Cyclooxygenase-2 selective inhibitors, compositions and methods of use

1. A compound of Formula (II), or a pharmaceutically acceptable salt thereof;

wherein the compound of Formula (II) is:

wherein:

A-B is:

C—N;

when A-B is C—N, sides e and g are double bonds, and sides d and f are single bonds, —X 2 —Y 2 -Z 2 is:

—N═CR 4 —CR 5 ═;

R 1 is:

(a) —S(O) 2 —CH 3 ;

(b) —S(O) 2 —NR 8 (D 1 );

(c) —S(O) 2 —N(D 1 )—C(O)—CF 3 ;

(d) —S(O)—(NH)—NH(D 1 ); or

(e) —S(O)—(NH)—N(D 1 )—C(O)—CF 3 ;

R 1 ′ at each occurrence is independently:

(a) hydrogen;

(b) halogen;

(c) methyl; or

(d) CH 2 OH;

R 2 is:

(a) lower alkyl;

(b) cycloalkyl;

(c) mono-, di- or tri-substituted phenyl or naphthyl, wherein the substituents are each independently:

(1) hydrogen;

(2) halo;

(3) alkoxy;

(4) alkylthio;

(5) CN;

(6) haloalkyl, preferably CF 3 ;

(7) lower alkyl;

(8) N 3 ;

(9) —CO 2 D 1 ;

(10) —CO 2 -lower alkyl;

(11) —(C(R 5 )(R 6 )) z —OD 1 ;

(12) —(C(R 5 )(R 6 )) z —O-lower alkyl;

(13) lower alkyl—CO 2 —R 5 ;

(14) —OD 1 ;

(15) haloalkoxy;

(16) amino;

(17) nitro;

(18) alkylsulfinyl; or

(19) heteroaryl;

R 3 is:

(a) hydrogen;

(b) haloalkyl, preferably CF 3 ;

(c) CN;

(d) lower alkyl;

(e) —(C(R e )(R f )) p —U—V;

(f)K;

(g) unsubstituted or substituted:

(1) lower alkyl-Q;

(2) lower alkyl-O— lower alkyl-Q;

(3) lower alkyl-S-lower alkyl-Q;

(4) lower alkyl-O-Q;

(5) lower alkyl-S-Q;

(6) lower alkyl-O—V;

(7) lower alkyl-S—V;

(8) lower alkyl-O—K; or

(9) lower alkyl-S—K;

wherein the substituent(s) reside on the lower alkyl group;

(h)Q;

(i) alkylcarbonyl;

(j) arylcarbonyl;

(k) alkylarylcarbonyl;

(l) arylalkylcarbonyl;

(m) carboxylic ester;

(n) carboxamido;

(o) cycloalkyl;

(p) mono-, di- or tri-substituted phenyl or naphthyl, wherein the substituents are each independently:

(1) hydrogen;

(2) halo;

(3) alkoxy;

(4) alkylthio;

(5) CN;

(6) haloalkyl, preferably CF 3 ;

(7) lower alkyl;

(8)N 3 ;

(9) —CO 2 D 1 ;

(10) —C 2 -lower alkyl;

(11) —(C(R 5 )(R 6 )) 2 —OD 1 ;

(12) —(C(R 5 )(R 6 )) z —O-lower alkyl;

(13) lower alkyl-CO 2 —R 5 ;

(14) —OD 1 ;

(15) haloalkoxy;

(16) amino;

(17) nitro; or

(18) alkylsulfinyl;

(q) alkenyl;

(r) alkynyl;

(s) arylalkyl;

(t) lower alkyl-OD 1 ;

(u) alkoxyalkyl;

(v) aminoalkyl;

(w) lower alkyl-CO 2 R 10 ;

(x) lower alkyl-C(O)NR 10 (R 10 );

(y) heterocyclicalkyl; or

(z) heterocyclic ring-C(O)—;

R 4 , R 4 ′, R 5 and R 5 ′ are each independently:

(a) hydrogen;

(b) amino;

(c) CN;

(d) lower alkyl;

(e) haloalkyl;

(f) alkoxy;

(g) alkylthio;

(h) Q;

(i) —O-Q;

(j) —S-Q;

(k) K;

(l) cycloalkoxy;

(m) cycloalkylthio;

(n) unsubstituted, mono-, or di-substituted phenyl or unsubstituted, mono-, or di-substituted benzyl, wherein the substituents are each independently:

(1) halo;

(2) lower alkyl;

(3) alkoxy;

(4) alkylthio;

(5) CN;

(6) haloalkyl, preferably CF 3 ;

(7) N 3 ;

(8) Q;

(9) nitro; or

(10) amino;

(o) unsubstituted, mono-, or di-substituted heteroaryl or unsubstituted, mono-, or di-substituted heteroarylmethyl, wherein the heteroaryl is a monocyclic aromatic ring of 5 atoms, said ring having one heteroatom which is S, O, or N, and, optionally, 1, 2, or 3 additional N atoms; or the heteroaryl is a monocyclic ring of 6 atoms, said ring having one heteroatom which is N, and, optionally, 1, 2, 3, or 4 additional N atoms; said substituents are each independently:

(1) halo;

(2) lower alkyl;

(3) alkoxy;

(4) alkylthio;

(5) CN;

(6) haloalkyl, preferably CF 3 ;

(7)N 3 ;

(8) —C(R 6 )(R 7 )—OD 1 ;

(9) —C(R 6 )(R 7 )—O-lower alkyl; or

(10) alkylsulfinyl

(p) —CON(R 8 )(R 8 );

(q) —CH 2 OR 8 ;

(r) —CH 2 OCN;

(s) unsubstituted or substituted:

(1) lower alkyl-Q;

(2) —O-lower alkyl-Q;

(3) —S-lower alkyl-Q;

(4) lower alkyl-O-lower alkyl-Q;

(5) lower alkyl-S-lower alkyl-Q;

(6) lower alkyl-O-Q;

(7) lower alkyl-S-Q;

(8) lower alkyl-O—K;

(9) lower alkyl-S—K;

(10) lower alkyl-O—V; or

(11) lower alkyl-S—V;

wherein the substituent(s) resides on the lower alkyl;

(t) cycloalkyl;

(u) aryl;

(v) arylalkyl;

(w) cycloalkylalkyl;

(x) aryloxy;

(y) arylalkoxy;

(z) arylalkylthio;

(aa) cycloalkylalkoxy;

(bb) heterocycloalkyl;

(cc) alkylsulfonyloxy;

(dd) alkylsulfonyl;

(ee) arylsulfonyl;

(ff) arylsulfonyloxy;

(gg) —C(O)R 10 ;

(hh) nitro;

(ii) amino;

(jj) aminoalkyl;

(kk) —C(O)-alkyl-heterocyclic ring;

(ll) halo;

(mm) heterocyclic ring;

(nn) —CO 2 D 1 ;

(oo) carboxyl;

(pp) amidyl; or

(qq) alkoxyalkyl;

alternatively, R 4 and R 5 together with the carbons to which they are attached are:

(a) cycloalkyl;

(b) aryl; or

(c) heterocyclic ring;

alternatively, R 4 and R 4 ′ or R 5 and R 5 ′taken together with the carbon to which they are attached are:

(a) cycloalkyl; or

(b) heterocyclic ring;

alternatively, R 4 and R 5 , R 4 ′ and R 5 ′, R 4 and R 5 ′, or R 4 ′and R 5 when substituents on adjacent carbon atoms taken together with the carbons to which they are attached are:

(a) cycloalkyl;

(b) heterocyclic ring; or

(c) aryl;

R 6 and R 7 are each independently:

(a) hydrogen;

(b) unsubstituted, mono- or di-substituted phenyl; unsubstituted, mono- or di-substituted benzyl; unsubstituted, mono- or di-substituted heteroaryl; mono- or di-substituted heteroarylmethyl, wherein said substituents are each independently:

(1) halo;

(2) lower alkyl;

(3) alkoxy;

(4) alkylthio;

(5)CN;

(6) haloalkyl, preferably CF 3 ;

(7) N 3 ;

(8) —C(R 14 )(R 15 )—OD 1 ; or

(9) —C(R 14 )(R 15 )—O-lower alkyl;

(c) lower alkyl;

(d) —CH 2 OR 8 ;

(e) CN;

(f) —CH 2 CN;

(g) haloalkyl, preferably fluoroalkyl;

(h) —CON(R 8 )(R 8 );

(i) halo; or

(j) —OR 8 ;

R 8 is:

(a) hydrogen;

(b) K; or

(c) R 9 ;

alternatively, R 5 and R 5 ′, R 6 and R 7 or R 7 and R 8 together with the carbon to which they are attached form a saturated monocyclic ring of 3, 4, 5, 6 or 7 atoms; optionally containing up to two heteroatoms selected from oxygen, S(O) o or NR l ;

R 9 is:

(a) lower alkyl;

(b) lower alkyl-CO 2 D 1 ;

(c) lower alkyl-NHD 1 ;

(d) phenyl or mono-, di- or tri-substituted phenyl, wherein the substituents are each independently:

(1) halo;

(2) lower alkyl;

(3) alkoxy;

(4) alkylthio;

(5) lower alkyl-CO 2 D 1 ;

(6) lower alkyl-NHD 1 ;

(7) CN;

(8) CO 2 D 1 ; or

(9) haloalkyl, preferably fluoroalkyl;

(e) benzyl, mono-, di- or tri-substituted benzyl, wherein the substituents are each independently:

(1) halo;

(2) lower alkyl;

(3) alkoxy;

(4) alkylthio;

(5) lower alkyl-CO 2 D 1 ;

(6) lower alkyl-NHD 1 ;

(7) CN;

(8) —CO 2 D 1 ; or

(9) haloalkyl, preferably CF 3 ;

(f) cycloalkyl;

(g) K; or

(h) benzoyl, mono-, di-, or trisubstituted benzoyl, wherein the substituents are each independently:

(1) halo;

(2) lower alkyl;

(3) alkoxy;

(4) alkylthio;

(5) lower alkyl-CO 2 D 1 ;

(6) lower alkyl-NHD 1 ;

(7) CN;

(8) —CO 2 D 1 ; or

(9) haloalkyl, preferably CF 3 ;

R 10 and R 10 ′ are each independently:

(a) hydrogen; or

(b) R 11 ;

R 11 is:

(a) lower alkyl;

(b) cycloalkyl;

(c) unsubstituted, mono-, di- or tri-substituted phenyl or naphthyl, wherein the substituents are each independently:

(1) halo;

(2) alkoxy;

(3) alkylthio;

(4) CN;

(5) haloalkyl, preferably CF 3 ;

(6) lower alkyl;

(7) N 3 ;

(8) —CO 2 D 1 ;

(9) —CO 2 -lower alkyl;

(10) —C(R 12 )(R 13 )—OD 1 ;

(11) —C(R 12 )(R 13 )—O-lower alkyl;

(12) lower alkyl—CO 2 D 1 ;

(13) lower alkyl-CO 2 R 12 ;

(14) benzyloxy;

(15) —O-(lower alkyl)-CO 2 D 1 ;

(16) —O-(lower alkyl)—CO 2 R 12 ; or

(17) —O-(lower alkyl)-NR 12 R 13 ;

(d) unsubstituted, mono-, di- or tri-substituted heteroaryl, wherein the heteroaryl is a monocyclic aromatic ring of 5 atoms, said ring having one heteroatom which is S, O, or N, and, optionally, 1, 2, or 3 additional N atoms; or said heteroaryl is a monocyclic ring of 6 atoms, said ring having one heteroatom which is N, and, optionally 1, 2, or 3 additional N atoms, and wherein said substituents are each independently:

(1) halo;

(2) lower alkyl;

(3) alkoxy;

(4) alkylthio;

(5) CN;

(6) haloalkyl, preferably CF 3 ;

(7) N 3 ;

(8) —C(R 12 )(R 13 )—OD 1 ; or

(9) —C(R 12 )(R 13 )—O-lower alkyl;

(e) unsubstituted, mono- or di-substituted benzoheterocycle, wherein the benzoheterocycle is a 5, 6, or 7-membered ring which contains 1 or 2 heteroatoms independently selected from O, S, or N, and, optionally, a carbonyl group or a sulfonyl group, wherein said substituents are each independently:

(1) halo;

(2) lower alkyl;

(3) alkoxy;

(4) alkylthio;

(5) CN;

(6) haloalkyl, preferably CF 3 ;

(7) N 3 ;

(8) —C(R 12 )(R 13 )—OD 1 ; or

(9) —C(R 12 )(R 13 )—O-lower alkyl;

(f) unsubstituted, mono- or di-substituted benzocarbocycle, wherein the carbocycle is a 5, 6, or 7-membered ring which optionally contains a carbonyl group, wherein said substituents are each independently:

(1) halo;

(2) lower alkyl;

(3) alkoxy;

(4) alkylthio;

(5) CN;

(6) haloalkyl, preferably CF 3 ;

(7) N 3 ;

(8) —C(R 12 )(R 13 )—OD 1 ; or

(9) —C(R 12 )(R 13 )—O-lower alkyl;

(g) hydrogen; or

(h) K

R 12 and R 13 are each independently:

(a) hydrogen;

(b) lower alkyl; or

(c) aryl; or

R 12 and R 13 together with the atom to which they are attached form a saturated monocyclic ring of 3, 4, 5, 6 or 7 atoms;

R 14 and R 15 are each independently:

(a) hydrogen; or

(b) lower alkyl; or

R 14 and R 15 together with the atom to which they are attached form a carbonyl, a thial, or a saturated monocyclic ring of 3, 4, 5, 6 or 7 atoms;

Q is:

(a) —C(O)—U-D 1 ;

(b) —CO 2 -lower alkyl;

(c) tetrazolyl-5-yl;

(d) —C(R 7 )(R 8 )(S-D 1 );

(e) —C(R 7 )(R 8 )(O-D 1 ); or

(f) —C(R 7 )(R 8 )(O-lower alkyl);

X 5 is:

(a) —(CR 31 R 32 ) a —;

(b) —(CR 31 R 32 ) bb -A 1 -;

(c) -A 1 -(CR 31 R 32 ) bb —;

(d) —CR 31 R 32 -A 1 -CR 31 R 32 —;

(e) —CR 31 ═;or

(f) -A 1 ;

A 1 is:

(a) oxygen;

(b) thio;

(c) sulfinyl;

(d) sulfonyl; or

(c) —N(R 33 )—;

R 31 and R 32 are each independently:

(a) hydrogen;

(b) lower alkyl;

(c) substituted lower alkyl;

(d) lower alkoxy;

(e) lower haloalkyl; or

(f) halo; or

R 31 and R 32 taken together are;

(a) oxo;

(b) thial;

(c) oxime; or

(d) hydrazone;

R 33 is:

(a) lower alkyl;

(b) hydrogen; or

(c) —C(O)H;

a is an integer equal to 1 or 3;

bb is an integer equal to 2 or 3;

D 1 is:

(a) hydrogen or

(b) D;

D is:

(a) V; or

(b) K;

U is:

(a) oxygen;

(b) sulfur; or

(c) —N(R a )(R i )—;

V is:

(a) —NO;

(b) —NO 2 ; or

(c) hydrogen

K is —W aa -E b -(C(R e )(R f )) p -E c -(C(R e )(R f )) x —W d —(C(R e )(R f )) y —W i -E j -W g -(C(R e )(R f )) z —U—V;

wherein aa, b, c, d, g, i and j are each independently an integer from 0 to 3;

p, x, y and z are each independently an integer from 0 to 10;

W at each occurrence is independently:

(a) —C(O)—;

(b) —C(S)—;

(c) -T-;

(e) alkyl;

(f) aryl;

(g) heterocyclic ring;

(h) arylheterocyclic ring, or

(i) —(CH 2 CH 2 O) q —;

E at each occurrence is independently a -T-group, an alkyl group, an aryl group, a heterocyclic ring, —(C(R e )(R f )) h —, an arylheterocyclic ring or —(CH 2 CH 2 O) q —;

h is an integer form 1 to 10;

q is an integer from 1 to 5;

R e and R f are each independently a hydrogen, an alkyl, a cycloalkoxy, a halogen, a hydroxy, an hydroxyalkyl, an alkoxyalkyl, an arylheterocyclic ring, a cycloalkylalkyl, a heterocyclicalkyl, an alkoxy, a haloalkoxy, an amino, an alkylamino, a dialkylamino, an arylamino, a diarylamino, an alkylarylamino, an alkoxyhaloalkyl, a haloalkoxy, a sulfonic acid, a sulfonic ester, an alkylsulfonic acid, an arylsulfonic acid, an arylalkoxy, an alkylthio, an arylthio, a cyano, an aminoalkyl, an aminoaryl, an aryl, an arylalkyl, a carboxamido, a alkylcarboxamido, an arylcarboxamido, an amidyl, a carboxyl, a carbamoyl, an alkylcarboxylic acid, an arylcarboxylic acid, an alkylcarbonyl, an arylcarbonyl, an ester, a carboxylic ester, an alkylcarboxylic ester, an arylcarboxylic ester, a haloalkoxy, a sulfonamido, an alkylsulfonamido, an arylsulfonamido, an alkylsulfonyl, an alkylsulfonyloxy, an arylsulfonyl, an arylsulfonyloxy, a urea, a nitro, -T-Q′-, or —(C(R g )(R h )) k -T-Q′ or R e and R f taken together are an oxo, a thial, a heterocyclic ring, a cycloalkyl group, an oxime, a hydrazone or a bridged cycloalkyl group;

Q′ is —NO or —NO 2 ;

k is an integer from 1 to 3;

T is independently a covalent bond, a carbonyl, an oxygen, —S(O) o —or —N(R a )R i —,

o is an integer from 0 to 2,

R a is a lone pair of electrons, a hydrogen or an alkyl group;

R i is a hydrogen, an alkyl, an aryl, an alkylcarboxylic acid, an arylcarboxylic acid, an alkylcarboxylic ester, an arylcarboxylic ester, an alkylcarboxamido, an arylcarboxamido, an alkylsulfinyl, an alkylsulfonyl, an alkylsulfonyloxy, an arylsulfinyl, an arylsulfonyloxy, an arylsulfonyl, a sulfonamido, a carboxamido, a carboxylic ester, an aminoalkyl, an aminoaryl, —OR′ i , —CH 2 —C(T-Q′)(R g )(R h ), a bond to an adjacent atom creating a double bond to that atom or —(N 2 O 2 —) − .M + , wherein M + is an organic or inorganic cation; with the proviso that when R i is —CH 2 —C(T-Q′)(R g )(R h ) or —(N 2 O 2 —)·M + ; then “-T-Q′” can be a hydrogen, an alkyl group, an alkoxyalkyl group, an aminoalkyl group, a hydroxy group or an aryl group;

R g and R h at each occurrence are independently R e ;

R′ i is independently selected from R i .

2. A composition comprising the compound of claim 1 and a pharmaceutically acceptable carrier.

3. The composition of claim 2 , further comprising at least one therapeutic agent.

4. The composition of claim 3 , wherein the therapeutic agent is a steroid, a nonsteroidal antiinflammatory compound, a 5-lipoxygenase (5-LO) inhibitor, a leukotriene B 4 receptor antagonist, a leukotriene A 4 hydrolase inhibitor, a 5-HT agonist, a 3-hydroxy-3-methyiglutaryl coenzyme A inhibitor, a H 2 antagonist, an antineoplastic agent, an antiplatelet agent, a thrombin inhibitor, a thromboxane inhibitor, a decongestant, a diuretic, a sedating or non-sedating anti-histamine, an inducible nitric oxide synthase inhibitor, an opioid, an analgesic, a Helicobacter pylori inhibitor, a proton pump inhibitor, an isoprostane inhibitor, or a mixture of two or more thereof.

5. The composition of claim 4 , wherein the nonsteroidal antiinflammatory compound is acetaminophen, aspirin, diclofenac, ibuprofen, ketoprofen, indomethacin or naproxen.

6. A composition comprising at least one compound of claim 1 and at least one compound that donates, transfers or releases nitric oxide, or induces the production of endogenous nitric oxide or endothelium-derived relaxing factor, or is a substrate for nitric oxide synthase.

7. The composition of claim 6 , further comprising a pharmaceutically acceptable carner.

8. The composition of claim 6 , wherein the compound that donates, transfers, or releases nitric oxide, or induces the production of endogenous nitric oxide or endothelium-derived relaxing factor or is a substrate for nitric oxide synthase is an S-nitrosothiol.

9. The composition of claim 8 , wherein the S-nitrosothiol is S-nitroso-N-acetylcysteine, S-nitroso-captopril, S-nitroso-N-acetylpenicillamine, S-nitroso-homocysteine, S-nitroso-cysteine, S-nitroso-glutathione, or S-nitroso-cysteinyl-glycine.

10. The composition of claim 8 , wherein the S-nitrosothiol is:

(i) HS(C(R e )(R f )) m SNO;

(ii) ONS(C(R e )(R f )) m R e ; or

(iii) H 2 N—CH(CO 2 H)—(CH 2 ) m —C(O)NH—CH(CH 2 SNO)—C(O)NH—CH 2 —CO 2 H;

wherein m is an integer from 2 to 20; R e and R f are each independently a hydrogen, an alkyl, a cycloalkoxy, a halogen, a hydroxy, an hydroxyalkyl, an alkoxyalkyl, an aryiheterocyclic ring, a cycloalkylalkyl, a heterocyclicalkyl, an alkoxy, a haloalkoxy, an amino, an alkylamino, a dialkylamino, an arylamino, a diarylamino, an alkylarylamino, an alkoxyhaloalkyl, a haloalkoxy, a sulfonic acid, a sulfonic ester, an alkylsulfonic acid, an arylsulfonic acid, an arylalkoxy, an alkylthio, an arylthio, a cyano, an aminoalkyl, an aminoaryl, an aryl, an arylalkyl, a carboxamido, a alkylcarboxamido, an arylcarboxamido, an amidyl, a carboxyl, a carbamoyl, an alkylcarboxylic acid, an arylcarboxylic acid, an alkylcarbonyl, an arylcarbonyl, an ester, a carboxylic ester, an alkylcarboxylic ester, an arylcarboxylic ester, a haloalkoxy, a sulfonamido, an alkylsulfonamido, an arylsulfonamido, an alkylsulfonyl, an alkylsulfonyloxy, an arylsulfonyl, an arylsulfonyloxy, a urea, a nitro, -T-Q′-, or —(C(R g )(R h )) k -T-Q′ or R e and R f taken together are an oxo, a methanthial, a heterocyclic ring, a cycloalkyl group, an oxime, a hydrazone or a bridged cycloalkyl group; Q′ is —NO or —NO 2 ; and T is independently a covalent bond, a carbonyl, an oxygen, —S(O) o — or —N(R a )R i —, wherein o is an integer from 0 to 2, R a is a lone pair of electrons, a hydrogen or an alkyl group; R i is a hydrogen, an alkyl, an aryl, an alkylcarboxylic acid, an arylcarboxylic acid, an alkylcarboxylic ester, an arylcarboxylic ester, an alkylcarboxamido, an arylcarboxamido, an alkylsulfinyl, an alkylsulfonyl, an alkylsulfonyloxy, an arylsulfinyl, an arylsulfonyloxy, an arylsulfonyl, a sulfonamido, a carboxamido, a carboxylic ester, an aminoalkyl, an aminoaryl, —CH 2 —C(T-Q′)(R g )(R h ), or —(N 2 O 2 —) − ·M + , wherein M + is an organic or inorganic cation; with the proviso that when R i is —CH 2 —C(T-Q′) (R g )(R h ) or —(N 2 O 2 —).M + ; then “-T-Q′” can be a hydrogen, an alkyl group, an alkoxyalkyl group, an aminoalkyl group, a hydroxy group or an aryl group; and R g and R h at each occurrence are independently R e .

11. The composition of claim 6 , wherein the compound that donates, transfers, or releases nitric oxide, or induces the production of endogenous nitric oxide or endothelium-derived relaxing factor, or is a substrate for nitric oxide synthase is L-arginine, L-homoarginine, N-hydroxy-L-arginine, nitrosated L-arginine, nitrosylated L-arginine, nitrosated N-hydroxy-L-arginine, nitrosylated N-hydroxy-L-arginine, nitrosated L-homoarginine, nitrosylated L-homoarginine), citrulline, omithine, glutamine, lysine, an arginase inhibitor or a nitric oxide mediator.

12. The composition of claim 6 , wherein the compound that donates, transfers, or releases nitric oxide, or induces the production of endogenous nitric oxide or endothelium-derived relaxing factor, or is a substrate for nitric oxide synthase is:

(i) a compound that comprises at least one ON—O— or ON—N— group;

(ii) a compound that comprises at least one O 2 N—O—, O 2 N—N— or O 2 N—S— or group;

(iii) a N-oxo-N-nitrosoamine having the formula: R 1″ R 2″ N—N(O-M + )-NO, wherein R 1″ and R 2″ are each independently a polypeptide, an amino acid, a sugar, an oligonucleotide, a straight or branched, saturated or unsaturated, aliphatic or aromatic, substituted or unsubstituted hydrocarbon, or a heterocyclic group, and M + is an organic or inorganic cation.

13. The composition of claim 12 , wherein the compound comprising at least one ON—O— or ON—N— group is an ON—O-polypeptide, an ON—N-polypeptide, an ON—O-amino acid, an ON—N-amino acid, an ON—O-sugar, an ON—N-sugar, an ON—O-oligonucleotide, an ON—N-oligonucleotide, a straight or branched, saturated or unsaturated, substituted or unsubstituted, aliphatic or aromatic ON—O-hydrocarbon, a straight or branched, saturated or unsaturated, substituted or unsubstituted, aliphatic or aromatic ON—N-hydrocarbon, an ON—O-heterocyclic compound or an ON—N-heterocyclic compound.

14. The composition of claim 12 , wherein compound comprising at least one O 2 N—O—, O 2 N—N— or O 2 N—S— group is an O 2 N—O-polypeptide, an O 2 N—N-polypeptide, an O 2 N—S-polypeptide, an O 2 N—O-amino acid, O 2 N—N-amino acid, O 2 N—S-amino acid, an O 2 N—O-sugar, an O 2 N—N-sugar, O 2 N—S-sugar, an O 2 N—O-oligonucleotide, an O 2 N—N-oligonucleotide, an O 2 N—S-oligonucleotide, , a straight or branched, saturated or unsaturated, aliphatic or aromatic, substituted or unsubstituted O 2 N—O-hydrocarbon, a straight or branched, saturated or unsaturated, aliphatic or aromatic, substituted or unsubstituted O 2 N—N-hydrocarbon, a straight or branched, saturated or unsaturated, aliphatic or aromatic, substituted or unsubstituted O 2 N—S-hydrocarbon, an O 2 N—O-heterocyclic compound, an O 2 N—N-heterocyclic compound or an O 2 N—S-heterocyclic compound.

15. The composition of claim 6 , further comprising at least one therapeutic agent.

16. The composition of claim 15 , wherein the therapeutic agent is a steroid, a nonsteroidal antiinflammatory compound, a 5-lipoxygenase (5-LO) inhibitor, a leukotriene B 4 receptor antagonist, a leukotriene A 4 hydrolase inhibitor, a 5-HT agonist, a HMG CoA inhibitor, a H 2 antagonist, an antineoplastic agent, an antiplatelet agent, a thrombin inhibitor, a thromboxane inhibitor, a decongestant, a diuretic, a sedating or non-sedating anti-histamine, an inducible nitric oxide synthase inhibitor, an opioid, an analgesic, a Helicobacter pylori inhibitor , a proton pump inhibitor, an isoprostane inhibitor, or a mixture of two or more thereof.

17. The composition of claim 16 , wherein the nonsteroidal antiinflammatory compound is acetaminophen, aspirin, diclofenac, ibuprofen, ketoprofen, indomethacin or naproxen.

18. A compound selected from the group consisting of:

1-(1-(cyclohexylmethyl)-3-(hydroxymethyl)pyrazol-5-yl)-4-(methylsulfonyl)benzene;

4-(1-(cyclohexylmethyl)-3-((2-hydroxyethoxy)methyl)pyrazol-5-yl)-1-(methylsulfonyl)benzene;

1-(3-(hydroxymethyl)-1-benzylpyrazol-5-yl)-4-(methylsulfonyl)benzene;

1-(3-((1E)-3-hydroxyprop-1-enyl)-1-(cyclohexylmethyl)pyrazol-5-yl)-4-(methylsulfonyl)benzene;

1-(1-(cyclohexylmethyl)-3-(3-hydroxypropyl)pyrazol-5-yl)-4-(methylsulfonyl)benzene;

1-(1-(cyclohexylmethyl)-3-vinylpyrazol-5-yl)-4-(methylsulfonyl)benzene;

methyl (2E)-3-(1-(cyclohexylmethyl)-5-(4-(methylsulfonyl)phenyl)pyrazol-3-yl) prop-2-enoate;

methyl 5-(4-(methylsulfonyl)phenyl)-1-benzylpyrazole-3-carboxylate;

1-(1-(cyclohexylmethyl)-3-((nitrooxy)methyl)pyrazol-5-yl)-4-(methylsulfonyl)benzene;

4-(1-(cyclohexylmethyl)-3-((2-(nitrooxy)ethoxy)methyl)pyrazol-5-yl)-1-(methylsulfonyl)benzene;

4-(methylsulfonyl)-1-(3-((nitrooxyl)methyl)-1-benzylpyrazol-5-yl)benzene;

1-(3-((1E)-3-nitrooxyprop-1-enyl)-1-(cyclohexylmethyl)pyrazol-5-yl)-4-(methylsulfonyl)benze;

1-(1-(cyclohexylmethyl)-3-(3-(nitrooxy)propyl)pyrazol-5-yl)-4-(methylsulfonyl) benzene;

or a pharmaceutically acceptable salt thereof.

19. A composition comprising at least one compound of claim 18 and a pharmaceutically acceptable carrier.

20. The composition of claim 19 , further comprising (i) at least one compound that donates, transfers or releases nitric oxide, induces the production of endogenous nitric oxide or endothelium-derived relaxing factor, or is a substrate for nitric oxide synthase; (ii) at least one therapeutic agent; or (iii) at least one compound that donates, transfers or releases nitric oxide, induces the production of endogenous nitric oxide or endothelium-derived relaxing factor, or is a substrate for nitric oxide synthase and at least one therapeutic agent.