Compounds and compositions as modulators of tlr signaling

Abstract

The present disclosure relates to compounds, pharmaceutical compositions comprising such compounds, and use of such compounds in methods of treatment or in medicaments for treatment of inflammatory diseases and certain neurological disorders that are related to inflammatory signaling processes, including but not limited to misfolded proteins.

1 - 92 . (canceled) 
     
     
         93 . A method of treating a disease or condition associated with TLR2 heterodimerization, comprising administering to a subject in need of such treatment an effective amount of at least one compound of Formula (A): 
       
         
           
           
               
               
           
         
         or a tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, 
         wherein 
         one of R 1  and R 2  is —OH and the other is —CN, halogen, —C(O)R a , —CH═NR j , —S(O)R b , —S(O) 2 R c , —NHC(O)R d , —NHS(O) 2 R e , —C 1 -C 6 alkyl-R f , —C 2 -C 6 alkenyl-R g , unsubstituted or substituted C 3 -C 8  cycloalkyl, unsubstituted or substituted C 3 -C 8  cycloalkenyl, or unsubstituted or substituted heterocycloalkyl;
 R a , R b , R c , and R e  are each independently H, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 haloalkyl, unsubstituted or substituted heterocyclyl, unsubstituted or substituted heteroaryl, benzoyl, or styryl; 
 R d  is H, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 haloalkyl, unsubstituted or substituted heterocyclyl, unsubstituted or substituted heteroaryl, or benzoyl; 
 R f  and R g  are each independently —OH, unsubstituted heteroaryl, —NR m R n , benzoyl, or styryl; 
 R m  and R n  are each independently H, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, or unsubstituted or substituted cycloalkyl; 
 R j  is unsubstituted or substituted heterocyclyl, unsubstituted or substituted heteroaryl, unsubstituted or substituted aryl, —OR k , —NHR k , —NHC(O)R k , —NHS(O) 2 R k , or —NHC(N)NHR aa ;
 R aa  is unsubstituted or substituted C 1 -C 6 alkyl, unsubstituted or substituted C 3 -C 8 cycloalkyl, unsubstituted or substituted aryl, unsubstituted or substituted heterocycloalkyl, or unsubstituted or substituted heteroaryl; 
 
 R k  is C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 8 cycloalkyl, or aryl, wherein the C 1 -C 6 alkyl of R k  is unsubstituted or substituted with heterocyclyl or heteroaryl; 
 
         R 3  is H, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, or halogen, wherein the C 1 -C 6 alkyl and C 1 -C 6 alkoxy of R 3  are each independently unsubstituted or substituted with one or more halogen; 
         wherein when R 2  is Br, R 3  is H, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, Cl, F, or I; 
         G 1  and G 2  are each independently CH or N, wherein when G 1  is N, G 2  is CH, and when G 2  is N, G 1  is CH; 
       
       
         
           
           
               
               
           
         
       
       indicates that the ring is aromatic;
 Y 1  is C or N; 
 Y 2  is CH, N, NH, S, or O; 
 Y 3  is C or N; 
 Y 4  is CH, N, NH, S, or O; 
 Y 5  is CR 7 , N, NH, S, or O; 
 wherein no more than one of Y 1 , Y 2 , Y 3 , Y 4 , and Y 5  is S or O and no more than four of Y 1 , Y 2 , Y 3 , Y 4 , and Y 5  are N or NH; 
 R 7  is H or C 1 -C 6 alkyl; 
 n is 0, 1, 2, or 3; 
 R 4  is alkoxy or 
 
       
         
           
           
               
               
           
         
       
       
         
           
           
               
               
           
         
       
       indicates that the ring is saturated, partially unsaturated, or fully unsaturated;
 G 3  is CH(X 1 —R 6a ), C(X 1 —R 6a ), N, N(X 1 —R 6a ), S, or O; 
 G 4  is CH(X 2 —R 6b ), C(X 2 —R 6b ), N, N(X 2 —R 6b ), S, or O; 
 G 5  is CH(X 3 —R 6c ), C(X 3 —R 6c ), N, N(X 3 —R 6c ), S, or O; 
 G 6  is CH(X 4 —R 6d ), C(X 4 —R 6d ), N, N(X 4 —R 6d ), S, or O; and 
 G 7  is N, C, or CH;
 X 1 , X 2 , X 3 , and X 4  are each independently absent, 
 
 
       
         
           
           
               
               
           
         
         
           
             m is 1-6; 
           
           R 6a , R 6b , R 6c , and R 6d  are each independently hydrogen, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, halo, —OH, —NR p R q , aryl, heterocyclyl, heteroaryl, —C 1 -C 6 alkyl-heterocyclyl, —OC(O)-heterocyclyl, —C(O)R h , —S(O) 2 NR w1 R w2 , —S(O) 2 R y , or —NR z1 S(O) 2 R z2 , wherein the C 1 -C 6 alkyl and C 1 -C 6 alkoxy of R 6a , R 6b , R 6c , and R 6d  are each independently unsubstituted or substituted with one or more groups selected from the group consisting of cycloalkyl and halogen; the aryl and heteroaryl of R 6a , R 6b , R 6c , and R 6d  are each independently unsubstituted or substituted with one or more groups selected from the group consisting of C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 3 -C 8 cycloalkyl, —OH, and C 1 -C 6 alkyl-OH; and the heterocyclyl, —C 1 -C 6 alkyl-heterocyclyl, and —OC(O)-heterocyclyl of R 6a , R 6b , R 6c , and R 6d  are each independently unsubstituted or substituted with one or more groups selected from the group consisting of C 1 -C 6 alkyl, C 1 -C 6 alkoxy, halo, —OH, C 1 -C 6 alkyl-OH, ═O, and ═S;
 each R h  is independently H, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 3 -C 8 cycloalkyl, or —NR r R s ; 
 each R p  is independently H or C 1 -C 6 alkyl; 
 each R q  is independently C 2 -C 3 alkyl, —C(O)R t , —C(O)OR u , or —C(O)NR v ; 
 each R r , R s , R w1 , and R z1  is independently H or C 1 -C 6 alkyl; and 
 
           each R t , R u , R w2 , R y , and R z2  is independently H, C 1 -C 6 alkyl, unsubstituted or substituted C 3 -C 8 cycloalkyl, or unsubstituted or substituted heterocyclyl; 
         
         or 
         G 5  is CH(X 3 —R 6c ) or C(X 3 —R 6c ), G 6  is CH(X 4 —R 6d ) or C(X 4 —R 6d ), and R 6c  and R 6d  are taken together with the carbon atoms to which they are attached to form a 6-membered aryl, a 6-membered heterocyclyl, or a 6-membered heteroaryl ring: wherein the 6-membered aryl, 6-membered heterocyclyl, and 6-membered heteroaryl rings are each independently unsubstituted or substituted. 
       
     
     
         94 . The method of  claim 93 , wherein the disease or condition is selected from the group consisting of: Alzheimer's disease, Parkinson's disease, fronto-temporal dementia, dementia with Lewy bodies (Lewy body disease), Parkinson's disease with dementia, multiple system atrophy, amyotrophic lateral sclerosis, Huntington's disease, Progressive Supranuclear Palsy (PSP), Niemann-Pick disease type C, inflammatory diseases, asthma, chronic obstructive pulmonary disease (COPD), chronic peptic ulcers, irritable bowel disease, tuberculosis, rheumatoid arthritis, osteoarthritis, chronic sinusitis, hepatitis, hepatitis B, hepatitis C, gout, lupus, pleurisy, eczema, gastritis, psoriasis, psoriatic arthritis, vasculitis, laryngitis, allergic reactions, multiple sclerosis, Crohn's disease, traumatic brain injury, CIDP (chronic inflammatory demyelinating polyneuropathy), stroke, ischemic heart disease, atopic dermatitis, acne vulgaris, rosacea, non-alcoholic fatty liver disease, non-alcoholic steatohepatisis, corneal wounds, corneal disorders, corneal HSV, Stargardt disease (Juvenile macular degeneration), age-related macular degeneration, sepsis, diabetic wounds, herpes simplex virus, and anti-fungal, anti-bacterial, anitviral and antitumor diseases or conditions. 
     
     
         95 - 110 . (canceled) 
     
     
         111 . The method of  claim 93 , wherein R 1  is —OH and R 2  is F, Cl, Br, —CN, —C(O)H, 
       
         
           
           
               
               
           
         
       
     
     
         112 . The method of  claim 93 , wherein R 2  is —OH and R 1  is F, Cl, Br, —CN, —C(O)H, 
       
         
           
           
               
               
           
         
       
     
     
         113 . The method of  claim 93 , wherein R 3  is —CH 3 , —OCH 3 , Cl, or F. 
     
     
         114 . The method of  claim 93 , wherein 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
     
     
         115 . The method of  claim 93 , wherein n is 0. 
     
     
         116 . The method of  claim 93 , wherein R 4  is 
       
         
           
           
               
               
           
         
       
     
     
         117 . The method of  claim 93 , wherein
 G 3  is C(X 1 —R 6a ); X 1  is absent,   
       
         
           
           
               
               
           
         
       
       m is 1-6; R 6a  is hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, halo, C 6 -C 12  aryl, 3- to 10-membered heterocyclyl, or 5- to 10-membered heteroaryl;
 G 4  is C(X 2 —R 6b ) or N; X 2  is absent, 
 
       
         
           
           
               
               
           
         
       
       m is 1-6; and R 6b  is hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, halo, C 6 -C 12  aryl, 3- to 10-membered heterocyclyl, or 5- to 10-membered heteroaryl;
 G 5  is C(X 3 —R 6c ); X 3  is absent, 
 
       
         
           
           
               
               
           
         
       
       m is 1-6; and R 6c  is hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, halo, C 6 -C 12  aryl, 3- to 10-membered heterocyclyl, or 5- to 10-membered heteroaryl;
 G 6  is C(X 4 —R 6d ); X 4  is absent, 
 
       
         
           
           
               
               
           
         
       
       m is 1-6; and R 6d  is hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, halo, C 6 -C 12  aryl, 3- to 10-membered heterocyclyl, or 5- to 10-membered heteroaryl; and 
       G 7  is C. 
     
     
         118 . The method of  claim 93 , wherein one or more of R 6a , R 6b , R 6c , and R 6d  are independently C 1 -C 6 alkyl, C 1 -C 6 alkoxy, halo, —OH, —NR p R q , aryl, heterocyclyl, heteroaryl, —C 1 -C 6 alkyl-heterocyclyl, —OC(O)-heterocyclyl, —C(O)R h , —S(O) 2 NR w1 R w2 , —S(O) 2 R y , or —NR z1 S(O) 2 R z2 . 
     
     
         119 . The method of  claim 93 , wherein G 1  is CH and G 2  is CH. 
     
     
         120 . The method of  claim 93 , wherein G 1  is N and G 2  is CH. 
     
     
         121 . The method of  claim 93 , wherein the compound is a compound of Table 1A, or a tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing.