Heterobicyclic sphingosine 1-phosphate analogs
View Patent ↗Compounds of formula (I): 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:
A l is —C(X 1 )═;
A 2 is —C(X 2 )═;
A 3 is —N═;
A 4 is —N═;
A 5 is —C(X 5 )═;
A 6 is —C(X 6 )═;
X 1 is hydrogen, halo, hydroxy, nitro, cyano, alkyl, haloalkyl, cycloalkyl, halocycloalkyl, alkoxy, haloalkoxy, cycloalkoxy, halocycloalkoxy, —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, 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, —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, —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 —;
Cy is cycloalkyl, cycloalkenyl, heterocyclyl, aryl, or heteroaryl; wherein Cy is optionally substituted by 1-6 substituents selected from the group consisting of hydrogen, halo, hydroxy, nitro, cyano, —NR f R g , alkyl, haloalkyl, cycloalkyl, cycloalkenyl, cycloalkylalkyl, cycloalkenylalkyl, heterocyclylalkyl, arylalkyl, heteroarylalkyl, alkoxy, haloalkoxy, cycloalkylalkoxy, cycloalkenylalkoxy, heterocyclylalkoxy, aryloxy, arylalkoxy, heteroaryloxy, heteroarylalkoxy, thioalkyl, alkenyl, alkynyl, cycloalkenyl, heterocyclyl, aryl, and heteroaryl;
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, 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, 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, or p-tolylsulfonyl;
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, 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, alkylsulfonyl, alkylaminosulfonyl, and dialkylaminosulfonyl;
or a pharmaceutically acceptable salt or prodrug thereof.
2. The compound of claim 1 , wherein W is —O—, or a pharmaceutically acceptable salt or prodrug thereof.
3. The compound of claim 1 , wherein R a and R b , independently, are each H or alkyl, or a pharmaceutically acceptable salt or prodrug thereof.
4. The compound of claim 1 , wherein Y is —OR f , or a pharmaceutically acceptable salt or prodrug thereof.
5. The compound of claim 1 , wherein Y is —OH or —O—P(O)(OR f )OR g , or a pharmaceutically acceptable salt or prodrug thereof.
6. The compound of claim 1 , wherein X 6 is H, halo, alkyl, cycloalkyl, or haloalkyl, or a pharmaceutically acceptable salt or prodrug thereof.
7. The compound of claim 1 , wherein 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, thioalkyl, alkenyl, alkynyl, cycloalkenyl, heterocyclyl, aryl, or heteroaryl;
or R 1a and R 1b , when taken together, are C 2 -C 5 alkylene optionally terminated by or interrupted by 1 or 2 oxygen atoms, or C 2 -C 5 alkenylene optionally terminated by or 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, 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 or interrupted by 1 or 2 oxygen atoms, or C 2 -C 5 alkenylene optionally terminated by or interrupted by 1 or 2 oxygen atoms;
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 , or a pharmaceutically acceptable salt or prodrug thereof.
8. The compound of claim 7 , wherein R 1a and R 2a are both hydrogen, or a pharmaceutically acceptable salt or prodrug thereof.
9. The compound of claim 7 , wherein Z 1 is —CH 2 CH 2 —, or a pharmaceutically acceptable salt or prodrug thereof.
10. The compound of claim 9 , wherein Z 2 is —CH 2 —, or a pharmaceutically acceptable salt or prodrug thereof.
11. The compound of claim 10 , wherein Z 3 is a bond, or a pharmaceutically acceptable salt or prodrug thereof.
12. The compound of claim 7 , 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, or a pharmaceutically acceptable salt or prodrug thereof.
13. A compound of formula (IV):
A 3 is —N═, A 4 is —N═, A 5 is —C(X 5 )═, and A 6 is —C(X 6 )═;
X 1 is hydrogen, halo, hydroxy, nitro, cyano, alkyl, haloalkyl, cycloalkyl, halocycloalkyl, alkoxy, haloalkoxy, cycloalkoxy, halocycloalkoxy, —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, 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, —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, —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 —;
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, or p-tolylsulfonyl;
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, 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, alkylsulfonyl, alkylaminosulfonyl, and dialkylaminosulfonyl;
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, thioalkyl, alkenyl, alkynyl, cycloalkenyl, heterocyclyl, aryl, or heteroaryl;
or R 1a and R 1b , when taken together, are C 2 -C 5 alkylene optionally terminated by or interrupted by 1 or 2 oxygen atoms, or C 2 -C 5 alkenylene optionally terminated by or interrupted by 1 or 2 oxygen atoms;
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 —;
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.
14. The compound of claim 13 , wherein Y is —OR f , or a pharmaceutically acceptable salt or prodrug thereof.
15. The compound of claim 13 , wherein Y is —OH or —O—P(O)(OR f )OR g , or a pharmaceutically acceptable salt or prodrug thereof.
16. The compound of claim 13 , wherein X 6 is H, halo, alkyl, cycloalkyl, or haloalkyl, or a pharmaceutically acceptable salt or prodrug thereof.
17. The compound of claim 13 , wherein Z 1 is —CH 2 CH 2 —, or a pharmaceutically acceptable salt or prodrug thereof.
18. The compound of claim 17 , wherein Z 2 is —CH 2 CH 2 —, or a pharmaceutically acceptable salt or prodrug thereof.
19. The compound of claim 18 , wherein R 1a is hydrogen, halo, hydroxy, alkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, arylalkyl, alkoxy, cycloalkylalkoxy, arylalkoxy, or aryl, or a pharmaceutically acceptable salt or prodrug thereof.
20. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a compound of formula (I):
wherein:
A l is —C(X 1 )═;
A 2 is —C(X 2 )═;
A 3 is —N═;
A 4 is —N═;
A 5 is —C(X 5 )═;
A 6 is —C(X 6 )═;
X 1 is hydrogen, halo, hydroxy, nitro, cyano, alkyl, haloalkyl, cycloalkyl, halocycloalkyl, alkoxy, haloalkoxy, cycloalkoxy, halocycloalkoxy, , —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, —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, —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, —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 —;
Cy is cycloalkyl, cycloalkenyl, heterocyclyl, aryl, or heteroaryl; wherein Cy is optionally substituted by 1-6 substituents selected from the group consisting of hydrogen, halo, hydroxy, nitro, cyano, —NR f R g , alkyl, haloalkyl, cycloalkyl, cycloalkenyl, cycloalkylalkyl, cycloalkenylalkyl, heterocyclylalkyl, arylalkyl, heteroarylalkyl, alkoxy, haloalkoxy, cycloalkylalkoxy, cycloalkenylalkoxy, heterocyclylalkoxy, aryloxy, arylalkoxy, heteroaryloxy, heteroarylalkoxy, thioalkyl, alkenyl, alkynyl, cycloalkenyl, heterocyclyl, aryl, and heteroaryl;
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, 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, 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, or p-tolylsulfonyl;
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, 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, alkylsulfonyl, alkylaminosulfonyl, and dialkylaminosulfonyl;
or a pharmaceutically acceptable salt or prodrug thereof.
21. The compound (R)-2-amino-2-(6-(trans-4-tert-butylcyclohexyloxy)-5-(trifluoromethyl)quinazoline-2-yl)propan-1-ol, or a pharmaceutically acceptable salt or prodrug thereof.