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

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. In some 55 m is 0 or l ; and embodiments , the negative allosteric modulator of mGlu2 p is 0 , 1 , 2 , or 3 n is 0 , 1 , 2 , or 3 ; and mGlu3 is a compound having the structure of Formula mis 0 or 1 ; and ( I ), Formula ( la ), Formula ( lb ), Formula ( Ic ) , Formula ( II ), p is 0 , 1 , 2 , or 3 . Formula ( Ila ), Formula ( IIb ), Formula ( IIC ) , Formula ( III ), 60 In some embodiments is a compound of Formula ( I) , or a Formula ( IIIa ), or Formula ( IIIb ) , Formula ( IV ), Formula pharmaceutically acceptable salt thereof, wherein ring ( IVa ), or Formula ( IVb ) , or a pharmaceutically acceptable isis thiszolylethiazolyl, oxadiazolyl , thiadiazolyl, triazolyl, imida salt thereof. zolyl, or isothiazolyl. In one aspect, described herein is a compound , or a 65 In some embodiments is a compound of Formula (I ) , or a pharmaceutically acceptable salt thereof, having the struc - pharmaceutically acceptable salt thereof, having the struc ture of Formula ( I ) : ture of Formula ( la ) : US 9 , 969 ,726 B2 US9 . (20 I) , ( laB2 ) , ( b ) , or (Ic ) , or a pharmaceutically acceptable salt · Formula ( la ) thereof, wherein n is 1 and R2 is F . In some embodiments is a compound of Formula ( I ) , ( la ) , ( lb ) , or ( Ic ), or a pharma ceutically acceptable salt thereof, wherein n is 0 . In some 5 embodiments is a compound of Formula ( I) , ( Ia ), ( Ib ), or ( Ic ), or a pharmaceutically acceptable salt thereof, wherein R ' is - CO H . In some embodiments is a compound of Formula ( I ) , or a (R4 ) p . 10 pharmaceutically acceptable salt thereof, having the struc Sotto ture : In some embodiments is a compound of Formula ( I) , or a pharmaceutically acceptable salt thereof, having the struc ture of Formula ( lb ) : 15

Formula ( Ib ) - Ph , HO2C 20

(R * ) p F 25 HO , C SonteIn some embodiments is a compound of Formula ( I ) , or a pero pharmaceutically acceptable salt thereof, having the struc ture of Formula ( Ic ): 30 F - CF3. HO2 Formula (Ic )

35 N prvo F

HO2C (R in B?&(R )p ; 40 wherein R * is substituted or unsubstituted C1 -Cgalkyl or F substituted or unsubstituted aryl . In some embodiments is a compoundsom of Formula ( Ic ), or a pharmaceutically acceptable * HO2Cpasso salt thereof, wherein Rº is unsubstituted phenyl. F In some embodiments is a compound of Formula (I ) , ( Ia ) , ( Ib ) , or ( Ic ), or a pharmaceutically acceptable salt thereof, wherein ring is a phenyl ring . In some embodiments is 50 a compound of Formula (I ) , (Ia ), ( b ), or ( Ic ), or a pharma - Ph , HO2C ceutically acceptable salt thereof, wherein ring ® is a parF heteroaryl ring . In some embodiments is a compound of Formula ( I ), ( Ia ), ( Ib ) , or ( Ic ), or a pharmaceutically accept- 55 able salt thereof, wherein ring is furanyl, thiophenyl, benzofuranyl, benzothiophenyl, or pyridinyl. In some embodiments is a compound of Formula ( I) , (la ), ( b ), or HO2C ( Ic ) , or a pharmaceutically acceptable salt thereof , wherein 60 p is 1 and R4 is halogen , — CF3, or - OCHz. In some embodiments is a compound of Formula ( I ) , ( la ) , ( lb ), or ( Ic ) , or a pharmaceutically acceptable salt thereof, wherein p is 0 . In some embodiments is a compound of Formula ( I) , MeO ( la ), ( lb ), or ( Ic ), or a pharmaceutically acceptable salt 65 - Ph, thereof, wherein n is 1 and R2 is halogen , — CF , or HO2C _ OCHZ. In some embodiments is a compound of Formula US 9, 969, 726 B2

- continued - continued

HO2C HO2C

- CI, HO2C HO2C - N OMe 20. ?20

HO2C N ' N N - NH ?25

C Ph , F HO2C ?30 HO , C

Ph . 35 bero HO2C SynoHOC OMe 40

- OMe, HOC HOC Droo 45 pero

OMe, HO2C 50 para HO2Cdoo

FF HO2C HO2C Do60 para 60

HOC 65 ottaCO2H , SpaHO2C US 9, 969, 726 B2 - continued ** * não-continued HO2C ooooooCO2H 3OMe HO2Cago

Ph - Ph . HO2C HO2C

- PhPh , HO2C

- Ph HO , C

Ph . HOZC PA

Ph, - CF3, ProbeHO2C HO2C

HO2C HO , C Ogie : ouiPh

- Ph , and ?? , ? HO , C De 2 US 9, 969, 726 B2 10 - continued In some embodiments is a compound of Formula ( II ) , or a pharmaceutically acceptable salt thereof, wherein ring is a heteroaryl ring selected from furanyl , thiophenyl, benzofuranyl, benzothiophenyl, thiazolyl, pyrrolyl, and pyridinyl. In some embodiments is a compound of Formula ( II ) , or a pharmaceutically acceptable salt thereof, having the struc CO2H ture of Formula ( IIa ) : 10 Formula ( IIa ) R ! In another aspect , described herein is a compound thathas the structure of Formula ( II ), or a pharmaceutically accept- 15 able salt thereof:

Formula ( II ) 20 F3C In someetode embodiments is a compound of Formula (II ), or a pharmaceutically acceptable salt thereof, having the struc ture of Formula ( IIb ) : 25 (R2 ) ni (R ?) m Formula ( IIb ) = CF3 ottore 30 wherein : ring is an aryl ring or heteroaryl ring ; X is a bond , O - , - S — , or — N (Rº ) ; R ! is CO2H , CN , C ( O )NHOH , C ( O ) NHOMe, at (R4 ) n. = C ( O ) NHSO, Me, – NHC( O ) Me, C ( O ) NHMe, odigde In some embodiments is a compound of Formula ( II ) , or a pharmaceutically acceptable salt thereof, having the struc - N HN 40 ture of Formula ( IIC ) : min Formula ( IIC ) mi o 45 CF3 HN HN 0 , or wi min 50 Rn( each R is independently halogen , OR ” , NO2, substi tuted or unsubstituted C1- C alkyl, or substituted or In some embodiments is a compound of Formula (II ) , unsubstituted C - Cofluoroalkyl; .. . 55 (IIa ) , ( IIb ), or (IIC ), or a pharmaceutically acceptable salt each R * is independently halogen , OR ” , - SR , substi thereof, wherein n is 1 and R² is halogen or — OCHz. In tuted or unsubstituted C ,- Cgalkyl, substituted or unsub some embodiments is a compound of Formula (II ) , ( IIa ) , stituted C - Cofluoroalkyl, substituted or unsubstituted ( IIb ) , or ( Ilc ) , or a pharmaceutically acceptable salt thereof, Cz- Cocycloalkyl, or substituted or unsubstituted aryl ; wherein n is 1 and R2 is F . In some embodiments is a R * is H , - CF2, — CHz, or substituted or unsubstituted 60 compound of Formula ( II) , ( Ila ) , ( IIb ) , or ( IIC ) , or a phar phenyl; maceutically acceptable salt thereof, wherein n is 0 . In some each R is independently hydrogen , or substituted or embodiments is a compound of Formula ( II ), ( IIa ), (IIb ), or unsubstituted C . -Calkyl ; ( IIC ), or a pharmaceutically acceptable salt thereof, wherein Róis hydrogen , or substituted or unsubstituted Rl is _ CO H . C - Coalkyl; 65 In some embodiments is a compound of Formula ( II ) , or n is 0 , 1 , 2 , or 3 ; and a pharmaceutically acceptable salt thereof, having the struc m is 0 , 1 or 2 . ture : US 9 ,969 , 726 B2 12 -continued CF3 COH, CF3 CO2H , * N

Fac F3C 10 COH , ????CF3 C0H ???

EN CNF , CO2H 20 ????CF3 CO2H ??

25 CF3 CO2H FC ???? ??3 ) CO2H , Me0 35 CF3 CO2H F , CNF , ?????CO2H 4 { CO2H NO . 45 F ,

CNF ,

CO2H 50) CF3 COH

F , 55

CNF , COH, CF , CO2H 66) ??? OMe,

OME 65 CNF , US 9 ,969 , 726 B2 13 14 - continued -continued CF3 CO2H CF3 CO2H 0Me, F ,

1010 C ?? COH ?? ??CO2H

Me( .

Me0 20 ????COH ?????CO2H F ,

???? ?? CO2H CF3 CO2H

?????CO2H CO2H

CO2H ?? CF3 CO2H ??: F ,

MeS * CE CO2H ??COH ???E .???? US 9 ,969 , 726 B2 15 16 - continued -continued CF3 CO2H CF3 CO2H

??? F3C

10 CF3 CO2H , ??????COH ?? N

\ ?? NH 20 CF3 COH, ???COH ???? " N 25

3 ) ?CO2H ???? C0H . F , F

FC CO2H 4 { ?????CE , CO2H . ???? F ,

COH CO2H ?? .???50

CF CO2H F , CO2H , or ????66) ???? 65 ????? US 9 , 969, 726 B2 17 18 - continued - NH . Formula ( IIIa )

CF3 5

10 Fac N (Rºm In another aspect, described herein is a compound that has wherein Rº is halogen , CN , unsubstituted heteroaryl, or the structure of Formula ( III ) , or a pharmaceutically accept- 15 — X — R *; and R * is substituted or unsubstituted aryl, or able salt thereof: substituted or unsubstituted heteroaryl. In some embodiments is a compound of Formula (III ), or a pharmaceutically acceptable salt thereof, having the struc Formula ( III) ture of Formula ( IIIb ) : R N 20 Formula ( IIIb )

( R ? ) R 3? ; 25 (R2 ) n IR:

30 wherein : . (Rº ) m Z is = N — or = C ( H ) ; R1 is halogen , _ OR , NO2, CN , substituted or unsubstituted C -Cgalkyl , substituted or unsubstituted wherein R3 is — CN , unsubstituted heteroaryl, or — X — R4 ; C . -Cafluoroalkyl , substituted or unsubstituted aryl, and R4 is substituted or unsubstituted C , -Coalkyl , substi substituted or unsubstituted heteroaryl, or — CO , R " ; 35 tuted or unsubstituted aryl, or substituted or unsubstituted each R2 is independently halogen , OR ” , NO2, substi heteroaryl. tuted or unsubstituted C , -Coalkyl , or substituted or unsubstituted C - Cofluoroalkyl; In some embodiments is a compound of Formula ( III) , R3 is hydrogen , halogen , CN , substituted or unsubsti - (IIIa ) , or (IIIb ), or a pharmaceutically acceptable salt tuted C . - C alkyl, substituted or unsubstituted 40 thereof, wherein n is 1 and R ’ is halogen or — CHz. In some C . - C fluoroalkyl. substituted or unsubstituted embodiments is a compound of Formula ( III ), (IIIa ), or Cz - C .cycloalkyl , substituted or unsubstituted (IIIb ) , or a pharmaceutically acceptable salt thereof, wherein C . - C heterocycloalkyl. substituted or unsubstituted nis 1 and R?is — CHz. In some embodiments is a compound aryl, unsubstituted heteroaryl, C ( O )NRPR10 , or of Formula ( III) , ( IIIa ) , or ( IIIb ) , or a pharmaceutically - X - R4 ; 45 acceptable salt thereof, wherein n is 0 . In some embodiments X is 0 % , - S — , - S ( O ) - - N (R7 ) , or - C = C — ; is a compound of Formula ( III) , ( IIIa ) , or (IIIb ) , or a R4 is substituted or unsubstituted C , -C alkyl, substituted pharmaceutically acceptable salt thereof, wherein R ' is or unsubstituted Cz- Cocycloalkyl, substituted or unsub - CF3. In some embodiments is a compound of Formula stituted aryl , or substituted or unsubstituted heteroaryl; (111 ) , ( Illa ), or ( IIIb ), or a pharmaceutically acceptable salt each R ' is independently hydrogen , or substituted or 50 thereof, wherein m is 0 . unsubstituted C - Cgalkyl; In another aspect, described herein is a compound that has RO is hydrogen , or substituted or unsubstituted the structure of Formula (IV ), or a pharmaceutically accept C1 - Cgalkyl; able salt thereof: R7 is hydrogen , or substituted or unsubstituted CZ - Cgalkyl; 55 each R8 is independently halogen , or substituted or unsub Formula ( IV ) stituted C -Coalkyl ; R and R10 are independently hydrogen , or substituted or unsubstituted C , - C alkyl; n is 0 , 1 , 2 , or 3 ; and 60 m is 0 , 1 , or 2 . FE( R ) In some embodiments is a compound of Formula (III ) , or a pharmaceutically acceptable salt thereof, wherein Z is R3; — N — In some embodiments is a compound of Formula ( III ), or 65 Im a pharmaceutically acceptable salt thereof, having the struc ture of Formula ( Illa ) : US 9, 969, 726 B2 19 wherein : 20 Z is = N - or = C (H ) ; Formula ( IVb ) R ! is halogen , OR ” , - NO2, CN , substituted or unsubstituted C -Cgalkyl , substituted or unsubstituted 5 C - Cofluoroalkyl , substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, or - CO2Rº; R2 is halogen , ORS, NO2, substituted or unsubstituted C2 -Cgalkyl , or substituted or unsubstituted C - Cofluoroalkyl; (Rºm R3 is hydrogen , halogen , CN , substituted or unsubsti wherein R3 is CN , unsubstituted heteroaryl, or — X — R4; tuted C -Cgalkyl , substituted or unsubstituted and R4 is substituted or unsubstituted C , -Coalkyl , substi C , - Cofluoroalkyl, substituted or unsubstituted tuted or unsubstituted aryl, or substituted or unsubstituted Cz- C .cycloalkyl , substituted or unsubstituted het C2- Cyheterocycloalkyl, substituted or unsubstituted In some embodiments is a compound of Formula (IV ) , aryl, unsubstituted heteroaryl, - C (O )NRÖR ', or 20 (IVA ), or (IVb ) , or a pharmaceutically acceptable salt - X - R ; thereof, wherein n is 1 and R2 is halogen or CHz. In some embodiments is a compound of Formula (IV ) , ( IVA ), or X is - O - , - S — , - S (O ) 2 - , - N ( R ?) — , or — C = C — ; ( IVb ), or a pharmaceutically acceptable salt thereof, wherein R4 is substituted or unsubstituted C -Cgalkyl , substituted nis 1 and R² is — CHz. In some embodiments is a compound or unsubstituted C3- C6cycloalkyl, substituted or unsub - 25 of Formula ( IV ) , ( IVa ) , or ( IVb ) , or a pharmaceutically acceptable salt thereof, wherein n is 0 . In some embodiments stituted aryl, or substituted or unsubstituted heteroaryl; is a compound of Formula ( IV ) , ( IVA ), or ( IVb ) , or a each R5 is independently hydrogen , or substituted or pharmaceutically acceptable salt thereof, wherein R ' is unsubstituted C , - Coalkyl ; CF3. In some embodiments is a compound of Formula R6 is hydrogen , or substituted or unsubstituted 30 (IV ), ( IVa ), or (IVb ), or a pharmaceutically acceptable salt C - Cgalkyl; thereof, wherein m is 0 . R ? is hydrogen , or substituted or unsubstituted In some embodiments is a compound , or a pharmaceuti C1 -Cgalkyl ; cally acceptable salt thereof, having the structure : R® is halogen , or substituted or unsubstituted C , -C alkyl; 35 R and R10 are independently hydrogen , or substituted or unsubstituted C , -Coalkyl ; FC . n is 0 , 1 , 2 , or 3 ; and m is 0 , 1 , or 2 . 40 In some embodiments is a compound of Formula (IV ), or a pharmaceutically acceptable salt thereof, wherein Z is = N / In some embodiments is a compound of Formula ( IV ), or 45 a pharmaceutically acceptable salt thereof, having the struc ture of Formula ( IVA ): F3C Formula (IV ) 50 Doo

55 R3; (R $) m . wherein R3 is halogen , CN , unsubstituted heteroaryl , or horo - X - R4; and R4 is substituted or unsubstituted aryl , or substituted or unsubstituted heteroaryl. In some embodiments is a compound of Formula ( IV ) , or 65 a pharmaceutically acceptable salt thereof, having the struc ture of Formula (IVb ) : US 9, 969, 726 B2 21 22 - continued - continued

F34 5

F3C C od

F ,

oroN sooothoma shoo- CF3 , FC

NH2, F3C Boote. Moondborao FCmons US 9, 969, 726 B2 23 24 -continued - continued

OMe, NH 10

20 boborhoodHO 25 mm thout30

35 mm CN ,

$ DalamF3C N

45 Dobar COOH ayamN 50 N

Donde 55 produce arok 60 Dohor US 9, 969, 726 B2 25 26 - continued -continued

F3C 34

u ZEZ

F3C F3C. IZ soogooFac . F3C

N - F , F3C .

O odoroooooohoopisNH2, :FC IZ OH ,

DoholNH thoro

Fac 60

oor 65 hong DynasNHCbz, US 9, 969, 726 B2 27 28 - continued -continued

5 10Desdhet 20

who 30

35 conF

CI,

45 CN . FC

CN , 55 F

60 F doCN . :edias 65 US 9, 969, 726 B2 29 30 - continued - continued

Br, redbo 20 waoBrn F2C

F C 13 N F3C .

Br,

OMe Meo . edhorN

or 55 EzC 0- 0

F3C

65 US 9 , 969, 726 B2 31 32 Any combination of the groups described above or below to a subject in need thereof, an effective amount of the for the various variables is contemplated herein . Throughout compound of Formula ( I) , ( la ), ( b ) , ( Ic ) , ( II ) , ( IIa ) , ( IIb ) , the specification , groups and substituents thereof are chosen ( IIC ), ( III ) , ( IIIa ) , ( IIIb ) , (IV ) , ( IVA ), or ( IVb ) . In another by one skilled in the field to provide stable moieties and aspect, described herein is a method of treating treatment compounds. 5 resistant depression ( TRD ) , the method comprising the step In one aspect, provided herein is a pharmaceutical com - of administering to a subject in need thereof, an effective position comprising a compound of Formula ( I ) , ( Ia ) , ( Ib ) , amount of the compound of Formula ( I ), ( la ) , ( Ib ), ( Ic ) , (II ) , ( Ic ) , (II ) , ( Ila ) , (Ilb ) , ( IIc ), ( III ) , ( IIIa ) , ( IIIb ) , ( IV ) , ( IVA ), or (Ila ) , ( IIb ) , ( IIC ), ( III) , (IIIa ) , ( IIIb ) , ( IV ) , ( IVA ) , or ( IVb ) . ( IVb ), or a pharmaceutically acceptable salt thereof, and at In another aspect , described herein is a method of treating least one pharmaceutically acceptable excipient. 10 schizophrenia , the method comprising the step of adminis In some embodiments , the compound of Formula (I ) , (Ia ) , tering to a subject in need thereof, an effective amount of the ( lb ) , ( Ic ) , ( II ) , ( IIa ) , ( IIb ), ( IIC ), ( III ) , ( IIIa ), ( IIIb ) , ( IV ) , compound of Formula ( I ) , ( la ) , ( lb ) , ( Ic ), ( II ) , ( IIa ), ( IIb ) , (IVA ) , or (IVb ) , or a pharmaceutically acceptable salt ( IIC ), ( III ) , ( IIIa ) , ( IIIb ) , ( IV ) , (IVa ) , or ( IVb ) . thereof, is formulated for administration to a mammal by In another aspect, described herein is a method of treating intravenous administration , subcutaneous administration , 15 a neurodegenerative disease , the method comprising the step oral administration , inhalation , nasal administration , dermal of administering to a subject in need thereof, an effective administration , or ophthalmic administration . In some amount of the compound of Formula (I ) , ( La ), ( lb ) , ( Ic ) , ( II ) , embodiments , the compound of Formula ( I ) , ( la ) , ( lb ) , ( Ic ), ( IIa ), ( IIb ) , ( IIC ) , ( III ) , ( IIIa ), ( IIIb ) , (IV ) , ( IVA ), or ( IVb ) . In ( II ) , ( IIa ), ( IIb ) , ( IIC ), ( III ) , (IIIa ) , ( IIIb ) , ( IV ) , ( IVA ) , or ( IVb ), another aspect , described herein is a method of treating a or a pharmaceutically acceptable salt thereof, is in the form 20 neurodegenerative disease , wherein the neurodegenerative of a tablet, a pill, a capsule , a liquid , a suspension , a gel , a disease is Alzheimer ' s disease, Parkinson 's disease , Hun dispersion , a solution , an emulsion , an ointment, or a lotion . tington ' s disease , or Lou Gehrig ' s disease ( Amyotrophic In another aspect , described herein is a method of treating Lateral Sclerosis or ALS ) , the method comprising the step of a central nervous disorder (CNS ) disorder , the method administering to a subject in need thereof, an effective comprising the step of administering to a subject in need 25 amount of the compound of Formula ( I) , ( Ia ) , ( Ib ), (Ic ), (II ) , thereof, an effective amount of the compound of Formula ( I ) , ( Ila ) , ( IIb ) , ( IIC ), ( III) , (IIIa ) , ( IIIb ) , ( IV ) , ( IVA ) , or ( IVb ) . ( la ), ( b ) , (Ic ), ( II ), ( IIa ), ( IIb ), ( IIC ), ( III ), ( IIIa ), (IIIb ), (IV ), In another aspect , described herein is a method of treating ( IVA ), or (IVb ), thereby treating the disorder. substance abuse , the method comprising the step of admin In some embodiments, the CNS disorder is schizophrenia . istering to a subject in need thereof, an effective amount of In some embodiments , the CNS disorder is depression . 30 the compound of Formula ( I) , (la ) , ( Ib ) , (Ic ) , ( II ) , ( IIa ) , ( IIb ), In some embodiments , the CNS disorder is treatment ( IIC ) , ( III) , ( IIIa ) , ( IIIb ) , ( IV ) , ( IVA ), or ( IVb ) , wherein the resistant depression ( TRD ). effective amount is sufficient to diminish , inhibit or elimi In some embodiments , the CNS disorder is anxiety . nate desire for and / or consumption of the substance in the In some embodiments , the CNS disorder is insomnia . subject. In some embodiments, the CNS disorder is psychosis . 35 In one aspect , described herein is a method of treating a In some embodiments , the CNS disorder is epilepsy . disease or condition by modulation of the mGlu2 receptor in In some embodiments, the CNS disorder is traumatic a subject in need thereof, which method comprises admin brain injury ( TBI). istering to the subject a therapeutically effective amount of In some embodiments , the CNS disorder is bipolar dis a compound of Formula (I ), ( la ) , ( lb ) , (Ic ), ( II ) , ( IIa ), ( IIb ) , order. 40 ( IIC ) , ( III ) , (IIIa ) , ( IIIb ) , ( IV ) , ( IVA ) , or (IVb ) , or a pharma In some embodiments , the CNS disorder is post traumatic ceutically acceptable salt thereof. In some embodiments , the stress disorder (PTSD ) . disease or condition is a CNS disorder. In some embodiments , the CNS disorder is associated In another aspect , described herein is a method of treating with a reduction in neurogenesis . a disease or condition by modulation of the mGlu3 receptor In some embodiments , the disorder is an addictive disor - 45 in a subject in need thereof, which method comprises der . administering to the subject a therapeutically effective In some embodiments , the CNS disorder is a neurode - amount of a compound of Formula ( I ) , (Ia ) , ( Ib ), ( Ic ) , ( II ) , generative disease . ( IIa ) , ( IIb ) , ( IIC ), ( III) , ( IIa ), ( IIIb ) , (IV ) , ( IVA ), or ( IVb ) , or In some embodiments, the neurodegenerative disease is a pharmaceutically acceptable salt thereof. In some embodi Alzheimer' s disease , Parkinson ' s disease , Huntington ' s dis - 50 ments , the disease or condition is a CNS disorder . ease , or Lou Gehrig ' s disease ( Amyotrophic Lateral Scle - In one aspect, described herein is a method of treating a rosis or ALS) . disease or condition by dual modulation of the mGlu2 /3 In another aspect , described herein is a method of treating receptors in a subject in need thereof, which method com cancer, the method comprising the step of administering to prises administering to the subject a therapeutically effective a subject in need thereof, an effective amount of the com - 55 amount of a compound of Formula (I ) , (la ), (Ib ), ( Ic ), ( II ), pound of Formula ( I) , ( la ) , ( lb ) , ( Ic ), (II ) , ( IIa ), (IIb ) , ( Ilc ), (Ila ) , ( IIb ), ( IIC ) , ( III) , (Ila ), ( IIIb ), ( IV ) , (IVa ) , or ( IVb ) , or ( III ) , (IIIa ) , ( IIIb ) , ( IV ) , ( IVa ), or (IVb ), thereby treating the a pharmaceutically acceptable salt thereof. In some embodi cancer . In some embodiments , the cancer is glioblastoma. In ments , the disease or condition is a CNS disorder . some embodiments , the cancer is melanoma . In any of the aforementioned aspects are further embodi In another aspect, described herein is a method of treating 60 ments in which : ( a ) the effective amount of the compound of pain , the method comprising the step of administering to a Formula (I ) , ( Ia ), ( Ib ), ( Ic ), ( II ), ( IIa ), ( IIb ), (IIC ), (III ), ( IIIa ), subject in need thereof , an effective amount of the com - ( IIIb ) , (IV ) , ( IVA ), or ( IVb ) , is systemically administered to pound of Formula ( I ), ( Ia ), ( b ), ( Ic ), ( II ) , ( IIa ), ( IIb ) , ( IIC ), the mammal; and /or (b ) the effective amount of the com ( III) , ( IIIa ) , ( IIIb ) , ( IV ) , ( IVA ) , or (IVb ) , thereby treating the pound of Formula ( I) , (la ) , ( lb ) , ( Ic ) , ( II ) , ( Ila ), ( IIb ), ( IIC ) , pain . 65 ( III ), ( IIIa ), ( IIIb ) , (IV ) , ( IVA ), or (IVb ) is administered orally In another aspect, described herein is a method of treating to the mammal; and / or ( c ) the effective amount of the depression , the method comprising the step of administering compound of Formula (I ) , ( Ia ) , ( lb ) , ( Ic ), ( II ), ( IIa ), ( IIb ), US 9 , 969 , 726 B2 33 34 ( IIC ) , ( III) , (IIIa ), ( IIIb ), (IV ) , ( IVA ), or ( IVb ) is intravenously In some embodiments , compounds and compositions pro administered to the mammal ; and / or ( d ) the effective amount vided herein are administered to a human . of the compound of Formula ( 1 ) , ( la ) , ( b ) , ( c ) , ( II) , ( IIa ) , In somsome embodiments , compounds and compositions pro ( IIb ), ( IIC ), ( III ) , ( IIIa ), ( IIIb ), ( IV ), (IVA ), or (IVb ) is vided herein are orally administered . administered by inhalation , and /or ( e ) the effective amount 5 In other embodiments , compounds of Formula ( I ), ( la ) , of the compound of Formula ( 1 ), (la ), (lb ), ( Ic ), ( II ), (lla ), ( b ), (Ic ) , (II ) , (IIa ), ( IIb ) , (IIC ), ( III) , (IIIa ), (IIIb ), (IV ), ( IIb ) , ( IIC ), ( III) , ( IIIa ) , ( IIIb ) , ( IV ) , ( IVA ) , or ( IVb) is (IVa ), or ( IVb ) provided herein are used in the manufacture administered by nasal administration ; or and / or ( f ) the effective amount of the compound of Formula (I ) , ( Ia ), ( Ib ) , of a medicament for the modulation of the mGlu2 receptor. ( Ic ) , ( II ) , ( IIa ) , ( IIb ) , ( IIC ), ( III ), ( IIIa ) , ( IIIb ) , ( IV ) , ( IVA ), or 10 In other embodiments , compounds of Formula ( I) , ( Ia ), ( b ) , ( IVb ) is administered by injection to the mammal; and /or ( g ) ( Ic ) , ( II ) , (IIa ) , (IIb ), ( IIC ), ( III ), ( IIIa ), ( IIIb ) , ( IV ) , ( IVA ), or the effective amount of the compound of Formula ( I ) , (la ) , (IVb ) provided herein are used in the manufacture of a ( lb ) , ( Ic ), ( II) , ( IIa ), ( IIb ), ( IIC ), ( III ) , ( IIIa ), (IIIb ), (IV ), medicament for the modulation of the mGlu3 receptor. In (IVA ) , or ( IVb ) is administered topically to the mammal; other embodiments , compounds of Formula ( I ) , ( la ) , ( lb ) , and /or ( h ) the effective amount of the compound of Formula 15 ( lc ) , ( II ) , ( lla ), (11b ) , ( llc ) , (III ) , ( Illa ) , ( Il1b ) , ( IV ) , ( Iva ), or ( I ) , ( Ia ), ( lb ) , ( c ) , ( II ) , ( IIa ), ( IIb ) , ( IIC ) , ( III) , ( IIIa ), ( IIIb ) , ( IVb ) provided herein are used in the manufacture of a ( IV ), (IVA ), or ( IVb ) is administered by ophthalmic admin - medicament for the dual modulation of the mGlu2 / 3 recep istration ; and/ or ( i ) the effective amount of the compound of tors . Formula ( I ) , ( La ) , ( lb ) , ( Ic ) , ( II) , (IIa ) , (Ilb ) , ( IIC ) , ( III ), ( IIIa ), Articles of manufacture , which include packaging mate ( IIIb ), (IV ) , ( IVA ), or ( IVb ) is administered rectally to the 20 rial , a compound of Formula ( I) , (Ia ), ( Ib ) , ( Ic ), ( II ), ( IIa ) , mammal; and /or (j ) the effective amount is administered ( IIb ) , ( IIC ) , (III ) , ( Ila ), ( IIIb ) , ( IV ) , ( IVA ), or ( IVb ) , or a ncnon - systemically or locally to the mammal. pharmaceutically acceptable salt thereof, within the pack In any of the aforementioned aspects are further embodi- aging material, and a label that indicates that the compound ments comprising single administrations of the effective or composition , or pharmaceutically acceptable salt, tautom amount of the compound of Formula ( I ) , (Ia ), ( lb ) , ( Ic ), ( II ) , 25 ers , pharmaceutically acceptable N -oxide , pharmaceutically ( Ila ), ( IIb ) , ( IIC ), (III ) , ( IIIa ), ( IIIb ) , ( IV ) , (IVA ) , or ( IVb ) , active metabolite , pharmaceutically acceptable prodrug, or including further embodiments in which (i ) the compound is pharmaceutically acceptable solvate thereof, is used for the administered once ; ( ii ) the compound is administered to the mammal multiple times over the span of one day ; ( iii ) treatment of diseases or conditions that would benefit from continually ; or (iv ) continuously . the modulation of the mGlu2 receptor, are provided . In any of the aforementioned aspects are further embodi 0 Articles of manufacture , which include packaging mate ments comprising multiple administrations of the effective rial , a compound of Formula (I ) , (la ), ( b ), (Ic ), ( II ), ( IIa ), amount of the compound of Formula ( I ) , (Ia ) , ( lb ) , (Ic ) , ( II ) , ( IIb ), (IIC ) , ( III ) , ( IIa ), ( IIIb ) , (IV ) , (IVa ), or (IVb ), or a ( IIa ), ( IIb ) , (IIC ), ( III ) , ( IIIa ), ( IIIb ) , ( IV ) , (IVA ) , or ( IVb ) , pharmaceutically acceptable salt thereof, within the pack including further embodiments in which ( i ) the compound is 35 aging material, and a label that indicates that the compound administered continuously or intermittently : as in a single or composition , or pharmaceutically acceptable salt , tautom dose ; ( ii ) the time between multiple administrations is every ers , pharmaceutically acceptable N -oxide , pharmaceutically 6 hours ; ( iii ) the compound is administered to the mammal active metabolite , pharmaceutically acceptable prodrug , or every 8 hours ; ( iv ) the compound is administered to the pharmaceutically acceptable solvate thereof, is used for the mammal every 12 hours ; ( v ) the compound is administered 40 treatment of diseases or conditions that would benefit from to the mammal every 24 hours. In further or alternative the modulation of the mGlu3 receptor, are provided . embodiments , themethod comprises a drug holiday , wherein Articles of manufacture , which include packaging mate the administration of the compound is temporarily sus - rial , a compound of Formula ( I) , ( Ia ), ( b ), ( Ic ), ( II ) , ( IIa ), pended or the dose of the compound being administered is ( IIb ), ( IIC ), (III ) , ( IIIa ), ( IIIb ) , ( IV ) , ( IVA) , or (IVb ), or a temporarily reduced ; at the end of the drug holiday , dosing 45 pharmaceutically acceptable salt thereof, within the pack of the compound is resumed . In one embodiment, the length aging material, and a label that indicates that the compound of the drug holiday varies from 2 days to 1 year. or composition , or pharmaceutically acceptable salt, tautom In any of the aforementioned aspects involving the admin - ers , pharmaceutically acceptable N - oxide, pharmaceutically istration of a compound of Formula ( I ) , ( la ) , ( b ) , ( Ic ) , ( II ) , active metabolite , pharmaceutically acceptable prodrug , or ( IIa ), ( IIb ), ( IIC ), (III ), (IIIa ), ( IIIb ), (IV ), ( IVA ) , or ( IVb ), or 50 pharmaceutically acceptable solvate thereof, is used for the a pharmaceutically acceptable salt thereof, to a subject are treatment of diseases or conditions that would benefit from further embodiments comprising administering at least one the dual modulation of the mGlu2 / 3 receptors, are provided additional agent in addition to the administration of a Other objects , features and advantages of the compounds , compound having the structure of Formula ( I ) , ( la ), ( Ib ) , methods and compositions described herein will become ( Ic ) , ( II ) , ( Ila ) , (Ilb ) , ( IIc ), (III ) , ( IIIa ) , ( IIIb ) , ( IV ) , (IVA ) , or 55 apparent from the following detailed description . It should ( IVb ) , or a pharmaceutically acceptable salt thereof. In be understood , however , that the detailed description and the various embodiments , the compound of Formula (I ) , (la ), specific examples, while indicating specific embodiments , ( lb ) , ( Ic ), (II ) , (IIa ) , (IIb ) , (IIC ) , ( III) , ( IIIa ), ( IIIb ) , (IV ) , are given by way of illustration only , since various changes ( IVA ) , or ( IVb ) and the additional agent are administered in and modifications within the spirit and scope of the instant any order, including simultaneously . In some embodiments , 60 disclosure will become apparent to those skilled in the art the compound of Formula ( I) , (la ) , ( b ), (Ic ) , ( II ), ( IIa ), ( IIb ), from this detailed description . ( IIC ) , ( III) , ( IIIa ) , ( IIIb ) , ( IV ) , ( IVa ) , or (IVb ) and the additional agent are administered to the subject in the same BRIEF DESCRIPTION OF THE DRAWINGS pharmaceutical composition or in separate pharmaceutical compositions. 65 FIG . 1 shows the antidepressant activity of Compounds In any of the embodiments disclosed herein , the subject is 182 and 191 by decreasing immobility and increasing swim a human . ming in the Forced Swim Test (FST ) . US 9 , 969 , 726 B2 35 36 DETAILED DESCRIPTION OF THE complex and that activation of the mGlu2 monomer sup INVENTION presses hallucinogen - specific signaling , while by contrast, the affinity of mGlu2/ 3 agonists was reduced in the presence Glutamate is the major excitatory neurotransmitter in the of an hallucinogen (Gonzalez -Maeso et al. Nature 2008 , central and peripheral nervous system and exerts its effects 5 452 (7183 ) : 93 - 97 ) . mainly through ionotropic ( iGlus ) and metabotropic gluta - In some embodiments , the compounds described herein mate receptors (mGlus ) . The mGlus are seven - transmem are mGlu2 /3 receptor NAMs. brane G protein - coupled receptors (GPCRs ) and the eight In some embodiments , the compounds described herein known members of the mGlu family are divided into three sub - groups based on sequence homology , signal transduc - 10 are used to treat a CNS disorder . In some embodiments , the tion and pharmacology : mGlul and mGlu5 belong to Group CNS disorder is depression . In some embodiments , the CNS I ,mGlu2 andmGlu3 belong to Group II and mGlu4 , mGlub , disorder is treatment resistant depression . In some embodi mGlu7 and mGlu8 belong to Group III. ments , the CNS disorder is psychosis . In some embodi The orthosteric binding site of the mGlus, which consists ments , the CNS disorder is anxiety . In some embodiments , of a large bi- lobed extracellular amino terminal domain , is 15 the CNS disorder is schizophrenia . In some embodiments , highly conserved , particularly within each group . For this the CNS disorder is anxiety . In some embodiments , the CNS reason it has been difficult to develop subtype - specific disorder is insomnia . In some embodiments , the CNS dis ligands (agonists and antagonists ) for these receptors . order is epilepsy . In some embodiments , the CNS disorder is Recently , advances have been made to develop highly traumatic brain injury ( TBI) . In some embodiments , the selective compounds which modulate the activity of these 20 CNS disorder is bipolar disorder. In some embodiments , the receptors by binding within the receptors transmembrane CNS disorder is post traumatic stress disorder. (PTSD ) . In heptahelical domain . These allosteric modulators are com some embodiments , the CNS disorder is associated with a pounds that bind receptors at a non - active or non -orthosteric reduction in neurogenesis . In another embodiment, the CNS site and thereby can modulate receptor function even if the disorder is an addictive disorder. endogenous ligand is also bound to the receptor (orthosteric 25 In some embodiments , the addictive disorder is nicotine site ) . As a result, an allosteric modulator does not have to addiction , alcohol addiction , opiate addiction , amphetamine compete with the ligand to impact the receptor ' s function addiction , methamphetamine addiction , or cocaine addic and permits a different approach to designing receptor tion . modulators , such as a more selective agent able to distin - In some embodiments , the addictive disorder is nicotine guish between the various mGlus and affect only the recep - 30 addiction . In some embodiments , the addictive disorder is tor( s ) of interest . As an example , the binding of an allosteric cocaine addiction . modulator may have a lower affinity to the site and still be in another aspect the disclosure provides methods for effective unlike most conventional antagonists that must treating substance abuse , by administering to a subject in block ligand - receptor interactions . Moreover , the modula - need thereof, an effective amount of a compound having tion of the allosteric site permits the natural processes of the 35 Formula I , wherein the effective amount is sufficient to endogenous ligand and associated receptor to continue. One diminish , inhibit or eliminate desire for and /or consumption type of allosteric modulator is a negative allosteric modu - of the substance in the subject. lator (NAM ) in which the modulator acts to decrease the In another aspect the disclosure provides methods for signal sent by the endogenous ligand via the receptor. treating substance abuse , wherein the substance is nicotine , Another type of modulator is the positive allosteric modu - 40 alcohol, opiates , amphetamines, methamphetamines , or lator (PAM ) which does not exhibit intrinsic agonism of the cocaine. receptor but facilitates or potentiates agonist -mediated In another aspect the disclosure provides a method for receptor activity . In some instances the modulator may be treating an addictive disorder, by a ) administering to a classified as an allosteric agonist in that it alone , without the subject in need thereof, an effective amount of a compound effects of the natural ligand , induces receptor activity . 45 having Formula I , during a first time period , wherein the first The GPCR contains two distinct domains ; a large extra - time period is a time period wherein the subject expects to cellular domain which binds glutamate at the orthosteric be in an environment wherein , or exposed to stimuli in the binding site and a heptahelical transmembrane domain , presence of which , the subject habitually uses an addictive which has been found to bind a variety of ligands at one or substance ; and b ) administering an effective amount of a more allosteric binding sites . Recent experimental findings 50 compound having Formula I during a second time period , show that GPCRs form homodimers , heterodimers and in wherein the second time period is a time period wherein the some cases hetero - oligomers with members of their own subject is suffering from withdrawal. class as well as with other unrelated GPCRs and impacts In some embodiments , the CNS disorder is a neurode their trafficking , signaling, and pharmacology (Milligan generative disease . Drug Discov Today 2006 , 11 ( 11 - 12 ) : 541 -549 ) . Although a 55 In some embodiments , the neurodegenerative disease is GPCR monomer is sufficient to activate a G protein , it is Alzheimer ' s disease . In some embodiments , the neurode believed that dimerization leads to stabilization of the active generative disease is Parkinson ' s disease . In some embodi conformation and enhancement of G protein activation . It m ents , the neurodegenerative disease is Huntington ' s dis has been clearly established that mGlus exist as constitutive ease . In some embodiments, the neurodegenerative disease dimers with the two subunits being linked by a disulfide 60 is Lou Gehrig ' s disease ( Amyotrophic Lateral Sclerosis or bridge (Romano et al. J Biol Chem 1996 , 271( 45 ) :28612 - ALS ) . 28616 ) . Recent studies have found that activation or inhi In some embodiments , the compounds described herein bition of either monomer of the dimer complex facilitates a are used to treat cancer. In some embodiments , the cancer is change in the activity or function of the adjoining monomer . glioblastoma. In some embodiments , the cancer is mela As an example , it was found that Gile protein regulation , 65 noma . which is necessary for the effects of hallucinogens, is In some embodiments , the compounds described herein enhanced by the formation of the 5HT2A /mGlu2 dimer are used to treat pain . US 9 , 969 , 726 B2 37 38 In some embodiments , the compounds described herein mGlu2 / 3 receptor modulators may attenuate discriminatory provide neuroprotection . cue - induced reinstatement of cocaine self -administration . In Anxiety addition , mGlu2 / 3 receptor negative modulators may Anxiety is an unpleasant state of inner turmoil, often reverse the reward deficits associated with early cocaine accompanied by nervous behavior , such as pacing back and 5 abstinence . forth , somatic complaints and rumination . It is the subjec Cocaine addiction is a chronic relapsing disorder and tively unpleasant feelings of dread over anticipated events, remains a major public health problem in the United States . such as the feeling of imminent death . Anxiety is a feeling The number of cases of cocaine abuse has steadily risen in of fear, worry, and uneasiness, usually generalized and the past decade . To date , a safe and effective pharmacologi unfocused as an overreaction to a situation that is only 10 cal treatment for cocaine dependence has yet to be identified , subjectively seen as menacing . It is often accompanied by which highlights the need to design new chemical entities muscular tension , restlessness , fatigue and problems in that may become future novel medications for cocaine concentration . Anxiety can be appropriate , but when expe - addiction . Recent evidence suggests that mGlus play a rienced regularly the individual may suffer from an anxiety significant role in the abuse -related effects of cocaine. For disorder . 15 example , repeated administration of cocaine has been shown In some embodiments , the compounds described herein to alter the function of mGlus , as well as their regulation by are mGlu2 / 3 receptor NAMs used for treating anxiety symp- cysteine / glutamate exchange in the nucleus accumbens. toms. The method includes administering to a subject in These findings suggest that mGlu2 /3 may be involved in the need thereof, an effective amount of at least one mGlu2 /3 development of cocaine dependence and may represent a receptor NAM , thereby treating the anxiety symptoms. 20 possible target for drug discovery against different aspects of Nicotine Addiction cocaine abuse and dependence . There are several sources of Nicotine dependence is an addiction to tobacco products motivation that contribute to the maintenance of cocaine caused by the drug nicotine . Nicotine dependence means a abuse . These include the positive reinforcing effects of person can ' t stop using the substance , even though it ' s cocaine and alleviation of the negative affective aspects of causing harm . Nicotine produces physical and mood -alter - 25 cocaine withdrawal. Further , conditioned stimuli previously ing effects in the human brain that are temporarily pleasing . associated with cocaine administration may elicit condi These effects increase the desire to use tobacco and lead to tioned " cravings ” leading to the reinstatement of cocaine dependence . At the same time, stopping tobacco use causes seeking behavior even after a prolonged period of absti withdrawal symptoms, including irritability and anxiety . nence . Recent studies suggest that the neuronalmechanisms In certain aspects , the effective amount of at least one 30 underlying drug self - administration are different from those negative allosteric modulator is administered to decrease mediating relapse vulnerability during abstinence , and dif nicotine consumption . For example , in one aspect an effec - ferent from those mediating the negative effects of early tive amount of a negative allosteric modulator of mGlu2 drug withdrawal. Therefore , it is important to explore con and / or mGlu3 , can be administered to decrease nicotine currently the neurochemical mechanisms that contribute to consumption . In certain aspects of the disclosure , a negative 35 the different aspects of cocaine dependence using animal allosteric modulator of mGlu2 and / or mGlu3 is administered models assessing the positive reinforcing effects of cocaine, while a subject is experiencing withdrawal. In another aspect the negative affective symptoms of early withdrawal, and of the disclosure , a negative allosteric modulator of mGlu2 cue - induced reinstatement of cocaine - seeking behavior after and / or mGlu3 is administered during a time period when a prolonged abstinence from drug intake. The discovery and subject is actively using an addictive substance. 40 preclinical testing of highly selective mGlu2 / 3 receptor Cocaine Addiction modulators with good brain penetration may significantly Cocaine addiction remains a major public health problem contribute to the discovery of novel therapeutic treatments in the United States . There are several sources ofmotivation for different aspects cocaine dependence . that contribute to the continuance of cocaine abuse , includ - The intravenous drug self -administration procedure pro ing : the positive reinforcing effects of cocaine; and the 45 vides a reliable and robust model of human drug consump alleviation of the negative affective aspects of cocaine tion . This procedure in animals provides a valid model of withdrawal. Conditioned stimuli previously associated with human drug abuse as studied in a controlled laboratory cocaine administration may also elicit conditioned " crav - situation . Self - administration of drugs of abuse is thought to ings ” leading to the reinstatement of cocaine - seeking behav - provide an operational measure of the rewarding effects of ior even after a prolonged period of abstinence . Recent 50 the drug . Increases in excitatory glutamatergic transmission studies indicate that the neuronal mechanisms underlying are likely to contribute to the positive reinforcing properties various aspects of drug abuse may differ necessitating the of addictive drugs . Neurochemical studies indicate that use of different treatments for specific aspects of drug systemic cocaine administration increase glutamate levels in dependence . To date , a safe and effective pharmacological the ventral tegmental area (VTA ) and the nucleus accum treatment for cocaine dependence has yet to be identified . 55 bens , brain structures that are integral components of the Thus , there remains a need for the design of new chemical extended amygdala , a brain circuit mediating the reward entities that can be used as novel medications for cocaine effects of all major drugs of abuse . The administration of a addiction . negative modulator of mGlu2 / 3 receptors may decrease It has been found that repeated cocaine exposure may cocaine self - administration in rats with extended access to alter the function of Group II metabotropic glutamate recep - 60 cocaine by decreasing glutamate neurotransmission in lim tors (mGlu2 and mGlu3 receptors ) , pointing to a possible bic structures similar to the effects of mGlu2 / 3 agonists . In role of these mGlu subtypes in the development of cocaine contrast, a negative modulator of mGlu2 / 3 receptors will dependence . The mGlu2 / 3 receptor negative modulators most likely have no effect on cocaine self -administration , or may decrease the reinforcing effects of self - administered possibly will shift the dose -response curve to the left , cocaine in rats that had extended access to cocaine, a 65 potentiating the reinforcing effects of cocaine . putative model of cocaine dependence while having no Another challenge for the treatment of drug addiction is effect in rats with limited access to cocaine . Negative chronic vulnerability to relapse . One of the factors that US 9 , 969 , 726 B2 39 40 precipitates drug craving and relapse to drug taking behavior drawal syndrome. The role of glutamate transmission in the in humans is environmental stimuli previously associated early phase of cocaine withdrawal has not been studied with drug - taking . These drug -associated stimuli can be extensively . However , based on the nicotine dependence divided into two categories : discrete drug cues ( e. g ., drug findings and the hypothesis of overlapping mechanisms of paraphernalia ) that are associated with the rewarding effects 5 withdrawal from different drugs of abuse , one may hypoth of the drug , and discriminatory and contextual drug cues esize that decreased glutamatergic neurotransmission will ( e . g . , specific environmental stimuli or specific environ - also partly mediate cocaine withdrawal in cocaine - depen ments ) that predict drug availability . In animals , discrete , dent subjects. discriminative and contextual conditioned cues can reinstate In some embodiments , the compounds described herein drug -seeking behavior , measured by variables derived from 10 are mGlu2 / 3 receptor NAM used for treating cocaine addic the reinstatement procedure . Recent data showed that rein - tion . statement of cocaine -seeking was attenuated by systemic Schizophrenia injections of N - acetylcysteine that leads to a tonic increase Schizophrenia is a devastating psychiatric illness that in nucleus accumbens glutamate levels in rats . Preliminary afflicts approximately 1 % of the worldwide population . The results in humans suggest that N - acetylcysteine attenuated 15 core symptoms observed in schizophrenic patients include cocaine craving in addicted humans. Further, exposure to positive symptoms (thought disorder , delusions, hallucina environmental cues previously paired with cocaine injec - tions, and paranoia ), negative symptoms (social withdrawal, tions increased glutamate in the nucleus accumbensA . a nhedonia , apathy, and paucity of speech ) and cognitive potential use for mGlu2 / 3 agonists as pharmacotherapeutic impairments such as deficits in perception , attention , learn agents to inhibit relapse was recently shown using different 20 ing , short- and long -term memory and executive function . rodent models of reinstatement. In some embodiments , The cognitive deficits in schizophrenia are one of the major mGlu2 / 3 agonists attenuate cocaine - seeking behavior disabilities associated with the illness and are considered a induced by discriminative cocaine -associated cues or by reliable predictor of long - term disability and treatment out cocaine priming . In addition , mGlu2 / 3 agonists have been come. Currently available antipsychotics effectively treat the shown to inhibit cue - induced reinstatement of heroin -seek - 25 positive symptoms, but provide modest effects on the nega ing, alcohol- seeking, nicotine - seeking , and also inhibited tive symptoms and cognitive impairments . Furthermore , food -seeking behavior. The decreases in cue - induced food some patients are unresponsive to current antipsychotic responding suggest that the administration of mGlu2 / 3 ago - treatments and several of these agents are associated with nist decreased motivation for a natural reinforcer also . adverse side effects , including disturbances in motor func Further , it has been hypothesized that susceptibility to 30 tion , weight gain , and sexual dysfunction . Thus , there is a relapse due to cue reactivity increases gradually over periods need for new treatment strategies for schizophrenia that of weeks or months . Thus , the administration of a negative provide major improvements in efficacy across multiple modulator of mGlu2 / 3 receptors during prolonged abstihati symptom clusters and have fewer adverse effects . nence from cocaine self- administration will decrease , while Although the underlying pathophysiology of schizophre a negative modulator of mGlu2 / 3 receptors will have no 35 nia remains unknown , accumulating evidence points to effect on cocaine -seeking behavior induced by discrimina - disruptions in multiple neurotransmitter systems that modu tive stimuli associated with cocaine availability . late neural circuits important for normal affect , sensory Avoidance and alleviation of the negative affective state processing , and cognition . In particular, early clinical find of early drug withdrawal with further drug abuse is hypoth - ings demonstrated that changes in glutamatergic transmis esized to be an important source of motivation that contrib - 40 sion produced by antagonists of the N -methyl - D -aspartate utes significantly to the development of compulsive drug use (NMDA ) subtype of ionotropic glutamate receptors , includ and relapse during early abstinence . It has been hypoth - ing phencyclidine (PCP ) , result in a state of psychosis in esized that susceptibility to relapse due to affective with humans that is similar to that observed in schizophrenic drawal symptoms peaks within days of cessation reflecting patients . These studies suggest that agents that increase early rise in withdrawal symptoms . Thus , pharmacological 45 NMDA receptor function have potential as therapeutics for treatments that reverse aspects of cocaine early withdrawal the treatment of all major symptom clusters (positive , nega would remove an important source of motivation that con - tive , cognitive ) of the disease . More recently , studies indi tributes to relapse to drug abuse shortly after the initial cate that reduced NMDA receptor function induces complex cessation of drug administration . Abrupt abstinence follow - changes in transmission through cortical and subcortical ing chronic exposure to drugs of abuse , including cocaine 50 circuits that involve both glutamatergic and GABAergic results in a negative affective state reflected in significant synapses and include downstream increases in transmission elevations in intracranial self - stimulation ( ICSS ) thresholds . at glutamatergic synapses in the prefrontal cortex . Impor ICSS thresholds are thought to provide an operationalmea - tantly , these circuit changes might share common features sure of brain reward function ; thus elevations in ICSS with changes in brain circuit activities that occur in schizo thresholds reflect deficits in brain reward function . This 55 phrenia patients . One hypothesis is that NMDA receptors threshold elevation is opposite to the lowering of ICSS involved in these symptoms might reside at glutamatergic thresholds observed after cocaine administration that reflects synapses on GABAergic projection neurons in midbrain an increase in brain reward function that most likely under - regions as well as GABAergic interneurons and glutamater lies, or at least relates to , cocaine ' s euphorigenic effects . gic projection neurons in key cortical and limbic regions For This increase in brain reward function associated with 60 example , under normal conditions the activation of NMDA cocaine consumption is considered essential for the estab - receptors localized on GABAergic projection neurons in lishment and maintenance of cocaine self -administration subcortical regions, such as the nucleus accumbens, pro behavior. The mechanisms that contribute to withdrawal- vides inhibitory control on excitatory glutamatergic thal induced reward deficits or reward facilitation remain amocortical neurons that project to pyramidal neurons in the unclear. Group II mGlus have been implicated in the syn - 65 prefrontal cortex (PFC ) . Hypofunction or blockade of these aptic adaptations that occur in response to chronic drug NMDA receptors on midbrain inhibitory GABAergic neu exposure and contribute to the aversive behavioral with rons could result in a disinhibition of glutamatergic thal US 9 , 969, 726 B2 41 42 amocortical inputs to pyramidal neurons in the PFC . This In some embodiments , group II mGlu receptor agonists disinhibition would lead to a subsequent increased activity are useful in the treatment of schizophrenia . In some of glutamatergic thalamic neurons and increased activity embodiments , selective mGlu2 / 3 NAMs represent a novel mediated by the DL - a -amino -3 -hydroxy - 5 -methylisoxasole approach to the treatment of these disorders that is devoid of 4 - propionate (AMPA ) subtype of glutamate receptors at 5 the adverse effects associated with currently available drugs . thalamocortical synapses in the PFC . Based on this model, In some embodiments, the compounds described herein manipulations that enhance NMDA receptor function , such are mGlu2 / 3 receptor NAM used for treating schizophrenia . as activation of metabotropic glutamate receptor subtype 5 The method includes administering to a subject in need (mGlu5 ) located on GABAergic neurons, have potential as thereof, an effective amount of at least one mGlu2 / 3 receptor a novel approach to the treatment of schizophrenia . An " NAM , thereby treating schizophrenia . alternative approach might be to reduce excitatory gluta - Alzheimer ' s Disease matergic transmission at key synapses , such as thalamocor Alzheimer' s disease ( AD ) , also known as Alzheimer tical synapses in the PFC , by activation of metabotropic disease , or just Alzheimer ' s , accounts for 60 % to 70 % of glutamate receptor subtypes 2 and 3 (mGlu2 and mGlu3 ) 16 cases of dementia . It is a chronic neurodegenerative disease presynaptically located in these synapses . Although other that usually starts slowly and gets worse over time. The most viable models of circuit changes associated with schizophre common early symptom is difficulty in remembering recent nia exist, this hypothesis provides one possible framework events ( short term memory loss ) . As the disease advances, within which to consider effects of ligands at mGlu receptors symptoms can include : problems with language , disorienta that might be relevant to schizophrenia . 20 tion ( including easily getting lost ) , mood swings, loss of A large number of preclinical and clinical studies provide motivation , not managing self- care , and behavioral issues . strong evidence that agonists ofmGlu2 and mGlu3 also have As a person ' s condition declines, she or he often withdraws potential as a novel approach to the treatment of schizo - from family and society . Gradually , bodily functions are lost, phrenia . Consistent with the animal studies , clinical studies ultimately leading to death . Although the speed of progres reveal that a highly selective agonist of group II mGlu 25 sion can vary , the average life expectancy following diag receptors has robust efficacy in improving ratings for posi- nosis is three to nine years . tive and negative symptoms in patients with schizophrenia . Various brain regions, including the cerebral cortex , hip Unlike currently marketed antipsychotic agents , there were pocampus , striatum , amygdala , frontal cortex and nucleus no major adverse events reported for the mGlu2 / 3 agonist in accumbens , display high levels of mGlu2 and mGlu3 recep the clinical studies to date . However , further clinical studies 30 tor binding . This distribution pattern suggests a role for the will be required to fully establish safety of these compounds mGlu2 / 3 receptor subtypes in the pathology of neuropsy after long - term dosing in schizophrenic patients , as well as chiatric disorders such as Alzheimer 's disease . assess possible efficacy on the cognitive impairments in In some embodiments , the compounds described herein these patients . Taken together, these findings represent an are mGlu2 / 3 receptor NAM used for treating Alzheimer ' s important breakthrough and could ultimately lead to intro - 35 disease . The method includes administering to a subject in duction of group II mGlu receptor activators as a funda - need thereof, an effective amount of at least one mGlu2 / 3 mentally novel approach to the treatment of schizophrenia . receptor NAM , thereby treating Alzheimer' s disease . As mentioned above , animal studies reveal that the psy - Huntington ' s Disease chotomimetic agents increase activity of glutamatergic syn - Huntington ' s disease (HD ) is a neurodegenerative genetic apses in the PFC , and hyperactivity of glutamate neurotrans - 40 disorder that affects muscle coordination and leads to mental mission in the PFC and limbic structures has been postulated decline and behavioral symptoms. Symptoms of the disease to play a critical role in the pathophysiology of schizophre - can vary between individuals and affected members of the nia . Interestingly , effects of psychotomimetic agents on same family , but usually progress predictably. The earliest glutamatergic transmission in the PFC are blocked by group symptoms are often subtle problems with mood or cogni II mGlu receptor agonists . Although it is not yet clear 45 tion . A general lack of coordination and an unsteady gait whether this action of group II mGlu receptor agonists is often follows. As the disease advances , uncoordinated , jerky mechanistically related to the antipsychotic actions of these body movements become more apparent , along with a compounds , these actions fit well with current models of decline in mental abilities and behavioral symptoms. Physi disruptions in subcortical and cortical circuits that might be cal abilities gradually worsen until coordinated movement involved in the psychotomimetic effects of NMDA receptor 50 becomes difficult. Mental abilities generally decline into antagonists and the range of symptoms observed in schizo - dementia . Complications such as pneumonia , heart disease , phrenia patients . Despite advances in development of group and physical injury from falls reduce life expectancy to II mGlu receptor agonists , it is not yet clear whether around twenty years from the point at which symptoms orthosteric agonists of these receptors will reach the market begin . Physical symptoms can begin at any age from infancy for broad clinical use . Long - term administration of group II 55 to old age , but usually begin between 35 and 44 years of age . mGlu receptor agonists induces robust tolerance in at least Excitotoxic injury to striatum by dysfunctional cortical one rodentmodel that has been used to predict antipsychotic input or aberrant glutamate uptake may contribute to Hun efficacy . These orthosteric agonists also activate both mGlu2 tington ' s disease (HD ) pathogenesis . Daily subcutaneous and mGlu3 and do not provide insights into which of these injection with a maximum tolerated dose (MTD ) of the group II mGlu receptor subtypes is most important for 60 mGlu2/ 3 agonist LY379268 ( 20 mg/ kg ) beginning at 4 clinical efficacy . Although , recent findings demonstrate that weeks has been found to dramatically improves the pheno the antipsychotic - like effects of mGlu2 /3 receptor agonists type in R6 / 2 mice ( the most commonly used animal model are absent in mGlu2 -knockout , but not mGlu3 -knockout , ofHuntington ' s disease ) (Reiner et al. Brain Research 1473 mice . Thus , it is possible that negative allosteric modulators ( 2012 ) 161 - 172 ) . For example , normalization ofmotor func of mGlu2 / 3 might be an alternative approach that could 65 tion in distance traveled , speed , the infrequency of pauses , provide greater selectivity and other potential advantages to and the ability to locomote in a straight line , and a rescue of orthosteric agonists. a 15 - 20 % striatal neuron loss at 10 weeks were observed . US 9 ,969 , 726 B2 43 44 In some embodiments , the compounds described herein and include levodapa ( L - DOPA ) , a precursor of dopamine , are mGlu2 /3 receptor NAM used for treating Huntington ' s and dopamine receptor agonists . These agents are effective disease. The method includes administering to a subject in in treating the symptoms of the disease in the early stages , need thereof, an effective amount of at least one mGlu2 / 3 but are less effective as the disease progresses when debili receptor NAM , thereby treating Huntington ' s disease . 5 tating side - effects such as “ on -off " fluctuations in efficacy Lou Gehrig ' s Disease (ALS ) and uncontrollable dyskinesias ( involuntary muscle move Amyotrophic lateral sclerosis (ALS ) is a debilitating ments ) ensue . More importantly , dopaminergic treatments disorder characterized by rapidly progressive motor neuron do not halt the disease progression . For these reasons, degeneration , which results into weakness , muscle atrophy several investigators have started to focus on nondopamin and spasticity . Riluzole is the only drug that improves 10 ergic interventions as symptomatic and neuroprotecive strat survival of ALS patients , only to a modest extent. Thus, egies in PD . there is an urgent need for treatments that slow the progres Studies have shown that Group II mGlu receptors play sion of ALS . Familial ALS ( FALS ) is caused by mutations some role in alleviating akinesia in the rat. In functional of several genes including SOD1 ( type - 1 superoxide dis - studies (Murray et al . Pharmacology, Biochemistry and mutase ). Although SOD1 mutations account for only 20 % of 15 Behavior 73 ( 2002 ) 455 - 466 ) , intracerebroventricular FALS and about 2 % of sporadic ALS , SOD1 mutant mice administration of LY379268 ( 1 , 5 , 10 , 20 nmol/ 2 ul) pro recapitulate several features of human ALS , and are widely duced a dose - dependent increase in locomotor activity in the employed as model for ALS . The validity of this model is reserpine ( 5 mg/ kg ip ) - treated rat. In contrast , systemic strengthened by the evidence that SOD1 aggregates are administration of LY379268 ( 0 . 1 , 1 , 10 mg/ kg ip ) did not detected in the spinal cord of people with sporadic ALS or 20 reverse reserpine - induced akinesia and failed to effect rota with ALS caused by mutations of genes other than SOD1. tional behaviour 1 month after unilateral lesioning of the The mechanisms by which SOD1 misfolding damages nigrostriatal tract by 6 -hydroxydopamine (6 -OHDA ; 4 mg motor neurons are only partially elucidated and involve infused into the substantia nigra (SN ) ). These results suggest glutamate excitotoxicity , mitochondrial dysfunction , disrup that mGlus may offer a nondopaminergic approach to the tion of axonal transport , and abnormalities in astrocytes and 25 treatment of PD . microglia . One of the potentialmechanisms of excitotoxicity In some embodiments , the compounds described herein in ALS is a reduced expression of the glutamate transporter , are mGlu2/ 3 receptor NAM used for treating Parkinson ' s GLT- 1 , which clears glutamate from the synapses. disease . The method includes administering to a subject in Enhancement of glial -derived neurotrophic factor need thereof, an effective amount of at least one mGlu2 / 3 (GDNF ) is an established therapeutic target for amyotrophic 30 receptor NAM , thereby treating Parkinson ' s disease . lateral sclerosis ( ALS ) . Activation of group II metabotropic Depression glutamate (mGlu ) receptors with the orthosteric agonist, Major depressive disorder (MDD ) is one of the most LY379268 , enhanced GDNF levels in cultured spinal cord common psychiatric illnesses worldwide having a profound astrocytes from wild - type mice and mGlu2 knockout mice , impact on public health . MDD is the most common cause of but not in astrocytes from mGlu3 knockoutmice . LY379268 35 disease burden in North America and the fourth leading protected Stemberger monoclonal incorporated antibody - 32 cause in the world as determined by the World Health ( SMI- 32 ) * motor neurons against excitotoxic death in mixed Organization . Existing treatments for MDD , such as selec cultures of spinal cord cells, and its action was abrogated by tive serotonin reuptake inhibitors ( SSRIs ), serotonin -norepi anti - GDNF antibodies. Acute systemic injection of nephrine reuptake inhibitors (SNRIs ) and tricyclic antide LY379268 ( 0 . 5 , 1 or 5 mg/kg , i . p . ) enhanced spinal cord 40 pressants ( TCAs) , have serious limitations in that they GDNF levels in wild - type and mGlu2 knockout mice , but usually take weeks to months to achieve their antidepressant not in mGlu3 knockout mice . No tolerance developed to the effects . It is during this latency period , that high rates of GDNF -enhancing effect of LY379268 when the drug was mortality and morbidity are noted . Despite the widespread continuously delivered for 28 days by means of s . c . osmotic availability of these effective treatments it is estimated that minipumps ( 0 . 5 - 5 mg/ day ) . Continuous infusion of 45 between 30 - 70 % of patients with MDD fail to fully respond LY379268 also enhanced the expression of the glutamate to these therapies . Treatment resistant depression ( TRD ) is transporter GLT - 1 , in the spinal cord . Continuous treatment a severely disabling disorder and those suffering from TRD with 1 or 5 mg/ kg /day with LY379268 had a beneficial effect have very limited treatment options. There is accumulating on neurological disability in SOD1G93A mice . At day 40 of evidence that the glutamatergic system plays an important treatment, LY379268 enhanced spinal cord levels of GDNF 50 role in the etiology , neurobiology and treatment of MDD . It and GLT- 1 , and rescued spinal cordmotor neurons, as has been shown that chronic administration of SSRIs cause assessed by stereologic counting of SMI- 32 + cells . up regulation of several glutamate receptor subunits impli In some embodiments, the compounds described herein cating glutamate neurotransmission as an action of standard are mGlu2 / 3 receptor NAM used for treating ALS . The antidepressants . There are many regulatory sites of the method includes administering to a subject in need thereof, 55 glutamatergic system that have shown potential for modu an effective amount of at least onemGlu2 / 3 receptor NAM , lating MDD . Regulation of the metabotropic glutamate thereby treating ALS . receptors has been the focus of significant research over the Parkinson 's Disease past several years. Antagonists ofmGlu2 / 3 have been shown Parkinson ' s disease (PD ) is a chronic movement disorder to have dose dependent antidepressant activity in several resulting from a disturbance in the normal functioning of the 60 animal models for depression ( i . e . forced - swim test, novelty basal ganglia , a collection of subcortical nuclei that are suppressed feeding, and mouse tail -suspension test) . Also , essential for the initiation and control of motor activity . The these compounds when chronically administered stimulate underlying pathology of the disease is a progressive degen - hippocampal neurogenesis similar to the neurogenic effects eration of the dopaminergic nigrostriatal tract that manifests observed for SSRIs. It has been shown that mGlu2 / 3 antago as a range ofmotor deficits including akinesia or bradyki- 65 nists increase extracellular levels of serotonin in the medial nesia , tremor, rigidity and postural instability . Current thera - prefrontal cortex which is attenuated by the AMPA receptor pies for PD are essentially based on dopamine replacement antagonist NBQX indicating that AMPA receptor stimula US 9 , 969, 726 B2 45 46 tion is responsible for the serotonin release . In rodents , wherein : antidepressant activity of mGlu2 / 3 antagonists is rapid and sustained for 24 hours following acute administration . This ring is a heteroaryl ring ; activity was block by the AMPA receptor antagonist NBQX or the mTOR inhibitor rapamycine . This finding is very 5 ring is an aryl ring or heteroaryl ring; similar to the recent human studies showing ketamine, an R ! is — CO , H , CN , C (O )NHOH , - C (O )NHOMe , N -methyl - D -aspartate (NMDA ) antagonist , that has an anti C( O ) NHSO, Me, _ NHC( O) Me, C( O )NHMe , depressant effect two hours after a sub - anaesthetic dose ( intravenous administration ) with effects lasting for up to two weeks . In rodents , this effect can be replicated and also 10 blocked by NBQX and rapamycin . HN Cancer Grade IV glioma ( glioblastoma , GBM ), is the most fre quent malignant brain cancer in adults , accounting for up to 45 % of all malignant tumors in the central nervous system 15 (CNS ) . GBMs arise from astrocytes , are usually highly malignant, and in 90 % of the cases occur spontaneously as HNT HN primary tumors . The National Institute of Health classifies 0 , or GBM as a rare disorder with a prevalence of approximately 4 cases per 100 , 000 . In the US, there are approximately mm 100 ,000 patients , with 10 , 000 new cases being diagnosed min every year . The prognosis of patients diagnosed with GBM is very poor, with a median survival of 12 - 15 months , only each R2 is independently halogen , — ORS, substituted or 10 % of patients surviving 5 years, and approximately 12 ,000 unsubstituted C -Coalkyl , or substituted or unsubsti GBM patients dying every year. The standard therapeutic - tuted C -Cofluoroalkyl ; approach involves surgical resection of the tumor followed each R * is independently substituted or unsubstituted by radiation therapy combined with temozolomide ( TMZ ) , C1 -Cgalkyl , substituted or unsubstituted a DNA alkylating agent . Although , TMZ is well tolerated , it C1- Cqfluoroalkyl, substituted or unsubstituted has limited efficacy in improving disease -free survival. Cz -Cocycloalkyl , or substituted or unsubstituted aryl; There are a few additional treatments including bevacice each R4 is independently halogen , - OR " , substituted or zumab ( Avastin ) , a humanized monoclonal antibody to the unsubstituted C - C alkyl, substituted or unsubstituted vascular endothelial growth factor ( VEGF) which blocks C , - Cofluoroalkyl, substituted or unsubstituted angiogenesis, and carmustine , also a DNA alkylating agent. Cz -Cocycloalkyl , or substituted or unsubstituted aryl; Unfortunately , in many cases within 7 months of treatmenteatment, 35 or two R * taken together with the carbon atoms to which tumors reoccur, after which patient survival is less than 1 they are attached to form a substituted or unsubstituted year . Thus , there is a significant unmet need for new , C2- Cgheterocycloalkyl; effective treatments for GBM . Hence, there are a large each R is independently hydrogen , or substituted or number of new approaches that are currently being studied unsubstituted C . -Cgalkyl ; in the clinic , including monoclonal antibodies , vaccines and 40 n is 0 , 1 , 2 , or 3 ; gene therapies . Recent evidence has emerged suggesting m is 0 or 1 ; and that mGlu2 / 3 receptor inhibitors may represent an additional p is 0 , 1 , 2 , or 3 treatment option for GBM patients . n is 0 , 1 , 2 , or 3 ; Moreover , there are data indicating that inhibition of m is 0 or 1 ; and mGluz could be useful to treat other types of cancers , such 45 p is 0 , 1 , 2 , or 3 . as melanoma. Mutations in the mGlu3 receptor have been In some embodiments is a compound of Formula ( I ) , or a identified in melanoma. The mGlu3 mutations identified in pharmaceutically acceptable salt thereof, wherein ring melanoma caused a gain - of- function , increasing anchor independent growth and migration . Therefore, it is reason W is a 5 -membered or a 6 -membered heteroaryl ring. In able to suggest a rationale for treating melanoma using some embodiments is a compound of Formula (I ) , or a mGlu2 / 3 antagonists or NAMs. pharmaceutically acceptable salt thereof, wherein ring Compounds In one aspect, described herein is a compound that has the is a 6 -membered heteroaryl ring. In some embodiments structure of Formula ( I ) , or a pharmaceutically acceptable is a compound of Formula ( 1 ) , or a pharmaceutically accept salt thereof: 55 able salt thereof, wherein ring is a 5 - membered het eroaryl ring . In some embodiments is a compound of For Formula ( I ) mula ( 1 ), or a pharmaceutically acceptable salt thereof, wherein ring is thiazolyl, oxadiazolyl, thiadiazolyl, tri azolyl, imidazolyl, or isothiazolyl. In some embodiments is 60 a compound of Formula ( I) , or a pharmaceutically accept able salt thereof, wherein ring is thiazolyl. In some ( R In) embodiments is a compound of Formula (I ) , or a pharma (R ?) m (R4 ) .p ; 65 ceutically acceptable salt thereof , wherein ring is oxadi azolyl. In some embodiments is a compound of Formula ( I ) , or a pharmaceutically acceptable salt thereof, wherein ring US 9 , 969 , 726 B2 47 48 pharmaceutically acceptable salt thereof , wherein n is 1 and is thiadiazolyl. In some embodiments is a compound of R2 is halogen , OR , substituted or unsubstituted Formula (I ) , or a pharmaceutically acceptable salt thereof, C - Coalkyl, substituted or unsubstituted C , - Cofluoroalkyl. wherein ring is triazolylriazolyl . In some embodimentsembodiments some 5 In some embodiments is a compound of Formula (I ), or a embodiments is a compound of Formula (I ) , or a pharma pharmaceutically acceptable salt thereof , wherein n is 1 and ceutically acceptable salt thereof, wherein ring is imi- R ’ is halogen , CF3, or OCH3. In some embodiments is dazolyl. In some embodiments is a compound of Formulauld a compound of Formula ( I ), or a pharmaceutically accept ( I ) , or a pharmaceutically acceptable salt thereof, wherein 10 able salt thereof, wherein n is 1 and R² is halogen . In some ring ? is isothiazolyl. In some embodiments is a com - embodiments is a compound of Formula ( 1 ), or a pharma pound of Formula ( I) , or a pharmaceutically acceptable salt ceutically acceptable salt thereof, wherein n is 1 and R2 is thereof, wherein m is 0 . In some embodiments is a com CF3. In some embodiments is a compound of Formula ( I) , pound of Formula ( I ) , or a pharmaceutically acceptable salt thereof, wherein m is 1 . 15 or a pharmaceutically acceptable salt thereof, wherein n is 1 In some embodiments is a compound of Formula ( I) , or a and R² is OCHZ. pharmaceutically acceptable salt thereof, wherein ring I n some embodiments is a compound of Formula ( I ) , or a pharmaceutically acceptable salt thereof, wherein Riis ® is an aryl ring . In some embodiments is a compound of - CO , H . In some embodiments is a compound of Formula Formula ( I) , or a pharmaceutically acceptable salt thereof, 20 ( I ) , or a pharmaceutically acceptable salt thereof , wherein R wherein ring ® is a phenyl ring . is CN . In some embodiments is a compound of Formula In some embodiments is a compound of Formula (1 ) , or a ( 1 ) , or a pharmaceutically acceptable salt thereof, wherein R pharmaceutically acceptable salt thereof, wherein ring is - C ( O )NHOH . In some embodiments is a compound of 25 Formula ( 1 ) , or a pharmaceutically acceptable salt thereof , ® is a heteroaryl ring . In some embodiments is a com - wherein Rl is - C ( O )NHOMe . In some embodiments is a pound of Formula (I ) , or a pharmaceutically acceptable salt compound of Formula (I ), or a pharmaceutically acceptable thereof, wherein ring is furanyl, thiophenyl, benzofura salt thereof, wherein Riis - C (O )NHSO ,Me . In some nyl, benzothiophenyl, or pyridinyl. In some embodiments is embodiments is a compound of Formula (I ) , or a pharma a compound of Formula ( I) , or a pharmaceutically acceptaccept- 30 ceutically acceptable salt thereof, wherein Riis - NHC ( O ) Me. In some embodiments is a compound of Formula ( I ), or able salt thereof, wherein ring ® is furanyl. In some a pharmaceutically acceptable salt thereof, wherein R ' is embodiments is a compound of Formula ( I) , or a pharma ceutically acceptable salt thereof, wherein ring is thio - 35 phenyl. In someembodiments is a compound of Formula ( I ) , or a pharmaceutically acceptable salt thereof, wherein ring - is benzofuranyl. In some embodiments is a compound of Formula ( I) , or a pharmaceutically acceptable salt thereof , 20 mi wherein ring is benzothiophenyl. In some embodiments is a compound of Formula ( I) , or a pharmaceutically accept In some embodiments is a compound of Formula (I ) , or a able salt thereof, wherein ring ® is pyridinyl. In some pharmaceutically acceptable salt thereof, wherein R ' is embodiments is a compound of Formula ( I) , or a pharma - 45 ceutically acceptable salt thereof, wherein p is 0 . In some embodiments is a compound of Formula ( I) , or a pharma ZE ceutically acceptable salt thereof, wherein p is 1 . In some embodiments is a compound of Formula ( I ) , or a pharma ceutically acceptable salt thereof, wherein p is 1 and R * is 50 halogen , — OR " , substituted or unsubstituted C , - Cgalkyl, nu substituted or unsubstituted C - Cofluoroalkyl . In some embodiments is a compound of Formula ( I ) , or a pharma ceutically acceptable salt thereof, wherein p is 1 and R4 is In some embodiments is a compound of Formula ( 1) , or a halogen , CF3, orOCHz. In some embodiments is a 55 pharmaceutically acceptable salt thereof , wherein Riis compound of Formula ( I ) , or a pharmaceutically acceptable salt thereof, wherein p is 1 and R4 is halogen . In some embodiments is a compound of Formula ( I ) , or a pharma ceutically acceptable salt thereof, wherein p is 1 and R4 is — CF2. In some embodiments is a compound of Formula ( I ) , 60 HN or a pharmaceutically acceptable salt thereof, wherein p is 1 and R4 is – OCHz. In some embodiments is a compound of Formula ( I ) , or a pharmaceutically acceptable salt thereof, wherein n is 0 . In some embodiments is a compound of Formula ( 1 ) , or a 65 pharmaceutically acceptable salt thereof, wherein n is 1. In In some embodiments is a compound of Formula (I ), or a some embodiments is a compound of Formula (I ) , or a pharmaceutically acceptable salt thereof, wherein Rl is US 9, 969, 726 B2 49 50 In some embodiments is a compound of Formula ( la ), or a pharmaceutically acceptable salt thereof , wherein p is 1 and R4 is halogen , OR ”, substituted or unsubstituted HN C / -Cgalkyl , substituted or unsubstituted C , -Cofluoroalkyl . 5 In some embodiments is a compound of Formula ( la ) , or a pharmaceutically acceptable salt thereof, wherein p is 1 and mm R * is halogen , CF3, or — OCHz. In some embodiments is a compound of Formula ( la ), or a pharmaceutically accept In some embodiments is a compound of Formula ( I ) , or a 10 able salt thereof , wherein p is 1 and R4 is halogen . In some embodiments is a compound of Formula ( la ) , or a pharma pharmaceutically acceptable salt thereof, wherein Rl is ceutically acceptable salt thereof, wherein p is 1 and R4 is CF > . In some embodiments is a compound of Formula ( la ) , or a pharmaceutically acceptable salt thereof, wherein p is 1 and R4 is OCHZ. HN In some embodiments is a compound of Formula ( la ) , or a pharmaceutically acceptable salt thereof, wherein n is 0 . In some embodiments is a compound of Formula ( la ) , or a pharmaceutically acceptable salt thereof, wherein n is 1 . In mm some embodiments is a compound of Formula ( la ), or a 20 pharmaceutically acceptable salt thereof, wherein n is 1 and In some embodiments , the compound of Formula ( I) has R2 is halogen , - OR " , substituted or unsubstituted the structure of Formula ( la ) : C -Coalkyl , substituted or unsubstituted C - Cofluoroalkyl. In some embodiments is a compound of Formula ( la ) , or a pharmaceutically acceptable salt thereof , wherein n is 1 and Formula (Ia ) 25 R2 is halogen , - CF2, or — OCHZ. In some embodiments is P / a compound of Formula ( la ) , or a pharmaceutically accept able salt thereof, wherein n is 1 and R2 is halogen . In some embodiments is a compound of Formula (la ) , or a pharma ceutically acceptable salt thereof, wherein n is 1 and R² is 30 CFz . In some embodiments is a compound of Formula ( Ia ) , or a pharmaceutically acceptable salt thereof, wherein Rn n is 1 and R² is OCHZ. In some embodiments is a compound of Formula (la ), or a pharmaceutically acceptable salt thereof, wherein R is In some embodiments is a compound of Formula ( la ), or - CO , H . a pharmaceutically acceptable salt thereof, wherein ring In some embodiments , the compound of Formula (I ) has the structure of Formula ( Ib ) : O is an aryl ring . In some embodiments is a compound of Formula ( la ), or a pharmaceutically acceptable salt thereof, 40 wherein ring ® is a phenyl ring . Formula ( Ib ) In some embodiments is a compound of Formula (Ia ), or a pharmaceutically acceptable salt thereof, wherein ring N ® is a heteroaryl ring . In some embodiments is a com - 45 pound of Formula ( Ia ), or a pharmaceutically acceptable salt (Ron (R™ ) p thereof, wherein ring ® is furanyl, thiophenyl, benzofura nyl, benzothiophenyl, or pyridinyl. In some embodiments is a compound of Formula ( la ), or a pharmaceutically accept In some embodiments is a compound of Formula (Ib ), or able salt thereof, wherein ring ® is furanylaranyl. InIn some a pharmaceutically acceptable salt thereof, wherein ring embodiments is a compound of Formula ( la ), or a pharma U is an aryl ring . In some embodiments is a compound of ceutically acceptable salt thereof, wherein ring is thio - Formula phenyl. In some embodiments is a compound of Formula 55 Formula ( Ib ), or a pharmaceutically acceptable salt thereof, ( la ), or a pharmaceutically acceptable salt thereof, wherein wherein ring is a phenyl ring . In some embodiments is a compound of Formula ( lb ), or ring ® is benzofuranyl. In some embodiments is a com pound of Formula ( la ), or a pharmaceutically acceptable salt a pharmaceutically acceptable salt thereof, wherein ring thereof, wherein ring is benzothiophenyl. In some 60 ® is a heteroaryl ring . In some embodiments is a com embodiments is a compound of Formula ( la ) , or a pharma pound of Formula ( lb ) , or a pharmaceutically acceptable salt thereof, wherein ring ® is furanyl, thiophenyl, benzofura ceutically acceptable salt thereof, wherein ring is nyl, benzothiophenyl, or pyridinyl. In some embodiments is pyridinyl. In some embodiments is a compound of Formula a compound of Formula (lb ) , or a pharmaceutically accept ( Ia ), or a pharmaceutically acceptable salt thereof, wherein 65 p is 0 . In some embodiments is a compound of Formula (la ) , able salt thereof, wherein ring ® is furanyl. In some or a pharmaceutically acceptable salt thereof , wherein p is 1 . embodiments is a compound of Formula ( lb ) , or a pharma US 9 , 969 , 726 B2 52 compound of Formula ( Ic ) , or a pharmaceutically acceptable ceutically acceptable salt thereof , wherein ring is thio salt thereof, wherein R is unsubstituted phenyl. phenyl. In some embodiments is a compound of Formula In some embodiments is a compound of Formula ( Ic ), or ( lb ) , or a pharmaceutically acceptable salt thereof , wherein a pharmaceutically acceptable salt thereof, wherein ring ring ® is benzofuranyl. In some embodiments is a com ® is an aryl ring . In some embodiments is a compound of pound of Formula ( Ib ), or a pharmaceutically acceptable salt Formula (Ic ) , or a pharmaceutically acceptable salt thereof, thereof, wherein ring is benzothiophenyl. In some wherein ring ® is a phenyl ring . embodiments is a compound of Formula (Ib ) , or a pharma 10 In some embodiments is a compound of Formula ( Ic ), or ceutically acceptable salt thereof, wherein ring is a pharmaceutically acceptable salt thereof, wherein ring pyridinyl. In some embodiments is a compound of Formula ( lb ) , or a pharmaceutically acceptable salt thereof, wherein is a heteroaryl ring . In some embodiments is a com p is 0 . In some embodiments is a compound of Formula ( lb ) , pound of Formula ( Ic ) , or a pharmaceutically acceptable salt or a pharmaceutically acceptable salt thereof, wherein p is 1. 15 they In some embodiments is a compound of Formula ( lb ) , or a· 15 thereof , wherein ring ) is furanyl, thiophenyl , benzofura pharmaceutically acceptable salt thereof, wherein p is 1 and nyl , benzothiophenyl, or pyridinyl. In some embodiments is R4 is halogen , — OR ' , substituted or unsubstituted a compound of Formula ( Ic ), or a pharmaceutically accept C , - C alkyl, substituted or unsubstituted C1 - Cgfluoroalkyl. able salt thereof, wherein ring B is furanyl. In some In some embodiments is a compound of Formula ( lb ) , or a 20 embodiments is a compound of Formula ( Ic ) , or a pharma pharmaceutically acceptable salt thereof , wherein p is 1 and R4 is halogen , CF3, or OCHz. In some embodiments is ceutically acceptable salt thereof, wherein ring ® is thio a compound of Formula ( Ib ), or a pharmaceutically accept phenyl. In some embodiments is a compound of Formula able salt thereof, wherein p is 1 and R4 is halogen . In some (Ic ) , or a pharmaceutically acceptable salt thereof, wherein embodiments is a compound of Formula ( lb ) , or a pharma - 25 ceutically acceptable salt thereof, wherein p is 1 and R * is ring is benzofuranyl. In some embodiments is a com -- CFz. In some embodiments is a compound of Formula pound of Formula ( lc ), or a pharmaceutically acceptable salt ( lb ) , or a pharmaceutically acceptable salt thereof, wherein thereof, wherein ring ® is benzothiophenyl. In some p is 1 and R4 is _ OCHZ. In some embodiments is a compound of Formula ( b ), or 30 embodiments is a compound of Formula ( Ic ) , or a pharma a pharmaceutically acceptable salt thereof, wherein n is 0 . In ceutically acceptable salt thereof, wherein ring is some embodiments is a compound of Formula ( lb ) , or a pyridinyl. In some embodiments is a compound of Formula pharmaceutically acceptable salt thereof, wherein n is 1 . In (Ic ) , or a pharmaceutically acceptable salt thereof, wherein some embodiments is a compound of Formula ( lb ) , or a p is 0 . In some embodiments is a compound of Formula ( Ic ) , pharmaceutically acceptable salt thereof, wherein n is 1 and 35 or a pharmaceutically acceptable salt thereof, wherein p is 1 . R2 is halogen , — OR ' , substituted or unsubstituted In some embodiments is a compound of Formula (Ic ), or a CZ - C alkyl, substituted or unsubstituted C - Cofluoroalkyl. pharmaceutically acceptable salt thereof, wherein p is 1 and In some embodiments is a compound of Formula ( Ib ), or a R4 is halogen, OR , substituted or unsubstituted pharmaceutically acceptable salt thereof, wherein n is 1 and C . - C alkyl, substituted or unsubstituted C , -Cofluoroalkyl . R2 is halogen , CF3, or — OCHz. In some embodiments is 40 In some embodiments is a compound of Formula ( Ic ), or a a compound of Formula ( Ib ), or a pharmaceutically accept- pharmaceutically acceptable salt thereof, wherein p is 1 and able salt thereof, wherein n is 1 and R2 is halogen . In some R4 is halogen , CF3, or — OCHz. In some embodiments is embodiments is a compound of Formula ( lb ) , or a pharma - a compound of Formula ( Ic ) , or a pharmaceutically accept ceutically acceptable salt thereof, wherein n is 1 and R2 is able salt thereof, wherein p is 1 and R4 is halogen . In some – CF3 . In some embodiments is a compound of Formula 45 embodiments is a compound of Formula ( Ic ) , or a pharma ( lb ) , or a pharmaceutically acceptable salt thereof, wherein ceutically acceptable salt thereof, wherein p is 1 and R * is n is 1 and R2 is — OCHz. _ CFz. In some embodiments is a compound of Formula In some embodiments is a compound of Formula ( Ib ) , or ( Ic ) , or a pharmaceutically acceptable salt thereof, wherein a pharmaceutically acceptable salt thereof, wherein Rl is p is 1 and R4 is _ OCH . - CO2H . 50 In some embodiments is a compound of Formula ( Ic ) , or In some embodiments is a compound of Formula ( I ) , or a a pharmaceutically acceptable salt thereof, wherein n is 0 . In pharmaceutically acceptable salt thereof, having the struc - some embodiments is a compound of Formula ( Ic ) , or a ture of Formula ( Ic ): pharmaceutically acceptable salt thereof, wherein n is 1 . In some embodiments is a compound of Formula (Ic ), or a 55 pharmaceutically acceptable salt thereof, wherein n is 1 and Formula ( Ic ) R2 is halogen , OR ” , substituted or unsubstituted C , - C alkyl, substituted or unsubstituted C . - C , fluoroalkyl. In some embodiments is a compound of Formula ( Ic ) , or a - pharmaceutically acceptable salt thereof, wherein n is 1 and B 60 R² is halogen , — CF3, or — OCHz. In some embodiments is a compound of Formula (Ic ) , or a pharmaceutically accept ( R4) , able salt thereof, wherein n is 1 and R2 is halogen . In some embodiments is a compound of Formula ( Ic ) , or a pharma Sotto ceutically acceptable salt thereof, wherein n is 1 and R2 is 65 CFz . In some embodiments is a compound of Formula wherein R * is substituted or unsubstituted C , -Coalkyl or ( Ic ), or a pharmaceutically acceptable salt thereof, wherein substituted or unsubstituted aryl . In some embodiments is a nis 1 and R² is OCHZ . US 9 ,969 , 726 B2 53 54 In some embodiments is a compound of Formula ( Ic ) , or pound of Formula ( II ) , or a pharmaceutically acceptable salt a pharmaceutically acceptable salt thereof, wherein R is CO , H . thereof, wherein ring is furanyl, thiophenyl, thiazolyl, In another aspect, described herein is a compound that has pyrrolyl, or pyridinyl. In some embodiments is a compound the structure of Formula ( II ). or a pharmaceutically accept- 5 of Formula ( 11 ) , or a pharmaceutically acceptable salt able salt thereof: thereof, wherein ring ? is furanyl. In some embodiments is a compound of Formula ( II ), or a pharmaceutically Formula (II ) acceptable salt thereof, wherein ring is thiophenyl. In 10 some embodiments is a compound of Formula (II ), or a pharmaceutically acceptable salt thereof, wherein ring is thiazolyl . In some embodiments is a compound of Formula ( II ), or a pharmaceutically acceptable salt thereof, 15 wherein ring is pyrrolyl. In some embodiments is a (R4 ) ni compound of Formula ( II ), or a pharmaceutically acceptable ottya(R3 ) m salt thereof, wherein ring is pyridinyl . In some embodi 20 ments is a compound of Formula ( II) , or a pharmaceutically wherein : acceptable salt thereof, wherein m is 0 . In some embodi ments is a compound of Formula ( II ), or a pharmaceutically ring is an aryl ring or heteroaryl ring ; acceptable salt thereof, wherein m is 1 . In some embodi X is a bond , 0 % , - S — , or — N ( R ) — ; ments is a compound of Formula ( II ) , or a pharmaceutically Ris — CO , H , — CN , - C ( O )NHOH , - C ( O )NHOMe , 25 acceptable salt thereof. wherein m is 1 and R * is halogen . C ( O )NHSO . Me, _ NHC( O ) Me, C ( O ) NHMe, ORS, SR®, substituted or unsubstituted C -Coalkyl , or substituted or unsubstituted C - Cofluoroalkyl. In some embodiments is a compound of Formula ( II ) , or a pharma ceutically acceptable salt thereof, wherein m is 1 and R3 is 30 N HN halogen , OCH3, CF3, or unsubstituted C -Cgalkyl . In some embodiments is a compound of Formula ( II ), or a pharmaceutically acceptable salt thereof, wherein m is 1 and mi R * is halogen . In some embodiments is a compound of mm 25 Formula ( II ), or a pharmaceutically acceptable salt thereof, wherein m is 1 and R3 is — OCHz. In some embodiments is HN HN a compound of Formula ( II ) , or a pharmaceutically accept o , or able salt thereof, wherein m is 1 and R3 is CF2 . In some embodiments is a compound of Formula (II ) , or a pharma 40 ceutically acceptable salt thereof , wherein m is 1 and R3 is mm unsubstituted C - Cgalkyl. In some embodiments is a com || pound of Formula ( II ) , or a pharmaceutically acceptable salt each R is independently halogen , - OR " , NO2, substi - thereof, wherein m is 1 and Ris — CHz. tuted or unsubstituted C -Cgalkyl , or substituted or In some embodiments is a compound of Formula ( II ), or unsubstituted C , - Cqfluoroalkyl; 45 a pharmaceutically acceptable salt thereof, wherein X is a each R is independently halogen , - OR " , - SR " , substi - bond , — O — , - S — , or — N ( H ) — . In some embodiments is tuted or unsubstituted C , - C alkyl, substituted or unsub - a compound of Formula (II ) , or a pharmaceutically accept stituted C - Cofluoroalkyl, substituted or unsubstituted able salt thereof, wherein X is a bond . In some embodiments Cz- Cacycloalkyl , or substituted or unsubstituted aryl; is a compound of Formula ( II ) , or a pharmaceutically R4 is H , CF3, — CHz, or substituted or unsubstituted 50 acceptable salt thereof, wherein X is O — . In some phenyl; embodiments is a compound of Formula ( II) , or a pharma each R is independently hydrogen , or substituted or ceutically acceptable salt thereof, wherein X is – S — . In unsubstituted C , -Coalkyl ; some embodiments is a compound of Formula ( II ) , or a Róis hydrogen , or substituted or unsubstituted pharmaceutically acceptable salt thereof, wherein X is C1- C alkyl; 55 — N ( H ) — , n is 0 , 1 , 2 , or 3 ; and In some embodiments is a compound of Formula ( II ) , or m is 0 , 1 or 2 . a pharmaceutically acceptable salt thereof, wherein R4 is H , In some embodiments is a compound of Formula ( II ) , or CF3, CHz, or substituted or unsubstituted phenyl. In a pharmaceutically acceptable salt thereof , wherein ring some embodiments is a compound of Formula ( II ) , or a 60 pharmaceutically acceptable salt thereof, wherein R * is H . In is an aryl ring . In some embodiments is a compound of some embodiments is a compound of Formula ( II ) , or a Formula ( II ), or a pharmaceutically acceptable salt thereof, pharmaceutically acceptable salt thereof, wherein R4 is wherein ring is a phenyl ring. CF3. In some embodiments is a compound of Formula In some embodiments is a compound of Formula ( II ), or ( II ) , or a pharmaceutically acceptable salt thereof, wherein e salt thereof wherein ring 65 R4 is CHz. In some embodiments is a compound of a pharmaceutically acceptable salt thereof, wherein ring 65 FormulaR ( II ), or a pharmaceutically acceptable salt thereof, ? is a heteroaryl ring . In some embodiments is a com wherein X is substituted phenyl. In some embodiments is a US 9 ,969 , 726 B2 55 56 compound of Formula ( II ) , or a pharmaceutically acceptable salt thereof, wherein X is unsubstituted phenyl. In some embodiments is a compound of Formula ( II ), or a pharmaceutically acceptable salt thereof, wherein n is 0 . In HN some embodiments is a compound of Formula ( II ), or a pharmaceutically acceptable salt thereof, wherein n is 1. In some embodiments is a compound of Formula ( II) , or a mi pharmaceutically acceptable salt thereof ,wherein n is 1 and 10 In some embodiments is a compound of Formula ( II) , or a R2 is halogen . - ORS, substituted or unsubstituted pharmaceutically acceptable salt thereof, wherein R ' is CZ -Cgalkyl , substituted or unsubstituted C , -Cofluoroalkyl . In some embodiments is a compound of Formula (II ), or a pharmaceutically acceptable salt thereof, wherein n is 1 and 15 HN

R2 is halogen , CF3, or - OCHZ. In some embodiments is w a compound of Formula ( II ), or a pharmaceutically accept able salt thereof, wherein n is 1 and R2 is halogen . In some embodiments is a compound of Formula ( II) , or a pharma- 20 ceutically acceptable salt thereof, wherein n is 1 and R is F . In some embodiments is a compound of Formula ( II ), or a In some embodiments is a compound of Formula ( II ) , or a pharmaceutically acceptable salt thereof , wherein Riis pharmaceutically acceptable salt thereof ,wherein n is 1 and R² is CFz. In some embodiments is a compound of 25 Formula ( II) , or a pharmaceutically acceptable salt thereof, wherein n is 1 and R2 is OCHZ. HN In some embodiments is a compound of Formula (II ), or a pharmaceutically acceptable salt thereof, wherein R ' is 30 - CO2H . In some embodiments is a compound of Formula w ( II ) , or a pharmaceutically acceptable salt thereof, wherein R ! is — CN . In some embodiments is a compound of In some embodiments , the compound of Formula ( II ) has Formula ( II ), or a pharmaceutically acceptable salt thereof, the structure of Formula ( IIa ) : wherein Riis - C ( O )NHOH . In some embodiments is a 35 compound of Formula ( II ) , or a pharmaceutically acceptable salt thereof, wherein R is C ( O ) NHOMe. In some Formula (IIa ) embodiments is a compound of Formula ( II ) , or a pharma CF3 ceutically acceptable salt thereof, wherein R isC O ) NHSO Me. In some embodiments is a compound of For - 40 mula ( II) , or a pharmaceutically acceptable salt thereof, wherein Ris - NHC ( O )Me . In some embodiments is a compound of Formula ( II) , or a pharmaceutically acceptable salt thereof, wherein Rl is 45 F3C ' N N In some embodiments is a compound of Formula ( IIa ), or a pharmaceutically acceptable salt thereof, wherein n is 0 . In 50 some embodiments is a compound of Formula ( IIa ), or a M pharmaceutically acceptable salt thereof, wherein n is 1 . In some embodiments is a compound of Formula ( IIa ) , or a pharmaceutically acceptable salt thereof, wherein n is 1 and R2 is halogen , OR " , substituted or unsubstituted In some embodiments is a compound of Formula ( II) , or a 55 C . - C alkyl, substituted or unsubstituted C . -Cofluoroalkyl . pharmaceutically acceptable salt thereof , wherein Rl is In some embodiments is a compound of Formula ( Ila ) , or a pharmaceutically acceptable salt thereof, wherein n is 1 and R² is halogen , CF3, or — OCHz. In some embodiments is a compound of Formula ( IIa ) , or a pharmaceutically accept 60 able salt thereof, wherein n is 1 and R is halogen . In some embodiments is a compound of Formula ( IIa ) , or a pharma ceutically acceptable salt thereof, wherein n is 1 and R2 is F . mm In some embodiments is a compound of Formula ( Ila ) , or a pharmaceutically acceptable salt thereof, wherein n is 1 and 65 R² is — CFz. In some embodiments is a compound of In some embodiments is a compound of Formula ( II) , or a Formula ( Ila ) , or a pharmaceutically acceptable salt thereof, pharmaceutically acceptable salt thereof, wherein Rl is wherein n is 1 and R² is -- OCHz. US 9 ,969 , 726 B2 57 58 In some embodiments is a compound of Formula (Ila ) , or maceutically acceptable salt thereof, wherein Rl is CO2H , a pharmaceutically acceptable salt thereof, wherein R ! is n is 1 and R2 is halogen , — CF3, or — OCHz . In some - CO2H . In some embodiments is a compound of Formula embodiments is a compound of Formula ( IIb ) , or a phar ( IIa ), or a pharmaceutically acceptable salt thereof, wherein maceutically acceptable salt thereof, wherein Rl is CO2H , R is — CO , H and n is 0 . In some embodiments is a 5 n is 1 and R2 is halogen . In some embodiments is a compound of Formula ( Ila ) , or a pharmaceutically accept compound of Formula ( IIb ) , or a pharmaceutically accept able salt thereof, wherein R is CO2H , n is 1 and R² is able salt thereof, wherein R is CO2H , n is 1 and R² is F . halogen , — ORS, substituted or unsubstituted C - Csalkyl, In some embodiments is a compound of Formula (IIb ) , or a substituted or unsubstituted C , - Cofluoroalkyl . In some pharmaceutically acceptable salt thereof, wherein R is embodiments is a compound of Formula ( IIa ), or a pharma- 10 CO , H , n is 1 and R2 is CFz. In some embodiments is ceutically acceptable salt thereof , wherein Ris - CO , H n , a compound of Formula ( IIb ) , or a pharmaceutically accept is 1 and R2 is halogen , — CFz, or — OCH . In some embodi- able salt thereof, wherein Rl is CO , H , n is 1 and R2 is ments is a compound of Formula ( IIa ) , or a pharmaceutically OCHZ. acceptable salt thereof, wherein Rl is – CO , H , n is 1 and R2 In some embodiments , the compound of Formula ( II ) has is halogen . In some embodiments is a compound of Formula 15 the structure of Formula ( IIC ) : ( IIa ) , or a pharmaceutically acceptable salt thereof, wherein R is CO2H , n is 1 and R2 is F . In some embodiments is a compound of Formula ( IIa ) , or a pharmaceutically accept Formula ( IIC ) able salt thereof , wherein R is – CO , H , n is 1 and R2 is CF3. In some embodiments is a compound of Formula 20 CF3 ( IIa ), or a pharmaceutically acceptable salt thereof, wherein Rl is CO , H , n is 1 and R2 is _ OCHZ. In some embodiments , the compound of Formula ( II) has the structure of Formula ( Ilb ) : 2525 l R47 Formula ( IIb ) In some embodiments is a compound of Formula ( IIC ) , or 30 a pharmaceutically acceptable salt thereof, wherein n is 0 . In some embodiments is a compound of Formula ( IIc ) , or a pharmaceutically acceptable salt thereof, wherein n is 1 . In some embodiments is a compound of Formula ( IIC ) , or a Rn( . pharmaceutically acceptable salt thereof, wherein n is 1 and 35 R2 is halogen , — ORS , substituted or unsubstituted op C -Cgalkyl , substituted or unsubstituted C1- Cofluoroalkyl. In some embodiments is a compound of Formula (IIC ) , or a In some embodiments is a compound of Formula ( IIb ), or pharmaceutically acceptable salt thereof, wherein n is 1 and a pharmaceutically acceptable salt thereof, wherein n is 0 . In R² is halogen , CF3, or - OCHZ. In some embodiments is some embodiments is a compound of Formula ( IIb ) , or a 40 a compound of Formula ( IIC ), or a pharmaceutically accept pharmaceutically acceptable salt thereof, wherein n is 1. In able salt thereof, wherein n is 1 and R2 is halogen . In some some embodiments is a compound of Formula ( IIb ) , or a embodiments is a compound of Formula (IIC ), or a pharma pharmaceutically acceptable salt thereof, wherein n is 1 and ceutically acceptable salt thereof, wherein n is 1 and R² is F . R ? is halogen , — OR ' , substituted or unsubstituted In some embodiments is a compound of Formula (IIC ) , or a C2 - Cgalkyl, substituted or unsubstituted C -Cofluoroalkyl . 45 pharmaceutically acceptable salt thereof, wherein n is 1 and In some embodiments is a compound of Formula ( IIb ) , or a R2 is — CFz. In some embodiments is a compound of pharmaceutically acceptable salt thereof, wherein n is 1 and Formula ( IIC ) , or a pharmaceutically acceptable salt thereof, R² is halogen , CF3, or OCHz. In some embodiments is wherein n is 1 and R2 is -- OCHZ. a compound of Formula (IIb ) , or a pharmaceutically accept- In some embodiments is a compound of Formula (IIC ), or able salt thereof, wherein n is 1 and R² is halogen . In some 50 a pharmaceutically acceptable salt thereof, wherein Rl is embodiments is a compound of Formula ( IIb ) , or a phar - CO2H . In some embodiments is a compound of Formula maceutically acceptable salt thereof, wherein n is 1 and R ? (IIC ), or a pharmaceutically acceptable salt thereof, wherein is F . In some embodiments is a compound of Formula ( IIb ) , Riis - CO , H and n is 0 . In some embodiments is a or a pharmaceutically acceptable salt thereof, wherein n is 1 compound of Formula ( IIC ), or a pharmaceutically accept and R2 is — CFz. In some embodiments is a compound of 55 able salt thereof, wherein Rl is CO , H , n is 1 and R2 is Formula ( Ilb ) , or a pharmaceutically acceptable salt thereof, halogen , — OR " , substituted or unsubstituted C - C alkyl, wherein n is 1 and R2 is _ OCHZ. substituted or unsubstituted C . - C . fluoroalkyl. In some In some embodiments is a compound of Formula ( IIb ) , or embodiments is a compound of Formula ( Ilc ), or a pharma a pharmaceutically acceptable salt thereof, wherein Rl is ceutically acceptable salt thereof, wherein Rl is — CO , H , n — CO , H . In some embodiments is a compound of Formula 60 is 1 and R² is halogen , CFz , or — OCHZ. In some embodi ( IIb ) , or a pharmaceutically acceptable salt thereof, wherein ments is a compound of Formula ( IIC ) , or a pharmaceutically R is CO H and n is 0 . In some embodiments is a acceptable salt thereof, wherein Ris CO , H , n is 1 and R2 compound of Formula (Ilb ) , or a pharmaceutically accept is halogen . In some embodiments is a compound of Formula able salt thereof, wherein Rl is – CO , H , n is 1 and R2 is (IIC ), or a pharmaceutically acceptable salt thereof, wherein halogen , OR ” , substituted or unsubstituted C , - Cgalkyl, 65 R is CO2H , n is 1 and R2 is F . In some embodiments is substituted or unsubstituted C , -Cafluoroalkyl . In some a compound of Formula ( IIC ) , or a pharmaceutically accept embodiments is a compound of Formula ( IIb ) , or a phar - able salt thereof, wherein Rl is — CO , H , n is 1 and R2 is US 9 , 969 , 726 B2 59 60 - CFz. In some embodiments is a compound of Formula pound of Formula ( III ), or a pharmaceutically acceptable salt ( IIC ), or a pharmaceutically acceptable salt thereof, wherein thereof , wherein m is 0 and R3 is halogen . In some embodi R is CO2H , n is 1 and R2 is — OCHZ. ments is a compound of Formula ( III ) , or a pharmaceutically In another aspect , described herein is a compound that has acceptable salt thereof, wherein m is 0 and R3 is CN . In the structure of Formula ( III ), or a pharmaceutically accept- 5 some embodiments is a compound of Formula ( III ) , or a pharmaceutically acceptable salt thereof, wherein m is O and able salt thereof: R3 is substituted or unsubstituted C , - Coalkyl. In some embodiments is a compound of Formula ( III ) , or a pharma Formula ( III ) ceutically acceptable salt thereof, wherein m is O and R3 is 10 substituted or unsubstituted aryl. In some embodiments is a compound of Formula ( III) , or a pharmaceutically accept X able salt thereof, wherein m is O and R3 is unsubstituted heteroaryl. In some embodiments is a compound of Formula (III ) , or a pharmaceutically acceptable salt thereof, wherein 15 m is 0 and R * is — X — R4. In some embodiments is a R3 compound of Formula ( III ) , or a pharmaceutically accept able salt thereof, wherein m is 0 , R3 is — X — R4, X is O — , and R * is substituted or unsubstituted aryl, or sub (Rºm stituted or unsubstituted heteroaryl. In some embodiments is 20 a compound of Formula (III ) , or a pharmaceutically accept wherein : able salt thereof, wherein m is 0 , R3 is - X - R4, X is Z is = N — or = C ( H ) ; - O - , and R4 is substituted or unsubstituted phenyl. In Riis halogen , OR ” , — NO ,, CN , substituted or some embodiments is a compound of Formula ( III) , or a unsubstituted C - Coalkyl, substituted or unsubstituted pharmaceutically acceptable salt thereof, wherein m is 0 , R3 C -Cofluoroalkyl , substituted or unsubstituted aryl, 25 is - X - R4, X iso - , and R * is substituted or unsubsti substituted or unsubstituted heteroaryl, or — CO Rº; tuted heteroaryl. In some embodiments is a compound of each R is independently halogen , OR , NO2, substi - Formula ( III ) , or a pharmaceutically acceptable salt thereof, tuted or unsubstituted C -Cgalkyl , or substituted or wherein m is 0 , R3 is — X — R4 , X is , and R4 is unsubstituted C - Cofluoroalkyl; unsubstituted pyridine . In some embodiments is a compound R * is hydrogen , halogen , — CN , substituted or unsubsti - 30 of Formula (III ), or a pharmaceutically acceptable salt tuted C1- Cgalkyl, substituted or unsubstituted thereof, wherein m is 0 , R² is X - R4 , X is O — , and R4 C , - C fluoroalkyl, substituted or unsubstituted is unsubstituted pyrimidine. In some embodiments is a Cz- Cocycloalkyl , substituted or unsubstituted compound of Formula ( III ), or a pharmaceutically accept C2- Cyheterocycloalkyl, substituted or unsubstituted able salt thereof, wherein m is 0 , R3 is - X - R4, X is aryl, unsubstituted heteroaryl, - C ( O )NR°R10 , or 350 - , and R4 is unsubstituted pyrazine . In some embodi - X - R4; ments is a compound of Formula ( III) , or a pharmaceutically X is - O - , S - , - S ( O ) 2 - , - N ( R ) - , or — C = C — ; acceptable salt thereof, wherein m is 0 , R² is - X - R4, X is R4 is substituted or unsubstituted C , -Cgalkyl , substituted - N (H ) — , and R4 is substituted or unsubstituted aryl, or or unsubstituted C3 -Cocycloalkyl , substituted or unsub - substituted or unsubstituted heteroaryl. In some embodi stituted aryl, or substituted or unsubstituted heteroaryl; 40 ments is a compound ofFormula ( III) , or a pharmaceutically each R is independently hydrogen , or substituted or acceptable salt thereof, wherein m is 0 , R² is - X - R4, X is unsubstituted C , - C alkyl; - N ( H ) - , and R4 is substituted or unsubstituted phenyl. In Rºis hydrogen , or substituted or unsubstituted some embodiments is a compound of Formula ( III) , or a C -C alkyl; pharmaceutically acceptable salt thereof, wherein m is 0 , R * R7 is hydrogen , or substituted or unsubstituted 45 is — X — R4, X is — N ( H ) — , and R4 is substituted or CZ -Cgalkyl ; unsubstituted heteroaryl . In some embodiments is a com each R8 is independently halogen , or substituted or unsub - pound of Formula (III ) , or a pharmaceutically acceptable salt stituted C -Cgalkyl ; thereof, wherein m is 0 , Rºis — X — R4 , X is N ( H ) — , and Rº and R10 are independently hydrogen , or substituted or R4 is unsubstituted pyridine . In some embodiments is a unsubstituted C , - Cgalkyl ; 50 compound of Formula ( III) , or a pharmaceutically accept n is 0 , 1 , 2 , or 3 ; and able salt thereof, wherein m is 0 , R * is — X — R4 , X is m is 0 , 1, or 2 . - N ( H ) - , and R4 is unsubstituted pyrimidine . In some In some embodiments is a compound of Formula ( III ), or embodiments is a compound of Formula ( III ), or a pharma a pharmaceutically acceptable salt thereof, wherein Z is ceutically acceptable salt thereof, wherein m is 0 , R3 is = N — . In some embodiments is a compound of Formula 55 — X — R4, X is — N ( H ) — , and R * is unsubstituted pyrazine . ( III) , or a pharmaceutically acceptable salt thereof, wherein In some embodiments is a compound of Formula ( III ) , or a Z is = C ( H ) pharmaceutically acceptable salt thereof, wherein m is 0 , R3 In some embodiments is a compound of Formula ( III) , or is - X - R4 , X is S , and R4 is substituted or unsubsti a pharmaceutically acceptable salt thereof, wherein m is 0 . tuted aryl, or substituted or unsubstituted heteroaryl. In some In some embodiments is a compound of Formula ( III ) , or a 60 embodiments is a compound of Formula ( III) , or a pharma pharmaceutically acceptable salt thereof, wherein m is 1 and ceutically acceptable salt thereof, wherein m is 0 , R3 is R® is halogen . - X - R4, X is - S — , and R4 is substituted or unsubstituted In some embodiments is a compound of Formula ( III ) , or phenyl. In some embodiments is a compound of Formula a pharmaceutically acceptable salt thereof, wherein m is 0 (III ) , or a pharmaceutically acceptable salt thereof, wherein and R * is halogen , — CN , substituted or unsubstituted 65 m is 0 , R is — X — R4, X is — S — , and R4 is substituted or C , - C alkyl, substituted or unsubstituted aryl, unsubstituted unsubstituted heteroaryl. In some embodiments is a com heteroaryl, or - X - R4. In some embodiments is a com pound of Formula (III ) , or a pharmaceutically acceptable salt US 9 ,969 , 726 B2 61 thereof, wherein m is 0 , R3 is — X — R4, X is S , and R4 is unsubstituted pyridine . In some embodiments is a com Formula ( IIIa ) pound of Formula ( III) , or a pharmaceutically acceptable salt thereof, wherein m is 0 , R3 is - X R , - S — , and R4 is unsubstituted pyrimidine . In some embodiments is a com - 5 pound of Formula ( III ) , or a pharmaceutically acceptable salt thereof, wherein m is 0 , Rºis — X — R4, X is S — , and R + is unsubstituted pyrazine . In some embodiments is a com R ? ; pound of Formula (III ) , or a pharmaceutically acceptable salt thereof, wherein m is 0 , R ’ is — X - R4, X is - S (O ) , — , and 10 R4 is substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl. In some embodiments is a com pound of Formula ( III ) , or a pharmaceutically acceptable salt wherein R3 is halogen , — CN , unsubstituted heteroaryl, or thereof, wherein m is 0 , R3 is - X - R4, X is - S (O ) 2 - , and 15 - X - R4 ; and R4 is substituted or unsubstituted aryl, or R4 is substituted or unsubstituted phenyl. In some embodi- substituted or unsubstituted heteroaryl . ments is a compound of Formula ( III) , or a pharmaceutically In some embodiments is a compound of Formula ( IIIa ), or acceptable salt thereof, wherein m is 0 , R² is — X — R4, X is a pharmaceutically acceptable salt thereof, wherein m is 0 . - S ( O ), — , and R4 is substituted or unsubstituted heteroaryl. In some embodiments is a compound of Formula (IIIa ), or In some embodiments is a compound of Formula ( III ) , or a 20 a pharmaceutically acceptable salt thereof, wherein m is 1 pharmaceutically acceptable salt thereof, wherein m is 0 , R3 and R8 is halogen . is - X - R4, X is - S ( O ) 2 - , and R4 is unsubstituted pyri - In some embodiments is a compound of Formula ( IIIa ) , or dine . In some embodiments is a compound of Formula ( III ), a pharmaceutically acceptable salt thereof, wherein m is 0 or a pharmaceutically acceptable salt thereof, wherein m is and Rºis halogen . In some embodiments is a compound of 0 , R3 is X - R4 , - S ( O )2 - , and R4 is unsubstituted 25 Formula ( IIIa ), or a pharmaceutically acceptable salt thereof, pyrimidine . In some embodiments is a compound of For wherein m is O and R3 is CN . In some embodiments is a mula ( III ), or a pharmaceutically acceptable salt thereof, compound of Formula (IIIa ), or a pharmaceutically accept able salt thereof, wherein m is 0) and R3 is unsubstituted wherein m is 0 , R3 is — X — R4 , X is - S ( O ) 2 - , and R * is heteroaryl. In some embodiments is a compound of Formula unsubstituted pyrazine . 30 ( IIIa ) , or a pharmaceutically acceptable salt thereof, wherein In some embodiments is a compound of Formula ( III ), or m is 0 and Rºis - X - R4. In some embodiments is a a pharmaceutically acceptable salt thereof, wherein Rl is compound of Formula ( IIIa ), or a pharmaceutically accept halogen , - OR " , substituted or unsubstituted C - Cgalkyl, or able salt thereof, wherein m is 0 , R3 is - X - R4, X is substituted or unsubstituted C -Cofluoroalkyl . In some 0 — , and R4 is substituted or unsubstituted aryl, or sub embodiments is a compound of Formula ( III) , or a pharma- 35 stituted or unsubstituted heteroaryl. In some embodiments is ceutically acceptable salt thereof, wherein R is halogen , a compound of Formula (IIIa ), or a pharmaceutically accept – CF3 , or — OCHz. In some embodiments is a compound of able salt thereof, wherein m is 0 , R is — X — R4, X is Formula ( III ) , or a pharmaceutically acceptable salt thereof, 0 % , and R + is substituted or unsubstituted phenyl. In wherein Rl is halogen . In some embodiments is a compound some embodiments is a compound of Formula ( IIIa ), or a of Formula (III ) , or a pharmaceutically acceptable salt 40 pharmaceutically acceptable salt thereof, wherein m is 0 , RP thereof, wherein Rl is - CF2. In some embodiments is a is — X — R *, X is 04 , and R * is substituted or unsubsti compound of Formula (III ) , or a pharmaceutically accept tuted heteroaryl. In some embodiments is a compound of Formula ( IIIa ) , or a pharmaceutically acceptable salt thereof, able salt thereof, wherein R is OCHZ. wherein m is 0 , R3 is — X — R4, X is O , and R4 is In some embodiments is a compound of Formula ( III) , or 45 unsubstituted pyridine . In some embodiments is a compound a pharmaceutically acceptable salt thereof, wherein n is 0 . In of Formula ( Illa ) , or a pharmaceutically acceptable salt some embodiments is a compound of Formula ( III ) , or a thereof, wherein m is 0 , R3 is — X — R4. X is O — , and R4 pharmaceutically acceptable salt thereof, wherein n is 1. In is unsubstituted pyrimidine . In some embodiments is a some embodiments is a compound of Formula (III ), or a compound of Formula ( IIIa ), or a pharmaceutically accept pharmaceutically acceptable salt thereof ,wherein n is 1 and 50 able salt thereof, wherein m is 0 , R3 is - X - R4, X is R2 is halogen , — ORS, substituted or unsubstituted 0 , and R4 is unsubstituted pyrazine . In some embodi C - Coalkyl, substituted or unsubstituted C - Cofluoroalkyl. ments is a compound of Formula ( IIIa ), or a pharmaceuti In some embodiments is a compound of Formula ( III ), or a cally acceptable salt thereof, wherein m is 0 , R3 is — X — R4, pharmaceutically acceptable salt thereof, wherein n is 1 and X is — N ( H ) , and R4 is substituted or unsubstituted aryl , R2 is halogen , CH , , - CFz , or - OCHz. In some embodi- 55 or substituted or unsubstituted heteroaryl. In some embodi ments is a compound of Formula ( III ) , or a pharmaceutically ments is a compound of Formula ( IIIa ) , or a pharmaceuti acceptable salt thereof, wherein n is 1 and R2 is halogen . In cally acceptable salt thereof, wherein m is 0 , Rºis — X — R * , some embodiments is a compound of Formula ( III ) , or a X is — N ( H ) — , and R + is substituted or unsubstituted pharmaceutically acceptable salt thereof, wherein n is 1 and phenyl . In some embodiments is a compound of Formula of 60 ( IIIa ), or a pharmaceutically acceptable salt thereof, wherein R2 is CHz. In some embodiments is a compound of m is 0 , R3 is — X — R , X is — N ( H ) — , and R4 is substituted Formula ( III ), or a pharmaceutically acceptable salt thereof, or unsubstituted heteroaryl. In some embodiments is a wherein n is 1 and R² is CF3. In some embodiments is a compound of Formula (IIIa ), or a pharmaceutically accept compound of Formula (III ) , or a pharmaceutically accept able salt thereof, wherein m is 0, R3 is - X - R4, X is able salt thereof, wherein n is 1 and R² is OCHZCz.. 65 — N (H ) — , and R4 is unsubstituted pyridine. In some In some embodiments , the compound of Formula ( III ) has embodiments is a compound of Formula ( IIIa ), or a phar the structure of Formula ( IIIa ) : maceutically acceptable salt thereof, wherein m is 0 , R3 is US 9 , 969 , 726 B2 63 64 - X - R4, X is — N ( H ) — , and R4 is unsubstituted pyrimi- a pharmaceutically acceptable salt thereof, wherein n is 1 dine . In some embodiments is a compound of Formula and R2 is halogen , CH , CFz, or — OCHz. In some (IIIa ), or a pharmaceutically acceptable salt thereof, wherein embodiments is a compound of Formula ( IIIa ) , or a phar m is 0 , R * is - X - R4, X is N ( H ) — , and R4 is unsubsti maceutically acceptable salt thereof, wherein n is 1 and R ? tuted pyrazine . In some embodiments is a compound of 5 is halogen . In some embodiments is a compound of Formula Formula ( IIIa ) , or a pharmaceutically acceptable salt thereof, ( IIIa ), or a pharmaceutically acceptable salt thereof , wherein wherein m is 0 , R is — X - R4, X is — S and R4 is nis 1 and R ’ is CHz. In some embodiments is a compound substituted or unsubstituted aryl, or substituted or unsubsti tuted heteroaryl. In some embodiments is a compound of of Formula (IIIa ), or a pharmaceutically acceptable salt Formula ( IIIa ), or a pharmaceutically acceptable salt thereof, 10 thereof, wherein n is 1 and R² is – CF3 . In some embodi wherein m is 0 , R is X - R , X is - S — , and R4 is ments is a compound of Formula ( IIIa ), or a pharmaceuti substituted or unsubstituted phenyl. In some embodiments is cally acceptable salt thereof, wherein n is 1 and R2 is a compound of Formula ( IIIa ) , or a pharmaceutically accept OCHZ. able salt thereof, wherein m is 0 , R3 is X - R4, X is S , In some embodiments , the compound of Formula ( III ) has and R4 is substituted or unsubstituted heteroaryl. In some 15 "the structure of Formula ( IIIb ) : embodiments is a compound of Formula ( IIIa ) , or a phar maceutically acceptable salt thereof, wherein m is 0 , R3 is - X - R4, X is - S — , and R4 is unsubstituted pyridine . In Formula ( IIIb ) some embodiments is a compound of Formula (IIIa ), or a N pharmaceutically acceptable salt thereof, wherein m is 0 , R9 20 is — X - R4, - S , and R4 is unsubstituted pyrimidine . In some embodiments is a compound of Formula (IIIa ), or a pharmaceutically acceptable salt thereof, wherein m is 0 , R3 is — X - R4, X is — S , and R4 is unsubstituted pyrazine . R : In some embodiments is a compound of Formula ( IIIa ), or 25 a pharmaceutically acceptable salt thereof, wherein m is 0 , R3 is — X — R4 , X is - S ( O ) , — and R4 is substituted or (Rºm unsubstituted aryl, or substituted or unsubstituted heteroaryl. In some embodiments is a compound of Formula ( IIIa ), or wherein R is — CN , substituted or unsubstituted heteroaryl , a pharmaceutically acceptable salt thereof, wherein m is 0 , 30 or — X — R4; and R4 is substituted or unsubstituted R * is X R4, X is - S (O )2 - , and R4 is substituted or C2 -Cgalkyl , substituted or unsubstituted aryl, or unsubsti unsubstituted phenyl. In some embodiments is a compound tuted heteroaryl. of Formula ( IIIa ), or a pharmaceutically acceptable salt In some embodiments is a compound of Formula (IIIb ), or thereof, wherein m is 0 , Rºis - X R4, X is - S (O )2 - , and a pharmaceutically acceptable salt thereof, wherein m is 0 . R4 is substituted or unsubstituted heteroaryl . In some 35 In some embodiments is a compound of Formula (IIIb ) , or embodiments is a compound of Formula ( IIIa ) , or a phar - a pharmaceutically acceptable salt thereof, wherein m is 1 maceutically acceptable salt thereof, wherein m is 0 , R3 is and R8 is halogen . - X - R4, X is - S ( O ) 2 - , and R * is unsubstituted pyridine . In some embodiments is a compound of Formula (IIIb ), or In some embodiments is a compound of Formula ( IIIa ) , or a pharmaceutically acceptable salt thereof, wherein m is 0 a pharmaceutically acceptable salt thereof, wherein m is 0 , 40 and Rºis CN . In some embodiments is a compound of R is — X — R - , - S ( O ) , — , and R4 is unsubstituted pyrimi- Formula ( IIIb ) , or a pharmaceutically acceptable salt dine . In some embodiments is a compound of Formula thereof, wherein m is 0 and R * is unsubstituted heteroaryl . In ( IIIa ), or a pharmaceutically acceptable salt thereof, wherein some embodiments is a compound of Formula (IIIb ) , or a m is 0 , R3 is - X - R4, X is - S ( O ) 2 - , and R * is unsub pharmaceutically acceptable salt thereof, wherein m is 0 and stituted pyrazine. 45 R3 is X - R4 . In some embodiments is a compound of In some embodiments is a compound of Formula (IIIa ), or Formula ( III) ), or a pharmaceutically acceptable salt a pharmaceutically acceptable salt thereof, wherein Rl is thereof , wherein m is 0 , R3 is X - R4 , X is - 0 , and R4 halogen , OR ” , substituted or unsubstituted C .- Cgalkyl, or is substituted or unsubstituted aryl, or substituted or unsub substituted or unsubstituted C , - Cofluoroalkyl. In some stituted heteroaryl. In some embodiments is a compound of embodiments is a compound of Formula ( IIIa ) , or a phar - 50 Formula ( IIIb ) , or a pharmaceutically acceptable salt maceutically acceptable salt thereof, wherein R is halogen , thereof, wherein m is 0 , R * is — X — R4, X is — O — , and R + - CF3, or — OCHz. In some embodiments is a compound of is substituted or unsubstituted phenyl. In some embodiments Formula ( IIIa ) , or a pharmaceutically acceptable salt thereof, is a compound of Formula ( IIIb ), or a pharmaceutically wherein R is halogen . In some embodiments is a compound acceptable salt thereof, wherein m is 0 , R3 is — X — R4 , X is of Formula ( IIIa ), or a pharmaceutically acceptable salt 55 - 0 — , and R4 is substituted or unsubstituted heteroaryl. In thereof, wherein Riis — CFz. In some embodiments is a some embodiments is a compound of Formula (IIIb ) , or a compound of Formula ( IIIa ) , or a pharmaceutically accept- pharmaceutically acceptable salt thereof, wherein m is 0 , R3 able salt thereof, wherein Rl is OCHZ. is - X - R4, X is O — , and R4 is unsubstituted pyridine . In some embodiments is a compound of Formula ( IIIa ), or In some embodiments is a compound of Formula ( IIIb ) , or a pharmaceutically acceptable salt thereof, wherein n is 0 . In 60 a pharmaceutically acceptable salt thereof, wherein m is 0 , some embodiments is a compound of Formula (IIIa ), or a R3 is — X — R4, X is O — , and R4 is unsubstituted pyrimi pharmaceutically acceptable salt thereof, wherein n is 1 . In dine . In some embodiments is a compound of Formula some embodiments is a compound of Formula ( IIIa ), or a ( IIIb ), or a pharmaceutically acceptable salt thereof, wherein pharmaceutically acceptable salt thereof, wherein n is 1 and mis 0 , R3 is — X — R4, X is 0 - , and R * is unsubstituted R2 is halogen , OR , substituted or unsubstituted 65 pyrazine . In some embodiments is a compound of Formula C , -Coalkyl , substituted or unsubstituted C , -Cofluoroalkyl . (IIIb ) , or a pharmaceutically acceptable salt thereof, wherein In some embodiments is a compound of Formula ( IIIa ), or mis 0 , R * is X — R4, X is — N (H ) — , and R + is substituted US 9 , 969 , 726 B2 65 66 or unsubstituted aryl , or substituted or unsubstituted het CF3, or - OCHz. In some embodiments is a compound of eroaryl. In some embodiments is a compound of Formula Formula ( IIIb ), or a pharmaceutically acceptable salt ( IIIb ) , or a pharmaceutically acceptable salt thereof, wherein thereof, wherein Rl is halogen . In some embodiments is a m is 0 , R is — X — R4, X is — N ( H ) — , and R * is substituted compound of Formula ( IIIb ) , or a pharmaceutically accept or unsubstituted phenyl. In some embodiments is a com - 5 able salt thereof, wherein Rl is CFz. In some embodi pound of Formula ( IIIb ), or a pharmaceutically acceptable ments is a compound of Formula ( IIIb ) , or a pharmaceuti salt thereof, wherein m is 0 , R3 is — X — R4, X is — N ( H ) - , and R4 is substituted or unsubstituted heteroaryl. In( Hsome ) ; cally acceptable salt thereof, wherein Rl is - OCHZ. embodiments is a compound of Formula (IIIb ), or a pharsome In some embodiments is a compound of Formula ( IIIb ), or maceutically acceptable salt thereof, wherein m is 0 , R² is 10 a pharmaceutically acceptable salt thereof, wherein n is 0 . In - X - R4, X is - N ( H ) , and R * is unsubstituted pyridine. some embodiments is a compound of Formula (IIIb ) , or a In some embodiments is a compound of Formula ( IIIb ) , or pharmaceutically acceptable salt thereof, wherein n is 1 . In a pharmaceutically acceptable salt thereof, wherein m is 0 , some embodiments is a compound of Formula ( IIIb ) , or a R3 is — X — R4, X is — N (H ) — , and R4 is unsubstituted pharmaceutically acceptable salt thereof , wherein n is 1 and pyrimidine. In some embodiments is a compound of For- 15 R2 is halogen , OR “ , substituted or unsubstituted mula ( IIIb ), or a pharmaceutically acceptable salt thereof, C , -Cgalkyl , substituted or unsubstituted C , -Cofluoroalkyl . wherein m is 0 , R * is - X - R4, X is - N ( H ) — , and R4 is In some embodiments is a compound of Formula ( II1b ) , or unsubstituted pyrazine . In some embodiments is a com a pharmaceutically acceptable salt thereof, wherein n is 1 pound of Formula ( IIIb ), or a pharmaceutically acceptable and R² is halogen , CH3, CF3, or — OCHz. In some salt thereof, wherein m is 0 , R3 is — X — R4, X is - S — , and 20 embodiments is a compound of Formula (IIIb ), or a phar R4 is substituted or unsubstituted aryl, or substituted or maceutically acceptable salt thereof, wherein n is 1 and R2 unsubstituted heteroaryl . In some embodiments is a com is halogen . In some embodiments is a compound of Formula pound of Formula ( IIIb ), or a pharmaceutically acceptable (IIIb ) , or a pharmaceutically acceptable salt thereof, wherein salt thereof, wherein m is 0, R3 is — X — R4, X is - S — , and nis 1 and R2 is – CH2. In some embodiments is a compound R4 is substituted or unsubstituted phenyl. In some embodi - 25 of Formula ( III) ) , or a pharmaceutically acceptable salt ments is a compound of Formula ( IIIb ), or a pharmaceuti thereof , wherein n is 1 and R2 is — CFz . In some embodi cally acceptable salt thereof, wherein m is 0 , R3 is X - R4, ments is a compound of Formula (IIIb ) , or a pharmaceuti X is - S — , and R4 is substituted or unsubstituted heteroaryl. cally acceptable salt thereof, wherein n is 1 and R2 is In some embodiments is a compound of Formula ( IIIb ), or OCHZ. a pharmaceutically acceptable salt thereof, wherein m is 0 , 30 In another aspect , described herein is a compound that has R?is — X — R4, X is - S — , and R is unsubstituted pyridine . the structure of Formula ( IV ) , or a pharmaceutically accept In some embodiments is a compound of Formula ( IIIb ) , or able salt thereof: a pharmaceutically acceptable salt thereof, wherein m is 0 , R? is - X - R4, S4 , and R4 is unsubstituted pyrimidine . In some embodiments is a compound of Formula (IIIb ), or 35 Formula ( IV ) a pharmaceutically acceptable salt thereof, wherein m is 0 , R * is — X — R4, X is S — , and R * is unsubstituted pyra zine . In some embodiments is a compound of Formula ( IIIb ) , or a pharmaceutically acceptable salt thereof, wherein mis 0 ,R3 is - X - R4, X is - S ( O ) 2 - , and R4 is substituted 40 (R2 ) NH or unsubstituted aryl, or substituted or unsubstituted het R eroaryl . In some embodiments is a compound of Formula ( IIIb ) , or a pharmaceutically acceptable salt thereof, wherein mis 0 , Rºis — X — R4, X is - S ( O ) 2 - , and R * is substituted ) or unsubstituted phenyl. In some embodiments is a com - 45 pound of Formula ( IIIb ) , or a pharmaceutically acceptable wherein : salt thereof, wherein m is 0 ,R is — X — R4, X is - S ( O ) , — , Z is = N - or = C ( H ) ; and R4 is substituted or unsubstituted heteroaryl. In some R ! is halogen , OR ", - NO2, CN , substituted or embodiments is a compound of Formula ( IIIb ) , or a phar unsubstituted C . - C alkyl, substituted or unsubstituted maceutically acceptable salt thereof, wherein m is 0 , R is 50 C - Cofluoroalkyl, substituted or unsubstituted aryl, - X - R4, X is - S ( O ) 2 - , and R + is unsubstituted pyridine. substituted or unsubstituted heteroaryl, or — CO , Rº; In some embodiments is a compound of Formula ( IIIb ) , or each R2 is independently halogen , - OR " , NO2, substi a pharmaceutically acceptable salt thereof, wherein m is 0 , tuted or unsubstituted C -Cgalkyl , or substituted or R * is — X — R4, - S ( O ) 2 - , and R4 is unsubstituted pyrimi unsubstituted C - Cofluoroalkyl; dine . In some embodiments is a compound of Formula 55 R2 is hydrogen , halogen , CN , substituted or unsubsti ( IIIb ) , or a pharmaceutically acceptable salt thereof, wherein tuted C -Coalkyl , substituted or unsubstituted m is 0 , R3 is X - R4, X is - S ( O ) 2 - , and R4 is unsub C -Cofluoroalkyl , substituted or unsubstituted stituted pyrazine . In some embodiments is a compound of Cz -Cocycloalkyl , substituted or unsubstituted Formula ( IIIb ) , or a pharmaceutically acceptable salt C2- C heterocycloalkyl, substituted or unsubstituted thereof, wherein m is 0 , R is X — R * , X is C = C — , and 60 aryl, unsubstituted heteroaryl, C (O )NR°R10 , or R4 is substituted or unsubstituted C .- Cgalkyl. - X - R4; In some embodiments is a compound of Formula ( IIIb ), or X is - O - , - S - , - S ( O )2 - , - N ( R ?) — , or — C = C — ; a pharmaceutically acceptable salt thereof, wherein Rl is R4 is substituted or unsubstituted C . - C alkyl, substituted halogen , - OR " , substituted or unsubstituted C - Coalkyl, or or unsubstituted Cz - Cocycloalkyl, substituted or unsub substituted or unsubstituted C - Cofluoroalkyl. In some 65 stituted aryl, or substituted or unsubstituted heteroaryl; embodiments is a compound of Formula ( IIIb ) , or a phar- each RS is independently hydrogen , or substituted or maceutically acceptable salt thereof, wherein Rl is halogen , unsubstituted C - C alkyl; US 9 ,969 , 726 B2 67 68 Róis hydrogen , or substituted or unsubstituted some embodiments is a compound of Formula (IV ) , or a C -Coalkyl ; pharmaceutically acceptable salt thereof, wherein m is 0 , R3 R7 is hydrogen , or substituted or unsubstituted is — X — R4, X is — N ( H ) — , and R4 is substituted or C1- Cgalkyl; unsubstituted heteroaryl. In some embodiments is a com each R is independently halogen , or substituted or unsub - 5 pound of Formula ( IV ) , or a pharmaceutically acceptable stituted C , -Coalkyl ; salt thereof, wherein m is 0 , R3 is — X — R4, X is — N (H ) — , Rº and R10 are independently hydrogen , or substituted or and R4 is unsubstituted pyridine . In some embodiments is a unsubstituted C , - Cgalkyl; compound of Formula (IV ) , or a pharmaceutically accept n is 0 , 1 , 2 , or 3 ; and able salt thereof, wherein m is 0 , R * is — X — R4, X is m is 0 , 1 , or 2 . 10 In some embodiments is a compound of Formula ( IV ) , or - N (H ) — , and R4 is unsubstituted pyrimidine . In some a pharmaceutically acceptable salt thereof, wherein Z is embodiments is a compound of Formula (IV ) , or a pharma = N — . In some embodiments is a compound of Formula ceutically acceptable salt thereof, wherein m is 0 , R3 is (IV ), or a pharmaceutically acceptable salt thereof, wherein - X - R4, X is - N ( H ) , and R4 is unsubstituted pyrazine . Z is = C ( H ) . 16 In some embodiments is a compound of Formula ( IV ) , or a In some embodiments is a compound of Formula (IV ), or pharmaceutically acceptable salt thereof, wherein m is 0 , Rº a pharmaceutically acceptable salt thereof, wherein m is 0 . is — X — R *, X is — S — , and R * is substituted or unsubsti In some embodiments is a compound of Formula ( IV ) , or a tuted aryl , or substituted or unsubstituted heteroaryl. In some pharmaceutically acceptable salt thereof, wherein m is 1 and embodiments is a compound of Formula (IV ) , or a pharma R8 is halogen . 20 ceutically acceptable salt thereof, wherein m is 0 , R is In some embodiments is a compound of Formula ( IV ) , or — X — R4, X is - S - , and R * is substituted or unsubstituted a pharmaceutically acceptable salt thereof, wherein m is phenyl. In some embodiments is a compound of Formula and R3 is halogen , CN , substituted or unsubstituted (IV ) , or a pharmaceutically acceptable salt thereof, wherein C -Cgalkyl , substituted or unsubstituted aryl, unsubstituted mis 0 , R is — X — R4, X is - S — , and R4 is substituted or heteroaryl, or — X - R4. In some embodiments is a com - 25 unsubstituted heteroaryl. In some embodiments is a com pound of Formula (IV ), or a pharmaceutically acceptable pound of Formula (IV ) , or a pharmaceutically acceptable salt thereof, wherein m is O and R is halogen . In some salt thereof, wherein m is 0 , R² is X - R4 , X is S , and embodiments is a compound of Formula (IV ) , or a pharma - R4 is unsubstituted pyridine . In some embodiments is a ceutically acceptable salt thereof, wherein m is O and R * is compound of Formula ( IV ) , or a pharmaceutically accept - CN . In some embodiments is a compound of Formula 30 able salt thereof, wherein m is 0 , R * is — X - R4 , S4 , and (IV ) , or a pharmaceutically acceptable salt thereof, wherein R * is unsubstituted pyrimidine . In some embodiments is a m is O and R * is substituted or unsubstituted C , - C alkyl. In compound of Formula (IV ) , or a pharmaceutically accept some embodiments is a compound of Formula (IV ) , or a able salt thereof, wherein mis 0 , R * is — X — R4, X is - S — , pharmaceutically acceptable salt thereof, wherein m is 0 and and R * is unsubstituted pyrazine. In some embodiments is a R * is substituted or unsubstituted aryl. In some embodiments 35 compound of Formula (IV ) , or a pharmaceutically accept is a compound of Formula ( IV ) , or a pharmaceutically able salt thereof, wherein m is 0 , R3 is — X — R , X is acceptable salt thereof, wherein m is O and R * is unsubsti - - S ( O ) 2 - , and R4 is substituted or unsubstituted aryl, or tuted heteroaryl. In some embodiments is a compound of substituted or unsubstituted heteroaryl. In some embodi Formula ( IV ) , or a pharmaceutically acceptable salt thereof, ments is a compound of Formula (IV ) , or a pharmaceutically wherein m is O and R3 is — X — R4 . In some embodiments is 40 acceptable salt thereof, wherein m is 0 , R3 is — X — R4, X is a compound of Formula ( IV ) , or a pharmaceutically accept - - S ( O ) - , and R * is substituted or unsubstituted phenyl. In able salt thereof, wherein m is 0 , R * is — X — R4 , X is some embodiments is a compound of Formula (IV ) , or a - 0 , and R4 is substituted or unsubstituted aryl, or sub pharmaceutically acceptable salt thereof, wherein m is 0 , R3 stituted or unsubstituted heteroaryl. In some embodiments is is - X - R4, X is - S ( O ) , — , and R4 is substituted or a compound of Formula (IV ) , or a pharmaceutically accept- 45 unsubstituted heteroaryl. In some embodiments is a com able salt thereof, wherein m is 0 , R * is — X — R4 , X is pound of Formula ( IV ) , or a pharmaceutically acceptable - 0 , and R4 is substituted or unsubstituted phenyl . In salt thereof, wherein m is 0 , R3 is — X — R4 , X is - S ( O ) - , some embodiments is a compound of Formula ( IV ) , or a and R * is unsubstituted pyridine . In some embodiments is a pharmaceutically acceptable salt thereof, wherein m is 0 , R compound of Formula (IV ) , or a pharmaceutically accept is — X — R4, X is 0 , and R4 is substituted or unsubsti - 50 able salt thereof, wherein m is 0 , R3 is — X — R -, - S ( O ) 2 - , tuted heteroaryl. In some embodiments is a compound of and R4 is unsubstituted pyrimidine . In some embodiments is Formula ( IV ) , or a pharmaceutically acceptable salt thereof, a compound of Formula (IV ) , or a pharmaceutically accept wherein m is 0 , R3 is — X — R4, X is 04 , and R4 is able salt thereof, wherein m is 0 , R3 is — X — R4 , X is unsubstituted pyridine . In some embodiments is a compound - S ( O ) 2 - , and R4 is unsubstituted pyrazine. of Formula ( IV ), or a pharmaceutically acceptable salt 55 In some embodiments is a compound of Formula (IV ) , or thereof, wherein m is 0 , R3 is - X - R4 , X is - 0 - , and R4 a pharmaceutically acceptable salt thereof, wherein Rl is is unsubstituted pyrimidine . In some embodiments is a halogen , — OR , substituted or unsubstituted C . - Cgalkyl, or compound of Formula (IV ) , or a pharmaceutically accept- substituted or unsubstituted C - Cofluoroalkyl. In some able salt thereof, wherein m is 0 , R3 is — X — R4 , X is embodiments is a compound of Formula (IV ) , or a pharma - 0 % , and R * is unsubstituted pyrazine . In some embodi - 60 ceutically acceptable salt thereof, wherein Rl is halogen , ments is a compound of Formula ( IV ) , or a pharmaceutically CF3 , or — OCHz. In some embodiments is a compound of acceptable salt thereof , wherein m is 0 , R² is — X — R4 , X is Formula ( IV ) , or a pharmaceutically acceptable salt thereof, - N ( H ) — , and R4 is substituted or unsubstituted aryl, or wherein Rl is halogen . In some embodiments is a compound substituted or unsubstituted heteroaryl. In some embodi - of Formula ( IV ) , or a pharmaceutically acceptable salt ments is a compound of Formula ( IV ) , or a pharmaceutically 65 thereof , wherein R is — CF3. In some embodiments is a acceptable salt thereof, wherein m is 0 , R ’ is — X — R4, X is compound of Formula (IV ) , or a pharmaceutically accept — N ( H ) — , and R4 is substituted or unsubstituted phenyl. In able salt thereof, wherein Rl is OCHz. US 9 , 969 ,726 B2 69 70 In some embodiments is a compound of Formula (IV ) , or wherein R3 is halogen , CN , unsubstituted heteroaryl, or a pharmaceutically acceptable salt thereof, wherein n is 0 . In — X — R4; and R4 is substituted or unsubstituted aryl, or some embodiments is a compound of Formula (IV ) , or a substituted or unsubstituted heteroaryl . pharmaceutically acceptable salt thereof, wherein n is 1 . In In some embodiments is a compound of Formula ( IVA ) , or some embodiments is a compound of Formula (IV ), or a 5 a pharmaceutically acceptable salt thereof, wherein m is 0 . pharmaceutically acceptable salt thereof, wherein n is 1 and In some embodiments is a compound of Formula ( IVA ), or R2 is halogen , — ORS, substituted or unsubstituted a pharmaceutically acceptable salt thereof, wherein m is 1 C1- C alkyl, substituted or unsubstituted C , -Cofluoroalkyl . and R8 is halogen . In some embodiments is a compound of Formula ( IV ) , or a In some embodiments is a compound of Formula (IVA ) , or pharmaceutically acceptable salt thereof, wherein n is 1 and 10 a pharmaceutically acceptable salt thereof, wherein m is 0 R2 is halogen , CH , , - CFz, or — OCHz. In some embodi- and R3 is halogen . In some embodiments is a compound of ments is a compound of Formula ( IV ) , or a pharmaceutically Formula ( IVA ) , or a pharmaceutically acceptable salt thereof, acacceptable salt thereof, wherein n is 1 and R ’ is halogen . In wherein m is O and R * is – CN . In some embodiments is a some embodiments is a compound of Formula ( IV ) , or a compound of Formula ( IVA ) , or a pharmaceutically accept pharmaceutically acceptable salt thereof, wherein n is 1 and 15 able salt thereof, wherein m is O and R is unsubstituted R2 is — CHz. In some embodiments is a compound of heteroaryl . In some embodiments is a compound of Formula Formula ( IV ) , or a pharmaceutically acceptable salt thereof, ( IVA ) , or a pharmaceutically acceptable salt thereof, wherein wherein n is 1 and R2 is CF3 . In some embodiments is a m is 0 and R3 is - X - R4. In some embodiments is a compound of Formula ( IV ) , or a pharmaceutically accept- compound of Formula ( IVA ) , or a pharmaceutically accept able salt thereof, wherein n is 1 and R² is — OCHz. 20 able salt thereof, wherein m is 0 , R3 is — X — R4, X is In some embodiments of the aforementioned embodi - 0 , and R4 is substituted or unsubstituted aryl, or sub ments, the compound of Formula (IV ) is a single enantiomer stituted or unsubstituted heteroaryl. In some embodiments is having the structure: a compound of Formula (IVa ), or a pharmaceutically accept able salt thereof, wherein m is 0 , R is X - R4, X is 25 - 0 % , and R4 is substituted or unsubstituted phenyl. In some embodiments is a compound of Formula ( IVA ) , or a pharmaceutically acceptable salt thereof, wherein m is 0 , R3 is - X R4, X is O - , and R4 is substituted or unsubsti tuted heteroaryl. In some embodiments is a compound of 30 Formula (IVA ) , or a pharmaceutically acceptable salt thereof , R3 wherein m is 0 , R * is — X — R * , X is 04 , and R * is TR] unsubstituted pyridine . In some embodiments is a compound of Formula ( IVA ), or a pharmaceutically acceptable salt (Rº ) m thereof, wherein m is 0 , R3 is - X - R4, X is — 0 , and R4 35 is unsubstituted pyrimidine . In some embodiments is a compound of Formula (IVA ), or a pharmaceutically accept In some embodiments of the aforementioned embodi able salt thereof, wherein m is 0 , R * is — X — R4, X is ments , the compound of Formula (IV ) is a single enantiomer - 0 % , and R * is unsubstituted pyrazine . In some embodi having the structure : ments is a compound of Formula (IVa ), or a pharmaceuti 40 cally acceptable salt thereof, wherein m is 0 , R3 is — X — R4, X is — N ( H ) — , and R4 is substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl. In some embodi ments is a compound of Formula (IVa ), or a pharmaceuti cally acceptable salt thereof, wherein m is 0 , R3 is — X — R4, H 45 X is — N ( H ) — and R4 is substituted or unsubstituted N phenyl. In some embodiments is a compound of Formula R . (IVA ) , or a pharmaceutically acceptable salt thereof, wherein m is 0 , Rºis — X — R * , X is — N ( H ) — , and R * is substituted or unsubstituted heteroaryl. In some embodiments is a (Rºm 50 compound of Formula ( IVA ), or a pharmaceutically accept able salt thereof, wherein m is 0 , R is — X - R4, X is In some embodiments , the compound of Formula ( IV ) has — N ( H ) — , and R4 is unsubstituted pyridine. In some the structure of Formula (IVa ) : embodiments is a compound of Formula (IVA ) , or a phar maceutically acceptable salt thereof, wherein m is 0 , R is 55 X - R4 , X is - N ( H ) , and R * is unsubstituted pyrimi Formula (IV ) dine. In some embodiments is a compound ofFormula (IVa ), or a pharmaceutically acceptable salt thereof, wherein m is 0 , R is — X — R4, X is — N (H ) — , and R4 is unsubstituted pyrazine . In some embodiments is a compound of Formula 60 ( IVA ) , or a pharmaceutically acceptable salt thereof, wherein m is 0 , R3 is — X — R4, X is - S — , and R4 is substituted or N unsubstituted aryl, or substituted or unsubstituted heteroaryl . R 3 In some embodiments is a compound of Formula (IVa ), or a pharmaceutically acceptable salt thereof, wherein m is 0 , 65 Rºis X R * , X is - S — , and R4 is substituted or unsub stituted phenyl . In some embodiments is a compound of Formula (IVA ), or a pharmaceutically acceptable salt thereof, US 9 , 969 , 726 B2 71 72 wherein m is 0 , R3 is — X — R + , X is S - , and R4 is In some embodiments of the aforementioned embodi substituted or unsubstituted heteroaryl. In some embodi ments , the compound of Formula ( IVa ) is a single ments is a compound of Formula ( IVA ), or a pharmaceuti - enantiomer having the structure: cally acceptable salt thereof, wherein m is 0 , R? is - X - R4, X is S — , and R4 is unsubstituted pyridine . In some 5 embodiments is a compound of Formula (IVa ), or a phar maceutically acceptable salt thereof, wherein m is 0 , R3 is - X - R4, - S — , and R4 is unsubstituted pyrimidine . In some embodiments is a compound of Formula (IVA ), or a pharmaceutically acceptable salt thereof, wherein m is 0 , R3 10 (R ?) n wonH is — X — R4 , X is - S — , and R4 is unsubstituted pyrazine . - R33 In some embodiments is a compound of Formula ( IVA ), or a pharmaceutically acceptable salt thereof , wherein m is 0 , N R3 is - X - R4, X is - S ( O ) 2 - , and R4 is substituted or 15 (Rºm unsubstituted aryl, or substituted or unsubstituted heteroaryl. In some embodiments is a compound of Formula ( IVa ), or I n some embodiments of the aforementioned embodi a pharmaceutically acceptable salt thereof, wherein m is 0 , ments , the compound of Formula ( IVa ) is a single R3 is - X - R4, X is - S ( O ) 2 - , and R is substituted or enantiomer having the structure : unsubstituted phenyl. In some embodiments is a compound 20 of Formula ( IVA ) , or a pharmaceutically acceptable salt thereof, wherein m is 0 , R ’ is — X — R4, X is - S ( O ) 2 - , and R4 is substituted or unsubstituted heteroaryl . In some embodiments is a compound of Formula ( IVA ) , or a phar maceutically acceptable salt thereof, wherein m is 0 , R * is 25 - X - R4, X is - S ( O ) 2 - , and R4 is unsubstituted pyridine . H In some embodiments is a compound of Formula ( IVA ), or (R2 ) , NH 110 a pharmaceutically acceptable salt thereof, wherein m is 0 , R R is — X — R - , - S ( O ) , — , and R4 is unsubstituted pyrimi dine . In some embodiments is a compound of Formula (IVA ) , 30 (R $) m or a pharmaceutically acceptable salt thereof , wherein m is 0 , Rºis - X - R4, X is - S ( O ) 2 - , and R * is unsubstituted pyrazine. In some embodiments , the compound of Formula (IV ) has In some embodiments is a compound of Formula (IVA ), or the structure of Formula ( IVb ) : a pharmaceutically acceptable salt thereof, wherein R is 35 halogen , - OR " , substituted or unsubstituted C ,- Cgalkyl , or substituted or unsubstituted C , - Cofluoroalkyl. In some Formula (IVb ) embodiments is a compound of Formula ( IVA ), or a phar maceutically acceptable salt thereof, wherein R ' is halogen , _ CFz , or — OCHz. In some embodiments is a compound of 40 Formula (IVA ), or a pharmaceutically acceptable salt thereof, wherein R ' is halogen . In some embodiments is a compound (R ? )n IZ of Formula (IVA ), or a pharmaceutically acceptable salt thereof, wherein Rl is CF3. In some embodiments is a compound of Formula (IVA ) , or a pharmaceutically accept - 45 able salt thereof, wherein R is OCHZ. (R $) m In some embodiments is a compound of Formula (IVA ) , or a pharmaceutically acceptable salt thereof, wherein n is 0 . In wherein R ’ is CN , substituted or unsubstituted heteroaryl, some embodiments is a compound of Formula (IVa ), or a or — X — R4; and R4 is substituted or unsubstituted pharmaceutically acceptable salt thereof, wherein n is 1 . In 50 C -Cgalkyl , substituted or unsubstituted aryl, or unsubsti some embodiments is a compound of Formula ( IVa ), or a tuted heteroaryl. pharmaceutically acceptable salt thereof, wherein n is 1 and In some embodiments is a compound of Formula (IVb ) , R2 is halogen , OR ", substituted or unsubstituted or a pharmaceutically acceptable salt thereof, wherein m is C -Cgalkyl , substituted or unsubstituted C -Cofluoroalkyl . 0 . In some embodiments is a compound of Formula (IVb ), In some embodiments is a compound of Formula ( IVA ), or 55 or a pharmaceutically acceptable salt thereof, wherein m is a pharmaceutically acceptable salt thereof, wherein n is 1 1 and R is halogen . and R² is halogen , CHz, CF3 , or OCHz. In some In some embodiments is a compound of Formula (IVb ) , embodiments is a compound of Formula (IVa ), or a phar- or a pharmaceutically acceptable salt thereof, wherein m is maceutically acceptable salt thereof, wherein n is 1 and R2 0 and R3 is — CN . In some embodiments is a compound of is halogen . In some embodiments is a compound of Formula 60 Formula (IVb ) , or a pharmaceutically acceptable salt ( IVA ), or a pharmaceutically acceptable salt thereof, wherein thereof, wherein m is O and R3 is unsubstituted heteroaryl. In n is 1 and R2 is — CHz. In some embodiments is a compound some embodiments is a compound of Formula ( IVb ) , or a of Formula ( IVA ), or a pharmaceutically acceptable salt pharmaceutically acceptable salt thereof, wherein m is 0 and thereof, wherein n is 1 and R2 is — CFz . In some embodi- R is — X — R . In some embodiments is a compound of ments is a compound of Formula (IVA ) , or a pharmaceuti - 65 Formula (IVb ) , or a pharmaceutically acceptable salt cally acceptable salt thereof, wherein n is 1 and R2 is thereof ,wherein m is 0 , R? is — X — R4, X is 0 , and R4 OCHz. is substituted or unsubstituted aryl, or substituted or unsub US 9 , 969 ,726 B2 73 74 stituted heteroaryl. In some embodiments is a compound of embodiments is a compound of Formula ( IVb) , or a phar Formula ( IVb ) , or a pharmaceutically acceptable salt maceutically acceptable salt thereof, wherein m is 0 , R3 is thereof, wherein m is 0 , R is - X - R4, X is 04 , and R * — X — R4, X is - S ( O ) 2 - , and R4 is unsubstituted pyridine . is substituted or unsubstituted phenyl. In some embodiments In some embodiments is a compound of Formula (IVb ) , or is a compound of Formula ( IVb) , or a pharmaceutically 5 a pharmaceutically acceptable salt thereof, wherein m is 0 , acceptable salt thereof, wherein m is 0 ,R is — X — R * , X is R3 is — X — R4, - S ( O ) - , and R4 is unsubstituted pyrimi - 0 , and R * is substituted or unsubstituted heteroaryl . In some embodiments is a compound of Formula ( IVb ) , or a dine. In some embodiments is a compound of Formula pharmaceutically acceptable salt thereof, wherein m is 0 , R3 (IVb ) , or a pharmaceutically acceptable salt thereof, wherein is — X — R4, X is - O - , and R4 is unsubstituted pyridine . 10 m is 0 , R * is — X — R4, X is - S (O )2 - , and R4 is unsub In some embodiments is a compound of Formula ( IVb ) , or stituted pyrazine. In some embodiments is a compound of a pharmaceutically acceptable salt thereof, wherein m is 0 , Formula (IVb ) , or a pharmaceutically acceptable salt R? is - X - R4 , X is 0 - , and R * is unsubstituted pyrimi thereof, wherein m is 0 , R3 is — X — R4, X is C = C — , and dine . In some embodiments is a compound of Formula R4 is substituted or unsubstituted C - Cgalkyl. (IVb ) , or a pharmaceutically acceptable salt thereof, wherein 155 In some embodiments is a compound of Formula (IVb ) , m is 0 , R3 is — X — R4 , X is O — , and R4 is unsubstituted or a pharmaceutically acceptable salt thereof, wherein Rl is pyrazine. In some embodiments is a compound of Formula halogen , — OR " , substituted or unsubstituted C , - C alkyl, or ( IVb) , or a pharmaceutically acceptable salt thereof, wherein substituted or unsubstituted C , - Cqfluoroalkyl. In some m is 0 , Rºis — X — R4 , X is N ( H ) — , and R * is substituted embodiments is a compound of Formula ( IVb ) , or a phar or unsubstituted aryl, or substituted or unsubstituted het - 20 maceutically acceptable salt thereof, wherein Rl is halogen , eroaryl. In some embodiments is a compound of Formula - CF3, or — OCHz. In some embodiments is a compound of ( IVb ) , or a pharmaceutically acceptable salt thereof, wherein Formula ( IVb ), or a pharmaceutically acceptable salt m is 0 , R3 is - X - R4 , X is - N ( H ) — , and R * is substituted thereof, wherein R ' is halogen . In some embodiments is a or unsubstituted phenyl. In some embodiments is a com - compound of Formula ( IVb ) , or a pharmaceutically accept pound of Formula (IVb ) , or a pharmaceutically acceptable 25 able salt thereof, wherein Rl is – CFz. In some embodi salt thereof, wherein m is 0 , Rºis — X — R *, X is — N ( H ) — , ments is a compound of Formula (IVb ) , or a pharmaceuti and R is substituted or unsubstituted heteroaryl. In some cally acceptable salt thereof, wherein Rl is - OCHZ. embodiments is a compound of Formula ( IVb ) , or a phar In some embodiments is a compound of Formula (IVb ) , maceutically acceptable salt thereof, wherein m is 0 , R * is or a pharmaceutically acceptable salt thereof, wherein n is 0 . - X - R4, X is - N (H ) — , and R * is unsubstituted pyridine . 30 In some embodiments is a compound of Formula ( IVb) , or In some embodiments is a compound of Formula (IVb ), or a pharmaceutically acceptable salt thereof, wherein n is 1 . In a pharmaceutically acceptable salt thereof, wherein m is 0 , some embodiments is a compound of Formula (IVb ), or a R3 is - X - R4, X is — N ( H ) — , and R4 is unsubstituted pharmaceutically acceptable salt thereof, wherein n is 1 and pyrimidine . In some embodiments is a compound of For R2 is halogen , ORS , substituted or unsubstituted mula ( IVD ) , or a pharmaceutically acceptable salt thereof, 35 C? ,. - Cgalkyl, substituted or unsubstituted C , -Cofluoroalkyl . wherein m is 0 , R is - X - R4, X is — N ( H ) , and R4 is In some embodiments is a compound of Formula (IVb ) , or unsubstituted pyrazine . In some embodiments is a com a pharmaceutically acceptable salt thereof, wherein n is 1 pound of Formula (IVb ), or a pharmaceutically acceptable and R2 is halogen , — CHz, — CFz, or — OCHz. In some salt thereof, wherein m is 0 , R3 is — X — R4, X is - S — , and embodiments is a compound of Formula ( IVb ) , or a phar R4 is substituted or unsubstituted aryl, or substituted or 40 maceutically acceptable salt thereof, wherein n is 1 and R ? unsubstituted heteroaryl. In some embodiments is a com is halogen . In some embodiments is a compound of Formula pound of Formula ( IVb ) , or a pharmaceutically acceptable ( IVb ), or a pharmaceutically acceptable salt thereof , wherein salt thereof, wherein m is 0 , Rºis - X - R4, X is - S — , and nis 1 and R2 is — CHz. In some embodiments is a compound R4 is substituted or unsubstituted phenyl. In some embodi of Formula ( IVb ) , or a pharmaceutically acceptable salt ments is a compound of Formula (IVb ) , or a pharmaceuti - 45 thereof, wherein n is 1 and R² is CF3. In some embodi cally acceptable salt thereof ,wherein m is 0 , Rºis - X R4, ments is a compound of Formula ( IVb ) , or a pharmaceuti X is S , and R4 is substituted or unsubstituted heteroaryl. In some embodiments is a compound of Formula ( IVb ) , or cally acceptable salt thereof, wherein n is 1 and R2 is a pharmaceutically acceptable salt thereof, wherein m is 0 , - OCHZ. Rºis — X — R4 , X is - S — , and R * is unsubstituted pyridine . 50 In some embodiments of the aforementioned embodi In some embodiments is a compound of Formula ( IVb ), or ' ments , the compound of Formula (IVb ) is a single a pharmaceutically acceptable salt thereof, wherein m is 0 , enantiomer having the structure : R ’ is - X - R4, S4 , and R * is unsubstituted pyrimidine . In some embodiments is a compound of Formula (IVb ), or a pharmaceutically acceptable salt thereof, wherein m is 0 , 55 R ’ is — X — R4, X is S , and R * is unsubstituted pyra zine . In some embodiments is a compound of Formula ( IVb ), or a pharmaceutically acceptable salt thereof, wherein 11111H m is 0 , R is X - R4, X is — S ( O )2 - , and R4 is substituted or unsubstituted aryl , or substituted or unsubstituted het- 60 R3 eroaryl. In some embodiments is a compound of Formula ( IVb ), or a pharmaceutically acceptable salt thereof, wherein mis 0 , R3 is — X — R4, X is - S ( O ) 2 - , and R * is substituted (RS )m or unsubstituted phenyl. In some embodiments is a com pound of Formula ( IVb ) , or a pharmaceutically acceptable 65 In some embodiments of the aforementioned embodi salt thereof, wherein m is 0 , Rºis X - R4 , X is - S ( O ) 2 - , ments , the compound of Formula ( IVb ) is a single and R4 is substituted or unsubstituted heteroaryl. In some enantiomer having the structure : US 9 , 969, 726 B2 75 76 side effects or toxicity , to improve the flavor of a drug or to alter other characteristics or properties of a drug . By virtue of knowledge of pharmacokinetic , pharmacodynamic pro cesses and drug metabolism in vivo , once a pharmaceuti cally active compound is known, the design of prodrugs of the compound is possible . ( see , for example , Nogrady ( 1985 ) Medicinal Chemistry A Biochemical Approach , DR. Oxford University Press, New York , pages 388 -392 ; Silver man ( 1992 ) , The Organic Chemistry of Drug Design and (Rº ) m 10 Drug Action , Academic Press , Inc ., San Diego , pages 352 401, Rooseboom et al. , Pharmacological Reviews, 56 :53 102 , 2004 ; Aesop Cho , “ Recent Advances in Oral Prodrug Further Forms of Compounds Discovery ” , Annual Reports in Medicinal Chemistry, Vol. In one aspect , the compound of Formula ( I ) , ( Ia ) , ( b ) , 41 , 395 -407 , 2006 ; T . Higuchi and V . Stella , Pro -drugs as ( Ic ) , (II ), (IIa ), (IIb ) , ( IIC ) , ( III ) , ( IIIa ), ( IIIb ), (IV ), (IVA ) , or 15 Novel Delivery Systems, Vol. 14 of the A . C . S . Symposium ( IVb ), possesses one or more stereocenters and each stereo - Series ) . center exists independently in either the R or S configura In some cases, some of the herein - described compounds tion . The compounds presented herein include all diastereo - may be a prodrug for another derivative or active compound . meric , enantiomeric , and epimeric forms as well as the In some embodiments , sites on the aromatic ring portion appropriate mixtures thereof. The compounds and methods 20 of compounds described herein are susceptible to various provided herein include all cis , trans , syn , anti , entgegen ( E ) , metabolic reactions Therefore incorporation of appropriate and zusammen ( Z ) isomers as well as the appropriate substituents on the aromatic ring structures will reduce , mixtures thereof . In certain embodiments , compounds minimize or eliminate this metabolic pathway . In specific described herein are prepared as their individual stereoiso - embodiments , the appropriate substituent to decrease or mers by reacting a racemic mixture of the compound with an 25 eliminate the susceptibility of the aromatic ring to metabolic optically active resolving agent to form a pair of diastereoi- reactions is , by way of example only , a halogen , or an alkyl someric compounds/ salts , separating the diastereomers and group . recovering the optically pure enantiomers . In some embodi In another embodiment, the compounds described herein ments , resolution of enantiomers is carried out using cova are labeled isotopically ( e . g . with a radioisotope ) or by lent diastereomeric derivatives of the compounds described 30 another other means , including , but not limited to , the use of herein . In another embodiment , diastereomers are separated chromophores or fluorescent moieties , bioluminescent by separation /resolution techniques based upon differences labels , or chemiluminescent labels . in solubility . In other embodiments , separation of stereoiso - Compounds described herein include isotopically - labeled mers is performed by chromatography or by the forming compounds, which are identical to those recited in the diastereomeric salts and separation by recrystallization , or 35 various formulae and structures presented herein , but for the chromatography , or any combination thereof. Jean Jacques , fact that one or more atoms are replaced by an atom having Andre Collet, Samuel H . Wilen , " Enantiomers , Racemates an atomic mass or mass number different from the atomic and Resolutions” , John Wiley And Sons , Inc. , 1981 . In one mass or mass number usually found in nature . Examples of aspect, stereoisomers are obtained by stereoselective syn isotopes that can be incorporated into the present com thesis . 40 pounds include isotopes of hydrogen , carbon , nitrogen , In some embodiments , compounds described herein are oxygen , sulfur , fluorine and chlorine , such as , for example , prepared as prodrugs . A “ prodrug” refers to an agent that is 2H , H , 13C , 14C , 15N , 180 , 170 , 35S , 18F, 36C1. In one aspect , converted into the parent drug in vivo . Prodrugs are often isotopically - labeled compounds described herein , for useful because, in some situations, they may be easier to example those into which radioactive isotopes such as PH administer than the parent drug . They may , for instance , be 45 and + 4C are incorporated , are useful in drug and/ or substrate bioavailable by oral administration whereas the parent is tissue distribution assays . In one aspect, substitution with not. The prodrug may also have improved solubility in isotopes such as deuterium affords certain therapeutic pharmaceutical compositions over the parent drug . In some advantages resulting from greater metabolic stability, such embodiments , the design of a prodrug increases the effective as, for example , increased in vivo half - life or reduced water solubility . An example , without limitation , of a pro - 50 dosage requirements . drug is a compound described herein , which is administered In additional or further embodiments, the compounds as an ester ( the " prodrug " ) to facilitate transmittal across a described herein are metabolized upon administration to an cell membrane where water solubility is detrimental to organism in need to produce a metabolite that is then used mobility but which then is metabolically hydrolyzed to the to produce a desired effect, including a desired therapeutic carboxylic acid , the active entity , once inside the cell where 55 effect . water- solubility is beneficial. A further example of a prodrug “ Pharmaceutically acceptable” as used herein , refers a might be a short peptide (polyaminoacid ) bonded to an acid material, such as a carrier or diluent, which does not group where the peptide is metabolized to reveal the active abrogate the biological activity or properties of the com moiety . In certain embodiments , upon in vivo administra - pound, and is relatively nontoxic , i . e ., the material may be tion , a prodrug is chemically converted to the biologically , 60 administered to an individual without causing undesirable pharmaceutically or therapeutically active form of the com - biological effects or interacting in a deleterious manner with pound . In certain embodiments , a prodrug is enzymatically any of the components of the composition in which it is metabolized by one or more steps or processes to the contained . biologically , pharmaceutically or therapeutically active form The term “ pharmaceutically acceptable salt” refers to a of the compound . 65 formulation of a compound that does not cause significant In one aspect, prodrugs are designed to alter the metabolic irritation to an organism to which it is administered and does stability or the transport characteristics of a drug , to mask not abrogate the biological activity and properties of the US 9 ,969 , 726 B2 77 78 compound . In some embodiments , pharmaceutically accept In other embodiments , the starting materials and reagents able salts are obtained by reacting a compound of Formula used for the synthesis of the compounds described herein are ( I) , ( la ) , ( Ib ) , ( Ic ) , ( II ) , ( IIa ) , ( IIb ) , ( IIC ), ( III) , ( IIIa ) , ( IIIb ) , synthesized or are obtained from commercial sources , such ( IV ) , ( IVA ), or ( IVb ) with acids. Pharmaceutically acceptable as , but not limited to , Sigma -Aldrich , Fisher Scientific salts are also obtained by reacting a compound of Formula 5 (Fisher Chemicals) , and Acros Organics . ( I ), ( la ), ( Ib ), (Ic ) , ( II ), ( IIa ) , ( IIb ) , ( IIc ), ( III ), ( IIIa ), ( IIIb ) , ( IV ), ( IVA ), or (IVb ) with a base to form a salt. In further embodiments , the compounds described herein , Compounds described herein may be formed as, and /or and other related compounds having different substituents used as. pharmaceutically acceptable salts . The type of are synthesized using techniques and materials described pharmaceutical acceptable salts , include , but are not limited 10 herein as well as those that are recognized in the field , such to : ( 1 ) acid addition salts , formed by reacting the free base as described , for example , in Fieser and Fieser ’ s Reagents form of the compound with a pharmaceutically acceptable : for Organic Synthesis, Volumes 1 - 17 ( John Wiley and Sons, inorganic acid , such as , for example , hydrochloric acid , 1991 ) ; Rodd ' s Chemistry of Carbon Compounds, Volumes hydrobromic acid , sulfuric acid , phosphoric acid , metaphos - 1 - 5 and Supplementals ( Elsevier Science Publishers , 1989 ) ; phoric acid , and the like ; or with an organic acid , such as, for 15 Organic Reactions, Volumes 1 -40 ( John Wiley and Sons, example , acetic acid , propionic acid , hexanoic acid , cyclo 1991 ) , Larock ' s Comprehensive Organic Transformations pentanepropionic acid , glycolic acid , pyruvic acid , lactic (VCH Publishers Inc . , 1989 ) , March , Advanced Organic acid , malonic acid , succinic acid , malic acid , maleic acid , Chemistry 4th Ed. , (Wiley 1992 ) ; Carey and Sundberg , fumaric acid , trifluoroacetic acid , tartaric acid , citric acid , Advanced Organic Chemistry 4th Ed . , Vols. A and B ( Plenum benzoic acid , 3 - ( 4 -hydroxybenzoyl ) benzoic acid , cinnamic 20 2000 , 2001 ), and Green and Wuts . Protective Groups in acid , mandelic acid , methanesulfonic acid , ethanesulfonic Organic Synthesis 3rd Ed . , (Wiley 1999 ) (all of which are acid , 1 , 2 - ethanedisulfonic acid , 2 -hydroxyethanesulfonic incorporated by reference for such disclosure ). General acid , benzenesulfonic acid , toluenesulfonic acid , 2 -naphtha lenesulfonic acid , 4 -methylbicyclo - [ 2 . 2 . 2 ]oct - 2 -ene - 1 - car methods for the preparation of compounds as disclosed boxylic acid , glucoheptonic acid , 4 ,4 '- methylenebis - ( 3 -hy - 25 herein1 may be derived from reactions and the reactions may droxy - 2 - ene - 1 - carboxylic acid ) , 3 -phenylpropionic acid , be modified by the use of appropriate reagents and condi trimethylacetic acid , tertiary butylacetic acid , lauryl sulfuric tions, for the introduction of the various moieties found in acid , gluconic acid , glutamic acid , hydroxynaphthoic acid , the formulae as provided herein . As a guide the following salicylic acid , stearic acid , muconic acid , butyric acid , sysynthetic methods may be utilized . phenylacetic acid , phenylbutyric acid , valproic acid , and the 30 In the reactions described , itmay be necessary to protect like ; ( 2 ) salts formed when an acidic proton present in the reactive functional groups , for example hydroxy , amino , parent compound is replaced by a metal ion , e . g . , an alkali imino , thio or carboxy groups, where these are desired in the metal ion ( e . g . lithium , sodium , potassium ), an alkaline earth final product, in order to avoid their unwanted participation ion ( e . g . magnesium , or calcium ) , or an aluminum ion . In in reactions. A detailed description of techniques applicable some cases , compounds described herein may coordinate 35 to the creation of protecting groups and their removal are with an organic base , such as, but not limited to , etha - described in Greene and Wuts , Protective Groups in Organic nolamine , diethanolamine, triethanolamine , tromethamine , N -methylglucamine , dicyclohexylamine , tris (hydroxymeth Synthesis , 3rd Ed ., John Wiley & Sons, New York , N . Y . , yl) methylamine . In other cases, compounds described herein 1999, and Kocienski, Protective Groups , Thieme Verlag , may form salts with amino acids such as , but not limited to , 40 New York , N . Y . , 1994 , which are incorporated herein by arginine , lysine, and the like . Acceptable inorganic bases reference for such disclosure ) . used to form salts with compounds that include an acidic In one aspect, compounds are synthesized as described in proton , include, but are not limited to , aluminum hydroxide , the Examples section . calcium hydroxide , potassium hydroxide , sodium carbonate , In some embodiments , compounds described herein may sodium hydroxide , and the like . 45 be synthesized via the following general reaction proce It should be understood that a reference to a pharmaceu - dures tically acceptable salt includes the solvent addition forms, particularly solvates. Solvates contain either stoichiometric As shown in Scheme A , in some embodiments , B -ke or non -stoichiometric amounts of a solvent, and may be toesters of general structure A - 2 ( 7 -methyl -4 -( 3 - phenoxy formed during the process of crystallization with pharma - 50 phenyl) - 8 - ( trifluoromethyl) - 1H -benzo [ b ] [ 1 , 4 ] diazepin - 2 ceutically acceptable solvents such as water, ethanol, and the (3H ) -one ) are prepared from the appropriately substituted like . Hydrates are formed when the solvent is water, or benzoate (ethyl or methyl ester ) A - 1 ( 4 - ( 3 -benzylphenyl ) alcoholates are formed when the solvent is alcohol. Solvates 7 -methyl - 8 - ( trifluoromethyl) - 1H -benzo [ b ] [ 1 , 4 ] diazepin - 2 of compounds described herein can be conveniently pre- ( 3H ) - one ) ( see Woltering et al Bioorg Med Chem Letts ., pared or formed during the processes described herein . In 55 2008 , 18 : 1091 - 1095 ( and references cited therein ) ] . Thus , addition , the compounds provided herein can exist in unsol - treatment of ethyl acetate (or a similar ester e . g . the tert vated as well as solvated forms. In general, the solvated butyl ester ) with a strong base such as LDA at low tem forms are considered equivalent to the unsolvated forms for perature in an organic solvent such as THF affords the the purposes of the compounds and methods provided corresponding anion which , upon condensation with A - 1, herein . 60 yields the B -ketoester A - 2 . The B -ketoester is then trans Synthesis of Compounds formed into the dioxin - 4 - one A - 3 by reaction with TFAA / In some embodiments , the synthesis of compounds TFA in acetone . In a similar fashion , starting with the described herein are accomplished using means described in appropriate heterocycle - ester , the B -ketoesters of structure the chemical literature , using the methods described herein , A - 4 are prepared . The substituent ' R ' on the aryl or or by a combination thereof. In addition , solvents , tempera - 65 heteroaryl ring is transformed using standard chemical pro tures and other reaction conditions presented herein may cedures to afford alternative compounds of structure A - 2 and vary . A - 3 US 9, 969, 726 B2 79 80 In some embodiments , the diamine B - 1 is reacted with Scheme A B - 2 in the presence of an organic base such as Et3N in a non - polar solvent such as toluene followed by heating to CO2Et Ri _ CO2R " 5 afford the amides B - 2 ( see Scheme B ) . Alternatively , B - 1 is reacted with A - 3 or A -4 to afford B -2 . The amides B -2 , are cyclized by heating in a high boiling solvent such as xylene A - 1 A - 2 to provide the benzodiazepine B - 3 and regioisomer B - 4 as a separable mixture . Alternatively , the diamine 2 -1 is treated with A - 2 in the presence of acetic acid at reflux to generate RI B - 3 and B - 4 directly as a separable mixture . The substituent ‘ Ri ' on the aryl ring or the substituents ‘ R ,' or ‘ Rz ' on the 15 benzodiazepine ring is transformed using standard chemical A - 3 procedures to afford alternative compounds of structure 2 - 3 and 2 - 4 . Such transformations involve, for example , (a ) - COR" 20 reduction e .g . in the case of R , or R2 or Rz= nitro group to heterocycle afford an aniline which is then further modified ; (b ) Pd R1 mediated cross coupling reactions where R , or R2 or Rz = Br A - 4 or I; ( c ) “ click - chemistry ” where R , or R2 or Rz contains an acetylene; and the like .

Scheme B

NH2 R3

H2N A - 2 , A - 3 or A - 4 - NH2 + RZ NH2 R2 -

B - 1 B - 2

- A - 2 , A - 3 or A - 4

x gode' N R2 B - 3 B - 4

) = aryl or heteroaryl ring US 9 ,969 , 726 B2 81 82 In some embodiments , specifically substituted benzodi -continued azepine cores are introduced by using substituted nitroani lines of general structure C - 1 ( see Scheme C) . Thus , the nitroaniline C - 1 may be transformed to C - 2 as described 5 R2 NH above. Reduction of the nitro group using standard proce dures then generates the aniline C -3 which can be cyclized NHB?c as described for Scheme 2 to generate the desired benzodi D -4 azepine C -4 . Dante Scheme C NH2

R2 R3 R3 3

- both–

R , NH 0

. NH2 C - 4 C -3

In some embodiments , the regioisomeric substituted nitroanilines of general structure D - 1 (Scheme D ) are used -continued as starting materials for C - 4 . Compound D - 1 is treated under standard conditions with Boc anyhdride to yield the Boc wwwRu protected aniline D - 2 . Reduction of the nitro group as 40 described above then yields D - 3 . Transformation of D - 3 to 2 D - 4 as described above is then followed by deprotection of the Boc group using acidic conditions to afford C - 3 . The R , and Rz substituents of D - 2 , D - 3 , D - 4 and C - 3 are further NH modified using standard chemical reactions as described in 45 Woltering et al Bioorg Med Chem Letts . , 2007, 17 , p C - 3 6811 -6815 . In some embodiments , hydrogenation of the N - C double Scheme D bond of the benzodiazepine E - 1 ( Scheme E ) is achieved by NH NHBoc 50 reduction of E - 1 in the presence of hydrogen and a catalyst such as 10 % Pd on carbon in an organic solvent such as ON ethanol. The reduction may also be carried out using boro hydride based reductants such as NaBH , or NaBH CN in protic solvents such as ethanol. Alternatively, reductants - R2 such as HSiClz are employed in the presence of an organic 55 Lewis Base in an organic solvent such as dichloromethane . R2 When a chiral Lewis Base is used as a catalyst, the reduction D - 1 may proceed in enantioselective fashion to generate pre NHBoc os dominantly one enantiomer (Chen et al. , J . Org . Chem ., 2011 , 76 , p 9109 -9115 ) . Similarly, enantioselective reduc HN 60 tion of E - 1 may be achieved using an asymmetric hydroge nation promoted by a chiral Lewis Acid catalyst and a dihydropyridine (Rueping et al. , Adv. Synth . Catal ., 2010 , -R2 352 , p 2629 - 2634 ) . In the presence of an acylating agent such as AcCl and pyridine , the reaction affords N - acylated R3 65 derivatives such as E - 3 . The amine function of E - 2 may also D - 3 undergo a reductive amination reaction using standard pro cedures to generate E - 3 in which the amine is alkylated . US 9, 969, 726 B2 83 84 - continued Scheme E

moet –- RaRº _

RO H enons R4 Rb . F - 5 F - 4

10 Loire - 10 In some embodiments , dihydrobenzodiazepines of gen E - 1 E - 2 eral structure G - 3 are prepared according to the reaction sequence shown in Scheme G ( see Wang et al. , Synlett, 2005 , 20 , 3042- 3046 ) . Thus reaction of a diamine such as G - 1 with N - cinnamoylbenzotriazoles G - 2 via a 1 , 4 -addition followed 15 by ring - closure then affords the desired compounds of general structure G - 3 .

Scheme G R3 LH 2020 -Z Ar 'N - N RC 1 E - 3 NityNH2 44

In some embodiments, dihydrobenzodiazepine com NH2NH pounds are prepared as shown in Scheme F (see Lee et al ., G1G1 G - 2 J. Org . Chem ., 1999 , 64, 3060 -3065 and Zhao et al. , J. Comb . Chem ., 2007, 9 , 1164 - 1176 ) . The fluoro - nitro ben 30 zoyl derivative F - 1 is coupled with a ß -amino acid ester F -2 to generate F - 3 . Reduction of the nitro group followed by ester hydrolysis and intramolecular amide bond formation EZ then affords F -4 . The benzoyl group X of F -4 is further 35 modified using standard procedures. Further derivatization G - 3 of the amine coupled with transformation of the benzoyl Racemic mixtures of dihydrobenzodiazepines may be group X then affords targets compounds of general structure a resolved to provide enantiomers substantially free of the F - 5 . opposite enantiomer using methods well known in the art . For example , the racemates may be separated using chiral phase HPLC or, alternatively , they may be separated by formation of diastereomeric salts by crystallization in the Scheme F presence of a chiral acid or base . RO Definitions CO2Et In the following description , certain specific details are set HNY forth in order to provide a thorough understanding of various Ra 50 embodiments . However, one skilled in the art will under stand that the invention may be practiced without these FF - 11 F - 2 details . In other instances , well -known structures have not been shown or described in detail to avoid unnecessarily obscuring descriptions of the embodiments . Unless the NO2 55 context requires otherwise , throughout the specification and claims which follow , the word " comprise ” and variations thereof, such as , " comprises” and “ comprising ” are to be V NHNH construed in an open , inclusive sense , that is , as “ including, but not limited to . ” Further, headings provided herein are for 60 convenience only and do not interpret the scope or meaning of the claimed invention . CO2Et As used in this specification and the appended claims, the F - 3 singular forms “ a ,” “ an , ” and “ the” include plural referents unless the content clearly dictates otherwise . It should also 65 be noted that the term “ or” is generally employed in its sense including “ and/ or ” unless the content clearly dictates other wise . US 9 , 969, 726 B2 85 86 The terms below , as used herein , have the following embodiments , the aryl is phenyl. Depending on the struc meanings , unless indicated otherwise : ture, an aryl group can be a monoradical or a diradical ( i. e ., “ Oxo ” refers to the = 0 substituent. an arylene group ). Unless stated otherwise specifically in the “ Thioxo ” refers to the = S substituent. specification , the term “ aryl ” or the prefix " ar- ” (such as in “ Alkyl” refers to a straight or branched hydrocarbon chain 5 “ aralkyl” ) is meant to include aryl radicals that are option radical, having from one to twenty carbon atoms, and which ally substituted . is attached to the rest of the molecule by a single bond . An alkyl comprising up to 10 carbon atoms is referred to as a “ Carboxy ” refers to CO , H . In some embodiments , C1 - C10 alkyl, likewise , for example , an alkyl comprising up carboxy moieties may be replaced with a “ carboxylic acid to 6 carbon atoms is a C , -C6 alkyl. Alkyls (and other 10 bioisostere ” , which refers to a functional group or moiety moieties defined herein ) comprising other numbers of car that exhibits similar physical and / or chemical properties as bon atoms are represented similarly . Alkyl groups include , a carboxylic acid moiety . A carboxylic acid bioisostere has but are not limited to , C7- C10 alkyl, C , - C , alkyl, C . - C , alkyl, similar biological properties to that of a carboxylic acid C - C , alkyl, C , - C . alkyl, C , -C , alkyl , C . - C4 alkyl, C ,- CZ group . A compound with a carboxylic acid moiety can have alkyl, C , - C2 alkyl, C2 -Cg alkyl, C3 - C , alkylLand and C4- Cg alkylkui. 15 the carboxylic acid moiety exchanged with a carboxylic acid Representative alkyl groups include , but are not limited to , bioisostere and have similar physical and /or biological prop methyl, ethyl, n - propyl, 1 -methylethyl ( i -propyl ) , n -butyl , erties when compared to the carboxylic acid -containing i -butyl , s- butyl , n -pentyl , 1, 1 -dimethylethyl (t - butyl) , compound . For example , in one embodiment, a carboxylic 3 -methylhexyl , 2 -methylhexyl , 1 - ethyl -propyl , and the like . acid bioisostere would ionize at physiological pH to roughly In some embodiments , the alkyl is methyl or ethyl. In some 20 the same extent as a carboxylic acid group . Examples of embodiments , the alkyl is - CH (CH3 ) 2 or — C (CH3 ) 3 . bioisosteres of a carboxylic acid include , but are not limited Unless stated otherwise specifically in the specification , an to : alkyl group may be optionally substituted as described below . “ Alkylene ” or “ alkylene chain ” refers to a straight or branched divalent hydrocarbon chain linking the rest of the 25 molecule to a radical group . In some embodiments , the NN alkylene is — CH2 – , CH2CH2 - , or — CH2CH2CH2 — . In some embodiments , the alkylene is CH , — . In some un embodiments, the alkylene is CH , CH , — . In some 30 ma mo embodiments , the alkylene is CH CH CH2 – “ Alkoxy ” refers to a radical of the formula OR where R is an alkyl radical as defined . Unless stated otherwise specifically in the specification , an alkoxy group may be optionally substituted as described below . Representative man alkoxy groups include , but are not limited to , methoxy , 35 mo ethoxy , propoxy , butoxy , pentoxy . In some embodiments , the ww alkoxy is methoxy . In some embodiments , the alkoxy is = 0 . ethoxy . " Heteroalkylene ” refers to an alkyl radical as described above where one or more carbon atoms of the alkyl is 40 min OH OH replaced with a 0 , N or S atom . " Heteroalkylene " or " heteroalkylene chain ” refers to a straight or branched divalent heteroalkyl chain linking the rest of the molecule to w a radical group . Unless stated otherwise specifically in the specification , the heteroalkyl or heteroalkylene group may 45 mum be optionally substituted as described below . Representative OH heteroalkyl groups include , but are not limited to - OCH OMe, OCH2CH2OMe, - OCH _ CH _ OCH CH _NH2 . Representative heteroalkylene and the like . groups include, but are not limited to _ OCH ,CH , O . 50 " Cycloalkyl” refers to a monocyclic or polycyclic non - OCH , CH ,OCH ,CH , O , or aromatic radical , wherein each of the atoms forming the ring - OCH CH OCH2CH2OCH CH20 ( i . e . skeletal atoms) is a carbon atom . Cycloalkyls may be “ Alkylamino ” refers to a radical of the formula NHR or saturated , or partially unsaturated . Cycloalkyls may be fused - NRR where each R is , independently , an alkyl radical as with an aromatic ring ( in which case the cycloalkyl is defined above . Unless stated otherwise specifically in the 55 bonded through a non -aromatic ring carbon atom ) . specification , an alkylamino group may be optionally sub - Cycloalkyl groups include groups having from 3 to 10 ring stituted as described below . atoms. Representative cycloalkyls include , but are not lim The term “ aromatic ” refers to a planar ring having a ited to , cycloalkyls having from three to ten carbon atoms, delocalized t - electron system containing 4n + 2 n electrons, from three to eight carbon atoms, from three to six carbon where n is an integer. Aromatics can be optionally substi - 60 atoms, or from three to five carbon atoms. Monocyclic tuted . The term " aromatic ” includes both aryl groups ( e . g ., cyclcoalkyl radicals include , for example , cyclopropyl , phenyl, naphthalenyl) and heteroaryl groups (e . g. , pyridinyl, cyclobutyl, cyclopentyl , cyclohexyl, cycloheptyl , and quinolinyl) . cyclooctyl. In some embodiments, the monocyclic cycl " Aryl” refers to an aromatic ring wherein each of the coalkyl is cyclopropyl, cyclobutyl , cyclopentyl or cyclo atoms forming the ring is a carbon atom . Aryl groups can be 65 hexyl. In some embodiments , the monocyclic cyclcoalkyl is optionally substituted . Examples of aryl groups include, but cyclopentyl. Polycyclic radicals include , for example , ada are not limited to phenyl, and naphthalenyl. In some mantyl, norbornyl, decalinyl, and 3 , 4 -dihydronaphthalen - 1 US 9 ,969 , 726 B2 87 88 ( 2H ) -one . Unless otherwise stated specifically in the speci zolyl , furyl, thienyl, isoxazolyl, thiazolyl, oxazolyl , isothi fication , a cycloalkyl group may be optionally substituted . azolyl, pyrrolyl , pyridazinyl, triazinyl, oxadiazolyl , “ Fused ” refers to any ring structure described herein thiadiazolyl , furazanyl, indolizine , indole , benzofuran , ben which is fused to an existing ring structure . When the fused zothiophene , indazole , benzimidazole , purine, quinolizine , ring is a heterocyclyl ring or a heteroaryl ring , any carbon 5 quinoline , isoquinoline , cinnoline , phthalazine , quinazoline . atom on the existing ring structure which becomes part of quinoxaline , 1, 8 -naphthyridine , and pteridine. Illustrative the fused heterocyclyl ring or the fused heteroaryl ring may examples ofmonocyclic heteroaryls include pyridinyl, imi be replaced with a nitrogen atom . dazolyl, pyrimidinyl , pyrazolyl, triazolyl, pyrazinyl, tetra " Halo " or " halogen ” refers to bromo, chloro , fluoro or zolyl , furyl, thienyl, isoxazolyl , thiazolyl, oxazolyl , isothi iodo . 10 azolyl, pyrrolyl, pyridazinyl , triazinyl, oxadiazolyl, “ Haloalkyl ” refers to an alkyl radical , as defined above , thiadiazolyl, and furazanyl. Illustrative examples of bicyclic that is substituted by one or more halo radicals , as defined above, e .g ., trifluoromethyl, difluoromethyl, fluoromethyl, heteroaryls include indolizine , indole , benzofuran , benzoth trichloromethyl, 2 , 2 , 2 - trifluoroethyl, 1 , 2 -difluoroethyl , iophene, indazole , benzimidazole, purine, quinolizine , qui 3 -bromo - 2 - fluoropropyl. 1 . 2 - dibromoethvl. and the like . 15 noline , isoquinoline , cinnoline , phthalazine, quinazoline , Unless stated otherwise specifically in the specification , a quinoxaline , 1 , 8 -naphthyridine , and pteridine . In some haloalkyl group may be optionally substituted . embodiments , heteroaryl is pyridinyl , pyrazinyl, pyrimidi “ Haloalkoxy ” refers to an alkoxy radical, as defined nyl, thiazolyl, thienyl, thiadiazolyl or furyl. In some embodi above, that is substituted by one or more halo radicals , as ments , a heteroaryl contains 0 - 4 N atoms in the ring. In some defined above, e. g ., trifluoromethoxy, difluoromethoxy , 20 embodiments , a heteroaryl contains 1- 4 N atoms in the ring. fluoromethoxy , trichloromethoxy , 2 , 2 , 2 - trifluoroethoxy, 1 , 2 In some embodiments , a heteroaryl contains 0 - 4 N atoms, difluoroethoxy , 3 - bromo - 2 - fluoropropoxy , 1 , 2 -dibromoeth 0 - 1 O atoms, and 0 - 1 S atoms in the ring . In some embodi oxy, and the like . Unless stated otherwise specifically in the ments , a heteroaryl contains 1 - 4 N atoms, 0 - 1 O atoms, and specification , a haloalkoxy group may be optionally substi - 0 - 1 S atoms in the ring . In some embodiments , heteroaryl is tuted . 25 a C , -Coheteroaryl . In some embodiments , monocyclic het " Heterocycloalkyl” or " heterocyclyl” or “ heterocyclic eroaryl is a C , -Czheteroaryl . In some embodiments , mono ring” refers to a stable 3 - to 14 -membered non - aromatic ring cyclic heteroaryl is a 5 -membered or 6 -membered het radical comprising 2 to 13 carbon atoms and from one to 6 eroaryl. In some embodiments , a bicyclic heteroaryl is a heteroatoms selected from the group consisting of nitrogen , Co - Coheteroaryl. oxygen , and sulfur. Unless stated otherwise specifically in 30 The term “ optionally substituted ” or “ substituted ” means the specification , the heterocycloalkyl radical may be a that the referenced group may be substituted with one or monocyclic , or bicyclic ring system , which may include more additional group ( s ) individually and independently fused (when fused with an aryl or a heteroaryl ring, the selected from alkyl, haloalkyl , cycloalkyl, aryl , heteroaryl, heterocycloalkyl is bonded through a non - aromatic ring heterocycloalkyl, OH , alkoxy , aryloxy , alkylthio , arylthio , atom ) or bridged ring systems. The nitrogen , carbon or 35 alkylsulfoxide , arylsulfoxide , alkylsulfone, arylsulfone , sulfur atoms in the heterocyclyl radical may be optionally CN , alkyne, C . - Cgalkylalkyne , halogen , acyl, acyloxy , oxidized . The nitrogen atom may be optionally quaternized . CO2H , CO alkyl, nitro , and amino , including mono The heterocycloalkyl radical is partially or fully saturated . and di- substituted amino groups (e . g . — NH2, — NHR , Examples of such heterocycloalkyl radicals include , but are — N ( R ) 2 ) , and the protected derivatives thereof. In some not limited to , dioxolanyl, thienyl[ 1, 3 ]dithianyl , decahy - 40 embodiments , optional substituents are independently droisoquinolyl, imidazolinyl, imidazolidinyl , isothiazolidi - selected from alkyl, alkoxy, haloalkyl, cycloalkyl, halogen , nyl , isoxazolidinyl, morpholinyl, octahydroindolyl, octahy - CN , - NH2, - NH (CH3 ) , - N (CH3 ) 2 , OH , CO H , droisoindolyl , 2 -oxopiperazinyl , 2 -oxopiperidinyl , and CO2alkyl . In some embodiments , optional substitu 2 -oxopyrrolidinyl , oxazolidinyl, piperidinyl, piperazinyl, ents are independently selected from fluoro , chloro , bromo , 4 -piperidonyl , pyrrolidinyl, pyrazolidinyl, quinuclidinyl, 45 iodo , CH3, CH2CH3, CF3, OCH3 , and OCF3. In thiazolidinyl , tetrahydrofuryl, trithianyl, tetrahydropyranyl, some embodiments , substituted groups are substituted with thiomorpholinyl, thiamorpholinyl, 1 -oxo - thiomorpholinyl, one or two of the preceding groups . In some embodiments , 1 ,1 -dioxo - thiomorpholinyl. The term heterocycloalkyl also an optional substituent on an aliphatic carbon atom (acyclic includes all ring forms of carbohydrates , including but not or cyclic , saturated or unsaturated carbon atoms, excluding limited to monosaccharides , disaccharides and oligosaccha - 50 aromatic carbon atoms) includes oxo GO( ) . rides. Unless otherwise noted , heterocycloalkyls have from The terms “ co -administration ” or the like, as used herein , 2 to 10 carbons in the ring . In some embodiments , hetero - are meant to encompass administration of the selected cycloalkyls have from 2 to 8 carbons in the ring . In some therapeutic agents to a single patient, and are intended to embodiments , heterocycloalkyls have from 2 to 8 carbons in include treatment regimens in which the agents are admin the ring and 1 or 2 N atoms. It is understood that when 55 istered by the same or different route of administration or at referring to the number of carbon atoms in a heterocy the same or different time. cloalkyl, the number of carbon atoms in the heterocycloalkyl The terms “ effective amount” or “ therapeutically effective is not the same as the total number of atoms ( including the amount, " as used herein , refer to a sufficient amount of an heteroatoms) that make up the heterocycloalkyl ( i. e . skeletal agent or a compound being administered which will relieve atoms of the heterocycloalkyl ring ) . Unless stated otherwise 60 to some extent one or more of the symptoms of the disease specifically in the specification , a heterocycloalkyl group or condition being treated . The result can be reduction may be optionally substituted . and /or alleviation of the signs , symptoms, or causes of a “ Heteroaryl” refers to an aryl group that includes one or disease , or any other desired alteration of a biological more ring heteroatoms selected from nitrogen , oxygen and system . For example, an “ effective amount” for therapeutic sulfur. The heteroaryl is monocyclic or bicyclic . Illustrative 65 uses is the amount of the composition comprising a com examples of monocyclic heteroaryls include pyridinyl, imi- pound as disclosed herein required to provide a clinically dazolyl , pyrimidinyl, pyrazolyl, triazolyl, pyrazinyl , tetra - significant decrease in disease symptoms. An appropriate US 9 , 969, 726 B2 89 90 “ effective ” amount in any individual case may be deter tautomers will exist . All tautomeric formsof the compounds mined using techniques , such as a dose escalation study . disclosed herein are contemplated . The exact ratio of the The term “ pharmaceutical combination ” as used herein , tautomers depends on several factors, including tempera means a product that results from the mixing or combining ture, solvent, and pH . Some examples of tautomeric inter of more than one active ingredient and includes both fixed conversions include : OH mm ?? mun mm H H woman - VA NHNH2, \ -\ NH \ ww H mm man NH otelman min w mm m

mm mn =p NH Rock - HockeyHN N 1 and non - fixed combinations of the active ingredients . The 30 Administration and Pharmaceutical Composition term “ fixed combination ” means that the active ingredients , In some embodiments , the compounds described herein e . g . a compound of Formula ( I ), ( Ia ), ( lb ) , ( Ic ), ( II ), ( Ila ), are formulated into pharmaceutical compositions. Pharma ( IIb ) , ( IIC ), ( III ), ( IIIa ), (IIIb ) , ( IV ), ( IVa ), or ( IVb ) and a ceutical compositions are formulated in a conventional co -agent , are both administered to a patient simultaneously 35 manner using one or more pharmaceutically acceptable in the form of a single entity or dosage. The term “ non - fixed inactive ingredients that facilitate processing of the active combination ” means that the active ingredients , e. g. a com compounds into preparations that can be used pharmaceu pound of Formula (I ) , ( La ) , ( Ib ) , (Ic ), ( II ), ( IIa ) , (IIb ) , (IIC ), tically. Proper formulation is dependent upon the route of ( III ), ( IIIa ) , ( IIIb ), ( IV ) , ( IVA ), or ( IVb ) and a co - agent, are administration chosen . A summary of pharmaceutical com administered to a patient as separate entities either simulta - 40 positions described herein can be found , for example , in neously , concurrently or sequentially with no specific inter - Remington : The Science and Practice of Pharmacy , Nine vening time limits , wherein such administration provides teenth Ed ( Easton , Pa. : Mack Publishing Company, 1995 ); effective levels of the two compounds in the body of the Hoover, John E ., Remington ' s Pharmaceutical Sciences , the Mack Publishing Co . , Easton , Pa . 1975 ; Liberman , H . A . and patient. The latter also applies to cocktail therapy , e . g . the 45 Lachman , L ., Eds ., Pharmaceutical Dosage Forms, Marcel administration of three or more active ingredients . Decker, New York , N . Y . , 1980 ; and Pharmaceutical Dosage The term “ subject” or “ patient” encompasses mammals . Forms and Drug Delivery Systems, Seventh Ed . (Lippincott Examples of mammals include , but are not limited to , Williams & Wilkins 1999 ) , herein incorporated by reference humans . In one embodiment, the mammal is a human . for such disclosure . The terms “ treat, ” “ treating” or “ treatment, ” as used 50 A pharmaceutical composition , as used herein , refers to a herein , include alleviating, abating or ameliorating at least mixture of a compound of Formula ( I ) , ( la ), ( Ib ), (Ic ) , ( II ), one symptom of a disease or condition , preventing addi ( IIa ), ( IIb ), ( IIC ) , ( III) , ( IIIa ), ( IIIb ), ( IV ) , (IVa ), or (IVb ) with other chemical components ( i. e . pharmaceutically accept tional symptoms, inhibiting the disease or condition , e . g ., able inactive ingredients ), such as carriers , excipients , bind arresting the development of the disease or condition , relievf the 55 ers , filling agents , suspending agents , flavoring agents , ing the disease or condition , causing regression of the sweetening agents , disintegrating agents , dispersing agents , disease or condition , relieving a condition caused by the surfactants , lubricants , colorants , diluents , solubilizers , disease or condition , or stopping the symptoms of the moistening agents, plasticizers , stabilizers , penetration disease or condition either prophylactically and /or therapeu enhancers , wetting agents , anti- foaming agents , antioxi tically . 60 dants , preservatives , or one or more combination thereof . A “ tautomer ” refers to a proton shift from one atom of a The pharmaceutical composition facilitates administration molecule to another atom of the same molecule . The com - of the compound to an organism . pounds presented herein may exist as tautomers . Tautomers Pharmaceutical formulations described herein are admin are compounds that are interconvertible by migration of a istrable to a subject in a variety of ways by multiple hydrogen atom , accompanied by a switch of a single bond 65 administration routes, including but not limited to , oral, and adjacent double bond . In bonding arrangements where parenteral ( e . g . , intravenous, subcutaneous, intramuscular, tautomerization is possible , a chemical equilibrium of the intramedullary injections , intrathecal, direct intraventricular, US 9 , 969 , 726 B2 91 92 intraperitoneal , intralymphatic , intranasal injections) , intra to the mammal every 24 hours . In further or alternative nasal, buccal, topical or transdermal administration routes . embodiments , themethod comprises a drug holiday , wherein The pharmaceutical formulations described herein include, the administration of the compound of Formula ( I ), ( la ), ( b ) , but are not limited to , aqueous liquid dispersions, self ( Ic ), ( II ), (IIa ), (IIb ) , ( IIC) , ( III) , (IIIa ), ( IIIb ) , ( IV ) , ( IVa ), or emulsifying dispersions , solid solutions, liposomal disper - 5 (IVb ) is temporarily suspended or the dose of the compound sions , aerosols , solid dosage forms, powders , immediate being administered is temporarily reduced , at the end of the release formulations, controlled release formulations , fast drug holiday, dosing of the compound is resumed . In one melt formulations, tablets , capsules, pills , delayed release embodiment, the length of the drug holiday varies from 2 formulations, extended release formulations , pulsatile days to 1 year. release formulations, multiparticulate formulations, and 10 In certain embodiments , the compound of Formula ( I ) , mixed immediate and controlled release formulations. ( la ), ( Ib ) , ( Ic ) , ( II ) , ( IIa ), ( IIb ) , ( IIC ) , ( III ), ( IIIa ), ( IIIb ), ( IV ) , In some embodiments , the compounds of Formula ( I ) , ( IVA ), or (IVb ) is administered in a local rather than systemic ( la ), ( Ib ) , ( Ic ) , ( II ) , (Ila ), ( IIb ) , ( IIC ) , ( III ), ( IIIa ), ( IIIb ), (IV ) , manner. (IVA ) , or ( IVb ) are administered orally . In some embodiments , the compound of Formula ( I ) , (la ), In some embodiments , the compounds of Formula ( I) , 15 (lb ) , ( Ic ), (II ) , ( IIa ), ( IIb ), ( IIC ), ( III ) , ( IIIa ), (IIIb ), (IV ), ( la ) , ( b ) , ( Ic ) , ( II ) , ( Ila ) , ( IIb ) , ( IIC ) , ( III ) , ( IIIa ), ( IIIb ) , ( IV ) , ( IVa ), or (IVb ) is administered topically . In some embodi ( IVA ) , or ( IVb ) are administered topically . In such embodiments , the compound of Formula ( I ) , ( Ia ) , ( Ib ) , ( Ic ) , ( II) , ments , the compound of Formula ( I ) , ( la ) , ( lb ) , ( Ic ) , ( II ), (Ila ), ( IIb ), ( IIC ) , ( III ), ( IIIa ) , ( IIIb ), ( IV ) , ( IVa ), or ( IVb ) is ( IIa ) , ( IIb ) , ( IIC ), (III ) , (IIIa ), ( IIIb ) , ( IV ) , ( IVA ) , or (IVb ) is administered systemically. formulated into a variety of topically administrable compo - 20 In some embodiments , the pharmaceutical formulation is sitions , such as solutions , suspensions , lotions , gels , pastes , in the form of a tablet. In other embodiments , pharmaceu shampoos, scrubs, rubs, smears , medicated sticks ,medicated tical formulations of the compounds of Formula (I ) , ( Ia ), bandages, balms, creams or ointments . In one aspect , the ( lb ) , ( Ic ) , ( II ), ( IIa ), ( IIb ), (IIC ), (III ), (IIIa ), ( IIIb ) , (IV ), compounds of Formula ( I ) are administered topically to the (IVA ) , or ( IVb ) are in the form of a capsule . skin . 25 In one aspect, liquid formulation dosage forms for oral In another aspect, the compounds of Formula ( I) , ( Ia ) , administration are in the form of aqueous suspensions or ( b ), ( c ), ( II ) , ( IIa ), ( IIb ), ( IIC ), ( III) , ( IIIa ), ( IIIb ), (IV ) , solutions selected from the group including, but not limited (IVA ) , or ( IVb ) are administered by inhalation . to , aqueous oral dispersions , emulsions, solutions, elixirs, In another aspect, the compounds of Formula ( I ) , (Ia ) , gels , and syrups. ( lb ) , ( Ic ) , ( II) , ( IIa ) , ( IIb ) , ( IIC ) , ( III) , ( IIIa ), ( IIIb ) , ( IV ) , 30 For administration by inhalation , a compound of Formula ( IVA ), or (IVb ) are formulated for intranasal administration . (I ), ( la ), ( Ib ), ( Ic ) , ( II ), (IIa ), ( IIb ), ( IIC ), (III ), ( IIIa ), ( IIIb ), Such formulations include nasal sprays , nasal mists , and the ( IV ) , ( IVA ), or (IVb ) is formulated for use as an aerosol, a like. mist or a powder. In another aspect, the compounds of Formula (I ) , ( Ia ) For buccal or sublingual administration , the compositions ( lb ) , ( Ic ) , ( II ) , ( IIa ), ( IIb ) , (IIC ) , ( III ) , ( IIIa ) , ( IIIb ), ( IV ) , 35 may take the form of tablets , lozenges , or gels formulated in ( IVA ) , or (IVb ) are formulated as eye drops . a conventional manner. In any of the aforementioned aspects are further embodi- In some embodiments , compounds of Formula ( 1 ) , ( la ) , ments in which the effective amount of the compound of ( b ), ( Ic ) , (II ) , ( IIa ), ( IIb ) , ( IIC ), ( III ) , ( IIIa ) , ( IIIb ) , ( IV ) , Formula ( I ) , ( Ia ) , ( b ) , ( Ic ), ( II ) , ( IIa ), ( IIb ), ( IIC ) , ( III) , ( IIIa ), (IVa ) , or ( IVb ) are prepared as transdermal dosage forms. ( IIIb ), (IV ), (IVa ), or (IVb ) is : (a ) systemically administered 40 In one aspect , a compound of Formula (I ) , (Ia ), ( Ib ), (Ic ) , to the mammal; and / or ( b ) administered orally to the mam ( II) , ( IIa ), ( IIb ) , ( IIC ) , (III ), ( IIIa ), ( IIIb ) , (IV ) , (IVA ) , or ( IVb ) mal; and / or ( c ) intravenously administered to the mammal; is formulated into a pharmaceutical composition suitable for and / or ( d ) administered by inhalation to the mammal ; and / or intramuscular , subcutaneous , or intravenous injection . ( e ) administered by nasal administration to the mammal ; or In some embodiments , the compound of Formula (I ) , (la ) , and / or ( f ) administered by injection to the mammal; and/ or 45 ( Ib ) , ( Ic ) , (II ) , ( IIa ) , (IIb ) , ( IIC ), (III ) , ( IIIa ) , (IIIb ) , ( IV ) , ( g ) administered topically to the mammal ; and / or ( h ) admin ( IVa ) , or ( IVb ) is be administered topically and can be istered by ophthalmic administration ; and /or ( i ) adminis formulated into a variety of topically administrable compo tered rectally to the mammal; and /or (j ) administered non - sitions, such as solutions, suspensions, lotions, gels , pastes, systemically or locally to the mammal. medicated sticks, balms, creams or ointments . In any of the aforementioned aspects are further embodi - 50 In some embodiments , the compounds of Formula ( I ) , ments comprising single administrations of the effective (Ia ) , ( Ib ) , ( Ic ) , ( II) , (IIa ) , ( Ilb ) , ( IIC ) , ( III) , ( IIIa ), ( IIIb ) , (IV ) , amount of the compound of Formula ( I) , ( Ia ), ( Ib ), ( Ic ), ( II ), (IVA ) , or ( IVb ) are formulated in rectal compositions such as ( Ila ), ( IIb ) , ( IIC ), (III ) , ( IIIa ), ( IIIb ) , ( IV ) , (IVA ) , or ( IVb ) , enemas, rectal gels , rectal foams, rectal aerosols , supposi including further embodiments in which ( i ) the compound is tories , jelly suppositories , or retention enemas . administered once ; (ii ) the compound is administered to the 55 Methods of Dosing and Treatment Regimens mammal multiple times over the span of one day ; ( iii ) In one embodiment, the compounds of Formula ( I) , (la ), continually ; or ( iv ) continuously . ( b ), (Ic ), ( II ), ( IIa ), (IIb ) , ( IIC ), ( III ), ( IIIa ), ( IIIb ), (IV ) , In any of the aforementioned aspects are further embodi- (IVA ) , or (IVb ) are used in the preparation of medicaments ments comprising multiple administrations of the effective for the treatment of diseases or conditions described herein . amount of the compound of Formula ( I ) , ( la ) , ( b ) , ( Ic ) , ( II ) , 60 In addition , a method for treating any of the diseases or ( Ila ), ( IIb ) , ( IIC ), (III ) , ( IIIa ), ( IIIb ) , ( IV ) , (IVA ) , or ( IVb ) , conditions described herein in a subject in need of such including further embodiments in which ( i ) the compound is treatment, involves administration of pharmaceutical com administered continuously or intermittently : as in a single positions that include at least one compound of Formula ( I ) , dose ; ( ii ) the time between multiple administrations is every ( la ) , ( b ) , ( Ic ), ( II ), ( IIa ), ( IIb ), (IIC ), ( III ) , ( IIIa ), ( IIIb ) , (IV ) , 6 hours ; ( iii ) the compound is administered to the mammal 65 (IVA ) , or ( IVb ) or a pharmaceutically acceptable salt, active every 8 hours ; ( iv ) the compound is administered to the metabolite , prodrug , or solvate thereof, in therapeutically mammal every 12 hours ; ( v ) the compound is administered effective amounts to said subject. US 9 ,969 , 726 B2 93 94 In certain embodiments , the compositions containing the a neurodegenerative disease or disorder are dementia , compounds of Formula ( I ) , ( la ) , ( Ib ) , ( Ic ) , ( II ) , ( IIa ) , (IIb ) , memory loss , dyskinesias, cognitive impairment, tremors , ( IIC ) , ( III ) , ( IIIa ) , ( IIIb ), ( IV ) , (IVA ), or (IVb ) are adminis rigidity , slowness of movement, postural instability , invol tered for prophylactic and /or therapeutic treatments . In cer untary jerking or writhing movements (chorea ) , slow or tain therapeutic applications, the compositions are adminis - 5 abnormal eye movements, difficulty with the physical pro tered to a patient already suffering from a disease or duction of speech or swallowing , psychiatric disorders , condition , in an amount sufficient to cure or at least partially muscle cramps and spasms, spasticity , constipation , fatigue , arrest at least one of the symptoms of the disease or excessive salivation , excessive phlegm , pain , sleep prob condition . Amounts effective for this use depend on the lems, uncontrolled outbursts of laughing or crying . severity and course of the disease or condition , previous 10 In some embodiments , the additional therapeutic agent is therapy , the patient' s health status , weight, and response to an Alzheimer ' s disease therapeutic agent. In some embodi the drugs, and the judgment of the treating physician . ments , the additional therapeutic agent is a cholinesterase Therapeutically effective amounts are optionally determined inhibitor. In some embodiments , the cholinesterase inhibitor by methods including , but not limited to , a dose escalation is donepezil, galantamine , or rivastigmine . In some embodi clinical trial . 15 ments , the additional therapeutic agent is memantine . In In prophylactic applications, compositions containing the some embodiments , the additional therapeutic agent is compounds of Formula ( I ), ( la ) , ( lb ) , ( Ic ) , ( II ) , ( IIa ) , ( IIb ) , latrepirdine , idalopridine , or cerlapirdine . ( IIC ), ( III) , (IIIa ), (IIIb ), ( IV ) , ( IVA ), or (IVb ) are adminis - In some embodiments , the additional therapeutic agent is tered to a patient susceptible to or otherwise at risk of a a Parkinson ' s disease therapeutic agent. In some embodi particular disease , disorder or condition . 20 ments , the additional therapeutic agent is levodopa . In some In certain embodiments , the dose of drug being adminis - embodiments , the additional therapeutic agent is carbidopa tered may be temporarily reduced or temporarily suspended levodopa . In some embodiments , the additional therapeutic for a certain length of time ( i. e . , a " drug holiday ” ) . agent is a Dopamine agonist. In some embodiments , the Doses employed for adult human treatment are typically dopamine agonist is ropinirole , pramipexole , or rotigotine . in the range of 0 . 01 mg - 5000 mg per day or from about 1 mg 25 In some embodiments , the additional therapeutic agent is a to about 1000 mg per day . In one embodiment, the desired MAO - B inhibitor . In some embodiments , the MAO - B dose is conveniently presented in a single dose or in divided inhibitor is selegiline or rasagiline. In some embodiments , doses. the additional therapeutic agent is a catechol O -methyltrans Combination Treatments ferase ( COMT) inhibitor. In some embodiments , the COMT In certain instances, it is appropriate to administer at least 30 inhibitor is entacapone or tolcapone . In some embodiments , one compound of Formula ( I ), ( Ia ) , ( Ib ) , ( Ic ), ( II ) , ( IIa ), ( IIb ), the additional therapeutic agent is an Anticholinergic . In ( IIC ), ( III ), ( IIIa ), ( IIIb ) , (IV ) , (IVA ), or (IVb ) in combination some embodiments , the anticholinergic is benztropine or with another therapeutic agent. trihexyphenidyl. In some embodiments, the additional thera In one specific embodiment, a compound of Formula ( I) , peutic agent is amantadine . ( la ), ( Ib ) , (Ic ), ( II ), ( IIa ), (IIb ), ( IIC ), ( III) , ( IIIa ), (IIIb ), (IV ), 35 In some embodiments , compounds of Formula (I ), (la ), ( IVA ), or ( IVb ) is co - administered with a second therapeutic ( lb ) , ( Ic ), ( II ), ( IIa ), ( IIb ), ( IIC ) , (III ), ( IIIa ), ( IIIb ) , ( IV ) , agent, wherein the compound of Formula ( I ) , ( Ia ) , ( b ) , ( Ic ) , (IVA ), or ( IVb ) are administered to a mammal in combina ( II ) , ( IIa ), ( IIb ) , ( IIC ), ( III ) , ( IIIa ), ( IIIb ), ( IV ), ( IVa ), or ( IVb ) tion with deep brain stimulation . and the second therapeutic agent modulate different aspects In some embodiments , the additional therapeutic agent is of the disease , disorder or condition being treated , thereby 40 a Huntington ' s disease therapeutic agent . In some embodi providing a greater overall benefit than administration of ments , the additional therapeutic agent is tetrabenazine . In either therapeutic agent alone . some embodiments , the additional therapeutic agent is an For combination therapies described herein , dosages of antipsychotic drug. In some embodiments , the antipsychotic the co - administered compounds vary depending on the type drug is haloperidol, chlorpromazine , risperidone , olanzapine of co - drug ( s ) employed , on the specific drug ( s ) employed , 45 or quetiapine . In some embodiments , the additional thera on the disease or condition being treated and so forth . In peutic agent is amantadine , levetiracetam , or clonazepam . In additional embodiments , when co -administered with one or some embodiments , the additional therapeutic agent is an more other therapeutic agents , the compound provided antidepressant. In some embodiments , the antidepressant is herein is administered either simultaneously with the one or citalopram , fluoxetine , or sertraline . In some embodiments , more other therapeutic agents , or sequentially . 50 the additional therapeutic agent is a mood - stabilizing drug . If administration is simultaneous, the multiple therapeutic In some embodiments , the mood - stabilizing drug is val agents are , by way of example only , provided in a single , proate, carbamazepine , or lamotrigine. unified form , or in multiple forms . In some embodiments , compounds of Formula (I ), (Ia ), In some embodiments , compounds of Formula ( I) , ( Ia ), ( lb ), ( Ic ) , ( II ) , ( Ila ) , ( Ilb ) , ( IIC ) , ( III ) , ( IIIa ) , (IIIb ) , ( IV ) , ( lb ), (Ic ), ( II ) , ( IIa ), ( IIb ), ( IIC ), ( III ), ( IIIa ), ( IIIb ), (IV ), 55 (IVA ) , or ( IVb ) are administered to a mammal in combina (IVA ) , or (IVb ) are administered to a mammal in combina tion with psychotherapy , speech therapy , physical therapy or tion with one or more additional neurodegenerative disease occupational therapy . or disorder therapeutic agent. In some embodiments , the In some embodiments , the additional therapeutic agent is neurodegenerative disease or disorder is Alzheimer ' s dis - a Lou Gehrig ' s Disease (Amyotrophic Lateral Sclerosis or ease , Parkinson ' s disease , Huntington ' s disease , or Lou 60 ALS ) therapeutic agent. In some embodiments , the addi Gehrig ' s Disease (Amyotrophic Lateral Sclerosis or ALS) . tional therapeutic agent is riluzole . In some embodiments , In some embodiments , compounds of Formula ( I ), ( Ia ) , ( lb ) , the additional therapeutic agent is baclofen , diazepam , tri ( Ic ) , ( II ), (IIa ), (IIb ), ( IIC ) , ( III ) , ( IIIa ), ( IIIb ) , ( IV ) , (IVA ), or hexyphenidyl or amitriptyline . ( IVb ) are administered to a mammal in combination with In some embodiments , compounds of Formula ( I ), ( la ) , one or more additional therapeutic agent that alleviate the 65 ( lb ) , ( Ic ) , ( II ) , ( IIa ), ( IIb ) , (IIC ), ( III ) , ( IIIa ), ( IIIb ) , ( IV ) , symptoms or side effects of a neurodegenerative disease or (IVA ) , or ( IVb ) are administered to a mammal in combina disorder. In some embodiments the symptoms or side effects tion with one or more additional neuropsychiatric disease or US 9 , 969 , 726 B2 95 96 disorder therapeutic agent. In some embodiments , the neu peaks or TMS as internal standards . Coupling constants are ropsychiatric disease or disorder is schizophrenia , anxiety , reported in Hz. HPLC -MS analyses were performed on a sleep disorder , eating disorder , psychosis , or addictions. Shimadzu 2010EV LCMS using the following conditions : In some embodiments , the additional therapeutic agent is Kromisil C18 column ( acetonitrile and 5 % water over 4 . 5 an antipsychotic . In some embodiments , the antipsychotic is 5 min ; flow rate of 1 mL /min ; UV photodiode array detection aripiprazole , asenapine , clozapine , iloperidone , lurasidone , from 200 to 300 nm reverse phase , 4 . 6 mm _ 50 mm ) ; a linear olanzapine , paliperidone, quetiapine, risperidone , ziprasi gradient from 10 % acetonitrile and 90 % water to 95 % . done , chlorpromazine , fluphenazine , haloperidol, or per phenazine. In some embodiments , the additional therapeutic General Synthetic Scheme for the Preparation of agent is an antidepressant. In some embodiments , the anti - 10 ( 2 - arylthiazol - 4 - yl ) biphenyl Carboxylic Acid depressant is a selective serotonin reuptake inhibitor (SSRI ) Derivatives or a serotonin norepinephrine reuptake inhibitor (SNRI ) . In some embodiments, the antidepressant is escitalopram , duloxetine , venlafaxine , or paroxetine . In some embodi ments, the additional therapeutic agent is an anti - anxiety 15 Scheme 1 medication . In some embodiments, the anti -anxiety medi cation is buspirone . In some embodiments , the additional Br therapeutic agent is a benzodiazepine . In some embodiments Br + Arb (OH )2 - 4 the benzodiazepine is alprazolam , chlordiazepoxide, diaz eparn , or lorazepam . 20 Br B (OH )2 In some embodiments , the additional therapeutic agent is a medication used to treat dependence . In some embodi ments , the medication used to treat dependence is subozone , methadone, naloxone, or acamprosate . Bra 1 ) i, 1 - 2 h In some embodiments , the additional therapeutic agent is 25 - Ar a medication used to treat cancer. In some embodiments , 2) HO2C B (OH )2 compounds of Formula ( I ) , ( Ia ), ( lb ) , ( Ic ) , ( II ) , ( IIa ) , ( IIb ), ( IIC ), ( III ), ( IIIa ), ( IIIb ), (IV ), (IVa ), or (IVb ) are adminis tered to a mammal in combination with conventional che motherapy , radiotherapy, hormonal therapy, and/ or immu - 30 notherapy. In some embodiments, the compounds of i, 6 -12 h Formula ( I ) , ( Ia ), ( b ) , ( Ic ), ( II ) , ( IIa ), ( IIb ), ( IIC ), ( III) , ( IIIa ) , HO2C ( IIIb ) , ( IV ) , ( IVA ) , or (IVb ) described herein can be co administered with conventional chemotherapeutic agents including alkylating agents ( e . g ., temozolomide , cyclophos - 35 phamide, ifosfamide , chlorambucil, busulfan , melphalan , Ar mechlorethamine , uramustine, thiotepa, nitrosoureas, etc . ), anti -metabolites ( e . g ., 5 - fluorouracil , azathioprine , metho trexate , leucovorin , capecitabine , cytarabine , floxuridine, a ) Pd (OAc ) 2 , Xantphos, K3PO4, THF ,60° C ., 18 h fludarabine , gemcitabine, pemetrexed , raltitrexed , etc . ), 40 i ) Pd (PPh3 ) 4 , 2M Na2CO3, DME, 80°C . plant alkaloids ( e . g . , vincristine , vinblastine , vinorelbine , vindesine , podophyllotoxin , paclitaxel , docetaxel, etc . ) , topoisomerase inhibitors ( e . g ., irinotecan , topotecan , amsa Example 1 : 4 -Fluoro - 3 '- ( 2 - phenylthiazol- 4 -yl ) biphe crine , etoposide ( VP16 ) , etoposide phosphate , teniposide , nyl- 3 - carboxylic Acid etc . ) , antitumor antibiotics ( e . g . , doxorubicin , adriamycin , 45 daunorubicin , epirubicin , actinomycin , bleomycin , mitomy cin , mitoxantrone , plicamycin , etc . ) , platinum -based com pounds ( e . g . cisplatin , oxaloplatin , carboplatin , etc . ) , EGFR inhibitors ( e . g ., gefitinib , erlotinib , etc . ), and the like. 50 EXAMPLES The following examples are intended to illustrate but not - Ph limit the disclosed embodiments . HO2C All reactions were performed in oven -dried glassware 55 under an atmosphere of argon with magnetic stirring . All solvents and chemicals used were purchased from Sigma Step 1 : 4 - Bromo - 2 - phenylthiazole Aldrich or Acros, and were used as received without further purification . Purity and characterization of compounds were established by a combination of liquid chromatography - 60 mass spectroscopy (LC -MS ) and NMR analytical tech Br niques and was > 95 % for all tested compounds . Silica gel column chromatography was carried out using pre -packed — Ph silica cartridges from RediSep ( ISCO Ltd . ) and eluted using an Isco Companion system . ' H - and 13 C -NMR spectra were 65 obtained on a Joel 400 spectrometer at 400 MHz. Chemical Under N , atmosphere Pd (OAc ) 2 (0 .084 g , 0 . 38 mmol) shifts are reported in d (ppm ) relative to residual solvent was combined with xantphos ( 0 .220 g , 0 .38 mmol) in 25 mL US 9 , 969, 726 B2 98 THF. After stirring for 5 min . , the resulting solution was and the combined organic layer was washed with brine , transferred to a round bottom flask containing 2 , 4 dibro followed by drying over anhydrous Na2SO4. Filtration and mothiazole ( 3 .64 g , 15 mmol) , phenylboronic acid ( 1 . 96 g , removal of the solvent afforded crude product that was 16 mmol) and K3PO4 ( 9 . 55 g , 45 mmol) . The resulting further purified by automated prep - HPLC to yield the reaction mixture was heated at 60° C . for 18 h and then 5 desired compoundOd as a whitewhite som solid prep ( 0 .- 083 Hip gproduc , 32 % ) . H NMR cooled to room temperature and filtered and washed with (400 MHz, DMSOD . ): 88 .34 ( s , 1H ) , 8 .27 ( s , 1H ) , 8 . 05 (dd , dichloromethane . Removal of the solvents under vacuum J = 2 . 3 Hz, 6 . 9 Hz , 1H ) , 8 .06 ( d , J = 7 . 8 Hz , 1H ) , 8 .02 - 7 .98 ( m , afforded the crude product which was purified by silica gel 3H ), 7. 64 (d , J = 7 . 3 Hz, 1H ), 7 . 56 (t , J = 7 .8 Hz , 1H ), column chromatography using hexanes :ethyl acetate to 7. 52 -7 .48 (m , 3H ), 7. 43 (t , J= 8 . 2 Hz , 1H ). HRMS (ESI ) afford 4 -bromo - 2 -phenylthiazole as a white solid ( 3 g , 84 % ) . " calcd . for C , H , AFNO , S [ M + H ] + : 376 .0802 . Found : ' H NMR (400 MHz, CDC1z ): 8 7 . 95 ( dd , J = 3 . 4 Hz, 8 . 2 Hz, 376 .0811 . 2H ), 7 . 47 - 7 . 46 ( m , 3H ) , 7 . 23 ( s , 1H ) . LRMS ( ESI) calcd . for C , H ,BrNS [ M + H ] * : 241 . 12 . Found : 241. 00 . Example 2 : 3 -( 2 - Phenylthiazol- 4 -yl ) biphenyl - 3 Step 2 : 4 - ( 3 - Bromophenyl) - 2 - phenylthiazole sulfonamide

Ph - Ph H2NO2S 25 To a mixture of 4 - bromo - 2 -phenylthiazole ( 3 . 0 g , 12 . 5 4 - ( 3 -Bromophenyl )- 2 - phenylthiazole ( 0 . 100 g , 0 .32 mmol) , 3 -bromophenylboronic acid (3 .0 g, 15 mmol) and mmol) , 3 -sulfamoylphenylboronic acid ( 0 .096 g , 0 . 48 tetrakistriphenylphosphinepalladium ( 0 ) ( 1 . 44 g , 1 . 25 mmol) mmol) , tetrakistriphenylphosphinepalladium (0 ) (0 .037 g , were in DME (40 mL ) was added a 2M Na . Co , solution (25 30 0 .032 mmol) and 2M Na2CO3 ( 0 .64 mL ) were dissolved in mL , 50 mmol) . The resulting solution was heated at reflux DME. The reaction mixture was then processed according to in an atmosphere of N , for 2 h . The reaction mixture was the general procedure described in Example 1 , step 2 , to cooled to room temperature and the solvent was removed afford the title compound as a white solid (0 .043 g , 34 % ) . ' H under vacuum and the residue was dissolved in dichlo NMR (400 MHz, DMSOdo ): 8 8 . 31 (s , 2H ) , 8 . 15 ( d , J = 1 . 4 romethane and washed with water. The organic layer was 35 Hz, 1H ), 8 .07 ( dd , J = 1 . 4 Hz, = 8 . 7 Hz, 1H ) , 8 .07 - 7 . 99 ( m , dried over anhydrous Na So . . The solvent was evaporated 2H ) , 7 . 96 ( d , J = 7 . 8 Hz, 1H ) , 7 .82 ( d , J = 7 . 8 Hz, 1H ) , in vacuum to obtain the crude product as a pale yellow solid . 7 .69 - 7 .64 ( m , 2H ) , 7 .61 ( t, J = 7 .8 Hz, 1H ) , 7 .53 - 7 .48 ( m , Column chromatography using hexanes/ ethyl acetate sol- 3H ) , 7 .41 ( s , 2H ) . HRMS (ESI ) calcd . for C2jH16N , 0 , S , vent system afforded 4 - ( 3 -bromophenyl ) - 2 - phenylthiazole [ M + H ] * : 393 . 0726 . Found : 393 . 0731. as a colorless solid ( 3 . 4 g , 86 % ) . H NMR ( 400 MHz, 40 CDC1z ) : 8 8 . 16 ( d , J = 1 . 8 Hz, 1H ) , 8 .03 - 8 .01 ( m , 2H ) , Example 3 : 4 - Fluoro - 3 '- ( 2 - phenylthiazol- 5 - yl) biphe 7 . 90 - 7 .87 ( m , 1H ) , 7 .48 - 7 .44 ( m , 5H ) , 7 .31 - 7 .38 ( m , 1H ) . nyl- 3 - carboxylic Acid LRMS ( ESI) calcd . for C15H1. BrNS [M + H ]* : 315 .97 . Found: 316 . 00 . 45 Step 3 : 4 -Fluoro - 3 '- ( 2 - phenylthiazol- 4 - yl) biphenyl 3 - carboxylic Acid

Ph 55 - CO2H HOC To a mixture of 4 - ( 3 -bromophenyl ) - 2 - phenylthiazole ( 0 . 224 g , 0 .71 mmol) , 5 - borono - 2 - fluorobenzoic acid (0 . 197 60 5 - ( 3 - Bromophenyl) - 2 -phenylthiazole ( 0 .325 g , 0 . 83 g , 1. 07 mmol ) and tetrakistriphenylphosphinepalladium ( 0 ) mmol) , 5 -borono - 2 - fluorobenzoic acid ( 0 .230 g , 1. 25 ( 0 .081 g, 0 .071 mmol) in DME (6 mL ) was added a 2M mmol) , tetrakistriphenylphosphinepalladium ( 0 ) ( 0 .096 g , Na2CO3 solution ( 1. 4 mL ). The resulting solution was 0. 083 mmol) and 2M Na2CO3 (1 .66 mL ) were dissolved in heated at reflux in an atmosphere of N , for 6 - 12 h . The DME . The reaction mixture was then processed according to reaction mixture was cooled to room temperature and 65 the general procedure described in Example 1, step 3 , to diluted with water and then acidified using IN HCl. The afford the title compound as a yellow solid ( 0 . 102 g , 33 % ) . aqueous phase was extracted with ethyl acetate (3x10 mL ) H NMR ( 400 MHz, DMSOd . ) : 8 8 .43 ( s , 1H ) , 8 . 12 (dd , US 9 ,969 , 726 B2 99 100 J = 3 . 4 Hz, 6 . 8 Hz, 1H ) , 7 . 98 - 7 . 95 ( m , 3H ) , 7 . 70 ( d , J = 8 . 2 Hz, Example 6 : 4 -Fluoro - 3 '- ( 2 -methylthiazol - 4 - yl) bi 1H ) , 7 .66 (d , J = 8 . 2 Hz , 1H ), 7. 55 (d , J = 7 .8 Hz , 1H ), phenyl- 3 -carboxylic Acid 7 .48 - 7 . 42 ( m , 5H ) . HRMS ( ESI) calcd . for C22H 4FNO2S [ M + H ] * : 376 .0802 . Found : 376 . 0809 . 5 Example 4 : 4 - Fluoro - 3 '- ( 2 - ( furan - 3 -yl ) thiazol- 4 -yl ) biphenyl- 3 -carboxylic Acid F 10 HO2C 4 -( 3 - Bromophenyl) - 2 -methylthiazole (0 . 101 g, 0 .4 F 15 mmol) , 5 -borono - 2 - fluorobenzoic acid ( 0 . 110 g , 0 .6 mmol) , tetrakistriphenylphosphinepalladium ( 0 ) ( 0 .046 g , 0 . 04 mmol) and 2M Na2CO3 (0 . 8 mL ) were dissolved in DME . ?? , ? The reaction mixture was then processed according to the general procedure described in Example 1 , step 3 , to afford 2005 20 the desired compound as a white solid (0 .022 g , 17 % ) . ' H 4 - ( 3 -Bromophenyl )- 2 -( furan - 3 - yl )thiazole ( 0 .152 g , 0 . 5 “ NMR ( 400 MHz, DMSOdo) : 88 . 17 ( s , 1H ) , 8 .09 - 8 .07 (over mmol) , 5 -borono - 2 -fluorobenzoic acid ( 0 . 138 g , 0 .75 mmol) lapping singlet and doublet , 2H ), 7 .93 (d , J= 7 . 8 Hz, 2H ), tetrakistriphenylphosphinepalladium (0 ) (0 .058 g , 0 .05 7 .83 ( d , J = 7 .3 Hz , 1H ), 7. 59 (d , J= 7 . 8 Hz, 1H ), 7 .50 ( t, J = 7 .3 mmolm ) and 2M Na2CO3 ( 1 mL ) were dissolved in DME . The Hz , 1H ) , 2 .70 ( s , 3H ). HRMS ( ESI) calcd . for C , H ,2FNO S reaction mixture was then processed according to the gen - 23 [ M + H ] " : 314 .0646 . Found: 314 . 0707. eral procedure described in Example 1 , step 3 , to afford the Example 7 : 4 - Fluoro - 3 '- ( 2 - ( furan - 2 - yl) thiazol - 4 - yl) title compound as a yellow solid ( 0 . 053 g , 29 % ). H NMR biphenyl- 3 - carboxylic Acid (400 MHz, DMSOD ): 8 8 .43 ( s, 1H ), 8 .23 (overlapping singlet and doublet, 2H ) , 8 . 11 ( dd , J = 2 . 8 Hz, 6 . 9 Hz, 1H ) , 30 8 .02 - 7. 97 (m , 2H ), 7 .82 (t , J= 3 .2 Hz, 1H ), 7 .63 ( d , J= 7 .8 Hz, 1H ), 7. 54 ( t, J= 7 .3 Hz, 1H ), 7. 44 - 7 .41 (m , 1H ), 7 .00 ( d , J = 1 . 4 Hz, 1H ). HRMS (ESI ) caled . for C20H 2FNOZSENO3 35 [ M + H ]* : 366 .0595 . Found : 366 .0600 . F Example 5 : 4 - Fluoro - 3' - ( 2 -( 6 -( trifluoromethyl) pyri HOC din - 3 -yl ) thiazol - 4 - yl) biphenyl - 3 -carboxylic Acid 40 4 -( 3 -Bromophenyl ) -2 - ( furan -2 - yl) thiazole ( 0 . 152 g , 0 .5 mmol) , 5 -borono - 2 - fluorobenzoic acid ( 0 . 138 g , 0 . 75 mmol) tetrakistriphenylphosphinepalladium ( 0 ) ( 0 .058 g , 0 .05 mmol) and 2M Na2CO3 ( 1 mL ) were dissolved in DME. The reaction mixture was then processed according to the gen 45 eral procedure described in Example 1 , step 3 , to afford the title compound as a yellow solid ( 0 . 020 g , 11 % ) . ' H NMR (400 MHz, DMSO ) : 88 .39 ( s , 1H ) , 8 . 24 ( s , 1H ) , 8 . 12 - 8 . 10 - CF3 ( m , 2H ) , 8 . 03 - 7 . 91 ( m , 2H ), 7 .65 ( d , J = 7 . 8 Hz, 1H ), 7 .57 (t , HOC J = 7 . 8 Hz , 1H ) , 7 .44 - 7 .40 ( m , 3H ) . HRMS ( ESI) calcd . for 50 C20H 2FNOZS [M + H ] *: 366 .0595 . Found : 366 .0599 . 4 -( 3 -Bromophenyl ) - 2 -( 6 -( trifluoromethyl ) pyridin -3 -yl ) Example 8 : 3 '- ( 2 -( Benzo [b ] thiophen -2 -yl ) thiazol- 4 thiazole (0 . 154 g , 0 . 4 mmol) , 5 -borono - 2 - fluorobenzoic acid yl) - 4 - fluorobiphenyl- 3 - carboxylic Acid (0 . 110 g , 0 .6 mmol) , tetrakistriphenylphosphinepalladium 55 ( 0 ) ( 0 .046 g , 0 . 04 mmol ) and 2M Na2CO3 ( 0 . 8 mL ) were dissolved in DME. The reaction mixture was then processed according to the general procedure described in Example 1 , step 3 , to afford the desired compound as a white solid 60 E ( 0 .052 g , 29 % ). ' H NMR (400 MHz, DMSOdo) : 89. 42 ( d , J = 1 . 8 Hz, 1H ) , 8 . 70 (dd , J = 2 . 3 Hz , 8 . 2 Hz, 1H ), 8 . 56 ( s , 1H ) , HO2C 8 . 35 ( s , 1H ), 8 . 17 - 8 . 11 ( m , 2H ), 8 .07 (d , J = 8 . 2 Hz, 1H ) , 8 . 03 - 7 . 99 ( m , 2H ) , 7 .72 - 7 .69 ( d , J = 7 . 8 Hz, 1H ) , 7 .63 - 7 . 58 Po65 2 - (benzo [ b ] thiophen - 2 - yl) - 4 - ( 3 -bromophenyl ) thiazole ( m , 1H ). HRMS (ESI ) calcd . for C22H12F4N2O2S [ M + H ] * : ( 0 . 149 g , 0 .4 mmol ), 5 -borono - 2 - fluorobenzoic acid (0 . 110 445 .0628 . Found: 445 .0623 . g , 0 .6 mmol ) tetrakistriphenylphosphinepalladium ( 0 ) ( 0 .046 US 9 ,969 , 726 B2 101 102 g , 0 .04 mmol ) and 2M Na2CO3 ( 1 mL ) were dissolved in Example 11 : 6 - Fluoro - 3 '- ( 2 - phenylthiazol- 4 -yl ) bi DME. The reaction mixture was then processed according to phenyl- 3 -carboxylic Acid the general procedure described in Example 1, step 3 , to afford the title compound as a yellow solid ( 0. 063 g , 34 % ). 5 ' H NMR (400 MHz , DMSOdo) : 88. 38 ( s , 1H ) , 8 . 24 ( s , 1H ) , 8 . 12 - 8. 10 ( m , 2H ), 8 .03 -7 .91 ( m , 4H ) , 7 .67 (d , J = 7. 8 Hz, 1H ), 7 .58 (t , J= 7 .8 Hz, 1H ), 7. 43 - 7. 39 (m , 4H ). HRMS (ESI ) calcd . for C24H 4FNO S2[ M + H ] *: 432. 0523 . Found : 10 432 .0515 . - Ph HO2C Example 9: 5 -Fluoro -3 ' - ( 2 -phenylthiazol - 4 -yl ) biphe nyl- 3 -carboxylic Acid 15 4 - ( 3 - Bromophenyl) - 2 -phenylthiazole ( 0 . 125 g , 0 . 4 mmol) , 3 -borono - 4 - fluorobenzoic acid ( 0 . 110 g , 0 .6 mmol) tetrakistriphenylphosphinepalladium ( 0 ) ( 0 .046 g , 0 .04 mmol) and 2M Na2CO3 ( 0 .8 mL ) were dissolved in DME . The reaction mixture was then processed according to the 20 general procedure described in Example 1 , step 3 , to afford the title compound as a colorless solid (0 .047 g, 31 % ) . ' H NMR (400 MHz , DMSOdo) : 8 8 . 29 ( s , 1H ), 8 .20 ( s , 1H ) , 8 . 11 - 8 . 09 ( m , 2H ) , 8 .01 - 7 .98 ( m , 3H ) , 7 . 59 ( t , J = 7 . 3 Hz , 1H ) , - Ph 7 .57 -7 .48 ( m , 4H ), 7 .42 (d , J = 8 . 7 Hz , 1H ) . HRMS (ESI ) HO2C 25 calcd . for C22H 4FNO S [M + H ]* : 376 .0802 . Found : 376 .0817 . 4 - ( 3 - Bromophenyl) - 2 -phenylthiazole ( 0 . 109 g , 0 . 35 Example 12 : 4 -Methoxy - 3 '- ( 2 - phenylthiazol- 4 - yl) mmol) , 5 -borono - 3 - fluorobenzoic acid ( 0 .097 g , 0 .525 [1 , 1' - biphenyl ] - 3 -carboxylic Acid mmol) tetrakistriphenylphosphinepalladium ( 0 ) ( 0 .040 g , 30 0 .035 mmol) and 2M Na2CO3 ( 0 . 7 mL ) were dissolved in DME . The reaction mixture was then processed according to the general procedure described in Example 1 , step 3 , to afford the title compound as a colorless solid ( 0 .043 g , 33 % ) . TH NMR ( 400 MHz, DMSod . ) : 8 8 . 37 ( s , 1H ) , 8 . 32 ( s , 1H ) , 35 8 . 11 ( d , J = 8 . 2 Hz, 1H ) , 8 .09 ( s , 1H ) , 8 .02 ( d , J = 7 . 8 Hz, 2H ) , Meo 7 .89 ( d , J = 10 . 0 Hz, 1H ) , 7 .71 ( d , J = 7 . 3 Hz, 1H ) , 7 .65 ( d , - Ph J = 8 . 2 Hz, 1H ) , 7 .59 ( t , J = 7 . 8 Hz, 1H ) , 7 . 53 - 7 . 49 ( m , 3H ) . HO2C LRMS (ESI ) calcd . for C22H 4FNO S [ M + H ] *: 376 .0802 . Found : 376 .0824 . 40 4 -( 3 - Bromophenyl )- 2 -phenylthiazole ( 0. 125 g , 0 .4 mmol) , 5 - borono - 2 -methoxybenzoic acid ( 0 .118 g , 0 . 6 Example 10 : 2 -Fluoro - 5 - ( 5 - ( 2 -phenylthiazol - 4 -yl ) mmol) tetrakistriphenylphosphinepalladium ( 0 ) ( 0 .046 g , thiophen - 2 - yl) benzoic acid 0 . 04 mmol) and 2M Na2CO3 ( 0 .8 mL ) were dissolved in 45 DME. The reaction mixture was then processed according to the general procedure described in Example 1 , step 3 , to afford the title compound as a pale yellow solid (0 .030 g , 19 % ). ' H NMR (400 MHz, DMSOd . ): 8 8 . 32 ( s , 1H ), 8 .24 ( s , 1H ) , 8 . 30 - 7 . 99 ( m , 3H ) , 7 . 93 ( d , J = 2 . 8 Hz, 1H ) , 7 .87 (dd , 50J= 2 . 3 Hz, 8 . 7 Hz, 1H ) , 7 .60 ( d , J = 8 . 2 Hz, 1H ) , 7 . 54 - 7 . 48 ( m , F 4H ) , 7 .21 (d , J = 8 .2 Hz , 1H ), 3. 84 (s , 3H ) . HRMS ( ESI) Ph calcd . for C23H / 2NO3S [ M + H ] * : 388 . 1002 . Found : HO2C 388 . 1020 . Example 13 : 5 -Nitro - 3 '- ( 2 -phenylthiazol - 4 -yl ) biphe 4 - ( 5 - Bromothiophen - 2 - yl) - 2 - phenylthiazole (0 . 113 g , nyl- 3 - carboxylic Acid 0 .35 mmol) , 3 -borono -5 - fluorobenzoic acid (0 .097 g , 0 .525 mmol) tetrakistriphenylphosphinepalladium (0 ) (0 .040 g , 0 .035 mmol) and 2M Na2CO3 (0 .7 mL ) were dissolved in DME . The reaction mixture was then processed according to 60 the general procedure described in Example 1 , step 3 , to afford the title compound as a yellow solid (0 .013 g , 10 % ) . IH NMR ( 400 MHz, DMSOdo ) : 8 8 . 12 ( s , 1H ) , 8 . 10 ( d , J = 2 . 8 Hz , 1H ) , 8 .03 - 8 .01 ( m , 3H ) , 7 .68 ( d , J = 3 . 7 Hz, 1H ) , - Ph 7 .61 ( d , J= 3 .7 Hz , 1H ), 7 .57 - 7 .54 (m , 3H ) , 7 .42 -7 .37 (m , 65 HO2C 1H ). HRMS (ESI ) calcd . for C20H 2FNO S2[ M + H ] *: 382 .0366 . Found : 382 .0348 . US 9 , 969, 726 B2 103 104 4 - (3 -Bromophenyl ) - 2 -phenylthiazole (0 . 125 g , 0 . 4 ' H NMR (400 MHz, DMSOD .) : 8 8 . 30 ( s, 1H ), 8 . 24 (s , 1H ), mmol) , 3- borono -5 - nitrobenzoic acid ( 0. 127 g, 0 .6 mmol) 8 .17 - 8 . 00 ( m , 3H ), 7 .76 - 7 .73 (m , 1H ) , 7. 68 -7 . 57 (m , 2H ), tetrakistriphenylphosphinepalladium (0 ) (0 . 046 g , 0 .04 7 .45 -7 . 43 (m , 2H ), 7. 20 ( t, J = 4 .6 Hz, 1H ) . HRMS (ESI ) mmol) and 2M Na2CO3 ( 0 . 8 mL ) were dissolved in DME. 5 calcd . for C20H / 2FO NS2 [ M + H ] * : 382 . 0366 . Found : The reaction mixture was then processed according to the 382 .0387 . general procedure described in Example 1 , step 3 , to afford the title compound as a pale yellow solid (0 .038 g , 24 % ) . 'H Example 16 : 3 '- ( 2 - (Benzofuran - 2 - yl) thiazol - 4 -yl ) - 4 NMR ( 400 MHz, DMSOdo ): 8 8 .69 ( s , 1H ) , 8 . 59 - 8 . 57 ( m , 10 fluorobiphenyl - 3 - carboxylic Acid 2H ) , 8 . 40 - 7 . 98 ( m , 2H ) , 8 . 17 ( d , J = 7 . 8 Hz , 1H ), 8 .03 - 8 .01 ( m , 2H ), 7 .80 (d , J = 7 .8 Hz, 1H ), 7 .67 (t , J= 7 .8 Hz, 1H ), 7. 52 -7 .50 ( m , 3H ) . HRMS (ESI ) calcd . for C22H14N OAS [ M + H ] * : 403. 0747 . Found : 403 . 0751 . 15 Example 14 : 3 ' -( 2 - Phenylthiazol -4 - yl) biphenyl - 3 carbonitrile HO2C 20 2 - (Benzofuran - 2 -yl ) - 4 -( 3 -bromophenyl ) thiazole (0 .142 g , 0 .4 mmol) , 3 -borono -2 - fluorobenzoic acid (0 .110 g, 0 .6 mmol) tetrakistriphenylphosphinepalladium (0 ) ( 0. 046 g , 0 .04 mmol) and 2M Na2CO3 (0 .8 mL ) were dissolved in Ph DME. The reaction mixture was then processed according to NC $ the general procedure described in Example 1 , step 3 , to afford the title compound as a white solid ( 0 .048 g , 29 % ). ' H 4 -( 3 -Bromophenyl ) - 2 -phenylthiazole ( 0 .125 g, 0. 4 30 NMR ( 400 MHz, DMSOD ) : 88. 46 ( s , 1H ) , 8 .27 ( s , 1H ) , mmol) , 3 -cyanophenylboronic acid (0 .088 g , 0 .6 mmol) 8 . 12 ( d , J = 6 . 8 Hz, 1H ), 8 . 06 ( d , J = 7 . 8 Hz, 1H ), 8 . 23 - 7 . 98 ( m , tetrakistriphenylphosphinepalladium (0 ) (0 .046 g , 0 .05 1H ), 7 .72 ( t, J = 7 . 8 Hz, 2H ), 7. 69 - 7. 67 ( m , 2H ), 7 .58 ( t, J= 7 .8 mmolm ) and 2M Na2CO3 ( 0 . 8 mL ) were dissolved in DME. Hz, 1H ), 7 . 45 - 7 .39 ( m , 2H ) , 7 . 32 (t , J = 7 . 8 Hz, 1H ). HRMS The reaction mixture was then processed according3 toto the 3535 (ESTESI ) calcd . for C24H 4FNO3S [M + H ]* : 416 .0751 . Found : general procedure described in Example 1 , step 3 , to afford 416 the title compound as a white solid ( 0 . 088 g , 65 % ) . ' H NMR (400 MHz , DMSOdo) : 88 . 36 ( s , 1H ) , 8 . 35 ( s , 1H ), 8 . 25 (s , Example 17 : 4 - Fluoro -4 '- ( 2 -phenylthiazol -4 -yl ) bi 1H ) , 8 . 10 ( d , J = 7 . 3 Hz, 2H ) , 8 . 03 (dd , J = 1 . 8 Hz, 9 . 2 Hz, 2H ) , 40 phenyl- 3 -carboxylic Acid 8 .02 ( d , J= 7 .8 Hz , 1H ), 7 .29 (d , J = 7. 8 Hz , 2H ), 7. 69 ( t, J = 7 .8 Hz, 1H ), 7 .59 (t , J= 7 .8 Hz , 1H ), 7 .51 - 7 .49 ( m , 2H ). HRMS (ESI ) calcd . for C22H 4N S [M + H ] *: 339. 0950 . Found : COH 339 .0963 . 4545 Example 15 : 4 -Fluoro - 3 '- ( 2 - ( thiophen - 2 -yl ) thiazol 4 -yl ) biphenyl -3 -carboxylic Acid

F 55 4 - ( 4 -Bromophenyl )- 2 - phenylthiazole ( 0 .126 g , 0 .4 mmol) , 3 -borono - 2 - fluorobenzoic acid ( 0 . 110 g , 0 .6 mmol) HO2C tetrakistriphenylphosphinepalladium ( 0 ) ( 0 .046 g , 0 .05 mmol) and 2M Na , CO , ( 0 . 8 mL ) were dissolved in DME . 4 - ( 3 - Bromophenyl) - 2 - ( thiophen - 2 -yl ) thiazole ( 0 .096 g , 60 The reaction mixture was then processed according to the 0 .3 mmol) , 5 -borono - 2 - fluorobenzoic acid (0 .083 g, 0 .45 general procedure described in Example 1 , step 3 , to afford mmol) tetrakistriphenylphosphinepalladium ( 0 ) ( 0 . 035 g , the title compound as a white solid ( 0 .091 g , 64 % ). ' H NMR ( 400 MHz, DMSOD .) : 8 8 . 33 ( s , 1H ) , 8 . 24 ( s , 1H ) , 8 . 06 ( d , 0 .03 mmol ) and 2M Na2CO3 (0 .6 mL ) were dissolved in J = 7 . 8 Hz , 1H ), 8 .02 - 7 . 99 ( m , 4H ) , 7 . 83 ( d , J = 8 . 2 Hz, 2H ) , DME . The reaction mixture was then processed according to 65 7 .66 ( d . J = 7 . 8 Hz. 11 ) . 7 .54 ( t . J = 7 . 8 Hz. 11 ) . 7 .50 - 7 ,45 ( m . the general procedure described in Example 1, step 3 , to 3H ) . HRMS (ESI ) calcd . for C , H , NO , S M + H ] *: afford the title compound as a yellow solid (0 .015 g , 13 % ). 376 .0802 . Found : 376 .0806 . US 9 ,969 , 726 B2 105 106 Example 18 : 4 - Fluoro - 2 - ( 2 - phenylthiazol- 4 - yl) bi 4 - Fluoro - 3 '- ( 2 - phenylthiazol - 4 - yl) biphenyl - 3 - carbalde phenyl- 3 -carboxylic Acid hyde ( 0 .020 g , 0 . 056 mmol) , hydroxylamine hydrochloride ( 0 . 008 g , 0 .112 mmol) and EtzN ( 0 .02 ml , 0 . 112 mmol) were taken in ethanol (2 mL ) and heated at reflux for 1 h . 5 The reaction mixture was cooled and passed through a short pad of celite . Volatilematerials were removed under vacuum to afford the crude oxime which was purified by automated prep -HPLC to give the desired product as a light yellow viscous liquid ( 0 .008 g , 40 % ) . 'H NMR (400 MHz, Ph DMSOdo) : 811. 68 ( s, 1H ), 8 .36 (s , 1H ), 8. 32 (s , 1H ), 8 .31 ( s , 1H ) , 8 . 06 - 8 . 05 ( m , 4H ) , 8 .02 - 8 .00 ( m , 1H ), 7 .68 - 7 .48 ( m , 6H ) . HRMS (ESI ) calcd . for C22H15FN OS [ M + H ] * : COH 375 .0962 . Found : 375 .0963 . 15 Example 21: 3 - Chloro - 3' -( 2 -phenylthiazol - 4 -yl ) 4 -( 2 -Bromophenyl ) -2 -phenyl - thiazole (0 . 126 g , 0 .4 biphenyl- 4 - carboxylic Acid mmol) , 3 - borono - 2 - fluorobenzoic acid ( 0 . 110 g , 0 .6 mmol) tetrakistriphenylphosphinepalladium ( 0 ) ( 0 . 046 g , 0 .05 mmol) and 2M Na2CO3 ( 0 .8 mL ) were dissolved in DME . 20 The reaction mixture was then processed according to the general procedure described in Example 1 , step 3 , to afford the title compound as a white solid ( 0 .021 g , 14 % ) . ' H NMR (400 MHz, DMSOdo) : 8 7 .83 - 7 .78 ( m , 1H ) , 7 .76 - 7 .70 ( m , HO2C1 2H ) , 7 .67 - 7 .65 ( m , 1H ) , 7 .52 - 7 .47 ( m , 2H ) , 7 .47 - 7 .38 ( m , Ph 5H ) , 7 .28 -7 .20 ( m , 2H ) . HRMS (ESI ) calcd . forº 25 C22H 4FNO2S [M + H ] *: 376 .0802 . Found : 376 .0809 . Example 19 : 4 - Fluoro - 3' - ( 2 -phenylthiazol - 4 -yl ) bi phenyl- 3 -carbaldehyde 4 - ( 3 -Bromophenyl ) - 2 - phenylthiazole ( 0 . 138 g 0 . 44 mmol) , 4 -borono - 2 - chlorobenzoic acid ( 0 . 132 g , 0 .66 30 mmol) tetrakistriphenylphosphinepalladium ( 0 ) ( 0 .051 g , 0 .044 mmol) and 2M Na2CO3 ( 0 .88 mL ) were dissolved in DME . The reaction mixture was then processed according to the general procedure described in Example 1, step 3 , to 35 afford the title compound as an off -white solid (0 . 063 g, 37 % ) . ' H NMR (400 MHz , DMSOdo ) : 8 8 . 37 (s , 1H ), 8 . 34 Ph ( s, 1H ), 8 .11 (d , J = 7 . 8 Hz , 1H ) , 8 .02 ( d , J= 7 .8 Hz , 2H ), OHC 7 .99 -7 .98 (m , 2H ), 7 .81 (d , J = 7 .8 Hz, 1H ), 7. 31 (d , J= 7 .8 Hz, 1H ) , 7 .59 ( d , J= 7 .8 Hz , 1H ), 7 .53 -7 .48 (m , 3H ). HRMS 4 - ( 3 -Bromophenyl ) -2 - (furan - 3 - yl )thiazole ( 0 . 314 g , 1 40 (ESI ) calcd . for C22H 4CINO S [ M + H ] * : 392 . 0507 . Found : mmol) , 4 - fluoro - 3 - formylphenylboronic acid ( 0 .252 g , 1 . 5 392 .0537 . mmol ) tetrakistriphenylphosphinepalladium (0 ) (0 .115 g, 0 .01 mmol ) and 2M Na2CO3 ( 2 mL ) were dissolved in Example 22 : 3' - ( 2 - Phenylthiazol- 4 -yl ) biphenyl -4 DME . The reaction mixture was then processed according to carboxylic Acid the general procedure described in Example 1, step 3 , to 45 afford the title compound as a white solid ( 0 . 121 g , 34 % ) . ' H NMR ( 400 MHz, DMSOdo) : 8 10 . 26 ( s , 1H ) , 8 . 34 ( s , 1H ) , 8 .33 ( s , 1H ) , 8 . 19 - 8 . 19 ( m , 2H ) , 8 .07 ( d , J = 7 . 8 Hz, 1H ) , 8 .02 - 8 . 00 ( m , 2H ) , 7 . 66 ( d , J = 7 . 8 Hz, 1H ) , 7 . 58 ( t , J = 7 . 8 Hz, 1H ) , 7 .53 - 7 . 48 ( m , 4H ) . HRMS ( ESI) calcd . for 50 C22H 4FNOS [M + H ]* : 360 .0896 . Found : 360 .0904 . HO2C Example 20 : 4 - Fluoro - 3' -( 2 -phenylthiazol - 4 -yl ) bi phenyl- 3 -carbaldehyde oxime 55 4 - ( 3 - Bromophenyl) - 2 - phenylthiazole ( 0 . 138 g , 0 .44 mmol) , 4 -boronobenzoic acid ( 0 . 109 g , 0 .66 mmol) tetrak istriphenylphosphinepalladium ( 0 ) ( 0 .051 g , 0 . 044 mmol) and 2M Na, CO , ( 0 .88 mL ) were dissolved in DME. The 60 reaction mixture was then processed according to the gen - Ph eral procedure described in Example 1 , step 3 , to afford the title compound as an off -white solid ( 0 . 060 g , 42 % ) . " H F NMR ( 400 MHz, DMSOd . ) : 88 . 33 ( s , 1H ) , 8 . 24 (s , 1H ) , 8 .07 -8 .00 ( m , 4H ), 7 .83 (d , J = 8 .2 Hz, 2H ), 7 .66 (d , J= 7 .8 Hz, HON 65 1H ) , 7 .53 ( t, J = 7 . 8 Hz , 1H ) , 7 .50 - 7 . 45 (m , 4H ) . HRMS ( ESI) calcd . for C22H15NO S [ M + H ] * : 358 .0896 . Found : 358 .0906 . US 9 ,969 , 726 B2 107 108 Example 23: 6 -Methoxy - 3 '- ( 2 - phenylthiazol- 4 - yl) 4 - ( 3 -Bromophenyl )- 2 - phenylthiazole ( 0 . 138 g 0 .44 biphenyl - 3 -carboxylic Acid mmol) , 2 -boronobenzoic acid (0 . 109 g , 0 .66 mmol) tetrak istriphenylphosphinepalladium (0 ) (0 . 051 g , 0 . 044 mmol ) and 2M Na2CO3 (0 .88 mL ) were dissolved in DME. The reaction mixture was then processed according to the gen OMe eral procedure described in Example 1 , step 3 , to afford the title compound as a pale yellow solid (0 . 020 g , 13 % ) . ' H NMR (400 MHz , DMSOdo) : 88. 02 - 7. 93 (m , 3H ), 7 . 56 - 7 .42 ( m , 8H ) , 7 .30 - 7 .24 (m , 3H ) . HRMS (ESI ) calcd . for - Ph C22H15NO S [M + H ] *: 358 .0896 . Found : 358. 0940 . HO2C Example 26 : 2 -Chloro - 3 '- ( 2 - phenylthiazol- 4 - yl) biphenyl - 4 - carboxylic Acid 4 -( 3 -Bromophenyl ) - 2 -phenylthiazole (0 .138 g 0 .44 15 mmol) , 3 -borono - 4 -methoxybenzoic acid ( 0 .129 g , 0 . 66 mmol) tetrakistriphenylphosphinepalladium ( 0 ) (0 .051 g , 0 . 044 mmol) and 2M Na2CO3 ( 0 .88 mL ) were dissolved in DME . The reaction mixture was then processed according to the general procedure described in Example 1 , step 3 , to 20 afford the title compound as an off -white solid ( 0 .056 g , HO2CM 33 % ) . ' H NMR (400 MHz, DMSOdo ) : 8 8 . 22 ( s , 1H ) , 8 .08 Ph ( s , 1H ) , 8 .02 - 7 . 98 ( m , 3H ) , 7 .95 (dd , J = 2 . 3 Hz, 8 . 7 Hz , 1H ) , 7 .84 ( d , J = 1 . 8 Hz , 1H ) , 7 .52 - 7 .43 ( m , 5H ) , 7 . 21 ( d , J = 8 . 7 Hz , 1H ), 3. 84 (s , 3H ). HRMS ( ESI) calcd . for C23H NO3S 25 [ M + H ] * : 388 . 1002 . Found : 388 . 1009 . 4 - ( 3 - Bromophenyl) - 2 -phenylthiazole (0 . 138 g 0 . 44 mmol) , 4 - borono - 3 - chlorobenzoic acid ( 0 . 132 g , 0 .66 Example 24 : 4 -Chloro - 3' - ( 2 -phenylthiazol - 4 - yl) mmol ) tetrakistriphenylphosphinepalladium (0 ) (0 .051 g , biphenyl - 3 - carboxylic Acid 0 . 044 mmol) and 2M Na2CO3 ( 0 .88 mL ) were dissolved in 30 DME. The reaction mixture was then processed according to the general procedure described in Example 1 , step 3 , to afford the title compound as a white solid ( 0 .053 g , 31 % ) . ' H NMR (400 MHz, DMSOdo) : 88 . 27 ( s , 1H ), 8 . 11 - 8 .09 (over 35 lapping singlet and doublet , 2H ), 8. 02 (s , 1H ), 7 . 99 ( d , J= 7 .4 Hz, 2H ), 7 .95 (d , J= 8 .2 Hz, 1H ), 7 .61 (d , J = 7 . 8 Hz , 1H ), 7 .59 CI ( t, J= 7 .8 Hz, 1H ) , 7 .49 - 7 .45 (m , 3H ) , 7 .42 (d , J = 7 . 3 Hz , 1H ). - Ph HRMS ( ESI) calcd . for C22H 4CINO S [M + H ] *: 392 .0507 . HO2C Found : 392 .0523 . 40 4 - ( 3 - Bromophenyl) - 2 -phenylthiazole ( 0 .063 g , 0 . 2 Example 27 : mmol) , 5 - borono - 2 -chlorobenzoic acid ( 0 . 067 g , 0 . 3 mmol) 2 - Fluoro - 5 - ( 2 - phenylthiazol- 4 - yl) benzoic acid tetrakistriphenylphosphinepalladium (0 ) (0 .023 g , 0 .02 mmol) and 2M Na2CO3 ( 0 .4 mL ) were dissolved in DME . The reaction mixture was then processed according to the 45 general procedure described in Example 1 , step 3 , to afford the title compound as a white solid ( 0 .020 g , 26 % ) . ' H NMR ( 400 MHz, DMSOd . ) : 8 8 . 35 ( s , 1H ) , 8 . 30 ( s , 1H ) , 8 . 07 ( d , J= 8 .2 Hz, 2H ), 8 .02 ( d, J= 8 .2 Hz , 2H ), 7. 88 ( d , J = 8. 2 Hz, 50 HO , C 1H ) , 7 .67 ( d , J = 7 . 8 Hz, 1H ) , 7 .61 ( d , J = 8 . 2 Hz , 1H ) , 7 . 56 ( t , J = 7 . 8 Hz, 1H ) , 7 .51 - 7 .49 ( m , 3H ) . HRMS ( ESI) calcd . for Ph C22H 4CINO2S [ M + H ]* : 392. 0507 . Found : 392 .0518 .

Example 25 : 3 '- ( 2 -Phenylthiazol - 4 - yl) biphenyl- 2 55 carboxylic Acid 4 - ( 3 - Bromophenyl) - 2 - phenylthiazole ( 0 . 121 g , 0 . 5 mmol) , 5 -borono - 2 - fluorobenzoic acid (0 .138 g , 0 .75 mmol) tetrakistriphenylphosphinepalladium ( 0 ) ( 0 .058 g , 0 . 05 mmol ) and 2M Na2CO3 ( 1 mL ) were dissolved in DME . The 60 reaction mixture was then processed according to the gen eral procedure described in Example 1 , step 3 , to afford the title compound as a tan solid ( 0 . 068 g , 45 % ) . ' H NMR (400 MHz, DMSOD ) : 88 .48 (dd , J = 2 . 3 Hz, 7 . 3 Hz, 1H ), 8 .26 ( s , 1H ) , 8 . 25 - 8 . 24 ( m , 1H ) , 7 .99 (dd , J = 5 . 0 Hz, 9 .6 Hz, 2H ) , CO2H 65 7 . 52 - 7 . 48 ( m , 3H ) , 7 .40 ( t , J = 9 . 2 Hz, 1H ) . HRMS ( ESI ) calcd . for C16H10FNOUS [ M + H ]" : 300 .0489 . Found : 300. 0506 . US 9 ,969 , 726 B2 109 US9969 ,726 B2 110 Example 28 : 3 '- ( 2 -Phenylthiazol - 4 - yl) biphenyl - 3 -continued semper carboxylic Acid POBr3, 100° C . 5 10 h HO2C

10 1 ) ArB (OH ) 2 , Ph i , 12 h HO2C 2 ) dil. HCI - Br 4 - ( 3 -Bromophenyl ) - 2 -phenylthiazole ( 0 . 138 g , 0 .44 HOC mmol ), 3 -boronobenzoic acid (0 . 109 g , 0 .66 mmol) tetrak - 15 istriphenylphosphinepalladium (0 ) (0 . 051 g , 0 . 044 mmol ) and 2M Na CO2 (0 .88 mL ) were dissolved in DME . The reaction mixture was then processed according to the gen eral procedure described in Example 1 , step 3 , to afford the Ar title compound as a white solid (0 . 065 g , 46 % ) . ' H NMR 20 ( 400 MHz, DMSOdo ) : 8 8 . 34 ( s , 1H ) , 8 . 30 ( s , 1H ) , 8 .22 ( s , HO2C 1H ) , 8 . 07 ( d , J = 7 . 8 Hz, 1H ) , 8 . 03 - 7 .98 ( m , 2H ), 7 . 94 ( d , i ) Pd( PPh3 ) 4 , 2M Na2CO3 J = 7 .3 Hz , 1H ), 7 .67 (d , J= 7 .3 Hz, 1H ) , 7 .66 -7 .55 (m , 3H ), 7 .52 -7 .48 ( m , 3H ). Found : 358 .00 . HRMS (ESI ) calcd . for C22H 5NO2S [M + H ]* : 358 .0896 . Found : 358 .0900 . 2525 Example 29 : 3 - ( 3 -[ 2 -( 3 ,4 -Dimethoxyphenyl ) - 1 ,3 General Synthetic Scheme for the Preparation of thiazol -4 -yl ] phenyl} benzoic acid ( 2 -arylthiazol - 4 -yl ) biphenyl Carboxylic Acid Derivatives

OMe Scheme 2

- OMe

+ ö HO2C

HO24 B (OH )2 Step 1 : 3 '- Acetylbiphenyl- 3 - carboxylic Acid 1 , 2 - 3 h B

# K2CO3, Mel HO2C Acetone , 60° C ., 1 h HO2C 50

1- ( 3- Bromophenyl) ethanone (10 g, 50 mmol) and 3 -bo 55 ronobenzoic acid (12 . 5 g , 75 mmol) were dissolved in DME 1 ) CuBr2 , EtOAc: CHCl3 ( 100 mL ) . To this solution was added palladium tetrakis MeO2C . reflux , 4 h triphenylphosphine ( 2 . 9 g , 2 . 5 mmol) and 2M Na2CO3 2 ) KSCN , EtOH , reflux 2 h solution (50 mL , 100 mmol) . The resulting mixture was heated to reflux for 2 - 3 h and cooled to room temperature . 60 The mixture was diluted with water and then acidified with 2N HC1. The crude acid was collected by filtration washed with water and diethyl ether and dried and used without any Me02C H2SO4/ AcOH further purification in the next step . Pale yellow solid (7 . 5 g , Do SCN Reflux , 12 h 62 % ) . ' H NMR ( 400 MHz , DMSO ) : 88 . 24 ( t , J = 1 . 8 Hz, 65 1H ) , 8 . 22 ( t , J = 1 . 8 Hz , 1H ) , 8 . 00 - 7 . 98 ( m , 4H ) , 7 .66 - 7 . 64 ( m , 2H ) , 2 .67 (s , 3H ) . LRMS ( ESI) calcd . for C13H1203 gy [ M + H ] * : 241. 07 . Found : 241 . 00 . US 9 ,969 , 726 B2 111 112 Step 2 : Acetylbiphenyl - 3 -methyl carboxylate A solution of ethyl 3 ' -( 2 -bromoacetyl ) biphenyl - 3 -car boxylate (5 . 12 g , 15 . 42 mmol) and potassium thiocyanate ( 5 .23 g , 53. 98 mmol) in ethanol was heated at reflux for 2 h . The reaction mixture was filtered hot and washed with hot 5 ethanol. Upon cooling the filtrate , a solid was collected by filtration . The solid was washed with cold ethanol and dried under vacuum to afford the title compound as a yellow solid ( 4 . 2 g , 94 % ) . ' H NMR (400 MHz, DMSOd ) : 8 8 . 23 ( t , Me02C J = 1 . 8 Hz , 1H ) , 8 . 19 ( t , J = 1 . 8 Hz, 1H ) , 7 . 97 - 7 . 94 ( m , 4H ) , 7 .62 - 7 .60 ( m , 2H ), 5 . 15 (s , 2H ), 3 .82 (s , 3H ). LRMS ( ESI) calcd . for C , H , 3NO3S [ M + H ] * : 312 . 06 . Found : 312 . 00 . Step 5 : 3 :- ( 2 - Oxo - 2 , 3 - dihydrothiazol- 4 - yl) biphenyl To a mixture of 3 ' -acetylbiphenyl - 3 -carboxylic acid ( 5 g , 15 3 - carboxylic Acid 20 .83 mmol) in acetone ( 100 mL ) was added Mel ( 2 . 6 mL , 42 mmol) and K2CO3 ( 5 . 7 g , 42 mmol) . The reaction mixture was heated at reflux for 1 h , cooled to room temperature , and then filtered through a short pad of celite and washed with acetone. Removal of the solvent under reduced pressure afforded 3 ' -acetylbiphenyl - 3 -methyl car boxylate as a reddish brown viscous liquid ( 4 g , 80 % ) . ' H NMR (400 MHz, CDC12 ) : 88 . 28 ( t , J = 1 . 8 Hz, 1H ) , 8 . 18 ( t , J = 1 . 8 Hz , 1H ), 8 . 00 - 7 . 98 ( m , 1H ), 7 . 82 ( m , 1H ), 7 .79 - 7 . 78 ( m , 2H ), 7 . 57 - 7 .53 ( m , 2H ) , 3 . 92 ( s , 3H ) , 2 . 65 ( s, 3H ) . LRMS (ESI ) calcd . for C16H 403[ M + H ]* : 255 .09 . Found : 25 HO2C 255 . 00 Step 3 : Methyl 50 % aqueous H2SO4 ( 100 mL ) was added to a solution of 3 '- ( 2 - bromoacetyl) biphenyl - 3 - carboxylate methyl 3 '- ( 2 -thiocyanatoacetyl ) biphenyl - 3 -carboxylate (4 .5 30 g , 14 . 46 mmol) in acetic acid ( 20 mL ) . The resulting mixture was heated at reflux for 12 h . The reaction mixture was cooled to room temperature and then poured into ice water. The precipitated compound was collected by filtration , MeO2C washed with water , and dried under vacuum to afford Br 35 3' - (2 -oxo -2 ,3 -dihydrothiazol - 4 - yl ) biphenyl- 3 -carboxylic acid as a yellow solid ( 4 . 3 g, quantitative yield ) . ' H NMR ( 400 MHz, DMSOdo) : 811. 89 (s , 1H ), 8 . 25 ( s , 1H ) , 8 . 10 ( d , J = 8 . 2 Hz , 1H ), 7 .93 -7 .91 (m , 2H ), 7. 66 - 7 .58 ( m , 4H ), 6 . 90 Cupric bromide (5 .27 g , 23. 62 mmol) was dissolved in 40 ( s , 1H ) , LRMS (ESI ) calcd . for C16H , NOZS [ M + H ] * : ethyl acetate andd brought to refluyreflux . Bé3' - AcetylbiphenylAcetylhinhenv1 -. 3 . 298 . 05 . Found : 298 . 00 . methyl carboxylate ( 4 g , 15 . 7 mmol) was dissolved in chloroform and rapidly added to the cupric bromide mixture and heated at reflux for 4 h . The solution was cooled and the Step 6 : 3 '- ( 2 - Bromothiazol- 4 -yl ) - [ 1, 1' - biphenyl] - 3 precipitated Cu ( I ) bromide was filtered off . The organic 15 carboxylic Acid layer was washed with water and brine solution , and dried over anhydrous Na2SO4 solution . Removal of the solvent under reduced pressure followed by chromatographic sepa ration using hexane :ethyl acetate afforded the title com pound as a yellow solid ( 5 . 12 g , 98 % ) . ' H NMR (400 MHz, 50 CDC12 ): 88 . 27 ( t , J = 1 . 8 Hz, 1H ) , 8 . 20 ( t , J = 1 . 8 Hz , 1H ) , 8 .08 -7 .95 ( m , 2H ), 7 .85 - 7 .78 (m , 2H ) , 7 .59 -7 .52 (m , 2H ), Br 4 . 50 ( s , 2H ) , 3 . 94 ( s , 3H ) . LRMS ( ESI) calcd . for C16H 3Br03 [ M + H ] * : 333 . 00 . Found : 333. 00 . HO2C Step 4 : Methyl 3 '- ( 2- thiocyanatoacetyl )biphenyl - 3 - 55 carboxylate 3 '- ( 2 -Oxo - 2 , 3 - dihydrothiazol- 4 - yl) biphenyl - 3 -carboxylic acid ( 4 .3 g , 14 .47 mmol ) and POBrz (45 g, 156 .70 mmol) were heated at 100° C . for 10 h . The reaction mixture was then cooled to room temperature and poured into ice water. The mixture was extracted with ethyl acetate (3x50 mL ), Me02 washed with brine and dried over Na S04 to 3' - (2 -bromothi SCN azol - 4 - yl) - [ 1 , 1 '- biphenyl ] - 3 -carboxylic acid as a tan solid ( 3 . 4 g , 68 % ). H NMR ( 400 MHz, DMSOda ) : 88 . 36 ( s, 1H ) , 65 8 .24 ( s , 1H ) , 8 . 21 ( s , 1H ) , 7 . 97 ( G , J = 7 .33 Hz, 3H ) , 7 .73 ( d , J = 7 . 8 Hz, 1H ), 7 .65 - 7 .57 (m , 2H ). LRMS ( ESI) calcd . for C16H10BrNO , [M + H ] * : 359 . 96 . Found : 360 .00 . US 9 ,969 , 726 B2 113 114 Step 7 : 3 - { 3 -[ 2 -( 3 ,4 -Dimethoxyphenyl ) - 1 ,3 -thiazol 3 '- ( 2 - Bromothiazol- 4 - yl) - [ 1 , 1 '- biphenyl] - 3 - carboxylic 4 - yl] phenyl} benzoic acid acid ( 0 . 107 g , 0 . 3 mmol) , 4 -methoxyphenylboronic acid ( 0 . 068 g , 0 .45 mmol) , tetrakistriphenylphosphinepalladium ( 0 ) ( 0 . 035 g , 0 . 03 mmol) and 2M Na2CO3 ( 0 .6 mL ) were 5 dissolved in DME . The reaction mixture was then processed according to the general procedure described in Example 1, OMe step 3 , to afford the title compound as a pale yellow solid ( 0 .022 g , 19 % ) . ' H NMR (400 MHz, DMSod . ) : 8 8 . 28 ( t, J = 1 . 8 Hz, 1H ) , 8 . 24 ( s , 1H ) , 8 . 22 ( t , J = 1 . 8 Hz, 1H ) , 8 .05 ( d , - OMe 10 1J= 7. 8 Hz,, 1H ), 7 . 97 - 7 . 94 ( m , 4H ), 7 .67 - 7 .56 ( m , 3H ), 7 . 06 HO? ( d , J = 8 . 7 Hz, 2H ) , 3 . 81 ( s , 3H ) . HRMS (ESI ) calcd . for C23H , NO3S [M + H ] * : 388 . 1002. Found : 388 . 1006 . 3 '- ( 2 -Bromothiazol - 4 - yl) - [ 1 , 1 '- biphenyl ]- 3 -carboxylic acid (0 . 178 g , 0 . 5 mmol) , 3 , 4 - dimethoxyphenylboronic acid 15 ( 0 . 136 g , 0 .75 mmol) , tetrakistriphenylphosphinepalladium Example 32 : 3 - [ 3 - ( 2 - ( 2 - Naphthyl) - 1 , 3 - thiazol- 4 - yl) ( 0 ) ( 0 .058 g , 0 .05 mmol) and 2M Na2CO3 ( 1 mL ) were phenyl] benzoic acid dissolved in DME. The reaction mixture was then processed according to the general procedure described in Example 1 , step 3 , to afford the title compound as a pale yellow solid ( 0 . 116 g , 56 % ). ' H NMR (400 MHz, DMSOdo ): 8 8 .29 (t , J = 1 .6 Hz, 1H ) , 8 .24 - 8 . 23 ( m , 2H ) , 8 . 06 ( d , J = 7 . 8 Hz , 1H ) , 8 .00 - 7 . 93 ( m , 2H ), 7 .64 - 7 . 53 ( m , 5H ), 7 .06 ( d , J = 8 . 7 Hz, 1H ) , 3 .84 ( s , 3H ) , 3 . 80 ( s , 3H ) . HRMS (ESI ) calcd . for C24H , NO S [ M + H ] * : 418 . 1108 . Found : 418 .1121 . 25 HO2C Example 30 : 3 - ( 3 - ( 2 -Naphthyl - 1 , 3 -thiazol - 4 -yl ) phe nyl] benzoic acid 3 '- ( 2 -Bromothiazol - 4 - yl) - [ 1 , 1' - biphenyl ] - 3 - carboxylic acid ( 0 . 108 g , 0 . 3 mmol) , 2 -naphthylboronic acid ( 0 .077 g , 30 0 .45 mmol ), tetrakistriphenylphosphinepalladium (0 ) (0 .035 g , 0 .03 mmol) and 2M Na2CO3 ( 0 .6 mL ) were dissolved in DME . The reaction mixture was then processed according to the general procedure described in Example 1 , step 3 , to 35 afford the title compound as a pale yellow solid ( 0 .057 g , 46 % ). ' H NMR (400 MHz , DMSO ): 8 8 . 64 ( s , 1H ), 8 . 43 HO , C ( s, 1H ), 8. 38 (s , 1H ), 8 .23 (s , 1H ), 8 .20 - 7. 99 (m , 7H ), 7. 72 -7 .60 ( m , 5H ). HRMS ( ESI) calcd . for C26H , NO S [ M + H ] * : 408 . 09. Found : 408 . 1054 . 40 3' - ( 2- Bromothiazol -4 - yl )- [ 1 ,1 '- biphenyl ]- 3 - carboxylic Example 33 : 3 - { 4 - [ 3 - ( 3 - Carboxyphenyl) phenyl] - 1 , acid (0 . 178 g , 0 . 5 mmol ), 1 - naphthylboronic acid ( 0 . 129 g , 3 -thiazol - 2 -yl } benzoic acid 0 .75 mmol) , tetrakistriphenylphosphinepalladium ( 0 ) ( 0 . 058 g , 0 .05 mmol ) and 2M Na2CO3 (1 mL ) were dissolved in 45 DME . The reaction mixture was then processed according to the general procedure described in Example 1 , step 3 , to afford the title compound as a white solid ( 0 .047 g , 23 % ) . ' H NMR ( 400 MHz, DMSOdo ): 8 8 .99 ( d , J = 8 . 7 Hz , 1H ) , 8 .51 ( s , 1H ) , 8 . 40 ( s , 1H ) , 8 .31 ( s, 1H ) , 8 . 14 - 7 . 99 ( m , 6H ) , 50 7 .68 -7 .50 ( m , 5H ) , 7 .52 -7 .50 ( m , 1H ) . Found : 408 .00 . HRMS (ESI ) calcd . for C26H / 7NO2S [M + H ] *: 408 .1053 . HO2C Found : 408 . 1061 . CO2H

Example 31: 3 - { 3 - [ 2 - ( 4 -Methoxyphenyl ) - 1 , 3 -thi 55 azol- 4 -yl ] phenyl} benzoic acid 3 '- ( 2 -Bromothiazol - 4 - yl )- [ 1, 1' - biphenyl ] -3 - carboxylic acid ( 0 . 100 g , 0 .28 mmol) , 3 -boronobenzoic acid (0 .070 g , 0 .42 mmol) , tetrakistriphenylphosphinepalladium ( 0 ) ( 0 .032 g , 0 . 028 mmol) and 2M Na Coz ( 0 .56 mL ) were dissolved 60 in DME. The reaction mixture was then processed according to the general procedure described in Example 1 , step 3 , to afford the title compound as a pale yellow solid ( 0 .045 g , 40 % ) . H NMR ( 400 MHz, DMSOd . ) : 8 8 .55 ( s , 1H ) , 8 . 44 - OMe ( s, 1H ), 8 .34 ( s, 1H ), 8 .27 ( s, 1H ), 8 . 13 ( d , J= 7 .8 Hz , 1H ), HO2C 65 8 . 07 ( d , J = 7 . 8 Hz, 1H ) , 8 .03 - 7 . 98 ( m , 2H ) , 7 .73 - 7 .60 ( m , 5H ) . HRMS (ESI ) calcd . for C23H15NOS [ M + H ]* : 402 .0795 . Found : 402 . 0801 . US 9 ,969 , 726 B2 115 116 Example 34 : 3 - [ 3 - ( 2 -( 2H ,3H - benzo [ e ] 1 , 4 - dioxin - 6 3' - ( 2- Bromothiazol -4 -yl ) - [ 1, 1' - biphenyl ]- 3 - carboxylic yl) - 1 , 3 - thiazol- 4 - yl) phenyl ] benzoic acid acid ( 0 .107 g , 0 . 3 mmol ), (E ) - styrylboronic acid ( 0 .067 g , 0 .45 mmol ), tetrakistriphenylphosphinepalladium (0 ) (0 .035 5 g , 0 . 03 mmol) and 2M Na2CO3 ( 0 .6 mL ) were dissolved in DME . The reaction mixture was then processed according to the general procedure described in Example 1 , step 3 , to afford the title compound as a pale yellow solid ( 0 . 053 g , 46 % ) . ' H NMR (400 MHz, DMSOD ) : 8 8 . 31 (s , 1H ) , 8 . 28 (s , 1H ) , 8 . 26 ( s , 1H ) , 8 . 06 ( d , J = 7 . 8 Hz, 1H ) , 8 . 02 - 7 . 99 ( m , HO2C 2H ) , 7. 76 (d , J= 7. 3 Hz , 2H ) , 7. 67 -7 .58 (m , 5H ), 7. 44 - 7 .37 3 '- ( 2 - Bromothiazol- 4 - yl) - [ 1 , 1 '- biphenyl] - 3 - carboxylic (m , 3H ) . HRMS (ESI ) calcd . for C24H , 2NO , S [ M + H ]* : acid ( 0 . 107 g , 0 . 3 mmol) , 2 , 3 - dihydrobenzo [b ] [ 1 ,4 ]dioxin - 15 384 . 1053 . Found : 384 . 1081 . 6 - ylboronic acid ( 0 .081 g , 0 . 45 mmol) , tetrakistriphenyl phosphinepalladium ( 0 ) ( 0 .035 g , 0 .03 mmol) and 2M Example 37: 4 -( 3 - (2H - Tetrazol- 5 -yl ) biphenyl - 3 -yl ) Na2CO3 (0 .6 mL ) were dissolved in DME. The reaction 2 - phenylthiazole mixture was then processed according to the general proce dure described in Example 1 , step 3 , to afford the title 20 compound as a yellow solid ( 0 . 040 g , 32 % ) . ' H NMR (400 MHz, DMSOdo) : 8 8 . 32 ( d , J = 1 . 8 Hz, 1H ) , 8 .27 - 8 . 26 ( m , 2H ) , 8 .09 - 7 . 98 ( m , 3H ) , 7 .71 - 7 .50 ( m , 5H ), 7 .02 (dd , J = 1 . 3 Hz, 8 . 7 Hz, 1H ) , 4 . 32 ( s , 4H ) . HRMS (ESI ) calcd . for 25 C24H17NO4S [ M + H ] * : 416 .0951 . Found : 416 .0960 . Example 35 : 3' - ( 2 -( 6 - Chloropyridin -3 - yl) thiazol- 4 yl) biphenyl - 3 - carboxylic Acid 30 N - NH 3' - ( 2 -Phenylthiazol - 4 -yl ) biphenyl - 3 - carbonitrile (0 . 169 g , 35 0 . 5 mmol) , sodium azide (0 .390 g , 6 mmol) , and ammonium chloride ( 0 .324 g , 6 mmol) were taken in DMF (6 mL) and the resulting mixture was heated at 100° C . for 1 h . The HOC reaction mixture cooled to room temperature and diluted 40 with water and followed a usual work up with ethyl acetate . 3 '- ( 2 -Bromothiazol - 4 -yl ) - [1 , 1' - biphenyl ] - 3 -carboxylic acid ( 0 . 107 g , 0 . 3 mmol) , 6 - chloropyridin - 3 - ylboronic acid The crude residue was purified by prep -HPLC to yield the ( 0 .071 g , 0 .45 mmol) , tetrakistriphenylphosphinepalladium desired compound as a white solid ( 0 . 104 g , 55 % ) . ' H NMR ( 0 ) ( 0 .035 g . 0 .03 mmol) and 2M Na . CO , ( 0 . 6 mL ) were (400 MHz, DMSOdo ) : 8 8 . 42 ( s , 2H ) , 8 . 37 ( s , 1H ), 8 . 15 - 8 . 06 dissolved in DME. The reaction mixture was then processed 45 ( m , 4H ), 8 . 00 ( d , J = 7 . 8 Hz, 1H ) , 7 .78 - 7 . 74 (m , 2H ) , 7 .66 ( t , according to the general procedure described in Example 1 , J = 7 . 8 Hz, 1H ) , 7 .58 - 7 .53 ( m , 3H ) . HRMS (ESI ) calcd . for step 3 , to afford the title compound as a pale yellow solid ( 0 .078 0 66 % ). TH NMR (400 MHZ. DMSodi: 89. 07 0 C22H15N55 ( M + H ] : 382 . 1121. Found : 382 . 1133 . J = 2 . 3 Hz, 1H ) , 8 .48 ( s , 1H ), 8 . 46 ( d , J = 2 . 3 Hz, 1H ) , 8 . 34 ( s , General Synthetic Scheme for the Preparation of Thiadiaz 1H ) , 8 . 27 (s , 1H ) , 8 . 11 (d , J = 7 . 8 Hz, 1H ), 8 .02 - 7 . 98 ( m , 2H ) , 50 ole Analogues 7. 73 -7 .60 (m , 4H ) . HRMS (ESI ) calcd. for C21H13CIN O S [ M + H ] " : 393 .0459 . Found : 393 .0466 . Example 36 : ( E ) - 3 '- ( 2 - Styrylthiazol- 4 - yl) biphenyl Scheme 3 3 -carboxylic Acid 55 Bri 5 mol % catalyst , CsF , - CI * " TX sondioxane :concertH20 80°C . 1 ) Br B (OH )2 , i 60 Br 2 ) HO2C , B (OH )2 , ii HO2C Ocho Rio F US 9, 969, 726 B2 117 118 Step 2 : -continued 3 -( 3 -Bromophenyl ) - 5 -phenyl - 1 ,2 ,4 -thiadiazole

HOC 10 Catalyst: PdCl2[ PBu ( pNMe2 — C6H4) ]2 i) Pd (PPh3 ) 4, 2M Na2CO3, DME , 80° C . , 1 - 2 h ii ) Pd ( dppf) 2Cl2 DME , 80° C ., 6 -12 h , dil•HCI 15 A mixture of 3 - bromo - 5 - phenyl- 1 , 2 , 4 - thiadiazole ( 0 . 770 g , 3 . 2 mmol) , 3 - bromophenylboronic acid ( 0 . 767 g , 3 .83 mmol) and tetrakistriphenylphosphinepalladium (0 ) (0 . 369 g , 0 .32 mmol ) were taken in 25 mL DME . To this 2M Example 38 : 4 - Fluoro -3 '- ( 5 - phenyl- 1 ,2 ,4 -thiadiazol 20 Na2CO3 (3 .2 mL, 6 .4 mmol) solution was added and the 3 -yl ) biphenyl -3 -carboxylic Acid resulting solution was heated at reflux in an atmosphere of N , for 2 h . It was then processed according to the general procedure in Example 1, step 2 , to afford the desired product 25 as a colorless solid ( 0 .657 g , 65 % ). ' H NMR (400 MHz, CDC1z ): 8 8. 54 ( t, J= 3 .7 Hz, 1H ), 8 .31 ( d , J= 7 .5 Hz , 1H ), 8 . 04 ( dd , J = 1 . 8 Hz, 9 . 6 Hz, 2H ), 7 .59 ( d , J = 8 . 2 Hz, 1H ) , 7 .54 -7 .49 ( m , 4H ), 7 .37 (t , J = 7. 8 Hz, 1H ) . LRMS (ESI ) F 30 calcd . for C14H , BrN _ S : 316 .97 . Found : 317 .00 . HO , C 1p ; 1p Step 3 : 4 - Fluoro -3 ' - ( 5 -phenyl - 1, 2, 4 - thiadiazol- 3 - yl ) 35 biphenyl -3 -carboxylic Acid Step 1 : 3 -Bromo - 5 -phenyl - 1 , 2 , 4 - thiadiazole

zo : HO2C toNS To a mixture of 3 - bromo- 5 - chloro - 1 , 2 , 4 - thiadiazole ( 2 g , 3 - (3 - Bromophenyl) - 5 -phenyl -1 , 2 ,4 - thiadiazole (0 .075 g , 10 mmol) , cesium fluoride ( 3 g , 20 mmol ), and phenylbo - 0 . 24 mmol) , 5 - borono - 2 -fluorobenzoic acid ( 0 . 064 g , 0 . 35 ronic acid (1 . 46 g , 12 mmol) in 1, 4 -dioxane w / 10 % H , 0 " mmol) , Pd (dppf )2Cl2 (0 . 018 g , 0 .024 mmol) and 2M ( 100 mL ) was added PdC1, {PtBu , ( p -NMe . -C .H2 )} (0 .354 , Na2CO3 (0 . 48 mL ) were dissolved in DME . The reaction 0 .5 mmol) . The resulting mixture was 80° C . for 16 h under mixture was then processed according to the general proce nitrogen atmosphere . Volatile materials were removed under dure described in Example 1 , step 3 , to afford the desired vacuum . The crude residue was portioned between water product as a white solid (0 .059 g , 66 % ). ' H NMR (400 MHz, and ethyl acetate . The organic phase was separated and the DMSOdo ): 8 8 .51 ( s , 1H ) , 8 . 30 ( d , J = 6 . 9 Hz, 2H ), 8 . 22 - 7 . 96 aqueous phase was extracted further with ethyl acetate . The ( m , 2H2H ) , 71 . 8686 (( d , J = 7. 8 Hz , 1H ), 7 .68 - 7 .55 ( m , 5H ). 7 .42 (t , combined organic extracts were dried over anhydrous J = 7 . 3 Hz, 1H ) . HRMS ( ESI) calcd . for C2, H 3FN20 , 5 Na2SO4 , filtered , and concentrated . Purification by flash [M + H ] ": 377. 0753 . Found : 377. 0770 . column chromatography on silica gel using hexanes: ethyl The following compounds were synthesized according to acetate gave the desired product as a colorless solid ( 2 . 03 g , the procedure described for 4 - fluoro - 3' -( 5 - phenyl- 1 ,2 ,4 84 % ) . ' H NMR (400 MHz, CDC13 ) : 8 7 . 96 (d , J = 7 .3 Hz, sthiadiazol- 3 -yl ) biphenyl - 3 -carboxylic acid (Example 38 ) 2H ), 7 .56 - 7 .62 ( m , 1H ) , 7 . 50 - 7 .56 ( m , 2H ) . LRMS ( ESI) using appropriate starting materials . Yields refer to the final calcd . for CzH BrN _ S : 240 .93 . Found : 240 .00 . coupling reaction . US 9 , 969 , 726 B2 119 120 Example 39 : 3 ' - ( 5 - Phenyl- 1 , 2 , 4 - thiadiazol- 3 - yl) Example 42 : 4 - Fluoro - 3 ' - ( 5 - (furan - 3 - yl) - 1 , 2 , 4 -thia biphenyl- 3 - carboxylic Acid diazol- 3 -yl ) biphenyl - 3 -carboxylic Acid

F 10 ?? , ? HOC

White solid (0 .023 g , 26 % ). H NMR ( 400 MHz, 15 DMSOdo) : 88 .75 (t , J = 0 .9 Hz , 1H ), 8 .47 (s , 1H ) , 8 .26 ( d , White solid (0 .054 g, 63 % ). ' H NMR (400 MHz, J= 7 .8 Hz, 1H ), 8 .02 -8 .00 ( m , 1H ), 7 .95 (t , J= 1 .8 Hz , 1H ), DMSOd . ) : 8 8 .53 ( s , 1H ) , 8 . 30 ( d , J = 7 . 8 Hz, 1H ) , 8 .23 ( s , 7 .86 - 7 .82 (m , 2H ), 7 .66 ( t, J = 7 .8 Hz , 1H ), 7 .36 ( t, J = 8 . 2 Hz , 1H ) , 8 . 10 ( d , J = 6 . 9 Hz , 2H ) , 7 . 98 ( t , J = 8 . 2 Hz , 2H ) , 7 . 86 ( d , 1H ) , 7 . 14 ( d , J = 1 . 8 Hz, 1H ) . LRMS (ESI ) calcd . for J= 7 .8 Hz , 1H ), 7 .68 -7 .57 (m , 5H ). HRMS (ESI ) calcd . for 20 C19H1 FN2O3S [ M + H ]* : 367. 05 . Found : 376 .00 . C21H 4FN202S [ M + H ]* : 359 . 0849 . Found : 359. 0856 . Example 43 : 5 -Fluoro - 3' - ( 5 -( furan - 3 -yl ) - 1, 2 ,4 - thia Example 40 : 5 - Fluoro -3 ' -( 5 -phenyl - 1, 2 ,4 - thiadiazol diazol- 3 -yl ) biphenyl - 3 -carboxylic Acid 3 - yl) biphenyl- 3 - carboxylic Acid 25

HO2C HO2C 35 DeoaWhite solid (0 .019 g , 21 % ). 'H NMR (400 MHz, DMSOdo) : 8 8 .77 ( s, 1H ), 8. 54 ( s, 1H ), 8 .33 ( d , J = 7 .8 Hz , 1H ) , 8 . 10 ( s, 1H ) , 7 . 97 (t , J= 1. 4 Hz, 1H ), 7 . 7 - 7 . 92 (m , 2H ), White solid (0 .032 g , 36 % ) . 'H NMR (400 MHz 7 .70 ( t, J = 7 .8 Hz, 2H ), 7 . 16 (d , J= 1. 8 Hz , 1H ). HRMS (ESI ) DMSOd . ) : 8 8 . 59 ( d , J = 1 . 4 Hz, 1H ) , 8 . 34 (dd , J = 0 . 9 Hz, 8 . 2 40 calcd . for C19H11FN203S [ M + H ] * : 367 .0547 . Found : Hz, 1H ) , 8 . 15 - 8 .09 ( m , 3H ), 7 . 92 ( t, J = 7 . 8 Hz, 2H ) , 7 . 72 - 367. 0552 . 7. 59 ( m , 5H ). HRMS (ESI ) calcd . for C21H 3FN202S [M + H ] *: 377. 755 . Found : 377 .0760 . General Synthetic Scheme for the Preparation of 3 ' - ( 5 -Phenylisothiazol - 3 - yl) - [ 1 , 1' -biphenyl ] - 3 -car Example 41: 6 -Fluoro - 3 '- ( 5 - phenyl- 1 , 2 , 4 -thiadiazol 45 boxylic Acid 3 - yl) biphenyl - 3 - carboxylic Acid

50 Scheme 4

Br CN 55 HO2CSaxo 60 White solid (0 .025 g , 28 % ). ' H NMR (400 MHz, NH2 DMSOd . ) : 8 8 .45 ( s , 1H ) , 8 . 19 ( s , 1H ) , 8 .35 ( d , J = 7 . 3 Hz , BI 1H ) , 8 . 11 - 8 . 09 ( m , 3H ) , 8 .02 - 7 .99 ( m , 1H ) , 7 .75 ( d , J = 7 . 8 ii Hz, 1H ), 7 .70 ( t, J = 7 . 8 Hz, 1H ) , 7 .64 - 7 .60 ( m , 2H ) , 7 .50 - 65 7 .40 (m , 1H ). LRMS (ESI ) calcd . for C21H 3FN202S [ M + H ] * : 377 .0755 . Found : 377 . 0759 . US 9 , 969, 726 B2 121 122 - continued added NaHCO3 ( 0 .084 g , 1 mmol) and the resulting mixture was stirred at room temperature for 15 h . Chloranil (0 .142 g, 0 .58 mmol) was added to the mixture and the stirring was continued for another 12 h . The reaction mixture was diluted Br 5 with ether and filtered and the filtrate was washed with saturated NaHCO3 solution . Evaporation off the organic layer under reduced pressure afforded the crude product (HO )2B CO2H , ili which was purified by column chromatography using hexa nes : ethyl acetate to obtain the desired product as a yellow 10 solid ( 0 . 180 g , 57 % ) . ' H NMR ( 400 MHz, CDC1z ): 8 8 . 14 ( t, J = 1 . 8 Hz, 1H ) , 7 . 90 ( dd , J = 1 . 4 Hz , 9 . 2 Hz , 1H ) , 7 .70 ( s , 1H ) , 7 .65 (dd , J = 1 . 4 Hz , 9 . 2 Hz, 2H ) , 7 .54 - 7 .52 ( m , 1H ) , 7 .48 - 7 .42 ( m , 3H ) , 7 . 34 ( t, J = 7 . 8 Hz, 1H ) . LRMS (ESI ) 15 calcd . for C15H BrNS [M + H ]* : 317. 22 . Found : 317 .00 . Step 3 : 3 '- ( 5 -Phenylisothiazol - 3 -yl ) -[ 1 , 1' - biphenyl ] Oy 3 - carboxylic Acid

COH 20 i) Cul, 2 , 2 '- bipyridine , NaO 'Bu , DMF, 80° C ., 12 h ii ) P4S10, NaHCO3, THF, rt, 15 h Chloranil, 12 h iii ) Pd( PPhz ) 4 , 2M Na2CO3, DME, reflux , 1 - 2 h dil•HCI

25 i Example 44 : 3' - ( 5 - Phenylisothiazol - 3 -yl ) - [ 1, 1' - bi 25 phenyl] - 3 -carboxylic Acid CO2H na maneno 30 obra 3 - ( 3 - Bromophenyl) - 5 - phenylisothiazole ( 0 . 180 g , 0 . 57 mmol) and 3 - boronobenzene boronic acid ( 0 . 141 g , 0 . 86 mmol) , tetrakistriphenylphosphinepalladium ( 0 ) ( 0 .065 g , 0 .057 mmol) and 2M Na ,coz ( 1 . 14 mL ) were dissolved in 33 DME. The reaction mixture was then processed according to the general procedure described in Example 1 , step 3 , to paso afford the desired product as a colorless solid ( 0 . 035 g , CO2H 17 % ) . ' H NMR ( 400 MHz, DMSO ) : 8 8 .53 ( s , 1H ) , 8 . 36 ( s , 1H ) , 8 . 24 ( s , 1H ) , 8 . 11 ( d , J = 7 . 8 Hz , 1H ) , 8 . 01 ( d , J = 7 . 8 40 Hz, 1H ) , 7 . 95 ( d , J = 7 . 8 Hz, 1H ), 7 . 82 (dd , J = 1 . 4 Hz, 8 . 2 Hz, Steps 1 and 2 : 2H ) , 7 . 76 ( d , J = 7 . 8 Hz, 1H ) , 7 .63 - 7 .59 ( m , 2H ) , 7 .52 - 7 . 45 3 - ( 3 - Bromophenyl) - 5 - phenylisothiazole ( m , 3H ) . HRMS ( ESI ) calcd . for C22H15NO , S [ M + H ] * : 358 .0896 . Found : 358 .0904 . 45 Example 45 : 4 -Fluoro - 3' - (5 -phenylthiophen - 3 - yl ) [ 1, 1' - biphenyl ] - 3 -carboxylic Acid

50 Scheme 5

i , ii, iii A mixture of acetophenone ( 0 .7 mL , 6 mmol) , 3 -bro - Br - mobenzonitrile (0 .91 g , 5 mmol) , Cu ( I) I ( 0 .095 g , 0 . 05 55 mmol) , 2 , 2 'bipyridine ( 0 . 0 .086 g , 0 .055 mmol) and NaO ‘Bu ( 0 . 96 g , 10 mmol ) in DMF ( 10 mL ) was heated at 80° C . for 24 h . After completion of the reaction , the solvent was evaporated , and the residue was extracted with ethyl acetate (3x25 mL ). The combined extracts were washed with water, 60 brine and dried over anhydrous Na2SO4. After evaporation of the solvent, the residue was purified by column chroma Quo HOC tography to give 0 . 302 g (20 % ) of the 3 - amino - 3 - ( 3 - bro i ) PhB (OH ) 2 , Pd ( PPh3) 4 , 2M Na2CO3, toluene :water , 100° C . , 4 h mophenyl) - 1- phenylprop - 2 -en - 1 -one as a reddish brown ii ) 3 - bromo -phenylboronicacid , Pd( PPh3) 4 , 2M Na2CO3, DME, reflux, 1 - 2 h solid . LRMS (ESI ) calcd . for C15H12BrNO [M + H ] *: 300 . 13 . 65 iii) 3 - borono -benzenecarboxylic acid, Pd (PPH3 ) 4 , 2M Na2CO3, DME , reflux , 12 h Found : 300 .00 . To a mixture of enaminone ( 0 . 302 g , 1 mmol) and P4S10 ( 0 . 134 g , 0 . 3 mmol ) in THF ( 10 mL ) was US 9 ,969 , 726 B2 123 124 A mixture of 2 , 4 -dibromo thiophene ( 0 . 500 g , 2 .07 - continued mmol) , benzene boronic acid ( 0 .253 g , 2 .07 mmol) , Na Coz ( 0 .438 g , 4 . 13 mmol ), and tetrakis (triphenylphosphine ) pal ladium ( 0 .012 g , 0 .01 ) in an oxygen free toluene/ water ( 1 : 1 ) solution was stirred at 100° C . for 4 h under nitrogen . The 5 reaction mixture was cooled to room temperature . The aqueous layer was extracted with ethyl acetate . The com bined organic layer was washed with brine , dried over Na2SO4, filtered , and concentrated to dryness . The product CO2H was purified by column chromatography using hexanes / 10 i ) Pd ( PPh3 ) 4 , 2M Na2CO3, DME, reflux ethyl acetate to afford 4 - bromo- 2 - phenylthiophene as a pale yellow solid ( 0 . 200 g , 42 % ) , LRMS (ESI ) calcd . for C10H , BrS [M + H ] * : 238 . 94 . Found : 239 . 00 . 4 - Bromo- 2 Example 46 : phenylthiophene (0 .200 g, 0 .84 mmol) and 3 -bromophenyl - 15 3 '- ( 5 - phenylfuran - 3 -yl ) biphenyl- 3 - carboxylic Acid boronic acid ( 0 .200 g , 1 mmol) and tetrakistriphenylphos phinepalladium (0 ) ( 0 .097 g , 0 .084 mmol) were dissolved in Step 1 : 4 - ( 3 -Bromophenyl ) - 2 -phenylfuran DME . The reaction mixture was then processed according to the general procedure described in Example 1 , step 2 , to afford 4 - ( 3 -bromophenyl ) - 2 - phenylthiophene as a colorless 20 solid ( 0 . 187 g , 65 % ) . LRMS (ESI ) calcd . for C16H / BrS [ M + H ] * : 314 . 98 . Found : 315 . 00 . 4 -( 3 -Bromophenyl ) - 2 -phe nylthiophene ( 0 . 157 g , 0 . 5 mmol) and 3 -borono - 4 - fluo robenzoic acid ( 0 . 143 g , 0 .75 mmol) tetrakistriphenylphos phinepalladium ( 0 ) ( 0 . 058 g , 0 .05 mmol) and 2M Na , C0z ( 1 25 mL ) were dissolved in DME . The reaction mixture was then processed according to the general procedure described in Example 1 , step 3 , to afford the title compound as a yellow To a solution of acetophenone ( 1. 03 g , 11 mmol) in solid ( 0 .080 g , 43 % ) . H NMR ( 400 MHz, DMSO ) : toluene ( 5 mL ) was added LiHMDS (7 . 1 mL , 1 . 5 M in THF ) 88 . 19 - 8 . 15 ( m , 2H ) , 8 . 09 - 8 .04 (m , 3H ), 7 . 85 ( d , J = 7 . 8 Hz, s at 0° C . The resulting mixture was stirred at the same 1H ), 7 . 80 ( d , J = 8 . 2 Hz, 2H ) , 7 .60 ( d , J = 7 . 8 Hz, 1H ) , temperature for 30 min . To this a solution of 3 ' -bromo 7 .57 -7 .55 ( m , 1H ), 7 .46 - 7 .33 ( m , 4H ). HRMS (ESI ) calcd . phenacylbromide ( 2 .77 g , 10 mml) in THF (10 mL ) was for C23H sFO2S [ M + H ] * : 375 . 0850 . Found : 375. 0892 . added and the resulting solution was stirred at room tem 25 perature for 12 h . The reaction mixture was diluted with water and extracted with ethyl acetate . The organic layer General Synthetic Scheme for the Preparation of washed with brine and dried over anhydrous sodium sulfate . 3 '- ( 5 - phenylfuran - 3 -yl ) biphenyl- 3 - carboxylic Acid Removal of solvent under reduced pressure afforded the crude product which was purified by column chromatogra 40 phy using hexanes : ethyl acetate solvent system to obtain the desired product as a yellow solid ( 2 g , 67 % ). ' H NMR (400 Scheme 6 MHz, CDC1z ) : 87. 74 ( d , J = 0 . 9 Hz, 1H ) , 7 .71 - 7 .66 ( m , 3H ) , 7 .45 - 7 . 39 ( m , 4H ), 7 .31 - 7 .23 (m , 2H ), 6 .92 ( d , J= 0 .9 Hz , 1H ) . LRMS ( ESI) calcd . for C16H _ BrO [ M + H ] * : 300 . 16 . Br 45 Found : 300 .00 . Step 2 : 3 '- ( 5 -Phenylfuran - 3 -yl ) biphenyl - 3 -carboxylic Acid

LiHMDS , Toluene : THF it, 12 h

omBr ooCO2H 60 4 - (3 -Bromophenyl )- 2- phenylfuran ( 0 . 100 g , 0 . 33 mmol ) (HO )2B CO2H , i and 3 - boronobenzene boronic acid ( 0 .082 g , 0 .49 mmol, tetrakistriphenylphosphinepalladium ( 0 ) ( 0 .038 g , 0 .033 mmol) and 2M Na2CO3 ( 0 .66 mL ) were dissolved in DME . 65 The reaction mixture was then processed according to the general procedure described in Example 1 , step 3 , to afford the title compound as a yellow solid (0 . 053 g , 47 % ). ' H US 9 , 969 , 726 B2 125 126 NMR ( 400 MHz, DMSO ) : 8 8 .41 ( s , 1H ) , 8 . 27 ( t, J = 1 . 4 Step 1 : 4 - ( 3 -Bromophenyl ) - 2 - phenyloxazole Hz , 1H ) , 8 .02 - 7 . 98 ( m , 3H ) , 7 .79 ( d , J = 7 . 3 Hz , 2H ) , 7 .72 ( d , J = 7 .8 Hz, 1H ) , 7 .66 -7 .60 (m , 3H ), 7 .59 (t , J= 7. 3 Hz, 1H ), 7 .46 ( t, J = 7 .8 Hz , 2H ), 7 .33 (t , J= 7 .3 Hz , 1H ). LRMS ( ESI) calcd . for C23H 603[ M + H ]* : 341. 37 . Found : 341. 00 . Bra General Synthetic Scheme for the Preparation of 3 '- ( 2 -phenyloxazol - 4 - yl) - [1 , 1' - biphenyl ] - 3 - carbox ylic Acid 10 To a solution of 3 -bromo -acetophenone ( 1 . 99 g , 10 mmol) in ACN ( 100 mL ) was added HDINB ( 5 . 56 g , 12 mmol) and stirred for 2 h with reflux . After cooling to room tempera ture, 3 -bromo -benzamide (3 .63 g , 30 mmol) was added in Scheme 7 one portion and the reaction mixture was refluxed for 15 additional 12 h . Solvent was removed under vacuum and the crude reaction mixture was diluted with dichloromethane and water. The organic layer washed with sodium bicarbon Br HDINB , ACN , reflux ate , water and dried over anhydrous sodium sulfate . After 1 - 2 h evaporation of the solvent, the residue was purified by column chromatography using hexanes: ethyl acetate to afford 4 - ( 3 -bromophenyl ) - 2 - phenyloxazole as a pale yellow NH2 solid ( 2 . 2 g , 73 % ). ' H NMR (400 MHz, CDC13 ) : Y 8 . 12 8 .09 ( m , 2H ) , 7 . 99 (t , J = 1 . 4 Hz, 1H ) , 7 . 95 ( s , 1H ) , 7 .72 ( d , J = 7 . 8 Hz , 1H ) , 7 .48 - 7 . 43 ( m , 4H ) , 7 .29 ( t, J = 7 . 8 Hz, 1H ) . LRMS (ESI ) calcd . for C15H /0BrON [M + H ] *: 301. 15 . 25 Found : 301. 13 . (HO )2B CO2H Step 2 : 3 '- ( 2 - Phenyloxazol- 4 -yl ) - [ 1, 1' - biphenyl ] - 3 carboxylic Acid Br 30

Bonn35 HO2C 4 -( 3 -Bromophenyl ) -2 -phenyloxazole ( 0 . 150 g , 0 .5 mmol) and 3 -boronobenzene boronic acid ( 0 . 124 g , 0 .75 mmol) , 40 tetrakistriphenylphosphinepalladium ( 0 ) ( 0 . 058 g , 0 . 05 poHO2C mmol ) and 2M Na2CO3 ( 1 mL ) were dissolved in DME . The reaction mixture was then processed according to the gen eral procedure described in Example 1 , step 3 , to afford the title compound as a white solid ( 0 . 065 g , 38 % ) . ' H NMR

NO O OH 45 (400 MHz, DMSOdo ) : 88 . 84 ( s , 1H ) , 8 . 21 ( s , 1H ) , 8 . 13 ( s , = 1H ), 8 .05 - 8 . 03 ( m , 2H ) , 7 .95 - 7 . 93 ( m , 2H ) , 7 . 88 (d , J = 7 . 8

= Hz, 1H ) , 7 .64 - 7 .52 ( m , 6H ) . HRMS ( ESI) calcd . for HDINBHDINB == IYOphO C22H 5NO3 [M + H ] *: 342. 1125 . Found : 342. 1131 . ON General Synthetic Scheme for the Preparation of i) Pd ( PPh3) 4 , 2M Na2CO3, DME, reflux, 1 - 2 h 50 3' - ( 5 -phenyl - 1 ,2 , 4 -oxadiazol - 3 -yl ) - [ 1 ,1 '- biphenyl ] -3 carboxylic Acid

Example 47 : 3 ' - ( 2 - Phenyloxazol- 4 - yl) - [ 1 , 1 '- biphe 55 nyl ] - 3 - carboxylic Acid Scheme 8 NOH 50 % N Br ACOH (cat ) NH2 100° C ., 30 min Verde+ - COH CICO2Et, EtzN , rt OET HO , C ugopii US 9 ,969 , 726 B2 127 128 -continued Step 2 : 3 '- ( 5 - Phenyl- 1 , 2 , 4 - oxadiazol- 3 - yl) - [ 1 , 1 ' (HO )2B0 CO2H biphenyl] - 3 - carboxylic Acid

Br the 5

HO2C

posn?HOC 15 3 - ( 3 -Bromophenyl ) - 5 - phenyl- 1 , 2 , 4 - oxadiazole ( 0 .283 g , i ) Pd( PPhz ) 4 , 2M Na2CO3, DME, reflux 0 .93 mmol) and 3 -boronobenzoic acid (0 .230 g , 1. 4 mmol) , tetrakistriphenylphosphinepalladium (0 ) (0 .107 g, 0. 05 mmol) and 2M Na2CO3 ( 1 . 86 mL) were dissolved in DME . Example 48 : 3 '- ( 5 -Phenyl - 1 ,2 , 4 -oxadiazol - 3 -yl ) - [ 1 , 20 The reaction mixture was then processed according to the 1 '- biphenyl] - 3 - carboxylic Acid general procedure described in Example 1 , step 3 , to afford som the title compound as a white solid (0 .053 g , 17 % ). 'H NMR (400 MHz, DMSOdo) : 88 .29 ( s , 1H ) , 8 .21 - 8 . 17 ( m , 3H ) , 25 8 . 09 ( d , J = 7 . 8 Hz, 1H ) , 7 .99 - 7 .97 ( m , 2H ) , 7 . 93 ( d , J = 7 . 8 Hz , 1H ), 7 .72 -7 .76 (m , 5H ). LRMS (ESI ) calcd . for C2 H24N203 [ M + H ] * : 343 . 35 . Found : 343. 00 .

30 General Synthetic Scheme for the Preparation of HOC 3' - ( 5 -phenylisoxazol - 3 -yl ) - [ 1, 1 '- biphenyl ] - 3 -carbox ylic Acid Step 1 : 3 -( 3 -Bromophenyl ) - 5 -phenyl - 1 ,2 ,4 -oxadiazole 35 Scheme 9

40 Bri Br polos Dyso 45 Br To a mixture of benzoic acid (0 .610 g , 5 mmol) and Et3N ( 1. 4 mL , 10 mmol) in dichloromethane at 0° C ., was added methyl chloroformate ( 0 . 46 mL , 6 mmol) drop wise . The 50 resulting mixture as gradually warmed to room temperature and stirred for additional 30 min . To this , 3 - bromo- N ' hydroxybenzimide ( 1 .05 g , 5 mmol) was added and stirred NHOH at 35 - 40° C . for 12 h . The reaction mixture was cooled to room temperature and washed with saturated sodium bicar Br bonate solution (20 mL ). The organic layer was washed with brine , dried over Na S04 followed by removal of the solvent under vacuum to afford the crude product. The crude product was purified by silica gel column chromatography using 60 hexane : ethyl acetate solvent system to give the title com pound as a white solid ( 1 . 4 g , 93 % ) . ' H NMR (400 MHz , CDC13 ) : 8 8 . 33 ( s , 1H ) , 8 . 19 ( d , J = 8 . 2 Hz , 2H ) , 8 . 10 ( dd , Br J = 1 . 4 Hz, 7 . 8 Hz , 1H ) , 7 . 63 - 7 . 50 ( m , 4H ) , 7 . 35 ( t, J = 8 . 2 Hz , 65 iv 1H ) . LRMS (ESI ) calcd . for C14H , BrN2O [ M + H ] * : 302 . 14 . Found : 302 .00 . US 9, 969, 726 B2 129 130 - continued 3 -( 3 - Bromophenyl) - 5 - phenylisoxazole ( 0 . 300 g , 1 mmol) ' 3 -boronobenzoic acid (0 .247 g, 1. 5 mmol) , tetrakistriph enylphosphinepalladium ( 0) ( 0 .115 g, 0. 1 mmol) and 2M 5 Na2CO3 (2 mL) were dissolved in DME . The reaction mixture was then processed according to the general proce dure described in Example 1 , step 3 , to afford the title HO2C compound as a yellow solid ( 0 . 247 g , 72 % ). ' H NMR (400 i) Cat PdCl2 (PPh3 ) 2 , Cat. Cul, Et3N , rt, 12 h MHz, DMSOD ): 88 . 25 ( s , 1H ) , 8 . 18 ( s , 1H ), 7 . 98 - 7 .88 ( m , ii ) NH2OH · HC1, Py , MeOH , rt iii ) Au?13 ( 1 mol % ), DCM , reflux , 30 min 5H ), 7. 81 (d , J = 7. 8 Hz, 1H ), 7 .72 (s , 1H ), 7 .66 - 7 .58 (m , 2H ), iv ) Pd( PPh3 ) 4, 2M Na2CO3, DME, reflux 7 . 56 - 7 . 47 ( m , 3H ) . LRMS ( ESI ) calcd . for C22H15NO3 [ M + H ]* : 342 . 11. Found : 342 .00 . HRMS (ESI ) calcd . for 15 C22H , 5N03 [ M + H ] * : 342 .1125 . Found : 342 .1156 . Example 49: 3' - ( 5 -Phenylisoxazol - 3 -yl ) -[ 1 ,1 '- biphe nyl] - 3 - carboxylic Acid General Synthetic Scheme for the Preparation of 3 '- ( 1, 5 -diphenyl - 1H - 1, 2 ,4 - triazol- 3 - yl) - [ 1 ,1 ' - biphe 20 nyl ] - 3 -carboxylic Acid

Scheme 10 25 Br - CN HOC AcCl, EtOH

?? Step 1 : 3 - ( 3 -Bromophenyl ) - 5 - phenylisoxazole 30 TEA . ArCOCI DCM , 30 - 40° C , 6 h ”

N Ph ArNHNH HCl TEA , DCM , OEt 30 -40° C ., 4 h 40 To a solution of 1- (3 -bromophenyl ) - 3 -phenylprop - 2- yn 1 - one oxime ( 0 . 966 g , 3. 22 mmol) in dichloromethane was added AuClz (0 .01 g ) . Themixture was then heated at reflux under an atmosphere of N2 for 30 min . The solvent was 45 Br evaporated and the crude residue was purified by column Ar + chromatography using hexanes: ethyl acetate to obtain 3 -( 3 bromophenyl ) - 5 - phenylisoxazole as a pale yellow solid AN ( 0 . 958 g , 99 % ). ' H NMR (400 MHz, CDC1z ) : 8 8 .01 (s , 1H ), 7 .81 - 7 .80 ( m , 3H ), 7 .57 (d , J = 8 . 2 Hz , 1H ) , 7 .56 - 7 .47 ( m , 30 3H ) , 7 .33 ( t, J = 7 . 8 Hz, 1H ) , 6 .79 ( s , 1H ) . LRMS (ESI ) calcd . HO2C for C15H? BrNO [ M + H ] * : 301. 15. Found : 301. 13 . B (OH ) 2 1) Pd (PPh3 ) 4 , 2M Na2CO3 DME , 80° C ., 30 min Step 2 : 3' - (5 -Phenylisoxazol - 3 - yl )- [ 1, 1' - biphenyl ] -3 2 ) dil•HCI carboxylic Acid 5555

A 0800HO2C :65 porHO2C US 9 , 969 , 726 B2 131 132 Example 49A : 3 ' - ( 1 , 5 - Diphenyl- 1H - 1 , 2 , 4 - triazol- 3 Step 4 : 3 ' - ( 1 , 5 - Diphenyl - 1H - 1 , 2 , 4 - triazol- 3 - yl) - [ 1 , yl) - [ 1 , 1' - biphenyl ] - 3 - carboxylic Acid 1 '- biphenyl ] - 3 -carboxylic Acid

10 — Ph HO2C HO2C Ph onPh : 15 3 - ( 3 -Bromophenyl ) - 1 , 5 - diphenyl- 1H - 1 , 2 , 4 - triazole (0 . 188 g , 0 . 5 mmol) and 3 - boronobenzene boronic acid Steps 1- 3 : ( 0 . 124 g , 0 .75 mmol) , tetrakistriphenylphosphinepalladium ( 0 ) (0 .058 g, 0 .05 mmol) and 2M Na2CO3 ( 1 mL ) were 3 - ( 3 -Bromophenyl ) - 1 , 5 - diphenyl- 1H - 1 , 2 , 4 - triazole dissolved in DME. The reaction mixture was then processed 20 according to the general procedure described in Example 1, step 3 , to afford the title compound as an off -white solid ( 0 . 121 g , 58 % . ' H NMR ( 400 MHz , DMSOda ) : 88 . 35 ( s . 1H ) , 8 .22 ( s , 1H ), 8 . 13 ( d , J = 7 . 8 Hz) , 7 . 97 ( t, J = 8 . 2 Hz, 2H ) , 7 .79 ( d , J = 7 .8 Hz , 1H ), 7 .60 (q , J= 7 .8 Hz, 2H ), 7 .51 - 7 .39 ( m , Br 5 10H ). HRMS (ESI ) calcd . for C27H19N302 [ M + H ] * : 2 418 . 1550 . Found : 418 . 1598 . Ph Example 50 : 3' - ( 1- Methyl - 5 - phenyl -1H -1 ,2 ,4 - tri N N azol- 3 - yl) - [ 1 , 1 '- biphenyl] - 3 - carboxylic Acid

Ph 30 Acetyl chloride ( 16 mL , 160 mmol) was added to a solution of 3 -bromo - benzonitrile ( 3 .64 g , 20 mmol) in ethanol ( 14 mL , 240 mmol) . The resulting mixture was stirred at room temperature for 16 h . Volatile materials were removed under vacuum to give ethyl 3 -bromobenzimidate ph hydrochloride as a white solid ( 3 . 5 g , 78 % ). ' H NMR (400 HOC MHz, CDC13 ) : 8 12. 06 (brs , 1H ) , 8 .53 ( d , J = 7 . 8 Hz, 1H ) , 8 . 33 ( s , 1H ) , 7 .79 ( d , J = 8 . 2 Hz, 1H ) , 7 . 45 ( t, J = 7 . 8 Hz, 1H ), 10 4 . 91 (t , q , J = 6 . 9 Hz, 2H ), 1 .61 ( t, J = 6 . 9 Hz , 3H ) . LRMS 3 - ( 3 - bromophenyl ) - 1 -methyl - 5 -phenyl - 1H - 1 , 2 , 4 -triazole (ESI ) calcd . for C , H , BrNO [ M + H ]* : 227 . 99 . Found : ( 0 . 157 g , 0 . 5 mmol) and 3 -boronobenzene boronic acid 228 . 00 . Benzoyl chloride ( 0 . 76 mL , 6 .58 mmol) was added ( 0 . 124 g , 0 .75 mmol) , tetrakistriphenylphosphinepalladium in dropwise to a solution of 3 - bromobenzimidate hydrochlo ( 0 ) ( 0 .058 g , 0 .05 mmol) and 2M Na2CO3 ( 1 mL ) were ride (1 .5 g , 6 .58 mmol) and EtZN (0 . 91 mL , 6 .58 mmol) in 45 dissolved in DME . The reaction mixture was then processed dichloromethane (50 mL ). The resulting mixture was stirred according to the general procedure described in Example 1 , at 30 -40° C . for 6 h . After cooling to room temperature , the step 3 , to afford the title compound as an off -white solid reaction mixture was poured into saturated sodium bicar - (0 .040 g , 23 % ). ' H NMR (400 MHz, DMSOdo ): 8 8 . 28 ( s , bonate solution . The organic layer was washed with water, 1H ) , 8 . 20 ( s , 1H ) , 8 . 08 - 8 . 02 ( m , 2H ) , 7 .94 ( t , J = 7 . 3 Hz, 2H ) , brine and dried over Na2SO4 to obtain ethyl ( Z ) - N -ben - 50507 , . 84 (dd , J = 4 . 2 Hz, 7 . 3 Hz, 2H ) , 7 . 75 ( d , J = 8 . 2 Hz, 1H ) , zoyl- 3 - bromobenzimidate as a colorless solid ( 2 . 2 g , quan 7 .60 - 7 .55 ( m , 4H ) . 4 . 01 ( s , 3H ) . HRMS ( ESI) calcd . for titative yield ) which was used for next step without further C22H N302 [M + H ]* : 356 .1394 . Found : 356 . 1432 . purification . LRMS (ESI ) calcd . for C16H 4BrNO2[ M + H ]* : Example 51: 3 ' - (1 , 5 - Diphenyl- 1H - 1 , 2 , 4 - triazol - 3 332 .02 . Found : 332 . 00 . Ethyl ( Z ) N -benzoyl - 3 -bromoben yl) -4 - fluoro - [ 1 , 1 '- biphenyl ] - 3 -carboxylic acid zimidate ( 2 . 2 g , 6 . 58 mmol) , phenyl hydrazine hydrochlo ride ( 1 . 9 g , 13. 16 mmol) , Et3N ( 1 . 8 mL , 13. 16 mmol) were taken in dichloromethane ( 50 mL ) and heated at 30 - 40° C . for 4 h . Cooled to room temperature and diluted with water and followed by a usual work up with dichloromethane . Evaporation of the solvent followed by silica gel column 60 chromatography using hexanes: ethyl acetate afforded 3 - ( 3 N bromophenyl) - 1 , 5 - diphenyl- 1H - 1 , 2 ,4 - triazole as a white - Ph solid ( 1 . 8 g , 73 % ) . ' H NMR (400 MHz, CDC13 ) : 88 .40 ( t, HOC J = 1 . 8 Hz , 1H ), 8 . 14 ( dd , J = 1 . 3 Hz , 8 . 2 Hz, 1H ) , 7 . 54 - 7 .52 65 Ph ( m , 3H ) , 7 .43 -7 .41 (m , 9H ). LRMS (ESI ) calcd . for C2H4BrNz [ M + H ] * : 376 .25 . Found : 376 .00 . US 9 ,969 , 726 B2 133 134 3 - ( 3 - Bromophenyl) - 1 , 5 - diphenyl- 1H - 1 , 2 , 4 - triazole Example 54 : 3 '- ( 1 -Benzyl - 5 - phenyl- 1H - 1 , 2 , 4 -tri (0 .100 g , 0 .27 mmol ) and 5 -borono - 2 - fluorobenzoic acid azol- 3 - yl ) - [ 1 , 1 '- biphenyl] - 3 - carboxylic Acid ( 0 .073 g , 0 .398 mmol) , tetrakistriphenylphosphinepalladium ( 0 ) ( 0 .031 g , 0 . 027 mmol) and 2M Na2CO3 ( 0 . 54 mL ) were dissolved in DME. The reaction mixture was then processed 5 according to the general procedure described in Example 1 , step 3 , to afford the title compound as an off -white solid ( 0 . 070 g , 59 % ), ' H NMR (400 MHz , DMSOdo ): 8 8 . 31 (s , 1H ), 8 . 12 - 8 . 08 (m , 2H ), 7 .99 - 7 .94 ( m , 2H ), 7. 76 (d , = 7. 3 Hz , 1H ), 7 .62 ( t, J = 7 . 8 Hz, 1H ) , 7 .51 - 7 . 36 ( m , 10H ). HRMS 10 Ph (ESI ) calcd . for C24H 3N202 [ M + H ] * : 436 . 1456 . Found : HOC 436 . 1464. Ph Example 52 : 3 '- ( 1 , 5 - Diphenyl - 1H - 1 , 2 , 4 - triazol - 3 yl) - 5 - fluorobiphenyl- 3 -carboxylic Acid 15 1 - Benzyl- 3 - ( 3 - bromophenyl) -5 - phenyl- 1H - 1 , 2 , 4 - triazole ( 0 . 100 g , 0 . 26 mmol) and 3 -boronobenzene boronic acid ( 0 . 066 g , 0 .40 mmol) , tetrakistriphenylphosphinepalladium (0 ) ( 0 .030 g , 0 .026 mmol) and 2M Na ,C0z (0 . 54 mL ) were 20 dissolved in DME. The reaction mixture was then processed according to the general procedure described in Example 1 , step 3 , to afford the title compound as an off -white solid — Ph ( 0 .025 g , 22 % ). ' H NMR (400 MHz, DMSOdo) : 88 . 29 (s , HO2C 25 1H ), 8. 19 ( s, 1H ) , 8 . 06 (d , J = 7. 8 Hz , 1H ), 7. 94 - 7 . 90 ( m , 2H ), 7 .76 ( d , J= 7 .8 Hz, 1H ), 7 .72 - 7 .68 (m , 2H ) , 7 .58 -7 .52 (m , Ph 5H ) , 7 .31 - 7 . 23 ( m , 3H ) , 7 . 12 ( d , J = 6 . 9 Hz , 2H ) , 5 .58 ( s , 2H ) . HRMS (ESI ) calcd . for C28H21FN202 [ M + H ] * : 432 . 1707 . 3 -( 3 - Bromophenyl) -1 , 5 -diphenyl - 1H - 1 ,2 , 4 -triazole Found : 432 . 1731 . ( 0 . 100 g , 0 . 27 mmol) and 3 -borono - 5 - fluorobenzoic acid 30 ( 0 . 073 g , 0 . 4 mmol) , tetrakistriphenylphosphinepalladium ( 0 ) ( 0 . 031 g , 0 . 027 mmol) and 2M Na2CO3 ( 0 .54 mL ) were Example 55 : 3 '- ( 1 - ( 4 -Methoxyphenyl ) - 5 - phenyl - 1H dissolved in DME. The reaction mixture was then processed 1 , 2 ,4 -triazol - 3 - yl) - [ 1 , 1' -biphenyl ]- 3 -carboxylic Acid according to the general procedure described in Example 1 , step 3 , to afford the title compound as a brown solid ( 0 .059 35 g , 50 % . H NMR (400 MHz , DMSOdo ) : 88 . 36 ( s , 1H ) , 8 . 15 ( d , = 7 . 3 Hz, 1H ) , 8 .05 ( s , 1H ) , 7 . 88 - 7 . 82 ( m , 2H ) , 7 .65 ( q , J = 7 .8 Hz , 2H ) , 7. 51 - 7 .40 (m , 10H ). HRMS (ESI ) calcd . for C2H , N202 [ M + H ] * : 436 . 1456 . Found : 436 . 1471 . 40 Example 53 : 3 '- ( 1- Phenyl- 5 - (thiophen -2 -yl ) - 1H -1 ,2 , Ph 4 - triazol- 3 -yl ) - [ 1, 1 ' - biphenyl ] - 3 - carboxylic Acid HO2C

OMe

50 ?? , ? 3 - ( 3 - Bromophenyl) - 1 - ( 4 -methoxyphenyl ) - 5 - phenyl- 1H 1, 2 , 4 -triazole (0 .105 g , 0 .26 mmol) and 3 -boronobenzene boronic acid (0 . 066 g , 0 .40 mmol ), tetrakistriphenylphos 3 -( 3 - Bromophenyl) -1 -phenyl - 5 -( thiophen -2 - yl) - 1H - 1. 2 . 55 phinepalladium (0 ) (0 .030 g , 0 .026 mmol) and 2M Na, CO ,3 4 - triazole (0 . 100 g , 0 . 26 mmol) and 3 -boronobenzene ( 0 .54 mL ) were dissolved in DME . The reaction mixture was boronic acid (0 . 066 g, 0 .40 mmol) , tetrakistriphenylphos then processed according to the general procedure described phinepalladium (0 ) ( 0 .031 g, 0 .027 mmol) and 2M Na2CO3Nazl0z in ExampleExample 1 , step 3 , to afford the title compound as an ( 0 . 54 mL ) were dissolved in DME . The reaction mixture was then processed according to the general procedure described 60 °off -white solid ( 0 .089 g , 76 % ). ' H NMR (400 MHz, in Example 1 , step 3 , to afford the title compound as an DMSOdo ) : 88 .34 ( s , 1H ) , 8 . 21 ( s , 1H ) , 8 . 12 ( d J = 7 . 8 Hz, off -white solid (0 .045 g , 41 % ). 'H NMR (400 MHz, 1H ), 7 .93 (t , J = 9 .6 Hz , 2H ), 7 .78 (d , J= 8 .2 Hz, 1H ), DMSOda ) : 0 8 . 31 ( s , 1H ), 8 .21 ( s , 1H ) , 8 .09 ( d , J = 7 . 8 Hz, 7 .63 - 7 .60 ( m , 2H ) . 7 . 53 ( d . J = 7 . 8 Hz 2H ). 7 . 50 - 7 . 40 ( m . 1H ) , 7 . 96 - 7 . 95 ( m , 1H ) , 7 . 87 ( d , J = 7 . 8 Hz , 1H ) , 7 .72 ( d , J = 4 . 1 Hz , 1H ), 7 .63 - 7 .58 (m , 8H ), 7. 04 (t , J= 4 . 1 Hz , 1H ), 6555 5Hh ), 7 .04 ( d , J= 8 .7 Hz, 2H ), 3 .79 (s , 3H ) . HRMS (ESI ) 6 . 99 (d , J = 2. 8 Hz, 1H ). HRMS (ESI ) calcd . for calcd . for C28H22N302 [ M + H ] * : 448 . 1656 . Found : C25H , ZFN202S [M + H ]* : 424 . 1114 . Found : 424 . 1131. 448 . 1667. US 9 ,969 , 726 B2 135 136 Example 56 : 3 '- ( 1 - ( 3 - Fluorophenyl) - 5 - phenyl- 1H - 1 , Example 58 : 3 '- ( 1 - Phenyl- 5 - ( 6 - (trifluoromethyl ) 2 , 4 - triazol- 3 - yl) - [ 1, 1 '- biphenyl] - 3 - carboxylic Acid pyridin - 3 -yl ) - 1H - 1 , 2 , 4 - triazol- 3 -yl ) - [ 1 , 1 ' - biphenyl] 3 - carboxylic Acid

Ph 10 HOC - CF3 HO2C 2 Ph 15 5 - ( 3 -( 3 -Bromophenyl ) - 1 -phenyl - 1H -1 , 2 ,4 - triazol- 5 -yl ) 3 - ( 3 -Bromophenyl ) - 1 - ( 3 - fluorophenyl) - 5 - phenyl- 1H - 1 , 2 , 2 -( trifluoromethyl) pyridine ( 0 .120 g, 0. 30 mmol) and 3 -bo 4 - triazole (0 . 102 g , 0 . 26 mmol) and 3 - boronobenzene 20 ronobenzene boronic acid ( 0 .076 g , 0 .45 mmol) tetrakistri boronic acid (0 . 066 g , 0 .40 mmol ), tetrakistriphenylphosInhos - phenylphosphinepalladiumphe (0 ) (0 . 035 g , 0 . 03 mmol) and 2M phinepalladium (0 ) ( 0 .030 g , 0 .026 mmol) and 2M Na2CO3 Na2CO3 ( 0 . 8 mL ) were dissolved in DME. The reaction ( 0 .54 mL ) were dissolved in DME . The reaction mixture was mixture was then processed according to the general proce then processed according to the general procedure described 25 dure described in Example 1 , step 3 , to afford the title in Example 1 , step 3 , to afford the title compound as a yellow compound as an off -white solid ( 0 .087 g , 60 % ) . ' H NMR solid (0 .076 g , 67 % ) , ' H NMR ( 400 MHz , DMSOD ) : 8 8 . 40 (400 MHz, DMSOdo ): 88 .85 (d , J = 1 .8 Hz , 1H ), 8. 37 (t , ( t, J = 1 . 8 Hz, 1H ), 8 .26 ( t, J = 1 . 4 Hz, 1H ), 8 . 17 ( d , J = 7 . 8 Hz , J = 1 . 8 Hz, 1H ), 8 . 21 ( t, J = 1 . 8 Hz, 1H ) , 8 . 16 - 8 . 14 ( m , 2H ) , 1H ), 8 .02 - 7. 98 ( m , 2H ), 7 .84 (d , J= 8 .2 Hz, 1H ), 7 .66 (q , 30 7 . 99 - 7 . 96 ( m , 3H ) , 7 . 82 ( d , J = 8 . 2 Hz, 1H ) , 7 .64 - 7 . 54 ( m , J = 7 .8 Hz , 2H ), 7 .60 - 7 .46 ( m , 9H ). HRMS (ESI ) calcd . for 7H ). HRMS (ESI ) calcd . for C27H , 7F3N402[ M + H ] *: C24H 3N302 [ M + H ] * : 436 . 1456 . Found : 436 . 1473 . 487 . 1376 . Found : 487 .1403 . Example 57 : 3 ' - ( 1 - (Naphthalen - 1 -yl ) - 5 -phenyl - 1H - 35 1 , 2 ,4 -triazol - 3 - yl) - [ 1 , 1' -biphenyl ]- 3 - carboxylic Acid Example 59 : 3 '- ( 5 - ( Furan - 3 - yl) - 1 - phenyl- 1H - 1, 2 , 4 triazol- 3 - yl )- [ 1 , 1' - biphenyl ] - 3 -carboxylic acid

• Ph # ?? , ? HO2C Ph

50 3 -( 3 -Bromophenyl ) - 1 - ( naphthalen - 1 - yl )- 5 -phenyl - 1H - 1 , 3 - ( 3 -Bromophenyl ) -5 - ( furan - 3 -yl ) - 1 - phenyl- 1H - 1 , 2 ,4 2 ,4 - triazole (0 .130 g, 0 .3 mmol ) and 3 -boronobenzene triazole ( 0 . 146 g , 0 .40 mmol) and 3 - boronobenzene boronic boronic acid ( 0 .076 g , 0 .45 mmol) tetrakistriphenylphos- 55 acid (0 .1 g , 0 .6 mmol) , tetrakistriphenylphosphinepalladium phinepalladium (0 ) ( 0 .035 g, 0 .03 mmol) and 2M Na2CO3 ( 0 ) (0 .046 g, 0. 04 mmol ) and 2M Na2CO3 (0 .8 mL ) were ( 0 .6 mL ) were dissolved in DME . The reaction mixture was dissolved in DME . The reaction mixture was then processed then processed according to the general procedure described according to the general procedure described in Example 1 , in Example 1 , step 3 , to afford the title compound as a yellow on step 3 , to afford the title compound as an off- white solid solid ( 0 .043 g . 31 % ). 1H NMR ( 400 MHZ . DMSO ) : 88 . 39 (0 .073 g, 45 % )' H NMR (400 MHZ, DMSOdo) : 88 .32 ( s, ( s , 1H ) , 8 . 21 ( s , 1H ), 8 . 19 (t , J = 8 . 2 Hz, 1H ) , 8 .09 ( d , J = 7 . 8 1H ) , 8 .20 ( s , 1H ), 8 . 09 ( d , J = 7 . 8 Hz, 1H ) , 7 .95 ( t, J = 6 . 9 Hz, Hz , 1H ), 7. 97 -7 .93 (m , 2H ), 7 .81 (d , J = 8 .2 Hz , 1H ) , 7. 76 2H ), 7. 83 (s , 1H ), 7 .78 ( d, J = 7 .8 Hz, 1H ), 7. 74 (t , J = 3. 2 Hz, (dd , J = 1 .0 Hz, 7 . 3 Hz, 1H ), 7 .63 - 7 .53 (m , 6H ), 7 .44 -7 .27 (m , a 1H ) , 7 .63 - 7 .60 ( m , 7H ), 6 .38 (d , J= 1 .4 Hz , 1H ). HRMS 6H ). HRMS (ESI ) calcd . for C3, H2, N202 [M + H ] *: (ESI ) calcd . for C25H , ,N203 [M + H ]* : 408 . 1343. Found : 468 . 1707 . Found : 468 . 1710 . 408 . 1355 . US 9 ,969 , 726 B2 137 138 Example 60 : 3' - ( 1 ,5 - Diphenyl- 1H - 1, 2 , 4 - triazol- 3 3 - ( 3 -Bromophenyl )- 1 , 5 - diphenyl- 1H - 1 , 2 , 4 - triazole yl) - [ 1, 1' - biphenyl ] -4 -carboxylic Acid (0 . 100 g , 0 .27 mmol) and 2 -boronofuran - 3 -carboxylic acid ( 0 . 061 g , 0 .40 mmol) , tetrakistriphenylphosphinepalladium ( 0 ) ( 0 .031 g , 0 . 027 mmol) and 2M Na2CO3 ( 0 . 54 mL ) were 5 dissolved in DME . The reaction mixture was then processed according to the general procedure described in Example 1 , step 3 , to afford the title compound as an off- white solid ( 0 .035 g , 32 % ), ' H NMR (400 MHz, DMSOdo) : 88 .65 (s , HOC 1H ), 8 . 13 (d , J = 7 . 8 Hz , 1H ), 8. 06 (d , J = 8 .2 Hz, 1H ), 7 .83 ( d , - Ph 10 J = 1 .8 Hz , 1H ), 7 .59 (t , J = 7 .8 Hz , 1H ), 7 .50 -7 .40 ( m , 10H ), 6 .85 ( d , J = 1 . 8 Hz , 1H ) . HRMS ( ESI) calcd . for C25H 2N203 Ph [ M + H ] * : 408. 1343 . Found : 408. 1357. 3 -( 3 -Bromophenyl ) -1 ,5 -diphenyl - 1H - 1 ,2 ,4 -triazole 15 Example 63 : 3 - ( 1 , 5 - Diphenyl - 1H - 1 , 2 , 4 - triazol - 3 ( 0 . 100 g , 0 .27 mmol) and 4 - boronobenzene boronic acid yl) -6 - fluoro - [ 1 , 1 ' -biphenyl ] - 3 - carboxylic acid ( 0 . 1 g , 0 .40 mmol) , tetrakistriphenylphosphinepalladium ( 0 ) ( 0 . 031 g , 0 . 027 mmol) and 2M Na2CO3 ( 0 . 54 mL ) were dissolved in DME . The reaction mixture was then processed according to the general procedure described in Example 1 , 20 step 3 , to afford the title compound as a yellow solid ( 0 .058 g , 52 % ). 'H NMR (400 MHz, DMSOdo) : 8 8. 23 ( s, 1H ), 8 . 18 ( s , 1H ) , 8 .02 ( d , J = 8 . 2 Hz, 2H ) , 7 .92 ( d , J = 8 . 7 Hz, 1H ) , 7 . 86 ( d , J = 8 . 2 Hz, 2H ) , 7 .45 ( d , J = 8 . 2 Hz, 1H ) , 7 .45 - 7 .0 ( m , 10H ). HRMS (ESI ) calcd . for C27H /9N302 [M + H ] *: 25 Ph 418 . 1550 . Found : 418 . 163 . HO2C Example 61 : 3 '- ( 1 , 5 -Diphenyl - 1H - 1 , 2 , 4 - triazol- 3 yl) - [ 1 , 1' - biphenyl ] - 2 - carboxylic Acid 3 - (3 -Bromophenyl ) - 1, 5 -diphenyl - 1H - 1, 2 , 4- triazole (0 .100 g , 0 .27 mmol) and 3 -borono -4 - fluorobenzoic acid (0 .072 g , 0 .40 mmol) , tetrakistriphenylphosphinepalladium ( 0 ) ( 0 .031 g , 0 . 027 mmol) and 2M Na2CO3 ( 0 . 54 mL ) were dissolved in DME . The reaction mixture was then processed 35 according to the general procedure described in Example 1, step 3 , to afford the title compound as an off -white solid Ph COH ( 0 . 025 g , 22 % ) . ' H NMR ( 400 MHz , DMSOdo ) : 8 . 25 ( d , J = 1 . 4 Hz, 1H ) , 8 . 16 - 8 . 14 ( m , 1H ) , 8 . 08 (dd , J = 2 .3 Hz, 7 . 8 Hz , 1H ) , 8 . 02 - 7 .97 ( m , 1H ) , 7 .67 - 7 .62 ( m , 2H ) , 7 .50 - 7 .41 Ph 40 (m , 11H ). HRMS ( ESI) calcd . for C22H13N302 [ M + H ]* : 436 . 1456 . Found : 436 . 1463 . 3 -( 3 - Bromophenyl) -1 , 5 -diphenyl - 1H - 1 ,2 , 4 -triazole ( 0 . 100 g , 0 . 27 mmol) and 2 -boronobenzene boronic acid Example 64 : 3 ' - ( 1 - Isopropyl- 5 -phenyl - 1H - 1 , 2 , 4 ( 0 . 1 g , 0 .40 mmol) , tetrakistriphenylphosphinepalladium ( 0 ) triazol- 3 -yl ) - [ 1, 1' - biphenyl ] -3 -carboxylic acid ( 0 . 031 g , 0 .027 mmol) and 2M Na2CO3 ( 0 . 54 mL ) were dissolved in DME . The reaction mixture was then processed according to the general procedure described in Example 1, step 3 , to afford the title compound as an off -white solid ( 0 . 025 g , 22 % ) , ' H NMR (400 MHz, DMSOd . ) : 88 . 09 ( d , J = 9 . 2 Hz, 1H ) , 8 . 06 ( s , 1H ) , 7 .77 ( d , J = 7 . 3 Hz, 1H ) , 7 . 52 - 7 . 42 ( m , 15H ) . HRMS (ESI ) calcd . for C22H , N20 , 50 [ M + H ] * : 418 . 1550 . Found : 418 . 1583 . Ph Example 62 : 2 - ( 3 - ( 1 , 5 - Diphenyl - 1H - 1 , 2 ,4 -triazol - 3 ?? , ? yl) phenyl) furan - 3 - carboxylic Acid 55

HO2C 3 -( 3 -Bromophenyl ) - 1- isopropyl- 5 -phenyl - 1H - 1, 2 ,4 - triaz ole ( 0 .092 g , 0 . 27 mmol) and 3 -boronobenzene boronic acid 60 ( 0 .066 g , 0 . 40 mmol) , tetrakistriphenylphosphinepalladium (0 ) ( 0 . 031 g , 0 . 027 mmol) and 2M Na2CO3 ( 0 .54 mL ) were dissolved in DME . The reaction mixture was then processed Ph according to the general procedure described in Example 1 , step 3 , to afford the title compound as an off -white solid Ph 65 ( 0 .07 g , 67 % ) . ' H NMR (400 MHz, DMSOd . ) : 8 8 .27 ( s , 1H ) , 8 . 19 ( s , 1H ) , 8 .06 ( d , J = 7 . 8 Hz, 1H ) , 7 . 95 ( dd , J = 1 . 4 Hz, 7 .8 Hz, 2H ), 7 .75 ( d , J = 7 . 8 Hz, 1H ) , 7 .69 - 7 . 67 ( m , 2H ) , US 9 , 969, 726 B2 139 140 7 .62 - 7 .55 ( m , 5H ) , 4 .68 - 4 .65 ( m , 1H ) , 1 .46 ( d , J = 6 . 9 Hz, 6 ). Example 67 : 3 ' - (1 , 2 - Diphenyl- 1H - imidazol- 4 -yl ) - [ 1 , HRMS ( ESI) calcd . for C24H2, N202 [ M + H ] * : 384 .1707 . 1' - biphenyl ] - 3 - carboxylic Acid Foundharun : 384 . 1754 . e some . Example 65 : 3 '- ( 5 -Phenyl - 1H -1 , 2 ,4 - triazol -3 -yl ) - [ 1, 1 '- biphenyl] - 3 - carboxylic Acid Scheme 11

Br 10 PhNH) , PhCHO NHOA2, 130° C ., 2 h (HO )2B . - CO2H Ph 15 BI HOC

3 -( 3 -Bromophenyl ) -5 -phenyl - 1- tosyl- 1H - 1 ,2 , 4 -triazole 20 (0 .122 g , 0 .27 mmol) and 3- boronobenzene boronic acid (0 .066 g, 0. 40 mmol) , tetrakistriphenylphosphinepalladium ( 0 ) ( 0 .031 g , 0 . 027 mmol) and 2M Na2CO3 (0 . 54 mL ) were dissolved in DME . The reaction mixture was then processed according to the general procedure described in Example 1 , step 3 , to afford the title compound as a yellow solid (0 .03 g , 31 % ). ' H NMR (400 MHz, DMSOD ): 8 8. 39 ( s, 1H ), CO2H 8 .29 ( s , 1H ), 8 . 14 -8 . 10 ( m , 3H ) , 8 .02 (t , J= 7 . 3 Hz , 2H ), 7. 75 30 ( d , J= 8 .2 Hz, 1H ) , 7 .67 (t , J= 7. 8 Hz, 1H ), 7. 75 - 7 . 46 (m , 5H ). HRMS (ESI ) calcd . for C2 H 5N202 [ M + H ] " : 342 . 1237 . i ) Pd (PPh34 , 2M Na2CO3, DME, reflux Found : 342. 1247 . 35 Example 66 : 3 '- ( 1 , 3 - Diphenyl- 1H - 1 , 2 , 4 - triazol- 5 Step 1: yl) - [ 1 , 1' - biphenyl ] - 3 -carboxylic Acid 4 - ( 3 - Bromophenyl) - 1 , 2 - diphenyl- 1H - imidazole

45 Br ?

Ph 50 - CO2H 50

5- ( 3- bromophenyl )- 1 , 3 - diphenyl- 1H -1 ,2 , 4- triazole and so A mixture of benzaldehyde ( 1. 06 g , 10 mmol) , aniline ( 0 . 100 g , 0 . 27 mmol) and 3 -boronobenzene boronic acid 55 (0 . 95 mL, 10 mmol) , 3 -bromo - phenacyl bromide ( 2 . 77 g , 10 ( 0 . 066 g , 0 . 40 mmol) , tetrakistriphenylphosphinepalladium mmol) and ammonium acetate ( 1 .54 g , 20 mmol) were ( 0 ) (0 .031 g , 0 .027 mmol) and 2M Na2CO3 ( 0 .54 mL ) were heated at 130° C . for 2 h . The reaction mixture was cooled dissolved in DME. The reaction mixture was then processed to room temperature . The product precipitated by the addi according to the general procedure described in Example 1, tion of 1 :1 acetone: water was collected by filtration and step 3 , to afford the title compound as an off -white solid dried to afford the desired compound as a yellow solid ( 2 .7 ( 0 . 046 g , 41 % ). ' H NMR ( 400 MHz, DMSOdo) : 88 . 12 ( dd , g , 72 % ). ' H NMR ( 400 MHz , CDC1z ) : 88 . 06 ( t, J = 1 . 8 Hz, J = 1. 4 Hz, 8 .2 Hz , 1H ), 7 .95 (s , 1H ), 7 .90 (d , J= 7. 8 Hz, 1H ), 1H ), 7. 80 (d , J = 9. 1 Hz, 1H ) , 7 .44 (s , 1H ), 7 .42 -7 .39 (m , 6H ), 7. 78 - 7. 71 ( m , 3H ), 7. 75 - 7. 49 (m , 11H ) . HRMS (ESI ) calcd . 7 .28 - 7 .24 ( m , 6H ). LRMS (ESI ) calcd . for C2H 3BrN , for C22H19N302 [M +H ] * : 418 . 1550 . Found: 418 . 1561. [ M + H ] * : 375 . 26 . Found : 375 . 00 . US 9 , 969 , 726 B2 141 142 Step 2: 3' -( 1, 2 -Diphenyl - 1H -imidazol - 4 -yl ) - [ 1 , 1' Example 68 : 3' - ( 5 -Phenyl - 1H - pyrazol- 3 -yl ) - [ 1 , 1 ' biphenyl] -3 -carboxylic Acid biphenyl ]- 3 - carboxylic Acid

NH OhoooCO2H COH Steps 1 - 2 : Prepared from 4 -( 3 -bromophenyl ) - 1 ,2 -diphenyl - 1H - imi 3 -( 3 - Bromophenyl) -5 -phenyl - 1H -pyrazole dazole ( 0 .097 g , 0 . 26 mmol) and 3 -boronobenzene boronic acid ( 0 .064 g , 0 .39 mmol) , tetrakistriphenylphosphinepalla dium ( 0 ) (0 .030 g , 0 .026 mmol ) and 2M Na2CO3 (0 .52 mL ) 20 were dissolved in DME . The reaction mixture was then processed according to the general procedure described in Example 1 , step 3 , to afford the title compound as a yellow solid ( 0 .046 g , 24 % ) . ' H NMR ( 400 MHz, DMSO ) : 88 . 28 ( s , 1H ) , 8 .24 ( s , 1H ) , 8 . 21 ( s , 1H ) , 7 . 97 ( q , J = 7 . 3 Hz, 3H ) , 25 7 .64 - 7 .31 ( m , 13H ) . HRMS (ESI ) calcd . for C28H20N202 M + H ] + : 417 . 1598 . Found : 417 . 1650 . NH General Synthetic Scheme for the Preparation of 3 - Bromobenzaldehyde ( 1. 85 g , 10 mmol) was added 3 '- ( 5 - Phenyl- 1H -pyrazol - 3 -yl ) - [ 1 , 1 ' -biphenyl ] - 3 30 slowly to a solution of tosyl hydrazine ( 2 g , 11 mmol) in carboxylic Acid MeOH ( 10 mL ) at 40° C . The resulting mixture was stirred at the same temperature for 2 h , then cooled to room temperature and diluted with water. The precipitated tosyl hydrazide was collected by filtration , washed with water and Scheme 12 35 dried under vacuum ( colorless solid , 2 .8 g ) . ' H NMR (400 MHz, CDC13 ) : 8 8 .72 ( s , 1H ) , 7 .87 ( d , J = 8 . 2 Hz , 2H ) , 7 .71 ( s , 1H ) , 7 .67 ( s , 1H ), 745 - 7 . 43 ( m , 2H ), 7 . 29 ( d , J = 8 . 2 Hz , 2H ) , 7 . 16 (t , J = 7 . 8 Hz, 1H ) , 2 .34 ( s , 3H ) . LRMS ( ESI) calcd . ? TSNHNH2 for C14H13BrN202S [ M + H ] * : 352. 98 . Found : 353 .00 . To a MeOH , 40° C . , 2 h 40 solution of hydrazide ( 0 . 706 g , 2 mmol) in toluene ( 3 mL ) at room temperature was added NaOEt ( 0 . 68 g , 12 mmol) . Br NHTS NaOEt, toluene , The resulting mixture was stirred at room temperature for 15 rt , 15 min min . Phenyl acetylene ( 1 .22 g , 12 mmol) was injected to the Phenylacetylene , reaction mixture and heated at 90° C . for 12 h . Upon cooling 90° C ., 12 h 45 and trituration with hexanes afforded 3 - ( 3 -bromophenyl ) - 5 phenyl - 1H -pyrazole as a colorless solid ( 0 .450 g , 75 % ) . ' H NMR (CDC12 ) : 87. 86 ( s , 1H ) , 7 .65 - 7 .63 ( m , 3H ) , 7 . 40 - 7 . 33 ( m , 4H ) , 7 .25 ( s , 1H ) , 7 .22 ( t , J = 7 . 8 Hz, 1H ) , 6 .78 ( s ( 1H ) . Br LRMS (ESI ) calcd . for C15H ¡ BrN2 [M + H ] * : 300 . 17 . 50 Found : 300 .00 . NH Step 3 : 3 ' - ( 5 - Phenyl- 1H -pyrazol - 3 -yl ) - [ 1 , 1 ' - biphe (HO )2B . - CO2H , i nyl ]- 3 -carboxylic Acid

?? NH COH CO2H i) Pd( PPh3) 4 , 2M posoNa2CO3, DME, reflux . cho 65 Prepared from 3 - ( 3 -bromophenyl ) - 5 - phenyl- 1H -pyrazole ( 0 . 150 g , 0 .5 mmol) and 3 -boronobenzene boronic acid US 9 ,969 , 726 B2 143 144 ( 0 . 124g, 0 . 75 mmol ), tetrakistriphenylphosphinepalladium Example 69 : 3 -( 4 -( Trifluoromethyl) - 6 - 6 -( trifluo ( 0 ) (0 .058 g , 0 .05 mmol) and 2M Na2CO ( 1 mL ) were romethyl) pyridin - 3 - yl) pyrimidin - 2 - y1) biphenyl- 3 dissolved in DME. The reaction mixture was then processed carboxylic Acid according to the general procedure described in Example 1 , step 3 , to afford the title compound as a yellow solid (0 .042 g , 25 % ). " H NMR (400 MHz, DMSOd , ): 68 .30 (s , 1H ), 8. 19 CF3 CO2H ( s, 1H ), 8 . 10 (t , J - 8 . 2 Hz , 2H ), 7. 90 - 7. 87 ( m , 3H ), 7. 69 - 7. 63 ( m , 2H ), 7 .58 (t , J = 7. 8 Hz, 1H ) , 7. 47 (t , J= 7 .3 Hz, 2H ), 7 .36 - 7 .34 ( m , 2H ). HRMS (ESI ) calcd . for C2HNO . 10 [ M + H ] +: 341. 1285 . Found: 341 .1324 . General Synthetic Scheme for the Preparation of 3 -( 4 -( Trifluoromethyl) - 6 - 6 - (trifluoromethyl ) pyri FCF ( din - 3 - yl )pyrimidin - 2 - y1) biphenyl Derivatives (Method 1 ) ? ????? Scheme 13

CO2H OMe 1 ) CDI, DCM , rt , 2h MeMgI 2 ) MeNHOMe•HCi, 12h THF, 0°C. . 5°C . , 2h FC F3C CNF , ?? CF3C02Et ??????? ???| NaH , Ether , | 0°C. - rt , 2h

CF3

NH 0 Urea , Cl POCI3 , DMF MeOH : HCl CF3 110°C. , 16h reflux, 40h CNF , F3C CNF , ?? CE??E ?????

B (OH )2 i , 1h * ?? cl F3C ??? ? F3C (

i, 6 - 12h (HO )2B Fac - X = CO2H , S0jNHz, NHCOR , CN , CONH2 Y = H , Cl , F , OMe, NO i ) Pd ( PPha )4 , 2M Na2CO3, DME , 80°C . ????? US 9 , 969, 726 B2 145 146 Step 1 : To a stirred solution of 1 - ( 6 - ( trifluoromethyl ) pyridin - 3 N -Methoxy - N -methyl - 6 - ( trifluoromethyl) nicotinamide yl) ethan - 1 -one ( 7 . 5 g , 39 .68 mmol) in diethyl ether (500 ( Intermediate B ) mL ) , was added NaH ( 1 . 19 g , 49 . 60 mmol) while the temperature was kept between 0 -5° C . After stirring at that 5 temperature for 30 min , ethyl trifluoroacetate ( 5 . 89 mL , 49 .60 mmol) was added to the reaction mixture . The reaction mixture was poured into ice water and acidified with 2N OME HC1. The organic layer was separated and aqueous layer extracted with ethyl acetate (3x20 mL ). The combined 10 organic layer was washed with water and brine . The organic F3C N phase was dried using Na, SO , and evaporated to give 4 , 4 ,4 - trifluoro - 1 - ( 6 - ( trifluoromethyl ) pyridin - 3 - yl) butane - 1 , 3 - dione as a pale yellow liquid ( as enol form , 9 . 3 g , 82 % ) . CDI ( 12 . 7 g , 78 . 5 mmol ) was added to a solution of ' H NMR ( 400 MHz , CDC13 ): 89 .62 ( s , 1H ) , 8 . 45 (d , J = 8 . 6 6 - ( trifluoromethyl) nicotinic acid ( 15 g , 78 . 5 mmol) in 15 Hz. 11 ) . 7 . 89 ( d . J = 73 Hz. 11 ) . 6 .61 ( s . 11 ) . CH , C1, ( 1 L ) . The resulting mixture was stirred for 2 h . N , O - Dimethylhydroxylamine hydrocloride (11 .54 g , 117 . 7 Step 4 : 6 - ( Trifluoromethyl) - 4 - ( 6 - ( trifluoromethyl) mmol) was added to this mixture in one portion . After stirring for 12 h at room temperature , the reaction mixture pyridin - 3 - yl) pyrimidin - 2 ( 1H ) - one ( Intermediate E ) was quenched by the addition of 0 . 1N NaOH solution . The dichloromethane layer was washed with water and brine. The organic phase was dried using Na SO , and evaporated to give N -methoxy - N -methyl - 6 - (trifluoromethyl ) nicotina CF3 mide as a viscous liquid ( 12 g , 66 % ) . LRMS (ESI ) calcd . for INHNH CH ,F3N202 [ M + H ] *: 235 . 18 , 449. 98 . Found : 235 . 00 . The 3 5 crude product was used for the next step without further purification . N o Step 2 : 1 -( 6 -( Trifluoromethyl) pyridin - 3 -yl ) ethan - 1 FzCN one ( Intermediate C ) 30 To a stirred solution of 4 , 4 , 4 - trifluoro - 1 - (6 - (trifluorom ethyl) pyridin - 3 -yl ) butane - 1 , 3 -dione ( 9 . 3 g , 32 mmol) and urea ( 3 .92 g , 60 . 06 mmol) in MeOH (500 mL ) was added cone. HC1 ( 50 mL ) . The reaction mixture was heated under reflux conditions for 40 h . The mixture was cooled and water was added . The mixture was stirred at 0° C . for 1 h . The precipitated 6 - trifluoromethyl) - 4 - (4 - ( trifluoromethyl) phe F3C N nyl ) pyrimidin - 2 ( 1H ) - one was collected by filtration , washed with water and dried to afford a brown solid ( 6 . 3 g , 64 % ) . N -Methoxy - N -methyl -6 -( trifluoromethyl) nicotinamide 40to LRMS (ESI ) calcd . for CzH ; F6N2O [ M + H ] * : 310 .17 . ( 12 g , 51 mmol) in dry THF (500 mL ) was cooled to 0° C . Found : 310 .00 . and kept for 10 min . To this cooled solution methylmagne sium iodide ( 18 . 8 mL, 3M solution in THF ) was added and Step 5 : 2 - Chloro - 4 - ( trifluoromethyl) -6 - ( 6 - ( trifluo stirred at the same temperature for 2 h . The reaction mixture romethyl) pyridin - 3 -yl ) pyrimidine ( Intermediate F ) was then quenched with the addition of saturated NH _ C1 45 solution and extracted with EtOAC ( 3x100 mL ) . The com bined organic layer was washed with brine . The organic phase was dried using Na S04 and evaporated to give 1 - ( 6 - ( trifluoromethyl) pyridin - 3 - yl) ethan - 1 - one as a pale yels low solid ( 9 .61 g , 99 % ). ' H NMR ( 400 MHz, CDC13 ) : 89 . 23 ( s , 1H ) , 8 . 40 ( d , J = 8 . 6 Hz, 1H ), 7 .79 ( d , J = 7 . 3 Hz, 1H ) , 2 . 68 ( s, 3H ). The crude product was used for the next step without further purification . Step 3 : 4 , 4 , 4 - Trifluoro - 1 - (6 - ( trifluoromethyl ) pyri 55 F3C N din - 3 - yl) butane - 1 , 3 -dione ( Intermediate D ) To a stirred solution of 6 - ( trifluoromethyl ) - 4 - ( 4 - ( trifluo romethyl) phenyl )pyrimidin - 2 (1H )- one (6 . 3 g, 20 mmol) in 60 phosphoroxychloride (20 mL ) was added DMF (5 - 10 drops ) and the reaction mixture was stirred at 110° C . for 16 h . The reaction mixture was cooled and excess solvent was CF3 removed under reduced pressure . Ice -water was added and the water layer was extracted three times with diethyl ether. F C 65 The combined organic layer washed with water and brine . The organic layer was dried over Na SO , and evaporated to give 2 -chloro -4 -( trifluoromethyl ) - 6 -( 6 -( trifluoromethyl) US 9 ,969 , 726 B2 147 148 pyridin - 3 - yl ) pyrimidine as a pale yellow solid (5 . 98 g , evaporated in vacuum to obtain the crude product. The crude 89 % ) . LRMS (ESI ) calcd . for CliH34C1F . N3[ M + H ] * : product was purified using automated prep -HPLC to yield 328 .61 . Found : 328 . 00 . the desired compound as a white solid (0 .082 g, 56 % ) . ' H NMR ( 400 MHz, DMSOdo ): 89. 65 ( s , 1H ), 8 . 96 ( d , J = 7 .8 Step 6 : 2 - ( 3 -Bromophenyl ) - 4 - ( trifluoromethyl) - 6 - 6 - 5 Hz , 1H ) , 8 .61 ( s , 2H ), 8 . 42 ( d , J= 7 . 3 Hz, 1H ), 8 . 16 (s , 1H ) , ( trifluoromethyl) pyridin -3 -yl ) pyrimidine 8 .03 ( d , J = 7 . 8 Hz, 1H ) , 8 .01 ( d , J = 7 . 3 Hz, 1H ) , 7 . 92 ( d , J = 7 . 8 Hz, 1H ) , 7 . 88 ( d , J = 7 . 3 Hz, 1H ) , 7 .60 - 7 . 57 ( m , 2H ). LRMS (ESI ) calcd . for C24H13FGN202[ M + H ] *: 490. 09 . Found : 489. 95 . 10 Example 70 : 4 -Chloro - 3' - ( 4 - ( trifluoromethyl) -6 -( 6 ( trifluoromethyl) pyridin - 3 - yl )pyrimidin -2 - yl )biphe Br nyl- 3 -carboxylic Acid

F C N CF3 CO2H A mixture of 2 -chloro - 4 -( trifluoromethyl) -6 - (6 - (trifluo - , romethyl) pyridin -3 -yl ) pyrimidine (3 .27 g , 10 mmol) , 3 -bro mophenylboronic acid ( 3 . 0 g , 15 mmol) and tetrakistriph enylphosphine palladium (0 ) ( 1 . 15 g , 1 mmol ) were dissolved in 40 mL of DME . To this mixture was added 2M Na2CO3 (20 mL , 40 mmol) solution and the resulting 26 F3C solution was heated at reflux in an atmosphere of N , for 1 h . The reaction mixture cooled to room temperature and the solvent was removed under vacuum and the residue was 2 -( 3 -Bromophenyl ) -4 -( trifluoromethyl) - 6 -( 6 -( trifluorom dissolved dichloromethane and washed with water and the ethyl) pyridin - 3 -yl ) pyrimidine (0 .086 g , 0 .2 mmol) , 5 -bo organic layer was dried over anhydrous Na S04. The sol- a rono - 2 - chlorobenzoic acid ( 0 . 060 g , 0 .3 mmol) , tetrakistri vent was evaporated in vacuum to obtain the crude product phenylphosphinepalladium ( 0 ) (0 .023 , 0 .02 mmol) , 2M as a yellow solid . Column chromatography using 4 : 1 Na2CO3 ( 0 . 4 mL , 0 . 8 mmol ) were dissolved in DME . The Hexanes /ethyl acetate solvent system afforded 2 - ( 3 -bro reaction mixture was then processed according to the gen mophenyl) - 4 - ( trifluoromethyl ) - 6 - ( 6 - ( trifluoromethyl) pyri eral procedure described in Example 69, step 7 , to afford the din - 3 - yl ) pyrimidine as a white solid ( 3 . 2 g . 74 % ). IH NMR desired compound as a white solid ( 0 . 056 g , 54 % ) . ' H NMR ( 400 MHz, CDC1z ) : 89 .50 (s , 1H ) , 8 . 72 - 8 . 70 ( m , 2H ) , 8 . 53 35 (400 MHz, DMSOdo) : 89 .77 ( s , 1H ) , 9 . 08 ( d , J = 8 . 2 Hz , 1H ) , ( d , J = 7. 8 Hz, 1H ), 7 . 96 ( s , 1H ) , 7 . 90 ( d , J = 8 . 2 Hz, 1H ), 7 .67 8 .73 ( s , 1H ) , 8 .72 ( s , 1H ) , 8 .54 ( d , J = 7 . 8 Hz, 1H ) , 8 . 14 ( d , ( d , J = 7 . 8 Hz, 1H ) , 7 . 40 ( t , J = 7 .8 Hz, 1H ). LRMS (ESI ) calcd . J = 8 . 2 Hz, 1H ) , 8 .06 ( s , 1H ) , 7 . 92 ( d , J = 7 . 8 Hz, 1H ) , 7 . 87 ( d , for C17H BrFGN3[ M + H ] * : 447 .98 , 449 .98 . Found : 448 . 0 , J = 8 . 3 Hz, 1H ) , 7 .72 (t , J = 7 . 8 Hz, 1H ) , 7 .65 ( d , J = 8 . 7 Hz, 450 . 0 1H ). LRMS (ESI ) calcd . for C24H12C1F .N202 [M + H ] *: 524 .05 . Found : 523. 90 . Step 7 : 3 '- ( 4 -( Trifluoromethyl) -6 - (6 - (trifluorom ethyl) pyridin - 3 - yl) pyrimidin - 2 - yl) biphenyl - 3 - car Example 71 : 3 '- ( 4 -( Trifluoromethyl) -6 - (6 -( trifluo boxylic Acid romethyl ) pyridin - 3 - yl) pyrimidin - 2 -yl ) biphenyl - 4 carboxylic Acid 45

COH

50 CO2H

FzC N ? ??? 55 FC???? A mixture of 2 - ( 3 - bromophenyl ) - 4 - ( trifluoromethyl ) -6 (6 - (trifluoromethyl ) pyridin - 3 -yl ) pyrimidine ( 0 .129 g , 0 . 3 2 - (3 - Bromophenyl) - 4 -( trifluoromethyl) - 6 -( 6 -( trifluorom mmol) , 3 -borono benzoic acid ( 0 .075 g , 0 . 45 mmol) and ethyl) pyridin - 3 - yl) pyrimidine ( 0 . 129 g , 0 . 3 mmol) , 4 -bo tetrakistriphenylphosphinepalladium ( 0 ) (0 . 034 g , 0 .03 60 ronobenzoic acid ( 0 .075 g , 0 .45 mmol) , tetrakistriphenyl mmol) were taken 4 mL of DME . To this 2M Na , C0 (0 .6 phosphinepalladium (0 ) (0 .034 , 0 .03 mmol) , 2M Na CO2 mL , 1 . 2 mmol) solution was added and the resulting solution (0 .6 mL , 1 . 2 mmol) were dissolved in DME. The reaction was refluxed in an atmosphere of N , for 6 - 12 h . The reaction mixture was then processed according to the general proce mixture cooled to room temperature and diluted with water dure described in Example 69 , step 7 , to afford the desired and then acidified using IN HC1. The product was extracted 65 compound as a white solid ( 0 .092 g , 63 % ) . ' H NMR ( 400 with ethyl acetate and washed with brine and the organic MHz, DMSOdo ) : 89 .73 ( s , 1H ) , 9 .06 (d , J = 8 . 2 Hz, 1H ) , 8 .69 layer was dried over anhydrous Na2SO4. The solvent was (s , 1H ) , 8 .59 (d , J = 8 .8 Hz , 2H ), 8 . 13 (d , J= 8. 2 Hz, 1H ), 8 .03 US 9 ,969 , 726 B2 149 150 ( d , J = 8 .7 Hz, 2H ), 7 . 93 ( d , J = 8 . 7 Hz. 2H ), 7 . 86 ( d , J = 8 . 2 Hz, Example 74 : 3 -Chloro - 3' - ( 4 - ( trifluoromethyl) - 6 -( 6 2H ). LRMS (ESI ) calcd . for C24H ,3F6N202 [ M + H ]* : ( trifluoromethyl) pyridin - 3 - yl) pyrimidin - 2 -yl ) biphe 490 . 09 . Found : 489 . 95 . nyl- 4 - carboxylic Acid Example 72 : 3 '- ( 4 -( Trifluoromethyl) - 6 -( 6 -( trifluo romethyl) pyridin -3 -yl ) pyrimidin - 2 -yl ) biphenyl - 2 carboxylic Acid CO2H 10 C3

F3C 15 . 2 - ( 3 -Bromophenyl ) - 4 - ( trifluoromethyl) - 6 - ( 6 - (trifluorom CO2H ethyl) pyridin -3 - yl) pyrimidine ( 0 . 1 g, 0 . 23 mmol) , 4 - borono F3C N 2 - chlorobenzoic acid ( 0. 069 g , 0 .35 mmol ), tetrakistriph 20 enylphosphinepalladium ( 0 ) (0 . 027 , 0 .023 mmol) , 2M 2 -( 3 -Bromophenyl ) - 4 -( trifluoromethyl) - 6 -( 6 -( trifluorom Na2CO3 ( 0 .46 mL , 0 .92 mmol) were dissolved in DME. The ethyl) pyridin -3 -yl ) pyrimidine (0 .129 g , 0. 3 mmol) , 2 -bo reaction mixture was then processed according to the gen ronobenzoic acid (0 .075 g, 0. 45 mmol) , tetrakistriphenyl eral procedure described in Example 69 , step 7, to afford the phosphinepalladium (0 ) (0 .034 , 0 .03 mmol) , 2M Na2CO3 25 desired compound as a white solid ( 0 . 072 g , 60 % ) . ' H NMR ( 0 . 6 mL , 1 . 2 mmol ) were dissolved in DME . The reaction mixture was then processed according to the general proce (400 MHz, CDC1z ) : 89. 75 ( s , 1H ) , 9 . 06 ( d , J = 7 . 8 Hz, 1H ) , dure described in Example 69 , step 7 , to afford the desired 8 .70 ( s , 1H ), 8 .52 (d , J = 8 .2 Hz, 1H ), 8 . 11 (d , J = 8 .2 Hz , 1H ), compound as a white solid ( 0 .052 g , 35 % ). ' H NMR (400 30 7 . 93 (d , J = 8. 2 Hz, 1H ), 7. 92 (d , J = 8. 2 Hz, 1H ), 7. 88 (d , J= 1. 3 MHz, DMSOdo ) : 89 .72 ( s , 1H ) , 9 .05 ( d , J = 8 . 2 Hz, 1H ) , 8 .70 Hz, 1H ) , 7 .78 ( dd , J = 1 . 8 Hz , 9 . 0 Hz, 1H ), 7 . 70 ( t, J = 7 . 8 Hz , Is 111 ) 8 . 40 ( s 111 ) Sud I = 82 , 11 ) 771 ( d I = 78 TH ) , 7 .65 ( d , J = 8 . 7 Hz, TH ) . LRMS ( ESI) calcd . for Hz, 1H ), 7 .62 - 7 .50 ( m , 4H ), 7. 46 - 7 .42 ( m , 2H ). LRMS (ESI D ) C24H12C1F241112 11 G. N302 . 302[ M + H ]* : 524 . 05 . Found : 523. 95 . calcd . for C24H 3F6N202 [M + H ]* : 490 .09 . Found : 489 . 90 . 35 Example 73 : 4 -Fluoro - 3 '- ( 4 - ( trifluoromethyl) -6 - (6 Example 75 : 5 -Nitro - 3 ' - ( 4 - ( trifluoromethyl ) - 6 - ( 6 (trifluoromethyl ) pyridin - 3 -yl ) pyrimidin - 2 - yl) biphe ( trifluoromethyl) pyridin - 3 - yl) pyrimidin - 2 -yl ) biphe nyl- 3 - carboxylic Acid nyl- 3 -carboxylic Acid 40

CF3 COH CF3 COH F 45

NO2 F C N ?????30 F3C ??? N 2 - ( 3 -Bromophenyl ) - 4 - ( trifluoromethyl) - 6 -( 6 - (trifluorom ethyl) pyridin - 3 - yl) pyrimidine ( 0 . 065 g , 0 . 15 mmol ), 5 -bo 2 - ( 3 - Bromophenyl) - 4 - ( trifluoromethyl ) -6 - (6 - (trifluorom rono - 2 - fluorobenzoic acid (0 .042 g , 0 .22 mmol) , tetrakistri - 55fethyl ) pyridin - 3 -yl ) pyrimidine (0 . 1 g, 0. 23 mmol) , 3 -borono phenylphosphinepalladium ( 0 ) ( 0. 017 , 0 .015 mmol) , 2M 5 - nitrobenzoic acid ( 0 .073 g , 0 . 35 mmol) , tetrakistriphenyl Na2CO3 ( 0 . 30 mL, 0 . 6 mmol ) were dissolved in DME. The phosphinepalladium (0 ) (0 .027 , 0 .023 mmol ), 2M Na2CO3 reaction mixture was then processed according to the gen (0 .46 mL, 0 .92 mmol) were dissolved in DME. The reaction eral procedure described in Example 69 , step 7 , to afford the mixture was then processed according to the general proce desired compound as a white solid (0 .042 g, 55 % ). ÎH NMRMD dure described in Example 69 , step 7 , to afford the desired ( 400 MHz, DMSOdo) : 89 .70 (s , 1H ), 9 .00 ( d, J = 8 . 2 Hz, 1H ), compound as an off- white solid (0 . 080 g, 65 % ). ' H NMR 8 .65 ( s, 1H ), 8 .61 (s , 1H ), 8 .45 (d , J = 7 .8 Hz , 1H ), 8. 09 - 8. 07 (400 MHz, DMSOdo) : 89. 71 (s , 1H ), 9 .02 (d , J= 7 .2 Hz, 1H ), ( m , 2H ) , 7 . 94 - 7 . 88 ( m , 1H ), 7 . 83 ( d , J = 7 . 8 Hz, 1H ) , 7 .63 (t , a 8 .68 ( s , 1H ) , 8 . 59 - 4 . 49 ( m , 5H ) , 8 . 08 ( d , J = 8 . 2 Hz, 1H ) , 7 . 96 J = 7 . 8 Hz , 1H ), 7 . 39 (t , J = 8 . 7 Hz, 1H ) . LRMS (ESI ) calcd . (d , J = 7 . 8 Hz, 1H ) , ( t, J = 7 . 8 Hz, 1H ) . LRMS ( ESI) calcd . for for C24H 2F , N302 [M + H ] *: 508. 08 . Found : 508. 00 . C24H 2F .N404 [ M + H ]* : 535. 07 . Found : 535. 25 . US 9 , 969, 726 B2 151 152 Example 76 : 5 - Fluoro - 3 ' - ( 4 - ( trifluoromethyl) - 6 - ( 6 Example 78 : 2 -Chloro - 3' - ( 4 - ( trifluoromethyl) - 6 -( 6 (trifluoromethyl ) pyridin - 3 -yl ) pyrimidin - 2 - yl) biphe ( trifluoromethyl) pyridin - 3 - yl) pyrimidin - 2 -yl ) biphe nyl- 3 - carboxylic Acid nyl- 4 - carboxylic Acid

CO2H 10

F3C N F3C N ????????15 2 -( 3 -Bromophenyl ) - 4 -( trifluoromethyl) - 6 -( 6 -( trifluorom 2 - ( 3 - Bromophenyl) -4 - ( trifluoromethyl) -6 - (6 - ( trifluorom ethyl) pyridin - 3 -yl ) pyrimidine ( 0 .086 g , 0 . 2 mmol) , 3 - bo - ethyl) pyridin - 3 - yl) pyrimidine (0 . 1 g , 0 .23 mmol ), 4 - borono rono - 5 - fluorobenzoic acid (0 .055 g, 0 .3 mmol) , tetrakistri - , 3 -chlorobenzoic acid (0 . 069 g , 0 . 35 mmol) , tetrakistriph phenylphosphinepalladium (0 ) (0 . 023 , 0. 02 mmol) , 2M enylphosphinepalladium (0 ) (0 .027 , 0. 023 mmol) , 2M Na2CO3 ( 0 . 4 mL, 0 .8 mmol) were dissolved in DME . The Na2CO3 (0 .46 mL , 0 .92 mmol ) were dissolved in DME. The reaction mixture was then processed according to the gen - reaction mixture was then processed according to the gen eral procedure described in Example 69, step 7 , to afford the s eral procedure described in Example 69, step 7 , to afford the desired compound as a white solid (0 .043 g , 43 % ). ' H NMR desired compound as a white solid (0 .050 g , 41 % ). ' H NMR ( 400 MHz, DMSOdo ): 89 .64 (s , 1H ), 8 .95 ( d, J = 8 . 2 Hz, 1H ), (400 MHZ, DMSOD ) : 89 . 46 ( s , 1H ) , 8 .65 (d , J = 8 . 2 Hz, 1H ) , 8 .59 ( s , 1H ) , 8 .58 ( s , 1H ), 8 . 37 ( d , J = 7 . 8 Hz , 1H ) , 8 .05 - 8 . 10 8 . 59 ( s , 1H ) , 8 . 75 ( d , J = 7 . 8 Hz, 1H ), 8 . 11 ( s , 1H ), 7 . 96 - 7 . 95 ( m , 2H ), 7 .85 - 7 .78 ( m , 1H ), 7 .76 (d , J = 7. 8 Hz, 1H ), 7 .57 ( t, on (m , 2H ), 7. 83 ( d , J= 7 .8 Hz, 1H ) , 7 .57 ( m , 2H ) , 7. 42 (d , J = 8 . 7 J= 7 .7 Hz, 1H ), 7 .35 (t , J= 8 .2 Hz, 1H ). LRMS (ESI ) calcd . - Hz, 1H ) . LRMS (ESI ) caled . for C24H ,2C1F6N202 [ M +H ] *: for C24H /2F ,N202 [M + H ] *: 508. 08 . Found : 508. 0 . 524 . 05 . Found : 523 . 95 .

Example 77 : 6 -Methoxy - 3 '- ( 4 - ( trifluoromethyl) - 6 35 (6 - (trifluoromethyl ) pyridin - 3 -yl ) pyrimidin - 2 - yl) bi Example 79 : 6 -Fluoro - 3' - ( 4 -( trifluoromethyl) -6 - (6 phenyl- 3 -carboxylic Acid (trifluoromethyl ) pyridin - 3 -yl ) pyrimidin - 2 - yl) biphe nyl- 3 -carboxylic Acid

40 COH ?? , ?

OMe F C N F C N ????? 50 2 -( 3 -Bromophenyl ) - 4 -( trifluoromethyl) -6 - (6 -( trifluorom ethyl) pyridin - 3 -yl ) pyrimidine (0 .086 g , 0 .2 mmol) , 3- bo 2 -( 3 -Bromophenyl ) - 4 -( trifluoromethyl) -6 - (6 - (trifluorom rono - 4 -methoxybenzoic acid ( 0 . 059 g , 0 . 3 mmol) , tetrakis ethyl ) pyridin - 3 - yl) pyrimidine (0 . 086 g , 0 . 2 mmol) , 3 - bo triphenylphosphinepalladium (0 ) ( 0 .023 , 0 . 02 mmol ), 2M crono- 4 - fluorobenzoic acid ( 0 . 055 g , 0 . 3 mmol) , tetrakistri Na2CO3 ( 0 . 4 mL , 0 . 8 mmol) were dissolved in DME . The phenylphosphinepalladium ( 0 ) ( 0 .046 , 0 . 03 mmol) , 2M reaction mixture was then processed according to the gen Na2CO3 (0 .4 mL , 0 . 8 mmol ) were dissolved in DME. The eral procedure described in Example 69 , step 7 , to afford the reaction mixture was then processed according to the gen desired compound as a white solid ( 0 . 068 g , 65 % ). ' H NMR eral procedure described in Example 69 , step 7 , to afford the (400 MHz, DMSOdo) : 89 .71 (s , 1H ), 9. 02 (d , J = 8 .2 Hz , 1H ), desired compound as a white solid (0 .044 g, 44 % ). ' H NMR 8 .68 ( s , 1H ) , 8 . 56 ( s , 1H ) , 8 .49 ( d , J = 7 . 8 Hz, 1H ) , 8 . 11 ( d , ( 400 MHZ, DMSOD ) : 89 .67 ( s , 1H ) , 9 . 00 ( d , J = 7 .8 Hz, 1H ) , J = 8 . 3 Hz, 1H ), 7 . 86 ( d , J = 7 . 8 Hz, 1H ), 7 . 86 (s , 1H ) , 8 .65 - 8 .64 ( m , 2H ) , 8 .62 ( d , J = 6 . 9 Hz , 1H ) , 8 . 06 ( d , J = 7 . 8 Hz , 7 .68 - 7 .62 ( m , 2H ), 7 .22 ( d , J = 8 . 7 Hz, 1H ), 3 .83 (s , 3H ). 4 2H ), 7 .99 ( d , J = 1 . 3 Hz, 1H ) , 7 . 85 ( dd , J = 3. 3 Hz , 6 .8 Hz , 1H ), LRMS (ESI ) calcd . for C25H , 3F6N203[ M + H ]* : 520 . 10 . 7. 75 - 7 . 62 ( m , 1H ), 7. 61 - 7. 60 (m , 1H ). LRMS (ESI ) caled . Found : 520 . 0 . for C24H 2F N302[ M + H ]* : 508. 08 . Found : 507. 95 . US 9 ,969 , 726 B2 153 154 Example 80 : 5 - ( 3 - ( 4 - ( Trifluoromethyl) - 6 - ( 6 -( trifluo Example 82 : 4 - Fluoro - 4 '- ( 4 - ( trifluoromethyl) - 6 - ( 6 romethyl) pyridin - 3 - yl) pyrimidin - 2 -yl ) phenyl) thio ( trifluoromethyl) pyridin - 3 - yl) pyrimidin - 2 -yl ) biphe phene - 2 - carboxylic Acid nyl- 3 - carboxylic Acid

CF3

N - CO2H 10

CO2H F3C N ? FzC oratorlar15 2 - ( 3 - Bromophenyl) - 4 - ( trifluoromethyl ) -6 - ( 6 - ( trifluorom ethyl) pyridin - 3 - yl ) pyrimidine ( 0 . 112 g , 0 . 25 mmol) , 5 - bo rono - 2 -chlorobenzoic acid ( 0 . 065 g , 0 . 375 mmol) , atetrak 2 - ( 4 -Bromophenyl ) - 4 -( trifluoromethyl) - 6 - ( 6 - ( trifluorom istriphenylphosphinepalladium ( 0 ) (0 .029 , 0 .025 mmol ), 2M - ethyl) pyridin - 3 - yl )pyrimidine (0 . 100 g , 0 . 23 mmol ), 5 -bo Na2CO3 ( 0 . 5 mL, 1 mmol) were dissolved in DME. Therono - 2 - fluorobenzoic acid (0 .064 g , 0 .35 mmol) , tetrakistri reaction mixture was then processed according to the gen phenylphosphinepalladium ( 0 ) ( 0 . 027 , 0 . 023 mmol ), 2M eral procedure described in Example 69 , step 7, to afford the Na2CO3 ( 0 . 46 mL, 0. 92 mmol) were dissolved in DME . The desired compound as an off -white solid ( 0 . 060 g , 48 % ) . ' H “ reaction mixture was then processed according to the gen NMR ( 400 MHz, DMSOdo) : 89. 71 ( s , 1H ), 9 . 02 ( d , J= 8 . 2 eral procedure described in Example 69 , step 7 , to afford the Hz, 1H ), 8 .67 ( s , 1H ) , 8 .66 ( s , 1H ) , 8 .42 ( d , J = 7 . 8 Hz, 1H ) , desired compound as a white solid (0 .072 g , 62 % ) . " H NMR 8 .10 ( d , 1H , J= 8 . 3 Hz) , 7 .90 ( d , J = 8 .2 Hz, 1H ) , 7 .69 - 7 .61 ( m , (400 MHz, DMSOD ) : 89 . 56 ( s , 1H ) , 8 .89 ( d , J = 8 .3 Hz, 1H ) , 3H ). LRMS (ESI ) calcd . for C24H4F6N202S [ M + H ] * : 8 .54 (s , 1H ), 8 .37 ( d , J = 8 . 2 Hz, 2H ) , 8 . 06 ( d , J = 8 . 2 Hz, 1H ) , 496 .05 . Found : 496 .0 . 8 .03 (d , J= 8 .2 Hz, 1H ), 8 .00 -7 .97 (m , 1H ), 7 .70 ( d , J= 8 .2 Hz, 2H ), 7 .31 ( t, J = 8 .7 Hz, 1H ) . Example 81: 4 ' -( 4 - ( Trifluoromethyl) -6 - (6 - ( trifluo romethyl ) pyridin - 3 - yl) pyrimidin - 2 -yl ) biphenyl - 4 35 Example 83 : 4 - Chloro - 4' -( 4 -( trifluoromethyl ) -6 -( 6 carboxylic Acid ( trifluoromethyl) pyridin - 3 -yl ) pyrimidin - 2 - yl) biphe nyl- 3 - carboxylic Acid

FzC N bila - CO2H F3C ??? 50 ci 2 -( 4 -Bromophenyl ) - 4 -( trifluoromethyl) - 6 -( 6 -( trifluorom ethyl) pyridin -3 -yl ) pyrimidine (0 .073 g , 0 . 17 mmol) , 4 - 50 - 2 -( 4 -Bromophenyl ) - 4 -( trifluoromethyl) - 6 -( 6 - ( trifluorom ronobenzoic acid (0 .042 g , 0. 253 mmol) , tetrakistriphenyl- 55 ethyl) pyridin - 3 -yl ) pyrimidine (0 . 100 g , 0 .23 mmol) , 5 -bo phosphinepalladium (0 ) ( 0 .019 , 0 .017 mmol ), 2M Na2CO3 rono -2 -chlorobenzoic acid ( 0 .069 g , 0 .35 mmol) , tetrakis ( 0 .34 mL , 0 .68 mmol) were dissolved in DME . The reaction triphenylphosphinepalladium ( 0 ) ( 0 .027 , 0 .023 mmol) , 2M mixture was then processed according to the general proce Na2CO3 (0 . 46 mL, 0. 92 mmol) were dissolved in DME. The dure described in Example 69 , step 7 , to afford the desired 60 reaction mixture was then processed according to the gen compound as a white solid (0 .049 g , 59 % ). 'H NMR (400 eral procedure described in Example 69 , step 7 , to afford the MHz, DMSOdo ): 89 .73 (s , 1H ) , 9 .06 (d , J = 8. 2 Hz , 1H ), 8. 69 desired compound as a white solid (0 .056 g , 46 % ). ' H NMR ( s, 1H ), 8 .59 ( d , J = 8 .7 Hz, 2H ), 8 .13 (d , J = 8. 2 Hz , 1H ), 8 .02 (400 MHz, DMSOD ) : 89 .71 (d , J= 8 . 8 Hz, 1H ) , 9. 06 - 9. 01 ( d , J = 8 . 7 Hz , 2H ) , 7 .92 ( d , J = 8 . 7 Hz, 2H ) , 7 . 86 ( d , J = 8 . 2 Hz, as ( m , 1H ) , 8 .69 - 8 .53 ( m , 3H ) , 8 . 12 - 8 .06 ( m , 2H ) , 7 .89 - 7 .87 2H ) . LRMS ( ESI) calcd . for C24H13F6N2O2[ M + H ] *: (m , 3H ), 7 .64 -7 .61 ( m , 1H ) . LRMS ( ESI) calcd . for 490 .09 . Found : 489 . 95 . C24H ,2C1FN302 [ M + H ] *: 524 .05 . Found : 524 .0 . US 9 , 969, 726 B2 155 156 Example 84 : 5 - Fluoro - 4 ' - ( 4 - ( trifluoromethyl) - 6 - ( 6 J= 8 . 2 Hz, 1H ), 7 .62 (d , J= 8 . 2 Hz, 1H ) , 2 . 76 (d , J= 4 . 1 Hz, (trifluoromethyl ) pyridin - 3 -yl ) pyrimidin - 2 - yl) biphe 3H ) . LRMS (ESI ) calcd . for C25H15CIF N40 [ M + H ] * : nyl- 3 - carboxylic Acid 537 .08 . Found : 536 . 95 . General Synthetic Scheme for the Preparation of 4 - aryl/ hereoaryl pyrimidin - 2 -yl - biphenyl Carboxylic Acid Derivatives (Method 2 )

Scheme 14 CF3 F3C N ?? 15 ArB (OH )2 i, 30 min . - 1 h F N ci CF 20 2 - ( 4 - Bromophenyl) -4 - ( trifluoromethyl) -6 -( 6 -( trifluorom , B (OH ) 2 ethyl) pyridin - 3 -yl ) pyrimidine (0 . 197 g , 0 .44 mmol) , 3 -bo rono - 5 -fluorobenzoic acid ( 0 .120 g , 0 .66 mmol) , tetrakistri i . 1 - 2 h phenylphosphinepalladium ( 0 ) ( 0 .050 , 0 . 044 mmol) , 2M Ar 220 Na2CO3 (0 .88 mL , 1. 6 mmol ) were dissolved in DME. The 25 reaction mixture was then processed according to the gen EY = eral procedure described in Example 69 , step 7 , to afford the desired compound as a white solid ( 0 . 115 g , 52 % ) . ' H NMR (400 MHz, DMSO ) : 89 .71 ( s , 1H ) , 9 .03 ( d , J = 8 . 2 Hz, 1H ) , 8 .67 (s , 1H ), 8 .56 (d , J = 8 . 2 Hz, 2H ), 8 .12 (d , J= 8 .2 Hz , 1H ), 30 8 . 07 ( s , 1H ) , 7 . 93 ( s , 1H ) , 7 . 91 ( s , 1H ) , 7 . 87 ( d , J = 8 . 7 Hz , Br (HO )2B _ C02H 1H ) , 7 .65 ( d , J = 8 . 7 Hz, 1H ) . LRMS ( ESI) calcd . for Ar C24H12F N202 [ M + H ] * : 508 . 08 . Found : 508 . 0 . 35 Example 85 : 4 - Chloro -N -methyl - 3 ' - (4 -( trifluorom ethyl) -6 - (6 - ( trifluoromethyl) pyridin - 3 -yl ) pyrimidin i , 6 - 12 h 2 -yl ) biphenyl - 3 -carboxamide to 40 3 COH F

Cl 45 45 Ar

i) Pd ( PPh3 ) 4, 2M Na2CO3, DME , 80°C . F C N o 50 tomto

4 - Chloro - 3 ' - ( 4 - (trifluoromethyl ) - 6 - ( 6 -( trifluoromethyl ) Example 86 : 4 - Fluoro - 3 '- ( 4 -phenyl - 6 - ( trifluorom pyridin - 3 -yl ) pyrimidin -2 -yl ) biphenyl - 3 - carboxylic acid ethyl) pyrimidin - 2 - yl ) biphenyl- 3 - carboxylic Acid ( 0 . 025 , 0 .047 mmol) was dissolved in DMF ( 2 mL ) at room 55 temperature . HOBt (0 . 008 g , 0 .06 mmol ) was added in one portion followed by EDC ( 0 .010 g , 0 . 06 mmol) . The result ing mixture was stirred at room temperature for 30 min . To this solution methylamine hydrochloride ( 0 . 005 g , 0 .071 ??? mmol) and triethylamine ( 0 . 009 mL , 0 . 07 mmol) were 60 F added and stirred for 2 h , and the organic phase was evaporated under reduced pressure . The crude product was purified using automated prep - HPLC to afford the amide as a white solid (0 .02 , 80 % ) . ' H NMR (400 MHz, DMSO ) : 89 . 78 ( s , 1H ) , 9 . 11 ( s , 1H ) , 9 . 08 ( s , 1H ) , 8 .54 ( d , J = 8 . 7 Hz, 65 1H ) , 8 . 46 - 8 .45 ( m , 1H ) , 8 . 16 ( d , J = 8 . 2 Hz, 1H ) , 7 .82 ( d , J = 6 . 9 Hz , 1H ) , 7 .76 (d , J = 8 . 2 Hz , 1H ) , 7 .73 ( s , 1H ) , 7 .71 ( t, Chat US 9 ,969 , 726 B2 157 158 Step 1 : 2 , 4 - Dichloro - 6 - (trifluoromethyl ) pyrimidine dium ( 0 ) ( 0 .079 g , 0 . 069 mmol) in 6 mL of DME was added a 2M Na2CO3 ( 1. 7 mL , 3 .4 mmol) solution . The reaction mixture was then processed according to the general proce dure described in Example 69 , step 6 , to afford the desired CF3 5 compound as a colorless solid ( 0 . 298 g , 79 % ) . ' H NMR (400 MHz, CDC12 ) : 88 .75 ( s , 1H ), 8 .55 ( d , J = 7 . 8 Hz , 1H ) , 8 .25 - 8 .23 ( m , 2H ) , 7 .91 ( s , 1H ) , 7 .65 ( d , J = 8 . 2 Hz, 1H ) , 7 .64 - 7 . 57 ( m , 3H ) , 7 .41 (t , J = 7 . 8 Hz, 1H ) . LRMS (ESI ) ci N calcd . for C13H10BrF3N2[ M + H ] *: 378 .99 , 380 .99 . Found : 10 379. 0 , 381 . 0 . 6 - Trifluromethyl uracil ( 3 g , 16 .66 mmol) was take in Step 4 : 4 - Fluoro - 3' - (4 -phenyl - 6 -( trifluoromethyl) CH ,CN ( 15 mL ) . To this was added N , N -dimethylaniline pyrimidin - 2- yl ) biphenyl - 3 -carboxylic Acid ( 1 . 96 mL , 15 . 37 mmol) and POC12 ( 5 .74 mL , 61. 48 mmol) . The resulting mixture was heated to reflux for 6 h . The 15 reaction mixture was cooled to room temperature and the volatile materials were removed in vacuum . The residue was CO2H dissolved in diethyl ether and washed with water. The organic layer was dried over Na , SO4, and the solvent was evaporated to afford the title compound as a yellow liquid 20 ( 2 .72 g , 74 % ) which was used for next step without further purification . ' H NMR (400 MHz , CDC13 ): 87. 63 ( s , 1H ) . Step 2 : 2 - Chloro - 4 -phenyl - 6 -( trifluoromethyl) pyrimidine 25 A mixture of 5 -borono - 2 - fluorobenzoic acid ( 0 . 108 g , 0 .6 mmol ), 2 -( 3 -bromophenyl ) - 4 - phenyl- 6 -( trifluoromethyl ) py rimidine ( 0 . 151 g , 0 . 4 mmol) and tetrakistriphenylphos CF3 20 . phinepalladium ( 0 ) ( 0 . 046 g , 0 .04 mmol) in 6 mL of DME was added a 2M Na2CO3 (0 .8 mL , 1. 6 mmol) solution was added . The reaction mixture was then processed according to the general procedure described in Example 69, step 7 , to afford the desired compound as a colorless solid ( 0 . 100 g , 58 % ) . ' H NMR ( 400 MHz , DMSOd . ) : 88 . 52 ( s , 1H ) , 8 . 36 ( d , J = 7 . 8 Hz, 1H ) , 8 .33 ( d , J = 7 . 3 Hz, 2H ) , 8 . 28 ( s , 1H ) , 8 . 05 (dd , J = 2 . 8 Hz, 6 . 8 Hz, 1H ) , 7 .84 - 7 .82 ( m , 1H ) , 7 .43 ( d , J = 7 . 8 Hz , 1H ) , 7 .55 - 7 .51 ( m , 4H ) , 7 . 34 ( t , J = 10 . 0 Hz, 1H ) . LRMS To a mixture of phenylboronic acid (0 .134 g , 1 .1 mmol) , (ESI ) calcd . for C24H 4F4N202[ M + H ]* : 439 .09 . Found : 2, 4 -dichloro -6 - ( trifluoromethyl) pyrimidine ( 0. 226 g , 1 40 438 .90 . mmol) and tetrakistriphenylphosphinepalladiumenalladium ( 0 ) (10 0 . 115. The following compounds (Examples 87 - 122 ) were syn mg, 0 . 1 mmol) in 4 mL of DME was added a 2M Na , Co , thesized from 2 , 4 - dichloro -6 - ( trifluoromethyl )pyrimidine ( 2 mL , 4 mmol) solution . The reaction mixture was then ( 0 .4 mmol, 1 equiv . ), boronic acid ( 1 .1 equiv ), 3 -bromophe processed according to the general procedure described in nylboronic acid ( 0 .44 mmol, 1 . 1 equiv ) , and appropriate Example 69 , step 6 , to afford the desired compound as a 45 borono benzoic acid derivatives ( 0 .6 mmol, 1 . 5 equiv . ) colorless solid ( 0 . 178 g , 69 % ). ' H NMR (400 MHz, CDC12 ) : according to the method described in Example 86 . 08 . 11 ( d , J = 8 . 3 Hz , 2H ) , 7 . 94 ( s , 1H ) , 7 . 63 - 7 .54 ( m , 3H ) . Example 87 : 4 - Fluoro -3 ' -( 4 - (4 -methoxyphenyl )- 6 LRMS (ESI ) calcd . for CuH CIF3N2[ M + H ]* : 259 .01 . ( trifluoromethyl) pyrimidin - 2 -yl )biphenyl - 3 -carbox Found : 259 .0 . ylic Acid Step 3 : 2- (3 -Bromophenyl ) -4 -phenyl - 6 -( trifluorom 50 ethyl) pyrimidine COH 55 F

60 . Me01 ??? Off -white solid (0 .09 g , 48 % ). ' H NMR (400 MHz, ? DMSOdo) : 89. 09 (s , 1H ), 8 .50 (dd , J= 2. 3 Hz , 8 .7 Hz , 1H ), To a mixture of 3 - bromophenylboronic acid (0 . 166 g , 0 . 83 65 4 . 46 ( s , 1H ) , 8 . 31 (d , J= 6 . 9 Hz, 1H ), 8 .25 (s , 1H ) , 8 . 04 (dd , mmol) , 2- chloro - 4 -phenyl - 6 -( trifluoromethyl) pyrimidine J = 2 .3 Hz, 8 .7 Hz, 1H ), 7 .84 -7 .82 ( m , 1H ), 7 .21 ( d , J = 7 .8 Hz, ( 0 . 178 g , 0 .69 mmol) and tetrakistriphenylphosphinepalla - 1H ), 7 .52 (t , J = 7 . 8 Hz, 1H ), 7 . 35 (t , J = 8 . 7 Hz, 1H ) , 6 . 85 ( d , US 9 ,969 , 726 B2 159 160 J = 8 .9 Hz, 1H ), 3 .87 (s , 3H ). LRMS (ESI ) calcd . 2H ), 6 .80 -6 . 79 ( m , 1H ). LRMS (ESI ) calcd . for CHF?NO , [ M + H ] +: 469. 10 . Found : 468. 90 . CHF? N , O , [ M + H ] +: 429. 07 . Found : 429. 0 . Example 87A : 4 -Fluoro -3 -( 4 -( thiophen - 2- yl ) - 6 Example 90: 3 -( 4 - (Furan - 2 -yl ) - 6 -( trifluoromethyl) (trifluoromethylpyrimidin - 2 - yl) biphenyl - 3 - carbox 5 pyrimidin - 2 -yl ) - 4 -methoxybiphenyl - 3 -carboxylic ylic Acid Acid

CO2H 10 CF3 COH OMe

Off?? -white solid ( 0 . 07g, 39 ) . HNMR 400MHz, Off -white solid ( 0 . 08 0 . 45 % ) . lH NMR 400MHz, DMSOds ) : 68 .58 ( s , 1H ) , 8 . 41 - 8 . 38 (m , 3H ), 8 . 12 (d , J = 6 . 9 DMSOd ) : 88. 56 ( s . 1H ) . 8 .37 ( d . J = 7. 8 Hz. 1H ) . 8 . 08 ( s . Hz, 1H ), 7 . 96 - 7 .95 ( m , 2H ) , 7 . 88 ( t, J = 8 . 7 HZ, 1H ), 7 . 70 - 1H ). 8 . 04 ( s . 1H ) , 7 . 92 ( d . J = 1 .8Hz , 1H ) . 7 .84 - 7 . 80 ( m . 2H ) . 7 . 67 ( m , 1H ) , 7 .44 ( t, J - 8 . 7 HZ, 1H ), 7 . 31 - 7 . 30 ( m , 1H ) . 7 . 77 ( d . J = 3 . 2 Hz. 1H ) , 7 . 63 - 7 . 59 ( m . 1H ) , 7 .23 ( d = 8 . 7 Hz LRMS (ESI ) calcd . for CoH2FN , O , S [ M + H ] * : 445 .04 . 1H ), 6 .81 -6 .80 (m , 1H ), 3 .88 (s , 3H ) . LRMS (ESI ) calcd . for Found : 444 . 80 . 25 C2H5FN , 0 [ M + H ] + : 441. 09 . Found : 441 . 0 . Example 88 : 4 - Fluoro - 3 -( 4 -( furan - 2 - yl) - 6 - (trifluo Example 91: 4 -Fluoro - 3 - ( 4 - o -tolyl - 6 -( trifluorom romethyl) pyrimidin -2 -y1 )biphenyl - 3 -carboxylic Acid ethyl) pyrimidin - 2 -y1 ) biphenyl - 3 -carboxylic acid

3 )

COH ??? CO2H

N 35

???? :40 ) ???? White solid (0 .075 g , 44 % ). IH NMR ( 400 MHz, White solid ( 0 . 04 2 , 22% ). IH NMR (400 MHz, DMSOd ): 58 . 55 ( S , TH ), 8 . 40 ( d , = 7. 8 HZ, TH ), 8 .07 (dd , DMSOd ) : 88 .59 ( s . 1H ) . 8 .39 ( d . J = 7 .8 Hz. 1H ) . 8 .90 - 8 .07 J = 2 .3 Hz, J - 8 . 7 Hz 1H ), 8. 06 (S , 1H ), 8. 00 (s , 1H ), ( m , 2H ), 7 .85 - 7 .68 ( m , 4H ), 7 .64 - 7 .26 ( m , 4H ), 2 .48 ( s, 3H ) . 7 .92 - 7 . 90 ( m , 1H ) , 7 . 82 ( d , J = 7 . 8 Hz, 1H ) , 7 . 75 ( d , J = 3 . 2 Hz, ?? LRMS (ESI ) calcd . for CsHF? N , O , [ M + H [ + : 453 .11 . 1H ), 7 .64 (t , J - 8. 7 Hz, 1H ), 7 .40 (t , J - 8 . 7 Hz , 1H ), 6 .80 - 6 .79 45 Found : 453 .0 . ( m , 1H ). LRMS (ESI ) calcd . for C2H2FN203[ M + H ] * : 429 .07 . Found : 428 . 85 . Example 92: 4 -Fluoro - 3 -( 4 -m -tolyl - 6 -( trifluorom Example 89: 5 -Fluoro -3 -( 4 -( furan -2 - y1) - 6 -( trifluo ethyl) pyrimidin - 2 - yl) biphenyl- 3 - carboxylic Acid romethyl) pyrimidin - 2- y1) biphenyl -3 -carboxylic Acid 5050) CO2H CO2H 55 ???? 66) ?? Off- white solid ( 0 . 069 g , 40 % ). IH NMR ( 400 MHz , White solid ( 0 . 60 g , 33 % ) . TH NMR (400 MHz, DMSOd ) : $ 8 .53 (s , 1H ) , 8 .38 ( d , J = 7 . 8 Hz, 1H ) , 8 .04 ( s , 65 DMSOd ) : 58 .68 ( s , 1H ) , 8 . 53 ( d , J = 7. 8 Hz, 1H ) , 8 . 29 ( s . 1H ) , 7 .98 ( S , 1H ) , 7 . 94 ( s , 1H ) , 7 .82 ( d , J - 8 . 2 HZ, 1H ), 1H ), 8 . 26 ( d , J = 7 .3 Hz, 1H ), 8 . 14 (dd , J = 3 . 4 Hz, 6 . 8 Hz, 1H ), 7 .74 -773 (m , 1H ) , 7 . 72 (d , J = 3 . 2 Hz , 1H ) , 7 .61 (q , J = 7 . 8 Hz , 7. 99 - 7 .93 ( m , 1H ) , 7. 89 ( d , J = 7. 8 Hz, 1H ), 7 .70 (t , J = 7. 8 Hz, US 9 ,969 , 726 B2 161 162 1H ), 7. 50 - 7 .41 ( m , 3H ), 7. 16 (d , J = 6. 8 Hz, 1H ), 2 .36 (s , 3H ). Hz, 1H ), 7 .41 - 7. 38 ( m , 3H ) . LRMS (ESI ) calcd . for LRMS ( ESI) calcd . for CsHF N2O [ M + H ] * : 453 . 11 . CHF?NO2 [ M + H ] * : 465 .41 . Found : 465. 0 . Found: 453 . 0 . Example 96 : 3 -( 4 - ( 4 - tert - Butylphenyl) - 6 - ( trifluo Example 93 : 3 - ( 4 -( 3 , 5 - Dimethylphenyl) - 6 -( trifluo - 5 romethyl) pyrimidin - 2 -y1 ) -4 - fluorobiphenyl- 3 -car romethyl) pyrimidin - 2 - yl ) - 4 - fluorobiphenyl- 3 - car boxylic Acid boxylic Acid

10 COH CF3 COH F N

20) White solid (0 .068 g , 34 % ). IH NMR ( 400 MHz, White solid ( 0 .072g , 38 % ). IH NMR 400MHz, DMSOds) : 68 .63 ( s , 1H ) , 8 .46 ( d , 1H , J = 7 . 8 Hz ), 8 . 38 ( s , DMSOd ,) : 88 .68 ( s, 1H ), 8 . 51 ( d , J = 7. 3 Hz , 1H ), 8 .45 ( s, 1H ) , 8 .33 ( d , 2H , J = 8 . 2 Hz) , 8 .10 (d , 1H , J = 9 . 0 Hz ), 1H ), 8 . 08 (s , 2H ), 7. 90 (d , J = 7 . 8 Hz , 2H ), 7 .69 (t , J= 7. 8 HZ , 7. 93 - 7. 92 (m , 1H ), 7. 84 ( d , 1H , J = 7. 8 Hz) , 7. 63 (t , 1H , J= 7. 8 1H ) , 7 .43 - 7 .41 ( m , 2H ), 7. 26 (s , 1H ) , 2 . 38 ( S , 6H ) . LRMS 25 Hz) , 7 .57 ( d , 2H , J - 8 . 2 HZ ) , 742 (t , 1H , J- 8 . 2 Hz) , 1 .32 ( s , (ESI ) calcd. for CuHgFN , O , [ M + H ]+ : 467 .13 . Found : 9H ). LRMS (ESI ) calcd . for CzgH2FN202[ M + H ]* : 467. 0 . 495 .16 . Found : 495 . 0 . Example 97: 4 -Fluoro - 3 - ( 4 -( 2 - fluoropyridin - 3 - y1 ) Example 94 : 4 - Fluoro - 3 -( 4 -( furan - 3 - yl) - 6 - (trifluo 6 -( trifluoromethyl ) pyrimidin - 2 -y1 ) biphenyl - 3 -car romethyl) pyrimidin - 2 - y1) biphenyl - 3 - carboxylic Acid 30 boxylic Acid

CO2H 35 COH

4 { NF Off- white ???? solid ( 0 .085g , 49 % ). TH NMR ( 400 MHz??, White solid (0 .102 g 56 % ). IH NMR ( 400 MHz, DMSOds) : $ 8 . 57 ( s , 1H ), 8 .37 ( d , I = 7 . 8 Hz, 1H ) , 8 .06 ( s , 45 DMSOds) : 68. 82 - 8 . 81 ( m , 1H ), 8 . 57 ( s , 1H ), 8 . 43 - 8 .42 1H ), 8 .00 ( s , 1H ) , 7 .93 ( d , J = 2 . 3 Hz , 1H ), 7 . 85 ( d , t = 8 . 2 Hz, (overlapping doublet and singlet, 2H ), 8 .20 (s , 1H ), 8 .07 (dd , 1H ), 7 . 78 ( d , J = 3 . 7 Hz, 1H ), 7 . 63 - 7 .23 ( m , 2H ), 6 .81 - 6 .80 J = 2 .8 Hz, 6 . 8 Hz, 1H ) , 7 . 93 - 7 . 92 ( m , 1H ) , 7 . 85 ( d . J = 7 . 8 Hz, ( m , 1H ). LRMS ( ESI) calcd , for C2H2FN , O , [ M + H ] * : 1H ), 7 . 63 ( t, I = 7 . 8 Hz, 1H ), 7 .61 - 7 .59 ( m , 1H ) , 7 .39 (t , J - 8 . 7 429 . 07. Found: 428 .85 . Hz, 1H ). LRMS (ESI ) calcd , for C2H2FsN , 02[ M + H ] * : Example 95: ( E ) - 4 -Fluoro - 3 - ( 4 - styryl- 6 - (trifluorom 50 458 .08 . Found : 458 . 0 . ethyl) pyrimidin - 2 - y1 )biphenyl - 3 - carboxylic Acid Example 98: 30- ( 4 - ( 4 - Chlorophenyl ) - 6 - ( trifluorom ethyl) pyrimidin -2 - y1) - 4 - fluorobiphenyl - 3 -carboxylic Acid COH 55 COH

66)

????White solid (0 .098 g , 53 % ). IH NMR ( 400 MHz , 65 ? ?? DMSOds) : 88 .68 (s , 1H ) , 8. 43 ( d , J= 7 .8 Hz, 1H ), 8 .20 - 8. 14 ( m , 2H ), 8 .01 - 7. 90 ( m , 2H ), 7. 22 - 7 . 63 (m , 5H ), 7 .56 (t , J = 7. 8 US 9 ,969 , 726 B2 163 164 White solid ( 0 .07 g 32 % ). IH NMR ( 400 MHz, Off -white solid ( 0 . 100g, 52 % ). " H NMR (400 MHz, DMSOd ) : 88 . 53 ( s , 1H ) , 8 .40 - 8 . 39 ( m , 4H ) , 8 . 07 ( dd , J - 2 . 5 ? DMSOd ): 88 .60 (s , 1H ), 8 .43 ( d , J - 8 .7 Hz, 1H ), 8 .18 ( s, Hz, 6 . 8 Hz, 1H ), 7 . 89 - 7 .88 ( m , 1H ), 7 .80 ( d , D = 7 . 8 HZ, 1H ) , 1H ) , 8 .17 ( s . 1H ), 8 .10 ( dd . J = 3 . 3 Hz. 6 . 9 Hz. 1H ), 7. 95 - 7 . 92 7 . 58 - 7 . 57 ( m , 3H ), 7 .38 ( t , J9. 0 Hz, 1H ) . LRMS (ESI ) ( m , 1H ), 7 . 85 (dd , J = 3 . 3 Hz, 6 . 9 Hz, 1H ) , 7 . 9 ( d , J = 7 . 9 Hz, calcd . for C2H5CIFN202 [ M + H ]* : 473 .06 . Found : 473( 5 .0 0 . 5 1H ) , 7 . 71 - 7 . 76 ( m , 2H ), 7. 48 - 7 . 32 ( m , 3H ). LRMS ( ESI) Example 99 : 3 - ( 4 - ( 3 , 4 - Dimethoxyphenyl ) - 6 - (trif calcd . for C6H4FN2O [ M + H ]+ : 479. 09 . Found : 479. 0 . luoromethyl )pyrimidin - 2 - y1) - 4 - fluorobiphenyl- 3 Example 102 : 3 -( 4 -( Benzo [ b ] thiophen - 2 -y1 ) -6 -( trif carboxylic Acid luoromethyl) pyrimidin - 2 - y1 ) - 4 - fluorobiphenyl- 3 10 carboxylic Acid

CO2H ? FF CF3 CO2H ?15 MeO .

Me0 ??? 20 Off -white solid ( 0 .092 g , 46 % ) . H NMR ( 400 MHz, DMSOd ) : $ 8 .67 (s , 1H ), 8 .45 ( d , J = 7 . 8 Hz, 1H ) , 8 .41 ( s , 1H ) , 8 . 13 ( d . J = 6 . 9 Hz, 1H ) , 8 .07 ( dd , J = 1 . 8 Hz, 9 . 0 Hz, 1H ) , Off -white solid (0 .120g , 61 % ). IH NMR (400 MHz, 7 . 98 - 7 .95 ) m , 2H ), 7 .87 (d , J = 6 . 9 Hz, 1H ), 7 . 66 ( t, J = 7 . 7 Hz???, ??25 DMSOd ) : 88 . 71 ( s , 1H ) , 8 .56 ( s , 1H ) , 8 . 53 ( s , 1H ) , 8 . 40 ( d , 1H ) , 7 . 42 (t , J = 10 Hz, 1H ), 7 .11 ( d , J - 8 . 7 Hz, 1H ), 3 .89 ( s, 1H , J = 7 . 8 Hz) , 8 . 12 (dd , 1H , J = 2 . 8 Hz, 6 . 9 Hz) , 8 .02 ( d , 1H , 3H ), 3. 84 ( s, 3H ). LRMS (ESI ) calcd . C2H8FN2O4[ M + J = 7 .8 Hz) , 7 .92 - 7 .85 ( m , 2H ), 7 .84 ( d , 1H , J = 7 .8 Hz) , 7 . 65 H ] + : 499 . 12. Found : 498 .95 . (t , 1H , J = 7 . 8 Hz) , 7 . 45 - 7 .41 ( m , 3H ) . LRMS (ESI ) calcd . for Example 100 : 4 -Fluoro - 3 -( 4 -( 2 - fluorophenyl) - 6 CHF? N , O , S [M + H ] + :495 . 07 . Found : 494. 95 . (trifluoromethyl ) pyrimidin - 2 -y1 ) biphenyl - 3 -carbox 30) ylic Acid Example 103 : 4 -Fluoro -3 -( 4 -( 4 - methylthio )phe nyl) - 6 - ( trifluoromethyl) pyrimidin - 2 - y1) biphenyl - 3 carboxylic Acid CO2H 35 FF CO2H

4 {

MeS Off -white solid ( 0 .060g , 33 % ). TH NMR ( 400 MHz, ?? ???DMSOd ): 68 .58 ( s , 1H ) , 8 .44 ( d , J - 8 . 2 Hz, 1H ) , 8 . 26 .(t , ???? I = 9 . 6 Hz. 1H . 8 .13 ( s . 1H ), 8 .08 ( dd . J = 2 . 8 Hz. 9 . 6 Hz. 1H ) . White Solid ( 0 .096g , 49 % ). " H NMR ( 400 MHz, 7 .92 - 7 .85 ( m . 1H ) . 7 .84 ( d . I = 7 . 8 Hz. 1H ) , 7 .64 (t . J = 73H DMSOd ) : 58 . 63 ( s , 1H ) , 8 .47 ( d , 2H , J - 8 .2 Hz ), 8 . 40 ( t , 2H , 1H ), 7. 43 - 7. 10 ( m , 3H ) . LRMS (ESI ) calcd . for J = 7 . 3 Hz) , 8 .11 ( dd , 1H , J = 2 . 3 Hz, J = 6 . 9 Hz) , 7 .95 - 7 .94 ( m , CH3FsN2O [ M + H ] * : 457 . 08 . Found : 456 .90 . 1H ) , 7. 86 (d , 1H , J = 7. 8 Hz ), 7. 67 (t , 1H , J = 7 . 8 Hz ), 50 7. 43 - 7. 38 ( m , 3H ), 2 . 53 ( s, 3H ). LRMS (ESI ) calcd . for Example 101 : 3 - ( 4 -( Benzofuran - 2 -y1 ) - 6 - (trifluo CsHqcFN202S [M + H ] +: 485. 08 . Found : 485. 0 . romethyl) pyrimidin -2 - y ) - 4 - fluorobiphenyl- 3 -car boxylic Acid Example 104 : 5 -Fluoro - 3 -( 4 - phenyl- 6 - ( trifluorom ethyl) pyrimidin - 2 -y1 ) biphenyl - 3 -carboxylic Acid 55

CF3 CO2H CO2H F N 66)

????? 65 ???? US 9 ,969 , 726 B2 165 166 White solid ( 0 . 095 g , 54 % ). TH NMR ( 400 MHz , | White solid ( 0 .060 g , 31 % ) . TH NMRR ( 400 MHz , DMSOde) : 68 .63 ( s, 1H) , 8. 49 ( 4, J - 7 . 8 Hz , 1H ) , 8. 41 - 8 .39 | DMSOde ): 88. 59 ( s, 1H) , 8 .39 ( d, J - 7. 8 Hz , 1H) , 8 .36 ( S , ( m, 2H) , 8. 00 (s ,1H ) , 7 . 89 - 7. 80 ( m, 3H ), 7. 66 - 7 .57 ( m ,SH ). TH ), 8. 12 ( dd , J = 4 . 6 Hz. 9. 1Hz , 1H ) 8. 06 ( d , J - 6 .9Hz , 1H) , LRMS ( ESI ) calcd . for CayHi - FAN . O . [ M + H ] : 439.09 . 795- 9 .89 ( m . 2H ), 7 . 69 ( t, JF7 .8Hz ,1HD . 7 .34 ( t . J - 9 . 0 Hz , Found: 438. 90 . 5 1H) , 7 .33 ( d , J - 6 .9 Hz, 1H ) . LRMS ( EST) calcd . for Example 105 : 3 -( 4 -( 3 , 5 - Bis ( trinuoromethyl) phe C HI CIFAN . O . S [ M + H] + : 479 . 01 . Found: 479 . 0 . nyl )- 6- (trihuoromethyl ) pyrimidin- 2 - yl )- 4- fluorobi Example 108 : 4 - Fluoro - 3 -( 4- ( triluoromethyl )- 6 -( 4 phenyl - 3 -carboxylic Acid ( trifluoromethyl ) phenyl) pyrimidin - 2- yl) biphenyl -3 10 carboxylic Acid COSH F CF3 COSH 15

20 CF3 Fac \ White solid ( 0 .07 g , 30 % ). TH NMR ( 400 MHz , White solid ( 0 .130 g , 64 % ). TH NMR ( 400 MHz , DMSOde) :69 .04 ( s ,1H ) , 8. 87 ( s ,1H ) , 8. 63 ( s ,1H ) , 8. 47 + 7 d ,, ?25 DMSOde) : 68 . 64 ( d J = 6 . 8 Hz, 3H ) , 8 . 62 ( s , 1H) , 8 .57 ( s , J = 7. 8 Hz , 1H ) , 8. 26 ( s ,TH ) , 8 . 15 ( s1H) , 7 . 96 - 7 . 93 ( m , 1H) , 1H) , 8 . 48 ( d , J - 8 . 7 Hz , 1H) , 8. 10 ( dd , J = 3 . 4 Hz , 6 . 8 Hz , 1H) , 7 .35 ( d, J - 7 . 8 Hz , 1H) , 7 . 90 ( s ,1H ) , 7. 68 (t , J = 7 . 8 Hz ,1H ) , 7 .96 - 7. 93 ( m, 3H ) , 7. 87 ( d , J - 7. 3 Hz ,1H ) , 7. 68 ( t, J - 7. 8 Hz , 7 .42 ( t , J - 9 . 0 Hz , 1H) . LRMS ( ESI calcd . for 1H) , 7. 41 ( t , J - 9. 0 Hz , 1H) . LRMS ( ESI ) calcd . for CHI - FIN. O . [ M + H] + : 575. 07. Found : 575 .0 . C HI FAN. O . [ M + H] + : 507. 08 . Found: 506. 95 . Example 106 : 3 '- ( 4 -( 1H - Pyrrol - 2- yl )- 6 -( triffuuorom 3030 ethyl ) pyrimidin - 2- yl) - 4 - nuorobiphenyl- 3 -carboxylic Example 109 : 4 - Fluoro -3 -( 4- ( thiazol- 2 - yl) - 6 -( trif Acid luoromethyl ) pyrimidin - 2 - yl) biphenyl -3 - carboxylic Acid 35 COSH CF3 COH

- NH

4 , Yellow solid ( 0 . 080 g , 47 % ). TH?? NMR ( 400 MHz:, Light yellow solid ( 0. 089 g ,50 % ). ?? " HNMR ( 400 MHz , DMSOde) : 612 . 16 ( s , 1H ) 8 . 78 ( s , 1H ) , 8 . 57 ( d, J - 7. 8 Hz , 1H) , 8 .14 ( ( dd , J - 4 . 5 Hz , 6 . 9 Hz , 1H) , 8. 11 ( 5 , “1H … ) , DMSOde) : 68. 58 ( S . IHD . 8 . 42 ( d . J - 7 . 8 Hz, 1H) . 8 . 26 ( s , 8 . 08 - 8. 00 ( m ,1H ) , 7. 86 ( d, JI = 7. 8 Hz, 1H) , 7 .65 (t , J - 7. 8 Hz , 11H) , 8. 19 - 8. 11 ( m ,3H ) , 7 . 96 - 7 . 89 ( m , 2H ) , 7. 69 ( t, J = 7. 8 Hz , 1H) , 747 -745 ( m . 3 ) , 631- 6 30 ( m . TH ) . TRMS ( EST) TH) , 7 . 42 ( t , J - 9 . 0 Hz , IHLRMS ( ESI ) calcd . for calied for CHEN. GAM+ H ]+ . 428 .09 . Found: 428 . 0. 50 CHILFINGOSS [ M+ H] + :446 . 05 .Found :446 . 0 . Example 110 : 3 '- ( 4- ( 4- Chloro - 2- luorophenyl) -6 Example 107 : 3 '- ( 4 -( 3 - Chlorothiophen - 2 - yl) - 6 -( trif ( trifluoromethyl ) pyrimidin- 2 - yl) - 4 -fluorobiphenyl - 3 luoromethyl ) pyrimidin- 2 - yl )- 4 - luorobiphenyl- 3 carboxylic Acid carboxylic Acid 55

CF ; COSH COH

F 60 ??? | 65 ?? US 9 , 969 , 726 B2 167 168 White solid ( 0 . 110 g , 56 % ) . ' H NMR (400 MHz, White solid ( 0 . 069 g , 37 % ). ' H NMR (400 MHz, DMSOdo) : 8 8 .89 ( s, 1H ), 8. 63 ( s, 1H ), 8 .47 ( d , J = 7. 8 Hz , DMSOdo) : 8 8. 92 ( s, 1H ), 8 .68 (s , 1H ), 8 .52 (d , J= 7 .8 Hz, 1H ) , 8 . 23 (s , 1H ) , 8 . 12 (dd , J = 3 . 4 Hz , 6 .8 Hz , 1H ) , 7 . 97 -7 . 89 1 H ) , 8 .26 ( s , 1H ), 7 .95 ( s , 1H ) , 7 . 93 - 7 .87 ( m , 4H ), 7 .69 ( t , ( m , 1H ) , 7 .87 ( d , J = 1. 4 Hz, 1H ) , 7 . 86 ( d , J = 7 . 8 Hz, 1H ) , 7 .65 ( t, J = 7 . 8 Hz , 1H ) , 7 .42 ( t, J = 8 . 7 Hz, 1H ) , 7 .40 ( s , 1H ) . LRMS 5 J = 7 . 8 Hz, 2H ) , 7 . 39 ( d , J = 1 . 8 Hz , 1H ) . LRMS (ESI ) calcd . (ESI ) calcd . for C24H / 2C1F3N202 [ M + H ] * : 491. 05. Found : 5 for C22H 2F4N203 [ M + H ] * : 429. 09 . Found : 429 .00 . 491. 0 . Example 114 : 6 -Fluoro - 3 '- ( 4 -( furan - 3 -yl ) -6 - (trifluo Example 111: 3' - (4 - (3 ,5 -Dimethylisoxazol - 4 -yl ) - 6 romethyl) pyrimidin - 2 - yl) biphenyl- 3 - carboxylic Acid ( trifluoromethyl) pyrimidin - 2 - yl) - 4 - fluorobiphenyl- 3 carboxylic Acid 10 CF3 CO2H CO2H

20 behy of Whiteothers solid (0 .042 g, 22 % ). 'H NMR (400 MHz, DMSOdo ) : 88 .89 ( s , 1H ) , 8 .60 ( s , 1H ) , 8 .54 ( d , J = 7 . 8 Hz , Yellow solid (0 . 130 g , 71 % ). ? H NMR ( 400 MHz, 1H ), 8 .26 (s , 1H ), 8 .09 ( dd , J = 2 .3 Hz, 6 .8 Hz, 1H ), 8 .07 - 8 . 00 DMSO ) : 88 .63 ( s , 1H ) , 8 . 39 ( d , J = 7 . 8 Hz, 1H ) , 8 . 14 - 8 . 13 ( m . 1H ) , 7 . 89 ( t, J = 3 .2 Hz, 1H ) , 7 .79 - 7 .77 ( m , 1H ), 7 .69 ( t , ( m , 1H ) , 7 . 97 - 7 .95 ( m , 1H ) , 7 .91 ( s , 1H ) , 7 . 90 ( d , J = 7 . 8 Hz, > > J = 7 . 8 Hz. 11 ). 7 .49 - 7 . 47 ( m . 11 ). 7 .36 ( d . J = 1 . 4 Hz. 1H ) . 1H ) , 7 .68 ( t, J = 7 . 8 Hz, 1H ), 7 .42 (t , J= 9. 6 Hz , 1H ), 2 .76 (s , LRMS (ESI ) calcd . for C22H , F _N203 [ M + H ] * : 429 .09 . 3H ), 2 .55 ( s , 3H ) . LRMS ( ESI) calcd . for C23H15F4N302 Found : 429 . 00 . [ M + H ] *: 458 .10 . Found : 457 .90 . Example 112 : 4 -Fluoro - 3 '- ( 4 - ( 5 -methylthiophen - 2 - 30 Example 115 : 3 '- (4 -( Furan - 3 -yl ) - 6 -( trifluoromethyl) yl) - 6 - ( trifluoromethyl) pyrimidin - 2 -yl ) biphenyl - 3 pyrimidin - 2 - yl) biphenyl - 3 - carboxylic acid carboxylic Acid CO2H 35 CF3 CO2H

White solid (0 .071 g , 39 % ). 'H NMR (400 MHz, ????? .46 DMSOd ???? . ) : 8 8 . 91 ( s , 1H ) , 8 . 67 ( s , 1H ) , 8 .50 ( d , J = 7 . 8 Hz , 1H ) , 8 .25 ( s , 1H ) , 8 . 22 ( s , 1H ) , 7 . 98 - 7 . 90 ( m , 4H ) , 7 .70 - 7 .64 White solid (0 .050 g, 27 % ) . H NMR (400 MHz, ( m , 2H ) , 7 . 32 ( d , J = 1 . 8 Hz, 1H ) . LRMS ( ESI) calcd . for DMSOd . ) : 8 8 .57 ( s , 1H ) , 8 . 40 ( d , J = 7 . 8 Hz, 1H ) , 8 . 39 ( s , C „ H , F . N O, M + H1+ : 411. 09 . Found : 411 .00 . 1H ) , 8 .21 ( d , J= 3. 7 Hz , 1H ), 8 .20 - 8 . 19 (m , 1H ), 7 .87 ( d , J = 7 . 8 Hz, 1H ) , 7 . 75 - 7 .66 ( m , 2H ) , 7 . 43 ( t , J = 8 . 7 Hz , 1H ) , Example 116 : 4 - Fluoro - 3 ' - ( 4 - ( pyridin - 3 -yl ) - 6 - ( trif 7 .02 - 7 .01 ( m , 1H ) , 2 .57 (s , 3H ) . LRMS ( ESI) calcd . Torfor 50 luoromethyl) pyrimidin - 2 -yl )biphenyl - 3 -carboxylic C23H 4F4N , O2S [ M + H ] * : 458 .07 . Found : 459 . 0 . Acid Example 113 : 5 - Fluoro - 3 ' - ( 4 - ( furan - 3 -yl ) - 6 - ( trifluo romethyl) pyrimidin - 2 -yl ) biphenyl - 3 -carboxylic Acid 55 CO2H F CO2H

65 White solid (0 . 062 g , 32 % ). ' H NMR (400 MHz, DMSO ) : 8 9 . 59 ( s , 1H ) , 8 .79 - 8 .78 ( m , 2H ) , 8 .67 ( s , 1H ) , ofesorios8 .59 (s , 1H ), 8 .51 ( d , J = 8 . 2 Hz, 1H ) , 8 . 12 ( dd, = 2 . 3 Hz, 6 . 9 US 9 , 969 , 726 B2 169 170 Hz , 1H ) , 7 . 98 - 7 . 96 ( m , 1H ) , 7 .89 ( d , J = 7 . 8 Hz, 1H ) , 7 .68 (t , 7 .61 ( t , J = 8 . 2 Hz, 3H ) , 7 .20 ( d , J = 1 . 8 Hz , 1H ) , 2 .49 ( s , 3H ) . J = 7 . 8 Hz, 1H ), 7 .63 - 7 .61 ( m , 1H ), 7 .45 - 7 .42 ( m , 1Hun ) . LRMSmense LRMS reg( ESI) tecalcd an . for C22H16N203 [ M + H ] * : 357. 12 . (ha ESI ) uncalcd persone . for C23H13F4N302 [ M + H ] * : 440 .09 . Found : Found : 357 .00 . 440 . 00 . Example 117 : 4 -Fluoro - 3 '- ( 4 -( furan - 3 -yl ) -6 -methyl Example 120 : 4 -Fluoro - 3 '- ( 4 - ( 6 -methoxypyridin - 3 pyrimidin - 2 -yl ) biphenyl - 3 -carboxylic acid yl) -6 - (trifluoromethyl ) pyrimidin - 2 -yl ) - [ 1 , 1' -biphe nyl] - 3 -carboxylic Acid 10 CO2H CO2H

White??? solid (0 . 064 g, 39 % ). 'H NMR (400 MHz-, 20 MeoMeO CN????? DMSOD ) : 8 8 .64 ( d , J = 8 . 2 Hz , 2H ), 8 . 46 ( d , J = 8 . 0 Hz, 1H ) , 8 . 11 (dd , J= 7 . 3 Hz, 2 . 7 Hz, 1H ) , 7 . 97 - 7 . 96 (m , 1H ) , 7 . 83 (t , Off -white solid (0 . 082 g , 45 % ) . LRMS (ESI ) calcd . J = 1 . 8 Hz, 1H ) , 7 .78 ( d , J = 7 . 8 Hz, 1H ) , 7 .61 - 7 . 59 ( m , 2H ) , CH ENOJM + H1+ : 470 . 10 . Found : 470 .00 . 7 .46 -7 .41 ( m , 1H ), 7 . 19 (d , J = 1. 0 Hz , 1H ) , 2 .53 (s , 3H ). LRMS ( ESI) calcd . for C22H , FN 02 [M + H ]* : 375 .11 . 25 Mul 3276. 0 . Found 4700. valve Found : 375 .00 . Example 121 : 5 -Fluoro - 3 '- ( 4 -( furan - 3 -yl ) -6 -methyl pyrimidin - 2 - yl) - [ 1 , 1' - biphenyl ]- 3 - carboxylic Acid Example 118 : 4 -Fluoro - 3 '- ( 4 - ( furan - 3 -yl ) pyrimidin 2 - yl) biphenyl- 3 - carboxylic Acid 30 CO2H CO2H

40 ?? - White solid ( 0 . 084 g , 56 % ) . LRMS (ESI ) calcd . White solid ( 0 .055 g , 35 % ) . H NMR (400 MHz, C22H15FN203[ M + H ]* : 375. 11 . Found : 375 .00 . DMSOdo ) : 88 .87 ( d , J = 5 . 5 Hz, 1H ) , 8 .68 ( d , J = 3 . 7 Hz , 2H ) , 8 .48 ( d , J= 7 .8 Hz, 1H ), 8 . 14 (dd , J= 6 .8 Hz, 2 .3 Hz , 1H ), 7 .99 -7 .98 ( m , 1H ), 7. 85 - 7. 81 (m , 2H ) , 7 .71 ( d , J= 5 .5 Hz, 45 Example 122 : 4 - Fluoro -3 '- (4 - ( thiophen -3 -yl ) - 6 -( trif 1H ), 7. 64 ( t, J= 7 .8 Hz, 1H ), 7. 44 - 7 .41 (m , 1H ), 7 .23 ( d , luoromethyl) pyrimidin - 2 -yl ) - [ 1, 1' -biphenyl ] -3 -car J = 1 . 4 Hz, 1H ) . LRMS (ESI ) calcd . for C21H13FN203 [ M + boxylic Acid H ] * : 361. 09. Found : 361 . 00 . Example 119 : 3' - (4 -( Furan - 3 -yl ) - 6 -methylpyrimidin 50 2 - yl) biphenyl- 3 - carboxylic Acid COH opihenju embonglie d F

CO2H 55

otros 60 Whitegringas solid ( 0 .092 g , 52 % ) . ' H NMR (400 MHz , DMSOdo) : 88 .89 -8 .88 (m , 1H ), 8 .66 (s , 1H ), 8 .50 (d , J = 7. 8 Hz, 1H ) , 8 . 38 ( s , 1H ) , 8 . 14 - 8 .09 ( m , 2H ), 8 . 02 - 7 . 98 ( m , 1H ) , White solid (0 . 037 g , 24 % ). ' H NMR (400 MHz, as 7 .88 (d , J = 7. 8 Hz, 1H ) , 7. 78 - 7. 76 (m , 1H ), 7. 68 (t , J= 7. 8 Hz, DMSOdo) : 8 8 .69 ( s , 1H ), 8 .63 ( s , 1H ), 8 . 49 ( d , J = 7 . 8 Hz , 1H ), 7 . 46 - 7 .42 ( m , 1H ) . LRMS (ESI ) calcd . 1H ), 8 . 22 (s , 1H ), 7. 94 (t , J = 6 .9 Hz , 2H ), 7 .84 - 7 . 83 (m , 2H ), C22H 2F4N2O2S [M + H ]* : 445 .05 . Found : 445 .00 . US 9 , 969, 726 B2 171 172 Example 123 : 2 - (3 -( 2H - Tetrazol- 5 - yl) biphenyl - 3 C . for 1 h . The reaction mixture was cooled to room yl) - 4 - ( trifluoromethyl) -6 - (6 - ( trifluoromethyl) pyri temperature and diluted with water and followed a usual din - 3 -yl ) pyrimidine work up with ethyl acetate . The crude residue was purified by prep - HPLC to yield the title compound . White solid 5 ( 0 . 150 g , 68 % ) . ' H NMR ( 400 MHz, DMSOdo) : 88 . 90 ( s , 1H ) , 8 .70 ( s , 1H ) , 8 . 50 ( d , J = 7 . 8 Hz , 1H ) , 8 . 33 ( dd , J = 2 . 8 Hz. Scheme 15 9 . 2 Hz, 1H ) , 8 .25 ( s , 1H ) , 8 .02 - 7 . 98 ( m , 1H ), 7 . 94 - 7 . 90 ( m , CF3 CN 2H ) , 7 .71 ( t, J = 7 . 8 Hz, 1H ) , 7 .60 - 7 . 58 ( m , 1H ) , 7 .39 (d , NaN3 , 10 529J= 1. 810 HzE , 1H ). LRMS (ESI ) calcd . C24H /2F N , [M + H ] *: NH4Cl 10 532 . 10 . Found : 532 .00 . DMF, Example 125 : 3 - ( 1 - ( 4 - ( Trifluoromethyl) - 6 - (6 - (trif 100° C ., 1 h luoromethyl) pyridin - 3 - yl) pyrimidin - 2 - yl) - 1H - imida 15 zol- 4 - yl) benzenesulfonamide FC N =ŽN - NH N N 20 ] 25 FCM F C N 'SO2NH2 3' - ( 4 - Trifluoromethyl) - 6 -( 6 -( trifluoromethyl) pyridin -3 2 - ( 4 -Iodo - 1H - imidazol- 1 -yl ) -4 -( trifluoromethyl ) -6 -( 6 yl) pyrimidin - 2 - yl )biphenyl - 3 - carbonitrile ( 0 .047 g 0 . 1 30 ( trifluoromethylpyridin - 3 - yl) pyrimidinel ( 0 .048 g , 0 . 1 mmol) , sodium azide ( 0 .078 g , 1 . 2 mmol) , and ammonium mmol) , 3 - sulfamoylphenylboronic acid ( 0 .030 g , 0 . 15 chloride (0 .078 g , 1 . 2 mmol) were taken in DMF ( 2 mL ) and mmol) , tetrakistriphenylphosphinepalladium ( 0 ) ( 0 . 011, 0 .01 the resulting mixture was heated at 100° C . for 1 h . The mmol) , 2M Na2CO3 (0 . 2 mL , 4 mmol) were dissolved in 4 reaction mixture was cooled to room temperature and mL of DME. The reaction mixture was then processed diluted with water and followed a usual work up with ethyl 35 according to the general procedure described in Example 69, acetate . The crude residue was purified by prep -HPLC to step 6 , to afford the title compound as a yellow solid ( 0 .014 yield the title compound as a white solid ( 0 .034 g , 67 % ). ' H g , 29 % ) . ' H NMR (400 MHz, DMSOd . ) : 89 .87 ( s , 1H ) , 9 . 18 NMR ( 400 MHz , DMSOdo ) : 89 . 78 ( s , 1H ) , 9 .04 ( dd , J = 1 . 8 (d , J = 8 .2 Hz, 1H ), 8. 96 (s , 1H ), 8 .67 (d , J = 8 .7 Hz, 2H ), 8 .43 Hz , 10 .0 Hz , 1H ), 8 .79 ( s, 1H ) , 8 .75 (s , 1H ), 8 .58 (d , J = 7 .8 (s , 1H ), 8 . 30 - 8 .15 ( m , 2H ), 7 .20 ( d , J = 7 . 8 Hz, 1H ), 7 .58 ( t, Hz, 1H ) , 8 . 37 ( s , 1H ) , 8 . 14 ( d , J = 8 . 2 Hz, 1H ) , 8 .06 ( d , J = 7 . 8 40 J = 9 , 0 Hz. 11 ) . 7 .38 ( s . 2H ) . LRMS ( ESI) calcd . for Hz, 1H ) , 7 .97 ( t , J = 8 . 7 Hz, 3H ) , 7 .75 ( d , J = 7 . 8 Hz , 2H ) . C LRMS (ESI ) calcd . for C24H 3F6N , [ M + H ] * : 514 . 11 . C20H12F6N /02S [M + H ] *: 515 .06 . Found : 515 .0 . Found : 514 .00 . Example 126 : 3 - ( 1 - (4 -( Trifluoromethyl) -6 -( 6 -( trif luoromethyl) pyridin - 3 - yl) pyrimidin - 2 -yl ) - 1H - imida Example 124 : 2 - (4 '- Fluoro - 3 '- (2H -tetrazol - 5 -yl ) - [ 1, 45 1 '- biphenyl] - 3 - yl) - 4 -( trifluoromethyl ) - 6 - ( 6 - ( trifluo zol- 4 -yl ) aniline romethyl) pyridin - 3 - yl) pyrimidine

CF3 50 N - NH CF3 F 55 La F3CF C prima NH2 60 2 -( 4 - Iodo - 1H - imidazol- 1 -yl ) - 4 -( trifluoromethyl) - 6 -( 6 FC N (trifluoromethyl ) pyridin - 3 - yl) pyrimidin ( 0 . 048 g , 0 . 1 mmol) , 3 -aminophenylboronic acid (0 .023 g , 0 . 15 mmol) , 4 - Fluoro - 3 '- ( 4 - ( trifluoromethyl ) -6 - (6 - ( trifluoromethyl) tetrakistriphenylphosphinepalladium (0 ) (0 .011 , 0 .01 mmol) , pyridin - 3 - yl) pyrimidin - 2 - yl) - [ 1 , 1 ' -biphenyl ] - 3 -carbonitrile 2M Na2CO3 (0 .2 mL , 4 mmol) were dissolved in 4 mL of ( 0 . 2 g , 0 . 489 mmol) , sodium azide ( 0 . 381 g , 5 . 86 mmol) , and 65 DME . The reaction mixture was then processed according to ammonium chloride ( 0 . 314 g , 5 . 59 mmol) were taken in the general procedure described in Example 69, step 6 , to DMF ( 5 mL ) and the resulting mixture was heated at 100 afford the title compound as a yellow solid (0 .011 g , 24 % ). US 9 ,969 , 726 B2 173 174 ' H NMR (400 MHz, DMSOdo ) : 811. 37 (s , 1H ), 9 .12 (s , 1H ), Step 1 : N - ( 3 -Bromophenyl ) -4 - ( furan - 2 - yl) -6 - ( trif 8 .67 ( d , J = 8 . 7 Hz, 2H ) , 8 .23 ( s , 1H ) , 7 .68 ( d , J = 8 . 2 Hz , 1H ) , luoromethyl) pyrimidin - 2 - amine 7 . 39 ( t, J = 7 . 8 Hz, 1H ), 6 . 73 (s , 1H ), 6 . 5 ( s , 1H ) , 6 . 1 ( s , 1H ) . LRMS ( ESI) calcd . for C20H12F6N6 [M + H ] * : 451. 10 . Found : 451. 0 . CF3 General Synthetic Scheme for the Preparation of 4 -Fluoro - 3 '- ( 4 -( furan - 2- yl )- 6 -( trifluoromethyl )py rimidin - 2 - yl) biphenyl Carboxylic Acid Derivatives 10 Scheme 16 v NHNH CF3 Bra XS

Potassium carbonate ( 0 . 103 g , 0 . 75 mmol) was added to a solution of 2 -chloro - 4 - ( furan - 2 - yl ) - 6 - (trifluoromethyl ) py CO2H 20 rimidine ( 0. 124 g , 0. 5 mmol ) and 3 -bromoaniline (0 .129 g, 0 .75 mmol) in CH3CN (5 mL ) . After stirring for 12 h at 80° C . , the organic phase was evaporated under reduced pressure and the crude material was partitioned between water and CH _ C12 . The aqueous layer was extracted with CH2Cl2 (HO )2B ( 3x15 mL ) . The organic layer was washed with IN HCl (5 mL ) and then dried over Na2SO4 and evaporated to give N - ( 3 -bromophenyl ) - 4 - ( furan - 2 - yl ) - 6 - ( trifluoromethyl ) py rimidin - 2 - amine ( 0 .158 g , 82 % ) . The crude product was - Br 20 used for the next step without further purification . LRMS CF3 (ESI ) calcd . for C15H ,BrF3N30 [ M + H ] *: 383. 98, 385 . 97 . Found : 384 . 0 , 386 . 0 . Step 2 : 4 -Fluoro - 3 '- ( 4 - ( furan - 2 - yl ) - 6 - ( trifluorom 35 ethyl) pyrimidin - 2 -ylamino )biphenyl - 3 -carboxylic Acid

CO2H 40 CE3 F i) K2CO3, CH3CN , 80º C .; ii) Pd (PPh3 ) 4 , 2M Na2CO3, DME , 80° C ., 12 h X = NH , O , S 45 NH Example 127 : 4 - Fluoro -3 '- ( 4 -( furan -2 -yl ) -6 - ( trifluo romethyl) pyrimidin - 2 - ylamino )biphenyl - 3 -carbox - CO2H ylic Acid 50

T] CF3 55 2 N - ( 3 - Bromophenyl) - 4 - ( furan - 2 - yl ) - 6 - ( trifluoromethyl ) N pyrimidin - 2 -amine ( 0 . 155 g , 0 .4 mmol) , 5 - borono - 5 - fluo robenzoic acid ( 0 . 110 g , 0 .6 mmol) , tetrakistriphenylphos NH phinepalladium ( 0 ) ( 0 . 060 g , 0 . 04 mmol) , 2M Na2CO3 ( 0 . 8 mL , 4 mmol) were dissolved in DME . The reaction mixture 60 was then processed according to the general procedure described in Example 69, step 7 , to afford the title compound - CO2H as a yellow solid ( 0 .088 g , 49 % ) . ' H NMR (400 MHz, DMSOd . ) : 810 . 35 ( s , 1H ) , 8 . 33 ( s , 1H ) , 8 . 14 ( dd , J = 2 . 8 Hz, 6 . 8 Hz, 1H ) , 8 .02 ( s , 1H ) , 7 . 90 - 7 .87 ( m , 1H ) , 7 .71 ( d , J = 9 . 0 65 Hz , 1H ) , 7 . 52 ( d , J = 3 . 3 Hz, 1H ) , 7 . 52 ( s , 1H ) , 7 . 43 ( t, J = 8 .2 Hz, 1H ), 7 .30 ( s , 1H ), 6 .77 ( m , 1H ) . LRMS (ESI ) calcd . for C22H / 3F4N303 [ M + H ] * : 444 . 08 . Found : 444. 0 . US 9 ,969 , 726 B2 175 176 Example 128 : 4 - Fluoro - 3 ' - ( 4 - ( furan - 2 - yl) - 6 - (trifluo 2 - ( 3 -Bromophenoxy ) - 4 - ( furan - 2 - yl) - 6 - ( trifluoromethyl) romethyl) pyrimidin - 2 -yloxy )biphenyl - 3 - carboxylic pyrimidine ( 0 . 154 g , 0 . 4 mmol) , 5 - borono - 5 - fluorobenzoic Acid acid ( 0 .110 g , 0 . 6 mmol) , tetrakistriphenylphosphinepalla dium ( 0 ) (0 .060 g , 0 .04 mmol) , 2M Na2CO3 (0 .8 mL , 4 5 mmol ) were dissolved in DME . The reaction mixture was then processed according to the general procedure described in Example 69 , step 7 , to afford the title compound as an off -white solid ( 0 .09 g , 51 % ) . ' H NMR ( 400 MHz , DMSO ) : 68 . 09 (dd , J = 2 . 3 Hz , 6 . 8 Hz, 1H ) , 8 .07 ( s , 1H ) , 10 8 . 03 - 7 . 92 ( m , 2H ) , 7 .66 - 7 .54 ( m , 4H ) , 7 . 38 ( t , J = 9 . 0 Hz, 1H ), 7 .31 (d , J = 7 . 8 Hz , 1H ), 6 .75 -6 .74 ( m , 1H ). LRMS (ESI ) calcd . for C22H12F2N204 [ M + H ] * : 445. 07 . Found : 445 .0 . CO2H 15 Example 129: 4 - Fluoro - 3 '- ( 4 - ( furan - 2 - yl) - 6 - ( trifluo F romethyl) pyrimidin - 2 - ylthio ) biphenyl- 3 - carboxylic Acid

Step 1 : 2 - ( 3 -Bromophenoxy ) - 4 - ( furan - 2 - yl) 16 -6 - ( triftrif - 20 luoromethyl) pyrimidine CF3 CF3

25 ' s

30 CO2H

Br Potassium carbonate (0 .103 g , 0. 75 mmol) was added to a solution of 2 - chloro -4 - ( furan -2 -yl ) - 6 -( trifluoromethyl ) py 35 rimidine ( 0 . 124 g , 0 . 5 mmol) and 3 - bromophenol ( 0 . 129 g , 0 .75 mmol ) in CH , CN (5 mL ) . After stirring for 2 h at 80° Step 1 : 2 - ( 3 - Bromophenylthio ) - 4 - ( furan - 2 - yl ) - 6 C . , the organic phase was evaporated under reduced pressure ( trifluoromethyl) pyrimidine and the crude material was partitioned between water and CH _ C12 . The aqueous layer was extracted with CH C12 ( 3x15 mL ). The organic layer was dried over Na , SO , and evaporated to give 2 -( 3 -bromophenoxy )- 4 -( furan -2 -yl ) -6 CF3 ( trifluoromethyl) pyrimidine ( 0 . 192 g , quantitative ) . The crude product was used for the next step without further purification . LRMS (ESI ) calcd . for C15H BrF3N202 45 [ M + H ] * : 384 . 97 , 386 . 99. Found : 385 . 0 , 387 . 0 . ' s Step 2 : 4 - Fluoro - 3 '- ( 4 - ( furan - 2 - yl) - 6 - ( trifluorom ethyl) pyrimidin -2 - yloxy )biphenyl - 3 -carboxylic Acid 50 Br

Potassium carbonate ( 0 . 103 g , 0 .75 mmol) was added to SS> a solution of 2 -chloro - 4 - ( furan - 2 - yl) - 6 - ( trifluoromethyl )py rimidine (0 . 124 g , 0 . 5 mmol) and 3 - bromobenzenethiol ( 0 . 08 mL , 0 . 75 mmol) in CH2CN ( 5 mL ) . After stirring for 2 h at 80° C ., the organic phase was evaporated under reduced pressure and the crude material was partitioned between water and CH , C1 , . The aqueous layer was extracted with CH C12 ( 3x15 mL ). The organic layer was dried over CO2H Na2SO4 and evaporated to give 2 - ( 3 - bromophenylthio ) - 4 ( furan - 2 -yl ) -6 -( trifluoromethyl ) pyrimidine ( 0 . 190 g , 94 % ). 65 The crude product was used for the next step without further purification . LRMS ( ESI) calcd . for C15H , BrF3N2OS [ M + H ] * : 400 . 94 , 402 . 94 . Found : 401 . 0 , 403 . 0 . US 9 , 969 , 726 B2 177 178 Step 2 : Fluoro - 3 '- ( 4 - ( furan - 2 - yl ) - 6 - ( trifluoromethyl) The resulting reaction mixture was sparged with N2 for 10 pyrimidin - 2 -ylthio )biphenyl - 3 - carboxylic Acid min and 4 - fluoro -phenylacetylene ( 0 .021 g , 0 . 18 mmol) ) was added to the reaction mixture . The resulting brown solution was heated to reflux for 2 h . After cooling, the reaction mixture was diluted with EtoAc and filtered through a pad of Celite . The filtrate was concentrated under reduced pressure and the crude product was purified by HPLC to give a white solid (0 .006 g , 21 % ). 'H NMR (400 MHz, DMSOdo ) : 89 .77 ( s , 1H ) , 9 . 18 ( d , J = 8 . 2 Hz, 1H ) , 8 . 76 10 ( s, 1H ), 8 .64 (s , 1H ), (d , J= 8 .2 Hz , 1H ), 8 . 16 (d , J = 7 .8 Hz , 1H ), 7. 79 ( d , J= 8 .2 Hz, 1H ), 7. 69 - 7. 66 (m , 3H ), 7 .58 ( t, J= 9. 0 Hz, 2H ) . LRMS ( ESI) calcd . for C25H / 2F ,N3 [M + H ] *: 488 .09 . Found : 488 . 0 . CO2H 15 General Scheme for the Synthesis of 4 - fluoro - 3 '- ( 4 ( furan - 3 - yl) - 6 - (trifluoromethyl ) pyrimidin - 2 - yl) - N hydroxy / N -methoxy - [ 1 , 1' - biphenyl ] - 3 - carboxamide Derivatives 2 -( 3 -Bromophenylthio )- 4 - ( furan - 2- yl ) - 6 -( trifluorom - 20 ethyl) pyrimidine (0 . 161 g , 0 . 4 mmol) , 5 -borono - 5 - fluo robenzoic acid ( 0 . 110 g , 0 . 6 mmol) , tetrakistriphenylphos Scheme 18 phinepalladium ( 0 ) ( 0 .060 g , 0 .04 mmol) , 2M Na2CO3 ( 0 . 8 ÇO2H mL , 4 mmol) were dissolved in DME . The reaction mixture CF3 CDI, was then processed according to the general procedure F . NHOR .HCI described in Example 69, step 7 , to afford the title compound DCM , as a yellow solid ( 0 . 120 g , 65 % ) . ' H NMR ( 400 MHz, rt, 1 h DMSO ) : 88 .62 ( s , 1H ) , 8 .45 ( d , J = 7 . 8 Hz, 1H ) , 8 . 20 ( s , 1H ), 7 .90 ( d , J = 7 . 8 Hz, 1H ) , 7 . 86 ( s , 1H ), 7 .70 - 7 .68 ( m , 3H ) , 7 .58 - 7 .52 ( m , 2H ) , 7 . 42 ( t , J = 9 . 0 Hz, 1H ) . LRMS (ESI ) 30 b calcd . for C22H / 2F4N203S [ M + H ] * : 461. 05 . Found : 460 .85 . Example 130 : 2 - ( 3 - ( ( 4 -Fluorophenyl ) ethynyl ) phe store nyl) - 4 - ( trifluoromethyl) - 6 - ( 6 - ( trifluoromethyl) pyri 1 din - 3 -yl ) pyrimidine 35 ! Scheme 17 R = H , Me

Example 131 : 4 - Fluoro - 3 ' - ( 4 - ( furan - 3 - yl) - 6 - ( trifluo 45 romethyl) pyrimidin - 2 -yl ) - N -hydroxy - [ 1 , 1 '- biphe nyl] -3 -carboxamide F C is DitF Pd (PPh3 ) 2Cl2 50 Cu ( I ) I, Et3N , THF : DMF LZ CF3 OH

s55

60 F3C siyatiN Tooferite a solution of 4 -fluoro - 3' - (4 -( furan -3 -yl ) - 6 - (trifluorom ethyl) pyrimidin -2 - yl) biphenyl - 3 - carboxylic acid (0 .043 g , To a stirred mixture of Pd (PPhz ) 2C1 , (0 . 004 g , 0 .006 0 . 1 mmol) in DCM (2 mL ), was added carbonyl diimidazole mmol) , copper iodide ( 0 . 002 , 0 . 009 mmol) and triethylam - (0 .018 g , 0 . 11 mmol) . The resulting mixture was stirred at ine ( 0 .03 mL , 0 .24 mmol) in THF : DMF ( 1 : 1 , 2 mL ) was 65 room temperature for 1 h . Hydroxylamine hydrochloride added 3 -bromophenyl ) - 4 - ( trifluoromethyl ) - 6 - 6 - ( trifluo - ( 0 .011 g , 0 .150 mmol) was added to the same reaction romethyl) pyridin - 3 -yl ) pyrimidine ( 0 .025 g , 0 .06 mmol) . mixture and stirring was continued for another 1 h after that US 9 , 969, 726 B2 179 180 time solvent was removed under reduced pressure. The Step 1 : 4 - Fluoro - 3 '- ( 4 - ( furan - 3 -yl ) -6 - ( trifluorom crude product was purified by reverse phase HPLC to give ethyl) pyrimidin - 2 - yl) - N ' -hydroxy -[ 1 , 1 '- biphenyl ] - 3 the title compound as a colorless solid (0 .028 g , 63 .2 % ) . ' H carboximidamide NMR (400 MHz , DMSO - do) : 8 11. 09 ( s, 1H ), 8 . 90 (s , 1H ), 8 .66 (s , 1H ), 8 .47 (d , J = 7 . 8 Hz, 1H ), 8 . 25 ( s , 1H ), 7 . 91 - 7 . 84 5 ( m , 4H ), 7 .65 ( t, J = 7 . 8 Hz, 1H ), 7 .42 - 7 .38 ( m , 2H ) . LC -MS HN ( ESI ) calcd for C22H13F4N203 [ M + H ] * : 444 . 36 . Found : H2NAOH?? 444 . 0 . CF3 10 Example 132 : 4 - Fluoro -3 '- ( 4 -( furan -3 -yl ) -6 - ( trifluo romethyl) pyrimidin - 2 - yl) - N -methoxy - [ 1 , 1 '- biphe nyl] - 3 -carboxamide

15 4 - Fluoro - 3 ' - ( 4 - ( furan - 3 -yl ) -6 - ( trifluoromethyl )pyrimidin COME 2 -yl ) biphenyl - 3 -carbonitrile ( 1 g , 2 .443 mmol) and hydrox ylamine (50 % aqueous solution , 0 .28 mL ) were taken in EtOH ( 10 mL ) and refluxed for 30 min in the presence of AcOH (few drops ) , cooled and diluted with water . The precipitated 4 - fluoro -3 ' -( 4 - (furan -3 - yl) -6 -( trifluoromethyl) pyrimidin -2 -yl ) -N '- hydroxy - [1 , 1' - biphenyl ] - 3 -carboximid 25 amide was collected by filtration and purified by silica gel column chromatography (Hexanes :Ethyl acetate , 4 : 1 ) to afford the desired compound as a white solid ( 0 .51 g , In a similar manner described for 4 - fluoro - 3 '- ( 4 - ( furan 47 . 2 % ) . LC -MS ( ESI) calcd for C22H14F4N 02 [ M + H ] * : 3 - yl) -6 - ( trifluoromethyl) pyrimidin - 2 - yl) - N -hydroxy - [ 1 , 1' - 443 . 38 . Found : 443 .00 . biphenyl] -3 -carboxamide ( Example 127 ) with appropriate 30 starting materials , the title compound was prepared as a colorless solid ( 0 .037 g , 81 % ). 'H NMR (DMSO - do ): 8 Step 2 : 3 - ( 4 - Fluoro - 3 ' - ( 4 - ( furan - 3 - yl) -6 - ( trifluorom 11 .67 ( s , 1H ), 8 .90 ( d , J = 3 . 4 Hz , 1H ) , 8 .65 ( d , J = 3 . 7 Hz, 1H ) , ethyl) pyrimidin - 2 -yl ) - [ 1 , 1 ' - biphenyl] - 3 - yl) - 1 , 2 , 4 8 . 46 (t , J = 5 . 5 Hz, 1H ) , 8 . 24 (t , J = 7 . 4 Hz, 1H ) , 7 .89 - 7 .68 ( m , oxadiazol- 5 (4H ) -one 4H ), 7 .66 - 7 .63 ( m , 1H ) , 7 . 44 - 7 . 38 ( m , 2H ) , 3 .72 ( s , 3H ) . 35 LC -MS (ESI ) calcd for C23H 5F4N203[ M + H ] * : 458 . 38 . Found : 458 . 0 . Example 133 : 3 - (4 - Fluoro - 3 '- ( 4 -( furan -3 -yl ) -6 - ( trif 40 luoromethyl) pyrimidin - 2 - yl ) -[ 1 , 1' - biphenyl ] -3 -yl ) - 1, 40 NH 2 , 4 - oxadiazol- 5 (4H ) -one CF3 F

Scheme 19 45 H2NN - OH DBU , F CDI 50 Dioxane, A mixture of 4 - fluoro -3 '- ( 4 -( furan -3 - yl) -6 -( trifluorom reflux , 3 h ethyl) pyrimidin - 2 - yl ) - N '- hydroxy - [ 1 , 1 ' -biphenyl ] - 3 - car boximidamide (0 .150 g , 0 .339 mmol) , carbonyl diimidazole ( 0 . 082 g , 0 .509 mmol) and DBU ( 0 .206 g , 1 .356 mmol) were taken in dioxane ( 5 mL ) and heated at reflux for 3 h . Excess solvent was removed under vacuum and diluted with water and pH adjusted to 4 - 5 with dil . HCl and extracted with ethyl NH acetate (3x5 mL ) . The organic layer washed with brine , CF3 dried over Na2SO4, followed by removal of the solvent F 60 under reduced pressure to yield the crude productwhich was purified by reverse phase HPLC to give the title compound as a white solid ( 0 . 085 g , 53 . 5 % ) . ' H NMR (DMSO - da ) : 8 8 .91 ( s , 1H ) , 8 .69 ( s , 1H ) , 8 . 49 ( d , J = 7 . 8 Hz , 1H ) , 8 . 26 ( s . 1H ) , 8 . 12 ( dd , J = 2 . 2 Hz, 6 . 4 Hz, 1H ) , 8 .06 - 8 .02 ( m , 1H ) , 65 7 . 92 - 7 . 90 ( m , 2H ) , 7 .69 ( t , J = 7 . 8 Hz, 1H ), 7 .60 - 7 .56 ( m , 1H ) , 7 . 40 ( d , J = 1 . 8 Hz, 1H ) . LC -MS (ESI ) calcd for C23H /2F4N403 [ M + H ]* : 469. 37 . Found : 469. 0 . US 9 ,969 , 726 B2 181 182 Example 134 : 3 - ( 4 -Fluoro - 3 '- ( 4 - ( furan - 3 -yl ) - 6 - ( trif - continued luoromethyl) pyrimidin - 2 - yl) - [ 1 , 1' - biphenyl] - 3 -yl ) - 1 , 2 , 4 - oxadiazole - 5 ( 4H ) - thione VH CF3 Scheme 20 F H2N OH DBU . 10 TCDI ACN , rt , 4 h 15 A mixture of 4 - fluoro - 3' - (4 -( furan - 3 -yl ) - 6 -( trifluorom ethyl) pyrimidin - 2 -yl ) - N '- hydroxy - [ 1 , 1 '- biphenyl] - 3 -car boximidamide (0 . 15 g , 0 .339 mmol) and thiocarbonyl diimi dazole (0 .072 g , 0 .407 mmol) in THF (5 mL ) was stirred at rt for 30 min . The mixture was diluted with water and NH 20 extracted with ethyl acetate ( 3x5 mL ) . The organic phase CF3 was washed with water and concentrated . The residue was redissolved in THF ( 5 mL ) , BFz .OEt , ( 0 . 241 g , 1 . 7 mmol ) was added , and the reaction mixture was stirred at rt for 1 h . The reaction mixture was diluted with water and extracted 25 with ethyl acetate ( 3x5 mL ). The organic layer washed with IN HCl and dried over anhydrous Na2SO4, removal of the solvent, followed by reverse phase HPLC yielded the title compound as a yellow solid ( 0 . 1 g , 60 . 9 % ) . ' H NMR ( DMSO - do ) : 88. 91 ( s , 1H ) , 8 .68 ( s , 1H ), 8 .49 ( d , J = 7 . 8 Hz, A mixture of 4 -fluoro - 3 '- (4 - ( furan -3 - yl) - 6 -( trifluorom - 30 1H ) , 8 .26 ( s , 1H ) , 8 . 10 ( d , J = 6 . 9 Hz, 1H ), 7 . 96 - 7 . 90 ( m , 4H ) , ethyl) pyrimidin - 2 - yl) - N '- hydroxy - [ 1 , 1' -biphenyl ] - 3 - car 7 .69 ( t, J = 7 . 8 Hz, 1H ) , 7 . 60 - 7 .56 (m , 1H ), 7 . 39 ( s , 1H ) . boximidamide ( 0 . 100 g , 0 .226 mmol) , thiocarbonyl diimi- LC -MS ( ESI) calcd for C , H , F .NO , S M + H ] : 485 .42 . dazole ( 0 .06 g, 0 .339 mmol) and DBU ( 0 . 138 g , 0 .904 Found : 485 . 0 . mmol) in acetonitrile ( 5 mL ) was stirred at rt for 4 h . Excess 35 Synthesis of Intermediates G - R solvent was removed under vacuum and diluted with water and pH adjusted to 4 -5 with dil . HCl and extracted with ethyl Ethyl 3 - ( 3 -bromophenyl ) - 3 - oxopropanoate (G ) acetate ( 3x5 mL ) . The organic layer washed with brine , dried over Na2SO4 , followed by removal of the solvent under reduced pressure to yield the crude product which was to purified by reverse phase HPLC to give the title compound BI LHMDS, THF as a white solid (0 .08 g , 73 . 1 % ) . ' H NMR (DMSO -do ) : 8 OEt EtOAC 8 . 91 ( s, 1H ), 8 .69 ( s, 1H ), 8 .49 ( d , J= 7 .8 Hz, 1H ), 8 .26 ( s , 1H ) , 8. 23 (dd , J= 2 . 8 Hz, 6 . 4 Hz, 1H ), 8 .06 - 8 .03 (m , 1H ), 45 7 .92 - 7 . 90 ( m , 2H ) , 7 .69 ( t, J = 7 . 8 Hz, 1H ) , 7 .60 - 7 . 56 ( m , O 1H ) , 7 .40 ( d , J = 1 . 8 Hz , 1H ) . LC -MS ( ESI) calcd for C23H /2F4N402S [ M + H ]* : 485. 42 . Found : 485. 0 . OEt 50 Example 135 : 3 - (4 -Fluoro - 3 '- ( 4 -( furan - 3 -yl ) -6 - ( trif luoromethyl) pyrimidin - 2- yl ) - [1 , 1 '- biphenyl ] - 3 -yl ) - 1, 2 , 4 - thiadiazol- 5 (4H ) -one To a stirred solution of 1 . 3 M LHMDS (25 mL , 32 . 7 55 mmol) in THF ( 10 mL ) was added EtOAC ( 1 . 9 g , 21 .8 mmol) at – 78° C . under inert atmosphere . After being stirred Scheme 21 for 15 min , ethyl- 3 - bromo benzoate ( 5 g , 21 . 8 mmol) was added and stirring was continued for 2 h ; progress of the H2N - OH reaction was monitored by TLC . The reaction was quenched TCDI, THFE , o60 with aq . NH4Cl ( 10 mL ) and extracted with EtOAC ( 3x20 30 min mL ) . The combined organic extracts were dried over anhy drous Na2SO4 and concentrated under reduced pressure to BFz. OEt2 , obtain the crude product. The crude material was purified by rt, 4 h silica gel column chromatography eluting with 4 % EtoAc / glago 65 Hexane to afford compound G ( 4 . 5 g , 76 . 9 % ) as a mixture with its enolic form as a brown oil . ' H NMR (500 MHz, CDC1z ) : 8 8 .07 ( s , 1H ) , 7 . 86 ( d , J = 7 . 5 Hz , 1H ) , 7 .73 - 7 .69 ( m , US 9 , 969 , 726 B2 183 184 1H ) , 7 .37 ( t, J = 7 .0 Hz, 1H ) , 4 .28 - 4 .26 ( m , 2H ), 3 . 92 ( s, 2H ), dried over Na2SO4, concentrated and purified by column 1 .24 ( t, J = 6 . 2 Hz, 3H ) . MS (ESI ) : m / z 298 . 8 [M – 1 ] . chromatography to give compound I. ( 4 . 2 g , yield : 58 . 3 % ) . 19 20 22 24). Se' H NMR con ( 400 MHz, DMSO - do) : 8 12. 32 (s , 1H ) , 8 .63 ( d , Methyl 3 -( 3 - cyanophenyl) - 3 -oxopropanoate (H ) J = 4 . 8 Hz, 2H ) , 8 . 52 ( d , J = 5 . 2 Hz, 1H ) , 7 .93 ( s , 2H ) , 7 .87 ( s , 5 1H ) , 7 .79 - 7 .84 ( m , 1H ) , 6 .22 ( s , 1H ) , 4 .22 - 4 . 28 ( m , 4H ) , 4 .10 -4 .15 ( m , 4H ), 4 .01 - 4 .08 (m , 2H ) , 1 .98 (s , 3H ) , 1 .25 1 .29 ( m , 3H ), 1 . 20 - 1 . 23 ( m , 6H ) . Methyl 3 - ( 2 - cyanopyridin - 4 - yl) - 3 - oxopropanoate ( 1) NO bo 10 NaH , Dry THF

Ac Ac C 15 NC m - CPBA TMSCN

puis - 0 ? 20 To a stirred solution of 3 -acetylbenzonitrile (1 g , 6 .89 mmol) in dry THF ( 30 mL ) under inert atmosphere was added sodium hydride (60 % ) ( 326 mg, 13. 5 mmol) portion wise at 0° C . followed by dimethyl carbonate ( 1 .24 g , 13 . 7 25 THF mmol) . The reaction mixture was heated to 60° C . and stirred for 7 h ; progress of the reaction was monitored by CN CN TLC . The reaction mixture was quenched with dil. HC1 ( 2 mL ) , diluted with water (50 mL ) and extracted with EtOAC ( 2x30 mL ) . The combined organic extracts were dried over 30 To the solution of 1 - ( pyridin - 4 - yl) ethanone ( 10 g , 82. 5 anhydrous Na ,SO , and concentrated under reduced pressure mmol) in DCM ( 150 mL ) was added m - CPBA ( 19 g , 90. 8 to obtain the crude product . The crude material was purified mmol) . The reaction mixture was stirred under reflux for 16 by silica gel column chromatography eluting with 10 % hrs . After removal of the solvent, the residue was washed EtOAc/ Hexane to afford compound H as a mixture of111 its 35 with MTBE to give 1 - ( pyridin - 4 - yl) ethanone N -oxide ( 10 g , enolic form ( 950 mg, 67 . 8 % ) as a pale yellow liquid . ' H 35 yieldW : 88 % ). NMR (500 MHz, DMSO - do ) : 8 8 .40 ( s , 1H ) , 8 . 31 - 8 .22 ( m , To a solution of 1 - (pyridin -4 - yl) ethanone N -oxide (0 .5 g , 1H ) , 8 . 19 - 8 . 12 ( m , 1H ) , 7 .77 - 7 .75 ( m , 1H ) , 4 .29 ( s , 2H ) , 3 . 65 mmol ) in DCM ( 8 mL) was added TMSCN (398 mg, 3 .64 ( s, 3H ). MS ( ESI) : m / z 204 [M + 1 ]* . 4 .01 mmol) . After stirring for 5 mins, dimethycarbamoyl Methyl 3 -( 2 - chloropyridin - 4 - yl) - 3 - oxopropanoate 40 chloride (431 mg, 4 .01 mmol) was added and the reaction mixture was stirred at room temperature for 16 hrs . 10 % of aq . K2CO3 ( 10 mL ) was added , the aqueous layer was extracted with DCM ( 8 mLx3 ) . The organic layer was dried over Na SO , and concentrated to give 4 - acetylpicolinoni LOH 45 trile (200 mg , 38 % ) . LC /MS : 147 . 1 ( M + 1 ) To the solution of t -BuOK (615 mg, 5 .48 mmol) in THF 1 ) CDI, MeCN , 50° C . ( 20 mL ) was added a solution of 4 - acetylpicolinonitrile (400 mg , 2 .74 mmol) in THF (20 mL ). Carbonic acid dimethyl ester ( 493 mg, 5 .48 mmol) was added and the reaction was OK 50 stirred at room temperature for 1 h and then with heating to ci MgCl2 60° C . for 3 hrs . The reaction was diluted with ethyl acetate ü (30 mL ) and aq .NH _ C1 (30 mL ) . The aqueous layer was extracted with ethyl acetate (30 mLx2 ) . The organic layer was dried over Na, SO , and concentrated and purified by flash chromatography (PE :EA = 100 : 1 – 5 : 1 ) to give com pound J (170 mg, 30 % ) . LC /MS : 204 . 6 ( M + 1 ) . ci Ethyl 3 -( 3- hydroxyphenyl ) -3 -oxopropanoate (K ) 60 To the solution of 2 - chloroisonicotinic acid ( 5 g , 31 . 7 mmol) in ACN ( 30 mL ) was added CDI ( 11 . 6 g , 71 .4 mmol) and the mixture was stirred at 25° C . for 1 h . potassium HO . 3 -methoxy - 3 -oxopropanoate (5 .4 g, 31. 7 mmol) and MgCl2 diethyl carbonate ( 2 .9 g , 31. 7 mmol) were added then the mixture was stirred 65 NaH , THF at 25° C . for 12 hrs. After removal of the solvent, the residue was extracted with EtOAC (20 mLx3 ). The organic layer was US 9 , 969, 726 B2 185 186 - continued the crude product . The crude product was purified by silica o gel column chromatography [ Eluent: 20 % EtoAc/ Hexanes ] HO . to afford 1 - ( 3 - ( pyridin - 2 - yloxy )phenyl ) ethanone ( 1 . 9 g , OET 41 % ) as colorless liquid . ' H NMR (400 MHz, DMSO -do ) : 5 8 8 . 15 - 8 . 14 ( m , 1H ), 7 . 89 - 7 . 88 ( m , 1H ) , 7 . 81 - 7 . 80 ( m , 1H ) , 7 .64 - 7 .63 ( m , 1H ), 7 .57 ( t , J = 8 . 0 Hz, 1H ), 7 .40 - 7 . 39 (m , 1H ), 7 . 17 - 7 . 14 ( m , 1H ) , 7 .09 - 7 .08 (m , 1H ) , 2 . 58 ( s , 3H ) . To a stirred solution of 3 -hydroxy acetophenone ( 3 g , 10 Step 2 : Ethyl 3 - oxo - 3 - ( 3 - (pyridin - 2 -yloxy ) phenyl) 22. 03 mmol) in dry THF ( 50 mL ) under inert atmosphere propanoate ( F ) was added sodium hydride (60 % ) ( 3 . 17 g , 0 .13 mmol) To a stirred solution of 1 -( 3 - (pyridin - 2 -yloxy ) phenyl ) portion wise at 0° C . After being stirred for 10 min , the ethanone ( 100 mg , 0 . 46 mmol) in dry THF ( 7 mL ) under reaction mixture was warmed to RT and diethyl carbonate inert atmosphere was added NaH (60 % ) (33 .8 mg, 1 . 40 ( 3 . 9 g , 33 . 05 mmol) was added ; heated to 70° C . and stirred 15 mmol) portion wise at 0° C . After being stirred for 10 min , for 12 h . The progress of the reaction was monitored by the reaction mixture was warmed to RT and was added TLC . After completion of the reaction , the reaction mixture diethyl carbonate (83 . 1 mg, 0 . 70 mmol) ; heated to 60 - 70° C . was diluted with water ( 30 mL ) and extracted with ethyl and stirred for 6 h . The progress of the reaction was acetate (3x25 mL ) . The combined organic extracts were 20 monitored by TLC . After completion of the reaction , the washed with water ( 30 mL ), dried over sodium sulfate , reaction mixture was diluted with water ( 30 mL ) and filtered and concentrated under reduced pressure to obtain extracted with ethyl acetate (2x20 mL ) . The combined the crude product. The crude product was purified by silica organic extracts were washed with water ( 20 mL ) , dried over gel column chromatography [ Eluent: 15 % EtoAc/ Hexanes ] sodium sulfate , filtered and concentrated under reduced to afford compound K ( 2 . 4 g , 52 % ) as a colorless liquid . ' H 25 pressure to obtain the crude product. The crude product was NMR (400 MHz, DMSO - do) : 8 9 .84 (s , 1H ) , 7 .40 -7 . 28 (m , purified by silica gel column chromatography [Eluent : 12 % 3H ), 7 . 07 - 7 .04 ( m , 1H ), 4 . 11 - 4 .08 ( m , 4H ) , 1 . 19 - 1 . 15 ( m , EtoAc/ Hexanes ) to afford intermediate F (50 mg, 38 % ) as 3H ) . a colorless liquid . lH NMR (500 MHz, DMSO - do ) : 8 8 . 14 - 8 .13 ( m , 1H ) , 7 . 90 - 7 . 86 ( m , 1H ) , 7 . 80 - 7 .79 ( m , 1H ) , Ethyl 3 - oxo - 3 - ( 3 - (pyridin - 2 - yloxy ) phenyl) pro 207.65 ( s , 1H ) , 7 .59 ( t , J = 7 . 5 Hz, 1H ) , 7 .44 ( d , J = 7 . 5 Hz, 1H ) , panoate (L ) 7 . 17 -7 . 14 ( m , 1H ), 7 .09 (d , J = 8 .0 Hz, 1H ), 4 . 18 ( s, 2H ), 4 . 12 -4 .08 ( m , 2H ), 1. 15 (s , 3H ). Ethyl 3 - ( 3 - ( 1H - indol- 1 - yl) phenyl) - 3 -oxopropanoate 35 ( M ) HO N ? ci NMP, 'BuOK

40 Br WQ Diethyl carbonate OC2H5 Xanthphos, PD2( dba ) 3, NaH , THF 1 , 4 -Dioxane , Cs2CO3 45 CogiaO Ethyl acetate COC2H5 LiHMDS , THF Poul 50 Style COC2H5 Step 1 : 1- (3 -( Pyridin -2 -yloxy ) phenyl )ethanone 55 To a stirred solution of 3 -hydroxy acetophenone (3 g , 22. 03 mmol) in N -methyl pyrrolidinone under inert atmo sphere were added 2 - chloropyridine ( 10 mL ) , and potassium tertiary butoxide (4 . 94 g, 44 . 06 mmol) at RT. The reaction 60 Step 1 : Ethyl 3 - ( 1H -indol - 1 -yl ) benzoate mixture was heated to 150° C . and stirred for 24 h . The progress of the reaction was monitored by TLC . After To a stirred solution of 1H - indole ( 3 g , 25. 60 mmol) in 1 , completion of the reaction , the reaction mixture was 4 -dioxane (200 mL ) under inert atmosphere were added quenched with 10 % NaOH solution (20 mL ) and extracted ethyl 3 - bromobenzoate (5 .86 g , 25 .60 mmol) , cesium car with CH , C12 (3x30 mL ) . The combined organic extracts 65 bonate ( 14 . 98 g , 46 .09 mmol) , xanthphos (663 .7 mg, 1. 28 were washed with water ( 30 mL ) , dried over sodium sulfate , mmol) at RT and purged with argon for 30 min . Then filtered and concentrated under reduced pressure to obtain Pd (dba )3 (937 .9 mg, 1. 02 mmol) was added and again US 9 , 969 , 726 B2 187 188 degassed for another 30 min ; heated to 60° C . and stirred for reaction mixture was filtered under vacuum and the filtrate 12 h . The progress of the reaction was monitored by TLC . was concentrated under reduced pressure to obtain the crude After completion of the reaction , the volatiles were evapo product. The crude product was purified by silica gel column rated under reduced pressure to obtain the crude product. chromatography [Eluent : 5 % EtOAc /Hexanes ] to afford The crude product was purified by silica gel column chro - 5 1 - ( 3 - phenoxyphenyl) ethanone ( 350 mg, 45 % ) as a colorless matography [ Eluent : 5 % EtOAc/ Hexanes ] to afford ethyl liquid . ' H NMR (400 MHz, DMSO -do ) : 8 7 .75 - 7 .73 (m , 3 - ( 1H - indol - 1 - yl )benzoate ( 1 . 3 g , 19 % ) as colorless liquid . 1H ) , 7 .56 - 7 . 52 (m , 1H ), 7 . 52 - 7 .48 ( m , 1H ), 7 . 45 - 7 . 41 ( m , ' H NMR (400 MHz , DMSO - do) : 8 8. 06 - 8 .04 (m , 1H ), 2H ) , 7 . 30 - 7 .29 ( m , 1H ), 7 . 17 - 7 .07 ( m , 1H ), 7 . 06 - 7. 04 ( m , 7 .98 -7 . 96 ( m , 1H ), 7 .89 - 7 .87 (m , 1H ) , 7 .76 -7 .67 (m , 3H ), 2H ) , 2 . 56 (s , 3H ) . 7 . 56 -7 .52 ( m , 1H ), 7 .25 - 7 .15 (m , 2H ) , 6 .75 -6 .73 (m , 1H ), 10 4 .39 - 4 . 32 ( m , 2H ) , 1 . 34 ( s , 3H ) . Step 2: Methyl 3 -oxo -3 -( 3 -phenoxyphenyl ) propanoate ( N ) Step 2 : Ethyl 3 -( 3 -( 1H - indol- 1 -yl ) phenyl) -3 -oxo propanoate ( M ) To a stirred solution of 1- (3 -phenoxyphenyl ) ethanone 15 (500 mg , 2. 35 mmol ) in dry THF (20 mL ) under inert To a stirred solution of 1 .49 M LiHMDS (5 .78 mL , 8. 64 atmosphere was added sodium hydride ( 141 . 5 mg, 5 . 89 mmol) in THF ( 20 mL ) under inert atmosphere was added mmol, 60 % ) portion wise at 0° C . After being stirred for 10 ethyl acetate ( 331. 6 mg, 3 .76 mmol) at - 78° C . After being min , dimethyl carbonate ( 531 . 1 mg, 5 . 89 mmol ) was added stirred for 10 min , ethyl 3 - 1H - indol - 1 - yl) benzoate ( 1 g , 20 and warmed to RT and the resulting solution was stirred at 3 . 76 mmol ) was added and stirring was continued for 4 h . 20 60 - 70° C . for 12 h . The progress of the reaction was The progress of the reaction was monitored by TLC . After monitored by TLC . After completion of the reaction , reac completion of the reaction , the reaction mixture was tion mixture was quenched with 10 % HCl solution (20 mL ) quenched with aq . NH _ C1 (20 mL ) and extracted with ethyl and diluted with water ( 30 mL ) and extracted with ethyl acetate (3x20 mL ) . The combined organic extracts were acetate (2x20 mL ) . The combined organic extracts were washed with water (20 mL ), dried over sodium sulfate , 25 washed with water ( 25 mL ), dried over sodium sulfate , filtered and concentrated under reduced pressure to obtain filtered and concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica the crude product. The crude material was purified by silica gel column chromatography [ Eluent : 10 % EtoAc/ Hexanes ] gel column chromatography [Eluent : 7 % EtOAc/ Hexanes ) to afford compound M (550 mg, 48 % ) as a brown oil . ' H to afford compound N ( 300 mg, 47 % ) as a colorless liquid . NMR ( 400 MHz , DMSO -do ) : 8 8 . 12 - 8 . 11 ( m , 1H ) , 8 . 10 - 30 ' H NMR ( 400 MHz , CDC1z ) : 8 7 .65 ( d , J = 7 .6 Hz, 1H ) , 7 .90 ( m , 2H ), 7 .77 - 7 .73 (m , 2H ), 7 .68 ( d , J= 7 .6 Hz, 1H ), 7 .55 - 7 .46 ( m , 1H ) , 7 . 44 - 7 . 38 ( m , 1H ) , 7 .37 - 7 . 33 ( m , 1H ) , 7 .60 ( d , J = 8 . 4 Hz, 1H ) , 7 . 24 - 7 .14 ( m , 2H ) , 6 . 76 - 6 . 74 ( m , 7 .25 -7 .23 ( m , 1H ), 7 .22 - 7 . 11 (m , 2H ) , 7 .02 ( d , J= 8 .4 Hz , 1H ) , 4 .31 ( s , 2H ) , 4 . 16 - 4 . 11 ( m , 2H ) , 1. 18 ( s , 3H ) . 2H ), 3. 96 ( s, 2H ), 3 .74 ( s, 3H ). Methyl 3 -oxo - 3 -( 3 -phenoxyphenyl ) propanoate ( N ) 35 Methyl 3 - ( 3 - (benzyloxy ) phenyl) - 3 - oxopropanoate (O )

OH B B HO OH Br Cu (OAC ) 2 Pyridine, DCM HO KI, K2CO3 ?? À Acetone Dimethyl carbonate ?? NaH , THF Dimethyl carbonate 50 NaH , THF

OCH3

55 OCH3

Step 1 : 1- (3 -Phenoxyphenyl )ethanone none 60 To a stirred mixture of molecular sieves (5 g ) in CH , C1, (25 mL ) under inert atmosphere were added 3 -hydroxy Step 1 : Synthesis of acetophenone (500 mg, 36 .72 mmol) , phenylboronic acid 1 -( 3 -( benzyloxy )phenyl ) ethanone ( 896 . 0 mg, 7 . 34 mmol) , copper acetate ( 1 . 46 g , 7 . 34 mmol) and pyridine ( 1 .45 g , 18. 36 mmol) at RT and stirred under 65 To a stirred solution of 3 -hydroxy acetophenone ( 1 g , 7 . 35 N , atmosphere for 48 h . The progress of the reaction was mmol) in acetone ( 25 mL ) under inert atmosphere were monitored by TLC . After completion of the reaction , the added potassium iodide (244 .1 mg, 1. 47 mmol ), potassium US 9 ,969 , 726 B2 189 190 carbonate ( 2 . 02 g , 14 . 70 mmol) and benzyl bromide ( 1 . 5 g , pressure to obtain the crude product . The crude product was 8 .82 mmol) at RT . The reaction mixture was heated at 70° purified by silica gel column chromatography [Eluent : 10 % C . and stirred for 20 h . The progress of the reaction was EtOAc /Hexanes ] to afford compound P (4 g, 67 .56 % ) as an monitored by TLC . After completion of the reaction , the off- white solid . ' H NMR ( 400 MHz, CDC13 ) : 8 8 . 46 - 8 .44 volatiles were evaporated under reduced pressure and the 5 m , 1H ) , 8 . 30 - 8 . 29 ( m , 1H ) , 8 .09 - 8 . 08 ( m , 1H ) , 7 . 71 ( t, J = 8 . 0 residue was diluted with water ( 30 mL ) and extracted with Hz, 1H ) , 4 .31 - 4 .04 ( m , 2H ) , 4 . 24 ( s , 2H ), 1 . 35 - 1 .25 ( m , 3H ) . EtOAC (2x30 mL ) . The combined organic extracts were washed with water (25 mL ), dried over sodium sulfate , 4 -( 3 -bromophenyl ) - 7 -methyl - 8 -( trifluoromethyl ) filtered and concentrated under reduced pressure to obtain 1H -benzo [ b ] [ 1 , 4 ] diazepin - 2 ( 3H ) - one ( 0 ) the crude product. The crude product was purified by silica gel column chromatography [Eluent : 7 % EtoAc/Hexanes ] to afford 1 - ( 3 - ( benzyloxy )phenyl ) ethanone ( 1 . 6 g , 69 % ) as a colorless liquid . ' H NMR (400 MHz, DMSO -do ) : 8 7 .55 NH2 Boc20Bocho , DM DMAP 7 . 51 ( m , 2H ) , 7 .45 - 7 . 25 ( m , 7H ) , 5 . 16 (s , 2H ) , 2 . 55 ( s , 3H ) . 15 THFTHE Step 2 : Methyl 3 - ( 3 - (benzyloxy ) - NO2 phenyl )- 3 -oxopropanoate ( O ) ?? NHBoc B To a stirred solution of 1 -( 3 -( benzyloxy ) phenyl) ethanone 20 ?? ( 500 mg, 2 .21 mmol) in dry THF ( 15 mL ) under inert K2CO3 atmosphere was added sodium hydride ( 132 . 7 mg, 5 .53 F3C NO2 Pd (PPh34 mmol, 60 % ) portion wise at 0° C . After being stirred for 10 1 , 4 -Dioxane :H20 min , dimethyl carbonate (498 . 2 mg, 5 .53 mmol) was added , NHB?cNHBoc warmed to RT and the resulting solution was stirred at 25 VY 10 % Pd = 0 60 -70° C . for 12 h . The progress of the reaction was EtOH monitored by TLC . After completion of the reaction , the F C V NO2NO2 reaction mixture was quenched with 10 % HCl solution ( 20 mL ) , diluted with water ( 30 mL ) and extracted with ethyl Br acetate (2x20 mL ). The combined organic extracts were 30 COC2H5 washed with water ( 25 mL ) , dried over sodium sulfate , filtered and concentrated under reduced pressure to obtain NHBoc the crude product. The crude material was purified by silica G gel column chromatography [ Eluent: 5 % EtoAc/ Hexanes ] toluene to afford compound 0 (500 mg, 80 % ) as a colorless liquid . 35 f3 NH2 H NMR ( 400 MHz , DMSO - da ) : 87. 55 - 7 .51 ( m , 2H ) , van CF3een 7 .48 - 7 . 45 ( m , 3H ) , 7 .42 - 7 . 40 ( m , 2H ), 7 . 38 - 7 .32 ( m , 2H ) , 5 . 18 (s , 2H ) , 4 . 20 ( s , 2H ) , 3 .64 ( s , 3H ) . TFA CH2Cl2 Br Ethyl 3 -( 3- nitrophenyl ) - 3 -oxopropanoate (P ) 40

NHBoc

45 OC2H5 EtoAc Duste LiHMDS , THF

Br 50 ON OEt

P 55 Step 1 : tert -Butyl 5 - chloro - 2 -nitro -4 - ( trifluorom To a stirred solution of LiHMDS ( 9 . 84 g , 58 . 97 mmol) in ethyl) phenylcarbamate dry THF (20 mL ) under inert atmosphere was added ethyl acetate ( 2 . 25 g , 25 .6 mmol) drop wise at - 78° C . under inert To a stirred solution of 5 -chloro -2 -nitro - 4 -( trifluorom atmosphere . After being stirred for 30 min , ethyl 3 - nitro 60 ethyl) aniline ( 1 . 3 g , 5 .42 mmol) in THF (20 mL ) was added benzoate ( 5 g , 25 .6 mmol) was added and stirred for 1 h at Boc anhydride ( 1 .77 g , 8 . 12 mmol) followed by DMAP ( 198 - 78° C . The progress of the reaction was monitored by TLC . mg, 1 .62 mmol) at 0° C . under inert atmosphere . The After completion of the reaction , the reaction mixture was resulting reaction mixture was allowed to warm to RT and quenched with aq . NH _ C1 solution (50 mL ) and extracted stirred for 2 hr. After the consumption of starting material with ethylacetate (2x50 mL ) . The combined organic extracts 65 (by TLC ) , the reaction mixture was concentrated under were washed with water ( 50 mL ) , dried over anhydrous reduced pressure . The crude material was purified by silica sodium sulfate , filtered and concentrated under reduced gel column chromatography eluting with 5 % ETOAc/ Hexane US 9 ,969 , 726 B2 191 192 to afford tert -butyl 5 - chloro - 2 -nitro - 4 - ( trifluoromethyl) phe carbamate ( 0 . 9 g , 1 . 74 mmol) in CH , C1, (20 mL ) was added nylcarbamate ( 1 . 3 g , 70 . 7 % ) as a pale yellow solid . ' H NMR TFA ( 9 mL ) at 0° C . under inert atmosphere . The resultant (500 MHz, CDC1z) : 89. 88 (bs , 1H ) , 8 .91 ( s , 1H ), 8 . 56 ( s , reaction mixture was allowed to warm to RT and stirred for 1H ) , 1 .54 ( d , J = 9 . 5 Hz, 9H ) . MS ( ESI) : 339 [ M - 1 ] . 12 h . The progress of the reaction was monitored by TLC . 5 The reaction mixture was quenched with aq . NaHCO3 Step 2 : tert -Butyl 5 -methyl - 2 - nitro - 4 - ( trifluorom solution ( 10 mL ) and extracted with CH , C1, ( 3x20 mL ) . The ethyl) phenylcarbamate combined organic extracts were dried over anhydrous Na, SO , and concentrated under reduced pressure to afford To a stirred solution of tert- butyl 5 - chloro - 2 - nitro - 4 compound Q (0 . 6 g , 86 .6 % ) as an off -white solid . ' H NMR ( trifluoromethyl) phenylcarbamate ( 1 . 3 g , 3 .82 mmol) in (400 MHz, DMSO - do) : d 10 .71 ( bs, 1H ), 8 . 24 ( s , 1H ) , 8 . 06 1 , 4 -dioxane : H2O ( 20 mL, 4 : 1 ) were added methylboronic ( d , = 8 . 4 Hz , 1H ), 7 .79 ( d , J = 6 . 0 Hz, 1H ) , 7 . 55 - 7 .50 ( m , 3H ), acid ( 0 . 228 g , 3 .82 mmol) and K2CO3 ( 1 . 58 g , 11. 47 mmol) 3 . 58 ( s , 2H ) , 2 . 45 ( s , 3H ) . MS (ESI ) : m / z 399 [ M + 2 ] · . at RT under inert atmosphere . The reaction mixture was degassed with argon for 30 min and then Pd (PPhz ) , ( 0 .44 g , 4 - ( 3 - Hydroxyphenyl) - 7 -methyl - 8 -( trifluoromethyl ) 0 . 38 mmol) was added and again degassed for another 30 1H -benzo [b ][ 1 , 4 ]diazepin - 2 ( 3H ) -one (R ) min . The resulting reaction mixture was heated to 100° C . 15 and stirred for 16 h . The progress of the reaction was monitored by TLC . After completion of the reaction , the reaction mixture was filtered through a bed of celite to NHBoc remove solids. The filtrate was then concentrated under _ K reduced pressure to obtain the crude product. The crude 20 Toluene material was purified by silica gel column chromatography FC4 CNH , eluting with 5 % EtoAc/ Hexane to afford tert- butyl 5 -methyl - 2 -nitro - 4 - ( trifluoromethyl) phenylcarbamate ( 1 g , Compound Q , 81 . 9 % ) as a pale yellow solid . ' H NMR (400 MHz, CDC12 ) : Step 3 d 9 . 86 (bs , 1H ) , 8 .60 (s , 1H ), 8. 47 (s , 1H ), 2. 55 (s , 3H ), 1. 54 25 ( d , J = 7 . 6 Hz , 9H ) . Step 3 : tert- Butyl 2 -amino - 5 -methyl - 4 -( trifluorom TFA ethyl )phenylcarbamate HO . CH2Cl2 To a stirred solution of tert -butyl 5 -methyl - 2 - nitro - 4 - 30 NH ( trifluoromethyl ) phenylcarbamate ( 1 . 0 g , 2 . 94 mmol) in NHBoc EtOH (20 mL ) was added 10 % Pd - C ( 5 mg ) at RT under inert atmosphere . The resulting reaction mixture was agi F3C tated under H , atmosphere (balloon pressure ) for 2 h at RT. The reaction mixture was filtered through a celite pad and 35 the filtrate was concentrated under reduced pressure to afford tert -butyl 2 -amino - 5 -methyl - 4 - ( trifluoromethyl ) phe nylcarbamate ( 0 . 7 g , 82 . 4 % ) as a pale yellow solid . ' H NMR - OH (500 MHz, CDC1z ) : 8 7 .41 - 7 . 39 ( m , 1H ) , 7 .03 ( s , 1H ) , 6 .42 (br s, 1H , Exc ), 3. 58 (br s, 2H , Exc ), 2 . 35 ( s, 3H ), 1. 52 ( s, 40 9H ) . MS ( ESI) : m / z 291 . 1 [ M + 1 ] + . Step 4 : tert -Butyl 2 -( 3 -( 3 -bromophenyl ) - 3 -oxopro panamido ) - 5 -methyl - 4 - ( trifluoromethyl ) phenylcar Step 1 : tert- Butyl 2 - ( 3 - ( 3 -hydroxyphenyl ) - 3 -oxopro bamate 45 panamido ) - 5 - methyl- 4 - ( trifluoromethyl) phenylcar bamate To a stirred solution of tert - butyl 2 - amino - 5 -methyl - 4 ( trifluoromethyl) phenylcarbamate ( 0 . 9 g , 3 .10 mmol) in To a stirred solution of tert -butyl 2 - amino - 5 -methyl - 4 toluene ( 20 mL ) was added compound G ( 0 . 92 g , 3 . 10 ( trifluoromethyl) phenylcarbamate ( 1 g , 3 . 44 mmol ) in tolu mmol) at RT under inert atmosphere . The resulting reaction 50 ene ( 20 mL ) under inert atmosphere was added compound K mixture was stirred for 12 h at 110° C . ; progress of the (717 . 24 mg, 3 .44 mmol) at RT. The reaction mixture was reaction was monitored by TLC . The reaction mixture was heated to 120° C . and stirred for 15 h . The progress of the reaction was monitored by TLC . After completion of the concentrated under reduced pressure . The crude material reaction , the volatiles were evaporated under reduced pres was triturated with hexane (50 mL ) to afford tert -butyl tri 55 sure to obtain the crude product . The crude product was 2 -( 3 - ( 3 - bromophenyl) - 3 -oxopropanamido ) - 5 -methyl - 4 - ( tri- 55 triturated with diethyl ether (2x10 mL ) to afford tert - butyl fluoromethyl) phenylcarbamate (0 . 9 g , 56 . 6 % ) as an off 2 -( 3 - ( 3 -hydroxyphenyl ) - 3 - oxopropanamido ) - 5 -methyl - 4 white solid . ? H NMR ( 400 MHz , DMSO - d . ) : 8 9 . 75 (bs , ( trifluoromethyl) phenylcarbamate ( 1. 3 g , 83 % ) as a color 1H ) , 8 .68 ( bs, 1H ) , 8 . 14 ( s , 1H ) , 8 . 01 ( d , J = 7 . 6 Hz, 1H ) , 7 .89 less liquid . ' H NMR ( 400 MHz, DMSO - d . ) : 8 14 . 02 ( s , 1H ) , ( d , J = 8 . 8 Hz, 1H ) , 7 . 81 ( s , 1H ) , 7 . 76 - 7 .72 ( m , 1H ) , 7 . 56 - 7 .49 9 . 85 ( s , 1H ) , 9 . 73 ( s , 1H ) , 7 . 88 ( s , 1H ) , 7 . 83 ( s , 1H ) , 7 . 73 ( s , ( m , 1H ) , 4 .22 ( s , 2H ), 2 . 39 ( s , 3H ) , 1 .48 ( d , J = 6 . 0 Hz, 9H ) . 60 11 ) . 7 . 47 ( d . J = 8 . 0 Hz. 11 ) . 7 . 38 - 7 . 34 ( m . 1H ) , 6 . 92 - 6 . 89 MS ( ESI) : m / z 513 [M - 2 ]. ( m , 1H ), 4 .14 (s , 2H ), 2 .50 -2 .49 (s , 3H ), 1. 49 (s , 9H ). Step 5 : 4 - ( 3 - Bromophenyl ) - 7 -methyl - 8 - ( trifluorom Step - 2 : 4 - ( 3 -Hydroxyphenyl ) - 7 -methyl - 8 - ( trifluo ethyl) - 1H -benzo [ b ][ 1 , 4 ]diazepin - 2 ( 3H ) - one ( Q ) romethyl) - 1H -benzo [b ][ 1, 4 ]diazepin - 2 ( 3H ) -one (R ) 65 To a stirred solution of tert- butyl 2 - ( 3 - ( 3 - bromophenyl) To a stirred solution of tert -butyl 2 -( 3 -( 3 -hydroxyphenyl ) 3 -oxopropanamido ) - 5 - methyl- 4 - (trifluoromethyl ) phenyl 3 - oxopropanamido ) - 5 -methyl - 4 - (trifluoromethyl ) phenyl US 9 ,969 , 726 B2 193 194 carbamate (1 . 3 g , 2 .87 mmol) in DCM ( 20 mL ) under inert Example 137 : 7 -Methyl - 4 - ( 3 - (pyrimidin - 2 - ylsulfo atmosphere was added TFA ( 4 mL ) at 0° C . The reaction nyl) phenyl) - 8 - ( trifluoromethyl) - 1H - benzo [b ] [ 1 , 4 ] mixture was warmed to RT and stirred for 6 h . The progress diazepin - 2 (3H ) -one of the reaction was monitored by TLC . After completion of 5 the reaction , the reaction mixture was diluted with water (40 mL ) and extracted with DCM ( 3x20 mL ). The combined organic extracts were washed with saturated NaHCO3 solu - F3C tion ( 2x20 mL ) , water ( 20 mL ) , dried over sodium sulfate , 10 mCPBA filtered and concentrated under reduced pressure to obtain DCM the crude product. The crude product was triturated with diethyl ether (2x15 mL ) to afford compound R (900 mg, 94 % ) as an off -white solid . H NMR (500 MHz, DMSO -do ) : 15 8 10 .64 ( s , 1H ) , 9 .74 (s , 1H ), 7 .50 - 7 .49 ( m , 2H ), 7 .48 (s , 1H ), 7 .33 ( t, J = 8. 0 Hz, 1H ), 6 . 96 (d , J = 9. 0 Hz, 1H ), 3 .49 - 3 . 38 ( m , 2H ) , 2 .44 ( s, 3H ). MS (ESI ) : m / z 335 [ M + 1 ] * HPLC : 98 . 2 % . 20 Example 136 : 7 -Methyl - 4 - ( 3 - (pyrimidin - 2 - ylthio ) phenyl ) - 8 - ( trifluoromethyl) - 1H -benzo [ b ][ 1 , 4 ] diaz epin - 2 (3H ) -one 25

To a stirred solution of 7 -methyl - 4 -( 3 - (pyrimidin -2 - yl N SH 30 thio )phenyl ) - 8 -( trifluoromethyl) - 1H -benzo [b ][ 1, 4 ]diazepin Pd2 (dba ) 3, Xanthophos , 2 (3H ) -one (Example 136 ) (50 mg, 0 .11 mmol) in CH C12 (7 Br Cs2CO3, mL ) under inert atmosphere was added m -chloro perbenzoic 1 , 4 Dioxane acid (50 mg, 0 . 29 mmol) at 0° C . The reaction mixture was 35 warmed to RT and stirred for 2 h . The progress of the reaction was monitored by TLC . After completion of the reaction , the reaction mixture was diluted with water ( 15 mL ) and extracted with CH C12 (3x15 mL ) . The combined organic extracts were washed with saturated NaHCO3 solu 40 tion ( 15 mL ) , water (15 mL ) , dried over sodium sulfate , filtered and concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography [ Eluent: 80 % EtOAc/ Hexanes ] to afford the title compound ( 5 mg, 9 % ) as pale yellow solid . 45 ' H NMR ( 400 MHz, DMSO - do) : 8 10 . 75 (s , 1H ) , 9 .05 - 9 .04 ( m , 2H ), 8 .62 ( s , 1H ) , 8 .44 ( d , J = 8 . 4 Hz, 1H ) , 8 . 19 ( d , J = 8 . 4 Hz, 1H ) , 7 .89 ( t , J = 7 . 6 Hz, 1H ) , 7 .81 ( t , J = 4 . 8 Hz, 1H ) , 7 . 53 ( d , J = 11. 6 Hz, 2H ) , 3 .64 ( s , 2H ) , 2 .50 ( s , 3H ) . MS ( ESI) : m / z To a stirred solution of compound Q (300 mg, 0 .75 mmol) 461 [ M + 1 ] * HPLC : 90 . 0 % . in 1 ,4 -dioxane ( 10 mL ) under inert atmosphere were added pyrimidine- 2 -thiol (84 mg, 0 .75 mmol ), cesium carbonate Example 138 : 7 -Methyl - 4 - ( 3 - ( ( 6 -methylpyridin - 2 (443 mg, 1 .36 mmol) , xanthphos (19 . 6 mg, 0 .03 mmol) at yl) ethynyl ) phenyl) - 8 - (trifluoromethyl ) - 1H -benzo [ b ] RT and purged with argon for 45 min . Then Pd , (dba ) z ( 27 . 7 [ 1 , 4 ]diazepin - 2 (3H ) -one mg, 0 . 03 mmol) was added and again purged for 10 min . These reaction mixture was heated to 100° C . and stirred for 12 h . The progress of the reaction was monitored by TLC . After completion of the reaction , the reaction mixture was filtered JI through celite pad . The filtrate was concentrated under F3C TMS- acetylene , reduced pressure to obtain the crude product. The crude 60 Pd (pph3 )2Cl2 product was purified by silica gel column chromatography Cul, Et3N , THF [ Eluent: 40 % EtoAc /Hexanes ] to afford the title compound (250 mg, 77 % ) as pale yellow solid . ' H NMR (400 MHz, Br DMSO - do) : 8 10 . 70 ( s , 1H ) , 8 .61 - 8 . 60 ( m , 2H ) , 8 . 29 - 8 . 28 ( m , 1H ) , 8 . 15 ( d , J = 8 .4 Hz, 1H ), 7 .81 ( d , J = 7 .6 Hz, 1H ) , 7 .66 65 (t , J = 8 . 0 Hz, 1H ) , 7 . 49 ( d , J = 8 . 0 Hz, 2H ) , 7 .26 ( t , J = 4 . 8 Hz, 1H ), 3 .61 - 3 .59 (m , 2H ), 2. 49 ( s, 3H ).