Bicyclic aryl sphingosine 1-phosphate analogs

Abstract

Compounds that have agonist activity at one or more of the S1P receptors are provided. The compounds are sphingosine analogs that, after phosphorylation, can behave as agonists at S1P receptors.

1 - 106 . (canceled) 
     
     
         107 . A method for treating relapsing-remitting multiple sclerosis in a mammal comprising administering to said mammal an effective amount of a compound of formula (IIa), (IIIa) or (IIIb): 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof, wherein:
 each of X 1 , X 2 , X 3 , X 4 , X 5 , and X 6 , independently, is hydrogen, halo, hydroxy, nitro, cyano, alkyl, haloalkyl, cycloalkyl, halocycloalkyl, alkoxy, haloalkoxy, cycloalkoxy, halocycloalkoxy, acyl, aminoacyl, —N(R f R g ), —N(R)SO 2 R g , —SO 2 R f , —S(O) 2 N(R f R g ), —CO 2 R f , trialkylamino, aryl, or heteroaryl; 
 W is —O—; 
 Cy has the formula: 
 
       
         
           
           
               
               
           
         
         wherein: 
         Z 1  is —CH 2 CH 2 —; 
         Z 2  is —CH 2 —; 
         Z 3  is a bond; 
         R 1a  and R 1b , independently, are hydrogen, halo, hydroxy, nitro, cyano, —NR f R g , alkyl, haloalkyl, cycloalkyl, cycloalkenyl, cycloalkylalkyl, cycloalkenylalkyl, heterocyclylalkyl, arylalkyl, heteroarylalkyl, alkoxy, cycloalkylalkoxy, cycloalkenylalkoxy, heterocyclylalkoxy, arylalkoxy, heteroarylalkoxy, acyl, cycloalkylacyl, cycloalkenylacyl, heterocyclylacyl, arylacyl, heteroarylacyl, thioalkyl, alkenyl, alkynyl, cycloalkenyl, heterocyclyl, aryl, or heteroaryl; 
         or R 1a  and R 1b , when taken together, are C 2 -C 5  alkylene or C 2 -C 5  alkenylene; 
         R 2a  and R 2b , independently, are hydrogen, halo, hydroxy, nitro, cyano, —NR f R g , alkyl, haloalkyl, cycloalkyl, cycloalkenyl, cycloalkylalkyl, cycloalkenylalkyl, heterocyclylalkyl, arylalkyl, heteroarylalkyl, alkoxy, cycloalkylalkoxy, cycloalkenylalkoxy, heterocyclylalkoxy, arylalkoxy, heteroarylalkoxy, acyl, cycloalkylacyl, cycloalkenylacyl, heterocyclylacyl, arylacyl, heteroarylacyl, thioalkyl, alkenyl, alkynyl, cycloalkenyl, heterocyclyl, aryl, or heteroaryl; 
         or R 1a  and R 2a , when taken together, are C 1 -C 5  alkylene or C 2 -C 5  alkenylene; 
       
       wherein R 1a , R 1b , R 2a , and R 2b  are each, independently, substituted with 0-5 substituents selected from halo, hydroxy, nitro, cyano, —NR f R g , or —CO 2 R f ;
 R 3  is -L 1 -J-L 2 -T 1 ; 
 L 1  is —C(R f R g )—; 
 J is —N(R f )—; or J is 
 
       
         
           
           
               
               
           
         
         
           wherein 
           each of D 1  and D 3 , independently, is 
         
       
       
         
           
           
               
               
           
         
         
           D 2  is —[C(R f R g )] k —, [C(R f R g )] k —N(R f )—, —[C(R f R g )] k —O—, —N(R f )—, or —N(R f )—[(CR f R g )] k —; and 
           D 4  is —[C(R f R g )] m —; 
           wherein k is 1 or 2; and m is 0, 1, 2, or 3; 
           provided that no more than 2 ring atoms of D 1 -D 4  are N or O; 
         
         L 2  is —C(R f R g )—, —C(R f R g )—, —C(G) 2 -, —C(R f R g )—C(R f R g )—, —C(R f R g )—C(R f R g )—, —C(R f R g )—C(G) 2 -, or a bond; 
         T 1  is —C(O)(OR f ), —C(O)N(R f )S(O) 2 R f , tetrazolyl, —S(O) 2 OR f , —C(O)NHC(O)—R f , —Si(O)OH, —B(OH) 2 , —N(R f )S(O) 2 R f , —S(O) 2 NR f , —O—P(O)(OR f )OR f , or —P(O) 2 (OR f ); 
         each G, independently, is hydrogen, hydroxy, a halogen, or trifluoromethyl; 
         each R f , independently, is hydrogen, hydroxy, halo, alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclyl or NH 2 ; wherein each of alkyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl and heterocycle are optionally substituted with 1 to 5 substituents independently selected from the group consisting of halo, oxo, —CN, —CHO, -CG 3 , —OH, —NO 2 , alkyl, —OCG 3 , alkoxy, cycloalkoxy, cycloalkenoxy, amino, alkylamino, dialkylamino, acylamino, aminoacyl, alkylsulfonyl, alkylaminosulfonyl, and dialkylaminosulfonyl; and 
         each R g , independently, is hydrogen, hydroxy, halo, alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, or heterocyclyl; wherein each of alkyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl and heterocycle are optionally substituted with 1 to 5 substituents independently selected from the group consisting of halo, oxo, —CN, —CHO, -CG 3 , —OH, —NO 2 , alkyl, —OCG 3 , alkoxy, cycloalkoxy, cycloalkenoxy, amino, alkylamino, dialkylamino, acylamino, aminoacyl, alkylsulfonyl, alkylaminosulfonyl, and dialkylaminosulfonyl. 
       
     
     
         108 . The method of  claim 107 , wherein T 1  is —C(O)(OR f ), —C(O)N(R f )S(O 2 R f ), —O—P(O)(OR f )OR f , —P(O 2 )(OR f ), tetrazolyl or —S(O) 2 OR f . 
     
     
         109 . The method of  claim 107 , wherein R 1a  and R 2a  are both hydrogen, and R 1b  is fluoro, chloro, bromo, iodo, methyl, trifluoromethyl, ethyl, propyl, isopropyl, n-butyl, i-butyl, t-butyl, n-pentyl, isopentyl, 1,1-dimethylpropyl, neopentyl, cyclopentyl, n-hexyl, cyclohexyl, methoxy, trifluoromethoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy, i-butoxy, t-butoxy, n-pentyloxy, i-pentyloxy, 1,1-dimethylpropoxy, neopentyloxy, cyclopentyloxy, n-hexyloxy, or cyclohexyloxy. 
     
     
         110 . The method of  claim 107 , or a pharmaceutically acceptable salt thereof, wherein:
 J is   
       
         
           
           
               
               
           
         
       
       and
 T 1  is —C(O)(OR f ), —C(O)N(R f )S(O 2 R), —O—P(O)(OR f )OR f , —P(O 2 )(OR f ), tetrazolyl, or —S(O) 2 OR f . 
 
     
     
         111 . The method of  claim 107 , wherein the compound is selected from the group consisting of:
 3-((6-(trans-4-tert-butylcyclohexyloxy)naphthalen-2-yl)methylamino)-N-(phenylsulfonyl)propanamide;   3-((6-(trans-4-tert-butylcyclohexyloxy)-5-(trifluoromethyl)naphthalen-2-yl)methylamino)-N-(phenylsulfonyl)propanamide;   2-((6-(trans-4-tert-butylcyclohexyloxy)naphthalen-2-yl)methylamino)propanoic acid;   3-((6-(trans-4-tert-butylcyclohexyloxy)naphthalen-2-yl)methylamino)butanoic acid;   2-(((6-(trans-4-tert-butylcyclohexyloxy)naphthalen-2-yl)methyl)(methyl)amino) acetic acid;   3-((6-(trans-4-tert-butylcyclohexyloxy)naphthalen-2-yl)methylamino)propanoic acid;   3-(((6-(trans-4-tert-butylcyclohexyloxy)naphthalen-2-yl)methyl)(methyl)amino) propanoic acid;   1-((6-(trans-4-tert-butylcyclohexyloxy)naphthalen-2-yl)methyl)azetidine-3-carboxylic acid;   1-((6-(trans-4-tert-butylcyclohexyloxy)naphthalen-2-yl)methyl)pyrrolidine-3-carboxylic acid;   1-((6-(trans-4-tert-butylcyclohexyloxy)naphthalen-2-yl)methyl)piperidine-4-carboxylic acid;   1-((6-(trans-4-tert-butylcyclohexyloxy)-5-(trifluoromethyl)naphthalen-2-yl)methyl)azetidine-3-carboxylic acid;   3-((6-(trans-4-tert-butylcyclohexyloxy)-5-(trifluoromethyl)naphthalen-2-yl)methylamino)propanoic acid;   3-((6-(trans-4-tert-butylcyclohexyloxy)naphthalen-2-yl)methylamino)-2,2-difluoropropanoic acid;   2,2-difluoro-3-((6-(spiro[5.5]undecan-3-yloxy)naphthalen-2-yl)methylamino)propanoic acid;   2-(((2-(trans-4-tert-butylcyclohexyloxy)naphthalen-6-yl)methyl)amino)acetic acid;   4-(((2-(trans-4-tert-butylcyclohexyloxy)naphthalen-6-yl)methyl)amino)butyric acid;   4-(((2-(trans-4-tert-butylcyclohexyloxy)naphthalen-6-yl)methyl)amino)butyric acid;   (R)-1-((2-(trans-4-tert-butylcyclohexyloxy)naphthalen-6-yl)methyl)piperidine-3-carboxylic acid;   (S)-1-((2-(trans-4-tert-butylcyclohexyloxy)naphthalen-6-yl)methyl)piperidine-3-carboxylic acid;   4-((2-(trans-4-tert-butylcyclohexyloxy)naphthalen-6-yl)methyl)butyric acid;   5-((2-(trans-4-tert-butylcyclohexyloxy)naphthalen-6-yl)methyl)pentanoic acid;   6-((2-(trans-4-tert-butylcyclohexyloxy)naphthalen-6-yl)methyl)hexanoic acid;   4-(6-(trans-4-tert-butylcyclohexyloxy)-3,4-dihydroisoquinolin-2(1H)-yl)butanoic acid;   4-(6-(cis-4-tert-butylcyclohexyloxy)-3,4-dihydroisoquinolin-2(1H)-yl)butanoic acid;   2-(((2-(trans-4-tert-butylcyclohexyloxy)naphthalen-6-yl)methyl)amino)ethylphosphonic acid;   2-(2-(5-(trans-4-tert-butylcyclohexyloxy)indolin- 1-yl)-2-oxoethylamino)ethylphosphonic acid;   3-amino-4-(5-(trans-4-tert-butylcyclohexyloxy)indolin-1-yl)-4-oxo-butanoic acid;   3-{[6-(4-tert-butyl-cyclohexyloxy)-8-methyl-naphthalen-2-ylmethyl]-amino}-propionic acid;   {[6-(4-tert-butyl-cyclohexyloxy)-8-methyl-naphthalen-2-ylmethyl]-amino}-acetic acid;   4-{[6-(4-tert-butyl-cyclohexyloxy)-8-methyl-naphthalen-2-ylmethyl]-amino}-butyric acid;   1-[6-(4-tert-butyl-cyclohexyloxy)-8-methyl-naphthalen-2-ylmethyl]-azetidine-3-carboxylic acid; and   1-[6-(4-tert-butyl-cyclohexyloxy)-8-methyl-naphthalen-2-ylmethyl]-pyrrolidine-3-carboxylate;   
       or a pharmaceutically acceptable salt thereof. 
     
     
         112 . The method of  claim 107 , further comprising administering to said mammal an effective amount of one or more drugs selected from the group consisting of: a corticosteroid, a bronchodilator, an antiasthmatic, an antiinflammatory, an antirheumatic, an immunosuppressant, an antimetabolite, an immunomodulator, an antipsoriatic, and an antidiabetic. 
     
     
         113 . A method for treating relapsing-remitting multiple sclerosis in a mammal comprising administering to said mammal an effective amount of a compound of formula (IIa): 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof, wherein:
 each of X 1 , X 2 , X 3 , X 4 , X 5 , and X 6 , independently, is hydrogen, halo, hydroxy, nitro, cyano, alkyl, haloalkyl, cycloalkyl, halocycloalkyl, alkoxy, haloalkoxy, cycloalkoxy, halocycloalkoxy, acyl, aminoacyl, —N(R f R g ), —N(R)SO 2 R g , —SO 2 R f , —S(O) 2 N(R f R g ), —CO 2 R f , trialkylamino, aryl, or heteroaryl; 
 W is —O—; 
 Cy has the formula: 
 
       
         
           
           
               
               
           
         
       
       wherein:
 Z 1  is —CH 2 CH 2 —; 
 Z 2  is —CH 2 —; 
 Z 3  is a bond; 
 R 1a  and R 1b , independently, are hydrogen, halo, hydroxy, nitro, cyano, —NR f R g , alkyl, haloalkyl, cycloalkyl, cycloalkenyl, cycloalkylalkyl, cycloalkenylalkyl, heterocyclylalkyl, arylalkyl, heteroarylalkyl, alkoxy, cycloalkylalkoxy, cycloalkenylalkoxy, heterocyclylalkoxy, arylalkoxy, heteroarylalkoxy, acyl, cycloalkylacyl, cycloalkenylacyl, heterocyclylacyl, arylacyl, heteroarylacyl, thioalkyl, alkenyl, alkynyl, cycloalkenyl, heterocyclyl, aryl, or heteroaryl; 
 or R 1a  and R 1b , when taken together, are C 2 -C 5  alkylene or C 2 -C 5  alkenylene; 
 R 2a  and R 2b , independently, are hydrogen, halo, hydroxy, nitro, cyano, —NR f R g , alkyl, haloalkyl, cycloalkyl, cycloalkenyl, cycloalkylalkyl, cycloalkenylalkyl, heterocyclylalkyl, arylalkyl, heteroarylalkyl, alkoxy, cycloalkylalkoxy, cycloalkenylalkoxy, heterocyclylalkoxy, arylalkoxy, heteroarylalkoxy, acyl, cycloalkylacyl, cycloalkenylacyl, heterocyclylacyl, arylacyl, heteroarylacyl, thioalkyl, alkenyl, alkynyl, cycloalkenyl, heterocyclyl, aryl, or heteroaryl; 
 or R 1a  and R 2a , when taken together, are C 1 -C 5  alkylene or C 2 -C 5  alkenylene; 
 wherein R 1a , R 1b , R 2a , and R 2b  are each, independently, substituted with 0-5 substituents selected from halo, hydroxy, nitro, cyano, —NR f R g , or —CO 2 R f ; 
 R 3  is -L 1 -J-L 2 -T 1 ; 
 L 1  is —C(R f R g )—; 
 J is —N(R f )—; or J is 
 
       
         
           
           
               
               
           
         
         
           wherein 
           each of D 1  and D 3 , independently, is 
         
       
       
         
           
           
               
               
           
         
         
           D 2  is —[C(R f R g )] k —, [C(R f R g )] k —N(R f )—, —[C(R f R g )] k —O—, —N(R f )—, or —N(R f )—[(CR f R g )] k —; and 
           D 4  is —[C(R f R g )] m —; 
           wherein k is 1 or 2; and m is 0, 1, 2, or 3; 
           provided that no more than 2 ring atoms of D 1 -D 4  are N or O; 
         
         L 2  is —C(R f R g )—, —C(R f R g )—, —C(G) 2 -, —C(R f R g )—C(R f R g )—, —C(R f R g )—C(R f R g )—, —C(R f R g )—C(G) 2   − , or a bond; 
         T 1  is —C(O)(OR f ), —C(O)N(R f )S(O) 2 R f , tetrazolyl, —S(O) 2 OR f , —C(O)NHC(O)—R f , —Si(O)OH, —B(OH) 2 , —N(R f )S(O) 2 R f , —S(O) 2 NR f , —O—P(O)(OR f )OR f , or —P(O) 2 (OR f ); 
         each G, independently, is hydrogen, hydroxy, a halogen, or trifluoromethyl; 
         each R f , independently, is hydrogen, hydroxy, halo, alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclyl or NH 2 ; wherein each of alkyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl and heterocycle are optionally substituted with 1 to 5 substituents independently selected from the group consisting of halo, oxo, —CN, —CHO, -CG 3 , —OH, —NO 2 , alkyl, —OCG 3 , alkoxy, cycloalkoxy, cycloalkenoxy, amino, alkylamino, dialkylamino, acylamino, aminoacyl, alkylsulfonyl, alkylaminosulfonyl, and dialkylaminosulfonyl; and 
         each R g , independently, is hydrogen, hydroxy, halo, alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, or heterocyclyl; wherein each of alkyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl and heterocycle are optionally substituted with 1 to 5 substituents independently selected from the group consisting of halo, oxo, —CN, —CHO, -CG 3 , —OH, —NO 2 , alkyl, —OCG 3 , alkoxy, cycloalkoxy, cycloalkenoxy, amino, alkylamino, dialkylamino, acylamino, aminoacyl, alkylsulfonyl, alkylaminosulfonyl, and dialkylaminosulfonyl. 
       
     
     
         114 . The method of  claim 113 , wherein T 1  is —C(O)(OR f ), —C(O)N(R f )S(O 2 R f ), —O—P(O)(OR f )OR f , —P(O 2 )(OR f ), tetrazolyl or —S(O) 2 OR f . 
     
     
         115 . The method of  claim 113 , wherein R 1a  and R 2a  are both hydrogen, and R 1b  is fluoro, chloro, bromo, iodo, methyl, triflurormethyl, ethyl, propyl, isopropyl, n-butyl, i-butyl, t-butyl, n-pentyl, isopentyl, 1,1-dimethylpropyl, neopentyl, cyclopentyl, n-hexyl, cyclohexyl, methoxy, trifluoromethoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy, i-butoxy, t-butoxy, n-pentyloxy, i-pentyloxy, 1,1-dimethylpropoxy, neopentyloxy, cyclopentyloxy, n-hexyloxy, or cyclohexyloxy. 
     
     
         116 . The method of  claim 113 , or a pharmaceutically acceptable salt thereof, wherein:
 J is   
       
         
           
           
               
               
           
         
       
       and
 T 1  is —C(O)(OR f ), —C(O)N(R f )S(O 2 R), —O—P(O)(OR f )OR f , —P(O 2 )(OR f ), tetrazolyl, or —S(O) 2 OR f . 
 
     
     
         117 . The method of  claim 113 , further comprising administering to said mammal an effective amount of one or more drugs selected from the group consisting of: a corticosteroid, a bronchodilator, an antiasthmatic, an antiinflammatory, an antirheumatic, an immunosuppressant, an antimetabolite, an immunomodulator, an antipsoriatic, and an antidiabetic.