Compounds as modulators of tlr2 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 . A compound of Formula (A) 
       
         
           
           
               
               
           
         
         or a tautomer, or a pharmaceutically acceptable salt of any of the foregoing, 
         wherein 
       
       
         
           
           
               
               
           
         
         indicates that the ring is saturated, partially unsaturated, or fully unsaturated; 
            indicates that the 
       
       
         
           
           
               
               
           
         
       
       is attached in either the E or Z configuration;
 G 1  and G 2  are each independently CR x , or N;
 R x  is hydrogen or halogen; 
 
 one of R 1  and R 2  is —OH and the other is selected from the group consisting of —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, and 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 aryl, —OR k , —NHR k , —NHC(O)R k , —NHS(O) 2 R k , or —NHC(NH)NH 2 ; 
 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; 
 
 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 1  or R 2  is —C 1 -C 6 alkyl-OH or —C 1 -C 6 alkyl-NR m R n , wherein R j  and IV are each C 1 -C 6 alkyl, R 3  is selected from the group consisting of C 1 -C 6 alkyl, C 2 -C 6 alkoxy, and halogen; 
 when R 1  or R 2  is unsubstituted or substituted C 3 -C 8  cycloalkyl, —NHC(O)CH 3 , or —S(O) 2 -R c , wherein R c  is an unsubstituted or substituted heterocyclyl, R 3  is selected from the group consisting of C 1 -C 6 alkyl, C 1 -C 6 alkoxy, and halogen; 
 when R 1  or R 2  is —CHO, R 3  is selected from the group consisting of hydrogen, C 2 -C 6 alkoxy, and halogen; 
 when R 1  or R 2  is —C(O)CH 3 , R 3  is selected from the group consisting of C 2 -C 6 alkoxy and halogen; 
 when R 1  or R 2  is —C(O)CH(Br)CH 3  or —C(O)CH(Br)CH 2 CH 3 , G 7  is C or CH; 
 when R 3  is hydrogen, no more than one of R 6a , R 6b , R 6c , and R 6d  is —CF 3 , no more than one of R 6a , R 6b , R 6c , and R 6d  is —CH 3 , and no more than one of R 6a , R 6b , R 6c , and R 6d  is —OH, 
 
 
 Y is absent and R 4  and R 5  come together to form —S—; 
 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, O, or absent; 
 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, —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, —OH, C 1 -C 6 alkyl-OH, ═O, and ═S; 
 R h  is selected from the group consisting of H, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, and C 3 -C 6 cycloalkyl, and —NR r R s , 
 R p  is H or C 1 -C 6 alkyl; 
 R q  is C 2 -C 3 alkyl, —C(O)R t , —C(O)OR u , —C(O)NR v ; 
 R r , R s , R w1 , and R z1  each independently selected from H and C 1 -C 6 alkyl; and 
 R t , R u , R v , R w2 , R y , and R z2  are each independently selected from H, C 1 -C 6 alkyl, unsubstituted or substituted C 3 -C 8 cycloalkyl, and 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 carbons 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; and 
         wherein no more than one of R 6a , R 6b , R 6c , and R 6d  is C 1 -C 6 alkoxy or —OH. 
       
     
     
         2 - 4 . (canceled) 
     
     
         5 . The compound of  claim 1 , or a tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein G 1  and G 2  are each CR x . 
     
     
         6 - 7 . (canceled) 
     
     
         8 . The compound of  claim 1 , or a tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein G 1  and G 2  are each CH. 
     
     
         9 - 10 . (canceled) 
     
     
         11 . The compound of  claim 1 , or a tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein R 1  is —OH and R 2  is selected from the group consisting of —C(O)R a , —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 cycloalkyl, unsubstituted or substituted cycloalkenyl, and unsubstituted or substituted heterocycloalkyl. 
     
     
         12 . The compound of  claim 1 , or a tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein R 1  is —OH and R 2  is selected from the group consisting of —C(O)R a , —S(O) 2 R c , —NHC(O)R d , —NHS(O) 2 R e , —C 2 -C 6 alkenyl-R g , and unsubstituted or substituted cycloalkenyl. 
     
     
         13 . The compound of  claim 1 , or a tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein R 1  is —OH and R 2  is —CH═NR j , wherein R j  is unsubstituted or substituted heterocyclyl, unsubstituted or substituted aryl, —OR k , —NHR k , —NHc(O)R k , —NHS(O) 2 R k , or —NHC(NH)NH 2 . 
     
     
         14 . The compound of  claim 1 , or a tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein R 1  is —OH and R 2  is selected from the group consisting of —CHO, —C(O)CH 3 , —C(O)CH 2 F, —C(O)CH═CH 2 , —S(O) 2 CH═CH 2 , —C(O)C═CH, —C(O)C═CCH 3 , —NHS(O) 2 CH═CH 2 , —NHC(O)CH═CH 2 , —C(O)C(═CH 2 )CH 3 , 
       
         
           
           
               
               
           
         
       
     
     
         15 . The compound of  claim 1 , or a tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein R 1  is —OH and R 2  is selected from the group consisting of 
       
         
           
           
               
               
           
         
       
     
     
         16 . The compound of  claim 1 , or a tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein R 2  is —OH and R 1  is selected from the group consisting of —C(O)R a , —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 cycloalkyl, unsubstituted or substituted cycloalkenyl, and unsubstituted or substituted heterocycloalkyl. 
     
     
         17 . The compound of  claim 1 , or a tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein R 2  is —OH and R 1  is selected from the group consisting of —C(O)R a , —S(O) 2 R c , —NHC(O)R d , —NHS(O) 2 R e , —C 2 -C 6 alkenyl-R g , and unsubstituted or substituted cycloalkenyl. 
     
     
         18 . The compound of  claim 1 , or a tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein R 2  is —OH and R 1  is —CH═NR j , wherein is unsubstituted or substituted heterocyclyl, unsubstituted or substituted aryl, —OR k , —NHR k , —NHc(O)R k , —NHS(O) 2 R k , or —NHC(NH)NH 2 . 
     
     
         19 . The compound of  claim 1 , or a tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein R 2  is —OH and R 1  is selected from the group consisting of —CHO, —C(O)CH 3 , —C(O)CH 2 F, —C(O)CH═CH 2 , —S(O) 2 CH═CH 2 , —C(O)C═CH, —C(O)C═CCH 3 , —NHS(O) 2 CH═CH 2 , —NHC(O)CH═CH 2 , —C(O)C(═CH 2 )CH 3 , 
       
         
           
           
               
               
           
         
       
     
     
         20 . The compound of  claim 1 , or a tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein R 2  is —OH and R 1  is selected from the group consisting of 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
     
     
         21 . (canceled) 
     
     
         22 . The compound of  claim 1 , or a tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein R 3  is selected from the group consisting of —OCH 3  or F. 
     
     
         23 - 25 . (canceled) 
     
     
         26 . The compound of  claim 1 , or a tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein 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  come together with the carbons 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. 
     
     
         27 . (canceled) 
     
     
         28 . The compound of  claim 1 , or a tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein G 7  is C or CH. 
     
     
         29 . The compound of  claim 1 , or a tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein G 3  is CH(X 1 −R 6a ) or 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 alkoxy, halo, or —C(O)R h , wherein C 1 -C 6 alkyl is unsubstituted or substituted with cycloalkyl or halogen; and R h  is selected from the group consisting of H, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, or C 3 -C 8 cycloalkyl. 
     
     
         30 . (canceled) 
     
     
         31 . The compound of  claim 1 , or a tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein G 4  is CH(X 2 -R 6b ) or C(X 2 -R 6b ); X 2  is absent; m is 1-6; R 6b  is hydrogen, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, halo, or —C(O)R h , wherein C 1 -C 6 alkyl is unsubstituted or substituted with cycloalkyl or halogen; and R h  is selected from the group consisting of H, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, or C 3 -C 8 cycloalkyl. 
     
     
         32 . (canceled) 
     
     
         33 . The compound of  claim 1 , or a tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein G 5  is CH(X 3 -R 6c ) or C(X 3 -R 6c ); X 3  is absent; m is 1-6;R 6c  is hydrogen, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, halo, or —C(O)R h , wherein C 1 -C 6 alkyl is unsubstituted or substituted with cycloalkyl or halogen; and R h  is selected from the group consisting of H, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, or C 3 -C 8 cycloalkyl. 
     
     
         34 - 36 . (canceled) 
     
     
         37 . The compound of  claim 1 , or a tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein G 6  is CH(X 4 -R 6d ) or C(X 4 -R 6d ); X 4  is absent; m is 1-6; R 6d  is hydrogen, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, halo, or —C(O)R h , wherein C 1 -C 6 alkyl is unsubstituted or substituted with cycloalkyl or halogen; and R h  is selected from the group consisting of H, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, or C 3 -C 8 cycloalkyl. 
     
     
         38 . (canceled) 
     
     
         39 . The compound of  claim 1 , or a tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein R 6a , R 6b , R 6c  and R 6d  are each independently hydrogen, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, halo, or —C(O)R h , wherein C 1 -C 6 alkyl is unsubstituted or substituted with cycloalkyl or halogen; and R h  is selected from the group consisting of H, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, and C 3 -C 8 cycloalkyl. 
     
     
         40 - 41 . (canceled) 
     
     
         42 . A compound of Table 1, or a tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein the compound is 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
     
     
         43 . A pharmaceutical composition comprising at least one compound according to  claim 1 , or a tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, optionally further comprising a pharmaceutically acceptable excipient. 
     
     
         44 . 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 according to  claim 1 , or a tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing. 
     
     
         45 . The method of  claim 44 , 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. 
     
     
         46 . A method of interfering with the heterodimerization of TLR2 in a cell, or modulating, preventing, slowing, reversing, or inhibiting TLR2 heterodimerization in a cell, comprising contacting the cell with an effective amount of at least one compound according to  claim 1 , or a tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, and/or with at least one pharmaceutical composition according to  claim 43 , wherein the contacting is in vitro, ex vivo, or in vivo.