S1P Receptor Modulating Compounds and Use Thereof

Abstract

The present invention relates to amides that have activity as S1P receptor modulating agents and the use of such compounds to treat diseases associated with inappropriate S1P receptor activity. The compounds may be used as immunomodulators, e.g., for treating or preventing diseases such as autoimmune and related immune disorders including systemic lupus erythematosus, inflammatory bowel diseases such as Crohn's disease and ulcerative colitis, type I diabetes, uveitis, psoriasis, myasthenia gravis, rheumatoid arthritis, non-glomerular nephrosis, hepatitis, Behçet's disease, glomerulonephritis, chronic thrombocytopenic purpura, hemolytic anemia, hepatitis and Wegner's granuloma; and for treating other conditions.

1 . A compound having the formula 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically-acceptable salt thereof, wherein:
 A is phenyl or a six-membered heteroaryl containing 1 or 2 N atoms, the phenyl and heteroaryl being substituted with 0, 1, 2, or 3 substituents selected from F, Cl, Br, OC 1-4 alk, C 1-4 alk, and C 1-4 haloalk; 
 B is phenyl or a six-membered heteroaryl containing 1 or 2 N atoms, the phenyl and heteroaryl being substituted with 0, 1, 2, or 3 substituents selected from F, Cl, Br, OC 1-4 alk, C 1-4 alk, and C 1-4 haloalk; 
 wherein at least one of A and B is a six-membered heteroaryl containing 1 or 2 N atoms and substituted with 0, 1, 2, or 3 substituents selected from F, Cl, Br, OC 1-4 alk C 1-4 alk, and C 1-4 haloalk; 
 L is —C≡C—, —CH 2 CH 2 —, —N(R a )C(═O)—, or —C(═O)N(R a )—; 
 R a  is, independently in each instance, H or C 1-6 alk; 
 R 1  is selected from C 1-6 alk, OC 1-5 alk, N(R a )C 1-5 alk, N(C 1-5 alk)C 1-5 alk, aryl, and heteroaryl; 
 X is selected from WC(═O)OR 6a , WP(═O)R 6b R 6c , WS(O) 2 OH, WCONHSO 3 H, and 1H-tetrazol-5-yl; 
 W is a direct bond, oxygen, or C 1-4 alk having one or more substituents independently selected from halogen, OH, cyano, NR a R a , arylamino, heteroarylamino, OC 1-4 alk, and CO 2 H; 
 R 6a  is hydrogen or C 1-4 alk; 
 R 6b  and R 6c  are independently hydrogen, OH, C 1-4 alk, or C 1-4 haloalk; 
 Y is residue of formula (a) wherein the left and right asterisks indicate the point of attachment 
 
       
         
           
           
               
               
           
         
       
       wherein the N, designated by the left asterisk, is attached to Z 1 , and the carbon, designated by the right asterisk, is attached to X, wherein
 Q is selected from a direct bond, C═O, C═S, SO 2 , C═ONR a , and (CR 10 R 11 ) m ; 
 m is 0, 1, 2, or 3; 
 R 7  and R 8  are independently selected from hydrogen, halogen, amino, C 1-5 alkamino, OH, cyano, C 1-6 alk, C 1-6 alk(OH), SC 1-5 alk, OC 1-5 alk, C 1-6 haloalk, and OC 1-5 alk; or R 7  and R 8  may be joined together with the atoms to which they are attached atoll form a 4- to 7-membered ring optionally containing an additional heteroatom selected from N, O, and S; 
 R 9  is selected from hydrogen, halogen, OH, cyano, C 1-6 alk, SC 1-5 alk, OC 1-5 alk, C 1-6 haloalk, and OC 1-5 haloalk; 
 R 10  and R 11  are independently selected from hydrogen, halogen, OH, cyano, C 1-6 alk, OC 1-5 alk, SC 1-5 alk, C 1-6 haloalk, and OC 1-5 haloalk; 
 Z 1  and Z 2  are independently selected from O, NR 3 , S, S(═O), S(═O) 2 , S(═O) 2 NR 3 , (CR 4 R 5 ) n , C═O, C═S, C═N—R 3 , and a direct bond, wherein n is 0, 1, 2, or 3; 
 R 3  is selected from hydrogen, OH, SO 2 , C═O, C═S, C═NH, C 1-6 alk, OC 1-5 alk, SC 1-5 alk, C 1-6 haloalk, OC 1-5 haloalk, aryl, and heteroaryl; or when Z 2  is a direct bond, R 3  is a C 3 -C 6  ring optionally containing a heteroatom; and 
 R 4  and R 5  are independently selected from hydrogen, halogen, OH, cyano, C 1-6 alk, OC 1-5 alk, SC 1-5 alk, C 1-6 haloalk, OC 1-5 haloalk, aryl, and heteroaryl, or R 4  and R 5  taken together with the carbon atom to which they are attached form C═O. 
 
     
     
         2 . A compound according to  claim 1 , wherein A is phenyl additionally substituted by 0, 1, 2, or 3 substituents selected from F, Cl, Br, OC 1-4 alk, C 1-4 alk, and C 1-4 haloalk. 
     
     
         3 . A compound according to  claim 1 , wherein B is phenyl additionally substituted by 0, 1, 2, or 3 substituents selected from F, Cl, Br, OC 1-4 alk, C 1-4 alk, and C 1-4 haloalk. 
     
     
         4 . (canceled) 
     
     
         5 . A compound according to  claim 1 , wherein L is —N(R a )C(═O)—. 
     
     
         6 . A compound according to  claim 1 , wherein L is —C(═O)N(R a )—. 
     
     
         7 . A compound according to  claim 1 , wherein —Y—X is 
       
         
           
           
               
               
           
         
       
     
     
         8 . A compound having the formula 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically-acceptable salt thereof, wherein:
 A is phenyl or a six-membered heteroaryl containing 1 or 2 N atoms, the phenyl and heteroaryl being substituted with 0, 1, 2, or 3 substituents selected from F, Cl, Br, OC 1-4 alk, C 1-4 alk, and C 1-4 haloalk; 
 B is phenyl or a six-membered heteroaryl containing 1 or 2 N atoms, the phenyl and heteroaryl being substituted with 0, 1, 2, or 3 substituents selected from F, Cl, Br, OC 1-4 alk, C 1-4 alk, and C 1-4 haloalk; 
 wherein at least one of A and B is a six-membered heteroaryl containing 1 or 2 N atoms and substituted with 0, 1, 2, or 3 substituents selected from F, Cl, Br, OC 1-4 alk C 1-4 alk, and C 1-4 haloalk; 
 L is —N(R a )C(═O)— or —C(═O)N(R a )—; 
 n is 0, 1, 2, or 3; 
 R a  is, independently in each instance, H or C 1-6 alk; 
 R 1  is selected from C 1-6 alk, OC 1-5 alk, N(R a )C 1-5 alk, N(C 1-5 alk)C 1-5 alk, aryl, and heteroaryl; 
 Z 2  is selected from O, NR 3 , S, S(═O), S(═O) 2 , S(═O) 2 NR 3 , (CR 4 R 5 ) n , C═O, C═S, C═N—R 3 , and a direct bond; wherein 
 R 3  is selected from hydrogen, OH, SO 2 , C═O, C═S, C═NH, C 1-6 alk, OC 1-5 alk, SC 1-5 alk, C 1-6 haloalk, OC 1-5 haloalk, aryl, and heteroaryl; or when Z 2  is a direct bond, R 3  is a C 3 -C 6  ring optionally containing a heteroatom; and 
 R 4  and R 5  are independently selected from hydrogen, halogen, OH, cyano, C 1-6 alk, OC 1-5 alk, SC 1-5 alk, C 1-6 haloalk, OC 1-5 haloalk, aryl, and heteroaryl, or R 4  and R 5  taken together with the carbon atom to which they are attached form C═O. 
 
     
     
         9 . A pharmaceutical composition comprising a compound according to  claim 1  and a pharmaceutically acceptable carrier or diluent. 
     
     
         10 . A method of treating a condition selected from transplant rejection related to solid organ transplant and islet cells; transplant rejection related to tissue; rheumatoid arthritis; lupus; insulin dependent diabetes; non-insulin dependent diabetes; multiple sclerosis; psoriasis; ulcerative colitis; inflammatory bowel disease; Crohn's disease; and acute and chronic lymphocytic leukemias and lymphomas, wherein treating is lessening or or reducing the symptoms of the condition, comprising administering to a patient in need thereof a compound according to  claim 1  in an amount effective to treat the condition. 
     
     
         11 . A compound according to  claim 1  that is
 Methyl 1-(4-(2-(5-benzylpyridin-2-yl)ethynyl)-3-fluorobenzyl)azetidine-3-carboxylate; 
 1-(4-(2-(5-benzylpyridin-2-yl)ethynyl)-3-fluorobenzyl)azetidine-3-carboxylic acid; or 
 1-(4-(2-(5-benzylpyridin-2-yl)ethyl)-3-fluorobenzyl)azetidine-3-carboxylic acid.