Modulators of sphingosine phosphate receptors
Compounds that activate a sphingosine-1-phosphate receptor of the subtype 1 are provided. Certain compounds selectively activate the receptor subtype 1 in relation to the sphinogosine-1-phosphate receptor subtype 3. Uses and methods of inventive compounds for treatment of malconditions wherein activation, agonism, inhibition or antagonism of the S1P1 is medically indicated are provided.
1. A compound of formula (I) or a pharmaceutically acceptable salt, tautomer, or stereoisomer, thereof:
wherein
a dashed line signifies that a single bond or a double bond can be present, provided that there are two double bonds and three single bonds in the ring comprising A 1 , A 2 , and A 3 ;
A 1 and A 3 are N and A 2 is O;
L 1 and L 2 are each independently a bond; or (CHR′) n wherein R′ is H or (C 1 -C 6 )alkyl and n is 1, 2, or 3;
J independently at each occurrence is F, Cl, Br, I, OR′, OC(O)N(R′) 2 , CN, CF 3 , OCF 3 , CHF 2 , NO 2 , methylenedioxy, ethylenedioxy, N(R′) 2 , N(R′)CH 2 CH 2 OR′, SR′, SOR′, SO 2 R′, SO 2 N(R′) 2 , SO 3 R′, C(O)R′, C(O)C(O)R′, C(O)CH 2 C(O)R′, C(S)R′, C(O)OR′, OC(O)R′, OC(O)OR′, C(O)N(R′) 2 , OC(O)N(R′) 2 , C(S)N(R′) 2 , (CH 2 ) 0-2 NHC(O)R′, (CH 2 ) 0-2 N(R′) 2 , (CH 2 ) 0-2 N(R′)N(R′) 2 , N(R′)N(R′)C(O)R′, N(R′)N(R′)C(O)OR′, N(R′)N(R′)CON(R′) 2 , N(R′)SO 2 R′, N(R′)SO 2 N(R′) 2 , N(R′)C(O)OR′, N(R′)C(O)R′, N(R′)N(R′), N(R′)C(S)R′, N(R′)C(O)N(R′) 2 , N(R′)C(S)N(R′) 2 , N(COR′)COR′, N(OR′)R′, C(═NH)N(R′) 2 , C(O)N(OR′)R′, or C(═NOR′)R′, wherein two J groups together can form a ring; wherein R′ is independently at each occurrence hydrogen or an alkyl, cycloalkyl, aryl, heterocyclyl, or heteroaryl wherein any alkyl, cycloalkyl, aryl, heterocyclyl or heteroaryl is substituted with 0-3 J;
R 5 a group of formula a-i
substituted with 0-5 J, wherein a wavy line indicates a point of attachment;
R 6 is cycloalkyl, aryl, heterocyclyl, or heteroaryl, wherein any cycloalkyl, aryl, heterocyclyl, or heteroaryl is mono- or pluri-substituted with J.
2. The compound of claim 1 wherein L 2 is bond.
3. A compound of formula I-C further substituted with 0-5 J:
wherein J independently at each occurrence is F, Cl, Br, I, OR′, OC(O)N(R′) 2 , CN, CF 3 , OCF 3 , CHF 2 , NO 2 , methylenedioxy, ethylenedioxy, N(R′) 2 , N(R′)CH 2 CH 2 OR′, SR′, SOR′, SO 2 R′, SO 2 N(R′) 2 , SO 3 R′, C(O)R′, C(O)C(O)R′, C(O)CH 2 C(O)R′, C(S)R′, C(O)OR′, OC(O)R′, OC(O)OR′, C(O)N(R′) 2 , OC(O)N(R′) 2 , C(S)N(R′) 2 , (CH 2 ) 0-2 NHC(O)R′, (CH 2 ) 0-2 N(R′) 2 , (CH 2 ) 0-2 N(R′)N(R′) 2 , N(R′)N(R′)C(O)R′, N(R′)N(R′)C(O)OR′, N(R′)N(R′)CON(R′) 2 , N(R′)SO 2 R′, N(R′)SO 2 N(R′) 2 , N(R′)C(O)OR′, N(R′)C(O)R′, N(R′)N(R′), N(R′)C(S)R′, N(R′)C(O)N(R′) 2 , N(R′)C(S)N(R′) 2 , N(COR′)COR′, N(OR′)R′, C(═NH)N(R′) 2 , C(O)N(OR′)R′, or C(═NOR′)R′, wherein two J groups together can form a ring; wherein R′ is independently at each occurrence hydrogen or an alkyl, cycloalkyl, aryl, heterocyclyl, or heteroaryl wherein any alkyl, cycloalkyl, aryl, heterocyclyl or heteroaryl is substituted with 0-3 J.
4. A compound of formula I-D further substituted with 0-3 J, and wherein R 7 and R 8 each independently are H, OR′, OC(O)N(R′) 2 , N(R′)N(R′) 2 , N(R′)CH 2 CH 2 OR′, CN, CHF 2 , CF 3 , OCF 3 , NO 2 , N(R′) 2 , SR′, SORT, SO 2 R′, SO 2 N(R′) 2 , SO 3 R′, or C(O)R′
wherein J independently at each occurrence is F, Cl, Br, I, OR′, OC(O)N(R′) 2 , CN, CF 3 , OCF 3 , CHF 2 , NO 2 , methylenedioxy, ethylenedioxy, N(R′) 2 , N(R′)CH 2 CH 2 OR′, SR′, SORT, SO 2 R′, SO 2 N(R′) 2 , SO 3 R′, C(O)R′, C(O)C(O)R′, C(O)CH 2 C(O)R′, C(S)R′, C(O)OR′, OC(O)R′, OC(O)OR′, C(O)N(R′) 2 , OC(O)N(R′) 2 , C(S)N(R′) 2 , (CH 2 ) 0-2 NHC(O)R′, (CH 2 ) 0-2 N(R′) 2 , (CH 2 ) 0-2 N(R′)N(R′) 2 , N(R′)N(R′)C(O)R′, N(R′)N(R′)C(O)OR′, N(R′)N(R′)CON(R′) 2 , N(R′)SO 2 R′, N(R′)SO 2 N(R′) 2 , N(R′)C(O)OR′, N(R′)C(O)R′, N(R′)N(R′), N(R′)C(S)R′, N(R′)C(O)N(R′) 2 , N(R′)C(S)N(R′) 2 , N(COR′)COR′, N(ORT)R′, C(═NH)N(R′) 2 , C(O)N(ORT)R′, or C(═NOR′)R′, wherein two J groups together can form a ring; wherein R′ is independently at each occurrence hydrogen or an alkyl, cycloalkyl, aryl, heterocyclyl, or heteroaryl wherein any alkyl, cycloalkyl, aryl, heterocyclyl or heteroaryl is substituted with 0-3 J.
5. The compound according to claim 1 wherein the compound of formula (I) is of formula I-F
wherein
R 7 and R 8 are each independently selected from H, OR″, N(R″) 2 , and SR″, wherein R″ is independently at each occurrence hydrogen or an alkyl, cycloalkyl, aryl, heterocyclyl, or heteroaryl, wherein any such alkyl, cycloalkyl, aryl, heterocyclyl or heteroaryl is substituted with 0-3 J;
X is F, Cl, Br, I, CHF 2 , CN, CF 3 , NO 2 , or OR′;
Y is hydrogen or an alkyl, cycloalkyl, aryl, heterocyclyl, or heteroaryl, wherein any such alkyl, cycloalkyl, aryl, heterocyclyl or heteroaryl is substituted with 0-3 J.
6. The compound according to claim 1 , wherein the compound of formula (I) is any of:
or any pharmaceutically acceptable salt, tautomer, or stereoisomer, thereof.
7. A pharmaceutical composition comprising a compound of claim 1 and a suitable excipient.
8. A pharmaceutical combination comprising the compound of claim 1 and a medicament.
9. The combination of claim 8 wherein the medicament is medically indicated for alleviation of symptoms of multiple sclerosis, transplant rejection, or adult respiratory distress syndrome.