Substituted pyrido[2,3-d]pyrimidines and methods for their use

1. A compound having the formula:

or a pharmaceutically acceptable salt thereof wherein:

A 4 is N;

X is —C(O)— or —CH 2 —;

R 1 and R 2 are members independently selected from the group consisting of H and (C 1 -C 4 )alkyl;

R 3 is a member selected from the group consisting of hydroxy, (C 1 -C 8 )alkoxy, amino, (C 1 -C 8 )alkylamino, di(C 1 -C 8 )alkylamino, (C 2 -C 8 )heteroalkyl, (C 3 -C 9 )heterocyclyl, (C 1 -C 8 )acylamino, amidino, guanidino, ureido, cyano, heteroaryl, —CONR 9 R 10 and —CO 2 R 11 ;

R 4 is substituted or unsubstituted benzyl, wherein said substituents are selected from the group consisting of halogen, halo(C 1 -C 4 )alkyl, halo(C 1 -C 4 )alkoxy, cyano, nitro and phenyl,

each R 9 , R 10 and R 11 is independently selected from the group consisting of H, (C 1 -C 8 )alkyl, (C 2 -C 8 )heteroalkyl, heteroaryl, aryl, heteroaryl(C 1 -C 6 )alkyl, heteroaryl(C 2 -C 8 )heteroalkyl, aryl(C 1 -C 8 )alkyl and aryl(C 2 -C 8 )heteroalkyl;

R 14 is a substituted or unsubstituted member selected from the group consisting of phenyl, pyridyl thiazolyl, thienyl and pyrimidinyl;

Q is —C(O)—;

L is (C 1 -C 8 )alkylene;

the subscript n is an integer from 0 to 4; and

each R a , is independently selected from the group consisting of halogen, —OR′, —OC(O)R′, —NR′R″, —SR′, —R′, —CN, —NO 2 , —CO 2 R′, —CONR′R″, —C(O)R′—OC(O)NR′R″, —NR″C(O)R′, —NR″C(O) 2 R′, —NR′—C(O)NR″R′″, —NH—C(NH 2 )═NH, —NR′C(NH 2 )═NH, —NH—C(NH 2 )═NR′, —S(O)R′, —S(O) 2 R′, —S(O) 2 NR′R″, —N 3 , —CH(Ph) 2 , perfluoro(C 1 -C 4 )alkoxy and perfluoro(C 1 -C 4 )alkyl, wherein R′, R″ and R′″ are each independently selected from the group consisting of H, (C 1 -C 8 )alkyl, (C 2 -C 8 )heteroalkyl, unsubstituted aryl, unsubstituted heteroaryl, (unsubstituted aryl)-(C 1 -C 4 )alkyl and (unsubstituted aryl)oxy —(C 1 -C 4 )alkyl.

2. The compound of claim 1 , wherein R 14 is selected from the group consisting of substituted phenyl, substituted pyridyl, substituted thiazolyl and substituted thienyl, wherein the substituents are selected from the group consisting of cyano, halogen, (C 1 -C 8 )alkoxy, (C 1 -C 8 )alkyl, (C 2 -C 8 )heteroalkyl, CONH 2 , methylenedioxy and ethylenedioxy.

3. The compound of claim 1 , wherein R 14 is substituted phenyl, wherein the substituents are selected from the group consisting of cyano, halogen, (C 1 -C 8 )alkoxy, (C 1 -C 8 )alkyl, (C 2 -C 8 )heteroalkyl, CONH 2 , methylenedioxy and ethylenedioxy.

4. The compound of claim 1 , wherein R 1 is selected from the group consisting of methyl, ethyl and propyl, and R 2 is hydrogen.

5. The compound of claim 1 , wherein L is (C 1 -C 4 )alkylene.

6. The compound of claim 1 , wherein R 3 is heteroaryl.

7. The compound of claim 1 , wherein R 1 and R 2 are each independently selected from the group consisting of H, methyl and ethyl; R 14 is phenyl; L is methylene, ethylene or propylene; and R 3 is selected from the group consisting of substituted or unsubstituted pyridyl and substituted or unsubstituted imidazolyl.

8. The compound of claim 1 , wherein X is —C(O)—.

9. The compound of claim 8 , wherein R 14 is a substituted or unsubstituted phenyl.

10. The compound of claim 1 , wherein R 14 is a substituted or unsubstituted phenyl.

11. A compound of having the formula:

or a pharmaceutically acceptable salt thereof wherein:

A 4 is N;

X is —C(O)— or —CH 2 —,

R 1 and R 2 are each methyl;

R 3 is a member selected from the group consisting of hydroxy, (C 1 -C 8 )alkoxy, amino, (C 1 -C 8 )alkylamino, di(C 1 -C 8 )alkylamino, (C 2 -C 8 )heteroalkyl, (C 3 -C 9 )heterocyclyl, (C 1 -C 8 )acylamino, amidino, guanidino, ureido, cyano, heteroaryl, —CONR 9 R 10 and —CO 2 R 11 ;

R 4 is a member selected from the group consisting of (C 1 -C 20 )alkyl, (C 2 -C 20 )heteroalkyl, heteroaryl, aryl, heteroaryl(C 1 -C 6 )alkyl, heteroaryl(C 2 -C 6 )heteroalkyl, aryl(C 1 -C 6 )alkyl and aryl(C 2 -C 6 )heteroalkyl;

each R 9 , R 10 and R 11 is independently selected from the group consisting of H, (C 1 -C 8 )alkyl, (C 2 -C 8 )heteroalkyl, heteroaryl, aryl, heteroaryl(C 1 -C 6 )alkyl, heteroaryl(C 2 -C 8 )heteroalkyl, aryl(C 1 -C 8 )alkyl and aryl(C 2 -C 8 )heteroalkyl

R 14 is a substituted or unsubstituted member selected from the group consisting of phenyl, pyridyl, thiazolyl, thienyl and pyrimidinyl;

Q is —C(O)—;

L is (C 1 -C 8 )alkylene;

the subscript n is an integer from 0 to 4; and

each R a is independently selected from the group consisting of halogen, —OR′, —OC(O)R′, —NR′R″, —SR′, —R′, —CN, —NO 2 , —CO 2 R′, —CONR′R″, —C(O)R′, —OC(O)NR′R″ —NR″C(O)R′, —NR″C(O) 2 R′, —NR′—C(O)NR″R′″, —NH—C(NH 2 )═NH, —NR′C(NH 2 )═NH, —NH—C(NH 2 )═NR′, —S(O)R′, —S(O) 2 R′, —S(O) 2 NR′R″, —N 3 , —CH(Ph) 2 , perfluoro(C 1 -C 4 ) alkoxy and perfluoro(C 1 -C 4 )alkyl, wherein R′, R″ and R′″ are each independently selected from the group consisting of H, (C 1 -C 8 )alkyl, (C 2 -C 8 )heteroalkyl, unsubstituted aryl, unsubstituted heteroaryl, (unsubstituted aryl)-(C 1 -C 4 )alkyl and (unsubstituted aryl)oxy-(C 1 -C 8 alkyl.

12. A compound having the formula:

or a pharmaceutically acceptable salt thereof wherein:

A 4 is N;

X is —C(O)— or —CH 2 —;

R 1 and R 2 are members independently selected from the group consisting of H and (C 1 -C 4 )alkyl;

R 3 is a member selected from the group consisting of (C 1 -C 8 )alkoxy, (C 3 -C 9 )heterocyclyl and (C 1 -C 8 )acylamino;

R 4 is a member selected from the group consisting of (C 1 -C 20 )alkyl, (C 2 -C 20 )heteroalkyl, heteroaryl, aryl, heteroaryl(C 1 -C 6 )alkyl, heteroaryl(C 2 -C 6 )heteroalkyl, aryl(C 1 -C 6 )alkyl and aryl(C 1 -C 6 )heteroalkyl;

R 14 is a substituted or unsubstituted member selected from the group consisting of phenyl, pyridyl, thiazolyl, thienyl and pyrimidinyl;

Q is —C(O)—;

L is (C 1 -C 8 )alkylene;

the subscript n is an integer from 0 to 4; and

each R a is independently selected from the group consisting of halogen, —OR′, —OC(O)R′, —NR′R″, —SR′, —R′, —CN, —NO 2 , —CO 2 R′, —CONR′R″, —C(O)R′, —OC(O)NR′R″, —NR″C(O)R′, —NR″C(O) 2 R′, —NR′—C(O)NR″R′″, —NH—C(NH 2 )═NH, —NR′C(NH 2 )═NH, —NH—C(NH 2 )═NR′, —S(O)R′, —S(O) 2 R′, —S(O) 2 NR′R″, —N 3 , —CH(Ph) 2 , perfluoro(C 1 -C 4 )alkoxy and perfluoro(C 1 -C 4 )alkyl, wherein R′, R″ and R′″ are each independently selected from the group consisting of H, (C 1 -C 8 )alkyl, (C 2 -C 8 )heteroalkyl, unsubstituted aryl, unsubstituted heteroaryl (unsubstituted aryl)-(C 1 -C 4 )alkyl and (unsubstituted aryl)oxy-(C 1 -C 4 )alkyl.

13. A compound having the formula:

or a pharmaceutically acceptable salt thereof wherein:

A 4 is N;

X is —C(O)— or —CH 2 —;

R 1 and R 2 are members independently selected from the group consisting of H and (C 1 -C 4 )alkyl;

R 3 is selected from the group consisting of substituted or unsubstituted pyridyl and substituted or unsubstituted imidazolyl;

R 4 is a member selected from the group consisting of (C 1 -C 20 )alkyl, (C 2 -C 20 )heteroalkyl, heteroaryl, aryl, heteroaryl(C 1 -C 6 )alkyl, heteroaryl(C 2 -C 6 )heteroalkyl, aryl(C 1 - 6 )alkyl and aryl(C 2 -C 6 )heteroalkyl;

R 14 is a substituted or unsubstituted member selected from the group consisting of phenyl, pyridyl, thiazolyl, thienyl and pyrimidinyl;

Q is —C(O)—;

L is (C 1 -C 8 )alkylene;

the subscript n is an integer from 0 to 4; and

each R a is independently selected from the group consisting of halogen, —OR′, —OC(O)R′, —NR′R″, —SR′, —R′, —CN, —NO 2 , —CO 2 R′, —CONR′R″, —C(O)R′—OC(O)NR′R″, —NR″C(O)R′, —NR″C(O) 2 R′, —NR′—C(O)NR″R′″, —NH—C(NH 2 )═NH, —NR′C(NH 2 )═NH, —NH—C(NH 2 )═NR′, —S(O)R′, —S(O) 2 R′, —S(O) 2 NR′R″, —N 3 , —CH(Ph) 2 , perfluoro(C 1 -C 4 )alkoxy and perfluoro(C 1 -C 4 )alkyl, wherein R′, R″ and R′″ are each independently selected from the group consisting of H, (C 1 -C 8 )alkyl, (C 2 -C 8 )heteroalkyl, unsubstituted aryl, unsubstituted heteroaryl, (unsubstituted aryl)-(C 1 -C 4 )alkyl and (unsubstituted aryl)oxy-(C 1 -C 4 )alkyl.

14. The compound of claim 13 , wherein R 14 is substituted phenyl, wherein the substituents are selected from the group consisting of cyano, halogen, (C 1 -C 8 )alkoxy, (C 1 -C 8 )alkyl, (C 2 -C 8 )heteroalkyl, CONH 2 , methylenedioxy and ethylenedioxy.

15. A compound having the formula:

or a pharmaceutically acceptable salt thereof wherein:

A 4 is N;

X is —C(O)— or —CH 2 —;

R 1 and R 2 are members independently selected from the group consisting of H and (C 1 -C 4 )alkyl;

R 3 is a member selected from the group consisting of hydroxy, (C 1 -C 8 )alkoxy, amino, (C 1 -C 8 )alkylamino, di(C 1 -C 8 )alkylamino, (C 2 -C 8 )heteroalkyl, (C 3 -C 9 )heterocyclyl, (C 1 -C 8 )acylamino, amidino, guanidino, ureido, cyano, heteroaryl, —CONR 9 R 10 and —CO 2 R 11 ;

R 4 is substituted or unsubstituted benzyl, wherein said substituents are selected from the group consisting of halogen, halo(C 1 -C 4 )alkyl, halo(C 1 -C 4 )alkoxy, cyano, nitro and phenyl;

each R 9 , R 10 and R 11 is independently selected from the group consisting of H, (C 1 -C 8 )alkyl, (C 2 -C 8 )heteroalkyl, heteroaryl, aryl, heteroaryl(C 1 -C 6 )alkyl, heteroaryl(C 2 -C 8 )heteroalkyl, aryl(C 1 -C 8 )alkyl and aryl(C 2 -C 8 )heteroalkyl;

R 14 is substituted or unsubstituted aryl or heteroaryl;

Q is—C(O)—;

L is (C 1 -C 8 )alkylene;

the subscript n is an integer from 0 to 4; and

each R a is independently selected from the group consisting of halogen, —OR′, —OC(O)R′, —NR′R″, —SR′, —R′, —CN, —NO 2 , —CO 2 R′, —CONR′R″, —C(O)R′, —OC(O)NR′R″, —NR″C(O)R′, —NR″C(O) 2 R′, —NR′—C(O)NR″R′″, —NH—C(NH 2 )═NH, —NR′C(NH 2 )═NH, —NH—C(NH 2 )═NR′, —S(O)R′, —S(O) 2 R′, —S(O) 2 NR′R″, —N 3 , —CH(Ph) 2 , perfluoro(C 1 -C 4 )alkoxy and perfluoro(C 1 -C 4 )alkyl, wherein R′, R″ and R′″ are each independently selected from the group consisting of H, (C 1 -C 8 )alkyl, (C 2 -C 8 )heteroalkyl, unsubstituted aryl, unsubstituted heteroaryl, (unsubstituted aryl)-(C 1 -C 4 )alkyl and (unsubstituted aryl)oxy-(C 1 -C 4 )alkyl.

16. The compound of claim 15 , wherein X is —C(O)—.

17. A pharmaceutical composition comprising the compound of claim 1 , 11 , 12 or 13 and a pharmaceutically acceptable carrier or diluent.

18. The pharmaceutical composition of claim 17 , wherein X is —C(O)—.

19. The pharmaceutical composition of claim 17 , wherein R 14 is a substituted or unsubstituted phenyl.

20. The pharmaceutical composition of claim 17 , wherein R 14 is selected from the group consisting of substituted phenyl, substituted pyridyl, substituted thiazolyl and substituted thienyl, wherein the substituents are selected from the group consisting of cyano, halogen, (C 1 -C 8 )alkoxy, (C 1 -C 8 )alkyl, (C 2 -C 8 )heteroalkyl, CONH 2 , methylenedioxy and ethylenedioxy.

21. The pharmaceutical composition of claim 17 , wherein L is (C 1 -C 4 )alkylene.

22. A method for the modulation of CXCR3 function in a cell, comprising contacting said cell with a compound of claim 1 , 11 , 12 or 13 .

23. A method for the modulation of CXCR3 function, comprising contacting a CXCR3 protein with a compound of claim 1 , 11 , 12 or 13 .

24. The method of claim 22 , wherein X is —C(O)—.

25. The method of claim 22 , wherein R 14 is a substituted or unsubstituted phenyl.

26. The method of claim 22 , wherein R 14 is selected from the group consisting of substituted phenyl, substituted pyridyl, substituted thiazolyl and substituted thienyl, wherein the substituents are selected from the group consisting of cyano, halogen, (C 1 -C 8 )alkoxy, (C 1 -C 8 )alkyl, (C 2 -C 8 )heteroalkyl, CONH 2 , methylenedioxy and ethylenedioxy.

27. The method of claim 26 , wherein R 14 is substituted phenyl, wherein the substituents are selected from the group consisting of cyano, halogen, (C 1 -C 8 )alkoxy, (C 1 -C 8 )alkyl, (C 2 -C 8 )heteroalkyl, CONH 2 , methylenedioxy and ethylenedioxy.

28. The method of claim 23 , wherein L is (C 1 -C 4 )alkylene.