Fused 1,4-diazepines as bet protein degraders

Abstract

The present disclosure provides compounds represented by Formula I: I, and the pharmaceutically acceptable salts, hydrates, and solvates thereof, wherein R 1 , R 2a , R 2b , R 3 , R 4 , Ar, L, X, Y, and B are as defined as set forth in the specification. The present disclosure also provides compounds of Formula I for use to treat a condition or disorder responsive to degradation of BET bromodomains such as cancer.

1 - 77 . (canceled) 
     
     
         78 . A compound having Formula XVIII: 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt or hydrate thereof, 
         wherein: 
         R 1  is selected from the group consisting of hydrogen and optionally substituted C 1-4  alkyl; 
         R 2a  is selected from the group consisting of, optionally substituted C 1-4  alkyl and (alkoxycarbonyl)alkyl; 
         R 2b  is selected from the group consisting of hydrogen, optionally substituted C 1-4  alkyl, and (alkoxycarbonyl)alkyl: or 
         R 2a  and R 2b  together with the carbon atom to which they are attached form a 3- to 6-membered cycloalkyl; 
         R 3  is selected from the group consisting of optionally substituted C 6-14  aryl and optionally substituted 5- to 14-membered heteroaryl; 
         R 4  is selected from the group consisting of hydrogen, halogen, optionally substituted C 1-4  alkyl, optionally substituted C 2-4  alkenyl, optionally substituted C 2-4  alkynyl, aralkyl, optionally substituted C 6-14  aryl, optionally substituted C 3-12  cycloalkyl, optionally substituted 3- to 14-membered heterocyclo, and optionally substituted 5- to 14-membered heteroaryl; 
       
       
         
           
           
               
               
           
         
       
       is a fused thienyl or fused phenyl group, wherein the fused phenyl group is additionally substituted with R 15 ;
 Y is —N═; 
 R 15  is selected from the group consisting of hydrogen, halogen, C 1-4  alkyl, and alkoxy; and 
 R 7  is selected from the group consisting of optionally substituted alkyl, hydroxyalkyl, optionally substituted aryl, and optionally substituted heteroaryl. 
 
     
     
         79 . The compound of  claim 78 , or a pharmaceutically acceptable salt or hydrate thereof, having Formula XIX: 
       
         
           
           
               
               
           
         
       
     
     
         80 . The compound of  claim 79 , or a pharmaceutically acceptable salt or hydrate thereof, having Formula XXIII: 
       
         
           
           
               
               
           
         
         wherein: 
         R 2a  is selected from the group consisting of hydrogen and C 1-3  alkyl; and 
         R 17a  and R 17b  are each independently selected from the group consisting of hydrogen, C 1-4  alkyl, haloalkyl, C 1-4  alkoxy, and halo. 
       
     
     
         81 . The compound of  claim 79 , or a pharmaceutically acceptable salt or hydrate thereof, wherein R 1  is C 1-4  alkyl. 
     
     
         82 . The compound of  claim 79 , or a pharmaceutically acceptable salt or hydrate thereof, wherein R 2a  is C 1-4  alkyl. 
     
     
         83 . The compound of  claim 80 , a pharmaceutically acceptable salt or hydrate thereof, wherein R 17a  and R 17b  are each independently selected from the group consisting of hydrogen and halo. 
     
     
         84 . The compound of  claim 78 , a pharmaceutically acceptable salt or hydrate thereof, having Formula XX: 
       
         
           
           
               
               
           
         
       
     
     
         85 . A compound, or a pharmaceutically acceptable salt or hydrate thereof, selected from the group consisting of:
 2-((1H-pyrazol-4-yl)ethynyl)-4-(4-chlorophenyl)-3,9-dimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepine;   (S)-2-((1H-pyrazol-4-yl)ethynyl)-4-(4-chlorophenyl)-3,6,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepine;   2-((1H-1,2,3-triazol-4-yl)ethynyl)-4-(4-chlorophenyl)-3,9-dimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepine;   (S)-2-((1H-1,2,3-triazol-4-yl)ethynyl)-4-(4-chlorophenyl)-3,6,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepine;   4-(4-chlorophenyl)-3,9-dimethyl-2-(pyridin-3-ylethynyl)-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepine;   (S)-4-(4-chlorophenyl)-3,6,9-trimethyl-2-(pyridin-3-ylethynyl)-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepine;   4-(4-chlorophenyl)-3,9-dimethyl-2-(pyridin-2-ylethynyl)-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepine;   (S)-4-(4-chlorophenyl)-3,6,9-trimethyl-2-(pyridin-2-ylethynyl)-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepine;   4-(6-((4-(4-chlorophenyl)-3,9-dimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-2-yl)ethynyl)pyridin-3-yl)butan-1-ol;   4-(6-((4-(4-chlorophenyl)-3,9-dimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-2-yl)ethynyl)pyridin-3-yl)butanal;   4-(4-chlorophenyl)-3,9-dimethyl-2-((5-(pent-4-yn-1-yl)pyridin-2-yl)ethynyl)-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepine;   6-((4-(4-chlorophenyl)-3,9-dimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-2-yl)ethynyl)pyridin-3-ol;   2-((5-(but-3-yn-1-yloxy)pyridin-2-yl)ethynyl)-4-(4-chlorophenyl)-3,9-dimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepine; and   4-(4-chlorophenyl)-3,9-dimethyl-2-((1-(pent-4-yn-1-yl)-1H-imidazol-4-yl)ethynyl)-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepine.   
     
     
         86 . A pharmaceutical composition comprising the compound of  claim 78 , or a pharmaceutically acceptable salt or hydrate thereof, and a pharmaceutically acceptable carrier. 
     
     
         87 . A method of treating a patient, the method comprising administering to the patient a therapeutically effective amount of the compound of  claim 78 , or a pharmaceutically acceptable salt or hydrate thereof, wherein the patient has cancer, a chronic autoimmune disorder, an inflammatory condition, a proliferative disorder, sepsis, or a viral infection. 
     
     
         88 . The method of  claim 87 , wherein the patient has cancer. 
     
     
         89 . A method of making a compound having Formula I: 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt or hydrate thereof, wherein: 
         R 1  is selected from the group consisting of hydrogen and optionally substituted C 1-4  alkyl; 
         R 2a  and R 2b  are each independently selected from the group consisting of hydrogen, optionally substituted C 1-4  alkyl, (alkoxycarbonyl)alkyl, and —CH 2 C(═O)NR 19a R 19b , or 
         R 2a  and R 2b  together with the carbon atom to which they are attached form a 3- to 6-membered cycloalkyl; 
         R 3  is selected from the group consisting of optionally substituted C 6-14  aryl and optionally substituted 5- to 14-membered heteroaryl 
         R 4  is selected from the group consisting of hydrogen, halogen, optionally substituted C 1-4  alkyl, optionally substituted C 2-4  alkenyl, optionally substituted C 2-4  alkynyl, aralkyl, optionally substituted C 6-14  aryl, optionally substituted C 3-12  cycloalkyl, optionally substituted 3- to 14-membered heterocyclo, and optionally substituted 5- to 14-membered heteroaryl; 
       
       
         
           
           
               
               
           
         
       
       is a fused thienyl or fused phenyl group, wherein the fused phenyl group is additionally substituted with R 15 ;
 R 15  is selected from the group consisting of hydrogen, halogen, C 1-4  alkyl, and alkoxy; 
 B is: 
 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         L is selected from the group consisting of alkylenyl, heteroalkylenyl, -A-(CH 2 ) m —W—(CH 2 ) n —, —(CH 2 ) m —W—(CH 2 ) u —O—(CH 2 ) v —, and —(CH 2 ) m —W—[(CH 2 ) w —O] x —(CH 2 ) v —; 
         A is selected from the group consisting of 5-membered heteroarylenyl and 6-membered heteroarylenyl; or 
         A is absent; 
         W is selected from the group consisting of phenylenyl, 5-membered heteroarylenyl, 6-membered heteroarylenyl, heterocyclenyl, and cycloalkylenyl; 
         m is 0, 1, 2, 3, 4, 5, 6, or 7; 
         n is 0, 1, 2, 3, 4, 5, 6, 7, or 8; 
         u is 0, 1, 2, or 3; 
         v is 1, 2, 3, or 4; 
         each w is independently 2, 3, or 4; 
         x is 2, 3, or 4; 
         X is selected from the group consisting of —C≡C—, —CH 2 —, —O—, —N(R 2c )—, —C(═O)N(R 2d )—, —N(R 2e )C(═O)CH 2 O—, and —N(R 2f )C(═O)CH 2 N(R 2g )—; or 
         X is absent; 
         wherein the carboxamide nitrogen atom of —N(R 2e )C(═O)CH 2 O— and —N(R 2f )C(═O)CH 2 N(R 2g )—, and the carbon atom of —C(═O)N(R 2d )— is attached to L; 
         R 2c , R 2d , R 2e , R 2f , and R 2g  are each independently selected from the group consisting of hydrogen and C 1-4  alkyl; 
         Z is selected from the group consisting of —CH 2  and —C(═O)—; 
         R 5  is selected from the group consisting of hydrogen, methyl, and fluoro; 
         A 1  is selected from the group consisting of —C(R 16a )═ and —N═; 
         A 2  is selected from the group consisting of —C(R 16b )═ and —N═; 
         A 3  is selected from the group consisting of —C(R 16c )═ and —N═; 
         R 16a  is selected from the group consisting of hydrogen, halo, and C 1-4  alkyl; 
         R 16b  is selected from the group consisting of hydrogen, halo, and C 1-4  alkyl; 
         R 16c  is selected from the group consisting of hydrogen, halo, and C 1-4  alkyl; and 
         R 19a  and R 19b  are independently selected from the group consisting of hydrogen, C 1-6  alkyl and optionally substituted aryl; or 
         R 19a  and R 19b  taken together with the nitrogen atom to which they are attached form a 4- to 8-membered optionally substituted heterocyclo, 
         the method comprising: 
         (1) reacting a compound having Formula X: 
       
       
         
           
           
               
               
           
         
         wherein: 
         X 1  is selected from the group consisting of —Br and —I; 
         R 1  is selected from the group consisting of hydrogen and optionally substituted C 1-4  alkyl; 
         R 2a  and R 2b  are each independently selected from the group consisting of hydrogen, optionally substituted C 1-4  alkyl, (alkoxycarbonyl)alkyl, and —CH 2 C(═O)NR 19a R 19b , or 
         R 2a  and R 2b  together with the carbon atom to which they are attached form a 3- to 6-membered cycloalkyl; 
         R 3  is selected from the group consisting of optionally substituted C 6-14  aryl and optionally substituted 5- to 14-membered heteroaryl; 
         R 4  is selected from the group consisting of hydrogen, halogen, optionally substituted C 1-4  alkyl, optionally substituted C 2-4  alkenyl, optionally substituted C 2-4  alkynyl, aralkyl, optionally substituted C 6-14  aryl, optionally substituted C 3-12  cycloalkyl, optionally substituted 3- to 14-membered heterocyclo, and optionally substituted 5- to 14-membered heteroaryl; 
       
       
         
           
           
               
               
           
         
       
       is a fused thienyl or fused phenyl group, wherein the fused phenyl group is additionally substituted with R 15 ; and
 R 15  is selected from the group consisting of hydrogen, halogen, C 1-4  alkyl, and alkoxy; 
 R 19a  and R 19b  are independently selected from the group consisting of hydrogen, C 1-6  alkyl and optionally substituted aryl; or 
 R 19a  and R 19b  taken together with the nitrogen atom to which they are attached form a 4- to 8-membered optionally substituted heterocyclo, 
 with a compound having Formula XI: 
 
       
         
           
           
               
               
           
         
         wherein: 
         B is selected from the group consisting of 
       
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         L is selected from the group consisting of alkylenyl, heteroalkylenyl, -A-(CH 2 ) m —W—(CH 2 ) n —, —(CH 2 ) m —W—(CH 2 ) u —O—(CH 2 ) v —, and —(CH 2 ) m —W—[(CH 2 ) w —O] x —(CH 2 ) v —; 
         A is selected from the group consisting of 5 membered heteroarylenyl and 6-membered heteroarylenyl; or 
         A is absent; 
         W is selected from the group consisting of phenylenyl, 5-membered heteroarylenyl, 6-membered heteroarylenyl, heterocyclenyl, and cycloalkylenyl; 
         m is 0, 1, 2, 3, 4, 5, 6, or 7; 
         n is 0, 1, 2, 3,4, 5, 6, 7, or 8; 
         u is 0, 1, 2, or 3; 
         v is 1, 2, 3, or 4; 
         each w is independently 2, 3, or 4; 
         x is 2, 3, or 4 
         X is selected from the group consisting of —C≡C—, —CH 2 —, —O—, —N(R 2c )—, —C(═O)N(R 2d )—, —N(R 2e )C(═O)CH 2 O—, and —N(R 2f )C(═O)CH 2 N(R 2g )—; or 
         X is absent; 
         wherein the carboxamide nitrogen atom of —N(R 2e )C(═O)CH 2 O— and —N(R 2f )C(═O)CH 2 N(R 2g )—, and the carbon atom of —C(═O)N(R 2d )— is attached to L; 
         R 2c , R 2d , R 2e , R 2f , and R 2g  are each independently selected from the group consisting of hydrogen and C 1-4  alkyl; 
         Z is selected from the group consisting of —CH 2  and —C(═O)—; 
         R 5  is selected from the group consisting of hydrogen, methyl, and fluoro; 
         A 1  is selected from the group consisting of —C(R 16a )═ and —N═; 
         A 2  is selected from the group consisting of —C(R 16b )═ and —N═; 
         A 3  is selected from the group consisting of —C(R 16c )═ and —N═; 
         R 16a  is selected from the group consisting of hydrogen, halo, and C 1-4  alkyl; 
         R 16b  is selected from the group consisting of hydrogen, halo, and C 1-4  alkyl; and 
         R 16 , is selected from the group consisting of hydrogen, halo, and C 1-4  alkyl, and 
         (2) isolating the compound having Formula I, or a pharmaceutically acceptable salt or solvate thereof. 
       
     
     
         90 . The method of  claim 89 , wherein the compound having Formula XI is selected from the group consisting of: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
     
     
         91 . The method of  claim 89 , wherein the compound having Formula I is a compound of Formula VI: 
       
         
           
           
               
               
           
         
       
     
     
         92 . The method of  claim 91 , wherein:
 R 2a  is selected from the group consisting of hydrogen and C 1-3  alkyl; and   R 17a  and R 17b  are each independently selected from the group consisting of hydrogen, C 1-4  alkyl, haloalkyl, C 1-4  alkoxy, and halo.   
     
     
         93 . The method of  claim 92 , wherein R 17a  and R 17b  are each independently selected from the group consisting of hydrogen and halo. 
     
     
         94 . The method of  claim 91 , wherein L is -A-(CH 2 ) m —W—(CH 2 ) n — and A is selected from the group consisting of 5-membered heteroarylenyl and 6-membered heteroarylenyl. 
     
     
         95 . The method of  claim 94 , wherein W is heterocyclenyl. 
     
     
         96 . The method of  claim 91 , wherein L is —(CH 2 ) m —W—(CH 2 ) n —.