Nitrosated and Nitrosylated Compounds, Compositions and Methods for the Treatment of Ophthalmic Disorders

1 . A method for treating an ophthalmic disorder in a patient in need thereof comprising administering to the patient a composition comprising a compound of Formula (I), (II), (III), (IV) or (V), or a pharmaceutically acceptable salt thereof,

wherein the compound of Formula (I) is:

wherein:

X 3 is:

(1) —CH(CH 3 ) 2 ;

(2) —C(CH 3 ) 3 ;

Y 3 is —C(O)—C 6 H 5 or D 1 ;

Z 3 is:

R 10 is:

(1) —C(O)—(CH 2 ) k —CH 3 ;

(2) —O—CH 2 —CH═CH 2 ;

(3) a hydrogen;

(4) methyl;

(5) methoxy;

(6) cyclopentyl;

(7) halo;

(8) —O—CH 2 —C(O)—ND 1 -CH 3 ;

(9) cyano;

(10) —CH 2 —CH═CH 2 ; or

R 11 is a hydrogen, methyl or a halo; or

R 10 and R 11 taken together are W 4 —U 4 —V 4 ;

wherein W 4 —U 4 —V 4 is

(1) —CH═C(R 14 )—ND 1 -;

(2) —CH═CH—CH 2 —;

(3) —CH 2 —CH═CH—;

(4) —CH═CH—CH═CH—;

(5) —O—CH 2 —CH(ONO 2 )—CH 2 —;

(6) —O—C(O)—CH═CH—;

(7) —(CH 2 ) 2 —C(O)—ND 1 -;

(8) —(CH 2 ) 3 —C(O)—;

(9) —CH 2 —CH(OD 1 )-CH(OD 1 )-CH 2 —;

(10) —S—(CH 2 ) 3 —;

R 12 is:

(1) —ND 1 -C(O)—(CH 2 ) k —CH 3 ;

(2) —(CH 2 ) k —C(O)—OD 1 ;

(3) —C(O)—(CH 2 ) k —CH 3 ;

(4) halo;

(5) —ND 1 -C(O)—N(C 2 H 5 ) 2 ;

(6) —CH 2 —C(O)—N(H)D 1 ;

(7) —O—C(O)—CH 3 ;

(10) —CH 2 —O—(CH 2 ) 2 —O—CH(CH 3 ) 2 ;

(11) methyl; or

(12) —(CH 2 ) 2 —O—CH 3 ;

R 13 is a hydrogen, methyl or halo;

R 14 is a hydrogen or a lower alkyl;

R 15 at each occurrence is independently selected from —OCH 3 , —OD 1 , —NO 2 , methyl or ND 1 -S(O) 2 —CH 3 ;

k is an integer from 0 to 4;

D 1 is a hydrogen, V 3 or K;

K is —(W 3 ) a -E b -(C(R e )(R f )) p1 -E c -(C(R e )(R f )) x —(W 3 ) d —(C(W)(R f )) y —(W 3 ) i -E j -(W 3 ) g (C(R e )(R f )) z —U 3 —V 3 ;

V 3 is —NO or —NO 2 ;

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

p 1 , x, y and z are each independently an integer from 0 to 10;

W 3 at each occurrence is independently —C(O)—, —C(S)—, -T 3 -, —(C(R e )(R f )) h —, an alkyl group, an aryl group, a heterocyclic ring, an arylheterocyclic ring, or —(CH 2 CH 2 O) q1 —;

E at each occurrence is independently -T 3 -, an alkyl group, an aryl group, —(C(R e )(R f )) h —, a heterocyclic ring, an arylheterocyclic ring, or —(CH 2 CH 2 O) q1 —;

T 3 at each occurrence is independently a covalent bond, a carbonyl, an oxygen, —S(O) o — or —N(R a )R i ;

h is an integer form 1 to 10;

q 1 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, an alkylaryl, an alkylcycloalkyl, an alkylheterocyclic ring, a cycloalkylalkyl, a cycloalkylthio, an arylalklythio, an arylalklythioalkyl, an alkylthioalkyl a cycloalkenyl, an heterocyclicalkyl, an alkoxy, a haloalkoxy, an amino, an alkylamino, a dialkylamino, an arylamino, a diarylamino, an alkylarylamino, an alkoxyhaloalkyl, 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, an alkylaryl, 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 sulfonamido, an alkylsulfonamido, an arylsulfonamido, an alkylsulfonyl, an alkylsulfonyloxy, an arylsulfonyl, arylsulphonyloxy, a sulfonic ester, an alkyl ester, an aryl ester, a urea, a phosphoryl, a nitro, K or R e and R f taken together with the carbons to which they are attached form a carbonyl, a methanthial, a heterocyclic ring, a cycloalkyl group, an aryl group, an oxime, a hydrazone or a bridged cycloalkyl group;

U 3 at each occurrence is independently 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 alkylaryl, an alkylsulfinyl, an alkylsulfonyl, an alkylsulfonyloxy, an arylsulfinyl, an arylsulfonyl, arylsulphonyloxy, a sulfonamido, a carboxamido, a carboxylic ester, an aminoalkyl, an aminoaryl, —CH 2 —C(U 3 —V 3 )(R e )(R f ), a bond to an adjacent atom creating a double bond to that atom, —(N 2 O 2 —) − .M 1 + , wherein M 1 + is an organic or inorganic cation; and

with the proviso that the compounds of Formula (I) must contain at least one NO group, and/or at least one NO 2 group; wherein the at least one NO group and/or the at least one NO 2 group is linked to the compound through an oxygen atom, a nitrogen atom or a sulfur atom; and

the compound of Formula (II) is:

wherein:

Y 4 is:

X 4 is:

(1) methyl;

Z 4 and Z 4 ′ are independently selected from a methyl or a hydrogen;

R 16 is:

(1) hydrogen;

(2) —C(O)—N(D 1 )H;

(3) —S(O)—CH 3 ; or

(4) —S(O) 2 —N(D 1 )H;

R 17 is a hydrogen, —OCH 3 or —NO 2 ;

o 1 is an integer from 0 to 2;

R 15 and D 1 are as defined herein; and

with the proviso that the compounds of Formula (II) must contain at least one NO group, and/or at least one NO 2 group; wherein the at least one NO group and/or the at least one NO 2 group is linked to the compound through an oxygen atom, a nitrogen atom or a sulfur atom; and

the compound of Formula (III) is:

wherein:

X 6 is:

(1) —U 3 D 1 ;

(2) —O—CH 2 —CH 3 ; or

Y 6 is:

(1) —CH 2 —S—R 21 ;

W 6 is:

V 6 is a hydrogen;

Z 6 is:

(1) hydrogen;

(2) methyl; or

(3) —(CH 2 ) 4 —N(H)D 1 ;

R 19 and R 20 are a hydrogen; or

R 19 and R 20 taken together are an oxo; or

R 20 and W 6 taken together are:

R 21 is:

(1) —C(O)—CH 2 —CH 3 ;

(2) hydrogen;

(3) K; or

R 22 is —U 3 D 1 or —OCH 2 —CH 3 ;

D 1 , U 3 and K are as defined herein; and

with the proviso that the compounds of Formula (III) must contain at least one NO group, and/or at least one NO 2 group; wherein the at least one NO group and/or the at least one NO 2 group is linked to the compound through an oxygen atom, a nitrogen atom or a sulfur atom; and

the compound of Formula (IV) is:

wherein:

B 6 is:

 or

(2) a nitrogen;

G 6 is:

D 6 is:

or B 6 and D 6 taken together form a phenyl ring;

Q 6 is a hydrogen; or

B 6 is a nitrogen and Q 6 is CH 2 and taken together form the ring:

U 3 and D 1 are as defined herein; and

with the proviso that the compounds of Formula (IV) must contain at least one NO group, and/or at least one NO 2 group; wherein the at least one NO group and/or the at least one NO 2 group is linked to the compound through an oxygen atom, a nitrogen atom or a sulfur atom; and

the compound of Formula (V) is:

wherein:

X 7 is a hydrogen;

Y 7 is

or X 7 and Y 7 taken together are:

R 23 is a hydrogen or —OCH 3 ;

R 22 , U 3 and D 1 are as defined herein; and

with the proviso that the compounds of Formula (V) must contain at least one NO group, and/or at least one NO 2 group; wherein the at least one NO group and/or the at least one NO 2 group is linked to the compound through an oxygen atom, a nitrogen atom or a sulfur atom.

2 . The method of claim 1 , wherein the composition further comprises a pharmaceutically acceptable carrier.

3 . The method of claim 1 , wherein the compound of Formula (I) is a nitrosated acebutolol, a nitrosylated acebutolol, a nitrosated and nitrosylated acebutolol, a nitrosated alprenolol, a nitrosylated alprenolol, a nitrosated and nitrosylated alprenolol, a nitrosated atenolol, a nitrosylated atenolol, a nitrosated and nitrosylated atenolol, a nitrosated befunolol, a nitrosylated befunolol, a nitrosated and nitrosylated befunolol, a nitrosated betaxolol, a nitrosylated betaxolol, a nitrosated and nitrosylated betaxolol, a nitrosated bevantolol, a nitrosylated bevantolol, a nitrosated and nitrosylated bevantolol, a nitrosated bisoprolol, a nitrosylated bisoprolol, a nitrosated and nitrosylated bisoprolol, a nitrosated bopindolol, a nitrosylated bopindolol, a nitrosated and nitrosylated bopindolol, a nitrosated bucindolol, a nitrosylated bucindolol, a nitrosated and nitrosylated bucindolol, a nitrosated bucumolol, a nitrosylated bucumolol, a nitrosated and nitrosylated bucumolol, a nitrosated bufetolol, a nitrosylated bufetolol, a nitrosated and nitrosylated bufetolol, a nitrosated bunitrolol, a nitrosylated bunitrolol, a nitrosated and nitrosylated bunitrolol, a nitrosated bupranolol, a nitrosylated bupranolol, a nitrosated and nitrosylated bupranolol, a nitrosated butofilolol, a nitrosylated butofilolol, a nitrosated and nitrosylated butofilolol, a nitrosated carazolol, a nitrosylated carazolol, a nitrosated and nitrosylated carazolol, a nitrosated carteolol, a nitrosylated carteolol, a nitrosated and nitrosylated carteolol, a nitrosated celiprolol, a nitrosylated celiprolol, a nitrosated and nitrosylated celiprolol, a nitrosated cetamolol, a nitrosylated cetamolol, a nitrosated and nitrosylated cetamolol, a nitrosated cloranolol, a nitrosylated cloranolol, a nitrosated and nitrosylated cloranolol, a nitrosated esmolol, a nitrosylated esmolol, a nitrosated and nitrosylated esmolol, a nitrosated indenolol, a nitrosylated indenolol, a nitrosated and nitrosylated indenolol, a nitrosated levobunolol, a nitrosylated levobunolol, a nitrosated and nitrosylated levobunolol, a nitrosated mepindolol, a nitrosylated mepindolol, a nitrosated and nitrosylated mepindolol, a nitrosated metipranolol, a nitrosylated metipranolol, a nitrosated and nitrosylated metipranolol, a nitrosated metoprolol, a nitrosylated metoprolol, a nitrosated and nitrosylated metoprolol, a nitrosated moprolol, a nitrosylated moprolol, a nitrosated and nitrosylated moprolol, a nitrosated nadolol, a nitrosylated nadolol, a nitrosated and nitrosylated nadolol, a nitrosated nipradilol, a nitrosylated nipradilol, a nitrosated and nitrosylated nipradilol, a nitrosated oxprenolol, a nitrosylated oxprenolol, a nitrosated and nitrosylated oxprenolol, a nitrosated penbutolol, a nitrosylated penbutolol, a nitrosated and nitrosylated penbutolol, a nitrosated pindolol, a nitrosylated pindolol, a nitrosated and nitrosylated pindolol, a nitrosated practolol, a nitrosylated practolol, a nitrosated and nitrosylated practolol, a nitrosated propranolol, a nitrosylated propranolol, a nitrosated and nitrosylated propranolol, a nitrosated talinolol, a nitrosylated talinolol, a nitrosated and nitrosylated talinolol, a nitrosated tertatolol, a nitrosylated tertatolol, a nitrosated and nitrosylated tertatolol, a nitrosated tilisolol, a nitrosylated tilisolol, a nitrosated and nitrosylated tilisolol, a nitrosated timolol, a nitrosylated timolol, a nitrosated and nitrosylated timolol, a nitrosated toliprolol, a nitrosylated toliprolol, a nitrosated and nitrosylated toliprolol, a nitrosated xibenolol, a nitrosylated xibenolol, a nitrosated and nitrosylated xibenolol; the compound of Formula (II) is a nitrosated amosulalol, a nitrosylated amosulalol, a nitrosated and nitrosylated amosulalol, a nitrosated arotinolol, a nitrosylated arotinolol, a nitrosated and nitrosylated arotinolol, a nitrosated bufuralol, a nitrosylated bufuralol, a nitrosated and nitrosylated bufuralol, a nitrosated carvedilol, a nitrosylated carvedilol, a nitrosated and nitrosylated carvedilol, a nitrosated dilevalol, a nitrosylated dilevalol, a nitrosated and nitrosylated dilevalol, a nitrosated labetalol, a nitrosylated labetalol, a nitrosated and nitrosylated labetalol, a nitrosated landiolol, a nitrosylated landiolol, a nitrosated and nitrosylated landiolol, a nitrosated nifenalol, a nitrosylated nifenalol, a nitrosated and nitrosylated nifenalol, a nitrosated pronethalol, a nitrosylated pronethalol, a nitrosated and nitrosylated pronethalol, a nitrosated sotalol, a nitrosylated sotalol, a nitrosated and nitrosylated sotalol, a nitrosated sulfinalol, a nitrosylated sulfinalol, a nitrosated and nitrosylated sulfinalol; the compound of Formula (III) is a nitrosated alacepril, a nitrosylated alacepril, a nitrosated and nitrosylated alacepril, a nitrosated captopril, a nitrosylated captopril, a nitrosated and nitrosylated captopril, a nitrosated ceronapril, a nitrosylated ceronapril, a nitrosated and nitrosylated ceronapril, a nitrosated enalapril, a nitrosylated enalapril, a nitrosated and nitrosylated enalapril, a nitrosated enalaprilat, a nitrosylated enalaprilat, a nitrosated and nitrosylated enalaprilat, a nitrosated fosinopril, a nitrosylated fosinopril, a nitrosated and nitrosylated fosinopril, a nitrosated imidapril, a nitrosylated imidapril, a nitrosated and nitrosylated imidapril, a nitrosated lisinopril, a nitrosylated lisinopril, a nitrosated and nitrosylated lisinopril, a nitrosated moveltipril, a nitrosylated moveltipril, a nitrosated and nitrosylated moveltipril, a nitrosated perindopril, a nitrosylated perindopril, a nitrosated and nitrosylated perindopril, a nitrosated ramipril, a nitrosylated ramipril, a nitrosated and nitrosylated ramipril, a nitrosated spirapril, a nitrosylated spirapril, a nitrosated and nitrosylated spirapril, a nitrosated trandolapril, a nitrosylated trandolapril, a nitrosated and nitrosylated trandolapril; the compound of Formula (IV) is a nitrosated benazepril, a nitrosylated benazepril, a nitrosated and nitrosylated benazepril, a nitrosated cilazapril, a nitrosylated cilazapril, a nitrosated and nitrosylated cilazapril, a nitrosated temocapril, a nitrosylated temocapril, a nitrosated and nitrosylated temocapril; the compound of Formula (V) is a nitrosated delapril, a nitrosylated delapril, a nitrosated and nitrosylated delapril, a nitrosated moexipril, a nitrosylated moexipril, a nitrosated and nitrosylated moexipril, a nitrosated quinapril, a nitrosylated quinapril, a nitrosated and nitrosylated quinapril, or a pharmaceutically acceptable salt thereof.

4 . The method of claim 1 , wherein K is:

(1) —Y—(CR 4 R 4 ′) p -T-(CR 4 R 4 ′) p —ONO 2 ;

wherein T is ortho, meta or para;

(4) —Y—(CR 4 R 4 ′) p —V—B-T-(CR 4 R 4 ′) p —ONO 2 ;

(5) —Y—(CR 4 R 4 ′) p -T-C(O)—(CR 4 R 4 ′) o —(CH 2 )—ONO 2 ;

(6) —Y—(CR 4 R 4 ′) p —C(Z)-(CH 2 ) q -T-(CR 4 R 4 ′) q —(CH 2 )—ONO 2 ;

(7) —Y—(CR 4 R 4 ′) p -T-(CH 2 ) q —V—(CR 4 R 4 ′) q —(CH 2 )—ONO 2 ;

(8) —Y—(CR 4 R 4 ′) p —V—(CH 2 ) q —V—(CR 4 R 4 ′) q —(CH 2 )—ONO 2 ;

(9) —Y—(CR 4 R 4 ′) o —(W) q —(CR 4 R 4 ′) o —(CH 2 )—ONO 2 ;

(10) —NR j —O—(CH 2 ) o —V—(CR 4 R 4 ′) q —(CH 2 )—ONO 2 ;

(11) —NR j —O—(CH 2 ) o —(W) q —(CR 4 R 4 ′) q —(CH 2 )—ONO 2 ;

(12) —O—NR j —(CH 2 ) o —(W) q —(CR 4 R 4 ′) q —(CH 2 )—ONO 2 ;

(13) —Y—(CH 2 ) o —(W) q —(CH 2 ) o —V—(CR 4 R 4 ′) o -Q′-(CR 4 R 4 ′) n —(CH 2 )—ONO 2 ;

(14) —Y—(CR 4 R 4 ′) p —V—(CH 2 ) o —(W) q —(CR 4 R 4 ′) q —(CH 2 )—ONO 2 ;

(15) —O—NR j —(CH 2 ) o —V—(CR 4 R 4 ′) q —(CH 2 )—ONO 2 ;

(16) —Y—(CR 4 R 4 ′) o -Q′-(CR 4 ′) o —V—(CR 4 R 4 ′) o —(CH 2 )—ONO 2 ;

(17) —Y—(CR 4 R 4 ′) o -Q′-(CR 4 R 4 ′) o —(W) q —(CR 4 R 4 ′) o —(CH 2 )—ONO 2 ;

(18) —Y—(CR 4 R 4 ′) p -T-(C 4 R 4 ′) p -Q′-(CR 4 R 4 ′) o —(CH 2 )—ONO 2 ;

(19) —Y—(CR 4 R 4 ′) q —C(Z)-(CR 4 R 4 ′) o —(CH 2 )—ONO 2 ;

(20) —Y—(CR 4 R 4 ′) p -Q′-(CR 4 R 4 ′) o —(CH 2 )—ONO 2 ;

(21) —Y—(CR 4 R 4 ′) q —P(O)MM′;

(22) —Y—(CR 4 R 4 ′) o -Q′-(CR 4 R 4 ′) o —(CH 2 )—ONO 2 ;

(23) —Y—(CR 4 R 4 ′) o -Q′-(CR 4 R 4 ′) o -T-(CR 4 R 4 ′) o —(CH 2 )—ONO 2 ;

(24) —Y—(CR 4 R 4 ′) q —(W) q —(CR 4 R 4 ′) o -Q′-(CR 4 R 4 ′) o —(CH 2 )—ONO 2 ;

(25) —Y—(CR 4 R 4 ′) q —V—(CR 4 R 4 ′) o -Q′-(CR 4 R 4 ′) o —(CH 2 )—ONO 2 ;

(26) —Y—(CR 4 R 4 ′) p -(T) o -(W) q —(CR 4 R 4 ′) o —(CH 2 )—ONO 2 ;

(27) —Y—(CR 4 R 4 ′) p —(W) q -(T) o -(CR 4 R 4 ′) o —(CH 2 )—ONO 2 ;

(28) —Y—(CR 4 R 4 ′) q —C(Z)-V—(CR 4 R 4 ′) q —(CH 2 )—ONO 2 ;

(29) —Y—(CR 4 R 4 ′) o —C(R 4 )(ONO 2 )—(CR 4 R 4 ′) q -(T) o -(W) q -(T) o -(CR 4 R 4 ′) o —R 5 ;

(30) —Y—(CR 4 R 4 ′) o —V—(CR 4 R 4 ′) o -Q′-(CR 4 R 4 ′) o —(CH 2 )—ONO 2 ;

(31) —Y—(CR 4 R 4 ′) q —C(Z)-Q′-(CR 4 R 4 ′) o —(CH 2 )—ONO 2 ;

(32) —Y—(CR 4 R 4 ′) p —V—(CR 4 R 4 ′) p —(CH 2 )—ONO 2 ;

(33) —Y—(CR 4 R 4 ′) p —V—(CH 2 ) q -(T) o -(CR 4 R 4 ′) q —(CH 2 )—ONO 2 ;

(34) —Y—(CR 4 R 4 ′) p -(T) o -Q′-(T) o -(CR 4 R 4 ′) q —(CH 2 )—ONO 2 ;

(35) —Y—(CR 4 R 4 ′) q —C(Z)-(CR 4 R 4 ′) q —V—(CR 4 R 4 ′) o -Q′-(CR 4 R 4 ′) o —(CH 2 )—ONO 2 ;

(36) —Y—(CR 4 R 4 ′) q —C(Z)-(CR 4 R 4 ′) q —(W) q —(CR 4 R 4 ′) o -Q′-(CR 4 R 4 ′) o —(CH 2 )—ONO 2 ;

(37) —NR j —O—(CH 2 ) o —V—(CR 4 R 4 ′) o -Q′-(CH 2 )—ONO 2 ;

(38) —NR j —O—(CH 2 ) o —(W) q —(CR 4 R 4 ′) o -Q′-(CH 2 )—ONO 2 ;

(39) —O—-NR j —(CH 2 ) o —(W) q —(CR 4 ′) o -Q′-(CH 2 )—ONO 2 ;

(40) —O—NR j —(CH 2 ) o —V—(CR 4 R 4 ′) o -Q′-(CH 2 )—ONO 2 ;

(41) —NR j —NR j —(CR 4 R 4 ′) p —(W) q -(T) o -(CR 4 R 4 ′) o —(CH 2 )—ONO 2 ;

(42) —Y—(CR 4 R 4 ′) o -Q′-(CR 4 R 4 ′) o —ONO 2 ; or

(43) —Y—(CR 4 R 4 ′) o —V—(CR 4 R 4 ′) o -Q-(CR 4 R 4 ′) o —ONO 2 ;

R 4 and R 4 ′ at each occurrence are independently a hydrogen, lower alkyl group, —OH, —CH 2 OH, —ONO 2 , —NO 2 or —CH 2 ONO 2 ; or R 4 and R 4 ′ taken together with the carbon atom to which they are attached are a cycloalkyl group or a heterocyclic ring;

V is —C(O)-T-, -T-C(O)—, -T-C(O)-T or T-C(O)—C(O)-T;

W is a covalent bond or a carbonyl group;

T at each occurrence is independently an oxygen, (S(O) o ) o or NR j ;

R j is a hydrogen, an alkyl group, an aryl group, a heterocyclic ring, an alkylcarbonyl group, an alkylaryl group, an alkylsulfinyl group, an alkylsulfonyl group, an arylsulfinyl group, an arylsulfonyl group, a sulfonamido group, a N-alkylsulfonamido group, a N,N-diarylsulfonamido group, a N-arylsulfonamido group, a N-alkyl-N-arylsulfonamido group, a carboxamido group or a hydroxyl group;

p at each occurrence is independently an integer from 1 to 6;

q at each occurrence is independently an integer from 1 to 3;

o at each occurrence is independently an integer from 0 to 2;

Y is independently a covalent bond, a carbonyl, an oxygen, —S(O) o — or —NR j ;

B is either phenyl or (CH 2 ) o ;

Q′ is a cycloalkyl group, a heterocyclic ring or an aryl group;

Z is (═O), (═N—OR 5 ), (═N—NR 5 R′ 5 ) or (═CR 5 R′ 5 );

M and M′ are each independently —O − H 3 N + —(CR 4 R′ 4 ) q —CH 2 ONO 2 or -T-(CR 4 R′ 4 ) o —CH 2 ONO 2 ; and

R 5 and R 5 ′ at each occurrence are independently a hydrogen, a hydroxyl group, an alkyl group, an aryl group, an alkylsulfonyl group, an arylsulfonyl group, a carboxylic ester, an alkylcarbonyl group, an arylcarbonyl group, a carboxamido group, an alkoxyalkyl group, an alkoxyaryl group, a cycloalkyl group or a heterocyclic ring.

5 . The method of claim 1 , wherein K is:

wherein T′ maybe oitho meta or para

wherein:

Y′ a covalent bond, a carbonyl, an oxygen, —S(O) o — or —NR 6 ;

T′ is oxygen, sulfur or NR 6 ;

X 5 is oxygen, (S(O) o ) o or NR 6 ;

R 6 is a hydrogen, a lower alkyl group, an aryl group;

R 7 is a lower alkyl group or an aryl group;

R 8 at each occurrence is independently is a hydrogen, a hydroxyl group, a lower alkyl group, an aryl group, —NO 2 , —CH 2 —ONO 2 or —CH 2 —OH;

n′ and m′ are each independently an integer from 0 to 10; and

o is an integer from 0 to 2.

6 . The method of claim 1 , wherein the compound of Formula (I) is a compound of Formula (VI), (VI), (VIII), (IX), (X) or (XI); the compound of Formula (II) is a compound of Formula (XII); the compound of Formula (III) is a compound of Formula (XIII), (XIV), (XV), (XVI), (XVII), (XVIII), (XIX) or (XX); the compound of Formula (IV) is a compound of Formula (XXI) or (XXI); and the compound of Formula (V) is a compound of Formula (XXIII), (XXIV), (XXV) or (XXVI); or a pharmaceutically acceptable salt thereof,

wherein the compound of Formula (VI) is:

and the compound of Formula (VII) is:

and the compound of Formula (VIII) is:

and the compound of Formula (IX) is:

and the compound of Formula (X) is:

and the compound of Formula (XI) is:

and the compound of Formula (XII) is:

and the compound of Formula (XIII) is:

and the compound of Formula (XIV) is:

and the compound of Formula (XV) is:

and the compound of Formula (XVI) is:

and the compound of Formula (XVII) is:

and the compound of Formula (XVIII) is:

and the compound of Formula (XIX) is:

and the compound of Formula (XX) is:

and the compound of Formula (XXI) is:

and the compound of Formula (XXII) is:

and the compound of Formula (XXII) is:

and the compound of Formula (XXIV) is:

and the compound of Formula (XXV) is:

and the compound of Formula (XXVI) is:

wherein

T′ is oxygen, sulfur or NR 6 ;

R 6 is a hydrogen, a lower alkyl group, an aryl group;

R m -R n taken together can be a hydrogen atom; or

R m is:

(i) —C—(O)—;

(ii) —C—(O)—NR 6 ;

(iii) —C(O)—O—;

(iv) —C(O)—S;

(v) —CH 2 —O—; or

(vi) —CH(CH 3 )—O—;

R n is:

a hydrogen or

wherein:

R 9 is a lower alkyl group;

T′ is oxygen, sulfur or NR 6 ;

R 6 is a hydrogen, a lower alkyl group, an aryl group; and

with the proviso that the compounds of Formula (IV) to Formula (XXVI) must contain at least one —NO 2 group.

7 . The method of calim 1 wherein the compound of Formula (III) is ethyl (2S)-2-(((1S)-2-((2S)-2-(((2S,6R)-6-(nitrooxy)-4,8-dioxabicyclo(3.3.0)oct-2-yl)oxycarbonyl)pyrrolidinyl)-1-methyl-2-oxoethyl)amino)-4-phenylbutanoate; (2S)-1-((2S)-2-(((1S)-1-(((2S,6R)-6-(nitrooxy)-4,8-dioxabicyclo(3.3.0)oct-2-yl)oxycarbonyl)-3-phenylpropyl)amino)propanoyl)pyrrolidine-2-carboxylic acid; (2S,6R)-6-(nitrooxy)-4,8-dioxabicyclo(3.3.0)oct-2-yl (2S)-2-(((1S)-2-((2S)-2-(((2S,6R)-6-(nitrooxy)-4,8-dioxabicyclo(3.3.0)Oct-2-yl)oxycarbonyl)pyrrolidinyl)-1-methyl-2-oxoethyl)amino)-4-phenylbutanoate or a pharmaceutically acceptable salt thereof:

8 . The method of claim 1 , wherein the ophthalmic disorder is an ophthalmic infection, a cataract, glaucoma, elevated intraocular pressure, ocular pain a dry eye disorder, ocular hypertension, ocular bleeding, a retinal disease, presbyopia, macular degeneration, choroidal neovascularization, a retinopathy or a retinitis.

9 . The method of claim 8 , wherein the ophthalmic disorder is an ophthalmic infection, glaucoma, ocular pain following corneal surgery, dry eye disorder, ocular hypertension, ocular bleeding, retinal diseases or disorders, or elevated intraocular pressure.

10 . The method of claim 8 , wherein the ophthalmic infection is an inflammation of the conjunctiva, an inflammation of the cornea or a corneal ulcer.

11 . The method of claim 2 , further comprising (i) at least one therapeutic agent; (ii) at least one nitric oxide donor compound; or (iii) at least one therapeutic agent and at least one nitric oxide donor compound.

12 . The method of claim 11 , wherein the therapeutic agent is an α-adrenergic receptor agonist, an α-adrenergic receptor antagonist, an angiotensin-converting enzyme (ACE) inhibitor, an antimicrobial compound, an antioxidant, a β-adrenergic antagonist, a carbonic anhydrase inhibitor, a hydralazine compound, a nonsteroidal antiinflammatory compound, a prostaglandin, a selective cyclooxygenase-2 inhibitor or a combination of two or more thereof.

13 . The method of claim 12 , wherein the therapeutic agent is at least one compound selected from the group consisting of an α-adrenergic receptor agonist, an angiotensin-converting enzyme (ACE) inhibitor, an antimicrobial compound, a β-adrenergic antagonist, a carbonic anhydrase inhibitor, a nonsteroidal antiinflammatory compound, a prostaglandin, a selective cyclooxygenase-2 (COX-2) inhibitor and a steroid.

14 . The method of claim 11 , wherein the nitric oxide donor compound is selected from the group consisting of a S-nitrosothiol, a nitrite, a nitrate, a S-nitrothiol, a sydnonimine, a NONOate, a N-nitrosoamine, a N-hydroxyl nitrosamine, a nitrosimine, a diazetine dioxide, an oxatriazole 5-imine, an oxime, a hydroxylamine, a N-hydroxyguanidine, a hydroxyurea and a furoxan.

15 . The method of claim 11 , wherein the nitric oxide donor compound is a compound that stimulates the endogenous production of nitric oxide or endothelium-derived relaxing factor in vivo, a compound that elevates endogenous levels of nitric oxide, a compound that is oxidized to produce nitric oxide, a compound that is a substrate for nitric oxide synthase or a compound that is a substrate for cytochrome P450.