STAT modulators

Abstract

The present invention provides compounds, compositions and methods for the inhibition or treatment of conditions or disorders modulated by the STAT transcription factors, particularly STAT4 and STAT6. Additionally, the compounds are useful for the diagnosis of conditions dependent on STAT signaling.

1 - 64 . (canceled)  
     
     
         65 . A method for modulating a STAT6-dependent condition in a host, comprising administering to said host a STAT6-modulating amount of a compound of the formula:  
       
         
           
           
               
               
           
         
       
       wherein 
 R 1  and R 2  are each members independently selected from the group consisting of hydrogen, (C 1 -C 8 )alkyl, (C 1 -C 8 )heteroalkyl, aryl, heteroaryl, aryl(C 1 -C 8 )alkyl, aryl(C 1 -C 8 )heteroalkyl, heteroaryl(C 1 -C 8 )alkyl, and heteroaryl(C 1 -C 8 )heteroalkyl, with the proviso that at least one of R 1  and R 2  is selected from the group consisting of aryl, heteroaryl, aryl(C 1 -C 8 )alkyl, aryl(C 1 -C 8 )heteroalkyl, heteroaryl(C 1 -C 8 )alkyl and heteroaryl(C 1 -C 8 )heteroalkyl;  
 A 1  is a member selected from the group consisting of L-α-amino acid fragments, D-α-amino acid fragments and fragments having the formula:  
                     
 wherein  
 R 3  is selected from the group consisting of hydrogen and (C 1 -C 4 ) alkyl;  
 R 4  and R 5  are each members independently selected from the group  
 consisting of hydrogen, (C 1 -C 8 )alkyl and (C 1 -C 8 )heteroalkyl, or can be individually combined with R 3  to form a 5-, 6-, 7- or 8-membered ring containing from one to three heteroatoms;  
 A 2  is a member selected from the group consisting of L-a:-amino acid fragments, D-α-amino acid fragments and fragments having the formula:  
                     
 wherein  
 R 6  is selected from the group consisting of hydrogen and (C 1 -C 4 )alkyl;  
 R 7  and R 8  are each members independently selected from the group consisting of hydrogen, (C 1 -C 8 )alkyl and (C 1 -C 8 )heteroalkyl, or can be combined with each other to form a 5-, 6-, 7- or 8-membered ring containing from zero to three heteroatoms;  
 X is a member selected from the group consisting of a bond, a (C 1 -C 4 ) saturated or unsaturated alkylene linking group and a (C 1 -C 4 ) saturated or unsaturated heteroalkylene linking group;  
 D a , D b  and D c  are each independently selected from the group consisting of ═N— and ═C(R 9 )— 
 wherein  
 each R 9  is independently selected from the group consisting of hydrogen, halogen, cyano, nitro, (C 1 -C 6 )alkyl, (C 1 -C 6 )heteroalkyl, (C 1 -C 6 )alkoxy, (C 1 -C 6 )thioalkoxy, —NR 10 R 11 , —C(O)OR 10 , —C(O)NR 10 R 11 , —O—C(O)OR 10 , —NR 11 —C(O)OR 10 , —NR 10 —SO 2 R 12 , —NR 10 —C(O)R 11 , —SO 2 NR 10 R 11 , and —OC(O)NR 10 R 11 ;  
 wherein  
 each R 10  and R 11  are each independently a member selected from the group consisting of hydrogen, (C 1 -C 8 )alkyl and (C 1 -C 8 )heteroalkyl, or when attached to the same nitrogen atom can be combined with each other to form a 5-, 6-, 7- or 8-membered ring containing from zero to three heteroatoms; and  
 each R 12  is independently a member selected from the group consisting of (C 1 -C 8 )alkyl, (C 1 -C 8 )heteroalkyl, aryl and heteroaryl;  
 U and Z are each independently selected from the group consisting of a single bond, —CH 2 —, —CH(OH)—, —C(O)—, —CH 2 O—, —CH 2 CH 2 —, —CH 2 C(O)—, —O—, —S—, —S—CH 2 —, —N(C(O)—(C 1 -C 8 )alkyl)-, —N(R 13 )— and —N(R 13 )—CH 2 —;  
 wherein  
 each R 13  is a member selected from the group consisting of hydrogen, (C 1 -C 8 )alkyl, aryl and (C 1 -C 8 )heteroalkyl;  
 Y 1  and Y 2  are each independently selected from the group consisting of —CO 2 H and —CO 2 R 14 ; and  
 R 14  is a member selected from the group consisting of (C 1 -C 9 )alkyl, and (C 1 -C 9 )heteroalkyl, or, alternatively, when Y 1  and Y 2  are each —CO 2 R 14 , each R 14  and the oxygen to which it is attached, join to form a 5-, 6-, 7- or 8-membered heterocyclic ring.  
 
     
     
         66 . The method of  claim 65 , wherein D a , D b  and D c  are each ═CH—.  
     
     
         67 . The method of  claim 65 , wherein X is a (C 2 -C 4 ) unsaturated alkylene linking group.  
     
     
         68 . The method of  claim 65 , wherein A 1  is selected from the group consisting of L-α-amino acid fragments.  
     
     
         69 . The method of  claim 65 , wherein A 2  is selected from the group consisting of L-α-amino acid fragments.  
     
     
         70 . The method of  claim 65 , wherein A 1  and A 2  are each independently selected from the group consisting of L-α-amino acid fragments.  
     
     
         71 . The method of  claim 65 , wherein A 1  and A 2  are each independently selected from the group consisting of L-α-amino acid fragments; X is a (C 2 -C 4 ) unsaturated alkylene linking group; and D a , D b  and D c  are each ═CH—.  
     
     
         72 . The method of  claim 65 , wherein U is selected from the group consisting of —CH 2 — and —CH(OH)—.  
     
     
         73 . The method of  claim 65 , wherein Z is selected from the group consisting of —CH 2 —, —O—, —NH— and —S—.  
     
     
         74 . The method of  claim 65 , wherein U is selected from the group consisting of —CH 2 — and —CH(OH)—; and Z is selected from the group consisting of —CH 2 —, —O—, —NH— and —S—.  
     
     
         75 . The method of  claim 65 , wherein A 1  and A 2  are each independently selected from the group consisting of a natural or unnatural L-α-amino acid fragments; X is a (C 2 -C 4 ) unsaturated alkylene linking group; D a , D b  and D c  are each =CH—; U is selected from the group consisting of —CH 2 — and —CH(OH)—; and Z is selected from the group consisting of —CH 2 —, —O—, —NH— and —S—.  
     
     
         76 . The method of  claim 75 , wherein X is an unsaturated alkylene moiety selected from the group consisting of —C(CH 3 )═CH and —CH═C(CH 3 ).  
     
     
         77 . The method of  claim 65 , wherein R 1  and R 2  are each members independently selected from the group consisting of (C 1 -C 8 )alkyl, aryl and aryl(C 1 -C 8 )alkyl.  
     
     
         78 . The method of  claim 75 , wherein R 1  and R 2  are each members independently selected from the group consisting of (C 1 -C 8 )alkyl, aryl and aryl(C 1 -C 8 )alkyl.  
     
     
         79 . The method of  claim 65 , wherein R 1  is an optionally substituted phenyl group.  
     
     
         80 . The method of  claim 65 , wherein R 1  is an optionally substituted phenyl group and R 2  is an optionally substituted benzyl group.  
     
     
         81 . The method of  claim 75 , wherein R 1  is an optionally substituted phenyl group.  
     
     
         82 . The method of  claim 75 , wherein R 1  is an optionally substituted phenyl group and R 2  is an optionally substituted benzyl group.  
     
     
         83 . The method of  claim 65 , wherein R 1  is an optionally substituted (C 1 -C 8 )alkyl or (C 1 -C 8 )heteroalkyl group and R 2  is an optionally substituted phenyl or benzyl group.  
     
     
         84 . The method of  claim 65 , wherein R 1  is a phenyl group substituted with up to two members selected from the group consisting of —NHCONH 2 , —C(NH)NH 2 , —CONH 2 , —CH 2 NHCO-(4-nitro-2-pyrazolyl), —CONHPh, —CH 2 NH 2 , —CH 2 NHCO—CH═CH-(3-nitrophenyl), —CH 3 , —Cl, —Br, —I, —CO 2 H, —CO 2 CH 3 , —OCH 3 , —OH, -Ph, —OPh, —CON(CH 3 ) 2 , —C(CH 3 ) 3 , —CH 2 NHAc, —CN and —CH 2 NHCO—CH═CH-(4-pyridyl).  
     
     
         85 . The method of  claim 75 , wherein R 1  is an optionally substituted (C 1 -C 8 )alkyl or (C 1 -C 8 )heteroalkyl group and R 2  is an optionally substituted phenyl or benzyl group.  
     
     
         86 . The method of  claim 75 , wherein R 1  is a phenyl group substituted with up to two members selected from the group consisting of —NHCONH 2 , —C(NH)NH 2 , —CONH 2 , —CH 2 NHCO-(4-nitro-2-pyrazolyl), —CONHPh, —CH 2 NH 2 , —CH 2 NHCO—CH═CH-(3-nitrophenyl), —CH 3 , —Cl, —Br, —I, —CO 2 H, —CO 2 CH 3 , —OCH 3 , —OH, -Ph, —OPh, —CON(CH 3 ) 2 , —C(CH 3 ) 3 , —CH 2 NHAc, —CN and —CH 2 NHCO—CH═CH-(4-pyridyl).  
     
     
         87 . The method of  claim 75 , wherein Z is —O—; R 1  is a member selected from the group consisting of an optionally substituted phenyl group or an optionally substituted heteroaryl; and R 2  is a member selected from the group consisting of (C 1 -C 8 )alkyl, (C 1 -C 8 )heteroalkyl, aryl(C 1 -C 8 )alkyl, aryl(C 1 -C 8 )heteroalkyl, heteroaryl(C 1 -C 8 )alkyl and heteroaryl(C 1 -C 8 )heteroalkyl.  
     
     
         88 . The method of  claim 68 , wherein A 1  is an L-α-amino acid fragment derived from L-tyrosine, L-serine, L-methionine, L-alanine and L-proline.  
     
     
         89 . The method of  claim 69 , wherein A 2  is an L-α-amino acid fragment derived from L-valine, L-leucine, L-methionine, L-lysine, L-isoluccine, L-threonine and L-tert-butylglycine.  
     
     
         90 . The method of  claim 75 , wherein A 1  is an L-α-amino acid fragment derived from L-tyrosine, L-serine, L-methionine, L-alanine and L-proline; and A is an L-α-amino acid fragment derived from L-valine, L-leucine, L-methionine, L-lysine, L-isoluecine, L-threonine and L-tert-butylglycine.  
     
     
         91 . The method of  claim 90 , wherein R 1  and R 2  are each members independently selected from the group consisting of substituted or unsubstituted (C 1 -C 8 )alkyl, substituted or unsubstituted aryl and substituted or unsubstituted aryl(C 1 -C 8 )alkyl.  
     
     
         92 . The method of  claim 91 , wherein A 1  is an L-α-amino acid fragment derived from L-alanine or L-proline; and A 2  is an L-α-amino acid fragment derived from L-valine, L-leucine, L-isoluecine, or L-tert-butylglycine.  
     
     
         93 . The method of  claim 91 , wherein A 1  is an L-α-amino acid fragment derived from L-proline; and A 2  is an L-α-amino acid fragment derived from L-tert-butylglycine.  
     
     
         94 . The method of  claim 65 , wherein said compound has the formula:  
       
         
           
           
               
               
           
         
       
       wherein 
 W 1  is a member selected from the group consisting of —H, —OR 15  and —NR 15 R 16 ;  
 W 1  and W 3  are each members independently selected from the group consisting of hydrogen, halogen, —R 17 , —CO 2 R 7 , —OR 17 , —NR 17 R 18  and —CONR 17 R 18 ;  
 wherein R 15 , R 16 , R 17  and R 18  are each members independently selected from the group consisting of hydrogen, aryl, (C 1 -C 8 )alkyl, (C 1 -C 8 )heteroalkyl, aryl(C 1 -C 8 )alkyl, aryl(C 1 -C 8 )heteroalkyl, alkylsulfonyl, arylsulfonyl and arylsulfinyl;  
 U and Z are each members independently selected from the group consisting of —CH 2 —, —CH(OH)—, —C(O)—, —O—, —S— and —N(R 13 )—.  
 
     
     
         95 . The method of  claim 65 , wherein said compound has the formula:  
       
         
           
           
               
               
           
         
       
       wherein 
 R 2  is a member selected from the group consisting of substituted or unsubstituted (C 1 -C 8 )alkyl;  
 W 1  is a member selected from the group consisting of —H, —OR and —NR 15 R 16 ;  
 W 2  is a member selected from the group consisting of hydrogen, halogen, —R 17 , —CO 2 R 17 , —OR 7  NR 17 R 18  and —CONR 17 R 18 ;  
 wherein R 15 , R 16 , R 17 , are each members independently selected from the group consisting of hydrogen, aryl, (C 1 -C 8 )alkyl, (C 1 -C 8 )heteroalkyl, aryl(C 1 -C 8 )alkyl, aryl(C 1 -C 8 )heteroalkyl, alkylsulfonyl, arylsulfonyl and arylsulfinyl;  
 U and Z are each members independently selected from the group consisting of —CH 2 —, —CH(OH)—, —C(O)—, —O—, —S— and —N(R 13 )—.  
 
     
     
         96 . The method of  claim 65 , wherein said compound has the formula:  
       
         
           
           
               
               
           
         
       
       wherein 
 W 1  is a member selected from the group consisting of —H, —OR 15  and —NR 15 R 16 ;  
 W 2  and W 3  are each members independently selected from the group consisting of hydrogen, halogen, —R 17 , —CO 2 R 17 , —OR 17 , —NR 17 R 18  and —CONR 17 R 18 ;  
 wherein R 15 , R 16 , R 17  and R 18  are each members independently selected from the group consisting of hydrogen, aryl, (C 1 -C 8 )alkyl, (C 1 -C 8 )heteroalkyl, aryl(C 1 -C 8 )alkyl, aryl(C 1 -C 8 )heteroalkyl, alkylsulfonyl, arylsulfonyl and arylsulfinyl;  
 U and Z are each members independently selected from the group consisting of —CH 2 —, —CH(OH)—, —C(O)—, —O—, —S— and —N(R 13 )—.  
 
     
     
         97 . A method in accordance with  claim 65 , wherein said STAT6-dependent condition is selected from the group consisting of allergic rhinitis, asthma, atopic dermatitis, contact dermatitis, anaphylaxis, food or drug induced allergy, conjunctivitis, uveitis, hypersensitivity reactions, alveolitis, psoriasis, Churg-Strauss syndrome, delayed-type hypersensitivity, urticaria, angiodema, eczema, scleroderma, and systemic lupus erythematosus.  
     
     
         98 . A method for treating a condition in a host, comprising administering to said host an effective amount of a compound of the formula:  
       
         
           
           
               
               
           
         
       
       wherein 
 R 1  and R 2  are each members independently selected from the group consisting of hydrogen, (C 1 -C 8 )alkyl, (C 1 -C 8 )heteroalkyl, aryl, heteroaryls aryl(C 1 -C 8 )alkyl, aryl(C 1 -C 8 )heteroalkyl, heteroaryl(C 1 -C 8 )alkyl, and heteroaryl(C 1 -C 8 )heteroalkyl with the proviso that at least one of R 1  and R 2  is selected from the group consisting of aryl, heteroalkyl, aryl(C 1 -C 8 )alkyl, aryl(C 1 -C 8 )heteroalkyl, heteroaryl(C 1 -C 8 )alkyl and heteroaryl(C 1 -C 8 )heteroalkyl:  
 A 1  is a member selected from the group consisting of L-α-amino acid fragments. D-α-amino acid fragments and fragments having the formula:  
                     
 wherein  
 R 3  is selected from the group consisting of hydrogen and (C 1 -C 4 )alkyl;  
 R 4  and R 5  are each members independently selected from the group consisting of hydrogen. (C 1 -C 8 )alkyl and (C 1 -C 8 )heteroalkyl, or can be individually combined with R 3  to form a 5-, 6-, 7- or 8-membered ring containing from one to three heteroatoms;  
 A 2  is a member selected from the group consisting of L-α-amino acid fragments, D-α-amino acid fragments and fragments having the formula:  
                     
 wherein  
 R 6  is selected from the group consisting of hydrogen and (C 1 -C 4 )alkyl:  
 R 7  and R 8  are each members independently selected from the group consisting of hydrogen, (C 1 -C 8 )alkyl and (C 1 -C 8 )heteroalkyl, or can be combined with each other to form a 5-, 6-, 7- or 8-membered ring containing from zero to three heteroatoms:  
 X is a member selected from the group consisting of a bond, a (C 1 -C 4 ) saturated or unsaturated alkylene linking group and a (C 1 -C 4 ) saturated or unsaturated heteroalkylene linking group;  
 D a , D b , and D c  are each independently selected from the group consisting of ═N— and ═C(R 9 )— 
 wherein  
 each R 9  is independently selected from the group consisting of hydrogen, halogen, cyano, nitro, (C 1 -C 6 )alkyl, (C 1 -C 6 )heteroalkyl, (C 1 -C 6 )alkoxy, (C 1 -C 6 )thioalkoxy, —NR 10 R 11 , —C(O)OR 10 , —C(O)NR 10 R 11 , —O—C(O)OR 10 , —NR 11 —C(O)OR 10 , —NR 10 —SO 2 R 12 , —NR 10 —C(O)R 11 , —SO 2 NR 10 R 11 , and —OC(O)NR 10 R 11 ;  
 wherein  
 each R 10  and R 11  are each independently a member selected from the group consisting of hydrogen, (C 1 -C 8 )alkyl and (C 1 -C 8 )heteroalkyl, or when attached to the same nitrogen atom can be combined with each other to form a 5-, 6-, 7- or 8-membered ring containing from zero to three heteroatoms: and  
 each R 12  is independently a member selected from the group consisting of (C 1 -C 8 )alkyl, (C 1 -C 8 )heteroalkyl, aryl and heteroaryl,  
 U and Z are each independently selected from the group consisting of a single bond, —CH 2 —, —CH(OH)—, —C(O)—, —CH 2 O—, —CH 2 CH 2 —, —CH 2 C(O)—, —O—, —S—, —S—CH 2 —, —N(C(O)—C 1 -C 9 )alkyl)-, —N(R 13 )— and —N(R 13 )—CH 2 —;  
 wherein  
 each R 13  is a member selected from the group consisting of hydrogen, (C 1 -C 8 )alkyl, aryl and (C 1 -C 8 )heteroalkyl;  
 Y 1  and Y 2  are each independently selected from the group consisting of —CO 2 H and —CO 2 R 14 ; and  
 R 14  is a member selected from the group consisting of (C 1 -C 9 )alkyl, and (C 1 -C 9 )heteroalkyl, or, alternatively, when Y 1  and Y 2  are each —CO 2 R 14 , each R 14  and the oxygen to which it is attached, join to form a 5-, 6-, 7- or 8-membered heterocyclic ring;  
 wherein said condition is selected from the group consisting of allergic rhinitis, asthma, atopic dermatitis, contact dermatitis, anaphylaxis, food or drug induced allergy, conjunctivitis, uveitis, hypersensitivity reactions, alveolitis, psoriasis, Churg-Strauss syndrome, delayed-type hypersensitivity, urticaria, angiodema, eczema, scleroderma, and systemic lupus erythematosus.  
 
     
     
         99 . The method in accordance with  claim 98 , wherein said compound of claim  1  is administered in combination with a second therapeutic agent.  
     
     
         100 . The method in accordance with  claim 99 , wherein said second therapeutic agent is selected from the group consisting of loratidine, fluticasone propionate, beclametasone diproprionate, budesonide, salmeterol xinafoate, ipratropium bromide, fexofenadine hydrochloride, cetirizine dihydrochloride, triamcinolone acetonide, cromolyn, salbutamol, montelukast sodium, ketotifen hydrogen fumarate, formoterol, zafirlukast, momefasone furoate, azelastine hydrochloride, epinastine, seratrodast, captropril, rampril, zofenopril, colchicine, enalapril, lisinopril, trandolapril, gold sodium thiomalate, calcipotriene, cyclosporine, vinblastine and dapsone.  
     
     
         101 . The method in accordance with  claim 99 , wherein'said compound of claim  1  and said second therapeutic agent are administered sequentially.  
     
     
         102 . A method in accordance with  claim 99 , wherein said compound of claim  1  and said second therapeutic agent are administered concurrently.  
     
     
         103 . A method in accordance with  claim 99 , wherein said compound of claim  1  and said second therapeutic agent are each administered at dosages of from {fraction (1/100)} to ½ of their dosages when administered individually.  
     
     
         104 . A method in accordance with  claim 99 , wherein said compound of claim  1  and said second therapeutic agent are each administered at dosages of from {fraction (1/10)} to ¼ of their dosages when administered individually.