Novel modulators of sphingosine phosphate receptors

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.

1 . A compound of formula (I) or a pharmaceutically acceptable salt, prodrug, tautomer, stereoisomer, hydrate, or solvate 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 , A 2 , and A 3  each independently is C or O or is N when the N is bonded to two adjacent ring atoms by a double bond and a single bond or is NR wherein R is H or (C 1 -C 6 )alkyl when the N is bonded to two adjacent ring atoms by two single bonds; provided that no more than one of A 1 , A 2 , and A 3  is C and that at least one of A 1 , A 2 , and A 3  is N or NR; provided that only one of A 1 , A 2 , and A 3  is O; 
         L 1  and L 2  are each independently a bond; (CHR′) n  wherein R′ is H or (C 1 -C 6 )alkyl and n is 1, 2, or 3; or a heteroaryl selected from the group consisting of thiophenyl, phenyl, furanyl, or benzothiophenyl and wherein such heteroaryl is substituted with 0-3 J; 
         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 , R′, O, S, C(O), S(O), 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; or wherein two R′ groups together with a nitrogen atom or with two adjacent nitrogen atoms to which they are bonded can together form a (C 3 -C 8 )heterocyclyl substituted with 0-3 J; optionally further comprising 1-3 additional heteroatoms selected from the group consisting of O, N, S, S(O) and S(O) 2 ; 
         R 5  is a mono- or bicyclic cycloalkyl, aryl, heterocyclyl, or heteroaryl; each of which is substituted with 0-5 J, wherein any cycloalkyl, aryl, heterocyclyl, or heteroaryl can be fused, bridged, or in a spiro configuration with one or more additional cycloalkyl, aryl, heterocyclyl, heteroaryl rings, any of which can be monocyclic, bicyclic or polycyclic, saturated, partially unsaturated, or aromatic, and any of which is substituted with 0-5 J; 
         R 6  is cycloalkyl, aryl, heterocyclyl, or heteroaryl, wherein any cycloalkyl, aryl, heterocyclyl, or heteroaryl is independently mono- or pluri-substituted with J, (C 1 -C 6 )alkyl, (C 2 -C 6 )alkenyl, (C 2 -C 6 )alkynyl, (C 1 -C 6 )haloalkyl, hydroxyl, halo, (C 1 -C 6 )haloalkoxy, cycloalkyl(C 1 -C 6 )alkyl, heterocyclyl(C 1 -C 6 ) alkyl, aryl(C 1 -C 6 )alkyl, heteroaryl(C 1 -C 6 )alkyl, OR 3  wherein R 3  comprises H or (C 1 -C 6 )alkyl or NR 4   2  wherein each R 4  independently comprises H or (C 1 -C 6 )alkyl or where two R 4  groups together with a nitrogen atom to which they are bonded form a (C 3 -C 8 )heterocyclyl which optionally further comprises 1-3 heteroatoms selected from the group consisting of N, O, S, S(O) and S(O) 2 ; or R 4  is optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted heterocyclyl, or optionally substituted heteroaryl; 
         wherein R 5  or R 6  is a heteroaryl or heterocyclyl ring; 
         wherein any alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, haloalkoxy, R 3 , R 4 , cycloalkyl, aryl, heterocyclyl, or heteroaryl can be further substituted with J; 
         and 
         provided that (i), (ii), (iii) or (iv) applies: 
         (i) L 1  is bond or (CHR′) n  and R 5  is a bicyclic ring moiety which is optionally substituted with 0-5 J where the bicyclic ring moiety is any one of a-i to a-xxviii wherein a wavy line indicates a point of attachment: 
       
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         provided that when R 5  is either a-xvii or a-xix that L 2  is bond or (CHR′) n ; 
         (ii) L 1  and L 2  are each independently a bond or (CHR′) n ; R 5  is a 6-membered heteroaryl ring moiety optionally substituted with 0-3 J 1 , wherein J 1  is OR′, CF 3 , Cl, Br, F, CN, O(C 1 -C 6 )alkoxy, O(C 1 -C 6 )cycloalkoxy, alkyl, or N(R′) 2  and wherein the 6-membered heteroaryl ring moiety is any one of b-i to b-xiii wherein a wavy line indicates a point of attachment: 
       
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         (iii) L 1  is a bond or (CHR′) n , and L 2  is a heteroaryl substituted with 0-3 J wherein the heteroaryl is c-i or c-ii wherein a wavy line indicates a point of attachment: 
       
       
         
           
           
               
               
           
         
         or 
         (iv) L 1  is a bond or (CHR′) n  and L 2  is a bond or (CHR′) n  or a phenyl substituted with 0-5 J; and R 5  and R 6  are independently selected from phenyl or heteroaryl each optionally substituted with 0-5 occurrences of J; provided that if L 2  is a bond and R 5  and R 6  are both phenyl, then R 5  is substituted with at least one of 4-CN, 3-alkyl-NHR′, 3-alkyl-OR′, 4-alkyl-OR′, or 2,3-dialkyl and R 6  is substituted with at least 4-OR′; 
         provided, that when (ii), (iii), or (iv) applies, that the compound of formula (I) is not one of the following: 
       
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
     
     
         2 - 12 . (canceled) 
     
     
         13 . The compound of  claim 1  wherein L 1  is bond and R 5  is a bicyclic ring moiety which is substituted with 0-5 J where the bicyclic ring moiety is any one of a-i to a-xxviii, wherein a wavy line indicates a point of attachment: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         wherein any of the bicyclic ring moieties is substituted with 0-5 J. 
       
     
     
         14 . The compound of  claim 1  wherein L 1  and L 2  are each a bond; R 5  is a 6-membered heteroaryl ring moiety substituted with 0-3 occurrences of J 1 ; wherein J 1  is selected from the group consisting of OR′, CF 3 , Cl, Br, F, CN, O(C 1 -C 6 )alkoxy, O(C 1 -C 6 )cycloalkoxy, alkyl, N(R′) 2 ; and wherein the optionally substituted 6-membered heteroaryl ring moiety of R 5  is any one of b-i to b-xiii: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         wherein each of the 6-membered heteroaryl ring moieties is substituted with 0-3 J 1 . 
       
     
     
         15 . The compound of  claim 1  wherein L 1  is a bond, and L 2  is c-i or c-ii, wherein a wavy line indicates a point of attachment: 
       
         
           
           
               
               
           
         
       
       wherein c-i and c-ii are further substituted with 0-2 J. 
     
     
         16 . The compound of  claim 1  wherein L 1  is a bond and L 2  is a bond or is phenyl substituted with 0-5 J; and R 5  and R 6  are independently selected from phenyl or heteroaryl each substituted with 0-5 J. 
     
     
         17 . The compound according to  claim 13  wherein the optionally substituted bicyclic ring moiety is any one of a-i to a-viii, 
       
         
           
           
               
               
           
         
       
       wherein any of the bicyclic ring moieties is substituted with 0-5 J. 
     
     
         18 . A compound according to  claim 17  having the formula I-B further substituted with 0-5 J: 
       
         
           
           
               
               
           
         
       
     
     
         19 .- 22 . (canceled) 
     
     
         23 . The compound according to  claim 13  wherein the bicyclic ring moiety is any one of a-ix to a-xv: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
       wherein any of the bicyclic ring moieties is substituted with 0-5 J. 
     
     
         24 . The compound according to  claim 23 , wherein the compound is any of: 
       
         
           
           
               
               
           
         
       
       or any pharmaceutically acceptable salt, tautomer, stereoisomer, solvate, hydrate, or prodrug thereof. 
     
     
         25 . The compound according to  claim 13  wherein the optionally substituted bicyclic ring moiety is any one of a-xvi to a-xxv: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
       wherein any of the bicyclic ring moieties is substituted with 0-5 J. 
     
     
         26 . The compound according to  claim 25 , wherein the compound is any of: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
       or any pharmaceutically acceptable salt, tautomer, stereoisomer, solvate, hydrate, or prodrug thereof. 
     
     
         27 . The compound according to  claim 14  where the optionally substituted 6-membered heteroaryl ring moiety of R 5  is any one of b-i to b-v, 
       
         
           
           
               
               
           
         
       
       wherein any of the 6-membered heteroaryl ring moieties is substituted with 0-3 J 1 . 
     
     
         28 . The compound according to  claim 27 , wherein the compound is any of: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
       or any pharmaceutically acceptable salt, tautomer, stereoisomer, solvate, hydrate, or prodrug thereof. 
     
     
         29 . The compound according to  claim 15 , wherein the compound is any of: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
       or any pharmaceutically acceptable salt, tautomer, stereoisomer, solvate, hydrate, or prodrug thereof. 
     
     
         30 . The compound according to  claim 1 , wherein the compound is any of: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
       or any pharmaceutically acceptable salt, tautomer, stereoisomer, solvate, hydrate, or prodrug thereof. 
     
     
         31 . The compound of  claim 30 , wherein the compound is any of the following: 
       or any pharmaceutically acceptable salt, tautomer, stereoisomer, solvate, hydrate, or prodrug thereof. 
     
     
         32 . The compound of  claim 30 , wherein the compound is any of: 
       
         
           
           
               
               
           
         
       
       or any pharmaceutically acceptable salt, tautomer, stereoisomer, solvate, hydrate, or prodrug thereof. 
     
     
         33 .- 65 . (canceled)