Bicyclic aryl sphingosine 1-phosphate analogs
View Patent ↗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. A compound of formula (I):
wherein:
X 1 is hydrogen, halo, hydroxy, nitro, cyano, alkyl, haloalkyl, cycloalkyl, halocycloalkyl, alkoxy, haloalkoxy, cycloalkoxy, halocycloalkoxy, acyl, aminoacyl, —NR f R g , —N(R f )SO 2 R g , —SO 2 R f , —SO 2 NR f R g , —CO 2 R f , trialkylamino, aryl, or heteroaryl;
X 2 is hydrogen, halo, hydroxy, nitro, cyano, alkyl, haloalkyl, cycloalkyl, halocycloalkyl, alkoxy, haloalkoxy, cycloalkoxy, halocycloalkoxy, acyl, aminoacyl, —NR f R g , —N(R f )SO 2 R g , —SO 2 R f , —SO 2 NR f R g , —CO 2 R f , trialkylamino, aryl, or heteroaryl;
X 3 is hydrogen, halo, hydroxy, nitro, cyano, alkyl, haloalkyl, cycloalkyl, halocycloalkyl, alkoxy, haloalkoxy, cycloalkoxy, halocycloalkoxy, acyl, aminoacyl, —NR f R g , —N(R f )SO 2 R g , —SO 2 R f , —SO 2 NR f R g , —CO 2 R f , trialkylamino, aryl, or heteroaryl;
X 4 is hydrogen, halo, hydroxy, nitro, cyano, alkyl, haloalkyl, cycloalkyl, halocycloalkyl, alkoxy, haloalkoxy, cycloalkoxy, halocycloalkoxy, acyl, aminoacyl, —NR f R g , —N(R f )SO 2 R g , —SO 2 R f , —SO 2 NR f R g , —CO 2 R f , trialkylamino, aryl, or heteroaryl;
X 5 is hydrogen, halo, hydroxy, nitro, cyano, alkyl, haloalkyl, cycloalkyl, halocycloalkyl, alkoxy, haloalkoxy, cycloalkoxy, halocycloalkoxy, acyl, aminoacyl, —NR f R g , —N(R f )SO 2 R g , —SO 2 R f , —SO 2 NR f R g , —CO 2 R f , trialkylamino, aryl, or heteroaryl;
X 6 is hydrogen, halo, hydroxy, nitro, cyano, alkyl, haloalkyl, cycloalkyl, halocycloalkyl, alkoxy, haloalkoxy, cycloalkoxy, halocycloalkoxy, acyl, aminoacyl, —NR f R g , —N(R f )SO 2 R g , —SO 2 R f , —SO 2 NR f R g , —CO 2 R f , trialkylamino, aryl, or heteroaryl;
Y is —OR f , —(CR f R g )OR f , —(CR f R g ) 2 OR f , —O—P(O)(OR f )OR g , —OC(O)R c , —C(O)OR c , —(CR f R g )—P(O)(OR f )OR g , —(C(OH)R f )—P(O)(OR f )OR g , —S—P(O)(OR f )OR g , tetrazole, —SO 2 NHR f , —SO 3 , —CONHR f , —Si(OH) 2 , or —B(OH) 2 ;
W is —CR f R g —, —NR f —, —O—, —S—, —SO—, or —SO 2 —;
L 1 is —CH 2 —, —CHF—, or —CF 2 —;
Z 4 is hydrogen, halo, alkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, or —OR f ;
or Z 4 is —CH 2 — bound to the carbon atom to which Y is bound,
or L 1 , Z 4 , Y, and the atoms to which they are bound form a 4-7 membered cycloalkyl group or a 4-7 membered heterocyclyl group having 1 or 2 heteroatoms selected from O and N;
R a is hydrogen, 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, —CF 3 , —OH, —NO 2 , alkyl, —OCF 3 alkoxy cycloalkoxy, cycloalkenoxy, amino, alkylamino, dialkylamino, acylamino, aminoacyl, alkylsulfonyl, alkylaminosulfonyl, and dialkylaminosulfonyl;
R b is hydrogen, 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, —CF 3 , —OH, —NO 2 , alkyl, —OCF 3 , alkoxy, cycloalkoxy, cycloalkenoxy, amino, alkylamino, dialkylamino, acylamino, aminoacyl, alkylsulfonyl, alkylaminosulfonyl, and dialkylaminosulfonyl;
or R b and Z 4 are taken to together to form —C(O)O— or ═C(R f )O—;
R c is alkyl, aryl, trifluoromethyl, methylsulfonyl, trifluoromethylsulfonyl, p-tolylsulfonyl, or a group selected such that —OCOR c is a leaving group;
each R f , independently, is hydrogen, 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, —CF 3 , —OH, —NO 2 , alkyl, —OCF 3 , alkoxy, cycloalkoxy, cycloalkenoxy, amino, alkylamino, dialkylamino, acylamino, aminoacyl, alkylsulfonyl, alkylaminosulfonyl, and dialkylaminosulfonyl;
each R g , independently, is hydrogen, 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, —CF 3 , —OH, —NO 2 , alkyl, —OCF 3 , alkoxy, cycloalkoxy, cycloalkenoxy, amino, alkylamino, dialkylamino, acylamino, aminoacyl, alkylsulfonyl, alkylaminosulfonyl, and dialkylaminosulfonyl;
Cy has the formula:
wherein
Z 1 is a bond, —[C(R d R e )] x —, —CR d ═CR e —, —O—, —NR f —;
Z 2 is a bond, —[C(R d R e )] y —, —CR d ═CR e —, —O—, —NR f —;
Z 3 is a bond, —[C(R d R e )] z —, —CR d ═CR e —, —O—, —NR f —;
each of x, y, and z, independently, is 1 to 3;
each R d , independently, is H, halo, hydroxy, alkyl, haloalkyl, alkenyl, alkoxy, cycloalkyl, —C(O)NR f R g , —NR f R g , —NR f C(O)R g , or —SO 2 NR f R g ;
each R e , independently, is H, halo, hydroxy, alkyl, haloalkyl, alkenyl, alkoxy, or cycloalkyl, —C(O)NR f R g , —NR f R g , —NR f C(O)R g , or —SO 2 NR f R g ;
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 optionally interrupted by 1 or 2 oxygen atoms, or C 2 -C 5 alkenylene optionally interrupted by 1 or 2 oxygen atoms;
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 optionally terminated-by interrupted by 1 or 2 oxygen atoms, or C 2 -C 5 alkenylene optionally interrupted by 1 or 2 oxygen atoms;
wherein R 1a , R 1b , R 2a , 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 ;
or a pharmaceutically acceptable salt or prodrug thereof.
2. The compound of claim 1 , or a pharmaceutically acceptable salt or prodrug thereof , wherein R 1a and R 2a are both hydrogen.
3. The compound of claim 1 , or a pharmaceutically acceptable salt or prodrug thereof , wherein Z 1 is —CH 2 CH 2 —.
4. The compound of claim 3 , or a pharmaceutically acceptable salt or prodrug thereof , wherein Z 2 is —CH 2 —.
5. The compound of claim 4 , or a pharmaceutically acceptable salt or prodrug thereof , wherein Z 3 is a bond.
6. The compound of claim 2 , or a pharmaceutically acceptable salt or prodrug thereof , wherein R 1b is fluoro, chloro, bromo, iodo, methyl, difluoromethyl, triflurormethyl, ethyl, 1,1-difluoroethyl, 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.
7. A compound of formula (II):
wherein
X 1 is hydrogen, halo, hydroxy, nitro, cyano, alkyl, haloalkyl, cycloalkyl, halocycloalkyl, alkoxy, haloalkoxy, cycloalkoxy, halocycloalkoxy, acyl, aminoacyl, —NR f R g , —N(R f )SO 2 R g , —SO 2 R f , —SO 2 NR f R g , —CO 2 R f , trialkylamino, aryl, or heteroaryl;
X 2 is hydrogen, halo, hydroxy, nitro, cyano, alkyl, haloalkyl, cycloalkyl, halocycloalkyl, alkoxy, haloalkoxy, cycloalkoxy, halocycloalkoxy, acyl, aminoacyl, —NR f R g , —N(R f )SO 2 R g , —SO 2 R f , —SO 2 NR f R g , —CO 2 R f , trialkylamino, aryl, or heteroaryl;
X 3 is hydrogen, halo, hydroxy, nitro, cyano, alkyl, haloalkyl, cycloalkyl, halocycloalkyl, alkoxy, haloalkoxy, cycloalkoxy, halocycloalkoxy, acyl, aminoacyl, —NR f R g , —N(R f )SO 2 R g , —SO 2 R f , —SO 2 NR f R g , —CO 2 R f , trialkylamino, aryl, or heteroaryl;
X 4 is hydrogen, halo, hydroxy, nitro, cyano, alkyl, haloalkyl, cycloalkyl, halocycloalkyl, alkoxy, haloalkoxy, cycloalkoxy, halocycloalkoxy, acyl, aminoacyl, —NR f R g , —N(R f )SO 2 R g , —SO 2 R f , —SO 2 NR f R g , —CO 2 R f , trialkylamino, aryl, or heteroaryl;
X 5 is hydrogen, halo, hydroxy, nitro, cyano, alkyl, haloalkyl, cycloalkyl, halocycloalkyl, alkoxy, haloalkoxy, cycloalkoxy, halocycloalkoxy, acyl, aminoacyl, —NR f R g , —N(R f )SO 2 R g , —SO 2 R f , —SO 2 NR f R g , —CO 2 R f , trialkylamino, aryl, or heteroaryl;
X 6 is hydrogen, halo, hydroxy, nitro, cyano, alkyl, haloalkyl, cycloalkyl, halocycloalkyl, alkoxy, haloalkoxy, cycloalkoxy, halocycloalkoxy, acyl, aminoacyl, —NR f R g , —N(R f )SO 2 R g , —SO 2 R f , —SO 2 NR f R g , —CO 2 R f , trialkylamino, aryl, or heteroaryl;
Y is —OR f , —(CR f R g )OR f , —(CR f R g ) 2 OR f , —O—P(O)(OR f )OR g , —OC(O)R c , —C(O)OR c , —(CR f R g )—P(O)(OR f )OR g , —(C(OH)R f )—P(O)(OR f )OR g , —S—P(O)(OR f )OR g , tetrazole, —SO 2 NHR f , —SO 3 , —CONHR f , —Si(OH) 2 , or —B(OH) 2 ;
Z 4 is hydrogen, halo, alkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, or —OR f ;
or Z 4 is —CH 2 — bound to the carbon atom to which Y is bound;
or Z 4 , Y, and the atoms to which they are bound form a 4-7 membered cycloalkyl group or a 4-7 membered heterocyclyl group having 1 or 2 heteroatoms selected from O and N;
R c is alkyl, aryl, trifluoromethyl, methylsulfonyl, trifluoromethylsulfonyl, p-tolylsulfonyl, or a group selected such that —OCOR c is a leaving group;
each R f , independently, is hydrogen, 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, —CF 3 , —OH, —NO 2 , alkyl, —OCF 3 , alkoxy, cycloalkoxy, cycloalkenoxy, amino, alkylamino, dialkylamino, acylamino, aminoacyl, alkylsulfonyl, alkylaminosulfonyl, and dialkylaminosulfonyl;
each R g , independently, is hydrogen, 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, —CF 3 , —OH, —NO 2 , alkyl, —OCF 3 , alkoxy, cycloalkoxy, cycloalkenoxy, amino, alkylamino, dialkylamino, acylamino, aminoacyl, alkylsulfonyl, alkylaminosulfonyl, and dialkylaminosulfonyl;
R 1a is 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;
Z 1 is a bond, —[C(R d R e )] x —, or —CR d ═CR e —;
Z 2 is a bond, —[C(R d R e )] y —, or —CR d ═CR e —;
provided that Z 1 and Z 2 are not both simultaneously a bond;
each of x and y independently, is 1 to 3;
each R d , independently, is hydrogen, halo, hydroxy, alkyl, alkenyl, alkoxy, or cycloalkyl;
each R e , independently, is hydrogen, halo, hydroxy, alkyl, alkenyl, alkoxy, or cycloalkyl;
or a pharmaceutically acceptable salt or prodrug thereof.
8. The compound of claim 7 , or a pharmaceutically acceptable salt or prodrug thereof, wherein Y is —OR f .
9. The compound of claim 8 , or a pharmaceutically acceptable salt or prodrug thereof, wherein Y is —OH or —O—P(O)(OR f )OR g .
10. The compound of claim 9 , or a pharmaceutically acceptable salt or prodrug thereof, wherein X 6 is H, halo, alkyl, cycloalkyl, or haloalkyl.
11. The compound of claim 10 , or a pharmaceutically acceptable salt or prodrug thereof, wherein Z 1 is —CH 2 CH 2 —.
12. The compound of claim 11 , or a pharmaceutically acceptable salt or prodrug thereof, wherein Z 2 is —CH 2 CH 2 —.
13. The compound of claim 12 , or a pharmaceutically acceptable salt or prodrug thereof, wherein R 1a is hydrogen, halo, hydroxy, alkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, arylalkyl, alkoxy, cycloalkylalkoxy, arylalkoxy, or aryl.
14. The compound of claim 7 , or a pharmaceutically acceptable salt or prodrug thereof, wherein Y is —OH or —OP(O)(OH) 2 ; Z 4 is H or —OH; X 1 , X 2 , X 3 , X 4 , and X 5 are each H; and X 6 is H, halo, alkyl, cycloalkyl, or haloalkyl.
15. The compound of claim 7 , or a pharmaceutically acceptable salt or prodrug thereof, wherein Z 1 is —(CH 2 ) x — and Z 2 is —(CH 2 ) y —.
16. The compound of claim 15 , or a pharmaceutically acceptable salt or prodrug thereof, wherein R 1a is alkyl, haloalkyl, cycloalkyl, aryl, or arylalkoxy.
17. The compound of claim 7 , or a pharmaceutically acceptable salt or prodrug thereof, having the formula:
18. A compound selected from the group consisting of: (R)-2-amino-2-(6-(cis-4-butylcyclohexyloxy)naphthalen-2-yl)propan-1-ol; (R)-2-amino-2-(6-(4-butylcyclohexyloxy)naphthalen-2-yl)propan-1-ol; (R)-2-amino-2-(6-(trans-4-butylcyclohexyloxy)naphthalen-2-yl)propan-1-ol; 2-amino-2-(6-(cis-4-butylcyclohexyloxy)naphthalen-2-yl)propane-1,3-diol; (R)-2-amino-2-(6-(cis-4-butylcyclohexyloxy)-5-(trifluoromethyl)naphthalen-2-yl)propan-1-ol; (R)-2-amino-2-(6-(cis-4-butylcyclohexyloxy)-5-(trifluoromethyl)naphthalen-2-yl)propan-1-phosphoric acid; (R)-2-amino-2-(6-(cis-4-butylcyclohexyloxy)naphthalen-2-yl)propyl dihydrogen phosphate; (R)-2-amino-2-(6-(trans-4-butylcyclohexyloxy)naphthalen-2-yl)propyl dihydrogen phosphate; (R)-2-amino-2-(6-(trans-4-tert-butylcyclohexyloxy)naphthalen-2-yl)propan-1-ol; (R)-2-amino-2-(6-(trans-4-tert-butylcyclohexyloxy)naphthalen-2-yl)propyl dihydrogen phosphate; (R)-2-amino-2-(6-(cis-4-(4-(pentan-3-yloxy)phenyl)cyclohexyloxy)naphthalen-2-yl)propan-1-ol; (R)-2-amino -2-(6-(cis-4-(4-isopropoxyphenyl)cyclohexyloxy)naphthalen-2-yl)propan-1-ol; (R)-2-amino-2-(6-(cis-4-(4-methoxyphenyl)cyclohexyloxy)naphthalen-2-yl)propan-1-ol; (R)-2-amino-2-(6-(cis-4-phenylcyclohexyloxy)naphthalen-2-yl)propan-1-ol; (R)-2-amino-2-(6-(cis-4-phenylcyclohexyloxy)-5-(trifluoromethy)naphthalen-2-yl)propan-1-ol; (R)-2-amino-2-{6-[trans -4-(1,1-dimethyl-propyl)-cyclohexyloxy]-5-trifluoromethyl-naphthalen-2-yl}-propan-1-ol; (R)-2-amino-2-(6-(4-pentylcyclohexyloxy)naphthalen-2-yl)propan-1-ol; (R)-2-amino-2-(6-(4-propylcyclohexyloxy)naphthalen-2-yl)propan-1-ol; (R)-2-amino-2-(6-(cis-4-methylcyclohexyloxy)naphthalen-2-yl)propan-1-ol; (R)-2-amino-2-(6-(cis-4-ethylcyclohexyloxy)naphthalen-2-yl)propan-1-ol; (R)-2-amino-2-(6-(4-(trifluoromethyl)cyclohexyloxy)naphthalen-2-yl)propan-1-ol; (R)-2-amino-2-(6-(4,4-dimethylcyclohexyloxy)naphthalen-2-yl)propan-1-ol; (R)-2-amino-2-(6-(trans-4-tert -butylcyclohexyloxy)naphthalen-2-yl)propan-1-ol; (R)-2-amino-2-(6-(trans-4-tert -butylcyclohexyloxy)-5-(trifluoromethypnaphthalen-2-yl)propan-1-ol; 2-amino-2-[6-(cis-4-butylcyclohexyloxy)-5-trifluoromethyl-naphthalen-2-yl]-propane-1,3-diol; 2-amino-2-[6-(cis-4-butylcyclohexyloxy)-5-iodo-naphthalen-2-yl]-propane-1,3-diol; 2-amino-2-[6-(trans-4-tert -butylcyclohexyloxy)-5-trifluoromethyl-naphthalen-2-yl]-propane-1,3-diol; 2-amino-2-[6-(trans -4-tert-butyl-cyclohexyloxy)-naphthalen-2-yl]-propane-1,3-diol; 2-amino-2-[6-(trans-4-tert-butyl -cyclohexyloxy)-5-iodo-naphthalen-2-yl]-propane-1,3-diol; 2-amino-2-(6-trans-[3-(benzyloxymethyl)cyclobutoxy]naphthalen-2-yl)propane-1,3-diol; 2-amino-2-(6-cis-[3-(benzyloxymethyl)cyclobutoxy]naphthalen-2-yl)propane-1,3-diol; 2-amino-2-[6-(3-trans -benzyloxymethylcyclobutoxy)-5-(trifluoromethy)naphthalen-2-yl]propane-1,3-diol; 2-amino-2-[6-(3-cis-benzyloxymethylcyclobutoxy)-5-(trifluoromethy)naphthalen-2-yl]propane-1,3-diol; (R)-2-amino-2-[6-(3-trans-benzyloxymethylcyclobutoxy)naphthalen-2-yl]propan-1-ol; (R)-2-amino-2-[6-(3-cis-benzyloxymethylcyclobutoxy)naphthalen-2-yl]propan-1-ol; (R)-2-amino-2-[6-(4-trans-tert-pentylcyclohexyloxy)naphthalen-2-yl]propan-1-ol; (R)-2-amino-2-[6-(4-cis-tert -pentylcyclohexyloxy)naphthalen-2-yl]propan-1-ol; (R)-2-amino-2-[6-(3-cis -benzyloxymethylcyclobutoxy)-5-trifluoromethylnaphthalen-2-yl]propan-1-ol; 2-amino-2-[6-(3-cis-(benzyloxymethyl)cyclobutoxy)naphthalen-2-yl]-3-hydroxypropyl dihydrogen phosphate; (R)-2-amino-2-{6- [trans-4-(1,1-dimethyl-propyl)-cyclohexyloxy]naphthalen-2-yl}-propan-1-ol; (R)-2-amino-2-(6-(trans-4-tert-butylcyclohexyloxy)-5-methoxynaphthalen-2-yl)propan-1-ol; (R)-2-amino-2-(6-(trans-4-butyl-cyclohexyloxy)-5-trifluoromethylnaphthalen-2-yl)propan-1-ol; (R)-2-amino-2-(6-(trans-4-butyl-cyclohexyloxy)naphthalen-2-yl)propan-1-ol; (R)-2-amino-2-(6-(trans-4-trifluoromethylcyclohexyloxy)-5-fluoronaphthalen-2-yl)propan-1-ol; (R)-2-Amino-2-[6-(decahydro-naphthalen-2-yloxy)-naphthalen-2-yl]-propan-1-ol; (R)-2-Amino-2-[6-(bicyclohexyl-4-yloxy)-naphthalen-2-yl]-propan-1-ol; (R)-2-Amino-2-[6-(4-isopropyl -cyclohexyloxy)-naphthalen-2-yl]-propan-1-ol; (R)-2-Amino-2-[6-(4-cyclopentyl -cyclohexyloxy)-naphthalen-2-yl]-propan-1-ol; (R)-2-Amino-2-[6-(4-sec-butyl-cyclohexyloxy) -naphthalen-2-yl]-propan-1-ol; (R)-2-Amino-2-[6-(cis-4cyclopentyl-cyclohexyloxy)-5-trifluoromethyl-naphthalen-2-yl]-propan-1-ol; (R)-2-Amino-2-[6-(trans-4-cyclopentyl -cyclohexyloxy)-5-trifluoromethyl-naphthalen-2-yl]-propan-1-ol; Phosphoric acid mono-{(R)-2-amino-2-[6-(4-cyclopentyl-cyclohexyloxy)-5-trifluoromethyl-naphthalen-2-yl]-propyl} ester; 2-Amino-2-[5-trifluoromethyl-6-(4-trifluoromethyl-cyclohexyloxy)-naphthalen-2-yl]-propane-1,3-diol; (R)-2-[6-(4-tert-butyl-cyclohexyloxy)-naphthalen-2-yl]-2-methylamino-propan-1-ol; phosphoric acid mono-{(R)-2-amino-2-{6-[4-(1,1-dimethylpropyl)-cyclohexyloxy)-5-trifluoromethyl-naphthalen-2-yl]-propyl}Ester; phosphoric acid mono-{(R)-2-amino-2-[6-(4-tert -butyl-cyclohexyloxy)-5-trifluoromethyl-naphthalen-2-yl]-propyl}Ester; (S)-2-amino-2-[6-(4-trans-tert-butyl-cyclohexyloxy)-5-trifluoromethyl-naphthalen-2-yl]-propan-1-ol; (S)-4-[6-(4-cis -tert-butyl-cyclohexyloxy)-naphthalen-2-yl]-4-methyl-oxazolidin-2-one; (S)-4-[6-(4-cis-tert -butyl-cyclohexyloxy)-5-trifluoromethyl-naphthalen-2-yl]-4-methyl-oxazolidin-2-one; (S)-2-amino-2-[6-(4-cis-tert-butyl-cyclohexyloxy)-5-trifluoromethyl-naphthalen-2-yl]-propan-1-ol; (R)-4-(6-hydroxy-5-(trifluoromethyDnaphthalen-2-yl)-4-methyloxazolidin-2-one; (R)-4-(6-(trans-4-tert-butylcyclohexyloxy)-5-(trifluoromethyl)naphthalen-2-yl)-4-methyloxazolidin-2-one; (R)-2-amino-2-(6-((4-tert-butylcyclohexyl)methyl)naphthalen-2-yl)propan-1-ol; 3-(6-(trans -4-tert-Butylcyclohexyloxy)naphthalen-2-yl)oxetan-3-amine; 3-(6-(trans-4-tert -butylcyclohexyloxy)-5-(trifluoromethyl)naphthalen-2-yl)oxetan-3-amine; (R)-2-Amino-2-(6-(cis-4-cyclohexylcyclohexyloxy)-5-(trifluoromethyl)naphthalen-2-yl)propan-1-ol; (R)-2-Amino-2-(6-(trans-4-cyclohexylcyclohexyloxy)-5-(trifluoromethyl)naphthalen-2-yl)propan-1-ol; (R)-2-amino-2-(6-(trans-4-cyclohexylcyclohexyloxy)-5-(trifluoromethyl)naphthalen-2-yl)propyl dihydrogen phosphate; (R)-2-Amino-2-(6-(cis-4-isopropylcyclohexyloxy)-5-(trifluoromethyl)naphthalen-2-yl)propan-1-ol; (R)-2-Amino-2-(6-(trans-4-isopropylcyclohexyloxy)-5-(frifluoromethyl)naphthalen-2-yl)propan-1-ol; (R)-2-Amino-2-(6-(trans-4-(1,1-difluoroethyl)cyclohexyloxy)-5-(trifluoromethyl)naphthalen-2-yl)propyl dihydrogen phosphate; 4-amino-4-(6-(trans-4-tert -butylcyclohexyloxy)-5-(trifluoromethyl)naphthalen-2-yl)pentanoic acid; (R)-2-amino-2-(6-(trans-4-tert-butylcyclohexyloxy)-5-cyclopropylnaphthalen-2-yl)propan-1-ol; (R)-2-amino-2-(6-(trans-4-tert-butylcyclohexyloxy)-5-methylnaphthalen-2-yl)propan-1-ol; (R)-2-amino-2-(6-(trans-4-tert-butylcyclohexyloxy)-5-vinylnaphthalen-2-yl)propan-1-ol; (R)-2-amino-2-(6-(trans -4-tert-butylcyclohexyloxy)-5-(4-(trifluoromethoxy)phenyl)naphthalen-2- yl)propan-1-ol; (R)-2-amino-2-(6-(trans-4-tert-butylcyclohexyloxy)-5-(4-(methylsulfonyl) phenyl)naphthalen-2-yl) propan-1-ol; (R)-2-amino-2-(6-(trans-4-tert-butylcyclohexyloxy)-5-(pyrimidin-5-yl)naphthalen -2-yl)propan-1-ol; (R)-2-amino-2-(6-(trans-4-tert-butylcyclohexyloxy)-5-(4-ethoxyphenyl)naphthalen-2-yl)propan-1-ol; (R)-2-amino-2-(6-(trans-4-tert-butylcyclohexyloxy) -5-phenylnaphthalen-2-yl)propan-1-ol; (R)-2-amino-2-(6-(trans-4-tert-butylcyclohexyloxy)-5-(3-chlorophenyl)naphthalen-2-yl)propan-1-ol; (R)-2-amino-2-(6-(trans-4-tert-butylcyclohexyloxy) -5-(4-chlorophenyl)naphthalen-2-yl)propan-1-ol; (R)-2-amino-2-(6-(trans-4-tert -butylcyclohexyloxy)-5-chloronaphthalen-2-yl)propan-1-ol; (R)-2-amino-2-(5-bromo-6-(trans-4-tert-butylcyclohexyloxy)naphthalen-2-yl)propan-1-ol; (R)-2-amino-2-(6-(trans-4-tert -butylcyclohexyloxy)-5,7,8-trichloronaphthalen-2-yl)propan-1-ol; (R)-2-amino-2-(6-(trans-4-tert -butylcyclohexyloxy)-5-fluoronaphthalen-2-yl)propan-1ol; 2-amino-2-(6-trans-4-tert -butylcyclohexyloxy)-5-(trifluoromethypnaphthalen-2-yl)-3-hydroxypropyl dihydrogen phosphate Enantiomer 1; 2-amino-2-(6-trans-4-tert-butylcyclohexyloxy)-5-(trifluoromethyl)naphthalen-2-yl)-3-hydroxypropyl dihydrogen phosphate Enantiomer 2; (R)-4-Methyl-4-[6-(4-trifluoromethyl-cyclohexyloxy)-naphthalen-2-yl]-oxazolidin-2-one; (R)-4-Methyl-4-[6-(cis-4-trifluoromethyl-cyclohexyloxy)-naphthalen-2-yl]-oxazolidin-2-one; (R)-4-Methyl-4-[6-(trans-4-trifluoromethyl-cyclohexyloxy)-naphthalen-2-yl]-oxazolidin-2-one; (R)-2-Amino-2-[6-(cis-4-trifluoromethyl-cyclohexyloxy)-naphthalen-2-yl]-propan-1-ol; (R)-2-Amino -2[6-(trans-4-trifluoromethyl-cyclohexyloxy)-naphthalen-2-yl]-propan-1-ol; Phosphoric acid mono-{(R)-2-amino-2[6-(trans-4-trifluoromethyl-cyclohexyloxy)- naphthalen-2-yl]-propyl}Ester; (R)-2-Amino-2-[5-trifluoromethyl-6-(trans-4-trifluoromethyl-cyclohexyloxy) -naphthalen-2-yl]-propan-1-ol; Phosphoric acid mono-{(R)-2-amino-2-[5-trifluoromethyl-6-(trans-4-trifluoromethyl-cyclohexyloxy)-naphthalen-2-yl]-propyl}Ester; (R)-2-Amino-2-[6-(4-pentyl-cyclohexyloxy)-naphthalen-2-yl]-propan-1-ol; (R)-2-Amino-2-[6-(cis-4-pentyl -cyclohexyloxy)-naphthalen-2-yl]-propan-1-ol; (R)-2-Amino-2-[6-(trans-4-pentyl -cyclohexyloxy)-naphthalen-2-yl]-propan-1-ol; 2-[6-(trans-4-tert-Butyl-cyclohexyloxy)-5-trifluoromethyl-naphthalen-2-yl]-propan-1-ol; 2-Amino-2-[6-(trans-4-tert-butyl-cyclohexyloxy) -5-trifluoromethyl-naphthalen-2-yl]-propan-1-ol; 4-Amino-4-[6-(trans-4-trifluoromethyl -cyclohexyloxy)-naphthalen-2-yl]-pentanoic acid; 4-Amino-4-[6-(cis-4-trifluoromethyl -cyclohexyloxy)-naphthalen-2-yl]-pentanoic acid; 4-Amino-4-[5-trifluoromethyl-6-(trans-4-trifluoromethyl-cyclohexyloxy)-naphthalen-2-yl]-pentanoic acid; 4-Amino-4[5-trifluoromethyl -6-(cis-4-trifluoromethyl-cyclohexyloxy)-naphthalen-2-yl]-pentanoic acid; (R)-2-amino-2-(6-(trans-4-(1,1-difluoroethyl)cyclohexyloxy)naphthalen-2-yl)propan-1-ol; (R)-2-amino-2-(6-(trans -4-(1,1-difluoropropyl)cyclohexyloxy)naphthalen-2-yl)propan-1-ol; (R)-2-amino-2-(6-(trans-4-(1,1-difluorobutyl)cyclohexyloxy)naphthalen-2-yl)propan-1-ol; (R)-2-amino-2-(6-(cis-4-(1,1-difluoroethyl)cyclohexyloxy)naphthalen-2-yl)propan-1-ol; (R)-2-amino-2-(6-(cis-4-(1,1-difluoropropyl)cyclohexyloxy)naphthalen-2-yl)propan-1-ol; (R)-2-amino-2-(6-(cis-4-(1,1-difluorobutyl)cyclohexyloxy)naphthalen-2-yl)propan-1-ol; (R)-2-amino-2-(6-(trans-4-(1,1-difluoroethyl)cyclohexyloxy)-5-(trifluoromethyl)naphthalen-2-yl)propan-1-ol; (R)-2-amino-2-(6-(trans-4-(1,1-difluoropropyl)cyclohexyloxy)-5-(trifluoromethyl)naphthalen-2-yl)propan-1-ol; (R)-2-amino-2-(6-(cis-4-tert-butylcyclohexyloxy)naphthalen-2-yl)propan-1-ol;
or a pharmaceutically acceptable salt or prodrug thereof.
19. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a compound of formula (I):
wherein:
X 1 is hydrogen, halo, hydroxy, nitro, cyano, alkyl, haloalkyl, cycloalkyl, halocycloalkyl, alkoxy, haloalkoxy, cycloalkoxy, halocycloalkoxy, acyl, aminoacyl, —NR f R g , —N(R f )SO 2 R g , —SO 2 R f , —SO 2 NR f R g , —CO 2 R f , trialkylamino, aryl, or heteroaryl;
X 2 is hydrogen, halo, hydroxy, nitro, cyano, alkyl, haloalkyl, cycloalkyl, halocycloalkyl, alkoxy, haloalkoxy, cycloalkoxy, halocycloalkoxy, acyl, aminoacyl, —NR f R g , —N(R f )SO 2 R g , —SO 2 R f , —SO 2 NR f R g , —CO 2 R f , trialkylamino, aryl, or heteroaryl;
X 3 is hydrogen, halo, hydroxy, nitro, cyano, alkyl, haloalkyl, cycloalkyl, halocycloalkyl, alkoxy, haloalkoxy, cycloalkoxy, halocycloalkoxy, acyl, aminoacyl, —NR f R g , —N(R f )SO 2 R g , —SO 2 R f , —SO 2 NR f R g , —CO 2 R f , trialkylamino, aryl, or heteroaryl;
X 4 is hydrogen, halo, hydroxy, nitro, cyano, alkyl, haloalkyl, cycloalkyl, halocycloalkyl, alkoxy, haloalkoxy, cycloalkoxy, halocycloalkoxy, acyl, aminoacyl, —NR f R g , —N(R f )SO 2 R g , —SO 2 R f , —SO 2 NR f R g , —CO 2 R f , trialkylamino, aryl, or heteroaryl;
X 5 is hydrogen, halo, hydroxy, nitro, cyano, alkyl, haloalkyl, cycloalkyl, halocycloalkyl, alkoxy, haloalkoxy, cycloalkoxy, halocycloalkoxy, acyl, aminoacyl, —NR f R g , —N(R f )SO 2 R g , —SO 2 R f , —SO 2 NR f R g , —CO 2 R f , trialkylamino, aryl, or heteroaryl;
X 6 is hydrogen, halo, hydroxy, nitro, cyano, alkyl, haloalkyl, cycloalkyl, halocycloalkyl, alkoxy, haloalkoxy, cycloalkoxy, halocycloalkoxy, acyl, aminoacyl, —NR f R g , —N(R f )SO 2 R g , —SO 2 R f , —SO 2 NR f R g , —CO 2 R f , trialkylamino, aryl, or heteroaryl;
Y is —OR f , —(CR f R g )OR f , —(CR f R g ) 2 OR f , —O—P(O)(OR f )OR g , —OC(O)R c , —C(O)OR c , —(CR f R g )—P(O)(OR f )OR g , —(C(OH)R f )—P(O)(OR f )OR g , —S—P(O)(OR f )OR g , tetrazole, —SO 2 NHR f , —SO 3 , —CONHR f , —Si(OH) 2 , or —B(OH) 2 ;
W is —CR f R g —, —NR f —, —O—, —S—, —SO—, or —SO 2 —;
L 1 is —CH 2 —, —CHF—, or —CF 2 —;
Z 4 is hydrogen, halo, alkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, or —OR f ;
or Z 4 is —CH 2 — bound to the carbon atom to which Y is bound;
or L 1 , Z 4 , Y, and the atoms to which they are bound form a 4-7 membered cycloalkyl group or a 4-7 membered heterocyclyl group having 1 or 2 heteroatoms selected from O and N;
R a is hydrogen, 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, —CF 3 , —OH, —NO 2 , alkyl, —OCF 3 , alkoxy, cycloalkoxy, cycloalkenoxy, amino, alkylamino, dialkylamino, acylamino, aminoacyl, alkylsulfonyl, alkylaminosulfonyl, and dialkylaminosulfonyl;
R b is hydrogen, 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, —CF 3 , —OH, —NO 2 , alkyl, —OCF 3 , alkoxy, cycloalkoxy, cycloalkenoxy, amino, alkylamino, dialkylamino, acylamino, aminoacyl, alkylsulfonyl, alkylaminosulfonyl, and dialkylaminosulfonyl;
or R b and Z 4 are taken to together to form —C(O)O— or ═C(R f )O—;
R c is alkyl, aryl, trifluoromethyl, methylsulfonyl, trifluoromethylsulfonyl, p-tolylsulfonyl, or a group selected such that —OCOR c is a leaving group;
each R f , independently, is hydrogen, 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, —CF 3 , —OH, —NO 2 , alkyl, —OCF 3 , alkoxy, cycloalkoxy, cycloalkenoxy, amino, alkylamino, dialkylamino, acylamino, aminoacyl, alkylsulfonyl, alkylaminosulfonyl, and dialkylaminosulfonyl;
each R g , independently, is hydrogen, 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, —CF 3 , —OH, —NO 2 , alkyl, —OCF 3 , alkoxy, cycloalkoxy, cycloalkenoxy, amino, alkylamino, dialkylamino, acylamino, aminoacyl, alkylsulfonyl, alkylaminosulfonyl, and dialkylaminosulfonyl;
Cy has the formula:
wherein
Z 1 is a bond, —[C(R d R e )] x —, —CR d ═CR e —, —O—, —NR f —;
Z 2 is a bond, —[C(R d R e )] y —, —CR d ═CR e —, —O—, —NR f —;
Z 3 is a bond, —[C(R d R e )] z —, —CR d ═CR e —, —O—, —NR f —;
each of x, y, and z, independently, is 1 to 3;
each R d , independently, is H, halo, hydroxy, alkyl, haloalkyl, alkenyl, alkoxy, cycloalkyl, —C(O)NR f R g , —NR f R g , —NR f C(O)R g , or —SO 2 NR f R g ;
each R e , independently, is H, halo, hydroxy, alkyl, haloalkyl, alkenyl, alkoxy, or cycloalkyl, —C(O)NR f R g , —NR f R g , —NR f C(O)R g , or —SO 2 NR f R g ;
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 to ether are C 2 -C 5 alkylene optionally interrupted by 1 or 2 oxygen atoms, or C 2 -C 5 alkenylene optionally interrupted by 1 or 2 oxygen atoms;
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 optionally interrupted by 1 or 2 oxygen atoms, or C 2 -C 5 alkenylene optionally interrupted by 1 or 2 oxygen atoms;
wherein R 1a , R 1b , R 2a , 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 ;
or a pharmaceutically acceptable salt or prodrug thereof.