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101 MULEBUHRMANNUS009969726B2 (12 ) United States Patent (10 ) Patent No 101 MULEBUHRMANNUS009969726B2 (12 ) United States Patent (10 ) Patent No. : US 9 , 969 , 726 B2 Cosford et al. (45 ) Date of Patent: May 15 , 2018 ( 54 ) METABOTROPIC GLUTAMATE RECEPTOR C07D 231/ 12 ( 2006 .01 ) NEGATIVE ALLOSTERIC MODULATORS C07D 409 / 14 ( 2006 . 01 ) (NAMS ) AND USES THEREOF C07D 413 /04 ( 2006 .01 ) C07D 401/ 14 (2006 .01 ) @( 71 ) Applicant: Sanford - Burnham Medical Research (Continued ) Institute , La Jolla , CA (US ) ( 52 ) U . S . CI. @( 72 ) Inventors : Nicholas David Peter Cosford , La CPC . .. COZD 417 / 14 (2013 . 01 ) ; A61K 31/ 505 Jolla , CA (US ) ; Dhanya (2013 .01 ) ; A61K 31/ 506 ( 2013. 01 ) ; C07D Raveendra - Panickar , La Jolla , CA 231/ 12 ( 2013 .01 ) ; C07D 233 /64 (2013 .01 ) ; (US ) ; Douglas J . Sheffler , La Jolla , CA C07D 239 /26 ( 2013 . 01 ) ; CO7D 243 / 12 (US ) (2013 .01 ) ; C07D 249 / 08 ( 2013 .01 ) ; C07D 261/ 08 ( 2013 .01 ) ; C07D 263 /32 ( 2013 . 01 ) ; @( 73 ) Assignee : SANFORD - BURNHAM MEDICAL C07D 271 /06 ( 2013 .01 ) ; C07D 275 / 02 RESEARCH INSTITUTE , La Jolla , ( 2013 . 01 ) ; C07D 277 / 26 ( 2013 .01 ) ; C07D CA (US ) 277 /30 ( 2013. 01 ) ; CO7D 285 /08 ( 2013 .01 ) ; C07D 307/ 38 ( 2013 .01 ) ; C07D 333 /24 ( * ) Notice : Subject to any disclaimer, the term of this ( 2013 .01 ) ; C07D 401/ 04 (2013 .01 ) ; C07D patent is extended or adjusted under 35 401/ 10 ( 2013 .01 ) ; C07D 401/ 14 ( 2013 .01 ) ; U . S . C . 154 (b ) by 0 days . days . CO7D 403 / 12 (2013 .01 ) ; C07D 405 /04 @( 21 ) Appl. No .: 15 /315 , 363 ( 2013 .01 ) ; C07D 405 / 10 (2013 .01 ) ; C07D 409 /02 (2013 . 01 ) ; C07D 409 / 04 ( 2013 .01 ) ; ( 22 ) PCT Filed : Jun . 9 , 2015 C07D 409 / 14 (2013 .01 ) ; C07D 413 / 04 (2013 .01 ) ; C07D 413 / 14 ( 2013 .01 ) ; C07D ( 86 ) PCT No .: PCT/ US2015 / 034964 417 /04 ( 2013 . 01 ) ; C07D 417/ 10 ( 2013 .01 ) $ 371 ( c ) ( 1 ), ( 58 ) Field of Classification Search ( 2 ) Date : Apr. 20 , 2017 None See application file for complete search history. ( 87 ) PCT Pub . No. : W02015 /191630 PCT Pub . Date : Dec . 17 , 2015 ( 56 ) References Cited U . S . PATENT DOCUMENTS (65 ) Prior Publication Data 2007 / 0232583 Al 10 / 2007 McArthur et al. US 2017 /0217951 A1 Aug . 3 , 2017 2007/ 0249645 A1 * 10 / 2007 Cochran .. CO7D 231/ 12 514 /275 2011/ 0263615 A1 * 10/ 2011 Gatti McArthur .. CO7D 401/ 04 Related U . S . Application Data 514 /256 (60 ) Provisional application No . 62 /009 , 910 , filed on Jun . 10 , 2014 . FOREIGN PATENT DOCUMENTS (51 ) Int. CI. wo WO -02083665 Al 10 / 2002 C07D 239 /26 ( 2006 .01 ) WO WO -03066623 AL 8 / 2003 CO7D 409 /02 ( 2006 . 01 ) (Continued ) A61K 31 /506 ( 2006 .01 ) A6IK 31/ 505 ( 2006 . 01 ) OTHER PUBLICATIONS CO7D 417 / 14 ( 2006 .01 ) CO7D 27730 ( 2006 .01 ) Chen et al. Enantioselective synthesis of 4 - substituted 4 , 5 - dihydro C07D 277 /26 ( 2006 .01 ) 1H - [ 1 , 5 ]benzodiazepin - 2 ( 3H ) - ones by the Lewis base - catalyzed C07D 417 / 04 ( 2006 . 01) hydrosilylation. J Org Chem 76 :9109 - 9115 ( 2011) . C07D 417 / 10 ( 2006 .01 ) (Continued ) CO7D 285 /08 ( 2006 .01 ) CO7D 275 /02 ( 2006 .01 ) Primary Examiner — Theodore R . West C07D 333 /24 ( 2006 . 01 ) (74 ) Attorney , Agent, or Firm — Wilson & Sonsini, C07D 30738 ( 2006 . 01 ) Goodrich & Rosati CO7D 263/ 32 ( 2006 . 01 ) C07D 271 / 06 ( 2006 .01 ) (57 ) ABSTRACT CO7D 261/ 08 ( 2006 . 01) Provided herein are small molecule active metabotropic C07D 249 /08 ( 2006 . 01 ) glutamate subtype - 2 and 3 receptor negative allosteric CO7D 409/ 04 (2006 .01 ) modulators (NAMs ) , compositions comprising the com CO7D 401/ 04 ( 2006 . 01 ) pounds, and methods of using the compounds and compo CO7D 405 /04 ( 2006 .01 ) sitions. CO7D 405 / 10 ( 2006 .01 ) CO7D 233 /64 ( 2006 .01 ) 6 Claims, 1 Drawing Sheet US 9 , 969 ,726 B2 Page 2 (51 ) Int. Cl. Nogrady . Medicinal Chemistry A Biochemical Approach , Oxford University Press, New York , pp . 388 - 392 ( 1985 ) . C07D 413 / 14 ( 2006 . 01 ) PCT/ US2015 /034964 International Preliminary Report on Patent C07D 403 / 12 (2006 . 01 ) ability dated Dec . 22 , 2016 . C07D 401 / 10 ( 2006 . 01 ) PCT/ US2015 /034964 International Search Report and Written CO7D 243 / 12 ( 2006 . 01 ) Opinion dated Sep . 1 , 2015 . Reddy et al. One -Pot , Three - Component Synthesis of Novel 4 -Phenyl - 2 - [ 3 - ( alkynyl/ alkenyl / aryl ) phenyl ] pyrimidine Libraries ( 56 ) References Cited via Michael Addition , Cyclization , and C — C Coupling Reactions: A New MCR Strategy . Synthesi 45 ( 1 ) : 75 - 84 ( 2013 ) . FOREIGN PATENT DOCUMENTS Romano et al. Metabotropic glutamate receptor 5 is a disulfide linked dimer . J Biol Chem 271 (45 ) :28612 - 28616 ( 1996 ) . wo WO - 03077918 A 9 / 2003 Rooseboom et al. Enzyme -catalyzed activation of anticancer WO WO - 2004058762 A1 7 / 2004 WO WO - 2005012263 A1 2 / 2005 prodrugs . Pharmacological Reviews 56 ( 1 ) :53 - 102 ( 2004 ) . WO WO - 2009153665 A2 12 /2009 Rueping et al . First Highly Enantioselective Synthesis of WO WO - 2011073119 A1 6 / 2011 Benzodiazepinones by Catalytic Hydrogenation . Adv. Synth . Catal . WO WO - 2013033246 A2 3 / 2013 352 : 2629 - 2634 ( 2010 ) . WO WO - 2015191630 A112 / 2015 Sheffler et al. Recent progress in the synthesis and characterization of group II metabotropic glutamate receptor allosteric modulators . ACS Chem Neurosci 2 :382 - 393 (2011 ) . OTHER PUBLICATIONS Silverman et al . Chapter 8 : Prodrugs and drug delivery systems. In : The Organic Chemistry of Drug Design and Drug Action . San Cho . Recent Advances in Oral Prodrug Discovery . Annual Reports Diego : Academic Press, Inc. p . 352 - 401 ( 1992 ) . in Medicinal Chemistry 41 : 395 - 407 (2006 ) . Wang et al . Efficient Syntheses of B - Amino - N - acylbenzotriazoles Gonzalez -Maeso et al. Identification of a serotonin /glutamate recep and Cinnamides through Regioselective 1 , 4 - or 1 , 2 - Addition of tor complex implicated in psychosis . Nature 452 (7183 ) :93 - 97 Amines to N - Cinnamoylbenzotriazoles. Synlett 20 : 3042 - 3046 ( 2008 ) . ( 2005) . Lee et al. Solid - Phase Synthesis of 3 , 4 , 5 - Substituted 1 , 5 Woltering et al . Synthesis and characterization of 8 - ethynyl - 1 , 3 Benzodiazepin - 2 -ones . J Org Chem 64 : 3060 - 3065 ( 1999 ) . dihydro -benzo [ b ] [ 1 , 4 ]diazepin - 2 -one derivatives : part 2 . New Milligan . G - protein -coupled receptor heterodimers: pharmacology , potent non -competitive metabotropic glutamate receptor 2 / 3 function and relevance to drug discovery . Drug Discov Today antagonists . Bioorg Med Chem Letts . 18 : 1091 - 1095 ( 2008 ) . 11 ( 11 - 12 ) :541 - 549 ( 2006 ) . Zhao et al . Solution -phase parallel synthesis of diverse 1 , 5 Murray et al . Evaluation of the mGluR 2 / 3 agonist LY379268 in benzodiazepin - 2 -ones . J Comb Chem 9 : 1164 - 1176 ( 2007 ) . rodent models of Parkinson ' s disease . Pharmacol Biochem Behav 73 :455 - 466 ( 2002 ) . * cited by examiner U . S . Patent May 15 , 2018 US 9 , 969, 726 B2 H H A *H MeanCounts I U ouon LIZZZZ Immobility Swimming Climbing O Vehicle LY341495 ( 1 mg /kg ) Example 182 ( 20 mg/ kg ) Example 191 (20 mg/ kg ) US 9 ,969 ,726 B2 2 METABOTROPIC GLUTAMATE RECEPTOR NEGATIVE ALLOSTERIC MODULATORS Formula ( I ) (NAMS ) AND USES THEREOF PRIORITY CLAIM This application is filed pursuant to 35 U . S . C . § 371 as a United States National Phase Application of International (R4 ) , Application No . PCT/ US2015 / 034964 , filed Jun . 9 , 2015 ; 10 (RP ) m (R4 ) p ; which claims benefit of U . S . Provisional Application No. 62/ 009, 910 , filed on Jun . 10 , 2014 , all of which are herein incorporated by reference in their entirety . wherein : ring is a heteroaryl ring ; STATEMENT OF GOVERNMENT SUPPORT 15 ring is an aryl ring or heteroaryl ring ; This invention was made in part with government support under grant RO1 MH087989 awarded by the National Insti R ' is CO, H , CN , C ( O ) NHOH , C ( O ) NHOMe, tute on Mental Health (NIMH ) . The government has certain C ( O ) NHSO, Me, NHC( O ) Me, C( O )NHMe , rights in the invention . $ FIELD OF THE INVENTION HN HN Described herein are metabotropic glutamate subtype - 2 25 0 , or and - 3 (mGlu2 / 3 ) (collectively Group II mGlus) receptor mim negative allosteric modulators (NAMs ) , methods ofmaking such compounds , pharmaceutical compositions and medi min caments comprising such compounds, and methods of using such compounds in the treatment of conditions, diseases, or 30 HN disorders in which metabotropic glutamate receptors are involved . mm SUMMARY OF THE INVENTION 35 each R2 is independently halogen , - OR " , substituted or Described herein are compounds and compositions , and unsubstituted C1- Cgalkyl, or substituted or unsubsti methods of using these compounds and compositions, as tuted C -Cofluoroalkyl ; negative allosteric modulators of the metabotropic gluta each R3 is independently substituted or unsubstituted mate receptor subtype 2 receptor (mGlu2 ) , and of the 40 C1- Cgalkyl, substituted or unsubstituted metabotropic glutamate receptor subtype 3 receptor C . - C fluoroalkyl, substituted or unsubstituted (mGlu3 ) ( collectively Group II mGlus ), and for treating Cz -Cocycloalkyl , or substituted or unsubstituted aryl; CNS disorders associated with Group II mGlus . each R4 is independently halogen , — OR , substituted or In one aspect , described herein is a method for treating or unsubstituted C , - C alkyl, substituted or unsubstituted preventing a disease or condition in a mammal that would * * C , - Cofluoroalkyl, substituted or unsubstituted benefit from the modulation of the metabotropic glutamate Cz- C . cycloalkyl, or substituted or unsubstituted aryl; receptor subtype 2 receptor (mGlu2 ) , and /or of the metabo or two R + taken together with the carbon atoms to which tropic glutamate receptor subtype 3 receptor (mGlu3 ) activi they are attached to form a substituted or unsubstituted ties comprising administering a modulator ofmGlu2 and / or 50 C2 -Coheterocycloalkyl ; mGlu3 to the mammal in need thereof . In some embodi each R is independently hydrogen , or substituted or ments , the modulator of mGlu2 and mGlu3 is a small unsubstituted C , - Coalkyl ; molecule . In some embodiments , the modulator of mGlu2 n is 0 , 1 , 2 , or 3 ; and mGlu3 is a negative allosteric modulator.
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