Biaryl compositions and methods for modulating a kinase cascade

1. A compound of formula (A):

or a pharmaceutically acceptable salt or solvate thereof, wherein:

X a is CR a or N;

X b is CR b or N;

X c is CR c or N;

X a is CR d or N;

R a is H, halogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, or C 2 -C 6 alkynyl;

R b is H, halogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, or C 2 -C 6 alkynyl;

R c is H, halogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, or C 2 -C 6 alkynyl;

R d is H, halogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, or C 2 -C 6 alkynyl;

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);

R 3 is H or O—(C 1 -C 6 alkyl);

R 4 is (a) H, (b) halogen, (c) OH, (d) COOH, (e) CONH 2 , (f) NHCOR 101 , (g) NR 101 COR 102 , (h) S(O) t R 101 , (i) C 1 -C 6 alkyl, (j) C 2 -C 6 alkenyl, (k) C 2 -C 6 alkynyl, (l) O—(C 1 -C 6 alkyl), (m) O—(C 2 -C 6 alkenyl), (n) O—(C 2 -C 6 alkynyl), (o) COO—(C 1 -C 6 alkyl), (p) COO—(C 2 -C 6 alkenyl), (q) COO—(C 2 -C 6 alkynyl), (r) CONH—(C 1 -C 6 alkyl), (s) CONH—(C 2 -C 6 alkenyl), (t) CONH—(C 2 -C 6 alkynyl), (u) CON(C 1 -C 6 alkyl) 2 , (v) CON(C 2 -C 6 alkenyl) 2 , (w) CON(C 2 -C 6 alkynyl) 2 , (x) (C 1 -C 6 alkyl) u -NH 2 , (y) (C 2 -C 6 alkenyl) u -NH 2 , (z) (C 2 -C 6 alkynyl) u -NH 2 , (aa1) (C 1 -C 6 alkyl) v -NH(C 1 -C 6 alkyl), (aa2) (C 1 -C 6 alkyl) v -NH(C 2 -C 6 alkenyl), (aa3) (C 1 -C 6 alkyl) v -NH(C 2 -C 6 alkynyl), (bb1) (C 2 -C 6 alkenyl) v —NH(C 1 -C 6 alkyl), (bb2) (C 2 -C 6 alkenyl) v —NH(C 2 -C 6 alkenyl), (bb3) (C 2 -C 6 alkenyl) v —NH(C 2 -C 6 alkynyl), (cc1) (C 2 -C 6 alkynyl) v -NH(C 1 -C 6 alkyl), (cc2) (C 2 -C 6 alkynyl) v -NH(C 2 -C 6 alkenyl), (cc3) (C 2 -C 6 alkynyl) v -NH(C 2 -C 6 alkynyl), (dd1) (C 1 -C 6 alkyl) w -N(C 1 -C 6 alkyl) 2 , (dd2) (C 1 -C 6 alkyl) w -N(C 2 -C 6 alkenyl) 2 , (dd3) (C 1 -C 6 alkyl) w -N(C 2 -C 6 alkynyl) 2 , (ee1) (C 2 -C 6 alkenyl) w -N(C 1 -C 6 alkyl) 2 , (ee2) (C 2 -C 6 alkenyl) w -N(C 2 -C 6 alkenyl) 2 , (ee3) (C 2 -C 6 alkenyl) w -N(C 2 -C 6 alkynyl) 2 , (ff1) (C 2 -C 6 alkynyl) w -N(C 1 -C 6 alkyl) 2 , (ff2) (C 2 -C 6 alkynyl) w -N(C 2 -C 6 alkenyl) 2 , (ff3) (C 2 -C 6 alkynyl) w -N(C 2 -C 6 alkynyl) 2 , (gg) 3-8 membered saturated, unsaturated, or partially saturated carbocycle, or (hh) 3-8 membered saturated, unsaturated, or partially saturated heterocycle, wherein each of (i)-(hh) is optionally substituted with one or more R 7 ;

is morpholinyl;

represents an aromatic, saturated, unsaturated, or partially saturated carbocycle comprising one or two 3-8 membered rings, or an aromatic, saturated, unsaturated, or partially saturated heterocycle comprising one or two 5-8 membered rings and one or more heteroatoms selected from N, O and S, wherein the two 3-8 membered rings or the two 5-8 membered rings can form a fused or bridged ring structure;

each R 5 is independently C 1 -C 6 alkyl;

each R 6 is independently (a) halogen, (b) OH, (e) CN, (g) C 1 -C 6 alkyl, or (j) O—(C 1 -C 6 alkyl, wherein each of (g) or (j) is optionally substituted with one or more R 9 ;

each R 7 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 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 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;

R 101 and R 102 are each independently H, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, or C 2 -C 6 alkynyl;

R 11 is H, halogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, or C 2 -C 6 alkynyl;

R 12 is H, halogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, or C 2 -C 6 alkynyl;

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

n is 0, 1, 2, 3, 4, 5, or 6;

t is 0, 1, or 2;

u is 0 or 1;

v is 0 or 1; and

w is 0 or 1.

2. The compound of claim 1 , wherein X a is N; and X b is CR b .

3. The compound of claim 1 , wherein X c is CR c ; and X d is CR d .

4. The compound of claim 1 , wherein R 3 is O—(C 1 -C 6 alkyl).

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

6. The compound of claim 1 , wherein R 5 is in the S-configuration.

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

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

9. The compound of claim 1 , wherein the compound is of formula (I):

or a pharmaceutically acceptable salt or solvate thereof, wherein:

X a is CR a or N;

X b is CR b or N;

X c is CR c or N;

X d is CR d or N;

R a is H, halogen, or C 1 -C 6 alkyl;

R b is H, halogen, or C 1 -C 6 alkyl;

R c is H, halogen, or C 1 -C 6 alkyl;

R d is H, halogen, or C 1 -C 6 alkyl;

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

R 3 is H or O—(C 1 -C 6 alkyl);

R 4 is (a) H, (b) halogen, (c) OH, (d) COOH, (e) CONH 2 , (f) NHCOR 101 , (g) NR 101 COR 102 , (h) S(O) t R 101 , (i) C 1 -C 6 alkyl, (j) O—(C 1 -C 6 alkyl), (k) COO—(C 1 -C 6 alkyl), (l) CONH—(C 1 -C 6 alkyl), (m) CON(C 1 -C 6 alkyl) 2 , (n) (C 1 -C 6 alkyl) u -NH 2 , (o) (C 1 -C 6 alkyl) v -NH(C 1 -C 6 alkyl), (p) (C 1 -C 6 alkyl) w -N(C 1 -C 6 alkyl) 2 , or (q) 5-6 membered saturated, unsaturated, or partially saturated carbocycle, wherein each of (i)-(q) is optionally substituted with one or more R 7 ;

{circle around (A)} is morpholinyl;

{circle around (B)} represents a 5-6 membered aromatic, saturated, unsaturated, or partially saturated carbocycle, or a 5-6 membered aromatic, saturated, unsaturated, or partially saturated heterocycle containing one or more heteroatoms selected from N, O and S;

each R 5 is independently C 1 -C 6 alkyl;

each R 6 is independently (a) halogen, (b) OH, (c) C 1 -C 6 alkyl, (e) O—(C 1 -C 6 alkyl), or (j) CN, wherein each of (c) or (e) is optionally substituted with one or more R 9 ;

each R 7 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 3 , 5-6 membered saturated, unsaturated, or partially saturated carbocycle, or 5-6 membered saturated, unsaturated, or partially saturated heterocycle containing 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 3 , 5-6 membered saturated, unsaturated, or partially saturated carbocycle, or 5-6 membered saturated, unsaturated, or partially saturated heterocycle containing one or more heteroatoms selected from N, O and S;

R 101 and R 102 are each independently H or C 1 -C 6 alkyl;

R 11 is H, halogen, or C 1 -C 6 alkyl;

R 12 is H, halogen, or C 1 -C 6 alkyl;

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

n is 0, 1, 2, 3, 4, 5, or 6;

t is 0, 1, or 2;

u is 0 or 1;

v is 0 or 1; and

w is 0 or 1.

10. The compound of claim 1 , wherein the compound is of formula (II) or (III):

or a pharmaceutically acceptable salt or solvate thereof, wherein n1 is 0, 1, 2, 3, 4, or 5.

11. The compound of claim 1 , wherein the compound is of the following formula:

or a pharmaceutically acceptable salt or solvate thereof.

12. The compound of claim 1 , wherein the compound is of the following formula:

or a pharmaceutically acceptable salt or solvate thereof, wherein:

n2 is 0, 1, 2, or 3;

n3 is 0, 1, or 2; and

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; and

R 61 is H or R 6 .

13. The compound of claim 12 , wherein R 5 is methyl.

14. The compound of claim 12 , wherein R 6 is halogen, C 1 -C 6 alkyl, O—C 1 -C 6 alkyl, or CN.

15. The compound of claim 12 , wherein R 6 is halogen.

16. The compound of claim 12 , wherein R 3 is O—(C 1 -C 6 alkyl).

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

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

or a pharmaceutically acceptable salt or solvate thereof.