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US 2003/0207906 A1Published application
Chemical compounds
AssigneeLilly ICOS LLC
InventorsMark W. Orme, Jason Scott Sawyer, Alain Claude-Marie Daugan, Francoise Gellibert, Romain Luc Marie Gosmini
Life of this patent
Estimating the term…
Abstract
Compounds of the general structural formula and use of the compounds and salts and solvates thereof, as therapeutic agents.
Claims29
A compound having a formula
- 54
- wherein R0, independently, is selected from the group consisting of halo, C1-6alkyl, aryl, heteroaryl, C3-8cycloalkyl, C3-8heterocycloalkyl, C3-8cycloalkylQ, C(═O)Ra, OC(═O)Ra, C(═O)ORa, C1-4alkyleneNRaRb, C1-4alkyleneHet, C1-4alkyleneC(═O)ORa, C(═O)NRaSO2Rc, C(═O)C1-4alkyleneHet, C(═O)NRaRb, C(═O)NRaRc, C(═O)NRaC1-4alkyleneORb, C(═O)NRaC1-4alkyleneHet, ORa, OC1-4alkyleneC(═O)ORa, OC1-4alkyleneNRaRb, OC1-4alkyleneHet, OC1-4alkyleneORa, OC1-4alkyleneNRaC(═O)ORb, NRaRb, NRaC1-4alkyleneNRaRb, NRaC(═O) Rb, NRaC(═O)NRaRb, N(SO2C1-4alkyl)2, NRa(SO2C1-4alkyl), nitro, trifluoromethyl, trifluoromethoxy, cyano, SO2NRaRb, SO2Ra, SORa, SRa, and OSO2CF3;
- R1 is selected from the group consisting of optionally substituted aryl, optionally substituted heteroaryl, an optionally substituted C3-8cycloalkyl ring, an optionally substituted C3-8heterocycloalkyl ring, an optionally substituted bicyclic ring
- 55
- wherein the fused ring A is a 5- or 6-membered ring, saturated or partially or fully unsaturated, and comprises carbon atoms and optionally one to three heteroatoms selected from oxygen, sulfur, and nitrogen, hydrogen, C1-6alkyl, arylC1-3alkyl, C1-3alkylenearyl, haloC1-6alkyl, C1-4alkyleneC(═O)ORa, C1-4alkylene(═O)NRaRb, C3-8cycloalkyl, C3-8cycloalkenyl, C3-8heterocycloalkenyl, C1-4alkyleneHet, C1-4alkyleneQRa, C2-6alkenyleneQRa, C1-4alkyleneQC1-4alkyleneQRa,
- 56
- and a spiro substituent having the structure
- 57
- R2 is selected from the group consisting of hydrogen, C1-6alkyl, C3-8cycloalkyl, C3-8heterocycloalkyl, C2-6alkenyl, C1-3alkylenearyl, arylC1-3alkyl, C(═O)Ra, aryl, heteroaryl, C(═O)Ra, C(═O)NRaRb, C(═O)NRaRc, C(═S)NRaRb, C(═S)NRaRc, SO2Ra, SO2NRaRb, S(═O) Ra, S(═O)NRaRb, C(═O)NRaC1-4alkyleneORa, C(═O)NRaC1-4alkyleneHet, C(═O)C1-4alkylenearyl, C(═O)C1-4alkyleneheteroaryl, C1-4alkylenearyl substituted with one or more of SO2NRaRb, NRaRb, C(═O)ORa, NRaSO2CF3, CN, NO2, (C(═O)Ra, ORa, C1-4alkyleneNRaRb, and OC1-4alkyleneNRaRb, C1-4alkyleneheteroaryl, C1-4alkyleneHet, C1-4alkyleneC(═O)C1-4alkylenearyl, C1-4alkyleneC(═O)C1-4alkyleneheteroaryl, C1-4alkyleneC(═O)Het, C1-4alkyleneC(═O)NRaRb, C1-4alkyleneORa, C1-4alkyleneNRaC(═O)Ra, C1-4alkyleneOC1-4alkyleneORa, C1-4alkyleneNRaRb, C1-4alkyleneC(═O)ORa, and C1-4alkyleneOC1-4alkyleneC(═O)ORa;
- X, Y, and Z, independently, are selected from N and CR3;
- R3, independently, is selected from the group consisting of hydrogen, C1-10alkyl, C2-10alkenyl, C2-10alkynyl, aryl, heteroaryl, arylC1-3alkyl, C1-3alkylenearyl, C(═O)ORa, C(═O)NRaRc, aryl, C1-4alkyleneNRaRb, halo, NO2, CF3, CF3O, ORa, OC(═O)Ra, OC1-4alkyleneC(═O)ORa, C1-4alkyleneOC1-4alkyleneC(═O)ORa, C(═O)NRaSO2Rc, C(═O)C1-4alkyleneHet, C2-6alkenyleneNRaRb, C(═O)NRaC1-4alkyleneORb, C(═O)NRaC1-4alkyleneHet, OC2-4alkyleneNRaRb, OC1-4alkyleneCH(ORa)CH2NRaRb, OC2-4alkyleneORa, OC2-4alkyleneNRaC(═O)ORb, NRaRb, NRaC1-4alkyleneNRaRb, NRaC(═O)Rb, NRaC(═O)NRaRb, N(SO2C1-4alkyl)2, NRa(SO2C1-4alkyl), SO2NRaRb, OSO2trifluoromethyl, C(═O)Ra, C1-3alkyleneORa, CN, and C1-6alkyleneC(═O)ORa;
- R4 and R5, independently, are selected from the group consisting of hydrogen, C1-6alkyl, aryl, heteroaryl, arylC1-3alkyl, C1-3alkylenearyl, C1-3alkyleneHet, C3-8 cycloalkyl, and C3-8heterocycloalkyl;
- Ra is selected from the group consisting of hydrogen, C1-6alkyl, aryl, arylC1-3alkyl, C1-3alkylenearyl, heteroaryl, heteroarylC1-3alkyl, and C1-3alkyleneheteroaryl;
- Rb is selected from the group consisting of hydrogen, C1-6alkyl, C3-8cycloalkyl, C1-3alkyleneN (Ra)2, aryl, arylC1-3alkyl, C1-3alkylenearyl, and heteroaryl;
- Rc is selected from the group consisting of hydrogen, C1-6alkyl, aryl, heteroaryl, arylC1-3alkyl, heteroarylC1-3alkyl, C1-3alkyleneN(Ra)2, C1-6alkylenearyl, C1-6alkyleneHet, haloC1-6alkyl, C3-8cycloalkyl, C3-8heterocycloalkyl, Het, C1-3alkyleneheteroaryl, C1-6alkyleneC(═O)ORa, and C1-3alkyleneC3-8heterocycloalkyl;
- or Ra and Rc are taken together to form a 5- or 6-membered ring, optionally containing at least one heteroatom;
- Rd is null or is selected from the group consisting of hydrogen, C1-6alkyl, aryl, heteroaryl, arylC1-3alkyl, heteroarylC1-3alkyl, C1-3alkylenearyl, and C1-3alkyleneheteroaryl;
- Q is O, S, or NRa;
- B is O, S, or NRd;
- C is O, S, or NRa;
- D is CRa or N;
- E is CRa, C(Ra)2, or NRd;
- and
- Het represents a 5- or 6-membered heterocyclic ring, saturated or partially or fully unsaturated, containing at least one heteroatom selected from the group consisting of oxygen, nitrogen, and sulfur, and optionally substituted with C1-4alkyl or C(═O)ORa;
- q is 0, 1, 2, 3, or 4;
- and
- pharmaceutically acceptable salts and hydrates thereof.
24 more elements
A compound selected from the group consisting of
- (+−)-5-benzo[1,3]dioxol-5-yl-3-(benzylamino-methyl)-6,11-dihydro-5H-indolizino[6,7-b]indole-1-carboxylic acid ethyl ester;
- (+−)-5-(2,3-dihydrobenzofuran-5-yl)-6,11-dihydro-5H-indolizino[6,7-b]indole-1-carboxylic acid;
- (+−)-3-aminomethyl-5-(2,3-dihydrobenzofuran-5-yl)-6,11-dihydro-5H-indolizino[6,7-b]indole-1-carboxylic acid ethyl ester;
- (+−)-5-benzofuran-5-yl-3-formyl-6,11-dihydro-5H-indolizino[6,7-b]indole-1-carboxylic acid ethyl ester;
- (+−)-5-benzo[1,3]dioxol-5-yl-6,11-dihydro-5H-indolizino[6,7-b]indole;
- (+−)-5-methoxy-2,06-dimethylphenyl)-6,11-dihydro-5H-indolizino[6,7-b]indole-1-carboxylic acid ethyl ester;
- (+−)-5-benzo[1,3]dioxol-5-yl-3-ethyl-6,11-dihydro-5H-indolizino[6,7-b]indole-1,2-dicarboxylic acid diethyl ester;
- (+−)-5-benzo[1,3]dioxol-5-yl-3-ethyl-6,11-dihydro-5H-indolizino[6,7-b]indole-1,2-dicarboxylic acid;
- (+−)-(+−)-5-benzo[1,3]dioxol-5-yl-6,11-dihydro-5H-indolizino[6,7-b]indole-1-carboxylic acid (tetrahydrofuran-2-yl-methyl)amide;
- (+−)-5-benzo[1,3]dioxol-5-yl-3-isopropyl-6,11-dihydro-5H-indolizino[6,7-b]indole-1,2-dicarboxylic acid diethyl ester;
- (+−)-5-benzo[1,3]dioxol-5-yl-3-isopropyl-6,11-dihydro-5H-indolizino[6,7-b]indole-1-carboxylic acid methyl-(1-methylpiperidin-4-yl)amide;
- (+−)-5-benzo[1,3]dioxol-5-yl-6;11-dihydro-5H-indolizino[6,7-b]indole-1-carboxylic acid (2-pyrazol-1-yl-ethyl)amide;
- (+−)-5-benzo[1,3]dioxol-5-yl-3-hydroxymethyl-6,11-dihydro-5H-indolizino[6,7-b]indole-1-carboxylic acid ethyl ester;
- (+−)-5-benzo[1,3]dioxol-5-yl-3-isopropyl-6,11-dihydro-5H-indolizino[6,7-b]indole-11-carboxylic acid ethyl ester;
- (+−)-5-benzo[1,3]dioxol-5-yl-6,11-dihydro-5H-indolizino[6,7-b]indole-1-carboxylic acid (1-oxypyridin-2-ylmethyl)amide;
- (+−)-5-benzo[1,3]dioxol-5-yl-6,11-dihydro-5H-indolizino[6,7-b]indole-1,2-dicarboxylic acid diethyl ester;
- (+−)-1-[1-(5-benzo[1,3]dioxol-5-yl-6,11-dihydro-5H-indolizino[6,7-b]indol-1-yl)methanoyl]piperidine-4-carboxylic acid;
- (+−)-5-benzo[1,3]dioxol-5-yl-3-formyl-6,11-dihydro-5H-indolizino[6,7-b]indole-1-carboxylic acid ethyl ester;
- (+−)-5-benzo[1,3]dioxol—5-yl-6,11-dihydro-5H-indolizino[6,7-b]indole-1-carboxylic acid (2-pyridin-2-yl-ethyl)amide;
- (+−)-5-benzo[1,3]dioxol-5-yl-6,11-dihydro-5H-indolizino[6,7-b]indole-1-carboxylic acid (pyridin-3-ylmethyl)amide;
- (+−)-5-benzo-[1,3]dioxol-5-yl-6,11-5H—indolizino-[6,7-b]indole-1-carboxylic acid (2-dimethylamine-ethyl)amide;
- (+−)-5-benzo[1,3]dioxol-5-yl-3-methyl-6,11-dihydro-5H-indolizino[6,7-b]indole-1-carbonitrile;
- (+−)-5-benzo[1,3]dioxol-5-yl-6,11-dihydro-5H-indolizino[6,7-b]indole-1-carboxylic acid (pyridin-2-ylmethyl)amide;
- (+−)-{[1-(5-benzo[1,3]dioxol-5-yl-6,11-dihydro-5H-indolizono[6,7-b]indol-1-yl)methanoyl]methylamino}acetic acid;
- (+−)-5-benzo[1,3]dioxol-5-yl-6,11-dihydro-5H-indolizino[6,7-b]indole-1-carboxylic acid (2-aminoethyl) amide;
- (+−)-5-benzo[1,3]dioxol-5-yl-3-methyl-6,11-dihydro-5H-indolizino[6,7-b]indole-1-carboxylic acid (2-morpholin-4-yl-ethyl)amide;
- (+−)-5-(4-methoxyphenyl)-6,11-dihydro-5H-indolizino[6,7-b]indole-1-carboxylic acid;
- (+−)-5-(4-methoxyphenyl)-6,11-dihydro-5H-indolizino[6,7-b]indole-1-carboxylic acid 3,4-dimethoxy-benzylamide;
- (+−)-5-(4-methoxyphenyl)-6,11-dihydro-5H-indolizino[6,7-b]indole-1-carboxylic acid (2-morpholin-4-yl-ethyl)amide;
- (+−)-5-benzo[1,3]dioxol-5-yl-6,11-dihydro-5H-indolizino[6,7-b]indole-1-carboxylic acid ethyl ester;
- (+−)-5-benzo[1,3]dioxol-5-yl,6,11-dihydro-5H-indolizino[6,7-b]indole-1-carboxylic acid;
- (+−)-5-benzo[1,3]dioxol-5-yl-6,11-dihydro-5H-indolizino[6,7-b]indole-2-carboxylic acid ethyl ester;
- (+−)-5-phenyl-6,11-dihydro-5H-indolizino[6,7-b]indole-2-carboxylic acid ethyl ester;
- (+−)-5-phenyl-6,11-dihydro-5H-indolizino[6,7-b]indole-1-carboxylic acid ethyl ester;
- (+−)-5-benzo[1,3]dioxol-5-yl-3-methyl-6,11-dihydro-5H-indolizino[6,7-b]indole-1-carboxylic acid ethyl ester;
- (+−)-5-phenyl-6,11-dihydro-5H-indolizino[6,7-b]indole-2-carboxylic acid;
- (+−)-5-phenyl-6,11-dihydro-5H-indolizino[6,7-b]indole-1-carboxylic acid 3,4-dimethoxybenzylamide;
- (+−)-5-(4-methoxyphenyl)-6,11-dihydro-5H-indolizino[6,7-b]indole-1-carboxylic acid ethyl ester;
- (+−)-5-(4-methoxyphenyl)-6,11-dihydro-5H-indolizino[6,7-b]indole-2-carboxylic acid ethyl ester;
- (+−)-5—benzo[1,3]dioxo-5—yl-3-methyl-6,11-dihydro-5H-indolizino[6,7-b]indole-1,2-dicarboxylic acid dimethyl ester;
- (+−)-5-benzo[1,3]dioxol-5-yl-3-ethyl-6,11-dihydro-5H-indolizino[6,7-b]indole-2-carboxylic acid (pyridin-2-ylmethyl)amide;
- (+−)-5-p-tolyl-6,11-dihydro-5H-indolizino[6,7-b]indole-1-carboxylic acid ethyl ester;
- (+−)-5-(4-chlorophenyl)-6,11-dihydro-5H-indolizino[6,7-b]indole-1-carboxylic acid ethyl ester;
- (+−)-5-benzofuran-5-yl-6,11-dihydro-5H-indolizino-[6,7-b]indole-1-carboxylic acid ethyl ester;
- (+−)-5-benzofuran-5-yl-6,11-dihydro-5H-indolizino-[6,7-b]indole-1-carboxylic acid;
- (+−)-5-benzo[1,3]dioxol-5-yl-6,11-dihydro-5H-indolizino[6,7-b]indole-1-carboxylic ac-id(4-methylpiperazin-1-yl)amide;
- (+−)-5-benzo[1,3]dioxol-5-yl-3-dimethylamino-methyl-6,11-dihydro-5H—indolizino[6,7b]indole-1-carboxylic acid ethyl ester;
- (+−)-5-benzo[1,3]dioxol-5-yl-3-ethyl-6,11-dihydro-5H-indolizino[6,7-b]indole-1-carboxylic acid (pyridin-2-ylmethyl)amide;
- (+−)-3-ethyl-5-(4-methoxy-2,6-dimethylphenyl)-6,11-dihydro-5H-indolizino[6,7-b]indole-1-carboxylic acid ethyl ester.;
- (+−)-5-benzo[1,3]dioxol-5-yl-3-ethyl-6,11-dihydro-5H-indolizino[6,7-b]indole-2-carboxylic acid ethyl ester;
- (+−)-5-benzo[1,3]dioxol-5-yl-3-ethyl-6,11-dihydro-5H-indolizino[6,7-b]indole-1-carboxylic acid ethyl ester;
- and pharmaceutically acceptable salts and solvates thereof.
49 more elements
A compound having the formula:
- 70 71
Dependencies are inferred from the claim text.