Benzodiazepine derivatives, compositions, and methods for treating cognitive impairment

1. A compound of formula II:

or a pharmaceutically acceptable salt, stereoisomer, Z (zusammen) isomer, E (entgegen) isomer or combination thereof, wherein:

m is an integer selected from 0-4;

each occurrence of R 1 , R 2 , R 4 , and R 5 are each independently selected from:

halogen, —R, —OR, —NO 2 , —NCS, —CN, —CF 3 , —OCF 3 , —SiR 3 , —N(R) 2 , —SR, —SOR, —SO 2 R, —SO 2 N(R) 2 , —SO 3 R, —(CR 2 ) 1-3 R, —(CR 2 ) 1-3 —OR, —(CR 2 ) 0-3 —C(O)NR(CR 2 ) 0-3 R, —(CR 2 ) 0-3 —C(O)NR(CR 2 ) 0-3 OR, —C(O)R, —C(O)C(O)R, —C(O)CH 2 C(O)R, —C(S)R, —C(S)OR, —C(O)OR, —C(O)C(O)OR, —C(O)C(O)N(R) 2 , —OC(O)R, —C(O)N(R) 2 , —OC(O)N(R) 2 , —C(S)N(R) 2 , —(CR 2 ) 0-3 NHC(O)R, —N(R)N(R)COR, —N(R)N(R)C(O)OR, —N(R)N(R)CON(R) 2 , —N(R)SO 2 R, —N(R)SO 2 N(R) 2 , —N(R)C(O)OR, —N(R)C(O)R, —N(R)C(S)R, —N(R)C(O)N(R) 2 , —N(R)C(S)N(R) 2 , —N(COR)COR, —N(OR)R, —C(═NH)N(R) 2 , —C(O)N(OR)R, —C(═NOR)R, —OP(O)(OR) 2 , —P(O)(R) 2 , —P(O)(OR) 2 , and —P(O)(H)(OR);

R 3 is selected from:

halogen, —R, —OR, —NO 2 , —NCS, —CN, —CF 3 , —OCF 3 , —SiR 3 , —N(R) 2 , —SR, —SOR, —SO 2 R, —SO 2 N(R) 2 , —SO 3 R, —(CR 2 ) 1-3 R, —(CR 2 ) 1-3 —OR, —(CR 2 ) 0-3 —C(O)NR(CR 2 ) 0-3 R, —(CR 2 ) 0-3 —C(O)NR(CR 2 ) 0-3 OR, —C(O)R, —C(O)C(O)R, —C(O)CH 2 C(O)R, —C(S)R, —C(S)OR, —C(O)OR, —C(O)C(O)OR, —C(O)C(O)N(R) 2 , —OC(O)R, —C(O)N(R) 2 , —OC(O)N(R) 2 , —C(S)N(R) 2 , —(CR 2 ) 0-3 NHC(O)R, —N(R)N(R)COR, —N(R)N(R)C(O)OR, —N(R)N(R)CON(R) 2 , —N(R)SO 2 R, —N(R)SO 2 N(R) 2 , —N(R)C(O)OR, —N(R)C(O)R, —N(R)C(S)R, —N(R)C(O)N(R) 2 , —N(R)C(S)N(R) 2 , —N(COR)COR, —N(OR)R, —C(═NH)N(R) 2 , —C(O)N(OR)R, —C(═NOR)R, —OP(O)(OR) 2 , —P(O)(R) 2 , —P(O)(OR) 2 , and —P(O)(H)(OR);

R 6 is independently —H or —(C1-C6)alkyl;

each R is independently selected from:

H—,

(C1-C12)-aliphatic-,

(C3-C10)-cycloalkyl-,

(C3-C10)-cycloalkenyl-,

[(C3-C10)-cycloalkyl]-(C1-C12)-aliphatic-,

[(C3-C10)-cycloalkenyl]-(C1-C12)-aliphatic-,

[(C3-C10)-cycloalkyl]-O—(C1-C12)-aliphatic-,

[(C3-C10)-cycloalkenyl]-O—(C1-C12)-aliphatic-,

(C6-C10)-aryl-,

(C6-C10)-aryl-(C1-C12)aliphatic-,

(C6-C10)-aryl-O—(C1-C12)aliphatic-,

(C6-C10)-aryl-N(R″)—(C1-C12)aliphatic-,

3- to 10-membered heterocyclyl-,

(3- to 10-membered heterocyclyl)-(C1-C12)aliphatic-,

(3- to 10-membered heterocyclyl)-O—(C1-C12)aliphatic-,

(3- to 10-membered heterocyclyl)-N(R″)—(C1-C12)aliphatic-,

5- to 10-membered heteroaryl-,

(5- to 10-membered heteroaryl)-(C1-C12)-aliphatic-,

(5- to 10-membered heteroaryl)-O—(C1-C12)-aliphatic-; and

(5- to 10-membered heteroaryl)-N(R″)—(C1-C12)-aliphatic-;

wherein said heterocyclyl has 1-4 heteroatoms independently selected from N, NH, O, S, SO, and SO 2 , and said heteroaryl has 1-4 heteroatoms independently selected from N, NH, O, and S;

wherein each occurrence of R is independently substituted with 0-5 R′;

or when two R groups bound to the same atom, the two R groups may be taken together with the atom to which they are bound to form a 3- to 10-membered aromatic or non-aromatic ring having 0-4 heteroatoms independently selected from N, NH, O, S, SO, and SO 2 , wherein said ring is optionally substituted with 0-5 R′, and wherein said ring is optionally fused to a (C6-C10)aryl, 5- to 10-membered heteroaryl, (C3-C10)cycloalkyl, or a 3- to 10-membered heterocyclyl;

wherein each occurrence of R′ is independently selected from halogen, —R″, —OR″, oxo, —CH 2 OR″, —CH 2 NR″) 2 , —C(O)N(R″) 2 , —C(O)OR″, —NO 2 , —NCS, —CN, —CF 3 , —OCF 3 and —N(R″) 2 ;

wherein each occurrence of R″ is independently selected from H, —(C1-C6)-alkyl, —(C1-C6)-aliphatic, (C3-C6)-cycloalkyl, 3- to 6-membered heterocyclyl, 5- to 10-membered heteroaryl-, (C6-C10)-aryl-, (5- to 10-membered heteroaryl)-(C1-C6)-alkyl-, (C6-C10)-aryl-(C1-C6)-alkyl-, (5- to 10-membered heteroaryl)-O—(C1-C6)-alkyl-, and (C6-C10)-aryl-O—(C1-C6)-alkyl-, wherein each occurrence of R″ is independently substituted with 0-3 substituents selected from: halogen, —R o , —OR o , oxo, —CH 2 OR o , —CH 2 N(R o ) 2 , —C(O)N(R o ) 2 , —C(O)OR o , —NO 2 , —NCS, —CN, —CF 3 , —OCF 3 and —N(R o ) 2 , wherein each occurrence of R o is independently selected from: —(C1-C6)-aliphatic, (C3-C6)-cycloalkyl, 3- to 6-membered heterocyclyl, 5- to 10-membered heteroaryl-, and (C6-C10)-aryl-.

2. The compound according to claim 1 , wherein the compound has a structure of formula II:

or a pharmaceutically acceptable salt, stereoisomer, Z (zusammen) isomer, E (entgegen) isomer or combination thereof, wherein:

m is 0-3;

each R 1 is independently selected from: halogen, —H, —(C1-C6)alkyl, —OH, —O((C1-C6)alkyl), —NO 2 , —CN, —CF 3 , and —OCF 3 , wherein R 1 is independently substituted with 0-5 R′;

R 2 is selected from:

—H, halogen, —(C1-C6)alkyl, —OH, —O((C1-C6)alkyl), —C(O)O((C1-C6)alkyl), —C(O)NR 2 ,

(C6-C10)-aryl-,

(C6-C10)-aryl-(C1-C12)aliphatic-,

(C6-C10)-aryl-O—(C1-C12)aliphatic-,

(C6-C10)-aryl-N(R″)—(C1-C12)aliphatic-,

(5- to 10-membered heteroaryl)-(C1-C12)aliphatic-,

(5- to 10-membered heteroaryl)-O—(C1-C12)aliphatic-,

(5- to 10-membered heteroaryl)-N(R″)—(C1-C12)aliphatic-,

(3- to 10-membered heterocyclyl)-(C1-C12)aliphatic-,

(3- to 10-membered heterocyclyl)-O—(C1-C12)aliphatic-, and

(3- to 10-membered heterocyclyl)-N(R″)—(C1-C12)aliphatic-,

wherein R 2 is independently substituted with 0-5 R′;

R 3 is selected from:

—(C1-C6)alkyl, —(C2-C6)alkenyl, —C—CH, —CN, halogen, —SO 2 ((C6-C10)-aryl), —SO 2 ((C1-C6)alkyl), —C(O)N((C1-C6)alkyl) 2 , —C(O)NH 2 , —C(O)O((C1-C6)alkyl), —C(O)((C1-C6)alkyl), —(C6-C10)aryl, 5- to 10-membered heteroaryl, and 5- to 10-membered heterocyclyl, wherein R 3 is independently substituted with 0-5 R′;

R 4 and R 5 are each independently selected from —H, halogen and -(C1-C6)alkyl;

R 6 is selected from —H and -(C1-C6)alkyl;

each R is independently selected from:

H—,

(C1-C12)-aliphatic-,

(C3-C10)-cycloalkyl-,

(C3-C10)-cycloalkenyl-,

[(C3-C10)-cycloalkyl]-(C1-C12)-aliphatic-,

[(C3-C10)-cycloalkenyl]-(C1-C12)-aliphatic-,

[(C3-C10)-cycloalkyl]-O—(C1-C12)-aliphatic-,

[(C3-C10)-cycloalkenyl]-O—(C1-C12)-aliphatic-,

(C6-C10)-aryl-,

(C6-C10)-aryl-(C1-C12)aliphatic-,

(C6-C10)-aryl-O—(C1-C12)aliphatic-,

(C6-C10)-aryl-N(R″)—(C1-C12)aliphatic-,

3- to 10-membered heterocyclyl-,

(3- to 10-membered heterocyclyl)-(C1-C12)aliphatic-,

(3- to 10-membered heterocyclyl)-O—(C1-C12)aliphatic-,

(3- to 10-membered heterocyclyl)-N(R″)—(C1-C12)aliphatic-,

5- to 10-membered heteroaryl-,

(5- to 10-membered heteroaryl)-(C1-C12)-aliphatic-,

(5- to 10-membered heteroaryl)-O—(C1-C12)-aliphatic-; and

(5- to 10-membered heteroaryl)-N(R″)—(C1-C12)-aliphatic-;

wherein said heterocyclyl has 1-4 heteroatoms independently selected from N, NH, O, S, SO, and SO 2 , and said heteroaryl has 1-4 heteroatoms independently selected from N, NH, O, and S;

wherein each occurrence of R is independently substituted with 0-5 R′;

or when two R groups bound to the same atom, the two R groups may be taken together with the atom to which they are bound to form a 3- to 10-membered aromatic or non-aromatic ring having 0-4 heteroatoms independently selected from N, NH, O, S, SO, and SO 2 , wherein said ring is optionally substituted with 0-5 R′, and wherein said ring is optionally fused to a (C6-C10)aryl, 5- to 10-membered heteroaryl, (C3-C10)cycloalkyl, or a 3- to 10-membered heterocyclyl;

wherein each occurrence of R′ is independently selected from halogen, —R″, —OR″, oxo, —CH 2 OR″, —CH 2 NR″) 2 , —C(O)N(R″) 2 , —C(O)OR″, —NO 2 , —NCS, —CN, —CF 3 , —OCF 3 and —N(R″) 2 ;

wherein each occurrence of R″ is independently selected from H, —(C1-C6)-alkyl, (C3-C6)-cycloalkyl, 3- to 6-membered heterocyclyl, 5- to 10-membered heteroaryl-, (C6-C10)-aryl-, (5- to 10-membered heteroaryl)-(C1-C6)-alkyl-, (C6-C10)-aryl-(C1-C6)-alkyl-, (5- to 10-membered heteroaryl)-O—(C1-C6)-alkyl-, and (C6-C10)-aryl-O—(C1-C6)-alkyl-.

3. The compound according to claim 1 , wherein the compound is selected from:

Cmp

No.

Structure

180

181

182

194

195

207

208

209

210

211

212

213

214

218

219

220

221

222

223

224

225

226

227

228

229

230

231

247

248

250

251

252

253

257

258

262

272

273

277

289

290

291

292

298

299

300

or a pharmaceutically acceptable salt, stereoisomer, Z (zusammen) isomer, E (entgegen) isomer or combination thereof.

4. The compound according to claim 1 , wherein the compound is selected from:

Com-

pound

Structure

180

181

182

194

195

207

208

209

210

211

212

213

214

or a pharmaceutically acceptable salt, stereoisomer, Z (zusammen) isomer, E (entgegen) isomer or combination thereof.

5. A pharmaceutical composition comprising a compound according to any one of claims 1 , 2 , 3 or 4 , or a pharmaceutically acceptable salt, stereoisomer, Z (zusammen) isomer, E (entgegen) isomer or combination thereof, in a therapeutically effective amount; and an acceptable carrier, adjuvant or vehicle.

6. The pharmaceutical composition according to claim 5 , wherein said composition further comprises a second therapeutic agent.

7. The pharmaceutical composition according to claim 6 , wherein the second therapeutic agent is selected from an antipsychotic, memantine and an acetylcholine esterase inhibitor (AChE-I).

8. The pharmaceutical composition according to claim 6 , wherein the second therapeutic agent is an antipsychotic selected from aripiprazole, olanzapine and ziprasidone, and the pharmaceutically acceptable salts, hydrates, solvates, and polymorphs thereof.

9. The pharmaceutical composition according to claim 6 , wherein the second therapeutic agent is memantine, a pharmaceutically acceptable salt, hydrate, solvate, or polymorph thereof.

10. The pharmaceutical composition according to claim 6 , wherein the second therapeutic agent is an AChE-I selected from Donepezil, Galantamine, and Rivastigmine, and the pharmaceutically acceptable salts, hydrates, solvates, and polymorphs thereof.