Granted Patent B2

US 9,163,022 · App. 14/477,302 · Granted Oct 20, 2015

Abstract

Claims (115)

1. A method of treating rheumatoid arthritis comprising administering to a human a compound of Formula (I) or a pharmaceutically acceptable salt thereof:

wherein:

A 1 is O or S;

A 2 is O or S;

U is N;

V is C—(CH 2 ) v R V ;

W is C—(CH 2 ) w R W ;

X is C—(CH 2 ) x R X ;

Y is C—(CH 2 ) y R Y ;

Z is C—(CH 2 ) z R Z ;

R 1 is —(CH 2 ) q R Q ;

R 2 is —(CH 2 ) s R S ;

wherein

each of q, s, w, x, y, and z individually is 0, 1, 2, 3, or 4;

v is zero;

R Q is selected from the group consisting of:

alkyl,

cycloalkyl,

phenyl,

benzyl,

tetrahydrofuranyl,

tetrahydropyranyl,

pyrrolidinyl,

piperidinyl, and

—OR 8 , wherein

the cycloalkyl is optionally substituted with one or more R c ;

the phenyl and benzyl are each independently optionally substituted with one or more R a ; and

the tetrahydrofuranyl, tetrahydropyranyl, pyrrolidinyl and piperidinyl are each independently optionally substituted with one or more R hc ;

R V is chloro or —OCH 3 ;

each of R S , R W , R X , R Y , and R Z is independently selected from the group consisting of

alkyl;

alkenyl;

alkynyl;

aryl;

aryl substituted with one or more R a ;

azido;

cyano;

cycloalkyl;

cycloalkyl substituted with one or more R c ;

fused cycloalkylaryl substituted with one or more R f1 ;

fused arylcycloalkyl substituted with one or more R f2 ;

fused heterocyclyaryl substituted with one or more R f3 ;

fused arylheterocyclyl substituted with one or more R f4 ;

fused cycloalkylheteroaryl substituted with one or more R f5 ;

fused heteroarylcycloalkyl substituted with one or more R f6 ;

fused heterocyclylheteroaryl substituted with one or more R f7 ;

halogen;

haloalkyl;

heterocyclyl;

heterocyclyl substituted with one or more R hc ;

heteroaryl;

heteroaryl substituted with one or more R ha ;

hydrogen;

—NR 3 R 4 ;

—C(O)NR 3 R 4 ;

—C(O)R 5 ;

—C(O) 2 R 6 ;

—S(O) n R 7 ;

—OR 8 ; and

nitro;

wherein

each of R 3 and R 4 is independently selected from the group consisting of H, acyl, alkyl, alkoxy, alkoxyalkyl, alkylsulfonyl, aryl, cycloalkyl, heterocyclyl and heteroaryl;

j is 0, 1, or 2;

each R 5 , R 6 , R 7 , and R 8 is independently selected from the group consisting of

 hydrogen;

 alkyl;

 alkenyl;

 alkynyl;

 alkoxy;

 aryl;

 aryl substituted with one or more R a ;

 cycloalkyl;

 cycloalkyl substituted with one or more R c ;

 halogen;

 haloalkyl;

 heterocyclyl;

 heterocyclyl substituted with one or more R hc ;

 heteroaryl; and

 heteroaryl substituted with one or more R ha ;

 wherein each of R a , R c , R f1 , R f2 , R f3 , R f4 , R f5 , R f6 , R f7 , R hc and R ha is independently selected from the group consisting of acyl, alkyl, alkenyl, alkynyl, alkoxy, amide, amino, aryl, cyano, cycloalkyl, halogen, haloalkyl, haloalkoxy, heteroaryl, hydroxy, nitro, —C(O)OR 9 , —SO 2 R 10 , —SR 11 , —C(O)R 12 , —C(O)NR 13 , —NH—SO 2 —R 14 , —SO 2 —NR 15 R 16 , and —SO 2 —CH 2 —SO 2 —CH 3 ; and wherein

 each of R 9 , R 10 , R 11 , R 12 , R 13 R 14 , R 15 , and R 16 is independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocyclyl, and heteroaryl.

2. The method of claim 1 , wherein A 1 and A 2 are each O.

3. The method of claim 1 , wherein R X is halogen or hydrogen and x is zero.

4. The method of claim 1 , wherein R 1 is cycloalkyl or cycloalkyl substituted with one or more R c .

5. The method of claim 4 , wherein the cycloalkyl is cyclopentyl or cyclohexyl substituted with one or more R c .

6. The method of claim 1 , wherein R S is selected from the group consisting of

hydrogen,

alkyl,

cycloalkyl,

phenyl,

benzyl,

furanyl,

thiophenyl,

isoxazolyl,

benzodioxolyl, and

indanyl,

—C(O)R 5 ,

—C(O) 2 R 6 , and

—OR 8 , wherein

the cycloalkyl is optionally substituted with one or more R c ;

the phenyl and benzyl are each independently optionally substituted with one or more R a ; and

the furanyl, thiophenyl, isoxazolyl, benzodioxolyl, and indanyl, are each independently optionally substituted with one or more R ha .

7. The method of claim 6 , wherein R 2 is phenyl substituted with one or more R a , and R a is halogen.

8. The method of claim 7 , wherein R 2 is 3-chlorophenyl.

9. The method of claim 8 , wherein R 1 is a 4-substituted cyclohexyl group.

10. The method of claim 9 , wherein R 1 is trans-4-cyclohexanecarboxylic acid.

11. The method of claim 10 , wherein the compound is in the form of a hydrochloric acid salt.

12. The method of claim 1 , wherein the compound is 1-cyclopentyl-7-methoxy-3-(4-methyl-thiophen-2-yl)-1H-pyrimido[5,4-c]quinoline-2,4-dione or a pharmaceutically acceptable salt thereof.

13. The method of claim 1 , wherein the compound is 1-cyclopentyl-7-methoxy-3-m-tolyl-1H-pyrimido[5,4-c]quinoline-2,4-dione or a pharmaceutically acceptable salt thereof.

14. The method of claim 1 , wherein the compound is 3-(3-chloro-phenyl)-1-(1-methane-sulfonyl-piperidin-4-yl)-7-methoxy-1H-pyrimido[5,4-c]-quinoline-2,4-dione or a pharmaceutically acceptable salt thereof.

15. The method of claim 1 , wherein the compound is trans-4-[3-(3-chloro-phenyl)-7-methoxy-2,4-dioxo-3,4-dihydro-2H-pyrimido-[5,4-c]quinolin-1-yl]-cyclohexanecarboxylic acid or a pharmaceutically acceptable salt thereof.

16. The method of claim 1 , wherein the compound is 3-(3-chloro-phenyl)-1-((R)-1-methane-sulfonyl-pyrrolidin-3-yl)-7-methoxy-1H-pyrimido[5,4-c]quinoline-2,4-dione or a pharmaceutically acceptable salt thereof.

17. The method of claim 1 , wherein the compound is 3-(3-chloro-phenyl)-1-((S)-1-methane-sulfonyl-pyrrolidin-3-yl)-7-methoxy-1H-pyrimido[5,4-c]quinoline-2,4-dione or a pharmaceutically acceptable salt thereof.

18. The method of claim 1 , wherein the compound is 3-(3-chloro-phenyl)-1-(1-ethanesulfonyl-piperidin-4-yl)-7-methoxy-1H-pyrimido-[5,4-c]quinoline-2,4-dione or a pharmaceutically acceptable salt thereof.

19. The method of claim 1 , wherein the compound is N-{4-[(S)-3-(3-chloro-phenyl)-7-methoxy-2,4-dioxo-3,4-dihydro-2H-pyrimido[5,4-c]quinolin-1-yl]-trans-cyclohexyl}-methanesulfonamide or a pharmaceutically acceptable salt thereof.

Assignments (9)