Methods and compositions for improving cognitive function

Abstract

To provide methods and compositions for improving the cognitive function.SOLUTION: There is provided a method, in a subject in need of treatment of a central nervous system (CNS) disorder with cognitive dysfunction or at risk of the disorder, for treating the disorder, delaying or slowing the progression of the cognitive dysfunction in the subject, or reducing the rate of decline of the cognitive function. The method includes administering to the subject a therapeutically effective amount of a synaptic vesicle glycoprotein 2A (SV2A) inhibitor or a pharmaceutically acceptable salt, hydrate, solvate or polymorph thereof.SELECTED DRAWING: None

Description

[Technical field]

[0001] This application claims priority and benefit from U.S. Provisional Patent Application No. 61 / 441,251, filed February 9, 2011. The contents and disclosure of this provisional application are incorporated herein by reference in their entirety.

[0002] FIELD OF THEINVENTION The present invention relates to methods and compositions for treating central nervous system (CNS) disorders associated with cognitive dysfunction. In particular, the present invention relates to a method for treating central nervous system (CNS) disorders associated with cognitive impairment. and the use of inhibitors of synaptic vesicle glycoprotein 2A (SV2A) alone in treating central nervous system (CNS) disorders associated with cognitive dysfunction in subjects at risk for or undergoing treatment with serotonin-dependent agonists. For use in combination with valproate, the subject includes, but is not limited to, subjects with or at risk for cognitive impairment associated with age-related cognitive impairment, mild cognitive impairment (MCI), amnesic MCI (aMCI), age-associated memory impairment (AAMI), Age Related Cognitive Decline (ARCD), dementia, Alzheimer's Disease (AD), prodromal AD, post-traumatic stress disorder (PTSD), schizophrenia, amyotrophic lateral sclerosis, and cancer treatment-related cognitive impairment. [Background technology]

[0003] BACKGROUND OF THEINVENTION Cognitive ability can decline as a result of normal aging or as a result of CNS disorders.

[0004] A significant number of older adults experience cognitive decline beyond that typical of normal aging. Such age-related cognitive loss is clinically characterized by progressive loss of memory, cognition, reasoning, and judgment. Mild cognitive impairment (MCI), age-associated memory impairment (AAMI), age-related cognitive decline (ARCD), or similar clinical classifications are included that relate to such age-related cognitive loss. By some estimates, there are more than 16 million AAMI patients in the United States alone (Barker et al., 1995), and it is estimated that 5.5 to 7 million people over the age of 65 in the United States suffer from MCI (Plassman et al., 2008).

[0005] Other central nervous system (CNS) disorders (e.g., dementia, Alzheimer's disease (AD), prodromal AD, traumatic brain injury, etc.) Post-traumatic stress disorder (PTSD), schizophrenia, amyotrophic lateral sclerosis (ALS), and cancer treatment Cognitive impairment associated with cognitive impairment (CIA) is also associated with cognitive impairment.

[0006] Therefore, effective treatment of central nervous system (CNS) disorders associated with cognitive impairment, as well as age-related cognitive impairment, is desired. Cognitive impairment, MCI, amnesic MCI, AAMI, ARCD, dementia, AD, prodromal AD, PTSD, schizophrenia, amyotrophic lateral sclerosis (ALS), cancer treatment-related cognitive impairment, and other conditions associated with cognitive impairment Patients who have been diagnosed with or are at risk for developing similar central nervous system (CNS) disorders There is a need to improve cognitive function in individuals with Summary of the Invention [Means for solving the problem]

[0007] Summary of the Invention According to a first aspect of the present invention, a subject suffering from a central nervous system (CNS) disorder accompanied by cognitive impairment is In a subject having or at risk of cognitive impairment, a method is provided for treating or improving cognitive function, delaying or slowing the progression of cognitive impairment, or reducing the rate of decline of cognitive function, the method comprising administering to the subject a therapeutically effective amount of an SV2A inhibitor or a pharmaceutically acceptable salt, hydrate, solvate, or polymorph thereof. In some embodiments of this aspect of the invention, these methods treat or improve cognitive function in the subject. In some embodiments of this aspect of the invention, these methods delay or slow the progression of cognitive impairment in the subject. In some embodiments of this aspect of the invention, these methods reduce the rate of decline of cognitive function in the subject. In some embodiments of this aspect of the invention, these methods prevent in the subject a CNS disorder associated with the cognitive impairment, or slow its progression. In other embodiments of this aspect of the invention, these methods reduce, ameliorate, or slow the progression of one or more symptoms associated with a CNS disorder associated with the cognitive impairment in the subject.

[0008] In some embodiments of this aspect of the invention, the CNS disorder associated with the cognitive impairment is age-related cognitive impairment (e.g., mild cognitive impairment (MCI), age-associated memory impairment (AAMI), age-related cognitive decline (ARCD)). In one embodiment of this aspect of the invention, the MCI is amnestic MCI. In some embodiments of this aspect of the invention, the CNS disorder associated with the cognitive impairment is dementia, Alzheimer's disease (AD), preclinical AD, post-traumatic stress disorder (PTSD), schizophrenia, amyotrophic lateral sclerosis (ALS) or cancer treatment-related cognitive impairment. In one embodiment of this aspect of the invention, the subject suffering from such a CNS disorder or cognitive impairment is a human patient.

[0009] ​Useful as SV2A inhibitors or pharmaceutically acceptable salts, hydrates, solvates, or polymorphs thereof in the methods and compositions of this aspect of the invention are, for example, those disclosed in U.S. Patent Application 12 / 580,464, International Patent Application No. PCT / US2009 / 005647, U.S. Patent Application 61 / 105,847, U.S. Patent Application 61 / 152,631, and U.S. Patent Application 61 / 175,536. However, any SV2A inhibitor or pharmaceutically acceptable salt, hydrate, solvate, or polymorph thereof can be used in the methods and compositions of this aspect of the invention. In other embodiments, the SV2A inhibitor is International Patent Application WO2010 / 144712; WO2010 / 002869; WO2008 / 132139; WO2007 / 065595; WO2006 / 128693; WO2006 / 128692; WO2005 / 054188; WO2004 / 087658; WO2002 / 094787; WO2001 / 062726; U.S. Patent Nos. 7,465,549; 7,244,747; 5,334,720; 4,696,943; 4,696,942; U.S. Patent Application Publication Nos. 20090312333; 20090018148; 20080081832; 2006258704; and selected from the group of SV2A inhibitors described in British Patent Nos. 1,039,113; and 1,309,692. is selected, or a pharmaceutically acceptable salt, hydrate, solvate, or polymorph thereof. In other embodiments, the SV2A inhibitor is selected from the group consisting of levetiracetam, brivaracetam, and seletracetam, or a derivative, analog, pharmaceutically acceptable salt, hydrate, solvate, or polymorph thereof. In other embodiments, the SV2A inhibitor is levetiracetam or a derivative, analog, pharmaceutically acceptable salt, hydrate, solvate, or polymorph thereof. In other embodiments, the SV2A inhibitor is brivaracetam or a derivative, analog, pharmaceutically acceptable salt, hydrate, solvate, or polymorph thereof. In other embodiments, the SV2A inhibitor is seletracetam or a derivative, analog, pharmaceutically acceptable salt, hydrate, solvate, or polymorph thereof.

[0010] In other embodiments of this aspect of the invention, the SV2A inhibitor or a pharmaceutically acceptable salt, hydrate, solvate, or polymorph thereof can be administered, for example, at the dosages disclosed in U.S. Patent Application 12 / 580,464, International Patent Application No. PCT / US2009 / 005647, U.S. Patent Application 61 / 105,847, U.S. Patent Application 61 / 152,631, U.S. Patent Application 61 / 175,536, and U.S. Patent Application 61 / 441,251. In other embodiments of this aspect of the invention, the SV2A inhibitor or a pharmaceutically acceptable salt, hydrate, solvate, or polymorph thereof is administered every 12 or 24 hours at about 0.1 mg / kg to 0.2 mg / kg, or about 0.01 mg / kg to 2.5 mg / kg, or about 0.1 mg / kg to 2.5 mg / kg or about 0.4 mg / kg to 2.5 mg / kg, or about 0.6 mg / kg to 1.8 mg / kg, or about 0.04 mg / kg to 2.5 mg / kg, or about 0.06 mg / kg to 1.8 mg / kg, or about 2.0 mg / kg to 4.0 mg / kg, or about 2.0 mg / kg to 3.0 mg / kg, or about 3.0 mg / kg to 4.0 mg / kg, or about 0.2 mg / kg to 0.4 mg / kg, or about 0.2 mg / kg to 0.3 mg / kg, or about 0.3 mg / kg to 0.4 mg / kg, or about 0.001 mg / kg to 5 mg / kg, or about 0.001 mg / kg to 0.5 mg / kg, or about 0.01 mg / kg to 0.5 mg / kg.

[0011] According to a second aspect of the present invention, a subject suffering from a central nervous system (CNS) disorder accompanied by cognitive impairment is Methods are provided for treating or improving cognitive function, delaying or slowing the progression of cognitive impairment, or reducing the rate of cognitive decline in a subject at or at risk thereof, comprising administering to the subject a therapeutically effective amount of an SV2A inhibitor or a pharma- ceutically acceptable salt, hydrate, solvate, or polymorph thereof in combination with valproate or an analog, derivative, or pharma- ceutically acceptable salt thereof. In some embodiments of this aspect of the invention, the methods improve or treat cognitive function in the subject. In some embodiments of this aspect of the invention, the methods delay or slow the progression of cognitive impairment in the subject. In some embodiments of this aspect of the invention, the methods reduce the rate of cognitive decline in the subject. In some embodiments of this aspect of the invention, the methods prevent CNS disorders associated with the cognitive impairment in the subject. In other embodiments of this aspect of the invention, the methods include administering to the subject one or more CNS disorders associated with said cognitive impairment. To relieve, improve, or slow the progression of symptoms.

[0012] In some embodiments of this aspect of the invention, the SV2A inhibitor and / or valproate are administered at sub-therapeutic doses compared to the doses that are therapeutically effective when administered in the absence of the other.

[0013] In some embodiments of this aspect of the invention, the CNS disorder associated with this cognitive impairment is age-related cognitive impairment (e.g., mild cognitive impairment (MCI), age-associated memory impairment (AAMI), age-related cognitive decline (ARCD)). In one embodiment of this aspect of the invention, this MCI is amnestic MCI. In some embodiments of this aspect of the invention, the CNS disorder associated with this cognitive impairment is dementia, Alzheimer's disease (AD), prodromal AD, post-traumatic stress disorder (PTSD), schizophrenia or a cognitive impairment associated with cancer treatment. In one embodiment, the subject suffering from such a cognitive impairment is a human patient.

[0014] Examples of SV2A inhibitors or pharmaceutically acceptable salts, hydrates, solvates, or polymorphs thereof useful in the methods and compositions of this aspect of the invention include, for example, U.S. Patent Application 12 / 580,464, International Patent Application No. PCT / US2009 / 005647, U.S. Patent Application 61 / 105,847, U.S. Examples include those disclosed in U.S. Provisional Patent Application No. 61 / 152,631, U.S. Provisional Patent Application No. 61 / 175,536, and U.S. Provisional Patent Application No. 61 / 441,251. However, any SV2A inhibitor or a pharmaceutically acceptable salt, hydrate, solvate, or polymorph thereof may be used in the methods and compositions of this aspect of the invention. In other embodiments, the SV2A inhibitor is selected from the group of SV2A inhibitors described in International Patent Applications WO2010 / 144712; WO2010 / 002869; WO2008 / 132139; WO2007 / 065595; WO2006 / 128693; WO2006 / 128692; WO2005 / 054188; WO2004 / 087658; WO2002 / 094787; WO2001 / 062726; U.S. Patent Nos. 7,465,549; 7,244,747; 5,334,720; 4,696,943; 4,696,942; U.S. Patent Application Publication Nos. 20090312333; 20090018148; 20080081832; 2006258704; and British Patent Nos. 1,039,113; and 1,309,692, or a pharmaceutically acceptable salt, hydrate, solvate, or polymorph thereof. In other embodiments, the SV2A inhibitor is selected from the group consisting of levetiracetam, brivaracetam, and seletracetam, or a derivative, analog, pharmaceutically acceptable salt, hydrate, solvate, or polymorph thereof. In other embodiments, the SV2A inhibitor is levetiracetam or a derivative, analog, pharmaceutically acceptable salt, hydrate, solvate, or polymorph thereof. In other embodiments, the SV2A inhibitor is brivaracetam or a derivative, analog, pharmaceutically acceptable salt, hydrate, solvate, or polymorph thereof. In other embodiments, the SV2A inhibitor is seletracetam or a derivative, analog, pharmaceutically acceptable salt, hydrate, solvate, or polymorph thereof.

[0015] In other embodiments of this aspect of the invention, an SV2A inhibitor or a pharmaceutically acceptable salt, hydrate, solvate, or polymorph thereof, administered in combination with valproate or an analog, derivative, or pharmaceutically acceptable salt thereof, may be administered, for example, in the dosages disclosed in U.S. Patent Application 12 / 580,464, International Patent Application No. PCT / US2009 / 005647, U.S. Patent Application 61 / 105,847, U.S. Patent Application 61 / 152,631, U.S. Patent Application 61 / 175,536, and U.S. Patent Application 61 / 441,251. In other embodiments of this aspect of the invention, an SV2A inhibitor or a pharmaceutically acceptable salt, hydrate, solvate, or polymorph thereof, administered in combination with valproate or an analog, derivative, or pharmaceutically acceptable salt thereof, is administered at a daily dose of about 0.01 mg / kg to 1 mg / kg, or about 0.001 mg / kg to 1 mg / kg, or about 0.1 mg / kg to 5 mg / kg, or about 0.05 mg / kg to 0.5 mg / kg, every 12 or 24 hours.

[0016] In certain embodiments of this aspect of the invention, valproate or an analog, derivative, or pharmaceutically acceptable salt thereof, administered in combination with an SV2A inhibitor or a pharmaceutically acceptable salt, hydrate, solvate, or polymorph thereof, is administered at a daily dose such that the subject maintains a total valproate blood level of 0.5 μg / ml plasma to 5 μg / ml plasma in the blood.

[0017] ​In other embodiments of this aspect of the invention, the SV2A inhibitor or a pharmaceutically acceptable salt, hydrate, solvate, or polymorph thereof is administered simultaneously with, sequentially with, or in a single formulation or separate formulations packaged together with valproate or an analog, derivative, or pharmaceutically acceptable salt thereof. In other embodiments of this aspect of the invention, the SV2A inhibitor or a pharmaceutically acceptable salt, hydrate, solvate, or polymorph thereof is administered via a different route from valproate or an analog, derivative, or pharmaceutically acceptable salt thereof. As used herein, "combination" includes administration by any of these formulations or routes of administration.

[0018] According to a third aspect of the invention, there is provided a pharmaceutical composition containing an SV2A inhibitor or a pharmaceutically acceptable salt thereof. In certain embodiments of this aspect of the invention, the SV2A inhibitor is present in an amount of 0.07 mg to 60 mg, 0.07 mg to 350 mg, 25 mg to 60 mg, 25 mg to 125 mg, 50 mg to 250 mg , 5 mg to 140 mg, 0.7 mg to 180 mg, 125 mg to 240 mg, 3 mg to 50 mg, or 3 mg to 60 mg. In other embodiments of this aspect of the invention, the SV2A inhibitor is present in an amount of 0.05 mg to 35 mg.

[0019] According to a fourth aspect of the invention, there is provided a pharmaceutical composition comprising an SV2A inhibitor or a pharma- ceutically acceptable salt thereof in combination with valproate or an analog, derivative, or pharma- ceutically acceptable salt thereof. In some embodiments of this aspect of the invention, the SV2A inhibitor or a pharma- ceutically acceptable salt thereof is present in an amount of 0.05 mg to 35 mg, 0.07 mg to 60 mg, 0.07 mg to 350 mg, 25 mg to 60 mg, 25 mg to 125 mg, 50 mg to 250 mg, 5 mg to 15 mg, 5 mg to 30 mg, 5 mg to 140 mg, 0.7 mg to 180 mg, 125 mg to 240 mg, 3 mg to 50 mg, or 0.07 mg to 50 mg, or 3 mg to 60 mg. In other embodiments, the SV2A inhibitor or a pharma- ceutically acceptable salt thereof is present in an amount of 0.05 mg to 35 mg, 0.07 mg to 60 mg, 0.07 mg to 350 mg, 25 mg to 60 mg, 25 mg to 125 mg, 50 mg to 250 mg, 5 mg to 15 mg, 5 mg to 30 mg, 5 mg to 140 mg, 0.7 mg to 180 mg, 125 mg to 240 mg, 3 mg to 50 mg, or 0.07 mg to 50 mg, or 3 mg to 60 mg. The amount of the compound of interest that may be present is less than 350 mg, less than 250 mg, less than 200 mg, less than 150 mg, less than 100 mg, less than 50 mg, less than 35 mg, less than 10 mg, less than 5 mg, less than 1 mg, less than 0.5 mg, less than 0.1 mg, less than 0.07 mg, or less than 0.05 mg.

[0020] According to a fifth aspect of the present invention, a subject suffering from a central nervous system (CNS) disorder accompanied by cognitive impairment is Methods of treating or improving cognitive function, delaying or slowing the progression of cognitive impairment, or reducing the rate of cognitive decline in a subject at or at risk thereof are provided, comprising administering to the subject a therapeutically effective amount of levetiracetam or a pharma- ceutically acceptable salt thereof. In some embodiments of this aspect of the invention, the methods improve or treat cognitive function in the subject. In some embodiments of this aspect of the invention, the methods delay or slow the progression of cognitive impairment in the subject. In some embodiments of this aspect of the invention, the methods reduce the rate of cognitive decline in the subject. In some embodiments of this aspect of the invention, the methods prevent or slow the progression of a CNS disorder associated with the cognitive impairment in the subject. This invention In other embodiments of this aspect of the disclosure, these methods reduce, improve, or slow the progression of one or more symptoms associated with a CNS disorder with cognitive impairment in the subject. in this subject.

[0021] In some embodiments of this aspect of the invention, the CNS disorder associated with the cognitive impairment is age-related cognitive impairment (e.g., mild cognitive impairment (MCI), age-associated memory impairment (AAMI), age-related cognitive decline (ARCD)). In one embodiment of this aspect of the invention, the MCI is amnestic MCI. In some embodiments of this aspect of the invention, the CNS disorder associated with the cognitive impairment is dementia, Alzheimer's disease (AD), preclinical AD, post-traumatic stress disorder (PTSD), schizophrenia, or a cognitive impairment associated with cancer treatment. In one embodiment, the subject suffering from such a cognitive impairment is a human patient.

[0022] In certain embodiments of this aspect of the invention, levetiracetam or a pharmaceutically acceptable salt, hydrate, solvate, or polymorph thereof is administered at a daily dose of about 1 mg / kg to 2 mg / kg, or about 0.1 mg / kg to 2.5 mg / kg, or about 0.4 mg / kg to 2.5 mg / kg, or about 0.6 mg / kg to 1.8 mg / kg, or about 2.0 mg / kg to 3.0 mg / kg, or about 3.0 mg / kg to 4.0 mg / kg, or about 2.0 mg / kg to 4.0 mg / kg, or about 0.1 mg / kg to 5 mg / kg, or about 70 mg to 140 mg, or about 7 mg to 180 mg, or about 25 mg to 180 mg, or about 40 mg to 130 mg, or about 140 mg to 300 mg, or about 200 mg to 300 mg, or about 140 mg to 200 mg, or about 7 mg to 350 mg, every 12 hours or every 24 hours.

[0023] In certain embodiments of this aspect of the invention, levetiracetam or a pharmaceutically acceptable salt, hydrate, solvate, or polymorph thereof is administered once every 12 hours or once every 24 hours at a daily dose that follows one of the daily dose ranges indicated as "+" listed in Table 1 or Table 2. or at a daily dose that follows one of the daily dose ranges indicated as "+" listed in Table 2.

[0024] According to a sixth aspect of the invention, there is provided a method of treating or improving cognitive function, delaying or slowing the progression of cognitive impairment, or reducing the rate of decline of cognitive function in a subject suffering from or at risk of suffering from a central nervous system (CNS) disorder associated with cognitive impairment, the method comprising administering to the subject a therapeutically effective amount of brivaracetam or a pharmaceutically acceptable salt thereof. In some embodiments of this aspect of the invention, these methods improve or treat cognitive function in the subject. In some embodiments of this aspect of the invention, these methods delay or slow the progression of cognitive impairment in the subject. In some embodiments of this aspect of the invention, these methods reduce the rate of decline of cognitive function in the subject. In some embodiments of this aspect of the invention, these methods prevent or slow the progression of the CNS disorder associated with this cognitive impairment in the subject. In other embodiments of this aspect of the invention, these methods alleviate, improve, or slow the progression of one or more symptoms associated with the CNS disorder associated with this cognitive impairment in the subject. or at a daily dose that follows one of the daily dose ranges indicated as "+" listed in Table 2. or slow the progression thereof. In some embodiments of this aspect of the invention, the CNS disorder associated with the cognitive impairment is age-related cognitive impairment (e.g., mild cognitive impairment (MCI), age-associated memory impairment (AAMI), age-related cognitive decline (ARCD)). In one embodiment of this aspect of the invention, the MCI is amnestic MCI. In some embodiments of this aspect of the invention, the cognitive impairment

[0025] In some embodiments of this aspect of the invention, the CNS disorder associated with the cognitive impairment is age-related cognitive impairment (e.g., mild cognitive impairment (MCI), age-associated memory impairment (AAMI), age-related cognitive decline (ARCD)). In one embodiment of this aspect of the invention, the MCI is amnestic MCI. In some embodiments of this aspect of the invention, the cognitive impairment CNS disorders associated with harm are dementia, Alzheimer's disease (AD), prodromal AD, post-traumatic stress disorder (PTSD), schizophrenia or cognitive impairment associated with cancer treatment. In one embodiment, the subject suffering from such cognitive impairment is a human patient.

[0026] In certain embodiments of this aspect of the invention, brivaracetam or a pharmaceutically acceptable salt, hydrate, solvate or polymorph thereof is administered at a daily dose of about 0.1 mg / kg to 0.2 mg / kg, or about 0.01 mg / kg to 2.5 mg / kg, or about 0.04 mg / kg to 2.5 mg / kg, or about 0.06 mg / kg to 1.8 mg / kg, or about 0.2 mg / kg to 0.4 mg / kg, or about 7 mg to 15 mg, or about 0.7 mg to 180 mg, or about 2.5 mg to 180 mg, or about 4.0 mg to 130 mg, or about 14 mg to 30 mg every 12 hours or every 24 hours.

[0027] In certain embodiments of this aspect of the invention, brivaracetam or a pharmaceutically acceptable salt, hydrate, solvate or polymorph thereof is a daily dose of at least 0.1 mg, at least 0.5 mg, at least 0.75 mg, at least 1.0 mg, at least 1.5 mg, or at least 2.0 mg every 12 hours or every 24 hours; but is administered at a daily dose of 2.5 mg or less, 5 mg or less, 10 mg or less, 15 mg or less, 20 mg or less, 25 mg or less, 30 mg or less, or 35 mg or less. In other embodiments, brivaracetam or a pharmaceutically acceptable salt, hydrate, solvate, or polymorph thereof is a daily dose of at least 0.0015 mg / kg, at least 0.0075 mg / kg, at least 0.01 mg / kg, at least 0.015 mg / kg, at least 0.02 mg / kg, or at least 0.03 mg / kg every 12 hours or every 24 hours; but It is administered at a daily dose.

[0028] In certain embodiments of this aspect of the invention, brivaracetam or a pharmaceutically acceptable salt, hydrate, solvate, or polymorph thereof is administered at a daily dose according to one of the daily dose ranges indicated as “+” listed in Table 3 or Table 4 every 12 hours or every 24 hours. For example, brivaracetam or a pharmaceutically acceptable salt, hydrate, solvate, or polymorph thereof is administered at a daily dose of 0.1 mg to 35 mg, 0.5 mg to 35 mg, 0.75 mg to 35 mg, 1.0 mg to 35 mg, 1.5 mg to 35 mg, 2.0 mg to 35 mg, 0.1 mg to 30 mg, 0.1 mg to 25 mg, 0.1 mg to 20 mg, 0.1 mg to 15 mg, 0.1 mg to 10 mg, 0.1 mg to 5 mg, 0.1 mg to 2.5 mg, 0.0015 mg / kg to 0.5 mg / kg, 0.0075 mg / kg to 0.5 mg / kg, 0.01 mg / kg to 0.5 mg / kg, 0.015 mg / kg to 0.5 mg / kg, 0.02 mg / kg to 0.5 mg / kg, 0.03 mg / kg to 0.5 mg / kg, 0.0015 mg / kg to 0.4 mg / kg, 0.0015 mg / kg to 0.3 mg / kg, 0.0015 mg / kg to 0.2 mg / kg, 0.0015 mg / kg to 0.15 mg / kg, 0.0015 mg / kg to 0.1 mg / kg, 0.0015 mg / kg to 0.05 mg / kg, or 0.0015 mg / kg to 0.04 mg / kg every 12 hours or every 24 hours.

[0029] According to a seventh aspect of the invention, there is provided a method of treating or improving cognitive function, delaying or slowing the progression of cognitive impairment, or reducing the rate of decline of cognitive function in a subject suffering from or at risk of suffering from a central nervous system (CNS) disorder associated with cognitive impairment, the method comprising administering to the subject a therapeutically effective amount of selectracetam or a pharmaceutically acceptable salt thereof. Any ​​In some embodiments, these methods improve or treat cognitive function in the subject. In some embodiments of this aspect of the invention, these methods delay or slow the progression of cognitive impairment in the subject. In some embodiments of this aspect of the invention, these methods reduce the rate of decline of cognitive function in the subject. In some embodiments of this aspect of the invention, these methods prevent or slow the progression of a CNS disorder associated with this cognitive impairment in the subject In other embodiments of this aspect of the invention, these methods reduce, improve, or slow the progression of one or more symptoms associated with a CNS disorder associated with this cognitive impairment in the subject.

[0030] In some embodiments of this aspect of the invention, the CNS dis order associated with this cognitive impairment is age-related cognitive impairment (e.g., mild cognitive impairment (MCI), age-associated memory impairment (AAMI), age-related cognitive decline (ARCD)). In one embodiment of this aspect of the invention, this MCI is amnestic MCI. In some embodiments of this aspect of the invention, the CNS dis order associated with this cognitive impairment is dementia, Alzheimer's disease (AD), prodromal AD, post-traumatic stress disorder (PTSD), schizophrenia or a cognitive impairment associated with cancer treatment. In one embodiment, the subject suffering from such a cognitive impairment is a human patient.

[0031] In certain embodiments of this aspect of the invention, sertraline or a pharmaceutically acceptable salt, hydrate, solvate, or polymorph thereof is administered once every 12 or 24 hours at a daily dose of at least 0.1 mg, at least 0.5 mg, at least 0.75 mg, at least 1.0 mg, at least 1.5 mg, or at least 2.0 mg; but at a daily dose of 2.5 mg or less, 5 mg or less, 10 mg or less, 15 mg or less, 20 mg or less, 25 mg or less, 30 mg or less, or 35 mg or less. In other embodiments, sertraline or a pharmaceutically acceptable salt, hydrate, solvate, or polymorph thereof is administered once every 12 or 24 hours at a daily dose of at least 0.0015 mg / kg, at least 0.0075 mg / kg, at least 0.01 mg / kg, at least 0.015 mg / kg, at least 0.02 mg / kg, or at least 0.03 mg / kg; but at a daily dose of 0.5 mg / kg or less, 0.4 mg / kg or less, 0.3 mg / kg or less, 0.2 mg / kg or less, 0.15 mg / kg or less, 0.1 mg / kg or less, 0.05 mg / kg or less, or 0.04 mg / kg or less per day.

[0032] In certain embodiments of this aspect of the invention, sertraline or a pharmaceutically acceptable salt, hydrate, solvate, or polymorph thereof is administered once every 12 or 24 hours as shown in Table 5 or administered at a daily dose that follows one of the daily dose ranges indicated as "+" listed in Table 6. For example, sertraline or a pharmaceutically acceptable salt, hydrate, solvate, or polymorph thereof may be administered at a daily dose of 0.1 mg to 35 mg, 0.5 mg to 35 mg, 0.75 mg to 35 mg, 1.0 mg to 35 mg, 1.5 mg to 35 mg, 2.0 mg to 35 mg, 0.1 mg to 30 mg, 0.1 mg to 25 mg, 0.1 mg to 20 mg, 0.1 mg to 15 mg, 0.1 mg to 10 mg, 0.1 mg to 5 mg, 0.1 mg to 2.5 mg, 0.0015 mg / kg to 0.5 mg / kg, 0.0075 mg / kg to 0.5 mg / kg, 0.01 mg / kg to 0.5 mg / kg, 0.015 mg / kg to 0.5 mg / kg, 0.02 mg / kg to 0.5 mg / kg, 0.03 mg / kg to 0.5 mg / kg, 0.0015 mg / kg to 0.4 mg / kg, 0.0015 mg / kg to 0.3 mg / kg, 0.0015 mg / kg to 0.2 mg / kg, 0.0015 mg / kg to 0.15 mg / kg, 0.0015 mg / kg to 0.1 mg / kg, 0.0015 mg / kg to 0.05 mg / kg, or 0.0015 mg / kg to 0.04 mg / kg, every 12 hours or every 24 hours. In one embodiment, for example, the following items are provided. (Item 1) A method for treating a central nervous system (CNS) disorder with cognitive impairment or at risk of the disorder in a subject, the method comprising treating the disorder, delaying or slowing the progression of cognitive impairment, or reducing the rate of decline of cognitive function in the subject, the method comprising administering to the subject a therapeutically effective amount of a synaptic vesicle protein 2A (SV2A) inhibitor or a pharmaceutically acceptable salt, hydrate, solvate, or polymorph thereof. (Item 2) The SV2A inhibitor or a pharmaceutically acceptable salt, hydrate, solvate, or polymorph thereof is selected from the group of SV2A inhibitors described in International Patent Application No. PCT / US2009 / 005647; International Patent Application Publication No. WO2010 / 144712; WO2010 / 002869; WO2008 / 132139; WO2007 / 065595; WO2006 / 128693; WO2006 / 128692; WO2005 / 054188; WO2004 / 087658; WO2002 / 094787; WO2001 / 062726; U.S. Patent Nos. 7,465,549; 7,244,747; 5,334,720; 4,696,943; 4,696,942; U.S. Patent Application Nos. 12 / 580,464; 61 / 105,847; 61 / 152,631; and 61 / 175,536; U.S. Patent Application Publication Nos. 20090312333; 20090018148; 20080081832; 2006258704; and the group of SV2A inhibitors described in British Patent Nos. 1,039,113; and 1,309,692; or is a pharmaceutically acceptable salt, hydrate, solvate, or polymorph thereof selected therefrom; or is a pharmaceutically acceptable salt, hydrate, solvate, or polymorph thereof for the method according to item 1. (Item 3) The method according to item 1, wherein the SV2A inhibitor or a pharmaceutically acceptable salt, hydrate, solvate, or polymorph thereof is selected from the group consisting of levetiracetam, seletracetam, and brivaracetam, or is a pharmaceutically acceptable salt, hydrate, solvate, or polymorph thereof. (Item 4) The method according to item 2, wherein the SV2A inhibitor or a pharmaceutically acceptable salt, hydrate, solvate, or polymorph thereof is levetiracetam or a pharmaceutically acceptable salt, hydrate, solvate, or polymorph thereof. (Item 5) The method according to item 2, wherein the SV2A inhibitor or a pharmaceutically acceptable salt, hydrate, solvate, or polymorph thereof is brivaracetam or a pharmaceutically acceptable salt, hydrate, solvate, or polymorph thereof. (Item 6) The method according to item 2, wherein the SV2A inhibitor or a pharmaceutically acceptable salt, hydrate, solvate, or polymorph thereof is sertraline or a pharmaceutically acceptable salt, hydrate, solvate, or polymorph thereof. (Item 7) The method according to any one of items 1 to 6, wherein the SV2A inhibitor or a pharmaceutically acceptable salt, hydrate, solvate, or polymorph thereof is administered at a daily dose of 0.1 mg / kg to 5 mg / kg every 12 hours or every 24 hours. (Item 8) The method according to item 7, wherein the daily dose is 0.1 mg / kg to 0.2 mg / kg. (Item 9) The SV2A inhibitor or a pharmaceutically acceptable salt, hydrate, solvate, or polymorph thereof is administered at a daily dose of 0.01 mg / kg to 2.5 mg / kg every 12 hours or every 24 hours and the method according to any one of items 1 to 6. (Item 10) The method according to item 9, wherein the daily dose is 0.1 mg / kg to 2.5 mg / kg. (Item 11) The method according to item 9, wherein the daily dose is 0.4 mg / kg to 2.5 mg / kg. (Item 12) The method according to item 9, wherein the daily dose is 0.6 mg / kg to 1.8 mg / kg. (Item 13) The method according to item 9, wherein the daily dose is 0.04 mg / kg to 2.5 mg / kg. (Item 14) The method according to item 9, wherein the daily dose is 0.06 mg / kg to 1.8 mg / kg. (Item 15) The method according to any one of items 1 to 6, wherein the SV2A inhibitor or a pharmaceutically acceptable salt, hydrate, solvate, or polymorph thereof is administered at a daily dose of 2 mg / kg to 4 mg / kg every 12 hours or every 24 hours. (Item 16) The method according to item 15, wherein the daily dose is 2 mg / kg to 3 mg / kg. (Item 17) The method according to item 15, wherein the daily dose is 3 mg / kg to 4 mg / kg. (Item 18) The method according to any one of items 1 to 6, wherein the SV2A inhibitor or a pharmaceutically acceptable salt, hydrate, solvate, or polymorph thereof is administered at a daily dose of 0.2 mg / kg to 0.4 mg / kg every 12 hours or every 24 hours. (Item 19) The method according to item 18, wherein the daily dose is 0.2 mg / kg to 0.3 mg / kg. (Item 20) The method according to item 18, wherein the daily dose is 0.3 mg / kg to 0.4 mg / kg. (Item 21) The method according to any one of items 1 to 6, wherein the SV2A inhibitor or a pharmaceutically acceptable salt, hydrate, solvate, or polymorph thereof is administered at a daily dose of 0.001 mg / kg to 5 mg / kg every 12 hours or every 24 hours. (Item 22) The method according to item 21, wherein the daily dose is 0.001 mg / kg to 0.5 mg / kg. (Item 23) The method according to item 21, wherein the daily dose is 0.01 mg / kg to 0.5 mg / kg. (Item 24) A method for treating a central nervous system (CNS) disorder with cognitive impairment or at risk of such a disorder, or for delaying or slowing the progression of cognitive impairment or reducing the rate of decline of cognitive function in a subject, the method comprising administering to the subject an SV2A inhibitor or a pharmaceutically acceptable salt, hydrate, solvate, or polymorph thereof in combination with valproate or a pharmaceutically acceptable salt thereof. (Item 25) The valproate or a pharmaceutically acceptable salt thereof is administered at a daily dose such that the subject maintains a total blood valproate level of 0.5 μg / ml plasma ~5 μg / ml plasma, and the SV2A inhibitor or a pharmaceutically acceptable salt, hydrate, solvate, or polymorph thereof is administered at a daily dose of 0.01 mg / kg to 1 mg / kg, the method according to item 24. (Item 26) The valproate or a pharmaceutically acceptable salt thereof is administered at a daily dose such that the subject maintains a total blood valproate level of 0.5 μg / ml plasma ~5 μg / ml plasma, and the SV2A inhibitor or a pharmaceutically acceptable salt, hydrate, solvate, or polymorph thereof is administered at a daily dose of 0.001 mg / kg to 1 mg / kg, the method according to item 24. (Item 27) The valproate or a pharmaceutically acceptable salt thereof is administered at a daily dose such that the subject maintains a total blood valproate level of 0.5 μg / ml plasma ~5 μg / ml plasma, and the SV2A inhibitor or a pharmaceutically acceptable salt, hydrate, solvate, or polymorph thereof is administered at a daily dose of 0.1 mg / kg to 5 mg / kg, the method according to item 24. (Item 28) The valproate or a pharmaceutically acceptable salt thereof is administered at a daily dose such that the subject maintains a total blood valproate level of 0.5 μg / ml plasma ~5 μg / ml plasma, and the SV2A inhibitor or a pharmaceutically acceptable salt, hydrate, solvate, or polymorph thereof is administered at a daily dose of 0.05 mg / kg to 0.5 mg / kg, the method according to item 24. (Item 29) The SV2A inhibitor or a pharmaceutically acceptable salt, hydrate, solvate, or polymorph thereof is selected from the group of SV2A inhibitors described in International Patent Application No. PCT / US2009 / 005647; International Patent Application Publication No. WO2010 / 144712; WO2010 / 002869; WO2008 / 132139; WO2007 / 065595; WO2006 / 128693; WO2006 / 128692; WO2005 / 054188; WO2004 / 087658; WO2002 / 094787; WO2001 / 062726; U.S. Patent Nos. 7,465,549; 7,244,747; 5,334,720; 4,696,943; 4,696,942; U.S. Patent Application Nos. 12 / 580,464; 61 / 105,847; 61 / 152,631; and 61 / 175,536; U.S. Patent Application Publication Nos. 20090312333; 20090018148; 20080081832; 2006258704; and is selected from the group of SV2A inhibitors described in British Patent Nos. 1,039,113; and 1,309,692; or is a pharmaceutically acceptable salt, hydrate, solvate, or polymorph thereof , the method according to any one of items 24 to 28. (Item 30) The SV2A inhibitor or a pharmaceutically acceptable salt, hydrate, solvate, or polymorph thereof is selected from the group consisting of levetiracetam, seletracetam, and brivaracetam, or is a pharmaceutically acceptable salt, hydrate, solvate, or polymorph thereof, the method according to any one of items 24 to 28. (Item 31) The SV2A inhibitor or a pharmaceutically acceptable salt, hydrate, solvate, or polymorph thereof is levetiracetam or a pharmaceutically acceptable salt, hydrate, solvate, or polymorph thereof, the method according to item 30. (Item 32) The SV2A inhibitor or a pharmaceutically acceptable salt, hydrate, solvate, or polymorph thereof is brivaracetam or a pharmaceutically acceptable salt, hydrate, solvate, or polymorph thereof, the method according to item 30. (Item 33) The method according to item 30, wherein the SV2A inhibitor or a pharmaceutically acceptable salt, hydrate, solvate, or polymorph thereof is sertraline or a pharmaceutically acceptable salt, hydrate, solvate, or polymorph thereof. (Item 34) The method according to any one of items 24 to 33, wherein the SV2A inhibitor or a pharmaceutically acceptable salt, hydrate, solvate, or polymorph thereof and the valproate or a pharmaceutically acceptable salt thereof are administered simultaneously. (Item 35) The method according to any one of items 24 to 33, wherein the SV2A inhibitor or a pharmaceutically acceptable salt, hydrate, solvate, or polymorph thereof and the valproate or a pharmaceutically acceptable salt thereof are administered in a single formulation. (Item 36) The method according to any one of items 24 to 33, wherein the SV2A inhibitor or a pharmaceutically acceptable salt, hydrate, solvate, or polymorph thereof and the valproate or a pharmaceutically acceptable salt thereof are administered sequentially. (Item 37) A pharmaceutical composition containing an SV2A inhibitor or a pharmaceutically acceptable salt, hydrate, solvate, or polymorph thereof, wherein the SV2A inhibitor or a pharmaceutically acceptable salt, hydrate, solvate, or polymorph thereof is present in an amount of 5 mg to 140 mg. (Item 38) A pharmaceutical composition containing an SV2A inhibitor or a pharmaceutically acceptable salt, hydrate, solvate, or polymorph thereof, wherein the SV2A inhibitor or a pharmaceutically acceptable salt, hydrate, solvate, or polymorph thereof is present in an amount of 0.7 mg to 180 mg. (Item 39) A pharmaceutical composition containing an SV2A inhibitor or a pharmaceutically acceptable salt, hydrate, solvate, or polymorph thereof, wherein the SV2A inhibitor or a pharmaceutically acceptable salt, hydrate, solvate, or polymorph thereof is present in an amount of 0.07 mg to 350 mg. (Item 40) A pharmaceutical composition comprising an SV2A inhibitor or a pharmaceutically acceptable salt, hydrate, solvate, or polymorph thereof, wherein the SV2A inhibitor or a pharmaceutically acceptable salt, hydrate, solvate, or polymorph thereof is present in an amount of 50 mg to 250 mg. (Item 41) A pharmaceutical composition comprising an SV2A inhibitor or a pharmaceutically acceptable salt, hydrate, solvate, or polymorph thereof, wherein the SV2A inhibitor or a pharmaceutically acceptable salt, hydrate, solvate, or polymorph thereof is present in an amount of 3 mg to 50 mg. (Item 42) A pharmaceutical composition comprising an SV2A inhibitor or a pharmaceutically acceptable salt, hydrate, solvate, or polymorph thereof, wherein the SV2A inhibitor or a pharmaceutically acceptable salt, hydrate, solvate, or polymorph thereof is present in an amount of 0.05 mg to 35 mg. (Item 43) A pharmaceutical composition comprising an SV2A inhibitor or a pharmaceutically acceptable salt, hydrate, solvate, or polymorph thereof and valproate or a pharmaceutically acceptable salt thereof, wherein the SV2A inhibitor or a pharmaceutically acceptable salt, hydrate, solvate, or polymorph thereof is present in an amount of 3 mg to 50 mg. (Item 44) A pharmaceutical composition comprising an SV2A inhibitor or a pharmaceutically acceptable salt, hydrate, solvate, or polymorph thereof and valproate or a pharmaceutically acceptable salt thereof, wherein the SV2A inhibitor or a pharmaceutically acceptable salt, hydrate, solvate, or polymorph thereof is present in an amount of 0.07 mg to 50 mg. (Item 45) A pharmaceutical composition comprising an SV2A inhibitor or a pharmaceutically acceptable salt, hydrate, solvate, or polymorph thereof and valproate or a pharmaceutically acceptable salt thereof. (Item 46) The composition according to item 45, wherein the SV2A inhibitor or a pharmaceutically acceptable salt, hydrate, solvate, or polymorph thereof in the composition is present in an amount of 0.05 mg to 35 mg. (Item 47) The composition according to item 45, wherein the SV2A inhibitor or a pharmaceutically acceptable salt, hydrate, solvate, or polymorph thereof in the composition is present in an amount of 0.07 mg to 350 mg. (Item 48) The composition according to item 45, wherein the SV2A inhibitor or a pharmaceutically acceptable salt, hydrate, solvate, or polymorph thereof in the composition is present in an amount of 50 mg to 250 mg. (Item 49) The composition according to item 45, wherein the SV2A inhibitor or a pharmaceutically acceptable salt, hydrate, solvate, or polymorph thereof is present in an amount of less than 350 mg, less than 250 mg, less than 200 mg, less than 150 mg, less than 100 mg, less than 50 mg, less than 35 mg, less than 10 mg, less than 5 mg, less than 1 mg, less than 0.5 mg, less than 0.1 mg, less than 0.07 mg, or less than 0.05 mg. (Item 50) A method for treating a central nervous system (CNS) disorder with cognitive impairment or at risk of the disorder in a subject, or delaying or slowing the progression of cognitive impairment in the subject, or reducing the rate of decline in cognitive function in the subject, the method comprising administering to the subject a therapeutically effective amount of levetiracetam or a pharmaceutically acceptable salt, hydrate, solvate, or polymorph thereof. (Item 51) The method according to item 50, wherein the levetiracetam or a pharmaceutically acceptable salt, hydrate, solvate, or polymorph thereof is administered at a daily dose of 1 mg / kg to 2 mg / kg every 12 hours or every 24 hours. (Item 52) The method according to item 50, wherein the levetiracetam or a pharmaceutically acceptable salt, hydrate, solvate, or polymorph thereof is administered once every 12 hours or once every 24 hours at a daily dose of 70 mg to 140 mg. The method according to item 50. (Item 53) The method according to item 50, wherein the levetiracetam or a pharmaceutically acceptable salt, hydrate, solvate, or polymorph thereof is administered once every 12 hours or once every 24 hours at a daily dose of 0.1 mg / kg to 2.5 mg / kg. (Item 54) The method according to item 50, wherein the levetiracetam or a pharmaceutically acceptable salt, hydrate, solvate, or polymorph thereof is administered once every 12 hours or once every 24 hours at a daily dose of 7 mg to 180 mg. (Item 55) The method according to item 50, wherein the levetiracetam or a pharmaceutically acceptable salt, hydrate, solvate, or polymorph thereof is administered once every 12 hours or once every 24 hours at a daily dose of 0.4 mg / kg to 2.5 mg / kg. (Item 56) The method according to item 50, wherein the levetiracetam or a pharmaceutically acceptable salt, hydrate, solvate, or polymorph thereof is administered once every 12 hours or once every 24 hours at a daily dose of 25 mg to 180 mg. The method according to item 50. (Item 57) The method according to item 50, wherein the levetiracetam or a pharmaceutically acceptable salt, hydrate, solvate, or polymorph thereof is administered once every 12 hours or once every 24 hours at a daily dose of 0.6 mg / kg to 1.8 mg / kg. (Item 58) The method according to item 50, wherein the levetiracetam or a pharmaceutically acceptable salt, hydrate, solvate, or polymorph thereof is administered once every 12 hours or once every 24 hours at a daily dose of 40 mg to 130 mg. The method according to item 50. (Item 59) The method according to item 50, wherein the levetiracetam or a pharmaceutically acceptable salt, hydrate, solvate, or polymorph thereof is administered at a daily dose of 2.0 mg / kg to 4.0 mg / kg every 12 hours or every 24 hours. (Item 60) The method according to item 50, wherein the levetiracetam or a pharmaceutically acceptable salt, hydrate, solvate, or polymorph thereof is administered at a daily dose of 140 mg to 300 mg every 12 hours or every 24 hours. (Item 61) The method according to item 50, wherein the levetiracetam or a pharmaceutically acceptable salt, hydrate, solvate, or polymorph thereof is administered at a daily dose of 3.0 mg / kg to 4.0 mg / kg every 12 hours or every 24 hours. (Item 62) The method according to item 50, wherein the levetiracetam or a pharmaceutically acceptable salt, hydrate, solvate, or polymorph thereof is administered at a daily dose of 200 mg to 300 mg every 12 hours or every 24 hours. (Item 63) The method according to item 50, wherein the levetiracetam or a pharmaceutically acceptable salt, hydrate, solvate, or polymorph thereof is administered at a daily dose of 2.0 mg / kg to 3.0 mg / kg every 12 hours or every 24 hours. (Item 64) The method according to item 50, wherein the levetiracetam or a pharmaceutically acceptable salt, hydrate, solvate, or polymorph thereof is administered at a daily dose of 140 mg to 200 mg every 12 hours or every 24 hours. (Item 65) The method according to item 50, wherein the levetiracetam or a pharmaceutically acceptable salt, hydrate, solvate, or polymorph thereof is administered at a daily dose of 0.1 mg / kg to 5 mg / kg every 12 hours or every 24 hours. (Item 66) The method according to item 50, wherein the levetiracetam or a pharmaceutically acceptable salt, hydrate, solvate, or polymorph thereof is administered at a daily dose of 7 mg / kg to 350 mg / kg every 12 hours or every 24 hours. (Item 67) The method according to item 50, wherein the levetiracetam or a pharmaceutically acceptable salt, hydrate, solvate, or polymorph thereof is administered at a daily dose according to Table 1 or Table 2 every 12 hours or every 24 hours. (Item 68) A method for treating a central nervous system (CNS) disorder with cognitive impairment or at risk of such a disorder in a subject, or delaying or slowing the progression of cognitive impairment in the subject, or reducing the rate of decline in cognitive function in the subject, the method comprising administering to the subject a therapeutically effective amount of brivaracetam or a pharmaceutically acceptable salt, hydrate, solvate, or polymorph thereof. (Item 69) (Item 69) The method according to item 68, wherein the brivaracetam or a pharmaceutically acceptable salt, hydrate, solvate, or polymorph thereof is administered at a daily dose of 0.1 mg / kg to 0.2 mg / kg every 12 hours or every 24 hours. (Item 70) The method according to item 68, wherein the brivaracetam or a pharmaceutically acceptable salt, hydrate, solvate, or polymorph thereof is administered at a daily dose of 7 mg to 15 mg every 12 hours or every 24 hours. as described. (Item 71) The method according to item 68, wherein the brivaracetam or a pharmaceutically acceptable salt, hydrate, solvate, or polymorph thereof is administered at a daily dose of 0.01 mg / kg to 2.5 mg / kg every 12 hours or every 24 hours. as described in item 68. (Item 72) The method according to item 68, wherein the brivaracetam or a pharmaceutically acceptable salt, hydrate, solvate, or polymorph thereof is administered at a daily dose of 0.7 mg to 180 mg every 12 hours or every 24 hours. (Item 73) The method according to item 68, wherein the brivaracetam or a pharmaceutically acceptable salt, hydrate, solvate, or polymorph thereof is administered at a daily dose of 0.04 mg / kg to 2.5 mg / kg every 12 hours or every 24 hours. (Item 74) The method according to item 68, wherein the brivaracetam or a pharmaceutically acceptable salt, hydrate, solvate, or polymorph thereof is administered at a daily dose of 2.5 mg to 180 mg every 12 hours or every 24 hours. (Item 75) The method according to item 68, wherein the brivaracetam or a pharmaceutically acceptable salt, hydrate, solvate, or polymorph thereof is administered at a daily dose of 0.06 mg / kg to 1.8 mg / kg every 12 hours or every 24 hours. (Item 76) The method according to item 68, wherein the brivaracetam or a pharmaceutically acceptable salt, hydrate, solvate, or polymorph thereof is administered at a daily dose of 4.0 mg to 130 mg every 12 hours or every 24 hours. (Item 77) The method according to item 68, wherein the brivaracetam or a pharmaceutically acceptable salt, hydrate, solvate, or polymorph thereof is administered at a daily dose of 0.2 mg / kg to 0.4 mg / kg every 12 hours or every 24 hours. (Item 78) The method according to item 68, wherein the brivaracetam or a pharmaceutically acceptable salt, hydrate, solvate, or polymorph thereof is administered at a daily dose of 14 mg to 30 mg every 12 hours or every 24 hours. (Item 79) The method according to item 68, wherein the brivaracetam or a pharmaceutically acceptable salt, hydrate, solvate, or polymorph thereof is administered once every 12 hours or once every 24 hours at a daily dose of 0.1 mg to 35 mg or 0.0015 mg / kg to 0.5 mg / kg. (Item 80) The method according to item 68, wherein the brivaracetam or a pharmaceutically acceptable salt, hydrate, solvate, or polymorph thereof is administered once every 12 hours or once every 24 hours at a daily dose of at least 0.1 mg, at least 0.5 mg, at least 0.75 mg, at least 1.0 mg, at least 1.5 mg, at least or 2.0 mg; and at a daily dose of 2.5 mg or less, 5 mg or less, 10 mg or less, 15 mg or less, 20 mg or less, 25 mg or less, 30 mg or less, or 35 mg or less. (Item 81) The method according to item 68, wherein the brivaracetam or a pharmaceutically acceptable salt, hydrate, solvate, or polymorph thereof is administered once every 12 hours or once every 24 hours at a daily dose of at least 0.0015 mg / kg, at least 0.0075 mg / kg, at least 0.01 mg / kg, at least 0.015 mg / kg, at least 0.02 mg / kg, or at least 0.03 mg / kg; and at a daily dose of 0.5 mg / kg or less, 0.4 mg / kg or less, 0.3 mg / kg or less, 0.2 mg / kg or less, 0.15 mg / kg or less, 0.1 mg / kg or less, 0.05 mg / kg or less, or 0.04 mg / kg or less. (Item 82) The method according to item 68, wherein the brivaracetam or a pharmaceutically acceptable salt, hydrate, solvate, or polymorph thereof is administered once every 12 hours or once every 24 hours at a daily dose according to Table 3 or Table 4. (Item 83) Needs treatment for a central nervous system (CNS) disorder with cognitive impairment or is at risk of such a disorder A method for treating a disorder, or delaying or slowing the progression of a cognitive disorder, or reducing the rate of decline of cognitive function in a subject, the method comprising administering to the subject a therapeutically effective amount of sertraline or a pharmaceutically acceptable salt, hydrate, solvate, or polymorph thereof. (Item 84) The method according to item 83, wherein the sertraline or a pharmaceutically acceptable salt, hydrate, solvate, or polymorph thereof is administered at a daily dose of 0.1 mg to 35 mg or 0.0015 mg / kg to 0.5 mg / kg every 12 hours or every 24 hours. (Item 85) The method according to item 83, wherein the sertraline or a pharmaceutically acceptable salt, hydrate, solvate, or polymorph thereof is administered at a daily dose of at least 0.1 mg, at least 0.5 mg, at least 0.75 mg, at least 1.0 mg, at least 1.5 mg, or at least 2.0 mg every 12 hours or every 24 hours; and at a daily dose of 2.5 mg or less, 5 mg or less, 10 mg or less, 15 mg or less, 20 mg or less, 25 mg or less, 30 mg or less, or 35 mg or less. (Item 86) The sertraline or a pharmaceutically acceptable salt, hydrate, solvate, or polymorph thereof is administered at a daily dose of at least 0.0015 mg / kg, at least 0.0075 mg / kg, at least 0.01 mg / kg, at least 0.015 mg / kg, at least 0.02 mg / kg, or at least 0.03 mg / kg every 12 hours or every 24 hours; and at a daily dose of 0.5 mg / kg or less, 0.4 mg / kg or less, 0.3 mg / kg or less, 0.2 mg / kg or less, 0.15 mg / kg or less, 0.1 mg / kg or less, 0.05 mg / kg or less, or 0.04 mg / kg or less, according to the method described in item 83. (Item 87) The method according to item 83, wherein the sertraline or a pharmaceutically acceptable salt, hydrate, solvate, or polymorph thereof is administered at a daily dose according to Table 5 or Table 6 every 12 hours or every 24 hours. (Item 88) The method according to any one of items 1, 24, 50, 68, and 83, wherein the CNS disorder with the cognitive impairment is an age-related cognitive impairment. (Item 89) The method according to item 88, wherein the age-related cognitive impairment is mild cognitive impairment. (Item 90) The method according to item 89, wherein the mild cognitive impairment is amnestic mild cognitive impairment. (Item 91) The method according to any one of items 1, 24, 50, 68, and 83, wherein the CNS disorder with the cognitive impairment is dementia. (Item 92) The method according to item 91, wherein the dementia is Alzheimer's disease. (Item 93) The method according to any one of items 1, 24, 50, 68, and 83, wherein the CNS disorder with the cognitive impairment is schizophrenia. (Item 94) The method according to any one of items 1, 24, 50, 68, and 83, wherein the CNS disorder with the cognitive impairment is amyotrophic lateral sclerosis. (Item 95) The method according to any one of items 1, 24, 50, 68, and 83, wherein the CNS disorder with the cognitive impairment is post-traumatic stress disorder. (Item 96) The method according to any one of items 1, 24, 50, 68, and 83, wherein the CNS disorder with the cognitive impairment is related to cancer treatment. BRIEF DESCRIPTION OF THE DRAWINGS

[0033]

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Figure 8A

Figure 8B

Figure 8C

Figure 9A

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Figure 18A

Figure 18B

DETAILED DESCRIPTION OF THE INVENTION

[0034] (Detailed Description of the Invention) Unless otherwise defined herein, scientific and technical terms used in this application shall have the meanings commonly understood by those skilled in the art. In general, the nomenclature and techniques related to cell and tissue culture, molecular biology, cell and cancer biology, neurobiology, neurochemistry, virology, immunology, microbiology, pharmacology, genetics, as well as protein and nucleic acid chemistry described in this specification are well known and generally used in the art.

[0035] The methods and techniques of the present invention are generally carried out according to conventional methods well known in the art, unless otherwise indicated, and as described in various general and more specific references cited and discussed throughout this specification. For example, see "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, 4th Edition", W.H. Freeman & Co., New York (2000); Griffiths et al., "Introduction to Genetic Analysis, 7th Edition", W.H. Freeman & Co., N.Y. (1999); Gilbert et al., "Developmental Biology, 6th Edition", Sinauer Associates, Inc., Sunderland, MA (2000).

[0036] The chemical terms used in this specification are used according to the conventional usage exemplified in "The McGraw-Hill Dictionary of Chemical Terms", edited by Parker S., McGraw-Hill, San Francisco, C.A. (1985).

[0037] All of the foregoing and any other publications, patents, and published patent applications referred to in this application are hereby incorporated by reference in their entirety, and in case of conflict, the present specification (including its specific definitions) shall govern.

[0038] Throughout this specification, the term "comprise" or variations thereof (such as "comprises" or "comprising") is to be understood to mean the inclusion of the stated integer (or component) or group of integers (or components) but not the exclusion of any other integer (or component) or group of integers (or components).

[0039] The singular forms "a", "an", and "the" include the plural unless the context clearly dictates otherwise.

[0040] The term "including" is used to mean "including but not limited to". "Including" and "including but not limited to" are used interchangeably.

[0041] As used herein, the term "agent" refers to an extract made from a chemical substance (such as an organic or inorganic compound, a mixture of chemical substances), a biopolymer (including nucleic acids, antibodies (including fragments thereof as well as humanized antibodies, chimeric antibodies, and human antibodies, and monoclonal antibodies), proteins or portions thereof (such as peptides), lipids, carbohydrates, etc.), or a biological substance (such as cells or tissues of bacteria, plants, fungi, or animals (especially mammals)). Agents include, for example, agents with known structures and agents with unknown structures. The SV2A inhibitory activity of such an agent may render the agent suitable as a "therapeutic agent" in the methods and compositions of the present invention.

[0042] "Patient", "subject", or "individual" are used interchangeably and refer to either a human or a non-human animal. These terms include mammals (including humans, primates, domestic animals (such as cows, pigs, etc.), companion animals (e.g., dogs, cats, etc.), and rodents (e.g., mice and rats), etc.).

[0043] "Cognitive function" or "cognitive state" each refer to any higher-order intellectual brain process or brain state involved in learning and / or memory (including, but not limited to, attention, information acquisition, information processing, working memory, short-term memory, long-term memory, prospective memory, retrospective memory, memory retrieval, discriminative learning, decision-making, regulation of inhibitory responses, attentional set shifting, delay of reinforcement learning, reversal learning, temporal integration of spontaneous behavior, and expression of interest in one's surroundings and self-governance).

[0044] In humans, cognitive function can be measured, for example (without limitation), by the Clinical Global Impression of Change scale (CIBIC-plus scale); the Mini Mental State Exam (MMSE); the Neuropsychiatric Inventory (NPI); the Clinical Dementia Rating Scale (CDR); the Cambridge Neuropsychological Test Automated Battery (CANTAB); the Sandoz Clinical Assessment-Geriatric (SCAG), the Buschke Selective Reminding Test (Buschke and Fuld, 1974); the Verbal Paired Associates subtest; the Logical Memory subtest; the W The Neuropsychiatric Inventory (NPI); the Clinical Dementia Rating Scale (CDR); the Cambridge Neuropsychological Test Automated Battery (CANTAB); the Sandoz Clinical Assessment-Geriatric (SCAG), the Buschke Selective Reminding Test (Buschke and Fuld, 1974); the Verbal Paired Associates subtest; the Logical Memory subtest; the W The Buschke Selective Reminding Test (Buschke and Fuld, 1974); the Verbal Paired Associates subtest; the Logical Memory subtest; the U The visual reproduction subtest of the Wechsler Memory Scale-Revised (WMS-R) (Wechsler, 1997); the Benton Visual Retention Test, or can be measured by an explicit three-alternative forced-choice method. See Folstein et al., J Psychiatric Res 12:189-98, (1975); Robbins et al., Dementia 5:266-81, (1994); Rey, L'examen clinique en psychologie, (1964); Kluger et al., J Geriatr Psychiatry Neurol 12:168-79, (1999); Marquis et al., 2002 and Masur et al., 1994.

[0045] In animal model systems, cognitive function can be measured by various conventional methods known in the art, including the Morris water maze (MWM), Barnes circular maze, elevated radial arm maze, T maze, or the use of any other maze in which animals use spatial information. Other tests known in the art can also be used to evaluate cognitive function, such as recognition of novel objects and odor recognition tasks.

[0046] 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 capable of measuring brain function. In animals, cognitive function can also be measured using electrophysiological techniques.

[0047] "Enhancement" of cognitive function refers to the effect on impaired cognitive function such that it becomes more similar to the function of normal non-impaired subjects. Cognitive function can be enhanced to any detectable degree, but in humans, preferably, it is enhanced sufficiently such that the impaired subject can carry out daily life at the same level of proficiency as a normal non-impaired subject.

[0048] In some cases, "promotion" of cognitive function of a subject suffering from age-related cognition refers to affecting impaired cognitive function so that it is more similar to the function of age-matched normal non-impaired subjects or young adult subjects.The cognitive function of this subject can be promoted to any detectable degree, but in humans, it is preferably promoted sufficiently so that impaired subjects can perform daily life at the same level of proficiency as age-matched normal non-impaired subjects or young adult subjects.

[0049] "Preservation" of cognitive function refers to an effect on normal cognitive function or impairment of cognitive function such that cognitive function is not deteriorated or does not fall below that observed in the subject in the first verbal report or diagnosis, or such deterioration is delayed.

[0050] "Improvement" of cognitive function includes promoting cognitive function and / or preserving cognitive function in a subject.

[0051] "Cognitive impairment" refers to cognitive function in a subject that is not as strong as expected in a normal, non-impaired subject. In some cases, cognitive function is reduced by about 5%, about 10%, about 30%, or more compared to expected cognitive function in a normal, non-impaired subject. In some cases, "cognitive impairment" in a subject suffering from age-related cognitive impairment refers to cognitive function that is not as strong as expected in an age-matched normal, non-impaired subject, or that is not as strong as expected in a young adult subject (i.e., in a cognitive test). , the function of the subject is not as strong as that of the subject having the mean score for a given age. This refers to cognitive function.

[0052] "Age-related cognitive impairment" refers to cognitive impairment in elderly subjects where the cognitive function is not as strong as that expected in normal subjects matched for age or in young adult subjects. In some cases, the cognitive function decreases by about 5%, about 10%, about 30%, or more compared to that expected in normal subjects matched for age. In some cases, the cognitive function is as expected in normal subjects matched for age but decreases by about 5%, about 10%, about 30%, about 50%, or more compared to that expected in young adult subjects. Age-related cognitive impairment can be related to mild cognitive impairment (MCI) (including amnestic MCI and non-amnestic MCI), age-related memory impairment (AAMI), and age-related cognitive decline (ARCD).

[0053] "Cognitive impairment" related to, associated with, or in Alzheimer's disease (AD) refers to the cognitive function in a subject that is not as strong as expected in a subject who has not been diagnosed with AD using conventional methodologies and standards.

[0054] "Mild cognitive impairment" or "MCI" refers to a condition characterized by isolated memory impairment without other cognitive abnormalities and relatively normal functional abilities. One set of criteria for the clinical features of MCI is specified by the following features: (1) complaint of memory impairment (reported by the patient, history provider, or physician), (2) normal activities of daily living (ADL), (3) normal global cognitive function, (4) abnormal memory compared to age (defined as scoring below the mean for a given age by more than 1.5 standard deviations), and (5) absence of dementia criteria (defined by the DSM-IV guidelines). Petersen et al., Srch. Neurol. 56:303-308 (1999); Petersen, "Mild cognitive impairment: Aging to Alzheimer's Disease." Oxford University Pr ess, N.Y. (2003).

[0055] The diagnosis of MCI typically requires an objective assessment of cognitive impairment that can be accrued by the use of well-established neuropsychological tests (Mini-Mental State Examination (MMSE), Cambridge Neuropsychological Test Automated Battery (CANTAB), and each test (e.g., Rey Auditory Verbal Learning Test (AVLT), Logical Memory Subtest of the Wechsler Memory Scale-Revised (WMS-R), and New York University (NYU) Paragraph Recall Test, etc.)). See Folstein et al., J Psychiatric Res 12:189-98 (1975); Robbins et al., Dementia 5:266-81 (1994); Kluger et al., J Geriatric Psychiatry Neurol 12:168-79 (1999).

[0056] "Age-associated memory impairment (AAMI)" refers to a decline in memory due to aging. A patient can be considered to have AAMI if they are at least 50 years old and meet all of the following criteria: a) the patient is aware of a decline in their memory ability; b) the patient's performance has deteriorated on standard memory tests compared to young adults; c) all other clear causes of memory decline, excluding normal aging, have been excluded (i.e., the memory decline cannot be attributed to other causes (such as a recent heart attack or head injury, depression, side effects of drug application, Alzheimer's disease, etc.)).

[0057] "Age-related cognitive decline (ARCD)" refers to the decline in memory and cognitive abilities that is a result of normal aging in humans (e.g., Craik and Salthouse, 1992). This also applies to substantially all mammalian species. Age-associated memory impairment refers to elderly individuals who have a decline in objective memory compared to their previous selves but have normal cognitive function compared to their peers (Crook et al., 1986). Age-appropriate memory decline is a less pejorative term 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 and Crook, 1993). The Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV) (1994) systematizes the diagnostic classification of ARCD.

[0058] Alzheimer's disease (AD) is characterized by memory loss in its early stages. Late-stage symptoms include impaired judgment, disorientation, confusion, behavioral changes, difficulty speaking, and motor deficits. Histologically, AD is characterized by entanglement of β-amyloid plaques and tau proteins.

[0059] Vascular dementia is caused by stroke. The symptoms overlap with those of AD, but there is no focus on memory impairment.

[0060] Dementia with Lewy bodies is characterized by abnormal deposits of α-synuclein in the brain that form intracellular neurons. Cognitive impairment can be similar to that of AD and may include memory and judgment impairment, as well as behavioral changes.

[0061] Frontotemporal dementia is characterized by gliosis, neuronal loss, superficial spongiform degeneration in the frontal cortex and / or frontotemporal lobe, and Pick bodies. Symptoms include changes in personality and behavior (such as a decline in social skills and language expression / understanding).

[0062] "Post-traumatic stress disorder (PTSD)" refers to an anxiety disorder characterized by an immediate or delayed response to a traumatic event (characterized by re-experiencing the trauma, psychological numbing or avoidance of stimuli related to the trauma, and increased arousal). Re-experiencing of the phenomenon includes intrusive memories, flashbacks, nightmares, and psychological or physiological distress in response to things that remind one of the trauma. Such responses cause anxiety and can have both chronic and acute significant effects on the patient's quality of life and physical and emotional health. PTSD is also related to impaired cognitive performance, and older individuals suffering from PTSD have a greater decline in cognitive performance compared to control patients.

[0063] "Schizophrenia" refers to a chronic, debilitating disorder characterized by a broad range of psychopathology (positive symptoms such as abnormal or distorted mental representations (e.g., hallucinations, delusions), negative symptoms characterized by a decrease in volition and goal-directed behavior (e.g., anhedonia, affective flattening, avolition), and cognitive dysfunction). Brain abnormalities have been proposed to underlie the full range of psychopathology in schizophrenia, but currently available antipsychotic medications are largely ineffective in treating cognitive dysfunction in patients.

[0064] "Amyotrophic lateral sclerosis" (also known as ALS) refers to a progressive, lethal neurodegenerative disease characterized by the degeneration of motor neurons (nerve cells in the central nervous system that control the movement of voluntary muscles). ALS is also characterized by neuronal degeneration in the entorhinal cortex and hippocampus, memory deficits, and neuronal hyperexcitability in different brain regions (e.g., the cortex).

[0065] "Cancer treatment-related cognitive dysfunction" refers to cognitive dysfunction that develops in subjects treated with cancer treatment (e.g., chemotherapy and radiation). The cytotoxicity of cancer treatment and other harmful side effects on the brain result in cognitive dysfunction in functions such as memory, learning, and attention.

[0066] The condition or "treatment" of a patient refers to taking measures to obtain a favorable or desired result (including clinical outcomes). Favorable or desired clinical outcomes include improvement in cognitive function, delay or slowing of the progression of cognitive dysfunction, reduction in the rate of decline of cognitive function, prevention or delay of the progression of a disease or disorder, or CNS disorders associated with cognitive dysfunction (e.g., age-related cognitive impairment, mild cognitive impairment (MCI), amnestic MCI, dementia, Alzheimer's disease (AD), prodromal AD, PTSD, schizophrenia, amyotrophic lateral sclerosis (ALS) or cancer treatment-related cognitive dysfunction). ​​​Reduction, alleviation, or delay in the progression of one or more related symptoms, including but not limited to these. Treating age-related cognitive impairment delays the conversion of age-related cognitive impairment (including but not limited to MCI, ARCD, and AAMI) to dementia (e.g., AD). This further includes

[0067] "Treating cognitive impairment" means taking measures to improve the cognitive function of a subject suffering from cognitive impairment such that the subject's performance in one or more cognitive tests improves to any detectable degree or further decline is prevented. Preferably, the subject's cognitive function is more closely similar to that of a subject without normal impairment after treatment of the cognitive impairment. Treatment of cognitive impairment in humans can improve cognitive function to any detectable degree, but preferably is improved sufficiently to enable a subject with impairment to perform daily activities of normal life at the same level of accuracy as a subject without normal impairment. In some cases, "treating cognitive impairment" means taking measures to improve the cognitive function of a subject suffering from cognitive impairment such that the subject's performance in one or more cognitive tests improves to any detectable degree or further decline is prevented. Preferably, the subject's cognitive function is more closely similar to that of a subject without normal impairment after treatment of the cognitive impairment. In some cases, "treating cognitive impairment" in a subject suffering from age-related cognitive impairment means taking measures to improve the cognitive function in that subject such that the subject's cognitive function is more closely similar to that of a subject without normal impairment adjusted for age or that of a young adult subject after treatment of the cognitive impairment. In some cases, "treating cognitive impairment" in a subject means performing a process for delaying or slowing the progression of cognitive impairment in a subject having cognitive impairment. In some cases, "treating cognitive impairment" in a subject means performing a process for reducing the rate of decline of cognitive function in a subject having cognitive impairment.

[0068] "Administering" or "administration" of a substance, compound, or agent to a subject can be done using one of a variety of methods known to those of ordinary skill in the art. For example, a compound or agent can be administered intravenously, intraarterially, intradermally, intramuscularly, intraperitoneally, intravenously, subcutaneously, intravitreally, sublingually, orally (by oral ingestion), intranasally (by inhalation), intraspinally, intracranially, and transdermally (e.g., by absorption through a skin conduit). A compound or agent can also be appropriately introduced by a refillable or biodegradable polymeric device or other device (e.g., patches and pumps) that provides for long-term, delayed, or controlled release of the compound or agent, or by a formulation. For example, it can be administered once, multiple times, and / or over one or more extended periods of time. In some aspects, administration includes both direct administration (including self-administration) and indirect administration (including the action of a prescription drug). For example, as used herein, a physician instructing a patient to self-administer a drug or to administer the drug to another person and / or prescribing a drug to the patient is administration of the drug to the patient.

[0069] The appropriate method of administering a substance, compound, or agent to a subject also depends, for example, on the age of the subject, whether the subject is active or inactive at the time of administration, whether the subject has a cognitive dysfunction at the time of administration, the extent of the dysfunction, and the chemical and biological properties of the compound or drug (e.g., solubility, digestibility, bioavailability, stability, and toxicity). In some embodiments, a compound or agent is orally administered to a subject, for example, by oral ingestion, or intravenously administered to a subject, for example, by injection. In some embodiments, an orally administered compound or agent is present in a long-term release formulation or a delayed release formulation or is administered using a device for such delayed or long-term release.

[0070] As used herein, administering an SV2A inhibitor or a pharmaceutically acceptable salt, hydrate, solvate, or polymorph thereof "in combination" or "together" with valproate or an analog, derivative, or pharmaceutically acceptable salt thereof includes co - administration and / or administration at different times (e.g., sequential administration). The term also includes administration in a single formulation and administration in separate formulations packaged together.

[0071] As used herein, the term "co - administration" means that an SV2A inhibitor or a pharmaceutically acceptable salt, hydrate, solvate, or polymorph thereof and valproate or an analog, derivative, or pharmaceutically acceptable salt thereof are administered with a time separation of about 15 minutes or less, and in some embodiments, about 10 minutes or less. When these drugs are co - administered, the SV2A inhibitor or a pharmaceutically acceptable salt, hydrate, solvate, or polymorph thereof and valproate or an analog, derivative, or pharmaceutically acceptable salt thereof may be included in the same dosage (e.g., a unit dosage form containing both the SV2A inhibitor and valproate) or in discontinuous dosages (e.g., the SV2A inhibitor or a pharmaceutically acceptable salt, hydrate, solvate, or polymorph thereof is contained in one dosage form and valproate or an analog, derivative, or pharmaceutically acceptable salt thereof is contained in another dosage form).

[0072] ​As used herein, the term "sequential administration" means that an SV2A inhibitor or a pharmaceutically acceptable salt, hydrate, solvate, or polymorph thereof, and a valproate or an analog, derivative, or pharmaceutically acceptable salt thereof are administered with a time separation of longer than about 15 minutes, in some embodiments longer than about 1 hour, or up to 12 hours. Either the SV2A inhibitor or valproate may be administered first. For sequential administration, the SV2A inhibitor or a pharmaceutically acceptable salt, hydrate, solvate, or polymorph thereof, and a valproate or an analog, derivative, or pharmaceutically acceptable salt thereof may be contained in a discontinuous dosage form (optionally contained in the same container or package).

[0073] A "therapeutically effective amount" of a drug or agent is an amount of the drug or agent that, when administered to a subject, has the intended therapeutic effect (e.g., improvement of cognitive function in a subject (e.g., a patient having a CNS disorder with cognitive impairment), or delay or slowing of the progression of cognitive impairment, or reduction in the rate of decline of cognitive function). The full therapeutic effect need not occur by a single administration and may occur only after administration of a series of doses. Thus, a therapeutically effective amount can be administered in one or multiple administrations. The exact effective amount required for a subject will depend, for example, on the size, health, and age of the subject, the nature and extent of the cognitive impairment, the treatment or combination of treatments selected for administration, and the mode of administration. One of ordinary skill in the art can readily determine the effective amount for a given situation by routine experimentation.

[0074] "Less than a therapeutic amount" means an amount less than the therapeutic amount at which the agent or compound of the invention is administered, i.e., an amount less than that normally used when the agent or compound is administered alone (i.e., individually, in the absence of other therapeutic agents or compounds) for treating a disorder involving cognitive insufficiency.

[0075] ​"Analog" is used herein to refer to a compound that is functionally similar to another chemical entity but does not share the same chemical structure. For example, an analog is sufficiently similar to a base compound or parent compound such that, as a result, this analog can be used in place of this base compound in therapeutic applications despite minor structural differences.

[0076] "Derivative" is used herein to refer to a chemical modification of a compound. Chemical modifications of a compound can include, for example, replacement of hydrogen with an alkyl group, an acyl group, or an amino group. Many other modifications are also possible.

[0077] The term "prodrug" is recognized in the art and is intended to encompass a compound or agent that is converted to an SV2A inhibitor or valproate under physiological conditions. A common way to make a prodrug is to select a moiety that is hydrolyzed or metabolized under physiological conditions to provide the desired compound or agent. In other embodiments, the prodrug is converted to an inhibitor of SV2A or valproate by the enzymatic activity of the host animal.

[0078] "Pharmaceutically acceptable salt" is used herein to refer to an agent or compound according to the invention in a therapeutically active, non-toxic, base salt form or acid salt form of a compound. Acid addition salt forms of a compound that occur in its free form as a base can be obtained by treatment of the free base form with a suitable acid such as an inorganic acid (e.g., hydrohalic acid (such as hydrochloric acid or hydrobromic acid), sulfuric acid, nitric acid, and phosphoric acid); or an organic acid (e.g., acetic acid, hydroxyacetic acid, propanoic acid, lactic acid, pyruvic acid, malonic acid, succinic acid, maleic acid, fumaric acid, malic acid, tartaric acid, citric acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, cyclic acid, salicylic acid, p-aminosalicylic acid, and pamoic acid, etc.). See, for example, WO01 / 062726.

[0079] (Description of the method of the present invention) The method of the present invention includes administration of an SV2A inhibitor or a pharmaceutically acceptable salt thereof. The method of the present invention further includes administration of an SV2A inhibitor or a pharmaceutically acceptable salt thereof in combination with administration of valproate or a pharmaceutically acceptable salt thereof. Agents or compounds of an SV2A inhibitor or valproate and pharmaceutically acceptable salts thereof also include hydrates, solvates, polymorphs, and prodrugs of these agents, compounds, and salts.

[0080] (Method for evaluating cognitive impairment) Animal models are important as a means for developing and evaluating treatments for CNS disorders associated with cognitive impairment. Characteristics that characterize cognitive impairment in animal models typically extend to cognitive impairment in humans. Thus, the efficacy in such animal models is expected to be predictive of the efficacy in humans. The degree of cognitive impairment in animal models for CNS disorders, and the efficacy of methods of treatment for this CNS disorder, can be tested and confirmed by the use of various cognitive tests.

[0081] The radial arm maze (RAM) behavioral task is one example of a cognitive test, particularly for testing spatial memory (Chappell et al. Neuropharmacology 37:481-487, 1998). The RAM apparatus consists of, for example, eight arms spaced equally apart. The arms of the maze project from each facet of a central platform. Food wells are located at the distal ends of each arm. Food is used as a reward. Blocks can be placed to prevent entry into any of the arms. A number of extra-maze cues surrounding the apparatus can also be provided. After the acclimation and training phases, the spatial memory of the subject is tested in this RAM under control conditions or under conditions treated with a test compound. can be tested. As part of this test, the subject is pre-trained prior to the trial with one of a range of dosages of vehicle control or test compound. At the start of each trial, a subset of the arms of the 8-arm maze is blocked. The subject is allowed to obtain food in the unblocked arms, and access to this arm is permitted during this initial "information stage" of the trial. The subject is then removed from the maze during a delay period (e.g., a 60-second delay, a 15-minute delay, a 1-hour delay, a 2-hour delay, a 6-hour delay, a 24-hour delay, or a longer delay) between this information stage and a subsequent "retention test" of this trial, and during this time, the barriers of the maze are removed, thus allowing access to all 8 arms. After this delay period, the subject is returned to the central platform (the barriers to the arms that were previously blocked have been removed), and is allowed to obtain the food reward remaining during this retention test stage of this trial. The identity and configuration of the blocked arms vary from trial to trial. The number of "errors" made by these subjects during this retention test stage is tracked. An error occurs in this trial if the subject enters an arm in which food has already been retrieved during the pre-delay component of this trial, or if the subject revisits an arm that has already been visited during the post-delay cycle. A smaller number of errors indicates better spatial memory. The number of errors made by test subjects under various test compound treatment regimens can then be compared for the efficacy of the test compound in treating CNS disorders with cognitive impairment. -m that were previously blocked have been removed), and is allowed to obtain the food reward remaining during this retention test stage of this trial. The identity and configuration of the blocked arms vary from trial to trial. The number of "errors" made by these subjects during this retention test stage is tracked. An error occurs in this trial if the subject enters an arm in which food has already been retrieved during the pre-delay component of this trial, or if the subject revisits an arm that has already been visited during the post-delay cycle. A smaller number of errors indicates better spatial memory. The number of errors made by test subjects under various test compound treatment regimens can then be compared for the efficacy of the test compound in treating CNS disorders with cognitive impairment. time, the barriers of the maze are removed, thus allowing access to all 8 arms. After this delay period, the subject is returned to the central platform (the barriers to the arms that were previously blocked have been removed), and is allowed to obtain the food reward remaining during this retention test stage of this trial. The identity and configuration of the blocked arms vary from trial to trial. The number of "errors" made by these subjects during this retention test stage is tracked. An error occurs in this trial if the subject enters an arm in which food has already been retrieved during the pre-delay component of this trial, or if the subject revisits an arm that has already been visited during the post-delay cycle. A smaller number of errors indicates better spatial memory. The number of errors made by test subjects under various test compound treatment regimens can then be compared for the efficacy of the test compound in treating CNS disorders with cognitive impairment.

[0082] used to evaluate the effect of a test compound on cognitive impairment in a CNS disorder model animal Another cognitive test that can be used is the Morris water maze. The water maze is a pool surrounded by a new set of patterns for the maze. The training protocol for the water maze can be based on a modified water maze task that has been shown to be hippocampus-dependent (de Hoz et al., Eur. J. Neurosci., 22:745-54, 2005; Steele and Morris, Hippocampus 9:118-36, 1999). The subject is trained to find the location of a submerged escape platform hidden below the surface of this pool. During this training trial, the subject is released into the maze (pool) from a random starting position around the pool. This starting position changes from trial to trial. If the subject does not find the location of the escape platform within a set time, the experimenter guides the subject to the platform and "teaches" the subject the location of the platform. After a delay period following the last training trial, a retention test is given with the escape platform absent to evaluate spatial memory. The level at which the subject prefers to search for the location of the (now absent) escape platform (e.g., measured by the time spent searching for its location or the number of times the mouse crosses its location) indicates better spatial memory, i.e., treatment of cognitive dysfunction. Subsequently, the preference for searching for the location of the escape platform under different treatment conditions can be compared for the efficacy of a test compound in treating CNS disorders associated with cognitive dysfunction.

[0083] A variety of tests for evaluating cognitive function in humans are known in the art. For example, but not limited to, the Clinical Global Impression of Change Plus Scale (CIBIC-plus); Mini-Mental State Examination (MMSE); Neuropsychiatric Inventory (NPI); Clinical Dementia Rating Scale (CDR); Cambridge Neuropsychological Test Automated Battery (CANTAB); Saint Louis Clinical Assessment for the Elderly (SCAG), Buschke Selective Reminding Test (Buschke and Fuld, 1974); Verbal Associates Subtest; Logical Memory Subtest; Visual Reproduction Subtest of the Wechsler Memory Scale-Revised (WMS-R) (Wechsler, 1997); or Benton Visual Retention Test. See Folstein et al., J Psychiatric Res 12:189-98, (1975); Robbins et al., Dementia 5:266-81, (1994); Rey, L'examen clinique en psychologie, (1964); Kluger et al., J Geriatr Psychiatry Neurol 12:168-79, (1999); Marquis et al., 2002 and Masur et al., 1994. Another example of a cognitive test in humans is the explicit three-alternative forced-choice method. In this test, the subject is presented with color photographs of common objects consisting of a mixture of three types of image pairs (similar pairs, identical pairs, and unrelated foils). A second pair of similar objects is referred to as the "lure". These image pairs are completely randomized and presented individually as a series of images. The subject is supported to make a determination as to whether the visible image is new, old, or similar. A "similar" response to the presentation of the lure stimulus indicates successful memory recall by the subject. Conversely, calling the lure stimulus "old" or "new" indicates that correct memory recall did not occur.

[0084] In addition to evaluating cognitive performance, the progression of age-related cognitive impairment and dementia, as well as the conversion of age-related cognitive impairment to dementia, can be monitored by evaluating surrogate changes in the subject's brain. Surrogate changes include changes in local brain volume, white matter integrity, and brain function by resting state fMRI (R-fMRI) and fluorodeoxyglucose positron emission tomography (FDG-PET). Changes that can be seen are included, but are not limited to these. Examples of local brain volumes useful in monitoring the progression of age-related cognitive impairment and dementia include a decrease in hippocampal volume, and a decrease in the volume or thickness of the entorhinal cortex. These volumes can be measured, for example, in a subject by MRI. Aisen et al., Alzheimer’s & Dementia 6:239-246 (2010). Periventricular white matter disruption has been shown to be associated with age and impaired cognitive function. For example, older adults with greater periventricular white matter disruption tend to perform worse in hippocampal-dependent memory tests. Periventricular white matter disruption can be monitored in a subject by ultra-high resolution diffusion tensor imaging (DTI). Yassa et al., PNAS 107:12687-12691 (2010). Resting state fMRI (R-fMRI) involves imaging the brain at rest and recording large amplitude spontaneous low frequency (<0.1 Hz) fluctuations of the fMRI signal (which are temporally correlated across functionally related regions). Seed-based functional connectivity, independent component analysis, and / or frequency domain analysis of the signal are used to reveal the functional connectivity between brain regions (especially regions whose connectivity increases and decreases with age and the degree of cognitive impairment and / or dementia). FDG-PET uses the uptake of FDG as a measure of local metabolic activity in the brain. A decrease in FDG uptake in regions such as the posterior cingulate cortex, the lateral parietal cortex, and the prefrontal cortex-related cortex has been shown to be associated with the degree of cognitive decline and dementia. Aisen et al., Alzheimer’s & Dementia 6:239-246 (2010), Herholz et al., NeuroImage 17:302-316 (2002). in a subject. Aisen et al., Alzheimer’s & Dementia 6:239-246 (2010). Periventricular white matter disruption has been shown to be associated with age and impaired cognitive function. For example, older adults with greater periventricular white matter disruption tend to perform worse in hippocampal-dependent memory tests. Periventricular white matter disruption can be monitored in a subject by ultra-high resolution diffusion tensor imaging (DTI). Yassa et al., PNAS 107:12687-12691 (2010). Resting state fMRI (R-fMRI) involves imaging the brain at rest and recording large amplitude spontaneous low frequency (<0.1 Hz) fluctuations of the fMRI signal (which are temporally correlated across functionally related regions). Seed-based functional connectivity, independent component analysis, and / or frequency domain analysis of the signal are used to reveal the functional connectivity between brain regions (especially regions whose connectivity increases and decreases with age and the degree of cognitive impairment and / or dementia). FDG-PET uses the uptake of FDG as a measure of local metabolic activity in the brain. A decrease in FDG uptake in regions such as the posterior cingulate cortex, the lateral parietal cortex, and the prefrontal cortex-related cortex has been shown to be associated with the degree of cognitive decline and dementia. Aisen et al., Alzheimer’s & Dementia 6:239-246 (2010), Herholz et al., NeuroImage 17:302-316 (2002). in a subject. Yassa et al., PNAS 107:12687-12691 (2010). Resting state fMRI (R-fMRI) involves imaging the brain at rest and recording large amplitude spontaneous low frequency (<0.1 Hz) fluctuations of the fMRI signal (which are temporally correlated across functionally related regions). Seed-based functional connectivity, independent component analysis, and / or frequency domain analysis of the signal are used to reveal the functional connectivity between brain regions (especially regions whose connectivity increases and decreases with age and the degree of cognitive impairment and / or dementia). FDG-PET uses the uptake of FDG as a measure of local metabolic activity in the brain. A decrease in FDG uptake in regions such as the posterior cingulate cortex, the lateral parietal cortex, and the prefrontal cortex-related cortex has been shown to be associated with the degree of cognitive decline and dementia. Aisen et al., Alzheimer’s & Dementia 6:239-246 (2010), Herholz et al., NeuroImage 17:302-316 (2002). Resting state fMRI (R-fMRI) involves imaging the brain at rest and recording large amplitude spontaneous low frequency (<0.1 Hz) fluctuations of the fMRI signal (which are temporally correlated across functionally related regions). Seed-based functional connectivity, independent component analysis, and / or frequency domain analysis of the signal are used to reveal the functional connectivity between brain regions (especially regions whose connectivity increases and decreases with age and the degree of cognitive impairment and / or dementia). FDG-PET uses the uptake of FDG as a measure of local metabolic activity in the brain. A decrease in FDG uptake in regions such as the posterior cingulate cortex, the lateral parietal cortex, and the prefrontal cortex-related cortex has been shown to be associated with the degree of cognitive decline and dementia. Aisen et al., Alzheimer’s & Dementia 6:239-246 (2010), Herholz et al., NeuroImage 17:302-316 (2002). has been shown to be associated with the degree of cognitive decline and dementia. Aisen et al., Alzheimer’s & Dementia 6:239-246 (2010), Herholz et al., NeuroImage 17:302-316 (2002).

[0085] (Age-related cognitive impairment) The present invention provides a method and composition for treating age-related cognitive impairment or its risk by using an SV2A inhibitor or a pharmaceutically acceptable salt, hydrate, solvate or polymorph thereof, alone or in combination with valproate or its analogs, derivatives or pharmaceutically acceptable salts. In certain embodiments, treatment includes improving cognitive function in a patient suffering from age-related cognitive impairment. In certain embodiments, treatment includes delaying or slowing the progression of age-related cognitive impairment. In certain embodiments, treatment includes reducing the rate of decline in cognitive function associated with age-related cognitive impairment. In certain embodiments, treatment includes preventing age-related cognitive impairment or delaying its progression. In certain embodiments, treatment includes reducing, improving, or delaying the progression of one or more symptoms associated with age-related cognitive impairment. In certain embodiments, treatment of age-related cognitive impairment slows the conversion to dementia (e.g., AD) of age-related cognitive impairment (including but not limited to MCI, ARCD, and AAMI). These methods and compositions can be used clinically in human patients in the treatment of age-related cognitive impairment (such as conditions like MCI, ARCD, and AAMI, or the risk thereof). The dosage of this composition and the dosing interval for this method, as described herein, are safe and effective in these uses.

[0086] In some embodiments, the subject to be treated by the methods and compositions of the present invention exhibits age-related cognitive impairment or is at risk of such impairment. In some embodiments, age-related cognitive impairment includes, but is not limited to, age-associated memory impairment (AAMI), mild cognitive impairment (MCI), and age-related cognitive decline (ARCD).

[0087] Animal models serve as an important means for developing and evaluating treatments for such age-related cognitive impairment. The characteristics that characterize age-related cognitive impairment in animal models typically extend to age-related cognitive impairment in humans. Thus, the efficacy in such animal models is expected to be predictive of the efficacy in humans.

[0088] Various animal models of age-related cognitive impairment are known in the art. For example, extensive behavioral characterization 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. 107:618-626, (1993)). In a behavioral assessment using the Morris water maze (MWM), rats were placed in this maze Learn and remember the position of the avoidance platform guided by the configuration of spatial cues around the path. The cognitive basis of behavior is tested in probe trials using measurements of the animal's spatial bias when searching for the position of the avoidance platform. Aged rats in this test population have no difficulty swimming to the visible platform, but when the platform is camouflaged, age-related dysfunction is detected and the use of spatial information is required. The behavior of individual aged rats of the outbred Long-Evans strain varies widely. For example, a proportion of these rats behave equivalently to young adults. However, about 40% - 50% deviate from the range of young behavior. This variability among aged rats reflects reliable individual differences. Thus, within the aged population, some animals have cognitive impairment and are designated as age-impaired (AI), and other animals have no cognitive impairment and are designated as age-unimpaired (AU). See, for example, Colombo et al., Proc. Natl. Acad. Sci. 94:14195 - 14199, (1997); Gallagher and Burwell, Neurobiol. Aging 10:691 - 708, (1989); Gallagher et al., Behav. Neurosci. 107:618 - 626, (1993); Rapp and Gallagher, Proc. Natl. Acad. Sci. 93:9926 - 9930, (1996); Nicolle et al., Neuroscience 74:741 - 756, (1996); Nicolle et al., J. Neurosci. 19:9604 - 9610, (1999); International Patent Application Publication WO2007 / 019312 and International Patent Application Publication WO 2004 / 048551 Such animal models of age-related cognitive impairment can be used to assay the effectiveness of the methods and compositions of the present invention in treating age-related cognitive impairment.

[0089] The efficacy of the methods and compositions of the present invention in treating age-related cognitive impairment can be evaluated using various cognitive tests, including the Morris water maze and radial arm maze as discussed above.

[0090] Dementia The present invention also provides methods and compositions for treating dementia by using an SV2A inhibitor or a pharmaceutically acceptable salt, hydrate, solvate or polymorph thereof, alone or in combination with valproate or an analog, derivative or pharmaceutically acceptable salt thereof. In certain embodiments, treatment includes improving cognitive function in a patient suffering from dementia. In certain embodiments, treatment includes delaying or slowing the progression of dementia. In certain embodiments, treatment includes reducing the rate of decline in cognitive function associated with dementia. In certain embodiments, treatment includes preventing dementia or delaying its progression. In certain embodiments, treatment includes reducing, improving or delaying the progression of one or more symptoms associated with dementia. In certain embodiments, the symptom to be treated is cognitive impairment. In certain embodiments, the dementia is Alzheimer's disease (AD), vascular dementia, dementia with Lewy bodies, or frontotemporal dementia. These methods and compositions can be used in human patients in clinical settings when treating dementia. The dosage of this composition and the dosing intervals for this method, as described herein, are safe and effective in these uses.

[0091] Animal models serve as an important means for developing and evaluating the treatment of dementia. The characteristics that characterize dementia in animal models typically extend to dementia in humans. Thus, the efficacy in such animal models is expected to be predictive of the efficacy in humans. Various animal models of dementia are known in the art, for example, PDAPP, Tg2576 , APP23, TgCRND8, J20, hPS2 Tg, and APP + PS1 transgenic mice. Sankaranarayanan, Curr. Top. Med. Chem. 6:609-627, 2006; Kobayashi et al. Genes Brain Behav. 4:173-196.2005; Ashe and Zahns, Neuron. 66:631-45, 2010. Such Animal models can be used to assay the effectiveness of the methods and compositions of the present invention in treating dementia.

[0092] The efficacy of the methods and compositions of the present invention in treating dementia, or cognitive dysfunction associated with dementia, can be evaluated in animal models of dementia and in human subjects suffering from dementia using various cognitive tests known in the art as discussed above.

[0093] (Post-traumatic stress disorder) The present invention also provides methods and compositions for treating post-traumatic stress disorder (PTSD) using an SV2A inhibitor or a pharmaceutically acceptable salt, hydrate, solvate or polymorph thereof, alone or in combination with valproate or an analog, derivative or pharmaceutically acceptable salt thereof. In certain embodiments, treatment includes improving cognitive function in a patient suffering from PTSD. In certain embodiments, treatment includes delaying or slowing the progression of PTSD. In certain embodiments, treatment includes reducing the rate of decline in cognitive function associated with PTSD. In certain embodiments, treatment includes preventing PTSD or delaying its progression. In certain embodiments, treatment includes reducing, improving or delaying the progression of one or more symptoms associated with PTSD. In certain embodiments, the symptom to be treated is cognitive dysfunction. These methods and compositions can be used in human patients in clinical settings when treating PTSD. The dosage of this composition and the dosing intervals for this method are safe and effective in these uses as described herein.

[0094] Patients with PTSD (and patients without PTSD who are less severely trauma-exposed) have smaller hippocampal volumes (Woon et al., Prog. Neuro-Psychopharm. & Biological Psych. 34, 1181-1188; Wang et al., Arch. Gen. Psychiatry 67:296-303, 2010). PTSD is also associated with cognitive-behavioral dysfunction. Elderly individuals with PTSD have a greater decline in cognitive-behavior compared to control patients (Yehuda et al., Bio. Psych. 60:714-721, 2006) and a greater probability of developing dementia (Yaffe et al., Arch. Gen. Psych. 678:608-613, 2010). Harmful cognitive behaviors are associated with it. Elderly individuals with PTSD have a greater decline in cognitive-behavior compared to control patients (Yehuda et al., Bio. Psych. 60:714-721, 2006) and a greater probability of developing dementia (Yaffe et al., Arch. Gen. Psych. 678:608-613, 2010).

[0095] Animal models serve as an important means for developing and evaluating treatments for PTSD. The features that characterize PTSD in animal models typically extend to PTSD in humans. Thus, the efficacy in such animal models is expected to be predictive of efficacy in humans. Various animal models of PTSD are known in the art.

[0096] One rat model of PTSD is time-dependent sensitization (TDS). TDS involves exposing the animal to a selectively stressful event and subsequent cues that situationally remind of the prior stress. The following is an example of TDS. Rats are placed in a restraint device and then in a swimming tank Place them and let them swim for a certain period of time (e.g., 20 minutes). After that, each rat is then immediately exposed to a gaseous anesthetic until it loses consciousness and is finally dried. These animals are left undisturbed for several days (e.g., 1 week). Then, these rats are exposed to a "restress" session consisting of the first stressor (e.g., a swimming session in a swimming tank) (Liberzon et al., Psychoneuroendocrinology 22:443-453, 1997; Harvey et al., Psychopharmacology 175:494-502, 2004). TDS results in an increase in the acoustic startle response (ASR) in rats, which is comparable to exaggerated acoustic startle, a prominent symptom of PTSD (Khan and Liberzon, Psychopharmacology 172:225-229, 2004). Such animal models of PTSD can be used to assay the effectiveness of the methods and compositions of the present invention in treating PTSD. The efficacy of the methods and compositions of the present invention in treating PTSD, or cognitive dysfunction associated with PTSD, can also be evaluated using various cognitive tests known in the art as discussed above, in animal models of PTSD and in human subjects suffering from PTSD.

[0097]

[0098] (Schizophrenia) ​The present invention further provides a method and composition for treating schizophrenia by using an SV2A inhibitor or a pharmaceutically acceptable salt, hydrate, solvate or polymorph thereof, alone or in combination with valproate or an analog, derivative or pharmaceutically acceptable salt thereof. In certain embodiments, the treatment includes improving cognitive function in a patient suffering from schizophrenia. In certain embodiments, the treatment includes delaying or slowing the progression of schizophrenia. In certain embodiments, the treatment includes reducing the rate of decline in cognitive function associated with schizophrenia. In certain embodiments, the treatment includes preventing schizophrenia or delaying its progression. In certain embodiments, the treatment includes reducing, improving, or delaying the progression of one or more symptoms associated with schizophrenia. In certain embodiments, the symptom to be treated is cognitive impairment. These methods and compositions can be used in human patients in clinical settings when treating schizophrenia. The dosage of this composition and the dosing interval for this method, as described herein, are safe and effective in these uses.

[0099] Cognitive impairment is also associated with schizophrenia. These occur prior to the onset of psychosis and are present in non-affected relatives. Cognitive impairment associated with schizophrenia constructs a good predictor of functional outcome and is a central feature of this disorder. The cognitive characteristics in schizophrenia reflect dysfunction in the prefrontal cortex and hippocampal circuitry. Patients suffering from schizophrenia also present hippocampal pathology (e.g., reduced hippocampal volume, reduced neuron size and hyperexcitability dysfunction). The imbalance between excitation and inhibition in these brain regions has also been documented in schizophrenic patients, suggesting that a drug target inhibition mechanism may be therapeutic. For example, Guidotti et al., Psychopharmacology 180:191-205, 2005; Zierhut, Psych.Res.Neuroimag.183:187-194, 2010; Wood et al., NeuroImage 52:62-63, 2010; Vinkers et al., Expert See Opin. Investig. Drugs 19:1217-1233, 2009; Young et al., Pharmacol. Ther. 122:150-202, 2009.

[0100] Animal models serve as an important means for developing and evaluating treatments for schizophrenia. The characteristics that characterize schizophrenia in animal models typically extend to schizophrenia in humans. Therefore, the efficacy in such animal models is expected to be predictive of efficacy in humans. Various animal models of schizophrenia are known in the art.

[0101] One animal model of schizophrenia is long-term treatment with methionine. Mice treated with methionine show reduced expression of GAD67 in the prefrontal cortex and hippocampus, similar to that reported in the brains of postmortem schizophrenic patients. These rats also show prepulse inhibition of startle and deficits in social interaction (Tremolizzo et al., PNAS, 99:17095-17100, 2002). Another animal model of schizophrenia is treatment of rats with methylazoxymethanol acetate (MAM). Pregnant female rats are administered MAM (20 mg / kg, intraperitoneally) on gestational day 17. MAM treatment recapitulates in the offspring the pathodevelopmental process to a schizophrenia-like phenotype (including anatomical changes, behavioral deficits, and altered neuronal information processing). More specifically, rats treated with MAM show a reduced density of parvalbumin-positive GABAergic interneurons in the prefrontal cortex and parts of the hippocampus. In behavioral tests, rats treated with MAM show low shows the potential suppression that has occurred. Potential suppression is a behavioral phenomenon in which learning regarding a result previously exposed and leading to any outcome is diminished. This tendency to ignore previous benign stimuli and reduce the formation of associations with such stimuli is thought to prevent sensory overload. Low-latency stimuli are indicators of psychosis. Latency stimuli can be tested in rats in the following manner. Rats are divided into two groups. One group is pre-exposed to a certain sound over multiple trials. The other group does not receive the presentation of the sound. Then, both groups are subjected to an auditory fear conditioning procedure. In this procedure, the same sound is presented simultaneously with a noxious stimulus (e.g., an electric shock to the foot). Subsequently, both groups are presented with both sounds, and the change in the locomotor activity of the rats during the presentation of the sound is monitored. After fear conditioning, the rats respond to the presentation of the sound by strongly reducing their locomotor activity. However, the group that was exposed to this sound prior to the conditioning period shows strong latent inhibition. The suppression of locomotor activity in response to the presentation of the sound is reduced. Conversely, rats treated with MAM show impaired latent inhibition. That is, exposure to the sound prior to the fear conditioning procedure has no significant effect on suppressing fear conditioning (see Lodge et al., J. Neurosci., 29:2344-2354, 2009). Such animal models of schizophrenia can be used to assay the effectiveness of the methods and compositions of the present invention in treating schizophrenia and related cognitive dysfunctions.

[0102] The efficacy of the methods and compositions of the present invention in treating schizophrenia, or cognitive dysfunctions associated with schizophrenia, can also be evaluated using various cognitive tests known in the art as discussed above, in animal models of schizophrenia and in human subjects suffering from schizophrenia.

[0103] (Amyotrophic Lateral Sclerosis (ALS)) The present invention provides a method and composition for treating ALS by using an SV2A inhibitor or a pharmaceutically acceptable salt, hydrate, solvate or polymorph thereof, alone or in combination with valproate or an analog, derivative or pharmaceutically acceptable salt thereof. In certain embodiments, the treatment includes improving cognitive function in a patient suffering from ALS. In certain embodiments, the treatment includes delaying or slowing the progression of ALS. In certain embodiments, the treatment includes reducing the rate of decline of cognitive function associated with ALS. In certain embodiments, the treatment includes preventing ALS or delaying its progression. In certain embodiments, the treatment includes reducing, improving or delaying the progression of one or more symptoms associated with ALS. In certain embodiments, the symptom to be treated is cognitive impairment. These methods and compositions can be used for human patients in clinical use when treating ALS. The dosage of this composition and the dosing interval for this method are safe and effective in these uses as described herein. In addition to motor neuron degeneration, ALS is characterized by neuronal degeneration in the entorhinal cortex and hippocampus, memory deficits, and neuronal hyperexcitability in different brain regions such as the cortex. The efficacy of the methods and compositions of the present invention in treating ALS, or cognitive impairment associated with ALS, can also be evaluated in animal models of ALS and in human subjects suffering from ALS using various cognitive tests known in the art as discussed above. (Cognitive impairment associated with cancer treatment) In addition to motor neuron degeneration, ALS is characterized by neuronal degeneration in the entorhinal cortex and hippocampus, memory deficits, and neuronal hyperexcitability in different brain regions such as the cortex. The efficacy of the methods and compositions of the present invention in treating ALS, or cognitive impairment associated with ALS, can also be evaluated in animal models of ALS and in human subjects suffering from ALS using various cognitive tests known in the art as discussed above. (Cognitive impairment associated with cancer treatment) In addition to motor neuron degeneration, ALS is characterized by neuronal degeneration in the entorhinal cortex and hippocampus, memory deficits, and neuronal hyperexcitability in different brain regions such as the cortex.

[0104] In addition to motor neuron degeneration, ALS is characterized by neuronal degeneration in the entorhinal cortex and hippocampus, memory deficits, and neuronal hyperexcitability in different brain regions such as the cortex. The efficacy of the methods and compositions of the present invention in treating ALS, or cognitive impairment associated with ALS, can also be evaluated in animal models of ALS and in human subjects suffering from ALS using various cognitive tests known in the art as discussed above.

[0105] The efficacy of the methods and compositions of the present invention in treating ALS, or cognitive impairment associated with ALS, can also be evaluated in animal models of ALS and in human subjects suffering from ALS using various cognitive tests known in the art as discussed above.

[0106] (Cognitive impairment associated with cancer treatment) The present invention further provides a method and composition for treating cognitive dysfunction associated with cancer treatment by using an SV2A inhibitor or a pharmaceutically acceptable salt, hydrate, solvate or polymorph thereof, alone or in combination with valproate or an analog, derivative or pharmaceutically acceptable salt thereof. In certain embodiments, the treatment comprises improving cognitive function in a patient suffering from cognitive dysfunction associated with cancer treatment. In certain embodiments, the treatment comprises delaying or slowing the progression of cognitive dysfunction associated with cancer treatment. In certain embodiments, the treatment comprises reducing the rate of decline in cognitive function of cognitive dysfunction associated with cancer treatment. In certain embodiments, the treatment comprises preventing cognitive dysfunction associated with cancer treatment or delaying its progression. In certain embodiments, the treatment comprises reducing, improving or delaying the progression of one or more symptoms of cognitive dysfunction associated with cancer treatment. These methods and compositions can be used in human patients in clinical settings when treating cognitive dysfunction associated with cancer treatment. The dosage of this composition and the dosing interval for this method are safe and effective in these uses as described herein.

[0107] Treatments used in cancer treatment (including chemotherapy, radiation, or combinations thereof) can cause cognitive dysfunction in patients in functions such as memory, learning and attention. The cytotoxicity of cancer treatment and other harmful side effects on the brain are the basis for this form of cognitive dysfunction, which can last for decades (Dietrich et al., Oncologist 13:1285-95, 2008; Soussain et al., Lancet 374:1639-51, 2009).

[0108] Cognitive dysfunction after cancer treatment reflects dysfunction in the frontal cortex and hippocampal circuits that are essential for normal cognition. In animal models, exposure to either chemotherapy or radiation adversely affects behavior in tests of cognition that are specifically dependent on these brain systems, particularly the hippocampus (Kim et al., J. Radiat. Res. 49:517-526, 2008; Yang et al., Neurobiol. Learning and Mem. 93:487-494, 2010). Thus, drugs that target these cortical and hippocampal systems may be neuroprotective in patients undergoing cancer therapy and may be effective in treating symptoms of cognitive dysfunction that may outlast the interventions used as cancer treatments.

[0109] Animal models serve as important tools for developing and evaluating the treatment of cognitive dysfunction associated with cancer therapy.The characteristics that characterize the cognitive dysfunction associated with cancer therapy in animal models typically extend to the cognitive dysfunction associated with cancer therapy in humans.Therefore, efficacy in such animal models is expected to be predictive of efficacy in humans.Various animal models of cognitive dysfunction associated with cancer therapy are known in the art.

[0110] Examples of animal models of cognitive impairment associated with cancer treatment include those that involve the administration of antitumor agents (e.g., cyclophosphamide (CYP)) or radiation (e.g., 60 One example is treating animals with Co gamma rays. (Kim et al., J.Radiat.Res.49:517-526,2008; Yang et al., Neurobiol.Learning and Mem.93:487-494,2010). The cognitive function of the animal model of cognitive dysfunction associated with cancer therapy can then be tested using cognitive tests to assess the effectiveness of the method and composition of the present invention in treating cognitive dysfunction associated with cancer therapy. The efficacy of the method and composition of the present invention in treating cognitive dysfunction associated with cancer therapy and human subjects suffering from cognitive dysfunction associated with cancer therapy uses various cognitive tests known in the art, as discussed above.

[0111] (SV2A inhibitor) "Synaptic vesicle protein-2 (SV2)" is a family of synaptic vesicle proteins consisting of three members named SV2A, SV2B, and SV2C. SV2A is the most widely distributed family member and is ubiquitously expressed in the brain. This protein is an integral membrane protein and has a low level of homology (20 - 30%) to the 12-transmembrane family of transport proteins in bacteria and fungi that transport sugars, citrate, and xenobiotics (Bajjalieh et al., Science. 257:1271 - 1273. (1992)). SV2 family proteins are present in the brain and endocrine cells and further in all synaptic vesicles and endocrine vesicles. The SV2 protein has been reported to play a role in normal synaptic function and functions in the maturation process of presynaptic vesicles that are converted into the Ca( 2+ ) and synaptotagmin-responsive state (Sudhof et al., 2009). Functionally, the SV2 protein has been reported to enhance synaptic currents and increase the probability of neurotransmitter release by maintaining the size of the readily releasable vesicle pool (Custer et al., 2006).

[0112] "SV2A inhibitor" refers to any agent, substance, or compound that binds to SV2A and reduces synaptic function by decreasing presynaptic vesicle release (e.g., Noyer et al., 1995; Fuks et al., 2003; Lynch et al., 2004; Gillard et al., 2006; Custer et al., 2006; Smedt et al., 2007; Yang et al., 2007; Meehan, "Levetiracetam has an activity-dependent effect on inhibitory transmission", Epilepsia, January 31, 2012; and Example 8 of WO2001 / 62726( (All of which are specifically incorporated herein by reference). A substance, compound, or agent is an SV2A inhibitor if, even though it does not itself bind to SV2A, another compound or agent binds to SV2A or causes or affects the ability to reduce synaptic function by reducing presynaptic vesicle release. As used herein, SV2A inhibitors include pharmaceutically acceptable salts of the inhibitor. Also included are hydrates, polymorphs, prodrugs, salts, and solvates of these inhibitors.

[0113] Among the SV2A inhibitors or pharmaceutically acceptable salts, hydrates, solvates, and polymorphs thereof useful in the methods and compositions of the present invention, for example, those disclosed in U.S. Patent Application 12 / 580,464, International Patent Application PCT / US2009 / 005647, U.S. Patent Application No. 61 / 105,847, U.S. Patent Application No. 61 / 152,631, and U.S. Patent Application No. 61 / 175,536. However, any SV2A inhibitor or pharmaceutically acceptable salt, hydrate, solvate, or polymorph thereof can be used in the methods and compositions of the present invention. In some embodiments, the SV2A inhibitor is selected from the group of SV2A inhibitors described in International Patent Applications WO2010 / 144712; WO2010 / 002869; WO2008 / 132139; WO2007 / 065595; WO2006 / 128693; WO2006 / 128692; WO2005 / 054188; WO2004 / 087658; WO2002 / 094787; WO2001 / 062726; U.S. Patent Nos. 7,465,549; 7,244,747; 5,334,720; 4,696,943; 4,696,942; U.S. Patent Application Publication Nos. 20090312333; 20090018148; 20080081832; 2006258704; and UK Patent Nos. 1,039,113; and 1,309,692. or pharmaceutically acceptable salts, hydrates, solvates, or polymorphs thereof. Other SV2A inhibitors may also be used in the present invention. The applicant also refers to the methods for preparing these compounds found in the documents cited above. Other synthetic methods can also be used. These methods are well known to those skilled in the art.

[0114] In some embodiments of the present invention, the SV2A inhibitor is selected from the group consisting of levetiracetam, brivaracetam, and seletracetam, or derivatives or analogs thereof, or pharmaceutically acceptable salts, solvates, hydrates, polymorphs, or prodrugs.

[0115] In some embodiments of the present invention, the SV2A inhibitor is levetiracetam or a salt, solvate, hydrate, polymorph or prodrug thereof. Levetiracetam refers to the International Union of Pure and Applied Chemistry (IUPAC) name of the compound (2S)-2-(2-oxopyrrolidin-1-yl)butanamide). Levetiracetam is a widely used anticonvulsant. Levetiracetam binds to a specific site in the CNS (synaptic vesicle protein 2A (SV2A)) (see, for example, Noyer et al. 1995; Fuks et al. 2003; Lynch et al. 2004; Gillard et al. 2006) and further, syn aptic activity has been shown to be directly inhibited by blocking presynaptic neurotransmitter release (Yang et al., 2007).

[0116] Among the SV2A inhibitors useful in the methods and compositions of the present invention, in particular, the following are: i) International Patent Application No. WO2001 / 062726: Formula I:

[0117]

Chemical formula

[0118] (wherein, X is -CA1 NR 5 R 6 、 -CA 1 OR 7 、 -CA 1 -R 8 、 or CN, A 1 and A 2 are, independently, oxygen, sulfur, or -NR 9 and R 1 is hydrogen, alkyl, aryl, or -CH2-R 1a where R 1a is aryl, heterocycle, halogen, hydroxy, amino, nitro, or cyano, R 2 、 R 3 、 and R 4 are the same or different and each is independently hydrogen, halogen, hydroxy, thiol, amino, nitro, nitrooxy, cyano, azide, carboxy, amide, sulfonic acid, sulfonamide, alkyl, alkenyl, alkynyl, ester, ether, aryl, heterocycle, or an oxy derivative, thio derivative, amino derivative, acyl derivative, sulfonyl derivative, or sulfinyl derivative, R 2a 、 R 3a 、 and R 4a are the same or different and each is independently hydrogen, halogen, alkyl, alkenyl, alkynyl, or aryl, R 5 、 R 6 、 R 7 、 and R 9 are the same or different and each is independently hydrogen, hydroxy, alkyl, aryl, heterocycle, or an oxy derivative, R 8 is hydrogen, hydroxy, thiol, halogen, alkyl, aryl, heterocycle, or a thio derivative, provided that R 2 、 R 3 、 R 4 、 R 2a 、 R 3a 、 and R 4aat least one of which is other than hydrogen, provided that the compound is a mixture of all possible isomers and X is -CONR 5 R 6 and A 2 is oxygen and R 1 is hydrogen, methyl, ethyl, or propyl, the substituent on the pyrrolidine ring is other than monomethyl, dimethyl, or trimethyl or monoethyl, provided that R 1 R 2 R 4 R 2a R 3a and R 4a are each hydrogen, A 2 is oxygen, and X is CONR 5 R 6 when R 3 is carboxy, ester, amide, substituted oxopyrrolidine, hydroxy, oxy derivative, amino, amino derivative, methyl, naphthyl, phenyl (optionally substituted with an oxy derivative or a halogen atom in the para position) different from the compound having or a pharmaceutically acceptable salt thereof.

[0119] In the following definitions, unless otherwise stated, R 11 and R 12 are the same or different and each is independently amide, alkyl, alkenyl, alkynyl, acyl, ester, ether, aryl, aralkyl, heterocycle, or an oxy derivative, thio derivative, acyl derivative, amino derivative, sulfonyl derivative, or sulfinyl derivative (optionally substituted by any suitable group (including but not limited to one or more moieties selected from the other groups below as substituents of lower alkyl or alkyl) as appropriate).

[0120] The term "oxy derivative" as used herein, -O-R 11 group (wherein R 11is defined to include those (defined as above other than "oxy derivatives"). Non-limiting examples are alkoxy, alkenyloxy, alkynyloxy, acyloxy, oxyester, oxyamide, alkylsulfonyloxy, alkylsulfinyloxy, arylsulfonyloxy, arylsulfinyloxy, aryloxy, aralkoxy, or heterocyclooxy (pentyloxy, allyloxy, methoxy, ethoxy, phenoxy, benzyloxy, 2-naphthyloxy, 2-pyridyloxy, methylenedioxy, carbonate, etc.).

[0121] The term "thio derivative", as used herein, is -S-R 11 group (wherein R 11 is defined as above other than "thio derivatives"). Non-limiting examples are alkylthio, alkenylthio, alkynylthio, and arylthio.

[0122] The term "amino derivative", as used herein, is -NHR 11 group or -NR 11 R 12 group (wherein R 11 and R 12 are defined as above). Non-limiting examples are mono- or di-alkyl-, alkenyl-, alkynyl-, and arylamino or mixed amino.

[0123] The term "acyl derivative", as used herein, refers to a group derived from a carboxylic acid and thus is defined to include a group of the formula R 11 -CO- (wherein R 11 is defined as above and may also be hydrogen). Non-limiting examples are formyl, acetyl, propionyl, isobutyryl, valeryl, lauroyl, heptanedioyl, cyclohexanecarbonyl, crotonoyl, fumaryl, acryloyl, benzoyl, naphthoyl, furoyl, nicotinoyl, 4-carboxybutanoyl, oxalyl, ethoxalyl, cysteinyl, oxamoyl.

[0124] The term "sulfonyl derivative", as used herein, refers to the group -SO2-R 11 (wherein R 11 is defined as above other than "sulfonyl derivative"). Non-limiting examples are alkylsulfonyl, alkenylsulfonyl, alkynylsulfonyl, and arylsulfonyl.

[0125] The term "sulfinyl derivative", as used herein, refers to the group -SO-R 11 (wherein R 11 is defined as above other than "sulfinyl derivative"). Non-limiting examples are alkylsulfinyl, alkenylsulfinyl, alkynylsulfinyl, and arylsulfinyl.

[0126] The term "alkyl", as used herein, refers to a saturated monovalent hydrocarbon group having a straight-chain, branched-chain, cyclic moiety, or a combination thereof, and containing 1 to 20 carbon atoms, preferably 1 to 6 carbon atoms for acyclic alkyl and 3 to 6 carbon atoms for cycloalkyl (in these two preferred cases, unless otherwise specified, "lower alkyl"). The alkyl moiety can be optionally substituted with 1 to 5 substituents independently selected from the group consisting of halogen, hydroxy, thiol, amino, nitro, cyano, thiocyanato, acyl, acyloxy, sulfonyl derivative, sulfinyl derivative, alkylamino, carboxy, ester, ether, amide, azide, cycloalkyl, sulfonic acid, sulfonamide, thio derivative, oxyester, oxyamide, heterocycle, vinyl, C1-5 alkoxy, C6-10 aryloxy, and C6-10 aryl.

[0127] Preferred alkyl groups are methyl, ethyl, propyl, isopropyl, butyl, isobutyl or tert-butyl, and 2,2,2-trimethylethyl (trifluoromethyl, trichloromethyl, 2,2,2-trichloroethyl, 1,1-dimethyl-2,2-dibromoethyl, 1,1-dimethyl-2,2,2-trichloroethyl, etc.), each optionally substituted by at least one substituent selected from the group consisting of halogen, hydroxy, thiol, amino, nitro, and cyano.

[0128] As used herein, the term "alkenyl" means having at least one double bond (such as ethenyl (= vinyl), 1-methyl-1-ethenyl, 2,2-dimethyl-1-ethenyl, 1-propenyl, 2-propenyl (= allyl), 1-butenyl, 2-butenyl, 3-butenyl, 4-pentenyl, 1-methyl-4-pentenyl, 3-methyl-1-pentenyl, 1-hexenyl, and 2-hexenyl, etc.), and being optionally substituted by at least one substituent selected from the group consisting of halogen, hydroxy, thiol, amino, nitro, cyano, aryl, and heterocycle (such as mono- and di-halovinyl where halo is fluoro, chloro, or bromo, etc.), and includes both branched and unbranched unsaturated hydrocarbon groups.

[0129] As used herein, the term "alkynyl" means containing at least one carbon-carbon triple bond (such as ethynyl and 2-propynyl (= propargyl), etc.), and being optionally substituted by at least one substituent selected from the group consisting of halogen, hydroxy, thiol, amino, nitro, cyano, aryl, and heterocycle (such as haloethynyl, etc.), and includes monovalent branched or unbranched hydrocarbon groups.

[0130] When present as a bridging group, alkyl, alkenyl, and alkynyl each represent a straight-chain or branched C1-12, preferably C1-4-alkylene moiety, or a C2-12-, preferably C2-4-alkenylene or -alkynylene moiety.

[0131] Groups to which branched derivatives are customarily classified by prefixes such as "n", "sec", and "iso" (e.g., "n-propyl", "sec-butyl") are in the n-form unless otherwise indicated.

[0132] As used herein, the term "aryl" is defined to include an organic group derived by removal of one hydrogen from an aromatic hydrocarbon consisting of 1 to 3 rings and containing 6 to 30 carbon atoms (such as phenyl and naphthyl), which are each optionally substituted by 1 to 5 substituents independently selected from halogen, hydroxy, thiol, amino, nitro, cyano, acyl, acyloxy, sulfonyl, sulfinyl, alkylamino, carboxy, ester, ether, amide, azide, sulfonic acid, sulfonamide, alkylsulfonyl, alkylsulfinyl, alkylthio, oxyester, oxyamide, aryl, C1-6-alkoxy, C6-10-aryloxy, C1-6-alkyl, C1-6-haloalkyl. The aryl group is preferably a monocyclic ring containing 6 to 10 carbon atoms. Preferred aryl groups are phenyl and naphthyl each optionally substituted by 1 to 5 substituents independently selected from halogen, nitro, amino, azide, C1-6-alkoxy, C1-6-alkylthio, C1-6-alkyl, C1-6-haloalkyl, and phenyl.

[0133] As used herein, the term "halogen" includes the atoms Cl, Br, F, and I.

[0134] As used herein, the term "hydroxy" represents a group of the formula -OH.

[0135] As used herein, the term "thiol" represents a group of the formula -SH.

[0136] As used herein, the term "cyano" represents a group of the formula -CN.

[0137] The term "nitro", as used herein, represents a group of the formula -NO2.

[0138] The term "nitrooxy", as used herein, represents a group of the formula -ONO2.

[0139] The term "amino", as used herein, represents a group of the formula -NH2.

[0140] The term "azido", as used herein, represents a group of the formula -N3.

[0141] The term "carboxy", as used herein, represents a group of the formula -COOH.

[0142] The term "sulfonic acid", as used herein, represents a group of the formula -SO3H.

[0143] The term "sulfonamide", as used herein, represents a group of the formula -SO2NH2.

[0144] The term "ester", as used herein, is defined to include a group of the formula -COO-R 11 (wherein R 11 , excluding oxy derivatives, thio derivatives, or amino derivatives, is defined as above).

[0145] The term "ether" is defined to include a group selected from C1-50 straight-chain or branched alkyl, C2-50 straight-chain or branched alkenyl groups or alkynyl groups, or combinations thereof, with one or more oxygen atoms intervening.

[0146] The term "amide" is defined to include groups of the formula -CONH2, -CONHR 11 , or -CONR 11 R 12 (wherein R 11 and R 12 are as defined above).

[0147] As used herein, the term "heterocyclic ring" is defined to include an aromatic or non-aromatic cyclic alkyl moiety, alkenyl moiety, or alkynyl moiety as defined above having at least one O, S, and / or N atom intervening in the carbocyclic structure, and optionally, one of the carbons of the carbocyclic structure can be replaced by a carbonyl. Non-limiting examples of aromatic heterocyclic rings are pyridyl, furyl, pyrrolyl, thienyl, isothiazolyl, imidazolyl, benzimidazolyl, tetrazolyl, quinazolinyl, quinolidinyl, naphthyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, quinolyl, isoquinolyl, isobenzofuranyl, benzothienyl, pyrazolyl, indolyl, indolizinyl, purinyl, isoindolyl, carbazolyl, thiazolyl, 1,2,4-thiadiazolyl, thieno(2,3-b)furanyl, furopyranyl, benzofuranyl, benzoxepinyl, isoxazolyl, oxazolyl, thianthrenyl, benzothiazolyl, or benzoxazolyl, cinnolinyl, phthalazinyl, quinoxalinyl, phenanthridinyl, acridinyl, perimidinyl, phenanthrolinyl, phenothiazinyl, phrazinyl, isochromanyl, indolinyl, xanthenyl, hypoxanthinyl, pteridinyl, 5-azacytidinyl, 5-azauracilyl, triazolopyridinyl, imidazolopyridinyl, pyrrolopyrimidinyl, and pyrazolopyrimidinyl, which are optionally substituted by other groups as described above for alkyl or alkyl groups. Non-limiting examples of non-aromatic heterocyclic rings are tetrahydrofuranyl, tetrahydropyranyl, piperidinyl, piperidyl, piperazinyl, imidazolidinyl, morpholino, morpholinyl, 1-oxaspiro(4.5)decan-2-yl, pyrrolidinyl, 2-oxo-pyrrolidinyl, sugar moieties (i.e., glucose, pentose, hexose, ribose, fructose, which can also be substituted), etc. (optionally substituted with any suitable group (including, but not limited to, one or more moieties selected from the other groups described above for lower alkyl or alkyl groups)).The term "complex ring" also includes bicyclic, tricyclic, and tetracyclic spiro groups (such as quinuclidinyl, 7-azabicyclo(2.2.1)heptanyl, 7-oxabicyclo(2.2.1)heptanyl, 8-azabicyclo(3.2.1)octanyl, etc.) in which any of the above complex rings is condensed with one or two rings independently selected from an aryl ring, cyclohexane ring, cyclohexene ring, cyclopentane ring, cyclopentene ring, or another monocyclic complex ring, or in which a monocyclic complex ring group is bridged by an alkylene group.

[0148] In the above definition, when substituents (R 2 , R 3 , R 4 , R 2a , R 3a , R 4a , R 5 , R 6 , R 7 , R 8 , etc.) are bonded to the remainder of the molecule via a heteroatom or a carbonyl, a straight-chain or branched C1-12-, preferably C1-4-alkylene bridge or C2-12, preferably C2-4-alkenylene bridge or -alkynylene bridge can be inserted as necessary between the heteroatom or carbonyl and the point of attachment to the remainder of the molecule.

[0149] Preferred examples of X are -COOR 7 or -CONR 5 R 6 (wherein R 5 , R 6 , and R 7 are preferably hydrogen, C1-4-alkyl, phenyl, or alkylphenyl).

[0150] Preferably, X is carboxy or -CONR 5 R 6 (wherein R 5 and R 6 are preferably hydrogen, C1-4-alkyl, phenyl, or alkylphenyl), and particularly -CONH2.

[0151] Preferably, A 1 and A 2 are each oxygen.

[0152] Preferably, R 1 is hydrogen, alkyl, especially C1-12 alkyl, especially lower alkyl or aryl, especially phenyl.

[0153] Preferred R 1 group examples are methyl, ethyl, propyl, isopropyl, butyl, iso- or ter-butyl, 2,2,2-trimethylethyl, or those substituted by at least one halogen atom (trifluoromethyl, trichloromethyl, 2,2,2-trichloroethyl, 1,1-dimethyl-2,2-dibromoethyl, 1,1-dimethyl-2,2,2-trichloroethyl, etc.) each optionally bonded via a methylene bridge.

[0154] R as ethyl 1 is particularly preferred.

[0155] Preferably, R 2 and R 2a are each independently hydrogen, halogen, or alkyl, especially lower alkyl.

[0156] Preferred R 2 and R 2a group examples are each independently hydrogen, halogen, or methyl, ethyl, propyl, isopropyl, butyl, iso or ter-butyl, 2,2,2-trimethylethyl, or those substituted by at least one halogen atom (trifluoromethyl, trichloromethyl, 2,2,2-trichloroethyl, 1,1-dimethyl-2,2-dibromoethyl, 1,1-dimethyl-2,2,2-trichloroethyl, etc.).

[0157] In particular, at least one of R 2 and R 2a is most preferably both hydrogen.

[0158] Preferably, R 3a, R 4 , and R 4a are, independently, hydrogen, alkyl, especially methyl, ethyl, or aryl, especially phenyl or aralkyl, especially benzyl.

[0159] Preferred R 3a group, R 4 group, and R 4a group examples are, independently, hydrogen, halogen, methyl, ethyl, propyl, isopropyl, butyl, iso- or tert-butyl, 2,2,2-trimethylethyl, or those substituted by at least one halogen atom (trifluoromethyl, trichloromethyl, 2,2,2-trichloroethyl, 1,1-dimethyl-2,2-dibromoethyl, 1,1-dimethyl-2,2,2-trichloroethyl, etc.).

[0160] In particular, at least one of R 4 and R 4a is hydrogen, most preferably both are hydrogen.

[0161] R 3a is especially hydrogen or alkyl, especially lower alkyl, and most preferably hydrogen.

[0162] Preferably, R 3is each optionally substituted by one or more substituents selected from hydrogen, hydroxy, halogen, cyano, thiocyanato, or alkoxy, and is C1-C12-alkyl, especially C1-C6-alkyl, bonded directly or via a thio group, sulfinyl group, sulfonyl group, carbonyl group, or oxycarbonyl group, optionally via a C1-4-alkylene bridge, especially methylene, to the ring; C2-C6-alkenyl or -alkynyl, especially C2-C3-alkenyl or -alkynyl, each optionally substituted by one or more halogens; azide; cyano; amide; carboxy; triazolyl, tetrazolyl, pyrrolidinyl, pyridyl, 1-oxidopyridyl, thiomorpholinyl, benzodioxolyl, furyl, oxazolyl, pyrimidinyl, pyrrolyl, thiadiazolyl, thiazolyl, thienyl, or piperazinyl, each optionally substituted by one or more substituents selected from halogen, C1-C6-alkyl, and phenyl, and bonded directly or via a carbonyl group or C1-4-alkylene bridge, especially methylene, to the ring; naphthyl; or phenyl, phenylalkyl, or phenylalkenyl, each optionally substituted by one or more substituents selected from halogen, C1-C6-alkyl, C1-C6 haloalkyl, C1-C6-alkoxy, C1-C6-alkylthio, amino, azide, phenyl, and nitro, and bonded directly or via oxy, sulfonyl, sulfonyloxy, carbonyl, carbonyloxy groups, optionally further via a C1-4-alkylene bridge, especially methylene, to the ring.

[0163] Also preferably, R 3is C1-C6-alkyl optionally substituted by one or more substituents selected from halogen, thiocyanato, azido, alkoxy, alkylthio, phenylsulfonyl; nitrooxy; C2-C3-alkenyl or -alkynyl optionally substituted by one or more halogens or acetyl respectively; tetrazolyl, pyridyl, furyl, pyrrolyl, thiazolyl, or thienyl; or phenyl or phenylalkyl optionally substituted by one or more substituents selected from halogen, C1-C6-alkyl, C1-C6 haloalkyl, C1-C6-alkoxy, amino, azido, phenyl, and nitro respectively, and each bonded to the ring directly or via sulfonyloxy, optionally further via a C1-C4-alkylene bridge, especially methylene.

[0164] Other preferred R 3 Examples of groups are hydrogen, halogen, or methyl, ethyl, propyl, isopropyl, butyl, iso- or tert-butyl, 2,2,2-trimethylethyl, or those substituted by at least one halogen atom (trifluoromethyl, trichloromethyl, 2,2,2-trichloroethyl, 1,1-dimethyl-2,2-dibromoethyl, 1,1-dimethyl-2,2,2-trichloroethyl, etc.).

[0165] R 3 is in particular C1-C4-alkyl optionally substituted by one or more substituents selected from halogen, thiocyanato, or azido; C2-C5-alkenyl or -alkynyl optionally substituted by one or more halogens respectively; thienyl; or phenyl optionally substituted by one or more substituents selected from halogen, C1-C6-alkyl, C1-C6 haloalkyl, or azido.

[0166] Preferred R 3 Further examples of groups are C1-C6 alkyl and C2-C6 haloalkenyl.

[0167] Preferably, R 5 and R 6is, independently, hydrogen, methyl, ethyl, propyl, isopropyl, butyl, iso- or tert-butyl, 2,2,2-trimethylethyl, especially hydrogen or methyl.

[0168] R 5 and R 6 at least one of which, most preferably both, is hydrogen.

[0169] Preferably, R 7 is hydrogen, methyl, ethyl, propyl, isopropyl, butyl, iso- or tert-butyl, 2,2,2-trimethylethyl, methoxy, ethoxy, phenyl, benzyl, or substituted by at least one halogen atom (such as trifluoromethyl, chlorophenyl, etc.).

[0170] Preferably, R 7 is hydrogen, methyl, or ethyl, especially hydrogen.

[0171] Preferably, R 8 is hydrogen, methyl, ethyl, propyl, isopropyl, butyl, iso- or tert-butyl, 2,2,2-trimethylethyl, phenyl, benzyl, or substituted by at least one halogen atom (such as trifluoromethyl, chlorobenzyl, etc.).

[0172] Preferably, R 8 is hydrogen or methyl.

[0173] Combinations of one or more of these preferred compound groups are particularly preferred.

[0174] A specific group of compounds of formula I (Compound 1A) includes the following compounds: A 2 is oxygen, X is -CONR 5 R 6 -COOR 7 -CO-R 8 or CN, R 1is hydrogen, or alkyl, aryl, halogen, hydroxy, amino, nitro, cyano, R 2 、R 3 、R 4 are the same or different and each independently is hydrogen or halogen, hydroxy, amino, nitro, cyano, acyl, acyloxy, sulfonyl derivative, sulfinyl derivative, amino derivative, carboxy, ester, ether, amide, sulfonic acid, sulfonamide, alkoxycarbonyl, thio derivative, alkyl, alkoxy, oxyester, oxyamide, aryl, oxy derivative, heterocycle, vinyl, and R 3 is further C2-5 alkenyl, C2-5 alkynyl, or azide each optionally substituted by one or more of halogen, cyano, thiocyano, azide, cyclopropyl, acyl, and / or phenyl; or phenylsulfonyloxy in which any phenyl moiety can be substituted by one or more of halogen, alkyl, haloalkyl, alkoxy, nitro, amino, and / or phenyl; most preferably represents methyl, ethyl, propyl, isopropyl, butyl, or isobutyl.

[0175] R 2a 、R 3a 、およびR 4a are hydrogen, R 5 、R 6 、R 7 are the same or different and each independently is hydrogen, hydroxy, alkyl, aryl, heterocycle, or oxy derivative, R 8 is hydrogen, hydroxy, thiol, halogen, alkyl, aryl, heterocycle, alkylthio, or thio derivative.

[0176] Among these compounds 1A, R 1 is preferably methyl, ethyl, propyl, isopropyl, butyl, or isobutyl; most preferably methyl, ethyl, or n-propyl.

[0177] R2 and R 4 is preferably, independently, hydrogen, halogen, methyl, ethyl, propyl, isopropyl, butyl, or isobutyl, and most preferably is hydrogen in each case.

[0178] R 3 is preferably C1-5 alkyl, C2-5 alkenyl, C2-C5 alkynyl, cyclopropyl, azide; phenyl; phenylsulfonyl; phenylsulfonyloxy, tetrazole, thiazole, thienyl, furyl, pyrrole, pyridine, each optionally substituted by one or more halogen, cyano, thiocyanato, azide, alkylthio, cyclopropyl, acyl, and / or phenyl; most preferably methyl, ethyl, propyl, isopropyl, butyl, or isobutyl.

[0179] X is preferably -COOH, -COOMe, -COOEt, or -CONH2; most preferably -CONH2.

[0180] A further specific group (Compound 1B) of the compounds of formula I comprises the following compounds: X is -CA 1 NH2, -CA 1 NHCH3, or -CA 1 N(CH3)2, and R 1 is alkyl or phenyl, R 3 is alkyl, alkenyl, alkynyl, cyano, isothiocyanato, ether, carboxyl, amide, aryl, heterocycle, or R 3 is CH2R 10 (wherein R 10is hydrogen, cycloalkyl, oxyester, oxyalkylsulfonyl, oxyarylsulfonyl, aminoalkylsulfonyl, aminoarylsulfonyl, nitrooxy, cyano, isothiocyanato, azide, alkylthio, arylthio, alkylsulfinyl, alkylsulfonyl, heterocycle, aryloxy, alkoxy, or trifluoroethyl), and R 3a is hydrogen, alkyl, or aryl (especially, provided that when R 3a is hydrogen, R 3 is other than methyl), or R 3 R 3a forms cycloalkyl, and R 2 、R 2a 、R 4 、and R 4a are each hydrogen.

[0181] Among the compounds of formula I, R 1 is preferably alkyl, especially C1-12-alkyl, more especially C1-6-alkyl, and most preferably ethyl, R 2 、R 2a 、R 3a 、and R 4a are preferably hydrogen, R 3is preferably substituted, each optionally, by one or more substituents selected from hydrogen; hydroxy, halogen, cyano, thiocyanato, or alkoxy, and is directly or via a thio group, a sulfinyl group, a sulfonyl group, a carbonyl group, or an oxycarbonyl group, optionally further via a C1-4 alkylene bridge, especially a methylene, bonded to a C1-12 alkyl, especially a C1-6 alkyl; a C2-6 alkenyl or -alkynyl, especially a C2-3 alkenyl or -alkynyl, each optionally substituted by one or more halogens; azide; cyano; amide; carboxy; a triazolyl, tetrazolyl, pyrrolidinyl, pyridyl, 1-oxidopyridyl, thiomorpholinyl, benzodioxolyl, furyl, oxazolyl, pyrimidinyl, pyrrolyl, thiadiazolyl, thiazolyl, thienyl, or piperazinyl, each optionally substituted by one or more substituents selected from halogen, C1-6 alkyl, and phenyl, and directly or via a carbonyl group or a C1-4 alkylene bridge, especially a methylene, bonded to the ring; naphthyl; or a phenyl, phenylalkyl, or phenylalkenyl, each optionally substituted by one or more substituents selected from halogen, C1-6 alkyl, C1-6 haloalkyl, C1-6 alkoxy, C1-6 alkylthio, amino, azide, phenyl, and nitro, and directly or via an oxy, sulfonyl, sulfonyloxy, carbonyl, or carbonyloxy group, optionally further via a C1-4 alkylene bridge, especially a methylene, bonded to the ring respectively, R 3a is preferably hydrogen or C1-4 alkyl, R 4 and R 4a are preferably independently hydrogen, C1-4 alkyl, phenyl, or benzyl.

[0182] A further group of compounds of formula I (Compound 1C) is where X is -CONR 5 R 6 and R 1When it is hydrogen, methyl, ethyl, or propyl, the substituents on the pyrrolidine ring are other than mono-, di-, or tri-methyl or mono-ethyl, including racemic compounds.

[0183] A further group of compounds of formula I (Compound 1D) is where X is -CONR 5 R 6 and R 1 is hydrogen or C1-6-alkyl, C2-6-alkenyl or -alkynyl, or cycloalkyl (each unsubstituted), the substituents in the ring are other than alkyl, alkenyl, or alkynyl (each unsubstituted), including racemic compounds.

[0184] A further specific group of compounds of formula I (Compound IE) is in its racemic form or in enantiomerically enriched form, preferably pure enantiomer, and includes the following compounds: X is -CA 1 NH2, R 1 is H, R 3 is azidomethyl, iodomethyl, ethyl optionally substituted by 1 to 5 halogen atoms, n-propyl optionally substituted by 1 to 5 halogen atoms, vinyl optionally substituted by 1 or 2 methyl and / or 1 to 3 halogen atoms, C1-4-alkyl, phenyl, or acetylene optionally substituted by halogen, R 3a is hydrogen or halogen, preferably fluorine, R 2 R 2a R 4 and R 4a are each hydrogen.

[0185] A further specific group of compounds of formula I (Compound 1F) is in its racemic form or in enantiomerically enriched form, preferably pure enantiomer, and includes the following compounds: X is -CA 1 NH2, R1 is H, R 3 is azido, oxynitro, C1-6-alkyl, C2-6-alkenyl, or C2-6-alkynyl optionally substituted by 1 to 6 halogen atoms, R 3a is hydrogen or halogen, preferably fluorine, R 2 , R 2a , R 4 , and R 4a are each hydrogen.

[0186] In all of the above ranges, when the carbon atom to which R 1 is attached is asymmetric, it is preferably in the "S" configuration.

[0187] In some embodiments, compounds useful in the methods and compositions of the invention are selected from the group consisting of: (2S)-2-[4-(Bromomethyl)-2-oxo-1-pyrrolidinyl]butanamide; (2S)-2-[(4R)-4-(Iodomethyl)-2-oxopyrrolidinyl]butanamide; (2S)-2-(2-Oxo-4-phenyl-1-pyrrolidinyl)butanamide; (2S)-2-[4-(Iodomethyl)-2-oxo-1-pyrrolidinyl]butanamide; (2S)-2-[4-(Chloromethyl)-2-oxo-1-pyrrolidinyl]butanamide; Benzenesulfonic acid {1-[(1S)-1-(aminocarbonyl)propyl]-5-oxo-3-pyrrolidinyl}methyl 4-methyl; (2S)-2-[(4R)-4-(Azidomethyl)-2-oxopyrrolidinyl]butanamide; 2-[4-(2,2-Dibromovinyl)-2-oxo-1-pyrrolidinyl]butanamide; Nitric acid {1-[(1S)-1-(aminocarbonyl)propyl]-5-oxo-3-pyrrolidinyl}methyl; (2S)-2-[2-Oxo-4-(1H-tetrazol-1-ylmethyl)-1-pyrrolidinyl]butanamide; 2-(2-Oxo-4-vinyl-1-pyrrolidinyl)butanamide; 2-{2-Oxo-4-[(phenylsulfonyl)methyl]-1-pyrrolidinyl}butanamide; (2S)-2-[(4R)-4-(2,2-Dibromovinyl)-2-oxopyrrolidinyl]butanamide; (2S)-2-[(4S)-4-(2,2-Dibromovinyl)-2-oxopyrrolidinyl]butanamide; (2S)-2-[4-(Isothiocyanatomethyl)-2-oxo-1-pyrrolidinyl]butanamide; 2-[2-Oxo-4-(1,3-thiazol-2-yl)-1-pyrrolidinyl]butanamide; (2S)-2-[2-Oxo-4-(2-thienyl)-1-pyrrolidinyl]butanamide; (2S)-2-[4-(2-Methoxyphenyl)-2-oxo-1-pyrrolidinyl]butanamide; (2S)-2-[4-(3-Methoxyphenyl)-2-oxo-1-pyrrolidinyl]butanamide; (2S)-2-[4-(4-Azidophenyl)-2-oxo-1-pyrrolidinyl]butanamide; (2S)-2-[2-Oxo-4-(3-thienyl)-1-pyrrolidinyl]butanamide; (2S)-2-[4-(3-Azidophenyl)-2-oxo-1-pyrrolidinyl]butanamide; (2S)-2-[2-Oxo-4-(3-thienyl)-1-pyrrolidinyl]butanamide; (2S)-2-[(4S)-2-Oxo-4-vinylpyrrolidinyl]butanamide; (2S)-2-[(4R)-2-Oxo-4-vinylpyrrolidinyl]butanamide; 2-[4-(2-Bromophenyl)-2-oxo-1-pyrrolidinyl]butanamide; 2-[2-Oxo-4-(3-pyridinyl)-1-pyrrolidinyl]butanamide; (2S)-2-(4-[1,1'-Biphenyl]-4-yl-2-oxo-1-pyrrolidinyl)butanamide; (2S)-2-{4-[(Methylsulfanyl)methyl]-2-oxo-1-pyrrolidinyl}butanamide; 2-[4-(Iodomethyl)-2-oxo-1-pyrrolidinyl]butanamide; (2S)-2-[(4R)-4-(Iodomethyl)-2-oxo-1-pyrrolidinyl]pentanamide; (2S)-2-[(4R)-4-(Iodomethyl)-2-oxopyrrolidinyl]propanamide; 2-(2-Oxo-4-propyl-1-pyrrolidinyl)propanamide; 2-(2-Oxo-4-propyl-1-pyrrolidinyl)butanamide; 2-(2-Oxo-4-pentyl-1-pyrrolidinyl)butanamide; (2S)-2-[(4R)-4-(Iodomethyl)-2-oxopyrrolidinyl]-N-methylbutanamide; (2S)-2-(4-Neopentyl-2-oxo-1-pyrrolidinyl)butanamide; (2S)-2-(4-Ethyl-2-oxo-1-pyrrolidinyl)butanamide; 2-[4-(2,2-Difluorovinyl)-2-oxo-1-pyrrolidinyl]butanamide; 2-[4-(2,2-Difluoroethyl)-2-oxo-1-pyrrolidinyl]butanamide; (2S)-2-[(4S)-2-Oxo-4-propylpyrrolidinyl]butanamide; (2S)-2-[(4R)-2-Oxo-4-propylpyrrolidinyl]butanamide; 2-{4-[(Z)-2-Fluoroethenyl]-2-oxo-1-pyrrolidinyl}butanamide; 2-[4-(2-Methyl-1-propenyl)-2-oxo-1-pyrrolidinyl]butanamide; 2-(4-Butyl-2-oxo-1-pyrrolidinyl)butanamide; 2-[4-(Cyclopropylmethyl)-2-oxo-1-pyrrolidinyl]butanamide; 2-(4-Isobutyl-2-oxo-1-pyrrolidinyl)butanamide; 2-[4-(4-Chlorophenyl)-2-oxo-1-pyrrolidinyl]butanamide; 2-[4-(3-Chlorophenyl)-2-oxo-1-pyrrolidinyl]butanamide; 2-{2-Oxo-4-[2-(trifluoromethyl)phenyl]-1-pyrrolidinyl}butanamide; 2-[4-(2-Fluorophenyl)-2-oxo-1-pyrrolidinyl]butanamide; 2-[4-(3-Methylphenyl)-2-oxo-1-pyrrolidinyl]butanamide; (2S)-2-[2-Oxo-4-(2-phenylethyl)-1-pyrrolidinyl]butanamide; (2S)-2-[4-(3-Bromophenyl)-2-oxo-1-pyrrolidinyl]butanamide; 2-{4-[3,5-Bis(trifluoromethyl)phenyl]-2-oxo-1-pyrrolidinyl}butanamide; 2-[4-(3,4-Dichlorophenyl)-2-oxo-1-pyrrolidinyl]butanamide; 2-[4-(2,4-Dichlorophenyl)-2-oxo-1-pyrrolidinyl]butanamide; 2-[4-(2-Furyl)-2-oxo-1-pyrrolidinyl]butanamide; (2S)-2-[2-Oxo-4-(3-phenylpropyl)-1-pyrrolidinyl]butanamide; (2S)-2-[4-(3,5-Dibromophenyl)-2-oxo-1-pyrrolidinyl]butanamide; 2-[4-(3,4-Dichlorophenyl)-2-oxo-1-pyrrolidinyl]butanamide; 2-(2-Oxo-4-propyl-1-pyrrolidinyl)butanamide; 2-[4-(3-Chlorophenyl)-2-oxo-1-pyrrolidinyl]butanamide; 2-(4-Ethynyl-2-oxo-1-pyrrolidinyl)butanamide; 2-[4-(2-Fluorophenyl)-2-oxo-1-pyrrolidinyl]butanamide; (2S)-2-[4-(Cyclopropylmethyl)-2-oxo-1-pyrrolidinyl}butanamide; (2S)-2-[(4S)-4-(2,2-Difluorovinyl)-2-oxopyrrolidinyl]butanamide; (2S)-2-[2-Oxo-4-(3,3,3-trifluoropropyl)-1-pyrrolidinyl]butanamide; 2-[4-(3-Methylphenyl)-2-oxo-1-pyrrolidinyl]butanamide; (2S)-2-[4-(Cyclopropylmethyl)-2-oxo-1-pyrrolidinyl]butanamide; (2S)-2-[(4R)-4-(2,2-Difluorovinyl)-2-oxopyrrolidinyl]butanamide; (2S)-2-[2-Oxo-4-(1H-pyrrol-1-yl)-1-pyrrolidinyl]butanamide; (2S)-2-(4-Allyl-2-oxo-1-pyrrolidinyl)butanamide; (2S)-2-[4-(2-Iodopropyl)-2-oxo-1-pyrrolidinyl}butanamide; (2S)-2-(4-Allyl-2-oxo-1-pyrrolidinyl)butanamide; (2S)-2-[2-Oxo-4-(2-oxopropyl)-1-pyrrolidinyl]butanamide; (2S)-2-[4-(2-Bromo-1H-pyrrol-1-yl)-2-oxo-1-pyrrolidinyl]butanamide; (2S)-2-(4-Methyl-2-oxo-4-propyl-1-pyrrolidinyl)butanamide; (2R)-2-[4-(2,2-Dichlorovinyl)-2-oxo-1-pyrrolidinyl]butanamide; 2-[4-(Bromoethynyl)-2-oxo-1-pyrrolidinyl]butanamide; 2-[(4S)-4-(2,2-Difluoropropyl)-2-oxopyrrolidinyl]butanamide; (2S)-2-[4-(Bromoethynyl)-2-oxo-1-pyrrolidinyl]butanamide; 2-(2-Oxo-4-propyl-1-pyrrolidinyl)pentanamide; 3-Cyclopropyl-2-(2-oxo-4-propyl-1-pyrrolidinyl)propanamide; 2-(2-Oxo-4-propyl-1-pyrrolidinyl)-3-(1,3-thiazol-4-yl)propanamide; 2-(2-Oxo-4-propyl-1-pyrrolidinyl)-4-pentenamide; (2S)-2-[(4R)-2-Oxo-4-vinylpyrrolidinyl]butanamide; (including all isomers and mixtures thereof or pharmaceutically acceptable salts thereof).

[0188] In some embodiments, the compounds useful in the methods and compositions of the invention are selected from the group consisting of: (2S)-2-[(4S)-4-(2,2-Difluorovinyl)-2-oxopyrrolidinyl]butanamide; (2S)-2-[(4S)-2-Oxo-4-propylpyrrolidinyl]butanamide; (2S)-2-[(4R)-2-Oxo-4-propylpyrrolidinyl]butanamide.

[0189] ii) International Patent Application No. WO2002 / 094787: Formula I:

[0190] [Chemical formula]

[0191] (wherein, n represents 0 or 1, whereby R 1 does not exist when n = 0, and R 1 exists when n = 1, A 1 represents an oxygen atom or a sulfur atom, X is -CONR 7 R 8,-COOR 9 ,-CO-R 10 、or CN, R 1 (if present), R 2 、R 3 、R 4 、and R 5 are the same or different and each independently is hydrogen, halogen, hydroxy, thiol, amino, nitro, nitrooxy, cyano, azide, carboxy, amide, sulfonic acid, sulfonamide, alkyl, alkenyl, alkynyl, ester, ether, aryl, heterocycle, or an oxy derivative, thio derivative, amino derivative, acyl derivative, sulfonyl derivative, or sulfinyl derivative, provided that at least one of the substituents R 1 (if present), R 2 、R 3 、R 4 、or R 5 selected from is not hydrogen, R 6 is hydrogen, alkyl, aryl, or -CH2-R 6a where R 6a is aryl, heterocycle, halogen, hydroxy, amino, nitro, or cyano, R 7 、R 8 、and R 9 are the same or different and each independently is hydrogen, hydroxy, alkyl, aryl, heterocycle, or an oxy derivative, R 10 is hydrogen, hydroxy, thiol, halogen, alkyl, aryl, heterocycle, or a thio derivative) of a compound, its pharmaceutically acceptable salts, geometric isomers (including cis and trans isomers, Z and E isomers), enantiomers, diastereomers, and mixtures thereof (including all possible mixtures of stereoisomers).

[0192] In the above formula, the substituents R 1 ~R 5At least one of them is different from hydrogen. Some unsubstituted compounds are mentioned in U.S. Patent Nos. 5,468,733 and 5,516,759. U.S. Patent No. 5,468,733 mentions acyclic substituted 2-oxo-1-pyrrolidinyl and 2-oxo-1-piperidinyl derivatives as inhibitors of the oncogene Ras protein. In particular, these compounds can block the ability of Ras to transform normal cells into cancer cells and can thus be included in some chemotherapy compositions for treating cancer.

[0193] U.S. Patent No. 5,516,759 mentions acyclic substituted 2-oxo-1-pyrrolidinyl, 2-oxo-1-piperidinyl, and azepanyl derivatives present at the N-terminus of dodecapeptides having LHRH (luteinizing hormone-releasing hormone) antagonist activity. Such LHRH antagonists are useful in treating various conditions where suppression of sex steroids plays an important role (including treatment of contraception, delayed puberty, benign prostatic hyperplasia, etc.).

[0194] In the following definitions, unless otherwise stated, R 11 and R 12 are the same or different and each independently is an amide, alkyl, alkenyl, alkynyl, acyl, ester, ether, aryl, aralkyl, heterocycle, or an oxy derivative, thio derivative, acyl derivative, amino derivative, sulfonyl derivative, or sulfinyl derivative (optionally substituted as necessary by any suitable group (including but not limited to one or more moieties selected from the following other groups as lower alkyl or substituents of alkyl)).

[0195] The term "oxy derivative" as used herein refers to an -O-R 11 group (wherein R 11is defined to include those defined as above other than "oxy derivatives". Non-limiting examples are alkoxy, alkenyloxy, alkynyloxy, acyloxy, oxyester, oxyamide, alkylsulfonyloxy, alkylsulfinyloxy, arylsulfonyloxy, arylsulfinyloxy, aryloxy, aralkoxy, or heterocyclooxy (pentyloxy, allyloxy, methoxy, ethoxy, phenoxy, benzyloxy, 2-naphthyloxy, 2-pyridyloxy, methylenedioxy, carbonate, etc.).

[0196] The term "thio derivative", as used herein, -S-R 11 group (wherein R 11 is defined as above other than "thio derivatives") is defined to include. Non-limiting examples are alkylthio, alkenylthio, alkynylthio, and arylthio.

[0197] The term "amino derivative", as used herein, -NHR 11 group or -NR 11 R 12 group (wherein R 11 and R 12 are defined as above) is defined to include. Non-limiting examples are mono- or di-alkyl-, alkenyl-, alkynyl-, and arylamino or mixed amino.

[0198] The term "acyl derivative", as used herein, refers to a group derived from a carboxylic acid and thus is defined to include a group of the formula R 11 -CO- (wherein R 11 is defined as above and can also be hydrogen). The formula -COR 11 (wherein R 11An acyl derivative selected from hydrogen, C1-12 alkyl, C2-12 alkenyl, C2-12 alkynyl, heterocycle, and aryl is preferred. Non-limiting examples are formyl, acetyl, propionyl, isobutyryl, valeryl, lauroyl, heptanedioyl, cyclohexanecarbonyl, crotonoyl, fumaroyl, acryloyl, benzoyl, naphthoyl, furoyl, nicotinoyl, 4-carboxybutanoyl, oxalyl, ethoxalyl, cysteinyl, oxamoyl.

[0199] As used herein, the term "sulfonyl derivative" refers to the formula -SO2-R 11 (wherein R 11 is defined as above other than "sulfonyl derivative"). Non-limiting examples are alkylsulfonyl, alkenylsulfonyl, alkynylsulfonyl, and arylsulfonyl.

[0200] As used herein, the term "sulfinyl derivative" refers to the formula -SO-R 11 (wherein R 11 is defined as above other than "sulfinyl derivative"). Non-limiting examples are alkylsulfinyl, alkenylsulfinyl, alkynylsulfinyl, and arylsulfinyl.

[0201] As used herein, the term "alkyl" has a straight-chain, branched-chain, cyclic moiety, or a combination thereof, and generally contains 1 to 20 carbon atoms, most often 1 to 12 carbon atoms, preferably 1 to 7 carbon atoms for acyclic alkyl and 3 to 7 carbon atoms for cycloalkyl (in these two preferred cases, unless otherwise specified, "lower alkyl"), and is independently selected from the group consisting of halogen, hydroxy, thiol, amino, nitro, cyano, thiocyanato, acyl, acyloxy, sulfonyl derivatives, sulfinyl derivatives, alkylamino, carboxy, ester, ether, amide, azide, cycloalkyl, sulfonic acid, sulfonamide, thio derivatives, alkylthio, oxyester, oxyamide, heterocycle, vinyl, alkoxy (preferably C1-5), aryloxy (preferably C6-10), and aryl (preferably C6-10), and is defined to include a monovalent saturated hydrocarbon group optionally substituted by preferably 1 to 5 substituents respectively selected therefrom.

[0202] An alkyl group containing 1 to 7 carbon atoms, optionally substituted by one or more substituents selected from hydroxy, halogen, cyano, thiocyanato, alkoxy, azide, alkylthio, cyclopropyl, acyl, and phenyl, is preferred. Most preferred are C1-4 alkyl and C3-7 cycloalkyl optionally substituted by one or more hydroxy, halogen, lower alkyl, and / or azide.

[0203] The most preferred alkyl groups are hydroxymethyl, propyl, butyl, 2,2,2-trifluoroethyl, 2-bromo-2,2-difluoroethyl, 2-chloro-2,2-difluoroethyl, 3,3,3-trifluoropropyl, cyclopropylmethyl, iodomethyl, azidomethyl, 2,2-difluoropropyl, 2-iodo-2,2-difluoroethyl.

[0204] As used herein, the term "lower alkyl" refers to a saturated, straight-chain, branched-chain, or cyclic hydrocarbon having from C1 to C7, unless otherwise indicated. Non-limiting examples include methyl, ethyl, propyl, isopropyl, butyl, tert-butyl (tertiobutyl), pentyl, cyclopropyl, cyclopentyl, isopentyl, neopentyl, hexyl, isohexyl, cyclohexyl, 3-methylpentyl, and 2,2-dimethylbutyl, optionally substituted by any suitable group (including, but not limited to, one or more moieties selected from the above groups for alkyl groups). Preferably, the lower alkyl is methyl.

[0205] As used herein, the term "alkenyl" is defined to include both branched and unbranched unsaturated hydrocarbon groups having at least one double bond and optionally substituted by at least one substituent selected from the group consisting of halogen, hydroxy, thiol, amino, thiocyanato, azide, alkylthio, cycloalkyl, acyl, nitro, cyano, aryl, and heterocycle.

[0206] Preferred alkenyl groups are C2-C12 alkenyl, particularly C2-C6 alkenyl (such as ethenyl (= vinyl), 1-methyl-1-ethenyl, 2,2-dimethyl-1-ethenyl, 1-propenyl, 2-propenyl (= allyl), 1-butenyl, 2-butenyl, 3-butenyl, 4-pentenyl, 1-methyl-4-pentenyl, 3-methyl-1-pentenyl, 1-hexenyl, and 2-hexenyl), optionally substituted by one or more substituents selected from halogen, cyano, thiocyanato, azide, alkylthio, cycloalkyl, phenyl, and acyl. Most preferred are vinyl optionally substituted by one or more halogen and / or lower alkyl, particularly 2,2-difluorovinyl, 2,2-dibromovinyl, and 2,2-dichlorovinyl.

[0207] As used herein, the term "alkynyl" is defined to include at least one carbon-carbon triple bond (e.g., ethynyl and 2-propynyl (= propargyl), etc.), and is optionally substituted by at least one substituent selected from the group consisting of halogen, hydroxy, thiol, amino, nitro, cyano, aryl, heterocycle, thiocyanato, azide, alkylthio, alkyl, and acyl, and includes a monovalent branched or unbranched hydrocarbon group.

[0208] Preferred alkynyl groups are C2-12 alkynyl, particularly C2-6 alkynyl, optionally substituted by one or more substituents selected from halogen, cyano, thiocyanato, azide, alkylthio, acyl, aryl (such as phenyl), and alkyl (preferably cycloalkyl).

[0209] Ethynyl, propynyl, and butynyl, particularly 1-propynyl, cyclopropyl ethynyl, 3-methyl-1-butynyl, and 3,3,3-trifluoro-1-propynyl, optionally substituted by lower alkyl or / and halogen, are most preferred.

[0210] When present as a bridging group, alkyl, alkenyl, and alkynyl each represent a straight-chain or branched C1-12, preferably C1-4-alkylene moiety, or a C2-12-, preferably C2-4-alkenylene or -alkynylene moiety.

[0211] Groups in which branched derivatives are customarily classified by prefixes such as "n", "sec", and "iso" (e.g., "n-propyl", "sec-butyl") are in the n-form unless otherwise indicated.

[0212] As used herein, the term "aryl" consists of at least one ring, generally 1 to 3 rings, and generally contains 6 to 30 carbon atoms, and is independently selected from halogen, hydroxy, thiol, amino, nitro, cyano, acyl, acyloxy, sulfonyl, sulfinyl, alkylamino, carboxy, ester, ether, amide, azide, sulfonic acid, sulfonamide, alkylsulfonyl, alkylsulfinyl, C1-6-alkylthio, oxyester, oxyamide, aryl, C1-6-alkoxy, C6-10-aryloxy, C1-6-alkyl, C1-6-haloalkyl. It is defined as an organic group (such as phenyl and naphthyl) derived by removing one hydrogen from an aromatic hydrocarbon optionally substituted by one or more substituents. An aryl group is preferably a monocyclic or bicyclic ring containing 6 to 10 carbon atoms. Preferred aryl groups are phenyl and naphthyl optionally substituted by one or more substituents independently selected from halogen, nitro, amino, azide, C1-6-alkoxy, C1-6-alkyl, C1-6-haloalkyl, sulfonyl, and phenyl.

[0213] Preferred aryl is phenyl (such as 3-chlorophenyl and 3-azidophenyl) optionally substituted by one or more halogens, lower alkyl, azide, or nitro.

[0214] As used herein, the term "halogen" includes the atoms Cl, Br, F, and I.

[0215] As used herein, the term "hydroxy" represents a group of the formula -OH.

[0216] As used herein, the term "thiol" represents a group of the formula -SH.

[0217] As used herein, the term "cyano" represents a group of the formula -CN.

[0218] The term "nitro", as used herein, represents a group of the formula -NO2.

[0219] The term "nitrooxy", as used herein, represents a group of the formula -ONO2.

[0220] The term "amino", as used herein, represents a group of the formula -NH2.

[0221] The term "azide", as used herein, represents a group of the formula -N3.

[0222] The term "carboxy", as used herein, represents a group of the formula -COOH.

[0223] The term "sulfonic acid", as used herein, represents a group of the formula -SO3H.

[0224] The term "sulfonamide", as used herein, represents a group of the formula -SO2NH2.

[0225] The term "ester", as used herein, is defined to include a group of the formula -COO-R 11 (wherein R 11 is defined as above, excluding oxy derivatives, thio derivatives, or amino derivatives). The formula -COOR 11 (wherein R 11 is selected from C1-12 alkyl, C2-12 alkenyl, C2-12 alkynyl, and aryl) esters are preferred. R 11 is most preferably an ester that is lower alkyl, especially methyl.

[0226] The term "ether" is defined to include a group selected from C1-50 straight or branched alkyl, C2-50 straight or branched alkenyl or alkynyl groups, or combinations thereof, with one or more oxygen atoms intervening.

[0227] The term "amide" is of the formula -CONH2, -CONHR 11 , or -CONR11 R 12 (wherein R 11 and R 12 are as defined above) is defined to include a group of

[0228] As used herein, the term "heterocyclic ring" has at least one O, S, and / or N atom intervening in the carbocyclic structure, and optionally, one of the carbons of the carbocyclic structure can be replaced by a carbonyl, and is optionally substituted by any suitable group (including but not limited to one or more moieties selected from the other groups described above for lower alkyl or alkyl groups), and is defined to include an aromatic or non-aromatic cyclic alkyl moiety, alkenyl moiety, or alkynyl moiety as defined above. Non-limiting examples of heterocyclic rings are pyridyl, furyl, pyrrolyl, thienyl, isothiazolyl, triazolyl, imidazolyl, benzimidazolyl, tetrazolyl, quinazolinyl, quinolidinyl, naphthyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, quinolyl, isoquinolyl, isobenzofuranyl, benzothienyl, pyrazolyl, indolyl, indolizinyl, purinyl, isoindolyl, carbazolyl, thiazolyl, 1,2,4-thiadiazolyl, thiomorpholinyl, thieno(2,3-b)furanyl, furopyranyl, benzofuranyl, benzoxepinyl, isoxazolyl, oxazolyl, thianthrenyl, benzothiazolyl, or benzoxazolyl, cinnolinyl, phthalazinyl, quinoxalinyl, 1-oxidopyridyl, phenanthridinyl, acridinyl, perimidinyl, phenanthrolinyl, phenothiazinyl, phrazinyl, benzodioxolyl, isochromanyl, indolinyl, xanthenyl, hypoxanthinyl, pteridinyl, 5-azacytidinyl, 5-azauracilyl, triazolopyridinyl, imidazolopyridinyl, pyrrolopyrimidinyl, pyrazolopyrimidinyl, tetrahydrofuranyl, tetrahydropyranyl, piperidinyl, piperidyl, piperazinyl, imidazolidinyl, morpholino, morpholinyl, 1-oxaspiro(4.5)decan-2-yl, pyrrolidinyl, 2-oxo-pyrrolidinyl, a sugar moiety (i.e., glucose, pentose, hexose, ribose, fructose, and these can also be substituted).The term "heterocyclic ring" also includes bicyclic, tricyclic, and tetracyclic spiro groups (such as quinuclidinyl, 7-azabicyclo(2.2.1)heptanyl, 7-oxabicyclo(2.2.1)heptanyl, 8-azabicyclo(3.2.1)octanyl, etc.) in which any of the above heterocyclic rings is condensed with one or two rings independently selected from an aryl ring, cyclohexane ring, cyclohexene ring, cyclopentane ring, cyclopentene ring, or another monocyclic heterocyclic ring, or a monocyclic heterocyclic group is bridged by an alkylene group.

[0229] The heterocyclic ring is preferably triazolyl, tetrazolyl, pyrrolidinyl, pyridyl, 1-oxidopyridyl, thiomorpholinyl, benzodioxolyl, furyl, oxazolyl, pyrimidinyl, pyrrolyl, thiadiazolyl, thiazolyl, thienyl, and piperazinyl, each optionally substituted by one or more substituents selected from halogen, alkyl, substituted alkyl, alkoxy, nitro, amino, acyl, and phenyl.

[0230] More preferably, the heterocyclic ring is selected from tetrazolyl, pyrrolidinyl, pyridyl, furyl, pyrrolyl, thiazolyl, and thienyl, each optionally substituted by one or more substituents selected from halogen, alkyl, halogen-substituted alkyl, acyl, alkoxy, nitro, amino, and phenyl, and in particular, selected from 2- and 3-thienyl optionally substituted by one or more halogen, acyl (such as formyl), cyano, and / or lower alkyl (such as methyl).

[0231] In the above definition, the substituents (R 1 、R 2 、R 3 、R 4 、R 5 、R 7 、R 8 、R 9 、R 10When, for example, etc. are bonded to the remainder of the molecule via a heteroatom or a carbonyl, a linear or branched C1-C12-, preferably C1-C4-alkylene bridge or C2-C12, preferably C2-C4-alkenylene bridge or -alkynylene bridge can be inserted, if necessary, between the heteroatom or carbonyl and the point of attachment to the remainder of the molecule. It should be understood that this is the case.

[0232] The term "R substituent" independently refers to R 1 , R 2 , R 3 , R 4 , or R 5 .

[0233] According to a preferred embodiment, the compound of formula I is as defined above when n represents 0. Since the compound has n = 0, it is a 6-membered ring structure (2-thioxo- or 2-oxo-piperidinyl derivative) in which R 1 is absent and is represented by the following formula (I-A).

[0234]

Chemical formula

[0235] According to the following examples, the compound of formula I is as defined above when n represents 1. Since the compound has n = 1, it is a 7-membered ring structure (2-thioxo- or 2-oxo-azepanyl derivative) in which R 1 is present and is represented by the following formula (I-B).

[0236]

Chemical formula

[0237] According to a more preferred embodiment, the compound is as defined above when n = 0, R 3 and / or R 4 are different from hydrogen and R 2 and R 5 represent hydrogen.

[0238] According to another more preferred embodiment, in the said compound, n = 1, R 2 , R 3 , and / or R 4 is different from hydrogen, and R 1 and R 5 are as defined above when they represent hydrogen.

[0239] According to an even more preferred embodiment, in the said compound, only one R substituent selected from R 3 or R 4 (when n = 0) or R 2 , R 3 , or R 4 (when n = 1) is different from hydrogen, and the remaining R substituents are hydrogen, and it is as defined above. Thus, the inventors refer to 1-substituted 2-thioxo-piperidinyl derivatives or 2-oxo-piperidinyl derivatives or 2-thioxo-azepanyl derivatives or 2-oxo-azepanyl derivatives.

[0240] According to another preferred embodiment, the compound of formula I is as defined above when A 1 represents an oxygen atom. Thus, the inventors refer to 2-oxo-piperidinyl derivatives or 2-oxo-azepanyl derivatives.

[0241] According to another preferred embodiment, the compound of formula I is as defined above when X is CONR 7 R 8 , especially CONH2. Thus, the inventors refer to amide derivatives of 2-oxo (or thioxo)-piperidinyl or 2-oxo (or thioxo)-azepanyl.

[0242] According to another preferred embodiment, the compound of formula I is as defined above when R 6 represents hydrogen, C1-4 alkyl, or a CH2-R 6a group, and R 6a represents a heterocyclic ring. Most preferably, R 6 is C1-4 alkyl, especially ethyl. R 6When R is ethyl, the present inventors refer to 2-(2-oxo (or thioxo)-1-piperidinyl) butanamide derivatives or 2-(2-oxo (or thioxo)-1-azepanyl) butanamide derivatives.

[0243] According to another preferred embodiment, for the compound of formula I, when R 6 is as defined above where the carbon atom to which it is attached has the S configuration. R 6 is ethyl, A is oxygen, X is CONR 7 R 8 the present inventors refer to (2S)-2-(2-oxo-1-piperidinyl) butanamide derivatives or (2S)-2-(2-oxo-1-azepanyl) butanamide derivatives.

[0244] According to one preferred embodiment, for the compound, when R 2 (when n = 1), R 3 , and R 4 are the same or different and each is independently hydrogen, halogen, nitro, nitrooxy, cyano, carboxy, amide, sulfonic acid, sulfonamide, alkyl, alkenyl, alkynyl, ester, ether, aryl, heterocycle, acyl derivative, sulfonyl derivative, or sulfinyl derivative, R 1 (when present), R 2 (when n = 0), and R 5 is hydrogen, R 6 is hydrogen, alkyl, aryl, or -CH2-R 6a and R 6a is as defined above when it is aryl, heterocycle, halogen, hydroxy, amino, nitro, or cyano.

[0245] According to this preferred embodiment, the compound generally has X as -COOCH3 when R 6 is benzyl and n = 1, and R 3 and R 4 are both hydrogen, R 2 is different from methyl, and R 2and R 3 When both are hydrogen, R 4 is a compound different from methyl.

[0246] According to another preferred embodiment, the compound is such that R 2 (when n = 1), R 3 , and R 4 are the same or different and each independently is hydrogen; cyano; carboxy; amide; C1-12 alkyl optionally substituted by one or more substituents each independently selected from hydroxy, halogen, cyano, thiocyanato, alkoxy, azide, alkylthio, cycloalkyl, acyl, aryl, and heterocycle; C2-12 alkenyl optionally substituted by one or more substituents each independently selected from halogen, cyano, thiocyanato, azide, alkylthio, alkyl, aryl, and acyl; C2-12 alkynyl optionally substituted by one or more substituents each independently selected from halogen, cyano, thiocyanato, azide, alkylthio, alkyl, aryl, and acyl; acyl derivative of the formula -CO-R 11 (wherein R 11 is selected from C1-12 alkyl, C2-12 alkenyl, C2-12 alkynyl, heterocycle, and aryl); ester of the formula -CO-O-R 11 (wherein R 11 is selected from C1-12 alkyl, C2-12 alkenyl, C2-12 alkynyl, and aryl); heterocycle selected from triazolyl, tetrazolyl, pyrrolidinyl, pyridyl, 1-oxidopyridyl, thiomorpholinyl, benzodioxolyl, furyl, oxazolyl, pyrimidinyl, pyrrolyl, thiadiazolyl, thiazolyl, thienyl, and piperazinyl optionally substituted by one or more substituents each independently selected from halogen, alkyl, substituted alkyl, alkoxy, nitro, amino, acyl, and phenyl; It is as defined above when it is aryl optionally substituted by one or more substituents selected from C1-6 alkyl, C1-6 haloalkyl, C1-6 alkoxy, C1-6 alkylthio, amino, azido, sulfonyl, aryl, and nitro.

[0247] According to another preferred embodiment, the compound is R 2 (when n = 1), R 3 , and R 4 are the same or different and each independently is hydrogen; C1-7 alkyl optionally substituted by one or more substituents selected from hydroxy, halogen, cyano, thiocyanato, alkoxy, azido, alkylthio, cyclopropyl, acyl, and phenyl; C2-6 alkenyl optionally substituted by one or more substituents selected from halogen, cyano, thiocyanato, azido, alkylthio, cycloalkyl, phenyl, and acyl; C2-6 alkynyl optionally substituted by one or more substituents selected from halogen, cyano, thiocyanato, azido, alkylthio, cycloalkyl, phenyl, and acyl; a heterocycle selected from tetrazolyl, pyrrolidinyl, pyridyl, furyl, pyrrolyl, thiazolyl, and thienyl optionally substituted by one or more substituents selected from halogen, alkyl, halogen-substituted alkyl, acyl, alkoxy, nitro, amino, and phenyl; It is as defined above when it is phenyl optionally substituted by one or more substituents selected from C1-6 alkyl, halogen-substituted alkyl, halogen, alkoxy, amino, azido, sulfonyl, phenyl, and nitro.

[0248] According to another preferred embodiment, the compound is the R 2 group, the R 3 group, and the R 4 group (when n = 1), or the R 3 group and the R 4When at least one of the R substituents selected from the group (where n = 0) independently represents C1-4 alkyl or C3-7 cycloalkyl optionally substituted by one or more halogen, hydroxy, lower alkyl, and / or azide, it is as defined above.

[0249] According to another preferred embodiment, the compound is an R 2 group, an R 3 group, and an R 4 group (where n = 1), or an R 3 group and an R 4 group (where n = 0), when at least one of the R substituents independently represents vinyl optionally substituted by one or more halogen and / or lower alkyl, it is as defined above.

[0250] According to another preferred embodiment, the compound is an R 2 group, an R 3 group, and an R 4 group (where n = 1), or an R 3 group and an R 4 group (where n = 0), when at least one of the R substituents independently represents ethynyl, propynyl, or butynyl optionally substituted by one or more halogen and / or lower alkyl, it is as defined above.

[0251] According to another preferred embodiment, the compound is an R 2 group, an R 3 group, and an R 4 group (where n = 1), or an R 3 group and an R 4 group (where n = 0), when at least one of the R substituents independently represents phenyl optionally substituted by one or more halogen, lower alkyl, azide, and / or nitro, it is as defined above.

[0252] According to another preferred embodiment, the compound is an R 2 group, an R 3 group, and an R 4Group (when n = 1), or R 3 Group and R 4 When at least one of the R substituents selected from the group (when n = 0) is independently 2-thienyl or 3-thienyl optionally substituted by one or more halogens, acyl, cyano, and / or lower alkyl, it is as defined above.

[0253] According to a particularly preferred embodiment, the compound is R 3 Group, R 4 Group, and R 2 Group (when n = 1) or R 3 Group and R 4 When at least one of the R substituents selected from the group (when n = 0) is hydroxymethyl, propyl, butyl, 3,3,3-trifluoropropyl, 2,2,2-trifluoroethyl, cyclopropylmethyl, iodomethyl, azidomethyl, 2-thienyl, 3-thienyl, phenyl, 3-chlorophenyl, 3-azidophenyl, 2,2-difluorovinyl, 2,2-dibromovinyl, 2,2-dichlorovinyl, 2-ethynyl, 5-methyl-2-thienyl, 5-formyl-2-ethynyl, 5-cyano-2-thienyl, 3-bromo-2-thienyl, 4-methyl-2-thienyl, 3,3,3-trifluoro-1-propynyl, l-propynyl, cyclopropylethynyl, 3-methyl-1-butynyl, 1-butynyl, 2,2-difluoropropyl, 2-chloro-2,2-difluoroethyl, 2-bromo-2,2-difluoroethyl, and 2-iodo-2,2-difluoroethyl, it is as defined above.

[0254] According to yet another preferred embodiment, the compound is R 1 , R 2 , R 4 , and R 5 Is as defined above when it is hydrogen.

[0255] According to yet another preferred embodiment, the compound is R 1 , R 2 , R 3 , and R 5is as defined above when it is hydrogen.

[0256] According to yet another preferred embodiment, the compound has n = 1 and R 1 , R 3 , R 4 , and R 5 are as defined above when they are hydrogen.

[0257] R 6 When the carbon atom to which it is attached is asymmetric, it is preferably in the "S" configuration in all of the above ranges.

[0258] Representative compounds useful in the methods and compositions of the invention as defined above are selected from the group consisting of: 2-[5-(Hydroxymethyl)-2-oxo-1-piperidinyl]butanamide, 2-(2-Oxo-5-propyl-1-piperidinyl)butanamide, 2-[2-Oxo-5-(3,3,3-trifluoropropyl)-1-piperidinyl]butanamide, 2-[5-(Cyclopropylmethyl)-2-oxo-1-piperidinyl]butanamide, 2-[5-(Iodomethyl)-2-oxo-1-piperidinyl]butanamide, 2-[5-(Azidomethyl)-2-oxo-1-piperidinyl]butanamide, 2-(2-Oxo-5-phenyl-1-piperidinyl)butanamide, 2-[2-Oxo-5-(2-thienyl)-1-piperidinyl]butanamide, 2-[2-Oxo-5-(3-thienyl)-1-piperidinyl]butanamide, 2-[5-(3-Chlorophenyl)-2-oxo-1-piperidinyl]butanamide, 2-[5-(3-azidophenyl)-2-oxo-1-piperidinyl]butanamide, 2-[5-(2,2-Difluorovinyl)-2-oxo-1-piperidinyl]butanamide, 2-[5-(2,2-Dibromovinyl)-2-oxo-1-piperidinyl]butanamide, 2-[5-(2,2-dichlorovinyl)-2-oxo-1-piperidinyl]butanamide, 2-(5-ethynyl-2-oxo-1-piperidinyl)butanamide, 2[5-(5-methyl-2-thienyl)-2-oxo-1-piperidinyl]butanamide, 2-[5-(5-formyl-2-thienyl)-2-oxo-1-piperidinyl]butanamide, 2-[5-(5-cyano-2-thienyl)-2-oxo-1-piperidinyl]butanamide, 2-[5-(3-bromo-2-thienyl)-2-oxo-1-piperidinyl]butanamide, 2-[5-(4-methyl-2-thienyl)-2-oxo-1-piperidinyl]butanamide, 2-[2-oxo-5-(3,3,3-trifluoro-1-propynyl)-1-piperidinyl]butanamide, 2-[2-oxo-5-(1-propynyl)-1-piperidinyl]butanamide, 2-[5-(cyclopropylethynyl)-2-oxo-1-piperidinyl]butanamide, 2-[5-(3-methyl-1-butynyl)-2-oxo-1-piperidinyl]butanamide, 2-[5-(1-butynyl)-2-oxo-1-piperidinyl]butanamide, 2-[5-(2,2-difluoropropyl)-2-oxo-1-piperidinyl]butanamide, 2-[5-(2-chloro-2,2-difluoroethyl)-2-oxo-1-piperidinyl]butanamide, 2-[5-(2-bromo-2,2-difluoroethyl)-2-oxo-1-piperidinyl]butanamide, 2-[4-(hydroxymethyl)-2-oxo-1-piperidinyl]butanamide, 2-(2-oxo-4-propyl-1-piperidinyl)butanamide, 2-[2-oxo-4-(3,3,3trifluoropropyl)-1-piperidinyl]butanamide, 2-[4-(Cyclopropylmethyl)-2-oxo-1-piperidinyl]butanamide, 2-[4-(iodomethyl)-2-oxo-1-piperidinyl]butanamide, 2-[4-(azidomethyl)-2-oxo-1-piperidinyl]butanamide, 2-(2-oxo-4-phenyl-1-piperidinyl)butanamide, 2-[2-oxo-4-(2-thienyl)-1-piperidinyl]butanamide, 2-[2-oxo-4-(3-thienyl)-1-piperidinyl]butanamide, 2-[4-(3-chlorophenyl)-2-oxo-1-piperidinyl]butanamide, 2-[4-(3-azidophenyl)-2-oxo-1-piperidinyl]butanamide, 2-[4-(2,2-difluorovinyl)-2-oxo-1-piperidinyl]butanamide, 2-[4-(2,2-dibromovinyl)-2-oxo-1-piperidinyl]butanamide, 2-[4-(2,2-dichlorovinyl)-2-oxo-1-piperidinyl]butanamide, 2-(4-ethynyl-2-oxo-1-piperidinyl)butanamide, 2-[4-(5-methyl-2-thienyl)-2-oxo-1-piperidinyl]butanamide, 2-[4-(5-formyl-2-thienyl)-2-oxo-1-piperidinyl]butanamide, 2-[4-(5-cyano-2-thienyl)-2-oxo-1-piperidinyl]butanamide, 2-[4-(3-bromo-2-thienyl)-2-oxo-1-piperidinyl]butanamide, 2-[4-(4-methyl-2-thienyl)-2-oxo-1-piperidinyl]butanamide, 2-[2-oxo-4-(3,3,3-trifluoro-1-propynyl)-1-piperidinyl]butanamide, 2-[2-oxo-4-(1-propynyl)-1-piperidinyl]butanamide, 2-[4-(Cyclopropylethynyl)-2-oxo-1-piperidinyl]butanamide, 2-[4-(3-Methyl-1-butynyl)-2-oxo-1-piperidinyl]butanamide, 2-[4-(1-Butynyl)-2-oxo-1-piperidinyl]butanamide, 2-[4-(2,2-Difluoropropyl)-2-oxo-1-piperidinyl]butanamide, 2-[4-(2-Chloro-2,2-difluoroethyl)-2-oxo-1-piperidinyl]butanamide, 2-[4-(2-Bromo-2,2-difluoroethyl)-2-oxo-1-piperidinyl]butanamide, 2[4-(2,2,2-Trifluoroethyl)-2-oxo-1-piperidinyl]butanamide, 2-[5-(Hydroxymethyl)-2-oxo-1-azepanyl]butanamide, 2-(2-Oxo-5-propyl-1-azepanyl)butanamide, 2-[2-Oxo-5-(3,3,3-trifluoropropyl)-1-azepanyl]butanamide, 2-[5-(Cyclopropylmethyl)-2-oxo-1-azepanyl]butanamide, 2-[5-(Iodomethyl)-2-oxo-1-azepanyl]butanamide, 2-[5-(Azidomethyl)-2-oxo-1-azepanyl]butanamide, 2-(2-Oxo-5-phenyl-1-azepanyl)butanamide, 2-[2-Oxo-5-(2-thienyl)-1-azepanyl]butanamide, 2-[2-Oxo-5-(3-thienyl)-1-azepanyl]butanamide, 2-[5-(3-Chlorophenyl)-2-oxo-1-azepanyl]butanamide, 2-[5-(3-Azidophenyl)-2-oxo-1-azepanyl]butanamide, 2-[5-(2,2-Difluorovinyl)-2-oxo-1-azepanyl]butanamide, 2-[5-(2,2-Dibromovinyl)-2-oxo-1-azepanyl]butanamide, 2-[5-(2,2-dichlorovinyl)-2-oxo-1-azepanyl]butanamide, 2-(5-ethynyl-2-oxo-1-azepanyl)butanamide, 2-[5-(5-Methyl-2-thienyl)-2-oxo-1-azepanyl]butanamide, 2-[5-(5-Formyl-2-thienyl)-2-oxo-1-azepanyl]butanamide, 2-[5-(5-Cyano-2-thienyl)-2-oxo-1-azepanyl]butanamide, 2-[5-(3-bromo-2-thienyl)-2-oxo-1-azepanyl]butanamide, 2-[5-(4-Methyl-2-thienyl)-2-oxo-1-azepanyl]butanamide, 2-[2-Oxo-5-(3,3,3-trifluoro-1-propynyl)-1-azepanyl]butanamide, 2-[2-Oxo-5-(1-propynyl)-1-azepanyl]butanamide, 2-[5-(Cyclopropylethynyl)-2-oxo-1-azepanyl]butanamide, 2-[5-(3-methyl-1-butynyl)-2-oxo-1-azepanyl]butanamide, 2-[5-(1-Butynyl)-2-oxo-1-azepanyl]butanamide, 2-[5-(2,2-Difluoropropyl)-2-oxo-1-azepanyl]butanamide, 2-[5-(2-Chloro-2,2-difluoroethyl)-2-oxo-1-azepanyl]butanamide, 2-[5-(2-Bromo-2,2-difluoroethyl)-2-oxo-1-azepanyl]butanamide, 2-[5-(2,2,2-Trifluoroethyl)-2-oxo-1-azepanyl]butanamide, 2-[6-(Hydroxymethyl)-2-oxo-1-azepanyl]butanamide, 2-(2-Oxo-6-propyl-1-azepanyl)butanamide, 2-[2-Oxo-6-(3,3,3-trifluoropropyl)-1-azepanyl]butanamide, 2-[6-(Cyclopropylmethyl)-2-oxo-1-azepanyl]butanamide, 2-[6-(Iodomethyl)-2-oxo-1-azepanyl]butanamide, 2-[6-(Azidomethyl)-2-oxo-1-azepanyl]butanamide, 2-(2-Oxo-6-phenyl-1-azepanyl)butanamide, 2-[2-Oxo-6-(2-thienyl)-1-azepanyl]butanamide, 2-[2-Oxo-6-(3-thienyl)-1-azepanyl]butanamide, 2-[6-(3-Chlorophenyl)-2-oxo-1-azepanyl]butanamide, 2-[6-(3-Azidophenyl)-2-oxo-1-azepanyl]butanamide, 2-[6-(2,2-Difluorovinyl)-2-oxo-1-azepanyl]butanamide, 2-[6-(2,2-Dibromovinyl)-2-oxo-1-azepanyl]butanamide, 2-[6-(2,2-Dichlorovinyl)-2-oxo-1-azepanyl]butanamide, 2-(6-Ethynyl-2-oxo-1-azepanyl)butanamide, 2-[6-(5-Methyl-2-thienyl)-2-oxo-1-azepanyl]butanamide, 2-[6-(5-Formyl-2-thienyl)-2-oxo-1-azepanyl]butanamide, 2-[6-(5-Cyano-2-thienyl)-2-oxo-1-azepanyl]butanamide, 2-[6-(3-Bromo-2-thienyl)-2-oxo-1-azepanyl]butanamide, 2-[6-(4-Methyl-2-thienyl)-2-oxo-1-azepanyl]butanamide, 2-[2-Oxo-6-(3,3,3-trifluoro-1-propynyl)-1-azepanyl]butanamide, 2-[2-Oxo-6-(1-propynyl)-1-azepanyl]butanamide, 2-[6-(Cyclopropyl ethynyl)-2-oxo-1-azepanyl]butanamide, 2-[6-(3-methyl-1-butynyl)-2-oxo-1-azepanyl]butanamide, 2-[6-(1-butynyl)-2-oxo-1-azepanyl]butanamide, 2-[6-(2,2-difluoropropyl)-2-oxo-1-azepanyl]butanamide, 2-[6-(2-chloro-2,2-difluoroethyl)-2-oxo-1-azepanyl]butanamide, 2-[6-(2-bromo-2,2-difluoroethyl)-2-oxo-1-azepanyl]butanamide, 2-[6-(2,2,2-trifluoroethyl)-2-oxo-1-azepanyl]butanamide, 2-[4-(Hydroxymethyl)-2-oxo-1-azepanyl]butanamide, 2-(2-oxo-4-propyl-1-azepanyl)butanamide, 2-[2-oxo-4-(3,3,3-trifluoropropyl)-1-azepanyl]butanamide, 2-[4-(Cyclopropylmethyl)-2-oxo-1-azepanyl]butanamide, 2-[4-(Iodomethyl)-2-oxo-1-azepanyl]butanamide, 2-[4-(Azidomethyl)-2-oxo-1-azepanyl]butanamide, 2-(2-oxo-4-phenyl-1-azepanyl)butanamide, 2-[2-oxo-4-(2-thienyl)-1-azepanyl]butanamide, 2-[2-oxo-4-(3-thienyl)-1-azepanyl]butanamide, 2-[4-(3-chlorophenyl)-2-oxo-1-azepanyl]butanamide, 2-[4-(3-azidophenyl)-2-oxo-1-azepanyl]butanamide, 2-[4-(2,2-difluorovinyl)-2-oxo-1-azepanyl]butanamide, 2-[4-(2,2-Dibromovinyl)-2-oxo-1-azepanyl]butanamide, 2-[4-(2,2-dichlorovinyl)-2-oxo-1-azepanyl]butanamide, 2-(4-ethynyl-2-oxo-1-azepanyl)butanamide, 2-[4-(5-Methyl-2-thienyl)-2-oxo-1-azepanyl]butanamide, 2-[4-(5-Formyl-2-thienyl)-2-oxo-1-azepanyl]butanamide, 2-[4-(5-Cyano-2-thienyl)-2-oxo-1-azepanyl]butanamide, 2-[4-(3-Bromo-2-thienyl)-2-oxo-1-azepanyl]butanamide, 2-[4-(4-Methyl-2-thienyl)-2-oxo-1-azepanyl]butanamide, 2-[2-Oxo-4-(3,3,3-trifluoro-1-propynyl)-1-azepanyl]butanamide, 2-[2-Oxo-4-(1-propynyl)-1-azepanyl]butanamide, 2-[4-(Cyclopropylethynyl)-2-oxo-1-azepanyl]butanamide, 2-[4-(3-methyl-1-butynyl)-2-oxo-1-azepanyl]butanamide, 2-[4-(1-Butynyl)-2-oxo-1-azepanyl]butanamide, 2-[4-(2,2-Difluoropropyl)-2-oxo-1-azepanyl]butanamide, 2-[4-(2-Chloro-2,2-difluoroethyl)-2-oxo-1-azepanyl]butanamide, 2-[4-(2-Bromo-2,2-difluoroethyl)-2-oxo-1-azepanyl]butanamide, 2-[4-(2,2,2-Trifluoroethyl)-2-oxo-1-azepanyl]butanamide.

[0259] In some embodiments, the compounds useful in the methods and compositions of the invention are selected from the group consisting of: (2S)-2-[5-(iodomethyl)-2-oxo-1-piperidinyl]butanamide, (2S)-2-[5-(azidomethyl)-2-oxo-1-piperidinyl]butanamide, 2-(2-oxo-5-phenyl-1-piperidinyl)butanamide, (2S)-2-[4-(iodomethyl)-2-oxo-1-piperidinyl]butanamide, 2-[5-(iodomethyl)-2-oxo-1-azepanyl]butanamide.

[0260] iii) International Patent Application No. WO2004 / 087658: Formula I:

[0261] [Chemical formula]

[0262] (wherein, R 1 is hydrogen, R 2 is hydrogen or C1-20 alkyl, R 3 is hydrogen, C1-20 alkyl, C4-8 cycloalkyl, C5-8 cycloalkenyl, aryl, aromatic or non-aromatic heterocyclic ring, C1-20 alkoxy, or a group of the formula -W-R 8 R 3a is hydrogen, C1-20 alkyl, or a group of the formula:

[0263] [Chemical formula]

[0264] or NR 3 R 3a is of the formula:

[0265] [Chemical formula] is a group of R 4 is hydrogen, R 5 is hydrogen; nitro; halogen; azide; cyano; -S-C1-4-alkyl; -SO-C1-4-alkyl; -SO2-C1-4-alkyl; -SONH2; unsubstituted or halogen-substituted C1-20-alkyl; or unsubstituted or halogen-substituted C1-20-alkoxy, R 6 is hydrogen, C1-20-alkyl, or halogen, R 7 is hydrogen, C1-20-alkyl, or halogen, W is C1-12-alkylene, -NH-, or -NHC(=O)-, X is O, S, or NH, Y is O, S, -CR 12 R 13 -, -NR 14 -, or -C(=O)-, R 8 is aryl or heterocycle, R 9 、R 10 、R 10a 、and R 11 is independently selected from hydrogen, C1-4-alkyl, halogen, hydroxy, or methoxycarbonyl, or R 10 and R 10a together form C3-6-alkylene, R 12 is hydrogen, C1-4-alkyl, halogen, or hydroxy, R 13 is hydrogen, or CR 12 R 13 is dioxolanyl, R 14 is aryl, heterocycle, or a group of the formula -V-R 15 of V is C 1~12 -alkylene, R15 is aryl or a heterocyclic ring, m is from 1 to 4, n is 0 or 1, R 2 is hydrogen, R 3 is H or 2,6 - diisopropylphenyl, and when R 3a is H, R 5 R 6 or R 7 (where at least one of them is different from hydrogen), or a pharmaceutically acceptable salt or stereoisomer thereof.

[0266] In another aspect, the compound is of formula I:

[0267]

Chemical formula

[0268] (wherein, R 1 is hydrogen, R 2 is hydrogen or C1 - 20 - alkyl, R 3 is hydrogen, C1 - 20 - alkyl, C4 - 8 - cycloalkyl, C5 - 8 - cycloalkenyl, aryl, aromatic or non - aromatic heterocyclic ring, C1 - 20 - alkoxy, or a group of formula - W - R 8 (end of formula), R 3a is hydrogen, C1 - 20 - alkyl, or a group of the formula:

[0269]

Chemical formula

[0270] (end of formula), or NR 3 R 3a is of the formula:

[0271]

Chemical formula

[0272] As used herein, the term "alkyl" is defined to include a monovalent saturated hydrocarbon group having a straight-chain, branched-chain, cyclic moiety, or a combination thereof, and containing 1 to 20 carbon atoms, preferably 1 to 6 carbon atoms, more preferably 1 to 4 carbon atoms for acyclic alkyl and 3 to 8 carbon atoms for cycloalkyl. The alkyl (Alliyl) moiety can be optionally substituted with 1 to 5 substituents independently selected from halogen, hydroxy, alkoxy, alkoxycarbonyl, ester, or alkylamino. Preferred alkyl groups are methyl, ethyl, n-propyl, isopropyl, trifluoromethyl, n-butyl, 2-fluoroethyl, 3-hydroxypropyl, 3-hydroxy-2,2-dimethylpropyl, 1-(hydroxymethyl)propyl, 3,3,3-trifluoro-2-hydroxypropyl, 3-ethoxypropyl, 2-ethoxy-2-oxoethyl, and 3-(dimethylamino)propyl.

[0273] As used herein, the term "cycloalkyl" refers to a monovalent group of 3 to 18 carbon atoms, preferably 4 to 8 carbon atoms, derived from a saturated cyclic or polycyclic hydrocarbon that can be substituted by any suitable group (including but not limited to one or more moieties selected from the above groups for alkyl groups). A preferred cycloalkyl group is cycloheptyl.

[0274] As used herein, the term "alkylene" refers to a divalent alkyl group having a straight-chain or branched-chain portion, containing 1 to 12 carbon atoms, preferably 1 to 6 carbon atoms, and optionally substituted by any suitable group (including but not limited to one or more moieties selected from the above groups for the alkyl group). Preferred alkylene groups are methylene, ethylene, hydroxyethylene, trimethylene, or propylene.

[0275] As used herein, the term "cycloalkenyl" is defined as a cyclic unsaturated hydrocarbon group having at least one double bond, containing 4 to 20 carbon atoms, preferably 5 to 8 carbon atoms, and optionally substituted by any suitable group (including but not limited to one or more moieties selected from the above groups for the alkyl group). A preferred cycloalkenyl group is 6-(hydroxymethyl)cyclohex-3-en-1-yl.

[0276] As used herein, the term "aryl" is defined as an organic group (such as phenyl and naphthyl) derived from an aromatic hydrocarbon consisting of 1 to 3 rings and containing 6 to 30 carbon atoms, optionally substituted by 1 to 5 substituents independently selected from halogen, hydroxy, nitro, C1-6-alkyl, C1-6-alkoxy, C1-6-alkylsulfonyl, trifluoromethylthio, or pyridinylalkyl, by removal of one hydrogen. The aryl group is preferably a phenyl group. Preferred aryl groups are phenyl, 3-hydroxyphenyl, 3-fluorophenyl, 3-methylphenyl, 4-methylphenyl, 4-hydroxyphenyl, 4-hydroxy-3-methoxyphenyl, 3-(2-pyridin-2-ylethyl)phenyl, 3,4-dimethylphenyl, 4-tert-butylphenyl, 4-methylsulfonylphenyl, 2-nitrophenyl, 2-chloro-6-fluorophenyl, 2-[(trifluoromethyl)thio]phenyl, 2-chlorophenyl, or 4-bromophenyl.

[0277] As used herein, the term "halogen" includes atoms of Cl, Br, F, and I.

[0278] As used herein, the term "nitro" represents a group of the formula -NO2.

[0279] As used herein, the term "hydroxy" represents a group of the formula -OH.

[0280] As used herein, the term "alkoxy" has the formula -OR b (wherein R b is an alkyl group as defined above).

[0281] As used herein, the term "ester" has the formula -COOR C (wherein R c is an alkyl group or an aryl group as defined above).

[0282] As used herein, the term "alkoxycarbonyl" has the formula -COOR d (wherein R d is an alkyl group as defined above).

[0283] As used herein, the term "amino" represents a group of the formula -NH2.

[0284] As used herein, the term "alkylamino" has the formula -NHR e or -NR e R f (wherein R e and R f are alkyl groups as defined above).

[0285] The term alkylsulfonyl, as used herein, is defined to represent a group of the formula -SO2-R g (wherein R g is C1-4 alkyl).

[0286] As used herein, the term "heterocyclic ring" is defined to include an aromatic or non-aromatic cycloalkyl or cycloalkenyl moiety as defined above having at least one O, S, and / or N atom intervening in the carbocyclic structure, and optionally replacing one of the carbons of the carbocyclic structure with a carbonyl.

[0287] Non-limiting examples of aromatic heterocyclic rings are pyrazolyl, furyl, imidazolyl, triazolyl, oxazolyl, pyridinyl, pyrrolyl, thienyl, isothiazolyl, benzimidazolyl, tetrazolyl, isoxazolyl, oxazolyl, thiazolyl, 1,2,4-thiadiazolyl, oxadiazole, pyridazinyl, pyrimidinyl, pyrazinyl, isoindolyl, triazolopyridinyl, imidazolopyridinyl, pyrrolopyrimidinyl, pyrazolopyrimidinyl, quinazolinyl, quinolidinyl, naphthyridinyl, quinolyl, isoquinolyl, isobenzofuranyl, benzothienyl, indolyl, indolizinyl, purinyl, carbazolyl, thieno(2,3-b)furanyl, thianthrenyl, benzothiazolyl, benzoxazolyl, cinnolinyl, quinoxalinyl, phenothiazinyl, isochromanyl, and xanthenyl, independently selected from 1 to 5 substituents selected from halogen, hydroxy, thiol, amino, nitro, cyano, azide, C1-6 alkoxy, C1-6 alkylthio, C1-6 alkyl, C1-6 haloalkyl, formyl, or ester, optionally substituted. More preferred aromatic heterocyclic rings are pyrazolyl, furyl, imidazolyl, triazolyl, oxazolyl, and pyridinyl.

[0288] Non-limiting examples of non-aromatic heterocycles are tetrahydrofuranyl, piperidinyl, piperidyl, piperazinyl, imidazolidinyl, morpholinyl, thiomorpholinyl, pyrrolidinyl, thiazolidinyl, indolinyl, tetrahydrobenzazocinyl, dihydroisochromenyl, tetrahydropyranyl, oxooctahydroquinolinyl, dioxolanyl, 1-oxaspiro(4.5)decan-2-yl, pyrrolidinyl, 2-oxo-pyrrolidinyl, 8-thiabicyclo[3.2.1]cyclooctanyl, 1,4-dithiepanyl, tetrahydro-2H-thiopyranyl, azepanyl, and azocanyl, optionally substituted with 1 to 5 substituents independently selected from halogen, hydroxy, thiol, amino, nitro, cyano, azide, C1-6-alkoxy, C1-6-alkylthio, C1-6-alkyl, C1-6-haloalkyl, formyl, or ester. More preferred non-aromatic heterocycles are tetrahydrofuranyl, piperidinyl, piperidyl, piperazinyl, imidazolidinyl, morpholinyl, thiomorpholinyl, pyrrolidinyl, thiazolidinyl, indolinyl, tetrahydro-1-benzazocin-1(2H)-yl, 3,4-dihydro-1H-isochromen-1-yl, tetrahydropyranyl, oxooctahydroquinolinyl, and dioxolanyl. The term "heterocycle" includes any of the above heterocycles condensed to 1 or 2 rings independently selected from an aryl ring, cycloalkyl ring, cycloalkenyl ring, or another monocyclic heterocycle, or bicyclic, tricyclic, and tetracyclic spiro groups (such as quinuclidinyl, 7-azabicyclo(2.2.1)heptanyl, 7-oxabicyclo(2.2.1)heptanyl, and 8-azabicyclo(3.2.1)octanyl) in which the monocyclic heterocyclic group is bridged by an alkylene group.

[0289] The term "pyridinylalkyl" as used herein refers to a group of the formula -R h -pyridinyl (wherein R h is C1-4-alkylene).

[0290] The term "azide" as used herein refers to a group of the formula -N3.

[0291] As used herein, the term "cyano" represents a group of the formula -CN.

[0292] Generally, R 2 is hydrogen or C1-4 alkyl.

[0293] Preferably, R 2 is hydrogen, methyl, or ethyl. More preferably, R 2 is hydrogen or methyl.

[0294] Generally, R 3 is hydrogen; C1-6 alkyl which is unsubstituted or substituted by 1 to 5 substituents selected from halogen, hydroxy, alkoxy, alkoxycarbonyl, or alkylamino; C5-7 cycloalkyl; (hydroxymethyl) cyclohexenyl; phenyl which is unsubstituted or substituted by 1 to 5 substituents selected from halogen, C1-4 alkyl, hydroxy, methoxy, nitro, methylsulfonyl, trifluoromethylthio, or pyridinylalkyl; pyridinyl which is unsubstituted or substituted by methoxy; triazolyl; C1-4 alkoxy; or a group of the formula -W-R 8 (wherein, Generally, W is C1-4 alkylene which is unsubstituted or substituted by halogen, hydroxy, C1-4 alkyl, or alkoxy; -NH-; or -NHC(=O)-, R 8 is phenyl which is unsubstituted or substituted by 1 to 5 substituents selected from halogen, C1-4 alkyl, hydroxy, methoxy, nitro, methylsulfonyl, or trifluoromethylthio; furyl which is unsubstituted or substituted by methyl; pyrazolyl; pyridinyl; morpholinyl; tetrahydrobenzazocinyl; piperidinyl which is unsubstituted or substituted by methyl; dihydroisochromenyl, or dihydroimidazolyl).

[0295] Preferably, R 3is hydrogen, n-butyl, cycloheptyl, 2-fluoroethyl, 3-hydroxypropyl, 3-hydroxy-2,2-dimethylpropyl, 1-(hydroxymethyl)propyl, 3,3,3-trifluoro-2-hydroxypropyl, 3-ethoxypropyl, 2-ethoxy-2-oxoethyl, 3-(dimethylamino)propyl, 6-(hydroxymethyl)cyclohex-3-en-1-yl, 3-hydroxyphenyl, 3-fluorophenyl, 3-(2-pyridin-2-ylethyl)phenyl, 3,4-dimethylphenyl, 4-tert-butylphenyl, benzyl, 4-hydroxy-3-methoxybenzyl, 4-methylsulfonylbenzyl, 2-nitrobenzyl, 2-chloro-6-fluorobenzyl, 2-[(trifluoromethyl)thio]benzyl, 2-hydroxy-2-phenylethyl, 2-(3,4-dimethoxyphenyl)ethyl, 2-(2-chlorophenyl)ethyl, 2-(4-methylphenyl)ethyl, (4-bromophenyl)amino, pyridin-3-yl, 6-methoxypyridin-3-yl, 4H-1,2,4-triazol-3-yl, pyridin-4-ylmethyl, (5-methyl-2-furyl)methyl, 3-(1H-pyrazol-1-yl)propyl, 2-morpholin-4-ylethyl, 2-((3,4,5,6-tetrahydro-1-benzazocin-1(2H)-yl)propyl, 2-(2-methylpiperidin-1-yl)ethyl, 3,4-dihydro-1H-isochromen-1-ylmethyl, methoxy, (4-pyridinylcarbonyl)amino, or 4,5-dihydro-1H-imidazol-2-ylamino. More preferably, R 3 is hydrogen.

[0296] Generally, R 3a is hydrogen, C1-C4-alkyl, or a group of the formula:

[0297]

Chemical formula

[0298] (wherein m is from 1 to 4).

[0299] Preferably, R 3a is hydrogen, methyl, or tetrahydrofuran-2-ylmethyl. More preferably, R 3a is hydrogen.

[0300] In another embodiment, NR 3 R 3a is unsubstituted or piperidinyl substituted by hydroxy; thiomorpholinyl; unsubstituted or thiazolidinyl substituted by C1-4-alkoxycarbonyl; 2,5-dihydro-1H-pyrrol-1-yl; 1,4-dioxa-8-azaspiro[4.5]dec-8-yl; 4-oxooctahydro-1(2H)-quinolinyl; or a group of the formula:

[0301]

Chemical formula

[0302] (wherein R 14 is pyridinyl; phenyl unsubstituted or substituted by halogen, hydroxy, C1-4-alkyl; or a group of the formula -V-R 15 (wherein V is unsubstituted C1-4-alkylene and R 15 is phenyl or morpholinyl)).

[0303] In a preferred embodiment, NR 3 R 3a is 4-pyridin-2-ylpiperazin-1-yl, 4-(3-methylphenyl)piperazin-1-yl, 4-(4-hydroxyphenyl)piperazin-1-yl, 4-(2-phenylethyl)piperazin-1-yl, 4-(2-morpholin-4-ylethyl)piperazin-1-yl, 3-hydroxypiperidin-1-yl, thiomorpholin-4-yl, 4-methoxycarbonyl-1,3-thiazolidin-3-yl, 2,5-dihydro-1H-pyrrol-1-yl, 1,4-dioxa-8-azaspiro[4.5]dec-8-yl, or 4-oxooctahydro-1(2H)-quinolinyl.

[0304] Generally, R5 is hydrogen, nitro, halogen, unsubstituted or halogen-substituted C1-4-alkyl, or unsubstituted or halogen-substituted C1-4-alkoxy.

[0305] Preferably, R 5 is hydrogen, methyl, ethyl, trifluoromethyl, trifluoromethoxy, n-propyl, isopropyl, nitro, or halogen. More preferably, R 5 is halogen or trifluoromethyl.

[0306] Generally, R 6 is hydrogen, C1-6-alkyl, or halogen.

[0307] Preferably, R 6 is hydrogen, methyl, or Cl. More preferably, R 6 is hydrogen.

[0308] Generally, R 7 is hydrogen, methyl, or halogen.

[0309] Preferably, R 7 is hydrogen, methyl, Br, F, or Cl. More preferably, R 7 is hydrogen, Br, or F.

[0310] Combinations of one or more of these preferred compound groups are particularly preferred.

[0311] In a preferred embodiment, the compound is of formula I:

[0312]

Chemical formula

[0313] (wherein, R 1 is hydrogen, R 2 is hydrogen or C1-4-alkyl, R 3 is hydrogen; C1-C6-alkyl which is unsubstituted or substituted by 1 to 5 substituents selected from halogen, hydroxy, alkoxy, alkoxycarbonyl, or alkylamino; C5-C7-cycloalkyl; (hydroxymethyl) cyclohexenyl; phenyl which is unsubstituted or substituted by 1 to 5 substituents selected from halogen, C1-C4-alkyl, hydroxy, methoxy, nitro, methylsulfonyl, trifluoromethylthio, or pyridinylalkyl; pyridinyl which is unsubstituted or substituted by methoxy; triazolyl; C1-C4-alkoxy; or a group of the formula -W-R 8 and R 3a is hydrogen, C1-C4-alkyl, or a group of the formula:

[0314]

Chemical formula

[0315] or NR 3 R 3a is piperidinyl which is unsubstituted or substituted by hydroxy; thiomorpholinyl; thiazolidinyl which is unsubstituted or substituted by C1-C4-alkoxycarbonyl; 2,5-dihydro-1H-pyrrol-1-yl; 1,4-dioxa-8-azaspiro[4.5]decan-8-yl; 4-oxooctahydro-1(2H)-quinolinyl; or a group of the formula:

[0316]

Chemical formula

[0317] and R 4 is hydrogen R 5 is hydrogen; nitro; halogen; C1-C4-alkyl which is unsubstituted or substituted by halogen; or C1-C4-alkoxy which is unsubstituted or substituted by halogen R6 is hydrogen, C1-6-allyl, or halogen, R7 is hydrogen, methyl, or halogen, W is unsubstituted or C1-4-alkylene substituted by halogen, hydroxy, C1-4-alkyl, or alkoxy; -NH-; or -NHC(=O)-, R8 is phenyl unsubstituted or substituted by 1 to 5 substituents selected from halogen, C1-4-alkyl, hydroxy, methoxy, nitro, methylsulfonyl, or trifluoromethylthio; furyl unsubstituted or substituted by methyl; pyrazolyl; pyridinyl; morpholinyl; tetrahydrobenzazocinyl; piperidinyl unsubstituted or substituted by methyl; dihydroisochromenyl, or dihydroimidazolyl, R 14 is pyridinyl; phenyl unsubstituted or substituted by halogen, hydroxy, C1-4-alkyl; or a group of formula -V-R 15 wherein, V is unsubstituted C1-4-alkylene, R 15 is phenyl or morpholinyl, m is 1 to 4, R 2 is hydrogen, R 3 is H or 2,6-diisopropylphenyl, and when R 3a is H, R 5 , R 6 , or R 7 of which at least one is different from hydrogen) or a pharmaceutically acceptable salt or stereoisomer thereof.

[0318] In a more preferred embodiment, the compound is of formula I:

[0319]

Chemical formula

[0320] (wherein, R 1 is hydrogen, R 2 is hydrogen, methyl, or ethyl, and R 3 is hydrogen, n-butyl, cycloheptyl, 2-fluoroethyl, 3-hydroxypropyl, 3-hydroxy-2,2-dimethylpropyl, 1-(hydroxymethyl)propyl, 3,3,3-trifluoro-2-hydroxypropyl, 3-ethoxypropyl, 2-ethoxy-2-oxoethyl, 3-(dimethylamino)propyl, 6-(hydroxymethyl)cyclohex-3-en-1-yl, 3-hydroxyphenyl, 3-fluorophenyl, 3-(2-pyridin-2-ylethyl)phenyl, 3,4-dimethylphenyl, 4-tert-butylphenyl, benzyl, 4-hydroxy-3-methoxybenzyl, 4-methylsulfonylbenzyl, 2-nitrobenzyl, 2-chloro-6-fluorobenzyl, 2-[(trifluoromethyl)thio]benzyl, 2-hydroxy-2-phenylethyl, 2-(3,4-dimethoxyphenyl)ethyl, 2-(2-chlorophenyl)ethyl, 2-(4-methylphenyl)ethyl, (4-bromophenyl)amino, pyridin-3-yl, 6-methoxypyridin-3-yl, 4H-1,2,4-triazol-3-yl, pyridin-4-ylmethyl, (5-methyl-2-furyl)methyl, 3-(1H-pyrazol-1-yl)propyl, 2-morpholin-4-ylethyl, 2-((3,4,5,6-tetrahydro-1-benzazocin-1(2H)-yl)propyl, 2-(2-methylpiperidin-1-yl)ethyl, 3,4-dihydro-1H-isochromen-1-ylmethyl, methoxy, (4-pyridinylcarbonyl)amino, or 4,5-dihydro-1H-imidazol-2-ylamino, and R 3a is hydrogen, methyl, or tetrahydrofuran-2-ylmethyl, or NR 3 R 3ais 4-pyridin-2-ylpiperazin-1-yl, 4-(3-methylphenyl)piperazin-1-yl, 4-(4-hydroxyphenyl)piperazin-1-yl, 4-(2-phenylethyl)piperazin-1-yl, 4-(2-morpholin-4-ylethyl)piperazin-1-yl, 3-hydroxypiperidin-1-yl, thiomorpholin-4-yl, 4-methoxycarbonyl-1,3-thiazolidin-3-yl, 2,5-dihydro-1H-pyrrol-1-yl, 1,4-dioxa-8-azaspiro[4.5]decan-8-yl, or 4-oxooctahydro-1(2H)-quinolinyl, R 4 is hydrogen, R 5 is hydrogen, methyl, ethyl, trifluoromethyl, trifluoromethoxy, n-propyl, isopropyl, nitro, or halogen, R 6 is hydrogen, methyl, or Cl, R 7 is hydrogen, methyl, Br, F, or Cl, R 2 is hydrogen, R 3 is H or 2,6-diisopropylphenyl, and R 3a is H, R 5 R 6 or R 7 at least one of which is different from hydrogen) or a pharmaceutically acceptable salt or a stereoisomer thereof.

[0321] More preferably, R 2 is hydrogen or methyl, R 3 is hydrogen, R 3a is hydrogen, R 5 is halogen or trifluoromethyl, R 6 is hydrogen, R 7 is hydrogen, Br, or F.

[0322] In all of the above ranges, when R 2 is C1-20-alkyl, R 2It is preferable that the carbon atom to which it binds has an "S" configuration.

[0323] In some embodiments, the compounds useful in the methods and compositions of the present invention are selected from the group consisting of: 2-(5-iodo-2-oxo-2,3-dihydro-1H-indol-1-yl)acetamide; 2-(5-chloro-2-oxo-2,3-dihydro-1H-indol-1-yl)acetamide; 2-(5,7-dibromo-2-oxo-2,3-dihydro-1H-indol-1-yl)acetamide; 2-(5-nitro-2-oxo-2,3-dihydro-1H-indol-1-yl)acetamide; 2-(5-methyl-2-oxo-2,3-dihydro-1H-indol-1-yl)acetamide; 2-(5-chloro-2-oxo-2,3-dihydro-1H-indol-1-yl)propanamide; (2R)-2-(5-chloro-2-oxo-2,3-dihydro-1H-indol-1-yl)propanamide; (2S)-2-(5-chloro-2-oxo-2,3-dihydro-1H-indol-1-yl)propanamide; 2-[2-oxo-5-(trifluoromethoxy)-2,3-dihydro-1H-indol-1-yl]acetamide; 2-(5-isopropyl-2-oxo-2,3-dihydro-1H-indol-1-yl)acetamide; 2-(5-ethyl-2-oxo-2,3-dihydro-1H-indol-1-yl)acetamide; 2-(5-fluoro-2-oxo-2,3-dihydro-1H-indol-1-yl)acetamide; 2-(5,7-dimethyl-2-oxo-2,3-dihydro-1H-indol-1-yl)acetamide; 2-(5-bromo-2-oxo-2,3-dihydro-1H-indol-1-yl)acetamide; 2-(2-oxo-5-propyl-2,3-dihydro-1H-indol-1-yl)acetamide; 2-[2-oxo-5-(trifluoromethyl)-2,3-dihydro-1H-indol-1-yl]acetamide; 2-(5,6-dimethyl-2-oxo-2,3-dihydro-1H-indol-1-yl)acetamide; 2-(7-chloro-2-oxo-2,3-dihydro-1H-indol-1-yl)acetamide; 2-(6-chloro-2-oxo-2,3-dihydro-1H-indol-1-yl)acetamide; 2-(5-chloro-2-oxo-2,3-dihydro-1H-indol-1-yl)butanamide;(+)-2-(5-chloro-2-oxo-2,3-dihydro-1H-indol-1-yl)butanamide; (-)-2-(5-chloro-2-oxo-2,3-dihydro-1H-indol-1-yl)butanamide; 2-(5-methyl-2-oxo-2,3-dihydro-1H-indol-1-yl)propanamide; (+)-2-(5-methyl-2-oxo-2,3-dihydro-1H-indol-1-yl)propanamide; (-)-2-(5-methyl-2-oxo-2,3-dihydro-1H-indol-1-yl)propanamide; 2-(5-bromo-2-oxo-2,3-dihydro-1H-indol-1-yl)propanamide; (-)-2-(5-bromo-2-oxo-2,3-dihydro-1H-indol-1-yl)propanamide; (+)-2-(5-bromo-2-oxo-2,3-dihydro-1H-indol-1-yl)propanamide; 2-(5-chloro-7-fluoro-2-oxo-2,3-dihydro-1H-indol-1-yl)acetamide; 2-(5-chloro-2-oxo-2,3-dihydro-1H-indol-1-yl)-N-(3-hydroxyphenyl)acetamide; 2-(5-chloro-2-oxo-2,3-dihydro-1H-indol-1-yl)-N-(3-fluorophenyl)acetamide; 2-(5-chloro-2-oxo-2,3-dihydro-1H-indol-1-yl)-N-[3-(2-pyridin-2-ylethyl)phenyl]acetamide; 2-(5-chloro-2-oxo-2,3-dihydro-1H-indol-1-yl)-N-[6-(hydroxymethyl)cyclohex-3-en-1-yl]acetamide; 5-chloro-1-[2-oxo-2-(4-pyridin-2-ylpiperazin-1-yl)ethyl]-1,3-dihydro-2H-indol-2-one; 5-chloro-1-{2-[4-(3-methylphenyl)piperazin-1-yl]-2-oxoethyl}-1,3-dihydro-2H-indol-2-one; 2-(5-chloro-2-oxo-2,3-dihydro-1H-indol-1-yl)-N-(4-hydroxy-3-methoxybenzyl)acetamide;2-(5-chloro-2-oxo-2,3-dihydro-1H-indol-1-yl)-N-(pyridin-4-ylmethyl)-N-(tetrahydrofuran-2-ylmethyl)acetamide; 5-chloro-1-[2-(3-hydroxypiperidin-1-yl)-2-oxoethyl]-1,3-dihydro-2H-indol-2-one; 2-(5-chloro-2-oxo-2,3-dihydro-1H-indol-1-yl)-N'-isonicotinoylacetohydrazide; 5-chloro-1-(2-oxo-2-thiomorpholin-4-ylethyl)-1,3-dihydro-2H-indol-2-one; 2-(5-chloro-2-oxo-2,3-dihydro-1H-indol-1-yl)-N-(4H-1,2,4-triazol-3-yl)acetamide; 2-(5-chloro-2-oxo-2,3-dihydro-1H-indol-1-yl)-N-[4-(methylsulfonyl)benzyl]acetamide; 1-[(5-chloro-2-oxo-2,3-dihydro-1H-indol-1-yl)acetyl]octahydroquinolin-4(1H)-one; N'-(4-bromophenyl)-2-(5-chloro-2-oxo-2,3-dihydro-1H-indol-1-yl)acetohydrazide; 2-(5-chloro-2-oxo-2,3-dihydro-1H-indol-1-yl)-N-(6-methoxypyridin-3-yl)acetamide; N-butyl-2-(5-chloro-2-oxo-2,3-dihydro-1H-indol-1-yl)acetamide; 2-(5-chloro-2-oxo-2,3-dihydro-1H-indol-1-yl)-N-(3-hydroxypropyl)acetamide; 2-(5-chloro-2-oxo-2,3-dihydro-1H-indol-1-yl)-N-[3-(dimethylamino)propyl]acetamide; 5-chloro-1-{2-oxo-2[4-(2-phenylethyl)piperazin-1-yl]ethyl}-1,3-dihydro-2H-indol-2-one; {[(5-chloro-2-oxo-2,3-dihydro-1H-indol-1-yl)acetyl]amino}acetic acid ethyl ester; 2-(5-chloro-2-oxo-2,3-dihydro-1H-indol-1-yl)-N-(3-ethoxypropyl)acetamide;2-(5-Chloro-2-oxo-2,3-dihydro-1H-indol-1-yl)-N-(2-fluoroethyl)acetamide; 2-(5-chloro-2-oxo-2,3-dihydro-1H-indol-1-yl)-N-methoxy-N-methylacetamide; 2-(5-chloro-2-oxo-2,3-dihydro-1H-indol-1-yl)-N-(3,4-dimethylphenyl)acetamide; N-(4-tert-butylphenyl)-2-(5-chloro-2-oxo-2,3-dihydro-1H-indol-1-yl)acetamide; 2-(5-chloro-2-oxo-2,3-dihydro-1H-indol-1-yl)-N-(3-hydroxy-2,2-dimethylpropyl)acetamide; 2-(5-chloro-2-oxo-2,3-dihydro-1H-indol-1-yl)-N-[1-(hydroxymethyl)propyl]acetamide; 2-(5-chloro-2-oxo-2,3-dihydro-1H-indol-1-yl)-N-(3,3,3-trifluoro-2-hydroxypropyl)acetamide; 2-(5-chloro-2-oxo-2,3-dihydro-1H-indol-1-yl)-N-(2-hydroxy-2-phenylethyl)acetamide; 5-chloro-1-{2-[4-(4-hydroxyphenyl)piperazin-1-yl]-2-oxoethyl}-1,3-dihydro-2H-indol-2-one; 2-(5-chloro-2-oxo-2,3-dihydro-1H-indol-1-yl)-N-(pyridin-4-ylmethyl)acetamide; 2-(5-chloro-2-oxo-2,3-dihydro-1H-indol-1-yl)-N-[(5-methyl-2-furyl)methyl]acetamide; 2-(5-chloro-2-oxo-2,3-dihydro-1H-indol-1-yl)-N-[3-(1H-pyrazol-1-yl)propyl]acetamide; Methyl 3-[(5-chloro-2-oxo-2,3-dihydro-1H-indol-1-yl)acetyl]-1,3-thiazolidine-4-carboxylate; 5-chloro-1-[2-(2,5-dihydro-1H-pyrrol-1-yl)-2-oxoethyl]-1,3-dihydro-2H-indol-2-one;2-(5-chloro-2-oxo-2,3-dihydro-1H-indol-1-yl)-N'-(4,5-dihydro-1H-imidazol-2-yl)acetohydrazide; 2-(5-chloro-2-oxo-2,3-dihydro-1H-indol-1-yl)-N-[2-(3,4-dimethoxyphenyl)ethyl]acetamide; 2-(5-chloro-2-oxo-2,3-dihydro-1H-indol-1-yl)-N-[2-(2-chlorophenyl)ethyl]acetanilide; 2-(5-chloro-2-oxo-2,3-dihydro-1H-indol-1-yl)-N-[2-(4-methylphenyl)ethyl]acetamide; 2-(5-chloro-2-oxo-2,3-dihydro-1H-indol-1-yl)-N-(2-morpholin-4-ylethyl)acetamide; 2-(5-chloro-2-oxo-2,3-dihydro-1H-indol-1-yl)-N-[2-(3,4,5,6-tetrahydro-1-benzazocin-1(2H)-yl)propyl]acetamide; 2-(5-chloro-2-oxo-2,3-dihydro-1H-indol-1-yl)-N-[2-(2-methylpiperidin-1-yl)ethyl]acetamide; 2-(5-chloro-2-oxo-2,3-dihydro-1H-indol-1-yl)-N-(2-nitrobenzyl)acetamide; 2-(5-chloro-2-oxo-2,3-dihydro-1H-indol-1-yl)-N-(3,4-dihydro-1H-isochromen-1-yl)ethyl]acetamide; N-(2-chloro-6-fluorobenzyl)-2-(5-chloro-2-oxo-2,3-dihydro-1H-indol-1-yl)acetamide; N-benzyl-2-(5-chloro-2-oxo-2,3-dihydro-1H-indol-1-yl)-N-methylacetamide; 2-(5-chloro-2-oxo-2,3-dihydro(dthydro)-1H-indol-1-yl)-N-{2-[(trifluoromethyl)thio]benzyl}acetamide; 5-chloro-1-[2-(1,4-dioxa-8-azaspiro[4.5]deca-8-yl)-2-oxoethyl]-1,3-dihydro-2H-indol-2-one; 2-(5-chloro-2-oxo-2,3-dihydro-1H-indol-1-yl)-N-cycloheptylacetamide;5-Chloro-1-{2-[4-(2-morpholin-4-ylethyl)piperazin-1-yl]-2-oxoethyl}-1,3-dihydro-2H-indol-2-one; and 2-(5-chloro-2-oxo-2,3-dihydro-1H-indol-1-yl)-N-pyridin-3-ylacetamide;

[0324] In some embodiments, the compounds useful in the methods and compositions of the invention are selected from the group consisting of: 2-(5-iodo-2-oxo-2,3-dihydro-1H-indol-1-yl)acetamide; 2-(5-chloro-2-oxo-2,3-dihydro-1H-indol-1-yl)acetamide; 2-(5,7-dibromo-2-oxo-2,3-dihydro-1H-indol-1-yl)acetamide; (2S)-2-(5-chloro-2-oxo-2,3-dihydro-1H-indol-1-yl)propanamide; 2-[2-oxo-5-(trifluoromethyl)-2,3-dihydro-1H-indol-1-yl]acetamide, and 2-(5-chloro-7-fluoro-2-oxo-2,3-dihydro-1H-indol-1-yl)acetamide.

[0325] In another embodiment, the compounds useful in the methods and compositions of the invention are selected from the group consisting of: 2-(5-chloro-2-oxo-2,3-dihydro-1H-indol-1-yl)acetamide and (2S)-2-(5-chloro-2-oxo-2,3-dihydro-1H-indol-1-yl)propanamide.

[0326] iv) U.S. Patent No. 7,244,747: Formula I:

[0327]

Chemical formula

[0328] (wherein, R 1 is hydrogen, C 1~20 alkyl, C 3~8Cycloalkyl, halogen, hydroxy, alkoxy, aryloxy, ester, amide, cyano, nitro, amino, guanidine, amino derivative, alkylthio, arylthio, alkylsulfonyl, arylsulfonyl, alkylsulfinyl, arylsulfinyl, aryl, or heterocycle, R 2 is hydrogen, C 1~20 alkyl, alkoxy, amino, halogen, hydroxy, ester, amide, nitro, cyano, carbamate, or aryl, R 3 is hydrogen, C 1~20 alkyl, alkoxy, amino, halogen, hydroxy, ester, amide, nitro, cyano, carbamate, or aryl, or R 2 and R 3 together with the imidazole ring form the following:

[0329]

Chemical formula

[0330] can form a 1H - benzimidazole ring of R 4 is hydrogen, C 1~20 alkyl, C 2~12 alkenyl, C 2~12 alkynyl, aryl, azide, alkoxycarbonylamino, arylsulfonyloxy, or heterocycle, R 4a is hydrogen or C 1~20 alkyl, or R 4 and R 4a together can form C 3~8 cycloalkyl, R 5 is hydrogen, or R 4 、R 4a 、and R 5can combine with the 2-oxo-1-pyrrolidine ring to form the following 1,3-dihydro-2H-indol-2-one ring, R 6 is hydrogen or C 1~20 alkyl, R 7 is hydrogen, or R 6 and R 7 are bonded together to form C 3~6 cycloalkyl, R 8 is hydrogen, halogen, nitro, cyano, C 1~20 alkyl, or alkoxy, R 9 is hydrogen, C 1~20 alkyl, halogen, hydroxy, alkoxy, aryloxy, ester, amide, cyano, nitro, amino, amino derivative, alkylthio, arylthio, alkylsulfonyl, arylsulfonyl, alkylsulfinyl, or arylsulfinyl, R 10 is hydrogen, C 1~20 alkyl, halogen, hydroxy, alkoxy, aryloxy, ester, amide, cyano, nitro, amino, amino derivative, alkylthio, arylthio, alkylsulfonyl, arylsulfonyl, alkylsulfinyl, or arylsulfinyl, R 11 is hydrogen, halogen, nitro, cyano, C 1~20 alkyl, or alkoxy, R 12 is hydrogen or halogen, R 13 is hydrogen, nitro, halogen, heterocycle, amino, aryl, unsubstituted or C 1~20 alkyl substituted by halogen, or alkoxy unsubstituted or substituted by halogen, R 14 is hydrogen, C 1~20 alkyl, or halogen, R 15 is hydrogen, C 1~20is alkyl or halogen, provided that when the group represented by the formula:

[0331]

Chem.

[0332] R, where R is different from hydrogen, 4 and the asterisk represents the bonding point of the substituent) has a compound or a pharmaceutically acceptable salt thereof. *

[0333] In a preferred embodiment, the compound has the formula I:

[0334]

Chem.

[0335] (wherein R 1 is hydrogen, C 1~20 alkyl, C 3~8 cycloalkyl, halogen, hydroxy, ester, amide, cyano, nitro, amino, guanidine, alkylthio, alkylsulfonyl, alkylsulfinyl, aryl, or heterocycle, R 2 is hydrogen, C 1~20 alkyl, halogen, cyano, ester, carbamate, or amide, R 3 is hydrogen, cyano, C 1~20 alkyl, halogen, or ester, or R 2 and R 3 together with the imidazole ring can form the following:

[0336]

Chem.

[0337] 1H - benzimidazole ring.​ R 4 is hydrogen, C 1~20 alkyl, C 2~12 alkenyl, or aryl, and R 4a is hydrogen, R 5 is hydrogen, or R 4 、R 4a 、and R 5 together with the 2-oxo-1-pyrrolidine ring form the following:

[0338]

Chemical formula

[0339] can form a 1,3-dihydro-2H-indol-2-one ring of the following: R 6 is hydrogen or C 1~20 alkyl, R 7 is hydrogen, or R 6 and R 7 are bonded together to form C 3~6 cycloalkyl, R 8 is hydrogen, R 9 is hydrogen, C 1~20 alkyl, halogen, or alkoxy, R 10 is hydrogen, C 1~20 alkyl, halogen, or cyano, R 11 is hydrogen, R 12 is hydrogen or halogen, R 13 is hydrogen, halogen, heterocycle, or C 1~20 alkyl, R 14 is hydrogen, R 15 is hydrogen, provided that

[0340] [Chem.]

[0341] is, when representing a group of the formula:

[0342] [Chem.]

[0343] R, when representing a group of: 4 is different from hydrogen), its tautomer, geometric isomers (including cis and trans isomers, Z and E isomers), enantiomers, diastereomers, and mixtures thereof (including all possible mixtures of stereoisomers), or a pharmaceutically acceptable salt thereof.

[0344] As used herein, the term "alkyl" refers to a monovalent saturated hydrocarbon group having a straight-chain (unbranched), branched, cyclic, or a combination thereof, and containing 1 to 20 carbon atoms, preferably 1 to 10 carbon atoms, and more preferably the alkyl group has 1 to 3 carbon atoms. The alkyl moiety can be optionally substituted with 1 to 5 substituents independently selected from the group consisting of halogen, hydroxy, cyano, azido, aryloxy, alkoxy, alkylthio, alkanoylamino, arylcarbonylamino, aminocarbonyl, methylaminocarbonyl, dimethylaminocarbonyl, or aryl. Usually, the alkyl group is, in this case, methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, t-butyl, 1-ethylpropyl, n-heptyl, 2,4,4-trimethylpentyl, n-decyl, chloromethyl, trifluoromethyl, 2-bromo-2,2-difluoroethyl, 2,2,2-trifluoroethyl, 3,3,3-trifluoropropyl, hydroxymethyl, cyanomethyl, azidomethyl, (acetylamino)methyl, (propionylamino)methyl, (benzoylamino)methyl, (4-chlorophenoxy)methyl, benzyl, 2-phenylethyl, or 2-(methylthio)ethyl. Preferred alkyl groups are methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, t-butyl, 1-ethylpropyl, 2,4,4-trimethylpentyl, chloromethyl, trifluoromethyl, 2,2,2-trifluoroethyl, hydroxymethyl, cyanomethyl, azidomethyl, (acetylamino)methyl, (propionylamino)methyl, (benzoylamino)methyl, or 2-(methylthio)ethyl. More preferred alkyl groups are methyl, ethyl, n-propyl, i-propyl, n-butyl, azidomethyl, or trifluoromethyl. Most preferred alkyl groups are methyl or n-propyl.

[0345] As used herein, the term "cycloalkyl" refers to a monovalent group of 3 to 8 carbon atoms, usually 3 to 6 carbon atoms, derived from a saturated cyclic hydrocarbon that can be substituted by any suitable group (including, but not limited to, one or more moieties selected from the groups described above for alkyl groups). Preferred cycloalkyl groups are cyclopropyl and cyclohexyl.

[0346] As used herein, the term "alkenyl" refers to a straight-chain, branched, or cyclic unsaturated hydrocarbon group having at least one carbon-carbon double bond and containing 2 to 12 carbon atoms, preferably usually 2 to 4 carbon atoms, or a combination thereof. The alkenyl group is optionally substituted by any suitable group (including, but not limited to, one or more moieties selected from the groups described above for alkyl groups). Usually, the alkenyl group is ethenyl (vinyl) optionally substituted by 1 to 3 halogens. Preferred alkenyl groups in this case are 2,2-difluorovinyl.

[0347] As used herein, the term "alkynyl" refers to a straight-chain, branched, or cyclic hydrocarbon group containing at least one carbon-carbon triple bond, containing 2 to 12 carbon atoms, preferably 2 to 6 carbon atoms, and optionally substituted by any suitable group (including, but not limited to, one or more moieties selected from the groups described above for alkyl groups), or a combination thereof. Preferably, the alkynyl group is a halogenoalkynyl group (haloalkynyl group).

[0348] Groups classified by prefixes such as "s", "i", and "t" (e.g., "i-propyl", "s-butyl") are branched derivatives.

[0349] As used herein, the term "aryl" when used herein refers to halogen, cyano, alkoxy, alkylthio, C 1~3It is defined as phenyl optionally substituted by 1 to 4 substituents independently selected from alkyl, or azide, preferably halogen or azide. Usually, the aryl group is, in this case, phenyl, 3-chlorophenyl, 3-fluorophenyl, 4-chlorophenyl, 4-fluorophenyl, 3,4-difluorophenyl, 3,5-difluorophenyl, 3-chloro-4-fluorophenyl, 2,3,4-trifluorophenyl, 2,4,5-trifluorophenyl, 2,3,5-trifluorophenyl, 3,4,5-trifluorophenyl, 3-azido-2,4-difluorophenyl, or 3-azido-2,4,6-trifluorophenyl. Preferably, the aryl group is phenyl, 3-chlorophenyl, 3-fluorophenyl, 4-chlorophenyl, 4-fluorophenyl, 3,4-difluorophenyl, 3,5-difluorophenyl, 3-chloro-4-fluorophenyl, 2,3,4-trifluorophenyl, 2,4,5-trifluorophenyl, 2,3,5-trifluorophenyl, 3,4,5-trifluorophenyl, or 3-azido-2,4-difluorophenyl. Most preferably, the aryl group is phenyl, 3-chlorophenyl, 3-fluorophenyl, 3,5-difluorophenyl, 2,3,4-trifluorophenyl, 2,4,5-trifluorophenyl, 2,3,5-trifluorophenyl, 3,4,5-trifluorophenyl, or 3-azido-2,4-difluorophenyl.

[0350] As used herein, the term "heterocyclic ring" is defined to include an aromatic or non-aromatic cycloalkyl moiety as defined above having at least one O, S, and / or N atom intervening in the carbocyclic structure. The heterocyclic moiety can be optionally substituted by an alkyl group or a halogen, and optionally, one of the carbons of the carbocyclic structure can be replaced by a carbonyl. Usually, the heterocyclic ring is 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-tetrahydrofuranyl, 1H-pyrrol-2-yl, 1-methyl-1H-pyrrol-2-yl, 1H-pyrazol-2-yl, 1H-pyrazol-3-yl, 4-chloro-1-methyl-1H-pyrazol-3-yl, 5-chloro-1,3-dimethyl-1H-pyrazol-4-yl, 1,2,3-thiadiazol-4-yl, 3,5-dimethyl-4-isothiazyl, 1H-imidazol-2-yl, 1-methyl-1H-imidazol-2-yl, 4-methyl-1H-imidazol-5-yl, or 2-methyl-1,3-thiazol-4-yl. Preferred heterocyclic rings are 1H-imidazol-2-yl, 1,2,3-thiadiazol-4-yl, 1H-pyrazol-3-yl, 2-furyl, 3-furyl, 2-thienyl, 1-methyl-1H-pyrrol-2-yl, 1H-pyrrol-2-yl.

[0351] As used herein, the term "halogen" includes a chlorine atom, a bromine atom, a fluorine atom, and an iodine atom. Usually, the halogen is chlorine, bromine, and fluorine. Preferred halogens are fluorine, bromine, and chlorine.

[0352] As used herein, the term "hydroxy" represents a group of the formula --OH.

[0353] As used herein, the term "alkoxy" represents a group of the formula -OR a (wherein R a is an alkyl group as defined above). The preferred alkoxy group is methoxy.

[0354] The term "aryloxy", as used herein, refers to the group of the formula --OR b (wherein R b is an aryl group as defined above). A preferred aryloxy group is phenoxy.

[0355] The term "ester", as used herein, refers to the group of the formula --COOR c (wherein R c is an alkyl group or an aryl group as defined above). A preferred ester group is methoxycarbonyl.

[0356] The term "amide", as used herein, refers to the group of the formula --CONH2.

[0357] The term "amino", as used herein, refers to the group of the formula --NH2.

[0358] The term "amino derivative", as used herein, refers to an alkylamino group or an arylamino group, and the terms "alkyl" and "aryl" are defined as above.

[0359] The term "cyano", as used herein, refers to the group of the formula --CN.

[0360] The term "nitro", as used herein, refers to the group of the formula -NO2.

[0361] The term "azide", as used herein, refers to the group of the formula --N3.

[0362] The term "guanidine", as used herein, refers to the group of the formula --NHC(=NH)NH2.

[0363] The term "alkylthio", as used herein, refers to the group of the formula --SR d (wherein R d is an alkyl group as defined above). A preferred alkylthio group is methylthio.

[0364] The term "alkylsulfonyl" as used herein refers to the group of the formula --S(=O)2R e (wherein R e is an alkyl group as defined above). A preferred alkylsulfonyl group is methylsulfonyl.

[0365] The term "alkylsulfinyl" as used herein refers to the group of the formula -S(=O)R f (wherein R f is an alkyl group as defined above). A preferred alkylsulfinyl group is methylsulfinyl.

[0366] The term "arylthio" as used herein refers to the group of the formula --SR g (wherein R g is an aryl group as defined above).

[0367] The term "arylsulfonyl" as used herein refers to the group of the formula --S(=O)2R h (wherein R h is an aryl group as defined above).

[0368] The term "arylsulfinyl" as used herein refers to the group of the formula --S(=O)R i (wherein R i is an aryl group as defined above).

[0369] The term "carbamate" as used herein refers to the group of the formula --N(H)C(O)OR j (wherein R j is alkyl or aryl as defined above). Usually, the carbamate group is (propoxycarbonyl)amino or (benzyloxycarbonyl)amino. A preferred carbamate group is (benzyloxycarbonyl)amino.

[0370] The term "alkanoylamino" as used herein refers to the group of the formula --NHC(=O)R k (wherein R krepresents a group of the formula (wherein the alkyl group is as defined above).

[0371] The term "(arylcarbonyl)amino" as used herein refers to a group of the formula --NHC(=O)R m (wherein R m is an aryl group as defined above). Preferred (arylcarbonyl)amino is benzoylamino.

[0372] Generally, R 1 is hydrogen; C 1~10 alkyl which is unsubstituted or substituted by halogen, hydroxy, cyano, methylthio, phenyl, or 4-chlorophenoxy; hydroxy; C 3~6 cycloalkyl; halogen; ester; amide; nitro; cyano; amino; phenyl; alkylthio; alkylsulfonyl; alkylsulfinyl; a heterocyclic ring which is unsubstituted or substituted by an alkyl group; or guanidine. Preferably, R 1 is hydrogen; methyl; ethyl; i-propyl; n-propyl; cyclopropyl; n-butyl; i-butyl; t-butyl; 1-ethylpropyl; 2,4,4-trimethylpentyl; hydroxymethyl; chloromethyl; trifluoromethyl; 2,2,2-trifluoroethyl; cyanomethyl; 2-(methylthio)ethyl; chloro; bromo; nitro; cyano; amino; aminocarbonyl; methoxycarbonyl; methylthio; methylsulfinyl; methylsulfonyl; phenyl; 2-furyl; 3-furyl; 1H-pyrrol-2-yl; 1-methyl-1H-pyrrol-2-yl; 2-thienyl; 1H-pyrazol-3-yl; 1,2,3-thiadiazol-4-yl, or 1H-imidazol-2-yl. More preferably, R 1 is hydrogen; methyl; ethyl; i-propyl; n-propyl; n-butyl; methylthio; nitro; cyano; amino; chloro, or 1H-pyrrol-2-yl. Most preferably, R 1 is hydrogen; methyl; methylthio; nitro; cyano; amino or chloro.

[0373] Generally, R 2is hydrogen; C which is unsubstituted or substituted by hydroxy, alkanoylamino, or benzoylamino 1~4 alkyl; halogen; ester; cyano; alkylcarbamate; [(N-methoxy-N-methyl)amino]carbonyl. Preferably, R 2 is hydrogen; methyl; hydroxymethyl; (acetylamino)methyl; (propionylamino)methyl; (benzoylamino)methyl; [(benzyloxy)carbonyl]amino; chloro or cyano. More preferably, R 2 is hydrogen; chloro or cyano.

[0374] Usually, R 3 is hydrogen; C which is unsubstituted or substituted by hydroxy 1~4 alkyl; halogen; ester or cyano. Preferably, R 3 is hydrogen; hydroxymethyl; chloro; cyano. More preferably, R 3 is hydrogen or cyano. Most preferably, R 3 is hydrogen.

[0375] Usually, R 4 is hydrogen; C which is unsubstituted or substituted by halogen 1~4 alkyl; C 2~4 alkenyl substituted by halogen, or a phenyl group which is unsubstituted or substituted by azide or / and halogen. Preferably, R 4 is hydrogen; n-propyl; 2,2-difluorovinyl; phenyl; 3-chlorophenyl; 3-fluorophenyl; 4-chlorophenyl; 4-fluorophenyl; 3,5-difluorophenyl; 3,4-difluorophenyl; 3-chloro-4-fluorophenyl; 2,3,4-trifluorophenyl; 2,4,5-trifluorophenyl; 2,3,5-trifluorophenyl; 3,4,5-trifluorophenyl; 3-azido-2,4-difluorophenyl, or 3-azido-2,4,6-trifluorophenyl. More preferably, R 4is hydrogen; n-propyl; 2,2-difluorovinyl; phenyl; 3-chlorophenyl; 3-fluorophenyl; 4-chlorophenyl; 4-fluorophenyl; 3,5-difluorophenyl; 3,4-difluorophenyl; 3-chloro-4-fluorophenyl; 2,3,4-trifluorophenyl; 2,4,5-trifluorophenyl; 2,3,5-trifluorophenyl; 3,4,5-trifluorophenyl, or 3-azido-2,4-difluorophenyl. Most preferably, R 4 is n-propyl; 2,2-difluorovinyl; phenyl; 3-chlorophenyl; 3-fluorophenyl; 3,5-difluorophenyl; 2,3,4-trifluorophenyl; 2,4,5-trifluorophenyl; 2,3,5-trifluorophenyl; 3,4,5-trifluorophenyl, or 3-azido-2,4-difluorophenyl.

[0376] Usually, R 4a is hydrogen.

[0377] Usually, R 5 is hydrogen.

[0378] Usually, R 6 is hydrogen or unsubstituted or substituted by hydroxy or azido C 1~10 alkyl. Preferably, R 6 is hydrogen or azidomethyl. More preferably, R 6 is hydrogen.

[0379] Usually, R 7 is hydrogen.

[0380] In another preferred embodiment, R 6 and R 7 are joined to form cyclopropyl.

[0381] In another preferred embodiment, R 2 and R 3 together with the imidazole ring are as follows:

[0382] [Chemical]

[0383] can form a 1H-benzimidazole ring.

[0384] Usually, R 8 is hydrogen.

[0385] Usually, R 9 is hydrogen; halogen; C 1~3 alkyl or alkoxy. Preferably, R 9 is hydrogen; methyl; chloro or methoxy. More preferably, R 9 is hydrogen.

[0386] Usually, R 10 is hydrogen; halogen; cyano; C which is unsubstituted or substituted by halogen 1~3 alkyl; or alkoxy. Preferably, R 10 is methyl; hydrogen; trifluoromethyl; fluoro; cyano, or methoxy. More preferably, R 10 is hydrogen; trifluoromethyl; fluoro or cyano.

[0387] Usually, R 11 is hydrogen.

[0388] In another preferred embodiment, R 4 , R 4a , and R 5 together with the 2-oxo-1-pyrrolidine ring form the following:

[0389] [Chemical]

[0390] can form a 1,3-dihydro-2H-indol-2-one ring.

[0391] Usually, R 12is hydrogen or halogen. Preferably, R 12 is hydrogen; chloro or fluoro. More preferably, R 12 is hydrogen.

[0392] Generally, R 13 is hydrogen; C 1~3 alkyl; halogen, or unsubstituted or alkyl group-substituted thiazolyl (such as methylthiazolyl). Preferably, R 13 is hydrogen; chloro; bromo or methyl. Most preferably, R 13 is chloro; bromo or methyl.

[0393] Generally, R 14 is hydrogen.

[0394] Generally, R 15 is hydrogen.

[0395] Combinations of one or more of these preferred compound groups are particularly preferred.

[0396] Generally, among the embodiments, the compound of formula I or a pharmaceutically acceptable salt thereof is as follows: R 1 is hydrogen; unsubstituted or C substituted by halogen, hydroxy, cyano, methylthio, phenyl, or 4-chlorophenoxy 1~10 alkyl; C 3~6 cycloalkyl; halogen; ester; amide; nitro; cyano; amino; phenyl; alkylthio; alkylsulfonyl; alkylsulfinyl; unsubstituted or alkyl group-substituted heterocycle; or guanidine, selected from R 2 is hydrogen; unsubstituted or C substituted by hydroxy, alkanoylamino, or benzoylamino 1~4 alkyl; halogen; ester; cyano; alkylcarbamate, or [(N-methoxy-N-methyl)amino]carbonyl, selected from R 3is hydrogen; C which is unsubstituted or substituted by hydroxy 1~4 alkyl; halogen; ester or cyano, selected from R 4 is hydrogen; C which is unsubstituted or substituted by halogen 1~4 alkyl; C substituted by halogen 2~4 alkenyl or phenyl group which is unsubstituted or substituted by azide or / and halogen, selected from R 4a is hydrogen, R 5 is hydrogen, R 6 is hydrogen or C which is unsubstituted or substituted by hydroxy or azide 1~10 alkyl, selected from R 7 is hydrogen, or R 6 and R 7 can combine to form cyclopropyl, or R 2 and R 3 together with the imidazole ring form the following:

[0397]

Chemical formula

[0398] can form the 1H - benzimidazole ring of R 8 is hydrogen, R 9 is hydrogen; halogen; C 1~3 alkyl; alkoxy, selected from R 10 is hydrogen; halogen; cyano or C which is unsubstituted or substituted by halogen 1~3 alkyl; or alkoxy, selected from R 11 is hydrogen, or R 4 、R4a and R 5 together with the 2-oxo-1-pyrrolidine ring form the following:

[0399]

Chemical formula

[0400] can form a 1,3-dihydro-2H-indol-2-one ring of R 12 is selected from hydrogen or halogen, R 13 is hydrogen; C 1~3 alkyl; halogen; thiazolyl (such as methylthiazolyl) which is unsubstituted or substituted by an alkyl group, R 14 is hydrogen, R 15 is hydrogen, provided that

[0401]

Chemical formula

[0402] represents a group of the formula:

[0403]

Chemical formula

[0404] when R 4 is different from hydrogen.

[0405] In a preferred embodiment, the compound of formula I or a pharmaceutically acceptable salt thereof is as follows: R 1is selected from hydrogen; methyl; ethyl; i-propyl; n-propyl; cyclopropyl; n-butyl; i-butyl; t-butyl; 1-ethylpropyl; 2,4,4-trimethylpentyl; trifluoromethyl; 2,2,2-trifluoroethyl; hydroxymethyl; chloromethyl; cyanomethyl; 2-(methylthio)ethyl; chloro; bromo; nitro; cyano; amino; aminocarbonyl; methoxycarbonyl; methylthio; methylsulfinyl; methylsulfonyl; phenyl; 2-furyl; 3-furyl; 1H-pyrrol-2-yl; 1-methyl-1H-pyrrol-2-yl; 2-thienyl; 1H-pyrazol-3-yl; 1,2,3-thiadiazol-4-yl; or 1H-imidazol-2-yl, R 2 is selected from hydrogen; methyl; hydroxymethyl; (acetylamino)methyl; (propionylamino)methyl; (benzoylamino)methyl; (benzyloxycarbonyl)amino; chloro; or cyano, R 3 is selected from hydrogen; hydroxymethyl; chloro; cyano, or R 2 and R 3 together with the imidazole ring are as follows:

[0406]

Chemical formula

[0407] can form a 1H-benzimidazole ring of the following: R 8 is hydrogen, R 9 is selected from hydrogen; methyl; chloro; methoxy, R 10 is selected from methyl; hydrogen; trifluoromethyl; fluoro; cyano; or methoxy, R 11 is hydrogen, R 4is selected from hydrogen; n-propyl; 2,2-difluorovinyl; phenyl; 3-chlorophenyl; 3-fluorophenyl; 4-chlorophenyl; 4-fluorophenyl; 3,5-difluorophenyl; 3,4-difluorophenyl; 3-chloro-4-fluorophenyl; 2,3,4-trifluorophenyl; 2,4,5-trifluorophenyl; 2,3,5-trifluorophenyl; 3,4,5-trifluorophenyl; 3-azido-2,4-difluorophenyl; or 3-azido-2,4,6-trifluorophenyl, R 4a is hydrogen, and R 5 is hydrogen, or R 4 , R 4a , and R 5 together with the 2-oxo-1-pyrrolidine ring form the following:

[0408]

Chemical formula

[0409] can form a 1,3-dihydro-2H-indol-2-one ring of R 12 is selected from hydrogen; chloro; fluoro, R 13 is selected from hydrogen; chloro; bromo; methyl, R 14 is hydrogen, R 15 is hydrogen, R 6 is selected from hydrogen; azidomethyl, R 7 is hydrogen, or R 6 and R 7 are bonded to form cyclopropyl, provided that

[0410]

Chemical formula

[0411] is of the formula:

[0412] [Chemical formula]

[0413] when representing a group of the formula: R 4 is different from hydrogen.

[0414] In a more preferred embodiment, the compound of formula I or a pharmaceutically acceptable salt thereof is as follows: R 1 is selected from hydrogen; methyl; ethyl; i-propyl; n-propyl; n-butyl; methylthio; nitro; cyano; amino; chloro; or 1H-pyrrol-2-yl, R 2 is selected from hydrogen; chloro; cyano, R 3 is selected from hydrogen; cyano, or R 2 and R 3 together with the imidazole ring form the following:

[0415] [Chemical formula]

[0416] can form a 1H-benzimidazole ring of: R 8 is hydrogen, R 9 is hydrogen, R 10 is selected from hydrogen; trifluoromethyl; fluoro; cyano, R 11 is hydrogen, R 4is selected from hydrogen; n-propyl; 2,2-difluorovinyl; phenyl; 3-chlorophenyl; 3-fluorophenyl; 4-chlorophenyl; 4-fluorophenyl; 3,5-difluorophenyl; 3,4-difluorophenyl; 3-chloro-4-fluorophenyl; 2,3,4-trifluorophenyl; 2,4,5-trifluorophenyl; 2,3,5-trifluorophenyl; 3,4,5-trifluorophenyl; or 3-azido-2,4-difluorophenyl, R 4a is hydrogen, R 5 is hydrogen or, R 4 R, 4a and R 5 together with the 2-oxo-1-pyrrolidine ring form the following:

[0417]

Chemical formula

[0418] a 1,3-dihydro-2H-indol-2-one ring of R 12 is hydrogen, R 13 is selected from methyl; chloro; bromo, R 14 is hydrogen, R 15 is hydrogen, R 6 is hydrogen, R 7 is hydrogen, provided that,

[0419]

Chemical formula

[0420] is of the formula:

[0421] [Chemistry]

[0422] When representing the group of R 4 is different from hydrogen.

[0423] In the most preferred embodiment, the compound of formula I or its pharmaceutically acceptable salt is as follows: R 1 is selected from hydrogen; methyl; methylthio; nitro; cyano; amino; chloro, R 2 is selected from hydrogen; chloro; cyano, R 3 is hydrogen, R 4 is selected from n-propyl; 2,2-difluorovinyl; phenyl; 3-chlorophenyl; 3-fluorophenyl; 3,5-difluorophenyl; 2,3,4-trifluorophenyl; 2,4,5-trifluorophenyl; 2,3,5-trifluorophenyl; 3,4,5-trifluorophenyl; 3-azido-2,4-difluorophenyl, R 4a is hydrogen, R 5 is hydrogen, or R 4 , R 4a , and R 5 together with the 2-oxo-1-pyrrolidine ring form the following:

[0424] [Chemistry]

[0425] can form a 1,3-dihydro-2H-indol-2-one ring of R 12 is hydrogen, R 13 is selected from chloro; bromo; methyl, R 14 is hydrogen, R15 is hydrogen, R 6 is hydrogen, R 7 is hydrogen.

[0426] In some embodiments, the compounds useful in the methods and compositions of the present invention are selected from the group consisting of: 1-(1H-imidazol-1-ylmethyl)pyrrolidin-2-one; 1-(1H-imidazol-1-ylmethyl)-4-phenylpyrrolidin-2-one; 4-(3-azido-2,4,6-trifluorophenyl)-1-(1H-imidazol-1-ylmethyl)pyrrolidin-2-one; 1-(1H-imidazol-1-ylmethyl)-4-propylpyrrolidin-2-one; (-)-4-(3-azido-2,4-difluorophenyl)-1-(1H-imidazol-1-ylmethyl)pyrrolidin-2-one; (+)-4-(3-azido-2,4-difluorophenyl)-1-(1H-imidazol-1-ylmethyl)pyrrolidin-2-one; 1-[(2-ethyl-1H-imidazol-1-yl)methyl]-4-propylpyrrolidin-2-one; 1-[(2-isopropyl-1H-imidazol-1-yl)methyl]-4-propylpyrrolidin-2-one; 1-[(2-methyl-1H-imidazol-1-yl)methyl]-4-propylpyrrolidin-2-one; 1-[(2-phenyl-1H-imidazol-1-yl)methyl]-4-propylpyrrolidin-2-one; 4-propyl-1-[(2-propyl-1H-imidazol-1-yl)methyl]pyrrolidin-2-one; (+)-1-(1H-imidazol-1-ylmethyl)-4-propylpyrrolidin-2-one; (-)-1-(1H-imidazol-1-ylmethyl)-4-propylpyrrolidin-2-one; 4-(2,2-difluorovinyl)-1-(1H-imidazol-1-ylmethyl)pyrrolidin-2-one; 4-(3-chlorophenyl)-1-(1H-imidazol-1-ylmethyl)pyrrolidin-2-one; 1-{[2-(methylthio)-1H-imidazol-1-yl]methyl}-4-propylpyrrolidin-2-one; 1-{[2-(methylsulfinyl)-1H-imidazol-1-yl]methyl}-4-propylpyrrolidin-2-one; 1-[(2-tert-butyl-1H-imidazol-1-yl)methyl]-4-propylpyrrolidin-2-one; 1-[1-(1H-imidazol-1-yl)cyclopropyl]pyrrolidin-2-one;1-[(2-Methyl-1H-imidazol-1-yl)methyl]-4-phenylpyrrolidin-2-one; 1-{[2-(Methylsulfonyl)-1H-imidazol-1-yl]methyl}-propylpyrrolidin-2-one; 1-[(2-Oxo-4-propylpyrrolidin-1-yl)methyl]-1H-imidazole-2-carboxamide, 4-(4-Fluorophenyl)-1-(1H-imidazol-1-ylmethyl)pyrrolidin-2-one; 1-(1H-imidazol-1-ylmethyl)-4-(3,4,5-trifluorophenyl)pyrrolidin-2-one; 4-(3-Fluorophenyl)-1-(1H-imidazol-1-ylmethyl)pyrrolidin-2-one; 4-(3,5-Difluorophenyl)-1-(1H-imidazol-1-ylmethyl)pyrrolidin-2-one; 4-(3,4-Difluorophenyl)-1-(1H-imidazol-1-ylmethyl)pyrrolidin-2-one; 4-(3-Chloro-4-fluorophenyl)-1-(1H-imidazol-1-ylmethyl)pyrrolidin-2-one; 4-(4-Chlorophenyl)-1-(1H-imidazol-1-ylmethyl)pyrrolidin-2-one; 1-(1H-imidazol-1-ylmethyl)-4-(2,3,4-trifluorophenyl)pyrrolidin-2-one; 1-(1H-imidazol-1-ylmethyl)-4-(2,3,5-trifluorophenyl)pyrrolidin-2-one; 1-(1H-imidazol-1-ylmethyl)-4-(2,4,5-trifluorophenyl)pyrrolidin-2-one; 1-{[2-(Hydroxymethyl)-1H-imidazol-1-yl]methyl}-4-propylpyrrolidin-2-one; 1-[(2-Oxo-4-propylpyrrolidin-1-yl)methyl]-1H-imidazole-2-carboxylic acid methyl; 1-[(2-Nitro-1H-imidazol-1-yl)methyl]-4-(3,4,5-trifluorophenyl)pyrrolidin-2-one; 1-{[2-Oxo-4-(3,4,5-trifluorophenyl)pyrrolidin-1-yl]methyl}-1H-imidazole-2-carbonitrile; 1-[(2-Amino-1H-imidazol-1-yl)methyl]-4-propylpyrrolidin-2-one; 1-[(2,4-Dichloro-1H-imidazol-1-yl)methyl]-4-(3,4,5-trifluorophenyl)pyrrolidin-2-one;1-[(5-Chloro-1H-imidazol-1-yl)methyl]-4-(3,4,5-trifluorophenyl)pyrrolidin-2-one; 1-{[2-oxo-4-(3,4,5-trifluorophenyl)pyrrolidin-1-yl]methyl}-1H-imidazole-4-carbonitrile; 1-{[2-oxo-4-(3,4,5-trifluorophenyl)pyrrolidin-1-yl]methyl}-1H-imidazole-5-carbonitrile; (+)-1-(1H-imidazol-1-ylmethyl)-4-phenylpyrrolidin-2-one; (-)-1-(1H-imidazol-1-ylmethyl)-4-phenylpyrrolidin-2-one; 1-{[2-oxo-4-(2,3,5-trifluorophenyl)pyrrolidin-1-yl]methyl}-1H-imidazole-5-carbonitrile; (-)-1-{[2-oxo-4-(2,3,4-trifluorophenyl)pyrrolidin-1-yl]methyl}-1H-imidazole-5-carbonitrile; (+)-1-{[2-oxo-4-(2,3,4-trifluorophenyl)pyrrolidin-1-yl]methyl}-1H-imidazole-5-carbonitrile; (-)-1-{[2-oxo-4-(2,3,4-trifluorophenyl)pyrrolidin-1-yl]methyl}-1H-imidazole-4-carbonitrile; (+)-1-{[2-oxo-4-(2,3,4-trifluorophenyl)-1-pyrrolidinyl]methyl}-1H-imidazole-4-carbonitrile; (-)-1-{[2-oxo-4-(3,4,5-trifluorophenyl)pyrrolidin-1-yl]methyl}-1H-imidazole-4-carbonitrile; (+)-1-{[2-oxo-4-(3,4,5-trifluorophenyl)pyrrolidin-1-yl]methyl}-1H-imidazole-4-carbonitrile; (+)-1-{[2-oxo-4-(2,4,5-trifluorophenyl)pyrrolidin-1-yl]methyl}-1H-imidazole-4-carbonitrile; (-)-1-{[2-oxo-4-(2,4,5-trifluorophenyl)pyrrolidin-1-yl]methyl}-1H-imidazole-4-carbonitrile; (-)-1-{[2-oxo-4-(2,3,5-trifluorophenyl)pyrrolidin-1-yl]methyl}-1H-imidazole-4-carbonitrile;(-)-1-{[2-Oxo-4-(3,4,5-trifluorophenyl)pyrrolidin-1-yl]methyl}-1H-imidazole-5-carbonitrile; 1-{[2-Oxo-4-(2,3,5-trifluorophenyl)pyrrolidin-1-yl]methyl}-1H-imidazole-5--carbonitrile; 1-{[2-Oxo-4-(2,3,5-trifluorophenyl)pyrrolidin-1-yl]methyl}-1H-imidazole-5--carbonitrile; 1-[(5-Methyl-2-phenyl-1H-imidazol-1-yl)methyl]-4-propylpyrrolidin-2-one; 1-[(5-Methyl-1H-imidazol-1-yl)methyl]-4-propylpyrrolidin-2-one; 1-[(5-Phenyl-1H-imidazol-1-yl)methyl]-4-propylpyrrolidin-2-one; 1-[(2-Ethyl-5-methyl-1H-imidazol-1-yl)methyl]-4-propylpyrrolidin-2-one; 1-[(2,5-Dimethyl-1H-imidazol-1-yl)methyl]-4-propylpyrrolidin-2-one; 1-[(2-Chloro-1H-imidazol-1-yl)methyl]-4-(3,4,5-trifluorophenyl)pyrrolidin--2-one; 1-[2-Azido-1-(1H-imidazol-1-yl)ethyl]-4-propylpyrrolidin-2-one; 1-[(4-Chloro-1H-imidazol-1-yl)methyl]-4-(3,4,5-trifluorophenyl)pyrrolidin--2-one; 1-[(2-Bromo-4,5-dichloro-1H-imidazol-1-yl)methyl]-4-propylpyrrolidin-2-one; 1-[(2-Chloro-1H-imidazol-1-yl)methyl]-4-propylpyrrolidin-2-one; (+)-1-{[2-Oxo-4-(3,4,5-trifluorophenyl)pyrrolidin-1-yl]methyl}-1H-imidazole-5-carbonitrile; 1-{[5-(Hydroxymethyl)-1H-imidazol-1-yl]methyl}-4-propylpyrrolidin-2-one; 1-{[4-(Hydroxymethyl)-1H-imidazol-1-yl]methyl}-4-propylpyrrolidin-2-one; 1-[(2-Oxo-4-propylpyrrolidin-1-yl)methyl]-1H-imidazole-5-ylcarbamic acid benzyl;N-[(1-{[2-Oxo-4-(3,4,5-trifluorophenyl)pyrrolidin-1-yl]methyl}-1H-imidazol-5-yl)methyl]acetamide; N-[(1-{[2-Oxo-4-(3,4,5-trifluorophenyl)pyrrolidin-1-yl]methyl}-1H-imidazol-5-yl)methyl]benzamide; N-[(1-{[2-Oxo-4-(3,4,5-trifluorophenyl)pyrrolidin-1-yl]methyl}-1H-imidazol-5-yl)methyl]propanamide; 1-(1H-Benzimidazol-1-ylmethyl)-4-propylpyrrolidin-2-one; 1-[(2-Methyl-1H-benzimidazol-1-yl)methyl]-4-propylpyrrolidin-2-one; 4-Propyl-1-[(2-propyl-1H-benzimidazol-1-yl)methyl]pyrrolidin-2-one; 1-[(2-Isopropyl-1H-benzimidazol-1-yl)methyl]-4-propylpyrrolidin-2-one; 4-Propyl-1-{[2-(trifluoromethyl)-1H-benzimidazol-1-yl]methyl}pyrrolidin-2-one; 1-{[2-(Methylthio)-1H-benzimidazol-1-yl]methyl}-4-propylpyrrolidin-2-one; 1-[(2-Amino-1H-benzimidazol-1-yl)methyl]-4-propylpyrrolidin-2-one; 1-{[2-(Chloromethyl)-1H-benzimidazol-1-yl]methyl}-4-propylpyrrolidin-2-one; {1-[(2-Oxo-4-propylpyrrolidin-1-yl)methyl]-1H-benzimidazol-2-yl}acetonitrile; 1-[(5-Methoxy-1H-benzimidazol-1-yl)methyl]-4-propylpyrrolidin-2-one; 1-[(5-Methyl-1H-benzimidazol-1-yl)methyl]-4-propylpyrrolidin-2-one; 1-[(5,6-Dimethyl-1H-benzimidazol-1-yl)methyl]-4-propylpyrrolidin-2-one; 1-{[2-Isopropyl-5-(trifluoromethyl)-1H-benzimidazol-1-yl]methyl}-4-propylpyrrolidin-2-one; 1-[(6-Chloro-1H-benzimidazol-1-yl)methyl]-4-propylpyrrolidin-2-one;1-[(2-Oxo-4-propylpyrrolidin-1-yl)methyl]-2-propyl-1H-benzimidazole-5-carbonitrile; 1-{[2-Ethyl-5-(trifluoromethyl)-1H-benzimidazol-1-yl]methyl}-4-propylpyrrolidin-2-one; 4-Propyl-1-{[2-(1H-pyrrol-2-yl)-1H-benzimidazol-1-yl]methyl}pyrrolidin-2-one; 1-[(5-Fluoro-2-propyl-1H-benzimidazol-1-yl)methyl]-4-propylpyrrolidine-; 2-One; 1-{[6-Methyl-2-(1H-pyrrol-2-yl)-1H-benzimidazol-1-yl]methyl}-4-propylpyrrolidin-2-one; 1-[(6-Methoxy-2-propyl-1H-benzimidazol-1-yl)methyl]-4-propylpyrrolidin-2-one; 2-Butyl-1-[(2-oxo-4-propylpyrrolidin-1-yl)methyl]-1H-benzimidazole-5-carbonitrile; 1-{[2-[2-(Methylthio)ethyl]-5-(trifluoromethyl)-1H-benzimidazol-1-yl]methyl}-4-propylpyrrolidin-2-one; 1-[(5-Fluoro-2-isobutyl-1H-benzimidazol-1-yl)methyl]-4-propylpyrrolidin-2-one; 1-{[5-Fluoro-2-(2,4,4-trimethylpentyl)-1H-benzimidazol-1-yl]methyl}-4-propylpyrrolidin-2-one; 2-Cyclopropyl-1-[(2-oxo-4-propylpyrrolidin-1-yl)methyl]-1H-benzimidazole-5-carbonitrile; 1-[(2-oxo-4-propylpyrrolidin-1-yl)methyl]-2-(1H-pyrazol-3-yl)-1H-benzimidazole-5-carbonitrile; 1-[(2-Cyclopropyl-5-fluoro-1H-benzimidazol-1-yl)methyl]-4-propylpyrrolidin-2-one; 1-[(5-Fluoro-2-isopropyl-1H-benzimidazol-1-yl)methyl]-4-propylpyrrolidin-2-one; 1-{[2-(3-Furyl)-6-methoxy-1H-benzimidazol-1-yl]methyl}-4-propylpyrrolidin-2-one; 1-[(2-Cyclopropyl-6-methoxy-1H-benzimidazol-1-yl)methyl]-4-propylpyrrolidin-2-one; 1-[(2-Isopropyl-6-methoxy-1H-benzimidazol-1-yl)methyl]-4-propylpyrrolidin-2-one; 1-[(2-oxo-4-propylpyrrolidin-1-yl)methyl]-2-(1,2,3-thiadiazol-4-yl)-1H-benzimidazole-5-carbonitrile; 1-{[2-(1H-imidazol-2-yl)-5-(trifluoromethyl)-1H-benzimidazol-1-yl]methyl}-4-propylpyrrolidin-2-one;1-{[5-Fluoro-2-(2,2,2-trifluoroethyl)-1H-benzoimidazol-1-yl]methyl}-4-propylpyrrolidin-2-one; 1-{[2-(1-ethylpropyl)-6-methoxy-1H-benzoimidazol-1-yl]methyl}-4-propylpyrrolidin-2-one; 1-{[6-methoxy-2-(1-methyl-1H-pyrrol-2-yl)-1H-benzoimidazol-1-yl]methyl}-4-propylpyrrolidin-2-one; 1-{[2-(2-furyl)-5-(trifluoromethyl)-1H-benzoimidazol-1-yl]methyl}-4-propylpyrrolidin-2-one; 4-propyl-1-{[2-thien-2-yl-5-(trifluoromethyl)-1H-benzoimidazol-1-yl]methyl}pyrrolidin-2-one; 1-{[2-(3-furyl)-5-(trifluoromethyl)-1H-benzoimidazol-1-yl]methyl}-4-propylpyrrolidin-2-one; 1-{[2-cyclopropyl-5-(trifluoromethyl)-1H-benzoimidazol-1-yl]methyl}-4-propylpyrrolidin-2-one; 4-propyl-1-{[2-(1H-pyrrol-2-yl)-5-(trifluoromethyl)-1H-benzoimidazol-1-yl]methyl}pyrrolidin-2-one; 1-(1H-imidazol-1-ylmethyl)-1,3-dihydro-2H-indol-2-one; 5-bromo-1-(1H-imidazol-1-ylmethyl)-1,3-dihydro-2H-indol-2-one; 5-chloro-1-(1H-imidazol-1-ylmethyl)-1,3-dihydro-2H-indol-2-one; 4-fluoro-1-(1H-imidazol-1-ylmethyl)-1,3-dihydro-2H-indol-2-one; 4-chloro-1-(1H-imidazol-1-ylmethyl)-1,3-dihydro-2H-indol-2-one; 1-(1H-imidazol-1-ylmethyl)-5-methyl-1,3-dihydro-2H-indol-2-one; 1-[(2-oxo-2,3-dihydro-1H-indol-1-yl)methyl]-1H-imidazole-5-carbonitrile; and 1-[(5-chloro-2-oxo-2,3-dihydro-1H-indol-1-yl)methyl]-1H-imidazole-5-carbonitrile.;

[0427] In some embodiments, the compounds useful in the methods and compositions of the present invention are selected from the group consisting of: 1-(1H-imidazol-1-ylmethyl)pyrrolidin-2-one, 1-(1H-imidazol-1-ylmethyl)-4-phenylpyrrolidin-2-one; 1-(1H-imidazol-1-ylmethyl)-4-propylpyrrolidin-2-one; (-)-4-(3-azido-2,4-difluorophenyl)-1-(1H-imidazol-1-ylmethyl)pyrrolidin-2-one; (+)-4-(3-azido-2,4-difluorophenyl)-1-(1H-imidazol-1-ylmethyl)pyrrolidin-2-one; 1-[(2-ethyl-1H-imidazol-1-yl)methyl]-4-propylpyrrolidin-2-one; 1-[(2-isopropyl-1H-imidazol-1-yl)methyl]-4-propylpyrrolidin-2-one; 1-[(2-methyl-1H-imidazol-1-yl)methyl]-4-propylpyrrolidin-2-one; 4-propyl-1-[(2-propyl-1H-imidazol-1-yl)methyl]pyrrolidin-2-one; (+)-1-(1H-imidazol-1-ylmethyl)-4-propylpyrrolidin-2-one; (-)-1-(1H-imidazol-1-ylmethyl)-4-propylpyrrolidin-2-one; 4-(2,2-difluorovinyl)-1-(1H-imidazol-1-ylmethyl)pyrrolidin-2-one; 4-(3-chlorophenyl)-1-(1H-imidazol-1-ylmethyl)pyrrolidin-2-one; 1-{[2-(methylthio)-1H-imidazol-1-yl]methyl}-4-propylpyrrolidin-2-one; 1-[(2-methyl-1H-imidazol-1-yl)methyl]-4-phenylpyrrolidin-2-one; 4-(4-fluorophenyl)-1-(1H-imidazol-1-ylmethyl)pyrrolidin-2-one; 1-(1H-imidazol-1-ylmethyl)-4-(3,4,5-trifluorophenyl)pyrrolidin-2-one; 4-(3-fluorophenyl)-1-(1H-imidazol-1-ylmethyl)pyrrolidin-2-one; 4-(3,5-difluorophenyl)-1-(1H-imidazol-1-ylmethyl)pyrrolidin-2-one; 4-(3,4-difluorophenyl)-1-(1H-imidazol-1-ylmethyl)pyrrolidin-2-one;4-(3-chloro-4-fluorophenyl)-1-(1H-imidazol-1-ylmethyl)pyrrolidin-2-one; 4-(4-chlorophenyl)-1-(1H-imidazol-1-ylmethyl)pyrrolidin-2-one; 1-(1H-imidazol-1-ylmethyl)-4-(2,3,4-trifluorophenyl)pyrrolidin-2-one; 1-(1H-imidazol-1-ylmethyl)-4-(2,3,5-trifluorophenyl)pyrrolidin-2-one; 1-(1H-imidazol-1-ylmethyl)-4-(2,4,5-trifluorophenyl)pyrrolidin-2-one; 1-[(2-nitro-1H-imidazol-1-yl)methyl]-4-(3,4,5-trifluorophenyl)pyrrolidin-2-one; 1-{[2-oxo-4-(3,4,5-trifluorophenyl)pyrrolidin-1-yl]methyl}-1H-imidazole-2-carbonitrile; 1-[(2-amino-1H-imidazol-1-yl)methyl]-4-propylpyrrolidin-2-one; 1-[(5-chloro-1H-imidazol-1-yl)methyl]-4-(3,4,5-trifluorophenyl)pyrrolidin-2-one; 1-{[2-oxo-4-(3,4,5-trifluorophenyl)pyrrolidin-1-yl]methyl}-1H-imidazole-4-carbonitrile; 1-{[2-oxo-4-(3,4,5-trifluorophenyl)pyrrolidin-1-yl]methyl}-1H-imidazole-5-carbonitrile; (+)-1-(1H-imidazol-1-ylmethyl)-4-phenylpyrrolidin-2-one; (-)-1-(1H-imidazol-1-ylmethyl)-4-phenylpyrrolidin-2-one; (+); 1-{[2-oxo-4-(3,4,5-trifluorophenyl)pyrrolidin-1-yl]methyl}-1H-imidazole-4-carbonitrile; 1-[(2-chloro-1H-imidazol-1-yl)methyl]-4-(3,4,5-trifluorophenyl)pyrrolidin-2-one; 1-[2-azido-1-(1H-imidazol-1-yl)ethyl]-4-propylpyrrolidin-2-one; 1-[(2-chloro-1H-imidazol-1-yl)methyl]-4-propylpyrrolidin-2-one;(+)-1-{[2-Oxo-4-(3,4,5-trifluorophenyl)pyrrolidin-1-yl]methyl}-1H-imidazole-5-carbonitrile; 1-[(2-Oxo-4-propylpyrrolidin-1-yl)methyl]-2-propyl-1H-benzimidazole-5-carbonitrile; 1-{[2-Ethyl-5-(trifluoromethyl)-1H-benzimidazol-1-yl]methyl}-4-propylpyrrolidin-2-one; 4-Propyl-1-{[2-(1H-pyrrol-2-yl)-1H-benzimidazol-1-yl]methyl}pyrrolidin-2-one; 1-[(5-Fluoro-2-propyl-1H-benzimidazol-1-yl)methyl]-4-propylpyrrolidin-2-one; 2-Butyl-1-[(2-oxo-4-propylpyrrolidin-1-yl)methyl]-1H-benzimidazole-5-carbonitrile; 1-[(5-Fluoro-2-isopropyl-1H-benzimidazol-1-yl)methyl]-4-propylpyrrolidin-2-one; 1-(1H-Imidazol-1-ylmethyl)-1,3-dihydro-2H-indol-2-one; 5-Bromo-1-(1H-imidazol-1-ylmethyl)-1,3-dihydro-2H-indol-2-one; 5-Chloro-1-(1H-imidazol-1-ylmethyl)-1,3-dihydro-2H-indol-2-one; 1-(1H-Imidazol-1-ylmethyl)-5-methyl-1,3-dihydro-2H-indol-2-one; 1-[(5-Chloro-2-oxo-2,3-dihydro-1H-indol-1-yl)methyl]-1H-imidazole-5-carbonitrile.;

[0428] In some embodiments, the compounds useful in the methods and compositions of the invention are selected from the group consisting of: 1-(1H-imidazol-1-ylmethyl)-4-phenylpyrrolidin-2-one; 1-(1H-imidazol-1-ylmethyl)-4-propylpyrrolidin-2-one; (-)-4-(3-azido-2,4-difluorophenyl)-1-(1H-imidazol-1-ylmethyl)pyrrolidin-2-one; (+)-4-(3-azido-2,4-difluorophenyl)-1-(1H-imidazol-1-ylmethyl)pyrrolidin-2-one; 4-(2,2-difluorovinyl)-1-(1H-imidazol-1-ylmethyl)pyrrolidin-2-one; 4-(3-chlorophenyl)-1-(1H-imidazol-1-ylmethyl)pyrrolidin-2-one; 1-{[2-(methylthio)-1H-imidazol-1-yl]methyl}-4-propylpyrrolidin-2-one; 1-[(2-methyl-1H-imidazol-1-yl)methyl]-4-phenylpyrrolidin-2-one; 1-(1H-imidazol-1-ylmethyl)-4-(3,4,5-trifluorophenyl)pyrrolidin-2-one; 4-(3-fluorophenyl)-1-(1H-imidazol-1-ylmethyl)pyrrolidin-2-one; 4-(3,5-difluorophenyl)-1-(1H-imidazol-1-ylmethyl)pyrrolidin-2-one; 1-(1H-imidazol-1-ylmethyl)-4-(2,3,4-trifluorophenyl)pyrrolidin-2-one; 1-(1H-imidazol-1-ylmethyl)-4-(2,3,5-trifluorophenyl)pyrrolidin-2-one; 1-(1H-imidazol-1-ylmethyl)-4-(2,4,5-trifluorophenyl)pyrrolidin-2-one; 1-[(2-nitro-1H-imidazol-1-yl)methyl]-4-(3,4,5-trifluorophenyl)pyrrolidin-2-one; 1-{[2-oxo-4-(3,4,5-trifluorophenyl)pyrrolidin-1-yl]methyl}-1H-imidazole-2-carbonitrile; 1-[(2-amino-1H-imidazol-1-yl)methyl]-4-propylpyrrolidin-2-one; 1-[(5-chloro-1H-imidazol-1-yl)methyl]-4-(3,4,5-trifluorophenyl)pyrrolidin-2-one;(+)-1-(1H-Imidazol-1-ylmethyl)-4-phenylpyrrolidin-2-one; (-)-1-(1H-Imidazol-1-ylmethyl)-4-phenylpyrrolidin-2-one; 1-[(2-Chloro-1H-imidazol-1-yl)methyl]-4-(3,4,5-trifluorophenyl)pyrrolidin-2-one; 1-[(2-Chloro-1H-imidazol-1-yl)methyl]-4-propylpyrrolidin-2-one; (+)-1-{[2-Oxo-4-(3,4,5-trifluorophenyl)pyrrolidin-1-yl]methyl}-1H-imidazole-5-carbonitrile; 5-Bromo-1-(1H-imidazol-1-ylmethyl)-1,3-dihydro-2H-indol-2-one; 5-Chloro-1-(1H-imidazol-1-ylmethyl)-1,3-dihydro-2H-indol-2-one; 1-(1H-imidazol-1-ylmethyl)-5-methyl-1,3-dihydro-2H-indol-2-one; 1-[(5-Chloro-2-oxo-2,3-dihydro-1H-indol-1-yl)methyl]-1H-imidazole-5-carbonitrile.;

[0429] In some embodiments, the compounds useful in the methods and compositions of the invention are selected from the group consisting of: (-)-4-(3-Azido-2,4-difluorophenyl)-1-(1H-imidazol-1-ylmethyl)pyrrolidin-2-one; (+)-4-(3-Azido-2,4-difluorophenyl)-1-(1H-imidazol-1-ylmethyl)pyrrolidin-2-one; 4-(3-Azido-2,4-difluorophenyl)-1-(1H-imidazol-1-ylmethyl)pyrrolidin-2-one.

[0430] v) International Patent Application No. WO2007 / 065595: Formula I:

[0431] [Chemical formula]

[0432] (wherein, R 1 is hydrogen or C1~6 is alkyl, R 2 is hydrogen or C 1~4 alkyl, R 3 is a group of the formula -CHR 5 R 6 or a benzyl group, R 4 is C alkyl optionally substituted by alkoxycarbonyl, C3-6 cycloalkyl, aryl, or heterocycle, 1~8 alkyl, R 5 is C2-4 alkyl, R 6 is C2-4 alkyl, amide, or -COOR 7 and R 7 is C1-4 alkyl), and enantiomers, diastereomers, and mixtures thereof (including all possible mixtures of stereoisomers), or a pharmaceutically acceptable salt thereof.

[0433] Generally, when R 3 is a benzyl group, R 4 is C alkyl optionally substituted by alkoxycarbonyl. 1~8

[0434] Generally, when R 3 is a group of the formula -CHR 5 R 6 R 4 is C 3~6 alkyl optionally substituted by cycloalkyl, aryl, or heterocycle. 1~8

[0435] ​​As used herein, the term "alkyl" refers to a monovalent saturated hydrocarbon group having a straight-chain (unbranched), branched portion, or a combination thereof, and containing 1 to 8 carbon atoms, preferably 1 to 6 carbon atoms, and more preferably the alkyl group has 1 to 4 carbon atoms. The alkyl moiety can be optionally substituted with 1 to 5 substituents independently selected from the group consisting of hydroxy, alkoxy, cyano, ethynyl, alkoxycarbonyl, acyl, aryl, or heterocycle. The alkyl moiety can be optionally substituted with cycloalkyl as defined below. Preferred alkyl groups are methyl, cyanomethyl, ethyl, 2-ethoxy-2-oxoethyl, 2-methoxyethyl, n-propyl, 2-oxopropyl, 3-hydroxypropyl, 2-propynyl, n-butyl, i-butyl, n-pentyl, 3-pentyl, n-hexyl, cyclohexylmethyl, benzyl, 2-bromobenzyl, 3-bromobenzyl, 4-bromobenzyl, 3-methoxybenzyl, 3-nitrobenzyl, 3-aminobenzyl, 4-(aminosulfonyl)benzyl, 1-phenylethyl, 2-phenylethyl, (3,5-dimethylisoxazol-4-yl)methyl, or (5-nitro-2-furyl)methyl. More preferred alkyl groups are methyl, ethyl, cyanomethyl, 2-methoxyethyl, n-propyl, 3-hydroxypropyl, 2-propynyl, n-butyl, 3-pentyl, n-hexyl, benzyl, 3-bromobenzyl, 3-methoxybenzyl, 3-nitrobenzyl, 3-aminobenzyl, (3,5-dimethylisoxazol-4-yl)methyl, or (5-nitro-2-furyl)methyl. Most preferred alkyl groups are methyl, ethyl, 3-methoxybenzyl, 3-nitrobenzyl, or (5-nitro-2-furyl)methyl.

[0436] As used herein, the term "cycloalkyl" refers to a monovalent group of 3 to 8, preferably 3 to 6 carbon atoms, derived from a saturated cyclic hydrocarbon that can be substituted with any suitable group (including, but not limited to, one or more moieties selected from the above groups for alkyl groups). A preferred cycloalkyl group is cyclohexyl.

[0437] When the term "aryl" is used herein, it is defined as a phenyl group optionally substituted by 1 to 4 substituents independently selected from halogen, amino, nitro, alkoxy, or aminosulfonyl. Preferred aryl groups are phenyl, 2-bromophenyl, 3-bromophenyl, 4-bromophenyl, 3-methoxyphenyl, 3-nitrophenyl, 3-aminophenyl, or 4-(aminosulfonyl)phenyl.

[0438] When the term "phenyl" is used herein, it refers to an aromatic hydrocarbon group of the formula -C6H5.

[0439] When the term "benzyl group" is used herein, it represents a group of the formula -CH2-aryl. Preferred benzyl groups are benzyl, 2-bromobenzyl, 3-bromobenzyl, 4-bromobenzyl, 3-methoxybenzyl, 3-nitrobenzyl, 3-aminobenzyl, or 4-(aminosulfonyl)benzyl. More preferred benzyl groups are benzyl, 3-bromobenzyl, 3-methoxybenzyl, 3-nitrobenzyl, or 3-aminobenzyl. Most preferred alkyl groups are 3-methoxybenzyl or 3-nitrobenzyl.

[0440] When the term "halogen" is used herein, it refers to a fluorine atom, a chlorine atom, a bromine atom, or an iodine atom. Preferred halogen is bromine.

[0441] When the term "hydroxy" is used herein, it represents a group of the formula -OH.

[0442] When the term "cyano" is used herein, it represents a group of the formula -CN.

[0443] When the term "amino" is used herein, it represents a group of the formula -NH2.

[0444] When the term "ethynyl" is used herein, it represents a group of the formula -C≡CH.

[0445] The term "alkoxy", as used herein, refers to the group of the formula -OR a (wherein R a is an alkyl group as defined above). A preferred alkoxy group is methoxy.

[0446] The term "nitro", as used herein, refers to the group of the formula -NO2.

[0447] The term "amide", as used herein, refers to the group of the formula -C(=O)NH2.

[0448] The term "acyl", as used herein, refers to the group of the formula -C(=O)R b (wherein R b is an alkyl group as defined above). A preferred acyl group is acetyl (-C(=O)Me).

[0449] The term "alkoxycarbonyl (or ester)", as used herein, refers to the group of the formula -COOR c (wherein R c is an alkyl group, provided that R c does not represent an alkyl that is α-substituted by hydroxy). A preferred alkoxycarbonyl group is ethoxycarbonyl.

[0450] The term "heterocycle", as used herein, refers to a 5-membered ring containing one or two heteroatoms selected from O or N. The heterocycle can be substituted by one or two C 1~4 alkyl or nitro. Preferred heterocycles are (3,5-dimethylisoxazol-4-yl) or (5-nitro-2-furyl). The most preferred heterocycle is (5-nitro-2-furyl).

[0451] Generally, R 1 is hydrogen or C 1~6 alkyl. Usually, R 1is C optionally substituted by hydrogen, hydroxy, alkoxy, cyano, ethynyl, alkoxycarbonyl, or acyl 1~6 alkyl. Preferably, R 1 is hydrogen, methyl, cyanomethyl, 2-ethoxy-2-oxoethyl, 2-methoxyethyl, n-propyl, 2-oxopropyl, 3-hydroxypropyl, 2-propynyl, n-pentyl, or n-hexyl. More preferably, R 1 is hydrogen, methyl, cyanomethyl, 2-methoxyethyl, n-propyl, 3-hydroxypropyl, or 2-propynyl. Most preferably, R 1 is hydrogen.

[0452] Generally, R 2 is hydrogen or C 1~4 alkyl. Usually, R 2 is hydrogen or unsubstituted C 1~4 alkyl. Preferably, R 2 is hydrogen, methyl, or n-butyl. More preferably, R 2 is methyl.

[0453] Generally, R 3 is a group of the formula -CHR 5 R 6 or a benzyl group. Preferably, R 3 is 3-pentyl, 1-(aminocarbonyl)propyl, 1-(ethoxycarbonyl)propyl, or 3-bromobenzyl. Most preferably, R 3 is 1-(ethoxycarbonyl)propyl.

[0454] Generally, R 4 is alkoxycarbonyl, C 3~6 cycloalkyl, aryl, or C optionally substituted by heterocycle 1~8 alkyl. Usually, R 4is C optionally substituted by cyclohexyl, phenyl, bromophenyl, aminophenyl, methoxyphenyl, nitrophenyl, aminosulfonylphenyl, 3,5-dimethylisoxazol-4-yl, 5-nitro-2-furyl, or ethoxycarbonyl 1~8 alkyl. Preferably, R 4 is n-butyl, i-butyl, n-pentyl, n-hexyl, cyclohexylmethyl, benzyl, 2-bromobenzyl, 3-bromobenzyl, 4-bromobenzyl, 3-methoxybenzyl, 3-nitrobenzyl, 3-aminobenzyl, 4-(aminosulfonyl)benzyl, 1-phenylethyl, 2-phenylethyl, (3,5-dimethylisoxazol-4-yl)methyl, (5-nitro-2-furyl)methyl, or 1-(ethoxycarbonyl)propyl. More preferably, R 4 is n-butyl, n-hexyl, benzyl, 3-bromobenzyl, 3-methoxybenzyl, 3-nitrobenzyl, 3-aminobenzyl, (3,5-dimethylisoxazol-4-yl)methyl, (5-nitro-2-furyl)methyl, or 1-(ethoxycarbonyl)propyl. Most preferably, R 4 is 3-methoxybenzyl, 3-nitrobenzyl, or (5-nitro-2-furyl)methyl.

[0455] Generally, R 5 is C 2~4 alkyl. Usually, R 5 is unsubstituted C 2~4 4 alkyl. Preferably, R 5 is ethyl.

[0456] Generally, R 6 is C 2~4 alkyl, amide, or -COOR 7 . Usually, R 6 is unsubstituted C 2~4 alkyl, amide, or -COOR 7 . Preferably, R 6 is ethyl, amide, or ethoxycarbonyl. Most preferably, R 6is ethoxycarbonyl.

[0457] Generally, R 7 is C 1~4 alkyl. Usually, R 7 is unsubstituted C 1~4 alkyl. Preferably, R 7 is ethyl.

[0458] In some embodiments, the compound is of formula I:

[0459]

Chemical formula

[0460] (wherein, R 1 is C 1~6 alkyl optionally substituted by hydrogen, hydroxy, alkoxy, cyano, ethynyl, alkoxycarbonyl, or acyl, R 2 is hydrogen or unsubstituted C 1~4 alkyl, R 3 is a group of formula -CHR 5 R 6 or a benzyl group, R 4 is C 1~8 alkyl optionally substituted by cyclohexyl, phenyl, bromophenyl, aminophenyl, methoxyphenyl, nitrophenyl, aminosulfonylphenyl, 3,5-dimethylisoxazol-4-yl, 5-nitro-2-furyl, or ethoxycarbonyl, R 5 is unsubstituted C 2~4 alkyl, R 6 is unsubstituted C 2~4 alkyl, amide, or -COOR 7 and R 7 is unsubstituted C 1~4 alkyl, provided that R 1 is hydrogen and R2 is methyl, and R 3 is -CHR 5 R 6 is, and R 6 is ethoxycarbonyl, and R 5 is ethyl, then R 4 is a compound having (different from n-propyl, i-propyl, n-pentyl, n-heptyl, 3-bromobenzyl, 4-chlorobenzyl, 4-methylbenzyl, or 2-phenylethyl), its enantiomers, diastereomers, and mixtures thereof (including all possible mixtures of stereoisomers), or a pharmaceutically acceptable salt thereof.

[0461] In the above embodiment, preferably, when R 3 is a benzyl group, R 4 is C 1~8 alkyl optionally substituted by alkoxycarbonyl.

[0462] In the above embodiment, preferably, when R 3 is a group of the formula -CHR 5 R 6 then R 4 is C 3~6 alkyl optionally substituted by cycloalkyl, aryl, or heterocycle. 1~8 is alkyl.

[0463] In a preferred embodiment, R 1 is hydrogen, methyl, cyanomethyl, 2-ethoxy-2-oxoethyl, 2-methoxyethyl, n-propyl, 2-oxopropyl, 3-hydroxypropyl, 2-propynyl, n-pentyl, or n-hexyl, R 2 is hydrogen, methyl, or n-butyl, R 3 is 3-pentyl, 1-(aminocarbonyl)propyl, 1-(ethoxycarbonyl)propyl, or 3-bromobenzyl, R 4is n-butyl, i-butyl, n-pentyl, n-hexyl, cyclohexylmethyl, benzyl, 2-bromobenzyl, 3-bromobenzyl, 4-bromobenzyl, 3-methoxybenzyl, 3-nitrobenzyl, 3-aminobenzyl, 4-(aminosulfonyl)benzyl, 1-phenylethyl, 2-phenylethyl, (3,5-dimethylisoxazol-4-yl)methyl, (5-nitro-2-furyl)methyl, or 1-(ethoxycarbonyl)propyl, provided that R 1 is hydrogen, R 2 is methyl, and R 3 is 1-(ethoxycarbonyl)propyl, then R 4 is different from n-pentyl, 3-bromobenzyl, or 2-phenylethyl.

[0464] In the above embodiment, preferably, when R 3 is 3-bromobenzyl, R 4 is C 1~8 alkyl optionally substituted by alkoxycarbonyl.

[0465] In the above embodiment, preferably, when R 3 is 3-pentyl, 1-(aminocarbonyl)propyl, or 1-(ethoxycarbonyl)propyl, R 4 is different from 1-(ethoxycarbonyl)propyl.

[0466] In a more preferred embodiment, R 1 is hydrogen, methyl, cyanomethyl, 2-methoxyethyl, n-propyl, 3-hydroxypropyl, or 2-propynyl, R 2 is methyl, R 3 is 3-pentyl, 1-(aminocarbonyl)propyl, 1-(ethoxycarbonyl)propyl, or 3-bromobenzyl, R 4is n-butyl, n-hexyl, benzyl, 3-bromobenzyl, 3-methoxybenzyl, 3-nitrobenzyl, 3-aminobenzyl, (3,5-dimethylisoxazol-4-yl)methyl, (5-nitro-2-furyl)methyl, or 1-(ethoxycarbonyl)propyl, provided that R 1 is hydrogen, R 2 is methyl, and R 3 is 1-(ethoxycarbonyl)propyl, R 4 is different from 3-bromobenzyl.

[0467] In the above embodiment, preferably, when R 3 is 3-bromobenzyl, R 4 is 1-(ethoxycarbonyl)propyl.

[0468] In the above embodiment, preferably, when R 3 is 3-pentyl, 1-(aminocarbonyl)propyl or 1-(ethoxycarbonyl)propyl, R 4 is different from 1-(ethoxycarbonyl)propyl.

[0469] In the most preferred embodiment, R 1 is hydrogen, R 2 is methyl, R 3 is 1-(ethoxycarbonyl)propyl, and R 4 is 3-methoxybenzyl, 3-nitrobenzyl, or (5-nitro-2-furyl)methyl.

[0470] A further embodiment is a compound in which R 2 is methyl, R 3 is a group of the formula -CHR 5 R 6 , R 5 is C 2~4 alkyl, R 6 is an amide or -COOR 7 , and R 7 is methyl or ethyl.

[0471] In some embodiments, the compounds useful in the methods and compositions of the present invention are selected from the group consisting of: ethyl 2-[(7-benzyl-1,3-dimethyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl)thio]butanoate; ethyl 2-{[7-(3-bromobenzyl)-1-(2-ethoxy-2-oxoethyl)-3-methyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl]thio}butanoate; ethyl 2-{[7-(3-bromobenzyl)-1-(2-methoxyethyl)-3-methyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl]thio}butanoate; ethyl 2-{[7-(3-bromobenzyl)-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl]thio}butanoate; ethyl 2-{[7-(3-bromobenzyl)-1,3-dimethyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl]thio}butanoate; ethyl 2-{[7-(2-bromobenzyl)-1,3-dimethyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl]thio}butanoate; ethyl 2-{[7-(3-bromobenzyl)-1-(cyanomethyl)-3-methyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl]thio}butanoate; ethyl 2-{[7-(3-bromobenzyl)-3-methyl-2,6-dioxo-1-propyl-2,3,6,7-tetrahydro-1H-purin-8-yl]thio}butanoate; ethyl 2-{[7-(3-bromobenzyl)-3-methyl-2,6-dioxo-1-(2-oxopropyl)-2,3,6,7-tetrahydro-1H-purin-8-yl]thio}butanoate; ethyl 2-{[7-(3-bromobenzyl)-1-(3-hydroxypropyl)-3-methyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl]thio}butanoate; ethyl 2-{[7-(3-bromobenzyl)-3-methyl-2,6-dioxo-1-(2-propynyl)-2,3,6,7-tetrahydro-1H-purin-8-yl]thio}butanoate; ethyl 2-{[7-(3-methoxybenzyl)-3-methyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl]thio}butanoate;Ethyl 2-{[3-methyl-7-(3-nitrobenzyl)-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl]thio}butanoate; Ethyl 2-{[7-(3-aminobenzyl)-3-methyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl]thio}butanoate; Ethyl 2-({7-[4-(aminosulfonyl)benzyl]-3-methyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl}thio)butanoate; Ethyl 2-{[7-(4-bromobenzyl)-1,3-dimethyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl]thio}butanoate; Ethyl 2-{[7-(cyclohexylmethyl)-1,3-dimethyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl]thio}butanoate; Ethyl 2-{[1,3-dimethyl-2,6-dioxo-7-(1-phenylethyl)-2,3,6,7-tetrahydro-1H-purin-8-yl]thio}butanoate; Ethyl 2-{[1,3-dimethyl-2,6-dioxo-7-(2-phenylethyl)-2,3,6,7-tetrahydro-1H-purin-8-yl]thio}butanoate; Ethyl 2-({7-[(3,5-dimethylisoxazol-4-yl)methyl]-3-methyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl}thio)butanoate; Ethyl 2-({3-methyl-7-[(5-nitro-2-furyl)methyl]-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl}thio)butanoate; Ethyl 2-[(7-butyl-3-methyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl)thio]butanoate; Ethyl 2-{[7-(3-bromobenzyl)-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl]thio}butanoate; Ethyl 2-[(1,7-dihexyl-3-methyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl)thio]butanoate; Ethyl 2-[(7-hexyl-3-methyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl)thio]butanoate;Ethyl 2-[(3-methyl-2,6-dioxo-1,7-dipentyl-2,3,6,7-tetrahydro-1H-purin-8-yl)thio]butanoate; 2-{[7-(3-bromobenzyl)-3-methyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl]thio}butanamide; 2-[(7-butyl-3-methyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl)thio]butanamide; 7-(3-bromobenzyl)-8-[(1-ethylpropyl)thio]-3-methyl-3,7-dihydro-1H-purin-2,6-dione; Ethyl 2-{8-[(3-bromobenzyl)thio]-1,3-dimethyl-2,6-dioxo-1,2,3,6-tetrahydro-7H-purin-7-yl}butanoate; and Ethyl 2-[(7-isobutyl-3-methyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl)thio]butanoate.;

[0472] In some embodiments, the compounds useful in the methods and compositions of the invention are selected from the group consisting of: ethyl 2-[(7-benzyl-1,3-dimethyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl)thio]butanoate; ethyl 2-{[7-(3-bromobenzyl)-1-(2-methoxyethyl)-3-methyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl]thio}butanoate; ethyl 2-{[7-(3-bromobenzyl)-1,3-dimethyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl]thio}butanoate; ethyl 2-{[7-(3-bromobenzyl)-1-(cyanomethyl)-3-methyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl]thio}butanoate; ethyl 2-{[7-(3-bromobenzyl)-3-methyl-2,6-dioxo-1-propyl-2,3,6,7-tetrahydro-1H-purin-8-yl]thio}butanoate; ethyl 2-{[7-(3-bromobenzyl)-1-(3-hydroxypropyl)-3-methyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl]thio}butanoate; ethyl 2-{[7-(3-bromobenzyl)-3-methyl-2,6-dioxo-1-(2-propynyl)-2,3,6,7-tetrahydro-1H-purin-8-yl]thio}butanoate; ethyl 2-{[7-(3-methoxybenzyl)-3-methyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl]thio}butanoate; ethyl 2-{[3-methyl-7-(3-nitrobenzyl)-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl]thio}butanoate; ethyl 2-{[7-(3-aminobenzyl)-3-methyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl]thio}butanoate; ethyl 2-({7-[(3,5-dimethylisoxazol-4-yl)methyl]-3-methyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl}thio)butanoate; ethyl 2-({3-methyl(methyi)-7-[(5-nitro-2-furyl)methyl]-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl}thio)butanoate;Ethyl 2-[(7-butyl-3-methyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl)thio]butanoate; Ethyl 2-[(7-hexyl-3-methyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl)thio]butanoate; 2-{[7-(3-bromobenzyl)-3-methyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl]thio}butanamide; 7-(3-bromobenzyl)-8-[(1-ethylpropyl)thio]-3-methyl-3,7-dihydro-1H-purine-2,6-dione; and Ethyl 2-{8-[(3-bromobenzyl)thio]-1,3-dimethyl-2,6-dioxo-1,2,3,6-tetrahydro-7H-purin-7-yl}butanoate.;

[0473] In some embodiments, the compounds useful in the methods and compositions of the invention are selected from the group consisting of: Ethyl 2-{[7-(3-methoxybenzyl)-3-methyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl]thio}butanoate; Ethyl 2-{[3-methyl-7-(3-nitrobenzyl)-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl]thio}butanoate; and Ethyl 2-({3-methyl-7-[(5-nitro-2-furyl)methyl]-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl}thio)butanoate.;

[0474] In some embodiments, these compounds are of formula II:

[0475]

Chemical formula

[0476] In the above embodiments, in some cases, when R 3 is a group of the formula --CHR 5 R 6 R 4 is C 3~6 cycloalkyl, aryl or C optionally substituted by a heterocycle 1~8 alkyl.

[0477] In some embodiments, these compounds are of formula II:

[0478]

Chemical formula

[0479] In some embodiments, these compounds are ethyl 2-[(7-heptyl-3-methyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl)thio]butanoate; 7-(3-bromobenzyl)-3-methyl-8-(propylthio)-3,7-dihydro-1H-purin-2,6-dione; ethyl 2-[(3-methyl-2,6-dioxo-7-pentyl-2,3,6,7-tetrahydro-1H-purin-8-yl)thio]butanoate; ethyl 2-{[7-(3-bromobenzyl)-3-methyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl-]thio}butanoate; ethyl 2-[(3-methyl-2,6-dioxo-7-propyl-2,3,6,7-tetrahydro Ethyl 7-(3-bromobenzyl)-8-[(3-chloro-2-hydroxypropyl)thio]-3-methyl-3,7-dihydro-1H-purine-2,6-dione; and ethyl 2-{[7-(3-bromobenzyl)-3-methyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl]thio}propionate is a compound of formula II selected from

[0480] In some embodiments, these compounds are of formula I:

[0481]

Chemical formula

[0482] ​In another embodiment, the compounds have Formula II:

[0483] [ka] Compounds having the formula: or a pharma- ceutically acceptable salt thereof, wherein , R 1 is hydrogen or C 1~6 is alkyl; R 2 is hydrogen or C 1~4 is alkyl; R 3 is the formula --CHR 5 R 6 or a benzyl group; R 4 is alkoxycarbonyl, C 3~6 Required by cycloalkyl, aryl or heterocycle C replaced as necessary 1~8 is alkyl; R 5 is hydrogen or C 1~4 is alkyl; R 6 is C 1~4 Alkyl, Amide or --COOR 7 and; R 7 is C 1~4 It is an alkyl.

[0484] vi) International Patent Application Publication No. WO2010 / 144712 In one embodiment, a compound comprising a LEV derivative of Formula 1 or Formula 2 is disclosed.

[0485] [ka] In Formula 2, n, and in Formulas 1 and 2, L, X, and Y are defined as follows: a) n is an integer having a value from 0 to 8; b) L is one of the group consisting of CH2, CO, NHCO, NHCOO, CONH, NH, O, or S, and combinations thereof; c) X is a terminal group, an aromatic group, an aryl group, or an aliphatic group having from 1 to 10 carbon atoms and / or hetero-chain atoms, saturated, unsaturated, substituted, unsubstituted, straight-chain, or branched-chain, said hetero-chain atoms being selected from the group consisting of oxygen, nitrogen, sulfur, or phosphorus, and combinations thereof; and d) Y is optional, and when present, is one of the functional groups selected from the group consisting of alcohol amine, amide, carboxylic acid, aldehyde, ester, iminoester, isocyanate, isothiocyanate, anhydride, thiol, thioacetone, diazonium, NHS, CO-NHS, O-NHS, maleimide; or e) Y is Yi-Z, where Yi is selected from the group consisting of COO, CO, O, CONH, NHCO, or NH, and Z is an operative group. In one embodiment of the method, the operative group of Z is selected from the group consisting of a detectable label, an antigen carrier, a capping agent, a terminal group, a protein, a lipoprotein, a glycoprotein, a polypeptide, a polysaccharide, a nucleic acid, a polynucleotide, teichoic acid, a radioisotope, an enzyme, an enzyme fragment, an enzyme donor fragment, an enzyme acceptor fragment, an enzyme substrate, an enzyme inhibitor, a coenzyme, a fluorescent moiety, a phosphorescent moiety, an anti-Stokes upconverting moiety, a chemiluminescent moiety, a luminescence moiety, a dye, a photosensitizer, a particle, a microparticle, a magnetic particle, a solid support, a liposome, a ligand, a receptor, a hapten radioisotope, and combinations thereof. In one embodiment of the method, the operative group of Z is selected from the group consisting of a detectable label, an antigen carrier, a capping agent, a terminal group, a protein, a lipoprotein, a glycoprotein, a polypeptide, a polysaccharide, a nucleic acid, a polynucleotide, teichoic acid, a radioisotope, an enzyme, an enzyme fragment, an enzyme donor fragment, an enzyme acceptor fragment, an enzyme substrate, an enzyme inhibitor, a coenzyme, a fluorescent moiety, a phosphorescent moiety, an anti-Stokes upconverting moiety, a chemiluminescent moiety, a luminescence moiety, a dye, a photosensitizer, a particle, a microparticle, a magnetic particle, a solid support, a liposome, a ligand, a receptor, a hapten radioisotope, and combinations thereof.

[0486] In one embodiment of the method, the operative group of Z is selected from the group consisting of a detectable label, an antigen carrier, a capping agent, a terminal group, a protein, a lipoprotein, a glycoprotein, a polypeptide, a polysaccharide, a nucleic acid, a polynucleotide, teichoic acid, a radioisotope, an enzyme, an enzyme fragment, an enzyme donor fragment, an enzyme acceptor fragment, an enzyme substrate, an enzyme inhibitor, a coenzyme, a fluorescent moiety, a phosphorescent moiety, an anti-Stokes upconverting moiety, a chemiluminescent moiety, a luminescence moiety, a dye, a photosensitizer, a particle, a microparticle, a magnetic particle, a solid support, a liposome, a ligand, a receptor, a hapten radioisotope, and combinations thereof. In one embodiment of the method, the operative group of Z is selected from the group consisting of a detectable label, an antigen carrier, a capping agent, a terminal group, a protein, a lipoprotein, a glycoprotein, a polypeptide, a polysaccharide, a nucleic acid, a polynucleotide, teichoic acid, a radioisotope, an enzyme, an enzyme fragment, an enzyme donor fragment, an enzyme acceptor fragment, an enzyme substrate, an enzyme inhibitor, a coenzyme, a fluorescent moiety, a phosphorescent moiety, an anti-Stokes upconverting moiety, a chemiluminescent moiety, a luminescence moiety, a dye, a photosensitizer, a particle, a microparticle, a magnetic particle, a solid support, a liposome, a ligand, a receptor, a hapten radioisotope, and combinations thereof.

[0487] vii) International Patent Application Publication No. WO2010 / 002869 The present invention relates to Formula I:

[0488]

Chemical formula

[0489] To provide a compound of formula I or a pharmaceutically acceptable salt thereof, wherein in formula I: each Z is independently selected from hydrogen and deuterium; R1 is an n-propyl group having from 0 to 7 deuterium atoms; R2 is an ethyl group having from 0 to 5 deuterium atoms, and when each R has 0 deuterium atoms, at least one Z is deuterium.

[0490] One embodiment of the present invention provides a compound of formula I, wherein R1 is selected from CD3CH2CH2-, CD3CD2CH2-, CD3CH2CD2-, CH3CH2CD2-, CH3CD2CD2-, CD3CD2CD2- or CH3CH2CH2-. In a more specific embodiment, R1 is CD3CD2CD2- or CD3CD2CH2-. In one aspect of these embodiments, both Z1 and Z2 are hydrogen. In another aspect of these embodiments, both Z1 and Z2 are deuterium.

[0491] In another embodiment, R2 is selected from CH3CH2-, CD3CH2-, CH3CD2-, or CD3CD2-. In a more specific embodiment, R2 is selected from CH3CH2- or CD3CD2-. In one aspect of these embodiments, both Z1 and Z2 are hydrogen. In another aspect of these embodiments, both Z1 and Z2 are deuterium.

[0492] ​​The variables R and Z as described above can be selected and combined to provide more specific embodiments of the present invention. For example, in one embodiment, R1 is CD3CH2CH2-, CD3CD2CH2-, CD3CH2CD2-, CH3CH2CD2-, CH3CD2CD2-, CD3CD2CD2- or CH3CH2CH2-; and R2 is selected from CH3CH2-, CD3CH2-, CH3CD2-, or CD3CD2-. In one aspect of this embodiment, R2 is CH3CH2- or CD3CD2-. In another embodiment, R1 is CD3CD2CD2- or CD3CD2CH2-; and R2 is selected from CH3CH2-, CD3CH2-, CH3CD2-, or CD3CD2-. In one aspect of this embodiment, R2 is CH3CH2- or CD3CD2-. In one aspect of this embodiment, R2 is CH3CH2- or CD3CD2-. In another embodiment, R1 is CD3CD2CD2- or CD3CD2CH2-; and R2 is selected from CH3CH2-, CD3CH2-, CH3CD2-, or CD3CD2-. In one aspect of this embodiment, R2 is CH3CH2- or CD3CD2-.

[0493] Examples of specific compounds of the present invention include the following:

[0494]

Chemical formula

[0495]

Chemical formula

[0496] R1 is hydrogen, substituted or unsubstituted C1-12 alkyl, substituted or unsubstituted aryl or substituted or unsubstituted 3- to 8-membered heterocycle.

[0497] R2 is hydrogen. Alternatively, R1 and R2 can be joined together in such a way as to form a C3-6 cycloalkyl. formula.

[0498] R3 is (a) a substituted or unsubstituted heteroaryl bonded to the remainder of the molecule through one of its C atoms, and this heteroaryl ring is: 1H-benzimidazol-6-yl; 1H-benzimidazol-7-yl; imidazo[1,2-a]pyridin-3-yl; imidazo[1,2-a]pyrimidin-3-yl; imidazo[1,2-b][1,2,4]triazin-7-yl; imidazo[1,2-b]pyridazin-3-yl; 5,6,7,8-tetrahydroimidazo[1,2-b]pyridazin-3-yl; imidazo[2,1-b][1,3,4]thiadiazol-5-yl; imidazo[2,1-b][1,3]thiazol-5-yl; 3H-imidazo[4,5-b]pyridin-7-yl; 1H-imidazol-4-yl; 1H-imidazol-5-yl; 1H-indol-2-yl; 1H-indol-3-yl; 1H-indol-4-yl; 1H-indol-7-yl; isoxazol-4-yl; 1H-pyrazol-4-yl; 1H-pyrazol-5-yl; 1H-pyrazolo[1,5-a]pyrimidin-3-yl; 1H-pyrazolo[3,4-b]pyridin-3-yl; pyridazin-4-yl; pyridin-2-yl; pyridin-3-yl; pyridin-4-yl; 1H-pyrrolo[2,3-b]pyridin-3-yl; 1H-pyrrolo[2,3-b]pyridin-4-yl; 1H-Pyrrolo[2,3-b]pyridin-5-yl; 1H-Pyrrolo[2,3-c]pyridin-2-yl; 1H-Pyrrolo[2,3-c]pyridin-3-yl; 1H-Pyrrolo[3,2-b]pyridin-3-yl; 1H-Pyrrolo[3,2-c]pyridin-2-yl; 1H-Pyrrolo[3,2-c]pyridin-3-yl; 1,3,4-Thiadiazol-2-yl; 1,3-Thiazol-5-yl; [1,2,4]Triazolo[4,3-b]pyridazin-7-yl; [1,2,4]Triazolo[4,3-b]pyridazin-8-yl; Indolizin-3-yl selected from the group consisting of; or R3 is, (b) a substituted or unsubstituted heterocyclic ring bonded to the remainder of the molecule through one of its N atoms, and this heterocyclic ring is: 1H-1,2,3-Benzotriazol-1-yl; 1H-Imidazo[4,5-b]pyridin-1-yl; 3H-Imidazo[4,5-b]pyridin-3-yl; 7H-Imidazo[4,5-c]pyridazin-7-yl; 1H-Indol-1-yl; 2,3-Dihydro-1H-indol-1-yl; 9H-Purin-9-yl; 1H-Pyrazolo[3,4-b]pyridin-1-yl; 2H-Pyrazolo[3,4-b]pyridin-2-yl; 1H-Pyrrolo[2,3-b]pyridin-1-yl; 1H-Pyrrolo[3,2-b]pyridin-1-yl; 3,4-Dihydroquinolin-1(2H)-yl; 8H-Isothiazolo[5,4-b]indol-8-yl; 1H-1,2,4-Triazol-1-yl; 1H-pyrrol-1-yl; 2-chloro-1H-benzimidazol-1-yl is selected from the group consisting of any of the following.

[0499] R4 in formula (I) is hydrogen; C1-12 alkyl optionally substituted by halogen, C1-4 alkoxy, C1-4 alkylthio, azide, nitrooxy or aryl; optionally C2-12 alkenyl optionally substituted by halogen; C2-12 alkynyl optionally substituted by halogen; azide; alkoxycarbonylamino; arylsulfonyloxy; substituted or unsubstituted aryl; or a group containing a 3- to 8-membered substituted or unsubstituted heterocyclic ring or is selected from the group consisting of these.

[0500] In certain embodiments, R4 is hydrogen; or R4 is C1-12 alkyl or C1-6 alkyl optionally substituted by halogen, C1 -4 alkoxy, C1-4 alkylthio, azide or nitrooxy; or R4 is C2-12 alkenyl or C1-6 alkenyl optionally substituted by halogen; or R4 is C2-12 alkynyl or C1-6 alkynyl optionally substituted by halogen; or R4 is alkoxycarbonylamino.

[0501] R5 is hydrogen.

[0502] Alternatively, R4, together with R5 and the 2-oxo-1-pyrrolidine ring, forms the following structure:

[0503]

Chemical formula

[0504] to form a 1,3-dihydro-2H-indol-2-one ring.

[0505] Asterisk * indicates the bonding point of the substituent; R6 is hydrogen or halogen.

[0506] R7 in formula (I) is hydrogen; nitro; halogen; heterocycle; amino; aryl; C1-12 alkyl substituted by at least one halogen; or C1-12 alkoxy substituted by at least one halogen, selected from the group consisting of or consisting of these groups.

[0507] R8 in formula (I) is selected from the group consisting of or consisting of hydrogen, C1-12 alkyl optionally substituted by halogen, or halogen.

[0508] R9 in formula (I) is selected from the group consisting of or consisting of hydrogen, C1-12 alkyl optionally substituted by halogen, or halogen.

[0509] A further aspect of the present invention lies in the compounds of formula (I) wherein both R1 and R2 are hydrogen.

[0510] R3 is: (a) a substituted or unsubstituted heterocycle bonded to the remainder of the molecule through one of its C atoms, and: 1H-benzimidazol-6-yl; 1H-benzimidazol-7-yl; imidazo[1,2-a]pyridin-3-yl; imidazo[1,2-a]pyrimidin-3-yl; imidazo[1,2-b][1,2,4]triazin-7-yl; imidazo[1,2-b]pyridazin-3-yl; 5,6,7,8-tetrahydroimidazo[1,2-b]pyridazin-3-yl; imidazo[2,1-b][1,3,4]thiadiazol-5-yl;​ Imidazo[2,1-b][1,3]thiazol-5-yl; 3H-Imidazo[4,5-b]pyridin-7-yl; 1H-Imidazol-4-yl; 1H-Imidazol-5-yl; 1H-Indol-2-yl; 1H-Indol-3-yl; 1H-Indol-4-yl; 1H-Indol-7-yl; Isoxazol-4-yl; 1H-Pyrazol-4-yl; 1H-Pyrazol-5-yl; 1H-Pyrazolo[1,5-a]pyrimidin-3-yl; 1H-Pyrazolo[3,4-b]pyridin-3-yl; Pyridazin-4-yl; Pyridin-2-yl; Pyridin-3-yl; Pyridin-4-yl; 1H-Pyrrolo[2,3-b]pyridin-3-yl; 1H-Pyrrolo[2,3-b]pyridin-4-yl; 1H-Pyrrolo[2,3-b]pyridin-5-yl; 1H-Pyrrolo[2,3-c]pyridin-2-yl; 1H-Pyrrolo[2,3-c]pyridin-3-yl; 1H-Pyrrolo[3,2-b]pyridin-3-yl; 1H-Pyrrolo[3,2-c]pyridin-2-yl; 1H-Pyrrolo[3,2-c]pyridin-3-yl; 1,3,4-Thiadiazol-2-yl; 1,3-Thiazol-5-yl; [1,2,4]Triazolo[4,3-b]pyridazin-7-yl; [1,2,4]Triazolo[4,3-b]pyridazin-8-yl; Indolizin-3-yl selected from the group consisting of.

[0511] Alternatively, R3 is: (b) a substituted or unsubstituted heterocyclic ring bonded to the remainder of the molecule through its N atom, and being: 1H-1,2,3-benzotriazol-1-yl; 1H-imidazo[4,5-b]pyridin-1-yl; 3H-imidazo[4,5-b]pyridin-3-yl; 7H-imidazo[4,5-c]pyridazin-7-yl; 1H-indol-1-yl; 2,3-dihydro-1H-indol-1-yl; 9H-purin-9-yl; 1H-pyrazolo[3,4-b]pyridin-1-yl; 2H-pyrazolo[3,4-b]pyridin-2-yl; 1H-pyrrolo[2,3-b]pyridin-1-yl; 1H-pyrrolo[3,2-b]pyridin-1-yl; 3,4-dihydroquinolin-1(2H)-yl; 8H-isothiazolo[5,4-b]indol-8-yl; 1H-1,2,4-triazol-1-yl; 1H-pyrrol-1-yl; 2-chloro-1H-benzimidazol-1-yl and is selected from the group consisting of or consisting of these.

[0512] In formula (I), R4 is hydrogen; C1-C12 alkyl optionally substituted by halogen or C1-4 alkoxy; C2-C12 alkenyl optionally substituted by halogen; C2-C12 alkynyl optionally substituted by halogen, and is selected from the group consisting of or consisting of these. In a further specific embodiment, R4 is n-propyl, 2,2,2-trifluoroethyl, 2-chloro-2,2-difluoroethyl, 2-bromo-2,2-difluoroethyl, 2,2-difluorovinyl

[0513] is. is.

[0514] In another specific embodiment, R4 is phenyl, 2,3,5-trifluorophenyl or 3-chloro-4-fluorophenyl.

[0515] R5 is hydrogen.

[0516] A further embodiment of the present invention is in a compound of formula (I) where R4 together with R5a forms a 1,3-dihydro-2H-indol-2-one ring

[0517]

Chemical formula

[0518] and the asterisk asterisk * indicates the point of attachment of the heteroarylalkylene substituent, and R6 is hydrogen; R7 is chlorine; R8 is hydrogen; R9 is hydrogen.

[0519] A further embodiment of the present invention is a substituted or unsubstituted heterocyclic ring in which R3 is attached to the remainder of the molecule via one of its C atoms: imidazo[1,2-a]pyrimidin-3-yl; imidazo[1,2-b][1,2,4]triazin-7-yl; imidazo[1,2-b]pyridazin-3-yl; 5,6,7,8-tetrahydroimidazo[1,2-b]pyridazin-3-yl; imidazo[2,1-b][1,3,4]thiadiazol-5-yl; imidazo[2,1-b][1,3]thiazol-5-yl; 3H-imidazo[4,5-b]pyridin-7-yl; 1H-imidazol-4-yl; 1H-imidazol-5-yl; 1H-imidazol-5-yl; isoxazol-4-yl; 1H-pyrazol-4-yl; 1H-pyrazol-5-yl; 1H-pyrazolo[1,5-a]pyrimidin-3-yl; 1H-pyrazolo[3,4-b]pyridin-3-yl; pyridin-3-yl; 1H-pyrrolo[2,3-b]pyridin-3-yl; 1H-pyrrolo[2,3-b]pyridin-4-yl; 1H-pyrrolo[2,3-b]pyridin-5-yl; 1H-pyrrolo[2,3-c]pyridin-2-yl; 1H-pyrrolo[2,3-c]pyridin-3-yl; 1,3-thiazol-5-yl; [1,2,4]triazolo[4,3-b]pyridazin-8-yl; indolizin-3-yl in the compound of formula (I) selected from the group consisting of.

[0520] In a further particular embodiment, R3 is a heterocyclic ring attached to the remainder of the molecule via one of its C atoms : imidazo[1,2-b]pyridazin-3-yl; imidazo[2,1-b][1,3,4]thiadiazol-5-yl; imidazo[2,1-b][1,3]thiazol-5-yl; 3H-imidazo[4,5-b]pyridin-7-yl; 1H-imidazol-4-yl; 1H-imidazol-5-yl; 1H-pyrazol-4-yl; 1H-pyrazolo[1,5-a]pyrimidin-3-yl; pyridin-3-yl; 1H-pyrrolo[2,3-b]pyridin-3-yl; 1H-pyrrolo[2,3-b]pyridin-4-yl; 1,3-thiazol-5-yl is selected from the group consisting of.

[0521] These heterocycles are optionally substituted, for example, by methyl, n-propyl, trifluoromethyl, cyclopropyl, bromine, chlorine, fluorine, iodine, methoxy, ethoxy, propoxy, isopropoxy, cyclopropyloxy, cyclopropylmethoxy, cyclobutylmethoxy, amino, methylamino, cyclopropylamino, cyclobutylamino, 1-pyrrolidinyl, cyano, phenyl, benzyl or 3-thienyl.

[0522] In a further specific embodiment, R3 is a heterocycle bonded to the remainder of the molecule via one of its C atoms and is 6-chloro-2-cyclopropylimidazo[1,2-b]pyridazin-3-yl, 6-(cyclopropyloxy)-2-(trifluoromethyl)imidazo[1,2-b]pyridazin-3-yl, 6-propoxy-2-(trifluoromethyl)imidazo[1,2-b]pyridazin-3-yl, 6- chloroimidazo[2,1-b][1,3]thiazol-5-yl, 2,6-dichloroimidazo[2,1-b][1,3]th iazol-5-yl, 5-chloro-1H-imidazol-4-yl, 5-bromo-1H-imidazol-4-yl l, 4-bromo-1H-imidazol-5-yl, 4-chloro-1H-imidazol-5-yl, 1H-imid azol-5-yl, 1-methyl-1H-imidazol-5-yl, 4-chloro-1-methyl-1H-imidazo l-5-yl, 1H-pyrazol-4-yl, 1H-pyrrolo[2,3-b]pyridin-3-yl, and is selected from the group consisting of.

[0523] A further embodiment of the present invention is a compound of formula (I) wherein R3 is a heterocycle bonded to the remainder of the molecule via one of its C atoms and is a substituted or unsubstituted imidazo[1,2-a]pyridin-3-yl.

[0524] This imidazo[1,2-a]pyridin-3-yl is optionally substituted, for example, by methyl, cyclopropyl, bromine, chlorine, fluorine, iodine.

[0525] In a further specific embodiment, R3 is a heterocyclic ring bonded to the remainder of the molecule via one of its C atoms and is selected from the group consisting of imidazo[1,2-a]pyridin-3-yl, 6-methylimidazo[1,2-a]pyridin-3-yl, 2-chloroimidazo[1,2-a]pyridin-3-yl.

[0526] A further embodiment of the present invention is that R3 is a substituted or unsubst...

Claims

【Claim 1】 The use or inhibitor described in the specification of the present application.

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