酸(100mg,0.60mmol),2-(4-溴-苯基)-吡咯烷盐酸盐(280mg,1.02mmol)和4-甲基吗啉(0.064mL,0.58mmol)在N,N-二甲基甲酰胺(2mL)的溶液中加入2-(1H-苯并三唑-1-基)-1,1,3,3-四甲基铵四氟硼酸盐(TBTU,83.0mg,0.26mmol)和1-羟基苯并三唑水合物(9.00mg,0.068mmol)。将其在室温搅拌过夜。将水加入混合物中,和水层用萃取乙酸乙酯。产物存在于水相。将其蒸发至干和粗产物通过快速色谱纯化(二氯甲烷/甲醇),得到41.1mg(19%)标题化合物,为白色晶体。
6.2.(S)-2-(4-氯-苯基)-吡咯烷-1-基]-(3-甲基-1H-吡唑并[3,4-b]吡啶-5-基)-甲酮155和[(R)-2-(4-氯-苯基)-吡咯烷-1-基]-(3-甲基-1H-吡唑并[3,4-b]吡啶-5-基)-甲酮156
将35.5mg(0.096mmol)溶于甲醇的外消旋混合物(0.5mL)通过手性HPLC,以60μL/运行部分,分离到所含的对映体纯物质中,得到13.8mg(39%)浅黄色晶体155和14.2mg(40%)浅黄色晶体156。HPLC/MS(手性):Rt 4.66min(以下方法,155),Rt 7.33min(以下方法,156)。
仪器:SFC Berger Minigram,柱:ChiralPak AD-H,洗脱液:CO2/甲醇+0.5%二乙基胺60:40,等度,流速:5mL/min,检测:220nm。
7.[(S)-2-(4-溴-苯基)-吡咯烷-1-基]-(3-甲基-1H-吲唑-5-基)-甲酮49
7.1. 5-溴-3-甲基-1H-吲唑
向用惰性氮气气氛吹扫和保持的50mL密封管加入1-(5-溴-2-氟苯基)乙-1-酮(6.00g,27.7mmol)和水合肼(30mL)。将溶液在117℃搅拌14h。将反应混合物在真空浓缩。将残余物溶于水和用20mL乙酸乙酯萃取3次。合并有机层,经无水硫酸钠干燥和浓缩。将残余物通过硅胶柱纯化,用石油醚:乙酸乙酯(5:1)洗脱。合并收集的级分和在真空浓缩。这得到3.00g(51%)5-溴-3-甲基-1H-吲唑,为黄色固体。
7.2. 3-甲基-1H-吲唑-5-甲酸甲酯
向用一氧化碳(5atm)气氛吹扫和保持的50mL钢槽反应器中加入5-溴-3-甲基-1H-吲唑(1.00g,4.74mmol),Pd(dppf)Cl2.CH2Cl2(400mg,0.49mmol),乙酸钾(1.40g,14.3mmol),N,N-二甲基甲酰胺(5mL)和甲醇(25mL)。将溶液在80℃搅拌14h。将反应混合物在真空浓缩。将残余物溶于水和用20mL乙酸乙酯萃取3次。合并有机层,经无水硫酸钠干燥和浓缩。将残余物通过硅胶柱纯化,用乙酸乙酯/石油醚(3:7)洗脱。这得到750mg(83%)3-甲基-1H-吲唑-5-甲酸甲酯,为黄色固体。
7.3. 3-甲基-1H-吲唑-5-甲酸
向100mL圆底烧瓶中加入3-甲基-1H-吲唑-5-甲酸甲酯(500mg,2.63mmol),氢氧化钠(210mg,5.25mmol),四氢呋喃(50mL)和水(13mL)。将溶液在50℃搅拌2h。将反应混合物在真空浓缩。将残余物溶于30mL水。用HCl溶液(1M)将溶液的pH值调整至3。通过过滤收集沉淀。这得到300mg(65%)3-甲基-1H-吲唑-5-甲酸,为黄色固体。
7.4[(S)-2-(4-溴-苯基)-吡咯烷-1-基]-(3-甲基-1H-吲唑-5-基)-甲酮49
向25-mL圆底烧瓶加入3-甲基-1H-吲唑-5-甲酸(80.0mg,0.45mmol),2-(4-氯苯基)吡咯烷(124mg,0.68mmol),二异丙基乙基胺(176mg,1.36mmol),1-[双(二甲基氨基)亚甲基]-1H-1,2,3-三唑并[4,5-b]吡啶鎓3-氧化物六氟磷酸盐(HATU,207mg,0.54mmol)和N,N-二甲基甲酰胺(5mL)。将溶液在25℃搅拌3h。反应混合物在真空浓缩。将残余物溶于水和用10mL乙酸乙酯萃取3次。合并有机层。粗产物(200mg)通过制备型-HPLC纯化(乙腈/水)。外消旋产物(150mg,87%)进一步通过手性制备型HPLC纯化,采用以下条件:柱:PhenomenexLux 5μCellose-4,250*21.2mm,5μm;流动相:己烷和乙醇(20%乙醇/己烷,等度,在21min内);检测器,UV 254/220nm。这得到80.0mg(46%)5-[[(2S)-2-(4-溴苯基)吡咯烷-1-基]羰基]-3-甲基-1H-吲唑49,为白色固体。
根据这些通用程序合成化合物47,48和50。
8.[(S)-2-(4-氯-苯基)-吡咯烷-1-基]-(3-甲基-1H-吡唑并[4,3-b]吡啶-5-基)-甲酮51
8.1. 3-甲基-1H-吡唑并[4,3-b]吡啶
向50mL密封管加入1-(3-氟吡啶-2-基)乙-1-酮(2.00g,14.4mmol)和水合肼(25mL)。将溶液在130℃搅拌3h。将反应混合物用50mL乙酸乙酯洗涤3次,经无水硫酸钠干燥和浓缩。将残余物通过硅胶柱纯化,用乙酸乙酯/石油醚(2:3)洗脱。这得到900mg(47%)3-甲基-1H-吡唑并[4,3-b]吡啶,为黄色固体。
8.2. 3-甲基-1-三苯甲基-1H-吡唑并[4,3-b]吡啶
在0℃向用惰性氮气气氛吹扫和保持的100mL圆底烧瓶加入3-甲基-1H-吡唑并[4,3-b]吡啶(2.43g,18.3mmol)和N,N-二甲基甲酰胺(20mL)。然后向反应混合物加入氢化钠(660mg,27.5mmol)和30min后加入(氯二苯基甲基)苯(5.60g,20.1mmol)。将溶液在25℃搅拌2h。然后通过添加5ml NH4Cl溶液将反应淬灭。将混合物在真空浓缩。将残余物溶于20mL乙酸乙酯,用30mL水洗涤3次,经无水硫酸钠干燥和浓缩。将残余物通过硅胶柱纯化,用石油醚:乙酸乙酯(3:1)洗脱。这得到3.00g(44%)3-甲基-1-(三苯基甲基)-1H-吡唑并[4,3-b]吡啶,为黄色固体。
8.3. 3-甲基-1-三苯甲基-1H-吡唑并[4,3-b]吡啶4-氧化物
在0℃向50mL圆底烧瓶加入3-甲基-1-(三苯基甲基)-1H-吡唑并[4,3-b]吡啶(3.00g,7.99mmol)和二氯甲烷(20mL)。然后加入间-氯过氧苯甲酸(1.50g,8.69mmol)。将溶液在25℃搅拌2h。反应混合物用20mL碳酸钠溶液洗涤3次,经无水硫酸钠干燥和在真空浓缩。将残余物通过硅胶柱纯化,用二氯甲烷/乙酸乙酯(1:1)洗脱。这得到2.70g(86%)3-甲基-1-三苯甲基-1H-吡唑并[4,3-b]吡啶4-氧化物,为灰白色固体。
8.4. 5-氯-3-甲基-1H-吡唑并[4,3-b]吡啶
向50mL密封管加入3-甲基-1-三苯甲基-1H-吡唑并[4,3-b]吡啶4-氧化物(2.84g,7.25mmol),磷酰氯(20mL)。将溶液在130℃搅拌1h。然后通过添加20mL水/冰浆液将反应淬灭。氢氧化钠溶液(6M)用于将混合物pH调整至7。溶液用200mL二氯甲烷萃取5次和合并有机层,经无水硫酸钠干燥和浓缩。残余物通过硅胶柱纯化,用二氯甲烷/甲醇(20:1)洗脱。这得到1.40g(98%)5-氯-3-甲基-1H-吡唑并[4,3-b]吡啶,为灰白色固体。
8.5. 3-甲基-1H-吡唑并[4,3-b]吡啶-5-甲酸甲酯
向用一氧化碳(5atm)气氛吹扫和保持的250mL钢槽反应器中加入5-氯-3-甲基-1H-吡唑并[4,3-b]吡啶(1.20g,7.16mmol),甲醇(160mL),乙酸钾(2.10g,21.4mmol)和Pd(dppf)Cl2.CH2Cl2(585mg,0.72mmol)。将溶液在80℃搅拌14h。反应混合物在真空浓缩。将残余物溶于50mL水。将溶液用60mL乙酸乙酯萃取3次和合并有机层和浓缩。将残余物通过硅胶柱纯化,用乙酸乙酯/石油醚(3:2)洗脱。这得到720mg(53%)3-甲基-1H-吡唑并[4,3-b]吡啶-5-甲酸甲酯,为灰白色固体。
8.6. 3-甲基-1H-吡唑并[4,3-b]吡啶-5-甲酸
向50mL圆底烧瓶加入3-甲基-1H-吡唑并[4,3-b]吡啶-5-甲酸甲酯(720mg,3.77mmol),四氢呋喃(10mL),水(2mL)和氢氧化钠(226mg,5.65mmol)。将溶液在50℃搅拌2h。反应混合物在真空浓缩。将残余物溶于20mL水。将形成的固体滤出。加入HCl溶液(1M)以将pH调整至7。通过过滤收集沉淀。这得到350mg(52%)3-甲基-1H-吡唑并[4,3-b]吡啶-5-甲酸,为灰白色固体。
8.7.[(S)-2-(4-氯-苯基)-吡咯烷-1-基]-(3-甲基-1H-吡唑并[4,3-b]吡啶-5-基)-甲酮51
向25mL圆底烧瓶加入3-甲基-1H-吡唑并[4,3-b]吡啶-5-甲酸(170mg,0.96mmol),2-(4-氯苯基)吡咯烷(261mg,1.44mmol),N,N-二甲基甲酰胺(4mL),1-[双(二甲基氨基)亚甲基]-1H-1,2,3-三唑并[4,5-b]吡啶鎓3-氧化物六氟磷酸盐(HATU,401mg,1.05mmol)和二异丙基乙基胺(372mg,2.88mmol)。将溶液在25℃搅拌1h。混合物在真空浓缩。将残余物通过制备型HPLC纯化(乙腈/水)。外消旋产物(80.0mg,24%)进一步通过手性制备型HPLC纯化,采用以下条件:柱:Phenomenex Lux 5u Cellose-4,250*21.2mm,5μm;流动相:己烷和甲醇(20%甲醇/己烷,等度,在12min内);检测器,UV 254/220nm。这得到35mg(11%)(2S)-2-(4-氯苯基)-1-([3-甲基-1H-吡唑并[4,3-b]吡啶-5-基]羰基)吡咯烷,为白色固体。
根据这些通用程序合成化合物52,53和54。
9.(3-氨基-1H-吡唑并[3,4-b]吡啶-5-基)-[(S)-2-(4-溴-苯基)-吡咯烷-1-基]-甲酮98
9.1. 5-溴-1H-吡唑并[3,4-b]吡啶-3-基胺
向100mL密封管中加入5-溴-2-氯吡啶-3-甲腈(2.50g,11.5mmol)和水合肼(30mL)。将溶液在130℃搅拌3h。反应混合物在真空浓缩。将残余物溶于30mL水。出现沉淀。通过过滤收集沉淀。这得到2.00g(82%)5-溴-1H-吡唑并[3,4-b]吡啶-3-胺,为黄色固体。
9.2. 3-氨基-1H-吡唑并[3,4-b]吡啶-5-甲酸甲酯
向用一氧化碳(5atm)气氛吹扫和保持的30mL钢槽反应器放入5-溴-1H-吡唑并[3,4-b]吡啶-3-胺(500mg,2.35mmol),Pd(dppf)Cl2.CH2Cl2(192mg,0.24mmol),乙酸钾(691mg,7.04mmol),N,N-二甲基甲酰胺(5mL)和甲醇(5mL)。将混合物在80℃搅拌14h,然后在真空浓缩。将溶液用20mL乙酸乙酯萃取3次和合并有机层。将残余物通过硅胶柱纯化,用乙酸乙酯/石油醚(7:3)洗脱。这得到200mg(44%)3-氨基-1H-吡唑并[3,4-b]吡啶-5-甲酸甲酯,为浅褐色固体。
9.3. 3-氨基-1H-吡唑并[3,4-b]吡啶-5-甲酸
向25-mL圆底烧瓶加入3-氨基-1H-吡唑并[3,4-b]吡啶-5-甲酸甲酯(200mg,1.04mmol),四氢呋喃(8mL),水(2mL)和氢氧化钠(84.0mg,2.10mmol)。将溶液在50℃搅拌3h。将混合物在真空浓缩。将残余物溶于10mL水。用氯化氢(1mol/L)将溶液的pH值调整至3。通过过滤收集沉淀。这得到100mg(54%)3-氨基-1H-吡唑并[3,4-b]吡啶-5-甲酸,为黄色固体。
9.4.(3-氨基-1H-吡唑并[3,4-b]吡啶-5-基)-[(S)-2-(4-溴-苯基)-吡咯烷-1-基]-甲酮98
向25-mL圆底烧瓶放入3-氨基-1H-吡唑并[3,4-b]吡啶-5-甲酸(40mg,0.22mmol),2-(4-溴苯基)吡咯烷(76.0mg,0.34mmol),N,N-二甲基甲酰胺(5mL),1-[双(二甲基氨基)亚甲基]-1H-1,2,3-三唑并[4,5-b]吡啶鎓3-氧化物六氟磷酸盐(HATU,94mg,0.25mmol),二异丙基乙基胺(87.0mg,0.67mmol)。将溶液在25℃搅拌1h。混合物在真空浓缩。将残余物溶于10mL乙酸乙酯。混合物用10mL水洗涤3次。粗产物通过制备型HPLC纯化(乙腈/水)。粗产物(50mg,59%)通过手性制备型HPLC纯化,采用以下条件:柱:Chiralpak IC,2*25cm,5μm;流动相:己烷-HPLC和乙醇-HPLC(保持50%乙醇-HPLC在20min内);检测器,UV 254/220nm。这得到19mg(21%)5-[[(2S)-2-(4-溴苯基)吡咯烷-1-基]羰基]-1H-吡唑并[3,4-b]吡啶-3-胺,为灰白色固体。
根据这些通用程序合成化合物96,97和99。
10.[2-(4-氯-苯基)-吡咯烷-1-基]-(3-三氟甲基-1H-吡唑并[3,4-b]吡啶-5-基)-甲酮(177)
10.1. 1,3-二甲基-1-(3-三氟甲基-1H-吡唑并[3,4-b]吡啶-5-羰基)-脲
将5-三氟甲基-2H-吡唑-3-基胺(500mg,3.31mmol)和1,3-二甲基-2,4-二氧代-1,2,3,4-四氢嘧啶-5-甲醛(586mg,3.31mmol)在乙酸(冰乙酸,40mL)的混合物回流6h。冷却后,将溶剂在减压下蒸发。将残余物溶于甲醇,将溶液静置过夜,将沉淀的晶体悬浮于乙醚,滤出和干燥。粗产物通过快速色谱纯化(二氯甲烷/甲醇),得到630mg(49%)标题化合物,为无色固体。HPLC(纯度)77%.HPLC/MS:Rt 1.66min(方法A)。
10.2. 3-三氟甲基-1H-吡唑并[3,4-b]吡啶-5-甲酸
将1,3-二甲基-1-(3-三氟甲基-1H-吡唑并[3,4-b]吡啶-5-羰基)-脲(630mg,1.61mmol)和氢氧化钠溶液的水(10%,16mL)混合物加热和在60℃搅拌2h。冷却后,将反应混合物过滤,和滤液用稀HCl酸化。滤出形成的沉淀,用水洗涤和干燥,得到206mg(51%)标题化合物,为米色固体。HPLC(纯度)92%.HPLC/MS:Rt 1.58min。
10.3.[2-(4-氯-苯基)-吡咯烷-1-基]-(3-三氟甲基-1H-吡唑并[3,4-b]吡啶-5-基)-甲酮
在RT向3-三氟甲基-1H-吡唑并[3,4-b]吡啶-5-甲酸(100mg,0.40mmol),2-(4-氯-苯基)-吡咯烷(115mg,0.60mmol)和4-甲基吗啉(0.064mL,0.58mmol)的N,N-二甲基甲酰胺(2mL)溶液中加入N-(3-二甲基氨基丙基)-N'-乙基碳二亚胺盐酸盐,DAPECI(92.0mg,0.48mmol)和1-羟基苯并三唑水合物(9.00mg,0.07mmol)和将反应混合物在RT搅拌过夜。将混合物倾入水中,滤出沉淀和在真空干燥。粗产物通过快速色谱纯化(n-庚烷/乙酸乙酯),得到69.0mg(44%)标题化合物,为白色固体。1H NMR(400MHz,DMSO-d6)ppm=8.90,8.55,8.49,7.84(4x s,2H,比率=2:3旋转异构体混合物),7.46,7.38,7.23,7.02(2x d,J=8.2Hz,2x d,J=7.7Hz,4H,比率=2:3旋转异构体混合物),5.23–5.10,4.98–4.87(2x m,1H,比率=2:3旋转异构体混合物),3.97–3.76,3.66–3.24(1x m,1x m+HDO,2H),2.46–2.30(m,1H),2.03–1.68(m,3H)。
62.7mg外消旋混合物通过制备型HPLC分离(SFC Berger Minigram,柱:ChiralPakAD-H,溶剂:CO2/甲醇85:15,流速:5ml/min,波长:220nm),得到化合物180(26.6mg,42%)和181(26.3mg,42%),为白色固体。
类似于这些程序合成化合物183和184。
11.[(S)-2-(4-氯-苯基)-吡咯烷-1-基]-(3-甲基-1H-吡唑并[3,4-c]吡啶-5-基)-甲酮(190)
11.1. 1-(2-溴-5-氟吡啶-4-基)乙-1-酮
向用惰性氮气气氛吹扫和保持的250mL三颈圆底烧瓶放入LDA(35.0mL,258mmol)的四氢呋喃(30mL)溶液。这接着在-78℃添加2-溴-5-氟吡啶(5.00g,28.4mmol)的四氢呋喃(20mL)溶液。将混合物在-78℃搅拌2h。在-78℃向混合物加入N-甲氧基-N-甲基乙酰胺(6.40g,62.1mmol)的四氢呋喃(20mL)溶液。将溶液温热至RT和在RT搅拌3h。混合物然后通过添加100mL水淬灭。将溶液用200mL乙酸乙酯萃取和有机层经无水硫酸钠干燥和在真空浓缩。将残余物经硅胶柱用石油醚/乙酸乙酯(50:1)纯化。这得到4.00g(65%)1-(2-溴-5-氟吡啶-4-基)乙-1-酮,为黄色油状物。
11.2 5-溴-3-甲基-1H-吡唑并[3,4-c]吡啶
向30mL密封管中放入1-(2-溴-5-氟吡啶-4-基)乙-1-酮(2.00g,9.17mmol),NH2NH2*水(500mg,9.99mmol)和乙烷-1,2-二醇(10mL)。将溶液在165℃在油浴中搅拌4h。混合物用100mL水稀释。通过过滤收集固体。这得到1.70g(87%)5-溴-3-甲基-1H-吡唑并[3,4-c]吡啶,为黄色固体。
11.3. 3-甲基-1H-吡唑并[3,4-c]吡啶-5-甲酸甲酯
向30mL密封管中放入5-溴-3-甲基-1H-吡唑并[3,4-c]吡啶(900mg,4.24mmol),Pd(dppf)Cl2(315mg,0.43mmol),KOAc(1.25g,12.7mmol)和N,N-二甲基甲酰胺(10mL)。这接着添加甲醇(10mL)和CO气体。将溶液在80℃在油浴中搅拌1h过夜。将混合物在真空浓缩。将残余物经硅胶柱用二氯甲烷/甲醇(20:1)纯化。这得到0.60g(74%)3-甲基-1H-吡唑并[3,4-c]吡啶-5-甲酸甲酯,为褐色固体。
11.4 3-甲基-1H-吡唑并[3,4-c]吡啶-5-甲酸
向50mL圆底烧瓶放入3-甲基-1H-吡唑并[3,4-c]吡啶-5-甲酸甲酯(300mg,1.57mmol),LiOH*H2O(328mg,7.82mmol),四氢呋喃(20mL)和水(5mL)。将溶液在60℃在油浴中搅拌5h。混合物在真空浓缩。用氯化氢(1M)将溶液pH调整至4。通过过滤收集固体。这得到190mg(68%)3-甲基-1H-吡唑并[3,4-c]吡啶-5-甲酸,为黄色固体。
11.5[(S)-2-(4-氯-苯基)-吡咯烷-1-基]-(3-甲基-1H-吡唑并[3,4-c]吡啶-5-基)-甲酮
向25mL圆底烧瓶放入3-甲基-1H-吡唑并[3,4-c]吡啶-5-甲酸(130mg,0.73mmol),(S)-2-(4-氯苯基)吡咯烷(172mg,0.95mmol),HATU(277mg,0.73mmol),二乙基乙酸酯(282mg,2.18mmol)和N,N-二甲基甲酰胺(4mL)。将溶液在RT搅拌3h。将混合物在真空浓缩。粗产物通过制备型-HPLC纯化(乙腈/水)。这得到20.0mg(8%)(2S)-2-(4-氯苯基)-1-([3-甲基-1H-吡唑并[3,4-c]吡啶-5-基]羰基)吡咯烷,为白色固体。1H NMR(300MHz,DMSO-d6)ppm=13.40(m,1H),9.00(s,0.67H),8.72(s,0.33H),8.14(s,0.67H),7.83(s,0.33H),7.40-7.32(m,3H),7.15-6.98(m,1H),5.84-5.82(m,0.33H),5.26-5.21(m,0.67H),4.10-4.02(m,0.67H),3.87-3.70(m,1.33H),2.55(s,2H),2.41(s,1H),2.38-2.27(m,1H),1.87-1.68(m,3H)。
类似于这些程序合成189。
12.[(S)-2-(4-氯-苯基)-吡咯烷-1-基]-(6-氟-3-甲基-1H-吲唑-5-基)-甲酮(206)
12.1. 5-溴-6-氟-3-甲基-1H-吲唑
向50mL圆底烧瓶放入乙烷-1,2-二醇(30mL),1-(5-溴-2,4-二氟苯基)乙-1-酮(5.95g,25.3mmol),NH2NH2*H2O(1.90g,38.0mmol)。将溶液在120℃在油浴中搅拌20h。混合物用200mL水稀释和用70mL乙酸乙酯萃取3次。将合并有机层在真空浓缩。这得到4.45g(77%)5-溴-6-氟-3-甲基-1H-吲唑,为黄色固体。
12.2.6-氟-3-甲基-1H-吲唑-5-甲酸甲酯
向250mL密封管放入甲醇(180mL),N,N-二甲基甲酰胺(10mL),5-溴-6-氟-3-甲基-1H-吲唑(4.00g,17.5mmol),Pd(dppf)Cl2*二氯甲烷(2.55g,3.12mmol)和乙酸钾(5.15g,52.4mmol)。将溶液在80℃在油浴中搅拌20h。混合物在真空浓缩。将残余物用100mL水稀释。将溶液用50mL乙酸乙酯萃取3次和将合并有机层蒸发至干。将残余物经硅胶柱用乙酸乙酯/己烷(1:3)纯化。这得到2.64g(73%)6-氟-3-甲基-1H-吲唑-5-甲酸甲酯,为黄色固体。
12.3 6-氟-3-甲基-1H-吲唑-5-甲酸
向100mL圆底烧瓶放入四氢呋喃(50mL),6-氟-3-甲基-1H-吲唑-5-甲酸甲酯(2.64g,12.7mmol),水(10mL)和LiOH(1.52g,63.47mmol)。将溶液在60℃在油浴中搅拌4h。混合物在真空浓缩。用氯化氢(12M)将溶液pH调整至4。通过过滤收集固体和丢弃。滤液在真空浓缩,得到2.21g(90%)6-氟-3-甲基-1H-吲唑-5-甲酸,为浅黄色固体。
12.4.[(S)-2-(4-氯-苯基)-吡咯烷-1-基]-(6-氟-3-甲基-1H-吲唑-5-基)-甲酮(206)
向25mL圆底烧瓶放入N,N-二甲基甲酰胺(5mL),6-氟-3-甲基-1H-吲唑-5-甲酸(200mg,1.03mmol),(2S)-2-(4-氯苯基)吡咯烷(243.261mg,1.34mmol),二乙基乙酸酯(399mg,3.09mmol)和HATU(392mg,1.03mmol)。将溶液在25℃搅拌1h。将固体滤出和粗产物通过制备型-HPLC纯化(乙腈/水),得到60mg(16%)5-[[(2S)-2-(4-氯苯基)吡咯烷-1-基]羰基]-6-氟-3-甲基-1H-吲唑,为白色固体。1H NMR(300MHz,CDCl3)ppm=7.78(d,0.65H),7.33-7.12(m,2.33H),7.09-7.06(m,1.90H),6.93-6.78(m,1.17H),5.36-5.32(m,0.69H),4.72-4.68(m,0.38H),4.00-3.90(m,0.75H),3.70-3.66(m,0.65H),3.49-3.45(m,0.65H),2.57-2.45(s,2H),2.43-2.39(m,1.02H),2.38-2.36(s,1.18H),2.07-2.00(m,1.14H),1.96-1.85(m,2.14H)。
类似于这些程序合成203。
13.[(S)-2-(4-氯-苯基)-吡咯烷-1-基]-(3-甲磺酰基-1H-吲唑-5-基)-甲酮(220)
13.1. 3-甲基硫基-1H-吲唑-5-甲酸
在2mL微波小瓶中称重3-碘代-1H-吲唑-5-甲酸乙基酯(100mg,0.32mmol),碘化铜(I)(6.02mg,0,03mmol)和甲烷硫醇钠(123μL,1.58mmol),并溶于无水二甲亚砜(4mL)和水(0.6mL)。使混合物在120℃在微波辐照下反应2h。混合物用0.5N HCl溶液(25mL)稀释和用乙酸乙酯萃取两次(50mL)。将合并有机层蒸发至干和通过快速色谱纯化(乙酸乙酯/甲醇),得到3-甲基硫基-1H-吲唑-5-甲酸(62.0mg,77%)为无色油状物。
13.2.[(S)-2-(4-氯-苯基)-吡咯烷-1-基]-(3-甲基硫基-1H-吲唑-5-基)-甲酮(210)
对3-甲基硫基-1H-吲唑-5-甲酸(62.0mg,0.24mmol),(S)-2-(4-氯-苯基)-吡咯烷盐酸盐(63.8mg,0.29mmol)和O-(1H-苯并三唑-1-基)-N,N,N',N'-四甲基脲鎓四氟硼酸盐(TBTU,157mg,0.49mmol)称重并溶于N,N-二甲基甲酰胺(2mL)和4-甲基吗啉(82.1μL,0.73mmol)。将透明溶液在RT搅拌30min。将反应混合物倾入饱和氯化铵溶液(30mL)。滤出沉淀,用水洗涤(10mL)和在70℃在真空干燥过夜,得到[(S)-2-(4-氯-苯基)-吡咯烷-1-基]-(3-甲基硫基-1H-吲唑-5-基)-甲酮(26.2mg,27%),为灰白色固体。
13.3.[(S)-2-(4-氯-苯基)-吡咯烷-1-基]-(3-甲磺酰基-1H-吲唑-5-基)-甲酮(220)
在12mL螺旋帽瓶中称重[(S)-2-(4-氯-苯基)-吡咯烷-1-基]-(3-甲基硫基-1H-吲唑-5-基)-甲酮(17.5mg,0.04mmol)和单过硫酸盐(过氧一硫酸钾,54.1mg,0.09mmol)并悬浮于N,N-二甲基甲酰胺(1mL)。将混合物在RT搅拌3天。悬浮液用NaHSO3溶液(3mL,~39%/水)淬灭。混合物用水稀释和用固体NaHCO3中和。将其用乙酸乙酯萃取两次(30mL)。将合并有机层干燥,过滤,蒸发至干和进一步通过快速色谱纯化(二氯甲烷/甲醇),得到12.4mg(71%)[(S)-2-(4-氯-苯基)-吡咯烷-1-基]-(3-甲磺酰基-1H-吲唑-5-基)-甲酮,为白色固体。
14.[(S)-2-(4-氯-苯基)-吡咯烷-1-基]-(3-氟-1H-吲唑-5-基)-甲酮(216)
14.1. 3-氟-1H-吲唑-5-甲酸
向螺旋帽瓶加入1H-吲唑-5-甲酸(64.0mg,0.38mmol)和悬浮于乙腈(8mL)和乙酸(冰乙酸,1mL)。向该混浊悬浮液中滴加溶于1mL乙腈的1-(氯甲基)-4-氟-1,4-二氮鎓二环[2.2.2]辛烷二四氟硼酸盐(214mg,0.57mmol)和将混合物在60℃搅拌过夜和在80℃搅拌4天。将混合物蒸发至干,将残余物溶于乙酸乙酯和用水洗涤两次和用盐水洗涤1次。有机相用硫酸钠干燥和将有机相蒸发至干。将残余物通过制备型色谱分离(乙腈/水),得到16mg(23%)白色固体。
14.2.[(S)-2-(4-氯-苯基)-吡咯烷-1-基]-(3-氟-1H-吲唑-5-基)-甲酮(216)
向3-氟-1H-吲唑-5-甲酸(16.0mg,0.09mmol)的N,N-二甲基甲酰胺(3mL)溶液中加入(S)-2-(4-氯-苯基)-吡咯烷盐酸盐(23.0mg,0.11mmol)、4-甲基吗啉(0.03mL,0.26mmol)和[(苯并三唑-1-基氧基)-二甲基氨基-亚甲基]-二甲基-铵四氟硼酸盐(TBTU),56.5mg,0.18mmol)和将混合物在60℃搅拌5min。混合物用乙酸乙酯稀释,用1N NaOH溶液、水和盐水洗涤1次。分离有机层和用硫酸钠干燥,过滤和蒸发至干。将残余物通过制备型色谱纯化(乙腈/水),得到17mg(55%)标题化合物,为灰白色固体。1H NMR(400MHz,DMSO-d6,90℃)ppm=12.43(s,1H),7.78(s,1H),7.54–7.39(m,2H),7.34–7.18(m,4H),5.12(t,J=6.7Hz,1H),3.86–3.76(m,1H),3.69–3.58(m,1H),2.43–2.33(m,1H),1.94–1.83(m,2H),1.83–1.72(m,1H)。
15.[(S)-2-(1H-吲唑-5-基)-吡咯烷-1-基]-(3-甲基-1H-吡唑并[3,4-b]吡啶-5-基)-甲酮(245)和[(R)-2-(1H-吲唑-5-基)-吡咯烷-1-基]-(3-甲基-1H-吡唑并[3,4-b]吡啶-5-基)-甲酮(246)
15.1. 2-(1H-吲唑-5-基)-1H-吡咯-1-甲酸叔-丁基酯
向用惰性氮气气氛吹扫和保持的250mL圆底烧瓶放入碳酸钠(1.08g,10.1mmol),水(20mL),乙二醇二甲基醚(100mL),5-溴-1H-吲唑(1.00g,5.08mmol),[1-[(叔丁氧基)羰基]-1H-吡咯-2-基]硼酸(1.29g,6.09mmol)和Pd(PPh3)4(586mg,0.51mmol)。将溶液在95℃在油浴中搅拌4h和冷却后用50mL水稀释。将溶液用50mL二氯甲烷萃取两次和将合并有机层浓缩至干。将残余物经硅胶柱用乙酸乙酯/石油醚(1:10)纯化。这得到1g(70%)2-(1H-吲唑-5-基)-1H-吡咯-1-甲酸叔-丁基酯,为黄色油状物。
15.2. 5-(吡咯烷-2-基)-1H-吲唑
向用氢气气氛吹扫和保持的20mL压力槽反应器放入2-(1H-吲唑-5-基)-1H-吡咯-1-甲酸叔-丁基酯(500mg,1.76mmol),乙醇(5.00mL),氯化氢(1N,0.50mL)和PtO2(40.1mg,0.18mmol)。将溶液在60℃在油浴中搅拌5天。将混合物在真空浓缩。将残余物经硅胶柱用甲醇/水(1:99)纯化。这得到200mg(61%)5-(吡咯烷-2-基)-1H-吲唑,为黄色油状物。
15.3[(S)-2-(1H-吲唑-5-基)-吡咯烷-1-基]-(3-甲基-1H-吡唑并[3,4-b]吡啶-5-基)-甲酮(245)和[(R)-2-(1H-吲唑-5-基)-吡咯烷-1-基]-(3-甲基-1H-吡唑并[3,4-b]吡啶-5-基)-甲酮(246)根据通用程序制备,得到29mg(7%)标题化合物,为白色固体。1HNMR(245,300Hz,DMSO-d6)ppm=13.11(s,1H),12.76(s,1H),8.52(s,1H),8.40-8.09(m,1H),7.95(s,1H),7.62-7.50(m,1H),7.50-7.35(m,1H),7.22(s,1H),5.24(s,1H),3.92-3.90(m,1H),3.79-3.72(m,1H),2.42-2.31(m,4H),1.97-1.90(m,3H).
16.[(2S,4R)-2-(4-氯-苯基)-4-甲基氨基-吡咯烷-1-基]-(3-甲基-1H-吡唑并[3,4-b]吡啶-5-基)-甲酮(254)
16.1.(3S)-3-[(叔-丁基二甲基甲硅烷基)氧基]-4-氯丁腈
向250mL圆底烧瓶放入(3S)-4-氯-3-羟基丁腈(5.00g,41.8mmol),N,N-二甲基甲酰胺(80mL),TBSCl(8.10g,53.74mmol),咪唑(5.60g,82.3mmol)。将反应混合物在RT搅拌1h过夜。将溶液用200mL乙酸乙酯稀释。混合物在真空浓缩。将残余物经硅胶柱用乙酸乙酯/石油醚(1:10)纯化。这得到7.80g(80%)(3S)-3-[(叔-丁基二甲基甲硅烷基)氧基]-4-氯丁腈,为无色液体。
16.2.(3S)-3-[(叔-丁基二甲基甲硅烷基)氧基]-5-(4-氯苯基)-3,4-二氢-2H-吡咯
向用惰性氮气气氛吹扫和保持的50mL 3-颈圆底烧瓶放入(3S)-3-[(叔-丁基二甲基甲硅烷基)氧基]-4-氯丁腈(300mg,1.28mmol)/甲基叔丁基醚(5mL)。这接着在0℃添加溴(4-氯苯基)镁(3.80mL,17.6mmol)。将混合物在25℃搅拌3h。向混合物加入乙二醇二甲基醚(5mL)和将溶液在RT搅拌2h。将溶液用50mL乙酸乙酯稀释。混合物在真空浓缩。将残余物经硅胶柱用石油醚/乙酸乙酯(50:1)纯化。这得到240mg(60%)(3S)-3-[(叔-丁基二甲基甲硅烷基)氧基]-5-(4-氯苯基)-3,4-二氢-2H-吡咯,为褐色油状物。
16.3.(2RS,4S)-4-[(叔-丁基二甲基甲硅烷基)氧基]-2-(4-氯苯基)吡咯烷
向50mL圆底烧瓶放入(3S)-3-[(叔-丁基二甲基甲硅烷基)氧基]-5-(4-氯苯基)-3,4-二氢-2H-吡咯(300mg,0.97mmol)/乙醇(6mL)。这接着添加PtO2(30mg,0.13mmol)。将溶液在RT在氢气气氛下搅拌1h过夜。滤出固体和丢弃。将滤液在真空浓缩,得到300mg(99%)(2RS,4S)-4-[(叔-丁基二甲基甲硅烷基)氧基]-2-(4-氯苯基)吡咯烷,为褐色油状物。
16.4.(2RS,4S)-4-[(叔-丁基二甲基甲硅烷基)氧基]-2-(4-氯苯基)-1-({3-甲基-1H-吡唑并[3,4-b]吡啶-5-基}羰基)吡咯烷
向50mL圆底烧瓶放入3-甲基-1H-吡唑并[3,4-b]吡啶-5-甲酸(300mg,1.69mmol),(2RS,4S)-4-[(叔-丁基二甲基甲硅烷基)氧基]-2-(4-氯苯基)吡咯烷(631mg,2.02mmol),HATU(640mg,1.68mmol),二乙基乙酸酯(652mg,5.04mmol)和N,N-二甲基甲酰胺(5mL)。将溶液在RT搅拌3h。将混合物在真空浓缩。将残余物经硅胶柱用二氯甲烷/甲醇(50:1)纯化。这得到250mg(31%)(2RS,4S)-4-[(叔-丁基二甲基甲硅烷基)氧基]-2-(4-氯苯基)-1-([3-甲基-1H-吡唑并[3,4-b]吡啶-5-基]羰基)吡咯烷,为黄色。
16.5.(3S,5RS)-5-(4-氯苯基)-1-({3-甲基-1H-吡唑并[3,4-b]吡啶-5-基}羰基)吡咯烷-3-醇
向25mL圆底烧瓶放入(2RS,4S)-4-[(叔-丁基二甲基甲硅烷基)氧基]-2-(4-氯苯基)-1-([3-甲基-1H-吡唑并[3,4-b]吡啶-5-基]羰基)吡咯烷(200mg,0.42mmol)/四氢呋喃(5mL)。在0℃加入TBAF(2mL,7.65mmol)和将溶液在0℃在水/冰浴中搅拌30分钟。将混合物在真空浓缩。将残余物施加到硅胶柱,采用二氯甲烷/甲醇(20:1)。这得到140mg(92%)(3S,5RS)-5-(4-氯苯基)-1-([3-甲基-1H-吡唑并[3,4-b]吡啶-5-基]羰基)吡咯烷-3-醇,为黄色固体。
16.6.(3S,5RS)-5-(4-氯苯基)-1-({3-甲基-1H-吡唑并[3,4-b]吡啶-5-基}羰基)吡咯烷-3-基甲烷磺酸酯
向25mL圆底烧瓶放入(3S,5RS)-5-(4-氯苯基)-1-([3-甲基-1H-吡唑并[3,4-b]吡啶-5-基]羰基)吡咯烷-3-醇(140mg,0.39mmol),二氯甲烷(10mL),三乙基胺(119mg,1.18mmol),甲磺酰氯(58.0mg,0.51mmol)。将溶液在0℃在水/冰浴中搅拌2h。将溶液用50mL二氯甲烷稀释。混合物经硫酸钠干燥和在真空浓缩。这得到140mg(82%)(3S,5RS)-5-(4-氯苯基)-1-([3-甲基-1H-吡唑并[3,4-b]吡啶-5-基]羰基)吡咯烷-3-基甲烷磺酸酯,为黄色油状物。
16.7.[(2S,4R)-2-(4-氯-苯基)-4-甲基氨基-吡咯烷-1-基]-(3-甲基-1H-吡唑并[3,4-b]吡啶-5-基)-甲酮
向30mL密封管放入(3S,5RS)-5-(4-氯苯基)-1-([3-甲基-1H-吡唑并[3,4-b]吡啶-5-基]羰基)吡咯烷-3-基甲烷磺酸酯(140mg,0.32mmol),甲胺(434mg,13.97mmol)和乙醇(8mL)。将溶液在100℃在油浴中搅拌1过夜。将混合物在真空浓缩。粗产物通过制备型-HPLC纯化(乙腈/水),得到5.00mg(4%)[(2S,4R)-2-(4-氯-苯基)-4-甲基氨基-吡咯烷-1-基]-(3-甲基-1H-吡唑并[3,4-b]吡啶-5-基)-甲酮,为白色固体。1H NMR(400MHz,DMSO-d6)ppm=13.38(s,1H),8.69(s,1H),8.52(s,1H),7.46(d,J=8Hz,2H),7.38(d,J=8Hz,2H),5.20(m,1H),4.11-4.07(m,1H),3.46-3.41(m,2H),2.59(s,3H),2.37-2.15(m,5H),1.84(m,2H)。
17.[(3S,4R)-3-(4-氯-苯基)-4-羟基-吡咯烷-1-基]-(3-甲基-1H-吡唑并[3,4-b]吡啶-5-基)-甲酮(256)
17.1. 3-(4-氯苯基)-4-羟基吡咯烷-1-甲酸叔-丁基酯
向用惰性氮气气氛吹扫和保持的100mL三颈圆底烧瓶放入1-溴-4-氯苯(2.33g,12.2mmol)/四氢呋喃(20mL)。向该溶液中经30min滴加n-BuLi(5.40mL,2.5mol/L),并在-80℃搅拌。然后在10min内向混合物滴加BF3*Et2O(1.80mL,14.2mmol),并在-80℃搅拌。再次在-80℃在搅拌下,滴加6-氧杂-3-氮杂二环[3.1.0]己烷-3-甲酸叔-丁基酯(1.00g,5.40mmol)的四氢呋喃(3mL)溶液。将溶液在-80℃搅拌3h。然后通过添加20mL水性碳酸氢钠使反应淬灭。混合物用20mL四氢呋喃/乙酸乙酯(1:1)萃取两次和将合并有机层在真空浓缩。将残余物经硅胶柱用石油醚/乙酸乙酯(5:2)纯化。这得到600mg(37%)3-(4-氯苯基)-4-羟基吡咯烷-1-甲酸叔-丁基酯,为无色油状物。
17.2. 4-(4-氯苯基)吡咯烷-3-醇
向50mL圆底烧瓶放入3-(4-氯苯基)-4-羟基吡咯烷-1-甲酸叔-丁基酯(600mg,2.01mmol)/二氯甲烷(15mL)和在RT加入三氟乙酸(3mL)。将溶液在RT搅拌2h。将混合物在真空浓缩。将残余物经硅胶柱用甲醇/水(1:99)纯化。这得到300mg(75%)4-(4-氯苯基)吡咯烷-3-醇,为无色油状物。
17.3.[(3S,4R)-3-(4-氯-苯基)-4-羟基-吡咯烷-1-基]-(3-甲基-1H-吡唑并[3,4-b]吡啶-5-基)-甲酮(256)和[(3R,4S)-3-(4-氯-苯基)-4-羟基-吡咯烷-1-基]-(3-甲基-1H-吡唑并[3,4-b]吡啶-5-基)-甲酮(255)
向25mL圆底烧瓶放入3-甲基-1H-吡唑并[3,4-b]吡啶-5-甲酸(150mg,0.85mmol),4-(4-氯苯基)吡咯烷-3-醇(201mg,1.02mmol),N,N-二甲基甲酰胺(5mL),EDCI(325mg,1.69mmol)和4-二甲基氨基吡啶(155mg,1.27mmol)。将溶液在RT搅拌3h。将残余物经硅胶柱用甲醇/二氯甲烷(3:10)纯化。粗产物通过制备型HPLC纯化(乙腈/水)。这得到30mg(10%)外消旋反式-[3-(4-氯-苯基)-4-羟基-吡咯烷-1-基]-(3-甲基-1H-吡唑并[3,4-b]吡啶-5-基)-甲酮,为白色固体。然后外消旋混合物通过手性HPLC(Chiralpak IB4.6*250mm,5μm,100%甲醇(0.1%二乙基胺)纯化,得到[(3S,4R)-3-(4-氯-苯基)-4-羟基-吡咯烷-1-基]-(3-甲基-1H-吡唑并[3,4-b]吡啶-5-基)-甲酮(256)和[(3R,4S)-3-(4-氯-苯基)-4-羟基-吡咯烷-1-基]-(3-甲基-1H-吡唑并[3,4-b]吡啶-5-基)-甲酮(255)。1H NMR(256,300Hz,DMSO-d6)ppm=13.15(s,1H),8.65-8.64(m,1H),8.36-8.35(m,1H),7.38-7.33(m,4H),5.30-5.00(m,1H),4.27-4.25(m,1H),4.04-3.98(m,1H),3.86-3.80(m,1H),3.65-3.59(m,1H),3.46-3.40(m,1H),3.32-3.24(m,1H),2.52(s,3H)。
18. 3-(4-氯苯基)吗啉代)(3-甲基-1H-吲唑-5-基)甲酮(178)
向3-甲基-1H-吲唑-5-甲酸(40mg,0.23mmol)/N,N-二甲基甲酰胺(1.9mL)加入HATU(104mg,0.272mmol),3-(4-氯苯基)吗啉盐酸盐(53mg,0.23mmol)和DIPEA(87μL,0.50mmol)。将反应混合物在RT搅拌过夜,浓缩和粗物质通过Biotage柱色谱(二氯甲烷/乙醇99/1至93/7)和通过制备型TLC(1mm,二氯甲烷/乙醇,98/2)纯化。然后将产物在SCX-2柱上过滤和用1N NH3/甲醇释放,得到标题化合物(5mg,6%收率)。1H NMR(500MHz,CD3OD)ppm=7.86-7.85(m,1H),7.60-7.51(m,3H),7.47-7.40(m,3H),5.70-5.40(bs,1H),4.49(d,J=12.4Hz,1H),4.00-4.64(bs,1H),4.00(dd,J=12.4,3.6Hz,1H),3.94-3.83(m,1H),3.73-3.64(m,1H),3.39-3.30(m,1H),2.56(s,3H).LC-MS(ESI,m/z,方法L)Rt=2.71min–356/358(M+H)+.ESI-HRMS:实测值:356.1153C19H19 35ClN3O2(M+H)+计算值:356.1160。
19.(2-(4-氯苯基)-4-甲基哌嗪-1-基)(3-甲基-1H-吲唑-5-基)甲酮(244)
19.1. 3-(4-氯苯基)-1-甲基哌嗪
在0℃向2-(4-氯苯基)哌嗪(200mg,1.02mmol)和三乙基胺(1.08mL,7.73mmol)的丙酮(3.2mL)溶液中滴加甲基碘(70μL,1.1mmol)。将反应在RT搅拌过夜。加入1个额外当量的甲基碘和1mL丙酮。将反应在RT搅拌另外5h。加入饱和NH4Cl溶液和乙酸乙酯,水层用乙酸乙酯萃取三次和有机层经MgSO4干燥,过滤和浓缩。粗混合物无需纯化用于以下步骤。
19.2.(2-(4-氯苯基)-4-甲基哌嗪-1-基)(3-甲基-1H-吲唑-5-基)甲酮
向3-甲基-1H-吲唑-5-甲酸(92mg,0.52mmol),HATU(238mg,0.626mmol)和3-(4-氯苯基)-1-甲基哌嗪(110mg,0.522mmol)中加入DIPEA(200μL,1.15mmol)和N,N-二甲基甲酰胺(4.4mL)。将反应混合物在RT搅拌2h和将溶剂蒸发(V10)。粗品通过Biotage柱色谱(二氯甲烷/乙醇99:1至80:20)接着通过制备型HPLC纯化。将产物在SCX柱上过滤和用1N NH3/甲醇释放,得到标题化合物(30mg,16%收率)。1H NMR(500MHz,CD3OD)ppm=7.84(s,1H),7.55–7.34(m,6H),5.64(bs,1H),3.92(bs,1H),3.51-3.44(m,1H),3.27-3.18(m,1H),2.78-2.72(m,1H),2.54(s,3H),2.53–2.48(m,1H),2.29(s,3H),2.20-2.14(m,1H).LC-MS(ESI,m/z,方法L)Rt=0.96min–369/371(M+H)+.ESI-HRMS:实测值:369.1471C20H22 35ClN4O(M+H)+计算值:369.1477。
20.(S)-(2-(4-氯苯基)吡咯烷-1-基)(3-甲氧基-1H-吡唑并[3,4-b]吡啶-5-基)甲酮(243)
20.1. 3-甲氧基-1H-吡唑并[3,4-b]吡啶-5-甲腈
将5-溴-3-甲氧基-1H-吡唑并[3,4-b]吡啶(300mg,1.32mmol)Pd(PPh3)4(152mg,0.132mmol)和氰化锌(170mg,1.45mmol)装入微波小瓶中和加入N,N-二甲基甲酰胺(8.7mL)。将反应混合物在60℃搅拌过夜。将溶剂蒸发和将粗混合物通过biotage柱色谱(二氯甲烷/乙醇99:1至96:4)纯化,得到标题化合物(160mg,含有17%三苯基氧化膦,58%校正收率)。1H NMR(500MHz,CD3OD)ppm=8.72(d,J=2.0Hz,1H),8.55(d,J=2.0Hz,1H),4.11(s,3H).LC-MS(ESI,m/z,方法M)Rt=0.96min-175(M+H)+。
20.2. 3-甲氧基-1H-吡唑并[3,4-b]吡啶-5-甲酸
向3-甲氧基-1H-吡唑并[3,4-b]吡啶-5-甲腈(160mg,0.919mmol)/乙醇(7.1mL)加入2M NaOH(6.9mL,13.78mmol)。将反应在100℃加热12h。将HCl/二氧杂环己烷(13.8mL,13.78mmol)加入至反应混合物中,将反应混合物在真空浓缩。粗品无需纯化用于下一步骤。
20.3.(S)-(2-(4-氯苯基)吡咯烷-1-基)(3-甲氧基-1H-吡唑并[3,4-b]吡啶-5-基)甲酮
向3-甲氧基-1H-吡唑并[3,4-b]吡啶-5-甲酸(59mg,0.31mmol),(S)-2-(4-氯苯基)吡咯烷盐酸盐(67mg,0.31mmol)和HATU(139mg,0.367mmol)加入N,N-二甲基甲酰胺(2.5mL)和DIPEA(117μL,0.672mmol)。将反应混合物在RT搅拌1h30,然后浓缩(V10),干燥装载到二氧化硅上和通过Biotage柱色谱(snap 25g,二氯甲烷/乙醇99:1至95:5)和通过制备型TLC(0.5mm,二氯甲烷/乙醇98:2)纯化,得到标题化合物(18mg,16%收率)。1H NMR(500MHz,CD3OD,2种旋转异构体)ppm=8.72(s,0.6H),8.39(s,0.6H),8.26(s,0.4H),7.86(s,0.4H),7.37(d,J=8.1Hz,1.2H),7.32(d,J=8.1Hz,1.2H),7.17(d,J=8.0Hz,0.8H),6.97(d,J=8.0Hz,0.8H),5.21(t,J=7.3Hz,0.6H),5.02-4.96(m,0.4H),4.09(s,1.8H),4.01(s,1.2H),4.00-3.85(m,1.4H),3.75-3.68(m,0.6H),2.50-2.40(m,1H),2.08-1.98(m,1.4H),1.96–1.83(m,1.6H).LC-MS(ESI,m/z,方法L)Rt=2.67min–357/359(M+H)+.ESI-HRMS:实测值:357.1111C18H18 35ClN4O2(M+H)+计算值:357.1113。
21.(S)-(2-(4-氟苯基)吡咯烷-1-基)(3-甲基-1H-吡唑并[4,3-b]吡啶-5-基)甲酮(242)
向3-甲基-1H-吡唑并[4,3-b]吡啶-5-甲酸(40mg,0.23mmol),HATU(103mg,0.271mmol)和(S)-2-(4-氟苯基)吡咯烷盐酸盐(45.5mg,0.226mmol)加入DIPEA(87μL,0.50mmol)和N,N-二甲基甲酰胺(1.9mL)。将反应混合物在RT搅拌1h。然后将反应混合物浓缩(V10),干燥装载到二氧化硅上和通过Biotage柱色谱(二氯甲烷/乙醇99:1至85:15)和通过制备型TLC(0.5mm,二氯甲烷/乙醇98:2)纯化,得到标题化合物(16mg,22%收率)。1H NMR(500MHz,CDCl3,2种旋转异构体)ppm=7.97(d,J=8.7Hz,0.45H),7.79(d,J=8.7Hz,0.45H),7.66(d,J=8.7Hz,0.55H),7.59(d,J=8.7Hz,0.55H),7.32-7.26(m,0.90H),7.01–6.93(m,2H),6.82–6.76(m,1.1H),5.89–5.84(m,0.55H),5.42-5.37(m,0.45H),4.39(dt,J=12.3,6.8Hz,0.45H),4.11(dt,J=12.3,6.8Hz,0.45H),4.06–3.94(m,1.1H),2.73(s,1.35H),2.48(s,1.65H),2.52-2.37(m,1.1H),2.10–1.85(m,2.9H).19F NMR(470MHz,CDCl3)ppm=-116.35.LC-MS(ESI,m/z,方法L)Rt=2.55min–325(M+H)+.ESI-HRMS:实测值:325.1456C18H18FN4O(M+H)+计算值:325.1459。
22.(2-(4-氯-3-氟苯基)吡咯烷-1-基)(3-甲基-1H-吡唑并[4,3-b]吡啶-5-基)甲酮(260)
22.1. 2-(4-氯-3-氟苯基)-1H-吡咯-1-甲酸叔-丁基酯
将(1-(叔丁氧基羰基)-1H-吡咯-2-基)硼酸(0.625g,2.96mmol),碳酸钠(1.05g,9.87mmol)和Pd(PPh3)4(0.285g,0.247mmol)装入烧瓶中,然后加入DME(50mL),水(10mL)和4-溴-1-氯-2-氟苯(0.300mL,2.47mmol)。将反应混合物在95℃搅拌3h30。加入水和二氯甲烷和分离各层。水层用二氯甲烷萃取和将有机层干燥和浓缩。粗品通过biotage柱色谱(环己烷/二氯甲烷100/0至90/10)纯化,得到标题化合物(600mg,82%收率)。1H NMR(500MHz,CDCl3)ppm=7.38-7.34(m,2H),7.15(dd,J=10.0,2.0Hz,1H),7.11-7.08(m,1H),6.24-6.20(m,2H),1.43(s,9H).LC-MS(ESI,m/z.方法K)Rt=1.67min–196/198(M-Boc+H)+。
22.2. 2-(4-氯-3-氟苯基)吡咯烷
向2-(4-氯-3-氟苯基)-1H-吡咯-1-甲酸叔-丁基酯(600mg,2.03mmol)/乙醇(11.9mL)加入HCl(867μl,9.13mmol)和PtO2(60mg)。在13℃ 27h后,将反应混合物在硅藻土上过滤和浓缩滤液。将甲醇(2mL)和4N HCl/二氧杂环己烷(2mL)加入至得到的残余物中。在RT 2h后,将反应混合物浓缩。将粗混合物在SCX2柱上过滤和用1N NH3/甲醇释放产物和用于下一步骤,无需进一步纯化。1H NMR(500MHz,CDCl3)ppm=7.30(dd,J=8.2,7.6Hz,1H),7.22-7.15(m,1H),7.11-7.04(m,1H),4.11(t,J=7.7Hz,1H),3.16(ddd,J=10.1,7.7,5.3Hz,1H),3.02(ddd,J=10.1,8.2,6.7Hz,1H),2.23-2.12(m,1H),1.96-1.77(m,2H),1.63-1.55(m,1H).LC-MS(ESI,m/z,方法K)Rt=0.69min–200/202(M+H)+。
22.3.(2-(4-氯-3-氟苯基)吡咯烷-1-基)(3-甲基-1H-吡唑并[4,3-b]吡啶-5-基)甲酮
将3-甲基-1H-吡唑并[4,3-b]吡啶-5-甲酸(80mg,0.45mmol)与N,N-二甲基甲酰胺(2.3mL)和三乙基胺(126μl,0.903mmol)混合。将悬浮液在冰/丙酮浴中冷却。将氯甲酸乙酯(43μl,0.45mmol)加入至冷却溶液和将反应搅拌15min。将2-(4-氯-3-氟苯基)吡咯烷盐酸盐(107mg,0.452mmol)/N,N-二甲基甲酰胺(2mL)溶液加入至反应混合物,将其在冷浴中搅拌另外30min。将反应在RT搅拌过夜。将水和二氯甲烷加入反应混合物中。分离各层和水层用乙酸乙酯萃取三次。有机层经MgSO4干燥和在真空浓缩。将粗物质溶于甲醇(3mL)和加入碳酸铯(147mg,0.452mmol)。将反应混合物在40℃搅拌1h。在蒸发溶剂后,粗品通过biotage柱色谱(二氯甲烷/乙醇,98/2至94/6)和通过在SCX柱上过滤纯化,得到标题化合物(18mg,11%收率)。1H NMR(500MHz,CDCl3,2种旋转异构体)ppm=7.98(d,J=8.8Hz,0.5H),7.85(dd,J=8.8,5.5Hz,1H),7.71(d,J=8.8Hz,0.5H),7.29(t,J=8.1Hz,0.5H),7.17(dd,J=8.3,7.4Hz,0.5H),7.09(dd,J=10.0,2.0Hz,0.5H),7.05(dd,J=8.1,2.1Hz,0.5H),6.88(dd,J=10.0,2.0Hz,0.5H),6.81(dd,J=8.3,2.1Hz,0.5H),5.92(dd,J=7.5,2.7Hz,0.5H),5.34(dd,J=7.8,5.3Hz,0.5H),4.38(dt,J=11.7,6.9Hz,0.5H),4.11(dt,J=11.7,6.9Hz,0.5H),4.02–3.94(m,1H),2.75(s,1.5H),2.49–2.34(m,2.5H),2.10–1.82(m,3H).LC-MS(ESI,m/z,方法K)Rt=1.40min–359/361(M+H)+.ESI-HRMS:实测值:359.1086C18H17 35ClFN4O(M+H)+计算值:359.1069。
23.(S)-(3-甲基-1H-吡唑并[4,3-b]吡啶-5-基)(2-(4-(三氟甲基)苯基)吡咯烷-1-基)甲酮(257)
23.1. 3-甲基-1H-吡唑并[4,3-b]吡啶
将1-(3-氟吡啶-2-基)乙酮(1.00g,7.19mmol)/单水合肼(12mL,247.00mmol)溶液在130℃在微波辐照下加热3h。加入水(50mL)和混合物用乙酸乙酯萃取(3x 25mL)。将合并有机层干燥(MgSO4),过滤和在真空浓缩。通过Biotage纯化(SNAP 50g柱,乙酸乙酯/乙醇95/5->70/30),得到奶油色固体(575mg,60%)。1H NMR(500MHz,DMSO-d6)δ12.87(br s,1H),8.46(dd,J=4.3,1.4Hz,1H),7.91(dd,J=8.5,1.4Hz,1H),7.33(dd,J=8.5,4.3Hz,1H),2.53(s,3H).13C NMR(126MHz,DMSO-d6)δ144.51,142.04,139.94,133.42,121.12,118.49,11.24.LCMS(方法M)Rt 0.52min,[M+H]+134;HRMS C7H8N3计算值:134.0718,实测值:134.0726。
23.2. 3-甲基-1-三苯甲基-1H-吡唑并[4,3-b]吡啶
在0℃向3-甲基-1H-吡唑并[4,3-b]吡啶(497mg,3.73mmol)的DMF(10mL)溶液中加入NaH(60%/矿物油;300mg,7.50mmol)和让混合物温热至RT和搅拌20min。然后加入三苯甲基氯(1.35g,4.84mmol)和将混合物在RT搅拌2.5h。用饱和水性NH4Cl(5mL)淬灭反应,和将混合物在真空浓缩。将残余物溶于乙酸乙酯(75mL)和用水洗涤(3x 50mL)。有机层经干燥(MgSO4),过滤,在真空浓缩,和将残余物通过Biotage(SNAP 50g柱,环己烷/二氯甲烷100/0->50/50)纯化,得到灰白色固体(1.086g,77%)。1H NMR(500MHz,CDCl3)δ8.47(dd,J=4.4,1.3Hz,1H),7.32-7.27(m,15H),6.90(dd,J=8.7,4.4Hz,1H),6.59(dd,J=8.7,1.3Hz,1H),2.69(s,3H).13C NMR(126MHz,CDCl3)δ144.43,142.72(3x ArC),142.66,135.23,130.46,130.18(6x ArCH),127.73(6x ArCH),127.52(3x ArCH),121.35,119.81,78.48,11.32.LCMS(方法M)Rt 1.67min,[M+H]+376;HRMS C26H22N3计算值:376.1814,实测值:376.1816。
23.3. 3-甲基-1-三苯甲基-1H-吡唑并[4,3-b]吡啶4-氧化物
在0℃向3-甲基-1-三苯甲基-1H-吡唑并[4,3-b]吡啶(108mg,0.29mmol)/二氯甲烷(0.8mL)溶液中加入mCPBA(77%;80mg,0.36mmol)。然后让混合物温热至RT和搅拌1.5h。然后反应混合物用二氯甲烷(10mL)稀释和用饱和水性NaHCO3(3x 10mL)洗涤。有机层通过相分离器过滤和在真空浓缩。所得残余物通过Biotage(SNAP 10g柱,二氯甲烷/乙酸乙酯100/0->70/30)纯化,得到白色固体(94mg,83%)。1H NMR(500MHz,CDCl3)δ8.03(d,J=6.0Hz,1H),7.35-7.29(m,9H),7.21-7.18(m,6H),6.75(dd,J=8.8,6.0Hz,1H),6.19(d,J=8.8Hz,1H),2.85(s,3H).13C NMR(126MHz,CDCl3)δ142.01(3x ArCH),139.70,138.83,132.14,130.26,130.10(6x ArCH),127.82(6x ArCH),120.97,113.41,79.14,14.26.LCMS(方法K)Rt 1.54min,[M+H]+392;HRMS C26H22N3O计算值:392.1757,实测值:392.1744。
23.4. 3-甲基-1-三苯甲基-1H-吡唑并[4,3-b]吡啶-5-甲腈
向3-甲基-1-三苯甲基-1H-吡唑并[4,3-b]吡啶4-氧化物(94mg,0.24mmol)和三乙基胺(0.05mL,0.36mmol)在乙腈(1mL)和二氯甲烷(0.2mL)混合物中的悬浮液加入TMS-CN(0.07mL,0.52mmol)。将所得混合物在回流加热18h。然后让混合物冷却至RT,在真空浓缩,和将残余物通过Biotage(SNAP 10g柱,二氯甲烷/乙酸乙酯100/0->70/30)纯化,得到无色油状物(81mg,84%)。1H NMR(500MHz,CDCl3)δ7.35-7.29(m,9H),7.25-7.20(m,7H),6.59(d,J=8.8Hz,1H),2.67(s,3H).LCMS(方法M)Rt 1.14min(未测得质量;仅测得三苯甲基的质量)。
23.5. 3-甲基-1-三苯甲基-1H-吡唑并[4,3-b]吡啶-5-甲酸
将3-甲基-1-三苯甲基-1H-吡唑并[4,3-b]吡啶-5-甲腈(112mg,0.28mmol)溶于乙醇(1.5mL)和加入2M NaOH(1mL,2.00mmol)。将所得混合物在130℃在微波辐照下加热1h。然后用2M HCl将pH调整至3和用二氯甲烷萃取(3x 20mL)。合并有机层通过相分离器过滤,在真空浓缩,和将残余物通过Biotage(SNAP 10g柱,二氯甲烷/乙酸乙酯100/0->75/25)纯化,得到白色固体(67mg,57%)。1H NMR(500MHz,CDCl3)δ7.85(d,J=8.9Hz,1H),7.39–7.26(m,9H),7.26–7.12(m,6H),6.72(d,J=8.9Hz,1H),2.68(s,3H).LCMS(方法M)Rt 1.54min,[M+Na]+442;HRMS C27H21N3O2Na计算值:442.1531,实测值:442.1542。
23.6.(S)-(3-甲基-1-三苯甲基-1H-吡唑并[4,3-b]吡啶-5-基)(2-(4-(三氟甲基)苯基)吡咯烷-1-基)甲酮
向3-甲基-1-三苯甲基-1H-吡唑并[4,3-b]吡啶-5-甲酸(67mg,0.16mmol)和(S)-2-(4-(三氟甲基)苯基)吡咯烷盐酸盐(70mg,0.28mmol)在DMF(0.8mL)中的混合物加入HATU(95mg,0.25mmol)和DIPEA(0.3mL,1.72mmol),和将所得混合物在RT搅拌18h。然后将混合物在真空浓缩和将残余物通过Biotage(SNAP 10g柱,环己烷/乙酸乙酯100/0->70/30)纯化,得到标题化合物,为旋转异构体混合物(78mg)。LCMS(方法M)Rt 1.71min,[M+H]+617;HRMSC38H32F3N4O计算值:617.2528,实测值:617.2556。
23.7.(S)-(3-甲基-1H-吡唑并[4,3-b]吡啶-5-基)(2-(4-(三氟甲基)苯基)吡咯烷-1-基)甲酮(257)
向(S)-(3-甲基-1-三苯甲基-1H-吡唑并[4,3-b]吡啶-5-基)(2-(4-(三氟甲基)苯基)吡咯烷-1-基)甲酮(78mg,0.13mmol)的二氯甲烷(0.8mL)溶液中加入TFA(0.2mL,2.60mmol)和将所得混合物在RT搅拌45min。然后将反应用饱和水性NaHCO3(6mL)淬灭和用乙酸乙酯萃取(3x 10mL)。将合并的有机层干燥(MgSO4),过滤,和在真空浓缩。将残余物通过Biotage(SNAP 10g柱,环己烷/乙酸乙酯100/0->0/100)纯化,得到标题化合物,为旋转异构体混合物(46mg,97%)。1H NMR(500MHz,CDCl3)δ7.98(d,J=8.7Hz,1H),7.82-7.74(m,2H),8.00-7.55(m,3H),7.47-7.42(m,4H),7.21(d,J=8.0Hz,2H),6.02-5.97(m,1H),5.47(br dd,J=7.8,5.2Hz,1H),4.45(dt,J=12.0,6.9Hz,1H),4.19(dt,J=12.4,6.8Hz,1H),4.08-4.01(m,2H),2.72(s,3H),2.51-2.42(m,2H),2.32(s,3H),2.10-1.98(m,4H),1.96-1.89(m,2H).13C NMR(126MHz,CDCl3)δ167.01,166.48,148.93,148.40,148.00,147.45(2xC),144.98,144.60,138.60,138.10,133.43,133.12,129.10,128.84,128.59,125.91(4xC),125.51(q,J=3.8Hz,2x C),125.8(q,J=3.8Hz,2x C),123.14,122.99,122.26,121.97,117.95,117.80,65.88,63.12,62.14,51.04,48.52,36.40,34.15,25.13,21.35,14.13,10.93,10.51.LCMS(方法M)Rt 1.31min,[M+H]+375;HRMS C19H18F3N4O计算值:375.1433,实测值:375.1429。
24.(3-氨基-1H-吡唑并[4,3-b]吡啶-5-基)-[(S)-2-(4-氯-苯基)-吡咯烷-1-基]-甲酮(265)
24.1. 5-溴-1H-吡唑并[3,4-c]吡啶-3-基胺
向10-mL密封管中放入2-溴-5-氟吡啶-4-甲腈(700mg,3.13mmol,90%),DMSO(5mL)和NH2NH2.H2O(2.5mL)。将混合物在120℃搅拌3h。反应混合物用50mL水稀释。分离有机层和水层用50mL乙酸乙酯萃取。合并有机层用20mL氯化钠洗涤两次,经Na2SO4干燥,过滤和蒸发至干。这得到600mg(81%)5-溴-1H-吡唑并[3,4-c]吡啶-3-胺,为黄色固体。
24.2. 3-氨基-1H-吡唑并[3,4-c]吡啶-5-甲酸甲酯
向用CO(g)气氛吹扫和保持的20-mL压力槽放入5-溴-1H-吡唑并[3,4-c]吡啶-3-胺(600mg,2.53mmol,90%),Pd(dppf)Cl2.CH2Cl2(104mg,0.13mmol),AcOK(498mg,5.07mmol),甲醇(5mL)和N,N-二甲基甲酰胺(5mL)。将所得溶液在80℃搅拌过夜。将所得溶液用10mL水稀释和用50mL乙酸乙酯萃取。将有机层蒸发至干。这得到500mg(72%)3-氨基-1H-吡唑并[3,4-c]吡啶-5-甲酸甲酯,为橙色固体。
24.3.3-氨基-1H-吡唑并[3,4-c]吡啶-5-甲酸
向50-mL圆底烧瓶放入LiOH(99.7mg,4.16mmol),水(3mL),四氢呋喃(10mL)和3-氨基-1H-吡唑并[3,4-c]吡啶-5-甲酸甲酯(500mg,2.08mmol,80%)。将溶液在50℃搅拌20h。混合物通过蒸发浓缩并加入10mL水。用氯化氢溶液(2N)将溶液的pH值调整至2。混合物用30mL乙酸乙酯萃取两次和合并有机层。有机相用20mL水洗涤两次,经硫酸钠干燥和在过滤后将其蒸发至干。这得到400mg(76%)3-氨基-1H-吡唑并[3,4-c]吡啶-5-甲酸,为黄色固体。
24.4(3-氨基-1H-吡唑并[4,3-b]吡啶-5-基)-[(S)-2-(4-氯-苯基)-吡咯烷-1-基]-甲酮(265)
向10-mL圆底烧瓶放入3-氨基-1H-吡唑并[3,4-c]吡啶-5-甲酸(100mg,0.39mmol,70%),2-(4-氯苯基)吡咯烷(112mg,0.59mmol),4-二甲基氨基吡啶(82.3mg,0.67mmol),EDCI(215mg,1.12mmol)和N,N-二甲基甲酰胺(5mL)。将反应混合物在RT搅拌3h。混合物在真空浓缩。将残余物施加到硅胶柱,使用甲醇:二氯甲烷(3:10)。粗的外消旋产物通过制备型-HPLC(乙腈/水),接着手性-制备型-HPLC分离(Chiralpak IB4.6*250mm,5μM,100%甲醇(0.1%二乙基胺)而纯化,得到13mg(9%)(3-氨基-1H-吡唑并[4,3-b]吡啶-5-基)-[(S)-2-(4-氯-苯基)-吡咯烷-1-基]-甲酮,为白色固体。1H NMR(300Hz,DMSO-d6)ppm=11.84(s,1H),8.65-8.64(m,1H),8.13(s,1H),7.27(s,4H),5.60-5.20(m,3H),4.12-3.90(m,1H),3.90-3.70(m,1H),2.41-2.29(m,1H),1.99-1.77(m,4H).LCMS(方法J)Rt 1.17min,[M+H]+342。
其余化合物自所描述或市售可得羧酸与所描述或市售可得胺合成(如2.2所述),部分接着进行如2.3所述的手性分离,得到2种或更多中不同的对映体。因此,合成化合物171-176,179,182,185-188,191-202,204-205,207-209,211-215,217-219,221-241,247-253,258-259和261-264。
生物活性
CDK8抑制活性的生物化学测定
基于FRET的Lanthascreen结合竞争测定:当结合用链霉亲和素-Eu-螯合物标记的CDK8时(通过生物素化的抗His抗体),染料标记的ATP竞争性探针用作FRET受体。结果是在647nm的荧光信号。在该探针被抑制剂竞争的情况下,不能再产生这样的信号。用于该测定的CDK8是与CycC共表达的蛋白质。
根据以下进行1536孔板中的测定的测定程序:将测定缓冲液中的2μL CDK8/生物素-抗His-Ab/SA-Eu混合物移液到微量培养板的孔中。
加入在20mM Hepes缓冲液/5%DMSO中的1μL化合物。将板振荡30秒,并在室温下温育20分钟。
加入测定缓冲液中的2μL Alexa647探针。将板再次振荡30秒,并在室温下在黑暗中温育60分钟。
然后在Perkin Elmer Envision(模式LANCE/TRF,激发340nm发射650nm)上读出板。
测定缓冲液为50mM Hepes pH 7.5(Merck#1.10110),10mM MgCl2(Merck#1.05833),1mM EGTA(Merck#1.08435),0.01%Brij-35(Pierce#28316)。
在5μl总测定体积中反应组分的最终浓度为:1%DMSO(Merck#1.02950),5nM CDK8(CDK8/CycC Invitrogen#PV4402),2nM生物素-a-His Ab(Invitrogen#PV6089),2nM SA-铕(Invitrogen#PV5899),10nM Alexa647-示踪剂(Invitrogen#PV5592)。
剂量反应曲线的化合物稀释度为30,10,3.2,1,0.32,0.2,0.032,0.01,0.0032,0.001μM(最终)或任选的(作为1:5稀释)30,6,1.2,0.24,0.048,0.0096,0.0019,0.0004,8e-5,2e-5μM。
使用Genedata Condoseo将读数拟合至IC50曲线。
为了评估化合物对CDK8的抑制潜力,确定IC50值,如下表1所示,其中使用以下分类:
表1
有意省略了实施例编号7,8,42,75,119,126,128,140,146,151,161,163,187,201,212,213,233和234。
Claims (17)
1.式(I)的化合物
(I),
其中:
X、Y独立地为CH或N,
Z为CH、C-Hal或N,
R1为H、LA、CA、NH2、NH(LA)或(LA)NH(LA)、Hal、-S(LA)、-SO2(LA)、O(LA),
Cyc为具有1或2个N原子,或1个N原子和1个O原子的3、4、5、6或7元脂族杂环,
R2为-LA-Ar或Ar,其相对于Cyc的环N原子位于2-或3-位,
R3为H、OH、NH2、COO(LA)、CONH2、CONH(LA)、NHCO(LA)、(LA)OH、NH(LA)或LA,其位于Cyc的任何位置,
Ar为单核或双核、脂族或芳族3、4、5、6、7、8、9或10元碳环或杂环,具有0、1、2、3或4个N、O和/或S原子,其可以是未被取代的,或被Hal、OH、CN、LA、O(LA)、S(LA)单取代或独立二取代,
LA为非支链或支链烷基,具有1、2、3、4或5个碳原子,其可以是饱和的或部分未饱和的,其中1、2或3个H原子可被Hal替代,
CA为具有3、4、5或6个碳原子的环烷基,或具有3、4、5或6个环碳原子和1或2个非环碳原子的环烷基烷基,
Hal为F、Cl、Br或I。
2.根据权利要求1所述的化合物,或其立体异构体或互变异构体、或前述每种的药学上可接受的盐,包括其所有比率的混合物,其中
X、Y、Z独立地为CH或N,
R1为H、LA、CA、NH2、NH(LA)或(LA)NH(LA),
Cyc为3、4、5、6或7元脂族杂环,具有1个N原子,
R2为-LA-Ar或Ar,其相对于Cyc的环N原子位于2-或3-位,
R3为H、OH、NH2、COO(LA)、CONH2、CONH(LA)或LA,其位于Cyc的任何位置,
Ar为单核或双核、脂族或芳族3、4、5、6、7、8、9或10元碳环或杂环,具有0、1、2、3或4个N、O和/或S原子,其可以是未被取代的,或被Hal、OH、CN、LA、O(LA)、S(LA)单取代或独立二取代,
LA为非支链或支链烷基,具有1、2、3、4或5个碳原子,其可以是饱和的或部分未饱和的,其中1、2或3个H原子可被Hal替代,
CA为具有3、4、5或6个碳原子的环烷基,或具有3、4、5或6个环碳原子和1或2个非环碳原子的环烷基烷基,
Hal为F、Cl、Br或I。
3.根据权利要求2所述的化合物,或其立体异构体或互变异构体、或前述每种的药学上可接受的盐,包括其所有比率的混合物,其中
X、Y独立地为CH或N,
Z为CH,
R1为H、LA、CA、NH2、NH(LA)或(LA)NH(LA),
Cyc为3、4、5、6或7元脂族杂环,具有1个N原子,
R2为-LA-Ar或Ar,其相对于Cyc的环N原子位于2-或3-位,
R3为H、NH2或LA,其位于Cyc的任何位置,
Ar为单核、芳族、6元碳环或杂环,具有0、1或2个N原子,其可以是未被取代的,或被Hal、OH、CN、LA、O(LA)、S(LA)单取代或独立二取代,
LA为非支链或支链烷基,具有1、2、3、4或5个碳原子,其可以是饱和的或部分未饱和的,其中1、2或3个H原子可被Hal替代,
CA为具有3、4、5或6个碳原子的环烷基,或具有3、4、5或6个环碳原子和1或2个非环碳原子的环烷基烷基,
Hal为F、Cl、Br或I。
4.根据权利要求1、2或3所述的化合物,其符合式(IIa)或(IIb),
(IIa),(IIb),
或其立体异构体或互变异构体、或前述每种的药学上可接受的盐,包括其所有比率的混合物。
5. 根据权利要求1或4所述的化合物,或其立体异构体或互变异构体、或前述每种的药学上可接受的盐,包括其所有比率的混合物,其中未更详细指定的残基具有在权利要求1中所指出的含义,但其中
在子式1中
Ar为单核、芳族、6元碳环或杂环,具有0、1或2个N原子,其为未被取代的,或被Hal、LA或O(LA)单取代,
在子式2中
X为N,
在子式3中
X为CH,
在子式4中
Y为CH,
在子式5中
Y为N,
在子式6中
Z为CH,
在子式7中
X为CH,
Y为N,
Z为CH,
在子式8中
X为N,
Y为CH,
Z为CH,
在子式9中
Ar为单核、芳族、6元碳环或杂环,具有0、1或2个N原子,其可以是未被取代的,或被Hal、OH、CN、LA、O(LA)、S(LA)单取代或独立二取代,
X为CH,
Y为N,
Z为CH,
在子式10中
Ar为单核、芳族、6元碳环或杂环,具有0、1或2个N原子,其可以是未被取代的,或被Hal、OH、CN、LA、O(LA)、S(LA)单取代或独立二取代,
X为N,
Y为CH,
Z为CH,
在子式11中
R1为LA或NH2、NHLA
在子式12中
Cyc具有4、5或6个环原子,
在子式13中
R3为H、OH、NH2或甲基,
在子式14中
R3为H,
在子式15中
R2为苄基,
R3为H、NH2或甲基,
Cyc具有6个环原子,
在子式16中
Cyc具有5或6个环原子,
R2为苯基,其为未被取代的,或被Hal或LA单取代或独立二取代,
在子式17中
Z为CH,
R2为苄基或苯基,所述苯基为未被取代的,或被Hal或LA单取代或独立二取代,
在子式18中
X为N或CH,
Y为CH,
Z为CH,
R1为甲基、正丙基、异丙基、环丙基、NH2、NHLA
在子式19中
Z为CH,
Cyc具有5个环原子,
在子式20中
Z为CH,
R2为苯基,其为未被取代的或被Br、Cl、甲基或CF3单取代,
R3为H,
在子式21中
Z为CH,
R2为苯基,其为未被取代的或被Br、Cl、甲基或CF3单取代,
R3为H,
在子式22中
Z为CH,
R2为苯基,其为未被取代的或被Br、Cl、甲基或CF3对位取代,
R3为H,
在子式23中
Y为CH,
Z为CH,
R1为甲基、正丙基、异丙基、环丙基或NH2,
在子式24中
X为N或CH,
Y为CH,
Z为CH,
R1为甲基、正丙基、异丙基、环丙基或NH2,
Cyc具有4、5或6个环原子,
在子式25中
X为N或CH,
Y为CH,
Z为CH,
R1为甲基、正丙基、异丙基、环丙基或NH2,
Cyc具有4、5或6个环原子,
R2为苯基,其为未被取代的或被Br、Cl、甲基或CF3对位取代,
R3为H,
在子式26中
X为N或CH,
Y为CH,
Z为CH,
R1为甲基、正丙基、异丙基、环丙基或NH2,
Cyc具有5个环原子,
R2为苯基,其为未被取代的或被Br、Cl、甲基或CF3对位取代,
R3为H,
在子式27中
R1为甲基、正丙基、异丙基、环丙基、甲基硫基、甲磺酰基、甲氧基、F或NH2,
在子式28中
R3为H、OH、NH2、甲基、乙酰胺基、2-羟基乙基或甲基氨基,
在子式29中
Z为CH或C(Hal),
Cyc具有4、5或6个环原子,其中1个原子为N和其它原子为C,
R2为苯基,其为未被取代的或被Br、Cl、F、甲基、甲氧基、异丙基或CF3对位取代,或被Cl和F独立地间位/对位二取代,
R3为H,
在子式30中
Z为CH或C(Hal),
Cyc具有4或5个环原子,其中1个原子为N和其它原子为C,
R2为苯基,其为未被取代的或被Br、Cl、F、甲基、甲氧基、异丙基或CF3对位取代,或被F间位取代和被Cl对位取代,
R3为H。
6.根据权利要求1所述的化合物,其中所述化合物选自:
[2-(4-溴-苯基)-吡咯烷-1-基]-(3-甲基-1H-吡唑并[3,4-b]吡啶-5-基)-甲酮,
[(S)-2-(4-溴-苯基)-吡咯烷-1-基]-(3-甲基-1H-吡唑并[3,4-b]吡啶-5-基)-甲酮,
[2-(4-溴-苯基)-吡咯烷-1-基]-(3-丙基-1H-吲唑-5-基)-甲酮,
[(S)-2-(4-溴-苯基)-吡咯烷-1-基]-(3-丙基-1H-吲唑-5-基)-甲酮,
[2-(4-氯-苯基)-吡咯烷-1-基]-(3-丙基-1H-吲唑-5-基)-甲酮,
[2-(4-氯-苯基)-吡咯烷-1-基]-(3-甲基-1H-吡唑并[3,4-b]吡啶-5-基)-甲酮,
[(S)-2-(4-氯-苯基)-吡咯烷-1-基]-(3-丙基-1H-吲唑-5-基)-甲酮,
[(S)-2-(4-氯-苯基)-吡咯烷-1-基]-(3-甲基-1H-吡唑并[3,4-b]吡啶-5-基)-甲酮,
[2-(4-氟-苯基)-哌啶-1-基]-(3-甲基-1H-吡唑并[3,4-b]吡啶-5-基)-甲酮,
[(S)-2-(4-氟-苯基)-哌啶-1-基]-(3-甲基-1H-吡唑并[3,4-b]吡啶-5-基)-甲酮,
(3-甲基-1H-吡唑并[3,4-b]吡啶-5-基)-(2-苯基-哌啶-1-基)-甲酮,
(3-甲基-1H-吡唑并[3,4-b]吡啶-5-基)-(2-苯基-吡咯烷-1-基)-甲酮,
[2-(3-氯-苯基)-吡咯烷-1-基]-(3-甲基-1H-吡唑并[3,4-b]吡啶-5-基)-甲酮,
(3-甲基-1H-吡唑并[3,4-b]吡啶-5-基)-(3-苯基-吡咯烷-1-基)-甲酮,
[2-(2-氯-苯基)-吡咯烷-1-基]-(3-甲基-1H-吡唑并[3,4-b]吡啶-5-基)-甲酮,
[2-(4-氟-苯基)-吡咯烷-1-基]-(3-甲基-1H-吡唑并[3,4-b]吡啶-5-基)-甲酮,
(3-甲基-1H-吡唑并[3,4-b]吡啶-5-基)-((S)-2-苯基-哌啶-1-基)-甲酮,
[(S)-2-(4-氯-苯基)-吡咯烷-1-基]-(3-异丁基-1H-吲唑-5-基)-甲酮,
[(S)-2-(2-氯-苯基)-吡咯烷-1-基]-(3-甲基-1H-吡唑并[3,4-b]吡啶-5-基)-甲酮,
(3-甲基-1H-吡唑并[3,4-b]吡啶-5-基)-((S)-2-苯基-吡咯烷-1-基)-甲酮,
(3-甲基-1H-吡唑并[3,4-b]吡啶-5-基)-((S)-3-苯基-吡咯烷-1-基)-甲酮,
[(S)-2-(4-氟-苯基)-吡咯烷-1-基]-(3-甲基-1H-吡唑并[3,4-b]吡啶-5-基)-甲酮,
[(S)-2-(3-氯-苯基)-吡咯烷-1-基]-(3-甲基-1H-吡唑并[3,4-b]吡啶-5-基)-甲酮,
[(S)-2-(4-氯-苯基)-吡咯烷-1-基]-(3-甲基-1H-吲唑-5-基)-甲酮,
[(S)-2-(4-溴-苯基)-吡咯烷-1-基]-(3-甲基-1H-吲唑-5-基)-甲酮,
[(S)-2-(4-氯-苯基)-吡咯烷-1-基]-(3-甲基-1H-吡唑并[4,3-b]吡啶-5-基)-甲酮,
[(S)-2-(4-溴-苯基)-吡咯烷-1-基]-(3-甲基-1H-吡唑并[4,3-b]吡啶-5-基)-甲酮,
[2-(4-氯-苯基)-氮杂环丁烷-1-基]-(3-甲基-1H-吡唑并[3,4-b]吡啶-5-基)-甲酮,
(3-甲基-1H-吡唑并[3,4-b]吡啶-5-基)-(2-对甲苯基-吡咯烷-1-基)-甲酮,
(3-甲基-1H-吡唑并[3,4-b]吡啶-5-基)-[2-(4-三氟甲基-苯基)-吡咯烷-1-基]-甲酮,
[3-(4-氯-苯基)-哌啶-1-基]-(3-甲基-1H-吡唑并[3,4-b]吡啶-5-基)-甲酮,
[3-(4-氯-苯基)-吡咯烷-1-基]-(3-甲基-1H-吡唑并[3,4-b]吡啶-5-基)-甲酮,
[2-(4-氯-苯基)-吡咯烷-1-基]-(3-环丙基-1H-吡唑并[3,4-b]吡啶-5-基)-甲酮,
(3-氨基-1H-吲唑-5-基)-[2-(4-溴-苯基)-吡咯烷-1-基]-甲酮,
(3-氨基-1H-吲唑-5-基)-[(S)-2-(4-溴-苯基)-吡咯烷-1-基]-甲酮,
(3-氨基-1H-吲唑-5-基)-[2-(4-氯-苯基)-吡咯烷-1-基]-甲酮,
(3-氨基-1H-吲唑-5-基)-[(S)-2-(4-氯-苯基)-吡咯烷-1-基]-甲酮,
(3-氨基-1H-吲唑-5-基)-(2-苯基-哌啶-1-基)-甲酮,
(3-氨基-1H-吲唑-5-基)-(2-苯基-吡咯烷-1-基)-甲酮,
(3-氨基-1H-吲唑-5-基)-[2-(4-氟-苯基)-吡咯烷-1-基]-甲酮,
(3-氨基-1H-吲唑-5-基)-((S)-2-苄基-哌啶-1-基)-甲酮,
(3-氨基-1H-吲唑-5-基)-((S)-2-苯基-哌啶-1-基)-甲酮,
(3-氨基-1H-吲唑-5-基)-((R)-2-苯基-哌啶-1-基)-甲酮,
(3-氨基-1H-吲唑-5-基)-[(S)-2-(4-氟-苯基)-哌啶-1-基]-甲酮,
(3-氨基-1H-吡唑并[3,4-b]吡啶-5-基)-[(S)-2-(4-氯-苯基)-吡咯烷-1-基]-甲酮,
(3-氨基-1H-吡唑并[3,4-b]吡啶-5-基)-[(S)-2-(4-溴-苯基)-吡咯烷-1-基]-甲酮,
(3-氨基-1H-吲唑-5-基)-[2-(4-氯-苯基)-氮杂环丁烷-1-基]-甲酮,
(3-氨基-1H-吲唑-5-基)-[2-(4-氟-苯基)-氮杂环丁烷-1-基]-甲酮,
(3-氨基-1H-吲唑-5-基)-[3-(4-氯-苯基)-吡咯烷-1-基]-甲酮,
(3-氨基-1H-吲唑-5-基)-[(S)-2-(4-氟-苯基)-吡咯烷-1-基]-甲酮,
(3-氨基-1H-吲唑-5-基)-[(S)-2-(4-氟-苯基)-氮杂环丁烷-1-基]-甲酮,
(3-甲基-1H-吡唑并[3,4-b]吡啶-5-基)-((S)-2-对甲苯基-吡咯烷-1-基)-甲酮,
[(S)-2-(2-甲氧基-苯基)-吡咯烷-1-基]-(3-甲基-1H-吡唑并[3,4-b]吡啶-5-基)-甲酮,
[(2R,3R)-3-氨基-2-(4-氟-苯基)-吡咯烷-1-基]-(3-甲基-1H-吡唑并[3,4-b]吡啶-5-基)-甲酮,
[(S)-2-(4-氯-苯基)-吡咯烷-1-基]-(3-环丙基-1H-吡唑并[3,4-b]吡啶-5-基)-甲酮,
[2-(4-溴-苯基)-吡咯烷-1-基]-(1H-吲唑-5-基)-甲酮,
[(S)-2-(4-溴-苯基)-吡咯烷-1-基]-(1H-吲唑-5-基)-甲酮,
(3-甲基-1H-吡唑并[3,4-b]吡啶-5-基)-[(S)-2-(4-三氟甲基-苯基)-吡咯烷-1-基]-甲酮,
(3-甲基-1H-吡唑并[3,4-b]吡啶-5-基)-[3-甲基-2-(4-三氟甲基-苯基)-吡咯烷-1-基]-甲酮,
N-4-(4-氯-苯基)-1-(3-甲基-1H-吡唑并[3,4-b]吡啶-5-羰基)-吡咯烷-3-基]-乙酰胺,
(3-氨基-1H-吲唑-5-基)-[2-(4-三氟甲基-苯基)-吡咯烷-1-基]-甲酮,
[(S)-2-(1H-吲唑-6-基)-吡咯烷-1-基]-(3-甲基-1H-吡唑并[3,4-b]吡啶-5-基)-甲酮,
(3-氯-1H-吲唑-5-基)-[(S)-2-(4-氯-苯基)-吡咯烷-1-基]-甲酮,
[(S)-2-(4-氟-苯基)-氮杂环丁烷-1-基]-(3-甲基-1H-吡唑并[3,4-b]吡啶-5-基)-甲酮,
[(S)-2-(4-氯-苯基)-吡咯烷-1-基]-(3-甲氧基-1H-吡唑并[3,4-b]吡啶-5-基)-甲酮,
(3-氯-1H-吲唑-5-基)-[3-(4-氯-苯基)-吡咯烷-1-基]-甲酮,
[2-(4-氯-苯基)-4-甲基-哌嗪-1-基]-(3-甲基-1H-吲唑-5-基)-甲酮,
[2-(4-氯-苯基)-吡咯烷-1-基]-(3-三氟甲基-1H-吡唑并[3,4-b]吡啶-5-基)-甲酮,
(3-氨基-1H-吲唑-5-基)-[(S)-2-(4-三氟甲基-苯基)-吡咯烷-1-基]-甲酮,
(3-氨基-1H-吲唑-5-基)-[2-(4-异丙基-苯基)-吡咯烷-1-基]-甲酮,
(3-氯-1H-吲唑-5-基)-[2-(4-三氟甲基-苯基)-吡咯烷-1-基]-甲酮,
[(S)-2-(4-氯-苯基)-氮杂环丁烷-1-基]-(3-甲基-1H-吡唑并[3,4-b]吡啶-5-基)-甲酮,
[(s)-2-(4-氯-苯基)-吡咯烷-1-基]-(3-甲基-1H-吡唑并[3,4-c]吡啶-5-基)-甲酮,
[2-(4-氯-3-氟-苯基)-吡咯烷-1-基]-(3-甲基-1H-吡唑并[3,4-b]吡啶-5-基)-甲酮,
[(S)-2-(4-氯-2-氟-苯基)-吡咯烷-1-基]-(3-甲基-1H-吡唑并[3,4-b]吡啶-5-基)-甲酮,
[3-(4-氯-苯基)-吗啉-4-基]-(3-甲基-1H-吲唑-5-基)-甲酮,
[(S)-2-(4-氯-苯基)-吡咯烷-1-基]-(3-氟-1H-吲唑-5-基)-甲酮,
[(S)-2-(4-甲氧基-苯基)-吡咯烷-1-基]-(3-甲基-1H-吡唑并[3,4-b]吡啶-5-基)-甲酮,
(3-甲基-1H-吡唑并[3,4-b]吡啶-5-基)-[(2S,3R)-3-甲基-2-(4-三氟甲基-苯基)-吡咯烷-1-基]-甲酮,
[(S)-2-(4-氯-苯基)-吡咯烷-1-基]-(3-三氟甲基-1H-吡唑并[3,4-b]吡啶-5-基)-甲酮,
[(S)-2-(4-氯-苯基)-吡咯烷-1-基]-(3-甲基硫基-1H-吲唑-5-基)-甲酮,
[2-(4-异丙基-苯基)-吡咯烷-1-基]-(3-甲基-1H-吡唑并[3,4-b]吡啶-5-基)-甲酮,
反式-[3-(4-氯-苯基)-4-羟基-吡咯烷-1-基]-(3-甲基-1H-吡唑并[3,4-b]吡啶-5-基)-甲酮,
(3-氨基-1H-吲唑-5-基)-[(S)-2-(4-异丙基-苯基)-吡咯烷-1-基]-甲酮,
[(S)-2-(4-氟-苯基)-吡咯烷-1-基]-(3-甲基-1H-吡唑并[4,3-b]吡啶-5-基)-甲酮,
(3-甲基-1H-吡唑并[4,3-b]吡啶-5-基)-[(S)-2-(4-三氟甲基-苯基)-吡咯烷-1-基]-甲酮,
[(S)-2-(4-氯-3-氟-苯基)-吡咯烷-1-基]-(3-甲基-1H-吡唑并[3,4-b]吡啶-5-基)-甲酮,
[2-(4-氯-3-氟-苯基)-吡咯烷-1-基]-(3-甲基-1H-吡唑并[4,3-b]吡啶-5-基)-甲酮,
[(S)-2-(4-异丙基-苯基)-吡咯烷-1-基]-(3-甲基-1H-吡唑并[3,4-b]吡啶-5-基)-甲酮,
[(S)-2-(4-氟-苯基)-氮杂环丁烷-1-基]-(3-甲基-1H-吲唑-5-基)-甲酮,
[(S)-2-(4-氯-苯基)-吡咯烷-1-基]-(3-甲基氨基-1H-吲唑-5-基)-甲酮,
[(S)-2-(4-氯-苯基)-吡咯烷-1-基]-(6-氟-3-甲基-1H-吲唑-5-基)-甲酮,
[(S)-2-(4-氯-苯基)-氮杂环丁烷-1-基]-(3-甲基-1H-吲唑-5-基)-甲酮。
7.药物组合物,其包含根据权利要求1至6中任一项所述的化合物、或其立体异构体或互变异构体、或前述每种的药学上可接受的盐、包括其所有比率的混合物作为活性成分;以及药学上可接受的载体。
8.根据权利要求1至6中任一项所述的化合物、或其立体异构体或互变异构体、或前述每种的药学上可接受的盐、包括其所有比率的混合物,其用于治疗过度增殖性疾病、炎性疾病或退行性疾病。
9.根据权利要求8使用的化合物、或其立体异构体或互变异构体、或前述每种的药学上可接受的盐、包括其所有比率的混合物,其中所述过度增殖性疾病是癌症。
10.根据权利要求9使用的化合物、或其立体异构体或互变异构体、或前述每种的药学上可接受的盐、包括其所有比率的混合物,其中,所述癌症选自脑、肺、结肠、表皮样、鳞状细胞、膀胱、胃、胰腺、乳腺、头部和颈部、肾区、肾脏、肝、卵巢、前列腺、子宫、食管、睾丸、妇科、甲状腺的癌症、黑素瘤、急性骨髓性白血病、多发性骨髓瘤、慢性骨髓性白血病、髓细胞白血病、卡波西肉瘤。
11.根据权利要求1至6中任一项所述的化合物、或其立体异构体或互变异构体、或前述每种的药学上可接受的盐、包括其所有比率的混合物在制备用于治疗过度增殖性疾病、炎性疾病或退行性疾病的药物中的用途。
12.根据权利要求11所述的用途,其中,所述疾病是癌症。
13.根据权利要求12所述的用途,其中,所述癌症选自脑、肺、结肠、表皮样、鳞状细胞、膀胱、胃、胰腺、乳腺、头部和颈部、肾区、肾脏、肝、卵巢、前列腺、子宫、食管、睾丸、妇科、甲状腺的癌症、黑素瘤、急性骨髓性白血病、多发性骨髓瘤、慢性骨髓性白血病、髓细胞白血病、卡波西肉瘤。
14.用于治疗过度增殖性疾病、炎性疾病或退行性疾病的方法,其包括将根据权利要求1至6中任一项所述的化合物、或其立体异构体或互变异构体、或前述每种的药学上可接受的盐、包括其所有比率的混合物给药至受试者。
15.根据权利要求14所述的方法,其中,所述癌症选自脑、肺、结肠、表皮样、鳞状细胞、膀胱、胃、胰腺、乳腺、头部和颈部、肾区、肾脏、肝、卵巢、前列腺、子宫、食管、睾丸、妇科、甲状腺的癌症、黑素瘤、急性骨髓性白血病、多发性骨髓瘤、慢性骨髓性白血病、髓细胞白血病、卡波西肉瘤。
16. 套装(试剂盒),其由以下的独立包装组成:
a)有效量的根据权利要求1至6中任一项所述的化合物、或其立体异构体或互变异构体、或前述每种的药学上可接受的盐、包括其所有比率的混合物,和
b)有效量的其它药物活性成分。
17.用于制造式(I)化合物的方法,其中,任选在存在活化剂的情况下,使式(IV)的化合物与式(III)的化合物反应,
(IV),
(III),
从而生成式(I)的化合物。
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CN111670183A (zh) * | 2017-08-07 | 2020-09-15 | Biocad股份公司 | 作为cdk8/19抑制剂的新型杂环化合物 |
CN114585609A (zh) * | 2019-06-27 | 2022-06-03 | 比奥根Ma公司 | 2h-吲唑衍生物及其在疾病治疗中的用途 |
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US11261184B2 (en) | 2017-10-02 | 2022-03-01 | Boehringer Ingelheim International Gmbh | [1,6]naphthyridine compounds and derivatives as CDK8/CDK19 inhibitors |
EP4255904A2 (en) * | 2020-12-03 | 2023-10-11 | Domain Therapeutics | Novel par-2 inhibitors |
AR124369A1 (es) | 2020-12-16 | 2023-03-22 | Amgen Inc | Inhibidores de prmt5 novedosos |
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