Substituted quinolones and methods of use

1. A compound having formula I

or pharmaceutically acceptable salts and N-oxides thereof; wherein

 is a single or double bond;

A is —CH 2 —, —CH(R a )—, or —C(R a ) 2 —, wherein each R a is absent or is C 1-4 alkyl;

R 1 is absent; or is hydrogen;

L 1 is —C(O)—;

R 2 is a 5-6 membered aryl or heteroaryl group;

R 3 —CH 2 —pyridyl;

wherein R 2 and the pyridyl portion of R 3 are each optionally substituted with 1-5 substituents selected from the group consisting of halogen, —CN, —NO 2 , —CO 2 R r , —OC(O)R r , —C(O)NR r R s , —C(O)R r ,—S(O)R t , —S(O) 2 R t , —R t , —C(NOR r )R s , —NR r —C(O)NR r R s , —NH—C(NH 2 )═NH, —NR t C(NH 2 )═NH, —NH—C(NH 2 )═NR t , —NH—C(NHR t )═NH, —NR r S(O) 2 R t , —NR r S(O) 2 R t , —NR r S(O) 2 NR r R s , —N 3 , —C(NR r V)═NV, —N(V)C(R r )═NV, —X 2 C(NOR r )R s , —X 2 C(NR r V)═NV, —X 2 N(V)C(R r )═NV, —X 2 NR r R s , —X 2 SR r , —X 2 CN, —X 2 NO 2 , —X 2 CO 2 R r , —X 2 OC(O)R r , —X 2 CONR r R s , —X 2 C(O)R r , —X 2 OC(O)NR r R s , —X 2 NR s C(O)R r , —X 2 NR s C(O) 2 R t , —X 2 NR r C(O)NR r R s , —X 2 NH—C(NH 2 )═NH, —X 2 NR t C(NH 2 )═NH, —X 2 NH—C(NH 2 )═NR t , —X 2 NH—C(NHR t )═NH, —X 2 S(O)R t , —X 2 S(O) 2 R t , —X 2 NR r S(O) 2 R t , —X 2 S(O) 2 NR r R s , —X 2 N 3 , —OR r , —SR r , —NR r R s ,—NR s C(O)R r , —NR s C(O) 2 R t , —S(O) 2 R t , —S(O) 2 NR r R s , —X 2 OR r , —O—X 2 OR r , —X 2 NR r R s , —O—X 2 NR r R s and —NR s —X 2 CO 2 R r , X 2 is C 1-8 alkylene, C 1-8 heteroalkylene, C 2-8 alkenylene, C 2-8 alkynylene, arylene or heteroarylene; and each R r and R s is independently selected from hydrogen, C 1-8 alkyl, C 1-8 haloalkyl, C 3-6 cycloalkyl, C 2-8 alkenyl, C 2-8 alkynyl, aryl and heteroaryl, or optionally, R r and R s 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 R t is independently selected from the group consisting of C 1-8 alkyl, C 1-8 haloalkyl, C 3-6 cycloalkyl, C 2-8 alkenyl, C 2-8 alkynyl, aryl and heteroaryl, V is independently selected from the group consisting of —R t , —CN, —CO 2 R r and —NO 2 , and each of X 2 , R r , R s and R t is optionally further substituted with from one to three members selected from the group consisting of —OH, —OR u , —OC(O)NHR u , —OC(O)N(R u ) 2 , —SH, —SR u , —S(O)R u , —S(O) 2 R u , —SO 2 NH 2 , —S(O) 2 NHR u , —S(O) 2 N(R u ) 2 , —NHS(O) 2 R u , —NR u S(O) 2 R u , —C(O)NH 2 , —C(O)NHR u , —C(O)N(R u ) 2 , —C(O)R u , —NHC(O)R u , —NR u C(O)R u , —NHC(O)NH 2 , —NR u C(O)NH 2 , —NR u C(O)NHR u , —NHC(O)NHR u , —NR u C(O)N(R u ) 2 , —NHC(O)N(R u ) 2 , —CO 2 H, —CO 2 R u , —NHCO 2 R u , —NR u CO 2 R u , —CN, —NO 2 , —NH 2 , —NHR u , —N(R u ) 2 , —NR u S(O)NH 2 and —NR u S(O) 2 NHR u , wherein each R u is independently an unsubstituted C 1-6 alkyl; and

each of the ring vertices a, b, c and d in formula I is C(H) or C(R 4 ), wherein R 4 at each occurrence is independently is selected from the group consisting of halogen, C 1-8 alkyl, C 1-8 haloalkyl, C 1-8 alkoxy and C 1-8 haloalkoxy, and optionally any two R 4 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.

2. The compound of claim 1 , wherein the compound has formula Ia

wherein A is CH;

and R 2 and the pyridyl portion of R 3 are each optionally substituted with 1-5 substituents selected from the group consisting of halogen, —CN, —NO 2 , —R t , —CO 2 R r , —CONR r R s , —N 3 , —X 2 NR r R s , —X 2 SR r , —X 2 CN, —X 2 NO 2 , —X 2 CO 2 R r , —X 2 CONR r R s , —X 2 C(O)R r , —X 2 NR s C(O)R r , —X 2 NR s C(O) 2 R t , —X 2 N 3 , —OR r , —SR r , —NR r R s , —NR s C(O)R r , —NR s C(O) 2 R t , —X 2 OR r and —NR s —X 2 CO 2 R r , X 2 is C 1-4 alkylene or C 1-4 heteroalkylene; and each R r and R s is independently selected from hydrogen, C 1-8 alkyl, C 1-8 haloalkyl, C 3-6 cycloalkyl, C 2-8 alkenyl, C 2-8 alkynyl, aryl and heteroaryl, or optionally, R r and R s 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 R t is independently selected from the group consisting of C 1-8 alkyl, C 1-8 haloalkyl, aryl and heteroaryl and each of X 2 , R r , R s and R t is optionally further substituted with from one to three members selected from the group consisting of —OH, —OR u , —OC(O)NHR u , —OC(O)N(R u ) 2 , —SH, —SR u , —S(O)R u , —S(O) 2 R u , —SO 2 NH 2 , —S(O) 2 NHR u , —S(O) 2 N(R u ) 2 , —NHS(O) 2 R u , —NR u S(O) 2 R u , —C(O)NH 2 , —C(O)NHR u , —C(O)N(R u ) 2 , —C(O)R u , —NHC(O)R u , —NR u C(O)R u , —NHC(O)NH 2 , —NR u C(O)NH 2 , —NR u C(O)NHR u , —NHC(O)NHR u , —NR u C(O)N(R u ) 2 , —NHC(O)N(R u ) 2 , —CO 2 H, —CO 2 R u , —NHCO 2 R u , —NR u CO 2 R u , —CN, —NO 2 , —NH 2 , —NHR u , —N(R u ) 2 , —NR u S(O)NH 2 and —NR u S(O) 2 NHR u , wherein each R u is independently an unsubstituted C 1-6 alkyl.

3. The compound of claim 1 or 2 , wherein R 2 is an optionally substituted phenyl ring.

4. The compound of claim 3 , wherein R 2 is a phenyl ring having the formula

wherein R 2a , R 2b , R 2c , R 2d and R 2e are each independently selected from the group consisting of hydrogen, halogen, —CN, —NO 2 , OR r , —SR r , —NR r R s , —CO 2 R r , C(O)NR r R s , optionally substituted C 1-8 alkyl, optionally substituted C 1-8 haloalkyl and optionally substituted C 3-6 cycloalkyl; and R r and R s are each independently selected from the group consisting of hydrogen, C 1-8 alkyl, C 1-8 haloalkyl, C 3-6 cycloalkyl, C 2-8 alkenyl and C 2-8 alkynyl.

5. The compound of claim 3 , wherein R 2 is selected from the group consisting of:

6. The compound of claim 2 , wherein the pyridyl group in R 3 has the formula

wherein R 3a is substituent selected from the group consisting of halogen, —CN, —NO 2 , —R t , —CO 2 R r , —CONR r R s , —N 3 , —X 2 NR r R s , —X 2 SR r , —X 2 CN, —X 2 NO 2 , —X 2 CO 2 R r , —X 2 CONR r R s , —X 2 C(O)R r , —X 2 NR s C(O)R r , —X 2 NR s C(O) 2 R t , —X 2 N 3 , —OR r , —SR r , —NR r R s , —NR s C(O)R r , —NR s C(O) 2 R t , —X 2 OR r and —NR s —X 2 CO 2 R r .

7. The compound of claim 2 , wherein the pyridyl group in R 3 is selected from the group consisting of:

8. The compound of claim 1 , wherein the ring vertices a, b, c and d are each CH.

9. The compound of claim 1 , wherein the ring vertices a, b, c and d are each independently selected from the group consisting of CH or C(R 4 ), wherein each R 4 is independently selected from the group consisting of halogen, C 1-8 alkyl, C 1-8 haloalkyl and C 1-8 alkoxy; or alternatively any two R 4 substituents located on adjacent ring vertices are combined to form a 5- to 6-membered ring having 1 to 2 heteroatoms selected from the group consisting of N and O.

10. The compound of claim 9 , wherein the ring vertices a, c and d are each CH; and the ring vertex b is CR 4 , wherein R 4 is a C 1-4 haloalkyl.

11. The compound of claim 9 , wherein the ring vertices a and d are each CH and the ring vertices b and c are each C(R 4 ) wherein the R 4 substituent are combined to form a 5- or 6-membered ring having two oxygen atoms.

12. The compound of claim 2 , wherein a, b, c and d are each CH; R 2 is phenyl, substituted with one or two groups selected from the group consisting of halogen, C 1-4 alkyl, C 1-4 alkoxy, or are combined to form a fused 6-member ring having two oxygen atom ring members; R 3 is a pyridylmethyl group optionally substituted with one or two groups selected from the group consisting of halogen and cyano.

13. The compound of claim 1 , wherein said compound is selected from the group consisting of:

3-(Pyridine-4-carbonyl)-1-pyridin-2-ylmethyl-H-quinolin-4-one;

3-(3,4-Dimethyl-benzoyl)-1-pyridin-2-ylmethyl-6-trifluoromethyl1H-quinolin-4-one;

8-(3,4-Dimethyl-benzoyl)-6-pyridin-4-ylmethyl-2,3dihydro-6H-[1,4]dioxino[2,3-g]quinolin-9-one;

8-(3,4-Dimethyl-benzoyl)-6-pyridin-3-ylmethyl-2,3-dihydro-6H-[1 ,4]dioxino[2,3-g]quinolin-9-one;

8-(3,4-Dimethyl-benzoyl)-6-pyridin-2-ylmethyl-2,3-dihydro-6H-[-1,4 ]dioxino[2,3-g]quinolin-9-one;

3-(3,4-Dimethyl-benzoyl)-1-pyridin-4-ylmethyl-1H-quinolin-4-one;

3-(3,4-Dimethyl-benzoyl)-1-pyridin-3-ylmethyl-1H-quinolin-4-one;

3-(3,4-Dimethyl-benzoyl)-1-pyridin-2-ylmethyl-1H-quinolin-4-one;

7-(3,4-Dimethyl-benzoyl)-5-pyridin-4-ylmethyl-5H-[1,3]dioxolo[4,5-g]quinolin-8-one;

7-(3,4-Dimethyl-benzoyl)-5-pyridin-3-ylmethyl-5H-[1,3]dioxolo[4,5-g]quinolin-8-one;

7-(3,4-Dimethyl-benzoyl)-5-pyridin-2-ylmethyl-5H-[1,3]dioxolo[4,5-g]quinolin-8-one;

3-(3-Methyl-benzoyl)-1-pyridin-2-ylmethyl-1H-quinolin-4-one;

3-(3,4-Dimethyl-benzoyl)-1-(6-methyl-pyridin-2ylmethyl)-1H-quinolin-4-one;

3-(2-Methyl-pyridine-4-carbonyl)-1-(6-methyl-pyridin-2-ylmethyl)-1H-quinolin-4-one;

1-(6-Bromo-pyridin-2-ylmethyl)-3-(3,4-dimethyl-benzoyl)-1H-quinolin-4-one;

1-(6-Methyl-pyridin-2-ylmethyl)-3-(pyridine-3-carbonyl)-1H-quinolin-4-one;

3-(3,4-Dimethyl-benzoyl)-1-(3-fluoro-pyridin-2-ylmethyl)-1H-quinolin-4-one;

3-(5,6-Dimethyl-pyridine-3-carbonyl)-1-(3-fluoro-pyridin-2-ylmethyl)-1H-quinolin-4-one;

3-(5,6-DimethyI-pyridine-3-carbonyI)-1-(6-oxazol-2-yl-pyridin-2-ylmethyl)-1H-quinolin-4-one;

3-(3,4-Dimethyl-benzoyl)-1-(6-phenyl-pyridin-2-ylmethyl)-1H-quinolin-4-one;

3-(3,4-Dimethyl-benzoyl)-1-(6-methyl-pyridin-2-ylmethyl)-1H-cinnolin-4-one;

3-(5,6-Dimethyl-pyridine-3-carbonyl)-1-(6-methyl-pyridin-2-ylmethyl)-1H-quinolin-4-one;

1-(6-Amino-pyridin-2-ylmethyl)-3-(3,4-dimethyl-benzoyl)-1H-quinolin-4-one;

N-{6-[3-(3,4-Dimethyl-benzoyl)-4-oxo-4H-quinolin-1-ylmethyl]-pyridin-2-yl}-acetamide;

1-(6-Bromo-pyridin-2-ylmethyl)-3-(3,4-dimethyl-benzoyl)-6-fluoro-1H-quinolin-4-one;

1-(6-Bromo-pyridin-2-ylmethyl)-3-(5,6-dimethyl-pyridine-3-carbonyl)-1H-quinolin-4-one;

1-(6-Bromo-pyridin-2-ylmethyl)-3-(3,4-dimethyl-benzoyl)-1H-quinolin-4-one; and

6-[3-(3,4-Dimethyl-benzoyl)-4-oxo-4H-quinolin-1-ylmethyl]-pyridine-2-carbonitrile.

14. A pharmaceutical composition comprising a compound of claim 1 , and a pharmaceutically acceptable excipient.

15. The pharmaceutical composition of claim 14 , wherein the compound is a compound of claim 2 .