Biaryl compositions and methods for modulating a kinase cascade

1. A compound of formula (VIIa), (VIIb), (VIIc), (VIId), or (VIIe):

or a pharmaceutically acceptable salt or solvate thereof, wherein:

n2 is 0, 1, 2, or 3;

n3 is 0, 1, or 2;

A 1 , A 2 , and A 3 are each independently CR 61 or N, and wherein only one of A 1 , A 2 , and A 3 is N;

each R 61 is independently H or R 6 ;

R 1 and R 2 are each independently H, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, or O—(C 1 -C 6 alkyl);

alternatively, R 1 and R 2 , together with the carbon atom to which they are attached, form a 3-8 membered saturated, unsaturated, or partially saturated carbocycle, or a saturated, unsaturated, or partially saturated heterocycle comprising one or two 5-7 membered rings and one or more heteroatoms selected from N, O, and S;

alternatively, one of R 1 and R 2 , together with the carbon atom to which R 1 or R 2 is attached and the adjacent

ring, form a 7-12 membered saturated, unsaturated, or partially saturated carbocycle, or a 7-12 membered saturated, unsaturated, or partially saturated heterocycle comprising one or more heteroatoms selected from N, O and S;

R 3 is C 1 -C 6 alkyl;

R 5 is (a) halogen, (b) OH, (c) CONH 2 , (d) COOH, (e) CN, (f) N 3 , (g) C 1 -C 6 alkyl, (h) C 2 -C 6 alkenyl, (i) C 2 -C 6 alkynyl, (j) O—(C 1 -C 6 alkyl), (k) O—(C 2 -C 6 alkenyl), (l) O—(C 2 -C 6 alkynyl), (m) COO—(C 1 -C 6 alkyl), (n) COO—(C 2 -C 6 alkenyl), (o) COO—(C 2 -C 6 alkynyl), (p) CONH—(C 1 -C 6 alkyl), (q) CONH—(C 2 -C 6 alkenyl), (r) CONH—(C 2 -C 6 alkynyl), (s) CON(C 1 -C 6 alkyl) 2 , (t) CON(C 2 -C 6 alkenyl) 2 , (u) CON(C 2 -C 6 alkenyl) 2 , (v1) (C 1 -C 6 alkyl) v -NH(C 1 -C 6 alkyl), (v2) (C 1 -C 6 alkyl) v -NH(C 2 -C 6 alkenyl), (v3) (C 1 -C 6 alkyl) v -NH(C 2 -C 6 alkynyl), (w1) (C 2 -C 6 alkenyl) v -NH(C 1 -C 6 alkyl), (w2) (C 2 -C 6 alkenyl) v -NH(C 2 -C 6 alkenyl), (w3) (C 2 -C 6 alkenyl) v -NH(C 2 -C 6 alkynyl), (x1) (C 2 -C 6 alkynyl) v -NH(C 1 -C 6 alkyl), (x2) (C 2 -C 6 alkynyl) v -NH(C 2 -C 6 alkenyl), (x3) (C 2 -C 6 alkynyl) v -NH(C 2 -C 6 alkynyl), (y1) (C 1 -C 6 alkyl) w -N(C 1 -C 6 alkyl) 2 , (y2) (C 1 -C 6 alkyl) w -N(C 2 -C 6 alkenyl) 2 , (y3) (C 1 -C 6 alkyl) w -N(C 2 -C 6 alkynyl) 2 , (z1) (C 2 -C 6 alkenyl) w -N(C 1 -C 6 alkyl) 2 , (z2) (C 2 -C 6 alkenyl) w -N(C 2 -C 6 alkenyl) 2 , (z3) (C 2 -C 6 alkenyl) w -N(C 2 -C 6 alkynyl) 2 , (aa1) (C 2 -C 6 alkynyl) w -N(C 1 -C 6 alkyl) 2 , (aa2) (C 2 -C 6 alkynyl) w -N(C 2 -C 6 alkenyl) 2 , (aa3) (C 2 -C 6 alkynyl) w -N(C 2 -C 6 alkenyl) 2 , (bb) S—(C 1 -C 6 alkyl), (cc) S(O)—(C 1 -C 6 alkyl), (dd) S(O) 2 —(C 1 -C 6 alkyl), (ee) S—(C 2 -C 6 alkenyl), (ff) S(O)—(C 2 -C 6 alkenyl), (gg) S(O) 2 —(C 2 -C 6 alkenyl), (hh) S—(C 2 -C 6 alkynyl), (ii) S(O)—(C 2 -C 6 alkynyl), (jj) S(O) 2 —(C 2 -C 6 alkynyl), (kk) an aromatic, saturated, unsaturated, or partially saturated carbocycle comprising one or two 3-8 membered rings, or (ll) an aromatic, saturated, unsaturated, or partially saturated heterocycle comprising one or two 5-7 membered rings and one or more heteroatoms selected from N, O and S, wherein each of (g)-(ll) is optionally substituted with one or more R 8 ;

each R 6 is independently (a) halogen, (b) OH, (c) CONH 2 , (d) COOH, (e) CN, (f) N 3 , (g) C 1 -C 6 alkyl, (h) C 2 -C 6 alkenyl, (i) C 2 -C 6 alkynyl, (j) O—(C 1 -C 6 alkyl), (k) O—(C 2 -C 6 alkenyl), (l) O—(C 2 -C 6 alkynyl), (m) COO—(C 1 -C 6 alkyl), (n) COO—(C 2 -C 6 alkenyl), (o) COO—(C 2 -C 6 alkynyl), (p) CONH—(C 1 -C 6 alkyl), (q) CONH—(C 2 -C 6 alkenyl), (r) CONH—(C 2 -C 6 alkynyl), (s) CON(C 1 -C 6 alkyl) 2 , (t) CON(C 2 -C 6 alkenyl) 2 , (u) CON(C 2 -C 6 alkynyl) 2 , (v1) (C 1 -C 6 alkyl)-NH(C 1 -C 6 alkyl), (v2) (C 1 -C 6 alkyl) v -NH(C 2 -C 6 alkenyl), (v3) (C 1 -C 6 alkyl) v -NH(C 2 -C 6 alkynyl), (w1) (C 2 -C 6 alkenyl) v -NH(C 1 -C 6 alkyl), (w2) (C 2 -C 6 alkenyl) v -NH(C 2 -C 6 alkenyl), (w3) (C 2 -C 6 alkenyl) v -NH(C 2 -C 6 alkynyl), (x1) (C 2 -C 6 alkynyl) v -NH(C 1 -C 6 alkyl), (x2) (C 2 -C 6 alkynyl) v -NH(C 2 -C 6 alkenyl), (x3) (C 2 -C 6 alkynyl) v -NH(C 2 -C 6 alkynyl), (y1) (C 1 -C 6 alkyl) w -N(C 1 -C 6 alkyl) 2 , (y2) (C 1 -C 6 alkyl) w -N(C 2 -C 6 alkenyl) 2 , (y3) (C 1 -C 6 alkyl) w -N(C 2 -C 6 alkynyl) 2 , (z1) (C 2 -C 6 alkenyl) w -N(C 1 -C 6 alkyl) 2 , (z2) (C 2 -C 6 alkenyl) w -N(C 2 -C 6 alkenyl) 2 , (z3) (C 2 -C 6 alkenyl) w -N(C 2 -C 6 alkynyl) 2 , (aa1) (C 2 -C 6 alkynyl) w -N(C 1 -C 6 alkyl) 2 , (aa2) (C 2 -C 6 alkynyl) w -N(C 2 -C 6 alkenyl) 2 , (aa3) (C 2 -C 6 alkynyl) w -N(C 2 -C 6 alkynyl) 2 , (bb) S—(C 1 -C 6 alkyl), (cc) S(O)—(C 1 -C 6 alkyl), (dd) S(O) 2 —(C 1 -C 6 alkyl), (ee) S—(C 2 -C 6 alkenyl), (ff) S(O)—(C 2 -C 6 alkenyl), (gg) S(O) 2 —(C 2 -C 6 alkenyl), (hh) S—(C 2 -C 6 alkynyl), (ii) S(O)—(C 2 -C 6 alkynyl), (jj) S(O) 2 —(C 2 -C 6 alkynyl), (kk) an aromatic, saturated, unsaturated, or partially saturated carbocycle comprising one or two 3-8 membered rings, or (ll) an aromatic, saturated, unsaturated, or partially saturated heterocycle comprising one or two 5-7 membered rings and one or more heteroatoms selected from N, O and S, wherein each of (g)-(ll) is optionally substituted with one or more R 9 ;

each R 8 is independently halogen, OH, O—(C 1 -C 6 alkyl), C 1 -C 6 haloalkyl, COO—(C 1 -C 6 alkyl), CONH—(C 1 -C 6 alkyl), CON(C 1 -C 6 alkyl) 2 , COOH, CN, N 3 , 5-6 membered saturated, unsaturated, or partially saturated carbocycle, or 5-6 membered saturated, unsaturated, or partially saturated heterocycle comprising one or more heteroatoms selected from N, O and S,

each R 9 is independently halogen, OH, O—(C 1 -C 6 alkyl), COO—(C 1 -C 6 alkyl), CONH—(C 1 -C 6 alkyl), CON(C 1 -C 6 alkyl) 2 , COOH, CN, N, 5-6 membered saturated, unsaturated, or partially saturated carbocycle, or 5-6 membered saturated, unsaturated, or partially saturated heterocycle comprising one or more heteroatoms selected from N, O and S,

v is 0 or 1, and

w is 0 or 1.

2. The compound of claim 1 , wherein R 5 is halogen, C 1 -C 6 alkyl, or O—C 1 -C 6 alkyl.

3. The compound of claim 1 , wherein R 5 is C 1 -C 6 alkyl.

4. The compound of claim 1 , wherein R 5 is methyl.

5. The compound of claim 1 , wherein R 6 is halogen, C 1 -C 6 alkyl, O—C 1 -C 6 alkyl, or CN.

6. The compound of claim 1 , wherein R 6 is halogen.

7. The compound of claim 1 , wherein R 6 is fluoro.

8. The compound of claim 1 , wherein R 6 is at the 2- or 4-position.

9. The compound of claim 1 , wherein R 3 is methyl.

10. The compound of claim 1 , wherein the compound is

or a pharmaceutically acceptable salt or solvate thereof.

11. A pharmaceutical composition comprising the compound of claim 1 , or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable carrier.

12. The compound of claim 1 , wherein the compound is

or a pharmaceutically acceptable salt thereof.

13. The compound of claim 1 , wherein the compound is

14. The compound of claim 1 , wherein the compound is of formula (VIIb):

15. The compound of claim 1 , wherein the compound is of formula (VIIa):

16. The compound of claim 1 , wherein the compound is of formula (VIIc):

17. The compound of claim 1 , wherein the compound is of formula (VIId):

18. The compound of claim 1 , wherein R 1 and R 2 are each H.

19. The compound of claim 1 , wherein n2 is 0 or 1.

20. The compound of claim 1 , wherein n3 is 0 or 1.

21. The compound of claim 1 , selected from the group consisting of

or a pharmaceutically acceptable salt or solvate thereof.

22. The compound of claim 1 , selected from the group consisting of

or a pharmaceutically acceptable salt or solvate thereof.

23. A pharmaceutical composition comprising the compound of claim 13 , or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable carrier.

24. A compound of the following structure:

or a pharmaceutically acceptable salt or solvate thereof.

25. A pharmaceutical composition comprising the compound of claim 24 , or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable carrier.