JP2021531293A - 自己免疫疾患治療用の新規ピペラジン化合物 - Google Patents
自己免疫疾患治療用の新規ピペラジン化合物 Download PDFInfo
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- JP2021531293A JP2021531293A JP2021503102A JP2021503102A JP2021531293A JP 2021531293 A JP2021531293 A JP 2021531293A JP 2021503102 A JP2021503102 A JP 2021503102A JP 2021503102 A JP2021503102 A JP 2021503102A JP 2021531293 A JP2021531293 A JP 2021531293A
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- JP
- Japan
- Prior art keywords
- piperazine
- piperazinyl
- methyl
- quinoline
- carbonitrile
- 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
- -1 piperazine compound Chemical class 0.000 title claims description 82
- GLUUGHFHXGJENI-UHFFFAOYSA-N diethylenediamine Natural products C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 title claims description 20
- 208000023275 Autoimmune disease Diseases 0.000 title description 3
- 150000001875 compounds Chemical class 0.000 claims abstract description 115
- 150000003839 salts Chemical class 0.000 claims abstract description 26
- 238000000034 method Methods 0.000 claims abstract description 14
- HBAQYPYDRFILMT-UHFFFAOYSA-N 8-[3-(1-cyclopropylpyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-methyl-3,8-diazabicyclo[3.2.1]octan-2-one Chemical class C1(CC1)N1N=CC(=C1)C1=NNC2=C1N=C(N=C2)N1C2C(N(CC1CC2)C)=O HBAQYPYDRFILMT-UHFFFAOYSA-N 0.000 claims abstract description 3
- 125000004193 piperazinyl group Chemical group 0.000 claims description 53
- 125000000217 alkyl group Chemical group 0.000 claims description 31
- 238000002360 preparation method Methods 0.000 claims description 31
- 101000669402 Homo sapiens Toll-like receptor 7 Proteins 0.000 claims description 27
- CIIFKVFOVFJZDM-UHFFFAOYSA-N quinoline-8-carbonitrile Chemical compound C1=CN=C2C(C#N)=CC=CC2=C1 CIIFKVFOVFJZDM-UHFFFAOYSA-N 0.000 claims description 26
- 102000008235 Toll-Like Receptor 9 Human genes 0.000 claims description 25
- 108010060818 Toll-Like Receptor 9 Proteins 0.000 claims description 25
- 102100039390 Toll-like receptor 7 Human genes 0.000 claims description 25
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 25
- 101000800483 Homo sapiens Toll-like receptor 8 Proteins 0.000 claims description 22
- 150000001412 amines Chemical class 0.000 claims description 21
- 102100033110 Toll-like receptor 8 Human genes 0.000 claims description 20
- 239000005557 antagonist Substances 0.000 claims description 20
- 201000000596 systemic lupus erythematosus Diseases 0.000 claims description 20
- MXFYYFVVIIWKFE-UHFFFAOYSA-N dicyclohexyl-[2-[2,6-di(propan-2-yloxy)phenyl]phenyl]phosphane Chemical compound CC(C)OC1=CC=CC(OC(C)C)=C1C1=CC=CC=C1P(C1CCCCC1)C1CCCCC1 MXFYYFVVIIWKFE-UHFFFAOYSA-N 0.000 claims description 14
- 238000006243 chemical reaction Methods 0.000 claims description 12
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 12
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 claims description 11
- 239000003054 catalyst Substances 0.000 claims description 11
- 238000005859 coupling reaction Methods 0.000 claims description 11
- 125000004916 (C1-C6) alkylcarbonyl group Chemical group 0.000 claims description 10
- GOJUJUVQIVIZAV-UHFFFAOYSA-N 2-amino-4,6-dichloropyrimidine-5-carbaldehyde Chemical group NC1=NC(Cl)=C(C=O)C(Cl)=N1 GOJUJUVQIVIZAV-UHFFFAOYSA-N 0.000 claims description 10
- 208000005777 Lupus Nephritis Diseases 0.000 claims description 10
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 10
- 239000007821 HATU Substances 0.000 claims description 9
- 230000008878 coupling Effects 0.000 claims description 9
- 238000010168 coupling process Methods 0.000 claims description 9
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 9
- NOVDNBNQZKLLBB-OYRHEFFESA-N 5-[(3R,5S)-3,5-dimethyl-4-[(4-piperazin-1-ylphenyl)methyl]piperazin-1-yl]quinoline-8-carbonitrile Chemical compound C1=2C(=CC=C(C=2C=CC=N1)N1C[C@@H](C)N([C@@H](C)C1)CC1=CC=C(N2CCNCC2)C=C1)C#N NOVDNBNQZKLLBB-OYRHEFFESA-N 0.000 claims description 8
- 238000006443 Buchwald-Hartwig cross coupling reaction Methods 0.000 claims description 8
- 239000003153 chemical reaction reagent Substances 0.000 claims description 8
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 8
- 230000002265 prevention Effects 0.000 claims description 8
- 125000004605 1,2,3,4-tetrahydroisoquinolinyl group Chemical group C1(NCCC2=CC=CC=C12)* 0.000 claims description 7
- 229940079593 drug Drugs 0.000 claims description 7
- 239000003814 drug Substances 0.000 claims description 7
- 229910052736 halogen Inorganic materials 0.000 claims description 7
- 125000004076 pyridyl group Chemical group 0.000 claims description 7
- 150000002367 halogens Chemical class 0.000 claims description 6
- 125000002490 anilino group Chemical group [H]N(*)C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 claims description 5
- 125000002147 dimethylamino group Chemical group [H]C([H])([H])N(*)C([H])([H])[H] 0.000 claims description 5
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 5
- 125000003386 piperidinyl group Chemical group 0.000 claims description 5
- 125000000714 pyrimidinyl group Chemical group 0.000 claims description 5
- FJKYCCYOQFNCJP-BGYRXZFFSA-N 5-[(3R,5S)-3,5-dimethyl-4-[(5-piperazin-1-ylpyridin-2-yl)methyl]piperazin-1-yl]quinoline-8-carbonitrile Chemical compound C1=2C(=CC=C(C=2C=CC=N1)N1C[C@@H](C)N([C@@H](C)C1)CC1=NC=C(C=C1)N1CCNCC1)C#N FJKYCCYOQFNCJP-BGYRXZFFSA-N 0.000 claims description 4
- JMDMWHPIXNHPQD-BGYRXZFFSA-N 5-[(3R,5S)-3,5-dimethyl-4-[(6-piperazin-1-ylpyridin-3-yl)methyl]piperazin-1-yl]quinoline-8-carbonitrile Chemical compound C1=2C(=CC=C(C=2C=CC=N1)N1C[C@@H](C)N([C@@H](C)C1)CC1=CN=C(C=C1)N1CCNCC1)C#N JMDMWHPIXNHPQD-BGYRXZFFSA-N 0.000 claims description 4
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 claims description 4
- 125000003545 alkoxy group Chemical group 0.000 claims description 4
- NOVDNBNQZKLLBB-NHCUHLMSSA-N 5-[(3R,5R)-3,5-dimethyl-4-[(4-piperazin-1-ylphenyl)methyl]piperazin-1-yl]quinoline-8-carbonitrile Chemical compound C1=2C(C#N)=CC=C(C=2C=CC=N1)N1C[C@H](N([C@H](C)C1)CC1=CC=C(N2CCNCC2)C=C1)C NOVDNBNQZKLLBB-NHCUHLMSSA-N 0.000 claims description 3
- VXACTESXFTUFKT-KDURUIRLSA-N 5-[(3R,5S)-3,5-dimethyl-4-[(5-piperazin-1-ylpyrimidin-2-yl)methyl]piperazin-1-yl]quinoline-8-carbonitrile Chemical compound C1(=C2N=CC=CC2=C(N2C[C@@H](N([C@H](C)C2)CC2=NC=C(C=N2)N2CCNCC2)C)C=C1)C#N VXACTESXFTUFKT-KDURUIRLSA-N 0.000 claims description 3
- ZBQOTKHGDKDWPB-AELKHGAFSA-N 5-[(3R,5S)-3,5-dimethyl-4-[[5-[4-(pyrrolidine-2-carbonyl)piperazin-1-yl]pyridin-2-yl]methyl]piperazin-1-yl]quinoline-8-carbonitrile Chemical compound C[C@@H]1CN(C[C@@H](N1CC1=NC=C(C=C1)N1CCN(CC1)C(=O)C1NCCC1)C)C1=C2C=CC=NC2=C(C=C1)C#N ZBQOTKHGDKDWPB-AELKHGAFSA-N 0.000 claims description 3
- QAGBOGIOESNRTO-SZPZYZBQSA-N 5-[(3R,5S)-4-[[5-[4-[2-(dimethylamino)acetyl]piperazin-1-yl]pyrimidin-2-yl]methyl]-3,5-dimethylpiperazin-1-yl]quinoline-8-carbonitrile Chemical compound C1=2C(=CC=C(C=2C=CC=N1)N1C[C@@H](N([C@@H](C1)C)CC1=NC=C(C=N1)N1CCN(CC1)C(=O)CN(C)C)C)C#N QAGBOGIOESNRTO-SZPZYZBQSA-N 0.000 claims description 3
- MFRYGXLWWNQIDF-SZPZYZBQSA-N 5-[(3S,5R)-3,5-dimethyl-4-[2-oxo-2-(5-piperazin-1-yl-1,3-dihydroisoindol-2-yl)ethyl]piperazin-1-yl]quinoline-8-carbonitrile Chemical compound C[C@@H]1CN(C[C@@H](N1CC(N1CC2=CC=C(C=C2C1)N1CCNCC1)=O)C)C1=C2C=CC=NC2=C(C=C1)C#N MFRYGXLWWNQIDF-SZPZYZBQSA-N 0.000 claims description 3
- RNBRLAKKDPWSNI-OYRHEFFESA-N 5-[(3S,5R)-3,5-dimethyl-4-[[5-(4-methylpiperazin-1-yl)pyridin-2-yl]methyl]piperazin-1-yl]quinoline-8-carbonitrile Chemical compound N1=C2C(=CC=C1)C(N1C[C@@H](N([C@@H](C1)C)CC1=NC=C(C=C1)N1CCN(CC1)C)C)=CC=C2C#N RNBRLAKKDPWSNI-OYRHEFFESA-N 0.000 claims description 3
- GJLNLVLJKGPNGG-UHFFFAOYSA-N 5-[3-methyl-4-[2-[4-(1-methylpiperidin-4-yl)piperidin-1-yl]-2-oxoethyl]piperazin-1-yl]quinoline-8-carbonitrile Chemical compound CC1CN(CCN1CC(=O)N1CCC(CC1)C1CCN(CC1)C)C1=C2C=CC=NC2=C(C=C1)C#N GJLNLVLJKGPNGG-UHFFFAOYSA-N 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
- 125000005843 halogen group Chemical group 0.000 claims description 3
- 125000004029 hydroxymethyl group Chemical group [H]OC([H])([H])* 0.000 claims description 3
- 150000002825 nitriles Chemical class 0.000 claims description 3
- 239000008194 pharmaceutical composition Substances 0.000 claims description 3
- 239000003795 chemical substances by application Substances 0.000 claims description 2
- 239000013543 active substance Substances 0.000 claims 1
- 125000004594 isoindolinyl group Chemical group C1(NCC2=CC=CC=C12)* 0.000 claims 1
- 239000000203 mixture Substances 0.000 abstract description 21
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 55
- 238000001819 mass spectrum Methods 0.000 description 45
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 43
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 31
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 30
- 239000011541 reaction mixture Substances 0.000 description 29
- 239000000243 solution Substances 0.000 description 29
- 210000004027 cell Anatomy 0.000 description 25
- 235000019439 ethyl acetate Nutrition 0.000 description 21
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 21
- OKKJLVBELUTLKV-MZCSYVLQSA-N Deuterated methanol Chemical compound [2H]OC([2H])([2H])[2H] OKKJLVBELUTLKV-MZCSYVLQSA-N 0.000 description 20
- 238000005481 NMR spectroscopy Methods 0.000 description 19
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 19
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- 230000005764 inhibitory process Effects 0.000 description 11
- MFRIHAYPQRLWNB-UHFFFAOYSA-N sodium tert-butoxide Chemical compound [Na+].CC(C)(C)[O-] MFRIHAYPQRLWNB-UHFFFAOYSA-N 0.000 description 11
- KDLHZDBZIXYQEI-UHFFFAOYSA-N palladium Substances [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 10
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- CWXPZXBSDSIRCS-UHFFFAOYSA-N tert-butyl piperazine-1-carboxylate Chemical compound CC(C)(C)OC(=O)N1CCNCC1 CWXPZXBSDSIRCS-UHFFFAOYSA-N 0.000 description 10
- RFIOZSIHFNEKFF-UHFFFAOYSA-M piperazine-1-carboxylate Chemical compound [O-]C(=O)N1CCNCC1 RFIOZSIHFNEKFF-UHFFFAOYSA-M 0.000 description 9
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- SHYNPYQEUWKLDI-UHFFFAOYSA-N methyl 2-(2-methylpiperazin-1-yl)acetate Chemical compound COC(=O)CN1CCNCC1C SHYNPYQEUWKLDI-UHFFFAOYSA-N 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- 210000001616 monocyte Anatomy 0.000 description 1
- 238000010172 mouse model Methods 0.000 description 1
- ULWOJODHECIZAU-UHFFFAOYSA-N n,n-diethylpropan-2-amine Chemical compound CCN(CC)C(C)C ULWOJODHECIZAU-UHFFFAOYSA-N 0.000 description 1
- 230000007935 neutral effect Effects 0.000 description 1
- 239000012299 nitrogen atmosphere Substances 0.000 description 1
- 231100000065 noncytotoxic Toxicity 0.000 description 1
- 230000002020 noncytotoxic effect Effects 0.000 description 1
- 231100000252 nontoxic Toxicity 0.000 description 1
- 230000003000 nontoxic effect Effects 0.000 description 1
- 238000000655 nuclear magnetic resonance spectrum Methods 0.000 description 1
- 210000000056 organ Anatomy 0.000 description 1
- 150000007530 organic bases Chemical class 0.000 description 1
- 150000002894 organic compounds Chemical class 0.000 description 1
- 210000001672 ovary Anatomy 0.000 description 1
- 230000002018 overexpression Effects 0.000 description 1
- 235000006408 oxalic acid Nutrition 0.000 description 1
- MUJIDPITZJWBSW-UHFFFAOYSA-N palladium(2+) Chemical compound [Pd+2] MUJIDPITZJWBSW-UHFFFAOYSA-N 0.000 description 1
- FJKROLUGYXJWQN-UHFFFAOYSA-N papa-hydroxy-benzoic acid Natural products OC(=O)C1=CC=C(O)C=C1 FJKROLUGYXJWQN-UHFFFAOYSA-N 0.000 description 1
- 230000008506 pathogenesis Effects 0.000 description 1
- 239000003208 petroleum Substances 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- 210000005134 plasmacytoid dendritic cell Anatomy 0.000 description 1
- 229920000768 polyamine Polymers 0.000 description 1
- 208000005987 polymyositis Diseases 0.000 description 1
- 239000013641 positive control Substances 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 159000000001 potassium salts Chemical class 0.000 description 1
- 238000001556 precipitation Methods 0.000 description 1
- 150000003141 primary amines Chemical class 0.000 description 1
- 229940002612 prodrug Drugs 0.000 description 1
- 239000000651 prodrug Substances 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 230000001737 promoting effect Effects 0.000 description 1
- 230000000069 prophylactic effect Effects 0.000 description 1
- 235000019260 propionic acid Nutrition 0.000 description 1
- 235000018102 proteins Nutrition 0.000 description 1
- 108090000623 proteins and genes Proteins 0.000 description 1
- 102000004169 proteins and genes Human genes 0.000 description 1
- 125000000246 pyrimidin-2-yl group Chemical group [H]C1=NC(*)=NC([H])=C1[H] 0.000 description 1
- IUVKMZGDUIUOCP-BTNSXGMBSA-N quinbolone Chemical compound O([C@H]1CC[C@H]2[C@H]3[C@@H]([C@]4(C=CC(=O)C=C4CC3)C)CC[C@@]21C)C1=CCCC1 IUVKMZGDUIUOCP-BTNSXGMBSA-N 0.000 description 1
- 230000009257 reactivity Effects 0.000 description 1
- 210000003289 regulatory T cell Anatomy 0.000 description 1
- 239000011347 resin Substances 0.000 description 1
- 229920005989 resin Polymers 0.000 description 1
- 230000002441 reversible effect Effects 0.000 description 1
- 230000006965 reversible inhibition Effects 0.000 description 1
- 238000012552 review Methods 0.000 description 1
- 206010039073 rheumatoid arthritis Diseases 0.000 description 1
- 235000009566 rice Nutrition 0.000 description 1
- 229960004889 salicylic acid Drugs 0.000 description 1
- 108010038379 sargramostim Proteins 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 238000007423 screening assay Methods 0.000 description 1
- 230000028327 secretion Effects 0.000 description 1
- 210000003491 skin Anatomy 0.000 description 1
- 235000009518 sodium iodide Nutrition 0.000 description 1
- 159000000000 sodium salts Chemical class 0.000 description 1
- 238000007921 solubility assay Methods 0.000 description 1
- 230000003595 spectral effect Effects 0.000 description 1
- 230000000087 stabilizing effect Effects 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 125000001424 substituent group Chemical group 0.000 description 1
- 150000003460 sulfonic acids Chemical class 0.000 description 1
- 230000001629 suppression Effects 0.000 description 1
- 230000002459 sustained effect Effects 0.000 description 1
- 208000011580 syndromic disease Diseases 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
- 229940095064 tartrate Drugs 0.000 description 1
- DXQXHFOCKKIWJL-NKWVEPMBSA-N tert-butyl (3r,4s)-3-amino-4-fluoropyrrolidine-1-carboxylate Chemical compound CC(C)(C)OC(=O)N1C[C@@H](N)[C@@H](F)C1 DXQXHFOCKKIWJL-NKWVEPMBSA-N 0.000 description 1
- NUZXPHIQZUYMOR-RKDXNWHRSA-N tert-butyl (3r,5r)-3,5-dimethylpiperazine-1-carboxylate Chemical compound C[C@@H]1CN(C(=O)OC(C)(C)C)C[C@@H](C)N1 NUZXPHIQZUYMOR-RKDXNWHRSA-N 0.000 description 1
- BNWCETAHAJSBFG-UHFFFAOYSA-N tert-butyl 2-bromoacetate Chemical compound CC(C)(C)OC(=O)CBr BNWCETAHAJSBFG-UHFFFAOYSA-N 0.000 description 1
- PUGUQINMNYINPK-UHFFFAOYSA-N tert-butyl 4-(2-chloroacetyl)piperazine-1-carboxylate Chemical compound CC(C)(C)OC(=O)N1CCN(C(=O)CCl)CC1 PUGUQINMNYINPK-UHFFFAOYSA-N 0.000 description 1
- OLOIFCYZWOTWRO-UHFFFAOYSA-N tert-butyl 6-amino-3,4-dihydro-1h-isoquinoline-2-carboxylate Chemical compound NC1=CC=C2CN(C(=O)OC(C)(C)C)CCC2=C1 OLOIFCYZWOTWRO-UHFFFAOYSA-N 0.000 description 1
- LHJSYLNUEZBFED-UHFFFAOYSA-N tert-butyl 9-oxa-3,7-diazabicyclo[3.3.1]nonane-3-carboxylate Chemical compound C1NCC2CN(C(=O)OC(C)(C)C)CC1O2 LHJSYLNUEZBFED-UHFFFAOYSA-N 0.000 description 1
- 125000005931 tert-butyloxycarbonyl group Chemical group [H]C([H])([H])C(OC(*)=O)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 150000003512 tertiary amines Chemical class 0.000 description 1
- 229960004559 theobromine Drugs 0.000 description 1
- ODBLHEXUDAPZAU-UHFFFAOYSA-N threo-D-isocitric acid Natural products OC(=O)C(O)C(C(O)=O)CC(O)=O ODBLHEXUDAPZAU-UHFFFAOYSA-N 0.000 description 1
- 230000000451 tissue damage Effects 0.000 description 1
- 231100000827 tissue damage Toxicity 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- YFTHZRPMJXBUME-UHFFFAOYSA-N tripropylamine Chemical compound CCCN(CCC)CCC YFTHZRPMJXBUME-UHFFFAOYSA-N 0.000 description 1
- 238000011144 upstream manufacturing Methods 0.000 description 1
- 150000003751 zinc Chemical class 0.000 description 1
- GTLDTDOJJJZVBW-UHFFFAOYSA-N zinc cyanide Chemical compound [Zn+2].N#[C-].N#[C-] GTLDTDOJJJZVBW-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
- A61P37/02—Immunomodulators
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/04—Ortho-condensed systems
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D498/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
- C07D498/08—Bridged systems
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D498/12—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains three hetero rings
- C07D498/18—Bridged systems
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- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
- Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
Abstract
Description
式中、
R1は、
であり、ここでR5はシアノ、C1−6アルコキシ、C1−6アルキルまたはハロゲンである;
R2は、C1−6アルキルである;
R3は、R3aまたは−COR3bであり、ここで
R3aは、ピペラジニルおよび(ヒドロキシC1−6アルキル)ピペラジニルで置換されたフェニル;
ピペラジニル、C1−6アルキルピペラジニル、9−オキサ−3,7−ジアザビシクロ[3.3.1]ノナニル、(ハロピロリジニル)アミノ、(ピロリジニルカルボニル)ピペラジニル若しくは(((C1−6アルキル)2アミノ)C1−6アルキルカルボニル)ピペラジニルで置換されたでピリジニル;または
ピペラジニル若しくは(((C1−6アルキル)2アミノ)C1−6アルキルカルボニル)ピペラジニルで置換されたピリミジニルである;
R3bは、ピペラジニルで置換された7,8−ジヒドロ−5H−1,6−ナフチリジニル;
ピペラジニルで置換された3,4−ジヒドロ−1H−イソキノリニル;
ピペラジニルで置換されたイソインドリニル;
ピペラジニルで置換されたフェニルアミノ;
1,2,3,4−テトラヒドロイソキノリニル;または
C1−6アルキルピペリジニルピペリジニルである;
R4は、C1−6アルキルまたはHである;
化合物、またはその薬学的に許容され得る塩、鏡像異性体もしくはジアステレオマーである。
式中、
R1は、
であり、ここでR5はシアノ、C1−6アルコキシ、C1−6アルキルまたはハロゲンである;
R2は、C1−6アルキルである;
R3は、R3aまたは−COR3bであり、ここで
R3aは、ピペラジニルおよび(ヒドロキシC1−6アルキル)ピペラジニルで置換されたフェニル;
ピペラジニル、C1−6アルキルピペラジニル、9−オキサ−3,7−ジアザビシクロ[3.3.1]ノナニル、(ハロピロリジニル)アミノ、(ピロリジニルカルボニル)ピペラジニル若しくは(((C1−6アルキル)2アミノ)C1−6アルキルカルボニル)ピペラジニルで置換されたピリジニル;または
ピペラジニル若しくは(((C1−6アルキル)2アミノ)C1−6アルキルカルボニル)ピペラジニルで置換されたピリミジニルである;
R3bは、ピペラジニルで置換された7,8−ジヒドロ−5H−1,6−ナフチリジニル;
ピペラジニルで置換された3,4−ジヒドロ−1H−イソキノリニル;
ピペラジニルで置換されたイソインドリニル;
ピペラジニルで置換されたフェニルアミノ;
1,2,3,4−テトラヒドロイソキノリニル;または
C1−6アルキルピペリジニルピペリジニルである;
R4は、C1−6アルキルまたはHである;
化合物、またはその薬学的に許容され得る塩、鏡像異性体もしくはジアステレオマーに関する。
式中、
R1は、
であり、ここで、R5は、シアノである;
R2は、C1−6アルキルである;
R3は、R3aまたは−COR3bであり、ここで
R3aは、ピペラジニルおよび(ヒドロキシC1−6アルキル)ピペラジニルで置換されたフェニル;
ピペラジニル、C1−6アルキルピペラジニル、9−オキサ−3,7−ジアザビシクロ[3.3.1]ノナニル、(ハロピロリジニル)アミノ、(ピロリジニルカルボニル)ピペラジニル若しくは(((C1−6アルキル)2アミノ)C1−6アルキルカルボニル)ピペラジニルで置換されたピリジニル;または
ピペラジニル若しくは(((C1−6アルキル)2アミノ)C1−6アルキルカルボニル)ピペラジニルで置換されたピリミジニルである;
R3bは、ピペラジニルで置換された7,8−ジヒドロ−5H−1,6−ナフチリジニル;
ピペラジニルで置換された3,4−ジヒドロ−1H−イソキノリニル;
ピペラジニルで置換されたイソインドリニル;
ピペラジニルで置換されたフェニルアミノ;
1,2,3,4−テトラヒドロイソキノリニル;または
C1−6アルキルピペリジニルピペリジニルである;
R4は、C1−6アルキルまたはHである;
化合物、またはその薬学的に許容され得る塩、鏡像異性体もしくはジアステレオマーに関する。
R1は、
であり、ここで、R5は、シアノである;
R2は、メチルである;
R3は、R3aまたは−COR3bであり、ここで
R3aは、ピペラジニルフェニル;(ヒドロキシメチル)ピペラジニルフェニル;ピペラジニルピリジニル;(メチルピペラジニル)ピリジニル;9−オキサ−3,7−ジアザビシクロ[3.3.1]ノナニルピリジニル;((フルオロピロリジニル)アミノ)ピリジニル;((ピロリジニルカルボニル)ピペラジニル)ピリジニル;(((ジメチルアミノ)アセチル)ピペラジニル)ピリジニル;ピペラジニルピリミジニル;または((ジメチルアミノ)アセチル)ピペラジニルピリミジニルである;
R3bは、ピペラジニル−7,8−ジヒドロ−5H−1,6−ナフチリジニル;ピペラジニル−3,4−ジヒドロ−1H−イソキノリニル;ピペラジニルイソインドリニル;ピペラジニルフェニルアミノ;1,2,3,4−テトラヒドロイソキノリニル;またはメチルピペリジニルピペリジニルである。
R4は、メチルまたはHである;
化合物、またはその薬学的に許容され得る塩、鏡像異性体もしくはジアステレオマーに関する。
5−[(3R,5S)−3,5−ジメチル−4−[(4−ピペラジン−1−イルフェニル)メチル]ピペラジン−1−イル]キノリン−8−カルボニトリル;
5−[(3R,5R)−3,5−ジメチル−4−[(4−ピペラジン−1−イルフェニル)メチル]ピペラジン−1−イル]キノリン−8−カルボニトリル;
5−[(3R,5S)−3,5−ジメチル−4−[(6−ピペラジン−1−イル−3−ピリジル)メチル]ピペラジン−1−イル]キノリン−8−カルボニトリル;
5−[(3S,5R)−3,5−ジメチル−4−[(5−ピペラジン−1−イルピリミジン−2−イル)メチル]ピペラジン−1−イル]キノリン−8−カルボニトリル;
5−[(3S,5R)−3,5−ジメチル−4−[(5−ピペラジン−1−イル−2−ピリジル)メチル]ピペラジン−1−イル]キノリン−8−カルボニトリル;
5−[(3S,5R)−4−[[5−[4−[2−(ジメチルアミノ)アセチル]ピペラジン−1−イル]ピリミジン−2−イル]メチル]−3,5−ジメチル−ピペラジン−1−イル]キノリン−8−カルボニトリル;
5−[(3S,5R)−3,5−ジメチル−4−[[5−(4−メチルピペラジン−1−イル)−2−ピリジル]メチル]ピペラジン−1−イル]キノリン−8−カルボニトリル;
5−[(3S,5R)−3,5−ジメチル−4−[[5−(9−オキサ−3,7−ジアザビシクロ[3.3.1]ノナン−3−イル)−2−ピリジル]メチル]ピペラジン−1−イル]キノリン−8−カルボニトリル;
5−[(3R,5S)−3,5−ジメチル−4−[[5−[[(3R、4S)−4−フルオロピロリジン−3−イル]アミノ]−2−ピリジル]メチル]ピペラジン−1−イル]キノリン−8−カルボニトリル;
5−[(3R,5S)−3,5−ジメチル−4−[[5−[4−(ピロリジン−2−カルボニル)ピペラジン−1−イル]−2−ピリジル]メチル]ピペラジン−1−イル]キノリン−8−カルボニトリル;
5−[(3S,5R)−4−[[5−[4−[2−(ジメチルアミノ)アセチル]ピペラジン−1−イル]−2−ピリジル]メチル]−3,5−ジメチル−ピペラジン−1−イル]キノリン−8−カルボニトリル;
5−[(3R,5S)−4−[[4−[2−(ヒドロキシメチル)ピペラジン−1−イル]フェニル]メチル]−3,5−ジメチル−ピペラジン−1−イル]キノリン−8−カルボニトリル;
5−[(3R,5S)−3,5−ジメチル−4−[2−オキソ−2−(2−ピペラジン−1−イル−7,8−ジヒドロ−5H−1,6−ナフチリジン−6−イル)エチル]ピペラジン−1−イル]キノリン−8−カルボニトリル;
5−[(3R,5S)−3,5−ジメチル−4−[2−オキソ−2−(6−ピペラジン−1−イル−3,4−ジヒドロ−1H−イソキノリン−2−イル)エチル]ピペラジン−1−イル]キノリン−8−カルボニトリル;
5−[(3R,5S)−3,5−ジメチル−4−[2−オキソ−2−(7−ピペラジン−1−イル−3,4−ジヒドロ−1H−イソキノリン−2−イル)エチル]ピペラジン−1−イル]キノリン−8−カルボニトリル;
5−[(3R,5S)−3,5−ジメチル−4−[2−オキソ−2−(5−ピペラジン−1−イルイソインドリン−2−イル)エチル]ピペラジン−1−イル]キノリン−8−カルボニトリル;
2−[4−(8−シアノ−5−キノリル)−2−メチル−ピペラジン−1−イル]−N−(4−ピペラジン−1−イルフェニル)アセトアミド;
2−[4−(8−シアノ−5−キノリル)−2−メチル−ピペラジン−1−イル]−N−(1,2,3,4−テトラヒドロイソキノリン−6−イル)アセトアミド;および
5−[3−メチル−4−[2−[4−(1−メチル−4−ピペリジル)−1−ピペリジル]−2−オキソ−エチル]ピペラジン−1−イル]キノリン−8−カルボニトリル;
から選択される化合物
またはその薬学的に許容され得る塩、鏡像異性体もしくはジアステレオマーである。
ここで、Xはハロゲンまたは脱離基、例えば、OTfまたはOMsである。YはNまたはCHである。R6は、ピペラジンなどの線状および環状アミンを含む第一級または第二級アミンである。R7とR8は保護基である。例えば、R7はBocで、R8はベンジルである。
ここで、Xはハロゲンまたは脱離基、例えば、OTfまたはOMsである。YはNまたはCHである。R6は、ピペラジンなどの線状および環状アミンを含む第一級または第二級アミンである。R7とR8は保護基である。例えば、R7はBocで、R8はベンジルである。
本発明はまた、以下の工程のいずれかを含む式(I)の化合物の調製方法であって
a) カップリング試薬および塩基の存在下での、式(VI)の化合物、
およびアミンHR3bのカップリング反応;
b) 触媒および塩基の存在下での、式(X)の化合物
およびアミンHR6のブッフバルト・ハートウィッグアミノ化反応。
(ここで、
ステップa)において、前記カップリング試薬は、例えば、HATUであり得る。塩基は、例えば、DIPEAであり得る。
ステップb)において、前記触媒は、例えば、Ruphos Pd−G2であり得る;前記塩基は、例えば、Cs2CO3であり得る。)
ACN:アセトニトリル
Boc2O:二炭酸ジ−tertブチル
Tf2O トリフル酸無水物
DCM:ジクロロメタン
DDI 薬物−薬物相互作用
DIPEA ジエチルイソプロピルアミン
DMA ジメチルアセトアミド
EAまたはEtOAc:酢酸エチル
FA:ギ酸
HATU:1−[ビス(ジメチルアミノ)メチレン]−1H−1,2,3−トリアゾロ[4,5−b]ピリジニウム 3−オキシドヘキサフルオロホスフェート
HLM ヒト肝臓ミクロソーム
hr 時間
hrs 時間
IC50:50%阻害濃度
LCMS 液体クロマトグラフィー質量分析
LYSA 凍結乾燥溶解度アッセイ
MS:質量分析法
PE:石油エーテル
prep−HPLC:分取高速液体クロマトグラフィー
rt:室温
RT:保持時間
RuPhos Pd G2:第2世代のクロロ(2−ジシクロヘキシルホスフィノ−2’,6’−ジイソプロポキシ−1,1’−ビフェニル)[2−(2’−アミノ−1,1’−ビフェニル)]パラジウム(II)
SFC:超臨界流体クロマトグラフィー
TFA:トリフルオロ酢酸
v/v 容積率
酸性条件I:A:H2O中の0.1%TFA、B:アセトニトリル中の0.1%TFA;
酸性条件II:A:H2O中の0.0375%TFA、B:アセトニトリル中の0.01875%TFA;
塩基性条件I:A:H2O中の0.1%NH3・H2O、B:アセトニトリル;
塩基性条件II:A:H2O中の0.025%NH3・H2O、B:アセトニトリル;
中性条件:A:H2O、B:アセトニトリル。
質量スペクトル(MS):概して、親質量が報告されていることを示すイオンのみであり、別段の記載がない限り、引用される質量イオンは、正の質量イオン(MH)+である。
NMRスペクトルは、Bruker Avance 400MHzを用いて取得した。
実施例1
精製した中間体をDCM(2mL)に溶解し、TFA(0.5mL)を添加した。反応混合物を室温で3時間撹拌し、次に濃縮して、粗化合物1f、MS:計算された283および285[(M+H)+]、測定した283および285[(M+H)+]を得た。
実施例2
実施例3
実施例4
実施例5
実施例6
実施例7
実施例8
実施例9
実施例10
実施例11
実施例12
実施例13
実施例14
実施例15
実施例16
実施例17
実施例18
実施例19
実施例20
Par(100%活性)=阻害剤を含有しない(DMSO対照を含有する)インキュベート物全部についての平均PAR、
%活性(検査阻害剤)
=[PAR(検査阻害剤)−PAR(0%活性)/[PAR(100%活性)−PAR(0%活性)]、
%阻害(検査阻害剤)=100−%活性(検査阻害剤)。
Claims (16)
- 式(I)の化合物であって、
式中、
R1は、
であり、ここで、R5はシアノ、C1−6アルコキシ、C1−6アルキルまたはハロゲンである;
R2は、C1−6アルキルである;
R3は、R3aまたは−COR3bであり、ここで
R3aは、ピペラジニルおよび(ヒドロキシC1−6アルキル)ピペラジニルで置換されたフェニル;
ピペラジニル、C1−6アルキルピペラジニル、9−オキサ−3,7−ジアザビシクロ[3.3.1]ノナニル、(ハロピロリジニル)アミノ、(ピロリジニルカルボニル)ピペラジニル若しくは(((C1−6アルキル)2アミノ)C1−6アルキルカルボニル)ピペラジニルで置換されたピリジニル;または
ピペラジニル若しくは(((C1−6アルキル)2アミノ)C1−6アルキルカルボニル)ピペラジニルで置換されたピリミジニルである;
R3bは、ピペラジニルで置換された7,8−ジヒドロ−5H−1,6−ナフチリジニル;
ピペラジニルで置換された3,4−ジヒドロ−1H−イソキノリニル;
ピペラジニルで置換されたイソインドリニル;
ピペラジニルで置換されたフェニルアミノ;
1,2,3,4−テトラヒドロイソキノリニル;または
C1−6アルキルピペリジニルピペリジニルである;
R4は、C1−6アルキルまたはHである;
化合物、またはその薬学的に許容され得る塩、鏡像異性体もしくはジアステレオマー。 - 式(I)の化合物であって、
式中、
R1は、
であり、ここで、R5は、シアノである;
R2は、C1−6アルキルである;
R3は、R3aまたは−COR3bであり、ここで
R3aは、ピペラジニルおよび(ヒドロキシC1−6アルキル)ピペラジニルで置換されたフェニル;
ピペラジニル、C1−6アルキルピペラジニル、9−オキサ−3,7−ジアザビシクロ[3.3.1]ノナニル、(ハロピロリジニル)アミノ、(ピロリジニルカルボニル)ピペラジニル若しくは(((C1−6アルキル)2アミノ)C1−6アルキルカルボニル)ピペラジニルで置換されたピリジニル;または
ピペラジニル若しくは(((C1−6アルキル)2アミノ)C1−6アルキルカルボニル)ピペラジニルで置換されたピリミジニルである;
R3bは、ピペラジニルで置換された7,8−ジヒドロ−5H−1,6−ナフチリジニル;
ピペラジニルで置換された3,4−ジヒドロ−1H−イソキノリニル;
ピペラジニルで置換されたイソインドリニル;
ピペラジニルで置換されたフェニルアミノ;
1,2,3,4−テトラヒドロイソキノリニル;または
C1−6アルキルピペリジニルピペリジニルである;
R4は、C1−6アルキルまたはHである;
化合物、またはその薬学的に許容され得る塩、鏡像異性体もしくはジアステレオマー。 - 請求項2に記載の化合物であって、
式中
R1は、
であり、ここで、R5は、シアノである;
R2は、メチルである;
R3は、R3aまたは−COR3bであって、ここで
R3aは、ピペラジニルフェニル;(ヒドロキシメチル)ピペラジニルフェニル;ピペラジニルピリジニル;(メチルピペラジニル)ピリジニル;9−オキサ−3,7−ジアザビシクロ[3.3.1]ノナニルピリジニル;((フルオロピロリジニル)アミノ)ピリジニル;((ピロリジニルカルボニル)ピペラジニル)ピリジニル;(((ジメチルアミノ)アセチル)ピペラジニル)ピリジニル;ピペラジニルピリミジニル;または((ジメチルアミノ)アセチル)ピペラジニルピリミジニルである;
R3bは、ピペラジニル−7,8−ジヒドロ−5H−1,6−ナフチリジニル;ピペラジニル−3,4−ジヒドロ−1H−イソキノリニル;ピペラジニルイソインドリニル;ピペラジニルフェニルアミノ;1,2,3,4−テトラヒドロイソキノリニル;またはメチルピペリジニルピペリジニルである;
R4は、メチルまたはHである;
化合物、またはその薬学的に許容され得る塩、鏡像異性体もしくはジアステレオマー。 - R3はR3aまたは−COR3bであり、ここで、R3aは、ピペラジニルで置換されたピリジニルであり、R3bは、ピペラジニルで置換されたイソインドリニルである、請求項2または3に記載の化合物、またはその薬学的に許容される塩、鏡像異性体もしくはジアステレオマー。
- 以下:
5−[(3R,5S)−3,5−ジメチル−4−[(4−ピペラジン−1−イルフェニル)メチル]ピペラジン−1−イル]キノリン−8−カルボニトリル;
5−[(3R、5R)−3,5−ジメチル−4−[(4−ピペラジン−1−イルフェニル)メチル]ピペラジン−1−イル]キノリン−8−カルボニトリル;
5−[(3R,5S)−3,5−ジメチル−4−[(6−ピペラジン−1−イル−3−ピリジル)メチル]ピペラジン−1−イル]キノリン−8−カルボニトリル;
5−[(3S、5R)−3,5−ジメチル−4−[(5−ピペラジン−1−イルピリミジン−2−イル)メチル]ピペラジン−1−イル]キノリン−8−カルボニトリル;
5−[(3S、5R)−3,5−ジメチル−4−[(5−ピペラジン−1−イル−2−ピリジル)メチル]ピペラジン−1−イル]キノリン−8−カルボニトリル;
5−[(3S、5R)−4−[[5−[4−[2−(ジメチルアミノ)アセチル]ピペラジン−1−イル]ピリミジン−2−イル]メチル]−3,5−ジメチル−ピペラジン−1−イル]キノリン−8−カルボニトリル;
5−[(3S、5R)−3,5−ジメチル−4−[[5−(4−メチルピペラジン−1−イル)−2−ピリジル]メチル]ピペラジン−1−イル]キノリン−8−カルボニトリル;
5−[(3S、5R)−3,5−ジメチル−4−[[5−(9−オキサ−3,7−ジアザビシクロ[3.3.1]ノナン−3−イル)−2−ピリジル]メチル]ピペラジン−1−イル]キノリン−8−カルボニトリル;
5−[(3R,5S)−3,5−ジメチル−4−[[5−[[(3R、4S)−4−フルオロピロリジン−3−イル]アミノ]−2−ピリジル]メチル]ピペラジン−1−イル]キノリン−8−カルボニトリル;
5−[(3R,5S)−3,5−ジメチル−4−[[5−[4−(ピロリジン−2−カルボニル)ピペラジン−1−イル]−2−ピリジル]メチル]ピペラジン−1−イル]キノリン−8−カルボニトリル;
5−[(3S、5R)−4−[[5−[4−[2−(ジメチルアミノ)アセチル]ピペラジン−1−イル]−2−ピリジル]メチル]−3,5−ジメチル−ピペラジン−1−イル]キノリン−8−カルボニトリル;
5−[(3R,5S)−4−[[4−[2−(ヒドロキシメチル)ピペラジン−1−イル]フェニル]メチル]−3,5−ジメチル−ピペラジン−1−イル]キノリン−8−カルボニトリル;
5−[(3R,5S)−3,5−ジメチル−4−[2−オキソ−2−(2−ピペラジン−1−イル−7,8−ジヒドロ−5H−1,6−ナフチリジン−6−イル)エチル]ピペラジン−1−イル]キノリン−8−カルボニトリル;
5−[(3R,5S)−3,5−ジメチル−4−[2−オキソ−2−(6−ピペラジン−1−イル−3,4−ジヒドロ−1H−イソキノリン−2−イル)エチル]ピペラジン−1−イル]キノリン−8−カルボニトリル;
5−[(3R,5S)−3,5−ジメチル−4−[2−オキソ−2−(7−ピペラジン−1−イル−3,4−ジヒドロ−1H−イソキノリン−2−イル)エチル]ピペラジン−1−イル]キノリン−8−カルボニトリル;
5−[(3R,5S)−3,5−ジメチル−4−[2−オキソ−2−(5−ピペラジン−1−イルイソインドリン−2−イル)エチル]ピペラジン−1−イル]キノリン−8−カルボニトリル;
2−[4−(8−シアノ−5−キノリル)−2−メチル−ピペラジン−1−イル]−N−(4−ピペラジン−1−イルフェニル)アセトアミド;
2−[4−(8−シアノ−5−キノリル)−2−メチル−ピペラジン−1−イル]−N−(1,2,3,4−テトラヒドロイソキノリン−6−イル)アセトアミド;および
5−[3−メチル−4−[2−[4−(1−メチル−4−ピペリジル)−1−ピペリジル]−2−オキソ−エチル]ピペラジン−1−イル]キノリン−8−カルボニトリル;
から選択される化合物、またはその薬学的に許容され得る塩、鏡像異性体もしくはジアステレオマー。 - 以下の工程:
a) カップリング試薬および塩基の存在下での、式(VI)の化合物、
およびアミンHR3bのカップリング反応;
b) 触媒および塩基の存在下での、式(X)の化合物、
およびアミンHR6のブッフバルト・ハートウィッグアミノ化反応;
のいずれかを含む、請求項1〜5のいずれか一項に記載の化合物の調製方法であって、
ステップa)において、前記カップリング試薬は、例えば、HATUであり得る;塩基は、例えば、DIPEAであり得る;
ステップb)において、前記触媒は、例えば、Ruphos Pd−G2であり得る;前記塩基は、例えば、Cs2CO3であり得る;Xは、ハロゲン、OTfまたはOMsである;Yは、NまたはCHである;R6は、ピペラジンである;R7は、Bocである;R8は、ベンジルである;R1、R2およびR4は、請求項1〜4のいずれか一項と同様に定義される、方法。 - 薬用活性物質として使用するための、請求項1〜5のいずれか一項に記載の化合物または薬学的に許容され得る塩、鏡像異性体もしくはジアステレオマー。
- 請求項1〜5のいずれか一項に記載の化合物と、治療上不活性である担体とを含む、医薬組成物。
- 全身性エリテマトーデスまたはループス腎炎の治療または予防のための、請求項1〜5のいずれか一項に記載の化合物の使用。
- 全身性エリテマトーデスまたはループス腎炎の治療または予防のための薬剤の調製のための、請求項1〜5のいずれか一項に記載の化合物の使用。
- TLR7アンタゴニストまたはTLR8アンタゴニストまたはTLR9アンタゴニストとしての、請求項1〜5のいずれか一項に記載の化合物の使用。
- TLR7アンタゴニストおよびTLR8アンタゴニストおよびTLR9アンタゴニストとしての、請求項1〜5のいずれか一項に記載の化合物の使用。
- TLR7アンタゴニストおよびTLR8アンタゴニストおよびTLR9アンタゴニストのための薬剤の調製のための、請求項1〜5のいずれか一項に記載の化合物の使用。
- 全身性エリテマトーデスまたはループス腎炎の治療または予防のための、請求項1〜5のいずれか一項に記載の化合物または薬学的に許容され得る塩、鏡像異性体もしくはジアステレオマー。
- 請求項6に記載の方法によって製造される場合の、請求項1〜5のいずれか一項に記載の化合物または薬学的許容され得る塩、鏡像異性体もしくはジアステレオマー。
- 全身性エリテマトーデスまたはループス腎炎の治療または予防のための方法であって、請求項1〜5のいずれか一項において定義される化合物の治療有効量を投与することを含む、方法。
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US11952363B2 (en) | 2024-04-09 |
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JP7366994B2 (ja) | 2023-10-23 |
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