|HAO WATUM UT US010087143B2TIL A T MAN AT MALAT (12 ) United States Patent (10 ) Patent No. : US 10 , 087 , 143 B2 Hadida - Ruah et al. (45 ) Date of Patent: * Oct. 2 , 2018

(54 ) PYRIDONE AMIDES AS MODULATORS OF 8 , 779 , 197 B2 7 / 2014 Chen 8 , 841, 483 B2 9 /2014 Joshi SODIUM CHANNELS 8 , 865, 771 B2 10 / 2014 Chen 9 ,051 , 270 B2 * 6 /2015 Hadida -Ruah ...... C07D 213 / 75 ( 71 ) Applicant: VERTEX PHARMACEUTICALS 9 , 108 ,903 B28 /2015 Hadida -Ruah INCORPORATED , Boston , MA (US ) 9 , 139 ,529 B2 9 /2015 Hadida -Ruah 9 , 163 ,042 B2 10 /2015 Anderson (72 ) Inventors : Sara Sabina Hadida - Ruah , La Jolla , 9 , 393 ,235 B2 * 7 / 2016 Hadida -Ruah ...... CO7D 213 / 75 CA (US ) ; Corey Anderson , San Diego , 9 ,421 , 196 B2 8 /2016 Hadida - Ruah CA (US ) ; Vijayalaksmi Arumugam , 9 , 464 , 102 B2 10 / 2016 Anderson San Marco , CA (US ) ; Iuliana Luci (Continued ) Asgian , San Diego , CA ( US ) ; Brian Richard Bear , Carlsbad , CA (US ) ; FOREIGN PATENT DOCUMENTS Andreas P . Termin , Encinitas, CA CN 101883758 11 / 2010 (US ) ; James Philip Johnson , San CN 102264722 11/ 2011 Diego , CA (US ) (Continued ) (73 ) Assignee : VERTEX PHARMACEUTICALS INCORPORATED , Boston , MA (US ) OTHER PUBLICATIONS ( * ) Notice: Subject to any disclaimer, the term of this Akopian , A .N ., L . Sivilotti, and J. N . Wood , “ A patent is extended or adjusted under 35 resistant voltage - gated expressed by sensory neu U . S .C . 154 (b ) by 0 days . rons. ” Nature, 1996 . 379 ( 6562 ) : p . 257 -62 ). This patent is subject to a terminal dis ( Continued ) claimer . Primary Examiner — D Margaret M Seaman (21 ) Appl. No. : 15 / 667, 722 ( 74 ) Attorney, Agent, or Firm — Brinks Gilson & Lione (22 ) Filed : Aug. 3 , 2017 (65 ) Prior Publication Data (57 ) ABSTRACT US 2018 / 0016235 A1 Jan . 18 , 2018 The invention relates to pyridone amide compounds of formula I and I ' or pharmaceutically acceptable salts thereof, Related U .S . Application Data useful as inhibitors of sodium channels : (63 ) Continuation of application No . 15 /174 ,896 , filed on Jun . 6 , 2016 , now Pat. No. 9 ,758 , 483 , which is a continuation of application No . 14 /699 , 437 , filed on I Apr . 29 , 2015 , now Pat . No . 9 , 393 , 235 , which is a (P8 continuation of application No. 14 / 167 ,759 , filed on VRO Jan . 29 , 2014 , now Pat. No . 9 ,051 ,270 . R2 (60 ) ProyProvisional application No . 61/ 759, 059 , filed on Jan . 31 , 2013 .

( 51 ) Int . Ci. - A61K 31/ 4412 ( 2006 . 01 ) CO7D 213 / 75 ( 2006 .01 ) I' CO7D 401/ 12 ( 2006 . 01)

CO7D 405 / 12 ( 2006 .01 ) - ( 52 ) U .S . CI. R2 CPC ...... C07D 213 / 75 ( 2013 .01 ) ; A61K 31 /4412 R9 ( 2013 .01 ) ; C07D 401/ 12 ( 2013 .01 ) ; C07D N 405 /12 (2013 . 01 ) (58 ) Field of Classification Search 7 CPC . . A61K 31 / 04 ; A61K 31/ 4412 ; CO7D 213 /75 ; R4 G C07D 405 / 12 ; C07D 401/ 12 See application file for complete search history . The invention also provides pharmaceutically acceptable (56 ) References Cited compositions comprising the compounds of the invention and methods of using the compositions in the treatment of U . S . PATENT DOCUMENTS various disorders , including pain . 8 ,389 ,734 B2 3 /2013 Chen 8 , 486 , 950 B2 7 /2013 Goodacre et al . 8 ,519 , 137 B2 8 / 2013 Joshi 51 Claims, No Drawings US 10 ,087 , 143 B2 Page 2

References Cited England , S ., “ Voltage - gated sodium channels : the search for subtype ( 56 ) selective . " Expert Opin Investig 17 ( 12 ) , p . U . S . PATENT DOCUMENTS 1849 -64 (2008 ) . Huang, H . L . , et al. , “ Proteomic profiling of neuromas reveals 9 ,758 ,483 B2 * 9 /2017 Hadida -Ruah ...... CO7D 213 / 75 alterations in protein composition and local protein synthesis in 9 ,783 ,501 B2 10 / 2017 Hadida - Ruah hyper- excitable nerves .” Mol Pain , 2008 . 4 : p . 33 . 9 , 828 , 397 B2 11/ 2017 Anderson Jarvis , M .F ., et al. , “ A - 803467 , a potent and selective NaV1. 8 2007 /0238733 A 10 / 2007 Joshi sodium , attenuates neuropathic and inflammatory 2009/ 0099233 Al 4 / 2009 Joshi pain in the rat. ” Proc Natl Acad Sci . USA, 2007 . 104 ( 20 ) : p . 8520 - 5 . 2009 /0118333 A1 5 / 2009 Chen Joshi, S . K ., et al . , “ Involvement of the TTX - resistant sodium 2009 /0118338 Al 5 / 2009 Chen channel Nav1. 8 in inflammatory and neuropathic ,but not post 2013 / 0231370 A1 9 / 2013 Chen operative , pain states .” Pain , 2006 . 123 ( 1 -2 ): pp . 75 -82 . 2014 / 0213616 Al 7 / 2014 Hadida - Ruah Krafte, D . S . and Bannon , A . W ., " Sodium channels and nociception : 2014 / 0221435 Al 8 / 2014 Hadida - Ruah recent concepts and therapeutic opportunities. ” Curr Opin Pharmacol 2014 / 0228371 Al 8 / 2014 Hadida -Ruah 8 ( 1) , p . 50 - 56 ( 2008 ) . 2015 /0166589 Al 6 / 2015 Anderson Lai, J ., et al . , “ Inhibition of by decreased expres 2015 / 0246028 Al 9 / 2015 Hadida -Ruah 2015 / 0328196 A1 11/ 2015 Hadida -Ruah sion of the tetrodotoxin - resistant sodium channel , NaV1. 8 ." Pain , 2015 / 0336945 A1 11/ 2015 Hadida -Ruah 2002. 95 ( 1- 2 ); p . 143 -52 . 2015 /0376174 Al 12 / 2015 Kawana et al . Qiu , F . , et al. , " Increased expression of tetrodotoxin -resistant sodium 2016 /0009743 AL 1 / 2016 Anderson channels NaV1 . 8 and NaV1. 9 within dorsal root ganglia in a rat 2016 / 0152561 A1 6 / 2016 Hadida -Ruah model of bone cancer pain .” Neurosci. Lett. 512( 2 ) : p . 61- 6 ) . 2016 /0376295 A1 12 / 2016 Anderson Renganathan , M ., T . R . Cummins, and S . G . Waxman , “ Contribution 2017 /0037009 A12 / 2017 Hadida - Ruah of Na ( V ) 1. 8 sodium channels to action potential electrogenesis in 2018 / 0016235 A1 1/ 2018 Hadida - Ruah DRG neurons .” J Neurophysiol. , 2001. 86 ( 2 ) : p . 629 -40 . 2018 / 0044361 A1 2 / 2018 Anderson et al . Roza , C ., et al. , “ The tetrodotoxin - resistant Na + channel NaV1. 8 is essential for the expression of spontaneous activity in damaged FOREIGN PATENT DOCUMENTS sensory axons of mice . " J Physiol. , 2003 . 550 ( Pt 3 ) : p . 921 - 6 ) . Ruangsri, S ., et al ., “ Relationship of axonal voltage- gated sodium 2003/ 034671 A 2 /2003 channel 1 . 8 (NaV1 . 8 ) mRNA accumulation to sciatic nerve injury 2005 - 531501 10 / 2005 induced painful neuropathy in rats. ” J Biol Chem . 286 (46 ): p . 2011 - 500599 1 / 2011 39836 -47 ). JP 2011 - 500600 1 / 2011 RU 2010 / 118467 11 / 2011 Rush , A . M . and T . R . Cummins, “ Painful Research : Identification of RU 2010 / 118481 11/ 2011 a Small -Molecule Inhibitor that Selectively Targets NaV1. 8 Sodium wo WO 2003 /068230 8 / 2003 Channels .” Mol Interv , 2007 . 7 ( 4 ) : p . 192 - 5 ) . WO WO 2005 /013914 2 / 2005 Rush , A . M . , et al. , “ A single sodium channel mutation produces WO WO 2007 / 120647 10 / 2007 hyper - or hypoexcitability in different types of neurons. ” Proc Natl WO WO2009 / 049181 Al 4 / 2009 Acad Sci USA , 2006 . 103 ( 21 ) : p . 8245- 50 ) . WO WO2009 /049183 A1 4 / 2009 Soderpalm , B . , “ : aspects of their mechanisms of WO WO 2010 / 072607 7 /2010 action .” Eur J Pain 6 Suppl A , p . 3 - 9 ( 2002 ) . wo WO 2010 / 137351 12 /2010 Strickland , I. T ., et al ., “ Changes in the expression of NaV1 . 7 , WO WO 2013 / 132376 AL 9 / 2013 NaV1 .8 and NaV1. 9 in a distinct population of dorsal root ganglia WO WO2015 /010065 1 / 2015 innervating the rat knee joint in a model of chronic inflammatory joint pain . ” Eur J Pain , 2008 . 12 ( 5 ) : p . 564 - 72 . Sun , W . , et al. , “ Reduced conduction failure of the main axon of OTHER PUBLICATIONS polymodal nociceptive C - fibres contributes to painful diabetic neuropathy in rats .” Brain . 135 ( Pt 2 ): p . 359 -75 . Black , J. A ., et al ., “ Multiple sodium channel isoforms andmitogen Wang , G . K . , Mitchell, J ., and Wang , S . Y . , “ Block of persistent late activated protein kinases are present in painful human neuromas. ” Na + currents by antidepressant sertraline and paroxetine. ” J Membr Ann Neurol, 2008 . 64 ( 6 ) : p . 644 -53 . Biol 222 ( 2 ) , p . 79 - 90 ( 2008 ) . Blair, N . T . and B . P . Bean , “ Roles of tetrodotoxin ( TTX ) -sensitive Yiangou , Y . , et al . , " SNS / PN3 and SNS2 /NaN sodium channel - like Na+ current, TTX - resistant Na + current, and Ca2 + current in the immunoreactivity in human adult and neonate injured sensory action potentials of nociceptive sensory neurons. ” J Neurosci ., nerves. ” FEBS Lett, 2000. 467 ( 2 - 3 ) : p . 249 - 52. 2002 . 22 ( 23 ) : p . 10277 -90 ) . International Search Report and Written Opinion of the Interna Catterall, W . A . , Goldin , A . L ., and Waxman , S . G . , International tional Searching Authority , International Patent Application No . Union of . XLVII . “ Nomenclature and structure PCT/ US2014 /013652 (dated Apr. 2 , 2014 ). function relationships of voltage- gated sodium channels . ” Pharmacol List of Vertex Na, , 1 . 8 Inhibitor Applications and Patents ( attached Rev 57 ( 4 ) , p . 397 ( 2005 ) . hereto as Exhibit A ). Chahine , M . , Chatelier , A ., Babich , O ., and Krupp , J. J ., “ Voltage CAS Registry No . 1119379 -37 - 1 (Mar . 12 , 2009 ). gated sodium channels in neurological disorders .” CNS Neurol CAS Registry No . 1223014 - 19 -4 (May 13 , 2010 ). Disord Targets 7 ( 2 ) , p . 144 - 58 ( 2008 ) . CAS Registry No. 1241310 - 16 - 6 (Sep . 15 , 2010 ). Choi, J. S . and S .G . Waxman , “ Physiological interactions between CAS Registry No. 1252156 -94 - 7 (Nov . 9 , 2010 ) . NaV1. 7 and NaV1. 8 sodium channels : a computer simulation CAS Registry No . 1258714 - 13 -4 ( Jan . 7 , 2011 ). study. ” J Neurophysiol. 106 (6 ): p . 3173 - 84 . CAS Registry No. 1258742 -89 - 0 ( Jan . 7 , 2011) . Coward , K ., et al ., “ Immunolocalization of SNS/ PN3 and NaN / CAS Registry No. 1281112 -60 - 4 ( Apr. 17, 2011 ) . SNS2 sodium channels in human pain states ." Pain , 2000 . 85 ( 1 - 2 ): CAS Registry No . 1281059 -52 -6 (Apr . 17 , 2011 ). p . 41- 50 . CAS Registry No . 1281024 -95 -0 (Apr . 17 , 2011 ). Dieleman , J. P . , et al ., “ Incidence rates and treatment of neuropathic CAS Registry No. 1287712 - 50 - 8 ( Apr. 29 , 2011 ) . pain conditions in the general population .” Pain , 2008 . 137 ( 3 ) : p . CAS Registry No. 1301902 -75 - 9 (May 29 , 2011) . 681 - 8 . CAS Registry No. 1311734 - 41 - 4 ( Jul. 7 , 2011 ) . Dong , X . W ., et al. , “ Small interfering RNA -mediated selective CAS Registry No. 1394673 - 41 - 6 (Sep . 18 , 2012 ). knockdown of Na( V ) 1 . 8 tetrodotoxin -resistant sodium channel reverses CAS Registry No. 1394698 - 15 - 7 (Sep . 18 , 2012 ). mechanical allodynia in neuropathic rats. ” Neuroscience, 2007 . 146 ( 2 ) : p . 812 -21 . * cited by examiner US 10 ,087 , 143 B2 PYRIDONE AMIDES AS MODULATORS OF nists that reduce Nay currents can prevent or reduce neural SODIUM CHANNELS signaling and Na ,, channels have long been considered likely targets to reduce pain in conditions where hyper - excitability CROSS -REFERENCE TO RELATED is observed (Chahine , M . , Chatelier , A . , Babich , O . , and APPLICATIONS 5 Krupp , J . J . , Voltage - gated sodium channels in neurological disorders. CNS Neurol Disord Drug Targets 7 ( 2 ) , p . 144 - 58 This application is a continuation of U . S . patent applica ( 2008 )) . Several clinically useful analgesics have been iden tion Ser . No . 15 / 174 , 896 , filed Jun . 6 , 2016 , which is a tified as inhibitors of Nay channels . The continuation of U . S . patent application Ser. No . 14 /699 .437 , drugs such as block pain by inhibiting Nay chan filed Apr. 29 , 2015 , which is a continuation of U . S . patent 10 nels , and other compounds , such as , lam application Ser . No . 14 / 167 , 759, filed Jan . 29, 2014 , which otrigine , and tricyclic antidepressants that have proven claimsthe benefit of U . S . Provisional Patent Application No . effective at reducing pain have also been suggested to act by 61/ 759 , 059 , filed Jan . 31 , 2013, all ofwhich are incorporated sodium channel inhibition (Soderpalm , B ., Anticonvulsants : herein by reference in their entireties . aspects of their mechanisms of action . Eur J Pain 6 Suppl 15 A , p . 3 - 9 (2002 ) ; Wang , G . K . ,Mitchell , J. , and Wang , S . Y. , TECHNICAL FIELD OF THE INVENTION Block of persistent late Na+ currents by antidepressant sertraline and paroxetine. J Membr Biol 222 (2 ) , p . 79 - 90 The invention relates to compounds useful as inhibitors of ( 2008 ) ) . sodium channels . The invention also provides pharmaceu The Nay ' s form a subfamily of the voltage - gated ion tically acceptable compositions comprising the compounds 20 channel super- family and comprises 9 isoforms, designated of the invention and methods of using the compositions in Nav1 . 1 -Na , 1 . 9 . The tissue localizations of the nine isoforms the treatment of various disorders including pain . vary greatly . Nay1. 4 is the primary sodium channel of skeletal muscle , and Nay1. 5 is primary sodium channel of BACKGROUND OF THE INVENTION cardiac myocytes. Nay ' s 1 . 7 , 1 . 8 and 1 . 9 are primarily 25 localized to the peripheral nervous system , while Nay ' s 1 . 1 , Pain is a protective mechanism that allows healthy ani- 1 .2 , 1 .3 , and 1. 6 are neuronal channels found in both the mals to avoid tissue damage and to prevent further damage central and peripheral nervous systems. The functional to injured tissue. Nonetheless there are many conditions behaviors of the nine isoforms are similar but distinct in the where pain persists beyond its usefulness , or where patients specifics of their voltage - dependent and kinetic behavior would benefit from inhibition of pain . Neuropathic pain is a 30 (Catterall , W . A ., Goldin , A . L . , and Waxman , S . G ., Inter form of chronic pain caused by an injury to the sensory national Union of Pharmacology . XLVII. Nomenclature and nerves (Dieleman , J. P ., et al. , Incidence rates and treatment structure - function relationships of voltage - gated sodium of neuropathic pain conditions in the general population channels . Pharmacol Rev 57 ( 4 ) , p . 397 ( 2005 ) ) . Pain , 2008 . 137 ( 3 ) : p . 681- 8 ) . Neuropathic pain can be Immediately upon their discovery, Nay1 . 8 channels were divided into two categories, pain caused by generalized 35 identified as likely targets for analgesia ( Akopian , A . N ., L . metabolic damage to the nerve and pain caused by a discrete Sivilotti , and J . N . Wood , A tetrodotoxin -resistant voltage nerve injury. The metabolic neuropathies include post her- gated sodium channel expressed by sensory neurons. petic neuropathy, diabetic neuropathy, and drug - induced Nature , 1996 . 379 (6562 ) : p . 257 -62 ). Since then , Na, 1 . 8 has neuropathy. Discrete nerve injuries indications include post been shown to be the most significant carrier of the sodium amputation pain , post- surgical nerve injury pain , and nerve 40 current that maintains action potential firing in small DRG entrapment injuries like neuropathic back pain . neurons (Blair , N . T . and B . P . Bean , Roles of tetrodotoxin Voltage - gated sodium channels (Nay 's ) play a critical role (TTX ) -sensitive Na + current , TTX -resistant Nat current, in pain signaling. Nay ' s are key biological mediators of and Ca + current in the action potentials of nociceptive electrical signaling as they are the primary mediators of the sensory neurons . J Neurosci. , 2002 . 22 (23 ): p . 10277 - 90 ). rapid upstroke of the action potential of many excitable cell 45 Nay1 . 8 is essential for spontaneous firing in damaged neu types ( e . g . neurons, skeletal myocytes , cardiac myocytes ) . rons , like those that drive neuropathic pain ( Roza , C ., et al. , The evidence for the role of these channels in normal The tetrodotoxin -resistant Na + channel Nay1. 8 is essential physiology, the pathological states arising from mutations in for the expression of spontaneous activity in damaged sodium channel genes , preclinical work in animal models , sensory axons ofmice . J . Physiol. , 2003. 550 ( Pt 3 ) : p . 921 - 6 ; and the clinical pharmacology of known sodium channel 50 Jarvis, M . F ., et al ., A - 803467 , a potent and selective Na , 1 . 8 modulating agents all point to the central role of Nay ' s in , attenuates neuropathic and inflam pain sensation (Rush , A . M . and T . R . Cummins, Painful matory pain in the rat. Proc Natl Acad Sci . USA , 2007 . Research : Identification of a Small- Molecule Inhibitor that 104 ( 20 ) : p . 8520 - 5 ; Joshi, S . K . , et al. , Involvement of the Selectively Targets Nav1. 8 Sodium Channels . Mol Interv, TTX -resistant sodium channel Nav1. 8 in inflammatory and 2007. 7 ( 4 ): p . 192 - 5 ); England , S ., Voltage - gated sodium 55 neuropathic , but not post -operative , pain states . Pain , 2006 . channels : the search for subtype - selective analgesics . Expert 123 ( 1 - 2 ) : pp . 75 - 82 ; Lai, J ., et al ., Inhibition of neuropathic Opin Investig Drugs 17 ( 12 ) , p . 1849 -64 ( 2008 ) ; Krafte , D . pain by decreased expression of the tetrodotoxin - resistant S . and Bannon , A . W . , Sodium channels and nociception : sodium channel, Nay1 . 8 . Pain , 2002 . 95 ( 1 - 2 ) : p . 143 -52 ; recent concepts and therapeutic opportunities . Curr Opin Dong , X . W . , et al. , Small interfering RNA -mediated selec Pharmacol 8 ( 1 ) , p . 50 -56 (2008 ) ). Nay ' s are the primary 60 tive knockdown of Na( v ) 1 . 8 tetrodotoxin - resistant sodium mediators of the rapid upstroke of the action potential of channel reverses mechanical allodynia in neuropathic rats . many excitable cell types ( e . g . neurons, skeletal myocytes , Neuroscience , 2007 . 146 ( 2 ) : p . 812 - 21 ; Huang, H . L ., et al. , cardiac myocytes ), and thus are critical for the initiation of Proteomic profiling of neuromas reveals alterations in pro signaling in those cells ( Hille , Bertil , Ion Channels of tein composition and local protein synthesis in hyper - excit Excitable Membranes, Third ed . (Sinauer Associates , Inc ., 65 able nerves. Mol Pain , 2008 . 4 : p . 33 ; Black , J . A ., et al. , Sunderland , Mass ., 2001 ) ) . Because of the role Nay ' s play Multiple sodium channel isoforms and mitogen -activated in the initiation and propagation of neuronal signals , antago protein kinases are present in painful human neuromas. Ann US 10 ,087 , 143 B2 Neurol , 2008 . 64 (6 ) : p . 644 -53 ; Coward , K ., et al. , Immu nolocalization of SNS /PN3 and NaN /SNS2 sodium channels in human pain states. Pain , 2000 . 85 ( 1 - 2 ) : p . 41 -50 ; Yian PA gou , Y. , et al ., SNS /PN3 and SNS2 /NaN sodium channel - RO like immunoreactivity in human adult and neonate injured 5 sensory nerves . FEBS Lett, 2000 . 467 ( 2 - 3 ) : p . 249 -52 ; D2 Ruangsri, S ., et al. , Relationship of axonal voltage -gated sodium channel 1 . 8 (Nay1 . 8 ) mRNA accumulation to sciatic nerve injury - induced painful neuropathy in rats . J Biol R3

Chem . 286 ( 46 ): p . 39836 - 47 ). The small DRG neurons ? 0 where Na, 1 . 8 is expressed include the nociceptors critical for pain signaling . Nayl. 8 is the primary channel that I mediates large amplitude action potentials in small neurons RO of the dorsal root ganglia (Blair , N . T . and B . P . Bean , Roles 15 of tetrodotoxin ( TTX ) - sensitive Na * current, TTX - resistant Na + current, and Ca2 + current in the action potentials of R9. nociceptive sensory neurons. J Neurosci. , 2002 . 22 ( 23 ) : p . NH 10277 -90 ). Na , 1 . 8 is necessary for rapid repetitive action R3 potentials in nociceptors , and for spontaneous activity of 20 damaged neurons . (Choi , J. S . and S . G . Waxman , Physi R4 G ological interactions between Nay1. 7 and Nay1. 8 sodium channels : a computer simulation study . J Neurophysiol . 106 ( 6 ) : p . 3173 - 84 ; Renganathan , M . , T . R . Cummins , and or a pharmaceutically acceptable salt thereof. S . G . Waxman , Contribution of Na( ) 1 . 8 sodium channels to 25 These compounds and pharmaceutically acceptable com action potential electrogenesis in DRG neurons. J Neuro - positions are useful for treating or lessening the severity of physiol. , 2001 . 86 ( 2 ) : p . 629 -40 ; Roza , C ., et al. , The a variety of diseases , disorders , or conditions , including , but tetrodotoxin - resistant Na+ channel Na , 1 . 8 is essential for not limited to , chronic pain , gut pain , neuropathic pain , the expression of spontaneous activity in damaged sensory musculoskeletal pain , acute pain , inflammatory pain , cancer axons of mice. J Physiol. , 2003 . 550 ( Pt 3 ): p . 921 -6 ). In 30 pain , idiopathic pain , multiple sclerosis , Charcot- Marie depolarized or damaged DRG neurons, Na , 1 . 8 appears to be Tooth syndrome, incontinence or cardiac arrhythmia . the primary driver ofhyper -excitablility (Rush , A . M ., et al ., A single sodium channel mutation produces hyper- or hypo DETAILED DESCRIPTION OF THE excitability in different types of neurons. Proc Natl Acad Sci 35 INVENTION USA , 2006 . 103 ( 21) : p . 8245 -50 ). In some animal pain models , Nay1 . 8 mRNA expression levels have been shown to increase in the DRG ( Sun , W ., et al. , Reduced conduction In one aspect, the invention provides compounds of failure of the main axon of polymodal nociceptive C - fibres formula I or I' contributes to painful diabetic neuropathy in rats . Brain . 40 135 ( Pt 2 ) : p . 359 - 75 ; Strickland , I . T ., et al. , Changes in the expression of NaV1. 7 , Na 1 . 8 and Nay1. 9 in a distinct population of dorsal root ganglia innervating the rat knee joint in a model of chronic inflammatory joint pain . Eur J Pain , 2008 . 12 (5 ): p . 564 -72 ; Qiu , F. , et al. , Increased 45 expression of tetrodotoxin -resistant sodium channels Nav1. 8 D1 VRO and Nay1. 9 within dorsal root ganglia in a rat model of bone cancer pain . Neurosci. Lett. 512 ( 2 ) : p . 61- 6 ) . The primary drawback to the known Nay inhibitors is so their poor therapeutic window , and this is likely a conse quence of their lack of isoform selectivity . Since Nay1. 8 is primarily restricted to the neurons that sense pain , selective R4 42 Nay1. 8 blockers are unlikely to induce the adverse events common to non - selective Nay blockers. Accordingly, there 55 remains a need to develop additional Nay channel antago nists preferably those that are more Nav1. 8 selective and (P8 more potent with increased metabolic stability and with o fewer side effects . 60 N SUMMARY OF THE INVENTION R3 Ó It has now been found that compounds of this invention , R4 Q- and pharmaceutically acceptable compositions thereof, are 65 useful as inhibitors of voltage - gated sodium channels . These compounds have the general formula I or I' : or a pharmaceutically acceptable salt thereof, US 10 ,087 , 143 B2 wherein , independently for each occurrence : cycloalkyl. As one of ordinary skill in the art will recognize , G is combinations of substituents envisioned by this invention are those combinations that result in the formation of stable or chemically feasible compounds . The term “ stable , " as mm used herein , refers to compounds that are not substantially Min altered when subjected to conditions to allow for their PS RS production , detection , and preferably their recovery , purifi in cation , and use for one or more of the purposes disclosed , orman ; herein . In some embodiments , a stable compound or chemi Ro X - RX 10 cally feasible compound is one that is not substantially R6 Y R altered when kept at a temperature of 40° C . or less , in the absence ofmoisture or other chemically reactive conditions , for at least a week . The phrase " optionally substituted ” may be used inter X is a bond or C , - C6 alkyl wherein said C . - C . alkyl is 15 changeably with the phrase " substituted or unsubstituted .” substituted with 0 - 6 halogen , wherein up to two non - adja In general, the term “ substituted ,” whether preceded by the cent CH2 units of said C , - C alkyl may be replaced with term “ optionally ” or not, refers to the replacement ofhydro - 0 % ; gen radicals in a given structure with the radical of a R® is absent, H , or C2 - C , cycloaliphatic , wherein up to two specified substituent. Specific substituents are described non - adjacent CH2 units of said C3- C , cycloaliphatic may be 20 above in the definitions and below in the description of replaced with O — and said Cz- C , cycloaliphatic is sub - compounds and examples thereof. Unless otherwise indi stituted with 0 - 3 substituents selected from halogen and cated , an optionally substituted group can have a substituent CZ -C4 alkyl; at each substitutable position of the group , and when more Rl is H , halogen , CN , or C . - C . alkyl wherein said C . -Co than one position in any given structure can be substituted alkyl is substituted with 0 -6 halogen and wherein up to two 25 with more than one substituent selected from a specified non -adjacent CH , units of said C . - C . alkylmay be replaced group , the substituent can be either the same or different at with 0 % ; every position . A ring substituent, such as a heterocy R2 is H , halogen , CN , or CZ -C6 alkyl wherein said C , -CO cloalkyl, can be bound to another ring , such as a cycloalkyl, alkyl is substituted with 0 - 6 halogen , wherein up to two to form a spiro -bicyclic ring system , e . g . , both rings share non - adjacent CH , units of said C . - C . alkyl may be replaced 30 one common atom . As one of ordinary skill in the art will with 0 % ; recognize , combinations of substituents envisioned by this R * is H , halogen , CN , or C -Co alkyl wherein said C . - Co invention are those combinations that result in the formation alkyl is substituted with 0 - 6 halogen , wherein up to two of stable or chemically feasible compounds . non - adjacent CH , units of said C1- C6 alkyl may be replaced The phrase " up to , " as used herein , refers to zero or any with 0 % ; 35 integer number that is equal or less than the number fol R4 is H , halogen , CN , or C -Co alkyl wherein said C , - C6 lowing the phrase . For example , " up to 4 ” means any one of alkyl is substituted with 0 - 6 halogen , wherein up to two 0 , 1 , 2 , 3 , and 4 . non -adjacent CH2 units of said C , - C . alkyl may be replaced The term “ aliphatic ,” “ aliphatic group ” or “ alkyl” as used with O ; herein , means a straight- chain ( i . e . , unbranched ) or R is H , halogen , CN , or X - R ' ; 40 branched , substituted or unsubstituted hydrocarbon chain R ' is H , halogen , CN , or — X — R * ; that is completely saturated or that contains one or more Róis H , halogen , CN , or — X — R ; units of unsaturation . Unless otherwise specified , aliphatic RO' is H , halogen , CN , or — X — R * ; groups contain 1 - 20 aliphatic carbon atoms . In some R ' is H , halogen , CN , or — X — RY; embodiments , aliphatic groups contain 1 - 10 aliphatic carbon R $ is halogen , or C , - C , alkyl wherein said C . - C . alkyl is 45 atoms. In other embodiments , aliphatic groups contain 1 - 8 substituted with 0 -6 halogen , wherein up to two non - adja - aliphatic carbon atoms. In still other embodiments , aliphatic cent CH2 units of said C - C . alkyl may be replaced with groups contain 1 - 6 aliphatic carbon atoms, and in yet other - 0 % ; embodiments aliphatic groups contain 1 - 4 aliphatic carbon p is an integer from 0 to 3 inclusive ; and atoms. Suitable aliphatic groups include, but are not limited Rºis H , or C1- C6 alkyl wherein up to two non - adjacent CH2 50 to , linear or branched , substituted or unsubstituted alkyl , units of said C . - C . alkyl may be replaced with 40 % alkenyl, alkynyl groups . For purposes of this invention , the chemical elements are The terms“ cycloaliphatic " or " cycloalkyl” mean a mono identified in accordance with the Periodic Table of the cyclic hydrocarbon ring , or a polycyclic hydrocarbon ring Elements, CAS version , Handbook of Chemistry and Phys - system that is completely saturated or that contains one or ics , 75th Ed . Additionally , general principles of organic 55 more units of unsaturation , but which is not aromatic and has chemistry are described in “ Organic Chemistry , ” Thomas a single point of attachment to the rest of the molecule . The Sorrell, University Science Books, Sausalito : 1999 , and term “ polycyclic ring system ,” as used herein , includes “ March ' s Advanced Organic Chemistry , ” 5th Ed ., Ed .: bicyclic and tricyclic 4 - to 12 -membered structures that form Smith , M . B . and March , J . , John Wiley & Sons, New York : at least two rings , wherein the two rings have at least one 2001 , the entire contents of which are hereby incorporated 60 atom in common ( e . g ., 2 atoms in common ) including fused , by reference . bridged , or spirocyclic ring systems. As described herein , compounds of the invention can The term “ halogen ” or “ halo ” as used herein , means F , C1, optionally be substituted with one or more substituents , such Br or I. Unless otherwise specified , the term " heterocycle ," as are illustrated generally above , or as exemplified by “ heterocyclyl, " " heterocycloaliphatic ," " heterocycloalkyl, ” particular classes , subclasses, and species of the invention . 65 or “ heterocyclic ” as used herein means non - aromatic , mono As described herein , the variables RP- Rº in formula I or I ' cyclic , bicyclic , or tricyclic ring systems in which one or encompass specific groups, such as, for example , alkyl and more ring atoms in one or more ring members is an US 10 ,087 , 143 B2 independently selected heteroatom . Heterocyclic ring can be therapeutic agents , are also useful in drug and /or substrate saturated or can contain one or more unsaturated bonds. In tissue distribution assays , as analytical tools or as probes in some embodiments , the " heterocycle, " " heterocycly1 ," " het other biological assays . In one aspect of the present inven erocycloaliphatic , " " heterocycloalkyl, ” or “ heterocyclic ” tion , tritiated ( e . g . , ' H ) and carbon - 14 ( e . g . , ' * C ) isotopes are group has three to fourteen ring members in which one or 5 useful given their ease of detectability . In another aspect of more ring members is a heteroatom independently selected the present invention , replacement of one or more hydrogen from oxygen , sulfur , nitrogen , or phosphorus , and each ring atoms with heavier isotopes such as deuterium , ( e . g ., ? H ) in the ring system contains 3 to 7 ring members . can afford certain therapeutic advantages . The term " heteroatom ” means oxygen , sulfur, nitrogen , In the formulas and drawings , a line transversing a ring phosphorus, or silicon ( including , any oxidized form of 10 andam bonded to an R group such as in nitrogen , sulfur, phosphorus, or silicon ; the quaternized form of any basic nitrogen or ; a substitutable nitrogen of a heterocyclic ring, for example N (as in 3 ,4 -dihydro -2H pyrrolyl) , NH (as in pyrrolidinyl ) or NR + (as in N - substi tuted pyrrolidinyl) ) . 15 The term " unsaturated , ” as used herein , means that a Voor moiety has one or more units of unsaturation but is not aromatic . The term “ alkoxy ,” or “ thioalkyl, ” as used herein , refers to an alkyl group , as previously defined , attached to the 20 Pure principal carbon chain through an oxygen (" alkoxy ” ) or sulfur ( “ thioalkyl” ) atom . The term “ aryl” used alone or as part of a larger moiety RI o as in “ aralkyl, ” “ aralkoxy, ” or “ aryloxyalkyl, ” refers to monocyclic , bicyclic , and tricyclic ring systems having a 25 NH total of five to fourteen ring carbon atoms, wherein at least one ring in the system is aromatic and wherein each ring in the system contains 3 to 7 ring carbon atoms. The term XR4 9 " aryl” may be used interchangeably with the term “ aryl G ring .” 30 The term " heteroaryl , ” used alone or as part of a larger means that the R group , i . e . the R $ group can be bonded to moiety as in " heteroaralkyl " or " heteroarylalkoxy ," refers to any carbon of that ring as valency allows. monocyclic , bicyclic , and tricyclic ring systems having a Within a definition of a term as , for example , X , RY, R1 , total of five to fourteen ring members , wherein at least one R ?, R , R4, RS, or Rº when a CH , unit or, interchangeably , ring in the system is aromatic , at least one ring in the system 35 methylene unit may be replaced by O — , it is meant to contains one or more heteroatoms, and wherein each ring in include any CH , unit , including a CH , within a terminal the system contains 3 to 7 ring members . The term “ het - methyl group . For example , CH2CH2CH2OH is within the eroaryl” may be used interchangeably with the term “ het - definition of C , - C , alkyl wherein up to two non - adjacent eroaryl ring " or the term " heteroaromatic . ” CH2 units may be replaced by 0 because the CH2 unit “ D ” and “ d ” both refer to deuterium . 40 of the terminalmethyl group has been replaced by O — . Unless otherwise stated , structures depicted herein are In another embodiment, the invention features a com also meant to include all isomeric ( e . g . , enantiomeric , diaste pound of formula I or I' and the attendant definitions , reomeric , and geometric (or conformational) ) forms of the wherein R ' is H . In another embodiment , Rl is halogen . In structure ; for example , the R and S configurations for each another embodiment, R is CN . In another embodiment, R1 asymmetric center, ( Z ) and ( E ) double bond isomers , and ( Z ) 45 is C , -Co alkyl wherein said C . - C . alkyl is substituted with and ( E ) conformational isomers . Therefore, single stereo - 0 -6 halogen . In another embodiment, R1 is CFz . chemical isomers as well as enantiomeric , diastereomeric , In another embodiment, the invention features a com and geometric (or conformational) mixtures of the present pound of formula I or I ' and the attendant definitions , compounds are within the scope of the invention . Unless wherein R2 is H . In another embodiment, R2 is halogen . In otherwise stated , all tautomeric forms of the compounds of 50 another embodiment , R² is Cl. In another embodiment, R² is the invention are within the scope of the invention . Thus , F . In another embodiment, R2 is CN . In another embodiment, included within the scope of the invention are tautomers of R2 is C - C6 alkyl wherein said C , -Co alkyl is substituted compounds of formula I and I' . The structures also include with 0 -6 halogen . In another embodiment , R ? is CF3. In zwitterionic forms of the compounds or salts of formula 1 another embodiment, R2 is C , - C . alkyl wherein said C , -CA and formula I' where appropriate . 55 alkyl is substituted with 0 - 6 halogen wherein one CH2unit Additionally , unless otherwise stated , structures depicted of said C - C6 alkyl is replaced with - 0 . In another herein are also meant to include compounds that differ only embodiment, R2 is OCF2 . In another embodiment , R2 is F , in the presence of one or more isotopically enriched or C1, CN , CF , or OCFz . isotopically - labeled atoms. The isotopically- labeled com In another embodiment, the invention features a com pounds may have one or more atoms replaced by an atom 60 pound of formula I or I ' and the attendant definitions , having an atomic mass or mass number usually found in wherein R * is H . In another embodiment, R3 is halogen . In nature . Examples of isotopes present in compounds of another embodiment, Ris Cl. In another embodiment, Rºis formula I and formula I' include isotopes of hydrogen , F . In another embodiment, R3 is CN . In another embodiment, carbon , nitrogen , oxygen , phosphorus, fluorine and chlorine , R * is C . - C . alkyl wherein said C . - C . alkyl is substituted such as, but not limited to , 2H , PH , 13C , 14C , 15N , 180 , 170 , 65 with 0 -6 halogen . In another embodiment , R3 is t -butyl . In 355 and 18F. Certain isotopically - labeled compounds of another embodiment, R3 is CF3. In another embodiment , R3 formula I or formula I' , in addition to being useful as is CF CFz . US 10 , 087 , 143 B2 10 In another embodiment, the invention features a com - wherein : pound of formula I or I' and the attendant definitions, R5 is H or — X — R '; wherein R4 is H . In another embodiment, R4 is halogen . In R5' is H or XRY; another embodiment , R * is CN . In another embodiment , R4 Róis H , halogen , CN , or - X - RX; is C , -C6 alkyl wherein said C .- C . alkyl is substituted with 5 R7 is H or — X — R ; 0 -6 halogen . In another embodiment, R4 is CF3. X is a bond or C -Co alkyl wherein said C . - C . alkyl is In another embodiment, the invention features a com - substituted with 0 - 6 halogen , wherein up to two non - adja pound of formula I or I' and the attendant definitions, cent CH , units of said C . - C6 alkyl may be replaced with wherein p is zero . In another embodiment, p is an integer - 0 — ; and from 1 to 3 and Rºis halogen . In another embodiment, p is 10 RY is absent, H , or Cz- C , cycloaliphatic , wherein up to two an integer from 1 to 3 andR is Cl. In another embodiment, non -adjacent CH , units of said C3 - C , cycloaliphatic may be p is an integer from 1 to 3 and Rºis C . - C . alkyl wherein said replaced with and said Cz- Cg cycloaliphatic is sub C1- C . alkyl is substituted with 0 - 6 halogen wherein one CH2 stituted with 0 - 3 substituents selected from halogen and unit of said C , - C6 alkyl is replaced with O — . In another C . - C , alkyl. embodiment, p is an integer from 1 to 3 and R8 is CH2. 15 In another embodiment, the invention features a com In another embodiment, the invention features a com - pound of formula I or I ' and the attendant definitions , pound of formula I or I' and the attendant definitions , wherein G is wherein Rº is H . In another embodiment, Rº is C , -C6 alkyl. In another embodiment, Rº is CHz. In another embodiment , Rº is C , -C6 alkyl wherein said C . - C . alkyl is substituted 20 with 0 - 6 halogen wherein one CH , unit of said C . -C . alkyl is replaced with O — . In another embodiment, Rº is mann CH2CH2OH . RS R . In another embodiment, the invention features a com pound of formula I or I' and the attendant definitions, 25 wherein G is Y RoR6

im In one embodiment R5 is H . In another embodiment, R is halogen . In another embodiment, R is Cl. In another embodiment, R $ is F. In another embodiment, R5 is CN . In another embodiment, RS is X - R * . In another embodi ment, RS is — X — R * wherein R * is absent. In another Ro Ro 35 embodiment, RS is - X - R * wherein R * is absent and X is C . - C . alkyl wherein said C . - C . alkyl is substituted with 0 - 6 halogen . In another embodiment, R is CHz . In another embodiment, RS is — X — R * wherein R * is absent and X is wherein : C , -C6 alkyl wherein said C . - C . alkyl is substituted with 0 - 6 R $ is H , halogen , CN , or — X — R * ; halogen wherein one CH , unit of said C - CG alkyl is R5' is H , halogen , CN , or — X — R ; replaced with 0 . In another embodiment, R ' is OCHZ, Rºis H , halogen , CN , or — X — R * ; OCH CH3, OCH2CH2CH3, or OCH (CH3 )2 . In another Ró' is H , halogen , CN , or — X — R * ; embodiment, RS is OCHZ. In another embodiment, RS is R ? is H , halogen , CN , or — X - R ; CH , OH . In another embodiment , R is OCFz. In another X is a bond or C . - C . alkyl wherein said C . - C . alkyl is 45 embodiment, R is OCHF2. substituted with 0 - 6 halogen and wherein up to two non - In another embodiment, the invention features a com adjacent CH2 units of said C . -C . alkyl may be replaced with pound of formula I or I' and the attendant definitions, - 0 % ; and R * is absent, H , or Cz- Cg cycloaliphatic , wherein up to two wherein G is non - adjacent CH2 units of said Cz - Cg cycloaliphatic may be 50 replaced with and said Cz- Cg cycloaliphatic is sub pa stituted with 0 - 3 substituents selected from halogen and C , -C4 alkyl. RS . In another embodiment, the invention features a com pound of formula I or I' and the attendant definitions, 55 wherein G is RO R mm 60 In one embodiment, R is H . In another embodiment, R is - X - R * . In another embodiment, RS is — X — R * wherein R * is absent. In another embodiment, RS is — X — R * wherein R * is absent and X is CZ -C6 alkyl wherein said Ro C -C6 alkyl is substituted with 0 - 6 halogen . In another 7 65 embodiment, RS is CHz. In another embodiment, RS is - X - R * wherein R * is absent and X is CZ -C6 alkyl wherein said C .- Cô alkyl is substituted with 0 -6 halogen wherein one US 10 ,087 , 143 B2 CH , unit of said C . -C . alkyl is replaced with O — . In another embodiment, R is OCHz, OCH CHz , OCH2CH2CH3, or OCH ( CH3) 2. In another embodiment, RS min is OCH?. In another embodiment, R5 is CH ,OH . In another or R -R3 embodiment, RS is OCF3. In another embodiment, R is 5 R5 R5 OCHF . In another embodiment, the invention features a com R6 pound of formula I or I ' and the attendant definitions , R6 wherein G is R ? In one embodiment Róis H . In another embodiment , Róis inn halogen . In another embodiment, Róis Cl. In another RS RS embodiment, Ris F . In another embodiment, R? is CN . In 15 another embodiment, Rº is — X — R . In another embodi ment, Róis - X - R * wherein R * is absent. In another embodiment, Róis - X - R * wherein R * is absent and X is R6 Po C . - C . alkyl wherein said C , -C6 alkyl is substituted with 0 -6 halogen . In another embodiment, R? is CHz . In another 20 embodiment, Ris — X — R * wherein R * is absent and X is In one embodiment RS' is H . In another embodiment, RS' is C . - C . alkyl wherein said C . - C . alkyl is substituted with 0 -6 halogen . In another embodiment, R is Cl. In another halogen wherein one CH2 unit of said CZ -C6 alkyl is embodiment, Rºis F . In another embodiment, R " is CN . In replaced with O — . In another embodiment, Rº is OCHZ. another embodiment, R ' is — X - R * . In another embodi In another embodiment, the invention features a com ment, RS' is — X — R * wherein R * is absent. In another 25 pound of formula I or I' and the attendant definitions , embodiment, R ' is - X R * wherein R * is absent and X is wherein G is C . - C . alkyl wherein said C . - C . alkyl is substituted with 0 - 6 halogen . In another embodiment, RS' is CHz. In another embodiment, R ' is - X - R * wherein R * is absent and X is CZ -C6 alkyl wherein said C . - C . alkyl is substituted with 0 - 6 mm halogen wherein one CH2 unit of said Cy -Co alkyl is ? replaced with O . In another embodiment, Rs' is OCHz, R ” . OCH CH3, OCH CH2CH3, or OCH (CH3 ) 2 . In another embodiment, R ' is OCHz. In another embodiment, RS is ? CH , OH . In another embodiment, RS' is OCF3. In another 35 Y R6 embodiment, RS is OCHF , . 7 In another embodiment, the invention features a com pound of formula I or I ' and the attendant definitions , In one embodiment, R ' is H . In another embodiment, RO' is wherein G is 40 halogen . In another embodiment, R " is Cl. In another embodiment, R is F . In another embodiment, Rºis CN . In waar another embodiment, Rºis — X - R * . In another embodi ment, Róis - X - R * wherein R * is absent. In another RS embodiment, R ' is — X — R * wherein R * is absent and X is 45 C1- C6 alkyl wherein said C . - C . alkyl is substituted with 0 - 6 halogen . In another embodiment, R " is CHz. In another R6 embodiment, Rºis — X — R $ wherein R * is absent and X is C . - C . alkyl wherein said C , -C6 alkyl is substituted with 0 -6 halogen wherein one CH , unit of said C . - C . alkyl is 50 replaced with O — . In another embodiment, Rois OCHz. In one embodiment, R is H . In another embodiment, RS is In another embodiment, the invention features a com - X - R * . In another embodiment, R is — X — R * wherein pound of formula I or I ' and the attendant definitions, RX is absent . In another embodiment, RS is X - R wherein G is wherein R * is absent and X is CZ -C6 alkyl wherein said C . - C . alkyl is substituted with 0 - 6 halogen . In another 55 embodiment, RS is CHz. In another embodiment, RS is - X - R * wherein R * is absent and X is C . - C . alkyl wherein said C . - C . alkyl is substituted with 0 - 6 halogen wherein one CH , unit of said C . - C . alkyl is replaced with - 0 % In RS RS . another embodiment, R is OCHZ, OCH CH3, 60 OCH CH CHz, or OCH ( CH3) 2 . In another embodiment, R " is OCH?. In another embodiment, Rº is CH , OH . In another Po y R6 embodiment, RS is OCFz. In another embodiment, RS is OCHFZ. In another embodiment , the invention features a com - 65 pound of formula I or I' and the attendant definitions, In one embodiment, R ? is H . In another embodiment, R7 is wherein G is halogen . In another embodiment, R7 is Cl. In another US 10 , 087 , 143 B2 13 14 embodiment, R ? is F . In another embodiment, R ' is CN . In In one embodiment, R ' is — X — R * wherein X is a bond and another embodiment, R7 is - X - R * . In another embodi - R * is Cz- C , cycloaliphatic and said Cz- Cg cycloaliphatic is ment, R7 is — X — R wherein R * is absent . In another substituted with 0 - 3 substituents selected from halogen and embodiment, R ? is - X - R * wherein R * is absent and X is C . - C4 alkyl. In another embodiment, R7 is - X - R * C . - C . alkyl wherein said C , - C alkyl is substituted with 0 -6 5 wherein X is a bond and R * is cyclopropyl. halogen . In another embodiment, R7 is CH3, CH2CH3, In another embodiment , the invention features a com CH CH _ CHz or isopropyl. In another embodiment, R ' is pound of formula I or I ' and the attendant definitions, CF3. In another embodiment, R ' is - X - R * wherein R * is absent and X is C , -C6 alkyl wherein said C , -C6 alkyl is wherein G is substituted with 0 - 6 halogen wherein two non - adjacent CH , 1 units of said C . - C . alkyl are replaced with 0 % . In another embodiment, R ' is OCH CH OCHz. In another embodi no ment, R7 is - X - R ' wherein R * is absent and X is CZ -C6 R5 alkyl wherein said C . - C . alkyl is substituted with 0 -6 or R halogen wherein one CH2 unit of said C . - C6 alkyl is replaced with 0 - . In another embodiment, R ' is OCHZ, R6- OCH CH , OCH CH2CH3, OC ( CH3) 3 , CH CH OCHz. In Y R6 another embodiment, RP is OCF3, OCH _CF3 , OCH CH , CH ,CF3 , or OCHF2. 20 In another embodiment, the invention features a com pound of formula I or I' and the attendant definitions , In one embodiment, R7 is — X — R * wherein X is C . - C . wherein G is alkyl wherein said C . - C . alkyl is substituted with 0 -6 halogen wherein one CH2 unit of said C1- C6 alkyl is 25 replaced with O — and R * is C3 - C , cycloaliphatic and said C3 - C , cycloaliphatic is substituted with up 0 - 3 substituents - RS. selected from halogen and C , - C4 alkyl. In another embodi ment, R ' is - X - R * wherein X is OCH , and R * is cyclo 30 propyl. In another embodiment , the invention features a com pound of formula I or I' and the attendant definitions, wherein G is : In one embodiment, R ? is H In another embodiment, R ? is z - X - R * . In another embodiment, R7 is — X — R wherein R * is absent. In another embodiment, R ? is - X - R * wherein R * is absent and X is CZ- C6 alkyl wherein said C . - C . alkyl is substituted with 0 -6 halogen . In another embodiment, R7 is CH2, CH , CHZ, CH , CH , CHz or isopro - 40 pyl. In another embodiment , R ? is CFz. In another embodi ment, R ' is — X — R * wherein R * is absent and X is C , -CA alkyl wherein said CZ -C6 alkyl is substituted with 0 - 6 Po Por halogen wherein two non -adjacent CH _ units of said C , -C6 alkyl are replaced with O — . In another embodiment, R ? 45 is OCH _ CH _ OCHz. In another embodiment, R is - X - RtRX Bag wherein R * is absent and X is C . - C . alkyl wherein said and G is selected from : C . - C . alkyl is substituted with 0 -6 halogen wherein one CH2 unit of said C . - C . alkyl is replaced with 0 - . In another embodiment, R ' is OCHz, OCH CH , OCH CH CH3, 50 OC ( CH3) 3 , CH2CH2OCHz. In another embodiment , R ' is SE OCF , OCH ,CF , OCH ,CH , CH ,CFz , or OCHF . min minn, m in , In another embodiment, the invention features a com pound of formula I or I' and the attendant definitions , wherein G is 55

ni 5555 or R RS 60 wa Y R6 R7 ButR ? 65 US 10,087 ,143 B2 15 16 -continued -continued nonne ??? Anne Nove, NN N( AMAN : NAM : NNNNNN ) ? F - F

Annue , LF, F ? -DHC F ?

nnnnnnnn nnnnn NNNN ( Unlin

? > 10?

F F

1F Annnnn

nnnnnn : nonne nnnnn : nnnnnn

CN

F HO

??

Anne nn A( pinnnnnnnnnn

Annnn ,

F ? F

-

F

F US 10 ,087 , 143 B2 17 18 - continued In another embodiment , the invention features a com pound of formula I or I' and the attendant definitions, m , mi , n im , wherein G is F 5

man mafunaX - R * 10 wherein : ime , mm , wi , X is a bond or C1- C6 alkyl wherein said C -C6 alkyl is substituted with 0 -6 halogen , wherein up to two non - adja cent CH2 units of said C - C . alkyl may be replaced with 15 - 0 % ; and R * is absent, H , or C3 -C4 cycloaliphatic , wherein up to two F F non - adjacent CH2 units of said C3 - C , cycloaliphatic may be F 7 replaced with O and said C3 -C , cycloaliphatic is sub stituted with up 0 - 3 substituents selected from halogen and C1- C4 alkyl. $ man ,$ In another embodiment, the invention features a com pound of formula I or I' and the attendant definitions , wherein G is - X - R * wherein X is C1- C6 alkyl wherein 25 said C . - C . alkyl is substituted with 0 -6 halogen wherein up F F to two non - adjacent CH , units of said C , -C6 alkyl may be replaced with O and R * is absent. In another embodi ment , X is CH2CH2CH (CH3 ) 3 or CH2CH (CH3 ) 2 and R * is absent . In another embodiment , X is CH2CH2CH2CFz or min 30 CH CH CF , and R * is absent. In another embodiment, the invention features a com pound of formula I or I' and the attendant definitions , or wherein G is — X - R wherein X is a bond and R * is C3 - Cg cycloaliphatic wherein up to two non -adjacent CH , of said C3 - C , cycloaliphatic may be replaced with and said C3- C , cycloaliphatic is substituted with 0 - 3 substituents selected from halogen and C . -C4 alkyl. In another embodi ment, X is a bond and R * is cyclobutane , cyclohexane , In another embodiment, the invention features a com bicyclo [ 2 . 2 . 1 ]heptane , or bicyclo [ 3 . 1 . 0 ]hexane . pound of formula I or I' and the attendant definitions, 40 In another embodiment, the invention features a com wherein G is : pound of formula I or I' and the attendant definitions , wherein G is - X - R * wherein X is C . - C . alkyl wherein said C . - C . alkyl is substituted with 0 - 6 halogen wherein up 45 to two non -adjacent CH2 units of said C , -C alkyl may be RS RS" replaced with O and R * is C3 -C , cycloaliphatic wherein up to two non - adjacent CH2 units of said C3 - C , cycloali phatic may be replaced with O — ; and said C3 - C , cycloa R6 liphatic is substituted with 0 - 3 substituents selected from 50 halogen and C , - C4 alkyl. In another embodiment, X is CH2 and R * is Cz- C , cycloaliphatic . In another embodiment, X is CH , and R * is cyclopropyl or cyclopentyl. In another and G is selected from embodiment, X is CH2 and R * is C3 -C , cycloaliphatic with up to 3 substituents selected from halogen and C , - C4 alkyl. 55 In another embodiment, X is CH , and R * is 1 -methylcyclo propyl, 2 , 2 - dimethylcyclopropyl or 2 , 2 - difluorocyclopropyl. mun In another embodiment, the invention features a com van pound of formula I or I ' and the attendant definitions, ni wherein G is — X — R * wherein X is C . - C . alkyl wherein 60 said C . - C . alkyl is substituted with 0 - 6 halogen wherein up or to two non - adjacent CH2 units of said C . - C . alkyl are replaced with O and R * is Cz- C , cycloaliphatic wherein up to two non -adjacent CH , of said C3 - Cg cycloaliphatic FFF F may be replaced with O and said Cz- Cg cycloaliphatic 65 is substituted with 0 - 3 substituents selected from halogen and C , -C4 alkyl. In another embodiment, X is CH and R * is C3 -Cg cycloaliphatic wherein one CH , unit of said C3- C , US 10 , 087 , 143 B2 19 20 cycloaliphatic is replaced with O — . In another embodi wherein , independently for each occurrence : ment, X is CH , and R * is 3 - tetrahydrofuran . Gis In another embodiment, the invention features a com pound of formula I or I' and the attendant definitions , ma wherein G is — X — R * and X - R * is selected from : nim ?? RS n , w an , mm , wan, or non ; 10 ROC X - RY RO R6

D7 15 X is a bond or C1- C6 alkyl wherein said C -C6 alkyl is , , , mm , n am substituted with 0 -6 halogen , wherein up to two non -adja ?? cent CH2 units of said C . - Co alkyl may be replaced with - 0 ; R * is absent, H , or Cz- C , cycloaliphatic , wherein up to two + F 20 non -adjacent CH , units of said Cz- C , cycloaliphatic may be

( replaced with O and said Cz- C , cycloaliphatic is sub F stituted with 0 -3 substituents selected from halogen and C1- C4 alkyl; mm , R2 is halogen , CN , or C , - Co alkylwherein said C . - C . alkyl ma is substituted with 0 - 6 halogen and wherein up to two 25 non - adjacent CH _ units of said C1- C6 alkyl may be replaced T with O ; Ris H , halogen , CN , or - X - R ' ; RS is H , halogen , CN , or — X - R ; Róis H , halogen , CN , or — X — R * ; 30 R™ is H , halogen , CN , or X - R * ; wan, ormai R ? is H , halogen , CN , or - X - R * ; R® is halogen , or C . - C . alkyl wherein said C .- C . alkyl is substituted with 0 - 6 halogen and wherein up to two non adjacent CH , units of said C , - Co alkyl may be replaced with - 0 % ; p is an integer from 0 to 3 inclusive ; and In another aspect, the invention provides a compound of unitsRºis Hof , orsaid C C- C. -. C alkyl . alkyl wherein may beup replaced to two non with -adjacent O CH2. formula I- A or I' - A : In another embodiment, the invention features a com pound of formula I - A or IP - A and the attendant definitions, wherein R2 is halogen . In another embodiment, R2 is C1. In another embodiment, R2 is F . In another embodiment, R2 is CN . In another embodiment, RP is C - C alkyl wherein said C - C alkyl is substituted with 0 - 6 halogen . In another I - A embodiment, R² is CFz. In another embodiment, R² is C . - C . 45 alkyl wherein said C , -C6 alkyl is substituted with 0 - 6 Wpg halogen wherein one CH2 unit of said C , -C alkyl is replaced with — — . In another embodiment , R is OCFz . In another embodiment, R2 is F , C1, CN , CF , or OCF2 . IZ In another embodiment, the invention features a com 50 pound of formula I - A or I' - A and the attendant definitions, wherein p is zero . In another embodiment , p is an integer 9 from 1 to 3 and Rºis halogen . In another embodiment, p is an integer from 1 to 3 and R8 is C1. In another embodiment, p is an integer from 1 to 3 and R8 is C - C , alkyl wherein said 5 C - C , alkyl is substituted with 0 - 6 halogen wherein one CH , I ' - A unit of said C . - C . alkyl is replaced with O . In another & embodiment, p is an integer from 1 to 3 and R8 is CH . In another embodiment, the invention features a com pound of formula I - A or I' - A and the attendant definitions , P2 wherein Rºis H . In another embodiment , Rºis C - C alkyl . 60OU In another embodiment, Rº is CHz. In another embodiment, Rº is C , -Co alkyl wherein said C . - C . alkyl is substituted with 0 -6 halogen wherein one CH , unit of said C . -C . alkyl is replaced with O — . In another embodiment, Rº is Q CH , CH ,OH . 65 In another embodiment, the invention features a com pound of formula I - A or I' - A and the attendant definitions, or a pharmaceutically acceptable salt thereof, wherein G is US 10 ,087 , 143 B2

mm RS

po R6 Y R6 > R? 10 P In one embodiment, RS is H . In another embodiment, RS is wherein : halogen . In another embodiment, R is Cl. In another Ris H , halogen , CN , or — X - R ; embodiment, RS is F . In another embodiment, R5 is CN . In R $' is H , halogen , CN , or - X - R * ; another embodiment, RS is - X - R * . In another embodi Róis H , halogen , CN , or - X - R¥; ment, RS is - X - R * wherein R * is absent. In another R6' is H , halogen , CN , or — X — R * ; embodiment, RS is - X - R * wherein R * is absent and X is R ? is H , halogen , CN , or — X — R ' ; C1- C6 alkyl wherein said C -C6 alkyl is substituted with 0 -6 X is a bond or C . - C . alkyl wherein said C .- C . alkyl is halogen . In another embodiment, Rºis CH3 . In another substituted with 0 -6 halogen , wherein up to two non -adja embodiment, RS is - X - R * wherein R * is absent and X is cent CH2H2 units ofof said C1C , -- C6 C alkyl may bebe replacedreplaced with C - C . alkyl wherein said C -C . alkyl is substituted with 0 -6 - 0 % ; and halogen wherein one CH , unit of said C -C6 alkyl is R * is absent, H , or Cz - C , cycloaliphatic , wherein up to two non - adjacent CH2 units of said C3 -C , cycloaliphatic may be replaced with O — . In another embodiment, R? is OCHz, replaced with and said Cz- Cg cycloaliphatic is sub OCH ,CH3 , OCH2CH2CH3, or OCH (CH3 ) 2 . In another stituted with 0 -3 substituents selected from halogen and embodiment, RS is OCHz. In another embodiment, RS is CZ -C4 alkyl. 20CH ,OH . In another embodiment, RS is OCFz. In another In another embodiment, the invention features a com - embodiment, Ris OCHF 2 . pound of formula I - A or I' - A and the attendant definitions, In another embodiment , the invention features a com wherein G is pound of formula I - A or IP- A and the attendant definitions , wherein G is 35

a RS w RS RS . RO

# Ro 7 wherein : RS is H , or - X - R ' ; In one embodiment, Ris H . In another embodiment, R is RS' is H , or - X - R "; 30 — X — R * . In another embodiment, R is — X — R * wherein Róis H , halogen , CN , or - X - RX ; R® is absent . In another embodiment, RS is — X — R * R ? is H , or — X — R "; wherein R * is absent and X is C -C6 alkyl wherein said X is a bond or CZ - C6 alkyl wherein said C . - C . alkyl is CZ -C6 alkyl is substituted with 0 - 6 halogen . In another substituted with 0 - 6 halogen , wherein up to two non - adja - 553 embodiment, RS is CHz. In another embodiment, R is cent CH2 units of said C .- C . alkyl may be replaced with - X - R * wherein R * is absent and X is C ,- C6 alkyl wherein - 0 — ; and said C , - C . alkyl is substituted with 0 -6 halogen wherein one CH , unit of said C - C . alkyl is replaced with 0 . In R * is absent, H , or C3- C , cycloaliphatic , wherein up to two another embodiment, RS is OCHZ, OCH CH3, non -adjacent CH _ units of said Cz- Cg cycloaliphatic may be 60 OCH CH CHz, or OCH ( CH3) 2 . In another embodiment, RS replaced with O and said C3 -C , cycloaliphatic is sub is OCHz. In another embodiment, R is CH ,OH . In another stituted with 0 - 3 substituents selected from halogen and embodiment, R is OCF3. In another embodiment, R is CZ -C4 alkyl. OCHF2. In another embodiment, the invention features a com - 65 In another embodiment, the invention features a com pound of formula I - A or I ' - A and the attendant definitions , pound of formula I - A or I ' - A and the attendant definitions , G wherein G is US 10 ,087 , 143 B2

w nim ma or RS RS RS R RSR RY5

Po R6 RO R7 R? 10 In one embodiment R5' is H . In another embodiment, R5' is in one embodiment, Rº is H . In another embodiment, Rºis halogen . In another embodiment, Róis Cl. In another halogen. In another embodiment, RS' is Cl. In another embodiment, Rºis F . In another embodiment, Ro is CN . In embodiment, Rºis F . In another embodiment, Rºis CN . In 15 another embodiment. R6 is -- X - RX. In another embodi another embodiment, RS' is - X - RX. In another embodi ment, Róis — X — R * wherein R * is absent. In another ment, R5' is - X - R¥ wherein R * is absent. In another embodiment, Rº is — X — R * wherein R * is absent and X is C . - C . alkyl wherein said C . -C . alkyl is substituted with 0 -6 embodiment, RS' is - X - R * wherein R * is absent and X is halogen . In another embodiment, R is CH2. In another C . - C , alkyl wherein said C . - C . alkyl is substituted with 0 -6 20 embodiment, Róis - X - R¥ wherein R¥ is absent and X is halogen . In another embodiment, R ” is CHz. In another C .- C . alkyl wherein said C , - C alkyl is substituted with 0 - 6 embodiment, R5' is - X - R wherein R * is absent and X is halogen wherein one CH2 unit of said C . - C . alkyl is 0 -6 replareplaced with O — . In another embodiment, R? is OCHZ. C . -C . alkyl wherein said C .- C . alkyl is substituted with 0 -6 In another embodiment, the invention features a com halogen wherein one CH2 unit of said C1 -C6 alkyl is 25 pound of formula I- A or I' - A and the attendant definitions. replaced with . In another embodiment, RS' is OCHZ, wherein G is OCH CH3, OCH CH CHz, or OCH (CH3 ) 2 . In another embodiment, RS' is OCHZ. In another embodiment, RS is CH , OH . In another embodiment, RS' is OCF3 . In another 30 embodiment, RS' is OCHFZ. In another embodiment, the invention features a com pound of formula I - A or IP - A and the attendant definitions, G 35 Y RoRH

man 5 In one embodiment , R ' is H . In another embodiment , R ' is 5 ? 40 halogen . In another embodiment, Róis Cl. In another embodiment, Rºis F . In another embodiment, Rºis CN . In another embodiment, RO' is — X — R " . In another embodi 6 ment, R ' is — X - RX wherein R * is absent. In another embodiment, Rºis — X — R * wherein R * is absent and X is 45 C . - C . alkyl wherein said C . - C . alkyl is substituted with 0 - 6 halogen . In another embodiment, Rºis CH2. In another In one embodiment R ' is H . In another embodiment , RS is embodiment, R is — X — R * wherein R * is absent and X is - X - RX. In another embodiment, R5' is X - R -` wherein C , - C alkyl wherein said C . - C . alkyl is substituted with 0 - 6 halogen wherein one CH2 unit of said C . -C . alkyl is R * is absent. In another embodiment, RS' is - X - R * 50 replaced with O — . In another embodiment, R ' is OCHZ. wherein R * is absent and X is C , - C6 alkyl wherein said In another embodiment, the invention features a com C - C , alkyl is substituted with 0 -6 halogen . In another pound of formula I - A or I' - A and the attendant definitions , embodiment, RS' is CHz. In another embodiment, RS' is wherein G is - X - R * wherein R® is absent and X is C . - C . alkyl whereins said C . - C . alkyl is substituted with 0 -6 halogen wherein one CH , unit of said C . - C . alkyl is replaced with O — . In another embodiment, R is OCHZ, OCH2CH3,

OCH2CH2CH3, or OCH (CH3 ) 2 . In another embodiment, RS" 60 is OCHz. In another embodiment, RS' is CH OH . In another embodiment, RS is OCF3 . In another embodiment , RS is OCHFZ. In another embodiment, the invention features a com pound of formula I- A or I' - A and the attendant definitions, In one embodiment. R7 is H . In another embodiment . R7 is wherein G is halogen . In another embodiment, R ? is Cl. In another US 10 , 087 , 143 B2 25 26 embodiment, R ? is F . In another embodiment, R ' is CN . In In one embodiment, R ' is — X — R * wherein X is a bond and another embodiment, R7 is - X - R * . In another embodi - R * is Cz- C , cycloaliphatic and said Cz- Cg cycloaliphatic is ment, R7 is — X — R wherein R * is absent . In another substituted with 0 - 3 substituents selected from halogen and embodiment, R ? is - X - R * wherein R * is absent and X is C . - C4 alkyl. In another embodiment, R7 is - X - R * C - C . alkyl wherein said C . - C . alkyl is substituted with 0 -6 5 wherein X is a bond and R * is cyclopropyl. halogen . In another embodiment, R7 is CH3, CH2CH3, In another embodiment , the invention features a com CH , CH ,CHz or isopropyl. In another embodiment, R ' is pound of formula I - A or I - A and the attendant definitions , CF3. In another embodiment, R ' is - X - R * wherein R * is absent and X is C , -C6 alkyl wherein said C , -C6 alkyl is wherein G is substituted with 0 - 6 halogen wherein two non - adjacent CH , 1 units of said C . - C . alkyl are replaced with 0 % . In another embodiment, R ' is OCH CH OCHz. In another embodi ment, R7 is - X - R ' wherein R * is absent and X is CZ -C6 oror Rd R . alkyl wherein said C . - C . alkyl is substituted with 0 -6 15 R5 halogen wherein one CH2 unit of said C . - C6 alkyl is replaced with 0 - . In another embodiment, R ' is OCHZ, OCH CH , OCH CH2CH3, OC ( CH3) 3 , CH CH OCHz. In Po VR6Po another embodiment, RP is OCF3, OCH _CF3 , R7 OCH CH2CH2CF3, or OCHF2. 20 In another embodiment, the invention features a com pound of formula I - A or I' - A and the attendant definitions , In one embodiment, R7 is — X — R * wherein X is C . -C . wherein G is alkyl wherein said C . -C6 alkyl is substituted with 0 -6 halogen wherein one CH2 unit of said C1- C6 alkyl is 5 replaced with O — and R * is Cz- Ce cycloaliphatic and said C3- C , cycloaliphatic is substituted with 0 - 3 substituents RS R5 selected from halogen and C . -C4 alkyl. In another embodi ment, R ' is - X - R * wherein X is OCH , and R * is cyclo 30 propyl. R6 In another embodiment , the invention features a com pound of formula I - A or I' - A and the attendant definitions , wherein G is : In one embodiment, R ' is H . In another embodiment, R ? is — X — R * . In another embodiment, R7 is — X — R * wherein R * is absent. In another embodiment, R7 is — X — R * wherein R * is absent and X is C , - C6 alkyl wherein said C . - C . alkyl is substituted with 0 -6 halogen . In another RS embodiment, R7 is CH2, CH , CHZ, CH , CH , CHz or isopro - 10 pyl. In another embodiment, R ' is CF3. In another embodi ment , R7 is — X — R * wherein R * is absent and X is C , -Co y alkyl wherein said CZ -C6 alkyl is substituted with 0 - 6 R6 halogen wherein two non - adjacent CH _ units of said C , - Co alkyl are replaced with O — . In another embodiment, R ? is OCH CH OCHz. In another embodiment , R ? is X — RY 45 wherein R * is absent and X is C . - C . alkyl wherein said and G is selected from : C . - C . alkyl is substituted with 0 - 6 halogen wherein one CH2 unit of said C . - C . alkyl is replaced with 0 - . In another F embodiment, R ? is OCHZ, OCH CH3, OCH CH CH3, 50s OC (CH3 ) 3 , CH CH OCHz. In another embodiment, R ' is F OCF3, OCH2CF3, OCH2CH2CH2CF3, or OCHF2. mm ni , ann , In another embodiment, the invention features a com pound of formula I - A or I' - A and the attendant definitions , wherein G is 55

mons win 5555 or R $ RE Rs 60 my n im , RO R6 Y R6 R7 ????65 US 10 ,087 , 143 B2 27 28 - continued -continued

mi w i , , F OH ö unmini niny F - F

ö mm , ni

F , F , F F ö

mann m in m in Ben F

un mu

F tét+07btetnot

mun , mi

mi

CN Rx mi May HO mRee Re, Lot Ottesmin , niin § mi , mun , mi ,

F F F a - F US 10 , 087 , 143 B2 29 30 - continued In another embodiment , the invention features a com pound of formula I - A or I' - A and the attendant definitions, m mm , n im , wherein G is 5

vina X - RX 10 wherein : mi , m an , X is a bond or C1- C6 alkyl wherein said C -C6 alkyl is substituted with 0 -6 halogen and wherein up to two non adjacent CH _ units of said C1- C6 alkyl may be replaced with 15 0 ; and R * is absent, H , or C3 -C4 cycloaliphatic , wherein up to two F non - adjacent CH2 units of said C3 - C , cycloaliphatic may be 1 replaced with O and said C3 -C , cycloaliphatic is sub stituted with 0 - 3 substituents selected from halogen and C1- C4 alkyl. , wi , In another embodiment, the invention features a com pound of formula I - A or I' - A and the attendant definitions , wherein G is - X - R * wherein X is C1- C6 alkyl wherein 25 said C , - C . alkyl is substituted with 0 - 6 halogen wherein up F to two non - adjacent CH , units of said C , -C6 alkyl may be replaced with O and R * is absent. In another embodi ment , X is CH2CH2CH (CH3 ) 3 or CH2CH (CH3 ) 2 and R * is absent . In another embodiment , X is CH2CH2CH2CFz or mainan min 30 CH CH CF , and R * is absent. In another embodiment, the invention features a com pound of formula I - A or I' - A and the attendant definitions , or wherein G is — X - R wherein X is a bond and R * is C3 - Cg cycloaliphatic wherein up to two non -adjacent CH , of said C3 - C , cycloaliphatic may be replaced with and said C3- C , cycloaliphatic is substituted with 0 - 3 substituents selected from halogen and C . -C4 alkyl. In another embodi ment, X is a bond and R * is cyclobutane , cyclohexane , In another embodiment , the invention features a com bicyclo [ 2 . 2 . 1 ]heptane , or bicyclo [ 3 . 1 . 0 ]hexane . pound of formula I - A or I' - A and the attendant definitions, 40 In another embodiment, the invention features a com wherein G is : pound of formula I- A or I' - A and the attendant definitions , wherein G is - X - R * wherein X is C . - C . alkyl wherein man said C . - C . alkyl is substituted with 0 - 6 halogen wherein up 45 to two non -adjacent CH2 units of said C , -C alkyl may be ???? RS replaced with O and R * is C3 -C , cycloaliphatic wherein up to two non - adjacent CH2 units of said C3 - C , cycloali phatic may be replaced with O — ; and said C3 - C , cycloa RO liphatic is substituted with 0 - 3 substituents selected from 50 halogen and C , - C4 alkyl. In another embodiment, X is CH2 and R * is Cz- C , cycloaliphatic . In another embodiment, X is CH , and R * is cyclopropyl or cyclopentyl. In another and G is selected from embodiment, X is CH2 and R * is C3 -C , cycloaliphatic with up to 3 substituents selected from halogen and C , - C4 alkyl. 55 In another embodiment, X is CH , and R * is 1 -methylcyclo propyl, 2 , 2 - dimethylcyclopropyl or 2 , 2 - difluorocyclopropyl. m in In another embodiment , the invention features a com mm pound of formula I - A or I' - A and the attendant definitions, ni wherein G is — X — R * wherein X is C , - C , alkyl wherein 60 said C . - C . alkyl is substituted with 0 - 6 halogen wherein up oror to two non - adjacent CH2 units of said C . - C . alkyl are replaced with O and R * is Cz- C , cycloaliphatic wherein up to two non -adjacent CH , of said C3 - Cg cycloaliphatic F - F may be replaced with O and said Cz- Cg cycloaliphatic -CL 65 is substituted with 0 - 3 substituents selected from halogen $ and C , -C4 alkyl. In another embodiment, X is CH and R * is C3 -Cg cycloaliphatic wherein one CH , unit of said C3- C , US 10 , 087 , 143 B2 31 32 cycloaliphatic is replaced with O — . In another embodi wherein , independently for each occurrence : ment, X is CH , and R * is 3 - tetrahydrofuran . Gis In another embodiment, the invention features a com pound of formula I - A or I' - A and the attendant definitions, wherein G is — X — R * and X - R * is selected from :

5 ma non mm mm or w ; 10 R6 X - RX RO R? 15 X is a bond or C , - Co alkyl wherein said C . - C . alkyl is substituted with 0 -6 halogen and wherein up to two non w adjacent CH _ units of said C . -Cô alkyl may be replaced with Toot - 0 FHF R * is absent, H , or Cz- C , cycloaliphatic , wherein up to two F 30 non - adjacent CH , units of said Cz- C , cycloaliphatic may be FF replaced with and said Cz- Cg cycloaliphatic is sub stituted with 0 - 3 substituents selected from halogen and CZ -C4 alkyl; BIFm . R3 is halogen , CN , or C , - C6 alkylwherein said C ,- C . alkyl mm ni is substituted with 0 - 6 halogen and wherein up to two 2 5 non -adjacent CH2 units of said C .- C . alkyl may be replaced with - 0 RS is H , halogen , CN , or X - R * ; RS is H , halogen , CN , or — X — R ; mengot w R is H , halogen , CN , or — X - R * ; mn 30 R is H , halogen , CN , or — X R ; mm R7 is H , halogen , CN , or — X — R ; R® is halogen , or C . - C . alkyl wherein said C , -Co alkyl is substituted with 0 - 6 halogen and wherein up to two non adjacent CH , units of said C , -C6 alkyl may be replaced with or 0 ; p is an integer from 0 to 3 inclusive ; and Rºis H , or C . - C . alkyl wherein up to two non -adjacent CH2 In another aspect , the invention provides a compound of units of said C - C , alkyl may be replaced with O — . formula 1 - B or I' - B : In another embodiment, the invention features a com 40 pound of formula I - B or I' - B and the attendant definitions, wherein R3 is halogen . In another embodiment, R3 is Cl. In another embodiment, R3 is F. In another embodiment, R * is CN . In another embodiment , R3 is C . - C . alkyl wherein said I- B CZ - C6 alkyl is substituted with 0 -6 halogen . In another 45 embodiment, R is t -butyl . In another embodiment, Rºis - RO CF3. In another embodiment, R is CF CF3. In another embodiment, the invention features a com pound of formula I - B or I' - B and the attendant definitions, NH wherein p is zero . In another embodiment, p is an integer 50 from 1 to 3 and Rºis halogen . In another embodiment, p is R3 an integer from 1 to 3 and Ris Cl. In another embodiment , p is an integer from 1 to 3 and R8 is C ,- C alkyl wherein said C , -Coalkyl is substituted with 0 - 6 halogen wherein one CH2 unit of said C . - C . alkyl is replaced with 0 % . In another 55 embodiment, p is an integer from 1 to 3 and R is CHz. In I ' - B another embodiment, p is an integer from 1 to 3 and Ris D . IP : In another embodiment, the invention features a com pound of formula I- B or I' - B and the attendant definitions , wherein Rºis H . In another embodiment, Rº is C , -Co alkyl. 60 In another embodiment, Rºis CHz. In another embodiment , N Rº is C -C . alkyl wherein said C . -C . alkyl is substituted with 0 -6 halogen wherein one CH , unit of said C . - C . alkyl 0 is replaced with O . In another embodiment, Rº is CH2CH2OH . 65 In another embodiment, the invention features a com pound of formula I - B or I' - B and the attendant definitions, or a pharmaceutically acceptable salt thereof, wherein G is US 10 ,087 , 143 B2 34 In one embodiment, R is H . In another embodiment, RS is halogen . In another embodiment, RS is Cl. In another embodiment, RS is F . In another embodiment , R5 is CN . In another embodiment, RS is - X - R * . In another embodi ? 5 ment, RS is - X - R * wherein R * is absent . In another embodiment, Ris X - R * wherein R * is absent and X is CZ- C6 alkyl wherein said C -Cd alkyl is substituted with 0 -6 R6 Y R6 halogen . In another embodiment, RS is CHz. In another R ? embodiment, RS is CD3. In another embodiment, RS is 10 - X - R * wherein R * is absent and X is C . - C . alkyl wherein wherein : said C . - C . alkyl is substituted with 0 -6 halogen wherein one R is H , halogen , CN , or — X — R¥; CH , unit of said Cy -Co alkyl is replaced with O — . In R® is H , halogen , CN , or — X - RA ; another embodiment , R is OCH3, OCH CHz or OCH (CH3 ) Róis H , halogen , CN , or — X — RY; 15 2 . In another embodiment, R is OCH?. In another embodi RO' is H , halogen , CN , or — X — R ; ment , R? is CH OH . In another embodiment, R is OCF3. In R ' is H , halogen , CN , or X - R * ; another embodiment, RS is OCHF , . X is a bond or C . - C . alkyl wherein said C . - C . alkyl is In another embodiment, the invention features a com substituted with 0 - 6 halogen and wherein up to two non pound of formula I - B or I' - B and the attendant definitions , adjacent CH _ units of said C , - C alkyl may be replaced with . . wherein G is - 0 % ; and R * is absent, H , or C3- Cg cycloaliphatic , wherein up to two non - adjacent CH _ units of said C3- Cg cycloaliphatic may be mm replaced with and said Cz - Cg cycloaliphatic is sub stituted with 0 - 3 substituents selected from halogen and R . C , - C4 alkyl . 25 In another embodiment, the invention features a com pound of formula I- B or I' - B and the attendant definitions, R6 wherein G is

30 w In one embodiment , RS is H . In another embodiment, R5 is RS - X - R * . In another embodiment, R is — X — R * wherein R * is absent. In another embodiment, RS is - X - R * wherein R * is absent and X is C , -C6 alkyl wherein said 35 C , -C6 alkyl is substituted with 0 -6 halogen . In another RO embodiment, Rºis CHz. In another embodiment, Ris CDz. 7 In another embodiment, R is — X — R * wherein R * is absent and X is C -C6 alkylwherein said C , - C , alkyl is substituted wherein : with 0 -6 halogen wherein one CH , unit of said C , -C alkyl Ris H , or -XR ; 40 is replaced with0 . In another embodiment, RS is RS' is H , or — X — R¥; OCH3, OCH CHz or OCH ( CH3) 2 . In another embodiment, Róis H , halogen , CN , or — X — R * ; R $ is OCHz. In another embodiment, R is CH , OH . In R7 is H , or — X — R * ; another embodiment, R is OCF3. In another embodiment, X is a bond or C , - C , alkyl wherein said C , -C6 alkyl is Rºis OCHF2. substituted with 0 -6 halogen and wherein up to two non - 45 In another embodiment, the invention features a com adjacent CH , units of said C . - C . alkyl may be replaced with pound of formula I - B or I' - B and the attendant definitions , - 0 — ; and wherein G is R * is absent, H , or C3 - C , cycloaliphatic , wherein up to two non - adjacent CH , units of said C3- C , cycloaliphatic may be replaced with O - and said C3 - C , cycloaliphatic is sub - 50 stituted with 0 - 3 substituents selected from halogen and C2 - C4 alkyl. mi In another embodiment, the invention features a com pound of formula I - B or I' - B and the attendant definitions, wherein G is 55 Ro y PoR6 R7 60 In one embodiment, RS' is H . In another embodiment , RS' is d 5 ? D . In another embodiment, Rs' is halogen . In another embodiment, R ' is C1. In another embodiment, R ' is F . In another embodiment, RS' is CN . In another embodiment, RS' R6 VR6po is — X — R * . In another embodiment, RS' is — X — R * R ? 65 wherein R * is absent. In another embodiment, R " is — X — R * wherein R * is absent and X is C . - C . alkyl wherein said CZ -C6 alkyl is substituted with 0 -6 halogen . In another US 10 ,087 , 143 B2 35 36 embodiment, RS is CHz. In another embodiment, R ' is - X - R * wherein R * is absent and X is C . - C . alkyl wherein said C .- Cô alkyl is substituted with 0 -6 halogen wherein one CH , unit of said C -C . alkyl is replaced with O — . In another embodiment , R5" is OCH3, OCH CH3 or 5 RS RS! OCH ( CH3) 2. In another embodiment, RS' is OCHz . In another embodiment, R * is CH OH . In another embodi ment, RS' is OCF3. In another embodiment, RS' is OCHF2. 6 In another embodiment, the invention features a com pound of formula I- B or I' - B and the attendant definitions, wherein G is In one embodiment, R ' is H . In another embodiment, RO' is halogen . In another embodiment, RO' is D . In another 15 embodiment, R '' is Cl. In another embodiment, Ró' is F . In 5 RSS another embodiment, Ró' is CN . In another embodiment, RO' is — X — R * . In another embodiment, RÓ' is — X — R * wherein R * is absent. In another embodiment , R ' is — X — R * wherein R * is absent and X is C , - C6 alkyl wherein said 20 C , -Co alkyl is substituted with 0 -6 halogen . In another embodiment, Rºis CHz. In another embodiment, R? is In one embodiment, RS' is H . In another embodiment, RS' is - X - RX wherein R * is absent and X is C , -C6 alkyl wherein D . In another embodiment, Rºis — X R . In another said C . - C . alkyl is substituted with 0 -6 halogen wherein one embodiment, RS' is — X — R * wherein R * is absent . In 25 CH , unit of said C - C . alkyl is replaced with 0 . In another embodiment , RS' is - X R * wherein R * is absent - another embodiment, RÓ' is OCHz. and X is C . - C . alkylwherein said C . - C . alkyl is substituted In another embodiment, the invention features a com with 0 - 6 halogen . In another embodiment, R5' is CH . In pound of formula I - B or I '- B and the attendant definitions , another embodiment, R " is — X — R * wherein R * is absent wherein G is and X is C , - C , alkyl wherein said C . - C . alkyl is substituted 30 with 0 - 6 halogen wherein one CH , unit of said C . - C . alkyl is replaced with O . In another embodiment, R is OCHZ, OCH CHz or OCH ( CH3) 2 . In another embodiment, RS' is OCHz. In another embodiment, RS' is CH OH . In another embodiment, RS' is OCF3. In another embodiment, 35 RS' is OCHF . In another embodiment, the invention features a com pound of formula I- B or I' - B and the attendant definitions , Y R6 wherein G is 40 R

warna In one embodiment, R ? is H . In another embodiment, R7 is winan halogen . In another embodiment, R ? is Cl. In another or R RS 45 embodiment, R7 is F . In another embodiment, R7 is CN . In another embodiment, R7 is - X - R * . In another embodi R6 ment, R is — X — R wherein R * is absent. In another R6- Y R6 embodiment, R7 is -- X - R * wherein R * is absent and X is > P CZ- C6 alkyl wherein said C -Cd alkyl is substituted with 0 -6 R? 50 halogen . In another embodiment, R7 is CH3, CH2CH3, CH2CH2CHz or isopropyl. In another embodiment, R ' is In one embodiment, R? is H . In another embodiment, Róis CF3. In another embodiment, R ' is - X - R * wherein R * is D . In another embodiment , R is halogen . In another absent and X is C - C . alkyl wherein said C -C . alkyl is embodiment, Ris C1. In another embodiment, Rº is F . In substituted with 0 - 6 halogen wherein two non -adjacent CH , another embodiment, Ris CN . In another embodiment , Rº 55 units of said C . - C . alkyl are replaced with - 0 . In another is — X — R * . In another embodiment , Róis - X - R * embodiment, R ' is OCH CH OCHz. In another embodi wherein R * is absent. In another embodiment, Róis - X ment, R ? is - X - R * wherein R * is absent and X is C . - C . R * wherein R * is absent and X is C . - C alkyl wherein said alkyl wherein said C - C . alkyl is substituted with 0 -6 C -Co alkyl is substituted with 0 - 6 halogen . In another embodiment, Róis CHz. In another embodiment, R? is 60 halogen wherein one CH , unit of said CZ - C6 alkyl is - X - R * wherein R * is absent and X is C , -C6 alkylwherein replaced with O . In another embodiment, R ? is OCHz, said C .- Cô alkyl is substituted with 0 -6 halogen wherein one OCH CH3, OCH CH CH3, OC (CH3 ) 3 , CH CH OCHz. In CH , unit of said C . - C . alkyl is replaced with O — . In another embodiment, R7 is OCF3, OCH CF3, another embodiment , R? is OCHz. OCH _CH _ CH _ CF3, or OCHF2 In another embodiment, the invention features a com - 65 In another embodiment, the invention features a com pound of formula I - B or I '- B and the attendant definitions , pound of formula I - B or I '- B and the attendant definitions , wherein G is wherein G is US 10 ,087 , 143 B2 37 38 In one embodiment, R ? is — X — R * wherein X is C . - C . alkyl wherein said C -C6 alkyl is substituted with 0 -6 halogen and wherein one CH , unit of said C . - C . alkyl is R RS replaced with O — and R * is C3- C , cycloaliphatic and said 5 Cz- Cg cycloaliphatic is substituted with 0 - 3 substituents selected from halogen and C . - C4 alkyl. In another embodi R6 ment, R ' is - X - R * wherein X is OCH and R * is cyclo propyl. In another embodiment , the invention features a com 10 pound of formula I -B or I' - B and the attendant definitions, In one embodiment, R ' is H . In another embodiment, R ' is wherein G is selected from : — X — R¥ . In another embodiment, R ? is — X — R * wherein R® is absent. In another embodiment, R ? is — X — R * F wherein R * is absent and X is CZ- C6 alkyl wherein said 15 CZ -C6 alkyl is substituted with 0 -6 halogen . In another F FF embodiment, R7 is CH3, CH2CH3, CH CH CHz or isopro n im win, n im pyl. In another embodiment, R ' is CF3. In another embodi ment, R ? is — X — R * wherein R * is absent and X is C , -C6 alkyl wherein said C . -C . alkyl is substituted with 0 - 6 20 halogen wherein two non - adjacent CH2 units of said C . - C alkyl are replaced with O — . In another embodiment, R7 is OCH _CH _ OCHz. In another embodiment , R7 is - X - R * wherein R * is absent and X is C . - C alkyl wherein said mm mm C . - C . alkyl is substituted with 0 - 6 halogen wherein one CH , 25 unit of said C - C , alkyl is replaced with O — . In another embodiment, R ? is OCHZ, OCH2CH3, OCH CH2CH3, OC (CH3 ) 3 , CH CH OCHz. In another embodiment, R ' is OCF3, OCH _ CF3 , OCH _ CH _ CH _ CF3 , or OCHF2 . 30 In another embodiment, the invention features a com my pound of formula I- B or I' - B and the attendant definitions , wherein G is

35

w inner 50R or RSR RS 40 ni mimi min PoR6 R6 y ROPOR6 #RYR 7 45 In one embodiment, R7 is — X — R * wherein X is a bond and R * is C3 -Cg cycloaliphatic and said C3 -C4 cycloaliphatic is substituted with 0 - 3 substituents selected from halogen and F CZ -C4 alkyl. In another embodiment , R7 is - X - R * wherein X is a bond and R * is cyclopropyl. 50 In another embodiment , the invention features a com pound of formula I - B or I' - B and the attendant definitions , num , mwa , wherein G is 55

min orRd RE

R6 R6 Y R6 R ? F US 10 ,087 , 143 B2 39 40 - continued -continued

minima, min ini miny

.

CN ö

nin , imun w

OH winan , win , Mini ,

wi , mi , mi ,

1)

F , min, vi min min

F - + F Hot mm , nim ni ,

maa, wi , mi , F . F ,. F F . F F

wi , n im ,

win F . IF

inn nam

or

mi mann

65 In another embodiment, the invention features a com pound of formula I- B or I' - B and the attendant definitions, D u a wherein G is: garantia US 10 ,087 , 143 B2 to two non - adjacent CH _ units of said C , -Co alkyl may be ma replaced with O — and R * is Cz -Cg cycloaliphatic wherein Rs -RS up to two non - adjacent CH2 units of said C3 - C , cycloali phatic may be replaced with O — ; and said C3 - C , cycloa 5 liphatic is substituted with 0 - 3 substituents selected from RO halogen and C -C4 alkyl. In another embodiment, X is CH2 and R * is Cz -Cg cycloaliphatic . In another embodiment, X is R? CH , and R * is cyclopropyl or cyclopentyl. In another embodiment, X is CH2 and R * is C3 -C , cycloaliphatic with and G is selected from 10 up to 3 substituents selected from halogen and C , -C4 alkyl. In another embodiment, X is CH , and R * is 1 -methylcyclo propyl, 2 , 2 - dimethylcyclopropyl or 2 , 2 - difluorocyclopropyl. In another embodiment, the invention features a com 15 pound of formula I - B or I' - B and the attendant definitions , wherein G is — X — R * wherein X is CZ - C6 alkyl wherein im said C - C alkyl is substituted with 0 -6 halogen wherein up Oror to two non - adjacent CH2 units of said CZ -C6 alkyl are replaced with O — and Ris C3 - C , cycloaliphatic wherein 20 up to two non - adjacent CH , of said C3 -Cg cycloaliphatic F - F may be replaced with and said Cz- Cg cycloaliphatic ??? is substituted with 0 - 3 substituents selected from halogen and C1- C4 alkyl. In another embodiment, X is CH , and R * is Cz - C , cycloaliphatic wherein one CH , unit of said Cz- Ce In another embodiment, the invention features a com - 25 cycloaliphatic is replaced with O — . In another embodi pound of formula I- B or I' - B and the attendant definitions, ment, X is CH , and R * is 3 - tetrahydrofuran . wherein G is In another embodiment , the invention features a com pound of formula I - B or I' - B and the attendant definitions , 30 wherein G is selected from : min X - RX mm nar mu ana wherein : 35 X is a bond or C , - Co alkyl wherein said C . - C . alkyl is substituted with 0 -6 halogen , wherein up to two non -adja cent CH2 units of said C , -C6 alkyl may be replaced with no - 0 % ; and 40 R * is absent, H , or C3- C , cycloaliphatic , wherein up to two Doornu non - adjacent CH2 units of said Cz- Cg cycloaliphatic may be replaced with O and said C3- C , cycloaliphatic is sub FF - F stituted with 0 - 3 substituents selected from halogen and F CZ -C4 alkyl. 45 In another embodiment , the invention features a com pound of formula I - B or I' - B and the attendant definitions, wherein G is - X - R wherein X is C , -C alkyl wherein said C .- C . alkyl is substituted with 0 -6 halogen wherein up to two non - adjacent CH2 units of said C . - C . alkyl may be 50 wa mm replaced with O and R * is absent. In another embodi ment, X is CH CH C ( CH3) 3 or CH CH ( CH3) 2 and R * is absent . In another embodiment , X is CH2CH2CH2CFz or CH , CH , CF , and R * is absent. F In another embodiment , the invention features a com - 55 pound of formula I- B or I' - B and the attendant definitions , s??? wherein G is - X - R * wherein X is a bond and R * is Cz- Cg n cycloaliphatic wherein up to two non - adjacent CH , of said Cz - Cg cycloaliphatic may be replaced with O and said mm Cz -Cg cycloaliphatic is substituted with 0 -3 substituents 60 selected from halogen and C -C4 alkyl. In another embodi ment, X is a bond and R * is cyclobutane , cyclohexane , bicyclo [ 2 . 2 . 1 ]heptane , or bicyclo [ 3 . 1 . O ] hexane. , or In another embodiment, the invention features a com pound of formula I - B or I' - B and the attendant definitions , 65 JOJ . wherein G is — X — R - wherein X is C , - C . alkyl wherein In another aspect, the invention provides a compound of said C , -C alkyl is substituted with 0 -6 halogen wherein up formula 1 - C or I' - C : US 10 , 087 , 143 B2 44 wherein R2 is halogen . In another embodiment, R2 is Cl. In I - C another embodiment, R² is F . In another embodiment, R2 is R8 RO CN . In another embodiment , R² is C . - C . alkyl wherein said C -C6 alkyl is substituted with 0 - 6 halogen . In another 5 embodiment, R2 is CFz. In another embodiment, R2 is C , - C6 alkyl wherein said C -C6 alkyl is substituted with 0 - 6 halogen wherein one CH , unit of said C . -C . alkyl is replaced with O — . In another embodiment, R2 is OCF3 . R3 In another embodiment, R2 is F , C1, CN , CFz or OCFz. 10 In another embodiment , the invention features a com 0 pound of formula I - C or I' - C and the attendant definitions , I' -C wherein R3 is halogen . In another embodiment, R3 is C1. In another embodiment , R? is F . In another embodiment, R3 is o CN . In another embodiment, Ris C . - C . alkyl wherein said 15 C , - C , alkyl is substituted with 0 - 6 halogen . In another Pg embodiment, R3 is t- butyl . In another embodiment, R3 is N CFz. In another embodiment, R * is CF CF2 . R3 In another embodiment, the invention features a com pound of formula I - C or I' - C and the attendant definitions , ! 20 wherein p is zero . In another embodiment, p is an integer from 1 to 3 and R® is halogen . In another embodiment, p is or a pharmaceutically acceptable salt thereof, an integer from 1 to 3 and R8 is Cl. In another embodiment , wherein , independently for each occurrence : p is an integer from 1 to 3 and R8 is C . - C . alkyl wherein said G is C -Coalkyl is substituted with 0 - 6 halogen wherein one CH , 25 unit of said C -C . alkyl is replaced with O . In another embodiment, p is an integer from 1 to 3 and R8 is CHz. In another embodiment , the invention features a com ins pound of formula 1 - C or I' - C and the attendant definitions , wherein Rºis H . In another embodiment , Rºis C - C . alkyl. R " 30 In another embodiment, Rºis CH2. In another embodiment, or win ; R® is C , -C6 alkyl wherein said C -C . alkyl is substituted R6 X - RA with 0 - 6 halogen wherein one CH , unit of said C . - C . alkyl PO is replaced with O — . In another embodiment, Rº is p> CH2CH2OH . IROR7 35 In another embodiment, the invention features a com . pound of formula I - C or I' - C and the attendant definitions , X is a bond or C , - C6 alkyl wherein said C . - C . alkyl is wherein G is substituted with 0 -6 halogen , wherein up to two non - adja cent CH2 units of said C1 - C , alkyl may be replaced with - 0 % ; 40 R * is absent, H , or Cz -Ce cycloaliphatic , wherein up to two non - adjacent CH , units of said Cz- Cg cycloaliphatic may be replaced with O and said C3 -Cg cycloaliphatic is sub Ps RS stituted with 0 - 3 substituents selected from halogen and C , -C4 alkyl; 45 R² is halogen , CN , or C . - C . alkyl wherein said C , -Co alkyl Y RoR6 is substituted with 0 - 6 halogen and wherein up to two non - adjacent CH2 units of said C . - C . alkyl may be replaced p > with 0 % ; R3 is halogen , CN , or C1- C6 alkyl wherein said C . - C . alkyl 50 wherein : is substituted with 0 - 6 halogen and wherein up to two R is H , halogen , CN , or — X — R ' ; non - adjacent CH2 units of said C . - C . alkylmay be replaced Rs is H , halogen , CN , or - X R * ; with 0 % ; Ris H , halogen , CN , or -- X - R * ; RS is H , halogen , CN , or — X — R * ; R® is H , halogen , CN , or — X — R * ; R® is H , halogen , CN , or — X — R * ; 55 R ’ is H , halogen , CN , or — X — R * ; Róis H , halogen , CN , or — X — R * ; X is a bond or C -C6 alkyl wherein said C . - C . alkyl is R ' is H , halogen , CN , or X - RY: substituted with 0 - 6 halogen , wherein up to two non - adja R ? is H , halogen , CN , or - X - RX; cent CH , units of said C , -C6 alkyl may be replaced with R ' is halogen or C . - C . alkyl wherein said C . - C . alkyl is - 0 — ; and substituted with 0 -6 halogen and wherein up to two non - 60 R * is absent, H , or C3 -Cg cycloaliphatic , wherein up to two adjacent CH , units of said C - C . alkyl may be replaced with non - adjacent CH , units of said Cz- Cg cycloaliphatic may be - 0 % ; replaced with and said Cz- C , cycloaliphatic is sub p is an integer from 0 to 3 inclusive ; and stituted with 0 - 3 substituents selected from halogen and Rºis H , or C1- C6 alkyl wherein up to two non - adjacent CH CZ -C4 alkyl. units of said C . - C . alkyl may be replaced with O - 65 In another embodiment, the invention features a com In another embodiment, the invention features a com - pound of formula 1 - C or I' - C and the attendant definitions , pound of formula 1 - C or I' - C and the attendant definitions, wherein G is US 10 ,087 , 143 B2 45 46 In one embodiment R5 is H . In another embodiment, RS is ma - X - R * . In another embodiment, RS is — X — R * wherein R * is absent. In another embodiment, RS is — X — R * R wherein R * is absent and X is CZ -C6 alkyl wherein said 5 C . - C . alkyl is substituted with 0 - 6 halogen . In another embodiment , R is CHz. In another embodiment, RS is R6 - X - R * wherein R * is absent and X is CZ -C6 alkyl wherein R> said C . - C . alkyl is substituted with 0 - 6 halogen wherein one CH , unit of said C . - C . alkyl is replaced with — O . In wherein : 10 another embodiment, RS is OCHZ, OCH ,CHz , RS is H , or X - RX; OCH , CH ,CH , , or OCH (CH2 ) . In another embodiment, RS R is H , or — X - R¥; is OCHz. In another embodiment, R is CH ,OH . In another Rºis H , halogen , CN , or X - R ' ; embodiment, R is OCF3. In another embodiment, R is R ? is H , or - X - RY; X is a bond or C . - C . alkyl wherein saidald C1C . - C6 C . alkyl is 1515 OCHF ,. . substituted with 0 -6 halogen and wherein up to two non In another embodiment, the invention features a com adjacent CH2 units of said C -C . alkylmay be replaced with pound of formula 1 - C or I' - C and the attendant definitions, - 0 % ; and wherein G is R * is absent, H , or C3 -C4 cycloaliphatic , wherein up to two non - adjacent CH2 units of said C3 - C , cycloaliphatic may be 20 replaced with O and said C2- C , cycloaliphatic is sub stituted with 0 - 3 substituents selected from halogen and is CZ - C4 alkyl . In another embodiment, the invention features a com pound of formula 1- C or I' - C and the attendant definitions , 25 wherein G is Y RO

mi In one embodiment RS' is H . In another embodiment, Rs' is 5 halogen . In another embodiment, R " is C1. In another embodiment, R5" is F . In another embodiment, RS' is CN . In another embodiment, RS' is — X — R ". In another embodi ROPo 35 Mentment, RS' is — X — R * wherein R * is absent. In another embodiment, RS' is — X — R * wherein R * is absent and X is R7 C . - C . alkyl wherein said C . - C . alkyl is substituted with 0 - 6 halogen . In another embodiment, RS is CHz. In another In one embodiment, RS is H . In another embodiment, RS is embodiment , RS' is — X — R * wherein R * is absent and X is halogen . In another embodiment, R ' is C1. In another C , -Coalkyl wherein said C . - C . alkyl is substituted with 0 -6 embodiment, Ris F . In another embodiment, Ris CN . In v halogen wherein one CH , unit of said C . - C . alkyl is another embodiment, RS is — X — R . In another embodi- replaced with 0 - . In another embodiment, R " is OCHZ, ment, R is — X — R * wherein R * is absent. In another OCH CH3, OCH2CH2CH3, or OCH (CH3 ) 2 . In another embodiment, RS is — X — R * wherein R * is absent and X is embodiment, RS' is OCHz. In another embodiment, RS' is C , -C6 alkyl wherein said C1 -C6 alkyl is substituted with 0 -6 CH , OH . In another embodiment, R5 ' is OCF > . In another halogen . In another embodiment, RS is CHz. In another 45 embodiment, R is — X — R * wherein R * is absent and X is embodiment, R " is OCHF2. C .- C . alkyl wherein said C , -Co alkyl is substituted with 0 -6 In another embodiment, the invention features a com halogen wherein one CH , unit of said C - C . alkyl is pound of formula I - C or I' - C and the attendant definitions, replaced with O . In another embodiment, RS is OCHZ, wherein G is OCH CH3, OCH CH2CH3, or OCH (CH3 ) 2 . In another 50 embodiment, R is OCHz. In another embodiment, R is CH ,OH . In another embodiment, RS is OCFz . In another embodiment, R is OCHF2. Rs RS . In another embodiment, the invention features a com pound of formula 1 - C or I '- C and the attendant definitions , 55 wherein G is Ro R wa 60 In one embodiment RS' is H . In another embodiment, RS' is - RS. halogen . In another embodiment, Rs' is Cl. In another embodiment, RS' is F . In another embodiment, R " is CN . In another embodiment, RS' is — X — R * . In another embodi ment, RS' is — X — R * wherein R * is absent. In another 65 embodiment, R is — X - R wherein R * is absent and X is C - C . alkyl wherein said C , - C . alkyl is substituted with 0 -6 halogen . In another embodiment, RS is CHz. In another US 10 , 087 , 143 B2 47 embodiment, R ' is — X — R * wherein R * is absent and X is C . - C . alkylwherein said C . -C . alkyl is substituted with 0 -6 halogen wherein one CH2 unit of said C1 -C6 alkyl is replaced with O — . In another embodiment, R ' is OCHZ, OCH CH3, OCH CH2CH3, or OCH (CH3 ) 2 . In another 5 embodiment, RS' is OCHz . In another embodiment, R " is CH ,OH . In another embodiment, RS is OCF3. In another embodiment, R5' is OCHF2 . R6 > In another embodiment, the invention features a com - 10 P pound of formula 1 - C or I' - C and the attendant definitions, wherein G is In one embodiment, R7 is H . In another embodiment, R7 is halogen . In another embodiment, R ? is Cl. In another embodiment, R7 is F . In another embodiment, R7 is CN . In 15 another embodiment, R ? is — X — R * . In another embodi mm Or RS RS ment, R7 is X - R¥ wherein R * is absent. In another RS R5 embodiment, R7 is - X - R * wherein R * is absent and X is C .- C . alkyl wherein said C , -C . alkyl is substituted with 0 -6 Po halogen . In another embodiment, R ? is CH3, CH2CH3, R6 RO CH , CH , CH , or isopropyl. In another embodiment, R ' is R CFz. In another embodiment, R7 is — X — R¥ wherein R * is absent and X is C1- C6 alkyl wherein said C -C6 alkyl is substituted with 0 - 6 halogen wherein two non -adjacent CH , units of said C . - C . alkyl are replaced with - 0 . In another In one embodiment , Róis H . In another embodiment, Róis 25 embodiment, R7 is OCH CH , OCHz. In another embodi halogen . In another embodiment, Róis Cl. In another ment, R ' is - X - R * wherein R * is absent and X is C .- C . embodiment, Ris F . In another embodiment , Ris CN . In alkyl wherein said C , -C6 alkyl is substituted with 0 - 6 another embodiment, R is — X — R *. In another embodi halogen wherein one CH2 unit of said C . - C . alkyl is ment, R? is — X R * wherein R * is absent. In another replaced with 40 . In another embodiment, R ? is OCHZ, embodiment, Rºis — X — R $ wherein R™ is absent and X is 30 OCH . CH . , OCH . CH . CH . , OC ( CH . ) . , CH , CH ,OCH , . In C , - C , alkyl wherein said C1- C , alkyl is substituted with 0 -6 another embodiment, R7 is OCF , OCH ,CF , halogen . In another embodiment, R is CHz . In another OCH2CH2CH2CF3, or OCHF2 . embodiment, Róis — X — R * wherein R * is absent and X is In another embodiment , the invention features a com C1 -C6 alkyl wherein said C . - C . alkyl is substituted with 0 - 6 halogen wherein one CH2 unit of said C -C6 alkyl is 35 pound of formula I - C or I' - C and the attendant definitions, replaced with O — . In another embodiment, R is OCHzS. » wherein G is In another embodiment , the invention features a com pound of formula I - C or I' - C and the attendant definitions, wherein G is 40

nim RS 45 R In one embodiment, R7 is H . In another embodiment, R7 is - X - RX . In another embodiment, R7 is — X — R * wherein Ro Po R * is absent. In another embodiment, R7 is — X - R * 50 wherein R * is absent and X is C . - C . alkyl wherein said C -C6 alkyl is substituted with 0 - 6 halogen . In another embodiment, R ' is CH3, CH2CH3, CH2CH2CHz or isopro In another embodiment, R ' is H . In another embodiment, RÓ pyl. In another embodiment, R ' is CF3. In another embodi is halogen . In another embodiment, R " is Cl. In another ment, R ? is — X — R * wherein R * is absent and X is C , - C . embodiment, Rº is F . In another embodiment, Rº is CN . In 55 alkyl wherein said C . - C . alkyl is substituted with 0 -6 another embodiment, R? is X — R * . In another embodi halogen wherein two non -adjacent CH2 units of said C -C6 ment, R ' is — X — R * wherein R * is absent. In another alkyl are replaced with O . In another embodiment, R ? embodiment, R is — X - R wherein R * is absent and X is is OCH CH OCHz. In another embodiment, R ? is — X — R * C . - C . alkyl wherein said C . - C . alkyl is substituted with 0 - 6 wherein R * is absent and X is C , - C6 alkyl wherein said halogen . In another embodiment, Rºis CHz. In another 60 C . - C . alkyl is substituted with 0 - 6 halogen wherein one CH . embodiment, R ' is - X - R * wherein R * is absent and X is unit of said C . - C . alkyl is replaced with O — . In another C . - C . alkyl wherein said C . - C . alkyl is substituted with 0 - 6 embodiment, R ? is OCHZ, OCH CH3, OCH2CH2CH3, halogen wherein one CH , unit of said C1 -C6 alkyl is OC ( CH3) 3 , CH CH OCHz. In another embodiment , R7 is replaced with — O — . In another embodiment, Rº is OCH3 O CF , OCH , CF, , OCH , CH , CH , CFz, or OCHF , . In another embodiment , the invention features a com - 65 In another embodiment, the invention features a com pound of formula 1 - C or I' - C and the attendant definitions , pound of formula 1 - C or I' - C and the attendant definitions , wherein G is wherein G is US 10 ,087 , 143 B2 49 50 - continued w mi or RS RS . min , n im , RS . R6 Y R6 ?

10 chann min In one embodiment, R ’ is — X — R * wherein X is a bond and R * is C3 -Cg cycloaliphatic and said C3 - Cg cycloaliphatic is substituted with 0 - 3 substituents selected from halogen and CZ -C4 alkyl. In another embodiment , R7 is - X - R¥ 15 wherein X is a bond and R * is cyclopropyl. In another embodiment, the invention features a com ni mimi inny pound of formula 1 - C or I' - C and the attendant definitions, wherein G is 20

mu Oror RS RS - R5 25 RO R6 Ro wu , nina , niin , R7 R ? 30

In one embodiment, R ? is — X — R * wherein X is C , -Co alkyl wherein said CZ -C6 alkyl is substituted with 0 - 6 halogen wherein one CH , unit of said Cy -C6 alkyl is 35 replaced with — and R * is C3- Cg cycloaliphatic and said Cz - C , cycloaliphatic is substituted with 0 -3 substituents selected from halogen and C -C4 alkyl . In another embodi ment, R ' is — X — R wherein X is OCH , and R * is cyclo propyl. 40 In another embodiment, the invention features a com F pound of formula I - C or I' - C and the attendant definitions , wherein G is : inmy mini , 45

min RS 50 RO y RC : 5056 R7 55 and G is selected from : m , min , minim

60 ma many minnan

F F F to :65 0000 US 10 , 087 , 143 B2 51 S2 - continued - continued

AMA NANAN Now , Nov+, Nov , CI ?

? + - F MAN , NNNNNN+ , NANMAN ,

Noved+P+ ,HO | F F A LF, F ? ?F ? HD?+bP nnnnn , +Annnno ,

?

nnue JAAMnnnn 30 ANA +Annne > Or

3535

luv ) Anonnnn ) vhAnne 2 In another embodiment, the invention features a com 40 pound of formula I- C or I- C and the attendant definitions, wherein G is:

? ??? NNNne 45 PS>

nnnnnne ) Annue ; nununune

50 HO

and G is selected from F S5 ???? www nulue nnnnnn MAMAN , nununo , Any , 600 - oror

F

6 F NF US 10 , 087 , 143 B2 53 54 In another embodiment, the invention features a com cycloaliphatic is replaced with O — . In another embodi pound of formula 1 - C or I' - C and the attendant definitions, ment, X is CH , and R * is 3 - tetrahydrofuran . wherein G is In another embodiment, the invention features a com pound of formula 1- C or I' - C and the attendant definitions, 5 wherein G is selected from : Win X - R¥ na na man 10 wherein : X is a bond or C -Co alkyl wherein said C . - C . alkyl is substituted with 0 - 6 halogen , wherein up to two non - adja cent CH2 units of said C1 -C6 alkyl may be replaced with n - 0 — ; and R * is absent, H , or C3 -C , cycloaliphatic , wherein up to two non -adjacent CH2 units of said C3- C , cycloaliphatic may be replaced with O — and said C3 - C , cycloaliphatic is sub stituted with 0 - 3 substituents selected from halogen and 20 F F C1 - C4 alkyl . F In another embodiment, the invention features a com pound of formula I - C or I' - C and the attendant definitions , www wherein G is — X — R * wherein X is C . - C . alkyl wherein mm said C . -C . alkyl is substituted with 0 -6 halogen wherein up 25 to two non - adjacent CH , units of said C , -C6 alkyl may be replaced with O and R * is absent. In another embodi ment, X is CH CH C ( CH3) ; or CH2CH (CH3 ) 2 and R * is absent . In another embodiment , X is CH2CH2CH2CFz or ma CH2CH2CFz and R * is absent. 30 warun In another embodiment, the invention features a com pound of formula 1 - C or I' - C and the attendant definitions, wherein G is — X — R * wherein X is a bond and R * is C3- C , cycloaliphatic wherein up to two non - adjacent CH , of said , or Cz - C , cycloaliphatic may be replaced with — O — and said 33 Cz- Cg cycloaliphatic is substituted with 0 -3 substituents selected from halogen and C . - C4 alkyl. In another embodi In another aspect, the invention provides a compound of ment , X is a bond and R * is cyclobutane , cyclohexane , formula I- D or I' - D : bicyclo [2 .2 . 1 ]heptane , or bicyclo [3 . 1. 0 ]hexane . In another embodiment, the invention features a com 40 to be in the morning and comment pound of formula 1 - C or I' - C and the attendant definitions, wherein G is - X - R wherein X is C , -C alkyl wherein said C -C . alkyl is substituted with 0 -6 halogen wherein up I - D to two non - adjacent CH2 units of said C . - C . alkyl may be 45 (Rp . replaced with O — and R * is C3 - Cg cycloaliphatic wherein A up to two non -adjacent CH , units of said Cz- Cg cycloali VRO phatic may be replaced with O — ; and said C3 -C , cycloa liphatic is substituted with 0 - 3 substituents selected from N halogen and C , - C4 alkyl. In another embodiment , X is CH , 50 and R * is C3 - C , cycloaliphatic . In another embodiment , X is CH , and R * is cyclopropyl or cyclopentyl. In another embodiment, X is CH and R * is C3 - Cg cycloaliphatic with up to 3 substituents selected from halogen and C , -C4 alkyl. In another embodiment, X is CH and R * is 1 -methylcyclo - 55 propyl, 2 ,2 -dimethylcyclopropyl or 2 ,2 - difluorocyclopropyl. I ' - D In another embodiment, the invention features a com R8 pound of formula 1 - C or I' - C and the attendant definitions , o wherein G is — X — R $ wherein X is C , -C6 alkyl wherein said C . -C . alkyl is substituted with 0 - 6 halogen wherein up 60 Po to two non - adjacent CH2 units of said C . - C . alkyl are NH replaced with — 0 — and R * is Cz - C , cycloaliphatic wherein up to two non -adjacent CH , of said Cz - Cg cycloaliphatic R3 may be replaced with and said Cz- Cg cycloaliphatic is substituted with 0 - 3 substituents selected from halogen 65 and C , -C4 alkyl. In another embodiment, X is CH , and R * is C3- C , cycloaliphatic wherein one CH2 unit of said Cz - C , or a pharmaceutically acceptable salt thereof, US 10 , 087 , 143 B2 55 56 wherein , independently for each occurrence : In another embodiment, the invention features a com G is pound of formula I - D or I' - D and the attendant definitions , wherein Rº is H . In another embodiment, Rº is C , - C6 alkyl. In another embodiment, Rº is CHz. In another embodiment, 5 Rº is CZ -C6 alkyl wherein said C . - C . alkyl is substituted RS with 0 -6 halogen wherein one CH2 unit of said C -Co alkyl RS is replaced with O — . In another embodiment, Rº is or wan : CH CH , OH . X - RX 10 In another embodiment, the invention features a com po ROROR6 . pound of formula I- D or I' - D and the attendant definitions, R ? wherein G is R ? X is a bond or C -Co alkyl wherein said C . - C . alkyl is 15 substituted with 0 - 6 halogen and wherein up to two non m in adjacent CH2 units of said C . - C . alkyl may be replaced with - 0 % ; R * is absent, H , or C3- Cg cycloaliphatic , wherein up to two non - adjacent CH2 units of said C3 -C , cycloaliphatic may be 20 replaced with and said Cz - C , cycloaliphatic is sub Y R6 stituted with 0 - 3 substituents selected from halogen and R > C1 - C4 alkyl ; Rl is halogen , CN , or C -C6 alkylI wherein Wheem salasaid C16 . -C . any alkyl wherein : is substituted with 0 - 6 halogen and wherein up to two 25 R5 is H . halogen , CN , or — X — Rº ; non - adjacent CH2 units of said C1 -C6 alkyl may be replaced with 0 ; RS' is H , halogen , CN , or - X - R * ; R3 is halogen , CN , or CZ -C6 alkyl wherein said C . - C . alkyl Ris H , halogen , CN , or — X — R ; is substituted with 0 - 6 halogen and wherein up to two Rois H , halogen , CN , or — X — R¥; non - adjacent CH , units of said C - C . alkyl may be replaced 30 with 0 % ; X is a bond or C1- C6 alkyl wherein said C -C6 alkyl is R is H , halogen , CN , or - X - R * ; substituted with 0 - 6 halogen and wherein up to two non RS' is H , halogen , CN , or — X — R * ; adjacent CH _ units of said C1- C6 alkyl may be replaced with Rºis H , halogen , CN , or — X — R * ; 0 ; and R is H , halogen , CN , or — X - R * ; 35 R * is absent , H , or C3- C , cycloaliphatic , wherein up to two R ? is H , halogen , CN , or — X — R " ; non - adjacent CH2 units of said C3 - C , cycloaliphatic may be R® is halogen , or C . - C . alkyl wherein said C . -C . alkyl is replaced with and said C3- C , cycloaliphatic is sub substituted with 0 - 6 halogen and wherein up to two non - stituted with 0 - 3 substituents selected from halogen and adjacent CH2 units of said C . - C . alkyl may be replaced with C , -C4 alkyl. - 0 % ; 40 In another embodiment, the invention features a com p is an integer from 0 to 3 inclusive ; and pound of formula I - D or I' - D and the attendant definitions , Rºis H , or C , -Chalkyl wherein up to two non -adjacent CH wherein G is units of said C1- C , alkylmay be replaced with 0 . In another embodiment, the invention features a com pound of formula I - D or I' - D and the attendant definitions, 45 mm wherein Rl is halogen . In another embodiment, Rl is CN . In another embodiment, R1 is C , - C , alkyl wherein said C . - C . alkyl is substituted with 0 - 6 halogen . In another embodi ment, Ri is CFZ. In another embodiment, the invention features a com - 50 pound of formula I - D or I' - D and the attendant definitions , wherein R3 is halogen . In another embodiment, R is Cl. In another embodiment , R? is F . In another embodiment, R3 is CN . In another embodiment, Ris C , - C , alkyl wherein said wherein : C . - C . alkyl is substituted with 0 - 6 halogen . In another 55 R is H , or — X — Rº ; embodiment, R * is t -butyl . In another embodiment, R * is RS' is H , or - X - R ' ; CF3. In another embodiment, R3 is CF CF3 . Ris H , halogen , CN , or - X - R " ; In another embodiment, the invention features a com - R ' is H , or — X — R "; pound of formula I - D or I' - D and the attendant definitions, X is a bond or C . - C . alkyl wherein said C . - C . alkyl is wherein p is zero . In another embodiment, p is an integer 60 substituted with 0 - 6 halogen and wherein up to two non from 1 to 3 and R8 is halogen . In another embodiment , p is adjacent CH _ units of said C , - C alkyl may be replaced with an integer from 1 to 3 and R8 is C1. In another embodiment, O ; and p is an integer from 1 to 3 and R8 is C , - C alkyl wherein said R * is absent, H , or C3 - C , cycloaliphatic , wherein up to two C . - C . alkyl wherein said C , - C alkyl is substituted with 0 - 6 non -adjacent CH , units of said Cz- C , cycloaliphatic may be halogen wherein one CH2 unit of said C -C6 alkyl is 65 replaced with O — and said C3- Cg cycloaliphatic is sub replaced with — — . In another embodiment, p is an integer stituted with 0 - 3 substituents selected from halogen and from 1 to 3 and R8 is CHz. CZ- C4 alkyl. US 10 ,087 , 143 B2 57 58 In another embodiment, the invention features a com pound of formula I - D or I' - D and the attendant definitions , wherein G is mm R5

R6 R . 10 Y PoR6 In one embodiment Rs' is H . In another embodiment, R ' is R7 halogen . In another embodiment, RS" is Cl. In another 15 embodiment, RS' is F . In another embodiment, RS' is CN . In In one embodiment , R $ is H . In another embodiment, R is halogen . In another embodiment, RS is Cl. In anotherS another embodiment , RS' is - X - R * . In another embodi embodiment, R is F . In another embodiment, R $ is CN . In ment, RS' is — X — R * wherein R * is absent. In another another embodiment, RS is — X — R *. In another embodi embodiment, RS' is - X - R * wherein R * is absent and X is ment, RS is — X — RY wherein R * is absent . In anotherEr 2020 C , - C alkyl wherein said C . -C . alkyl is substituted with 0 -6 embodiment, RS is — X — R * wherein R * is absent and X is halogen . In another embodiment, RS' is CHz. In another C . - C . alkylwherein said C . - C . alkyl is substituted with 0 - 6 embodiment, R ' is - X - R * wherein R * is absent and X is halogen . In another embodiment, R5 is CHz. In another C - C . alkyl wherein said C , -C6 alkyl is substituted with 0 -6 embodiment , R is - X - R¥ wherein R¥ is absent and X is 25 halogen wherein one CH , unit of said C .- C , alkyl is CZ -C6 alkyl wherein said C . - C . alkyl is substituted with 0 -6 replaced with O — . In another embodiment, Rá ' is OCH3, halogen wherein one CH , unit of said C - C6 alkyl is OCH CH3, OCH _ CH2CH3, or OCH ( CH3) 2 . In another replaced with O — . In another embodiment, R $ is OCHz, embodiment , RS' is OCHz. In another embodiment , RS' is OCH2CH3, OCH2CH2CH3, or OCH ( CH3) 2 . In another 30 CH ,OH . In another embodiment, RS' is OCFz. In another embodiment, R $ is OCHz. In another embodiment , R is CH ,OH . In another embodiment, RS is OCFz. In another embodiment, RS ' is OCHF2. embodiment, RS is OCHF . In another embodiment, the invention features a com In another embodiment, the invention features a com - pound of formula I - D or I' - D and the attendant definitions, pound of formula I - D or I' - D and the attendant definitions, 35 wherein G is wherein G is mm wa B RS - RS Ro R6 # R > In one embodiment RS' is H . In another embodiment, RS' is In one embodiment, R is H . In another embodiment, R is - X - R *. In another embodiment, R is — X — R * wherein - X - R *. In another embodiment, R ' is — X — R * wherein R * is absent. In another embodiment, RS is - X - R * 50 R * is absent. In another embodiment, RS' is — X — R * wherein R * is absent and X is C , - C6 alkyl wherein said wherein R * is absent and X is C , -C6 alkyl wherein said C . - C . alkyl is substituted with 0 -6 halogen . In another CZ - C6 alkyl is substituted with 0 -6 halogen . In another embodiment, R5 is CH . In another embodiment. R5 is embodiment, R is CHz. In another embodiment, R is - X _ R¥ wherein R * is absent and X is C . - C . alkyl whereinin 5555 - X - R¥ wherein R * is absent and X is C , - C alkyl wherein said C . - C . alkyl is substituted with 0 - 6 halogenhalogen wherein one said C . - C . alkyl is substituted with 0 -6 halogen wherein one CH , unit of said C -C6 alkyl is replaced with O . In CH , unit of said C - C6 alkyl is replaced with O — . In another embodiment , RS is OCHz, OCH CH3, another embodiment, R is OCH3, OCH2CH3, OCH . CH . CH . , or OCH ( CH , ). . In another embodiment . R5 20 OCH2CH2CH3, or OCH (CH3 ) 2 . In another embodiment, Rº is OCHz. In another embodiment, R5 is CH2OH . In another is OCHz. In another embodiment, RS' is CH OH . In another embodiment, R5 is OCF , . In another embodiment, R5 is embodiment, Rºis OCF3. In another embodiment, Rºis OCHF OCHF 2 In another embodiment, the invention features a com - as In another embodiment, the invention features a com pound of formula I- D or I' - D and the attendant definitions , pound of formula I - D or I' - D and the attendant definitions , wherein G is wherein G is US 10 ,087 , 143 B2 e 60 embodiment, R7 is F . In another embodiment, R7 is CN . In mm another embodiment, R ? is - X - R * . In another embodi num ment, R ? is - X - R * wherein R * is absent. In another or R $ RE embodiment, R is X — R * wherein R * is absent and X is 5 C , - C6 alkyl wherein said C . - C . alkyl is substituted with 0 -6 halogen . In another embodiment , R ’ is CH3, CH2CH3, R6 CH2CH2CHz or isopropyl. In another embodiment , R ? is R6 Y R6 CF3. In another embodiment, R is - X - R * wherein R * is absent and X is C1 - C , alkyl wherein said C1- C , alkyl is substituted with 0 -6 halogen wherein two non -adjacent CH , In one embodiment , Róis H . In another embodiment, Rois units of said C . -Coalkyl are replaced with O . In another halogen . In another embodiment , Róis Cl. In another embodiment, R ’ is OCH CH _ OCHz. In another embodi embodiment, Ris F . In another embodiment, Ris CN . In ment, R ? is — X — R * wherein R * is absent and X is CZ - Co another embodiment, Róis - X - R * . In another embodi - 155 alkyl wherein said C . -C . alkyl is substituted with 0 -6 ment, Ró is — X — R * wherein R * is absent. In another halogen wherein one CH2 unit of said C . - C . alkyl is embodiment, Ris — X — R * wherein R * is absent and X is replaced with O — . In another embodiment, R ' is OCH3, C . - C . alkyl wherein said C -C . alkyl is substituted with 0 -6 OCH CH3, OCH CH2CH3, OC (CH3 ) 3 , CH ,CH ,OCHZ . In halogen . In another embodiment, R? is CHz. In another another embodiment, R ? is OCF3, OCH _ CF3, embodiment, Rºis — X — RY wherein RY is absent and X is 20 OCH2CH2CH2CF3, or OCHF 2 . C . - C . alkyl wherein said C . - C . alkyl is substituted with 0 - 6 In another embodiment , the invention features a com halogen wherein one CH2 unit of said C . - C . alkyl is pound of formula I- D or I' - D and the attendant definitions , replaced with O — . In another embodiment, R is OCHZ. wherein G is In another embodiment, the invention features a com pound of formula I - D or I' - D and the attendant definitions, 25 wherein G is RS

im 30 R 5 R ” . 7

Y 25 In one embodiment, R ' is H . In another embodiment, R ' is R6 RoRO - X - R * . In another embodiment , R7 is — X — R * wherein R * is absent. In another embodiment, R7 is — X — R * wherein R * is absent and X is C , - C6 alkyl wherein said In one embodiment. R6' is H . In another embodiment. R6' is C1- C6 alkyl is substituted with 0 -6 halogen . In another halogen . In another embodiment, Ró' is Cl. In another 40 embodimentembodiment,, R ? is CH3 , CH2CH3, CH CH CHz or isopro embodiment, Rºis F . In another embodiment, Rºis CN . In pyl. In another embodiment, R ' is CFz. In another embodi another embodiment, R ' is — X - RX . In another embodi ment, R ' is — X — R * wherein R * is absent and X is C . - C . ment, Rais — X - RX wherein R * is absent. In another alkyl wherein said CZ -C6 alkyl is substituted with 0 -6 embodiment, Rºis — X — R * wherein R * is absent and X is halogen wherein two non - adjacent CH , units of said C , - Ca C . - C . alkylwherein said C . - C . alkyl is substituted with 0 - 6 45 alkyl are replaced with — — . In another embodiment, R ' halogen . In another embodiment, Ró' is CHz. In another is OCH _CH _OCHz . In another embodiment, R is - X - R * embodiment, R " is — X — R * wherein R * is absent and X is wherein R * is absent and X is CZ - C6 alkyl wherein said C . - C . alkylwherein said C , -C6 alkyl is substituted with 0 -6 CZ- C6 alkyl is substituted with 0 - 6 halogen wherein one CH , halogen wherein one CH2 unit of said C . - C . alkyl is unit of said C -Co alkyl is replaced with O — . In another replaced with O — . In another embodiment, RO' is OCHOCHZ . 50 embodiment, R ? is OCH3, OCH2CH3, OCH CH2CH3 , In another embodiment, the invention features a com OC (CH3 ) 3 , CH CH OCHz. In another embodiment, R ' is pound of formula I - D or I' - D and the attendant definitions, OCF , OCH ,CF , OCH , CH ,CH ,CFz , or OCHF . In another embodiment, the invention features a com wherein G is pound of formula I - D or I' - D and the attendant definitions , 55 wherein G is

a R5 ni or RS -RS 60 RS R5s Y R6 Y PoR6 og R In one embodiment , R7 is H . In another embodiment, R7 is halogen . In another embodiment, R ' is C1. In another US 10 ,087 , 143 B2 61 62 In one embodiment , R is — X — R * wherein X is a bond and - continued R * is Cz- Cg cycloaliphatic and said C3 - C , cycloaliphatic is substituted with 0 - 3 substituents selected from halogen and ima C2- C4 alkyl. In another embodiment, R ? is - X - R * in wherein X is a bond and R¥ is cyclopropyl. 5 In another embodiment , the invention features a com pound of formula I - D or I' - D and the attendant definitions , F wherein G is ó wwwnmont , wennwir

mu men or R $ RS ó RO RO Y R6 F p > to In one embodiment, R7 is - X - R * wherein X is C . - C . alkyl wherein said C . - C . alkyl is substituted with 0 - 6 inn niny halogen wherein one CH2 unit of said C1 -C6 alkyl is replaced with O — andRis Cz- Cg cycloaliphatic and said C3 - C , cycloaliphatic is substituted with 0 - 3 substituents selected from halogen and C - C4 alkyl. In another embodi ment, R ' is - X - R * wherein X is OCH , and R * is cyclo propyl. 30 In another embodiment , the invention features a com pound of formula I - D or I' - D and the attendant definitions , wherein G is : F F

mi RS taitani minni mi Y R6 totant > P and G is selected from : ROK F Rain ni mm

* * wi , nimi

my wi ,

F IL F US 10 , 087 , 143 B2 63 4 -continued - continued

Nov , AMAN , N NNN ) + ?

F??F Apr, Momo , n ur ,

TL F " ? DF, F +?+?,+S ?F +ANAN , unive

* E

30 Ann Munny

Or

35 F NE

nulune 2 In another embodiment , the invention features a com 40 pound of formula I - D or I - D and the attendant definitions , wherein G is :

nnnne 45 Rs

nnnnnnn ? NANMA 50 RY

and G is selected from IF 55 non NANA nul nully , 60 ???????? - oror

?T F ??????? 6 ?? NF US 10 , 087 , 143 B2 65 66 In another embodiment, the invention features a com cycloaliphatic is replaced with O — . In another embodi pound of formula I - D or I' - D and the attendant definitions , ment, X is CH , and R * is 3 -tetrahydrofuran . wherein G is In another embodiment, the invention features a com pound of formula I - D or I '- D and the attendant definitions , 5 wherein G is selected from : min min man mm X - RY 10 wherein : X is a bond or C -Co alkyl wherein said C . - C . alkyl is substituted with 0 - 6 halogen , wherein up to two non - adja n cent CH2 units of said C1 -C6 alkyl may be replaced with - 0 % ; and 15 R * is absent, H , or C3 -C , cycloaliphatic , wherein up to two non -adjacent CH2 units of said C3- C , cycloaliphatic may be F replaced with O — and said C3 - C , cycloaliphatic is sub F stituted with 0 - 3 substituents selected from halogen and 20 F , F C1 - C4 alkyl . In another embodiment, the invention features a com novin pound of formula I- D or I' - D and the attendant definitions , man man wherein G is — X — R * wherein X is C . - C . alkyl wherein said C . -C . alkyl is substituted with 0 -6 halogen wherein up 25 to two non - adjacent CH , units of said C , -C6 alkyl may be replaced with O and R * is absent. In another embodi man ment, X is CH CH C ( CH3) ; or CH2CH (CH3 ) 2 and R * is mm absent . In another embodiment , X is CH2CH2CH2CFz or CH CH CF2 and R * is absent. 30 In another embodiment, the invention features a com pound of formula I- D or I' - D and the attendant definitions , wherein G is — X — R * wherein X is a bond and R * is C3- C , , or cycloaliphatic wherein up to two non - adjacent CH , of said Cz - C , cycloaliphatic may be replaced with and said 35 In another aspect , the invention provides a compound of C2- C , cycloaliphatic is substituted with 0 - 3 substituents formula I - E or I - E selected from halogen and C . - C4 alkyl. In another embodi I - E ment , X is a bond and R * is cyclobutane, cyclohexane, 59 bicyclo [2 .2 . 1 ]heptane , or bicyclo [3 . 1. 0 ]hexane . 40 - Re In another embodiment, the invention features a com pound of formula I - D or I' - D and the attendant definitions, R2 wherein G is - X - R wherein X is C , -C alkyl wherein said C -C . alkyl is substituted with 0 -6 halogen wherein up N to two non - adjacent CH2 units of said C . - C . alkyl may be 45 replaced with O — and R * is C3 - Cg cycloaliphatic wherein up to two non -adjacent CH , units of said Cz- Cg cycloali Ps phatic may be replaced with O — ; and said C3 -C , cycloa liphatic is substituted with 0 - 3 substituents selected from halogen and C , - C4 alkyl. In another embodiment , X is CH , 50 and R * is C3 - C , cycloaliphatic . In another embodiment , X is I - E CH , and R * is cyclopropyl or cyclopentyl. In another embodiment, X is CH and R * is C3 - Cg cycloaliphatic with up to 3 substituents selected from halogen and C , -C4 alkyl. In another embodiment, X is CH and R * is 1 -methylcyclo - 55 propyl, 2 ,2 -dimethylcyclopropyl or 2 ,2 - difluorocyclopropyl. In another embodiment, the invention features a com N pound of formula I -D or I' - D and the attendant definitions, wherein G is — X — R $ wherein X is C , -C6 alkyl wherein said C . -C . alkyl is substituted with 0 - 6 halogen wherein up 60 to two non - adjacent CH2 units of said C . - C . alkyl are replaced with O — and R * is C3 - C , cycloaliphatic wherein up to two non -adjacent CH , of said Cz - Cg cycloaliphatic may be replaced with and said Cz- Cg cycloaliphatic is substituted with 0 - 3 substituents selected from halogen 65 7 and C , -C4 alkyl. In another embodiment, X is CH , and R * is C3- C , cycloaliphatic wherein one CH2 unit of said Cz - C , or a pharmaceutically acceptable salt thereof, US 10 ,087 , 143 B2 68 wherein , independently for each occurrence : and X is C , - C . alkyl wherein said C1- C6 alkyl is substituted R² is halogen , CN , or C , - C . alkyl wherein said C , - C alkyl with 0 - 6 halogen wherein one CH , unit of said C , - C alkyl is substituted with 0 -6 halogen , wherein up to two non is replaced with 0 . In another embodiment, R ? is adjacent CH2 units of said C . - C . alkyl may be replaced with OCHZ, OCH CH3, OCH CH2CH3, OC (CH3 ) 3 , - 0 % RS is halogen , CN , or — X — R ' ; 5 CH CH OCHz. In another embodiment , R ? is OCF3, R7 is halogen , CN , or - X - R ' ; OCH _ CF3, OCH2CH2CH2CF3, or OCHF2. X is a bond or C , -C6 alkyl wherein said C -C6 alkyl is In another embodiment, the invention features a com substituted with 0 -6 halogen and wherein up to two nonn - poundpound ofof 10formula I- E or I' - E and the attendant definitions, adjacent CH , units of said C . - C . alkylmay be replaced with 10 wherein R ' is — X — R ^ wherein X is a bond and R ^ is C2- Co - 0 % ; cycloaliphatic and said C3 - C , cycloaliphatic is substituted R * is absent, H , or C3 - C , cycloaliphatic , wherein up to two with 0 - 3 substituents selected from halogen and C -C4 alkyl. non - adjacent CH , units of said Cz- C , cycloaliphatic may be In another embodiment, R ' is — X — R wherein X is a bond replaced with and said C3- Cg cycloaliphatic is sub - and R * is cyclopropyl . stituted with 0 - 3 substituents selected from halogen and 15 In another embodiment, the invention features a com C , - C4 alkyl ; R® is halogen or C . - C . alkyl wherein said C . - C . alkyl is pound of formula I - E or I '- E and the attendant definitions, substituted with 0 - 6 halogen and wherein up to two non wherein R ' is - X R * wherein X is C . - C . alkyl wherein adjacent CH2 units of said C , -C6 alkyl may be replaced with said C . - C . alkyl is substituted with 0 -6 halogen wherein one - 0 % ; 20 CH , unit of said C ,- C alkyl is replaced with O — and RX p is an integer from 0 to 3 inclusive; and is C3 - Cg cycloaliphatic and said C3 -Cg cycloaliphatic is Rºis H , or C , -C6 alkyl wherein up to two non - adjacent CH _ substituted with 0 - 3 substituents selected from halogen and units of said C .- C . alkyl may be replaced with O — . . CZ- C4 alkyl . In another embodiment, R ? is - X - R * In another embodiment , the invention features a com - wherein X is OCH2 and R ^ is cyclopropyl. pound of formula I - E or I' - E and the attendant definitions, 25 In another embodiment, the invention features a com wherein R2 is halogen . In another embodiment, R2 is Cl. In pound of formula I - E or I' - E and the attendant definitions, another embodiment, R2 is F . In another embodiment, R² is wherein p is zero . In another embodiment, p is an integer CN . In another embodiment, R ’ is C1- C . alkyl wherein said from 1 to 3 and R8 is halogen . In another embodiment, p is C , - Ca alkyl is substituted with 0 - 6 halogen . In another an integer from 1 to 3 and R8 is C1. In another embodiment, embodiment, R ' is CFz. In another embodiment, R ' is C1- C6 30 p is an integer from 1 to 3 and R8 is C . - C . alkyl wherein said alkyl wherein said C -Co alkyl is substituted with 0 - 6 C . - C . alkyl is substituted with 0 -6 halogen wherein one CH , halogen wherein one CH2 unit of said C . -C alkyl is replaced with O — . In another embodiment, R2 is OCF3 unit of said C1- C6 alkyl is replaced with O — . In another In another embodiment, R² is F , C1, CN , CF , or OCFz. 3. embodiment, p is an integer from 1 to 3 and R is CHz . In another embodiment, the invention features a com - 35 In another embodiment, the invention features a com pound of formula I - E or I' - E and the attendant definitions, pound of formula I - E or I' - E and the attendant definitions , wherein R5 is halogen . In another embodiment, R5 is Cl. In wherein Rºis H . In another embodiment, Rº is C , - C6 alkyl . another embodiment, RS is F . In another embodiment , RS is In another embodiment, Rº is CH3. In another embodiment, CN . In another embodiment, RS is — X — R * . In another Rº is C , - C , alkyl wherein said C . - C . alkyl is substituted embodiment, RS is - X - RX wherein R * is absent. In 40 with 0 - 6 halogen wherein one CH , unit of said C . - C . alkyl another embodiment, RS is - X - R * wherein R * is absent is replaced with . In another embodiment, Rº is and X is C , - C alkyl wherein said C . -C . alkyl is substituted CH , CH OH . with 0 -6 halogen . In another embodiment, R is CHz. In another embodiment , Ris - X - R * wherein R * is absent In another embodiment, the invention features a com and X is C1- C6 alkyl wherein said C1- C6 alkyl is substituted 45 pound of formula I- E or I' - E and the attendant definitions , with 0 - 6 halogen wherein one CH , unit of said C . - C . alkyl * wherein ring A is selected from : is replaced with O — . In another embodiment, R5 is OCH3, OCH CH3, OCH2CH2CH3, or OCH (CH3 ) 2 . In another embodiment, R5 is OCH?. In another embodiment, R $ is CH2OH . In another embodiment, R is OCF3 . In 50 mi mi ni another embodiment, R is OCHFZ. In another embodiment, the invention features a com pound of formula I - E or I' - E and the attendant definitions, wherein R ’ is halogen . In another embodiment, R ' is Cl. In another embodiment, R ' is F . In another embodiment, R ' is 55 CN . In another embodiment, R ' is X RX . In another embodiment, R7 is — X — R wherein RX is absent . In Ci Ci , F another embodiment , R ' is - X - R * wherein R * is absent ???? and X is C1- C6 alkyl wherein said C1- C6 alkyl is substituted via wir min with 0 - 6 halogen . In another embodiment, R ' is CH3, 60 CH2CH3, CH CH CHz or isopropyl . In another embodi ment, R ' is CFz. In another embodiment, R7 is — X — R * HO wherein R * is absent and X is CZ -C6 alkyl wherein said C -C6 alkyl is substituted with 0 -6 halogen wherein two non - adjacent CH2 units of said C . - C . alkyl are replaced with 65 - 0 . In another embodiment, R ' is OCH CH OCHz. In F 2 F F another embodiment , R ' is - X - R * wherein R * is absent 2015 US 10 ,087 , 143 B2 70 -continued R * is absent, H , or C3- Cg cycloaliphatic , wherein up to two non - adjacent CH _ units of said C3 - C , cycloaliphatic may be min replaced with and said C3- C , cycloaliphatic is sub stituted with 0 - 3 substituents selected from halogen and E . 5 C1- C4 alkyl; R8 is halogen or C - C alkyl wherein said C1- C6 alkyl is substituted with 0 - 6 halogen and wherein up to two non adjacnet CH , units of said C -C6 alkylmay be replaced with - 0 FF , O , or 10 p is an integer from 0 to 3 inclusive ; and Rºis H , or C . - C . alkyl wherein up to two non - adjacent CH2 nina units of said C . - C . alkyl may be replaced with OM . In another embodiment, the invention features a com pound of formula I - F or I' - F and the attendant definitions , 15 wherein R * is halogen . In another embodiment, R * is Cl. In another embodiment, R3 is F. In another embodiment, R3 is CN . In another embodiment , Ris C . - C . alkyl wherein said CZ - C6 alkyl is substituted with 0 - 6 halogen . In another embodiment, R is t -butyl . In another embodiment, R * is 20 CFz. In another embodiment, Rºis CF CFz . In another embodiment, the invention features a com In another aspect , the invention provides a compound of pound of formula I- F or I' - F and the attendant definitions , formula I - F or I' - F : wherein R5 is halogen . In another embodiment, R5 is C1. In another embodiment, Ris F . In another embodiment, Ris 25 CN . In another embodiment, R is — X — R * . In another I - F embodiment, RS is — X — R * wherein R * is absent. In another embodiment, R is X — R * wherein R * is absent RO and X is CZ -C6 alkyl wherein said C . - C . alkyl is substituted with 0 - 6 halogen . In another embodiment, R is CHz. In 30 another embodiment, RS is CDz. In another embodiment, RS is — X — R wherein R * is absent and X is C , -C . alkyl wherein said C -C6 alkyl is substituted with 0 - 6 halogen wherein one CH , unit of said C -C6 alkyl is replaced with - 0 % . In another embodiment , R is OCHZ, OCH CHz, RS 35 OCH CH2CH3, or OCH (CH3 ) 2. In another embodiment, RS is OCHz. In another embodiment, Ris CH OH . In another embodiment, R is OCF3. In another embodiment, R is AY OCHF2. R7 In another embodiment, the invention features a com TL 40 pound of formula I - F or I ' - F and the attendant definitions , wherein R7 is halogen . In another embodiment, R ' is Cl. In another embodiment, R7 is F . In another embodiment, R7 is CN . In another embodiment, R7 is — X — R * . In another embodiment, R ? is — X — R wherein R * is absent. In ??? 45 another embodiment, R ' is - X - R * wherein R * is absent and X is C , -C6 alkyl wherein said C - C alkyl is substituted with 0 -6 halogen . In another embodiment , R ? is CHz , CH2CH3, CH2CH2CHz or isopropyl. In another embodi ment, R7 is CFz. In another embodiment, R7 is — X - R * 50 wherein R * is absent and X is C . - C . alkyl wherein said C . - C alkyl is substituted with 0 - 6 halogen wherein two non - adjacent CH _ units of said C . - C . alkyl are replaced with - 0 - . In another embodiment, R ? is OCH _ CH OCHz. In another embodiment, R ' is — X — R * wherein R * is absent 55 and X is C . - C . alkyl wherein said C , -Co alkyl is substituted or a pharmaceutically acceptable salt thereof, with 0 -6 halogen wherein one CH , unit of said C . - C . alkyl wherein , independently for each occurrence : is replaced with O — . In another embodiment , R ? is R ’ is halogen , CN , or C ,- C . alkyl wherein said C , -Co alkyl OCHZ, OCH CH3, OCH CH2CH3, OC (CH3 )3 , is substituted with 0 - 6 halogen , wherein up to two non - CH CH OCHz. In another embodiment, R7 is OCF3, adjacent CH _ units of said C -Co alkyl may be replaced with 60 OCH _ CF3, OCH CH2CH2CF3, or OCHF2. - 0 % ; In another embodiment, the invention features a com R5 is halogen , CN , or — X — R * ; pound of formula I - F or I' - F and the attendant definitions, R ' is halogen , CN , or — X — R ; wherein R ’ is X - R wherein X is a bond and R * is Cz- C , X is a bond or C1 -C6 alkyl wherein said C . - C . alkyl is cycloaliphatic and said Cz- C , cycloaliphatic is substituted substituted with 0 - 6 halogen and wherein up to two non - 65 with 0 - 3 substituents selected from halogen and C , - C4 alkyl. adjacent CH _ units of said C - C alkylmay be replaced with In another embodiment, R ' is - X - R * wherein X is a bond - 0 % ; and R * is cyclopropyl. US 10 ,087 , 143 B2 72 In another embodiment, the invention features a com - continued pound of formula I - F or I' - F and the attendant definitions , wherein R7 is - X - R * wherein X is CZ -C6 alkyl wherein said C .- Cô alkyl is substituted with 0 -6 halogen wherein one CH , unit of said C . - C . alkyl is replaced with O — and RX 5 is C3- Cg cycloaliphatic and said Cz- Cg cycloaliphatic is substituted with 0 - 3 substituents selected from halogen and CZ -C4 alkyl. In another embodiment , R7 is - X - R * wherein X is OCH , and R * is cyclopropyl. In another embodiment , the invention features a com 10 pound of formula I - F or I' - F and the attendant definitions, wherein p is zero . In another embodiment, p is an integer In another aspect, the invention provides a compound of from 1 to 3 and R8 is halogen . In another embodiment , p is formula 1- G or I' - G : an integer from 1 to 3 and Rºis C1. In another embodiment, 15 p is an integer from 1 to 3 and R8 is C - Co alkyl wherein said C1 - C alkyl is substituted with 0 -6 halogen wherein one CH2 I- G unit of said C1- C6 alkyl is replaced with O — . In another embodiment, p is an integer from 1 to 3 and R8 is CH2. In another embodiment, p is an integer from 1 to 3 and R is D . 20 In another embodiment, the invention features a com pound of formula I- F or I' - F and the attendant definitions , wherein Rº is H . In another embodiment, Rº is C . - C . alkyl. In another embodiment, Rº is CHz. In another embodiment , Rº is C , - Co alkyl wherein said C . - C . alkyl is substituted u with 0 - 6 halogen wherein one CH , unit of said C . - C . alkyl is replaced with O — . In another embodiment, Rº is CH CH ,OH . In another embodiment, the invention features a com - 30 Gi pound of formula I - F or I' - F and the attendant definitions , I ' - G wherein ring A is selected from :

35 PO ma mi ni

40

CI , > Gli ??? 45 or a pharmaceutically acceptable salt thereof, mwan mu wherein , independently for each occurrence : R2 is halogen , CN , or C , -C , alkylwherein said C . - C , alkyl 50 is substituted with 0 -6 halogen and wherein up to two HO non - adjacent CH2 units of said C -C6 alkyl may be replaced with 0 — ; R * is halogen , CN , or C , - C? alkylwherein said C ,- C . alkyl F , is substituted with 0 - 6 halogen and wherein up to two F , 55 non -adjacent CH2 units of said C1- C6 alkylmay be replaced ??? with O ; R $ is halogen , CN , or - X - R * ; R ? is halogen , CN , or X - R * ; nun wi nim X is a bond or C -Co alkyl wherein said C . - C . alkyl is 60 substituted with 0 -6 halogen and wherein up to two non F adjacent CH _ units of said C .- C . alkyl may be replaced with 0 ; R * is absent, H , or C3 -C4 cycloaliphatic , wherein up to two non -adjacent CH2 units of said C3- C , cycloaliphatic may be F , 65 replaced with and said Cz - Cg cycloaliphatic is sub Lo , o , or stituted with 0 - 3 substituents selected from halogen and $ 35 CZ -C4 alkyl ; US 10 ,087 , 143 B2 73 74 R8 is halogen or C -C6 alkyl wherein said C . - C . alkyl is wherein R ’ is - X - R * wherein X is a bond and R * is C3- C , substituted with 0 -6 halogen and wherein up to two non cycloaliphatic and said Cz - Cg cycloaliphatic is substituted adjacent CH2units of said C1- C . alkyl may be replaced with with 0 - 3 substituents selected from halogen and C , -C4 alkyl . - O ; In another embodiment , R ' is — X — R * wherein X is a bond p is an integer from 0 to 3 inclusive ; and 5 and R * is cyclopropyl. Rºis H , or C , -C6 alkyl wherein up to two non - adjacent CH _ units of said C . - C . alkyl may be replaced with O — . . In another embodiment , the invention features a com In another embodiment, the invention features a com pound of formula 1 - G or I' -G and the attendant definitions , pound of formula 1 - G or I' - G and the attendant definitions, wherein R7 is — X — R * wherein X is C -Co alkyl wherein wherein R2 is halogen . In another embodiment. R2 is C1. In 10 said C1- C6 alkyl is substituted with 0 - 6 halogen and wherein another embodiment. R2 is F . In another embodiment. R2 is one CH2 unit of said C , -C6 alkyl is replaced with — and CN . In another embodiment. R2 is C . - C . alkyl wherein said R * is C3 -Cg cycloaliphatic and said Cz - C , cycloaliphatic is C . - C . alkyl is substituted with 0 -6 halogen . In another substituted with 0 - 3 substituents selected from halogen and embodiment, R2 is CF3. In another embodiment, R2 is C . - C . C -C4 alkyl. In another embodiment, R7 is — X — RY alkyl wherein said C . -C . alkyl is substituted with 0 - 6 15 wherein X is OCH , and R * is cyclopropyl. halogen wherein one CH2 unit of said C1 - C6 alkyl is In another embodiment, the invention features a com replaced with 0 - . In another embodiment, R² is OCF3. In another embodiment, R² is F, C1, CN , CF , or OCF3. pound of formula I -G or I' - G and the attendant definitions , In another embodiment, the invention features a com wherein p is zero . In another embodiment, p is an integer pound of formula I - G or I' - G and the attendant definitions , 20 from 1 to 3 and R® is halogen . In another embodiment, p is wherein R3 is halogen . In another embodiment, R3 is Cl. In an integer from 1 to 3 and R8 is Cl. In another embodiment , another embodiment , R? is F . In another embodiment, R? is p is an integer from 1 to 3 and R8 is C . - C . alkyl wherein said CN . In another embodiment , R ’ is C , - C6 alkyl wherein said C1- C6 alkyl is substituted with 0 -6 halogen wherein one CH2 C . - C . alkyl is substituted with 0 - 6 halogen . In another unit of said C1 -C6 alkyl is replaced with 40 - . In another embodiment. R3 is t- butyl . In another embodiment, R3 is 25 embodiment, p is an integer from 1 to 3 and Rºis CH3. CF3. In another embodiment, R * is CF2CF3. In another embodiment , the invention features a com In another embodiment, the invention features a com - pound of formula 1 - G or I' -G and the attendant definitions , pound of formula I - G or I' - G and the attendant definitions, wherein Rºis H . In another embodiment, Rºis C , -C6 alkyl . wherein Ris halogen . In another embodiment, Ris Cl. In In another embodiment, Rº is CH , . In another embodiment, another embodiment, R ' is F . In another embodiment, Ris 30 Rº is C . - C . alkyl wherein said C . - C . alkyl is substituted CN . In another embodiment, R is — X — R * . In another embodiment, RS is — X — R * wherein R * is absent. In with 0 -6 halogen wherein one CH , unit of said C , -C6 alkyl another embodiment , RS is - X - R * wherein R * is absent is replaced with O . In another embodiment, Rº is and X is C , - C . alkylwherein said C , -C alkyl is substituted CH2CH2OH . with 0 - 6 halogen . In another embodiment. R5 is CH . . In 35 In another embodiment, the invention features a com another embodiment, R5 is — X — RY wherein RY is absent pound of formula I - G or I' - G and the attendant definitions , and X is C . - C . alkylwherein said C . - C . alkyl is substituted wherein ring A is selected from : with 0 - 6 halogen wherein one CH2 unit of said C - C , alkyl is replaced with O — In another embodiment, RS is OCH3, OCH CH3, OCH CH CHz, or OCH (CH3 ) 2 . In 40 another embodiment, Ris OCHZ. In another embodiment, mi ni ni R5 is CH ,OH . In another embodiment, RS is OCF2 . In w another embodiment, R is OCHF2. In another embodiment, the invention features a com pound of formula I - G or I' - G and the attendant definitions , 45 wherein R7 is halogen . In another embodiment , R ' is Cl. In another embodiment, R ' is F . In another embodiment, R ' is CN . In another embodiment, R ? is - X - R * . In another CI CI , F embodiment, R ' is — X - R * wherein R * is absent . In ???? another embodiment, R ' is — X - R * wherein R * is absent 50 min wi mi and X is C1- C6 alkyl wherein said C1- C6 alkyl is substituted with 0 - 6 halogen . In another embodiment, R7 is CHz, CH2CH3, CH2CH2CHz or isopropyl. In another embodi HO ment, R ? is CFz. In another embodiment , R7 is — X — R * wherein R * is absent and X is C , - C6 alkyl wherein said 55 C -C6 alkyl is substituted with 0 - 6 halogen wherein two non - adjacent CH2 units of said C , - C . alkyl are replaced with F , F , - 0 % . In another embodiment, R ' is OCH CHQOCHz. In mm ma* another embodiment, R7 is — X RY wherein R * is absent and X is C , - Coalkyl wherein said C . -Co alkyl is substituted 60 with 0 -6 halogen wherein one CH , unit of said C . -C . alkyl is replaced with O — . In another embodiment, R ? is OCHZ, OCH CHz, OCH CH2CH3, OC (CH3 ) 3 , CH , CH ,OCHz . In another embodiment, R ' is OCF3, OCH , CF3, OCH CH CH CF3, or OCHF2. ) , or In another embodiment, the invention features a com F pound of formula 1 - G or I' - G and the attendant definitions , US 10 ,087 , 143 B2 75 76 -continued R8 is halogen or C - C alkyl wherein said C1- C6 alkyl is substituted with 0 - 6 halogen and wherein up to two non adjacent CH2 units of said C . - C . alkyl may be replaced with 0 ; un p is an integer from 0 to 3 inclusive ; and Rºis H , or C . - C . alkyl wherein up to two non - adjacent CH _ units of said C . - C . alkyl may be replaced with — — In another embodiment , the invention features a com pound of formula 1 - H or I' - H and the attendant definitions , 10 wherein Rl is halogen . In another embodiment, R ' is CN . In another embodiment, Ris C , - C , alkyl wherein said C - C alkyl is substituted with 0 - 6 halogen . In another embodi In another aspect , the invention provides a compound of ment. Rl is CF . formula 1 - H or I ' - H : In another embodiment , the invention features a com pound of formula 1 - H or I' - H and the attendant definitions , wherein R3 is halogen . In another embodiment, R ’ is Cl. In I - H another embodiment, Ris F . In another embodiment, R * is CN . In another embodiment, R is C ,- Co alkyl wherein said VRO C . - C . alkyl is substituted with 0 - 6 halogen . In another 20 embodiment, R * is t -butyl . In another embodiment, R * is CFz. In another embodiment, R * is CF , CFz. N In another embodiment, the invention features a com pound of formula I - H or I' - H and the attendant definitions, R3 wherein Ris halogen . In another embodiment, Ris C1. In 25 another embodiment, R is F . In another embodiment, R is CN . In another embodiment, RS is - X - R * . In another embodiment, Rºis — X - R wherein R * is absent. In llalliinianother embodiment, R * is — X — R * wherein R * is absent and X is C , - C , alkyl wherein said C , - Co alkyl is substituted 30 with 0 - 6 halogen . In another embodiment, R ' is CHz. In I ' - H another embodiment, R is - X - R * wherein R * is absent and X is C . - C . alkyl wherein said C - C . alkyl is substituted with 0 -6 halogen wherein one CH , unit of said C . -C . alkyl is replaced with O — . In another embodiment, RS is 35 OCHZ, OCH2CH3, OCH2CH2CH3, or OCH (CH3 ) 2. In Po another embodiment, R is OCHZ. In another embodiment, R5 is CH ,OH . In another embodiment , RS is OCF3. In R3 another embodiment, Ris OCHF2 . In another embodiment, the invention features a com 40 pound of formula I - H or I' - H and the attendant definitions, wherein R ' is halogen . In another embodiment, R ' is Cl. In another embodiment, R7 is F . In another embodiment, R7 is CN . In another embodiment, R7 is — X — R * . In another

? embodiment, R ? is — X — R wherein R * is absent. In 45 another embodiment, R ? is — X — R $ wherein R * is absent and X is C , - C . alkyl wherein said C1- C6 alkyl is substituted or a pharmaceutically acceptable salt thereof, with 0 -6 halogen . In another embodiment , R ? is CHz , wherein , independently for each occurrence : CH2CH3, CH2CH2CHz or isopropyl. In another embodi Rl is halogen , CN , or C . - C . alkyl wherein said C . - C . alkyl ment, R7 is CFz. In another embodiment, R7 is X — R is substituted with 0 - 6 halogen and wherein up to two 50 wherein R * is absent and X is CZ - C6 alkyl wherein said non - adjacent CH2 units of said C . - C . alkyl may be replaced C - C alkyl is substituted with 0 - 6 halogen wherein two with 0 % ; non -adjacent CH2 units of said C , - C . alkyl are replaced with R ’ is halogen , CN , or C , -C alkyl wherein said C . - C . alkyl 0 – . In another embodiment, R is OCH _CHQOCHz . In is substituted with 0 - 6 halogen and wherein up to two another embodiment, R7 is - X - R * wherein R * is absent non - adjacent CH , units of said C , -Co alkyl may be replaced 55 and X is C -Co alkyl wherein said C . - C . alkyl is substituted with 0 % ; with 0 -6 halogen wherein one CH , unit of said C . - C . alkyl R is halogen , CN , or X - R * ; is replaced with 0 - . In another embodiment, R ? is R ? is halogen , CN , or X - R * ; OCHZ, OCH2CH3, OCH CH2CH3, OC ( CH3) 3 , X is a bond or C - C6 alkyl wherein said C . - C . alkyl is CH CH OCHz. In another embodiment, R7 is OCF3, substituted with 0 -6 halogen and wherein up to two non - 60 OCH _ CF3, OCH _ CH CH CF3, or OCHF2. adjacent CH _ units of said C , - C alkyl may be replaced with In another embodiment, the invention features a com - 0 % ; pound of formula I - H or I ' - H and the attendant definitions , R * is absent, H , or C3- C , cycloaliphatic , wherein up to two wherein R ' is - X - R * wherein X is a bond and R * is Cz- C , non - adjacent CH , units of said Cz - C , cycloaliphatic may be cycloaliphatic and said Cz - Cg cycloaliphatic is substituted replaced with O - and said C3- Cg cycloaliphatic is sub - 65 with 0 - 3 substituents selected from halogen and C , - C4 alkyl. stituted with 0 - 3 substituents selected from halogen and In another embodiment, R7 is - X - R * wherein X is a bond C /- C4 alkyl; and R * is cyclopropyl. US 10 , 087 , 143 B2 77 78 In another embodiment, the invention features a com In another aspect , the invention provides a compound of pound of formula I - H or I' - H and the attendant definitions, formula I -J or I' - J : wherein R ' is — X — R * wherein X is C , -Co alkyl wherein said C . - C . alkyl is substituted with 0 - 6 halogen wherein one CH , unit of said C . - C . alkyl is replaced with O — and R * 5 I - J is C3 - C , cycloaliphatic and said Cz - C , cycloaliphatic is I- J substituted with 0 - 3 substituents selected from halogen and C . - C . alkyl. In another embodiment, RP is — X — R * VRO wherein X is OCH , and Ris cyclopropyl. In another embodiment, the invention features a com - 1 pound of formula I- H or I' - H and the attendant definitions, 10 NH wherein p is zero . In another embodiment, p is an integer from 1 to 3 and R8 is halogen . In another embodiment , p is an integer from 1 to 3 and R8 is Cl. In another embodiment, p is an integer from 1 to 3 and R8 is C . - Cô alkyl wherein said C , -Coalkyl is substituted with 0 -6 halogen wherein one CH , 15 to unit of said C -Ce alkyl is replaced with O . In another embodiment, p is an integer from 1 to 3 and R8 is CHZ. li In another embodiment, the invention features a com G pound of formula I - H or I' - H and the attendant definitions , wherein Rº is H . In another embodiment, Rº is C , - C alkyl. 20 I ' - J In another embodiment, Rº is CHz. In another embodiment, R® is C , - Co alkyl wherein said C - Co alkyl is substituted with 0 - 6 halogen wherein one CH , unit of said C - C . alkyl is replaced with - 0 % In another embodiment, Rº is CH , CH ,OH . 25 NH In another embodiment, the invention features a com pound of formula I - H or I' - H and the attendant definitions, wherein ring A is selected from :

30 nin navian ina ina ma ? 35 or a pharmaceutically acceptable salt thereof, wherein , independently for each occurrence : R2 is halogen , CN , or CZ - C alkyl wherein said C . - C . alkyl is substituted with 0 - 6 halogen and wherein up to two non -adjacent CH2 units of said C1- C6 alkyl may be replaced mi mm with 0 % ; R7 is halogen , CN , or - X - R * ; ?? X is a bond or C , - C6 alkyl wherein said C -C6 alkyl is substituted with 0 -6 halogen and wherein up to two non 45 adjacent CH _ units of said C - C . alkyl may be replaced with ? - - 0 % ; F F R * is absent, H , or C3 - C , cycloaliphatic , wherein up to two non - adjacent CH _ units of said Cz- Cg cycloaliphatic may be im mi replaced with and said Cz- Cg cycloaliphatic is sub 50 stituted with 0 - 3 substituents selected from halogen and F C , -C4 alkyl; R® is H , halogen , or C , -Co alkyl wherein said C - Co alkyl is substituted with 0 - 6 halogen and wherein up to two non adjacent CH _ units of said C .- C . alkyl may be replaced with F tototor 55 0 ; p is an integer from 0 to 3 inclusive ; and Rº is H , or C , - C alkyl wherein up to two non -adjacent CH2 min units of said C , - Co alkyl may be replaced with O — . In another embodiment, the invention features a com 60 pound of formula I- J or I' - J and the attendant definitions, wherein R2 is halogen . In another embodiment, R2 is Cl. In another embodiment, R2 is F . In another embodiment, R2 is CN . In another embodiment, R2 is C . - C . alkyl wherein said C -C6 alkyl is substituted with 0 - 6 halogen . In another 65 embodiment, R² is CFz. In another embodiment, R² is C , - C . alkyl wherein said C1- C , alkyl is substituted with 0 - 6 halogen wherein one CH2 unit of said C . - C6 alkyl is US 10 , 087 , 143 B2 replaced with . In another embodiment, R2 is OCF3 . In another embodiment , R2 is F , C1, CN , CF , or OCF2 . In another embodiment, the invention features a com win win pound of formula I - J or I' - J and the attendant definitions , wherein R ’ is halogen . In another embodiment, R7 is Cl. In 5 another embodiment, R7 is F . In another embodiment, R7 is CN . In another embodiment, R ? is — X — R " . In another embodiment, R ? is — X — R * wherein R * is absent. In another embodiment, R ' is - X - R * wherein R * is absent 10 F and X is C - C6 alkyl wherein said C . - C . alkyl is substituted with 0 - 6 halogen . In another embodiment, R ? is CHz, CH2CH3, CH2CH2CHz or isopropyl. In another embodi ment, R ? is CF3 . In another embodiment, R ' is - X - R * mi mi wherein R * is absent and X is CZ - C6 alkyl wherein said 15 C1- C6 alkyl is substituted with 0 -6 halogen wherein two non - adjacent CH _ units of said C . - C . alkyl are replaced with - 0 . In another embodiment, R ? is OCH CH , OCHz. In another embodiment, R7 is - X - R * wherein R * is absent 20 Kita and X is C .- C . alkyl wherein said C .- C . alkyl is substituted with 0 -6 halogen wherein one CH , unit of said C . -C . alkyl is replaced with0 In another embodiment, R7 is OCH3, OCH ,CHz , OCH CH2CH3, OC( CH3) 3 , 25 F F CH _ CH _OCHz . In another embodiment, R ? is OCF3, OCH CF3 , OCH CH CH CF3, or OCHF2. F In another embodiment, the invention features a com min min mir pound of formula I - J or I' - J and the attendant definitions , 30 wherein R7 is — X — R * wherein X is a bond and R * is Cz- Cg cycloaliphatic and said C3- C , cycloaliphatic is substituted with 0 - 3 substituents selected from halogen and C . -C4 alkyl.

In another embodiment, R ? is — X — R * wherein X is a bond 35 CN and R * is cyclopropyl . In another embodiment, the invention features a com pound of formula I -J or I' - J and the attendant definitions , wherein 12 " is - X - R * wherein X is C , -C6 alkyl wherein said C . - C . alkyl is substituted with 0 - 6 halogen wherein one CH , unit of said C .- C . alkyl is replaced with and R * min mi min mi is Cz -Cg cycloaliphatic and said Cz- Cg cycloaliphatic is substituted with 0 - 3 substituents selected from halogen and CZ - C4 alkyl. In another embodiment, R7 is - X - R * 45 wherein X is OCH , and R * is cyclopropyl. In another embodiment, the invention features a com pound of formula I - J or I' - J and the attendant definitions , wherein p is zero . In another embodiment , p is an integer 50 L from 1 to 3 and R® is halogen . In another embodiment, p is an integer from 1 to 3 and R8 is Cl. In another embodiment, p is an integer from 1 to 3 and R® is C - C . alkyl wherein said M C . - C , alkyl is substituted with 0 - 6 halogen wherein one CH , unit of said C - C , alkyl is replaced with O — . In another 55 embodiment, p is an integer from 1 to 3 and R8 is CHz. In another embodiment, the invention features a com pound of formula I - J or I' - J and the attendant definitions , wherein Rºis H . In another embodiment, Rº is C , - C , alkyl. In another embodiment, Rº is CHz. In another embodiment, 60 Rº is C , -C6 alkyl wherein said C . -C . alkyl is substituted with 0 -6 halogen wherein one CH , unit of said C , -C alkyl FF; is replaced with0 . In another embodiment, Rº is CH ,CH ,OH . F F or, In another embodiment, the invention features a com - 65 pound of formula I - J or I' - J and the attendant definitions, In another aspect , the invention provides a compound of wherein ring B is selected from : formula I- K or I' - K : US 10 , 087 , 143 B2 82 CN . In another embodiment, R ' is - X - R * . In another I - K embodiment, R ' is — X - R * wherein R * is absent. In ( R another embodiment, R ' is - X R wherein R * is absent P9 and X is C , -C6 alkyl wherein said C . - C . alkyl is substituted 5 with 0 - 6 halogen . In another embodiment, R ? is CH3, CH ,CH , , CH , CH ,CHz or isopropyl. In another embodi ment, R ' is CFz. In another embodiment, R7 is — X - R * wherein R * is absent and X is C , - C , alkyl wherein said C , -C6 alkyl is substituted with 0 - 6 halogen wherein two R3 non - adjacent CH , units of said C , - C , alkyl are replaced with 0 — . In another embodiment, R ' is OCH CH OCHz. In another embodiment, R7 is — X — R * wherein R * is absent to and X is C , - C . alkyl wherein said C1- C6 alkyl is substituted B with 0 -6 halogen wherein one CH , unit of said C . -C . alkyl is replaced with - 0 . In another embodiment, R ' is 15 OCH3, OCH CHZ, OCH CH2CH3, OC (CH3 ) 3 , TILK CH , CH , OCHz. In another embodiment, RP is OCF2, OCH CF3, OCH2CH2CH2CF3, or OCHF2. In another embodiment, the invention features a com 50 pound of formula I - K or I' - K and the attendant definitions, 20 wherein R is — X — R * wherein X is a bond and R * is C3 -C , PO cycloaliphatic and said C3- C , cycloaliphatic is substituted with 0 - 3 substituents selected from halogen and C , -C4 alkyl. R3 In another embodiment, R is - X - R wherein X is a bond and R * is cyclopropyl. 25 In another embodiment, the invention features a com pound of formula I - K or I' - K and the attendant definitions, wherein R7 is - X - R * wherein X is C ,- Co alkyl wherein said C . - C . alkyl is substituted with 0 - 6 halogen wherein one CH , unit of said C , -Co alkyl is replaced with O — and R * 7 30 is C3 - C , cycloaliphatic and said C3 - C , cycloaliphatic is substituted with 0 - 3 substituents selected from halogen and or a pharmaceutically acceptable salt thereof, CZ- C4 alkyl . In another embodiment, R7 is - X - R * wherein , independently for each occurrence : wherein X is OCH , and R * is cyclopropyl . Rºis halogen , CN , or C - C alkyl wherein said C . - C . alkyl In another embodiment, the invention features a com is substituted with 0 -6 halogen and wherein up to two » pound of formula 1 - K or I' - K and the attendant definitions , non - adjacent CH _ units of said C . - C . alkyl may be replaced wherein p is zero . In another embodiment , p is an integer from 1 to 3 and Rº is halogen . In another embodiment, with 0 % ; wherein p is an integer from 1 to 3 and R8 is Cl. In another R7 is halogen , CN , or — X — R * ; embodiment, wherein p is an integer from 1 to 3 and R8 is X is a bond or C -Co alkyl wherein said C . - C . alkyl is 40 C . - C . alkyl wherein said C , -C6 alkyl is substituted with 0 -6 substituted with 0 - 6 halogen and wherein up to two non halogen wherein one CH , unit of said C , - Ca alkyl is adjacent CH _ units of said C - C alkyl may be replaced with replaced with O — . In another embodiment, R? is CHz. 0 ; In another embodiment, the invention features a com R * is absent, H , or C2- C , cycloaliphatic , wherein up to two pound of formula I- K or I '- K and the attendant definitions, non -adjacent CH2 units of said C3- Cg cycloaliphatic may be 45 wherein Rº is H . In another embodiment. R9 is C . - C . alkvl. replaced with and said C3- Cg cycloaliphatic is sub In another embodiment , Rº is CHz. In another embodiment, stituted with 0 - 3 substituents selected from halogen and Rºis C . - C . alkyl wherein said C1- C6 alkyl is substituted C1 - C4 alkyl ; with 0 - 6 halogen wherein one CH , unit of said C , - C , alkyl R® is halogen or C , -C . alkyl wherein said C , -C alkyl is is replaced with O — . In another embodiment , Rº is substituted with 0 -6 halogen and wherein up to two non - 50 CH . CH . OH . adjacent CH2 units of said C1- C6 alkyl may be replaced with In another embodiment, the invention features a com - 0 — ; p is an integer from 0 to 3 inclusive ; and pound of formula I - K or I' - K and the attendant definitions , Rºis H , or C , - C , alkyl wherein up to two non -adjacent CH , wherein ring B is selected from : units of said C . - C . alkyl may be replaced with O . 55 In another embodiment, the invention features a com pound of formula I - K or I' - K and the attendant definitions , wherein R3 is halogen . In another embodiment, R3 is Cl. In mun inn ni another embodiment, R * is F . In another embodiment, R * is X CN . In another embodiment, R3 is C . -C . alkyl wherein said 60 CZ - C6 alkyl is substituted with 0 - 6 halogen . In another embodiment, R3 is t -butyl . In another embodiment, R is CF3. In another embodiment, R3 is CF CF3. In another embodiment, the invention features a com ?00É CI . 9 pound of formula I - K or I' - K and the attendant definitions , 65 wherein R ' is halogen . In another embodiment, R ' is Cl. In F another embodiment, R ' is F . In another embodiment, R7 is US 10 ,087 , 143 B2 83 8484 -continued I - L N - R9P9 van

R3

F - F I' - L the 17

PO nomwa fun manwanitarne wa olun womanentorn Git 30 or a pharmaceutically acceptable salt thereof, wherein , independently for each occurrence : R2 is halogen , CN , or CZ - C . alkyl wherein said C - C . alkyl 35 is substituted with 0 - 6 halogen and wherein up to two non - adjacent CH2 units of said C , - C . alkyl may be replaced with O ; minmusan mirmed mi R ’ is halogen , CN , or C , - C6 alkyl wherein said C , - C6 alkyl 40 is substituted with 0 - 6 halogen and wherein up to two non - adjacent CH , units of said C - C . alkyl may be replaced with O ; R ? is halogen , CN , or — X — R ; X is a bond or C - C . alkyl wherein said C . - C . alkyl is IL 45 substituted with 0 - 6 halogen and wherein up to two non adjacent CH2 units of said C , -C6 alkyl may be replaced with , F 0 ; R * is absent, H , or Cz- Cg cycloaliphatic , wherein up to two non - adjacent CH , units of said Cz- C , cycloaliphatic may be 50 replaced with and said C3 - C , cycloaliphatic is sub stituted with 0 - 3 substituents selected from halogen and mu mi C , -C4 alkyl; R $ is halogen or C . - C . alkyl wherein said C . - C . alkyl is substituted with 0 -6 halogen and wherein up to two non 55 adjacent CH2 units of said C , - C alkyl may be replaced with 0 - ; p is an integer from 0 to 3 inclusive; and Rºis H , or C , -C alkylwherein up to two non -adjacent CH _ units of said C . - C . alkylmay be replaced with 0 % 60 In another embodiment , the invention features a com F pound of formula I - L or I' - L and the attendant definitions , wherein R² is halogen . In another embodiment, R² is C1. In or, a another embodiment, R² is F . In another embodiment, R² is CN . In another embodiment, R2 is C , -Co alkyl wherein said tot 65 C , -Co alkyl is substituted with 0 - 6 halogen . In another In another aspect , the invention provides a compound of embodiment , R2 is CFz. In another embodiment, R2 is C , -C6 foreningformula Ie - L ror en Iget' - L : the inven alkyl wherein said C . - C . alkyl is substituted with 0 - 6 US 10 ,087 , 143 B2 85 86 halogen wherein one CH , unit of said C . - C . alkyl is with 0 -6 halogen wherein one CH , unit of said C . - C . alkyl replaced with 50 % . In another embodiment, R2 is OCFz. is replaced with O — . In another embodiment, Rº is In another embodiment, R2 is F , C1, CN , CFz or OCF3. CH2CH2OH . monthkustaka In another embodiment, the invention features a com - . In another embodiment, the invention features a com pound of formula I - L or I' - L and the attendant definitions, pound of formula I- L or I' - L and the attendant definitions, wherein R * is halogen . In another embodiment, Rº is Cl. In wherein ring B is selected from : another embodiment , R? is F . In another embodiment, R3 is CN . In another embodiment , Rº is C1- C6 alkyl wherein said C . - C . alkyl is substituted with 0 - 6 halogen . In another 10 embodiment, R3 is t -butyl . In another embodiment, R3 is nim ni mi CF3. In another embodiment, R is CF2CF3. In another embodiment, the invention features a com 1 pound of formula I - L or I' - L and the attendant definitions, wherein R7 is halogen . In another embodiment, R7 is Cl. In 15 another embodiment, R ' is F . In another embodiment, R ' is CN . In another embodiment, R ' is — X R . In another F CI embodiment, R7 is — X — R * wherein R * is absent. In F another embodiment , R ' is - X - R * wherein R * is absent F and X is C . - C . alkyl wherein said C . - C . alkyl is substituted with 0 - 6 halogen . In another embodiment, RP is CHz, CH2CH3, CH2CH2CH3 or isopropyl . In another embodi ment, R7 is CFz. In another embodiment , R7 is - X - R * mm na wherein R * is absent and X is CZ -C6 alkyl wherein said 25 1 C . - C . alkyl is substituted with 0 - 6 halogen wherein two ncnon - adjacent CH , units of said C , -C6 alkyl are replaced with - 0 % . In another embodiment, R ? is OCH CH OCHz. In another embodiment, R ? is — X — R * wherein R * is absent and X is C , - C alkyl wherein said C . -C . alkyl is substituted 30 with 0 - 6 halogen wherein one CH , unit of said C . - C . alkyl is replaced with _ 0 . In another embodiment, R ? is OCHZ, OCH CH3, OCH CH CHz, OC (CH3 ) 3 , CH _CH OCHz. In another embodiment, R ? is OCF3 , OCH CF3 , OCH2CH2CH2CF3, or OCHF2. OCF39 35 F F In another embodiment , the invention features a com pound of formula I - L or I' - L and the attendant definitions , wherein R ’ is — X — R * wherein X is a bond and R * is C3 -C , cycloaliphatic and said Cz - Cg cycloaliphatic is substituted 20 with 0 - 3 substituents selected from halogen and C , -C4 alkyl. mi niin minn In another embodiment, R ' is — X — R * wherein X is a bond and R * is cyclopropyl . In another embodiment , the invention features a com pound of formula I - L or I' - L and the attendant definitions , 45 2 tete wherein R7 is - X - R * wherein X is C .- C . alkyl wherein said C , - C6 alkyl is substituted with 0 - 6 halogen wherein one CN CH , unit of said C . - C . alkyl is replaced with O — and R * is C3 - C , cycloaliphatic and said C3 - C , cycloaliphatic is substituted with 0 - 3 substituents selected from halogen and 30 C2- C4 alkyl. In another embodiment, R ? is - X - R * wherein X is OCH , and R * is cyclopropyl. In another embodiment , the invention features a com pound of formula I - L or I' - L and the attendant definitions, 65 wherein p is zero . In another embodiment, p is an integer from 1 to 3 and R is halogen . In another embodiment, p is an integer from 1 to 3 and Ris Cl. In another embodiment, mm mu p is an integer from 1 to 3 and R is C - C alkyl wherein said C . - C . alkyl is substituted with 0 -6 halogen wherein one CH , 60 unit of said C , - C alkyl is replaced with O — . In another to embodiment, p is an integer from 1 to 3 and R® is CHz. In another embodiment, the invention features a com pound of formula I - L or I' - L and the attendant definitions , F F wherein Rº is H . In another embodiment, Rºis C , -C6 alkyl. 65 In another embodiment, Rº is CHz. In another embodiment, Rºis C , -C7 alkyl wherein said C -C . alkyl is substituted US 10 ,087 , 143 B2 87 88 -continued replaced with and said C3 - C , cycloaliphatic is sub stituted with 0 - 3 substituents selected from halogen and mwa CZ- C4 alkyl; R® is H , halogen , or C , -Co alkyl wherein said C . - C . alkyl is 5 substituted with 0 -6 halogen and wherein up to two non adjacent CH2 units of said C , -C6 alkyl may be replaced with 0 ; p is an integer from 0 to 3 inclusive ; and Rºis H , or C , - C alkyl wherein up to two non -adjacent CH , Hhhh 10 units of said C . - C . alkyl may be replaced with O — . In another embodiment, the invention features a com > F F pound of formula I - M or I '- M and the attendant definitions , wherein Rl is halogen . In another embodiment , R ' is CN . In F or, another embodiment, Rl is C , - Ca alkyl wherein said C . - C . 15 alkyl is substituted with 0 -6 halogen . In another embodi In another aspect, the invention provides a compound of ment, R * is CF3 . Korea In another embodiment, the invention features a com formula I- M or I' - M : pound of formula I- M or I' - M and the attendant definitions, wherein Ris halogen . In another embodiment, R * is C1. In I- M 20 another embodiment, Rºis F. In another embodiment, R3 is CN . In another embodiment, R ’ is C , - C , alkyl wherein said RO C , -Co alkyl is substituted with 0 -6 halogen . In another embodiment, R3 is t -butyl . In another embodiment, R3 is CFz . In another embodiment, R3 is CF ,CFz . 25 In another embodiment , the invention features a com NH pound of formula I -M or I' - M and the attendant definitions, wherein R ' is halogen . In another embodiment, R ' is C1. In another embodiment, R ’ is F . In another embodiment, R is CN . In another embodiment, R ' is — X — R . In another 30 embodiment , R7 is - X - RX wherein R * is absent. In another embodiment, R7 is - X - R * wherein R * is absent and X is C . - C . alkyl wherein said C - C . alkyl is substituted with 0 -6 halogen . In another embodiment, R7 is CHz , CH2CH3, CH2CH2CHz or isopropyl. In another embodi T - M 35 ment, R ? is CFz. In another embodiment, R ? is - X - R * wherein R * is absent and X is C , - C6 alkyl wherein said C . - C alkyl is substituted with 0 - 6 halogen wherein two non - adjacent CH2 units of said C , - C . alkyl are replaced with FO R9 O — . In another embodiment, R is OCH ,CH ,OCHz . In 40 another embodiment, R is — X — R * wherein R * is absent and X is C , - C . alkyl wherein said C1- C6 alkyl is substituted R3 with 0 -6 halogen wherein one CH , unit of said C . -C . alkyl is replaced with O — . In another embodiment, R ? is OCHZ, OCH ,CH , OCH , CH ,CH , OC (CH3 ) 2 , 45 CH CH OCH?. In another embodiment, R7 is OCF3, OCH _ CF3, OCH CH2CH2CF3, or OCHF2. Gli In another embodiment, the invention features a com pound of formula 1- M or I' - M and the attendant definitions , wherein R7 is - X - R * wherein X is a bond and R * is C3- C , 50 cycloaliphatic and said Cz - Cg cycloaliphatic is substituted or a pharmaceutically acceptable salt thereof, with 0 - 3 substituents selected from halogen and C . -C4 alkyl . wherein , independently for each occurrence : In another embodiment, R7 is — X — R * wherein X is a bond R is halogen , CN , or C , -Co alkyl wherein said C1- C6 alkyl and RX is cyclopropyl. is substituted with 0 - 6 halogen and wherein up to two In another embodiment, the invention features a com non -adjacent CH , units of said C - C alkyl may be replaced 55 pound of formula I- M or I' - M and the attendant definitions, with _ 06 ; wherein R ' is - X - R * wherein X is C , - Co alkyl wherein R is halogen , CN , or C , - C . alkyl wherein said Cy - C6 alkyl said C . - C . alkyl is substituted with 0 -6 halogen wherein one is substituted with 0 - 6 halogen and wherein up to two CH , unit of said C , -C alkyl is replaced with O — and R * non - adjacent CH _ units of said C , -Co alkyl may be replaced is C3 -C , cycloaliphatic and said C3 - C , cycloaliphatic is witho ; 60 substituted with 0 - 3 substituents selected from halogen and R ? is halogen , CN , or - X R '; CZ -C4 alkyl. In another embodiment, R7 is - X - R * X is a bond or C , -C6 alkyl wherein said C -C . alkyl is wherein X is OCH , and R * is cyclopropyl. substituted with 0 -6 halogen and wherein up to two non In another embodiment, the invention features a com adjacent CH _ units of said C -Co alkyl may be replaced with pound of formula I- M or I' - M and the attendant definitions, — 0 — ; 65 wherein p is zero . In another embodiment , p is an integer R * is absent, H , or Cz- Cg cycloaliphatic , wherein up to two from 1 to 3 and R8 is halogen . In another embodiment, p is non -adjacent CH2 units of said C3- Cg cycloaliphatic may be an integer from 1 to 3 and R8 is C1. In another embodiment, US 10 , 087 , 143 B2 89 90 p is an integer from 1 to 3 and R® is C - C . alkylwherein said - continued C . - C . alkyl is substituted with 0 -6 halogen wherein one CH , unit of said C1- C6 alkyl is replaced with O — . In another un m embodiment, p is an integer from 1 to 3 and R8 is CHz. min In another embodiment, the invention features a com pound of formula I - M or I' - M and the attendant definitions , wherein Rº is H . In another embodiment, Rº is C - C . alkyl. to In another embodiment, Rº is CHz. In another embodiment, Rº is C , -Co alkyl wherein said C . - C . alkyl is substituted 10 FO F with 0 - 6 halogen wherein one CH2 unit of said C - C alkyl is replaced with O — . In another embodiment, Rº is CH2CH2OH . In another embodiment, the invention features a com pound of formula I -M or I' - M and the attendant definitions, 15 ma wherein ring B is selected from :

20

ni w mi F 25 thator, In another aspect , the invention provides a compound of formula I - N or I '- N : , 3030

I - NN NORS 005ni . # taitrote I ' - N F TF 77 ? N - RP

nim mwa ni ?

???? 60 or a pharmaceutically acceptable salt thereof , wherein , independently for each occurrence : R² is halogen , CN , or CZ - C . alkyl wherein said C . -C . alkyl is substituted with 0 -6 halogen and wherein up to two non - adjacent CH _ units of said C . - C . alkyl may be replaced with 0 % ; R $ is halogen , CN , or - X - R * ; US 10 ,087 , 143 B2 91 92 X is a bond or CZ- C6 alkyl wherein said C . -C . alkyl is substituted with 0 -6 halogen and wherein up to two non FF adjacent CH _ units of said C , - C6 alkyl may be replaced with m F - F in inn - 0 % ; R * is absent, H , or C3- C , cycloaliphatic , wherein up to two 5 non -adjacent CH2 units of said C3- C , cycloaliphatic may be replaced with O and said C3 - C , cycloaliphatic is sub stituted with 0 - 3 substituents selected from halogen and C1 -C4 alkyl ; R® is halogen , or C , -C6 alkyl wherein said C , -Co alkyl is substituted with 0 - 6 halogen and wherein up to two non adjacent CH2 units of said C , -C6 alkyl may be replaced with - 0 % ; p is an integer from 0 to 3 inclusive ; and Rºis H , or C . - C . alkyl wherein up to two non -adjacent CH2 15 units of said C . - C . alkyl may be replaced with In another embodiment , the invention features a com mm pound of formula I - N or I' - N and the attendant definitions , wherein R² is halogen . In another embodiment , R2 is Cl. In 20 another embodiment , R2 is F . In another embodiment, R2 is F CN . In another embodiment, R2 is C , - Co alkyl wherein said , or C . - C . alkyl is substituted with 0 - 6 halogen . In another embodiment, R2 is CFz. In another embodiment, R2 is C , - C . Youtros alkyl wherein said C . - C . alkyl is substituted with 0 - 6 255 . In another aspect , the invention provides a compound of halogen wherein one CH , unit of said C . -C . alkyl is - formula 1 - 0 or I' - O : replaced with O — . In another embodiment, R2 is OCF3. In another embodiment, R2 is F , C1, CN , CFz or OCF3. I - O In another embodiment, the invention features a com 10407 pound of formula I - N or I' - N and the attendant definitions, 30 wherein R is halogen . In another embodiment, R is Cl. In VRO another embodiment, RS is F. In another embodiment, R is CN . In another embodiment, R is — X - RX . In another embodiment, R ' is — X — R ' wherein R * is absent1 . In" 2535 another embodiment, Rºis — X R wherein R * is absent and X is C . - C . alkyl wherein said C . - C . alkyl is substituted with 0 - 6 halogen . In another embodiment, R is CH2. In RS another embodiment, RS is — X — R * wherein R * is absent and X is C1- C6 alkyl wherein said C1- C6 alkyl is substituted 40 with 0 - 6 halogen wherein one CH , unit of said C1- C6 alkyl I ' - O is replaced with O — . In another embodiment, R is OCH3, OCH CH3, OCH2CH2CH3, or OCH (CH3 ) 2 . In another embodiment, R is OCHz. In another embodiment, RS is CH , OH . In another embodiment, RS is OCFz. In 45 another embodiment, R is OCHF2 . N R ? In another embodiment, the invention features a com pound of formula I - N or I' - N and the attendant definitions , R3 wherein p is zero . In another embodiment, p is an integer from 1 to 3 and R8 is halogen . In another embodiment, p is 30 an integer from 1 to 3 andR is Cl. In another embodiment, p is an integer from 1 to 3 and R8 is C . - C . alkyl wherein said C - Coalkyl is substituted with 0 - 6 halogen wherein one CH , unit of said C , - C alkyl is replaced with O — . In another 55 or a pharmaceutically acceptable salt thereof, embodiment, p is an integer from 1 to 3 and R * is CHz. wherein , independently for each occurrence : In another embodiment, the invention features a com R is halogen , CN , or C , -C alkyl wherein said C . - C . alkyl pound of formula I - N or I' - N and the attendant definitions, is substituted with 0 - 6 halogen and wherein up to two wherein Rºis H . In another embodiment, Rºis C1 -C6 alkyl. non - adjacent CH , units of said C . - C . alkylmay be replaced In another embodiment, Rº is CHz. In another embodiment, 60 with 04 : Rº is C , - C . alkyl wherein said C . - C . alkyl is substituted R5 is halogen , CN , or — X — R¥; with 0 -6 halogen wherein one CH , unit of said C . -C . alkyl X is a bond or C . -C . alkyl wherein said C -C6 alkyl is is replaced with 0 . In another embodiment, Rº is substituted with 0 -6 halogen and wherein up to two non CH , CH OH . adjacent CH _ units of said C .- C . alkyl may be replaced with In another embodiment, the invention features a com - 65 - 0 — ; pound of formula I- N or I' - N and the attendant definitions, R * is absent, H , or C3- C , cycloaliphatic , wherein up to two wherein ring C is selected from : non - adjacent CH2 units of said Cz- Cg cycloaliphatic may be US 10 , 087 , 143 B2 93 94 replaced with and said C3 -C , cycloaliphatic is sub - continued stituted with 0 - 3 substituents selected from halogen and CZ -C4 alkyl; R® is halogen , or C . - C . alkyl wherein said C - C . alkyl is wa min substituted with 0 -6 halogen and wherein up to two non - 5 adjacent CH _ units of said C , - C6 alkyl may be replaced with - 0 % ; p is an integer from 0 to 3 inclusive ; and Rºis H , or C1- C6 alkyl wherein up to two non - adjacent CH2 units of said C . - C . alkyl may be replaced with 0 % In another embodiment, the invention features a com pound of formula 1 - 0 or I' - O and the attendant definitions , wherein R3 is halogen . In another embodiment, R ’ is Cl. In another embodiment, R3 is F . In another embodiment, R is 16 CN . In another embodiment, R is C ,- C . alkyl wherein said , orOr CZ - C6 alkyl is substituted with 0 - 6 halogen . In another embodiment, R3 is t -butyl . In another embodiment , R3 is In another aspect , the invention provides a compound of CF3. In another embodiment, R3 is CF CF3. formula I- P or I' - P : In another embodiment , the invention features a com - 20 amore per le line pound of formula 1 - O or I' - O and the attendant definitions, wherein Ris halogen . In another embodiment , Rºis C1. In I - P another embodiment, Ris F . In another embodiment, RS is 863 CN . In another embodiment, RS is — X — R " . In another embodiment, RS is — X — R * wherein R * is absent. In 25 another embodiment , RS is - X - R * wherein R * is absent and X is C1- C6 alkyl wherein said C - C . alkyl is substituted with 0 -6 halogen . In another embodiment, R is CHz. In R3 another embodiment, R $ is - X - R * wherein R * is absent and X is C -Co alkyl wherein said C - C alkyl is substituted 30 with 0 - 6 halogen wherein one CH , unit of said C1- C6 alkyl is replaced with O — . In another embodiment, R is OCH3, OCH CH3, OCH CH2CH3, or OCH (CH3 ) 2 . In another embodiment, R? is OCHz. In another embodiment, as I '- P R5 is CH ,OH . In another embodiment, RS is OCF3. In PA another embodiment, R is OCHF2. In another embodiment, the invention features a com pound of formula 1 - 0 or I' - O and the attendant definitions , R? wherein p is an integer from 1 to 3 and R is halogen . In 40 another embodiment, p is an integer from 1 to 3 and R8 is Cl. In another embodiment, p is an integer from 1 to 3 and R8 is C . - C . alkyl wherein said C . - C . alkyl is substituted with 0 -6 halogen wherein one CH2 unit of said C - C . alkyl is replaced with O — . In another embodiment, p is an integer 45 from 1 to 3 and Ris CH2. In another embodiment, the invention features a com pound of formula 1 - 0 or I' - O and the attendant definitions , or a pharmaceutically acceptable salt thereof, wherein Rº is H . In another embodiment, Rº is C , - C , alkyl. wherein , independently for each occurrence : In another embodiment, Rºis CH2. In another embodiment, 50 R2 is halogen , CN , or C . - C . alkyl wherein said C . - C . alkyl Rºis C , - C alkyl wherein said C , -Co alkyl is substituted is substituted with 0 -6 halogen and wherein up to two with 0 - 6 halogen wherein one CH , unit of said C -C6 alkyl non -adjacent CH2 units of said C , -Co alkyl may be replaced is replaced with O — . In another embodiment, Rº is with _ 06 ; CH CH , OH . R is halogen , CN , or C , - C , alkyl wherein said C . - C . alkyl In another embodiment, the invention features a com - 55 is substituted with 0 -6 halogen and wherein up to two pound of formula 1 - 0 or I' - O and the attendant definitions, non - adjacent CH , units of said C . - C , alkyl may be replaced wherein ring C is selected from : with 0 % ; R $ is halogen , CN , or - X - R * ; X is a bond or C1- C6 alkyl wherein said C -C6 alkyl is T] 60 substituted with 0 -6 halogen and wherein up to two non adjacent CH _ units of said C .- C . alkyl may be replaced with im F M min 0 ; R * is absent, H , or C3 -C4 cycloaliphatic , wherein up to two non -adjacent CH2 units of said C3- C , cycloaliphatic may be 65 replaced with O and said C3 -C , cycloaliphatic is sub stituted with 0 - 3 substituents selected from halogen and CZ -C4 alkyl ; US 10 , 087 , 143 B2 95 96 R® is H , halogen , or C , -C6 alkyl wherein said C . - C . alkyl is substituted with 0 -6 halogen , wherein up to two non -adja FF cent CH2 units of said C -C6 alkyl may be replaced with - F in inn - 0 % ; p is an integer from 0 to 3 inclusive ; and R9 is H , or C , -C6 alkyl wherein up to two non -adjacent CH _ units of said C , - C . alkyl may be replaced with0 In another embodiment , the invention features a com pound of formula I - P or I' - P and the attendant definitions, 10 wherein R2 is halogen . In another embodiment, R2 is Cl. In vi another embodiment, R2 is F . In another embodiment, R2 is CN . In another embodiment, R2 is C , - C , alkyl wherein said C , - C alkyl is substituted with 0 - 6 halogen . In another embodiment, R² is CF3. In another embodiment ,R² is C , -Co 15 alkyl wherein said C . - C . alkyl is substituted with 0 - 6 halogen wherein one CH , unit of said C - C alkyl is w replaced with 40 % . In another embodiment, R² is OCFz. In another embodiment, R2 is F , C1, CN , CFz or OCF3 . 20 In another embodiment , the invention features a com FF pound of formula I -P or I' - P and the attendant definitions, , or wherein R3 is halogen . In another embodiment, Rº is Cl. In another embodiment , R? is F . In another embodiment, R3 is CN . In another embodiment, R3 is C .- C . alkyl wherein said 25 In another aspect, the invention provides a compound of C -Co alkyl is substituted with 0 - 6 halogen . In another formula I- Q or I' - Q : embodiment, R3 is t -butyl . In another embodiment, R3 is CF3. In another embodiment, Rº is CF2CF3. I1- Q In another embodiment, the invention features a com - 30 (R8 pound of formula I - P or I' - P and the attendant definitions, wherein Ris halogen . In another embodiment, RS is Cl. In VRO another embodiment, RS is F . In another embodiment, RS is CN . In another embodiment, Rºis — X - RX. In another Fotore39 N embodiment, R is — X — R $ wherein R * is absent. In 35 another embodiment , R5 is — X — R * wherein R * is absent and X is C1- C6 alkyl wherein said C1- C6 alkyl is substituted with 0 - 6 halogen . In another embodiment, R is CH2. In another embodiment, Ris — X - R wherein R * is absent and X is C , -Co alkyl wherein said C . - C . alkyl is substituted 40 with 0 - 6 halogen wherein one CH , unit of said C1- C6 alkyl G is replaced with O — . In another embodiment, R is OCHZ, OCH CH3 , OCH CH2CH3, or OCH ( CH3) 2 . In I' - Q another embodiment, R is OCHz. In another embodiment, RS is CH , OH . In another embodiment, RS is OCFz. In 45 another embodiment, R is OCHF2. =O In another embodiment , the invention features a com P9 pound of formula I - P or I' - P and the attendant definitions , EZ wherein p is zero . In another embodiment, p is an integer from 1 to 3 and R8 is halogen . In another embodiment, p is 3 an integer from 1 to 3 and Ris Cl. In another embodiment, p is an integer from 1 to 3 and R8 is C . - C . alkyl wherein said C -Coalkyl is substituted with 0 -6 halogen wherein one CH , unit of said C , -C6 alkyl is replaced with O — . In another PO embodiment, p is an integer from 1 to 3 and R8 is CHZ. - In another embodiment , the invention features a com 7 pound of formula I - P or I' - P and the attendant definitions , wherein Rº is H . In another embodiment, Rº is C , - Co alkyl. In another embodiment, Rºis CH , . In another embodiment, or a pharmaceutically acceptable salt thereof, Rºis C , -C6 alkyl wherein said C , -C6 alkyl is substituted wherein , independently for each occurrence: with 0 - 6 halogen wherein one CH , unit of said C . - C . alkyl R² is halogen , CN , or C , -Co alkylwherein said C . - C . alkyl is replaced with0 In another embodiment, Rº is is substituted with 0 -6 halogen and wherein up to two CH2CH2OH . non - adjacent CH , units of said C . - C . alkyl may be replaced In another embodiment, the invention features a com - 65 with O ; pound of formula I- P or I' - P and the attendant definitions , Ris halogen , CN , or — X — R *; wherein ring C is selected from : R ? is halogen , CN , or X - R * ; US 10 , 087 , 143 B2 97 98 X is a bond or C , - C6 alkyl wherein said C . - C . alkyl is with 0 - 3 substituents selected from halogen and C . -C4 alkyl . substituted with 0 - 6 halogen and wherein up to two non In another embodiment, R ' is - X - R * wherein X is a bond adjacent CH2 units of said C . - C . alkyl may be replaced with and R * is cyclopropyl. 0 ; R * is absent, H , or Cz - Cg cycloaliphatic , wherein up to two 5 In another embodiment, the invention features a com non - adjacent CH2 units of said C3 -C , cycloaliphatic may be pound of formula 1 -Q or I' - Q and the attendant definitions , replaced with O and said C3- C , cycloaliphatic is sub wherein R is - X R * wherein X is C , - C , alkyl wherein stituted with 0 - 3 substituents selected from halogen and said C . - C . alkyl is substituted with 0 - 6 halogen wherein one C1 -C4 alkyl; CH , unit of said C1- C6 alkyl is replaced with O — and R * R® is H , halogen , or C , - C , alkyl wherein said C . - C . alkyl is 10 is C3- Cg cycloaliphatic and said C3 - Cg cycloaliphatic is substituted with 0 -6 halogen and wherein up to two non substituted with 0 - 3 substituents selected from halogen and adjacent CH , units of said C . -C . alkyl may be replaced with C , -C4 alkyl. In another embodiment, R ' is — X — R - O ; wherein X is OCH , and R * is cyclopropyl . p is an integer from 0 to 3 inclusive ; and In another embodiment , the invention features a com R is H , or C . - C . alkyl wherein up to two non -adjacent CH2 15 pound of formula I -Q or I' - Q and the attendant definitions , units of said C . - C . alkyl may be replaced with O — . In another embodiment, the invention features a com wherein p is zero . In another embodiment, p is an integer pound of formula I - Q or I' - Q and the attendant definitions , from 1 to 3 and R is halogen . In another embodiment, p is wherein R2 is halogen . In another embodiment, R2 is Cl. In an integer from 1 to 3 and R8 is Cl. In another embodiment , another embodiment, R2 is F. In another embodiment, R2 is 20 p is an integer from 1 to 3 and R8 is C , -C6 alkyl wherein said CN . In another embodiment, R2 is C ,- Cd alkyl wherein said C .- C . alkyl is substituted with 0 -6 halogen wherein one CH , C . - C . alkyl is substituted with 0 -6 halogen . In another unit of said C -C6 alkyl is replaced with O — . In another embodiment, R² is CFz. In another embodiment, R2 is C , -Co embodimentem , p is an integer from 1 to 3 and R® is CHz . alkyl wherein said C -C6 alkyl is substituted with 0 -6 In another embodiment, the invention features a com halogen wherein one CH , unit of said C . - C . alkyl is 25 pound of formula 1 - Q or I' - Q and the attendant definitions, replaced with 0 . In another embodiment , R2 is OCFz. wherein Rº is H . In another embodiment, Rº is C . - C . alkyl. In another embodiment, R² is F , C1, CN , CFz or OCF3. In another embodiment, Rº is CH3. In another embodiment, In another embodiment, the invention features a com - Rº is C . - C . alkyl wherein said C . - C . alkyl is substituted pound of formula 1 - Q or I' - Q and the attendant definitions, with 0 - 6 halogen wherein one CH , unit of said C . - C . alkyl wherein Rº is halogen . In another embodiment, Rºis Cl. In 30 is replaced with O . In another embodiment. Rº is another embodiment , R is F . In another embodiment, R is CN . In another embodiment, R is — X — R . In another CH2CH2OH . embodiment, Róis - X - R * wherein R * is absent . In In another embodiment, the invention features a com another embodiment , Ris - X - R * wherein R * is absent pound of formula I -Q or I' - Q and the attendant definitions , and X is C . - C . alkyl wherein said C . - C . alkyl is substituted 35 wherein ring D is selected from : with 0 - 6 halogen . In another embodiment , R? is CH3. In another embodiment, Róis - X - R * wherein R * is absent and X is C1- C alkyl wherein said C -C6 alkyl is substituted with 0 - 6 halogen wherein one CH , unit of said C . - C . alkyl mi , or min. is replaced with - 0 % In another embodiment, R is 40 OCHZ. In another embodiment, the invention features a com pound of formula I - Q or I' - Q and the attendant definitions , wherein R ' is halogen . In another embodiment, Ris Cl. In F another embodiment, R ' is F . In another embodiment, R7 is 45 CN . In another embodiment, R ' is — X — R * . In another embodiment, R7 is — X — R wherein R * is absent. In $ $ another embodiment , R ' is - X - R * wherein R * is absent and X is C , - C , alkyl wherein said C , - C alkyl is substituted In another aspect, the invention provides a compound of with 0 - 6 halogen . In another embodiment , R ? is CH3, 50 Torformula I- R or I' - R : CH2CH3, CH2CH2CHz or isopropyl . In another embodi ment, R ' is CFz . In another embodiment, R ' is — X — R * wherein R * is absent and X is C . - C . alkyl wherein said I - R CZ -C6 alkyl is substituted with 0 - 6 halogen wherein two V- RO non -adjacent CH _ units of said C , -C . alkyl are replaced with 55 - 0 . In another embodiment, R ' is OCH _ CH _ OCHz. In another embodiment , R ' is - X - R * wherein R * is absent and X is C1 - C . alkylwherein said C . - C . alkyl is substituted N with 0 - 6 halogen wherein one CH , unit of said C1- C6 alkyl is replaced with O — . In another embodiment, R ' is 60 R3 OCHZ, OCH CHz, OCH CH CH3, OC ( CH3) 3 , CH _CH _ OCHz. In another embodiment, R ? is OCF3, OCH CF3, OCH CH2CH2CF3 , or OCHF2. In another embodiment, the invention features a com pound of formula I - Q or I' - Q and the attendant definitions , 65 wherein R ’ is - X - R * wherein X is a bond and R * is C3- C , cycloaliphatic and said C3- C , cycloaliphatic is substituted US 10 , 087 , 143 B2 99 100 - continued CN . In another embodiment, R7 is - X - R * . In another I ' - R embodiment, R ? is — X — R * wherein R * is absent. In (Rº ) , another embodiment, R7 is - X - R * wherein R * is absent and X is C , -C , alkyl wherein said C , -C . alkyl is substituted 5 with 0 - 6 halogen . In another embodiment, R7 is CH3, CH2CH3, CH2CH2CHz or isopropyl . In another embodi N NRE ment, R7 is CF2 . In another embodiment, R7 is — X — R * wherein R * is absent and X is C , -C6 alkyl wherein said R3 C . - C . alkyl is substituted with 0 -6 halogen wherein two 10 non -adjacent CH _ units of said C , -C . alkylare replaced with 0 . In another embodiment, R ' is OCH _ CH _ OCHZ. In

D another embodiment, R ? is — X — R * wherein R * is absent and X is C , -C6 alkyl wherein said C , -Co alkyl is substituted with 0 -6 halogen wherein one CH , unit of said C .- C . alkyl G 15 is replaced with 0 - . In another embodiment, R ? is OCHz, OCH CHz, OCH CH CHz, OC (CH3 ) 3 , CH2CH2OCHz. In another embodiment, R is OCF3, or a pharmaceutically acceptable salt thereof, OCH CF3, OCH CH2CH2CF3, or OCHFZ. wherein , independently for each occurrence : In another embodiment, the invention features a com R3 is halogen , CN , or C1- C6 alkyl wherein said C1- C6 alkyl 20 pound of formula I - R or I' - R and the attendant definitions, is substituted with 0 - 6 halogen and wherein up to two wherein R7is — X — R * wherein X is a bond and R * is C3- C , non - adjacent CH2 units of said C . - C . alkylmay be replaced cycloaliphatic and said C3 - C , cycloaliphatic is substituted with 0 % ; with 0 - 3 substituents selected from halogen and C . - C4 alkyl. Róis halogen , CN , or — X — R " ; In another embodiment, R ' is - X - R wherein X is a bond R ? is halogen , CN , or — X — R * ; 25 and R * is cyclopropyl. X is a bond or C . - C . alkyl wherein said C . - C6 alkyl is In another embodiment, the invention features a com substituted with 0 - 6 halogen and wherein up to two non - pound of formula I - R or I' - R and the attendant definitions, adjacent CH _ units of said C - C , alkyl may be replaced with wherein R7 is — X — R * wherein X is C , -C6 alkyl wherein - 0 % ; said C . - C . alkyl is substituted with 0 - 6 halogen wherein one R * is absent, H , or Cz - Cg cycloaliphatic , wherein up to two 30 CH , unit of said C . - C . alkyl is replaced with O and R * non - adjacent CH , units of said C3- C , cycloaliphatic may be is Cz- Cg cycloaliphatic and said Cz- Cg cycloaliphatic is replaced with O and said Cz- C , cycloaliphatic is sub - substituted with 0 - 3 substituents selected from halogen and stituted with 0 - 3 substituents selected from halogen and C . - C4 alkyl. In another embodiment, R7 is - X - R * C1 -C4 alkyl ; wherein X is OCH and R * is cyclopropyl. R® is H , halogen , or C . - C . alkyl wherein said C . - C . alkyl is 35 In another embodiment, the invention features a com substituted with 0 - 6 halogen and wherein up to two non - pound of formula I - R or I ' - R and the attendant definitions , adjacent CH2 units of said C . - C . alkyl may be replaced with wherein p is zero . In another embodiment , p is an integer - 0 % ; from 1 to 3 and Ris halogen . In another embodiment, p is p is an integer from 0 to 3 inclusive; and an integer from 1 to 3 and R8 is C1. In another embodiment, Rºis H , or CZ -C6 alkyl wherein up to two non - adjacent CH , 40 p is an integer from 1 to 3 and R8 is C . - C . alkyl wherein said units of said C - Co alkyl may be replaced with 404 C , - Coalkyl is substituted with 0 - 6 halogen wherein one CH2 In another embodiment , the invention features a com - unit of said C . - C . alkyl is replaced with 0 - . In another pound of formula I -R or I' - R and the attendant definitions, embodiment, p is an integer from 1 to 3 and R8 is CHz. wherein R * is halogen . In another embodiment , Rºis Cl. In In another embodiment, the invention features a com another embodiment ,Ris F . In another embodiment , Rºis 45 pound of formula I - R or I' - R and the attendant definitions , CN . In another embodiment, Rºis C -Co alkyl wherein said wherein Rºis H . In another embodiment , Rºis C , - C , alkyl. C . - C . alkyl is substituted with 0 - 6 halogen . In another In another embodiment, Rº is CHz. In another embodiment, embodiment, R * is t- butyl . In another embodiment, R * is Rºis C , -C , alkyl wherein said C . - C . alkyl is substituted CFz. In another embodiment, R3 is CF , CF2. with 0 -6 halogen wherein one CH , unit of said C . - C . alkyl In another embodiment, the invention features a com - 50 is replaced with — — In another embodiment, Rº is pound of formula I - R or I ' - R and the attendant definitions , CH , CH , OH . wherein Róis halogen . In another embodiment, Ris Cl. In In another embodiment, the invention features a com another embodiment, R is F . In another embodiment , Róis pound of formula I - R or I' - R and the attendant definitions, CN . In another embodiment, R is — X — R * . In another wherein ring D is selected from : embodiment, R™ is — X - R * wherein R * is absent. In 55 another embodiment , Róis - X - R * wherein R * is absent and X is C . - C . alkyl wherein said C . - C . alkyl is substituted with 0 -6 halogen . In another embodiment, Rº is CHz. In mm , or m . another embodiment, R? is — X — R * wherein R * is absent and X is C . - C . alkyl wherein said C . - C . alkyl is substituted 60 with 0 -6 halogen wherein one CH , unit of said C . -C . alkyl is replaced with 0 % . In another embodiment, Rº is OCHZ. In another embodiment, the invention features a com pound of formula I- R or I' - R and the attendant definitions , 65 F wherein R7 is halogen . In another embodiment , R ' is Cl. In another embodiment, R ' is F . In another embodiment, R7 is US 10 , 087 , 143 B2 101 102 In another aspect , the invention provides a compound of CN . In another embodiment , R² is C . - C . alkyl wherein said formula I - S or I' - S : C . - C , alkyl is substituted with 0 -6 halogen . In another embodiment, R² is CFz. In another embodiment, R2 is C , -Co alkyl wherein said C . - Co alkyl is substituted with 0 -6 I - S 5 halogen wherein one CH , unit of said C . - C . alkyl is replaced with O — . In another embodiment, R2 is OCFz. In another embodiment, R2 is F , C1, CN , CF , or OCF3. VRO In another embodiment, the invention features a com pound of formula I - S or I' - S and the attendant definitions, 10 wherein R * is halogen . In another embodiment, R * is Cl. In another embodiment, R * is F . In another embodiment, R3 is R3 CN . In another embodiment, R3 is C - Co alkyl wherein said CZ- C6 alkyl is substituted with 0 - 6 halogen . In another G embodiment, R3 is t -butyl . In another embodiment, R * is A 15 CFz. In another embodiment, Ris CF , CFz. In another embodiment, the invention features a com R6 pound of formula I - S or I' - S and the attendant definitions , agent wherein R™ is halogen . In another embodiment, Róis Cl. In I ' - S another embodiment, Rºis F . In another embodiment, Ris (R : 20 CN . In another embodiment, R is — X — R . In another embodiment, Róis — X — R * wherein R * is absent. In

O another embodiment , Rºis — X - R * wherein R * is absent and X is CZ -C6 alkyl wherein said C . - C . alkyl is substituted E with 0 - 6 halogen . In another embodiment, Rºis CH2. In NH 25 another embodiment, R is — X — R * wherein R * is absent and X is C , -C6 alkyl wherein said C . - C . alkyl is substituted R3 with 0 -6 halogen wherein one CH , unit of said C . - C . alkyl is replaced with 0 - . In another embodiment, Róis OCHZ. A 30 In another embodiment, the invention features a com RO pound of formula I - S or I' - S and the attendant definitions, wherein R7 is halogen . In another embodiment, R7 is C1. In 2 another embodiment , R7 is F . In another embodiment, R7 is CN . In another embodiment, R ' is X - R * . In another or a pharmaceutically acceptable salt thereof, 35 embodiment, R7 is — X - R wherein R is absent. In another embodiment, R ’ is — X — R * wherein R * is absent wherein , independently for each occurrence : and X is C1- C6 alkyl wherein said C , -C6 alkyl is substituted R2 is halogen , CN , or C ,- C alkyl wherein said C . -C . alkyl with 0 -6 halogen . In another embodiment, R ? is CH3, is substituted with 0 - 6 halogen and wherein up to two CH2CH3, CH2CH2CHz or isopropyl. In another embodi non -adjacent CH _ units of said C . - C . alkyl may be replaced“ 40 ment, R7 is CF3. In another embodiment, R7 is - X R * with 0 % ; wherein R * is absent and X is CZ - C6 alkyl wherein said Rºis halogen , CN , or C , - C6 alkyl wherein said C , - C . alkyl C . - C , alkyl is substituted with 0 - 6 halogen wherein two is substituted with 0 - 6 halogen and wherein up to two non - adjacent CH2 units of said C , - C . alkyl are replaced with non - adjacent CH2 units of said C , -C alkyl may be replaced - 0 . In another embodiment, R ' is OCH CH OCHz. In with _ 0 — ; 45 another embodiment , R ' is - X RX wherein R * is absent R™ is halogen , CN , or X - R ' ; and X is C , - C . alkyl wherein said C1- C6 alkyl is substituted R7 is halogen , CN , or — X — R * ; with 0 -6 halogen wherein one CH , unit of said C , - C , alkyl X is a bond or C - C , alkyl wherein said C -Co alkyl is is replaced with0 In another embodiment, R ? is substituted with 0 -6 halogen and wherein up to two non - OCHZ, OCH CH3, OCH CH CH3, OC (CH3 ) 3 , adjacent CH _ units of said C , -Co alkyl may be replaced with 50 CH CH OCHz. In another embodiment, R ? is OCF3, OCH _ CF3, OCH CH2CH2CF3 , or OCHF2. R * is absent, H , or C3 - Cg cycloaliphatic , wherein up to two In another embodiment, the invention features a com non - adjacent CH2 units of said C3 - Cg cycloaliphatic may be pound of formula I -S or I' - S and the attendant definitions , replaced with — o and said Cz- Cg cycloaliphatic is sub wherein R ' is — X — R * wherein X is a bond and R * is Cz - C , stituted with 0 -3 substituents selected from halogen and 55 cycloaliphatic and said C3 -C , cycloaliphatic is substituted C -C4 alkyl; with 0 - 3 substituents selected from halogen and C . - C4 alkyl. R® is halogen , or CZ -C6 alkyl wherein said C .- Cô alkyl is In another embodiment,Ris - X - R wherein X is a bond substituted with 0 -6 halogen and wherein up to two non and R * is cyclopropyl. adjacent CH , units of said C -Co alkyl may be replaced with In another embodiment, the invention features a com - 0 % ; 60 pound of formula I - S or I' - S and the attendant definitions , p is an integer from 0 to 3 inclusive; and wherein R ? is — X — R * wherein X is C , -Co alkyl wherein Rºis H , or C . - C . alkyl wherein up to two non - adjacent CH , said C . - C . alkyl is substituted with 0 - 6 halogen wherein one units of said C .- C . alkyl may be replaced with O — . CH , unit of said C , - C alkyl is replaced with O — and R * In another embodiment , the invention features a com - is C3- Cg cycloaliphatic and said C3- Cg cycloaliphatic is pound of formula I - S or I' - S and the attendant definitions, 65 substituted with 0 - 3 substituents selected from halogen and wherein R2 is halogen . In another embodiment, R2 is Cl. In C . - C4 alkyl. In another embodiment, R7 is - X - R * another embodiment , R2 is F . In another embodiment, R2 is wherein X is OCH , and R * is cyclopropyl. US 10 ,087 , 143 B2 103 104 In another embodiment, the invention features a com TABLE 1 - continued pound of formula I - S or I' - S and the attendant definitions , wherein p is zero . In another embodiment , p is an integer from 1 to 3 and R8 is halogen . In another embodiment, p is Compound Numbers , Structures and Chemical Names an integer from 1 to 3 and R8 is Cl. In another embodiment, 5 p is an integer from 1 to 3 and R8 is C . - C . alkyl wherein said C . - C . alkyl is substituted with 0 - 6 halogen wherein one CH , unit of said C , - Cd alkyl is replaced with 0 - . In another N embodiment, p is an integer from 1 to 3 and R is CHz. In another embodiment , the invention features a com 10 pound of formula I - S or I' - S and the attendant definitions, wherein Rº is H . In another embodiment, Rº is C , - C alkyl. In another embodiment, Rº is CHz. In another embodiment, HN . R® is C . - C6 alkyl wherein said C . - C6 alkyl is substituted 15 with 0 - 6 halogen wherein one CH2 unit of said C . - C . alkyl is replaced with O — . In another embodiment, Rº is CH2CH2OH . In another embodiment, the invention features a com CF3 pound of formula I -S or I' - S and the attendant definitions, 2 - ( 4- fluorophenoxy ) - N - ( 2 -oxo wherein ring D is selected from : 1 , 2 -dihydropyridin - 4 -yl ) - 5 ( trifluoromethyl )benzamide

25 3

n ino m , or me 30 VH

F 35 HNO

In another embodiment , the invention features a com pound of formula I or I' , wherein the compound or a pharmaceutically acceptable salt thereof, is selected from 40 Table 1 . Compounds names in Table 1 were generated using 2 - ( 4 - fluorophenoxy )- N - ( 6 - oxo ChemBioDrawUltra version 12 .0 from Cambridge Soft / 1 ,6 - dihydropyridin - 3 Chem Office 2010 . yl) benzamide 45 TABLE 1 4 . Compound Numbers , Structures and Chemical Names

NH

HN . HN

CF3 2 - ( 4 - fluorophenoxy ) - N - ( 2 - oxo 2 - ( 4 - fluorophenoxy )- N - ( 6 -oxo 1 ,2 -dihydropyridin -4 1 ,6 - dihydropyridin - 3 -yl ) - 5 yl) benzamide ( trifluoromethyl )benzamide US 10 ,087 , 143 B2 105 106 TABLE 1 - continued TABLE 1 - continued Compound Numbers , Structures and Chemical Names Compound Numbers , Structures and Chemical Names

HN HN

F Meo

CF3 CF3 2 - ( 4 - fluorophenoxy ) - N - ( 2 - oxo 2 - ( 4- ( 2 -methoxyethoxy )phenoxy ) 1 , 2 -dihydropyridin - 4 -yl ) - 4 N - (2 -oxo - 1, 2 -dihydropyridin - 4 (trifluoromethyl ) benzamide yl) - 4 - ( trifluoromethyl )benzamide .a 25 9

NH

HN .

CF3 CF3 2 - ( 4- fluorophenoxy ) - N - ( 6 -oxo N - ( 2 - oxo - 1 , 2 -dihydropyridin - 4 1 ,6 - dihydropyridin - 3 -yl ) - 4 yl ) - 2 - phenoxy - 4 (trifluoromethyl ) benzamide ( trifluoromethyl )benzamide 7 10

HN .

F FF Me CF3 CF3 2 - (2 ,4 -difluorophenoxy ) - N -( 2 2- ( 4 - fluoro -2 -methylphenoxy ) - N oxo - 1, 2 - dihydropyridin - 4 - yl )- 4 ( 2 -oxo - 1 , 2 - dihydropyridin - 4 - yl) - 4 (trifluoromethyl ) benzamide ( trifluoromethyl) benzamide US 10 , 087 , 143 B2 . 107 108 TABLE1- continued TABLE1- continued Compound Numbers , Structures and Chemical Names Compound Numbers , Structures and Chemical Names 5 14

HN. HN,

Me CF3 N -( 2 - 0x0 - 1 , 2 - dihydropyridinu - 4 4 - chlof0 - 2 -( 2 - chloro - 4 yl } - 2 -fo - tolyloxy) - 4 Huorophenoxy) - N -( 2 - Oxo - 1 , 2 ( trifluoromethyl) benzamide dihydropyridin - 4 - yl) bellzamide

12 ? 1515

HN 20 HNHN

Me CF3 N - ( 2 - 0x0 - 1 , 2 - dihydrojpyridinu - 4 4 - chloro - 2 -( 4 - duorophenoxy) - N _ yl )- 2 -( p -tolyloxy ) - 4 ( 2 - 0x0- 1 ,2 - dihydropyridin - 4 (trifluoromethyl )benzamide yl) benzamide

13 ? 16

HN. HN. OMe 20

4 - chloro - 2 - ( 2 , 4 - dinnoroplenoxy ) 4 - chloro - 2 - 4 - duoro- 2 N -( 2 - 0x0- 1 , 2 - dihydropyridin - 4 methoxyphenoxy )- N -( 2 - Oxo -1 ,2 yl) benzamide dihydropyridin - 4- yl) belZamide US 10, 087 ,143 B2 109 110 TABLE1- conitinnued TABILE1 - continued Compound Numbers, Structures and Chemical Names Compound Numbers , Structures and Chemical Names

j

_s HN H . Me _c

Me

Cl 4 -chloro - 2 - 4 - duoro - 2 methylphen0xy )- N -( 2 - 0XO - 1 , 2 4 - chloro- 2 -( 2 - duoro - 6 methylphenoxy) - N - ( 2 -Oxo - 1 -2 dihydropyridin - 4 - yl) benzamide dihydropyridinl - 4 -yl ) benlZamlide 25 _2v 18 l

HN

_

4 - Cyano - 2 -( 4 - HuorOphenloxy) - N 4 - chloro - 2 - ( 2 - chloro - 6 _ Huorrophenoxy) - N -( 2 - 0x0 - 1 , 2 ( 2- 0x0- 1 , 2 - dihydropyridin - 4 dihydropyridin - 4 - yl) benzamide yl) benzamide _22

_ HR0 HN. F

4 - chloro - 2 - ( 2 , 6 - diduorophenoxy) 4 - cyan0 - 2 - ( 4 - Huoro - 2 N -( 2 - 0x0- 1 , 2 - dihydropyridin - 4 methoxypheloxy ) - N - ( 2 - 0x0- 1 , 2 yl } benzanmlide dihydropyridin - 4 - yl ) benzamide US 10 , 087 , 143 B2 111 112. TABLE 1 - continued TABLE 1 -continued Compound Numbers , Structures and Chemical Names Compound Numbers, Structures and Chemical Names

26

HN HN . Me

SCF3 2 - ( 2 , 6 - difluorophenoxy ) - N - ( 2 OX0 - 1 , 2 - dihydropyridin - 4 - yl) - 5 ( trifluoromethyl) benzamide | 4 - cyano- 2 - ( 4 - fluoro- 2 methylphenoxy )- N - ( 2 - 0x0 -1 , 2 dihydropyridin - 4 - yl ) benzamide | 25 27

24

HN.

HN .

Me N - ( 2 - 0X0 - 1 , 2 -dihydropyridin - 4 | yl) - 2 - ( p -tolyloxy ) - 5 CF3 (trifluoromethyl )benzamide 2 - ( 2 , 4 - difluorophenoxy ) - N - ( 2 oxo - 1 , 2 - dihydropyridin - 4 - yl ) - 5 (trifluoromethyl ) benzamide 45 28

25

HN HN .

NC Me 2 - ( 4 -cyanophenoxy ) - N - ( 2 - 0XO N - ( 2 - 0x0 - 1 , 2 - dihydropyridin - 4 1 , 2 -dihydropyridin - 4 - yl ) - 5 | yl ) - 2 - ( o - tolyloxy ) - 5 (trifluoromethyl )benzamide (trifluoromethyl )benzamide US 10 ,087 , 143 B2 113 114 TABLE 1- continued TABLE 1 - continued Compound Numbers , Structures and Chemical Names Compound Numbers , Structures and Chemical Names

29

10

HN . HN .

CFz 20 CF3 2 - ( 2 - chloro - 4 - fluorophenoxy ) - N N - ( 2 -oxo - 1 , 2 -dihydropyridin - 4 ( 2 -oxo - 1 ,2 -dihydropyridin - 4 -yl ) - 5 yl) - 2 - phenoxy -5 (trifluoromethyl ) benzamide ( trifluoromethyl) benzamide 25 30 33

30

HN 35 HN .

40 OMe CFz F OCF3 2 - ( 4 - fluoro - 2 -methoxyphenoxy ) 2- ( 2 , 4 - difluorophenoxy )- N -( 2 N - ( 2 - oxo - 1 , 2 - dihydropyridin - 4 oxo - 1 , 2 - dihydropyridin - 4 - yl) - 5 yl )- 5 - (trifluoromethyl )benzamide ( trifluoromethoxy ) benzamide 45 31 3434

50

HN 55 HN

60 F Me CF3 OCF3 2 - ( 4 - fluoro - 2 -methylphenoxy ) - N 2- ( 2 , 6 - difluorophenoxy )- N -( 2 ( 2 -oxo - 1 ,2 -dihydropyridin - 4 -yl ) - 5 oxo - 1 ,2 -dihydropyridin - 4 -yl ) - 5 ( trifluoromethyl )benzamide (trifluoromethoxy )benzamide 65 US 10 ,087 , 143 B2 115 116 TABLE 1- continued TABLE 1 - continued Compound Numbers , Structures and Chemical Names Compound Numbers , Structures and Chemical Names

38

10

HN . HN .

20 Me OCF3 OCF3 N - ( 2 -oxo - 1 , 2 -dihydropyridin - 4 2 - ( 4 - fluorophenoxy ) - N - (2 -oxo yl) - 2 - (p - tolyloxy ) - 5 1 , 2 -dihydropyridin - 4 - yl) - 5 (trifluoromethoxy ) benzamide ( trifluoromethoxy )benzamide 25 36 39

30 N

HN . 35 HN . F

40 Me v OCF3OCFz Me OCFz N - ( 2 -oxo - 1 , 2 -dihydropyridin - 4 2 - ( 2- fluoro -6 -methylphenoxy )- N yl) - 2 - ( o - tolyloxy ) - 5 ( 2 - oxo - 1 , 2 - dihydropyridin - 4 - yl) - 5 ( trifluoromethoxy )benzamide (trifluoromethoxy )benzamide 45 37 40

50

55 HN

60 OCF3 Me OCF3 2 - ( 2 - chloro - 4 - fluorophenoxy) - N 2- ( 4 - fluoro -2 -methylphenoxy )- N ( 2 -oxo - 1 ,2 -dihydropyridin - 4 -yl ) - 5 ( 2 -oxo - 1 , 2 - dihydropyridin -4 -yl )- 5 ( trifluoromethoxy )benzamide (trifluoromethoxy ) benzamide 65 US 10 ,087 , 143 B2 | 117 118 | TABLE 1- continued | TABLE 1- continued Compound Numbers , Structures and Chemical Names Compound Numbers , Structures and Chemical Names

-

HN .

SOCF3 N - ( 2 - 0x0 - 1 , 2 - dihydropyridin- 4 2 - (4 - ethoxyphenoxy ) - N - ( 2 - 080 | yl ) - 2 -phenoxy - 5 | 1 , 2 - dihydropyridin - 4 - yl ) - 5 ( trifluoromethoxy )benzamide (trifluoromethyl ) benzamide 3 42. 14545

HN . HN .

F OMe OMe OCF Me | 2 - ( 4 - fluoro- 2 - methoxyphenoxy ) N - ( 2 - 0x0 - 1 , 2 -dihydropyridin - 4 2 - ( 4 - methoxyphenoxy ) - N - ( 2 - 0x0 yl ) - 5 - ( trifluoromethoxy ) benzamide 1 , 2 - dihydropyridin- 4 - yl ) - 5 ( trifluoromethyl) benzamide

| 46

? HN

HN . |2 HN .

SCFCF . 2 - ( 4 - fluorophenoxy ) - N - ( 2 - 0x0 2 - ( 2 -ethoxyphenoxy ) - N - ( 2 -0x0 1 ,2 - dihydropyridin- 4 - yl) - 6 1 , 2 - dihydropyridin- 4 - yl ) - 5 ( trifluoromethyl) benzamide ( trifluoromethyl) benzamide US 10 ,087 , 143 B2 119 . | 120 TABLE 1 -continued | TABLE 1- continued Compound Numbers , Structures and Chemical Names Compound Numbers , Structures and Chemical Names

5

10. HN

HN. HN . OMe 15 Me

Me CER 20 2 -( 2 - methoxy -4 - methylphenoxy) 2 - ( 4 - chloro - 2 - methylphenoxy ) - N | N - ( 2 - 0x0 - 1 , 2 - dihydropyridin- 4 ( 2 - 0x0 - 1 ,2 - dihydropyridin- 4 - yl ) - 5 | yl ) - 5 - ( trifluoromethyl ) benzamide (trifluoromethyl ) benzamide

15 51

30

HN. HN OMe 35

CFA 2 - ( 2 - fluoro- 6 - methoxyphenoxy ) 2 - ( 4 -chloro - 2 - fluorophenoxy ) - N N - ( 2 - 0X0 - 1 , 2 - dihydropyridin- 4 ( 2 - 0x0- 1 ,2 - dihydropyridin - 4 - yl ) - 5 yl) -5 - (trifluoromethyl )benzamide ( trifluoromethyl) benzamide 45 49. | 52

50

HN . 55 OMe HN .

60 Me IF 2 - ( 2 - chloro- 4 - methoxyphenoxy ) | 2 - ( 5 - fluoro - 2 - methoxyphenoxy ) N - ( 2 - 0x0 - 1 , 2 - dihydropyridin - 4 N- (2 - 0X0- 1 ,2 - dihydropyridin- 4 | yl ) - 5 - ( trifluoromethyl ) benzamide 65 | yl) - 5 - ( trifluoromethyl ) benzamide US 10 ,087 , 143 B2 121 122 TABLE 1- continued TABLE 1 - continued Compound Numbers , Structures and Chemical Names Compound Numbers , Structures and Chemical Names 5 56

HN HN . Me

'CF3 OF ,

N - ( 2 - oxo - 1 , 2 - dihydropyridin - 4 2 - ( 5- fluoro - 2 -methylphenoxy ) - N yl) - 2 - ( 4 - propoxyphenoxy ) - 5 ( 2 -oxo - 1 , 2 - dihydropyridin - 4 - yl) - 5 (trifluoromethyl )benzamide 25 ( trifluoromethyl )benzamide 54 57

HN , 20 HN OMe Meo .

CF3 2 - ( 3 - fluoro - 2 -methoxyphenoxy ) N - (2 -oxo - 1, 2 -dihydropyridin -4 2 - ( 3 - fluoro- 5 -methoxyphenoxy ) yl )- 5 - (trifluoromethyl )benzamide N -( 2 - oxo -1 , 2 - dihydropyridin -4 yl) -5 - ( trifluoromethyl )benzamide 55 58

HN F HN .

Meo CF3CF2 CF3 2 - ( 2 - fluoro - 4 -methoxyphenoxy ) 2 - ( 4 - chlorophenoxy ) - N - ( 2 - oxo N - ( 2 -oxo - 1 , 2 -dihydropyridin - 4 1 , 2 - dihydropyridin - 4 -yl ) - 5 yl) - 5 -( trifluoromethyl )benzamide ( trifluoromethyl )benzamide US 10 ,087 , 143 B2 123 124 TABLE 1 - continued TABLE 1 - continued Compound Numbers, Structures and Chemical Names Compound Numbers , Structures and Chemical Names 59 5

HN . HN

Meo CH3 CF3 N - ( 2 -oxo - 1 , 2 -dihydropyridin - 4 2 - ( 3 - fluoro - 4 -methoxyphenoxy ) yl) - 2 - ( 2 -propoxyphenoxy ) - 5 N - (2 -oxo - 1, 2 -dihydropyridin -4 ( trifluoromethyl) benzamide yl) - 5 - trifluoromethyl )benzamide 25 63

ý

HN . HN . Me Me

Me01 CF3 N - ( 6 - chloro - 2 -oxo - 1 , 2 2 - ( 4 -methoxy - 2 -methylphenoxy ) dihydropyridin - 4 -yl )- 2 - ( 4 - fluoro N - ( 2 - oxo - 1 , 2 - dihydropyridin - 4 2 -methylphenoxy ) - 5 yl) - 5 - (trifluoromethyl ) benzamide ( trifluoromethyl) benzamide 64

Me

HNHN . Me 20 HN .

CF CE , g 2 - ( 4 - fluoro - 2 -methylphenoxy ) - N ( 6 -methyl - 2 -oxo - 1 , 2 2 - ( 2 - isopropoxyphenoxy ) - N -( 2 dihydropyridin - 4 - yl) - 5 oxo - 1 , 2- dihydropyridin - 4 -yl ) - 5 ( trifluoromethyl) benzamide en ( trifluoromethyl) benzamide US 10 ,087 , 143 B2 125 126 TABLE 1 - continued TABLE 1 -continued Compound Numbers , Structures and Chemical Names Compound Numbers , Structures and Chemical Names

69

HN .

CF3 HN 2 - ( 2 - chlorophenoxy ) - N - ( 2 - oxo 1 , 2 - dihydropyridin - 4 -yl )- 5 ( trifluoromethyl )benzamide 66 ZT

5 - chloro - 2 - ( 2 , 4 - difluorophenoxy ) N - ( 2 - 0X0 - 1 , 2 - dihydropyridin - 4 yl )benzamide HN . ()

AL C1 |#A 5 - chloro - 2 - 2 - chloro - 4 fluorophenoxy) -N - 2 - ox0- 1 , 2 dihydropyridin - 4 - ylbenzamide

6 HN . OMe

HN . Me 5 - chloro - 2 - 4 - fluoro - 2 methoxyphenoxy )- N - ( 2 - 0X0- 1 , 2 dihydropyridin - 4 - yl) benzamide Cl | 71 5 - chloro - 2 - 4 - fluorophenoxy )- N ( 2 - 0XO - 1 , 2 - dihydropyridin - 4 |jxkxjxnxxyl) benzamide

HN . HN Me

Me ) | C1 5 - chloro - 2 - ( 3 - fluoro - 4 5 - chloro - 2 - 4 - fluoro - 2 methoxyphenoxy) - N -( 2 -ox0 - 1 , 2 methylphenoxy ) - N - 2 - oxO - 1 , 2 dihydropyridin - 4 - y1 )benzamide dihydropyridin - 4 - ylbenzamide | US 10 ,087 , 143 B2 127 128 TABLE 1 - continued TABLE 1 -continued Compound Numbers , Structures and Chemical Names Compound Numbers , Structures and Chemical Names 75

H 10

HN . HNHNO . OCF3

CF3 F300 CF2 20 N -( 2 - oxo -1 , 2 -dihydropyridin -4 N - ( 2 - oxo - 1 , 2 - dihydropyridin - 4 yl) - 2 - ( 2 yl) - 2 - ( 4 (trifluoromethoxy )phenoxy ) - 5 (trifluoromethoxy ) phenoxy ) -5 ( trifluoromethyl )benzamide (trifluoromethyl ) benzamide

73

30

HN . 35 HN . OCHF

40 CF3 F2HCO 2 - ( 2 - (difluoromethoxy )phenoxy ) 2 - ( 4 - ( difluoromethoxy )phenoxy ) N - ( 2 - oxo - 1 , 2 -dihydropyridin - 4 N - ( 2 -oxo - 1 , 2 -dihydropyridin - 4 yl) -5 - (trifluoromethyl ) benzamide yl) - 5 - ( trifluoromethyl )benzamide 45 77 14

50 HN

55 HN . 2

60 F Fac CF2 CF3 N - ( 2 - oxo - 1 , 2 - dihydropyridin - 4 2 - ( 2 -chloro - 4 -fluorophenoxy ) - N yl) - 5 - (trifluoromethyl ) - 2 - ( 4 ( 2 - oxo - 1 , 2 - dihydropyridin - 4 - yl) - 4 ( trifluoromethyl) phenoxy ) benzamide 65 ( trifluoromethyl) benzamide US 10 ,087 , 143 B2 129 130 TABLE 1 - continued TABLE 1 - continued Compound Numbers , Structures and Chemical Names Compound Numbers , Structures and Chemical Names 78 81

HN .

Meo CF3 CF3 2 - (4 - chlorophenoxy ) - N -( 2 - oxo 1, 2 -dihydropyridin -4 -yl ) - 4 2 - ( 3 - fluoro - 4 -methoxyphenoxy ) ( trifluoromethyl )benzamide N -( 2 -oxo -1 , 2 -dihydropyridin - 4 yl) - 4 - ( trifluoromethyl) benzamide 79 82

HNHN 20 HN .

F3CO F2HCO1 CF3 CF3 N - ( 2 - oxo - 1 , 2 - dihydropyridin - 4 yl) - 2 - ( 4 2 - (2 - (difluoromethoxy )phenoxy ) ( trifluoromethoxy )phenoxy ) - 4 N -( 2 -oxo -1 , 2 -dihydropyridin - 4 ( trifluoromethyl )benzamide yl ) - 4 - ( trifluoromethyl) benzamide

80 8383

HN 0 HN OCF3 OCHF

CF3 CF3 N - (2 -oxo -1 ,2 - dihydropyridin -4 yl) - 2 - ( 2 2 - ( 2 - (difluoromethoxy )phenoxy ) (trifluoromethoxy )phenoxy ) - 4 N - (2 -oxo - 1 , 2 - dihydropyridin - 4 (trifluoromethyl ) benzamide yl) - 4 - (trifluoromethyl ) benzamide US 10 ,087 , 143 B2 131 132 TABLE 1 - continued TABLE 1 - continued Compound Numbers , Structures and Chemical Names Compound Numbers , Structures and Chemical Names

84 5

HN . F HN OMe HNO

Meo CF3 2 - ( 2 - fluoro - 4 -methoxyphenoxy ) N - (2 -oxo - 1, 2 -dihydropyridin - 4 yl) - 4 -( trifluoromethyl ) benzamide 2 - (3 - fluoro - 2 -methoxyphenoxy ) N -( 2 - oxo - 1 , 2 - dihydropyridin - 4 85 yl) - 4 -( trifluoromethyl )benzamide 25 88 OH

L

??? F3C L CF3 2 -( 4 - fluorophenoxy ) - N - ( 2 -oxo 2 - (4 - fluorophenoxy )- N - ( 1 - (2 1 , 2 - dihydropyridin - 4 - yl) - 4 hydroxyethyl) - 2 -oxo - 1 , 2 (perfluoroethyl )benzamide dihydropyridin - 4 - yl ) - 4 (trifluoromethyl )benzamide 80. 86

HN . Me

Meo

1 CF3 FzC F 2 - (4 - fluoro - 2 -methylphenoxy ) - N ( 5 -methyl - 2 - oxo - 1 , 2 2 - ( 3 - fluoro - 4 -methoxyphenoxy ) dihydropyridin - 4 - yl) - 4 N - ( 2 - oxo - 1 , 2 - dihydropyridin - 4 (trifluoromethyl ) benzamide yl) - 4 - (perfluoroethyl )benzamide US 10 , 087 , 143 B2 133 134 TABLE 1 - continued TABLE 1 -continued Compound Numbers , Structures and Chemical Names Compound Numbers, Structures and Chemical Names 90 N

HN HN . Me

CF3 Me CE Me N - ( 2 -oxo - 1 , 2 - dihydropyridin - 4 N - ( 2 -oxo - 1 , 2 - dihydropyridin - 4 yl) - 5 -( trifluoromethyl) - 2 - ( 2 ,3 ,4 yl) - 5 - ( trifluoromethyl) - 2 - ( 2 , 4 , 5 trifluorophenoxy )benzamide trimethylphenoxy )benzamide 94

8

HN . 7 Me Me Me

Me 6 Me Me N - ( 2 -oxo - 1 , 2 -dihydropyridin - 4 yl ) - 5 - ( trifluoromethyl) - 2 - ( 2 , 3 ,5 5 - fluoro - N - ( 2 - oxo - 1 , 2 trimethylphenoxy ) benzamide dihydropyridin -4 -yl ) - 2 -( 2 , 3 , 5 5 trimethylphenoxy )benzamide 92 95

4

HN . 3 HN .

Me CF3 3

2 - ( 2, 3 -difluoro -4 -methylphenoxy ) 5 - fluoro -N -( 2 -oxo - 1, 2 N - ( 2 - oxo - 1 , 2 - dihydropyridin - 4 dihydropyridin - 4 -yl ) - 2 yl) -5 -( trifluoromethyl )benzamide 6 phenoxybenzamide US 10 ,087 , 143 B2 135 136 | TABLE 1 -continued | TABLE 1- continued Compound Numbers , Structures and Chemical Names Compound Numbers , Structures and Chemical Names

96 99

N . HN .

F 5 - fluoro - 2 - ( 4 - isopropylphenoxy ) 2 - ( 4 -cyclopropylphenoxy )- 5 N - ( 2 - 0x0- 1 , 2 - dihydropyridin - 4 fluoro - N - ( 2 - 0x0 - 1 , 2 yl )benzamide dihydropyridin - 4 - yl ) benzamide | 100 97

HN

HN .

F

5 - fluoro - N - ( 2 - 0X0 - 1 , 2 2 - ( 4 -( tert- butoxy ) phenoxy ) - 5 dihydropyridin - 4 - yl) - 2 - ( 4 fluoro - N - ( 2 - 0X0 - 1 , 2 propoxyphenoxy )benzamide dihydropyridin- 4 - yl ) benzamide 1 101 98.

2 HN. HN .

F3C0 | 5 - fluoro - N - ( 2 - 0X0 - 1 , 2 2 -( 4 -ethoxyphenoxy ) - 5 - fluoro- N dihydropyridin- 4 - yl ) - 2 - ( 4 ( 2 - 0x0 - 1 , 2 - dihydropyridin - 4 ( trifluoromethoxy )phenoxy ) benza yl )benzamide mide | US 10 ,087 , 143 B2 137 138 TABLE 1 - continued TABLE 1 - continued Compound Numbers , Structures and Chemical Names Compound Numbers , Structures and Chemical Names 5 102 105

HN . Me

OMe

F Me Me 5 - fluoro - 2 - ( 4 - ( 2 methoxyethyl) phenoxy )- N - ( 2 - oxo 5 - fluoro - N - ( 2 -oxo - 1 , 2 1 ,2 -dihydropyridin -4 dihydropyridin - 4 - yl) - 2 - ( 2 , 4 , 5 yl )benzamide trimethylphenoxy )benzamide 103 106106

8

7 HN HN . Me

6 Meo 2 - ( 2 - chloro - 4 -methoxyphenoxy ) 2 - ( 4- fluoro - 2 -methylphenoxy ) - N 5 - fluoro - N - ( 2 -oxo - 1 , 2 ( 2 -0X0 -1 , 2 -dihydropyridin - 4 -yl ) - 5 dihydropyridin - 4 -yl ) benzamide 5 ( trifluoromethyl) benzamide

104 107

4

3 HN HN .

3

Meo 5 - fluoro - 2 - ( 4 -methoxyphenoxy ) 5 - fluoro - N - ( 2 -oxo - 1 , 2 N -( 2 - oxo - 1 ,2 -dihydropyridin - 4 dihydropyridin - 4 -yl ) - 2 - ( 4 - ( 2 , 2 ,2 yl) benzamide 0 trifluoroethoxy )phenoxy )benzamide US 10 ,087 , 143 B2 139 140 TABLE 1 - continued TABLE 1 - continued Compound Numbers, Structures and Chemical Names Compound Numbers , Structures and Chemical Names 108 i 111

N 3 OMe HNO

HN

ü F F30 F

2 - ( 4 2 - ( 4 - fluoro- 2 -methoxyphenoxy ) (cyclopropylmethoxy )phenoxy )- 5 N - ( 2 - oxo - 1 , 2 - dihydropyridin - 4 fluoro - N - ( 2 - oxo - 1 , 2 yl) - 4 - ( perfluoroethyl) benzamide dihydropyridin -4 -yl ) benzamide 112 109 Bu

ý

HN . 20 HN . Me CI

F3C Il 4 -chloro - 2 - ( 2 - chloro - 4 2- ( 4 - fluoro -2 - methylphenoxy ) - N fluorophenoxy ) - 5 - fluoro - N - ( 2 ( 2 - oxo - 1 , 2 - dihydropyridin - 4 - yl) - 4 oX0 - 1, 2 -dihydropyridin -4 (perfluoroethyl )benzamide yl) benzamide 113 110 113 N

HN . HN

Me F CF3 g C1 2 - ( 2 - chloro - 3 - fluoro - 4 methoxyphenoxy )- N -( 2 -oxo - 1 ,2 4 , 5 -dichloro - 2 - ( 4- fluorophenoxy ) dihydropyridin - 4 -yl ) - 4 N -( 2 -oxo - 1 , 2 - dihydropyridin - 4 (trifluoromethyl ) benzamide en yl) benzamide US 10, 087 ,143 B2 141 142 TABLE1- conitinnued TABLEl- COintinued Compound Numbers, Structures and Chemical Names Compound Numbers , Structures and Chemical Names 5 11 ? 114

HN. HN, OMe

FF - ? CF3 Cl 2 -isobutoxy - N -( 2 -0x0 - 1, 2 4, 5 - dichloro - 2 -( 4 - Huoro - 2 dihydropyridin - 4 - yl) - 4 methoxyphelloxy )- N -( 2 - Oxo- 1 , 2 (trifluoromethyl ) benzamide dihydropyridin - 4 - yl) benZamlide 25 118 115

HN HN ? 0

F

CF3 2 - ( (2R } - bicyclo[ 2 . 2 .1 ] heptanl - 2 4 , 5 - dichloro - 2 -( 3 - Huoro - 4 yloxy )- N -( 2 - 0x0 -1 , 2 methoxyplenoXy) - N -( 2 - 0x0 - 1 , 2 dihydrOpyridin - 4 - yl) - 4 dimhydropyridin - 4- yl) benzamide ( triduoromethyl) benzamide 119 116 _ 119

HN. HN

CF3 CF3 2 -( ( 1 2 - (isopertyloxy ) - N -( 2 - Oxo- 1 , 2 _ methylcyclopropyl ) methoxy) - N dihydropyridin - 4 - yl) - 4 ( 2 - 0x0 - 1 , 2 - dihydropyridin - 4 - yl) - 4 ( trifluoromethyl) benzamide ( trifluoromethyl) benzamide US 10 ,087 , 143 B2 143 144 TABLE 1 - continued TABLE 1 - continued Compound Numbers , Structures and Chemical Names Compound Numbers , Structures and Chemical Names 120 55 123

10

HN . CF, HN

CF3 20 CF2 2 - (cyclopentylmethoxy ) - N - ( 2 - oxo N - ( 2 -oxo - 1 , 2 -dihydropyridin - 4 1 , 2 - dihydropyridin - 4 - yl) - 4 yl) - 2 -( 4 ,4 ,4 -trifluorobutoxy )- 4 ( trifluoromethyl) benzamide ( trifluoromethyl) benzamide 124 121 25

HN . HN

CF3 CF3 2 - (( 2 ,2 N - ( 2 - oxo - 1 , 2 - dihydropyridin - 4 dimethylcyclopropyl) methoxy )- N yl )- 2 - ( ( tetrahydrofuran - 3 (2 - oxo - 1, 2 - dihydropyridin -4 - yl ) -4 yl )methoxy ) - 4 ( trifluoromethyl )benzamide ( trifluoromethyl) benzamide 125 122 125 N

HN . HN .

CF3 CF3 2 - ( ( 1R ,5S ) -bicyclo [ 3 . 1 . 0 ] hexan - 3 2 -cyclobutoxy - N - ( 2 - oxo - 1 , 2 yloxy ) - N - ( 2 -oxo - 1 , 2 dihydropyridin - 4 -yl ) - 4 dihydropyridin - 4 - yl) - 4 ( trifluoromethyl) benzamide ( trifluoromethyl) benzamide US 10, 087 ,143 B2 145 146 TABLE1 -Colltiilled TABLE 1- continued Compound Numbers , Structures and Chemical Names Compound Numbers , Structures and Chemical Names

126 129

F F HN. CF

CF3 2 - (( 2 , 2 diHuorocyclopropyl )rmethoxy )- N 4 - chloro- N - ( 2 - OXO- 1 , 2 ( 2 -0XO - 1 , 2 - dihydropyridiln - 4 - yl ) - 4 dihydropyridin - 4 - yl )- 2 -( 4, 4, 4 (trifluoromethyl )benzamide trifluorobutoxy )benzamide 12 _ 130130 4 ?_

HN.

_ HN

8_ CF3 ' CF3 2- ( bicyclo [ 2. 2 . 1 ]heptall - 2- yloxy) 2 -( cyclopentylmethoxy) - N - ( 2 -0x0 _ N -( 2- Oxo- 1 ,2 - dihydropyridin -4 1 , 2 - dihydropyridin - 4 - yl ) - 5 yl) - 4 - (triduolomethyl ) benzamide A ( trifluoromethyl )benzamide _ 128 _ 131

s_

HN

_ HN

8_ CE3 ' CF3 2 - ( cyclohexyloxy ) - N - ( 2 - 0x0 - 1 , 2 2 - isobutoxy- N - ( 2 - 0x0 - 1 , 2 dihydropyridinl - 4 - yl ) - 4 dihydropyridin - 4 - yl )- 5 ( trifluoromethyl) benzamide 8 ( trifluoromethyl) benzamide US 10, 087, 143 B2 147 148 TABLE 1 - continued TABLE 1 -continued Compound Numbers , Structures and Chemical Names Compound Numbers , Structures and Chemical Names 132 135

HN . HN .

Fc

lib? 44 CF3 CF3 N - ( 2 - oxo- 1 , 2 - dihydropyridin - 4 2 - ( ( 1 , 5S) - bicyclo[ 3 . 1 . 0 ] hexan- 3 yl - 5 - ( trifluoromethyl) - 2 - ( 3 , 3 , 3 N - ( 2 - 0x0 - 1 , 2 - dihydropyridin - 4 - yl trifluoropropoxy )benzamide ( trifluoromethyl) benzamide 25 133 25 136

F3HN HN .

CF3 OCF3 N - ( 2 - oxo- 1 , 2 - dihydropyridin - 4 2 -( cyclopentylmethoxy) - N - ( 2 - 0x0 yl) - 2 - 4, 4 ,4 - trifuorobutoxy )- 5 1 , 2 - dihydropyridin - 4 - yl - 5 ( trifluoromethyl) benzamide ( trifluoromethoxy )benzamide

134 | 137137

HN0HN HN

CF3 CF3 2 - ( ( 2, 2 dimethylcyclopropyl) methoxy) - N 2 - ( cyclohexyloxy) - N - ( 2 - 0x0- 1 , 2 ( 2- 0x0- 1 , 2 - dihydropyridin - 4 - yl - 5 dihydropyridin - 4- yl - 5 ( trifluoromethyl) benzamide ( trifluoromethoxy )benzamide US 10 ,087 , 143 B2 149 150 TABLE 1 -continued TABLE 1 -continued Compound Numbers , Structures and Chemical Names Compound Numbers , Structures and Chemical Names

138 141

HN .

HN CNF ,

OCF ; 4 - (tert -butyl - N - ( 2 - ox ( - 1 , 2 | N - ( 2 - oxo- 1 , 2 - dihydropyridin - 4 dihydropyridin - 4 - yl) - 2 - ( ( 6 yl) - 5 - (trifluoromethoxy ) - 2 - ( 3 , 3 , 3 ( trifluoromethyl) pyridin - 3 trifluoropropoxy )benzamide yl) oxybenzamide 2525 139 142142

NH

HN

CF3 HN

F , C

OCF3 N - ( 2 -ox ( - 1 , 2 - dihydropyridin - 4 4 - (tert -butyl - N - ( 6 - x6 - 1 , 6 yl )- 2 -( 4 ,4 , 4 - trifluorobutoxy )- 5 dihydropyridin - 3 - yl ) - 2 - ( ( 6 ( trifluoromethoxy )benzamide (trifluoromethyl ) pyridin - 3 y1 ) oxybenzamide 140 143

HN HN0HN

CNF , CF , 2 - ( ( 2 , 2 4 -chloro - N - 2 -oxo - 1 , 2 dimethylcyclopropyl) methoxy ) - N dihydropyridin - 4 -yl ) - 2 - ( ( 6 ??( 2 -oxO - 1 ,2 - dihydropyridin - 4 -yl )- 5 (trifluoromethyl ) pyridin - 3 ( trifluoromethoxy )benzamide yl )oxybenzamide US 10 , 087 , 143 B2 151 152 TABLE 1 - continued TABLE 1 - continued Compound Numbers , Structures and Chemical Names Compound Numbers , Structures and Chemical Names 144 147

3 HN . HN

F C Me CF3 CF3 N - ( 2 - oxo - 1 , 2 - dihydropyridin - 4 yl) - 4 - ( trifluoromethyl) - 2 - ( ( 6 2 - ( (2 -methylpyridin -3 -yl ) oxy )- N ( trifluoromethyl) pyridin - 3 ( 2 - oxo - 1 , 2 - dihydropyridin - 4 -yl ) - 4 yl) oxy )benzamide ( trifluoromethyl) benzamide 145 148148 25

NH 30 HN .

HN .

35 F C N

F3C 40 CF3 4 -( tert - butyl) - N - ( 1 -methyl - 2 - oxo 1 ,2 - dihydropyridin - 4 -yl ) - 2- (( 6 N -( 6 -oxo - 1 ,6 -dihydropyridin - 3 ( trifluoromethyl )pyridin - 3 yl) - 4 - ( trifluoromethyl ) - 2 - ( (6 yl) oxy )benzamide ( trifluoromethyl) pyridin - 3 yl) oxy ) benzamide 45 149149 146

50

HN .

HN 55

CNF

Me

CF3 4 - tert- butyl ) - N -( 1 -methyl - 6 - oxo 1 ,6 -dihydropyridin -3 -yl ) - 2 -( 6 2 - ( ( 6 -methylpyridin - 3 -yl )oxy )- N ( trifluoromethyl) pyridin - 3 ( 2 -oxo - 1, 2 -dihydropyridin - 4 - yl )- 4 (trifluoromethyl ) benzamide yl) oxy )benzamide US 10 ,087 , 143 B2 | 153 154 | TABLE 1 - continued TABLE 1 - continued Compound Numbers, Structures and Chemical Names Compound Numbers, Structures and Chemical Names - : 153153 5 150

HN. HN .

CF

Me CF3 Me 2 - (2 - methylpyridin - 3 - yl ) oxy ) - N CF3 1 ( 2 - 0x0 - 1 , 2 - dihydropyridin - 4 - yl ) - 5 ( trifluoromethyl ) benzamide 2 - ( 4 - fluoro - 2 - methylphenoxy ) - N ( 2 - 0x0 - 1 , 2 - dihydropyridin- 4 - yl) 4 , 6 - bis( trifluoromethyl) benzamide 151 154

HN

HN . HN . C

Me OMe | 2 - ( ( 2 - methylpyridin - 3 - yl )oxy ) - N CF3 ( 2 - 0x0- 1 , 2 - dihydropyridin - 4 - yl ) - 5 2 - ( 4 - fluoro- 2 - methoxyphenoxy ) ( trifluoromethoxy ) benzamide N -( 2- 0x0- 1 ,2 -dihydropyridin - 4 | yl )- 4 , 6 152 bis ( trifluoromethyl )benzamide 155

HN HN . |

F CF CF3 2 - ( 2 , 4 - difluorophenoxy ) - N - ( 2 2 - ( 4 - fluorophenoxy )- N - ( 2 - 0x0 OXO - 1 , 2 -dihydropyridin - 4 - yl ) - 4 , 6 1 , 2 - dihydropyridin - 4 - yl) - 4 , 6 bis ( trifluoromethyl) benzamide bis ( trifluoromethyl) benzamide US 10 ,087 , 143 B2 155 156 TABLE 1- continued TABLE 1 - continued Compound Numbers , Structures and Chemical Names Compound Numbers , Structures and Chemical Names 159 156

7

- 10 HN

HN .

OH CF3 15 CF3 2 -( ( 5 - fluoro - 2 hydroxybenzyl) oxy )- N - ( 2 - oxo CFz 20 1 , 2 -dihydropyridin - 4 -yl ) - 4 ( trifluoromethyl )benzamide N - ( 2 -oxo - 1 , 2 -dihydropyridin - 4 yl) - 2 - phenoxy - 4 , 6 160 bis (trifluoromethyl ) benzamide 25 157

HN .

HO . HN

5 - fluoro - N - ( 2 -oxo - 1 , 2 dihydropyridin - 4 - yl) - 2 - ( 4 - ( 4 , 4 , 4 trifluorobutoxy) phenoxy )benzamide F In one embodiment, the compound is 4 , 5 -dichloro - 2 - ( 4 CF3 fluoro -2 -methoxyphenoxy ) -N -( 2 -oxo - 1, 2 - dihydropyridin 4 -yl ) benzamide or a pharmaceutically acceptable salt 2 - ( 4 - fluoro - 2 ( hydroxymethyl) phenoxy )- N - ( 2 thereof. oxo - 1 ,2 -dihydropyridin - 4 -yl ) - 4 In another embodiment, the compound is 2 - ( 4 - fluoro - 2 ( trifluoromethyl) benzamide 45 methoxyphenoxy ) - N - ( 2 -oxo - 1 , 2 - dihydropyridin - 4 - yl ) - 4 (perfluoroethyl ) benzamide or a pharmaceutically acceptable 158 salt thereof. In another embodiment, the compound is 4 , 5 - dichloro - 2 ( 4 - fluorophenoxy )- N -( 2 -oxo - 1 ,2 - dihydropyridin -4 -yl ) benz 50 amide or a pharmaceutically acceptable salt thereof. In another embodiment, the compound is 4 ,5 -dichloro - 2 ( 3 - fluoro - 4 - methoxyphenoxy ) - N - ( 2 -oxo - 1 , 2 -dihydropyri din - 4 - yl) benzamide or a pharmaceutically acceptable salt HNHN thereof. OMe In another embodiment, the compound is 2 - ( 4 - fluoro - 2 methoxyphenoxy )- N -( 2 -oxo - 1, 2 -dihydropyridin -4 - yl) -5 (trifluoromethyl ) benzamide or a pharmaceutically accept able salt thereof. In another embodiment , the compound is N - ( 2 -oxo - 1 , 2 F dihydropyridin - 4 -yl ) - 2 -( 4 -( trifluoromethoxy )phenoxy )- 4 CF3 (trifluoromethyl ) benzamide or a pharmaceutically accept able salt thereof. 2 - ( 4 - fluoro - 2 -methoxyphenoxy ) N -( 2 -oxo - 1 , 2 -dihydropyridin -4 In another embodiment, the compound is 2 - (4 - fluorophe yl) - 4 - (trifluoromethyl ) benzamide 65 noxy ) - N - ( 2 -oxo - 1 , 2 -dihydropyridin - 4 - yl) - 4 - (perfluoro ethyl )benzamide or a pharmaceutically acceptable salt thereof . US 10 , 087 , 143 B2 157 158 In another embodiment, the compound is 5 -chloro - 2 -( 4 - It will also be appreciated that certain of the compounds fluoro - 2 -methoxyphenoxy )- N -( 2 -oxo - 1 ,2 - dihydropyridin of invention can exist in free form for treatment, or where 4 - yl) benzamide or a pharmaceutically acceptable salt appropriate , as a pharmaceutically acceptable derivative thereof. thereof . According to the invention , a pharmaceutically In another embodiment, the compound is N - ( 2 -oxo - 1 ,2 - 5 acceptable derivative includes , but is not limited to , phar dihydropyridin - 4 - yl) - 2 - ( 4 -( trifluoromethoxy )phenoxy ) -5 - maceutically acceptable salts , esters , salts of such esters , or any other adduct or derivative which upon administration to (trifluoromethyl ) benzamide or a pharmaceutically accept a subject in need is capable of providing , directly or indi able salt thereof. rectly , a compound as otherwise described herein , or a In another embodiment, the compound is 2 - ( 4 -fluoro - F2 10 metabolite or residue thereof. methylphenoxy )- N - ( 2 -oxo - 1 , 2 -dihydropyridin - 4 - yl) - 4 -( trif As used herein , the term “ pharmaceutically acceptable luoromethyl) benzamide or a pharmaceutically acceptable salt” refers to those salts which are , within the scope of salt thereof. sound medical judgement, suitable for use in contact with In another embodiment, the compound is 2 - ( 4 - fluoro - 2 the tissues of humans and lower animals without undue methylphenoxy ) - N - ( 2 - oxo - 1 , 2 - dihydropyridin - 4 - yl) - 5 - ( trif- 15 toxicity , irritation , allergic response and the like , and are luoromethyl) benzamide or a pharmaceutically acceptable commensurate with a reasonable benefit / risk ratio . A “ phar salt thereof. maceutically acceptable salt ” means any non -toxic salt or In another embodiment, the compound is 2 - ( 2 - chloro - 4 salt of an ester of a compound of this invention that , upon fluorophenoxy ) - N - ( 2 -oxo - 1 , 2 -dihydropyridin - 4 -yl ) - 5 - ( trif administration to a recipient, is capable of providing , either luoromethyl) benzamide or a pharmaceutically acceptable 20 directly or indirectly , a compound of this invention or an salt thereof. inhibitorily active metabolite or residue thereof . As used In another embodiment, the compound is 5 - chloro - 2 - ( 4 - herein , the term " inhibitorily active metabolite or residue fluoro -2 -methylphenoxy ) - N -( 2 -oxo - 1, 2 -dihydropyridin -4 - thereof” means that a metabolite or residue thereof is also an yl) benzamide or a pharmaceutically acceptable salt thereof. inhibitor of a voltage - gated sodium channel . In another embodiment, the compound is 4 - chloro - 2 - ( 4 - 25 Pharmaceutically acceptable salts are well known in the fluoro - 2 -methylphenoxy ) - N - ( 2 -oxo - 1 , 2 - dihydropyridin - 4 - art . For example , S . M . Berge , et al. describe pharmaceuti yl) benzamide or a pharmaceutically acceptable salt thereof. cally acceptable salts in detail in J. Pharmaceutical Sci In another embodiment, the compound is 5 -chloro -2 - ( 2 ences, 1977 , 66 , 1 - 19 , incorporated herein by reference . chloro -4 - fluorophenoxy )- N -( 2 - oxo - 1, 2 - dihydropyridin -4 Pharmaceutically acceptable salts of the compounds of this yl) benzamide or a pharmaceutically acceptable salt thereof. 30 invention include those derived from suitable inorganic and In another embodiment, the compound is 2 - ( (5 - fluoro - 2 organic acids and bases. Examples of pharmaceutically hydroxybenzyl) oxy )- N -( 2 -oxo - 1, 2 -dihydropyridin - 4 -yl ) - 4 - acceptable , nontoxic acid addition salts are salts of an amino ( trifluoromethyl ) benzamide or a pharmaceutically accept group formed with inorganic acids such as hydrochloric able salt thereof. acid , hydrobromic acid , phosphoric acid , sulfuric acid and In another embodiment, the compound is N - ( 2 -oxo - 1 , 2 - 35 perchloric acid or with organic acids such as acetic acid , dihydropyridin - 4 - yl ) - 2 - (o - tolyloxy ) - 5 - ( trifluoromethyl )ben - oxalic acid , maleic acid , tartaric acid , citric acid , succinic zamide or a pharmaceutically acceptable salt thereof. acid or malonic acid or by using other methods used in the In another embodiment, the compound is 2 - ( 2 , 4 - difluo - art such as ion exchange . Other pharmaceutically acceptable rophenoxy ) - N - ( 2 - oxo - 1 , 2 - dihydropyridin - 4 -yl ) - 4 - ( trifluo salts include adipate , alginate , ascorbate , aspartate , benze romethyl) benzamide or a pharmaceutically acceptable salt 40 nesulfonate , benzoate , bisulfate, borate , butyrate , thereof. ate , camphorsulfonate , citrate , cyclopentanepropionate , dig In another embodiment, the compound is N - ( 2 - oxo - 1 , 2 - luconate , dodecylsulfate , ethanesulfonate , formate , dihydropyridin - 4 -yl ) - 2 - ( 2 -( trifluoromethoxy ) phenoxy ) -5 - fumarate , glucoheptonate , glycerophosphate , gluconate , ( trifluoromethyl) benzamide or a pharmaceutically accept- hemisulfate , heptanoate , hexanoate , hydroiodide , 2 -hy able salt thereof. 45 droxy - ethanesulfonate , lactobionate , lactate , laurate , lauryl In another embodiment, the compound is 2 - (4 - fluorophe - sulfate , malate , maleate , malonate , methanesulfonate , noxy ) - N - ( 2 - oxo - 1 , 2 - dihydropyridin - 4 - yl) - 5 - ( trifluorom - 2 -naphthalenesulfonate , nicotinate , nitrate , oleate , oxalate , ethyl) benzamide or a pharmaceutically acceptable salt palmitate , pamoate , pectinate , persulfate , 3 -phenylpropi thereof. onate , phosphate , picrate , pivalate , propionate , stearate , suc Salts , Compositions, Uses, Formulation , Administration and 50 cinate , sulfate , tartrate , thiocyanate , p - toluenesulfonate , Additional Agents undecanoate , valerate salts , and the like . Salts derived from Pharmaceutically Acceptable Salts and Compositions appropriate bases include alkali metal, alkaline earth metal, As discussed herein , the invention provides compounds ammonium and N + (C1 . 4 alkyl) , salts . This invention also that are inhibitors of voltage - gated sodium channels , and envisions the quaternization of any basic nitrogen - contain thus the present compounds are useful for the treatment of 55 ing groups of the compounds disclosed herein . Water or diseases, disorders, and conditions including , but not limited oil - soluble or dispersable products may be obtained by such to chronic pain , gut pain , neuropathic pain ,musculoskeletal quaternization . Representative alkali or alkaline earth metal pain , acute pain , inflammatory pain , cancer pain , idiopathic salts include sodium , lithium , potassium , calcium , magne pain , multiple sclerosis , Charcot- Marie - Tooth syndrome, sium , and the like . Further pharmaceutically acceptable salts incontinence or cardiac arrhythmia . Accordingly, in another 60 include , when appropriate , nontoxic ammonium , quaternary aspect of the invention , pharmaceutically acceptable com - ammonium , and amine cations formed using counterions positions are provided , wherein these compositions com - such as halide , hydroxide , carboxylate , sulfate , phosphate , prise any of the compounds as described herein , and option nitrate , lower alkyl sulfonate and aryl sulfonate . ally comprise a pharmaceutically acceptable carrier, As described herein , the pharmaceutically acceptable adjuvant or vehicle . In certain embodiments, these compo - 65 compositions of the invention additionally comprise a phar sitions optionally further comprise one or more additional maceutically acceptable carrier, adjuvant, or vehicle , which , therapeutic agents . as used herein , includes any and all solvents , diluents , or US 10 ,087 , 143 B2 159 160 other liquid vehicle , dispersion or suspension aids, surface amount of a compound , a pharmaceutically acceptable salt active agents , isotonic agents , thickening or emulsifying thereof or a pharmaceutical composition of the compounds agents , preservatives , solid binders , lubricants and the like , of formula I or formula I' . as suited to the particular dosage form desired . Remington ' s In yet another aspect, the invention features a method of Pharmaceutical Sciences , Sixteenth Edition , E . W . Martin 5 treating or lessening the severity in a subject of gut pain , (Mack Publishing Co . , Easton . Pa ., 1980 ) discloses various wherein gut pain comprises inflammatory bowel disease carriers used in formulating pharmaceutically acceptable pain , Crohn ' s disease pain or interstitial cystitis pain wherein said method comprises administering an effective compositions and known techniques for the preparation amount of a compound , a pharmaceutically acceptable salt thereof. Except insofar as any conventional carrier medium 10 thereof or a pharmaceutical composition of the compounds is incompatible with the compounds of the invention , such of formula I or formula I' . as by producing any undesirable biological effect or other In yet another aspect, the invention features a method of wise interacting in a deleterious manner with any other treating or lessening the severity in a subject of neuropathic component( s ) of the pharmaceutically acceptable composi pain , wherein neuropathic pain comprises post -herpetic neu tion , its use is contemplated to be within the scope of this 15 ralgia , diabetic neuralgia , painful HIV - associated sensory invention . Some examples of materials which can serve as neuropathy, trigeminal neuralgia , burning mouth syndrome , pharmaceutically acceptable carriers include , but are not post -amputation pain , phantom pain , painful neuroma; trau limited to , ion exchangers, alumina , aluminum stearate , matic neuroma ;Morton ' s neuroma ; nerve entrapment injury , lecithin , serum proteins, such as human serum albumin , spinal stenosis , carpal tunnel syndrome, radicular pain , buffer substances such as phosphates, , sorbic acid , or 20 sciatica pain ; nerve avulsion injury , brachial plexus avulsion potassium sorbate , partial glyceride mixtures of saturated injury ; complex regional pain syndrome, drug therapy vegetable fatty acids, water, salts or electrolytes, such as induced neuralgia , cancer chemotherapy induced neuralgia , protamine sulfate , disodium hydrogen phosphate , potassium anti -retroviral therapy induced neuralgia ; post spinal cord hydrogen phosphate, sodium chloride , salts , colloidal injury pain , idiopathic small - fiber neuropathy, idiopathic silica , trisilicate , polyvinyl pyrrolidone , poly - 25 sensory neuropathy or trigeminal autonomic cephalalgia acrylates, waxes , polyethylene -polyoxypropylene - block wherein said method comprises administering an effective polymers , wool fat, sugars such as lactose , glucose and amount of a compound , a pharmaceutically acceptable salt sucrose ; starches such as corn starch and potato starch ; thereof or a pharmaceutical composition of the compounds of formula I or formula I' . cellulose and its derivatives such as sodium carboxymethylod 30 In yet another aspect, the invention features a method of cellulose , ethyl cellulose and cellulose acetate ; powdered treating or lessening the severity in a subject of musculo tragacanth ; malt ; gelatin ; talc ; excipients such as cocoa skeletal pain , wherein musculoskeletal pain comprises butter and suppository waxes; oils such as peanut oil, osteoarthritis pain , back pain , cold pain , burn pain or dental cottonseed oil ; safflower oil; sesame oil ; olive oil ; corn oil pain wherein said method comprises administering an effec and soybean oil , glycols , such a propylene glycom or poly 35 tive amount of a compound , a pharmaceutically acceptable ethylene glycol; esters such as ethyl oleate and ethyl laurate ; salt thereof or a pharmaceutical composition of the com agar; buffering agents such as magnesium hydroxide and pounds of formula I or formula I' . aluminum hydroxide ; alginic acid ; pyrogen - free water ; iso - In yet another aspect, the invention features a method of tonic saline ; Ringer ' s solution ; ethyl , and phosphate treating or lessening the severity in a subject of inflamma buffer solutions , as well as other non - toxic compatible 40 tory pain , wherein inflammatory pain comprises rheumatoid lubricants such as sodium lauryl sulfate and magnesium arthritis pain or vulvodynia wherein said method comprises stearate , as well as coloring agents , releasing agents , coating administering an effective amount of a compound , a phar agents , sweetening , flavoring and perfuming agents , preser - maceutically acceptable salt thereof or a pharmaceutical vatives and antioxidants can also be present in the compo - composition of the compounds of formula I or formula I' . sition , according to the judgment of the formulator. 45 In yet another aspect, the invention features a method of In another aspect , the invention features a pharmaceutical treating or lessening the severity in a subject of idiopathic composition comprising the compound of the invention and pain , wherein idiopathic pain comprises pain a pharmaceutically acceptable carrier . wherein said method comprises administering an effective In another aspect, the invention features a pharmaceutical amount of a compound , a pharmaceutically acceptable salt composition comprising a therapeutically effective amount 50 thereof or a pharmaceutical composition of the compounds of the compound or a pharmaceutically acceptable salt of formula I or formula I' . thereof of the compounds of formula I or formula I ' and one In yet another aspect, the invention features a method or more pharmaceutically acceptable carriers or vehicles. wherein the subject is treated with one or more additional Uses of Compounds and Pharmaceutically Acceptable Salts therapeutic agents administered concurrently with , prior to , and Compositions 55 or subsequent to treatment with an effective amount of a In another aspect , the invention features a method of compound , a pharmaceutically acceptable salt thereof or a inhibiting a voltage - gated sodium channel in a subject pharmaceutical composition of the compounds of formula I comprising administering to the subject a compound of or formula I' . formula I or formula I ' or a pharmaceutically acceptable salt In another aspect, the invention features a method of thereof or a pharmaceutical composition thereof . In another 60 inhibiting a voltage - gated sodium channel in a subject aspect , the voltage - gated sodium channel is Nav1. 8 . comprising administering to the subject an effective amount In yet another aspect, the invention features a method of of a compound , a pharmaceutically acceptable salt thereof or treating or lessening the severity in a subject of chronic pain , a pharmaceutical composition of the compounds of formula gut pain , neuropathic pain , musculoskeletal pain , acute pain , I or formula I' . In another aspect, the voltage - gated sodium inflammatory pain , cancer pain , idiopathic pain , multiple 65 channel is Nav1. 8 . sclerosis , Charcot- Marie - Tooth syndrome, incontinence or In another aspect , the invention features a method of cardiac arrhythmia comprising administering an effective inhibiting a voltage - gated sodium channel in a biological US 10 , 087 , 143 B2 161 162 sample comprising contacting the biological sample with an compound , a pharmaceutically acceptable salt thereof or a effective amount of a compound , a pharmaceutically accept pharmaceutical composition of the compounds of formula I able salt thereof or a pharmaceutical composition of the or formula I' . In one aspect , the neuropathic pain is selected compounds of formula I or formula I' . In another aspect, the from post -herpetic neuralgia , diabetic neuralgia , painful voltage - gated sodium channel is Nav1. 8 . 5 HIV -associated sensory neuropathy, trigeminal neuralgia , In another aspect, the invention features a method of burning mouth syndrome, post -amputation pain , phantom treating or lessening the severity in a subject of acute pain , chronic pain , neuropathic pain , inflammatory pain , arthritis , pain , painful neuroma, traumatic neuroma, Morton ' s neu migraine, cluster headaches , trigeminal neuralgia , herpetic roma, nerve entrapment injury , spinal stenosis , carpal tunnel neuralgia , general neuralgias , epilepsy , epilepsy conditions, 10 syndrome, radicular pain , sciatica pain , nerve avulsion neurodegenerative disorders , psychiatric disorders , anxiety , injury , brachial plexus avulsion , complex regional pain depression , dipolar disorder, myotonia , arrhythmia , move syndrome, drug therapy induced neuralgia , cancer chemo ment disorders , neuroendocrine disorders , ataxia , multiple therapy induced neuralgia , anti - retroviral therapy induced sclerosis , irritable bowel syndrome, incontinence , visceral neuralgia , post spinal cord injury pain , idiopathic small - fiber pain . osteoarthritis pain . postherpetic neuralgia , diabetic 15 neuropathy, idiopathic sensory neuropathy or trigeminal neuropathy, radicular pain , sciatica , back pain , head pain , autonomic cephalalgia . neck pain , severe pain , intractable pain , nociceptive pain , Manufacture of Medicaments breakthrough pain , postsurgical pain , cancer pain , stroke , In one aspect, the invention provides the use of a com cerebral ischemia, traumatic brain injury , amyotrophic lat pound or pharmaceutical composition described herein for eral sclerosis , stress induced angina , exercise induced 20 the manufacture of a medicament for use in inhibiting a angina , palpitations, hypertension , or abnormal gastro - intes voltage - gated sodium channel . In another aspect , the volt tinal motility , comprising administering an effective amount age - gated sodium channel is Na , 1 . 8 . of a compound , a pharmaceutically acceptable salt thereof or In yet another aspect, the invention provides the use of a a pharmaceutical composition of the compounds of formula compound or pharmaceutical composition described herein I or formula I' . 25 for the manufacture of a medicament for use in treating or In another aspect, the invention features a method of lessening the severity in a subject of chronic pain , gut pain , treating or lessening the severity in a subject of femur cancer neuropathic pain , musculoskeletal pain , acute pain , inflam pain ; non -malignant chronic bone pain ; rheumatoid arthritis ; matory pain , cancer pain , idiopathic pain , multiple sclerosis , osteoarthritis ; spinal stenosis ; neuropathic low back pain ; Charcot- Marie - Tooth syndrome, incontinence or cardiac myofascial pain syndrome; fibromyalgia ; temporomandibu - 30 arrhythmia . lar joint pain ; chronic visceral pain , abdominal pain ; pan - In yet another aspect, the invention provides the use of a creatic pain ; IBS pain ; chronic and acute headache pain ; compound or pharmaceutical composition described herein migraine ; tension headache ; cluster headaches , chronic and for the manufacture of a medicament for use in treating or acute neuropathic pain , post- herpetic neuralgia; diabetic lessening the severity in a subject of gut pain , wherein gut neuropathy ; HIV -associated neuropathy ; trigeminal neural - 35 pain comprises inflammatory bowel disease pain , Crohn ' s gia ; Charcot- Marie Tooth neuropathy ; hereditary sensory disease pain or interstitial cystitis pain . neuropathies; peripheral nerve injury ; painful neuromas; In yet another aspect , the invention provides the use of a ectopic proximal and distal discharges ; radiculopathy ; che compound or pharmaceutical composition described herein motherapy induced neuropathic pain ; radiotherapy - induced for the manufacture of a medicament for use in a treating or neuropathic pain ; post -mastectomy pain ; central pain ; spinal 40 lessening the severity in a subject of neuropathic pain , cord injury pain ; post -stroke pain ; thalamic pain ; complex wherein neuropathic pain comprises post -herpetic neuralgia , regional pain syndrome; phantom pain ; intractable pain ; diabetic neuralgia , painful HIV -associated sensory neuropa acute pain , acute post- operative pain ; acute musculoskeletal thy, trigeminal neuralgia , burning mouth syndrome, post pain ; joint pain ; mechanical low back pain ; neck pain ; amputation pain , phantom pain , painful neuroma; traumatic tendonitis ; injury / exercise pain ; acute visceral pain ; pyelo - 45 neuroma ; Morton ' s neuroma; nerve entrapment injury , spi nephritis ; appendicitis ; cholecystitis ; intestinal obstruction ; nal stenosis , carpal tunnel syndrome, radicular pain , sciatica hernias; chest pain , cardiac pain ; pelvic pain , renal colic pain ; nerve avulsion injury, brachial plexus avulsion injury ; pain , acute obstetric pain , labor pain ; cesarean section pain ; complex regional pain syndrome, drug therapy induced acute inflammatory , burn and trauma pain ; acute intermittent neuralgia , cancer chemotherapy induced neuralgia , anti pain , endometriosis ; acute herpes zoster pain ; sickle cell 50 retroviral therapy induced neuralgia ; post spinal cord injury anemia ; acute pancreatitis ; breakthrough pain ; orofacial pain , idiopathic small - fiber neuropathy, idiopathic sensory pain ; sinusitis pain ; dental pain ; multiple sclerosis (MS ) neuropathy or trigeminal autonomic neuropathy. pain ; pain in depression ; leprosy pain ; Behcet ' s disease pain ; In yet another aspect, the invention provides the use of a adiposis dolorosa ; phlebitic pain ; Guillain -Barre pain ; pain - compound or pharmaceutical composition described herein ful legs and moving toes ; Haglund syndrome; erythromela - 55 for the manufacture of a medicament for use in treating or lgia pain ; Fabry ' s disease pain ; bladder and urogenital lessening the severity in a subject of musculoskeletal pain , disease; urinary incontinence ; hyperactivity bladder ; painful wherein musculoskeletal pain comprises osteoarthritis pain , bladder syndrome; interstitial cyctitis ( IC ) ; prostatitis ; com - back pain , cold pain , burn pain or dental pain . plex regional pain syndrome (CRPS ) , type I and type II ; In yet another aspect , the invention the invention provides widespread pain , paroxysmal extreme pain , pruritis , tinnitis , 60 the use of a compound or pharmaceutical composition or angina - induced pain , comprising administering an effec - described herein for the manufacture of a medicament for tive amount of a compound , a pharmaceutically acceptable use in treating or lessening the severity in a subject of salt thereof or a pharmaceutical composition of the com - inflammatory pain , wherein inflammatory pain comprises pounds of formula I or formula I' . rheumatoid arthritis pain or vulvodynia . In another aspect, the invention features a method of 65 In yet another aspect, the invention provides the use of a treating or lessening the severity in a subject of neuropathic compound or pharmaceutical composition described herein pain comprising administering an effective amount of a for the manufacture of a medicament for use in treating or US 10 ,087 , 143 B2 163 164 lessening the severity in a subject of idiopathic pain , wherein lessening the severity of neuropathic pain . In one aspect, the idiopathic pain comprises fibromyalgia pain . neuropathic pain is selected from post -herpetic neuralgia , In yet another aspect , the invention provides the use of a diabetic neuralgia , painful HIV - associated sensory neuropa compound or pharmaceutical composition described herein thy, trigeminal neuralgia , burning mouth syndrome, post for the manufacture of a medicament in combination with 5 amputation pain , phantom pain , painful neuroma, traumatic one or more additional therapeutic agents administered neuroma, Morton ' s neuroma, nerve entrapment injury , spi concurrently with , prior to , or subsequent to treatment with nal stenosis, carpal tunnel syndrome, radicular pain , sciatica the compound or pharmaceutical composition . painpar , nerve avulsion injury , brachial plexus avulsion , com In another aspect, the invention provides the use of a plex regional pain syndrome, drug therapy induced neural compound or pharmaceutical composition described herein 10 gia , cancer chemotherapy induced neuralgia , anti -retroviral for the manufacture of a medicament for use in treating or therapy induced neuralgia , post spinal cord injury pain , lessening the severity of acute pain , chronic pain , neuro - idiopathic small - fiber neuropathy , idiopathic sensory neu pathic pain , inflammatory pain , arthritis , migraine, cluster ropathy or trigeminal autonomic cephalalgia . headaches , trigeminal neuralgia , herpetic neuralgia , general Administration of Pharmaceutically Acceptable Salts and neuralgias , epilepsy , epilepsy conditions, neurodegenerative 15 Compositions . disorders , psychiatric disorders , anxiety , depression , dipolar In certain embodiments of the invention an “ effective disorder, myotonia , arrhythmia , movement disorders , neu - amount" of the compound , a pharmaceutically acceptable roendocrine disorders , ataxia , multiple sclerosis , irritable salt thereof or pharmaceutically acceptable composition is bowel syndrome, incontinence, visceral pain , osteoarthritis that amount effective for treating or lessening the severity of pain , postherpetic neuralgia , diabetic neuropathy , radicular 20 one or more of chronic pain , gut pain , neuropathic pain , pain , sciatica , back pain , head pain , neck pain , severe pain , musculoskeletal pain , acute pain , inflammatory pain , cancer intractable pain , nociceptive pain , breakthrough pain , post pain , idiopathic pain , multiple sclerosis , Charcot- Marie surgical pain , cancer pain , stroke , cerebral ischemia , trau - Tooth syndrome, incontinence or cardiac arrhythmia . matic brain injury , amyotrophic lateral sclerosis , stress The compounds and compositions , according to the induced angina , exercise induced angina , palpitations, 25 method of the invention , may be administered using any hypertension , or abnormal gastro - intestinal motility . amount and any route of administration effective for treating In another aspect, the invention provides the use of a or lessening the severity of one or more of the pain or compound or pharmaceutical composition described herein non - pain diseases recited herein . The exact amount required for the manufacture of a medicament for use in treating or will vary from subject to subject , depending on the species , lessening the severity of femur cancer pain ; non -malignant 30 age , and general condition of the subject, the severity of the chronic bone pain ; rheumatoid arthritis ; osteoarthritis ; spinal infection , the particular agent, its mode of administration , stenosis ; neuropathic low back pain ; myofascial pain syn - and the like . The compounds of the invention are preferably drome; fibromyalgia ; temporomandibular joint pain ; chronic formulated in dosage unit form for ease of administration visceral pain , abdominal pain ; pancreatic pain ; IBS pain ; and uniformity of dosage . The expression “ dosage unit chronic and acute headache pain ; migraine ; tension head - 35 form ” as used herein refers to a physically discrete unit of ache ; cluster headaches ; chronic and acute neuropathic pain , agent appropriate for the subject to be treated . It will be post - herpetic neuralgia ; diabetic neuropathy; HIV -associ - understood , however , that the total daily usage of the com ated neuropathy ; trigeminal neuralgia ; Charcot- Marie Tooth pounds and compositions of the invention will be decided by neuropathy ; hereditary sensory neuropathies; peripheral the attending physician within the scope of sound medical nerve injury ; painful neuromas ; ectopic proximal and distal 40 judgment . The specific effective dose level for any particular discharges; radiculopathy ; chemotherapy induced neuro - subject or organism will depend upon a variety of factors pathic pain ; radiotherapy -induced neuropathic pain ; post - including the disorder being treated and the severity of the mastectomy pain ; central pain ; spinal cord injury pain ; disorder ; the activity of the specific compound employed ; post - stroke pain ; thalamic pain ; complex regional pain syn - the specific composition employed ; the age, body weight, drome; phantom pain ; intractable pain ; acute pain , acute 45 general health , sex and diet of the subject; the time of post - operative pain ; acute musculoskeletal pain ; joint pain ; administration , route of administration , and rate of excretion mechanical low back pain ; neck pain ; tendonitis ; injury of the specific compound employed ; the duration of the exercise pain ; acute visceral pain ; pyelonephritis ; appendi- treatment; drugs used in combination or coincidental with citis ; cholecystitis; intestinal obstruction ; hernias; chest the specific compound employed , and like factors well pain , cardiac pain ; pelvic pain , renal colic pain , acute 50 known in the medical arts. The term “ subject” or “ patient, " obstetric pain , labor pain ; cesarean section pain ; acute as used herein , means an animal, preferably a mammal, and inflammatory , burn and trauma pain ; acute intermittent pain , most preferably a human . endometriosis ; acute herpes zoster pain ; sickle cell anemia ; The pharmaceutically acceptable compositions of this acute pancreatitis ; breakthrough pain ; orofacial pain ; sinus - invention can be administered to humans and other animals itis pain ; dental pain ; multiple sclerosis (MS ) pain ; pain in 55 orally , rectally , parenterally, intracisternally , intravaginally , depression ; leprosy pain ; Behcet' s disease pain ; adiposis intraperitoneally , topically ( as by powders , ointments, or dolorosa ; phlebitic pain ; Guillain -Barre pain ; painful legs drops) , bucally , as an oral or nasal spray , or the like , and moving toes; Haglund syndrome; erythromelalgia pain ; depending on the severity of the infection being treated . In Fabry ' s disease pain ; bladder and urogenital disease ; urinary certain embodiments , the compounds of the invention may incontinence; hyperactivity bladder ; painful bladder syn - 60 be administered orally or parenterally at dosage levels of drome ; interstitial cyctitis ( IC ) ; prostatitis , complex regional about 0 .01 mg/ kg to about 50 mg/ kg and preferably from pain syndrome (CRPS ) , type I and type II ; widespread pain , about 1 mg/ kg to about 25 mg/ kg , of subject body weight per paroxysmal extreme pain , pruritis , tinnitis , or angina - in - day, one or more times a day, to obtain the desired thera duced pain . peutic effect. In another aspect , the invention provides the use of a 65 Liquid dosage forms for oral administration include , but compound or pharmaceutical composition described herein are not limited to , pharmaceutically acceptable emulsions, for the manufacture of a medicament for use in treating or microemulsions, solutions , suspensions , syrups and elixirs . US 10 , 087 , 143 B2 165 166 In addition to the active compounds , the liquid dosage forms cose, mannitol , and silicic acid , b ) binders such as, for may contain inert diluents commonly used in the art such as, example , carboxymethylcellulose , alginates, gelatin , poly for example , water or other solvents , solubilizing agents and vinylpyrrolidinone , sucrose, and acacia , c ) humectants such emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl as glycerol, d ) disintegrating agents such as agar - agar, carbonate , ethyl acetate , benzyl alcohol, benzyl benzoate , 5 calcium carbonate , potato or tapioca starch , alginic acid , propylene glycol, 1 , 3 - butylene glycol, dimethylformamide , certain silicates, and sodium carbonate , e ) solution retarding oils ( in particular , cottonseed , groundnut, corn , germ , olivelive , agents such as paraffin , f ) absorption accelerators such as castor, and sesame oils ) , glycerol, tetrahydrofurfuryl alco - quaternary ammonium compounds , g ) wetting agents such hol, polyethylene glycols and fatty acid esters of sorbitan , as , for example , cetyl alcohol and glycerolmonostearate , h ) and mixtures thereof. Besides inert diluents , the oral com - 10 absorbents such as kaolin and bentonite clay , and i ) lubri positions can also include adjuvants such as wetting agents , cants such as talc , calcium stearate , magnesium stearate , emulsifying and suspending agents , sweetening, flavoring , solid polyethylene glycols , sodium lauryl sulfate , and mix and perfuming agents . tures thereof. In the case of capsules, tablets and pills , the Injectable preparations , for example , sterile injectable dosage form may also comprise buffering agents . aqueous or oleaginous suspensions may be formulated 15 Solid compositions of a similar type may also be according to the known art using suitable dispersing or employed as fillers in soft and hard - filled gelatin capsules wetting agents and suspending agents . The sterile injectable using such excipients as lactose ormilk sugar as well as high preparation may also be a sterile injectable solution , sus molecular weight polyethylene glycols and the like . The pension or emulsion in a nontoxic parenterally acceptable solid dosage forms of tablets , dragees, capsules , pills , and diluent or solvent , for example , as a solution in 1 , 3 - - 20 granules can be prepared with coatings and shells such as diol. Among the acceptable vehicles and solvents that may enteric coatings and other coatings well known in the be employed are water, Ringer ' s solution , U . S . P . and iso - pharmaceutical formulating art . They may optionally con tonic sodium chloride solution . In addition , sterile , fixed oils tain opacifying agents and can also be of a composition that are conventionally employed as a solvent or suspending they release the active ingredient( s ) only, or preferentially , in medium . For this purpose any bland fixed oil can be 25 a certain part of the intestinal tract, optionally , in a delayed employed including synthetic mono - or diglycerides . In manner. Examples of embedding compositions that can be addition , fatty acids such as oleic acid are used in the used include polymeric substances and waxes . Solid com preparation of injectables . positions of a similar type may also be employed as fillers The injectable formulations can be sterilized , for example , in soft and hard - filled gelatin capsules using such excipients by filtration through a bacterial- retaining filter, or by incor - 30 as lactose or milk sugar as well as high molecular weight porating sterilizing agents in the form of sterile solid com - polyethylene glycols and the like . positions which can be dissolved or dispersed in sterile The active compounds can also be in microencapsulated water or other sterile injectable medium prior to use. form with one or more excipients as noted above. The solid In order to prolong the effect of a compound of the dosage forms of tablets , dragees , capsules, pills , and gran invention , it is often desirable to slow the absorption of the 35 ules can be prepared with coatings and shells such as enteric compound from subcutaneous or intramuscular injection coatings , release controlling coatings and other coatings This may be accomplished by the use of a liquid suspension well known in the pharmaceutical formulating art . In such of crystalline or amorphous material with poor water solu - solid dosage forms the active compound may be admixed bility . The rate of absorption of the compound then depends with at least one inert diluent such as sucrose , lactose or upon its rate of dissolution that, in turn , may depend upon 40 starch . Such dosage forms may also comprise , as is normal crystal size and crystalline form . Alternatively , delayed practice , additional substances other than inert diluents , e . g . , absorption of a parenterally administered compound form is tableting lubricants and other tableting aids such a magne accomplished by dissolving or suspending the compound in sium stearate and microcrystalline cellulose . In the case of an oil vehicle. Injectable depot forms are made by forming capsules , tablets and pills , the dosage forms may also microencapsule matrices of the compound in biodegradable 45 comprise buffering agents . They may optionally contain polymers such as polylactide -polyglycolide . Depending opacifying agents and can also be of a composition that they upon the ratio of compound to polymer and the nature of the release the active ingredient( s ) only, or preferentially , in a particular polymer employed , the rate of compound release certain part of the intestinal tract, optionally , in a delayed can be controlled . Examples of other biodegradable poly - manner. Examples of embedding compositions that can be mers include poly ( orthoesters ) and poly ( anhydrides) . Depot 50 used include polymeric substances and waxes. injectable formulations are also prepared by entrapping the Dosage forms for topical or transdermal administration of compound in liposomes or microemulsions that are compat - a compound of this invention include ointments , pastes, ible with body tissues . creams, lotions, gels , powders , solutions , sprays , inhalants Compositions for rectal or vaginal administration are or patches. The active component is admixed under sterile preferably suppositories which can be prepared by mixing 55 conditions with a pharmaceutically acceptable carrier and the compounds of this invention with suitable non - irritating any needed preservatives or buffers as may be required . excipients or carriers such as cocoa butter , polyethylene Ophthalmic formulation , eardrops, and eye drops are also glycol or a suppository wax which are solid at ambient contemplated as being within the scope of this invention . temperature but liquid at body temperature and therefore Additionally , the invention contemplates the use of trans melt in the rectum or vaginal cavity and release the active 60 dermal patches , which have the added advantage of provid compound ing controlled delivery of a compound to the body . Such Solid dosage forms for oral administration include cap - dosage forms are prepared by dissolving or dispensing the sules , tablets , pills, powders , and granules . In such solid compound in the proper medium . Absorption enhancers can dosage forms, the active compound is mixed with at least also be used to increase the flux of the compound across the one inert, pharmaceutically acceptable excipient or carrier 65 skin . The rate can be controlled by either providing a rate such as sodium citrate or dicalcium phosphate and/ or a ) controlling membrane or by dispersing the compound in a fillers or extenders such as starches , lactose , sucrose , glu - polymer matrix or gel. US 10 , 087 , 143 B2 167 168 As described generally above , the compounds of the & Dohme Corp ., a subsidiary of Merck & Co . , Inc . , 2011 , invention are useful as inhibitors of voltage - gated sodium and the Food and Drug Administration website , www . fda channels . In one embodiment , the compounds and compo - .gov , the entire contents ofwhich are hereby incorporated by sitions of the invention are inhibitors of Nay1 . 8 and thus, reference . without wishing to be bound by any particular theory , the 5 In another embodiment, additional appropriate therapeu compounds and compositions are particularly useful for tic agents are selected from the following : treating or lessening the severity of a disease , condition , or (1 ) an , e. g. , ,hydromor disorder where activation or hyperactivity of Nay1 . 8 is phone , , , levallorphan , metha implicated in the disease , condition , or disorder . When done , meperidine , , , , dihydroco activation or hyperactivity of Nay1 . 8 is implicated in a 10 deine , , , propoxyphene, nalmefene , particular disease , condition , or disorder, the disease , con nalorphine , naloxone, naltrexone , , butorpha dition , or disorder may also be referred to as a “ Na , 1 . 8 nol, or ; mediated disease , condition or disorder .” Accordingly , in ( 2 ) a nonsteroidal antiinflammatory drug (NSAID ), e . g . oranother lessening aspect the , theseverity invention of a providesdisease , conditiona method, foror disordertreating 15 , , , , fenbufen , fenopro where activation or hyperactivity of Na , 1 . 8 is implicated in fen , flufenisal, , , indomethacin , keto the disease state . profen , , , , The activity of a compound utilized in this invention as an , , , , nitroflurbi inhibitor of Na , 1 . 8 may be assayed according to methods profen , olsalazine, , phenylbutazone , , described generally in the Examples herein , or according to 20 sulfasalazine, , or ; methods available to one of ordinary skill in the art. ( 3 ) a sedative , e . g . amobarbital, aprobarbital, Additional Therapeutic Agents butabarbital, butalbital, mephobarbital, metharbital, metho It will also be appreciated that the compounds and phar - hexital, , phenobarbital, secobarbital , talbutal, maceutically acceptable compositions of the invention can thiamylal or thiopental; be employed in combination therapies , that is , the com - 25 ( 4 ) a benzodiazepine having a sedative action , e . g . pounds and pharmaceutically acceptable compositions can chlordiazepoxide , clorazepate , diazepam , flurazepam , lora be administered concurrently with , prior to , or subsequent z epam , oxazepam , temazepam or triazolam ; to , one or more other desired therapeutics or medical pro - ( 5 ) a histamine ( H ) antagonist having a sedative action , cedures. The particular combination of therapies ( therapeu - e . g . , pyrilamine , , chlorphe tics or procedures ) to employ in a combination regimen will 30 niramine or chlorocyclizine; take into account compatibility of the desired therapeutics ( 6 ) a sedative such as glutethimide, , meth and / or procedures and the desired therapeutic effect to be aqualone or dichloralphenazone ; achieved . It will also be appreciated that the therapies (7 ) a skeletal , e . g . , , employed may achieve a desired effect for the same disorder , , or ( for example , an inventive compound may be administered 35 ; concurrently with another agent used to treat the same ( 8 ) an NMDA , e . g . disorder ), or they may achieve different effects ( e .g ., control (( + ) - 3 -hydroxy - N -methylmorphinan ) or its metabolite dex of any adverse effects ) . As used herein , additional therapeu - trorphan ( ( + ) - 3 - hydroxy - N -methylmorphinan ) , , tic agents that are normally administered to treat or prevent , pyrroloquinoline quinine , cis- 4 - (phosphonom a particular disease, or condition , are known as “ appropriate 40 ethyl) - 2 - piperidinecarboxylic acid , , EN -3231 for the disease , or condition , being treated .” For example , (MorphiDex® ), a combination formulation of morphine and exemplary additional therapeutic agents include , but are not dextromethorphan ) , , or limited to : nonopioid analgesics ( indoles such as Etodolac , including an NR2B antagonist , e . g . , or Indomethacin , Sulindac, Tolmetin ; naphthylalkanones such ( - ) - ( R ) -6 - { 2 - [ 4 - ( 3 - fluorophenyl ) - 4 -hydroxy - 1 - piperidinyl] sa Nabumetone ; oxicams such as Piroxicam ; para -amino - 45 1 -hydroxyethyl - 3 , 4 -dihydro - 2 ( 1H ) - quinolinone ; phenol derivatives , such as Acetaminophen ; propionic acids ( 9 ) an alpha - adrenergic , e . g . doxazosin , tamsulosin , clo such as , Flurbiprofen , Ibuprofen , , nidine , guanfacine , dexmedetomidine , modafinil , or Naproxen , Naproxen sodium , Oxaprozin ; salicylates such as 4 - amino -6 , 7 -dimethoxy - 2 - ( 5 -methane - sulfonamido - 1 , 2 , 3 , Aspirin , Choline magnesium trisalicylate , Diflunisal; fena - 4 - tetrahydroisoquinolin - 2 - yl ) - 5 - ( 2 - pyridyl) quinazoline ; mates such as meclofenamic acid , Mefenamic acid ; and 50 ( 10 ) a , e . g . , imip pyrazoles such as Phenylbutazone ) ; or opioid ( narcotic ) ramine , or ; agonists ( such as Codeine , Fentanyl, , Lev - ( 11 ) an , e. g . carbamazepine ( Tegretol® ), orphanol, Meperidine, , Morphine , Oxycodone , , topiramate , (Vimpat® ) or val Oxymorphone, Propoxyphene, Buprenorphine , Butorpha proate ; nol, , Nalbuphine , and Pentazocine ) . Additionally , 55 (12 ) a tachykinin (NK ) antagonist , particularly an NK - 3 , nondrug analgesic approaches may be utilized in conjunc - NK - 2 or NK - 1 antagonist, e . g . ( alphaR , 9R ) - 7 - [ 3 , 5 -bis ( trif tion with administration of one or more compounds of the luoromethyl) benzyl ] -8 , 9, 10 ,11 - tetrahydro - 9 -methyl - 5 -( 4 invention . For example , anesthesiologic ( intraspinal infu methylphenyl) - 7H - [ 1 , 4 ]diazocino [ 2 , 1 - g ] [ 1 , 7 ] -naphthyri sion , neural blockade ), neurosurgical (neurolysis of CNS dine - 6 - 13 -dione ( TAK -637 ) , 5 - [ [ ( 2R ,3S ) - 2 - [ (1R ) - 1 - 13 , 5 - bis pathways ) , neurostimulatory ( transcutaneous electrical 60 (trifluoromethyl ) phenyl ] ethoxy - 3 - ( 4 - fluorophenyl) - 4 nerve stimulation , dorsal column stimulation ), physiatric morpholinyl] -methyl ] - 1 , 2 -dihydro - 3H - 1 , 2 , 4 - triazol - 3 -one ( physical therapy , orthotic devices , diathermy) , or psycho - (MK - 869 ), aprepitant, lanepitant, dapitant or 3 - [ [ 2 logic ( cognitive methods- hypnosis , biofeedback , or behav methoxy - 5 - ( trifluoromethoxy )phenyl ] -methylamino ] - 2 ioral methods) approaches may also be utilized . Additional phenylpiperidine (2S , 3S ) ; appropriate therapeutic agents or approaches are described 65 (13 ) a muscarinic antagonist , e . g . oxybutynin , , generally in The Merck Manual, Nineteenth Edition , Ed . propiverine , tropsium chloride , , , Robert S . Porter and Justin L . Kaplan , Merck Sharp temiverine and ipratropium ; US 10 , 087 , 143 B2 169 170 (14 ) a COX - 2 selective inhibitor , e .g . , rofe (28 ) metabotropic glutamate subtype 1 receptor coxib , , , deracoxib , , or (mGluR1 ) antagonist ; ; (29 ) a serotonin reuptake inhibitor such as sertraline, (15 ) a coal -tar analgesic , in particular ; sertraline metabolite demethylsertraline , , norflu ( 16 ) a neuroleptic such as droperidol, , 5 oxetine ( fluoxetine desmethyl metabolite ) . fluvoxamine , , perphenazine, , mesoridazine , trif luoperazine , fluphenazine, , olanzapine, risperi paroxetine , citalopram , citalopram metabolite desmethylci done , ziprasidone , quetiapine , , aripiprazole , talopram , escitalopram , d ,l - fenfluramine , femoxetine, ifox sonepiprazole , blonanserin , iloperidone , perospirone , raclo etine , cyanodothiepin , litoxetine , dapoxetine, nefazodone , pride, zotepine, bifeprunox , asenapine , lurasidone, amisul- 10 cericlamine and trazodone ; pride, balaperidone, palindore , eplivanserin , osanetant, ( 30 ) a noradrenaline (norepinephrine ) reuptake inhibitor, rimonabant, meclinertant, Miraxion® or sarizotan ; such as maprotiline, lofepramine , mirtazepine , oxaprotiline , ( 17 ) a vanilloid receptor agonist ( e . g . resinferatoxin or fezolamine, tomoxetine , mianserin , , bupropion civamide) or antagonist ( e . g . capsazepine , GRC - 15300 ) ; metabolite hydroxybupropion , nomifensine and viloxazine ( 18 ) a beta -adrenergic such as ; 15 (Vivalan® ), especially a selective noradrenaline reuptake ( 19 ) a local anaesthetic such as ; inhibitor such as reboxetine, in particular ( S , S ) - reboxetine ; ( 20 ) a corticosteroid such as dexamethasone ; (31 ) a dual serotonin -noradrenaline reuptake inhibitor, (21 ) a 5 -HT receptor agonist or antagonist , particularly a such as venlafaxine , venlafaxine metabolite O - desmethyl 5 -HT1B / 10 agonist such as eletriptan , sumatriptan , naratrip venlafaxine , , clomipramine metabolite desm tan , zolmitriptan or rizatriptan ; 20 ethylclomipramine , (Cymbalta® ), (22 ) a 5 -HT24 receptor antagonist such as R ( + ) - alpha - ( 2 , and ; 3 -dimethoxy - phenyl) - 1 - [ 2 - ( 4 - fluorophenylethyl) ] - 4 -piperi - (32 ) an inducible nitric oxide synthase ( iNOS) inhibitor dinemethanol (MDL - 100907 ) ; such as S - [ 2 - [ ( 1 - iminoethyl) amino ) ethyl] - L -homocysteine , ( 23 ) a cholinergic (nicotinic ) analgesic , such as isproni - SUS - [ 2 - [ ( 1 - iminoethyl) -aminoJethyl ) - 4 , 4 - dioxo - L - cysteine , cline ( TC - 1734 ) , ( E ) - N -methyl - 4 - ( 3 -pyridinyl ) - 3 -buten - 1 - 25 S - [ 2 - [ ( 1 - iminoethyl) amino ) ethyl] - 2 -methyl - L - cysteine, (2S , amine (RJR -2403 ) , ( R ) - 5 - ( 2 -azetidinylmethoxy ) - 2 -chloro 5Z ) - 2 - amino - 2 -methyl - 7 - [ ( 1 -iminoethyl ) amino ] - 5 -hep pyridine ( ABT- 594 ) or nicotine ; tenoic acid , 2 - [ [ ( 1R , 3S ) - 3 - amino - 4 -hydroxy - 1 - ( 5 - thiaz ( 24 ) ® , Tramadol ER (Ultram ER® ) , Tapent olyl) -butyl ] thio ] - S - chloro - S -pyridinecarbonitrile ; 2 - [ [ ( 1R , adol ER (Nucynta® ); 3S ) -3 -amino - 4 -hydroxy - 1 -( 5 - thiazolyl) butyl ]thio ] -4 (25 ) a PDE5 inhibitor, such as 5 - [ 2 - ethoxy - 5 - ( 4 -methyl - 30 chlorobenzonitrile , (2S ,4R ) - 2 - amino - 4 - [ 2 -chloro - 5 1 - piperazinyl- sulphonyl ) phenyl] - 1 -methyl - 3 - n - propyl - 1 ,6 - ( trifluoromethyl) phenyl] thio )- 5 -thiazolebutanol , 2 - [[ (1R , dihydro -7H -pyrazolo [ 4, 3 -d ]pyrimidin - 7 -one ( sildenafil) , 3S ) -3 - amino - 4 -hydroxy - 1 -( 5 - thiazolyl) butyl] thio ]- 6 (6R , 12aR ) - 2 , 3 ,6 , 7 , 12 , 12a -hexahydro - 2 -methyl - 6 - ( 3 , 4 (trifluoromethyl ) -3 -pyridinecarbonitrile , 2 -[ [ (1R ,3S )- 3 methylenedioxyphenyl) - pyrazino [ 2 ' , 1 ' :6 , 1 ] -pyrido [ 3 ,4 - b ] in amino - 4 -hydroxy - 1 - ( 5 - thiazolyl )butyl ] thio ] - 5 dole - 1 ,4 -dione (IC -351 or tadalafil ), 2 -[ 2 -ethoxy -5 -( 4 -ethyl - 35 chlorobenzonitrile , N -[ 4 - [2 - ( 3 -chlorobenzylamino ) ethyl] piperazin - 1 -yl - 1- sulphonyl) -phenyl ] -5 -methyl - 7 -propyl - phenyl] thiophene -2 -carboxamidine , NXN - 462 , or 3H - imidazo [ 5 , 1 - f ][ 1 , 2 , 4 ] triazin - 4 - one ( vardenafil ), 5 - ( 5 - guanidinoethyldisulfide; acetyl- 2 -butoxy - 3 -pyridinyl ) - 3 -ethyl - 2 - ( 1 - ethyl - 3 (33 ) an acetylcholinesterase inhibitor such as donepezil; azetidinyl) - 2 , 6 -dihydro - 7H -pyrazolo [ 4 , 3 - d ]pyrimidin - 7 ( 34 ) a prostaglandin E2 subtype 4 (EP4 ) antagonist such one, 5 - ( 5 - acetyl- 2 - propoxy - 3 -pyridinyl ) - 3 - ethyl- 2 - ( 1 - 40 as N - [ ( { 2 - [ 4 - ( 2 - ethyl- 4 ,6 - dimethyl- 1H - imidazo [ 4 , 5 - c ] pyri isopropyl- 3 - azetidinyl) - 2 ,6 - dihydro - 7H - pyrazolo [ 4 , 3 - d ] din - 1 - yl) phenyl] ethyl} amino ) - carbonyl] - 4 -methylbenzene pyrimidin - 7 -one , 5- [ 2 - ethoxy -5 -( 4 - ethylpiperazin - 1 - sulfonamide or 4 -[ ( 15 )- 1 -( {[ 5 -chloro - 2 -( 3 - fluorophenoxy ) ylsulphonyl) pyridin - 3 - yl] - 3 - ethyl- 2 - [ 2 -methoxyethyl ] - 2 ,6 - pyridin - 3 - yl ] carbonyl } amino ) ethyl] benzoic acid ; dihydro -7H - pyrazolo [ 4 , 3 - d ] pyrimidin - 7 - one , 4 - [ ( 3 - chloro (35 ) a leukotriene B4 antagonist; such as 1 - ( 3 - biphenyl 4 -methoxybenzyl ) amino ] - 2 - [ (2S ) - 2 - (hydroxymethyl ) 45 4 - ylmethyl- 4 - hydroxy - chroman - 7 -yl ) - cyclopentanecarbox pyrrolidin - 1 - yl] - N - ( pyrimidin - 2 - ylmethyl )pyrimidine - 5 ylic acid ( CP - 105696 ), 5 - [ 2 - ( 2 - Carboxyethyl ) - 3 - [ 6 - ( 4 carboxamide, 3 -( 1 -methyl - 7 -oxo -3 -propyl - 6 ,7 -dihydro - 1H - methoxyphenyl) -5E -hexenyl ] oxyphenoxyl - valeric acid pyrazolo [4 , 3 - d ]pyrimidin -5 -yl ) -N - [2 -( 1 -methylpyrrolidin - (ONO - 4057) or DPC - 11870 ; 2 -yl ) ethyl ] - 4 -propoxybenzenesulfonamide ; ( 36 ) a 5 - lipoxygenase inhibitor, such as zileuton , 6 - [( 3 (26 ) an alpha - 2 -delta ligand such as (Neu - 50 fluoro -5 -[ 4 -methoxy - 3 ,4 ,5 , 6 -tetrahydro - 2H - pyran -4 -yl ] ) rontin® ), gabapentin GR (Gralise® ), gabapentin , enacarbil phenoxy -methyl ] - 1 -methyl - 2 - quinolone (ZD - 2138 ) , or 2 ,3 , ( Horizant® ) , (Lyrica® ) , 3 -methyl gabapentin , 5 - trimethyl - 6 - ( 3 -pyridylmethyl ) - 1 , 4 -benzoquinone ( CV ( 1 [ alpha ], 3 [ alpha ], 5 [ alpha ] ) ( 3 - amino -methyl - bicyclo [ 3 . 2 . 0 ) 6504 ) ; hept - 3 - yl) -acetic acid , (3S ,5R ) - 3 - aminomethyl- 5 -methyl - ( 37) a sodium channel blocker, such as lidocaine , lido heptanoic acid , ( 3S ,5R )- 3 - amino -5 -methyl - heptanoic acid , 55 caine plus cream (ZRS - 201 ) or eslicarbazepine ( 3S , 5R ) - 3 - amino - 5 -methyl - octanoic acid , ( 2S , 4S ) - 4 - ( 3 acetate ; chlorophenoxy ) , ( 2S ,4S ) - 4 - ( 3 - fluorobenzyl ) - proline , ( 38 ) an Nav1. 7 blocker, such as XEN - 402 and such as [( 1R ,5R ,6S ) -6 - (aminomethyl ) bicyclo [ 3 .2 . 0 ]hept - 6 - yl] acetic those disclosed in WO2011 / 140425 ; WO2012 / 106499 ; acid , 3 - ( 1 - aminomethyl- cyclohexylmethyl) - 4H -[ 1 , 2 ,4 ]ox ?? - WO2012 / 112743 ; WO2012 / 125613 or PCT /US2013 /21535 adiazol- 5 - one , C - [ 1 - ( 1H - tetrazol- 5 - ylmethyl) -cycloheptyl ] - 60 the entire contents of each application hereby incorporated methylamine , ( 3S ,4S ) - ( 1 -aminomethyl - 3 ,4 - dimethyl- cyclo by reference . pentyl) - acetic acid , (3S ,5R ) - 3 - aminomethyl- 5 -methyl - ( 39 ) an Nay1. 8 blocker, such as those disclosed in octanoic acid , (3S ,5R ) - 3 -amino - 5 -methyl - nonanoic acid , WO2008 / 135826 and WO2006 /011050 the entire contents ( 3S ,5R ) - 3 -amino - 5 -methyl - octanoic acid , ( 3R ,4R , 5R ) - 3 - of each application hereby incorporated by reference. amino - 4 , 5 -dimethyl - heptanoic acid and ( 3R ,4R , 5R ) - 3 - 65 ( 40 ) a combined Nay1. 7 and Nay1 . 8 blocker, such as amino - 4 , 5 - dimethyl -octanoic acid ; DSP -2230 or BL -1021 ; (27 ) a such as KHK -6188 ; (41 ) a 5 -HT3 antagonist , such as ondansetron ; US 10 , 087 , 143 B2 171 172 (42 ) a TPRV 1 receptor agonist, such as ( Neu - coated with a composition comprising a compound of the rogesX® , Qutenza® ) ; and the pharmaceutically acceptable invention as described generally above , and in classes and salts and solvates thereof ; subclasses herein , and a carrier suitable for coating said (43 ) a nicotinic receptor antagonist , such as varenicline ; implantable device . Suitable coatings and the general prepa ( 44 ) an N - type antagonist, such as 5 ration of coated implantable devices are described in U . S . Z - 160 ; Pat. Nos. 6 ,099 ,562 ; 5 , 886 ,026 ; and 5 , 304 , 121 . The coatings ( 45 ) a nerve growth factor antagonist , such as tanezumab ; are typically biocompatible polymeric materials such as a hydrogel polymer , polymethyldisiloxane , polycaprolactone , ( 46 ) an endopeptidase stimulant, such as senrebotase ; polyethylene glycol, polylactic acid , ethylene vinyl acetate , (47 ) an angiotensin II antagonist, such as EMA -401 ; and mixtures thereof. The coatings may optionally be further In one embodiment, the additional appropriate therapeutic 10 covered by a suitable topcoat of fluorosilicone , polysacca agents are selected from V - 116517 , Pregabalin , controlled rides , polyethylene glycol, phospholipids or combinations release Pregabalin , Ezogabine (Potiga® ) . Ketamine/ amitrip thereof to impart controlled release characteristics in the tyline topical cream ( Amiket® ), AVP - 923 , composition . ( E - 2007 ) , Ralfinamide, transdermal ( Eladur® ) , Another aspect of the invention relates to inhibiting CNV1014802 , JNJ- 10234094 (Carisbamate ), BMS - 954561 15 Na ,, 1 . 8 activity in a biological sample or a subject, which or ARC- 4558. method comprises administering to the subject, or contact The amount of additional therapeutic agent present in the ing said biological sample with a compound of formula I or compositions of this invention will be no more than the formula I' or a composition comprising said compound . The amount that would normally be administered in a composi term “ biological sample , " as used herein , includes, without tion comprising that therapeutic agent as the only active 20 limitation , cell cultures or extracts thereof; biopsied material agent. The amount of additional therapeutic agent in the obtained from a mammal or extracts thereof; and blood , presently disclosed compositions will range from about 10 % saliva , urine, feces , semen , tears , or other body fluids or to 100 % of the amount normally present in a composition extracts thereof. comprising that agent as the only therapeutically active Inhibition of Nav1. 8 activity in a biological sample is agent. 25 useful for a variety of purposes that are known to one of skill The compounds of this invention or pharmaceutically in the art. Examples of such purposes include, but are not acceptable compositions thereof may also be incorporated limited to , the study of sodium channels in biological and into compositions for coating an implantable medical pathological phenomena ; and the comparative evaluation of device , such as prostheses , artificial valves, vascular grafts , new sodium channel inhibitors . stents and catheters . Accordingly , the invention , in another 30 SCHEMES AND EXAMPLES aspect, includes a composition for coating an implantable device comprising a compound of the invention as described The compounds of the invention may be prepared readily generally above , and in classes and subclasses herein , and a using the following methods. Illustrated below in Scheme 1 carrier suitable for coating said implantable device . In still through Scheme 3 are general methods for preparing the another aspect , the invention includes an implantable device compounds of the present invention .

Scheme 1: General Preparation of Compounds of Formula I

R ! 0 RO Rl O NH R2 R2R ? I 2 OH XXXR3 R4 (e ) G - OH (b ) refo- on

RO RO NH

P3 Y F R3 0

Q= US 10 ,087 , 143 B2 173 174 - continued

2 R2 0H

R3 R4 R4 ( a ) 2 -Methoxypyridin - 4 -amine , coupling agent ( i. e . HATU , EDCI, HOBT) , base (ie , N - methylmorpholine, Et3N ), solvent ( i. e . DMF, dichloromethane) ; ( b ) SO2Cl2 , DMF in a solvent ( i. e dichloromethane) ; (c ) 2 -Methoxypyridin - 4 - amine, base ( i. e . pyridine ), solvent ( i. e . dichloromethane, DMF ); ( d ) TMSI or HBr, solvent (ie , acetonitrile or acetic acid ); (e ) base (i . e . Cs2CO3, Na2CO3, K2CO3, NaHCO3) , solvent ( DMF, NMP, dioxane ), heat .

Scheme 2 : General Preparation of Compounds of Formula I' ?? ? R1 0 R1 0

(a ) ( d ) 13? 3. R4 R4 R4 ??? )? ( G - OH ??

/ / 0 R ?

3? 3?? 4 ???? ?? R1R / 0 R1 0

0H

R3 R3 "

R4 R4 G ( a ) 6 -Methoxypyridin - 3 -amine , coupling agent (i . e . HATL , EDCI, HOBT??) , base ( i. e . N -methylmorpholine , EtN ), solvent (i . e . DMF, dichloromethane) ; (b ) S0gCl2 , DMF in a solvent (i .e dichloromethane ); (c ) 6 -Methoxypyridin - 3 -amine , base ( i. e . pyridine ), solvent ( i. e . dichloromethane, DMF ); ( d ) TMSI or HBr, solvent ( i. e . acetonitrile or acetic acid ); ( e ) base (i . e . Cs2CO3, Na2CO3, KgCO3, NaHCO3 ), solvent (DMF , NMP, dioxane ) , heat. ????

55 -continued

Scheme 3 : General Preparation of Compounds of Formula I ?? R1 0 R1 0 LZ 3 - R4 ?? US 10 ,087 , 143 B2 175 176 -continued dried over sodium sulfate , filtered and concentrated under reduced pressure . The product was slurried in hexane , the hexane was decanted and the product was dried under reduced pressure to yield 2 - fluoro - N - ( 2 -methoxy - 4 5 pyridyl) -4 - (trifluoromethyl ) benzamide ( 25 . 7 g , 74 % ) as a cream solid . ESI -MS m / z calc . 314 . 07 , found 315 . 3 ( M + 1 ) + ; O Retention time: 1 . 49 minutes ( 3 minutes run ). ' H NMR (400 MHz , DMSO - d6 ) S 10. 96 ( s , 1H ), 8 . 15 - 8 . 04 ( m , 1H ) , 8 .00 - 7 .85 ( m , 2H ) , 7 .76 ( d , J = 8 . 1 Hz, 1H ) , 7 . 26 - 7 . 15 ( m , ?? 2H ) , 3 . 85 ( s , 3H ) ppm . To 2 - fluoro - N -( 2 -methoxy -4 -pyridyl ) -4 - (trifluoromethyl ) 23R37 benzamide ( 1 . 00 g , 3 . 18 mmol) in acetic acid ( 6 . 0 mL ) was R4 G added HBr ( 33 % in acetic acid ) ( 3 . 9 mL of 33 % w / v , 15 . 91 (a ) Rº - X ( X = CI, Br or I ), base ( i. e . NaH ) , solvent ( i. e ., DMF) , heat or ( b ) coupling 15 mmol) and the mixture stirred at 100° C . for 6 hours . agent (i . e . HATU ) , base ( i. e . Et3N ), solvent (i . e . dichloromethane ) . Additional HBr ( 2 mL , 33 % in acetic acid ) was added and the mixture was stirred at room temperature overnight. The mixture was then heated at 100° C . for 2 hours before it was EXAMPLES cooled to room temperature . The mixture was partitioned 20 between ethyl acetate and water . The layers were separated General Methods. and the aqueous layer was extracted with ethyl acetate (3x ) . IH NMR ( 400 MHz ) spectra were obtained as solutions in The combined organics were washed with water and brine an appropriate deuterated solvent such as dimethyl sulfox - (2x ) , dried over sodium sulfate , filtered and concentrated ide -da (DMSO ) . Mass spectra (MS ) were obtained using an under reduced pressure . The solid was slurried in methyl Applied Biosystems API EX LC /MS system . Compound 25 tert -butyl ether and filtered to give 2 - fluoro -N -( 2 -oxo - 1H purity and retention times were determined by reverse phase pyridin - 4 - yl) - 4 - ( trifluoromethyl) benzamide (731 mg, 76 % ) . HPLC using a Kinetix C18 column (50x2 . 1 mm , 1. 7 um ESI- MS m / z calc . 301 .05 , found 301 .3 ( M + 1) *; Retention particle ) from Phenomenex ( pn : 00B -4475 -AN )) , and a dual time: 1. 35 minutes (3 minute run ) . ' H NMR (400 MHz, gradient run from 1 - 99 % mobile phase B over 3 minutes . 20 DMSO -d6 ) 8 11 .33 (s , 1H ) , 10 .70 (s , 1H ), 7 . 96 -7 .85 ( m , Mobile phase A = H , 0 ( 0 . 05 % CF , CO , H ) . Mobile phase 2H ) , 7 .75 ( d . J = 8 . 2 Hz, 1H ) , 7 . 35 ( d , J = 7 . 2 Hz, 1H ) , 6 .81 ( d , B = CH2CN (0 .05 % CF2C02H ) . Flow rate = 2 mL/ min , injec J = 1. 9 Hz, 1H ), 6 .41 (dd , J= 7 .2 , 2 . 1 Hz, 1H ) ppm . tion volume= 3 uL , and column temperature = 50° C . Silica gel chromatography was performed using silica gel- 60 with a particle size of 230 - 400 mesh . Pyridine , dichloromethane Example 2 (CH _ C12 ) , tetrahydrofuran ( THF ) , dimethylformamide (DMF ) , acetonitrile (ACN ) , methanol (MeOH ) , and 1 , 4 dioxane were from Baker or Aldrich and in some cases the Preparation of 2 - fluoro - N -( 2 - oxo - 1, 2 -dihydropyri reagents were Aldrich Sure - Seal bottles kept under dry din - 4 -yl ) - 5 - ( trifluoromethyl) benzamide nitrogen . All reactions were stirred magnetically unless ac otherwise noted . Example 1 Preparation of 2 - fluoro - N - ( 2 -oxo - 1 , 2 -dihydropyri 45 din -4 -yl ) - 4 -( trifluoromethyl) benzamide F C NH

50 ?? A solution of 2 - fluoro - 5 -( trifluoromethyl) benzoyl chlo ride ( 25 g , 110 . 3 mmol) in dichloromethane (125 . 0 mL ) was added drop -wise to a mixture of 2 -methoxypyridin - 4 -amine N 55 ( 13 . 7 g , 110 .3 mmol) , pyridine ( 26 . 8 mL , 330 . 9 mmol) and dichloromethane (500 . 0 mL ) at 0° C . The mixture was F3C F allowed to warm to room temperature and was stirred at that temperature overnight. The mixture was poured into 1N HC1 A solution of 2 - fluoro -4 - ( trifluoromethyl) benzoyl chlo - ( 200 mL ) and dichloromethane ( 200 mL ) . The layers were ride (25 . 0 g , 110 . 3 mmol) in dichloromethane ( 125 . 0 mL ) 60 separated and the organic layer was dried over sodium was added drop -wise to a mixture of 2 -methoxypyridin - 4 - sulfate , filtered and concentrated under reduced pressure to amine (13 . 7 g , 110 . 3 mmol) , pyridine (26 . 8 mL , 330 . 9 give 2 - fluoro - N - ( 2 -methoxy - 4 - pyridyl ) - 5 - ( trifluoromethyl) mmol) and dichloromethane (500 .0 mL ) at 0° C . The mix benzamide ( 33 .6 g, 97. 00 % ) as an off -white solid . ESI- MS ture was allowed to warm to room temperature and was m / z calc . 314 . 07 , found 315 . 2 ( M + 1 ) + ; Retention time: 1 . 44 stirred at that temperature overnight. The mixture was 65 minutes ( 3 minutes run ) . ' H NMR (400 MHz, DMSO -d6 ) d poured into IN HC1 ( 200 mL ) and dichloromethane (200 10 . 94 ( s , 1H ), 8 . 12 - 8 . 07 ( m , 2H ) , 8 .07 - 7 . 98 ( m , 1H ) , 7 .65 ( t , mL ). The layers were separated and the organic layer was J = 9 .2 Hz, 1H ) , 7. 24 - 7 .19 ( m , 2H ), 3 . 85 ( s, 3H ) ppm . US 10 , 087 , 143 B2 177 178 To 2 - fluoro - N - ( 2 -methoxy - 4 -pyridyl ) - 5 - (trifluoromethyl ) Example 4 benzamide ( 3 .54 g , 11 .27 mmol) in acetonitrile (118 . 0 mL ) was added TMSI ( 4 . 0 mL , 28 . 18 mmol) . The reaction was Preparation of 5 -chloro - 2 - fluoro - N - ( 2 -oxo -1 ,2 -dihy stirred at 50° C . overnight. The acetonitrile was evaporated dropyridin - 4 -yl ) benzamide and the crude re- dissolved in ethyl acetate . The organics 5 were washed with water, dried over sodium sulfate , filtered and concentrated . Purification by silica gel chromatography using a gradient of ethyl acetate in hexanes ( 0 - 100 % ) and then methanol in dichloromethane ( 0 - 20 % ) gave 2 - fluoro N - ( 2 -oxo - 1H -pyridin - 4 - yl) - 5 - ( trifluoromethyl) benzamide 101 NH ( 3 g , 89 % ) , as a brown solid . ESI- MS m /z calc. 300 .05 , found 301. 3 ( M + 1 ) + ; Retention time: 1 .34 minutes ( 3 min utes run ). ' H NMR (400 MHz , DMSO - d6 ) 10 .85 ( s , 1H ), NH 8 . 10 (dd , J = 6 .0 , 2 .2 Hz, 1H ), 8 . 03 ( m , 1H ), 7. 65 (t , J= 9 .2 Hz, 1H ) , 7 .49 ( d , J= 7 . 1 Hz , 1H ), 6 .97 ( d , J= 2 .0 Hz, 1H ), 6 .57 ( dd , J = 7 . 2 , 2 . 1 Hz, 1H ) , 5 .07 ( s, 2H ) ppm . A solution of 5 - chloro - 2 - fluoro - benzoic acid ( 5 . 0 g , 28 .64 mmol) , HATU ( 10 .89 g , 28 . 64 mmol ) , 2 -methoxypyridin Example 3 4 - amine ( 3 .6 g , 28 .64 mmol) and EtzN ( 15 .98 mL , 114 .60 mmol) in dichloromethane (45 . 0 mL ) was stirred at room Preparation of 4 -chloro - 2 - fluoro - N - ( 2 -oxo -1 ,2 -dihy temperature overnight. The crude mixture was purified by dropyridin - 4 - yl) benzamide column chromatography eluting with a gradient of ethyl acetate in hexanes ( 0 - 50 % ) to yield 5 -chloro - 2 - fluoro - N -( 2 25 methoxy -4 - pyridyl) benzamide (3 .8 g , 47 % ) as a white solid . ESI- MS m / z calc . 280 .04 , found 281. 3 ( M + 1 ) *; Retention time: 1 .31 minutes (3 minutes run ). To 5 -chloro - 2- fluoro -N -( 2 -methoxy -4 -pyridyl )benzamide ( 3 . 8 g , 13 .50 mmol) in acetonitrile ( 126 . 3 mL ) was added 30 TMSI ( 7 . 7 mL , 54. 00 mmol) . The reaction was stirred at 50° ?? C . overnight. The acetonitrile was evaporated and the crude re - dissolved in ethyl acetate . The organics were washed with water, dried over sodium sulfate, filtered and concentrated . Purification by silica gel chromatography using a gradient of 35 ethyl acetate in hexanes (0 - 100 % ) and then methanol in dichloromethane ( 0 -20 % ) yielded 5 - chloro - 2 - fluoro - N - ( 2 oxo - 1H - pyridin - 4 - yl) benzamide ( 950 mg, 26 % ) as a white A solution of 4 - chloro - 2 - fluoro - benzoic acid ( 7 . 0 g , 40 . 10 solid . ESI -MS m / z calc . 266 .03 , found 267. 1 ( M + 1 ) * ; Reten mmol) , HATU (15 .25 g , 40 .10 mmol) , 2 -methoxypyridin - 40 tion time: 1. 24 minutes (3 minutes run ). 4 -amine (4 .98 g , 40 .10 mmol ) and EtzN (22 . 4 mL , 160 .4 Example 5 mmol ) in dichloromethane (63 .0 mL ) was stirred at room temperature overnight. The crude mixture was purified by Preparation of 5 - chloro - 2 - fluoro - N - ( 2 -oxo - 1 , 2 -dihy column chromatography eluting with a gradient of ethyl 45 dropyridin - 4 -yl ) benzamide acetate in hexanes ( 0 - 50 % ) to yield 4 - chloro - 2 - fluoro - N - ( 2 methoxy - 4 -pyridyl ) benzamide ( 4 . 35 g , 39 % ), as a white solid . ESI- MS m / z calc . 280 . 04 , found 281. 3 ( M + 1 ) * ; Reten tion time: 1 . 31 minutes ( 3 minutes run ) . ' H NMR (400 MHz, DMSO - d6 ) 8 10 . 80 ( s , 1H ) , 8 . 09 ( m , 1H ) , 7 . 73 ( t, J = 8 . 0 Hz, 50 1H ) , 7 . 66 ( dd , J = 10 . 1 , 1 . 9 Hz, 1H ) , 7 . 46 (dd , J = 8 . 3 , 1 . 9 Hz , NH 1H ), 7. 21 (m , 2H ), 3 .84 (s , 3H ) ppm . To 4 -chloro - 2 - fluoro -N - ( 2 -methoxy -4 -pyridyl ) benzamide ( 4 . 35 g , 15 . 50 mmol) in acetonitrile ( 145. 0 mL ) was added 55 TMSI ( 8 . 8 mL , 62. 0 mmol) . The reaction was stirred at 50° NC C . overnight . The acetonitrile was evaporated and the crude solid was triturated with ethylacetate . The solid was isolated A solution of 4 -cyano -2 - fluoro -benzoic acid (6 .7 g , 40 . 58 by filtration and washed with ethyl acetate to give 4 - chloro mmol) , HATU ( 15 . 4 g , 40 . 58 mmol ) , 2 -methoxypyridin - 4 o 60 amine ( 5 .0 g , 40 .58 mmol) and EtzN ( 22 .62 mL , 162 .3 2 - fluoro - N - ( 2 - oxo - 1H - pyridin - 4 - yl) benzamide (3 . 8 g , mmol) in dichloromethane (60 . 3 mL ) was stirred at room 92 % ) . ESI -MS m / z calc . 266 .02 , found 267. 1 ( M + 1 ) + ; temperature overnight. The crude mixture was purified by Retention time: 1 .23 minutes (3 minutes run ) . ' H NMR (400 column chromatography using a gradient of ethyl acetate in MHz , DMSO - 06 ) 8 10 . 86 ( s , 1H ) , 7 .73 ( t, J = 8 . 0 Hz , 1H ) , hexanes ( 0 -50 % ) to yield 4 - cyano - 2 - fluoro - N - ( 2 -methoxy 7 .68 ( dd , J = 10 . 1 , 1 . 9 Hz, 1H ) , 7 .60 ( d , J = 7 . 1 Hz, 1H ) , 7 .47 65 4 -pyridyl ) benzamide ( 7 . 3 g , 66 % ) as a white solid . ESI- MS ( dd , J = 8 .3 , 2 .0 Hz, 1H ), 7 . 11 (d , J= 2 . 0 Hz, 1H ), 6 .71 (dd , m /z calc . 271. 07 , found 272 .1 (M + 1 )+ ; Retention time: 1. 17 J = 7 . 1, 2 . 1 Hz, 1H ) ppm . minutes ( 3 minutes run ) . US 10 ,087 , 143 B2 179 180 To 4 -cyano -2 - fluoro - N -( 2 -methoxy -4 -pyridyl ) benzamide Example 7 ( 7 . 3 g , 26 . 99 mmol) in acetonitrile (244 . 0 mL ) was added TMSI ( 9 .99 mL , 70 . 17 mmol) . The reaction was stirred at Preparation of 2 - fluoro - N -( 2 -oxo - 1 , 2 - dihydropyri 50° C . overnight. The acetonitrile was evaporated and the din - 4 - yl) - 4 - (perfluoroethyl ) benzamide crude solid was triturated with ethyl acetate. The solid was 5 isolated by filtration and washed with ethyl acetate to give 4 - cyano - 2 - fluoro - N - ( 2 - oxo - 1H -pyridin - 4 - yl )benzamide as a tan solid . ESI- MS m / z calc . 257 .06 , found 258 . 1 ( M + 1 ) + ; Retention time: 1 .08 minutes ( 3 minutes run ). ' H NMR ( 400 MHz, DMSO - d6 ) 8 10 . 94 ( s , 1H ) , 8 . 11 ( t, J = 11 . 4 Hz, 1H ) , 10 NH 7 .88 ( m , 2H ), 7 .53 ( d , J = 7 . 1 Hz , 1H ), 7 .01 (d , J = 2 .0 Hz , 1H ), 6 .60 (dd , J = 7 . 2 , 2 . 1 Hz, 1H ) ppm . N Example 6 F3CF, C v F Preparation of 2 - fluoro -N -( 2 -oxo - 1, 2 - dihydropyri A solution of 4 - bromo - 2 - fluoro - benzoyl chloride ( 2 g , din - 4 - yl) - 5 - ( trifluoromethoxy ) benzamide 8 .42 mmol) in dichloromethane ( 10. 0 mL ) was added drop 20 wise to a mixture of 2 -methoxypyridin -4 - amine ( 1. 0 g , 8 .42 mmol) , pyridine ( 2 . 0 mL , 25 . 27 mmol) and dichloromethane ( 40 . 0 mL ) at 0° C . The mixture was allowed to warm to room temperature and was stirred at that temperature over night. The mixture was poured into 1N HCl (200 mL ) and dichloromethane ( 200 mL ) . The layers were separated and the organic layer was dried over sodium sulfate , filtered and NH concentrated under reduced pressure to give 4 -bromo - 2 fluoro - N - ( 2 -methoxy - 4 -pyridyl ) benzamide ( 1 .2 g , 44 % ) as F3CO an off -white solid . ESI -MS m / z calc . 323 . 99 , found 325 . 1 NH ( M + 1 ) *; Retention time: 1. 37 minutes (3 minutes run ) . ' H NMR (400 MHz , DMSO - d6 ) 8 10 . 80 ( s, 1H ), 8 .11 - 8 . 06 (m , 1H ) , 7 .79 (dd , J = 9 . 8 , 1 . 7 Hz , 1H ) , 7 .68 - 7 .62 ( m , 1H ) , 7 .59 (dd , J = 8 . 3 , 1 . 7 Hz, 1H ) , 7 . 23 - 7 . 18 ( m , 2H ), 3 . 84 ( s , 3H ) A solution of 2 - fluoro - 5 - ( trifluoromethoxy )benzoic acid 35 ppm . ( 5 . 3 g , 23 .47 mmol) , HATU ( 8 . 92 g , 23 .47 mmol) , To a stirred solution of 4 -bromo - 2 - fluoro - N -( 2 -methoxy 2 -methoxypyridin - 4 - amine ( 2 . 9 g , 23 . 47 mmol) and EtzN 4 -pyridyl ) benzamide (800 mg, 2 . 46 mmol) and copper ( 1 .6 g , 24 .61 mmol) in DMSO ( 15 mL ), in a bomb, 1 , 1 , 1 , 2 , 2 ( 13 .09 mL , 93 .88 mmol) in dichloromethane (47 . 4 mL ) was pentafluoro8 , - 2 - iodo - ethane ( 4 . 1 g , 16 .47 mmol) was bubbled stirred at room temperature overnight. The crude mixture 40 through . The vessel was sealed and heated at 120° C . for 16 was purified by column chromatography eluting with a 40 hours . The reaction mixture was diluted with water and gradient of ethyl acetate in hexanes ( 0 - 50 % ) to yield filtered through a plug of silica and then extracted with ethyl 2 - fluoro - N - ( 2 -methoxy - 4 - pyridyl ) - 5 - (trifluoromethoxy ) acetate (4x ). The organics combined , washed with brine , benzamide (5 . 03 g , 65 % ) as a white solid . ESI- MS m / z calc . dried over Na2SO4 , filtered and evaporated to dryness to 330 . 06 , found 331 . 1 ( M + 1 ) " ; Retention time : 1 . 48 minutes 45 vield a crude mixture that was purified by column chroma ( 3 minutes run ). ' H NMR (400 MHz, DMSO - d6 ) 8 10 .90 ( s, tographyog using a gradient of ethyl acetate in hexanes 1H ) , 8 . 10 ( m , 1H ), 7 .73 (dd , J = 5 . 1 , 3 .2 Hz, 1H ), 7 .66 (m , (0 - 40 % ) to give 2 - fluoro - N - ( 2 -methoxy - 4 -pyridyl ) - 4 - ( 1, 1 , 2 , 1H ) , 7 .55 ( t, J= 9 .2 Hz , 1H ), 7 .21 (dd , J= 3 . 7 , 1. 8 Hz , 2H ), 2 ,2 -pentafluoroethyl ) benzamide (200 mg , 22 % ) as an off 3 .84 (s , 3H ) ppm . white solid . ESI- MS m / z calc. 364 .06 , found 365 . 3 ( M + 1 ) + ; To 2 - fluoro - N - ( 2 -methoxy - 4 - pyridyl) - 5 - ( trifluo - » Retention time: 1 . 39 minutes ( 3 minutes run ). ' H NMR ( 400 romethoxy )benzamide ( 5 . 0 g , 15 .23 mmol) in acetonitrile MHz, DMSO - d6 ) d 10 . 98 ( s , 1H ) , 8 . 11 ( d , J = 6 . 3 Hz, 1H ) , ( 167 .6 mL ) was added TMSI ( 5 . 6 mL , 39. 60 mmol) . The 7 .95 (dd , J = 7 .4 Hz , 1H ) , 7 .89 (d , J = 9 . 9 Hz, 1H ), 7 .72 ( d , J = 9 . 1 Hz, 1H ) , 7 .23 - 7 . 19 ( m , 2H ) , 3 .85 ( s , 3H ) ppm . reaction was stirred at 50° C . overnight. The acetonitrile was 2 - fluoro - N -( 2- methoxy - 4 -pyridyl ) -4 - (1 ,1 ,2 , 2, 2- penta evaporated and the crude re -dissolved in ethyl acetate . The 55 fluoroethyl )benzamide (200 mg , 0 .55 mmol ) in HBr in organics were washed with water , dried over sodium sulfate , acetic acid ( 1 . 3 mL of 33 % w / v , 5 .49 mmol) was stirred at filtered and concentrated . Purification by silica gel chroma 100° C . for 2 hours , at this time 1 ml of HBr in acetic acid tography a gradient of ethyl acetate in hexanes ( 0 - 100 % ) (33 % w / v ) was added and the mixture was stirred at 100° C . followed by methanol in dichloromethane ( 0 - 20 % ) yielded on for 4 hours , then cooled to room temperature . The reaction 2 - fluoro - N - ( 2 - oxo - 1H -pyridin - 4 - yl) - 5 - ( trifluoromethoxy ) mixture was diluted with water and a precipitate formed . benzamide (3 g , 62 % ), as a grey solid . ESI- MS m / z calc . The precipitate was filtered off , washed with water (2x ) , cold 316 . 05 , found 317. 1 ( M + 1 ) * ; Retention time: 1 . 39 minutes methyl- tert - butyl ether and dried under vacuum to give ( 3 minutes run ) . ‘ H NMR (400 MHZ, DMSO - d6 ) o 10 . 80 ( S , 2 - fluoro - N - ( 2 - ox0 - 1H - pyridin - 4 - yl ) - 4 - ( 1 , 1 , 2 , 2 , 2 - pentafluo 1H ) , 7 .73 ( m , 1H ) , 7 .67 ( dd , J = 8 . 7 , 3 . 7 Hz, 1H ) , 7 .55 ( t, 65 roethyl) benzamide ( 138 mg, 72 % ) as a light grey solid . J = 9 . 1 Hz, 1H ) , 7 .48 ( d , J = 7 . 1 Hz, 1H ) , 6 . 96 ( d , J = 2 . 0 Hz, ESI- MS m / z calc . 350 . 05 , found 351 . 3 ( M + 1 ) + ; Retention 1H ), 6 .55 (dd , = 7 .2 , 2. 1 Hz , 1H ) ppm . time: 1 . 3 minutes ( 3 minutes run ). US 10 , 087 , 143 B2 181 182 Example 8 A solution of 2 -methoxypyridin - 4 - amine ( 186 . 2 mg, 1 . 5 mmol) , 4 , 5 - dichloro - 2 - fluoro -benzoic acid ( 285 . 1 mg, 1 . 36 Preparation of 2 , 5 -difluoro - N - (2 -oxo - 1 ,2 - dihydro mmol) , HATU (622 . 4 mg, 1 .64 mmol) and n -methylmor pyridin - 4 -yl ) benzamide pholine (299 .9 UL , 2. 73 mmol) in DMF ( 3 mL ) was stirred at room temperature for 16 hours . The reaction mixture was poured into water and extracted with ethyl acetate (3x ). The organics were combined , washed with water (3x ) , brine and dried over Na S04, filtered through a short plug of silica and evaporated to dryness . The material was taken up in HBr ( in NH acetic acid ) ( 6 .689 mL of 33 % w / v , 27 . 28 mmol) and stirred F at 95° C . for 16 h . The solution was cooled to room temperature , filtered and solid product washed with water ( 2x ) and then ether (2x ) and dried under vacuum to give F 5 4 , 5 - dichloro - 2 - fluoro - N - ( 2 -oxo - 1H -pyridin - 4 - yl) benzamide (250 mg, 61 % ) as an off white solid . ESI- MS m / z calc . A solution of 2 ,5 -difluorobenzoyl chloride ( 2 . 0 mL , 16 . 14 299. 99 , found 301. 3 ( M + 1 ) * ; Retention time: 1 . 16 minutes mmol) and dichloromethane ( 14 .25 mL ) was added drop wise to a mixture of 2 -methoxypyridin - 4 -amine ( 2 . 0 g , 16 . 14 mmol) , pyridine ( 3 . 9 mL , 48 . 42 mmol ) and dichlo - 20 Example 10 romethane (57 . 0 mL ) at 0° C . The mixture was allowed to warm to room temperature and was stirred at that tempera ture overnight. The mixture was poured into IN HCl and dichloromethane . The layers were separated and the organic Preparation of 4 - chloro - 2 ,5 - difluoro - N - ( 2 - oxo - 1 , 2 layer was dried over sodium sulfate , filtered and concen - 25 dihydropyridin -4 -yl ) benzamide trated under reduced pressure to give a tan solid . The solid was slurried in hexanes ( 150 mL ) and was filtered to give 2 , 5 -difluoro - N - ( 2 -methoxy - 4 -pyridyl ) benzamide ( 2 .61 g , 61 % ) as a tan solid . ESI- MS m / z calc . 264 .07 , found 265. 3 ( M + 1 ) + : Retention time: 1 . 22 minutes ( 3 minutes run ) . H 30 NMR (400 MHz, DMSO - d6 ) d 10 .83 (s , 1H ), 8 . 12 - 8 .05 ( m , 30 NH 1H ) , 7 . 58 ( ddd , J = 8 . 3 , 5 . 4 , 2 . 9 Hz, 1H ), 7 .52 - 7 .41 (m , 2H ) , 7 .25 - 7 . 19 (m , 2H ), 3 .84 ( s, 3H ) ppm . To 2 , 5 - difluoro - N - ( 2 -methoxy - 4 -pyridyl ) benzamide ( 2 .60 g , 9 .84 mmol) in acetic acid (15 .60 mL ) was added HBr 33 % in acetic acid (12 . 1 mL of 33 % w /v , 49. 20 mmol) 35 and the mixture was stirred at 90° C . for 5 h . Additional HBr (10 mL , 33 % in acetic acid ) was added and the mixture was stirred at 90° C . overnight. The mixture was cooled to room A solution of 4 - chloro -2 ,5 -difluoro -benzoyl chloride (5 g, temperature and was poured into water ( 200 mL ). The 23 . 70 mmol) in dichloromethane (25 mL ) was added drop mixture was stirred and the solid was collected by filtration . 40 wise to a mixture of 2 -methoxypyridin - 4 - amine ( 2 . 94 g , The solid was washed with water (2x50 mL ) . The solid was 23 .70 mmol) , pyridine ( 5 .75 mL , 71. 10 mmol) and dichlo slurried in hexanes (2x50 mL ) and filtered to give 2 , 5 difluoro - N - ( 2 -oxo - 1H -pyridin - 4 - yl) benzamide ( 2 . 30 g , 9 . 19 romethane ( 100 .0 mL ) at 0° C . The mixture was allowed to mmol, 93 % ) . ESI- MS m / z calc . 250 . 05 , found 251 . 3 warm to room temperature and was stirred at that tempera ( M + 1 ) + ; Retention time: 1 . 16 minutes ( 3 minutes run ). 'H451 45 ture for 43 hours . The mixture was poured into 1N HCl ( 50 NMR (400 MHz , DMSO -d6 ) 8 11. 31 ( s, 1H ) , 10 .59 (s , 1H ), mL ) . The mixture was filtered using dichloromethane and 7 . 56 ( ddd , J = 8 . 2 , 5 . 4 , 3 . 0 Hz, 1H ) , 7 .46 ( pd , J = 9 . 1 , 4 . 4 Hz, the solid was isolated . The solid was dried under vacuum to 2H ) , 7 . 33 ( d , J = 7 .2 Hz, 1H ) , 6 .81 ( d , J = 2 . 0 Hz, 1H ) , 6 .42 yield 4 - chloro - 2, 5 -difluoro - N -( 2 -methoxy -4 -pyridyl ) benz ( dd , J = 7 . 2 , 2 . 1 Hz, 1H ) ppm . 50 amide (6 . 2 g , 88 % ) as a pink solid . ' H NMR (400 MHz, Example 9 DMSO -d6 ) 10 . 89 (s , 1H ) , 8 . 16 -8 .05 ( m , 1H ), 7 .97 - 7 .75 ( m , 2H ), 7 . 29 - 7 . 15 ( m , 2H ), 3 . 85 ( s , 3H ) ppm . ESI- MS m / z Preparation of 4 , 5 -dichloro - 2 - fluoro - N - ( 2 -oxo - 1 , 2 calc . 298 . 03 , found 299 . 3 ( M + 1 ) + ; Retention time: 1. 43 dihydropyridin - 4 - yl )benzamide minutes ( 3 minutes run ) . 55 To 4 -chloro - 2 ,5 -difluoro -N -( 2 -methoxy -4 -pyridyl )benz amide ( 3 g , 10 . 04 mmol) in HOAC ( 15 . 9 mL )was added HBr 33 % in HOAC ( 12 .31 mL of 33 % w / v , 50 .20 mmol) and the mixture was stirred at 90° C . for 5 h . Additional HBr ( 10 mL , NH 60 33 % in HOAc ) was added and the mixture was stirred at 90° C . overnight. The mixture was cooled to room temperature and was poured into water ( 100 mL ) . The mixture was stirred and the solid was collected by filtration . The solid 65 was washed with water ( 2x50 mL ). The solid was slurried in que hexanes (2x50 mL ) and filtered to give 4 - chloro - 2 , 5 - dif luoro - N - (2 -oxo - 1H -pyridin - 4 -yl ) benzamide ( 969. 7 mg, US 10 , 087 , 143 B2 183 184 34 % ) as a cream colored solid . ESI- MS m / z calc . 284 . 02 , Example 12 found 285. 3 ( M + 1 ) +; Retention time: 1. 36 minutes ( 3 min run ) . Preparation of N -( 2 -oxo -1 , 2 -dihydropyridin -4 -yl )- 2 ( 4 -( trifluoromethoxy )phenoxy ) -4 - ( trifluoromethyl) Example 11 benzamide ( 79 ) Preparation of 2 - fluoro - N - ( 2 -oxo - 1 , 2 - dihydropyri din -4 -yl ) - 4 ,6 -bis ( trifluoromethyl )benzamide

NH

CF3 0 NH IZ

F C

2 -Methoxypyridin -4 -amine (632 . 1 mg, 5 .09 mmol) and DIEA ( 1 . 8 mL , 10 . 18 mmol) were dissolved in DMF ( 15 25 OCF3 mL ) and treated dropwise with a solution of 2 - fluoro - 4 ,6 bis ( trifluoromethyl) benzoyl chloride (1500 mg, 5 .09 mmol) CS2CO3 (651 . 0 mg, 2 mmol ) was added to a solution of in DME ( 2 mL ) . After 2 hours , the reaction was diluted with 2 - fluoro - N - ( 2 - oxo - 1 , 2 - dihydropyridin - 4 - yl) - 4 - ( trifluorom ethyl acetate , washed with 50 % saturated sodium bicarbon - 30 ethyl) benzamide ( 60 . 0 mg, 0 . 2 mmol) and 4 - (trifluo ate solution ( 2x20 mL ), water, and brine. The solution was romethoxy )phenol ( 259 .1 UL , 2 mmol) in DMF ( 1 mL ) and dried over anhydrous Na2SO4, filtered , and dried down to a the reaction was stirred at 100° C . for 1 hour. The reaction purple residue. Silica gel chromatography using a gradient was filtered and purified by reverse phase HPLC using a of ethyl acetate //hexanehexane (( 10 10 -- 99 %% ) providedprovided 2 - fluoro -- N - ( 2 - 3525 gradient of acetonitrile in water ( 10 - 99 % ) and HClAct asas a methoxypyridin - 4 - yl) - 4 , 6 -bis ( trifluoromethyl ) benzamide modifier to yield N - ( 2 - oxo - 1 , 2 - dihydropyridin - 4 - yl) - 2 - (4 ( 1. 2 g . 67 % ) as a beige solid . ' H NMR (400 MHz, DMSO - (trifluoromethoxy ) phenoxy ) -4 - ( trifluoromethyl) benzamide 06 ) 8 11. 29 (s , 1H ), 8. 42 ( d. J= 8 .6 Hz. 1H ), 8 . 17 (s , 1H ), 8 . 13 (79 ) (25 . 7 mg, 28 % ). ESI- MS m /z calc . 458 .07 , found 459 .5 3H ( M + 1 ) * ; Retention time: 1 . 80 minutes ( 3 minutes run ) . (dd , J = 5 .4 , 0 . 9 Hz , 1H ), 7 .14 -7 .10 (m , 2H ), 3. 85 (s , 3H ) 40 (M + 1 ) ; Keten ppm . ESI- MS m / z calc . 382 .05 , found 383 . 1 ( M + 1 ) + ; Reten Example 13 tion time : 1 .48 minutes ( 3 minutes run ) . To a mixture of sodium iodide ( 2 .54 g , 16 . 95 mmol) in Preparation of 2 - ( (5 - fluoro - 2 -hydroxybenzyl ) oxy ) acetonitrile (75 mL) under nitrogen was added TMSC1( 2 . 15 N -( 2 -oxo - 1 ,2 -dihydropyridin -4 -yl ) - 4 -( trifluorom mL, 16 .95 mmol) and the mixture was stirred at 25° C . for 45 ethyl) benzamide ( 159) 30 min . Thereafter, anhydrous acetonitrile ( 130 . 0 ml) was added to this solution followed by 2 - fluoro - N - ( 2 -methoxy 4 -pyridyl ) -4 ,6 -bis ( trifluoromethyl) benzamide ( 1. 2 g , 3 . 14 mmol) . The resulting reaction mixture was heated with 50 stirring at 80° C . for 5 h and at 60° C . for 12 hours . The reaction was cooled , diluted with water, and extracted with ethyl acetate . The organic layer was dried over Na2SO4, filtered and concentrated to a dark yellow -orange solid . The 55 NH solid was triturated with ethyl acetate /hexanes several times to remove dark red color, then with dichloromethane to NH remove yellow color, then finally with hexanes . The result ing solid was dried under vacuum to provide 2 - fluoro - N OH ( 2 - oxo - 1H -pyridin - 4 - yl) - 4 , 6 - bis ( trifluoromethyl) benzamide 60 ( 960 mg, 83 % ) as an off- white solid . ' H NMR (400 MHz, DMSO - d6 ) 8 11. 41 ( s , 1H ) , 11 .03 ( s , 1H ), 8 .41 ( d , J = 8 . 4 Hz , 1H ) , 8 . 16 ( d , J = 1 . 7 Hz, 1H ) , 7 . 37 ( d , J = 7 . 1 Hz , 1H ), 6 .71 ( d , J = 2 .0 Hz, 1H ), 6. 31 (dd , J= 7 . 2, 2 .1 Hz, 1H ) ppm . ESI-MS 65 F m /z calc . 368 .04 , found 369 .1 (M + 1 ) + ; Retention time: 1. 28 minutes ( 3 minutes run ). US 10 , 087 , 143 B2 185 186 To a solution of 2 - fluoro - N -( 2 - oxo - 1H - pyridin - 4 - yl) - 4 Example 15 ( trifluoromethyl) benzamide (211 . 2 mg, 0 .70 mmol) and Preparation of 2 - (4 - fluoro -2 -( hydroxymethyl ) phe 4 - fluoro - 2 - ( hydroxymethyl) phenol (100 mg, 0 .70 mmol) in noxy ) - N -( 2 - oxo - 1 , 2 - dihydropyridin - 4 - yl) - 4 - ( trifluo N -methyl pyrrolidinone (3 mL ) was added cesium carbonate romethyl) benzamide ( 157 ) (687 . 8 mg, 2 . 1 mmol ) and the mixture was heated at 100° C . for 2 hours . The reaction was cooled to 25° C ., filtered and purified by reverse phase HPLC using a gradient of acetoni trile /water ( 10 to 99 % ) and HCl as a modifier to yield 2 - [ ( 5 - fluoro - 2 - hydroxy - phenyl) methoxy ] - N - ( 2 - oxo - 1H - 10 pyridin -4 -yl ) - 4 -( trifluoromethyl) benzamide (159 ) ( 10 .5 mg, NH 3 % ) as a yellow solid . ' H NMR ( 400 MHz, DMSO - d6 ) 11 . 52 ( s , 1H ) , 10 .49 ( s , 1H ) , 10 .04 ( s , 1H ), 7 . 84 ( d , J = 8 . 2 Hz, 1H ) , 7 .78 ( d , J = 7 .4 Hz, 1H ), 7 .33 -7 .23 ( m , 2H ), 7 .05 - 6 .91 15 ( m , 2H ) , 6 . 91 - 6 .79 ( m , 2H ) , 6 .61 (dd , J = 7 . 4 , 2 . 4 Hz, 1H ) , FC 4 . 96 (s , 2H ) ppm . ESI -MS m /z calc . 422 .09 , found 423 . 3 ( M + 1 ) + ; Retention time : 1 .83 minutes ( 3 minutes ) . OH Example 14 20 F Preparation of 2 - ( 4 - fluoro - 2 -methylphenoxy ) - N - ( 2 oxo - 1 , 2 - dihydropyridin - 4 -yl ) - 4 - (trifluoromethyl ) 2 -Fluoro - N - ( 2 -oxo - 1H - pyridin - 4 - yl) - 4 - ( trifluoromethyl) benzamide ( 10 ) 25 benzamide (625 .3 mg, 2 .08 mmol) , potassium carbonate (287 . 9 mg, 2 . 08 mmol) and 4 - fluoro - 2 - (hydroxymethyl ) phenol (296 mg, 2. 08 mmol) were added to 1- methylpyrro lidin - 2 - one ( 3 . 0 mL ) and the reaction was stirred at 80° C . for 10 minutes . The reaction was filtered and the compound NH was purified by reverse phase preparative chromatography utilizing a gradient of 10 - 99 % acetonitrile in water contain ing HCl as a modifier to yield 2 - [ 4 - fluoro - 2 - (hydroxym IZ 35 ethyl) phenoxy ]- N - ( 2 -oxo - 1H -pyridin - 4 -yl ) - 4 - (trifluorom F C ethyl )benzamide ( 157) ( 10 .3 mg, 1 % ) as a white solid . ' H NMR (400 MHz, DMSO - d6 ) d 11 . 44 ( s , 1H ), 10 . 66 (s , 1H ) , 7 . 86 ( d , J = 7 . 9 Hz, 1H ) , 7 .61 ( d , J = 8 . 0 Hz, 1H ) , 7 .41 - 7 .27 ( m , 2H ), 7 .24 -7 . 12 ( m , 1H ), 7 . 12 - 7 .07 (m , 1H ) , 7 .04 ( s, 1H ), 40 6 . 80 ( d , J = 2 . 1 Hz, 1H ), 6 . 43 (dd , J = 7 . 3 , 2 . 2 Hz, 1H ) , 4 . 47 (s , 2H ) ppm . ESI- MS m / z calc . 422 .09 , found 423 . 2 ( M + 1 ) + ; Retention time: 1 .32 minutes (3 minutes run ). Example 16 A mixture of 2 - fluoro - N - ( 2 -oxo - 1H -pyridin - 4 -yl ) - 4 - ( trif- 45 luoromethyl )- benzamide ( 13 .6 g , 45. 30 mmol) , 4 - fluoro - 2 Preparation of 2 - ( 3 - fluoro - 4 -methoxyphenoxy ) - N methyl- phenol ( 17 . 1 g , 135 . 9 mmol) , Cs_ C03 ( 44 . 28 g , ( 2 - oxo - 1 ,2 -dihydropyridin -4 -yl ) - 4 - (trifluoromethyl ) 135 . 9 mmol) and DMF ( 340 .0 mL ) was heated at 100° C . for benzamide (81 ) 1 .5 hours . The mixture was cooled to room temperature and 50 was poured into water ( 500 mL ) . The mixture was stirred vigorously for 30 min before it was filtered . The solid was washed with water ( 250 mL ) and was slurried with methyl tert- butyl ether ( 200 mL) . The mixture was filtered and the 55 NH solid was slurried with hexanes ( 2x400 mL ) and the filtrate was dried under vacuum to give 2- (4 - fluoro -2 -methyl - phe NH noxy ) -N -( 2 -oxo - 1H -pyridin -4 -yl ) -4 - ( trifluoromethyl) benz amide ( 10 ) (13 . 1 g , 70 % ) as a solid . ESI- MS m / z calc . 60 F C 406 .09 , found 407. 5 ( M + 1 ) * ; Retention time: 1 . 73 minutes ( 3 minutes run ). ' H NMR (400 MHz , DMSO - d6 ) & 11. 28 (s , 1H ) , 10 .63 ( s , 1H ) , 7 .84 ( d , J = 7 . 8 Hz , 1H ) , 7 .60 ( d , J = 7 . 1 Hz , 1H ), 7 . 31 ( d , J = 7 .2 Hz, 1H ), 7 . 26 - 7 .20 ( m , 1H ), 7 . 14 - 7 .06 a F ( m , 2H ) , 7 .00 - 6 . 95 ( m , 1H ) , 6 . 75 ( d , J = 1 . 8 Hz, 1H ) , 6 .38 (dd , OMe J = 7 . 2 , 2 . 1 Hz, 1H ) , 2 . 16 (s , 3H ) ppm . US 10 , 087 , 143 B2 187 188 Cs2CO3 (651 .6 mg, 2 . 0 mmol) was added to a solution of - continued 2 - fluoro - N - ( 2 - oxo - 1 , 2 - dihydropyridin - 4 -yl ) - 4 - ( trifluorom ethyl) benzamide (60 .0 mg , 0 .2 mmol) and 3 - fluoro -4 Cmpd methoxyphenol ( 284 . 3 mg, 2 . 0 mmol) in DMF ( 1 mL ) and No . Product Alcohol the reaction was stirred at 100° C . for 1 hour. The reaction 5 125 2 - ( ( 1R ,5S ) (1R ,5S ) - 3 was filtered and purified by reverse phase HPLC using a bicyclo [ 3 . 1 . 0 ]hexan bicyclo [ 3 . 1 .0 ]hexanol gradient of acetonitrile in water ( 10 - 99 % ) and HCl as a 3 -yloxy ) - N - ( 2 - oxo - 1 , 2 modifier to yield 2 -( 3 - fluoro - 4 -methoxyphenoxy )- N -( 2 dihydropyridin - 4 -yl ) - 4 oxo - 1 , 2 - dihydropyridin - 4 - yl) - 4 - ( trifluoromethyl) benzamide (trifluoromethyl )benzamide (81 ) ( 45 . 6 mg, 54 % ) . ESI- MS m / z calc . 422 .09 , found 423 .31 126 2 - ( 2 , 2 2 , 2 ( M + 1 ) *; Retention time: 1. 65 minutes (3 minutes run ). difluorocyclopropyl) methoxy ) - difluorocyclopropyl )methanol Following a similar procedure as described above for N - (2 -oxo - 1, 2 -dihydropyridin compound 81 , the following compounds were prepared from 4 -yl ) - 4 ( trifluoromethyl) benzamide 2 - fluoro - N - (2 -oxo - 1 , 2 -dihydropyridin - 4 -yl ) - 4 -( trifluorom - 15 8 2 - ( 4 - ( 2 4 - ( 2 -methoxyethoxy )phenol ethyl) benzamide in each case and using the alcohols methoxyethoxy )phenoxy )- N described below . ( 2 -oxo - 1 , 2 -dihydropyridin - 4 yl) -4 - ( trifluoromethyl) benzamide 127 2 - (bicyclo [ 2 . 2 . 1 ]heptan - 2 - norbornan - 2 -ol Cmpd 20 No. Product Alcohol yloxy ) - N - ( 2 - oxo - 1 , 2 dihydropyridin - 4 - yl) - 4 144 N - ( 2 - oxo - 1 , 2 -dihydropyridin - 6 - ( trifluoromethyl) pyridin - 3 ( trifluoromethyl )benzamide 4 -yl ) - 4 - ( trifluoromethyl) - 2 ? (( 6 - (trifluoromethyl ) pyridin N -( 2 -oxo - 1 ,2 -dihydropyridin -4 - phenol 3 - yl )oxy ) benzamide yl ) - 2 - phenoxy - 4 116 2 - (isopentyloxy ) - N - ( 2 -oxo isopentanol 25 ( trifluoromethyl) benzamide 1 , 2 -dihydropyridin -4 -yl ) -4 11 N - ( 2 - oxo - 1 , 2 - dihydropyridin - 4 - 2 -methylphenol ( trifluoromethyl) benzamide yl) - 2 - (o - tolyloxy ) - 4 5 2 - ( 4 - fluorophenoxy ) - N - ( 2 4 - fluorophenol (trifluoromethyl ) benzamide oxo - 1 , 2 - dihydropyridin - 4 yl) - 4 128 2- ( cyclohexyloxy ) - N - (2 -oxo - 1, 2 - cyclohexanol ( trifluoromethyl) benzamide 30 dihydropyridin - 4 - yl) - 4 2 - ( 2 , 4 - difluorophenoxy ) - N 2 , 4 -difluorophenol ( trifluoromethyl) benzamide (2 - oxo - 1 ,2 -dihydropyridin 12 N - ( 2 - oxo - 1 , 2 - dihydropyridin - 4 - 4 -methylphenol 4 -yl ) - 4 yl) - 2 - (p - tolyloxy )- 4 ( trifluoromethyl) benzamide ( trifluoromethyl) benzamide 117 2 - isobutoxy - N - ( 2 - oxo - 1 , 2 isobutanol dihydropyridin - 4 -yl ) - 4 77 2 - (2 - chloro - 4 - fluorophenoxy ). 2 - chloro - 4 - fluoro -phenol ( trifluoromethyl) benzamide 35 N - ( 2 -oxo - 1 , 2 -dihydropyridin 146 2 - ( ( 6 -methylpyridin - 3 6 -methyl - 3 -pyridinol 4 -yl ) - 4 yl) oxy ) - N - ( 2 -oxo - 1 , 2 ( trifluoromethyl) benzamide dihydropyridin - 4 - yl) - 4 78 2 - ( 4 - chlorophenoxy ) - N - ( 2 - oxo - 4 - chlorophenol ( trifluoromethyl) benzamide 118 2 - [( 1R ,2R ,4S )- norbornan ( 1R ,2R ,4S )- norbornan an - 2 - -01ol 1 , 2 -dihydropyridin -4 - yl) -4 2 - yl] oxy - N - ( 2 -oxo - 1H 40 ( trifluoromethyl) benzamide pyridin - 4 - yl) - 4 80 N - ( 2 - oxo - 1 , 2 - dihydropyridin - 2 ( trifluoromethyl) benzamide 4 -yl ) - 2 - ( 2 ( trifluoromethoxy )phenol 147 2 - (( 2 -methylpyridin - 3 2- methyl - 3 -pyridinol (trifluoromethoxy )phenoxy ) -4 yl) oxy ) - N - ( 2 - oxo - 1 , 2 dihydropyridin -4 - yl) - 4 (trifluoromethyl )benzamide ( trifluoromethyl) benzamide 45 82 2 - ( 4 4 - (difluoromethoxy ) phenol 119 2 - ( ( 1 1 (difluoromethoxy ) phenoxy )- N methylcyclopropyl) methoxy ) - methylcyclopropyl) methanol N - ( 2 - oxo - 1 , 2 -dihydropyridin ( 2 -oxo - 1 , 2- dihydropyridin - 4 4 - yl) - 4 yl) -4 - ( trifluoromethyl) benzamide ( trifluoromethyl) benzamide 83 2 - ( 2 2 - ( difluoromethoxyphenol 120 2 -( cyclopentylmethoxy ) - N cyclopentylmethanol 50 (difluoromethoxy )phenoxy ) - N ( 2 -oxo - 1 , 2 - dihydropyridin (2 -oxo - 1, 2 -dihydropyridin -4 4 - yl) - 4 ( trifluoromethyl )benzamide yl) - 4 - ( trifluoromethyl ) benzamide 121 N -( 2 -oxo - 1 ,2 -dihydropyridin tetrahydrofuran - 3 84 2 - ( 2 -fluoro - 4 -methoxyphenoxy ) - 2 - fluoro - 4 -methoxy -phenol 4 - yl ) - 2 ylmethanol N - ( 2 -oxo - 1 , 2 - dihydropyridin - 4 ( tetrahydrofuran - 3 55 yl ) - 4 - (trifluoromethyl ) benzamide upBb? yl) methoxy ) - 4 ( trifluoromethyl) benzamide 87 2 - ( 3 - fluoro - 2 -methoxyphenoxy ) - 3 - fluoro - 2 -methoxy -phenol 122 2 - cyclobutoxy- N - ( 2 -oxo - 1 ,2 cyclobutanol N - ( 2 -oxo - 1 , 2 -dihydropyridin - 4 dihydropyridin - 4 -yl ) - 4 yl ) -4 - (trifluoromethyl ) benzamide ( trifluoromethyl) benzamide 2 - chloro - 3 - fluoro - 4 -methoxy 123 N - ( 2 -oxo - 1 ,2 - dihydropyridin - 4 , 4 , 4 - trifluorobutanol 110 2 - (2 - chloro - 3 - fluoro - 4 4 -yl ) - 2 - ( 4 , 4 , 4 60 methoxyphenoxy ) - N - (2 - oxo - 1 , 2- phenol trifluorobutoxy ) - 4 dihydropyridin -4 - yl) - 4 (trifluoromethyl )benzamide (trifluoromethyl )benzamide 124 2 - {( 2 ,2 2 , 2 dimethylcyclopropyl) methoxy ) dimethylcyclopropyl) methanol 158 2- ( 4 - fluoro -2 - methoxyphenoxy ). 4- fluoro -2 - methoxyphenol N - ( 2 -oxo - 1 , 2 -dihydropyridin N -( 2 - oxo -1 , 2 - dihydropyridin -4 4 - yl) - 4 yl) - 4 - (trifluoromethyl ) benzamide ( trifluoromethyl) benzamide US 10 , 087 , 143 B2 189 190 Example 17 Cs, C03 (651 . 6 mg, 2 .0 mmol) was added to a solution of Preparation of 2 - (4 - fluoro -2 -methoxyphenoxy ) -N 2 - fluoro - N - ( 2 -oxo - 1, 2 -dihydropyridin - 4 -yl ) - 5 - (trifluorom ( 2 -oxo - 1 ,2 - dihydropyridin -4 -yl ) - 5 -( trifluoromethyl) ethyl) benzamide (60 . 0 mg, 0 . 2 mmol ) and 4 - fluoro - 3 benzamide ( 30 ) 5 methoxyphenol (228 ul, 2. 0 mmol) in DMF (1 mL ) and the reaction was stirred at 100° C . for 1 hour. The reaction was filtered and purified by reverse phase HPLC using a gradient NH of acetonitrile in water ( 10 - 99 % ) and HCl as a modifier to yield 2 - (4 - fluoro - 2 -methoxyphenoxy ) - N -( 2 -oxo - 1, 2 -dihy N dropyridin -4 - yl )- 5 -( trifluoromethyl) benzamide ( 30 ) (67 .9 mg, 80 % ). ESI- MS m / z calc . 422 .09 , found 423 .2 ( M + 1) *; OMe 15 Retention time: 1 . 56 minutes ( 3 minutes run ) . Following a similar procedure as described above for compound 30 , the following compounds were prepared from 20 2 - fluoro - N -( 2 -oxo - 1, 2 -dihydropyridin - 4 -yl ) - 5 - ( trifluorom ethyl) benzamide and the following alcohols .

Cmpd No. Product Alcohol 72 N - ( 2 - oxo - 1 , 2 - dihydropyridin - 4 - yl) - 2 - ( 4 4 - (trifluoromethoxy )phenol ( trifluoromethoxy )phenoxy ) - 5 ( trifluoromethyl) benzamide 31 2 - (4 - fluoro - 2 -methylphenoxy ) -N - ( 2 - oxo - 1 ,2 4 - fluoro - 2 -methyl -phenol dihydropyridin - 4 -yl ) - 5 ( trifluoromethyl) benzamide 2 - ( 4 -methoxy - 2 -methylphenoxy ) - N - ( 2 -oxo - 1 , 2 - 4 -methoxy - 2 -methyl - phenol dihydropyridin - 4 -yl ) - 5 ( trifluoromethyl) benzamide 2 - ( 4 -chloro - 2 -methylphenoxy ) - N - ( 2 - oxo - 1 , 2 4 - chloro - 2 -methyl -phenol dihydropyridin - 4 -yl ) - 5 ( trifluoromethyl) benzamide 44 2 - ( 4 - ethoxyphenoxy ) - N - ( 2 -oxo - 1 , 2 4 - ethoxyphenol dihydropyridin - 4 - yl) - 5 (trifluoromethyl )benzamide 49 2 - ( 2 -chloro - 4 -methoxyphenoxy ) - N - ( 2 -oxo - 1 ,2 - 2 -chloro -4 -methoxy -phenol dihydropyridin - 4 -yl ) - 5 ( trifluoromethyl) benzamide 90 N - ( 2 - oxo - 1 , 2 -dihydropyridin - 4 -yl ) - 5 2 ,3 , 4 -trifluorophenol ( trifluoromethyl ) - 2 - ( 2 , 3 , 4 trifluorophenoxy )benzamide 2 - ( 2 -chloro - 4 - fluorophenoxy ) - N - ( 2 -oxo - 1 , 2 2 - chloro - 4 - fluoro -phenol dihydropyridin - 4 - yl) - 5 ( trifluoromethyl) benzamide 54 2 - ( 3 - fluoro - 2 -methoxyphenoxy )- N - ( 2 -oxo - 1 , 2- 3 - fluoro -2 -methoxy - phenol dihydropyridin - 4 - yl) - 5 ( trifluoromethyl )benzamide 2 - ( 3 - fluoro - 4 -methoxyphenoxy ) - N - ( 2 -oxo - 1 , 2 - 3 - fluoro - 4 -methoxy -phenol dihydropyridin - 4 -yl ) - 5 ( trifluoromethyl) benzamide 8 N - ( 2 -oxo - 1 , 2 - dihydropyridin - 4 - yl ) - 2 - ( 2 2 -propoxyphenol propoxyphenoxy ) - 5 - ( trifluoromethyl) benzamide 2- ( 4 - ( difluoromethoxy ) phenoxy )- N -( 2 -oxo -1 , 2 - 4 -( difluoromethoxy ) phenol dihydropyridin - 4 - yl) - 5 ( trifluoromethyl) benzamide N - ( 2 -oxo - 1 , 2 -dihydropyridin - 4 - yl) - 2 - ( 0 2 -methylphenol tolyloxy) - 5 - ( trifluoromethyl) benzamide N - ( 2 - oxo - 1 , 2 -dihydropyridin - 4 - yl) - 2 - ( 4 4 -propoxyphenol propoxyphenoxy ) - 5 - ( trifluoromethyl) benzamide N - ( 2 - oxo - 1 , 2 - dihydropyridin - 4 - yl) - 2 - ( 2 2 - (trifluoromethoxy )phenol ( trifluoromethoxy ) phenoxy ) - 5 ( trifluoromethyl) benzamide 2 2 - (4 - fluorophenoxy ) - N - ( 2 -oxo - 1 , 2 4 - fluorophenol dihydropyridin - 4 - yl) - 5 ( trifluoromethyl) benzamide US 10 ,087 , 143 B2 191 192 -continued Cmpd No . Product Alcohol 76 2 - (2 - ( difluoromethoxy) phenoxy )- N - ( 2 -oxo - 1 , 2 - 2 - (difluoromethoxy ) phenol dihydropyridin - 4 - yl) - 5 ( trifluoromethyl) benzamide 58 2 -( 4 -chlorophenoxy ) - N - (2 -oxo - 1, 2 4 - chlorophenol dihydropyridin - 4 -yl ) - 5 ( trifluoromethyl) benzamide 24 2 - ( 2 , 4 -difluorophenoxy ) - N - ( 2 - oxo - 1 , 2 2, 4 - difluorophenol dihydropyridin - 4 -yl ) - 5 (trifluoromethyl ) benzamide 46 2 - ( 2 - ethoxyphenoxy) - N - ( 2 -oxo - 1 , 2 2 - ethoxyphenol dihydropyridin - 4 - yl) - 5 (trifluoromethyl )benzamide 2- (4 -methoxyphenoxy ) - N - (2 -oxo - 1, 2 4 -methoxyphenoxy dihydropyridin - 4 - yl) - 5 ( trifluoromethyl) benzamide 2 - ( 5 - fluoro - 2 -methylphenoxy ) - N - ( 2 - oxo - 1 , 2 - 5 - fluoro - 2 -methyl - phenol dihydropyridin - 4 -yl ) - 5 ( trifluoromethyl) benzamide 55 2 - ( 2 - fluoro- 4 -methoxyphenoxy ) - N -( 2 -oxo - 1 , 2 - 2 - fluoro - 4 -methoxy - phenol dihydropyridin - 4 - yl) - 5 ( trifluoromethyl) benzamide 2- ( 4 - chloro - 2 - fluorophenoxy) -N - (2 -oxo - 1 , 2 4 - chloro - 2 - fluoro -phenol dihydropyridin - 4 -yl ) - 5 ( trifluoromethyl )benzamide 52 2 - (5 - fluoro - 2 -methoxyphenoxy ) - N - ( 2 -oxo - 1 ,2 5 - fluoro - 2 -methoxy -phenol dihydropyridin - 4 - yl) - 5 ( trifluoromethyl) benzamide 65 2 -( 2 - chlorophenoxy ) - N - (2 -oxo - 1, 2 2 -chlorophenol dihydropyridin - 4 - yl) - 5 ( trifluoromethyl) benzamide 2- ( 2 - isopropoxyphenoxy) - N -( 2 -oxo -1 , 2 2 - isopropoxyphenol dihydropyridin - 4 - yl) - 5 ( trifluoromethyl) benzamide 61 2 - ( 4 - fluoro - 2 -methylphenoxy ) - N - (6 -methyl - 2 - 4 - fluoro - 2 -methyl - phenol oxo - 1 ,2 -dihydropyridin - 4 -yl ) - 5 ( trifluoromethyl) benzamide 2 - ( 2 -methoxy - 4 -methylphenoxy ) - N - (2 -oxo - 1, 2 - 2 -methoxy -4 -methyl -phenol dihydropyridin - 4 -yl ) - 5 ( trifluoromethyl) benzamide 2 - ( 2 , 3 - difluoro - 4 -methylphenoxy ) - N - ( 2 -oxo - 1 , 2 - 2 , 3 -difluoro - 4 -methyl dihydropyridin - 4 - yl) - 5 phenol ( trifluoromethyl) benzamide 32 N -( 2 - oxo - 1, 2 - dihydropyridin -4 - yl) - 2- phenoxy - 5 . phenol ( trifluoromethyl )benzamide 132 N - ( 2 - oxo - 1 , 2 - dihydropyridin - 4 - yl) -5 3 , 3 ,3 -trifluoropropanol ( trifluoromethyl) - 2 - ( 3 , 3 , 3 trifluoropropoxy )benzamide 27 N - ( 2 - oxo - 1 ,2 -dihydropyridin - 4 -yl ) -2 - ( p 4 -methylphenol tolyloxy ) - 5 - ( trifluoromethyl) benzamide - ( 2 -oxo - 1 , 2 -dihydropyridin - 4 - yl) - 5 2 , 3 , 5 -trimethylphenol ( trifluoromethyl) - 2 - ( 2 , 3 , 5 trimethylphenoxy )benzamide 2 -( 4 - cyanophenoxy) - N -( 2 -oxo -1 , 2 4 -cyanophenol dihydropyridin - 4 - yl) - 5 ( trifluoromethyl) benzamide 93 N - ( 2 - oxo - 1 ,2 - dihydropyridin - 4 - yl) - 5 2 , 4 , 5 -trimethylphenol (trifluoromethyl ) - 2 - ( 2 , 4 , 5 trimethylphenoxy ) benzamide 131 2 - isobutoxy - N - ( 2 -oxo - 1 , 2 -dihydropyridin - 4 - yl) - 5 - isobutanol ( trifluoromethyl) benzamide 135 2 -[ [ ( 1R ,5S )- 3 -bicyclo [ 3. 1 .0 ]hexanyl ] oxy ]- N -( 2 - (1R ,5S ) - 3 oxo - 1H -pyridin - 4 -yl ) - 5 bicyclo[ 3 . 1 . 0 ]hexanol ( trifluoromethyl) benzamide 48 2 - ( 2 - fluoro - 6 -methoxyphenoxy ) - N -( 2 -oxo - 1 ,2 - 2 - fluoro- 6 -methoxy -phenol dihydropyridin - 4 - yl) - 5 (trifluoromethyl ) benzamide 86 2 -( 4 - fluoro - 2 -methylphenoxy )- N - (5 -methyl - 2 - 4 - fluoro - 2 -methyl - phenol oxo - 1 ,2 -dihydropyridin - 4 -yl ) - 4 ( trifluoromethyl) benzamide 130 2 - ( cyclopentylmethoxy) - N - ( 2 - oxo - 1 , 2 cyclopentylmethanol dihydropyridin - 4 - yl) - 5 ( trifluoromethyl) benzamide 74 N - ( 2 - oxo - 1 , 2 -dihydropyridin - 4 - yl) - 5 4 - (trifluoromethyl ) phenol ( trifluoromethyl ) - 2 - ( 4 (trifluoromethyl ) phenoxy) benzamide US 10 ,087 , 143 B2 193 194 -continued Cmpd No . Product Alcohol 133 N - ( 2 -oxo - 1 , 2 - dihydropyridin - 4 - yl) - 2 - ( 4 , 4 , 4 4 ,4 , 4 - trifluorobutanol trifluorobutoxy ) - 5 - ( trifluoromethyl) benzamide 150 2 - (( 2 -methylpyridin - 3- yl ) oxy ) -N - ( 2 -oxo - 1 ,2 2 -methyl - 3 -pyridinol dihydropyridin - 4 - yl) - 5 ( trifluoromethyl) benzamide 57 2 - ( 3 - fluoro - 5 -methoxyphenoxy ) - N -( 2 -oxo - 1 ,2 - 3 - fluoro - 5 -methoxy -phenol dihydropyridin - 4 - yl) - 5 ( trifluoromethyl) benzamide 26 2- (2 , 6 -difluorophenoxy )- N -( 2 -oxo -1 , 2 2 , 6 - difluorophenol dihydropyridin - 4 - yl) - 5 ( trifluoromethyl) benzamide 134 2 - ( ( 2 , 2 - dimethylcyclopropyl )methoxy ) - N - ( 2 -oxo - 2 , 2 - dimethylcyclopropyl )methanol 1 , 2 - dihydropyridin - 4 - yl ) - 5 (trifluoromethyl ) benzamide

Example 18 -continued 20 Preparation of 5 - chloro - 2 - (4 - fluoro - 2 -methoxyphe Cmpd noxy ) - N -( 2 -oxo - 1 , 2 - dihydropyridin - 4 - yl) benzamide No . Product Alcohol (70 ) 71 5- chloro -2 - ( 3 - fluoro - 4 -methoxyphenoxy )- N - 3 - fluoro -4 ( 2 -oxo - 1 , 2 - dihydropyridin- 4 -yl )benzamide methoxy 25 phenol

Example 19 NH 30 Preparation of 4 - chloro -2 -( 4 - fluoro - 2 -methoxyphe noxy ) - N - ( 2 - oxo - 1 , 2 - dihydropyridin - 4 - yl )benzamide NH ( 16 )

ales OMe

??

? NH Cs2CO3 (879 . 9 mg, 2 . 7 mmol) was added to a solution of 2 - fluoro - N - ( 2 - oxo - 1 , 2 - dihydropyridin - 4 - yl) - 5 - chlorobenz amide (72 .0 mg, 0 .27 mmol ) and 4 -fluoro -3 -methoxyphenol 45 OMe ( 307. 7 ul, 2 . 7 mmol) in DMF ( 1 mL ) and the reaction was stirred at 100° C . for 1 hour. The reaction was filtered and purified by reverse phase HPLC using a gradient of acetoni trile in water ( 10 - 99 % ) and HC1 as a modifier to yield 5 -chloro - 2 - (4 - fluoro - 2 -methoxyphenoxy )- N - ( 2 -oxo - 1, 2 -di - 50 hydropyridin - 4 -yl ) benzamide (70 ) (31 . 8 mg, 30 % ). ESI- MS m /z calc . 388 .06 , found 389. 10 (M + 1) * ; Retention time: 1 .52 minutes ( 3 minutes run ) . Cs2CO3 ( 651. 6 mg, 2 . 0 mmol) was added to a solution of Following a similar procedure as described above for 2 - fluoro - N - ( 2 - 0X0 - 1 , 2 - dihydropyridin - 4 - yl) - 4 -chlorobenz compound 70 the following compounds were prepared from c amide ( 53. 3 mg, 0 .20 mmol ) and 4 - fluoro - 3 -methoxyphenol 5 -chloro -2 - (4 - fluoro -2 -methoxyphenoxy )- N - ( 2 -oxo - 1, 2 -di (284 . 3 mg, 2 . 0 mmol) in DMF ( 1 mL ) and the reaction was hydropyridin - 4 - yl) benzamide and the following alcohols . stirred at 100° C . for 1 hour. The reaction was filtered and purified by reverse phase HPLC using a gradient of acetoni trile in water ( 10 - 99 % ) and HCl as a modifier to yield Cmpd 60 4 -chloro - 2 - (4 - fluoro - 2 -methoxyphenoxy ) - N -( 2 -oxo - 1, 2 -di No. Product Alcohol hydropyridin - 4 -yl ) benzamide ( 16 ) (22 . 1 mg, 28 % ) . ESI-MS 5 - chloro - 2 - ( 4 - fluoro - 2 -methylphenoxy ) - N - ( 2 - 4 - fluoro - 2 m / z calc . 388 . 06 , found 389 . 15 ( M + 1 ) * ; Retention time: oxo - 1 , 2 - dihydropyridin - 4 -yl ) benzamide methyl- phenol 1 .53 minutes ( 3 minutes run ). 66 5 - chloro - 2 - ( 2 - chloro - 4 - fluorophenoxy ) - N - ( 2 2 - chloro - 4 oxo - 1 , 2 -dihydropyridin - 4 - yl) benzamide fluoro -phenol Following a similar procedure as described above for 5 - chloro - 2 - (4 - fluorophenoxy ) - N -( 2 - 0X0 - 1 .2 - 4 - fluorophenol 65 compound 16 , the following compounds were prepared from dihydropyridin - 4 -yl ) benzamide 4 - chloro - 2 - ( 4 - fluoro - 2 -methoxyphenoxy ) - N - ( 2 -oxo - 1 , 2 - di hydropyridin - 4 - yl) benzamide and the following alcohols . US 10 , 087 , 143 B2 195 196 Cmpd No. Product Alcohol 20 4 -chloro - 2 - ( 4 - fluoro - 2 -methylphenoxy )- N - ( 2 - 4 - fluoro - 2 -methyl - phenol oxo - 1 , 2 - dihydropyridin - 4 - yl) benzamide 4 -chloro -2 -( 2 -chloro - 4 - fluorophenoxy ) - N -( 2 2 - chloro -4 - fluoro -phenol oxo - 1 , 2 - dihydropyridin - 4 -yl ) benzamide 15 4 - chloro - 2 - ( 4 - fluorophenoxy ) - N - ( 2 - oxo - 1 , 2 4 -fluorophenol dihydropyridin - 4 - yl) benzamide 4 - chloro - 2- ( 2 , 4 - difluorophenoxy )- N -( 2 - oxo - 2, 4 - difluorophenol 1 , 2 - dihydropyridin - 4 - yl) benzamide 4 -chloro - N -( 2 -oxo - 1, 2 -dihydropyridin - 4 -yl ) - 2- 4 ,4 , 4 -trifluorobutanol ( 4 , 4 , 4 - trifluorobutoxy )benzamide 4 - chloro - 2 - ( 2 - fluoro - 6 -methylphenoxy ) - N - ( 2 - 2 - fluoro - 6 -methyl - phenol oxo - 1 , 2 - dihydropyridin - 4 -yl ) benzamide 4 - chloro - N - ( 2 -oxo - 1 , 2 -dihydropyridin - 4 - yl ) - 2 - 6 - (trifluoromethyl ) - 3 -pyridinol (( 6 - (trifluoromethyl ) pyridin - 3 yl) oxy )benzamide 19 4 - chloro - 2 - ( 2 , 6 - difluorophenoxy) - N - ( 2 - oxo 2, 6 - difluorophenol 1H - pyridin - 4 -yl ) benzamide 18 4 - chloro - 2 - ( 2 -chloro - 6 - fluorophenoxy ) - N - ( 2 - 2 - chloro - 6 - fluoro - phenol oxo - 1 , 2 - dihydropyridin - 4 -yl ) benzamide

Example 20 -continued Preparation of 4 , 5 -dichloro - 2 - ( 4 - fluoro - 2 -methoxy Cmpd phenoxy ) - N - (2 -oxo - 1 , 2 - dihydropyridin - 4 - yl) benz - 25 NoNo. Product Alcohol amide ( 114 ) 115 4 , 5 -dichloro - 2 - ( 3 - fluoro - 4 -methoxyphenoxy ) 3 - fluoro -4 N - (2 -oxo - 1, 2 -dihydropyridin - 4 -yl ) benzamide methoxy phenol

30 Example 21 NH Preparation of 2 - ( 4 - fluoro - 2 -methylphenoxy ) - N - ( 2 oxo - 1 ,2 -dihydropyridin - 4 -yl ) - 5 -( trifluoromethoxy ) NH 35 benzamide ( 40 )

OMe 40 F3CO IZ 45 Cs, C03 (97 . 7 mg, 0 .3 mmol) was added to a solution of 4 ,5 - dichloro - 2 - fluoro - N - ( 2 - oxo - 1 , 2 -dihydropyridin - 4 - yl ) benzamide (30 .1 mg, 0 . 1 mmol) and 4 - fluoro - 3 -methoxy phenol ( 42 .6 mg, 0 . 3 mmol ) in NMP ( 0 . 5 mL ) and the reaction was stirred at 90° C . for 2 hours . The reaction was 50 filtered and purified by reverse phase HPLC using a gradient of acetonitrile in water ( 1 - 99 % ) and HCl as a modifier to yield 4 , 5 - dichloro - 2 - ( 4 - fluoro - 2 -methoxyphenoxy ) - N - ( 2 Cs, C03 ( 651 .6 mg, 2 mmol) was added to a solution of oxo - 1 , 2 -dihydropyridin - 4 -yl ) benzamide ( 114 ) ( 13 .2 mg, 2 - fluoro -N -( 2 -oxo - 1, 2 -dihydropyridin -4 -yl ) -5 -( trifluo 30 % ) . ESI -MS m / z calc . 422 .02 , found 4235 . 3 ( M + 1 )) * ; 3555 romethoxybenzamideromethoxy )benzamide 1632(63 . 2 mg, 0 . 2 mmol) and 4 - fluoro - 3 Retention time: 1 . 57 minutes (3 minutes run ) . methylphenol ( 252 . 3 mg, 2 mmol) in DMF ( 1 mL ) and the Following a similar procedure as described above for reaction was stirred at 100° C . for 1 hours. The reaction was compound 114 , the following compounds were prepared filtered and purified by reverse phase HPLC using a gradient from 4 , 5 -dichloro - 2 - fluoro - N - ( 2 - oxo - 1 , 2 - dihydropyridin - 4 of acetonitrile in water ( 10 -99 % ) and HCl as a modifier to yl) benzamide and the following alcohols . 60 yield 2 - ( 4 - fluoro - 2 -methylphenoxy ) - N - ( 2 -oxo - 1 , 2 - dihydro pyridin - 4 - yl) - 5 - (trifluoromethoxy )benzamide ( 40 ) ( 36 .3 mg, 43 % ). ESI- MS m / z calc . 422 .09 , found 423 . 9 ( M + 1 ) + ; Cmpd Retention time: 1 .64 minutes ( 3 minutes run ). No. Product Alcohol Following a similar procedure as described above for 113 4 ,5 - dichloro - 2 - ( 4 - fluorophenoxy ) - N -( 2 -oxo - 4 - fluorophenol 65 compound 40 , the following compounds were prepared from 1 , 2 - dihydropyridin - 4 - yl) benzamide 2 - fluoro - N - ( 2 -oxo - 1 , 2 -dihydropyridin - 4 - yl) - 5 - ( trifluo romethoxy ) benzamide and the following alcohols .