IP Library › Granted Patent US 10,039,769

Granted Patent B2

US 10,039,769 · App. 15/610,153 · Granted Aug 7, 2018

Substituted triazolobenzodiazepines

Inventor: Scott L. Harbeson (Cambridge, MA)

Assignee: Concert Pharmaceuticals, Inc.

A61K31/5517 A61K45/06 C07B59/002 C07D487/04 C07B2200/05

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Quick Facts

Patent No.: US 10,039,769
App. No.: 15/610,153
Granted: Aug 7, 2018
Kind: B2

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USPTO Patent Center↗ Full Patent PDF↗

Abstract

This invention relates to novel substituted triazolobenzodiazepines of the Formula I: wherein each of the variables are defined herein and pharmaceutically acceptable salts thereof. This invention also provides compositions comprising a compound of this invention and the use of such compositions in methods of treating diseases and conditions that are beneficially treated by administering I-BET762.

Claims (569)

1. A method of treating a subject suffering from carcinoma or hematological cancer, the method comprising a step of administering to the subject in need thereof a compound of Formula I:

or a pharmaceutically acceptable salt thereof, wherein

Y 1a and Y 1b are the same and are hydrogen or deuterium;

Y 2 is hydrogen or deuterium;

R 1 and R 2 are each independently selected from CH 3 and CD 3 ;

R 3 is selected from CH 2 CH 3 , CH 2 CD 3 , CD 2 CH 3 , and CD 2 CD 3 ; and

if R 1 and R 2 are each CH 3 , R 3 is CH 2 CH 3 , and Y 2 is hydrogen, then Y 1a and Y 1b are each deuterium; and wherein any atom not designated as deuterium is present at its natural isotopic abundance.

2. The method of claim 1 , wherein the carcinoma is selected from lung, breast, colon, and midline carcinomas.

3. The method of claim 1 , wherein for the compound of Formula I, Y 1a and Y 1b are hydrogen.

4. The method of claim 1 , wherein for the compound of Formula I, Y 1a and Y 1b are deuterium.

5. The method of claim 1 , wherein for the compound of Formula I, R 3 is selected from CH 2 CH 3 and CD 2 CD 3 .

6. The method of claim 3 , wherein the compound of Formula I is selected from any one of the compounds set forth in the table below:

Compound

Y 2

R 1

R 2

R 3

101

—CH 3

—CD 2 CD 3

102

—CH 3

—CD 2 CH 3

103

—CH 3

—CH 2 CD 3

104

—CD 3

—CH 3

—CH 2 CH 3

105

—CH 3

—CD 3

—CH 2 CH 3

106

—CH 3

—CH 2 CH 3

107

—CD 3

—CH 3

—CH 2 CH 3

108

—CH 3

—CD 3

—CH 2 CH 3

109

—CH 3

—CD 2 CD 3

110

—CH 3

—CD 2 CH 3

111

—CH 3

—CH 2 CD 3

112

—CD 3

—CH 2 CH 3

113

—CD 3

—CH 3

—CD 2 CD 3

114

—CD 3

—CH 3

—CD 2 CH 3

115

—CD 3

—CH 3

—CH 2 CD 3

116

—CH 3

—CD 3

—CD 2 CD 3

117

—CH 3

—CD 3

—CD 2 CH 3

118

—CH 3

—CD 3

—CH 2 CD 3

119

—CD 3

—CH 2 CH 3

120

—CD 3

—CH 3

—CD 2 CD 3

121

—CD 3

—CH 3

—CD 2 CH 3

122

—CD 3

—CH 3

—CH 2 CD 3

123

—CH 3

—CD 3

—CD 2 CD 3

124

—CH 3

—CD 3

—CD 2 CH 3

125

—CH 3

—CD 3

—CH 2 CD 3

126

—CD 3

—CD 2 CD 3

127

—CD 3

—CD 2 CH 3

128

—CD 3

—CH 2 CD 3

129

—CD 3

—CD 2 CD 3

130

—CD 3

—CD 2 CH 3

131

—CD 3

—CH 2 CD 3

or a pharmaceutically acceptable salt thereof.

7. The method of claim 4 , wherein the compound of Formula I is selected from any one of the compounds set forth in the table below:

Compound

Y 2

R 1

R 2

R 3

200

—CH 3

—CH 2 CH 3

201

—CH 3

—CD 2 CD 3

202

—CH 3

—CD 2 CH 3

203

—CH 3

—CH 2 CD 3

204

—CD 3

—CH 3

—CH 2 CH 3

205

—CH 3

—CD 3

—CH 2 CH 3

206

—CH 3

—CH 2 CH 3

207

—CD 3

—CH 3

—CH 2 CH 3

208

—CH 3

—CD 3

—CH 2 CH 3

209

—CH 3

—CD 2 CD 3

210

—CH 3

—CD 2 CH 3

211

—CH 3

—CH 2 CD 3

212

—CD 3

—CH 2 CH 3

213

—CD 3

—CH 3

—CD 2 CD 3

214

—CD 3

—CH 3

—CD 2 CH 3

215

—CD 3

—CH 3

—CH 2 CD 3

216

—CH 3

—CD 3

—CD 2 CD 3

217

—CH 3

—CD 3

—CD 2 CH 3

218

—CH 3

—CD 3

—CH 2 CD 3

219

—CD 3

—CH 2 CH 3

220

—CD 3

—CH 3

—CD 2 CD 3

221

—CD 3

—CH 3

—CD 2 CH 3

222

—CD 3

—CH 3

—CH 2 CD 3

223

—CH 3

—CD 3

—CD 2 CD 3

224

—CH 3

—CD 3

—CD 2 CH 3

225

—CH 3

—CD 3

—CH 2 CD 3

226

—CD 3

—CD 2 CD 3

227

—CD 3

—CD 2 CH 3

228

—CD 3

—CH 2 CD 3

229

—CD 3

—CD 2 CD 3

230

—CD 3

—CD 2 CH 3

231

—CD 3

—CH 2 CD 3

or a pharmaceutically acceptable salt thereof.

8. The method of claim 1 , wherein for the compound of Formula I, the compound has an isotopic enrichment factor for each designated deuterium atom of at least 6000 (90% deuterium incorporation).

9. The method of claim 1 , wherein for the compound of Formula I, the compound has an isotopic enrichment factor for each designated deuterium atom of at least 6333.3 (95% deuterium incorporation).

10. The method of claim 6 , wherein the compound of Formula I is selected from any one of the compounds set forth in the table below:

Compound

Y 2

R 1

R 2

R 3

101

—CH 3

—CD 2 CD 3

105

—CH 3

—CD 3

—CH 2 CH 3

108

—CH 3

—CD 3

—CH 2 CH 3

109

—CH 3

—CD 2 CD 3

112

—CD 3

—CH 2 CH 3

113

—CD 3

—CH 3

—CD 2 CD 3

116

—CH 3

—CD 3

—CD 2 CD 3

117

—CH 3

—CD 3

—CD 2 CH 3

118

—CH 3

—CD 3

—CH 2 CD 3

119

—CD 3

—CH 2 CH 3

120

—CD 3

—CH 3

—CD 2 CD 3

123

—CH 3

—CD 3

—CD 2 CD 3

124

—CH 3

—CD 3

—CD 2 CH 3

125

—CH 3

—CD 3

—CH 2 CD 3

126

—CD 3

—CD 2 CD 3

127

—CD 3

—CD 2 CH 3

128

—CD 3

—CH 2 CD 3

129

—CD 3

—CD 2 CD 3

130

—CD 3

—CD 2 CH 3

131

—CD 3

—CH 2 CD 3

or a pharmaceutically acceptable salt thereof, wherein the compound has an isotopic enrichment factor for each designated deuterium atom of at least 6000 (90% deuterium incorporation).

11. The method of claim 7 , wherein the compound of Formula I is selected from any one of the compounds set forth in the table below:

Compound

Y 2

R 1

R 2

R 3

201

—CH 3

—CD 2 CD 3

205

—CH 3

—CD 3

—CH 2 CH 3

206

—CH 3

—CH 2 CH 3

207

—CD 3

—CH 3

—CH 2 CH 3

208

—CH 3

—CD 3

—CH 2 CH 3

209

—CH 3

—CD 2 CD 3

212

—CD 3

—CH 2 CH 3

213

—CD 3

—CH 3

—CD 2 CD 3

216

—CH 3

—CD 3

—CD 2 CD 3

217

—CH 3

—CD 3

—CD 2 CH 3

218

—CH 3

—CD 3

—CH 2 CD 3

219

—CD 3

—CH 2 CH 3

220

—CD 3

—CH 3

—CD 2 CD 3

223

—CH 3

—CD 3

—CD 2 CD 3

224

—CH 3

—CD 3

—CD 2 CH 3

225

—CH 3

—CD 3

—CH 2 CD 3

226

—CD 3

—CD 2 CD 3

227

—CD 3

—CD 2 CH 3

228

—CD 3

—CH 2 CD 3

229

—CD 3

—CD 2 CD 3

230

—CD 3

—CD 2 CH 3

231

—CD 3

—CH 2 CD 3

or a pharmaceutically acceptable salt thereof, wherein the compound has an isotopic enrichment factor for each designated deuterium atom of at least 6000 (90% deuterium incorporation).

12. The method of claim 10 , wherein for the compound of Formula I, the compound has an isotopic enrichment factor for each designated deuterium atom of at least 6333.3 (95% deuterium incorporation).

13. The method of claim 11 , wherein for the compound of Formula I, the compound has an isotopic enrichment factor for each designated deuterium atom of at least 6333.3 (95% deuterium incorporation).

14. The method of claim 1 , wherein the method is a method of treating a subject suffering from hematological cancer.

Assignments (1)

ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Jan 21, 2018

From: HARBESON, SCOTT L.

To: CONCERT PHARMACEUTICALS, INC.

Reel/Frame 044683/0162 →

Continuity (3)

Continuation 15117544

Provisional Application 61937701 · Feb 10, 2014

Related Publication 20170258807A1 · Sep 14, 2017