Back to results
US 7,115,621 B2Granted
Chemical compounds
AssigneeLilly ICOS LLC
InventorsJason S. Sawyer, Mark W. Orme, James D. Copp
Life of this patent
Estimating the term…
Abstract
Compounds of general structural formula (I) and use of the compounds and salts and solvates thereof, as therapeutic agents as inhibitors of phosphodiesterase 5 cardiovascular disorders
Claims39
A compound having a formula
- 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 aryl optionally substituted with one or both of alkoxy and halo, an optionally substituted C3-8cycloalkyl ring, an optionally substituted C3-8heterocycloalkyl ring, an optionally substituted bicyclic ring
- wherein the fused ring A is a 5- or 6-membered ring, saturated or partially or fully unsaturated, and contains 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, C1-4alkyleneC(═O)NRaRb, C3-8cycloalkyl, C3-8cycloalkenyl, C3-8heterocycloalkenyl, C1-4alkyleneHet, C1-4alkyleneQRa, C2-6alkenyleneQRa, C1-4alkyleneQC1-4alkyleneQRa,
- and a spiro substituent having a structure
- R2 is selected from the group 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 C1-4alkyleneaC1-4alkyleneC(═O)ORa;
- R3 is selected from the group consisting of C(═O)Rb, C(═O)ORb, C(═O)NRaRb, C(═O)NRaRc, C(═S)NRaRb, C(═S)NRaRc, C(═O)Het, C(═O)NRaC1-4alkyleneORa, C(═O)NRaC1-4alkyleneHet, C(═O)C1-4alkylenearyl, C(═O)C1-4alkyleneheteroaryl, C(═O)NRaC1-4alkylenearyl, C(═O)NRaC1-4alkyleneC3-8cycloalkyl, C(═O)NRbSO2Rc, C(═O)NRaC1-4alkyleneOC1-6alkyl, C(═O)NRaC1-4alkyleneheteroaryl, NRaRc, NRaC(═O)Rb, NRaC(═O)NRaRc, NRa(SO2C1-4alkyl), N(SO2C1-4alkyl)2, ORa, NRaC(═O)C1-4alkyleneN(Rb)2, NRaC(═O)C1-4alkyleneC(═O)ORa, NRa(C═O)C1-3alkylenearyl, NRaC(═O)C1-3alkyleneC3-8heterocycloalkyl, NRaC(═O)C1-3alkyleneHet, and C(═O)NRaSO2Rb;
- R4 is selected from the group consisting of hydrogen, C1-6alkyl, aryl, heteroaryl, arylC1-3alkyl, C1-3alkylenearyl, C1-3alkyleneHet, C3-8cycloalkyl, and C3-8heterocycloalkyl;
- X is selected from the group consisting of C(═O), (CH2)tC(═O), C(═O)C≡C, C(═S), SO, SO2, SO2C(Ra)═CRa, CRa═CRa, C(═O)NRa, and C(═N—ORa);
- Y is Ra;
- Ra is selected from the group consisting of hydrogen, C1-6alkyl, C3-6cycloalkyl, phenyl, phenylC1-3alkyl, and C1-3alkylenephenyl;
- 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;
- Q is O, S, or NRh;
- B is O, S, or NRh;
- C is O, S, or NRa;
- D is CRa, or N;
- E is CRa, C(Ra)2, or NRh;
- and
- Rh is null or is selected from the group consisting of hydrogen, C1-6alkyl, aryl, heteroaryl, arylC1-3alkyl, heteroarylC1-3alkyl, C1-3alkylenearyl, and C1-3alkyleneheteroaryl;
- 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;
- n is 1;
- q is 0, 1, 2, 3, or 4;
- t is 1, 2, 3, or 4;
- or a pharmaceutically acceptable salt or solvate thereof.
22 more elements
A compound selected from the group consisting of
- or a pharmaceutically acceptable salt or solvate thereof.
A compound having a formula
- 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 aryl substituted with one or both of halo and methoxy, optionally substituted heteroaryl, an optionally substituted C3-8cycloalkyl ring, an optionally substituted C3-8heterocycloalkyl ring, an optionally substituted bicyclic ring
- wherein the fused ring A is a 5- or 6-membered ring, saturated or partially or fully unsaturated, and contains carbon atoms and optionally one to three heteroatoms selected from oxygen, sulfur, and nitrogen, C1-4alkyleneC(═O)ORa, C1-4alkyleneC(═O)NRaRb, C3-8cycloalkyl, C3-8cycloalkenyl, C3-8heterocycloalkenyl, C1-4alkyleneHet, C1-4alkyleneQRa, C2-6alkenyleneQRa, C1-4alkyleneQC1-4alkyleneQRa,
- and a spiro substituent having a structure
- 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;
- R3 is selected from the group consisting of C(═O)Rb, C(═O)NRaRb, C(═O)NRaRc, C(═S)NRaRb, C(═S)NRaRc, C(═O)Het, C(═O)NRaC1-4alkyleneORa, C(═O)NRaC1-4alkyleneHet, C(═O)C1-4alkylenearyl, C(═O)C1-4alkyleneheteroaryl, C(═O)NRaC1-4alkylenearyl, C(═O)NRaC1-4alkyleneC3-8cycloalkyl, C(═O)NRbSO2Rc, C(═O)NRaC1-4alkyleneOC1-6alkyl, C(═O)NRaC1-4alkyleneheteroaryl, NRaRc, NRaC(═O)Rb, NRaC(═O)NRaRc, NRa(SO2C1-4alkyl), N(SO2C1-4alkyl)2, ORa, NRaC(═O)C1-4alkyleneN(Rb)2, NRaC(═O)C1-4alkyleneC(═O)ORa, NRa(C═O)C1-3alkylenearyl, NRaC(═O)C1-3alkyleneC3-8heterocycloalkyl, NRaC(═O)C1-3alkyleneHet, and C(═O)NRaSO2Rb;
- R4 is selected from the group consisting of hydrogen, C1-6alkyl, aryl, heteroaryl, arylC1-3alkyl, C1-3alkylenearyl, C1-3alkyleneHet, C3-8cycloalkyl, and C3-8heterocycloalkyl;
- Ra is selected from the group consisting of hydrogen, C1-6alkyl, C3-6cycloalkyl, 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;
- Q is O, S, or NRh;
- B is O, S, or NRh;
- C is O, S, or NRa;
- D is CRa or N;
- E is CRa, C(Ra)2, or NRh;
- and
- Rh is null or is selected from the group consisting of hydrogen, C1-6alkyl, aryl, heteroaryl, arylC1-3alkyl, heteroarylC1-3alkyl, C1-3alkylenearyl, and C1-3alkyleneheteroaryl;
- 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;
- or a pharmaceutically acceptable salt or solvate thereof.
18 more elements
A compound selected from the group consisting of
- or a pharmaceutically acceptable salt or solvate thereof.
Dependencies are inferred from the claim text.