Hedgehog pathway modulators

1. A compound having the structure of Formula I:

wherein:

Q 1 is selected from an aryl, heteroaryl, cycloalkyl, and heterocycloalkyl, wherein the aryl, heteroaryl, cycloalkyl and heterocycloalkyl of Q 1 are optionally substituted with 1 to 3 substituents independently selected from R 9 , R 10 , R 11 R 12 and R 13 ;

Y 1 is N or CR 3 ;

Y 2 is N or CR 4 ;

Y 3 is N or CR 2 ;

Y 4 is N or CR 8 ;

Y 6 is N;

Y 5 is CR 8 ;

Y 7 is N or N + O − ;

L 1 is selected from a bond, —O—, —O(CR 14 R 14 ) m —, and —(CR 14 R 14 ) m O—;

L 2 is selected from a bond, —(CR 14 R 14 ) m —, —(CR 14 R 15 ) m , —C(O)—, —C(O)(CR 14 R 14 ) m — and —C(O)(CR 14 R 15 ) m ;

each L 3 is independently selected from a bond, —(CR 14 R 14 ) m —, —C(O)—, —C(O)O—, and —O(CR 14 R 15 ) m —;

R 1 is H or C 1 -C 6 alkyl;

R 2 , R 3 and R 4 are each independently selected from H, C 1 -C 6 alkyl and L 3 NR 16 R 17 ;

each R 5 is independently selected from H, CN, halogen, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, halosubstituted-C 1 -C 6 alkoxy, L 3 OR 13 , C(O)OR 13 and L 3 NR 16 R 17 ;

each R 6 is independently selected from H, S(O)R 13 , SO 2 R 13 , SO 2 NR 16 R 17 , L 3 NR 16 R 17 , C(O)OR 13 , OR 13 , NR 16 R 17 , C(O)NR 16 R 17 , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 3 -C 8 cycloalkyl, heteroaryl, heterocycloalkyl,

a cyclic sulfinyl selected from

a cyclic sulfonyl selected from

an aryl and a C 1 -C 6 alkyl substituted with 1-4 OH groups,

 wherein the heteroaryl, heterocycloalkyl, C 3 -C 8 cycloalkyl, cyclic sulfinyl, cyclic sulfonyl and aryl of R 6 are optionally substituted with 1-4 substituents selected from halo, CN, C 1 -C 6 alkyl, halosubstituted-C 1 -C 6 alkyl, C 1 -C 6 alkoxy, halosubstituted-C 1 -C 6 alkoxy and C 1 -C 6 alkyl substituted with 1-4-OH groups;

each R 7 is independently selected from H and C 1 -C 6 alkyl, or n is 1 and R 7 is oxo;

each R 8 is independently selected from H and C 1 -C 6 alkyl;

each R 9 , R 10 , R 11 and R 12 are independently selected from H, CN, halo, C 1 -C 6 alkyl, halosubstituted-C 1 -C 6 alkyl, C 1 -C 6 alkoxy, halosubstituted-C 1 -C 6 alkoxy, L 3 OR 13 , L 3 NR 16 R 17 , L 3 R 13 , L 3 R 14 , phenyl optionally substituted with 1 to 3 substituents selected from C 1 -C 6 alkyl, halo, CN, L 3 NR 16 R 17 and OR 13 , and heteroaryl optionally substituted with 1 to 3 substituents selected from C 1 -C 6 alkyl, halo, CN, L 3 NR 16 R 17 and L 3 OR 13 ;

alternatively R 10 and R 11 together with the carbon atoms to which they are attached form a phenyl optionally substituted with 1 to 3 substituents selected from C 1 -C 6 alkyl, halo, CN, L 3 NR 16 R 17 and L 3 OR 13 , or R 10 and R 11 together with the carbons atoms to which they are attached form a 5-6 membered heteroaryl optionally substituted with 1 to 3 substituents selected from C 1 -C 6 alkyl, halo, CN, L 3 NR 16 R 17 and L 3 OR 13 ;

alternatively R 11 and R 12 together with the carbon atoms to which they are attached form a phenyl optionally substituted with 1 to 3 substituents selected from C 1 -C 6 alkyl, halo, CN, L 3 NR 16 R 17 and L 3 OR 13 , or R 10 and R 11 together with the carbons atoms to which they are attached form a 5-6 membered heteroaryl optionally substituted with 1 to 3 substituents selected from C 1 -C 6 alkyl, halo, CN, L 3 NR 16 R 17 and L 3 OR 13 ;

each R 13 is independently selected from H, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 3 -C 8 cycloalkyl, C 3 -C 8 heterocycloalkyl, heteroaryl, aryl and C 1 -C 6 alkyl substituted with 1-4-OH groups, where the heteroaryl and aryl of R 13 are optionally substituted with 1 to 3 substituents selected from C 1 -C 6 alkyl, C r C 6 haloalkyl, C 3 -C 8 cycloalkyl, C 3 -C 8 heterocycloalkyl, and C 1 -C 6 alkyl substituted with 1-4-OH groups;

each R 14 and R 15 are independently selected from H, halo, OH, CN, C 1 -C 6 alkyl, C 1 -C 6 alkyl substituted with 1-4-OH groups, halosubstituted-C 1 -C 6 alkyl, C 1 -C 6 alkoxy and halosubstituted-C 1 -C 6 alkoxy;

or R 14 and R 15 together with the carbon they are attached form a C 3 -C 8 cycloalkyl;

each R 16 and R 17 are independently selected from H, C 1 -C 6 alkyl and C 1 -C 6 alkyl substituted with 1-4-OH groups;

or R 16 and R 17 together with the N atom they are attached form a C 3 -C 8 heterocycloalkyl;

each m is independently 1, 2, 3, 4, 5 or 6;

each n is independently 1, 2, 3, 4, 5 or 6,

and the pharmaceutically acceptable salts, hydrates, N-oxides and stereoisomers thereof.

2. The compound of claim 1 , wherein R 1 is H.

3. The compound of claim 2 , wherein

Q 1 is selected from phenyl, pyrrolyl, pyrazolyl, imidazolyl, benzimidazolyl, benzoxazolyl, purinyl, thiazolyl, oxazolyl, pyridinyl, indolyl, thiazolo[5,4-d]pyrimidinyl, 1H-imidazo[4,5-c]pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl, quinolinyl and isoquinolinyl, each of which is optionally substituted with 1 to 3 substituents independently selected from R 9 and R 13 .

4. The compound of claim 3 , wherein

L 1 is a bond, and Q 1 is selected from phenyl, imidazolyl, benzimidazolyl, benzoxazolyl, purinyl, thiazolo[5,4-d]pyrimidinyl, oxazolyl, pyrazolyl, pyridinyl, 1H-imidazo[4,5-c]pyridinyl, indolyl, pyrimidinyl, pyridazinyl, pyrazinyl, quinolinyl and isoquinolinyl, each of which is optionally substituted with 1 to 3 substituents independently selected from R 9 and R 13 ;

or

L 1 is —O—, —O(CR 14 R 14 ) m —, or —(CR 14 R 14 ) m O—, and Q 1 is selected from phenyl and pyridine, each of which is optionally substituted with 1 to 3 substituents independently selected from R 9 and R 13 .

5. The compound of claim 4 , wherein

L 2 is a bond, and

each R 6 is independently selected from H, S(O)R 13 , SO 2 R 13 , SO 2 NR 16 R 17 , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 3 -C 8 cycloalkyl, heteroaryl, heterocycloalkyl,

a cyclic sulfinyl selected from

and

a cyclic sulfonyl selected from

and

 and a C 1 -C 6 alkyl substituted with 1-4 OH groups,

wherein the heteroaryl, heterocycloalkyl, C 3 -C 8 cycloalkyl, cyclic sulfinyl, and cyclic sulfonyl of R 6 are optionally substituted with 1-4 substituents selected from C 1 -C 6 alkyl and C 1 -C 6 alkyl substituted with 1-4-OH groups;

or

L 2 is —(CR 14 R 14 ) m —, —(CR 14 R 15 ) m —, —C(O)(CR 14 R 14 ) m —, or —C(O)(CR 14 R 15 ) m , and

each R 6 is independently selected from S(O)R 13 , SO 2 R 13 , N 16 R 17 , OR 13 , —C(O)OR 13 , C(O)NR 16 R 17 , C 1 -C 6 haloalkyl, heteroaryl, heterocycloalkyl, C 3 -C 8 cycloalkyl and C 1 -C 6 alkyl substituted with 1-4 OH groups,

wherein the heteroaryl, heterocycloalkyl and C 3 -C 8 cycloalkyl of R 6 are optionally substituted with 1-4 substituents selected from C 1 -C 6 alkyl and C 1 -C 6 alkyl substituted with 1-4-OH groups,

or

L 2 is —C(O)—, and

each R 6 is independently selected from —NR 16 R 17 , —OR 13 , C(O)OR 13 , C 1 -C 6 alkyl, C 3 -C 8 cycloalkyl, and C 1 -C 6 alkyl substituted with 1-4 OH groups,

wherein the C 3 -C 8 cycloalkyl of R 6 is optionally substituted with 1-4 substituents selected from C 1 -C 6 alkyl and C 1 -C 6 alkyl substituted with 1-4-OH groups.

6. The compound of claim 5 , wherein

L 2 is a bond, and

each R 6 is independently selected from H, S(O)R 13 , SO 2 R 13 , SO 2 NR 16 R 17 , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, cyclopropyl, cyclohexyl, cycloheptyl,

tetrazolyl, piperidinyl, dioxolanyl, tetrahyrdopyanyl, a cyclic sulfinyl selected from

a cyclic sulfonyl selected from

and a C 1 -C 6 alkyl substituted with 1-4 OH groups,

 wherein the cyclopropyl, cyclohexyl, cycloheptyl, tetrazolyl, piperidinyl, dioxolanyl, tetrahyrdopyanyl, cyclic sulfinyl, and cyclic sulfonyl of R 6 are optionally substituted with 1-4 substituents selected from C 1 -C 6 alkyl and C 1 -C 6 alkyl substituted with 1-4-OH groups;

or

L 2 is (CR 14 R 14 ) m —, —(CR 14 R 15 ) m —, —C(O)(CR 14 R 14 ) m —, or —C(O)(CR 14 R 15 ) m , and

each R 6 is independently selected from S(O)R 13 , SO 2 R 13 , N 16 R 17 , OR 13 , —C(O)OR 13 , C(O)NR 16 R 17 , C 1 -C 6 haloalkyl, C 1 -C 6 alkyl substituted with 1-4 OH groups, cyclopropyl, cyclohexyl, cycloheptyl, tetrazolyl, piperidinyl, dioxolanyl, tetrahyrdopyanyl, and a C 1 -C 6 alkyl substituted with 1-4 OH groups,

wherein the cyclopropyl, cyclohexyl, cycloheptyl, tetrazolyl, piperidinyl, dioxolanyl, tetrahyrdopyanyl of R 6 are optionally substituted with 1-4 substituents selected from C 1 -C 6 alkyl and C 1 -C 6 alkyl substituted with 1-4-OH groups,

or

L 2 is —C(O)—, and

each R 6 is independently selected from —NR 16 R 17 , —OR 13 , C(O)OR 13 , C 1 -C 6 alkyl, cyclopropyl, cyclohexyl, cycloheptyl, and a C 1 -C 6 alkyl substituted with 1-4 OH groups,

wherein the cyclopropyl, cyclohexyl, cycloheptyl of R 6 is optionally substituted with 1-4 substituents selected from C 1 -C 6 alkyl and C 1 -C 6 alkyl substituted with 1-4-OH groups.

7. The compound of claim 6 , wherein each R 9 is independently selected from H, CN, F, Cl, methyl, ethyl, isopropyl, tert-butyl, —CF 3 , —OCH 3 , —OCH 2 CH 3 , —OCF 3 , L 3 OR 13 , L 3 NR 16 R 17 , L 3 R 13 , L 3 R 14 , pyridinyl, pyrimidinyl, thiazolyl, furanyl, tetrazolyl and phenyl optionally substituted with 1 to 2 substituents selected from CN, L 3 NR 16 R 17 and OR 13 ,

wherein the pyridinyl, pyrimidinyl, thiazolyl, furanyl and tetrazolyl are optionally substituted with 1 to 2 substituents selected from C 1 -C 6 alkyl, L 3 NR 16 R 17 and L 3 OR 13 .

8. The compound of claim 7 , wherein each R 13 is independently selected from H, C 1 -C 6 alkyl and heteroaryl,

where the heteroaryl of R 13 are optionally substituted with 1 to 3 substituents selected from C 1 -C 6 alkyl and C 1 -C 6 alkyl substituted with 1-4-OH groups.

9. The compound of claim 8 , wherein each R 13 is independently selected from H, methyl, ethyl, isopropyl, tert-butyl and pyrazolyl.

10. The compound of claim 9 , wherein each R 14 and R 15 are independently selected from H, F methyl ethyl, OH and CN.

11. The compound of claim 10 , wherein each R 16 and R 17 are independently selected from H, methyl, ethyl and C 1 -C 6 alkyl substituted with 1-4-OH groups.

12. The compound of claim 11 , wherein R 2 and R 3 are each H, and R 4 is H or —C(O)N(CH 3 ) 2 .

13. The compound of claim 12 , wherein each R 5 is independently selected from H, Cl, F, CN, methyl, methoxy, —OCF 3 , —CH 2 OH, —C(O)OH, —CH 2 N(CH 3 ) 2 and —C(O)NHCH 3 .

14. The compound of claim 13 , wherein each R 5 is —Cl or methyl.

15. The compound of claim 14 , wherein Y 1 is CH; Y 2 is CH; Y 3 is CH; Y 4 is N; Y 5 is CH; Y 6 is N and Y 7 is N.

16. The compound of claim 1 , selected from

4-{5-[(6-methanesulfonyl-5,6,7,8-tetrahydro-2,6-naphthyridin-1-yl)amino]-2-methylphenyl}benzonitrile;

N-[4-chloro-3-(5-phenyl-1H-imidazol-2-yl)phenyl]-6-methanesulfonyl-5,6,7,8-tetrahydro-2,6-naphthyridin-1-amine;

6-methanesulfonyl-N-[4-methyl-3-(5-methylpyridin-2-yl)phenyl]-5,6,7,8-tetrahydro-2,6-naphthyridin-1-amine;

N-[3-(5-fluoropyridin-2-yl)-4-methylphenyl]-6-methanesulfonyl-5,6,7,8-tetrahydro-2,6-naphthyridin-1-amine;

7-methanesulfonyl-N-[4-methyl-3-(5-methylpyridin-2-yl)phenyl]-5H,6H,7H,8H-pyrido[3,4-d]pyrimidin-4-amine;

4-(4-{[4-methyl-3-(5-methylpyridin-2-yl)phenyl]amino}-5H,6H,7H,8H-pyrido[3,4-d]pyrimidin-7-yl)-thiane-1,1-dione;

3-(4-{[4-methyl-3-(5-methylpyridin-2-yl)phenyl]amino}-5H,6H,7H,8H-pyrido[3,4-d]pyrimidin-7-yl)-thietane-1,1-dione;

N-[4-methyl-3-(5-methylpyridin-2-yl)phenyl]-7-(propane-2-sulfonyl)-5H,6H,7H,8H-pyrido[3,4-d]pyrimidin-4-amine;

7-(ethanesulfonyl)-N-[4-methyl-3-(5-methylpyridin-2-yl)phenyl]-5H,6H,7H,8H-pyrido[3,4-d]pyrimidin-4-amine;

N-[3-(5-fluoropyridin-2-yl)-4-methylphenyl]-7-methanesulfonyl-5H,6H,7H,8H-pyrido[3,4-d]pyrimidin-4-amine;

7-(ethanesulfonyl)-N-[3-(5-fluoropyridin-2-yl)-4-methylphenyl]-5H,6H,7H,8H-pyrido[3,4-d]pyrimidin-4-amine;

N-[3-(5-fluoropyridin-2-yl)-4-methylphenyl]-7-(propane-2-sulfonyl)-5H,6H,7H,8H-pyrido[3,4-d]pyrimidin-4-amine;

3-(4-{[3-(isoquinolin-3-yl)-4-methylphenyl]amino}-5H,6H,7H,8H-pyrido[3,4-d]pyrimidin-7-yl)-thietane-1,1-dione;

N-[3-(isoquinolin-3-yl)-4-methylphenyl]-7-(2-methanesulfonylethyl)-5H,6H,7H,8H-pyrido[3,4-d]pyrimidin-4-amine;

N-[3-(isoquinolin-3-yl)-4-methylphenyl]-7-methanesulfonyl-5H,6H,7H,8H-pyrido[3,4-d]pyrimidin-4-amine;

N-[3-(isoquinolin-3-yl)-4-methylphenyl]-6-methanesulfonyl-5,6,7,8-tetrahydro-2,6-naphthyridin-1-amine;

3-(5-{[3-(isoquinolin-3-yl)-4-methylphenyl]amino}-1,2,3,4-tetrahydro-2,6-naphthyridin-2-yl)-thietane-1,1-dione;

4-(4-{[3-(isoquinolin-3-yl)-4-methylphenyl]amino}-5H,6H,7H,8H-pyrido[3,4-d]pyrimidin-7-yl)-thiane-1,1-dione, and

4-(5-{[3-(isoquinolin-3-yl)-4-methylphenyl]amino}-1,2,3,4-tetrahydro-2,6-naphthyridin-2-yl)-thiane-1,1-dione.

17. A pharmaceutical compositions for treating a disease associated with the hedgehog pathway comprising a therapeutically effective amount of a compound of Formula (I) of claim 1 and one or more pharmaceutically acceptable excipients.

18. A compound selected from:

5-[(6-methanesulfonyl-5,6,7,8-tetrahydro-2,6-naphthyridin-1-yl)amino]-2-methyl-N-phenylbenzamide;

and

5-({7-methanesulfonyl-5H,6H,7H,8H-pyrido[3,4-d]pyrimidin-4-yl}amino)-2-methyl-N-phenylbenzamide.