IP Library › Granted Patent US 7,470,685
Granted Patent B2
US 7,470,685 · App. 11/041,537 · Granted Dec 30, 2008

Pyrimidine compounds

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Quick Facts
Patent No.
US 7,470,685
App. No.
11/041,537
Granted
Dec 30, 2008
Kind
B2
Abstract

This invention features pyrimidine compounds of formula (I): R 1 is in which one of R a and R b is H or alkyl, and the other is aryl or heteroaryl optionally substituted with R d and R e m ; each of R 2 and R 4 is H; R 3 is H, alkyl, aryl, heteroaryl, cyclyl, heterocyclyl, or alkylcarbonyl; R 5 is H or alkyl; n is 0, 1, 2, 3, 4, 5, or 6; X is NR c ; Y is covalent bond, CH 2 , C(O), C═N—R c , C═N—OR c , C═N—SR c , O, S, S(O), S(O 2 ), or NR c ; Z is N or CH; one of U and V is N, and the other is CR c ; and W is O, S, S(O), S(O 2 ), NR c , or NC(O)R c ; in which R c is H, alkyl, aryl, heteroaryl, cyclyl, heterocyclyl, or alkylcarbonyl; R d is halogen, CN, alkyl, alkyloxy, alkylcarbonyl, alkyloxycarbonyl, aryloxycarbonyl, heteroaryloxycarbonyl, hydroxyalkyl, alkylamino, or alkylaminocarbonyl; R e is halogen, CN, hydroxyl, alkyl, aryl, heteroaryl, alkoxyl, aryloxyl, or heteroaryloxyl; and m is 0, 1, 2, 3, or 4. The pyrimidine compounds can be used to treat an IL-12 overproduction-related disorder (e.g., rheumatoid arthritis, sepsis, Crohn's disease, multiple sclerosis, psoriasis, or insulin-dependent diabetes mellitus).

Claims (73)

1. A method for treating an interleukin-12 overproduction-related disorder, selected from rheumatoid arthritis, sepsis, Crohns's disease, multiple sclerosis, psoriasis, or insulin-dependent diabetes mellitus, comprising administering to a subject in need thereof an effective amount of a compound of formula (I):

wherein

R 1 is

 in which one of R a and R b is H or alkyl, and the other is aryl or heteroaryl optionally substituted with R d and R e m ;

each of R 2 and R 4 is H;

R 3 is H, alkyl, aryl, heteroaryl, cyclyl, heterocyclyl, or alkylcarbonyl;

R 5 is H or alkyl;

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

X is NR c ;

Y is covalent bond, CH 2 , C(O), C═N—R c , C═N—OR c , C═N—SR c , O, S, S(O), S(O 2 ), or NR c ;

Z is N or CH;

one of U and V is N, and the other is CR c and

W is O, S, S(O), S(O 2 ), NR c , or NC(O)R c ;

in which R c is H, alkyl, aryl, heteroaryl, cyclyl, heterocyclyl, or alkylcarbonyl;

R d is halogen, CN, alkyl, alkyloxy, alkylcarbonyl, alkyloxycarbonyl, aryloxycarbonyl, heteroaryloxycarbonyl, hydroxyalkyl, alkylamino, or alkylaminocarbonyl;

R e is halogen, CN, hydroxyl, alkyl, aryl, heteroaryl, alkoxyl, aryloxyl, or heteroaryloxyl; and

m is 0, 1, 2, 3, or 4; or a pharmaceutically acceptable salt thereof.

2. The method of claim 1 , wherein the compound is

3. The method of claim 1 , wherein the compound is

4. A pharmaceutical composition comprising a compound of formula (I)

wherein

R 1 is

 in which one of R a and R b is H or alkyl, and the other is aryl or heteroaryl optionally substituted with R d and R e m ;

each of R 2 and R 4 is H;

R 3 is H, alkyl, aryl, heteroaryl, cyclyl, heterocyclyl, or alkylcarbonyl;

R 5 is H or alkyl;

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

X is NR c ;

Y is covalent bond, CH 2 , C(O), C═N—R c , C═N—OR c , C═N—SR c , O, S, S(O), S(O 2 ), or NR c ;

Z is N or CH;

one of U and V is N, and the other is CR c and W is O, S, S(O), S(O 2 ), NR c , or NC(O)R c ;

in which R c is H, alkyl, aryl, heteroaryl, cyclyl, heterocyclyl, or alkylcarbonyl;

R d is halogen, CN, alkyl, alkyloxy, alkylcarbonyl, alkyloxycarbonyl, aryloxycarbonyl, heteroaryloxycarbonyl, hydroxyalkyl, alkylamino, or alkylaminocarbonyl;

R e is halogen, CN, hydroxyl, alkyl, aryl, heteroaryl, alkoxyl, aryloxyl, or heteroaryloxyl; and

m is 0, 1, 2, 3, or 4;

and a pharmaceutically acceptable carrier.

5. The pharmaceutical composition of claim 4 , wherein one of R a and R b is H or alkyl; and the other is

in which R d , R e , and m are as defined in claim 4 .

6. The pharmaceutical composition of claim 5 , wherein one of R a and R b is H; and the other is

in which R d is as defined in claim 4 .

7. The pharmaceutical composition of claim 4 , wherein X is NH.

8. The pharmaceutical composition of claim 7 , wherein one of R a and R b is H or alkyl; and the other is

in which R d , R e , and m are as defined in claim 4 .

9. The pharmaceutical composition of claim 8 , wherein one of R a and R b is H; and the other is

in which R d is as defined in claim 4 .

10. The pharmaceutical composition of claim 4 , wherein n is 2.

11. The pharmaceutical composition of claim 4 , wherein R 3 is heteroaryl or heterocyclyl.

12. The pharmaceutical composition of claim 4 , wherein Y is O.

13. The pharmaceutical composition of claim 12 , wherein n is 2.

14. The pharmaceutical composition of claim 13 , wherein R 3 is heteroaryl or heterocyclyl.

15. The pharmaceutical composition of claim 4 , wherein U is N and V is CH.

16. The pharmaceutical composition of claim 15 , wherein Z is N and W is O.

17. The pharmaceutical composition of claim 16 , wherein Y is O.

18. The pharmaceutical composition of claim 17 , wherein n is 2.

19. The pharmaceutical composition of claim 18 , wherein R 3 is heteroaryl or heterocyclyl.

20. The pharmaceutical composition of claim 19 , wherein R 3 is pyridin-2-yl.

21. The pharmaceutical composition of claim 20 , wherein X is NH.

22. The compound of claim 21 , wherein one of R a and R b is H or alkyl; and the other is

in which R d , R e , and m are as defined in claim 4 .

23. The pharmaceutical composition of claim 22 , wherein one of R a and R b is H; and the other is

in which R d is as defined in claim 4 .

24. The pharmaceutical composition of claim 23 , wherein R d is halogen.

25. The pharmaceutical composition of claim 23 , wherein R d is CN, hydroxyalkyl, alkylamino, alkylaminocarbonyl, or alkyloxycarbonyl.

26. The pharmaceutical composition of claim 23 , wherein R d is alkyloxycarbonyl.

27. The pharmaceutical composition of claim 19 , wherein R 3 is 1H-pyridin-2-one.

28. The pharmaceutical composition of claim 27 , wherein X is NH.

29. The pharmaceutical composition of claim 28 , wherein one of R a and R b is H or alkyl; and the other is

in which R d , R e , and m are as defined in claim 4 .

30. The pharmaceutical composition of claim 29 , wherein one of R a and R b is H; and the other is

in which R d is as defined in claim 4 .

31. The pharmaceutical composition of claim 30 , wherein R d is alkyl.

32. The pharmaceutical composition of claim 30 , wherein R d is halogen.

33. The pharmaceutical composition of claim 30 , wherein R d is methoxycarbonyl.

Assignments (1)
CHANGE OF NAME Recorded Aug 9, 2017
From: SYNTA PHARMACEUTICALS CORPORATION
To: MADRIGAL PHARMACEUTICALS, INC.
Reel/Frame 043239/0357 →