Fused 1,4-oxazepines and related analogs as BET bromodomain inhibitors

1. A compound having Formula II:

or a pharmaceutically acceptable salt or hydrate thereof,

wherein:

R 1 is C 1-4 alkyl;

R 2a and R 2b are each independently selected from the group consisting of hydrogen and C 1-4 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 3a and R 3b are each independently selected from the group consisting of hydrogen and C 1-4 alkyl;

R 4 is selected from the group consisting of aralkyl and optionally substituted C 3-7 cycloalkyl;

R 5 is selected from the group consisting of hydrogen, halogen, C 1-4 alkyl, optionally substituted C 2-4 alkynyl, and substituted 5- to 14-membered heteroaryl; and Y is —O—.

2. The compound of claim 1 having Formula V:

or a pharmaceutically acceptable salt or hydrate thereof.

3. The compound of claim 2 , wherein:

R 21 is C 1-4 alkyl;

R 4 is selected from the group consisting of aralkyl and optionally substituted C 3-7 cycloalkyl; and

R 5 is selected from the group consisting of hydrogen, halogen, C 1-4 alkyl, optionally substituted C 2-4 alkynyl, and substituted 5- to 14-membered heteroaryl, or a pharmaceutically acceptable salt or hydrate thereof.

4. The compound of claim 1 , wherein R 4 is aralkyl, or a pharmaceutically acceptable salt or hydrate thereof.

5. The compound of claim 1 having Formula VIII:

or a pharmaceutically acceptable salt or hydrate thereof, wherein:

R 2a is selected from the group consisting of hydrogen and C 1-3 alkyl;

R 16 is selected from the group consisting of hydroxyalkyl, optionally substituted aryl, and optionally substituted heteroaryl; and

R 17a is selected from the group consisting of hydrogen and halo.

6. The compound of claim 5 , or a pharmaceutically acceptable salt or hydrate thereof, wherein R 16 is optionally substituted heteroaryl.

7. A compound having Formula XI:

or pharmaceutically acceptable salts or hydrates thereof, wherein:

R 2a is selected from the group consisting of hydrogen and C 1-3 alkyl;

Z is heteroarylenyl;

R 17a is selected from the group consisting of hydrogen and halo;

R 18 is selected from the group consisting of —CHO, —CO 2 H, —OH, and halo; and

n is 0, 1, 2, 3, 4, 5, or 6.

8. A compound, or a pharmaceutically acceptable salt or hydrate thereof, selected from the group consisting of:

2,9-dimethyl-4H,6H-thieno[2,3-e][1,2,4]triazolo[3,4-c][1,4]oxazepine;

3-bromo-2,9-dimethyl-4H,6H-thieno[2,3-e][1,2,4]triazolo[3,4-c][1,4]oxazepine;

2,9-dimethyl-3-phenyl-4H,6H-thieno[2,3-e][1,2,4]triazolo[3,4-c][1,4]oxazepine;

3-benzyl-2,9-dimethyl-4H,6H-thieno[2,3-e][1,2,4]triazolo[3,4-c][1,4]oxazepine;

2,9-dimethyl-3-(quinolin-4-yl)-4H,6H-thieno[2,3-e][1,2,4]triazolo[3,4-c][1,4]oxazepine;

2,9-dimethyl-N-phenyl-4H,6H-thieno[2,3-e][1,2,4]triazolo[3,4-c][1,4]oxazepin-3-amine;

N-(3-cyclopropyl-1-methyl-1H-pyrazol-5-yl)-2,9-dimethyl-4H,6H-thieno[2,3-e][1,2,4]triazolo[3,4-c][1,4]oxazepin-3-amine;

3-(3-chlorobenzyl)-2,9-dimethyl-4H,6H-thieno[2,3-e][1,2,4]triazolo[3,4-c][1,4]oxazepine;

3-(4-chlorobenzyl)-2,9-dimethyl-4H,6H-thieno[2,3-e][1,2,4]triazolo[3,4-c][1,4]oxazepine;

3-(2-chlorobenzyl)-2,9-dimethyl-4H,6H-thieno[2,3-e][1,2,4]triazolo[3,4-c][1,4]oxazepine;

benzyl (S)-3-bromo-2,6,9-trimethyl-4H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepine-5(6H)-carboxylate;

benzyl (S)-3-benzyl-2,6,9-trimethyl-4H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepine-5(6H)-carboxylate;

(S)-3-benzyl-2,6,9-trimethyl-5,6-dihydro-4H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepine;

benzyl 3-benzyl-2,9-dimethyl-4H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepine-5(6H)-carboxylate;

3-benzyl-2,9-dimethyl-5,6-dihydro-4H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepine;

benzyl (R)-3-benzyl-2,6,9-trimethyl-4H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepine-5(6H)-carboxylate;

(R)-3-benzyl-2,6,9-trimethyl-5,6-dihydro-4H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepine;

ethyl (S)-3-benzyl-2,6,9-trimethyl-4H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepine-5(6H)-carboxylate;

(S)-1-(3-benzyl-2,6,9-trimethyl-4H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-5(6H)-yl)propan-1-one;

(S)-3-benzyl-2,5,6,9-tetramethyl-5,6-dihydro-4H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepine;

benzyl (S)-3-benzyl-6-(2-methoxy-2-oxoethyl)-2,9-dimethyl-4H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepine-5(6H)-carboxylate;

(S)-3-benzyl-N-ethyl-2,6,9-trimethyl-4H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepine-5(6H)-carboxamide;

methyl (S)-2-(3-benzyl-2,9-dimethyl-5,6-dihydro-4H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl)acetate;

2,9-dimethyl-3-(1-phenylvinyl)-4H,6H-thieno[2,3-e][1,2,4]triazolo[3,4-c][1,4]oxazepine;

ethyl (S)-2-(3-benzyl-2,6,9-trimethyl-4H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-5(6H)-yl)acetate;

(S)-3-benzyl-2,6,9-trimethyl-5-(phenethylsulfonyl)-5,6-dihydro-4H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepine;

(S)-3-benzyl-5-(cyclopropylmethyl)-2,6,9-trimethyl-5,6-dihydro-4H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepine;

2,9-dimethyl-3-(1-phenylethyl)-4H,6H-thieno[2,3-e][1,2,4]triazolo[3,4-c][1,4]oxazepine;

(S)-3-benzyl-5-cyclobutyl-2,6,9-trimethyl-5,6-dihydro-4H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepine;

3-benzyl-9-methyl-4H,6H-thieno[2,3-e][1,2,4]triazolo[3,4-c][1,4]oxazepine;

3-benzyl-2-bromo-9-methyl-4H,6H-thieno[2,3-e][1,2,4]triazolo[3,4-c][1,4]oxazepine;

5-(3-benzyl-9-methyl-4H,6H-thieno[2,3-e][1,2,4]triazolo[3,4-c][1,4]oxazepin-2-yl)pyridin-2-amine;

3-benzyl-2-ethynyl-9-methyl-4H,6H-thieno[2,3-e][1,2,4]triazolo[3,4-c][1,4]oxazepine;

(R)-3-benzyl-2,5,6,9-tetramethyl-5,6-dihydro-4H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepine;

3-benzyl-2,5,9-trimethyl-5,6-dihydro-4H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepine;

7-bromo-1-methyl-4H,6H-benzo[e][1,2,4]triazolo[3,4-c][1,4]oxazepine;

1-methyl-N-phenyl-4H,6H-benzo[e][1,2,4]triazolo[3,4-c][1,4]oxazepin-7-amine;

7-benzyl-1-methyl-4H,6H-benzo[e][1,2,4]triazolo[3,4-c][1,4]oxazepine;

1-methyl-7-(phenylthio)-4H,6H-benzo[e][1,2,4]triazolo[3,4-c][1,4]oxazepine;

1-methyl-7-phenoxy-4H,6H-benzo[e][1,2,4]triazolo[3,4-c][1,4]oxazepine;

7-((λ1-oxidanyl)(phenyl)-λ3-sulfanyl)-1-methyl-4H,6H-benzo[e][1,2,4]triazolo[3,4-c][1,4]oxazepine;

1-methyl-7-(phenylsulfonyl)-4H,6H-benzo[e][1,2,4]triazolo[3,4-c][1,4]oxazepine;

1-methyl-7-(1-phenylvinyl)-4H,6H-benzo[e][1,2,4]triazolo[3,4-c][1,4]oxazepine;

7-(1H-inden-3-yl)-1-methyl-4H,6H-benzo[e][1,2,4]triazolo[3,4-c][1,4]oxazepine;

1-methyl-7-(4-(trifluoromethoxy)benzyl)-4H,6H-benzo[e][1,2,4]triazolo[3,4-c][1,4]oxazepine;

1-methyl-7-(1-phenylethyl)-4H,6H-benzo[e][1,2,4]triazolo[3,4-c][1,4]oxazepine;

7-(2,3-dihydro-1H-inden-1-yl)-1-methyl-4H,6H-benzo[e][1,2,4]triazolo[3,4-c][1,4]oxazepine;

1-methyl-7-(1-phenylcyclopropyl)-4H,6H-benzo[e][1,2,4]triazolo[3,4-c][1,4]oxazepine;

7-(3,4-dihydronaphthalen-1-yl)-1-methyl-4H,6H-benzo[e][1,2,4]triazolo[3,4-c][1,4]oxazepine;

1-methyl-7-(1,2,3,4-tetrahydronaphthalen-1-yl)-4H,6H-benzo[e][1,2,4]triazolo[3,4-c][1,4]oxazepine;

3-(3,4-dihydronaphthalen-1-yl)-2,9-dimethyl-4H,6H-thieno[2,3-e][1,2,4]triazolo[3,4-c][1,4]oxazepine;

(1-methyl-4H,6H-benzo[e][1,2,4]triazolo[3,4-c][1,4]oxazepin-7-yl)(phenyl)methanone;

3-(1H-inden-3-yl)-2,9-dimethyl-4H,6H-thieno[2,3-e][1,2,4]triazolo[3,4-c][1,4]oxazepine;

2,9-dimethyl-3-(1,2,3,4-tetrahydronaphthalen-1-yl)-4H,6H-thieno[2,3-e][1,2,4]triazolo[3,4-c][1,4]oxazepine;

3-(2,3-dihydro-1H-inden-1-yl)-2,9-dimethyl-4H,6H-thieno[2,3-e][1,2,4]triazolo[3,4-c][1,4]oxazepine;

3-(6,7-dihydro-5H-benzo[7]annulen-9-yl)-2,9-dimethyl-4H,6H-thieno[2,3-e][1,2,4]triazolo[3,4-c][1,4]oxazepine;

3-(6-fluoro-3,4-dihydronaphthalen-1-yl)-2,9-dimethyl-4H,6H-thieno[2,3-e][1,2,4]triazolo[3,4-c][1,4]oxazepine;

3-(7-fluoro-3,4-dihydronaphthalen-1-yl)-2,9-dimethyl-4H,6H-thieno[2,3-e][1,2,4]triazolo[3,4-c][1,4]oxazepine;

7-(6,7-dihydro-5H-benzo[7]annulen-9-yl)-1-methyl-4H,6H-benzo[e][1,2,4]triazolo[3,4-c][1,4]oxazepine;

1-methyl-7-(6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-yl)-4H,6H-benzo[e][1,2,4]triazolo[3,4-c][1,4]oxazepine;

7-(6-fluoro-1,2,3,4-tetrahydronaphthalen-1-yl)-1-methyl-4H,6H-benzo[e][1,2,4]triazolo[3,4-c][1,4]oxazepine;

7-(7-fluoro-1,2,3,4-tetrahydronaphthalen-1-yl)-1-methyl-4H,6H-benzo[e][1,2,4]triazolo[3,4-c][1,4]oxazepine;

2,9-dimethyl-3-(6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-yl)-4H,6H-thieno[2,3-e][1,2,4]triazolo[3,4-c][1,4]oxazepine;

3-(6-fluoro-1,2,3,4-tetrahydronaphthalen-1-yl)-2,9-dimethyl-4H,6H-thieno[2,3-e][1,2,4]triazolo[3,4-c][1,4]oxazepine;

3-(7-fluoro-1,2,3,4-tetrahydronaphthalen-1-yl)-2,9-dimethyl-4H,6H-thieno[2,3-e][1,2,4]triazolo[3,4-c][1,4]oxazepine;

2′,9′-dimethyl-3′-(1,2,3,4-tetrahydronaphthalen-1-yl)-4′H-spiro[cyclopropane-1,6′-thieno[2,3-e][1,2,4]triazolo[3,4-c][1,4]oxazepine;

8-chloro-1-methyl-7-(1,2,3,4-tetrahydronaphthalen-1-yl)-4H,6H-benzo[e][1,2,4]triazolo[3,4-c][1,4]oxazepine;

1-methyl-8-(1-methyl-1H-pyrazol-4-yl)-7-(1,2,3,4-tetrahydronaphthalen-1-yl)-4H,6H-benzo[e][1,2,4]triazolo[3,4-c][1,4]oxazepine;

5-(1-methyl-7-(1,2,3,4-tetrahydronaphthalen-1-yl)-4H,6H-benzo[e][1,2,4]triazolo[3,4-c][1,4]oxazepin-8-yl)pyridin-2-amine;

7-bromo-8-chloro-1-methyl-4H,6H-benzo[e][1,2,4]triazolo[3,4-c][1,4]oxazepine;

7-benzyl-8-chloro-1-methyl-4H,6H-benzo[e][1,2,4]triazolo[3,4-c][1,4]oxazepine;

5-(7-benzyl-1-methyl-4H,6H-benzo[e][1,2,4]triazolo[3,4-c][1,4]oxazepin-8-yl)pyridin-2-amine;

7-benzyl-1-methyl-8-(1-methyl-1H-pyrazol-4-yl)-4H,6H-benzo[e][1,2,4]triazolo[3,4-c][1,4]oxazepine;

8-chloro-7-(3,4-dihydronaphthalen-1-yl)-1-methyl-4H,6H-benzo[e][1,2,4]triazolo[3,4-c][1,4]oxazepine;

7-benzyl-1-methyl-8-(1H-pyrazol-4-yl)-4H,6H-benzo[e][1,2,4]triazolo[3,4-c][1,4]oxazepine;

2-(4-(7-benzyl-1-methyl-4H,6H-benzo[e][1,2,4]triazolo[3,4-c][1,4]oxazepin-8-yl)-1H-pyrazol-1-yl)acetamide;

7-benzyl-8-(3,6-dihydro-2H-pyran-4-yl)-1-methyl-4H,6H-benzo[e][1,2,4]triazolo[3,4-c][1,4]oxazepine;

7-benzyl-8-(4,5-dihydrofuran-3-yl)-1-methyl-4H,6H-benzo[e][1,2,4]triazolo[3,4-c][1,4]oxazepine;

7-benzyl-1-methyl-8-(tetrahydro-2H-pyran-4-yl)-4H,6H-benzo[e][1,2,4]triazolo[3,4-c][1,4]oxazepine;

7-benzyl-8-(furan-3-yl)-1-methyl-4H,6H-benzo[e][1,2,4]triazolo[3,4-c][1,4]oxazepine;

7-benzyl-1-methyl-8-(tetrahydrofuran-3-yl)-4H,6H-benzo[e][1,2,4]triazolo[3,4-c][1,4]oxazepine;

7-benzyl-1-methyl-8-((trimethylsilyl)ethynyl)-4H,6H-benzo[e][1,2,4]triazolo[3,4-c][1,4]oxazepine;

7-benzyl-8-ethynyl-1-methyl-4H,6H-benzo[e][1,2,4]triazolo[3,4-c][1,4]oxazepine;

4-(7-benzyl-1-methyl-4H,6H-benzo[e][1,2,4]triazolo[3,4-c][1,4]oxazepin-8-yl)but-3-yn-1-ol;

(S)-3-benzyl-6,9-dimethyl-2-((1-methyl-1H-pyrazol-4-yl)ethynyl)-4H,6H-thieno[2,3-e][1,2,4]triazolo[3,4-c][1,4]oxazepine;

3-benzyl-9-methyl-2-((1-methyl-1H-imidazol-5-yl)ethynyl)-4H,6H-thieno[2,3-e][1,2,4]triazolo[3,4-c][1,4]oxazepine;

3-benzyl-9-methyl-2-(pyridin-4-ylethynyl)-4H,6H-thieno[2,3-e][1,2,4]triazolo[3,4-c][1,4]oxazepine;

3-benzyl-9-methyl-2-(pyridin-3-ylethynyl)-4H,6H-thieno[2,3-e][1,2,4]triazolo[3,4-c][1,4]oxazepine;

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-amine;

3-benzyl-9-methyl-2-(morpholinomethyl)-4H,6H-thieno[2,3-e][1,2,4]triazolo[3,4-c][1,4]oxazepine;

3-benzyl-9-methyl-2-(1H-pyrazol-4-yl)-4H,6H-thieno[2,3-e][1,2,4]triazolo[3,4-c][1,4]oxazepine;

3-benzyl-9-methyl-2-(1-methyl-1H-pyrazol-4-yl)-4H,6H-thieno[2,3-e][1,2,4]triazolo[3,4-c][1,4]oxazepine;

3-benzyl-2-cyclopropyl-9-methyl-4H,6H-thieno[2,3-e][1,2,4]triazolo[3,4-c][1,4]oxazepine;

3-benzyl-9-methyl-2-(prop-1-en-2-yl)-4H,6H-thieno[2,3-e][1,2,4]triazolo[3,4-c][1,4]oxazepine;

3-benzyl-2-(3,6-dihydro-2H-pyran-4-yl)-9-methyl-4H,6H-thieno[2,3-e][1,2,4]triazolo[3,4-c][1,4]oxazepine;

4-(3-benzyl-9-methyl-4H,6H-thieno[2,3-e][1,2,4]triazolo[3,4-c][1,4]oxazepin-2-yl)but-3-yn-1-ol;

3-benzyl-9-methyl-2-(tetrahydro-2H-pyran-4-yl)-4H,6H-thieno[2,3-e][1,2,4]triazolo[3,4-c][1,4]oxazepine;

3-benzyl-2-isopropyl-9-methyl-4H,6H-thieno[2,3-e][1,2,4]triazolo[3,4-c][1,4]oxazepine;

4-(3-benzyl-9-methyl-4H,6H-thieno[2,3-e][1,2,4]triazolo[3,4-c][1,4]oxazepin-2-yl)butan-1-ol;

3-(3-fluorobenzyl)-2,9-dimethyl-4H,6H-thieno[2,3-e][1,2,4]triazolo[3,4-c][1,4]oxazepine;

3-((2,9-dimethyl-4H,6H-thieno[2,3-e][1,2,4]triazolo[3,4-c][1,4]oxazepin-3-yl)methyl)benzonitrile;

3-(2-fluorobenzyl)-2,9-dimethyl-4H,6H-thieno[2,3-e][1,2,4]triazolo[3,4-c][1,4]oxazepine;

3-(4-fluorobenzyl)-2,9-dimethyl-4H,6H-thieno[2,3-e][1,2,4]triazolo[3,4-c][1,4]oxazepine;

3-(3,5-difluorobenzyl)-2,9-dimethyl-4H,6H-thieno[2,3-e][1,2,4]triazolo[3,4-c][1,4]oxazepine;

3-(3,4-difluorobenzyl)-2,9-dimethyl-4H,6H-thieno[2,3-e][1,2,4]triazolo[3,4-c][1,4]oxazepine;

3-((1H-indol-1-yl)methyl)-2,9-dimethyl-4H,6H-thieno[2,3-e][1,2,4]triazolo[3,4-c][1,4]oxazepine;

3-((1H-pyrrol-1-yl)methyl)-2,9-dimethyl-4H,6H-thieno[2,3-e][1,2,4]triazolo[3,4-c][1,4]oxazepine;

3-(tert-butoxymethyl)-2,9-dimethyl-4H,6H-thieno[2,3-e][1,2,4]triazolo[3,4-c][1,4]oxazepine;

3-benzyl-2,6,9-trimethyl-4H,6H-thieno[2,3-e][1,2,4]triazolo[3,4-c][1,4]oxazepine;

3-benzyl-9-methyl-4H,6H-thieno[2,3-e][1,2,4]triazolo[3,4-c][1,4]oxazepine-2-carbonitrile;

3-(4-fluorobenzyl)-9-methyl-2-((1-methyl-1H-pyrazol-4-yl)ethynyl)-4H,6H-thieno[2,3-e][1,2,4]triazolo[3,4-c][1,4]oxazepine;

3-((1H-pyrazol-1-yl)methyl)-2,9-dimethyl-4H,6H-thieno[2,3-e][1,2,4]triazolo[3,4-c][1,4]oxazepine;

(S)-4-(3-benzyl-6,9-dimethyl-4H,6H-thieno[2,3-e][1,2,4]triazolo[3,4-c][1,4]oxazepin-2-yl)but-3-yn-1-ol;

(R)-3-benzyl-2,6,9-trimethyl-4H,6H-thieno[2,3-e][1,2,4]triazolo[3,4-c][1,4]oxazepine;

tert-butyl 2-(3-benzyl-2,9-dimethyl-4H,6H-thieno[2,3-e][1,2,4]triazolo[3,4-c][1,4]oxazepin-6-yl)acetate;

1-(1-methyl-4H,6H-benzo[e][1,2,4]triazolo[3,4-c][1,4]oxazepin-7-yl)-1-phenylethane-1,2-diol;

(S)-3-bromo-6,9-dimethyl-4H,6H-thieno[2,3-e][1,2,4]triazolo[3,4-c][1,4]oxazepine;

(S)-3-benzyl-6,9-dimethyl-4H,6H-thieno[2,3-e][1,2,4]triazolo[3,4-c][1,4]oxazepine;

(S)-3-benzyl-2-bromo-6,9-dimethyl-4H,6H-thieno[2,3-e][1,2,4]triazolo[3,4-c][1,4]oxazepine;

(S)-3-benzyl-6,9-dimethyl-2-((1-methyl-1H-imidazol-5-yl)ethynyl)-4H,6H-thieno[2,3-e][1,2,4]triazolo[3,4-c][1,4]oxazepine;

(S)-3-benzyl-6,9-dimethyl-2-(pyridin-4-ylethynyl)-4H,6H-thieno[2,3-e][1,2,4]triazolo[3,4-c][1,4]oxazepine;

(S)-3-benzyl-6,9-dimethyl-2-(pyridin-3-ylethynyl)-4H,6H-thieno[2,3-e][1,2,4]triazolo[3,4-c][1,4]oxazepine;

(S)-5-((3-benzyl-6,9-dimethyl-4H,6H-thieno[2,3-e][1,2,4]triazolo[3,4-c][1,4]oxazepin-2-yl)ethynyl)pyridin-2-amine;

(S)-3-(4-fluorobenzyl)-6,9-dimethyl-4H,6H-thieno[2,3-e][1,2,4]triazolo[3,4-c][1,4]oxazepine;

(S)-2-bromo-3-(4-fluorobenzyl)-6,9-dimethyl-4H,6H-thieno[2,3-e][1,2,4]triazolo[3,4-c][1,4]oxazepine;

(S)-3-(4-fluorobenzyl)-6,9-dimethyl-2-((1-methyl-1H-pyrazol-4-yl)ethynyl)-4H,6H-thieno[2,3-e][1,2,4]triazolo[3,4-c][1,4]oxazepine;

2,9-dimethyl-3-((1-methyl-1H-pyrazol-4-yl)methyl)-4H,6H-thieno[2,3-e][1,2,4]triazolo[3,4-c][1,4]oxazepine;

2,3,9-trimethyl-4H,6H-thieno[2,3-e][1,2,4]triazolo[3,4-c][1,4]oxazepine;

2,6,9-trimethyl-4H,6H-thieno[2,3-e][1,2,4]triazolo[3,4-c][1,4]oxazepine;

3-bromo-2,6,9-trimethyl-4H,6H-thieno[2,3-e][1,2,4]triazolo[3,4-c][1,4]oxazepine;

tert-butyl 2-(2,9-dimethyl-4H,6H-thieno[2,3-e][1,2,4]triazolo[3,4-c][1,4]oxazepin-6-yl)acetate;

tert-butyl 2-(3-bromo-2,9-dimethyl-4H,6H-thieno[2,3-e][1,2,4]triazolo[3,4-c][1,4]oxazepin-6-yl)acetate;

2′-bromo-9′-methyl-4′H-spiro[cyclopropane-1,6′-thieno[2,3-e][1,2,4]triazolo[3,4-c][1,4]oxazepine];

2′,9′-dimethyl-4′H-spiro[cyclopropane-1,6′-thieno[2,3-e][1,2,4]triazolo[3,4-c][1,4]oxazepine];

3′-bromo-2′,9′-dimethyl-4′H-spiro[cyclopropane-1,6′-thieno[2,3-e][1,2,4]triazolo[3,4-c][1,4]oxazepine];

3′-benzyl-2′,9′-dimethyl-4′H-spiro[cyclopropane-1,6′-thieno[2,3-e][1,2,4]triazolo[3,4-c][1,4]oxazepine];

3-bromo-9-methyl-4H,6H-thieno[2,3-e][1,2,4]triazolo[3,4-c][1,4]oxazepine;

3-chloro-9-methyl-4H,6H-thieno[2,3-e][1,2,4]triazolo[3,4-c][1,4]oxazepine;

3-(4-fluorobenzyl)-9-methyl-4H,6H-thieno[2,3-e][1,2,4]triazolo[3,4-c][1,4]oxazepine;

2-bromo-3-(4-fluorobenzyl)-9-methyl-4H,6H-thieno[2,3-e][1,2,4]triazolo[3,4-c][1,4]oxazepine;

(S)-3-chloro-6,9-dimethyl-4H,6H-thieno[2,3-e][1,2,4]triazolo[3,4-c][1,4]oxazepine;

(S)-3-(3-benzyl-6,9-dimethyl-4H,6H-thieno[2,3-e][1,2,4]triazolo[3,4-c][1,4]oxazepin-2-yl)-N,N-dimethylprop-2-yn-1-amine;

(S)-3-benzyl-2-(3-methoxyprop-1-yn-1-yl)-6,9-dimethyl-4H,6H-thieno[2,3-e][1,2,4]triazolo[3,4-c][1,4]oxazepine;

benzyl 3-bromo-2,9-dimethyl-4H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepine-5(6H)-carboxylate;

benzyl (S)-3-bromo-6-(2-methoxy-2-oxoethyl)-2,9-dimethyl-4H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepine-5(6H)-carboxylate;

3-benzyl-9-methyl-2-(pyridin-2-ylethynyl)-4H,6H-thieno[2,3-e][1,2,4]triazolo[3,4-c][1,4]oxazepine;

(S)-3-benzyl-6,9-dimethyl-2-(pyridin-2-ylethynyl)-4H,6H-thieno[2,3-e][1,2,4]triazolo[3,4-c][1,4]oxazepine;

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)butanal;

3-benzyl-9-methyl-2-((1-methyl-1H-pyrazol-4-yl)ethynyl)-4H,6H-thieno[2,3-e][1,2,4]triazolo[3,4-c][1,4]oxazepine;

2-((1H-pyrazol-4-yl)ethynyl)-3-benzyl-9-methyl-4H,6H-thieno[2,3-e][1,2,4]triazolo[3,4-c][1,4]oxazepine; and

(S)-3-benzyl-2,6,9-trimethyl-4H,6H-thieno[2,3-e][1,2,4]triazolo[3,4-c][1,4]oxazepine.

9. A pharmaceutical composition comprising the compound of claim 1 , or a pharmaceutically acceptable salt or hydrate thereof, and a pharmaceutically acceptable carrier.

10. A method of treating a patient, 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 breast cancer.

11. The method of claim 10 further comprising administering a therapeutically effective amount of a second therapeutic agent useful in the treatment of breast cancer.

12. 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, hydrate, or solvate thereof, to a patient having cancer, a chronic autoimmune disorder, an inflammatory condition, a proliferative disorder, sepsis, or a viral infection.

13. The kit of claim 12 , wherein the patient has cancer.

14. The kit of claim 12 further comprising one or more additional therapeutic agents.

15. The compound of claim 1 , wherein R 2a and R 2b are each independently selected from the group consisting of hydrogen and C 1-4 alkyl, and R 3a and R 3b are hydrogen, or a pharmaceutically acceptable salt or hydrate thereof.

16. The compound of claim 1 , wherein R 4 is optionally substituted C 3-7 cycloalkyl selected from the group consisting of:

or a pharmaceutically acceptable salt or hydrate thereof.