Nitrosated and nitrosylated cyclooxygenase-2 inhibitors, compositions and methods of use

1. A compound of Formula (I) or a pharmaceutically acceptable salt thereof:

wherein the compound of formula (I) is:

wherein:

when side b is a double bond, and sides a and c are single bonds, —X 1 —Y 1 -Z 1 - is:

(a) —CR 4 (R 5 )—CR 5 (R 5 ′)—CR 4 (R 5 )—;

(b) —C(O)—CR 4 (R 4 ′)—CR 5 (R 5 ′)—;

(c) —CR 4 (R 4 ′)—CR 5 (R 5 ′)—C(O)—;

(d) —(CR 5 (R 5 ′)) k —O—C(O)—;

(e) —C(O)—O—(CR 5 (R 5 ′)) k —;

(f) —CR 4 (R 4 ′)—NR 3 —CR 5 (R 5 ′)—;

(g) —CR 5 (R 5 ′)—NR 3 —C(O)—;

(h) —CR 4 ═CR 4′ —S—;

(i) —S—CR 4 ═CR 4 ′—;

(j) —S—N═CR 4 —;

(k) —CR 4 ═N—S—;

(l) —N═CR 4 —O—;

(m) —O—CR 4 ═N—;

(n) —NR 3 —CR 4 ═N—;

(o) —N═CR 4 —S—;

(p) —S—CR 4 ═N—;

(q) —C(O)—NR 3 —CR 5 ′(R 5 ′)—;

(r) —R 3 N—CR 5 ═CR 5 ′—;

(s) —CR 4 ═CR 5 —NR 3 —;

(t) —O—N═CR 4 —;

(u) —CR 4 ═N—O—;

(v) —N═N—S—;

(w) —S—N═N—;

(x) —R 3 N—CR 4 ═N—;

(y) —N═CR 4 —NR 3 —;

(z) —R 3 N—N═N—;

(aa) —N═N—NR 3 —;

(bb) —CR 4 (R 4′ )—O—CR 5 (R 5 ′)—;

(cc) —CR 4 (R 4′ )—S—CR 5 (R 5 ′)—;

(dd) —CR 4 (R 4′ )—C(O)—CR 5 (R 5 ′)—;

(ee) —CR 4 (R 4′ )—CR 5 (R 5 ′)—C(S)—;

(ff) —(CR 5 (R 5 ′)) k —O—C(S)—;

(gg) —C(S)—O—(CR 5 (R 5 ′)) k —;

(hh) —(CR 5 (R 5 ′)) k —NR 3 —C(S)—;

(ii) —C(S)—NR 3 —(CR 5 (R 5 ′)) k —;

(jj) —(CR 5 (R 5 ′)) k —S—C(O)—;

(kk) —C(O)—S—(CR 5 (R 5 ′)) k —;

(ll) —O—CR 4 ═CR 5 —;

(mm) —CR 4 ═CR 5 —O—;

(nn) —C(O)—NR 3 —S—;

(oo) —S—NR 3 C(O)—;

(pp) —C(O)—NR 3 —O—;

(qq) —O—NR 3 —C(O)—;

(rr) —NR 3 —CR 4 ═CR 5 —;

(ss) —CR 4 ═N—NR 3 ;

(tt) —NR 3 —N═CR 4 —;

(uu) —C(O)—NR 3 —NR 3 —;

(vv) —NR 3 —NR 3 —C(O)—;

(ww) —C(O)—O—NR 3 —;

(xx) —NR 3 —O—C(O)—;

(yy) —CR 4 R 4′ —CR 5 R 5′ ;

(zz) —C(O)—CR 4 R 4′ —

(aaa) —CR 4 R 4′ —C(O)—;

(bbb) —C(S)—CR 4 R 4′ —;

(ccc) —CR 4 R 4′ —C(S)—;

(ddd) —C(═NR 3 )—CR 4 R 4′ —; or

(eee) —CR 4 R 4′ —C(═NR 3 )—;

when sides a and c are double bonds and side b is a single bond, —X 1 —Y 1 -Z 1 - is:

(a) ═CR 4 —O—CR 5 ═;

(b) ═CR 4 —NR 3 —CR 5 ═;

(c) ═N—S—CR 4 ═;

(d) ═CR 4 —S—N═;

(e) ═N—O—CR 4 ═;

(f) ═CR 4 —O—N═;

(g) ═N—S—N═;

(h) ═N—O—N═;

(i) ═N—NR 3 —CR 4 ═;

(j) ═CR 4 —NR 3 —N═;

(k) ═N—NR 3 —N═;

(l) ═CR 4 —S—CR 5 ═; or

(m) ═CR 4 —CR 4 (R 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 );

(e) —S(O)—(NH)—N(D 1 )—C(O)—CF 3 ;

(f) —P(O)(CH 3 )NH(D 1 );

(g) —P(O)(CH 3 ) 2 ;

(h) —C(S)—NH(D 1 );

(i) —S(O)(NH)CH 3 ;

(j) —P(O)(CH 3 )OD 1 ; or

(k) —P(O)(CH 3 )NH(D 1 );

R 1′ is:

(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;

(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;

(d) 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 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; wherein the substituents are each independently:

(1) hydrogen;

(2) halo;

(3) lower alkyl;

(4) alkoxy;

(5) alkylthio;

(6) CN;

(7) haloalkyl;

(8) N 3 ;

(9) —C(R 5 )(R 6 )—OD 1 ;

(10) —C(R 5 )(R 6 )—O-lower alkyl; or

(11) alkylsulfinyl;

(e) benzoheteroaryl which includes the benzo fused analogs of (d);

(f) —NR 10 R 11 ;

(g) —SR 11 ;

(h) —OR 11 ;

(i) —R 11 ;

(j) alkenyl;

(k) alkynyl;

(l) unsubstituted, mono-, di-, tri- or tetra-substituted cycloalkenyl, wherein the substituents are each independently:

(1) halo;

(2) alkoxy;

(3) alkylthio;

(4) CN;

(5) haloalkyl;

(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 —R 12 ;

(13) benzyloxy;

(14) —O-(lower alkyl)-CO 2 R 12 ;

(15) —O-(lower alkyl)-NR 11 R 13 ; or

(16) alkylsulfinyl;

(m) mono-, di-, tri- or tetra-substituted heterocycloalkyl group of 5, 6 or 7 members, or a benzoheterocycle, wherein said heterocycloalkyl or benzoheterocycle contains 1 or 2 heteroatoms selected from O, S, or N and, optionally, contains a carbonyl group or a sulfonyl group, and wherein said substituents are each independently:

(1) halo;

(2) lower alkyl;

(3) alkoxy;

(4) alkylthio;

(5) CN;

(6) haloalkyl;

(7) N 3 ;

(8) —C(R 12 )(R 13 )—OD 1 ;

(9) —C(R 12 )(R 13 )—O-lower alkyl; or

(10) alkylsulfinyl;

(n) styryl, mono or di-substituted styryl, wherein the substituent are each independently:

(1) halo;

(2) alkoxy;

(3) alkylthio;

(4) CN;

(5) haloalkyl;

(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 —R 12 ;

(13) benzyloxy;

(14) —O-(lower alkyl)-CO 2 R 12 ; or

(15) —O-(lower alkyl)-NR 12 R 13 ;

(o) phenylacetylene, mono- or di-substituted phenylacetylene, wherein the substituents are each independently:

(1) halo;

(2) alkoxy;

(3) alkylthio;

(4) CN;

(5) haloalkyl;

(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 —R 12 ;

(13) benzyloxy;

(14) —O-(lower alkyl)-CO 2 R 12 ; or

(15) —O-(lower alkyl)-NR 12 R 13 ;

(p) fluoroalkenyl;

(q) mono- or di-substituted bicyclic heteroaryl of 8, 9 or 10 members, containing 2, 3, 4 or 5 heteroatoms, wherein at least one heteroatom resides on each ring of said bicyclic heteroaryl, said heteroatoms are each independently O, S and N and said substituents are each independently:

(1) hydrogen;

(2) halo;

(3) lower alkyl;

(4) alkoxy;

(5) alkylthio;

(6) CN;

(7) haloalkyl;

(8) N 3 ;

(9) —C(R 5 )(R 6 )—OD 1 ; or

(10) —C(R 5 )(R 6 )—O-lower alkyl;

(r) K;

(s) aryl;

(t) arylalkyl;

(u) cycloalkylalkyl;

(v) —C(O)R 11 ;

(u) hydrogen;

(v) arylalkenyl;

(w) arylalkoxy;

(x) alkoxy;

(y) aryloxy;

(z) cycloalkoxy;

(aa) arylthio;

(bb) alkylthio;

(cc) arylalkylthio; or

(dd) cycloalkylthio;

R 3 is:

(a) hydrogen;

(b) haloalkyl;

(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;

(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; 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;

(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;

(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;

(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;

(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 i ;

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;

(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;

(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;

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;

(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;

(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;

(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;

(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;

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-;

(d) —(C(R e )(R f )) h —;

(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-;

(b) alkyl;

(c) aryl;

(d) —(C(R e )(R f )) h —;

(e) heterocyclic ring;

(f) arylheterocyclic ring; or

(g) —(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;

(b) alkyl;

(c) cycloalkoxy;

(d) halogen;

(e) hydroxy;

(f) hydroxyalkyl;

(g) alkoxyalkyl;

(h) arylheterocyclic ring;

(i) cycloalkylalkyl;

(j) heterocyclicalkyl;

(k) alkoxy;

(l) haloalkoxy;

(m) amino;

(n) alkylamino;

(o) dialkylamino;

(p) arylamino;

(q) diarylamino;

(r) alkylarylamino;

(s) alkoxyhaloalkyl;

(t) haloalkoxy;

(u) sulfonic acid;

(v) alkylsulfonic acid;

(w) arylsulfonic acid;

(x) arylalkoxy;

(y) alkylthio;

(z) arylthio;

(aa) cyano;

(bb) aminoalkyl;

(cc) aminoaryl;

(dd) alkoxy;

(ee) aryl;

(ff) arylalkyl;

(gg) carboxamido;

(hh) alkylcarboxamido;

(ii) arylcarboxamido;

(jj) amidyl;

(kk) carboxyl;

(ll) carbamoyl;

(mm) alkylcarboxylic acid;

(nn) arylcarboxylic acid;

(oo) alkylcarbonyl;

(pp) arylcarbonyl;

(qq) ester;

(rr) carboxylic ester;

(ss) alkylcarboxylic ester;

(tt) arylcarboxylic ester;

(uu) haloalkoxy;

(vv) sulfonamido;

(ww) alkylsulfonamido;

(xx) arylsulfonamido;

(yy) alkylsulfonyl,

(zz) alkylsulfonyloxy,

(aaa) arylsulfonyl,

(bbb) arylsulphonyloxy

(ccc) sulfonic ester;

(ddd) carbamoyl;

(eee) urea;

(fff) nitro; or

(ggg) —U—V; or

R e and R f taken together are:

(a) oxo;

(b) thial; or

R e and R f taken together with the carbon to which they are attached are:

(a) heterocyclic ring;

(b) cycloalkyl group; or

(c) bridged cycloalkyl group;

k is an integer from 1 to 2;

T at each occurrence is independently:

(a) a covalent bond,

(b) carbonyl,

(c) an oxygen,

(d) —S(O) o —; or

(e) —N(R a )R i —;

o is an integer from 0 to 2;

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);

R a is:

(a) a lone pair of electron;

(b) hydrogen; or

(c) lower alkyl;

R i is:

(a) hydrogen;

(b) alkyl;

(c) aryl;

(d) alkylcarboxylic acid;

(e) arylcarboxylic acid;

(f) alkylcarboxylic ester;

(g) arylcarboxylic ester;

(h) alkylcarboxamido;

(i) arylcarboxamido;

(j) alkylsulfinyl;

(k) alkylsulfonyl;

(l) alkylsulfonyloxy,

(m) arylsulfinyl;

(n) arylsulfonyl;

(o) arylsulphonyloxy;

(p) sulfonamido;

(q) carboxamido;

(r) carboxylic ester;

(s) aminoalkyl;

(t) aminoaryl;

(u) —CH 2 —C(U—V)(R e )(R f );

(v) a bond to an adjacent atom creating a double bond to that atom; or

(w) —(N 2 O 2 —) − .M + , wherein M + is an organic or inorganic cation;

with the proviso that the compounds of formula I must contain at least one nitrite, nitrate, thionitrite or thionitrate group.

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

3. The composition of claim 2 , 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.

4. The composition of claim 3 , wherein the therapeutic agent is a steroid, a nonsteroidal antiinflammatory compound, a 5-lipoxygenase inhibitor, a leukotriene B 4 receptor antagonist, a leukotriene A 4 hydrolase inhibitor, a 5-HT agonist, a 3-hydroxy-3-methylglutaryl coenzyme A inhibitor, a H 2 receptor antagonist, an antineoplastic agent, an antiplatelet agent, 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 or naproxen.

6. The composition of claim 3 , further comprising a pharmaceutically acceptable carrier.

7. A kit comprising at least one compound of claim 1 .

8. The kit of claim 7 , 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.

9. The kit of claim 8 , wherein the 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; the at least one therapeutic agent; or the 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; are in the form of separate components in the kit.

10. A compound selected from the group consisting of 4-{5((nitrooxy)methyl)-3-phenylisoxazol-4-yl}benzenesulfonamide, 2-(1-methyl-4-(nitrosothio)-4-piperidyl)ethyl 3-(N-{(4-(5-methyl-3-phenylisoxazol-4-yl)phenyl)sulfonyl}carbamoyl)propanoate, 3-methyl-N-{(4-(5-methyl-3-phenylisoxazol-4-yl)phenyl)sulfonyl}-3-(nitrosothio)butanamide, or a pharmaceutically acceptable salt thereof.

11. A composition comprising at least one compound of claim 10 and a pharmaceutically acceptable carrier.

12. The composition of claim 11 , 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.

13. A kit comprising at least one compound of claim 10 .