Bicyclic aryl sphingosine 1-phosphate analogs
Compounds that have agonist activity at one or more of the S1P receptors are provided. The compounds are sphin-gosine analogs that, after phosphorylation, can behave as agonists at S1P receptors.
1. A method for treatment of neuropathic pain 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 f )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 G)-, —C(G) 2 -, —C(R f R g )—C(R f R g )—, —C(R f R g )—C(R f 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.
2. The method of claim 1 , 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 .
3. The method of claim 1 , wherein R 1a and R 2a are both hydrogen, and R 1b is fluoro, chloro, bromo, iodo, methyl, trifluorormethyl, 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.
4. The method of claim 1 , or a pharmaceutically acceptable salt thereof, wherein:
J is
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 .
5. The method of claim 1 , 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.
6. The method of claim 1 , 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.
7. A method for treatment of neuropathic pain 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 f )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 ) 13 , 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 G)-, —C(G) 2 -, —C(R f R g )—C(R f R g )—, —C(R f R g )—C(R f 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.
8. The method of claim 7 , 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 .
9. The method of claim 7 , 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.
10. The method of claim 7 , or a pharmaceutically acceptable salt thereof, wherein:
J iS
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 .
11. The method of claim 7 , 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.