Aryl hydrocarbon receptor modulator

Abstract

two Ra are independently H or two Ra together form ═O or ═N—W3—R1; A is a C6 to C10 aromatic ring unsubstituted or substituted with 1 to 3 R, or a C2-C10 heteroaromatic ring interrupted by 1 to 5 heteroatoms selected from N, O, and S or a 4 to 7 membered nonaromatic heterocyclic ring containing C═N and interrupted by 1 to 3 heteroatoms selected from N, O, and S, with either one unsubstituted or substituted with 1 to 3 R; Q is R, or is a C6 to C10 aromatic ring or a C2 to C10 heteroaromatic ring unsubstituted or substituted with 1 to 3 R and interrupted by 1 to 5 heteroatoms selected from N, O, and S; and R is Rc which is C-attached or RN which is N-attached. The compounds of formula (I) of the present invention can regulate AhR activity, and can be used to inhibit the growth of cancer cells and inhibit the metastasis and invasion of tumor cells.

1 . An aryl hydrocarbon receptor modulator of formula (I), and a pharmaceutically acceptable salt thereof, 
       
         
           
           
               
               
           
         
       
       wherein:
 R′ is H, CN, CH 2 (OH)R 0 , C m H 2m+1 , C n H 2n-1 , C n H 2n-3 , 
 
       
         
           
           
               
               
           
         
       
       where W 0  is O or NH; W 1  is a linker bond, C(R 0 ) 2 , C(R 0 ) 2 O, C(R 0 ) 2 OC(R 0 ) 2  or C(R 0 ) 2 OC(R 0 ) 2 C(R 0 ) 2 ; when W is C, S, or S(O), W 2  is a linker bond, O, NR 0 , CH(N(R 0 ) 2 ) or OCH 2 C(O); when W is P(OR 0 ), W 2  is O or NR 0 ; each R 0  is independently H, C m H 2m+1 , C m H 2m+1 OC(O), C m H 2m+1-r X r , C m H 2m+1 OC(O)C m H 2m , (cyclic C 4 H 8 NO)C m H 2m , CH 3 (OCH 2 CH 2 )—, or CH 3 (OCH 2 CH 2 ) n OCH 2 ;
 two R a  are independently H or two R a  together form ═O, ═N—CN or ═N—W 3 —R 1 , W 3  is O or NH, R 1  is H, C m H 2m+1 , C m H 2m+1 C(O), C m H 2m+1 OC(O), or C m H 2m+1 S(O) 1-2 , 
 A is a C 6  to C 10  aromatic ring unsubstituted or substituted with 1 to 3 R, or a C 2 -C 10  heteroaromatic ring interrupted by 1 to 5 heteroatoms selected from N, O, and S or a 4 to 7 membered nonaromatic heterocyclic ring containing C═N and interrupted by 1 to 3 heteroatoms selected from N, O, and S, with either one unsubstituted or substituted with 1 to 3 R; 
 Q is R, or a C 6  to C 10  aromatic ring unsubstituted or substituted with 1 to 3 R, or a 3 to 10 membered, preferably 4 to 7 membered, more preferably 5 to 6 membered heterocyclic ring, preferably heteroaromatic ring unsubstituted or substituted with 1 to 3 R, interrupted by 1 to 5, preferably 1 to 3, more preferably 2 to 3 heteroatoms selected from N, O, and S; 
 R is R C  which is C-attached or R N  which is N-attached, where each R C  is independently X, CN, R″, —Y—OR″, —Y—C(O)R″, —Y—OC(O)R″, —Y—C(O)OR″, —Y—OC(O)OR″, —Y—NR″ 2 , —Y—C(O)NR″ 2 , —Y—NR″C(O)R″, —Y—NR″C(O)NR″ 2 , —Y—OC(O)NR″ 2 , —Y—NR″C(O)OR″, —Y—S(O) 1-2 R″, —Y—S(O) 1-2 NR″ 2 , or —Y—NR″S(O) 1-2 R″; each R N  is independently CN, R″, —Y—OR″, —Y—C(O)R″, —Y—OC(O)R″, —Y—C(O)OR″, —Y—OC(O)OR″, —Y—NR″ 2 , —Y—C(O)NR″ 2 , —Y—NR″C(O)R″, —Y—NR″C(O)NR″ 2 , —Y—OC(O)NR″ 2 , —Y—NR″C(O)OR″, —Y—S(O) 1-2 R″, —Y—S(O) 1-2 NR″ 2 , or —Y—NR″S(O) 1-2 R″; 
 R″ is H, D, C m H 2m+1 , C n H 2n-1 , C n H 2n-3 , C m H 2m+1-r X r , C n H 2n-1-s X s , or C n H 2n-3-t X t ; 
 Y is a linker bond, —C m H 2m —, —C n C 2n-2 —, —C n H 2n-4 —, —C n H 2m-i X i —, —C n H 2n-2-j X j —, or —C n H 2n-4-k X k —; 
 m=1 to 8, n=2 to 8, u=1 to 5, r≤2m+1, t≤2n−3, i≤2m, j≤2n−2, k≤2n−4, and X is halogen; preferably, m=1 to 5, more preferably 1 to 3; n=2 to 6, more preferably 2 to 4; u=1 to 4, more preferably 1 to 3; and X is F, Cl, or Br. 
 
     
     
         2 . The aryl hydrocarbon receptor modulator of  claim 1 , wherein A is 
       
         
           
           
               
               
           
         
       
       and in which case, formula (1) becomes formula (I1), 
       
         
           
           
               
               
           
         
         in formula (I1), one of A 1 , A 2 , and A 3  is O, S, or N(R) and the other two are independently C(R) or N respectively. 
       
     
     
         3 . The aryl hydrocarbon receptor modulator of  claim 2 , wherein one of A 1 , A 2 , and A 3  is O, S, or N(R) and the other two are each independently N. 
     
     
         4 . The aryl hydrocarbon receptor modulator of  claim 3 , wherein A 3  is N; and in which case, formula (I1) becomes formula (Ia), 
       
         
           
           
               
               
           
         
         in formula (Ia), A 1  is O, S, or N(R), and A 2  is N; or A 2  is O, S, or N(R), and A 1  is N. 
       
     
     
         5 . The aryl hydrocarbon receptor modulator of  claim 2 , wherein A 2  is CH; and in which case, formula (I1) becomes formula (Ib), 
       
         
           
           
               
               
           
         
         in formula (Ib), A 1  is N or C(R), and A 3  is O, S, or N(R); or A 1  is O, S, or N(R), and A 3  is N or C(R). 
       
     
     
         6 . The aryl hydrocarbon receptor modulator of  claim 2 , wherein A 1  is N, A 3  is C(R), and two R a  together form ═N—W 3 —R 1 ; and in which case, formula (I1) becomes formula (Ic), 
       
         
           
           
               
               
           
         
         in formula (Ic), A 2  is O, S, or N(R). 
       
     
     
         7 . The aryl hydrocarbon receptor modulator of  claim 2 , wherein A 1  is N, A 3  is C(R), and two R a  are H; and in which case, formula (I1) becomes formula (Id), 
       
         
           
           
               
               
           
         
         in formula (Id), A 2  is O, S, or N(R). 
       
     
     
         8 . The aryl hydrocarbon receptor modulator of  claim 2 , wherein A 1  is N, A 3  is C(R), and R′ is 
       
         
           
           
               
               
           
         
       
       and in which case, formula (I1) becomes formula (Ie), 
       
         
           
           
               
               
           
         
         in formula (Ie), A 2  is O, S, or N(R). 
       
     
     
         9 . The aryl hydrocarbon receptor modulator of  claim 2 , wherein A 1  is N, A 3  is C(R), and R′ is 
       
         
           
           
               
               
           
         
       
       and in which case, formula (I1) becomes formula (If), 
       
         
           
           
               
               
           
         
         in formula (If), A 2  is O, S, or N(R), and each R 0  is independently H or Ac. 
       
     
     
         10 . The aryl hydrocarbon receptor modulator of  claim 1 , wherein Q is 
       
         
           
           
               
               
           
         
       
       one of B 1 , B 2 , B 3 , and B 4  is O, S, or N(R) and the other three are each independently C(R) or N;
 or, Q is 
 
       
         
           
           
               
               
           
         
       
       and B 5  to B 9  are C(R); or one or two of B 5  to B 9  are N, and the others are each independently C(R). 
     
     
         11 . The aryl hydrocarbon receptor modulator of  claim 2 , wherein A 1  is N, A 2  is S, A 3  is CH, and Q is a 5 membered heteroaromatic ring; and in which case, formula (I1) becomes formula (Ig), 
       
         
           
           
               
               
           
         
       
       where one of B 2 , B 3 , and B 4  is O, S, or N(R), and the others are each independently C(R) or N. 
     
     
         12 . The aryl hydrocarbon receptor modulator of  claim 2 , wherein A 1  is N, A 2  is S, A 3  is CH, and Q is a 5 membered nonaromatic heterocyclic ring containing C═N; and in which case, formula (I1) becomes formula (Ih), 
       
         
           
           
               
               
           
         
         B 4  is O, S, or N(R). 
       
     
     
         13 . The aryl hydrocarbon receptor modulator of  claim 1 , wherein A is a nonaromatic heterocyclic ring interrupted by N and S, and Q is R; and in which case, formula (I) becomes formula (I2), 
       
         
           
           
               
               
           
         
       
     
     
         14 . The aryl hydrocarbon receptor modulator of  claim 1 , wherein A is 
       
         
           
           
               
               
           
         
       
       and in which case, formula (I) becomes formula (I3), 
       
         
           
           
               
               
           
         
         in formula (I3), Z r  to Z 5  are each independently C(Q); or one or two of Z r  to Z 5  are N, and the others are each independently C(Q); or adjacent two of Z r  to Z 5  are C(Q) which together form a 5 to 6 membered carbocyclic ring or a 5 to 6 membered heterocyclic ring interrupted by 1 to 3 heteroatoms selected from N, O, and S, and the other three are each independently C(Q), or two of the other three are each independently C(Q) and the remaining one is N, or one of the other three is C(Q) and the remaining two are N. 
       
     
     
         15 . The aryl hydrocarbon receptor modulator of  claim 1 , wherein in formula (I), R′ is one of the following substituents: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
     
     
         16 . The aryl hydrocarbon receptor modulator of  claim 3 , wherein in formula (I1), 
       
         
           
           
               
               
           
         
       
       is one of the following substituents: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
     
     
         17 . The aryl hydrocarbon receptor modulator of  claim 5 , wherein in formula (Ib), 
       
         
           
           
               
               
           
         
       
       is one of the following substituents: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
     
     
         18 . The aryl hydrocarbon receptor modulator of  claim 2 , wherein in formula (I1), 
       
         
           
           
               
               
           
         
       
       is one of the following substituents: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
     
     
         19 . The aryl hydrocarbon receptor modulator of  claim 1 , wherein the aryl hydrocarbon receptor modulator is: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
     
     
         20 - 29 . (canceled) 
     
     
         30 . A method of treating cancer in a patient in need thereof, comprising administering a therapeutically effective amount of an aryl hydrocarbon receptor modulator of  claim 1  to the patient.