WO2011071716A1 - Composés hétérocycliques contenant un cœur indole - Google Patents
Composés hétérocycliques contenant un cœur indole Download PDFInfo
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- WO2011071716A1 WO2011071716A1 PCT/US2010/058271 US2010058271W WO2011071716A1 WO 2011071716 A1 WO2011071716 A1 WO 2011071716A1 US 2010058271 W US2010058271 W US 2010058271W WO 2011071716 A1 WO2011071716 A1 WO 2011071716A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- indole
- oxo
- carboxamide
- mmol
- methyl
- Prior art date
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- 150000002391 heterocyclic compounds Chemical class 0.000 title description 2
- 125000001041 indolyl group Chemical group 0.000 title 1
- 150000001875 compounds Chemical class 0.000 claims abstract description 244
- 238000000034 method Methods 0.000 claims abstract description 32
- 101000945090 Homo sapiens Ribosomal protein S6 kinase alpha-3 Proteins 0.000 claims abstract description 10
- 102100033643 Ribosomal protein S6 kinase alpha-3 Human genes 0.000 claims abstract description 10
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 10
- 230000001105 regulatory effect Effects 0.000 claims abstract description 6
- SIKJAQJRHWYJAI-UHFFFAOYSA-N Indole Chemical compound C1=CC=C2NC=CC2=C1 SIKJAQJRHWYJAI-UHFFFAOYSA-N 0.000 claims description 19
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 19
- 150000003839 salts Chemical class 0.000 claims description 14
- PZOUSPYUWWUPPK-UHFFFAOYSA-N indole Natural products CC1=CC=CC2=C1C=CN2 PZOUSPYUWWUPPK-UHFFFAOYSA-N 0.000 claims description 9
- RKJUIXBNRJVNHR-UHFFFAOYSA-N indolenine Natural products C1=CC=C2CC=NC2=C1 RKJUIXBNRJVNHR-UHFFFAOYSA-N 0.000 claims description 9
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 7
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 6
- 201000010099 disease Diseases 0.000 claims description 5
- JUHDVODXPWTTBZ-JKSUJKDBSA-N (3s,4r)-n-(1-benzylpyrazol-4-yl)-3,4-dimethyl-1-oxo-3,4-dihydro-2h-pyrazino[1,2-a]indole-7-carboxamide Chemical compound N([C@H]([C@H](N1C2=C3)C)C)C(=O)C1=CC2=CC=C3C(=O)NC(=C1)C=NN1CC1=CC=CC=C1 JUHDVODXPWTTBZ-JKSUJKDBSA-N 0.000 claims description 4
- UABDEGYXSZJSQL-UHFFFAOYSA-N 5-methyl-n-(1-methylbenzimidazol-2-yl)-1-oxo-2,3,4,5-tetrahydro-[1,4]diazepino[1,2-a]indole-8-carboxamide Chemical compound CC1CCNC(=O)C2=CC3=CC=C(C(=O)NC=4N(C5=CC=CC=C5N=4)C)C=C3N12 UABDEGYXSZJSQL-UHFFFAOYSA-N 0.000 claims description 4
- GAPIXBCBFHEVGO-UHFFFAOYSA-N n-[2-(tert-butylcarbamoyl)-1-methylimidazol-4-yl]-4,4-dimethyl-1-oxo-2,3-dihydropyrazino[1,2-a]indole-7-carboxamide Chemical compound N1=C(C(=O)NC(C)(C)C)N(C)C=C1NC(=O)C1=CC=C(C=C2N3C(C)(C)CNC2=O)C3=C1 GAPIXBCBFHEVGO-UHFFFAOYSA-N 0.000 claims description 4
- 230000003176 fibrotic effect Effects 0.000 claims description 3
- 208000017169 kidney disease Diseases 0.000 claims description 3
- AMQAOXDPHJIPPA-WDEREUQCSA-N (3s,4r)-3,4-dimethyl-n-(5-methyl-1,2-oxazol-3-yl)-1-oxo-3,4-dihydro-2h-pyrazino[1,2-a]indole-7-carboxamide Chemical compound N([C@H]([C@H](N1C2=C3)C)C)C(=O)C1=CC2=CC=C3C(=O)NC=1C=C(C)ON=1 AMQAOXDPHJIPPA-WDEREUQCSA-N 0.000 claims description 2
- UJOPJGOMKOBTAA-UONOGXRCSA-N (3s,4r)-n-(1-ethylbenzimidazol-2-yl)-3,4-dimethyl-1-oxo-3,4-dihydro-2h-pyrazino[1,2-a]indole-7-carboxamide Chemical compound C1=CC=C2N(CC)C(NC(=O)C=3C=C4N5[C@H](C)[C@H](C)NC(=O)C5=CC4=CC=3)=NC2=C1 UJOPJGOMKOBTAA-UONOGXRCSA-N 0.000 claims description 2
- IQXDKRZFXZPPQO-DLBZAZTESA-N (3s,4r)-n-[1-[3-(dimethylamino)propyl]benzimidazol-2-yl]-3,4-dimethyl-1-oxo-3,4-dihydro-2h-pyrazino[1,2-a]indole-7-carboxamide Chemical compound C1=CC=C2N(CCCN(C)C)C(NC(=O)C3=CC=C4C=C5C(=O)N[C@H]([C@H](N5C4=C3)C)C)=NC2=C1 IQXDKRZFXZPPQO-DLBZAZTESA-N 0.000 claims description 2
- UJOPJGOMKOBTAA-KBPBESRZSA-N (3s,4s)-n-(1-ethylbenzimidazol-2-yl)-3,4-dimethyl-1-oxo-3,4-dihydro-2h-pyrazino[1,2-a]indole-7-carboxamide Chemical compound C1=CC=C2N(CC)C(NC(=O)C=3C=C4N5[C@@H](C)[C@H](C)NC(=O)C5=CC4=CC=3)=NC2=C1 UJOPJGOMKOBTAA-KBPBESRZSA-N 0.000 claims description 2
- KNOWVQTVZVKLHZ-OAHLLOKOSA-N (4r)-n-(1-benzylpyrazol-4-yl)-4-methyl-1-oxo-3,4-dihydro-2h-pyrazino[1,2-a]indole-7-carboxamide Chemical compound C([C@H](N1C2=C3)C)NC(=O)C1=CC2=CC=C3C(=O)NC(=C1)C=NN1CC1=CC=CC=C1 KNOWVQTVZVKLHZ-OAHLLOKOSA-N 0.000 claims description 2
- LZCWQKSZGMFDDP-IAGOWNOFSA-N (4r,5r)-n-(1-benzylpyrazol-4-yl)-4,5-dimethyl-1-oxo-2,3,4,5-tetrahydro-[1,4]diazepino[1,2-a]indole-8-carboxamide Chemical compound C([C@H]([C@H](N1C2=C3)C)C)NC(=O)C1=CC2=CC=C3C(=O)NC(=C1)C=NN1CC1=CC=CC=C1 LZCWQKSZGMFDDP-IAGOWNOFSA-N 0.000 claims description 2
- PHOBEHXJQHTMIX-UHFFFAOYSA-N 4,4-dimethyl-1-oxo-n-(1-propan-2-ylbenzimidazol-2-yl)-2,3-dihydropyrazino[1,2-a]indole-7-carboxamide Chemical compound C1=CC=C2N(C(C)C)C(NC(=O)C=3C=C4N5C(C)(C)CNC(=O)C5=CC4=CC=3)=NC2=C1 PHOBEHXJQHTMIX-UHFFFAOYSA-N 0.000 claims description 2
- LEZHPBJZDSCULQ-UHFFFAOYSA-N 4,4-dimethyl-1-oxo-n-(3-phenyl-1,2-oxazol-5-yl)-2,3-dihydropyrazino[1,2-a]indole-7-carboxamide Chemical compound C1=C2N3C(C)(C)CNC(=O)C3=CC2=CC=C1C(=O)NC(ON=1)=CC=1C1=CC=CC=C1 LEZHPBJZDSCULQ-UHFFFAOYSA-N 0.000 claims description 2
- RPJBWKAEGZXBIP-UHFFFAOYSA-N 4,4-dimethyl-n-(1-methylbenzimidazol-2-yl)-1-oxo-2,3-dihydropyrazino[1,2-a]indole-7-carboxamide Chemical compound C1=CC=C2N(C)C(NC(=O)C=3C=C4N5C(C)(C)CNC(=O)C5=CC4=CC=3)=NC2=C1 RPJBWKAEGZXBIP-UHFFFAOYSA-N 0.000 claims description 2
- DZZWBKKISQMUOR-UHFFFAOYSA-N 4-methyl-1-oxo-n-(1-propan-2-ylbenzimidazol-2-yl)-3,4-dihydro-2h-pyrazino[1,2-a]indole-7-carboxamide Chemical compound C1=CC=C2N(C(C)C)C(NC(=O)C=3C=C4N5C(C)CNC(=O)C5=CC4=CC=3)=NC2=C1 DZZWBKKISQMUOR-UHFFFAOYSA-N 0.000 claims description 2
- UAYPDTAQGNMZQJ-UHFFFAOYSA-N 4-methyl-n-(1-methylbenzimidazol-2-yl)-1-oxo-3,4-dihydro-2h-pyrazino[1,2-a]indole-7-carboxamide Chemical compound C1=CC=C2N(C)C(NC(=O)C3=CC=C4C=C5C(=O)NCC(N5C4=C3)C)=NC2=C1 UAYPDTAQGNMZQJ-UHFFFAOYSA-N 0.000 claims description 2
- 125000004938 5-pyridyl group Chemical group N1=CC=CC(=C1)* 0.000 claims description 2
- 208000024172 Cardiovascular disease Diseases 0.000 claims description 2
- 208000008839 Kidney Neoplasms Diseases 0.000 claims description 2
- 206010038389 Renal cancer Diseases 0.000 claims description 2
- 208000026935 allergic disease Diseases 0.000 claims description 2
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 2
- 239000000969 carrier Substances 0.000 claims description 2
- 208000027866 inflammatory disease Diseases 0.000 claims description 2
- 201000010982 kidney cancer Diseases 0.000 claims description 2
- GXXJBZJVBOXDTR-UHFFFAOYSA-N n-(1-benzylpyrazol-4-yl)-1-oxo-2,3,4,5-tetrahydro-[1,4]diazepino[1,2-a]indole-8-carboxamide Chemical compound C=1C=C2C=C3C(=O)NCCCN3C2=CC=1C(=O)NC(=C1)C=NN1CC1=CC=CC=C1 GXXJBZJVBOXDTR-UHFFFAOYSA-N 0.000 claims description 2
- UJPVUJGUWHZDAJ-UHFFFAOYSA-N n-(1-benzylpyrazol-4-yl)-4,4-difluoro-1-oxo-3,5-dihydro-2h-[1,4]diazepino[1,2-a]indole-8-carboxamide Chemical compound C1=C2N3CC(F)(F)CNC(=O)C3=CC2=CC=C1C(=O)NC(=C1)C=NN1CC1=CC=CC=C1 UJPVUJGUWHZDAJ-UHFFFAOYSA-N 0.000 claims description 2
- CEVWSVXHCJJEKH-UHFFFAOYSA-N n-(1-ethyl-5-methylbenzimidazol-2-yl)-1-oxo-2,3,4,5-tetrahydro-[1,4]diazepino[1,2-a]indole-8-carboxamide Chemical compound O=C1NCCCN2C3=CC(C(=O)NC=4N(C5=CC=C(C)C=C5N=4)CC)=CC=C3C=C21 CEVWSVXHCJJEKH-UHFFFAOYSA-N 0.000 claims description 2
- NRGYMIVHSWOTKI-UHFFFAOYSA-N n-(1-ethylbenzimidazol-2-yl)-1-oxo-2,3,4,5-tetrahydro-[1,4]diazepino[1,2-a]indole-8-carboxamide Chemical compound O=C1NCCCN2C3=CC(C(=O)NC=4N(C5=CC=CC=C5N=4)CC)=CC=C3C=C21 NRGYMIVHSWOTKI-UHFFFAOYSA-N 0.000 claims description 2
- HWYOGDNWFXHSKA-UHFFFAOYSA-N n-(1-ethylbenzimidazol-2-yl)-4,4-dimethyl-1-oxo-2,3-dihydropyrazino[1,2-a]indole-7-carboxamide Chemical compound C1=CC=C2N(CC)C(NC(=O)C=3C=C4N5C(C)(C)CNC(=O)C5=CC4=CC=3)=NC2=C1 HWYOGDNWFXHSKA-UHFFFAOYSA-N 0.000 claims description 2
- WHDSOABWAQPMLK-UHFFFAOYSA-N n-(1-ethylbenzimidazol-2-yl)-4-methyl-1-oxo-3,4-dihydro-2h-pyrazino[1,2-a]indole-7-carboxamide Chemical compound C1=CC=C2N(CC)C(NC(=O)C=3C=C4N5C(C)CNC(=O)C5=CC4=CC=3)=NC2=C1 WHDSOABWAQPMLK-UHFFFAOYSA-N 0.000 claims description 2
- QDJIKBFFRCVUSA-UHFFFAOYSA-N n-(1-ethylbenzimidazol-2-yl)-5-methyl-1-oxo-2,3,4,5-tetrahydro-[1,4]diazepino[1,2-a]indole-8-carboxamide Chemical compound O=C1NCCC(C)N2C3=CC(C(=O)NC=4N(C5=CC=CC=C5N=4)CC)=CC=C3C=C21 QDJIKBFFRCVUSA-UHFFFAOYSA-N 0.000 claims description 2
- QLEJMZSGBHLAJO-UHFFFAOYSA-N n-(1h-benzimidazol-2-yl)-4-methyl-1-oxo-3,4-dihydro-2h-pyrazino[1,2-a]indole-7-carboxamide Chemical compound C1=CC=C2NC(NC(=O)C3=CC=C4C=C5C(=O)NCC(N5C4=C3)C)=NC2=C1 QLEJMZSGBHLAJO-UHFFFAOYSA-N 0.000 claims description 2
- BMPLTNNXXFVKEU-UHFFFAOYSA-N n-(1h-benzimidazol-2-yl)-5-methyl-1-oxo-2,3,4,5-tetrahydro-[1,4]diazepino[1,2-a]indole-8-carboxamide Chemical compound CC1CCNC(=O)C2=CC3=CC=C(C(=O)NC=4NC5=CC=CC=C5N=4)C=C3N12 BMPLTNNXXFVKEU-UHFFFAOYSA-N 0.000 claims description 2
- SQURCMDQNPTKFN-UHFFFAOYSA-N n-(1h-indol-2-yl)-4-methyl-1-oxo-3,4-dihydro-2h-pyrazino[1,2-a]indole-7-carboxamide Chemical compound C1=CC=C2NC(NC(=O)C3=CC=C4C=C5C(=O)NCC(N5C4=C3)C)=CC2=C1 SQURCMDQNPTKFN-UHFFFAOYSA-N 0.000 claims description 2
- QCBWBIFENZHWFF-UHFFFAOYSA-N n-(2-carbamoylphenyl)-4,4-dimethyl-1-oxo-2,3-dihydropyrazino[1,2-a]indole-7-carboxamide Chemical compound C1=C2N3C(C)(C)CNC(=O)C3=CC2=CC=C1C(=O)NC1=CC=CC=C1C(N)=O QCBWBIFENZHWFF-UHFFFAOYSA-N 0.000 claims description 2
- IGJVUIUYHUKAST-UHFFFAOYSA-N n-(2-methoxypyridin-4-yl)-1-oxo-2,3,4,5-tetrahydro-[1,4]diazepino[1,2-a]indole-8-carboxamide Chemical compound C1=NC(OC)=CC(NC(=O)C=2C=C3N4CCCNC(=O)C4=CC3=CC=2)=C1 IGJVUIUYHUKAST-UHFFFAOYSA-N 0.000 claims description 2
- WMGGYIKBPUVPFM-UHFFFAOYSA-N n-(3-ethylimidazo[4,5-b]pyridin-2-yl)-1-oxo-2,3,4,5-tetrahydro-[1,4]diazepino[1,2-a]indole-8-carboxamide Chemical compound O=C1NCCCN2C3=CC(C(=O)NC=4N(C5=NC=CC=C5N=4)CC)=CC=C3C=C21 WMGGYIKBPUVPFM-UHFFFAOYSA-N 0.000 claims description 2
- QYLAYPRSSJNQDC-UHFFFAOYSA-N n-(6-chloro-1-ethylbenzimidazol-2-yl)-1-oxo-2,3,4,5-tetrahydro-[1,4]diazepino[1,2-a]indole-8-carboxamide Chemical compound O=C1NCCCN2C3=CC(C(=O)NC=4N(C5=CC(Cl)=CC=C5N=4)CC)=CC=C3C=C21 QYLAYPRSSJNQDC-UHFFFAOYSA-N 0.000 claims description 2
- RSWPBNBGJPFMPY-UHFFFAOYSA-N n-(6-chloro-1h-benzimidazol-2-yl)-1-oxo-2,3,4,5-tetrahydro-[1,4]diazepino[1,2-a]indole-8-carboxamide Chemical compound O=C1NCCCN2C3=CC(C(=O)NC=4NC5=CC=C(C=C5N=4)Cl)=CC=C3C=C21 RSWPBNBGJPFMPY-UHFFFAOYSA-N 0.000 claims description 2
- XVXFGPGPMWYPAS-UHFFFAOYSA-N n-(6-chloro-1h-benzimidazol-2-yl)-5-methyl-1-oxo-2,3,4,5-tetrahydro-[1,4]diazepino[1,2-a]indole-8-carboxamide Chemical compound CC1CCNC(=O)C2=CC3=CC=C(C(=O)NC=4NC5=CC=C(Cl)C=C5N=4)C=C3N12 XVXFGPGPMWYPAS-UHFFFAOYSA-N 0.000 claims description 2
- FQRXBLBVYPOLRR-UHFFFAOYSA-N n-(6-methoxypyrimidin-4-yl)-1-oxo-2,3,4,5-tetrahydro-[1,4]diazepino[1,2-a]indole-8-carboxamide Chemical compound C1=NC(OC)=CC(NC(=O)C=2C=C3N4CCCNC(=O)C4=CC3=CC=2)=N1 FQRXBLBVYPOLRR-UHFFFAOYSA-N 0.000 claims description 2
- ULMVWXOBBULOQQ-UHFFFAOYSA-N n-(6-methyl-1h-benzimidazol-2-yl)-1-oxo-2,3,4,5-tetrahydro-[1,4]diazepino[1,2-a]indole-8-carboxamide Chemical compound O=C1NCCCN2C3=CC(C(=O)NC=4NC5=CC=C(C=C5N=4)C)=CC=C3C=C21 ULMVWXOBBULOQQ-UHFFFAOYSA-N 0.000 claims description 2
- NWWJMBOCMRICQS-UHFFFAOYSA-N n-[1-[3-(dimethylamino)propyl]benzimidazol-2-yl]-4,4-dimethyl-1-oxo-2,3-dihydropyrazino[1,2-a]indole-7-carboxamide Chemical compound C1=CC=C2N(CCCN(C)C)C(NC(=O)C=3C=C4N5C(C)(C)CNC(=O)C5=CC4=CC=3)=NC2=C1 NWWJMBOCMRICQS-UHFFFAOYSA-N 0.000 claims description 2
- UNZXJJNYRSXYJL-UHFFFAOYSA-N n-[1-[3-(dimethylamino)propyl]benzimidazol-2-yl]-4-methyl-1-oxo-3,4-dihydro-2h-pyrazino[1,2-a]indole-7-carboxamide Chemical compound C1=CC=C2N(CCCN(C)C)C(NC(=O)C3=CC=C4C=C5C(=O)NCC(N5C4=C3)C)=NC2=C1 UNZXJJNYRSXYJL-UHFFFAOYSA-N 0.000 claims description 2
- VMJFJZPFKKPMJU-UHFFFAOYSA-N n-[2-(cyclopentylcarbamoyl)-1-methylimidazol-4-yl]-4,4-dimethyl-1-oxo-2,3-dihydropyrazino[1,2-a]indole-7-carboxamide Chemical compound CN1C=C(NC(=O)C=2C=C3N4C(C)(C)CNC(=O)C4=CC3=CC=2)N=C1C(=O)NC1CCCC1 VMJFJZPFKKPMJU-UHFFFAOYSA-N 0.000 claims description 2
- MYNPMSCRXYCTGE-UHFFFAOYSA-N n-[2-(cyclopentylcarbamoyl)-1-methylimidazol-4-yl]-5-methyl-1-oxo-2,3,4,5-tetrahydro-[1,4]diazepino[1,2-a]indole-8-carboxamide Chemical compound C1=C2N3C(C)CCNC(=O)C3=CC2=CC=C1C(=O)NC(N=1)=CN(C)C=1C(=O)NC1CCCC1 MYNPMSCRXYCTGE-UHFFFAOYSA-N 0.000 claims description 2
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- ZXHDZOUUAQKTSO-MRXNPFEDSA-N (5r)-n-(1-benzylpyrazol-4-yl)-5-methyl-1-oxo-2,3,4,5-tetrahydro-[1,4]diazepino[1,2-a]indole-8-carboxamide Chemical compound C([C@H](N1C2=C3)C)CNC(=O)C1=CC2=CC=C3C(=O)NC(=C1)C=NN1CC1=CC=CC=C1 ZXHDZOUUAQKTSO-MRXNPFEDSA-N 0.000 claims 1
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Classifications
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/12—Antihypertensives
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/12—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains three hetero rings
- C07D487/20—Spiro-condensed systems
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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
- C07D491/12—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 three hetero rings
- C07D491/20—Spiro-condensed systems
Definitions
- the present invention relates to novel compounds which inhibit RSK, methods of making such compounds and their use as medicaments.
- RSKs ribosomal s6 kinases
- AGC subfamily in the human kinome
- RSKs ribosomal s6 kinases
- Each of the 4 RSK isoforms are products of separate genes and are characterized by 75% - 80% sequence identity. While the RSK isoforms are widely distributed among human tissues, their variable tissue expression patterns indicate that they may have distinct physiologic/pathologic roles.
- the RSK isoforms are activated by growth factors, cytokines, peptide hormones and neurotransmitters that stimulate the Ras-ERK pathway.
- NHE1 Na + /H + exchanger isoform 1
- RSK-mediated phosphorylation of NHE1 at S703 is responsible for increased NHE1 activity following Ang II stimulation, oxidative stress, and myocardial injury.
- NHE1 is a highly validated target for its role in both ischemia reperfusion (I/R) injury and congestive heart failure.
- Increased NHE1 activity correlates to the extent of myocardial damage following I/R, while NHE1 inhibitors administered in a prophylactic manner are capable of preserving cardiac function after I/R.
- NHE1 activity is observed in isolated myocytes from failing human hearts and in animal models of hypertrophy suggesting chronic activation of this exchanger in cardiovascular pathologies.
- Adverse events such as headache, eye pain, and paresthesia, were reported in clinical trials, and it is hypothesized that these events are due to direct and complete NHE1 inhibition which impairs its physiological function of maintaining intracellular pH.
- alternate approaches that do not inhibit basal NHE1 activity but regulate activity during periods of cardiovascular stress may offer an additional safety margin.
- RSK has been recognized as a predominant kinase that phosphorylates the c-terminal regulatory region of NHE1 and is required for NHE1 activation in response to I/R, oxidative stress, and receptor activation by Ang II and phenylephrine.
- Recent studies by Maekawa et al. (Naoya Maekawa, Jun-ichi Abe, Tetsuro Shishido, Seigo Itoh, Bo Ding, Virendra K. Sharma, Shey-Shing Sheu, Burns C. Blaxall and Bradford C. Berk Circulation 113:2516-2523, 2006) demonstrated that that RSK was rapidly activated in the heart tissue exposed to I/R.
- the invention relates to a compound selected from those identified as Examples 1 to 239 in Table 1 below, and any combination thereof, and pharmaceutically acceptable salts thereof.
- Table 1
- the invention relates to a compound selected from the group consisting of:
- the invention relates to a compound selected from the group consisting of:
- the invention also relates to pharmaceutical preparations, containing as active substance one or more compounds of the invention, or the pharmaceutically acceptable derivatives thereof, optionally combined with conventional excipients and/or carriers.
- Compounds of the invention also include their isotopically-labelled forms.
- An isotopically-labelled form of an active agent of a combination of the present invention is identical to said active agent but for the fact that one or more atoms of said active agent have been replaced by an atom or atoms having an atomic mass or mass number different from the atomic mass or mass number of said atom which is usually found in nature.
- isotopes which are readily available commercially and which can be incorporated into an active agent of a combination of the present invention in accordance with well established procedures, include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, fluorine and chlorine, e.g., 2 H, 3 H, 13 C, 14 C, 15 N, 18 0, 17 0, 31 P, 32 P, 35 S, 18 F, and 36 C1, respectively.
- An active agent of a combination of the present invention, a prodrug thereof, or a pharmaceutically acceptable salt of either which contains one or more of the above-mentioned isotopes and/or other isotopes of other atoms is contemplated to be within the scope of the present invention.
- the invention includes the use of any compounds of described above containing one or more asymmetric carbon atoms may occur as racemates and racemic mixtures, single enantiomers, diastereomeric mixtures and individual diastereomers. Isomers shall be defined as being enantiomers and diastereomers. All such isomeric forms of these compounds are expressly included in the present invention. Each stereogenic carbon may be in the R or S configuration, or a combination of configurations. Some of the compounds of the invention can exist in more than one tautomeric form. The invention includes methods using all such tautomers.
- the invention includes pharmaceutically acceptable derivatives of compounds depicted in Table 1.
- a "pharmaceutically acceptable derivative” refers to any pharmaceutically acceptable salt or ester, or any other compound which, upon administration to a patient, is capable of providing (directly or indirectly) a compound useful for the invention, or a pharmacologically active metabolite or pharmacologically active residue thereof.
- a pharmacologically active metabolite shall be understood to mean any compound of the invention capable of being metabolized enzymatically or chemically. This includes, for example, hydroxylated or oxidized derivative compounds of the invention.
- Pharmaceutically acceptable salts include those derived from pharmaceutically acceptable inorganic and organic acids and bases.
- suitable acids include hydrochloric, hydrobromic, sulfuric, nitric, perchloric, fumaric, maleic, phosphoric, glycolic, lactic, salicylic, succinic, toluene-p-sulfuric, tartaric, acetic, citric, methanesulfonic, formic, benzoic, malonic, naphthalene-2- sulfuric and benzenesulfonic acids.
- Other acids, such as oxalic acid while not themselves pharmaceutically acceptable, may be employed in the preparation of salts useful as intermediates in obtaining the compounds and their pharmaceutically acceptable acid addition salts.
- Salts derived from appropriate bases include alkali metal (e.g., sodium), alkaline earth metal (e.g., magnesium), ammonium and N-(CT -C4 alkyl)4 + salts.
- prodrugs of compounds of the invention include those compounds that, upon simple chemical transformation, are modified to produce compounds of the invention. Simple chemical transformations include hydrolysis, oxidation and reduction. Specifically, when a prodrug is administered to a patient, the prodrug may be transformed into a compound disclosed hereinabove, thereby imparting the desired pharmacological effect.
- Step 1 Synthesis of ethyl 4-methyl-3-nitrobenzoate 4-Methyl-3-nitrobenzoic acid (71 g, 0.39 mol) is dissolved in dry ethanol (600 mL) and dry HCl gas is bubbled into the solution for 5 min. The reaction mixture is heated to 90 °C under N 2 for 20 h. The solvent is removed under vacuum to afford the title compound as a straw-colored liquid (80.0 g, 98%).
- Step 2 Synthesis of ethyl 4-(3-ethoxy-2,3-dioxopropyl)-3-nitrobenzoate
- Ethyl 4-(3-ethoxy-2,3-dioxopropyl)-3-nitrobenzoate (91 g, 0.29 mol) is suspended in 800 mL of acetic acid and it is heated with stirring to 75 °C. Once the solid is dissolved, water (600 mL) is added. Zinc dust (189 g, 2.9 mol) is added carefully in small portions and the reaction temperature is kept below 85 °C. The mixture is then stirred vigorously for 1 hour after the addition. EtOAc (1500 mL) is added and the mixture was filtered through Celite.
- Step 1 Synthesis of diethyl l-(l-cyanoethyl)-1H-indole-2,6-dicarboxylate
- Step 2 Synthesis of ethyl 4-methyl-1-oxo-1,2,3,4-tetrahydropyrazino[1,2-a]indole-7- carboxylate
- Step 3 Synthesis of 4-methyl-1-oxo-1,2,3,4-tetrahydropyrazino[1,2-a]indole-7- carboxylic acid
- a suspension of ethyl 4-methyl-1-oxo-1,2,3,4-tetrahydropyrazino[1,2-a]indole-7- carboxylate (3.2 g, 11.8 mmol) in THF:ethanol (1: 1, 50 mL) is added IN NaOH solution (43 mL, 43 mmol). The reaction mixture is heated at 75 °C for 18 h. The solvents are removed and the residue is dissolved in water. The aqueous solution is washed with ether and acidified to pH 4 using 3N HCl solution. The resulting white solid is filtered and rinsed more ether to afford the title compound (2.2 g, 76%).
- Step 1 Synthesis of tert-butyl [(2S)-2-hydroxypropyl]carbamate To a stirred solution of (2S)-1-aminopropan-2-ol (2.0 g, 26.6 mmol) in CH 2 C1 2 (50mL) is added a solution of di-tert-butyl dicarbonate (6.1 g, 28 mmol) in CH 2 C1 2 (50mL). The reaction mixture is stirred for 18h. The solution is washed with citric acid and NaHC0 3 , dried (Na 2 S0 4 ) and evaporated to afford the title compound (5.1 g, crude) as colorless oil.
- Step 2 Synthesis of tert-butyl (5S)-5-methyl-1,2,3-oxathiazolidine-3-carboxylate 2- oxide
- Step 3 Synthesis of tert-butyl (5S)-5-methyl-1,2,3-oxathiazolidine-3-carboxylate 2,2- dioxide
- Step 4 Synthesis of diethyl l- ⁇ (2R)-1-[(tert-butoxycarbonyl)amino]propan-2-yl ⁇ - 1H-indole-2,6-dicarboxylate
- a stirred suspension of 60% NaH (371 mg, 9.3 mmol) in DMF (10 mL) is cooled in an ice bath, and a solution of diethyl 1H-indole-2,6-dicarboxylate (Intermediate A, 2.6 g, 10.1 mmol) in DMF (10 mL) is added.
- This compound is synthesized using the similar procedure used to prepare (4R)-4-methyl- l-oxo-1,2,3,4-tetrahydropyrazino[1,2-a]indole-7-carboxylic acid (Intermediate C), replacing (2S)-1-aminopropan-2-ol with (2R)-1-aminopropan-2-ol in Step 1. 4,4-dimethyl-1-oxo-1,2,3,4-tetrahydropyrazino[1,2-a]indole-7-
- Step 1 Synthesis of diethyl l-(cyanomethyl)-1H-indole-2,6-dicarboxylate
- Step 2 Synthesis of diethyl l-(2-cyanopropan-2-yl)-1H-indole-2,6-dicarboxylate
- Step 3 Synthesis of ethyl 4,4-dimethyl-1-oxo-1,2,3,4-tetrahydropyrazino[1,2- a]indole-7-carboxylate
- Step 4 Synthesis of 4,4-dimethyl-1-oxo-1,2,3,4-tetrahydropyrazino[1,2-a]indole-7- carboxylic acid
- Step 1 Synthesis of 3-aminobutan-2-ol Ammonium formate (9.0 g, 142.9 mmol) is added to a solution of 3-nitrobutan-2-ol (2.5 g, 21.0 mmol) in methanol (20 mL). Palladium on carbon (250 mg) is then added as a slurry in methanol. The reaction mixture is stirred at room temperature for 18 h. Celite is added and the mixture is filtered though a plug of more Celite. The solid is washed with methanol and the filtrates are combined and concentrated to afford the title compound (2.42 g, 129%) which is used in the next step without purification.
- Step 2 Synthesis of tert-butyl (3-hydroxybutan-2-yl)carbamate
- Step 3 Synthesis of tert-butyl 4,5-dimethyl-1,2,3-oxathiazolidine-3-carboxylate 2- oxide
- Step 4 Synthesis of tert-butyl 4,5-dimethyl-1,2,3-oxathiazolidine-3-carboxylate 2,2- dioxide
- Step 5 Synthesis of diethyl l- ⁇ 3-[(tert-butoxycarbonyl)amino]butan-2-yl ⁇ -1H- indole-2,6-dicarboxylate
- reaction mixture is stirred for 30 min at 0 °C and then is warmed to room temperature and stirred for 65 h. Water is added and the mixture is stirred for 15 min before EtOAc (50 mL) is added. Then the organic layer is separated, washed with aqueous NFLCl solution, water, and brine, dried (MgS0 4 ) and concentrated to afford the crude title compound, which was used directly in the next reaction.
- Step 6 Synthesis of ethyl cis-3,4-dimethyl-1-oxo-1,2,3,4-tetrahydropyrazino[1,2- Gc]indole-7-carboxylate and ethyl trans-3,4-dimethyl-1-oxo-1,2,3,4- tetrahydropyrazino[1,2-cc]indole-7-carboxylate
- Step 7a Synthesis of cis-3,4-dimethyl-1-oxo-1,2,3,4-tetrahydropyrazino[1,2- Gc]indole-7-carboxylic acid
- Step 7b Synthesis of trans-3,4-dimethyl-1-oxo-1,2,3,4-tetrahydropyrazino[1,2- a]indole-7-carboxylic acid
- Step 1 Separation of ethyl (3R,4S)-3,4-dimethyl-1-oxo-1,2,3,4- tetrahydropyrazino[1,2-a]indole-7-carboxylate and ethyl (3S,4R)-3,4-dimethyl-1- oxo-1,2,3,4-tetrahydropyrazino[1,2-a]indole-7-carboxylate
- Racemic cis-3,4-dimethyl- 1-oxo- 1 ,2,3,4-tetrahydropyrazino[ 1 ,2-a]indole-7-carboxylic acid (Intermediate F, 1.9 g, 6.7 mmol) is separated on a preparative chiral column (Chiralpak AD, 5cmx50cm, 20u, Chiral Technologies, West Chester, PA) using Gilson preparative HPLC (Mobile Phase: 12% isopropanol in heptane; Flow rate: 100 mL/min) to afford ethyl (3S,4R)-3,4-dimethyl-1-oxo-1,2,3,4-tetrahydropyrazino[1,2-a]indole-7- carboxylate (870 mg, 46%) and ethyl (3R,4S)-3,4-dimethyl-1-oxo-1,2,3,4- tetrahydropyrazino[1,2-a]indole-7
- Step 2b Synthesis of (3S,4R)-3,4-Dimethyl-1-oxo-1,2,3,4-tetrahydro-pyrazino[1,2- a]indole-7-carboxylic acid
- Ethyl (3S,4R)-3,4-dimethyl-1-oxo-1,2,3,4-tetrahydropyrazino[1,2-a]indole-7-carboxylate (870 mg, 3.0 mmol) is suspended in ethanol (25 mL) and 1M NaOH solution (7.6 mL, 7.6 mmol) is added. The reaction mixture is heated at 80 °C for 1 h and then cooled to room temperature. The mixture is acidified with 1M HCl solution and ethanol is removed. The resulting solid is filtered, rinsed with water and dried to afford the title compound (760mg, 97%).
- Step 1 Synthesis of diethyl l-(2-cyanoethyl)-1H-indole-2,6-dicarboxylate
- Step 2 Synthesis of ethyl l-oxo-2,3,4,5-tetrahydro-1H-[1,4]diazepino[1,2-a]indole-8- carboxylate
- Step 3 Synthesis of l-oxo-2,3,4,5-tetrahydro-1H-[1,4]diazepino[1,2-a]indole-8- carboxylic acid
- Step 1 Synthesis of tert-butyl (3-hydroxybutyl)carbamate
- 4-aminobutan-2-ol 1.0 g, 11.2 mmol
- CH 2 CI 2 20 mL
- di-tert-butyl dicarbonate 2.45 g, 11.2 mmol
- the reaction mixture is stirred for 18 h.
- the solution is washed with citric acid and NaHCC"3, dried (MgS0 4 ) and evaporated to afford the title compound (2.1 g, 99%) as colorless oil.
- Step 2 Synthesis of tert-butyl 6-methyl-1,2,3-oxathiazinane-3-carboxylate 2-oxide
- Step 3 Synthesis of tert-butyl 6-methyl-1,2,3-oxathiazinane-3-carboxylate 2,2- dioxide
- Step 4 Synthesis of diethyl l- ⁇ 4-[(tert-butoxycarbonyl)amino]butan-2-yl ⁇ -1H- indole-2,6-dicarboxylate
- Step 6 Synthesis of 5-methyl-1-oxo-2,3,4,5-tetrahydro-1H-[1,4]diazepino[1,2- a]indole-8-carboxylic acid
- Step 1 Synthesis of (3S)-3-hydroxybutanamide Ethyl (3S)-3-hydroxybutanoate (200 g, 1.5 mol) is added to 25% NH 4 OH aqueous solution (2.0 L) in a sealed tube. The reaction mixture is heated at 60 °C for 16 h. The solvent is removed azeotropically with toluene to afford the title crude compound (176 g, 82%) as a white crystalline solid which is used in the next step without purification.
- Step 2 Synthesis of tert-butyl [(3S)-3-hydroxybutyl]carbamate
- Step 3 Synthesis of tert-butyl (6S)-6-methyl-1,2,3-oxathiazinane-3-carboxylate 2- oxide
- Step 4 Synthesis of tert-butyl (6S)-6-methyl-1,2,3-oxathiazinane-3-carboxylate 2,2- dioxide
- Step 5 Synthesis of diethyl l- ⁇ (2R)-4-[(tert-butoxycarbonyl)amino]butan-2-yl ⁇ -1H- indole-2,6-dicarboxylate
- a stirred suspension of 60% NaH (840 mg, 21 mmol) in NMP (40 mL) is cooled in an ice bath, and a solution of diethyl 1H-indole-2,6-dicarboxylate (Intermediate A, 5.8 g, 22 mmol) in NMP (20 mL) is added.
- Step 6 Synthesis of ethyl (5R)-5-methyl-1-oxo-2,3,4,5-tetrahydro-1H- [1,4]diazepino[1,2-a]indole-8-carboxylate
- Step 7 Synthesis of (5R)-5-methyl-1-oxo-2,3,4,5-tetrahydro-1H-[1,4]diazepino[1,2- a]indole-8-carboxylic acid
- a solution of (5R)-5-methyl-1-oxo-2,3,4,5-tetrahydro-1H-[1,4]diazepino[1,2-a]indole- 8-carboxylate (3.65 g, crude)in ethanol (30 mL) is added IM NaOH solution (13.8 mL, 13.8 mmol).
- the reaction mixture is refluxed for 2 h.
- the reaction mixture is acidified with IM HCl and ethanol is removed under vacuum.
- the resulting solid is collected by filtration, is washed with water and dried to afford the title compound (2.1 g, 41% for 3 steps) as a solid.
- Step 2 Synthesis of tert-butyl [(3R)-3-hydroxybutyl]carbamate
- THF trifluoroethyl
- borane-methyl sulfide 9.2 mL, 97.0 mmol
- 6M HCl solution 3 mL
- the reaction mixture is refluxed for 2 h and is then basified to pH 9 by addition of Na 2 C0 3 solution.
- Step 3 Synthesis of tert-butyl (6R)-6-methyl-1,2,3-oxathiazinane-3-carboxylate 2- oxide
- Step 4 Synthesis of tert-butyl (6R)-6-methyl-1,2,3-oxathiazinane-3-carboxylate 2,2- dioxide
- a solution of tert-butyl (6R)-6-methyl-1,2,3-oxathiazinane-3-carboxylate 2-oxide (2.3 g, 9.6 mmol) in acetonitrile (25 mL) and water (15 mL) cooled to 0 °C is added sodium periodate (3.1 g, 14.3 mmol) in one portion. After 5 min, the pH of the mixture is adjusted to 7-8 by addition of saturated Na 2 HP0 4 solution.
- Step 5 Synthesis of diethyl l- ⁇ (2S)-4-[(tert-butoxycarbonyl)amino]butan-2-yl ⁇ -1H- indole-2,6-dicarboxylate
- reaction mixture is stirred for 30 min at 0 °C and is warmed to room temperature and stirred for 72 h. Water and NH 4 C1 solution are added and the mixture is stirred for 15 min. The aqueous mixture is extracted with EtOAc (50 mL) and the organic layer is washed with water, brine, dried (MgS0 4 ) and concentrated to afford the title crude compound (1.1 g) which is used in the next step without purification.
- Step 6 Synthesis of ethyl (5S)-5-methyl-1-oxo-2,3,4,5-tetrahydro-1H- [1,4]diazepino[1,2-a]indole-8-carboxylate
- diethyl l- ⁇ (2S)-4-[(tert-butoxycarbonyl)amino]butan-2-yl ⁇ -1H-indole- 2,6-dicarboxylate 891 mg, 2.1 mmol
- TFA 3 mL
- Step 7 Synthesis of (5S)-5-methyl-1-oxo-2,3,4,5-tetrahydro-1H-[1,4]diazepino[1,2- a]indole-8-carboxylic acid
- Step 1 Synthesis of tert-butyl (3-hydroxy-2-methylpropyl)carbamate
- 3-amino-2-methylpropan-1-ol hydrochloride salt 2.0 g, 15.9 mmol
- CH 2 CI 2 100 mL
- triethylamine 3.3 mL, 23.9 mmol
- di-tert- butyl dicarbonate 3.8 g, 17.5 mmol
- the mixture is stirred for 36 h and then saturated NH 4 CI solution (150 mL) is added.
- the mixture is stirred for 10 min and the organic layer is separated and washed with saturated NaHC0 3 , dried (Na 2 S0 4 ) and concentrated to afford the title compound which is used in next step without purification.
- Step 2 Synthesis of diethyl l- ⁇ 3-[(tert-butoxycarbonyl)amino]-2-methylpropyl ⁇ -1H- indole-2,6-dicarboxylate
- Step 3 Synthesis of ethyl 4-methyl-1-oxo-2,3,4,5-tetrahydro-1H-[1,4]diazepino[1,2- a]indole-8-carboxylate
- Step 4 Synthesis of 4-methyl-1-oxo-2,3,4,5-tetrahydro-1H-[1,4]diazepino[1,2- a]indole-8-carboxylic acid
- Step 1 Synthesis of 2-methyl-3-oxobutanamide
- a suspension of ethyl 2-methyl-3-oxobutanoate (72 g, 499 mmol) in ammonium hydroxide (300 mL) is stirred vigorously at room temperature for 4 days.
- the resulting crystalline precipitate is filtered and discarded.
- the filtrate is concentrated under vacuum to afford an oil that crystallizes on standing.
- the solid is collected and dried to afford the title compound (26.7 g, 46%).
- Step 3 Synthesis of tert-butyl (3-hydroxy-2-methylbutyl)carbamate
- a stirred solution of 4-amino-3-methylbutan-2-ol (2.4 g, 23.1 mmol) in CH 2 CI 2 (30 mL) is added a solution of di-tert-butyl dicarbonate (5.0 g, 23.1 mmol) in CH 2 C1 2 (20 mL).
- the reaction is stirred for 18 h at room temperature.
- the solution is washed with 1M NaHS0 4 , dried over (MgS0 4 ) and concentrated. Purification of the residue by flash column chromatography using EtOAc in hexanes affords the title compound (3.4 g, 73%) as a colorless oil.
- Step 4 Synthesis of tert-butyl 5,6-dimethyl-1,2,3-oxathiazinane-3-carboxylate 2- oxide
- thionyl chloride 5.4 g, 45.4 mmol
- acetonitrile 25 mL
- a solution of tert-butyl (3-hydroxy-2-methylbutyl)carbamate 3.7 g, 18.1 mmol
- acetonitrile 35mL
- Step 5 Synthesis of tert-butyl cis-5,6-dimethyl-1,2,3-oxathiazinane-3-carboxylate 2,2-dioxide
- Step 6 Synthesis of diethyl l- ⁇ (2,3-syn)-4-[(tert-butoxycarbonyl)amino]-3- methylbutan-2-yl ⁇ -1H-indole-2,6-dicarboxylate
- a suspension of 60% sodium hydride (119 mg, 3.0 mmol) in DMF (3 mL) is cooled to 0 °C and a solution of diethyl 1H-indole-2,6-dicarboxylate (Intermediate A, 934 mg, 3.6 mmol) is added. After the mixture is stirred for 20 min at 0 °C, a solution of tert-butyl cis-5,6-dimethyl-1,2,3-oxathiazinane-3-carboxylate 2,2-dioxide (790 mg, 3.0 mmol) in DMF (2.0 mL) is added. The reaction mixture is warmed to room temperature and stirred for 16 h.
- Step 7 Synthesis of ethyl trans-4,5-dimethyl-1-oxo-2,3,4,5-tetrahydro-1H- [1,4]diazepino[1,2-a]indole-8-carboxylate
- Step 8 Synthesis of trans-4,5-dimethyl-1-oxo-2,3,4,5-tetrahydro-1H- [1,4]diazepino[1,2-a]indole-8-carboxylic acid
- This compound is synthesized using the similar procedure used to prepare trans-4,5- dimethyl-1-oxo-2,3,4,5-tetrahydro-1H-[1,4]diazepino[1,2-a]indole-8-carboxylic acid (Intermediate O), replacing the tert-butyl cis-5,6-dimethyl-1,2,3-oxathiazinane-3- carboxylate 2,2-dioxide with tert-butyl trans-5,6-dimethyl-1,2,3-oxathiazinane-3- carboxylate 2,2-dioxide in step 6.
- Step 1 Synthesis of tert-butyl (3-hydroxy-2,2-dimethylpropyl)carbamate
- Step 2 Synthesis of diethyl l- ⁇ 3-[(tert-butoxycarbonyl)amino]-2,2-dimethylpropyl ⁇ - 1H-indole-2,6-dicarboxylate
- diethyl 1H-indole-2,6-dicarboxylate 25.3 g, 97 mmol
- tert-butyl (3- hydroxy-2,2-dimethylpropyl)carbamate (19.7, 97 mmol)
- triphenylphosphine 50.9 g, 194 mmol
- diisopropyl azodicarboxylate 40.2 mL, 194 mmol.
- Step 3 Synthesis of ethyl 4,4-dimethyl-1-oxo-2,3,4,5-tetrahydro-1H- [1,4]diazepino[1,2-a]indole-8-carboxylate
- Step 4 Synthesis of 4,4-dimethyl-1-oxo-2,3,4,5-tetrahydro-1H-[1,4]diazepino[1,2- a]indole-8-carboxylic acid
- Ethyl 4,4-dimethyl-1-oxo-2,3,4,5-tetrahydro-1H-[1,4]diazepino[1,2-a]indole-8- carboxylate (7.6 g, 25.3 mmol) is dissolved in ethanol (250 mL) and 1M NaOH solution (88.6 mL, 88.6 mmol) is added. The reaction mixture is heated at 80 °C for 2 h.
- Step 2 Synthesis of 2,2-difluoropropane-1,3-diyl bis(4-methylbenzenesulfonate)
- 2-difluoropropane-1,3-diol 2.5 g, 22.3 mmol
- CH 2 CI 2 100 mL
- triethylamine 14.3 mL, 111.5 mmol
- 4-methyl-benzenesulfonyl chloride 12.8 g, 66.9 mmol
- the reaction mixture is stirred for 16 h at room temperature. Water (35 mL) is added and the organic layer is separated and washed with more water (2x35 mL).
- the organic layer is concentrated and the crude compound is purified by flash column chromatography using EtOAc in heptane to afford the title compound (6.7 g, 71%).
- Step 3 Synthesis of diethyl l-(2,2-difluoro-3- ⁇ [(4- methylphenyl)sulfonyl]oxy ⁇ propyl)- 1H-indole-2,6-dicarboxylate
- Step 4 Synthesis of diethyl l-(3-azido-2,2-difluoropropyl)-1H-indole-2,6- dicarboxylate
- diethyl l-(2,2-difluoro-3- ⁇ [(4-methylphenyl)sulfonyl]oxy ⁇ propyl)-1H- indole-2,6-dicarboxylate 4.7 g, 59% pure, 5.5 mmol
- sodium azide 908 mg, 13.8 mmol
- the mixture is heated at 95 °C for 40 h. Water (250 mL) is added and the mixture is extracted with EtOAc (3 x 250 mL).
- Step 5 Synthesis of diethyl l-(3-amino-2,2-difluoropropyl)-1H-indole-2,6- dicarboxylate
- Step 7 Synthesis of 4,4-difluoro-1-oxo-2,3,4,5-tetrahydro-1H-[1,4]diazepino[1,2- a]indole-8-carboxylic acid
- Step 1 Synthesis of [l-(aminomethyl)cyclopropyl]methanol
- a solution of lithium aluminum hydride (34 g, 899 mmol) in THF (400 mL) is added a solution of ethyl l-(cyanomethyl)cyclopropanecarboxylate (25 g, 179 mmol) in THF (100 mL) at 0 °C.
- the reaction mixture is stirred at room temperature for 4 h.
- the reaction mixture is cooled to 0 °C and ice cold water (60 mL) is added.
- the mixture is extracted with EtOAc (2 X 300 mL).
- the organic layers are combined, dried (Na 2 S0 4 ) and concentrated to afford the title crude compound (20 g) which is used in the next step without purification.
- Step 2 Synthesis of tert-butyl ⁇ [l-(hydroxymethyl)cyclopropyl]methyl ⁇ carbamate
- Di-tert-butyl dicarbonate (40.5 mL, 197 mmol) is added to a stirred solution of [1- (aminomethyl)cyclopropyl]methanol (20 g, 198 mmol) in CH 2 C1 2 (600 mL) at room temperature.
- the reaction mixture is stirred at same temperature for 40 h.
- saturated NH 4 C1 solution 250 mL
- the organic layer is separated, washed with saturated NaHC0 3 solution (100 mL), dried (Na 2 S0 4 ) and concentrated to afford the title compound (20 g, 56 % for 2 steps) as a white solid.
- Step 3 Synthesis of diethyl l-[(l- ⁇ [(tert- butoxycarbonyl)amino]methyl ⁇ cyclopropyl)methyl]-1H-indole-2,6-dicarboxylate
- Step 4 Synthesis of diethyl l- ⁇ [l-(aminomethyl)cyclopropyl]methyl ⁇ -1H-indole-2,6- dicarboxylate TFA (120 mL) is added to a solution of crude diethyl l-[(l- ⁇ [(tert- butoxycarbonyl)amino]methyl ⁇ cyclopropyl)methyl]- 1H-indole-2,6-dicarboxylate (36 g, 81 mmol) in CH 2 C1 2 (700 mL) at room temperature. The reaction mixture is stirred for 2 h and the solvent is evaporated.
- Step 5 Synthesis of ethyl l'-oxo-2',3'-dihydro-l'H-spiro[cyclopropane-1,4'- [1,4]diazepino[1,2-a]indole]-8'-carboxylate
- Triethylamine (36.3 mL, 260.8 mmol) is added to the mixture of crude diethyl 1- ⁇ [1- (aminomethyl)cyclopropyl]methyl ⁇ -1H-indole-2,6-dicarboxylate (30 g, 86.9 mmol) and K 2 C0 3 (36 g, 260.8 mmol) in ethanol (800 mL).
- reaction mixture is heated at 80 C for 2 h and it is cooled to room temperature and stirred for another 16 h.
- Solid K 2 C0 3 is removed by filtration and the filtrate is concentrated to afford the crude compound which is purified by flash column chromatography using 3 % methanol in CH 2 C1 2 to afford the title compound (9.2 g, 31% for 3 steps) as a white solid.
- Step 6 Synthesis of l'-oxo-2',3'-dihydro-l'H-spiro[cyclopropane-1,4'- [1,4]diazepino[1,2-a]indole]-8'-carboxylic acid
- Step 1 Synthesis of tert-butyl ⁇ [l-(hydroxymethyl)cyclobutyl]methyl ⁇ carbamate
- Di-tert-butyl dicarbonate 23.19 mL, 104 mmol
- CH 2 CI 2 700 mL
- Saturated NH 4 CI 300 mL
- the organic layer is separated, washed with saturated NaHC0 3 (100 mL), dried (Na 2 S0 4 ) and concentrated to afford the title compound (20 g, 89%) as a white solid.
- Step 2 Synthesis of diethyl l-[(l- ⁇ [(tert- butoxycarbonyl)amino]methyl ⁇ cyclobutyl)methyl]-1H-indole-2,6-dicarboxylate
- tert-butyl ⁇ [l-(hydroxymethyl)cyclobutyl]methyl ⁇ carbamate (12 g, 55.76 mmol)
- diethyl 1H-indole-2,6-dicarboxylate 14.56 g, 55.76 mmol
- triphenylphosphine 29.2 g, 111.5 mmol.
- diisopropyl azodicarboxylate 22.41 mL, 111.5 mmol
- Step 3 Synthesis of diethyl l- ⁇ [l-(aminomethyl)cyclobutyl]methyl ⁇ -1H-indole-2,6- dicarboxylate
- Step 4 Synthesis of ethyl l'-oxo-2',3'-dihydro-l'H-spiro[cyclobutane-1,4'- [1,4]diazepino[1,2-a]indole]-8'-carboxylate
- Triethylamine (23.3 mL, 167.5 mmol) is added to a mixture of crude l-(l-aminomethyl- cyclobutylmethyl)-lH-indole-2,6-dicarboxylic acid diethyl ester from the preceding step and K 2 C0 3 (23.16 g, 167.5 mmol) in ethanol (1.2 L).
- the reaction mixture is heated at 80 °C for 2 h then is cooled down to room temperature and stirred for another 16 h.
- Step 5 Synthesis of l'-oxo-2',3'-dihydro-l'H-spiro[cyclobutane-1,4'- [1,4]diazepino[1,2-a]indole]-8'-carboxylic acid
- a solution of ethyl -oxo-2',3'-dihydro-l'H-spiro[cyclobutane-1,4'-[1,4]diazepino[1,2- a]indole]-8'-carboxylate 7 g, 22.4 mmol
- ethanol 240 mL
- NaOH 2.24 g, 56 mmol
- the reaction mixture is heated at 80 °C for 2 h.
- Acetic acid(35.8 mL) and water (314 mL) are added and the resulting solid is filtered, rinsed with water and dried to afford the title compound (4 g, 64%) as a white solid.
- Step 1 Synthesis of ethyl 4-cyanotetrahydro-2H-pyran-4-carboxylate
- Step 3 Synthesis of tert-butyl ⁇ [4-(hydroxymethyl)tetrahydro-2H-pyran-4- yl]methyl ⁇ carbamate
- Step 4 Synthesis of diethyl l-[(4- ⁇ [(tert-butoxycarbonyl)amino]methyl ⁇ tetrahydro- 2H-pyran-4-yl)methyl]-1H-indole-2,6-dicarboxylate
- tert-butyl ⁇ [4-(hydroxymethyl)tetrahydro-2H-pyran-4- yl] methyl ⁇ carbamate 10 g, 40.81 mmol
- diethyl 1H-indole-2,6-dicarboxylate (Intermediate A, 10.65 g, 40.81 mmol)
- triphenylphosphine (21.3 g, 81.63 mmol) in THF (110 mL) at room temperature is added diisopropyl azodicarboxylate (16 mL, 81.63 mmol).
- reaction mixture is stirred for 60 h and the solvent is removed under vacuum.
- residue is purified by flash column chromatography using 12% EtOAc in petroleum ether to afford a mixture of diethyl l-[(4- ⁇ [(tert- butoxycarbonyl)amino]methyl ⁇ tetrahydro-2H-pyran-4-yl)methyl]-1H-indole-2,6- dicarboxylate and un-reacted diethyl 1H-indole-2,6-dicarboxylate as a white solid.
- the mixture is used in the next step without further purification.
- Step 5 Synthesis of diethyl l- ⁇ [4-(aminomethyl)tetrahydro-2H-pyran-4-yl]methyl ⁇ - 1H-indole-2,6-dicarboxylate
- TFA 60 mL
- the reaction mixture is stirred at room temperature for 2 h.
- Step 6 Synthesis of ethyl l-oxo-2,2',3,3',5',6'-hexahydro-1H-spiro[1,4-diazepino[1,2- a]indole-4,4'-pyran]-8-carboxylate
- Step 7 Synthesis of l-oxo-2,2',3,3',5',6'-hexahydro-1H-spiro[1,4-diazepino[1,2- a]indole-4,4'-pyran]-8-carboxylic acid
- Step 1 Synthesis of tert-butyl 4-cyanopiperidine-1-carboxylate
- Di-tert-butyl dicarbonate (26.4 mL, 109.0 mmol) is added dropwise to a solution of piperidine-4-carbonitrile (10 g, 90.9 mmol) in CH 2 C1 2 (120 mL) at 0 °C.
- the reaction mixture is warmed to room temperature and stirred for 1 h.
- the solvent is evaporated, a small amount of n-hexane is added and the mixture is cooled to 0 °C for 1 h.
- the resulting solid is collected by filtration and dried to afford the title compound (14 g, 73.6%) as a white solid.
- Step 2 Synthesis of tert-butyl 4-[(benzyloxy)methyl]-4-cyanopiperidine-1- carboxylate
- Step 3 Synthesis of tert-butyl 4-(aminomethyl)-4-[(benzyloxy)methyl]piperidine-1- carboxylate
- Step 4 Synthesis of tert-butyl 4-[(benzyloxy)methyl]-4- ⁇ [(tert- butoxycarbonyl)amino]methyl ⁇ piperidine-1-carboxylate
- Di-tert-butyl dicarbonate (3.4 mL, 14.28 mmol) is added dropwise to a solution of tert- butyl 4-(aminomethyl)-4-[(benzyloxy)methyl]piperidine-1-carboxylate (4 g, 11.9 mmol) in CH 2 C1 2 (130 mL) at 0 °C.
- the reaction mixture is warmed to room temperature and stirred for 1 h.
- Step 6 Synthesis of diethyl l- ⁇ [l-(tert-butoxycarbonyl)-4- ⁇ [(tert- butoxycarbonyl)amino]methyl ⁇ piperidin-4-yl]methyl ⁇ -1H-indole-2,6-dicarboxylate
- the mixture is partitioned between water and ethyl acetate, and the organic layer is separated.
- the aqueous layer is extracted with ethyl acetate (2 x 200 mL).
- the combined organic layers are dried (Na 2 S0 4 ), and concentrated.
- the residue is purified by flash column chromatography using 15% EtOAc in petroleum ether to afford the title compound (17 g, 32%) as a dark brown oil.
- Step 7 Synthesis of ethyl l-oxo-2,3-dihydro-1H-spiro[1,4-diazepino[1,2-a]indole- 4,4'-piperidine]-8-carboxylate
- Trifluoroacetic acid (13.4 mL, 173.8 mmol) is added dropwise to the solution of diethyl 1 - ⁇ [ 1 -(tert-butoxycarbonyl)-4- ⁇ [(tert-butoxycarbonyl)amino]methyl ⁇ piperidin-4- yl]methyl ⁇ -1H-indole-2,6-dicarboxylate (17 g, 29.0 mmol) in CH 2 C1 2 (200 mL) at 0 °C. The reaction mixture is stirred for 3 h at room temperature and then is basified with aqueous K 2 C0 3 solution until the pH is 8. The aqueous layer is separated and extracted with CH 2 CI 2 (2 x 250 mL).
- Step 8 Synthesis of l'-tert-butyl 8-ethyl l-oxo-2,3-dihydro-1H,l'H-spiro[1,4- diazepino[1,2-a]indole-4,4'-piperidine]-l',8-dicarboxylate
- Step 9 Synthesis of l'-(tert-butoxycarbonyl)-1-oxo-2,3-dihydro-1H-spiro[1,4- diazepino[1,2-a]indole-4,4'-piperidine]-8-carboxylic acid
- l'-tert-butyl 8-ethyl l-oxo-2,3-dihydro-1H,l'H-spiro[1,4-diazepino[1,2- a]indole-4,4'-piperidine]-l',8-dicarboxylate 5.0 g, 11.3 mmol
- ethanol 120 mL
- 0 °C is added 1M NaOH solution (34 mL, 34 mmol).
- the reaction mixture is warmed to room temperature and is stirred for 16 h.
- the solvent is evaporated and water is added into the residue.
- the mixture is cooled to 0 °C and acidified with 10 % acetic acid.
- the resulting solid is collected by filtration, washed with water and dried to afford the title compound (3.3 g, 72%) as an off white solid.
- Step 1 Synthesis of tert-butyl (4-hydroxybutan-2-yl)carbamate
- Step 2 Synthesis of diethyl l- ⁇ 3-[(tert-butoxycarbonyl)amino]butyl ⁇ -1H-indole-2,6- dicarboxylate
- Step 3 Synthesis of ethyl 3-methyl-1-oxo-2,3,4,5-tetrahydro-1H-[1,4]diazepino[1,2- a]indole-8-carboxylate
- Step 4 Synthesis of 3-methyl-1-oxo-2,3,4,5-tetrahydro-1H-[1,4]diazepino[1,2- a]indole-8-carboxylic acid
- ethanol 10 mL
- 1M NaOH solution 1.0 mL, 1.0 mmol
- the reaction mixture is heated at 80 °C for 2 h.
- Acetic acid (3 mL) is and water (60 mL) are added and the mixture is concentrated.
- the residue is purified by preparative HPLC to afford the title compound (63 mg, 58%).
- Step 1 Synthesis of tert-butyl (4-hydroxy-2-methylbutan-2-yl)carbamate To a solution of 3-amino-3-methylbutan-1-ol (1.0 g, 9.7 mmol) in EtOAc (5 mL) is added di-tert-butyl dicarbonate (2.1 g, 9.7 mmol). The mixture is stirred for 16 h and the solvent is evaporated to afford the crude title compound which is used in the next step without purification.
- Step 2 Synthesis of diethyl l- ⁇ 3-[(tert-butoxycarbonyl)amino]-3-methylbutyl ⁇ -1H- indole-2,6-dicarboxylate
- Step 3 Synthesis of l-(3-amino-3-methylbutyl)-1H-indole-2,6-dicarboxylic acid
- CH 2 CI 2 3 mL
- TFA 1.5 mL
- the mixture is stirred at room temperature for 2 h.
- the solvent is evaporated and the residue dried in vacuo.
- Step 4 Synthesis of 3,3-dimethyl-1-oxo-2,3,4,5-tetrahydro-1H-[1,4]diazepino[1,2- a]indole-8-carboxylic acid
- Step 2 Synthesis of N-hydroxy-2-(2-phenyl-1,3-dioxolan-2-yl)ethanimidamide
- Sodium hydroxide (3.1 g, 77 mmol) is added to hydroxylamine hydrochloride (5.2 g, 75 mmol) at 0 °C and is stirred for 15 min.
- a solution of (2-phenyl-1,3-dioxolan-2- yl)acetonitrile (7 g, 37 mmol) in methanol (25 mL) is added dropwise to the reaction mixture at 0°C.
- the reaction mixture is allowed to warm to room temperature and is heated at 90 °C for 16 h.
- the solvent was evaporated under reduced pressure to afford the title compound as a brown solid (7 g, 85%) which is used in the next step without purification.
- Step 1 Synthesis of l-methyl-5-nitro-1H-pyrazolo[3,4-b]pyridine
- acetic acid 3 mL
- nitromalonaldehyde sodium salt 474 mg, 3.00 mmol
- reaction mixture is heated to 108 °C for 1 h.
- the reaction mixture is allowed to cool to room temperature and is stirred for 16 h.
- the solvent is evaporated under reduced pressure and the residue is purified by flash column chromatography using a gradient of 0-100% ethyl acetate in heptane to afford the title compound as a solid (100 mg, 19%).
- Step 2 Synthesis of l-methyl-1H-pyrazolo[3,4-b]pyridin-5-amine
- Step 1 Synthesis of 6-chloro-N 2 -ethylpyridine-2,3-diamine
- ethanol 20 mL
- iron powder 2.52 g, 45.2 mmol
- ammonium chloride 2.42 g, 45.2 mmol
- water 8 mL
- the mixture is heated in a microwave reactor at 140 °C for 30 min.
- the mixture is diluted with EtOAc, filtered and evaporated to afford the title compound as a brown oil (1.55 g, 100%) which was used in the next step without purification.
- Step 2 Synthesis of 5-chloro-3-ethyl-3H-imidazo[4,5-b]pyridin-2-amine
- 6-chloro-N -ethylpyridine-2,3-diamine 401 mg, 2.34 mmol
- ethanol 10 mL
- 3M solution of cyanogen bromide in DCM 0.93 mL, 2.8 mmol
- the solution is stirred for 6 h at room temperature.
- the solution is basified with ammonia in methanol and evaporated.
- the residue is purified via flash column chromatography using a gradient of 0-15% methanol in CH 2 C1 2 containing 1% NH 4 OH to afford the title compound (212 mg, 46%).
- Step 1 Synthesis of l-methyl-2-nitro-1H-imidazole
- Step 1 Synthesis of l-azido-3,3-dimethylbutan-2-one
- Step 3 Synthesis of ethyl [(3,3-dimethyl-2-oxobutyl)amino](oxo)acetate
- Step 4 Synthesis of ethyl 5-tert-butyl-1,3-oxazole-2-carboxylate
- Step 6 Synthesis of benzyl (5-tert-butyl-1,3-oxazol-2-yl)carbamate
- Step 7 Synthesis of 5-tert-butyl-1,3-oxazol-2-amine
- benzyl (5-tert-butyl-1,3-oxazol-2-yl)carbamate 5.0 g, 18.2 mmol
- methanol 100 mL
- 10% palladium on carbon 500 mg, 0.5 mmol
- the reaction is stirred at room temperature for 3 h under hydrogen atmosphere.
- the reaction mixture is filtered through Celite and the filtrate is concentrated.
- the residue is purified by flash column chromatography to afford the title compound (1.7 g, 68%) as a light brown solid.
- Step 2 Synthesis of N-(propan-2-yl)benzene-1,2-diamine
- 2-nitro-N-(propan-2-yl)aniline 828 mg, 4.6 mmol
- ethanol 10 mL
- ammonium formate 428 mg, 23 mmol
- the suspension is carefully filtered through a bed of Celite and the filtrate is rinsed with additional ethanol (10 mL).
- the filtrate is concentrated and the residue is partitioned between water and ethyl acetate.
- the organic layer is dried (Na 2 S0 4 ) and concentrated.
- the crude material is purified by chromatography through a short bed of silica gel using 5% methanol in CH2C12 to afford the title compound (552 mg, 80%) as an oil.
- Step 3 Synthesis of l-(propan-2-yl)-1H-benzimidazol-2-amine; hydrobromide
- Step 3 Synthesis of 5-chloro-1-methyl-1H-benzimidazol-2-amine; hydrobromide
- 4-chloro-N ⁇ methylbenzene-l ⁇ -diamine 592 mg, 3.4 mmol
- ethanol 10 mL
- 3M solution of cyanogen bromide 1.35 mL, 4.04 mmol
- the reaction is stirred for several days and is diluted with diethyl ether.
- the resulting solid is collected by filtration to afford the title compound (663 mg, 66%).
- Step 1 Synthesis of N,N,2,2-tetramethyl-N'-(2-nitrophenyl)propane-1,3-diamine
- DMSO dimethyl sulfoxide
- 2-fluoro-2-nitrobenzene 353 mg, 2.5 mmol
- Hunig's base 0.65 mL, 3.8 mmol
- the reaction flask is sealed and heated to 80 °C for 16 h.
- the reaction is cooled to room temperature, is poured over ice water and is extracted with CH 2 CI 2 .
- the organic layer is washed with water, brine, is dried (Na 2 S0 4 ) and concentrated to afford the title crude compound (635 mg, crude) as an orange oil.
- Step 3 Synthesis of l-[3-(dimethylamino)-2,2-dimethylpropyl]-1H-benzimidazol-2- amine; dihydrobromide
- Step 1 Synthesis of 4-(5-chloro-2-nitrobenzyl)morpholine
- morpholine 2.8 mL, 32.3 mmol
- THF 100 mL
- 5-chloro-2- nitrobenzaldehyde 5 g, 26.9 mmol
- sodium triacetoxyborohydride 11.4 g, 53.9 mmol
- HO Ac 3.2 mL, 53.9 mmol
- the reaction is stirred for 16 h.
- the reaction is poured into a saturated aqueous Na 2 C0 3 solution and extracted with ethyl acetate.
- the combined extracts are washed with water, brine, dried (Na 2 S0 4 ) and concentrated to afford a clear oil.
- Step 6 Synthesis of 5-chloro-3-(morpholin-4-ylmethyl)benzene-1,2-diamine
- tin (II) chloride 1.1 g, 6 mmol
- 4-chloro-2-(morpholin-4-ylmethyl)-6-nitroaniline 543 mg, 2 mmol
- the reaction is stirred for 1 h.
- the thick slurry is filtered and the filter cake rinsed with HCl.
- the filter cake is dissolved in water (10 mL), is treated with 2M aqueous K 2 C0 3 and is extracted with CH 2 C1 2 .
- the organic layer is separated, dried (Na 2 S0 4 ) and concentrated to afford the title compound (458 mg, 95%) as an oil.
- Examples 158-173 are synthesized according to the procedure for Example 157, substituting either commercially available reagents or the appropriate intermediates described above.
- Examples 182-206 are synthesized according to the procedure for Example 181, substituting either commercially available reagents or the appropriate intermediates described above.
- Example 207 l-oxo-N-[3-(trifluoromethyl)-1,2-oxazol-5-yl]-2,3,4,5-tetrahydro-1H- [1,4]diazepino[1,2-a]indole-8-carboxamide
- Examples 208-210 are synthesized according to the procedure for Example 207, substituting either commercially available reagents or the appropriate intermediates described above.
- a 0.5-2 mL microwave reactor vial is charged with a mixture of l-oxo-2,3,4,5- tetrahydro-1H-[1,4]diazepino[1,2-a]indole-8-carboxylic acid (Intermediate J, 100 mg, 0.41 mmol) and 5-benzyl-3-aminoisoxazole (107 mg, 0.61 mmol) in pyridine (500 ⁇ ) and the vial is sealed with a Teflon lined septa cap. The mixture is cooled to 0 °C and phosphorous oxychloride (40 ⁇ , 0.43 mmol) is added.
- Examples 213 and 214 are synthesized according to the procedure for Example 212, substituting either commercially available reagents or the appropriate intermediates described above.
- Example 215 N-(2-carbamoylphenyl)-1-oxo-2,3,4,5-tetrahydi
- Step 1 Synthesis of 3-(l-trityl-1H-imidazol-4-yl)aniline (3-Aminophenyl)boronic acid (1.0 g, 7.3 mmol), 4-bromo-1-trityl-1H-imidazole (2.8 g, 7.3 mmol), tri-i-butylphosphonium tetrafluoroborate (424 mg, 1.5 mmol) and KF (1.4 g, 24.1 mmol) are added into dry THF (20 mL) and argon is bubbled through the mixture for 10 min.
- Tris-(dibenzylideneacetone) dipalladium(O) (669 mg, 0.7 mmol) is added and the reaction mixture is sealed and heated at 60 °C for 16 h. The solid is filtered and the filtrate is diluted with EtOAc (250 mL). The solution is washed with water (3x100 mL), brine (100 mL), dried (Na 2 S0 4 ) and concentrated. The crude material is purified by flash column chromatography using methanol in CH 2 C1 2 to afford the title compound (1.1 g, 36%).
- Step 2 Synthesis of l-oxo-N-[3-(l-trityl-1H-imidazol-4-yl)phenyl]-2,3,4,5- tetrahydro- 1H- [ 1 ,4] diazepino[l ,2-a] indole-8-carboxamide
- l-oxo-2,3,4,5-tetrahydro-1H-[1,4]diazepino[1,2-a]indole-8-carboxylic acid (Intermediate J, 61 mg, 0.25 mmol) in DMF (1.5 mL) is added benzotriazol-1-yl- oxytripyrrolidinophosphonium hexafluorophosphate (194 mg, 0.37 mmol).
- Step 3 Synthesis of N-[3-(1H-imidazol-4-yl)phenyl]-1-oxo-2,3,4,5-tetrahydro-1H- [1,4]diazepino[1,2-a]indole-8-carboxamide
- Step 1 Synthesis of l-oxo-N-[3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)phenyl]-2,3,4,5-tetrahydro-1H-[1,4]diazepino[1,2-a]indole-8-carboxamide
- the solution is added to a microwave vial containing 3- bromo-1H-pyrazole (29.8 mg, 0.15 mmol).
- the resulting mixture is heated in a microwave reactor at 150 °C for 30 minutes.
- the mixture is filtered through Celite (100 mg) washed with ethyl acetate (3x1 mL) and concentrated in vacuo.
- the residue is purified by mass triggered HPLC to provide the title compound as a (31 mg, 39%).
- Example 228 is synthesized according to the procedure for Example 227, substituting either commercially available reagents or the appropriate intermediates described above.
- Step 1 Synthesis of methyl 2- ⁇ [(l-oxo-2,3,4,5-tetrahydro-1H-[1,4]diazepino[1,2- a]indol-8-yl)carbonyl]amino ⁇ benzoate
- Step 2 Synthesis of 2- ⁇ [(l-oxo-2,3,4,5-tetrahydro-1H-[1,4]diazepino[1,2-a]indol-8- yl)carbonyl]amino ⁇ benzoic acid
- Step 3 Synthesis of N-[2-(methylcarbamoyl)phenyl]-1-oxo-2,3,4,5-tetrahydro-1H- [1,4]diazepino[1,2-a]indole-8-carboxamide
- Example 230 is synthesized according to the procedure for Example 229, substituting either commercially available reagents or the appropriate intermediates described above.
- Example 231 N-[2-(tert-butylcarbamoyl)-1-methyl-1H-imidazol-4-yl]-4,4-dimethyl- l-oxo-1,2,3,4-tetrahydropyrazino[1,2-a]indole-7-carboxamide
- Step 1 Synthesis of ethyl 4- ⁇ [(4,4-dimethyl-1-oxo-1,2,3,4-tetrahydropyrazino[1,2- a]indol-7-yl)carbonyl]amino ⁇ -1-methyl-1H-imidazole-2-carboxylate
- Step 2 Synthesis of 4- ⁇ [(4,4-dimethyl-1-oxo-1,2,3,4-tetrahydropyrazino[1,2-a]indol- 7-yl)carbonyl]amino ⁇ -1-methyl-1H-imidazole-2-carboxylic acid
- Step 3 Synthesis of N-[2-(tert-butylcarbamoyl)-1-methyl-1H-imidazol-4-yl]-4,4- dimethyl-1-oxo-1,2,3,4-tetrahydropyrazino[1,2-a]indole-7-carboxamide
- 4- ⁇ [(4,4-dimethyl-1-oxo-1,2,3,4-tetrahydropyrazino[1,2-a]indol-7- yl)carbonyl]amino ⁇ -1-methyl-1H-imidazole-2-carboxylic acid (104 mg, 0.27 mmol) in DMF (2 mL) are added N-hydroxybenzotriazole (74 mg, 0.55 mmol) and l-ethyl-3-(3- dimethylaminopropyl) carbodiimide (105 mg, 0.55 mmol).
- Example 236 N- ⁇ l-[3-(dimethylamino)propyl]-1H-benzimidazol-2-yl ⁇ -1-oxo-2,3- dihydro-1H-spiro[1,4-diazepino[1,2-a]indole-4,4'-piperidine]-8-carboxamide
- Step 1 Synthesis of tert-butyl 8-( ⁇ l-[3-(dimethylamino)propyl]-1H-benzimidazol-2- yl ⁇ carbamoyl)-1-oxo-2,3-dihydro-1H,l'H-spiro[1,4-diazepino[1,2-a]indole-4,4'- piperidine] - 1 ' -carboxylate
- Step 2 Synthesis of N- ⁇ l-[3-(dimethylamino)propyl]-1H-benzimidazol-2-yl ⁇ -1-oxo- 2,3-dihydro-1H-spiro[1,4-diazepino[1,2-a]indole-4,4'-piperidine]-8-carboxamide
- tert-Butyl 8-( ⁇ l-[3-(dimethylamino)propyl]-1H-benzimidazol-2- yl ⁇ carbamoyl)-1-oxo-2,3-dihydro-1H,l'H-spiro[1,4-diazepino[1,2-a]indole-4,4'- piperidine]-l '-carboxylate (302 mg, 0.49 mmol) in CH 2 C1 2 (7 mL) is added TFA (1 mL).
- Examples 237-239 are synthesized according to the procedure for Example 236, substituting either commercially available reagents or the appropriate intermediates described above.
- Table 3 lists the mass spectral data and the retention times for Examples 1 to 239.
- Human RSK2 protein purchased from Invitrogen, is used to measure kinase activity utilizing Kinase Glo Plus (Promega) a homogeneous assay technology, which uses a luciferin-luciferase based ATP detection reagent to quantify residual ATP.
- Kinase Glo Plus Promega
- the assay is performed using 0.75 nM His-RSK2, 0.75 ⁇ ATP and 1.0 ⁇ S6 Kinase/RSK Substrate Peptide 1 (Upstate, catalog # 12-124), in assay buffer consisting of 25 mM HEPES, pH 7.5, 10 mM MgCl 2 , 5 mM MnCl 2 , 50 mM KCl, 0.2% BSA, 0.01% CHAPS, 100 ⁇ Na 3 V0 4 , 0.5 mM DTT, and 1% DMSO. Solutions of test compounds at various concentrations are prepared by 1:3 fold serial dilution of a 1 mM solution of compound in DMSO. The DMSO solutions are further diluted with assay buffer to a final concentration of DMSO of 5%.
- the assay is performed in a 384 well, white, non-binding plate (Corning, catalogue#3574). Solutions of test compounds (10 ⁇ ) are transferred to a dry assay plate, followed by addition of 20 ⁇ ⁇ kinase and 20 ⁇ ⁇ ATP + Substrate Peptide 1 described above. The kinase reaction mixture is incubated for 90 minutes at 28 °C followed by addition of 30 ⁇ ⁇ of ATP detection reagent for 15 minutes at room temperature. The relative light unit (RLU) signal is measured on a LJL Analyst (Molecular Devices) in luminescence mode using 384 aperture. The RLU signals were converted to percent of control (POC) values using the formula:
- POC 100 * (BCTRL-SignalV(BCTRL-PCTRL), where Signal is the test well RLU signal, BCTRL is the average of background (negative control), which consists of ATP + peptide and compound buffer, well signals on the plate, and PCTRL is the average of positive control, which consists of kinase, ATP + peptide, and compound buffer, well signals on the plate.
- BCTRL is the average of background (negative control), which consists of ATP + peptide and compound buffer, well signals on the plate
- PCTRL is the average of positive control, which consists of kinase, ATP + peptide, and compound buffer, well signals on the plate.
- POC as a function of test compound concentration are fitted to a 4-parameter logistic equation of the form:
- A, B, C, and D are fitted parameters (parameter B is fixed at zero POC), and x and y are the independent and dependent variables, respectively.
- the IC 50 (50% inhibitory concentration) is determined as the inflection point parameter, C.
- Compounds are assessed for their ability to inhibit the phosphorylation of the transcription factor CREB (cAMP Response Element Binding) by RSK2 in cells.
- CREB cAMP Response Element Binding
- a cell monolayer of exponentially growing HLR-CREB cells (PathDetect® HeLa Luciferase Reporter CREB cells, Stratagene) is prepared by the following method. In a 100 mm culture dish, 7.5 x 10 5 HLR-CREB cells are added to 10 mL culture medium consisting of RPMI-1640, 10% heat inactivated FCS, 2 mM glutamine, and 50 ⁇ g/mL gentamycin. The cells are allowed to adhere overnight, at which point 6 mL of medium is removed.
- the cell monolayer is transfected using Effectene (Quiagen) with RSK2 by the following method.
- a mixture of DNA, pCMV6-XL-RSK2 (1.0 ⁇ g) and pCDNA 3.1 (1.0 ⁇ g) is added to 300 ⁇ ⁇ DNA-condensation buffer.
- the complexes are formed by addition of 16 ⁇ L ⁇ enhancer, and the mixture is incubated for 5 minutes at room temperature.
- 60 ⁇ L ⁇ Effectene is added, and the mixture is incubated for an additional 10 minutes at room temperature.
- the final volume is adjusted to 2.0 mL with complete media, and added to the cell monolayer.
- Five hours after transfection, the cells are plated into white 96 well culture plates (Greiner Bio-One 655083).
- the results are represented as the percent luciferase activity relative to the control measured in the absence of inhibitors (POC).
- the IC 50 (50% inhibitory concentration) was determined as the inflection point parameter, C. Each data point represents an average of triplicate observations.
- AlamarBlue results are represented as the percent fluorescent units relative to the control measured in the absence of inhibitors (POC).
- Each data point represents an average of triplicate observations.
- the compounds of the invention are effective inhibitors of RSK2. Therefore, in one embodiment of the invention, there is provided methods of treating RSK2 regulated disorders using compounds of the invention. In another embodiment, there is provided methods of treating cardiovascular, inflammatory, allergic, pulmonary and fibrotic diseases, renal diseases and cancer using compounds of the invention.
- the inhibition or modulation of RSK2 activity is an attractive means for preventing and treating a variety of diseases mediated by RSKs. These include:
- Cardiovascular diseases including atherosclerosis, myocardial infarction, stroke, aortic aneurysm, sickle cell crisis, ischemia-reperfusion injury, pulmonary arterial hypertension and sepsis;
- Allergic diseases including asthma, allergic rhinitis, rhinosinusitis, atopic dermatitis and urticaria;
- Fibrotic diseases including airway remodeling in asthma, idiopathic pulmonary fibrosis, scleroderma, asbestosis;
- Pulmonary syndromes including adult respiratory distress syndrome, viral bronchiolitis, obstructive sleep apnea, chronic obstructive pulmonary disease, cystic fibrosis, and bronchopulmonary dysplasia;
- Inflammatory diseases including rheumatoid arthritis, osteoarthritis, gout,
- Cancer including solid tumors, leukemias and lymphomas.
- Renal diseases such as glomerulonephritis.
- a therapeutically effective dose will generally be in the range from about 0.01 mg to about 100 mg/kg of body weight per dosage of a compound of the invention; preferably, from about 0.1 mg to about 20 mg/kg of body weight per dosage.
- the dosage range would be from about 0.7 mg to about 7000 mg per dosage of a compound of the invention, preferably from about 7.0 mg to about 1400 mg per dosage.
- Some degree of routine dose optimization may be required to determine an optimal dosing level and pattern.
- the active ingredient may be administered from 1 to 6 times a day.
- the compounds of the invention are typically administered in the form of a pharmaceutical composition.
- Such compositions can be prepared using procedures well known in the pharmaceutical art and comprise at least one compound of the invention.
- the compounds of the invention may also be administered alone or in combination with adjuvants that enhance stability of the compounds of the invention, facilitate administration of pharmaceutical compositions containing them in certain embodiments, provide increased dissolution or dispersion, increased antagonist activity, provide adjunct therapy, and the like.
- the compounds according to the invention may be used on their own or in conjunction with other active substances according to the invention, optionally also in conjunction with other pharmacologically active substances.
- the compounds of this invention are administered in a therapeutically or pharmaceutically effective amount, but may be administered in lower amounts for diagnostic or other purposes.
- Administration of the compounds of the invention, in pure form or in an appropriate pharmaceutical composition can be carried out using any of the accepted modes of administration of pharmaceutical compositions.
- administration can be, for example, orally, buccally (e.g., sublingually), nasally, parenterally, topically, transdermally, vaginally, or rectally, in the form of solid, semi-solid, lyophilized powder, or liquid dosage forms, such as, for example, tablets, suppositories, pills, soft elastic and hard gelatin capsules, powders, solutions, suspensions, or aerosols, or the like, preferably in unit dosage forms suitable for simple administration of precise dosages.
- the pharmaceutical compositions will generally include a conventional pharmaceutical carrier or excipient and a compound of the invention as the/an active agent, and, in addition, may include other medicinal agents, pharmaceutical agents, carriers, adjuvants, diluents, vehicles, or combinations thereof.
- Such pharmaceutically acceptable excipients, carriers, or additives as well as methods of making pharmaceutical compositions for various modes or administration are well-known to those of skill in the art. The state of the art is evidenced, e.g., by Remington: The Science and Practice of Pharmacy, 20th Edition, A.
- the forms of the compounds of the invention utilized in a particular pharmaceutical formulation will be selected (e.g., salts) that possess suitable physical characteristics (e.g., water solubility) that are required for the formulation to be efficacious.
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Abstract
La présente invention concerne de nouveaux composés qui inhibent RSK, des procédés permettant de fabriquer lesdits composés et des compositions pharmaceutiques comprenant lesdits composés. L'invention concerne également des procédés permettant de traiter des troubles régulés par RSK2 à l'aide des composés de l'invention.
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JP2012543144A JP2013512952A (ja) | 2009-12-07 | 2010-11-30 | インドールコアを含有する複素環化合物 |
US13/513,954 US9150577B2 (en) | 2009-12-07 | 2010-11-30 | Heterocyclic compounds containing an indole core |
EP10787970A EP2509980A1 (fr) | 2009-12-07 | 2010-11-30 | Composés hétérocycliques contenant un c ur indole |
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US26717509P | 2009-12-07 | 2009-12-07 | |
US61/267,175 | 2009-12-07 |
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EP (1) | EP2509980A1 (fr) |
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Cited By (7)
Publication number | Priority date | Publication date | Assignee | Title |
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US9073926B2 (en) | 2009-12-07 | 2015-07-07 | Boehringer Ingelheim International Gmbh | Heterocyclic compounds containing a pyrrolopyridine or benzimidazole core |
US9440957B2 (en) | 2012-06-06 | 2016-09-13 | Novartis Ag | Compounds and compositions for modulating EGFR Activity |
US9771366B2 (en) | 2016-02-19 | 2017-09-26 | Phoenix Molecular Design | Substituted tetrahydropyrido[3′,2′:4,5]pyrrolo[1,2-a]pyrazine-2-carboxamides as RSK inhibitors |
US10246466B2 (en) | 2014-01-24 | 2019-04-02 | Tp Therapeutics, Inc. | Diaryl macrocycles as modulators of protein kinases |
US10316044B2 (en) | 2015-07-02 | 2019-06-11 | Tp Therapeutics, Inc. | Chiral diaryl macrocycles as modulators of protein kinases |
WO2022251597A1 (fr) | 2021-05-28 | 2022-12-01 | Verge Analytics, Inc. | Méthodes de traitement de troubles neurologiques avec des modulateurs de la protéine ribosomale s6 kinase alpha-1 (rsk1) et de la protéine ribosomale s6 kinase alpha-3 (rsk2) |
EP4327877A2 (fr) | 2018-04-20 | 2024-02-28 | XRad Therapeutics, Inc. | Inhibiteurs doubles de l'atm et de l'adn-pk destinés à être utilisés dans une thérapie antitumorale |
Families Citing this family (3)
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US10059701B2 (en) * | 2015-09-18 | 2018-08-28 | Merck Patent Gmbh | Heteroaryl compounds as IRAK inhibitors and uses thereof |
US20200078273A1 (en) * | 2018-09-07 | 2020-03-12 | Michael J. McKinnon-Dane | Method and apparatus for removal of contaminants from surfaces |
CN117186098A (zh) * | 2022-06-07 | 2023-12-08 | 上海科恩泰生物医药科技有限公司 | 一种具有rsk抑制作用的羧酰胺衍生物、包含其的药物组合物及其用途 |
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- 2010-11-30 WO PCT/US2010/058271 patent/WO2011071716A1/fr active Application Filing
- 2010-11-30 EP EP10787970A patent/EP2509980A1/fr not_active Withdrawn
- 2010-11-30 US US13/513,954 patent/US9150577B2/en active Active
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Cited By (10)
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US9073926B2 (en) | 2009-12-07 | 2015-07-07 | Boehringer Ingelheim International Gmbh | Heterocyclic compounds containing a pyrrolopyridine or benzimidazole core |
US9440957B2 (en) | 2012-06-06 | 2016-09-13 | Novartis Ag | Compounds and compositions for modulating EGFR Activity |
US10246466B2 (en) | 2014-01-24 | 2019-04-02 | Tp Therapeutics, Inc. | Diaryl macrocycles as modulators of protein kinases |
US10618912B2 (en) | 2014-01-24 | 2020-04-14 | Turning Point Therapeutics, Inc. | Diaryl macrocycles as modulators of protein kinases |
US10316044B2 (en) | 2015-07-02 | 2019-06-11 | Tp Therapeutics, Inc. | Chiral diaryl macrocycles as modulators of protein kinases |
US9771366B2 (en) | 2016-02-19 | 2017-09-26 | Phoenix Molecular Design | Substituted tetrahydropyrido[3′,2′:4,5]pyrrolo[1,2-a]pyrazine-2-carboxamides as RSK inhibitors |
US10081632B2 (en) | 2016-02-19 | 2018-09-25 | Phoenix Molecular Designs | Substituted tetrahydropyrido[3′,2′:4,5]pyrrolo[1,2-α]pyrazine-2-carboxamides as RSK inhibitors |
US10758530B2 (en) | 2016-02-19 | 2020-09-01 | Phoenix Molecular Designs | Carboxamide derivatives useful as rsk inhibitors |
EP4327877A2 (fr) | 2018-04-20 | 2024-02-28 | XRad Therapeutics, Inc. | Inhibiteurs doubles de l'atm et de l'adn-pk destinés à être utilisés dans une thérapie antitumorale |
WO2022251597A1 (fr) | 2021-05-28 | 2022-12-01 | Verge Analytics, Inc. | Méthodes de traitement de troubles neurologiques avec des modulateurs de la protéine ribosomale s6 kinase alpha-1 (rsk1) et de la protéine ribosomale s6 kinase alpha-3 (rsk2) |
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US9150577B2 (en) | 2015-10-06 |
US20130109679A1 (en) | 2013-05-02 |
EP2509980A1 (fr) | 2012-10-17 |
JP2013512952A (ja) | 2013-04-18 |
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