Bridged aryl piperazines derivatives useful for the treatment of cns, gi-urinary and reproductive disorders

Abstract

The present invention is directed to bridged aryl piperazine derivatives, pharmaceutical compositions containing them and their use in the treatment of depression and related disorders. The compounds of the present invention are serotonin transport inhibitors and/or modulators of 5HT 1A .

We claim: 
     
         1 . A compound selected from the group consisting of formula (I) 
       
         
           
           
               
               
           
         
         and formula 
       
       
         
           
           
               
               
           
         
         wherein 
            is a single or double bond; 
         a is an integer from 0 to 1; 
         L 1  is selected from the group consisting of —C 1-4 alkyl-, —CH 2 —C 2-4 alkenyl-, —CH 2 —C 2-4 alkynyl-, —SO 2 —, —C(O)—, —C(O)O—, —(C 1-4 alkyl)-C(O)—, —(C 1-4 alkyl)-O—, —(C 1-4 alkyl)-C(O)O—, —(C 2-4 alkyl)-NR A , —(C 1-4 alkyl)-SO 2 —, —C(O)—(C 1-4 alkyl)-, —O—(C 1-4 alkyl), —C(O)O—(C 1-4 alkyl)-, —NR A —(C 1-4 alkyl)-, —(C 1-4 alkyl)-O—(C 1-4 alkyl)-, —(C 1-4 alkyl)-C(O)—(C 1-4 alkyl)-, —(C 1-4 alkyl)-OC(O)—(C 1-4 alkyl)-, —(C 1-4 alkyl)-C(O)O—(C 1-4 alkyl)-, —(C 2-4 alkyl)-NR A -(C 1-4 alkyl)-, —(C 1-4 alkyl)-SO 2 —(C 1-4 alkyl)-, —C(O)—NR A —, —C(O)—NR A —(C 1-4 alkyl)-, —NR A —C(O)— and —NR A —C(O)—(C 1-4 alkyl)-; 
         wherein the —C 1-4 alkyl- or C 2-4 alkyl, whether alone or as part of a substituent group is optionally substituted with one or more substituents independently selected from the group consisting of hydroxy, C 1-4 alkoxy, amino, (C 1-4 alkyl)amino, di(C 1-4 alkyl)amino, phenyl, SH and S(C 1-4 alkyl); 
         wherein R A  is selected from the group consisting of hydrogen, —C 1-4 alkyl phenyl, —C(O)—(C 1-4 alkyl), —C(O)-carbocyclyl, —C(O)-heterocyclyl, —SO 2 —(C 1-4 alkyl)-SO 2 -carbocyclyl and —SO 2 -heterocyclyl; 
         provided that the chain length of L 1 , not counting branching, is one to six atoms; 
         R 1  is selected from the group consisting of heteroaryl and heterocycloalkyl; 
         wherein the heteroaryl or heterocycloalkyl, whether alone or as part of a substituent group is optionally substituted with one or more substituents independently selected from the group consisting of halogen, hydroxy, carboxy, oxo, C 1-4 alkyl, C 1-4 alkoxy, halogenated C 1-4 alkyl, halogenated C 1-4 alkoxy, hydroxy substituted C 1-4 alkyl, cyano, nitro, amino, C 1-4 alkylamino, di(C 1-4 alkyl)amino, [1,3]dioxolanyl, alkoxy-C(O)—, NR B R C —C(O)— and —SO 2 —NR B R C ; 
         wherein R B  and R C  are each independently selected from the group consisting of hydrogen and C 1-4 alkyl; 
         b is an integer from 0 to 1; 
         L 2  is selected from the group consisting of —C 1-4 alkyl-, —CH 2 —C 2-4 alkenyl-, —CH 2 —C 2-4 alkynyl-, —SO 2 —, —C(O)—, —C(O)O—, —(C 1-4 alkyl)-C(O)—, —(C 1-4 alkyl)-O—, —(C 1-4 alkyl)-C(O)O—, —(C 2-4 alkyl)-NR D , —(C 1-4 alkyl)-SO 2 —, —C(O)—(C 1-4 alkyl)-, —O—(C 1-4 alkyl), —C(O)O—(C 1-4 alkyl)-, —NR D —(C 1-4 alkyl)-, —(C 1-4 alkyl)-O—(C 1-4 alkyl)-, —(C 1-4 alkyl)-C(O)—(C 1-4 alkyl)-, —(C 1-4 alkyl)-OC(O)—(C 1-4 alkyl)-, —(C 1-4 alkyl)-C(O)O—(C 1-4 alkyl)-, —(C 2-4 alkyl)-NR D —(C 1-4 alkyl)-, —(C 1-4 alkyl)-SO 2 —(C 1-4 alkyl)-, —C(O)—NR D —, —C(O)—NR D —(C 1-4 alkyl)-, —NR D —C(O)— and —NR D —C(O)—(C 1-4 alkyl)-; 
         wherein the —C 1-4 alkyl- or C 2-4 alkyl, whether alone or as part of a substituent group is optionally substituted with one or more substituents independently selected from the group consisting of hydroxy, C 1-4 alkoxy, amino, (C 1-4 alkyl)amino, di(C 1-4 alkyl)amino, phenyl, SH and S(C 1-4 alkyl); 
         wherein R D  is selected from the group consisting of hydrogen, —C 1-4 alkyl phenyl, —C(O)—(C 1-4 alkyl), —C(O)-carbocyclyl, —C(O)-heterocyclyl, —SO 2 —(C 1-4 alkyl)-SO 2 -carbocyclyl and —SO 2 -heterocyclyl; 
         provided that the chain length of L 2 , not counting branching, is one to six atoms; 
         R 2  is selected from the group consisting of hydrogen, C 1-4 alkyl, cycloalkyl, partially unsaturated carbocyclyl, aryl, biphenyl, heteroaryl and heterocycloalkyl; 
         wherein the partially unsaturated carbocyclyl, aryl, heteroaryl or heterocycloalkyl, whether alone or as part of a substituent group is optionally substituted with one or more substituents independently selected from the group consisting of halogen, hydroxy, carboxy, oxo, C 1-4 alkyl, C 1-4 alkoxy, halogenated C 1-4 alkyl, halogenated C 1-4 alkoxy, hydroxy substituted C 1-4 alkyl, cyano, nitro, amino, C 1-4 alkylamino, di(C 1-4 alkyl)amino, [1,3]dioxolanyl, —C 1-4 alkoxy-C(O)—, NR E R F —C(O)— and —SO 2 —NR E R F ; 
         wherein R E  and R F  are each independently selected from the group consisting of hydrogen and C 1-4 alkyl; 
         provided that the chain length of L 1 , not counting branching, plus the chain length of L 2 , not counting branching, is not greater than about 12 atom; 
         provided further that when a is 0 and b is 0 then R 1  and R 2  are not each hydrogen; 
         or a pharmaceutically acceptable salt thereof. 
       
     
     
         2 . A compound as in  claim 1 , selected from the group consisting of formula (I) and formula (II), wherein
    is a single or double bond;   a is an integer from 0 to 1;   L 1  is selected from the group consisting of —C 1-4 alkyl-, —CH 2 —C 2-4 alkenyl-, —CH 2 —C 2-4 alkynyl-, —C(O)—, —C(O)O—, —(C 1-4 alkyl)-C(O)—, —(C 1-4 alkyl)-O—, —(C 1-4 alkyl)-C(O)O—, —(C 2-4 alkyl)-NR A , —C(O)—(C 1-4 alkyl)-, —C(O)O—(C 1-4 alkyl)-, —(C 1-4 alkyl)-O—(C 1-4 alkyl)-, —C(O)—NR A —, —C(O)—NR A —(C 1-4 alkyl)-, —NR A —C(O)— and —NR A —C(O)—(C 1-4 alkyl)-;   wherein the —C 1-4 alkyl-, whether alone or as part of a substituent group is optionally substituted with one to two substituents independently selected from the group consisting of hydroxy, C 1-4 alkoxy, amino, (C 1-4 alkyl)amino, di(C 1-4 alkyl)amino and phenyl;   wherein R A  is selected from the group consisting of hydrogen, —C 1-4 alkyl phenyl and —C(O)—(C 1-4 alkyl);   provided that the chain length of L 1 , not counting branching, is one to six atoms;   R 1  is selected from the group consisting of heteroaryl and heterocycloalkyl;   wherein the heteroaryl or heterocycloalkyl, whether alone or as part of a substituent group is optionally substituted with one to three substituents independently selected from the group consisting of halogen, hydroxy, carboxy, oxo, C 1-4 alkyl, C 1-4 alkoxy, fluorinated C 1-4 alkyl, fluorinated C 1-4 alkoxy, hydroxy substituted C 1-4 alkyl, cyano, nitro, amino, C 1-4 alkylamino, di(C 1-4 alkyl)amino, [1,3]dioxolanyl, C 1-4 alkoxy-C(O)— and NR B R C —C(O)—;   wherein R B  and R C  are each independently selected from the group consisting of hydrogen and C 1-4 alkyl;   b is an integer from 0 to 1;   L 2  is selected from the group consisting of —C 1-4 alkyl-, —CH 2 —C 2-4 alkenyl-, —CH 2 —C 2-4 alkynyl-, —C(O)—, —C(O)O—, —(C 1-4 alkyl)-C(O)—, —(C 1-4 alkyl)-O—, —(C 1-4 alkyl)-C(O)O—, —(C 2-4 alkyl)-NR D , —C(O)—(C 1-4 alkyl)-, —C(O)O—(C 1-4 alkyl)-, —(C 1-4 alkyl)-O—(C 1-4 alkyl)-, —(C 2-4 alkyl)-NR D —(C 1-4 alkyl)-, —C(O)—NR D —, —C(O)—NR D —(C 1-4 alkyl)-, —NR D —C(O)— and —NR D —C(O)—(C 1-4 alkyl)-;   wherein the —C 1-4 alkyl-, whether alone or as part of a substituent group is optionally substituted with one to two substituents independently selected from the group consisting of hydroxy, C 1-4 alkoxy, amino, (C 1-4 alkyl)amino, di(C 1-4 alkyl)amino and phenyl;   wherein R D  is selected from the group consisting of hydrogen, —C 1-4 alkyl phenyl and —C(O)—(C 1-4 alkyl);   provided that the chain length of L 2 , not counting branching, is one to six atoms;   R 2  is selected from the group consisting of hydrogen, C 1-4 alkyl, cycloalkyl, aryl, biphenyl, heteroaryl and heterocycloalkyl;   wherein the aryl, heteroaryl or heterocycloalkyl, whether alone or as part of a substituent group is optionally substituted with one to three substituents independently selected from the group consisting of halogen, hydroxy, carboxy, oxo, C 1-4 alkyl, C 1-4 alkoxy, fluorinated C 1-4 alkyl, fluorinated C 1-4 alkoxy, hydroxy substituted C 1-4 alkyl, cyano, nitro, amino, C 1-4 alkylamino, di(C 1-4 alkyl)amino, [1,3]dioxolanyl, C 1-4 alkoxy-C(O)— and —C(O)—NR E R F —C(O)—;   wherein R E  and R F  are each independently selected from the group consisting of hydrogen and C 1-4 alkyl;   provided that the chain length of L 1 , not counting branching, plus the chain length of L 2 , not counting branching, is not greater than about 12 atom;   provided further that when a is 0 and b is 0 then R 1  and R 2  are not each hydrogen;   or a pharmaceutically acceptable salt thereof.   
     
     
         3 . A compound as in  claim 2 , selected from the group consisting of formula (I) and formula (II), wherein
    is a single or double bond;   a is an integer from 0 to 1;   L 1  is selected from the group consisting of —C 1-4 alkyl-, —C(O)O—, —C(O)—, —C(O)—C 1-4 alkyl-, —C(O)—NR A — and —C(O)—C 1-4 alkyl-; wherein the C 1-4 alkyl, whether alone or as part of a substitutent group, is optionally substituted with phenyl; and wherein R A  is phenyl;   R 1  is selected from the group consisting of heteroaryl and heterocycloalkyl;   b is an integer from 0 to 1;   L 2  is selected from the group consisting of —C 1-4 alkyl-, —CH 2 —C 2-4 alkynyl-, —C 1-4 alkyl-O—, —C 2-4 alkyl-NH—, —C 2-4 alkyl-NH—C 1-4 alkyl- and —C(O)O—; wherein the C 1-4 alkyl or C 2-4 alkyl, whether alone or as part of a substituent group is optionally substituted with hydroxy;   provided that the chain length of L 2 , not counting branching, is one to six atoms;   R 2  is selected from the group consisting of hydrogen, C 1-4 alkyl, C 3-8 cycloalkyl, aryl, biphenyl, heteroaryl and heterocycloalkyl;   wherein the aryl, heteroaryl or heterocycloalkyl, whether alone or as part of a substituent group, is optionally substituted with one to two substituents independently selected from the group consisting of oxo, carboxy, halogen, C 1-4 alkyl, C 1-4 alkoxy, trifluoromethyl, hydroxy substituted C 1-4 alkyl, di(C 1-4 alkyl)amino-carbonyl-, C 1-4 alkoxy-carbonyl- and [1,3]dioxolanyl;   provided that the chain length of L 1 , not counting branching, plus the chain length of L 2 , not counting branching, is not greater than about 12 atom;   provided further that when a is 0 and b is 0 then R 1  and R 2  are not each hydrogen;   or a pharmaceutically acceptable salt thereof.   
     
     
         4 . A compound as in  claim 3 , selected from the group consisting of formula (I) and formula (II), wherein
    is a single or double bond;   a is an integer from 0 to 1;   L 1  is selected from the group consisting of —CH 2 —, —C(O)O—, —C(O)—, —C(O)—CH(phenyl)-, —C(O)—N(phenyl)- and —C(O)—CH 2 —CH 2 -;   R 1  is selected from the group consisting of 3-quinolinyl, 5-quinolinyl and 6-(2,3-dihydro-benzo[1,4]dioxinyl);   b is an integer from 0 to 1;   L 2  is selected from the group consisting of —C(O)O—, —CH 2 —, —CH 2 —CH 2 —, —CH 2 —CC—, —CH 2 —CH 2 —O—, —CH 2 —CH 2 —CH 2 —O—, —CH 2 —CH 2 —CH(OH)—, —CH 2 —CH 2 —NH—, —CH 2 —CH(S—OH)—CH 2 —O—, —CH 2 —CH(R—OH)—CH 2 —O— and —CH 2 —CH(S—OH)—CH 2 —NH—CH 2 —;   R 2  is selected from the group consisting of hydrogen, t-butyl, cyclooctyl, 2-chlorophenyl, 3-chlorophenyl, 4-fluorophenyl, 4-t-butylphenyl, 2-methoxyphenyl, 3-methoxyphenyl, 4-methoxyphenyl, 3-trifluoromethylphenyl, 3,4-dichlorophenyl, 2,4-dimethoxy-phenyl, 3-methyl-4-fluoro-phenyl, 3-trifluoromethyl-4-chloro-phenyl, 2-naphthyl, 1-(8-methyl-naphthyl), 2-(6-methoxy-naphthyl), 4-(9H-carbazolyl), 2-biphenyl, 2-indanyl, 4-indolyl, 4-(1-methyl-indolyl), 4-(2-methyl-indolyl), 1-(4-hydroxymethyl-indolyl), (2-methyl-5-fluoro-indolyl), 4-(2-methyl-7-chloro-indolyl), 4-(2,7-dimethyl-indolyl), 4-(2,5-dimethyl-indolyl), 4-(2-dimethylamino-carbonyl-indolyl), 4-(2-methoxy-carbonyl-indolyl), 4-(2-methoxy-carbonyl-7-methyl-indolyl), 4-(2-methoxy-carbonyl-7-chloro-indolyl), 4-(2-methoxy-carbonyl-6-methoxy-indolyl), 4-3-benzothienyl, 3-(1H-quinazoline-2,4-dione), 2-pyridyl, 3-(6-methyl-pyridyl), 4-quinolinyl, 4-(7-chloro-quinolinyl), 5-quinolinyl, 5-(3,4-dihydro-1H-quinolin-2-one), 6-(2,3-dihydro-benzo[1,4]dioxinyl), 8-(7,8-dihydro-3H-6,9-dioxa-3-aza-cyclopenta[a]naphthyl), 3R-(7,8-dimethoxy-3a,4-dihydro-3H-chromeno[4,3-c]isoxazolyl and 3S-(7,8-dimethoxy-3a,4-dihydro-3H-chromeno[4,3-c]isoxazolyl;   provided further that when a is 0 and b is 0 then R 1  and R 2  are not each hydrogen;   or a pharmaceutically acceptable salt thereof.   
     
     
         5 . A compound as in  claim 4 , selected from the group consisting of a compound of formula (I) wherein
    is a single or double bond;   a is an integer from 0 to 1;   L 1  is selected from the group consisting of —CH 2 — and —C(O)O—;   R 1  is selected from the group consisting of 3-quinolinyl, 5-quinolinyl and 6-(2,3-dihydro-benzo[1,4]dioxinyl);   b is an integer from 0 to 1;   L 2  is selected from the group consisting of —C(O)O—, —CH 2 —, —CH 2 —CH 2 —, —CH 2 —CC—, —CH 2 —CH 2 —O—, —CH 2 —CH 2 —CH 2 —O—, —CH 2 —CH 2 —CH(OH)—, —CH 2 —CH 2 —NH—, —CH 2 —CH(S—OH)—CH 2 —O—, —CH 2 —CH(R—OH)—CH 2 —O— and —CH 2 —CH(S—OH)—CH 2 —NH—CH 2 —;   R 2  is selected from the group consisting of hydrogen, t-butyl, cyclooctyl, 2-chlorophenyl, 3-chlorophenyl, 4-fluorophenyl, 4-t-butylphenyl, 2-methoxyphenyl, 3-methoxyphenyl, 4-methoxyphenyl, 3-trifluoromethylphenyl, 3,4-dichlorophenyl, 2,4-dimethoxy-phenyl, 3-methyl-4-fluoro-phenyl, 3-trifluoromethyl-4-chloro-phenyl, 1-(8-methyl-naphthyl), 2-(6-methoxy-naphthyl), 4-(9H-carbazolyl), 2-biphenyl, 2-indanyl, 4-indolyl, 4-(2-methyl-indolyl), 1-(4-hydroxymethyl-indolyl), (2-methyl-5-fluoro-indolyl), 4-(2-methyl-7-chloro-indolyl), 4-(2,7-dimethyl-indolyl), 4-(2,5-dimethyl-indolyl), 4-(2-dimethylamino-carbonyl-indolyl), 4-(2-methoxy-carbonyl-indolyl), 4-(2-methoxy-carbonyl-7-methyl-indolyl), 4-(2-methoxy-carbonyl-7-chloro-indolyl), 4-(2-methoxy-carbonyl-6-methoxy-indolyl), 4-3-benzothienyl, 3-(1H-quinazoline-2,4-dione), 2-pyridyl, 3-(6-methyl-pyridyl), 4-quinolinyl, 4-(7-chloro-quinolinyl), 5-quinolinyl, 5-(3,4-dihydro-1H-quinolin-2-one), 6-(2,3-dihydro-benzo[1,4]dioxinyl), 8-(7,8-dihydro-3H-6,9-dioxa-3-aza-cyclopenta[a]naphthyl), 3R-(7,8-dimethoxy-3a,4-dihydro-3H-chromeno[4,3-c]isoxazolyl and 3S-(7,8-dimethoxy-3a,4-dihydro-3H-chromeno[4,3-c]isoxazolyl;   provided further that when a is 0 and b is 0 then R 1  and R 2  are not each hydrogen;   or a pharmaceutically acceptable salt thereof.   
     
     
         6 . A compound as in  claim 5 , selected from the group consisting of a compound of formula (I) wherein
    is a double bond;   a is an integer from 0 to 1;   L 1  is —CH 2 —;   R 1  is selected from the group consisting of 3-quinolinyl, 5-quinolinyl and 6-(2,3-dihydro-benzo[1,4]dioxinyl);   b is an integer from 0 to 1;   L 2  is selected from the group consisting of —CH 2 —, —CH 2 —CH 2 —, —CH 2 —CC—, —CH 2 —CH 2 —O—, —CH 2 —CH 2 —CH 2 —O—, —CH 2 —CH 2 —CH(OH)—, —CH 2 —CH 2 —NH—, —CH 2 —CH(S—OH)—CH 2 —O—, —CH 2 —CH(R—OH)—CH 2 —O— and —CH 2 —CH(S—OH)—CH 2 —NH—CH 2 —;   R 2  is selected from the group consisting of hydrogen, cyclooctyl, 2-chlorophenyl, 3-chlorophenyl, 4-fluorophenyl, 4-t-butylphenyl, 2-methoxyphenyl, 3-methoxyphenyl, 4-methoxyphenyl, 3-trifluoromethylphenyl, 3,4-dichlorophenyl, 2,4-dimethoxy-phenyl, 3-methyl-4-fluoro-phenyl, 3-trifluoromethyl-4-chloro-phenyl, 1-(8-methyl-naphthyl), 2-(6-methoxy-naphthyl), 4-(9H-carbazolyl), 2-indanyl, 4-indolyl, 4-(2-methyl-indolyl), 1-(4-hydroxymethyl-indolyl), (2-methyl-5-fluoro-indolyl), 4-(2-methyl-7-chloro-indolyl), 4-(2,7-dimethyl-indolyl), 4-(2,5-dimethyl-indolyl), 4-(2-dimethylamino-carbonyl-indolyl), 4-(2-methoxy-carbonyl-indolyl), 4-(2-methoxy-carbonyl-7-methyl-indolyl), 4-(2-methoxy-carbonyl-7-chloro-indolyl), 4-(2-methoxy-carbonyl-6-methoxy-indolyl), 4-3-benzothienyl, 3-(1H-quinazoline-2,4-dione), 2-pyridyl, 3-(6-methyl-pyridyl), 4-quinolinyl, 4-(7-chloro-quinolinyl), 5-quinolinyl, 5-(3,4-dihydro-1H-quinolin-2-one), 6-(2,3-dihydro-benzo[1,4]dioxinyl), 8-(7,8-dihydro-3H-6,9-dioxa-3-aza-cyclopenta[a]naphthyl), 3R-(7,8-dimethoxy-3a,4-dihydro-3H-chromeno[4,3-c]isoxazolyl and 3S-(7,8-dimethoxy-3a,4-dihydro-3H-chromeno[4,3-c]isoxazolyl;   provided further that when a is 0 and b is 0 then R 1  and R 2  are not each hydrogen;   or a pharmaceutically acceptable salt thereof.   
     
     
         7 . A compound as in  claim 4 , selected from the group consisting of a compound of formula (I) wherein
    is a double bond;   a is an integer from 0 to 1;   L 1  is selected from the group consisting of —CH 2 — and —C(O)O—;   R 1  is selected from the group consisting of 3-quinolinyl, 5-quinolinyl and 6-(2,3-dihydro-benzo[1,4]dioxinyl);   b is an integer from 0 to 1;   L 2  is selected from the group consisting of —C(O)O—, —CH 2 —, —CH 2 —CH 2 —, —CH 2 —CC—, —CH 2 —CH 2 —O—, —CH 2 —CH 2 —CH 2 —O—, —CH 2 —CH 2 —CH(OH)—, —CH 2 —CH 2 —NH—, —CH 2 —CH(S—OH)—CH 2 —O—, —CH 2 —CH(R—OH)—CH 2 —O— and —CH 2 —CH(S—OH)—CH 2 —NH—CH 2 —;   R 2  is selected from the group consisting of hydrogen, t-butyl, cyclooctyl, 2-chlorophenyl, 3-chlorophenyl, 4-fluorophenyl, 4-t-butylphenyl, 2-methoxyphenyl, 3-methoxyphenyl, 4-methoxyphenyl, 3-trifluoromethylphenyl, 3,4-dichlorophenyl, 2,4-dimethoxy-phenyl, 3-methyl-4-fluoro-phenyl, 3-trifluoromethyl-4-chloro-phenyl, 2-naphthyl, 1-(8-methyl-naphthyl), 2-(6-methoxy-naphthyl), 4-(9H-carbazolyl), 2-indanyl, 4-indolyl, 4-(1-methyl-indolyl), 4-(2-methyl-indolyl), 1-(4-hydroxymethyl-indolyl), (2-methyl-5-fluoro-indolyl), 4-(2-methyl-7-chloro-indolyl), 4-(2,7-dimethyl-indolyl), 4-(2,5-dimethyl-indolyl), 4-(2-dimethylamino-carbonyl-indolyl), 4-(2-methoxy-carbonyl-indolyl), 4-(2-methoxy-carbonyl-7-methyl-indolyl), 4-(2-methoxy-carbonyl-7-chloro-indolyl), 4-(2-methoxy-carbonyl-6-methoxy-indolyl), 4-3-benzothienyl, 3-(1H-quinazoline-2,4-dione), 2-pyridyl, 3-(6-methyl-pyridyl), 4-quinolinyl, 4-(7-chloro-quinolinyl), 5-quinolinyl, 5-(3,4-dihydro-1H-quinolin-2-one), 6-(2,3-dihydro-benzo[1,4]dioxinyl), 8-(7,8-dihydro-3H-6,9-dioxa-3-aza-cyclopenta[a]naphthyl), 3R-(7,8-dimethoxy-3a,4-dihydro-3H-chromeno[4,3-c]isoxazolyl and 3S-(7,8-dimethoxy-3a,4-dihydro-3H-chromeno[4,3-c]isoxazolyl;   provided further that when a is 0 and b is 0 then R 1  and R 2  are not each hydrogen;   or a pharmaceutically acceptable salt thereof.   
     
     
         8 . A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a compound of  claim 1 . 
     
     
         9 . A pharmaceutical composition made by mixing a compound of  claim 1  and a pharmaceutically acceptable carrier. 
     
     
         10 . A process for making a pharmaceutical composition comprising mixing a compound of  claim 1  and a pharmaceutically acceptable carrier. 
     
     
         11 . A compound selected from the group consisting of formula (CI) 
       
         
           
           
               
               
           
         
         and formula (CII) 
       
       
         
           
           
               
               
           
         
         wherein 
            is a single or double bond; 
         a is an integer from 0 to 1; 
         L 1  is selected from the group consisting of —C 1-4 alkyl-, —CH 2 —C 2-4 alkenyl-, —CH 2 —C 2-4 alkynyl-, —SO 2 —, —C(O)—, —C(O)O—, —(C 1-4 alkyl)-C(O)—, —(C 1-4 alkyl)-O—, —(C 1-4 alkyl)-C(O)O—, —(C 2-4 alkyl)-NR A , —(C 1-4 alkyl)-SO 2 —, —C(O)—(C 1-4 alkyl)-, —O—(C 1-4 alkyl), —C(O)O—(C 1-4 alkyl)-, —NR A —(C 1-4 alkyl)-, —(C 1-4 alkyl)-O—(C 1-4 alkyl)-, —(C 1-4 alkyl)-C(O)—(C 1-4 alkyl)-, —(C 1-4 alkyl)-OC(O)—(C 1-4 alkyl)-, —(C 1-4 alkyl)-C(O)O—(C 1-4 alkyl)-, —(C 2-4 alkyl)-NR A —(C 1-4 alkyl)-, —(C 1-4 alkyl)-SO 2 —(C 1-4 alkyl)-, —C(O)—NR A —, —C(O)—NR A —(C 1-4 alkyl)-, —NR A —C(O)— and —NR A —C(O)—(C 1-4 alkyl)-; 
         wherein the —C 1-4 alkyl- or C 2-4 alkyl, whether alone or as part of a substituent group is optionally substituted with one or more substituents independently selected from the group consisting of hydroxy, C 1-4 alkoxy, amino, (C 1-4 alkyl)amino, di(C 1-4 alkyl)amino, phenyl, SH and S(C 1-4 alkyl); 
         wherein R A  is selected from the group consisting of hydrogen, —C 1-4 alkyl phenyl, —C(O)—(C 1-4 alkyl), —C(O)-carbocyclyl, —C(O)-heterocyclyl, —SO 2 —(C 1-4 alkyl)-SO 2 -carbocyclyl and —SO 2 -heterocyclyl; 
         provided that the chain length of L 1 , not counting branching, is one to six atoms; 
         R 1  is selected from the group consisting of heteroaryl and heterocycloalkyl; 
         wherein the cycloalkyl, partially unsaturated carbocyclyl, aryl, heteroaryl or heterocycloalkyl, whether alone or as part of a substituent group is optionally substituted with one or more substituents independently selected from the group consisting of halogen, hydroxy, carboxy, oxo, C 1-4 alkyl, C 1-4 alkoxy, halogenated C 1-4 alkyl, halogenated C 1-4 alkoxy, hydroxy substituted C 1-4 alkyl, cyano, nitro, amino, C 1-4 alkylamino, di(C 1-4 alkyl)amino, [1,3]dioxolanyl, alkoxy-C(O)—, NR B R C —C(O)— and —SO 2 —NR B R C C; 
         wherein R B  and R C  are each independently selected from the group consisting of hydrogen and C 1-4 alkyl; 
         b is an integer from 0 to 1; 
         L 2  is selected from the group consisting of —C 1-4 alkyl-, —CH 2 —C 2-4 alkenyl-, —CH 2 —C 2-4 alkynyl-, —SO 2 —, —C(O)—, —C(O)O—, —(C 1-4 alkyl)-C(O)—, —(C 1-4 alkyl)-O—, —(C 1-4 alkyl)-C(O)O—, —(C 2-4 alkyl)-NR D , —(C 1-4 alkyl)-SO 2 —, —C(O)—(C 1-4 alkyl)-, —O—(C 1-4 alkyl), —C(O)O—(C 1-4 alkyl)-, —NR D —(C 1-4 alkyl)-, —(C 1-4 alkyl)-O—(C 1-4 alkyl)-, —(C 1-4 alkyl)-C(O)—(C 1-4 alkyl)-, —(C 1-4 alkyl)-OC(O)—(C 1-4 alkyl)-, —(C 1-4 alkyl)-C(O)O—(C 1-4 alkyl)-, —(C 2-4 alkyl)-NR D —(C 1-4 alkyl)-, —(C 1-4 alkyl)-SO 2 —(C 1-4 alkyl)-, —C(O)—NR D —, —C(O)—NR D —(C 1-4 alkyl)-, —NR D —C(O)— and —NR D —C(O)—(C 1-4 alkyl)-; 
         wherein the —C 1-4 alkyl- or C 2-4 alkyl, whether alone or as part of a substituent group is optionally substituted with one or more substituents independently selected from the group consisting of hydroxy, C 1-4 alkoxy, amino, (C 1-4 alkyl)amino, di(C 1-4 alkyl)amino, phenyl, SH and S(C 1-4 alkyl); 
         wherein R D  is selected from the group consisting of hydrogen, —C 1-4 alkyl phenyl, —C(O)—(C 1-4 alkyl), —C(O)-carbocyclyl, —C(O)-heterocyclyl, —SO 2 —(C 1-4 alkyl)-SO 2 -carbocyclyl and —SO 2 -heterocyclyl; 
         provided that the chain length of L 2 , not counting branching, is one to six atoms; 
         R 2  is selected from the group consisting of hydrogen, C 1-4 alkyl, cycloalkyl, partially unsaturated carbocyclyl, aryl, biphenyl, heteroaryl and heterocycloalkyl; 
         wherein the heteroaryl or heterocycloalkyl, whether alone or as part of a substituent group is optionally substituted with one or more substituents independently selected from the group consisting of halogen, hydroxy, carboxy, oxo, C 1-4 alkyl, C 1-4 alkoxy, halogenated C 1-4 alkyl, halogenated C 1-4 alkoxy, hydroxy substituted C 1-4 alkyl, cyano, nitro, amino, C 1-4 alkylamino, di(C 1-4 alkyl)amino, [1,3]dioxolanyl, —C 1-4 alkoxy-C(O)—, NR E R F —C(O)— and —SO 2 —NR E R F ; 
         wherein R E  and R F  are each independently selected from the group consisting of hydrogen and C 1-4 alkyl; 
         provided that the chain length of L 1 , not counting branching, plus the chain length of L 2 , not counting branching, is not greater than about 12 atom; 
         provided further that when a is 0 and b is 0 then R 1  and R 2  are not each hydrogen; 
         provided further than when   is a double bond, X and Y are each ═O, a is 0, R 1  is hydrogen, b is 1 and L 2  is —CH 2 —, then R 2  is other than 2,4-dimethoxyphenyl; 
         provided further than when   is a double bond, X and Y are each ═O, a is 1, L 1  is —CH 2 —, b is 0 and R 2  is hydrogen, then R 1  is other than 2,4-dimethoxyphenyl; 
         provided further than when   is a single bond, X and Y are each ═O, a is 1, L 1  is —CH(CH 3 )—, b is 1 and L 2  is —CH(CH 3 )—, then R 1  and R 2  are not each phenyl; 
         or a pharmaceutically acceptable salt thereof. 
       
     
     
         12 . A compound selected from the group consisting of formula (CIII) 
       
         
           
           
               
               
           
         
         and formula (CIV) 
       
       
         
           
           
               
               
           
         
         wherein 
            is a single or double bond; 
         X and Y are each independently selected from the group consisting of hydrogen and ═O; 
         a is an integer from 0 to 1; 
         L 1  is selected from the group consisting of —C 1-4 alkyl-, —CH 2 —C 2-4 alkenyl-, —CH 2 —C 2-4 alkynyl-, —SO 2 —, —C(O)—, —C(O)O—, —(C 1-4 alkyl)-C(O)—, —(C 1-4 alkyl)-O—, —(C 1-4 alkyl)-C(O)O—, —(C 2-4 alkyl)-NR A , —(C 1-4 alkyl)-SO 2 —, —C(O)—(C 1-4 alkyl)-, —O—(C 1-4 alkyl), —C(O)O—(C 1-4 alkyl)-, —NR A —(C 1-4 alkyl)-, —(C 1-4 alkyl)-O—(C 1-4 alkyl)-, —(C 1-4 alkyl)-C(O)—(C 1-4 alkyl)-, —(C 1-4 alkyl)-OC(O)—(C 1-4 alkyl)-, —(C 1-4 alkyl)-C(O)O—(C 1-4 alkyl)-, —(C 2-4 alkyl)-NR A —(C 1-4 alkyl)-, —(C 1-4 alkyl)-SO 2 —(C 1-4 alkyl)-, —C(O)—NR A —, —C(O)—NR A —(C 1-4 alkyl)-, —NR A —C(O)— and —NR A —C(O)—(C 1-4 alkyl)-; 
         wherein the —C 1-4 alkyl- or C 2-4 alkyl, whether alone or as part of a substituent group is optionally substituted with one or more substituents independently selected from the group consisting of hydroxy, C 1-4 alkoxy, amino, (C 1-4 alkyl)amino, di(C 1-4 alkyl)amino, phenyl, SH and S(C 1-4 alkyl); 
         wherein R A  is selected from the group consisting of hydrogen, —C 1-4 alkyl phenyl, —C(O)—(C 1-4 alkyl), —C(O)-carbocyclyl, —C(O)-heterocyclyl, —SO 2 —(C 1-4 alkyl)-SO 2 -carbocyclyl and —SO 2 -heterocyclyl; 
         provided that the chain length of L 1 , not counting branching, is one to six atoms; 
         R 1  is selected from the group consisting of heteroaryl and heterocycloalkyl; 
         wherein the heteroaryl or heterocycloalkyl, whether alone or as part of a substituent group is optionally substituted with one or more substituents independently selected from the group consisting of halogen, hydroxy, carboxy, oxo, C 1-4 alkyl, C 1-4 alkoxy, halogenated C 1-4 alkyl, halogenated C 1-4 alkoxy, hydroxy substituted C 1-4 alkyl, cyano, nitro, amino, C 1-4 alkylamino, di(C 1-4 alkyl)amino, [1,3]dioxolanyl, alkoxy-C(O)—, NR B R C —C(O)— and —SO 2 —NR B R C ; 
         wherein R B  and R C  are each independently selected from the group consisting of hydrogen and C 1-4 alkyl; 
         b is an integer from 0 to 1; 
         L 2  is selected from the group consisting of —C 1-4 alkyl-, —CH 2 —C 2-4 alkenyl-, —CH 2 —C 2-4 alkynyl-, —SO 2 —, —C(O)—, —C(O)O—, —(C 1-4 alkyl)-C(O)—, —(C 1-4 alkyl)-O—, —(C 1-4 alkyl)-C(O)O—, —(C 2-4 alkyl)-NR D , —(C 1-4 alkyl)-SO 2 —, —C(O)—(C 1-4 alkyl)-, —O—(C 1-4 alkyl), —C(O)O—(C 1-4 alkyl)-, —NR D —(C 1-4 alkyl)-, —(C 1-4 alkyl)-O—(C 1-4 alkyl)-, —(C 1-4 alkyl)-C(O)—(C 1-4 alkyl)-, —(C 1-4 alkyl)-OC(O)—(C 1-4 alkyl)-, —(C 1-4 alkyl)-C(O)O—(C 1-4 alkyl)-, —(C 2-4 alkyl)-NR D —(C 1-4 alkyl)-, —(C 1-4 alkyl)-SO 2 —(C 1-4 alkyl)-, —C(O)—NR D —, —C(O)—NR D —(C 1-4 alkyl)-, —NR D —C(O)— and —NR D —C(O)—(C 1-4 alkyl)-; 
         wherein the —C 1-4 alkyl- or C 2-4 alkyl, whether alone or as part of a substituent group is optionally substituted with one or more substituents independently selected from the group consisting of hydroxy, C 1-4 alkoxy, amino, (C 1-4 alkyl)amino, di(C 1-4 alkyl)amino, phenyl, SH and S(C 1-4 alkyl); 
         wherein R D  is selected from the group consisting of hydrogen, —C 1-4 alkyl phenyl, —C(O)—(C 1-4 alkyl), —C(O)-carbocyclyl, —C(O)-heterocyclyl, —SO 2 —(C 1-4 alkyl)-SO 2 -carbocyclyl and —SO 2 -heterocyclyl; 
         provided that the chain length of L 2 , not counting branching, is one to six atoms; 
         R 2  is selected from the group consisting of hydrogen, C 1-4 alkyl, cycloalkyl, partially unsaturated carbocyclyl, aryl, biphenyl, heteroaryl and heterocycloalkyl; 
         wherein the partially unsaturated carbocyclyl, aryl, heteroaryl or heterocycloalkyl, whether alone or as part of a substituent group is optionally substituted with one or more substituents independently selected from the group consisting of halogen, hydroxy, carboxy, oxo, C 1-4 alkyl, C 1-4 alkoxy, halogenated C 1-4 alkyl, halogenated C 1-4 alkoxy, hydroxy substituted C 1-4 alkyl, cyano, nitro, amino, C 1-4 alkylamino, di(C 1-4 alkyl)amino, [1,3]dioxolanyl, —C 1-4 alkoxy-C(O)—, NR E R F —C(O)— and —SO 2 —NR E R F ; 
         wherein R E  and R F  are each independently selected from the group consisting of hydrogen and C 1-4 alkyl; 
         provided that the chain length of L 1 , not counting branching, plus the chain length of L 2 , not counting branching, is not greater than about 12 atom; 
         provided further that when a is 0 and b is 0 then R 1  and R 2  are not each hydrogen; 
         provided further than when   is a double bond, X and Y are each ═O, a is 0, R 1  is hydrogen, b is 1 and L 2  is —CH 2 —, then R 2  is other than 2,4-dimethoxyphenyl; 
         provided further than when   is a double bond, X and Y are each ═O, a is 1, L 1  is —CH 2 —, b is 0 and R 2  is hydrogen, then R 1  is other than 2,4-dimethoxyphenyl; 
         provided further than when   is a single bond, X and Y are each ═O, a is 1, L 1  is —CH(CH 3 )—, b is 1 and L 2  is —CH(CH 3 )—, then R 1  and R 2  are not each phenyl; 
         or a pharmaceutically acceptable salt thereof.