HYDROXYLAMINE COMPOUNDS AND METHODS OF THEIR USE
The present disclosure provides compounds that include hydroxylamines of formula I or II, pharmaceutical compositions, and methods for their use. The methods utilize hydroxylamine compounds and/or their pharmaceutical compositions for the treatment of angiogenesis, hepatitis, complement-mediated pathologies, drusen-mediated pathologies, macular degeneration and certain other ophthalmic conditions, inflammation, arthritis, and related diseases and for the inhibition of complement activation.
1 . A compound of Formula I:
or a pharmaceutically acceptable salt thereof
wherein:
A and B are each H, or taken together form a double bond between the ring atoms to which they are attached, provided that when A and B form a double bond, R 4 is other than H;
Z is —O— or —C(B)(R 2 )—, provided that when n is 0, then Z is —C(B)(R 2 )—;
R 1 and R 3 are each independently H, alkyl, or halo;
R 2 is halo, —OR 4 , —N(R 5 )R 6 , —CN, —(C═O)N(R 5 )R 6 , or —C[(R 7 )(R 8 )] m R 9 , or when A is H, B and R 2 taken together form ═O; or when A and B taken together form a double bond between the ring atoms to which they are attached, R 1 and R 2 taken together with the atoms through which they are attached, form an optionally substituted C 6 aromatic ring;
m is 1 or 2;
n is 0, 1, or 2;
R 4 is H, alkyl, or
R 5 is H or alkyl;
R 6 is alkyl,
—C(═O)—R 11 , or —S(═O) 2 —R 11 ; or R 5 and R 6 taken together with the nitrogen atom to which they are attached form a morpholine ring;
R 7 and R 8 are each H or alkyl;
R 9 is H, alkyl, —OH, —CH 2 OCH 2 -cycloalkyl, —O-alkyl, furanyl, tetrahydrofuranyl, —C(═O)-furanyl, —CH 2 —C(═O)-morpholin-4-yl; —CN, or —N(R 5 )R 6 ;
R 10 is H, alkyl, aralkyl, heterocycloalkyl, heteroaryl, —NH 2 , alkylamino, dialkylamino, halo, or
and
R 11 is alkyl, cycloalkyl, —NH(3,5-di-tertiary butyl-4-hydroxyphenyl), —NH-(4,5-dihydroxy-2-methylphenyl), or
provided that the compound of formula I is other than 1,4-dihydroxy-2,2,6,6-tetramethylpiperidine, 1-hydroxy-4-methoxy-2,2,6,6-tetramethylpiperidine, 1-hydroxy-4-ethoxy-2,2,6,6-tetramethylpiperidine, 1-hydroxy-4-amino-2,2,6,6-tetramethylpiperidine, 1-hydroxy-4-acetamido-2,2,6,6-tetramethylpiperidine, 1-hydroxy-2,2,6,6-tetramethyl-piperidin-4-one, 1-hydroxy-2,2,5,5-tetramethyl-pyrrolidin-3-one, 2,2,5,5-tetramethyl-pyrrolidine-1,3-diol, 3-hydroxymethyl-2,2,5,5-tetramethyl-2,5-dihydro-pyrrol-1-ol, 3-bromo-2,2,6,6-tetramethyl-piperidine-1,4-diol, 3-bromo-4-methoxy-2,2,6,6-tetramethyl-piperidine-1-ol, 3-chloro-2,2,6,6-tetramethyl-piperidine-1,4-diol, 1-hydroxy-4-methanesulfonamido-2,2,6,6-tetramethylpiperidine, 4-chloro-1-hydroxy-2,2,6,6-tetramethylpiperidine, 3-bromo-1-hydroxy-2,2,6,6-tetramethyl-piperidin-4-one, 3-chloro-1-hydroxy-2,2,6,6-tetramethyl-piperidin-4-one, 1-Hydroxy-2,2,5,5-tetramethyl-pyrrolidin-3-one, 4-bromo-1-hydroxy-2,2,6,6-tetramethylpiperidine, 2,2,6,6-tetramethyl-4-morpholin-4-yl-3,6-dihydro-2H-pyridin-1-ol, 3-ethoxymethyl-2,2,5,5-tetramethyl-2,5-dihydro-pyrrol-1-ol, 3-(N,N-dimethylaminomethyl)-2,2,5,5-tetramethyl-2,5-dihydro-pyrrol-1-ol, 3-(N,N-diethylaminomethyl)-2,2,5,5-tetramethyl-2,5-dihydro-pyrrol-1-ol, 3-(N-tertiarybutylaminomethyl)-2,2,5,5-tetramethyl-2,5-dihydro-pyrrol-1-ol, 3-(N-pyrrolidinomethyl)-2,2,5,5-tetramethyl-2,5-dihydro-pyrrol-1-ol, 3-(N-piperidinomethyl)-2,2,5,5-tetramethyl-2,5-dihydro-pyrrol-1-ol, or 2,5-dihydro-2,2,5,5-tetramethyl-1H-pyrrole-1-hydroxy-3-carboxamide.
2 . The compound according to claim 1 , wherein the heterocycloalkyl is morpholinyl or pyrrolidinyl.
3 . The hydrochloride salt of the compound of claim 1 .
4 . The compound according to claim 1 , wherein A and B are each H.
5 . The compound according to claim 1 , wherein A and B taken together form a double bond between the ring atoms to which they are attached.
6 . The compound according to claim 1 , wherein Z is —C(B)(R 2 )—.
7 . The compound according to claim 1 , R 1 and R 3 are each H.
8 . The compound according to claim 1 , wherein at least one of R 1 and R 3 is alkyl or halo.
9 . The compound according to claim 1 , wherein R 2 is halo, —OR 4 , —N(R 5 )R 6 , —(C═O) N(R 5 )R 6 , or —C[(R 7 )(R 8 )] m R 9 .
10 . The compound according to claim 9 , wherein R 2 is —OR 4 , —N(R 5 )R 6 , —(C═O) N(R 5 )R 6 , or —C[(R 7 )(R 8 )] m R 9 .
11 . The compound according to claim 9 , wherein R 2 is —OR 4 , —N(R 5 )R 6 , or —C[(R 7 )(R 8 )] m R 9 .
12 . The compound according to claim 1 , wherein R 1 and R 2 taken together with the atoms through which they are attached, form an optionally substituted C 6 aromatic ring.
13 . The compound according to claim 1 , wherein m is 1 and n is 0 or 1.
14 . The compound according to claim 13 , wherein n is 1.
15 . The compound according to claim 13 , wherein n is 0.
16 . The compound according to claim 1 , wherein R 4 is alkyl, or
17 . The compound according to claim 16 , wherein R 4 is
18 . The compound according to claim 1 , wherein R 5 is H.
19 . The compound according to claim 1 , wherein R 6 is alkyl,
—C(═O)—R 11 , or —S(═O) 2 —R 11 .
20 . The compound according to claim 19 , wherein R 6 is
—C(═O)—R 11 , or —S(═O) 2 —R 11 .
21 . The compound according to claim 1 , wherein R 5 and R 6 taken together with the nitrogen atom to which they are attached form a morpholine ring.
22 . The compound according to claim 1 , wherein at least one of R 7 and R 8 is H.
23 . The compound according to claim 10 , wherein R 2 is —C(═O)NH 2 .
24 . The compound according to claim 1 , wherein R 9 is —OH, —CH 2 —C(═O)-morpholin-4-yl; or —N(R 5 )R 6 .
25 . The compound according to claim 1 , wherein R 10 is H, morpholinyl, halo, or
26 . The compound according to claim 1 , wherein R 11 is alkyl, cycloalkyl, —NH(3,5-di-tertiary butyl-4-hydroxyphenyl), —NH-(4,5-dihydroxy-2-methylphenyl), or
27 . The compound according to claim 26 , wherein R 11 is alkyl, cycloalkyl, or
28 . The compound according to claim 26 , wherein R 11 is —NH(3,5-di-tertiary butyl-4-hydroxyphenyl) or —NH-(4,5-dihydroxy-2-methylphenyl).
29 . The compound according to claim 1 , wherein the compound of formula I is:
4-(2,2,6,6-tetramethylpiperidin-1-hydroxy-4-yl)morpholine;
4-(4-(2,2,6,6-tetramethylpiperidin-1-hydroxyl-4-yloxy)-1,2,5-thiazol-3-yl)morpholine;
2,2,3,5,6,6-Hexamethyl-piperidine-1,4-diol;
N-(2,2,6,6-tetramethylpiperidin-1-hydroxyl-4-yl)morpholine-4-carboxamide;
4-cyano-1-hydroxyl-2,2,6,6-tetramethylpiperidine;
4-(4-chloro-1,2,5-thiadiazol-3-yloxyl)-1-hydroxyl-2,2,6,6-tetramethylpiperidine;
1-hydroxyl-4-(4-(2,2,6,6-tetramethylpiperidin-1-hydroxyl-4-yloxy)-1,2,5-thiadiazol-3-yloxy)-2,2,6,6-tetramethylpiperidine;
1,1,3,3-tetramethylisoindolin-2-hydroxyl-5-carboxylic acid;
3,3,5,5-1-hydroxy-tetramethylmorpholine;
1-hydroxy-2,2,5,5-tetramethylpyrrolidine-3-carboxamide;
1-hydroxy-1,2,3,6-tetrahydro-2,2,6,6-tetramethylpyridin-4-yl)methanol;
N-(1-hydroxy-2,2,6,6-tetramethylpiperidin-4-yl)-3-morpholinopropanamide;
4,5-dihydroxy-2-methyl-N-(1-hydroxy-2,2,6,6-tetramethylpiperidin-4-yl)benzamide;
N-(3,5-di-tert-butyl-4-hydroxyphenyl)-1-hydroxy-2,2,6,6-tetramethylpiperidine-4-carboxamide;
1-hydroxy-2,2,6,6-tetramethyl-4-(2H-tetrazol-5-yl)piperidine;
N-(1-hydroxy-2,2,6,6-tetramethylpiperidin-4-yl)cyclopropanecarboxamide;
4-(4-(1-hydroxy-2,2,5,5-tetramethylpyrrolidin-3-yloxy)-1,2,5-thiadiazol-3-yl)morpholine;
1-hydroxy-2,2,5,5-tetramethylpyrrolidin-3-yl)methanol;
(1-hydroxy-2,2,6,6-tetramethylpiperidin-4-yl)methanol;
1-hydroxy-1,2,3,6-tetrahydro-2,2,6,6-tetramethylpyridine;
((1-hydroxy-2,5-dihydro-2,2,5,5-tetramethyl-1H-pyrrol-3-yl)methyl)morpholine;
1-hydroxy-2,2,5,5-tetramethylpyrrolidin-3-one; or
N-(1-hydroxy-2,2,5,5,-tetramethylpyrrolidin-3-yl)cyclopropanecarboxamide;
or a pharmaceutically acceptable salt thereof.
30 . The compound according to claim 29 , or a hydrochloride salt thereof.
31 . The compound of claim 1 , wherein the compound is 4-(4-(2,2,6,6-tetramethylpiperidin-1-hydroxyl-4-yloxy)-1,2,5-thiazol-3-yl)morpholine or a pharmaceutically acceptable salt thereof.
32 . A compound of Formula II:
or a pharmaceutically acceptable salt thereof,
wherein:
A is H;
Z is —O— or —C(B)(R 2 )—, provided that when n is 0, then Z is —C(B)(R 2 )—;
B is H, alkyl, aryl, or heteroaralkyl, or A and B taken together form a double bond between the ring atoms through which they are connected, provided that when A and B form a double bond, R 4 is other than H;
R 1 is H, alkyl, aryl, hydroxy, or halo; or A and R 1 taken together form ═O, provided that when A and R 1 taken together form ═O, then Z is —O—;
R 3 is H, alkyl, or halo;
R 2 is H, halo, aryl, aralkyl, heteroaryl, —OR 4 , —SR 4 , —N(R 5 )R 6 , —ONO 2 , —CN,_C(═O)-aryl, —C(═O)NH 2 , —(C═O)N(R 5 )R 6 , or —C[(R 7 )(R 8 )] m R 9 , or R 1 and R 2 taken together with the atoms through which they are connected form an aryl ring, provided that:
when R 1 and R 2 taken together with the atoms through which they are connected form an aryl ring, then A and B are absent;
when R 2 is other than —OH, then B is other than alkyl, aryl, or heteroaralkyl;
when R 2 is H, then R 1 is H, and A and B taken together form a double bond between the ring atoms through which they are connected;
when R 2 is —C(═O)NH 2 , then A and B are H, and n is 0; and
when A is H, B and R 2 taken together form ═O or ═CH(R 12 );
m is 1, 2, or 3;
n is 0, 1, or 2;
R 4 is H, alkyl, aryl, aralkyl, heteroaryl,
R 5 is H, alkyl, aryl, or aralkyl;
R 6 is alkyl, aralkyl, heteroaryl,
—C(═O)—R 11 , —C(═NH)-alkyl, or —S(═O) 2 —R 1 l; or R 5 and R 6 taken together with the nitrogen atom to which they are attached form a heterocycloalkyl ring;
p is 0, 1, or 2;
R 7 and R 8 are each H or alkyl;
R 9 is H, alkyl, —OH, —CH 2 OCH 2 -cycloalkyl, —O-alkyl, —O-aryl, —ONO 2 , heterocycloalkyl, heteroaryl, —C(═O)-aryl, —C(═O)-heteroaryl, —CH 2 —C(═O)-heterocycloalkyl; alkylheteroaryloxy, —CN, or —N(R 5 )R 6 ;
R 10 is H, alkyl, aryl, aralkyl, arylheterocycloalkyl, heterocycloalkyl, heteroaryl, —NH 2 , cyano, carboxy, alkoxycarbonyl, alkylamino, dialkylamino, halo, haloarylheterocycloalkyl, heteroaroylheterocycloalkyl, heteroarylheterocycloalkyl, C(═O)-heterocycloalkyl,
R 11 is alkyl, cycloalkyl, aryl, aralkenyl, heterocycloalkyl, halobenzo[1,2,5]oxadiazolyl, heteroarylheterocycloalkyl, heterocycloalkylalkyl-(3,5-di-tertiary butyl-4-hydroxyphenyl), -(4,5-dihydroxy-2-methylphenyl), or
R 12 is —C(═O)-heterocycloalkylaryl or C(═O)-heterocycloalkyl;
provided that the compound of formula I is other than 1,4-dihydroxy-2,2,6,6-tetramethylpiperidine, 1-hydroxy-4-methoxy-2,2,6,6-tetramethylpiperidine, 1-hydroxy-4-ethoxy-2,2,6,6-tetramethylpiperidine, 1-hydroxy-4-amino-2,2,6,6-tetramethylpiperidine, 1-hydroxy-4-acetamido-2,2,6,6-tetramethylpiperidine, 1-hydroxy-2,2,6,6-tetramethyl-piperidin-4-one, 1-hydroxy-2,2,5,5-tetramethyl-pyrrolidin-3-one, 2,2,5,5-tetramethyl-pyrrolidine-1,3-diol, 3-hydroxymethyl-2,2,5,5-tetramethyl-2,5-dihydro-pyrrol-1-ol, 3-bromo-2,2,6,6-tetramethyl-piperidine-1,4-diol, 3-bromo-4-methoxy-2,2,6,6-tetramethyl-piperidine-1-ol, 3-chloro-2,2,6,6-tetramethyl-piperidine-1,4-diol, 1-hydroxy-4-methanesulfonamido-2,2,6,6-tetramethylpiperidine, 4-chloro-1-hydroxy-2,2,6,6-tetramethylpiperidine, 3-bromo-1-hydroxy-2,2,6,6-tetramethyl-piperidin-4-one, 3-chloro-1-hydroxy-2,2,6,6-tetramethyl-piperidin-4-one, 4-bromo-1-hydroxy-2,2,6,6-tetramethylpiperidine, 2,2,6,6-tetramethyl-4-morpholin-4-yl-3,6-dihydro-2H-pyridin-1-ol, 3-ethoxymethyl-2,2,5,5-tetramethyl-2,5-dihydro-pyrrol-1-ol, 3-(N,N-dimethylaminomethyl)-2,2,5,5-tetramethyl-2,5-dihydro-pyrrol-1-ol, 3-(N,N-diethylaminomethyl)-2,2,5,5-tetramethyl-2,5-dihydro-pyrrol-1-ol, 3-(N-tertiarybutylaminomethyl)-2,2,5,5-tetramethyl-2,5-dihydro-pyrrol-1-ol, 3-(N-pyrrolidinomethyl)-2,2,5,5-tetramethyl-2,5-dihydro-pyrrol-1-ol, 3-(N-piperidinomethyl)-2,2,5,5-tetramethyl-2,5-dihydro-pyrrol-1-ol, 1-hydroxy-2,2,5,5-tetramethylpyrrolidine-3-carboxamide, or 2,5-dihydro-2,2,5,5-tetramethyl-1H-pyrrole-1-hydroxy-3-carboxamide.
33 . The compound according to claim 32 , wherein when R 10 is heterocycloalkyl the heterocycloalkyl is morpholinyl or pyrrolidinyl.
34 . The hydrochloride salt of the compound of claim 32 .
35 . The compound according to claim 32 , wherein A and B are each H.
36 . The compound according to claim 32 , wherein A and B taken together form a double bond between the ring atoms to which they are attached.
37 . A compound according to claim 36 , wherein at least one of R 1 and R 2 is aryl.
38 . A compound according to claim 37 , wherein R 1 and R 2 are independently aryl.
39 . A compound according to claim 38 , wherein R 1 and R 2 are each independently optionally substituted phenyl.
40 . The compound according to claim 32 , wherein Z is —C(B)(R 2 )—.
41 . The compound according to claim 32 , R 1 and R 3 are each H.
42 . The compound according to claim 41 , wherein R 2 is heteroaryl, —OR 4 , —N(R 5 )R 6 , —ONO 2 , —(C═O) N(R 5 )R 6 , or —C[(R 7 )(R 8 )] m R 9 .
43 . A compound according to claim 42 , wherein when R 2 is heteroaryl, the heteroaryl is tetrazolyl.
44 . The compound according to claim 41 , wherein R 2 is —OR 4 , —N(R 5 )R 6 , or —C[(R 7 )(R 8 )] m R 9 .
45 . A compound according to claim 44 , wherein R 2 is —OH.
46 . A compound according to claim 45 , wherein B is alkyl or aryl.
47 . The compound according to claim 32 , wherein R 1 and R 2 taken together with the atoms through which they are attached, form an optionally substituted phenyl ring.
48 . The compound according to claim 32 , wherein m is 1 or 2 and n is 0 or 1.
49 . The compound according to claim 48 , wherein n is 1.
50 . The compound according to claim 48 , wherein n is 0.
51 . The compound according to claim 32 , wherein R 4 is H, alkyl, aralkyl, heteroaryl, or
52 . The compound according to claim 51 , wherein R 4 H or
53 . The compound according to claim 32 , wherein R 5 is H.
54 . The compound according to claim 32 , wherein R 6 is
—C(═O)—R 11 , or —S(═O) 2 —R 11 .
55 . The compound according to claim 32 , wherein R 5 and R 6 taken together with the nitrogen atom to which they are attached form a morpholine ring.
56 . The compound according to claim 32 , wherein at least one of R 7 and R 8 is H.
57 . The compound according to claim 32 , wherein R 9 is —OH.
58 . A compound according to claim 32 , wherein Z is —O—.
59 . A compound according to claim 58 , wherein A and R 1 taken together form ═O.
60 . The compound according to claim 32 , wherein R 10 is H, morpholinyl, halo, or
61 . A compound according to claim 32 , wherein R 10 is optionally substituted morpholinyl, optionally substituted N-alkylpiperazinyl
62 . The compound according to claim 32 , wherein R 11 is alkyl, aryl, aralkenyl, heteroaryl, heterocycloalkyl, -(3,5-di-tertiary butyl-4-hydroxyphenyl), -(4,5-dihydroxy-2-methylphenyl), or
63 . A compound according to claim 62 , wherein when R 11 is aryl, the aryl is 3,5-di-tert-butyl-4-hydroxyphenyl or 4,5-dihdroxy-2-methylphenyl.
64 . A compound according to claim 63 , wherein R 11 is alkyl, aralkenyl, or
65 . A compound according to claim 63 , wherein R 11 is -(3,5-di-tertiary butyl-4-hydroxyphenyl) or -(4,5-dihydroxy-2-methylphenyl).
66 . A compound of claim 1 that is:
4-(4-(2,2,6,6-tetramethylpiperidin-1-hydroxyl-4-yloxy)-1,2,5-thiadiazol-3-yl)morpholine;
1,3-Dihydroxy-2,2,5,5-Tetramethyl-pyrrolidine;
2,5-dihydro-2,2,5,5-tetramethyl-1-hydroxyl-1H-pyrrol-3-yl)methanol;
4,5-dihydroxy-2-methyl-N-(1-hydroxy-2,2,6,6-tetramethylpiperidin-4-yl)benzamide;
N-(3,5-di-t-butyl-4-hydroxyphenyl)-1-hydroxy-2,2,6,6-tetramethylpiperidine-4-carboxamide;
1-hydroxy-2,2,6,6-tetramethyl-4-(2H-tetrazol-5-yl)piperidine;
N-Hydroxyl-3,3,5,5-tetramethylmorpholin-2-one;
1,4-dihydroxy-4-n-butyl-2,2,6,6-tetramethylpiperidine;
1,4-Dihydroxy-4-phenyl-2,2,6,6-tetrmethylpiperidine;
4-Benzyloxy-1-hydroxy-2,2,6,6-tetramethylpiperidine;
5-(2,5,-dihydro-4-(3,4,5-trimethoxyphenyl)-1-hydroxy-2,2,5,5-tetramethyl-1H-pyrrol-3-yl)-2-methoxybenzaldehyde;
1-Hydroxy-2,3,6-trihydro-4-(3,4,5-trimethoxyphenyl)-2,2,6,6-tetramethylpiperidine;
4-[(4-methylpiperazin-1-yl)]-3-[(2,2,6,6-tetramethyl-1-Hydroxy piperidinyl)]-1,2,5-thiadiazole;
4-(4-(1-hydroxy 2,2,6,6-tetramethylpiperidin-4-yloxy)-1,2,5-thiadiazol-3-yl)thiomorpholine;
4-(4-Fluorophenyl)-1-hydroxyl-2,2,6,6-tetramethylpiperidin-4-ol;
4-O-nitro-1-hydroxy-2,2,6,6-tetramethylpiperidine;
1,4-bis(1-hydroxy-2,26,6-tetramethylpiperidin-4-yloxy)-1,2,5-thiadiazol-3-yl)piperazine; or
3,4-dihydro-6-hydroxy-2,5,7,8-tetramethyl-N-(1-hydroxy-2,2,6,6-tetramethylpiperidin-4-yl)-2H-chromene-2-carboxamide;
or a pharmaceutically acceptable salt thereof.
67 . The compound of claim 66 that is:
4-(4-(2,2,6,6-tetramethylpiperidin-1-hydroxyl-4-yloxy)-1,2,5-thiadiazol-3-yl)morpholine;
1,3-Dihydroxy-2,2,5,5-tetramethyl-pyrrolidine;
2,5-dihydro-2,2,5,5-tetramethyl-1-hydroxyl-1H-pyrrol-3-yl)methanol;
1,4-dihydroxy-4-n-butyl-2,2,6,6-tetramethylpiperidine;
1,4-Dihydroxy-4-phenyl-2,2,6,6-tetrmethylpiperidine;
5-(2,5,-dihydro-4-(3,4,5-trimethoxyphenyl)-1-hydroxy-2,2,5,5-tetramethyl-1H-pyrrol-3-yl)-2-methoxybenzaldehyde; or
4-[(4-methylpiperazin-1-yl)]-3-[(2,2,6,6-tetramethyl-1-Hydroxy piperidinyl)]-1,2,5-thiadiazole;
or a pharmaceutically acceptable salt thereof.
68 . The compound of claim 67 that is:
4-(4-(2,2,6,6-tetramethylpiperidin-1-hydroxyl-4-yloxy)-1,2,5-thiadiazol-3-yl)morpholine;
1,4-dihydroxy-4-n-butyl-2,2,6,6-tetramethylpiperidine;
1,4-Dihydroxy-4-phenyl-2,2,6,6-tetrmethylpiperidine; or
4-[(4-methylpiperazin-1-yl)]-3-[(2,2,6,6-tetramethyl-1-Hydroxy piperidinyl)]-1,2,5-thiadiazole;
or a pharmaceutically acceptable salt thereof.
69 . The compound according to claim 66 , or a hydrochloride salt thereof.
70 . A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a compound of formula I:
or a pharmaceutically acceptable salt thereof,
wherein:
A and B are each H, or taken together form a double bond between the ring atoms to which they are attached, provided that when A and B form a double bond, R 4 is other than H;
Z is —O— or —C(B)(R 2 )—, provided that when n is 0, then Z is —C(B)(R 2 )—;
R 1 and R 3 are each independently H, alkyl, or halo;
R 2 is halo, —OR 4 , —N(R 5 )R 6 , —CN, —(C═O)NH 2 , or —C[(R 7 )(R 8 )] m R 9 , or when A is H, B and R 2 taken together form ═O; or when A and B taken together form a double bond between the ring atoms to which they are attached, R 1 and R 2 taken together with the atoms through which they are attached, form an optionally substituted C 6 aromatic ring;
m is 1 or 2;
n is 0, 1, or 2;
R 4 is H, alkyl, or
R 5 is H or alkyl;
R 6 is alkyl,
—C(═O)—R 11 , or —S(═O) 2 —R 11 ; or R 5 and R 6 taken together with the nitrogen atom to which they are attached form a morpholine ring;
R 7 and R 8 are each H or alkyl;
R 9 is H, alkyl, —OH, —CH 2 OCH 2 -cycloalkyl, —O-alkyl, furanyl, tetrahydrofuranyl, —C(═O)-furanyl, —CH 2 —C(═O)-morpholin-4-yl; —CN, or —N(R 5 )R 6 ;
R 10 is H, alkyl, aralkyl, heterocycle, heteroaryl, —NH 2 , alkylamino, dialkylamino, morpholinyl, pyrrolidinyl, halo, or
R 11 is alkyl, cycloalkyl, —NH(3,5-di-tertiary butyl-4-hydroxyphenyl), —NH-(4,5-dihydroxy-2-methylphenyl),
71 . A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a compound of formula II:
or a pharmaceutically acceptable salt thereof,
wherein:
A is H;
Z is —O— or —C(B)(R 2 )—, provided that when n is 0, then Z is —C(B)(R 2 )—;
B is H, alkyl, aryl, or heteroaralkyl, or A and B taken together form a double bond between the ring atoms through which they are connected, provided that when A and B form a double bond, R 4 is other than H;
R 1 is H, alkyl, aryl, hydroxy, or halo; or A and R 1 taken together form ═O, provided that when A and R 1 taken together form ═O, then Z is —O—;
R 3 is H, alkyl, or halo;
R 2 is H, halo, aryl, aralkyl, heteroaryl, —OR , —SR 4 , —N(R 5 )R 6 , —ONO 2 , —CN,_C(═O)-aryl,
C(═O)NH 2 , —(C═O)N(R 5 )R 6 , or —C[(R 7 )(R 8 )] m R 9 , or R 1 and R 2 taken together with the through which they are connected form an aryl ring, provided that:
when R 1 and R 2 taken together with the atoms through which they are connected form an aryl ring, then A and B are absent;
when R 2 is other than —OH, then B is other than alkyl, aryl, or heteroaralkyl;
when R 2 is H, then R 1 is H, and A and B taken together form a double bond between the ring atoms through which they are connected;
when R 2 is —C(═O)NH 2 , then A and B are H, and n is 0; and
when A is H, B and R 2 taken together form ═O or ═CH(R 12 );
m is 1, 2, or 3;
n is 0, 1, or 2;
R 4 is H, alkyl, aryl, aralkyl, heteroaryl,
R 5 is H, alkyl, aryl, or aralkyl;
R 6 is alkyl, aralkyl, heteroaryl,
—C(═O)—R 11 , —C(═NH)-alkyl, or —S(═O) 2 —R 11 ; or R 5 and R 6 taken together with the nitrogen atom to which they are attached form a heterocycloalkyl ring;
p is 0, 1, or 2;
R 7 and R 8 are each H or alkyl;
R 9 is H, alkyl, —OH, —CH 2 OCH 2 -cycloalkyl, —O-alkyl, —O-aryl, —ONO 2 , heterocycloalkyl, heteroaryl, —C(═O)-aryl, —C(═O)-heteroaryl, —CH 2 —C(═O)-heterocycloalkyl; alkylheteroaryloxy, —CN, or —N(R 5 )R 6 ;
R 10 is H, alkyl, aryl, aralkyl, arylheterocycloalkyl, heterocycloalkyl, heteroaryl, —NH 2 , cyano, carboxy, alkoxycarbonyl, alkylamino, dialkylamino, halo, haloarylheterocycloalkyl, heteroaroylheterocycloalkyl, heteroarylheterocycloalkyl, C(═O)-heterocycloalkyl,
R 11 is alkyl, cycloalkyl, aryl, aralkenyl, heterocycloalkyl, halobenzo[1,2,5]oxadiazolyl, heteroarylheterocycloalkyl, heterocycloalkylalkyl -(3,5-di-tertiary butyl-4-hydroxyphenyl), -(4,5-dihydroxy-2-methylphenyl), or
R 12 is —C(═O)-heterocycloalkylaryl or C(═O)-heterocycloalkyl.
72 . A pharmaceutical composition of claim 70 , wherein compound of formula I is other than 1,4-dihydroxy-2,2,6,6-tetramethylpiperidine, 1-hydroxy-4-methoxy-2,2,6,6-tetramethylpiperidine, 1-hydroxy-4-ethoxy-2,2,6,6-tetramethylpiperidine, 1-hydroxy-4-amino-2,2,6,6-tetramethylpiperidine, 1-hydroxy-4-acetamido-2,2,6,6-tetramethylpiperidine, 1-hydroxy-2,2,6,6-tetramethyl-piperidin-4-one, 1-hydroxy-2,2,5,5-tetramethyl-pyrrolidin-3-one, 2,2,5,5-tetramethyl-pyrrolidine-1,3-diol, 3-hydroxymethyl-2,2,5,5-tetramethyl-2,5-dihydro-pyrrol-1-ol, 3-bromo-2,2,6,6-tetramethyl-piperidine-1,4-diol, 3-bromo-4-methoxy-2,2,6,6-tetramethyl-piperidine-1-ol, 3-chloro-2,2,6,6-tetramethyl-piperidine-1,4-diol, 1-hydroxy-4-methanesulfonamido-2,2,6,6-tetramethylpiperidine, 4-chloro-1-hydroxy-2,2,6,6-tetramethylpiperidine, 3-bromo-1-hydroxy-2,2,6,6-tetramethyl-piperidin-4-one, 3-chloro-1-hydroxy-2,2,6,6-tetramethyl-piperidin-4-one, 4-bromo-1-hydroxy-2,2,6,6-tetramethylpiperidine, 2,2,6,6-tetramethyl-4-morpholin-4-yl-3,6-dihydro-2H-pyridin-1-ol, 3-ethoxymethyl-2,2,5,5-tetramethyl-2,5-dihydro-pyrrol-1-ol, 3-(N,N-dimethylaminomethyl)-2,2,5,5-tetramethyl-2,5-dihydro-pyrrol-1-ol, 3-(N,N-diethylaminomethyl)-2,2,5,5-tetramethyl-2,5-dihydro-pyrrol-1-ol, 3-(N-tertiarybutylaminomethyl)-2,2,5,5-tetramethyl-2,5-dihydro-pyrrol-1-ol, 3-(N-pyrrolidinomethyl)-2,2,5,5-tetramethyl-2,5-dihydro-pyrrol-1-ol, 3-(N-piperidinomethyl)-2,2,5,5-tetramethyl-2,5-dihydro-pyrrol-1-ol, 1-hydroxy-2,2,5,5-tetramethylpyrrolidine-3-carboxamide, or 2,5-dihydro-2,2,5,5-tetramethyl-1H-pyrrole-1-hydroxy-3-carboxamide.
73 . The pharmaceutical composition of claim 34 , wherein the compound of formula II is other than 1,4-dihydroxy-2,2,6,6-tetramethylpiperidine, 1-hydroxy-4-methoxy-2,2,6,6-tetramethylpiperidine, 1-hydroxy-4-ethoxy-2,2,6,6-tetramethylpiperidine, 1-hydroxy-4-amino-2,2,6,6-tetramethylpiperidine, 1-hydroxy-4-acetamido-2,2,6,6-tetramethylpiperidine, 1-hydroxy-2,2,6,6-tetramethyl-piperidin-4-one, 1-hydroxy-2,2,5,5-tetramethyl-pyrrolidin-3-one, 2,2,5,5-tetramethyl-pyrrolidine-1,3-diol, 3-hydroxymethyl-2,2,5,5-tetramethyl-2,5-dihydro-pyrrol-1-ol, 3-bromo-2,2,6,6-tetramethyl-piperidine-1,4-diol, 3-bromo-4-methoxy-2,2,6,6-tetramethyl-piperidine-1-ol, 3-chloro-2,2,6,6-tetramethyl-piperidine-1,4-diol, 1-hydroxy-4-methanesulfonamido-2,2,6,6-tetramethylpiperidine, 4-chloro-1-hydroxy-2,2,6,6-tetramethylpiperidine, 3-bromo-1-hydroxy-2,2,6,6-tetramethyl-piperidin-4-one, 3-chloro-1-hydroxy-2,2,6,6-tetramethyl-piperidin-4-one, 4-bromo-1-hydroxy-2,2,6,6-tetramethylpiperidine, 2,2,6,6-tetramethyl-4-morpholin-4-yl-3,6-dihydro-2H-pyridin-1-ol, 3-ethoxymethyl-2,2,5,5-tetramethyl-2,5-dihydro-pyrrol-1-ol, 3-(N,N-dimethylaminomethyl)-2,2,5,5-tetramethyl-2,5-dihydro-pyrrol-1-ol, 3-(N,N-diethylaminomethyl)-2,2,5,5-tetramethyl-2,5-dihydro-pyrrol-1-ol, 3-(N-tertiarybutylaminomethyl)-2,2,5,5-tetramethyl-2,5-dihydro-pyrrol-1-ol, 3-(N-pyrrolidinomethyl)-2,2,5,5-tetramethyl-2,5-dihydro-pyrrol-1-ol, 3-(N-piperidinomethyl)-2,2,5,5-tetramethyl-2,5-dihydro-pyrrol-1-ol, or 2,5-dihydro-2,2,5,5-tetramethyl-1H-pyrrole-1-hydroxy-3-carboxamide.