Substituted quinolones and methods of use

A pharmaceutical composition comprising a compound and a pharmaceutically acceptable excipient, wherein said compound has formula

• or pharmaceutically acceptable salts and N-oxides thereof;
• wherein
• is a single or double bond;
• A is —N(H)—, —N(Ra)—, —CH2—, —CH(Ra)—, —C(Ra)2—, wherein Ra is absent or is C1-4 alkyl;
• R1 is absent;
• or alternatively is hydrogen or C1-4 alkyl;
• L1 is —C(O)—;
• R2 is —Re;
• R3 is selected from the group consisting of —X1—Re and —Re;
• wherein X1 is a C1-2 alkylene;
• and each Re is independently a 5-6 membered aryl or heteroaryl group that is optionally substituted with 1-5 substituents selected from the group consisting of halogen, —CN, —NO2, —CO2Rr, —OC(O)Rr, —C(O)NRrRs, —C(O)Rr, —S(O)Rt, —S(O)2Rt, —Rt, —C(NORr)Rs, —NRr—C(O)NRrRs, —NH—C(NH2)═NH, —NRtC(NH2)═NH, —NH—C(NH2)═NRt, —NH—C(NHRt)═NH, —NRrS(O)2Rt, —NRrS(O)2Rt, —NRrS(O)2NRrRs, —N3, —C(NRrV)═NV, —N(V)C(Rr)═NV, —X2C(NORr)Rs, —X2C(NRrV)═NV, —X2N(V)C(Rr)═NV, —X2NRrRs, —X2SRr, —X2CN, —X2NO2, —X2CO2Rr, —X2OC(O)Rr, —X2CONRrRs, —X2C(O)Rr, —X2OC(O)NRrRs, —X2NRsC(O)Rr, —X2NRsC(O)2Rt, —X2NRrC(O)NRrRs, —X2NH—C(NH2)═NH, —X2NRtC(NH2)═NH, —X2NH—C(NH2)═NRt, —X2NH—C(NHRt)═NH, —X2S(O)Rt, —X2S(O)2Rt, —X2NRrS(O)2Rt, —X2S(O)2NRrRs, —X2N3, —ORr, —SRr, —NRrRs, —NRsC(O)Rr, —NRsC(O)2Rt, —S(O)2Rt, S(O)2NRrRs, —X2ORr, —O—X2ORr, —X2NRrRs, —O—X2NRrRs and —NRs—X2CO2Rr, wherein any two substituents located on adjacent atoms in Re can be combined to form a 5- to 7-membered ring having optionally having from 1-3 heteroatoms selected from N, O or S;
• X2 is C1-8 alkylene, C1-8 heteroalkylene, C2-8 alkenylene, C2-8 alkynylene, arylene or heteroarylene;
• and each Rr and Rs is independently selected from hydrogen, C1-8 alkyl, C1-8 haloalkyl, C3-6 cycloalkyl, C2-8 alkenyl, C2-8 alkynyl, aryl and heteroaryl, or optionally, Rr and Rs when attached to the same nitrogen atom can be combined with the nitrogen atom to form a five or six-membered ring having from 0 to 2 additional heteroatoms as ring members selected from N, O or S, and wherein each Rt is independently selected from the group consisting of C1-8 alkyl, C1-8 haloalkyl, C3-6 cycloalkyl, C2-8 alkenyl, C2-8 alkynyl, aryl and heteroaryl, V is independently selected from the group consisting of —Rt, —CN, —CO2Rr and —NO2, and each of X2, Rr, Rs and Rt is optionally further substituted with from one to three members selected from the group consisting of —OH, —ORu, —OC(O)NHRu, —OC(O)N(Ru)2, —SH, —SRu, —S(O)Ru, —S(O)2Ru, —SO2NH2, —S(O)2NHRu, —S(O)2N(Ru)2, —NHS(O)2Ru, —NRuS(O)2Ru, —C(O)NH2, —C(O)NHRu, —C(O)N(Ru)2, —C(O)Ru, —NHC(O)Ru, —NRuC(O)Ru, —NHC(O)NH2, —NRuC(O)NH2, —NRuC(O)NHRu, —NHC(O)NHRu, —NRuC(O)N(Ru)2, —NHC(O)N(Ru)2, —CO2H, —CO2Ru, —NHCO2Ru, —NRuCO2Ru, —CN, —NO2, —NH2, —NHRu, —N(Ru)2, —NRuS(O)NH2 and —NRuS(O)2NHRu, wherein each Ru is independently an unsubstituted C1-6 alkyl;
• and
• each of the ring vertices a, b, c and d in formula I is N, N—O, C(H) or C(R4), wherein R4 at each occurrence is independently is selected from the group consisting of halogen, C1-8 alkyl, C1-8 haloalkyl, C1-8 alkoxy and C1-8 haloalkoxy, and optionally any two R4 substituents located on adjacent ring vertices are combined to form a 5- to 6-membered ring having from 0- to 2 heteroatom ring members selected from the group consisting of N, O and S.

A method of treating a disease or disorder in a mammal, said method comprising administering to said subject a therapeutically effective amount of a compound, for a period of time sufficient to treat said cancer;

• wherein said compound has formula
• or pharmaceutically acceptable salts and N-oxides thereof;
• wherein
• is a single or double bond;
• A is —N(H)—, —N(Ra)—, —CH2—, —CH(Ra)—, —C(Ra)2—, wherein Ra is absent or is C1-4 alkyl;
• R1 is absent;
• or alternatively is selected from the group consisting of hydrogen and C1-6 alkyl;
• L1 is —C(O)—;
• R2 is —Re;
• R3 is selected from the group consisting of —X1—Re and —Re;
• wherein X1 is a C1-2 alkylene;
• and each Re is independently a 5-6 membered aryl or heteroaryl group that is optionally substituted with 1-5 substituents selected from the group consisting of halogen, —CN, —NO2, —CO2Rr, —OC(O)Rr, —C(O)NRrRs, —C(O)Rr, —S(O)Rt, —S(O)2Rt, —Rt, —C(NORr)Rs, —NRr—C(O)NRrRs, —NH—C(NH2)═NH, —NRtC(NH2)═NH, —NH—C(NH2)═NRt, —NH—C(NHRt)═NH, —NRrS(O)2Rt, —NRrS(O)2Rt, —NRrS(O)2NRrRs, —N3, —C(NRrV)═NV, —N(V)C(Rr)═NV, —X2C(NORr)Rs, —X2C(NRrV)═NV, —X2N(V)C(Rr)═NV, —X2NRrRs, —X2SRr, —X2CN, —X2NO2, —X2CO2Rr, —X2OC(O)Rr, —X2CONRrRs, —X2C(O)Rr, —X2OC(O)NRrRs, —X2NRsC(O)Rr, —X2NRsC(O)2Rt, —X2NRrC(O)NRrRs, —X2NH—C(NH2)═NH, —X2NRtC(NH2)═NH, —X2NH—C(NH2)═NRt, —X2NH—C(NHRt)═NH, —X2S(O)Rt, —X2S(O)2Rt, —X2NRrS(O)2Rt, —X2S(O)2NRrRs, —X2N3, —ORr, —SRr, —NRrRs, —NRsC(O)Rr, —NRsC(O)2Rt, —S(O)2Rt, —S(O)2NRrRs, —X2ORr, —O—X2Rr, —X2NRrRs, —O—X2NRrRs and —NRs—X2CO2Rr, wherein any two substituents located on adjacent atoms in Re can be combined to form a 5- to 7-membered ring having optionally having from 1-3 heteroatoms selected from N, O or S;
• X2 is C1-8 alkylene, C1-8 heteroalkylene, C2-8 alkenylene, C2-8 alkynylene, arylene or heteroarylene;
• and each Rr and Rs is independently selected from hydrogen, C1-8 alkyl, C1-8 haloalkyl, C3-6 cycloalkyl, C2-8 alkenyl, C2-8 alkynyl, aryl and heteroaryl, or optionally, Rr and Rs when attached to the same nitrogen atom can be combined with the nitrogen atom to form a five or six-membered ring having from 0 to 2 additional heteroatoms as ring members selected from N, O or S, and wherein each Rt is independently selected from the group consisting of C1-8 alkyl, C1-8 haloalkyl, C3-6 cycloalkyl, C2-8 alkenyl, C2-8 alkynyl, aryl and heteroaryl, V is independently selected from the group consisting of —Rt, —CN, —CO2Rr and —NO2, and each of X2, Rr, Rs and Rt is optionally further substituted with from one to three members selected from the group consisting of —OH, —ORu, —OC(O)NHRu, —OC(O)N(Ru)2, —SH, —SRu, —S(O)Ru, —S(O)2Ru, —SO2NH2, —S(O)2NHRu, —S(O)2N(Ru)2, —NHS(O)2Ru, —NRuS(O)2Ru, —C(O)NH2, —C(O)NHRu, —C(O)N(Ru)2, —C(O)Ru, —NHC(O)Ru, —NRuC(O)Ru, —NHC(O)NH2, —NRuC(O)NH2, —NRuC(O)NHRu, —NHC(O)NHRu, —NRuC(O)N(Ru)2, —NHC(O)N(Ru)2, —CO2H, —CO2Ru, —NHCO2Ru, —NRuCO2Ru, —CN, —NO2, —NH2, —NHRu, —N(Ru)2, —NRuS(O)NH2 and —NRuS(O)2NHRu, wherein each Ru is independently an unsubstituted C1-6 alkyl;
• and
• each of the ring vertices a, b, c and d in formula I is N, N—O, C(H) or C(R4), wherein R4 at each occurrence is independently is selected from the group consisting of halogen, C1-8 alkyl, C1-8 haloalkyl, C1-8 alkoxy and C1-8 haloalkoxy, and optionally any two R4 substituents located on adjacent ring vertices are combined to form a 5- to 6-membered ring having from 0- to 2 heteroatom ring members selected from the group consisting of N, O and S.

A method of inhibiting the binding of chemokines I-TAC or SDF-1 to a CCXCKR2 receptor, comprising contacting a compound with a cell that expresses the CCXCKR2 receptor for a time sufficient to inhibit the binding of the chemokines to the CCXCKR2 receptor;

• wherein said compound has the formula
• or pharmaceutically acceptable salts and N-oxides thereof;
• wherein
• is a single or double bond;
• A is —N(H)—, —N(Ra)—, —CH2—, —CH(Ra)—, —C(Ra)2—, wherein Ra is absent or is C1-4 alkyl;
• R1 is absent;
• or alternatively is selected from the group consisting of hydrogen and C1-6 alkyl;
• L1 is —C(O)—;
• R2 is —Re;
• R3 is selected from the group consisting of —X1—Re and —Re;
• wherein X1 is a C1-2 alkylene;
• and each Re is independently a 5-6 membered aryl or heteroaryl group that is optionally substituted with 1-5 substituents selected from the group consisting of halogen, —CN, —NO2, —CO2Rr, —OC(O)Rr, —C(O)NRrRs, —C(O)Rr, —S(O)Rt, —S(O)2Rt, —Rt, —C(NORr)Rs, —NRrC(O)NRrRs, —NH—C(NH2)═NH, —NRtC(NH2)═NH, —NH—C(NH2)═NRt, —NH—C(NHRt)═NH, —NRrS(O)2Rt, —NRrS(O)2Rt, —NRrS(O)2NRrRs, —N3, —C(NRrV)═NV, —N(V)C(Rr)═NV, —X2C(NORr)Rs, —X2C(NRrV)═NV, —X2N(V)C(Rr)═NV, —X2NRrRs, —X2SRr, —X2CN, —X2NO2, —X2CO2Rr, —X2OC(O)Rr, —X2CONRrRs, —X2C(O)Rr, —X2OC(O)NRrRs, —X2NRsC(O)Rr, —X2NRsC(O)2Rt, —X2NRrC(O)NRrRs, —X2NH—C(NH2)═NH, —X2NRtC(NH2)═NH, —X2NH—C(NH2)═NRt, —X2NH—C(NHRt)═NH, —X2S(O)Rt, —X2S(O)2Rt, —X2NRrS(O)2Rt, —X2S(O)2NRrRs, —X2N3, —ORr, —SRr, —NRrRs, —NRsC(O)Rr, —NRsC(O)2Rt, —S(O)2Rt, —S(O)2NRrRs, —X2ORr, —OX2ORr, —X2NRrRs, —O—X2NRrRs and —NRs—X2CO2Rr, wherein any two substituents located on adjacent atoms in Re can be combined to form a 5- to 7-membered ring having optionally having from 1-3 heteroatoms selected from N, O or S;
• X2 is C1-8 alkylene, C1-8 heteroalkylene, C2-8 alkenylene, C2-8 alkynylene, arylene or heteroarylene;
• and each Rr and Rs is independently selected from hydrogen, C1-8 alkyl, C1-8 haloalkyl, C3-6 cycloalkyl, C2-8 alkenyl, C2-8 alkynyl, aryl and heteroaryl, or optionally, Rr and Rs when attached to the same nitrogen atom can be combined with the nitrogen atom to form a five or six-membered ring having from 0 to 2 additional heteroatoms as ring members selected from N, O or S, and wherein each Rt is independently selected from the group consisting of C1-8 alkyl, C1-8 haloalkyl, C3-6 cycloalkyl, C2-8 alkenyl, C2-8 alkynyl, aryl and heteroaryl, V is independently selected from the group consisting of —Rt, —CN, —CO2Rr and —NO2, and each of X2, Rr, Rs and Rt is optionally further substituted with from one to three members selected from the group consisting of —OH, —ORu, —OC(O)NHRu, —OC(O)N(Ru)2, —SH, —SRu, —S(O)Ru, —S(O)2Ru, —SO2NH2, —S(O)2NHRu, —S(O)2N(Ru)2, —NHS(O)2Ru, —NRuS(O)2Ru, —C(O)NH2, —C(O)NHRu, —C(O)N(Ru)2, —C(O)Ru, —NHC(O)Ru, —NRuC(O)Ru, —NHC(O)NH2, —NRuC(O)NH2, —NRuC(O)NHRu, —NHC(O)NHRu, —NRuC(O)N(Ru)2, —NHC(O)N(Ru)2, —CO2H, —CO2Ru, —NHCO2Ru, —NRuCO2Ru, —CN, —NO2, —NH2, —NHRu, —N(Ru)2, —NRuS(O)NH2 and —NRuS(O)2NHRu, wherein each Ru is independently an unsubstituted C1-6 alkyl;
• and
• each of the ring vertices a, b, c and d in formula I is N, N—O, C(H) or C(R4), wherein R4 at each occurrence is independently is selected from the group consisting of halogen, C1-8 alkyl, C1-8 haloalkyl, C1-8 alkoxy and C1-8 haloalkoxy, and optionally any two R4 substituents located on adjacent ring vertices are combined to form a 5- to 6-membered ring having from 0- to 2 heteroatom ring members selected from the group consisting of N, O and S.