JP2016510783A - ブロモドメイン阻害薬としてのフロピリジン - Google Patents
ブロモドメイン阻害薬としてのフロピリジン Download PDFInfo
- Publication number
- JP2016510783A JP2016510783A JP2015562111A JP2015562111A JP2016510783A JP 2016510783 A JP2016510783 A JP 2016510783A JP 2015562111 A JP2015562111 A JP 2015562111A JP 2015562111 A JP2015562111 A JP 2015562111A JP 2016510783 A JP2016510783 A JP 2016510783A
- Authority
- JP
- Japan
- Prior art keywords
- methyl
- pyridin
- methylsulfonyl
- furo
- piperazin
- 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
- 229940125763 bromodomain inhibitor Drugs 0.000 title claims description 15
- YRTCKZIKGWZNCU-UHFFFAOYSA-N furo[3,2-b]pyridine Chemical compound C1=CC=C2OC=CC2=N1 YRTCKZIKGWZNCU-UHFFFAOYSA-N 0.000 title 1
- 150000001875 compounds Chemical class 0.000 claims abstract description 252
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 29
- 238000002560 therapeutic procedure Methods 0.000 claims abstract description 6
- 150000003839 salts Chemical class 0.000 claims description 149
- 125000000217 alkyl group Chemical group 0.000 claims description 115
- -1 (4- (5-Methyl-2-((2-methyl-4- (methylsulfonyl) piperazin-1-yl) methyl) -4-oxo-4,5-dihydrofuro [3,2 -c] pyridin-7-yl) pyridin-2-yl) cyclopropanecarboxamide Chemical compound 0.000 claims description 91
- 229910052757 nitrogen Inorganic materials 0.000 claims description 58
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 56
- 229910052799 carbon Inorganic materials 0.000 claims description 52
- 125000002947 alkylene group Chemical group 0.000 claims description 46
- 229910052739 hydrogen Inorganic materials 0.000 claims description 43
- 125000000623 heterocyclic group Chemical group 0.000 claims description 41
- 238000000034 method Methods 0.000 claims description 40
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 37
- DLFVBJFMPXGRIB-UHFFFAOYSA-N Acetamide Chemical compound CC(N)=O DLFVBJFMPXGRIB-UHFFFAOYSA-N 0.000 claims description 36
- 201000010099 disease Diseases 0.000 claims description 35
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 34
- 206010028980 Neoplasm Diseases 0.000 claims description 27
- 201000011510 cancer Diseases 0.000 claims description 25
- 239000003814 drug Substances 0.000 claims description 24
- 125000006272 (C3-C7) cycloalkyl group Chemical group 0.000 claims description 23
- 125000005843 halogen group Chemical group 0.000 claims description 22
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 20
- 229910052720 vanadium Inorganic materials 0.000 claims description 20
- 230000001154 acute effect Effects 0.000 claims description 19
- XEEYBQQBJWHFJM-UHFFFAOYSA-N Iron Chemical compound [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 claims description 18
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 18
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 17
- FYNCIYHECMWXPK-UHFFFAOYSA-N 5h-furo[3,2-c]pyridin-4-one Chemical group O=C1NC=CC2=C1C=CO2 FYNCIYHECMWXPK-UHFFFAOYSA-N 0.000 claims description 16
- 125000001153 fluoro group Chemical group F* 0.000 claims description 14
- 125000004105 2-pyridyl group Chemical group N1=C([*])C([H])=C([H])C([H])=C1[H] 0.000 claims description 13
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 claims description 13
- 238000004519 manufacturing process Methods 0.000 claims description 13
- 230000001684 chronic effect Effects 0.000 claims description 12
- 230000001363 autoimmune Effects 0.000 claims description 11
- 208000036142 Viral infection Diseases 0.000 claims description 10
- 230000004968 inflammatory condition Effects 0.000 claims description 10
- 229910052760 oxygen Inorganic materials 0.000 claims description 10
- 230000009385 viral infection Effects 0.000 claims description 10
- 239000013543 active substance Substances 0.000 claims description 9
- ZEXMGFHHBCQZFB-TZHYSIJRSA-N 5-methyl-2-[[(2r)-2-methyl-4-methylsulfonylpiperazin-1-yl]methyl]-7-[3-(oxetan-2-ylmethoxy)pyridin-4-yl]furo[3,2-c]pyridin-4-one Chemical compound C[C@@H]1CN(S(C)(=O)=O)CCN1CC1=CC(C(N(C)C=C2C=3C(=CN=CC=3)OCC3OCC3)=O)=C2O1 ZEXMGFHHBCQZFB-TZHYSIJRSA-N 0.000 claims description 8
- 125000004432 carbon atom Chemical group C* 0.000 claims description 8
- 230000028709 inflammatory response Effects 0.000 claims description 8
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 8
- 208000030852 Parasitic disease Diseases 0.000 claims description 7
- 230000001580 bacterial effect Effects 0.000 claims description 7
- 239000003085 diluting agent Substances 0.000 claims description 7
- 230000002538 fungal effect Effects 0.000 claims description 7
- 125000004076 pyridyl group Chemical group 0.000 claims description 7
- 125000001424 substituent group Chemical group 0.000 claims description 7
- 239000003053 toxin Substances 0.000 claims description 7
- 231100000765 toxin Toxicity 0.000 claims description 7
- 108700012359 toxins Proteins 0.000 claims description 7
- 230000003612 virological effect Effects 0.000 claims description 7
- ZEXMGFHHBCQZFB-SJORKVTESA-N 5-methyl-2-[[(2r)-2-methyl-4-methylsulfonylpiperazin-1-yl]methyl]-7-[3-[[(2s)-oxetan-2-yl]methoxy]pyridin-4-yl]furo[3,2-c]pyridin-4-one Chemical compound C[C@@H]1CN(S(C)(=O)=O)CCN1CC1=CC(C(N(C)C=C2C=3C(=CN=CC=3)OC[C@H]3OCC3)=O)=C2O1 ZEXMGFHHBCQZFB-SJORKVTESA-N 0.000 claims description 6
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 6
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 6
- 239000003937 drug carrier Substances 0.000 claims description 5
- JJTCJPMDVVZKFT-UHFFFAOYSA-N n-[4-[2-[(3,3-difluoropiperidin-1-yl)methyl]-5-methyl-4-oxofuro[3,2-c]pyridin-7-yl]pyridin-2-yl]acetamide Chemical compound C1=NC(NC(=O)C)=CC(C=2C=3OC(CN4CC(F)(F)CCC4)=CC=3C(=O)N(C)C=2)=C1 JJTCJPMDVVZKFT-UHFFFAOYSA-N 0.000 claims description 5
- FDLRRZYLHCNCKI-UHFFFAOYSA-N 5-methyl-2-(morpholin-4-ylmethyl)-7-[2-(oxan-4-ylmethoxy)pyridin-4-yl]furo[3,2-c]pyridin-4-one Chemical compound C1=2OC(CN3CCOCC3)=CC=2C(=O)N(C)C=C1C(C=1)=CC=NC=1OCC1CCOCC1 FDLRRZYLHCNCKI-UHFFFAOYSA-N 0.000 claims description 4
- YYLOVEDYTPNZLM-UHFFFAOYSA-N 5-methyl-2-[(4-methylsulfonylpiperazin-1-yl)methyl]-7-(3-phenylmethoxyphenyl)furo[3,2-c]pyridin-4-one Chemical compound C1=2OC(CN3CCN(CC3)S(C)(=O)=O)=CC=2C(=O)N(C)C=C1C(C=1)=CC=CC=1OCC1=CC=CC=C1 YYLOVEDYTPNZLM-UHFFFAOYSA-N 0.000 claims description 4
- VJSUIISNWBLXEU-UHFFFAOYSA-N 5-methyl-2-[(4-methylsulfonylpiperazin-1-yl)methyl]-7-[2-(1-phenylethylamino)pyridin-4-yl]furo[3,2-c]pyridin-4-one Chemical compound C=1C=CC=CC=1C(C)NC(N=CC=1)=CC=1C(C=1O2)=CN(C)C(=O)C=1C=C2CN1CCN(S(C)(=O)=O)CC1 VJSUIISNWBLXEU-UHFFFAOYSA-N 0.000 claims description 4
- ORGIADDXKMFHEG-UHFFFAOYSA-N 5-methyl-2-[(4-methylsulfonylpiperazin-1-yl)methyl]-7-[2-(oxan-4-ylmethoxy)pyridin-4-yl]furo[3,2-c]pyridin-4-one Chemical compound C1=2OC(CN3CCN(CC3)S(C)(=O)=O)=CC=2C(=O)N(C)C=C1C(C=1)=CC=NC=1OCC1CCOCC1 ORGIADDXKMFHEG-UHFFFAOYSA-N 0.000 claims description 4
- WEMVJRAJRHBMHP-UHFFFAOYSA-N 5-methyl-2-[(4-methylsulfonylpiperazin-1-yl)methyl]-7-[3-(1-phenylethylamino)phenyl]furo[3,2-c]pyridin-4-one Chemical compound C=1C=CC=CC=1C(C)NC(C=1)=CC=CC=1C(C=1O2)=CN(C)C(=O)C=1C=C2CN1CCN(S(C)(=O)=O)CC1 WEMVJRAJRHBMHP-UHFFFAOYSA-N 0.000 claims description 4
- FZCIRGODGLUISW-UHFFFAOYSA-N 5-methyl-2-[(4-methylsulfonylpiperazin-1-yl)methyl]-7-[5-(1-phenylethoxy)pyridin-3-yl]furo[3,2-c]pyridin-4-one Chemical compound C=1C=CC=CC=1C(C)OC(C=1)=CN=CC=1C(C=1O2)=CN(C)C(=O)C=1C=C2CN1CCN(S(C)(=O)=O)CC1 FZCIRGODGLUISW-UHFFFAOYSA-N 0.000 claims description 4
- CZTJIXVUZMIAJF-LJQANCHMSA-N 5-methyl-2-[[(2r)-2-methyl-4-methylsulfonylpiperazin-1-yl]methyl]-7-[2-(2-pyrrolidin-1-ylethoxy)pyridin-4-yl]furo[3,2-c]pyridin-4-one Chemical compound C[C@@H]1CN(S(C)(=O)=O)CCN1CC1=CC(C(N(C)C=C2C=3C=C(OCCN4CCCC4)N=CC=3)=O)=C2O1 CZTJIXVUZMIAJF-LJQANCHMSA-N 0.000 claims description 4
- JBFGXWICIPTWHK-GOSISDBHSA-N 5-methyl-2-[[(2r)-2-methyl-4-methylsulfonylpiperazin-1-yl]methyl]-7-[2-[2-(2-oxopyrrolidin-1-yl)ethoxy]pyridin-4-yl]furo[3,2-c]pyridin-4-one Chemical compound C[C@@H]1CN(S(C)(=O)=O)CCN1CC1=CC(C(N(C)C=C2C=3C=C(OCCN4C(CCC4)=O)N=CC=3)=O)=C2O1 JBFGXWICIPTWHK-GOSISDBHSA-N 0.000 claims description 4
- ZEXMGFHHBCQZFB-IAGOWNOFSA-N 5-methyl-2-[[(2r)-2-methyl-4-methylsulfonylpiperazin-1-yl]methyl]-7-[3-[[(2r)-oxetan-2-yl]methoxy]pyridin-4-yl]furo[3,2-c]pyridin-4-one Chemical compound C[C@@H]1CN(S(C)(=O)=O)CCN1CC1=CC(C(N(C)C=C2C=3C(=CN=CC=3)OC[C@@H]3OCC3)=O)=C2O1 ZEXMGFHHBCQZFB-IAGOWNOFSA-N 0.000 claims description 4
- UGUGLNIFVYATCV-UHFFFAOYSA-N 5-methyl-7-[2-(oxan-4-ylmethoxy)pyridin-4-yl]-2-(1,4-oxazepan-4-ylmethyl)furo[3,2-c]pyridin-4-one Chemical compound C1=2OC(CN3CCOCCC3)=CC=2C(=O)N(C)C=C1C(C=1)=CC=NC=1OCC1CCOCC1 UGUGLNIFVYATCV-UHFFFAOYSA-N 0.000 claims description 4
- UVHOTKWPYIGJOA-UHFFFAOYSA-N 7-(3,4-dimethoxyphenyl)-5-methyl-2-(morpholin-4-ylmethyl)furo[3,2-c]pyridin-4-one Chemical compound C1=C(OC)C(OC)=CC=C1C1=CN(C)C(=O)C2=C1OC(CN1CCOCC1)=C2 UVHOTKWPYIGJOA-UHFFFAOYSA-N 0.000 claims description 4
- SBTNGPOTCXTYMB-UHFFFAOYSA-N 7-(3,4-dimethoxyphenyl)-5-methyl-2-[(3-methylmorpholin-4-yl)methyl]furo[3,2-c]pyridin-4-one Chemical compound C1=C(OC)C(OC)=CC=C1C1=CN(C)C(=O)C2=C1OC(CN1C(COCC1)C)=C2 SBTNGPOTCXTYMB-UHFFFAOYSA-N 0.000 claims description 4
- SVUMANNVOCNDAY-UHFFFAOYSA-N 7-(3,4-dimethoxyphenyl)-5-methyl-2-[(4-methylsulfonylpiperazin-1-yl)methyl]furo[2,3-d]pyridazin-4-one Chemical compound COC=1C=C(C=CC1OC)C1=NN(C(C2=C1OC(=C2)CN2CCN(CC2)S(=O)(=O)C)=O)C SVUMANNVOCNDAY-UHFFFAOYSA-N 0.000 claims description 4
- VPGFVXUZUMEVBI-UHFFFAOYSA-N 7-(3,4-dimethoxyphenyl)-5-methyl-2-[(4-methylsulfonylpiperazin-1-yl)methyl]furo[3,2-c]pyridin-4-one Chemical compound C1=C(OC)C(OC)=CC=C1C1=CN(C)C(=O)C2=C1OC(CN1CCN(CC1)S(C)(=O)=O)=C2 VPGFVXUZUMEVBI-UHFFFAOYSA-N 0.000 claims description 4
- NQSYBFFTCCDUGQ-OAHLLOKOSA-N 7-(3,4-dimethoxyphenyl)-5-methyl-2-[[(2r)-2-methyl-4-methylsulfonylpiperazin-1-yl]methyl]furo[3,2-c]pyridin-4-one Chemical compound C1=C(OC)C(OC)=CC=C1C1=CN(C)C(=O)C2=C1OC(CN1[C@@H](CN(CC1)S(C)(=O)=O)C)=C2 NQSYBFFTCCDUGQ-OAHLLOKOSA-N 0.000 claims description 4
- QETXRIOCXCNBFV-MRXNPFEDSA-N 7-[2-(cyclopropylmethoxy)pyridin-4-yl]-5-methyl-2-[[(2r)-2-methyl-4-methylsulfonylpiperazin-1-yl]methyl]furo[3,2-c]pyridin-4-one Chemical compound C[C@@H]1CN(S(C)(=O)=O)CCN1CC1=CC(C(N(C)C=C2C=3C=C(OCC4CC4)N=CC=3)=O)=C2O1 QETXRIOCXCNBFV-MRXNPFEDSA-N 0.000 claims description 4
- AHCHFHKAQDTGRP-UHFFFAOYSA-N 7-[3-(benzylamino)phenyl]-5-methyl-2-[(4-methylsulfonylpiperazin-1-yl)methyl]furo[3,2-c]pyridin-4-one Chemical compound C1=2OC(CN3CCN(CC3)S(C)(=O)=O)=CC=2C(=O)N(C)C=C1C(C=1)=CC=CC=1NCC1=CC=CC=C1 AHCHFHKAQDTGRP-UHFFFAOYSA-N 0.000 claims description 4
- HCVSIOCDDCCEEX-UHFFFAOYSA-N 7-[3-(cyclopropylmethoxy)pyridin-4-yl]-5-methyl-2-[(4-methylsulfonylpiperazin-1-yl)methyl]furo[3,2-c]pyridin-4-one Chemical compound C1=2OC(CN3CCN(CC3)S(C)(=O)=O)=CC=2C(=O)N(C)C=C1C1=CC=NC=C1OCC1CC1 HCVSIOCDDCCEEX-UHFFFAOYSA-N 0.000 claims description 4
- PQMREPVBNKVBFM-MRXNPFEDSA-N 7-[3-(cyclopropylmethoxy)pyridin-4-yl]-5-methyl-2-[[(2R)-2-methyl-4-methylsulfonylpiperazin-1-yl]methyl]furo[3,2-c]pyridin-4-one Chemical compound C1(CC1)COC=1C=NC=CC1C=1C2=C(C(N(C1)C)=O)C=C(O2)CN2[C@@H](CN(CC2)S(=O)(=O)C)C PQMREPVBNKVBFM-MRXNPFEDSA-N 0.000 claims description 4
- ZRIWCCGYWSMJPP-UHFFFAOYSA-N 7-[3-(cyclopropylmethylamino)pyridin-4-yl]-5-methyl-2-[(4-methylsulfonylpiperazin-1-yl)methyl]furo[3,2-c]pyridin-4-one Chemical compound C1=2OC(CN3CCN(CC3)S(C)(=O)=O)=CC=2C(=O)N(C)C=C1C1=CC=NC=C1NCC1CC1 ZRIWCCGYWSMJPP-UHFFFAOYSA-N 0.000 claims description 4
- NNADKDPXRPINPF-AAFJCEBUSA-N 7-[3-[(2,2-difluorocyclopropyl)methoxy]pyridin-4-yl]-5-methyl-2-[[(2r)-2-methyl-4-methylsulfonylpiperazin-1-yl]methyl]furo[3,2-c]pyridin-4-one Chemical compound C[C@@H]1CN(S(C)(=O)=O)CCN1CC1=CC(C(N(C)C=C2C=3C(=CN=CC=3)OCC3C(C3)(F)F)=O)=C2O1 NNADKDPXRPINPF-AAFJCEBUSA-N 0.000 claims description 4
- YWNGWHICJNAASW-CQSZACIVSA-N N-[4-[5-methyl-2-[(1R)-1-(4-methylsulfonylpiperazin-1-yl)ethyl]-4-oxofuro[3,2-c]pyridin-7-yl]pyridin-2-yl]acetamide Chemical compound CN1C(C2=C(C(=C1)C1=CC(=NC=C1)NC(C)=O)OC(=C2)[C@@H](C)N2CCN(CC2)S(=O)(=O)C)=O YWNGWHICJNAASW-CQSZACIVSA-N 0.000 claims description 4
- ASSGIDPIKQABBH-OAHLLOKOSA-N N-methyl-N-[4-[5-methyl-2-[[(2R)-2-methyl-4-methylsulfonylpiperazin-1-yl]methyl]-4-oxofuro[3,2-c]pyridin-7-yl]pyridin-2-yl]acetamide Chemical compound CN(C(C)=O)C1=NC=CC(=C1)C=1C2=C(C(N(C1)C)=O)C=C(O2)CN2[C@@H](CN(CC2)S(=O)(=O)C)C ASSGIDPIKQABBH-OAHLLOKOSA-N 0.000 claims description 4
- YWNGWHICJNAASW-AWEZNQCLSA-N n-[4-[5-methyl-2-[(1s)-1-(4-methylsulfonylpiperazin-1-yl)ethyl]-4-oxofuro[3,2-c]pyridin-7-yl]pyridin-2-yl]acetamide Chemical compound N1([C@@H](C)C=2OC3=C(C(N(C)C=C3C=3C=C(NC(C)=O)N=CC=3)=O)C=2)CCN(S(C)(=O)=O)CC1 YWNGWHICJNAASW-AWEZNQCLSA-N 0.000 claims description 4
- QQTMSFFWDWGMFQ-UHFFFAOYSA-N n-[4-[5-methyl-2-[(4-methylsulfonylpiperazin-1-yl)methyl]-4-oxofuro[3,2-c]pyridin-7-yl]pyridin-2-yl]acetamide Chemical compound C1=NC(NC(=O)C)=CC(C=2C=3OC(CN4CCN(CC4)S(C)(=O)=O)=CC=3C(=O)N(C)C=2)=C1 QQTMSFFWDWGMFQ-UHFFFAOYSA-N 0.000 claims description 4
- YWNGWHICJNAASW-UHFFFAOYSA-N n-[4-[5-methyl-2-[1-(4-methylsulfonylpiperazin-1-yl)ethyl]-4-oxofuro[3,2-c]pyridin-7-yl]pyridin-2-yl]acetamide Chemical compound C=1C(C(N(C)C=C2C=3C=C(NC(C)=O)N=CC=3)=O)=C2OC=1C(C)N1CCN(S(C)(=O)=O)CC1 YWNGWHICJNAASW-UHFFFAOYSA-N 0.000 claims description 4
- MCTBSAVNHXJNFR-CQSZACIVSA-N n-[4-[5-methyl-2-[[(2r)-2-methyl-4-methylsulfonylpiperazin-1-yl]methyl]-4-oxofuro[3,2-c]pyridin-7-yl]pyridin-2-yl]acetamide Chemical compound C[C@@H]1CN(S(C)(=O)=O)CCN1CC1=CC(C(N(C)C=C2C=3C=C(NC(C)=O)N=CC=3)=O)=C2O1 MCTBSAVNHXJNFR-CQSZACIVSA-N 0.000 claims description 4
- ASNAWWMWJGMFDW-CQSZACIVSA-N n-[5-[5-methyl-2-[[(2r)-2-methyl-4-methylsulfonylpiperazin-1-yl]methyl]-4-oxofuro[3,2-c]pyridin-7-yl]pyridin-3-yl]acetamide Chemical compound C[C@@H]1CN(S(C)(=O)=O)CCN1CC1=CC(C(N(C)C=C2C=3C=C(NC(C)=O)C=NC=3)=O)=C2O1 ASNAWWMWJGMFDW-CQSZACIVSA-N 0.000 claims description 4
- 125000003566 oxetanyl group Chemical group 0.000 claims description 4
- 125000000719 pyrrolidinyl group Chemical group 0.000 claims description 4
- VVULLKQYMRSJHE-UHFFFAOYSA-N 2-(1,4-diazepan-1-ylmethyl)-7-(3,4-dimethoxyphenyl)-5-methylfuro[3,2-c]pyridin-4-one Chemical compound C1=C(OC)C(OC)=CC=C1C1=CN(C)C(=O)C2=C1OC(CN1CCNCCC1)=C2 VVULLKQYMRSJHE-UHFFFAOYSA-N 0.000 claims description 3
- XZBPCZMBXNAIQV-UHFFFAOYSA-N 2-[(3,3-difluoropiperidin-1-yl)methyl]-5-methyl-7-[2-(oxan-4-ylmethoxy)pyridin-4-yl]furo[3,2-c]pyridin-4-one Chemical compound C1=2OC(CN3CC(F)(F)CCC3)=CC=2C(=O)N(C)C=C1C(C=1)=CC=NC=1OCC1CCOCC1 XZBPCZMBXNAIQV-UHFFFAOYSA-N 0.000 claims description 3
- LJYRYWKCKYKAET-GOSISDBHSA-N 5-methyl-2-[(1r)-1-(4-methylsulfonylpiperazin-1-yl)ethyl]-7-[2-(oxan-4-ylmethoxy)pyridin-4-yl]furo[3,2-c]pyridin-4-one Chemical compound N1([C@H](C)C=2OC3=C(C(N(C)C=C3C=3C=C(OCC4CCOCC4)N=CC=3)=O)C=2)CCN(S(C)(=O)=O)CC1 LJYRYWKCKYKAET-GOSISDBHSA-N 0.000 claims description 3
- LJYRYWKCKYKAET-SFHVURJKSA-N 5-methyl-2-[(1s)-1-(4-methylsulfonylpiperazin-1-yl)ethyl]-7-[2-(oxan-4-ylmethoxy)pyridin-4-yl]furo[3,2-c]pyridin-4-one Chemical compound N1([C@@H](C)C=2OC3=C(C(N(C)C=C3C=3C=C(OCC4CCOCC4)N=CC=3)=O)C=2)CCN(S(C)(=O)=O)CC1 LJYRYWKCKYKAET-SFHVURJKSA-N 0.000 claims description 3
- LXQMPGUFEUSBHM-UHFFFAOYSA-N 5-methyl-2-[(4-methylsulfonylpiperazin-1-yl)methyl]-7-[2-(oxan-4-ylmethoxy)pyridin-4-yl]furo[2,3-d]pyridazin-4-one Chemical compound CN1N=C(C2=C(C1=O)C=C(O2)CN2CCN(CC2)S(=O)(=O)C)C2=CC(=NC=C2)OCC2CCOCC2 LXQMPGUFEUSBHM-UHFFFAOYSA-N 0.000 claims description 3
- LJYRYWKCKYKAET-UHFFFAOYSA-N 5-methyl-2-[1-(4-methylsulfonylpiperazin-1-yl)ethyl]-7-[2-(oxan-4-ylmethoxy)pyridin-4-yl]furo[3,2-c]pyridin-4-one Chemical compound C=1C(C(N(C)C=C2C=3C=C(OCC4CCOCC4)N=CC=3)=O)=C2OC=1C(C)N1CCN(S(C)(=O)=O)CC1 LJYRYWKCKYKAET-UHFFFAOYSA-N 0.000 claims description 3
- LDNCGMMSYNRWBO-MRXNPFEDSA-N 5-methyl-2-[[(2r)-2-methyl-4-methylsulfonylpiperazin-1-yl]methyl]-7-[3-(oxetan-3-ylmethoxy)pyridin-4-yl]furo[3,2-c]pyridin-4-one Chemical compound C[C@@H]1CN(S(C)(=O)=O)CCN1CC1=CC(C(N(C)C=C2C=3C(=CN=CC=3)OCC3COC3)=O)=C2O1 LDNCGMMSYNRWBO-MRXNPFEDSA-N 0.000 claims description 3
- GAJMGOCHIMRYAH-UHFFFAOYSA-N 7-(3,4-dimethoxyphenyl)-5-methyl-2-(piperidin-1-ylmethyl)furo[3,2-c]pyridin-4-one Chemical compound C1=C(OC)C(OC)=CC=C1C1=CN(C)C(=O)C2=C1OC(CN1CCCCC1)=C2 GAJMGOCHIMRYAH-UHFFFAOYSA-N 0.000 claims description 3
- KIWPYLUFZAGLGZ-MRXNPFEDSA-N 7-[2-(2-methoxyethoxy)pyridin-4-yl]-5-methyl-2-[[(2r)-2-methyl-4-methylsulfonylpiperazin-1-yl]methyl]furo[3,2-c]pyridin-4-one Chemical compound C1=NC(OCCOC)=CC(C=2C=3OC(CN4[C@@H](CN(CC4)S(C)(=O)=O)C)=CC=3C(=O)N(C)C=2)=C1 KIWPYLUFZAGLGZ-MRXNPFEDSA-N 0.000 claims description 3
- DDNKKCFLCRCHDR-MRXNPFEDSA-N 7-[3-(cyclopropylmethylamino)pyridin-4-yl]-5-methyl-2-[[(2r)-2-methyl-4-methylsulfonylpiperazin-1-yl]methyl]furo[3,2-c]pyridin-4-one Chemical compound C[C@@H]1CN(S(C)(=O)=O)CCN1CC1=CC(C(N(C)C=C2C=3C(=CN=CC=3)NCC3CC3)=O)=C2O1 DDNKKCFLCRCHDR-MRXNPFEDSA-N 0.000 claims description 3
- HZGGLQPIMIBGMU-UHFFFAOYSA-N n-[4-[2-[(3-fluoropiperidin-1-yl)methyl]-5-methyl-4-oxofuro[3,2-c]pyridin-7-yl]pyridin-2-yl]acetamide Chemical compound C1=NC(NC(=O)C)=CC(C=2C=3OC(CN4CC(F)CCC4)=CC=3C(=O)N(C)C=2)=C1 HZGGLQPIMIBGMU-UHFFFAOYSA-N 0.000 claims description 3
- JUWVNUCBAGPWBE-UHFFFAOYSA-N n-[4-[5-methyl-2-[2-(4-methylsulfonylpiperazin-1-yl)propan-2-yl]-4-oxofuro[3,2-c]pyridin-7-yl]pyridin-2-yl]acetamide Chemical compound C1=NC(NC(=O)C)=CC(C=2C=3OC(=CC=3C(=O)N(C)C=2)C(C)(C)N2CCN(CC2)S(C)(=O)=O)=C1 JUWVNUCBAGPWBE-UHFFFAOYSA-N 0.000 claims description 3
- GCELDXCALWQMOW-OAHLLOKOSA-N n-[4-[5-methyl-2-[[(2r)-2-methyl-4-methylsulfonylpiperazin-1-yl]methyl]-4-oxofuro[3,2-c]pyridin-7-yl]pyridin-2-yl]propanamide Chemical compound C1=NC(NC(=O)CC)=CC(C=2C=3OC(CN4[C@@H](CN(CC4)S(C)(=O)=O)C)=CC=3C(=O)N(C)C=2)=C1 GCELDXCALWQMOW-OAHLLOKOSA-N 0.000 claims description 3
- 125000003718 tetrahydrofuranyl group Chemical group 0.000 claims description 3
- SKWUKCZJCFEDGL-UHFFFAOYSA-N 2-(1,4-diazepan-1-ylmethyl)-5-methyl-7-[2-(pyridin-2-ylmethylamino)pyridin-4-yl]furo[3,2-c]pyridin-4-one Chemical compound C1=2OC(CN3CCNCCC3)=CC=2C(=O)N(C)C=C1C(C=1)=CC=NC=1NCC1=CC=CC=N1 SKWUKCZJCFEDGL-UHFFFAOYSA-N 0.000 claims description 2
- WUQUNDCQNMGOJS-UHFFFAOYSA-N 2-[(2-aminoethylamino)methyl]-7-(3,4-dimethoxyphenyl)-5-methylfuro[3,2-c]pyridin-4-one Chemical compound C1=C(OC)C(OC)=CC=C1C1=CN(C)C(=O)C2=C1OC(CNCCN)=C2 WUQUNDCQNMGOJS-UHFFFAOYSA-N 0.000 claims description 2
- DDBJXQIYRNMXCR-UHFFFAOYSA-N 2-[(3-fluoropiperidin-1-yl)methyl]-7-(4-methoxyphenyl)-5-methylfuro[3,2-c]pyridin-4-one Chemical compound C1=CC(OC)=CC=C1C1=CN(C)C(=O)C2=C1OC(CN1CC(F)CCC1)=C2 DDBJXQIYRNMXCR-UHFFFAOYSA-N 0.000 claims description 2
- 125000004485 2-pyrrolidinyl group Chemical group [H]N1C([H])([H])C([H])([H])C([H])([H])C1([H])* 0.000 claims description 2
- XGYILSHXIHSUOO-UHFFFAOYSA-N 3-(cyclopropylmethoxy)-4-[5-methyl-2-[(4-methylsulfonylpiperazin-1-yl)methyl]-4-oxofuro[3,2-c]pyridin-7-yl]benzoic acid Chemical compound C1=2OC(CN3CCN(CC3)S(C)(=O)=O)=CC=2C(=O)N(C)C=C1C1=CC=C(C(O)=O)C=C1OCC1CC1 XGYILSHXIHSUOO-UHFFFAOYSA-N 0.000 claims description 2
- DSTYYMIHIUMGID-CYBMUJFWSA-N 5-methyl-2-[[(2r)-2-methyl-4-methylsulfonylpiperazin-1-yl]methyl]-7-(2-oxo-1,3-dihydropyrrolo[2,3-b]pyridin-4-yl)furo[3,2-c]pyridin-4-one Chemical compound C[C@@H]1CN(S(C)(=O)=O)CCN1CC1=CC(C(N(C)C=C2C=3C=4CC(=O)NC=4N=CC=3)=O)=C2O1 DSTYYMIHIUMGID-CYBMUJFWSA-N 0.000 claims description 2
- ANZGHRYXXJSLFU-MRXNPFEDSA-N 5-methyl-2-[[(2r)-2-methyl-4-methylsulfonylpiperazin-1-yl]methyl]-7-(3-propan-2-yloxypyridin-4-yl)furo[3,2-c]pyridin-4-one Chemical compound CC(C)OC1=CN=CC=C1C1=CN(C)C(=O)C2=C1OC(CN1[C@@H](CN(CC1)S(C)(=O)=O)C)=C2 ANZGHRYXXJSLFU-MRXNPFEDSA-N 0.000 claims description 2
- ZYZMKDLDCHNQEM-OAHLLOKOSA-N 5-methyl-2-[[(2r)-2-methyl-4-methylsulfonylpiperazin-1-yl]methyl]-7-[3-(oxetan-3-yloxy)pyridin-4-yl]furo[3,2-c]pyridin-4-one Chemical compound C[C@@H]1CN(S(C)(=O)=O)CCN1CC1=CC(C(N(C)C=C2C=3C(=CN=CC=3)OC3COC3)=O)=C2O1 ZYZMKDLDCHNQEM-OAHLLOKOSA-N 0.000 claims description 2
- XIMCNZHZTMYTKK-TZHYSIJRSA-N 5-methyl-2-[[(2r)-2-methyl-4-methylsulfonylpiperazin-1-yl]methyl]-7-[3-(oxolan-3-yloxy)pyridin-4-yl]furo[3,2-c]pyridin-4-one Chemical compound C[C@@H]1CN(S(C)(=O)=O)CCN1CC1=CC(C(N(C)C=C2C=3C(=CN=CC=3)OC3COCC3)=O)=C2O1 XIMCNZHZTMYTKK-TZHYSIJRSA-N 0.000 claims description 2
- GPNARNKKVSQDKQ-GOSISDBHSA-N 5-methyl-2-[[(2r)-2-methyl-4-methylsulfonylpiperazin-1-yl]methyl]-7-[3-[2-(2-oxopyrrolidin-1-yl)ethoxy]pyridin-4-yl]furo[3,2-c]pyridin-4-one Chemical compound C[C@@H]1CN(S(C)(=O)=O)CCN1CC1=CC(C(N(C)C=C2C=3C(=CN=CC=3)OCCN3C(CCC3)=O)=O)=C2O1 GPNARNKKVSQDKQ-GOSISDBHSA-N 0.000 claims description 2
- HVJNEUPSYMMECJ-CYBMUJFWSA-N 7-(2-aminopyridin-4-yl)-5-methyl-2-[[(2r)-2-methyl-4-methylsulfonylpiperazin-1-yl]methyl]furo[3,2-c]pyridin-4-one Chemical compound C[C@@H]1CN(S(C)(=O)=O)CCN1CC1=CC(C(N(C)C=C2C=3C=C(N)N=CC=3)=O)=C2O1 HVJNEUPSYMMECJ-CYBMUJFWSA-N 0.000 claims description 2
- PZYFABOJKXAFSS-CQSZACIVSA-N 7-(3-aminophenyl)-5-methyl-2-[[(2r)-2-methyl-4-methylsulfonylpiperazin-1-yl]methyl]furo[3,2-c]pyridin-4-one Chemical compound C[C@@H]1CN(S(C)(=O)=O)CCN1CC1=CC(C(N(C)C=C2C=3C=C(N)C=CC=3)=O)=C2O1 PZYFABOJKXAFSS-CQSZACIVSA-N 0.000 claims description 2
- WWQFFZOCZFZRSP-OAHLLOKOSA-N 7-(3-cyclopropyloxypyridin-4-yl)-5-methyl-2-[[(2r)-2-methyl-4-methylsulfonylpiperazin-1-yl]methyl]furo[3,2-c]pyridin-4-one Chemical compound C[C@@H]1CN(S(C)(=O)=O)CCN1CC1=CC(C(N(C)C=C2C=3C(=CN=CC=3)OC3CC3)=O)=C2O1 WWQFFZOCZFZRSP-OAHLLOKOSA-N 0.000 claims description 2
- YADJSPPQXGQMCB-OAHLLOKOSA-N 7-(3-ethoxypyridin-4-yl)-5-methyl-2-[[(2r)-2-methyl-4-methylsulfonylpiperazin-1-yl]methyl]furo[3,2-c]pyridin-4-one Chemical compound CCOC1=CN=CC=C1C1=CN(C)C(=O)C2=C1OC(CN1[C@@H](CN(CC1)S(C)(=O)=O)C)=C2 YADJSPPQXGQMCB-OAHLLOKOSA-N 0.000 claims description 2
- PSNZFFGOHFCPKC-CYBMUJFWSA-N 7-(3-hydroxypyridin-4-yl)-5-methyl-2-[[(2r)-2-methyl-4-methylsulfonylpiperazin-1-yl]methyl]furo[3,2-c]pyridin-4-one Chemical compound C[C@@H]1CN(S(C)(=O)=O)CCN1CC1=CC(C(N(C)C=C2C=3C(=CN=CC=3)O)=O)=C2O1 PSNZFFGOHFCPKC-CYBMUJFWSA-N 0.000 claims description 2
- SJNJBIGYYCYNFE-MRXNPFEDSA-N 7-[2-(cyclopropylmethylamino)pyridin-3-yl]-5-methyl-2-[[(2r)-2-methyl-4-methylsulfonylpiperazin-1-yl]methyl]furo[3,2-c]pyridin-4-one Chemical compound C[C@@H]1CN(S(C)(=O)=O)CCN1CC1=CC(C(N(C)C=C2C=3C(=NC=CC=3)NCC3CC3)=O)=C2O1 SJNJBIGYYCYNFE-MRXNPFEDSA-N 0.000 claims description 2
- KXDRQTINKBLAEK-TZHYSIJRSA-N 7-[3-(1-methoxypropan-2-yloxy)pyridin-4-yl]-5-methyl-2-[[(2R)-2-methyl-4-methylsulfonylpiperazin-1-yl]methyl]furo[3,2-c]pyridin-4-one Chemical compound COCC(C)OC=1C=NC=CC1C=1C2=C(C(N(C1)C)=O)C=C(O2)CN2[C@@H](CN(CC2)S(=O)(=O)C)C KXDRQTINKBLAEK-TZHYSIJRSA-N 0.000 claims description 2
- XDBXEJKUSHELKX-CQSZACIVSA-N 7-[3-(2,2-difluoroethoxy)pyridin-4-yl]-5-methyl-2-[[(2r)-2-methyl-4-methylsulfonylpiperazin-1-yl]methyl]furo[3,2-c]pyridin-4-one Chemical compound C[C@@H]1CN(S(C)(=O)=O)CCN1CC1=CC(C(N(C)C=C2C=3C(=CN=CC=3)OCC(F)F)=O)=C2O1 XDBXEJKUSHELKX-CQSZACIVSA-N 0.000 claims description 2
- DOVCDUXMNSLCHD-OAHLLOKOSA-N 7-[3-(2-fluoroethoxy)pyridin-4-yl]-5-methyl-2-[[(2r)-2-methyl-4-methylsulfonylpiperazin-1-yl]methyl]furo[3,2-c]pyridin-4-one Chemical compound C[C@@H]1CN(S(C)(=O)=O)CCN1CC1=CC(C(N(C)C=C2C=3C(=CN=CC=3)OCCF)=O)=C2O1 DOVCDUXMNSLCHD-OAHLLOKOSA-N 0.000 claims description 2
- PEZPDAJVRQMYEJ-OAHLLOKOSA-N 7-[3-(2-hydroxyethoxy)pyridin-4-yl]-5-methyl-2-[[(2r)-2-methyl-4-methylsulfonylpiperazin-1-yl]methyl]furo[3,2-c]pyridin-4-one Chemical compound C[C@@H]1CN(S(C)(=O)=O)CCN1CC1=CC(C(N(C)C=C2C=3C(=CN=CC=3)OCCO)=O)=C2O1 PEZPDAJVRQMYEJ-OAHLLOKOSA-N 0.000 claims description 2
- HODLGFLRFMOVJV-MRXNPFEDSA-N 7-[3-(2-methoxyethoxy)pyridin-4-yl]-5-methyl-2-[[(2r)-2-methyl-4-methylsulfonylpiperazin-1-yl]methyl]furo[3,2-c]pyridin-4-one Chemical compound COCCOC1=CN=CC=C1C1=CN(C)C(=O)C2=C1OC(CN1[C@@H](CN(CC1)S(C)(=O)=O)C)=C2 HODLGFLRFMOVJV-MRXNPFEDSA-N 0.000 claims description 2
- BJQQEUIUICVSTJ-TZHYSIJRSA-N 7-[3-(2-methoxypropoxy)pyridin-4-yl]-5-methyl-2-[[(2r)-2-methyl-4-methylsulfonylpiperazin-1-yl]methyl]furo[3,2-c]pyridin-4-one Chemical compound COC(C)COC1=CN=CC=C1C1=CN(C)C(=O)C2=C1OC(CN1[C@@H](CN(CC1)S(C)(=O)=O)C)=C2 BJQQEUIUICVSTJ-TZHYSIJRSA-N 0.000 claims description 2
- JQMULURWMSIZFQ-MRXNPFEDSA-N 7-[3-(cyclopropylmethoxy)pyridin-2-yl]-5-methyl-2-[[(2r)-2-methyl-4-methylsulfonylpiperazin-1-yl]methyl]furo[3,2-c]pyridin-4-one Chemical compound C[C@@H]1CN(S(C)(=O)=O)CCN1CC1=CC(C(N(C)C=C2C=3C(=CC=CN=3)OCC3CC3)=O)=C2O1 JQMULURWMSIZFQ-MRXNPFEDSA-N 0.000 claims description 2
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- FWKQTJUDPNLEAU-UHFFFAOYSA-N 7-[3-(cyclopropylmethoxy)pyridin-4-yl]-5-methyl-2-[(3-oxopiperazin-1-yl)methyl]furo[3,2-c]pyridin-4-one Chemical compound C1=2OC(CN3CC(=O)NCC3)=CC=2C(=O)N(C)C=C1C1=CC=NC=C1OCC1CC1 FWKQTJUDPNLEAU-UHFFFAOYSA-N 0.000 claims description 2
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- CLEJMDYLDKKEMP-UHFFFAOYSA-N 7-[3-(cyclopropylmethoxy)pyridin-4-yl]-5-methyl-2-[(4-methyl-3-oxopiperazin-1-yl)methyl]furo[3,2-c]pyridin-4-one Chemical compound C1C(=O)N(C)CCN1CC1=CC(C(N(C)C=C2C=3C(=CN=CC=3)OCC3CC3)=O)=C2O1 CLEJMDYLDKKEMP-UHFFFAOYSA-N 0.000 claims description 2
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- KFCNMDRHLRAMNQ-UHFFFAOYSA-N n-[4-[2-(1,4-diazepan-1-ylmethyl)-5-methyl-4-oxofuro[3,2-c]pyridin-7-yl]pyridin-2-yl]acetamide Chemical compound C1=NC(NC(=O)C)=CC(C=2C=3OC(CN4CCNCCC4)=CC=3C(=O)N(C)C=2)=C1 KFCNMDRHLRAMNQ-UHFFFAOYSA-N 0.000 claims description 2
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- APPVCTWDFGBJAV-UHFFFAOYSA-N n-[4-[2-[(4-acetyl-1,4-diazepan-1-yl)methyl]-5-methyl-4-oxofuro[3,2-c]pyridin-7-yl]pyridin-2-yl]acetamide Chemical compound C1=NC(NC(=O)C)=CC(C=2C=3OC(CN4CCN(CCC4)C(C)=O)=CC=3C(=O)N(C)C=2)=C1 APPVCTWDFGBJAV-UHFFFAOYSA-N 0.000 claims description 2
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
- C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
- C07D491/04—Ortho-condensed systems
- C07D491/044—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring
- C07D491/048—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring the oxygen-containing ring being five-membered
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
- A61K31/34—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/4353—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 ortho- or peri-condensed with heterocyclic ring systems
- A61K31/4355—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 ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a five-membered ring having oxygen as a ring hetero atom
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
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Abstract
Description
Vは、N又はC-R2であり、
Wは、N又はC-R8であり、
Xは、N、CH又はC(CH3)であり、
Yは、N又はC-R5であり、
Zは、N又はC-R15であり、
Qは、N又はCHであり、
R1は、C1〜4アルキル又は重水素化C1〜4アルキルであり、
R2は、存在する場合、H、OH、C1〜4アルキル、ハロ、-CF3、-NH2、-OC1〜4アルキル、-NHC(O)H、-NHC(O)C1〜4アルキル、-N(CH3)C(O)C1〜4アルキル、-NHC(O)NH2、-NHC(O)C1〜4アルキレンNH2、-N(CH3)C(O)NH2、-N(CH3)C(O)C1〜4アルキレンNH2、-NHC2〜4アルキレンOCH3、-N(CH3)C2〜4アルキレンOCH3、-OC2〜4アルキレンOCH3、-OC2〜4アルキレンOHであるか、又は
R2は、-G-CH2CH(R3)(R4)、-G-CH(R3)(R4)及び-G-R3から選択される基であり、ここで、
Gは、NH、N(CH3)、O、C(O)NH又はNHC(O)であり、
R3は、フェニル、ピリジニル、C3〜7シクロアルキル、又は=Oで置換されていてもよい複素環であり、
R4は、H又はC1〜4アルキルであり、
R5は、存在する場合、H、C1〜4アルキル、ハロ、-CF3、CN、OH、-OC1〜4アルキル、-CH2NH2、-OCF3、-SO2CH3、-C(O)NHC1〜4アルキル又は-CO2Hであり、
R6は、-NR11R12、又は基
Dは、CH又はNであり、
Eは、N、O、CH又はSO2であり、
R7は、存在する場合、H、OH、C1〜4アルキル、-NH2、-SO2C1〜4アルキル、-SO2フェニル、-SO2ベンジル、-SO2N(CH3)2、-NHSO2CH3、-C(O)C1〜4アルキル、-C(O)フェニルであり、
R8は、存在する場合、H、C1〜4アルキル、ハロ、-CF3、CN、OH、-OC1〜4アルキル、-OC2〜4アルキレンOC1〜4アルキル、-OCF3、-OC1〜4アルキレンF、-OC1〜4アルキレンCHF2、-OC2〜4アルキレンOH、-Oフェニル、-OC1〜4アルキレンフェニル、-NHC3〜7シクロアルキル、-NHC1〜4アルキレンC3〜7シクロアルキル、-OC3〜7シクロアルキル、-OC1〜4アルキレンC3〜7シクロアルキル、-NHC4〜6複素環、-NHC1〜4アルキレンC4〜6複素環、-OC4〜6複素環又は-OC1〜4アルキレンC4〜6複素環であり、ここでC3〜7シクロアルキル又はC4〜6複素環はそれぞれ、ハロ、OH、オキソ、C1〜4アルキル及び-NH2から独立に選択される1つ又は2つの置換基で置換されていてもよいか、又は
R8とR2は、それらが結合している炭素原子と一緒になって、オキソで置換されていてもよい複素環を形成し、
R9は、H、C1〜4アルキル、-C(O)NH2、-CO2CH3、-CF3、ハロ、OH、-OC1〜4アルキル、-CH2OH、-C(O)NHCH3、-C(O)NH(CH3)2、-CH2OC1〜4アルキル又は-CH2OCH2C3〜7シクロアルキルであり、
R10は、H、C1〜4アルキル、-C(O)NH2、-CO2CH3、-CF3、ハロ、OH、-OC1〜4アルキル又はオキソであり、
R11は、H、C1〜4アルキル又はSO2CH3であり、
R12は、H、C1〜4アルキル、C2〜4アルキレンNHR13、SO2CH3、複素環、又はSO2を含む複素環であり、
R13は、H又はSO2CH3であり、
R14は、H又はC1〜4アルキルであり、
R15は、H、C1〜4アルキル又はNHC(O)C1〜4アルキルであり、
R16は、H又はC1〜4アルキルであり、
n及びmは、それぞれ、0、1及び2から独立に選択される整数であり、但し、V、W、X、Y及びZのうち2種以下はNである]、又はその塩に関する。
Wは、N又はC-R8であり、
Xは、N、CH又はC(CH3)であり、
Yは、N又はC-R5であり、
Zは、N又はC-R15であり、
Qは、N又はCHであり、
R1は、C1〜4アルキルであり、
R2は、H、OH、C1〜4アルキル、ハロ、-CF3、-NH2、-OC1〜4アルキル、-NHC(O)H、-NHC(O)C1〜4アルキル、-N(CH3)C(O)C1〜4アルキル、-NHCH(CH3)CH2OCH3、-N(CH3)CH2CH2OCH3、-OCH2CH2OCH3、-OCH2CH2CH2OH、-OCH(CH3)CH2OCH3であるか、又は
R2は、-G-CH2CH(R3)(R4)、-G-CH(R3)(R4)及び-G-R3から選択される基であり、ここで、
Gは、NH、N(CH3)、O、C(O)NH又はNHC(O)であり、
R3は、フェニル、ピリジニル、C3〜7シクロアルキル、又は=Oで置換されていてもよい複素環であり、
R4は、H又はC1〜4アルキルであり、
R5は、H、C1〜4アルキル、ハロ、-CF3、CN、OH、-OC1〜4アルキル、-CH2NH2、-OCF3又は-SO2CH3であり、
R6は、-NR11R12、又は基
Dは、CH又はNであり、
Eは、N、O、CH又はSO2であり、
R7は、存在する場合、H、OH、C1〜4アルキル、-NH2、-SO2C1〜4アルキル、-SO2フェニル、-SO2ベンジル、-SO2N(CH3)2、-NHSO2CH3、-C(O)C1〜4アルキル、-C(O)フェニルであり、
R8は、H、C1〜4アルキル、ハロ、-CF3、CN、OH、-OC1〜4アルキル、-OCF3、-OCH2フェニル、-NHCH2C3〜7シクロアルキル又は-OCH2C3〜7シクロアルキルであり、
R9は、H、C1〜4アルキル、-C(O)NH2、-CO2CH3、-CF3、ハロ、OH、-OC1〜4アルキル、-CH2OH、-C(O)NHCH3又は-C(O)NH(CH3)2、-CH2OC1〜4アルキル又は-CH2OCH2C3〜7シクロアルキルであり、
R10は、H、C1〜4アルキル、-C(O)NH2、-CO2CH3、-CF3、ハロ、OH又は-OC1〜4アルキルであり、
R11は、H、C1〜4アルキル又はSO2CH3であり、
R12は、H、C1〜4アルキル、C1〜4アルキレンNHR13、SO2CH3、複素環、又はSO2を含む複素環であり、
R13は、H又はSO2CH3であり、
R14は、H又はC1〜4アルキルであり、
R15は、H、C1〜4アルキル又はNHC(O)C1〜4アルキルであり、
n及びmは、それぞれ、0、1及び2から独立に選択される整数であり、但し、W、X、Y及びZのうち2種以下はNである]、又はその塩に関する。
Wは、C-R8であり、
Yは、N又はC-R5であり、
Zは、N又はCHであり、
R2は、H、-OCH3、-NHC(O)CH3、-NHC(O)CH2CH3、-N(CH3)C(O)CH3であるか、又は
R2は、-G-CH2CH(R3)(R4)及び-G-CH(R3)(R4)から選択される基であり、ここで、
Gは、NH、O又はNHC(O)であり、
R3は、フェニル、ピリジニル、シクロプロピル、又は=Oで置換されていてもよい複素環であり、
R4は、H又はメチルであり、
R5は、H、-OCH3又は-CH2NH2であり、
Eは、N、O、CH又はSO2であり、
R7は、存在する場合、H又は-SO2CH3であり、
R8は、H、-NHCH2シクロプロピル又は-OCH2シクロプロピルであり、
R9は、H、メチル又はフルオロであり、
R10は、H又はフルオロであり、
R14は、H又はメチルであり、
n及びmは、それぞれ、1及び2から独立に選択される整数である]、又はその塩
である。
Wは、N又はC-R8であり、
X及びZは、それぞれ独立して、N又はCHであり、
Yは、N又はC-R5であり、
R1は、C1〜4アルキルであり、
R2は、H、OH、C1〜4アルキル、ハロ、-CF3、-NH2、-OC1〜4アルキル、-NHC(O)H、-NHC(O)Me、-NHC(CH3)CH2OCH3、-N(CH3)CH2OCH3、-N(CH3)CH2CH2OCH3、-OCH2CH2OCH3、-OCH2CH2CH2OH、-OCH(CH3)CH2OCH3であるか、又は
R2は、-G-CH(R3)(R4)基であり、ここで、
Gは、NH、NCH3、O又はC(O)NHであり、
R3は、フェニル、ピリジニル、C3〜7シクロアルキル、又は複素環であり、
R4は、H又はC1〜4アルキルであり、
R5は、H、C1〜4アルキル、ハロ、-CF3、CN、OH、-OC1〜4アルキル、-CH2NH2、-OCF3又は-SO2CH3であり、
R6は、-NR11R12、又は基
Dは、CH又はNであり、
Eは、N、O、CH又はSO2であり、
R7は、存在する場合、H、OH、C1〜4アルキル、-NH2、-SO2C1〜4アルキル、-SO2フェニル、-SO2ベンジル、-SO2N(CH3)2、-NHSO2CH3、-C(O)C1〜4アルキル、又は-C(O)フェニルであり、
R8は、H、C1〜4アルキル、ハロ、-CF3、CN、OH、-OC1〜4アルキル、-OCF3又は-OCH2フェニルであり、
R9は、H、C1〜4アルキル、-CONH2又は-CO2CH3であり、
R10は、H、C1〜4アルキル、-CONH2又は-CO2CH3であり、
R11は、H又はC1〜4アルキルであり、
R12は、H、C1〜4アルキル、C1〜4アルキレンNHR13、SO2CH3又は複素環であり、
R13は、H又はSO2CH3であり、
nは、0、1又は2である]、又はその塩である。
7-[3,4-ビス(メチルオキシ)フェニル]-5-メチル-2-{[4-(メチルスルホニル)-1-ピペラジニル]メチル}フロ[3,2-c]ピリジン-4(5H)-オン;
(R)-N-(4-(5-メチル-2-((2-メチル-4-(メチルスルホニル)ピペラジン-1-イル)メチル)-4-オキソ-4,5-ジヒドロフロ[3,2-c]ピリジン-7-イル)ピリジン-2-イル)アセトアミド;
7-(3-(ベンジルオキシ)フェニル)-5-メチル-2-((4-(メチルスルホニル)ピペラジン-1-イル)メチル)フロ[3,2-c]ピリジン-4(5H)-オン;
7-(3-(ベンジルアミノ)フェニル)-5-メチル-2-((4-(メチルスルホニル)ピペラジン-1-イル)メチル)フロ[3,2-c]ピリジン-4(5H)-オン;
2-(((2-アミノエチル)アミノ)メチル)-7-(3,4-ジメトキシフェニル)-5-メチルフロ[3,2-c]ピリジン-4(5H)-オン;
7-(4-(アミノメチル)フェニル)-5-メチル-2-((4-(メチルスルホニル)ピペラジン-1-イル)メチル)フロ[3,2-c]ピリジン-4(5H)-オン;
5-メチル-2-((4-(メチルスルホニル)ピペラジン-1-イル)メチル)-7-(2-((テトラヒドロ-2H-ピラン-4-イル)メトキシ)ピリジン-4-イル)フロ[3,2-c]ピリジン-4(5H)-オン;
7-(3,4-ジメトキシフェニル)-5-メチル-2-(ピペリジン-1-イルメチル)フロ[3,2-c]ピリジン-4(5H)-オン;
7-(3,4-ジメトキシフェニル)-5-メチル-2-(モルホリノメチル)フロ[3,2-c]ピリジン-4(5H)-オン;
(R)-7-(3,4-ジメトキシフェニル)-5-メチル-2-((2-メチル-4-(メチルスルホニル)ピペラジン-1-イル)メチル)フロ[3,2-c]ピリジン-4(5H)-オン;
2-((1,4-ジアゼパン-1-イル)メチル)-7-(3,4-ジメトキシフェニル)-5-メチルフロ[3,2-c]ピリジン-4(5H)-オン;
5-メチル-2-((4-(メチルスルホニル)ピペラジン-1-イル)メチル)-7-(5-(1-フェニルエトキシ)ピリジン-3-イル)フロ[3,2-c]ピリジン-4(5H)-オン;
2-((3,3-ジフルオロピペリジン-1-イル)メチル)-5-メチル-7-(2-((テトラヒドロ-2H-ピラン-4-イル)メトキシ)ピリジン-4-イル)フロ[3,2-c]ピリジン-4(5H)-オン;
5-メチル-2-((4-(メチルスルホニル)ピペラジン-1-イル)メチル)-7-(2-((1-フェニルエチル)アミノ)ピリジン-4-イル)フロ[3,2-c]ピリジン-4(5H)-オン;
5-メチル-2-((4-(メチルスルホニル)ピペラジン-1-イル)メチル)-7-(3-((1-フェニルエチル)アミノ)フェニル)フロ[3,2-c]ピリジン-4(5H)-オン;
7-(3,4-ジメトキシフェニル)-5-メチル-2-((3-メチルモルホリノ)メチル)フロ[3,2-c]ピリジン-4(5H)-オン;
N-(4-(2-((3-フルオロピペリジン-1-イル)メチル)-5-メチル-4-オキソ-4,5-ジヒドロフロ[3,2-c]ピリジン-7-イル)ピリジン-2-イル)アセトアミド;
N-(4-(2-((3,3-ジフルオロピペリジン-1-イル)メチル)-5-メチル-4-オキソ-4,5-ジヒドロフロ[3,2-c]ピリジン-7-イル)ピリジン-2-イル)アセトアミド;
2-((3-フルオロピペリジン-1-イル)メチル)-7-(4-メトキシフェニル)-5-メチルフロ[3,2-c]ピリジン-4(5H)-オン;
5-メチル-2-(モルホリノメチル)-7-(2-((テトラヒドロ-2H-ピラン-4-イル)メトキシ)ピリジン-4-イル)フロ[3,2-c]ピリジン-4(5H)-オン;
5-メチル-2-(1-(4-(メチルスルホニル)ピペラジン-1-イル)エチル)-7-(2-((テトラヒドロ-2H-ピラン-4-イル)メトキシ)ピリジン-4-イル)フロ[3,2-c]ピリジン-4(5H)-オン;
(S)-5-メチル-2-(1-(4-(メチルスルホニル)ピペラジン-1-イル)エチル)-7-(2-((テトラヒドロ-2H-ピラン-4-イル)メトキシ)ピリジン-4-イル)フロ[3,2-c]ピリジン-4(5H)-オン;
(R)-5-メチル-2-(1-(4-(メチルスルホニル)ピペラジン-1-イル)エチル)-7-(2-((テトラヒドロ-2H-ピラン-4-イル)メトキシ)ピリジン-4-イル)フロ[3,2-c]ピリジン-4(5H)-オン;
2-((1,4-オキサゼパン-4-イル)メチル)-5-メチル-7-(2-((テトラヒドロ-2H-ピラン-4-イル)メトキシ)ピリジン-4-イル)フロ[3,2-c]ピリジン-4(5H)-オン;
(R)-7-(2-(シクロプロピルメトキシ)ピリジン-4-イル)-5-メチル-2-((2-メチル-4-(メチルスルホニル)ピペラジン-1-イル)メチル)フロ[3,2-c]ピリジン-4(5H)-オン;
(R)-N-(4-(5-メチル-2-((2-メチル-4-(メチルスルホニル)ピペラジン-1-イル)メチル)-4-オキソ-4,5-ジヒドロフロ[3,2-c]ピリジン-7-イル)ピリジン-2-イル)シクロプロパンカルボキサミド;
(R)-N-(4-(5-メチル-2-((2-メチル-4-(メチルスルホニル)ピペラジン-1-イル)メチル)-4-オキソ-4,5-ジヒドロフロ[3,2-c]ピリジン-7-イル)ピリジン-2-イル)プロピオンアミド;
(R)-7-(2-(2-メトキシエトキシ)ピリジン-4-イル)-5-メチル-2-((2-メチル-4-(メチルスルホニル)ピペラジン-1-イル)メチル)フロ[3,2-c]ピリジン-4(5H)-オン;
(R)-5-メチル-2-((2-メチル-4-(メチルスルホニル)ピペラジン-1-イル)メチル)-7-(2-(2-(ピロリジン-1-イル)エトキシ)ピリジン-4-イル)フロ[3,2-c]ピリジン-4(5H)-オン;
2-((1,1-ジオキシドチオモルホリノ)メチル)-5-メチル-7-(2-((テトラヒドロ-2H-ピラン-4-イル)メトキシ)ピリジン-4-イル)フロ[3,2-c]ピリジン-4(5H)-オン;
5-メチル-2-((4-(メチルスルホニル)ピペラジン-1-イル)メチル)-7-(2-((テトラヒドロ-2H-ピラン-4-イル)メトキシ)ピリジン-4-イル)フロ[2,3-d]ピリダジン-4(5H)-オン;
(R)-N-メチル-N-(4-(5-メチル-2-((2-メチル-4-(メチルスルホニル)ピペラジン-1-イル)メチル)-4-オキソ-4,5-ジヒドロフロ[3,2-c]ピリジン-7-イル)ピリジン-2-イル)アセトアミド;
7-(3-(シクロプロピルメトキシ)ピリジン-4-イル)-5-メチル-2-((4-(メチルスルホニル)ピペラジン-1-イル)メチル)フロ[3,2-c]ピリジン-4(5H)-オン;
(R)-7-(3-(シクロプロピルメトキシ)ピリジン-4-イル)-5-メチル-2-((2-メチル-4-(メチルスルホニル)ピペラジン-1-イル)メチル)フロ[3,2-c]ピリジン-4(5H)-オン;
7-(3,4-ジメトキシフェニル)-5-メチル-2-((4-(メチルスルホニル)ピペラジン-1-イル)メチル)フロ[2,3-d]ピリダジン-4(5H)-オン;
2-((1,4-ジアゼパン-1-イル)メチル)-5-メチル-7-(2-((ピリジン-2-イルメチル)アミノ)ピリジン-4-イル)フロ[3,2-c]ピリジン-4(5H)-オン;
(R)-5-メチル-2-((2-メチル-4-(メチルスルホニル)ピペラジン-1-イル)メチル)-7-(2-(2-(2-オキソピロリジン-1-イル)エトキシ)ピリジン-4-イル)フロ[3,2-c]ピリジン-4(5H)-オン;
N-(4-(5-メチル-2-(1-(4-(メチルスルホニル)ピペラジン-1-イル)エチル)-4-オキソ-4,5-ジヒドロフロ[3,2-c]ピリジン-7-イル)ピリジン-2-イル)アセトアミド;
(R)-N-(4-(5-メチル-2-(1-(4-(メチルスルホニル)ピペラジン-1-イル)エチル)-4-オキソ-4,5-ジヒドロフロ[3,2-c]ピリジン-7-イル)ピリジン-2-イル)アセトアミド;
(S)-N-(4-(5-メチル-2-(1-(4-(メチルスルホニル)ピペラジン-1-イル)エチル)-4-オキソ-4,5-ジヒドロフロ[3,2-c]ピリジン-7-イル)ピリジン-2-イル)アセトアミド;
N-(4-(5-メチル-2-((4-(メチルスルホニル)ピペラジン-1-イル)メチル)-4-オキソ-4,5-ジヒドロフロ[3,2-c]ピリジン-7-イル)ピリジン-2-イル)アセトアミド;
(R)-N-(5-(5-メチル-2-((2-メチル-4-(メチルスルホニル)ピペラジン-1-イル)メチル)-4-オキソ-4,5-ジヒドロフロ[3,2-c]ピリジン-7-イル)ピリジン-3-イル)アセトアミド;
7-(3-((シクロプロピルメチル)アミノ)ピリジン-4-イル)-5-メチル-2-((4-(メチルスルホニル)ピペラジン-1-イル)メチル)フロ[3,2-c]ピリジン-4(5H)-オン;
(R)-7-(3-((シクロプロピルメチル)アミノ)ピリジン-4-イル)-5-メチル-2-((2-メチル-4-(メチルスルホニル)ピペラジン-1-イル)メチル)フロ[3,2-c]ピリジン-4(5H)-オン;
5-メチル-2-(((R)-2-メチル-4-(メチルスルホニル)ピペラジン-1-イル)メチル)-7-(3-(オキセタン-2-イルメトキシ)ピリジン-4-イル)フロ[3,2-c]ピリジン-4(5H)-オン;
5-メチル-2-(((R)-2-メチル-4-(メチルスルホニル)ピペラジン-1-イル)メチル)-7-(3-((R)-オキセタン-2-イルメトキシ)ピリジン-4-イル)フロ[3,2-c]ピリジン-4(5H)-オン;
5-メチル-2-(((R)-2-メチル-4-(メチルスルホニル)ピペラジン-1-イル)メチル)-7-(3-((S)-オキセタン-2-イルメトキシ)ピリジン-4-イル)フロ[3,2-c]ピリジン-4(5H)-オン;
(R)-7-(3-(シクロプロピルメトキシ)ピリジン-2-イル)-5-メチル-2-((2-メチル-4-(メチルスルホニル)ピペラジン-1-イル)メチル)フロ[3,2-c]ピリジン-4(5H)-オン;
5-メチル-2-((2-メチルピペラジン-1-イル)メチル)-7-(2-((テトラヒドロ-2H-ピラン-4-イル)メトキシ)ピリジン-4-イル)フロ[3,2-c]ピリジン-4(5H)-オン;
(R)-5-メチル-2-((2-メチル-4-(メチルスルホニル)ピペラジン-1-イル)メチル)-7-(3-(オキセタン-3-イルメトキシ)ピリジン-4-イル)フロ[3,2-c]ピリジン-4(5H)-オン;
2-((4-アセチル-2-メチルピペラジン-1-イル)メチル)-5-メチル-7-(2-((テトラヒドロ-2H-ピラン-4-イル)メトキシ)ピリジン-4-イル)フロ[3,2-c]ピリジン-4(5H)-オン;
N-(3-(5-メチル-2-((4-(メチルスルホニル)ピペラジン-1-イル)メチル)-4-オキソ-4,5-ジヒドロフロ[3,2-c]ピリジン-7-イル)フェニル)アセトアミド;
(R)-7-(2-((シクロプロピルメチル)アミノ)ピリジン-3-イル)-5-メチル-2-((2-メチル-4-(メチルスルホニル)ピペラジン-1-イル)メチル)フロ[3,2-c]ピリジン-4(5H)-オン;
(R)-7-(3-アミノフェニル)-5-メチル-2-((2-メチル-4-(メチルスルホニル)ピペラジン-1-イル)メチル)フロ[3,2-c]ピリジン-4(5H)-オン;
2-((1,4-ジアゼパン-1-イル)メチル)-5-メチル-7-(3-((ピリジン-2-イルメチル)アミノ)フェニル)フロ[3,2-c]ピリジン-4(5H)-オン;
(R)-7-(3-エトキシピリジン-4-イル)-5-メチル-2-((2-メチル-4-(メチルスルホニル)ピペラジン-1-イル)メチル)フロ[3,2-c]ピリジン-4(5H)-オン;
N-(3-(2-((1,4-ジアゼパン-1-イル)メチル)-5-メチル-4-オキソ-4,5-ジヒドロフロ[3,2-c]ピリジン-7-イル)フェニル)ピコリンアミド;
(R)-N-(6-(5-メチル-2-((2-メチル-4-(メチルスルホニル)ピペラジン-1-イル)メチル)-4-オキソ-4,5-ジヒドロフロ[3,2-c]ピリジン-7-イル)ピリジン-2-イル)アセトアミド;
2-((1,4-ジアゼパン-1-イル)メチル)-7-(3-(シクロプロピルメトキシ)ピリジン-4-イル)-5-メチルフロ[3,2-c]ピリジン-4(5H)-オン;
7-(3-(シクロプロピルメトキシ)ピリジン-4-イル)-5-メチル-2-((4-メチル-1,4-ジアゼパン-1-イル)メチル)フロ[3,2-c]ピリジン-4(5H)-オン;
5-メチル-2-((4-メチル-1,4-ジアゼパン-1-イル)メチル)-7-(3-((ピリジン-2-イルメチル)アミノ)フェニル)フロ[3,2-c]ピリジン-4(5H)-オン;
(R)-7-(3-イソプロポキシピリジン-4-イル)-5-メチル-2-((2-メチル-4-(メチルスルホニル)ピペラジン-1-イル)メチル)フロ[3,2-c]ピリジン-4(5H)-オン;
(R)-7-(2-アミノピリジン-4-イル)-5-メチル-2-((2-メチル-4-(メチルスルホニル)ピペラジン-1-イル)メチル)フロ[3,2-c]ピリジン-4(5H)-オン;
(R)-7-(3-ヒドロキシピリジン-4-イル)-5-メチル-2-((2-メチル-4-(メチルスルホニル)ピペラジン-1-イル)メチル)フロ[3,2-c]ピリジン-4(5H)-オン;
7-(3-((2,2-ジフルオロシクロプロピル)メトキシ)ピリジン-4-イル)-5-メチル-2-(((R)-2-メチル-4-(メチルスルホニル)ピペラジン-1-イル)メチル)フロ[3,2-c]ピリジン-4(5H)-オン;
(R)-N-(4-(5-(2H3)メチル-2-((2-メチル-4-(メチルスルホニル)ピペラジン-1-イル)メチル)-4-オキソ-4,5-ジヒドロフロ[3,2-c]ピリジン-7-イル)ピリジン-2-イル)アセトアミド;
(R)-5-メチル-2-((2-メチル-4-(メチルスルホニル)ピペラジン-1-イル)メチル)-7-(3-(2-(2-オキソピロリジン-1-イル)エトキシ)ピリジン-4-イル)フロ[3,2-c]ピリジン-4(5H)-オン;
(R)-5-アミノ-N-(3-(5-メチル-2-((2-メチル-4-(メチルスルホニル)ピペラジン-1-イル)メチル)-4-オキソ-4,5-ジヒドロフロ[3,2-c]ピリジン-7-イル)フェニル)ペンタンアミド;
N-(4-(5-メチル-2-(2-(4-(メチルスルホニル)ピペラジン-1-イル)プロパン-2-イル)-4-オキソ-4,5-ジヒドロフロ[3,2-c]ピリジン-7-イル)ピリジン-2-イル)アセトアミド;
(R)-7-(3-(2-メトキシエトキシ)ピリジン-4-イル)-5-メチル-2-((2-メチル-4-(メチルスルホニル)ピペラジン-1-イル)メチル)フロ[3,2-c]ピリジン-4(5H)-オン;
3-(シクロプロピルメトキシ)-4-(5-メチル-2-((4-(メチルスルホニル)ピペラジン-1-イル)メチル)-4-オキソ-4,5-ジヒドロフロ[3,2-c]ピリジン-7-イル)安息香酸;
3-(シクロプロピルメトキシ)-N-エチル-4-(5-メチル-2-((4-(メチルスルホニル)ピペラジン-1-イル)メチル)-4-オキソ-4,5-ジヒドロフロ[3,2-c]ピリジン-7-イル)ベンズアミド;
5-メチル-2-(((R)-2-メチル-4-(メチルスルホニル)ピペラジン-1-イル)メチル)-7-(3-((テトラヒドロフラン-3-イル)メトキシ)ピリジン-4-イル)フロ[3,2-c]ピリジン-4(5H)-オン;
5-メチル-2-(((R)-2-メチル-4-(メチルスルホニル)ピペラジン-1-イル)メチル)-7-(3-((テトラヒドロフラン-2-イル)メトキシ)ピリジン-4-イル)フロ[3,2-c]ピリジン-4(5H)-オン;
7-(3-(シクロプロピルメトキシ)ピリジン-4-イル)-5-メチル-2-((3-オキソピペラジン-1-イル)メチル)フロ[3,2-c]ピリジン-4(5H)-オン;
(R)-7-(3-(2-フルオロエトキシ)ピリジン-4-イル)-5-メチル-2-((2-メチル-4-(メチルスルホニル)ピペラジン-1-イル)メチル)フロ[3,2-c]ピリジン-4(5H)-オン;
(R)-7-(3-シクロプロポキシピリジン-4-イル)-5-メチル-2-((2-メチル-4-(メチルスルホニル)ピペラジン-1-イル)メチル)フロ[3,2-c]ピリジン-4(5H)-オン;
(R)-7-(3-(2,2-ジフルオロエトキシ)ピリジン-4-イル)-5-メチル-2-((2-メチル-4-(メチルスルホニル)ピペラジン-1-イル)メチル)フロ[3,2-c]ピリジン-4(5H)-オン;
(R)-7-(3-(2-ヒドロキシエトキシ)ピリジン-4-イル)-5-メチル-2-((2-メチル-4-(メチルスルホニル)ピペラジン-1-イル)メチル)フロ[3,2-c]ピリジン-4(5H)-オン;
7-(3-(シクロプロピルメトキシ)ピリジン-4-イル)-5-メチル-2-((4-メチル-3-オキソピペラジン-1-イル)メチル)フロ[3,2-c]ピリジン-4(5H)-オン;
(R)-5-メチル-2-((2-メチル-4-(メチルスルホニル)ピペラジン-1-イル)メチル)-7-(2-オキソ-2,3-ジヒドロ-1H-ピロロ[2,3-b]ピリジン-4-イル)フロ[3,2-c]ピリジン-4(5H)-オン;
7-(3-(2-メトキシプロポキシ)ピリジン-4-イル)-5-メチル-2-(((R)-2-メチル-4-(メチルスルホニル)ピペラジン-1-イル)メチル)フロ[3,2-c]ピリジン-4(5H)-オン;
7-(3-((1-メトキシプロパン-2-イル)オキシ)ピリジン-4-イル)-5-メチル-2-(((R)-2-メチル-4-(メチルスルホニル)ピペラジン-1-イル)メチル)フロ[3,2-c]ピリジン-4(5H)-オン;
(R)-5-メチル-2-((2-メチル-4-(メチルスルホニル)ピペラジン-1-イル)メチル)-7-(3-(オキセタン-3-イルオキシ)ピリジン-4-イル)フロ[3,2-c]ピリジン-4(5H)-オン;
5-メチル-2-(((R)-2-メチル-4-(メチルスルホニル)ピペラジン-1-イル)メチル)-7-(3-((テトラヒドロフラン-3-イル)オキシ)ピリジン-4-イル)フロ[3,2-c]ピリジン-4(5H)-オン;
5-メチル-2-(((R)-2-メチル-4-(メチルスルホニル)ピペラジン-1-イル)メチル)-7-(3-(((S)-テトラヒドロフラン-3-イル)オキシ)ピリジン-4-イル)フロ[3,2-c]ピリジン-4(5H)-オン;及び
5-メチル-2-(((R)-2-メチル-4-(メチルスルホニル)ピペラジン-1-イル)メチル)-7-(3-(((R)-テトラヒドロフラン-3-イル)オキシ)ピリジン-4-イル)フロ[3,2-c]ピリジン-4(5H)-オン;
N-(4-(5-メチル-4-オキソ-2-((5-オキソ-1,4-ジアゼパン-1-イル)メチル)-4,5-ジヒドロフロ[3,2-c]ピリジン-7-イル)ピリジン-2-イル)アセトアミド;
N-(4-(2-((1,4-オキサゼパン-4-イル)メチル)-5-メチル-4-オキソ-4,5-ジヒドロフロ[3,2-c]ピリジン-7-イル)ピリジン-2-イル)アセトアミド;
N-(4-(5-メチル-2-((4-メチルピペラジン-1-イル)メチル)-4-オキソ-4,5-ジヒドロフロ[3,2-c]ピリジン-7-イル)ピリジン-2-イル)アセトアミド;
N-(4-(5-メチル-2-((4-メチル-1,4-ジアゼパン-1-イル)メチル)-4-オキソ-4,5-ジヒドロフロ[3,2-c]ピリジン-7-イル)ピリジン-2-イル)アセトアミド;
N-(4-(2-((1,4-ジアゼパン-1-イル)メチル)-5-メチル-4-オキソ-4,5-ジヒドロフロ[3,2-c]ピリジン-7-イル)ピリジン-2-イル)アセトアミド;
N-(4-(2-((1,1-ジオキシドチオモルホリノ)メチル)-5-メチル-4-オキソ-4,5-ジヒドロフロ[3,2-c]ピリジン-7-イル)ピリジン-2-イル)アセトアミド;
N-(4-(5-メチル-4-オキソ-2-((3-オキソピペラジン-1-イル)メチル)-4,5-ジヒドロフロ[3,2-c]ピリジン-7-イル)ピリジン-2-イル)アセトアミド;
N-(4-(5-メチル-2-((4-(メチルスルホンアミド)ピペリジン-1-イル)メチル)-4-オキソ-4,5-ジヒドロフロ[3,2-c]ピリジン-7-イル)ピリジン-2-イル)アセトアミド;
(S)-N-(4-(2-((3-ヒドロキシピペリジン-1-イル)メチル)-5-メチル-4-オキソ-4,5-ジヒドロフロ[3,2-c]ピリジン-7-イル)ピリジン-2-イル)アセトアミド;
N-(4-(5-メチル-4-オキソ-2-(ピペラジン-1-イルメチル)-4,5-ジヒドロフロ[3,2-c]ピリジン-7-イル)ピリジン-2-イル)アセトアミド;
N-(4-(2-((4-エチル-3-オキソピペラジン-1-イル)メチル)-5-メチル-4-オキソ-4,5-ジヒドロフロ[3,2-c]ピリジン-7-イル)ピリジン-2-イル)アセトアミド;
N-(4-(5-メチル-2-((4-(メチルスルホニル)ピペリジン-1-イル)メチル)-4-オキソ-4,5-ジヒドロフロ[3,2-c]ピリジン-7-イル)ピリジン-2-イル)アセトアミド;
N-(4-(2-(((1,1-ジオキシドテトラヒドロ-2H-チオピラン-3-イル)アミノ)メチル)-5-メチル-4-オキソ-4,5-ジヒドロフロ[3,2-c]ピリジン-7-イル)ピリジン-2-イル)アセトアミド;
N-(4-(2-(((1,1-ジオキシドテトラヒドロチオフェン-3-イル)アミノ)メチル)-5-メチル-4-オキソ-4,5-ジヒドロフロ[3,2-c]ピリジン-7-イル)ピリジン-2-イル)アセトアミド;
N-(4-(2-((2,5-ジメチル-4-(メチルスルホニル)ピペラジン-1-イル)メチル)-5-メチル-4-オキソ-4,5-ジヒドロフロ[3,2-c]ピリジン-7-イル)ピリジン-2-イル)アセトアミド;
N-(4-(2-((4-エチル-2-メチルピペラジン-1-イル)メチル)-5-メチル-4-オキソ-4,5-ジヒドロフロ[3,2-c]ピリジン-7-イル)ピリジン-2-イル)アセトアミド;
N-(4-(5-メチル-2-((4-メチル-5-オキソ-1,4-ジアゼパン-1-イル)メチル)-4-オキソ-4,5-ジヒドロフロ[3,2-c]ピリジン-7-イル)ピリジン-2-イル)アセトアミド;
N-(4-(5-メチル-2-((7-メチル-5-オキソ-1,4-ジアゼパン-1-イル)メチル)-4-オキソ-4,5-ジヒドロフロ[3,2-c]ピリジン-7-イル)ピリジン-2-イル)アセトアミド;
N-(4-(5-メチル-2-((2-メチル-5-オキソ-1,4-ジアゼパン-1-イル)メチル)-4-オキソ-4,5-ジヒドロフロ[3,2-c]ピリジン-7-イル)ピリジン-2-イル)アセトアミド;
N-(4-(2-((1,1-ジオキシド-1,4-チアゼパン-4-イル)メチル)-5-メチル-4-オキソ-4,5-ジヒドロフロ[3,2-c]ピリジン-7-イル)ピリジン-2-イル)アセトアミド;
N-(4-(5-メチル-2-((3-メチル-1,1-ジオキシドチオモルホリノ)メチル)-4-オキソ-4,5-ジヒドロフロ[3,2-c]ピリジン-7-イル)ピリジン-2-イル)アセトアミド;
N-(4-(5-メチル-2-((2-メチル-1,1-ジオキシドチオモルホリノ)メチル)-4-オキソ-4,5-ジヒドロフロ[3,2-c]ピリジン-7-イル)ピリジン-2-イル)アセトアミド;
N-(4-(2-((4-アセチル-1,4-ジアゼパン-1-イル)メチル)-5-メチル-4-オキソ-4,5-ジヒドロフロ[3,2-c]ピリジン-7-イル)ピリジン-2-イル)アセトアミド;
N-(4-(5-メチル-2-(モルホリノメチル)-4-オキソ-4,5-ジヒドロフロ[3,2-c]ピリジン-7-イル)ピリジン-2-イル)アセトアミド;
N-(4-(2-((4-アセチル-2-メチルピペラジン-1-イル)メチル)-5-メチル-4-オキソ-4,5-ジヒドロフロ[3,2-c]ピリジン-7-イル)ピリジン-2-イル)アセトアミド;
N-(4-(5-メチル-2-((4-メチル-3-オキソピペラジン-1-イル)メチル)-4-オキソ-4,5-ジヒドロフロ[3,2-c]ピリジン-7-イル)ピリジン-2-イル)アセトアミド;
(S)-N-(4-(5-メチル-2-((3-メチル-4-(メチルスルホニル)ピペラジン-1-イル)メチル)-4-オキソ-4,5-ジヒドロフロ[3,2-c]ピリジン-7-イル)ピリジン-2-イル)アセトアミド;
N-(4-(5-メチル-2-((4-(メチルスルホニル)-2-オキソピペラジン-1-イル)メチル)-4-オキソ-4,5-ジヒドロフロ[3,2-c]ピリジン-7-イル)ピリジン-2-イル)アセトアミド;
N-(4-(2-((4-エチルピペラジン-1-イル)メチル)-5-メチル-4-オキソ-4,5-ジヒドロフロ[3,2-c]ピリジン-7-イル)ピリジン-2-イル)アセトアミド;
N-(4-(5-メチル-4-オキソ-2-(ピロリジン-1-イルメチル)-4,5-ジヒドロフロ[3,2-c]ピリジン-7-イル)ピリジン-2-イル)アセトアミド
N-(4-(5-メチル-4-オキソ-2-(ピペリジン-1-イルメチル)-4,5-ジヒドロフロ[3,2-c]ピリジン-7-イル)ピリジン-2-イル)アセトアミド;
N-(4-(5-メチル-4-オキソ-2-((3-オキソ-1,4-ジアゼパン-1-イル)メチル)-4,5-ジヒドロフロ[3,2-c]ピリジン-7-イル)ピリジン-2-イル)アセトアミド;
(R)-N-(4-(5-メチル-2-((2-メチル-3-オキソピペラジン-1-イル)メチル)-4-オキソ-4,5-ジヒドロフロ[3,2-c]ピリジン-7-イル)ピリジン-2-イル)アセトアミド;
から選択されるか、又はそれらの塩である。
5-メチル-2-(((R)-2-メチル-4-(メチルスルホニル)ピペラジン-1-イル)メチル)-7-(3-(オキセタン-2-イルメトキシ)ピリジン-4-イル)フロ[3,2-c]ピリジン-4(5H)-オン;
5-メチル-2-(((R)-2-メチル-4-(メチルスルホニル)ピペラジン-1-イル)メチル)-7-(3-((R)-オキセタン-2-イルメトキシ)ピリジン-4-イル)フロ[3,2-c]ピリジン-4(5H)-オン;及び
5-メチル-2-(((R)-2-メチル-4-(メチルスルホニル)ピペラジン-1-イル)メチル)-7-(3-((S)-オキセタン-2-イルメトキシ)ピリジン-4-イル)フロ[3,2-c]ピリジン-4(5H)-オン;
から選択されるか、又はそれらの塩である。
5-メチル-2-(((R)-2-メチル-4-(メチルスルホニル)ピペラジン-1-イル)メチル)-7-(3-((R)-オキセタン-2-イルメトキシ)ピリジン-4-イル)フロ[3,2-c]ピリジン-4(5H)-オン又はその塩である。
である。
である。
である。
と反応させることを含む、式(II)の化合物を調製する方法を提供する。
R1I(VI)
(式中、R1は、上で定義した通りである)と反応させることを含む、式(V)の化合物を調製する方法を提供する。
R1I(VI)
(式中、R1は、上で定義した通りである)と反応させることを含む、式(XVII)の化合物を調製する方法を提供する。
R1I(VI)
(式中、R1は、上で定義した通りである)と反応させることを含む、式(XVI)の化合物を調製する方法を提供する。一実施形態において、VはC-R2であり、ここでR2は、上で定義した通りである。
と反応させることを含む、式(XXIII)の化合物を調製する方法を提供する。一実施形態において、VはC-R2であり、ここでR2は、上で定義した通りである。
言及されるすべての温度は℃である。
以下の化合物の名称は、化合物命名プログラム「ACD Name Pro 6.02」又はChemDraw Ultra 12.0を使用して得られた。
AcOH 酢酸
ACN アセトニトリル
BINAP 2,2'-ビス(ジフェニルホスフィノ)-1,1'-ビナフチル
BBr3 三臭化ホウ素
BOC tert-ブチルオキシカルボニル
BrettPhos 2-(ジシクロヘキシルホスフィノ)-3,6-ジメトキシ-2'-4'-6'-トリ-i-プロピル-1,1'-ビフェニル
BuLi ブチルリチウム
tBuOH tert-ブタノール
CaCO3 炭酸カルシウム
Cbz カルボベンジルオキシ
CDCl3 重水素化クロロホルム
Comin's reagent N-(5-クロロピリジン-2-イル)-1,1,1-トリフルオロ-N-((トリフルオロメチル)スルホニル)メタンスルホンアミド
Cs2CO3 炭酸セシウム
CHCl3 クロロホルム
CH3CN アセトニトリル
CV カラム容積
DavePhos 2-ジシクロヘキシルホスフィノ-2'-(ジメチルアミノ)ビフェニル
DCE 1,2-ジクロロエタン
DCM ジクロロメタン
DIAD ジイソプロピルアゾジカルボキシレート
DIPEA ジイソプロピルエチルアミン
DMAP 4-ジメチルアミノピリジン
1,2-DME 1,2-ジメトキシエタン
DMF N,N-ジメチルホルムアミド
DMSO ジメチルスルホキシド
DMSO-d6 重水素化ジメチルスルホキシド
DPPA ジフェニルホスホリルアジド
Et3N トリエチルアミン
Et2O ジエチルエーテル
EtOH エタノール
EtOAc 酢酸エチル
FMOC フルオレニルメチルオキシカルボニル
h 時間
HATU O-(7-アザベンゾトリアゾール-1-イル)-N,N,N',N'-テトラメチルウロニウムヘキサフルオロホスフェート
HCl 塩酸
HCO2H ギ酸
HOAt 1-ヒドロキシ-7-アザベンゾトリアゾール
HOBt 1-ヒドロキシベンゾトリアゾール
HPLC 高速液体クロマトグラフィー
i-PrOAc 酢酸イソプロピル
i-Pr2O ジイソプロピルエーテル
i-PrOH イソプロピルアルコール
K2CO3 炭酸カリウム
KOH 水酸化カリウム
LCMS 液体クロマトグラフィー-質量分析法
LDA リチウムジイソプロピルアミド
LiCl 塩化リチウム
LiOH 水酸化リチウム
M モル(濃度)
mCPBA メタ-クロロペルオキシ安息香酸
MeCN アセトニトリル
MeI ヨウ化メチル
MeOH-d4 重水素化メタノール
MeOH メタノール
2-MeTHF 2-メチルテトラヒドロフラン
MDAP 質量分析計直結自動分取クロマトグラフィー
MgSO4 硫酸マグネシウム
min 分
MS 質量分析法
N 規定(濃度)
N2 窒素
Na2CO3 炭酸ナトリウム
NaI ヨウ化ナトリウム
NaH 水素化ナトリウム
NaHCO3 炭酸水素ナトリウム
NaNO2 亜硝酸ナトリウム
Na(OAc)3BH トリアセトキシ水素化ホウ素ナトリウム
NaOtBu tert-ブトキシナトリウム
NaOH 水酸化ナトリウム
Na2SO4 硫酸ナトリウム
NBS N-ブロモスクシンイミド
NEt3 トリエチルアミン
NH3 アンモニア
NMP N-メチル-2-ピロリドン
NMR 核磁気共鳴分光法
OTf トリフルオロメタンスルホネート
PEPPSI ピリジン促進前駆触媒調製、安定化及び開始(pyridine-enhanced precatalyst preparation stabilization and initiation)
Pd/C パラジウム炭素
PdCl2(PPh3)2 二塩化ビス(トリフェニルホスフィン)パラジウム(II)
PdCl2(dppf) 二塩化[1,1'-ビス(ジフェニルホスフィノ)フェロセン]パラジウム(II)
Pd2(dba)3 トリス(ジベンジリデンアセトン)二パラジウム(0)
Pd(PPh3)4 テトラキス(トリフェニルホスフィン)パラジウム(0)
P(OPh)2(O)OH リン酸ジフェニル
PPh3 トリフェニルホスフィン
ppm 百万分率
Rh cat. ロジウム触媒
Rt 保持時間
rt 室温
SCX 強陽イオン交換
SPE 固相抽出
TBAF フッ化テトラ-n-ブチルアンモニウム
TBME tert-ブチルメチルエーテル
Tf2O トリフルオロメタンスルホン酸無水物
TFA トリフルオロ酢酸
THF テトラヒドロフラン
TMSCl 塩化トリメチルシリル
TPPTS 3,3',3"-ホスフィニジントリス(ベンゼンスルホン酸)三ナトリウム塩
UPLC 超高速液体クロマトグラフィー
Xantphos 1,1'-(9,9-ジメチル-9H-キサンテン-4,5-ジイル)ビス[1,1-ジフェニルホスフィン]
ギ酸法
LC条件
UPLC分析は、40℃において、Acquity UPLC BEH C18カラム(50mm×内径2.1mm、1.7μmの充填径)で行った。
採用される溶媒は、次の通りとした:
A=0.1%v/vギ酸の水溶液
B=0.1%v/vギ酸のアセトニトリル溶液
採用される勾配は、次の通りとした:
MS条件
MS :Waters ZQ
イオン化方式 :交互走査陽及び陰イオンエレクトロスプレー
走査範囲 :100〜1000AMU
走査時間 :0.27秒
走査間遅延 :0.10秒
LCMS分析は、40℃において、Agilent1200-6110 LCMS、ハロ-C18カラム(4.6mm×50mm、充填直径2.7μm)で行った。
採用される溶媒は、次の通りとした:
A=0.05%v/vギ酸の水溶液
B=0.05%v/vギ酸のアセトニトリル溶液
採用される勾配は次の通りとした:全時間は2.5分である
MS条件
MSAgilent : 1200-6120LCMS
イオン化方式 : ESI陽イオン及び陰イオン走査範囲100〜1000AMU
乾燥ガス流量(L/分) : 12
ネブライザー圧(psig) : 35
乾燥ガス温度(℃) : 350
キャピラリー電圧(v) : 3000
LC条件
UPLC分析は、Acquity UPLC BEH C18カラム(50mm×内径2.1mm、充填直径1.7μm)を用い40℃で実施した。
採用される溶媒は、次の通りとした:
A=アンモニア溶液でpH10に調整された10mM炭酸水素アンモニウム/水
B=アセトニトリル
採用される勾配は、次の通りとした:
MS条件
MS :Waters ZQ
イオン化方式 :交互走査陽及び陰イオンエレクトロスプレー
走査範囲 :100〜1000AMU
走査時間 :0.27秒
走査間遅延 :0.10秒
スペクトルは、302K又はVTスペクトルでの392〜393Kのいずれかにて、400又は600mHz NMR装置で実行した。
LCMS(2分、ギ酸):Rt=0.63分、MH+256/258
1H NMR (400MHz, DMSO-d6)δ-ppm 3.32 (m, 2H), 2.9 (m, 1H), 2.83 (s, 3H), 2.7-2.54 (m, 3H), 2.3 (広幅 s, 1H), 2.2 (t, 1H), 0.97 (d, 3H)
LCMS(2分、ギ酸):Rt=0.53分、MH+418/420
7-ブロモ-5-メチル-4-オキソ-4,5-ジヒドロフロ[3,2-c]ピリジン-2-カルボアルデヒド(調製については中間体2を参照、45g、176mmol)及び(R)-3-メチル-1-(メチルスルホニル)ピペラジン、塩酸塩(調製については中間体4bを参照、71.7g、334mmol)を、窒素下で2-MeTHF(2192mL)中に懸濁させた。Et3N(61.2mL、439mmol)を添加し、混合物を10分間撹拌した。ナトリウムトリアセトキシボロヒドリド(74.5g、351mmol)を約10分間かけて少量ずつ添加し、混合物を室温で撹拌した。2時間後、反応物を真空中で濃縮した。残留物を飽和NaHCO3(1000mL)で慎重にクエンチし、次いでDCM(2×1000mL)で抽出した。合わせた有機物をNa2SO4で乾燥させ、濾過し、真空中で濃縮して、橙色固体を得た。これを、精製のために、5gの規模の反応からの粗生成物のバッチと合わせた。合わせた生成物を最少量のDCMに溶かす試みは、若干の不溶性物質があったために失敗したので、混合物を濾過した。濾液を約200mLのDCMに濃縮し、これを1500gのSNAPカートリッジ上に装填し、DCM中の0%メタノール中2M NH3で1.6CVにわたって、次いで0〜5%メタノール中2M NH3で10.6CVにわたって溶離し、次いで3CVにわたって5%に保持した(15mA閾値収集、400mL画分)。適切な画分を真空中で濃縮して、クリーム色固体を得た。混合した画分を合わせ、真空中で濃縮し、次いで340gのSNAPカートリッジ及び同じ条件を使用して再度カラムにかけた(51mL画分)。適切な画分を真空中で濃縮して、クリーム色固体を得た。2つのバッチを最少量のDCM中で合わせ、真空中で濃縮して、(R)-7-ブロモ-5-メチル-2-((2-メチル-4-(メチルスルホニル)ピペラジン-1-イル)メチル)フロ[3,2-c]ピリジン-4(5H)-オン(64.055g))をクリーム色固体として得た。1H NMR (400MHz, CDCl3)δ-ppm 7.37 (1H, s), 6.88 (1H, s), 3.92 (2H, AB d), 3.63 (3H, s), 3.53 (2H, m), 2.97 (2H, m), 2.78 (3H, s), 2.64 (3H, m), 1.26 (3H, d). LCMS (2分, 高pH): Rt = 0.77分, MH+ 418/420.
1,4-ジオキサン(3mL)中の(R)-7-ブロモ-5-メチル-2-((2-メチル-4-(メチルスルホニル)ピペラジン-1-イル)メチル)フロ[3,2-c]ピリジン-4(5H)-オン(調製については中間体5を参照、230mg、0.550mmol)、トリエチルアミン(0.307mL、2.199mmol)及びPEPPSI-IPr(37.5mg、0.055mmol)の混合物に、窒素を2分間吹き込んで発泡させた。4,4,5,5-テトラメチル-1,3,2-ジオキサボロラン(0.479mL、3.30mmol)を滴下添加し、窒素を溶液に吹き込んで発泡させ、次いでこれをマイクロ波中で100℃に3時間加熱した。反応混合物を酢酸エチルで希釈し、セライトに通して濾過し、次いで真空中で濃縮すると、黄色半固体(522mg、234%)が残った。
LCMS(2分、ギ酸):Rt=0.76分、MH+531
LCMS(2分、ギ酸):Rt=0.77分、MH+531
LCMS(2分、ギ酸):Rt=0.47分、MH+325/327
LCMS(2分、高pH):Rt=1.05分、MH+440/442
LCMS(2分、ギ酸):Rt=0.43分、MH+341/343
LCMS(2分、高pH):Rt=0.89分、MH+343/345
LCMS(2分、ギ酸):Rt=0.43分、MH+341/343。生成物は約30%の7-ブロモ-2-(ヒドロキシメチル)-5-メチルフロ[3,2-c]ピリジン-4(5H)-オン(Rt=0.56分)を含有する。
LCMS(2分、ギ酸):Rt=0.89分、MH+457
1H NMR (400MHz, DMSO-d6)δ-ppm 3.58 (1H, m), 3.21 (1H, d), 3.15-3.09 (4H, m), 2.86 (3H, s), 2.64-2.60 (2H, m), 2.51-2.44 (2H, m), 1.25 (3H, d)
1H NMR (400MHz, DMSO-d6)δ-ppm 7.46-7.32 (m, 5H), 7.27-7.22 (m, 2H), 7.13 (m,1H), 7.03 (m, 1H), 5.13 (s, 2H)
LCMS(2分、高pH):Rt=0.59分、MH+243(質量イオンはボロン酸に対応することが観察された)
LCMS(2分、ギ酸):Rt=1.18分、MH+278/280
LCMS(2分、ギ酸):Rt=0.62分、MH+244(質量イオンはボロン酸に対応することが観察された)
1H NMR (400MHz, CDCl3)δ-ppm 7.34-7.28 (m, 4H), 7.22 (m, 1H), 6.9 (t, 1H), 6.73 (m, 1H), 6.66 (t, 1H), 6.38 (m, 1H), 4.44 (q, 1H), 1.49 (d, 3H)
LCMS(2分、ギ酸):Rt=1.34分、MH+324及びRt=0.76分、MH+242(追加の質量イオンはボロン酸に対応する)
LCMS(2分、ギ酸):Rt=1.21分、MH+228/230
LCMS(2分、ギ酸):Rt=0.61分、MH+194(質量イオンはボロン酸に対応することが観察された)
LCMS(2分、ギ酸):Rt=0.37分、MH+207(質量イオンはLCMS条件下でのボロン酸への加水分解と一致することが観察された)。
LCMS(2分、高pH):Rt=0.84分、MH+229/231
LCMS(2分、ギ酸):Rt=0.34分、MH+195(質量イオンはLCMS条件下でのボロン酸への加水分解と一致することが観察された)。
LCMS(2分、ギ酸):Rt=0.44分、MH+198(質量イオンはLCMS条件下でのボロン酸への加水分解と一致することが観察された)。
LCMS(2分、ギ酸):Rt=0.33分、MH+237(質量イオンはLCMS条件下でのボロン酸への加水分解と一致することが観察された)。
LCMS(2分、ギ酸):Rt=0.59分、MH+361
LCMS(2分、ギ酸):Rt=0.87分、MH+532
LCMS(2分、高pH):Rt=0.65分、MH+215/217
LCMS(2分、ギ酸):Rt=0.37分、MH+=195(質量イオンはLCMS条件下でのボロン酸への加水分解と一致することが観察された)。
LCMS(2分、ギ酸):Rt=0.35分、MH+194(質量イオンはLCMS条件下でのボロン酸への加水分解と一致することが観察された)。
LCMS(2分、ギ酸):Rt=0.57分、MH+317
LCMS(2分、ギ酸):Rt=0.57分、MH+317
LCMS(2分、ギ酸):Rt=0.8分、MH+477
LCMS:MH+440/442
LCMS:M/Z230は、LCMS条件下でのボロン酸エステルの加水分解を示した。
1H NMR (400MHz, CDCl3)δ-ppm 8.56 (1H, d), 8.14 (1H, d), 7.61 (1H, t), 7.31 (1H, d), 7.17 (1H, t), 6.89 (2H, m), 6.67 (1H, br.s), 4.69 (2H, d), 1.31 (12H, s).
LCMS(2分、ギ酸):Rt=0.82分、MH+285/287
LCMS(2分、ギ酸):Rt=0.46分、MH+=251、LCMS条件下でのボロン酸への加水分解と一致する。
1H NMR (400MHz, CDCl3)δ-ppm 8.15 (1H, d), 7.19 (1H, d), 7.12 (1H, s), 4.42 (2H, t), 3.67 (2H, t), 3.53 (2H, t), 2.38 (2H, t), 2.00 (2H, m), 1.34 (12H, s).
LCMS(2分、高pH):Rt=0.67分、MH+400
LCMS(2分、ギ酸):Rt=0.59分、MH+215/217
LCMS(2分、ギ酸):Rt=0.55分、MH+518
LCMS(2分、ギ酸):Rt=0.55分、MH+518
LCMS(2分、ギ酸):Rt=0.33分、MH+418
LCMS(2分、ギ酸):Rt=0.57分、MH+=244/246。
LCMS(2分、ギ酸):Rt=0.87分、MH+=264/266。
LCMS(2分、ギ酸):Rt=0.61分、MH+=232/234。
LCMS(2分、ギ酸):Rt=0.69分、MH+=258/260。
LCMS(2分、ギ酸):Rt=0.71分、MH+=258/260。
7-[3,4-ビス(メチルオキシ)フェニル]-5-メチル-2-{[4-(メチルスルホニル)-1-ピペラジニル]メチル}フロ[3,2-c]ピリジン-4(5H)-オン
LCMS(2分、ギ酸):Rt=0.59分、MH+462
(R)-N-(4-(5-メチル-2-((2-メチル-4-(メチルスルホニル)ピペラジン-1-イル)メチル)-4-オキソ-4,5-ジヒドロフロ[3,2-c]ピリジン-7-イル)ピリジン-2-イル)アセトアミド
LCMS(2分、ギ酸):Rt=0.46分、MH+474
7-(3-(ベンジルオキシ)フェニル)-5-メチル-2-((4-(メチルスルホニル)ピペラジン-1-イル)メチル)フロ[3,2-c]ピリジン-4(5H)-オン
LCMS(2分、高pH):Rt=1.10分、MH+508,
7-(3-(ベンジルアミノ)フェニル)-5-メチル-2-((4-(メチルスルホニル)ピペラジン-1-イル)メチル)フロ[3,2-c]ピリジン-4(5H)-オン
LCMS(2分、高pH):Rt=1.04分、MH+=507
2-(((2-アミノエチル)アミノ)メチル)-7-(3,4-ジメトキシフェニル)-5-メチルフロ[3,2-c]ピリジン-4(5H)-オン二塩酸塩
LCMS(2分、ギ酸):Rt=0.48分、MH+=358
7-(4-(アミノメチル)フェニル)-5-メチル-2-((4-(メチルスルホニル)ピペラジン-1-イル)メチル)フロ[3,2-c]ピリジン-4(5H)-オン塩酸塩
LCMS(2分、高pH):Rt=0.65分、MH+=431
5-メチル-2-((4-(メチルスルホニル)ピペラジン-1-イル)メチル)-7-(2-((テトラヒドロ-2H-ピラン-4-イル)メトキシ)ピリジン-4-イル)フロ[3,2-c]ピリジン-4(5H)-オン
LCMS(2分、ギ酸):Rt=0.64分、MH+517
7-(3,4-ジメトキシフェニル)-5-メチル-2-(ピペリジン-1-イルメチル)フロ[3,2-c]ピリジン-4(5H)-オン
7-(3,4-ジメトキシフェニル)-5-メチル-2-(モルホリノメチル)フロ[3,2-c]ピリジン-4(5H)-オン
LCMS(2分、ギ酸):Rt=0.55分、MH+385
(R)-7-(3,4-ジメトキシフェニル)-5-メチル-2-((2-メチル-4-(メチルスルホニル)ピペラジン-1-イル)メチル)フロ[3,2-c]ピリジン-4(5H)-オン
2-((1,4-ジアゼパン-1-イル)メチル)-7-(3,4-ジメトキシフェニル)-5-メチルフロ[3,2-c]ピリジン-4(5H)-オン
5-メチル-2-((4-(メチルスルホニル)ピペラジン-1-イル)メチル)-7-(5-(1-フェニルエトキシ)ピリジン-3-イル)フロ[3,2-c]ピリジン-4(5H)-オン
2-((3,3-ジフルオロピペリジン-1-イル)メチル)-5-メチル-7-(2-((テトラヒドロ-2H-ピラン-4-イル)メトキシ)ピリジン-4-イル)フロ[3,2-c]ピリジン-4(5H)-オン
LCMS(2分、高pH):Rt=1.02分、MH+474
5-メチル-2-((4-(メチルスルホニル)ピペラジン-1-イル)メチル)-7-(2-((1-フェニルエチル)アミノ)ピリジン-4-イル)フロ[3,2-c]ピリジン-4(5H)-オン
5-メチル-2-((4-(メチルスルホニル)ピペラジン-1-イル)メチル)-7-(3-((1-フェニルエチル)アミノ)フェニル)フロ[3,2-c]ピリジン-4(5H)-オン
LCMS(2分、ギ酸):Rt=0.89分、MH+522
7-(3,4-ジメトキシフェニル)-5-メチル-2-((3-メチルモルホリノ)メチル)フロ[3,2-c]ピリジン-4(5H)-オン
N-(4-(2-((3-フルオロピペリジン-1-イル)メチル)-5-メチル-4-オキソ-4,5-ジヒドロフロ[3,2-c]ピリジン-7-イル)ピリジン-2-イル)アセトアミド
N-(4-(2-((3,3-ジフルオロピペリジン-1-イル)メチル)-5-メチル-4-オキソ-4,5-ジヒドロフロ[3,2-c]ピリジン-7-イル)ピリジン-2-イル)アセトアミド
2-((3-フルオロピペリジン-1-イル)メチル)-7-(4-メトキシフェニル)-5-メチルフロ[3,2-c]ピリジン-4(5H)-オン塩酸塩
LCMS(2分、高pH):Rt=1.0分、MH+371
5-メチル-2-(モルホリノメチル)-7-(2-((テトラヒドロ-2H-ピラン-4-イル)メトキシ)ピリジン-4-イル)フロ[3,2-c]ピリジン-4(5H)-オン
LCMS(2分、ギ酸):Rt=0.6分、MH+440
5-メチル-2-(1-(4-(メチルスルホニル)ピペラジン-1-イル)エチル)-7-(2-((テトラヒドロ-2H-ピラン-4-イル)メトキシ)ピリジン-4-イル)フロ[3,2-c]ピリジン-4(5H)-オンホルメート
LCMS(2分、ギ酸):Rt=0.67分、MH+531
(S)-5-メチル-2-(1-(4-(メチルスルホニル)ピペラジン-1-イル)エチル)-7-(2-((テトラヒドロ-2H-ピラン-4-イル)メトキシ)ピリジン-4-イル)フロ[3,2-c]ピリジン-4(5H)-オン及び(R)-5-メチル-2-(1-(4-(メチルスルホニル)ピペラジン-1-イル)エチル)-7-(2-((テトラヒドロ-2H-ピラン-4-イル)メトキシ)ピリジン-4-イル)フロ[3,2-c]ピリジン-4(5H)-オン
DMF(0.5mL)中の5-ヨード-4-メトキシ-1-メチル-2'-((テトラヒドロ-2H-ピラン-4-イル)メトキシ)-[3,4'-ビピリジン]-6(1H)-オン(調製については中間体19を参照、250mg、0.548mmol)、1-(ブタ-3-イン-2-イル)-4-(メチルスルホニル)ピペラジン(調製については中間体20を参照、356mg、1.644mmol)、ヨウ化銅(I)(25.04mg、0.131mmol)及びビス(トリフェニルホスフィン)パラジウム(II)ジクロリド(15.00mg、0.021mmol)の混合物を、マイクロ波を使用して120℃で6時間加熱した。
LCMS(2分、ギ酸):Rt=0.67分、MH+531
実施例21b:19mg、白色固体。LCMS(2分、ギ酸):Rt=0.67分、MH+531。キラルHPLCによるエナンチオマー純度=98% e.e
絶対的立体化学の帰属は行わなかった。
2-((1,4-オキサゼパン-4-イル)メチル)-5-メチル-7-(2-((テトラヒドロ-2H-ピラン-4-イル)メトキシ)ピリジン-4-イル)フロ[3,2-c]ピリジン-4(5H)-オン
LCMS(2分、ギ酸):Rt=0.6分、MH+454
(R)-7-(2-(シクロプロピルメトキシ)ピリジン-4-イル)-5-メチル-2-((2-メチル-4-(メチルスルホニル)ピペラジン-1-イル)メチル)フロ[3,2-c]ピリジン-4(5H)-オン
LCMS(2分、ギ酸):Rt=0.74分、MH+487
(R)-N-(4-(5-メチル-2-((2-メチル-4-(メチルスルホニル)ピペラジン-1-イル)メチル)-4-オキソ-4,5-ジヒドロフロ[3,2-c]ピリジン-7-イル)ピリジン-2-イル)シクロプロパンカルボキサミド
LCMS(2分、ギ酸):Rt=0.56分、MH+=500
(R)-N-(4-(5-メチル-2-((2-メチル-4-(メチルスルホニル)ピペラジン-1-イル)メチル)-4-オキソ-4,5-ジヒドロフロ[3,2-c]ピリジン-7-イル)ピリジン-2-イル)プロピオンアミド
LCMS(2分、ギ酸):Rt=0.53分、MH+=488
(R)-7-(2-(2-メトキシエトキシ)ピリジン-4-イル)-5-メチル-2-((2-メチル-4-(メチルスルホニル)ピペラジン-1-イル)メチル)フロ[3,2-c]ピリジン-4(5H)-オン
(R)-5-メチル-2-((2-メチル-4-(メチルスルホニル)ピペラジン-1-イル)メチル)-7-(2-(2-(ピロリジン-1-イル)エトキシ)ピリジン-4-イル)フロ[3,2-c]ピリジン-4(5H)-オン
2-((1,1-ジオキシドチオモルホリノ)メチル)-5-メチル-7-(2-((テトラヒドロ-2H-ピラン-4-イル)メトキシ)ピリジン-4-イル)フロ[3,2-c]ピリジン-4(5H)-オン
LCMS:MH+488
5-メチル-2-((4-(メチルスルホニル)ピペラジン-1-イル)メチル)-7-(2-((テトラヒドロ-2H-ピラン-4-イル)メトキシ)ピリジン-4-イル)フロ[2,3-d]ピリダジン-4(5H)-オン
LCMS(2分、ギ酸):Rt=0.78分、MH+518
(R)-N-メチル-N-(4-(5-メチル-2-((2-メチル-4-(メチルスルホニル)ピペラジン-1-イル)メチル)-4-オキソ-4,5-ジヒドロフロ[3,2-c]ピリジン-7-イル)ピリジン-2-イル)アセトアミド
7-(3-(シクロプロピルメトキシ)ピリジン-4-イル)-5-メチル-2-((4-(メチルスルホニル)ピペラジン-1-イル)メチル)フロ[3,2-c]ピリジン-4(5H)-オン
(R)-7-(3-(シクロプロピルメトキシ)ピリジン-4-イル)-5-メチル-2-((2-メチル-4-(メチルスルホニル)ピペラジン-1-イル)メチル)フロ[3,2-c]ピリジン-4(5H)-オン
7-(3,4-ジメトキシフェニル)-5-メチル-2-((4-(メチルスルホニル)ピペラジン-1-イル)メチル)フロ[2,3-d]ピリダジン-4(5H)-オン
2-((1,4-ジアゼパン-1-イル)メチル)-5-メチル-7-(2-((ピリジン-2-イルメチル)アミノ)ピリジン-4-イル)フロ[3,2-c]ピリジン-4(5H)-オン塩酸塩
(R)-5-メチル-2-((2-メチル-4-(メチルスルホニル)ピペラジン-1-イル)メチル)-7-(2-(2-(2-オキソピロリジン-1-イル)エトキシ)ピリジン-4-イル)フロ[3,2-c]ピリジン-4(5H)-オン
N-(4-(5-メチル-2-(1-(4-(メチルスルホニル)ピペラジン-1-イル)エチル)-4-オキソ-4,5-ジヒドロフロ[3,2-c]ピリジン-7-イル)ピリジン-2-イル)アセトアミド、ギ酸塩
(R)-N-(4-(5-メチル-2-(1-(4-(メチルスルホニル)ピペラジン-1-イル)エチル)-4-オキソ-4,5-ジヒドロフロ[3,2-c]ピリジン-7-イル)ピリジン-2-イル)アセトアミド及び(S)-N-(4-(5-メチル-2-(1-(4-(メチルスルホニル)ピペラジン-1-イル)エチル)-4-オキソ-4,5-ジヒドロフロ[3,2-c]ピリジン-7-イル)ピリジン-2-イル)アセトアミド
(R)-N-(4-(5-メチル-2-(1-(4-(メチルスルホニル)ピペラジン-1-イル)エチル)-4-オキソ-4,5-ジヒドロフロ[3,2-c]ピリジン-7-イル)ピリジン-2-イル)アセトアミド及び(S)-N-(4-(5-メチル-2-(1-(4-(メチルスルホニル)ピペラジン-1-イル)エチル)-4-オキソ-4,5-ジヒドロフロ[3,2-c]ピリジン-7-イル)ピリジン-2-イル)アセトアミドを得た。各試料について絶対的立体化学の帰属は行わなかった。
第1の溶離異性体(18mg)、キラル分析HPLCにより99.8%単一エナンチオマー。LCMS(2分、ギ酸):Rt=0.49分、MH+474。
第2の溶離異性体(19mg)、キラル分析HPLCにより99.6%単一エナンチオマー。LCMS(2分、ギ酸):Rt=0.48分、MH+474。
分析方法:Chiralpak ID3 50mm×4.6mm、3ミクロンカラム。移動相:UV DAD検出(280nm、帯域幅140nm、基準400nm(帯域幅20nm))で、f=1mL/分でのメタノール中0.2% v/vイソプロピルアミン。
N-(4-(5-メチル-2-((4-(メチルスルホニル)ピペラジン-1-イル)メチル)-4-オキソ-4,5-ジヒドロフロ[3,2-c]ピリジン-7-イル)ピリジン-2-イル)アセトアミド
LCMS(2分、高pH):Rt=0.64分、MH+460
(R)-N-(5-(5-メチル-2-((2-メチル-4-(メチルスルホニル)ピペラジン-1-イル)メチル)-4-オキソ-4,5-ジヒドロフロ[3,2-c]ピリジン-7-イル)ピリジン-3-イル)アセトアミド
7-(3-((シクロプロピルメチル)アミノ)ピリジン-4-イル)-5-メチル-2-((4-(メチルスルホニル)ピペラジン-1-イル)メチル)フロ[3,2-c]ピリジン-4(5H)-オン
(R)-7-(3-((シクロプロピルメチル)アミノ)ピリジン-4-イル)-5-メチル-2-((2-メチル-4-(メチルスルホニル)ピペラジン-1-イル)メチル)フロ[3,2-c]ピリジン-4(5H)-オン
LCMS(2分、ギ酸):Rt=0.48分、MH+486。
5-メチル-2-(((R)-2-メチル-4-(メチルスルホニル)ピペラジン-1-イル)メチル)-7-(3-(オキセタン-2-イルメトキシ)ピリジン-4-イル)フロ[3,2-c]ピリジン-4(5H)-オン
1,4-ジオキサン(5mL)中の(R)-7-ブロモ-5-メチル-2-((2-メチル-4-(メチルスルホニル)ピペラジン-1-イル)メチル)フロ[3,2-c]ピリジン-4(5H)-オン(調製については中間体5を参照、120mg、0.287mmol)、4,4,5,5-テトラメチル-1,3,2-ジオキサボロラン(0.250mL、1.721mmol)及びトリエチルアミン(0.160mL、1.147mmol)の懸濁液に、PEPPSI-SIPr(17mg、0.025mmol)を添加した。混合物を100℃で3時間還流させた。反応混合物をEtOAcで希釈し、セライトに通して濾過し、次いで真空中で濃縮して、粗製の(R)-5-メチル-2-((2-メチル-4-(メチルスルホニル)ピペラジン-1-イル)メチル)-7-(4,4,5,5-テトラメチル-1,3,2-ジオキサボロラン-2-イル)フロ[3,2-c]ピリジン-4(5H)-オンを黄色油状物(391mg)として得た。純度は22.3%と推定され、更に精製することなくステップ2において直接使用した。
マイクロ波バイアル内の1,2-DME(3mL)中の、ステップ1からの粗製の(R)-5-メチル-2-((2-メチル-4-(メチルスルホニル)ピペラジン-1-イル)メチル)-7-(4,4,5,5-テトラメチル-1,3,2-ジオキサボロラン-2-イル)フロ[3,2-c]ピリジン-4(5H)-オン(391mg、22.3% w/w、0.187mmol)、粗製の4-ブロモ-3-(オキセタン-2-イルメトキシ)ピリジン(調製については中間体67を参照、80mg、59.5% w/w、0.195mmol)及び水中2M炭酸ナトリウム(0.749mL、1.499mmol)の撹拌懸濁液に、テトラキス(トリフェニルホスフィン)パラジウム(0)(12mg、10.38μmol)を添加した。マイクロ波バイアルを密封し、Biotage initiator microwaveに入れ、120℃で30分間加熱した。混合物をEtOAc(25mL)及び水(25mL)で希釈した。2つの層を分離し、水相をEtOAc(5×25mL)で再抽出した。有機相を、疎水性フリットを使用して乾燥させ、真空中で濃縮した。残留物をDMSO(4mL)に溶解し、MDAPによって精製した。適切な画分を合わせ、真空中で濃縮して、黄色油状物を得た。残留物をMeOHに溶解し、MeOHで予め調整したアミノ-プロピルカートリッジ(2g)上に装填した。カートリッジをMeOHで溶離し、適切な画分を合わせ、真空中で濃縮して、5-メチル-2-(((R)-2-メチル-4-(メチルスルホニル)ピペラジン-1-イル)メチル)-7-(3-(オキセタン-2-イルメトキシ)ピリジン-4-イル)フロ[3,2-c]ピリジン-4(5H)-オンを黄色油状物(32.2mg、34.2%)として得た。LCMS(2分、ギ酸):Rt=0.44分、MH+503。
5-メチル-2-(((R)-2-メチル-4-(メチルスルホニル)ピペラジン-1-イル)メチル)-7-(3-((R)-オキセタン-2-イルメトキシ)ピリジン-4-イル)フロ[3,2-c]ピリジン-4(5H)-オン
5-メチル-2-(((R)-2-メチル-4-(メチルスルホニル)ピペラジン-1-イル)メチル)-7-(3-((S)-オキセタン-2-イルメトキシ)ピリジン-4-イル)フロ[3,2-c]ピリジン-4(5H)-オン
5-メチル-2-(((R)-2-メチル-4-(メチルスルホニル)ピペラジン-1-イル)メチル)-7-(3-((R)-オキセタン-2-イルメトキシ)ピリジン-4-イル)フロ[3,2-c]ピリジン-4(5H)-オン(実施例42)(32mg)を得た。キラルHPLC-純度98.8%(4.6mm×25cm Chiralpak IAカラム、40% EtOH/ヘプタン、f=1.0mL/分、波長215nm)。LCMS(2分、ギ酸):Rt=0.42分、MH+503を得た。
また、
5-メチル-2-(((R)-2-メチル-4-(メチルスルホニル)ピペラジン-1-イル)メチル)-7-(3-((S)-オキセタン-2-イルメトキシ)ピリジン-4-イル)フロ[3,2-c]ピリジン-4(5H)-オン(実施例43)(36mg)も得た。キラルHPLC、純度98.4%(4.6mm×25cm Chiralpak IAカラム、40% EtOH/ヘプタン、f=1.0mL/分、波長215nm)。LCMS(2分、ギ酸):Rt=0.42分、MH+503。
5-メチル-2-(((R)-2-メチル-4-(メチルスルホニル)ピペラジン-1-イル)メチル)-7-(3-((R)-オキセタン-2-イルメトキシ)ピリジン-4-イル)フロ[3,2-c]ピリジン-4(5H)-オン
(R)-4-ブロモ-3-(オキセタン-2-イルメトキシ)ピリジン(調製については中間体69を参照、19.83g、81mmol)を、炭酸セシウム(37.8g、116mmol)、トルエン(200mL)及びメタノール(60mL)と混合し、窒素を反応混合物に吹き込んで発泡させることにより20分間脱気した。Pd(PPh3)4(6.70g、5.80mmol)及び(R)-5-メチル-2-((2-メチル-4-(メチルスルホニル)ピペラジン-1-イル)メチル)-7-(4,4,5,5-テトラメチル-1,3,2-ジオキサボロラン-2-イル)フロ[3,2-c]ピリジン-4(5H)-オン(調製については中間体5aを参照、30g、58.0mmol)を添加し、加熱を18時間続けた。混合物を冷却し、真空中で蒸発させ、残留物をDCM(300mL)と水(500mL)とに分配した。水層をDCM(300mL)で抽出し、合わせた有機物を乾燥させ、真空中で蒸発させて、淡黄色泡状物を得た。不純生成物を750gのシリカカラム上に装填し、10容量のアセトンで、次いで30%メタノール/アセトンで溶離した。適切な画分を真空中で蒸発させて、淡黄色泡状物を得、これをDCM(300mL)に溶解し、チオウレイドプロピルシリカ(thioureidopropyl silica)(Aldrich、30g)で処理した。混合物を30分間撹拌し、次いで濾過した。シリカをDCM(200mL)で洗浄し、濾液を真空中で蒸発させて、表題化合物(11.1g、22.09mmol、収率38.1%)をベージュ色の泡状物として得た。これを、ChiralPak 1A 20um 5×20cmカラムを使用するキラルHPLCによる最終精製のために、更なるバッチと合わせた。移動相は、118mL/分の流速及び230nmでの検出でのメタノールであった。適切な画分を合わせ、メタノールを蒸発させた。残留物をDCM及びEtOAcから再度蒸発させて、淡黄色泡状物を得、これを真空オーブン内で乾燥させて、表題化合物を得た。1H NMR (400MHz, CDCl3)δ-ppm 8.46 (1H, s), 8.38 (1H, d), 7.88 (1H, s), 7.59 (1H, d), 6.88 (1H, s), 5.13 (1H, m), 4.68 (1H, m), 4.43 (1H, m), 4.30 (2H, d), 3.90 (2H, s), 3.68 (3H, s), 3.50 (2H, m), 2.93 (2H, m), 2.73 (3H, s), 2.74 (1H, m), 2.60 (4H, m), 1.22 (3H, d). LCMS (2分, ギ酸): Rt = 0.44分, MH+ 503. キラルHPLC純度 >99%.
(R)-5-メチル-2-((2-メチル-4-(メチルスルホニル)ピペラジン-1-イル)メチル)-7-(3-(オキセタン-3-イルメトキシ)ピリジン-4-イル)フロ[3,2-c]ピリジン-4(5H)-オン
7-(3-((2,2-ジフルオロシクロプロピル)メトキシ)ピリジン-4-イル)-5-メチル-2-(((R)-2-メチル-4-(メチルスルホニル)ピペラジン-1-イル)メチル)フロ[3,2-c]ピリジン-4(5H)-オン
N-(4-(5-メチル-2-(2-(4-(メチルスルホニル)ピペラジン-1-イル)プロパン-2-イル)-4-オキソ-4,5-ジヒドロフロ[3,2-c]ピリジン-7-イル)ピリジン-2-イル)アセトアミド
(R)-7-(3-(2-メトキシエトキシ)ピリジン-4-イル)-5-メチル-2-((2-メチル-4-(メチルスルホニル)ピペラジン-1-イル)メチル)フロ[3,2-c]ピリジン-4(5H)-オン
5-メチル-2-(((R)-2-メチル-4-(メチルスルホニル)ピペラジン-1-イル)メチル)-7-(3-((テトラヒドロフラン-3-イル)メトキシ)ピリジン-4-イル)フロ[3,2-c]ピリジン-4(5H)-オン
5-メチル-2-(((R)-2-メチル-4-(メチルスルホニル)ピペラジン-1-イル)メチル)-7-(3-((テトラヒドロフラン-2-イル)メトキシ)ピリジン-4-イル)フロ[3,2-c]ピリジン-4(5H)-オン
N-(4-(5-メチル-4-オキソ-2-((5-オキソ-1,4-ジアゼパン-1-イル)メチル)-4,5-ジヒドロフロ[3,2-c]ピリジン-7-イル)ピリジン-2-イル)アセトアミド
N-(4-(5-メチル-2-((4-メチル-3-オキソピペラジン-1-イル)メチル)-4-オキソ-4,5-ジヒドロフロ[3,2-c]ピリジン-7-イル)ピリジン-2-イル)アセトアミド
(S)-N-(4-(5-メチル-2-((3-メチル-4-(メチルスルホニル)ピペラジン-1-イル)メチル)-4-オキソ-4,5-ジヒドロフロ[3,2-c]ピリジン-7-イル)ピリジン-2-イル)アセトアミド
N-(4-(5-メチル-2-((4-(メチルスルホニル)-2-オキソピペラジン-1-イル)メチル)-4-オキソ-4,5-ジヒドロフロ[3,2-c]ピリジン-7-イル)ピリジン-2-イル)アセトアミド
副生成物、N-(4-(2,5-ジメチル-3-(4-(メチルスルホニル)-2-オキソピペラジン-1-イル)-4-オキソ-4,5-ジヒドロフロ[3,2-c]ピリジン-7-イル)ピリジン-2-イル)アセトアミド(18mg、収率7%)も得た。1H NMR (400MHz, DMSO-d6)δ-ppm 10.55 (1H, s), 8.58 (1H, s), 8.38 (1H, d), 8.17 (1H, s), 7.46 (1H, dd), 4.02 (3H, m), 3.61 (3H, m), 3.59 (3H, s), 3.10 (3H, s), 2.30 (3H, s), 2.13 (3H, s). LCMS (2分, 高pH): Rt = 0.65分, MH+ 474.
式(I)の化合物を、次のアッセイ法の1つ以上で試験することができる:
時間分解蛍光共鳴エネルギー移動(TR-FRET)アッセイ
結合を、時間分解蛍光共鳴エネルギー移動結合アッセイを使用して評価した。このアッセイは、タンパク質のN-末端の6His精製タグを、ドナーフルオロフォアとして作用するタンパク質へのユーロピウムの結合を可能にするユーロピウムキレート(PerkinElmer AD0111)で標識された抗-6His抗体に関するエピトープとして利用する。ブロモドメインBRD2、BRD3、BRD4及びBRDTの小分子高親和性結合剤を、Alexa Fluor647(参照化合物X)で標識し、この標識は、FRET対でアクセプターとして作用する。
反応混合物を、蒸発乾固させた。固体をアセトニトリル/水/酢酸(5/4/1、<1ml)中に溶解し、濾過し、Phenomenex Jupiter C18分取カラムに適用し、次の勾配(A=0.1%トリフルオロ酢酸/水、B=0.1%TFA/90%アセトニトリル/10%水)、流速=10ml/分、AU=20/10(214nm)で溶離した:
5〜35%、t=0分:B=5%、t=10分:B=5%、t=100分:B=35%、t=115分:B=100%(分離勾配:0.33%/分)。
競合化合物の不在下で、ユーロピウムを励起すると、ドナーはλ=618nmでの発光を引き起こし、この発光はAlexaで標識されたブロモドメイン結合化合物を励起し、λ=647nMで測定可能なエネルギー移動の増加につながる。これらのタンパク質に結合できる十分な濃度の化合物の存在下では、相互作用が妨害され、蛍光共鳴エネルギー移動の定量可能な降下につながる。
ヒトの組換えブロモドメイン[(BRD2(1〜473)(Y113A)及び(Y386A)、BRD3(1〜435)(Y73A)及び(Y348A)、BRD4(1〜477)(Y97A)及び(Y390A)、並びにBRDT(1〜397)(Y66A)及び(Y309A)]を、N-末端に6-Hisタグを付けて大腸菌(E.coli)細胞中で発現させた(BRD2/3/4についてはpET15bベクター中、BRDTについてはpET28aベクター中で)。Hisでタグを付けたブロモドメインのペレットを、50mM HEPES(pH7.5)、300mM NaCl、10mMイミダゾール、及び1μl/mlプロテアーゼ阻害薬からなるカクテル液に再懸濁させ、超音波処理を使用して大腸菌細胞から抽出し、ニッケルセファロース高速カラムを使用して精製し、タンパク質を洗浄し、次いで50mM HEPES(pH7.5)、150mM NaCl、500mMイミダゾールからなる緩衝液での0〜500mMイミダゾールのカラム容積の20倍を超える線形勾配で溶離した。最終精製を、Superdex 200分取級サイズ排除カラムにより完了した。精製されたタンパク質を、20mM HEPES(pH7.5)及び100mM NaCl中、-80℃で貯蔵した。タンパク質の同定は、ペプチド質量フィンガープリンティング及び質量分析で確認された予想分子量により確認された。
すべてのアッセイ成分を、50mM HEPES(pH7.4)、50mM NaCl、5%グリセロール、1mM DTT及び1mM CHAPSからなる緩衝組成物中に溶解した。ブロモドメインタンパク質の最終濃度は、10nMとし、Alexa Fluor647リガンドをKdで存在させた。これらの成分を予め混合し、この反応混合物の5μlを、Greiner社製384ウェル黒色低容積マイクロタイタープレート中の種々の濃度の試験化合物又はDMSO媒体(最終的に0.5%DMSO)の50nlを含むすべてのウェルに添加し、暗所において室温で30分間インキュベートした。最終濃度が1.5nMの抗-6Hisユーロピウムキレートを含む5μlの検出混合物をすべてのウェルに添加し、少なくとも30分間の暗所での更なるインキュベーションを実施した。次いで、プレートを、Envision社製プレートリーダーで読み取った(λex=317nm、ドナーλem=615nm、アクセプターλem=665nm、二色LANCEデュアル)。時間分解蛍光強度の測定を、双方の発光波長で行い、アクセプター/ドナーの比率を、計算し、データ解析に使用した。すべてのデータを、各プレート上の16の高い阻害薬対照(WO2011/054846A1の実施例11)及び16の低い(DMSO)対照ウェルの平均に対して正規化した。次いで、次の形態の4つのパラメーターの曲線フィッティングを適用した。
Y=a+((b-a)/(1+ (10Λ×/10Λc)Λd)
式中、「a」は最小値であり、「b」はHill勾配であり、「c」はpIC50であり、「d」は最大値である。
BRD4 BD2に比較したBRD4 BD1に対する選択性は、次のように計算した。
選択性=BRD4 BD1 pIC50-BRD4 BD2 pIC50
pIC50値は、log10単位として表わされる。
Claims (57)
- 式(I)の化合物
Vは、N又はC-R2であり、
Wは、N又はC-R8であり、
Xは、N、CH又はC(CH3)であり、
Yは、N又はC-R5であり、
Zは、N又はC-R15であり、
Qは、N又はCHであり、
R1は、C1〜4アルキル又は重水素化C1〜4アルキルであり、
R2は、存在する場合、H、OH、C1〜4アルキル、ハロ、-CF3、-NH2、-OC1〜4アルキル、-NHC(O)H、-NHC(O)C1〜4アルキル、-N(CH3)C(O)C1〜4アルキル、-NHC(O)NH2、-NHC(O)C1〜4アルキレンNH2、-N(CH3)C(O)NH2、-N(CH3)C(O)C1〜4アルキレンNH2、-NHC2〜4アルキレンOCH3、-N(CH3)C2〜4アルキレンOCH3、-OC2〜4アルキレンOCH3、-OC2〜4アルキレンOHであるか、又は
R2は、-G-CH2CH(R3)(R4)、-G-CH(R3)(R4)及び-G-R3から選択される基であり、ここで、
Gは、NH、N(CH3)、O、C(O)NH又はNHC(O)であり、
R3は、フェニル、ピリジニル、C3〜7シクロアルキル、又は=Oで置換されていてもよい複素環であり、
R4は、H又はC1〜4アルキルであり、
R5は、存在する場合、H、C1〜4アルキル、ハロ、-CF3、CN、OH、-OC1〜4アルキル、-CH2NH2、-OCF3、-SO2CH3、-C(O)NHC1〜4アルキル又は-CO2Hであり、
R6は、-NR11R12、又は基
Dは、CH又はNであり、
Eは、N、O、CH又はSO2であり、
R7は、存在する場合、H、OH、C1〜4アルキル、-NH2、-SO2C1〜4アルキル、-SO2フェニル、-SO2ベンジル、-SO2N(CH3)2、-NHSO2CH3、-C(O)C1〜4アルキル、-C(O)フェニルであり、
R8は、存在する場合、H、C1〜4アルキル、ハロ、-CF3、CN、OH、-OC1〜4アルキル、-OC2〜4アルキレンOC1〜4アルキル、-OCF3、-OC1〜4アルキレンF、-OC1〜4アルキレンCHF2、-OC2〜4アルキレンOH、-Oフェニル、-OC1〜4アルキレンフェニル、-NHC3〜7シクロアルキル、-NHC1〜4アルキレンC3〜7シクロアルキル、-OC3〜7シクロアルキル、-OC1〜4アルキレンC3〜7シクロアルキル、-NHC4〜6複素環、-NHC1〜4アルキレンC4〜6複素環、-OC4〜6複素環又は-OC1〜4アルキレンC4〜6複素環であり、ここでC3〜7シクロアルキル又はC4〜6複素環はそれぞれ、ハロ、OH、オキソ、C1〜4アルキル及び-NH2から独立に選択される1つ又は2つの置換基で置換されていてもよいか、又は
R8とR2は、それらが結合している炭素原子と一緒になって、オキソで置換されていてもよい複素環を形成し、
R9は、H、C1〜4アルキル、-C(O)NH2、-CO2CH3、-CF3、ハロ、OH、-OC1〜4アルキル、-CH2OH、-C(O)NHCH3、-C(O)NH(CH3)2、-CH2OC1〜4アルキル又は-CH2OCH2C3〜7シクロアルキルであり、
R10は、H、C1〜4アルキル、-C(O)NH2、-CO2CH3、-CF3、ハロ、OH、-OC1〜4アルキル又はオキソであり、
R11は、H、C1〜4アルキル又はSO2CH3であり、
R12は、H、C1〜4アルキル、C2〜4アルキレンNHR13、SO2CH3、複素環、又はSO2を含む複素環であり、
R13は、H又はSO2CH3であり、
R14は、H又はC1〜4アルキルであり、
R15は、H、C1〜4アルキル又はNHC(O)C1〜4アルキルであり、
R16は、H又はC1〜4アルキルであり、
n及びmは、それぞれ、0、1及び2から独立に選択される整数であり、但し、V、W、X、Y及びZのうち2種以下はNである]、又はその塩。 - Vが、C-R2である、請求項1に記載の化合物又はその塩。
- Wが、C-R8である、請求項1又は請求項2に記載の化合物又はその塩。
- R8が、H、OH、-OC1〜4アルキル、-OC2〜4アルキレンOCH3、-OC1〜4アルキレンF、-OC1〜4アルキレンCHF2、-OC2〜4アルキレンOH、-NHCH2C3〜7シクロアルキル、-OC3〜7シクロアルキル、-OCH2 C3〜7シクロアルキル、-O-C4〜6複素環、-OCH2C4〜6複素環又は-OCH2CH2C4〜6複素環であり、ここで、C3〜7シクロアルキル又はC4〜6複素環は、それぞれ、フルオロ及びオキソから独立に選択される1つ又は2つの置換基で置換されていてもよい、請求項3に記載の化合物又はその塩。
- R8が、H、OH、-OCH2CH3、-OCH(CH3)2、-OCH2CH2OCH3、-OCH2CH(CH3)OCH3、-OCH(CH3)CH2OCH3、-OCH2CH2F、-OCH2CHF2、-OCH2CH2OH、-NHCH2シクロプロピル、-Oシクロプロピル、-OCH2シクロプロピル、-Oテトラヒドロフラニル、-Oオキセタニル、-OCH2テトラヒドロフラニル、-OCH2オキセタニル又は-OCH2CH2ピロリジニルであり、ここで、C3〜7シクロアルキル又はC4〜6複素環は、それぞれ、フルオロ及びオキソから独立に選択される1つ又は2つの置換基で置換されていてもよい、請求項4に記載の化合物又はその塩。
- R8が、H、C1〜4アルキル又は-OCH2C3〜7シクロアルキルである、請求項3に記載の化合物又はその塩。
- R8がHである、請求項6に記載の化合物又はその塩。
- WがNである、請求項1又は請求項2に記載の化合物又はその塩。
- XがCHである、請求項1から8のいずれか一項に記載の化合物又はその塩。
- YがC-R5である、請求項1から9のいずれか一項に記載の化合物又はその塩。
- R5が、H、-OCH3又は-CH2NH2である、請求項10に記載の化合物又はその塩。
- YがNである、請求項1から9のいずれか一項に記載の化合物又はその塩。
- ZがNである、請求項1から12のいずれか一項に記載の化合物又はその塩。
- ZがC-R15である、請求項1から12のいずれか一項に記載の化合物又はその塩。
- R15がHである、請求項14に記載の化合物又はその塩。
- QがCHである、請求項1から15のいずれか一項に記載の化合物又はその塩。
- R1がメチルである、請求項1から16のいずれか一項に記載の化合物又はその塩。
- R2が、H、-OC1〜4アルキル、-NHC(O)C1〜4アルキル又は-N(CH3)C(O)C1〜4アルキルである、請求項1から17のいずれか一項に記載の化合物又はその塩。
- R2が、H、-OCH3、-NHC(O)CH3、-NHC(O)CH2CH3又は-N(CH3)C(O)CH3である、請求項18に記載の化合物又はその塩。
- R2が、-G-CH(R3)(R4)基である、請求項1から17のいずれか一項に記載の化合物又はその塩。
- R2が、-G-CH2CH(R3)(R4)基である、請求項1から17のいずれか一項に記載の化合物又はその塩。
- Gが、NH、O又はNHC(O)である、請求項20又は請求項21に記載の化合物又はその塩。
- R3が、フェニル、ピリジニル、シクロプロピル、テトラヒドロピラニル、ピロリジニル、又は=Oで置換されているピロリジニルである、請求項20から22のいずれか一項に記載の化合物又はその塩。
- R4が、H又はメチルである、請求項20から24のいずれか一項に記載の化合物又はその塩。
- DがNである、請求項26に記載の化合物又はその塩。
- Eが、N、O又はCHである、請求項26又は請求項27に記載の化合物又はその塩。
- EがNである、請求項28に記載の化合物又はその塩。
- R7が、H又は-SO2CH3である、請求項26から29のいずれか一項に記載の化合物又はその塩。
- R7が、-SO2CH3である、請求項30に記載の化合物又はその塩。
- R9が、H、メチル又はフルオロである、請求項26から30のいずれか一項に記載の化合物又はその塩。
- R10が、H又はフルオロである、請求項26から32のいずれか一項に記載の化合物又はその塩。
- nが1である、請求項26から33のいずれか一項に記載の化合物又はその塩。
- mが1又は2である、請求項26から34のいずれか一項に記載の化合物又はその塩。
- R6が-NR11R12である、請求項1から25のいずれか一項に記載の化合物又はその塩。
- R11がHである、請求項37に記載の化合物又はその塩。
- R12が-CH2CH2NHR13であり、R13がHである、請求項37又は請求項38に記載の化合物又はその塩。
- 7-[3,4-ビス(メチルオキシ)フェニル]-5-メチル-2-{[4-(メチルスルホニル)-1-ピペラジニル]メチル}フロ[3,2-c]ピリジン-4(5H)-オン;
(R)-N-(4-(5-メチル-2-((2-メチル-4-(メチルスルホニル)ピペラジン-1-イル)メチル)-4-オキソ-4,5-ジヒドロフロ[3,2-c]ピリジン-7-イル)ピリジン-2-イル)アセトアミド;
7-(3-(ベンジルオキシ)フェニル)-5-メチル-2-((4-(メチルスルホニル)ピペラジン-1-イル)メチル)フロ[3,2-c]ピリジン-4(5H)-オン;
7-(3-(ベンジルアミノ)フェニル)-5-メチル-2-((4-(メチルスルホニル)ピペラジン-1-イル)メチル)フロ[3,2-c]ピリジン-4(5H)-オン;
2-(((2-アミノエチル)アミノ)メチル)-7-(3,4-ジメトキシフェニル)-5-メチルフロ[3,2-c]ピリジン-4(5H)-オン;
7-(4-(アミノメチル)フェニル)-5-メチル-2-((4-(メチルスルホニル)ピペラジン-1-イル)メチル)フロ[3,2-c]ピリジン-4(5H)-オン;
5-メチル-2-((4-(メチルスルホニル)ピペラジン-1-イル)メチル)-7-(2-((テトラヒドロ-2H-ピラン-4-イル)メトキシ)ピリジン-4-イル)フロ[3,2-c]ピリジン-4(5H)-オン;
7-(3,4-ジメトキシフェニル)-5-メチル-2-(ピペリジン-1-イルメチル)フロ[3,2-c]ピリジン-4(5H)-オン;
7-(3,4-ジメトキシフェニル)-5-メチル-2-(モルホリノメチル)フロ[3,2-c]ピリジン-4(5H)-オン;
(R)-7-(3,4-ジメトキシフェニル)-5-メチル-2-((2-メチル-4-(メチルスルホニル)ピペラジン-1-イル)メチル)フロ[3,2-c]ピリジン-4(5H)-オン;
2-((1,4-ジアゼパン-1-イル)メチル)-7-(3,4-ジメトキシフェニル)-5-メチルフロ[3,2-c]ピリジン-4(5H)-オン;
5-メチル-2-((4-(メチルスルホニル)ピペラジン-1-イル)メチル)-7-(5-(1-フェニルエトキシ)ピリジン-3-イル)フロ[3,2-c]ピリジン-4(5H)-オン;
2-((3,3-ジフルオロピペリジン-1-イル)メチル)-5-メチル-7-(2-((テトラヒドロ-2H-ピラン-4-イル)メトキシ)ピリジン-4-イル)フロ[3,2-c]ピリジン-4(5H)-オン;
5-メチル-2-((4-(メチルスルホニル)ピペラジン-1-イル)メチル)-7-(2-((1-フェニルエチル)アミノ)ピリジン-4-イル)フロ[3,2-c]ピリジン-4(5H)-オン;
5-メチル-2-((4-(メチルスルホニル)ピペラジン-1-イル)メチル)-7-(3-((1-フェニルエチル)アミノ)フェニル)フロ[3,2-c]ピリジン-4(5H)-オン;
7-(3,4-ジメトキシフェニル)-5-メチル-2-((3-メチルモルホリノ)メチル)フロ[3,2-c]ピリジン-4(5H)-オン;
N-(4-(2-((3-フルオロピペリジン-1-イル)メチル)-5-メチル-4-オキソ-4,5-ジヒドロフロ[3,2-c]ピリジン-7-イル)ピリジン-2-イル)アセトアミド;
N-(4-(2-((3,3-ジフルオロピペリジン-1-イル)メチル)-5-メチル-4-オキソ-4,5-ジヒドロフロ[3,2-c]ピリジン-7-イル)ピリジン-2-イル)アセトアミド;
2-((3-フルオロピペリジン-1-イル)メチル)-7-(4-メトキシフェニル)-5-メチルフロ[3,2-c]ピリジン-4(5H)-オン;
5-メチル-2-(モルホリノメチル)-7-(2-((テトラヒドロ-2H-ピラン-4-イル)メトキシ)ピリジン-4-イル)フロ[3,2-c]ピリジン-4(5H)-オン;
5-メチル-2-(1-(4-(メチルスルホニル)ピペラジン-1-イル)エチル)-7-(2-((テトラヒドロ-2H-ピラン-4-イル)メトキシ)ピリジン-4-イル)フロ[3,2-c]ピリジン-4(5H)-オン;
(S)-5-メチル-2-(1-(4-(メチルスルホニル)ピペラジン-1-イル)エチル)-7-(2-((テトラヒドロ-2H-ピラン-4-イル)メトキシ)ピリジン-4-イル)フロ[3,2-c]ピリジン-4(5H)-オン;
(R)-5-メチル-2-(1-(4-(メチルスルホニル)ピペラジン-1-イル)エチル)-7-(2-((テトラヒドロ-2H-ピラン-4-イル)メトキシ)ピリジン-4-イル)フロ[3,2-c]ピリジン-4(5H)-オン;
2-((1,4-オキサゼパン-4-イル)メチル)-5-メチル-7-(2-((テトラヒドロ-2H-ピラン-4-イル)メトキシ)ピリジン-4-イル)フロ[3,2-c]ピリジン-4(5H)-オン;
(R)-7-(2-(シクロプロピルメトキシ)ピリジン-4-イル)-5-メチル-2-((2-メチル-4-(メチルスルホニル)ピペラジン-1-イル)メチル)フロ[3,2-c]ピリジン-4(5H)-オン;
(R)-N-(4-(5-メチル-2-((2-メチル-4-(メチルスルホニル)ピペラジン-1-イル)メチル)-4-オキソ-4,5-ジヒドロフロ[3,2-c]ピリジン-7-イル)ピリジン-2-イル)シクロプロパンカルボキサミド;
(R)-N-(4-(5-メチル-2-((2-メチル-4-(メチルスルホニル)ピペラジン-1-イル)メチル)-4-オキソ-4,5-ジヒドロフロ[3,2-c]ピリジン-7-イル)ピリジン-2-イル)プロピオンアミド;
(R)-7-(2-(2-メトキシエトキシ)ピリジン-4-イル)-5-メチル-2-((2-メチル-4-(メチルスルホニル)ピペラジン-1-イル)メチル)フロ[3,2-c]ピリジン-4(5H)-オン;
(R)-5-メチル-2-((2-メチル-4-(メチルスルホニル)ピペラジン-1-イル)メチル)-7-(2-(2-(ピロリジン-1-イル)エトキシ)ピリジン-4-イル)フロ[3,2-c]ピリジン-4(5H)-オン;
2-((1,1-ジオキシドチオモルホリノ)メチル)-5-メチル-7-(2-((テトラヒドロ-2H-ピラン-4-イル)メトキシ)ピリジン-4-イル)フロ[3,2-c]ピリジン-4(5H)-オン;
5-メチル-2-((4-(メチルスルホニル)ピペラジン-1-イル)メチル)-7-(2-((テトラヒドロ-2H-ピラン-4-イル)メトキシ)ピリジン-4-イル)フロ[2,3-d]ピリダジン-4(5H)-オン;
(R)-N-メチル-N-(4-(5-メチル-2-((2-メチル-4-(メチルスルホニル)ピペラジン-1-イル)メチル)-4-オキソ-4,5-ジヒドロフロ[3,2-c]ピリジン-7-イル)ピリジン-2-イル)アセトアミド;
7-(3-(シクロプロピルメトキシ)ピリジン-4-イル)-5-メチル-2-((4-(メチルスルホニル)ピペラジン-1-イル)メチル)フロ[3,2-c]ピリジン-4(5H)-オン;
(R)-7-(3-(シクロプロピルメトキシ)ピリジン-4-イル)-5-メチル-2-((2-メチル-4-(メチルスルホニル)ピペラジン-1-イル)メチル)フロ[3,2-c]ピリジン-4(5H)-オン;
7-(3,4-ジメトキシフェニル)-5-メチル-2-((4-(メチルスルホニル)ピペラジン-1-イル)メチル)フロ[2,3-d]ピリダジン-4(5H)-オン;
2-((1,4-ジアゼパン-1-イル)メチル)-5-メチル-7-(2-((ピリジン-2-イルメチル)アミノ)ピリジン-4-イル)フロ[3,2-c]ピリジン-4(5H)-オン;
(R)-5-メチル-2-((2-メチル-4-(メチルスルホニル)ピペラジン-1-イル)メチル)-7-(2-(2-(2-オキソピロリジン-1-イル)エトキシ)ピリジン-4-イル)フロ[3,2-c]ピリジン-4(5H)-オン;
N-(4-(5-メチル-2-(1-(4-(メチルスルホニル)ピペラジン-1-イル)エチル)-4-オキソ-4,5-ジヒドロフロ[3,2-c]ピリジン-7-イル)ピリジン-2-イル)アセトアミド;
(R)-N-(4-(5-メチル-2-(1-(4-(メチルスルホニル)ピペラジン-1-イル)エチル)-4-オキソ-4,5-ジヒドロフロ[3,2-c]ピリジン-7-イル)ピリジン-2-イル)アセトアミド;
(S)-N-(4-(5-メチル-2-(1-(4-(メチルスルホニル)ピペラジン-1-イル)エチル)-4-オキソ-4,5-ジヒドロフロ[3,2-c]ピリジン-7-イル)ピリジン-2-イル)アセトアミド;
N-(4-(5-メチル-2-((4-(メチルスルホニル)ピペラジン-1-イル)メチル)-4-オキソ-4,5-ジヒドロフロ[3,2-c]ピリジン-7-イル)ピリジン-2-イル)アセトアミド;
(R)-N-(5-(5-メチル-2-((2-メチル-4-(メチルスルホニル)ピペラジン-1-イル)メチル)-4-オキソ-4,5-ジヒドロフロ[3,2-c]ピリジン-7-イル)ピリジン-3-イル)アセトアミド;
7-(3-((シクロプロピルメチル)アミノ)ピリジン-4-イル)-5-メチル-2-((4-(メチルスルホニル)ピペラジン-1-イル)メチル)フロ[3,2-c]ピリジン-4(5H)-オン;
(R)-7-(3-((シクロプロピルメチル)アミノ)ピリジン-4-イル)-5-メチル-2-((2-メチル-4-(メチルスルホニル)ピペラジン-1-イル)メチル)フロ[3,2-c]ピリジン-4(5H)-オン;
5-メチル-2-(((R)-2-メチル-4-(メチルスルホニル)ピペラジン-1-イル)メチル)-7-(3-(オキセタン-2-イルメトキシ)ピリジン-4-イル)フロ[3,2-c]ピリジン-4(5H)-オン;
5-メチル-2-(((R)-2-メチル-4-(メチルスルホニル)ピペラジン-1-イル)メチル)-7-(3-((R)-オキセタン-2-イルメトキシ)ピリジン-4-イル)フロ[3,2-c]ピリジン-4(5H)-オン;
5-メチル-2-(((R)-2-メチル-4-(メチルスルホニル)ピペラジン-1-イル)メチル)-7-(3-((S)-オキセタン-2-イルメトキシ)ピリジン-4-イル)フロ[3,2-c]ピリジン-4(5H)-オン;
(R)-7-(3-(シクロプロピルメトキシ)ピリジン-2-イル)-5-メチル-2-((2-メチル-4-(メチルスルホニル)ピペラジン-1-イル)メチル)フロ[3,2-c]ピリジン-4(5H)-オン;
5-メチル-2-((2-メチルピペラジン-1-イル)メチル)-7-(2-((テトラヒドロ-2H-ピラン-4-イル)メトキシ)ピリジン-4-イル)フロ[3,2-c]ピリジン-4(5H)-オンヒドロクロリド;
(R)-5-メチル-2-((2-メチル-4-(メチルスルホニル)ピペラジン-1-イル)メチル)-7-(3-(オキセタン-3-イルメトキシ)ピリジン-4-イル)フロ[3,2-c]ピリジン-4(5H)-オン;
2-((4-アセチル-2-メチルピペラジン-1-イル)メチル)-5-メチル-7-(2-((テトラヒドロ-2H-ピラン-4-イル)メトキシ)ピリジン-4-イル)フロ[3,2-c]ピリジン-4(5H)-オンヒドロクロリド;
N-(3-(5-メチル-2-((4-(メチルスルホニル)ピペラジン-1-イル)メチル)-4-オキソ-4,5-ジヒドロフロ[3,2-c]ピリジン-7-イル)フェニル)アセトアミド;
(R)-7-(2-((シクロプロピルメチル)アミノ)ピリジン-3-イル)-5-メチル-2-((2-メチル-4-(メチルスルホニル)ピペラジン-1-イル)メチル)フロ[3,2-c]ピリジン-4(5H)-オン;
(R)-7-(3-アミノフェニル)-5-メチル-2-((2-メチル-4-(メチルスルホニル)ピペラジン-1-イル)メチル)フロ[3,2-c]ピリジン-4(5H)-オン;
2-((1,4-ジアゼパン-1-イル)メチル)-5-メチル-7-(3-((ピリジン-2-イルメチル)アミノ)フェニル)フロ[3,2-c]ピリジン-4(5H)-オン;
(R)-7-(3-エトキシピリジン-4-イル)-5-メチル-2-((2-メチル-4-(メチルスルホニル)ピペラジン-1-イル)メチル)フロ[3,2-c]ピリジン-4(5H)-オン;
N-(3-(2-((1,4-ジアゼパン-1-イル)メチル)-5-メチル-4-オキソ-4,5-ジヒドロフロ[3,2-c]ピリジン-7-イル)フェニル)ピコリンアミド;
(R)-N-(6-(5-メチル-2-((2-メチル-4-(メチルスルホニル)ピペラジン-1-イル)メチル)-4-オキソ-4,5-ジヒドロフロ[3,2-c]ピリジン-7-イル)ピリジン-2-イル)アセトアミド;
2-((1,4-ジアゼパン-1-イル)メチル)-7-(3-(シクロプロピルメトキシ)ピリジン-4-イル)-5-メチルフロ[3,2-c]ピリジン-4(5H)-オン;
7-(3-(シクロプロピルメトキシ)ピリジン-4-イル)-5-メチル-2-((4-メチル-1,4-ジアゼパン-1-イル)メチル)フロ[3,2-c]ピリジン-4(5H)-オン;
5-メチル-2-((4-メチル-1,4-ジアゼパン-1-イル)メチル)-7-(3-((ピリジン-2-イルメチル)アミノ)フェニル)フロ[3,2-c]ピリジン-4(5H)-オンヒドロクロリド;
(R)-7-(3-イソプロポキシピリジン-4-イル)-5-メチル-2-((2-メチル-4-(メチルスルホニル)ピペラジン-1-イル)メチル)フロ[3,2-c]ピリジン-4(5H)-オン;
(R)-7-(2-アミノピリジン-4-イル)-5-メチル-2-((2-メチル-4-(メチルスルホニル)ピペラジン-1-イル)メチル)フロ[3,2-c]ピリジン-4(5H)-オン;
(R)-7-(3-ヒドロキシピリジン-4-イル)-5-メチル-2-((2-メチル-4-(メチルスルホニル)ピペラジン-1-イル)メチル)フロ[3,2-c]ピリジン-4(5H)-オン;
7-(3-((2,2-ジフルオロシクロプロピル)メトキシ)ピリジン-4-イル)-5-メチル-2-(((R)-2-メチル-4-(メチルスルホニル)ピペラジン-1-イル)メチル)フロ[3,2-c]ピリジン-4(5H)-オン;
(R)-N-(4-(5-(2H3)メチル-2-((2-メチル-4-(メチルスルホニル)ピペラジン-1-イル)メチル)-4-オキソ-4,5-ジヒドロフロ[3,2-c]ピリジン-7-イル)ピリジン-2-イル)アセトアミド;
(R)-5-メチル-2-((2-メチル-4-(メチルスルホニル)ピペラジン-1-イル)メチル)-7-(3-(2-(2-オキソピロリジン-1-イル)エトキシ)ピリジン-4-イル)フロ[3,2-c]ピリジン-4(5H)-オン;
(R)-5-アミノ-N-(3-(5-メチル-2-((2-メチル-4-(メチルスルホニル)ピペラジン-1-イル)メチル)-4-オキソ-4,5-ジヒドロフロ[3,2-c]ピリジン-7-イル)フェニル)ペンタンアミド;
N-(4-(5-メチル-2-(2-(4-(メチルスルホニル)ピペラジン-1-イル)プロパン-2-イル)-4-オキソ-4,5-ジヒドロフロ[3,2-c]ピリジン-7-イル)ピリジン-2-イル)アセトアミド;
(R)-7-(3-(2-メトキシエトキシ)ピリジン-4-イル)-5-メチル-2-((2-メチル-4-(メチルスルホニル)ピペラジン-1-イル)メチル)フロ[3,2-c]ピリジン-4(5H)-オン;
3-(シクロプロピルメトキシ)-4-(5-メチル-2-((4-(メチルスルホニル)ピペラジン-1-イル)メチル)-4-オキソ-4,5-ジヒドロフロ[3,2-c]ピリジン-7-イル)安息香酸;
3-(シクロプロピルメトキシ)-N-エチル-4-(5-メチル-2-((4-(メチルスルホニル)ピペラジン-1-イル)メチル)-4-オキソ-4,5-ジヒドロフロ[3,2-c]ピリジン-7-イル)ベンズアミド;
5-メチル-2-(((R)-2-メチル-4-(メチルスルホニル)ピペラジン-1-イル)メチル)-7-(3-((テトラヒドロフラン-3-イル)メトキシ)ピリジン-4-イル)フロ[3,2-c]ピリジン-4(5H)-オン;
5-メチル-2-(((R)-2-メチル-4-(メチルスルホニル)ピペラジン-1-イル)メチル)-7-(3-((テトラヒドロフラン-2-イル)メトキシ)ピリジン-4-イル)フロ[3,2-c]ピリジン-4(5H)-オン;
7-(3-(シクロプロピルメトキシ)ピリジン-4-イル)-5-メチル-2-((3-オキソピペラジン-1-イル)メチル)フロ[3,2-c]ピリジン-4(5H)-オン;
(R)-7-(3-(2-フルオロエトキシ)ピリジン-4-イル)-5-メチル-2-((2-メチル-4-(メチルスルホニル)ピペラジン-1-イル)メチル)フロ[3,2-c]ピリジン-4(5H)-オン;
(R)-7-(3-シクロプロポキシピリジン-4-イル)-5-メチル-2-((2-メチル-4-(メチルスルホニル)ピペラジン-1-イル)メチル)フロ[3,2-c]ピリジン-4(5H)-オン;
(R)-7-(3-(2,2-ジフルオロエトキシ)ピリジン-4-イル)-5-メチル-2-((2-メチル-4-(メチルスルホニル)ピペラジン-1-イル)メチル)フロ[3,2-c]ピリジン-4(5H)-オン;
(R)-7-(3-(2-ヒドロキシエトキシ)ピリジン-4-イル)-5-メチル-2-((2-メチル-4-(メチルスルホニル)ピペラジン-1-イル)メチル)フロ[3,2-c]ピリジン-4(5H)-オン;
7-(3-(シクロプロピルメトキシ)ピリジン-4-イル)-5-メチル-2-((4-メチル-3-オキソピペラジン-1-イル)メチル)フロ[3,2-c]ピリジン-4(5H)-オン;
(R)-5-メチル-2-((2-メチル-4-(メチルスルホニル)ピペラジン-1-イル)メチル)-7-(2-オキソ-2,3-ジヒドロ-1H-ピロロ[2,3-b]ピリジン-4-イル)フロ[3,2-c]ピリジン-4(5H)-オン;
7-(3-(2-メトキシプロポキシ)ピリジン-4-イル)-5-メチル-2-(((R)-2-メチル-4-(メチルスルホニル)ピペラジン-1-イル)メチル)フロ[3,2-c]ピリジン-4(5H)-オン;
7-(3-((1-メトキシプロパン-2-イル)オキシ)ピリジン-4-イル)-5-メチル-2-(((R)-2-メチル-4-(メチルスルホニル)ピペラジン-1-イル)メチル)フロ[3,2-c]ピリジン-4(5H)-オン;
(R)-5-メチル-2-((2-メチル-4-(メチルスルホニル)ピペラジン-1-イル)メチル)-7-(3-(オキセタン-3-イルオキシ)ピリジン-4-イル)フロ[3,2-c]ピリジン-4(5H)-オン;
5-メチル-2-(((R)-2-メチル-4-(メチルスルホニル)ピペラジン-1-イル)メチル)-7-(3-((テトラヒドロフラン-3-イル)オキシ)ピリジン-4-イル)フロ[3,2-c]ピリジン-4(5H)-オン;
5-メチル-2-(((R)-2-メチル-4-(メチルスルホニル)ピペラジン-1-イル)メチル)-7-(3-(((S)-テトラヒドロフラン-3-イル)オキシ)ピリジン-4-イル)フロ[3,2-c]ピリジン-4(5H)-オン;及び
5-メチル-2-(((R)-2-メチル-4-(メチルスルホニル)ピペラジン-1-イル)メチル)-7-(3-(((R)-テトラヒドロフラン-3-イル)オキシ)ピリジン-4-イル)フロ[3,2-c]ピリジン-4(5H)-オン;
N-(4-(5-メチル-4-オキソ-2-((5-オキソ-1,4-ジアゼパン-1-イル)メチル)-4,5-ジヒドロフロ[3,2-c]ピリジン-7-イル)ピリジン-2-イル)アセトアミド;
N-(4-(2-((1,4-オキサゼパン-4-イル)メチル)-5-メチル-4-オキソ-4,5-ジヒドロフロ[3,2-c]ピリジン-7-イル)ピリジン-2-イル)アセトアミド;
N-(4-(5-メチル-2-((4-メチルピペラジン-1-イル)メチル)-4-オキソ-4,5-ジヒドロフロ[3,2-c]ピリジン-7-イル)ピリジン-2-イル)アセトアミド;
N-(4-(5-メチル-2-((4-メチル-1,4-ジアゼパン-1-イル)メチル)-4-オキソ-4,5-ジヒドロフロ[3,2-c]ピリジン-7-イル)ピリジン-2-イル)アセトアミド;
N-(4-(2-((1,4-ジアゼパン-1-イル)メチル)-5-メチル-4-オキソ-4,5-ジヒドロフロ[3,2-c]ピリジン-7-イル)ピリジン-2-イル)アセトアミド;
N-(4-(2-((1,1-ジオキシドチオモルホリノ)メチル)-5-メチル-4-オキソ-4,5-ジヒドロフロ[3,2-c]ピリジン-7-イル)ピリジン-2-イル)アセトアミド;
N-(4-(5-メチル-4-オキソ-2-((3-オキソピペラジン-1-イル)メチル)-4,5-ジヒドロフロ[3,2-c]ピリジン-7-イル)ピリジン-2-イル)アセトアミド;
N-(4-(5-メチル-2-((4-(メチルスルホンアミド)ピペリジン-1-イル)メチル)-4-オキソ-4,5-ジヒドロフロ[3,2-c]ピリジン-7-イル)ピリジン-2-イル)アセトアミド;
(S)-N-(4-(2-((3-ヒドロキシピペリジン-1-イル)メチル)-5-メチル-4-オキソ-4,5-ジヒドロフロ[3,2-c]ピリジン-7-イル)ピリジン-2-イル)アセトアミド;
N-(4-(5-メチル-4-オキソ-2-(ピペラジン-1-イルメチル)-4,5-ジヒドロフロ[3,2-c]ピリジン-7-イル)ピリジン-2-イル)アセトアミド;
N-(4-(2-((4-エチル-3-オキソピペラジン-1-イル)メチル)-5-メチル-4-オキソ-4,5-ジヒドロフロ[3,2-c]ピリジン-7-イル)ピリジン-2-イル)アセトアミド;
N-(4-(5-メチル-2-((4-(メチルスルホニル)ピペリジン-1-イル)メチル)-4-オキソ-4,5-ジヒドロフロ[3,2-c]ピリジン-7-イル)ピリジン-2-イル)アセトアミド;
N-(4-(2-(((1,1-ジオキシドテトラヒドロ-2H-チオピラン-3-イル)アミノ)メチル)-5-メチル-4-オキソ-4,5-ジヒドロフロ[3,2-c]ピリジン-7-イル)ピリジン-2-イル)アセトアミド;
N-(4-(2-(((1,1-ジオキシドテトラヒドロチオフェン-3-イル)アミノ)メチル)-5-メチル-4-オキソ-4,5-ジヒドロフロ[3,2-c]ピリジン-7-イル)ピリジン-2-イル)アセトアミド;
N-(4-(2-((2,5-ジメチル-4-(メチルスルホニル)ピペラジン-1-イル)メチル)-5-メチル-4-オキソ-4,5-ジヒドロフロ[3,2-c]ピリジン-7-イル)ピリジン-2-イル)アセトアミド;
N-(4-(2-((4-エチル-2-メチルピペラジン-1-イル)メチル)-5-メチル-4-オキソ-4,5-ジヒドロフロ[3,2-c]ピリジン-7-イル)ピリジン-2-イル)アセトアミド;
N-(4-(5-メチル-2-((4-メチル-5-オキソ-1,4-ジアゼパン-1-イル)メチル)-4-オキソ-4,5-ジヒドロフロ[3,2-c]ピリジン-7-イル)ピリジン-2-イル)アセトアミド;
N-(4-(5-メチル-2-((7-メチル-5-オキソ-1,4-ジアゼパン-1-イル)メチル)-4-オキソ-4,5-ジヒドロフロ[3,2-c]ピリジン-7-イル)ピリジン-2-イル)アセトアミド;
N-(4-(5-メチル-2-((2-メチル-5-オキソ-1,4-ジアゼパン-1-イル)メチル)-4-オキソ-4,5-ジヒドロフロ[3,2-c]ピリジン-7-イル)ピリジン-2-イル)アセトアミド;
N-(4-(2-((1,1-ジオキシド-1,4-チアゼパン-4-イル)メチル)-5-メチル-4-オキソ-4,5-ジヒドロフロ[3,2-c]ピリジン-7-イル)ピリジン-2-イル)アセトアミド;
N-(4-(5-メチル-2-((3-メチル-1,1-ジオキシドチオモルホリノ)メチル)-4-オキソ-4,5-ジヒドロフロ[3,2-c]ピリジン-7-イル)ピリジン-2-イル)アセトアミド;
N-(4-(5-メチル-2-((2-メチル-1,1-ジオキシドチオモルホリノ)メチル)-4-オキソ-4,5-ジヒドロフロ[3,2-c]ピリジン-7-イル)ピリジン-2-イル)アセトアミド;
N-(4-(2-((4-アセチル-1,4-ジアゼパン-1-イル)メチル)-5-メチル-4-オキソ-4,5-ジヒドロフロ[3,2-c]ピリジン-7-イル)ピリジン-2-イル)アセトアミド;
N-(4-(5-メチル-2-(モルホリノメチル)-4-オキソ-4,5-ジヒドロフロ[3,2-c]ピリジン-7-イル)ピリジン-2-イル)アセトアミド;
N-(4-(2-((4-アセチル-2-メチルピペラジン-1-イル)メチル)-5-メチル-4-オキソ-4,5-ジヒドロフロ[3,2-c]ピリジン-7-イル)ピリジン-2-イル)アセトアミド;
N-(4-(5-メチル-2-((4-メチル-3-オキソピペラジン-1-イル)メチル)-4-オキソ-4,5-ジヒドロフロ[3,2-c]ピリジン-7-イル)ピリジン-2-イル)アセトアミド;
(S)-N-(4-(5-メチル-2-((3-メチル-4-(メチルスルホニル)ピペラジン-1-イル)メチル)-4-オキソ-4,5-ジヒドロフロ[3,2-c]ピリジン-7-イル)ピリジン-2-イル)アセトアミド;
N-(4-(5-メチル-2-((4-(メチルスルホニル)-2-オキソピペラジン-1-イル)メチル)-4-オキソ-4,5-ジヒドロフロ[3,2-c]ピリジン-7-イル)ピリジン-2-イル)アセトアミド;
N-(4-(2-((4-エチルピペラジン-1-イル)メチル)-5-メチル-4-オキソ-4,5-ジヒドロフロ[3,2-c]ピリジン-7-イル)ピリジン-2-イル)アセトアミド;
N-(4-(5-メチル-4-オキソ-2-(ピロリジン-1-イルメチル)-4,5-ジヒドロフロ[3,2-c]ピリジン-7-イル)ピリジン-2-イル)アセトアミド
N-(4-(5-メチル-4-オキソ-2-(ピペリジン-1-イルメチル)-4,5-ジヒドロフロ[3,2-c]ピリジン-7-イル)ピリジン-2-イル)アセトアミド;
N-(4-(5-メチル-4-オキソ-2-((3-オキソ-1,4-ジアゼパン-1-イル)メチル)-4,5-ジヒドロフロ[3,2-c]ピリジン-7-イル)ピリジン-2-イル)アセトアミド;
(R)-N-(4-(5-メチル-2-((2-メチル-3-オキソピペラジン-1-イル)メチル)-4-オキソ-4,5-ジヒドロフロ[3,2-c]ピリジン-7-イル)ピリジン-2-イル)アセトアミド;
から選択される化合物、又はそれらの塩。 - 5-メチル-2-(((R)-2-メチル-4-(メチルスルホニル)ピペラジン-1-イル)メチル)-7-(3-((R)-オキセタン-2-イルメトキシ)ピリジン-4-イル)フロ[3,2-c]ピリジン-4(5H)-オンである化合物、又はその塩。
- 請求項1から41のいずれか一項に記載の化合物又はその薬学的に許容される塩。
- 請求項42に記載の式(I)の化合物又はその薬学的に許容される塩、及び1種以上の薬学的に許容される担体、希釈剤又は賦形剤を含む、医薬組成物。
- 請求項42に記載の式(I)の化合物又はその薬学的に許容される塩を、1種以上の他の治療上活性な薬剤と共に含む組合せ。
- 治療で使用するための、請求項42に記載の式(I)の化合物又はその薬学的に許容される塩。
- ブロモドメイン阻害薬の必要を示す疾患又は状態の処置で使用するための、請求項42に記載の式(I)の化合物又はその薬学的に許容される塩。
- 疾患又は状態が急性又は慢性の自己免疫状態及び/又は炎症状態である、請求項46に記載の使用のための化合物又はその薬学的に許容される塩。
- 疾患又は状態に、細菌、ウイルス、真菌、寄生虫の感染、又はこれらの毒素に対する炎症応答が関与する、請求項46に記載の使用のための化合物又はその薬学的に許容される塩。
- 疾患又は状態がウイルス感染症である、請求項46に記載の使用のための化合物又はその薬学的に許容される塩。
- 疾患又は状態が、がんである、請求項46に記載の使用のための化合物又はその薬学的に許容される塩。
- ブロモドメイン阻害薬の必要を示す疾患又は状態を処置するための医薬の製造における、請求項42に記載の式(I)の化合物又はその薬学的に許容される塩の使用。
- 治療有効量の請求項42に記載の式(I)の化合物又はその薬学的に許容される塩を投与することを含む、それを必要とする対象において、ブロモドメイン阻害薬の必要を示す疾患又は状態を処置する方法。
- 疾患又は状態が、急性又は慢性の自己免疫状態及び/又は炎症状態である、請求項52に記載の処置方法。
- 疾患又は状態に、細菌、ウイルス、真菌、寄生虫の感染、又はこれらの毒素に対する炎症応答が関与する、請求項52に記載の処置方法。
- 疾患又は状態がウイルス感染症である、請求項52に記載の処置方法。
- 疾患又は状態が、がんである、請求項52に記載の処置方法。
- 対象がヒトである、請求項52から56のいずれか一項に記載の処置方法。
Applications Claiming Priority (5)
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Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JP2022551299A (ja) * | 2019-10-08 | 2022-12-08 | ハイヘ バイオファーマ カンパニー、リミテッド | Brd4阻害活性を有する化合物、その調製方法および用途 |
Families Citing this family (48)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2014080291A2 (en) | 2012-11-21 | 2014-05-30 | Rvx Therapeutics Inc. | Biaryl derivatives as bromodomain inhibitors |
US9073878B2 (en) | 2012-11-21 | 2015-07-07 | Zenith Epigenetics Corp. | Cyclic amines as bromodomain inhibitors |
AU2013365926B9 (en) | 2012-12-21 | 2019-01-17 | Zenith Epigenetics Ltd. | Novel heterocyclic compounds as bromodomain inhibitors |
WO2014143768A1 (en) | 2013-03-15 | 2014-09-18 | Incyte Corporation | Tricyclic heterocycles as bet protein inhibitors |
CN109939113B (zh) | 2013-06-21 | 2022-02-15 | 恒翼生物医药科技(上海)有限公司 | 双环溴结构域抑制剂 |
EP3010917B1 (en) | 2013-06-21 | 2018-01-31 | Zenith Epigenetics Ltd. | Novel substituted bicyclic compounds as bromodomain inhibitors |
CA2917319A1 (en) | 2013-07-08 | 2015-01-15 | Incyte Holdings Corporation | Tricyclic heterocycles as bet protein inhibitors |
US9855271B2 (en) | 2013-07-31 | 2018-01-02 | Zenith Epigenetics Ltd. | Quinazolinones as bromodomain inhibitors |
AU2014337064B2 (en) | 2013-10-18 | 2019-03-14 | Celgene Quanticel Research, Inc. | Bromodomain inhibitors |
WO2015081189A1 (en) | 2013-11-26 | 2015-06-04 | Incyte Corporation | Bicyclic heterocycles as bet protein inhibitors |
US9399640B2 (en) | 2013-11-26 | 2016-07-26 | Incyte Corporation | Substituted pyrrolo[2,3-c]pyridines and pyrazolo[3,4-c]pyridines as BET protein inhibitors |
US9309246B2 (en) | 2013-12-19 | 2016-04-12 | Incyte Corporation | Tricyclic heterocycles as BET protein inhibitors |
BR112016024626B1 (pt) | 2014-04-23 | 2023-03-21 | Incyte Holdings Corporation | Compostos 1h-pirrolo[2,3-c]piridin-7(6h)-onas e pirazolo[3,4-c]piridin-7 (6h)-onas, uso dos mesmos, composição farmacêutica que os compreende e método de inibição de uma proteína bet |
EP3194406B8 (en) | 2014-09-15 | 2021-03-31 | Incyte Corporation | Tricyclic heterocycles for use as bet protein inhibitors |
WO2016087942A1 (en) | 2014-12-01 | 2016-06-09 | Zenith Epigenetics Corp. | Substituted pyridines as bromodomain inhibitors |
US10710992B2 (en) | 2014-12-01 | 2020-07-14 | Zenith Epigenetics Ltd. | Substituted pyridinones as bromodomain inhibitors |
US10292968B2 (en) | 2014-12-11 | 2019-05-21 | Zenith Epigenetics Ltd. | Substituted heterocycles as bromodomain inhibitors |
CA2966450A1 (en) | 2014-12-17 | 2016-06-23 | Olesya KHARENKO | Inhibitors of bromodomains |
JP6815318B2 (ja) | 2014-12-23 | 2021-01-20 | ダナ−ファーバー キャンサー インスティテュート,インコーポレイテッド | 二官能性分子によって標的化タンパク質分解を誘導する方法 |
US9694084B2 (en) | 2014-12-23 | 2017-07-04 | Dana-Farber Cancer Institute, Inc. | Methods to induce targeted protein degradation through bifunctional molecules |
GB201504694D0 (en) | 2015-03-19 | 2015-05-06 | Glaxosmithkline Ip Dev Ltd | Covalent conjugates |
WO2017007612A1 (en) | 2015-07-07 | 2017-01-12 | Dana-Farber Cancer Institute, Inc. | Methods to induce targeted protein degradation through bifunctional molecules |
TW201722966A (zh) | 2015-10-29 | 2017-07-01 | 英塞特公司 | Bet蛋白質抑制劑之非晶固體形式 |
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EP3445750A4 (en) | 2016-04-18 | 2019-11-27 | Celgene Quanticel Research, Inc. | THERAPEUTIC COMPOUNDS |
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WO2017197056A1 (en) * | 2016-05-10 | 2017-11-16 | C4 Therapeutics, Inc. | Bromodomain targeting degronimers for target protein degradation |
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PE20190623A1 (es) | 2016-06-20 | 2019-04-26 | Incyte Corp | Formas solidas cristalinas de un inhibidor de bet |
AU2017312970B2 (en) * | 2016-08-16 | 2021-08-12 | Merck Patent Gmbh | 2-oxo-imidazopyridines as reversible BTK inhibitors and uses thereof |
WO2018064589A1 (en) | 2016-09-29 | 2018-04-05 | Dana-Farber Cancer Institute, Inc. | Targeted protein degradation using a mutant e3 ubiquitin ligase |
WO2018094553A1 (zh) * | 2016-11-22 | 2018-05-31 | 上海联影医疗科技有限公司 | 显示方法和装置 |
US10617680B2 (en) | 2017-04-18 | 2020-04-14 | Celgene Quanticel Research, Inc. | Therapeutic compounds |
EP3641762A4 (en) | 2017-06-20 | 2021-03-10 | C4 Therapeutics, Inc. | N / O BONDED DEGRONS AND DEGRONIMERS FOR PROTEIN DEGRADATION |
EP3679026A1 (en) | 2017-09-04 | 2020-07-15 | C4 Therapeutics, Inc. | Glutarimide |
WO2019043217A1 (en) | 2017-09-04 | 2019-03-07 | F. Hoffmann-La Roche Ag | DIHYDROBENZIMIDAZOLONES |
CN111278816B (zh) | 2017-09-04 | 2024-03-15 | C4医药公司 | 二氢喹啉酮 |
GB201716369D0 (en) | 2017-10-06 | 2017-11-22 | Glaxosmithkline Intellectual Property (No 2) Ltd | Compounds |
GB201716392D0 (en) | 2017-10-06 | 2017-11-22 | Glaxosmithkline Intellectual Property (No 2) Ltd | Compounds |
EP3710002A4 (en) | 2017-11-16 | 2021-07-07 | C4 Therapeutics, Inc. | DEGRADER AND DEGRONE FOR TARGETED PROTEIN DEGRADATION |
CN108358793B (zh) * | 2018-02-12 | 2021-03-23 | 三峡大学 | 一种由炔烃合成的仲胺类化合物及其合成方法 |
CN111902141A (zh) | 2018-03-26 | 2020-11-06 | C4医药公司 | 用于ikaros降解的羟脑苷脂结合剂 |
CN112312904A (zh) | 2018-04-16 | 2021-02-02 | C4医药公司 | 螺环化合物 |
EP3997070A4 (en) | 2019-07-02 | 2023-07-26 | Nuvation Bio Inc. | HETEROCYCLIC COMPOUNDS USED AS BET INHIBITORS |
EP4143166A1 (en) * | 2020-04-29 | 2023-03-08 | Nuvation Bio Inc. | Heterocyclic compounds as bet inhibitors |
US11833155B2 (en) | 2020-06-03 | 2023-12-05 | Incyte Corporation | Combination therapy for treatment of myeloproliferative neoplasms |
CN116135858A (zh) * | 2021-11-16 | 2023-05-19 | 中国科学院广州生物医药与健康研究院 | 一种呋喃并吡啶酮类化合物及其应用 |
Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2013027168A1 (en) * | 2011-08-22 | 2013-02-28 | Pfizer Inc. | Novel heterocyclic compounds as bromodomain inhibitors |
JP2013510107A (ja) * | 2009-11-05 | 2013-03-21 | グラクソスミスクライン エルエルシー | ベンゾジアゼピンブロモドメイン阻害剤 |
Family Cites Families (13)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
GB9004781D0 (en) | 1990-03-02 | 1990-04-25 | Glaxo Group Ltd | Device |
FR2795730B1 (fr) * | 1999-07-01 | 2001-08-31 | Adir | Nouveaux inhibiteurs de metalloproteases, leur procede de preparation et les compositions pharmaceutiques qui les contiennent |
EP1217000A1 (en) | 2000-12-23 | 2002-06-26 | Aventis Pharma Deutschland GmbH | Inhibitors of factor Xa and factor VIIa |
AU2004234110A1 (en) | 2003-04-25 | 2004-11-11 | Rega Foundation | Heterocyclic compounds for use in the treatment of viral infections |
DK1699512T3 (da) | 2003-11-03 | 2012-09-17 | Glaxo Group Ltd | Fluiddispenseringsindretning |
UA108351C2 (uk) | 2009-03-27 | 2015-04-27 | Інгібітори реплікації вірусу гепатиту c | |
SG178504A1 (en) | 2009-08-26 | 2012-04-27 | Takeda Pharmaceutical | Fused heterocyclic ring derivative and use thereof |
JP5722781B2 (ja) | 2009-08-26 | 2015-05-27 | 武田薬品工業株式会社 | 縮合複素環誘導体およびその用途 |
GB0919423D0 (en) | 2009-11-05 | 2009-12-23 | Glaxosmithkline Llc | Novel compounds |
GB0919434D0 (en) | 2009-11-05 | 2009-12-23 | Glaxosmithkline Llc | Novel compounds |
CN102276616B (zh) | 2011-08-04 | 2013-09-04 | 中国科学院长春应用化学研究所 | 一种呋喃[3,2-c]吡啶-4(5H)-酮类化合物合成方法 |
WO2013097052A1 (en) | 2011-12-30 | 2013-07-04 | Abbott Laboratories | Bromodomain inhibitors |
AU2014337064B2 (en) * | 2013-10-18 | 2019-03-14 | Celgene Quanticel Research, Inc. | Bromodomain inhibitors |
-
2014
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Patent Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JP2013510107A (ja) * | 2009-11-05 | 2013-03-21 | グラクソスミスクライン エルエルシー | ベンゾジアゼピンブロモドメイン阻害剤 |
WO2013027168A1 (en) * | 2011-08-22 | 2013-02-28 | Pfizer Inc. | Novel heterocyclic compounds as bromodomain inhibitors |
Non-Patent Citations (2)
Title |
---|
JOURNAL OF MEDICINAL CHEMISTRY, vol. 54, no. 11, JPN6018000197, 2011, pages 3827 - 3838 * |
JOURNAL OF ORGANIC CHEMISTRY, vol. 69, no. 6, JPN6018000196, 2004, pages 1872 - 1879 * |
Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JP2022551299A (ja) * | 2019-10-08 | 2022-12-08 | ハイヘ バイオファーマ カンパニー、リミテッド | Brd4阻害活性を有する化合物、その調製方法および用途 |
JP7405468B2 (ja) | 2019-10-08 | 2023-12-26 | ハイヘ バイオファーマ カンパニー、リミテッド | Brd4阻害活性を有する化合物、その調製方法および用途 |
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EP2970323A1 (en) | 2016-01-20 |
RU2015137103A (ru) | 2017-04-26 |
CN105189515B (zh) | 2018-07-03 |
ES2654362T3 (es) | 2018-02-13 |
WO2014140077A1 (en) | 2014-09-18 |
JP6280573B2 (ja) | 2018-02-14 |
KR20150128842A (ko) | 2015-11-18 |
CN105189515A (zh) | 2015-12-23 |
CA2903357A1 (en) | 2014-09-18 |
RU2655727C9 (ru) | 2018-07-06 |
AU2014230816A1 (en) | 2015-10-01 |
US9670221B2 (en) | 2017-06-06 |
BR112015022782A2 (pt) | 2017-07-18 |
US20160016966A1 (en) | 2016-01-21 |
RU2655727C2 (ru) | 2018-05-30 |
EP2970323B1 (en) | 2017-10-18 |
AU2014230816B9 (en) | 2016-12-15 |
AU2014230816B2 (en) | 2016-12-01 |
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