Benzodiazepine derivatives, compositions, and methods for treating cognitive impairment

A compound of formula V-a:

• or a pharmaceutically acceptable salt, hydrate, solvate, polymorph, isomer, or combination thereof, wherein:
• U and the two carbon atoms designated by α and β together form a 5- or 6-membered aromatic ring having 0-2 nitrogen atoms;
• A is C, CR6, or N;
• B and F are each independently selected from C, CR6, and N, wherein B and F cannot both be N;
• D is N, NR7, O, CR6 or C(R6)2;
• E is N, NR7, CR6 or C(R6)2;
• W is N, NR7, CR6 or C(R6)2;
• X is N, NR7, O, CR6 or C(R6)2;
• Y and Z are each independently selected from C, CR6, and N, wherein Y and Z cannot both be N;
• V is C or CR6,
• or when Z is C or CR6, V is C, CR6, or N;
• wherein when the ring formed by X, Y, Z, V and W is
• then R2 is —OR8, —SR8, —(CH2)nOR8, —(CH2)nO(CH2)nR8, —(CH2)pR8 and —(CH2)nN(R″)R10;
• and wherein R2 is independently substituted with 0-5 R′;
• m and n are independently integers selected from 0-4;
• p is an integer selected from 2-4;
• each occurrence of the bond “” is either a single bond or a double bond;
• each occurrence of R1, R2, R4, and R5 are each independently selected from:
• halogen, —R, —OR, —NO2, —NCS, —CN, —CF3, —OCF2H —OCF3, —SiR3, —N(R)2, —SR, —SOR, —SO2R, —SO2N(R)2, —SO3R, —(CR2)1-3R, —(CR2)1-3—OR, —(CR2)1-3—O(CR2)1-3—R, —(CR2)0-3—C(O)NR(CR2)0-3R, —(CR2)0-3—C(O)NR(CR2)0-3OR, —C(O)R, —C(O)C(O)R, —C(O)CH2C(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, —(CR2)0-3NHC(O)R, —N(R)N(R)COR, —N(R)N(R)C(O)OR, —N(R)N(R)CON(R)2, —N(R)SO2R, —N(R)SO2N(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, —P(O)(H)(OR), CH2CF3, and CHF2;
• each occurrence of R8 is —H, —(C1-C6) alkyl, —(C3-C6) cycloalkyl, —(C1-C6) alkyl-(C3-C6) cycloalkyl, —(C1-C6) alkyl-(C6-C10) aryl, —(C6-C10) aryl, -5-10 membered heteroaryl, or —(C1-C6) alkyl-5-10 membered heteroaryl;
• wherein each R8 excluding —H and —(C1-C6) alkyl is independently substituted by 0-5 of -halogen, —(C1-C6) alkyl, —CF3, —OCF3, or O—(C1-C6) alkyl;
• R3 is absent or is selected from:
• halogen, —R, —OR, —NO2, —NCS, —CN, —CF3, —OCF3, —SiR3, —N(R)2, —SR, —SOR, —SO2R, —SO2N(R)2, —SO3R, —(CR2)1-3R, —(CR2)1-3—OR, —(CR2)0-3—C(O)NR(CR2)0-3R, —(CR2)0-3—C(O)NR(CR2)0-3OR, —C(O)R, —C(O)C(O)R, —C(O)CH2C(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, —(CR2)0-3NHC(O)R, —N(R)N(R)COR, —N(R)N(R)C(O)OR, —N(R)N(R)CON(R)2, —N(R)SO2R, —N(R)SO2N(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, —P(O)(H)(OR), C≡C—R9, COOMe, COOEt, —(C1-C6)alkyl-C≡C—R10, CH2—OR10, and CH2—O—CH2—R10;
• wherein each of R9 is selected from —H, —(C1-C6) alkyl, —(C6-C10) aryl, -5-10 membered heteroaryl, —(C1-C6) alkyl-(C6-C10) aryl, —(C1-C6) alkyl-5-10 membered heteroaryl, —(C3-C6) cycloalkyl, —(C1-C6) alkyl-(C3-C6) cycloalkyl, —C(O)—(C6-C10) aryl, —(C3-C6)cycloalkyl-(C6-C10)aryl,
• wherein each R9 is independently substituted with 0-5 R11;
• wherein each occurrence of R11 is independently selected from -halogen, —CF3, —OH, —OCF3, OCHF2, —O—(C1-C6)alkyl, —O—CH2—(C3-C6)cycloalkyl, —CN, —SCH3 —(C6-C10) aryl, —(C1-C6)alkyl, and -5 to 10 membered heteroaryl,
• wherein R10 is selected from —H, —(C1-C6) alkyl, —(C6-C10) aryl, -5-10 membered heteroaryl, —(C3-C6) cycloalkyl, —CH2—(C3-C6) cycloalkyl, —CH2—(C6-C10) aryl, and —CH2-5-10-membered heteroaryl,
• wherein each R10 is independently substituted with 0-5 R′;
• wherein R7 is selected from —(C1-C6)alkyl, —(C3-C6)cycloalkyl, -5 to 10 membered heteroaryl, —(C6-C10) aryl, —(C6-C10)aryl-(C1-C6)alkyl, and -5 to 10 membered heteroaryl-(C1-C6)alkyl, and -5-10 membered heteroaryl,
• wherein each R7 is independently substituted with 0-5 R′;
• each R6 is independently —H or —(C1-C6)alkyl;
• each R7 is independently —H or —(C1-C6)alkyl;
• each R8 is independently —(C1-C6)alkyl, —(C3-C10)-cycloalkyl, (C6-C10)-aryl, or 5- to 10-membered heteroaryl, wherein each occurrence of R8 is independently substituted with 0-5 R′;
• each R10 is independently —(C3-C10)-cycloalkyl, 3- to 10-membered heterocyclyl-, (C6-C10)-aryl, or 5- to 10-membered heteroaryl, wherein each occurrence of R10 is independently substituted with 0-5 R′;
• 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 SO2, 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 SO2, 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, —CH2OR″, —CH2NR″2, —C(O)N(R″)2, —C(O)OR″, —NO2, —NCS, —CN, —CF3, —OCF3 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, —Ro, —ORo, oxo, —CH2ORo, —CH2N(Ro)2, —C(O)N(Ro)2, —C(O)ORo, —NO2, —NCS, —CN, —CF3, —OCF3 and —N(Ro)2, wherein each occurrence of Ro is independently selected from:
• —(C1-C6)-aliphatic, (C3-C6)-cycloalkyl, 3- to 6-membered heterocyclyl, 5- to 10-membered heteroaryl-, and (C6-C10)-aryl-.