BET bromodomain protein degraders with cleavable linkers
The present disclosure provides compounds represented by Formula (I): Formula (I) and the pharmaceutically acceptable salts and solvates thereof, wherein R 1 , R 2a , R 2b , R 3a , R 3b , R 4 , Y, ═, Ar, W, L, and B are as defined as set forth in the specification. The present disclosure also provides compounds of Formula (I)I for use to treat a condition or disorder responsive to inhibition and/or degradation of BET bromodomains such as cancer.
1. 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 independently selected from the group consisting of hydrogen, optionally substituted C 1-4 alkyl, —CH 2 C(═O)OR 18 , 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;
is a single bond, R 3a and R 3b are independently selected from the group consisting of hydrogen and optionally substituted C 1-4 alkyl; and Y is selected from the group consisting of —O—, —S—, and —NR 10 —; or
is a double bond, R 3a is selected from the group consisting of optionally substituted C 6-14 aryl and optionally substituted 5- to 14-membered heteroaryl; R 3b is absent; and Y is —N═;
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, optionally substituted 5- to 14-membered heteroaryl, —NR 6a R 6b , —OR 7 , —SR 8a , —S(═O)R 8b , —S(═O) 2 R 8c , —C(═O)R 9 , (heteroaryl)alkyl, and alkoxyalkyl;
R 6a and R 6b are each independently selected from the group consisting of hydrogen, optionally substituted C 1-6 alkyl, aralkyl, optionally substituted C 6-14 aryl, optionally substituted C 3-12 cycloalkyl, optionally substituted 3- to 14-membered heterocyclo, optionally substituted 5- to 14-membered heteroaryl, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, alkyl sulfonyl, aryl sulfonyl, and carboxamido; or
R 6a and R 6b taken together with the nitrogen atom to which they are attached form an optionally substituted 4- to 8-membered heterocyclo;
R 7 is selected from the group consisting of hydrogen, optionally substituted C 1-4 alkyl, aralkyl, optionally substituted C 6-14 aryl, optionally substituted C 3-12 cycloalkyl, optionally substituted 3- to 14-membered heterocyclo, optionally substituted 5- to 14-membered heteroaryl, alkylcarbonyl, and carboxamido;
R 8a is selected from the group consisting of optionally substituted C 1-4 alkyl, 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;
R 8b is selected from the group consisting of optionally substituted C 1-4 alkyl, 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;
R 8c is selected from the group consisting of optionally substituted C 1-4 alkyl, aralkyl, optionally substituted C 6-14 aryl, optionally substituted C 3-12 cycloalkyl, optionally substituted 3- to 14-membered heterocyclo, optionally substituted 5- to 14-membered heteroaryl, and amino;
R 9 is selected from the group consisting of hydrogen, optionally substituted C 1-4 alkyl, aralkyl, optionally substituted C 6-14 aryl, optionally substituted C 3-12 cycloalkyl, optionally substituted 3- to 14-membered heterocyclo, optionally substituted 5- to 14-membered heteroaryl, alkoxy, and amino;
R 10 is selected from the group consisting of hydrogen, optionally substituted C 1-6 alkyl, optionally substituted C 6-14 aryl, optionally substituted C 3-12 cycloalkyl, optionally substituted 3- to 14-membered heterocyclo, optionally substituted 5- to 14-membered heteroaryl, (C 3-6 cycloalkyl)C 1-4 alkyl, aralkyl, (alkoxycarbonyl)alkyl, —C(═O)R 11 , —SO 2 R 12 , —C(═O)—OR 13 , and —C(═O)—NR 14a R 14b ;
R 11 is selected from the group consisting of optionally substituted C 1-6 alkyl, optionally substituted C 6-14 aryl, optionally substituted C 3-12 cycloalkyl, optionally substituted 3- to 14-membered heterocyclo, optionally substituted 5- to 14-membered heteroaryl, and aralkyl;
R 12 is selected from the group consisting of optionally substituted C 1-6 alkyl, optionally substituted C 6-14 aryl, optionally substituted C 3-12 cycloalkyl, optionally substituted 3- to 14-membered heterocyclo, optionally substituted 5- to 14-membered heteroaryl, and aralkyl;
R 13 is selected from the group consisting of optionally substituted C 1-6 alkyl, optionally substituted C 6-14 aryl, optionally substituted C 3-12 cycloalkyl, optionally substituted 3- to 14-membered heterocyclo, optionally substituted 5- to 14-membered heteroaryl, and aralkyl;
R 14a and R 14b are each independently selected from the group consisting of hydrogen, optionally substituted C 1-6 alkyl, optionally substituted C 6-14 aryl, optionally substituted C 3-12 cycloalkyl, 3- to 14-membered heterocyclo, optionally substituted 5- to 14-membered heteroaryl, and aralkyl; or
R 14a and R 14b taken together with the nitrogen atom to which they are attached form an optionally substituted 4- to 8-membered heterocyclo;
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 selected from the group consisting of:
L is -L -E-L 2 -X—, wherein L 1 is attached to W;
L 1 is selected from the group consisting of alkylenyl and heteroalkylenyl;
E is —C(═O)—O—;
L 2 is selected from the group consisting of alkylenyl and heteroalkylenyl; or
L 2 is absent;
W is selected from the group consisting of phenylenyl, 5-membered heteroarylenyl, 6-membered heteroarylenyl, heterocyclenyl, and cycloalkylenyl;
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—, —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 )—, the carbon atom of —C(═O)N(R 2d )—, and the piperidine nitrogen atom of
is attached to L 2 ;
with the proviso that when L 2 is absent, X is selected from the group consisting of —C≡C—, —CH 2 —, and —O—;
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;
R 18 is selected from the group consisting of hydrogen and C 1-6 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.
2. The compound of claim 1 having Formula II:
or a pharmaceutically acceptable salt or hydrate thereof.
3. The compound of claim 2 having Formula III:
or a pharmaceutically acceptable salt or hydrate thereof.
4. The compound of claim 3 having Formula VI:
or a pharmaceutically acceptable salt or hydrate thereof.
5. The compound of claim 4 having Formula VII:
or a pharmaceutically acceptable salt or hydrate thereof.
6. The compound of claim 2 having Formula XI:
or a pharmaceutically acceptable salt or hydrate thereof.
7. The compound of claim 4 having Formula XIV:
or a pharmaceutically acceptable salt or hydrate thereof.
8. The compound of claim 4 having Formula XV:
or a pharmaceutically acceptable salt or hydrate thereof, wherein R 17a and R 17b are independently selected from the group consisting of hydrogen, C 1-4 alkyl, haloalkyl, C 1-4 alkoxy, and halo.
9. The compound of claim 7 having Formula XIX:
or a pharmaceutically acceptable salt or hydrate thereof, wherein:
R 2a is selected from the group consisting of C 1-4 alkyl and CH 2 C(═O)NR 19a R 19b ;
R 17c and R 17d are independently selected from the group consisting of hydrogen, C 1-4 alkyl, haloalkyl, C 1-4 alkoxy, and halo; and
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.
10. The compound of claim 1 , or a pharmaceutically acceptable salt or hydrate thereof, wherein L 1 is alkylenyl.
11. The compound of claim 1 , or a pharmaceutically acceptable salt or hydrate thereof, wherein L 2 is selected from the group consisting of alkylenyl and heteroalkylenyl.
12. The compound of claim 1 , or a pharmaceutically acceptable salt or hydrate thereof, wherein X is selected from the group consisting of —C≡C—, —CH 2 —, —O—, —N(H)—,
13. The compound of claim 1 , or a pharmaceutically acceptable salt or hydrate thereof, wherein B is B-1.
14. The compound of claim 13 , or a pharmaceutically acceptable salt or hydrate thereof, wherein:
A 1 is —C(R 16a )═ and R 16a is selected from the group consisting of hydrogen and halo;
A 2 is —C(R 16b )═ and R 16b is selected from the group consisting of hydrogen and halo;
A 3 is —C(R 16c )═ and R 16c is selected from the group consisting of hydrogen and halo;
Z is —C(═O)—; and
R 5 is hydrogen.
15. The compound of claim 1 , or a pharmaceutically acceptable salt or hydrate thereof, selected from the group consisting of:
3-(4-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)amino)piperidin-1-yl)propyl 4-(4-(((S)-4-(4-chlorophenyl)-3,9-dimethyl-6-(2-(4-methylpiperazin-1-yl)-2-oxoethyl)-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-2-yl)ethynyl)-1H-pyrazol-1-yl)butanoate;
2-(3-(4-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)amino)piperidin-1-yl)propoxy)ethyl 4-(4-(((S)-4-(4-chlorophenyl)-3,9-dimethyl-6-(2-(4-methylpiperazin-1-yl)-2-oxoethyl)-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-2-yl)ethynyl)-1H-pyrazol-1-yl)butanoate;
3-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)prop-2-yn-1-yl 2-(4-(((S)-4-(4-chlorophenyl)-3,6,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-2-yl)ethynyl)-1H-pyrazol-1-yl)acetate;
3-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)prop-2-yn-1-yl 2-(4-(((S)-4-(4-chlorophenyl)-3,6,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-2-yl)ethynyl)-1H-pyrazol-1-yl)acetate;
3-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)oxy)propyl 4-(4-(((S)-4-(4-chlorophenyl)-3,6,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-2-yl)ethynyl)-1H-pyrazol-1-yl)butanoate;
2-(2-(2-((3-(2-(2,6-dioxopiperidin-3-yl)-1oxoisoindolin-4-yl)prop-2-yn-1-yl)oxy)ethoxy)ethoxy)ethyl 4-(4-(((S)-4-(4-chlorophenyl)-3,9-dimethyl-6-(2-(4-methylpiperazin-1-yl)-2-oxoethyl)-6H-theino[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-2-yl)ethynyl)-1H-pyrazol-1-yl)butanoate;
3-(2-(4((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)amino)piperidin-1-yl)ethoxy)propyl 4-(4-(((S)-4-(4-chlorophenyl)-3,9-dimethyl-6-(2-(4-methylpiperazin-1-yl)-2-oxoethyl)-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-2-yl)ethynyl)-1H-pyrazol-1-yl)butanoate;
3-(2-(4((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)amino)piperidin-1-yl)ethoxy)propyl 4-(4-(((S)-4-(4-chlorophenyl)-3,6,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-2-yl)ethynyl)-1H-pyrazol-1-yl)butanoate;
3-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)oxy)propyl 4-(4-(((S)-4-(4-chlorophenyl)-3,9-dimethyl-6-(2-(4-methylpiperazin-1-yl)-2-oxoethyl)-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-2-yl)ethynyl)-1H-pyrazol-1-yl)butanoate;
2-(2-(2-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)oxy)ethoxy)ethoxy)ethyl 4-(4-(((S)-4-(4-chlorophenyl)-3,9-dimethyl-6-(2-(4-methylpiperazin-1-yl)-2-oxoethyl)-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-2-yl)ethynyl)-1H-pyrazol-1-yl)butanoate;
2-(4((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)amino)piperidin-1-yl)ethyl 4-(4-(((S)-4-(4-chlorophenyl)-3,6,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-2-yl)ethynyl)-1H-pyrazol-1-yl)butanoate;
2-(4-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)amino)piperidin-1-yl)ethyl 4-(4-(((S)-4-(4-chlorophenyl)-3,9-dimethyl-6-(2-(4-methylpiperazin-1-yl)-2-oxoethyl)-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-2-yl)ethynyl)-1H-pyrazol-1-yl)butanoate;
2-(2-(4-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)amino)piperidin-1-yl)ethoxy)ethyl 4-(4-(((S)-4-(4-chlorophenyl)-3,9-dimethyl-6-(2-(4-methylpiperazin-1-yl)-2-oxoethyl)-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-2-yl)ethynyl)-1H-pyrazol-1-yl)butanoate;
2-(2-(2-(4-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)amino)piperidin-1-yl)ethoxy)ethoxy)ethyl 4-(4-(((S)-4-(4-chlorophenyl)-3,9-dimethyl-6-(2-(4-methylpiperazin-1-yl)-2-oxoethyl)-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-2-yl)ethynyl)-1H-pyrazol-1-yl)butanoate;
3-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)oxy)propyl 4-(4-((3-benzyl-9-methyl-4H,6H-thieno[2,3-e][1,2,4]triazolo[3,4-c][1,4]oxazepin-2-yl)ethynyl)-1H-pyrazol-1-yl)butanoate;
4-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)but-3-yn-1-yl 4-(4-((3-benzyl-9-methyl-4H,6H-thieno[2,3-e][1,2,4]triazolo[3,4-c][1,4]oxazepin-2-yl)ethynyl)-1H-pyrazol-1-yl)butanoate;
3-(4-((3-benzyl-9-methyl-4H,6H-thieno[2,3-e][1,2,4]triazolo[3,4-c][1,4]oxazepin-2-yl)ethynyl)-1H-pyrazol-1-yl)propyl 3-(2-(2,6-dioxopiperidin-3-yl)-oxoisoindolin-4-yl)propanoate;
3-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)amino)propyl 4-(4-((3-benzyl-9-methyl-4H,6H-thieno[2,3-e][1,2,4]triazolo[3,4-c][1,4]oxazepin-2-yl)ethynyl)-1H-pyrazol-1-yl)butanoate;
3-(4-((3-benzyl-9-methyl-4H,6H-thieno[2,3-e][1,2,4]triazolo[3,4-c][1,4]oxazepin-2-yl)ethynyl)-1H-pyrazol-1-yl)propyl 5-(2-(2,6-dioxopiperidin-3-yl)-oxoisoindolin-4-yl)pentanoate;
3-(4-((3-benzyl-9-methyl-4H,6H-thieno[2,3-e][1,2,4]triazolo[3,4-c][1,4]oxazepin-2-yl)ethynyl)-1H-pyrazol-1-yl)propyl 4-(2-(2,6-dioxopiperidin-3-yl)-oxoisoindolin-4-yl)butanoate;
3-(4-((3-benzyl-9-methyl-4H,6H-thieno[2,3-e][1,2,4]triazolo[3,4-c][1,4]oxazepin-2-yl)ethynyl)-1H-pyrazol-1-yl)propyl 4-(2-(2,6-dioxopiperidin-3-yl)-oxoisoindolin-4-yl)but-3-ynoate;
2-(2-(2-(2-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)oxy)ethoxy)ethoxy)ethoxy)ethyl 4-(4-((3-benzyl-9-methyl-4H,6H-thieno[2,3-e][1,2,4]triazolo[3,4-c][1,4]oxazepin-2-yl)ethynyl)-1H-pyrazol-1-yl)butanoate;
(3-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)oxy)propoxy)methyl 4-(4-((3-benzyl-9-methyl-4H,6H-thieno[2,3-e][1,2,4]triazolo[3,4-c][1,4]oxazepin-2-yl)ethynyl)-1H-pyrazol-1-yl)butanoate;
3-(4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)piperazin-1-yl)propyl 4-(4-((3-benzyl-9-methyl-4H,6H-thieno[2,3-e][1,2,4]triazolo[3,4-c][1,4]oxazepin-2-yl)ethynyl)-1H-pyrazol-1-yl)butanoate;
3-(4-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)amino)piperidin-1-yl)propyl 4-(4-((3-benzyl-9-methyl-4H,6H-thieno[2,3-e][1,2,4]triazolo[3,4-c][1,4]oxazepin-2-yl)ethynyl)-1H-pyrazol-1-yl)butanoate;
2-(2-(4-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)amino)piperidin-1-yl)ethoxy)ethyl 4-(4-((3-benzyl-9-methyl-4H,6H-thieno[2,3-e][1,2,4]triazolo[3,4-c][1,4]oxazepin-2-yl)ethynyl)-1H-pyrazol-1-yl)butanoate;
2-(2-(2-(4-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)amino)piperidin-1-yl)ethoxy)ethoxy)ethyl 4-(4-((3-benzyl-9-methyl-4H,6H-thieno[2,3-e][1,2,4]triazolo[3,4-c][1,4]oxazepin-2-yl)ethynyl)-1H-pyrazol-1-yl)butanoate;
4-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)but-3-yn-1-yl 3-(3-((3-benzyl-9-methyl-4H,6H-thieno[2,3-e][1,2,4]triazolo[3,4-c][1,4]oxazepin-2-yl)ethynyl)-1H-pyrazol-1-yl)propanoate;
4-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)butyl 3-(3-((3-benzyl-9-methyl-4H,6H-thieno[2,3-e][1,2,4]triazolo[3,4-c][1,4]oxazepin-2-yl)ethynyl)-1H-pyrazol-1-yl)propanoate;
3-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)amino)propyl 3-(3-((3-benzyl-9-methyl-4H,6H-thieno[2,3-e][1,2,4]triazolo[3,4-c][1,4]oxazepin-2-yl)ethynyl)-1H-pyrazol-1-yl)propanoate;
2-(4-((3-benzyl-9-methyl-4H,6H-thieno[2,3-e][1,2,4]triazolo[3,4-c][1,4]oxazepin-2-yl)ethynyl)-1H-pyrazol-1-yl)ethyl 5-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)pent-4-ynoate;
2-(4-((3-benzyl-9-methyl-4H,6H-thieno[2,3-e][1,2,4]triazolo[3,4-c][1,4]oxazepin-2-yl)ethynyl)-1H-pyrazol-1-yl)ethyl 5-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)pentanoate;
2-(4-((3-benzyl-9-methyl-4H,6H-thieno[2,3-e][1,2,4]triazolo[3,4-c][1,4]oxazepin-2-yl)ethynyl)-1H-pyrazol-1-yl)ethyl 5-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)pent-4-ynoate;
4-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)butyl 2-(4-((3-benzyl-9-methyl-4H,6H-thieno[2,3-e][1,2,4]triazolo[3,4-c][1,4]oxazepin-2-yl)ethynyl)-1H-pyrazol-1-yl)acetate;
4-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)butyl 4-(4-((3-benzyl-9-methyl-4H,6H-thieno[2,3-e][1,2,4]triazolo[3,4-c][1,4]oxazepin-2-yl)ethynyl)-1H-pyrazol-1-yl)butanoate;
3-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)propyl 4-(4-((3-benzyl-9-methyl-4H,6H-thieno[2,3-e][1,2,4]triazolo[3,4-c][1,4]oxazepin-2-yl)ethynyl)-1H-pyrazol-1-yl)butanoate;
3-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)oxy)propyl 2-(4-((3-benzyl-9-methyl-4H,6H-thieno[2,3-e][1,2,4]triazolo[3,4-c][1,4]oxazepin-2-yl)ethynyl)-1H-pyrazol-1-yl)acetate;
3-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)propyl 2-(4-((3-benzyl-9-methyl-4H,6H-thieno[2,3-e][1,2,4]triazolo[3,4-c][1,4]oxazepin-2-yl)ethynyl)-1H-pyrazol-1-yl)acetate;
3-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)prop-2-yn-1-yl 2-(4-((3-benzyl-9-methyl-4H,6H-thieno[2,3-e][1,2,4]triazolo[3,4-c][1,4]oxazepin-2-yl)ethynyl)-1H-pyrazol-1-yl)acetate;
4-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)but-3-yn-1-yl 2-(4-((3-benzyl-9-methyl-4H,6H-thieno[2,3-e][1,2,4]triazolo[3,4-c][1,4]oxazepin-2-yl)ethynyl)-1H-pyrazol-1-yl)acetate;
3-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)prop-2-yn-1-yl 4-(4-((3-benzyl-9-methyl-4H,6H-thieno[2,3-e][1,2,4]triazolo[3,4-c][1,4]oxazepin-2-yl)ethynyl)-1H-pyrazol-1-yl)butanoate;
2-(4-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)amino)piperidin-1-yl)ethyl 4-(5-((3-benzyl-9-methyl-4H,6H-thieno[2,3-e][1,2,4]triazolo[3,4-c][1,4]oxazepin-2-yl)ethynyl)pyridin-2-yl)butanoate;
2-(4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)piperazin-1-yl)ethyl 4-(5-((3-benzyl-9-methyl-4H,6H-thieno[2,3-e][1,2,4]triazolo[3,4-c][1,4]oxazepin-2-yl)ethynyl)pyridin-2-yl)butanoate; and
2-(4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)piperazin-1-yl)ethyl 4-(4-((3-benzyl-9-methyl-4H,6H-thieno[2,3-e][1,2,4]triazolo[3,4-c][1,4]oxazepin-2-yl)ethynyl)-1H-pyrazol-1-yl)butanoate.
16. A pharmaceutical composition comprising the compound of claim 1 , or a pharmaceutically acceptable salt or hydrate thereof, and a pharmaceutically acceptable carrier.
17. A method of inhibiting BET bromodomain proteins and/or degrading BET bromodomain proteins in a patient in need thereof, the method comprising administering to the patient a therapeutically effective amount of the compound of claim 1 , 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.
18. A kit comprising the compound of claim 1 , or a pharmaceutically acceptable salt, or hydrate thereof, and instructions for administering the compound, or a pharmaceutically acceptable salt, or hydrate thereof.
19. A method of making a compound of claim 1 having Formula I, wherein L is -L 1 -C(═O)—O-L 2 -X—, the method comprising:
reacting a compound having Formula XX:
wherein R 20 is —CO 2 H, with a compound having Formula XXXIX:
HO-L 2 -X—B; XXXIX
or
reacting a compound having Formula XX:
wherein R 20 is —OH, with a compound having Formula XL:
HO 2 C-L 2 -X—B, XL
and
isolating the compound having Formula I.