US 2011 0212928A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2011/0212928 A1 Gallagher et al. (43) Pub. Date: Sep. 1, 2011

(54) METHODS AND COMPOSITIONS FOR A6II 3/473 (2006.01) IMPROVING COGNITIVE FUNCTION A63L/407 (2006.01) A6II 3/55 (2006.01) (75) Inventors: Michela Gallagher, Baltimore, MD A6IP 25/00 (2006.01) (US); Rebecca Haberman, A6IP 25/28 (2006.01) Baltimore, MD (US); Ming Teng A6IP 25/18 (2006.01) Koh, Baltimore, MD (US) (52) U.S. Cl...... 514/129; 514/319; 514/297: 514/411; 514/215 (73) Assignee: THE JOHNS HOPKINS INVERSITY. Baltimore, MD (57) ABSTRACT The invention relates to methods and compositions for (21) Appl. No.: 13/024,294 improving cognitive function by using a combination of a synaptic vesicle protein 2A (SV2A) inhibitor and an acetyl (22) Filed: Feb. 9, 2011 cholinesterase inhibitor (AChEI) or their pharmaceutically acceptable salts, hydrates, Solvates, polymorphs thereof. In Related U.S. Application Data particular, it relates to the use of a combination of an SV2A (60) Provisional9, 2010 application No. 61/302.760, filed on Feb. inhibitordisorder withand alcognitive AChEI impairmentin treating a in central a Subject nervous in need system or at s risk thereof, including, without limitation, Subjects having or O O at risk for age-related cognitive impairment, Mild Cognitive Publication Classification Impairment (MCI), dementia, Alzheimer's Disease (AD), (51) Int. Cl. prodromal AD, post traumatic stress disorder (PTSD), A6 IK3I/662 (2006.01) Schizophrenia, amyotrophic lateral Sclerosis (ALS), and can A6 IK 3/445 (2006.01) cer-therapy-related cognitive impairment. Patent Application Publication Sep. 1, 2011 Sheet 1 of 17 US 2011/0212928A1

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METHODS AND COMPOSITIONS FOR patients and display a use-limiting side effect profile. Another IMPROVING COGNITIVE FUNCTION AChEI, donepezil (also known as “ARICEPTTM), appears more effective than tacrine. With donepezil, Alzheimer's dis ease patients show slight cognitive improvements (Barner et 0001. This application claims priority and benefit from al, 1998; Rogers et al., 1998), but the usefulness of donepezil U.S. Provisional Patent Application 61/302.760 (filed Feb. 9, is limited due to its moderate efficacy and side effects. The 2010), the contents and disclosures of which are incorporated long-term therapeutic efficacy of donepezil has also been herein by reference in its entirety. increasingly questioned (Maggini et al., 2006; Petersenet al., 2006). There is, therefore, a need for more effective treatment FIELD OF THE INVENTION for disorders involving cognitive dysfunction and in particu lar cognitive impairment, in AD patients. 0002 The invention relates to methods and compositions for improving cognitive function by using a combination of a SUMMARY OF THE INVENTION synaptic vesicle protein 2A (SV2A) inhibitor and an acetyl cholinesterase inhibitor (AChEI). In particular, it relates to 0008. In accordance with a first aspect of the present the use of a combination of an SV2A inhibitor and an AChEI invention, there is provided a method for treating, or improv in treating central nervous system (CNS) disorders with cog ing cognitive function in, a Subject Suffering from a central nitive impairment in a Subject in need or at risk thereof, nervous system (CNS) disorder with cognitive impairment, including, without limitation, Subjects having or at risk for or at risk thereof, the method comprising the step of admin age-related cognitive impairment, Mild Cognitive Impair istering to said Subject a therapeutically effective amount of ment (MCI), amnestic MCI, Age-Associated Memory an SV2A inhibitor or a pharmaceutically acceptable salt, Impairment (AAMI), Age Related Cognitive Decline hydrate, solvate, or polymorph thereof in combination with a (ARCD), dementia, Alzheimer's Disease (AD), prodromal therapeutically effective amount of an AChEI or a pharma AD, post traumatic stress disorder (PTSD), schizophrenia, ceutically acceptable salt, hydrate, Solvate, or polymorph amyotrophic lateral Sclerosis (ALS) and cancer-therapy-re thereof. In some embodiments of this invention, the methods lated cognitive impairment. of this invention prevent or slow the progression of said CNS disorder with cognitive impairment in said Subject. In other BACKGROUND OF THE INVENTION embodiments of this invention, the methods of this invention alleviate, ameliorate, or slow the progression, of one or more 0003 Cognitive ability may decline as a normal conse symptoms associated with said CNS disorder with cognitive quence of aging or as a consequence of a central nervous impairment in said Subject. disorder. 0009. In one embodiment of the invention, the SV2A 0004. A significant population of elderly adults experi inhibitor and/or the AChEI are administered at doses that are ences a decline in cognitive ability that exceeds what is typi Subtherapeutic as compared to the doses at which they are cal in normal aging. Such age-related loss of cognitive func therapeutically effective when administered in the absence of tion is characterized clinically by progressive loss of memory, the other. cognition, reasoning, and judgment. Mild Cognitive Impair 0010. In some embodiments of the invention, the CNS ment (MCI), Age-Associated Memory Impairment (AAMI), disorder with cognitive impairment is age-related cognitive Age-Related Cognitive Decline (ARCD) or similar clinical impairment, such as Mild Cognitive Impairment (MCI), Age groupings are among those related to Such age-related loss of Associated Memory Impairment (AAMI), Age Related Cog cognitive function. According to some estimates, there are nitive Decline (ARCD). In one embodiment of the invention, more than 16 million people with AAMI in the U.S. alone the MCI is amnestic MCI. In some embodiments of the inven (Barker et al., 1995), and MCI is estimated to affect 5.5-7 tion, the CNS disorder with cognitive impairment is demen million in the U.S. over the age of 65 (Plassman et al., 2008). tia, Alzheimer's Disease (AD), prodromal AD, post traumatic 0005. Other central nervous system (CNS) disorders, such stress disorder (PTSD), schizophrenia, amyotrophic lateral as dementia, Alzheimer's Disease (AD), prodromal AD, post Sclerosis (ALS), or cancer-therapy-related cognitive impair traumatic stress disorder (PTSD), schizophrenia, amyo ment. In one embodiment, the subject that suffers such CNS trophic lateral Sclerosis (ALS), and cancer-therapy-related disorder or such cognitive impairment is a human patient. cognitive impairment, are also associated with cognitive 0011. The SV2A inhibitor or a pharmaceutically accept impairment. able salt, hydrate, solvate or polymorph thereof that is useful 0006. There is, therefore, a need for effective treatment for in the methods and compositions of this invention include central nervous system (CNS) disorders with cognitive those disclosed in, for example, U.S. patent application Ser. impairment and to improve cognitive function in patients No. 12/580,464, International Patent Application PCT/ diagnosed with age-related cognitive impairment, MCI. US2009/005647, U.S. Patent Application 61/105,847, U.S. amnestic MCI, AAMI. ARCD, dementia, AD, prodromal AD, Patent Application 61/152,631, and U.S. Patent Application PTSD, schizophrenia, amyotrophic lateral sclerosis (ALS), 61/175,536. However, any SV2A inhibitor or a pharmaceuti cancer-therapy-related cognitive impairment, and similar cally acceptable salt, hydrate, Solvate or polymorph thereof central nervous system (CNS) disorders with cognitive may be used in the methods and compositions of the inven impairment or at risk of developing them. tion. In other embodiments, the SV2A inhibitor is selected 0007 Tacrine hydrochloride (“COGNEXTM), the first from the group of SV2A inhibitors referred to in International FDA approved drug for Alzheimer's disease (AD) is an Patent Applications WO2010/144712: WO2010/002869; AChEI (Cutler et al., 1993). Other examples of clinically used WO2008/132139; WO2007/065595; WO2006/128693; AChEIs include galantamine (“REMINYLTM) or rivastig WO2006/128692; WO2005/054188: WO2004/087658; mine (EXELONTM) These drugs, however, have shown lim WO2002/094787; WO2001/062726; U.S. Pat. Nos. 7,465, ited Success in cognitive improvement in Alzheimer's disease 549; 7,244,747; 5,334,720; 4,696,943; 4,696,942; U.S. US 2011/0212928 A1 Sep. 1, 2011

Patent Application Publication Numbers 20090312333; 12/580,464, International Patent Application PCT/US2009/ 20090018148; 20080081832; 2006258704; and UK Patent 005647, U.S. Patent Application 61/105,847, U.S. Patent Numbers 1,039,113; and 1,309,692 or their pharmaceutically Application 61/152,631, and U.S. Patent Application 61/175, acceptable salts, hydrates, Solvates, or polymorphs. In other 536. In other embodiments of the invention, the SV2A inhibi embodiments, the SV2A inhibitor is selected from the group tor or a pharmaceutically acceptable salt, hydrate, Solvate or consisting of levetiracetam, brivaracetam, and seletracetam polymorph thereof is administered every 12 or 24 hours at a or derivatives or analogs or pharmaceutically acceptable daily dose of about 0.001 mg/kg to 5 mg/kg. In other embodi salts, hydrates, Solvates, or polymorphs thereof. In other ments of the invention, the SV2A inhibitor or a pharmaceu embodiments, the SV2A inhibitor is levetiracetam or a tically acceptable salt, hydrate, solvate or polymorph thereof derivative oran analog or a pharmaceutically acceptable salt, is administered every 12 or 24 hours at a daily dose of about hydrate, Solvate, or polymorph thereof. 0.1 to 5 mg/kg, or about 1 to 2 mg/kg, or about 0.1 to 0.2 0012 AChEI or a pharmaceutically acceptable salt, mg/kg, or about 0.01 to 2.5 mg/kg, or about 0.1 to 2.5 mg/kg, hydrate, solvate or polymorph thereof that is useful in the or about 0.4 to 2.5 mg/kg, or about 0.6 to 1.8 mg/kg, or about methods and compositions of this invention include those 0.04 to 2.5 mg/kg, or about 0.06 to 1.8 mg/kg, or about 0.01 disclosed in, for example, International Patent Applications to 1 mg/kg, or about 0.001 to 1 mg/kg, or about 0.5 mg/kg to WO2010/057088; WO2009/008769; WO2008/097.546; 5 mg/kg, or about 0.05 mg/kg to 0.5 mg/kg. In some embodi WO2008/074896; WO2008/073452: WO2007/127474; ments, a subtherapeutic amount of the SV2A inhibitor or a WO2007/107846; WO2006/097588; WO2006/071274; pharmaceutically acceptable salt, hydrate, Solvate or poly WO2006/0703.94: WO2006/060082: WO2006/040688; WO2005/092009; WO2005/079789; WO2005/074535: morph thereof is used. WO2005/0727 13: WO 2005/042475; WO2005/0395.80; 0014. Such subtherapeutic amount, may be, for example, a WO2005/027975; WO2004/084884: WO2004/080393; daily dose of less than 5 mg/kg, less than 2.5 mg/kg, less than WO2004/052348; WO2004/037234: WO2004/034963: 2 mg/kg, less than 1.5 mg/kg, less than 1 mg/kg, less than 0.5 WO2004/032929; WO2003/101458: WO2003/091220; mg/kg, less than 0.1 mg/kg, less than 0.05 mg/kg, less than WO2003/082820; WO2003/082794; WO2003/020289; 0.01 mg/kg, less than 0.005 mg/kg, or less than 0.001 mg/kg, WO2002/074293.; WO2002/032412: WO2001/08514.5; administered every 12 or 24 hours. WO2001/078728; WO2001/066114; WO2001/066096; 0015. In other embodiments of the invention, the AChEI or WO2001/021590; WO2001/000215; WO2000/033840; a pharmaceutically acceptable salt, hydrate, Solvate or poly WO2000/030446; WO2000/023057; WO2000/015205; morph thereof is administered every 12 or 24 hours at a daily WO2000/009483; WO2000/007600; WO2000/002549; dose of about 0.1 to 10 mg. In some embodiments, a subthera WO1999/047131; WO1999/008672; WO1999/007359; peutic amount of the AChEI or a pharmaceutically acceptable WO1998/039000: WO1998/030243: WO1997/138993; WO1997/119059; WO1997/038993; WO1997/029750; salt, hydrate, Solvate or polymorph thereof is administered. In WO1997/021681; WO1997/013754; WO1997/008146; some embodiments, the subtherapeutic amount of the AChEI WO1996/040682: WO1994/029255; WO1994/020476; administered is a daily dose of less than about 10 mg, less than WO1994/019356; WO1993/116690: WO1993/113100; about 5 mg, less than about 2 mg, less than about 1 mg, less WO1993/0071.40; WO1993/003041: WO1993/003034; than about 0.5 mg. WO1992/019238; WO1992/017475; WO1991/003467; and 0016. In other embodiments of the invention, the SV2A WO1988/008708; U.S. Pat. Nos. 7,846,930; 7,732,162: inhibitor and the AChEI, or their pharmaceutically acceptable 7,635,709; 7,378,425; 6,495,700; 6,479,523; 6,372,760; salts, hydrates, Solvates or polymorphs are administered 6,245,911; 6,140,321; 5,985,864; 5,965,571; 5,965,569; simultaneously, or sequentially, or in a single formulation or 5,750,542; 5,744,476; 5,693,668; 5,668,117: 5,663,448: in separate formulations packaged together. In other embodi 5,622,976; 5,603,176; 5,602, 176; 5,574,046; 5,455,245; ments, the SV2A inhibitor and the AChEI, or their pharma 5,391,553: 5,389,629; 5,364,864; 5,338,548; 5,302,593; ceutically acceptable salts, hydrates, Solvates or polymorphs 5,300,517: 5,288,758: 5,246,947; 5,231,093; 5,187,165; are administered via different routes. As used herein, "com 5,166, 181; 5,106,856; 5,102,891; 5,100,901: 4,950,658: bination' includes administration by any of these formula 4,948,807; 4,948,807; 4,948,807; 4,914,102; 4,895,841; tions or routes of administration. 4,895,841; 4,816,456; 4,663,318; 4,663,318; 4,663,318; and 0017. In some embodiments of the invention, the com 2,701.225; Japanese Patent Application Nos. 4-216704 and bined treatment has a longer or improved therapeutic effect in 4-187674, Canadian Patent No. 2,180,703, European Patent the subject than is attained by administering the AChEI or a Application Publication Nos. 298202; 23.6684; 409676: pharmaceutically acceptable salt, hydrate, Solvate or poly 411534; 468187;477903: 481429:487071; 611769; 703901; morph thereof in the absence of the SV2A inhibitor or a 1050303; 2018874; and 2260839; U.S. Publication Nos. pharmaceutically acceptable salt, Solvate, hydrate, or poly 20010036949; 200201 19963; 20030078252: 2003069289; morph thereof by at least about 1.5.x, or 2.0x, or 2.5.x, or 3.0x. 20040082644; 2005.0245504; 20050124642: 20060052428; or 3.5x, or 4.0x, or 4.5x, or 5.0x, or 5.5.x, or 6.0x, or 6.5x, or 20070275959; 20080103105; 20080261950; 20090124659; 7.0x, or 7.5x, or 8.0x, or 8.5x, or 9.0x, or 9.5x, or 10x, or 20100152108; 2010O227852; and 20100311697. However, greater than about 10x. any AChEI or a pharmaceutically acceptable salt, hydrate, 0018. In other embodiments of the invention, the com Solvate or polymorph may be used in the methods and com bined treatment has a longer or improved therapeutic effect in positions of this invention. the subject than is attained by administering the SV2A inhibi 0013. In other embodiments of the invention, the SV2A tor or a pharmaceutically acceptable salt, hydrate, Solvate or inhibitor or a pharmaceutically acceptable salt, hydrate, Sol polymorph thereof in the absence of the AChEI or a pharma vate or polymorph thereof can be administered at doses as ceutically acceptable salt, hydrate, Solvate or polymorph disclosed, for example, in U.S. patent application Ser. No. thereof by at least about 1.5.x, or 2.0x, or 2.5.x, or 3.0x, or US 2011/0212928 A1 Sep. 1, 2011

3.5x, or 4.0x, or 4.5x, or 5.0x, or 5.5.x, or 6.0x, or 6.5x, or or an extended release form. In some embodiments, the com 7.0x, or 7.5x, or 8.0x, or 8.5x, or 9.0x, or 9.5x, or 10x, or position is in a unit dosage form. In other embodiments, the greater than about 10x. two components of the compositions are in separate delivery 0019. In accordance with another aspect of the present forms packaged together. invention, there is provided a method of increasing the thera 0024. In some embodiments of this invention, the compo peutic index of an AChEI or a pharmaceutically acceptable sition comprises levetiracetam or a derivative oran analog or salt, hydrate, solvate or polymorph thereof in a method of a pharmaceutically acceptable salt, hydrate, Solvate or poly treating a central nervous system (CNS) disorder with cogni morph thereof and donepezil a derivative or an analog or a tive impairment in a subject in need or at risk thereof, com pharmaceutically acceptable salt, hydrate, Solvate or poly prising administering an SV2A inhibitor or a pharmaceuti morph thereof. cally acceptable salt, hydrate, Solvate or polymorph thereof in 0025. In some embodiments of this invention, the SV2A combination with an AChEI or a pharmaceutically acceptable inhibitor or a pharmaceutically acceptable salt, hydrate, Sol salt, hydrate, Solvate or polymorph thereof to said subject. vate or polymorph thereof in the composition is present in an 0020. In some embodiments, the increase in the therapeu amount of 0.07-350 mg, or 50-250 mg. or 3-50 mg. In some tic index of the AChEI or a pharmaceutically acceptable salt, embodiments, the SV2A inhibitor or a pharmaceutically hydrate, Solvate or polymorph thereof is greater than the acceptable salt, hydrate, Solvate or polymorph thereof is therapeutic index of the AChEI when administered in the present in an amount less than 350 mg, less than 250 mg, less absence of the SV2A inhibitor or a pharmaceutically accept than 200 mg, less than 150 mg, less than 100 mg, less than 50 able salt, hydrate, Solvate or polymorph thereof or a pharma mg, less than 10 mg, less than 5 mg, less than 1 mg, less than ceutically acceptable salt, hydrate, Solvate or polymorph of 0.5 mg, less than 0.1 mg, or less than 0.07 mg. the AChEI when administered in the absence of the SV2A 0026. In some embodiments of this invention, the AChEI inhibitor or a pharmaceutically acceptable salt, hydrate, Sol or a pharmaceutically acceptable salt, hydrate, Solvate or vate or polymorph thereof by at least about 1.5.x, or 2.0x, or polymorph thereof is present in an amount of 0.1 mg to 10 mg. 2.5.x, or 3.0x, or 3.5x, or 4.0x, or 4.5x, or 5.0x, or 5.5.x, or In some embodiments, the AChEI or a pharmaceutically 6.0x, or 6.5x, or 7.0x, or 7.5x, or 8.0x, or 8.5x, or 9.0x, or acceptable salt, hydrate, Solvate or polymorph thereof is 9.5x, or 10x, or greater than about 10x. present in an amount of less than 10 mg, less than 5 mg, less 0021. In accordance with another aspect of the present than 2 mg, less than 1 mg, or less than 0.5 mg. invention, there is provided a method of increasing the thera peutic index of an SV2A inhibitor or a pharmaceutically BRIEF DESCRIPTION OF THE DRAWINGS acceptable salt, hydrate, Solvate or polymorph thereof in a 0027 FIG. 1 depicts the effects of administering levetirac method of treating a central nervous system (CNS) disorder etam on the spatial memory retention of ten aged-impaired with cognitive impairment in a Subject in need or at risk rats (AI) in an eight-arm Radial Arm Maze (RAM) test. Six thereof, comprising administering an SV2A inhibitor or a treatment conditions are employed: Vehicle control, levetirac pharmaceutically acceptable salt, hydrate, Solvate or poly etam (1.25 mg/kg/day), levetiracetam (2.5 mg/kg/day), leve morph thereof in combination with an AChEI or a pharma tiracetam (5 mg/kg/day), levetiracetam (10 mg/kg/day) and ceutically acceptable salt, hydrate, Solvate or polymorph levetiracetam (20 mg/kg/day). In the RAM task used, there is thereof to said subject. a one-hour delay between presentation of a subset of arms (5 0022. In some embodiments, the increase in the therapeu arms available and 3 arms blocked) and completion of the tic index of the SV2A inhibitor or a pharmaceutically accept eight-arm win-shift task (eight arms available). Rats are pre able salt, hydrate, Solvate or polymorphthereof is greater than treated 30-40 minutes before daily trials with a one-time the therapeutic index of the SV2A inhibitor, hydrate, solvate drug/control treatment. The number of errors made by the rats or polymorph when administered in the absence of the AChEI during the retention phase is used as a measure of spatial or a pharmaceutically acceptable salt, hydrate, Solvate or memory retention. Errors are defined as instances when rats polymorph thereof or a pharmaceutically acceptable salt, enter an arm from which food has already been retrieved in hydrate, solvate or polymorph of the SV2A inhibitor when the pre-delay component of the trial or when rats re-visit an administered in the absence of the AChEI or a pharmaceuti arm in the post-delay session that had already been visited. cally acceptable salt, hydrate, Solvate or polymorph thereof Paired t-tests are used to compare the number of errors by at least about 1.5.x, or 2.0x, or 2.5.x, or 3.0x, or 3.5x, or between different doses of levetiracetam and vehicle control. 4.0x, or 4.5x, or 5.0x, or 5.5.x, or 6.0x, or 6.5.x, or 7.0x, or 0028 FIG.2 depicts the effects of administering donepezil 7.5.x, or 8.0x, or 8.5x, or 9.0x, or 9.5.x, or 10x, or greater than only and administering a combination of donepezil and leve about 10x. tiracetam on the spatial memory retention of eight aged 0023. In accordance with another aspect of this invention, impaired rats (AI) in an eight-arm Radial Arm Maze (RAM) there is provided a pharmaceutical composition for treating, test. Four treatment conditions are employed: Vehicle control, or improving cognitive function in, a Subject suffering from a donepezil only (1 mg/kg/day), donepezil (2 mg/kg/day), and central nervous system (CNS) disorder with cognitive impair a combination of donepezil (1 mg/kg/day) and levetiracetam ment, or at risk thereof, the composition comprising an SV2A (2.5 mg/kg/day). In the RAM task used, there is a two-hour inhibitor and an AChEI or their pharmaceutically acceptable delay between presentation of a subset of arms (5 arms avail salts, hydrates, Solvates or polymorphs. In some embodi able and 3 arms blocked) and completion of the eight-arm ments, the composition is in a solid form. In some embodi win-shift task (eight arms available). Rats are pre-treated ments, the composition is in a liquid form. In some embodi 30-40 minutes before daily trials with a one-time drug/control ments, the composition is in an aqueous solution. In some treatment. The number of errors made by the rats during the embodiments, the composition is in a Suspension form. In retention phase is used as a measure of spatial memory reten Some embodiments, the composition is in a Sustained release tion. Errors are defined as instances when rats enter an arm form, or a controlled release form, or a delayed release form, from which food has already been retrieved in the pre-delay US 2011/0212928 A1 Sep. 1, 2011

component of the trial or when rats re-visit an arm in the 0043 FIG. 11A shows the difference between the control post-delay session that have already been visited. Paired (placebo) subjects and the aNCI subjects treated with pla t-tests are used to compare the number of errors between cebo or with levetiracetam (125 mg twice a day for two different doses of drug treatment and vehicle control. Relative weeks) in their performance of the Benton Visual Retention to vehicle control treatment, a combination of donepezil (1 Test. mg/kg/day) and levetiracetam (2.5 mg/kg/day) significantly 0044 FIG. 11B is a table of the data represented in FIG. improves memory performance (t(7)=2.16, p=0.034). 11A. 004.5 FIG. 12A shows the difference between the control 0029 FIG.3 depicts the experimental design of the human (placebo) subjects and the aNCI subjects treated with pla trials for levetiracetam treatment. cebo or with levetiracetam (125 mg twice a day for two 0030 FIG. 4A depicts the average activity in the left CA3 weeks) in their performance of the Verbal Paired Associates of aMCI subjects with placebo treatment and age-matched Test—Recognition. control Subjects with placebo treatment during the presenta 0046 FIG. 12B is a table of the data represented in FIG. tion of lure stimuli that the subject correctly identified as 12A. “similar 0047 FIG. 13 A shows the difference between the control 0031 FIG. 4B depicts the average activity in the left CA3 (placebo) subjects and the aNCI subjects treated with pla of aMCI subjects with placebo treatment or levetiracetam cebo or with levetiracetam (125 mg twice a day for two treatment (125 mg twice a day for two weeks) during the weeks) in their performance of the Verbal Paired Associates presentation of lure stimuli that the subject correctly identi Test Delayed Recall. fied as “similar.” 0048 FIG. 13B is a table of the data represented in FIG. 13A 0032 FIG. 4C is a table of the data represented in FIGS. 0049 FIG. 14A is a table showing the subject selection 4A and 4.B. process for the human levetiracetam trial described in 0033 FIG. 5A depicts the average activity in the left Example 2. entorhinal cortex of age-matched control Subjects with pla 0050 FIG. 14B is a table showing the characteristics of the cebo treatment and aMCI subjects with placebo treatment subjects selected for the human levetiracetam trial described during the presentation of lure stimuli that the Subject cor in Example 2. rectly identified as “similar.” 0034 FIG. 5B depicts the average activity in the left DETAILED DESCRIPTION OF THE INVENTION entorhinal cortex of the same aMCI subjects with placebo 0051. Unless otherwise defined herein, scientific and tech treatment or levetiracetam treatment (125 mg twice a day for nical terms used in this application shall have the meanings two weeks) during the presentation of lure stimuli that the that are commonly understood by those of ordinary skill in the subject correctly identified as “similar.” art. Generally, nomenclature used in connection with, and 0035 FIG.5C is a table of the data represented in FIGS. techniques of cell and tissue culture, molecular biology, cell 5A and 5B. and cancer biology, neurobiology, neurochemistry, Virology, 0036 FIG. 6A depicts an example of the sequence of immunology, microbiology, pharmacology, genetics and pro images shown to Subjects in the explicit 3-alternative forced tein and nucleic acid chemistry, described herein, are those choice task described in Example 2. well known and commonly used in the art. 0037 FIG. 6B shows sample pairs of similar (“lure') 0.052 The methods and techniques of the present inven images. tion are generally performed, unless otherwise indicated, according to conventional methods well known in the art and 0038 FIG. 7 shows the difference between theaMCI (pla as described in various general and more specific references cebo) Subjects and age-matched control (placebo) subjects in that are cited and discussed throughout this specification. See, their performance of the explicit 3-alternative forced choice e.g. “Principles of Neural Science', McGraw-Hill Medical, task described in Example 2. Each bar represents the propor New York, N.Y. (2000); Motulsky, “Intuitive Biostatistics”, tion of the Subject responses (old, similar, or new) when Oxford University Press, Inc. (1995); Lodish et al., “Molecu presented with a lure image. lar Cell Biology, 4th ed., W. H. Freeman & Co., New York 0039 FIG.8 shows the difference between the same aMCI (2000); Griffiths et al., “Introduction to Genetic Analysis, 7th subjects with placebo treatment or with levetiracetam treat ed., W. H. Freeman & Co., N.Y. (1999); Gilbert et al., ment (125 mg twice a day for two weeks) in their performance “Developmental Biology, 6th ed., Sinauer Associates, Inc., of the explicit 3-alternative forced choice task described in Sunderland, Mass. (2000). Example 2. Each bar represents the proportion of the subjects 0053 Chemistry terms used herein are used according to responses (old, similar, or new) when presented with a lure conventional usage in the art, as exemplified by “The image. McGraw-Hill Dictionary of Chemical Terms”. Parker S., Ed., 0040 FIG. 9 is a table of the data represented in FIGS. 7 McGraw-Hill, San Francisco, C.A. (1985). and 8. 0054 All of the above, and any other publications, patents 004.1 FIG. 10A shows the difference between the age and published patent applications referred to in this applica matched control (placebo) subjects and the aMCI subjects tion are specifically incorporated by reference herein. In case treated with placebo or with levetiracetam (125 mg twice a of conflict, the present specification, including its specific day for two weeks) in their performance of the Bushke Selec definitions, will control. tive reminding Test Delayed Recall. 0055 Throughout this specification, the word “comprise' 0042 FIG. 10B is a table of the data represented in FIG. or variations such as “comprises” or “comprising will be 10A understood to imply the inclusion of a stated integer (or US 2011/0212928 A1 Sep. 1, 2011 components) or group of integers (or components), but not the 0063 Cognitive function may also be measured using exclusion of any other integer (or components) or group of imaging techniques such as Positron Emission Tomography integers (or components). (PET), functional magnetic resonance imaging (fMRI), 0056. The singular forms “a,” “an,” and “the include the Single Photon Emission Computed Tomography (SPECT), or plurals unless the context clearly dictates otherwise. any other imaging technique that allows one to measure brain 0057 The term “including is used to mean “including but function. In animals, cognitive function may also be mea not limited to”. “Including and “including but not limited to Sured with electrophysiological techniques. are used interchangeably. 0064 “Promoting cognitive function refers to affecting 0058. The term "agent' is used hereinto denote a chemical compound (such as an organic or inorganic compound, a impaired cognitive function so that it more closely resembles mixture of chemical compounds), a biological macromol the function of a normal, unimpaired subject. Cognitive func ecule (such as a nucleic acid, an antibody, including parts tion may be promoted to any detectable degree, but in humans thereofas well as humanized, chimeric and human antibodies preferably is promoted sufficiently to allow an impaired sub and monoclonal antibodies, a protein or portion thereof, e.g., ject to carry out daily activities of normal life at the same level a peptide, a lipid, a carbohydrate), or an extract made from of proficiency as a normal, unimpaired Subject. biological materials such as bacteria, plants, fungi, or animal 0065. In some cases, “promoting cognitive function in a (particularly mammalian) cells or tissues. Agents include, for Subject affected by age-related cognitive refers to affecting example, agents which are known with respect to structure, impaired cognitive function so that it more closely resembles and those which are not known with respect to structure. The the function of an aged-matched normal, unimpaired Subject, SV2A inhibitory activity or the AChEI activity of such agents or the function of a young adult Subject. Cognitive function of may render them suitable as “therapeutic agents' in the meth that Subject may be promoted to any detectable degree, but in ods and compositions of this invention. humans preferably is promoted sufficiently to allow an 0059. A “patient”, “subject', or “individual” are used impaired subject to carry out daily activities of normal life at interchangeably and refer to either a human or a non-human the same level of proficiency as an aged-matched normal, animal. These terms include mammals, such as humans, pri unimpaired Subject or as a young adult Subject. mates, livestock animals (including bovines, porcines, etc.), 0.066 “Preserving cognitive function refers to affecting companion animals (e.g., canines, felines, etc.) and rodents normal or impaired cognitive function Such that it does not (e.g., mice and rats). decline or does not fall below that observed in the subject 0060 "Cognitive function” or “cognitive status” refers to upon first presentation or diagnosis, or delays such decline. any higher order intellectual brain process or brain state, respectively, involved in learning and/or memory including, 0067 "Improving cognitive function includes promoting but not limited to, attention, information acquisition, infor cognitive function and/or preserving cognitive function in a mation processing, working memory, short-term memory, Subject. long-term memory, anterograde memory, retrograde 0068 “Cognitive impairment” refers to cognitive function memory, memory retrieval, discrimination learning, deci in Subjects that is not as robust as that expected in a normal, Sion-making, inhibitory response control, attentional set unimpaired subject. In some cases, cognitive function is shifting, delayed reinforcement learning, reversal learning, reduced by about 5%, about 10%, about 30%, or more, com the temporal integration of Voluntary behavior, and express pared to cognitive function expected in a normal, unimpaired ing an interest in one's Surroundings and self-care. Subject. In some cases, “cognitive impairment in Subjects 0061 Inhumans, cognitive function may be measured, for affected by aged-related cognitive impairment refers to cog example and without limitation, by the clinical global impres nitive function in Subjects that is not as robust as that expected sion of change scale (CIBIC-plus scale); the Mini Mental in an aged-matched normal, unimpaired Subject, or the func State Exam (MMSE); the Neuropsychiatric Inventory (NPI); tion of a young adult Subject (i.e. Subjects with mean scores the Clinical Dementia Rating Scale (CDR); the Cambridge for a given age in a cognitive test). Neuropsychological Test Automated Battery (CANTAB); the 0069. "Age-related cognitive impairment” refers to cogni Sandoz Clinical Assessment-Geriatric (SCAG), the Buschke tive impairment in aged subjects, wherein their cognitive Selective Reminding Test (Buschke and Fuld, 1974); the Ver function is not as robust as that expected in an age-matched bal Paired Associates subtest; the Logical Memory subtest; normal Subject or as that expected in young adult Subjects. In the Visual Reproduction subtest of the Wechsler Memory Some cases, cognitive function is reduced by about 5%, about Scale-Revised (WMS-R) (Wechsler, 1997); the Benton 10%, about 30%, or more, compared to cognitive function Visual Retention Test, or the explicit 3-alternative forced expected in an age-matched normal Subject. In some cases, choice task. See Folstein et al., J Psychiatric Res 12: 189-98, cognitive function is as expected in an age-matched normal (1975); Robbins et al., Dementia 5: 266-81, (1994); Rey, subject, but reduced by about 5%, about 10%, about 30%, Lexamen clinique en psychologie, (1964); Kluger et al., J about 50% or more, compared to cognitive function expected Geriatr Psychiatry Neurol 12:168-79, (1999); Marquis et al., in a young adult Subject. Age-related impaired cognitive 2002 and Masur et al., 1994. function may be associated with Mild Cognitive Impairment 0062. In animal model systems, cognitive function may be (MCI) (includingamestic MCI and non-amnestic MCI), Age measured in various conventional ways known in the art, Associated Memory Impairment (AAMI), and Age-related including using a Morris Water Maze (MWM), Barnes circu Cognitive Decline (ARCD). lar maze, elevated radial arm maze, T maze or any other 0070 "Cognitive impairment' associated with AD or mazes in which the animals use spatial information. Other related to AD or in AD refers to cognitive function in subjects tests known in the art may also be used to assess cognitive that is not as robust as that expected in Subjects who have not function, such as novel object recognition and odor recogni been diagnosed AD using conventional methodologies and tion tasks. standards. US 2011/0212928 A1 Sep. 1, 2011

(0071. “Mild Cognitive Impairment” or “MCI” refers to a 0078 Dementia with Lewy bodies is characterized by condition characterized by isolated memory impairment abnormal deposits of alpha-synuclein that form inside neu unaccompanied other cognitive abnormalities and relatively rons in the brain. Cognitive impairment may be similar to AD, normal functional abilities. One set of criteria for a clinical including impairments in memory and judgment and behav characterization of MCI specifies the following characteris ior changes. 007.9 Frontotemporal dementia is characterized by glio tics: (1) memory complaint (as reported by patient, infor sis, neuronal loss, Superficial spongiform degeneration in the mant, or physician), (2) normal activities of daily living frontal cortex and/oranterior temporal lobes, and Picks' bod (ADLS), (3) normal global cognitive function, (4) abnormal ies. Symptoms include changes in personality and behavior, memory for age (defined as scoring more than 1.5 standard including a decline in Social skills and language expression/ deviations below the mean for a givenage), and (5) absence of comprehension. indicators of dementia (as defined by DSM-IV guidelines). 0080) “Post traumatic stress disorder (PTSD) refers to an Petersen et al., Srch. Neurol. 56: 303-308 (1999); Petersen, anxiety disorder characterized by an immediate or delayed “Mild cognitive impairment: Aging to Alzheimer's Disease.” response to a catastrophic event, characterized by re-experi Oxford University Press, N.Y. (2003). encing the trauma, psychic numbing or avoidance of stimuli 0072 Diagnosis of MCI usually entails an objective associated with the trauma, and increased arousal. Re-expe assessment of cognitive impairment, which can be garnered riencing phenomena include intrusive memories, flashbacks, through the use of well-established neuropsychological tests, nightmares, and psychological or physiological distress in including the Mini Mental State Examination (MMSE), the response to trauma reminders. Such responses produce anxi Cambridge Neuropsychological Test Automated Battery ety and can have significant impact, both chronic and acute, (CANTAB) and individual tests such as Rey Auditory Verbal on a patient’s quality of life and physical and emotional Learning Test (AVLT), Logical Memory Subtest of the health. PTSD is also associated with impaired cognitive per formance, and older individuals with PTSD have greater revised Wechsler Memory Scale (WMS-R) and the New York decline in cognitive performance relative to control patients. University (NYU) Paragraph Recall Test. See Folstein et al., I0081. “Schizophrenia' refers to a chronic debilitating dis JPsychiatric Res 12: 189-98 (1975); Robbins et al., Dementia order, characterized by a spectrum of psychopathology, 5:266-81 (1994): Klugeret al., J Geriatric Psychiatry Neurol including positive symptoms such as aberrant or distorted 12:168-79 (1999). mental representations (e.g., hallucinations, delusions), nega 0073 "Age-Associate Memory Impairment (AAMI)” tive symptoms characterized by diminution of motivation and refers to a decline in memory due to aging. A patient may be adaptive goal-directed action (e.g., anhedonia, affective flat considered to have AAMI if he or she is at least 50 years old tening, avolition), and cognitive impairment. While abnor and meets all of the following criteria: a) The patient has malities in the brain are proposed to underlie the full spectrum noticed a decline in memory performance, b) The patient of psychopathology in Schizophrenia, currently available performs worse on a standard test of memory compared to antipsychotics are largely ineffective in treating cognitive young adults, c) All other obvious causes of memory decline, impairments in patients. except normal aging, have been ruled out (in other words, the I0082 Amyotrophic lateral sclerosis also known as memory decline cannot be attributed to other causes such as a ALS, refers to a progressive, fatal, neurodegenerative disease recent heart attack or head injury, depression, adverse reac characterized by a degeneration of motor neurons, the nerve tions to medication, Alzheimer's disease, etc.). cells in the central nervous system that control Voluntary muscle movement. ALS is also characterized by neuronal 0074) “Age-Related Cognitive Decline (ARCD) refers to degeneration in the entorhinal cortex and hippocampus, declines in memory and cognitive abilities that are a normal memory deficits, and neuronal hyperexcitability in different consequence of aging in humans (e.g., Craik & Salthouse, brain areas such as the cortex. 1992). This is also true in virtually all mammalian species. I0083) “Cancer-therapy-related cognitive impairment' 0075 Age-Associated Memory Impairment refers to refers to cognitive impairment that develops in Subjects that older persons with objective memory declines relative to their are treated with cancer therapies Such as chemotherapy and younger years, but cognitive functioning that is normal rela radiation. Cytotoxicity and other adverse side-effects on the tive to their age peers (Crook et al., 1986). Age-Consistent brain of cancer therapies result in cognitive impairment in Memory Decline is a less pejorative label which emphasizes Such functions as memory, learning and attention. that these are normal developmental changes (Crook, 1993; I0084 “Treating a condition or patient refers to taking Larrabee, 1996), are not pathophysiological (Smith et al., steps to obtain beneficial or desired results, including clinical 1991), and rarely progress to overt dementia (Youngjohn & results. Beneficial or desired clinical results include, but are Crook, 1993). The DSM-IV (1994) has codified the diagnos not limited to, preventing or slowing the progression of the tic classification of ARCD. disease or disorder, or alleviation, amelioration, or slowing the progression, of one or more symptoms associated with 0076 Alzheimer's disease (AD) is characterized by CNS disorders with cognitive impairment, Such as age-re memory deficits in its early phase. Later symptoms include lated cognitive impairment, Mild Cognitive Impairment impaired judgment, disorientation, confusion, behavior (MCI), amnestic MCI, dementia, Alzheimer's Disease (AD), changes, trouble speaking, and motor deficits. Histologically, prodromal AD, PTSD, schizophrenia, amyotrophic lateral AD is characterized by beta-amyloid plaques and tangles of Sclerosis (ALS), or cancer therapy-related cognitive impair protein tau. ment. Treating age-related cognitive impairment further com 0077 Vascular dementia is caused by strokes. Symptoms prises slowing the conversion of age-related cognitive impair overlap with those of AD, but without the focus on memory ment (including, but not limited to MCI, ARCD and AAMI) impairment. into dementia (e.g., AD). US 2011/0212928 A1 Sep. 1, 2011

0085. “Treating cognitive impairment” refers to taking 0088. As used herein, administration of an SV2A inhibitor steps to improve cognitive functionina Subject with cognitive and an AChEI orpharmaceutically acceptable salts, hydrates, impairment so that the Subject's performance in one or more solvates, or polymorphs thereof "in combination” or cognitive tests is improved to any detectable degree, or is “together includes simultaneous administration and/or prevented from further decline. Preferably, that subject's cog administration at different times. Such as sequential adminis nitive function, after treatment of cognitive impairment, more tration. It also includes administration in a single formulation closely resembles the function of a normal, unimpaired Sub or in separate formulation packaged together. ject. Treatment of cognitive impairment in humans may 0089. The term “simultaneous administration,” as used improve cognitive function to any detectable degree, but is herein, means that the SV2A inhibitor and the AChEI, or their preferably improved sufficiently to allow the impaired sub pharmaceutically acceptable salts, hydrates, Solvates, or ject to carry out daily activities of normal life at the same level polymorphs, are administered with a time separation of no of proficiency as a normal, unimpaired subject. In some cases, more than about 15 minutes, and in some embodiments no “treating cognitive impairment” refers to taking steps to more than about 10 minutes. When the drugs are administered improve cognitive function in a Subject with cognitive impair simultaneously, the SV2A inhibitor and the AChEI, or their ment so that the Subject's performance in one or more cogni salts, hydrates, Solvates, or polymorphs, may be contained in tive tests is improved to any detectable degree, or is prevented the same dosage (e.g., a unit dosage form comprising both the from further decline. Preferably, that subject's cognitive func SV2A inhibitor and the AChEI) or in discrete dosages (e.g., tion, after treatment of cognitive impairment, more closely the SV2A inhibitor or its salt, hydrate, solvate, or polymorph resembles the function of a normal, unimpaired Subject. In is contained in one dosage form and the AChEI or its salt, Some cases, “treating cognitive impairment in a subject hydrate, Solvate, or polymorphis contained in another dosage affecting by age-related cognitive impairment refers to tak form). ings steps to improve cognitive function in the Subject so that 0090 The term “sequential administration” as used herein the Subject's cognitive function, after treatment of cognitive means that the SV2A inhibitor and the AChEI, or their phar impairment, more closely resembles the function of an age maceutically acceptable salts, hydrates, Solvates, polymor matched normal, unimpaired subject, or the function of a phs, are administered with a time separation of more than young adult Subject. about 15 minutes, and in Some embodiments more than about I0086) “Administering or “administration of a substance, one hour, or up to 12 hours. Either the SV2A inhibitor or the a compound or an agent to a Subject can be carried out using AChEI may be administered first. The SV2A inhibitor and the one of a variety of methods known to those skilled in the art. AChEI, or their salts, hydrates, solvents, or polymorphs, for For example, a compound or an agent can be administered, sequential administration may be contained in discrete dos intravenously, arterially, intradermally, intramuscularly, age forms, optionally contained in the same container or intraperitonealy, intravenously, Subcutaneously, ocularly, package. Sublingually, orally (by ingestion), intranasally (by inhala 0091. A “therapeutically effective amount of a drug or tion), intraspinally, intracerebrally, and transdermally (by agent is an amount of a drug or an agent that, when adminis absorbtion, e.g., through a skin duct). A compound or agent tered to a subject will have the intended therapeutic effect, can also appropriately be introduced by rechargeable or bio e.g. improving cognitive function in a Subject, e.g., a patient degradable polymeric devices or other devices, e.g., patches having a CNS disorder with cognitive impairment. The full and pumps, or formulations, which provide for the extended, therapeutic effect does not necessarily occur by administra slow, or controlled release of the compound or agent. Admin tion of one dose, and may occur only after administration of istering can also be performed, for example, once, a plurality a series of doses. Thus, a therapeutically effective amount of times, and/or over one or more extended periods. In some may be administered in one or more administrations. The aspects, the administration includes both direct administra precise effective amount needed for a subject will depend tion, including self-administration, and indirect administra upon, for example, the Subject's size, health and age, the tion, including the act of prescribing a drug. For example, as nature and extent of the cognitive impairment, and the thera used herein, a physician who instructs apatient to self-admin peutics or combination of therapeutics selected for adminis ister a drug, or to have the drug administered by another tration, and the mode of administration. The skilled worker and/or who provides a patient with a prescription for a drug is can readily determine the effective amount for a given situa administering the drug to the patient. tion by routine experimentation. 0087 Appropriate methods of administering a substance, a compound or an agent to a subject will also depend, for 0092 "Subtherapeutic amount” refers to an amount example, on the age of the Subject, whether the Subject is administered of an agent or compound of the invention that is active or inactive at the time of administering, whether the less than the therapeutic amount, that is, less than the amount Subject is cognitively impaired at the time of administering, normally used when said agent or compound is administered the extent of the impairment, and the chemical and biological alone (i.e., individually and in the absence of other therapeu properties of the compound or agent (e.g. solubility, digest tic agents or compounds) to treat disorders involving cogni ibility, bioavailability, stability and toxicity). In some tive dysfunction. embodiments, a compound oran agent is administered orally, 0093 “Analog is used herein to refer to a compound e.g., to a subject by ingestion, or intravenously, e.g., to a which functionally resembles another chemical entity, but Subject by injection. In some embodiments, the orally admin does not share the identical chemical structure. For example, istered compound or agent is in an extended release or slow an analog is Sufficiently similar to a base or parent compound release formulation, or administered using a device for Such Such that it can Substitute for the base compound in therapeu slow or extended release. tic applications, despite minor structural differences. US 2011/0212928 A1 Sep. 1, 2011

0094 “Derivative' is used herein to refer to the chemical allowing access to all eight arms. After the delay period, modification of a compound. Chemical modifications of a subjects are placed back onto the center platform (with the compound can include, for example, replacement of hydro barriers to the previously blocked arms removed) and allowed gen by an alkyl, acyl, or amino group. Many other modifica to obtain the remaining food rewards during this retention test tions are also possible. phase of the trial. The identity and configuration of the 0095. The term “prodrug is art-recognized and is blocked arms vary across trials. The number of "errors' the intended to encompass compounds or agents which, under Subjects make during the retention test phase is tracked. An physiological conditions, are converted into an SV2A inhibi error occurs in the trial if the subjects entered an arm from tor or an AChEI. A common method for making a prodrug is which food had already been retrieved in the pre-delay com to select moieties which are hydrolyzed or metabolized under ponent of the trial, or if it re-visits an arm in the post-delay physiological conditions to provide the desired compound or session that had already been visited. A fewer number of agent. In other embodiments, the prodrug is converted by an errors would indicate better spatial memory. The number of enzymatic activity of the host animal to an inhibitor of SV2A errors made by the test Subject, under various test compound or an AChEI. treatment regimes, can then be compared for efficacy of the 0096 “Pharmaceutically acceptable salts' is used herein test compound in treating CNS disorders with cognitive to refer to an agent or a compound according to the invention impairment. that is a therapeutically active, non-toxic base and acid salt 0100 Another cognitive test that may be used to assess the form of the agents and compounds of the invention. effects of a test compound on the cognitive impairment of a CNS disorder model animal is the Morris water maze A water DESCRIPTION OF METHODS OF THE maze is a pool Surrounded with a novel set of patterns relative INVENTION to the maze. The training protocol for the water maze may be based on a modified water maze task that has been shown to 0097. The methods of this invention comprise administra be hippocampal-dependent (de HoZ. et al., Eur: J. Neurosci., tion of an SV2A inhibitor or a pharmaceutically acceptable 22:745-54, 2005; Steele and Morris, Hippocampus 9:118-36, salt thereof in combination with administration of an AChEI 1999). The subject is trained to locate a submerged escape or a pharmaceutically acceptable salt thereof. The agents or platform hidden underneath the surface of the pool. During compounds of the SV2A inhibitor or the AChEI and their the training trial, a Subject is released in the maze (pool) from pharmaceutically acceptable salts also include hydrates, Sol random starting positions around the perimeter of the pool. Vates, polymorphs, and prodrugs of those agents, compounds, The starting position varies from trial to trial. If the subject and salts. does not locate the escape platform within a set time, the experimenter guides and places the Subject on the platform to Methods of Assessing Cognitive Impairment “teach the location of the platform. After a delay period 0098 Animal models serve as an important resource for following the last training trial, a retention test in the absence developing and evaluating treatments for CNS disorders with of the escape platform is given to assess spatial memory. The cognitive impairment. Features that characterize cognitive subject's level of preference for the location of the (now impairment in animal models typically extend to cognitive absent) escape platform, as measured by, e.g., the time spent impairment in humans. Efficacy in Such animal models is, in that location or the number of crossings of that location thus, expected to be predictive of efficacy in humans. The made by the mouse, indicates better spatial memory, i.e., extent of cognitive impairment in an animal model for a CNS treatment of cognitive impairment. The preference for the disorder, and the efficacy of a method of treatment for said location of the escape platform under different treatment CNS disorder may be tested and confirmed with the use of a conditions, can then be compared for efficacy of the test variety of cognitive tests. compound in treating CNS disorders with cognitive impair 0099 A Radial Arm Maze (RAM) behavioral task is one ment. example of a cognitive test, specifically testing spacial 0101 There are various tests known in the art for assessing memory (Chappell et al. Neuropharmacology 37: 481-487. cognitive function in humans, for example and without limi 1998). The RAM apparatus consists of, e.g., eight equidis tation, the clinical global impression of change scale (CIBIC tantly spaced arms. A maze arm projects from each facet of a plus scale); the MiniMental State Exam (MMSE); the Neu centerplatform. A food well is located at the distal end of each ropsychiatric Inventory (NPI); the Clinical Dementia Rating arm. Food is used as a reward. Blocks can be positioned to Scale (CDR); the Cambridge Neuropsychological Test Auto prevent entry to any arm. Numerous extra maze cues Sur mated Battery (CANTAB); the Sandoz Clinical Assessment rounding the apparatus may also be provided. After habitua Geriatric (SCAG), the Buschke Selective Reminding Test tion and training phases, spatial memory of the Subjects may (Buschke and Fuld, 1974); the Verbal Paired Associates sub be tested in the RAM under control or test compound-treated test; the Logical Memory subtest; the Visual Reproduction conditions. As a part of the test, subjects are pretreated before subtest of the Wechsler Memory Scale-Revised (WMS-R) trials with a vehicle control or one of a range of dosages of the (Wechsler, 1997); or the Benton Visual Retention Test. See test compound. At the beginning of each trial, a Subset of the Folstein et al., J Psychiatric Res 12: 189-98, (1975); Robbins arms of the eight-arm maze is blocked. Subjects are allowed et al., Dementia 5:266-81, (1994); Rey, Lexamen cliniqueen to obtain food on the unblocked arms to which access is psychologie, (1964); Kluger et al., J Geriatr Psychiatry Neu permitted during this initial “information phase' of the trial. rol 12:168-79, (1999); Marquis et al., 2002 and Masur et al., Subjects are then removed from the maze for a delay period, 1994. Another example of a cognitive test in humans is the e.g., a 60 second delay, a 15 minute delay, a one-hour delay, a explicit 3-alternative forced choice task. In this test, subjects two-hour delay, a six hour delay, a 24 hour delay, or longer) are presented with color photographs of common objects between the information phase and the subsequent “retention consisting of a mix of three types of image pairs: similar pairs, test, during which the barriers on the maze are removed, thus identical pairs and unrelated foils. The second of the pair of US 2011/0212928 A1 Sep. 1, 2011

similar objects is referred to as the “lure'. These image pairs such as MCI, ARCD and AAMI or for the risk thereof. The are fully randomized and presented individually as a series of dose of the composition and dosage interval for the methodis, images. Subjects are instructed to make a judgment as to as described herein, one that is safe and efficacious in those whether the objects seen are new, old or similar. A “similar applications. response to the presentation of a lure stimulus indicates suc 0104. In some embodiments, a subject to be treated by the cessful memory retrieval by the Subject. By contrast, calling methods and compositions of this invention exhibits age the lure stimulus “old” or “new” indicates that correct related cognitive impairment or is at risk of Such impairment. memory retrieval did not occur. In some embodiments, the age-related cognitive impairment 0102. In addition to assessing cognitive performance, the includes, without limitation, Age-Associated Memory progression of age-related cognitive impairment and demen Impairment (AAMI), Mild Cognitive Impairment (MCI) and tia, as well as the conversion of age-related cognitive impair Age-related Cognitive Decline (ARCD). ment into dementia, may be monitored by assessing Surrogate 0105 Animal models serve as an important resource for changes in the brain of the Subject. Surrogate changes developing and evaluating treatments for Such age-related include, without limitation, changes in regional brain Vol cognitive impairments. Features that characterize age-related umes, perforant path degradation, and changes seen in brain cognitive impairment in animal models typically extend to function through resting state fMRI (R-fMRI) and fluorode age-related cognitive impairment in humans. Efficacy in Such oxyglucose positron emission tomography (FDG-PET). animal models is, thus, expected to be predictive of efficacy in Examples of regional brain Volumes useful in monitoring the humans. progression of age-related cognitive impairment and demen 0106 Various animal models of age-related cognitive tia include reduction of hippocampal Volume and reduction in impairment are known in the art. For example, extensive volume or thickness of entorhinal cortex. These volumes may behavioral characterization has identified a naturally occur be measured in a subject by, for example, MRI. Aisen et al. ring form of cognitive impairment in an outbred strain of aged Alzheimer's & Dementia 6:239-246 (2010). Perforant path Long-Evans rats (Charles River Laboratories; Gallagher et degradation has been shown to be linked to age, as well as al., Behav Neurosci. 107:618-626, (1993)). In a behavioral reduced cognitive function. For example, older adults with assessment with the Morris Water Maze (MWM), rats learn more perforant path degradation tend to perform worse in and remember the location of an escape platform guided by a hippocampus-dependent memory tests. Perforant path degra configuration of spatial cues Surrounding the maze. The cog dation may be monitored in Subjects through ultrahigh-reso nitive basis of performance is tested in probe trials using lution diffusion tensor imaging (DTI). Yassa et al., PNAS measures of the animal's spatial bias in searching for the 107:12687-12691 (2010). Resting-state fMRI (R-fMRI) location of the escape platform. Aged rats in the study popu involves imaging the brain during rest, and recording large lation have no difficulty swimming to a visible platform, but amplitude spontaneous low-frequency (<0.1 Hz) fluctuations an age-dependent impairment is detected when the platform in the fMRI signal that are temporally correlated across func is camouflaged, requiring the use of spatial information. Per tionally related areas. Seed-based functional connectivity, formance for individual aged rats in the outbred Long-Evans independent component analyses, and/or frequency-domain strain varies greatly. For example, a proportion of those rats analyses of the signals are used to reveal functional connec perform on a par with young adults. However, approximately tivity between brain areas, particularly those areas whose 40-50% fall outside the range of young performance. This connectivity increase or decrease with age, as well as the variability among aged rats reflects reliable individual differ extent of cognitive impairment and/or dementia. FDG-PET ences. Thus, within the aged population Some animals are uses the uptake of FDG as a measure of regional metabolic cognitively impaired and designated aged-impaired (AI) and activity in the brain. Decline of FDGuptake in regions such as other animals are not impaired and are designated aged-un the posterior cingulated cortex, temporoparietal cortex, and impaired (AU). See, e.g., Colombo et al., Proc. Natl. Acad. prefrontal association cortex has been shown to relate to the Sci. 94: 14195-14199, (1997); Gallagher and Burwell, Neu extent of cognitive decline and dementia. Aisen et al., Alzhe robiol. Aging 10: 691-708, (1989); Gallagher et al. Behav. imer's & Dementia 6:239-246 (2010), Herholz et al., Neu Neurosci. 107:618-626, (1993); Rapp and Gallagher, Proc. roImage 17:302-316 (2002). Natl. Acad. Sci. 93:9926-9930, (1996); Nicolle et al., Neu roscience 74:741-756, (1996); Nicolleet al., J. Neurosci. 19: Age-Related Cognitive Impairment 9604-9610, (1999); International Patent Publication 0103) This invention provides methods and compositions WO2007/019312 and International Patent Publication WO for treating age-related cognitive impairment or the risk 2004/048551. Such an animal model of age-related cognitive thereof using an SV2A inhibitor or a pharmaceutically impairment may be used to assay the effectiveness of the acceptable salt thereof in combination with an AChEI or a methods and compositions this invention in treating age pharmaceutically acceptable salt thereof. In certain embodi related cognitive impairment. ments, treatment comprises preventing or slowing the pro 0107 The efficacy of the methods and compositions of gression, of age-related cognitive impairment. In certain this invention in treating age-related cognitive impairment embodiments, treatment comprises alleviation, amelioration may be assessed using a variety of cognitive tests, including or slowing the progression, of one or more symptoms asso the Morris water maze and the radial arm maze, as discussed ciated with age-related cognitive impairment. In certain above. embodiments, treatment of age-related cognitive impairment comprises slowing the conversion of age-related cognitive Dementia impairment (including, but not limited to MCI, ARCD and 0108. This invention also provides methods and composi AAMI) into dementia (e.g., AD). The methods and composi tions for treating dementia using an SV2A inhibitor or a tions may be used for human patients in clinical applications pharmaceutically acceptable salt thereof in combination with in the treating age-related cognitive impairment in conditions an AChEI or a pharmaceutically acceptable salt thereof. In US 2011/0212928 A1 Sep. 1, 2011

certain embodiments, treatment comprises preventing or 0114. One rat model of PTSD is Time-dependent sensiti slowing the progression, of dementia. In certain embodi zation (TDS). TDS involves exposure of the animal to a ments, treatment comprises alleviation, amelioration, or severely stressful event followed by a situational reminder of slowing the progression of one or more symptoms associated the prior stress. The following is an example of TDS. Rats are with dementia. In certain embodiments, the symptom to be placed in a restrainer, then placed in a Swim tank and made to treated is cognitive impairment. In certain embodiments, the Swim for a period of time, e.g., 20min Following this, each rat dementia is Alzheimer's disease (AD), Vascular dementia, is then immediately exposed to a gaseous anesthetic until loss dementia with Lewy bodies, or frontotemporal dementia. The of consciousness, and finally dried. The animals are left methods and compositions may be used for human patients in undisturbed for a number of days, e.g., one week. The rats are clinical applications in treating dementia. The dose of the then exposed to a "restress' session consisting of an initial composition and dosage interval for the method is, as stressor, e.g., a Swimming session in the Swim tank (Liberzon described herein, one that is safe and efficacious in those et al., Psychoneuroendocrinology 22: 443-453, 1997; Harv applications. ery et al., Psychopharmacology 175:494-502, 2004). TDS 0109 Animal models serve as an important resource for results in an enhancement of the acoustic startle response developing and evaluating treatments for dementia. Features (ASR) in the rat, which is comparable to the exaggerated that characterize dementia in animal models typically extend acoustic startle that is a prominent symptom of PTSD (Khan to dementia in humans. Thus, efficacy in Such animal models and Liberzon, Psychopharmacology 172: 225-229, 2004). is expected to be predictive of efficacy in humans. Various Such animal models of PTSD may be used to assay the animal models of dementia are known in the art, Such as the effectiveness of the methods and compositions of this inven PDAPP, Tg2576, APP23, TgCRND8, J20, hPS2 Tg, and tion of the invention in treating PTSD. APP-PS1 transgenic mice. Sankaranarayanan, Curr: Top. 0115 The efficacy of the methods and compositions of Medicinal Chem. 6: 609-627, 2006; Kobayashi et al. Genes this invention in treating PTSD, or cognitive impairment Brain Behavi. 4: 173-196. 2005; Ashe and Zahns, Neuron. 66: associated with PTSD, may also be assessed in animals mod 631-45, 2010. Such animal models of dementia may be used els of PTSD, as well as human subjects with PTSD, using a to assay the effectiveness of the methods and compositions of variety of cognitive tests known in the art, as discussed above. this invention of the invention in treating dementia. 0110. The efficacy of the methods and compositions of Schizophrenia this invention in treating dementia, or cognitive impairment 0116. This invention additionally provides methods and associated with dementia, may be assessed in animals models compositions for treating schizophrenia using an SV2A of dementia, as well as human Subjects with dementia, using inhibitor or a pharmaceutically acceptable salt thereof in a variety of cognitive tests known in the art, as discussed combination with an AChEI or a pharmaceutically acceptable above. salt thereof. In certain embodiments, treatment comprises preventing or slowing the progression, of Schizophrenia. In Post Traumatic Stress Disorder certain embodiments, treatment comprises alleviation, ame 0111. This invention also provides methods and composi lioration or slowing the progression, of one or more symp tions for treating post traumatic stress disorder (PTSD) using toms associated with Schizophrenia. In certain embodiments, an SV2A inhibitor or a pharmaceutically acceptable salt the symptom to be treated is cognitive impairment. The meth thereof in combination with an AChEI or a pharmaceutically ods and compositions may be used for human patients in acceptable salt thereof. In certain embodiments, treatment clinical applications in treating schizophrenia. The dose of comprises preventing or slowing the progression, of PTSD. In the composition and dosage interval for the method is, as certain embodiments, treatment comprises alleviation, ame described herein, one that is safe and efficacious in those lioration, or slowing the progression of one or more symp applications. toms associated with PTSD. In certain embodiments, the 0117 Cognitive impairments are also associated with symptom to be treated is cognitive impairment. The methods Schizophrenia. They precede the onset of psychosis and are and compositions may be used for human patients in clinical present in non-affected relatives. The cognitive impairments applications in treating PTSD. The dose of the composition associated with Schizophrenia constitute a good predictor for and dosage interval for the methodis, as described herein, one functional outcome and are a core feature of the disorder. that is safe and efficacious in those applications. Cognitive features in Schizophrenia reflect dysfunction in 0112 Patients with PTSD (and, to a lesser degree trauma frontal cortical and hippocampal circuits. Patients with exposed patients without PTSD) have smaller hippocampal Schizophrenia also present hippocampal pathologies such as volumes (Woon et al., Prog. Neuro-Psychopharm. & Biologi reductions in hippocampal Volume, reductions in neuronal cal Psych. 34, 1181-1188: Wang et al., Arch. Gen. Psychiatry size and dysfunctional hyperactivity. An imbalance in exci 67:296-303, 2010). PTSD is also associated with impaired tation and inhibition in these brain regions has also been cognitive performance. Older individuals with PTSD have documented in Schizophrenic patients suggesting that drugs greater declines in cognitive performance relative to control targeting inhibitory mechanisms could be therapeutic. See, patients (Yehuda et al., Bio. Psych. 60: 714-721, 2006) and e.g., Guidotti et al., Psychopharmacology 180: 191-205, have a greater likelihood of developing dementia (Yaffe et al., 2005; Zierhut, Psych. Res. Neuroimag. 183:187-194, 2010; Arch. Gen. Psych. 678: 608-613, 2010). Wood et al., NeuroImage 52:62-63, 2010; Vinkers et al., 0113 Animal models serve as an important resource for Expert Opin. Investig. Drugs 19:1217-1233, 2009: Young et developing and evaluating treatments for PTSD. Features that al., Pharmacol. Ther: 122:150-202, 2009. characterize PTSD in animal models typically extend to 0118 Animal models serve as an important resource for PTSD in humans. Thus, efficacy in such animal models is developing and evaluating treatments for schizophrenia. Fea expected to be predictive of efficacy in humans. Various ani tures that characterize schizophrenia in animal models typi mal models of PTSD are known in the art. cally extend to schizophrenia in humans. Thus, efficacy in US 2011/0212928 A1 Sep. 1, 2011

such animal models is expected to be predictive of efficacy in In certain embodiments, the symptom to be treated is cogni humans. Various animal models of schizophrenia are known tive impairment. The methods and compositions may be used in the art. for human patients in clinical applications in treating ALS. 0119. One animal model of schizophrenia is protracted The dose of the composition and dosage interval for the treatment with methionine. Methionine-treated mice exhibit method is, as described herein, one that is safe and efficacious deficient expression of GAD67 in frontal cortex and hippoc in those applications. ampus, similar to those reported in the brain of postmortem I0122. In addition to the degeneration of motor neurons, schizophrenia patients. They also exhibit prepulse inhibition ALS is characterized by neuronal degeneration in the entorhi of startle and social interaction deficits (Tremonlizzo et al., nal cortex and hippocampus, memory deficits, and neuronal PNAS, 99: 17095-17100, 2002). Another animal model of hyperexcitability in different brain areas such as the cortex. schizophrenia is methylaoxymethanol acetate (MAM)-treat I0123. The efficacy of the methods and compositions of ment in rats. Pregnant female rats are administered MAM (20 this invention in treating ALS, or cognitive impairment asso mg/kg, intraperitoneal) on gestational day 17. MAM-treat ciated with ALS, may also be assessed in animal models of ment recapitulate a pathodevelopmental process to Schizo ALS, as well as human Subjects with ALS, using a variety of phrenia-like phenotypes in the offspring, including anatomi cognitive tests known in the art, as discussed above. cal changes, behavioral deficits and altered neuronal information processing. More specifically, MAM-treated rats Cancer Therapy-Related Cognitive Impairment display a decreased density of parvalbumin-positive 0.124. This invention additionally provides methods and GABAergic interneurons in portions of the prefrontal cortex compositions for treating cancer therapy-related cognitive and hippocampus. In behavioral tests, MAM-treated rats dis impairment using an SV2A inhibitor or a pharmaceutically play reduced latent inhibition. Latent inhibition is a behav acceptable salt thereof in combination with an AChEI or a ioral phenomenon where there is reduced learning about a pharmaceutically acceptable salt thereof. In certain embodi stimulus to which there has been prior exposure with any ments, treatment comprises preventing or slowing the pro consequence. This tendency to disregard previously benign gression, of cancer therapy-related cognitive impairment. In stimuli, and reduce the formation of association with Such certain embodiments, treatment comprises alleviation, ame stimuli is believed to prevent sensory overload. Low latent lioration or slowing the progression, of one or more symp inhibition is indicative of psychosis. Latent inhibition may be toms associated with cancer therapy-related cognitive impair tested in rats in the following manner Rats are divided into ment. The methods and compositions may be used for human two groups. One group is pre-exposed to a tone over multiple patients in clinical applications in treating cancer therapy trials. The other group has no tone presentation. Both groups related cognitive impairment. The dose of the composition are then exposed to an auditory fear conditioning procedure, and dosage interval for the methodis, as described herein, one in which the same tone is presented concurrently with a that is safe and efficacious in those applications. noxious stimulus, e.g. an electric shock to the foot. Subse 0.125. Therapies that are used in cancer treatment, includ quently, both groups are presented with the tone, and the rats ing chemotherapy, radiation, or combinations thereof, can change in locomotor activity during tone presentation is cause cognitive impairment in patients, in Such functions as monitored. After the fear conditioning the rats respond to the memory, learning and attention. Cytotoxicity and other tone presentation by strongly reducing locomotor activity. adverse side-effects on the brain of cancer therapies are the However, the group that has been exposed to the tone before basis for this form of cognitive impairment, which can persist the conditioning period displays robust latent inhibition: the for decades. (Dietrich et al., Oncologist 13:1285-95, 2008: Suppression of locomotor activity in response to tone presen Soussain et al., Lancet 374:1639-51, 2009). tation is reduced. MAM-treated rats, by contrast show 0.126 Cognitive impairment following cancer therapies impaired latent inhibition. That is, exposure to the tone pre reflects dysfunction in frontal cortical and hippocampal cir vious to the fear conditioning procedure has no significant cuits that are essential for normal cognition. In animal mod effect in Suppressing the fear conditioning. (see Lodge et al., els, exposure to either chemotherapy or radiation adversely J. Neurosci., 29:2344-2354, 2009) Such animal models of affects performance on tests of cognition specifically depen schizophrenia may be used to assay the effectiveness of the dent on these brain systems, especially the hippocampus methods and compositions of the invention in treating schizo (Kim et al., J. Radiat. Res. 49:517-526, 2008; Yang et al., phrenia. Neurobiol. Learning and Mem. 93:487-494, 2010). Thus, 0120. The efficacy of the methods and compositions of drugs targeting these cortical and hippocampal systems could this invention in treating Schizophrenia, or cognitive impair be neuroprotective in patients receiving cancer therapies and ment associated with Schizophrenia, may also be assessed in efficacious in treating symptoms of cognitive impairment that animal models of Schizophrenia, as well as human Subjects may last beyond the interventions used as cancer therapies. with Schizophrenia, using a variety of cognitive tests known I0127. Animal models serve as an important resource for in the art, as discussed above. developing and evaluating treatments for cancer therapy-re lated cognitive impairment. Features that characterize cancer Amyotropic Lateral Sclerosis (ALS) therapy-related cognitive impairment in animal models typi 0121 This invention additionally provides methods and cally extend to cancer therapy-related cognitive impairment compositions for treating ALS using an SV2A inhibitor or a in humans. Thus, efficacy in Such animal models is expected pharmaceutically acceptable salt thereof in combination with to be predictive of efficacy in humans. an AChEI or a pharmaceutically acceptable salt thereof. In I0128 Various animal models of cancer therapy-related certain embodiments, treatment comprises preventing or cognitive impairment are known in the art. slowing the progression, of ALS. In certain embodiments, I0129. Examples of animal models of cancer therapy-re treatment comprises alleviation, amelioration or slowing the lated cognitive impairment include treating animals with anti progression, of one or more symptoms associated with ALS. neoplastic agents such as cyclophosphamide (CYP) or with US 2011/0212928 A1 Sep. 1, 2011

radiation, e.g., "Cogamma-rays. (Kim et al., J. Radiat. Res. Patent Application Publication Numbers 20090312333; 49:517-526, 2008; Yang et al., Neurobiol. Learning and Mem. 20090018148; 20080081832; 2006258704; and UK Patent 93:487-494, 2010). The cognitive function of animal models Numbers 1,039,113; and 1,309,692 or their pharmaceutically of cancer therapy-related cognitive impairment may then be acceptable salts, hydrates, Solvates, or polymorphs. Other tested with cognitive tests to assay the effectiveness of the SV2A inhibitors may also be used in this invention. Appli methods and compositions of the invention in treating cancer cants also refer to methods of preparing these compounds therapy-related cognitive impairment. The efficacy of the found in the documents cited above. Other synthetic methods methods and compositions of this invention in treating cancer may also be used. These methods are well known to those therapy-related cognitive impairment, as well as human Sub skilled in the art. jects with cancer therapy-related cognitive impairment, using 0133. In some embodiments of this invention, the SV2A a variety of cognitive tests known in the art, as discussed inhibitor is selected from the group consisting of levetirac above. etam, brivaracetam, and seletracetam or derivatives or ana logs or pharmaceutically acceptable salts, Solvates, hydrates, SV2A Inhibitor polymorphs, or prodrugs thereof. 0130 “Synaptic vesicle protein-2 (SV2) is a family of 0.134. In some embodiments of this invention, the SV2A synaptic vesicle proteins, which consists of three members, inhibitor is levetiracetam or salts, Solvates, hydrates, poly designated SV2A, SV2B, and SV2C. SV2A is the most morphs or prodrugs thereof. Levetiracetam refers to the Inter widely distributed family member, being expressed ubiqui national Union of Pure and Applied Chemistry (IUPAC) tously in the brain. The proteins are integral membrane pro name of the compound (2S)-2-(2-oxopyrrolidin-1-yl)butana teins and have a low-level homology (20-30%) to the twelve mide). Levetiracetam is a widely used antiepileptic drug. transmembrane family of bacterial and fungal transporter Levetiracetam binds to a specific site in the CNS: the synaptic proteins that transport Sugar, citrate, and Xenobiotics (Baj vesicle protein 2A (SV2A) (See, e.g., Noyer et al. 1995: Fuks jalieh et al., Science. 257: 1271-1273. (1992)). SV2 family et al. 2003; Lynch et al. 2004; Gillard et al. 2006) and has proteins are present in the brain and endocrine cells, and further been shown to directly inhibit synaptic activity and further are present in all synaptic and endocrine vesicles. SV2 neurotransmission by inhibiting presynaptic neurotransmit proteins are reported to play a role in normal synaptic func ter release (Yang et al., 2007). tion, and functions in a maturation step of primed vesicles that 0.135 Among the SV2A inhibitors useful for the methods converts the vesicles into a Ca(*)- and synaptotagmin-re and compositions of this invention are the following: sponsive state (Sudhofet al., 2009). Functionally, SV2 pro (0.136 i) International Patent Application WO 2001/ teins are reported to enhance synaptic currents and increase O62726: the probability of transmitter release by maintaining the size 0.137. A compound having the formula I or a pharmaceu of the readily releasable pool of vesicles (Custer et al., 2006). tically acceptable salt thereof, 0131 “SV2A inhibitor refers to any agent, substance or compound that binds to SV2A and reduces synaptic function by reducing pre-synaptic vesicle release (See, e.g., Noyer et (I) al. 1995: Fuks et al. 2003; Lynch et al. 2004; Gillard et al. 2006; Custeret al., 2006:Smedt et al., 2007:Yanget al., 2007: and Example 8 of WO 2001/62726, all of which are specifi cally incorporated herein by reference.) A substance, or a compound or an agent is an SV2A inhibitor even if it does not itself bind to SV2A, as long as it causes, or affects the ability of another compound or agent to bind SV2A or reduce Syn aptic function by reducing pre-synaptic vesicle release. SV2A inhibitors, as used herein, include pharmaceutically 0138 wherein X is - CANRR or CAOR7 or acceptable salts of the inhibitors thereof. They also include - CA'-R or CN: hydrates, polymorphs, prodrugs, salts, and Solvates of these I0139 A' and A are independently oxygen, sulfur or inhibitors. NR; 0132 Among the SV2A inhibitors or pharmaceutically I0140) R' is hydrogen, alkyl, aryl or —CH R'" wherein acceptable salts, hydrates, Solvates and polymorphs thereof R" is aryl, heterocycle, halogen, hydroxy, amino, nitro or that are useful in the methods and compositions of this inven cyano; tion are those disclosed, for example, U.S. patent application 0141 R, R and Rare the same or different and each is Ser. No. 12/580,464, International Patent Application PCT/ independently hydrogen, halogen, hydroxy, thiol, amino, US2009/005647, U.S. Patent Application 61/105,847, U.S. nitro, nitrooxy, cyano, azido, carboxy, amido, Sulfonic acid, Patent Application 61/152,631, and U.S. Patent Application Sulfonamide, alkyl, alkenyl, alkynyl, ester, ether, aryl, hetero 61/175,536. However, any SV2A inhibitor or a pharmaceuti cycle, or an oxy derivative, thio derivative, amino derivative, cally acceptable salt, hydrate, Solvate or polymorph thereof acyl derivative, sulfonyl derivative or sulfinyl derivative: may be used in the methods and compositions of the inven 0.142 R, R and R“are the same or different and each tion. In some embodiments, the SV2A inhibitor is selected is independently hydrogen, halogen, alkyl, alkenyl, alkynyl from the group of SV2A inhibitors referred to in International or aryl; Patent Applications WO2010/144712: WO2010/002869; 0143 R. R. R7 and Rare the same or different and each WO2008/132139; WO2007/065595; WO2006/128693; is independently hydrogen, hydroxy, alkyl, aryl, heterocycle WO2006/128692; WO2005/054188: WO2004/087658; or an oxy derivative; and WO2002/094787; WO2001/062726; U.S. Pat. Nos. 7,465, I0144 R is hydrogen, hydroxy, thiol, halogen, alkyl, aryl, 549; 7,244,747: 5,334,720; 4,696,943; 4,696,942; U.S. heterocycle or a thio derivative: US 2011/0212928 A1 Sep. 1, 2011

(0145 with the provisos that at least one of as R. R. R. substituted by 1 to 5 substituents independently selected from R, R and R' is other than hydrogen; and that when the the group consisting of halogen, hydroxy, thiol, amino, nitro, compound is a mixture of all possible isomers, X is cyano, thiocyanato, acyl, acyloxy, Sulfonyl derivative, Sulfi —CONR'R''. A is oxygen and R' is hydrogen, methyl, ethyl nyl derivative, alkylamino, carboxy, ester, ether, amido, or propyl then Substitution on the pyrolidine ring is other than azido, cycloalkyl, Sulfonic acid, Sulfonamide, thio derivative, mono-, di-, or tri-methyl or mono-ethyl; and that when R. R. oxyester, oxyamido, heterocycle, vinyl, C1-5-alkoxy, C6-10 R. R. Rand R“are each hydrogen, A is oxygen and X aryloxy and C6-10-aryl. is CONRR then R is different from carboxy, ester, amido, 0154 Preferred alkyl groups are methyl, ethyl, propyl, Substituted oxo-pyrrolidine, hydroxy, oxy derivative, amino, isopropyl, butyl, iso or ter-butyl, and 2.2.2-trimethylethyl amino derivatives, methyl, naphthyl, phenyl optionally Sub each optionally substituted by at least one substituent selected stituted by oxy derivatives or in the para position by an halo from the group consisting of halogen, hydroxy, thiol, amino, gen atom. nitro and cyano. Such as trifluoromethyl, trichloromethyl, 0146 In the definitions set forth below, unless otherwise 2.2.2-trichloroethyl, 1,1-dimethyl-2,2-dibromoethyl, 1,1- stated, R'' and R'' are the same or different and each is dimethyl-2.2.2-trichloroethyl. independently amido, alkyl, alkenyl, alkynyl, acyl, ester, 0155 The term “alkenyl' as used herein, is defined as ether, aryl, aralkyl, heterocycle or an oxy derivative, thio including both branched and unbranched, unsaturated hydro derivative, acyl derivative, amino derivative, sulfonyl deriva carbon radicals having at least one double bond Such as ethe tive, or sulfinyl derivative, each optionally substituted with nyl (vinyl), 1-methyl-1-ethenyl, 2,2-dimethyl-1-ethenyl, any Suitable group, including, but not limited to, one or more 1-propenyl, 2-propenyl (allyl), 1-butenyl, 2-butenyl, 3-bute moieties selected from lower alkyl or other groups as nyl, 4-pentenyl, 1-methyl-4-pentenyl, 3-methyl-1-pentenyl, described below as substituents for alkyl. 1-hexenyl, 2-hexenyl, and the like and being optionally Sub 0147 The term “oxy derivative', as used herein is defined stituted by at least one substituent selected from the group as including —O R'' groups wherein R'' is as defined consisting of halogen, hydroxy, thiol, amino, nitro, cyano, above except for “oxy derivative'. Non-limiting examples are aryland heterocycle Such as mono- and di-halo vinyl where alkoxy, alkenyloxy, alkynyloxy, acyloxy, oxyester, oxya halo is fluoro, chloro or bromo. mido, alkylsulfonyloxy, alkylsulfinyloxy, arylsulfonyloxy, 0156 The term “alkynyl as used herein, is defined as arylsulfinyloxy, aryloxy, aralkoxy or heterocyclooxy Such as including a monovalent branched or unbranched hydrocar pentyloxy, allyloxy, methoxy, ethoxy, phenoxy, benzyloxy, bon radical containing at least one carbon-carbon triple bond, 2-naphthyloxy, 2-pyridyloxy, methylenedioxy, carbonate. for example ethynyl, 2-propynyl ( propargyl), and the like 0148. The term “thio derivative” as used herein, is defined and being optionally Substituted by at least one Substituent as including S R' groups wherein R' is as defined selected from the group consisting of halogen, hydroxy, thiol, above except for “thio derivative'. Non-limiting examples are amino, nitro, cyano, aryl and heterocycle. Such as haloethy alkylthio, alkenylthio, alkynylthio and arylthio. nyl. 0149. The term “amino derivative' as used herein, is 0157. When present as bridging groups, alkyl, alkenyl and defined as including NHR'' or NR'R'' groups wherein alkynyl represent straight- or branched chains, C1-12, pref R'' and R'' are as defined above. Non-limiting examples are erably C1-4-alkylene or C2-12-, preferably C2-4-alkenylene mono- or di-alkyl-, alkenyl-, alkynyl- and arylamino or mixed or -alkynylene moieties respectively. amino. 0158 Groups where branched derivatives are convention 0150. The term “acyl derivative' as used herein, repre ally qualified by prefixes such as “n”, “sec”, “iso’ and the like sents a radical derived from carboxylic acid and thus is (e.g., “n-propyl', 'sec-butyl') are in the n-form unless other defined as including groups of the formula R'—CO , wise stated. wherein R'' is as defined above and may also be hydrogen. 0159. The term “aryl as used herein, is defined as includ Non-limiting examples are formyl, acetyl, propionyl, isobu ing an organic radical derived from an aromatic hydrocarbon tyryl, Valeryl, lauroyl, heptanedioyl, cyclohexanecarbonyl, consisting of 1-3 rings and containing 6-30 carbon atoms by crotonoyl, fumaroyl, acryloyl, benzoyl, naphthoyl, furoyl, removal of one hydrogen, such as phenyl and naphthyl each nicotinoyl 4-carboxybutanoyl, oxalyl ethoxalyl, cysteinyl, optionally substituted by 1 to 5 substituents independently oxamoyl. selected from halogen, hydroxy, thiol, amino, nitro, cyano, 0151. The term “sulfonyl derivative' as used herein, is acyl, acyloxy, Sulfonyl, Sulfinyl, alkylamino, carboxy, ester, defined as including a group of the formula -SO. R', ether, amido, azido, Sulfonic acid, Sulfonamide, alkylsulfo wherein R'' is as defined above except for “sulfonyl deriva nyl, alkylsulfinyl, alkylthio, oxyester, oxyamido, aryl, C1-6- tive'. Non-limiting examples are alkylsulfonyl, alkenylsulfo alkoxy, C6-10-aryloxy, C1-6-alkyl, C1-6-haloalkyl. Aryl nyl, alkynylsulfonyl and arylsulfonyl. radicals are preferably monocyclic containing 6-10 carbon 0152 The term "sulfinyl derivative' as used herein, is atoms. Preferred aryl groups are phenyl and naphthyl each defined as including a group of the formula -SO-R'', optionally substituted by 1 to 5 substituents independently wherein R'' is as defined above except for “sulfinyl deriva selected from halogen, nitro, amino, azido, C1-6-alkoxy, tive'. Non-limiting examples are alkylsulfinyl, alkenylsulfi C1-6-alkylthio, C1-6-alkyl, C1-6-haloalkyl and phenyl. nyl, alkynylsulfinyl and arylsulfinyl. 0160 The term “halogen', as used herein, includes an 0153. The term “alkyl, as used herein, is defined as atom of Cl, Br, F. I. including Saturated, monovalent hydrocarbon radicals having 0.161 The term “hydroxy’, as used herein, represents a straight, branched or cyclic moieties or combinations thereof group of the formula —OH. and containing 1-20 carbon atoms, preferably 1-6 carbon 0162 The term “thiol, as used herein, represents a group atoms for non-cyclic alkyl and 3-6 carbon atoms for of the formula—SH. cycloalkyl (in these two preferred cases, unless otherwise 0163 The term “cyano”, as used herein, represents a specified, “lower alkyl). Alkyl moieties may optionally be group of the formula—CN. US 2011/0212928 A1 Sep. 1, 2011

0164. The term "nitro', as used herein, represents a group 0.175. In the above definitions it is to be understood that of the formula - NO. when a substituent such as R,R,R,R,R,R,R,R, 0.165. The term "nitrooxy’, as used herein, represents a R", R is attached to the rest of the molecule via a heteroatom group of the formula —ONO. or a carbonyl, a straight- or branched chain, C1-12-, prefer 0166 The term “amino', as used herein, represents a ably C1-4-alkylene or C2-12, preferably C2-4-alkenylene or group of the formula —NH. -alkynylene bridge may optionally be interposed between the heteroatom or the carbonyl and the point of attachment to the 0167. The term “azido’, as used herein, represents a group rest of the molecule. of the formula - N. (0176 Preferred examples of X are -COOR or 0168 The term “carboxy’, as used herein, represents a - CONRR, wherein R, R and R7 are preferably hydro group of the formula—COOH. gen, C1-4-alkyl, phenyl or alkylphenyl. 0169. The term "sulfonic acid, as used herein, represents (0177 Preferably X is carboxy or -CONRR, wherein a group of the formula—SOH. R and R are preferably hydrogen, C1-4-alkyl, phenyl or 0170 The term "sulfonamide', as used herein, represents alkylphenyl, especially —CONH2. a group of the formula—SONH. (0178 Preferably A' and Aare each oxygen. 0171 The term “ester', as used herein is defined as includ (0179 Preferably R' is hydrogen, alkyl, especially C1-12 ing a group of formula -COO R' wherein R'' is as alkyl, particularly lower alkyl or aryl especially phenyl. defined above except oxy derivative, thio derivative or amino (0180 Examples of preferred R' groups are methyl, ethyl, derivative. propyl, isopropyl, butyl, iso- or ter-butyl, 2.2.2-trimethyl 0172. The term “ether is defined as including a group ethyl each optionally attached via a methylene bridge or the selected from C1-50-straight or branched alkyl, or C2-50 same Substituted by at least one halogenatom Such as trifluo straight or branched alkenyl or alkynyl groups or a combina romethyl, trichloromethyl, 2.2.2-trichloroethyl, 1,1-dim tion of the same, interrupted by one or more oxygen atoms. ethyl-2,2-dibromoethyl, 1,1-dimethyl-2.2.2-trichloroethyl. 0173 The term "amido' is defined as including a group of 0181) R' as ethyl is especially preferred. formula CONH, or CONHR'' or CONR'R'' 0182 Preferably Rand R* are independently hydrogen, wherein R'' and R'' are as defined above. halogen or alkyl, especially lower alkyl. 0.174. The term "heterocycle', as used herein is defined as (0183 Examples of preferred R and R" groups are inde including an aromatic or non aromatic cyclic alkyl, alkenyl, pendently hydrogen, halogen or methyl, ethyl, propyl, iso or alkynyl moiety as defined above, having at least one O.S propyl, butyl, iso or ter-butyl, 2.2.2-trimethylethyl or the and/or Natom interrupting the carbocyclic ring structure and same Substituted by at least one halogenatom Such as trifluo optionally, one of the carbon of the carbocyclic ring structure romethyl, trichloromethyl, 2.2.2-trichloroethyl, 1,1-dim may be replaced by a carbonyl. Non-limiting examples of ethyl-2,2-dibromoethyl, 1,1-dimethyl-2.2.2-trichloroethyl. aromatic heterocycles are pyridyl, furyl, pyrrolyl, thienyl, 0.184 Especially at least one and most preferably both of isothiazolyl, imidazolyl, benzimidazolyl, tetrazolyl, R° and R* are hydrogen. quinazolinyl, quinolizinyl, naphthyridinyl, pyridazinyl, pyri 0185. Preferably R. RandR“are independently hydro midinyl, pyrazinyl, quinolyl, isoquinolyl, isobenzofuranyl. gen, alkyl, especially methyl or ethyl oraryl especially phenyl benzothienyl, pyrazolyl, indolyl, indolizinyl, purinyl, isoin or aralkyl, especially benzyl. dolyl, carbazolyl, thiazolyl, 1,2,4-thiadiazolyl, thieno (2,3-b) 0186 Examples of preferred R, R and R“ groups are furanyl, furopyranyl, benzofuranyl, benzoxepinyl, isoox independently hydrogen, halogen or methyl, ethyl, propyl. azolyl, oxazolyl, thianthrenyl, benzothiazolyl, or benzox isopropyl, butyl, iso or ter-butyl, 2.2.2-trimethylethyl or the azolyl, cinnolinyl, phthalazinyl, quinoxalinyl, phenanthridi same Substituted by at least one halogenatom Such as trifluo nyl, acridinyl, perimidinyl, phenanthrolinyl, phenothiazinyl, romethyl, trichloromethyl, 2.2.2-trichloroethyl, 1,1-dim furazanyl, isochromanyl, indolinyl, Xanthenyl, hypoxanthi ethyl-2,2-dibromoethyl, 1,1-dimethyl-2.2.2-trichloroethyl. nyl, pteridinyl, 5-azacytidinyl, 5-azauracilyl, thiazolopyridi 0187. Especially at least one and most preferably both of nyl, imidazolopyridinyl, pyrrolopyrimidinyl, and pyrazol R" and R“are hydrogen. opyrimidinyl optionally substituted by alkyl or as described 0188 R is particularly hydrogen or alkyl, especially above for the alkyl groups. Non-limiting examples of non lower alkyl and is most preferably hydrogen. aromatic heterocycles are tetrahydrofuranyl, tetrahydropyra (0189 Preferably R is hydrogen, C1-12-alkyl, especially nyl, piperidinyl, piperidyl, piperazinyl, imidazolidinyl, mor C1-6-alkyl, each optionally substituted by one or more sub pholino, morpholinyl, 1-oxaspiro(4.5)dec-2-yl, pyrrolidinyl, stituents selected from hydroxy, halogen, cyano, thiocyanato 2-oxo-pyrrolidinyl, Sugar moieties (i.e. glucose, pentose, or alkoxy and attached to the ring either directly or via a thio. hexose, ribose, fructose, which may also be substituted) or the Sulfinyl, Sulfonyl, carbonyl or oxycarbonyl group and option same which can optionally be substituted with any suitable ally, a C1-4-alkylene bridge, particularly methylene; C2-6- group, including but not limited to one or more moieties alkenyl or -alkynyl, especially C2-3-alkenyl or -alkynyl each selected from lower alkyl, or other groups as described above optionally substituted by one or more halogens; azido: cyano; for the alkyl groups. The term "heterocycle” also includes amido: carboxy; triazolyl, tetrazolyl pyrrolidinyl, pyridyl, bicyclic, tricyclic and tetracyclic, Spiro groups in which any 1-oxidopyridyl, thiomorpholinyl, benzodioxolyl, furyl, of the above heterocyclic rings is fused to one or two rings oxazolyl, pyrimidinyl, pyrrolyl, thiadiazolyl, thiazolyl, thie independently selected from an aryl ring, a cyclohexane ring, nyl or piperazinyl each optionally Substituted by one or more a cyclohexene ring, a cyclopentane ring, a cyclopentene ring substituents selected from halogen, C1-6-alkyl and phenyl or another monocyclic heterocyclic ring or where a monocy and attached to the ring either directly or via a carbonyl group clic heterocyclic group is bridged by an alkylene group. Such or a C1-4-alkylene bridge, particularly methylene; naphthyl; as quinuclidinyl, 7-azabicyclo(2.2.1)heptanyl, 7-Oxabicyclo or phenyl, phenylalkyl or phenylalkenyl each optionally Sub (2.2.1) heptanyl, 8-azabicyclo(3.2.1)octanyl. stituted by one or more substituents selected from halogen, US 2011/0212928 A1 Sep. 1, 2011

C1-6-alkyl, C1-6 haloalkyl, C1-6-alkoxy, C1-6-alkylthio. one or more halogen, cyano, thiocyano, azido, cyclopropyl. amino, azido, phenyl and nitro and each attached to the ring acyl and/or phenyl; or phenylsulfonyloxy whereby any phe either directly or via an oxy, Sulfonyl, Sulfonyloxy, carbonyl nyl moiety may be substituted by one or more halogen, alkyl, or carbonyloxy group and optionally additionally a C1-4- haloalkyl, alkoxy, nitro, amino, and/or phenyl; most prefer alkylene bridge, particularly methylene. ably methyl, ethyl, propyl, isopropyl, butyl, or isobutyl. (0190. Also, preferably, R is C1-6-alkyl optionally substi (0206 R, R and Rare hydrogen: tuted by one or more Substituents selected from halogen, 0207 R. R. R7 are the same or different and each is thiocyanato, azido, alkoxy, alkylthio, phenylsulfonyl: independently hydrogen, hydroxy, alkyl, aryl, heterocycle or nitrooxy; C2-3-alkenyl or -alkynyl each optionally substi oxy derivative; and tuted by one or more halogens or by acetyl, tetrazolyl, (0208 R is hydrogen, hydroxy, thiol, halogen, alkyl, aryl, pyridyl, furyl, pyrrolyl, thiazolyl or thienyl; or phenyl or heterocycle, alkylthio or thio derivative. phenylalkyl each optionally substituted by one or more sub 0209. Within these Compounds 1A, R' is preferably stituents selected from halogen, C1-6-alkyl, C1-6 haloalkyl, methyl, ethyl, propyl, isopropyl, butyl, or isobutyl; most pref C1-6-alkoxy, amino, azido, phenyl and nitro and each erably methyl, ethyl or n-propyl. attached to the ring either directly or via a sulfonyloxy and (0210 RandR are preferably independently hydrogen or optionally additionally a C1-4-alkylene bridge, particularly halogen or methyl, ethyl, propyl, isopropyl, butyl, isobutyl, methylene. and, most preferably, are each hydrogen. (0191). Other examples of preferred R groups are hydro 0211 R is preferably C1-5 alkyl, C2-5 alkenyl, C2-C5 gen, halogen or methyl, ethyl, propyl, isopropyl, butyl, iso or alkynyl, cyclopropyl azido, each optionally substituted by ter-butyl, 2.2.2-trimethylethyl or the same substituted by at one or more halogen, cyano, thiocyano, azido, alkylthio. least one halogen atom Such as trifluoromethyl, trichlorom cyclopropyl, acyl and/or phenyl; phenyl; phenylsulfonyl: ethyl, 2.2.2-trichloroethyl, 1,1-dimethyl-2,2-dibromoethyl, phenylsulfonyloxy, tetrazole, thiazole, thienyl, furyl, pyrrole, 1,1-dimethyl-2.2.2-trichloroethyl. pyridine, whereby any phenyl moiety may be substituted by (0192 R is especially C1-4-alkyloptionally substituted by one or more halogen, alkyl, haloalkyl, alkoxy, nitro, amino, one or more Substituents selected from halogen, thiocyanato and/or phenyl; most preferably methyl, ethyl, propyl, isopro or azido; C2-5-alkenyl or -alkynyl, each optionally Substi pyl, butyl, or isobutyl. tuted by one or more halogens; thienyl; or phenyl optionally 0212 X is preferably -COOH or -COOMe or substituted by one or more substituents selected from halo - COOEt or -CONH; most preferably – CONH2. gen, C1-6-alkyl, C1-6 haloalkyl or azido. 0213. A further particular group of compounds of formula (0193 Further examples of preferred R groups are C1-6 I (Compounds 1B) comprises those wherein, alkyl and C2-6 haloalkenyl. 0214 X is - CANH –CA'NHCH or - CAN(CH) (0194 Preferably Rand Rare independently hydrogen, methyl, ethyl, propyl, isopropyl, butyl, iso or ter-butyl, 2.2, 0215) R' is alkyl or phenyl: 2-trimethylethyl, especially hydrogen or methyl. (0216) R is alkyl, alkenyl, alkynyl, cyano, isothiocyanato, 0.195 Especially at least one and most preferably both of ether, carboxyl, amido, aryl, heterocycle; or Rand Rare hydrogen. 0217 R is CHR' wherein R' is hydrogen, cycloalkyl, (0196) Preferably R’ is hydrogen, methyl, ethyl, propyl, oxyester, oxyalkylsulfonyl, oxyarylsulfonyl, aminoalkylsul isopropyl, butyl, iso or tert-butyl, 2.2.2-trimethylethyl, meth fonyl, aminoarylsulfonyl, nitrooxy, cyano, isothiocyanato, oxy, ethoxy, phenyl, benzyl or the same Substituted by at least azido, alkylthio, arylthio, alkylsulfinyl, alkylsulfonyl, hetero one halogen atom such as trifluoromethyl, chlorophenyl. cycle, aryloxy, alkoxy or trifluoroethyl; (0197) Preferably R’ is hydrogen, methyl or ethyl espe (0218 R is hydrogen, alkyl or aryl (especially with the cially hydrogen. proviso that when R is hydrogen, Rother than methyl); (0198 Preferably R is hydrogen, methyl, ethyl, propyl, 0219 or RR form a cycloalkyl: isopropyl, butyl, iso or ter-butyl, 2.2.2-trimethylethyl, phe 0220 and R. R. Rand R“are each hydrogen. nyl, benzyl or the same Substituted by at least one halogen 0221) Within the compounds of formula I, atom such as trifluoromethyl, chlorobenzyl. 0222 R is preferably alkyl especially C1-12- more par (0199 Preferably R is hydrogen or methyl. ticularly C1-6-alkyl and is most preferably ethyl; 0200 Combinations of one or more of these preferred 0223 R. R. R. and Rare preferably hydrogen: compound groups are especially preferred. 0224 R is preferably selected from hydrogen; C1-12 0201 A particular group of compounds of formula I alkyl, especially C1-6-alkyl, each optionally substituted by (Compounds 1A) comprises those wherein, one or more Substituents selected from hydroxy, halogen, (0202) A is oxygen; cyano, thiocyanato or alkoxy and attached to the ring either 0203 X is CONRR or COOR7 or CO R or directly or via a thio. Sulfinyl, Sulfonyl, carbonyl or oxycar CN: bonyl group and optionally additionally a C1-4-alkylene 0204) R' is hydrogen or alkyl, aryl, halogen, hydroxy, bridge, particularly methylene; C2-6-alkenyl or -alkynyl, amino, nitro, cyano; especially C2-3-alkenyl or -alkynyl, each optionally Substi 0205 R. R. R. are the same or different and each is tuted by one or more halogens; azido; cyano; amido: carboxy; independently hydrogen or halogen, hydroxy, amino, nitro, triazolyl, tetrazolyl pyrrolidinyl, pyridyl, 1-oxidopyridyl, cyano, acyl, acyloxy, a Sulfonyl derivative, a Sulfinyl deriva thiomorpholinyl, benzodioxolyl, furyl, oxazolyl pyrimidi tive, an amino derivative, carboxy, ester, ether, amido, Sul nyl, pyrrolyl, thiadiazolyl, thiazolyl, thienyl or piperazinyl fonic acid, Sulfonamide, alkoxycarbonyl, a thio derivative, each optionally substituted by one or more substituents alkyl, alkoxy, oxyester, oxyamido, aryl, an oxy derivative, selected from halogen, C1-6-alkyl and phenyl and attached to heterocycle, vinyl and R may additionally represent C2-5 the ring either directly or via a carbonyl group or a C1-4- alkenyl, C2-5 alkynyl or azido each optionally substituted by alkylene bridge, particularly methylene; naphthyl, or phenyl, US 2011/0212928 A1 Sep. 1, 2011 phenylalkyl or phenylalkenyl each optionally substituted by 0249 (2S)-2-(4R)-4-(azidomethyl)-2-oxopyrrolidinyl one or more Substituents selected from halogen, C1-6-alkyl, butanamide; C1-6 haloalkyl, C1-6-alkoxy, C1-6-alkylthio, amino, azido, 0250) 2-4-(2,2-dibromovinyl)-2-oxo-1-pyrrolidinylbu phenyl and nitro and each attached to the ring either directly tanamide; or via an oxy, Sulfonyl, Sulfonyloxy, carbonyl or carbonyloxy 0251 1-(1S)-1-(aminocarbonyl)propyl-5-oxo-3- group and optionally additionally a C1-4-alkylene bridge, pyrrolidinyl)methyl nitrate; particularly methylene; 0252 (2S)-2-2-oxo-4-(1H-tetraazol-1-ylmethyl)-1-pyr 0225 R is preferably hydrogen or C1-4-alkyl: rolidinylbutanamide: 0226 Rand R“are preferably, independently hydrogen, 0253 2-(2-oxo-4-vinyl-1-pyrrolidinyl)butanamide: C1-4-alkyl, phenyl or benzyl. 0254 2-2-oxo-4-(phenylsulfonyl)methyl-1-pyrrolidi 0227. A further group of compounds of formula I (Com nylbutanamide; pounds 1C) comprises those in racemic form wherein, when 0255 (2S)-2-(4R)-4-(2,2-dibromovinyl)-2-oxopyrro X is CONRR and R' is hydrogen, methyl, ethyl or propyl. lidinylbutanamide: then Substitution on the pyrrolidine ring is other than mono-, 0256 (2S)-2-(4S)-4-(2,2-dibromovinyl)-2-oxopyrrolidi di-, or tri-methyl or mono-ethyl. nylbutanamide; 0228. A further group of compound of formula I (Com 0257 (2S)-2-[4-(isothiocyanatomethyl)-2-oxo-1-pyrro pounds 1D) comprises those in racemic form wherein, when lidinylbutanamide: X is CONRR and R' is hydrogen or C1-6-alkyl, C2-6- 0258 2-2-oxo-4-(1,3-thiazol-2-yl)-1-pyrrolidinylbu alkenyl or -alkynyl or cycloalkyl, each unsubstituted, then tanamide; substitution in the ring is other than by alkyl, alkenyl or 0259 (2S)-2-2-oxo-4-(2-thienyl)-1-pyrrolidinylbutana alkynyl, each unsubstituted. 0229. A further particular group of compounds of formula mide; I (Compounds 1E) comprises those wherein, 0260 (2S)-2-[4-(2-methoxyphenyl)-2-oxo-1-pyrrolidi 0230 X is - CANH: nylbutanamide; 0231) R' is H; 0261 (2S)-2-[4-(3-methoxyphenyl)-2-oxo-1-pyrrolidi 0232 R is azidomethyl, iodomethyl, ethyl optionally nylbutanamide; Substituted by 1 to 5 halogen atoms, n-propyl optionally 0262 (2S)-2-[4-(4-azidophenyl)-2-oxo-1-pyrrolidinyl substituted by 1 to 5 halogen atoms, vinyl optionally substi butanamide; tuted by one or two methyl, and/or 1 to 3 halogen atoms, 0263 (2S)-2-2-oxo-4-(3-thienyl)-1-pyrrolidinylbutana acetylene optionally substituted by C1-4-alkyl, phenyl or mide; halogen; 0264 (2S)-2-[4-(3-azidophenyl)-2-oxo-1-pyrrolidinyl 0233 R' is hydrogen or halogen, preferably fluorine; butanamide; 0234 and R. R. Rand R“are each hydrogen; 0265 (2S)-2-2-oxo-4-(3-thienyl)-1-pyrrolidinylbutana 0235 as their racemates or in enantiomerically enriched mide; form, preferably the pure enantiomers. 0266 (2S)-2-(4S)-2-oxo-4-vinylpyrrolidinylbutana 0236 A further particular group of compounds of formula mide; I (Compounds 1F) comprises those wherein, 0267 (2S)-2-(4R)-2-oxo-4-vinylpyrrolidinylbutana 0237 X is - CANH: mide; 0238) R' is H; 0268 2-4-(2-bromophenyl)-2-oxo-1-pyrrolidinylbu 0239 R is C1-6-alkyl, C2-6-alkenyl or C2-6-alkynyl tanamide; optionally Substituted by azido, oxynitro, 1 to 6 halogen 0269 2-2-oxo-4-(3-pyridinyl)-1-pyrrolidinylbutana atoms; mide; 0240) R' is hydrogen or halogen, preferably fluorine; and 0270 (2S)-2-(4-11'-biphenyl-4-yl-2-oxo-1-pyrrolidi R. R. RandR" are each hydrogen; as their racemates or nyl)butanamide; in enantiomerically enriched form, preferably the pure enan (0271 (2S)-2-4-(methylsulfanyl)methyl-2-oxo-1- tiomers. pyrrolidinylbutanamide: 0241. In all the above mentioned scopes when the carbon 0272 2-4-(iodomethyl)-2-oxo-1-pyrrolidinylbutana atom to which R" is attached is asymmetric it is preferably in mide; the “S”-configuration. 0273 (2S)-2-(4R)-4-(iodomethyl)-2-oxo-1-pyrrolidi 0242. In some embodiments, compounds useful in the nylpentanamide; methods and compositions of this invention are selected from 0274 (2S)-2-(4R)-4-(iodomethyl)-2-oxopyrrolidinyl the group consisting of propanamide; 0243 (2S)-2-[4-(bromomethyl)-2-oxo-1-pyrrolidinylbu 0275 2-(2-oxo-4-propyl-1-pyrrolidinyl)propanamide: tanamide: 0276 2-(2-oxo-4-propyl-1-pyrrolidinyl)butanamide: 0244 (2S)-2-(4R)-4-(iodomethyl)-2-oxopyrrolidinyl 0277 2-(2-oxo-4-pentyl-1-pyrrolidinyl)butanamide: butanamide; 0278 (2S)-2-(4R)-4-(iodomethyl)-2-oxopyrrolidinyl 0245 (2S)-2-(2-oxo-4-phenyl-1-pyrrplidinyl)butana N-methylbutanamide: mide; 0279 (2S)-2-(4-neopentyl-2-oxo-1-pyrrolidinyl)butana 0246 (2S)-2-[4-(iodomethyl)-2-oxo-1-pyrrolidinylbu mide; tanamide: 0280 (2S)-2-(4-ethyl-2-oxo-1-pyrrolidinyl)butanamide: 0247 (2S)-2-[4-(chloromethyl)-2-oxo-1-pyrrolidinylbu 0281 2-4-(2,2-difluorovinyl)-2-oxo-1-pyrrolidinylbu tanamide: tanamide; 0248 {1-(1S)-1-(aminocarbonyl)propyl-5-oxo-3- 0282 2-4-(2,2-difluoroethyl)-2-oxo-1-pyrrolidinylbu pyrrolidinyl)methyl 4-methylbenzenesulfonate; tanamide;

US 2011/0212928 A1 Sep. 1, 2011

0343 R', Rand Rare the same or different and each is 0353. The term “sulfonyl derivative', as used herein, is independently hydrogen, hydroxy, alkyl, aryl, heterocycle or defined as including a group of the formula -SO, R', an oxy derivative; and wherein R'' is as defined above except for "sulfonyl deriva 0344) R' is hydrogen, hydroxy, thiol, halogen, alkyl, aryl, tive'. Non-limiting examples are alkylsulfonyl, alkenylsulfo heterocycle or a thio derivative: nyl, alkynylsulfonyl and arylsulfonyl. 0345 their pharmaceutically acceptable salts, geometrical 0354. The term “sulfinyl derivative', as used herein, is isomers (including cis and trans, Z and E isomers), enanti defined as including a group of the formula - SO R', omers, diastereoisomers and mixtures thereof (including all wherein R'' is as defined above except for “sulfinyl deriva possible mixtures of stereoisomers). tive'. Non-limiting examples are alkylsulfinyl, alkenylsulfi 0346) In the above formula, at least one substituent R' to nyl, alkynylsulfinyl and arylsulfinyl. R is different from hydrogen. Some non-substituted com pounds are referred to in U.S. Pat. Nos. 5,468,733 and 5,516, 0355 The term “alkyl, as used herein, is defined as 759. U.S. Pat. No. 5,468,733 refers to non-ring substituted including saturated, monovalent hydrocarbon radicals having 2-oxo-1-pyrrolidinyl and 2-oxo-1-piperidinyl derivatives as straight, branched or cyclic moieties or combinations thereof inhibitors of the oncogene Ras protein. In particular, these and generally containing 1-20 carbon atoms, most often 1 to compounds block the ability of Ras to transform normal cells 12 carbonatoms, preferably 1-7 carbon atoms for non-cyclic to cancer cells, and therefore can be included in several che alkyl and 3-7 carbon atoms for cycloalkyl (in these two pre motherapeutic compositions for treating cancer. ferred cases, unless otherwise specified, “lower alkyl), each (0347 U.S. Pat. No. 5,516,759 refers to non-ring substi optionally substituted by, preferably 1 to 5, substituents inde tuted 2-oxo-1-pyrrolidinyl, 2-oxo-1-piperidinyl and azepanyl pendently selected from the group consisting of halogen, derivatives present at the N-terminus of dodecapeptides pos hydroxy, thiol, amino, nitro, cyano, thiocyanato, acyl, acy sessing LHRH (luteinizing hormone-releasing hormone) loxy, Sulfonyl derivative, Sulfinyl derivative, alkylamino, car antagonistic activity. Such LHRH antagonists are useful in boxy, ester, ether, amido, azido, cycloalkyl, Sulfonic acid, the treatment of a variety of conditions in which Suppression Sulfonamide, thio derivative, alkylthio, oxyester, oxyamido, of sex steroids plays a key role including contraception, delay heterocycle, vinyl, alkoxy (preferably C1-5), aryloxy (pref of puberty, treatment of benign prostatic hyperplasia a.o. erably C6-10) and aryl (preferably C6-10). 0348. In the definitions set forth below, unless otherwise 0356. Preferred are alkyl groups containing 1 to 7 carbon stated, R'' and R'' are the same or different and each is atoms, each optionally substituted by one or more substitu independently amido, alkyl, alkenyl, alkynyl, acyl, ester, ents selected from hydroxy, halogen, cyano, thiocyanato, ether, aryl, aralkyl. heterocycle or an oxy derivative, thio alkoxy, azido, alkylthio, cyclopropyl, acyl and phenyl. Most derivative, acyl derivative, amino derivative, sulfonyl deriva preferred are C1-4 alkyl and C3-7 cycloalkyl, each optionally tive, or sulfinyl derivative, each optionally substituted with Substituted by one or more hydroxy, halogen, lower alkyl any Suitable group, including, but not limited to, one or more or/and azido. moieties selected from lower alkyl or other groups as 0357 Most preferred alkyl groups are hydroxymethyl, described below as substituents for alkyl. propyl, butyl, 2.2.2-trifluoroethyl 2-bromo-2,2-difluoroet 0349 The term “oxy derivative', as used herein, is defined hyl, 2-chloro-2,2-difluoroethyl, 3,3,3-trifluoropropyl, cyclo as including —O R'' groups wherein R'' is as defined propylmethyl, iodomethyl, azidomethyl, 2,2-difluoropropyl. above except for “oxy derivative'. Non-limiting examples are 2-iodo-2,2-difluoroethyl. alkoxy, alkenyloxy, alkynyloxy, acyloxy, oxyester, oxya 0358. The term “lower alkyl, as used herein, and unless mido, alkylsulfonyloxy, alkylsulfinyloxy, arylsulfonyloxy, otherwise specified, refers to C to C.7 Saturated Straight, arylsulfinyloxy, aryloxy, aralkoxy or heterocyclooxy Such as branched or cyclic hydrocarbon. Non limiting examples are pentyloxy, allyloxy, methoxy, ethoxy, phenoxy, benzyloxy, methyl, ethyl, propyl, isopropyl, butyl, tertiobutyl, pentyl, 2-naphthyloxy. 2-pyridyloxy, methylenedioxy, carbonate. cyclopropyl, cyclopentyl, isopentyl, neopentyl, hexyl, iso 0350. The term “thio derivative’, as used herein, is defined hexyl, cyclohexyl, 3-methypenty1, 2,2-dimethylbutyl, as including S R' groups wherein R' is as defined optionally Substituted with any Suitable group, including but above except for “thio derivative'. Non-limiting examples are not limited to one or more moieties selected from groups as alkylthio, alkenylthio, alkynylthio and arylthio. described above for the alkyl groups. Preferably, lower alkyl 0351. The term “amino derivative’, as used herein, is is methyl. defined as including NHR'' or NR'R'' groups wherein 0359. The term “alkenyl', as used herein, is defined as R'' and R'' are as defined above. Non-limiting examples are including both branched and unbranched, unsaturated hydro mono- or di-alkyl-, alkenyl-, alkynyl- and arylamino or mixed carbon radicals having at least one double bond, and being amino. optionally substituted by at least one substituent selected 0352. The term “acyl derivative’, as used herein, repre from the group consisting of halogen, hydroxy, thiol, amino, sents a radical derived from carboxylic acid and thus is thiocyanato, azido, alkylthio, cycloalkyl, acyl, nitro, cyano, defined as including groups of the formula R'—CO , aryland heterocycle. wherein R'' is as defined above and may also be hydrogen. 0360 Preferred alkenyl groups are C2-C12 alkenyls, espe Preferred are acyl derivatives of formula –COR'' wherein cially C2-6 alkenyls, such as ethenyl (vinyl), 1-methyl-1- R'' is selected from hydrogen, C1-12 alkyl, C2-12 alkenyl, ethenyl, 2.2-dimethyl-1-ethenyl, 1-propenyl, 2-propenyl C2-12 alkenyl, heterocyle and aryl. Non-limiting examples (allyl), 1-butenyl, 2-butenyl, 3-butenyl, 4-pentenyl, 1-me are formyl, acetyl, propionyl, isobutyryl, Valeryl, lauroyl, thyl-4-pentenyl, 3-methyl-1-pentenyl, 1-hexenyl, 2-hexenyl heptanedioyl, cyclohexanecarbonyl, crotonoyl, fumaroyl, and the like, optionally being substituted by one or more acryloyl, benzoyl, naphthoyl, furoyl, nicotinoyl, 4-carbox Substituents selected from halogen, cyano, thiocyanato, ybutanoyl, oxalyl ethoxalyl, cysteinyl, oxamoyl. azido, alkylthio, cycloalkyl, phenyl and acyl. Most preferred US 2011/0212928 A1 Sep. 1, 2011 is vinyl, optionally Substituted by one or more halogen or/and 0376. The term “carboxy’, as used herein, represents a lower alkyl, and especially 2,2-difluorovinyl, 2,2-dibromovi group of the formula—COOH. nyl and 2,2-dichlorovinyl. 0377 The term “sulfonic acid, as used herein, represents 0361. The term “alkynyl as used herein, is defined as a group of the formula—SOH. including a monovalent branched or unbranched hydrocar bon radical containing at least one carbon-carbon triple bond, 0378. The term "sulfonamide', as used herein, represents for example ethynyl, 2-propynyl (propargyl), and the like, a group of the formula—SONH. and being optionally Substituted by at least one Substituent 0379 The term “ester, as used herein, is defined as selected from the group consisting of halogen, hydroxy, thiol, including a group of formula—COO R' wherein R'' is as amino, nitro, cyano, aryl, heterocycle, thiocyanato, azido, defined above except oxy derivative, thio derivative or amino alkylthio, alkyl and acyl. derivative. Preferred are esters of formula – COOR'' 0362 Preferred alkynyl groups are C2-12 alkynyl, espe wherein R' is selected from C1-12 alkyl, C2-12 alkenyl, cially C2-6 alkynyl, optionally being substituted by one or C2-12 alkynyl and aryl. Most preferred are esters where R' more Substituents selected from halogen, cyano, thiocyanato, is a lower alkyl, especially methyl. azido, alkylthio, acyl, aryl Such as phenyl and alkyl, prefer ably cycloalkyl. 0380. The term “ether is defined as including a group 0363 Most preferred are ethynyl, propynyl and butynyl, selected from C1-50-straight or branched alkyl, or C2-50 optionally Substituted by lower alkyl or/and halogen, and straight or branched alkenyl or alkynyl groups or a combina especially 1-propynyl, cyclopropylethynyl, 3-methyl-1-buty tion of the same, interrupted by one or more oxygen atoms. nyl and 3,3,3-trifluoro-1-propynyl. 0381. The term "amido' is defined as including a group of 0364. When present as bridging groups, alkyl, alkenyl and formula CONH, or CONHR'' or CONR'R'' alkynyl represent straight- or branched chains, C1-12, pref wherein R'' and R'' are as defined above. erably C1-4-alkylene or C2-12-, preferably C2-4-alkenylene 0382. The term "heterocycle', as used herein, is defined as or -alkynylene moieties respectively. including an aromatic or non aromatic cyclic alkyl, alkenyl, 0365 Groups where branched derivatives are convention or alkynyl moiety as defined above, having at least one O.S ally qualified by prefixes such as “n”, “sec”, “iso’ and the like and/or Natom interrupting the carbocyclic ring structure and (e.g. “n-propyl', 'sec-butyl') are in the n-form unless other optionally, one of the carbon of the carbocyclic ring structure wise stated. may be replaced by a carbonyl, and optionally being Substi 0366. The term “aryl', as used herein, is defined as includ tuted with any suitable group, including but not limited to one ing an organic radical derived from an aromatic hydrocarbon or more moieties selected from lower alkyl, or other groups as consisting of at least one ring, most often 1 to 3 rings and described above for the alkyl groups. Non-limiting examples generally containing 6-30 carbon atoms by removal of one of heterocycles are pyridyl, furyl, pyrrolyl, thienyl, isothiaz hydrogen, such as phenyl and naphthyl, each optionally Sub olyl, triazolyl, imidazolyl, benzimidazolyl, tetrazolyl, stituted by one or more substituents independently selected quinazolinyl, quinolizinyl, naphthyridinyl, pyridazinyl, pyri from halogen, hydroxy, thiol, amino, nitro, cyano, acyl, acy midinyl, pyrazinyl, quinolyl, isoquinolyl, isobenzofuranyl. loxy, Sulfonyl, Sulfinyl, alkylamino, carboxy, ester, ether, benzothienyl, pyrazolyl, indolyl, indolizinyl, purinyl, isoin amido, azido, Sulfonic acid, Sulfonamide, alkylsulfonyl, dolyl, carbazolyl, thiazolyl, 1,2,4-thiadiazolyl, thiomorpholi alkylsulfinyl, C1-6-alkylthio, oxyester, oxyamido, aryl, nyl, thieno (2,3-b) furanyl, furopyranyl, benzofuranyl, ben C1-6-alkoxy, C6-10-aryloxy, C1-6-alkyl, C1-6-haloalkyl. ZOXepinyl, isooxazolyl, Oxazolyl, thianthrenyl, Aryl radicals are preferably monocyclic or bicyclic contain benzothiazolyl, or benzoxazolyl, cinnolinyl, phthalazinyl, ing 6-10 carbon atoms. Preferred aryl groups are phenyl and quinoxalinyl, 1-oxidopyridyl, phenanthridinyl, acridinyl, naphthyl each optionally substituted by one or more substitu perimidinyl, phenanthrolinyl, phenothiazinyl, furazanyl. ents independently selected from halogen, nitro, amino, benzodioxolyl, isochromanyl, indolinyl, Xanthenyl, hypox azido, C1-6-alkoxy, C1-6-alkyl, C1-6-haloalkyl, sulfonyland anthinyl, pteridinyl, 5-azacytidinyl, 5-aZauracilyl, triazol phenyl. opyridinyl, imidazolopyridinyl, pyrrolopyrimidinyl, pyrazol 0367 Preferred aryl is phenyl, optionally substituted by opyrimidinyl, tetrahydrofuranyl, tetrahydropyranyl. one or more halogen, lower alkyl, azido or nitro. Such as piperidinyl, piperidyl, piperazinyl, imidazolidinyl, mor 3-chlorophenyl and 3-azidophenyl. pholino, morpholinyl, 1-oxaspiro(4.5)dec-2-yl, pyrrolidinyl, 0368. The term “halogen', as used herein, includes an 2-oxo-pyrrolidinyl, Sugar moieties (i.e. glucose, pentose, atom of Cl, Br, F. I. hexose, ribose, fructose, which may also be substituted) 0369. The term “hydroxy’, as used herein, represents a optionally substituted by alkyl or as described above for the group of the formula —OH. alkyl groups. The term "heterocycle” also includes bicyclic, 0370. The term “thiol, as used herein, represents a group tricyclic and tetracyclic, Spiro groups in which any of the of the formula—SH. above heterocyclic rings is fused to one or two rings indepen 0371. The term “cyano”, as used herein, represents a dently selected from an aryl ring, a cyclohexane ring, a cyclo group of the formula—CN. hexene ring, a cyclopentane ring, a cyclopentene ring or 0372. The term "nitro', as used herein, represents a group another monocyclic heterocyclic ring or where a monocyclic of the formula - NO. heterocyclic group is bridged by an alkylene group. Such as 0373 The term "nitrooxy’, as used herein, represents a quinuclidinyl, 7-azabicyclo(2.2.1)heptanyl, 7-Oxabicyclo(2. group of the formula —ONO. 2.1)heptanyl, 8-azabicyclo(3.2.1)octanyl. 0374. The term “amino', as used herein, represents a 0383. The heterocycle is preferably selected from triaz group of the formula —NH. olyl, tetrazolyl pyrrolidinyl, pyridyl, 1-oxidopyridyl, thio 0375. The term “azido’, as used herein, represents a group morpholinyl, benzodioxolyl, furyl, oxazolyl, pyrimidinyl, of the formula—N. pyrrolyl, thiadiazolyl, thiazolyl, thienyl and piperazinyl, each US 2011/0212928 A1 Sep. 1, 2011 20 optionally substituted by one or more substituents selected n=1, is different from hydrogen and the remaining R substitu from halogen, alkyl, Substituted alkyl, alkoxy, nitro, amino, ent(s) is/are hydrogen. We hereby refer to a mono-substituted acyl and phenyl. 2-thioxo- or 2-oxo-piperidinyl or 2-thioxo- or 2-oxo-aZepa 0384 More preferably the heterocycle is selected from nyl derivatives. tetrazolyl, pyrrolidinyl, pyridyl, furyl, pyrrolyl, thiazolyl and 0392 According to another preferred embodiment, com thienyl, each optionally substituted by one or more substitu pounds of formula I are as defined above wherein A' repre ents selected from halogen, alkyl, halogen Substituted alkyl, sents an oxygen atom. We hereby refer to 2-oxo-piperidinyl acyl, alkoxy, nitro, amino and phenyl, and especially from 2 or 2-oxo-azepanyl derivatives. and 3-thienyl, optionally Substituted by one or more halogen, 0393 According to another preferred embodiment, com acyl Such as formyl, cyano and/or lower alkyl, such as methyl. pounds of formula I are as defined above wherein X is 0385. In the above definitions it is to be understood that CONR'R'', especially CONH. We hereby refer to amido when a substituent such as R', R. R. R. R. R. R. R. R' derivatives of 2-oxo (or thioxo)-piperidinyl or 2-oxo (or is attached to the rest of the molecule via a heteroatom or a thioxo)-azepanyl. carbonyl, a straight- or branched chain, C1-12-, preferably 0394 According to another preferred embodiment, com C1-4-alkylene or C2-12, preferably C2-4-alkenylene or pounds of formula I are as defined above wherein R repre -alkynylene bridge may optionally be interposed between the sents hydrogen, C1-4 alkyl, or a CH R group wherein heteroatom or the carbonyl and the point of attachment to the R" represents a heterocycle. Most preferably R is a C1-4 rest of the molecule. alkyl, especially ethyl. When R is ethyl we refer to 2-(2-oxo 0386 The term “R substituent” refers to R', R. R. R. or (or thioxo)-1-piperidinyl)butanamide or 2-(2-oxo (or R, independently. thioxo)-1-azepanyl)butanamide derivatives. 0387 According to a preferred embodiment, a compound 0395 According to another preferred embodiment, com of formula I is as defined above wherein in represents 0. The pounds of formula I are as defined above wherein the carbon compound is a 6-ring structure (2-thioxo- or 2-oxo-piperidi atom to which R is attached is of the S configuration. In case nyl derivative) wherein R' is not existent since n=0, and is where R is ethyl, A is oxygen and X is CONR'R' we refer depicted by the formula (I-A). then to (2S)-2-(2-oxo-1-piperidinyl) butanamide or (2S)-2- (I-A) (2-oxo-1-azepanyl)butanamide derivatives. R4 0396 According to a preferred embodiment, the com pound is as defined above wherein R when n=1, Rand R' R3 R5 are the same or different and each is independently hydrogen, halogen, nitro, nitrooxy, cyano, carboxy, amido, Sulfonic acid, Sulfonamide, alkyl, alkenyl, alkynyl, ester, ether, aryl, R2 N Al heterocycle, acyl derivative, sulfonyl derivative or sulfinyl derivative; R6 1. X 0397) R' when existent, R when n=0 and Rare hydro gen, 0388 According to a following embodiment, the com 0398 R is hydrogen, alkyl, aryl or -CH R wherein pound of formula I is as defined above whereinn represents 1. R" is aryl, heterocycle, halogen, hydroxy, amino, nitro or The compound is a 7-ring structure (2-thioXo- or 2-oxo cyano; azepanyl derivative) wherein R' is existent since n=1 and 0399. According to this preferred embodiment, the com depicted by the formula (I-B). pound is generally such that when R is benzyl, X is - COOCH and n=1, R is different from methyl when R and R are both hydrogen and R is different from methyl (I-B) when R and Rare both hydrogen. 0400. According to another preferred embodiment, the compound is as defined above wherein R when n=1, Rand Rare the same or different and each is independently hydro gen; cyano; carboxy; amido: 04.01 C1-12 alkyl, each optionally substituted by one or more substituents selected from hydroxy, halogen, cyano, thiocyanato, alkoxy, azido, alkyltio, cycloalkyl, acyl, aryland heterocycle; 0402 C2-12 alkenyl, each optionally substituted by one or 0389. According to a more preferred embodiment, said more Substituents selected from halogen, cyano, thiocyanato, compound is as defined above wherein n=0, Rand/or Rare azido, alkylthio, alkyl, aryland acyl: different from hydrogen and RandR represent hydrogen. 0403 C2-12 alkynyl, each optionally substituted by one or 0390 According to another more preferred embodiment, more Substituents selected from halogen, cyano, thiocyanato, said compound is as defined above wherein n=1, R. R. azido, alkylthio, alkyl, aryl and acyl; acyl derivative of for and/or Rare different from hydrogen and wherein RandR mula—CO R', wherein R'' is selected from C1-12 alkyl, represent hydrogen. C2-12 alkenyl, C2-12 alkynyl, heterocycle and aryl; 0391. According to a yet more preferred embodiment, said 0404 ester of formula –CO-O-R'' wherein R'' is compound is as defined above wherein only one R substituent selected from C1-12 alkyl, C2-12 alkenyl, C2-12 alkynyl and chosen from R or R' when n=0 or from R, R or R' when US 2011/0212928 A1 Sep. 1, 2011

04.05 heterocycle selected from triazolyl, tetrazolyl pyr 0418 According to aparticular preferred embodiment, the rolidinyl, pyridyl, 1-oxidopyridyl, thiomorpholinyl, benzo compound is as defined above wherein at least one of the R dioxolyl, furyl, oxazolyl pyrimidinyl, pyrrolyl, thiadiazolyl, substituents chosen from the group R, RandR when n=1 thiazolyl, thienyl and piperazinyl, each optionally substituted or from the group R and R' when n=0, is hydroxymethyl, by one or more Substituents selected from halogen, alkyl, propyl, butyl, 3,3,3-trifluoropropyl. 2.2.2-trifluoroethyl, Substituted alkyl, alkoxy, nitro, amino, acyl and phenyl: cyclopropylmethyl, iodomethyl, azidomethyl 2-thienyl, 3-thienyl, phenyl, 3-chlorophenyl, 3-azidophenyl, 2,2-dif 04.06 aryl, each optionally substituted by one or more luorovinyl, 2,2-dibromovinyl, 2,2-dichlorovinyl, 2-ethynyl, substituents selected from C1-6 alkyl, C1-6 haloalkyl, C1-6 5-methyl-2-thienyl, 5-formyl-2-ethynyl, 5-cyano-2-thienyl, alkoxy, C1-6 alkylthio, amino, azido, Sulfonyl, aryland nitro. 3-bromo-2-thienyl, 4-methyl-2-thienyl, 3,3,3-trifluoro-1- 0407 According to another preferred embodiment, the propynyl, 1-propynyl, cyclopropylethynyl, 3-methyl-1-buty compound is as defined above, wherein R when n=1, Rand nyl, 1-butynyl, 2,2-difluoropropyl, 2-chloro-2,2-difluoroet Rare the same or different and each is independently hydro hyl, 2-bromo-2,2-difluoroethyl and 2-iodo-2,2-difluoroethyl. gen, 0419 According to yet another preferred embodiment, the 0408 C1-7 alkyl, each optionally substituted by one or compound is as defined above wherein R', R, R and Rare more Substituents selected from hydroxy, halogen, cyano, hydrogen. thiocyanato, alkoxy, azido, alkyltio, cyclopropyl, acyl and 0420 According to even another preferred embodiment, phenyl: the compound is as defined above wherein R', R. RandR 04.09 C2-6 alkenyl, each optionally substituted by one or are hydrogen. more Substituents selected from halogen, cyano, thiocyanato, 0421. According to even another preferred embodiment, azido, alkylthio, cycloalkyl, phenyl and acyl: the compound is as defined above wherein n=1 and R', R. R. 0410 C2-6 alkynyl, each optionally substituted by one or and Rare hydrogen. more Substituents selected from halogen, cyano, thiocyanato, 0422. In all the above-mentioned scopes when the carbon azido, alkylthio, cycloalkyl, phenyl and acyl: atom to which R is attached is asymmetric it is preferably in 0411 heterocycle selected from tetrazolyl pyrrolidinyl, the"S-configuration. pyridyl, furyl, pyrrolyl, thiazolyl and thienyl, each optionally 0423 Representative compounds useful in the methods substituted by one or more substituents selected from halo and compositions of this invention as defined above are gen, alkyl, halogen Substituted alkyl, acyl, alkoxy, nitro, selected from the group consisting of amino and phenyl: 0424 2-5-(hydroxymethyl)-2-oxo-1-piperidinylbutana 0412 phenyl, each optionally substituted by one or more mide, substituents selected from C1-6 alkyl, halogen substituted alkyl, halogen, alkoxy, amino, azido, Sulfonyl, phenyl and 0425 2-(2-oxo-5-propyl-1-piperidinyl)butanamide, nitro. 0426 2-2-oxo-5-(3,3,3-trifluoropropyl)-1-piperidinyl 0413. According to another preferred embodiment, the butanamide, compound is as defined above wherein at least one of the R 0427 2-5-(cyclopropylmethyl)-2-oxo-1-piperidinylbu substituents chosen from the group R, R and R' when n=1 tanamide, or from the group R and R' when n=0, represents indepen 0428 2-5-(iodomethyl)-2-oxo-1-piperidinylbutana dently C1-4-alkyl or C3-7-cycloalkyl, optionally substituted mide, by one or more halogen, hydroxy, lower alkyl and/or azido. 0429 2-5-(azidomethyl)-2-oxo-1-piperidinylbutana 0414. According to another preferred embodiment, the mide, compound is as defined above wherein at least one of the R 0430) 2-(2-oxo-5-phenyl-1-piperidinyl)butanamide, substituents chosen from the group R, R and R' when n=1 0431 2-2-oxo-5-(2-thienyl)-1-piperidinylbutanamide, or from the group R and R' when n=0, represents indepen 0432 2-2-oxo-5-(3-thienyl)-1-piperidinylbutanamide, dently vinyl, optionally Substituted by one or more halogen 0433 2-5-(3-chlorophenyl)-2-oxo-1-piperidinylbutana or/and lower alkyl. mide, 0415. According to another preferred embodiment, the 0434 2-5-(3-azidophenyl)-2-oxo-1-piperidinylbutana compound is as defined above wherein at least one of the R mide, substituents chosen from the group R, R and R' when n=1 0435 2-5-(2,2-difluorovinyl)-2-oxo-1-piperidinylbu or from the group R and R' when n=0, represents indepen tanamide, dently ethynyl, propynyl or butynyl, optionally substituted by 0436 2-5-(2,2-dibromovinyl)-2-oxo-1-piperidinylbu one or more halogen and/or lower alkyl. tanamide, 0416. According to another preferred embodiment, the 0437 2-5-(2,2-dichlorovinyl)-2-oxo-1-piperidinylbu compound is as defined above wherein at least one of the R substituents chosen from the group R, R and R' when n=1 tanamide, or from the group R and R' when n=0, represents indepen 0438 2-(5-ethynyl-2-oxo-1-piperidinyl)butanamide, dently phenyl, optionally Substituted by one or more halogen, 0439 2-5-(5-methyl-2-thienyl)-2-oxo-1-piperidinylbu lower alkyl, azido and/or nitro. tanamide, 0417. According to another preferred embodiment, the 0440 2-5-(5-formyl-2-thienyl)-2-oxo-1-piperidinylbu compound is as defined above wherein at least one of the R tanamide, substituents chosen from the group R, R and R' when n=1 0441 2-5-(5-cyano-2-thienyl)-2-oxo-1-piperidinylbu or from the group R and R' when n=0, represents indepen tanamide, dently 2- or 3-thienyl, optionally substituted by one or more 0442 2-5-(3-bromo-2-thienyl)-2-oxo-1-piperidinylbu halogen, acyl, cyano or/and lower alkyl. tanamide,

US 2011/0212928 A1 Sep. 1, 2011 24

0579 R is hydrogen, C1-20-alkyl, C4-8-cycloalkyl, 0601 wherein C5-8-cycloalkenyl, aryl, aromatic or non aromatic hetero 0602) R' is hydrogen, cycle, C1-20-alkoxy, or a group of formula – W. R. R." is 0603 R’ is hydrogen or C1-20-alkyl, hydrogen, C1-20-alkyl or a group of formula: 10604 R is hydrogen, C1-20-alkyl, C4-8-cycloalkyl, C5-8-cycloalkenyl, aryl, aromatic or non aromatic hetero cycle, C1-20-alkoxy, or a group of formula – W. R. N1X S 0605 R is hydrogen, C1-20-alkyl or a group of formula: -R9, X 0580 or NR'R' is a group of formula 1stry R9,

0606 or NR'R' is a group of formula / Iy-R" O //R11 -N Y or -N |, n R10 R11 /-y-R 0. // 0581) R' is hydrogen, -N Y or -N s 0582 R is hydrogen; nitro; halogen; azido: cyano; ln —S C1-4-alkyl; —SO C1-4-alkyl; —SO C1-4-alkyl: —SONH; C1-20-alkyl unsubstituted or substituted by halo 0607 R is hydrogen, gen; or C1-20-alkoxy unsubstituted or substituted by halo 0608 R is hydrogen; nitro; halogen; C1-20-alkyl unsub gen, stituted or substituted by halogen; or C1-20-alkoxy unsubsti 0583 R is hydrogen, C1-20-alkyl or halogen, tuted or substituted by halogen, 0584) R' is hydrogen, C1-20-alkyl or halogen, 0609 R is hydrogen, C1-20-alkyl or halogen, 0585 W is C1-12-alkylene, NH or -NHC(=O) , 10610) R' is hydrogen, C1-20-alkyl or halogen, 0586 X is O, S or NH, 0587 Yis O, S, CR'R' NR' or C(=O) , 0611) W is C1-12-alkylene, NH or -NHC(=O) , 0588 R is aryl or heterocycle, 0612 X is O, S or NH, 0589 R. R', R'' and R'' are independently selected 0613 Y is O, S, CR'R'' - NR' or C(=O) , from hydrogen, C1-4-alkyl, halogen, hydroxy or methoxy 0614 R is aryl or heterocycle, carbonyl, 0615 R. R', R'' and R'' are independently selected 0590 or R'' and R' together form a C3-6-alkylene, from hydrogen, C1-4-alkyl, halogen, hydroxy or methoxy 0591) R' is hydrogen, C1-4-alkyl, halogen or hydroxy, carbonyl, 0592) R' is hydrogen, 0616 or R'' and R' together form a C3-6-alkylene, 0593 or CR'R' is dioxolanyl, 0617 R" is hydrogen, C1-4-alkyl, halogen or hydroxy, 0594) R'' is aryl, heterocycle or a group of formula 0618 R" is hydrogen, V R', 0619 or CR'R' is dioxolanyl, 0595 V is C-alkylene, 0620) R' is aryl, heterocycle or a group of formula 0596) R' is aryl or heterocycle, V R', 0597 m is 1 to 4, 0621 V is C1-12-alkylene, 0598 n is 0 or 1, 0622) R' is aryl or heterocycle, 0599 and at least one of R, R or R7 is different from 0623 m is 1 to 4, hydrogen when R is hydrogen, R is H or 2,6-diisopropy 0624 n is 0 or 1, lphenyl, and R is H. 0625 and at least one of R, R or R7 is different from 0600. In another aspect, the compound has the formula I or hydrogen when R is hydrogen, R is H or 2,6-diisopropy a pharmaceutically acceptable salt thereof or stereoisomeric lphenyl, and R is H. forms thereof, 0626. The term “alkyl, as used herein, is defined as including saturated, monovalent hydrocarbon radicals having (I) straight, branched or cyclic moieties or combinations thereof R4 and containing 1-20 carbon atoms, preferably 1-6 carbon atoms and more preferably 1-4 carbon atoms for non-cyclic R alkyl and 3-8 carbon atoms for cycloalkyl. Alliyl moieties may optionally be substituted by 1 to 5 substituents indepen O dently selected from halogen, hydroxy, alkoxy, alkoxycarbo 6 N nyl, ester or alkylamino. Preferred alkyl groups are methyl, R NR3 R3a ethyl, n-propyl, isopropyl, trifluoromethyl, n-butyl, 2-fluoro R7 R2 R1 ethyl, 3-hydroxypropyl, 3-hydroxy-2,2-dimethylpropyl. O 1-(hydroxymethyl) propyl. 3,3,3-trifluoro-2-hydroxypropyl, 3-ethoxypropyl, 2-ethoxy-2-oxoethyl and 3-(dimethy lamino) propyl. US 2011/0212928 A1 Sep. 1, 2011

0627 The term “cycloalkyl, as used herein, refers to a 0641 Non-limiting examples of aromatic heterocycles are monovalent group of 3 to 18 carbon atoms, preferably 4-8 pyrazolyl, furyl, imidazolyl, triazolyl, oxazolyl pyridinyl, carbon atoms, derived from a saturated cyclic or polycyclic pyrrolyl, thienyl, isothiazolyl, benzimidazolyl, tetrazolyl, hydrocarbon which may be substituted by any suitable group isooxazolyl, oxazolyl, thiazolyl, 1,2,4-thiadiazolyl, oxadiaz including but not limited to one or more moieties selected ole, pyridazinyl, pyrimidinyl, pyrazinyl, isoindolyl, triazol from groups as described above for the alkyl groups. Pre opyridinyl, imidazolopyridinyl, pyrrolopyrimidinyl, pyrazol ferred cycloalkyl group is cycloheptyl. opyrimidinyl, quinazolinyl, quinolizinyl, naphthyridinyl, 0628. The term “alkylene', as used herein, represents a quinolyl, isoquinolyl, isobenzofuranyl, benzothienyl, divalent alkyl group, having straight or branched moieties, containing 1-12 carbon atoms, preferably 1-6 carbon atoms, indolyl, indolizinyl, purinyl, carbazolyl, thieno (2,3-b) fura and being optionally Substituted with any Suitable group, nyl, thianthrenyl, benzothiazolyl, benzoxazolyl, cinnolinyl, including but not limited to one or more moieties selected quinoxalinyl, phenothiazinyl, isochromanyl and Xanthenyl, from groups as described above for the alkyl groups. Pre optionally substituted by 1 to 5 substituents independently ferred alkylene groups are methylene, ethylene, hydroxyeth selected from halogen, hydroxy, thiol, amino, nitro, cyano, ylene, trimethylene or propylene. azido, C1-6-alkoxy, C1-6-alkylthio, C1-6-alkyl, C1-6-ha 0629. The term “cycloalkenyl', as used herein, is defined loalkyl, formyl or ester. More preferred aromatic hetero as a cyclic unsaturated hydrocarbon radical having at least cycles are pyrazolyl, furyl, imidazolyl, triazolyl, oxazolyland one double bond, containing 4-20 carbon atoms, preferably pyridinyl. 5-8 carbon atoms, and being optionally Substituted with any 0642. Non-limiting examples of non aromatic hetero Suitable group, including but not limited to one or more moi cycles are tetrahydrofuranyl, piperidinyl, piperidyl, piperazi eties selected from groups as described above for the alkyl nyl, imidazolidinyl, morpholinyl, thiomorpholinyl, pyrrolidi groups. Preferred cycloalkenyl group is 6-(hydroxymethyl) nyl, thiazolidinyl, indolinyl, tetrahydrobenzazocinyl, cyclohex-3-en-1-yl. dihydroisochromenyl, tetrahydropyranyl, oxooctahydro 0630. The term “aryl', as used herein, is defined as includ quinolinyl, dioxolanyl, 1-oxaspiro(4.5)dec-2-yl, pyrrolidi ing an organic radical derived from an aromatic hydrocarbon nyl, 2-oxo-pyrrolidinyl, 8-thiabicyclo3.2.1 cyclooctanyl. consisting of 1-3 rings and containing 6-30 carbon atoms by 1,4-dithiepanyl, tetrahydro-2H-thiopyranyl, azepanyl and removal of one hydrogen, Such as phenyl and naphthyl each optionally substituted by 1 to 5 substituents independently azocanyl, optionally substituted by 1 to 5 substituents inde selected from halogen, hydroxy, nitro, C1-6-alkyl, C1-6- pendently selected from halogen, hydroxy, thiol, amino, alkoxy, C1-6-alkylsulfonyl, trifluoromethylthio or pyridiny nitro, cyano, azido, C1-6-alkoxy, C1-6-alkylthio, C1-6-alkyl, lalkyl. Aryl radicals are preferably phenyl radicals. Preferred C1-6-haloalkyl, formyl orester. More preferred non aromatic aryl groups are phenyl, 3-hydroxyphenyl, 3-fluorophenyl, heterocycles are tetrahydrofuranyl, piperidinyl, piperidyl, 3-methylphenyl, 4-methylphenyl, 4-hydroxyphenyl, 4-hy piperazinyl, imidazolidinyl, morpholinyl, thiomorpholinyl, droxy-3-methoxyphenyl, 3-(2-pyridin-2-ylethyl) phenyl, pyrrolidinyl, thiazolidinyl, indolinyl, tetrahydro-1-benzazo 3,4-dimethylphenyl, 4-tert-butylphenyl, 4-methylsulfo cin-1 (2H)-y1, 3,4-dihydro-1H-isochromen-1-yl, tetrahydro nylphenyl, 2-nitrophenyl, 2-chloro-6-fluorophenyl, 2-(trif pyranyl, oxooctahydroquinolinyl and dioxolanyl. The term luoromethyl)thiophenyl, 2-chlorophenyl or 4-bromophenyl. "heterocycle also includes bicyclic, tricyclic and tetracyclic, 06.31 The term “halogen', as used herein, includes an spiro groups in which any of the above heterocyclic rings is atom of Cl, Br, F. I. fused to one or two rings independently selected from an aryl 0632. The term "nitro', as used herein, represents a group ring, a cycloalkyl ring, a cycloalkenyl ring or another mono of the formula - NO. cyclic heterocyclic ring or where a monocyclic heterocyclic 0633. The term “hydroxy’, as used herein, represents a group is bridged by an alkylene group. Such as quinuclidinyl, group of the formula —OH. 7-azabicyclo(2.2.1)heptanyl, 7-Oxabicyclo(2.2.1)heptanyl 0634. The term “alkoxy’, as used herein, represents a and 8-azabicyclo(3.2.1)octanyl. group of formula -OR wherein R is an alkyl group, as 0643. The term "pyridinylalkyl, as used herein, repre defined above. sents a group of formula—R'-pyridinyl in which R" is C1-4- 0635. The term “ester', as used herein, represents a group alkylene. of formula—COOR wherein R is an alkyl group or an aryl 0644. The term “azido” as used herein, represents a group group, as defined above. of the formula - N. 0636. The term “alkoxycarbonyl', as used herein, repre 0645. The term “cyano” as used herein, represents a group sents a group of formula -COOR wherein R is an alkyl of the formula—CN. group, as defined above. (0646) Generally, R is hydrogen or C1-4-alkyl. 0637. The term “amino', as used herein, represents a (0647 Preferably, R is hydrogen, methyl or ethyl. More group of the formula —NH. preferably, R is hydrogen or methyl. 0638. The term “alkylamino', as used herein, represents a (0648 Generally, R is hydrogen; C1-6-alkyl unsubstituted group of formula-NHR or NR'R' wherein RandR are or substituted by 1 to 5 substituents selected from halogen, alkyl group as defined above. hydroxy, alkoxy, alkoxycarbonyl or alkylamino: C5-7-cy 0639. The term alkylsulfonyl, as used herein is defined as cloalkyl: (hydroxymethyl)cyclohexenyl; phenyl unsubsti representing a group of formula —SO, R, wherein R is tuted or substituted by 1 to 5 substituents selected from halo C1-4-alkyl. gen, C1-4-alkyl, hydroxy, methoxy, nitro, methylsulfonyl, 0640 The term "heterocycle', as used herein is defined as trifluoromethylthio or pyridinylalkyl; pyridinyl unsubstituted including an aromatic or non aromatic cycloalkyl or cycloalk or Substituted by methoxy; triazolyl; C1-4-alkoxy; or a group enyl moiety as defined above, having at least one O. Sand/or of formula - W R wherein: Natom interrupting the carbocyclic ring structure and option 0649 Generally, Wis C1-4-alkylene unsubstituted or sub ally, one of the carbon of the carbocyclic ring structure may be stituted by halogen, hydroxy, C1-4-alkyl or alkoxy; —NH : replaced by a carbonyl. or —NHC(=O)—, and US 2011/0212928 A1 Sep. 1, 2011 26

0650 R is phenyl unsubstituted or substituted by 1 to 5 10658 Generally, R is hydrogen, nitro, halogen, C1-4- Substituents selected from halogen, C1-4-alkyl, hydroxy, alkyl, unsubstituted or substituted by halogen, or C1-4- methoxy, nitro, methylsulfonyl or trifluoromethylthio; furyl alkoxy unsubstituted or substituted by halogen. unsubstituted or substituted by methyl; pyrazolyl; pyridinyl: 0659 Preferably, R is hydrogen, methyl, ethyl, trifluo morpholinyl; tetrahydrobenzazocinyl; piperidinyl unsubsti romethyl, trifluoromethoxy, n-propyl, isopropyl. nitro, or halogen. More preferably, R is halogen or trifluoromethyl. tuted or substituted by methyl; dihydroisochromenyl or dihy 10660 Generally, R is hydrogen, C1-6-alkyl or halogen. droimidazolyl. 0661 Preferably, R is hydrogen, methyl or C1. More pref 0651) Preferably, R is hydrogen, n-butyl, cycloheptyl, erably, R is hydrogen. 2-fluoroethyl, 3-hydroxypropyl, 3-hydroxy-2,2-dimethyl 10662 Generally, R is hydrogen, methyl or halogen. propyl, 1-(hydroxymethyl) propyl. 3,3,3-trifluoro-2-hydrox 0663 Preferably, R is hydrogen, methyl, Br, F or Cl. ypropyl, 3-ethoxypropyl, 2-ethoxy-2-oxoethyl, 3-(dimethy More preferably, R is hydrogen, Br or F. lamino) propyl, 6-(hydroxymethyl)cyclohex-3-en-1-yl, 0664 Combinations of one or more of these preferred 3-hydroxyphenyl, 3-fluorophenyl, 3-(2-pyridin-2-ylethyl) compound groups are especially preferred. phenyl, 3,4-dimethylphenyl, 4-tert-butylphenyl, benzyl, 0665. In a preferred embodiment, the compound has the 4-hydroxy-3-methoxybenzyl, 4-methylsulfonylbenzyl, 2-ni formula I or a pharmaceutically acceptable salt thereof or trobenzyl, 2-chloro-6-fluorobenzyl, 2-(trifluoromethyl) stereoisomeric forms thereof, thiobenzyl, 2-hydroxy-2-phenylethyl, 2-(3,4-dimethox yphenyl)ethyl, 2-(2-chlorophenyl)ethyl, 2-(4-methylphenyl) (I) ethyl, (4-bromophenyl) amino, pyridin-3-yl, 6-methoxypyridin-3-yl 4H-1,2,4-triazol-3-yl, pyridin-4-yl methyl, (5-methyl-2-furyl) methyl, 3-(1H-pyrazol-1-yl)pro pyl, 2-morpholin-4-ylethyl 2-((3,4,5,6-tetrahydro-1-benza Zocin-1 (2H)-yl) propyl, 2-(2-methylpiperidin-1-yl)ethyl, 3,4-dihydro-1H-isochromen-1-ylmethyl, methoxy, (4-py ridinylcarbonyl) amino or 4.5-dihydro-1H-imidazol-2- ylamino. More preferably, R is hydrogen. 0652 Generally, R is hydrogen, C1-4-alkylor a group of formula 10666 wherein R' is hydrogen, 0667 R’ is hydrogen or C1-4-alkyl, 10668 R is hydrogen; C1-6-alkyl unsubstituted or substi tuted by 1 to 5 substituents selected from halogen, hydroxy, alkoxy, alkoxycarbonyl or alkylamino: C5-7-cycloalkyl: (hy 15, droxymethyl)cyclohexenyl; phenyl unsubstituted or substi tuted by 1 to 5 substituents selected from halogen, C1-4-alkyl, 0653 wherein m is 1 to 4. hydroxy, methoxy, nitro, methylsulfonyl, trifluoromethylthio 0654 Preferably, R is hydrogen, methyl or tetrahydro or pyridinylalkyl; pyridinyl unsubstituted or substituted by furan-2-ylmethyl. More preferably, R is hydrogen. methoxy; triazolyl; C1-4-alkoxy; or a group of formula 0655. In another embodiment, NR'R' is piperidinyl W R, unsubstituted or substituted by hydroxy; thiomorpholinyl: 0669 R is hydrogen, C1-4-alkyl or a group of formula thiazolidinyl unsubstituted or substituted by C1-4-alkoxycar bonyl: 2,5-dihydro-1H-pyrrol-1-yl: 1,4-dioxa-8-azaspiro4. 5dec-8-yl: 4-oxooctahydro-1 (2H)-quinolinyl; or a group of formula -hy 0670) or NRR" is piperidinyl unsubstituted or substi tuted by hydroxy; thiomorpholinyl; thiazolidinyl unsubsti tuted or substituted by C1-4-alkoxycarbonyl: 2,5-dihydro 1H-pyrrol-1-yl; 1,4-dioxa-8-azaspiro4.5 dec-8-yl; 0656 wherein R'' is pyridinyl; phenyl unsubstituted or 4-oxooctahydro-1 (2H)-quinolinyl; or a group of formula Substituted by halogen, hydroxy, C1-4-alkyl; or a group of formula—V R' wherein V is unsubstituted C1-4-alkylene and R' is phenyl or morpholinyl. 0657. In a preferred embodiment, NR'R' is 4-pyridin-2- -N N-R 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, 0671) R' is hydrogen, 3-hydroxypiperidin-1-yl, thiomorpholin-4-yl 4-methoxy 0672 R is hydrogen; nitro; halogen; C1-4-alkyl, unsub carbonyl-1,3-thiazolidin-3-yl, 2,5-dihydro-1H-pyrrol-1-yl, stituted or substituted by halogen; or C1-4-alkoxy unsubsti 1,4-dioxa-8-azaspiro4.5 dec-8-yl or 4-oxooctahydro-1 tuted or substituted by halogen, (2H)-quinolinyl. 0673) R' is hydrogen, C1-6-allyl or halogen,

US 2011/0212928 A1 Sep. 1, 2011 29

0714) R' is hydrogen, C-2 alkyl, halogen, hydroxy, 10727) R' is hydrogen, C-2 alkyl, C-2 alkenyl or aryl; alkoxy, aryloxy, ester, amido, cyano, nitro, amino, amino 0728) R' is hydrogen: derivative, alkylthio, arylthio, alkylsulfonyl, arylsulfonyl, 0729) R is hydrogen; alkylsulfinyl or arylsulfinyl: (0730 or R. R* and R can form together with the 2-oxo 0715I R' is hydrogen, halogen, nitro, cyano, Cao alkyl 1-pyrrolidine ring the following 1,3-dihydro-2H-indol-2-one or alkoxy; cycle 0716) R' is hydrogen or halogen; 0717) R' is hydrogen, nitro, halogen, heterocycle, amino, R12 aryl, Co alkyl unsubstituted or substituted by halogen, or R3 alkoxy unsubstituted or substituted by halogen; R4 0718I R' is hydrogen, Co alkyl or halogen; Rg 0719) R' is hydrogen, Co alkyl or halogen; 0720 with the proviso that R is different from hydrogen R 14 when represents a group of formula R5 N: O N: O; R15 R8 R9 (0731) R' is hydrogen or Co alkyl: R10. (0732 R is hydrogen; or Rand R7 are linked together to *N form a C cycloalkyl; (0733 R is hydrogen: (0734) R is hydrogen, Co alkyl, halogen or alkoxy; -S N R11 (0735) R' is hydrogen, Co alkyl, halogen or cyano; (0736) R' is hydrogen; 0721 The asterisk * indicates the point of attachment of (0737 R'' is hydrogen or halogen: the substituents. (0738) R' is hydrogen, halogen, heterocycle or Coalkyl: 0722. In a preferred embodiment, the compounds have the (0739) R' is hydrogen; formula I, their tautomers, geometrical isomers (including cis 0740) R' is hydrogen: and trans, Z and E isomers), enantiomers, diastereoisomers 10741) with the proviso that R is different from hydrogen and mixtures thereof (including all possible mixtures of ste when reoisomers), or pharmaceutically acceptable salts thereof,

R2 (I) 1. Y-R R1 s

0742 represents a group of formula

R8 R9

I0723 wherein R' is hydrogen, Coalkyl, Css cycloalkyl, R10. halogen, hydroxy, ester, amido, cyano, nitro, amino, guani *N dine, alkylthio, alkylsulfonyl, alkylsulfinyl, aryl or hetero cycle; -S N R11 0724 R is hydrogen, Cao alkyl, halogen, cyano, ester, carbamate or amido; 0743. The term “alkyl, as used herein, represents satu 0725 R is hydrogen, cyano, Cao alkyl, halogen orester; rated, monovalent hydrocarbon radicals having straight (un 0726) or R and R can form together with the imidazole branched) or branched or cyclic or combinations thereof and ring the following 1H-benzimidazole cycle containing 1-20 carbonatoms, preferably 1-10 carbonatoms, more pre preferred alkyl groups have 1-3 carbonatoms. Alkyl moieties may optionally be substituted by 1 to 5 substituents R8 R9 independently selected from the group consisting of halogen, hydroxy, cyano, azido, aryloxy, alkoxy, alkylthio, alkanoy R2 lamino, arylcarbonylamino, aminocarbonyl, methylami R10: nocarbonyl, dimethylaminocarbonyl or aryl. Usually alkyl groups, in the present case, are methyl, ethyl, n-propyl, i-pro S. R3 usS. pyl. n-butyl, i-butyl, t-butyl, 1-ethylpropyl, n-heptyl, 2.4.4- 1s N R11 trimethylpentyl, n-decyl, chloromethyl, trifluoromethyl, 2-bromo-2,2-difluoroethyl, 2.2.2-trifluoroethyl, 3,3,3-trif luoropropyl, hydroxymethyl, cyanomethyl, azidomethyl, US 2011/0212928 A1 Sep. 1, 2011 30

(acetylamino)methyl, (propionylamino)methyl, (benzoy cycles are 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-furyl, 3-furyl, lamino)methyl, (4-chlorophenoxy)methyl, benzyl, 2-phenyl 2-thienyl, 3-thienyl, 2-tetrahydrofuranyl, 1 H-pyrrol-2-yl, ethyl or 2-(methylthio)ethyl. Preferred alkyl groups are 1-methyl-1H-pyrrol-2-yl, 1H-pyrazol-2-yl, 1 H-pyrazol-3-yl, methyl, ethyl, n-propyl, i-propyl. n-butyl, i-butyl, t-butyl, 4-chloro-1-methyl-1H-pyrazol-3-yl, 5-chloro-1,3-dimethyl 1-ethylpropyl. 2,4,4-trimethylpentyl, chloromethyl, trifluo 1H-pyrazol-4-yl, 1,2,3-thiadiazol-4-yl, 3,5-dimethyl-4- romethyl, 2.2.2-trifluoroethyl, hydroxymethyl, cyanomethyl, isothiazyl, 1H-imidazol-2-yl, 1-methyl-1H-imidazol-2-yl, azidomethyl, (acetylamino)methyl, (propionylamino)me 4-methyl-1H-imidazol-5-yl, or 2-methyl-1,3-thiazol-4-yl. thyl, (benzoylamino)methyl or 2-(methylthio)ethyl. More Preferred heterocycles are 1H-imidazol-2-yl, 1,2,3-thiadia preferred alkyl groups are methyl, ethyl, n-propyl, i-propyl. Zol-4-yl, 1H-pyrazol-3-yl 2-furyl, 3-furyl, 2-thienyl, 1-me n-butyl, azidomethyl or trifluoromethyl. Most preferred alkyl thyl-1H-pyrrol-2-yl, 1 H-pyrrol-2-yl. groups are methyl or n-propyl. 0750. The term “halogen', as used herein, includes an 0744. The term “cycloalkyl, as used herein, represents a atom of chlorine, bromine, fluorine, iodine. Usually halogens monovalent group of 3 to 8 carbon atoms, usually 3-6 carbon are chlorine, bromine and fluorine. Preferred halogens are atoms derived from a saturated cyclic hydrocarbon, which fluorine, bromine and chlorine. may be substituted by any suitable group including but not 0751. The term “hydroxy’, as used herein, represents a limited to one or more moieties selected from groups as group of formula—OH. described above for the alkyl groups. Preferred cycloalkyl 0752. The term “alkoxy’, as used herein, represents a groups are cyclopropyl and cyclohexyl. group of formula—OR 0745. The term “alkenyl as used herein, represents 0753 wherein R is an alkyl group, as defined above. straight, branched or cyclic unsaturated hydrocarbon radicals Preferred alkoxy group is methoxy. or combinations thereof having at least one carbon-carbon 0754. The term “aryloxy’, as used herein, represents a double bond, containing 2-12 carbon atoms, preferably usu group of formula -OR wherein R is an aryl group, as ally 2-4 carbon atoms. Alkenyl groups are being optionally defined above. Preferred aryloxy group is phenoxy. Substituted with any suitable group, including but not limited to one or more moieties selected from groups as described 0755. The term “ester', as used herein, represents a group above for the alkyl groups. Usually an alkenyl group is ethe of formula —COOR wherein R is an alkyl group or aryl nyl (vinyl) optionally substituted by 1 to 3 halogens. Pre group, as defined above. Preferred ester group is methoxy ferred alkenyl group, in the present case, is 2,2-difluorovinyl. carbonyl. 0746. The term a "alkynyl” as used herein, represents 0756. The term "amido’, as used herein, represents a straight, branched or cyclic hydrocarbon radicals or combi group of formula—CONH2. nations thereof containing at least one carbon-carbon triple 0757. The term “amino', as used herein, represents a bond, containing 2-12 carbon atoms, preferably 2-6 carbon group of formula —NH. atoms, and being optionally substituted by any Suitable 0758. The term “aminoderivative', as used herein, repre group, including but not limited to one or more moieties sents an alkylamino oran arylamino group, wherein the terms selected from groups as described above for the alkyl groups. “alkyl and “aryl” are defined as above. Preferably an alkynyl group is a halogenoalkynyl group (ha 0759. The term “cyano”, as used herein, represents a loalkynyl group). group of formula—CN. 0747 Groups qualified by prefixes such as “s”, “i', “t” and 0760. The term "nitro', as used herein, represents a group the like (e.g. “i-propyl', 's-butyl') are branched derivatives. of formula—NO. 0748. The term “aryl” as used herein, is defined as phenyl 0761 The term “azido’, as used herein, represents a group optionally substituted by 1 to 4 substituents independently of formula—N. selected from halogen, cyano, alkoxy, alkylthio, Calkyl or 0762. The term “guanidine', as used herein, represents a azido, preferably halogen or azido. Usually aryl groups, in the group of formula - NHC(=NH)NH2. present case are phenyl, 3-chlorophenyl, 3-fluorophenyl, 4-chlorophenyl, 4-fluorophenyl, 3,4-difluorophenyl, 3,5-dif 0763 The term “alkylthio', as used herein, represents a luorophenyl, 3-chloro-4-fluorophenyl, 2,3,4-trifluorophenyl, group of formula - SR" wherein R is an alkyl group, as 2,4,5-trifluorophenyl, 2,3,5-trifluorophenyl, 3,4,5-trifluo defined above. Preferred alkylthio group is methylthio. rophenyl, 3-azido-2,4-difluorophenyl or 3-azido-2,4,6-trif 0764. The term “alkylsulfonyl', as used herein, represents luorophenyl. Preferably, aryl groups are phenyl, 3-chlorophe a group of formula—S(=O)R wherein R is an alkyl group, nyl, 3-fluorophenyl, 4-chlorophenyl, 4-fluorophenyl, 3,4- as defined above. Preferred alkylsulfonyl group is methylsul difluorophenyl, 3,5-difluorophenyl, 3-chloro-4- fonyl. fluorophenyl, 2,3,4-trifluorophenyl, 2,4,5-trifluorophenyl, 0765. The term “alkylsulfinyl', as used herein, represents 2,3,5-trifluorophenyl, 3,4,5-trifluorophenyl or 3-azido-2,4- a group of formula—S(=O)R wherein R is an alkyl group, difluorophenyl. Most preferred aryl groups are phenyl, as defined above. Preferred alkylsulfinyl group is methylsulfi 3-chlorophenyl, 3-fluorophenyl, 3,5-difluorophenyl, 2,3,4- nyl. trifluorophenyl, 2,4,5-trifluorophenyl, 2,3,5-trifluorophenyl, 0766 The term “arylthio', as used herein, represents a 3,4,5-trifluorophenyl or 3-azido-2,4-difluorophenyl. group of formula —SR wherein R is an aryl group, as 0749. The term "heterocycle', as used herein, is defined as defined above. including an aromatic or non aromatic cycloalkyl moiety as 0767 The term “arylsulfonyl', as used herein, represents a defined above, having at least one O. Sand/or Natom inter group of the formula - S(=O).R" wherein R' is an aryl rupting the carbocyclic ring structure. Heterocyclic ring moi group, as defined above. eties can be optionally Substituted by alkyl groups orhalogens 0768. The term “arylsulfinyl', as used herein, represents a and optionally, one of the carbon of the carbocyclic ring group of the formula—S(=O)R’ wherein R is an aryl group, structure may be replaced by a carbonyl. Usually hetero as defined above. US 2011/0212928 A1 Sep. 1, 2011

0769 The term “carbamate” as used herein, represents a (0778. Usually, R is hydrogen or Coalkyl unsubstituted group of formula—N(H)C(O)OR, wherein R is an alkyl or or substituted by hydroxy or azido. Preferably, Rishydrogen an aryl, as defined above. Usually carbamate groups are (pro or azidomethyl. More preferably R is hydrogen. poxycarbonyl)amino or (benzyloaxycarbonyl)amino. Pre (0779. Usually R7 is hydrogen. ferred carbamate group is (benzyloaxycarbonyl)amino 0780. In other preferred embodiments, R and R7 are linked to form a cyclopropyl. 0770. The term “alkanoylamino” as used herein, repre 0781. In other preferred embodiments, RandR can form sents a group of the formula-NHC(=O)R’ wherein R is an together with the imidazole ring the following 1H-benzimi alkyl group, as defined above. dazole cycle 0771. The term “(arylcarbonyl)amino” as used herein, represents a group of the formula —NHC(=O)R" wherein R8 R9 R" is an aryl group, as defined above. Preferred (arylcarbo nyl)amino is benzoylamino. R2 0772. Usually, R is hydrogen; Coalkyl unsubstituted or R10. Substituted by halogen, hydroxy, cyano, methylthio, phenyl or 4-chlorophenoxy; hydroxy, C. cycloalkyl; halogen; ester, amido; nitro; cyano; amino; phenyl; alkylthio; alkyl R1 s RI N R11 sulfonyl: alkylsulfinyl; heterocycle unsubstituted or substi tuted by alkyl groups; or guanidine. Preferably, R is hydro 0782. Usually,Sually, R is1s hydroghydrogen. gen; methyl; ethyl; i-propyl; n-propyl; cyclopropyl. n-butyl: 0783. Usually, R is hydrogen; halogen; C alkyl or i-butyl; t-butyl: 1-ethylpropyl; 2,4,4-trimethylpentyl: alkoxy. Preferably, R is hydrogen; methyl; chloro or meth hydroxymethyl; chloromethyl; trifluoromethyl; 2.2.2-trifluo oxy. More preferred R is hydrogen. roethyl; cyanomethyl: 2-(methylthio)ethyl; chloro; bromo: 10784) Usually, R' is hydrogen; halogen; cyano: C-alkyl nitro; cyano; amino; aminocarbonyl: methoxycarbonyl: unsubstituted or substituted by halogens; or alkoxy. Prefer methylthio; methylsulfinyl: methylsulfonyl; phenyl: 2-furyl; ably, R' is methyl; hydrogen; trifluoromethyl; fluoro; cyano 3-furyl; 1H-pyrrol-2-yl: 1-methyl-1H-pyrrol-2-yl: 2-thienyl: or methoxy. More preferred R' is hydrogen; trifluoromethyl; 1H-pyrazol-3-yl: 1,2,3-thiadiazol-4-yl or 1H-imidazol-2-yl. fluoro or cyano. More preferably, R is hydrogen; methyl; ethyl: i-propyl; 0785 Usually, R'' is hydrogen. n-propyl; n-butyl, methylthio; nitro; cyano; amino; chloro or 0786. In other preferred embodiments, R, R and Rican 1H-pyrrol-2-yl. Most preferably, R is hydrogen; methyl: form together with the 2-oxo-1-pyrrolidine ring the following methylthio; nitro; cyano; amino or chloro. 1,3-dihydro-2H-indol-2-one cycle (0773) Usually, R is hydrogen; Calkyl unsubstituted or Substituted by hydroxy, alkanoylamino or benzoylamino; halogen; ester; cyano; alkyl carbamate; (N-methoxy-N-me R12 thyl)aminolcarbonyl. Preferably, R is hydrogen; methyl: R4 R3 hydroxymethyl: (acetylamino)methyl: (propionylamino)m- Rg ethyl; (benzoylamino)methyl, (benzyloxy)carbonylamino; chloro or cyano. More preferably, R is hydrogen; chloro or R 14 cyano. R5 N: O N: O; (0774. Usually, R is hydrogen; C. alkyl unsubstituted or R15 substituted by hydroxy; halogen; ester or cyano. Preferably, R is hydrogen; hydroxymethyl: chloro; cyano. More prefer 0787. Usually, R' is hydrogen or halogen. Preferably R' ably, R is hydrogen or cyano. Most preferred R is hydrogen. is hydrogen; chloro or fluoro. More preferred R' is hydro (0775. Usually, R is hydrogen; C. alkyl unsubstituted or gen. Substituted by halogens: Calkenyl substituted by halogens 10788 Usually, R' is hydrogen: Cs alkyl; halogen or or phenyl group unsubstituted or substituted by azido or/and thiazolyl unsubstituted or Substituted by alkyl groups, such as halogens. Preferably, R is hydrogen; n-propyl; 2.2-difluo methylthiazolyl. Preferably R' is hydrogen; chloro; bromo rovinyl; phenyl: 3-chlorophenyl: 3-fluorophenyl: 4-chlo or methyl. Most preferred R' is chloro; bromo or methyl. rophenyl: 4-fluorophenyl: 3,5-difluorophenyl: 3,4-difluo 0789. Usually R'' is hydrogen. rophenyl: 3-chloro-4-fluorophenyl: 2,3,4-trifluorophenyl: 0790. Usually, R' is hydrogen. 2,4,5-trifluorophenyl: 2,3,5-trifluorophenyl: 3,4,5-trifluo 0791 Combinations of one or more of these preferred rophenyl: 3-azido-2,4-difluorophenyl or 3-azido-2,4,6-trif compound groups are especially preferred. luorophenyl. More preferably, R is hydrogen; n-propyl; 2.2- 0792 Generally, among the embodiments, the compounds difluorovinyl; phenyl: 3-chlorophenyl: 3-fluorophenyl: of formula I, orpharmaceutically acceptable salts thereof, are those wherein 4-chlorophenyl: 4-fluorophenyl: 3,5-difluorophenyl: 3,4-dif 10793 R' is selected from hydrogen; Co alkyl unsubsti luorophenyl: 3-chloro-4-fluorophenyl: 2,3,4-trifluorophenyl: tuted or Substituted by halogen, hydroxy, cyano, methylthio. 2,4,5-trifluorophenyl: 2,3,5-trifluorophenyl: 3,4,5-trifluo phenyl or 4-chlorophenoxy, C. cycloalkyl; halogen; ester; rophenyl or 3-azido-2,4-difluorophenyl. Most preferably, R' amido; nitro; cyano; amino; phenyl; alkylthio; alkylsulfonyl: is n-propyl: 2,2-difluorovinyl; phenyl: 3-chlorophenyl: alkylsulfinyl; heterocycle unsubstituted or substituted by 3-fluorophenyl: 3,5-difluorophenyl: 2,3,4-trifluorophenyl: alkyl group; or guanidine; 2,4,5-trifluorophenyl: 2,3,5-trifluorophenyl: 3,4,5-trifluo 10794 R is selected from hydrogen; C, alkyl unsubsti rophenyl or 3-azido-2,4-difluorophenyl. tuted or substituted by hydroxy, alkanoylamino or benzoy 0776 Usually, R" is hydrogen. lamino; halogen; ester, cyano; alkyl carbamate or (N-meth 0777 Usually, R is hydrogen. oxy-N-methyl)aminocarbonyl. US 2011/0212928 A1 Sep. 1, 2011 32

0795 R is selected from hydrogen; C, alkyl unsubsti 0814. In a preferred embodiment, the compounds of for tuted or Substituted by hydroxy; halogen; ester or cyano; 0796 R is selected from hydrogen; C alkyl unsubsti mula I, or pharmaceutically acceptable salt thereof, are those tuted or Substituted by halogens, Calkenyl Substituted by wherein halogens or phenyl group unsubstituted or Substituted by 0815I R' is selected from hydrogen; methyl; ethyl: i-pro azido or/and halogens; pyl; n-propyl; cyclopropyl. n-butyl; i-butyl; t-butyl, 1-ethyl 0797 R is hydrogen; 0798 R is hydrogen; propyl; 2,4,4-trimethylpentyl; trifluoromethyl; 2.2.2-trifluo 0799 R is selected from hydrogen or Co alkyl unsub roethyl; hydroxymethyl: chloromethyl; cyanomethyl: stituted or substituted by hydroxy or azido: 2-(methylthio)ethyl, chloro; bromo; nitro; cyano; amino; 0800 R is hydrogen; aminocarbonyl: methoxycarbonyl: methylthio; methylsulfi 0801 or R and R can be linked to form a cyclopropyl; nyl: methylsulfonyl: phenyl: 2-furyl; 3-furyl; 1H-pyrrol-2-yl: 0802 or R and R can form together with the imidazole 1-methyl-1H-pyrrol-2-yl: 2-thienyl: 1H-pyrazol-3-yl: 1,2,3- ring the following 1H-benzimidazole cycle thiadiazol-4-yl; or 1H-imidazol-2-yl; R8 R9 (0816 R is selected from hydrogen; methyl; hydroxym R2 ethyl, (acetylamino)methyl: (propionylamino)methyl; (ben R10. Zoylamino)methyl, (benzyloxycarbonyl)amino; chloro; or cyano; 0817 R is selected from hydrogen; hydroxymethyl: RI ls RI 1s R11 chloro; cyano; (0818 or R and R can form together with the imidazole 0803 R is hydrogen: ring the following 1H-benzimidazole cycle 0804 R is selected from hydrogen; halogen; C alkyl: alkoxy; (0805) R' is selected from hydrogen; halogen; cyano or C. alkyl unsubstituted or substituted by halogens; or R8 R9 alkoxy; (0806 R'' is hydrogen: R2 0807 or R. R* and Rican form together with the 2-oxo R10 1-pyrrolidine ring the following 1,3-dihydro-2H-indol-2-one g g cycle R1 J.s N R3 RI J.N R11 2 R13 R R4 Rg 0819 R is hydrogen; (0820 R is selected from hydrogen; methyl; choro; meth A R 14 oxy; R5 N: O N: O; R15 0821) R' is selected from methyl; hydrogen; trifluorom ethyl; fluoro; cyano; or methoxy; (0808 R is selected from hydrogen or halogen; 0822 R'' is hydrogen: 0809 R' is selected from hydrogen; C, alkyl; halogen; 0823 R is selected from hydrogen; n-propyl; 2.2-difluo thiazolyl unsubstituted or Substituted by alkyl groups, such as methylthiazolyl; rovinyl; phenyl: 3-chlorophenyl: 3-fluorophenyl: 4-chlo 0810 R is hydrogen: rophenyl: 4-fluorophenyl: 3,5-difluorophenyl: 3,4-difluo 0811) R' is hydrogen; rophenyl: 3-chloro-4-fluorophenyl: 2,3,4-trifluorophenyl: 0812 with the proviso that R is different from hydrogen 2,4,5-trifluorophenyl: 2,3,5-trifluorophenyl: 3,4,5-trifluo when rophenyl: 3-azido-2,4-difluorophenyl; or 3-azido-2,4,6-trif luorophenyl. (0824) R' is hydrogen; R is hydrogen; 0825 or R. R* and Rican form together with the 2-oxo 1-pyrrolidine ring the following 1,3-dihydro-2H-indol-2-one cycle 0813 represents a group of formula R12 R13

lsS. R11 US 2011/0212928 A1 Sep. 1, 2011

0826) R' is selected from hydrogen; chloro; fluoro; 0847 or R. R* and Rican form together with the 2-oxo 0827) R' is selected from hydrogen; chloro; bromo: 1-pyrrolidine ring the following 1,3-dihydro-2H-indol-2-one methyl; cycle 0828 R'' is hydrogen: 0829) R' hydrogen: R12 0830) R' is selected from hydrogen; azidomethyl: R13 0831) R' is hydrogen: R4 0832 or Rand Rare linked to form a cyclopropyl: Rg 0833 with the proviso that R is different from hydrogen R 14 when R5 N: O N: O R15

0848 wherein 0849 R' is hydrogen; 0850 R is selected from methyl: chloro: bromo: E: ES"ydrogen; 0853 R is hydrogen: 0834 represents a group of formula 108540855 withR is thehydrogen; proviso that R is different- 0 from hydrogen when R2

R1 s "

0856 represents a group of formula 0835. In a more preferred embodiment, the compounds of formula I, or pharmaceutically acceptable salt thereof, are R8 R9 those wherein 0836) R' is selected from hydrogen; methyl; ethyl: i-pro pyl; n-propyl; n-butyl, methylthio; nitro; cyano; amino; R10. chloro; or 1H-pyrrol-2-yl: *N 0837 R’ is selected from hydrogen; chloro; cyano; 0838 R is selected from hydrogen; cyano; ls N R11 0839 or R and R can form together with the imidazole ring the following 1H-benzimidazole cycle 0857. In a most preferred embodiment, the compounds of formula I, or pharmaceutically acceptable salt thereof, are those wherein R8 R9 10858) R' is selected from hydrogen; methyl: methylthio; nitro; cyano; amino; chloro; R2 10859 R is selected from hydrogen; chloro; cyano; R10 0860 R is hydrogen; *N N R3 *N 0861) R' is selected from n-propyl; 2.2-difluorovinyl; phe nyl: 3-chlorophenyl: 3-fluorophenyl: 3,5-difluorophenyl; 2.3, 4-trifluorophenyl; 2,4,5-trifluorophenyl: 2,3,5-trifluorophe -S N -S N R11 nyl: 3,4,5-trifluorophenyl: 3-azido-2,4-difluorophenyl: 0862 R is hydrogen: 0863 R is hydrogen: 0840 R is hydrogen: 0864 or R. R* and Rican form together with the 2-oxo 0841) R' is hydrogen: 1-pyrrolidine ring the following 1,3-dihydro-2H-indol-2-one 0842) R' is selected from hydrogen; trifluoromethyl: cycle fluoro; cyano; 0843 R'' is hydrogen; 0844 R is selected from hydrogen; n-propyl; 2.2-difluo rovinyl; phenyl: 3-chlorophenyl: 3-fluorophenyl: 4-chlo rophenyl: 4-fluorophenyl: 3,5-difluorophenyl: 3,4-difluo rophenyl: 3-chloro-4-fluorophenyl: 2,3,4-trifluorophenyl: 2,4,5-trifluorophenyl: 2,3,5-trifluorophenyl: 3,4,5-trifluo rophenyl: or 3-azido-2,4-difluorophenyl: 0845 R“ is hydrogen; 0846 R is hydrogen:

US 2011/0212928 A1 Sep. 1, 2011 36 ylmethyl)pyrrolidin-2-one; 1-2-(methylthio)-1H 0886. Usually when R is a group of formula CHRR imidazol-1-yl)methyl-4-propylpyrrolidin-2-one; 1-(2- then R is Cls alkyl optionally substituted by C. cycloalkyl, methyl-1H-imidazol-1-yl)methyl-4-phenylpyrrolidin-2- aryl or heterocycle. one: 1-(1H-imidazol-1-ylmethyl)-4-(3,4,5-trifluorophenyl) pyrrolidin-2-one; 4-(3-fluorophenyl)-1-(1H-imidazol-1- 0887. The term “alkyl, as used herein, is a group which ylmethyl)pyrrolidin-2-one: 4-(3,5-difluorophenyl)-1-(1H represents Saturated, monovalent hydrocarbon radicals hav imidazol-1-ylmethyl)pyrrolidin-2-one: 1-(1H-imidazol-1- ing straight (unbranched) or branched moieties, or combina ylmethyl)-4-(2,3,4-trifluorophenyl)pyrrolidin-2-one: 1-(1H tions thereof, and containing 1-8 carbon atoms, preferably imidazol-1-ylmethyl)-4-(2,3,5-trifluorophenyl)pyrrolidin-2- 1-6 carbon atoms; more preferably alkyl groups have 1-4 one: 1-(1H-imidazol-1-ylmethyl)-4-(2,4,5-trifluorophenyl) carbon atoms. Alkyl moieties may optionally be substituted pyrrolidin-2-one: 1-(2-nitro-1H-imidazol-1-yl)methyl-4- by 1 to 5 substituents independently selected from the group (3,4,5-trifluorophenyl)pyrrolidin-2-one; 1-2-oxo-4-(3,4,5- consisting of hydroxy, alkoxy, cyano, ethynyl, alkoxycarbo trifluorophenyl)pyrrolidin-1-yl)methyl)-1H-imidazole-2- nyl, acyl, aryl or heterocycle. Alkyl moieties may be option carbonitrile; 1-(2-amino-1H-imidazol-1-yl)methyl-4- ally substituted by a cycloalkyl as defined hereafter. Preferred propylpyrrolidin-2-one; 1-(5-chloro-1H-imidazol-1-yl) alkyl groups are methyl, cyanomethyl, ethyl, 2-ethoxy-2- methyl-4-(3,4,5-trifluorophenyl)pyrrolidin-2-one; (+)-1- oxoethyl, 2-methoxyethyl, n-propyl, 2-oxopropyl, 3-hydrox (1H-imidazol-1-ylmethyl)-4-phenylpyrrolidin-2-one: (-)-1- ypropyl. 2-propynyl. n-butyl, i-butyl, n-pentyl, 3-pentyl, (1H-imidazol-1-ylmethyl)-4-phenylpyrrolidin-2-one: 1-(2- n-hexyl, cyclohexylmethyl, benzyl, 2-bromobenzyl, 3-bro chloro-1H-imidazol-1-yl)methyl-4-(3,4,5-trifluorophenyl) mobenzyl, 4-bromobenzyl, 3-methoxybenzyl, 3-nitrobenzyl, pyrrolidin-2-one: 1-(2-chloro-1H-imidazol-1-yl)methyl-4- 3-aminobenzyl, 4-(aminosulfonyl)benzyl, 1-phenylethyl, propylpyrrolidin-2-one; (+)-1-(2-oxo-4-(3,4,5- 2-phenylethyl, (3,5-dimethylisoxazol-4-yl)methyl or (5-ni trifluorophenyl)pyrrolidin-1-yl)-methyl)-1H-imidazole-5- tro-2-furyl)methyl. More preferred alkyl groups are methyl, carbonitrile; 5-bromo-1-(1H-imidazol-1-ylmethyl)-1,3- ethyl, cyanomethyl, 2-methoxyethyl, n-propyl, 3-hydrox dihydro-2H-indol-2-one: 5-chloro-1-(1H-imidazol-1- ypropyl. 2-propynyl. n-butyl, 3-pentyl, n-hexyl, benzyl, ylmethyl)-1,3-dihydro-2H-indol-2-one: 1-(1H-imidazol-1- 3-bromobenzyl, 3-methoxybenzyl, 3-nitrobenzyl, 3-ami ylmethyl)-5-methyl-1,3-dihydro-2H-indol-2-one: 1-(5- nobenzyl, (3,5-dimethylisoxazol-4-yl)methyl or (5-nitro-2- chloro-2-oxo-2,3-dihydro-1H-indol-1-yl)methyl)-1H furyl)methyl. Most preferred alkyl groups are methyl, ethyl, imidazole-5-carbo-nitrile. 3-methoxybenzyl, 3-nitrobenzyl or (5-nitro-2-furyl)methyl. 0874. In some embodiments, compounds useful in the 0888. The term "cycloalkyl, as used herein, represents a methods and compositions of this invention are selected from monovalent group of 3 to 8, preferably 3 to 6 carbon atoms the group consisting of: (-)-4-(3-azido-2,4-difluorophenyl)- derived from a saturated cyclic hydrocarbon, which may be 1-(1H-imidazol-1-ylmethyl)pyrrolidin-2-1-one; (+)-4-(3- Substituted by any suitable group including but not limited to azido-2,4-difluorophenyl)-1-(1H-imidazol-1-ylmethyl)pyr one or more moieties selected from groups as described above rolidin-2-one; 4-(3-azido-2,4-difluorophenyl)-1-(1H for the alkyl groups. Preferred cycloalkyl group is cyclo imidazol-1-ylmethyl)pyrrolidin-2-one. hexyl. 0875 v) International Patent Application WO 2007/ 0889. The term “aryl as used herein, is defined as a phe O65595: nyl group optionally Substituted by 1 to 4 substituents inde 0876 Compounds having formula I, their enantiomers, pendently selected from halogen, amino, nitro, alkoxy or diastereoisomers and mixtures thereof (including all possible aminosulfonyl. Preferred aryl groups are phenyl, 2-bro mixtures of stereoisomers), or pharmaceutically acceptable mophenyl, 3-bromophenyl, 4-bromophenyl, 3-methoxyphe salts thereof, nyl, 3-nitrophenyl, 3-aminophenyl or 4-(aminosulfonyl)phe nyl. 0890. The term “phenyl', as used herein, represents an (I) O R4 aromatic hydrocarbon group of formula—CHs. R! M 0891. The term “benzyl group', as used herein, represents n N N a group of formula —CH2-aryl. Preferred benzyl groups are S benzyl, 2-bromobenzyl, 3-bromobenzyl, 4-bromobenzyl, 3-methoxybenzyl, 3-nitrobenzyl, 3-aminobenzyl or 4-(ami O J2N N R3 nosulfonyl)benzyl. More preferred benzyl groups are benzyl, 3-bromobenzyl, 3-methoxybenzyl, 3-nitrobenzyl or 3-ami k nobenzyl. Most preferred alkyl groups are 3-methoxybenzyl or 3-nitrobenzyl. 0877 wherein 0878) R' is hydrogen or C, alkyl; 0892. The term “halogen', as used herein, represents an 0879 R is hydrogen or Calkyl: atom of fluorine, chlorine, bromine, or iodine. Preferred halo 0880 R is a group of formula CHRR or a benzyl gen is bromine group; 0893. The term “hydroxy’, as used herein, represents a 0881) R' is Cls alkyl optionally substituted by alkoxycar group of formula—OH. bonyl, C3-6 cycloalkyl, aryl or heterocycle; 0894. The term “cyano”, as used herein, represents a 0882 R is C2-4 alkyl: group of formula—CN. 0883 R is C2-4 alkyl, amido or -COOR7: 0895. The term “amino', as used herein, represents a 0884 R7 is C1-4 alkyl: group of formula —NH. 0885 Usually when R is a benzyl group, then R is Cls 0896. The term “ethynyl', as used herein, represents a alkyl optionally substituted by alkoxycarbonyl. group of formula—C=CH. US 2011/0212928 A1 Sep. 1, 2011 37

0897. The term “alkoxy’, as used herein, represents a 0910. In some embodiments, the compounds are those group of formula —OR wherein R is an alkyl group, as having formula I, and their enantiomers, diastereoisomers defined above. Preferred alkoxy group is methoxy. and mixtures thereof (including all possible mixtures of Ste 0898. The term "nitro', as used herein, represents a group reoisomers), or pharmaceutically acceptable salts thereof, of formula—NO. 0899. The term "amido’, as used herein, represents a (I) group of formula—C(=O)NH2. O R4 0900. The term “acyl, as used herein, represents a group R / of formula C(=O)R’ wherein R is an alkyl group, as NN N defined here above. Preferred acyl group is acetyl ( C(=O) Me). O1. N N2 vR3 0901. The term “alkoxycarbonyl (or ester), as used herein, represents a group of formula—COOR wherein R is R2 an alkyl group; with the proviso that R does not represent an alkyl alpha-substituted by hydroxy. Preferred alkoxycarbonyl 0911 wherein group is ethoxycarbonyl. (0912) R' is hydrogen, Calkyl optionally substituted by 0902. The term "heterocycle', as used herein, represents a hydroxy, alkoxy, cyano, ethynyl, alkoxycarbonyl or acyl: 5-membered ring containing one or two heteroatoms selected (0913 R’ is hydrogen or unsubstituted C. alkyl: from O or N. The heterocycle may be substituted by one or (0914 R is a group of formula CHR, R or a benzyl two C alkyl or nitro. Preferred heterocycles are (3,5-dim group; ethylisoxazol-4-yl) or (5-nitro-2-furyl). Most preferred het (0915I R' is Cls alkyl optionally substituted by cyclo erocycle is (5-nitro-2-furyl). hexyl, phenyl, bromophenyl, aminophenyl, methoxyphenyl, (0903 Generally R' is hydrogenor C-alkyl. Usually R' is nitrophenyl, aminosulfonylphenyl, 3,5-dimethylisoxazol-4- hydrogen or Ce alkyl optionally Substituted by hydroxy, y1, 5-nitro-2-furyl or ethoxycarbonyl: alkoxy, cyano, ethynyl, alkoxycarbonyl or acyl. Preferably R' 10916 R is unsubstituted C. alkyl: is hydrogen, methyl, cyanomethyl, 2-ethoxy-2-oxoethyl, (0917 R is unsubstituted C. alkyl, amido or -COOR7: 2-methoxyethyl, n-propyl, 2-oxopropyl, 3-hydroxypropyl. (0918 R7 is unsubstituted Calkyl: 2-propynyl, n-pentylorn-hexyl. More preferably R' is hydro (0919 with the proviso that when R' is hydrogen, R is gen, methyl, cyanomethyl, 2-methoxyethyl, n-propyl, 3-hy methyl, R is CHR, R, R is ethoxycarbonyl and R is droxypropyl or 2-propynyl. Most preferably R' is hydrogen. ethyl, then R is different from n-propyl, i-propyl. n-pentyl, (0904 Generally R is hydrogenor C, alkyl. Usually Ris n-heptyl, 3-bromobenzyl, 4-chlorobenzyl, 4-methylbenzyl or hydrogen or unsubstituted C, alkyl. Preferably R is hydro 2-phenylethyl. gen, methyl or n-butyl. More preferably, R is methyl. 0920. In the above embodiment, preferably, when R is a 0905 Generally R is a group of formula—CHRR or a benzyl group, then R is Cls alkyl optionally substituted by benzyl group. Preferably R is 3-pentyl, 1-(aminocarbonyl) alkoxycarbonyl. propyl, 1-(ethoxycarbonyl)propyl or 3-bromobenzyl. Most 0921. In the above embodiment, preferably, when R is a preferably R is 1-(ethoxycarbonyl)propyl. group of formula—CHRR, then R is Cls alkyl optionally (0906 Generally R' is Cls alkyl optionally substituted by Substituted by C. cycloalkyl, aryl or heterocycle. alkoxycarbonyl, C. cycloalkyl, aryl or heterocycle. Usually 0922. In a preferred embodiment, R" is Cls alkyl optionally substituted by cyclohexyl, phenyl, 0923 R' is hydrogen, methyl, cyanomethyl, 2-ethoxy-2- bromophenyl, aminophenyl, methoxyphenyl, nitrophenyl, oxoethyl, 2-methoxyethyl, n-propyl, 2-oxopropyl, 3-hydrox aminosulfonylphenyl, 3,5-dimethylisoxazol-4-yl, 5-nitro-2- furyl or ethoxycarbonyl. Preferably R is n-butyl, i-butyl, ypropyl. 2-propynyl, n-pentyl or n-hexyl, n-pentyl, n-hexyl, cyclohexylmethyl, benzyl, 2-bromoben 0924 R is hydrogen, methyl or n-butyl: Zyl, 3-bromobenzyl, 4-bromobenzyl, 3-methoxybenzyl, 3-ni 0925 R is 3-pentyl, 1-(aminocarbonyl)propyl. trobenzyl, 3-aminobenzyl, 4-(aminosulfonyl)benzyl, 1-phe 1-(ethoxycarbonyl)propyl or 3-bromobenzyl: nylethyl 2-phenylethyl, (3,5-dimethylisoxazol-4-yl)methyl, 10926) R' is n-butyl, i-butyl, n-pentyl, n-hexyl, cyclohexy (5-nitro-2-furyl)methyl or 1-(ethoxycarbonyl)propyl. More lmethyl, benzyl, 2-bromobenzyl, 3-bromobenzyl, 4-bro preferably R' is n-butyl, n-hexyl, benzyl, 3-bromobenzyl, mobenzyl, 3-methoxybenzyl, 3-nitrobenzyl, 3-aminobenzyl, 3-methoxybenzyl, 3-nitrobenzyl, 3-aminobenzyl, (3,5-dim 4-(aminosulfonyl)benzyl, 1-phenylethyl 2-phenylethyl, ethylisoxazol-4-yl)methyl, (5-nitro-2-furyl)methyl or (3,5-dimethylisoxazol-4-yl)methyl, (5-nitro-2-furyl)methyl 1-(ethoxycarbonyl)propyl. Most preferably R' is 3-methoxy or 1-(ethoxycarbonyl)propyl; benzyl, 3-nitrobenzyl or (5-nitro-2-furyl)methyl. 0927 with the proviso that when R' is hydrogen, R is (0907 Generally R is C. alkyl. Usually R is unsubsti methyl and R is 1-(ethoxycarbonyl)propyl, then R is differ tuted C-4 alkyl. Preferably R is ethyl. ent from n-pentyl, 3-bromobenzyl or 2-phenylethyl. 0908 Generally R is C. alkyl, amido or -COOR7. 0928. In the above embodiment, preferably, when R is Usually R is unsubstituted C. alkyl, amido or -COOR7. 3-bromobenzyl, then R is Cls alkyl optionally substituted Preferably R is ethyl, amido or ethoxycarbonyl. Most pref by alkoxycarbonyl. erably R is ethoxycarbonyl. 0929. In the above embodiment, preferably, when R is (0909 Generally R7 is C alkyl. Usually R7 is unsubsti 3-pentyl, 1-(aminocarbonyl)propyl or 1-(ethoxycarbonyl) tuted C. alkyl. Preferably, R is ethyl. propyl, then R is different from 1-(ethoxycarbonyl)propyl.

US 2011/0212928 A1 Sep. 1, 2011 39

0943. In some embodiments, the compounds are those yl)thiobut-anoate; 7-(3-bromobenzyl)-8-3-chloro-2-hy having formula II, their enantiomers, diastereoisomers and droxypropyl)thiol-3-methyl-3,7-dihydro-1H-purine-2,6-di mixtures thereof (including all possible mixtures of stereoi one; and ethyl 2-7-(3-bromobenzyl)-3-methyl-2,6-dioxo Somers), or pharmaceutically acceptable salts: 2,3,6,7-tetrahydro-1H-purin-8-yl-thiopropanoate. 0948. In some embodiments, the compounds are com pounds of formula I, their enantiomers, diastereoisomers and mixtures thereof (including all possible mixtures of stereoi (II) Somers), or pharmaceutically acceptable salts O R4

RS \ (I) O R4 O1. N N2 vR3 k RS \ O1. N N2 vR3 wherein R.Sup. 1 is hydrogen or C. sub.1-6 alkyl; R.Sup.2 is hydrogen or C. Sub. 1-4 alkyl; k R.Sup.3 is a group of formula—CHR.Sup.5R. Sup.6 or a ben Zyl group; wherein R.Sup.4 is C. sub. 1-8 alkyl optionally substituted by alkoxy R.sup. 1 is hydrogen or C. sub.1-6 alkyl; carbonyl, C.sub-3-6 cycloalkyl, aryl or heterocycle: R.Sup.2 is hydrogen or C. Sub. 1-4 alkyl; R.Sup.3 is a group of formula—CHR.Sup.5R.Sup.6 or a ben R.Sup.5 is hydrogen or C. sub. 1-4 alkyl; Zyl group; R.Sup.6 is C. sub. 1-4 alkyl, amido or COOR. Sup.7: R.Sup.4 is C. sub. 1-8 alkyl optionally substituted by alkoxy R.Sup.7 is C. sub. 1-4 alkyl: carbonyl, C.sub-3-6 cycloalkyl, aryl or heterocycle: 0944. In the above embodiment, in some cases, when R.Sup.5 is C. sub.2-4 alkyl: R.Sup.3 is a benzyl group, then R. Sup.4 is C. sub. 1-8 alkyl R.Sup.6 is C. sub.2-4 alkyl, amido or COOR.sup.7: optionally substituted by alkoxycarbonyl. R.Sup.7 is C. sub. 1-4 alkyl: 0945. In the above embodiment, in some cases, when 0949. In another embodiment, the compounds are com R.Sup.3 is a group of formula —CHR. Sup.5R.Sup.6, then pounds having formula II, their enantiomers, diastereoiso R.Sup.4 is C. Sub. 1-8 alkyl optionally substituted by C. Sub.3-6 mers and mixtures thereof (including all possible mixtures of cycloalkyl, aryl or heterocycle. Stereoisomers), or pharmaceutically acceptable salts thereof, 0946. In some embodiments, the compounds are those compounds of formula II, their enantiomers, diastereoiso (II) mers and mixtures thereof (including all possible mixtures of O R4 Stereoisomers), or pharmaceutically acceptable salts R / NN N (II) X-sV O R4 O N N R3 R M NN N R2 wherein O1. N N2 vR3 R.sup. 1 is hydrogen or C. sub.1-6 alkyl; R.Sup.2 is hydrogen or C. Sub. 1-4 alkyl; k R.Sup.3 is a group of formula—CHR.Sup.5R.Sup.6 or a ben Zyl group; wherein R.Sup.4 is C. sub. 1-8 alkyl optionally substituted by alkoxy R.sup. 1 is hydrogen or C. sub.1-6 alkyl; carbonyl, C.sub-3-6 cycloalkyl, aryl or heterocycle: R.Sup.5 is hydrogen or C. sub. 1-4 alkyl; R.Sup.2 is hydrogen or C. Sub. 1-4 alkyl; R.Sup.6 is C. sub. 1-4 alkyl, amido or COOR.sup.7: R.Sup.3 is a group of formula—CHR.Sup.5R. Sup.6 or a ben R.Sup.7 is C. sub. 1-4 alkyl: Zyl group; 0950 iv) International Patent Application Publication No. R.Sup.4 is C. sub. 1-8 alkyl optionally substituted by alkoxy WO2O1 Of 144712 carbonyl, C.sub-3-6 cycloalkyl, aryl or heterocycle: 0951. In one embodiment, a chemical composition that R.Sup.5 is hydrogen or C. sub. 1-4 alkyl; includes a LEV derivative of Formula 1 or Formula 2 is R.Sup.6 is C. sub. 1-4 alkyl, amido or COOR. Sup.7: disclosed. R.Sup.7 is C. sub. 1-4 alkyl. 0947. In some embodiments, the compounds are com Formula I pounds of formula II selected from ethyl 2-7-heptyl-3-me thyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl)thiobu tanoate; 7-(3-bromobenzyl)-3-methyl-8-(propylthio)-3,7- dihydro-1H-purine-2,-6-dione; ethyl 2-(3-methyl-2,6- dioxo-7-pentyl-2,3,6,7-tetrahydro-1H-purin-8-yl)thiobut anoate; ethyl 2-7-(3-bromobenzyl)-3-methyl-2,6-dioxo-2, 3,6,7-tetrahydro-1H-purin-8-yl-thiobutanoate; ethyl 2-3- methyl-2,6-dioxo-7-propyl-2,3,6,7-tetrahydro-1H-purin-8- US 2011/0212928 A1 Sep. 1, 2011 40

CH3CH2CD2-, CH3CD2CD2-, CD3CD2CD2- or -continued CH3CH2CH2-. In a more specific embodiment, R1 is Formula 2 CD3CD2CD2- or 0956 CD3CD2CH2-. In one aspect of these embodi O ments, Z1 and Z2 are both hydrogen. In another aspect of these embodiments, Z1 and Z2 are both deuterium. Yn 1 Lin NH2 0957. In another embodiment, R2 is selected from X cgi-n- CH3CH2-, CD3CH2-, CH3CD2-, or CD3CD2-. In a more O specific embodiment, R2 is selected from CH3CH2- or CD3CD2-. In one aspect of these embodiments, Z1 and Z2 n of Formula 2 and L, X, and Y of Formulas 1 and 2 are are both hydrogen. In another aspect of these embodiments, defined as follows: a) n is an integer with a value of 0 to 8; b) Z1 and Z2 are both deuterium. L is one of the group consisting of CH2, CO. NHCO, NHCOO, CONH, NH, O, or S, and combinations thereof; c) 0958. The R and Z variables as described above may be X is an end group, an aromatic group, an aryl group, or a selected and taken together to provide more specific embodi saturated, unsaturated, Substituted, unsubstituted, straight ments of this invention. For example, in one embodiment, R1 chain, or branched chain aliphatic group having from 1 to 10 is CD3CH2CH2-, CD3CD2CH2-, CD3CH2CD2 carbon and/or hetero chain atoms, the hetero chain atoms CH3CH2CD2-, CH3CD2CD2-, CD3CD2CD2- or being selected from the group consisting of oxygen, nitrogen, CH3CH2CH2-; and R2 is selected from CH3CH2-, Sulfur, or phosphorus, and combinations thereof, and d)Y is CD3CH2-, CH3CD2-, or CD3CD2-. In one aspect of this optional and if present is one of a functional group selected embodiment, R2 is CH3CH2- or CD3CD2-. from group consisting of alcohol amine, amide, carboxylic acid, aldehyde, ester, iminoester, isocyanate, isothiocyanate, 0959. In another embodiment, R1 is CD3CD2CD2- or anhydride, thiol, thiolacetone, diazonium, NHS, CO. NHS, CD3CD2CH2-; and R2 is selected from CH3CH2-, O. NHS, maleimido: ore)Y is a Yi-Z where Yi is selected CD3CH2-, CH3CD2-, or CD3CD2-. In one aspect of this from the group consisting of COO, CO, O, CONH, NHCO, or embodiment, R2 is CH3CH2- or CD3CD2-. NH and Z is an operative group. 0960 Examples of specific compounds of this invention 0952. In one embodiment of the method, the operative include the following: group of Z is selected from the group consisting of detectable labels, antigenic carriers, coupling agents, end groups, pro teins, lipoproteins, glycoproteins, polypeptides, polysaccha Compound 100 rides, nucleic acids, polynucleotides, teichoic acids, radioac tive isotopes, enzymes, enzyme fragments, enzyme donor fragments, enzyme acceptor fragments, enzyme substrates, enzyme inhibitors, coenzymes, fluorescent moieties, phos phorescent moieties, anti-Stokes up-regulating moieties, D DYs DC HD chemiluminescent moieties, luminescent moieties, dyes, sen D De1N sitizers, particles, microparticles, magnetic particles, Solid D Supports, liposomes, ligands, receptors, hapten radioactive Compound 101 O isotopes, and combinations thereof. D 0953 vii) International Patent Application Publication D O No. WO2O1 O/OO2869 D w N 0954 The present invention provides a compound of For NH2: D HY mula I: DC D Hc1 Compound 102 (I) O H D O D- \ N NH2; and HY DC D D HC1 Compound 103 ora pharmaceutically acceptable salt thereof, wherein: each Z is independently selected from hydrogen and deuterium; R1 is an n-propyl group having Zero to seven deuterium atoms; R2 is an ethyl group having Zero to five deuterium atoms, and when each R has Zero deuterium atoms, at least one Z is deuterium. 0955 One embodiment of this invention provides com pounds of Formula I wherein R1 is selected from CD3CH2CH2-, CD3CD2CH2-, CD3CH2CD2-, US 2011/0212928 A1 Sep. 1, 2011 41

0961 viii) 20090312333 or R3 is 0962. The compounds of the present invention are those covered by formula (I), their diastereomers and mixtures, or a 1002 (b) a substituted or unsubstituted heterocycle linked pharmaceutically acceptable salt thereof. to the rest of the molecule via one of its N atoms, said het erocycle is selected from the group consisting of 1003 1H-1,2,3-benzotriazol-1-yl: (I) 1004 1H-imidazo[4,5-b]pyridin-1-yl: 1005 3H-imidazo[4,5-b]pyridin-3-yl: 1006 7H-imidazo[4,5-cpyridazin-7-yl; 1007 1H-indol-1-yl: R5 N O 1008 2,3-dihydro-1H-indol-1-yl: 1009 9H-purin-9-yl: 1. R3 1010 1H-pyrazolo 3,4-bipyridin-1-yl; R2 1011 2H-pyrazolo 3,4-bipyridin-2-yl; 1012 1H-pyrrolo2,3-bipyridin-1-yl; R1 is hydrogen, substituted or unsubstituted C1-12 alkyl, 1H-pyrrolo3.2-bipyridin-1-yl; substituted or unsubstituted aryl or substituted or unsubsti 1013 tuted 3-8 membered heterocycle. 1014 3,4-dihydroquinolin-1 (2H)-yl: R2 is hydrogen. Alternatively, R1 and R2 may be linked 1015 8H-isothiazolo.5,4-bindol-8-yl: together in such a way to form a C3-6 cycloalkyl. 1016 1H-1,2,4-triazol-1-yl: R3 is either 1017 1H-pyrrol-1-yl; 0963 (a) a substituted or unsubstituted heterocycle linked 2-chloro-1H-benzimidazol-1-yl. to the rest of the molecule via one of its C atoms, said hetero 1018 cycle is selected from the group consisting of: R4 in formula (I) is selected from the group comprising or 0964) 1H-benzimidazol-6-yl: consisting of hydrogen; C1-12 alkyl optionally Substituted by 0965 1H-benzimidazol-7-yl: halogen, C1-4 alkoxy, C1-4 alkylthio, azido, nitrooxy or an 0966) imidazo 1,2-alpyridin-3-yl; aryl; C2-12 alkenyl optionally substituted by halogen; C2-12 0967 imidazo[1,2-alpyrimidin-3-yl: alkynyl optionally Substituted by halogen; azido; alkoxycar 0968 imidazo 1.2-b1,2,4-triazin-7-yl; bonylamino: arylsulfonyloxy; a substituted or unsubstituted 0969 imidazo 1,2-bipyridazin-3-yl: aryl; or a 3-8 membered substituted or unsubstituted hetero 0970) 5,6,7,8-tetrahydroimidazo 1,2-bipyridazin-3-yl: cycle; 0971) imidazo[2,1-b1,3,4thiadiazol-5-yl: 1019. In a specific embodiment R4 is hydrogen; or R4 is 0972) imidazo[2,1-b1,3thiazol-5-yl: C1-12 alkyl or a C1-6 alkyl, optionally substituted by halo 0973 3H-imidazo[4,5-b]pyridin-7-yl: gen, C1-4 alkoxy, C1-4 alkylthio, azido or nitrooxy; or R4 is 0974) 1H-imidazol-4-yl: C2-12 alkenyl or a C1-6 alkenyl optionally substituted by 0975) 1H-imidazol-5-yl; halogen; or R4 is C2-12 alkynyl or a C1-6 alkynyl optionally 0976) 1H-indol-2-yl: Substituted by halogen; or R4 is alkoxycarbonylamino. 0977 1H-indol-3-yl; 1020 R5 is hydrogen: 0978 1H-indol-4-yl: 1021 Alternatively R4 may form together with R5 and the 0979 1H-indol-7-yl; 2-oxo-1-pyrrolidine ring a 1,3-dihydro-2H-indol-2-one ring 0980 isoxazol-4-yl: of the following structure: 0981) 1H-pyrazol-4-yl: 0982) 1H-pyrazol-5-yl: 0983. 1 H-pyrazolo 1.5-alpyrimidin-3-yl: 0984 1H-pyrazolo 3,4-bipyridin-3-yl: 0985 pyridazin-4-yl: 0986 pyridin-2-yl: 0987 pyridin-3-yl: 0988 pyridin-4-yl: 0989 1H-pyrrolo[2,3-bipyridin-3-yl; 0990) 1H-pyrrolo[2,3-bipyridin-4-yl; 0991) 1H-pyrrolo[2,3-bipyridin-5-yl; 1022. The asterisk * indicates the point of attachment of 0992 1H-pyrrolo[2.3-clpyridin-2-yl: the substituents; 0993 1H-pyrrolo[2.3-clpyridin-3-yl: 1023 R6 is hydrogen or halogen. 0994) 1H-pyrrolo[3.2-bipyridin-3-yl; 1024 R7 in formula (I) is selected from the group com 0995) 1H-pyrrolo[3.2-cpyridin-2-yl: prising or consisting of hydrogen; nitro; halogen; hetero 0996) 1H-pyrrolo[3.2-cpyridin-3-yl: cycle; amino: aryl; C1-12 alkyl optionally substituted by at 0997. 1,3,4-thiadiazol-2-yl; least one halogen; or C1-12 alkoxy optionally substituted by 0998 1,3-thiazol-5-yl: at least one halogen. 0999 (1,2,4-triazolo 4,3-bipyridazin-7-yl: 1025 R8 in formula (I) is selected from the group com 1000 1,2,4-triazolo 4,3-bipyridazin-8-yl: prising or consisting of hydrogen, C1-12 alkyl optionally 1001 indolizin-3-yl: Substituted by halogen, or halogen. US 2011/0212928 A1 Sep. 1, 2011 42

1026 R9 in formula (I) is selected from the group com 1077 1H-pyrrolo2,3-bipyridin-1-yl; prising or consisting of hydrogen, C1-12 alkyl optionally 1078 1H-pyrrolo3.2-bipyridin-1-yl; Substituted by halogen, or halogen. 1079 3,4-dihydroquinolin-1 (2H)-yl: 1027. A further aspect of the present invention consists in 1080 8H-isothiazolo.5,4-bindol-8-yl: compounds of formula (I) wherein 1081) 1H-1,2,4-triazol-1-yl: R1 and R2 are both hydrogen. 1082 1H-pyrrol-1-yl; 1083 2-chloro-1H-benzimidazol-1-yl. R3 is: 1084 R4 in formula (I) is selected from the group com prising or consisting of hydrogen; C1-12 alkyl optionally 1028 (a) a substituted or unsubstituted heterocycle linked substituted by halogen or C1-4 alkoxy; C2-12 alkenyl option to the rest of the molecule via one of its Catoms selected from ally substituted by halogen; C2-12 alkynyl optionally substi the group consisting of tuted by halogen. 1029 1H-benzimidazol-6-yl: 1085. In a further specific embodiment R4 is n-propyl, 1030) 1H-benzimidazol-7-yl: 2.2.2-trifluoroethyl, 2-chloro-2,2-difluoroethyl, 2 bromo-2, 1031 imidazo 1,2-alpyridin-3-yl; 2-difluoroethyl, 2,2-difluorovinyl. 1032 imidazo 1,2-alpyrimidin-3-yl: 1086. In another specific embodiment R4 is phenyl, 2.3, 1033 imidazo 1.2-b1,2,4-triazin-7-yl; 5-trifluorophenyl or 3-chloro-4-fluorophenyl. 1034 imidazo 1,2-bipyridazin-3-yl: 1087 R5 is hydrogen: 1035 5,6,7,8-tetrahydroimidazo 1,2-bipyridazin-3-yl: 1088 A further embodiment of the present invention con 1036 imidazo[2,1-b1,3,4thiadiazol-5-yl: sists in compounds of formula (I) wherein R4 forms together 1037) imidazo[2,1-b1,3thiazol-5-yl: with R5a 1,3-dihydro-2H-indol-2-one ring 1038 3H-imidazo[4,5-b]pyridin-7-yl: 1039) 1H-imidazol-4-yl: 1040 1H-imidazol-5-yl: R6 1041 1H-indol-2-yl; R7 1042) 1H-indol-3-yl: 1043) 1H-indol-4-yl: 1044) 1H-indol-7-yl: R8 1045 isoxazol-4-yl: N: O 1046 1H-pyrazol-4-yl: R9 1047 1H-pyrazol-5-yl: 1048. 1 H-pyrazolo 1.5-alpyrimidin-3-yl: 1089. The asterisk * indicates the point of attachment of 1049 1H-pyrazolo 3,4-bipyridin-3-yl: the heteroarylalkylene substituent, and wherein 1050 pyridazin-4-yl: R6 is hydrogen; 1051 pyridin-2-yl: R7 is chlorine; 1052 pyridin-3-yl: R8 is hydrogen; 1053 pyridin-4-yl: R9 is hydrogen. 1054 1H-pyrrolo2,3-bipyridin-3-yl; 1090. A further embodiment of the present invention con 1055 1 H-pyrrolo[2,3-bipyridin-4-yl; sists in compounds of formula (I) wherein R3 is a substituted 1056 1H-pyrrolo[2,3-bipyridin-5-yl; or unsubstituted heterocycle linked to the rest of the molecule 1057 1H-pyrrolo2.3-cpyridin-2-yl; via one of its C atoms and is selected from the group consist 1058 1H-pyrrolo2.3-cpyridin-3-yl; ing of 1059 1H-pyrrolo[3.2-bipyridin-3-yl; 1091) imidazol-2-alpyrimidin-3-yl; 1060 1H-pyrrolo3.2-cpyridin-2-yl; 1092 imidazo[1,2-b1,2,4-triazin-7-yl: 1061 1H-pyrrolo3.2-cpyridin-3-yl; 1093 imidazo[1,2-bipyridazin-3-yl; 1062 1,3,4-thiadiazol-2-yl: 1094) 5,6,7,8-tetrahydroimidazo[1,2-bipyridazin-3-yl; 1063. 1,3-thiazol-5-yl: 1095 imidazo[2.1-b1,3,4thiadiazol-5-yl: 1064 1.2.4 triazolo 4,3-bipyridazin-7-yl: 1096 imidazo[2.1-b1.3thiazol-5-yl: 1065 (1.2.4 triazolo 4,3-bipyridazin-8-yl: 1097 3H-imidazo[4,5-b]pyridin-7-yl: 1066 indolizin-3-yl. 1098 1H-imidazol-4-yl: 1099) 1H-imidazol-5-yl: Alternatively R3 is: 1100 isoxazol-4-yl; 1101 1067 (b) a substituted or unsubstituted heterocycle linked 1102 1H-pyrazol-5-yl: to the rest of the molecule via one of its Natoms selected from 1103 1H-pyrazolo 1.5-alpyrimidin-3-yl: the group consisting of 1104 1H-pyrazolo 3,4-bipyridin-3-yl; 1068 1H-1,2,3-benzotriazol-1-yl; 1105 pyridin-3-yl: 1069 1H-imidazo[4,5-b]pyridin-1-yl: 1106 1H-pyrrolo2,3-bipyridin-3-yl; 1070 3H-imidazo[4,5-b]pyridin-3-yl: 1107 1H-pyrrolo2,3-bipyridin-4-yl; 1071 7H-imidazo[4,5-cpyridazin-7-yl; 1108 1H-pyrrolo2,3-bipyridin-5-yl; 1072) 1H-indol-1-yl: 1109 1H-pyrrolo2.3-cpyridin-2-yl: 1073 2,3-dihydro-1H-indol-1-yl: 1110 1H-pyrrolo2.3-cpyridin-3-yl: 1074) 9H-purin-9-yl: 1111 1,3-thiazol-5-yl: 1075 1H-pyrazolo 3,4-bipyridin-1-yl: 1112 1.2.4 triazolo 4,3-bipyridazin-8-yl; 1076 2H-pyrazolo 3,4-bipyridin-2-yl: 1113 indolizin-3-yl. US 2011/0212928 A1 Sep. 1, 2011

1114. In a further specific embodiment R3 is a heterocycle 1144 Said heterocycles may optionally be substituted by linked to the rest of the molecule via one of its C atoms and is trifluoromethyl, cyclopropyl, bromine, chlorine, fluorine, selected from the group consisting of: methoxy or cyano. 1115 imidazo 1,2-bipyridazin-3-yl: 1145. In a further specific embodiment R3 is a heterocycle 1116 imidazo[2,1-b1,3,4thiadiazol-5-yl: linked to the rest of the molecule via one of its C atoms and is 1117 imidazo[2,1-b1,3thiazol-5-yl: selected from the group consisting of 6-bromo-2-chloro-3H 1118 3H-imidazo[4,5-b]pyridin-7-yl: imidazo[4,5-b]pyridin-3-yl, 6-bromo-2-cyclopropyl-3H 1119 1H-imidazol-4-yl; imidazo[4,5-b]pyridin-3-yl, 1H-pyrrolo3.2-bipyridin-1-yl, 1120 1H-imidazol-5-yl; 2,5-dichloro-1H-pyrrol-1-yl, 2-chloro-5-methoxy-1H-benz 1121 1 H-pyrazol-4-yl: imidazol-1-yl, 5-bromo-2-chloro-1H-benzimidazol-1-yl or 1122 1H-pyrazolo 1.5-alpyrimidin-3-yl: 2,5-dichloro-1H-benzimidazol-1-yl. 1123 pyridin-3-yl: 1146 A further embodiment of the present invention con 1124 1H-pyrrolo2,3-bipyridin-3-yl; sists in compounds of formula (I) wherein R1,R2 and R5 are 1125 1H-pyrrolo2,3-bipyridin-4-yl; hydrogen. 1126 1,3-thiazol-5-yl: 1147 R4 is a C1-6 alkyl optionally substituted by halogen, 1127 Said heterocycles are optionally substituted by e.g. a a C2-6 alkenyl optionally substituted by halogen or C2-12 methyl, n-propyl, trifluoromethyl, cyclopropyl, bromine, alkynyl optionally Substituted by halogen. chlorine, fluorine, iodine, methoxy, ethoxy, propoxy, isopro 1148 R3 is selected from the group consisting of: poxy, cyclopropyloxy, cyclopropylmethoxy, cyclobutyl 1149 imidazo 1,2-bipyridazin-3-yl: methoxy, amino, methylamino, cyclopropylamino, cyclobu 1150 imidazo[2,1-b1,3,4thiadiazol-5-yl: tylamino. 1-pyrrolidinyl, cyano, phenyl, benzyl or 3-thienyl. 1151) imidazo[2,1-b1,3thiazol-5-yl: 1128 Inafurther specific embodiment R3 is a heterocycle 1152 3H-imidazo[4,5-b]pyridin-7-yl: linked to the rest of the molecule via one of its C atoms and is 1153) 1H-imidazol-4-yl: selected from the group consisting of 6-chloro-2-cyclopro 1154) 1H-imidazol-5-yl: pylimidazo 1.2-bipyridazin-3-yl, 6-(cyclopropyloxy)-2-(tri 1155 1 H-pyrazol-4-yl: fluoromethyl)imidazo 1,2-bipyridazin-3-yl, 6-propoxy-2- 1156 1H-pyrazolo 1.5-alpyrimidin-3-yl: (trifluoromethyl)imidazo 1,2-bipyridazin-3-yl, 1157 pyridin-3-yl: 6-chloroimidazo[2,1-b1,3thiazol-5-yl, 2,6-dichloroimi 1158) 1 H-pyrrolo2,3-bipyridin-3-yl; dazo[2.1-b1,3thiazol-5-yl, 5-chloro-1H-imidazol-4-yl, 1159 1H-pyrrolo[2,3-bipyridin-4-yl: 5-bromo-1H-imidazol-4-yl, 4-bromo-1H-imidazol-5-yl, 1160) 1,3-thiazol-5-yl: 4-chloro-1H-imidazol-5-yl, 1H-imidazol-5-yl, 1-methyl and optionally Substituted by methyl, n-propyl, trifluorom ethyl, cyclopropyl, bromine, chlorine, fluorine, iodine, meth 1H-imidazol-5-yl, 4-chloro-1-methyl-1H-imidazol-5-yl, oxy, ethoxy, propoxy, isopropoxy, cyclopropyloxy, cyclopro 1H-pyrazol-4-yl, 1H-pyrrolo2,3-bipyridin-3-yl. pylmethoxy, cyclobutylmethoxy, amino, methylamino, 1129. A further embodiment of the present invention con cyclopropylamino, cyclobutylamino. 1-pyrrolidinyl, cyano, sists in compounds of formula (I) wherein R3 is a heterocycle phenyl, benzyl or 3-thienyl. linked to the rest of the molecule via one of its C atoms and is 1161. A further embodiment of the present invention con a substituted or unsubstituted imidazo[1,2-alpyridin-3-yl. sists in compounds of formula (I) wherein R1,R2 and R5 are 1130 Said imidazo 1,2-alpyridin-3-yl is optionally sub hydrogen. stituted by e.g. a methyl, cyclopropyl, bromine, chlorine, 1162 R4 is a C1-6 alkyl optionally substituted by halogen, fluorine, iodine. a C2-6 alkenyl optionally substituted by halogen or C2-12 1131. In a further specific embodiment R3 is a heterocycle alkynyl optionally Substituted by halogen. linked to the rest of the molecule via one of its C atoms and is 1163 R3 is selected from the group consisting of selected from the group consisting of imidazol-2-alpyridin 1164 3H-imidazo[4,5-b]pyridin-3-yl: 3-yl, 6-methylimidazo 1,2-alpyridin-3-yl, 2-chloroimidazo 1165 1H pyrrolo3.2-bipyridin-1-yl: 1,2-alpyridin-3-yl. 1166 1H-pyrrol-1-yl: 1132 A further embodiment of the present invention con 1167 2-chloro-1H-benzimidazol-1-yl: sists in compounds of formula (I) wherein R3 is a substituted optionally substituted by trifluoromethyl, cyclopropyl, bro or unsubstituted heterocycle linked to the rest of the molecule mine, chlorine, fluorine, methoxy or cyano. via one of its Natoms and is selected from the group consist 1168 A further embodiment of the invention consists in ing of compounds of formula (I), their diastereomers and mixtures, 1133 3H-imidazo[4,5-b]pyridin-3-yl: or a pharmaceutically acceptable salt thereof. 1134 1H-indol-1-yl; 1135 1H-pyrrolo2,3-bipyridin-1-yl; 1136 1H-pyrrolo 3,2-bipyridin-1-yl; (I) 1137) 1H-pyrrol-1-yl: 1138 2-chloro-1H-benzimidazol-1-yl. 1139 A specific further embodiment of the present inven tion consists in compounds of formula (I) wherein R3 is a heterocycle linked to the rest of the molecule via one of its N R5 N O atoms and is selected from the group consisting of 1140 3H-imidazo[4,5-b]pyridin-3-yl: 1. R3 1141 1H-pyrrolo 3,2-bipyridin-1-yl; R2 1142) 1H-pyrrol-1-yl: 1143 2-chloro-1H-benzimidazol-1-yl: R1,R2 and R5 are hydrogen. US 2011/0212928 A1 Sep. 1, 2011 44

R3 is a substituted or unsubstituted heterocycle linked to the 1209 Alternatively, R4 can form together with R5 and the rest of the molecule via one of its C atoms, said heterocycle is 2-oxo-1-pyrrolidine ring the following 1,3-dihydro-2H-in selected from the group consisting of: dol-2-one cycle 1169) 1H-benzimidazol-6-yl: 1170 1H-benzimidazol-7-yl: 1171 imidazol-2-alpyridin-3-yl; 1172 imidazol-2-alpyrimidin-3-yl; 1173 imidazo[1,2-b1,2,4-triazin-7-yl: 1174) imidazo[1,2-bipyridazin-3-yl; N: O 1175 5,6,7,8-tetrahydroimidazo[1,2-bipyridazin-3-yl; imidazo[2.1-b1,3,4thiadiazol-5-yl: wherein theasterisk* indicates the point of attachment of the 1176 Substituents; 1177 imidazo[2.1-b1.3thiazol-5-yl: R6 is hydrogen or halogen; 1178) 3H-imidazo[4,5-b]pyridin-7-yl: 1210. In this embodiment R4 may not be hydrogen when 1H-imidazol-4-yl: R3 is substituted 1H-pyrazol-5-yl. Also this embodiment 1179 does not comprise 5-(2-oxo-1'-pyrrolidinyl)methyl-1,3,4-tri 1180) 1H-imidazol-5-yl: carbomethoxy-pyrazole which is disclosed in A. Padwa et al 1181 1H-indol-2-yl: J. Org. Chem. 2000, 65,5223-5232 without any biological 1182 1H-indol-3-yl: activity though. 1211. In this embodiment wherein R3 is an aromatic 1183. 1H-indol-4-yl: 5-membered heterocycle linked to the rest of the molecule via 1184 1H-indol-7-yl: one of its C atoms, specific moieties R3 may be selected from isoxazol-4-yl; 1,3-thiazol-5-yl, 1H-imidazol-4-yl, 1H-imidazol-5-yl, 1185) 1H-pyrazol-4-yl, 1H-pyrazol-5-yl, 2-oxo-2,3-dihydro-1,3- 1186 thiazol-5-yl, each of them being optionally substituted by 1 to 1187 1H-pyrazol-5-yl: 3 substituents independently selected from methyl, chlorine, 1188) 1H-pyrazolo 1.5-alpyrimidin-3-yl: bromine, amino, methylamino, dimethylamino, (2-oxo-4- propyl-pyrrolidin-1-yl)methyl, 1-pyrrolidinyl, amido, cyano, 1189. 1H-pyrazolo 3,4-bipyridin-3-yl; methoxy, phenyl, 4-methylphenyl-Sulfonyl, benzyl or 2-(ben 1190) pyridazin-4-yl; Zylamino)-2-oxoethyl. 1191) pyridin-2-yl; 1212. In this embodiment, more specific moieties R3 are selected from 2-(methylamino)-1,3-thiazol-5-yl: 2-pyrroli 1192) pyridin-3-yl: din-1-yl-1,3-thiazol-5-yl: 5-bromo-1H-imidazol-4-yl: 1193) pyridin-4-yl; 5-chloro-1H-imidazol-4-yl: 1H-imidazol-5-yl: 1-methyl 1194 1H-pyrrolo2,3-bipyridin-3-yl: 1H-imidazol-5-yl 4-bromo-1-methyl-1H-imidazol-5-yl: 4-chloro-1H-imidazol-5-yl: 4-chloro-1-methyl-1H-imida 1195. 1H-pyrrolo2,3-bipyridin-4-yl: Zol-5-yl: 4-cyano-1-methyl-1H-imidazol-5-yl: 1H-pyrazol 1196 1H-pyrrolo2,3-bipyridin-5-yl: 4-yl: 3,5-dimethyl-1H-pyrazol-4-yl: 3-methyl-1H-pyrazol 1197 1H-pyrrolo2.3-cpyridin-2-yl: 4-yl. 1H-pyrrolo2.3-cpyridin-3-yl: 1213. In this embodiment, most specific moieties R3 are 1198) selected from 5-bromo-1H-imidazol-4-yl; 5-chloro-1H-imi 1199) 1H-pyrrolo3.2-bipyridin-3-yl: dazol-4-yl: 1H-imidazol-5-yl 4-bromo-1-methyl-1H-imida 1200 1H-pyrrolo3.2-cpyridin-2-yl: Zol-5-yl: 4-chloro-1-methyl-1H-imidazol-5-yl: 1H-pyrazol 1201) 1H-pyrrolo3.2-cpyridin-3-yl: 4-yl. 1,3,4-thiadiazol-2-yl: 1214 Still in this embodiment, a specific moiety R1 is 1202 selected from hydrogen or ethyl. 1203 1,3-thiazol-5-yl: 1215 Still in this embodiment, a specific moiety R4 is 1204 1,2,4-triazolo 4,3-bipyridazin-7-yl; selected from hydrogen, n-propyl. 2,3,5-trifluorophenyl or 1205 1,2,4-triazolo 4,3-bipyridazin-8-yl; phenyl. indolizin-3-yl: 1216 A further embodiment of the present invention con 1206 sists in compounds having the specific formula (Ia). 1207 Particularly preferred are imidazo 1,2-alpyridin-3- yl; imidazol-2-alpyrimidin-3-yl; imidazo 1.2-bipyridaZin 3-yl: 1H-imidazol-4-yl: 1H-imidazol-5-yl: (Ia) R4 is a substituted or unsubstituted phenyl moiety; 1208 A further embodiment of the present invention con sists in compounds of formula (I) wherein R1 is hydrogen or C1-12 alkyl: R2 is hydrogen; R3 is an aromatic 5-membered heterocycle linked to the rest of the molecule via one of its C atoms; R4 is hydrogen, C1-12 alkyl or aryl; R5 is hydrogen;

US 2011/0212928 A1 Sep. 1, 2011 50

1512 1-(8H-isothiazolo 5,4-bindol-8-ylmethyl)-4-pro 1544. According to this invention we provide novel com pylpyrrolidin-2-one; pounds of the formula I, 1513 1-(1H-1,2,4-triazol-1-ylmethyl)pyrrolidin-2-one: 1514 1-(2,5-dichloro-1H-pyrrol-1-yl)methyl-4-propy lpyrrolidin-2-one; R 1515 1-(2-chloro-1H-pyrrol-1-yl)methyl-4-propylpyr rolidin-2-one; R (CH2) 1516 1-(2-chloro-1H-benzimidazol-1-yl)methyl-4- R N O R propylpyrrolidin-2-one; 5

1517 1-(2-chloro-1H-benzimidazol-1-yl)methyl-4- R4 s2 \ phenylpyrrolidin-2-one; V 1518 2-chloro-1-(2-oxo-4-propylpyrrolidin-1-yl)me R6. thyl)-1H-benzimidazole-5-carbonitrile; 1519 2-chloro-1-(2-oxo-4-propylpyrrolidin-1-yl)me wherein, R1, R2, R3 and R4, which may be the same or thyl)-1H-benzimidazole-6-carbonitrile; different independently represent hydrogen, C1-6 alkyl, phe 1520 4-propyl-1-(2,5,6-trichloro-1H-benzimidazol-1- nyl or phenyl Substituted by one or more halogen, hydroxyl, yl)methylpyrrolidin-2-one: nitro, amino, C1-6 alkyl or C1-C6 alkoxy groups; 1521 1-(2-chloro-6-methoxy-1H-benzimidazol-1-yl) R5 and R6 independently represent hydrogen, C1-C6 alkyl or methyl-4-propylpyrrolidin-2-one; C3-C6 cycloalkyl, or R5 and R6 together with the nitrogen 1522 1-(2-chloro-5-methoxy-1H-benzimidazol-1-yl) form a C4-6 N heterocycle; methyl-4-propylpyrrolidin-2-one; m represents an integer from 1-2; and 1523 1-(2-chloro-6-nitro-1H-benzimidazol-1-yl)me in represents an integer from 1-3: thyl-4-propylpyrrolidin-2-one; provided that, 1524 1-(2-chloro-5-nitro-1H-benzimidazol-1-yl)me two of the substituents R1, R2, R3 and R4 independently thyl-4-propylpyrrolidin-2-one; represent phenyl or substituted phenyl and the other two 1525 1-(2-chloro-6-methyl-1H-benzimidazol-1-yl)me independently represent hydrogen or C1-6 alkyl; thyl-4-propylpyrrolidin-2-one; or a pharmaceutically acceptable acid addition salt thereof. 1526 1-(2-chloro-1H-benzimidazol-1-yl)methyl)-4-(2, 1545 Pharmaceutically acceptable acid addition salts of 2-difluorovinyl)pyrrolidin-2-one: the compounds of formula I include salts of mineral acids, for example, hydrohalic acids, e.g. hydrochloric or hydrobromic; 1527 1-(6-bromo-2-chloro-1H-benzimidazol-1-yl)me or organic acids, e.g. formic, acetic or lactic acids. The acid thyl-4-propylpyrrolidin-2-one; may be polybasic, for example Sulphuric, fumaric, maleic or 1528 1-(5-bromo-2-chloro-1H-benzimidazol-1-yl)me citric acid. thyl-4-propylpyrrolidin-2-one; 1546. This invention also relates to all stereoisomeric 1529 1-(2-chloro-6-fluoro-1H-benzimidazol-1-yl)me forms and optical enantiomeric forms of the compounds of thyl-4-propylpyrrolidin-2-one; formula I. 1530 1-(2-chloro-5-fluoro-1H-benzimidazol-1-yl)me 1547. In the compounds of formula I: alkyl groups which thyl-4-propylpyrrolidin-2-one; R1, R2, R3, R4, R5 and R6 may represent include methyl, 1531 1-(2,6-dichloro-1H-benzimidazol-1-yl)methyl-4- ethyl, propyl, isopropyl. n-butyl, iso-butyl and S-butyl: propylpyrrolidin-2-one; cycloalkyl groups which R5 and R6 may represent include 1532 1-(2,5-dichloro-1H-benzimidazol-1-yl)methyl-4- cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl, propylpyrrolidin-2-one; C1-6 alkoxy groups include methoxy, ethoxy and propoxy, 1533 1-2-chloro-6-(trifluoromethyl)-1H-benzimida halogen groups include fluorine, chlorine, bromine or iodine; Zol-1-yl)methyl-4-propylpyrrolidin-2-one; 1548 We prefer compounds of formula I or a pharmaceu 1534 1-2-chloro-5-(trifluoromethyl)-1H-benzimida tically acceptable acidaddition salt thereof, in which: Zol-1-yl)methyl-4-propylpyrrolidin-2-one; R1 is hydrogen, phenyl or substituted phenyl, preferably phe 1535 1-(2-chloro-1H-benzimidazol-1-yl)methylpyrro nyl: R2 is hydrogen, phenyl or substituted phenyl, preferably phe lidin-2-one; nyl: 1536 1-(2-chloro-6-hydroxy-1H-benzimidazol-1-yl) R3 is hydrogen, phenyl or substituted phenyl, preferably methyl-4-propylpyrrolidin-2-one; hydrogen; 1537 1-(pyridin-4-ylmethyl)pyrrolidin-2-one, and R4 is hydrogen, phenyl or substituted phenyl, preferably 1538 1-(2-chloro-5-hydroxy-1H-benzimidazol-1-yl) hydrogen; methyl-4-propylpyrrolidin-2-one. R5 is hydrogen, C1-3 alkyl or cyclopropyl, preferably hydro 1539 viii) U.S. Pat. No. 4,696,943 gen or methyl; 1540. The present invention relates to the novel compound R6 is hydrogen, C1-3 alkyl or cyclopropyl, preferably hydro (S)-alpha-ethyl-2-oxo-1-pyrrolidineacetamide. gen or methyl; 1541 ix) U.S. Pat. No. 4,696,942 m represents an integer from 1-2 preferably 2: 1542. The present invention relates to the novel com in represents an integer from 1-2, preferably 1. pound, (R)-alpha-ethyl-2-oxo-1-pyrrolidineacetamide 1549. We especially prefer compounds of formula I in 1543 x) U.S. Pat. No. 5,334,720 which R1 and R2 are both phenyl. US 2011/0212928 A1 Sep. 1, 2011

1550 We especially prefer compounds of formula I in C1-20 alkyl, halogen, hydroxy, alkoxy, aryloxy, ester, amido, which one of R5 and R6 is hydrogen and the other is hydrogen cyano, nitro, amino, amino derivative, alkylthio, arylthio. or methyl. alkylsulfonyl, arylsulfonyl, alkylsulfinyl or arylsulfinyl: 1551 xi) International Patent Application Publication No. R10 is hydrogen, C1-20 alkyl, halogen, hydroxy, alkoxy, WO2005/0541.88 aryloxy, ester, amido, cyano, nitro, amino, amino derivative, 1552. In one aspect the invention therefore provides a alkylthio, arylthio, alkylsulfonyl, arylsulfonyl, alkylsulfinyl compound having the formula I or a pharmaceutically accept or arylsulfinyl: able salt thereof, R11 is hydrogen, halogen, nitro, cyano, C1-20 alkyl or alkoxy; R12 is hydrogen or halogen; R13 is hydrogen, nitro, halogen, heterocycle, amino, aryl, (I) C1-20 alkyl unsubstituted or substituted by halogen, or alkoxy unsubstituted or substituted by halogen; R14 is hydro gen, C1-20 alkyl or halogen; R15 is hydrogen, C1 20 alkyl or halogen; with the proviso that R4 is different from hydrogen when

wherein R1 is hydrogen, C1-20 alkyl, C3-23 cycloalkyl, halogen, hydroxy, alkoxy, aryloxy, ester, amido, cyano, nitro, amino, guanidine, amino derivative, alkylthio, arylthio, alkylsulfo nyl, arylsulfonyl, alkylsulfinyl, arylsulfinyl, aryl or hetero cycle; R2 is hydrogen, C1 20 alkyl, alkoxy, amino, halogen, hydroxy, ester, amido, nitro, cyano, carbamate, or aryl; R3 is hydrogen, C1 20 alkyl, alkoxy, amino, halogen, hydroxy, ester, amido, nitro, cyano, carbamate, or aryl; or R2 and R3 can form together with the imidazole ring the following 1H-benzimidazole cycle

R8 R9 1553. The asterisk * indicates the point of attachment of R2 the substituents. R10; 1554. In a preferred embodiment, the invention concerns a *N *N compound having the formula I, their tautomers, geometrical S. S. isomers (including cis and trans, Z and E isomers), enanti RI JS-N RI N N R11 omers, diastereoisomers and mixtures thereof (including all possible mixtures of Stereoisomers), or pharmaceutically R4 is hydrogen, C1-20 alkyl, C2-12 alkenyl, C2-12 alkynyl, acceptable salts thereof, aryl, azido, alkoxycarbonylamino, arylsulfonyloxy or hetero cycle; R4a is hydrogen or C1-20 alkyl; or R4 and R4a can form together a C3-8 cycloalkyl; R5 is hydrogen; or R4, R4a (I) and R5 can form together with the 2-oxo-1-pyrrolidine ring the following 1,3-dihydro-2H-indol-2-one cycle

RI 3 R12 R4 Rig R 14

N: O; R5 N: O R15 wherein R1 is hydrogen, C1-20 alkyl, C3-8 cycloalkyl, halogen, R6 is hydrogen or C1-20 alkyl; R7 is hydrogen; or R6 and R7 hydroxy, ester, amido, cyano, nitro, amino, guanidine, alky are linked together to form a C3-6 cycloalkyl; R8 is hydrogen, lthio, alkylsulfonyl, alkylsulfinyl, aryl or heterocycle; R2 is halogen, nitro, cyano, C1-20 alkyl oralkoxy; R9 is hydrogen, hydrogen, C1 20 alkyl, halogen, cyano, ester, carbamate or US 2011/0212928 A1 Sep. 1, 2011 52 amido: R3 is hydrogen, cyano, C1 20 alkyl, halogen or ester; lamino, aminocarbonyl, methylaminocarbonyl, dimethy or R2 and R3 can form together with the imidazole ring the laminocarbonyl or aryl. Usually alkyl groups, in the present following 1H-benzimidazole cycle case, are methyl, ethyl, n-propyl, i-propyl. n-butyl, i-butyl, t-butyl, 1-ethylpropyl, n-heptyl, 2,4,4-trimethylpentyl, n-de cyl, chloromethyl, trifluoromethyl, 2-bromo-2,2-difluoroet R8 R9 hyl, 2.2.2-trifluoroethyl, 3,3,3-trifluoropropyl, hydroxym ethyl, cyanomethyl, azidomethyl, (acetylamino) methyl, R2 (propionylamino) methyl, (benzoylamino) methyl, (4-chlo R10; rophenoxy) methyl, benzyl, 2-phenylethyl or 2-(methylthio) *N *N ethyl. Preferred alkyl groups are methyl, ethyl, n-propyl. S. S. i-propyl. n-butyl, i-butyl, t-butyl, 1-ethylpropyl. 2,4,4-trim RI JS-N R1 us N R11 ethylpentyl, chloromethyl, trifluoromethyl, 2.2.2-trifluoroet hyl, hydroxymethyl, cyanomethyl, azidomethyl, (acety R4 is hydrogen, C1-20 alkyl, C2-12 alkenyl or aryl; R4a is lamino) methyl, (propionylamino) methyl, (benzoylamino) hydrogen; methyl or 2-(methylthio)ethyl. More preferred alkyl groups R5 is hydrogen; or R4, R4a and R5 can form together with the are methyl, ethyl, n-propyl, i-propyl. n-butyl, azidomethyl or 2-oxo-1-pyrrolidine ring the following 1,3-dihydro-2H-in trifluoromethyl. Most preferred alkyl groups are methyl or dol-2-one cycle n-propyl. 1556. The term "cycloalkyl, as used herein, represents a monovalent group of 3 to 8 carbon atoms, usually 3-6 carbon atoms derived from a saturated cyclic hydrocarbon, which R13 R12 may be substituted by any suitable group including but not R4 limited to one or more moieties selected from groups as described above for the alkyl groups. Preferred cycloalkyl groups are cyclopropyl and cyclohexyl. Dy" N: O; 1557. The term “alkenyl as used herein, represents R5 N: O R15 straight, branched or cyclic unsaturated hydrocarbon radicals or combinations thereof having at least one carbon-carbon double bond, containing 2-12 carbon atoms, preferably usu R6 is hydrogen or C1 20 alkyl; R7 is hydrogen; or R6 and R7 ally 2-4 carbon atoms. Alkenyl groups are being optionally are linked together to forma C3-6 cycloalkyl; R8 is hydrogen; Substituted with any Suitable group, including but not limited R9 is hydrogen, C1-20 alkyl, halogen or alkoxy; R10 is to one or more moities selected from groups as described hydrogen, C1 20 alkyl, halogen or cyano; R11 is hydrogen; above for the alkyl groups. Usually an alkenyl group is ethe R12 is hydrogen or halogen; R13 is hydrogen, halogen, het nyl (vinyl) optionally substituted by 1 to 3 halogens. Pre erocycle or C1 20 alkyl; R14 is hydrogen; R15 is hydrogen; ferred alkenyl group, in the present case, is 2,2-difluorovinyl. with the proviso that R4 is different from hydrogen when 1558. The term “alkynyl' as used herein, represents straight, branched or cyclic hydrocarbon radicals or combi R2 nations thereof containing at least one carbon-carbon triple bond, containing 2-12 carbon atoms, preferably 2-6 carbon atoms, and being optionally substituted by any Suitable group, including but not limited to one or more moities selected from groups as described above for the alkyl groups. Preferably an alkynyl group is a halogenoalkynyl group (ha loalkynyl group). 1559 Groups qualified by prefixes such as “s”, “i', “t” and the like (e.g. “i-propyl', 's-butyl') are branched derivatives. 1560. The term “aryl' as used herein, is defined as phenyl R8 R9 optionally substituted by 1 to 4 substituents independently selected from halogen, cyano, alkoxy, alkylthio, C13 alkyl or R10. azido, preferably halogen oraZido. Usually aryl groups, in the present case are phenyl, 3-chlorophenyl, 3-fluorophenyl, *N 4-chlorophenyl, 4-fluorophenyl, 3,4-difluorophenyl, 3,5-dif luorophenyl, 3-chloro-4-fluorophenyl, 2,3,4-trifluorophenyl, -S N R11 2,4,5-trifluorophenyl, 2,3,5-trifluorophenyl, 3,4,5-trifluo rophenyl, 3-azido-2,4-difluorophenyl or 3-azido-2,4,6-trif 1555. The term “alkyl, as used herein, represents satu luorophenyl. Preferably, aryl groups are phenyl, 3-chlorophe rated, monovalent hydrocarbon radicals having straight (un nyl, 3-fluorophenyl, 4-chlorophenyl, 4-fluorophenyl, 3,4- branched) or branched or cyclic or combinations thereof and difluorophenyl, 3,5-difluorophenyl, 3-chloro-4- containing 1-20 carbonatoms, preferably 1-10 carbon atoms, fluorophenyl, 2,3,4-trifluorophenyl, 2,4,5-trifluorophenyl, more preferably 1-4 carbon atoms; most preferred alkyl 2,3,5-trifluorophenyl, 3,4,5-trifluorophenyl or 3-azido-2,4- groups have 1-3 carbonatoms. Alkyl moieties may optionally difluorophenyl. Most preferred aryl groups are phenyl, be substituted by 1 to 5 substituents independently selected 3-chlorophenyl, 3-fluorophenyl, 3,5-difluorophenyl, 2,3,4- from the group consisting of halogen, hydroxy, cyano, azido, trifluorophenyl, 2,4,5-trifluorophenyl, 2,3,5-trifluorophenyl, aryloxy, alkoxy, alkylthio, alkanoylamino, arylcarbony 3,4,5-trifluorophenyl or 3-azido-2,4-difluorophenyl. US 2011/0212928 A1 Sep. 1, 2011

1561. The term "heterocycle', as used herein, is defined as 1579. The term “arylsulfinyl', as used herein, represents a including an aromatic or non aromatic cycloalkyl moiety as group of the formula —S(=O) Ri wherein Ri is an aryl defined above, having at least one O. Sand/or Natom inter group, as defined above. rupting the carbocyclic ring structure. Heterocyclic ring 1580. The term “carbamate” as used herein, represents a moities can be optionally substituted by alkyl groups or halo group of formula—N(H)C(O) OR1, wherein Riis an alkyl or gens and optionally, one of the carbon of the carbocyclic ring an aryl, as defined above. Usually carbamate groups are (pro structure may be replaced by a carbonyl. Usually hetero poxycarbonyl)amino or (benzyloaxycarbonyl)amino. One cycles are 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-furyl, 3-furyl, carbamate group is (benzyloaxycarbonyl)amino. 2-thienyl, 3-thienyl, 2-tetrahydrofuranyl, 1 H-pyrrol-2-yl, 1581. The term “alkanoylamino” as used herein, repre 1-methyl-1H-pyrrol-2-yl, 1H-pyrazol-2-yl, 1 H-pyrazol-3-yl, sents a group of the formula—NHC(=O) Rk wherein Rk is 4-chloro-1-methyl-1H-pyrazol-3-yl, 5-chloro-1,3-dimethyl an alkyl group, as defined above. 1H-pyrazol-4-yl, 1,2,3-thiadiazol-4-yl, 3,5-dimethyl-4- 1582. The term “(arylcarbonyl) amino” as used herein, isothiazyl, 1H-imidazol-2-yl, 1-methyl-1H-imidazol-2-yl, represents a group of the formula—NHC(=O) Rim wherein 4-methyl-1H-imidazol-5-yl, or 2-methyl-1,3-thiazol-4-yl. Rm is an aryl group, as defined above. One (arylcarbonyl) Preferred heterocycles are 1H-imidazol-2-yl, 1,2,3-thiadia amino is benzoylamino. Zol-4-yl, 1H-pyrazol-3-yl 2-furyl, 3-furyl, 2-thienyl, 1-me 1583. Usually, RI is hydrogen; C1 10 alkyl unsubstituted thyl-1H-pyrrol-2-yl, 1 H-pyrrol-2-yl. or Substituted by halogen, hydroxy, cyano, methylthio, phe 1562. The term “halogen', as used herein, includes an nyl or 4-chlorophenoxy; hydroxy; C3-6 cycloalkyl; halogen; atom of chlorine, bromine, fluorine, iodine. Usually halogens ester, amido; nitro; cyano; amino; phenyl; alkylthio; alkyl are chlorine, bromine and fluorine. Preferred halogens are sulfonyl: alkylsulfinyl; heterocycle unsubstituted or substi fluorine, bromine and chlorine. tuted by alkyl groups; or guanidine. 1563 The term “hydroxy’, as used herein, represents a 1584. In some embodiments, RI is hydrogen; methyl: group of formula—OH. ethyl; i-propyl; n-propyl, cyclopropyl; n-butyl, i-butyl; t-bu 1564. The term “alkoxy’, as used herein, represents a tyl: 1-ethylpropyl; 2,4,4-trimethylpentyl; hydroxymethyl: group of formula —ORa wherein Ra is an alkyl group, as chloromethyl; trifluoromethyl; 2.2.2-trifluoroethyl; cyanom defined above. Preferred alkoxy group is methoxy. ethyl: 2-(methylthio) ethyl; chloro; bromo; nitro; cyano; 1565. The term “aryloxy’, as used herein, represents a amino; aminocarbonyl: methoxycarbonyl: methylthio; meth group of formula —ORb wherein Rb is an aryl group, as ylsulfinyl: methylsulfonyl: phenyl: 2-furyl; 3-furyl; 1H-pyr defined above. Preferred aryloxy group is phenoxy. rol-2-yl, 1-methyl-1H-pyrrol-2-yl, 2-thienyl; 1H-pyrazol-3- 1566. The term “ester', as used herein, represents a group yl: 1,2,3-thiadiazol-4-yl or 1H-imidazol-2-yl. More of formula – COORC wherein Rc is an alkyl group or aryl preferably, RI is hydrogen; methyl, ethyl; i-propyl; n-propyl; group, as defined above. Preferred ester group is methoxy n-butyl; methylthio; nitro; cyano; amino; chloro or 1H-pyr carbonyl. rol-2-yl. Most preferably, RI is hydrogen; methyl: meth 1567. The term "amido’, as used herein, represents a ylthio; nitro; cyano; amino or chloro. group of formula—CONH2. 1585 Usually, R2 is hydrogen: C14 alkyl unsubstituted or 1568. The term “amino', as used herein, represents a Substituted by hydroxy, alkanoylamino or benzoylamino; group of formula—NH2. halogen; ester; cyano; alkyl carbamate; (N-methoxy-N-me 1569. The term “aminoderivative', as used herein, repre thyl)aminocarbonyl. Preferably, R2 is hydrogen; methyl: sents an alkylamino oran arylamino group, wherein the terms hydroxymethyl: (acetylamino) methyl: (propionylamino) “alkyl and “aryl” are defined as above. methyl: (benzoylamino) methyl: (benzyloxy)carbonyl 1570. The term “cyano”, as used herein, represents a amino; chloro or cyano. In some embodiments, R2 is hydro group of formula—CN. gen; chloro or cyano. 1571. The term "nitro', as used herein, represents a group 1586. Usually, R3 is hydrogen: C14 alkyl unsubstituted or of formula - NO2. Substituted by hydroxy; halogen; ester or cyano. In some 1572 The term “azido’, as used herein, represents a group embodiments, R3 is hydrogen; hydroxymethyl; chloro; of formula —N3. cyano. 1573 The term “guanidine', as used herein, represents a 1587. In some embodiments, R3 is hydrogen or cyano. In group of formula –NHC(=NH) NH2. Some embodiments R3 is hydrogen. 1574. The term “alkylthio', as used herein, represents a 1588 Usually, R4 is hydrogen: C14 alkyl unsubstituted or group of formula —SRd wherein Rd is an alkyl group, as substituted by halogens; C24 alkenyl substituted by halogens defined above. One alkylthio group is methylthio. or phenyl group unsubstituted or substituted by azido or/and 1575. The term “alkylsulfonyl', as used herein, represents halogens. Preferably, R4 is hydrogen; n-propyl; 2.2-difluo a group of formula —S(=O)2Re wherein Re is an alkyl rovinyl; phenyl: 3-chlorophenyl: 3-fluorophenyl: 4-chlo group, as defined above. One alkylsulfonyl group is methyl rophenyl: 4-fluorophenyl: 3,5-difluorophenyl: 3,4-difluo sulfonyl. rophenyl: 3-chloro-4-fluorophenyl: 2,3,4-trifluorophenyl: 1576. The term “alkylsulfinyl', as used herein, represents 2,4,5-trifluorophenyl: 2,3,5-trifluorophenyl: 3,4,5-trifluo a group of formula—S(=O) Rf wherein Rf is an alkyl group, rophenyl: 3-azido-2,4-difluorophenyl or 3-azido-2,4,6-trif as defined above. One alkylsulfinyl group is methylsulfinyl. luorophenyl. More preferably, R4 is hydrogen; n-propyl; 2.2- 1577. The term “arylthio', as used herein, represents a difluorovinyl; phenyl: 3-chlorophenyl: 3-fluorophenyl: group of formula —SRg wherein Rg is an aryl group, as 4-chlorophenyl: 4-fluorophenyl: 3,5-difluorophenyl: 3,4-dif defined above. luorophenyl: 3-chloro-4-fluorophenyl: 2,3,4-trifluorophenyl: 1578. The term “arylsulfonyl', as used herein, represents a 2,4,5-trifluorophenyl: 2,3,5-trifluorophenyl: 3,4,5-trifluo group of the formula —S(=O)2Rh wherein Rh is an aryl rophenyl or 3-azido-2,4-difluorophenyl. Most preferably, R4 group, as defined above. is n-propyl: 2,2-difluorovinyl; phenyl: 3-chlorophenyl: US 2011/0212928 A1 Sep. 1, 2011 54

3-fluorophenyl: 3,5-difluorophenyl: 2,3,4-trifluorophenyl: alkyl unsubstituted or substituted by hydroxy, alkanoylamino 2,4,5-trifluorophenyl: 2,3,5-trifluorophenyl: 3,4,5-trifluo or benzoylamino; halogen; ester; cyano; alkyl carbamate or rophenyl or 3-azido-2,4-difluorophenyl. (N-methoxy-N-methyl)aminocarbonyl. R3 is selected from hydrogen; C1 4 alkyl unsubstituted or 1589. Usually, R4a is hydrogen. Substituted by hydroxy; halogen; ester or cyano; R4 is 1590. Usually, R5 is hydrogen. selected from hydrogen: C14 alkyl unsubstituted or substi 1591. Usually, R6 is hydrogen or C1-1-0 alkyl unsubsti tuted by halogens; C24 alkenyl substituted by halogens or tuted or substituted by hydroxy or azido. Preferably, R6 is phenyl group unsubstituted or Substituted by azido or/and hydrogen or azidomethyl. More preferably R6 is hydrogen. halogens: 1592. Usually R7 is hydrogen. R" is hydrogen; R5 is hydrogen; R6 is selected from hydro 1593. In other embodiments, R6 and R7 are linked to form gen or C1-10 alkyl unsubstituted or substituted by hydroxy or a cyclopropyl. azido; 1594. In other embodiments, R2 and R3 can form together R7 is hydrogen; or R6 and R7 can be linked to form a cyclo propyl; or R2 and R3 can form together with the imidazole with the imidazole ring the following 1H-benzimidaole cycle ring the following 1H-benzimidazole cycle R8 R9 R8 R9 R2 R10. R2 R10. J. N R3 J. *N *N RI s R1 s R11 S. S. R1 N RI N R11

1595. Usually, R8 is hydrogen. R8 is hydrogen; R9 is selected from hydrogen; halogen; C1-3 1596 Usually, R9 is hydrogen; halogen: 1-3 alkyl or alkyl; alkoxy; alkoxy. In some embodiments, R9 is hydrogen; methyl; R10 is selected from hydrogen; halogen; cyano or Cil alkyl chloro or methoxy. In some embodiments R9 is hydrogen. unsubstituted or substituted by halogens; or alkoxy; R1 is 1597. Usually, RIO is hydrogen; halogen; cyano; C1 3 hydrogen; or R4, R“ and R5 can form together with the alkyl unsubstituted or substituted by halogens; or alkoxy. In 2-oxo-1-pyrrolidine ring the following 1,3-dihydro-2H-in some embodiments, RIO is methyl: hydrogen; trifluorom dol-2-one cycle ethyl; fluoro; cyano or methoxy. In some embodiments R10 is hydrogen; trifluoromethyl; fluoro or cyano. 1598. Usually, RI 1 is hydrogen. 1599. In other embodiments, R4, R* and R5 can form R13 R12 together with the 2-oxo-1-pyrrolidine ring the following 1,3- R4 dihydro-2H-indol-2-one cycle

Dy" N: O; R5 N: O R15 R13 R12 is selected from hydrogen or halogen; R13 is selected from hydrogen; CI-3 alkyl; halogen; thiazolyl unsubstituted or substituted by alkyl groups, such as methylthiazolyl; R14 is hydrogen; R15 is hydrogen; with the proviso that R4 is different from hydrogen when 1600. Usually, R12 is hydrogen or halogen. In some embodiments R12 is hydrogen; chloro or fluoro. In some embodiments R12 is hydrogen. 1601. Usually, R13 is hydrogen; C13 alkyl; halogen or thiazolyl unsubstituted or Substituted by alkyl groups, such as methylthiazolyl. In some embodiments R13 is hydrogen; chloro; bromo or methyl. In some embodiments R13 is chloro; bromo or methyl. 1602. Usually R14 is hydrogen. 1603. Usually, R15 is hydrogen. 1604. In a general embodiment of the invention, the com pounds of formula I, or pharmaceutically acceptable salts thereof, are those wherein RI is selected from hydrogen; C1 10 alkyl unsubstituted or Substituted by halogen, hydroxy, cyano, methylthio, phenyl or 4-chlorophenoxy; C3 6 cycloalkyl; halogen; ester, amido; nitro; cyano; amino; phenyl; alkylthio; alkylsulfonyl; alkyl sulfinyl; heterocycle unsubstituted or substituted by alkyl group; or guanidine; R2 is selected from hydrogen; C1-4 US 2011/0212928 A1 Sep. 1, 2011

1605. In an embodiment of the invention, the compounds represents a group of formula of formula I, or pharmaceutically acceptable Salt thereof, are those wherein RI is selected from hydrogen; methyl; ethyl; i-propyl; n-pro R8 R9 pyl, cyclopropyl. n-butyl, i-butyl; t-butyl: 1-ethylpropyl; 2.4. 4-trimethylpentyl; trifluoromethyl; 2.2.2-trifluoroethyl: hydroxymethyl; chloromethyl; cyanomethyl: 2-(methylthio) R10. ethyl, chloro; bromo; nitro; cyano; amino; aminocarbonyl: *N methoxycarbonyl: methylthio; methylsulfinyl: methylsulfo nyl; phenyl: 2-furyl; 3-furyl; 1H-pyrrol-2-yl: 1-methyl-1H R1 1s R11 pyrrol-2-yl: 2-thienyl: 1H-pyrazol-3-yl: 1,2,3-thiadiazol-4- yl; or 1H-imidazol-2-yl; R2 is selected from hydrogen; methyl; hydroxymethyl, (acetylamino) methyl: (propiony 1606. In one embodiment of the invention, the compounds lamino) methyl, (benzoylamino) methyl, (benzyloxycarbo of formula I, or pharmaceutically acceptable salt thereof, are nyl)amino; chloro; or cyano; R3 is selected from hydrogen; those wherein hydroxymethyl; chloro; cyano; or R2 and R3 can form R1 is selected from hydrogen; methyl, ethyl; i-propyl; n-pro together with the imidazole ring the following 1H-benzimi pyl; n-butyl, methylthio; nitro; cyano; amino; chloro; or dazole cycle 1H-pyrrol-2-yl; R2 is selected from hydrogen; chloro; cyano; R3 is selected from hydrogen; cyano; or R2 and R3 can form together with the imidazole ring the following 1H-benzimi R8 R9 dazole cycle R2 R10 R8 R9 *N *N R2 S. S. R10 NX-R N RI *N N R3 *N R8 is hydrogen; R9 is selected from hydrogen; methyl: choro; lsS. us N R11 methoxy; R10 is selected from methyl; hydrogen; trifluoromethyl: fluoro; cyano; or methoxy; R is hydrogen; R4 is selected from R8 is hydrogen; R9 is hydrogen; hydrogen; n-propyl; 2.2-difluorovinyl; phenyl: 3-chlorophe R10 is selected from hydrogen; trifluoromethyl; fluoro; cyano; nyl: 3-fluorophenyl: 4-chlorophenyl: 4-fluorophenyl: 3,5-di R11 is hydrogen; R4 is selected from hydrogen; n-propyl; fluorophenyl: 3,4-difluorophenyl: 3-chloro-4-fluorophenyl: 2,2-difluorovinyl; phenyl: 3-chlorophenyl: 3-fluorophenyl: 2,3,4-trifluorophenyl; 2,4,5-trifluorophenyl: 2,3,5-trifluo 4-chlorophenyl: 4-fluorophenyl: 3,5-difluorophenyl: 3,4-dif rophenyl: 3,4,5-trifluorophenyl: 3-azido-2,4-difluorophenyl: luorophenyl: 3-chloro-4-fluorophenyl: 2,3,4-trifluorophenyl: or 3-azido-2,4,6-trifluorophenyl. 2,4,5-trifluorophenyl: 2,3,5-trifluorophenyl: 3,4,5-trifluo R4a is hydrogen; R5 is hydrogen; or R4, R“ and R5 can form rophenyl; or 3-azido-2,4-difluorophenyl; R" is hydrogen; R5 together with the 2-oxo-1-pyrrolidine ring the following 1,3- is hydrogen; or R4, R4a and R5 can form together with the dihydro-2H-indol-2-one cycle 2-oxo-1-pyrrolidine ring the following 1,3-dihydro-2H-in dol-2-one cycle R13 R12 2 4 R13 R R4 R Rig Dy" N: YO R5 N: O R15 R5 N: O N: O R15 R12 is selected from hydrogen; chloro; fluoro; R13 is selected from hydrogen; chloro; bromo; methyl; R14 is hydrogen; wherein R12 is hydrogen; R13 is selected from methyl: R15 hydrogen; R6 is selected from hydrogen; azidomethyl: chloro; bromo; R14 is hydrogen; R15 hydrogen; R6 is hydro R7 is hydrogen; or R6 and R7 are linked to form a cyclopro gen; R7 is hydrogen; with the proviso that R4 is different from pyl; with the proviso that R4 is different from hydrogen when hydrogen when

US 2011/0212928 A1 Sep. 1, 2011

4-propyl-1-(2-(1H-pyrrol-2-yl)-1H-benzimidazol-1-yl) 1613. The compounds of formula I containing acidic pro methylpyrrolidin-2-one: 1-(5-fluoro-2-propyl-1H-benz tons may be converted into their therapeutically active, non imidazol-1-yl) methyl-4-propylpyrrolidin-2-one: 2-butyl-1- toxic base addition salt forms, e.g. metal or amine salts, by (2-oxo-4-propylpyrrolidin-1-yl) methyl)-1H treatment with appropriate organic and inorganic bases. benzimidazole-5-carbonitrile; 1-(5-fluoro-2-isopropyl-1H Appropriate base salt forms include, for example, ammonium benzimidazol-1-yl) methyl-4-propylpyrrolidin-2-one; salts, alkali and earth alkaline metal salts, e.g. lithium, 1-(1H-imidazol-1-ylmethyl)-1,3-dihydro-2H-indol-2-one: Sodium, potassium, magnesium, calcium salts and the like, 5-bromo-1-(1H-imidazol-1-ylmethyl)-1,3-dihydro-2H-in salts with organic bases, e.g. N-methyl-D-glucamine, hydra dol-2-one; 5-chloro-1-(1H-imidazol-1-ylmethyl)-1,3-dihy bamine salts, and salts with amino acids such as, for example, dro-2H-indol-2-one: 1-(1H-imidazol-1-ylmethyl)-5-methyl arginine, lysine and the like. 1,3-dihydro-2H-indol-2-one: 1-(5-chloro-2-oxo-2,3- 1614 Conversely said salt forms can be converted into the dihydro-1H-indol-1-yl) methyl)-1H-imidazole-5- free forms by treatment with an appropriate base or acid. carbonitrile. 1615 Compounds of the formula I and their salts can be in 1610. In some embodiments, compounds are: 1-(1H-imi the form of a solvate, which is included within the scope of the dazol-1-ylmethyl)-4-phenylpyrrolidin-2-one: 1-(1H-imida present invention. Such solvates include for example Zol-1-ylmethyl)-4-propylpyrrolidin-2-one: (-)-4-(3-azido-2, hydrates, alcoholates and the like. 4-difluorophenyl)-1-(1H-imidazol-1-ylmethyl) pyrrolidin-2- one; (+)-4-(3-azido-2,4-difluorophenyl)-1-(1H-imidazol-1- 1616. Many of the compounds of formula I and some of ylmethyl) pyrrolidin-2-one: 4-(2,2-difluorovinyl)-1-(1H their intermediates have at least one stereogenic center in imidazol-1-ylmethyl) pyrrolidin-2-one: 4-(3-chlorophenyl)- their structure. This stereogenic center may be present in a R 1-(1H-imidazol-1-ylmethyl) pyrrolidin-2-one: 1-2- or a S configuration, said R and S notation is used in corre (methylthio)-1H-imidazol-1-yl)methyl-4-propylpyrrolidin spondence with the rules described in Pure Appl. Chem. 45 2-one; 1-(2-methyl-1H-imidazol-1-yl)methyl-4- (1976) 11-30. phenylpyrrolidin-2-one: 1-(1H-imidazol-1-ylmethyl)-4-(3,4, 1617 The invention also relates to all stereoisomeric 5-trifluorophenyl) pyrrolidin-2-one: 4-(3-fluorophenyl)-1- forms such as enantiomeric and diastereoisomeric forms of (1H-imidazol-1-ylmethyl) pyrrolidin-2-one; 4-(3.5- the compounds of formula I or mixtures thereof (including all difluoromethyl)-1-(1H-imidazol-1-ylmethyl) pyrrolidin-2- possible mixtures of stereoisomers). one: 1-(1H-imidazol-1-ylmethyl)-4-(2,3,4-trifluorophenyl) 1618. Some of the compounds of formula I may also exist pyrrolidin-2-one: 1-(1H-imidazol-1-ylmethyl)-4-(2,3,5-trif. in tautomeric forms. Such forms although not explicity indi luorophenyl) pyrrolidin-2-one: 1-H-imidazol-1-ylmethyl)-4- cated in the above formula are intended to be included within (2,4,5-trifluorophenyl) pyrrolidin-2-one: 1-(2-nitro-1H-imi the scope of the present invention. dazol-1-yl) methyl-4-(3,4,5-trifluorophenyl) pyrrolidin-2- 1619. In another preferred embodiment, the present inven one; 1-2-oxo-4-(3,4,5-trifluorophenyl) pyrrolidin-1-yl) tion concerns also compounds of formula IA and their tauto methyl)-1H-imidazole-2-carbonitrile; 1-(2-amino-1H meric form IB 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-phe R4 R4 nylpyrrolidin-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- 2) tly chloro-1H-imidazol-1-yl) methyl-4-propylpyrrolidin-2- R5 N O R5 N O 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: R6R7 1 N- N R3 T R6-1sR7 N N R3 5-chloro-1-(1H-imidazol-1-ylmethyl)-1,3-dihydro-2H-in S. dol-2-one: 1-(1H-imidazol-1-ylmethyl)-5-methyl-1,3-dihy HO N O N dro-2H-indol-2-one: 1-(5-chloro-2-oxo-2,3-dihydro-1H-in (LA) (IB) dol-1-yl)methyl)-1H-imidazole-5-carbonitrile. 1611. Some compounds are: (-)-4-(3-azido-2,4-difluo rophenyl)-1-(1H-imidazol-1-ylmethyl) pyrrolidin-2-one: 1620. With respect to the present invention reference to a (+)-4-(3-azido-2,4-difluorophenyl)-1-(1H-imidazol-1-ylm compound or compounds is intended to encompass that com ethyl) pyrrolidin-2-one: 4-(3-azido-2,4-difluorophenyl)-1- pound in each of its possible isomeric forms and mixtures thereof, unless the particular isomeric form is referred to (1H-imidazol-1-ylmethyl) pyrrolidin-2-one. specifically. 1612. The acid addition salt form of a compound of for mula I that occurs in its free form as a base can be obtained by 1621 Compounds according to the present invention may treating the free base with an appropriate acid such as an exist in different polymorphic forms. Although not explicitly inorganic acid, for example, a hydrohalic Such as hydrochlo indicated in the above formula, such forms are intended to be ric or hydrobromic, Sulfuric, nitric, phosphoric and the like; included within the scope of the present invention. or an organic acid, Such as, for example, acetic, trifluoroace 1622. The invention also includes within its scope pro tic, hydroxyacetic, propanoic, lactic, pyruvic, malonic, suc drug forms of the compounds of formula I and its various cinic, maleic, fumaric, malic, tartaric, citric, methane Sub-Scopes and Sub-groups. Sulfonic, ethanesulfonic, benzenesulfonic, p-toluenesulfonic, 1623 xii) U.S. Patent Application Publication No. cyclic, Salicylic, p-aminosalicylic, pamoic and the like. 2009 OO18148 US 2011/0212928 A1 Sep. 1, 2011 59

1624. In one aspect the invention provides compounds isoxazol-4-yl)methyl or (5-nitro-2-furyl)methyl. Most pre having formula I, their enantiomers, diastereoisomers and ferred alkyl groups are methyl, ethyl 3-methoxybenzyl, mixtures thereof (including all possible mixtures of stereoi 3-nitrobenzyl or (5-nitro-2-furyl)methyl. Somers), or pharmaceutically acceptable salts thereof, 1629. The term "cycloalkyl, as used herein, represents a monovalent group of 3 to 8, preferably 3 to 6 carbon atoms derived from a saturated cyclic hydrocarbon, which may be (I) Substituted by any suitable group including but not limited to O R4 one or more moieties selected from groups as described above R! / for the alkyl groups. Preferred cycloalkyl group according to NN N the present invention is cyclohexyl. X-sV 1630. The term “aryl as used herein, is defined as a phe O N N R3 nyl group optionally Substituted by 1 to 4 substituents inde pendently selected from halogen, amino, nitro, alkoxy or k aminosulfonyl. Preferred aryl groups are phenyl, 2-bro mophenyl, 3-bromophenyl, 4-bromophenyl, 3-methoxyphe wherein nyl, 3-nitrophenyl, 3-aminophenyl or 4-(aminosulfonyl)phe R1 is hydrogen or C1-6 alkyl; nyl. R2 is hydrogen or C1-4 alkyl; 1631. The term “phenyl', as used herein, represents an R3 is a group of formula —CHR5R6 or a benzyl group: aromatic hydrocarbon group of formula—C6H5. R4 is C1-8 alkyl optionally substituted by alkoxycarbonyl, 1632. The term “benzyl group', as used herein, represents C3-6 cycloalkyl, aryl or heterocycle: a group of formula —CH2-aryl. Preferred benzyl groups are R5 is C2-4 alkyl: benzyl, 2-bromobenzyl, 3-bromobenzyl, 4-bromobenzyl, R6 is C2-4 alkyl, amido or -COOR7: 3-methoxybenzyl, 3-nitrobenzyl, 3-aminobenzyl or 4-(ami R7 is C1-4 alkyl: nosulfonyl)benzyl. More preferred benzyl groups are benzyl, 1625. In one aspect, the invention provides compounds: 3-bromobenzyl, 3-methoxybenzyl, 3-nitrobenzyl or 3-ami When R1 is hydrogen, R2 is methyl, R3 is —CHR5R6, R6 is nobenzyl. In some embodiments alkyl groups are 3-methoxy ethoxycarbonyl and R5 is ethyl, then R4 is different from benzyl or 3-nitrobenzyl. methyl, n-propyl, i-propyl. n-pentyl, n-heptyl, 3-bromoben 1633. The term “halogen', as used herein, represents an Zyl, 4-chlorobenzyl, 4-methylbenzyl or 2-phenylethyl: atom of fluorine, chlorine, bromine, or iodine. In some When R1 is hydrogen, R2 is methyl, R3 is benzyl, then R4 is embodiments the halogen is bromine different from i-propyl. n-butyl, 3-methylbutyl, benzyl, phe 1634 The term “hydroxy’, as used herein, represents a nylethyl-, or 3-phenylpropyl; group of formula—OH. When R1 and R2 are methyl, R3 is benzyl, R4 is different 1635. The term “cyano”, as used herein, represents a from methyl 3-methylbutyl, benzyl, 3-phenylpropyl or group of formula—CN. 4-chlorophenylmethyl: 1636. The term “amino', as used herein, represents a Finally 8-(2-chloro-benzylsulfanyl)-3-methyl-7-octyl-3,7- group of formula NH2. dihydro-purine-2,6-dione is considered. 1637. The term “ethynyl', as used herein, represents a 1626. Usually when R3 is a benzyl group, then R4 is C1-8 group of formula—C=CH. alkyl optionally substituted by alkoxycarbonyl. 1638. The term “alkoxy’, as used herein, represents a 1627. Usually when R3 is a group of formula—CHR5R6, group of formula —ORa wherein Ra is an alkyl group, as then R4 is C1-8 alkyl optionally substituted by C3-6 defined above. In some embodiments the alkoxy group is cycloalkyl, aryl or heterocycle. methoxy. 1628. The term “alkyl, as used herein, is a group which 1639. The term "nitro', as used herein, represents a group represents saturated, monovalent hydrocarbon radicals hav of formula - NO2. ing straight (unbranched) or branched moieties, or combina 1640. The term "amido’, as used herein, represents a tions thereof, and containing 1-8 carbon atoms, preferably group of formula—C(=O)NH2. 1-6 carbon atoms; more preferably alkyl groups have 1-4 1641. The term “acyl, as used herein, represents a group carbon atoms. Alkyl moieties may optionally be substituted of formula —C(=O)Rb wherein Rb is an alkyl group, as by 1 to 5 substituents independently selected from the group defined here above. In some embodiments the acyl group is consisting of hydroxy, alkoxy, cyano, ethynyl, alkoxycarbo acetyl ( C(=O)Ne). nyl, acyl, aryl or heterocycle. Alkyl moieties may be option 1642. The term “alkoxycarbonyl (or ester), as used ally substituted by a cycloalkyl as defined hereafter. Preferred herein, represents a group of formula—COORc wherein Rc alkyl groups according to the present invention are methyl, is an alkyl group; with the proviso that Ric does not represent cyanomethyl, ethyl, 2-ethoxy-2-oxoethyl, 2-methoxyethyl, an alkyl alpha-Substituted by hydroxy. In some embodiments n-propyl, 2-oxopropyl, 3-hydroxypropyl. 2-propynyl. n-bu the alkoxycarbonyl group is ethoxycarbonyl. tyl, i-butyl, n-pentyl, 3-pentyl, n-hexyl, cyclohexylmethyl, 1643. The term "heterocycle', as used herein, represents a benzyl, 2-bromobenzyl, 3-bromobenzyl, 4-bromobenzyl, 5-membered ring containing one or two heteroatoms selected 3-methoxybenzyl, 3-nitrobenzyl, 3-aminobenzyl, 4-(amino from O or N. The heterocycle may be substituted by one or sulfonyl)benzyl, 1-phenylethyl 2-phenylethyl, (3,5-dimeth two C1-4 alkyl or nitro. In some embodiments the hetero ylisoxazol-4-yl)methyl or (5-nitro-2-furyl)methyl. More pre cycles are (3,5-dimethylisoxazol-4-yl) or (5-nitro-2-furyl). ferred alkyl groups are methyl, ethyl, cyanomethyl, Most preferred heterocycle is (5-nitro-2-furyl). 2-methoxyethyl, n-propyl, 3-hydroxypropyl. 2-propynyl, 1644 Generally R1 is hydrogen or C1-6 alkyl. Usually R1 n-butyl, 3-pentyl, n-hexyl, benzyl, 3-bromobenzyl, 3-meth is hydrogen or C1-6 alkyl optionally substituted by hydroxy, oxybenzyl, 3-nitrobenzyl, 3-aminobenzyl, (3,5-dimethyl alkoxy, cyano, ethynyl, alkoxycarbonyl or acyl. In some US 2011/0212928 A1 Sep. 1, 2011 60 embodiments R1 is hydrogen, methyl, cyanomethyl, R5 is unsubstituted C2-4 alkyl; 2-ethoxy-2-oxoethyl, 2-methoxyethyl, n-propyl, 2-oxopro R6 is unsubstituted C2-4 alkyl, amido or COOR7; pyl, 3-hydroxypropyl. 2-propynyl, n-pentyl or n-hexyl. In R7 is unsubstituted C1-4 alkyl; Some embodiments R1 is hydrogen, methyl, cyanomethyl, with the proviso that when R1 is hydrogen, R2 is methyl, R3 2-methoxyethyl, n-propyl, 3-hydroxypropyl or 2-propynyl. is —CHR5R6, R6 is ethoxycarbonyl and R5 is ethyl, then R4 In some embodiments R1 is hydrogen. is different from n-propyl, i-propyl. n-pentyl, n-heptyl, 3-bro 1645 Generally R2 is hydrogen or C1-4 alkyl. Usually R2 mobenzyl, 4-chlorobenzyl, 4-methylbenzyl or 2-phenylethyl. is hydrogen or unsubstituted C1-4 alkyl. In some embodi 1652. In the above embodiment, sometimes, when R3 is a ments R2 is hydrogen, methyl or n-butyl. In some embodi benzyl group, then R4 is C1-8 alkyl optionally substituted by ments, R2 is methyl. alkoxycarbonyl. 1646 Generally R3 is a group of formula—CHR5R6 or a 1653. In the above embodiment, sometimes, when R3 is a benzyl group. In some embodiments R3 is 3-pentyl, 1-(ami group of formula —CHR5R6, then R4 is C1-8 alkyl option nocarbonyl)propyl, 1-(ethoxycarbonyl)propyl or 3-bro ally substituted by C3-6 cycloalkyl, aryl or heterocycle. mobenzyl. In some embodiments R3 is 1-(ethoxycarbonyl) 1654. In one embodiment, propyl. R1 is hydrogen, methyl, cyanomethyl, 2-ethoxy-2-oxoethyl, 1647 Generally R4 is C1-8 alkyl optionally substituted by 2-methoxyethyl, n-propyl, 2-oxopropyl, 3-hydroxypropyl. alkoxycarbonyl, C3-6 cycloalkyl, aryl or heterocycle. Usu 2-propynyl. n-pentyl or n-hexyl, ally R4 is C1-8 alkyl optionally substituted by cyclohexyl, R2 is hydrogen, methyl or n-butyl: phenyl, bromophenyl, aminophenyl, methoxyphenyl, nitro R3 is 3-pentyl, 1-(aminocarbonyl)propyl, 1-(ethoxycarbo phenyl, aminosulfonylphenyl, 3.5-dimethylisoxazol-4-yl, nyl)propyl or 3-bromobenzyl: 5-nitro-2-furyl or ethoxycarbonyl. In some embodiments R4 R4 is n-butyl, i-butyl, n-pentyl, n-hexyl, cyclohexylmethyl, is n-butyl, i-butyl, n-pentyl, n-hexyl, cyclohexylmethyl, ben benzyl, 2-bromobenzyl, 3-bromobenzyl, 4-bromobenzyl, Zyl. 2-bromobenzyl, 3-bromobenzyl, 4-bromobenzyl, 3-methoxybenzyl, 3-nitrobenzyl, 3-aminobenzyl, 4-(amino 3-methoxybenzyl, 3-nitrobenzyl, 3-aminobenzyl, 4-(amino sulfonyl)benzyl, 1-phenylethyl 2-phenylethyl, (3,5-dimeth sulfonyl)benzyl, 1-phenylethyl 2-phenylethyl, (3,5-dimeth ylisoxazol-4-yl)methyl, (5-nitro-2-furyl)methyl O ylisoxazol-4-yl)methyl, (5-nitro-2-furyl)methyl O 1-(ethoxycarbonyl)propyl; 1-(ethoxycarbonyl)propyl. In some embodiments R4 is n-bu with the proviso that when R1 is hydrogen, R2 is methyl and tyl, n-hexyl, benzyl, 3-bromobenzyl, 3-methoxybenzyl, 3-ni R3 is 1-(ethoxycarbonyl)propyl, then R4 is different from trobenzyl, 3-aminobenzyl, (3,5-dimethylisoxazol-4-yl)me n-pentyl, 3-bromobenzyl or 2-phenylethyl. thyl, (5-nitro-2-furyl)methyl or 1-(ethoxycarbonyl)propyl. In 1655. In the above embodiment, sometimes, when R3 is some embodiments R4 is 3-methoxybenzyl, 3-nitrobenzyl or 3-bromobenzyl, then R4 is C1-8 alkyl optionally substituted (5-nitro-2-furyl)methyl. by alkoxycarbonyl. 1648 Generally R5 is C2-4 alkyl. Usually R5 is unsubsti 1656. In the above embodiment, sometimes, when R3 is tuted C2-4 alkyl. In some embodiments R5 is ethyl. 3-pentyl, 1-(aminocarbonyl)propyl or 1-(ethoxycarbonyl) 1649 Generally R6 is C2-4 alkyl, amido or -COOR7. propyl, then R4 is different from 1-(ethoxycarbonyl)propyl. Usually R6 is unsubstituted C2-4 alkyl, amido or —COOR7. 1657. In a more preferred embodiment, R1 is hydrogen, In some embodiments R6 is ethyl, amido or ethoxycarbonyl. methyl, cyanomethyl, 2-methoxyethyl, n-propyl, 3-hydrox In some embodiments R6 is ethoxycarbonyl. ypropyl or 2-propynyl: 1650 Generally R7 is C1-4 alkyl. Usually R7 is unsubsti R2 is methyl: tuted C1-4 alkyl. In some embodiments, R7 is ethyl. R3 is 3-pentyl, 1-(aminocarbonyl)propyl, 1-(ethoxycarbo 1651. Usually the invention provides compounds having nyl)propyl or 3-bromobenzyl: formula I, their enantiomers, diastereoisomers and mixtures R4 is n-butyl, n-hexyl, benzyl, 3-bromobenzyl, 3-methoxy thereof (including all possible mixtures of stereoisomers), or benzyl, 3-nitrobenzyl, 3-aminobenzyl, (3,5-dimethylisox pharmaceutically acceptable salts thereof, azol-4-yl)methyl, (5-nitro-2-furyl)methyl or 1-(ethoxycarbo nyl)propyl; with the proviso that when R1 is hydrogen, R2 is methyl and (I) R3 is 1-(ethoxycarbonyl)propyl, then R4 is different from O R4 3-bromobenzyl. 1658. In the above embodiment, sometimes, when R3 is RS \ 3-bromobenzyl, then R4 is 1-(ethoxycarbonyl)propyl: 1659. In the above embodiment, sometimes, when R3 is O1. N N2 vR3 3-pentyl, 1-(aminocarbonyl)propyl or 1-(ethoxycarbonyl) propyl, then R4 is different from 1-(ethoxycarbonyl)propyl: k 1660. In one embodiment, R1 is hydrogen; R2 is methyl: R3 is 1-(ethoxycarbonyl)propyl; and R4 is 3-methoxybenzyl, wherein 3-nitrobenzyl or (5-nitro-2-furyl)methyl. R1 is hydrogen, C1-6 alkyl optionally substituted by hydroxy, 1661. A further embodiment consists in compounds alkoxy, cyano, ethynyl, alkoxycarbonyl or acyl: wherein R2 is methyl, R3 is a group of formula —CHR5R6 R2 is hydrogen or unsubstituted C1-4 alkyl: with R5 being C2-4 alkyl, R6 being amido or —COOR7 and R3 is a group of formula —CHR5R6 or a benzyl group: R7 being methyl or ethyl. R4 is C1-8 alkyl optionally substituted by cyclohexyl, phenyl, 1662. In some embodiments, compounds are ethyl 2-(7- bromophenyl, aminophenyl, methoxyphenyl, nitrophenyl, benzyl-1,3-dimethyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-pu aminosulfonylphenyl, 3,5-dimethylisoxazol-4-yl, 5-nitro-2- rin-8-yl)thiobutanoate; ethyl 2-7-(3-bromobenzyl)-1-(2- furyl or ethoxycarbonyl: ethoxy-2-oxoethyl)-3-methyl-2,6-dioxo-2,3,6,7-tetrahydro

US 2011/0212928 A1 Sep. 1, 2011 62

1671. With respect to the present invention reference to a 1678. In some embodiments, the compounds also include compound or compounds is intended to encompass that com optionally substituted N-alkylated 2-oxo-azepanyl deriva pound in each of its possible isomeric forms and mixtures tives. Preferably, those compounds are alkyl amides deriva thereof, unless the particular isomeric form is referred to tives substituted on the positions 4 and/or 5 and/or 6 and/or 7 specifically. of the 2-oxo-azepanyl ring. Examples of optionally Substi 1672 Compounds according to the present invention may tuted N-alkylated 2-oxo-azepanyl derivatives include, but are exist in different polymorphic forms. Although not explicitly not limited to, compounds such as those referred to in inter national patent application PCT/EP02/05503 such as 2-5- indicated in the above formula, such forms are intended to be (iodomethyl)-2-oxo-1-azepanylbutanamide. included within the scope of the present invention. 1679 xiv) U.S. Patent Application Publication No. 1673 xiii) U.S. Pat. No. 7,465,549 2006258704 1674. In some embodiments, the compound includes 1680. This invention provides novel compounds of the optionally substituted N-alkylated 2-oxo-pyrrolidine deriva formula I tives. In some embodiments, those compounds are alkyl amides derivatives substituted on the positions 4 and/or 5 of (I) the pyrrolidone ring. Examples of optionally substituted N-alkylated 2-oxo-pyrrolidine derivatives include, but are not limited to, compounds such as (2S)-2-(4S)-4-(2,2-difluo rovinyl)-2-oxopyrrolidinylbutanamide, (2S)-2-(4R)-2- oXo-4-propylpyrrolidinylbutanamide, (2S)-2-(4S)-2-oxo 4-propylpyrrolidinylbutanamide, and (2S)-2-[4-(3- azidophenyl)-2-oxopyrrolidin-1-ylbutanamide. 1675. In some embodiments, the compounds further include optionally substituted N-alkylated 2-oxo-piperidinyl derivatives. In some embodiments, those compounds are alkyl amides derivatives substituted on the position 4 and/or 5 and/or 6 of the 2-oxo-piperidinyl ring. Examples of option ally substituted N-alkylated 2-oxo-pyrrolidine derivatives wherein include, but are not limited to, compounds such as those in represents 0 or 1 whereby R-1 > is not existent when n=0 referred to in international patent application PCT/EP02/ and R3 1> is existent when n=1: 05503 such as (2S)-2-5-(iodomethyl)-2-oxo-1-piperidinyl A-1 > represents an oxygen or a Sulfur atom; butanamide, (2S)-2-5-(azidomethyl)-2-oxo-1-piperidinyl butanamide, 2-(2-oxo-5-phenyl-1-piperidinylbutanamide, X is CONR<7>R<8>, COOR-9), CO R-10> or (2S)-2-[4-(iodomethyl)-2-oxo-1-piperidinylbutanamide, CN: and (2S)-2-[4-(2-fluoro-2-methylpropyl)-2-oxo-1-pyrrolidi 1681 R-1 > when existent, R-2), R3D. R-4D and R-5> nylbutanamide. are the same or different and each is independently hydrogen, 1676. In some embodiments, the compounds include any halogen, hydroxy, thiol, amino, nitro, nitrooxy, cyano, azido, acetam compound of formula I, in racemic or isomeric form, carboxy, amido, Sulfonic acid, Sulfonamide, alkyl, alkenyl, or a pharmaceutically acceptable salt thereof, alkynyl, ester, ether, aryl, heterocycle, or an oxy derivative, thio derivative, amino derivative, acyl derivative, sulfonyl derivative or sulfinyl derivative, (I) R provided that at least one of the substituents R chosen from R<1> when existent, R3D, R32, R-4> or R3> is not hydrogen; R-6> is hydrogen, alkyl, aryl or —CH2-R-6ad wherein O N R3 R-6a is aryl, heterocycle, halogen, hydroxy, amino, nitro or R1 cyano; N R<7>, R3D and R39 are the same or different and each is R2 YR4 independently hydrogen, hydroxy, alkyl, aryl, heterocycle or O an oxy derivative; and Rs.10 is hydrogen, hydroxy, thiol, halogen, alkyl, aryl, het erocycle or a thio derivative: wherein their pharmaceutically acceptable salts, geometrical Isomers R represents hydrogen or hydroxy: (including cis and trans, Zand E isomers), enantiomers, dias R1 and R2 represent independently hydrogen or an alkyl tereoisomers and mixtures thereof (including all possible group of 1-4 carbon atoms; and mixtures of Stereoisomers). R3 and R4 represent independently hydrogen, an alkyl group 1682. In the above formula, at least one substituent R-1> of 1-4 carbonatoms or —(CH2)n-NR5R6 wherein n is 1, 2 or to R-5> is different from hydrogen. Some non-substituted 3 and R5 and R6 represent independently hydrogen or an compounds are referred to in U.S. Pat. Nos. 5,468,733 and alkyl group of 1-4 carbon atoms. 5,516,759. U.S. Pat. No. 5,468,733 discloses non-ring sub 1677 An example of such an acetam compound includes, stituted 2-oxo-1-pyrrolidinyl and 2-oxo-1-piperidinyl deriva but is not limited to, a compound of formula I wherein R, R1, tives as inhibitors of the oncogene Ras protein. In particular, R2, R3 and R4 are hydrogen, 2-oxo-pyrrolidineacetamide, these compounds block the ability of Ras to transform normal known by the generic name piracetam as described in UK cells to cancer cells, and therefore can be included in several Patents Nos. 1,039,113 and 1,309,692. chemotherapeutic compositions for treating cancer. US 2011/0212928 A1 Sep. 1, 2011

1683 U.S. Pat. No. 5,516,759 discloses non-ring substi optionally substituted by, preferably 1 to 5, substituents inde tuted 2-oxo-1-pyrrolidinyl, 2-oxo-1-piperidinyl and azepanyl pendently selected from the group consisting of halogen, derivatives present at the N-terminus of dodecapeptides pos hydroxy, thiol, amino, nitro, cyano, thiocyanato, acyl, acy sessing LHRH (luteinizing hormone-releasing hormone) loxy, Sulfonyl derivative, Sulfinyl derivative, alkylamino, car antagonistic activity. Such LHRH antagonists are useful in boxy, ester, ether, amido, azido, cycloalkyl, Sulfonic acid, the treatment of a variety of conditions in which Suppression Sulfonamide, thio derivative, alkylthio, oxyester, oxyamido, of sex steroids plays a key role including contraception, delay heterocycle, vinyl, alkoxy (preferably C1-5), aryloxy (pref of puberty, treatment of benign prostatic hyperplasia a.o. erably C6-10) and aryl (preferably C6-10). 1692. In some embodiments are alkyl groups containing 1 1684. In the definitions set forth below, unless otherwise to 7 carbonatoms, each optionally substituted by one or more stated, R-11 > and R312 are the same or different and each Substituents selected from hydroxy, halogen, cyano, thiocy is independently amido, alkyl, alkenyl, alkynyl, acyl, ester, anato, alkoxy, azido, alkylthio, cyclopropyl, acyl and phenyl. ether, aryl, aralkyl, heterocycle or an oxy derivative, thio Most preferred are C1-4 alkyl and C3-7 cycloalkyl, each derivative, acyl derivative, amino derivative, sulfonyl deriva optionally Substituted by one or more hydroxy, halogen, tive, or sulfinyl derivative, each optionally substituted with lower alkyl or/and azido. any Suitable group, including, but not limited to, one or more 1693. In some embodiments are alkyl groups are moieties selected from lower alkyl or other groups as hydroxymethyl, propyl, butyl, 2.2.2-trifluoroethyl, 2-bromo described below as substituents for alkyl. 2,2-difluoroethyl, 2-chloro-2,2-difluoroethyl, 3,3,3-trifluo 1685. The term “oxy derivative', as used herein, is defined ropropyl, cyclopropylmethyl, iodomethyl, azidomethyl, 2.2- as including —O R-11 > groups wherein R-11 > is as defined above except for “oxy derivative'. Non-limiting difluoropropyl, 2-iodo-2,2-difluoroethyl. examples are alkoxy, alkenyloxy, alkynyloxy, acyloxy, 1694. The term “lower alkyl, as used herein, and unless otherwise specified, refers to C1 to C7 saturated straight, oxyester, oxyamido, alkylsulfonyloxy, alkylsulfinyloxy, aryl branched or cyclic hydrocarbon. Non limiting examples are Sulfonyloxy, arylsulfinyloxy, aryloxy, aralkoxy or heterocy methyl, ethyl, propyl, isopropyl, butyl, tertiobutyl, pentyl, clooxy Such as pentyloxy, allyloxy, methoxy, ethoxy, phe cyclopropyl, cyclopentyl, isopentyl, neopentyl, hexyl, iso noXy, benzyloxy, 2-naphthyloxy, 2-pyridyloxy, hexyl, cyclohexyl, 3-methypenty1, 2,2-dimethylbutyl, methylenedioxy, carbonate. optionally Substituted with any Suitable group, including but 1686. The term “thio derivative', as used herein, is defined not limited to one or more moieties selected from groups as as including —S R-11D groups wherein R-11 > is as described above for the alkyl groups. Preferably, lower alkyl defined above except for “thio derivative'. Non-limiting is methyl. examples are alkylthio, alkenylthio, alkynylthio and arylthio. 1695. The term “alkenyl', as used herein, is defined as 1687. The term “amino derivative’, as used herein, is including both branched and unbranched, unsaturated hydro defined as including - NHR<11> or - NR<11>R<12> carbon radicals having at least one double bond, and being groups wherein R-11 > and R-12 are as defined above. optionally substituted by at least one substituent selected Non-limiting examples are mono- or di-alkyl-, alkenyl-, alky from the group consisting of halogen, hydroxy, thiol, amino, nyl- and arylamino or mixed amino. thiocyanato, azido, alkylthio, cycloalkyl, acyl, nitro, cyano, 1688. The term “acyl derivative’, as used herein, repre aryland heterocycle. sents a radical derived from carboxylic acid and thus is 1696. In some embodiments are alkenyl groups are defined as including groups of the formula R-11 >-CO , C2-C12 alkenyls, especially C2-6alkenyls, such as ethenyl wherein R-11 > is as defined above and may also be hydro (vinyl), 1-methyl-1-ethenyl, 2,2-dimethyl-1-ethenyl, 1-pro gen. Preferred are acyl derivatives of formula —COR<11> penyl, 2-propenyl (allyl), 1-butenyl, 2-butenyl, 3-butenyl, wherein R-11 > is selected from hydrogen, C1-12 alkyl, 4-pentenyl, 1-methyl-4-pentenyl, 3-methyl-1-pentenyl, C2-12 alkenyl, C2-12 alkenyl, heterocyle and aryl. Non-lim 1-hexenyl, 2-hexenyl and the like, optionally being Substi iting examples are formyl, acetyl, propionyl, isobutyryl, tuted by one or more Substituents selected from halogen, Valeryl, lauroyl, heptanedioyl, cyclohexanecarbonyl, croto cyano, thiocyanato, azido, alkylthio, cycloalkyl, phenyl and noyl, fumaroyl, acryloyl, benzoyl, naphthoyl, furoyl, nicoti acyl. Most preferred is vinyl, optionally substituted by one or noyl, 4-carboxybutanoyl, oxalyl ethoxalyl, cysteinyl, oxam more halogen or/and lower alkyl, and especially 2,2-difluo oyl. rovinyl, 2,2-dibromovinyl and 2,2-dichlorovinyl. 1689. The term "sulfonyl derivative’, as used herein, is 1697. The term “alkynyl as used herein, is defined as defined as including a group of the formula - SO R-11 >, including a monovalent branched or unbranched hydrocar wherein R-11 > is as defined above except for “sulfonyl bon radical containing at least one carbon-carbon triple bond, derivative'. Non-limiting examples are alkylsulfonyl, alk for example ethynyl, 2-propynyl (propargyl), and the like, enylsulfonyl, alkynylsulfonyl and arylsulfonyl. and being optionally Substituted by at least one Substituent 1690. The term “sulfinyl derivative’, as used herein, is selected from the group consisting of halogen, hydroxy, thiol, defined as including a group of the formula - SO R-11 >, amino, nitro, cyano, aryl, heterocycle, thiocyanato, azido, wherein R-11 > is as defined above except for “sulfinyl alkylthio, alkyl and acyl. derivative'. Non-limiting examples are alkylsulfinyl, alk 1698. In some embodiments are alkynyl groups are C2-12 enylsulfinyl, alkynylsulfinyl and arylsulfinyl. alkynyl, especially C2-6 alkynyl, optionally being Substituted 1691. The term “alkyl, as used herein, is defined as by one or more Substituents selected from halogen, cyano, including Saturated, monovalent hydrocarbon radicals having thiocyanato, azido, alkylthio, acyl, aryl Such as phenyl and straight, branched or cyclic moieties or combinations thereof alkyl, preferably cycloalkyl. and generally containing 1-20 carbon atoms, most often 1 to 1699. In some embodiments are ethynyl, propynyl and 12 carbonatoms, preferably 1-7 carbon atoms for non-cyclic butynyl, optionally substituted by lower alkyl or/and halogen, alkyl and 3-7 carbon atoms for cycloalkyl (in these two pre and especially 1-propynyl, cyclopropylethynyl, 3-methyl-1- ferred cases, unless otherwise specified, “lower alkyl), each butynyl and 3,3,3-trifluoro-1-propynyl. US 2011/0212928 A1 Sep. 1, 2011 64

1700. When present as bridging groups, alkyl, alkenyl and 1717 The term "amido' is defined as including a group of alkynyl represent straight- or branched chains, C1-12, pref formula CONH2 O CONHR311> O erably C1-4-alkylene or C2-12-, preferably C2-4-alkenylene - CONR3|1>R<12> wherein R3 11- and R312) are as or -alkynylene moieties respectively. defined above. 1701 Groups where branched derivatives are convention 1718. The term "heterocycle', as used herein, is defined as ally qualified by prefixes such as “n”, “sec”, “iso’ and the like including an aromatic or non aromatic cyclic alkyl, alkenyl, (e.g. “n-propyl', 'sec-butyl') are in the n-form unless other or alkynyl moiety as defined above, having at least one O.S wise stated. and/or Natom interrupting the carbocyclic ring structure and optionally, one of the carbon of the carbocyclic ring structure 1702. The term “aryl', as used herein, is defined as includ may be replaced by a carbonyl, and optionally being Substi ing an organic radical derived from an aromatic hydrocarbon tuted with any suitable group, including but not limited to one consisting of at least one ring, most often 1 to 3 rings and or more moieties selected from lower alkyl, or other groups as generally containing 6-30 carbon atoms by removal of one described above for the alkyl groups. Non-limiting examples hydrogen, such as phenyl and naphthyl, each optionally Sub of heterocycles are pyridyl, furyl, pyrrolyl, thienyl, isothiaz stituted by one or more substituents independently selected olyl, triazolyl, imidazolyl, benzimidazolyl, tetrazolyl, from halogen, hydroxy, thiol, amino, nitro, cyano, acyl, acy quinazolinyl, quinolizinyl, naphthyridinyl, pyridazinyl, pyri loxy, Sulfonyl, Sulfinyl, alkylamino, carboxy, ester, ether, midinyl, pyrazinyl, quinolyl, isoquinolyl, isobenzofuranyl. amido, azido, Sulfonic acid, Sulfonamide, alkylsulfonyl, benzothienyl, pyrazolyl, indolyl, indolizinyl, purinyl, isoin alkylsulfinyl, C1-6-alkylthio, oxyester, oxyamido, aryl, dolyl, carbazolyl, thiazolyl, 1,2,4-thiadiazolyl, thiomorpholi C1-6-alkoxy, C6-10-aryloxy, C1-6-alkyl, C1-6-haloalkyl. nyl, thieno (2,3-b)furanyl, furopyranyl, benzofuranyl, ben Aryl radicals are preferably monocyclic or bicyclic contain ZOXepinyl, isooxazolyl, Oxazolyl, thianthrenyl, ing 6-10 carbon atoms. Preferred aryl groups are phenyl and benzothiazolyl, or benzoxazolyl, cinnolinyl, phthalazinyl, naphthyl each optionally substituted by one or more substitu quinoxalinyl, 1-oxidopyridyl, phenanthridinyl, acridinyl, ents independently selected from halogen, nitro, amino, perimidinyl, phenanthrolinyl, phenothiazinyl, furazanyl. azido, C1-6-alkoxy, C1-6-alkyl, C1-6-haloalkyl, sulfonyland benzodioxolyl, isochromanyl, indolinyl, Xanthenyl, hypox phenyl. anthinyl, pteridinyl, 5-azacytidinyl, 5-aZauracilyl, triazol 1703. In some embodiments the aryl is phenyl, optionally opyridinyl, imidazolopyridinyl, pyrrolopyrimidinyl, pyrazol Substituted by one or more halogen, lower alkyl, azido or opyrimidinyl, tetrahydrofuranyl, tetrahydropyranyl. nitro. Such as 3-chlorophenyl and 3-azidophenyl. piperidinyl, piperidyl, piperazinyl, imidazolidinyl, mor 1704. The term “halogen', as used herein, includes an pholino, morpholinyl, 1-oxaspiro(4.5)dec-2-yl, pyrrolidinyl, atom of Cl, Br, F. I. 2-oxo-pyrrolidinyl, Sugar moieties (i.e. glucose, pentose, 1705. The term “hydroxy’, as used herein, represents a hexose, ribose, fructose, which may also be substituted) group of the formula —OH. optionally substituted by alkyl or as described above for the alkyl groups. The term "heterocycle” also includes bicyclic, 1706 The term “thiol, as used herein, represents a group tricyclic and tetracyclic, Spiro groups in which any of the of the formula—SH. above heterocyclic rings is fused to one or two rings indepen 1707. The term “cyano”, as used herein, represents a dently selected from an aryl ring, a cyclohexane ring, a cyclo group of the formula—CN. hexene ring, a cyclopentane ring, a cyclopentene ring or 1708. The term "nitro', as used herein, represents a group another monocyclic heterocyclic ring or where a monocyclic of the formula - NO2. heterocyclic group is bridged by an alkylene group. Such as 1709. The term "nitrooxy’, as used herein, represents a quinuclidinyl, 7-azabicyclo(2.2.1)heptanyl, 7-Oxabicyclo(2. group of the formula —ONO2. 2.1)heptanyl, 8-azabicyclo(3.2.1)octanyl. 1710. The term “amino', as used herein, represents a 1719. The heterocycle may be selected from triazolyl, tet group of the formula —NH2. razolyl, pyrrolidinyl, pyridyl, 1-oxidopyridyl, thiomorpholi 1711. The term “azido’, as used herein, represents a group nyl, benzodioxolyl, furyl, oxazolyl pyrimidinyl, pyrrolyl, of the formula - N3. thiadiazolyl, thiazolyl, thienyl and piperazinyl, each option ally substituted by one or more substituents selected from 1712. The term “carboxy’, as used herein, represents a halogen, alkyl, Substituted alkyl, alkoxy, nitro, amino, acyl group of the formula—COOH. and phenyl. In some embodiments the heterocycle is selected 1713 The term "sulfonic acid, as used herein, represents from tetrazolyl pyrrolidinyl, pyridyl, furyl, pyrrolyl, thiaz a group of the formula—SO3H. olyl and thienyl, each optionally substituted by one or more 1714. The term "sulfonamide', as used herein, represents Substituents selected from halogen, alkyl, halogen Substituted a group of the formula—SO2NH2. alkyl, acyl, alkoxy, nitro, amino and phenyl, and especially 1715. The term “ester', as used herein, is defined as from 2- and 3-thienyl, optionally substituted by one or more including a group of formula – COO R-11 > wherein halogen, acyl Such as formyl, cyano and/or lower alkyl. Such R-11 > is as defined above except oxy derivative, thio deriva as methyl. tive or amino derivative. Preferred are esters of formula 1720. In the above definitions it is to be understood that —COOR-11 > wherein R-11D is selected from C1-12 alkyl, when a substituent such as R-1 >, R3D, R<3>, R-4>, R3>, C2-12 alkenyl, C2-12 alkynyl and aryl. Most preferred are R<7>, R3>, R-9), R310> is attached to the rest of the esters where R-11 > is a lower alkyl, especially methyl. molecule via a heteroatom or a carbonyl, a straight- or 1716. The term “ether is defined as including a group branched chain, C1-12-, preferably C1-4-alkylene or C2-12, selected from C1-50-straight or branched alkyl, or C2-50 preferably C2-4-alkenylene or -alkynylene bridge may straight or branched alkenyl or alkynyl groups or a combina optionally be interposed between the heteroatom or the car tion of the same, interrupted by one or more oxygen atoms. bonyl and the point of attachment to the rest of the molecule. US 2011/0212928 A1 Sep. 1, 2011

1721. The acid addition salt form of a compound of for cologically active. For example, metabolically cleavable mula (I) that occurs in its free form as a base can be obtained groups form a class of groups well known to practitioners of by treating said free base form with an appropriate acid Such the art. They include, but are not limited to Such groups as as an inorganic acid, for example, a hydrohalic Such as hydro alkanoyl (i.e. acetyl, propionyl, butyryl, and the like), unsub chloric or hydrobromic, Sulfuric, nitric, phosphoric and the stituted and Substituted carbocyclic aroyl (such as benzoyl, like; oran organic acid, such as, for example, acetic, hydroxy Substituted benzoyland 1- and 2-maphthoyl), alkoxycarbonyl acetic, propanoic, lactic, pyruvic, malonic, Succinic, maleic, (such as ethoxycarbonyl), trialkylsilyl (such as trimethyl- and fumaric, malic, tartaric, citric, methanesulfonic, ethane triethylsilyl), monoesters formed with dicarboxylic acids Sulfonic, benzenesulfonic, p-toluenesulfonic, cyclamic, Sali (such as Succinyl), phosphate, Sulfate, Sulfonate, Sulfonyl, cylic, p-aminosalicylic, pamoic and the like. sulfinyl and the like. The compounds bearing the biotrans 1722. The compounds of formula (I) containing acidic formable groups have the advantage that they may exhibit protons may be converted into their therapeutically active, improved bioavailability as a result of enhanced solubility non-toxic base addition salt form, e.g. metal oramine salts, by and/or rate of absorption conferred upon the parent com treatment with appropriate organic and inorganic bases. pound by virtue of the presence of the biotransformable Appropriate base salt forms include, for example, ammonium group. T. Higuchi and V. Stella, “Pro-drugs as Novel Delivery salts, alkali and earth alkaline metal salts, e.g. lithium, System”, Vol. 14 of the A.C.S. Symposium Series: “Bior Sodium, potassium, magnesium, calcium salts and the like, eversible Carriers in Drug Design, ed. Edward B. Roche, salts with organic bases, e.g. N-methyl-D-glucamine, hydra American Pharmaceutical Association and Pergamon Press, bamine salts, and salts with amino acids such as, for example, 1987. arginine, lysine and the like. 1733. The term “R substituent refers to R-1 >, R-2D, 1723 Conversely said salt forms can be converted into the R<3>, R-4> or R3>, independently. free forms by treatment with an appropriate base or acid. 1734. According to one embodiment, the present inven 1724 Compounds of the formula I and their salts can be in tion relates to a compound of formula I as defined above the form of a solvate, which is included within the scope of the wherein in represents 0. The compound is a 6-ring structure present invention. Such solvates include for example (2-thioxo- or 2-oxo-piperidinyl derivative) wherein R-1 > is hydrates, alcoholates and the like. not existent since n=0, and is depicted by the formula (I-A). 1725. Many of the compounds of formula I and some of their intermediates have at least one stereogenic center in (I-A) their structure. This stereogenic center may be present in a R R4 or a S configuration, said R and S notation is used in corre spondence with the rules described in Pure Appl. Chem. R3 R5 (1976), 45, 11-30. 1726. The invention also relates to all stereoisomeric forms such as enantiomeric and diastereoisomeric forms of R2 N Al the compounds of formula I or mixtures thereof (including all possible mixtures of stereoisomers). R6 1. X 1727. Furthermore, certain compounds of formula I which contain alkenyl groups may exist as Z (Zusammen) or E (entgegen) isomers. In each instance, the invention includes 1735. According to a following embodiment, the present both mixture and separate individual isomers. invention relates to a compound of formula I according to the 1728 Multiple substituents on the piperidinyl or the invention as defined above wherein in represents 1. The com aZepanyl ring can also stand in either cis or trans relationship pound is a 7-ring structure (2-thioxo- or 2-oxo-azepanyl to each other with respect to the plane of the piperidinyl or the derivative) wherein R-1 > is existent since n=1 and depicted aZepanyl ring. by the formula (I-B). 1729. Some of the compounds of formula I may also exist in tautomeric forms. Such forms although not explicitly indi cated in the above formula are intended to be included within (I-B) the scope of the present invention. 1730. With respect to the present invention reference to a compound or compounds is intended to encompass that com pound in each of its possible isomeric forms and mixtures thereof unless the particular isomeric form is referred to spe cifically. 1731. The invention also includes within its scope prodrug forms of the compounds of formula I and Its various sub Scopes and Sub-groups. 1732. The term “prodrug as used herein includes com 1736. According to one embodiment, the invention relates pound forms which are rapidly transformed in vivo to the to said compound as defined above wherein n=0, R3 and/or parent compound according to the invention, for example, by R-4D are different from hydrogen and R-2 and R-5> rep hydrolysis in blood. Prodrugs are compounds bearing groups resent hydrogen. which are modified by biotransformation prior to exhibiting 1737 According to another embodiment, the invention their pharmacological action. Such groups include moieties relates to said compound as defined above wherein n=1, which are readily oxidised, cyclised or cleaved, which com R-2), R3 and/or R-4D are different from hydrogen and pound after biotransformation remains or becomes pharma wherein R-1 > and R-5> represent hydrogen. US 2011/0212928 A1 Sep. 1, 2011 66

1738. According to another embodiment, the invention 1752 C2-12 alkenyl, each optionally substituted by one or relates to said compound as defined above wherein only one more Substituents selected from halogen, cyano, thiocyanato, R substituent chosen from R3> or R-4 when n=0 or from azido, alkylthio, alkyl, aryland acyl: R-2), R3 or R-4 when n=1, is different from hydrogen 1753 C2-12 alkynyl, each optionally substituted by one or and the remaining R Substituent(s) is/are hydrogen. We more Substituents selected from halogen, cyano, thiocyanato, hereby refer to a mono-substituted 2-thioxo- or 2-oxo-pip azido, alkylthio, alkyl, aryl and acyl; acyl derivative of for eridinyl or 2-thioxo- or 2-oxo-azepanyl derivatives. mula—CO R311 >, wherein R311 > is selected from C1-12 1739. According to another embodiment, the present alkyl, C2-12 alkenyl, C2-12 alkynyl, heterocycle and aryl; invention relates to compounds of formula I according to the 1754 ester of formula – CO-O-R-11 > wherein invention as defined above wherein A-1D represents an oxy R-11 > is selected from C1-12 alkyl, C2-12 alkenyl, C2-12 gen atom. We hereby refer to 2-oxo-piperidinyl or 2-oxo alkynyl and aryl; aZepanyl derivatives. 1755 heterocycle selected from triazolyl, tetrazolyl pyr 1740. According to another embodiment, the present rolidinyl, pyridyl, 1-oxidopyridyl, thiomorpholinyl, benzo invention relates to compounds of formula I according to the dioxolyl, furyl, oxazolyl pyrimidinyl, pyrrolyl, thiadiazolyl, invention as defined above wherein X is CONR<7> R3>, thiazolyl, thienyl and piperazinyl, each optionally substituted especially CONH2. We hereby refer to amido derivatives of by one or more Substituents selected from halogen, alkyl, 2-oxo(or thioxo)-piperidinyl or 2-oxo(or thioxo)-azepanyl. Substituted alkyl, alkoxy, nitro, amino, acyl and phenyl: 1741. According to another embodiment, the present 1756 aryl, each optionally substituted by one or more invention relates to compounds of formula I according to the substituents selected from C1-6 alkyl, C1-6 haloalkyl, C1-6 invention as defined above wherein R-6> represents hydro alkoxy, C1-6 alkylthio, amino, azido, Sulfonyl, aryland nitro. gen, C1-4 alkyl, or a CH2-R-6ad group wherein R-6ad 1757 According to another embodiment, the present represents a heterocycle. Most preferably R-6> is a C1-4 invention relates to a compound as defined above, wherein alkyl, especially ethyl. When R-6 is ethyl we refer to 2-(2- R<2> when n=1, R3D and R-4 are the same or different OXO(or thioxo)-1-piperidinyl)butanamide or 2-(2-oxo(or and each is independently hydrogen; thioxo)-1-azepanyl)butanamide derivatives. 1758 C-, alkyl, each optionally substituted by one or 1742. According to another embodiment, the present more substituents selected from hydroxy, halogen, cyano, invention relates to compounds of formula I according to the thiocyanato, alkoxy, azido, alkyltio, cyclopropyl, acyl and invention as defined above wherein the carbonatom to which phenyl: R-6) is attached is of the S configuration. In case where 1759 C2-6 alkenyl, each optionally substituted by one or R<6> is ethyl, A is oxygen and X is CONR<7> R<8>, we more Substituents selected from halogen, cyano, thiocyanato, refer then to (2S)-2-(2-oxo-1-piperidinyl)butanamide or azido, alkylthio, cycloalkyl, phenyl and acyl: (2S)-2-(2-oxo-1-azepanyl)butanamide derivatives. 1760 C2-6 alkynyl, each optionally substituted by one or 1743. According to one embodiment, the present inven more Substituents selected from halogen, cyano, thiocyanato, tion relates to a compound as defined above wherein R-2s azido, alkylthio, cycloalkyl, phenyl and acyl: when n=1, R3 and R-4 are the same or different and each 1761 heterocycle selected from tetrazolyl pyrrolidinyl, is independently hydrogen, halogen, nitro, nitrooxy, cyano, pyridyl, furyl, pyrrolyl, thiazolyl and thienyl, each optionally carboxy, amido, Sulfonic acid, Sulfonamide, alkyl, alkenyl, substituted by one or more substituents selected from halo alkynyl, ester, ether, aryl, heterocycle, acyl derivative, Sulfo gen, alkyl, halogen Substituted alkyl, acyl, alkoxy, nitro, nyl derivative or sulfinyl derivative: amino and phenyl: 1744) R-1 > when existent, R-2D when n=0 and R-5> are hydrogen; 1762 phenyl, each optionally substituted by one or more 1745 R<6> is hydrogen, alkyl, aryl or -CH2-R<6ad substituents selected from C1-6 alkyl, halogen substituted wherein R-6a is aryl, heterocycle, halogen, hydroxy, amino, alkyl, halogen, alkoxy, amino, azido, Sulfonyl, phenyl and nitro or cyano; nitro. 1763. According to another embodiment, the present 1746 provided that, when R-6> is hydrogen, X is invention relates to a compound as defined above wherein at —CONR<7>R<8> and that the compound is least one of the R substituents chosen from the group R-22, 1747 neither methyl (2R)-2-(6R)-6-methyl-2-oxoazepa R3> and R-4 when n=1 or from the group R3> and R-4D nyl-3-phenylpropanoate when n=0, represents independently C1-4-alkyl or C3-7-cy 1748 nor methyl (2S)-2-(4R)-4-methyl-2-oxoazepanyl cloalkyl, optionally Substituted by one or more halogen, 3-phenylpropanoate. hydroxy, lower alkyl and/or azido. 1749 According to this embodiment, the compound is 1764. According to another embodiment, the present generally such that when R-6> is benzyl, X is —COOCH3 invention relates to a compound as defined above wherein at and n=1, R-2 is different from methyl when R3> and least one of the R substituents chosen from the group R-22, R-4D are both hydrogen and R-4D is different from methyl R3> and R-4 when n=1 or from the group R3> and R-4D when R-2 and R3> are both hydrogen. when n=0, represents independently vinyl, optionally substi 1750. According to another embodiment, the present tuted by one or more halogen or/and lower alkyl. invention relates to a compound as defined above wherein 1765 According to another embodiment, the present R<2> when n=1, R3D and R-4D are the same or different invention relates to a compound as defined above wherein at and each is independently hydrogen; cyano; carboxy; amido; least one of the R substituents chosen from the group R-22, 1751 C1-12 alkyl, each optionally substituted by one or R3> and R-4D when n=1 or from the group R3 and R-4D more Substituents selected from hydroxy, halogen, cyano, when n=0, represents independently ethynyl, propynyl or thiocyanato, alkoxy, azido, alkyltio, cycloalkyl, acyl, aryland butynyl, optionally Substituted by one or more halogen and/or heterocycle; lower alkyl.

US 2011/0212928 A1 Sep. 1, 2011 69

1785. Where A=Y is either of a 2-oxo-piperidin-1-yland a 1789. In a specific embodiment R is hydrogen, methyl, 2-oxo-azepan-1-yl, R, R and Ra are all hydrogen, then R ethyl and R is hydrogen. In a specific embodiment R3 is could not be a 2-phenylimidazol-2-alpyridin-3-yl. CONH2. 1790. In a further specific embodiment R is 1H-imidazol 1786. In a specific embodiment A=Y is selected from the 1-yl, 1H-imidazol-4-yl, 1H-imidazol-5-yl, imidazo 1,2-a list consisting of: pyridin-3-yl or imidazol-2-bipyridazin-3-yl. In a specific embodiment Ra is a C I.g. alkyl which may optionally be Substituted by a halogen; or a phenyl. R4a R4a R4a 1791. In another specific embodiment R b is hydrogen, Y. X X halogen, nitro, cyano or a C-Lugalkyl optionally Substituted by a halogen. N X. O C.N O N AO 1792. In still a further embodiment compounds may be used in the treatment of the above mentioned disorders, in particular of epilepsy, having the formula (I-E), as wells as its Ra geometrical isomers, enantiomers, diastereomers and mix R4aJ. o : ClX tures, or a pharmaceutically acceptable salt thereof, R*- N R'l- N 21 O 2 N-CA,

RI ls R3 O R(s wherein X is O or S: 1793 R-I is hydrogen or C I.g. alkyl, in a more specific * \ / embodiment hydrogen; R3 is an imidazolyl, an imidazopyridinyl, an imidazopy so ridazinyl; R b is hydrogen; nitro; cyano; halogen; C I.g R alkyl optionally Substituted by halogen; C I.g. alkoxy { \ optionally substituted by halogen. 1794. A further aspect of the present invention consists in novel compounds having the formula (I-A), their geometrical o "S) X isomers, enantiomers, diastereomers and mixtures, or a phar N maceutically acceptable salt thereof, N O s (I-A) R4a V

N O N O S. X.O R4i. R4i. ls,

RayN O o N O wherein R1 is hydrogen or C I.g. alkyl, preferably hydrogen, methyl or ethyl; in a more specific embodiment R is ethyl. R3 is —CONH2, an imidazolyl, an imidazopyridinyl, an imidazopyridazinyl, preferably R is —CONH2. wherein X is O or S, in a more specific embodiment 0; in Ra is either hydrogen or an aryl; with the proviso that 2-(5- another embodiment, X is S. oxoimidazolidin-1-yl)acetamide is excluded. Preferably Ra 1787. The asterisks in the above illustration indicate the is an aryl, e.g. a phenyl which may be substituted preferably attachment sites of the substituent Ra. by halogen, nitro, alkoxy, in particular by nitro. 1788. In a specific embodiment, when R is CONR5R6 1795. In a particular embodiment, when R is CONH2 and R is C-lug alkyl, the carbon atom to which R—I and R and R is C—I.g. alkyl, the carbon atom to which R1 and R are attached is preferably in the “S”-configuration. are attached is preferably in the “S”-configuration. US 2011/0212928 A1 Sep. 1, 2011 70

1796. A further aspect of the present invention consists in halogen. Preferably, Ra is C—I.g. alkyl optionally substi novel compounds having the formula (I-B1 or I-B2), their tuted by halogen or C2 g alkenyl optionally Substituted by geometrical isomers, enantiomers, diastereomers and mix halogen. tures, or a pharmaceutically acceptable salt thereof, 1799. In a particular embodiment, when R is CONH2 and R is C—I.g. alkyl, the carbon atom to which R—I and R are attached is preferably in the “S”-configuration. (I-B1) 1800. A further aspect of the present invention consists in novel compounds having the formula (I-C), their geometrical isomers, enantiomers, diastereomers and mixtures, or a phar maceutically acceptable salt thereof,

(I-B2)

wherein R1 is hydrogen or C I.g. alkyl, in particular hydrogen, methyl or ethyl. wherein X informula (I-B2) is either S or O, in a more specific R3 is —CONH2, an imidazolyl, an imidazopyridinyl, an embodiment S; imidazopyridazinyl; in particular R is —CONH2 R1 is hydrogen or C I.g. alkyl, preferably hydrogen, methyl Ra is methyl, ethyl, butyl optionally substituted by halogen or ethyl; in a more specific embodiment R is ethyl. or C-1.4 alkoxy, an unsubstituted phenyl or a phenyl Substi R3 is —CONH2, an imidazolyl, an imidazopyridinyl, an tuted by halogen, a C-I.g. alkyl optionally substituted by imidazopyridazinyl; preferably R is —CONH2 halogen or a C-1.4 alkoxy; or Rais a C2-6 alkenyl optionally Ra is hydrogen; C I.g. alkyl optionally substituted by halo substituted by halogen. Preferably, Ra is methyl, optionally Substituted by halogen, an unsubstituted phenyl or a phenyl gen or C-1.4 alkoxy; an aryl; or C2.g. alkenyl optionally Substituted by halogen. substituted by halogen. Preferably, Ra is C—I.g. alkyl 1801. In a particular embodiment, when R is —CONH2 optionally substituted by halogen or C2-6 alkenyl optionally and R is C—I.g. alkyl, the carbon atom to which R1 and RB Substituted by halogen oran aryl. In a more specific embodi are attached is preferably in the “S”-configuration. ment Rais C—I.g. alkyl optionally substituted by halogen or 1802. A further aspect of the present invention consists in aryl. compounds having the formula (I-D1 or I-D2), their geo 1797. In a particular embodiment, when R is CONH2 metrical isomers, enantiomers, diastereomers and mixtures, and R is C—I.g. alkyl, the carbon atom to which R—I and R or a pharmaceutically acceptable salt thereof, are attached is preferably in the “S”-configuration. 1798. A further aspect of the present invention consists in (I-D1) novel compounds having the formula (I-B3), their geometri Ra cal isomers, enantiomers, diastereomers and mixtures, or a pharmaceutically acceptable salt thereof, Cl R1 1. R3 (I-D2) : :

wherein R1 is either hydrogen or C-ug alkyl, preferably hydrogen, methyl or ethyl; more preferably R1 is ethyl. wherein R3 is —CONH2, an imidazolyl, an imidazopyridinyl, an R—I is hydrogen or C I.g. alkyl, in particular hydrogen; R3 imidazopyridazinyl; preferably R is —CONH2 Ra is is an imidazolyl, an imidazopyridinyl or an imidazopyridazi C—I 5 alkyl optionally substituted by halogen or C-1.4 nyl. In one embodiment, R is 1H-imidazol-1-yl, 1H-imida alkoxy; an aryl; or C2 g alkenyl optionally substituted by Zol-4-yl, 1H-imidazol-5-yl, imidazo 1,2-alpyridin-3-yl or US 2011/0212928 A1 Sep. 1, 2011 imidazo 1.2-bipyridazin-3-yl. In a more specific embodi ment, R is 1H-imidazol-1-yl, 1H-imidazol-4-yl, 1H-imida Zol-5-yl, imidazol-2-alpyridin-3-yl; Ra is hydrogen, (I-F4) C I.g. alkyl optionally substituted by halogen or C-1.4 R alkoxy: aryl; or C2-galkenyl optionally substituted by halo { \ gen. In a specific embodiment, Ra is C—I.g. alkyl optionally substituted by halogen: aryl; or C2-6 alkenyl optionally sub stituted by halogen. In a more specific embodiment Ra is C I.g. alkyl optionally Substituted by halogen; or aryl; e.g., propyl or phenyl: N O with the proviso that when R and Ra are hydrogen, R is not 2-phenylimidazol-2-alpyridin-3-yl. s 1803. A further aspect of the present invention consists in compounds having the formula (I-F1, I-F2 or I-F3), their wherein geometrical isomers, enantiomers, diastereomers and mix R—I is hydrogen or C I.g. alkyl, preferably hydrogen; tures, or a pharmaceutically acceptable salt thereof, R3 is an imidazolyl, an imidazopyridinyl or an imidazopy ridazinyl: more specifically R is 1H-imidazol-1-yl, 1H-imi dazol-4-yl, 1H-imidazol-5-yl, imidazo[1,2-alpyridin-3-yl or imidazo[1,2-bipyridazin-3-yl. More specifically R is (I-F1) 1H-imidazol-4-yl or imidazo 1,2-alpyridin-3-yl. Rb is hydrogen; halogen; nitro; cyano: C-1.4 alkyl optionally substituted by halogen: C-1.4 alkoxy optionally substituted CO21 N O by halogen; specifically R is hydrogen, halogen or cyano. 1806. In a particular embodiment, when R is —CONH2 and R is C—I.g. alkyl, the carbon atom to which R—I and R RI 1. are attached is preferably in the “S”-configuration. 1807. A further aspect of the present invention consists in N compounds having either of the formula (I-G1, I-G2 or I-G3), their geometrical isomers, enantiomers, diastereomers and 21 mixtures, or a pharmaceutically acceptable salt thereof.

N O

(I-F3) 1s. Cly N O wherein R—I is hydrogen or C I.g. alkyl, preferably hydrogen, 1s, methyl or ethyl; more preferably, R is hydrogen. (I-G3) R3 is —CONH2, an imidazolyl, an imidazopyridinyl or an imidazopyridazinyl; in a more specific embodiment R3 is —CONH2, 1H-imidazol-1-yl, 1H-imidazol-4-yl, 1 H-imida Zol-5-yl, imidazol-2-alpyridin-3-yl or imidazo 1.2-bpy ridazin-3-yl. Rb is hydrogen; halogen; nitro; cyano; C1.4 alkyl optionally substituted by halogen; C-1.4 alkoxy option ally substituted by halogen. In a more specific embodiment R is hydrogen, halogen or cyano, more specifically halogen. wherein 1804. In a particular embodiment, when R is —CONH2 R—I is hydrogen or C I.g. alkyl; preferably hydrogen; and R is C—I.g. alkyl, the carbon atom to which R1 and RB R3 is —CONH2, an imidazolyl, an imidazopyridinyl, an are attached is preferably in the “S”-configuration. imidazopyridazinyl; in a more specific embodiment R is 1805. A further aspect of the present invention consists in —CONH2, 1H-imidazol-1-yl, 1H-imidazol-4-yl, 1 H-imida compounds having the formula (I-F4), their geometrical iso Zol-5-yl, imidazol-2-alpyridin-3-yl or imidazol-2-bpy mers, enantiomers, diastereomers and mixtures, or a pharma ridazin-3-yl. In a even more specific embodiment R3 is an ceutically acceptable salt thereof, 1H-imidazol-4-yl or imidazo 1,2-alpyridin-3-yl:

US 2011/0212928 A1 Sep. 1, 2011

1815 "C2-6 alkynyl refers to alkynyl groups preferably tic, hydroxyacetic, propanoic, lactic, pyruvic, malonic, suc having from 2 to 6 carbon atoms and having at least 1-2 sites cinic, maleic, fumaric, malic, tartaric, citric, methane of alkynyl unsaturation, preferred alkynyl groups include Sulfonic, ethanesulfonic, benzenesulfonic, p-toluenesulfonic, ethynyl ( C=CH), propargyl ( CH2C=CH), and the like. cyclamic, salicylic, p-aminosalicylic, pamoic and the like. 1816 “C3.8 cycloalkyl refers to a saturated carbocyclic 1831. The compounds of formula (I) containing acidic group of from 3 to 8 carbon atoms having a single ring (e.g., protons may be converted into their therapeutically active, cyclohexyl) or multiple condensed rings (e.g., norbornyl). non-toxic base addition salt forms, e.g. metal or amine salts, Preferred cycloalkyl include cyclopropyl, cyclobutyl, cyclo by treatment with appropriate organic and inorganic bases. pentyl, cyclohexyl, norbornyl and the like. Appropriate base salt forms include, for example, ammonium 1817) “Heterocycloalkyl” refers to a C3.8 cycloalkyl salts, alkali and earth alkaline metal salts, e.g. lithium, group according to the definition above, in which 1 to 3 Sodium, potassium, magnesium, calcium salts and the like, carbon atoms are replaced by hetero atoms chosen from the salts with organic bases, e.g. N-methyl-D-glucamine, hydra group consisting of O, S, NR, R being defined as hydrogen or bamine salts, and salts with amino acids such as, for example, C I.g. alkyl. arginine, lysine and the like. 1818 “Alkoxy” refers to the group -O-R where R 1832 Conversely said salt forms can be converted into the includes "C-lug alkyl, "C2-6 alkenyl', "C2-6 alkynyl', free forms by treatment with an appropriate base or acid. “C3.8 cycloalkyl, "heterocycloalkyl”, “aryl”, “heteroaryl'. 1833 Compounds of the formula (I) and their salts can be 1819 “Amino” refers to the group - NRR' where each R, in the form of a solvate, which is included within the scope of R" is independently hydrogen, “C I.g. alkyl, "C2-6 alk the present invention. Such solvates include for example enyl”, “C2-6 alkynyl', “C3-8 cycloalkyl, "heterocy hydrates, alcoholates and the like. cloalkyl”, “aryl', "heteroaryl', and where R and R', together 1834. Many of the compounds of formula (I) and some of with the nitrogenatom to which they are attached, can option their intermediates have at least one stereogenic center in ally form a 3-8-membered heterocycloalkyl ring. their structure. This stereogenic center may be present in a R 1820 “Amido” refers to the group –C(=O)NRR' where or a S configuration, said R and S notation is used in corre each R, R is independently hydrogen, “C I 5 alkyl, "C2-6 spondence with the rules described in Pure Appl. Chem. 45 alkenyl”, “C2-6 alkynyl”, “C3.8 cycloalkyl”, “heterocy (1976) 11-30. cloalkyl”, “aryl', 1835. The invention also relates to all stereoisomeric 1821) "heteroaryl', and where R and R', together with the forms such as enantiomeric and diastereoisomeric forms of nitrogenatom to which they are attached, can optionally form the compounds of formula (I) or mixtures thereof (including a 3-8-membered heterocycloalkyl ring. all possible mixtures of stereoisomers). With respect to the 1822 “Acylamino” refers to the group - NRC(O)R’ present invention reference to a compound or compounds is wherein R and R' are as defined hereabove for the amino intended to encompass that compound in each of its possible group. isomeric forms and mixtures thereof, unless the particular 1823 “Ureido” refers to the group - NR"C(O)NRR' isomeric form is referred to specifically. wherein R and R' are as defined hereabove for the amino 1836 Compounds according to the present invention may group, and R" is as defined hereabove. “Sulfanyl refers to the exist in different polymorphic forms. Although not explicitly group —SR where R is “C I.g. alkyl, "C2-6 alkenyl', indicated in the above formula, such forms are intended to be “C2-6 alkynyl”, “C3.8 cycloalkyl”, “heterocycloalkyl, included within the scope of the present invention. “aryl” or “heteroaryl'. 1837 Some of the compounds of formula (I) may also 1824) “Sulfinyl refers to the group—S(=O)R where Ris exist in tautomeric forms. Such forms although not explicity “C Ig alkyl”, “C2-6 alkenyl”, “C2-6 alkynyl”, “C3.8 indicated in the above formula are intended to be included cycloalkyl, "heterocycloalkyl”, “aryl” or "heteroaryl”. within the scope of the present invention. 1825 "Sulfonyl refers to the group - S(=O)2R where R 1838. The invention also includes within its scope pro is “C Ig alkyl”, “C2-6 alkenyl”, “C2-6 alkynyl”, “C3.8 drug forms of the compounds of formula (I) and its various cycloalkyl, "heterocycloalkyl”, “aryl” or "heteroaryl”. Sub-Scopes and Sub-groups. 1826 “Halogen refers to fluoro, chloro, bromo and iodo 1839. In a specific embodiment, the present invention con atOmS. cerns a compound selected from the group consisting of 1827 “Substituted or unsubstituted: Unless otherwise (2S)-2-3-(4-nitrophenyl)-5-oxoimidazolidin-1-yl)butana constrained by the definition of the individual substituent, the above set out groups, like “alkyl”, “alkenyl', 'alkynyl', mide; (2S)-2-3-(2,4-dinitrophenyl)-5-oxoimidazolidin-1- “aryland ylbutanamide; (2S)-2-(5-oxo-3-phenylimidazolidin-1-yl) 1828) "heteroaryl etc. groups can optionally be substi butanamide: 2-5-(iodomethyl)-2-oxo-1,3-oxazolidin-3-yl) tuted with from 1 to 5 substituents selected from the group butanamide: 2-(2-oxo-2,5-dihydro-1H-pyrrol-1-yl) consisting of “C Igalkyl, "C2-6 alkenyl', "C2-6 alkynyl', butanamide: 2-(2-oxo-4-phenyl-2,5-dihydro-1H-pyrrol-1- 1829 “cycloalkyl, "heterocycloalkyl, “amino', yl)butanamide: 2-(4-methyl-2-oxo-2,5-dihydro-1H-pyrrol “amido”, “acylamino”, “ureido”, “aryl”, “heteroaryl', 1-yl)butanamide; (+)-(2S)-2-(2-oxo-4-propyl-2,5-dihydro “alkoxy”, “halogen', cyano, hydroxy, mercapto, nitro, 1H-pyrrol-1-yl)butanamide; (2S)-2-(2-oxo-5-propyl-1,3- “amido”, “sulfanyl”, “sulfinyl', “sulfonyl and the like. thiazol-3(2H)-yl)butanamide: 2-(2-oxo-5-propyl-1,3- 1830. The acid addition salt form of a compound of for thiazol-3(2H)-yl)propanamide: 2-(5-butyl-2-oxo-1,3- mula (I) that occurs in its free form as a base can be obtained thiazolidin-3-yl)butanamide: 2-(5-butyl-2-oxo-1,3- by treating the free base with an appropriate acid Such as an thiazolidin-3-yl)propanamide; 2-(2-oxo-5-phenyl-1,3- inorganic acid, for example, a hydrohalic Such as hydrochlo thiazolidin-3-yl)propanamide; 2-(2-oxo-5-propyl-1,3- ric or hydrobromic, Sulfuric, nitric, phosphoric and the like; thiazolidin-3-yl)butanamide: 2-(2-oxo-5-phenyl-1,3- or an organic acid, Such as, for example, acetic, trifluoroace thiazolidin-3-yl)butanamide: 2-(2-oxo-5-propyl-1,3-

US 2011/0212928 A1 Sep. 1, 2011

temocaptril, trandolapril, piperidinyl-alkanoyl heterocyclic 1851. In additional embodiments, an AChE inhibitor is a compounds, N-benzyl-piperidine derivatives, 4-(1-benzylpi carbamate Such as physostigmine, neostigmine, or rivastig peridyl)-substituted fused quinoline derivatives, monoamine mine as non-limiting examples. Physostigmine, also known acridines and their derivatives, cyclic amide derivatives, car as 1,2,3.3a,8.8a-hexahydro-13a,8-trimethyl-, methylcar bonic acid derivatives, saliclate, obidoxime, trimedoxime, bamate (ester) or (3aS,8aR)-pyrrolo2,3-bindol-5-ol, is ref diacetyl monoxim, demecarium, icopezil (5,7-dihydro-3-(2- erenced by CAS number 57-47-6. It is a tertiary amine (1-(phenylmethyl)-4-piperidinyl)ethyl)-6H-pyrrolo(3.2-f)-1, capable of crossing the blood-brain barrier. 2-benzisoxazol-6-one), heptylphysostigmine, E-2020, Citi 1852 Neostigmine, or m-hydroxyphenyl)trimethyl-dim coline, Velnacrine maleate, Sulfonyl fluorides such as ethylcarbamate(ester) ammonium, is referenced by CAS methanesulfonyl fluoride (Moos and Hershenson, 1989) and number 59-99-4. phenylmethylsulfonyl fluoride (Ferris, 1990; Pope and 1853 Rivastigmine is also known as rivastigmine tartrate Padilla, 1990), huperzine B, miotine, suronacrine and its O (S)- N-Ethyl-N-methyl-3-1-(dimethylamino)ethyl maleate, 7-methoxytacrine, SM-10888 and its citrate, ENA phenyl carbamate hydrogen-(2R,3R)-tartrate or SDZ ENA 713, TAK-147, CP-118954, zifrosilone, (SR.9R)-5-(r- 713 or ENA 713. The reference for rivastigmine is CAS chloro-2-hydroxy-3-methoxybenzylidene-amino)-11-eth Registry Number 123441-03-2. lidene-7-methyl-1,2,5,6,9,10-hexahydro-5.9- 1854. In further embodiments, an AChE inhibitor is a car methanocyclooctabpyridin-2-one (ZT 1), stacofylline, SPH bamate phenanthrine derivative such as galantamine or its 1371, SPH 1373 and SPH 1375, tolserine, 1-(3-fluoroben hydrogen bromide form as non-limiting examples. Zyl)-4-(2-fluoro-5,6-dimethoxy-1-indanone-2-yl) methyl 1855 Galantamine is also known as (4aS,6R,8aS)-4-a.5, piperidine hydrochloride (ER 127528), thiatolserine, (-)-12 9,10,11,12-hexahydro-3-methoxy-11-methyl-6H-benzofuro amino-3-chloro-9-ethyl-6,7,10,11-tetrahydro-7, 11 (3a,3,2-ef)(2)benzazepin-6-ol and is often used in its hydro methanocyclooctablquinoline hydrochloride (huperine X), gen bromide form. Galantamine is referenced by CAS N,N-dimethylcarbamic acid 4-1 (S)-(methylamino)-3-(4-ni number 357-70-0. trophenoxy)propylphenyl ester hemifumarate (RS 1259), 1856. An AChE inhibitor may also be a piperidine deriva 2-2-(1-benzylpiperidin-4-yl)ethyl-2,3-dihydro-9-meth tive, such as donepezil as a non-limiting example. Donepezil oxy-1H-pyrrolo3,4-bduinolin-1-one hemifumerate (T82), is also known as 2,3-dihydro-5,6-dimethoxy-2-((1-(phenyl 1,3-dichloro-6,7,8,9,10,12-hexahydroazepino.2.1-b- methyl)-4-piperidinyl)methyl)-1H-inden-1-one, and is refer quinazoline (CI 1002), N-heptylcarbamic acid, 2.4a, 9-trim enced by CAS number 120014-06-4. ethyl-2,3,4,4a,9.9a-hexahydro-1,2-oxazino 6.5-bindol-6-yl 1857 Itopride may also be an AChE inhibitor for use in ester-L-tartrate (CHF 2060), 3-(2-1-(1,3-dioxolan-2-ylm embodiments disclosed herein. Itopride HCl is referenced by ethyl) piperidin-4-yl)ethyl)-3,4-dihydro-2H-1,3-benzox CAS Registry Number 122898-67-3. In one embodiment, a azine-2,4-dione hydrochloride (E 2030), N-10-(diethy total daily dose range for itopride HCl is from about 25 mg to lamino) decylcarbamic acid (3aS,8aR)-13a,8-trimethyl-1, about 1000 mg. or between about 100 mg to about 300 mg. In 2.3.3a,8.8a-hexahydropyrrolo2,3-bindol-5-yl ester (MF Some embodiments, the AChE inhibitor, or neurogenic agent, 247), 5-amino-6-chloro-4-hydroxy-3,4-dihydro-1H-thiopy is the N-oxide derivative of itopride, which is the primary rano-3,4-bduinoline (MF 8615), N-8-(cis-2,6-dimethyl human metabolite of itopride HC1. morpholin-4-yl) octylcarbamic acid (3aS,8aR)-1.3a.8-trim 1858. Another AChE inhibitor for use in the disclosed ethyl-1,2,3.3a,8.8a-hexahydropyrrolo2,3-bindol-5-yl ester embodiments is (-)-huperzine A, which is also referred to as L-bitartrate hydrate (MF 268), (-)N-(3-piperidinopropyl)-N- Hup.A and 1-amino-13-ethylidene-1'-methyl-6-aza-tricyclo demethylgalantamine (SPH 1286), N-propargyl-3Raminoin 7.3.1.02.7trideca-207),3,10-trien-5-one. It is referenced by dan-5-yl-ethyl methyl carbamate (TV 3326), cryptotanshi CAS number 1025 18-79-6. none, dihydrotanshinone I, and tanshinone I. 1859. A further embodiment of an ACHE inhibitor is 1846 Among the acetylcholinesterase inhibitors useful phenserine, the structure and synthesis of which is described for the methods and compositions of this invention are those in U.S. Pat. No. 6,495,700. compounds or agents as referred to in: 1860 Although galantamine is only an example of an 1847 i) U.S. Patent Application Publication No. acetylcholinesterase inhibitor for use in the present invention, 2008O103105 other acetylcholinesterase inhibitors may equally be used. 1848. In one embodiment, an AChe is metrifonate, which Examples of Such compounds include galantamine deriva is also known as metriphonate or trichlorfon or its active tives. Such as those compounds of formula (I): metabolite, 2,2-dimethyldichlorovinyl phosphate (or dichlo rvos or DDVP). Metrifonate is represented by the following formula: (CH3O)2-PO CHOH OC13. (I) 1849. Echothiophate is also known as ecothiopate, echothiophate iodide, phospholine iodide, (2-Mercaptoethyl) trimethylammonium S-ester with O,O'-diethylphospho rothioate, BRN 1794.025, ecothiopatum, or phospholine. Echothiophate is referenced by CAS Registry Number 6736 O3-4. 1850. In other embodiments, an ACHE inhibitor is an ami noacridine Such as tacrine or ipidacrine as non-limiting examples. Tacrine/COGNEXR (1,2,3,4-tetrahydro-9-ami noacridine hydrochloride) is also known as tetrahydroami noacridine or THA. Tacrine is referenced by CAS Registry Number 321-64-2. Ipidacrine is also known as Amiridin. US 2011/0212928 A1 Sep. 1, 2011 76 in which: 1861. In the compounds of formula (I) above, except the dotted line indicates that there is a single or double car where otherwise indicated, alkyl groups may be straight or bon-carbon bond; branched chain and preferably have from 1 to 10 carbon the two symbols R1 are the same as or different from each atoms, and examples of these include the methyl, ethyl, pro other and each represents a hydrogenatom, a hydroxy group, pyl, isopropyl, butyl, isobutyl, sec-butyl, t-butyl, pentyl, an alkyl group, an aryl group, an aralkyl group, a hydroxy hexyl, heptyl, octyl, nonyl and decyl groups. Alkoxy groups alkyl group, a thioalkyl group, a carboxyalkyl group, a car and other simple derivatives of the alkyl groups likewise boxyalkylamino group, an alkylamino group, an acyl group, preferably have from 1 to 10, more preferably from 1 to 6, a cyano group, a Sulphhydryl group, a C1-C6 alkoxy group, carbon atoms. an alkylthio group, an aryloxy group, an arylthio group, an aliphatic or aromatic carbamoyl group, an aralkoxy group, an 1862 Aryl and heterocyclic groups may be unsubstituted aralkylthio group, an aryloxymethyl group, an alkanoyloxy or they may be substituted by one or more substituents group, a hydroxyalkanoyloxy group, a benzoyloxy group, a selected from the groups and atoms defined for R3, provided benzoyloxy group Substituted by one or more groups R3, as that any R3 substituent may not itself be further substituted by defined below, or an aryloxycarbonyl group; a Substituted aryl or heterocyclic group. R2 represents a hydrogenatom, a C1-C6 alkyl group, a C2-C6 1863 Preferred halogen atoms are the fluorine, chlorine, alkenyl group (e.g. an allyl group), an aralkyl group, said bromine and iodine atoms. alkyl, alkenylandaralkyl groups being unsubstituted or being 1864 Preferred compounds of formula (I) are those in Substituted by at least one halogen atom, a cycloalkyl group, which the alkyl groups contain from 1 to 8, more preferably a hydroxy group, an alkoxy group, a nitro group, an amino from 1 to 6, carbon atoms, halogen atoms are fluorine, chlo group, an aminoalkyl group, an acylamino group, an aromatic rine or bromine atoms, aryl groups are the phenyl group or non-aromatic heterocyclic group (e.g. an C- or B-furyl (which may be substituted or unsubstituted, preferably group, an C- or B-thienyl group, an C- or B-thenyl group, a unsubstituted), cycloalkyl groups contain from 3 to 7 ring pyridyl group, a pyrazinyl group, or a pyrimidyl group), an carbon atoms (preferably cyclopropyl or cyclobutyl), acyl alkyl group Substituted by an aromatic heterocyclic group, an groups are lower (e.g. C2-C6 alkanoyl groups) and heterocy aryl group (e.g. a phenyl group), an aralkyl group, a cyano clic groups are aromatic and contain from 5 to 8 ring atoms group, an aroyl group, or a cycloalkylmethyl group; (e.g. the thienyl, furyl, pyridyl, pyrrolyl or pyrazinyl groups). the symbols R3 are the same as or different from each other 1865 Particularly preferred compounds for use in the and each represents a hydrogen atom, a hydroxy group, an present invention are those compounds of formula (II): alkyl group, an aryl group, an aralkyl group, a hydroxyalkyl group, a thioalkyl group, a Sulphhydryl group, a C1-C6 (II) alkoxy group, an aryloxy group, an arylthio group, an ORI aralkoxy group, an aralkylthio group, a nitro group, an amino group, an alkylamino group, an arylamino group, an aralky lamino group, a halogen atom or a trifluoromethyl group; the symbols R4 are the same as or different from each other O and each represents a hydrogen atom, a halogen atom, a trifluoromethyl group, or a C1-C4 alkyl group; the two sym R2O R4a bols R5 are the same as or different from each other and each 5 represents a hydrogen atom, or a hydroxymethyl group; N R6 represents a hydrogen atom or a C1-C6 alkyl group, or, V when the symbol R1 attached to the same carbon atom as R6 R3a represents a hydrogenatom, R6 represents a group of formula (Ia): where:

R'' and R* are the same as or different from each other and each represents a hydrogen atom, an acyl group (preferably a lower alkanoyl group, Such as an acetyl group) or a C1-C6 alkyl group (such as a methyl, ethyl, propyl or isopropyl group); R3a represents an alkyl, alkenyl or aralkyl group, any of which may be unsubstituted or substituted by one or more halogenatoms, or it represents a cycloalkyl, hydroxy, alkoxy, nitro, amino, aminoalkyl, acylamino, aromatic heterocyclic, aroyl, aroylalkyl or cyano group; and R4a represents a hydrogen or halogen atom; and pharmaceutically acceptable salts thereof, especially the hydrobromide, hydrochloride, methylsulphonate or methio where Ra represents a linking bond, and R1,R2, R3, R4, R5, dide. X and Y are as defined for formula (I); 1866. Of these compounds, we particularly prefer galan or R6 and the symbol R1 attached to the same carbonatom as tamine and its salts or donepezil and its salts, especially the R6 together represent a semicarbazone; halides, such as galantamine hydrobromide or donepezil X represents an oxygen atom or a group of formula - NR3. hydrochloride. where R3 is as defined above; 1867 Galantamine derivatives which may be used in the Y represents a nitrogen atom or a phosphorus atom; present invention include norgalantamine, norgalantamine and pharmaceutically acceptable salts thereof. derivatives and epigalantamine. US 2011/0212928 A1 Sep. 1, 2011 77

1868. Other compounds which may be used as the acetyl cholinesterase inhibitor include: physostigmine, tacrine and -continued tacrine analogues, fasciculin, metrifonate, heptyl-physostig mine, norpyridostigmine, norneostigmine, neostigmine, pyridostigmine, huperzine or a prodrug therefor, rivastigmine or a prodrug therefor, gossypol or phenserine, or a prodrug therefor. 1869. Another particularly preferred acetylcholinesterase inhibitoris donepezil and its salts, especially the halides, such as donepezil hydrochloride. 1870 ii) U.S. Patent Application Publication No. 20070275959 1871. In one embodiment, the invention is a carbamoyl ester having the following structure: rO NRR O wherein A is selected from the group consisting of an unsub stituted aryl, a substituted aryl, an unsubstituted heteroaryl and a substituted heteroaryl; and R1 and R2 are each, inde pendently or in combination, selected from the group consist ing of a hydrogen, an unsubstituted alkyl, a Substituted alkyl, an unsubstituted aralkyl, a substituted aralkyl, an unsubsti tuted heteroalkyl, a substituted heteroalkyl, an unsubstituted heteroaralkyl, a substituted heteroaralkyl, an unsubstituted aryl, a Substituted aryl, an unsubstituted heteroaryl, a Substi tuted heteroaryl, an unsubstituted cycloalkyl, a substituted (2) indicates text missing or illegible when filed cycloalkyl, an unsubstituted heterocycloalkyl and a Substi tuted heterocycloalkyl. 1872. In an additional embodiment, the invention is a car wherein R, R and Rare each, independently or in combi bamoyl ester selected from the group consisting of: nation, selected from the group consisting of a hydrogen, an unsubstituted alkyl, a substituted alkyl, an unsubstituted aralkyl, a Substituted aralkyl, an unsubstituted heteroalkyl, a substituted heteroalkyl, an unsubstituted heteroaralkyl, a sub (2) (p stituted heteroaralkyl, an unsubstituted aryl, a substituted (?) O N aryl, an unsubstituted heteroaryl, a Substituted heteroaryl, an NN n(?) unsubstituted cycloalkyl, a Substituted cycloalkyl, an unsub stituted heterocycloalkyl and a substituted heterocycloalkyl. (2) r 1873. In still another embodiment, the invention is a car R3 p bamoyl ester selected from the group consisting of: (2) G-7 "N1,No. R (3) Y NN O r N YR, R R3 O O N R (2) O O N -XN R N YR, / 1. (2) N O / US 2011/0212928 A1 Sep. 1, 2011 78

-continued R GE 1 O ty 1. r YR, R31 Y O J R wherein R is hydrogen or (C1-C6) alkyl; J is oxygen, sulfur o, or NR'; R is hydrogen or (C1-C4) alkyl; and Q is oxygen, o1N r YR, sulfur, NH, CHCH3, C(CH3)2, CH=CH-, or (CH2), O wherein is an integer from 1 to 3: y X is oxygen or Sulfur, R Y is -(CH2)m-, -CH=CH(CH2)n-, - NR<4)

1880) 5,7-dihydro-3-2-1-(2-methyl-4-thiazolemethyl)- 1895 h) An acetylcholinesterase inhibitor as inf) wherein 4-piperidinylethyl-6H-pyrrolo 4.5-f-1,2-benzisoxazol the alkyl group or groups of said carbonate or carbamate 6-one; groups comprise from 4 to 6 carbon atoms. 1881 3-2-1-(3-bromophenylmethyl)-4-piperidinyl 1896 i) An acetylcholinesterase inhibitor as ina) wherein ethyl-5,7-dihydro-6H-pyrrolo4.5-f-1,2-benzisoxazol said acetylcholinesterase inhibitor is selected from the group 6-one; consisting of analogs of galanthamine or lycoramine wherein 1882 3-2-1-(4-bromophenylmethyl)-4-piperidinyl the methoxy group thereof is replaced by an aryl carbamate or ethyl-5,7-dihydro-6H-pyrrolo4.5-f-1,2-benzisoxazol carbonate group wherein said aryl group is selected from 6-one; phenyl, naphthyl, substituted phenyl and substituted naphthyl 1883) 5,7-dihydro-3-3-1-(phenylmethyl)-4-piperidinyl groups wherein said Substituent is selected from alkyl and propyl-6H-pyrrolo4.5-f-1,2-benzisoxazol-6-one: alkoxy groups of from 1 to 6 carbon atoms, trifluoro methyl 1884 6,8-dihydro-3-2-1-(phenylmethyl)-4-piperidinyl groups and halo groups. ethyl-7H-pyrrolo5,4-g-1,2-benzisoxazal-7-one; and 1897 j) An acetylcholinesterase inhibitor as in b) wherein 1885 5,7-dihydro-3-3-1-(phenylmethyl)-4-piperidinyl said acetylcholinesterase inhibitor is selected from the group ethyl-6H-pyrrolo 4.5-f-1,2-benzisoxazol-6-one: consisting of analogs of galanthamine and lycoramine 1886. In some embodiments of the invention, the com wherein the hydroxy group thereof is replaced by an aryl pound of Formula 1 is 5,7-dihydro-3-3-1-(phenylmethyl)- carbamate or carbonate group wherein said aryl group is 4-piperidinylethyl-6H-pyrrolo4.5-f-1,2-benzisoxazol-6- selected from phenyl, naphthyl, substituted phenyl and sub OC. stituted naphthyl groups wherein said Substituent is selected 1887 iv) International Patent Application Publication No. from alkyl and alkoxy groups of from 1 to 6 carbon atoms, WO2OOO/O3O446 trifluoro methyl groups and halo groups. 1888 a). An acetylcholinesterase inhibitor selected from 1898 k) An acetylcholinesterase inhibitor as in b) wherein the group consisting of galanthamine, lycoramine and ana said acetylcholinesterase inhibitor is selected from the group logs of said compounds wherein the methoxy group thereofis consisting of galanthamine, lycoramine and analogs thereof replaced by another alkoxy group of from one to six carbon wherein the hydroxy group of such compounds is replaced by atoms, a hydroxy group, hydrogen, an alkanoyloxy group, a a hydrogen or alkoxy group of from one to six carbon atoms benzoyloxy or substituted benzoyloxy group, a carbonate or an acyl group of from one to seven carbon atoms. group or a carbamate group. 1899. 1) An acetylcholinesterase inhibitor as ina) wherein 1889 b) An acetylcholinesterase inhibitor is selected from said acetylcholinesterase inhibitor is selected from the group the group consisting of analogs of galanthamine and lyc consisting of analogs of galanthamine and lycoramine oramine wherein the hydroxy group of galanthamine or lyc wherein the hydroxy group of galanthamine or lycoramine is oramine is replaced by an alkoxy group of from one to six replaced by an alkoxy group of from one to six carbon atoms, carbonatoms, hydrogen, analkanoyloxy group, a benzoyloxy hydrogen, an alkanoyloxy group, a benzoyloxy or Substituted or Substituted benzoyloxy group, a carbonate group or a car benzoyloxy group, a carbonate group or a carbamate group. bamate group. 1900 v) International Patent Application Publication No. 1890, c) An acetylcholinesterase inhibitor is selected from WO2006/070394 the group consisting of analogs of galanthamine and lyc 1901. An AChEI that is a quinoline derivative represented oramine wherein the N-methyl group of galanthamine or by formula 1 and 2 below: lycoramine is replaced by hydrogen, alkyl, benzyl or a cyclo propylmethyl group or a substituted or unsubstituted benzoy loxy group. O 1891 d) An acetylcholinesterase inhibitor as ina) selected from the group consisting of galanthamine, lycoramine and , - R analogs thereof wherein the methoxy group of Such com O H pounds is replaced by a hydrogen, hydroxy oralkoxy group of N from two to six carbonatoms oran acyloxy group of from one to seven carbon atoms. 2 1892 e) An acetylcholinesterase inhibitor as ina) wherein N said acetylcholinesterase inhibitor is selected from the group consisting of analogs of galanthamine or lycoramine wherein 2 the methoxy group thereof is replaced by a mono or dialkyl O carbamate or carbonate group wherein the alkyl groups con tain from 1 to 8 carbon atoms |- R 1893 f) An acetylcholinesterase inhibitor as ine) wherein O H the alkyl group or groups of said carbonate or carbamate groups comprise from 4 to 6 carbon atoms 1894 g) An acetylcholinesterase inhibitor as ina) wherein said acetylcholinesterase inhibitor is selected from the group consisting of analogs of galanthamine or lycoramine wherein CR the hydroxy group thereof is replaced by a mono or dialkyl carbamate or carbonate group wherein the alkyl groups con tain from 1 to 8 carbon atoms. wherein Ri-alkyl, aryl; R2=H, alkyl, aralkyl. US 2011/0212928 A1 Sep. 1, 2011 80

1902. In one embodiment, substituted carbamic acid quinolinyl esters obtained are selected from the group con sisting of Ia. hexyl-carbamic acid quinolin-6-yl ester Ib. hep p-P tyl-carbamic acid quinolin-6-yl ester Ic. (2-chloro-phenyl)- B1 B4 carbamic acid quinolin-6-yl ester Id. (3-bromo-phenyl)- R carbamic acid quinolin-6-yl ester 2a. hexyl-carbamic acid 1,2,3,4-tetrahydro-quinolin-6-yl ester 2b. heptyl-carbamic -YG R \ / N acid 1.2.3,4-tetrahydro-quinolin-6-yl ester 2c. (3-bromo N phenyl)-carbamic acid 1.2.3,4-tetrahydro-quinolin-6-yl ester E R3, P y: O 2d. (2-chloro-phenyl)-carbamic acid 1.2.3,4-tetrahydro B7-B, quinolin-6-yl ester 2e. (4-chloro-3-trifluoromethyl-phenyl)- R4 carbamic acid 1.2.3,4-tetrahydro-quinolin-6-yl ester (2) 2f. (4-bromo-phenyl)-carbamic acid 1.2.3,4-tetrahydro s-Y quinolin-6-yl ester 2g. heptyl-carbamic acid 1-benzyl-1,2,3,4-tetrahydro-quino Ne-Y. lin-6-yl ester 2h. hexyl-carbamic acid 1-benzyl-1,2,3,4-tetrahydro-quino () lin-6-yl ester (2) indicates text missing or illegible when filed 2i. (2-chloro-phenyl)-carbamic acid 1-benzyl-1,2,3,4-tet rahydro-quinolin-6-yl ester 2. (3-bromo-phenyl)-carbamic L is independently selected from —C(R)(R")— —CO -0- acid 1-benzyl-1,2,3,4-tetrahydro-quinolin-6-yl ester or —NR - n is Zero, one, two, three, four, five, six, seven, 2k. (4-chloro-3-trifluoromethyl-phenyl)-carbamic acid eight, nine or ten R and R' are independently selected from 1-benzyl-1,2,3,4-tetrahydro-quinolin-6-yl ester hydrogen, alkyl, aryl, heteroaryl, halo, haloalkyl, alkoxy, 21. (4-bromo-phenyl)-carbamic acid 1-benzyl-1,2,3,4-tet hydroxyl, nitro and alkylthio D is independently selected rahydro-quinolin-6-yl ester 2m. hexyl-carbamic acid 1-me from —C(R9)-, =C , or—N—A1, A2, AS, A4, AS, A7, AS, thyl-1,2,3,4-tetrahydro-quinolin-6-yl ester 2n. heptyl-car B1, B2, Bs, B4, Bs, B6, B7, Bs, G and E are independently selected from —CO , —C(Rio)(Rn)- =C(Rio)-. bamic acid 1-methyl-1,2,3,4-tetrahydro-quinolin-6-yl ester - N(R12)- =N-, - O - S(O)t-Ri, R2, R3, R4, R9, Rio 2O. (2-chloro-phenyl)-carbamic acid 1-methyl-1,2,3,4-tet and Ril are independently selected from hydrogen, alkyl, rahydro-quinolin-6-yl ester 2p. (3-bromo-phenyl)-carbamic alkoxy, hydroxyl, alkylthio, cycloalkyl, haloalkyl, halo, aryl, acid 1-methyl-1,2,3,4-tetrahydro-quinolin-6-yl ester 2d. —(Z)n-, aryl, heteroaryl, - O(R7), C(O)R7, C(O)OR7, (4-chloro-3-trifluoromethyl-phenyl)-carbamic acid 1-me —S(O)t, cyano, nitro and mercapto, aryl Substituted by alkyl, thyl-1,2,3,4-tetrahydro-quinolin-6-yl ester 2r. (4-bromo-phe alkoxy, hydroxy, halo, haloalkyl, nitro or alkylthio; and het nyl)-carbamic acid 1-methyl-1,2,3,4-tetrahydro-quinolin-6- eroaryl Substituted by alkyl, alkoxy, hydroxy, halo, haloalkyl, nitro or alkylthio R5, R6, and R12 are independently selected yl ester from hydrogen, alkyl, alkoxy, hydroxyl, cycloalkyl, 1903. In one embodiment of the invention, when R1 is aryl haloalkyl, aryl, heteroaryl, aryl substituted by alkyl, alkoxy, it is selected from the group consisting of 2-chloro, 3-bromo, hydroxy, halo, haloalkyl, or alkylthio; and heteroaryl substi 4-bromo and 4-chloro-3-trifluoromethyl-phenyl. tuted by alkyl, alkoxy, hydroxy, halo, haloalkyl, nitro or alky 1904. In another embodiment of the invention, R2 is lthio Z is independently selected from —C(R7)(R8)- selected from the group consisting of methyl and benzyl. - C(O)-, -O-, - C(=NR7)-, -S(O)t, N (R7)-R7 and RS are independently selected from hydrogen, alkyl, alkoxy, 1905 vi) International Patent Application Publication No. alkylthio, cycloalkyl, haloalkyl, halo, aryl, heteroaryl, cyano, WO2004/032929 nitro, mercapto, aryl Substituted by alkyl, alkoxy, hydroxy, 1906 An embodiment is directed to the compounds rep halo, haloalkyl, nitro or alkylthio; and heteroaryl substituted resented by the general formula I by alkyl, alkoxy, hydroxy, halo, haloalkyl, nitro or alkylthiot is Zero, one or two. Formula I In general, we have the proviso that when X is:

B8 Bs A-A. v M wherein: X is one of the following radicals: US 2011/0212928 A1 Sep. 1, 2011

a) in no case each of the atoms in the groups A1-A4, AS-AS, 1911 “alkoxycarbonyl refers to a radical of formula B1-B4, and Bs-Bs are at the same time=C(Rio)-, and b) in no —C(O)CRa, where Ra is an alkyl radical as described above, case each of the atoms in one of the two groups A1-A4 and e.g. methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, AS-AS, and each of the atoms in one of the two groups B1-B4 etc. alkylthio “refers to a radical of formula—SRa, where Ra and is an alkyl radical as described above, e.g. methylthio, eth Bs-Bs are at the same time=C(Rio)-. ylthio, propylthio, etc. 1907. In a related aspect, the invention is directed to the 1912 “amino refers to a radical of formula-NH2 “aryl compounds within the formula (I) and represented by the refers to a phenyl or naphthyl radical. The aryl radical may general formula Ia and IIa. optionally be substituted by one or more substituents selected from among the group comprising hydroxy, mercapto, halo Formula Ia gens, alkyl, phenyl, alkoxy, haloalkyl, nitro, cyano, dialky

lamino, aminoalkyl, acyl and alkoxycarbonyl as they are defined here. 1913) “acyl refers to a radical of formula - C(O) Ra O and —C(O)—Rb, where Ra is an alkyl radical as described above and Rb is an aryl radical as described above, e.g. acetyl, R4a propionyl, benzoyl, and similar. H f N() 1914 "carboxy” refers to a radical of formula –C(O)OH le “cyano” refers to a radical of formula —CN “cycloalkyl refers to stable cycles of 3 to 10 monocyclic or bicyclic members that are saturated or partially saturated and consist Formula IIa exclusively of carbon and hydrogen atoms. This term also R3a includes cycloalkylo radicals, which may optionally be Sub or (2) stituted by one or more substituents chosen independently / from the group comprising alkyl, halogen, hydroxy, amino, \ / S-N cyano, nitro, alkoxy, carboxy and alkoxycarbonyl "halogens' refers to bromine, chlorine, iodine or fluorine “haloalkyl N NH OneNN N NO refers to an alkyl radical, as defined above, which is substi \ / tuted by one or more halogens, also as defined above, e.g. () trifluoromethyl, trichloromethyl, 2.2.2-trifluoroethyl, 1-fluo romethyl-2-fluoroethyl, and similar. (2) indicates text missing or illegible when filed 1915) "heterocycle” refers to a heterocyclic radical. The heterocycle refers to a stable cycle of 3 to 15 members com prising carbonatoms and one to five heteroatoms chosen from Where: X is —C(R1a) (R2a)-. —CO —O— or NR1a-; the group comprising nitrogen, oxygen and Sulphur. For the n is Zero, one, two, three, four, five, six, seven, eight, nine or purposes of this invention, the heterocycle may be a mono ten; cyclic, bicyclic or tricyclic system that may include fused R1a and R2a are independently selected from hydrogen, rings, and the nitrogen, carbon or Sulphur atoms may option alkyl, aryl, halo, haloalkyl; R3a, R4a and R5a are indepen ally be oxidised, the nitrogenatom may optionally be quater dently selected from hydrogen, alkyl, cycloaklyl, haloalkyl, nised, and the heterocycle may be partly or totally saturated or halo, aryl, —(Z) n-aryl, heteroaryl, OR3a, —C(O)R3a, aromatic. Examples of these heterocycles include, but are not —C(O)CR3a, S(O)t-; t is zero, one or two: Z is indepen limited to, azepines, benzimidazole, benzothiazole, furan, dently selected from C(R3a)(R4a)-. —C(O)— —O , isothiazole, imidazole, indole, piperidine, piperazine, purine, —C(=NR3a)-, -S(O)t-, N(R3a)-. quinoline, thiadiazole, tetrahydrofuran. The heterocycle may optionally be substituted by R3 and R4 as defined in the DEFINITIONS Summary of the invention. 1908 Invi), the following terms have the following mean 1916 “mercapto” refers to a radical of formula - SH ing: "alkyl refers to a straight-line or branched hydrocarbon "nitro' refers to a radical of formula —N02. chain comprising only atoms of carbon and hydrogen and 1917. In the chain-(L)n-(L)n-(L)n-(L)n-(L)n-, the or each containing no unsaturated bonds, having from one to eight group -(L)n- is preferably —(CH2)n- (where n is not Zero), carbon atoms and bound to the remainder of the molecule by a single bond, e.g. methyl, ethyl, n-propyl. i-propyl. n-butyl, CO. NH or NCH3 t-butyl, n-pentyl, etc. The alkyl radicals may optionally be 1918 Preferably there are at least one or two groups -(L)n- substituted by one or more substituents chosen independently where n is not zero. Suitably the chain is of the formula from the group comprising halogens, hydroxyl, alcoxides, —(CH2)n-, -(CH2)n-NRa—(CH2)n-, -(CH2)n-NRa— carboxy, cyano, carbonyl, acyl, alkoxycarbonyl, amino, nitro, CO-, -(CH2)n-NRa-CO-(CH2)n- or -(CH2)n- mercapto and alkylthio. NRa—(CH2)n-NRa—CO , where the or each n is not zero, 1909 Preferably, alkyl is C1-C6 alkyl. and the or each Ra is NH or —NCHs—, usually prefer 1910) “alkoxy” refers to a radical of formula – ORa, ably NH-. where Rais an alkyl radical as described above, e.g. methoxy, 1919. The total for the sum of the n integers is preferably ethoxy, propoxy, etc. in the range 2 to 15. US 2011/0212928 A1 Sep. 1, 2011

1920. In the formula: heptylaminol-methyl-indan-1-one (1), and 5,6-Dimethoxy 2-6-(1,2,3,4-tetrahydro-acridin-9-ylamino)-hexylaminol methyl-indan-1-one (2) A - A 1927. From those compounds in which X is represented by A V Al A4 the following formula:

each A group (that it, A1 to As) is preferably —CH or Bs Bs —CH2-, though one or both of A2 and A7 can be halo, w W especially chloro, when the remaining A groups are=CH-. Some AChEIs are those in which X is represented by the following formula: each B group (that it, Bi to Bs) is preferably —CH or —CH2-, though one or both of B2 and B7 can be halo, especially chloro, when the remaining B groups are=CH-. Some compounds are those in which X is 9-acridinyl, 6-chloro-1,2,3,4-tetrahydro-acridin-9-yl and 1,2,3,4-tetrahy dro-acridin-9-yl. Within these compounds are those in which the cyclic part of formula I represents: 9-acridinyl, 6-chloro 1,2,3,4-tetrahydro-acridin-9-ylor 1,2,3,4-tetrahydro-acridin 9-yl; within these compounds are included, among others, the following compounds: —N-2-(6-Chloro-1,2,3,4,4a,9a hexahydro-acridin-9-ylamino)-ethyl-N'-(6-chloro-1,2,3,4- tetrahydro-acridin-9-yl)-N-methyl-ethane-1,2-diamine (19), 1921 Preferably D is CH-, =C- or - N - Prefer —N-Acridin-9-yl-N'-(1,2,3,4-tetrahydro-acridin-9-yl)- ably E is —CO , —CH2-. nonane-1,9-diamine (20) - N-Acridin-9-yl-N2-(1,2,3,4,4a, 1922 —CH , —N O— or - S - Preferably G is 9a-hexahydro-acridin-9-ylamino)-ethyl-N'-methyl-ethane —CO—, —CH2-. —CH-, or—N—. 1,2-diamine (21), —N-2-(Acridin-9-ylamino)-ethyl-N'-(6- 1923 Preferably Rito R4 are hydrogen. chloro-1,2,3,4-tetrahydro-acridin-9-yl)-N-methyl-ethane-1, 1924. In some embodiments, within these compounds are 2-diamine (22), —N-Acridin-9-yl-N'-(6-chloro-1,2,3,4- those in which X is: phthalimidyl (1,3-dioxo-1,3-dihydro tetrahydro-acridin-9-yl)-heptane-1,7-diamine (23), and isoindol-2-yl), indol-2-yl, indanon-2-yl, benzimidazol-2-yl, —N-Acridin-9-yl-N'-(6-chloro-1,2,3,4-tetrahydro-acridin indandion-2-yl, indazol-2-yl, benzofuran-2-yl, ben 9-yl)-octane-1,8-diamine (24). Zothiophen-2-yl or benzotriazol-2-yl. 1928. From those compounds in which X is represented by 1925. In some embodiments are those in which X is the following formula: phthalimide (1,3-dioxo-1,3-dihydro-isoindol-2-yl) and the cyclic part of formula I represents 9-acridinyl, 1,2,3,4-tet rahydro-acridin-9-yl or 6-chloro, 1,2,3,4-tetrahydro-acridin 9-yl. Some compounds are: 2-6-(acridin-9-ylamino)-hexyl isoindole-1,3-dione (6), 2-7-(acridin-9-ylamino)-heptyl isoindole-1,3-dione (7), 2-8-(acridin-9-ylamino)-octyl isoindole-1,3-dione (8), 2-9-(acridin-9-ylamino)-nonyl isoindole-1,3-dione (9), N-7-(6-Chloro-1,2,3,4-tetrahydro acridin-9-ylamino)-heptyl-2-(1,3-dioxo-1,3-dihydro isoindol-2-yl)-acetamide (10), N-(3-3-(6-Chloro-1,2,3,4- tetrahydro-acridin-9-ylamino)-propyl-methyl-amino the groups R5 and R6 are suitably alkyl or substituted alkyl, propyl)-2-(1,3-dioxo-1,3-dihydro-isoindol-2-yl)-acetamide notably alkoxycarbonylalkyl. The preferred compounds are (11), N-6-(6-Chloro-1,2,3,4-tetrahydro-acridin-9-ylamino)- those in which the cyclic part of formula I represents: hexyl)-2-(1,3-dioxo-1,3-dihydro-isoindol-2-yl)-acetamide 9-acridinyl, 6-chloro, 1,2,3,4-tetrahydro-acridin-9-yl or 1.2, (12), 2-6-(1,2,3,4-Tetrahydro-acridin-9-ylamino)-hexy 3,4-tetrahydro-acridin-9-yl; within these compounds are lamino-indan-1,3-dione (3), 2-7-(1,2,3,4-Tetrahydro-acri included, among others, the following compounds: 2-Ethyl din-9-ylamino)-heptyl-isoindole-1,3-dione (4), and 2-8-(1, 4-isopropyl-5-7-(1,2,3,4-tetrahydro-acridin-9-ylamino)- 2,3,4-Tetrahydro-acridin-9-ylamino)-octyl-isoindole-1,3- heptyl-iminio-1,2,4thiadiazolidin-3-one (13), -2-Ethyl-4- dione (5). isopropyl-5-9-(1,2,3,4-tetrahydro-acridin-9-ylamino)- 1926. Some compounds are those in which X is 1-in nonyl-iminio-1,2,4thiadiazolidin-3-one (14), 4-isopropyl danon-2-yl and the cyclic part of formula I represents 1.2.3, 3-oxo-5-9-(1,2,3,4-tetrahydro-acridin-9-ylamino)-nonyl 4-tetrahydro-acridin-9yl; within these compounds are iminio-1,2,4thiadiazolidine-2-carboxylic acid ethyl ester included, among others, the following compounds: 5.6- (15), 4-Ethyl-2-propyl-5-7-(1,2,3,4-tetrahydro-acridin-9- Dimethoxy-2-7-(1,2,3,4-tetrahydro-acridin-9-ylamino)- ylamino)-heptyl-imino-1,2,4thiadiazolidin-3-one (16),