Heterocyclic compounds

Abstract

Heterocyclic compounds and methods of making them and using them.

1 - 40 . (canceled)  
     
     
         41 . A compound of formula (I)  
       
         
           
           
               
               
           
         
       
       wherein 
 R 1  is R a , R a R b —, R a —O—R b —, or (R c )(R d )N—R b —, where R a  is H, cyano, —(C═O)N(R c )(R d ), —C(═NH)(NH 2 ), C 1-10 alkyl, C 3-8 alkenyl, C 3-8 cycloalkyl, C 2-5 heterocyclic radical, where R b  is C 1-8 alkylene, C 2-8 alkenylene, C 3-8 cycloalkylene, bivalent C 3-8 heterocyclic radical, or phenylene; and R c  and R d  are each independently H, C 1-8 alkyl, C 2-8 alkenyl, C 3-8 cycloalkyl, or phenyl;  
 R 2′  is H, methyl, ethyl, NR p R q , —(CO)NR p R q , —(CO)OR r , —CH 2 NR p R q , or CH 2 OR r ; where R p , R q , and R r  are independently selected from C 1-6 alkyl, C 3-6 cycloalkyl, phenyl; (C 3-6 cycloalkyl)(C 1-2 alkylene), benzyl or phenethyl; or R p  and R q  taken together with the nitrogen to which they are attached, form a 4-7 membered heterocyclic ring with 0 or 1 additional heteroatoms selected from O, S, and N;  
 R 3′  is H, methyl, ethyl, NR s R t , —(CO)NR s R t , —(CO)OR u , —CH 2 NR s R t , or CH 2 OR u ; where R s , R t , and R u  are independently selected from C 1-6 alkyl, C 3-6 cycloalkyl, phenyl; (C 3-6 cycloalkyl)(C 1-2 alkylene), benzyl or phenethyl; or R s  and R t  taken together with the nitrogen to which they are attached, form a 4-7 membered heterocyclic ring with 0 or 1 additional heteroatoms selected from O, S, and N;  
 R 5′  is methyl, ethyl, or H;  
 R 6′  is methyl, ethyl, or H;  
 R 7′  is methyl, ethyl, or H;  
 X 4  is NR 1  or S;  
 X 1  is CR 3 ;  
 R 3  is F, Cl, Br, CHO, R f , R f R g —, R f —O—R g —, or (R h )(R i )N—R g —, where R f  is H, C 1-6 alkyl, C 2-6 alkenyl, C 3-6 Cycloalkyl, C 2-5 heterocyclic radical, or phenyl; where R g  is C 1-6 alkylene, C 2-6 alkenylene, C 3-6 cycloalkylene, bivalent C 3-6 heterocyclic radical, or phenylene; and R h  and R i  are each independently H, C 1-6 alkyl, C 2-6 alkenyl, C 3-6 cycloalkyl, or phenyl;  
 X 2  is NR e  or O, provided that X 2  is NR e  where X 1  is N; R e  is H or C 1-6 alkyl;  
 X 3  is N;  
 Z is ═O or ═S;  
 each of R 4  and R 6  is independently H, F, Cl, Br, I, COOH, OH, nitro, amino, cyano, C 1-4 alkoxy, or C 1-4 alkyl;  
 R 5  is H, F, Cl, Br, I, (C═O)R j , OH, nitro, NR j R k , cyano, phenyl, —OCH 2 —Ph, C 1-4 alkoxy, or C 1-4 alkyl;  
 R 7  is H, F, Cl, Br, I, (C═O)R m , OH, nitro, NR l R m , cyano, phenyl, —OCH 2 —Ph C 1-4 alkoxy, or C 1-4 alkyl;  
 wherein each of R j , R k , R l , and R m  is independently selected from H, C 1-6 alkyl, hydroxy, phenyl, benzyl, phenethyl, and C 1-6 alkoxy;  
 each of the above hydrocarbyl (including alkyl, alkoxy, phenyl, benzyl, cycloalkyl, and so on) or heterocyclic groups being independently and optionally substituted with between 1 and 3 substituents selected from C 1-3 alkyl, halo, hydroxy, amino, and C 1-3 alkoxy;  
 wherein n is 0, 1, or 2; where n is 2, the moiety —(CHR 5′ ) n=2 — is —(CHR 5′ —CHR 7′ )— where CHR 5′  is between CHR 6′  and CHR 7′ ;  
 provided at least one of R 1 , R 2′ , R 3 , R 4 , R 5 , R 6 , and R 7  is other than H when Z is O;  
 and provided, where Z is O, n=1, and each of R 4 , R 5 , R 6 , R 7 , R 2′ , R 3′ , R 5′ , and R 6′  is H, then (a) where X 2  is NH, then R 1  is (i) not methyl, pyridyl, phenyl, or benzyl, and (b) where X 2  is O, then R 1  is not methyl;  
 and provided, where Z is O, X 2  is NH, n=1, R 1  is methyl, each of R 4 , R 6 , R 7 , R 2′ , R 3′ , R 5′ , and R 6′  is H, then R 5  is not methoxy;  
 or a pharmaceutically acceptable salt, ester, or amide thereof.  
 
     
     
         42 . A compound of  claim 41  of the formula  
       
         
           
           
               
               
           
         
       
       wherein 
 R 1  is R a , R a R b —, R a —O—R b —, or (R c )(R d )N—R b —, where R a  is H, C 1-10 alkyl, C 3-8  alkenyl, C 3-8 cycloalkyl, C 2-5 heterocyclic radical, or phenyl; where R b  is C 1-8 alkylene, C 3-8 alkenylene, C 3-8 cycloalkylene, bivalent C 3-8  heterocyclic radical, or phenylene; and R c  and R d  are each independently H, C 1-8 alkyl, C 2-8 alkenyl, C 3-8 cycloalkyl, or phenyl;  
 R 2  is ortho or meta, and is methyl or H;  
 X 1  is CR 3 ;  
 R 3  is F, Cl, Br, R f , R f R g —, R f —O—R g—, or (R   h )(R i )N—R g —, where R f  is H, C 1-6 alkyl, C 2-6 alkenyl, C 3-6 cycloalkyl, C 2-5 heterocyclic radical, or phenyl; where R g  is C 1-6 alkylene, C 2-6 alkenylene, C 3-6 cycloalkylene, bivalent C 3-6 heterocyclic radical, or phenylene; and R h  and R i  are each independently H, C 1-6 alkyl, C 2-6 alkenyl, C 3-6 cycloalkyl, or phenyl;  
 X 2  is NR e  or O, provided that X 2  is NR e  where X 1  is N; R e  is H or C 1-6 alkyl;  
 X 3  is N;  
 Z is ═O or ═S;  
 each of R 4  and R 6  is independently H, F, Cl, Br, I, COOH, OH, nitro, amino, cyano, C 1-4 alkoxy, or C 1-4 alkyl;  
 R 5  is H, F, Cl, Br, I, (C═O)R j , OH, nitro, NR j R k , cyano, —OCH 2 —Ph, C 1-4 alkoxy, or C 1-4 alkyl;  
 R 7  is H, F, Cl, Br, I, (C═O)R m , OH, nitro, NR l R m , cyano, C 1-4 alkoxy, or C 1-4 alkyl; wherein each of R j , R k , R l , and R m  is independently selected from H, C 1-6 alkyl, hydroxy, phenyl, benzyl, phenethyl, and C 1-6 alkoxy;  
 each of the above hydrocarbyl or heterocyclic groups being independently and optionally substituted with between 1 and 3 substituents selected from C 1-3 alkyl, halo, hydroxy, amino, and C 1-3 alkoxy;  
 provided at least one of R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , and R 7  is other than H when Z is O;  
 or a pharmaceutically acceptable salt, ester, or amide thereof.  
 
     
     
         43 . A compound of  claim 41 , wherein R 1  is R a , R a R b —, R a —O—R b —, or (R c )(R d )N—R b —, where R a  is H, C 1-10 alkyl, C 2-5 alkenyl, C 3-8  cycloalkyl, C 2-5 heterocyclic radical, or phenyl; where R b  is C 1-6 alkylene, or C 2-8 alkenylene; and R c  and R d  are each independently H, C 1-8 alkyl, C 2-8 alkenyl, C 3-8 cycloalkyl, or phenyl; 
 R 2′  is methyl or H;    R 3′  is methyl or H;    R 5′  is methyl or H;    R 6′  is methyl or H;    R 7′  is methyl or H;    X 1  is CR 3 ;    R 3  is F, Cl, Br, methyl, ethyl, or propyl;    X 2  is NR e  or O, provided that X 2  is NR e  where X 1  is N; R e  is H or C 1-6 alkyl;    X 3  is N;    Z is ═O or ═S;    each of R 4  and R 6  is independently H, F, Cl, Br, I, COOH, OH, nitro, amino, cyano, C 1-3 alkoxy, or C 1-3  alkyl;    R 5  is H, F, Cl, Br, I, (C═O)R j , OH, nitro, NR j R k , cyano, —OCH 2 —Ph, C 1-4 alkoxy, or C 1-4 alkyl;    R 7  is H, F, Cl, Br, I, (C═O)R m , OH, nitro, NR l R m , cyano, C 1-4 alkoxy, or C 1-4 alkyl; wherein each of R j , R k , R l , and R m  is independently selected from H, C 1-6 alkyl, hydroxy, phenyl, benzyl, phenethyl, and C 1-6 alkoxy;    each of the above hydrocarbyl or heterocyclic groups being independently and optionally substituted with between 1 and 3 substituents selected from C 1-3 alkyl, halo, hydroxy, amino, and C 1-3 alkoxy;    n is 1;    provided at least one of R 1 , R 2′ , R 3 , R 4 , R 5 , R 6 , and R 7  is other than H when Z is O;    or a pharmaceutically acceptable salt, ester, or amide thereof.    
     
     
         44 . A compound of  claim 41 , wherein 
 R 1  is H, methyl, or ethyl;    one of R 2′  and R 3′  is methyl, and the other is H, where R 1  is H;    R 2  is otherwise H;    X 1  is CR 3 ; R 3  is H, F, Cl, or Br;    X 2  is NR e  or O;    R e  is H or C 1-3 alkyl;    Z is ═O or ═S;    each of R 4  and R 6  is independently H, OH, C 1-4 alkyl, C 1-4 alkoxy, cyano, or amino;    R 5  is H, F, Cl, Br, COOH, OH, amino, cyano, C 1-4 alkoxy, or C 1-4 alkyl; and    R 7  is H, F, Cl, Br, C 14  alkyl, C 1-4 alkoxy, cyano, or amino; provided at least one of R 5  and R 7  is not H.    
     
     
         45 . A compound of  claim 41 , wherein 
 R 1  is H, methyl, or ethyl;    R 2′  and R 3′  are independently methyl or H;    X 1  is CR 3  or N; R 3  is H, F, or Cl;    X 2  is NR e  or O, provided that X 2  is NR e  where X 1  is N; R e  is H or C 1-6 alkyl;    Z is ═O or ═S;    each of R 4  and R 6  is H;    R 5  is H, F, Cl, Br, methyl, ethyl, or propyl; and    R 7  is H, F, Cl, Br, or C 1-4 alkyl; provided at least one of R 5  and R 7  is not H.    
     
     
         46 . A compound of  claim 41 , wherein X 2  is N.  
     
     
         47 . A compound of  claim 41 , wherein X 2  is O.  
     
     
         48 . A compound of  claim 41 , wherein R 1  is H, methyl or ethyl.  
     
     
         49 . A compound of  claim 48 , wherein R 1  is methyl.  
     
     
         50 . A compound of  claim 41 , wherein R 2′  is H.  
     
     
         51 . A compound of  claim 41 , wherein R 2′  is methyl.  
     
     
         52 . A compound of  claim 41 , wherein R 3  is H or Cl.  
     
     
         53 . A compound of  claim 52 , wherein R 3  is Cl.  
     
     
         54 . A compound of  claim 41 , wherein R 5  is F, Cl, Br, or methyl and R 7  is F, Cl, or Br.  
     
     
         55 . A compound of  claim 41 , wherein each of R 5  and R 7  is independently selected from H, F, Cl, Br, and methyl, provided at least one of R 5  and R 7  is not H.  
     
     
         56 . A compound of  claim 41 , wherein each of R 4  and R 6  is independently H, methyl, or Cl.  
     
     
         57 . A compound of  claim 41 , wherein R 3  is H or Cl; R 5  is F, Cl, Br, or methyl; and R 7  is H, F, Cl, or Br.  
     
     
         58 . A compound of  claim 57 , wherein each of R 4  and R 6  is independently H, methyl, or Cl.  
     
     
         59 . A compound of  claim 41 , wherein Z is ═S.  
     
     
         60 . A compound of  claim 41  selected from: (5-bromo-benzofuran-2-yl)-(4-methyl-piperazin-1-yl)methanone; and (1H-indol-2-yl)-(4-methyl-piperazin-1-yl)methanethione.  
     
     
         61 . A pharmaceutical composition comprising a compound of  claim 41  and a pharmaceutically acceptable carrier.  
     
     
         62 . A pharmaceutical composition comprising a compound of  claim 42  and a pharmaceutically acceptable carrier.  
     
     
         63 . A pharmaceutical composition comprising a compound of  claim 43  and a pharmaceutically acceptable carrier.  
     
     
         64 . A pharmaceutical composition of  claim 61 , comprising a compound selected from (5-bromo-benzofuran-2-yl)-(4-methyl-piperazin-1-yl)methanone; and (1H-indol-2-yl)-(4-methyl-piperazin-1-yl)methanethione.  
     
     
         65 . A packaged drug comprising (a) a pharmaceutical composition comprising a compound of  claim 41  and a pharmaceutically acceptable carrier, and (b) instructions for the administration of said composition for the treatment or prevention of an H 4 -mediated disease or condition.  
     
     
         66 . A method for treating an H 4 -mediated condition in a patient, said method comprising administering to the patient a pharmaceutically effective amount of a composition comprising a compound of  claim 41 .  
     
     
         67 . A method for treating an H 4 -mediated condition in a patient, said method comprising administering to the patient a pharmaceutically effective H 4 -inhibiting amount of a composition comprising a compound of  claim 41 .  
     
     
         68 . A method of  claim 67  wherein said compound is a compound of  claim 42 .  
     
     
         69 . A method of  claim 67 , wherein said compound is a compound of  claim 43 .  
     
     
         70 . A method of  claim 67 , wherein said compound is selected from: (5-bromo-benzofuran-2-yl)-(4-methyl-piperazin-1-yl)methanone; and (1H-indol-2-yl)-(4-methyl-piperazin-1-yl)methanethione.  
     
     
         71 . A method of  claim 67 , wherein said H 4 -mediated condition is selected from: inflammatory disorders, asthma, psoriasis, rheumatoid arthritis, ulcerative colitis, Crohn's disease, inflammatory bowel disease, multiple sclerosis, allergic disorders, autoimmune disease, lymphatic disorders, and immunodeficiency disorders.  
     
     
         72 . A method of  claim 71 , wherein said H 4 -mediated condition is an inflammatory disorder or an allergic disorder.  
     
     
         73 . A method of  claim 72 , wherein said inflammatory disorder is an inflammation-mediated condition selected from: acute inflammation, allergic inflammation, and chronic inflammation.  
     
     
         74 . A method for treating asthma in a patient, said method comprising administering to the patient a pharmaceutically effective amount of a composition comprising a compound of  claim 41 .  
     
     
         75 . A method for treating an allergic disorder in a patient, said method comprising administering to the patient a pharmaceutically effective amount of a composition comprising a compound of  claim 41.