Substituted 6,6-fused nitrogenous heterocyclic compounds and uses thereof

1. A compound of formula (I)

or a pharmaceutically acceptable salt thereof, having the subformula Ia, Ib, Ic, or Id, selected from the group consisting of

or an N-oxide thereof; wherein

Y is absent or is selected from the group consisting of —C(═O)—, —N(H)C(═O)—, —N(R a )C(═O)—, —O—C(═O)—, —N(H)S(O) 1-2 —, —N(R a )S(O) 1-2 — and —S(O) 2 —, wherein R a is selected from the group consisting of C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 heteroalkyl, C 2-6 alkenyl and C 2-6 alkynyl;

R 2 is —(X b ) 0-1 —R b , wherein X b is selected from the group consisting of C 1-6 alkylene, C 2-6 alkenylene, C 2-6 alkynylene, C 1-6 heteroalkylene, 3-6 membered cycloalkylene and 3-6 membered heterocycloalkylene, R b is selected from the group consisting of hydrogen, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 heteroalkyl, C 2-6 alkenyl, C 2-6 alkynyl,3-6 membered cycloalkyl, 3-6 membered heterocycloalkyl, 6-10 membered aryl and 5-10 membered heteroaryl, wherein the aliphatic and aromatic portions of X b and R b are each independently optionally substituted with 1 to 5 R b1 substituents selected from the group consisting of C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 heteroalkyl, F, Cl, Br, I, —OH, —NH 2 , —SH, —CN, —NO 2 , —N 3 , —C(═O)OH, C 1-6 alkoxy, C 1-6 alkylamino, C 1-6 dialkylamino, —(C 1-4 alkenylene) 0-1 -C(═O)—(C 1-4 alkyl), —(C 1-4 alkenylene) 0-1 -C(═O)O—(C 1-4 alkyl), —(C 1-4 alkenylene) 0-1 -C(═O)N(H)—(C 1-4 alkyl), —(C 1-4 alkenylene) 0-1 -C(═O)N(C 1-4 alkyl) 2 , —(C 1-4 alkenylene) 0-1 -S(O) 2 —(C 1-4 alkyl), —(C 1-4 alkenylene) 0-1 -C(═O)—(C 1-4 heteroalkyl) and —(C 1-4 alkenylene) 0-1 -C(═O)—(C 3-6 heterocycloalkyl), and wherein if R b is a 6 membered aryl or a 5-6 membered heteroaryl then any two substituents attached to adjacent atoms said aryl or heteroaryl are optionally combined to from a 3-6 membered carbocyclic or a 3-6 membered heterocyclic ring comprising 1-3 heteroatoms selected from N, O and S, and optionally substituted with 1 to 3 R b1 substituents;

X 1 is N or N + —O − ;

X 2 , X 3 and X 4 are each C, or one of X 2 , X 3 and X 4 is N or N + —O − and the remainder of X 2 , X 3 and X 4 are each C;

R 3 is selected from the group consisting of hydrogen, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 alkylamino, C 1-6 dialkyamino, F, Cl, Br, I, —CN, —CF 3 , —OCF 3 , —SF 5 and —N 3 ;

R 4 is selected from the group consisting of hydrogen, C 1-6 alkyl, C 1-6 haloalkyl, F, Cl, Br, I, —CN, —NO 2 , —N 3 , —SH, —OH, C 1-6 alkoxy, —CF 3 , —OCF 3 , —SF 5 , C 1-6 alkylamino and C 1-6 dialkylamino, or is absent if X 4 is N or N + —O;

R 5 is (X c ) 0-1 —R c , wherein X c is selected from the group consisting of C 1-6 alkylene, C 2-6 alkenylene, C 2-6 heteroalkylene, C 2-6 alkynylene, —N(H)—, —N(R xc )—, —O—, —S(O) 2 —, —C(═O)—, —C(═O)O—, —C(═O)N(H)—, —N(H)C(═O)— and —OC(═O)—, wherein R xc is selected from the group consisting of C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 heteroalkyl, C 2-6 alkenyl, C 2-6 alkynyl, and wherein R c is selected from the group consisting of hydrogen, F, Cl, Br, I, —CN,—NO 2 , —NH 2 , —OH, —CF 3 , —OCF 3 , —SF 5 , C 1-6 alkoxy, C 1-6 alkylamino, C 1-6 dialkylamino, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 heteroalkyl, C 2-6 alkenyl, C 2-6 alkynyl, 3-6 membered cycloalkyl, 3-6 membered heterocycloalkyl, 6 membered aryl and 5-6 membered heteroaryl, wherein the aliphatic and aromatic portions of X c and R c are optionally substituted with 1 to 5 R c1 substituents selected from the group consisting of C 1-6 alkyl, C 1-6 heteroalkyl, F, Cl, Br, I, —OH, —NH 2 , —SH, —CN, —NO 2 , —N 3 , —C(═O)OH, —N(C 1-6 alkyl) 2 , —NH(C 1-6 alkyl), —O(C 1-6 alkyl), —(C 1-4 alkenylene) 0-1 -C(═O)—(C 1-4 alkyl), —(C 1-4 alkenylene) 0-1 -C(═O)O—(C 1-4 alkyl), —(C 1-4 alkenylene) 0-1 -C(═O)N(H)—(C 1-4 alkyl), —(C 1-4 alkenylene) 0-1 -C(═O)N(C 1-4 alkyl) 2 , —(C 1-4 alkenylene) 0-1 -S(O) 2 —(C 1-4 alkyl), —(C 1-4 alkenylene) 0-1 -C(═O)—(C 1-4 heteroalkyl) and —(C 1-4 alkenylene) 0-1 -C(═O)—(C 3-6 heterocycloalkyl), or R 5 is absent if X 3 is N or N + —O − ;

R 6 is selected from the group consisting of hydrogen, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 heteroalkyl, C 1-6 alkoxy, C 1-6 alkylamino, C 1-6 dialkylamino, C 2-6 alkenyl, C 2-6 alkynyl, F, Cl, Br, I, —OH, —NH 2 , —SH, —CN, —NO 2 , —CF 3 , —OCF 3 , —SF 5 and —N 3 , or R 6 is absent if X 2 is N or N + —O − ;

A is selected from the group consisting of —(X d ) 0-1 —N(H)C(═O)—, —(X d ) 0-1 —N(R d )C(═O)—, —X d —, —(X d ) 0-1 —C(═O)N(H)—, —(X d ) 0-1 —C(═O)N(R d )—, —(X d ) 0-1 —C(═O)—, —C(═O)—(X d ) 0-1 —, —(X d ) 0-1 —OC(═O)—, —(X d ) 0-1 C(═O)O— and wherein the X d group in A is selected from the group consisting of C 1-6 alkylene, C 2-6 alkenylene C 1-6 heteroalkylene, 6-10 membered arylene and a 5-10 membered heteroarylene comprising 1 to 3 heteroatoms selected from N, O and S, wherein said X d is optionally substituted with 1 to 5 R d1 substituents selected from the group consisting of C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkylamino, C 1-6 dialkylamino, F, Cl, Br, I, —OH, —NH 2 , —SH, —CN, —NO 2 —CF 3 —OCF 3 , —SF 5 , and —N 3 ;

B is selected from the group consisting of C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 heteroalkyl, C 2-6 alkenyl, C 2-6 alkynyl, 3-6 membered cycloalkyl, 4-9 membered heterocycloalkyl, 6-10 membered aryl and 5-6 membered heteroaryl, wherein the aliphatic or aromatic portions of B are independently optionally substituted with 1 to 5 R B1 substituents selected from the group consisting of C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 heteroalkyl, C 1-6 alkoxy, C 1-6 alkylamino, C 1-6 dialkylamino, C 3-6 heterocycloalkyl, F, Cl, Br, I, —OH, —NH 2 , —SH, —CF 3 , —OCF 3 , —SF 5 , —(X e ) 0-1 —CN, —(X e ) 0-1 —NO 2 , —(X e ) 0-1 —N 3 , —(X e ) 0- 1 —OH, —(X e ) 0-1 —H, —(X e ) 0-1 —N(H)R e , —(X e ) 0-1 —N(R e ) 2 , —(X e ) 0-1 —SR e , —(X e ) 0-1 —C(O)R e , —(X e ) 0-1 —S(O) 2 R e , —(X e ) 0-1 —S(O)R e , —N(H)S(O) 2 R e , —N(R e )S(O) 2 R e , —(X e ) 0-1 C(═O)OR e , —(X e ) 0-1 —C(═O)OH, —(X e ) 0-1 —C(═O)N(H)R e , —(X e ) 0-1 —C(═O)N(R e )R e , —(X e ) 0-1 —N(H)C(═O)R e , —(X e ) 0-1 —N(R e )C(═O)R e , wherein if B is a 6 membered aryl or a 5-6 membered heteroaryl then any two substituents attached to adjacent atoms of said aryl or heteroaryl are optionally combined to from a 3-6 membered carbocyclic or a 3-6 membered heterocyclic ring optionally comprising 1-3 heteroatoms selected from N, O and S, and optionally substituted with 1 to 3 R B1 substituents; wherein X e is selected from the group consisting of C 1-6 alkylene, C 2-6 alkenylene, C 2-6 alkynylene, C 1-6 heteroalkylene, C 3-6 cycloalkylene and C 3-6 heterocycloalkylene, and R e at each occurrence is independently selected from the group consisting of C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 heteroalkyl, C 2-6 alkenyl, C 2-6 alkynyl, 3-7 membered cycloalkyl, 3-7 membered heterocycloalkyl, phenyl and 5-6 membered heteroaryl, wherein the aliphatic or aromatic portions of X e and R e are each independently optionally substituted with 1 to 5 R e1 substituents selected from the group consisting of C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkylamino, C 1-6 dialkylamino, F, Cl, Br, I, —OH, —NH 2 , —SH, —CN, —NO 2 , —CF 3 , —OCF 3 , —SF 5 and —N 3 , and wherein any two R e groups attached to the same nitrogen atom are optionally combined to form a 3-7 membered heterocyclic or 5-10 membered heteroaryl ring comprising 1-3 heteroatoms selected from N, O and S; and

wherein if X 3 is N, R 3 is H, R 4 is H or NH 2 , R 6 is —OH and —Y—R 2 is other than H, then -A-B is not thiazol-4-yl substituted with 2-thiophenyl-S(O) 2 CH 2 —, phenyl-S(O) 2 —CH 2 —, 4-pyridyl, or pyridyl-S(O) 2 CH 2 —, if X 3 is N, R 3 is H or Cl, R 4 is H, R 6 is —OH, —NH 2 , or —NHCH 3 and —Y—R 2 is hydrogen, 4-tetrahydropyranyl, 4-((CH 3 CH 2 ) 2 N(CH 2 ) 3-4 O)-phenyl, (CH 3 CH 2 ) 2 N(CH 2 ) 4 —, 3-(4-methylpiperazinyl)-propyl or trifluoroacetyl, then -A-B is not 2-chlorophenyl, 2-methylphenyl, 2,6-dichlorophenyl, 3,5-dimethoxyphenyl, 3,4-dimethoxypheny, phenyl, 2-chloro-6-(2-ethoxyethoxy)phenyl, if X 3 is N, R 3 , R 4 and R 6 are each H, and —Y—R 2 is hydrogen, cyclohexyl, (CH 3 CH 2 ) 2 NCH 2 CH 2 —, CH 3 N(H)CH 2 CH 2 —, (CH 3 ) 2 NCH 2 CH 2 —, (CH 3 ) 3 CC(═O)— or 2-(4-morpholinyl)ethyl, then -A-B is not 3,4-dimethoxyphenyl or optionally substituted pyridine-2-on-3-yl, if X 4 is N, R 3 is H, R 5 is isopropyl, R 6 is methoxy, -A-B is propyl or isopropyl, then —Y—R 2 is other than optionally substituted pyridyl, if X 4 is N, R 3 , R 5 , R 6 are each H, -A-B is methyl, then —Y—R 2 is other than hydrogen, if R 3 , R 4 , R 5 and R 6 are each H, and —Y—R 2 is hydrogen, cyclohexyl, (CH 3 CH 2 ) 2 NCH 2 CH 2 —, CH 3 N(H)CH 2 CH 2 —, (CH 3 ) 2 NCH 2 CH 2 —, (CH 3 ) 3 CC(═O)— or 2-(4-morpholinyl)ethyl, then -A-B is not 3,4-dimethoxyphenyl or optionally substituted pyridine-2-on-3-yl, if R 3 , R 4 and R 5 are each hydrogen, —Y—R 2 is other than hydrogen, then one of R 6 and -A-B is other than ethoxy.

2. The compound of claim 1 , wherein R 3 , R 4 and R 6 , if present, are each independently selected from the group consisting of hydrogen, C 1-6 alkyl, C 1-6 haloalkyl, —CF 3 , —OCF 3 , —SF 5 , F, Cl, Br and I.

3. The compound of claim 1 , wherein in R 2 , X b is absent or is selected from C 1-6 alkylene and 3-6 membered cycloalkylene; and R b is selected from the group consisting of hydrogen, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 heteroalkyl, C 2-6 alkenyl, C 2-6 alkynyl, 3-6 membered cycloalkyl, 3-6 membered heterocycloalkyl, 6-10 membered aryl, and 5-10 membered heteroaryl, wherein X b and R b are each independently optionally substituted.

4. The compound of claim 3 , wherein in R 2 , X b is absent.

5. The compound of claim 3 , wherein in R 2 , R b is selected from the group consisting of hydrogen, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 heteroalkyl, C 2-6 alkenyl and C 2-6 alkynyl.

6. The compound of claim 3 , wherein in R 2 , R b is optionally substituted with from 1 to 5 R b1 groups selected from the group consisting of F, Cl, Br, I, OH, NH 2 , SH, CN, NO 2 , C 1-6 alkoxy, C 1-6 alkylamino and C 1-6 dialkylamino.

7. The compound of claim 1 , wherein in R 2 , R b is selected from the group consisting of cycloprop-1-yl, cyclobut-1-yl, cyclopent-1-yl, pyrimidin-2-yl, pyrimidin-4-yl, pyrimidin-5-yl, pyridin-2-yl, pyridin-4-yl, pyridin-3-yl, pyridin-2-on-6-yl, pyridine-2-on-5-yl, pyridine-2-on-4-yl, pyridine-2-on-3-yl, cyclohex-1-yl, phenyl, 4,5-dihydrooxazol-2-yl, oxazol-2-yl, piperidin-4-yl, piperidin-3-yl, piperidin-2-yl, piperidin-1-yl, piperazin-1-yl, piperazin-2-yl, piperazin-3-yl, morpholin-2-yl, morpholin-3-yl, morpholin-4-yl, tetrahydropyran-4-yl, tetrahydropyran-2-yl, tetrahydropyran-3-yl, oxetan-3-yl, oxetan-2-yl, pyrazol-5-yl, pyrazol-1-yl, pyrazol-3-yl, pyrazol-4-yl, methyl, ethyl, propyl, isopropyl, butyl, iso-butyl, tert-butyl, pyrrolidin-3-yl, pyrrolidin-2-yl, 2-tetrahydrofuranyl, 3-tetrahydrofuranyl and 3-oxabicyclo[3.1.0]hexan-6-yl, wherein said R b is further optionally substituted.

8. The compound of claim 1 , wherein Y is absent or is selected from the group consisting of —C(═O)—, —N(H)C(═O)—, —N(R a )C(═O)— and —S(O) 2 —.

9. The compound of claim 8 , wherein in R 2 R b is selected from the group consisting of cycloprop-1-yl, cyclobut-1-yl, cyclopent-1-yl, pyrimidin-2-yl, pyrimidin-4-yl, pyrimidin-5-yl, pyridin-2-yl, pyridin-4-yl, pyridin-3-yl, pyridin-2-on-6-yl, pyridine-2-on-5-yl, pyridine-2-on-4-yl, pyridine-2-on-3-yl, cyclohex-1-yl, phenyl, 4,5-dihydrooxazol-2-yl, oxazol-2-yl, piperidin-4-yl, piperidin-3-yl, piperidin-2-yl, piperidin-1-yl, piperazin-1-yl, piperazin-2-yl, piperazin-3-yl, morpholin-2-yl, morpholin-3-yl, morpholin-4-yl, tetrahydropyran-4-yl, tetrahydropyran-2-yl, tetrahydropyran-3-yl, oxetan-3-yl, oxetan-2-yl, pyrazol-5-yl, pyrazol-1-yl, pyrazol-3-yl, pyrazol-4-yl, methyl, ethyl, propyl, isopropyl, butyl, iso-butyl, tert-butyl, pyrrolidin-3-yl, pyrrolidin-2-yl, 2-tetrahydrofuranyl, 3-tetrahydrofuranyl and 3-oxabicyclo[3.1.0]hexan-6-yl, and wherein R 2 is optionally substituted.

10. The compound of claim 9 , wherein Y is —C(═O)—.

11. The compound of claim 7 , wherein in R 2 , R b is selected from the group as set forth on FIG. 1-A and FIG. 1-B .

12. The compound of claim 1 , wherein the X d group in A is selected from the group consisting of phenylene, pyridylene, pyrimidinylene, pyridazinylene, pyrazinylene, and wherein said X d is optionally substituted.

13. The compound of claim 12 , wherein A is selected from the group consisting of

14. The compound of claim 1 , wherein A is selected from the group consisting of:

15. The compound of claim 1 , wherein B is selected from the group consisting of phenyl, pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, pyrrolidin-1-yl, pyrrolidin-2-yl, pyrrolidin-3-yl, pyrazol-1-yl, pyrazol-3-yl, pyrazol-4-yl, pyrazol-5-yl, thiazol-2-yl, thiazol-4-yl, thiazol-5-yl, pyridin-4-on-3-yl, pyridin-4-on-2-yl, pyridin-4-on-1-yl, pyridin-2-on-1-yl, pyridin-2-on-3-yl, pyridin-2-on-4-yl, pyrrol-1-yl, pyrrol-3-yl, pyrrol-4-yl, pyridazin-3-yl, pyridazin-4-yl, pyridazin-5-yl, pyrazin-2-yl, cyclohexyl, cyclobutyl, cyclopropyl, cyclopentyl, morpholin-4-yl, morpholin-2-yl, morpholin-3-yl, piperazin-1-yl, piperazin-2-yl, cyclopentyl, piperidin-1-yl, piperidin-4-yl, piperidin-2-yl, piperidin-3-yl, indol-5-yl, indol-4-yl, indol-3-yl, indol-2-yl, pyridimdin-5-yl, pyridimdin-4-yl, pyrimidin-2-yl, indazol-3-yl, indazol-4-yl, indazol-5-yl, indazol-6-yl, indazol-7-yl, indolin-2-on-4-yl, indolin-2-on-5-yl, indolin-2-on-6-yl, indolin-2-on-7-yl, tetrahydropyran-4-yl, tetrahydropyran-3-yl, tetrahydropyran-2-yl, tetrahydrofuran-2-yl, tetrahydrofuran-3-yl, tetrahydrofuran-4-yl, wherein B is optionally substituted and wherein any two substituent located on adjacent atoms of B are optionally combined to form an optionally substuted 5 to 7 membered heterocyclic ring comprising 1 to 3 heteroatoms selected from N, O and S.

16. The compound of claim 1 , wherein B is selected from the group consisting of methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, wherein B is optionally substituted.

17. The compound of claim 12 , wherein B is selected from the group consisting of phenyl, pyridin-2-yl, pyridin-3-yl and pyridin-4-yl, wherein the B is optionally substituted with 1 to 3 R B1 substitutents selected from the group consisting of C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 heteroalkyl, C 1-6 alkoxy, C 1-6 alkylamino, C 1-6 dialkylamino, F, Cl, Br, I, —OH, —NH 2 , —SH, —(X e ) 0-1 —CN, —(X e ) 0-1 —NO 2 , —(X e ) 0-1 —N 3 , —(X e ) 0-1 —N(H)R e , —(X e ) 0-1 —N(R 2 ) 2 , —(X e ) 0-1 —SR e , —(X e ) 0-1 —C(O)R e , —(X e ) 0-1 —S(O) 2 R e , —(X e ) 0-1 —S(O)R e , —(X e ) 0-1 —C(═O)OR e , —(X e ) 0-1 —C(═O)N(H)R e , —(X e ) 0-1 —C(═O)N(R e )R e , —(X e ) 0-1 —N(H)C(═O)R e and —(X e ) 0-1 —N(R e )C(═O)R e , and wherein any two substituent located on adjacent atoms of B are optionally combined to form an optionally substuted 5 to 7 membered heterocyclic ring comprising 1 to 3 heteroatoms selected from N, O and S.

18. The compound of claim 14 , wherein B is selected from the group consisting of

19. The compound of claim 1 , wherein B is selected from the group as set forth on FIG. 2-A , FIG. 2-B , FIG. 2-C , FIG. 2-D and FIG. 2-E .

20. The compound of claim 1 , wherein R 5 is (X c )—R c , wherein X c is absent or is selected from the group consisting of C 1-6 alkylene, —N(H)—, —N(R xc )—, —O—, —S(O) 2 —, and R c is selected from the group consisting of hydrogen, F, Cl, Br, I, —CN, —NO 2 , —CF 3 , —OCF 3 , —SF 5 , C 1-6 alkyl, C 1-6 heteroalkyl, piperidin-1-yl, piperidin-2-yl, piperidin-3-yl, piperidin-4-yl, cyclopropyl, cyclopentyl, phenyl, pyrdin-2-yl, pyridin-3-yl, pyridine-4-yl- pyrazol-3-yl, pyrazol-4-yl, pyrazol-5-yl, thiazol-2-yl, thiazol-3-yl, thiazol-5-yl, piperazin-1yl, piperazin-2-yl, pyrrolidin-1-yl, pyrrolidin-2-yl, pyrroldin-3-yl, tetrahydrofuran-2-yl, tetrahydrofuran-3-yl, wherein R c is optionally substituted.

21. A compound of formula I of claim 1 selected from the group consisting of the compounds in Table 1 and Table 1b.

22. A pharmaceutical composition comprising a compound in accordance with claim 1 and a pharmaceutically acceptable carrier, diluent or excipient.