Inhibitors of c-Jun N-terminal kinases (JNK) and other protein kinases

1. A compound of formula I or II:

or a pharmaceutically acceptable salt thereof, wherein:

each W is nitrogen;

each R 1 , R 2 , and R 3 is independently selected from halogen, QR, Q (n) CN, Q (n) NO 2 , or Q (n) Ar 2 ; wherein:

R 1 and R 2 or R 2 and R 3 are optionally taken together to form a 4-8 membered saturated, partially unsaturated, or fully unsaturated ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur;

n is zero or one;

Q is a C 1-4 alkylidene chain wherein one methylene unit of Q is optionally replaced by O, S, NR, NRCO, NRCONR, NRCO 2 , CO, CO 2 , CONR, OC(O)NR, SO 2 , SO 2 NR, NRSO 2 , NRSO 2 NR, C(O)C(O), or C(O)CH 2 C(O);

each R is independently selected from hydrogen or an optionally substituted C 1 -C 4 aliphatic, wherein:

two R bound to the same nitrogen atom are optionally taken together with the nitrogen atom to form a 3-7 membered saturated, partially unsaturated, or fully unsaturated ring having 1-2 additional heteroatoms independently selected from nitrogen, oxygen, or sulfur;

R 4 is Ar 1 , T-Ar 2 , or T (n) -Ar 3 ;

T is a C 1-2 alkylidene chain wherein one methylene unit of T is optionally replaced by O, NR, NRCO, NRCONR, NRCO 2 , CO, CO 2 , CONR, OC(O)NR, SO 2 , SO 2 NR, NRSO 2 , NRSO 2 NR, C(O)C(O), or C(O)CH 2 C(O);

Ar 1 is a 5-6 membered monocyclic or 8-10 membered bicyclic saturated, partially unsaturated, or fully unsaturated ring system; wherein:

Ar 1 is optionally substituted with up to five substituents, wherein the first substituent is selected from R x or R 5 and wherein any additional substituents are independently selected from R 5 ;

each R x is independently selected from a 5-6 membered aryl ring having 0-3 heteroatoms selected from nitrogen, oxygen, or sulfur, wherein:

R x is optionally substituted with 1-3 R 5 ;

each R 5 is independently selected from R, halogen, NO 2 , CN, OR, SR, N(R) 2 , NRC(O)R, NRC(O)N(R) 2 , NRCO 2 R, C(O)R, CO 2 R, C(O)N(R) 2 , OC(O)N(R) 2 , SOR, SO 2 R, SO 2 N(R) 2 , NRSO 2 R, NRSO 2 N(R) 2 , C(O)C(O)R, or C(O)CH 2 C(O)R, wherein when the R 4 group of said compound of formula II is Ar 1 , each R 5 is independently selected from R, halogen, NO 2 , OR, or N(R) 2 ;

Ar 2 is a 5-6 membered saturated, partially unsaturated, or fully unsaturated monocyclic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or an 8-10 membered saturated, partially unsaturated, or fully unsaturated bicyclic ring system having 0-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur; wherein:

Ar 2 is optionally substituted with up to five substituents, wherein the first substituent is selected from R x or R 5 and wherein any additional substituents are independently selected from R 5 ;

Ar 3 is a 6-membered aryl ring having 0-2 nitrogens, wherein:

Ar 3 is substituted with one Z-R 6 group and optionally substituted with 1-3 R 5 ;

Z is a C 1 -C 6 alkylidene chain wherein up to two non-adjacent methylene units of Z are optionally replaced by CO 2 , COCO, CONR, OCONR, NRNR, NRNRCO, NRCO, NRCO 2 , NRCONR, SO, SO 2 , NRSO 2 , SO 2 NR, NRSO 2 NR, O, S, or NR; and

R 6 is selected from Ar 2 , R, halogen, NO 2 , CN, OR, SR, N(R) 2 , NRC(O)R, NRC(O)N(R) 2 , NRCO 2 R, C(O)R, CO 2 R, OC(O)R, C(O)N(R) 2 , OC(O)N(R) 2 , SOR, SO 2 R, SO 2 N(R) 2 , NRSO 2 R, NRSO 2 N(R) 2 , C(O)C(O)R, or C(O)CH 2 C(O)R;

provided that:

(i) when R 4 is phenyl substituted with at least two OR, wherein R is not hydrogen, then the at least two OR occupy positions on the phenyl ring other than simultaneously meta and para; and

(ii) said compound is other than a compound of formula III

wherein:

A is a phenyl ring substituted with one or more groups selected from halogen, CN, OC(O)NH 2 , CO 2 R 10 , COR 10 , SO 2 N(R 10 ) 2 , N(R 10 ) 2 , OR 10 , or fluoro-alkyl, wherein each R 10 is independently selected from hydrogen or a C 1 -C 7 alkyl group optionally substituted with NH 2 , NH(C 1 -C 7 alkyl), or N(C 1 -C 7 alkyl) 2 ; and

B is selected from halogen, CN, OC(O)NH 2 , CO 2 R 10 , COR 10 , SO 2 N(R 10 ) 2 , N(R 10 ) 2 , OR 10 , fluoro-(C 1 -C 7 alkoxy), or fluoro-(C 1 -C 7 alkyl).

2. The compound according to claim 1 , wherein:

R 1 , R 2 , and R 3 are independently selected from halogen, QR or QAr 2 ;

Q is a C 1-3 alkylidene chain wherein one methylene unit of Q is optionally replaced by —O—, —S—, —NHCO—, or —NR—; and

Ar 2 is an optionally substituted 5-6 membered saturated, partially unsaturated, or fully unsaturated ring having 0-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

3. The compound according to claim 2 , wherein:

R 1 , R 2 , and R 3 are independently selected from OH, OCH 3 , OCH 2 CH 3 , NHCOMe, NH 2 , NH(C 1-4 aliphatic), N(C 1-4 aliphatic) 2 , O(CH 2 ) 2 morpholin-4-yl, O(CH 2 ) 2 NH 2 , O(CH 2 ) 2 NH(C 1-4 aliphatic), O(CH 2 ) 2 N(C 1-4 aliphatic) 2 , bromo, chloro, or fluoro; or

R 1 and R 2 or R 2 and R 3 are taken together to form

and

Ar 2 is selected from morpholin-4-yl, pyrrolidin-1-yl, piperidin-1-yl, thiomorpholin-4-yl, pyrazol-1-yl, or imidazol-1-yl.

4. The compound according to claim 1 , wherein:

R 4 is selected from:

(a) an optionally substituted 6-membered saturated, partially unsaturated, or aryl ring having 0-3 nitrogens;

(b) an optionally substituted 9-10 membered bicyclic aryl ring having 0-2 nitrogens; or

(c) an optionally substituted 5 membered heteroaryl ring having 2-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

5. The compound according to claim 4 , wherein said ring is substituted with 1-3 groups independently selected from R x , R, halogen, NO 2 , OR, N(R) 2 , or Z-R 6 .

6. The compound according to claim 5 , wherein R x is selected from a phenyl, pyridyl, or pyrimidinyl ring optionally substituted with 1-2 R 5 .

7. The compound according to claim 5 , wherein Z is a C 1-4 alkylidene chain wherein one methylene unit of Z is optionally replaced by —O—, —S—, —SO 2 —, or —NH—.

8. The compound according to claim 4 , wherein said ring is selected from a substituted phenyl, cyclohexyl, naphthyl, pyridyl, pyrimidinyl, triazinyl, thiazolyl, thiadiazolyl, pyrazolyl, isoxazolyl, indazolyl, or benzimidazolyl ring.

9. The compound according to claim 8 , wherein said ring is optionally substituted with 1-2 groups independently selected from chloro, fluoro, bromo, methyl, ethyl, t-butyl, isopropyl, cyclopropyl, nitro, OMe, OEt, CF 3 , NH 2 , benzyl, benzyloxy, OH, methylene dioxy, SO 2 NH 2 , phenoxy, O-pyridinyl, SO 2 phenyl, nitrophenoxy, aminophenoxy, S-dimethylpyrimidine, NHphenyl, NH-methoxyphenyl, pyridinyl, aminophenyl, phenol, chloro-fluoro-phenyl, dimethylaminophenyl, CF 3 -phenyl, dimethylphenyl, chlorophenyl, fluorophenyl, methoxyphenoxy, chlorophenoxy, ethoxyphenoxy, or fluorophenoxy.

10. A compound according to claim 1 , selected from the following compounds of formulae I and II:

Compounds of Formula I

No.

R 4

I-1 

I-2 

I-3 

I-4 

I-5 

I-7 

I-8 

I-9 

I-10

I-11

I-12

I-13

I-14

I-15

I-16

I-17

I-21

I-22

I-23

I-24

I-25

I-26

I-27

I-28

I-29

I-30

I-31

I-32

I-33

I-34

I-35

I-36

I-37

I-38

I-39

I-44

I-49

I-53

I-56

I-61

I-62

I-63

I-65

I-66

I-67

I-68

I-69

I-70

I-71

I-72

I-73

I-74

I-75

I-76

I-77

I-78

I-79

I-81

I-82

I-83

I-84

I-85

I-86

I-87

I-88

I-89

I-90

I-91

I-92

I-93

I-94

Compounds of Formula II

No.

R 4

II-1 

II-2 

II-3 

II-4 

II-7 

II-8 

II-9 

II-11

II-12

II-13

II-14

II-15

II-16

II-17

II-18

II-19

II-20

II-21

II-22

II-23

II-24

II-25

II-26

II-27

II-28

II-29

II-30

II-31

II-32

II-33

II-34

II-35

II-36

II-37

II-38

II-39

II-40

II-41

II-42

II-43

II-44

II-45

II-46

II-47

II-48

II-49

II-50

II-51

II-52

II-53

II-54

II-55

II-56

II-57

II-58

II-59

II-60

II-61

II-62

II-63

II-64

II-65

II-66

II-67

II-68

II-69

II-70

II-71

II-72

II-73

II-74

II-75

II-76

II-77

II-78

II-79

II-80

II-81

II-82

II-83

II-84

11. A composition comprising a compound according to any of claims 1 - 10 and a pharmaceutically acceptable carrier, adjuvant, or vehicle.

12. The composition according to claim 11 , additionally comprising an additional therapeutic agent selected from an anti-proliferative agent, an anti-inflammatory agent, an immunomodulatory agent, a neurotrophic factor, an agent for treating cardiovascular disease, an agent for treating liver disease, an anti-viral agent, an agent for treating blood disorders, an agent for treating diabetes, or an agent for treating immunodeficiency disorders.

13. A compound of formula I or II:

or a pharmaceutically acceptable salt thereof, wherein:

W is nitrogen;

each R 1 , R 2 , and R 3 is independently selected from halogen, QR, Q (n) CN, Q (n) NO 2 , or Q (n) Ar 2 ; wherein:

R 1 and R 2 or R 2 and R 3 are optionally taken together to form a 4-8 membered saturated, partially unsaturated, or fully unsaturated ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur;

n is zero or one;

Q is a C 1-4 alkylidene chain wherein one methylene unit of Q is optionally replaced by O, S, NR, NRCO, NRCONR, NRCO 2 , CO, CO 2 , CONR, OC(O)NR, SO 2 , SO 2 NR, NRSO 2 , NRSO 2 NR, C(O)C(O), or C(O)CH 2 C(O);

each R is independently selected from hydrogen or an optionally substituted C 1 -C 4 aliphatic, wherein:

two R bound to the same nitrogen atom are optionally taken together with the nitrogen atom to form a 3-7 membered saturated, partially unsaturated, or fully unsaturated ring having 1-2 additional heteroatoms independently selected from nitrogen, oxygen, or sulfur;

R 4 is Ar 1 , T-Ar 2 , or T (n) -Ar 3 ;

T is a C 1-2 alkylidene chain wherein one methylene unit of T is optionally replaced by O, NR, NRCO, NRCONR, NRCO 2 , CO, CO 2 , CONR, OC(O)NR, SO 2 , SO 2 NR, NRSO 2 , NRSO 2 NR, C(O)C(O), or C(O)CH 2 C(O);

Ar 1 is a 5-6 membered monocyclic or 8-10 membered bicyclic saturated, partially unsaturated, or fully unsaturated ring system; wherein:

Ar 1 is optionally substituted with up to five substituents, wherein the first substituent is selected from R x or R 5 and wherein any additional substituents are independently selected from R 5 ;

each R x is independently selected from a 5-6 membered aryl ring having 0-3 heteroatoms selected from nitrogen, oxygen, or sulfur, wherein:

R x is optionally substituted with 1-3 R 5 ;

each R 5 is independently selected from R, halogen, NO 2 , CN, SR, N(R) 2 , NRC(O)R, NRC(O)N(R) 2 , NRCO 2 R, C(O)R, CO 2 R, OC(O)N(R) 2 , SOR, SO 2 R, SO 2 N(R) 2 , NRSO 2 R, NRSO 2 N(R) 2 , C(O)C(O)R, or C(O)CH 2 C(O)R;

Ar 2 is a 5-6 membered saturated, partially unsaturated, or fully unsaturated monocyclic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur or an 8-10 membered saturated, partially unsaturated, or fully unsaturated bicyclic ring system having 0-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur; wherein:

Ar 2 is optionally substituted with up to five substituents, wherein the first substituent is selected from R x or R 5 and wherein any additional substituents are independently selected from R 5 ;

Ar 3 is a 6-membered aryl ring having 0-2 nitrogens, wherein:

Ar 3 is substituted with one Z-R 6 group and optionally substituted with 1-3 R 5 ;

Z is a C 1 -C 6 alkylidene chain wherein up to two non-adjacent methylene units of Z are optionally replaced by CO 2 , COCO, CONR, OCONR, NRNR, NRNRCO, NRCO, NRCO 2 , NRCONR, SO, SO 2 , NRSO 2 , SO 2 NR, NRSO 2 NR, S, or NR; and

R 6 is selected from Ar 2 , R, halogen, NO 2 , CN, OR, SR, N(R) 2 , NRC(O)R, NRC(O)N(R) 2 , NRCO 2 R, C(O)R, CO 2 R, OC(O)R, C(O)N(R) 2 , OC(O)N(R) 2 , SOR, SO 2 R, SO 2 N(R) 2 , NRSO 2 R, NRSO 2 N(R) 2 , C(O)C(O)R, or C(O)CH 2 C(O)R;

provided that:

(i) when R 4 is phenyl substituted with two OR, wherein R is not hydrogen, the two OR occupy positions on the phenyl ring other than simultaneously meta and para; and

(ii) said compound is other than a compound of formula III

wherein:

A is a phenyl ring substituted with one or more groups selected from halogen, CN, OC(O)NH 2 , CO 2 R 10 , COR 10 , SO 2 N(R 10 ) 2 , N(R 10 ) 2 , OR 10 , or fluoro-alkyl, wherein each R 10 is independently selected from hydrogen or a C 1 -C 7 alkyl group optionally substituted with NH 2 , NH(C 1 -C 7 alkyl), or N(C 1 -C 7 alkyl) 2 ; and

B is selected from halogen, CN, OC(O)NH 2 , CO 2 R 10 , COR 10 , SO 2 N(R 10 ) 2 , N(R 10 ) 2 , OR 10 , or fluoro-(C 1 -C 7 alkyl).

14. The compound according to claim 13 , wherein:

R 1 , R 2 , and R 3 are independently selected from halogen, QR or QAr 2 ;

Q is a C 1-3 alkylidene chain wherein one methylene unit of Q is optionally replaced by —O—, —S—, —NHCO—, or —NR—; and

Ar 2 is an optionally substituted 5-6 membered saturated, partially unsaturated, or fully unsaturated ring having 0-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

15. The compound according to claim 14 , wherein:

R 1 , R 2 , and R 3 are independently selected from OH, OCH 3 , OCH 2 CH 3 , NHCOMe, NH 2 , NH(C 1-4 aliphatic), N(C 1-4 aliphatic) 2 , O(CH 2 ) 2 morpholin-4-yl, O(CH 2 ) 2 NH 2 , O(CH 2 ) 2 NH(C 1-4 aliphatic), O(CH 2 ) 2 N(C 1-4 aliphatic) 2 , bromo, chloro, or fluoro; or

R 1 and R 2 or R 2 and R 3 are taken together to form

and

Ar 2 is selected from morpholin-4-yl, pyrrolidin-1-yl, piperidin-1-yl, thiomorpholin-4-yl, pyrazol-1-yl, or imidazol-1-yl.

16. The compound according to claim 15 , wherein:

R 4 is selected from:

(a) an optionally substituted 6-membered saturated, partially unsaturated, or aryl ring having 0-3 nitrogens;

(b) an optionally substituted 9-10 membered bicyclic aryl ring having 0-2 nitrogens; or

(c) an optionally substituted 5 membered heteroaryl ring having 2-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

17. The compound according to claim 16 , wherein said ring is substituted with 1-3 groups independently selected from R x , R, halogen, NO 2 , N(R) 2 , or Z-R 6 .

18. The compound according to claim 17 , wherein R x is selected from a phenyl, pyridyl, or pyrimidinyl ring optionally substituted with 1-2 R 5 .

19. A composition comprising a compound according to claim 13 and a pharmaceutically acceptable carrier, adjuvant, or vehicle.

20. The composition according to claim 19 , additionally comprising an additional therapeutic agent selected from an anti-proliferative agent, an anti-inflammatory agent, an immunomodulatory agent, a neurotrophic factor, an agent for treating cardiovascular disease, an agent for treating liver disease, an anti-viral agent, an agent for treating blood disorders, an agent for treating diabetes, or an agent for treating immunodeficiency disorders.

21. A compound of formula I or II:

or a pharmaceutically acceptable salt thereof, wherein:

W is nitrogen;

each R 1 , R 2 , and R 3 is independently selected from halogen, QR, Q (n) CN, Q (n) NO 2 , or Q (n) Ar 2 ; wherein:

R 1 and R 2 or R 2 and R 3 are optionally taken together to form a 4-8 membered saturated, partially unsaturated, or fully unsaturated ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur;

n is zero or one;

Q is a C 1-4 alkylidene chain wherein one methylene unit of Q is optionally replaced by O, S, NR, NRCO, NRCONR, NRCCO 2 , CO, CO 2 , CONR, OC(O)NR, SO 2 , SO 2 NR, NRSO 2 , NRSO 2 NR, C(O)C(O), or C(O)CH 2 C(O);

each R is independently selected from hydrogen or an optionally substituted C 1 -C 4 aliphatic, wherein:

two R bound to the same nitrogen atom are optionally taken together with the nitrogen atom to form a 3-7 membered saturated, partially unsaturated, or fully unsaturated ring having 1-2 additional heteroatoms independently selected from nitrogen, oxygen, or sulfur;

R 4 selected from:

Ar 2 is a 5-6 membered saturated, partially unsaturated, or fully unsaturated monocyclic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or an 8-10 membered saturated, partially unsaturated, or fully unsaturated bicyclic ring system having 0-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur; wherein:

Ar 2 is optionally substituted with up to five substituents, wherein the first substituent is selected from R x or R 5 and wherein any additional substituents are independently selected from R 5 ;

each R x is independently selected from a 5-6 membered aryl ring having 0-3 heteroatoms selected from nitrogen, oxygen, or sulfur, wherein:

R x is optionally substituted with 1-3 R 5 ;

each R 5 is independently selected from R, halogen, NO 2 , CN, SR, N(R) 2 , NRC(O)R, NRC(O)N(R) 2 , NRCO 2 R, C(O)R, CO 2 R, OC(O)N(R) 2 , SOR, SO 2 R, SO 2 N(R) 2 , NRSO 2 R, NRSO 2 N(R) 2 , C(O)C(O)R, or C(O)CH 2 C(O)R;

provided that:

(i) when R 4 is phenyl substituted with two OR, wherein R is not hydrogen, the two OR occupy positions on the phenyl ring other than simultaneously meta and para; and

(ii) said compound is other than a compound of formula III

wherein:

A is a phenyl ring substituted with one or more groups selected from halogen, CN, OC(O)NH 2 , CO 2 R 10 , COR 10 , SO 2 N(R 10 ) 2 , N(R 10 ) 2 , OR 10 , or fluoro-alkyl, wherein

each R 10 is independently selected from hydrogen or a C 1 -C 7 alkyl group optionally substituted with NH 2 , NH(C 1 -C 7 alkyl), or N(C 1 -C 7 alkyl) 2 ; and

B is selected from halogen, CN, OC(O)NH 2 , CO 2 R 10 , COR 10 , SO 2 N(R 10 ) 2 , N(R 10 ) 2 , OR 10 , or fluoro-(C 1 -C 7 alkyl).

22. The compound according to claim 21 , wherein:

R 1 , R 2 , and R 3 are independently selected from halogen, QR or QAr 2 ;

Q is a C 1-3 alkylidene chain wherein one methylene unit of Q is optionally replaced by —O—, —S—, —NHCO—, or —NR—; and

Ar 2 is an optionally substituted 5-6 membered saturated, partially unsaturated, or fully unsaturated ring having 0-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

23. The compound according to claim 22 , wherein:

R 1 , R 2 , and R 3 are independently selected from OH, OCH 3 , OCH 2 CH 3 , NHCOMe, NH 2 , NH(C 1-4 aliphatic), N(C 1-4 aliphatic) 2 , O(CH 2 ) 2 morpholin-4-yl, O(CH 2 ) 2 NH 2 , O(CH 2 ) 2 NH(C 1-4 aliphatic), O(CH 2 ) 2 N(C 1-4 aliphatic) 2 , bromo, chloro, or fluoro; or

R 1 and R 2 or R 2 and R 3 are taken together to form

and

Ar 2 is selected from morpholin-4-yl, pyrrolidin-1-yl, piperidin-1-yl, thiomorpholin-4-yl, pyrazol-1-yl, or imidazol-1-yl.

24. A composition comprising a compound according to claim 21 and a pharmaceutically acceptable carrier, adjuvant, or vehicle.

25. The composition according to claim 24 , additionally comprising an additional therapeutic agent selected from anti-proliferative agent, an anti-inflammatory agent, an immunomodulatory agent, a neurotrophic factor, an agent for treating cardiovascular disease, an agent for treating liver disease, an anti-viral agent, an agent for treating blood disorders, an agent for treating diabetes, or an agent for treating immunodeficiency disorders.