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EP-4032889-B1 - BENZODIAZEPINE DERIVATIVES, COMPOSITIONS, AND METHODS FOR TREATING COGNITIVE IMPAIRMENT

EP4032889B1EP 4032889 B1EP4032889 B1EP 4032889B1EP-4032889-B1

Inventors

  • MEKONNEN, BELEW
  • BUTERA, JOHN, A.
  • HUANG, JIANXING

Dates

Publication Date
20260506
Application Date
20141219

Claims (20)

  1. A compound of formula IV: or a pharmaceutically acceptable salt, hydrate, solvate, polymorph, enantiomer, diastereomer, Z (zusammen) isomer, E (entgegen) isomer, tautomer, or combination thereof, wherein: R 2 is selected from: -OR 8 , -SR 8 , -(CH 2 ) n OR 8 , or -(CH 2 ) n O(CH 2 ) n R 8 , and wherein R 2 is independently substituted with 0-5 R'; m and n are independently integers selected from: 0-4; each occurrence of R 1 , 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 0R, -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 absent or 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 0R, -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 -H or -(C1-C6)alkyl; each R 8 is independently -(C1-C6)alkyl, -(C3-C10)-cycloalkyl, (C6-C10)-aryl, or 5- to 10-membered heteroaryl, wherein each occurrence of R 8 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-C 10)-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 ; and 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-, or (C6-C10)-aryl-O-(C1-C6)-alkyl-.
  2. A compound of formula IV according to claim 1: or a pharmaceutically acceptable salt, hydrate, solvate, polymorph, enantiomer, diastereomer, Z (zusammen) isomer, E (entgegen) isomer, tautomer, or combination thereof, wherein: R 2 is -OR 8 , -SR 8 , or -(CH 2 ) n OR 8 ; m and n are independently integers selected from: 0-4; each occurrence of R 1 , 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 0R, -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 absent or 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 0R, -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 -H or -(C1-C6)alkyl; each R 8 is independently -(C1-C6)alkyl, -(C3-C10)-cycloalkyl, (C6-C10)-aryl, or 5- to 10-membered heteroaryl, wherein each occurrence of R 8 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-C 10)-aryl-, (C6-C10)-aryl-(C1-C12)aliphatic-, (C6-C10)-aryl-O-(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-, 5- to 10- membered heteroaryl-, (5- to 10- membered heteroaryl)-(C1-C12)-aliphatic-, and (5- to 10- membered heteroaryl)-O-(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-, or (C6-C10)-aryl-O-(C1-C6)-alkyl-.
  3. The compound according to claim 1 or 2, or a pharmaceutically acceptable salt, hydrate, solvate, polymorph, enantiomer, diastereomer, Z (zusammen) isomer, E (entgegen) isomer, tautomer, or combination thereof, wherein R 2 is selected from: -OR 8 , -SR 8 , -(CH 2 ) n OR 8 , -or (CH 2 ) n O(CH 2 ) n R 8 , and wherein each R 8 is independently -(C1-C6)alkyl, -(C3-C10)-cycloalkyl, (C6-C10)-aryl, or 5- to 10- membered heteroaryl, wherein each occurrence of R 8 is independently substituted with 0-5 R'; and n is an integer selected from: 0-4.
  4. The compound according to claim 3, or a pharmaceutically acceptable salt, hydrate, solvate, polymorph, enantiomer, diastereomer, Z (zusammen) isomer, E (entgegen) isomer, tautomer, or combination thereof, wherein R 2 is -OR 8 ; -(CH 2 ) n OR 8 or -(CH 2 ) n O(CH 2 ) n R 8 .
  5. The compound according to claim 4, or a pharmaceutically acceptable salt, hydrate, solvate, polymorph, enantiomer, diastereomer, Z (zusammen) isomer, E (entgegen) isomer, tautomer, or combination thereof, wherein when R 2 is OR 8 , R 8 is (C6-C10)-aryl; and when R 2 is - (CH 2 ) n OR 8 or -(CH 2 ) n O(CH 2 ) n R 8 , R 8 is -(C1-C6)alkyl, (C6-C10)-aryl, or 5- to 10- membered heteroaryl, wherein each occurrence of R 8 is independently substituted with 0-5 R'.
  6. The compound according to any one of claims 1-5, or a pharmaceutically acceptable salt, hydrate, solvate, polymorph, enantiomer, diastereomer, Z (zusammen) isomer, E (entgegen) isomer, tautomer, or combination thereof, wherein each occurrence of R 1 is independently selected from: halogen, -R, -OR, -NO 2 , -CN, -CF 3 , -OCF 3 , -N(R) 2 , or -N(R)SO 2 R, wherein each occurrence of R is independently substituted with 0-5 R'.
  7. The compound according to claim 6, or a pharmaceutically acceptable salt, hydrate, solvate, polymorph, enantiomer, diastereomer, Z (zusammen) isomer, E (entgegen) isomer, tautomer, or combination thereof, wherein each occurrence of R 1 is independently selected from: halogen, -H, -(C1-C6)alkyl, -OH, -O((C1-C6)alkyl), -NO 2 , -CN, -CF 3 , -OCF 3 , -NH 2 , -N((C1-C6)alkyl) 2 , -N((C1-C6)alkyl)SO 2 ((C1-C6)alkyl), and -NHSO 2 ((C1-C6)alkyl), wherein said alkyl is independently substituted with 0-5 R'.
  8. The compound according to claim 7, or a pharmaceutically acceptable salt, hydrate, solvate, polymorph, enantiomer, diastereomer, Z (zusammen) isomer, E (entgegen) isomer, tautomer, or combination thereof, wherein each occurrence of R 1 is independently selected from: -H, - F, -Cl, -Br, -OH, -Me, -Et, -OMe, -OEt, -NO 2 , -CN, -CF 3 , -OCF 3 , -NH 2 , -NMe 2 , -NEt 2 , - NHSO 2 Me, and -NHSO 2 Et.
  9. The compound according to any one of claims 1-8, or a pharmaceutically acceptable salt, hydrate, solvate, polymorph, enantiomer, diastereomer, Z (zusammen) isomer, E (entgegen) isomer, tautomer, or combination thereof, wherein R 3 is selected from: halogen, -R, -CN, -CF 3 , -SO 2 R, -C(O)N(R) 2 , -C(O)R, and -C(O)OR, wherein each occurrence of R is independently substituted with 0-5 R'.
  10. The compound according to claim 9, or a pharmaceutically acceptable salt, hydrate, solvate, polymorph, enantiomer, diastereomer, Z (zusammen) isomer, E (entgegen) isomer, tautomer, or combination thereof, wherein R 3 is selected from: -H, -C(O)OMe, -C(O)Et, - C(O)Nme 2 , -C(O)NH 2 , -C(O)Oet, -C(O)OCH 2 (tert-butyl), -C(O)OCH 2 CF 3 ,-C(O)O(isopropyl),-C(O)Net 2 ,-CHF 2 , -CN, -C≡C, -SO 2 Me, -SO 2 Et, -SO 2 Ph(Me), -CF 3 , - CHF 2 , -Me, -Et, -Br, -Cl, -CH 2 Ph, and wherein R 9 is selected from: -H, -Me, -Et, -CF 3 , isopropyl, -Ome, -Oet, -O-isopropyl, - CH 2 Nme 2 , - tert -butyl, and cyclopropyl.
  11. The compound according to any one of claims 1-10, or a pharmaceutically acceptable salt, hydrate, solvate, polymorph, enantiomer, diastereomer, Z (zusammen) isomer, E (entgegen) isomer, tautomer, or combination thereof, wherein R 4 and R 5 are each independently selected from: -H, halogen, and -R, wherein each occurrence of R is independently substituted with 0-5 R', or R 4 and R 5 may be taken together with the carbon atom to which they are bound to form a 3- to 10-membered aromatic or non-aromatic ring having 0-3 additional heteroatoms independently selected from: N, O, S, SO, and SO 2 , wherein said ring is substituted with 0-5 R'.
  12. The compound according to claim 11, or a pharmaceutically acceptable salt, hydrate, solvate, polymorph, enantiomer, diastereomer, Z (zusammen) isomer, E (entgegen) isomer, tautomer, or combination thereof, wherein both R 4 and R 5 are -H.
  13. A compound according to claim 1 selected from: Compound Structure 55 56 103 104 105 118 119 120 122 123 124 128 129 130 131 137 138 141 142 147 148 156 157 158 159 162 163 164 165 166 169 171 172 173 174 175 176 177 178 179 or a pharmaceutically acceptable salt, hydrate, solvate, polymorph, enantiomer, diastereomer, Z (zusammen) isomer, E (entgegen) isomer, tautomer, or combination thereof.
  14. A pharmaceutical composition comprising a compound according to any one of claims 1-13, or a pharmaceutically acceptable salt, hydrate, solvate, polymorph, enantiomer, diastereomer, Z (zusammen) isomer, E (entgegen) isomer, tautomer, or combination thereof, in a therapeutically effective amount; and an acceptable carrier, adjuvant or vehicle.
  15. The pharmaceutical composition according to claim 14, wherein said composition further comprises a second therapeutic agent.
  16. The pharmaceutical composition according to claim 15, wherein the second therapeutic agent is selected from: an antipsychotic, memantine, and an acetylcholine esterase inhibitor (AChE-I), or a pharmaceutically acceptable salt, hydrate, solvate, or polymorph thereof.
  17. The pharmaceutical composition according to claim 16, wherein the second therapeutic agent is selected from: an antipsychotic selected from: aripiprazole, olanzapine, and ziprasidone, or a pharmaceutically acceptable salt, hydrate, solvate, or polymorph thereof; memantine, or a pharmaceutically acceptable salt, hydrate, solvate, or polymorph thereof; and an AChE-I selected from: Donepezil, Galantamine, and Rivastigmine, or a pharmaceutically acceptable salt, hydrate, solvate, or polymorph thereof.
  18. A compound according to any one of claims 1-13, or a pharmaceutically acceptable salt, hydrate, solvate, polymorph, enantiomer, diastereomer, Z (zusammen) isomer, E (entgegen) isomer, tautomer, or combination thereof, or a pharmaceutical composition according to any one of claims 14-17, for use in a method of treating cognitive impairment associated with a central nervous system (CNS) disorder.
  19. The compound or pharmaceutical composition for use according to claim 18, wherein the CNS disorder is age-related cognitive impairment, Mild Cognitive Impairment (MCI), amnestic Mild Cognitive Impairment (aMCI), Dementia, Alzheimer's disease, schizophrenia or bipolar disorder, amyotrophic lateral sclerosis (ALS), post-traumatic stress disorder (PTSD), associated with cancer therapy, mental retardation, Parkinson's disease (PD), autism, compulsive behavior, and substance addiction.
  20. A compound according to any one of claims 1-13, or a pharmaceutically acceptable salt, hydrate, solvate, polymorph, enantiomer, diastereomer, Z (zusammen) isomer, E (entgegen) isomer, tautomer, or combination thereof, or a pharmaceutical composition according to any one of claims 14-17, for use as a medicament.

Description

Related Applications This application claims the benefit of and priority from U.S. Provisional Patent Applications 61/919,390, filed December 20, 2013, 61/919,394, filed December 20, 2013, and 62/075,743, filed November 5, 2014. Statement of Government Support This invention was made with government support under Grant No. U01 AG041140 awarded by the National Institutes of Health (NIH), and in particular, its National Institute of Aging (NIA) division, an agency of the United States Government. Field of the Invention The invention relates to compounds, compositions and compositions for use in methods of treating cognitive impairment associated with central nervous system (CNS) disorders in a subject in need of treatment. The scope of the invention is defined by the appended claims. Background of the Invention Cognitive ability may decline as a normal consequence of aging or as a consequence of a central nervous disorder. For example, a significant population of elderly adults experiences a decline in cognitive ability that exceeds what is typical in normal aging. Such age-related loss of cognitive function is characterized clinically by progressive loss of memory, cognition, reasoning, and judgment. Mild Cognitive Impairment (MCI), Age-Associated Memory Impairment (AAMI), Age-Related Cognitive Decline (ARCD) or similar clinical groupings are among those related to such age-related loss of cognitive function. According to some estimates, there are more than 16 million people with AAMI in the U.S. alone (Barker et al., 1995), and MCI is estimated to affect 5.5 - 7 million in the U.S. over the age of 65 (Plassman et al., 2008). Cognitive impairment is also associated with other central nervous system (CNS) disorders, such as dementia, Alzheimer's Disease (AD), prodromal AD, post traumatic stress disorder (PTSD), schizophrenia, bipolar disorder (in particular, mania), amyotrophic lateral sclerosis (ALS), cancer-therapy-related cognitive impairment, mental retardation, Parkinson's disease (PD), autism spectrum disorders, fragile X disorder, Rett syndrome, compulsive behavior, and substance addiction. There is, therefore, a need for effective treatment of cognitive impairment associated with central nervous system (CNS) disorders and to improve cognitive function in patients diagnosed with, for example, age-related cognitive impairment, MCI, amnestic MCI, AAMI, ARCD, dementia, AD, prodromal AD, PTSD, schizophrenia or bipolar disorder (in particular, mania), amyotrophic lateral sclerosis (ALS), cancer-therapy-related cognitive impairment, mental retardation, Parkinson's disease (PD), autism spectrum disorders, fragile X disorder, Rett syndrome, compulsive behavior, and substance addiction and similar central nervous system (CNS) disorders with cognitive impairment or at risk of developing them. GABAA receptors (GABAA R) are pentameric assemblies from a pool of different subunits (α1-6, β1-3, γ1-3, δ, ε, π, θ) that form a Cl- permeable channel that is gated by the neurotransmitter γ-aminobutyric acid (GABA). Various pharmacological effects, including anxiety disorders, epilepsy, insomnia, pre-anesthetic sedation, and muscle relaxation, are mediated by different GABAA subtypes. Various studies have demonstrated that reduced GABA signaling is linked to various CNS disorders with cognitive impairment. In particular, the α5-containing GABAA Rs, which are relatively sparse in the mammalian brain, play a role in modifying learning and memory. Previous studies demonstrated a reduction of hippocampal expression of the α5 subunit of the GABAA receptor in rats with age-related cognitive decline (see International Patent Publication WO 2007/019312). Such results suggest that upregulation of α5-containing GABAA R function may be effective in the treatment of cognitive impairment associated with said CNS disorders. WO 02/40487 discusses compounds having affinity to the α5-containing GABAA R. Thus, there is a need for positive allosteric modulators of α5-containing GABAA R that are useful in therapeutic preparations for the treatment of cognitive impairment associated with said CNS disorders. Summary of the Invention The present invention addresses the aforementioned need by providing a compound or a pharmaceutically acceptable salt, hydrate, solvate, polymorph, enantiomer, diastereomer, Z (zusammen) isomer, E (entgegen) isomer, tautomer, or combination thereof, or a pharmaceutical composition, in accordance with the appended claims. For context, discussed herein is a compound of formula I: 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 selected from 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