Trisubstituted carbocyclic cyclophilin binding compounds and their use

A compound of the following Formula I:

• 36
• and pharmaceutically acceptable derivatives thereof;
• where V is attached at position 4, 5, or 6, and is selected from the group consisting of C1-C4 alkyloxy, C1-C4 alkyl, C2-C4 alkenyloxy which is optionally substituted with Q, C1-C4 alkoxycarbonyl, Cl-C6 alkylcarbamoyl which is optionally substituted with amino or C1-C4 alkoxycarbonylamino;
• di-(C1-C4 alkyl)carbamoyl, C1-C4 alkanoyl, Q-substituted C1-C6 alkyl, alkenyl, or alkynyl, CO—W, and —(CH2)n—W;
• wherein W is Q, —Z′—(CH2)m—Q, —N═CH—(CH2)m—Q, COOCH3, COCH3, hydroxyl, mercaptyl, amino, nitro, halo, carboxy, trifluoromethyl, or C6 alkylamino substituted with amino or C1-C4 alkoxycarbonylamino;
• n and m are independently 0-4;
• n′ is 0-3;
• Z′ is O, S, NH, or NR;
• where X and Y are the same or different, and may independently be:
• 37
• and where Y may further be:
• Q,
• 38
• or C1-C6 straight or branched chain alkyl, alkenyl, or alkynyl which is substituted at one or several positions with Q, and which further is optionally substituted at one or several positions by hydroxyl, mercaptyl, or carbonyl oxygen;
• wherein Z is O or S;
• and wherein R may independently be:
• Q,
• or C1-C6 straight or branched chain lower alkyl, alkenyl or alkynyl which is substituted at one or several positions with Q, and which further is optionally substituted in one or several positions by hydroxyl, mercaptyl, or carbonyl oxygen, and wherein one or more of the carbon atoms are optionally replaced with O, N, NH, S, SO, or SO2;
• and wherein Q is a mono-, bi-, or tricyclic, carbo- or heterocyclic ring which is saturated, partially saturated, or aromatic, and wherein the individual ring sizes are 5-6 members, and wherein each heterocyclic ring, if present, contains 1-4 heteroatoms independently selected from the group consisting of O, N, and S in any chemically stable order and oxidation state, and wherein Q is optionally substituted in one or several positions with:
• halo;
• hydroxyl;
• mercaptyl;
• nitro;
• trifluoromethyl;
• aminocarbonyl;
• arylaminocarbonyl in which the aryl is optionally halogenated and optionally substituted with trifluoromethyl or cyano;
• C1-C4 alkylsulfonyl;
• C1-C4 alklylthio;
• oxo;
• cyano;
• carboxy;
• C1-C6 alkyl or alkenyl;
• C1-C4 alkoxy;
• C1-C5 alkoxycarbonyl;
• C1-C4 alkenyloxy;
• phenoxy;
• phenyl;
• cyanophenyl;
• benzyloxy;
• benzyl;
• amino;
• C1-C4 alkylamino;
• di-(C1-C4) alkylamino;
• C1-C4 alkylcarbamoyl;
• di(C1-C4)alkylcarbamoyl;
• or a combination thereof;
• provided that:
• when X and Y are
• 39
• or a combination thereof, and
• n′ is 0, and
• n is 0, and
• V is halo, hydroxyl, nitro, trifluoromethyl, C1-C4 alkoxy or -alkenyloxy, phenoxy, benzyloxy, amino, or Q,
• then R is not Q, or C1-C3 branched or straight chain alkyl substituted with Q.