BR112016014564B1 - COMPOUNDS DERIVED FROM BENZODIAZEPINE, PHARMACEUTICAL COMPOSITION COMPRISING SAID COMPOUNDS AND USE THEREOF FOR THE TREATMENT OF COGNITIVE DEFICIENCY ASSOCIATED WITH A DISORDER OF THE CENTRAL NERVOUS SYSTEM - Google Patents

Abstract

BENZODIAZEPINE DERIVATIVES, COMPOSITIONS AND METHODS FOR THE TREATMENT OF COGNITIVE DISABILITY. This invention relates to benzodiazepine derivatives, compositions comprising therapeutically effective amounts of those benzodiazepine derivatives, and methods of using those derivatives or compositions in treating cognitive impairment associated with central nervous system (CNS) disorders. In particular, it relates to the use of an (Alpha)5-containing GABAA receptor agonist (e.g., an (Alpha)5-containing GABAA receptor positive allosteric modulator), as described herein, in the treatment of cognitive impairment. associated with central nervous system (CNS) disorders in an individual who requires or is at risk thereof, which includes, without limitation, individuals who have or are at risk for age-related cognitive impairment, moderate cognitive impairment (MCI), MCI amnestic (aMCI), age-associated memory impairment (AAMI), age-related cognitive impairment (ARCD), dementia, Alzheimer's disease (AD), prodromal AD, post-traumatic stress disorder (PTSD), schizophrenia, bipolar disorder, amyotrophic lateral sclerosis (ALS), cancer therapy-related cognitive impairment, mental retardation, Parkinson's disease (PD), autism spectrum disorders, fragile X syndrome, Rett syndrome, compulsive behavior, and substance dependence.

Description

RELATED REQUESTS

[001] This application claims the benefit and priority of the provisional patent applications in U.S. 61/919,390, filed December 20, 2013, 61/919,394, filed December 20, 2013, and 62/075,743 filed November 5 2014.

[002] Each of the previously mentioned requests is incorporated into this document by way of reference, in its entirety.

FIELD OF INVENTION

[003] The invention relates to compounds, cognition and methods for treating cognitive impairment associated with central nervous system (CNS) disorders in an individual in need of treatment or at risk of said cognitive impairment.

BACKGROUND OF THE INVENTION

[004] Cognitive capacity can decline as a normal consequence of aging or as a consequence of a central nervous system disorder.

[005] For example, a significant population of older adults experience impairment in cognitive capacity that exceeds what is typical in normal aging. Such age-related loss of cognitive function is clinically characterized by progressive loss of memory, cognition, reasoning, and judgment. Moderate cognitive impairment (MCI), age-associated memory impairment (AAMI), age-related cognitive impairment (ARCD), or similar clinical groups 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 United States alone (Barker et al., 1995) and MCI is estimated to affect 5.5 to 7 million in the United States over the age of 65 ( Plassman et al., 2008).

[006] 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 syndrome, Rett syndrome, compulsive behavior, and substance dependence.

[007] 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), cognitive impairment related to cancer therapy, mental retardation, Parkinson's disease (PD), autism spectrum disorders, fragile X syndrome, Rett syndrome, compulsive behavior and substance dependence and similar central nervous system (CNS) disorders with cognitive impairment or at risk of developing them.

[008] GABAA receptors (GABAA R) are pentameric sets from a grouping of different subunits (α1-6, β1-3, Y1-3, δ, ε, π, θ) that form a channel permeable to Cl - which is controlled by the neurotransmitter Y-aminobutyric acid (GABA). Several pharmacological effects, which include anxiety disorders, epilepsy, insomnia, pre-anesthetic sedation and muscle relaxation, are mediated by different subtypes of GABAA.

[009] Several studies have demonstrated that reduced GABA signaling is linked to several CNS disorders with cognitive impairment. In particular, α5-containing GABAA Rs, which are relatively scarce in the mammalian brain, play a role in modifying learning and memory. Previous studies have demonstrated reduced hippocampal expression of the GABAA receptor α5 subunit in rats with age-related cognitive impairment (see international patent publication WO 2007/019312). Such results suggest that upregulation of α5-containing GABAA R function may be effective in treating cognitive impairment associated with said CNS disorders.

[010] Thus, there is a need for positive allosteric modulators of GABAA R containing α5 that are useful in therapeutic preparations for the treatment of cognitive impairment associated with said CNS disorders.

SUMMARY OF THE INVENTION

[011] The present invention addresses the aforementioned need by providing a compound of formula I:

[012] or an isomer, polymorph, solvate, hydrate, pharmaceutically acceptable salt or combination thereof, wherein:

[013]U and the two carbon atoms designated as α and β together form a 5- or 6-member aromatic ring that has 0 to 2 nitrogen atoms;

[014]A is C, CR6 or N;

[015] B and F are each independently selected from C, CR6 and N, where B and F cannot both be N;

[016]D is selected from N, NR7, O, CR6 or C(R6)2;

[017]E is N, NR7, CR6 or C(R6)2;

[018]W is N, NR7, CR6 or C(R6)2;

[019]X is N, NR7, O, CR6 or C(R6)2;

[020] Y and Z are each independently selected from C, CR6 and N, where Y and Z cannot both be N;

[021]V is C or CR6,

[022] or when Z is C or CR6, V is C, CR6 or N;

[023] in which 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 by 0 to 5 R';

[024]m and n are integers independently selected from 0 to 4;

[025]p is an integer selected from 2 to 4;

[026] each occurrence of the call is it a single bond or a double bond;

[027] each occurrence of R1, R2, R4 and R5 is each independently selected from:

[028]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) COLOR, -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 and -P(O)(H)(OR);

[029]R3 is absent or selected from:

[030]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) COLOR, -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 and -P(O)(H)(OR);

[031] each R6 is independently -H or -(C1-C6)alkyl;

[032] each R7 is independently -H or -(C1-C6)alkyl;

[033] 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 by 0 to 5 R';

[034] each R10 is independently -(C3-C10)-cycloalkyl, heterocyclyl-(C6-C10)-aryl of 3 to 10 members or heteroaryl of 5 to 10 members, wherein each occurrence of R10 is independently substituted by 0 to 5R';

[035] each R is independently selected from:

[036]H,

[037](C1-C12)-aliphatic-,

[038](C3-C10)-cycloalkyl-,

[039](C3-C10)-cycloalkenyl-,

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

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

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

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

[044](C6-C10)-aryl-,

[045](C6-C10)-aryl-(C1-C12)aliphatic-,

[046](C6-C10)-aryl-O-(C1-C12)aliphatic-,

[047](C6-C10)-aryl-N(R’’)-(C1-C12)aliphatic-,

[048] 3- to 10-membered heterocyclyl,

[049](3- to 10-membered heterocyclyl)-(C1-C12)aliphatic-,

[050](3- to 10-membered heterocyclyl)-O-(C1-C12)aliphatic-,

[051](3- to 10-membered heterocyclyl)-N(R’’)-(C1-C12)aliphatic-,

[052] 5- to 10-membered heteroaryl,

[053](5- to 10-membered heteroaryl)-(C1-C12)-aliphatic-,

[054](5- to 10-membered heteroaryl)-O-(C1-C12)-aliphatic-; It is

[055](5- to 10-membered heteroaryl)-N(R’’)-(C1-C12)-aliphatic-;

[056] wherein said heterocyclyl has 1 to 4 heteroatoms independently selected from N, NH, O, S, SO and SO2 and said heteroaryl has 1 to 4 heteroatoms independently selected from N, NH, O and S;

[057] in which each occurrence of R is independently replaced by 0 to 5 R’;

[058] or when two R groups bonded to the same atom, the two R groups may be taken together with the atom to which they are bonded to form a 3 to 10 membered aromatic or non-aromatic ring having 0 to 4 hete - roatoms independently selected from N, NH, O, S, SO and SO2, wherein said ring is optionally substituted by 0 to 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;

[059]wherein each occurrence of R’ is independently selected from halogen, -R’’, -OR’’, oxo,

[060]-CH2OR'', -CH2NR''2, -C(O)N(R'')2, -C(O)OR'', -NO2, -NCS, -CN, -CF3, -OCF3 and -N(R'')2;

[061] 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 members-, (C6-C10)-aryl-, (5- to 10-membered heteroaryl)-(C1-C6)-alkyl-, (C6-C10)-aryl-(C1-C6)-alkyl-, (heteroaryl of 5 to 10 members)-O-(C1-C6)-alkyl or (C6-C10)-aryl-O-(C1-C6)-alkyl-.

[062] Some embodiments of this application provide a compound of formula I:

[063] or an isomer, polymorph, solvate, hydrate, pharmaceutically acceptable salt or combination thereof, wherein:

[064]U and the two carbon atoms designated as α and β together form a 5- or 6-member aromatic ring that has 0 to 2 nitrogen atoms;

[065]A is C, CR6 or N;

[066] B and F are each independently selected from C, CR6 and N, where B and F cannot both be N;

[067]D is selected from N, NR7, O, CR6 or C(R6)2;

[068]E is N, NR7, CR6 or C(R6)2;

[069]W is N, NR7, CR6 or C(R6)2;

[070]X is N, NR7, O, CR6 or C(R6)2;

[071] Y and Z are each independently selected from C, CR6 and N, where Y and Z cannot both be N;

[072]V is C or CR6,

[073] or when Z is C or CR6, V is C, CR6 or N;

[074] in which, when the ring formed by X, Y, Z, V and W is , then R2 is -OR8,

[075]-SR8 or -(CH2)nOR8;

[076]m and n are each independently an integer selected from 0 to 4;

[077]each occurrence of the call is it a single bond or a double bond;

[078] each occurrence of R1, R2, R4 and R5 is each independently selected from:

[079]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) COLOR, -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 and -P(O)(H)(OR);

[080]R3 is missing or selected from:

[081]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) COLOR, -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 and -P(O)(H)(OR);

[082] each R6 is independently -H or -(C1-C6)alkyl;

[083] each R7 is independently -H or -(C1-C6)alkyl;

[084] 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 by 0 to 5 R';

[085] each R is independently selected from:

[086] H,

[087](C1-C12)-aliphatic-,

[088](C3-C10)-cycloalkyl-,

[089](C3-C10)-cycloalkenyl-,

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

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

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

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

[094](C6-C10)-aryl-,

[095](C6-C10)-aryl-(C1-C12)aliphatic-,

[096](C6-C10)-aryl-O-(C1-C12)aliphatic-,

[097] 3- to 10-membered heterocyclyl,

[098](3- to 10-membered heterocyclyl)-(C1-C12)aliphatic-,

[099](3- to 10-membered heterocyclyl)-O-(C1-C12)aliphatic-,

[0100] 5- to 10-membered heteroaryl,

[0101](5- to 10-membered heteroaryl)-(C1-C12)-aliphatic-, and

[0102](5- to 10-membered heteroaryl)-O-(C1-C12)-aliphatic-;

[0103] wherein said heterocyclyl has 1 to 4 heteroatoms independently selected from N, NH, O, S, SO and SO2 and said heteroaryl has 1 to 4 heteroatoms independently selected from N, NH, O and S;

[0104] wherein each occurrence of R is independently replaced by 0 to 5 R’;

[0105] or when two R groups bonded to the same atom, the two R groups may be taken together with the atom to which they are bonded to form a 3 to 10 membered aromatic or non-aromatic ring having 0 to 4 hete - roatoms independently selected from N, NH, O, S, SO and SO2, wherein said ring is optionally substituted by 0 to 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;

[0106] wherein each occurrence of R’ is independently selected from halogen, -R’’, -OR’’, oxo,

[0107]-CH2OR'', -CH2NR''2, -C(O)N(R'')2, -C(O)OR'', -NO2, -NCS, -CN, -CF3, -OCF3 and -N(R'')2;

[0108] 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 members)-O- (C1-C6)-alkyl or (C6-C10)-aryl-O-(C1-C6)-alkyl-.

[0109] In another aspect, the present invention provides a compound of formula II:

[0110] or an isomer, polymorph, solvate, hydrate, pharmaceutically acceptable salt or combination thereof, wherein m, R1, R2, R3, R4, R5 and R6 are as defined in formula I.

[0111] In another aspect, the present invention provides a compound of formula III:

[0112] or an isomer, polymorph, solvate, hydrate, pharmaceutically acceptable salt or combination thereof, wherein m, R1, R2, R3, R4, R5 and R6 are as defined in formula I.

[0113] In another aspect, the present invention provides a compound of formula IV:

[0114] or a pharmaceutically acceptable isomer, polymorph, solvate, hydrate, salt or combination thereof, wherein R2 is -OR8, -SR8 or -(CH2)nOR8, wherein R2 is independently substituted by 0 to 5 R'e where m, n, R1, R3, R4, R5, R6 and R8 are as defined in formula I.

[0115] In another aspect, the present invention provides a compound of formula IV:

[0116] or an isomer, polymorph, solvate, hydrate, pharmaceutically acceptable salt or combination thereof, wherein R2 is -(CH2)nO(CH2)nR8, -(CH2)pR8 or

[0117]-(CH2)nN(R'')R10, where R2 is independently replaced by 0 to 5 R' and where m, n, p, R1, R3, R4, R5, R6, R8, R10 and R'' are as defined herein.

[0118] The present invention also provides pharmaceutical compositions comprising a compound of formulas I, II, III or IV, or an isomer, polymorph, solvate, hydrate, pharmaceutically acceptable salt or combination thereof.

[0119] In some embodiments, the compounds of formula I are positive allosteric modulators of the GABAA α5 receptor. In some embodiments, the compounds of formula II are positive allosteric modulators of the GABAA α5 receptor. In some embodiments, the compounds of formula III are positive allosteric modulators of the GABAA α5 receptor. In some embodiments, the compounds of formula IV are positive allosteric modulators of the GABAA α5 receptor. Compounds of formula I, II, III or IV can be used to treat the conditions described herein, such as through activity as positive allosteric modulators of the GABAA α5 receptor.

[0120] In another aspect of the invention, there is presented a method for treating cognitive impairment associated with a CNS disorder in an individual in need of treatment or at risk of said cognitive impairment, the method comprising the step of administering to said individual a therapeutically effective amount of a compound of the invention or an isomer, polymorph, solvate, hydrate, pharmaceutically acceptable salt or combination thereof. In some embodiments, CNS disorder with cognitive impairment includes, without limitation, age-related cognitive impairment, moderate cognitive impairment (MCI), amnestic MCI (aMCI), age-associated memory impairment (AAMI), age-related cognitive impairment (ARCD), dementia, Alzheimer's disease (AD), prodromal AD, post-traumatic stress disorder (PTSD), schizophrenia, bipolar disorder, amyotrophic lateral sclerosis (ALS), cancer therapy-related cognitive impairment, mental retardation, Parkinson's (PD), autism spectrum disorders, fragile X syndrome, Rett syndrome, compulsive behavior and substance dependence. In another aspect of the invention, there is provided a method for preserving or improving cognitive function in an individual in need of such treatment, the method comprising the step of administering to said individual a therapeutically effective amount of a compound of the invention or a isomer, polymorph, solvate, hydrate, pharmaceutically acceptable salt or combination thereof. In certain embodiments of the invention, a compound of the invention or an isomer, polymorph, solvate, hydrate, pharmaceutically acceptable salt or combination thereof is administered every 12 or 24 hours.

DETAILED DESCRIPTION OF FIGURES

[0121] Figure 1 is a graph representing the effects of administration of methyl 3,5-diphenylpyridazine-4-carboxylate on spatial memory retention of ten rats with aging-related disability (AI) in a radial maze test of eight arms (RAM - "Radial Arm Maze"). Black bars refer to rats treated with vehicle alone; open bars refer to rats treated with methyl 3,5-diphenylpyridazine-4-carboxylate at different doses; Hatched bar refers to rats treated with the combination of TB21007 and methyl 3,5-diphenylpyridazine-4-carboxylate.

[0122] Figure 2 is a graph showing the effect of methyl 3,5-diphenylpyridazine-4-carboxylate (administered intravenously) on the binding of Ro154513 in the hippocampus and cerebellum. Methyl 3,5-diphenylpyridazine-4-carboxylate blocked Ro154513 binding in the hippocampus but did not affect Ro15413 binding in the cerebellum.

[0123] Figure 3 is a graph showing dose-dependent GABAA α5 receptor occupancy by intravenously administered methyl 3,5-diphenylpyridazine-4-carboxylate, with receptor occupancy determined by the ratio of hippocampal exposure (a region of high density of the GABAA receptor α5) of RO 15-4513 and exposure of cerebellum (a region of low density of the GABAA receptor α5) of RO 15-4513, or with the use of the GABAA selective compound α5 L-655,708 (10 mg/kg, i.v.) to define total occupancy.

[0124] Figure 4 is a graph showing exposure occupancy relationships for methyl 3,5-diphenylpyridazine-4-carboxylate in the hippocampus. Methyl 3,5-diphenylpyridazine-4-carboxylate occupies about 32% of GABAA α5 receptors at exposures that are behaviorally active in mice with age-related deficiency.

[0125] Figures 5 is a graph representing the effect of ethyl 3-methoxy-7-methyl-9H-benzo[f]imidazo[1,5-a][1,2,4]triazolo[4,3- d][1,4]diazepine-10-carboxylate on the spatial memory retention of ten rats with age-related disability (AI) in an eight-arm radial maze (RAM) test.

[0126] Figure 5 shows the effect of ethyl 3-methoxy-7-methyl-9H-benzo[f]imidazo[1,5-a][1,2,4]triazolo[4,3-d][1 ,4]diazepine-10-carboxylate on spatial memory retention of ten rats with age-related deficiency (AI) in the RAM test, in which vehicle control was tested 3 times and different doses of ethyl 3-methoxy-7 -methyl-9H-benzo[f]imidazo[1,5-a][1,2,4]triazolo[4,3-d][1,4]diazepine-10-carboxylate were tested twice; In Figure 5, black bars refer to rats treated with vehicle alone and open bars refer to rats treated with ethyl 3-methoxy-7-methyl-9H-benzo[f]imidazo[1,5- a][1 ,2,4]triazolo[4,3-d][1,4]diazepine-10-carboxylate in different doses.

[0127] Figure 6 is a graph showing the effect of ethyl 3-methoxy-7-methyl- 9H-benzo[f]imidazo[1,5-a][1,2,4]triazolo[4,3- d][1,4]diazepine-10-carboxylate (administered intravenously) on the binding of Ro154513 in the hippocampus and cerebellum. Ethyl 3-methoxy-7-methyl-9H-benzo[f]imidazo[1,5-a][1,2,4]triazolo[4,3-d][1,4]diazepine-10-carboxylate blocked the Ro154513 binding in the hippocampus, but did not affect Ro15413 binding in the cerebellum.

[0128] Figure 7 is a graph showing dose-dependent GABAA α5 receptor occupancy by ethyl 3-methoxy-7-methyl-9H-benzo[f]imidazo[1,5-a][1,2, 4]triazolo[4,3-d][1,4]diazepine-10-carboxylate administered intravenously, as calculated by the ratio of hippocampal exposure (a region of high GABAA receptor α5 density) to RO 15- 4513 and exposure of cerebellum (a region with low GABAA α5 receptor density) of RO 15-4513 to define total occupancy.

[0129] Figure 8(A) to (C) are graphs showing the effect of 6,6 dimethyl-3-(3-hydroxypropyl)thio-1-(thiazol-2-yl)-6,7-dihydro- 2-Benzothiophen-4(5H)-one, as compared with the vehicle dimethyl sulfoxide (DMSO), in rats with age-related deficiency using a Morris water maze behavioral task.

[0130] Figure 8(A) shows escape latency (i.e., the average time in seconds that rats take to find the hidden platform in the pool of water) during training in rats that received 6,6 dimethyl-3 -(3-hydroxypropyl)thio-1-(thiazol-2-yl)-6,7-dihydro-2-benzothiophen-4(5H)-one and rats receiving DMSO vehicle; Figure 8(B) shows the amount of time spent in the target annular space and opposite annular space by rats receiving 6,6 dimethyl-3-(3-hydroxypropyl)thio-1-(thiazol-2-yl)-6, 7-dihydro-2-benzothiophen-4(5H)-one and rats receiving DMSO vehicle; Figure 8(C) shows the number of crossings into target annular space and opposite annular space by rats receiving 6,6 dimethyl-3-(3-hydroxypropyl)thio-1-(thiazol-2-yl)-6,7 -dihydro-2-benzothiophen-4(5H)-one and rats receiving DMSO vehicle.

DETAILED DESCRIPTION OF THE INVENTION DEFINITIONS

[0131] Except where otherwise defined in this document, the technical and scientific terms used in this application must have the meanings that are commonly understood by those skilled in the art. Generally speaking, the nomenclature used in connection with, and techniques of, chemistry, cell and tissue culture, molecular biology, cell and cancer biology, neurobiology, neurochemistry, virology, immunology, microbiology, pharmacology, genetics, and chemistry. protein and nucleic acid, described herein, are those well known and commonly used in the art.

[0132] The methods and techniques of the present invention are, in general, carried out, except where otherwise indicated, in accordance with conventional methods well known in the art and as described in several general and more specific references that are cited and discussed throughout this descriptive report. See, for example, “Principles of Neural Science", McGraw-Hill Medical, New York, N.Y. (2000); Motulsky, “Intuitive Biostatistics”, Oxford University Press, Inc. (1995); Lodish et al., “Molecular Cell Biology, 4a. Edition". W. H. Freeman & Co., New York (2000); Griffiths et al., “Introduction to Genetic Analysis, 7th Edition", W. H. Freeman & Co., N.Y. (1999); and Gilbert et al., “Developmental Biology, 6a. Edition", Sinauer Associates, Inc., Sunderland, MA (2000).

[0133] The chemical terms used herein are used in accordance with conventional usage in the art, as exemplified by “The McGraw-Hill Dictionary of Chemical Terms", Parker S., Ed., McGraw-Hill, San Francisco, C. A. (1985).

[0134]All publications. patents and published patent applications mentioned in this application are specifically incorporated herein by reference. In case of conflict, this descriptive report, including its specific definitions, will prevail.

[0135] Throughout this specification, the term “comprise” or variations such as “comprises” or “comprising” will be intended to imply the inclusion of a mentioned integer (or components) or group of integers (or components), but not to the exclusion of any other integer (or components) or group of integers (or components).

[0136] The singular forms “a” and “the” include plurals, except where the context clearly stipulates otherwise.

[0137] The term “include” is used to refer to “include, but not limited to”. “Include” and “include but not limited to” are used interchangeably.

[0138] The term “agent” is used herein to denote a chemical compound (such as an organic or inorganic compound (which includes, as a compound of the present invention), a mixture of chemical compounds), a biological macromolecule (such as a nucleic acid, an antibody, which includes parts thereof, as well as humanized, chimeric and human antibodies and monoclonal antibodies, a protein or portion thereof, for example, a peptide, a lipid, a carbohydrate), or an extract made from biological materials such as bacteria, plants, fungi, or animal (particularly mammalian) cells or tissues. Agents include, for example, agents that are known with respect to the structure and those that are not known with respect to the structure. The α5-containing GABAA receptor agonist activity of such agents may make them suitable as “therapeutic agents” in the methods and compositions of this invention.

[0139] A “patient”, “individual” or “subject” are used interchangeably and refer to a human being or a non-human animal. These terms include mammals such as humans, primates, farm animals (which include cattle, swine, etc.), pet (e.g., canines, felines, etc.), and rodents (e.g., mice and rats).

[0140] “Cognitive function” or “cognitive state” refers to any state of the brain or higher order intellectual brain process, respectively, involved in learning and/or memory that includes, but is not limited to, attention, acquisition of information, information processing, working memory, short-term memory, long-term memory, anterograde memory, retrograde memory, memory retrieval, discrimination learning, decision making, inhibitory response control, attentional set shifting, learning by delayed reinforcement, reversal learning, the temporal integration of voluntary behavior, expression of an interest in one's environment and self-care, speed of processing, reasoning and problem solving, and social cognition.

[0141] In humans, cognitive function can be measured, for example and without limitation, by the Clinical Global Impression of Change scale (CIBIC-plus scale); the Mini-Mental State Examination (MMSE); the neuropsychiatric inventory (NPI); the Clinical Dementia Rating Scale (CDR); the Cambridge Automated Neuropsychological Test Battery (CANTAB); the Sandoz Clinical Geriatric Assessment (SCAG), the Buschke Selective Recall Test (Buschke and Fuld, 1974); the associated pairs verbal subtest; the logical memory subtest; the visual reproduction subtest of the Wechsler Memory Scale-Revised (WMS-R) (Wechsler, 1997); the Benton visual retention test, or the explicit 3-alternative forced choice task, or MATRICS consensus neuropsychological test battery. See Folstein et al., J Psychiatric Res 12: 189 to 198, (1975); Robbins et al., Dementia 5: 266 to 281, (1994); Rey, L'examen clinique en psychology, (1964); Kluger et al., J Geriatr Psychiatry Neurol 12:168 to 179, (1999); Marquis et al., 2002 and Masur et al., 1994. See also Buchanan, R.W., Keefe, R.S.E., Umbricht, D., Green, M.F., Laughren, T., and Marder, S.R. (2011), The FDA-NIMH-MATRICS guidelines for clinical trial design of cognitive-enhancing drugs: what do we know 5 years later? Schizophr. Bull. 37, 1209 to 1217.

[0142] In animal model systems, cognitive function can be measured in several conventional ways known in the art, which include the use of a Morris water maze (MWM), Barnes circular maze, elevated radial maze, T-maze or any other maze in which animals use spatial information. Cognitive function can be assessed by reversal learning, extradimensional set shifting, conditional discrimination learning, and reward expectation assessments. Other tests known in the art can also be used to assess cognitive function, such as the innovative object recognition and odor recognition tasks.

[0143] Cognitive function can also be measured using imaging techniques such as positron emission tomography (PET), functional magnetic resonance imaging (fMRI), single photon emission computed tomography (SPECT) or any other imaging technique that allows an individual to measure brain function. In animals, cognitive function can also be measured with electrophysiological techniques.

[0144] “Promoting” cognitive function refers to affecting impaired cognitive function so that it closely resembles the function of a normal, unimpaired individual. Cognitive function may be promoted to any detectable degree, but in humans, preferably, it is promoted sufficiently to allow an impaired individual to perform normal daily life activities at a level of proficiency as close as possible to that of an individual. normal, unimpaired person or a normal, age-appropriate, unimpaired individual.

[0145] In some cases, “promoting” cognitive function in an individual affected by age-related cognitive impairment refers to affecting the impaired cognitive function so that it closely resembles the function of a normal individual commensurate with their age and unimpaired, or the function of a young adult individual. That individual's cognitive function may be promoted to any detectable degree, but in humans, preferably, it is promoted sufficiently to allow an impaired individual to perform normal daily life activities at a level of proficiency as close as possible to that of an individual. unimpaired normal, a young adult individual, or a normal, age-appropriate, unimpaired individual.

[0146] “Preserving” cognitive function refers to affecting normal or impaired cognitive function so that it does not degenerate or does not decline below that observed in the individual under the first presentation or diagnosis, or delays such degeneration.

[0147] “Improving” cognitive function includes promoting cognitive function and/or preserving cognitive function in an individual.

[0148] “Cognitive impairment” refers to cognitive function in individuals that is not as robust as that expected in a normal, unimpaired individual. In some cases, cognitive function is reduced by about 5%, about 10%, about 30% or more, compared to the cognitive function expected in a normal, unimpaired individual. In some cases, “cognitive impairment” in individuals affected by age-related cognitive impairment refers to cognitive function in individuals that is not as robust as that expected in a normal, age-matched, unimpaired individual, or the function of an individual young adult (i.e., individuals with average scores for a given age on a cognitive test).

[0149] “Age-related cognitive impairment” refers to cognitive impairment in aging individuals, in which their cognitive function is not as robust as that expected in a normal individual commensurate with their age or as expected in young adult individuals. In some cases, cognitive function is reduced by about 5%, about 10%, about 30% or more, compared to the cognitive function expected in a normal individual commensurate with their age. In some cases, cognitive function is as expected in a normal individual commensurate with his age, but reduced by about 5%, about 10%, about 30%, about 50% or more, compared with normal cognitive function. expected in a young adult individual. Age-related impaired cognitive function may be associated with moderate cognitive impairment (MCI) (which includes amnestic MCI and non-amnestic MCI), age-associated memory impairment (AAMI), and age-related cognitive impairment (ARCD).

[0150] "Cognitive impairment" associated with AD or related to AD or in AD refers to cognitive function in individuals that is not as robust as that expected in individuals who have not been diagnosed with AD using conventional standards and methodologies.

[0151] “Moderate cognitive impairment” or “MCI” refers to a condition characterized by isolated memory impairment unaccompanied by other cognitive abnormalities and relatively normal functional capabilities. A set of criteria for a clinical characterization of MCI specifies the following features: (1) memory complaint (as reported by the patient, informant, or physician), (2) normal activities of daily living (ADLs), (3) global cognitive function normal, (4) abnormal memory for age (defined as a score greater than 1.5 standard deviations below the mean for a given age), and (5) absence of indicators of dementia (as defined by DSM-IV guidelines). Petersen et al., Srch. Neurol. 56: 303 to 308 (1999); Petersen, “Mild cognitive impairment: Aging to Alzheimer’s Disease.” Oxford University Press, N. Y. (2003). Cognitive impairment in individuals with MCI may involve any mental process or area of cognition other than memory, language, association, attention, perception, problem solving, executive function, and visuospatial skills. See, for example, Winbald et al., J. Intern. Med. 256:240 to 240, 2004; Meguro, Acta. Neurol. Taiwan. 15:55 to 57, 2008; Ellison et al., CNS Spectr. 13:66 to 72, 2008, Petersen, Semin. Neurol. 27:22 to 31, 2007. MCI is further subdivided into amnestic MCI (aMCI) and non-amnestic MCI, characterized by the deficiency (or lack thereof) of memory in particular. MCI is defined as aMCI if memory is impaired given the individual's age and educational level. If, on the other hand, the individual's memory is intact across age and education, but other cognitive domains other than memory are impaired, such as language, executive function, or visuospatial skills, MCI is defined as non-amnesic MCI. Both aMCI and non-amnestic MCI can be subdivided into multiple-domain or single-domain MCI. The single domain of aMCI refers to a condition in which memory, but not other cognitive areas, is impaired. Multiple domain aMCI refers to a condition in which memory and at least one other cognitive area are impaired. Non-amnestic MCI is single-domain or multiple-domain depending on whether no more than one different cognitive area of memory is impaired. See, for example, Peterson and Negash, CNS Spectr. 13:45 to 53, 2008.

[0152] The diagnosis of MCI typically provides an objective assessment of cognitive impairment, which can be gathered through the use of well-established neuropsychological tests, which include the Mini-Mental State Examination (MMSE), the Automated Battery of Neuropsychological Tests of Cambridge (CANTAB) and individual tests such as the Rey Auditory Verbal Learning Test (AVLT), the Logical Memory subtest of the Wechsler Revised Memory Scale (WMS-R), and the New York University Paragraph Recall Test ( NYU). See Folstein et al., J Psychiatric Res 12: 189 to 198 (1975); Robbins et al., Dementia 5: 266 to 281 (1994); Kluger et al., J Geriatric Psychiatry Neurol 12:168 to 179 (1999).

[0153] "Age-associated memory impairment (AAMI)" refers to an impairment of memory due to aging. A patient may be considered to have AAMI if the patient is at least 50 years of age and meets all of the following criteria: a) The patient has noted impairment in memory performance, b) The patient shows worsening on a standard memory test in compared to young adults, c) All other obvious causes of memory impairment, except normal aging, have been eliminated (in other words, memory impairment may not be attributed to other causes, such as a recent heart attack or spinal injury). headache, depression, adverse drug reactions, Alzheimer's disease, etc.).

[0154] "Age-related cognitive impairment (ARCD)" refers to impairments in memory and cognitive abilities that are a normal consequence of aging in humans (e.g., Craik & Salthouse, 1992). This is also true of virtually all mammal species. Age-associated memory impairment refers to older people with objective memory impairment relative to their younger years, but cognitive function that is normal relative to people of the same age group (Crook et al., 1986). Age-consistent memory impairment is a less pejorative label that emphasizes that these are normal developmental changes (Crook, 1993; Larrabee, 1996), are not pathophysiological (Smith et al., 1991), and rarely progress to overt dementia. (Youngjohn & Crook, 1993). The DSM-IV (1994) has codified the diagnostic classification of ARCD.

[0155] “Dementia” refers to a condition characterized by severe cognitive impairment that interferes with normal activities of daily life. Individuals with dementia also exhibit other symptoms, such as impaired judgment, changes in personality, disorientation, confusion, behavioral changes, speech difficulties, and motor deficits. There are different types of dementias, such as Alzheimer's disease (AD), vascular dementia, dementia with Lewy bodies, and frontotemporal dementia.

[0156] Alzheimer's disease (AD) is characterized by memory deficits in its early phase. Later symptoms include impaired judgment, disorientation, confusion, behavioral changes, speech difficulties, and motor deficits. Histologically, AD is characterized by beta-amyloid plaques and tau protein tangles.

[0157] Vascular dementia is caused by cerebrovascular accidents. The symptoms overlap with those of AD, but without the focus on memory impairment.

[0158] Dementia with Lewy bodies is characterized by abnormal deposits of alpha-synuclein that form internal neurons in the brain. Cognitive impairment can be similar to AD, which includes impairments in memory and judgment and changes in behavior.

[0159] Frontotemporal dementia is characterized by gliosis, neuronal loss, superficial spongiform degeneration in the frontal cortex and/or anterior temporal lobes and Picks bodies. Symptoms include changes in personality and behavior, which include impairment in social skills and language comprehension/expression.

[0160] “Posttraumatic stress disorder (PTSD)” refers to an anxiety disorder characterized by an immediate or delayed response to a catastrophic event, characterized by re-experiencing the trauma, psychic numbness or avoidance of stimuli associated with the trauma, and increased stimulation . The phenomena of experience again include intrusive memories, flashbacks to the past, nightmares, and psychological or physiological agony in response to reminders of the trauma. Such responses produce anxiety and can have a significant impact, both chronic and acute, on a patient's physical and emotional health and quality of life. PTSD is also associated with impaired cognitive performance and older individuals with PTSD have greater impairment in cognitive performance relative to control patients.

[0161] “Schizophrenia” refers to a chronic debilitating disorder characterized by a spectrum of psychopathology, which includes positive symptoms such as distorted or abnormal mental representations (e.g., hallucinations, delusions), negative symptoms characterized by decreased motivation and action adaptive goal-directed (e.g., lack of ability to experience pleasure, affective blunting, apathy) and cognitive impairment. Although abnormalities in the brain are proposed to underlie the full spectrum of psychopathology in schizophrenia, currently available antipsychotics are largely ineffective in treating cognitive impairments in patients.

[0162] "Bipolar disorder" or "BP" or "manic depressive disorder" or "manic depressive illness" refers to a chronic psychological/mood disorder that may be characterized by significant changes in mood that include periods of depression and periods of manic euphoria. BP can be diagnosed by a knowledgeable physician based on medical and personal history, interview consultation, and physical examinations. The term "mania" or "manic periods", or other variants, refers to periods in which an individual exhibits some or all of the following characteristics: racing thoughts, rapid speech, high levels of activity and agitation, as well as a sense of prideful self-esteem, euphoria, poor judgment, insomnia, impaired concentration, and aggressiveness.

[0163]“Amyotrophic lateral sclerosis", also known as ALS, refers to a progressive and fatal neurodegenerative disease characterized by a degeneration of motor neurons, the nerve cells in the central nervous system that control voluntary muscle movement. ALS is also characterized by neuronal degeneration in the entorhinal cortex and hippocampus, memory deficits and neuronal hyperexcitability in different areas of the brain, such as the cortex.

[0164] “Cancer therapy-related cognitive impairment” refers to cognitive impairment that develops in individuals who are treated with cancer therapies, such as chemotherapy and radiation. Cytotoxicity and other adverse side effects on the brain from cancer therapies result in cognitive impairment in such functions as memory, learning, and attention.

[0165] Parkinson's disease (PD) is a neurological disorder characterized by a decrease in voluntary movements. The afflicted patient has reduced motor activity and slower voluntary movements compared to the normal individual. The patient has the characteristic "mask" face, a tendency to rush while walking, a hunched posture, and generalized muscle weakness. There is a "definite" stiffness typical of passive movements. Another important characteristic of the disease is tremor of the extremities that occurs at rest and decreases during movement.

[0166] “Autism”, for use in the present invention, refers to an autism spectrum disorder characterized by a disorder of neural development that leads to impaired communication and social interaction by repetitive and restricted behavior. “Autism spectrum disorder” refers to a group of developmental disabilities that includes: autism; Asperger syndrome; pervasive developmental disorder not otherwise specified (PDD-NOS or atypical autism); Rett syndrome; and childhood disintegrative disorder.

[0167] Mental retardation is a widespread disorder characterized by significantly impaired cognitive function and deficits in adaptive behaviors. Mental retardation is often defined as an intelligence quotient (IQ) score of less than 70. Congenital causes are among many underlying causes for mental retardation. Dysfunction in neuronal communication is also considered one of the underlying causes for mental retardation (Myrrhe van Spronsen and Casper C. Hoogenraad, Curr. Neurol. Neurosci. Rep. 2010, 10, 207 to 214).

[0168] In some cases, mental retardation includes, but is not limited to, Down syndrome, velocardiofacial syndrome, fetal alcohol syndrome, fragile X syndrome, Klinefelter syndrome, neurofibromatosis, congenital hypothyroidism, Williams syndrome, phenylketonuria (PKU), Smith-Lemli-Opitz syndrome, Prader-Willi syndrome, Phelan-McDermid syndrome, Mowat-Wilson syndrome, ciliopathy, Lowe syndrome, and siderium type X-linked mental retardation. Down syndrome is a disorder that includes a combination of birth defects that include some degree of mental retardation, characteristic facial features, and often heart defects, increased infections, problems with vision and hearing, and other health problems. Fragile X syndrome is a prevalent form of inherited mental retardation that occurs with a frequency of 1 in 4,000 males and 1 in 8,000 females. The syndrome is also characterized by developmental delay, hyperactivity, attention deficit disorder, and autistic-like behavior. There is no effective treatment for fragile X syndrome.

[0169] Obsessive-compulsive disorder ("OCD") is a mental condition that is most commonly characterized by repetitive, intrusive, unwanted thoughts (obsessions) that result in compulsive behaviors and mental actions that an individual feels compelled to perform (compulsion) . Current epidemiological data indicate that OCD is the fourth most common mental disorder in the United States. Some studies suggest that the prevalence of OCD is between one and three percent, although the prevalence of clinically recognized OCD is much lower, suggesting that many individuals with the disorder may go undiagnosed. Patients with OCD are often diagnosed by a psychologist, psychiatrist, or psychoanalyst according to the diagnostic criteria in the Diagnostic and Statistical Manual of Mental Disorders, 4a. edition, text revision (DSM-IV-TR) (2000), which include characteristics of obsessions and compulsions.

[0170] Substance dependence (e.g., drug dependence, alcohol dependence) is a mental disorder. Addiction is not triggered instantly upon exposure to the substance of abuse. Rather, it involves multiple complex neural adaptations that develop over different time courses ranging from hours to days to months (Kauer J. A. Nat. Rev. Neurosci. 2007, 8, 844 to 858). The path to addiction generally begins with the voluntary use of one or more controlled substances, such as narcotics, barbiturates, methamphetamines, alcohol, nicotine, and any of a variety of other such controlled substances. Over time, with prolonged use of the controlled substance(s), the voluntary ability to abstain from the controlled substance(s) is compromised due to the effects of prolonged use on the brain function and, therefore, behavior. As such, substance dependence in general is characterized by desire, seeking and compulsive use of the substance that persists even in the face of negative consequences. Cravings may represent changes in the patient's underlying neurobiology that likely need to be addressed in a meaningful way if recovery is to be achieved. Substance dependence is also characterized, in many cases, by withdrawal symptoms that, for some substances, are life-threatening (e.g., alcohol, barbiturates) and in others can result in substantial morbidity (which may include nausea, vomiting, fever, dizziness and excessive sweating), agony and diminished ability to recover. For example, alcoholism, also known as alcohol dependence, is one such substance dependence. Alcoholism is mainly characterized by four symptoms which include cravings, loss of control, physical dependence and tolerance. These symptoms may also characterize dependence on other controlled substances. The desire for alcohol, as well as other controlled substances, is often as strong as the need for food or water. Thus, an alcoholic may continue to drink despite serious legal, health, and/or family consequences.

[0171] "Treatment" of a condition or patient refers to taking steps to obtain desired or beneficial results, which include clinical results. Beneficial or desired clinical results include, but are not limited to, preventing or slowing the progression of the disease. disease or disorder, or alleviation, improvement, or slowing the progression, of one or more symptoms of cognitive impairment associated with CNS disorders, such as age-related cognitive impairment, moderate cognitive impairment (MCI), amnestic MCI (aMCI), memory impairment age-related cognitive impairment (ARCD), dementia, Alzheimer's disease(AD), prodromal AD, post-traumatic stress disorder (PTSD), schizophrenia, bipolar disorder, amyotrophic lateral sclerosis (ALS), disability cognitive impairment related to cancer therapy, mental retardation, Parkinson's disease (PD), autism spectrum disorders, fragile X syndrome, Rett syndrome, compulsive behavior, and substance dependence. In some embodiments, treatment comprises preventing or slowing the progression of a CNS disorder (such as one as described herein). In certain modalities, treatment comprises alleviating, improving or slowing the progression of one or more symptoms associated with that CNS disorder. In certain embodiments, the symptom being treated is cognitive impairment or cognitive impairment. Treatment of age-related cognitive impairment further comprises slowing the conversion of age-related cognitive impairment (which includes, but is not limited to, MCI, ARCD, and AAMI) into dementia (e.g., AD).

[0172] “Treatment of cognitive impairment” refers to taking steps to improve cognitive function in an individual with cognitive impairment such that the individual's performance on one or more cognitive tests is improved to any detectable degree, or is impeded of further decrease. Ideally, this individual's cognitive function, after treatment of cognitive impairment, becomes very similar to the function of a normal, unimpaired individual. Treatment of cognitive impairment in humans can improve cognitive function to any detectable degree , but is preferably improved in a manner sufficient to enable the impaired individual to perform activities of normal daily living at the same level of proficiency as a normal, unimpaired individual. In some cases, “cognitive impairment treatment” refers to taking provisions to improve cognitive function in an individual with cognitive impairment so that the individual's performance on one or more cognitive tests is improved to any detectable degree, or is prevented from further diminishing. Preferably, this cognitive function of the individual, after treatment for cognitive impairment, becomes very similar to the function of a normal, unimpaired individual. In some cases, “cognitive impairment treatment” in an individual affected by age-related cognitive impairment refers to taking steps to improve cognitive function in the individual so that the individual's cognitive function, after treatment for cognitive impairment, is very similar to the function of a normal, age-compatible, unimpaired individual, or the function of a young adult individual.

[0173] "Administering" or "administration of" a substance, a compound or an agent to an individual can be carried out using a variety of methods known to those skilled in the art. For example, a compound or agent may be administered intravenously, arterially, intradermally, intramuscularly, intraperitoneally, intravenously, subcutaneously, ocularly, sublingually, orally (by ingestion), intranasally (by inhalation), intraspinally, intracerebrally, and transdermally. - mica (by absorption, for example, through a skin duct). A compound or agent may also be suitably introduced by means of biodegradable or rechargeable polymeric devices or other devices, for example, patches and pumps, or formulations, which provide controlled, extended or slow release of the compound or agent. Administration may also be carried out, for example, once, a plurality of times and/or over one or more extended periods. In some aspects, administration includes both direct administration, which includes self-administration, and indirect administration, which includes the action of prescribing a drug. For example, for use in the present invention, a physician who instructs a patient to self-administer a drug, or have the drug administered by another, and/or who provides a patient with a prescription for a drug is administering the drug to the patient. patient.

[0174] Suitable methods for administering a substance, compound or agent to an individual will also depend, for example, on the age of the individual, whether the individual is active or inactive at the time of administration, whether the individual is cognitively impaired at the time of administration, the extent of the deficiency, and the chemical and biological properties of the compound or agent (e.g., solubility, digestibility, bioavailability, stability, and toxicity). In some embodiments, a compound or an agent is administered orally, e.g., to a subject by ingestion, or intravenously, e.g., to a subject by injection. In some embodiments, the orally administered compound or agent is in an extended-release or slow-release formulation, or administered using a device for such extended-release or slow-release.

[0175] For use in the present invention, an “α5-containing GABAA receptor agonist”, “α5-containing GABAA R agonist” or an “α5 GABAA receptor agonist”, and other variations, for use in the present invention, if refer to a compound that enhances the function of the α5-containing GABAA receptor (GABAA R), that is, a compound that increases GABA-controlled Cl- currents. In some embodiments, the α5-containing GABAA R agonist, for use herein invention, relates to a positive allosteric modulator, which potentiates GABA activity. α5-containing GABAA receptor agonists suitable for use in the present invention include α5-containing GABAA receptor agonists of all formulas and the of specific α5-containing GABAA receptor described herein and its hydrates, solvates, polymorphs, salts (e.g., pharmaceutically acceptable salts), isomers (e.g., stereoisomers, E/Z isomers and tautomers) and combinations thereof.

[0176] “Antipsychotic”, “antipsychotic agent”, “antipsychotic drug” or “antipsychotic compound” refers to (1) a typical or atypical antipsychotic; (2) an agent that is selected from dopaminergic agents, glutamatergic agents, NMDA receptor positive allosteric modulators, glycine reuptake inhibitors, glutamate reuptake inhibitor, metabotropic glutamate receptor agonists (mGluRs) or modulators positive allosteric modulators (PAMs) (e.g., mGluR2/3 agonists or PAMs), positive allosteric modulators (PAMs) of gluR5 glutamate receptor, positive allosteric modulators (PAMs) of M1 muscarinic acetylcholine receptor (mAChR), M1 muscarinic acetylcholine receptor (mAChR) antagonists histamine H3, AMPA/kainate receptor antagonists, ampakines (CX-516), glutathione prodrugs, noradrenergic agents, serotonin receptor modulators, cholinergic agents, CB1 cannabinoid antagonists, neurokinin 3 antagonists, neurotensin, MAO B inhibitors, PDE10 inhibitors, nNOS inhibitors, neurosteroids and neurotrophic factors, alpha-7 agonists or positive allosteric modulators (PAMs) PAMs, serotonin 2C agonists; and/or (3) an agent that is useful in treating one or more signs or symptoms of schizophrenia or bipolar disorder (in particular, mania).

[0177] “Typical antipsychotics”, for use in the present invention, refer to conventional antipsychotics, which produce antipsychotic effects, as well as movement-related adverse effects in relation to disturbances in the nigrostriatal dopamine system. These extrapyramidal side effects (EPS) include Parkinson's disease, akathisia, tardive dyskinesia, and dystonia. See Baldessarini and Tarazi in Goodman & Gilman's The Pharmacological Basis of Therapeutics, 10th edition, 2001, pages 485 to 520.

[0178] "Atypical antipsychotics", for use in the present invention, refer to antipsychotic drugs that produce antipsychotic effects with little or no EPS and include, but are not limited to, aripiprazole, asenapine, clozapine, iloperidone, olanzapine, lurasidone, paliperidone , quetiapine, risperidone and ziprasidone. "Atypical" antipsychotics differ from conventional antipsychotics in their pharmacological profiles. Although conventional antipsychotics are characterized primarily by blockade of the dopamine D2 receptor, atypical antipsychotics show antagonistic effects on multiple receptors that include 5HTa and 5HTc serotonin receptors and varying degrees of receptor affinities. Atypical antipsychotic drugs are commonly referred to as serotonin/dopamine antagonists, reflecting the influential hypothesis that greater affinity for the 5HT2 receptor than for the D2 receptor is under the action of "atypical" antipsychotic drugs or "second generation" antipsychotic drugs. However, atypical antipsychotics often exhibit side effects, which include, but are not limited to, weight gain, diabetes (e.g., type II diabetes mellitus), hyperlipidemia, QTc prolongation, myocarditis, sexual side effects, extrapyramidal side effects and cataracts. Therefore, atypical antipsychotics do not represent a homogeneous class, given their differences in the context of both the relief of clinical symptoms and their potential to induce side effects, such as those listed above. Additionally, the common side effects of atypical antipsychotics, as described above, often limit the antipsychotic doses that can be used for these agents.

[0179] Memantine is chemically known as 3,5-dimethyladamantan-1-amine or 3,5-dimethyltricyclo[3.3.1.13.7]decan-1-amine, which is an N-methyl-D- receptor antagonist. aspartate (NMDA) non-competitive with moderate affinity. Trademarks for memantine include: Axura® and Akatinol® (Merz), Namenda® (Forest Laboratories), Ebixa® and Abixa® (Lundbeck), and Memox® (Unipharm). Memantine is approved for the treatment of moderate to severe Alzheimer's disease (AD) in the United States at a dose of up to 28 mg/day. Memantine derivatives or analogs, which include compounds that structurally or chemically resemble memantine, are also useful in the present invention. Such memantine derivatives or analogs include, but are not limited to, those compounds disclosed in U.S. patents 3,391,142; 4,122,193; 4,273,774; and 5,061,703; publication of patent application in the U.S. US20040087658, US20050113458, US20060205822, US20090081259, US20090124659 and US20100227852; publication of patent application in EP EP2260839A2; patent in EP EP1682109B1; and publication of PCT application in WO2005079779, all of which are incorporated herein by reference. Memantine, for use in the present invention, includes memantine and its derivatives and analogues, as well as hydrates, polymorphs, prodrugs, salts and solvates thereof. Memantine, for use in the present invention, also includes a composition comprising memantine or a derivative, an analogue or a prodrug, polymorph, solvate, hydrate or pharmaceutically acceptable salt thereof, wherein the composition comprises, additionally and optionally, at least one additional therapeutic agent (such as a therapeutic agent useful in treating a CNS disorder or associated cognitive impairments thereof). In some embodiments, the memantine composition suitable for use in the present invention comprises memantine and a second therapeutic agent which is donepezil (under the trade name Aricept).

[0180] “Acetylcholinesterase inhibitor” or “AChE-I”, for use in the present invention, refers to an agent that inhibits the ability of the cholinesterase enzyme to break down the neurotransmitter acetylcholine, thereby increasing the concentration and duration of acetylcholine, particularly in brain synapses or neuromuscular junctions. AChE-Is suitable for use in this application may include, for example, the subcategories of (i) reversible non-competitive inhibitors or reversible competitive inhibitors, (ii) irreversible inhibitors and (iii) quasi-irreversible inhibitors.

[0181] The term "simultaneous administration", for use in the present invention, means that an α5-containing GABAA receptor agonist (e.g., a positive allosteric modulator of the α5-containing GABAA receptor) and a second therapeutic agent (e.g., example, an antipsychotic, memantine, or an AChE-I), or its polymorphs, solvates, hydrates, or pharmaceutically acceptable salts, are administered with a time separation of no more than about 15 minutes and, in some embodiments, no more. than about 10 minutes. When drugs are administered simultaneously, the α5-containing GABAA receptor agonist (e.g., a positive allosteric modulator of the α5-containing GABAA receptor) and a second therapeutic agent (e.g., an antipsychotic, memantine, or an AChE-I), or their salts, hydrates, solvates or polymorphs, may be contained in the same dosage (e.g., a unit dosage form comprising both an α5-containing GABAA receptor agonist (e.g., an α5-containing GABAA receptor positive allosteric modulator) and a second therapeutic agent (e.g., an antipsychotic, memantine, or an AChE-I) or in distinct dosages (e.g., an α5-containing GABAA receptor agonist (e.g., an α5-containing GABAA receptor positive allosteric modulator) or its salt, hydrate, solvate or polymorph, is contained in a dosage form and a second therapeutic agent (e.g., an antipsychotic, memantine or an AChE-I), or its salt, hydrate, solvate or polymorph, is contained in other dosage form).

[0182] The term "sequential administration", for use in the present invention, means that an α5-containing GABAA receptor agonist (e.g., a positive allosteric modulator of the α5-containing GABAA receptor) and a second therapeutic agent (e.g., a example, an antipsychotic, memantine, or an AChE-I), or polymorphs, solvates, hydrates, or pharmaceutically acceptable salts thereof, are administered with a time separation greater than about 15 minutes and, in some embodiments, greater than about of one hour, or up to 12 to 24 hours. The α5-containing GABAA receptor agonist (e.g., an α5-containing GABAA receptor positive allosteric modulator) or a second therapeutic agent (e.g., an antipsychotic, memantine, or an AChE-I) may be administered first. The α5-containing GABAA receptor agonist (e.g., a positive allosteric modulator of the α5-containing GABAA receptor) and a second therapeutic agent (e.g., an antipsychotic, memantine, or an AChE-I), or their salts, hydrates , solvents or polymorphs, for sequential administration may be contained in distinct dosage forms, optionally contained in the same container or package.

[0183] A "therapeutically effective amount" of a drug or agent is an amount of a drug or agent that, when administered to an individual, will have the intended therapeutic effect, e.g., enhancement of cognitive function in an individual, e.g. , a patient who has cognitive impairment associated with a CNS disorder. The full therapeutic effect does not necessarily occur upon administration of one dose and may occur only after administration of a series of doses. In this way, a therapeutically effective amount can be administered in one or more administrations. The precise effective amount needed by an individual will depend, for example, on the size, age and health of the individual, the nature and extent of cognitive impairment or other symptoms of the CNS disorder (such as age-related cognitive impairment, moderate cognitive impairment (MCI), dementia, Alzheimer's disease (AD), prodromal AD, post-traumatic stress disorder (PTSD), schizophrenia, bipolar, ALS, cognitive impairment related to cancer therapy, mental retardation, Parkinson's disease ( PD), autism spectrum disorders, fragile X syndrome, Rett syndrome, compulsive behavior and substance dependence) and the therapeutic agents or combination of therapeutic agents selected for administration and mode of administration. The skilled artisan can readily determine the effective amount for a given situation through routine experimentation.

[0184] The compounds of the present invention also include prodrugs, analogues or derivatives. The term "prodrug" is recognized in the art and is intended to encompass compounds or agents that, under physiological conditions, are converted into positive allosteric modulators of α5-containing GABAA. A common method for producing a prodrug consists of selecting chemical moieties that are hydrolyzed or metabolized under physiological conditions to provide the desired agent or compound. In other embodiments, the prodrug is converted through an enzymatic activity of the host animal into a positive allosteric modulator of the GABAA α5 receptor.

[0185] "Analog" is used herein to refer to a compound that functionally resembles another chemical entity, but does not share the identical chemical structure. For example, an analogue is sufficiently similar to a parent or base compound that it can replace the parent compound in therapeutic applications, despite minimal structural differences.

[0186] "Derivative" is used herein to refer to the chemical modification of a compound. Chemical modifications of a compound may include, for example, the replacement of hydrogen with an alkyl, acyl or amino group. Many other modifications are also possible.

[0187] The term "aliphatic", for use in the present invention, refers to a branched or straight-chain alkyl, alkenyl or alkynyl. It is understood that alkenyl or alkynyl modalities require at least two carbon atoms in the aliphatic chain. Aliphatic groups typically contain from 1 (or 2) to 12 carbons, such as from 1 (or 2) to 4 carbons.

[0188] The term "aryl", for use in the present invention, refers to a bicyclic or monocyclic carbocyclic aromatic ring system. Aryl, for use in the present invention, includes a (C6-C12)-aryl-. For example, aryl, for use in the present invention, may be a monocyclic C6C10 or bicyclic C8-C12 carbocyclic aromatic ring system. In some embodiments, the aryl for use in the present invention may be a (C6-C10)-aryl-. Phenyl (or Ph) is an example of a monocyclic aromatic ring system. Bicyclic aromatic ring systems include systems in which both rings are aromatic, for example, naphthyl, and systems in which only one of the two rings is aromatic, for example, tetralin.

[0189] The term “heterocyclic”, for use in the present invention, refers to a monocyclic or bicyclic non-aromatic ring system that has 1 to 4 heteroatoms or heteroatom groups in each ring selected from O, N, NH, S , SO or SO2 in a chemically stable arrangement. The heterocyclic, for use in the present invention, includes a 3 to 12 membered heterocyclyl having 1 to 4 heteroatoms independently selected from O, N, NH, S, SO or SO2. For example, the heterocyclic for use in the present invention may be an 8- to 12-membered bicyclic or 3 to 10-membered monocyclic non-aromatic ring system having 1 to 4 heteroatoms or heteroatom groups in each ring selected from O , N, NH, S, SO or SO2 in a chemically stable arrangement. In some embodiments, the heterocyclic for use in the present invention includes a 3 to 10 membered heterocyclyl that has 1 to 4 heteroatoms independently selected from O, N, NH, S, SO or SO2. In one embodiment of a "heterocyclyl" bicyclic non-aromatic ring system, one or both rings may contain said heteroatom or heteroatom groups. In another embodiment of bicyclic "heterocyclyl", one of the two rings may be aromatic. In yet another embodiment of the heterocyclic ring system, a non-aromatic heterocyclic ring may optionally be fused to an aromatic carbocycle.

[0190] Examples of heterocyclic rings include 3-1H-benzimidazol-2-one, 3-(1-alkyl)-benzimidazol-2-one, 2-tetrahydrofuranyl, 3-tetrahydrofuranyl, 2-tetrahydrothiophenyl, 3-tetrahydrothiophenyl, 2 -morpholino, 3-morpholino, 4-morpholino, 2-thiomorpholino, 3-thiomorpholino, 4-thiomorpholino, 1-pyrrolidinyl, 2-pyrrolidinyl, 3-pyrrolidinyl, 1-tetrahydropiperazinyl, 2-tetrahydropiperazinyl, 3-tetrahydropiperazinyl, 1-piperidinyl , 2-piperidinyl, 3-piperidinyl, 1-pyrazolinyl, 3-pyrazolinyl, 4-pyrazolinyl, 5-pyrazolinyl, 1-piperidinyl, 2-piperidinyl, 3-piperidinyl, 4-piperidinyl, 2-thiazolidinyl, 3-thiazolidinyl, 4 - thiazolidinyl, 1-imidazolidinyl, 2-imidazolidinyl, 4-imidazolidinyl, 5-imidazolidinyl, indolinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, benzothiolane, benzodithiane and 1,3-dihydro-imidazol-2-one.

[0191] The term “heteroaryl”, for use in the present invention, refers to a monocyclic or bicyclic aromatic ring system that has 1 to 4 heteroatoms or heteroatom groups in each ring selected from O, N, NH or S in a chemically stable arrangement. Heteroaryl for use in the present invention includes a 5- to 12-membered heteroaryl that has 1 to 4 heteroatoms independently selected from O, N, NH, or S. In some embodiments, the heteroaryl for use in the present invention , may be a 5- to 10-membered heteroaryl that has 1 to 4 heteroatoms independently selected from O, N, NH, or S. For example, the heteroaryl, for use in the present invention, may be a monocyclic aromatic ring system of 5- to 10-membered or 8- to 12-membered bicyclic that has 1 to 4 heteroatoms or heteroatom groups selected from O, N, NH, or S on one or both rings in a chemically stable arrangement. In such embodiment of bicyclic "heteroaryl" aromatic ring system:

[0192] - both rings are aromatic; It is

[0193] - one or both rings may contain said heteroatom or heteroatom groups.

[0194] Examples of heteroaryl rings include 2-furanyl, 3-furanyl, N-imidazolyl, 2-imidazolyl, 4-imidazolyl, 5-imidazolyl, benzimidazolyl, 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl, 2-oxazolyl , 4-oxazolyl, 5-oxazolyl, N-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl, pyridazinyl (e.g. 3-pyridazinyl), 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, tetrazolyl (e.g. 5-tetrazolyl), triazolyl (e.g. 2-triazolyl and 5-triazolyl), 2-thienyl, 3-thienyl, benzofuryl , benzothiophenyl, indolyl (e.g., 2-indolyl), pyrazolyl (e.g., 2-pyrazolyl), isothiazolyl, 1,2,3-oxadiazolyl, 1,2,5-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,3-triazolyl, 1,2,3-thiadiazolyl, 1,3,4-thiadiazolyl, 1,2,5-thiadiazolyl, purinyl, pyrazinyl, 1,3,5-triazinyl, quinolinyl (e.g. , 2-quinolinyl, 3-quinolinyl, 4-quinolinyl) and isoquinolinyl (e.g., 1-isoquinolinyl, 3-isoquinolinyl or 4-isoquinolinyl).

[0195] The term "cycloalkyl or cycloalkenyl" refers to a bridged, fused or monocyclic bicyclic carbocyclic ring system that is non-aromatic. For example, cycloalkyl or cycloalkenyl, for use in the present invention, may be a bridged, fused, or C3C10 monocyclic C8-C12 bicyclic carbocyclic ring system that is non-aromatic. Cycloalkenyl rings have one or more unsaturation units. Preferred cycloalkyl or cycloalkenyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclohexenyl, cycloheptyl, cycloheptenyl, norbornyl, adamantyl and decalinyl.

[0196] For use in the present invention, carbon atom designations may have the indicated integer and any intervening integer. For example, the number of carbon atoms in a (C1-C4)-alkyl group is 1, 2, 3, or 4. It should be understood that this designation refers to the total number of atoms in the appropriate group. For example, in a (C3-C10)-heterocyclyl, the total number of carbon atoms and heteroatoms is 3 (as in aziridine), 4, 5, 6 (as in morpholine), 7, 8, 9, or 10.

[0197] "Pharmaceutically acceptable salt" is used herein to refer to an agent or a compound according to the invention that is a non-toxic and therapeutically active acid, base salt form of the compounds. The acid addition salt form of a compound occurring in its free form as a base can be obtained by treating said free base form with a suitable acid, such as an inorganic acid, for example a hydrohalic acid, such as hydrochloric or hydrobromic, sulfuric, nitric, phosphoric and similar; or an organic acid, such as, for example, acetic, hydroxyacetic, propanoic, lactic, pyruvic, malonic, succinic, maleic, fumaric, malic, tartaric, citric, methanesulfonic, ethanesulfonic, benzenesulfonic, p-toluenesulfonic, cyclic, salicylic, p- aminosalicylic, pamoic and similar. See, for example, document WO 01/062726.

[0198] Compounds containing acidic protons can be converted into their non-toxic and therapeutically active base addition salt form, for example, amine or metal salts, by treatment with suitable inorganic and organic bases. Suitable base addition salt forms include, for example, ammonium salts, alkaline earth and alkali metal salts, for example, lithium, sodium, potassium, magnesium, calcium salts and the like, salts with organic bases, e.g. , N-methyl-D-glucamine, hydrabamine salts and salts with amino acids, such as, for example, arginine, lysine and the like. Conversely, said salt forms can be converted into free forms by treatment with a suitable acid or base.

[0199] The compounds and their salts can be in the form of a solvate, which is included within the scope of the present invention. Such solvates include, for example, hydrates, alcoholates and the like. See, for example, document WO 01/062726.

[0200] For use in the present invention, the term "hydrate" refers to a combination of water with a compound in which the water retains its molecular state as water and is absorbed, adsorbed or contained within a crystal lattice of the substrate compound .

[0201] For use in the present invention, the term "polymorph" refers to different crystalline forms of the same compound and other solid-state molecular forms that include pseudo-polymorphs, such as hydrates (e.g., bound water present in the crystalline structure) and solvates (e.g., bound solvents other than water) of the same compound. Different crystalline polymorphs have different crystal structures due to different compaction of the molecules in the lattice. This results in different crystal symmetry and/or unit cell parameters that directly influence their physical properties, such as the X-ray diffraction characteristics of crystals or powders. A different polymorph, for example, will generally diffract at a different set of angles and will generate different values for the intensities. Therefore, X-ray powder diffraction can be used to identify different polymorphs, or a solid form comprising more than one polymorph, in a reliable and reproducible way. Crystalline polymorphic forms are of interest to the pharmaceutical industry and especially to those involved in the development of suitable dosage forms. If the polymorphic form is not kept constant during stability or clinical studies, the exact dosage form used or studied may not be comparable from batch to batch. It is also desirable to have processes for producing a compound with the selected polymorphic form in a high purity when the compound is used in clinical studies or commercial products, since the impurities present can produce undesirable toxicological effects. Certain polymorphic forms may exhibit enhanced thermodynamic stability or may be more readily manufactured in high purity in large quantities and thus are more suitable for inclusion in pharmaceutical formulations. Certain polymorphs may exhibit other advantageous physical properties such as lack of hygroscopic tendencies, improved solubility, and enhanced rates of dissolution due to different lattice energies.

[0202] This application covers all isomers of the compounds of formulas I to IV. “Isomer”, for use in the present invention, includes optical isomers (such as stereoisomers, e.g., enantiomers and diastereoisomers), Z (zu-sammen) or E (entgegen) isomers and tautomers. Many of the compounds useful in the methods and compositions of this invention have at least one stereogenic center in their structure. This stereogenic center can be present in an R or S configuration, said R and S notation is used in correspondence with the rules described in Pure Appl. Chem. (1976), 45, 11a 30. The invention also relates to all stereoisomeric forms, such as enantiomeric and diastereoisomeric forms of the compounds or mixtures thereof (which include all possible mixtures of stereoisomers). See, for example, document WO 01/062726. Additionally, certain compounds that contain groups can exist as Z (zusammen) or E (entgegen) isomers. In each case, the invention includes both mixed isomers and separate individual isomers. Multiple substituents on a piperidinyl or azepanyl ring may also stand in cis or trans relationship to each other relative to the plane of the piperidinyl or azepanyl ring. Some of the compounds may also exist in tautomeric forms. Such forms, although not explicitly indicated in the formulas described herein, are intended to be within the scope of the present invention. With respect to the methods and compositions of the present invention, reference to a compound or compounds is intended to encompass that compound in each of its possible isomeric forms and mixtures thereof, except where the particular isomeric form is specifically mentioned. See, for example, document WO 01/062726.

[0203] The compounds of the invention enhance the function of α5-containing GABAA R, that is, they are α5-containing GABAA R agonists (e.g., positive allosteric modulators of the α5-containing GABAA receptor) and are capable of increasing controlled Cl- currents by GABA.

[0204] The invention additionally provides pharmaceutical compositions comprising one or more compounds of the invention together with a pharmaceutically acceptable excipient or carrier. In some embodiments, the pharmaceutical compositions of this application may additionally comprise a second therapeutic agent, such as an antipsychotic, memantine, or an AChE-I.

[0205] The invention further provides methods for treating cognitive impairment associated with said CNS disorders that are responsive to positive allosteric modulators of the α5-containing GABAA receptor, e.g., age-related cognitive impairment, moderate cognitive impairment (MCI). ), amnestic MCI (aMCI), age-associated memory impairment (AAMI), age-related cognitive impairment (ARCD), dementia, Alzheimer's disease (AD), prodromal AD, post-traumatic stress disorder (PTSD), schizophrenia, bipolar disorder, amyotrophic lateral sclerosis (ALS), cognitive impairment related to cancer therapy, mental retardation, Parkinson's disease (PD), autism spectrum disorders, fragile X syndrome, Rett syndrome, compulsive behavior, and substance dependence . In certain embodiments, the method is a method for treating age-related cognitive impairment, moderate cognitive impairment (MCI), amnestic MCI (aMCI), age-associated memory impairment (AAMI), age-related cognitive impairment (ARCD) , dementia, Alzheimer's disease (AD), prodromal AD, post-traumatic stress disorder (PTSD), schizophrenia, bipolar disorder, amyotrophic lateral sclerosis (ALS), cancer therapy-related cognitive impairment, mental retardation, Parkinson's disease (PD ), autism spectrum disorders, fragile X syndrome, Rett syndrome, compulsive behavior, and substance dependence. In certain embodiments, treatment comprises preventing or slowing the progression of a CNS disorder as described herein (such as those described herein). In certain embodiments, treatment comprises relieving, improving, or slowing the progression of one or more symptoms associated with the CNS disorder. In certain embodiments, the symptom being treated is cognitive impairment or cognitive impairment. In another aspect of the invention, there is provided a method for preserving or improving cognitive function in an individual in need of such treatment, the method comprising the step of administering to said individual a therapeutically effective amount of a compound of the invention or a isomer, polymorph, solvate, hydrate, pharmaceutically acceptable salt or combination thereof.

[0206] The various CNS disorders with cognitive impairment (e.g., age-related cognitive impairment, moderate cognitive impairment (MCI), amnestic MCI (aMCI), age-associated memory impairment (AAMI), age-related cognitive impairment ( ARCD), dementia, Alzheimer's disease (AD), prodromal AD, post-traumatic stress disorder (PTSD), schizophrenia, bipolar disorder, amyotrophic lateral sclerosis (ALS), cancer therapy-related cognitive impairment, mental retardation, Parkinson's disease (PD), autism spectrum disorders, fragile X syndrome, Rett syndrome, compulsive behavior, and substance dependence) can have a variety of etiologies. However, the symptom of cognitive impairment in each of the disorders mentioned above may have overlapping causes. Thus, a composition or treatment method that treats cognitive impairment in one CNS disorder may also treat cognitive impairment in another.

BENZODIAZEPINE DERIVATIVES

[0207] The present invention provides a compound of formula I:

[0208] or an isomer, polymorph, solvate, hydrate, pharmaceutically acceptable salt or combination thereof, wherein:

[0209]U and the two carbon atoms designated as α and β together form a 5- or 6-membered aromatic ring that has 0 to 2 nitrogen atoms;

[0210]A is C, CR6 or N;

[0211] B and F are each independently selected from C, CR6 and N, where B and F cannot both be N;

[0212]D is selected from N, NR7, O, CR6 or C(R6)2;

[0213]E is N, NR7, CR6 or C(R6)2;

[0214]W is N, NR7, CR6 or C(R6)2;

[0215]X is N, NR7, O, CR6 or C(R6)2;

[0216] Y and Z are each independently selected from C, CR6 and N, where Y and Z cannot both be N;

[0217]V is C or CR6,

[0218] or when Z is C or CR6, V is C, CR6 or N;

[0219] in which 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 by 0 to 5 R';

[0220]m and n are integers independently selected from 0 to 4;

[0221]p is an integer selected from 2 to 4;

[0222]each occurrence of the call is it a single bond or a double bond;

[0223] each occurrence of R1, R2, R4 and R5 is each independently selected from:

[0224]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) COLOR, -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 and -P(O)(H)(OR);

[0225]R3 is missing or selected from:

[0226]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) COLOR, -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 and -P(O)(H)(OR);

[0227] each R6 is independently -H or -(C1-C6)alkyl;

[0228] each R7 is independently -H or -(C1-C6)alkyl;

[0229] 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 by 0 to 5 R';

[0230] 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 by 0 at 5R';

[0231] each R is independently selected from:

[0232] H,

[0233](C1-C12)-aliphatic-,

[0234](C3-C10)-cycloalkyl-,

[0235](C3-C10)-cycloalkenyl-,

[0236][(C3-C10)-cycloalkyl]-(C1-C12)-aliphatic-,

[0237][(C3-C10)-cycloalkenyl]-(C1-C12)-aliphatic-,

[0238][(C3-C10)-cycloalkyl]-O-(C1-C12)-aliphatic-,

[0239][(C3-C10)-cycloalkenyl]-O-(C1-C12)-aliphatic-,

[0240](C6-C10)-aryl-,

[0241](C6-C10)-aryl-(C1-C12)aliphatic-,

[0242](C6-C10)-aryl-O-(C1-C12)aliphatic-,

[0243](C6-C10)-aryl-N(R’’)-(C1-C12)aliphatic-,

[0244] 3- to 10-membered heterocyclyl,

[0245](3- to 10-membered heterocyclyl)-(C1-C12)aliphatic-,

[0246](3- to 10-membered heterocyclyl)-O-(C1-C12)aliphatic-,

[0247](3- to 10-membered heterocyclyl)-N(R’’)-(C1-C12)aliphatic-,

[0248] 5- to 10-membered heteroaryl,

[0249](5- to 10-membered heteroaryl)-(C1-C12)-aliphatic-,

[0250](5- to 10-membered heteroaryl)-O-(C1-C12)-aliphatic-; It is

[0251](5- to 10-membered heteroaryl)-N(R’’)-(C1-C12)-aliphatic-;

[0252] wherein said heterocyclyl has 1 to 4 heteroatoms independently selected from N, NH, O, S, SO and SO2 and said heteroaryl has 1 to 4 heteroatoms independently selected from N, NH, O and S;

[0253] wherein each occurrence of R is independently replaced by 0 to 5 R';

[0254] or when two R groups bonded to the same atom, the two R groups may be taken together with the atom to which they are bonded to form a 3 to 10 membered aromatic or non-aromatic ring having 0 to 4 hete - roatoms independently selected from N, NH, O, S, SO and SO2, wherein said ring is optionally substituted by 0 to 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;

[0255] 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;

[0256] 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 members)-O- (C1-C6)-alkyl or (C6-C10)-aryl-O-(C1-C6)-alkyl-.

[0257] Some embodiments provide a compound of formula I:

[0258] or an isomer, polymorph, solvate, hydrate, pharmaceutically acceptable salt or combination thereof, wherein:

[0259]U and the two carbon atoms designated as α and β together form a 5- or 6-membered aromatic ring that has 0 to 2 nitrogen atoms;

[0260]A is C, CR6 or N;

[0261] B and F are each independently selected from C, CR6 and N, where B and F cannot both be N;

[0262]D is selected from N, NR7, O, CR6 or C(R6)2;

[0263]E is N, NR7, CR6 or C(R6)2;

[0264]W is N, NR7, CR6 or C(R6)2;

[0265]X is N, NR7, O, CR6 or C(R6)2;

[0266] Y and Z are each independently selected from C, CR6 and N, where Y and Z cannot both be N;

[0267]V is C or CR6,

[0268] or when Z is C or CR6, V is C, CR6 or N;

[0269] in which, when the ring formed by X, Y, Z, V and W is then, R2 is -OR8,

[0270]-SR8 or -(CH2)nOR8;

[0271] m and n are each independently an integer selected from 0 to 4;

[0272] each occurrence of the call is it a single bond or a double bond;

[0273] each occurrence of R1, R2, R4 and R5 is each independently 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)COLOR, -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);

[0274]R3 is missing or selected from:

[0275]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) COLOR, -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 and -P(O)(H)(OR);

[0276] each R6 is independently -H or -(C1-C6)alkyl;

[0277] each R7 is independently -H or -(C1-C6)alkyl;

[0278] 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 by 0 to 5 R';

[0279] each R is independently selected from:

[0280]H,

[0281](C1-C12)-aliphatic-,

[0282](C3-C10)-cycloalkyl-,

[0283](C3-C10)-cycloalkenyl-,

[0284][(C3-C10)-cycloalkyl]-(C1-C12)-aliphatic-,

[0285][(C3-C10)-cycloalkenyl]-(C1-C12)-aliphatic-,

[0286][(C3-C10)-cycloalkyl]-O-(C1-C12)-aliphatic-,

[0287][(C3-C10)-cycloalkenyl]-O-(C1-C12)-aliphatic-,

[0288](C6-C10)-aryl-,

[0289](C6-C10)-aryl-(C1-C12)aliphatic-,

[0290](C6-C10)-aryl-O-(C1-C12)aliphatic-,

[0291] 3- to 10-membered heterocyclyl,

[0292](3- to 10-membered heterocyclyl)-(C1-C12)aliphatic-,

[0293](3- to 10-membered heterocyclyl)-O-(C1-C12)aliphatic-,

[0294] 5- to 10-membered heteroaryl,

[0295](5- to 10-membered heteroaryl)-(C1-C12)-aliphatic-, and

[0296](5- to 10-membered heteroaryl)-O-(C1-C12)-aliphatic-;

[0297] wherein said heterocyclyl has 1 to 4 heteroatoms independently selected from N, NH, O, S, SO and SO2 and said heteroaryl has 1 to 4 heteroatoms independently selected from N, NH, O and S;

[0298] wherein each occurrence of R is independently replaced by 0 to 5 R';

[0299] or when two R groups bonded to the same atom, the two R groups may be taken together with the atom to which they are bonded to form a 3 to 10 membered aromatic or non-aromatic ring having 0 to 4 hete - roatoms independently selected from N, NH, O, S, SO and SO2, wherein said ring is optionally substituted by 0 to 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;

[0300] 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;

[0301] 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 members)-O- (C1-C6)-alkyl or (C6-C10)-aryl-O-(C1-C6)-alkyl-.

[0302] In some embodiments of a compound of formula I, X, Y, Z, V and W together form a 5-membered aromatic or non-aromatic ring that has 1 to 4 nitrogen atoms, in which said ring is replaced by 0 to 3 R6 and 0 to 2 R7. In some embodiments, X, Y, Z, V and W together form a 5-membered aromatic ring having 1 to 3 nitrogen atoms, wherein said ring is replaced by 0 to 2 R6 and 0 to 1 R7.

[0303] In certain embodiments, X, Y, Z, V and W form a ring that is selected from:

[0304] In some embodiments, X, Y, Z, V and W form a ring that is selected from:

[0305] In some embodiments of a compound of formula I, W is N. In some embodiments, W is N and X, Y, Z, V and W form a ring that is selected from:

[0306] In some embodiments, W is N and X, Y, Z, V and W form a ring that is selected from:

[0307] In certain embodiments of a compound of formula I, the ring formed by X, Y, Z, V and W is:

[0308] In certain embodiments of a compound of formula I, the ring formed by X, Y, Z, V and W is:

[0309] In certain embodiments of a compound of formula I, the ring formed by X, Y, Z, V and W is selected from:

[0310] In certain embodiments of a compound of formula I, the ring formed by X, Y, Z, V and W is selected from:

[0311] In some embodiments, the ring formed by X, Y, Z, V and W is:

[0312] In some embodiments, the ring formed by X, Y, Z, V and W is:

[0313] In some embodiments of a compound of formula I, A, B, D, E and F together form a 5-membered aromatic or non-aromatic ring that has 1 to 4 nitrogen atoms, in which said ring is substituted by 0 to 3 R6 and 0 to 2 R7. In certain embodiments, A, B, D, E and F together form a 5-membered aromatic ring having 1 to 3 nitrogen atoms, wherein said ring is replaced by 0 to 2 R6 and 0 to 1 R7.

[0314] In some embodiments of a compound of formula I, A, B, D, E and F form a ring that is selected from:

[0315] In certain embodiments of a compound of formula I, the ring formed by A, B, D, F and E is:

[0316] In some embodiments of a compound of formula I, the compound has a structure of formula II:

[0317] or an isomer, polymorph, solvate, hydrate, pharmaceutically acceptable salt or combination thereof, wherein m, R1, R2, R3, R4, R5 and R6 are as defined in formula I.

[0318] In some embodiments of a compound of formula I, the compound has a structure of formula III:

[0319] or an isomer, polymorph, solvate, hydrate, pharmaceutically acceptable salt or combination thereof, wherein m, R1, R2, R3, R4, R5 and R6 are as defined in formula I.

[0320] In some embodiments of a compound of formula I, the compound has a structure of formula IV:

[0321] or a pharmaceutically acceptable isomer, polymorph, solvate, hydrate, salt or combination thereof, wherein R2 is -OR8, -SR8 or -(CH2)nOR8, wherein R2 is independently substituted by 0 to 5 R'e wherein m, n, R1, R3, R4, R5, R6 and R8 are as defined in formula I. In some embodiments, R2 is -OR8. In some embodiments, R2 is -(CH2)nOR8.

[0322] In some embodiments of a compound of formula I, the compound has a structure of formula IV:

[0323] or an isomer, polymorph, solvate, hydrate, pharmaceutically acceptable salt or combination thereof, wherein R2 is -(CH2)nO(CH2)nR8, -(CH2)pR8 or -(CH2)nN(R'' )R10, where R2 is independently replaced by 0 to 5 R'and where m, n, p, R1, R3, R4, R5, R6, R8, R10 and R'' are as defined herein. In some embodiments, R2 is -(CH2)nO(CH2)nR8.

[0324] In some embodiments of a compound of formula I, II, III or IV, each occurrence of R1 is selected from: halogen, -R, -OR, -NO2, -CN, -CF3, -OCF3, - N(R)2, -N(R)SO2R, where each occurrence of R is independently replaced by 0 to 5 R'. In some embodiments, each occurrence of R1 is independently selected from: halogen, -H, -(C1-C6)alkyl, -OH, -O((C1-C6)alkyl), -NO2, -CN, -CF3 , -OCF3, -NH2, -N((C1-C6)alkyl)2, -N((C1-C6)alkyl)SO2((C1-C6)alkyl) and -NHSO2((C1-C6)alkyl), wherein said alkyl is independently substituted by 0 to 5 R'. In certain embodiments, each occurrence of R1 is independently selected from: -H, -F, -Cl, -Br, -OH, -Me, -Et, -OMe, -OEt, -NO2, -CN, -CF3 , -OCF3, -NH2, -NMe2, -NEt2, -NHSO2Me and - NHSO2Et. In certain embodiments of a compound of any one of formulas I to IV, at least one R1 is -OR. In some embodiments, the at least one R1 is -O((C1-C6)alkyl), such as -OMe.

[0325] In some embodiments of a compound of formula I, II or III, R2 is selected from: halogen, -R, -OR, -NO2, -(CR2)1-3R, -(CR2)1-3 -OR, -CN, -CF3, -C(O)NR2, -C(O)OR and -OCF3, where each occurrence of R is independently replaced by 0 to 5 R'. In some embodiments, R2 is selected from:

[0326]-H, -(C1-C6)alkyl, -CH2-O((C1-C6)alkyl ), -(C((C1-C6)alkyl)2)1-3- O((C1-C6 )alkyl), -OH, -O((C1-C6)alkyl), -NO2, -CN, -CF3, -OCF3, (C3-C10)- cycloalkyl-, -C(O)N((C1-C6 )alkyl)2, -C(O)O((C1-C6)alkyl), 3- to 10-membered heterocyclyl-,

[0327](C6-C10)aryl-, 5- to 10-membered heteroaryl-,

[0328](C6-C10)aryl-(C1-C12)aliphatic-,

[0329](C6-C10)aryl-O-(C1-C12)aliphatic-,

[0330](C6-C10)aryl-N(R’’)-(C1-C12)aliphatic-,(C6-C10)aryl-(C1-C12)aliphatic-O-,

[0331](5- to 10-membered heteroaryl)-(C1-C12)-aliphatic-,

[0332](5- to 10-membered heteroaryl)-O-(C1-C12)-aliphatic-,

[0333](5- to 10-membered heteroaryl)-N(R’’)-(C1-C12)-aliphatic-,

[0334](5- to 10-membered heteroaryl)-(C1-C12)-aliphatic-O-,

[0335](3- to 10-membered heterocyclyl)-(C1-C12)aliphatic-,

[0336](3- to 10-membered heterocyclyl)-O-(C1-C12)aliphatic-,

[0337](3- to 10-membered heterocyclyl)-N(R’’)-(C1-C12)aliphatic- and

[0338](3- to 10-membered heterocyclyl)-(C1-C12)aliphatic-O-, wherein R2 is independently substituted by 0 to 5 R'.

[0339] In some embodiments of a compound of formula I, II or III, R2 is selected from:

[0340]-H, -Me, -Et, propyl, isopropyl, butyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, -CF3, -C(O)OMe, -C(O)OEt, - OMe, -CH2OMe, -CH2OEt, -CH2OPh, -CH2-pyrrolidine, -CH2-morpholine, -CH2-pyridine, -CH2Ph, wherein said R2 is replaced by 0 to 3 R'. In some embodiments of a compound of formula I, II or III, R2 is -Me replaced by 0 to 3 R' selected from -R'', -OR'', oxo, -CH2OR'', -CH2NR'' 2, -C(O)N(R'')2, -C(O)OR'', -NO2, -NCS, -CN, -CF3, -OCF3 and - N(R'')2, where R'' is independently selected from H, -(C1-C6)-alkyl, (C6-C10)-aryl- and (C6-C10)-aryl-(C1-C6)-alkyl-. In some embodiment, R2 is -Me which is independently replaced by 0 to 3 R' selected from -N(Me)2, -N(Et)2and -N(Me)(CH2Ph).

[0341] In some embodiments of a compound of formula I, II or III, R2 is selected from: -CH2Ph, -CH2CH2Ph, -Ph, -OCH2Ph, -CH2OPh, - OCH2CH2Ph, -CH2CH2OPh, -CH2-pyrrolidine, -CH2-morpholine, -CH2-pyridine and -CH2Ph wherein said Ph, pyrrolidine, pyridine or morpholine is replaced by 0 to 5 R'. In some embodiments of a compound of formula I, II or III, R2 is selected from: -CH2Ph, -CH2CH2Ph, -Ph, -OCH2Ph, -CH2OPh, -OCH2CH2Ph, -CH2CH2OPh, -CH2-pyrrolidine, -CH2- morpholine, -CH2-pyridine and -CH2Ph, wherein said Ph, pyrrolidine, pyridine or morpholine is replaced by 0 to 5 R' independently selected from halogen, (C1-C6)-alkyl, -OH, -O( (C1-C6)-alkyl), -CH2OH, -CH2O(C1-C6)-alkyl), -CH2N(C1-C6)-alkyl)2, -C(O)O(C1-C6)-alkyl), -C(O)N(C1-C6)-alkyl)2, -NO2, -CN, -CF3, -OCF3 and -N(C1-C6)-alkyl)2. In some of the above embodiments, the -Ph, pyrrolidine, pyridine or morpholine of R2 is replaced by 0 to 5 R' independently selected from -F, -Cl, -CN, -Me, -Et, -OMe and -OEt . In some embodiments of a compound of formula I, II or III, R2 is -CH2Ph, -CH2OPh, -CH2-pyridine, -CH2-pyrrolidine or -CH2-morpholine, wherein said -Ph, pyrrolidine, pyridine or Morpholine is replaced by 0 to 3 R' independently selected from -F, -Cl, -CN, -Me and -OMe.

[0342] In some embodiments of a compound of formula IV, R2 is -OR8, - SR8, -(CH2)nOR8, -(CH2)nO(CH2)nR8, -(CH2)pR8 or -(CH2)nN(R '')R10, wherein each R8 is independently -(C1-C6)alkyl, -(C3-C10)-cycloalkyl, (C6-C10)-aryl or heteroaryl of 5 to 10 members, wherein each occurrence of R8 is independently replaced by 0 to 5 R'; n is an integer selected from 0 to 4; p is an integer selected from 2 to 4; and 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 by 0 to 5 R'. In some embodiments, R2 is OR8. In some embodiments, R2 and OR8, where R8 is (C6-C10)-aryl, replaced by 0 to 5 R'. In some embodiments, R2 is OR8, where R8 is (C6-C10)-aryl, substituted by 0 to 3 halogens (such as -F). In some embodiments, R2 is -(CH2)nOR8 or -(CH2)nO(CH2)nR8. In some embodiments, R2 is -(CH2)nOR8 or -(CH2)nO(CH2)nR8, where R8 is -(C1-C6)alkyl, (C6-C10)-aryl or 5- to 10-membered heteroaryl , where each occurrence of R8 is independently replaced by 0 to 5 R'.

[0343] In some embodiments of a compound of formula I, II, III or IV, R3 is selected from: halogen, -R, -CN, -CF3, -SO2R, -C(O)N(R)2 , -C(O)R and -C(O)OR, where each occurrence of R is independently replaced by 0 to 5 R'. In some embodiments, R3 is selected from: -F, -Br, -Cl, -(C1-C6)alkyl, -CN, -CEC, -CF3, -SO2((C1-C6)alkyl), -C (O)N((C1-C6)alkyl)2, -C(O)NH2, -C(O)((C1-C6)alkyl), -SO2((C6-C10)-aryl), -C( O)O((C1-C6)alkyl), -(C2-C6)-alkenyl, -(C2-C6)-alkynyl, -(C6-C10)-aryl, 5- to 10-membered heteroaryl- and 3-membered heterocyclyl to 10 members-, wherein said alkyl, alkenyl, alkynyl, aryl, heteroaryl or heterocyclyl- is independently substituted by 0 to 5 R'. In some embodiments of a compound of formula I, II, III or IV, R3 is selected from: -H, -C(O)OMe, -C(O)Et, -C(O)NMe2, -C( O)NH2, -C(O)OEt, - C(O)OCH2(tert-butyl), -C(O)OCH2CF3, -C(O)O(isopropyl),-C(O)NEt2,-CHF2, -CN, -C=C, -SO2Me, -SO2Et, -SO2Ph(Me), -CF3, -CHF2, -Me, -Et, -Br, -Cl, -CH2Ph,

[0344] wherein R9 is selected from -H, -Me, -Et, -CF3, isopropyl, -OMe, -OEt, -O-isopropyl, -CH2NMe2, -tert-butyl and cyclopropyl.

[0345] In certain embodiments of a compound of formula I, II, III or IV, R3 is -C(O)OMe or -C(O)OEt. In certain embodiments of a compound of formula I, II, III or IV, R3 is , wherein R9 is selected from -H, -Me, -Et, -CF3, isopropyl, -OMe, -OEt, -O-isopropyl, -CH2NMe2, -tert-butyl and cyclopropyl.

[0346] In some embodiments of a compound of formula I, II, III or IV, R4 and R5 are each independently selected from -H, halogen and -R, wherein each occurrence of R is independently replaced by 0 to 5 R', or R4 and R5 may be taken together with the carbon atom to which they are bonded to form a 3 to 10 membered aromatic or non-aromatic ring that has 0 to 3 additional heteroatoms independently selected from N , O, S, SO and SO2, wherein said ring is replaced by 0 to 5 R'. In some embodiments, R4 and R5 are each independently selected from -H, -Me, -Et, -F, or R4 and R5 are taken together with the carbon atom to which they are bonded to form a ring. aliphatic from 3 to 8 members. In certain embodiments, both R4 and R5 are -H.

[0347] In some embodiments, the present invention provides a compound of formula II:

[0348] or an isomer, polymorph, solvate, hydrate, pharmaceutically acceptable salt or combination thereof, wherein:

[0349]m is 0 to 3;

[0350] each R1 is independently selected from: halogen, -H, - (C1-C6)alkyl, -OH, -O((C1-C6)alkyl), -NO2, -CN, -CF3, -OCF3 , wherein said alkyl is independently substituted by 0 to 5 R';

[0351]R2 is selected from:

[0352]-(C1-C6)alkyl, -OH, -O((C1-C6)alkyl), -C(O)O((C1-C6)alkyl),

[0353](C6-C10)-aryl-(C1-C12)aliphatic-, (C6-C10)-aryl-O-(C1-C12)aliphatic-,

[0354](C6-C10)-aryl-(C1-C12)aliphatic-O-, (3- to 10-membered heterocyclyl)- (C1-C12)aliphatic-, (5- to 10-membered heteroaryl)-(C1- C12)-aliphatic-, (5 to 10 membered heteroaryl)-O-(C1-C12)-aliphatic and (5 to 10 membered heteroaryl)-(C1-C12)-aliphatic-O-, wherein said alkyl , aryl or heteroaryl is independently substituted by 0 to 5 R';

[0355]R3 is selected from:

[0356]-(C1-C6)alkyl, -SO2((C1-C6)alkyl), -C(O)N((C1-C6)alkyl)2, and -C(O)O((C1-C6 )alkyl), wherein said alkyl is independently substituted by 0 to 5 R';

[0357] R’ is as defined herein;

[0358] R4 and R5 are each independently selected from - H, halogen and -(C1-C6)alkyl; It is

[0359] R6 is selected from -H and -(C1-C6)alkyl.

[0360] In some embodiments of a compound of formula II, m is 0, 1 or 2; when m is 1 or 2, at least one occurrence of R1 is halogen or -O((C1- C6)alkyl) (such as -F and -OMe);

[0361] R2 is selected from:

[0362]-(C1-C6)alkyl (e.g. -Me), (C6-C10)-aryl-(C1-C12)aliphatic- (e.g.

[0363]-CH2Ph), (C6-C10)-aryl-O-(C1-C12)aliphatic- (e.g. -CH2OPh) and (3- to 10-membered heterocyclyl)-(C1-C12)aliphatic- (e.g. example, -CH2-pyrrolidine and -CH2-morpholine), wherein aryl (e.g., -Ph) or heterocyclyl (e.g., pyrrolidine or morpholine) is independently substituted by 0 to 5 R' independently selected from -F , -Me and -OMe and wherein said alkyl (e.g., -Me) is independently substituted by 0 to 3 R' selected from -N(Et)2 and -N(Me)(CH2Ph).

[0364]R3 is -C(O)O((C1-C6)alkyl) (for example, -COOEt);

[0365] R4 and R5 are both -H; It is

[0366]R6 is -H.

[0367] In some embodiments, the present invention provides a compound of formula II:

[0368] or an isomer, polymorph, solvate, hydrate, pharmaceutically acceptable salt or combination thereof, wherein:

[0369]m is 0 to 3;

[0370] each R1 is independently selected from: halogen, -H, - (C1-C6)alkyl, -OH,

[0371]-O((C1-C6)alkyl), -NO2, -CN, -CF3, -OCF3, where R1 is independently substituted by 0 to 5 R’;

[0372]R2 is selected from:

[0373]-(C1-C6)alkyl, -OH, -O((C1-C6)alkyl), -C(O)O((C1-C6)alkyl),

[0374](C6-C10)-aryl-(C1-C12)aliphatic-,

[0375](C6-C10)-aryl-O-(C1-C12)aliphatic-,

[0376](C6-C10)-aryl-N(R’’)-(C1-C12)aliphatic-,

[0377](5- to 10-membered heteroaryl)-(C1-C12)aliphatic-,

[0378](5- to 10-membered heteroaryl)-O-(C1-C12)aliphatic-,

[0379](5- to 10-membered heteroaryl)-N(R’’)-(C1-C12)aliphatic-,

[0380](3- to 10-membered heterocyclyl)-(C1-C12)aliphatic-,

[0381](3- to 10-membered heterocyclyl)-O-(C1-C12)aliphatic-,

[0382](3- to 10-membered heterocyclyl)-N(R’’)-(C1-C12)aliphatic-,

[0383] wherein R2 is independently replaced by 0 to 5 R’;

[0384]R3 is selected from:

[0385]-(C1-C6)alkyl, -C=C, -CN, halogen, -SO2((C6-C10)-aryl), -SO2((C1-C6)alkyl), -C(O)N ((C1-C6)alkyl)2, -C(O)NH2, -C(O)O((C1-C6)alkyl), -C(O)((C1-C6)alkyl), -(C6- C10)aryl, 5 to 10 membered heteroaryl, wherein R3 is independently substituted by 0 to 5 R';

[0386] R4 and R5 are each independently selected from - H, halogen and -(C1-C6)alkyl;

[0387] R6 is selected from -H and -(C1-C6)alkyl; It is

[0388] R’ and R’’ are as defined herein.

[0389] In some embodiments of a compound of formula II:

[0390]m is 0, 1 or 2;

[0391] when m is 1 or 2, at least one occurrence of R1 is halogen or - O((C1-C6)alkyl);

[0392]R2 is selected from:

[0393]-(C1-C6)alkyl, (C6-C10)-aryl-(C1-C12)aliphatic-, (C6-C10)aryl-O-(C1-C12)aliphatic-, (heteroaryl from 5 to 10 members)-(C1-C12)aliphatic- and (3 to 10 membered heterocyclyl)-(C1-C12)aliphatic-, wherein R2 is independently substituted by 0 to 3 R';

[0394] R3 is halogen, -CN, -C=C, -C(O)NH2, -(C1-C6)alkyl, -C(O)((C1- C6)alkyl), -C(O)O ((C1-C6)alkyl), -SO2(Ph(Me)), , wherein R3 is independently substituted by 0 to 3 R' and wherein R9 is selected from -H, -Me, -Et, -CF3, isopropyl, -OMe, -tert-butyl and cyclopropyl;

[0395] R4 and R5 are both -H;

[0396]R6 is -H; It is

[0397] R’ is as defined herein;

[0398] In some embodiments of a compound of formula II, R3 is:

[0399], wherein R9 is selected from -H, -Me, -Et, -CF3, isopropyl, -OMe and -tert-butyl.

[0400] In some embodiments, the present invention provides a compound of formula III:

[0401] or an isomer, polymorph, solvate, hydrate, pharmaceutically acceptable salt or combination thereof, wherein:

[0402]m is 0, 1 or 2 and, when m is 1 or 2, at least one occurrence of R1 is -O((C1-C6)alkyl) (such as -OMe);

[0403]R2 is selected from:

[0404]-(C1-C6)alkyl (e.g. -Me) and (C6-C10)-aryl-(C1-C12)aliphatic- (e.g. -CH2Ph);

[0405]R3 is -C(O)O((C1-C6)alkyl) (for example, -COOEt);

[0406] R4 and R5 are both -H; It is

[0407]R6 is -H.

[0408] In another aspect, the present invention provides a compound of formula IV:

[0409] or an isomer, polymorph, solvate, hydrate, pharmaceutically acceptable salt or combination thereof, wherein:

[0410]m is 0, 1 or 2 and, when m is 1 or 2, at least one occurrence of R1 is -O((C1-C6)alkyl) (such as -OMe);

[0411] R2 is OR8, where R8 is (C6-C10)-aryl (such as phenyl), substituted by 0 to 3 halogens (such as -F);

[0412]R3 is -C(O)O((C1-C6)alkyl) (for example, -COOEt);

[0413] R4 and R5 are both -H; It is

[0414]R6 is -H.

[0415] In another aspect, the present invention provides a compound of formula IV:

[0416] or an isomer, polymorph, solvate, hydrate, pharmaceutically acceptable salt or combination thereof, wherein:

[0417]m is 0 to 3;

[0418] when m is 1 or 2, at least one occurrence of R1 is -halogen or -O((C1-C6)alkyl);

[0419] each R1 is independently selected from: halogen, -H, - (C1-C6)alkyl, -OH,

[0420]-O((C1-C6)alkyl), -NO2, -CN, -CF3, -OCF3, where R1 is independently substituted by 0 to 5 R’;

[0421]R2 is selected from -OR8, -SR8, -(CH2)nOR8, - (CH2)nO(CH2)nR8, -(CH2)pR8 and

[0422]-(CH2)nN(R’’)R10, where n is an integer selected from 0 to 4; p is an integer selected from 2 to 4; 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 by 0 to 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 by 0 to 5 R '; and wherein R2 is independently substituted by 0 to 5 R';

[0423]R3 is selected from:

[0424]-H, -CN, halogen, -(C1-C6)alkyl, -SO2((C1-C6)alkyl), -C(O)N((C1-C6)alkyl)2, -C(O )((C1-C6)alkyl), -C(O)O((C1-C6)alkyl), and

[0425], wherein R9 is selected from -Me, -Et, isopropyl, -CF3, -OMe, -OEt, -O-isopropyl, -CH2NMe2 and cyclopropyl; and wherein R3 is independently substituted by 0 to 5 R';

[0426] R4 and R5 are each independently selected from - H, halogen and -(C1-C6)alkyl;

[0427] R6 is selected from -H and -(C1-C6)alkyl; It is

[0428] R’ and R’’ are as defined herein.

[0429] In some embodiments of a compound of formula IV:

[0430]m is 0, 1 or 2;

[0431] R2 is -OR8, -(CH2)nOR8, -(CH2)nO(CH2)nR8, where n is 1 and where R8 is -(C1-C6)alkyl, (C6-C10)-aryl or 5 to 10 membered heteroaryl, wherein R8 is independently substituted by 0 to 3 R';

[0432] R3 is halogen, -H, -CN, -(C1-C6)alkyl, C(O)((C1-C6)alkyl), -C(O)O((C1-C6)alkyl), , wherein said alkyl is independently substituted by 0 to 3 R'; R9 is selected from -Me, -Et, isopropyl and -CF3;

[0433] R4 and R5 are both -H;

[0434]R6 is -H; It is

[0435]R’ is as defined herein;

[0436] Examples of particular compounds of the present application include:

[0437] and its isomer, polymorph, solvate, hydrate, pharmaceutically suitable salt or combination thereof.

[0438] The invention also includes various combinations of R1, R2 and R3, as described above. These combinations can, in turn, be combined with any or all of the values of the other variables described in this document. For example, R1 can be -OR or halogen; R2 can be (C1-C4)-alkyl-, -OR8, -(CH2)nOR8 or -(CH2)nO(CH2)nR8; and optionally R3 is -C(O)OR or -C(O)N(R)2. In another example, R1 is -OR or halogen; R2 is (C1-C4)-alkyl-, -OR8, -(CH2)nOR8 or -(CH2)nO(CH2)nR8; and R3 is a 5- or 6-membered heteroaryl, such as

[0439] For each of the examples above, the compounds may have the specific values of the groups described in this document.

[0440] Any embodiment described herein is also intended to represent unidentified forms, as well as isotopicly identified forms of the compounds, except where otherwise indicated. Isotopicly identified compounds have structures represented by the formulas given herein, except that one or more atoms are replaced by an atom having a selected mass number or atomic mass. Examples of isotopes that can be incorporated into compounds of the invention include the isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine and chlorine, such as 2H, 3H, 11C, 13C, 14C, 15N, 18F, 31P, 32P, 35S , 36Cl, 125I, respectively. The invention includes various isotopicly identified compounds, as defined herein, for example, in which radioactive isotopes, such as 3H, 13C and 14C, are present. Such isotopicly identified compounds are useful in metabolic studies (preferably with 14C), reaction kinetics studies (with, for example, 2H or 3H), detection or imaging techniques such as positron emission tomography (PET). or single proton emission computed tomography (SPECT) which includes drug or substrate tissue distribution assays, or in radioactive treatment of patients. In particular, an 18F or identified compound may be particularly preferred for PET or SPECT studies. The isotopicly identified compounds of this invention and prodrugs thereof can generally be prepared by carrying out the procedures disclosed in the schemes or in the examples and preparations described below, by substituting a readily available isotopicly identified reagent for a readily available identified reagent. in a non-isotopic way.

[0441] Any of the individual embodiments cited herein may define formula I, II, III or IV individually or be combined to produce a preferred embodiment of this invention.

GENERAL SYNTHETIC METHODOLOGY

[0442] The compounds of this invention can generally be prepared by methods known to those skilled in the art. Schemes 1 to 10 below provide general synthetic routes for preparing compounds of formulas I to IV. Other equivalent schemes, which will be readily evident to one skilled in organic chemistry, can alternatively be used to synthesize various portions of the molecules, as illustrated by the general schemes below.

[0443] Scheme 1. General synthesis of a compound of formula I in which X, Y, Z, V and W form a 1,2,3-triazole ring, or a compound of formula II.

[0444] Scheme 2. General synthesis of a compound of formula I or III, in which X, Y, Z, V and W form a pyrazole ring.

[0445] Scheme 3. General synthesis of a compound of formula I in which X, Y, Z, V and W form a substituted 1,2,3-triazole phenoxy ring, or a compound of formula II.

[0446] Scheme 4. General synthesis of compounds of formula I or II to allow divergent functionalization on the triazole ring formed by X, Y, Z, V and W.

[0447] Scheme 5. General synthesis of a compound of formula I in which X, Y, Z, V and W form a substituted aminomethyl 1,2,3-triazole ring, or a compound of formula II.

[0448] Scheme 6. General synthesis of a compound of formula I in which X, Y, Z, V and W form a substituted aralkyl or substituted heteroaralkyl 1,2,3-triazole ring, or a compound of formula II.

[0449] Scheme 7. General synthesis of a compound of formula I or IV, in which X, Y, Z, V and W form a substituted 1,2,4-triazole ring.

[0450] Scheme 8. General synthesis of a compound of formula I in which X, Y, Z, V and W form a substituted methyl 2,3-triazole ring, or a compound of formula II.

[0451] Scheme 9. General synthesis of a compound of formula I in which X, Y, Z, V and W form a substituted 1,2,3-triazole benzyl ring, or a compound of formula II.

[0452] Scheme 10. General synthesis of a compound of formula I, II or IV in which X, Y, Z, V and W form a substituted triazole ring, such as a 1,2,3-triazole ring or a of 1, 2, 4-triazole and the upper imidazole is replaced by a 1,2,4-oxdizole ring, as illustrated in 10(a) and 10(b).

[0453] As would be recognized by skilled professionals, compounds of formulas I to IV with variables beyond those represented above can be prepared by varying chemical reagents or synthetic routes.

PHARMACEUTICAL COMPOSITIONS AND METHODS OF ADMINISTRATION

[0454] The present invention provides a pharmaceutical composition comprising a pharmaceutically acceptable carrier and a compound of formulas I to IV, or isomers, polymorphs, solvates, hydrates, pharmaceutically acceptable salts or combinations thereof.

[0455] The basic nitrogen-containing groups present in the compounds of the invention can be quaternized with agents such as lower alkyl halides, such as iodides, bromides and methyl, ethyl, propyl and butyl chloride; dialkyl sulfates, such as dimethyl, diethyl, dibutyl and diamyl sulfates, long-chain halides, such as decyl, lauryl, myristyl and stearyl iodides, bromides and chlorides, aralkyl halides, such as benzyl and phenethyl bromides, and others . Dispersible, oil- or water-soluble products are thus formed.

[0456] It will be noted that the compounds and agents used in the compositions of this invention, preferably, should readily penetrate the blood-brain barrier when administered peripherally. Compounds that cannot penetrate the blood-brain barrier, however, can still be effectively administered directly into the central nervous system, for example, via an intraventricular or other neurocompatible route.

[0457] In some embodiments of this invention, the GABAA R positive allosteric modulator containing α5 is formulated with a pharmaceutically acceptable carrier. Pharmaceutically acceptable carriers that can be used in such compositions include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, serum proteins such as human serum albumin, buffer substances such as phosphates, glycine, sorbic acid , potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinyl pyrrolidone, cellulose-based substances, polyethylene glycol, sodium carboxy methylcellulose, polyacrylates, waxes, block polymers of polyethylene and polyoxypropylene, polyethylene glycol and lanolin. In other embodiments, no carrier is used. For example, the α5-containing GABAA R agonist (e.g., a positive allosteric modulator of the α5-containing GABAA receptor) can be administered alone or as a component of a pharmaceutical formulation (therapeutic composition). The α5-containing GABAA R agonist (e.g., an α5-containing GABAA receptor positive allosteric modulator) can be formulated for administration in any manner convenient for use in human medicine.

[0458] In some embodiments, the therapeutic methods of the invention include administering the composition of a compound or agent topically, systemically or locally. For example, therapeutic compositions of compounds or agents of the invention may be formulated for administration by, for example, injection (e.g., intravenous, subcutaneous, or intramuscular), inhalation or insufflation (through the mouth or nose), or administration oral, buccal, sublingual, transdermal, nasal or parenteral. The compositions of compounds or agents described herein can be formulated as part of an implant or device, or formulated for slow or extended release. When administered parenterally, the therapeutic composition of compounds or agents for use in this invention is preferably in a physiologically acceptable pyrogen-free form. General techniques and formulations can be found in Remington’s Pharmaceutical Sciences, Meade Publishing Co., Easton, PA.

[0459] In certain embodiments, pharmaceutical compositions suitable for parenteral administration may comprise the positive allosteric modulator of GABAA R containing α5 in combination with one or more pharmaceutically acceptable sterile non-aqueous or aqueous isotonic emulsions, suspensions, dispersions or solutions, or sterile powders that can be reconstituted into sterile injectable dispersions or solutions shortly before use, which may contain antioxidants, buffers, bacteriostatics, solutes that make the formulation isotonic with the blood of the intended recipient, or suspending or thickening agents. Examples of suitable aqueous and non-aqueous carriers that may be employed in the pharmaceutical compositions of the invention include water, ethanol, polyols (such as glycerol, propylene glycol, polyethylene glycol and the like) and suitable mixtures thereof, vegetable oils such as olive oil and injectable organic esters such as ethyl oleate. Adequate fluidity can be maintained, for example, through the use of coating materials such as lecithin, through maintaining the required particle size in the case of dispersion, and through the use of surfactants.

[0460] A composition comprising a GABAA R positive allosteric modulator containing α5 may also contain adjuvants, such as preservatives, wetting agents, emulsifying agents and dispersing agents. Prevention of the action of microorganisms can be ensured through the inclusion of various antifungal and antibacterial agents, for example, parabens, chlorobutanol, phenol, sorbic acid and the like. It may also be desirable to include isotonic agents such as sugars, sodium chloride and the like in the compositions. Furthermore, prolonged absorption of the injectable pharmaceutical form may be caused by the inclusion of agents that delay absorption, such as aluminum monostearate and gelatin.

[0461] In certain embodiments of the invention, compositions comprising a GABAA R positive allosteric modulator containing α5 can be administered orally, for example, in the form of capsules, stamps, pills, tablets, lozenges (with the use of a flavored base, typically sucrose and acacia or tragacanth), powders, granules, or as a solution or suspension in an aqueous or non-aqueous liquid, or as a liquid oil-in-water or water-in-oil emulsion, as a hi elixir syrup, or as lozenges (with the use of an inert base such as gelatin and glycerin, or sucrose and acacia) and the like, each containing a predetermined amount of the GABAA positive allosteric modulator R containing α5 as an active ingredient.

[0462] In solid dosage forms for oral administration (capsules, tablets, pills, tablets, powders, granules and the like), one or more compositions comprising the GABAA R positive allosteric modulator containing α5 can be mixed with one or more pharmaceutically acceptable carriers such as sodium citrate or dicalcium phosphate and/or any of the following:

[0463] fillers or extenders, such as starches, lactose, sucrose, glucose, mannitol and/or silicic acid; (2) binders, such as, for example, carboxy methylcellulose, alginates, gelatin, polyvinyl pyrrolidone, sucrose and/or acacia; (3) humectants, such as glycerol; (4) disintegrating agents, such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates and sodium carbonate; (5) solution retarding agents such as paraffin; (6) absorption accelerators, such as quaternary ammonium compounds; (7) wetting agents, such as, for example, cetyl alcohol and glycerol monostearate; (8) absorbents, such as kaolin and bentonite clay; (9) lubricants, such as talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate and mixtures thereof; and (10) coloring agents. In the case of capsules, tablets and pills, the pharmaceutical compositions may also comprise buffering agents. Solid compositions of a similar type may also be employed as fillers in hard or soft filled gelatin capsules using excipients such as lactose or milk sugars, as well as high molecular weight polyethylene glycols and the like.

[0464] Liquid dosage forms for oral administration include pharmaceutically acceptable elixirs, syrups, suspensions, solutions, microemulsions and emulsions. In addition to the α5-containing GABAA R positive allosteric modulator, liquid dosage forms may contain inert diluents commonly used in the art, such as water or other solvents, solubilizing agents and emulsifiers, such as ethyl alcohol (ethanol), isopropyl alcohol, ethyl carbonate , ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, oils (in particular, cottonseed, peanut, corn, germ, olive, castor and sesame oils), glycerol, tetrahydrofuryl alcohol , polyethylene glycols and sorbitan fatty acid esters and mixtures thereof. In addition to inert diluents, oral compositions may also include adjuvants, such as wetting agents, suspending and emulsifying agents, sweeteners, flavors, colors, perfumes and preservative agents.

[0465] Suspensions, in addition to active compounds, may contain suspending agents, such as ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar and tragacanth and mixtures thereof.

[0466] As described herein, the compounds, agents and compositions thereof can be administered for slow, controlled or extended release. The term “extended release” is widely recognized in the art of pharmaceutical sciences and is used herein to refer to a controlled release of an active agent or compound from a dosage form into an environment at (all or during) an extended period of time, e.g., greater than or equal to one hour. An extended-release dosage form will release the drug at a substantially constant rate over an extended period of time or a substantially constant amount of drug will be released incrementally over an extended period of time. The term “extended release” used herein includes the terms “controlled release”, “extended release”, “sustained release”, “delayed release” or “slow release”, as these terms are used in pharmaceutical science. In some embodiments, the extended-release dosage is administered in the form of a patch or a pump. One skilled in the art, such as a physician, is readily able to determine the required amount of allosteric modulator(s) α5-containing GABAA R positive(s) to treat the individual using the compositions and methods of the invention. It is understood that the dosage regimen will be determined for an individual, taking into account, for example, several factors that modify the action of the α5-containing GABAA R positive allosteric modulator, the severity or stage of the disease, route of administration, and unique characteristics. for the individual, such as age, weight, size and extent of cognitive impairment.

[0467] It is a well-known fact in the art that normalization for body surface area is a suitable method for extrapolating doses between species. To calculate the human equivalent dose (HED) from a dosage used in the treatment of age-dependent cognitive impairment in rats, the formula HED (mg/kg) = rat dose (mg/kg) x 0.16 can be employed (see Estimating the Safe Starting Dose in Clinical Trials for Therapeutics in Adult Healthy Volunteers, December 2002, Center for Biologics Evaluation and Research). For example, using this formula, a dosage of 10 mg/kg in rats is equivalent to 1.6 mg/kg in humans. This conversion is based on a more general formula HED = animal dose in mg/kg x (animal weight in kg/human weight in kg) 0.33.

[0468] In certain embodiments of the invention, the dose of the α5-containing GABAA R positive allosteric modulator is between 0.0001 and 100 mg/kg/day (which, given a typical 70 kg human subject, is between 0.007 and 7,000 mg/day).

[0469] In certain embodiments of the invention, the administration interval is once every 12 or 24 hours. Administration at less frequent intervals, such as once every 6 hours, may also be used.

[0470] If administered by an implant, a device, or a slow or extended release formulation, the α5-containing GABAA R positive allosteric modulator can be administered once, or one or more times periodically throughout the lifetime of the patient as necessary. Other administration intervals intermediate to or shorter than these dosage intervals for clinical applications may also be used and may be determined by one skilled in the art following the methods of this invention.

[0471] The desired time of administration can be determined by routine experimentation by one skilled in the art. For example, the α5-containing GABAA R positive allosteric modulator may be administered over a period of 1 to 4 weeks, 1 to 3 months, 3 to 6 months, 6 to 12 months, 1 to 2 years or longer, until the patient's lifespan.

[0472] In addition to the GABAA R positive allosteric modulator containing α5, the compositions of this invention may also include other therapeutically useful agents. These other therapeutically useful agents can be administered in a single formulation, simultaneously or sequentially with the α5-containing GABAA R positive allosteric modulator, in accordance with the methods of the invention.

[0473] It will be understood by those skilled in the art that the compositions described herein can be adapted and modified as appropriate for the application being treated and that the compositions described herein can be employed in other suitable applications. For example, the compositions of this application may additionally comprise a second therapeutic agent. Such other additions and modifications will not deviate from the scope in question.

PHARMACEUTICAL COMPOSITIONS WITH ANTIPSYCHOTICS

[0474] The compounds or compositions of this application can be used in combination with an antipsychotic in the treatment of cognitive impairment associated with schizophrenia or bipolar disorder, in an individual who has or is at risk for said schizophrenia or bipolar disorder (e.g., mania ). The antipsychotic or a pharmaceutically acceptable polymorph, solvate, hydrate or salt thereof that is useful in the methods and compositions of this invention include both typical and atypical antipsychotics. In some embodiments, the compounds or compositions of the present invention can be used to treat one or more positive and/or negative symptoms, as well as cognitive impairment, associated with schizophrenia. In some embodiments, the compounds or compositions of the present invention can be used to treat one or more symptoms, as well as cognitive impairment, associated with bipolar disorder (in particular, mania). In some embodiments of this invention, the compounds or compositions of this invention prevent or slow the progression of cognitive impairment of schizophrenia or bipolar disorder (in particular, mania) in said individual.

[0475] In some embodiments, antipsychotics suitable for use in the present invention are selected from atypical antipsychotics. Such atypical antipsychotics include, but are not limited to, those disclosed in, for example, U.S. patents 4,734,416; 5,006,528; 4,145,434; 5,763,476; 3,539,573; 5,229,382; 5,532,372; 4,879,288; 4,804,663; 4,710,500; 4,831,031; and 5,312,925 and EP patents EP402644 and EP368388 and the pharmaceutically acceptable polymorphs, solvates, hydrates and salts thereof.

[0476] In some embodiments, atypical antipsychotics suitable for use in the present invention include, but are not limited to, aripiprazole, asenapine, clozapine, iloperidone, olanzapine, lurasidone, paliperidone, quetiapine, risperidone and ziprasidone and the polymorphs, solvates, hydrates and pharmaceutically acceptable salts thereof. In some embodiments, the antipsychotic suitable for use in the present invention is selected from aripiprazole (Bristol-Myers Squibb), olanzapine (Lilly) and ziprasidone (Pfizer) and the pharmaceutically acceptable polymorphs, solvates, hydrates and salts of the same.

[0477] In some embodiments, antipsychotics suitable for use in the present invention are typical antipsychotics which include, but are not limited to, acepromazine, benperidol, bromazepam, bromperidol, chlorpromazine, chlorprothixene, clothiapine, cyamemazine, diazepam, dixirazine, droperidol , flupenthixol, fluphenazine, fluspirilene, haloperidol, heptaminol, isopropamide iodide, levomepromazine, levosulpiride, loxapine, melperone, mesoridazine, molindone, oxypertin, oxyprotepin, penfluridol, perazine, periciazine, perphenazine, pimozide, pipamperone, pipotiazine, prochlorperaz ina, promazine , promethazine, protypendyl, pyridoxine, sulpiride, sultopride, tetrabenazine, thioproperazine, thioridazine, tiapride, thiothixene, trifluoperazine, triflupromazine, trihexyphenidyl and zuclopenthixol and the pharmaceutically acceptable polymorphs, solvates, hydrates and salts thereof.

[0478] In some embodiments of the present invention, the antipsychotic or a pharmaceutically acceptable polymorph, solvate, hydrate or salt thereof may be selected from compounds that are dopaminergic agents (such as dopamine D1 receptor agonists or antagonists, dopamine D2 receptor partial agonists or antagonists, dopamine D3 receptor partial agonists or antagonists, dopamine D4 receptor antagonists), glutamatergic agents, N-methyl-D-aspartate (NMDA) receptor positive allosteric modulators, inhibitors glycine reabsorption, glutamate reabsorption inhibitor, positive allosteric modulators (PAMs) or metabotropic glutamate receptor (mGluRs) agonists (e.g., mGluR2/3 agonists or PAMs), positive allosteric modulators (PAMs) gluR5 glutamate receptor, positive allosteric modulators (PAMs) of the M1 muscarinic acetylcholine receptor (mAChR), histamine H3 receptor antagonists, α-amino-3-hydroxy-5-methylisoxazol-4-acid receptor antagonists propionic acid (AMPA)/kainate, ampakines (CX-516), glutathione prodrugs, noradrenergic agents (such as alpha-2 adrenergic receptor antagonists or agonists and catechol-O-methyl transferase (COMT) inhibitors), receptor modulators serotonin (such as 5-HT2A receptor antagonists, 5-HT1A receptor partial agonists, 5-HT2C agonists and 5-HT6 antagonists, serotonin 2C agonists), cholinergic agents (such as PAMs or alpha-receptor agonists) 7 nicotinic, alpha4-beta2 nicotinic receptor agonists, allosteric modulators of nicotinic receptors and acetylcholinesterase inhibitors, muscarinic receptor antagonists and agonists), CB1 cannabinoid antagonists, neurokinin 3 antagonists, neurotensin agonists, monoamine oxidase (MAO) B inhibitors , PDE10 inhibitors, neuronal nitric oxide synthase (nNOS) inhibitors, neurosteroid and neurotrophic factors.

[0479] In some embodiments, a positive allosteric modulator of the GABAA receptor containing α5, as described herein, and an antipsychotic as described herein, or pharmaceutically acceptable polymorphs, solvates, hydrates or salts thereof, are administered simultaneously or sequentially, in a single formulation or in separate formulations packaged together. In other embodiments, the α5-containing GABAA receptor positive allosteric modulator and the antipsychotic, or pharmaceutically acceptable polymorphs, solvates, hydrates or salts thereof, are administered via different routes. For use in the present invention, "combination" includes administration through any of these formulations or routes of administration.

PHARMACEUTICAL COMPOSITIONS WITH MEMANTINE

[0480] The compounds or compositions of this application can be used in combination with memantine, a derivative or an analogue thereof in the treatment of cognitive impairment associated with central nervous system (CNS) disorders in an individual in need or at risk of the same, which includes, without limitation, individuals with or at risk for age-related cognitive impairment, moderate cognitive impairment (MCI), amnestic MCI, age-associated memory impairment (AAMI), age-related cognitive impairment (ARCD), dementia, Alzheimer's disease (AD), prodromal AD, post-traumatic stress disorder (PTSD), schizophrenia or bipolar disorder, amyotrophic lateral sclerosis (ALS), and cognitive impairment related to cancer therapy.

[0481] Memantine, chemically known as 3,5-dimethyladamantan-1-amine or 3,5-dimethyltricyclo[3.3.1.13.7]decan-1-amine, is an N-methyl-D-aspartate receptor antagonist (NMDA) non-competitive with moderate affinity. Trademarks for memantine include: Axura® and Akatinol® (Merz), Namenda® (Forest Laboratories), Ebixa® and Abixa® (Lundbeck), and Memox® (Unipharm). Memantine is currently available in the United States and in more than 42 countries around the world. It is approved for the treatment of moderate to severe Alzheimer's disease (AD) in the United States at a dose of up to 28 mg/day. Memantine and some of its derivatives and analogs that are useful in the present invention are disclosed in U.S. patents 3,391,142; 4,122,193; 4,273,774; and 5,061,703, all of which are incorporated herein by reference. Other memantine analogs or derivatives that are useful in the present invention include, but are not limited to, those compounds disclosed in U.S. patent application publication US20040087658, US20050113458, US20060205822, US20090081259, US20090124659 and US20100227852; publication of patent application in EP EP2260839A2; patent in EP EP1682109B1; and publication of PCT application in WO2005079779, all of which are incorporated herein by reference. Memantine, for use in the present invention, includes memantine and its derivatives and analogues, as well as hydrates, polymorphs, prodrugs, salts and solvates thereof. Memantine, for use in the present invention, also includes a composition comprising memantine or a derivative, analogue or prodrug, polymorph, solvate, hydrate or pharmaceutically acceptable salt thereof, wherein the composition additionally and optionally comprises, at least one additional therapeutic agent (such as a therapeutic agent useful in treating a CNS disorder or associated cognitive impairments thereof). In some embodiments, the memantine composition suitable for use in the present invention comprises memantine and a second therapeutic agent which is donepezil (under the trade name Aricept).

[0482] In other embodiments of the invention, the positive allosteric modulator of the GABAA receptor containing α5 and memantine (or the memantine analogue/derivative), or their prodrugs, polymorphs, solvates, hydrates or pharmaceutically acceptable salts , are administered simultaneously or sequentially, in a single formulation or in separate formulations packaged together. In other embodiments, the GABAA receptor positive allosteric modulator containing α5 and memantine (or the memantine analogue/derivative), or its prodrugs, polymorphs, solvates, hydrates or pharmaceutically acceptable salts, are administered via different routes. . For use in the present invention, "combination" includes administration through any of these formulations or routes of administration.

PHARMACEUTICAL COMPOSITIONS WITH ACETYLCHOLINE ESTRASE INHIBITORS (AChE-Is)

[0483] The compounds or compositions of this application can be used in combination with an acetylcholine esterase inhibitor in the treatment of cognitive impairment associated with central nervous system (CNS) disorders in an individual who requires or is at risk thereof, which includes , without limitation, individuals with or at risk for age-related cognitive impairment, moderate cognitive impairment (MCI), amnestic MCI, age-associated memory impairment (AAMI), age-related cognitive impairment (ARCD), dementia, Alzheimer's disease (AD), prodromal AD, post-traumatic stress disorder (PTSD), schizophrenia or bipolar disorder, amyotrophic lateral sclerosis (ALS), and cognitive impairment related to cancer therapy.

[0484] The AChE-Is known to a person skilled in the art may belong to the subcategories of (i) reversible non-competitive inhibitors or reversible competitive inhibitors, (ii) irreversible inhibitors and (iii) quasi-irreversible inhibitors.

[0485] In certain embodiments, AChE-Is useful in the present invention include those described in PCT applications WO2014039920 and WO2002032412; patents in EP 468187; 481429-A; and U.S. patents 4,816,456; 4,895,841; 5,041,455; 5,106,856; 5,602,176; 6,677,330; 7,340,299; 7,635,709; 8,058,268; 8,741,808; and 8,853,219, all of which are incorporated herein by reference.

[0486] In certain embodiments, typical AChE-Is that can be used in accordance with this invention include, but are not limited to, ungeremin, ladostigil, demecarium, ecothiophate (phospholine), edrophonium (Tensilon), tacrine (Cognex), Pralidoxime (2-PAM), pyridostigmine (Mestinon), physostigmine (serine, Antilirium), abmenonium (Mytelase), galantamine (Reminyl, Razadyne), rivastigmine (Exelon, SZD-ENA-713), Huperzine A, Icopezil, neostigmine (Prostigmin , Vagostigmin), Aricept (Donepezil, E2020), Lactucopicrin, monoamine acridines and their derivatives, piperidine and piperazine derivatives, N-benzyl-piperidine derivatives, heterocyclic piperidinyl-alkanoyl compounds, 4-fused quinoline derivatives (1-benzyl:piperidyl)-substituted and cyclic amide derivatives. Other typical AChE-Is include carbamates and organophosphate compounds such as Metrifonate (Trichlorfon). Benzazepinols, such as galantamine, are also useful AChE-Is. In some embodiments, AChE-Is suitable for use in combination with the compounds and compositions of this application include: Donepezil (aricept), Galantamine (razadyne) or Rivastigmine (exelon).

[0487] In other embodiments of the invention, the positive allosteric modulator of the GABAA receptor containing α5 and AChE-I or its prodrugs, polymorphs, solvates, hydrates or pharmaceutically acceptable salts, are administered simultaneously or sequentially, in a single formulation or in separate formulations packaged together. In other embodiments, the α5-containing GABAA receptor positive allosteric modulator and AChE-I, or pharmaceutically acceptable prodrugs, polymorphs, solvates, hydrates or salts thereof, are administered via different routes. For use in the present invention, "combination" includes administration through any of these formulations or routes of administration.

METHODS FOR ASSESSING COGNITIVE DISABILITY

[0488] Animal models serve as an important resource for the development and evaluation of treatments for cognitive impairment associated with CNS disorders. The traits that characterize cognitive impairment in animal models typically extend to cognitive impairment in humans. It is therefore expected that efficacy in such animal models will be predictive of efficacy in humans. The extent of cognitive impairment in an animal model for a CNS disorder and the effectiveness of a treatment method for said CNS disorder can be tested and confirmed using a variety of cognitive tests.

[0489] A radial maze behavior task (RAM) is an example of a cognitive test, which specifically tests spatial memory (Chappell et al. Neuropharmacology 37: 481 to 487, 1998). The RAM apparatus consists of, for example, eight equidistantly spaced arms. An arm of the maze projects from each facet of a central platform. A food cavity is situated at the distal end of each arm. Food is used as a reward. Blocks can be positioned to prevent entry for either arm. Numerous extra maze clues surrounding the apparatus can also be provided. After the habituation and training phases, subjects' spatial memory can be tested in the RAM under compound-treated or control conditions. As a part of the test, subjects are pretreated prior to testing with a vehicle control or one of a range of dosages of the test compound. At the beginning of each trial, a subset of the arms of the eight-arm maze are blocked. Subjects are allowed to obtain food in the non-blocked arms, to which access is permitted during this initial “information phase” of the trial. Subjects are then removed from the maze during a delay period, e.g., a 60-second delay, a 15-minute delay, a one-hour delay, a two-hour delay, a six-hour delay, a 24 hours or more between the information phase and the subsequent “retention test,” during which the barriers in the maze are removed, thereby allowing access to all eight arms. After the delay period, the Subjects are placed back on the central platform (with the barriers to the previously blocked arms removed) and allowed to obtain the remaining food rewards during this retention test phase of the trial. The identity and configuration of the blocked arms vary across trials. The number of “errors" that subjects make during the retention test phase is tracked. An error occurs in the trial if subjects enter an arm from which food has already been retrieved in the pre-delay component of the trial or if it visits an arm again in the post-delay session that has already been visited. A smaller number of errors would indicate better spatial memory. The number of errors made by the test subject under various test compound treatment regimens can then be compared regarding the effectiveness of the test compound in treating cognitive impairment associated with CNS disorders.

[0490] Another cognitive test that can be used to evaluate the effects of a test compound on cognitive impairment in an animal model of CNS disorder is the Morris water maze. A water maze is a swimming pool surrounded with an innovative set of patterns in relation to the maze. The training protocol for the water maze may be based on a modified water maze task that has been shown to be hippocampal dependent (de Hoz et al., Eur. J. Neurosci., 22:745 to 754, 2005; Steele and Morris, Hippocampus 9:118 to 136, 1999). The individual is trained to locate a submerged escape platform hidden beneath the pool surface. During the training trial, an individual is released into the maze (pool) from random starting positions around the perimeter of the pool. The starting position varies from trial to trial. If the subject does not locate the escape platform within a set time, the experimenter guides and places the subject on the platform to “teach” the platform location. After a delay period after the last training trial, a retention test in the absence of the escape platform is given to assess spatial memory. The individual's level of preference for the (now absent) escape platform location, as measured by, for example, the time spent at that location or the number of crossings of that location made by the mouse, indicates better spatial memory, i.e., treatment of cognitive impairment. The preference for escape platform location under several different treatment conditions can then be compared regarding the effectiveness of the test compound in treating cognitive impairment associated with CNS disorders.

[0491] There are several tests known in the art for the assessment of cognitive function in humans, for example and without limitation, the Clinical Global Impression of Change scale (CIBIC-plus scale); the Mini-Mental State Examination (MMSE); the neuropsychiatric inventory (NPI); the Clinical Dementia Rating Scale (CDR); the Cambridge Automated Neuropsychological Test Battery (CANTAB); the Sandoz Clinical Geriatric Assessment (SCAG), the Buschke Selective Recall Test (Buschke and Fuld, 1974); the associated pairs verbal subtest; the logical memory subtest; the visual reproduction subtest of the Wechsler Memory Scale-Revised (WMS-R) (Wechsler, 1997); the Benton visual retention test, or the MATRICS consensus neuropsychological test battery that includes tests of working memory, processing speed, attention, verbal learning, visual learning, reasoning and problem solving, and social cognition. See Folstein et al., J Psychiatric Res 12: 189 to 198, (1975); Robbins et al., Dementia 5: 266 to 281, (1994); Rey, L'examen clinique en psychology, (1964); Kluger et al., J Geriatr Psychiatry Neurol 12:168 to 179, (1999); Marquis et al., 2002 and Masur et al., 1994. See also Buchanan, R.W., Keefe, R.S.E., Umbricht, D., Green, M.F., Laughren, T., and Marder, S.R. (2011), The FDA-NIMH- MATRICS guidelines for clinical trial design of cognitive-enhancing drugs: what do we know 5 years later? Schizophr. Bull. 37, 1209 to 1217. Another example of a cognitive test in humans is the explicit 3-alternative forced choice task. In this test, subjects are presented with color photographs of common objects that consist of a mixture of three types of image pairs: similar pairs, identical pairs, and unrelated contrasts. The second among the pair of similar objects is called the "bait". These image pairs are completely randomized and presented individually as a series of images. Individuals are instructed to make a judgment regarding whether the objects seen are new, old, or similar. A “similar” response to the presentation of a bait stimulus indicates successful memory retrieval by the individual. In contrast, calling the bait stimulus “old” or “new” indicates that correct memory retrieval did not occur.

[0492] In addition to assessing cognitive performance, the progression of age-related cognitive impairment and dementia, as well as the conversion of age-related cognitive impairment into dementia, can be monitored by assessing surrogate changes in the individual's brain. Surrogate changes include, but are not limited to, changes in regional brain volumes, degradation of perforant trajectory, and changes seen in brain function via resting-state fMRI (R-fMRI) and fluorodeoxyglucose positron emission tomography (FDG- PET). Examples of regional brain volumes useful in monitoring the progression of age-related cognitive impairment and dementia include reduction in hippocampal volume and reduction in volume or thickness of the entorhinal cortex. These volumes can be measured in an individual using, for example, MRI. Aisen et al., Alzheimer’s & Dementia 6:239 to 246 (2010). Perforator trajectory degradation has been shown to be linked to age as well as reduced cognitive function. For example, older adults with more perforant trajectory degradation tend to show worse tests of hippocampus-dependent memory. Perforator trajectory degradation can be monitored in individuals through ultra-high resolution diffusion tensor imaging (DTI). Yassa et al., PNAS 107:12687–12691 (2010). Resting-state fMRI (R-fMRI) involves imaging the brain during rest and recording spontaneous, large-amplitude (<0.1 Hz) low-frequency fluctuations in the fMRI signal that are temporally correlated across related areas from a functional point of view. Source-based functional connectivity, independent component analyses, and/or frequency domain analyzes of signals are used to reveal the functional connectivity between brain areas, particularly those areas whose connectivity increases or decreases with age, as well as the extent cognitive impairment and/or dementia. FDG-PET uses FDG uptake as a measure of regional metabolic activity in the brain. Decreased FDG absorption in regions such as the posterior cingulate cortex, temporoparietal cortex, and prefrontal association cortex has been shown to be related to the extent of cognitive impairment and dementia. Aisen et al., Alzheimer’s & Dementia 6:239 to 246 (2010), Herholz et al., NeuroImage 17:302 to 316 (2002).

AGE-RELATED COGNITIVE DISABILITY

[0493] The invention provides methods and compositions for treating age-related cognitive impairment or the risk thereof with the use of a positive allosteric modulator of the α5-containing GABAA receptor (i.e., a compound of the invention), such as that selected from compounds or isomers, polymorphs, solvates, hydrates, pharmaceutically acceptable salts, or combinations thereof, as described herein. In certain embodiments, treatment comprises preventing or slowing the progression of age-related cognitive impairment. In certain embodiments, treatment comprises relieving, improving, or slowing the progression of one or more symptoms associated with age-associated cognitive impairment. In certain embodiments, treatment of age-related cognitive impairment comprises slowing the conversion of age-related cognitive impairment (which includes, but is not limited to, MCI, ARCD, and AAMI) into dementia (e.g., AD). The methods and compositions can be used for human patients in clinical applications in the treatment of age-related cognitive impairment in conditions such as MCI, ARCD and AAMI or for the risk thereof. The dose of the composition and dosage interval for the method are, as described herein, those that are safe and effective in those applications. In some embodiments of the invention, there is provided a method for preserving or enhancing cognitive function in an individual with age-related cognitive impairment, the method comprising the step of administering to said individual a therapeutically effective amount of a compound of the invention or an isomer, polymorph, solvate, hydrate, pharmaceutically acceptable salt or combination thereof.

[0494] In some embodiments, an individual to be treated by the methods and compositions of this invention exhibits age-related cognitive impairment or is at risk for such impairment. In some embodiments, age-related cognitive impairment includes, but is not limited to, age-related memory impairment (AAMI), moderate cognitive impairment (MCI), and age-related cognitive impairment (ARCD).

[0495] Animal models serve as an important resource for developing and evaluating treatments for such age-related cognitive impairments. The traits that characterize age-related cognitive impairment in animal models typically extend to cognitive impairment in humans. It is therefore expected that efficacy in such animal models will be predictive of efficacy in humans.

[0496] Several animal models of age-related cognitive impairment are known in the art. For example, extensive behavioral characterization has identified a naturally occurring form of cognitive impairment in an outbred strain of aged Long-Evans rats (Charles River Laboratories; Gallagher et al., Behav. Neurosci. 107:618 to 626, ( 1993)). In a behavioral assessment with the Morris water maze (MWM), rats learn and remember the location of an escape platform guided by a configuration of spatial cues that surround the maze. The cognitive basis of performance is tested in probe trials using measurements of the animal's spatial inclination in searching for the location of the escape platform. Aged mice in the study population have no difficulty swimming to a visible platform, but an age-dependent impairment is detected when the platform is camouflaged, requiring the use of spatial information. Performance for individual aged mice in the outbred Long-Evans strain varies greatly. For example, a proportion of those rats act in pairs with young adults. However, approximately 40 to 50% fell outside the youth performance range. This variability among aged mice reflects reliable individual differences. Thus, within the aging population, some animals are cognitively impaired and designated as designated with age-related disability (AI) and other animals are not harmed and are designated as not with age-related disability (AU). See, for example, Colombo et al., Proc. Natl. Academic. Sci. 94: 14,195 to 14,199, (1997); Gallagher and Burwell, Neurobiol. Aging 10: 691 to 708, (1989); Gallagher et al. Behav. Neurosci. 107:618 to 626, (1993); Rapp and Gallagher, Proc. Natl. Academic. Sci. 93: 9,926 to 9,930, (1996); Nicolle et al., Neuroscience 74: 741 to 756, (1996); Nicolle et al., J. Neurosci. 19: 9,604 to 9,610, (1999); international patent publication in WO2007/019312 and international patent publication in WO 2004/048551. Such an animal model of age-related cognitive impairment can be used to evaluate the effectiveness of the methods and compositions of this invention in treating age-related cognitive impairment.

[0497] The effectiveness of the methods and compositions of this invention in treating age-related cognitive impairment can be assessed using a variety of cognitive tests, which include the Morris water maze and the radial maze, as discussed herein. document.

INSANITY

[0498] The invention also provides methods and compositions for treating dementia with the use of a positive allosteric modulator of the α5-containing GABAA receptor, such as that selected from the compounds or isomers, polymorphs, solvates, hydrates, pharmaceutically acceptable salts or combinations thereof, as described in this document. In certain embodiments, treatment comprises preventing or slowing the progression of dementia. In certain embodiments, treatment comprises relieving, improving, or slowing the progression of one or more symptoms associated with dementia. In certain embodiments, the symptom being treated is cognitive impairment. In some embodiments of the invention, there is provided a method for preserving or enhancing cognitive function in an individual with dementia, the method comprising the step of administering to said individual a therapeutically effective amount of a compound of the invention or an isomer, polymorph. , solvate, hydrate, pharmaceutically acceptable salt or combination thereof. In certain embodiments, the dementia is Alzheimer's disease (AD), vascular dementia, dementia with Lewy bodies, or frontotemporal dementia. The methods and compositions can be used for human patients in clinical applications in the treatment of dementia. The dose of the composition and dosage interval for the method are, as described herein, those that are safe and effective in those applications.

[0499] Animal models serve as an important resource for the development and evaluation of treatments for dementia. The traits that characterize dementia in animal models typically extend to dementia in humans. It is therefore expected that efficacy in such animal models will be predictive of efficacy in humans. Several animal models of dementia are known in the art, such as the PDAPP, Tg2576, APP23, TgCRND8, J20, hPS2 Tg and APP + PS1 transgenic mice. Sankaranarayanan, Curr. Top. Medicinal Chem. 6: 609 to 627, 2006; Kobayashi et al. Brain Behavior Genes. 4: 173 to 196. 2005; Ashe and Zahns, Neuron. 66: 631 to 645, 2010. Such animal models of dementia can be used to evaluate the effectiveness of the methods and compositions of this invention in treating dementia.

[0500] The effectiveness of the methods and compositions of this invention in treating dementia, or cognitive impairment associated with dementia, can be evaluated in animal models of dementia, as well as human subjects with dementia, with the use of a variety of known cognitive tests in the art, as discussed herein.

POSTTRAUMATIC STRESS DISORDER

[0501] The invention also provides methods and compositions for treating post-traumatic stress disorder (PTSD) with the use of a positive allosteric modulator of the α5-containing GABAA receptor, such as that selected from the compounds or isomers, polymorphs , solvates, hydrates, pharmaceutically acceptable salts or combinations thereof, as described herein. In certain embodiments, treatment comprises preventing or slowing the progression of PTSD. In certain embodiments, treatment comprises relieving, improving, or slowing the progression of one or more symptoms associated with PTSD. In certain embodiments, the symptom being treated is cognitive impairment. In some embodiments of the invention, there is provided a method for preserving or enhancing cognitive function in an individual with PTSD, the method comprising the step of administering to said individual a therapeutically effective amount of a compound of the invention or an isomer, polymorph. , solvate, hydrate, pharmaceutically acceptable salt or combination thereof. The methods and compositions can be used for human patients in clinical applications in the treatment of PTSD. The dose of the composition and dosage interval for the method are, as described herein, those that are safe and effective in those applications.

[0502] Patients with PTSD (and, patients exposed to trauma to a lesser degree without PTSD) have smaller hippocampal volumes (Woon et al., Prog. NeuroPsychopharm. & Biological Psych. 34, 1,181 to 1,188; Wang et al. , Arch. Gen. Psychiatry 67:296 to 303, 2010). PTSD is also associated with impaired cognitive performance. Elderly individuals with PTSD have greater impairments in cognitive performance relative to control patients (Yehuda et al., Bio. Psych. 60:714 to 721, 2006) and are more likely to develop dementia (Yaffe et al., Arch . Gen. Psych. 678: 608 to 613, 2010).

[0503] Animal models serve as an important resource for the development and evaluation of treatments for PTSD. The traits that characterize PTSD in animal models typically extend to PTSD in humans. It is therefore expected that efficacy in such animal models will be predictive of efficacy in humans. Several animal models of PTSD are known in the art.

[0504] One mouse model of PTSD is time-dependent sensitization (TDS). TDS involves exposing the animal to a severely stressful event followed by a memory of the previous stressful situation. The following is an example of TDS. Rats are placed in a holding facility, then placed in a swimming tank and forced to swim for a period of time, e.g. 20 min. After this, each rat is then immediately exposed to a gaseous anesthetic until they lose consciousness and finally die. The animals are left to rest for several days, for example a week. The rats are then exposed to a “stress again” session consisting of an initial stressor, for example, a swimming session in the swim tank (Liberzon et al., Psychoneuroendocrinology 22: 443 to 453, 1997; Harvery et al., Psychopharmacology 175:494 to 502, 2004). TDS results in an intensification of the acoustic startle response (ASR) in the rat, which is comparable to the exaggerated acoustic startle that is a prominent symptom of PTSD (Khan and Liberzon, Psychopharmacology 172: 225 to 229, 2004). Such animal models of PTSD can be used to evaluate the effectiveness of the methods and compositions of this invention in treating PTSD.

[0505] The effectiveness of the methods and compositions of this invention in treating PTSD, or cognitive impairment associated with PTSD, can also be evaluated in animal models of PTSD, as well as human subjects with PTSD, with the use of a variety of cognitive tests known in the art, as discussed herein.

SCHIZOPHRENIA AND BIPOLAR DISORDER

[0506] The invention further provides methods and compositions for treating schizophrenia or bipolar disorder (in particular, mania) with the use of a positive allosteric modulator of the α5-containing GABAA receptor, such as that selected from the compounds or isomers, polymorphs , solvates, hydrates, pharmaceutically acceptable salts or combinations thereof, as described herein. In certain embodiments, treatment comprises preventing or slowing the progression of schizophrenia or bipolar disorder (in particular, mania). Schizophrenia is characterized by a broad spectrum of psychopathology, which includes positive symptoms such as distorted or abnormal mental representations (e.g., hallucinations, delusions), or symptoms associated with dopamine dysregulation (e.g., hyperdopaminergic responses, of hyperdopaminergic behavior, dopaminergic hyperactivity or hyperlocomotor activity or psychosis), negative symptoms characterized by decreased motivation and adaptive goal-directed action (e.g., lack of ability to experience pleasure, affective blunting, apathy), and cognitive impairment. In certain modalities, treatment comprises alleviating, improving or slowing the progression of one or more positive and/or negative symptoms, as well as cognitive impairment, associated with schizophrenia. Additionally, there are several other psychiatric illnesses, such as schizotypal and schizoaffective disorder, other acute or chronic psychoses, and bipolar disorder (in particular, mania), that do not have overlapping symptomatology with schizophrenia. In some embodiments, treatment comprises relieving, improving, or slowing the progression of one or more symptoms, as well as cognitive impairment, associated with bipolar disorder (in particular, mania). In some embodiments of the invention, there is provided a method for preserving or enhancing cognitive function in an individual with schizophrenia or bipolar disorder, the method comprising the step of administering to said individual a therapeutically effective amount of a compound of the invention or a isomer, polymorph, solvate, hydrate, pharmaceutically acceptable salt or combination thereof. The methods and compositions can be used for human patients in clinical applications in the treatment of schizophrenia or bipolar disorder (in particular, mania). The dose of the composition and dosage interval for the method are, as described herein, those that are safe and effective in those applications.

[0507] Cognitive impairments are associated with schizophrenia. They precede the onset of psychosis and are present in unaffected relatives. Cognitive impairments associated with schizophrenia are a good predictor of functional outcome and are a central feature of the disorder. Cognitive characteristics in schizophrenia reflect dysfunction in hippocampal and frontal cortical circuits. Patients with schizophrenia also present with hippocampal pathologies, such as reductions in hippocampal volume, reductions in neuronal size, and dysfunctional hyperactivity. An imbalance in excitation and inhibition in these brain regions has also been documented in schizophrenic patients, suggesting that drugs that target inhibitory mechanisms could be therapeutic. See, for example, Guidotti et al., Psychopharmacology 180: 191 to 205, 2005; Zierhut, Psych. Neuroimaging Res. 183:187 to 194, 2010; Wood et al., NeuroImage 52:62-63, 2010; Vinkers et al., Expert Opinion. Investigation. Drugs 19:1,217 to 1,233, 2009; Young et al., Pharmacol. The R. 122:150 to 202, 2009.

[0508] Animal models serve as an important resource for the development and evaluation of treatments for schizophrenia. The traits that characterize schizophrenia in animal models typically extend to schizophrenia in humans. It is therefore expected that efficacy in such animal models will be predictive of efficacy in humans. Several animal models of schizophrenia are known in the art.

[0509] An animal model of schizophrenia is prolonged treatment with methionine. Methionine-treated mice exhibit deficient expression of GAD67 in the frontal cortex and hippocampus, similar to that reported in the brains of schizophrenia patients after death. They also exhibit startle prepulse inhibition and social interaction deficits (Tremonlizzo et al., PNAS, 99: 17,095 to 17,100, 2002). Another animal model of schizophrenia is methyloxymethanol acetate (MAM) treatment in rats. Pregnant female rats are administered MAM (20 mg/kg, intraperitoneal) on day 17 of gestation. MAM treatment summarizes a pathological developmental process toward schizophrenia-like phenotypes in offspring, which includes anatomical changes, behavioral deficits, and altered neuronal information processing. More specifically, MAM-treated rats exhibit a decreased density of parvalbumin-positive GABAergic interneurons in portions of the prefrontal cortex and hippocampus. In behavioral tests, MAM-treated rats exhibit reduced latent reduction. Latent inhibition is a behavioral phenomenon in which there is reduced learning about a stimulus to which there has been previous exposure with any consequence. This tendency to previously neglect benign stimuli and reduce association formation with such stimuli is believed to prevent sensory overload. Low latent inhibition is indicative of psychosis. Latent inhibition can be tested in rats in the following way. The mice are divided into two groups. A group is pre-exposed to a sound on multiple trials. The other group has no sound presentation. Both groups are then exposed to an auditory fear conditioning procedure, in which the same sound is presented at the same time as a noxious stimulus, for example, an electric shock to the feet. Subsequently, both groups are presented with the sound and the rats' change in locomotor activity during the yes presentation is monitored. After fear conditioning, rats respond to sound presentation by strongly reducing locomotor activity. However, the group that has been exposed to the sound prior to the conditioning period exhibits robust latent inhibition: the suppression of locomotor activity in response to yes presentation is reduced. MAM-treated rats, in contrast, show impaired latent inhibition. That is, sound exposure prior to the fear conditioning procedure has no significant effect on the suppression of fear conditioning. (see Lodge et al., J. Neurosci., 29:2344-2354, 2009) Such animal models of schizophrenia can be used to evaluate the effectiveness of the methods and compositions of this invention in treating schizophrenia or bipolar disorder (in particular, mania).

[0510] MAM-treated rats exhibit a significantly accentuated locomotor response (or abnormal locomotor activity) to low dose administration of D-amphetamine. MAM-treated rats also exhibit significantly greater numbers of spontaneously firing dopamine (DA) neurons. These results are believed to be a consequence of excessive hippocampal activity due to the fact that in MAM-treated rats, inactivation of the ventral hippocampus (vHipp) (e.g., by intra-vHipp administration of a sodium channel blocker, tetrodotoxin (TTX), to MAM rats) completely reversed the elevated DA neuron population activity and also normalized the increased amphetamine-induced locomotor behavior. The correlation of hippocampal dysfunction and hyperresponsiveness of the DA system is believed to underlie the increased response to amphetamine in MAM-treated animals and psychosis in patients with schizophrenia. See Lodge D. J. et al. Neurobiology of Disease (2007), 27(42), 11,424 a11,430. The use of MAM-treated rats in the above study may be suitable for use in evaluating the effectiveness of the methods and compositions of the present invention in treating schizophrenia or bipolar disorder (in particular, mania). For example, the methods and compositions of this invention can be evaluated, using animals treated with MAM, regarding their effects on the regulation of the central hippocampus (vHipp), on the activity of a population of high DA neurons and on the response hyperactive locomotor response to amphetamine in animals treated with MAM.

[0511] In rats treated with MAM, hippocampal dysfunction (HPC) leads to hyperactivity of the dopamine system. A benzodiazepine positive allosteric modulator (PAM), selective for the α5 subunit of the GABAA receptor, SH-053-2'F-R-CH3, is tested for its effects on hippocampal output (HPC). The effect of SH-053-2'F-R-CH3 on the hyperactive locomotor response to amphetamine in MAM-treated animals is also examined. α5GABAAR PAM reduces the number of spontaneously active DA neurons in the ventral tegmental area (VTA) of MAM rats to levels observed in saline-treated rats (control group), both when administered systemically and when directly infused into the HPC ventral. Furthermore, HPC neurons in both saline-treated and MAM-treated animals show diminished cortex-elicited responses following α5GABAAR PAM treatment. Furthermore, the enhanced locomotor response to amphetamine observed in MAM-treated rats is reduced following α5GABAAR PAM treatment. See Gill KM et al. Neuropsychopharmacology (2011), 1 to 9. The use of MAM-treated rats in the above study may be suitable for use in the present invention to evaluate the effectiveness of the methods and compositions of the invention in treating schizophrenia or bipolar disorder (in particular, mania ). For example, the methods and compositions of this invention can be evaluated, using animals treated with MAM, for their effects on hippocampal output (HPC) and on the hyperactive locomotor response to amphetamine in animals treated with MAM.

[0512] Administration of MAM to pregnant rats on embryonic day 15 (E15) severely impairs spatial memory or the ability to learn the spatial location of four items in an eight-arm radial maze in offspring. Furthermore, mice treated with MAM at embryonic day 17 (E17) are able to reach the performance level of control mice in the early stages of training, but are unable to process and retrieve spatial information when delayed by 30 min. is interposed, indicating a significant impairment in working memory. See Gourevitch R. et al. (2004). Behav. Pharmacol, 15, 287 to 292. Such animal models of schizophrenia can be used to evaluate the effectiveness of the methods and compositions of the invention in treating schizophrenia or bipolar disorder (in particular, mania).

[0513] Apomorphine-induced climbing (AIC) and stereotype (AIS) in mice is another animal model useful in this invention. Agents are administered to mice at a desired dose level (e.g., via intraperitoneal administration). Subsequently, for example, thirty minutes later, experimental mice are challenged with apomorphine (e.g., at 1 mg/kg sc). Five minutes after apomorphine injection, the sniff-lick-gnaw syndrome (stereotypic behavior) and apomorphine-induced climbing behavior are scored and recorded for each animal. Readings can be repeated every 5 min. during a 30 min test session. Scores for each animal are totaled across the 30 min testing session. for each syndrome (escalation and stereotypical behavior). If an effect achieved at least 50% inhibition, an ID50 value (95% confidence interval) is calculated using a nonlinear least squares calculation with inverse prediction. Stereotype scores can be expressed as a percentage of control values observed in vehicle-treated (e.g., saline-treated) mice receiving apomorphine. See Grauer S. M. et al. Psychopharmacology (2009) 204, 37 to 48. This animal model can be used to evaluate the effectiveness of the methods and compositions of the invention in treating schizophrenia or bipolar disorder (in particular, mania).

[0514] In another well-established preclinical model of schizophrenia, rats chronically exposed to ketamine, a non-competitive N-methyl-D-aspartate (NMDA) receptor antagonist, produce positive and negative psychotic symptoms and cognitive impairment. Male Long-Evans rats are injected intraperitoneally with ketamine (30 mg/kg twice daily) for two weeks during their youth (2 months of age). Rats are behaviorally tested when they reach adulthood (approximately 4 to 5 months of age) regarding behavioral symptoms upon exposure to ketamine and the effectiveness of treatment in alleviating these symptoms. See, for example, Enomoto et al. Progress in Neuro-Psychopharmacology & Biological Psychiatry 33 (2009) 668 to 675.

[0515] The effectiveness of the methods and compositions of this invention in treating schizophrenia or cognitive impairment associated therewith, can also be evaluated in animal models of schizophrenia or bipolar disorder (in particular, mania), as well as human subjects with schizophrenia, with the use of a variety of cognitive tests known in the art, as discussed herein.

AMYOTROPHIC LATERAL SCLEROSIS (ALS)

[0516] The invention further provides methods and compositions for treating ALS with the use of a positive allosteric modulator of the α5-containing GABAA receptor, such as that selected from the compounds or isomers, polymorphs, solvates, hydrates, salts pharmaceutically acceptable or combinations thereof, as described in this document. In certain embodiments, treatment comprises preventing or slowing the progression of ALS. In certain embodiments, treatment comprises relieving, improving, or slowing the progression of one or more symptoms associated with ALS. In certain embodiments, the symptom being treated is cognitive impairment. In some embodiments of the invention, there is provided a method for preserving or enhancing cognitive function in an individual with ALS, the method comprising the step of administering to said individual a therapeutically effective amount of a compound of the invention or an isomer, polymorph. , solvate, hydrate, pharmaceutically acceptable salt or combination thereof. The methods and compositions can be used for human patients in clinical applications in the treatment of ALS. The dose of the composition and dosage interval for the method are, as described herein, those that are safe and effective in those applications.

[0517] In addition to the degeneration of motor neurons, ALS is characterized by neuronal degeneration in the entorhinal cortex and hippocampus, memory deficits and neuronal hyperexcitability in different areas of the brain, such as the cortex.

[0518] The effectiveness of the methods and compositions of this invention in treating ALS, or cognitive impairment associated with ALS, can also be evaluated in animal models of ALS, as well as human subjects with ALS with the use of a variety of known cognitive tests. in the art, as discussed herein.

COGNITIVE DISABILITY RELATED TO CANCER THERAPY

[0519] The invention further provides methods and compositions for treating cognitive impairment related to cancer therapy with the use of a positive allosteric modulator of the α5-containing GABAA receptor, such as that selected from the compounds or isomers, polymorphs, solvates, hydrates, pharmaceutically acceptable salts or combinations thereof, as described herein. In certain embodiments, treatment comprises preventing or slowing the progression of cognitive impairment related to cancer therapy. In certain embodiments, treatment comprises alleviating, improving or slowing the progression of one or more symptoms associated with cognitive impairment associated with cancer therapy. In some embodiments of the invention, there is provided a method for preserving or improving cognitive function in an individual with cognitive impairment related to cancer therapy, the method comprising the step of administering to said individual a therapeutically effective amount of a compound of the invention or an isomer, polymorph, solvate, hydrate, pharmaceutically acceptable salt or combination thereof. The methods and compositions can be used for human patients in clinical applications in the treatment of cognitive impairment related to cancer therapy. The dose of the composition and dosage interval for the method are, as described herein, those that are safe and effective in those applications.

[0520]Therapies that are used in the treatment of cancer, which include chemotherapy, radiation, or combinations thereof, can cause cognitive impairment in patients, in functions such as memory, learning and attention. Cytotoxicity and other adverse side effects on the brain from cancer therapies are the basis for this form of cognitive impairment, which can persist for decades. (Dietrich et al., Oncologist 13:1285 to 1295, 2008; Soussain et al., Lancet 374:1639 to 1651, 2009).

[0521] Cognitive impairment following cancer therapies reflects dysfunction in circuits of the hippocampus and frontal cortex that are essential for normal cognition. In animal models, exposure to chemotherapy or radiation adversely affects performance on tests of cognition specifically dependent on these brain systems, especially the hippocampus (Kim et al., J. Radiat. Res. 49:517 to 526, 2008 ; Yang et al., Neurobiol. Learning and Mem. 93:487 to 494, 2010). Thus, drugs that target these hippocampus and cortex systems could be neuroprotective in patients receiving cancer therapies and effective in treating symptoms of cognitive impairment that may persist beyond interventions used as cancer therapies.

[0522] Animal models serve as an important resource for the development and evaluation of treatments for cognitive impairment related to cancer therapy. The traits that characterize cancer therapy-related cognitive impairment in animal models typically extend to cancer therapy-related cognitive impairment in humans. It is therefore expected that efficacy in such animal models will be predictive of efficacy in humans. Several animal models of cognitive impairment related to cancer therapy are known in the art.

[0523] Examples of animal models of cognitive impairment related to cancer therapy include treating animals with antineoplastic agents, such as cyclophosphamide (CYP) or with radiation, for example, 60Co gamma rays. (Kim et al., J. Radiat. Res. 49:517 to 526, 2008; Yang et al., Neurobiol. Learning and Mem. 93:487 to 494, 2010). The cognitive function of animal models of cancer therapy-related cognitive impairment can then be tested with cognitive tests to evaluate the effectiveness of the methods and compositions of the invention in treating cancer therapy-related cognitive impairment. The effectiveness of the methods and compositions of this invention in treating cognitive impairment related to cancer therapy, as well as human subjects with cognitive impairment related to cancer therapy, with the use of a variety of cognitive tests known in the art, as discussed in this document.

PARKINSON'S DISEASE (PD)

[0524] Parkinson's disease (PD) is a neurological disorder characterized by a decrease in voluntary movements. The afflicted patient has reduced motor activity and slower voluntary movements compared to the normal individual. The patient has the characteristic "mask" face, a tendency to rush while walking, a hunched posture, and generalized muscle weakness. There is a "definite" stiffness typical of passive movements. Another important characteristic of the disease is tremor of the extremities that occurs at rest and decreases during movement.

[0525] Parkinson's disease, whose etiology is unknown, belongs to a group of the most common movement disorders called parkinsonism, which affects approximately one person in every thousand. These other disorders grouped under the name of parkinsonism can result from viral infection, syphilis, arteriosclerosis, trauma, and exposure to toxic chemicals and narcotics. However, it is believed that inappropriate loss of synaptic stability can lead to disruption of neuronal circuits and brain disease. Whether the result of genetics, drug use, the aging process, viral infections, or other diverse causes, dysfunction in neuronal communication is considered the underlying cause for many neurological diseases such as PD (Myrrhe van Spronsen and Casper C. Hoogenraad, Curr. Neurol. Neurosci. Rep. 2010, 10, 207 to 214).

[0526] Regardless of the cause of the disease, the main pathological characteristic is the degeneration of dopaminergic cells in the basal ganglia, especially in the substantia nigra. Due to the premature death of dopamine-containing neurons in the substantia nigra, the largest structure of the basal ganglia, the striatum, will have reduced input from the substantia nigra, resulting in decreased dopamine release. Understanding the underlying pathology leads to the introduction of the first successful treatment that can alleviate Parkinson's disease. Virtually all approaches to disease therapy are based on dopamine replacement. Drugs currently used in treatment can be converted into dopamine after crossing the blood-brain barrier or can stimulate dopamine synthesis and reduce its breakdown. Unfortunately, the main pathological event, the degeneration of cells in substantia nigra, is not helped. The disease continues to progress and often after a certain period of time, dopamine replacement treatment will lose its effectiveness.

[0527] The invention provides methods and compositions for treating PD with the use of an α5-containing GABAA receptor positive allosteric modulator, such as that selected from the compounds or isomers, polymorphs, solvates, hydrates, pharmaceutically acceptable salts or combinations of them, as described in this document. In certain embodiments, treatment comprises preventing or slowing the progression of PD. In certain embodiments, treatment comprises relieving, improving, or slowing the progression of one or more symptoms associated with PD. In certain embodiments, the symptom being treated is cognitive impairment. For example, the methods and compositions of the disclosure can be used to improve cognitive/motor impairments symptomatic of Parkinson's disease. Furthermore, the methods and compositions of the disclosure may be useful for treating memory impairment symptomatic of Parkinson's disease. In some embodiments of the invention, there is provided a method for preserving or improving cognitive function in an individual with PD, the method comprising the step of administering to said individual a therapeutically effective amount of a compound of the invention or an isomer. , polymorph, solvate, hydrate, pharmaceutically acceptable salt or combination thereof.

[0528] There are several animal models for PD. Exemplary animal models for PD include the reserpine model, the methamphetamine model, the 6-hydroxydopamine (6-OHDA) model, the 1-methyl-4-phenyl-1,2,3,6 model. - tetrahydropyridine (MPTP), the paraquat (PQ)-Maneb model, the rotenone model, the 3-nitrotyrosine model and genetic models using transgenic mice. Transgenic models include mice that overexpress α-synuclein, express human mutant forms of α-synuclein, or mice that express aLRKK2 mutations. See the analysis of these models by Ranjita B. et al. (Ranjita B. et al. BioEssays 2002, 24, 308 to 318). Additional information regarding these animal models is readily available from Jackson Laboratories (see also http://research.jax.org/grs/parkinsons.html), as well as in numerous publications disclosing the use of these validated models.

[0529] The effectiveness of the methods and compositions of this invention in treating PD, or cognitive impairment associated with PD, can be evaluated in any of the above animal models of PD, as well as human subjects with PD, with the use of a variety of cognitive tests known in the art, as discussed herein.

AUTISM

[0530] Autism is a neurodevelopmental disorder characterized by dysfunction in three core behavioral dimensions: repetitive behaviors, social deficits, and cognitive deficits. The repetitive behavior domain involves compulsive behaviors, unusual attachments to objects, rigid adherence to routines or rituals, and repetitive motor mannerisms such as stereotypes and self-stimulatory behaviors. The social deficit dimension involves deficits in reciprocal social interactions, lack of eye contact, diminished ability to continue a conversation, and impaired daily interaction skills. Cognitive deficits may include language abnormalities. Autism is a disabling neurological disorder that affects thousands of Americans and encompasses several subtypes, with many putative causes and few documented improvement treatments. Autism spectrum disorders may be present at birth or may have a later onset, for example, at ages two or three. There are no well-defined biological markers for autism. The diagnosis of the disorder is made by considering the degree to which the child is compatible with the behavioral syndrome, which is characterized by unsatisfactory communication skills, peculiarities in social and cognitive abilities and maladaptive behavior patterns. Dysfunction in neuronal communication is considered one of the underlying causes of autism (Myrrhe van Spronsen and Casper C. Hoogenraad, Curr. Neurol. Neurosci. Rep. 2010, 10, 207 to 214). Recent studies have shown that there is a deficit of GABAA α5 in autism spectrum disorder (ASD) and support further investigation of the GABA system in this disorder (Mendez MA, et al. Neuropharmacology. 2013, 68:195 to 201).

[0531] The invention also provides methods and compositions for treating autism with the use of a positive allosteric modulator of the GABAA receptor containing α5, such as that selected from compounds or isomers, polymorphs, solvates, hydrates, pharmaceutical salts acceptable or combinations thereof, as described in this document. In certain embodiments, treatment comprises preventing or slowing the progression of autism. In certain embodiments, treatment comprises alleviating, improving, or slowing the progression of one or more symptoms associated with autism. In certain embodiments, the symptom being treated is cognitive impairment or cognitive impairment. For example, the methods and compositions of revelation can be used to improve the cognitive/motor deficits symptomatic of autism. In some embodiments of the invention, there is provided a method for preserving or enhancing cognitive function in an individual with autism, the method comprising the step of administering to said individual a therapeutically effective amount of a compound of the invention or an isomer, polymorph. , solvate, hydrate, pharmaceutically acceptable salt or combination thereof.

[0532] The valproic acid (VPA) mouse model of autism using in vitro electrophysiological techniques, established by Rodier et al. (Rodier, P. M. et al. Reprod. Toxicol. 1997, 11, 417 to 422) is one of the most extensively established trauma-based animal models of autism and is based on the observation that pregnant women treated with VPA in the 1960s, during a circumscribed time window of embryogenesis, had a much higher risk of giving birth to an autistic child than the normal population. The offspring of pregnant rats exposed to VPA show several anatomical and behavioral symptoms typical of autism, such as decreased numbers of cerebellar Purkinje neurons, impaired social interaction, repetitive behaviors, as well as other symptoms of autism, which include enhanced fear memory processing. . See, Rinaldi T. et al. Frontiers in Neural Circuits, 2008, 2, 1 to 7. Another mouse model, BTBR T+tf/J (BTBR) mice, an established model with robust behavioral phenotypes relevant to the three diagnostic behavioral symptoms of autism-- unusual social interactions, repetitive behaviors, and impaired communication—was used to probe the efficacy of a selective negative allosteric modulator of the mGluR5 receptor, GRN-529. See, for example, Silverman J. L. et al. Sci Transl. Med. 2012, 4, 131.

[0533] The effectiveness of the methods and compositions of this invention in treating autism, or cognitive deficits associated with autism, can be evaluated in the VPA-treated rat model of autism or the BTBR T+tf/J (BTBR) mouse model. as well as human subjects with autism, using a variety of cognitive tests known in the art, as discussed in this document.

MENTAL RETARDATION

[0534] Mental retardation is a widespread disorder characterized by significantly impaired cognitive function and deficits in adaptive behaviors. Mental retardation is often defined as an intelligence quotient (IQ) score of less than 70. Congenital causes are among many underlying causes for mental retardation. Dysfunction in neuronal communication is also considered one of the underlying causes for mental retardation (Myrrhe van Spronsen and Casper C. Hoogenraad, Curr. Neurol. Neurosci. Rep. 2010, 10, 207 to 214).

[0535] In some cases, mental retardation includes, but is not limited to, Down syndrome, velocardiofacial syndrome, fetal alcohol syndrome, fragile X syndrome, Klinefelter syndrome, neurofibromatosis, congenital hypothyroidism, Williams syndrome, phenylketonuria (PKU), Smith-Lemli-Opitz syndrome, Prader-Willi syndrome, Phelan-McDermid syndrome, Mowat-Wilson syndrome, ciliopathy, Lowe syndrome, and siderium type X-linked mental retardation. Down syndrome is a disorder that includes a combination of birth defects that include some degree of mental retardation, characteristic facial features, and often heart defects, increased infections, problems with vision and hearing, and other health problems. Fragile X syndrome is a prevalent form of inherited mental retardation that occurs with a frequency of 1 in 4,000 males and 1 in 8,000 females. The syndrome is also characterized by developmental delay, hyperactivity, attention deficit disorder, and autistic-like behavior. There is no effective treatment for fragile X syndrome.

[0536] The present invention contemplates the treatment of mild mental retardation, moderate mental retardation, severe mental retardation, profound mental retardation and unspecified severity of mental retardation. Such mental retardation may be, but is not required to be, associated with chromosomal changes (e.g., Down syndrome due to trisomy 21), heredity, pregnancy and perinatal problems, and other severe mental disorders. This invention provides methods and compositions for treating mental retardation with the use of an α5-containing GABAA receptor positive allosteric modulator, such as that selected from the compounds or isomers, polymorphs, solvates, hydrates, pharmaceutically acceptable salts or combinations thereof. , as described in this document. In certain embodiments, treatment comprises preventing or slowing the progression of mental retardation. In certain embodiments, treatment comprises alleviating, improving, or slowing the progression of one or more symptoms associated with mental retardation. In certain embodiments, the symptom to be treated is cognitive impairment/deficit. For example, the methods and compositions of the disclosure can be used to improve cognitive/motor impairments symptomatic of mental retardation. In some embodiments of the invention, there is provided a method for preserving or improving cognitive function in an individual with mental retardation, the method comprising the step of administering to said individual a therapeutically effective amount of a compound of the invention or a isomer, polymorph, solvate, hydrate, pharmaceutically acceptable salt or combination thereof.

[0537] Several animal models have been developed for mental retardation. For example, a knockout mouse model has been developed for fragile X syndrome. Fragile X syndrome is a common form of mental retardation caused by the absence of the FMR1 protein, FMRP. Two homologues of FMRP have been identified, FXR1P and FXR2P. FXR2P shows high expression in brain and testis, like FMRP. Both Fxr2 and FmR1 knockout mice and FmR1/Fxr2 double knockout mice are believed to be useful models for mental retardation such as fragile X syndrome. See, Bontekoe C. J. M. et al. Hum. Mol. Ge net. 2002, 11 (5): 487 to 498.

[0538] The effectiveness of the methods and compositions of this invention in treating mental retardation, or cognitive impairment/deficit associated with mental retardation, can be evaluated in these animal models and in other animal models developed for mental retardation, as well as human subjects with mental retardation, using a variety of cognitive tests known in the art, as discussed herein.

COMPULSIVE BEHAVIOR (OBSESSIVE-COMPULSIVE DISORDER)

[0539] Obsessive-compulsive disorder ("OCD") is a mental condition that is most commonly characterized by repetitive, intrusive, unwanted thoughts (obsessions) that result in compulsive behaviors and mental actions that an individual feels compelled to perform (compulsion) . Current epidemiological data indicate that OCD is the fourth most common mental disorder in the United States. Some studies suggest that the prevalence of OCD is between one and three percent, although the prevalence of clinically recognized OCD is much lower, suggesting that many individuals with the disorder may go undiagnosed. Patients with OCD are often diagnosed by a psychologist, psychiatrist, or psychoanalyst according to the diagnostic criteria in the Diagnostic and Statistical Manual of Mental Disorders, 4a. edition, text revision (DSM-IV-TR) (2000), which include characteristics of obsessions and compulsions. Characteristics of obsession include: (1) recurring and persistent images, urges, or thoughts that are experienced as intrusive and that cause agony or marked anxiety; (2) the thoughts, impulses, or images are not simply excessive worries about real-life problems; and (3) the person attempts to ignore or suppress such thoughts, impulses, or images, or to neutralize them with some other thought or action. The person recognizes that the obsessive images, impulses, or thoughts are a product of their own mind and are not based in reality. Characteristics of compulsion include: (1) repetitive behaviors or mental actions that the person feels compelled to perform in response to an obsession, or in accordance with rules that need to be rigidly applied; (2) the behaviors or mental actions are intended to prevent or reduce agony or prevent some fearful situation or event; however, these behaviors or mental actions are not actually connected to the problem or are excessive.

[0540]Individuals with OCD typically undertake tasks (or compulsions) to seek relief from obsession-related anxiety. Repetitive behaviors such as washing hands, counting, checking, or cleaning are often performed with the hope of stopping obsessive thoughts or making them go away. Performing these "rituals", however, only provides temporary relief. People with OCD may also be diagnosed with a spectrum of other mental disorders, such as generalized anxiety disorder, anorexia nervosa, panic attack, or schizophrenia.

[0541] Dysfunction in neuronal communication is considered one of the underlying causes for obsession disorder (Myrrhe van Spronsen and Casper C. Hoogenraad, Curr. Neurol. Neurosci. Rep. 2010, 10, 207 to 214). Studies suggest that OCD may be related to abnormal levels of a neurotransmitter called serotonin. First-line treatment of OCD consists of behavioral therapy, cognitive therapy, and medications. Medications for treatment include serotonin reuptake inhibitors (SRIs) such as paroxetine (Se- Roxat™, Paxil®, Xetanor™, ParoMerck™, Rexetin™), sertraline (Zoloft®, Stimuloton™), fluoxetine (Prozac ®, Bioxetin™), escitalopram (Lexapro®) and fluvoxamine (Luvox®), as well as tricyclic antidepressants, in particular clomipramine (Anafranil®). Benzodiazepines are also used in treatment. Up to 40 to 60% of patients, however, fail to respond adequately to SRI therapy and an even greater proportion of patients fail to experience complete remission of their symptoms.

[0542] The invention provides methods and compositions for treating OCD with the use of an α5-containing GABAA receptor agonist (e.g., an α5-containing GABAA receptor positive allosteric modulator), such as that selected from the compounds or isomers, polymorphs, solvates, hydrates, pharmaceutically acceptable salts or combinations thereof, as described herein. In certain embodiments, treatment comprises preventing or slowing the progression of OCD. In certain embodiments, treatment comprises relieving, improving, or slowing the progression of one or more symptoms associated with OCD. In certain embodiments, the symptom being treated is cognitive impairment or cognitive impairment. For example, the methods and compositions of the disclosure can be used to treat cognitive deficits in OCD and/or to improve cognitive function in patients with OCD. In some embodiments of the invention, there is provided a method for preserving or enhancing cognitive function in an individual with OCD, the method comprising the step of administering to said individual a therapeutically effective amount of a compound of the invention or an isomer, polymorph. , solvate, hydrate, pharmaceutically acceptable salt or combination thereof.

[0543] A quinpirole-sensitized rat model has been developed for OCD. The compulsive checking behavior of quinpirole-sensitized rats is subject to interruption, which is a characteristic attribute of OCD compulsions. Additionally, a programming-induced polydipsia (SIP) rodent model of obsessive-compulsive disorder was used to evaluate the effects of the innovative 5-HT2C receptor agonist WAY-163909. See, for example, Rosenzweig-Lipson S. et al. Psychopharmacology (Berl) 2007, 192, 159 to 170.

[0544] The effectiveness of the methods and compositions of this invention in treating OCD, or cognitive impairment or cognitive deficits associated with OCD, can be evaluated in the above animal models and in other animal models developed for OCD, as well as human subjects with OCD , using a variety of cognitive tests known in the art, as discussed herein.

SUBSTANCE DEPENDENCE

[0545] Substance dependence (e.g., drug substance dependence, alcohol substance dependence) is a mental disorder. Addiction is not triggered instantly upon exposure to the substance of abuse. Rather, it involves multiple complex neural adaptations that develop over different time courses ranging from hours to days to months (Kauer J. A. Nat. Rev. Neurosci. 2007, 8, 844 to 858). The path to substance dependence generally begins with the voluntary use of one or more controlled substances, such as narcotics, barbiturates, methamphetamines, alcohol, nicotine, and any of a variety of other such controlled substances. Over time, with prolonged use of the controlled substance(s), the voluntary ability to abstain from the controlled substance(s) is compromised due to the effects of prolonged use about brain function and, thus, about behavior. As such, substance dependence in general is characterized by desire, seeking and compulsive use of the substance that persists even in the face of negative consequences. Cravings may represent changes in the patient's underlying neurobiology that likely need to be addressed in a meaningful way if recovery is to be achieved. Substance dependence is also characterized, in many cases, by withdrawal symptoms that, for some substances, are life-threatening (e.g., alcohol, barbiturates) and in others can result in substantial morbidity (which may include nausea, vomiting, fever, dizziness and excessive sweating), agony and decreased ability to recover. For example, alcoholism, also known as alcohol dependence, is one such substance dependence. Alcoholism is mainly characterized by four symptoms which include cravings, loss of control, physical dependence and tolerance. These symptoms may also characterize substance dependence on other controlled substances. The desire for alcohol, as well as other controlled substances, is often as strong as the need for food or water. Thus, an alcoholic may continue to drink despite serious legal, health, and/or family consequences.

[0546] Recent work exploring the effects of alcohol abuse, central stimulants, and opiates on the central nervous system (CNS) has demonstrated a variety of mental health-related adverse effects, which include substance-induced impairments in cognition. See, Nyberg F. Cognitive Impairments in Drug Addicts, chapter 9. In several laboratories and clinics, substantial impairments of brain function are observed resulting from these drugs. Among the harmful effects of alcohol abuse on the brain are those that contribute to accelerated obsolescence. One observation that has received special attention during recent years is the fact that chronic drug users exhibit considerable impairment in areas of the brain associated with memory and executive function. A notable neuroadaptation caused by addictive drugs such as alcohol, central stimulants, and opiates involves diminished neurogenesis in the subgranular zone (SGZ) of the hippocampus. In fact, it has been proposed that diminished adult neurogenesis in the SGZ could modify hippocampal function in such a way that it would contribute to relapse and sustained addictive behavior. The possibility also arises that diminished neurogenesis may contribute to the cognitive deficits produced by this drug abuse.

[0547] The invention provides methods and compositions for treating substance dependence with the use of a positive allosteric modulator of the α5-containing GABAA receptor, such as that selected from the compounds or isomers, polymorphs, solvates, hydrates, salts pharmaceutically acceptable products or combinations thereof, as described herein. In certain embodiments, treatment comprises preventing or slowing the progression of substance dependence. In certain embodiments, treatment comprises relieving, improving, or slowing the progression of one or more symptoms associated with substance dependence. In certain embodiments, the symptom being treated is cognitive impairment. For example, the methods and compositions of the disclosure can be used to treat cognitive impairment and/or to improve cognitive function in patients with substance dependence. In some embodiments of the invention, there is provided a method for preserving or enhancing cognitive function in an individual with substance dependence, the method comprising the step of administering to said individual a therapeutically effective amount of a compound of the invention or an isomer , polymorph, solvate, hydrate, pharmaceutically acceptable salt or combination thereof. Several animal models have been developed to study substance dependence. For example, the Marchigian Sardinian alcohol preference (msP) rat model was developed to study the neurobiology of alcoholism. See, Ciccocioppo R. et al. Substance addiction Biology 2006, 11, 339 to 355.

[0548] The effectiveness of the methods and compositions of this invention in treating substance dependence, or cognitive impairment associated with substance dependence, can also be evaluated in animal models of substance dependence, as well as human subjects with substance dependence, with the use of a variety of cognitive tests known in the art, as discussed herein.

RESEARCH DOMAIN CRITERIA (RDoC)

[0549] The invention further provides methods and compositions for treating deficiency in neurological disorders and neuropsychiatric conditions with the use of a positive allosteric modulator of GABAA R containing α5, or isomer, polymorph, solvate, hydrate, pharmaceutical salt acceptable or combinations thereof, as described herein. In certain embodiments, treatment comprises alleviating, improving, or slowing the progression of one or more symptoms associated with such deficiency. In another aspect of the invention, there are provided methods and compositions for preserving or improving cognitive function in an individual in need of such treatment, with the use of a compound of the invention or an isomer, polymorph, solvate, hydrate, pharmaceutical salt. acceptable or combination thereof.

[0550] Research Domain Criteria (RDoC) is expected to augment clinical criteria, such as DSM and ICD, for diagnosing disease and disorders affecting the nervous system (see, e.g., Am. J. Psychiatry 167 :7 (2010)). The RDoC is intended to provide classification based on discoveries in genomics and neuroscience as well as clinical observation. The high expression of α5-containing GABAA receptors in specific neural circuits in the nervous system could be therapeutic targets for the neural circuit dysfunction identified under RDoC.

ASSAYS FOR GABAA α5 SUBUNIT BINDING AND RECEPTOR POSITIVE ALLOSTERIC MODULATOR ACTIVITY

[0551] The affinity of test compounds for a GABAA receptor comprising the GABAA α5 subunit can be determined using receptor binding assays that are known in the art. See, for example, U.S. Patent No. 7,642,267 and U.S. Patent No. 6,743,789, which are incorporated herein by reference.

[0552] The activity of the test compounds as a positive allosteric modulator of α5-containing GABAA R can be tested using electrophysiological methods known in the art. See, for example, U.S. Patent No. 7,642,267 and Guidotti et al., Psychopharmacology 180: 191 to 205, 2005. Positive allosteric modulator activity can be tested, for example, by evaluating the conductance of GABA-induced chloride of GABAA receptors comprising the α5 subunit of GABAA. Cells expressing such receptors can be exposed to an effective amount of a compound of the invention. Such cells can be placed in vivo in contact with compounds of the invention through contact with a bodily fluid containing the compound, for example, through contact with cerebrospinal fluid. In vitro tests can be carried out by placing cells in contact with a compound of the invention in the presence of GABA. Increased GABA-induced chloride conductance in cells expressing GABAA receptors comprising the α5 subunit of GABAA in the presence of the test compound would indicate the positive allosteric modulator activity of said compound. Such changes in conductance can be detected, for example, with the use of a voltage clamp assay performed on Xenopus oocytes injected with GABAA receptor subunit mRNA (which includes GABAA α5 subunit RNA), HEK 293 cells transfected with plasmids encoding GABAA receptor subunits or cultured neurons, in vivo or ex vivo.

[0553] It will be understood by the person skilled in the art that the methods described herein may be adapted and modified as appropriate for the application being addressed and that the methods described herein may be employed in other suitable applications, and that such other additions and modifications will not deviate from the scope thereof.

[0554] This invention will be better understood from the Examples that follow. However, one skilled in the art will readily observe that the specific methods and results discussed are merely illustrative of the invention, as more fully described in the embodiments that follow hereafter. Example 1: Synthesis of Compound 1 Scheme 11.

[0555] To a stirred mixture of 5-methoxy-2-nitroaniline (5 g, 29.7 mmol) in HCl (conc. 39 ml) at 0 °C was added dropwise a solution of NaNO2 (2.05 g, 29.7 mmol) in H2O (19 ml). The internal temperature was maintained below 10 °C. After addition, the mixture was stirred at room temperature for 1 h. The diazonium salt was collected through filtration and was used in the next step. To the diazonium salt in a crystallization dish under rapid stirring at room temperature was added dropwise a solution of NaN3 (1.93 g, 29.6 mmol) in H2O (7 ml). After the gas emission stopped (3 h), it was filtered. The collected solid was recrystallized from MeOH to give 4.342 g (75% yield for 2 steps) of product 13 as a yellow solid. To a mixture of phenylazide 13 (1.94 g, 10 mmol) and diethyl 1,3-acetone dicarboxylate (2.20 ml, 12 mmol) in EtOH (40 ml) at room temperature was added Et3N (1.67 ml, 12 mmol). After the mixture was stirred at room temperature for 60 h, the initial suspension became a clear yellow solution. The solution was concentrated in vacuo and the residue was purified by chromatography (24 g RediSep silica gel column, 10% to 40% EtOAc in hexanes) to give 2.905 g of triazole 14 as a yellow solid. MS: [M+1] = 379.

[0556] The above triazole 14 (2.95 g, 7.66 mmol) in EtOH (50 ml) with Pd/C (10 wt%, 407 mg, 0.38 mmol) was stirred under H2 (flask) for 24 hours. It was filtered through Celite. The filtrate was concentrated and the residue was purified by chromatography (24 g RediSep silica gel column, 10% to 50% EtOAc in hexanes) to give 2.453 g of aniline 15 as a white solid. (70% yield for two steps) MS: [M+1] = 349.

[0557] Compound 15 (2.45 g, 7.03 mmol) and catalytic amount of p-TsOH^ H2O (24 mg) in p-xylene (30 ml) were heated in an oil bath at 140 ° C. one day to the next. The mixture was cooled and filtered. The solid was washed with cold EtOAc. After drying, 1.88 g (88% yield) of lactam 16 were generated. MS: [M+1] = 303.

[0558] To a suspension of lactam ester 16 (837 mg, 2.77 mmol) in THF (20 ml) at room temperature was added LiBH4 (2 M in THF, 1.39 ml, 2.78 mmol). After the mixture was stirred at room temperature for 60 h, more LiBH4 (2 M in THF, 0.28 ml, 0.56 mmol) was added and it was stirred at room temperature for an additional 24 h. A mixture of EtOAc/EtOH (10 ml/10 ml) was added to the reaction and it was concentrated in vacuo. The residue was taken up in EtOAc/CH2Cl2/MeOH and loose silica gel was added. After the volatile solvents were evaporated, the solid was loaded onto a 24 g RediSep silica gel column. Chromatography (solvent A: EtOAc, solvent B: 10:1 by volume CH2Cl2/MeOH; gradient eluent: A to B) generated 540 mg (75% yield) of alcohol 17 as a white solid. MS: [M+1] = 261.

[0559] To a solution of alcohol 17 (105.4 mg, 0.40 mmol) and CBR4 (336 mg, 1.01 mmol) in DMF (3 ml) was slowly added a solution of PPh3 (255 mg, 0. 97 mmol) in DMF (1 ml) for 20 min. After addition, TLC showed that the reaction was complete. Water was added to cool the reaction and the mixture was extracted with EtOAc three times. The combined extracts were washed sequentially with H2O, brine and dried with Na2SO4. Filtration and concentration generated the crude product. Chromatography (12 g RediSep silica gel column, 30% EtOAc CH2Cl2 in CH2Cl2) generated 439.2 mg of a mixture of bromide 18 ([M+1] = 324) and Ph3PO. The above mixture (439 mg) in EtOAc/EtOH (8 ml/8 ml) with Pd/C (10 wt%, 200 mg, 0.19 mmol) was stirred under H2 (flask) for 2 h, then was filtered through Celite. The filtrate was concentrated and the residue was purified by chromatography (12 g RediSep silica gel column, solvent A: 1:1 by volume CH2Cl2/hexanes, solvent B: EtOAc; gradient eluent: A to B) to give 99 mg (~80% yield for 2 steps) of product 19 as a white solid. MS: [M+1] = 245.

[0560] In a separate vial, 1,2,3-triazole (55.3 mg, 0.80 mmol) in CH3CN (1 ml) at 0 °C was treated with i-Pr2NEt (146 μl, 0.84 mmol ), followed by POCI3 (23 μl, 0.25 mmol). The solution was stirred at 0°C for 2 h. Lactam 19 was added in one batch and the resulting suspension was heated in an 80 °C oil bath for 20 h. Water was added to cool the reaction. It was extracted with EtOAc three times. The combined extracts were washed with brine and dried with Na2SO4. Filtration and concentration generated 48.8 mg of crude product 20, which was used directly in the next step. A solution of KO-t-Bu (37.2 mg, 0.33 mmol) in DMF (0.5 ml) was cooled to -50 °C. Ethyl isocyanacetate (40 μl, 0.36 mmol) was added dropwise. The mixture was stirred at -50°C for 1 h. The above crude product 20 in DMF (1 ml) was added dropwise. The mixture was allowed to warm naturally to 10°C and stirred at 10°C for 1 h. Saturated aqueous NH4Cl solution was added and it was extracted with EtOAc three times. The combined extracts were washed sequentially with water, brine and dried with Na2SO4. Filtration and concentration generated the crude product.

[0561] Chromatography (12 g silica gel column of RediSep, solvent A: 1:1 by volume CH2Cl2/hexanes, solvent B: EtOAc; gradient eluent: 20% to 80% B in A) to generate 15 mg (21% yield for 2 steps) of Compound 1 (Example 1) as an off-white solid. MS: [M+1] = 340. 1H-NMR (500 MHz, CDCl3) δ: 7.74 (s,1H), 7.63 (d, 1H, J=3Hz), 7.51 (d, 1H , J=8.5Hz), 7.14 (dd, 1H, J=3.0, 8.5Hz), 4.44 (q, 2H, J=7.0Hz), 3.95 (s, 3H) , 2.44 (s, 3H), 1.45 (t, 3H, J=7.0Hz). Example 2: Synthesis of Compound 2:

[0562] The compound of Example 2 was synthesized in a synthetic route analogous to that described for Example 1, with the use of 5-fluoro-2-nitro-aniline as the starting material to generate Compound 2 as a light brown solid : MS: [M+1] = 328. 1H-NMR (500 MHz, CDCl3) δ: 7.90 (br dd, 1H, J=2.5, 8.5Hz), 7.77 (s, 1H) , 7.62 (br dd, 1H, J=5.0, 9.0Hz), 7.35 (m, 1H), 4.45 (q, 2H, J=7.0Hz), 2.45 (s , 3H), 1.45 (t, 3H, J=7.0Hz). Example 3: Synthesis of Compound 3:

[0563] The compound of Example 3 was synthesized in a synthetic route analogous to that described for Example 1, with the use of 2-nitro-aniline as the starting material to generate Compound 3 as a light yellow solid: MS: [ M+1] = 310; 1H-NMR (500 MHz, CDCl3) δ: 8.161 (br d, 1H, J=8.5Hz), 7.81 (s, 1H), 7.66 (m, 3H), 4.45 (q, 2H , J=7.0Hz), 2.45 (s, 3H), 1.46 (t, 3H, J=7.0Hz). Example 4: Synthesis of Compound 110

[0564] Acetamide oxime was subjected to azeotropic distillation three times in toluene before use. To a suspension of acetamide oxime (30 mg, 0.4 mmol) in THF (1 ml) was added 60% NaH in an oil dispersion (16 mg, 0.4 mmol). The suspension was stirred at room temperature for 15 min. Ester compound 2 (65 mg, 0.2 mmol) was added. The vial containing the ester was rinsed with THF (1 ml), which was added to the reaction mixture. The resulting brown suspension was stirred at room temperature for 30 min, then heated to 70°C for 2 h and 30 min. The suspension was cooled with MeOH. The solvent was evaporated and the crude oil was purified by chromatography (4 g RediSep silica gel column, eluted with 70% EtOAc in hexanes) to give 28 mg (41% yield) of product. MS: [M+1] = 338. 1HNMR (CDCl3) δ: 7.92 (1H, dd, J= 2.5, 8.5 Hz), 7.90 (1H, s), 7.67 (1H , dd, J= 4.5, 9.5 Hz), 7.38 (1H, m), 2.51 (3H, s), 2.46 (3H, s). Example 5: Synthesis of Compound 167

[0565] The compound was prepared in an analogous manner from Compound 1 to generate Compound 167: MS: [M+1] = 350. 1HNMR (CDCl3) δ: 7.87 (1H, s), 7.65 ( 1H, d, J= 3 Hz), 7.55 (1H, d, J= 9 Hz), 7.17 (1H, dd, J= 2.5, 9 Hz), 3.96 (3H, s) , 2.5 (3H, s), 2.45 (3H, s). Scheme 12. Example 6: Synthesis of Compound 4:

[0566] To a solution of compound 17 prepared as in Example 1 (260 mg) in DMSO (4 ml) and CH2Cl2 (6 ml) was added Et3N (0.7 ml, 5 mmol), followed by Py«SO3 (398 mg, 2.5 mmol). It was stirred at room temperature for 1 h. The reaction mixture was poured into water and extracted with EtOAc three times. The combined extracts were washed sequentially with H2O, brine and dried with Na2SO4. Filtration and concentration generated 198.5 mg of crude aldehyde 21, which was used without further purification. To a suspension of aldehyde 21 (198.5 mg, 0.77 mmol) in THF (10 ml) at 0°C was added dropwise PhMgBr (1 M in THF, 1.54 ml, 1.54 mmol). It was stirred at 0 °C for 30 min. Saturated aqueous NH4Cl solution was added and extracted with EtOAc three times.

[0567] The combined extracts were washed with brine and dried with Na2SO4. Filtration and concentration generated 252.9 mg of benzyl alcohol 22 as a brown foamy solid. This was used in the next step without further purification. To a solution of the above crude alcohol 22 in CH2Cl2 (8 ml) with Et3SiH (0.60 ml, 3.76 mmol) was added TFA (0.64 ml, 8.27 mmol). The reaction solution was stirred at room temperature for 4 h. After concentration, the residue was purified by chromatography (12 g RediSep silica gel column, 20% to 80% EtOAc in hexanes) to generate 34.1 mg (12% yield for four steps) of the reduced product 23 as a white frothy solid. MS: [M+1] = 321.

[0568] In a separate vial, a solution of 1,2,4-triazole (27 mg, 0.39 mmol) in CH3CN (0.5 ml) at 0 °C was treated with i-Pr2NEt (72 μl, 0 .41 mmol), followed by POCl3 (11 μl, 0.12 mmol). The mixture was stirred at 0°C for 2 h. Lactam material 23 (32.2 mg, 0.1 mmol, solid) was added in one batch to the reaction mixture and was heated in an oil bath at 80 ° C for 20 h. The mixture was cooled to room temperature and a creamy solid precipitate was observed. Water (0.5 ml) was added and stirred at room temperature for 5 min. The solid precipitate was collected by filtration and washed with 0.5 ml of water, followed by drying under high vacuum to give 15.8 mg (42% yield) of adduct 24 as an off-white fluffy solid. MS: [M+1] = 372. A solution of KO-t-Bu (9.5 mg, 85 μmol) in DMF (0.5 ml) was cooled to -50 °C. Ethyl isocyanacetate (10.4 μl, 95 μmol) was added dropwise. The resulting mixture was stirred at -50°C for 1 h. Triazole amidine 24 (15.8 mg, 42 μmol, solid) was added in one batch. The stirred mixture was allowed to warm naturally to 10°C in 1 h and maintained at 10°C for 1 h. Saturated aqueous NH4Cl solution was added and it was extracted with EtOAc three times. The combined extracts were washed sequentially with H2O, brine and dried with Na2SO4. Filtration and concentration generated the crude product. Chromatography (4 g silica gel column of RediSep. Solvent A: 1:1 by volume CH2Cl2/hexanes, solvent B: EtOAc; gradient eluent: A to 50% B in A) gave 16.8 mg ( 95% yield of the compound of Example 6 as a white solid. MS: [M+1] = 416. 1H-NMR (500 MHz, CDCl3) δ: 7.74 (s,1H), 7.63 (d, 1H, J=3.0Hz), 7.50 (d , 1H, J= 9.0Hz), 7.30 (br d, 2H, J=7.0Hz), 7.29 (br d, 2H, 7.5Hz), 7.20 (m, 1H), 7 .13 (dd, 1H, J=2.5, 9.0Hz), 4.41 (q, 2H, J=7.5Hz), 4.17 (s, 2H), 3.95 (s, 3H) , 1.43 (t, 3H, 7.5 Hz). Example 7: Synthesis of Compound 5:

[0569] The compound of Example 7 was synthesized in a synthetic route analogous to that described for Example 6, with the use of 2-nitro-aniline as the starting material to generate Compound 5 as a brown solid: MS: [M +1] = 386. 1H-NMR (500 MHz, CDCl3) δ: 8.16 (br d, 1H, J=7.0Hz), 7.81 (s, 1H), 7.60-7.68 ( m, 3H), 7.34 (br d, 2H, J=8.0Hz), 7.29 (br d, 2H, J=7.0Hz), 7.20 (m,1H), 4.42 ( q, 2H, J=7.0Hz), 4.18 (s, 2H), 1.44 (t, 3H, J=7.0Hz). Example 8: Synthesis of Compound 6:

[0570] The compound of Example 8 was synthesized in a synthetic route analogous to that described for Example 6, with the use of 5-fluoro-2-nitro-aniline as the starting material to generate compound 8 as a brown solid: MS: [M+1] = 404. 1H-NMR (500 MHz, CDCl3) δ: 7.90 (dd, 1H, J=3.5, 8.5Hz), 7.77 (s, 1H), 7 .61 (dd, 1H, J=5.0, 10.5Hz), 7.28-7.37 (m, 5H), 7.21 (m, 1H), 4.43 (q, 2H, J= 7.0Hz), 4.17 (s, 2H), 1.44 (t, 3H, J=7.0Hz). Example 9: Synthesis of Compound 44:

[0571] The compound of Example 9 was synthesized in a synthetic route analogous to that described for Example 6, with the use of 5-fluoro-2-nitro-aniline as the starting material to generate the compound of Example 9 as a solid brownish: MS: [M+1] = 418. 1H-NMR (500 MHz, CDCl3) δ: 7.89 (br d, 1H, J=9.5Hz), 7.76 (s, 1H), 7, 60 (dd, 1H, J=5.5, 10.0Hz), 7.35 (br t, 1H, J=6.0Hz), 7.22 (br d, 2H, J=8.5Hz), 7 .09 (br d, 2H, J=7.5Hz), 4.43 (q, 2H, J=7.5Hz), 4.12 (s, 2H), 2.30 (s, 3H), 1, 44 (t, 3H, J=7.5Hz). Example 10: Synthesis of Compound 45:

[0572] The compound of Example 10 was synthesized in a synthetic route analogous to that described for Example 6, with the use of 5-fluoro-2-nitro-aniline as the starting material to generate the compound of Example 10 as a solid brownish: MS: [M+1] = 438. 1H-NMR (500 MHz, CDCl3) δ: 7.90 (dd, 1H, J=3.0, 8.0Hz), 7.77 (s, 1H) , 7.61 (dd, 1H, J=5.0, 9.0Hz), 7.36 (m, 1H), 7.25 (br s, 4H), 4.42 (q, 2H, J=7 .0Hz), 4.14 (s, 2H), 1.44 (t, 3H, J=7.0Hz). Example 11: Synthesis of Compound 46:

[0573] The compound of Example 11 was synthesized in a synthetic route analogous to that described for Example 6, with the use of 5-fluoro-2-nitro-aniline as the starting material to generate the compound of Example 11 as a solid yellowish: MS: [M+1] = 422. 1H-NMR (500 MHz, CDCl3) δ: 7.90 (dd, 1H, J=3.0, 8.5Hz), 7.77 (s, 1H) , 7.61 (dd, 1H, J=5.0, 9.0Hz), 7.36 (m, 1H), 7.28 (m, 2H), 6.96 (m, 2H), 4.42 (q, 2H, J=7.5Hz), 4.14 (s, 2H), 1.44 (t, 3H, J=7.0Hz). Example 12: Synthesis of Compound 47:

[0574] The compound of Example 12 was synthesized in a synthetic route analogous to that described for Example 6, with the use of 2-nitro-aniline as the starting material to generate the compound of Example 12 as a yellowish solid: MS: [M+1] = 420. 1H-NMR (500 MHz, CDCl3) δ: 8.16 (br d, 1H, J=7.0 Hz), 7.80 (s, 1H), 7.64 (m , 3H), 7.25 (m, 4H), 4.41 (q, 2H, J=7.0 Hz), 4.14 (s, 2H), 1.44 (t, 3H, J=8, 0 Hz). Example 13: Synthesis of Compound 109:

[0575] Acetamide oxime (50 mg, 0.67 mmol) was subjected to azeotropic distillation with toluene 3 times. THF (5 ml) was then added 60% NaH in oil dispersion (25 mg, 0.62 mmol). The suspension was stirred at room temperature for 30 min. 2 ml of this suspension was added to ester compound 6 (40 mg, 0.099 mmol) and the resulting solution was heated at 70 °C for 3 h. The solution was cooled with water. The solution was extracted with EtOAc (3x). The combined organic phases were washed with brine, dried over MgSO4. Filtration and concentration generated the crude product. Chromatography (12 g silica gel column of RediSep. Eluted with 50% EtOAc in hexanes) gave 6 mg (20% yield) of the product Compound 109 as a yellow solid. MS: [M+1] = 414). 1HNMR (CDCl3) δ: 7.93 (1H, dd, J= 3, 8.5 Hz), 7.89 (1H, s), 7.65 (1H, dd, J= 5.5, 9 Hz) , 7.38 (1H, m), 7.23 (5H, m), 4.2 (2H, s), 2.50 (3H, s). Example 14: Synthesis of Compound 7:

[0576] To a stirred mixture of 5-methoxy-2-nitroaniline (5 g, 29.7 mmol) in HCl (conc. 12.9 ml) at 0 °C was added dropwise a solution of NaNO2 (2.05 g, 29.7 mmol) in H2O (8 ml). The internal temperature was maintained below 5 °C. After addition, the mixture was allowed to warm naturally to room temperature in 1 h. The mixture was cooled to 0°C and a solution of SnCl2^2H2O (20.13 g, 89.2 mmol) in HCl (conc. 13 ml) was added slowly dropwise. After addition, it was stirred at room temperature for 2 h. The resulting yellow solid was collected via filtration and washed with cold 6 N HCl (0 °C). After drying in a vacuum oven, it generated 3.245 g (50% yield) of brown solid as aryl hydrazine 25. MS: [M+H2O+Na] = 224. In a separate flask, a mixture of 1.3 Diethyl-acetonedicarboxylate (2.426 g, 12 mmol) and diethoxymethyl acetate (1.946 g, 12 mmol) was heated under microwave radiation at 100 °C for 1 h. The reaction mixture was concentrated in vacuo and the residual volatile component was removed by co-distillation with toluene (5 ml) in vacuo to generate the condensation product 26, which was used directly in the next step.

[0577] Product 26 from the above was dissolved in EtOH (30 ml). Molecular sieves (4 A, 2 g) and hydrazine hydrochloride 25 (2.19 g, 10 mmol) were added. The suspension was stirred at room temperature for 24 h. It was filtered through Celite and the solid was washed with EtOAc (10 ml X 3). The filtrate was concentrated. The residue was purified by chromatography (40 g silica gel column of RediSep, 10% to 40% EtOAc in hexanes) to generate 2.091 g of pyrrole 27 which was used without further purification in the next step. MS: [M+1] = 378.

[0578] The above nitro group 27 (2.09 g, 5.5 mmol) was reduced in EtOH (40 ml) with Pd/C (10 wt%, 295 mg, 0.28 mmol) under H2 (flask) for 18 hours. The mixture was filtered through Celite. The filtrate was concentrated and the residue was purified by chromatography (24 g RediSep silica gel column, hexanes to 50% EtOAc in hexanes) to give 1.127 g of uncyclized product 28 as a sticky yellow oil ([M+ 1] = 348), plus 154 mg of cyclized product 29 as a gray solid (MS: [M+1] = 302). Uncyclized aniline 28 (1.127 g, 3.2 mmol) in p-xylene (20 ml) was treated with catalytic amount of p-TsOH^ H2O (15 mg) in an oil bath at 140 ° C for 20 h. The reaction mixture was cooled, concentrated and the residue was triturated with cold EtOAc (0 °C). Filtration yielded 559 mg of lactam product 29 as a yellow solid. The total weight of the combined lactam 29 product is 713 mg (24% for 3 steps). MS: [M+1] = 302.

[0579] To a suspension of ester 29 (566 mg, 1.88 mmol) in CH2Cl2 (35 ml) at -78 °C was added Dibal-H (1 M in hexane, 6.60 ml, 6.60 mmol) . The suspension was stirred for 10 min. at -78°C. The cold bath was removed and it was stirred for 20 min, while the temperature was raised to room temperature. At this point, TLC showed ~80% completion of the reaction. It was cooled to -78 °C and more Dibal-H (1 M in hexane, 1.0 ml, 1.0 mmol) was added. After stirring at -78 °C for 30 min, LCMS showed that the reaction proceeded to completion. The reaction was cooled by adding aqueous Rochelle saline (20%) followed by EtOAc. It was vigorously stirred at room temperature until it became a clear two-layer mixture. The layers were separated and the aqueous layer was extracted with EtOAc three times. The combined organic phase was washed with brine and dried over Na2SO4. Filtration and concentration gave 480 mg of crude alcohol 30 as a slightly yellow solid. MS: [M+1] = 260.

[0580] To a solution of alcohol 30 (200 mg, 0.77 mmol) and CBR4 (640 mg, 1.93 mmol) in DMF (8 ml) was added a solution of PPh3 (486 mg, 1.85 mmol) in DMF (2 ml) slowly over 30 min. After addition, it was stirred at room temperature for 30 min. Water was added to cool the reaction and the mixture was extracted with EtOAc three times. The combined extracts were washed sequentially with H2O, brine and dried with Na2SO4. Filtration and concentration generated the crude product. Chromatography (12g silica gel column of RediSep, solvent A: 1:1 by volume CH2Cl2/hexanes, solvent B: EtOAc; gradient eluent: 10% to 40% B in A) generated 221 mg of a mixture of bromide 31 and Ph3PO.

[0581] The above mixture in EtOAc/EtOH (8 ml/8 ml) with Pd/C (10% by weight, 200 mg, 0.19 mmol) was stirred under H2 (flask) for 1 h. It was filtered through Celite. The filtrate was concentrated and the residue was purified by chromatography (12 g RediSep silica gel column, solvent A: 1:1 by volume CH2Cl2/hexanes, solvent B: EtOAc; gradient eluent: 10% a 40% B in A) to generate 146 mg of a mixture of reduction product 32 ([M+1] = 244) and Ph3PO.

[0582] In a separate vial, 1,2,4-triazole (81 mg, 1.17 mmol) in CH3CN (1 ml) at 0 °C was treated with i-Pr2NEt (214 μl, 1.23 mmol), followed by POCI3 (34μl, 0.36 mmol). The solution was stirred at 0°C for 2 h. Lactam 32 (~60% purity by LCMS) was added in one batch and the resulting suspension was heated in an 80 °C oil bath for 18 h. Water was added to cool the reaction. It was extracted with EtOAc three times. The combined extracts were washed sequentially with H2O, brine and dried with Na2SO4. Filtration and concentration generated 126.6 mg of crude product 33 as a yellow glue, which was used directly in the next reaction. MS: [M+1] = 295. A solution of KO-t-Bu (97 mg, 0.86 mmol) in DMF (1 ml) was cooled to -50 °C. Ethyl isocyanacetate (104μl, 0.95 mmol) was added dropwise. The mixture was stirred at -50°C for 1 h. The above crude product 33 in DMF (1.5 ml) was added dropwise. The mixture was allowed to warm naturally to 10°C and stirred at 10°C for 1 h. Saturated aqueous NH4Cl solution was added and it was extracted with EtO-Ac three times. The combined extracts were washed sequentially with water, brine and dried with Na2SO4. Filtration and concentration generated the crude product. Chromatography (12g silica gel column of RediSep, solvent A: 1:1 by volume CH2Cl2/hexanes, solvent B: EtOAc; gradient eluent: 10% to 40% B in A) to generate 22 mg of a white solid, which was further purified by preparatory TLC (developed with 1:1 A/B) to generate 12.8 mg of the final product Compound 7 (Example 14) as a white solid. MS: [M+1] = 339. 1H-NMR (500 MHz, CDCl3) δ: 7.70 (s, 1H), 7.56 (s, 1H), 7.50 (d, 1H, J=3 ,0Hz), 7.43 (d, 1H, J=8.5Hz), 7.00 (dd, 1H, J=2.5, 9.5Hz), 5.29 (br s, 1H), 4, 44 (q, 2H, J=7.0Hz), 3.92 (s, 3H), 3.55 (br s, 1H), 2.17 (s, 3H), 1.45 (t, 3H, J =7.0Hz). Example 15: Synthesis of Compound 8: Scheme 14.

[0583] To a solution of alcohol 30 (261 mg, 1.0 mmol) that was prepared in Example 14 in DMSO (4 ml) and CH2Cl2 (6 ml) was added Et3N (0.7 ml, 5 mmol), followed by of Py» SO3 (398 mg, 2.5 mmol). It was stirred at room temperature for 1 h. The reaction mixture was poured into water and extracted with EtOAc three times. The combined extracts were washed sequentially with H2O, brine and dried with Na2SO4. Filtration and concentration gave 226 mg of crude aldehyde 34 as a yellow solid. This was used in the next step without further purification. MS: [M+1] = 258.

[0584] To a suspension of crude aldehyde 34 (202 mg, 0.79 mmol) in THF (10 ml) at 0 °C was added dropwise PhMgBr (1 M in THF, 1.58 ml, 1.58 mmol) . It was stirred at 0 °C for 30 min. Saturated aqueous NH4Cl solution was added and extracted with EtOAc three times. The combined extracts were washed with brine and dried with Na2SO4. Filtration and concentration gave 275 mg of crude product 35 as a yellow foamy solid, which was used in the next step without purification.

[0585] To a solution of the above crude alcohol 35 in CH2Cl2 (10 ml) with Et3SiH (0.66 ml, 4.10 mmol) was added TFA (0.70 ml, 9.02 mmol). The reaction solution was stirred at room temperature for 1 h. After concentration, the residue was purified by chromatography (24 g RediSep silica gel column, 10% to 50% EtOAc in hexanes) to generate 187.8 mg (59% yield for three steps) of product 36 as a gray solid. MS: [M+1] = 320.

[0586] In a separate vial, a solution of 1,2,4-triazole (127 mg, 1.83 mmol) in CH3CN (1.6 ml) at 0 °C was treated with i-Pr2NEt (336 μl, 1 .93 mmol), followed by POCl3 (53μl, 0.56 mmol). The mixture was stirred at 0°C for 2 h. Lactam 36 (150 mg, 0.47 mmol, solid) was added in one batch to the reaction mixture and heated in an oil bath at 80 ° C for 18 h. The mixture was cooled to room temperature and the solid precipitate was observed. Water (2.1 ml) was added and it was stirred at room temperature for 10 min. Filtration, washing the solid with 2 ml of water, followed by drying under high vacuum gave 118.8 mg (69% yield) of the triazole amidine 37 as an off-white fluffy solid. MS: [M+1] = 371. A solution of KO-t-Bu (72 mg, 0.64 mmol) in DMF (2 ml) was cooled to -50 °C. Ethyl isocyanacetate (77 μl, 0.71 mol) was added dropwise. The resulting mixture was stirred at -50°C for 1 h. Triazole amidine 37 (118.8 mg, 42 μmol, solid) was added in batch. The stirred mixture was allowed to warm naturally to 10°C in 1 h and maintained at 10°C for 1 h. Saturated aqueous NH4Cl solution was added and it was extracted with EtOAc three times. The combined extracts were washed sequentially with H2O, brine and dried with Na2SO4. Filtration, concentration, then chromatography (12 g silica gel column of RediSep. solvent A: 1:1 by volume CH2Cl2/hexanes, solvent B: EtOAc; gradient eluent: A to 40% B in A) gave 125.1 mg (94% yield) of Compound 8 as a white solid. MS: [M+1] = 415. 1H-NMR (500 MHz; CDCl3) δ: 7.72 (s, 1H), 7.54 (s, 1H), 7.51 (br s,1H), 7 .44 (br d, 1H, J=9.5Hz), 7.29 (br d, 2H, J=7.5Hz), 7.20 (m, 3H), 7.01 (br d, 1H, J =7.5Hz), 5.30 (br s, 1H), 4.38 (q, 2H, J=7.0Hz), 3.92 (br s, 5H), 3.54 (br s, 1H) , 1.41 (t, 3H, J=7.0Hz). Example 16: Synthesis of Compound 9: Scheme 15.

[0587] LiOH (1.09 g, 45.5 mmol) was added to a stirring solution of ester 16 (prepared in Example 1) (2.75 g, 9.10 mmol) in THF (24 ml) and water ( 20 ml) at room temperature. MeOH (4 ml) was added and stirring continued for 2 h at room temperature, at which point LCMS indicated complete consumption of the ester. Under concentration in vacuum, the reaction mixture was acidified to pH 3 to 4 by adding 2N HCl (20 ml). After 20 min of stirring, the reaction mixture was cooled to 0 °C, a solid precipitate was collected by filtration, washed with 3 to 4 ml of water and dried to yield 1.59 g (64%) of the acid. corresponding 38 as a grayish solid. MS: [M+1] = 275. To acid 38 (1.59 g, 5.8 mmol) suspended and stirred in DCM (30 ml) was added EDC (5.6 g, 29.2 mmol), benzyl alcohol (2.5 g, 23.2 mmol) and DMAP (3.54 g, 29.2 mmol). After 3 days of stirring at room temperature, the reaction was concentrated in vacuo. Water (80 ml) was added to the slurry, followed by diethyl ether (40 ml) and the mixture was stirred vigorously for 40 min, at which point the slurry became a precipitate and was collected via suction filtration. . The solid was washed with water and a small amount of diethyl ether and dried to give 1.65 g (78%) of benzyl ester 39 as a white solid. MS: [M+1] = 365.

[0588] The compound 1,2,4-triazole (1.22 g, 17.7 mmol) in CH3CN (15 ml) at 0 °C was treated with i-Pr2NEt (3.24 ml, 18.6 mmol) , followed by POCl3 (0.507 ml, 5.44 mmol). The solution was stirred at 0°C for 2 h. Benzyl ester 39 (1.65 g, 4.53 mmol) was added in batch and the resulting suspension was heated in an oil bath at 80 °C for 18 h. LCMS showed that 5 to 10% of starting lactam remained. In a separate vial, 1,2,4-triazole (307 mg, total 4.9 eq.) in CH3CN (3.8 ml) was treated with i-Pr2NEt (0.82 ml, total 5.1 eq. .) and POCl3 (0.127 ml; total 1.5 eq.) at 0 °C for 2 h. The resulting clear solution was transferred to the above reaction mixture. After heating for 2 h at 80 °C, the reaction was cooled to room temperature, water was added slowly to cool the reaction (10 min.). Upon cooling in an ice bath, the solids formed were collected by filtration, washed with water (5 ml) and dried to give 1.61 g (86%) of product 40 as a slightly yellow solid. MS: [M+1] = 416.

[0589] A solution of KO-t-Bu (0.739 g, 6.59 mmol) in DMF (11 ml) was cooled to -50 °C. Ethyl isocyanacetate (0.810Dml, 7.00 mmol) was added dropwise. The mixture was stirred at -50°C for 1 h. The above triazole intermediate 40 (1.61 g, 3.87 mmol) was added. The mixture was stirred at -50°C for 30 min. and slowly allowed to warm naturally to room temperature over 4 to 5 h. Saturated aqueous NH4Cl solution (10 ml) was added, followed by EtOAc (10 ml). The mixture was subjected to sonication to break down solid blocks, then stirred gently for 30 min. The precipitate was collected by filtration, washed with water, Et2O and dried to give the crude product as a white solid. The filtrate was partitioned between water and EtOAc; the aqueous layer was separated and extracted with EtOAc twice; the combined EtOAc layer was washed with brine and dried with MgSO4. Filtration and solvent removal generated a solid residue that was combined with the solid obtained above for chromatographic purification, using a 24 g RediSep silica gel column and gradient elution with 0.5 to 5% MeOH in DCM, to generate 1.78 g (100%) of imidazole 41 as a white solid. MS: [M+1] = 460. Benzyl ester 41 (1.78 g, 3.87 mmol) was subjected to hydrogenolysis (hydrogen balloon) in the presence of a catalytic amount of 10% Pd on charcoal in a mixture of THF (40 ml), MeOH (20 ml) and EtOAc (20 ml) solvents for 20 h. LCMS showed complete disappearance of the starting material. The solid catalyst was removed by Celite filtration and rinsed repeatedly with a sufficient amount of 30% MeOH in DCM until almost all products were recovered (TLC monitoring). The filtrate containing the product was concentrated in vacuo to give 1.22 g (85%) of acidic product 42 which was obtained as a yellowish solid. MS: [M+1] = 370.

[0590] To acid 42 (1.22 g, 3.30 mmol) suspended and stirred in THF (25 ml) at 0 °C was added the borane dimethylsulfide complex (2M THF; 19 ml, 38 mmol) by drip. The ice bath was removed and the reaction mixture was stirred at room temperature for 16 h. Under cooling in an ice bath, the reaction was carefully cooled with MeOH (20 ml) and then stirred at room temperature overnight. Solvents were removed in vacuo. MeOH was added and removed in vacuum twice more. Purification by ISCO (24 g RediSep column) using a gradient of 1 to 8% MeOH in DCM gave 0.625 g (53%) of alcohol product 43 as a white solid. MS: [M+1] = 356.

[0591] Diisopropyl azodicarboxylate (48.3 mg, 0.233 mmol) was added dropwise into a stirring solution of alcohol 43 (37.5 mg, 0.106 mmol), phenol (14.9 mg, 0.158 mmol) and Ph3P (55 .6 mg, 0.212 mmol) in anhydrous THF (0.8 ml) at 0 °C. The ice bath was removed and stirring continued at room temperature for 16 h. LCMS showed complete disappearance of the starting alcohol. The reaction mixture was partitioned between sat. NaHCO3 and EtOAc. The organic layer was separated and washed with water, brine and dried over MgSO4. The desired product was isolated from the reaction mixture by two consecutive preparatory TLC (4% MeOH in DCM and hexanes/EtOAc/MeOH = 47.5 / 47.5 / 5, by volume) to give 5.3 mg ( 12%) product which is Compound 9 as a white solid. MS: [M+1] = 432. 1H-NMR (500 MHz, CDCl3) δ: 7.77 (s, 1H), 7.63 (d, 1H, J=3.5 Hz), 7.53 ( d, 1H, J=9.0 Hz), 7.31 (m, 2H), 7.17 (dd, 1H, J=3.0, 8.5 Hz), 7.08 (d, 2H, J =7.0 Hz), 6.99 (t, 1H, J=6.5 Hz), 5.30 (s, 2H), 4.40 (q, 2H, J=7.0 Hz), 3, 96 (s, 3H), 1.38 (t, 3H, J=7.0 Hz). Example 17: Synthesis of Compound 10:

[0592] The compound of Example 17 was synthesized in a synthetic route analogous to that described for Example 16, with the use of 4-fluoro-phenol in the last step to generate Compound 10 (4.9 mg) as a white solid: MS: [M+1] = 450. 1H- NMR (500 MHz, CDCl3) δ: 7.76 (s, 1H), 7.64 (d, 1H, J=3.5 Hz), 7.53 ( d, 1H, J=8.0Hz), 7.17 (dd, 1H, J=2.5, 8.0Hz), 7.01 (m, 4H), 5.26 (s, 2H), 4 .40 (q, 2H, J=7.0Hz), 3.96 (s, 3H), 1.40 (t, 3H, J=7.0Hz). Example 18: Synthesis of Compound 11:

[0593] The compound of Example 18 was synthesized in a synthetic route analogous to that described for Example 16, with the use of 3-methoxy-phenol in the last step to generate Compound 11 (6.1 mg) as a white solid: MS: [M+1] = 462. 1H- NMR (500 MHz, CDCl3) δ: 7.76 (s, 1H), 7.63 (d, 1H, J=2.5 Hz), 7.53 ( d, 1H, J=9.0Hz), 7.15-7.22 (m, 2H), 6.67 (m, 2H), 6.55 (br dd, 1H, J=2.5, 8, 0 Hz), 5.28 (s, 2H), 4.39 (q, 2H, J=7.0 Hz), 3.96 (s, 3H), 3.81 (s, 3H), 1.39 (t, 3H, J=7.0 Hz). Example 19: Synthesis of Compound 12:

[0594] The compound of Example 19 was synthesized in a synthetic route analogous to that described for Example 16, with the use of 2,4-dimethylphenol in the last step to generate Compound 12 (3.1 mg) as a white solid: MS: [M+1] = 460. 1H- NMR (500 MHz, CDCl3) δ: 7.76 (s, 1H), 7.65 (d, 1H, J=3.0Hz), 7.53 (d , 1H, J=9.0 Hz), 7.17 (dd, 1H, J=2.5, 8.5 Hz), 6.98 (m, 3H), 5.26 (s, 2H), 4 .37 (q, 2H, J=7.0 Hz), 3.96 (s, 3H), 2.26 (s, 3H), 2.20 (s, 3H), 1.36 (t, 3H, J=7.0Hz). Example 20: Synthesis of Compound 107:

[0595] To a solution of alcohol 43 in which X = F (prepared in a manner identical to the example in which X = OCH3) (60 mg, 0.17 mmol) in THF (0.8 ml) was added phenol (30 mg, 0.32 mmol), triphenylphosphine (84 mg, 0.32 mmol). The reaction mixture was stirred at room temperature for 15 min. It was then cooled with an ice bath and DIAD (64 μl, 0.32 mmol) in THF (0.2 ml) was added slowly. The ice bath was removed and the reaction mixture was stirred at room temperature for 18 h. LCMS also indicated the presence of some starting material. Phenol (10 mg), triphenylphosphine (28 mg), and DIAD (21 μl) were added to the reaction mixture and stirred for another hour. The solvent was evaporated and the crude material was purified by chromatography (12g RediSep silica gel column. Elution solvent: EtOAc) and prep TLC (elution solvent: 5% MeOH/47.5% EtOAc/47 .5% hexanes) to generate 11.4 mg (16% yield) of the product Compound 107. [M+1] = 421). 1HNMR (CDCl3) δ 7.92 (1H, dd, J= 3.5, 8.5 Hz), 7.80 (1H, s), 7.63 (1H, dd, J= 5, 10 Hz), 7.38 (1H, m), 7.31 (2H, t, J= 8.5 Hz), 7.07 (2H, d, J= 8.5 Hz), 7.00 (1H, t, J = 8.5 Hz), 5.3 (2H, s), 4.39 (2H, q, J= 7 Hz), 1.38 (3H, t, J= 7 Hz). Example 21: Synthesis of Compound 111:

[0596] To a suspension of alcohol 43 (X = Me) (160 mg, 0.47 mmol) in acetonitrile (9 ml) was added POBR3 (405 mg, 1.41 mmol). The reaction mixture was heated at 80 °C for 5 h. The reaction mixture was cooled with an ice bath and sat. NaHCO3 solution. aq. was added. The resulting solution was extracted with DCM (3X). The combined organic phases were washed with brine and dried over MgSO4. The solvent was concentrated to give the desired product, 166 mg, 88% yield, [M+1] = 403).

[0597] To a suspension of the above alkyl bromide derivative (30 mg, 0.075 mmol) in deoxygenated DME (2.7 ml) was added 3-pyridine boronic acid (14 mg, 0.11 mmol) and a 2M solution of Na2CO3 (0.22 ml, 0.44 mmol). The suspension was stirred at room temperature for 5 min, then PdCl2(PPh3)2 (10 mg, 0.015 mmol) was added. The suspension was heated in one MW at 85 °C for 1 hour. The reaction mixture was cooled and diluted with water and extracted with EtOAc (twice). The combined extracts were washed with brine and dried with MgSO4. Filtration and concentration generated the crude product which was purified by 2 prep TLC (elution system: 3% MeOH in DCM) to generate 5.3 mg (18% yield) of the product Compound 111. MS: [M+1 ]= 401. 1HNMR (CDCl3) δ 8.66 (1H, bs), 8.48 (1H, bs), 7.96 (1H, s), 7.79 (1H, s), 7.66 (1H , d, J= 8 Hz), 7.50 (1H, d, J= 8 Hz), 7.43 (1H, d, J= 7 Hz), 7.23 (1H, m), 4.42 ( 2H, q, J= 7 Hz), 4.18 (2H, s), 2.54 (3H, s), 1.44 (3H, t, J= 7Hz). Example 22: Synthesis of Compound 48: Scheme 16.

[0598] To alcohol 43 (186 mg, 0.523 mmol) stirring in DMSO (1 ml) and dichloromethane (2.5 ml) at room temperature was added triethylamine (0.394 ml, 2.82 mmol) and trioxide complex of pyridine sulfur (225 mg, 1.41 mmol). After 3 h of stirring, the reaction was cooled with water (5 ml) and extracted with ethyl acetate three times. The combined organic solution was washed with water, brine and dried over MgSO4. The aldehyde product 57 was isolated by ISCO fast column chromatography (4g RediSep column) using a gradient elution of 0.5 to 8% MeOH in DCM. 84.4 mg (46%) was obtained as a yellowish foamy solid. MS: [M+1] = 354.

[0599] To a stirring solution of aldehyde 57 (15.5 mg, 0.0439 mmol) in 1,2-dichloroethane (0.3 ml) at room temperature was added pyrrolidine (5.5 ul, 0.0658 mmol ). After 2 min. After stirring, the solution became clear and NaBH(OAc)3 (14.4 mg) was added. The reaction mixture was stirred for 4 h and cooled with saturated NaHCO3 and extracted with ethyl acetate three times. The combined organic layer was washed with water, brine and dried over Na2SO4. Prep TLC with 10% MeOH in DCM gave 13.1 mg (73%) of the desired Compound 48 as a clear membranous solid. MS: [M+1] = 409. 1H-NMR (500 MHz, CDCl3) δ: 7.74 (s, 1H), 7.62 (d, 1H, J=3.0Hz), 7.51 (d , 1H, J=9.0Hz), 7.14 (dd, 1H, J=3.5, 9.0Hz), 4.42 (q, 2H, J=6.5Hz), 3.94 (s, 3H), 3.87 (br s, 2H), 2.65 (br s, 4H), 1.79 (br s, 4H), 1.44 (t, 3H, J=7.0Hz). Example 23: Synthesis of Compound 49:

[0600] The compound of Example 23 was synthesized in a synthetic route analogous to that described for Example 22, with the use of morpholine in the last step to generate the compound of Example 23 as a transparent membranous solid: MS: [M+1] = 425. 1H-NMR (500MHz, CDCl3) δ: 7.75 (s, 1H), 7.63 (d, 1H, J=3.0 Hz), 7.52 (d, 1H, J=9, 5 Hz), 7.15 (dd, 1H, J=3.0, 9.0 Hz), 4.42 (q, 2H, J=7.5 Hz), 3.95 (s, 3H), 3 .76 (br s, 2H), 3.71 (br s, 4H), 2.57 (br s, 4H), 1.44 (t, 3H, J=8.0 Hz). Example 24: Synthesis of Compound 50:

[0601] The compound of Example 24 was synthesized in a synthetic route analogous to that described for Example 22, with the use of diethylamine in the last step to generate the compound of Example 24 as a transparent membranous solid: MS: [M+1] = 411. 1H-NMR (500 MHz, CDCl3) δ: 7.74 (s, 1H), 7.64 (br d, 1H, J=3.0 Hz), 7.51 (d, 1H, J= 9.0Hz), 7.15 (dd, 1H, J=2.5, 9.0Hz), 4.43 (q, 2H, J=6.5Hz), 3.96 (s, 3H), 3.86 (br s, 2H), 2.64 (br s, 4H), 1.44 (t, 3H, J=8.5 Hz), 1.15 (br s, 6H). Example 25: Synthesis of Compound 51:

[0602] The compound of Example 25 was synthesized in a synthetic route analogous to that described for Example 22, with the use of methyl benzyl amine in the last step to generate the compound of Example 25 as a transparent membranous solid: MS: [M+ 1] = 459. 1H-NMR (500 MHz, CDCl3) δ: 7.75 (s, 1H), 7.63 (d, 1H, J=3.0 Hz), 7.51 (d, 1H, J =8.5 Hz), 7.36 (br d, 2H, J=8.0 Hz), 7.30 (m, 2H), 7.23 (m, 1H), 7.15 (dd, 1H, J=3.0, 9.0 Hz), 4.38 (q, 2H, J=7.5 Hz), 3.95 (s, 3H), 3.85 (br s, 2H), 3.63 (br s, 2H), 2.25 (s, 3H), 1.41 (t, 3H, J=7.0 Hz). Example 26: Synthesis of Compound 170:

[0603] Isobutyramidoxime (41.8 mg, 0.41 mmol) and ester 48 (27.9 mg, 0.0683 mmol) in a round bottom flask was subjected to azeotropic distillation in toluene in a Rotavap several times, suspended in Anhydrous THF (0.6 ml) and then cooled to 0 °C. NaH (60% oil suspensions; 10.9 mg, 0.273 mmol) was added. The ice bath was removed and the reaction mixture was stirred at RT for 20 min. before being heated at 70 °C for 6 h and cooled. Water (4 ml) was added and the mixture was extracted with EtOAc three times. The combined organic solution was washed with brine and dried over MgSO4. Prep. TLC with 10% MeOH in EtOAc gave 10.4 mg (34%) of the desired product Compound 170 as a clear membranous solid. MS: [M+1] = 447. Example 27: Synthesis of Compound 52: Scheme 17.

[0604] Starting alcohol 43 (160 mg, 0.45 mmol) was treated with phosphorous oxide tribromide (400 mg, 1.4 mmol) in acetonitrile (10 ml) at 80 ° C for 5 h. The reaction was cooled to 0 °C, quenched with sat. NaHCO3 and extracted with dichloromethane twice. The combined dichloromethane solution was washed with brine and dried over MgSO4. Vacuum filtration and solvent removal generated 173.3 mg (92%) of the bromide as a yellowish foamy solvent. MS: [M+1] =418.

[0605] To a suspension of bromide (55 mg, 0.131 mmol) in dimethoxyethane (2 ml; degassed) was added 2M Na2CO3 (0.39 ml, 0.78 mmol) and 3-chlorophenyl boronic acid (42.2 mg , 0.27 mmol). The reaction mixture was stirred at room temperature for 2 min, then Pd(PPh3)4 (75 mg, 0.065 mmol) was added and the suspension was heated in an oil bath at 80 °C for 90 min. Under cooling, the reaction mixture was diluted with EtOAc and washed with brine. The aqueous layer was separated and extracted with EtOAc three times. All organic layers were combined and dried with Na2SO4, then filtered and the solvent was removed in vacuo. The product was isolated through successive prep TLC purifications, using 20% hexanes in EtOAc followed by 5% MeOH in DCM. 9.6 mg of product (Compound 52) was obtained as a brownish solid. MS: [M+1] = 450. 1H-NMR (500 MHz, CDCl3) δ: 7.75 (s, 1H), 7.64 (d, 1H, J=3.0 Hz), 7.51 ( d, 1H, J=9.5 Hz), 7.31 (br s, 1H), 7.23 (br s, 1H), 7.17 (m, 3H), 4.43 (q, 2H, J =7.0Hz), 4.15 (s, 2H), 3.96 (s, 3H), 1.44 (t, 3H, J=8.0Hz). Example 28: Synthesis of Compound 53:

[0606] The compound of Example 28 was synthesized in a synthetic route analogous to that described for Example 27, with the use of 3-cyanophenyl boronic acid in the last step to generate the compound of Example 28 as a brownish solid: MS: [M +1] = 441. 1H-NMR (500 MHz, CDCl3) δ: 7.75 (s, 1H), 7.66 (br s, 1H), 7.64 (d, 1H, J=3.0 Hz ), 7.61 (br d, 1H, J=7.5 Hz), 7.39 (t, 1H, J=7.5 Hz), 7.16 (dd, 1H, J=3.5, 9 .5 Hz), 4.45 (q, 2H, J=7.0H), 4.20 (s, 2H), 3.96 (s, 3H), 1.45 (t, 3H, J=7, 0 Hz). Example 29: Synthesis of Compound 54:

[0607] The compound of Example 29 was synthesized in a synthetic route analogous to that described for Example 27, starting with the alcohol in which R1 = methyl and with the use of 2-chlorophenyl boronic acid in the last step to generate the compound of Example 29 as a brownish solid: MS: [M+1] = 434. Example 30: Synthesis of Compound 101:

[0608] The compound of Example 30 was synthesized in a synthetic route analogous to that described for Example 27, starting with the alcohol in which R1 = methyl and with the use of phenylboronic acid in the last step to generate the compound of Example 30 as a brownish solid product that was purified by chromatography (4 g RediSep silica gel column. Elution solvent: EtOAc) then a TLC prep (elution system: 40% DCM/40% hexanes/17% EtOAc / 3% MeOH) to generate 5.9 mg (31% yield) of the product Compound 101. MS: [M+1]= 402. 1HNMR (CDCl3) δ 7.96 (1H, s), 7.77 (1H, s), 7.55 (1H, m), 7.47 (1H, m), 7.32 (5H, m), 4.41 (2H, q, J= 7 Hz), 4.17 (2H, s), 2.53 (3H, s), 1.43 (3H, t, J= 7 Hz). Example 31: Synthesis of Compound 102:

[0609] To a suspension of the bromide in EtOAc (2 ml) and MeOH (2 ml) 10% activated Pd/C (5 mg) was added. The suspension was stirred under a hydrogen atmosphere for 48 h. The solution was filtered through celite. The filtrate was concentrated and purified by chromatography (4 g RediSep silica gel column. Elution solvent: EtOAc) to give 15.9 mg (33%) of the desired product Compound 102. MS: [M+1] = 324. 1HNMR (CDCl3) δ 7.96 (1H, s), 7.78 (1H, s), 7.49 (1H, d, J= 9 Hz), 7.42 (1H, d, J= 8 Hz), 4.43 (2H, q, J= 7.5 Hz), 2.53 (3H, s), 2.44 (3H, s), 1.45 (3H, t, J= 7.5 Hz). Example 32: Synthesis of Compound 108:

[0610] To a suspension of the bromide derivative in which R1 = OMe, (18 mg; 0.043 mmol) in deoxygenated DME (2 ml) was added 2-chlorophenyl boronic acid (10 mg, 0.065 mmol) and a 2 M solution of Na2CO3 (0.13 ml, 0.26 mmol). The suspension was stirred at room temperature for 15 min, then PdCl2dppf (7 mg, 0.009 mmol) was added. The suspension was heated in an oil bath at 85 °C for 1 hour. The reaction mixture was diluted with water and extracted with EtOAc (twice). The combined extracts were washed with brine and dried with Na2SO4. Filtration and concentration generated the crude product which was purified by PrepTLC (elution system: 5% MeOH/47.5% Hex/47.5% EtOAc) to generate 3.5 mg (18% yield) of the product Compound 108. MS: [M+1]= 451. 1HNMR (CDCl3) δ 7.77 (1H, s), 7.63 (1H, d, J= 3 Hz), 7.52 (1H, d, J= 11.5 Hz), 7.36 (1H, m), 7.31 (1H, m), 7.18 (2H, m), 7.14 (1H, dd, J= 3.9 Hz) , 4.38 (2H, q, J= 7 Hz), 4.27 (2H, s), 3.94 (3H, s), 1.41 (3H, t, J= 7 Hz). Scheme 18a. Scheme 18b. Example 33: Synthesis of Compound 55:

[0611] To a solution of compound 58 (6.6 g, 33.5 mmol) in dichloromethane (100 ml) were added DIPEA (8.65 g, 67 mmol), HOBt (5.4 g, 36.85 mmol ) and EDCI (9.6 g, 50.3 mmol). After about 15 min. stirring, to the homogeneous reaction mixture was added a solution of 2,4-dimethoxybenzyl amine (5.6 g, 33.5 mmol) in dichloromethane (50 ml) dropwise under nitrogen atmosphere. The resulting mixture was stirred under a nitrogen atmosphere at room temperature for 16 h. The reaction mixture was washed successively with 1 N NaOH (100 ml), water (100 ml) and brine (100 ml). The organic phase was then dried with Na2SO4 and evaporated to give a crude solid product 59 which crystallized from ethyl ether. Filtration and drying by open air suction yielded a pure off-white solid product 9.8 g (96%), (MS: [M+1] = 347).

[0612] To a solution of compound 59 (9.8 g, 28.3 mmol) in MeOH/EtOAc (1:1, 100 ml) was added 10% wet Pd-C (1.8 g, 10% mmol ). After three consecutive vacuum treatments and nitrogen washing, the heterogeneous reaction mixture was subjected to balloon hydrogenation at atmospheric pressure until hydrogen absorption ceased, about 4 h. The reaction mixture was filtered through a celite block and evaporated to yield the pure desired product 60 as a brown oil 8.63g (96%), (MS: [M+1 = 317]). This product was used directly in the next step.

[0613] To a solution of compound 60 (8.63 g, 27.3 mmol) in dichloromethane (100 ml) was added triethylamine (5.5 g, 54.6 mmol). The mixture was cooled with an ice bath and treated with bromine acetyl chloride (5.2 g, 32.76 mmol) under a nitrogen atmosphere. The ice bath was removed and the mixture left to stir for 18 h. The reaction mixture was washed successively with saturated NaHCO3 (100 ml), water (100 ml) and brine (100 ml). The organic phase was then dried with Na2SO4 and evaporated to give a crude solid product 61. The crude product was crystallized from methanol, filtered and dried to give a pure brown solid product 10.3 g (87%), [ MS: 439].

[0614] To a solution of compound 61 (10 g, 22.9 mmol) in DMF (1,000 ml) was added K2CO3 (4.8 g, 45.8 mmol). The mixture was heated at 50°C for 24 h. LCMS showed complete conversion to the desired product. The mixture was cooled to room temperature and the inorganic solid was filtered. The solvent was removed under high vacuum. The resulting crude product 62 was crystallized from methanol, filtered and dried to give a pure brown solid product 6.4g (78%), (MS: [M+1] = 357).

[0615] To compound 62 (4.46 g, 12.52 mmol) dissolved in 2.5:1 THF/DMF (50 ml) at -20 °C was added t-BuOK (97%, 1.88 g , 16.28 mmol). The mixture was allowed to warm naturally to 25°C and, after stirring for 30 min, was cooled again to -20°C. After the dropwise addition of diethyl chlorophosphate (2.35 ml, 16.28 mmol), the mixture was stirred for 3 h while allowed to warm naturally from -20 to 25 °C. The reaction mixture was cooled again to 0 °C and ethyl isocyanacetate (1.92 ml, 17.53 mmol) was added to it. Subsequent cooling to -78 °C was followed by addition of t-BuOK (97%, 1.88 g, 16.28 mmol) and stirring at RT for 5 h. Progress was monitored by LC/MS. The reaction was cooled by addition of 1:1 saturated NaHCO3/H2O (140 ml), the precipitate was filtered, washed with H2O and air-dried overnight to yield 4.81 g (85%) of derivative of imidazole 63 as a yellow solid (MS: [M+1] = 452).

[0616] To compound 63 (4.81 g, 10.65 mmol) in dichloromethane (35 ml) at 0 °C was added trifluoroacetic acid (35 ml) followed by dripping trifluoromethane sulfonic acid (1.9 ml, 21.31 mmol). The mixture was allowed to warm naturally to RT, stirred for 2 h, then concentrated to give a residue which was dissolved in dichloromethane (120 ml). The crude solution was partitioned between cooled saturated NaHCO3 and dichloromethane. The organic extractions were combined, dried (MgSO4), filtered and concentrated to produce 3.2 g (99%) of deprotected product 64 (brown solid) of sufficient purity to undergo the next step (MS: [M+1] = 302).

[0617] To lactam 64 (51.8 mg, 0.172 mmol) and N,N-dimethyl-p-toluidine (93.0 mg, 0.688 mmol) stirring in chlorobenzene (1 ml) under nitrogen was added POCl3 (52. 7 mg, 0.344 mmol). The reaction was then heated to 135 °C for 2 h. Upon cooling to room temperature, phenoxy acetic acid hydrazide (228.4 mg, 1.36 mmol) was added in situ to imino-chloride 65, followed by DIPEA (90 µl). The reaction was stirred at room temperature for 30 min, then heated to 100 °C for 90 min. The reaction mixture was cooled, saturated NaHCO3 (aq.) was added and extracted with ethyl acetate three times; the combined organic layer was washed with brine and dried over MgSO4. After filtration and concentration, the product as Compound 55 was isolated by ISCO fast column chromatography (4 g RediSep column, 1 to 10% MeOH in DCM as elution gradient) as a white solid, Weight: 8.6 mg. MS: [M+1] = 432. 1H-NMR (500 MHz, CDCl3) δ: 7.81 (s, 1H), 7.71 (d, 1H, J=3.5 Hz), 7.52 ( d, 1H, J=9.0 Hz), 7.32 (m, 2H), 7.21 (dd, 1H, J=2.5, 8.5 Hz), 7.11 (d, 2H, J =8.5 Hz), 7.02 (m, 1H), 5.44 (s, 2H), 4.38 (q, 2H, J=7.5 Hz), 3.94 (s, 3H), 1.39 (t, 3H, J=7.0 Hz). Example 34: Synthesis of Compound 56:

[0618] The compound of Example 34 was synthesized in a synthetic route analogous to that described for Example 33, with the use of 4-fluorophenoxyacetic acid hydrazide in the last step to generate the compound of Example 34 as a yellowish solid: MS: [M+1] = 450. 1H-NMR (500 MHz, CDCl3) δ: 7.82 (s, 1H), 7.73 (d, 1H, J=3.5 Hz), 7.53 ( d, 1H, J=10.0 Hz), 7.22 (dd, 1H, J=3.5, 9.0 Hz), 7.08-6.99 (m, 4H), 5.41 (s , 2H), 4.41 (q, 2H, J=7.0 Hz), 3.95 (s, 3H), 1.42 (t, 3H, J=6.5 Hz). Example 35: Synthesis of Compound 103:

[0619] The compound of Example 35 was synthesized in a synthetic route analogous to that described for Example 33, with the use of 2-methoxy acetic acid hydrazide in the last step to generate the compound of Example 35 as a yellowish solid: MS: [M+1] = 370. Example 36: Synthesis of Compound 118:

[0620] Acetamide oxime (8.4 mg, 0.108 mmol) was subjected to azeotropic distillation in toluene three times in a Rotavap, then suspended in THF (1.0 ml). NaH (60% mineral suspension; 3.3 mg, 0.081 mmol) was added and the mixture was stirred at RT for 10 min. Ester 55 (23.2 mg, 0.054 mmol) was added next. After 40 min of stirring at RT, the reaction mixture was heated to 70 °C for 4 h. Under cooling, cold water (5 ml) was added to the reaction mixture and ppts were collected by filtration, washed with water and dried to give 9.7 mg (41%) of the desired product as a yellowish solid. MS: [M+1] = 442. Example 37: Synthesis of Compound 128:

[0621] The compound of Example 37 was synthesized in a synthetic route analogous to that described for Example 36 above, with the use of ester Compound 103 in the last step to generate the compound of Example 37 as a brownish solid: MS: [M+ 1] = 380. Example 38: Synthesis of Compound 130:

[0622] The compound of Example 38 was synthesized in a synthetic route analogous to that described for Example 36, starting with ester Compound 103 and condensation with isobutyramidoxime to generate the compound of Example 38 as a yellowish solid: MS: [M+1 ] = 408. Example 39: Synthesis of Compound 119:

[0623] To the carboxylic acid (13.9 mg, 0.0345 mmol; obtained through LiOH hydrolysis of the precursor ester 55) while stirring in DCM (0.2 ml) was added neopentyl alcohol (30.4 mg, 0.345 mmol ), DMAP (4.2 mg, 0.0345 mmol) and EDC (20 mg, 0.104 mmol). After five hours of stirring, the reaction mixture was diluted with EtOAc, washed with sat. NH4Cl, sat. NaHCO3, brine and dry with MgSO4. Purification by silica gel chromatography using a gradient of 0 to 8% MeOH in EtOAc yielded 11.7 mg (72%) of the desired product Compound 119 as a yellowish solid. MS: [M+1] = 474. Example 40: Synthesis of Compound 120:

[0624] The compound of Example 40 was synthesized in a synthetic route analogous to that described for Example 39 above, with the use of 2-propyl alcohol in the last step to generate the compound of Example 40 as a yellowish solid: MS: [M +1] = 446. Example 41: Synthesis of Compound 129:

[0625] Compound 103 (Scheme 18a) (66.1 mg, 0.179 mmol) was hydrolyzed in a THF/water/MeOH solvent system (1.8 ml total, 6/5/1 ratio) by LiOH treatment (21.4 mg, 0.895 mmol) at RT for 2 h. Dil. HCl was added to acidify (pH ~3) the reaction mixture. The precipitate was collected by filtration, washed with water and dried to give 49.0 mg (80%) of the acid as a brownish solid.

[0626] The acid thus obtained was stirred in DMF (0.7 ml) at 0 °C. NaHCO3 (48.1 mg, 0.572 mmol) was added, followed by N-bromosuccinamide (96.7 mg, 0.543 mmol). After stirring overnight, the reaction was diluted with EtO-Ac and washed with sat. NaHCO3. Aq. The aqueous layer was separated and extracted with EtOAc. The combined organic layer was washed with brine, dried over MgSO4, filtered and concentrated. The product bromide was obtained by silica gel column chromatography with a gradient elution of 0 to 13% MeOH in EtOAc as a white solid (Compound 129). Weight: 28.6 mg (53%). MS: [M+1] = 377. Example 42: Synthesis of Compound 131:

[0627] Compound 129 (22.6 mg, 0.060 mmol) was hydrogenated in 10% Pd-C in EtOAc (1 ml) and MeOH (1 ml) for 16 h. Filtration through Celite and removal of solvent gave 14.9 mg (84%) of the bromine-free product Compound 131 as a slightly yellowish solid. MS: [M+1] = 298. Example 43: Synthesis of Compound 122:

[0628] The phenoxy analogue (Scheme 18a, R1 = OPh) of acid 66 (20.4 mg, 0.0506 mmol) was suspended and stirred in DCM (0.5 ml) at RT. Carbonyl diimidazole (16.4 mg, 0.101 mmol) was added. After stirring for 2 h, the resulting suspension was cooled to 0 °C and ammonia (30 μl) was added dropwise. After stirring for 20 min. , the ice bath was removed and the reaction was allowed to proceed at RT for 1 h. The reaction was concentrated by removing DCM in vacuo. Water (3 ml) was added and the precipitate was collected by filtration, washed with water and dried to give 16.2 mg of the crude primary amide which was used without further purification.

[0629] The primary amide (16.2 mg, 0.0402 mmol) was treated with POCl3 (46.2 mg, 0.302 mmol) in 1,4-dioxane (0.5 ml) at 95 ° C for one day. the other. The reaction mixture was then cooled with sat. NaHCO3 (5 ml), cooled to 0 °C and the precipitate collected by suction filtration, washed with water and dried to give 13.6 mg (88%) of the nitrile as a brownish solid, Compound 122. MS: [ M+1] = 385. Example 44: Synthesis of Compound 123:

[0630] To acid 66 (15.8 mg, 0.0392 mmol) stirring in THF (0.15 ml) and DCM (0.15 ml) was added N,O-dimethyl hydroxylamine HCl (4.6 mg, 0.047 mmol) and N-hydroxylbenzotriazole hydrate (6.0 mg). EDC (11.3 mg, 0.0588 mmol) and triethylamine (11.9 mg, 0.118 mmol) were then added and the reaction was stirred at RT for 12 h, diluted with EtOAc, washed with sat. NH4Cl, brine and dry with MgSO4. Vacuum filtration and solvent removal generated 14.4 mg (82%) of Weinreb's amide which was used without further purification.

[0631] To Weinreb's amide (14.4 mg, 0.0323 mmol) stirring in THF (0.3 ml) at 0 °C was added ethyl magnesium bromide etherate (3M; 0.323 ml). The reaction was allowed to warm naturally to RT and stirred for 14 h, cooled to sat. NH4Cl, extracted with EtOAc three times; the combined organic layer washed with brine and dried with MgSO4. Filtration and solvent removal gave the crude ketone product which was purified by prep. TLC using 8% MeOH in EtOAc. Weight: 4.6 mg (34%) of Compound 123. MS: [M+1] = 416. Example 45: Synthesis of Compound 124:

[0632] The Weinreb amide (18.0 mg, 0.0403 mmol) described above was treated with DIBAL (1M THF; 0.363 ml) at -78 ° C for 1 h, then, still at -78 ° C, cooled with Rochelle saline solution (20%) overnight. The aqueous solution was extracted with EtOAc three times; the combined organic layer was washed with brine and dried over MgSO4. Filtration and vacuum solvent removal generated 13.7 mg of crude aldehyde which was used without further purification.

[0633] The crude aldehyde (13.7 mg) in DCM (0.7 ml) at RT was treated with Deoxo-Fluor (54.8 mg, 0.248 mmol) for 16 h. The reaction was cooled with sat. NaHCO3 (5 ml) for 20 min., extracted with EtOAc three times; the combined organic layer washed with brine and dried with MgSO4. Filtration and solvent removal followed by prep TLC purification using 10% MeOH in EtOAc yielded 7.5 mg (52%) of the desired difluoride Compound 124 as a yellowish solid. MS: [M+1] = 410. Example 46: Synthesis of Compound 142:

[0634] Weinreb's amide (8.8 mg, 0.0197 mmol) from above in THF (0.15 ml) at 0 °C was treated with phenylmagnesium bromide (1M THF; 0.54 ml) for 2.5 h, cooled with sat. NH4Cl, extracted with EtOAc twice; the combined organic layer washed with brine and dried with MgSO4. Filtration and solvent removal generated the crude ketone which was used without further purification. The ketone in THF (0.5 ml) was treated with NaBH4 (6 mg) at RT for 2 h, then cooled with sat. NH4Cl, extracted with EtOAc three times; the combined organic layer washed with brine and dried with MgSO4. Filtration and solvent removal yielded crude alcohol which was used without further purification. The alcohol thus obtained in DCM (1.4 ml) was treated with triethylsilane (86.4 mg, 0.75 mmol) and trifluoroacetic acid (171.0 mg, 1.5 mmol) at 40 °C for one day. for the other, then concentrated in vacuo, diluted with EtOAc, washed with sat. NaHCO3, brine and dried with MgSO4. Filtration and solvent removal gave the crude benzyl product which was purified by silica gel column chromatography using 0 to 12% MeOH in EtOAc as eluent; 3.6 mg of Compound 142 was obtained as a yellowish solid. MS: [M+1] = 450. Scheme 19: Example 47: Synthesis of Compound 106:

[0635] To lactam 64 (185.7 mg, 0.616 mmol) in chlorobenzene (5 ml) was added N,N-dimethyl-p-toluidine (333.3 mg, 2.465 mmol) and phosphorous oxychloride (188.9 mg, 1.232 mmol). The reaction mixture was heated to 135 °C for 2 h, cooled to RT and formyl hydrazide (296.0 mg, 4.93 mmol) was added, followed by diisopropyl ethyl amine (238.8 mg, 1.85 mmol). After 30 min. stirring at RT, the reaction was heated to 100 °C for 1 h, cooled and sat. (15 ml) added, extracted with EtOAc twice; the combined organic layer washed with brine and dried with MgSO4. Filtration and solvent removal gave the crude triazole product which was purified by silica gel column chromatography using 0 to 15% MeOH eluting from EtOAc, 35.9 mg (18%) were obtained as a brownish solid. MS: [M+1] = 326.

[0636] The above triazole in DCM (1 ml) was treated with N-bromosuccinamide (37.6 mg, 0.21 mmol) at 0 °C. The reaction was allowed to warm naturally to RT slowly and continued at RT overnight, diluted with EtOAc, washed with sat. NaHCO3, brine and dried with MgSO4. Filtration and solvent removal generated crude bromide, which was purified by silica gel column chromatography using 0 to 10% MeOH in an EtOAc gradient; 22.9 mg (51%) of Compound 106 was obtained as an off-white solid. [MS]: 406. Example 48: Synthesis of Compound 104:

[0637] A microwave reaction vessel was charged with phenol (20.3 mg, 0.216 mmol), the bromide substrate from Example 47 (29.1 mg, 0.0719 mmol), Cs2CO3 (117. 0 mg, 0.360 mmol), diethyl 1,3-acetonedicarboxylate (14.5 mg, 0.0719 mmol) and DMF (0.5 ml). The vessel was rinsed with nitrogen gas. CuI (6.8 mg, 0.036 mmol) was added and the mixture was stirred at RT for 5 min. before being heated to 140 °C under MW radiation conditions for 60 min. The reaction mixture was diluted with EtOAc, washed with water; the aqueous layer was separated and extracted with EtOAc twice; the combined organic solution was washed with brine and dried over MgSO4. Filtration and solvent removal gave the crude ether product which was purified by prep TLC using 5% MeOH in DCM; 6.6 mg of Compound 104 was obtained as a yellowish solid. MS: [M+1] = 418. Example 49: Synthesis of Compound 105:

[0638] The compound of Example 49 was synthesized in a synthetic route analogous to that described for Example 48 above, with the use of 3-methoxy phenol in place of phenol, to generate the compound of Example 49 as a yellowish foamy solid: MS : [M+1] = 448. Scheme 20: Example 50: Synthesis of Compound 112:

[0639] To a solution of Compound 2 (160 mg, 0.49 mmol) in THF (6 ml), water (5 ml) and MeOH (1 ml) was added LiOH (59 mg, 2.45 mmol). The solution was stirred at room temperature for 3 h. The solution was concentrated and the crude material was acidified with 1N HCl to pH 3 to 4. No solids were observed. EtOAc was added and the organic phase was extracted (3x). The combined extracts were washed with brine and dried with MgSO4. Filtration and concentration gave 112 mg (77% yield) of the desired carboxylic acid product as an orange solid MS: [M+1] = 300.

[0640] To a suspension of acid (30 mg, 0.1 mmol) in dichloroethane (0.2 ml) was added thionyl chloride (0.4 ml; 5 mmol) and DMF (20 μl). The resulting solution was heated at 70°C for 1 hour. Another 0.2 ml of thionyl chloride was added and the solution was heated for another 30 min. The solvent was removed. The raw material was dried under vacuum.

[0641] Crude acid chloride (0.1 mmol) was suspended in isopropanol and stirred at room temperature for 18 h. The solvent was evaporated and the crude material was purified by chromatography. (4 g RediSep silica gel column, eluted with 10% MeOH in DCM) to generate 8.6 mg (25% yield) of the product Compound 112 [M+1] =342). 1HNMR (CDCl3) δ 7.90 (1H, d, J= 9 Hz), 7.79 (1H, bs), 7.63 (1H, bs), 7.36 (1H, bs), 3.48 ( 1H, m), 2.45 (3H, s), 1.43 (6H, d, J= 6.5 Hz). Example 51: Synthesis of Compound 113:

[0642] The crude acid chloride prepared above (0.066 mmol) was suspended in dichloroethane (1 ml) and 2,2-dimethyl-1-propanol (300 mg, 3.4 mmol) was added. The solution was stirred at room temperature for 18 h. No products were formed. To the above solution, DMAP (5 mg, 0.004 mmol) and DCC (15 mg, 0.073 mmol) were added. The solution was stirred at room temperature for 2 h. The reaction mixture was directly applied to a TLC prep (elution system: 75% EtO-Ac in hexanes) to generate 7.2 mg (30% yield) of product Compound 113. MS: [M+1]= 370. 1HNMR (CDCl3) δ 7.91 (1H, dd, J= 3, 9 Hz), 7.79 (1H, s), 7.61 (1H, dd, J= 4.5, 9 Hz), 7, 35 (1H, m), 4.11 (2H, s), 2.44 (3H, s), 1.07 (9H, s). Example 52: Synthesis of Compound 114:

[0643] The crude acid chloride prepared above (0.066 mmol) was suspended in dichloroethane (1 ml) and 2,2,2-trifluoroethanol (0.1 ml, 1.4 mmol) followed by triethylamine (0.6 ml, 4.3 mmol) was added. The solution was stirred at room temperature for 2 h and 30 min. The solvent was evaporated and the crude material was purified by chromatography. (4 g RediSep silica gel column, eluted with EtOAc) then purified with a prep TLC (elution system: 70% EtOAc in hexanes) to generate 8.1 mg (32% yield) of the Compound product 114 [M+1] = 382). 1HNMR (CDCl3) δ 7.91 (1H, dd, J= 3.5, 9.5 Hz), 7.83 (1H, s), 7.63 (1H, dd, J= 4.5, 9, 5 Hz), 7.35 (1H, m), 4.77 (2H, m), 2.43 (3H, s). Example 53: Synthesis of Compound 136:

[0644] To a solution of acid prepared in Example 50 (100 mg, 0.33 mmol) in DMF (1.5 ml) cooled with an ice bath was added NaHCO3 (111 mg, 1.32 mmol) followed by NBS (117 mg, 0.66 mmol). The solution was stirred at room temperature for 14 h. The reaction mixture was diluted with water and extracted with EtOAc (5X). The combined extracts were washed with brine (2x) and dried with MgSO4. Filtration and concentration generated a crude product. Chromatography (4 g silica gel column of RediSep, eluted with EtOAc) to generate 93 mg (85% yield) of product Compound 136 [M+1] =334). 1HNMR (CDCl3) δ 7.87 (1H, dd, J= 2.5, 8.5 Hz), 7.72 (1H, s), 7.56 (1H, dd, J= 6, 10 Hz), 7.33 (1H, m), 2.44 (3H, s). Example 54 Synthesis of Compound 139:

[0645] General coupling procedure: To a solution of Compound 136 (20 mg, 0.061 mmol) in degassed DME (0.9 ml) and water (0.1 ml) was added phenylboronic acid (11 mg, 0.092 mmol), cesium carbonate (80 mg, 0.24 mmol) and Pd Cl2dppf (5 mg, 0.066 mmol). The suspension was heated at 80°C for one hour. The reaction mixture was diluted with water, extracted with EtOAc (3X). The combined extracts were washed with brine (2x) and dried with MgSO4. Filtration and concentration gave a crude product which was purified by prep TLC (elution system: 3% MeOH in EtOAc).

[0646] Compound 139 was prepared using phenylboronic acid. 10.8 mg (54% yield) of the product was obtained. MS: [M+1] = 332. 1HNMR (CDCl3) δ 7.87 (1H, dd, J= 3.5, 9.5 Hz), 7.85 (1H, s), 7.63 (3H, m), 7.50 (2H, t, J= 6.5 Hz), 7.35 (2H, m), 2.41 (3H, s). Example 55: Synthesis of Compound 140:

[0647] Compound 140 was prepared in a similar way using 3-pyridine boronic acid. 8.9 mg (27% yield) of product was obtained. MS: [M+1] = 333. 1HNMR (CDCl3) δ 8.86 (1H, s), 8.63 (1H, d, J= 5 Hz), 8.01 (1H, m), 7.90 (2H, m), 7.64 (1H, dd, J= 5.5, 9 Hz), 7.44 (1H, m), 7.36 (1H, m), 2.39 (3H, s) . Example 56: Synthesis of Compound 152:

[0648] Compound 152 was prepared using 1-methylpyrazol-4-boronic acid, HCl. 12.5 mg (63% yield) of product was obtained. MS: [M+1] = 336. 1HNMR (CDCl3 + MeOD4) δ 9.04 (1H, bs), 7.99 (1H, bs), 7.75 (2H, m), 7.41 (2H, m), 3.95 (3H, s), 2.32 (3H, s). Example 57: Synthesis of Compound 154:

[0649] Compound 154 was prepared using pinacol ester of 2-methylpyridine-4-boronic acid. 7.1 mg (34% yield) of product was obtained. MS: [M+1] = 347. 1HNMR (CDCl3) δ 8.6 (1H, d, J= 6 Hz), 7.89 (1H, dd, J= 3.5, 8.5 Hz), 7 .87 (1H, s), 7.64 (1H, dd, J= 5.5, 9 Hz), 7.48 (1H, s), 7.36 (2H, m), 2.64 (3H, s), 2.41 (3H, s). Scheme 21: Example 58: Synthesis of Compound 117:

[0650] In a 100 ml round bottom flask, lactam ester 16' (2 g, 7.35 mmol; which was prepared in a manner analogous to 16 described in Scheme 11) was dissolved in 60 ml of anhydrous THF . The solution was stirred at room temperature under a nitrogen atmosphere. LiBH4 (2 M in THF, 4 ml, 8 mmol) was added slowly. The reaction mixture was stirred under a nitrogen atmosphere for 18 h. More LiBH4 (2 M in THF, 2 ml, 4 mmol) was added slowly. The reaction mixture was stirred for another 24 h. A mixture of EtOAc/EtOH (20 ml/20 ml) was added to the reaction mixture and it was concentrated. The residue was taken up in MeOH and silica gel was added. After the volatile solvents were evaporated, the solid was loaded onto a 40 g RediSep silica gel column. The desired product was eluted with 5:1 volume CH2Cl2/MeOH. The alcohol was obtained as a white solid (1.14 g, 67% yield). MS: [M+1] =231.

[0651] Alcohol (1.14 g, 4.96 mmol) was suspended in 16 ml of 33% HBr in AcOH and heated at 80 ° C for 18 h. The solution was cooled with an ice bath and diluted with EtOAc. A white solid could be observed. Slowly, a sat. NaHCO3 solution. aq. was added. Large amounts of EtOAc and MeOH were used to solubilize the solid. The organic phase was extracted (3x) and the combined organic phases were washed with brine, dried with MgSO4. Filtration and concentration yielded a crude product that was used in the next step without further purification. MS: [M+1] = 293.

[0652] To a solution of alkyl bromide derivative (4.96 mmol) in EtOAc (50 ml), MeOH (200 ml) and THF (50 ml) was added wet 10% Pd/C (250 mg) and the resulting suspension was stirred under a hydrogen atmosphere for 7 days. The suspension was filtered through Celite and the resulting solution was concentrated and co-evaporated with toluene. The crude product was used in the next step without further purification.

[0653] To a solution of 1,2,4-triazole (2.7 g, 39.7 mmol) in anhydrous CH3CN (20 ml) at 0 °C was added i-Pr2NEt (7.6 ml, 43.6 mmol). Once all the triazole was dissolved, POCl3 (1.11 ml, 11.9 mmol) was added. The mixture was stirred at 0°C for 2 h. The solution was transferred to the vial containing lactam (4.96 mmol). The resulting solution was heated in an oil bath at 80 °C for 16 h. The viscous mixture was cooled with an ice bath and the solvent evaporated. Diluted with EtOAc and water was added. It was extracted with EtOAc five times. The combined extracts were washed with brine and dried with MgSO4. Filtration and concentration generated a crude product, which was used directly in the next reaction. MS: [M+1]=266.

[0654] A solution of KOtBu (1.11 g, 9.92 mmol) in DMF (10 ml) was cooled to -50 ° C under a nitrogen atmosphere. Ethyl isocyanacetate (1.2 ml, 10.9 mmol) was added slowly. The mixture was stirred at -60°C to -40°C for 1 h. The above crude 1,2,4-triazole intermediate from step 4 (4.96 mmol) in DMF (5 ml) was added slowly. The mixture was left to warm naturally for 16 h. Saturated aqueous NH4Cl solution was added and it was extracted with EtOAc three times. The combined extracts were washed with brine (3x) and dried with MgSO4. Filtration and concentration generated a crude product. Chromatography (24 g RediSep silica gel column, eluted with 70% EtOAc in hexanes) to generate 296 mg (20% yield for 4 steps) of product. MS: [M+1] =310.

[0655] To a solution of ester derivative (260 mg, 0.84 mmol) in THF (6 ml), water (5 ml) and MeOH (1 ml) was added LiOH (117 mg, 4.85 mmol). The solution was stirred at room temperature for 3 h. The solution was concentrated and the crude material was acidified with 1N HCl to pH 3 to 4. The solid was collected through multiple filtrations to generate 178 mg (75% yield) of the desired product. MS: [M+1] = 282.

[0656] To a suspension of acid (80 mg, 0.28 mmol) in THF (2 ml) was added CDI (50 mg, 0.31 mmol). The suspension was heated at 65°C for 3 h. LCMS indicated that the reaction was incomplete. More CDI (10 mg) was added and the solution heated for another hour. The solution was cooled to room temperature and an NH4OH solution (1 ml) was added. The solution was stirred for one hour. The solid was collected via filtration to give 33 mg (42%) of Compound 117 as the desired product as a white solid. MS: [M+1] = 281. 1HNMR (MeOD4) δ 8.1 (1H, s), 7.9 (1H, s), 7.73 (3H, m), 7.07 (2H, s) , 2.40 (3H, s). Example 59: Synthesis of Compound 115:

[0657] To a suspension of Compound 117 (8 mg, 0.029 mmol) and triethylamine (8 μl; 0.058 mmol) in THF (1 ml) trifluoroacetic anhydride (8 μl; 0.058 mmol) was added. The reaction mixture was stirred at room temperature for 16 h. LCMS indicated only 30% conversion. More trifluoroacetic anhydride (30 μl) and triethylamine (30 μl) were added. The solution became clear and was stirred for another hour. The reaction was cooled with MeOH. The solvent was evaporated and the crude material was purified by prep TLC (elution system: 70% EtOAc in hexanes) to give 6.6 mg (83%) of Compound 115. MS: [M+1] = 263. NMR of 1H (CDCl3) δ 8.17 (1H, d, J= 7 Hz), 7.88 (1H, s), 7.67 (3H, m), 2.46 (3H, s). Example 60: Synthesis of Compound 127:

[0658] To a suspension of Compound 115 (16 mg, 0.06 mmol) in EtOH (0.8 ml) and water (0.2 ml) was added hydroxylamine hydrochloride (6 mg, 0.09 mmol) and carbonate of potassium (12 mg, 0.09 mmol). The suspension was heated at 80°C for 16 h. The solution was diluted with EtOAc and washed with water. The aqueous layer was separated and extracted with EtOAc (3x). The combined organic phases were washed with brine, dried over MgSO4. Filtration and concentration gave 12.2 mg (67% yield) of the desired product. MS: [M+1] = 296.

[0659] A suspension of oxime (10 mg, 0.034 mmol) in acetic anhydride (0.5 ml) was heated at 110 ° C for 1 hour. Then, the solution was heated to 130 °C for 1 hour. Finally, the temperature was increased to 140°C and heated for another 2 h. The reaction mixture was cooled and EtOH (1 ml) was added to the reaction mixture, which was heated for 16 h at 80 °C. The solvent was evaporated and the crude material was purified by prep TLC (elution system: EtOAc) to give 6.1 mg (56% yield) of the desired product Compound 127. MS: [M+1] =320). 1H NMR (CDCl3) δ 8.16 (1H, m), 7.92 (1H, s), 7.65 (3H, m), 2.68 (3H, s), 2.46 (3H, s ). Example 61: Synthesis of Compound 133:

[0660] To a solution of isobutyric acid (19 μl, 0.2 mmol) in THF (0.5 ml) CDI (10 mg, 0.062 mmol) was added. The solution was stirred at room temperature for 2 h. The solution was then transferred to a vial containing the oxime derivative described above (12 mg, 0.041 mmol) and heated at 70 °C for 2 h. LCMS indicated that the reaction was incomplete. Another batch of reagent (isobutyric acid and CDI) was prepared and added to the reaction mixture which was heated at 70 °C for another hour. LCMS indicated that all starting material was consumed. The solvent was evaporated and the crude material was suspended in isobutyric acid (1 ml) and heated at 130°C for one hour. The solvent was evaporated and the crude material was purified by prep TLC (elution system: 70% EtOAc in hexanes) to give 6.7 mg (71%) of the desired product Compound 133. MS: [M+1] = 348 1H NMR (CDCl3) δ 8.16 (1H, m), 7.92 (1H, s), 7.65 (3H, m), 3.32 (1H, m), 2.46 (3H, s), 1.5 (6H, d, J= 7 Hz). Example 62: Synthesis of Compound 126:

[0661] Acetamide oxime was subjected to azeotropic distillation three times in toluene before use. To a suspension of acetamide oxime (24 mg, 0.32 mmol) in THF (1 ml) was added 60% NaH in an oil dispersion (13 mg, 0.32 mmol). The suspension was stirred at room temperature for 15 min. Compound 3 (50 mg, 0.16 mmol) was added. The vial containing the ester was rinsed with DMF (1 ml), which was added to the reaction mixture. The resulting brown suspension was stirred at room temperature for 30 min, then heated at 70 °C for 2 h. The suspension was cooled with water and the solution was kept in the refrigerator overnight. The solid was collected through multiple filtrations to give 16 mg (31% yield) of the product Compound 126. MS: [M+1] = 320. 1H NMR (CDCl3) δ 8.18 (1H, m), 7.94 (1H, s), 7.67 (3H, m), 2.51 (3H, s), 2.46 (3H, s). Example 63: Synthesis of Compound 125:

[0662] A suspension of the carboxylic acid derived from Compound 3 (30 mg, 0.11 mmol), N,O-dimethylhydroxylamine hydrochloride (13 mg, 0.13 mmol), 1-hydroxy benzotriazole hydrate (17 mg, 0.11 mmol) and triethylamine (46 μl, 0.33 mmol) in THF (0.3 ml) and DCM (0.3 ml) 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride ( 32 mg, 0.17 mmol). The solution was stirred at room temperature for 16 h. The reaction mixture was cooled with saturated ammonium chloride solution and extracted with EtOAc (3x). The combined extracts were washed with brine and dried with MgSO4. Filtration and concentration generated 31.2 mg (88% yield) of an orange solid that was used in the next step without further purification. MS: [M+1] = 325.

[0663] To a solution of the above Weinreb amide derivative (31.2 mg, 0.093 mmol) in THF (0.5 ml) cooled to -78 °C was added a 3 M solution of ethyl magnesium bromide (0 .31 ml, 0.93 mmol). The reaction mixture was stirred below -10°C for a period of 60 min, then cooled with saturated ammonium chloride solution and extracted with EtOAc (2x). The combined extracts were washed with brine and dried with MgSO4. Filtration and concentration generated a crude product. Chromatography (4 g silica gel column of Redi-Sep, eluted with 80% EtOAc in hexanes) to generate 11.1 mg (41% yield) of product Compound 125. MS: [M+1] = 294. 1H NMR (CDCl3) δ 8.15 (1H, m), 7.76 (1H, s), 7.65 (3H, m), 3.08 (2H, q, J= 7 Hz), 2, 44 (3H, s), 1.22 (3H, t, J= 7 Hz). Example 64: Synthesis of Compound 132:

[0664] To a solution of isobutyronitrile (2.6 ml; 29 mmol) in EtOH (30 ml) and water (10 ml) was added hydroxylamine hydrochloride (2.01 g, 29 mmol) and potassium carbonate (4 g , 29 mmol). The resulting suspension was heated at 80°C for 16 h. The solvent was removed under vacuum. The residue was co-evaporated with toluene. The crude material was washed with EtOH and filtered to remove sodium chloride. The filtrate was evaporated, co-evaporated with toluene several times and dried under vacuum to give 2 g (69%) of N-hydroxybutyramidine.

[0665] To a suspension of N-hydroxybutyramidine (47 mg, 0.46 mmol) in THF (1 ml) was added 60% NaH in oil dispersion (18 mg, 0.46 mmol). The suspension was stirred at room temperature for 30 min. Compound 3 (47 mg, 0.15 mmol) in THF (1 ml) was added. The resulting suspension was stirred at room temperature for 30 min, then heated at 70°C for 2 h. After one hour, only 50% conversion was observed. No changes were observed after another hour. More reagent (N-hydroxybutyramidine and NaH), as described above, was prepared and added to the reaction mixture which was heated for another 40 min. At this point, LCMS showed that the reaction was complete. The suspension was cooled with water. Some MeOH was added to aid complete dissolution and the solution was extracted with EtOAc (3x). The combined extracts were washed with brine (3x) and dried with MgSO4. Filtration and concentration generated a crude product. Chromatography (4 g RediSep silica gel column, eluted with EtOAc) to generate 20 mg (38% yield) of product Compound 132. MS: [M+1] =348. 1H NMR (CDCl3) δ 8.18 (1H, d, J= 8 Hz), 7.93 (1H, s), 7.69 (3H, m), 3.22 (1H, m), 2, 46 (3H, s), 1.43 (6H, d, J= 9.5 Hz) Example 65: Synthesis of Compound 161:

[0666] To a solution of acid derived from Compound 3 (90 mg, 0.32 mmol) in DMF (2 ml) cooled with an ice bath was added NaHCO3 (108 mg, 1.28 mmol) followed by NBS (114 mg, 0.64 mmol). The solution was stirred at room temperature for 18 h. The reaction mixture was diluted with water and extracted with EtOAc (3x). The combined extracts were washed with brine (2x) and dried with MgSO4. Filtration and concentration generated a crude product. Chromatography (4 g silica gel column of RediSep, eluted with EtOAc) to give 54 mg (53% yield) of product. MS: [M+1]=316.

[0667] To a solution of bromide derivative (30 mg, 0.1 mmol) in dioxane (1 ml) and triethylamine (1 ml) was added TMS-acetylene (71 μl, 0.5 mmol), CuI (2 mg , 0.01 mmol) and PdCl2(PPh3)2 (7 mg, 0.01 mmol). The solution was heated at 110 °C for 6 h. More Pd catalyst (7 mg) and TMS-acetylene (0.2 ml) were added and the reaction mixture heated for an additional 12 h. At this point, LCMS showed about 80% conversion. More Pd catalyst (7 mg) and TMS-acetylene (0.2 ml) were added and the reaction mixture heated for an additional 12 h. LCMS showed complete conversion. The reaction mixture was then diluted with water and extracted with EtOAc (3x). The combined extracts were washed with brine (2x) and dried with MgSO4. Filtration and concentration generated a crude product. Chromatography (4 g silica gel column of RediSep, eluted with 70% EtOAc in hexanes) to give 23 mg (69% yield) of product. MS: [M+1] =334.

[0668] To a solution of alkyne derivative (23 mg, 0.069 mmol) in MeOH (0.6 ml) and H2O (0.2 ml) was added KOH (4 mg, 0.076 mmol) at 0 °C. The solution was allowed to warm naturally to room temperature over 16 h. The reaction mixture was diluted with saturated aqueous ammonium chloride solution and extracted with EtOAc (2X). The combined extracts were washed with brine (2x) and dried with MgSO4. Filtration and concentration gave a crude product which was purified by prep TLC (elution system: 80% EtOAc in hexanes) to give 8.1 mg (45% yield) of product Compound 161. MS: [M+1 ]=262. 1H NMR (CDCl3) δ 8.13 (1H, m), 7.76 (1H, s), 7.62 (3H, m), 4.09 (2H, bs), 3.28 (1H, s ), 2.44 (3H, s). Example 66: Synthesis of Compound 146:

[0669] To a solution of 3-amino-2-methylacrolein (65 mg, 0.76 mmol) in anhydrous THF (2 ml) was added 60% NaH in oil dispersion (30 mg, 0.76 mmol). The suspension was stirred at room temperature for 15 min. Compound 115 (50 mg, 0.19 mmol) was added and the reaction mixture was heated at 65 °C for 3 h. The reaction mixture was cooled with an ice bath and water was added. The reaction mixture was stored in the refrigerator overnight. The solid was collected by filtration to give 27.5 mg (44% yield) of a white solid Compound 146. MS: [M+1] = 330. 1H NMR (CDCl3) δ 8.66 (2H, s), 8.15 (1H, m), 7.89 (1H, s), 7.65 (3H, m), 2.44 (3H, s), 2.36 (3H, s). Example 67: Synthesis of Compound 153:

[0670] To a suspension of acid derived from Compound 3 (30 mg, 0.11 mmol) in dichloroethane (0.2 ml) was added thionyl chloride (1 ml; 13.8 mmol) and DMF (20 μl ). The resulting solution was heated at 70°C for 1 hour. The solvent was removed. The raw material was dried under vacuum. The crude material was suspended in isopropanol (2 ml) and stirred at room temperature for 16 h. The solvent was evaporated, co-evaporated with methanol and the crude material was purified by prep TLC (elution system: EtOAc) to give 7.2 mg (21% yield) of the product Compound 153. MS: [M+1] =324. 1HNMR (CDCl3) δ 8.15 (1H, d, J= 8 Hz), 7.81 (1H, s), 7.64 (3H, m), 5.32 (1H, q, J= 7 Hz) , 2.45 (3H, s), 1.43 (6H, d, J= 7Hz). Scheme 22 Example 68: Synthesis of Compound 116:

[0671] An alternative route to substituted nitrile imidazole derivatives has also been implemented. As an example, Compound 116 was prepared from the imino derivative as shown in Scheme 22. A solution of isocyanacetonitrile (206 mg, 3.12 mmol) in DMF (7 ml) was cooled to -50 °C under an atmosphere of nitrogen. KOtBu (320 mg, 2.85 mmol) was added. The mixture was stirred at -50°C for 1 h. The imino derivative (prepared in the identical manner as the imino derivative shown above in Scheme 21) (350 mg, 1.24 mmol) was added slowly at -50°C. The mixture was left to warm naturally for 16 h. Saturated aqueous NH4Cl solution was added and it was extracted with EtOAc three times. The combined extracts were washed with brine (3x) and dried with MgSO4. Filtration and concentration generated a crude product. Chromatography (12 g RediSep silica gel column, eluted with 70% EtOAc in hexanes) to generate 230 mg (70% yield) of the product Compound 116. MS: [M+1] =281. 1H NMR (CDCl3) δ 7.92 (1H, dd, J= 3, 8.5 Hz), 7.81 (1H, s), 7.61 (1H, dd, J= 4.5, 9 Hz ), 7.38 (1H, m), 2.47 (3H, s). Example 69: Synthesis of Compound 145:

[0672] To a suspension of cyanide derivative Compound 116 (50 mg, 0.18 mmol) in EtOH (1.6 ml) and water (0.4 ml) was added hydroxylamine hydrochloride (17 mg, 0.24 mmol ) and potassium carbonate (28 mg, 0.2 mmol). The suspension was heated to 80 °C for 30 min, then cooled to room temperature. A solid precipitate was collected through filtration to give 37.8 mg (68% yield) of the desired amino oxime product, [M+1] = 314.

[0673] The suspension of amide oxime (10 mg, 0.032 mmol) in acetic anhydride (0.5 ml) was heated at 140 ° C for 4 h. The reaction mixture was cooled and EtOH (1 ml) was added to the reaction mixture, which was heated for 16 h at 80 °C. The solvent was evaporated and the crude material was purified by prep TLC (elution system: EtOAc) to give 6.6 mg (61% yield) of the desired product Compound 145. MS: [M+1] = 338. NMR 1H (CDCl3) δ 7.91 (1H, dd, J= 3.5, 8.5 Hz), 7.89 (1H, s), 7.65 (1H, dd, J= 5.5, 10 Hz ), 7.35 (1H, m), 2.69 (3H, s), 2.45 (3H, s). Example 70: Synthesis of Compound 149:

[0674] To a solution of isobutyric acid (30 μl, 0.32 mmol) in THF (0.5 ml) CDI (16 mg, 0.096 mmol) was added. The solution was stirred at room temperature for 2 h. The above amide oxime derivative (10 mg, 0.032 mmol) was added and the reaction mixture was heated at 70 °C for 45 min. The solvent was evaporated and the crude material was suspended in isobutyric acid (1 ml) and heated at 130°C for 3 h. The solvent was evaporated and the crude material was purified by prep TLC (elution system: 80% EtOAc in hexanes) to give 10.6 mg (91%) of the desired product Compound 149. MS: [M+1] = 366 . 1H NMR (CDCl3) δ 7.90 (1H, dd, J= 3.5, 9 Hz), 7.89 (1H, s), 7.66 (1H, dd, J= 4.5, 8 .5 Hz), 7.36 (1H, m), 3.32 (1H, q, J= 6.5 Hz), 2.46 (3H, s), 1.49 (6H, d, J= 8 Hz). Example 71: Synthesis of Compound 150:

[0675] A suspension of the above amide oxime (10 mg, 0.032 mmol) in trifluoroacetic anhydride (0.5 ml) was heated under reflux for 10 min. The solvent was evaporated and the crude material was purified by prep TLC (elution system: 80% EtOAc in hexanes) to give 11.8 mg (94%) of the desired product Compound 150. MS: [M+1] = 392 .1H NMR (CDCl3) δ 7.92 (2H, m), 7.69 (1H, dd, J= 5.5, 9.5 Hz), 7.39 (1H, m), 2.45 ( 3H, s). Example 72: Synthesis of Compound 151:

[0676] To a solution of formic acid (12 μl, 0.32 mmol) in THF (0.5 ml) CDI (16 mg, 0.096 mmol) was added. The solution was stirred at room temperature for 2 h. The above amide oxime derivative (10 mg, 0.032 mmol) was added and the reaction mixture was heated at 70 °C for 45 min. The solvent was evaporated and the crude material was suspended in formic acid (1 ml) and heated at 60°C for 3 h. The solvent was evaporated and the crude material was purified by prep TLC (elution system: 80% EtOAc in hexanes) to give 2.1 mg (20%) of the desired product Compound 151. MS: [M+1] = 324 .1H NMR (CDCl3) δ 8.83 (1H, s), 7.92 (1H, dd, J= 3.5, 8 Hz), 7.91 (1H, s), 7.65 (1H, dd, J= 4.5, 9Hz), 7.37 (1H, m), 2.45 (3H, s). Example 73: Synthesis of Compound 155:

[0677] To a solution of propionic acid (22 μl, 0.29 mmol) in THF (0.5 ml) CDI (14 mg, 0.087 mmol) was added. The solution was stirred at room temperature for 1 hour. The above amide oxime derivative (10 mg, 0.032 mmol) in THF (0.5 ml) was added and the reaction mixture was heated at 70 °C for 90 min. The solvent was evaporated and the crude material was suspended in propionic acid (1 ml) and heated at 130 °C for 1 h. The solvent was evaporated and the crude material was purified by prep TLC (elution system: 80% EtOAc in hexanes) to give 9.4 mg (94%) of the desired product Compound 155. MS: [M+1] = 352 . 1H NMR (CDCl3) δ 7.91 (1H, dd, J= 2, 8.5 Hz), 7.88 (1H, s), 7.65 (1H, dd, J= 6, 9.5 Hz), 7.36 (1H, m), 3.01 (2H, q, J= 8.5 Hz), 2.46 (3H, s), 1.48 (3H, t, J= 8.5 Hz). Example 74: Synthesis of Compound 160:

[0678] To a solution of pivalic acid (30 mg, 0.29 mmol) in THF (0.5 ml) CDI (14 mg, 0.087 mmol) was added. The solution was stirred at room temperature for 1 hour. The above amide oxime derivative (10 mg, 0.032 mmol) in THF (0.5 ml) was added and the reaction mixture was heated at 70 °C for 90 min. The solvent was evaporated and the crude material was suspended in acetic acid (1 ml) and heated under reflux for 3 h. The solvent was evaporated and the crude material was purified by prep TLC (elution system: 80% EtOAc in hexanes) to give 7.4 mg (67%) of the desired product Compound 160. MS: [M+1] = 380 .1H NMR (CDCl3) δ 7.90 (1H, dd, J= 2.7, 9 Hz), 7.88 (1H, s), 7.65 (1H, dd, J= 4.5, 9 Hz), 7.35 (1H, m), 2.47 (3H, s), 1.53 (9H, s). Example 75: Synthesis of Compound 143:

[0679] A solution of KOtBu (40 mg, 0.36 mmol) in DMF (3 ml) was cooled to -50 ° C under a nitrogen atmosphere. p-Toluenesulfonylmethyl isocyanide (76 mg, 0.39 mmol) was added. The mixture was stirred at -50°C for 1 h. The imino derivative from Scheme 22 (50 mg, 0.18 mmol) was added and the mixture was allowed to warm naturally to room temperature over 16 h. Saturated aqueous NH4Cl solution was added and it was extracted with EtO-Ac five times. The combined extracts were washed with brine (3x) and dried with MgSO4. Filtration and concentration generated the crude product. Chromatography (4 g silica gel column of RediSep, eluted with 70% EtOAc in hexanes) followed by a prep TLC (elution system: 30% EtOAc in DCM) to generate 22.2 mg (30% yield) of a white solid Compound 143. MS: [M+1] =410. 1H NMR (CDCl3) δ 7.91 (2H, d, J= 8 Hz), 7.87 (1H, dd, J= 2.5, 8.5 Hz), 7.74 (1H, s), 7.65 (1H, dd, J= 5.5, 9 Hz), 7.34 (3H, m), 2.50 (3H, s), 2.42 (3H, s). Example 76: Synthesis of Compound 144:

[0680] To 3-ethoxymethacrolein (100 mg, 0.88 mmol) was added 7 N ammonia in methanol (1.3 ml, 8.8 mmol). The solution was stirred at room temperature for 16 h. The solvent was evaporated and the crude yellow solid corresponding to 3-amino-2-methylacroleine was used in the next step without further purification.

[0681] To a solution of 3-amino-2-methylacrolein (7 mg, 0.087 mmol) in anhydrous THF (1 ml) was added 60% NaH in oil dispersion (6 mg, 0.16 mmol). The suspension was stirred at room temperature for 15 min. The cyanide derivative (22 mg, 0.079 mmol) in THF (1 ml) was added and the reaction mixture was heated at 65 °C for 1 hour. As described above, a new batch of reagents was prepared with 3-amino-2-methylacrolein (20 mg) and NaH (20 mg) in THF (1 ml) and added to the reaction mixture which was heated at 65 °C for more another time. LCMS indicated completion of the reaction. The reaction mixture was cooled with methanol. The solvent was evaporated. The crude material was suspended in water and a solid was collected by filtration to give 5.2 mg (19% yield) of a light red solid Compound 144. MS: [M+1] = 348. 1H NMR ( CDCl3) δ 8.67 (2H, s), 7.90 (1H, d, J=9.5 Hz), 7.85 (1H, s), 7.65 (1H, dd, J= 4.5 , 9 Hz), 7.34 (1H, m), 2.44 (3H, s), 2.36 (3H, s). Scheme 23 Example 77: Synthesis of Compound 121:

[0682] To a solution of 1,2,4-triazole (2.03 g, 29.4 mmol) in anhydrous CH3CN (20 ml) at 0 °C was added i-Pr2NEt (5.6 ml, 32.4 mmol). Once all the triazole was dissolved, POCl3 (0.82 ml, 8.8 mmol) and compound 16' (1 g, 3.68 mmol) were added. The mixture was stirred at 0°C for 2 h. The resulting solution was heated in an oil bath at 80 °C for 16 h. The mixture was cooled with an ice bath, diluted with EtOAc and water was added. It was extracted with EtOAc three times. The combined extracts were washed with brine and dried with MgSO4. Filtration and concentration generated 1.05 g (88% yield) of an orange solid, which was used directly in the next step. MS: [M+1] =324.

[0683] A solution of KOtBu (696 mg, 6.2 mmol) in DMF (15 ml) was cooled to -50 ° C under a nitrogen atmosphere. Ethyl isocyanacetate (0.75 ml, 6.8 mmol) was added slowly. The mixture was stirred at -50°C for 1 h. The above crude product from step 1 (1 g, 3.1 mmol) was added and the mixture was allowed to warm naturally to room temperature over 18 h. Saturated aqueous NH4Cl solution was added and it was extracted with EtOAc eight times. The combined extracts were washed with brine (3x) and dried with MgSO4. Filtration and concentration generated the crude product. Chromatography (24 g silica gel column of RediSep, eluted with 70% EtOAc in hexanes) to generate 950 mg (83% yield) of product. MS: [M+1] = 368.

[0684] To a solution of diester (200 mg, 0.54 mmol) in anhydrous THF (4 ml) stirred at room temperature under a nitrogen atmosphere was added LiBH4 (2 M in THF, 0.66 ml, 1.3 mmol). The reaction mixture was stirred under a nitrogen atmosphere for 24 h. A mixture of EtOAc/EtOH (3 ml/3 ml) was added to the reaction mixture and it was concentrated. The residue was taken up in MeOH and silica gel was added. After the volatile solvents were evaporated, the solid was loaded onto a 4 g RediSep silica gel column. The desired product was eluted with 10:1 volume CH2Cl2/MeOH. The diol was obtained as a solid (60 mg, 39% yield). MS: [M+1] = 284.

[0685] The diol (60 mg, 0.21 mmol) was suspended in 5 ml of 33% HBr in AcOH and heated at 80 ° C for 18 h. The solution was cooled with an ice bath and diluted with EtOAc. Slowly, a saturated aqueous solution of NaHCO3 was added. The solution was extracted with EtOAc (3x) and the combined organic phases were washed with brine, dried over MgSO4. Filtration and concentration yielded a crude product that was used in the next step without further purification. MS: [M+1] = 408.

[0686] To a solution of dialkyl bromide derivative (0.21 mmol) in EtOAc (10 ml) and MeOH (10 ml) was added 10% wet Pd/C (catalytic amount) and the resulting suspension was stirred under an atmosphere of hydrogen for 60 h. The suspension was filtered through Celite and the resulting solution was concentrated. The crude product was purified by multiple prep TLC (elution system: 3% MeOH in EtOAc) to generate 6.2 mg (12% yield in 2 steps) of the desired product Compound 121. MS: [M+1] = 252. 1H NMR (CDCl3) δ 8.09 (1H, m), 7.74 (1H, s), 7.56 (3H, m), 7.90 (2H, m), 2.42 (3H , s), 2.29 (3H, s). Example 78: Synthesis of Compound 135:

[0687] Compound 135 was synthesized in a manner analogous to Compound 121 as follows: In a solution of 1,2,4-triazole (952 mg, 13.8 mmol) in anhydrous CH3CN (20 ml) at 0 ° C was added i-Pr2NEt (2.6 ml, 15.2 mmol). Once all the triazole was dissolved, POCl3 (0.45 ml, 4.8 mmol) and lactam ester (1 g, 3.45 mmol) were added. The mixture was stirred at 0°C for 2 h. The resulting solution was heated in an oil bath at 80 °C for 16 h. The mixture was cooled with an ice bath, diluted with EtOAc and water was added. It was extracted with EtOAc three times. The combined extracts were washed with brine and dried with MgSO4. Filtration and concentration generated 1.03 g (87% yield) of an orange solid, which was used directly in the next step. MS: [M+1]=342. A solution of KOtBu (658 mg, 5.9 mmol) in DMF (15 ml) was cooled to −50 °C under a nitrogen atmosphere. Ethyl isocyanacetate (0.71 ml, 6.5 mmol) was added slowly. The mixture was stirred at -50°C for 1 h. The above crude product from step 1 (1 g, 2.9 mmol) was added and the mixture was allowed to warm naturally to room temperature over 18 h. Saturated aqueous NH4Cl solution was added and it was extracted with EtOAc eight times. The combined extracts were washed with brine (3x) and dried with MgSO4. Filtration and concentration generated the crude product. Chromatography (24 g RediSep silica gel column, eluted with 70% EtOAc in hexanes) to generate 1.02 g (90% yield) of product. MS: [M+1] = 386.

[0688] To a solution of diester (600 mg, 1.56 mmol) in anhydrous THF (8 ml) stirred at room temperature under a nitrogen atmosphere was added LiBH4 (2 M in THF, 3.1 ml, 6.24 mmol). The reaction mixture was stirred under a nitrogen atmosphere for 24 h. A mixture of EtOAc/EtOH (10 ml/10 ml) was added to the reaction mixture and it was concentrated. The residue was taken up in MeOH and silica gel was added. After the volatile solvents were evaporated, the solid was loaded onto a 12 g RediSep silica gel column. The desired product was eluted with 10:1 volume CH2Cl2/MeOH. The diol was obtained as a solid (187 mg, 40% yield). MS: [M+1] = 302.

[0689] The diol (80 mg, 0.27 mmol) was suspended in 7 ml of 33% HBr in AcOH and heated at 80 ° C for 48 h. The solution was cooled with an ice bath and diluted with EtOAc. Slowly, a saturated aqueous solution of NaHCO3 was added. The solution was extracted (3x) and the combined organic phases were washed with brine, dried over MgSO4. Filtration, concentration and co-evaporation with toluene gave 100 mg (88% yield) of a beige solid which was used in the next step without further purification. MS: [M+1] = 426.

[0690] To a solution of dialkyl bromide derivative (70 mg, 0.16 mmol) in EtOAc (10 ml) and MeOH (10 ml) was added 10% Pd/C (catalytic amount) and the resulting suspension was stirred under a hydrogen atmosphere for 48 h. The suspension was filtered through Celite and the resulting solution was concentrated. The crude product was purified by multiple prep TLC (elution system 1: 75% EtOAc in hexanes; elution system 2: 5% MeOH in EtOAc; elution system 3: EtOAc) to yield 4.1 mg (10% yield) of the desired product Compound 135. MS: [M+1] =270. 1H NMR (CDCl3) δ 7.84 (1H, dd, J= 2.5, 9 Hz), 7.70 (1H, s), 7.54 (1H, dd, J= 5, 8 Hz), 7.30 (1H, m), 2.42 (3H, s), 2.28 (3H, s). Example 79: Synthesis of Compound 134:

[0691] To a suspension of dialkyl bromide derivative described in Scheme 23, R = H, (30 mg, 0.074 mmol) in EtOH (1 ml) and heated to 80 ° C, a freshly prepared 2 M NaOEt solution was added (75 μl, 0.15 mmol). The solution was heated for 10 min. The solvent was evaporated. The crude material was suspended in EtOAc and filtered. The filtrate was concentrated and purified by prep TLC (elution system: EtOAc) to generate 3.1 mg (12% yield) of the desired product Compound 134. MS: [M+1] = 340. Scheme 24 Example 80: Synthesis of Compound 137:

[0692] To a solution of 5-fluoro-2-nitrobenzoic acid (6.6 g, 35.66 mmol) in dichloromethane (100 ml) were added DIPEA (9.22 g, 71.3 mmol), HOBt (6 .0 g, 39.2 mmol) and EDCI (10.2 g, 53.5 mmol). After about 15 min. stirring, to the reaction mixture was added a solution of 2,4-dimethoxybenzyl amine (5.96 g, 35.66 mmol) in dichloromethane (50 ml) dropwise under nitrogen atmosphere. The resulting mixture was stirred under a nitrogen atmosphere at room temperature for 16 h. The reaction mixture was washed successively with 1N HCl (100 ml), sat. (100 ml) and brine (100 ml). The organic phase was then dried with MgSO4. Filtration and removal of solvent under vacuum produced a yellowish solid, weight: 9.3 g (78%). MS: [M+1] = 335.

[0693] To the nitro benzene analog (9.3 g, 27.8 mmol) suspended and stirred in a solvent mixture of HOAc/THF/MeOH/H2O (25/100/50/25 ml) at RT was added powder of Zn. The mixture was heated at 70 °C for 20 h, cooled and filtered. The solid was rinsed with THF and the combined filtrate was concentrated in vacuo. To the resulting slurry was added sat. NaHCO3. slowly and carefully to avoid excessive formation until the pH reached 7 to 8. The mixture was extracted with EtOAc (3x); combined organic layer washed with brine and dried with MgSO4. Filtration and solvent removal gave the crude amine product as a dark brown gum paste, weight: 8.7 g.

[0694] To a solution of the aniline from above (8.7 g) in dichloromethane (150 ml) was added triethylamine (3.37 g, 33.4 mmol). The mixture was cooled with an ice bath and treated with bromine acetyl chloride (4.81g, 30.6 mmol) under a nitrogen atmosphere. The ice bath was removed and the mixture left to stir for 72 h. The reaction mixture was concentrated in vacuo, the resulting slurry treated with Et2O (100 ml) and water (100 ml). The product precipitate was collected by filtration and dried to give 5.6 g of product as a brown solid. The Et2O layer was separated from the aqueous layer and diluted with DCM (50 ml), washed with brine and dried with MgSO4. Filtration and solvent removal generated 5.3 g of additional product as a foamy brown solid. Total Weight: 11 g (100%).

[0695] To a solution of the bromide (11 g) in DMF (550 ml) was added K2CO3 (7.1 g, 51.7 mmol). The mixture was heated at 50°C for 48 h. The mixture was cooled to room temperature and the inorganic solid was removed by filtration. The filtrate was concentrated in vacuo, treated with water/MeOH (60/10 ml), extracted with DCM (3x); the combined organic layer was washed with brine and dried over MgSO4. Filtration and solvent removal followed by silica gel column chromatography using 5 to 50% EtOAc in DCM generated 3.2 g (36%) of the 7-membered lactam as a brownish solid. MS: [M+1] = 345.

[0696] To the lactam (1.32 g, 3.83 mmol) dissolved and stirred in THF (20 ml) and DMF (3 ml) at -20 °C was added t-BuOK (0.645 g, 5.75 mmol) . After 30 min. stirring at -20 °C, diethyl chlorophosphate (1.19 ml, 6.89 mmol) was added dropwise and the mixture was stirred for 3 h while heating from -20 to 20 °C. The reaction mixture was cooled to -78 °C and ethyl isocanoacetate (0.791 ml, 6.89 mmol) was added to it, followed by the addition of t-BuOK (0.645 g, 5.75 mmol) and continued stirring. from one day to the next, while the temperature reached RT. The reaction was cooled with saturated NH4Cl, extracted with EtO-Ac (2x); the combined organic solution was washed with brine and dried over MgSO4. Filtration and solvent removal gave a crude product which was purified by silica gel column chromatography using 15 to 100% EtOAc in DCM, weight: 0.861 g (47%), as a brown solid. MS: [M+1] = 440.

[0697] To the imidazole ester from above (861 mg) in dichloromethane (5 ml) at 0 °C was added trifluoroacetic acid (5 ml) followed by trifluoromethane sulfonic acid (0.345 ml). The mixture was allowed to warm naturally to RT, stirred for 3 h, then concentrated to give a residue which was dissolved in dichloromethane (50 ml). To which sat. NaHCO3 was added. (50 ml), followed by 20 min. of agitation. The pH of the upper aqueous layer was tested basic and was separated, extracted with DCM (3x); the combined DCM solution was washed with brine and dried over MgSO4. Filtration and solvent removal gave 0.58 g (100%) of the lactam as a yellowish solid. MS: [M+1] = 290.

[0698] To lactam (209.1 mg, 0.723 mmol) and N,N-dimethyl-p-toluidine (234.7 mg, 1.74 mmol) stirring in chlorobenzene (2.5 ml) under nitrogen was added POCl3 (133.0 mg, 0.867 mmol). The reaction was then heated to 135 °C for 2 h. Upon cooling to room temperature, phenoxy acetic acid hydrazide (189.0 mg, 1.08 mmol) was added, followed by DIPEA (0.455 ml). The reaction was stirred at room temperature for 30 min, then heated to 100 °C for 60 min. The reaction mixture was cooled, saturated NaHCO4 (aq.) was added and extracted with ethyl acetate three times; the combined organic layer was washed with brine and dried over MgSO4. After filtration and concentration, the product was isolated by ISCO flash column chromatography using 0 to 10% MeOH in EtOAc, weight: 116.7 mg (36%) of Compound 137 as a yellowish membrane solid. MS: [M+1] = 420. Example 81: Synthesis of Compound 156:

[0699] Ethyl ester of Compound 137 (244.2 mg, 0.582 mmol) in a THF/water/MeOH solvent system (6.0 ml total, 6/5/1 ratio) was treated with LiOH (69 .7 mg, 2.91 mmol) at RT for 4 h, concentrated in vacuo, acidified to pH ~3 and the precipitate collected by filtration. After washing with water and drying, 179.3 mg (79%) of the acid was obtained as a yellowish solid. MS: [M+1] = 392.

[0700] To the acid (10.8 mg, 0.0276 mmol) stirring in DCM (0.1 ml) at RT was added EDCI (21.3 mg, 0.11 mmol), DMAP (6.7 mg, 0 .0552 mmol) and isopropyl alcohol (13.2 mg, 0.221 mmol). After 12 h, the reaction was diluted with EtOAc, washed with sat. NaHCO3; the aqueous layer separated and extracted with EtOAc, the combined organic layer was washed with brine and dried with MgSO4. Filtration and prep TLC purification of the concentrate using 10% MeOH in EtOAc yielded 8.7 mg (73%) of the isopropyl ester of Compound 156 as a yellowish foamy solid. MS: [M+1] = 434. Example 82: Synthesis of Compound 138:

[0701] Acetamide oxime (10.7 mg, 0.144 mmol) was subjected to azeotropic distillation four times in toluene and added to the ethyl ester of Compound 137 (9.5 mg, 0.0226 mmol). THF (0.3 ml) was added, followed by 60% NaH in oil suspension (4.5 mg, 0.112 mmol). The reaction mixture was stirred at RT for 30 min, then heated to 70 °C for 2 h, cooled to RT and the solvent removed in vacuo, water (1.5 ml) added to cool the reaction, stirred for 20 min. and cooled to 4 °C. The precipitate was collected by filtration, washed with water and dried to give 5.2 mg (59%) of the oxadiazole product Compound 138 as a light yellow solid. MS: [M+1] = 430. Example 83: Synthesis of Compound 141:

[0702] The Compound of Example 83 was synthesized in a synthetic route analogous to that described for Example 82, with the use of isobutyramidoxime in place of acetamide oxime to generate the compound of Example 83 as a yellowish solid: MS: [M+1 ] = 458. Example 84: Synthesis of Compound 157:

[0703] To the acid prepared above in Example 81 (60.2 mg, 0.154 mmol) stirring in DCM (0.7 ml) at RT was added carbonyl diimidazole (49.9 mg, 0.308 mmol). The mixture was stirred for 40 min, then cooled to 0°C and ammonia (0.112 ml) added, allowed to warm naturally to RT, while stirring continued overnight. The reaction was concentrated, water (8 ml) added and stirred well for 30 min. The resulting precipitate was collected by filtration, washed with water and dried to yield 51.1 mg (85%) of the primary amide as a brownish solid. MS: [M+1] = 391.

[0704] The amide (51.1 mg) from above was treated with POCl3 (200.8 mg, 1.31 mmol) in 1,4-dioxane (0.9 ml) at 90 ° C for 14 h. Under cooling to RT, the reaction was carefully quenched with sat. NaHCO3. (5 ml), stirred for 20 min. The precipitate was collected by filtration, washed with water and dried to give 40.9 mg (85%) of nitrile product Compound 157 as a brownish solid. MS: [M+1] = 373. Example 85: Synthesis of Compound 147:

[0705] To nitrile (45.8 mg, 0.123 mmol) in a round bottom flask was added hydroxylamine hydrochloride (14.5 mg, 0.209 mmol), K2CO3 (22.3 mg, 0.161 mmol), ethanol (0. 6 ml) and water (0.15 ml). The reaction mixture was heated to 80 °C for 30 min, cooled and concentrated in vacuo. The resulting slurry was treated with water (1.5 ml), sonicated to aid mixing, and stirred at RT for 1 h before being cooled to 4°C. The resulting precipitate was collected by filtration, washed with water (1 ml) and dried to give 40.8 mg (82%) of auto as an off-white solid. MS: [M+1] = 406.

[0706] Isobutyric acid (31.4 mg, 0.582 mmol) was treated with carbonyl diimidazole (28.4 mg, 0.175 mmol) in THF (0.5 ml) for 2 h. N-hydroxycarboxamide adduct (11.8 mg, 0.0291 mmol) was added and the reaction was stirred at RT for 30 min. More isobutyric acid (0.5 ml) was added and the reaction mixture was heated at 110 °C for 16 h, cooled, sat. (8 ml) added and extracted with EtOAc (3x); the combined organic washed with brine and dried with MgSO4. TLC Prep (5% MeOH in EtOAc) of the concentrated filtrate gave 11.2 mg (84%) of the oxadiazole Compound 147 as a white solid. MS: [M+1] = 458. Example 86: Synthesis of Compound 148:

[0707] The Compound of Example 86 was synthesized in a synthetic route analogous to that described for Example 85, with the use of acetic acid in place of isobutyric acid to generate the compound of Example 86 as a white solid: MS: [M+ 1] = 430. Example 87: Synthesis of Compound 158:

[0708] The Compound of Example 87 was synthesized in a synthetic route analogous to that described for Example 85, with the use of propionic acid in place of isobutyric acid to generate the compound of Example 87 as a white solid: MS: [M+ 1] = 444. Example 88: Synthesis of Compound 159:

[0709] Trifluoroacetic anhydride (196.9 mg, 0.938 mmol) was added to the suspended N-hydroxycarboxamide adduct (19.0 mg, 0.0469 mmol) and stirred in THF (0.2 ml) at RT. After 30 min. stirring, the reaction was heated to 70 ° C for 1 h, cooled to RT and diluted with EtOAc (10 ml), to which sat. NaHCO3 was added. and stirred for 30 min. The aqueous layer was separated and extracted with EtOAc (1x), the combined organic layer was washed with brine and dried over MgSO4. Filtration and solvent removal generated a slurry to which nBuOH (5 ml) and HOAc (0.5 ml) were added. It was heated at 115 °C for 16 h, cooled and concentrated in vacuo, diluted with EtOAc, washed with sat. NaHCO3, brine and dried with MgSO4. TLC Prep (5% MeOH in EtOAc) of the concentrated filtrate gave 11.5 mg (51%) of the desired trifluoromethyl oxadiazole analogue Compound 159 as a yellowish solid. MS: [M+1] = 484. Scheme 25 Example 89: Synthesis of Compound 162:

[0710] To lactam 62 (503.4 mg, 1.42 mmol) stirring in THF (2.9 ml) and DMF (0.8 ml) at -20 ° C was added tBuOK (240.2 mg). After 30 min. After stirring, diethyl chlorophosphate (377.7 mg, 2.12 mmol) was added dropwise and the reaction mixture was slowly allowed to warm naturally to 8 °C in 3 h, before being cooled to -20 °C. 2.26 ml (2.26 mmol) of oxadiazole isocyanate (ref. JMC, 1996, 39, 170; prepared as 1M THF solution) was added. The reaction mixture was further cooled to -78 °C, tBuOK (238.4 mg) was added and the reaction was slowly allowed to warm naturally to RT overnight. The sat. NH4Cl. (5ml) was added and the mixture was extracted with EtOAc (2x), washed with brine and dried over MgSO4. Under filtration and concentration, the product was isolated by silica gel column chromatography using a gradient elution of 0 to 10% MeOH in EtOAc to generate 246.0 mg of imidazole product as a yellowish solid. . MS: [M+1] = 462.

[0711] The imidazole (246.0 mg, 0.533 mmol) obtained above was stirred in DCM (3 ml). Trifluoroacetic acid (3 ml) was added, followed by trifluoromethyl sulfonic acid (160.0 mg, 1.07 mmol). After 3 h of stirring, the reaction was diluted with DCM (20 ml), washed with sat. NaHCO3; the aqueous layer was separated and extracted with DCM (2x), the combined DCM solution was washed with brine and dried over MgSO4. Filtration and vacuum solvent removal gave 208.7 mg of the crude lactam product as a yellowish flaky solid. [M+1] = 312.

[0712] Phosphorous oxychloride (29.9 mg, 0.195 mmol) was added to a solution of the lactam obtained above (22.5 mg, 0.0723 mmol) and N,N-dimethyl-p-toluidine (51.8 mg , 0.383 mmol) under stirring in chlorobenzene (0.45 ml) under a nitrogen atmosphere. The reaction mixture was heated to 135 °C for 3 h, then cooled to RT. Diisopropylethylamine (75.7 mg, 0.586 mmol) and phenoxy acetic hydrazide (50.1 mg, 0.302 mmol) were added and the reaction mixture was heated at 100 °C for 14 h, cooled to RT and partitioned between sat. and EtOAc. The aqueous layer was separated and extracted with EtOAc; the combined EtOAc solution was washed with brine and dried over MgSO4. Under filtration and concentration, the product Compound 162 was isolated by silica gel column chromatography using a gradient elution of 0 to 10% MeOH in EtOAc as a yellowish solid. Weight: 11.8 mg (37%). MS: [M+1] = 442. Example 90: Synthesis of Compound 163:

[0713] The Compound of Example 90 was synthesized in a synthetic route analogous to that described for Example 89, with the use of 4-fluorophenoxy acetic hydrazide in place of phenoxy acetic hydrazide to generate the compound of Example 90 as a yellowish solid : MS: [M+1] = 460. Example 91: Synthesis of Compound 164:

[0714] The Compound of Example 91 was synthesized in a synthetic route analogous to that described for Example 89, with the use of methoxy acetic hydrazide in place of phenoxy acetic hydrazide to generate the compound of Example 91 as a yellowish solid: MS: [ M+1] = 380. Example 92: Synthesis of Compound 165:

[0715] Preparation of benzyloxy acetic hydrazide: Diimidazole carbonyl (1.52 g, 9.39 mmol) was added to benzyloxy acetic acid (1.2 g, 7.22 mmol) under stirring in THF (60 ml) at 0 °C. The ice bath was removed and stirring continued for 1 h. The resulting cloudy solution was added to stirring hydrazine (0.927 g, 28.9 mmol) in THF (40 ml) at RT. After 16 h, the reaction mixture was concentrated to a slurry, to which water (120 ml) was added, extracted with DCM (3x); the combined DCM solution washed with brine and dried with MgSO4. Filtration and solvent removal gave 0.908 g (70%) of the hydrazide as a clear viscous oil. It was subjected to azetrope formation in toluene a few times before use. The Compound of Example 92 was synthesized in a synthetic route analogous to that described for Example 89, with the use of benzyloxy acetic hydrazide in place of phenoxy acetic hydrazide to generate the compound of Example 92 as a yellowish solid: MS: [M+1 ] = 456. Example 93: Synthesis of Compound 166:

[0716] Compound 165 from above (58.5 mg, 0.128 mmol) was treated with 10% Pd-C (catalytic) in EtOAc (4 ml) and MeOH (4 ml) under hydrogen atmosphere for 2 h . The catalyst was removed by Celite filtration. Conc. HCl was added to the filtrate. (0.89 ml) and the mixture was stirred at RT for 16 h. Excess Na2CO3 (aq.) was added and the solution was extracted with EtOAc (2x); the combined organic solution was washed with brine and dried over MgSO4. TLC Prep of the concentrated filtrate using 15% MeOH in EtOAc generated 14.9 mg of the primary amide ([M+1] = 417) as a yellowish solid. This primary amide was treated with phosphorous oxychloride (54.9 mg, 0.358 mmol) in 1,4-dioxane (1 ml) at 90 °C for 14 h. Under cooling, the reaction mixture was diluted with EtOAc, washed with sat. NaHCO3; the aqueous layer separated and extracted with EtOAc (1x), the combined organic solution was washed with brine and dried over MgSO4. TLC Prep of the concentrated filtrate using 5% MeOH in EtOAc generated 5.2 mg of the desired nitrile product Compound 166 as white needles. [M+1] = 399. Scheme 26 Example 94: Synthesis of Compound 169:

[0717] To lactam 62 (2.23 g, 6.24 mmol) stirring in THF (10 ml) and DMF (3 ml) at -20 °C was added tBuOK (1.05 g, 9.36 mmol) . After 30 min. After stirring, diethyl chlorophosphate (1.66 g, 9.36 mmol) was added dropwise and the reaction mixture was slowly allowed to warm naturally to 8 to 10 °C in 3 h, before being cooled to -20 °C. W. 10.0 ml (10.0 mmol) of oxadiazole isocyanate (ref. JMC, 1996, 39, 170; prepared as 1M THF solution) was added. The reaction mixture was further cooled to -78 °C, tBuOK (1.05g, 9.36 mmol) was added and the reaction was slowly allowed to warm naturally to RT overnight. The sat. NH4Cl. (20 ml) was added and the mixture was extracted with EtOAc (3x), washed with brine and dried over MgSO4. Under filtration and concentration, the product was isolated via silica gel column chromatography using a gradient elution of 10 to 100% EtOAc in DCM to generate 1.07 g (35%) of imidazole product. as a yellowish frothy solid. MS: [M+1] = 490.

[0718] The imidazole (1.07 g, 2.18 mmol) obtained above was stirred in DCM (11 ml). Trifluoroacetic acid (11 ml) was added, followed by trifluoromethyl sulfonic acid (0.656 g, 4.37 mmol). After 4 h of stirring, the reaction was concentrated in vacuo, diluted with DCM (50 ml), washed with sat. NaHCO3; the aqueous layer was separated and extracted with DCM (2x), the combined DCM solution was washed with brine and dried over MgSO4. Filtration and removal of solvent under vacuum gave 0.872 g of the crude lactam product as a brownish solid. [M+1] = 340.

[0719] Phosphorous oxychloride (51.0 mg, 0.333 mmol) was added to a solution of the lactam obtained above (45.0 mg, 0.133 mmol) and N,N-dimethyl-p-toluidine (89.6 mg, 0.663 mmol) under stirring in chlorobenzene (0.60 ml) under a nitrogen atmosphere. The reaction mixture was heated to 135 °C for 3 h, then cooled to RT. Diisopropylethylamine (137.5 mg, 1.06 mmol) and methoxy acetic hydrazide (83.1 mg, 0.798 mmol) was added and the reaction mixture was heated at 100 °C for 4 h, cooled to RT, diluted with EtOAc, washed with sat. NaHCO3, brine and dried with MgSO4. Under filtration and concentration, the product Compound 169 was isolated by silica gel column chromatography using a gradient elution of 0 to 13% MeOH in EtOAc as a brownish solid. Weight: 14.3 mg (26%). MS: [M+1] = 408. Example 95: Synthesis of Compound 171:

[0720] The Compound of Example 95 was synthesized in a synthetic route analogous to that described for Example 94, with the use of phenoxy acetic hydrazide in place of methoxy acetic hydrazide to generate the compound of Example 95 as a yellowish solid: MS: [ M+1] = 470. Example 96: Synthesis of Compound 172:

[0721] The Compound of Example 96 was synthesized in a synthetic route analogous to that described for Example 94, with the use of 4-fluoro-phenoxy acetic hydrazide in place of methoxy acetic hydrazide to generate the compound of Example 96 as a yellowish solid : MS: [M+1] = 488. Example 97: Synthesis of Compound 173:

[0722] The Compound of Example 97 was synthesized in a synthetic route analogous to that described for Example 94, with the use of ethoxy acetic hydrazide in place of methoxy acetic hydrazide to generate the compound of Example 97 as a yellowish solid: MS: [ M+1] = 422. Example 98: Synthesis of Compound 174:

[0723] The Compound of Example 98 was synthesized in a synthetic route analogous to that described for Example 94, with the use of 2-fluoro-phenoxy acetic hydrazide in place of methoxy acetic hydrazide to generate the compound of Example 98 as a yellowish solid : MS: [M+1] = 488. Example 99: Synthesis of Compound 175:

[0724] The Compound of Example 99 was synthesized in a synthetic route analogous to that described for Example 94, with the use of 2-chloro-phenoxy acetic hydrazide in place of methoxy acetic hydrazide to generate the compound of Example 99 as a yellowish solid : MS: [M+1] = 504. Example 100: Synthesis of Compound 176:

[0725] Preparation of 3-pyridyloxy acetic hydrazide: A solution of ethyl 3-pyridyloxy acetic (0.50 g, 2.76 mmol) and hydrazine (0.31 g, 9.66 mmol) in isopropyl alcohol (35 ml ) was heated at 85 °C for 30 h, cooled and concentrated in vacuo. The resulting white solid was dissolved in a small amount of sat. NaCl solution. and extracted with EtOAc repeatedly. The combined organic solution was dried with MgSO4. Filtration and solvent removal generated 177 mg of the desired acetic hydrazide as a white solid. Residual water moisture was removed by azeotropic distillation in toluene. The Compound of Example 100 was synthesized in a synthetic route analogous to that described for Example 94, with the use of 3-pyridyloxy acetic hydrazide in place of methoxy acetic hydrazide to generate the compound of Example 100 as a yellowish solid: MS: [M +1] = 471.

[0726] The Compound of Example 101 was synthesized in a synthetic route analogous to that described for Example 94, with the use of 1-naphthoxy acetic hydrazide in place of methoxy acetic hydrazide to generate the compound of Example 101 as an off-white solid : MS: [M+1] = 520. Example 102: Synthesis of Compound 179:

[0727] The Compound of Example 102 was synthesized in a synthetic route analogous to that described for Example 94, with the use of 3-fluorophenoxy acetic hydrazide in place of methoxy acetic hydrazide to generate the compound of Example 102 as a yellowish solid: MS : [M+1] = 488. Example 103: Synthesis of Compound 178:

[0728] Phosphorous oxychloride (64.8 mg, 0.422 mmol) was added to a solution of oxadiazolyl imidazole lactam (57.5 mg, 0.169 mmol) and N,N-dimethyl-p-toluidine (114.6 mg, 0.847 mmol) under stirring in chlorobenzene (0.70 ml) under a nitrogen atmosphere. The reaction mixture was heated to 135 °C for 3 h, then cooled to RT. Diisopropylethylamine (174.7 mg, 1.35 mmol), t-BuOH (0.3 ml) and 2-hydroxyacetic hydrazide (91.3 mg, 1.01 mmol) were added. The reaction mixture was stirred at RT for 20min, then allowed to warm naturally to 50°C for one hour, followed by heating to 80°C for one hour, before finally being heated to 100°C for one day. To the other. Under cooling to RT, the reaction was diluted with EtOAc, washed with brine and dried with MgSO4. Silica gel column chromatography of the concentrated filtrate using a gradient elution of 0 to 20% MeOH in EtOAc generated the desired hydroxymethyl triazole product as a yellowish solid. Weight: 18.1 mg (27%). MS: [M+1] = 394.

[0729] To a solution of hydroxymethyl triazole from the above (18.1 mg, 0.046 mmol), cyclopentyl bromide (274.0 mg, 1.84 mmol) and HMPA (16.5 mg, 0.092 mmol) under stirring in THF (0.5 ml) NaH (60% suspension; 18.4 mg, 0.46 mmol) was added. After 10 min, the reaction was heated to 100 °C for 6 h, cooled, quenched with sat. and extracted with EtOAc (2x), washed with brine and dried with MgSO4. TLC Prep of the concentrated filtrate using 8% MeOH in EtOAc generated 5.5 mg (26%) of the desired ether Compound 178 as a yellowish solid. [M+1] = 462. Scheme 27 Example 104: Synthesis of Compound 168:

[0730] To a suspension of benzyl glycinate hydrochloride (5 g, 24.8 mmol) in DCM (100 ml) was added EDC.HCl (6.2 g, 33.2 mmol) and triethylamine (5.2 ml , 37.2 mmol). The suspension was cooled to -50°C, then formic acid (1.4 ml, 37.2 mmol) in DCM (5 ml) was added. The reaction mixture was stirred at -50°C for one hour, then at 4°C for 3 h. The solution was diluted with 1N HCl and extracted with DCM (2x). The combined organic phases were washed with brine and dried over MgSO4. Filtration and concentration generated 3.89 g (81% yield) of formylated glycine as an oil (M+1=194).

[0731] To a solution of formylated glycine derivative (1 g, 5.2 mmol) in DCM (30 ml) was added triethylamine (3.2 ml, 23 mmol). The solution was cooled to -50 °C and POCl3 (1.9 ml, 20.8 mmol) was added slowly. The solution was stirred at -50°C for 10 min, then stirred at room temperature for 40 min. The solution turned light reddish brown. It was diluted with DCM and a 20% sodium carbonate solution (100 ml) was added. The reaction mixture was stirred vigorously for 15 min. The organic phase was separated twice and dried with MgSO4. Filtration and concentration generated the desired benzyl isocyanacetate in quantitative yield that was used in the next step without further purification.

[0732] To a solution of 1,2,4-triazole (914 mg, 13.2 mmol) in anhydrous CH3CN (20 ml) at 0 °C was added i-Pr2NEt (2.5 ml, 14.6 mmol) . Once all the triazole was dissolved, POCl3 (0.43 ml, 4.6 mmol) was added. The mixture was stirred at 0°C for 2 h. Lactam 16' ester (1 g, 3.31 mmol) was added. The resulting solution was heated in an oil bath at 80 °C for 16 h. The mixture was cooled with an ice bath. Diluted with EtOAc, then water was added. The aqueous layer was separated and extracted with EtOAc four times. The combined organic extracts were washed with brine and dried with MgSO4. Filtration and concentration generated a light yellow solid which was used directly in the next step (M+1=354).

[0733] A solution of benzyl isocyanacetate (892 mg, 5.1 mmol) in DMF (10 ml) was cooled to -50 ° C under a nitrogen atmosphere. KOtBu (514 mg, 4.6 mmol) was added. The mixture was stirred at -50°C for 1 h. The triazole derivative prepared above (900 mg, 2.55 mmol) in DMF (5 ml) was added slowly at -50 °C. The mixture was allowed to warm naturally to room temperature over 16 h. Saturated aqueous NH4Cl solution was added and it was extracted with EtOAc three times. The combined extracts were washed with brine (3x) and dried with MgSO4. Filtration and concentration generated a crude product. Chromatography (24 g silica gel column of RediSep, eluted with 70% EtOAc in hexanes) to give 886 mg (76% yield) of product (M+1=460).

[0734] To a solution of benzyl ester derivative (770 mg, 1.68 mmol) in EtOAc (10 ml) and MeOH (30 ml) was added wet Pd/C (60 mg) and the resulting suspension was stirred under a hydrogen atmosphere for 48 h. The suspension was filtered through Celite and the resulting solution was concentrated. The crude debenzylated product (530 mg, 86% yield) was used in the next step without further purification (M+1= 370).

[0735] To a suspension of acid (530 mg, 1.44 mmol) in DCM (10 ml) was added CDI (931 mg, 5.75 mmol). The solution was stirred at room temperature for 2 h. The solution was cooled with an ice bath and an NH4OH solution (6 ml) was added. The solution was stirred for 30 min. and it was concentrated. The solid was collected via filtration and washed with water to give 422 mg (80%) of the desired product as a brown solid. (M+1= 369).

[0736] To a suspension of primary amide derivative (422 mg, 1.15 mmol) in dioxane (10 ml) POCI3 (160 μl, 1.7 mmol) was added. The suspension was heated at 90°C for 2 h. The resulting solution was cooled with an ice bath and quenched with a saturated aqueous solution of NaHCO3. The solid was collected via filtration to generate 308 mg (77% yield) of the desired cyanide derivative. (M+1= 351).

[0737] To a suspension of cyanide derivative (150 mg, 0.44 mmol) in EtOH (4 ml) and water (1 ml) was added hydroxylamine hydrochloride (40 mg, 0.57 mmol) and potassium carbonate ( 67 mg, 0.48 mmol). The suspension was stirred at room temperature for 16 h. LCMS indicated about 50% conversion. More hydroxylamine hydrochloride (40 mg, 0.57 mmol) and potassium carbonate (67 mg, 0.48 mmol) were added and stirred for another 24 h. The solution was diluted with EtOAc and washed with water. The combined organic phases were washed with brine, dried over MgSO4. Filtration and concentration gave 145 mg (86% yield) of the desired product. (M+1= 384).

[0738] To a solution of acetic acid (0.22 ml, 3.8 mmol) in THF (5 ml) was added CDI (123 mg, 0.76 mmol). The solution was stirred at room temperature for 2 h. The solution was then poured into a flask containing the oxime derivative (145 mg, 0.38 mmol) and heated at 70 °C for 1 hour. The solvent was evaporated and the crude material was suspended in acetic acid (8 ml) and heated at 130°C for one hour. The solvent was evaporated and the crude material was triturated with water to give 134 mg (86%) of the desired product (M+1=408).

[0739] To a suspension of ester derivative (50 mg, 0.12 mmol) in THF (1 ml) was added lithium aluminum hydride (7 mg, 0.18 mmol). The suspension was stirred at room temperature for 2 h. LCMS indicated about 70% conversion over some other side products and some starting material remaining. More lithium aluminum hydride (4 mg) was added and the reaction mixture was stirred at room temperature for another 30 min. The reaction mixture was cooled with 1N HCl. The solution was extracted with EtOAc (3x). The combined organic phases were washed with brine, dried over MgSO4. Filtration and concentration generated 20 mg (45% yield) of the desired alcohol product. (M+1= 366).

[0740] To a suspension of alcohol (20 mg, 0.055 mmol) in dioxane (1 ml) was added POBR3 (31 mg, 0.11 mmol). The reaction mixture was heated at 110 °C for 1 hour. The reaction mixture was cooled with an ice bath and sat. NaHCO3 solution. aq. was added. The resulting solution was extracted with EtOaAc (3X). The combined organic phases were washed with brine and dried over MgSO4. The solvent was concentrated to give 22 mg (96% yield) of the desired product (M+1=428).

[0741] To a vial containing alkyl bromide derivative (22 mg, 0.052 mmol) was added 3-fluorophenol (58 mg, 0.52 mmol) in dioxane (1 ml) and potassium carbonate (72 mg, 0.52 mmol) mmol). The reaction mixture was heated at 90 °C for 1 hour. The reaction mixture was diluted with sat. NaHCO3 solution. aq. The resulting solution was extracted with EtOac (3X). The combined organic phases were washed with brine and dried over MgSO4. Filtration and concentration generated a crude product. Purification by prep TLC (elution system: EtOAc) to generate 5 mg (21% yield) of the desired product Compound 168 (M+1=460). 1H NMR (CDCl3) δ 7.87 (1H, s), 7.65 (1H,d, J= 3.5 Hz), 7.57 (1H, d, J= 10 Hz), 7.24 ( 1H, m), 7.19 (1H, dd, J= 3.5, 9 Hz), 6.77 (1H, dd, J= 2.5, 9.5 Hz), 6.72 (2H, m ), 5.26 (2H, s), 3.97 (3H, s), 2.48 (3H, s).

[0742] With the implementation of similar and analogous reactions to those shown in Schemes 1 to 27, the following compounds are also specifically contemplated in this application:

[0743] Example 105: Assessment of the activity of the positive allosteric modulator of the α5-containing GABAA receptor (GABAAR)

[0744] Step 1: Establish clones of GABAAR subunits (α5, β3, Y2, α1, α2 and α3) and prepare the corresponding cRNAs: Human clones of GABAA-R subunits α5, β3, Y2, α1, α2 and α3 are obtained from commercial resources (e.g., OriGene, http://www.origene.com and Genescript, http://www.genescript.com). These clones are manipulated into vector pRC, pCDM, pcDNA and pBluescript KSM (for oocyte expression) or other equivalent expression vectors. Conventional transfection agents (e.g., Fu-Gene, Lipofectamine 2000, or others) are used to temporarily transfect host cells.

[0745]Step 2 - Functional GABAAR assay of α5β3Y2, α1β3Y2, α2β3Y2 and α3β3Y2 subtypes in Xenopus oocyte expression system: The cRNAs encoding the α5, β3, Y2, α1, α2 and α3 subunits are transcribed in vitro using the T3 mMESSAGE mMACHINE kit (Ambion) and injected (in a ratio of α:β:Y = 2:2:1 or other optimized conditions) into freshly prepared oocytes from Xenopus laevis. After two days of culture, GABA-controlled Cl currents from oocytes are performed using TEVC settings (Warner Instruments, Inc., Foster City, CA). GABA, benzodiazepine and diazepam are used as reference compounds to validate the system.

[0746] Step 3 - Evaluate the test compounds for positive allosteric modulator activity in the α5β3Y2 subtype and test off-target activity in the β3Y2 subtypes coupled to α1 to α3 when the EC50 selectivity cutoff = 5 μM is achieved: GABA-controlled Cl- current from oocytes is measured in the TEVC configuration in the presence of the test compounds. The positive allosteric modulator activity of each of the test compounds is tested in a 5-point dose response assay. The test compounds include some reference compounds (literature EC50 values for the α5β3Y2 subtype are in the range of 3 to 10 μM). EC5os in the α5β3Y2 subtype are obtained for each compound. If the EC50 in α5β3Y2 is < 5 μM, then the EC50 of the other three subtypes (α1β2Y2, α2β3Y2 and α3β3Y2) is additionally determined individually in order to test the selectivity of compounds in the α5β3Y2 subtype over other subtypes.

[0747] Step 4 - Evaluate additional test compounds on the α5β3Y2 subtype and test for off-target activities when the selectivity cutoff of EC50=0.5 μM is reached: The second batch of test compounds is tested using the same strategy, but with a lower EC50 cutoff (0.5 μM). Again, the EC50s of the α5β3Y2 subtype for each of the compounds are determined. The α1 to α3-coupled β3Y2 subtypes are tested only if the EC50 for the α5-containing receptor is < 0.5 μM.

[0748] Example 106: Evaluation of Compounds regarding the Binding and Activity of Positive Allosteric Modulator on GABAA α5 Receptors

Binding activity of test compounds on GABAAR

[0749] Membrane preparation and tissue culture: Ligation was performed on Ltk cells that stably express GABAA receptors: α1βlY2, α2β3Y2, α3β3Y2 and α5β3Y2 (supplied by Merck Co., NJ, USA). Cells were seeded in 100 mm culture dishes in DMEM/F12 medium containing 10% serum and antibiotics in 5% CO2 and allowed to grow for 1 to 2 days. GABAAR expression was then induced by dexamethasone as follows: 0.5 μM for 1 day for GABAA R containing α5 and 2 μM for 3 days for GABAA R containing α1, α2 and α3. After induction, cells were collected by scraping in Dulbecco's phosphate-buffered saline (DPBS, pH 7.4, Invitrogen, Carlsbad, CA, USA) and centrifuged at 150 x g for 10 min. The pellet was washed twice by resuspension and centrifugation. Cell pellets from at least 5 different preparations were combined, suspended in binding assay buffer (50 mM KH2PO4; 1 mM EDTA; 0.2 M KCl, pH 7.4) and membranes prepared by of sonication (3 to 5 times, 30 seconds) using the Branson 150 sonifier (G.Heinmann, Germany). Protein content was determined using the BCA assay (Bio-Rad Labs, Reinach, Switzerland) with bovine serum albumin (Sigma Aldrich, St. Louis, MO, USA) as the standard. Aliquots were prepared and stored at −20°C during further use in binding assays.

[0750] Ligand binding: Saturation binding curves were obtained by incubating membranes with increasing concentrations (0.01 to 8 nM) of [3H]Rol5-1788 (Flumazepil, 75 to 85 Ci/mmol, PerkinElmer, MA, USA), with non-specific binding measured in the presence of 10 μM diazepam. Inhibition of [3H]Rol5-1788 binding of test compounds was performed at radioligand concentrations at or less than the Kd values for GABAA Rs containing α1, α2, α3, and α5 determined from the saturation curves.

[0751] All binding assays were performed for 1 h at 4 ° C in assay buffer. The total assay volume was 0.5 ml containing 0.2 mg/ml protein for GABAA R membranes containing α5 and 0.4 mg/ml for GABAA R membranes containing α1, α2 and α3. Incubations were terminated by filtration through GF/B filters using a 24-Cell Harvestor cell harvester (Brandel, Gaithersburg, MD, USA) followed by 3 washes with ice-cold assay buffer. Filters were transferred to scintillation vials, 5 ml of scintillation liquid added, mixed by vortexing and kept in the dark. The following day, radioactivity was obtained using a scintillation counter (Beckman Coulter, Brea, CA, USA). All assays were performed in triplicate.

[0752] Data analysis: Saturation and inhibition curves were obtained using GraphPad Prism software (GraphPad Software, Inc., CA, USA). The equilibrium dissociation constants (Ki values) of the unidentified ligand were determined using the Cheng-Prusoff equation Ki = IC50/ (1+S/Kd), where IC50 is the concentration of unidentified ligand that inhibits 50 % ligand binding [3H], S is the radioligand concentration and Kd is the equilibrium dissociation constant of the radioactive ligand. A logarithmic range of compounds (1 nM to 10 μM) was used to determine Ki values which are presented as Mean ± SD from triplicate assays.

[0753](B) Positive allosteric modulator activity of test compounds on GABAA R of subtype α5β2Y2

[0754] The compounds of the present invention were initially subjected to screening at 100 nM for their ability to potentiate a GABA EC20 concentration in oocytes containing GABAA receptors (α5β2Y2), using a protocol essentially similar to that presented above .

[0755] On day 1, 1 ng/32 nL of GABAA α5β2Y2 cDNA was injected into an oocyte. The test starts on day 2. The cDNA injected into the oocytes was a mixture of alpha, beta and gamma, its ratio is 1:1:10 (by weight) and the total weight of the 3 mixed subunits to be injected into an oocyte it was 1 ng in 32 nl of volume. The injected oocytes can also be tested on day 3. In such a case, the amount of cDNA injected into the oocytes should be reduced by 20%.

[0756] The compounds of the present invention were tested using the following procedures.

GABA dose response

[0757]8 oocytes were placed in 8 OpusXpress chambers and superfused with modified Barth's saline (MBS) at 3 ml/min. Glass electrodes backfilled with 3M KCl (0.5 to 3 megohms) were used. The membrane potential of oocytes was clamped by voltage at -60 mV.

[0758] The average EC20 GABA obtained from the previous tests was applied five to six times to stabilize the oocytes. Oocytes were washed with MBS for 5 to 10 min. between each application of GABA.

[0759] The GABA dose response was performed to obtain the GABA EC20 value.

[0760] Control test (Diazepam or methyl 3,5-diphenylpyridazine-4-carboxylate)

[0761] New oocytes were used to perform a new test.

[0762]EC20 GABA was applied five to six times to stabilize the oocytes. Oocytes were washed with MBS for 5 to 10 min. between each application of GABA.

[0763]EC20 GABA was applied to obtain current (IGABA). Oocytes were washed with MBS for 5 to 10 min.

[0764] 1 μM diazepam or methyl 3,5-diphenylpyridazine-4-carboxylate was pre-applied for 40 seconds, followed by co-application of 1 μM diazepam or methyl 3,5-diphenylpyridazine-4-carboxylate and EC20 GABA to get Itest. Itest was divided by IGABA to obtain potentiation (%).

Test Compounds in Multiple Doses

[0765] Repeat the above steps 1), 2) and 3) in the control test.

[0766]2).The first concentration of a test compound was pre-applied for 40 seconds, followed by co-application of the test compound of the same concentration and EC20 GABA to obtain Itest. Divide Itest by IGABA to obtain the potentiation (%).

[0767] 3).Discard all tested oocytes, new oocytes were used and the above steps 1) and 2) were repeated to test the second concentration of the same compound. Each oocyte was used for only one concentration test for a single test compound. The steps were repeated for other test compounds.

[0768] In some embodiments, the compounds of this application have a binding affinity (as represented by Ki) on GABAARs containing α5 less than 200 nM, less than 180 nM, less than 150 nM or less than 100 nM. In some embodiments, the compounds of this application have a binding affinity (as represented by Ki) on α5-containing GABAARs of less than 50 nM. In some embodiments, the compounds of this application have a binding affinity (as represented by Ki) on α5-containing GABAARs of less than 10 nM.

[0769] In some embodiments, the compounds of this application are selective for α5-containing GABAARs over α1-containing GABAARs. In some embodiments, the compounds of this application are more than 50-fold, more than 100-fold, more than 500-fold, or more than 1,000 selective for α5-containing GABAARs relative to α1-containing GABAARs.

[0770] In some embodiments, the compounds of this application have an EC50 on GABAARs containing α5 less than 500 nM, less than 100 nM or less than 50 nM. In some embodiments, the compounds of this application have an EC50 on GA-BAARs containing α5 less than 25 nM.

[0771] In some embodiments, the compounds of this application potentiate GABAARs containing α5 to more than 10%, more than 25%, more than 50% or more than 75% at 100 nM. In some embodiments, the compounds of this application potentiate α5-containing GABAARs to greater than 10%, greater than 25%, greater than 50%, or greater than 75% at 1,000 nM.

[0772] Screening results from PAM binding and functional activity tests are summarized in Tables 1 and 2 below.

[0773] The following Table 1 illustrates the GABA α5 binding Ki's ranges associated with the compounds of this invention: Table 1

[0774] The following Table 2 illustrates the ranges of GABA α5 functional potentiation associated with the compounds of this invention: Table 2

[0775] Selected compounds of this invention demonstrate > 10-fold binding selectivity versus GABA α1, GABA α2 or GABA α3.

[0776] Example 107: Effect of Methyl 3,5-diphenylpyridazine-4-carboxylate in rats with aging-related deficiency (AI)

[0777] Methyl 3,5-diphenylpyridazine-4-carboxylate, which corresponds to compound number 6 in van Niel et al. J. Med. Chem. 48:6004 to 6011 (2005), is a selective α5-containing GABAA R agonist. It has an in vitro efficacy of α5 of +27 (EC20). The effect of methyl 3,5-diphenylpyridazine-4-carboxylate in rats with age-related deficiency was studied using a RAM task. Furthermore, receptor occupancy by methyl 3,5-diphenylpyridazine-4-carboxylate in α5-containing GABAA receptor was also studied. (A) Effect of Methyl 3,5-diphenylpyridazine-4-carboxylate in rats with age-related disability using a radial maze (RAM) behavioral task.

[0778] The effects of methyl 3,5-diphenylpyridazine-4-carboxylate on in vivo spatial memory retention of rats with aging-related disability (AI) were evaluated in a radial maze (RAM) behavioral task using vehicle control and four different dose levels of methyl 3,5-diphenylpyridazine-4-carboxylate (0.1 mg/kg, 0.3 mg/kg, 1 mg/kg and 3 mg/kg, ip). Behavioral RAM tasks were performed on eight AI rats. All five treatment conditions (vehicle and four dose levels) were tested in all eight rats.

[0779] The RAM apparatus used consisted of eight equidistantly spaced arms. An elevated maze arm (7 cm wide x 75 cm long) projected from each facet of a central octagonal platform (30 cm diameter, 51.5 cm high). The transparent sidewalls on the arms were 10 cm high and angled at 65° to form a channel. A food well (4 cm in diameter, 2 cm in depth) was situated at the distal end of each arm. Froot LoopsTM (Kellogg Company) were used as rewards. Blocks constructed of PlexiglasTM (30 cm high x 12 cm wide) could be positioned to prevent entry into any arm. Numerous extra maze clues surrounding the apparatus were also provided.

[0780] AI rats were initially subjected to a pre-training test (Chappell et al. Neuropharmacology 37: 481 to 487, 1998). The pre-training test consisted of a habituation phase (4 days), a training phase on the standard gain-change task (18 days), and another training phase (14 days), in which a brief delay was imposed between the presentation of a subset of arms designated by the experimenter (e.g., 5 arms available and 3 arms blocked) and the completion of the eight-arm gain-shift task (i.e., with all eight arms available).

[0781] In the habituation phase, rats were familiarized with the maze during an 8-minute session on four consecutive days. In each of these sessions, food rewards were spread across the RAM, initially on the central platform and arms and then progressively confined to the arms. After this habituation phase, a standard training protocol was used, in which a food pellet was situated at the end of each arm. Rats received one trial each day for 18 days. Each daily trial ended when all eight food pellets had been obtained or when 16 choices had been made or 15 minutes had elapsed. After completion of this training phase, a second training phase was carried out in which the memory demand was increased by imposing a brief delay during the test. At the beginning of each trial, three arms of the eight-arm maze were blocked. Rats were allowed to obtain food in the five arms to which access was allowed during this initial “information phase” of the trial. The rats were then removed from the maze for 60 seconds, during which time the barriers in the maze were removed, thus allowing access to all eight arms. The rats were then placed back on the central platform and allowed to obtain the remaining food rewards during this “retention test” phase of the trial. The identity and configuration of the blocked arms varied across trials.

[0782]The number of “errors” that the AI rats made during the retention test phase was tracked. An error occurs on trial if the rat entered an arm from which food had already been retrieved in the pre-delay component of the trial or if the rat re-visited an arm in the post-delay session that had already been visited.

[0783] After completion of the pre-training test, the rats were subjected to trials with longer delay intervals, i.e., a two-hour delay, between the information phase (presentation with some arms blocked) and the test retention (presentation of all arms). During the delay interval, place the rats on the testing room side of the maze, on carts in their individual home cages. AI rats were pretreated 30 to 40 minutes before daily trials with a single opportunity of the following five conditions:

[0784] vehicle control - 5% dimethyl sulfoxide, 25% polyethylene glycol 300 and 70% distilled water; 2) methyl 3,5-diphenylpyridazine-4-carboxylate at 0.1 mg/kg; 3) methyl 3,5-diphenylpyridazine-4-carboxylate at 0.3 mg/kg; 4) methyl 3,5-diphenylpyridazine-4-carboxylate in 1 mg/kg); and 5) methyl 3,5-diphenylpyridazine-4-carboxylate at 3 mg/kg; through intraperitoneal (i.p.) injection. Injections were given on alternating days with intervening treatment suspension days. Each AI rat was treated with all five conditions within the test period. To counteract any potential bias, the effect of the drug was assessed using an ascending-descending dose series, that is, the dose series was first given in an ascending order and then repeated in a descending order. Therefore, each dose had two determinations.

[0785] Parametric statistics (paired t-tests) were used to compare the retention test performance of AI rats on the two-hour delay version of the RAM task in the context of different doses of methyl 3,5-diphenylpyridazine-4- carboxylate and vehicle control (see Figure 1). The average number of errors that occurred in the tests were significantly lower with the 3 mg/kg methyl 3,5-diphenylpyridazine-4-carboxylate treatment (mean number of errors ± standard error of the mean (SEM) = 1.31 ± 0.40) than with the use of vehicle control (average number of errors ± SEM = 3.13 ± 0.62). Relative to the vehicle control treatment, methyl 3,5-diphenylpyridazine-4-carboxylate significantly improved memory performance at 3 mg/kg (t(7) = 4.233, p = 0.004).

[0786] The therapeutic dose of 3 mg/kg became ineffective when AI rats were simultaneously treated with 0.3 mg/kg of TB21007, an α5-containing GABAA R inverse agonist. The average number of errors made by rats with the combined treatment of TB21007/methyl 3,5-diphenylpyridazine-4-carboxylate (0.3 mg/kg of TB21007 with 3 mg/kg of methyl 3,5-diphenylpyridazine-4-carboxylate ) was 2.88 ± 1.32 and was not different from rats treated with the vehicle control (3.13 ± 1.17 mean errors). Thus, the effect of methyl 3,5-diphenylpyridazine-4-carboxylate on spatial memory is a GABAA receptor α5-dependent effect (see Figure 1).

[0787](B) Effect of Methyl 3,5-diphenylpyridazine-4-carboxylate on GABAA receptor occupancy containing α5

Animals

[0788] Adult male Long Evans rats (265 to 295 g, Charles River, Portage, MI, n=4/group) were used for GABAA α5 receptor occupancy studies. Mice were individually housed on ventilated stainless steel shelves on a 12:12 light/dark cycle. Food and water were available ad libitum. In additional studies to evaluate compound exposures at behaviorally active doses, young or aged Long Evan rats (n= 2 to 4/group) were used for these studies.

Compounds

[0789]Ro 15-4513 was used as a receptor occupancy (RO) tracer for GABAAα5 receptor sites in the hippocampus and cerebellum. Ro 15-4513 was chosen as the tracer based on its selectivity for GABAA α5 receptors over other alpha subunit-containing GABAA receptors and due to the fact that it has been used successfully for GABAA α5 RO studies. in animals and humans (see, e.g., Lingford-Hughes et al., J. Cereb. Blood Flow Metab. 22:878 to 889 (2002); Pym et al., Br. J. Pharmacol. 146: 817 to 825 (2005); and Maeda et al., Synapse 47: 200 to 208 (2003)). Ro 15-4513 (1 μg/kg), was dissolved in 25% hydroxyl-propyl beta-cyclodextrin and administered i.v. 20 sec. prior to RO assessments. Methyl 3,5-diphenylpyridazine-4-carboxylate (0.1 to 10 mg/kg) was synthesized by Nox Pharmaceuticals (India) and was dissolved in 25% hydroxyl-propyl beta-cyclodextrin and administered i.v. 15 sec. before tracer injection. The compounds were administered in a volume of 0.5 ml/kg, except for the larger dose of methyl 3,5-diphenylpyridazine-4-carboxylate (10 mg/kg) which was administered in a volume of 1 ml/kg. due to solubility limitations.

Tissue preparation and analysis

[0790] The rats were sacrificed by cervical dislocation 20 seconds after tracer injection. The entire brain was quickly removed and lightly rinsed with sterile water. Trunk blood was collected in EDTA-coated eppendorf tubes and stored on wet ice until study completion. The hippocampus and cerebellum were dissected and stored in 1.5 ml eppendorf tubes and placed on wet ice until tissue extraction. In a drug-naïve rat, six cortical brain tissue samples were collected for use in generating standard curve and blank samples.

[0791] Acetonitrile containing 0.1% formic acid was added to each sample in a volume four times the weight of the tissue sample. For the standard curve samples (0.1 to 30 ng/g), a calculated volume of standard reduced the volume of acetonitrile. The sample was homogenized (FastPrep-24, Lysing Matrix D; 5.5 m/s, for 60 seconds or 7 to 8 watts of power using a sonic probe dismemberer; Fisher Scientific) and centrifuged for 16 minutes in 14,000rpm. The supernatant solution (100 μl) was diluted with 300 μl of sterile water (pH 6.5). This solution was then mixed carefully and analyzed by LC/MS/MS for Ro 15-4513 (tracer) and methyl 3,5-diphenylpyridazine-4-carboxylate.

[0792] For plasma exposures, blood samples were centrifuged at 14,000 rpm for 16 minutes. After centrifugation, 50 μl of supernatant (plasma) from each sample was added to 200 μl of acetonitrile plus 0.1% formic acid. For the standard curve samples (1 to 1,000 ng/ml), a calculated volume of standard reduced the volume of acetonitrile. The samples were subjected to sonication for 5 minutes in an ultrasonic water bath, followed by centrifugation for 30 minutes at 16,000 RPM. 100 μl of supernatant was removed from each sample vial and placed in a new automated glass sample vial, followed by the addition of 300 μl of sterile water (pH 6.5). This solution was then mixed carefully and analyzed by LC/MS/MS for methyl 3,5-diphenylpyridazine-4-carboxylate.

[0793] Receptor occupancy was determined by the ratio method that compared occupancy in the hippocampus (a region of high GABAAα5 receptor density) with occupancy in the cerebellum (a region of low GABAAα5 receptor density) and additionally by a high dose of GABAAα5 negative allosteric modulator L-655,708 (10 mg/kg, i.v.) to define full occupancy.

[0794] Vehicle administration followed by tracer administration of 1 μg/kg, i.v., of Ro 15-4513 resulted in >5-fold higher levels of Ro 15-4513 in the hippocampus (1.93 ± 0.05 ng/g ) compared to the cerebellum (0.36 ± 0.02 ng/g). Methyl 3,5-diphenylpyridazine-4-carboxylate (0.01 to 10 mg/kg, i.v.) dose-dependently reduced hippocampal Ro 15-4513 binding without affecting cerebellar Ro 15-4513 levels ( Figure 2) with a dose of 10 mg/kg, i.v., demonstrating >90% occupancy (Figure 3). Both RO calculation methods yield very similar results with ED50 values for methyl 3,5-diphenylpyridazine-4-carboxylate as 1.8 mg/kg or 1.1 mg/kg based on the ratio method or with the use of L- 755,608 to define the occupation.

[0795] Exposure of methyl 3,5-diphenylpyridazine-4-carboxylate was below the limits of quantification (BQL) at 0.01 mg/kg, i.v., in both plasma and hippocampus, but was detectable at low levels in the hippocampus at 0.1 mg/kg, i.v. (see Table 3). Hippocampal exposure was linear as a 10-fold increase in dose from 0.1 to 1 mg/kg, i.v., resulted in a 12-fold increase in exposure. Increasing the dose from 1 to 10 mg/kg, i.v., only increased exposure by ~5-fold. Plasma exposure increased 12-fold as the dose increased from 1 to 10 mg/kg, i.v.

[0796] Table 3: % GABAA α5 receptor occupancy by methyl 3,5-diphenylpyridazine-4-carboxylate (0.01 to 10 mg/kg, iv). Hippocampal and plasma exposure of methyl 3,5-diphenylpyridazine-4-carboxylate by treatment group in young Long Evans rats.

[0797] Additional studies were conducted in aged Long-Evans rats to determine exposures at behaviorally relevant doses in cognition studies. Exposure in young Long-Evans rats was also determined to tie in with receptor occupancy studies that were conducted in young Long-Evans rats. Exposures in young and aged Long-Evans rats were relatively similar (Table 4, Figure 4). Increasing the dose by 3-fold from 1 to 3 mg/kg, ip, resulted in a greater than dose-proportional increase in exposure in young and aged rats in both the hippocampus and plasma with increases falling in the range from 4.5 to 6.6 times.

[0798] Table 4: Hippocampal and plasma exposure of methyl 3,5-diphenylpyridazine-4-carboxylate in young Long Evans rats by treatment group

[0799] In RO studies, an exposure of 180 ng/g in the hippocampus (1 mg/kg, i.v.) represented 32 to 39% receptor occupancy depending on the method used to determine RO. This exposure is comparable to that observed in aged rats at 3 mg/kg, i.p., suggesting that 30 to 40% RO is required for cognitive efficacy in this model.

[0800] These studies demonstrated that methyl 3,5-diphenylpyridazine-4-carboxylate produced a dose-dependent increase in GABAA a5 receptor occupancy. Methyl 3,5-diphenylpyridazine-4-carboxylate also demonstrated good brain exposure with brain/plasma ratios > 1. Studies further demonstrated that methyl 3,5-diphenylpyridazine-4-carboxylate produced its cognitive optimizing effects by modulating positive allosteric expression of the GABAA receptor subtype a5.

[0801] Example 108: Effect of ethyl 3-methoxy-7-methyl-9H-benzo[f]imidazo[1,5- a][1,2,4]triazolo[4,3-d][1,4 ]diazepine-10-carboxylate in mice with aging-related deficiency (AI)

[0802] Ethyl 3-methoxy-7-methyl-9H-benzo[f]imidazo[1,5-a][1,2,4]triazolo[4,3- d][1,4]diazepine-10- carboxylate, which corresponds to compound number 49 in Achermann et al. Bioorg. Med. Chem. Lett., 19:5746 to 5752 (2009), is a selective α5-containing GABAA R agonist.

[0803] The effect of ethyl 3-methoxy-7-methyl-9H-benzo[f]imidazo[1,5-a][1,2,4]triazolo[4,3-d][1,4]diazepine -10-carboxylate on the in vivo spatial memory retention of mice with aging-related disability (AI) was evaluated in a radial maze (RAM) behavioral task that is essentially similar to the task as described in Example 107 (A), with the use of vehicle control (25% cyclodextrin, which was tested 3 times: at the beginning, middle and end of the ascending/descending series) and six different dose levels (0.1 mg/kg, 0.3 mg/kg , 1 mg/kg, 3 mg/kg, 10 mg/kg and 30 mg/kg, each dose was tested twice) of ethyl 3-methoxy-7-methyl-9H-benzo[f]imidazo[1,5- a][1,2,4]triazolo[4,3-d][1,4]diazepine-10-carboxylate. The same experiment is repeated using the same vehicle control and doses of ethyl 3-methoxy-7-methyl-9H-benzo[f]imidazo[1,5-a][1,2,4]triazolo[4, 3- d][1,4]diazepine-10-carboxylate, in which the vehicle control was tested 5 times, at a dose of 3 mg/kg ethyl 3-methoxy-7-methyl-9H-benzo[f]imidazo [1,5-a][1,2,4]triazolo[4,3- d][1,4]diazepine-10-carboxylate was tested 4 times and the other doses of ethyl 3-methoxy-7-methyl- 9H-benzo[f]imidazo[1,5-a][1,2,4]triazolo[4,3-d][1,4]diazepine-10-carboxylate were tested twice.

[0804] Parametric statistics (paired t-tests) were used to compare the retention test performance of AI rats on the four-hour delay version of the RAM task in the context of different doses of ethyl 3-methoxy-7-methyl- 9H-benzo[f]imidazo[1,5-a][1,2,4]triazolo[4,3-d][1,4]diazepine-10-carboxylate and vehicle control (see Figure 5). Regarding vehicle control treatment, ethyl 3-methoxy-7-methyl-9H-benzo[f]imidazo[1,5-a][1,2,4]triazolo[4,3-d][1, 4]diazepine-10-carboxylate significantly improved memory performance at 3 mg/kg (t(7) = 4.13, p = 0.004, or t(7) = 3.08, p = 0.018) and at 10 mg /kg (t(7) = 2.82, p=0.026).

[0805] The effect of ethyl 3-methoxy-7-methyl-9H-benzo[f]imidazo[1,5-a][1,2,4]triazolo[4,3-d][1,4]diazepine -10-carboxylate on α5-containing GABAA receptor occupancy was also studied following a procedure that is essentially similar to that as described in Example 107(B) (see above). This study demonstrated that ethyl 3-methoxy-7-methyl-9H-benzo[f]imidazo[1,5- a][1,2,4]triazolo[4,3-d][1,4]diazepine-10 -carboxylate (0.01 to 10 mg/kg, i.v.) reduced Ro 15-4513 binding in the hippocampus without affecting cerebellar Ro 15-4513 levels (Figure 6) at a dose of 10 mg/kg, i.v. , demonstrating occupancy >90% (Figure 7).

[0806] Example 109: Effect of 6,6 dimethyl-3-(3-hydroxypropyl)thio-1-(thiazol-2-yl)-6,7-dihydro-2-benzothiophen-4(5H)-one in rats with aging-related disability using a Morris water maze behavior task

[0807]6,6 dimethyl-3-(3-hydroxypropyl)thio-1-(thiazol-2-yl)-6,7-dihydro-2-benzothiophen-4(5H)-one, which corresponds to compound 44 in Chambers et al. J. Med. Chem. 46:2227 to 2240 (2003) is a selective α5-containing GABAA R agonist.

[0808] The effects of 6,6 dimethyl-3-(3-hydroxypropyl)thio-1-(thiazol-2-yl)-6,7-dihydro-2-benzothiophen-4(5H)-one on the retention of In vivo spatial memory of mice with aging-related impairment (AI) were assessed in a Morris water maze behavior task. A water maze is a swimming pool surrounded with an innovative set of patterns in relation to the maze. The training protocol for the water maze may be based on a modified water maze task that has been shown to be hippocampal dependent (de Hoz et al., Eur. J. Neurosci., 22:745 to 754, 2005; Steele and Morris, Hippocampus 9:118 to 136, 1999).

[0809] Elderly rats with cognitive impairment were unilaterally implanted with a cannula in the lateral ventricle. Stereotactic coordinates were 1.0 mm posterior to bregma, 1.5 mm lateral to medial, and 3.5 mm ventral to the skull surface. After approximately one week of recovery, rats were pretrained in a water maze for 2 days (6 trials per day) to locate a submerged escape platform hidden beneath the pool surface, where the location of the escape platform was varied. from day to day. No intracerebroventricular (ICV) infusions were given during pretraining.

[0810] After pre-training, rats received an ICV infusion of 100 μg of 6,6 dimethyl-3-(3-hydroxypropyl)thio-1-(thiazol-2-yl)-6,7-dihydro-2- benzothiophen-4(5H)-one (n = 6) in 5 μl of DMSO or vehicle DMSO (n = 5) 40 min. before water maze testing and training. Training consisted of 8 trials per day for 2 days, in which the hidden escape platform remained in the same location. Rats were given 60 seconds to locate the platform with an intertrial interval of 60 seconds.

[0811] Rats received a probe test (120 seconds) 24 h after the end of training, in which the escape platform was removed.

[0812] During training, there were 4 blocks, where each block had 4 training trials.

[0813] Rats treated with vehicle and 6,6-dimethyl-3-(3-hydroxypropyl)thio-1-(thiazol-2-yl)-6,7-dihydro-2-benzothiophen-4(5H)-one found the escape platform at approximately the same time as at the beginning of training (block 1). In this training block, rats treated with vehicle and 6,6-dimethyl-3-(3-hydroxypropyl)thio-1-(thiazol-2-yl)-6,7-dihydro-2-benzothiophen-4(5H)- It took both of them about 24 seconds to find the escape platform. However, rats treated with 6,6-dimethyl-3-(3-hydroxypropyl)thio-1-(thiazol-2-yl)-6,7-dihydro-2-benzothiophen-4(5H)-one were able to find the platform more proficiently (i.e., faster) at the end of training (block 4) than those treated with vehicle alone. In block 4, rats treated with 6,6-dimethyl-3-(3-hydroxypropyl)thio-1-(thiazol-2-yl)-6,7-dihydro-2-benzothiophen-4(5H)-one took ca. It took 9.6 seconds to find the escape platform, while vehicle-treated rats took about 19.69 seconds. These results suggested that 6,6 dimethyl-3-(3-hydroxypropyl)thio-1-(thiazol-2-yl)-6,7-dihydro-2-benzothiophen-4(5H)-one improved learning of the water maze in rats (see Figure 8(A)).

[0814]During a test trial 24 h after training, the escape platform was removed. The rats' search/swim pattern was used to measure whether the rats remembered where the escape platform was located during pre-trial training in order to test the rats' long-term memory. In this trial, the “target annular space” is a designated area 1.5 times the size of the escape platform surrounding the area where the platform was situated during pre-trial training. The “opposite annular space” is a control area of the same size as the size of the target annular space, which is situated opposite the target annular space in the pool. If the rats had good long-term memory, they would tend to search the area surrounding the location where the platform was during pre-trial training (i.e., the “target” annular space; not the “opposite” annular space). The “time in ring space” is the amount of time in seconds that the rat spends in the target or opposite ring space area. The “number(s) of crossings” in ring space is the number of times the rat swam through the target or opposite area of ring space.

[0815] Rats receiving vehicle spent the same amount of time in the target annular space and opposite annular space, which indicates that these rats did not appear to remember where the platform was during pre-trial training. In contrast, rats treated with 6,6-dimethyl-3-(3-hydroxypropyl)thio-1-(thiazol-2-yl)-6,7-dihydro-2-benzothiophen-4(5H)-one took a longer significantly larger in the target annular space and crossed the “target annular space” more frequently, compared to the time they spent in or the number of times they crossed the “opposite annular space”. These results suggest that 6,6 dimethyl -3-(3-hydroxypropyl)thio-1-(thiazol-2-yl)-6,7-dihydro-2-benzothiophen-4(5H)-one improved the long-term memory of rats in the water maze task ( see, Figures 8(B) and 8(C)).

[0816] The compounds of the present invention demonstrated a positive allosteric modulatory effect on the GABAA α5 receptor (See, for example, Example 106). These compounds will enhance the effects of GABA on the α5 GABAA receptor. Therefore, the compounds of the present invention should produce cognitive enhancing effects in animals with age-related disabilities (such as rats), similar to the effects produced by other selective GABAA α5 receptor agonists, such as methyl 3,5-diphenylpyridazine-4-carboxylate , ethyl 3-methoxy-7-methyl-9H-benzo[f]imidazo[1,5-a][1,2,4]triazolo[4,3-d][1,4]diazepine-10-carboxylate and 6,6 dimethyl-3-(3-hydroxypropyl)thio-1-(thiazol-2-yl)-6,7-dihydro-2-benzothiophen-4(5H)-one (See, for example, Examples 28 to 30).

Claims (51)

1. Compound CHARACTERIZED by the fact that it has formula II: or a pharmaceutically acceptable salt, enantiomer, Z-isomer (zusammen), E-isomer (entgegen) and tautomer or combination thereof, wherein: m is an integer selected from 0 to 4; each occurrence of R1, R2, R4 and R5 is independently 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, or -P(O)(H)(OR); R3 is absent or 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)COLOR, -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, or -P(O)( H)(OR); each R6 is independently -H or -alkyl (C1-C6); each R is independently selected from: H-, (C1-C12)-aliphatic-, -cycloalkyl(C3-C10)-, -cycloalkenyl(C3-C10)-, [cycloalkyl(C3-C10)]-(C1-C12 )- aliphatic-, [cycloalkenyl(C3-C10)]-(C1-C12)-aliphatic-, [cycloalkyl(C3-C10)]-O-(C1-C12)-aliphatic-, [cycloalkenyl(C3-C10) ]-O-(C1-C12)-aliphatic-, aryl(C6-C10)-, aryl(C6-C10)-(C1-C12)aliphatic-, aryl(C6-C10)-O-(C1-C12) aliphatic-, aryl(C6-C10)-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, ( 5-10 membered heteroaryl)-(C1-C12)-aliphatic-, (5-10 membered heteroaryl)-O-(C1-C12)-aliphatic-; or (5- to 10-membered heteroaryl)-N(R'')-(C1-C12)-aliphatic-; wherein said heterocyclyl has 1 to 4 heteroatoms independently selected from N, NH, O, S, SO, or SO2, and said heteroaryl has 1 to 4 heteroatoms independently selected from N, NH, O, or S; wherein each occurrence of R is independently replaced by 0 to 5 R'; or when two R groups bond to the same atom, the two R groups may be taken together with the atom to which they are bonded to form a 3- to 10-membered aromatic or non-aromatic ring having 0 to 4 heteroatoms independently selected from N , NH, O, S, SO and SO2, wherein said ring is optionally substituted by 0 to 5 R', and wherein said ring is optionally fused to an aryl (C6-C10), 5 to 10 membered heteroaryl , cycloalkyl (C3-C10) 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 or -N(R'')2; wherein each occurrence of R'' is independently selected from H, -alkyl(C1-C6), -cycloalkyl(C3-C6), 3- to 6-membered heterocyclyl, 5- to 10-membered heteroaryl, -aryl(C6-C10 ), (5-10 membered heteroaryl)-alkyl(C1-C6), - aryl(C6-C10)-alkyl(C1-C6), (5-10 membered heteroaryl)-O-alkyl(C1-C6) or - aryl(C6-C10)-O-alkyl(C1-C6)-. 2. Compound CHARACTERIZED by the fact that it has formula III: or a pharmaceutically acceptable salt, enantiomer, Z-isomer (zusammen), E-isomer (entgegen) and tautomer or combination thereof, wherein: m is an integer selected from 0 to 4; each occurrence of R1, R2, R4 and R5 is independently 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, or -P(O)(H)(OR); R3 is absent or 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)COLOR, -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, or -P(O)( H)(OR); each R6 is independently -H or -alkyl (C1-C6); each R is independently selected from: H-, (C1-C12)-aliphatic-, cycloalkyl(C3-C10)-, cycloalkenyl(C3-C10)-, [cycloalkyl(C3-C10)]-(C1-C12)- aliphatic-, [cycloalkenyl(C3-C10)]-(C1-C12)-aliphatic-, [cycloalkyl(C3-C10)]-O-(C1-C12)-aliphatic-, [cycloalkenyl(C3-C10)]- O-(C1-C12)-aliphatic-, aryl(C6-C10)-, aryl(C6-C10)-(C1-C12)aliphatic-, aryl(C6-C10)-O-(C1-C12)aliphatic- , aryl(C6-C10)-N(R'')-(C1-C12)aliphatic-, 3- to 10-membered heterocyclyl, (3- to 10-membered heterocyclyl)-(C1-C12)aliphatic-, (heterocyclyl of 3 to 10 members)-O-(C1-C12)aliphatic-, (3 to 10 member heterocyclyl)-N(R'')-(C1-C12)aliphatic-, 5 to 10 member heteroaryl, (heteroaryl of 5 to 10 members)-(C1-C12)-aliphatic-, (5 to 10 member heteroaryl)-O-(C1-C12)-aliphatic-; or (5- to 10-membered heteroaryl)-N(R'')-(C1-C12)-aliphatic-; wherein said heterocyclyl has 1 to 4 heteroatoms independently selected from N, NH, O, S, SO, or SO2, and said heteroaryl has 1 to 4 heteroatoms independently selected from N, NH, O, or S; wherein each occurrence of R is independently replaced by 0 to 5 R'; or when two R groups bond to the same atom, the two R groups may be taken together with the atom to which they are bonded to form a 3- to 10-membered aromatic or non-aromatic ring having 0 to 4 heteroatoms independently selected from N , NH, O, S, SO and SO2, wherein said ring is optionally substituted by 0 to 5 R', and wherein said ring is optionally fused to an aryl (C6-C10), heteroaryl of 5 to 10 members, cycloalkyl (C3-C10) 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 or -N(R'')2; wherein each occurrence of R'' is independently selected from H, -alkyl(C1-C6), -cycloalkyl(C3-C6), 3- to 6-membered heterocyclyl, 5- to 10-membered heteroaryl, -aryl(C6-C10 ), (5-10 membered heteroaryl)-alkyl(C1-C6), - aryl(C6-C10)-alkyl(C1-C6), (5-10 membered heteroaryl)-O-alkyl(C1-C6) or - aryl(C6-C10)-O-alkyl(C1-C6)-. 3. Compound CHARACTERIZED by the fact that it has formula IV: or a pharmaceutically acceptable salt, enantiomer, Z-isomer (zusammen), E-isomer (entgegen) and tautomer or combination thereof, wherein: R2 is -OR8, -SR8, -(CH2)nOR8, -(CH2)nO(CH2 )nR8, or -(CH2)nN(R'')R10; and wherein R2 is independently substituted by 0 to 5 R'; men are integers independently selected from 0 to 4; each occurrence of R1, R4 and R5 is independently 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, or -P (O)(H)(OR); R3 is absent or 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)COLOR, -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, or -P(O)( H)(OR); each R6 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 by 0 to 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 by 0 to 5 R'; each R is independently selected from: H-, (C1-C12)-aliphatic-, cycloalkyl(C3-C10)-, cycloalkenyl(C3-C10)-, [cycloalkyl(C3-C10)]-(C1-C12)- aliphatic-, [cycloalkenyl(C3-C10)]-(C1-C12)-aliphatic-, [cycloalkyl(C3-C10)]-O-(C1-C12)-aliphatic-, [cycloalkenyl(C3-C10)]- O-(C1-C12)-aliphatic-, aryl(C6-C10)-, aryl(C6-C10)-(C1-C12)aliphatic-, aryl(C6-C10)-O-(C1-C12)aliphatic- , aryl(C6-C10)-N(R'')-(C1-C12)aliphatic-, 3- to 10-membered heterocyclyl, (3- to 10-membered heterocyclyl)-(C1-C12)aliphatic-, (heterocyclyl of 3 to 10 members)-O-(C1-C12)aliphatic-, (3 to 10 member heterocyclyl)-N(R'')-(C1-C12)aliphatic-, 5 to 10 member heteroaryl, (heteroaryl of 5 to 10 members)-(C1-C12)-aliphatic-, (5 to 10 member heteroaryl)-O-(C1-C12)-aliphatic-; or (5- to 10-membered heteroaryl)-N(R'')-(C1-C12)-aliphatic-; wherein said heterocyclyl has 1 to 4 heteroatoms independently selected from N, NH, O, S, SO, or SO2, and said heteroaryl has 1 to 4 heteroatoms independently selected from N, NH, O, or S; wherein each occurrence of R is independently replaced by 0 to 5 R'; or when two R groups bond to the same atom, the two R groups may be taken together with the atom to which they are bonded to form a 3- to 10-membered aromatic or non-aromatic ring having 0 to 4 heteroatoms independently selected from N , NH, O, S, SO and SO2, wherein said ring is optionally substituted by 0 to 5 R', and wherein said ring is optionally fused to an aryl (C6-C10), heteroaryl of 5 to 10 members, cycloalkyl (C3-C10) 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 or -N(R'')2; wherein each occurrence of R'' is independently selected from H, -alkyl(C1-C6), -cycloalkyl(C3-C6), 3- to 6-membered heterocyclyl, 5- to 10-membered heteroaryl, -aryl(C6-C10 ), (5-10 membered heteroaryl)-alkyl(C1-C6), - aryl(C6-C10)-alkyl(C1-C6), (5-10 membered heteroaryl)-O-alkyl(C1-C6) or - aryl(C6-C10)-O-alkyl(C1-C6)-. 4. Compound according to claim 1 or 2, or a pharmaceutically acceptable salt, enantiomer, Z-isomer (zusammen), E-isomer (entgegen) and tautomer or combination thereof, CHARACTERIZED by the fact that R2 is selected from: halogen , -R, -OR, -NO2, -(CR2)1-3R, -(CR2)1-3-OR, -CN, -CF3, - C(O)NR2, -C(O)OR or -OCF3 , where each occurrence of R is independently replaced by 0 to 5 R'. 5. Compound, according to claim 4, or a pharmaceutically acceptable salt, enantiomer, Z-isomer (zusammen), E-isomer (entgegen) and tautomer or combination thereof, CHARACTERIZED by the fact that R2 is selected from: -H, -C1-C6 alkyl, -CH2-O(C1-C6 alkyl), -(C(C1-C6 alkyl)2)1-3- O(C1-C6 alkyl), -OH , -O(alkyl(C1-C6)), -NO2, -CN, -CF3, -OCF3, - cycloalkyl(C3-C10)-, -C(O)N(alkyl(C1-C6))2, - C(O)O(alkyl(C1-C6)), 3- to 10-membered heterocyclyl-, aryl(C6-C10), 5- to 10-membered heteroaryl-, aryl(C6-C10)-(C1-C12)aliphatic -, aryl(C6-C10)-O-(C1-C12)aliphatic-, aryl(C6-C10)-N(R'')-(C1-C12)aliphatic-, aryl(C6-C10)-(C1 -C12)aliphatic-O-, (5- to 10-membered heteroaryl)-(C1-C12)-aliphatic-, (5- to 10-membered heteroaryl)-O-(C1-C12)-aliphatic-, (5-membered heteroaryl) to 10 members)-N(R'')-(C1-C12)-aliphatic-, (heteroaryl of 5 to 10 members)-(C1-C12)-aliphatic-O-, (heterocyclyl of 3 to 10 members)- (C1-C12)aliphatic-, (3- to 10-membered heterocyclyl)-O-(C1-C12)aliphatic-, (3- to 10-membered heterocyclyl)-N(R'')-(C1-C12)aliphatic- , or (3 to 10 membered heterocyclyl)-(C1-C12)aliphatic-O-, wherein said R2 is independently substituted by 0 to 5 R'. 6. Compound, according to claim 5, or a pharmaceutically acceptable salt, enantiomer, Z-isomer (zusammen), E-isomer (entgegen) and tautomer or combination thereof, CHARACTERIZED by the fact that R2 is selected from: -H, -Me, -Et, propyl, isopropyl, butyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, -CF3, -C(O)OMe, -C(O)OEt, -OMe, -CH2OMe, - CH2OEt, -CH2OPh, -CH2-pyrrolidine, -CH2-morpholine, -CH2-pyridine, or -CH2Ph, wherein said R2 is replaced by 0 to 3 R'. 7. Compound according to claim 6, or a pharmaceutically acceptable salt, enantiomer, Z-isomer (zusammen), E-isomer (entgegen) and tautomer or combination thereof, CHARACTERIZED by the fact that R2 is -Me replaced by 0 to 3 R' independently selected from -R'', -OR'', oxo, - CH2OR'', -CH2NR''2, -C(O)N(R'')2, -C(O)OR'' , -NO2, -NCS, -CN, -CF3, -OCF3 or - N(R'')2, where R'' is independently selected from H, -alkyl(C1-C6)-, aryl-( C6-C10)- or -aryl(C6-C10)-alkyl(C1-C6)-. 8. Compound, according to claim 5, or a pharmaceutically acceptable salt, enantiomer, Z-isomer (zusammen), E-isomer (entgegen) and tautomer or combination thereof, CHARACTERIZED by the fact that R2 is selected from: - CH2Ph, -CH2CH2Ph, -Ph, -OCH2Ph, -CH2OPh, -OCH2CH2Ph, -CH2CH2OPh, -CH2-pyrrolidine, -CH2-morpholine, or -CH2-pyridine, wherein said Ph, pyrrolidine, pyridine or morpholine is replaced by 0 to 5 R'. 9. Compound, according to claim 8, or a pharmaceutically acceptable salt, enantiomer, Z-isomer (zusammen), E-isomer (entgegen) and tautomer or combination thereof, CHARACTERIZED by the fact that said -Ph, pyrrolidine, pyridine or morpholine is replaced by 0 to 5 R' independently selected from -F, -Cl, -CN, -Me, -Et, -OMe or -OEt. 10. Compound, according to claim 5, or a pharmaceutically acceptable salt, enantiomer, Z-isomer (zusammen), E-isomer (entgegen) and tautomer or combination thereof, CHARACTERIZED by the fact that R2 is -Me, - C( O)OEt, -CH2Ph, -CH2OPh, -CH2-pyrrolidine, -CH2-pyridine or -CH2-morpholine, wherein said -Ph, pyrrolidine, pyridine or morpholine is replaced by 0 to 3 R' independently selected from -F , -Me or -OMe. 11. Compound according to claim 3, or a pharmaceutically acceptable salt, enantiomer, Z-isomer (zusammen), E-isomer (entgegen) and tautomer or combination thereof, CHARACTERIZED by the fact that R2 is OR8, SR8, (CH2 )nOR8, -(CH2)nO(CH2)nR8, or -(CH2)nN(R'')R10, wherein each R8 is independently -alkyl(C1-C6), -cycloalkyl(C3-C10), -aryl (C6-C10), or 5 to 10 membered heteroaryl, wherein each occurrence of R8 is independently substituted by 0 to 5 R'; n is an integer selected from 0 to 4; p is an integer selected from 2 to 4; and 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 by 0 to 5 R' . 12. Compound, according to claim 11, or a pharmaceutically acceptable salt, enantiomer, Z-isomer (zusammen), E-isomer (entgegen) and tautomer or combination thereof, CHARACTERIZED by the fact that R2 is -OR8. 13. Compound according to claim 11, or a pharmaceutically acceptable salt, enantiomer, Z-isomer (zusammen), E-isomer (entgegen) and tautomer or combination thereof, CHARACTERIZED by the fact that R2 is - (CH2)nOR8 or -(CH2)nO(CH2)nR8. 14. Compound, according to claim 12, or a pharmaceutically acceptable salt, enantiomer, Z-isomer (zusammen), E-isomer (entgegen) and tautomer or combination thereof, CHARACTERIZED by the fact that R8 is aryl (C6- C10) replaced by 0 to 5 R'. 15. Compound, according to claim 13, or a pharmaceutically acceptable salt, enantiomer, Z-isomer (zusammen), E-isomer (entgegen) and tautomer or combination thereof, CHARACTERIZED by the fact that R8 is - alkyl (C1-C6 ), -aryl (C6-C10) or 5- to 10-membered heteroaryl, wherein each occurrence of R8 is independently substituted by 0 to 5 R'. 16. Compound according to any one of claims 1 to 15, or a pharmaceutically acceptable salt, enantiomer, Z-isomer (zusammen), E-isomer (entgegen) and tautomer or combination thereof, CHARACTERIZED by the fact that each occurrence of R1 is selected from: halogen, -R, -OR, -NO2, -CN, -CF3, -OCF3, -N(R)2 or -N(R)SO2R, where each occurrence of R is independently replaced by 0 to 5 R'. 17. Compound according to claim 16, or a pharmaceutically acceptable salt, enantiomer, Z-isomer (zusammen), E-isomer (entgegen) and tautomer or combination thereof, CHARACTERIZED by the fact that each occurrence of R1 is independently selected from among : halogen, -H, -alkyl(C1- C6), -OH, -O(alkyl(C1-C6)), -NO2, -CN, -CF3, -OCF3, -NH2, -N(alkyl(C1- C6))2, - N(alkyl(C1-C6))SO2(alkyl(C1-C6)) or -NHSO2(alkyl(C1-C6)), wherein said alkyl is independently substituted by 0 to 5 R' . 18. Compound according to claim 17, or a pharmaceutically acceptable salt, enantiomer, Z-isomer (zusammen), E-isomer (entgegen) and tautomer or combination thereof, CHARACTERIZED by the fact that each occurrence of R1 is independently selected from among :-H, -F, -Cl, -Br, -OH, -Me, -Et, -OMe, -OEt, -NO2, -CN, -CF3, -OCF3, -NH2, -NMe2, -NEt2, - NHSO2Me or -NHSO2Et. 19. Compound, according to claim 16, or a pharmaceutically acceptable salt, enantiomer, Z-isomer (zusammen), E-isomer (entgegen) and tautomer or combination thereof, CHARACTERIZED by the fact that at least one R1 is -OR. 20. Compound according to claim 19, or a pharmaceutically acceptable salt, enantiomer, Z-isomer (zusammen), E-isomer (entgegen) and tautomer or combination thereof, CHARACTERIZED by the fact that the at least one R1 is -O ((C1-C6)alkyl). 21. Compound according to claim 20, or a pharmaceutically acceptable salt, enantiomer, Z-isomer (zusammen), E-isomer (entgegen) and tautomer or combination thereof, CHARACTERIZED by the fact that the at least one R1 is -OMe . 22. Compound according to any one of claims 1 to 21, or a pharmaceutically acceptable salt, enantiomer, Z-isomer (zusammen), E-isomer (entgegen) and tautomer or combination thereof, CHARACTERIZED by the fact that R3 is selected from : halogen, -R, -CN, -CF3, -SO2R, -C(O)N(R)2, -C(O)R or -C(O)OR, where each occurrence of R is independently replaced by 0 to 5 R'. 23. Compound, according to claim 22, or a pharmaceutically acceptable salt, enantiomer, Z-isomer (zusammen), E-isomer (entgegen) and tautomer or combination thereof, CHARACTERIZED by the fact that R3 is selected from: -H, -F, -Br, -Cl, -alkyl(C1-C6), -CN, -C=C, -CF3, -SO2(alkyl(C1- C6)), -C(O)N(alkyl(C1- C6))2, -C(O)NH2, -C(O)(alkyl(C1-C6)), -SO2(aryl(C6- C10)), -C(O)O(alkyl(C1-C6) ), -alkenyl(C2-C6), -alkynyl(C2-C6), -aryl(C6-C10), 5- to 10-membered heteroaryl- or 3- to 10-membered heterocyclyl-, wherein said alkyl, alkenyl, alkynyl, aryl, heteroaryl or heterocyclyl is independently substituted by 0 to 5 R'. 24. Compound, according to claim 23, or a pharmaceutically acceptable salt, enantiomer, Z-isomer (zusammen), E-isomer (entgegen) and tautomer or combination thereof, CHARACTERIZED by the fact that R3 is selected from: -H, -C(O)OMe, -C(O)Et, -C(O)NMe2, -C(O)NH2, -C(O)OEt, - C(O)OCH2(tert-butyl), -C( O)OCH2CF3,-C(O)O(isopropyl),-C(O)NEt2, -CHF2, -CN, - CEC, -SO2Me, -SO2Et, -SO2Ph(Me), -CF3, -CHF2, -Me , -Et, -Br, -Cl, -CH2Ph, wherein R9 is selected from -H, -Me, -Et, -CF3, isopropyl, -OMe, -OEt, -O-isopropyl, -CH2NMe2, -tert-butyl and cyclopropyl. 25. Compound according to claim 24, or a pharmaceutically acceptable salt, enantiomer, Z-isomer (zusammen), E-isomer (entgegen) and tautomer or combination thereof, CHARACTERIZED by the fact that R3 is - C(O)OMe or -C(O)OEt. 26. Compound, according to claim 24, or a pharmaceutically acceptable salt, enantiomer, Z-isomer (zusammen), E-isomer (entgegen) and tautomer or combination thereof, CHARACTERIZED by the fact that R3 is: wherein R9 is selected from -H, -Me, -Et, -CF3, isopropyl, -OMe, -OEt, -O-isopropyl, -CH2NMe2, -tert-butyl or cyclopropyl. 27. Compound according to any one of claims 1 to 26, or a pharmaceutically acceptable salt, enantiomer, Z-isomer (zusammen), E-isomer (entgegen) and tautomer or combination thereof, CHARACTERIZED by the fact that each R4 and R5 is independently selected from -H, halogen or -R, wherein each occurrence of R is independently substituted by 0 to 5 R', or R4 and R5 may be taken together with the carbon atom to which they are bonded, to form a 3 to 10 membered aromatic or non-aromatic ring having 0 to 3 additional heteroatoms independently selected from N, O, S, SO and SO2, wherein said ring is replaced by 0 to 5 R'. 28. Compound according to claim 27, or a pharmaceutically acceptable salt, enantiomer, Z-isomer (zusammen), E-isomer (entgegen) and tautomer or combination thereof, CHARACTERIZED by the fact that R4 and R5 are each independently selected from -H, -Me, -Et or -F, or R4 and R5 are taken together with the carbon atom to which they are attached to form a 3 to 8 membered aliphatic ring. 29. Compound, according to claim 28, or a pharmaceutically acceptable salt, enantiomer, Z-isomer (zusammen), E-isomer (entgegen) and tautomer or combination thereof, CHARACTERIZED by the fact that both R4 and R5 are -H. 30. Compound, according to claim 1, CHARACTERIZED by the fact that said compound has a structure of formula II: or a pharmaceutically acceptable salt, enantiomer, Z-isomer (zusammen), E-isomer (entgegen) and tautomer or combination thereof, wherein: m is 0 to 3; each R1 is independently selected from: halogen, -H, -C1-C6 alkyl, -OH, -O(C1-C6 alkyl), -NO2, -CN, -CF3, or -OCF3, wherein the said alkyl is independently substituted by 0 to 5 R'; R2 is selected from: -alkyl(C1-C6), -OH, -O(alkyl(C1-C6)), -C(O)O(alkyl(C1-C6)), -aryl(C6-C10)- (C1-C12)aliphatic-, -aryl(C6-C10)-O-(C1- C12)aliphatic-, -aryl(C6-C10)-(C1-C12)aliphatic-O-, (heteroaryl from 5 to 10 members)- (C1-C12)-aliphatic-, (5- to 10-membered heteroaryl)-O-(C1-C12)-aliphatic- or (5- to 10-membered heteroaryl)-(C1-C12)-aliphatic -O-, wherein said alkyl, aryl or heteroaryl is independently substituted by 0 to 5 R'; R3 is selected from: -alkyl(C1-C6), -SO2(alkyl(C1-C6)), -C(O)N(alkyl(C1-C6))2, or -C(O)O(alkyl( C1-C6)), wherein said alkyl is independently substituted by 0 to 5 R'; R4 and R5 are each independently selected from -H, halogen or -alkyl (C1-C6); and R6 is selected from -H or -alkyl (C1-C6). 31. Compound, according to claim 30, or a pharmaceutically acceptable salt, enantiomer, Z-isomer (zusammen), E-isomer (entgegen) and tautomer or combination thereof, CHARACTERIZED by the fact that: m is 0, 1 or 2 ; when m is 1 or 2, at least one occurrence of R1 is halogen or - O(alkyl(C1-C6)); R2 is selected from: -alkyl(C1-C6), -aryl(C6-C10)-(C1-C12)aliphatic- or -aryl(C6-C10)-O-(C1-C12)aliphatic-, where the said aryl is independently substituted by 0 to 5 R' independently selected from -F, -Me and -OMe; R3 is -C(O)O((C1-C6)alkyl); R4 and R5 are both -H; and R6 is -H. 32. Compound, according to claim 1, CHARACTERIZED by the fact that said compound has a structure of formula II: or a pharmaceutically acceptable salt, enantiomer, Z-isomer (zusammen), E-isomer (entgegen) and tautomer or combination thereof, wherein: m is 0 to 3; each R1 is independently selected from: halogen, -H, -C1-C6 alkyl, -OH, -O(C1-C6 alkyl), -NO2, -CN, -CF3, or -OCF3, wherein the said R1 is independently substituted by 0 to 5 R'; R2 is selected from: -alkyl(C1-C6), -OH, -O(alkyl(C1-C6)), -C(O)O(alkyl(C1-C6)), -aryl(C6-C10)- (C1-C12)aliphatic-, -aryl(C6-C10)-O-(C1-C12)aliphatic-, -aryl(C6-C10)-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-, or (3-membered heterocyclyl) to 10 members)-N(R'')-(C1-C12)aliphatic-, where R2 is independently substituted by 0 to 5 R'; R3 is selected from: -alkyl(C1-C6), -C=C, -CN, halogen, -SO2(aryl(C6-C10)), -SO2(alkyl(C1-C6)), -C(O) N(alkyl(C1-C6))2, -C(O)NH2, -C(O)O(alkyl(C1-C6)), -C(O)(alkyl(C1-C6)), -aryl( C6-C10), or 5-10 membered heteroaryl, wherein R3 is independently substituted by 0-5 R'; R4 and R5 are each independently selected from -H, halogen or -alkyl (C1-C6); and R6 is selected from -H or -alkyl (C1-C6). 33. Compound, according to claim 32, or a pharmaceutically acceptable salt, enantiomer, Z-isomer (zusammen), E-isomer (entgegen) and tautomer or combination thereof, CHARACTERIZED by the fact that: m is 0, 1 or two; when m is 1 or 2, at least one occurrence of R1 is halogen or - O(alkyl(C1-C6)); R2 is selected from: -alkyl(C1-C6), -aryl(C6-C10)-(C1-C12)aliphatic-, aryl(C6-C10)-O-(C1-C12)aliphatic-, (heteroaryl of 5 to 10 members)-(C1-C12)aliphatic- or (3 to 10 member heterocyclyl)-(C1-C12)aliphatic-, wherein R2 is independently substituted by 0 to 3 R'; wherein R3 is independently substituted by 0 to 3 R' and wherein R9 is selected from -H, -Me, -Et, -CF3, isopropyl, -OMe, -tert-butyl or cyclopropyl; R4 and R5 are both -H; and R6 is -H. 34. Compound, according to claim 33, or a pharmaceutically acceptable salt, enantiomer, Z-isomer (zusammen), E-isomer (entgegen) and tautomer or combination thereof, CHARACTERIZED by the fact that R3 is: wherein R9 is selected from -H, -Me, -Et, -CF3, isopropyl, -OMe or - tert-butyl. 35. Compound, according to claim 2, CHARACTERIZED by the fact that said compound has a structure of formula III: or a pharmaceutically acceptable salt, enantiomer, Z-isomer (zusammen), E-isomer (entgegen) and tautomer or combination thereof, wherein: m is 0, 1 or 2 and, when m is 1 or 2, at least one occurrence of R1 is - O(alkyl(C1-C6)); R2 is selected from: -alkyl(C1-C6) or -aryl(C6-C10)-(C1-C12)aliphatic-; R3 is -C(O)O((C1-C6)alkyl); R4 and R5 are both -H; and R6 is -H. 36. Compound, according to claim 3, CHARACTERIZED by the fact that said compound has a structure of formula IV: or a pharmaceutically acceptable salt, enantiomer, Z-isomer (zusammen), E-isomer (entgegen) and tautomer or combination thereof, wherein: m is 0, 1 or 2 and, when m is 1 or 2, at least one occurrence of R1 is - O(alkyl(C1-C6)); R2 is OR8, where R8 is -aryl (C6-C10) substituted by 0 to 3 halogen; R3 is -C(O)O((C1-C6)alkyl); R4 and R5 are both -H; and R6 is -H. 37. Compound, according to claim 3, CHARACTERIZED by the fact that said compound has a structure of formula IV: or a pharmaceutically acceptable salt, enantiomer, Z-isomer (zusammen), E-isomer (entgegen) and tautomer or combination thereof, wherein: m is 0 to 3; when m is 1 or 2, at least one occurrence of R1 is -halogen or -O(alkyl(C1-C6)); each R1 is independently selected from: halogen, -H, -C1-C6 alkyl, -OH, -O(C1-C6 alkyl), -NO2, -CN, -CF3, or -OCF3, where R1 is independently substituted by 0 to 5 R'; R2 is selected from -OR8, -SR8, -(CH2)nOR8, -(CH2)nO(CH2)nR8, or - (CH2)nN(R'')R10, where n is an integer selected from 0 to 4; p is an integer selected from 2 to 4; each R8 is independently -(C1-C6)alkyl, -(C3-C10)cycloalkyl, -aryl(C6-C10) or 5- to 10-membered heteroaryl, wherein each occurrence of R8 is independently substituted by 0 to 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 by 0 to 5 R'; and wherein R2 is independently substituted by 0 to 5 R'; R3 is selected from: -H, -CN, halogen, -alkyl(C1-C6), -SO2(alkyl(C1-C6)), -C(O)N(alkyl(C1-C6))2, -C (O)(alkyl(C1-C6)), -C(O)O(alkyl(C1-C6)), , wherein R9 is selected from -Me, -Et, isopropyl, -CF3, -OMe, -OEt, -O-isopropyl, -CH2NMe2 or cyclopropyl; wherein R3 is independently substituted by 0 to 5 R'; R4 and R5 are each independently selected from -H, halogen or -alkyl (C1-C6); and R6 is selected from -H or -alkyl (C1-C6). 38. Compound, according to claim 37, or a pharmaceutically acceptable salt, enantiomer, Z-isomer (zusammen), E-isomer (entgegen) and tautomer or combination thereof, CHARACTERIZED by the fact that: m is 0, 1 or 2 ; R2 is OR8, -(CH2)nOR8, or -(CH2)nO(CH2)nR8, where n is 1, and where R8 is -(C1-C6)alkyl, -aryl(C6-C10) or heteroaryl of 5 to 10 members, where R8 is independently replaced by 0 to 3 R'; R3 is halogen, -H, -CN, -alkyl(C1-C6), C(O)(alkyl(C1-C6)), -C(O)O(alkyl(C1-C6)), , wherein said alkyl is independently substituted by 0 to 3 R'; R9 is selected from -Me, -Et, isopropyl or -CF3; R4 and R5 are both -H; and R6 is -H. 39. Compound CHARACTERIZED by the fact that it is selected from: or a pharmaceutically acceptable salt, enantiomer, Z-isomer (zusammen), E-isomer (entgegen) and tautomer or combination thereof. 40. Pharmaceutical composition CHARACTERIZED by the fact that it comprises a compound, as defined in any one of claims 1 to 39, or a pharmaceutically acceptable salt, enantiomer, Z-isomer (zusammen), E-isomer (entgegen) and tautomer or combination thereof, in a therapeutically effective amount; and an acceptable vehicle, adjuvant or carrier. 41. Pharmaceutical composition, according to claim 40, CHARACTERIZED by the fact that said composition additionally comprises a second therapeutic agent. 42. Pharmaceutical composition according to claim 41, CHARACTERIZED by the fact that the second therapeutic agent is selected from an antipsychotic, memantine or an acetylcholine esterase inhibitor (AChE-I). 43. Pharmaceutical composition, according to claim 42, CHARACTERIZED by the fact that the second therapeutic agent is an antipsychotic selected from aripiprazole, olanzapine and ziprasidone, or a pharmaceutically acceptable salt, hydrate, solvate and polymorph thereof. 44. Pharmaceutical composition according to claim 42, CHARACTERIZED by the fact that the second therapeutic agent is memantine, or a pharmaceutically acceptable salt, hydrate, solvate or polymorph thereof. 45. Pharmaceutical composition, according to claim 42, CHARACTERIZED by the fact that the second therapeutic agent is an AChE-I selected from: (i) Donepezil, or pharmaceutically acceptable salt, hydrate, solvate or polymorph thereof; (ii) Galantamine or Rivastigmine, or a pharmaceutically acceptable salt thereof. 46. Use of a pharmaceutical composition, as defined in any one of claims 40 to 45, CHARACTERIZED by the fact that it is for the preparation of a medicament for the treatment of cognitive impairment associated with a disorder of the central nervous system (CNS) in a individual in need of this. 47. Use, according to claim 46, CHARACTERIZED by the fact that the CNS disorder is one or more of: age-related cognitive impairment, dementia, schizophrenia, bipolar disorder, amyotrophic lateral sclerosis (ALS), post-traumatic stress disorder -traumatic (PTSD), mental retardation, Parkinson's disease (PD), autism, compulsive behavior and substance dependence. 48. Use, according to claim 46, CHARACTERIZED by the fact that the CNS disorder is moderate cognitive impairment (MCI). 49. Use, according to claim 48, CHARACTERIZED by the fact that the moderate cognitive impairment is amnestic moderate cognitive impairment (AMCI). 50. Use, according to claim 46, CHARACTERIZED by the fact that the CNS disorder is Alzheimer's disease. 51. Use, according to claim 46, CHARACTERIZED by the fact that the CNS disorder is associated with cancer therapy.