US 2009029 1988A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2009/0291988 A1 Oballa (43) Pub. Date: Nov. 26, 2009

(54) REVERSIBLE INHIBITORS OF MONOAMINE Publication Classification OXDASEAAND B (51) Int. Cl. A6II 3/165. (2006.01) (76) Inventor: Renata Oballa, Kirkland (CA) CD7C 255/46 (2006.01) CD7C 235/34 (2006.01) C07C 237/24 (2006.01) Correspondence Address: C07D 213/56 (2006.01) MERCK AND CO., INC C07C 2 II/27 (2006.01) PO BOX 2000 A 6LX 3L/275 (2006.01) RAHWAY, NJ 07065-0907 (US) A6II 3/448 (2006.01) A63/37 (2006.01) A6IP 25/00 (2006.01) (21) Appl. No.: 11/922,120 (52) U.S. Cl...... 514/357; 558/410; 564/171.564/164: 546/337; 564/442: 514/646; 514/622; 514/620 (22) PCT Fled: Jun. 14, 2006 (57) ABSTRACT The instant invention relates to compounds of formula I, (86). PCT No.: PCTFCAO6/OO981 diagrammed below, wherein R3, E, D Ey. are defined in the application, which are useful as reversible inhibitors of S371 (c)(1), monoamine oxidase-B and/or monoamine oxidase-A, and (2), (4) Date: Dec. 13, 2007 therefore useful to treat or prevent neurological diseases or conditions in mammals, preferably humans. Related U.S. Application Data (I) (60) Provisional application No. 60/690,411, filed on Jun. -n1 14, 2005. US 2009/029 1988 A1 Nov. 26, 2009

REVERSIBLE INHIBITORS OF MONOAMINE haloalkyl, arylalkyl and heteroarylalkyl groups are optionally OXIDASEAAND B substituted with one to six halo: or R' and R can be taken together with the carbon atom to BACKGROUND OF THE INVENTION which they are attached to form a Cs cycloalkyl ring which is optionally substituted with one to six halo: 0001. The catecholamine-oxidizing enzyme monoamine D is aryl, heteroaryl, C.s cycloalkyl or heterocyclyl wherein oxidase-B (MAO-B) has been hypothesized to be an impor each said aryl, heteroaryl, cycloalkyl and heterocyclyl tant determining factor in neurological disorders such as Par groups, which may be monocyclic or bicyclic, is optionally kinson's disease. MAO-B regulates levels of brain neu substituted on either the carbon or the heteroatom with one to rotransmitters, including dopamine. Catalysis of five substituents independently selected from the group con neurotransmitters by monamine oxidase also produces sisting of C alkyl, haloalkyl, halo or cyano; hydrogen peroxide which is a primary originator of oxidative E is aryl, heteroaryl, Css cycloalkyl or heterocyclyl wherein stress which in turn can lead to cellular damage. Inhibition of each said aryl, heteroaryl, cycloalkyl and heterocyclyl MAO-B, along with supplementation of dopamine via groups, which may be monocyclic or bicyclic, is optionally levodopa, is one of the major antiparkinsonian therapies cur substituted on either the carbon or the heteroatom with one to rently in use. Current MAO-B inhibitors (propargylamines) five substituents independently selected from the group con are irreversible an have also been shown to bind to GAPDH. sisting of C alkyl, haloalkyl, halo or cyano; 0002 Inhibitors of monoamine oxidase-A (MAO-A) are R is hydrogen, Co alkyl, Coalkenyl, C2-alkynyl, C useful for the treatment of depression and anxiety as MAO-A alkyloxy, halo, nitro, cyano, aryl, heteroaryl, Cs cycloalkyl, predominantly metabolizes neurotransmitters considered to heterocyclyl, -C(O)CR,-C(O)OSICH(CH), OR, be important in these disorders. MAO-A inhibitors may also OR, C(O)R, RC(O)R, C(O)R, C(O)N(R) be useful for the treatment of panic disorder, obsessive-com (R), C(O)N(R)(R7), C(O)N(R)(R), C(R)(R) pulsive disorder and post-traumatic stress disorder. Revers OH, SR', SR, RSR, R, C(R), C(R)(R) ible monoamine oxidase A inhibitors such as moclobamide N(R), NRC(O)NRS(O).R., SOR, SO(R7), are useful for the treatment of depression and anxiety and - SOR, SON(R)(R), SOCH(R)(R), SON have a lower propensity to cause hypertension than irrevers (R)C(O)(R7), -SO.(R)C(O)N(R7), OSOR, N(R) ible MAO-A inhibitors. (R), N(R)C(O)N(R)(R), N(R)C(O)R, N(R)C (O)R, N(R)C(O)OR, N(R)SO.(R), C(R)(R) SUMMARY OF THE INVENTION NRC(R)(R)R, C(R)(R)N(R)R, C(R)(R)N(R) (R), C(R)(R)SC(R)(R)(R), RS C(R)(R) 0003. The instant invention relates to compounds which NRC(R)(R)(R), C(R)(R)N(R)(R), C(R)(R)C are useful as reversible inhibitors of MAO-B and/or MAO-A. (R)(R)N(R)(R), C(O)C(R)(R)N(R)(R), C(R) One embodiment of the present invention is illustrated by a (R)N(R)C(O)R, C(O)C(R)(R)S(R), C(R)(R)C(O) compound of Formula I, and the pharmaceutically acceptable N(R)(R), C(R)(R)C(O)OH, - B(OH), OCHO or salts, esters, stereoisomers and N-oxide derivatives thereof: 4.4.5.5-tetramethyl-1,3,2-dioxaborolan-2-yl; wherein said alkyl, alkenyl, alkynyl, alkyloxy, aryl, heteroaryl, cycloalkyl and heterocyclyl groups are optionally Substituted on either the carbon or the heteroatom with one to five substituents -n1 independently selected from C alkyl, halo, keto, cyano, haloalkyl, hydroxyalkyl, OR, NO, NH, -NHS(O) R., RSOR7, SOR7, SO(R7), SR 7, SR, DETAILED DESCRIPTION OF THE INVENTION - SON(R)(R), SON(R)C(O)(R7), C(R)(R)N (R)(R), C(R)(R)OH, COOH, C(R)(R)C(O)N 0004. The present invention relates to compounds of the (R)(R), C(O)(R)(R), C(O)NH, C(O)NHR'. following formula: N(R)C(R)(R)(R), N(R)CO(R), NH(CH),OH, NHC(O)OR, Si(CH), heterocycyl, aryl, or het eroaryl; R" is hydrogen, aryl, aryl(C) alkyl, heteroaryl, heteroaryl 1n 1 (C)alkyl, C-scycloalkyl, C-scycloalkyl (Cl)alkyl or het erocyclyl (Cl)alkyl wherein said groups are optionally Sub wherein Y is hydrogen, C(R')(R)X, C(O)R', C(O)R’, C(O) stituted with one, two, or three substituents independently OR', CH(OH)R’, (Calkyl)C(O)CR'ROH, (Calkyl) selected from halo, alkoxy or - SOR: CR'ROH, (Calkyl)OH, SOR, C alkyl, aryl, het R is hydrogen or C. alkyl; eroaryl, Css cycloalkyl or heterocyclyl wherein each said R is hydrogen or C. alkyl; aryl, heteroaryl, cycloalkyl and heterocyclyl groups, which R’ is hydrogen or C alkyl which is optionally substituted may be monocyclic or bicyclic, is optionally substituted on with one, two, or three substituents independently selected either the carbon or the heteroatom with one to five substitu from halo, alkoxy, cyano, NR or - SR; ents independently selected from C alkyl, halo, cyano or R" is hydrogen, C alkyl, (C. alkyl)aryl, (Calkyl)hy hydroxyl: droxyl. —O(C-alkyl), hydroxyl, halo, aryl, heteroaryl, Cs X is hydrogen, NH or OH: cycloalkyl or heterocyclyl, wherein said alkyl, aryl, het R" is hydrogen or C, alkyl which is optionally substituted eroaryl, cycloalkyl and heterocyclyl groups are optionally with one to six halo, hydroxyl, O(C- alkyl) or carbonyl: substituted on either the carbon or the heteroatom with one, R is hydrogen, C. alkyl, aryl, heteroaryl, arylalkyl, het two, or three Substituents independently selected from C. eroarylalkyl or hydroxyl wherein said alkyl, aryl, heteroaryl, alkyl or halo: US 2009/029 1988 A1 Nov. 26, 2009

R’ is hydrogen, C. alkyl, (C. alkyl)aryl, (C- alkyl)hy 0023. 1-4-(1-amino-2,2-difluoroethyl)biphenyl-4-yl)cy droxyl. —O(C-alkyl), hydroxyl, halo, aryl, heteroaryl, Cs clopropanecarboxylic acid; cycloalkyl or heterocyclyl, wherein said alkyl, aryl, het 0024 2-4-2,2-difluoro-1-hydroxyethyl)-2-fluorobiphe eroaryl, cycloalkyl and heterocyclyl groups are optionally nyl-4-yl)acetamide: substituted on either the carbon or the heteroatom with one, 0025 2.2-difluoro-1-4-(4-methyl-1,3-thiazol-2-yl)phe two, or three substituents independently selected from C. nylethanol: alkyl or halo: 0026 1-4'-(2,2-difluoro-1-hydroxyethyl)biphenyl-4-yl)- or R and R' can be taken together with the carbon atom to 2-methylpropan-2-ol; which they are attached or are between them to form a Cs 0027 1-6-4-(2,2-difluoro-1-hydroxyethyl)phenylpyri cycloalkyl ring or Cls heterocyclyl ring wherein said 3-8 din-3-yl)cyclopropanol: membered ring system may be optionally Substituted with 0028 1-4 (2,2-difluoro-1-hydroxyethyl)-2-fluorobiphe one or two Substituents independently selected from C. nyl-4-yl)cyclopropanol: alkyl and halo; 0029 (1R)-1-4'-(1S)-1-amino-2,2,2-trifluoroethylbi each m is independently selected from an integer from Zero to phenyl-4-yl)-2,2-difluoroethanol: two: 0030) 2-4'-(2,2-difluoro-1-hydroxyethyl)-2-fluorobiphe or a pharmaceutically acceptable salt, Stereoisomer or N-ox nyl-4-yl)-2-methylpropanamide; ide derivative thereof. 0031 2-4(1-amino-2,2-difluoroethyl)-2-fluorobiphe 0005. In a class of the invention, X is OH or hydrogen. nyl-4-yl)-2-methylpropanamide; 0006. In a class of the invention, D is aryl. 0032 2-2-fluoro-4'-(1R)-2,2,2-trifluoro-1-hydroxy 0007. In a class of the invention, E is aryl or heteroaryl, ethylbiphenyl-4-yl)-2-methylpropanamide; wherein said aryl or heteroaryl group is optionally substituted 0033 1-4'-(2,2-difluoro-1-hydroxyethyl)biphenyl-4-yl) on either the carbon or the heteroatom with one to five sub cyclopropanecarboxamide; stituents independently selected from C alkyl, haloalkyl or 0034). 1-4-6-(2,2,2-trifluoro-1-hydroxyethyl)pyridin-3- halo. yl)phenyl)cyclopropanecarboxamide: 0008. In a class of the invention, R is hydrogen or C. 0035 1-(3-fluoro-4-6-(2.2.2-trifluoro-1-hydroxyethyl) alkyl which is optionally substituted with one to three fluoro. pyridin-3-ylphenyl)cyclopropanecarboxamide; In a subclass of the invention, R' is hydrogen or Cls alkyl. 0036) 1-biphenyl-4-yl-2.2.2-trifluoroethanol: 0009. In a class of the invention, R is hydrogen or C. 0037 (1-biphenyl-4-yl-2.2.2-trifluoroethyl)amine: alkyl. I0038 2,2-difluoro-1-4'-(1R)-2.2.2-trifluoro-1-hy 0010. In a class of the invention, R is hydrogen, C. droxyethylbiphenyl-4-yl)ethanone; alkyl, Cs cycloalkyl, -C(O)R. —C(R)(R)OH, 0039) 1-4'-(1S)-1-amino-2,2,2-trifluoroethylbiphenyl SOR, C(R)(R)C(O)N(R)(R') or C(R)(R)C(O)OH, 4-yl)-2,2-difluoroethanone; wherein said alkyl or cycloallyl groups are optionally Substi 0040 1,1-difluoro-2-4'-[(1R)-2.2.2-trifluoro-1-hy tuted on either the carbon or the heteroatom with one to five droxyethylbiphenyl-4-yl)propan-2-ol; Substituents independently selected from C alkyl, cyano, 0041) 2-4'-(1S)-1-amino-2,2,2-trifluoroethylbiphenyl halo, C(O)NH2 or —OR". In a subclass of the invention, R 4-yl)-1,1-difluoropropan-2-ol; is Cls cycloalkyl which is optionally substituted with cyano. 0042. 1-4'-(2,2-difluoro-1-hydroxyethyl)-2-fluorobiphe In a further subclass of the invention, R is cyclopropanecar nyl-4-yl)cyclopropanecarbonitrile; bonitrile. 0043. 1-4'-(2,2-difluoro-1-hydroxyethyl)-2-fluorobiphe 0011 Reference to the preferred embodiments set forth nyl-4-yl)cyclopropanecarboxamide above is meant to include all combinations of particular and 0044) 2,2-difluoro-1-4-(methylsulfonyl)biphenyl-4-yl) preferred groups unless stated otherwise. ethanol: 0012 Specific embodiments of the present invention 0045 2.2.2-trifluoro-1-4-(methylsulfonyl)biphenyl-4- include, but are not limited to: yl)ethane-1,1-diol; 0013 1-4"-(1-amino-2,2-difluoroethyl)biphenyl-4-yl) 0046) 1-(4-bromophenyl)-2,2-difluoroethanone; cyclopropanecarboxamide: 0047 N-cyclopropyl-1-4'-(2,2-difluoro-1-hydroxy 0014 1-4'-(1S)-1-amino-2,2-difluoroethylbiphenyl-4- ethyl)-2-fluorobiphenyl-4-yl)cyclopropanecarboxamide; yl)-N-cyclopropylcyclopropanecarboxamide: 0048 1-4-(1-amino-2,2-difluoroethyl)-2-fluorobiphe 0015 1-4'-(1S)-1-amino-2,2,2-trifluoroethyl)-2-fluoro nyl-4-yl)-N-cyclopropylcyclopropanecarboxamide: biphenyl-4-yl)cyclopropanecarboxamide; 0049 1-(4-bromophenyl)-2,2-difluoroethanol: 0016 1-2-fluoro-4'-(1R)-2.2.2-trifluoro-1-hydroxy 0050. 1-4'-(1R)-1-amino-2,2,2-trifluoro-1-methyl ethylbiphenyl-4-yl)cyclopropanecarboxamide: ethylbiphenyl-4-yl)cyclopropanecarboxamide; 0017 1-4'-(1S)-2,2-difluoro-1-hydroxyethylbiphenyl 0051 1-4'-(2.2.2-trifluoro-1-hydroxy-1-methylethyl)bi 4-yl)cyclopropanecarboxamide: phenyl-4-yl)cyclopropanecarboxamide; 0018 1-4'-(1R)-2,2-difluoro-1-hydroxyethylbiphenyl 0052 1-4'-(2,4-difluorophenyl)(hydroxy)methylbi 4-yl)cyclopropanecarboxamide: phenyl-4-yl)cyclopropanecarboxamide: 0019 1-4'-(1-amino-2,2-difluoroethyl)-2-fluorobiphe 0053 1-4'-amino(2,4-difluorophenyl)methylbiphenyl nyl-4-yl)cyclopropanecarboxamide; 4-yl)cyclopropanecarboxamide: 0020) 2-4'-(1R)-2.2.2-trifluoro-1-hydroxyethylbiphe 0054 1-4'-(2,2-difluoro-1-hydroxyethyl)-3'-fluorobi nyl-4-yl)propanoic acid; phenyl-4-yl)cyclopropanecarboxamide; 0021 (2S)-2-4'-[(1R)-2,2,2-trifluoro-1-hydroxyethyl 0055 (1R)-1-4'-(2,2-difluoro-1-hydroxyethyl)biphenyl biphenyl-4-yl)propanoic acid; 4-yl)-2.2.2-trifluoroethanol: 0022 (2S)-2-4'-[(1R)-2,2,2-trifluoro-1-hydroxyethyl 0056 1-4'-(1S)-1-amino-2,2,2-trifluoroethylbiphenyl biphenyl-4-yl)propanamide; 4-yl)-2,2-difluoroethanol:

US 2009/029 1988 A1 Nov. 26, 2009

0122 1-4'-(1-hydroxy-1-methylethyl)biphenyl-4-yl) nus, tics, dystonia, obesity, bulimia nervosa, compulsive eat ethanone; ing disorders, eating disorders associated with excessive food 0123 2-(1,1':4'1"-terphenyl-4-yl)propan-2-ol; intake, osteoarthritis, repetitive motion pain, dental pain, can 0.124 2-(1,1':2", 1"-terphenyl-4-yl)propan-2-ol; cer pain, myofascial pain, perioperative pain, chronic pain, 0.125 2-(1,1':3", 1"-terphenyl-4-yl)propan-2-ol; neuropathic pain, post-traumatic pain, trigeminal neuralgia, 0126 2-4-(methylsulfonyl)biphenyl-4-yl)propan-2-ol; migraine, attention-deficit hyperactivity disorder, conduct 0127 1-4'-(1-hydroxy-1-methylethyl)biphenyl-3-yl)cy disorder, muscular spasms, urinary incontinence, amyo clopropanecarbonitrile; trophic lateral Sclerosis, neuronal damage, ocular damage, 0128 2,2'-biphenyl-4,4'-diyldipropan-2-ol; retinopathy, macular degeneration of the eye, hearing loss, 0129 2-3'-(methylsulfonyl)biphenyl-4-yl)propan-2-ol; tinnitus, emesis, brain edema or sleep disorders. 0130 1-2-fluoro-4'-(1-hydroxy-1-methylethyl)biphe (0145 An embodiment of the invention is a method of nyl-4-yl)cyclopropanecarboxylic acid; inhibiting MAO-A activity in a mammal in need thereof, I0131 2-4-(methylsulfonyl)methylbiphenyl-4- comprising administering to the mammal a therapeutically yl)propan-2-ol; effective amount of any of the compounds or any of the 0132) 1-4'-(1-hydroxy-1-methylethyl)biphenyl-4-yl)cy pharmaceutical compositions described above. clopropanecarboxamide; 014.6 Another embodiment of the invention is a method of 0.133 1-2-fluoro-4'-(1-hydroxy-1-methylethyl)biphe inhibiting MAO-B activity in a mammal in need thereof, nyl-4-yl)methanesulfonamide: comprising administering to the mammal a therapeutically I0134 1-6-4-(1-hydroxy-1-methylethyl)phenylpyridin effective amount of any of the compounds or any of the 3-yl)cyclopropanecarbonitrile; pharmaceutical compositions described above. 0135 1-4'-(1-hydroxy-1-methylethyl)biphenyl-3-yl)cy 0147 Another embodiment of the invention is a method of clopropanecarboxamide; inhibiting MAO-A and/or B activity in a mammal in need 0136. 2-(4-pyridin-3-ylbiphenyl-4-yl)propan-2-ol; thereof, comprising administering to the mammal atherapeu 0.137 3-4-(1-hydroxy-1-methylethyl)phenylquinoline tically effective amount of any of the compounds or any of the 2-carbonitrile; pharmaceutical compositions described above. 0138 1-4'-(1-hydroxy-1-methylethyl)biphenyl-4-yl)-N- 0.148. Another embodiment of the invention is a method of methylcyclopropanecarboxamide: treating or preventing mood disorders, depression, bipolar I0139 (1-4'-(1-hydroxy-1-methylethyl)biphenyl-4-yl) disorders, Substance-induced mood disorders, anxiety disor cyclopropylcarbonyl)(methylene)-2-azanyl)acetonitril ders, cognitive disorders, delirium, amnestic disorders, 0140) 2-(4-isopropoxybiphenyl-4-yl)propan-2-ol; Alzheimer's disease, Schizophrenia, Schizophreniform disor 0141 1-2-fluoro-4'-(1-hydroxy-1-methylethyl)biphe der, schizoaffective disorder, delusional disorder, brief psy nyl-4-yl)cyclopropanecarboxamide; chotic disorder, shared psychotic disorder, addictive behav or a pharmaceutically acceptable salt, Stereoisomer or N-ox iors, movement disorders, akinesias, akinetic-rigid ide derivative thereof. syndromes, Parkinson's disease, medication-induced parkin 0142. Also included within the scope of the present inven Sonism, Gilles de la Tourette's syndrome, epilepsy, dyskine tion is a pharmaceutical composition which is comprised of a sias, chorea, myoclonus, tics, dystonia, obesity, bulimia ner compound of Formula I as described above and a pharmaceu Vosa, compulsive eating disorders, eating disorders tically acceptable carrier. The invention is also contemplated associated with excessive food intake, osteoarthritis, repeti to encompass a pharmaceutical composition which is com tive motion pain, dental pain, cancer pain, myofascial pain, prised of a pharmaceutically acceptable carrier and any of the perioperative pain, chronic pain, neuropathic pain, post-trau compounds specifically disclosed in the present application, matic pain, trigeminal neuralgia, migraine, attention-deficit alone or in combination with any other disclosed compound. hyperactivity disorder, conduct disorder, muscular spasms, These and other aspects of the invention will be apparent from urinary incontinence, amyotrophic lateral sclerosis, neuronal the teachings contained herein. damage, ocular damage, retinopathy, macular degeneration of the eye, hearing loss, tinnitus, emesis, brain edema or sleep Utilities disorders in a mammal in need thereof, comprising adminis 0143. The compounds of the present invention are inhibi tering to the mammal a therapeutically effective amount of tors of MAO-A and/or MAO-B and are therefore useful to any of the compounds or any of the pharmaceutical compo treat or prevent neurological diseases or conditions in mam sitions described above. nals, preferably humans. 0.149 Another embodiment of the invention is a method of 0144) “Neurological diseases or conditions” refers to treating depression in a mammal in need thereof, comprising abnormalities of neurotransmitter synthesis, storage, release, administering to the mammal a therapeutically effective or degradation or changes in the number and affinity of recep amount of any of the compounds or any of the pharmaceutical tors which can affect neurotransmission and cause clinical compositions described above. The utility of MAO inhibitors disorders. Neurological diseases or conditions includes, but is in the treatment of depression is known in the literature, see, not limited to, mood disorders, depression, bipolar disorders, Liebowitz, MR, et al., “Reversible and irreversible monoam Substance-induced mood disorders, anxiety disorders, cogni ine oxidase inhibitors in other psychiatric disorders.” Acta tive disorders, delirium, amnestic disorders, Alzheimer's dis Psychiatr Scand Suppl. 1990; 360:29-34. ease, Schizophrenia, Schizophreniform disorder, Schizoaffec 0150. Another embodiment of the invention is a method of tive disorder, delusional disorder, brief psychotic disorder, treating anxiety in a mammal in need thereof, comprising shared psychotic disorder, addictive behaviors, movement administering to the mammal a therapeutically effective disorders, akinesias, akinetic-rigid syndromes, Parkinson's amount of any of the compounds or any of the pharmaceutical disease, medication-induced parkinsonism, Gilles de la compositions described above. The utility of MAO inhibitors Tourette's syndrome, epilepsy, dyskinesias, chorea, myoclo in the treatment of anxiety is known in the literature, see, US 2009/029 1988 A1 Nov. 26, 2009

Galynker I, et al., “Low-Dose Risperidone and Quetiapine as 0156 Another embodiment of the invention is a method of Monotherapy for Comorbid Anxiety and Depression.” J Clin treating pain in a mammal in need thereof, comprising admin Psychiatry. 2005 April: 66(4):544. istering to the mammal atherapeutically effective amount of any of the compounds or any of the pharmaceutical compo 0151. Another embodiment of the invention is a method of sitions described above. Pain includes repetitive motion pain, treating Substance induced mood disorders in a mammal in dental pain, cancer pain, myofascial pain, perioperative pain, need thereof, comprising administering to the mammal a chronic pain, neuropathic pain, post-traumatic pain, trigemi therapeutically effective amount of any of the compounds or nal neuralgia and migraine. The utility of MAO inhibitors in any of the pharmaceutical compositions described above. The the treatment of pain is known in the literature, see, Pirildar S, utility of MAO inhibitors in the treatment of substance et al., “A preliminary open-label study of moclobemide treat induced mood disorders is known in the literature, see, Taka ment of pain disorder.” Psychopharmacol Bull. 2003 Sum hashi S, et al., “Monoamine oxidase activity in blood platelets mer; 37(3): 127-34; Silberstein, SD, et al., “Preventive treat in alcoholism.” Folia Psychiatr Neurol Jpn. 1976:30(4):455 ment of migraine: an overview.” Cephalalgia. 1997 April; 62 17(2):67-72. 0152 Another embodiment of the invention is a method of O157 Another embodiment of the invention is a method of treating delirium and delusional disorder in a mammal in treating attention-deficit hyperactivity disorder in a mammal need thereof, comprising administering to the mammal a in need thereof, comprising administering to the mammal a therapeutically effective amount of any of the compounds or therapeutically effective amount of any of the compounds or any of the pharmaceutical compositions described above. The any of the pharmaceutical compositions described above. The utility of MAO inhibitors in the treatment of delirium and utility of MAO inhibitors in the treatment of attention-deficit delusional disorder is known in the literature, see, C. L. DeV hyperactivity disorder is known in the literature, see, Spencer ane and J. Mintzer, "Risperidone in the management of psy T.J., “ADHD treatment across the life cycle. J Clin Psychia chiatric and neurodegenerative disease in the elderly: an try. 2004; 65 Suppl 3:22-6. update.” Psychopharmacol Bull. 2003; 37(4): 116-32. 0158 Another embodiment of the invention is a method of 0153. Another embodiment of the invention is a method of treating eating disorders in a mammal in need thereof, com treating amnestic disorder in a mammal in need thereof, com prising administering to the mammal atherapeutically effec prising administering to the mammal atherapeutically effec tive amount of any of the compounds or any of the pharma tive amount of any of the compounds or any of the pharma ceutical compositions described above. The utility of MAO ceutical compositions described above. The utility of MAO inhibitors in the treatment of eating disorders, bulimia ner inhibitors in the treatment of amnestic disorders is known in Vosa is known in the literature, see, AS. Kaplan, Academy the literature, see, Purdon, S. E. et al., “Neuropsychological for Eating Disorders International Conference on Eating Dis change in early phase Schizophrenia during 12 months of orders. Denver, Colo., USA, May 29-31, 2003.” Expert Opin treatment with olanzapine, risperidone, orhaloperidol. Arch. Investig Drugs. 2003 August; 12(8): 1441-3. Gen. Psychiatry 57 (2000), pp. 249-258. 0159. Another embodiment of the invention is a method of 0154 Another embodiment of the invention is a method of treating sleep disorders in a mammal in need thereof, com treating Alzheimer's disease in a mammal in need thereof, prising administering to the mammal atherapeutically effec comprising administering to the mammal a therapeutically tive amount of any of the compounds or any of the pharma effective amount of any of the compounds or any of the ceutical compositions described above. The utility of MAO pharmaceutical compositions described above. The utility of inhibitors in the treatment of sleep disorders, is known in the MAO inhibitors in the treatment of Alzheimer's disease is literature, see, Hublin, C., et al., “Selegiline in the treatment known in the literature, see, Ono, K. et al., “Anti-Parkinsonian of narcolepsy.” Neurology 44: 2095-2101; Louden, MB, et agenst have anti-amyloidogenic activity for Alzheimer's al., “Activation of selegiline (1-deprenyl) of REM sleep beta-amyloid fibrils in vitro. Neurochem Int. 2006 March; behaviour disorder in parkinsonism.” West Virg Med J 91: 48(4):275-85. 101. O155 Another embodiment of the invention is a method of (0160 Another embodiment of the invention is a method of treating epilepsy in a mammal in need thereof, comprising treating mood disorders in a mammal in need thereof, com administering to the mammal a therapeutically effective prising administering to the mammal atherapeutically effec amount of any of the compounds or any of the pharmaceutical tive amount of any of the compounds or any of the pharma compositions described above. The utility of MAO inhibitors ceutical compositions described above. The utility of MAO in the treatment of seizures is known in the literature, see, inhibitors in the treatment of mood disorders, including bipo Jobe A, et al., “Three children with a syndrome of obesity and lar disorders, is known in the literature, see, Gutierrez, B, et overgrowth, atypical psychosis, and seizures: a problem in al., “Association analysis between a functional polymor neuropsychopharmacology.” J Child Neurol. 2000 August; phism in the monoamine oxidase A gene promoter and severe 15 (8):518-28. Another embodiment of the invention is a mood disorders.” Psychiatr Genet. 2004 December, 14(4): method of treating Parkinson's disease in a mammal in need 2O3-8. thereof, comprising administering to the mammal atherapeu 0.161 Another embodiment of the invention is a method of tically effective amount of any of the compounds or any of the treating cognitive disorders in a mammal in need thereof, pharmaceutical compositions described above. The utility of comprising administering to the mammal a therapeutically MAO inhibitors in the treatment of Parkinsonfs disease is effective amount of any of the compounds or any of the known in the literature, see, Weinstock, et al., “A novel cho pharmaceutical compositions described above. The utility of linesterdas and brain-selective monoamine oxidase inhibitor MAO inhibitors in the treatment of cognitive disorders, is for the treatment of dementia comorbid with depression and known in the literature, see, Schneider L. S., “New therapeutic Parkinson's disease. Prog. Neuropsychopharmacol. Biol. approaches to cognitive impairment. 3 Clin Psychiatry. Psychiatry 27 (2003), pp. 555-561. 1998: 59 Suppl 11:8-13. US 2009/029 1988 A1 Nov. 26, 2009

0162 Another embodiment of the invention is a method of prising administering to the mammal atherapeutically effec treating Schizophrenia in a mammal in need thereof, compris tive amount of any of the compounds or any of the pharma ing administering to the mammal atherapeutically effective ceutical compositions described above. The utility of MAO amount of any of the compounds or any of the pharmaceutical inhibitors in the treatment of conduct disorder is known in the compositions described above. The utility of MAO inhibitors literature, see, Haberstick, BC., “Monoamine oxidase A in the treatment of Schizophrenia, including Schizophreni (MAOA) and antisocial behaviors in the presence of child form disorder and schizoaffective disorder, is known in the hood and adolescent maltreatment.” Am J Med Genet B Neu literature, see, Toren, P., et al., “Benefit-risk assessment of ropsychiatr Genet. 2005 May 5: 135(1):59-64. atypical antipsychotics in the treatment of schizophrenia and (0169. Another embodiment of the invention is a method of comorbid disorders in children and adolescents.” Drug Saf. treating ocular damage in a mammal in need thereof, com 2004; 27(14): 1135-56. prising administering to the mammal atherapeutically effec 0163 Another embodiment of the invention is a method of tive amount of any of the compounds or any of the pharma treating movement disorders in a mammal in need thereof, ceutical compositions described above. The utility of MAO comprising administering to the mammal a therapeutically inhibitors in the treatment of ocular damage, including retin effective amount of any of the compounds or any of the opathy and macular degeneration of the eye, is known in the pharmaceutical compositions described above. The utility of literature, see, Xu L, et al., “1-Deprenyl, blocking apoptosis MAO inhibitors in the treatment of movement disorders, and regulating gene expression in cultured retinal neurons.” including dyskinesias, dystonia and akinesia, is known in the Biochem Pharmacol. 1999 Oct. 1:58(7): 1183-90. literature, see, Waters C., “Other pharmacological treatments (0170 Another embodiment of the invention is a method of for motor complications and dyskinesias.” Mov Disord. 2005 treating myoclonus, Gilles de la Tourette's syndrome, dysto May; 20 Suppl 11:S3844; Pearce, JK, et al., “The monoamine nia and tics in a mammal in need thereof, comprising admin reuptake blocker brasofensine reverses akinesia without dys istering to the mammal atherapeutically effective amount of kinesia in MPTP-treated and levodopa-primed common mar any of the compounds or any of the pharmaceutical compo mosets.” Mov Disord. 2002 September; 17(5):877-86. sitions described above. The utility of MAO inhibitors in the 0164. Another embodiment of the invention is a method of treatment of myoclonus, Gilles de la Tourette's syndrome, treating hearing loss in a mammal in need thereof, comprising dystonia and tics is known in the literature, see, J. Jankovic administering to the mammal a therapeutically effective and J. Beach.J., “Long-term effects of tetrabenazine in hyper amount of any of the compounds or any of the pharmaceutical kinetic movement disorders. Neurology. 1997 February; compositions described above. The utility of MAO inhibitors 48(2):358-62. in the treatment of hearing loss, including tinnitus, is known (0171 Another embodiment of the invention is a method of in the literature, see, Sharpe M H. Auditory attention in early treating obesity in a mammal in need thereof, comprising Parkinson's disease: an impairment in focused attention.” administering to the mammal a therapeutically effective Neuropsychologia. 1992 January: 30(1): 101-6. amount of any of the compounds or any of the pharmaceutical 0165 Another embodiment of the invention is a method of compositions described above. The utility of MAO inhibitors treating brain edema in a mammal in need thereof, compris in the treatment of obesity is known in the literature, see, ing administering to the mammal atherapeutically effective Visentin V, et al., “Alteration of amine oxidase activity in the amount of any of the compounds or any of the pharmaceutical adipose tissue of obese subjects.” Obes Res. 2004 March; compositions described above. The utility of MAO inhibitors 12(3):547-55 in the treatment of brain edema is known in the literature, see, 0172 Another embodiment of the invention is a method of Huang W. “Neuroprotective effect of rasagiline, a selective treating osteoarthritis in a mammal in need thereof, compris monoamine oxidase-B inhibitor, against closed head injury in ing administering to the mammal atherapeutically effective the mouse” Eur J Pharmacol. 1999 Feb. 5; 366(2-3):127-35. amount of any of the compounds or any of the pharmaceutical 0166 Another embodiment of the invention is a method of compositions described above. The utility of MAO inhibitors treating neuronal damage in a mammal in need thereof, com in the treatment of osteoarthritis is known in the literature, prising administering to the mammal atherapeutically effec see, Chambers M. G. et al., “Chondrocytic monoamine oxi tive amount of any of the compounds or any of the pharma dase activity in the development of natural murine osteoar ceutical compositions described above. The utility of MAO hritis.” Int J Exp Pathol. 1992 April; 73(2): 115-23. inhibitors in the treatment of neuronal damage is known in the (0173 Another embodiment of the invention is a method of literature, see, Mandel S, et al., “Mechanism of neuroprotec treating chorea in a mammal in need thereof, comprising tive action of the anti-Parkinson drug rasagiline and its administering to the mammal a therapeutically effective derivatives.” Brain Res Brain Res Rev. 2005 April;48(2):379 amount of any of the compounds or any of the pharmaceutical 87. compositions described above. The utility of MAO inhibitors 0167 Another embodiment of the invention is a method of in the treatment of chorea is known in the literature, see, J. treating amyotrophic lateral Sclerosis in a mammal in need Mann and E. Chiu, “Platelet monoamine oxidase activity in thereof, comprising administering to the mammal atherapeu Huntington's chorea. J Neurol Neurosurg, Psychiatry. 1978 tically effective amount of any of the compounds or any of the September; 41 (9):809-12. pharmaceutical compositions described above. The utility of 0.174 Exemplifying the invention is the use of a pharma MAO inhibitors in the treatment of amyotrophic lateral scle ceutical composition comprising a compound as described rosis is known in the literature, see, Orru, S., “Association of herein for the manufacture of a medicament for the treatment monoamine oxidase Balleles with age at onset in amyo of mood disorders, depression, bipolar disorders, Substance trophic lateral sclerosis.” Neuromuscul Disord. 1999 Decem induced mood disorders, anxiety disorders, cognitive disor ber, 9(8):593-7. ders, delirium, amnestic disorders, Alzheimer's disease, 0168 Another embodiment of the invention is a method of Schizophrenia, Schizophreniform disorder, Schizoaffective treating conduct disorder in a mammal in need thereof, com disorder, delusional disorder, brief psychotic disorder, shared US 2009/029 1988 A1 Nov. 26, 2009

psychotic disorder, addictive behaviors, movement disorders, multilamellar vesicles. Liposomes can beformed from a vari akinesias, akinetic-rigid syndromes, Parkinson's disease, ety of phospholipids, Such as cholesterol, Stearylamine or medication-induced parkinsonism, Gilles de la Tourette's phosphatidylcholines. syndrome, epilepsy, dyskinesias, chorea, myoclonus, tics, 0.178 Compounds of the present invention may also be dystonia, obesity, bulimia nervosa, compulsive eating disor ders, eating disorders associated with excessive food intake, delivered by the use of monoclonal antibodies as individual osteoarthritis, repetitive motion pain, dental pain, cancer carriers to which the compound molecules are coupled. The pain, myofascial pain, perioperative pain, chronic pain, neu compounds of the present invention may also be coupled with ropathic pain, post-traumatic pain, trigeminal neuralgia, soluble polymers as targetable drug carriers. Such polymers migraine, attention-deficit hyperactivity disorder, conduct can include polyvinylpyrrolidone, pyran copolymer, polyhy disorder, muscular spasms, urinary incontinence, amyo droxypropylmethacrylamide-phenol, polyhydroxy-ethylas trophic lateral Sclerosis, neuronal damage, ocular damage, partamide-phenol, or polyethyleneoxide-polylysine Substi retinopathy, macular degeneration of the eye, hearing loss, tuted with palmitoyl residues. Furthermore, the compounds tinnitus, emesis, brain edema or sleep disorders in a mammal of the present invention may be coupled to a class of biode in need thereof. gradable polymers useful in achieving controlled release of a 0.175. The compounds of this invention may be adminis drug, for example, polylactic acid, polyglycolic acid, copoly tered to mammals, preferably humans, either alone or, pref mers of polyactic and polyglycolic acid, polyepsilon capro erably, in combination with pharmaceutically acceptable car lactone, polyhydroxybutyric acid, polyorthoesters, polyac riers or diluents, optionally with known adjuvants, such as etals, polydihydropyrans, polycyanoacrylates and alum, in a pharmaceutical composition, according to standard crosslinked or amphipathic block copolymers of hydrogels. pharmaceutical practice. The compounds can be adminis 0179 The instant compounds are also useful in combina tered orally or parenterally, including the intravenous, intra tion with known agents useful for treating or preventing mood muscular, intraperitoneal, Subcutaneous, rectal and topical disorders, depression, bipolar disorders, Substance-induced routes of administration. mood disorders, anxiety disorders, cognitive disorders, 0176). In the case of tablets for oral use, carriers which are delirium, amnestic disorders, Alzheimer's disease, Schizo commonly used include lactose and corn starch, and lubricat phrenia, schizophreniform disorder, schizoaffective disorder, ing agents, such as magnesium Stearate, are commonly added. delusional disorder, brief psychotic disorder, shared psy For oral administration in capsule form, useful diluents chotic disorder, addictive behaviors, movement disorders, include lactose and dried corn starch. For oral use of a thera akinesias, akinetic-rigid syndromes, Parkinson's disease, peutic compound according to this invention, the selected medication-induced parkinsonism, Gilles de la Tourette's compound may be administered, for example, in the form of syndrome, epilepsy, dyskinesias, chorea, myoclonus, tics, tablets or capsules, or as an aqueous solution or Suspension. dystonia, obesity, bulimia nervosa, compulsive eating disor For oral administration in the form of a tablet or capsule, the ders, eating disorders associated with excessive food intake, active drug component can be combined with an oral, non osteoarthritis, repetitive motion pain, dental pain, cancer toxic, pharmaceutically acceptable, inert carrier Such as lac pain, myofascial pain, perioperative pain, chronic pain, neu tose, starch, Sucrose, glucose, methyl cellulose, magnesium ropathic pain, post-traumatic pain, trigeminal neuralgia, Stearate, dicalcium phosphate, calcium Sulfate, mannitol, Sor migraine, attention-deficit hyperactivity disorder, conduct bitol and the like; for oral administration in liquid form, the disorder, muscular spasms, urinary incontinence, amyo oral drug components can be combined with any oral, non trophic lateral Sclerosis, neuronal damage, ocular damage, toxic, pharmaceutically acceptable inert carrier Such as etha retinopathy, macular degeneration of the eye, hearing loss, nol, glycerol, water and the like. Moreover, when desired or tinnitus, emesis, brain edema or sleep disorders. Combina necessary, Suitable binders, lubricants, disintegrating agents tions of the presently disclosed compounds with other agents and coloring agents can also be incorporated into the mixture. useful in treating or preventing neurological conditions are Suitable binders include starch, gelatin, natural Sugars such as within the scope of the invention. A person of ordinary skill in glucose or beta-lactose, corn Sweeteners, natural and Syn the art would be able to discern which combinations of agents thetic gums such as acacia, tragacanth or sodium alginate, would be useful based on the particular characteristics of the carboxymethylcellulose, polyethylene glycol, waxes and the drugs and the disease involved. Such agents include the fol like. Lubricants used in these dosage forms include Sodium lowing: an anti-depressant, an anti-anxiety agent, an anti oleate, sodium Stearate, magnesium Stearate, sodium ben Alzheimer's agent, a sedative, a hypnotic, an anxiolytic, an Zoate, Sodium acetate, sodium chloride and the like. Disinte antipsychotic, a cyclopyrrolone, an imidazopyridine, a pyra grators include, without limitation, starch, methyl cellulose, Zolopyrimidine, a minor tranquilizer, a melatonin agonist, a agar, bentonite, Xanthan gum and the like. When aqueous melatonin antagonist, a melationergic agent, a benzodiaz Suspensions are required for oral use, the active ingredient is epine, a barbiturate, a 5HT-2 antagonist, levodopa, an anti combined with emulsifying and Suspending agents. If cholinergic, a trihexyphenidyl hydrochloride, a COMT desired, certain Sweetening or flavoring agents may be added. inhibitor, an antioxidant, an A2a adenosine receptor antago For intramuscular, intraperitoneal, Subcutaneous and intrave nist, a cholinergic agonist, a NMDA receptor antagonist, a nous use, sterile solutions of the active ingredient are usually serotonin receptor antagonist, a monoamine oxidase inhibi prepared, and the pH of the solutions should be suitably tor, a dopamine receptor agonist, a neuroleptic agent, an adjusted and buffered. For intravenous use, the total concen anoretic agent, a selective serotonin reuptake inhibitor, a tration of solutes should be controlled in order to render the halogenated amphetamine derivative, an opiate agonist, a preparation isotonic. lipoxygenase inhibitor, an interleukin inhibitor, an NMDA 0177. The compounds of the present invention can also be antagonist, an inhibitor of nitric oxide, a non-steroidal anti administered in the form of liposome delivery systems, such inflammatory agent, a cytokine-suppressing antiinflamma as Small unilamellar vesicles, large unilamellar vesicles and tory agent, a pain reliever, a potentiator, an H2-antagonist, US 2009/029 1988 A1 Nov. 26, 2009 simethicone, aluminum hydroxide, magnesium hydroxide, a inhibitors such as galantamine, rivastigmine, donepezil, and decongestant, an antitussive, and an antihistamine. tacrine; growth hormone secretagogues such as ibutamoren, 0180 Exemplifying the invention is a pharmaceutical ibutamoren mesylate, and capromorelin; histamine H. composition comprising a compound as described herein and antagonists; AMPA agonists; PDE IV inhibitors; GABA another agent selected from: an anti-depressant, an anti-anxi inverse agonists; or neuronal nicotinic agonists. ety agent, an anti-Alzheimer's agent, a sedative, a hypnotic, 0184. In another embodiment, the subject compound may an anxiolytic, an antipsychotic, a cyclopyrrolone, an imida be employed in combination with sedatives, hypnotics, anxi Zopyridine, a pyrazolopyrimidine, a minor tranquilizer, a olytics, antipsychotics, antianxiety agents, cyclopyrrolones, melatonin agonist, a melatonin antagonist, a melationergic imidazopyridines, pyrazolopyrimidines, minor tranquilizers, agent, a benzodiazepine, a barbiturate, a 5HT-2 antagonist, melatonin agonists and antagonists, melationergic agents, levodopa, an anticholinergic, a trihexyphenidyl hydrochlo benzodiazepines, barbiturates, 5HT-2 antagonists, and the ride, a COMT inhibitor, an antioxidant, an A2a adenosine like. Such as: adinazolam, allobarbital, alonimid, alprazolam, receptor antagonist, a cholinergic agonist, a NMDA receptor amitriptyline, amobarbital, amoxapine, bentazepam, benzoc antagonist, a serotonin receptor antagonist, a monoamine tamine, brotizolam, bupropion, buSprione, butabarbital, oxidase inhibitor, a dopamine receptoragonist, a neuroleptic butalbital, capuride, carbocloral, chloral betaine, chloral agent, an anoretic agent, a selective serotonin reuptake inhibi hydrate, chlordiazepoxide, clomipramine, clonazepam, clo tor, a halogenated amphetamine derivative, an opiate agonist, peridone, cloraZepate, clorethate, clozapine, cyprazepam, a lipoxygenase inhibitor, an interleukin inhibitor, an NMDA desipramine, dexclamol, diazepam, dichloralphenaZone, antagonist, an inhibitor of nitric oxide, a non-steroidal anti divalproex, diphenhydramine, doxepin, estazolam, ethchlor inflammatory agent, a cytokine-suppressing antiinflamma Vynol, etomidate, fenobam, flunitrazepam, flurazepam, flu tory agent, a pain reliever, a potentiator, an H2-antagonist, Voxamine, fluoxetine, fosazepam, glutethimide, halazepam, simethicone, aluminum hydroxide, magnesium hydroxide, a hydroxy Zine, imipramine, lithium, lorazepam, decongestant, an antitussive, and an antihistamine. lormetazepam, maprotiline, mecloqualone, melatonin, 0181. Accordingly, the subject compounds may be used mephobarbital, meprobamate, methaqualone, midaflur, alone or in combination with other agents which are known to midazolam, nefazodone, nisobamate, nitrazepam, nortrip be beneficial in the subject indications or other drugs that tyline, oxazepam, paraldehyde, paroxetine, pentobarbital, affect receptors or enzymes that either increase the efficacy, perlapine, perphenazine, phenelzine, phenobarbital, safety, convenience, or reduce unwanted side effects or tox prazepam, promethazine, propofol, protriptyline, quazepam, icity of the compounds of the present invention. The subject reclazepam, roletamide, secobarbital, sertraline, Suproclone, compound and the other agent may be co-administered, either temazepam, thioridazine, tracazolate, tranylcypromaine, tra in concomitant therapy or in a fixed combination. The follow Zodone, triazolam, trepipam, tricetamide, triclofos, trifluop ing list of combinations is illustrative only and not intended to erazine, trimetozine, trimipramine, uldazepam, Venlafaxine, be limiting in any way. Zaleplon, Zolazepam, Zolpidem, and salts thereof, and com 0182. In one embodiment, the subject compound may be binations thereof, and the like, or the Subject compound may employed in combination with an anti-depressant or anti be administered in conjunction with the use of physical meth anxiety agent, including norepinephrine reuptake inhibitors ods such as with light therapy or electrical stimulation. (including tertiary amine tricyclics and secondary amine tri 0185. In another embodiment, the subject compound may cyclics), selective serotonin reuptake inhibitors (SSRIs), be employed in combination with levodopa (with or without monoamine oxidase inhibitors (MAOIs), reversible inhibi a selective extracerebral decarboxylase inhibitor such as car tors of monoamine oxidase (RIMAS), serotonin and norad bidopa or benserazide), anticholinergics such as biperiden renaline reuptake inhibitors (SNRIs), corticotropin releasing (optionally as its hydrochloride or lactate salt) and trihex factor (CRF) antagonists, C.-adrenoreceptor antagonists, neu yphenidyl (benzhexol)hydrochloride, COMT inhibitors such rokinin-1 receptor antagonists, atypical anti-depressants, as entacapone, MOA-B inhibitors, antioxidants, A2a adenos benzodiazepines, 5-HT agonists or antagonists, especially ine receptor antagonists, cholinergic agonists, NMDA recep 5-HT, partial agonists, and corticotropin releasing factor tor antagonists, serotonin receptor antagonists and dopamine (CRF) antagonists. Specific agents include: amitriptyline, receptor agonists such as alentemol, bromocriptine, clomipramine, doxepin, imipramine and trimipramine; fenoldopam, lisuride, naxagolide, pergolide and pramipex amoxapine, desipramine, maprotiline, nortriptyline and pro ole. It will be appreciated that the dopamine agonist may be in triptyline; fluoxetine, fluvoxamine, paroxetine and Sertraline; the form of a pharmaceutically acceptable salt, for example, isocarboxazid, phenelzine, tranylcypromine and selegiline; alentemol hydrobromide, bromocriptine mesylate, moclobemide: Venlafaxine: aprepitant; bupropion, lithium, fenoldopam mesylate, naxagolide hydrochloride and per nefazodone, traZodone and Viloxazine; alprazolam, chlor golide mesylate. Lisuride and pramipexol are commonly used diazepoxide, clonazepam, chloraZepate, diazepam, in a non-salt form. halazepam, lorazepam, oxazepam and prazepam; buspirone, 0186. In another embodiment, the subject compound may flesinoxan, gepirone and ipsapirone, and pharmaceutically be employed in combination with acetophenazine, alentemol. acceptable salts thereof. benzhexol, bromocriptine, biperiden, chlorpromazine, chlo 0183 In another embodiment, the subject compound may rprothixene, clozapine, diazepam, fenoldopam, fluiphenazine, be employed in combination with anti-Alzheimer's agents; haloperidol, levodopa, levodopa with benserazide, levodopa beta-secretase inhibitors; gamma-secretase inhibitors; HMG with carbidopa, lisuride, loxapine, mesoridazine, molin CoA reductase inhibitors; NSAID's including ibuprofen; dolone, naxagolide, olanzapine, pergolide, perphenazine, Vitamin E; anti-amyloid antibodies; CB-1 receptor antago pimozide, pramipexole, risperidone, Sulpiride, tetrabenazine, nists or CB-1 receptor inverse agonists; antibiotics such as trihexyphenidyl, thioridazine, thiothixene or trifluoperazine. doxycycline and rifampin: N-methyl-D-aspartate (NMDA) 0187. In another embodiment, the subject compound may receptor antagonists, such as memantine; cholinesterase be employed in combination with a compound from the phe US 2009/029 1988 A1 Nov. 26, 2009 nothiazine, thioxanthene, heterocyclic dibenzazepine, buty with known pharmaceutically acceptable agent(s) when a rophenone, diphenylbutylpiperidine and indolone classes of combination formulation is inappropriate. neuroleptic agent. Suitable examples of phenothiazines (0191 The term “administration' and variants thereof include chlorpromazine, mesoridazine, thioridazine, acetophenazine, fluiphenazine, perphenazine and trifluopera (e.g., “administering a compound) in reference to a com zine. Suitable examples of thioxanthenes include chlorpro pound of the invention means introducing the compound or a thixene and thiothixene. An example of a dibenzazepine is prodrug of the compound into the system of the animal in clozapine. An example of abutyrophenone is haloperidol. An need of treatment. When a compound of the invention or example of a diphenylbutylpiperidine is pimozide. An prodrug thereof is provided in combination with one or more example of an indolone is molindolone. Other neuroleptic other active agents (e.g., a cytotoxic agent, etc.), “adminis agents include loxapine, Sulpiride and risperidone. It will be tration' and its variants are each understood to include con appreciated that the neuroleptic agents when used in combi current and sequential introduction of the compound or pro nation with thesubject compound may be in the form of a drug thereof and other agents. The present invention includes pharmaceutically acceptable salt, for example, chlorprom within its scope prodrugs of the compounds of this invention. azine hydrochloride, mesoridazine besylate, thioridazine In general, such prodrugs will be functional derivatives of the hydrochloride, acetophenazine maleate, fluiphenazine hydro compounds of this invention which are readily convertible in chloride, flurphenazine enathate, fluiphenazine decanoate, tri vivo into the required compound. Thus, in the methods of fluoperazine hydrochloride, thiothixene hydrochloride, halo treatment of the present invention, the term “administering peridol decanoate, loxapine Succinate and molindone shall encompass the treatment of the various conditions hydrochloride. Perphenazine, chlorprothixene, clozapine, described with the compound specifically disclosed or with a haloperidol, pimozide and risperidone are commonly used in compound which may not be specifically disclosed, but a non-salt form. which converts to the specified compound in vivo after administration to the patient. Conventional procedures for the 0188 In another embodiment, the subject compound may selection and preparation of Suitable prodrug derivatives are be employed in combination with an anoretic agent Such as described, for example, in “Design of Prodrugs, ed. H. aminorex, amphechloral, amphetamine, benzphetamine, Bundgaard, Elsevier, 1985, which is incorporated by refer chlorphentermine, clobenzorex, cloforex, clominorex, clor ence herein in its entirety. Metabolites of these compounds termine, cyclexedrine, dexfenfluramine, dextroamphet include active species produced upon introduction of com amine, diethylpropion, diphemethoxidine, N-ethylamphet pounds of this invention into the biological milieu. amine, fenbutrazate, fenfluramine, fenisorex, femproporex, fluidorex, fluminorex, furfurylmethylamphetamine, levamfe (0192 As used herein, the term “composition' is intended tamine, levophacetoperane, mazindol, mefenorex, metam to encompass a product comprising the specified ingredients fepramone, metharnphetamine, norpseudoephedrine, pen in the specified amounts, as well as any product which results, torex, phendimetrazine, phenmetrazine, phentermine, directly or indirectly, from combination of the specified phenylpropanolamine, picilorex and Sibutramine; selective ingredients in the specified amounts. serotonin reuptake inhibitor (SSRI); halogenated amphet 0193 The term “therapeutically effective amount’ as used amine derivatives, including chlorphentermine, cloforex, clo herein means that amount of active compound or pharmaceu rtermine, dexfenfluramine, fenfluramine, picilorex and tical agent that elicits the biological or medicinal response in Sibutramine; and pharmaceutically acceptable salts thereof. a tissue, system, animal or human that is being sought by a 0189 In another embodiment, the subject compound may researcher, Veterinarian, medical doctor or other clinician. be employed in combination with an opiate agonist, a lipoxy 0194 The terms “treating or “treatment of a disease as genase inhibitor, such as an inhibitor of 5-lipoxygenase, a used herein includes: preventing the disease, i.e. causing the cyclooxygenase inhibitor, Such as a cyclooxygenase-2 inhibi clinical symptoms of the disease not to develop in a mammal tor, an interleukin inhibitor, such as an interleukin-1 inhibitor, that may be exposed to or predisposed to the disease but does an NMDA antagonist, an inhibitor of nitric oxide oran inhibi not yet experience or display symptoms of the disease; inhib tor of the synthesis of nitric oxide, a non-steroidal antiinflam iting the disease, i.e., arresting or reducing the development matory agent, or a cytokine-suppressing antiinflammatory of the disease or its clinical symptoms; or relieving the dis agent, for example with a compound Such as acetaminophen, ease, i.e., causing regression of the disease or its clinical asprin, codiene, fentanyl, ibuprofen, indomethacin, ketoro symptoms. lac, morphine, naproxen, phenacetin, piroXicam, a steroidal 0.195 The present invention also encompasses a pharma analgesic, Sufentanyl. Sunlindac, tenidap, and the like. Simi ceutical composition useful in the treatment of neurological larly, the Subject compound may be administered with a pain conditions, comprising the administration of a therapeuti reliever, a potentiator Such as caffeine, an H2-antagonist, cally effective amount of the compounds of this invention, simethicone, aluminum or magnesium hydroxide; a decon with or without pharmaceutically acceptable carriers or dilu gestant Such as phenylephrine, phenylpropanolamine, ents. Suitable compositions of this invention include aqueous pseudophedrine, oxymetazoline, ephinephrine, naphazoline, Solutions comprising compounds of this invention and phar Xylometazoline, propylhexedrine, or levo-desoxy-ephedrine; macologically acceptable carriers, e.g., saline, at a pH level. an antitussive such as codeine, hydrocodone, caramiphen, e.g., 7.4. The solutions may be introduced into a patient's carbetapentane, or dextramethorphan; a diuretic; and a sedat bloodstream by local bolus injection. ing or non-sedating antihistamine. 0196. When a compound according to this invention is 0190. If formulated as a fixed dose, such combination administered into a human Subject, the daily dosage will products employ the compounds of this invention within the normally be determined by the prescribing physician with the dosage range described below and the other pharmaceutically dosage generally varying according to the age, weight, and active agent(s) within its approved dosage range. Compounds response of the individual patient, as well as the severity of the of the instant invention may alternatively be used sequentially patient's symptoms. US 2009/029 1988 A1 Nov. 26, 2009

0197) In one exemplary application, a suitable amount of described in: E. L. Eliel and S. H. Wilen, Stereochemistry of compound is administered to a mammal undergoing treat Carbon Compounds, John Wiley & Sons, New York, 1994, ment for a cathepsin dependent condition. Oral dosages of the pages 1119-1190), and occur as racemates, racemic mixtures, present invention, when used for the indicated effects, will range between about 0.01 mg per kg of body weight per day and as individual diastereomers, with all possible isomers and (mg/kg/day) to about 100 mg/kg/day, preferably 0.01 to 10 mixtures thereof, including optical isomers, being included in mg/kg/day, and most preferably 0.1 to 5.0 mg/kg/day. For oral the present invention. In addition, the compounds disclosed administration, the compositions are preferably provided in herein may exist as tautomers and both tautomeric forms are the form of tablets containing 0.01, 0.05, 0.1, 0.5, 1.0, 2.5, 5.0, intended to be encompassed by the scope of the invention, 10.0, 15.0, 25.0, 50.0, 100 and 500 milligrams of the active even though only one tautomeric structure is depicted. For ingredient for the symptomatic adjustment of the dosage to example, any claim to compound A below is understood to the patient to be treated. A medicament typically contains include tautomeric structure B, and vice versa, as well as from about 0.01 mg to about 500 mg of the active ingredient, mixtures thereof. preferably, from about 1 mg to about 100 mg of active ingre dient. Intravenously, the most preferred doses will range from about 0.1 to about 10 mg/lkg/minute during a constant rate infusion. Advantageously, compounds of the present inven OH O tion may be administered in a single daily dose, or the total RI RI daily dosage may be administered in divided doses of two, Xs X NH three or four times daily. Furthermore, preferred compounds for the present invention can be administered in intranasal form via topical use of Suitable intranasal vehicles, or via luN transdermal routes, using those forms of transdermal skin patches well known to those of ordinary skill in the art. To be administered in the form of a transdermal delivery system, the dosage administration will, of course, be continuous rather than intermittent throughout the dosage regimen. 0198 The compounds of the present invention can be used (0202) When any variable (e.g. R1, R. Ra etc.) occurs in combination with other agents useful for treating neuro more than one time in any constituent, its definition on each logical conditions. The individual components of such com occurrence is independent at every other occurrence. Also, binations can be administered separately at different times combinations of substituents and variables are permissible during the course of therapy or concurrently in divided or only if Such combinations result in stable compounds. Lines single combination forms. The instant invention is therefore drawn into the ring systems from substituents indicate that the to be understood as embracing all such regimes of simulta indicated bond may be attached to any of the substitutable neous or alternating treatment and the term “administering is ring carbon atoms. If the ring system is polycyclic, it is to be interpreted accordingly. It will be understood that the intended that the bond be attached to any of the suitable Scope of combinations of the compounds of this invention carbon atoms on the proximal ring only. with other agents useful for treating neurological conditions 0203. It is understood that substituents and substitution includes in principle any combination with any pharmaceu patterns on the compounds of the instant invention can be tical composition useful for treating disorders related to neu selected by one of ordinary skill in the art to provide com rological functioning. pounds that are chemically stable and that can be readily 0199 The scope of the invention therefore encompasses synthesized by techniques known in the art, as well as those the use of the instantly claimed compounds in combination methods set forth below, from readily available starting mate with a second agent selected from: an anti-depressant, an rials. If a substituent is itself substituted with more than one anti-anxiety agent, an anti-Alzheimer's agent, a sedative, a group, it is understood that these multiple groups may be on hypnotic, an anxiolytic, an antipsychotic, a cyclopyrrolone, the same carbon or on different carbons, so long as a stable an imidazopyridine, a pyrazolopyrimidine, a minor tranquil structure results. The phrase “optionally substituted with one izer, a melatonin agonist, a melatonin antagonist, a melaton or more substituents' should be taken to be equivalent to the ergic agent, a benzodiazepine, a barbiturate, a 5HT-2 antago phrase “optionally substituted with at least one substituent nist, levodopa, an anticholinergic, a trihexyphenidyl and in such cases the preferred embodiment will have from hydrochloride, a COMT inhibitor, an antioxidant, an A2a Zero to three substituents. adenosine receptor antagonist, a cholinergic agonist, a 0204 As used herein, “alkyl is intended to include both NMDA receptorantagonist, a serotonin receptor antagonist, a branched and straight-chain Saturated aliphatic hydrocarbon monoamine oxidase inhibitor, a dopamine receptoragonist, a groups having one to ten carbon atoms unless otherwise neuroleptic agent, an anoretic agent, a selective serotonin specified. For example, C-Co, as in "C-Clo alkyl is reuptake inhibitor, a halogenated amphetamine derivative, an defined to include groups having 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 opiate agonist, a lipoxygenase inhibitor, an interleukin inhibi carbons in a linear, branched, or cyclic arrangement. For tor, an NMDA antagonist, an inhibitor of nitric oxide, a non example, "C-Clo alkyl specifically includes methyl, ethyl, steroidal antiinflammatory agent, a cytokine-Suppressing propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, and antiinflammatory agent, a pain reliever, a potentiator, an H2-antagonist, simethicone, aluminum hydroxide, magne SO. O. sium hydroxide, a decongestant, an antitussive, and an anti 0205 "Alkoxy” or “alkyloxy' represents an alkyl group as histamineand the pharmaceutically acceptable salts and mix defined above, unless otherwise indicated, wherein said alkyl tures thereof. group is attached through an oxygen bridge. Examples of 0200. These and other aspects of the invention will be alkoxy include methoxy, ethoxy and the like. apparent from the teachings contained herein. 0206. The term “cycloalkyl shall mean cyclic rings of alkanes of three to eight total carbon atoms, unless otherwise DEFINITIONS indicated, or any number within this range (i.e., cyclopropyl. 0201 The compounds of the present invention may have cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or cyclooc asymmetric centers, chiral axes, and chiral planes (as tyl). US 2009/029 1988 A1 Nov. 26, 2009

0207. If no number of carbon atoms is specified, the term but are not limited to, benzyl, fluorobenzyl, chlorobenzyl, “alkenyl refers to a non-aromatic hydrocarbon radical, phenylethyl, phenylpropyl, fluorophenylethyl, and chlo straight or branched, containing from 2 to 10 carbon atoms rophenylethyl. Examples of alkylaryl include, but are not and at least 1 carbon to carbon double bond. Preferably 1 limited to, toluoyl, ethylphenyl, and propylphenyl. carbon to carbon double bond is present, and up to 4 non 0215. The term "heteroarylalkyl as used herein, shall aromatic carbon-carbon double bonds may be present. Thus, refer to a system that includes a heteroaryl portion, where "C-C alkenyl' means an alkenyl radical having from 2 to 6 heteroaryl is as defined above, and contains an alkyl portion. carbon atoms. Alkenyl groups include ethenyl, propenyl, Examples of heteroarylalkyl include, but are not limited to, butenyland cyclohexenyl. As described above with respect to thienylmethyl, thienylethyl, thienylpropyl, pyridylmethyl, alkyl, the straight, branched or cyclic portion of the alkenyl pyridylethyl and imidazoylmethyl. group may contain double bonds and may be substituted if a 0216. The term “cycloalkylalkyl includes an alkyl por Substituted alkenyl group is indicated. tion where alkyl is as defined above and also includes a 0208. The term “alkynyl' shall mean a substituting univa cycloalkyl portion where cycloalkyl is as defined above. lent group derived by conceptual removal of one hydrogen Examples of cycloalkylalkyl include, but are not limited to, atom from a straight or branched-chain acyclic unsaturated cyclopropylmethyl, cyclopentylmethyl, cyclohexylmethyl, hydrocarbon containing at least one triple bond (i.e., cyclopropylethyl, and the like. C=CH, -CHC=CH, -C=CCH, -CHC=CCH 0217. The term “heterocycloalkylalkyl or “heterocycly (CH3)2, etc.). lalkyl includes an alkyl portion where alkyl is as defined 0209. In certain instances, substituents may be defined above and also includes a heterocycloalkyl portion where with a range of carbons that includes Zero, such as (Co-C) heterocycloalkyl is as defined above. Examples of heterocy alkylene-aryl. If aryl is taken to be phenyl, this definition cloalkylalkyl include, but are not limited to, morpholinylm would include phenyl itself as well as —CHPh. ethyl, piperazinylmethyl, pyrrolidinylmethyl, and the like. —CHCHPh, CH(CH)CHCH(CH)Ph, and so on. 0218. The term “hydroxyalkyl or “alkylhydroxyl” means 0210. As used herein, “aryl' is intended to mean any stable a linear monovalent hydrocarbon radical of one to six carbon monocyclic or bicyclic carbon ring of up to 12 atoms in each atoms or a branched monovalent hydrocarbon radical of three ring, wherein at least one ring is aromatic. Examples of Such to six carbons Substituted with one or two hydroxy groups, aryl elements include phenyl, naphthyl, tetrahydronaphthyl, provided that if two hydroxy groups are present they are not indanyl, biphenyl, phenanthryl, anthryl or acenaphthyl. In both on the same carbon atom. Representative examples cases where the aryl Substituent is bicyclic and one ring is include, but are not limited to, hydroxymethyl, 2-hydroxy non-aromatic, it is understood that attachment is via the aro ethyl, 2-hydroxypropyl, 3-hydroxypropyl, and the like. matic ring. 0219. The term “heterocycle” or “heterocyclyl as used 0211. The term "heteroaryl', as used herein, represents a herein is intended to mean a 5- to 10-membered nonaromatic stable monocyclic, bicyclic or tricyclic ring of up to 10 atoms ring, unless otherwise specified, containing from 1 to 4 het in each ring, wherein at least one ring is aromatic and contains eroatoms selected from the group consisting of O, N, S, SO, from 1 to 4 heteroatoms selected from the group consisting of or SO, and includes bicyclic groups. “Heterocyclyl” there O, N and S. Heteroaryl groups within the scope of this defi fore includes, but is not limited to the following: piperazinyl, nition include but are not limited to: benzoimidazolyl, ben piperidinyl, pyrrolidinyl, morpholinyl, thiomorpholinyl, tet Zofuranyl, benzofurazanyl, benzopyrazolyl, benzotriazolyl, rahydropyranyl, dihydropiperidinyl, tetrahydrothiophenyl benzothiophenyl, benzoxazolyl, carbazolyl, carbolinyl, cin and the like. If the heterocycle contains a nitrogen, it is under nolinyl, furanyl, indolinyl, indolyl, indolazinyl, indazolyl, stood that the corresponding N-oxides thereof are also isobenzofuranyl, isoindolyl, isoquinolyl, isothiazolyl, isox encompassed by this definition. azolyl, naphthpyridinyl, oxadiazolyl, oxazolyl, oxazoline, 0220. The present invention also includes N-oxide deriva isoxazoline, pyranyl, pyrazinyl, pyrazolyl pyriclazinyl, pyri tives and protected derivatives of compounds of Formula I. dopyridinyl, pyridyl, pyrimidinyl, pyrrolyl, quinazolinyl, For example, when compounds of Formula I contain an oxi quinolyl, quinoxalinyl, tetrazolyl, tetraZolopyridyl, thiadiaz dizable nitrogen atom, the nitrogen atom can be converted to olyl, thiazolyl, thienyl, triazolyl, dihydrobenzoimidazolyl, an N-oxide by methods well known in the art. Also when dihydrobenzofuranyl, dihydrobenzothiophenyl, dihydroben compounds of Formula I contain groups such as hydroxy, ZOxazolyl, dihydroindolyl, dihydroquinolinyl, methylene carboxy, thiol or any group containing a nitrogen atom(s), dioxybenzene, benzothiazolyl, benzothienyl, quinolinyl, iso these groups can be protected with a suitable protecting quinolinyl, oxazolyl, and tetra-hydroquinoline. In cases groups. A comprehensive list of Suitable protective groups where the heteroaryl substituent is bicyclic and one ring is can be found in T. W. Greene, Protective Groups in Organic non-aromatic or contains no heteroatoms, it is understood that Synthesis, John Wiley & Sons, Inc. 1981, the disclosure of attachment is via the aromatic ring or via the heteroatom which is incorporated herein by reference in its entirety. The containing ring, respectively. If the heteroaryl contains nitro protected derivatives of compounds of Formula I can be pre gen atoms, it is understood that the corresponding N-oxides pared by methods well known in the art. thereof are also encompassed by this definition. 0221) Whenever the term “alkyl or “aryl” or either of 0212. As appreciated by those of skill in the art, “halo' or their prefix roots appear in a name of a Substituent (e.g., aryl “halogen as used herein is intended to include chloro, fluoro, Cos alkyl) it shall be interpreted as including those limita bromo and iodo. The term “keto' means carbonyl (C=O). tions given above for “alkyl and “aryl. Designated numbers 0213. The term “haloalkyl means an alkyl radical as of carbon atoms (e.g., Co) shall refer independently to the defined above, unless otherwise specified, that is substituted number of carbon atoms in an alkyl or cyclic alkyl moiety or with one to five, preferably one to three halogen. Represen to the alkyl portion of a larger substituent in which alkyl tative examples include, but are not limited to trifluorom appears as its prefix root. ethyl, dichloroethyl, and the like. 0222. The pharmaceutically acceptable salts of the com 0214. The term “arylalkyl includes an alkyl portion pounds of this invention include the conventional non-toxic where alkyl is as defined above and to include an aryl portion salts of the compounds of this invention as formed inorganic where aryl is as defined above. Examples of arylalkyl include, or organic acids. For example, conventional non-toxic salts US 2009/029 1988 A1 Nov. 26, 2009

include those derived from inorganic acids such as hydro 0262 NaOH sodium hydroxide chloric, hydrobromic, Sulfuric, Sulfamic, phosphoric, nitric 0263 NaSO, sodium sulfate and the like, as well as salts prepared front organic acids Such 0264. NBS=N-bromosuccinimide as acetic, propionic. Succinic, glycolic, Stearic, lactic, malic, tartaric, citric, ascorbic, pamoic, maleic, hydroxymaleic, phe 0265 NHammonia nylacetic, glutamic, benzoic, Salicylic, Sulfanilic, 2-acetoxy 0266 NHCl-ammonium chloride benzoic, fumaric, toluenesulfonic, methanesulfonic, ethane 0267 Pd/C palladium on carbon disulfonic, oxalic, isethionic, trifluoroacetic and the like. The 0268 PdCl(dppf)=1,1'-bis(diphenylphosphino)fer preparation of the pharmaceutically acceptable salts rocenedichloropalladium(II) described above and other typical pharmaceutically accept 0269 Pd(dba)-tris(dibenzylideneacetone)dipalladium able salts is more fully described by Berget al., “Pharmaceu (O) tical Salts.” J. Pharm Sci., 1977:66:1-19, hereby incorporated 0270 PG-protecting group by reference. The pharmaceutically acceptable salts of the (0271 PPh-triphenylphosphine compounds of this invention can be synthesized from the (0272 PPTS pyridinium p-toluenesulfonate compounds of this invention which contain a basic or acidic moiety by conventional chemical methods. Generally, the (0273 iPr-Nli=lithium diisopropyl amide salts of the basic compounds are prepared either by ion (0274 PyBOP=benzotriazol-1-yloxytris(pyrrolidino) exchange chromatography or by reacting the free base with phosphonium-hexafluorophosphate Stoichiometric amounts or with an excess of the desired salt (0275 rt room temperature forming inorganic or organic acid in a suitable solvent or 0276 sat. aq.-saturated aqueous various combinations of solvents. Similarly, the salts of the (0277 TFA=trifluoroacetic acid acidic compounds are formed by reactions with the appropri (0278 THF-tetrahydrofuran ate inorganic or organic base. 0223 For purposes of this specification, the following 0279 tic=thin layer chromatography abbreviations have the indicated meanings: (0280 Me-methyl 0224 AcOH-acetic acid (0281 Et-ethyl 0225 BH.MeS-borane-methyl sulfide complex 0282) n-Pr-normal propyl 0226 Boc=t-butyloxycarbonyl (0283 i-Prisopropyl 0227 Boc-O-di-tert-butyl dicarbonate 0284 n-Bu-normal butyl 0228 BuLi-butyl lithium (0285) i-Buisobutyl 0229 CC1-carbon tetrachloride 0286 S-Bu-secondary butyl 0230 CHC1-methylene chloride (0287 t-Bu=tertiary butyl 0231 CHCN-acetonitrile 0288 The novel compounds of the present invention can 0232 CHC1-chloroform be prepared according to the following general procedures 0233. CsCO=cesium carbonate using appropriate materials and are further exemplified by the 0234 CuI-copper iodide following specific examples. The compounds illustrated in 0235 DIAD-diisopropylazodicarboxylate the examples are not, however, to be construed as forming the 0236 DIP-Cl=B-chlorodiisopinocampheylborane only genus that is considered as the invention. The following 0237 DMA-N,N-dimethyl acetamide examples further illustrate details for the preparation of the 0238 DMAP-4-(dimethylamino)pyridine compounds of the present invention. Those skilled in the art 0239 DMF-N,N-dimethylformamide will readily understand that known variations of the condi 0240 DMSO-dimethylsulfoxide tions and processes of the following preparative procedures 0241 DPPA-diphenylphosphoryl azide can be used to prepare these compounds. All temperatures are 0242 EDC1=1-(3-dimethylaminopropyl)-3-ethylcarbodi degrees Celsius unless otherwise noted. imide hydrochloride 0243 EtO-diethyl ether Schemes 0244 EtN=triethylamine 0245 EtOAc=ethyl acetate 0289 Compounds of the present invention can be pre 0246 EtOH=ethanol pared according to Scheme 1, as indicated below. Thus a 0247 HATU=o-7-azabenzotriazol-1-yl)-N,N,N',N'-tet dihalo aromatic compound can be mono-lithiated and reacted with either ethyl difluoroacetate or ethyl trifluoroacetate to ramethyluronium hexafluorophosphate HOAc-acetic acid generate the difluoroketone or trifluoroketone, respectively. 0248 KCO potassium carbonate Reduction of the ketone with sodium borohydride provides 0249 KOBu' potassium tert-butoxide the alcohol. This reduction can also be performed enantiose (0250 LiOH=lithium hydroxide lectively with chiral reagents such as alpineborane or B-chlo 0251 mCPBA metachloroperbenzoic acid rodiisopinocampheylborane. If the substituent on D system is 0252 MeOH methanol a halogen, a palladium-catalyzed Suzuki coupling with an 0253 MeSOH-methane sulfonic acid appropriate boronic acid provides compounds of the current 0254 MgSO magnesium sulfate invention. Alternatively, the difluoroketone or trifluoroketone 0255 Ms methanesulfonyl-mesyl can be converted to the corresponding primary amine by first 0256 MsCl-methanesulfonyl chloride forming the N-trimethylsilyl-ketimine followed by in situ reduction with BH MeS. The reduction of the imine can 0257 MTBE-methyl tert-butyl ether also be performed enantioselectively with B-butyl-diphe 0258 NaBH-sodium borohydride nylpyrrolidino-oxazaborolidine. The primary amine can be 0259 NaH=sodium hydride further elaborated with a palladium-catalyzed Suzuki cou 0260 NaCO=sodium carbonate pling with an appropriate boronic acid to provide compounds 0261 NaHCO=sodium hydrogencarbonate of the current invention. US 2009/029 1988 A1 Nov. 26, 2009

Scheme 1 CF/CF2H CF/CF2H D 1) n-BuLi Halo NaBH4 Halo 1. Halo 1'N, Halo 2) O n D-N O MeOH n D OH E 1\o lsCF2H/CF *1) BHLiN(SiMe3) MeS R 1 in B(OH(OH)2 aq. Na2CO3, DMF, PdCl2(dppf), A

CF,3V-12 CF-H R3 -En B(OH)2 CF,3V-12 CF-H CF,3V-12 CF-H a R31Y E YD11. NH, aq.PdCl2(dppf), Na2CO3, DMF,A Hal ND11. NH, R31Y E ND11. No

0290 Compoundsp of the ppresent invention mavy also be prepared according to Scheme 2, as indicated below. Thus a -continued dihalo aromatic compound can be mono-lithiated and reacted with an aryl or heteroarylaldehyde to generate the corre Halo N sponding alcohol. If the substituent on the D system of the D OH resultant alcohol is a halogen, a palladium-atalyzed Suzuki Y E coupling with an appropriate boronic acid provides com R3 YBOH), aq. Na2CO3, DMF, pounds of the current invention. Alternatively, the alcohol can PdCl2(dppf), A be converted to the corresponding primary amine via a mit sonobu reaction with azide and reduction of the azide to the amine using conditions such as 1,3-propanedithiol and tri HCIFC CF3/CH E ethylamine. The amine can then be converted to compounds R 1 in D OH of the present invention by elaborating the Dring via a Suzuki coupling.

Scheme 2 Aryl/Heteroaryl Halo Halo 1) n-BuLi n D1 Halo n Dls OH 2) Aryl/Heteroaryl r H Y E 1) PPh3, DIAD R3 SBOH), O (PhO)2P(O)N aq. Na2CO3, DMF, 2) 1,3-propanedithiol PdCl2(dppf), A EtN

E Aryl/Heteroaryl R3 Y SBOH), Aryl/Heteroaryl Aryl/Heteroaryl a Y Halo 1. Y R31 E ND 1. NH2 n D NH2 R31'NDE lsOH

0291 Compounds of the present invention may also be 0292 Compounds of the current invention may also be prepared according to Scheme 3, as indicated below. A dihalo prepared according to Scheme 4. The difluoroketone or trif aromatic compound can be mono-lithiated and reacted with luoroketone generated in Scheme 1 can be converted to the acetone or hexafluoroacetone to generate the corresponding corresponding tertiary alcohol by reaction with an alkyl tertiary alcohol. This alcohol can be converted into com pounds of the current invention by the method described in lithium. This alcohol can then be elaborated to compounds of Scheme 3. the current invention via a Suzuki coupling reaction.

Scheme 3 Scheme 4 1 in ---1) n-BuLi Halo Halo 2) O Alkyllithium ls Halo n -N -- HC/FC CF/CH O O US 2009/029 1988 A1 Nov. 26, 2009 14

Step 3: Preparation of -continued 1-bromo-4-(bromomethyl)-2-fluorobenzene alkyl CF3/CF2H Halo 0298 To a room temperature solution of 4-bromo-3-fluo ND OH rotoluene (10.6 g) in 150 mL of carbon tetrachloride were E added benzoyl peroxide (100 mg) and N-bromosuccinimide Y (10g). The mixture was heated at 80°C. (with shine light) for R3 YBOH), 4 hours. The reaction mixture was cooled to 0°C. and filtered aq. Na2CO3, DMF, through celite, washed with hexanes and the solvent removed PdCl2(dppf), A in vacuo. The crude material was purified by chromatography on SiO, using hexanes to yield the title compound containing Alkyl, CF3/CF2H ~30% of 1-bromo-4-(dibromomethyl)-2-fluorobenzene as Y E impurity. R3 ND OH 0299 H NMR (CDCOCD) 87.66-7.10 (1H, m), 7.42 0293. The following examples describe the synthesis of (1H, d), 7.29 (1H, d), 4.66 (2H, s). selected compounds of the present invention and are included for illustrative purposes and do not limit the scope of the Step 4: Preparation of invention in any way. (4-bromo-3-fluorophenyl)methanol 0300. To a room temperature solution of 1-bromo-4-(bro EXAMPLE1 momethyl)-2-fluorobenzene from Step 3 (11.8 g) in DMF (150 mL) was added sodium acetate (10.8 g). The mixture Synthesis of 1-4'-(2,2-difluoro-1-hydroxyethyl)-2- was heated at 80° C. for 16 hours. It was cooled to room fluorobiphenyl-4-yl)cyclopropanecarbonitrile temperature and poured into ice and saturated aqueous sodium bicarbonate (200 mL), and extracted with diethyl 0294 ether (2x100 mL). The combined extracts were washed with brine, dried with magnesium sulfate and the solvent removed F F in vacuo. The crude material was purified by chromatography on SiO, using ethyl acetate and hexanes (1:25 to 1:10) to yield 4-bromo-3-fluorobenzyl acetate (containing about 15% of OH 4-bromo-3-fluorobenzaldehyde). The residue was dissolved in methanol (100 mL), cooled to 0°C. and sodium methoxide (250mg) was added. The reaction mixture was stirred at room temperature for 2 hours. It was cooled to 0°C. and sodium borohydride was added (1.5 g). The mixture was stirred at 0° s O C. for 1 hour and poured into ice and Saturated aqueous /\ F ammonium chloride (200 mL). The mixture was extracted with ethyl acetate (2x100 mL). The combined extracts were washed with brine, dried with magnesium sulfate and the Step 1: Synthesis of solvent removed in vacuo. The residue was purified by chro 1-(4-bromophenyl)-2,2-difluoroethanol matography on SiO, using ethyl acetate and hexanes (1:5 to 1:3) to yield the title compound. 0295) To a cold (0°C.) solution of 1-(4-bromophenyl)-2, 2-difluoroethanone (1.07 g. 4.55 mmol) in MeOH (30 mL) (0301 HNNMR (CDCOCD) 87.55-7.65 (1H, m), 7.28 was added NaBH (260 mg. 6.83 mmol) portionwise. The (1H, d), 7.15 (1H, d), 4.63 (2H, d), 4.50 (1H, t). reaction was warmed tort and stirred for 16h. Acetone (5 mL) was added followed by water (10 mL). The mixture was Step 5: Preparation of concentrated under reduced pressure followed by the addition (4-bromo-3-fluorophenyl)acetonitrile of EtO (50 mL) and 0.1 NHCl (25 mL). The layers were 0302) To a -78°C. solution of (4-bromo-3-fluorophenyl) separated and the organic extract was washed with brine methanol from Step 4 (7.2 g) and triethylamine (5.9 mL) in (1x50 mL), dried (MgSO) and concentrated to yield the title dichloromethane (300 mL) was slowly added methane compound. sulphonyl chloride (3.0 mL). The reaction mixture was stirred at 0°C. for 1 hour and then poured into ice and saturated Step 2: Synthesis of 2,2-difluoro-1-4-(4.4.5.5-tet aqueous ammonium chloride and partitioned. The aqueous ramethyl-1,3,2-dioxaborolan-2-yl)phenylethanol layer was extracted with dichloromethane (1x150 mL). The combined extracts were washed with brine, dried with mag 0296. A solution of 1-(4-bromophenyl)-2,2-difluoroetha nesium sulfate and the solvent removed in vacuo. The residue nol (1.07 g. 4.55 mmol), potassium acetate (1.33 g, 13.5 was dissolved in DMF (150 mL) and sodium cyanide (5.1 g) mmol) and bis(pinacolato)diboron (1.37 g, 5.4 mmol) in was added. The reaction mixture was stirred at room tempera DMF (20 mL) was bubbled with nitrogen for 5 minutes then ture for 2 hours and poured into ice and water (100 mL). The PdCldppf (184 mg. 0.225 mmol) was added and the reaction aqueous phase was extracted with ethyl acetate (2x100 mL). mixture was stirred at 80°C. overnight. The reaction mixture The combined organic extracts were washed with brine, dried was concentrated under reduced pressure and filtered through with magnesium Sulfate and the solvent removed in vacuo. a plug of silica gel to remove any insoluables. The filtrate was The residue was purified by chromatography on SiO, using concentrated to afford the title compound which was used as ethyl acetate and hexanes (1:10 to 1:5) to yield the title com such in Step 7. pound. 0297 'HNMRö (ppm)(Acetone): 7.75 (2H, m), 7.48 (2H, (0303 H NMR (CDCOCD) & 7.70-7.78 (1H, m), 7.39 d), 5.90 (1H, dt), 5.30 (1H, d), 4.87 (1H, m), 1.31 (12H, s). (1H, d), 7.28 (1H, d), 4.09 (2H, s). US 2009/029 1988 A1 Nov. 26, 2009

Step 6: Preparation of mL) and iodomethane (18 mL) in THF (900 mL) at -20°C. 1-(4-bromo-3-fluorophenyl)cyclopropanecarbonitrile was added dropwise lithium bis(trimethylsilyl)amide (1M in 0304) To a room temperature solution of (4-bromo-3-fluo THF, 586 mL) over 30 minutes. The reaction mixture was rophenyl)acetonitrile from Step 5 (6.4 g) in a solution of 7.5 stirred at -20°C. for 2 hand warmed up to room temperature mL of sodium hydroxide (50% in water W/W) were added over 2 hand finally stirred at room temperature for 2 h. "H 1-bromo-2-chloroethane (4.0 mL) and benzyltriethylammo NMR of an aliquot showed 50% conversion. The reaction nium chloride (204 mg). The mixture was heated at 60° C. for mixture was cooled to -20°C. and lithium bis(trimethylsilyl) 5 hours. The reaction mixture was cooled to room tempera ture and poured into water (100 mL). The aqueous phase was amide (1M in THF, 140 mL) was added. The mixture was extracted with ethyl acetate (200 mL). The combined organic warmed up to room temperature over 2 hand aged overnight extracts were washed with water (100 mL), hydrogen chlo at room temperature. "H NMR of an aliquot showed 75% ride (100 mL, 10% HCl in water) and brine and then dried conversion. The reaction mixture was poured into ice and 6N with magnesium sulfate and the solvent removed in vacuo. HCl (190 mL), partitioned and extracted with ether (2x400 The residue was purified by Swish using methyl t-butyl ether mL). The combined organic extracts were washed with a and hexanes to yield the title compound. saturated NaCl solution, dried (MgSO) and concentrated 0305 H NMR (CDCOCD) & 7.69-7.73 (1H, m), 7.28 under vacuum to yield the title compound. H NMR showed (1H, d), 7.25 (1H, d), 1.80-1.87 (2H, m), 1.59-1.65 (2H, m). about 20% of 4-bromophenylacetic acid. It was used as such Step 7: Synthesis of 1-4'-(2,2-difluoro-1-hydroxy in Step 3. ethyl)-2-fluorobiphenyl-4-yl)cyclopropanecarboni 0311 "H NMR of title compound (CDCOCD) & 7.52 trile (2H, d), 7.32 (2H, d), 3.79 (1H, q), 1.46 (3H, d). Peaks of 0306 To a solution of 1-(4-bromo-3-fluorophenyl)tyclo starting material not listed. propanecarbonitrile from step 6 (72 mg, 0.30 mmol) and 2,2-difluoro-1-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan Step 3 2-(4-bromophenyl)propanamide 2-yl)phenylethanol from step 2 (85 mg, 0.30 mmol) in DMF (3 mL) was added a solution of 2.0 M sodium carbonate (440 0312 To a solution of 2-(4-bromophenyl)propanoic acid uL, 0.89 mmol). The mixture was bubbled with nitrogen for (4.0g, 17.5 mmol) in chloroform (175 mL) at 0°C. was added 10 minutes and then PdClddpf (12 mg, 0.015 mmol) was triethylamine (3.9 mL. 27.7 mmol) followed by isobutyl chlo added. The solution was heated in the microwave at 120° C. roformate (3.4 mL. 25.9 mmol). The reaction mixture was for 500 seconds. EtO (50 mL) and water (50 mL) were added stirred at 0°C. for 2 h. Then ammonia gas was bubbled into and the layers were separated. The aqueous phase was the reaction mixture for 15 minutes and warmed up to room extracted with EtO (3x50 mL) and the combined organic temperature for 1 h. The reaction mixture was poured to onto extracts were washed with brine (1x50 mL), dried (NaSO) and concentrated. The resulting residue was flash chromato ice/water and extracted with CHCl (2x150 mL). The com graphed (50:50 EtOAc/Hexanes) to afford the title com bined organic layers were washed with a saturated NaCl pound. solution, dried (MgSO) and concentrated under vacuum fol 0307 H NMR 8 (ppm)(Acetone): 7.59 (5H, m), 7.35 (1H, lowed by Swish in MTBE/Hexanes to afford the title com d), 7.19 (1H, d), 5.97 (1H, dt), 4.92 (1H, dt), 1.82 (2H, m), pound as colorless powder. "H NMR (CDCOCD) & 7.50 1.62 (2H, m). (2H, d), 7.35 (2H, d), 6.83 (1H, s), 6.22(1H, s), 3.69 (1H, q), EXAMPLE 2 1.40 (3H, d). Synthesis of 2-4'-[(1R)-2.2.2-trifluoro-1-hydroxy Step 4: Preparation of 2-4-(4.4.5.5-tetramethyl-1,3, ethylbiphen-4-yl)propanamide 2-dioxaborolan-2-yl)phenylpropanamide 0308 0313 A solution of 2-(4-bromophenyl)propanamide (500 mg, 2.192 mmol), potassium acetate (753 mg, 7.67 mmol) and bis(pinacolato)diboron, 98% (724 mg, 2.85 mmol) in DMF (20 mL) was bubbled with nitrogen for 15 minutes then PdCldppf (90 mg 0.11 mmol) was added and bubbled again with nitrogen for 10 minutes. The reaction mixture was stirred at 65° C. overnight, poured onto ice/water and extracted with 50% EtOAc/Hexanes (3x50 mL). The com bined organic layers were washed with a saturated NaCl Solution, dried (MgSO4) and concentrated under vacuum. The residue was purified by chromatography on silica gel (EtOAc/Hexane, 1:1 to 2:1) to afford the title compound. 0314 H NMR (CDCOCD) 7.70 (2H, d), 7.40 (2H, d), Step 1: Synthesis of 6.75 (1H, s), 6.21 (1H, s), 3.70 (1H, q), 1.41 (3H, d), 1.34 (1R)-1-(4-bromophenyl)-2.2.2-trifluoroethanol (12H, s). 0309 1-(4-Bromophenyl)-2.2.2-trifluoroethanone was Step 5: Synthesis of 2-4'-[(1R)-2.2.2-trifluoro-1- reduced enantioselectively with (-)DIP-Cl to afford the title hydroxyethylbiphenyl-4-yl)propanamide compound as reported in Tetrahedron Asymmetry 1994, 1075. 0315) To a solution of 2-4-(4.4.5.5-tetramethyl-1,3,2-di oxaborolan-2-yl)phenylpropanamide from Step 4 (140 mg. Step 2: Preparation of 2-(4-bromophenyl)propanoic 0.51 mmol) and (1R)-1-(4-bromophenyl)-2.2.2-trifluoroet acid hanol from Step 1 (156 mg, 0.61 mmol) in DMF (6 mL) was 0310. To a solution of 4-bromophenylacetic acid (60 g), added a solution of 2.0 M sodium carbonate (650 uL. 1.3 1,3-Dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (60.5 mmol). The mixture was bubbled with nitrogen for 10 min US 2009/029 1988 A1 Nov. 26, 2009

utes then PdClddpf (25 mg, 0.031 mmol) was added. The hol (110 mL) was added a solution of 56 mL of sodium mixture was bubbled again with nitrogen for 10 minutes. hydroxide (25% NaOH in water W/W). The mixture was Then the reaction mixture was stirred at 80°C. for 2 h, poured heated at 100° C. overnight. It was cooled to room tempera onto an ice/saturated NaHCO, solution and extracted with ture and poured into ice and hydrogen chloride (1 N), and EtOAc (3x50 mL). The combined organic layers were extracted with dichloromethane (2x100 mL). The combined washed with a saturated NaCl solution, dried (MgSO) and extracts were washed with brine, dried with magnesium sul concentrated under vacuum. Purification by chromatography fate and the solvent removed in vacuo to yield the title com on silica gel using automatized gradiant pump system Com pound. biFlash (EtOAc/Hexane, 50:50 to 80:20 for 30 minutes) 0322 'HNMR (CDCOCD) 87.50 (2H,d), 7.35 (2H,d), afforded the title compound as pale yellow powder. 1.53-1.60 (2 um), 1.18-1.22 (2H, m). 0316 H NMR (500 MHz, Acetone): 8 7.72 (d. J=8.4 Hz, 2H); 7.65 (dd, J=3.2, 8.2 Hz, 4H); 7.49 (d. J=8.2 Hz, 2H); 6.80 Step 4: Preparation of (s, 1H); 6.20 (s, 1H); 5.90 (d. J–5.5 Hz, 1H); 5.32-5.26 (m, 1-(4-bromophenyl)cyclopropanecarboxamide 1H); 3.75 (q, J=7.0 Hz, 1H); 1.46 (d. J=7.1 Hz, 3H). MS 0323 To a -15°C. solution of 14-bromophenyl)cyclopro (+APCI); 324.2. panecarboxylic acid from Step 3 (1.5 g) in chloroform (60 EXAMPLE 3 mL) were slowly added isobutyl chloroformate (900 uL) and triethylamine (1.1 mL). The reaction mixture was stirred at Synthesis of 1-4'-(1S)-1-amino-2,2-difluoroethyl -15°C. for 2 hours. Then it was saturated with ammonia gas biphenyl-4-yl)cyclopropanecarboxamide and stirred at -15° C. for 10 minutes. The reaction mixture was allowed to stand at room temperature for 1 hour then 0317 poured into water (60 mL) and partitioned. The aqueous layer was extracted with dichloromethane (2x60 mL). The com bined extracts were washed with brine, dried with magnesium sulfate and the solvent removed in vacuo. The residue was purified by Swish using diethyl ether and hexanes to yield the title compound. 0324 'HNMR (CDCOCD) 87.54 (2H,d), 7.40 (2H,d), O NH2 6.45 (1H, bs), 5.96 (1H, bs), 1.42-1.48 (2H, m), 0.98-1.02 (2H, m). Step 5: Synthesis of 1-4-(4.4.5.5-tetramethyl-1,3,2- dioxaborolan-2-yl)phenylcyclopropanecarboxamide 0325 A solution of 14-bromophenyl)cyclopropanecar boxamide (9.4g, 39.2 mmol), potassium acetate (13.45 g, 137 Step 1: Synthesis of mmol) and bis(pinacolato)diboron, 98% (12.95 g, 51 mmol. (1S)-1-(4-bromophenyl)-2,2-difluoroethylamine 1.3 eq) in DMF (150 mL) was bubbled with nitrogen for 15 minutes then PdCldppf (1.6 g. 1.959 mmol) was added and 0318. The title compound was synthesized starting from bubbled again with nitrogen for 10 minutes. The reaction 1-(4-bromophenyl)-2,2-difluoroethanone as described in the mixture was stirred at 65°C. overnight, poured unto ice/water synthesis of (1S)-1-(4-bromophenyl)-2.2.2-trifluoroetha and extracted with 50% EtOAc/Hexanes (3x300 mL). The namine (example 8) combined organic layers were washed with a saturated NaCl Step 2: Preparation of Solution, dried (MgSO4) and concentrated under vacuum. 1-(4-bromophenyl)cyclopropanecarbonitrile The residue was purified by chromatography on silica gel (EtOAc/Hexane, 1:1 to 2:1) followed by trituration with 0319. To a room temperature solution of 4-bromopheny MTBE/Hexanes to afford the title compound as light beige lacetonitrile (18.0 g) in a solution of 22 mL of sodium hydrox solid powder. ide (50% in water W/W) were added 1-bromo-2-chloroethane 0326) "H NMR 6 (ppm)(Acetone): 7.74 (2H, d, J=8.0 Hz), and (12.0 mL) and benzyltriethylammonium chloride (627 7.46 (2H, d, J=8.0 Hz), 6.34 (1H, s), 5.80 (1H, s), 1.48-1.46 mg). The mixture was heated at 60° C. overnight. The reac (2H, m), 1.36 (12H, s), 1.00 (2H, q, J=3.4 Hz). tion mixture was cooled to room temperature and diethyl ether was added (300 mL) and partitioned. The ether layer Step 6: Synthesis of 1-4'-(1S)-1-amino-2,2-difluo was washed with water (100 mL), hydrogen chloride (100 roethylbiphenyl-4-yl)cyclopropanecarboxamide mL, 10% HCl in water), brine and dried with magnesium 0327. To a solution of (1S)-1-(4-bromophenyl)-2,2-dif sulfate. Upon removal of the solvent in vacuo, the residue was luoroethylamine from Step 1 (2.1 g, 8.9 mmol) and 1-4-(4. purified by Swish using diethyl ether and hexanes to yield the 4.5.5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenylcyclopro title compound. panecarboxamide from Step 5 (3.0 g, 10.45 mmol) in DMF 0320 "H NMR (CDCOCD) & 7.60 (2H, d), 7.35 (2H,d), (40 mL) was added a solution of 2.0 M sodium carbonate (11 1.74-1.80 (2H, m), 1.52-1.57 (2H, m). mL, 22 mmol). The mixture was bubbled with nitrogen for 10 Step 3: Preparation of minutes then PdCldppf (400 mg. 0.49 mmol) was added. The 1-(4-bromophenyl)cyclopropanecarboxylic acid mixture was bubbled again with nitrogen for 10 minutes. Then the reaction mixture was stirred at 80°C. for 2 h, poured 0321) To a room temperature solution of 1-(4-bromophe into an icy saturated NaHCO solution and extracted with nyl)cyclopropanecarbonitrile from Step 2 (13 g) in ethyl alco EtOAc (3x150 mL). The combined organic layers was US 2009/029 1988 A1 Nov. 26, 2009

washed with a saturated NaCl solution, dried (MgSO) and rated and the organic phase was washed with 1 N NaOH (25 concentrated under vacuum. The residue was purified by mL), dried (Na2SO4) and concentrated. The resulting residue chromatography on silica gel (EtOAc/Hexanes, 60:40 to was flash chromatographed (70:30 EtOAc/Hexanes) to afford 75:25 then 10% EtOH/EtOAc) followed by trituration in the title compound. MTBE/hexanes to afford the title compound as pale yellow 0333 HNMR 8 (ppm)(Acetone): 7.65 (4H, m), 7.50 (4H, powder. m), 7.05 (1H, t), 6.95 (1H, t), 6.70 (1H,bs), 6.15 (1H, s), 5.95 0328 HNMR 8 (ppm)(CDOD): 7.68 (4H, dd, J=2.3,8.3 (1H, bs), 1.49 (2H, m), 1.05 (2H, m). Hz), 7.53 (4H, dd, J=3.6, 8.2 Hz), 6.05-5.81 (1H, m), 4.23-4. 17 (1H, m), 1.56 (2H, q, J–3.5 Hz), 1.15 (2H, q, J–3.5 Hz). EXAMPLE 5 MS (+APCI)–317.0. E.E.-100% (determined by Chiralcel Synthesis of 1-4'-amino(2,4-difluorophenyl)me OD 4.6x250 mm, 80% Hexanes/20% EtOH/0.1% diethy thylbiphenyl-4-yl)cyclopropanecarboxamide lamine, Rt=19.447 minutes). 0329. Optical rotation=+11.3 (c=1, MeOH) 0334 EXAMPLE 4

Synthesis of 1-4'-(2,4-difluorophenyl)(hydroxy) methylbiphenyl-4-yl)cyclopropanecarboxamide 0330

Step 1: Synthesis of (4-bromophenyl)(2,4-difluorophenyl)methyl azide 0335 To a solution of (4-bromophenyl)(2,4-difluorophe nyl)methanol from Step 1, Example 4 (1.65 g, 5.5 mmol) and PPhs (1.73g, 6.6 mmol) in dry THF (30 mL) was added DIAD (1.3 mL, 6.6 mmol) followed by DPPA (1.45 mL, 6.6 mmol). Step 1: Synthesis of The reaction was stirred at rt for 5 hat which time water (50 (4-bromophenyl)(2,4-difluorophenyl)methanol mL) was added. The layers were separated and the aqueous 0331. To a cold (-78° C.), stirred solution of 1,4-dibro phase was extracted with EtO (2x100 mL). The combined mophenyl (12.3 g, 52 mmol) in Et2O (200 mL) was added organic extracts were dried (Na2SO4) and concentrated. The n-BuLi (2.5 M in hexanes, 19.2 mL, 48 mmol) and the reac resulting residue was flash chromatographed (5:95 EtOAc/ tion was stirred for 1 h. This mixture was then added to a cold Hexanes) to afford the title compound. (-78°C.) solution of 2,4-difluorobenzaldehyde (4.4 mL, 40 mmol) and stirred at -78°C. for 2 h. Water was added (200 Step 2: Synthesis of mL) and the layers were separated. The aqueous layer was (4-bromophenyl)(2,4-difluorophenyl)methylamine extracted with EtO (2x250 mL) and the combined organic 0336 To a solution of (4-bromophenyl)(2,4-difluorophe extracts were dried (NaSO) and concentrated. The resulting nyl)methyl azide (1.16 g, 3.58 mmol) in MeOH (15 mL) was residue was flash chromatographed (15:85 EtOAc/Hexanes) added 1,3-propanedithiol (1.1 mL, 10.7 mmol) followed by to afford the title compound. EtN (1.5 mL, 10.7 mmol). The reaction was stirred at rt for 4 hand then concentrated. The resulting residue was flash chro Step 2: Synthesis of 1-4'-(2,4-difluorophenyl)(hy matographed (50:50 EtOAc/Hexanes to 70:30 EtOAc/Hex droxy)methylbiphenyl-4- anes) to afford the title compound. yl)cyclopropanecarboxamide Step 3: Synthesis of 1-4'-amino(2,4-difluorophe 0332 To a solution of (4-bromophenyl)(2,4-difluorophe nyl)methylbiphenyl-4-yl)cyclopropanecarboxamide nyl)methanol from Step 1 (90 mg, 0.3 mmol), 1-4-(4.4.5.5- tetramethyl-1,3,2-dioxaborolan-2-yl)phenylcyclopropan 0337 To a solution of (4-bromophenyl)(2,4-difluorophe ecarboxamide from Step 5. Example 3 (170 mg, 0.36 mmol) nyl)methylamine from Step 2 (90 mg, 0.3 mmol), 1-4-(4.4, and PdCl(dppf) (12 mg, 0.015 mmol) in dry DMF (4 mL) 5.5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)cyclopro was added aqueous NaCO (2 M. 450 uL, 0.9 mmol). The panecarboxamide from Step 5. Example 3 (170 mg, 0.36 solution was heated at 80° C. for 16 h. The reaction mixture mmol) and PdCl2(dppf) (12 mg, 0.015 mmol) in dry DMF (4 was cooled to room temperature followed by the addition of 1 mL) was added aqueous NaCO (2 M. 450 uL, 0.9 mmol). MNaOH (5 mL) and EtO (50 mL). The layers were sepa The solution was heated at 80° C. for 16 h. The reaction US 2009/029 1988 A1 Nov. 26, 2009

mixture was cooled to room temperature followed by the (10 mL) was added and the layers were separated. The aque addition of 1 MNaOH (5 mL) and EtO (50 mL). The layers ous phase was extracted with EtOAc (3x50 mL) and the were separated and the organic phase was washed with 1 N combined organic extracts were washed with brine (1x50 NaOH (25 mL), dried (NaSO)and concentrated. The result mL), dried (Na2SO4) and concentrated. The resulting residue ing residue was flash chromatographed (95:5 EtOAc/Hex was flash chromatographed (60:40 EtOAc/Hexanes) to afford anes) to afford the title compound. 'H NMR 6 (ppm)(Ac the title compound. etone): 7.60 (4H, m), 7.51 (4H, m), 6.98 (2H, m), 6.60 (1H, (0342 H NMR 6 (ppm)(Acetone): 7.80-7.65 (6H, m), 7.50 (2H, d), 6.40 (1H, s), 5.85 (1H, s), 1.80 (3H, s), 1.45 (2H, bs), 6.02 (1H, s), 5.92 (1H, bs), 1.49 (2H, m), 1.03 (2H, m). m), 1.02 (2H, m). EXAMPLE 6 EXAMPLE 7 Synthesis of 1-4'-(2.2.2-trifluoro-1-hydroxy-1-meth Synthesis of 1-(4-6-(2.2.2-trifluoro-1-hydroxyethyl) ylethyl)biphenyl-4-yl)cyclopropanecarboxamide yridine-3-yl)phenyl)cyclopropanecarboxamide 0338 0343

21 OH

HN

Step 1: Synthesis of 1-4'-4-(trifluoroacetyl)biphe Step 1: Synthesis of nyl-4-yl)cyclopropanecarboxamide 1-(5-bromopyridin-2-yl)-2.2.2-trifluoroethanone 0344) To a cold (-78°C.) solution of 2,5-dibromopyridine 0339. To a solution of 1-(4-bromophenyl)-2.2.2-trifluoro (8.0 g, 33.9 mmol) in toluene (230 mL) was added n-Bulli ethanone (133 mg 0.53 mmol), 1-4-(4.4.5.5-tetramethyl-1, (2.5 M in hexanes, 13.5 mL, 33.8 mol) and the mixture was 3.2-dioxaborolan-2-yl)phenylcyclopropanecarboxamide stirred for 30 min. 2.2.2-Trifluoroethyl trifluoroacetate (5.0 from Step 5. Example 3 (151 mg 0.53 mmol) and PdCl mL, 37.3 mmol) was added dropwise over 15 min and then the (dppf) (43 mg 0.053 mmol) in dry DMF (4 mL) was added mixture was stirred at -78° C. for 2 h. The mixture was aqueous NaCO, (2M, 0.8 mL, 1.58 mmol). The solution was allowed to warm to room temperature and then quenched with heated in the microwave at 120° C. for 500 seconds. EtO (50 sat. aq. NHCl (50 mL). The layers were separated and the mL) and water (50 mL) were added and the layers were aqueous phase was extracted with EtOAc (3x100 mL). The separated. The aqueous phase was extracted with EtO (3x50 combined organic extracts were dried (MgSO) and concen LL) and the combined organic extracts were washed with trated. The residue was subjected to flash column chromatog brine (1x50 mL), dried (NaSO) and concentrated. The raphy (gradient elution: 15:85 EtOAc:hexanes to 40:60 resulting residue was flash chromatographed (50:50 EtOAc/ EtOAc:hexanes) to afford the title compound. Hexanes) to afford the title compound. 0340 "H NMR 6 (ppm)(Acetone): 8.25 (2H, d), 8.03 (2H, Step 2: Synthesis of d), 7.83 (2H, d), 7.62 (2H, d), 6.47 (1H, s), 5.96 (1H, s), 1.5 1-(5-bromopyridin-2-yl)-2.2.2-trifluoroethanol (2H, m), 1.07 (2H, m). 0345 To a cold (0°C.) solution of 15-bromopyridin-2-yl)- 2.2.2-trifluoroethanone from Step 1 (1.7 g. 6.7 mmol) in Step 2: Synthesis of 1-4'-(2.2.2-trifluoro-1-hydroxy MeOH (80 mL) was added solid NaBH (0.5g, 13.2 mmol) 1-methylethyl)biphenyl-4-yl)cyclopropanecarboxa and the mixture was stirred for 30 min followed by quenching mide with AcOH (1 mL). The solvent was removed and the residue was diluted with water (50 mL) and extracted with EtOAc 0341 To a cold (-78° C.) solution of 1-4'-(trifluoro (3x50 mL). The combined organic extracts were washed with acetyl)biphenyl-4-yl)cyclopropanecarboxamide from Step 1 sat. aq. NaHCO (1x50 mL), brine (1x50 mL) and dried (89 mg, 0.27 mmol) in THF (3 mL) was added Melli (1.6M (NaSO). Concentration of the dried extracts afforded the in Et2O, 340 uL, 0.54 mmol) and stirred for 2 h. Saturated aq. title compound as a light brown oil. NHCl (10 mL) was added and the layers were separated. The (0346 H NMR 6 (ppm)(Acetone): 8.70 (1H, d, J=2.0 Hz), aqueous phase was extracted with EtOAc (3x50 mL) and the 8.13 (1H, dd, J–2.3, 8.4Hz), 7.66 (1H, d. J=8.4Hz), 6.02(1H, combined organic extracts were washed with brine (1x50 mL), dried (Na2SO4) and concentrated. The "H NMR of the d, J=6.5 Hz), 5.26-5.20 (1H, m). residue indicated 50:50 starting material to product. Hence, Step 3: Synthesis of the residue was redissolved in THF (3 mL), cooled to -78°C. 1-4-6-(2,2,2-trifluoro-1-hydroxyethyl) and an additional aliquot of Melli (1.3 mL, 2 mmol) was yridine-3-yl)phenyl)cyclopropanecarboxamide added. The reaction was stirred at -78°C. for 1 h, warmed to 0347 To a solution 1-(5-bromopyridin-2-yl)-2.2.2-trif 0°C. for 10 min and then tort for 10 min. Saturated aq. NHCl luoroethanol from Step 2 (128 mg 0.5 mmol), 1-4-(4.4.5.5- US 2009/029 1988 A1 Nov. 26, 2009 tetramethyl-1,3,2-dioxaborolan-2-yl)phenylcyclopropan remove (R)-diphenylprolinol and filtered. The organic layer ecarboxamide from Step 5. Example 3 (220 mg. 0.77 mmol) was dried and filtered. A solution of hydrogen chloride (2 M and PdCl2(dppf) (41 mg 0.05 mmol) in dry DMF (5 mL) was in EtO, 40 mL) was added to the crude solution of amine. A added aqueous NaCO, (2 M,900 uL. 1.8 mmol). The solu white precipitate formed. After aging at rt for 1 h, the slurry tion was heated at 85°C. for 3 h. EtO (50 mL) and water (50 was filtered and the solids were washed with MTBE (10 mL) mL) were added and the layers were separated. The aqueous to afford (1S)-1-(4-bromophenyl)-2.2.2-trifluoroethanamine phase was extracted with EtO (3x50 mL) and the combined hydrochloride as a white powder. organic extracts were washed with brine (1x50 mL), dried 0352 H NMR 8 (ppm)(CDOD): 7.73 (2H, d, J=8.5), (NaSO) and concentrated. The resulting residue was flash 7.51 (2H, d, J=8.5).5.42 (1H, q, J=7.4). chromatographed (5:95 EtOH/CH,Cl) to afford the title compound as a white powder. 0348 H NMR 6 (ppm)(Acetone): 8.90 (1H, d, J=1.9 Hz), EXAMPLE 9 8.19 (1H, dd, J=2.3, 8.2 Hz), 7.76-7.74 (3H, m), 7.59 (2H, d, Synthesis of (1R)-1-(4-bromophenyl)-2.2.2-trifluoro J=8.3 Hz), 6.37 (1H, s), 5.92 (1H, d. J=6.6 Hz), 5.88 (1H, s), ethanamine 5.31-5.25 (1H, m), 1.47 (2H, q, J–3.4 Hz), 1.04 (2H, q, J-34 Hz). MS (+ESI): 337 (M+1)* 0353 EXAMPLE 8 Synthesis of (1S)-1-(4-bromophenyl)-2.2.2-trifluoro F ethanamine "N- F 0349 NH2 F F F Br

0354. The title compound was synthesized in an identical NH2 manner to (1S)-1-(4-bromophenyl)-2,2,2-trifluoroetha namine (Example 8) using (S)-B-butyl-diphenylpyrrolidino Br oxazaborolidine as catalyst.

EXAMPLE 10 Step 1: Synthesis of 1-(4-bromophenyl)-2.2.2-trifluoroethanimine Synthesis of 1-(4-bromophenyl)-2.2.2-trifluoroet 0350 1-(4-Bromophenyl)-2.2.2-trifluoroethanone (491 hylamine mg, 2.82 mmol) was dissolved in toluene (10 mL) at rt. A solution of lithium bis(trimethylsilylamide) (1 M in THF, 0355 3.15 mL, 3.15 mmol) was added over a 10 min period. The reaction was stirred at rt for 15 min and then concentrated to yield N-1-(4-bromophenyl)-2.2.2-trifluoroethylidene-1,1, F 1-trimethylsilanamine. Solvolysis of the N-TMS-ketimine F F took place by stirring at rt for 16 h in MeCH. Upon removal of MeOH, the title compound was generated. NH2 Step 2: Synthesis of (1S)-1-(4-bromophenyl)-2.2.2-trifluoroethanamine Br 0351. A solution of (R)-B-butyl-diphenylpyrrolidino-ox azaborolidine (0.3 M in toluene, 3.14 mL, 0.94 mmol) was 0356, 1-(4-Bromophenyl)-2.2.2-trifluoroethanone (491 dissolved in toluene (10 mL) and cooled to -15° C., and mg, 2.82 mmol) was dissolved in toluene (10 mL) at rt. A catecholborane (6.01 mL, 56.5 mmol) was added to the solu solution of lithium bis(trimethylsilylamide) (1 M in THF, tion. A solution of 1-(4-bromophenyl)-2.2.2-trifluoroetha 3.15 mL, 3.15 mmol) was added over a 10 min period. The namine from Step 1 (10g, 37.6 mmol) in toluene (40 mL) was reaction was stirred at rt for 15 min. and BH MeS (2M in added dropwise via syringe pump over a period of 2.5h. After toluene, 2.82 mL, 5.73 mmol) was added. The reaction mix the addition was complete, the reaction mixture was stirred at ture was stirred at rt for 20 min. After cooling to 0°C., aq. 2 -15°C. for 18 h. The reaction was quenched with aqueous 1 N NaOH (4 mL) was carefully added dropwise over 5 min. N HCl (50 mL) and allowed to warm to room temperature, The mixture was stirred at rt for 90 min. The layers were and the layers were separated. The aqueous layer was basified separated, and the organic layer was washed with aqueous 2 with 10 N NaOH to Ph 12. The aqueous layer was extracted N NaOH (5 mL) and water (5 mL), dried (MgSO), and with MTBE (1x50 mL). The layers were separated, and the filtered. Concentration of the filtrate provided the title com organic layer was washed with aqueous 2NNaOH (2x50 mL) pound. Alternatively, to the solution of crude free amine in and water (50 mL). The organic layer was treated with toluene was added a solution of HCl (4M in 1,4-dioxane, 1 Amberlite IRC-50S ion-exchange resin (5 g) for 40 minto mL). A white precipitate formed and the solids were washed US 2009/029 1988 A1 Nov. 26, 2009 20 with MTBE (10 mL) to afford 1-(4-bromophenyl)-2.2.2- The combined organic extracts were washed with brine (1x), trifluoroethylamine hydrochloride as a white powder. dried (NaSO) and concentrated under reduced pressure. The residue was purified by chromatography on silica gel (EtOAC/ EXAMPLE 11 Toluene, 0:1 to 1:9) and then swished with hexanes overnight Synthesis of 1-(4-bromophenyl)-2,2-difluoroethyl to afford, after filtration, the title compound as light beige solid powder. amine 0363 H NMR 8 (ppm)(Acetone): 7.71 (2H, d), 7.55 (2H, 0357 d), 4.10 (1H, s), 1.58 (6H, s), 1.38 (12H, s). Step 3: Synthesis of 1-2-fluoro-4'-(1-hydroxy-1- methylethyl)biphenyl-4-yl)cyclopropanecarbonitrile 0364. A solution of 2-4-(4.4.5.5-tetramethyl-1,3,2-diox aborolan-2-yl)phenylpropan-2-ol from step 2 above (1.35 g, NH2 5.2 mmol) and 1-(4-bromo-3-fluorophenyl)cyclopropanecar bonitrile from step 6. Example 1 (1.03 g, 4.3 mmol) in DMF Br (21 mL) was degassed followed by the addition of PdCldppf (350 mg, 0.4 mmol) and 2Maqueous NaCO, (6.4 mL, 12.9 mmol). The reaction mixture was stirred at 90° C. for 4 hand 0358. The same procedure used to synthesize of 1-(4- then diluted with water and extracted with EtOAc (4x). The bromophenyl)-2.2.2-trifluoroethylamine (Example 10) was combined organic extracts were washed with brine (2x), dried used to generate the title compound. The only difference is (NaSO) and concentrated under reduced pressure. The resi that 1-(4-bromophenyl)-2,2-difluoroethanone was used as due was purified by chromatography on silica gel (EtOAC/ the starting material. Hexanes, 0:1 to 2:8 to 3:7) to afford the title compound as white solid powder. EXAMPLE 12 0365 H NMR 8 (ppm)(Acetone): 7.67 (2H, d, J=8.4 Hz), Synthesis of 1-2-fluoro-4'-(1-hydroxy-1-methyl 7.60 (1H, d, J=8.1 Hz), 7.57-7.53 (2H, m), 7.35 (1H, dd, ethyl)biphenyl-4-yl)cyclopropanecarbonitrile J=2.0, 8.0 Hz), 7.22 (1H, dd, J=2.0, 12.1 Hz), 4.13 (1H, s), 0359 1.85 (2H, q, J–4.2 Hz), 1.67-1.63 (2H, m), 1.58 (6H, s). EXAMPLE 13 Synthesis of 1-(2-fluoro-1,1':4'1"-terphenyl-4-yl) OH cyclopropanecarbonitrile 0366

Step 1: Synthesis of 2-(4-bromophenyl)propan-2-ol 0360. To a cold (0° C.) solution of 1-(4-bromophenyl) ethanone (10g, 50.2 mmol) in benzene (50 mL) was added MeMgBr (3M in EtO, 22.3 mL, 66.8 mmol). The reaction was stirred at 0°C. for 30 minutes and then quenched with aq. NHC1. The mixture was extracted with 40% EtOAc/hex anes, dried (NaSO) and concentrated under vacuum. The residue was purified by chromatography on silica gel (EtOAC/ Step 1: Synthesis of 1-3-fluoro-4-(4,4,5,5-tetram Toluene, 0:1 to 1:9) to afford the title compound as light beige ethyl-1,3,2-dioxaborolan-2-yl)phenylcyclopropan solid powder. ecarbonitrile 0361 HNMRö (ppm)(Acetone): 7.5 (2H, d), 7.4 (2H, d), 0367 A solution of 1-(4-bromo-3-fluorophenyl)cyclopro 1.6 (6H, s). panecarbonitrile from Step 6. Example 1 (2 g, 8.3 mmol), Step 2: Synthesis of 2-4-(4.4.5.5-tetramethyl-1,3,2- potassium acetate (2.4 g. 24.4 mmol) and bis(pinacolato) dioxaborolan-2-yl)phenylpropan-2-ol diboron (3.2g, 12.5 mmol) in DMF (25 mL) was degassed followed by the addition of PdCldppf (0.34g, 0.4 mmol). 0362. A solution of 2-(4-bromophenyl)propan-2-ol (6 g. The reaction mixture was stirred at 85°C. overnight and then 28 mmol), potassium acetate (8.2g, 84 mmol) and bis(pina diluted with water and extracted with EtOAc (3x). The com colato)diboron (10.6 g. 42 mmol) in DMF (80 mL) was bined organic extracts were washed with brine (1x), dried degassed followed by the addition of PdCldppf (1.14g, 1.4 (NaSO) and concentrated under reduced pressure. The resi mmol). The reaction mixture was stirred at 90° C. overnight due was swished with hexanes overnight to afford, after fil and then diluted with water and extracted with EtOAc (3x). tration, the title compound as light beige Solid powder.

US 2009/029 1988 A1 Nov. 26, 2009 28

NaOH R is hydrogen, Cl-, alkyl, C-calkenyl, C2-alkynyl, C alkyloxy, halo, nitro, cyano, aryl, heteroaryl, Cs 0381 Solution 1N in water (5.5 ml per plate) cycloalkyl, heterocyclyl, -C(O)OR, —C(O)OSiCH (CH), OR, OR, C(O)R, RC(O)R, Procedure C(O)R, C(O)N(R)(R), C(O)N(R)(R7), (0382 To black 96-well plate (Microfluorl Black C(O)N(R)(R), C(R)(R)OH, SR 7, SR, #7005): RSR, R, C(R), C(R)(R)N(R), 0383 25ul buffer NRC(O)NRS(O).R., SOR, SO(R7), (0384 1 ul compound or DMSO (final 100, 33, 11, 3.7, - SOR, -SON(R)(R), SOCH(R)(R), 1.2,0.4, 0.14, 0.05, 0.015, 0.005 uM) - SON(R)C(O)(R7), - SO(R)C(O)N(R7), (0385 25 ul MAO-A 20 ug/ml or MAO-B 80 ug/ml OSOR, N(R)(R), N(R)C(O)N(R)(R), (final 5 or 20 ug/ml respectively) or buffer for back N(R)C(O)R, N(R)C(O)R, N(R)C(O)OR, ground control N(R)SO.(R), C(R)(R)NRC(R)(R)R, 0386 Shake C(R)(R)N(R)R, C(R)(R)N(R)(R), (0387 Incubate at RT for 10 min. C(R)(R)SC(R)(R)(R), RS C(R)(R) (0388. Add 50 uL kynuramine 40 uM (final 20 uM). NRC(R)(R)(R), C(R)(R)N(R)(R), C(R) Shake. Incubate at 37° C. for 30 min for MAO-A and 40 (R)C(R)(R)N(R)(R), C(O)C(R)(R)N(R)(R), min for MAO-B. C(R)(R)N(R)C(O)R, C(O)C(R)(R)S(R), (0389 Stop reaction by adding 50 uL of NaOH 1N. C(R)(R)C(O)N(R)(R), C(R)(R)C(O)OH, Shake. —B(OH), —OCHO or 4.4.5.5-tetramethyl-1,3,2- 0390 Read in SpectraMax(RGemini (endpoint mode, dioxaborolan-2-yl; wherein said alkyl, alkenyl, alkynyl, top read, Exc=312 nm, Em=425 nm, cutoff 420 nm, 30 alkyloxy, aryl, heteroaryl, cycloalkyl and heterocyclyl read/well, PMT-high); readout should be 1000-2000 groups are optionally Substituted on either the carbon or FU for DMSO controls. the heteroatom with one to five substituents indepen 0391 Calculate ICs with Softmax(R) Pro. dently selected from C alkyl, halo, keto, cyano, 1. A compound of the formula: haloalkyl, hydroxyalkyl, OR, NO, -NH2, NHS(O).R., RSOR7, SOR7, SO(R7), - SR 7, SR, SON(R)(R), SON(R)C(O) E Y (R7), C(R)(R)N(R)(R), C(R)(R)OH, R3 1. N1 COOH, C(R)(R)C(O)N(R)(R), C(O)(R) (R), C(O)NH, C(O)NHR', N(R)C(R)(R) wherein Y is hydrogen, C(R)(R)X, C(O)R', C(O)R’, (R), N(R)CO(R), NH(CH),OH, -NHC(O) C(O)OR', CH(OH)R’, (Calkyl)C(O)CR'ROH, (C- OR, Si(CH), heterocycyl, aryl, or heteroaryl; 6alkyl)CR'ROH, (Calkyl)OH, SOR, C alkyl, R" is hydrogen, aryl, aryl (Cla) alkyl, heteroaryl, het aryl, heteroaryl, Css cycloalkyl or heterocyclyl wherein eroaryl(C)alkyl, C-scycloalkyl, C-scycloalkyl (C- each said aryl, heteroaryl, cycloalkyl and heterocyclyl 4)alkyl or heterocyclyl (C 14)alkyl wherein said groups groups, which may be monocyclic orbicyclic, is option are optionally substituted with one, two, or three sub ally substituted on either the carbon or the heteroatom stituents independently selected from halo, alkoxy or with one to five substituents independently selected - SOR": from C alkyl, halo, cyano or hydroxyl: R is hydrogen or C. alkyl: X is hydrogen, NH or OH: R is hydrogen or C- alkyl; R" is hydrogen or C-alkyl which is optionally substituted R’ is hydrogen or Calkyl which is optionally substituted with one to six halo, hydroxyl, O(C-alkyl) or carbonyl: with one, two, or three substituents independently R is hydrogen, C. alkyl, aryl, heteroaryl, arylalkyl, het selected from halo, alkoxy, cyano, NR or - SR; eroarylalkyl or hydroxyl wherein said alkyl, aryl, het R" is hydrogen, Ce alkyl, (C. alkyl)aryl, (C. alkyl) eroaryl, haloalkyl, arylalkyl and heteroarylalkyl groups hydroxyl. —O(C- alkyl), hydroxyl, halo, aryl, het are optionally substituted with one to six halo: eroaryl, Css cycloalkyl or heterocyclyl, wherein said or R' and R can be taken together with the carbonatom to alkyl, aryl, heteroaryl, cycloalkyl and heterocyclyl which they are attached to form a C-s cycloalkyl ring groups are optionally Substituted on either the carbon or which is optionally substituted with one to six halo: the heteroatom with one, two, or three substituents inde D is aryl, heteroaryl, Cs cycloalkyl or heterocyclyl pendently selected from C alkyl or halo; wherein each said aryl, heteroaryl, cycloalkyl and het R’ is hydrogen, C. alkyl, (C- alkyl)aryl, (C- alkyl) erocyclyl groups, which may be monocyclic orbicyclic, hydroxyl. —O(C- alkyl), hydroxyl, halo, aryl, het is optionally substituted on either the carbon or the het eroaryl, Css cycloalkyl or heterocyclyl, wherein said eroatom with one to five substituents independently alkyl, aryl, heteroaryl, cycloalkyl and heterocyclyl Selected from the group consisting of C alkyl, groups are optionally Substituted on either the carbon or haloalkyl, halo or cyano; the heteroatom with one, two, or three substituents inde E is aryl, heteroaryl, Cs cycloalkyl or heterocyclyl pendently selected from C alkyl or halo; wherein each said aryl, heteroaryl, cycloalkyl and het or RandR' can be taken together with the carbon atom to erocyclyl groups, which may be monocyclic orbicyclic, which they are attached or are between them to form a is optionally substituted on either the carbon or the het Cs cycloalkyl ring or Cls heterocyclyl ring wherein eroatom with one to five substituents independently said 3-8 membered ring system may be optionally Sub Selected from the group consisting of C alkyl, stituted with one or two substituents independently haloalkyl, halo or cyano; Selected from C alkyl and halo;

US 2009/029 1988 A1 Nov. 26, 2009

8. A method of treating mood disorders, depression, bipo serotonin receptor antagonist, a monoamine oxidase inhibi lar disorders, Substance-induced mood disorders, anxiety dis tor, a dopamine receptor agonist, a neuroleptic agent, an orders, cognitive disorders, delirium, amnestic disorders, anoretic agent, a selective serotonin reuptake inhibitor, a Alzheimer's disease, Schizophrenia, Schizophreniform disor halogenated amphetamine derivative, an opiate agonist, a lipoxygenase inhibitor, an interleukin inhibitor, an NMDA der, schizoaffective disorder, delusional disorder, brief psy antagonist, an inhibitor of nitric oxide, a non-steroidal anti chotic disorder, shared psychotic disorder, addictive behav inflammatory agent, a cytokine-suppressing antiinflamma iors, movement disorders, akinesias, akinetic-rigid tory agent, a pain reliever, a potentiator, an H2-antagonist, syndromes, Parkinson's disease, medication-induced parkin simethicone, aluminum hydroxide, magnesium hydroxide, a Sonism, Gilles de la Tourette's syndrome, epilepsy, dyskine decongestant, an antitussive, and an antihistamine. sias, chorea, myoclonus, tics, dystonia, obesity, bulimia ner 10. A method of treating mood disorders, depression, bipo Vosa, compulsive eating disorders, eating disorders lar disorders, Substance-induced mood disorders, anxiety dis associated with excessive food intake, osteoarthritis, repeti orders, cognitive disorders, delirium, amnestic disorders, tive motion pain, dental pain, cancer pain, myofascial pain, Alzheimer's disease, Schizophrenia, Schizophreniform disor perioperative pain, chronic pain, neuropathic pain, post-trau der, schizoaffective disorder, delusional disorder, brief psy matic pain, trigeminal neuralgia, migraine, attention-deficit chotic disorder, shared psychotic disorder, addictive behav hyperactivity disorder, conduct disorder, muscular spasms, iors, movement disorders, akinesias, akinetic-rigid urinary incontinence, amyotrophic lateral Sclerosis, neuronal syndromes, Parkinson's disease, medication-induced parkin damage, ocular damage, retinopathy, macular degeneration Sonism, Gilles de la Tourette's syndrome, epilepsy, dyskine of the eye, hearing loss, tinnitus, emesis, brain edema or sleep sias, chorea, myoclonus, tics, dystonia, obesity, bulimia ner disorders in a mammal in need thereof by administering a Vosa, compulsive eating disorders, eating disorders therapeutically effective amount of a compound according to associated with excessive food intake, osteoarthritis, repeti claim 1. tive motion pain, dental pain, cancer pain, myofascial pain, 9. A pharmaceutical composition comprising a compound perioperative pain, chronic pain, neuropathic pain, post-trau of claim 1 and another agent selected from the group consist matic pain, trigeminal neuralgia, migraine, attention-deficit ing of an anti-depressant, an anti-anxiety agent, an anti hyperactivity disorder, conduct disorder, muscular spasms, Alzheimer's agent, a sedative, a hypnotic, an anxiolytic, an urinary incontinence, amyotrophic lateral sclerosis, neuronal antipsychotic, a cyclopyrrolone, an imidazopyridine, a pyra damage, ocular damage, retinopathy, macular degeneration Zolopyrimidine, a minor tranquilizer, a melatonin agonist, a of the eye, hearing loss, tinnitus, emesis, brain edema or sleep melatonin antagonist, a melatonergic agent, a benzodiaz disorders in a mammal in need thereof by administering a epine, a barbiturate, a 5HT-2 antagonist, levodopa, an anti therapeutically effective amount of a composition according cholinergic, a trihexyphenidyl hydrochloride, a COMT to claim 9. inhibitor, an antioxidant, an A2a adenosine receptor antago nist, a cholinergic agonist, a NMDA receptor antagonist, a