Modulators of sphingosine phosphate receptors
AssigneeThe Scripps Research Institute
InventorsEdward Roberts, Hugh Rosen, Steven Brown, Miguel A. Guerrero, Xuemei Peng, Ramulu Poddutoori
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Abstract
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.
Claims9
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 A1, A2, and A3;
- A1 and A3 are N and A2 is O;
- L1 and L2 are each independently a bond;
- or (CHR′)n wherein R′ is H or (C1-C6)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, CF3, OCF3, CHF2, NO2, methylenedioxy, ethylenedioxy, N(R′)2, N(R′)CH2CH2OR′, SR′, SOR′, SO2R′, SO2N(R′)2, SO3R′, C(O)R′, C(O)C(O)R′, C(O)CH2C(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, (CH2)0-2NHC(O)R′, (CH2)0-2N(R′)2, (CH2)0-2N(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′)SO2R′, N(R′)SO2N(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;
- R5 a group of formula a-i
- substituted with 0-5 J, wherein a wavy line indicates a point of attachment;
- R6 is cycloalkyl, aryl, heterocyclyl, or heteroaryl, wherein any cycloalkyl, aryl, heterocyclyl, or heteroaryl is mono- or pluri-substituted with J.
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, CF3, OCF3, CHF2, NO2, methylenedioxy, ethylenedioxy, N(R′)2, N(R′)CH2CH2OR′, SR′, SOR′, SO2R′, SO2N(R′)2, SO3R′, C(O)R′, C(O)C(O)R′, C(O)CH2C(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, (CH2)0-2NHC(O)R′, (CH2)0-2N(R′)2, (CH2)0-2N(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′)SO2R′, N(R′)SO2N(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.
A compound of formula I-D further substituted with 0-3 J, and wherein R7 and R8 each independently are H, OR′, OC(O)N(R′)2, N(R′)N(R′)2, N(R′)CH2CH2OR′, CN, CHF2, CF3, OCF3, NO2, N(R′)2, SR′, SORT, SO2R′, SO2N(R′)2, SO3R′, or C(O)R′
- wherein J independently at each occurrence is F, Cl, Br, I, OR′, OC(O)N(R′)2, CN, CF3, OCF3, CHF2, NO2, methylenedioxy, ethylenedioxy, N(R′)2, N(R′)CH2CH2OR′, SR′, SORT, SO2R′, SO2N(R′)2, SO3R′, C(O)R′, C(O)C(O)R′, C(O)CH2C(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, (CH2)0-2NHC(O)R′, (CH2)0-2N(R′)2, (CH2)0-2N(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′)SO2R′, N(R′)SO2N(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.
Dependencies are inferred from the claim text.