IP Library › Granted Patent US 6,919,347

Granted Patent B2

US 6,919,347 · App. 10/046,616 · Granted Jul 19, 2005

Bradykinin B1 receptor antagonists

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Quick Facts

Patent No.: US 6,919,347
App. No.: 10/046,616
Granted: Jul 19, 2005
Kind: B2

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Abstract

Bradykinin B 1 -receptor antagonists of formula are disclosed. The compounds are useful for treating diseases associated with inappropriate bradykinin receptor activity, such as diabetic vasculopathy, inflammation, pain, hyperalgesia, asthma, rhinitis, septic shock, atherosclerosis and multiple sclerosis. Pyrimidines, triazines, and anilines in which Q is imidazolyl or pyrrolyl are particularly preferred.

Claims (403)

1. A compound of formula

wherein:

A is A 1 or A 2 ;

A 1 is R 4 R 5 N—C(O)—,

A 2 is chosen from R 7 C(O)NH—, R 7 S(O) 2 NH—, R 4 NH—, and R 4 O—;

Q is chosen from imidazolyl, methylimidazolyl, pyrrolyl, methylpyrrolyl, pyrazolyl, methylpyrazolyl, hydroxymethylimidazolyl, (dimethylaminomethyl)imidazolyl, furanyl, methylfuranyl, thienyl, oxazolyl, thiazolyl, pyridinyl, quinolinyl, 1-methylpyrimidin-2-onyl, phenyl, fluorophenyl, hydroxymethyl, tetrahydropyranyloxymethyl, imidazolylmethyl, pyrrolylmethyl, —CH═N—OCH 3 and

W is chosen from H, Cl, F, R 8 , C 1 -C 4 -alkylaryl, —OR 8 , —SR 8 , —NR 9 R 10 and —NHC(O)R 11 , with the proviso that when Q is imidazolyl, W is not H, Cl, F or R 8 ;

R 1 is chosen from alkyl, cycloalkyl, alkenyl, C 1 -C 3 -alkylcycloalkyl, heterocyclyl, C 1 -C 3 -alkylheterocyclyl, aryl, C 1 -C 3 -alkylaryl, heteroaryl, C 1 -C 3 -alkylheteroaryl, (C 1 -C 3 -alkyloxy)alkyl, (C 1 -C 3 -alkyloxy)cycloalkyl, (C 1 -C 3 -alkylthio)alkyl, (C 1 -C 3 -alkylthio)cycloalkyl and (C 1 -C 3 -alkylsulfonyl)alkyl;

R 2 is H or C 1 -C 3 -alkyl, or R 1 and R 2 taken together form a 5- to 7-membered ring structure optionally containing O, S or NR 12 ;

R 3 is H or C 1 -C 6 -alkyl, or, when n is zero, R 2 and R 3 taken together may form a 6-membered ring, which may be fused to a six-membered saturated or aromatic carbocycle;

R 4 is chosen from H, aryl, heteroaryl, C 1 -C 4 -alkyl substituted with from one to three aryl or heteroaryl residues,

wherein J 1 and J 2 are independently chosen from H, F, Cl, CN, NO 2 and CH 3 , and G is chosen from —CH 2 —, —CH 2 CH 2 —, —CH 2 CH 2 CH 2 —, —OCH 2 —, —CH 2 O—, —CH 2 CH 2 O—, —OCH 2 CH 2 —, —O—, —N(lower alkyl)-, —N(lower alkyl)CH 2 —, —CH 2 N(lower alkyl)-, —S—, —SO—, —SO 2 —, —CH 2 S—, —SCH 2 —, —CH 2 SO—, —SOCH 2 —, —CH 2 SO 2 —, and —SO 2 CH 2 —;

R 5 is H or C 1 -C 3 -alkyl, with the proviso that both R 3 and R 5 cannot be alkyl;

R 6 is aryl;

R 7 is aryl or C 1 -C 3 -alkylaryl;

R 8 is chosen from alkyl, aryl, heteroaryl, substituted alkyl, C 1 -C 4 -alkylaryl, C 1 -C 4 -alkylheterocyclyl and C 1 -C 4 -alkylheteroaryl;

R 9 is chosen from H, alkyl, alkenyl, substituted alkyl, cycloalkyl, aryl, alkoxy, heteroaryl, fluoroalkyl, C 1 -C 4 -alkylcycloalkyl, (C 1 -C 4 -alkoxy)alkyl, (C 1 -C 4 -alkoxycarbonyl)alkyl, (C 1 -C 4 -alkylthio)alkyl, heterocyclyl, C 1 -C 4 -alkylheterocyclyl, C 1 -C 4 -alkylaryl, and C 1 -C 4 -alkylheteroaryl;

R 10 is H or C 1 -C 3 -alkyl, or

R 9 and R 10 taken together may form a 5- to 7-membered ring structure optionally containing O, S, SO, SO 2 or NR 12 , said ring optionally substituted with —OH, —CN, —COOH or —COOCH 3 ;

R 11 is aryl;

R 12 is chosen from H, C 1 -C 3 -alkyl, alkoxycarbonyl, methoxyacetyl and aryl;

m is zero or one; and

n is zero or one, with the proviso that when A is A 2 , m and n cannot both be zero.

2. A 4-pyrimidinamine according to claim 1 wherein:

Q is chosen from pyrrol-1-yl, imidazol-1-yl, furan-3-yl, 2-methylimidazol-1-yl and 4-methylimidazol-1-yl;

A is R 4 R 5 N—C(O)—;

W is Cl, NHR 9 , N(CH 3 )R 9 , OR 8 , SR 8 , R 8 , morpholin-4-yl;

R 1 is chosen from alkyl, cycloalkyl, C 1 -C 3 -alkylaryl, C 1 -C 3 -alkylcycloalkyl, C 1 -C 3 -alkylheterocyclyl, C 1 -C 3 -alkylheteroaryl

R 2 , R 3 and R 5 are H;

R 8 is C 1 -C 4 -alkylaryl;

R 9 is chosen from hydrogen, alkyl, substituted alkyl, (C 1 -C 4 )-alkoxy, C 1 -C 4 -alkylcycloalkyl, C 1 -C 4 -alkylaryl, heterocyclyl, C 1 -C 4 -alkylheteroaryl, C 1 -C 4 -alkylheterocyclyl; and

m and n are zero.

3. A 4-pyrimidinamine according to claim 2 wherein W is NHR 9 and

R 9 is chosen from hydrogen; methyl; ethyl; 2,2,2-trifluoroethyl; allyl; cyclopropyl; 2-cyanoethyl; propargyl; methoxy; methoxyethyl; cyclopropyl; cyclopropylmethyl; (methylthio)ethyl; 3-methoxypropyl; 3-pyridyl; 2-(3-pyridyl)ethyl; 2-(2-pyridyl)ethyl; 3-pyridylmethyl; 4-pyridylmethyl; 4-pyridylmethyl-N-oxide; 2-pyridazinylmethyl; sulfolan-3-yl; 3-tetrahydrofuranyl; 2-tetrahydrofuranylmethyl; 3-(1-imidazolyl)propyl; 1-t-butoxycarbonyl-4-piperidinyl; 1-t-butoxycarbonyl-4-piperidinylmethyl; 2-(hydroxyimino)propyl; 2-(methoxyimino)propyl; 2-oxo-1-propyl; and

wherein

R 14 is chosen from H, Cl, F, CN, NO 2 , SO 2 NH 2 , CF 3 , COOCH 3 , OCH 3 , OH, SO 2 CH 3 , N(CH 3 ) 2 and COOH;

R 15 is chosen from H, OCH 3 and Cl; and

p is 1 or 2.

4. A 4-pyrimidinamine according to claim 2 wherein W is

and

R 12 is t-butoxycarbonyl, methoxyacetyl or phenyl.

5. A compound of formula

wherein:

A is

R 1 is chosen from n-butyl; cyclohexylmethyl; cyclopentylmethyl; 2-methylpropyl; 3-methyl-1-butyl; cyclohexyl; 2,2-dimethylpropyl; benzyl; 2-thienylmethyl; 1-t-butoxycarbonyl-4-piperidinyl; 4-chlorobenzyl; 2-pyranylmethyl; 4-pyranylmethyl; 4-pyranyl and 1,1-dimethylethyl;

R 2 and R 3 are H;

Q is imidazolyl or pyrrolyl;

R 6 is aryl;

R 4 is chosen from H, aryl, heteroaryl, C 1 -C 4 -alkyl substituted with from one to three aryl or heteroaryl residues,

R 7 is aryl or C 1 -C 3 -alkylaryl;

W is NHR 9 ; and

R 9 is alkyl, cycloalkyl or

wherein

R 14 is chosen from H, Cl, F, CN, NO 2 , SO 2 NH 2 , CF 3 , COOCH 3 , OCH 3 , SO 2 CH 3 , N(CH 3 ) 2 and COOH; and

R 15 is chosen from H, OCH 3 and Cl;

m is zero or one; and

n is zero or one, with the proviso that when A is chosen from R 7 C(O)NH—, R 7 S(O) 2 NH—, R 4 NH—, and R 4 O—, m and n cannot both be zero.

6. A compound of formula

wherein:

two of X, Y and Z are N and the other of X, Y and Z is CH;

A is R 4 R 5 N—C(O)—;

Q is chosen from heteroaryl, aryl, —CH 2 R 13 , —CH═N—OCH 3 and

W is chosen from H, Cl, F, R 8 , C 1 -C 4 -alkylaryl, —OR 8 , —SR 8 , —NR 9 R 10 and —NHC(O)R 11 , with the proviso that when Q is imidazolyl, W is not H, Cl, F or R 8 ;

R 1 is chosen from isopropyl; n-butyl; cyclohexylmethyl; cyclopentylmethyl; naphthylmethyl; cyclohexylethyl; 2-methylpropyl; 3-methyl-1-butyl; cyclohexyl; 2,2-dimethylpropyl; benzyl; 2-thienylmethyl; 1-t-butoxycarbonyl-4-piperidinyl; 4-methoxybenzyl; 4-chlorobenzyl; 3,4-dichlorobenzyl; 2-pyranylmethyl; 4-pyranylmethyl; 4-pyranyl and 1,1-dimethylethyl;

R 2 , R 3 and R 5 are H;

R 4 is chosen from H, aryl, heteroaryl, C 1 -C 4 -alkyl substituted with from one to three aryl or heteroaryl residues,

R 7 is aryl or C 1 -C 3 -alkylaryl;

R 8 is chosen from alkyl, aryl, heteroaryl, substituted alkyl, C 1 -C 4 -alkylaryl, C 1 -C 4 -alkylheterocyclyl and C 1 -C 4 -alkylheteroaryl;

R 10 is H or C 1 -C 3 -alkyl, or

R 9 and R 10 taken together may form a 5- to 7-membered ring structure optionally containing O, S, SO, SO 2 or NR 12 , said ring optionally substituted with —OH, —CN, —COOH or —COOCH 3 ;

R 11 is aryl;

R 12 is chosen from H, C 1 -C 3 -alkyl, alkoxycarbonyl, methoxyacetyl and aryl;

R 13 is chosen from —OH, —OTHP, 1-imidazolyl, and 1-pyrrolyl;

m is zero or one; and

n is zero or one, with the proviso that when A is chosen from R 7 C(O)NH—, R 7 S(O) 2 NH—, R 4 NH—, and R 4 O—, m and n cannot both be zero.

7. A pyrimidine according to claim 6 wherein:

R 4 is pyridinyl, pyridinylmethyl, tetrahydronaphthalenyl, indanylmethyl, furanylmethyl, substituted phenyl, or

R 16 is chosen from H, Cl, F, CN, NO 2 , SO 2 NH 2 , CF 3 , CH 3 , COOCH 3 , OCH 3 , SO 2 CH 3 , SOCH 3 , N(CH 3 ) 2 , tetrazol-5-yl, CONH 2 , C(═NOH)NH 2 and COOH; and

R 17 is chosen from H, OCH 3 , F and Cl.

8. A pyrimidine according to claim 6 wherein R 4 is

one of J 1 and J 2 is H and the other is H, Cl or CN and G is chosen from —CH 2 —, —CH 2 CH 2 —, —OCH 2 —, —O— and —CH 2 N(lower alkyl)-.

9. A compound of formula

wherein:

A is A 1 or A 2 ;

A 1 is R 4 R 5 N—C(O)—,

A 2 is chosen from R 7 C(O)NH—, R 7 S(O) 2 NH—, R 4 NH—, and R 4 O—;

Q is chosen from heteroaryl, aryl, —CH 2 R 13 , —CH═N—OCH 3 and

W is chosen from H, Cl, F, R 8 , C 1 -C 4 -alkylaryl, —OR 8 , —SR 8 , —NR 9 R 10 and —NHC(O)R 11 , with the proviso that when Q is imidazolyl, W is not H, Cl, F or R 8 ;

R 2 is H or C 1 -C 3 -alkyl, or R 1 and R 2 taken together form a 5- to 7-membered ring structure optionally containing O, S or NR 12 ;

R 3 is H or C 1 -C 6 -alkyl, or, when n is zero, R 2 and R 3 taken together may form a 6-membered ring, which may be fused to a six-membered saturated or aromatic carbocycle;

R 4 is chosen from H, aryl, heteroaryl, C 1 -C 4 -alkyl substituted with from one to three aryl or heteroaryl residues,

R 5 is H or C 1 -C 3 -alkyl, with the proviso that both R 3 and R 5 cannot be alkyl;

R 6 is aryl;

R 7 is aryl or C 1 -C 3 -alkylaryl;

R 8 is chosen from alkyl, aryl, heteroaryl, substituted alkyl, C 1 -C 4 -alkylaryl, C 1 -C 4 -alkylheterocyclyl and C 1 -C 4 -alkylheteroaryl;

R 10 is H or C 1 -C 3 -alkyl; or

R 9 and R 10 taken together may form a 5- to 7-membered ring structure optionally containing O, S, SO, SO 2 or NR 12 , said ring optionally substituted with —OH, CN, —COOH or —COOCH 3 ;

R 11 is aryl;

R 12 is chosen from H, C 1 -C 3 -alkyl, alkoxycarbonyl, methoxyacetyl and aryl;

R 13 is chosen from —OH, —OTHP, 1-imidazolyl, and 1-pyrrolyl;

m is zero or one; and

n is zero or one, with the proviso that when A is A 2 , m and n cannot both be zero.

10. A 2-pyrimidinamine according to claim 9 wherein Q is chosen from imidazolyl, pyrrolyl, pyridinyl, fluorophenyl and 2-thienyl.

11. A 2-pyrimidinamine according to claim 10 wherein

A is R 4 R 5 N—C(O)—;

W is H, Cl, NHR 9 or OR 8 ;

R 1 is chosen from alkyl and C 1 -C 3 -alkylcycloalkyl;

R 2 , R 3 and R 5 are H;

R 4 is C 1 -C 4 -alkylaryl or C 1 -C 4 -alkylheteroaryl;

R 8 is C 1 -C 4 -alkylaryl;

R 9 is chosen from hydrogen, alkyl, fluoroalkyl, (C 1 -C 4 -alkoxy)alkyl, (C 1 -C 4 -alkylthio)alkyl, C 1 -C 4 -alkylcycloalkyl, C 1 -C 4 -alkylaryl, heterocyclyl, C 1 -C 4 -alkylheteroaryl, C 1 -C 4 -alkylheterocyclyl; and

m and n are zero.

12. A 2-pyrimidinamine according to claim 11 wherein W is NHR 9 and

R 9 is

wherein

R 14 is chosen from H, F, Cl, CN, NO 2 , SO 2 NH 2 , CF 3 , COOCH 3 , OCH 3 , SO 2 CH 3 , N(CH 3 ) 2 and COOH; and

R 15 is chosen from H, OCH 3 and Cl.

13. A compound of formula

wherein:

A is R 4 R 5 N—(O)—;

Q is is chosen from imidazolyl and pyrrolyl;

W is NHR 9 ;

R 1 is chosen from cyclohexylmethyl; 2-methylpropyl and 3-methyl-1-butyl;

R 2 , R 3 and R 5 are H;

R 4 and R 9 are benzyl or substituted benzyl;

m is zero; and

n is zero.

14. A compound of formula

wherein:

two of X, Y and Z are N and the other of X, Y and Z is CH;

A is A 1 or A 2 ;

A 1 is R 4 R 5 N—C(O)—,

A 2 is chosen from R 7 C(O)NH—, R 7 S(O) 2 NH—, R 4 NH—, and R 4 O—;

Q is chosen from heteroaryl, aryl, —CH 2 R 13 , —CH═N—OCH 3 and

W is chosen from H, Cl, F, R 8 , C 1 -C 4 -alkylaryl, —OR 8 , —SR 8 , —NR 9 R 10 and —NHC(O)R 11 , with the proviso that when Q is imidazolyl, W is not H, Cl, F or R 8 ;

R 2 is H or C 1 -C 3 -alkyl, or R 1 and R 2 taken together form a 5- to 7-membered ring structure optionally containing O, S or NR 12 ;

R 3 is H or C 1 -C 6 -alkyl, or, when n is zero, R 2 and R 3 taken together may form a 6-membered ring, which may be fused to a six-membered saturated or aromatic carbocycle;

R 4 is

having the R configuration at the carbon indicated with an asterisk, wherein J 1 and J 2 are independently chosen from H, F, Cl, CN, NO 2 and CH 3 , and G is chosen from —CH 2 —, —CH 2 CH 2 —, —CH 2 CH 2 CH 2 —, —OCH 2 —, —CH 2 O—, —CH 2 CH 2 O—, —OCH 2 CH 2 —, —O—, —N(lower alkyl)-, —N(lower alkyl)CH 2 —, —CH 2 N(lower alkyl)-, —S—, —SO—, —SO 2 —, —CH 2 S—, —SCH 2 —, —CH 2 SO—, —SOCH 2 —, —CH 2 SO 2 —, and —SO 2 CH 2 —;

R 5 is H or C 1 -C 3 -alkyl, with the proviso that both R 3 and R 5 cannot be alkyl;

R 6 is aryl;

R 7 is aryl or C 1 -C 3 -alkylaryl;

R 8 is chosen from alkyl, aryl, heteroaryl, substituted alkyl, C 1 -C 4 -alkylaryl, C 1 -C 4 -alkylheterocyclyl and C 1 -C 4 -alkylheteroaryl;

R 10 is H or C 1 -C 3 -alkyl; or

R 9 and R 10 taken together may form a 5- to 7-membered ring structure optionally containing O, S, SO, SO 2 or NR 12 , said ring optionally substituted with —OH, —CN, —COOH or —COOCH 3 ;

R 11 is aryl;

R 12 is chosen from H, C 1 -C 3 -alkyl, alkoxycarbonyl, methoxyacetyl and aryl;

R 13 is chosen from —OH, —OTHP, 1-imidazolyl, and 1-pyrrolyl;

m is zero or one; and

n is zero or one, with the proviso that when A is A 2 , m and n cannot both be zero.

15. A pyrimidine according to claim 9 wherein R 4 is

having the R configuration at the carbon indicated with an asterisk.

16. A compound of formula

wherein:

two of X, Y and Z are N and the other of X, Y and Z is CH;

A is A 1 or A 2 ;

A 1 is R 4 R 5 N—C(O)—;

A 2 is chosen from R 7 C(O)NH—, R 7 S(O) 2 NH—, R 4 NH—, and R 4 O—;

Q is chosen from aryl, —CH 2 R 13 , —CH═N—OCH 3 and

heteroaryl other than 1-imidazolyl and 1-triazolyl;

W is chosen from H, Cl, F, R 8 , C 1 -C 4 -alkylaryl, —OR 8 , —SR 8 , —NR 9 R 10 and —NHC(O)R 11 , with the proviso that when Q is imidazolyl, W is not H, Cl, F or R 8 ;

R 2 is H or C 1 -C 3 -alkyl, or R 1 and R 2 taken together form a 5- to 7-membered ring structure optionally containing O, S or NR 12 ;

R 3 is H or C 1 -C 6 -alkyl, or, when n is zero, R 2 and R 3 taken together may form a 6-membered ring, which may be fused to a six-membered saturated or aromatic carbocycle;

R 4 is chosen from H, aryl, heteroaryl, C 1 -C 4 -alkyl substituted with from one to three aryl or heteroaryl residues,

wherein J 1 and J 2 are independently chosen from H, F, Cl, CN, NO 2 and CH 3 , and G is chosen from —CH 2 —, —CH 2 CH 2 —, —CH 2 CH 2 CH 2 —, —OCH 2 —, CH 2 O—, —CH 2 CH 2 O—, —OCH 2 CH 2 —, —O—, —N(lower alkyl)-, —N(lower alkyl)CH 2 —, —CH 2 N(lower alkyl)-, —S—, —SO—, —SO 2 —, —CH 2 S—, —SCH 2 —, —CH 2 SO—, —SOCH 2 —, —CH 2 SO 2 —, and —SO 2 CH 2 —;

R 5 is H or C 1 -C 3 -alkyl, with the proviso that both R 3 and R 5 cannot be alkyl;

R 6 is aryl;

R 7 is aryl or C 1 -C 3 -alkylaryl;

R 8 is chosen from alkyl, aryl, heteroaryl, substituted alkyl, C 1 -C 4 -alkylaryl, C 1 -C 4 -alkylheterocyclyl and C 1 -C 4 -alkylheteroaryl;

R 10 is H or C 1 -C 3 -alkyl, or

R 9 and R 10 taken together may form a 5- to 7-membered ring structure optionally containing O, S, SO, SO 2 or NR 12 , said ring optionally substituted with —OH, —CN, —COOH or —COOCH 3 ;

R 11 is aryl;

R 12 is chosen from H, C 1 -C 3 -alkyl, alkoxycarbonyl, methoxyacetyl and aryl;

R 13 is chosen from —OH, —OTHP, 1-imidazolyl, and 1-pyrrolyl;

m is zero or one; and

n is zero or one, with the proviso that when A is A 2 , m and n cannot both be zero.

17. A 4-pyrimidinamine according to claim 16 , wherein Z is CH, having the formula

18. A 4-pyrimidinamine according to claim 17 wherein Q is chosen from methylimidazolyl, pyrrolyl, methylpyrrolyl, pyrazolyl, methylpyrazolyl, furanyl, methylfuranyl, thienyl, oxazolyl, thiazolyl, pyridinyl, quinolinyl, 1-methylpyrimidin-2-onyl, phenyl, fluorophenyl, hydroxymethyl, 2-imidazolyl, tetrahydropyranyloxymethyl, imidazolylmethyl, pyrrolylmethyl, —CH═N—OCH 3 and

19. A 4-pyrimidinamine according to claim 18 wherein:

Q is chosen from pyrrol-1-yl, imidazol-1-yl, furan-3-yl, 2-methylimidazol-1-yl and 4-methylimidazol-1-yl;

A is R 4 R 5 N—C(O)—;

W is Cl, NRH 9 , N(CH 3 )R 9 , OR 8 , SR 8 , R 8 , morpholin-4-yl,

R 1 is chosen from alkyl, cycloalkyl, C 1 -C 3 -alkylaryl, C 1 -C 3 -alkylcycloalkyl, C—C 3 -alkylheterocyclyl, C 1 -C 3 -alkylheteroaryl;

R 2 , R 3 and R 5 are H;

R 8 is C 1 -C 4 -alkylaryl;

R 9 is chosen from hydrogen, alkyl, substituted alkyl, (C 1 -C 4 )-alkoxy, C 1 -C 4 -alkylcycloalkyl, C 1 -C 4 -alkylaryl, heterocyclyl, C 1 -C 4 -alkylheteroaryl, C 1 -C 4 -alkylheterocyclyl; and

m and n are zero.

20. A 4-pyrimidinamine according to claim 19 wherein W is NHR 9 and

wherein

R 14 is chosen from H, Cl, F, CN, NO 2 , SO 2 NH 2 , CF 3 , COOCH 3 , OCH 3 , OH, SO 2 CH 3 , N(CH 3 ) 2 and COOH;

R 15 is chosen from H, OCH 3 and Cl; and

p is 1 or 2.

21. A 4-pyrimidinamine according to claim 19 wherein W is

R 12 is t-butoxycarbonyl, methoxyacetyl or phenyl.

22. A 4-pyrimidinamine according to claim 16 wherein

Z is CH;

A is

R 2 and R 3 are H;

Q is pyrrolyl;

W is NHR 9 ; and

R 9 is alkyl, cycloalkyl or

wherein

R 14 is chosen from H, Cl, F, CN, NO 2 , SO 2 NH 2 , CF 3 , COOCH 3 , OCH 3 , SO 2 CH 3 , N(CH 3 ) 2 and COOH; and

R 15 is chosen from H, OCH 3 and Cl.

23. A pyrimidine according to claim 16 wherein:

A is R 4 R 5 N—C(O)—;

R 2 , R 3 and R 5 are H;

R 4 is pyridinyl, pyridinylmethyl, indanylmethyl, furanylmethyl, tetrahydronaphthalenyl, substituted phenyl, or

R 16 is chosen from H, Cl, F, CN, NO 2 , SO 2 NH 2 , CF 3 , CH 3 , COOCH 3 , OCH 3 , SO 2 CH 3 , N(CH 3 ) 2 and COOH; and

R 17 is chosen from H, OCH 3 , F and Cl.

24. A pyrimidine according to claim 16 wherein R 4 is

25. A pyrimidine according to claim 24 , wherein one of J 1 and J 2 is H and the other is H, Cl or CN and G is chosen from —CH 2 —, —CH 2 CH 2 —, —OCH 2 —, —O— and —CH 2 N(lower alkyl)-.

26. A 2-pyrimidinamine according to claim 16 , wherein Y is CH, having the formula

27. A 2-pyrimidinamine according to claim 26 wherein Q is chosen from pyrrolyl, pyridinyl, fluorophenyl and 2-thienyl.

28. A 2-pyrimidinamine according to claim 27 wherein

A is R 4 R 5 N—C(O)—;

W is H, Cl, NHR 9 or OR 8 ;

R 1 is chosen from alkyl and C 1 -C 3 -alkylcycloalkyl;

R 2 , R 3 and R 5 are H;

R 4 is C 1 -C 4 -alkylaryl or C 1 -C 4 -alkylheteroaryl;

R 8 is C 1 -C 4 -alkylaryl;

m and n are zero.

29. A 2-pyrimidinamine according to claim 28 wherein W is NHR 9 and

R 9 is

wherein

R 14 is chosen from H, F, Cl, CN, NO 2 , SO 2 NH 2 , CF 3 , COOCH 3 , OCH 3 , SO 2 CH 3 , N(CH 3 ) 2 and COOH; and

R 15 is chosen from H, OCH 3 and Cl.

30. A 2-pyrimidineamine according to claim 26 wherein R 4 is

one of J 1 and J 2 is H and the other is H, Cl or CN and G is chosen from —CH 2 —, —CH 2 CH 2 —, —OCH 2 —, —O— and —CH 2 N(lower alkyl)-.

31. A 4-pyrimidinamine according to claim 16 , wherein X is CH, having the formula

32. A 4-pyrimidinamine according to claim 31 wherein Q is pyrrolyl and m and n are zero.

33. A 4-pyrimidinamine according to claim 32 wherein:

A is R 4 R 5 N—C(O)—;

W is NHR 9 ;

R 1 is chosen from cyclohexylmethyl; 2-methylpropyl and 3-methyl-1-butyl;

R 2 , R 3 and R 5 are H; and

R 4 and R 9 are benzyl or substituted benzyl.

34. A 4-pyrimidineamine according to claim 31 wherein R 4 is

one of J 1 and J 2 is H and the other is H, Cl or CN and G is chosen from —CH 2 —, —CH 2 CH 2 —, —OCH 2 —, —O— and —CH 2 N(lower alkyl)-.

35. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a compound according to any of claims 1 , 6 , 9 , or 14 .

36. A pharmaceutical composition according to claim 35 additionally comprising a steroidal or nonsteroidal antiinflammatory drug (NSAID).

37. A pharmaceutical composition according to claim 35 additionally comprising a cyclooxygenase inhibitor.

38. A pharmaceutical composition according to claim 35 additionally comprising a selective cyclooxygenase-2 inhibitor.

39. A pharmaceutical composition according to claim 35 additionally comprising a selective cyclooxygenase-1 inhibitor.

40. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a compound according to claim 16 .

41. A pharmaceutical composition according to claim 40 additionally comprising a steroidal or nonsteroidal antiinflammatory drug (NSAID).

42. A pharmaceutical composition according to claim 40 additionally comprising a nonsteroidal antiinflammatory drug (NSAID).

43. A pharmaceutical composition according to claim 42 wherein said NSAID is chosen from arylpropionic acids, arylacetic acids, arylbutyric acids, fenamic acids, arylcarboxylic acids, pyrazoles, pyrazolones, salicylic acids; and oxicams.

44. A pharmaceutical composition according to claim 40 additionally comprising a cyclooxygenase inhibitor.

45. A pharmaceutical composition according to claim 44 wherein said cyclooxygenase inhibitor is ibuprofen or a salicylic acid derivative.

46. A pharmaceutical composition according to claim 40 additionally comprising a selective cyclooxygenase-2 inhibitor.

47. A pharmaceutical composition according to claim 46 wherein said selective cyclooxygenase-2 inhibitor is rofecoxib or celecoxib.

48. A pharmaceutical composition according to claim 40 additionally comprising a selective cyclooxygenase-I inhibitor.

49. A pharmaceutical composition according to claim 40 additionally comprising a steroidal antiinflammatory drug.

50. A pharmaceutical composition according to claim 49 wherein said steroidal antiinflammatory drug is chosen from finasteride, beclomethasone and hydrocortisone.

51. A method of treating vasculopathy comprising administering to a subject in need of such treatment a therapeutically effective amount of a compound of formula I

wherein:

two of X, Y and Z are N and the other of X, Y and Z is CH;

A is A 1 or A 2 ;

A 1 is R 4 R 5 N—(O)—,

A 2 is chosen from R 7 C(O)NH—, R 7 S(O) 2 NH—, R 4 NH—, and R 4 O—;

Q is chosen from heteroaryl, aryl, —CH 2 R 13 , —CH═N—OCH 3 and

W is chosen from H, Cl, F, R 8 , C 1 -C 4 -alkylaryl, —OR 8 , —SR 8 , —NR 9 R 10 and —NHC(O)R 11 , with the proviso that when Q is imidazolyl, W is not H, Cl, F or R 8 ;

R 2 is H or C 1 -C 3 -alkyl, or R 1 and R 2 taken together form a 5- to 7-membered ring structure optionally containing O, S or NR 12 ;

R 3 is H or C 1 -C 6 -alkyl, or, when n is zero, R 2 and R 3 taken together may form a 6-membered ring, which may be fused to a six-membered saturated or aromatic carbocycle;

R 4 is chosen from H, aryl, heteroaryl, C 1 -C 4 -alkyl substituted with from one to three aryl or heteroaryl residues,

R 5 is H or C 1 -C 3 -alkyl, with the proviso that both R 3 and R 5 cannot be alkyl;

R 6 is aryl;

R 7 is aryl or C 1 -C 3 -alkylaryl;

R 8 is chosen from alkyl, aryl, heteroaryl, substituted alkyl, C 1 -C 4 -alkylaryl, C 1 -C 4 -alkylheterocyclyl and C 1 -C 4 -alkylheteroaryl;

R 10 is H or C 1 -C 3 -alkyl, or

R 9 and R 10 taken together may form a 5- to 7-membered ring structure optionally containing O, S, SO, SO 2 or NR 12 , said ring optionally substituted with —OH, —CN, —COOH or —COOCH 3 ;

R 11 is aryl;

R 12 is chosen from H, C 1 -C 3 -alkyl, alkoxycarbonyl, methoxyacetyl and aryl;

R 13 is chosen from —OH, —OTHP, 1-imidazolyl, and 1-pyrrolyl;

m is zero or one; and

n is zero or one, with the proviso that when A is A 2 , m and n cannot both be zero.

52. The method according to claim 51 wherein said vasculopathy is diabetic vasculopathy.

53. The method according to claim 51 wherein said vasculopathy is hypertensive vasculopathy.

54. A method of treating asthma comprising administering to a subject in need of such treatment a therapeutically effective amount of a compound of formula I

wherein:

two of X, Y and Z are N and the other of X, Y and Z is CH;

A is A 1 or A 2 ;

A 1 is R 4 R 5 N—C(O)—,

A 2 is chosen from R 7 C(O)NH—, R 7 S(O) 2 NH—, R 4 NH—, and R 4 O—;

Q is chosen from heteroaryl, aryl, —CH 2 R 13 , —CH═N—OCH 3 and

W is chosen from H, Cl, F, R 8 , C 1 -C 4 -alkylaryl, —OR 8 , —SR 8 , —NR 9 R 10 and —NHC(O)R 11 , with the proviso that when Q is imidazolyl, W is not H, Cl, F or R 8 ;

R 2 is H or C 1 -C 3 -alkyl, or R 1 and R 2 taken together form a 5- to 7-membered ring structure optionally containing O, S or NR 12 ;

R 3 is H or C 1 -C 6 -alkyl, or, when n is zero, R 2 and R 3 taken together may form a 6-membered ring, which may be fused to a six-membered saturated or aromatic carbocycle;

R 4 is chosen from H, aryl, heteroaryl, C 1 -C 4 -alkyl substituted with from one to three aryl or heteroaryl residues,

R 5 is H or C 1 -C 3 -alkyl, with the proviso that both R 3 and R 5 cannot be alkyl;

R 6 is aryl;

R 7 is aryl or C 1 -C 3 -alkylaryl;

R 8 is chosen from alkyl, aryl, heteroaryl, substituted alkyl, C 1 -C 4 -alkylaryl, C 1 -C 4 -alkylheterocyclyl and C 1 -C 4 -alkylheteroaryl;

R 10 is H or C 1 -C 3 -alkyl, or

R 9 and R 10 taken together may form a 5- to 7-membered ring structure optionally containing O, S, SO, SO 2 or NR 12 , said ring optionally substituted with —OH, —CN, —COOH or —COOCH 3 ;

R 11 is aryl;

R 12 is chosen from H, C 1 -C 3 -alkyl, alkoxycarbonyl, methoxyacetyl and aryl;

R 13 is chosen from —OH, —OTHP, 1-imidazolyl, and 1-pyrrolyl;

m is zero or one; and

n is zero or one, with the proviso that when A is A 2 , m and n cannot both be zero.

55. A method of treating pain or hyperalgesia comprising administering to a subject in need of such treatment a therapeutically effective amount of a compound of formula I

wherein:

two of X, Y and Z are N and the other of X, Y and Z is CH;

A is A 1 or A 2 ;

A 1 is R 4 R 5 N—C(O)—,

A 2 is chosen from R 7 C(O)NH—, R 7 S(O) 2 NH—, R 4 NH—, and R 4 O—;

Q is chosen from heteroaryl, aryl, —CH 2 R 13 , —CH═N—OCH 3 and

W is chosen from H, Cl, F, R 8 , C 1 -C 4 -alkylaryl, —OR 8 , —SR 8 , —NR 9 R 10 and —NHC(O)R 11 , with the proviso that when Q is imidazolyl, W is not H, Cl, F or R 8 ;

R 2 is H or C 1 -C 3 -alkyl, or R 1 and R 2 taken together form a 5- to 7-membered ring structure optionally containing O, S or NR 12 ;

R 3 is H or C 1 -C 6 -alkyl, or, when n is zero, R 2 and R 3 taken together may form a 6-membered ring, which may be fused to a six-membered saturated or aromatic carbocycle;

R 4 is chosen from H, aryl, heteroaryl, C 1 -C 4 -alkyl substituted with from one to three aryl or heteroaryl residues,

R 5 is H or C 1 -C 3 -alkyl, with the proviso that both R 3 and R 5 cannot be alkyl;

R 6 is aryl;

R 7 is aryl or C 1 -C 3 -alkylaryl;

R 8 is chosen from alkyl, aryl, heteroaryl, substituted alkyl, C 1 -C 4 -alkylaryl, C 1 -C 4 -alkylheterocyclyl and C 1 -C 4 -alkylheteroaryl;

R 10 is H or C 1 -C 3 -alkyl; or

R 9 and R 10 taken together may form a 5- to 7-membered ring structure optionally containing O, S, SO, SO 2 or NR 12 , said ring optionally substituted with —OH, —CN, —COOH or —COOCH 3 ;

R 11 is aryl;

R 12 is chosen from H, C 1 -C 3 -alkyl, alkoxycarbonyl, methoxyacetyl and aryl;

R 13 is chosen from —OH, —OTHP, 1-imidazolyl, and 1-pyrrolyl;

m is zero or one; and

n is zero or one, with the proviso that when A is A 2 , m and n cannot both be zero.

56. The method according to claim 55 wherein said pain is chronic pain, pain associated with inflammation or dental pain.

57. The method of treating pain or hyperalgesia according to claim 55 additionally comprising administering a steroidal or nonsteroidal antiinflammatory drug (NSAID).

58. The method of treating pain or hyperalgesia according to claim 57 wherein an NSAID is administered.

59. The method of treating pain or hyperalgesia according to claim 55 additionally comprising administering a cyclooxygenase inhibitor.

60. The method of treating pain or hyperalgesia according to claim 59 wherein said cyclooxygenase inhibitor is a selective cyclooxygenase-2 inhibitor.

61. The method of treating pain or hyperalgesia according to claim 59 wherein said cyclooxygenase inhibitor is a selective cyclooxygenase-1 inhibitor.

62. A method of treating post-capillary resistance or diabetic symptoms associated with insulitis comprising administering to a subject in need of such treatment a therapeutically effective amount of a compound of formula I

wherein:

two of X, Y and Z are N and the other of X, Y and Z is CH;

A is A 1 or A 2 ;

A 1 is R 4 R 5 N—(O)—,

A 2 is chosen from R 7 C(O)NH—, R 7 S(O) 2 NH—, R 4 NH—, and R 4 O—;

Q is chosen from heteroaryl, aryl, —CH 2 R 13 , —CH═N—OCH 3 and

W is chosen from H, Cl, F, R 8 , C 1 -C 4 -alkylaryl, —OR 8 , —SR 8 , —NR 9 R 10 and —NHC(O)R 11 , with the proviso that when Q is imidazolyl, W is not H, Cl, F or R 8 ;

R 2 is H or C 1 -C 3 -alkyl, or R 1 and R 2 taken together form a 5- to 7-membered ring structure optionally containing O, S or NR 12 ;

R 3 is H or C 1 -C 6 -alkyl, or, when n is zero, R 2 and R 3 taken together may form a 6-membered ring, which may be fused to a six-membered saturated or aromatic carbocycle;

R 4 is chosen from H, aryl, heteroaryl, C 1 -C 4 -alkyl substituted with from one to three aryl or heteroaryl residues,

wherein J 1 and J 2 are independently chosen from H, F, Cl, CN, NO 2 and CH 3 and G is chosen from —CH 2 —, —CH 2 CH 2 —, —CH 2 CH 2 CH 2 —, —OCH 2 —, —CH 2 O—, —CH 2 CH 2 O—, —OCH 2 CH 2 —, —O—, —N(lower alkyl)-, —N(lower alkyl)CH 2 —, —CH 2 N(lower alkyl)-, —S—, —SO—, —SO 2 —, —CH 2 S—, —SCH 2 —, —CH 2 SO—, —SOCH 2 —, —CH 2 SO 2 —, and —SO 2 CH 2 —;

R 5 is H or C 1 -C 3 -alkyl, with the proviso that both R 3 and R 5 cannot be alkyl;

R 6 is aryl;

R 7 is aryl or C 1 -C 3 -alkylaryl;

R 8 is chosen from alkyl, aryl, heteroaryl, substituted alkyl, C 1 -C 4 -alkylaryl, C 1 -C 4 -alkylheterocyclyl and C 1 -C 4 -alkylheteroaryl;

R 10 is H or C 1 -C 3 -alkyl; or

R 9 and R 10 taken together may form a 5- to 7-membered ring structure optionally containing O, S, SO, SO 2 or NR 12 , said ring optionally substituted with —OH, —CN, —COOH or —COOCH 3 ;

R 11 is aryl;

R 12 is chosen from H, C 1 -C 3 -alkyl, alkoxycarbonyl, methoxyacetyl and aryl;

R 13 is chosen from —OH, —OTHP, 1-imidazolyl, and 1-pyrrolyl;

m is zero or one; and

n is zero or one, with the proviso that when A is A 2 , m and n cannot both be zero.

63. The method according to claim 62 wherein said diabetic symptoms associated with insulitis comprise hyperglycemia, diuresis, proteinuria and increased nitrile and kallikrein urinary excretion.

64. A method of treating edema comprising administering to a subject in need of such treatment a therapeutically effective amount of a compound of formula I

wherein:

two of X, Y and Z are N and the other of X, Y and Z is CH;

A is A 1 or A 2 ;

A 1 is R 4 R 5 N—C(O)—,

A 2 is chosen from R 7 C(O)NH—, R 7 S(O) 2 NH—, R 4 NH—, and R 4 O—;

Q is chosen from heteroaryl, aryl, —CH 2 R 13 , —CH═N—OCH 3 and

W is chosen from H, Cl, F, R 8 , C 1 -C 4 -alkylaryl, —OR 8 , —SR 8 , —NR 9 R 10 and —NHC(O)R 11 , with the proviso that when Q is imidazolyl, W is not H, Cl, F or R 8 ;

R 2 is H or C 1 -C 3 -alkyl, or R 1 and R 2 taken together form a 5- to 7-membered ring structure optionally containing O, S or NR 12 ;

R 3 is H or C 1 -C 6 -alkyl, or, when n is zero, R 2 and R 3 taken together may form a 6-membered ring, which may be fused to a six-membered saturated or aromatic carbocycle;

R 4 is chosen from H, aryl, heteroaryl, C 1 -C 4 -alkyl substituted with from one to three aryl or heteroaryl residues,

R 5 is H or C 1 -C 3 -alkyl, with the proviso that both R 3 and R 5 cannot be alkyl;

R 6 is aryl;

R 7 is aryl or C 1 -C 3 -alkylaryl;

R 8 is chosen from alkyl, aryl, heteroaryl, substituted alkyl, C 1 -C 4 -alkylaryl, C 1 -C 4 -alkylheterocyclyl and C 1 -C 4 -alkylheteroaryl;

R 10 is H or C 1 -C 3 -alkyl; or

R 9 and R 10 taken together may form a 5- to 7-membered ring structure optionally containing O, S, SO, SO 2 or NR 12 , said ring optionally substituted with —OH, —CN, —COOH or —COOCH 3 ;

R 11 is aryl;

R 12 is chosen from H, C 1 -C 3 -alkyl, alkoxycarbonyl, methoxyacetyl and aryl;

R 13 is chosen from —OH, —OTHP, 1-imidazolyl, and 1-pyrrolyl;

m is zero or one; and

n is zero or one, with the proviso that when A is A 2 , m and n cannot both be zero.