(12) Patent Application Publication (10) Pub. No.: US 2009/0291988 A1 Oballa (43) Pub
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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).