Inhibitors of Cytosolic Phospholipase A2

1 . A compound having the Formula I:

wherein:

n 1 is 1 or 2;

n 2 is 1 or 2;

n 3 is 1 or 2;

n 5 is 0, 1 or 2;

X 2 is a bond, O, —CH 2 — or SO 2 ;

each R 5 is independently H or C 1-3 alkyl;

R 6 is H or C 1-6 alkyl;

R 7 is selected from the group consisting of OH, benzyloxy, CH 3 , CF 3 , OCF 3 , C 1-3 alkoxy, halogen, COH, CO(C 1-3 alkyl), CO(OC 1-3 alkyl) quinoline-5-yl, quinoline-8-yl, 3,5-dimethylisoxazol-4-yl, thiophene-3-yl, pyridin-4-yl pyridine-3-yl, —CH 2 -Q, and phenyl optionally substituted by from one to three independently selected R 30 groups;

R 8 is selected from the group consisting of H, OH, NO 2 , CF 3 , C 1-3 alkoxy, halogen, CO(C 1-3 alkyl), CO(OC 1-3 alkyl), quinoline-5-yl quinoline-8-yl, 3,5-dimethylisoxazol-4-yl, thiophene-3-yl, —CH 2 -Q, and phenyl substituted by from one to three independently selected R 30 groups;

Q is OH, dialkylamino,

R 20 is selected from the group consisting of H, C 1-3 alkyl and CO(C 1-3 alkyl); and

R 30 is selected from the group consisting of dialkylamino, CN and OCF 3 ;

provided that:

a) when each R 5 is H, R 6 is H, n 5 is 0, and R 8 is H, then R 7 cannot be chlorine;

b) when each R 5 is H, R 6 is H, n 5 is 0, X 2 is O or —CH 2 —, and R 8 is H, then R 7 cannot be CH 3 ;

c) when each R 5 is H, and R 6 is H, then R 7 and R 8 cannot both be fluorine;

d) when each R 5 is H, R 6 is H, and X 2 is O, then R 7 and R 8 cannot both be chlorine;

e) when each R 5 is H, R 6 is H, X 2 is O, and R 8 is NO 2 , then R 7 cannot be fluorine; and

f) when each R 5 is H, R 6 is H, X 2 is SO 2 , and R 8 is H, then R 7 cannot be fluorine or chlorine;

or a pharmaceutically acceptable salt thereof.

2 . A compound or salt of claim 1 wherein X 2 is CH 2 .

3 . A compound or salt of claim 2 wherein n 3 is 1.

4 . A compound or salt of claim 2 wherein n 1 is 1.

5 . A compound or salt of claim 2 wherein n 2 is 1.

6 . A compound or salt of claim 2 wherein n 3 is 1; n 1 is 1; and n 2 is 1.

7 . A compound or salt of claim 2 wherein R 6 is H.

8 . A compound or salt of claim 2 wherein:

n 3 is 1;

n 1 is 1;

n 2 is 1;

R 6 is H;

R 7 is selected from the group consisting of CH 3 , CF 3 , OCF 3 , halogen, COOCH 3 , COH, CH 2 OH, diethylaminomethyl, quinoline-5-yl, quinoline-8-yl, 3,5-dimethylisoxazol-4-yl, thiophene-3-yl, pyridin-4-yl, pyridine-3-yl, phenyl, 4-dimethylamino-phen-1-yl, 2-trifluoromethoxy-phen-1-yl, 2-cyano-phen-1-yl, morpholine-1-yl-methyl, piperazine-1-yl methyl, 4-acetyl-piperazine-1-yl methyl, and 4-methyl-piperazine-1-yl methyl; and

R 8 is selected from the group consisting of H, halogen, CF 3 and NO 2 .

9 . A compound or salt of claim 8 wherein R 5 is H.

10 . A compound or salt of claim 8 wherein R 5 is CH 3 .

11 . A compound or salt of claim 1 wherein X 2 is O.

12 . A compound or salt of claim 11 wherein n 3 is 1.

13 . A compound or salt of claim 11 wherein n 1 is 1.

14 . A compound or salt of claim 11 wherein n 2 is 1.

15 . A compound or salt of claim 11 wherein R 6 is H.

16 . A compound or salt of claim 11 wherein n 3 is 1; n 1 is 1; and n 2 is 1.

17 . A compound or salt of claim 11 wherein:

n 3 is 1;

n 1 is 1;

n 2 is 1;

R 6 is H;

R 7 is selected from the group consisting of benzyloxy, OH, halogen, CH 3 and CF 3 ; and

R 8 is selected from the group consisting of H, halogen, and NO 2 .

18 . A compound or salt of claim 17 wherein R 5 is H.

19 . A compound or salt of claim 17 wherein R 5 is CH 3 .

20 . A compound or salt of claim 17 wherein R 7 is CF 3 , and R 8 is H.

21 . A compound or salt of claim 1 wherein X 2 is SO 2 .

22 . A compound or salt of claim 1 wherein X 2 is SO 2 , and n 5 is 2.

23 . A compound or salt of claim 22 wherein n 3 is 1.

24 . A compound or salt of claim 22 wherein n 1 is 1.

25 . A compound or salt of claim 22 wherein n 2 is 1.

26 . A compound or salt of claim 22 wherein n 3 is 1; n 1 is 1; and n 2 is 1.

27 . A compound or salt of claim 22 wherein:

n 3 is 1;

n 1 is 1;

n 2 is 1;

R 6 is H;

R 7 is CF 3 ; and

R 8 is H.

28 . A compound or salt of claim 1 , wherein n 1 is 1; n 2 is 1 or 2; n 3 is 1, n 5 is 0; X 2 is CH 2 , each R 5 and each R 6 is H; and R 7 and R 8 are independently selected from the group consisting of H, F, CF 3 , OCF 3 , OH, quinoline-5-yl and quinoline-8-yl, provided that R 7 and R 8 are not both H.

29 . A compound or salt of claim 28 , wherein n 2 is 1.

30 . A compound of Formula II:

wherein:

X is a bond or O;

n 1 is 1 or 2;

n 2 is 1 or 2;

n 6 is 1 or 2;

R 5 is H or CH 3 ;

R 6 is H or C 1-6 alkyl; and

R 8 is selected from the group consisting of H, OH, NO 2 , CF 3 , OCF 3 , OCH 3 , halogen, COCH 3 , COOCH 3 , dimethylamino, diethylamino and CN;

or a pharmaceutically acceptable salt thereof.

31 . A compound or salt of claim 30 wherein n 1 is 1.

32 . A compound or salt of claim 30 wherein n 2 is 1.

33 . A compound or salt of claim 30 wherein n 6 is 2.

34 . A compound or salt of claim 30 wherein R 5 is H.

35 . A compound or salt of claim 30 wherein n 1 is 1; n 2 is 1; and n 6 is 2.

36 . A compound or salt of claim 30 wherein R 6 is H.

37 . A compound or salt of claim 30 wherein R 5 is H; R 6 is H, n 1 is 1, n 2 is 1; and n 6 is 2.

38 . A compound or salt of claim 37 wherein R 8 is selected from the group consisting of H, CF 3 , OCF 3 and halogen.

39 . A compound or salt of claim 37 wherein R 8 is H.

40 . A compound of claim 1 that is selected from the group consisting of:

a) 4-{2-[2-[2-({[2-(benzyloxy)benzyl]sulfonyl}amino)ethyl]-5-chloro-1-(diphenylmethyl)-1H-indol-3-yl]ethoxy}benzoic acid;

b) 4-{2-[5-chloro-1-(diphenylmethyl)-2-(2-{[(2-hydroxybenzyl)sulfonyl]amino}ethyl)-1H-indol-3-yl]ethoxy}benzoic acid;

c) 4-{2-[5-chloro-2-(2-{[(2,6-dibromobenzyl)sulfonyl]amino}ethyl)-1-(diphenylmethyl)-1H-indol-3-yl]ethoxy}benzoic acid;

d) 4-(2-{1-benzhydryl-5-chloro-2-[2-methyl-6-nitro-phenylmethanesulfonylamino)-ethyl-1-H-indol-3-yl}-ethoxy)-benzoic acid;

e) 4-(2-{5-chloro-1-(diphenylmethyl)-2-[2-({[2-(trifluoromethyl)benzyl]sulfonyl}amino)ethyl]-1H-indol-3-yl}ethoxy)benzoic acid;

f) 4-(2-{5-chloro-1-(diphenylmethyl)-2-[2-({[2-fluoro-6-(trifluoromethyl)benzyl]sulfonyl}amino)ethyl]-1H-indol-3-yl}ethoxy)benzoic acid;

g) 4-{3-[5-chloro-2-(2-{[(2,6-dibromobenzyl)sulfonyl]amino}ethyl)-1-(diphenylmethyl)-1H-indol-3-yl]propyl}benzoic acid;

h) 4-{3-[5-chloro-2-(2-{[(2,6-dichlorobenzyl)sulfonyl]amino}ethyl)-1-(diphenylmethyl)-1H-indol-3-yl]propyl}benzoic acid;

i) 4-(3-{1-benzhydryl-5-chloro-2-[2-(2-methyl-6-nitro-phenylmethanesulfonylamino)-ethyl-1H-indol-3-yl}propyl)-benzoic acid;

j) 4-(3-{5-chloro-1-(diphenylmethyl)-2-[2-({[2-(trifluoromethyl)benzyl]sulfonyl}amino)ethyl]-1H-indol-3-yl}propyl)benzoic acid;

k) 4-(3-{5-chloro-1-(diphenylmethyl)-2-[2-(methyl{[2-(trifluoromethyl)benzyl]sulfonyl}amino)ethyl]-1H-indol-3-yl}propyl)benzoic acid;

l) 4-{3-[2-[2-({[2,6-bis(trifluoromethyl)benzyl]sulfonyl}amino)ethyl]-5-chloro-1-(diphenylmethyl)-1H-indol-3-yl]propyl}benzoic acid;

m) 4-(3-{5-chloro-1-(diphenylmethyl)-2-[2-({[2-(methoxycarbonyl)benzyl]sulfonyl}amino)ethyl]-1H-indol-3-yl}propyl)benzoic acid;

n) 4-(3-{5-chloro-1-(diphenylmethyl)-2-[2-({[2-fluoro-6-(trifluoromethyl)benzyl]sulfonyl}amino)ethyl]-1H-indol-3-yl}propyl)benzoic acid;

o) 4-[3-(5-chloro-1-(diphenylmethyl)-2-{2-[({2-[2-(trifluoromethyl)phenyl]ethyl}sulfonyl)amino]ethyl}-1H-indol-3-yl)propyl]benzoic acid;

p) 4-{3-[5-chloro-1-(diphenylmethyl)-2-(2-{[(2-formylbenzyl)sulfonyl]amino}ethyl)-1H-indol-3-yl]propyl}benzoic acid;

q) 4-(3-{5-chloro-1-(diphenylmethyl)-2-[2-({[2-(morpholin-4-ylmethyl)benzyl]sulfonyl}amino)ethyl]-1H-indol-3-yl}propyl)benzoic acid;

r) 4-{3-[5-chloro-2-{2-[({2-[(diethylamino)methyl]benzyl}sulfonyl)amino]ethyl}-1-(diphenylmethyl)-1H-indol-3-yl]propyl}benzoic acid;

s) 4-(3-{5-chloro-1-(diphenylmethyl)-2-[2-({[2-(hydroxymethyl)benzyl]sulfonyl}amino)ethyl]-1H-indol-3-yl}propyl)benzoic acid;

t) 4-(3-{5-chloro-1-(diphenylmethyl)-2-[2-({[2-(piperazin-1-ylmethyl)benzyl]sulfonyl}amino)ethyl]-1H-indol-3-yl}propyl)benzoic acid;

u) 4-{3-[2-{2-[({2-[(4-acetylpiperazin-1-yl)methyl]benzyl}sulfonyl)amino]ethyl}-5-chloro-1-(diphenylmethyl)-1H-indol-3-yl]propyl}benzoic acid;

v) 4-[3-(5-chloro-1-(diphenylmethyl)-2-{2-[({2-[(4-methylpiperazin-1-yl)methyl]benzyl}sulfonyl)amino]ethyl}-1H-indol-3-yl)propyl]benzoic acid;

w) 4-[3-(5-chloro-1-(diphenylmethyl)-2-{2-[({1-[2-(trifluoromethyl)phenyl]ethyl}sulfonyl)amino]ethyl}-1H-indol-3-yl)propyl]benzoic acid;

x) 4-{3-[2-(2-{[(2-bromobenzyl)sulfonyl]amino}ethyl)-5-chloro-1-(diphenylmethyl)-1H-indol-3-yl]propyl}benzoic acid;

y) 4-(3-{5-chloro-1-(diphenylmethyl)-2-[2-({[2-(trifluoromethoxy)benzyl]sulfonyl}amino)ethyl]-1H-indol-3-yl}propyl)benzoic acid;

z) 4-{3-[5-chloro-2-(2-{[(3-chloro-6-fluoro-2-methylbenzyl)sulfonyl]amino}ethyl)-1-(diphenylmethyl)-1H-indol-3-yl]propyl}benzoic acid;

aa) 4-(3-{5-chloro-1-(diphenylmethyl)-2-[2-({[2-nitro-6-(trifluoromethyl)benzyl]sulfonyl}amino)ethyl]-1H-indol-3-yl}propyl)benzoic acid;

ab) 4-{3-[5-chloro-1-(diphenylmethyl)-2-(2-{[(2-fluorobenzyl)sulfonyl]amino}ethyl)-1H-indol-3-yl]propyl}benzoic acid;

ac) 4-{3-[2-(2-{[(biphenyl-2-ylmethyl)sulfonyl]amino}ethyl)-5-chloro-1-(diphenylmethyl)-1H-indol-3-yl]propyl}benzoic acid;

ad) 4-{3-[5-chloro-1-(diphenylmethyl)-2-(2-{[(2-pyridin-4-ylbenzyl)sulfonyl]amino}ethyl)-1H-indol-3-yl]propyl}benzoic acid;

ae) 4-{3-[5-chloro-1-(diphenylmethyl)-2-(2-{[(2-pyridin-3-ylbenzyl)sulfonyl]amino}ethyl)-1H-indol-3-yl]propyl}benzoic acid;

af) 4-(3-{5-chloro-1-(diphenylmethyl)-2-[2-({[2-(3-thienyl)benzyl]sulfonyl}amino)ethyl]-1H-indol-3-yl}propyl)benzoic acid;

ag) 4-{3-[5-chloro-2-[2-({[2-(3,5-dimethylisoxazol-4-yl)benzyl]sulfonyl}amino)ethyl]-1-(diphenylmethyl)-1H-indol-3-yl]propyl}benzoic acid;

ah) 4-{3-[5-chloro-1-(diphenylmethyl)-2-(2-{[(2-quinolin-5-ylbenzyl)sulfonyl]amino}ethyl)-1H-indol-3-yl]propyl}benzoic acid;

ai) 4-{3-[5-chloro-2-{2-[({[4′-(dimethylamino)biphenyl-2-yl]methyl}sulfonyl)amino]ethyl}-1-(diphenylmethyl)-1H-indol-3-yl]propyl}benzoic acid;

aj) 4-[3-(5-chloro-1-(diphenylmethyl)-2-{2-[({[2′-(trifluoromethoxy)biphenyl-2-yl]methyl}sulfonyl)amino]ethyl}-1H-indol-3-yl)propyl]benzoic acid;

ak) 4-{3-[5-chloro-2-[2-({[(2′-cyanobiphenyl-2-yl)methyl]sulfonyl}amino)ethyl]-1-(diphenylmethyl)-1H-indol-3-yl]propyl}benzoic acid;

al) 3-{4-[(2-{5-chloro-1-(diphenylmethyl)-2-[2-({[2-(trifluoromethyl)benzyl]sulfonyl}amino)ethyl]-1H-indol-3-yl}ethyl)sulfony]phenyl}propanoic acid;

am) 3-(4-{[2-(5-chloro-1-(diphenylmethyl)-2-{2-[({1-[2-(trifluoromethyl)phenyl]ethyl}sulfonyl)amino]ethyl}-1H-indol-3-yl)ethyl]sulfonyl}phenyl)propanoic acid;

an) 4-{3-[5-chloro-1-(diphenylmethyl)-2-(2-{[(2-hydroxybenzyl)sulfonyl]amino}ethyl)-1H-indol-3-yl]propyl}benzoic acid; and

ao) 4-{3-[5-chloro-1-(diphenylmethyl)-2-(2-{[(2-quinolin-5-ylbenzyl)sulfonyl]amino}ethyl)-1H-indol-3-yl]propyl}benzoic acid;

or a pharmaceutically acceptable salt thereof.

41 . A method of treating inflammation caused or potentiated by prostaglandins, leukotrienes, or platelet activation factor, in a mammal, the method comprising administering to a mammal in need thereof a pharmaceutically acceptable amount of a compound of claim 1 , or a pharmaceutically acceptable salt thereof.

42 . A method of treating pain caused or potentiated by prostaglandins, leukotrienes, or platelet activation factor, in a mammal, the method comprising administering to a mammal in need thereof a pharmaceutically acceptable amount of a compound of claim 1 , or a pharmaceutically acceptable salt thereof.

43 . A method of treatment of asthma in a mammal, the method comprising administering to a mammal in need thereof a pharmaceutically effective amount of a compound of the claim 1 , or a pharmaceutically acceptable salt thereof.

44 . A method of treatment of arthritic and rheumatic disorders in a mammal, the method comprising administering to a mammal in need thereof a pharmaceutically effective amount of a compound of claim 1 , or a pharmaceutically acceptable salt thereof.

45 . A method of claim 44 wherein the disorder is rheumatoid arthritis.

46 . A method of claim 44 wherein the disorder is osteoarthritis.

47 . A method of claim 44 wherein the disorder is juvenile arthritis.

48 . A method of treating or preventing a disease or disorder in a mammal, or preventing progression of symptoms such a disease or disorder, wherein the disease or disorder is selected from the group consisting of stroke, atherosclerosis, multiple sclerosis, Parkinson's disease, central nervous system damage resulting from stroke, central nervous system damage resulting from ischemia, and central nervous system damage resulting from trauma, the method comprising administering to a mammal in need thereof a pharmaceutically acceptable amount of a compound of claim 1 , or a pharmaceutically acceptable salt thereof.

49 . A method of claim 48 wherein the disease or disorder is stroke.

50 . A method of claim 48 wherein the disease or disorder is atherosclerosis.

51 . A method of claim 48 wherein the disease or disorder is multiple sclerosis.

52 . A method of claim 48 wherein the disease or disorder is Parkinson's disease.

53 . A method of claim 48 wherein the disease or disorder is central nervous system damage resulting from stroke, from ischemia, or from trauma.

54 . A method for treating or preventing venous or arterial thrombosis in a mammal, or preventing progression of a symptom of said thrombosis, the method comprising administering to a mammal in need thereof a pharmaceutically acceptable amount of a compound of claim 1 , or a pharmaceutically acceptable salt thereof.

55 . A method of claim 54 , wherein the thrombosis is atherothrombosis.

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