RU2808424C2 - Pyridonamides as sodium channels modulators - Google Patents

Abstract

FIELD: pharmaceuticals.

SUBSTANCE: invention relates to a process for the preparation of a compound of formula I or a pharmaceutically acceptable salt thereof. In formula (I): R¹ is H, halogen, CN, or C₁-C₆ alkyl, where the said C₁-C₆ alkyl is substituted with 0–6 halogens, and where up to two non-adjacent CH₂ units of the said C₁-C₆ alkyl may be substituted on -O-; R² is H, halogen, CN, or C₁-C₆ alkyl, where the said C₁-C₆ alkyl is substituted with 0–6 halogens, where up to two non-adjacent CH₂ units of the said C₁-C₆ alkyl may be replaced by -O-; R³ is H, halogen, CN or C₁-C₆ alkyl, where the said C₁-C₆ alkyl is substituted with 0–6 halogens, where up to two non-adjacent CH₂ units of the said C₁-C₆ alkyl may be replaced by -O-; R⁴ is H, halogen, CN, or C₁-C₆ alkyl, where the said C₁-C₆ alkyl is substituted with 0–6 halogens, where up to two non-adjacent CH₂ units of the said C₁-C₆ alkyl may be replaced by -O-; R⁵ is H, halogen, CN or -XR^x; R^5' is H, halogen, CN or -XR^x; R⁶ is H, halogen, CN or -XR^x; R^6' is H, halogen, CN or -XR^x; R⁷ is H, halogen, CN or -XR^x; X is a bond or C₁-C₆ alkyl, where the said C₁-C₆ alkyl is substituted with 0–6 halogens, where up to two non-adjacent CH₂ units of the said C₁-C₆ alkyl may be replaced by -O-; and R^x is absent or is H or C₃-C₈ cycloaliphatic group, where up to two non-adjacent CH₂ units of the specified C₃-C₈ cycloaliphatic group can be replaced by -O-, and where the said C₃-C₈ cycloaliphatic group substituted with 0–3 substituents selected from halo and C₁-C₄ alkyl. The method includes the following: reaction of a compound of formula A with a compound of formula B in the presence of a first base to give a compound of formula I, and optional reaction of a compound of formula I with an acid or a second base to give a pharmaceutically acceptable salt. A compound of formula A and a compound of formula C are also provided. The invention makes it possible to obtain pyridonamide compounds of formula I or pharmaceutically acceptable salts thereof that can be used as sodium channel inhibitors.

EFFECT: obtaining pyridonamides as sodium channels modulators.

30 cl, 4 tbl, 30 ex

Description

CROSS REFERENCE TO RELATED APPLICATIONS

This application claims priority to U.S. Provisional Patent Application No. 61/759,059, filed January 31, 2013, the entire contents of which are incorporated herein by reference.

TECHNICAL FIELD OF THIS INVENTION

This invention relates to compounds useful as sodium channel inhibitors. The present invention also provides pharmaceutically acceptable compositions containing the compounds of the present invention and methods of using the compositions for the treatment of various disorders, including pain.

BACKGROUND OF THE INVENTION

Pain is a protective mechanism that allows healthy animals to avoid tissue damage and prevent further damage to already damaged tissue. However, there are many conditions where pain persists beyond its usefulness, or where pain inhibition would be beneficial to the patient.

Neuropathic pain is a form of chronic pain caused by damage to sensory nerves (Dieleman, JP, et al., Incidence rates and treatment of neuropathic pain conditions in the general population. Pain , 2008. 137 (3): p. 681-8). Neuropathic pain can be divided into two categories, pain caused by generalized metabolic nerve damage and pain caused by individual nerve damage. Metabolic neuropathies include postherpetic neuropathy, diabetic neuropathy, and drug-induced neuropathy. Individual nerve injuries include post-amputation pain, post-surgical nerve injury, and nerve entrapment injuries such as neuropathic back pain.

Voltage-gated sodium channels (Na _v ) play a critical role in pain signaling. Na _v are key biological mediators of electrical signaling, as they are the primary transmitters of the fast upward action potential of many excitable cell types (eg, neurons, skeletal myocytes, cardiac myocytes). Evidence for a role for these channels in normal physiology, pathological conditions arising from mutations in sodium channel genes, preclinical work in animal models, and the clinical pharmacology of known sodium channel modulating agents all point to a central role for Na _v in pain (Rush, A.M. and TR Cummins, Painful Research: Identification of a Small-Molecule Inhibitor that Selectively Targets ΝαγΙ-8 Sodium channels. Mol Interv, 2007. 7 (4): p. 192-5); England, S., Voltage-gated sodium channels: the search for subtype-selective analgesics. Expert Opin Investig Drugs 17 (12), p. 1849-64 (2008); Krafte, D.S. and Bannon, A.W., Soduim channels and nociception: recent concepts and therapeutic opportunities. Curr Opin Pharmacol 8 (1), p. 50-56 (2008)). Na _v are the primary transmitters of the rapid upward action potential of many excitable cell types (eg, neurons, skeletal myocytes, cardiac myocytes), and are therefore critical for promoting signaling in these cells (Hille, Bertil, Ion Channels of Excitable Membranes , Third ed. (Sinauer Associates, Inc., Sunderland, MA, 2001)). Due to the role that _Nav play in stimulating and propagating neural signals, antagonists that reduce _Nav currents can prevent or reduce neuronal signaling, and _Nav channels are considered the most likely targets for reducing pain in conditions in which there is hyperexcitability (Chahine , M., Chatelier, A., Babich, O., and Krupp, J. J., Voltage-gated sodium channels in neurological disorders. CNS Neurol Disord Drug Targets 7 (2), pp. 144-58 (2008). Several clinically useful analgesics have been identified as Na _v channel inhibitors. Local anesthetics such as lidocaine block pain through inhibition of Na _v channels, and other compounds such as carbamazepine, lamotrigine and tricyclic antidepressants, which have been shown to be effective in reducing pain, are also thought to inhibit the sodium channel (Soderpalm, B., Anticonvulsants : aspects of their mechanisms of action.Eur J Pain 6 Suppl A , pp. 3-9 (2002);Wang, G. K., Mitchell, J., and Wang, S.Y., Block of persistent late Na ⁺ currents by antidepressant sertraline and paroxetine J Membr Biol 222 (2), pp. 79-90 (2008).

Na _v form a subfamily of the voltage-gated ion channel superfamily and include 9 isoforms, designated Na _v 1.1 - Na _v 1.9. The tissue localization of the nine isoforms varies widely. Na _v 1.4 is the primary sodium channel of skeletal muscle, and Na _v 1.5 is the primary sodium channel of cardiac myocytes. Na _v 1.7, 1.8 and 1.9 are primarily localized in the peripheral nervous system, and Na _v 1.1, 1.2, 1.3 and 1.6 are neural channels found in both the central and peripheral nervous systems. The functional behavior of the nine isoforms is similar, but differs in the specificity of their voltage-dependent and kinetic behavior (Catterall, WA, Goldin, AL and Waxman, SG, International Union of Pharmacology. XL VII. Nomenclature and structure-function relationships of voltage-dependent sodium channels. Pharmacol Rev 57 (4), p 397 (2005)).

Immediately following its discovery, Na _v 1.8 channels were identified as likely targets for analgesia (Akopian, AN, L. Sivilotti and JN Wood, A tetrodotoxin-resistant voltage-dependent sodium channel expressed by sensory neurons. Nature , 1996. 379 (6562 ): p. 257-62). Since then, Na _v 1.8 has been shown to be the most significant carrier of sodium current, which is supported by action potentials arising in small GGC neurons (Blair, NT and BP Bean, Roles of tetrodotoxin (TTX)-sensitive Na+ current, TTX-resistant Na ⁺ current and Ca ²⁺ current in the action potentials of nociceptive sensory neurons. J Neurosci ., 2002. 22 (23): p. 10277-90). Na _v 1.8 is essential for the expression _of spontaneous activity ⁱⁿ damaged sensory axons of mice. J. Physiol. , 2003. 550 (Pt 3): p. 921 -6; Jarvis, MF, et al., A-803467, a potent and selective Na _v 1.8 sodium channel blocker, attenuates neuropathic and inflammatory pain in the rat. Proc Natl Acad Sci. USA, 2007. 104 (20): p. 8520-5; Joshi, SK, et al., Involvement of the TTX-resistant sodium channel Na _v 1.8 in inflammatory and neuropathic, but not post-operative, pain states. Pain , 2006. 123 (1-2): pp. 75-82; Lai, J., et al., Inhibition of neuropathic pain by decreased expression of the tetrodotoxin-resistant sodium channel, Na _v 1.8. Pain , 2002. 95 (1-2): p. 143-52; Dong, X. W., et al., Small interfering RNA-mediated selective knockdown of Na( _v )1.8 tetrodotoxin-resistant sodium channel reverses mechanical allodynia in neuropathic rats. Neuroscience , 2007. 146 (2): p. 812-21; Huang, H.L., et al., Proteomic profiling of neuromas reveals alterations in protein composition and local protein synthesis in hyper-excitable nerves. Mol Pain , 2008. 4 : p. 33; Black, JA, et al., Multiple sodium channel isoforms and mitogen-activated protein kinases are present in painful human neuromas. Ann Neurol , 2008. 64 (6): p. 644-53; Coward, K., et al., Immunolocalization of SNS/PN3 and NaN/SNS2 sodium channels in human pain states. Pain , 2000. 85 (1-2): p. 41 -50; Yiangou, Y., et al., SNS/PN3 and SNS2/NaN sodium channel-like immunoreactivity in human adult and neonate injured sensory nerves. FEBS Lett , 2000. 467 (2-3): p. 249-52; Ruangsri, S., et al., Relationship of axonal voltage-dependent sodium channel 1.8 (Na _v 1.8) mRNA accumulation to sciatic nerve injury-induced painful neuropathy in rats. J Biol Chem . 286 (46): p. 39836-47). Small GGC neurons expressing Na _v 1.8 include nociceptors critical for pain signals. Na _v 1.8 is a primary channel that mediates large amplitude action potentials in small dorsal root ganglion neurons (Blair, NT and BP Bean, Roles of tetrodotoxin (TTX)-sensitive Na ⁺ current, TTX-resistant Na ⁺ current and Ca ²⁺ current in the action potentials of nociceptive sensory neurons. J Neurosci ., 2002. 22 (23): p. 10277-90). Na _v 1.8 is required for fast repetitive action potentials in nociceptors and for spontaneous activity of damaged neurons. (Choi, JS and SG Waxman, Physiological interactions between Na _v 1.7 and Na _v 1.8 sodium channels: a computer simulation study. J Neurophysiol . 106 (6): p. 3173-84; Renganathan, M., TR Cummins and SG Waxman "Contribution of Na( _v )1.8 sodium channels to action potential electrogenesis in DRG neurons. J Neurophysiol ., 2001. 86 (2): p. 629-40; Roza, C, et al., The tetrodotoxin-resistant Na ⁺ channel Na _v 1.8 is essential for the expression of spontaneous activity in damaged sensory axons of mice. J Physiol ., 2003. 550 (Pt 3): p. 921-6). In depolarized or damaged GGC neurons, Na _v 1.8 appears to be the primary driver of hyperexcitability (Rush, AM, et al., A single sodium channel mutation produces hyper- or hypoexcitability in different types of neurons. Proc Natl Acad Sci USA , 2006. 103 (21): p. 8245-50). In several animal models of pain, Na _v 1.8 mRNA expression levels have been shown to be increased in GCTs (Sun, W., et al., Reduced conduction failure of the main axon of polymodal nociceptive C-fibres contributes to painful diabetic neuropathy in rats. Brain 135 (Pt 2): pp. 359-75; Strickland, IT, et al., Changes in the expression of Na _v 1.7, Na _v 1.8 and Na _v 1.9 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 expression of tetrodotoxin-resistant sodium channels Na _v 1.8 and Na _v 1.9 within dorsal root ganglia in a rat model of bone cancer pain. Neurosci. Lett . 512 (2): p. 61-6).

The main disadvantage of the known Na _v inhibitors is their poor therapeutic window, and this appears to be a consequence of their lack of isoform selectivity. Since Na _v 1.8 is primarily limited to neurons that experience pain, it is unlikely that selective Na _v 1.8 blockers cause the side effects associated with non-selective Na _v blockers. Therefore, there remains a need to develop additional Na _v channel antagonists, preferably those that are more selective for Na _v 1.8 and more potent in terms of increased metabolic stability, and have fewer side effects.

SUMMARY OF THE INVENTION

The compounds of this invention and pharmaceutically acceptable compositions thereof have been found to be useful as voltage-gated sodium channel inhibitors. These compounds have the general formula I or I':

or a pharmaceutically acceptable salt thereof.

These compounds and pharmaceutically acceptable compositions are useful for treating or reducing the severity of a variety of diseases, disorders or conditions, including, but not limited to, chronic pain, bowel pain, neuropathic pain, musculoskeletal pain, acute pain, inflammatory pain, cancer pain , idiopathic pain, multiple sclerosis, Charcot-Marie-Tooth syndrome, urinary incontinence or cardiac arrhythmia.

Detailed Description of the Invention

In one aspect, the invention provides compounds of formula I or I'

or a pharmaceutically acceptable salt thereof,

where, independently for each case:

G is

X is a bond or C ₁ -C ₆ alkyl, wherein said C ₁ -C ₆ alkyl is substituted with 0-6 halogen atoms, where up to two non-adjacent CH ₂ units of said C ₁ -C ₆ alkyl may be replaced by -O-;

R ^x is absent, is H or a C ₃ -C ₈ cycloaliphatic group, where up to two non-adjacent CH ₂ units of the specified C ₃ -C ₈ cycloaliphatic group can be replaced by -O-, and the specified C ₃ -C ₈ cycloaliphatic group is replaced by 0 -3 substituents selected from halogen and C ₁ -C ₄ alkyl;

R ¹ is H, halogen, CN or C ₁ -C ₆ alkyl, wherein said C ₁ -C ₆ alkyl is substituted with 0-6 halogen atoms, and where up to two non-adjacent CH ₂ units of said C ₁ -C ₆ alkyl may be replaced to -O-;

R ² is H, halogen, CN or C ₁ -C ₆ alkyl, wherein said C ₁ -C ₆ alkyl is substituted with 0-6 halogen atoms, where up to two non-adjacent CH ₂ units of said C ₁ -C ₆ alkyl may be replaced by -O-;

R ³ is H, halogen, CN or C ₁ -C ₆ alkyl, wherein said C ₁ -C ₆ alkyl is substituted with 0-6 halogen atoms, where up to two non-adjacent CH ₂ units of said C ₁ -C ₆ alkyl may be replaced by -O-;

R ⁴ is H, halogen, CN or C ₁ -C ₆ alkyl, wherein said C ₁ -C ₆ alkyl is substituted with 0-6 halogen atoms, where up to two non-adjacent CH ₂ units of said C ₁ -C ₆ alkyl may be replaced by -O-;

R ⁵ is H, halogen, CN or -XR ^x ;

R ^5' is H, halogen, CN or -XR ^x ;

R ⁶ is H, halogen, CN or -XR ^x ;

R ^6' is H, halogen, CN or -XR ^x ;

R ⁷ is H, halogen, CN or -XR ^x ;

R ⁸ is halogen or C ₁ -C ₆ alkyl, wherein said C ₁ -C ₆ alkyl is substituted with 0-6 halogen atoms, where up to two non-adjacent CH ₂ units of said C ₁ -C ₆ alkyl may be replaced by -O-;

p is an integer from 0 to 3 inclusive; And

R ⁹ is H or C ₁ -C ₆ alkyl, where up to two non-adjacent CH ₂ units of said C ₁ -C ₆ alkyl can be replaced by -O-.

For the purposes of this invention, chemical elements are identified in accordance with the Periodic Table of the Elements, CAS version, Handbook of Chemistry and Physics, ^75th Ed. In addition, the general principles of organic chemistry are described in "Organic Chemistry," Thomas Sorrell, University Science Books, Sausalito: 1999 and "March's Advanced Organic Chemistry," ^5th Ed., Ed.: Smith, M.B. and March, J., John Wiley & Sons, New York: 2001, the entire contents of which are incorporated herein by reference.

As described herein, the compounds of this invention may optionally be substituted with one or more substituents such as those shown generally above or those represented by specific classes, subclasses and species herein. As described herein, the variables R ¹ -R ⁹ in formula I or I' include certain groups, such as, for example, alkyl and cycloalkyl. As will be understood by one skilled in the art, the combinations of substituents provided in this invention include those combinations that provide stable or chemically useful compounds. The term “stable” as used herein refers to compounds that are substantially unchanged under conditions allowing their preparation, determination and, preferably, their recovery, purification and use for one or more of the purposes described herein. In some embodiments, a stable compound or chemically useful compound is one that is substantially unchanged when stored at a temperature of 40° C. or less, in the absence of moisture or other reactive conditions, for at least a week.

The phrase "optionally substituted" may be used interchangeably with the phrase "substituted or unsubstituted." In general, the term "substituted", with or without the addition of the term "optionally", refers to the replacement of hydrogen radicals in a given structure by a radical of a specified substituent. Specific substituents are described above in the description and below in the description of the compounds and examples thereof. Unless otherwise indicated, an optionally substituted group may have a substituent on each substitutable position of the group, and if more than one position in any given structure can be substituted by more than one substituent selected from a particular group, the substituents may be the same or different at each position. A ring substituent, such as heterocycloalkyl, can be bonded to another ring, such as cycloalkyl, to produce a spirobicyclic ring system, eg, both rings sharing one atom. One skilled in the art will appreciate that the combinations of substituents contemplated by this invention include those combinations that provide stable or chemically useful compounds.

The phrase "up to" as used herein refers to zero or any integer that is equal to or less than the number specified in the phrase. For example, "up to 4" means any of 0, 1, 2, 3, and 4.

The term “aliphatic,” “aliphatic group,” or “alkyl” as used herein means a straight (ie, unbranched) or branched, substituted or unsubstituted hydrocarbon chain that is fully saturated or that contains one or more units of unsaturation. Unless otherwise stated, aliphatic groups contain 1-20 aliphatic carbon atoms. In some embodiments, the aliphatic groups contain 1-10 aliphatic carbon atoms. In other embodiments, aliphatic groups contain 1-8 aliphatic carbon atoms. In other embodiments, the aliphatic groups contain 1-6 aliphatic carbon atoms, and in other embodiments, the aliphatic groups contain 1-4 aliphatic carbon atoms. Suitable aliphatic groups include, but are not limited to, linear or branched, substituted or unsubstituted alkyl, alkenyl, alkynyl groups.

The terms “cycloaliphatic” or “cycloalkyl” mean a monocyclic hydrocarbon ring or polycyclic hydrocarbon ring system that is fully saturated, or that contains one or more units of unsaturation, but that is non-aromatic and has a single point of attachment to the remainder of the molecule. The term "polycyclic ring system" as used herein includes bicyclic and tricyclic 4- to 12-membered structures that form at least two rings, where the two rings share at least one atom in common (e.g., 2 atoms in common), including fused, bridged or spirocyclic ring systems.

The term "halogen" or "halo" as used herein means F, Cl, Br or I. Unless otherwise specified, the term "heterocycle", "heterocyclyl", "heterocycloaliphatic", "heterocycloalkyl" or "heterocyclic" as used herein means a non-aromatic, monocyclic, bicyclic or tricyclic ring system in which one or more ring atoms in one or more ring members is an independently selected heteroatom. The heterocyclic ring may be saturated or may contain one or more unsaturated bonds. In some embodiments, a "heterocyclic", "heterocyclyl", "heterocycloaliphatic", "heterocycloalkyl" or "heterocyclic" group has from three to fourteen ring members, in which one or more ring members are heteroatoms independently selected from oxygen, sulfur, nitrogen or phosphorus, and each ring in the ring system contains from 3 to 7 ring members.

The term "heteroatom" means oxygen, sulfur, nitrogen, phosphorus or silicon (including any oxidized form of nitrogen, sulfur, phosphorus or silicon; the quaternized form of any basic nitrogen or; a substituted heterocyclic ring nitrogen, e.g. N (as in 3,4-dihydro -2H -pyrrolil), NH (as in pyrrolidinyl) or NR ⁺ (as in N-substituted pyrrolidinyl)).

The term "unsaturated" as used herein means that the group 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 defined above, attached to the carbon backbone via an oxygen (“alkoxy”) or sulfur (“thioalkyl”) atom.

The term "aryl", alone or as part of a larger group such as "aralkyl", "aralkoxy" or "aryloxyalkyl", refers to monocyclic, bicyclic and tricyclic ring systems containing only five to fourteen carbon atoms in the ring, where, according to at least one ring in the system is aromatic, and where each ring in the system contains from 3 to 7 carbon atoms in the ring. The term "aryl" may be used interchangeably with the term "aryl ring".

The term "heteroaryl", alone or as part of a larger group such as "heteroaralkyl" or "heteroarylalkoxy" refers to monocyclic, bicyclic and tricyclic ring systems containing a total of five to fourteen carbon atoms per ring, where at least one ring in a system is aromatic, where at least one ring in the system contains one or more heteroatoms, and where each ring in the system contains from 3 to 7 ring members. The term "heteroaryl" may be used interchangeably with the term "heteroaryl ring" or the term "heteroaromatic".

"D" and "d" both refer to deuterium.

Unless otherwise noted, structures depicted herein also include all isomeric (eg, enantiomeric, diastereomeric, and geometric (or conformational)) forms of the structure; for example, R and S configurations for each asymmetric center, (Z) and (E) double bond isomers, and (Z) and (E) conformational isomers. Therefore, individual stereochemical isomers, as well as enantiomeric, diastereomeric and geometric (or conformational) mixtures in accordance with this invention are included within the scope of this invention. Unless otherwise indicated, all tautomeric forms of the compounds of this invention are included within the scope of this invention. Thus, the tautomers of the compounds of formula I and I' are included within the scope of this invention. Structures also include zwitterionic forms of compounds or salts of Formula I and Formula I', as appropriate.

Additionally, unless otherwise indicated, the structures depicted herein include compounds that differ only in the presence of one or more isotopically enriched or isotopically labeled atoms. Isotopically labeled compounds may have one or more atoms replaced by an atom having an atomic mass or mass number normally found in nature. Examples of isotopes present in compounds of Formula I and Formula I' include isotopes of hydrogen, oxygen, phosphorus, fluorine and chlorine, such as, but not limited to, ² H, ³ H, ¹³ C, ¹⁴ C, ¹⁵ N, ¹⁸ O, ¹⁷ O, ³⁵ S and ¹⁸ F. Certain isotopically labeled compounds of formula I and formula I', in addition to being used as therapeutic agents, can also be used in drug and/or substrate tissue distribution studies, as analytical tools or as samples in other biological studies. In one aspect of the present invention, tritiated (eg, ³ H) and carbon-14 (eg, ¹⁴ C) isotopes are used due to their ease of determination. In another aspect of the present invention, replacement of one or more hydrogen atoms with heavier isotopes such as deuterium (eg, ^2H ) may provide certain therapeutic benefits.

In formulas and drawings, a line intersecting the ring and associated with the group R, since in

means that the group R, i.e. the R ⁸ group can be bonded to any carbon atom of this ring, as valency allows.

In the definition of a term such as X, R ^X , R ¹ , R ² , R ³ , R ⁴ , R ⁸ or R ⁹ , if the CH ₂ unit or, interchangeably, the methylene unit, can be replaced by -O-, it includes any CH ₂ unit, including the CH ₂ at the terminal methyl group. For example, CH ₂ CH ₂ CH ₂ OH falls within the definition of C ₁ -C ₆ alkyl, where up to two non-adjacent CH ₂ units can be replaced by -O-, since the CH ₂ unit of the terminal methyl group is replaced by -O-.

In another embodiment, the invention includes a compound of formula I or I' and the accompanying definitions, wherein R ¹ is H. In another embodiment, R ¹ is halogen. In another embodiment, R ¹ is CN. In another embodiment, R ¹ is C ₁ -C ₆ alkyl, wherein said C ₁ -C ₆ alkyl is substituted with 0-6 halogen atoms. In another embodiment, R ¹ is CF ₃ .

In another embodiment, this invention includes a compound of formula I or I' and the accompanying definitions, wherein R ² is H. In another embodiment, R ² is halogen. In another embodiment, R ² is Cl. In another embodiment, R ² is F. In another embodiment, R ² is CN. In another embodiment, R ² is C ₁ -C ₆ alkyl, wherein said C ₁ -C ₆ alkyl is substituted with 0-6 halogen atoms. In another embodiment, R ² is CF ₃ . In another embodiment, R ² is C ₁ -C ₆ alkyl, wherein said C ₁ -C ₆ alkyl is replaced by 0-6 halogen atoms, wherein one CH ₂ unit of said C ₁ -C ₆ alkyl is replaced by -O-. In another embodiment, R ² is OCF ₃ . In another embodiment, R ² is F, Cl, CN, CF ₃ or OCF ₃ .

In another embodiment, this invention includes a compound of formula I or I' and the accompanying definitions, wherein R ³ is H. In another embodiment, R ³ is halogen. In another embodiment, R ³ is Cl. In another embodiment, R ³ is F. In another embodiment, R ³ is CN. In another embodiment, R ³ is C ₁ -C ₆ alkyl, wherein said C ₁ -C ₆ alkyl is substituted with 0-6 halogen atoms. In another embodiment, R ³ is tert-butyl. In another embodiment, R ³ is CF ₃ . In another embodiment, R ³ is CF ₂ CF ₃ .

In another embodiment, this invention includes a compound of formula I or I' and the accompanying definitions, wherein R ⁴ is H. In another embodiment, R ⁴ is halogen. In another embodiment, R ⁴ is CN. In another embodiment, R ⁴ is C ₁ -C ₆ alkyl, wherein said C ₁ -C ₆ alkyl is substituted with 0-6 halogen atoms. In another embodiment, R ⁴ is CF ₃ .

In another embodiment, the present invention includes a compound of formula I or I' and the accompanying definitions, where p is zero. In another embodiment, p is an integer from 1 to 3 and R ⁸ is a halogen. In another embodiment, p is an integer from 1 to 3 and R ⁸ is Cl. In another embodiment, p is an integer from 1 to 3 and R ⁸ is a C ₁ -C ₆ alkyl, wherein said C ₁ -C ₆ alkyl is replaced by 0-6 halogen atoms, wherein one CH ₂ unit of said C ₁ -C ₆ alkyl is replaced to -O-. In another embodiment, p is an integer from 1 to 3 and R ⁸ is CH ₃ .

In another embodiment, this invention includes a compound of formula I or I' and the accompanying definitions, wherein R ⁹ is H. In another embodiment, R ⁹ is C ₁ -C ₆ alkyl. In another embodiment, R ⁹ is CH ₃ . In another embodiment, R ⁹ is C ₁ -C ₆ alkyl, wherein said C ₁ -C ₆ alkyl is replaced by 0-6 halogen atoms, wherein one CH ₂ unit of said C ₁ -C ₆ alkyl is replaced by -O-. In another embodiment, R ⁹ is CH ₂ CH ₂ OH.

In another embodiment, this invention includes a compound of formula I or I' and the accompanying definitions, wherein G is

,

Where:

R ⁵ is H, halogen, CN or -XR ^x ;

R ^5' is H, halogen, CN or -XR ^x ;

R ⁶ is H, halogen, CN or -XR ^x ;

R ^6' is H, halogen, CN or -XR ^x ;

R ⁷ is H, halogen, CN or -XR ^x ;

X is a bond or C ₁ -C ₆ alkyl, wherein said C ₁ -C ₆ alkyl is substituted with 0-6 halogen atoms and where up to two non-adjacent CH ₂ units of said C ₁ -C ₆ alkyl can be replaced by -O-; And

R ^x is absent, is H or a C ₃ -C ₈ cycloaliphatic group, where up to two non-adjacent CH ₂ units of the specified C ₃ -C ₈ cycloaliphatic group can be replaced by -O-, and the specified C ₃ -C ₈ cycloaliphatic group is replaced by 0 -3 substituents selected from halogen and C ₁ -C ₄ alkyl.

In another embodiment, this invention includes a compound of formula I or I' and the accompanying definitions, wherein G is

,

Where:

R ⁵ is H or -XR ^x ;

R ^5' is H or -XR ^x ;

R ⁶ is H, halogen, CN or -XR ^x ;

R ⁷ is H or -XR ^x ;

X is a bond or C ₁ -C ₆ alkyl, wherein said C ₁ -C ₆ alkyl is substituted with 0-6 halogen atoms, where up to two non-adjacent CH ₂ units of said C ₁ -C ₆ alkyl may be replaced by -O-; And

R ^x is absent, is H or a C ₃ -C ₈ cycloaliphatic group, where up to two non-adjacent CH ₂ units of the specified C ₃ -C ₈ cycloaliphatic group can be replaced by -O-, and the specified C ₃ -C ₈ cycloaliphatic group is replaced by 0 -3 substituents selected from halogen and C ₁ -C ₄ alkyl.

In another embodiment, this invention includes a compound of formula I or I' and the accompanying definitions, wherein G is

.

In one embodiment, R ⁵ is H. In another embodiment, R ⁵ is halogen. In another embodiment, R ⁵ is Cl. In another embodiment, R ⁵ is F. In another embodiment, R ⁵ is CN. In another embodiment, R ⁵ is -XR ^x . In another embodiment, R ⁵ is -XR ^x where R ^x is absent. In another embodiment, R ⁵ is -XR ^x , where R ^x is absent and X is C ₁ -C ₆ alkyl, wherein said C ₁ -C ₆ alkyl is substituted with 0-6 halogen atoms. In another embodiment, R ⁵ is CH ₃ . In another embodiment, R ⁵ is -XR ^x , where R ^x is absent and X is a C ₁ -C ₆ alkyl, wherein said C ₁ -C ₆ alkyl is substituted with 0-6 halogen atoms, where one CH ₂ unit of said C ₁ -C ₆ alkyl is replaced by -O-. In another embodiment, R ⁵ is OCH ₃ , OCH ₂ CH ₃ , OCH ₂ CH ₂ CH ₃ or OCH(CH ₃ ) ₂ . In another embodiment, R ⁵ is OCH ₃ . In another embodiment, R ⁵ is CH ₂ OH. In another embodiment, R ⁵ is OCF ₃ . In another embodiment, R ⁵ is OCHF ₂ .

In another embodiment, this invention includes a compound of formula I or I' and the accompanying definitions, wherein G is

.

In one embodiment, R ⁵ is H. In another embodiment, R ⁵ is -XR ^x . In another embodiment, R is -XR ^x , where R ^x is absent. In another embodiment, R is -XR ^x , where R ^x is absent and X is C ₁ -C ₆ alkyl, wherein said C ₁ -C ₆ alkyl is substituted with 0-6 halogen atoms. In another embodiment, R ⁵ is CH ₃ . In another embodiment, R ⁵ is -XR ^x , where R ^x is absent and X is a C ₁ -C ₆ alkyl, wherein said C ₁ -C ₆ alkyl is substituted with 0-6 halogen atoms, where one CH ₂ unit of said C ₁ -C ₆ alkyl is replaced by -O-. In another embodiment, R ⁵ is OCH ₃ , OCH ₂ CH ₃ , OCH ₂ CH ₂ CH ₃ or OCH(CH ₃ ) ₂ . In another embodiment, R ⁵ is OCH ₃ . In another embodiment, R ⁵ is CH ₂ OH. In another embodiment, R ⁵ is OCF ₃ . In another embodiment, R ⁵ is OCHF ₂ .

In another embodiment, this invention includes a compound of formula I or I' and the accompanying definitions, wherein G is

.

In one embodiment, R ^5' is H. In another embodiment, R ^5' is halogen. In another embodiment, R ^5' is Cl. In another embodiment, R ^5' is F. In another embodiment, R ^5' is CN. In another embodiment, R ^5' is -XR ^x . In another embodiment, R ^5' is -XR ^x , where R ^x is absent. In another embodiment, R ^5' is -XR ^x , where R ^x is absent and X is C ₁ -C ₆ alkyl, wherein said C ₁ -C ₆ alkyl is substituted with 0-6 halogen atoms. In another embodiment, R ^5' is CH ₃ . In another embodiment, R ^5' is -XR ^x , where R ^x is absent and X is a C ₁ -C ₆ alkyl, wherein said C ₁ -C ₆ alkyl is substituted with 0-6 halogen atoms, where one CH ₂ unit of said C ₁ - C ₆ alkyl is replaced with -O-. In another embodiment, R ^5' is OCH ₃ , OCH ₂ CH ₃ , OCH ₂ CH ₂ CH ₃ or OCH(CH ₃ ) ₂ . In another embodiment, R ^5' is OCH ₃ . In another embodiment, R ^5' is CH ₂ OH. In another embodiment, R ^5' is OCF ₃ . In another embodiment, R ^5' is OCHF ₂ .

In another embodiment, this invention includes a compound of formula I or I' and the accompanying definitions, wherein G is

.

In one embodiment, R ⁵ is H. In another embodiment, R ⁵ is -XR ^x . In another embodiment, R ⁵ is -XR ^x where R ^x is absent. In another embodiment, R ⁵ is -XR ^x , where R ^x is absent and X is C ₁ -C ₆ alkyl, wherein said C ₁ -C ₆ alkyl is substituted with 0-6 halogen atoms. In another embodiment, R ⁵ is CH ₃ . In another embodiment, R ⁵ is -XR ^x , where R ^x is absent and X is a C ₁ -C ₆ alkyl, wherein said C ₁ -C ₆ alkyl is substituted with 0-6 halogen atoms, where one CH ₂ unit of said C ₁ -C ₆ alkyl is replaced by -O-. In another embodiment, R ⁵ is OCH ₃ , OCH ₂ CH ₃ , OCH ₂ CH ₂ CH ₃ or OCH(CH ₃ ) ₂ . In another embodiment, R ⁵ is OCH ₃ . In another embodiment, R ⁵ is CH ₂ OH. In another embodiment, R ⁵ is OCF ₃ . In another embodiment, R ⁵ is OCHF ₂ .

In another embodiment, this invention includes a compound of formula I or I' and the accompanying definitions, wherein G is

.

In one embodiment, R ⁶ is H. In another embodiment, R ⁶ is halogen. In another embodiment, R ⁶ is Cl. In another embodiment, R ⁶ is F. In another embodiment, R ⁶ is CN. In another embodiment, R ⁶ is -XR ^x . In another embodiment, R ⁶ is -XR ^x where R ^x is absent. In another embodiment, R ⁶ is -XR ^x , where R ^x is absent and X is C ₁ -C ₆ alkyl, wherein said C ₁ -C ₆ alkyl is substituted with 0-6 halogen atoms. In another embodiment, R ⁶ is CH ₃ . In another embodiment, R ⁶ is -XR ^x , where R ^x is absent and X is a C ₁ -C ₆ alkyl, wherein said C ₁ -C ₆ alkyl is substituted with 0-6 halogen atoms, where one CH ₂ unit of said C ₁ -C ₆ alkyl is replaced by -O-. In another embodiment, R ⁶ is OCH ₃ .

In another embodiment, this invention includes a compound of formula I or I' and the accompanying definitions, wherein G is

.

In one embodiment, R ^6' is H. In another embodiment, R ^6' is halogen. In another embodiment, R ⁶ is Cl. In another embodiment, R ^6' is F. In another embodiment, R ^6' is CN. In another embodiment, R ^6' is -XR ^x . In another embodiment, R ⁶ is -XR ^x where R ^x is absent. In another embodiment, R ^6' is -XR ^x , where R ^x is absent and X is C ₁ -C ₆ alkyl, wherein said C ₁ -C ₆ alkyl is substituted with 0-6 halogen atoms. In another embodiment, R ^6' is CH ₃ . In another embodiment, R ^6' is -XR ^x , where R ^x is absent and X is a C ₁ -C ₆ alkyl, wherein said C ₁ -C ₆ alkyl is substituted with 0-6 halogen atoms, where one CH ₂ unit of said C ₁ - C ₆ alkyl is replaced with -O-. In another embodiment, R ^6' is OCH ₃ .

In another embodiment, this invention includes a compound of formula I or I' and the accompanying definitions, wherein G is

.

In one embodiment, R ⁷ is H. In another embodiment, R ⁷ is halogen. In another embodiment, R ⁷ is Cl. In another embodiment, R ⁷ is F. In another embodiment, R ⁷ is CN. In another embodiment, R ⁷ is -XR ^x . In another embodiment, R ⁷ is -XR ^x where R ^x is absent. In another embodiment, R ⁷ is -XR ^x , where R ^x is absent and X is C ₁ -C ₆ alkyl, wherein said C ₁ -C ₆ alkyl is substituted with 0-6 halogen atoms. In another embodiment, R ⁷ is CH ₃ , CH ₂ CH ₃ , CH2CH ₂ CH ₃ or isopropyl. In another embodiment, R ⁷ is CF ₃ . In another embodiment, R ⁷ is -XR ^x , where R ^x is absent and X is a C ₁ -C ₆ alkyl, wherein said C ₁ -C ₆ alkyl is substituted with 0-6 halogen atoms, where two non-adjacent CH ₂ units of said C ₁ - C ₆ alkyls are replaced with -O-. In another embodiment, R ⁷ is OCH ₂ CH ₂ OCH ₃ . In another embodiment, R ⁷ is -XR ^x , where R ^x is absent and X is a C ₁ -C ₆ alkyl, wherein said C ₁ -C ₆ alkyl is substituted with 0-6 halogen atoms, where one CH ₂ unit of said C ₁ -C ₆ alkyl is replaced by -O-. In another embodiment, R ⁷ is OCH ₃ , OCH ₂ CH ₃ OCH ₂ CH ₂ CH ₃ , OC(CH ₃ ) ₃ , CH ₂ CH ₂ OCH ₃ . In another embodiment, R ⁷ is OCF ₃ , OCH ₂ CF ₃ , OCH ₂ CH ₂ CH ₂ CF ₃ or OCHF ₂ .

In another embodiment, this invention includes a compound of formula I or I' and the accompanying definitions, wherein G is

.

In one embodiment, R ⁷ is H. In another embodiment, R ⁷ is -XR ^x . In another embodiment, R ⁷ is -XR ^x where R ^x is absent. In another embodiment, R ⁷ is -XR ^x , where R ^x is absent and X is C ₁ -C ₆ alkyl, wherein said C ₁ -C ₆ alkyl is substituted with 0-6 halogen atoms. In another embodiment, R ⁷ is CH ₃ , CH ₂ CH ₃ , CH ₂ CH ₂ CH ₃ or isopropyl. In another embodiment, R ⁷ is CF ₃ . In another embodiment, R ⁷ is -XR ^x , where R ^x is absent and X is a C ₁ -C ₆ alkyl, wherein said C ₁ -C ₆ alkyl is substituted with 0-6 halogen atoms, where two non-adjacent CH ₂ units of said C ₁ - C ₆ alkyls are replaced with -O-. In another embodiment, R ⁷ is OCH ₂ CH ₂ OCH ₃ . In another embodiment, R ⁷ is -XR ^x , where R ^x is absent and X is a C ₁ -C ₆ alkyl, wherein said C ₁ -C ₆ alkyl is substituted with 0-6 halogen atoms, where one CH ₂ unit of said C ₁ -C ₆ alkyl is replaced by -O-. In another embodiment, R ⁷ is OCH ₃ , OCH ₂ CH ₃ OCH ₂ CH ₂ CH ₃ , OC(CH ₃ ) ₃ , CH ₂ CH ₂ OCH ₃ . In another embodiment, R ⁷ is OCF ₃ , OCH ₂ CF ₃ , OCH ₂ CH ₂ CH ₂ CF ₃ or OCHF ₂ .

In another embodiment, this invention includes a compound of formula I or I' and the accompanying definitions, wherein G is

.

In one embodiment, R ⁷ is -XR ^x where X is a bond and R ^x is a C ₃ -C ₈ cycloaliphatic group, and said C ₃ -C ₈ cycloaliphatic group is substituted with 0-3 substituents selected from halogen and C ₁ -C ₄ alkyl. In another embodiment, R ⁷ is -XR ^x , where X is a bond and R ^x is cyclopropyl.

In another embodiment, this invention includes a compound of formula I or I' and the accompanying definitions, wherein G is

.

In one embodiment, R ⁷ is -XR ^x where X is a C ₁ -C ₆ alkyl, wherein said C ₁ -C ₆ alkyl is replaced by 0-6 halogen atoms, wherein one CH ₂ unit of said C ₁ -C ₆ alkyl is replaced by -O- and R ^x is a C ₃ -C ₈ cycloaliphatic group, and said C ₃ -C ₈ cycloaliphatic group is substituted with up to 0-3 substituents selected from halogen and C ₁ -C ₄ alkyl. In another embodiment, R ⁷ is -XR ^x where X is OCH ₂ and R ^x is cyclopropyl.

In another embodiment, this invention includes a compound of formula I or I' and the accompanying definitions wherein G is:

and G are selected from:

In another embodiment, the invention includes a compound of formula I or I' and the accompanying definitions, wherein G is:

and G are selected from:

In another embodiment, this invention includes a compound of formula I or I' and the accompanying definitions, wherein G is

,

Where:

X is a bond or C ₁ -C ₆ alkyl, wherein said C ₁ -C ₆ alkyl is substituted with 0-6 halogen atoms, where up to two non-adjacent CH ₂ units of said C ₁ -C ₆ alkyl may be replaced by -O-; And

R ^x is absent, is H or a C ₃ -C ₈ cycloaliphatic group, where up to two non-adjacent CH ₂ units of the specified C ₃ -C ₈ cycloaliphatic group can be replaced by -O-, and the specified C ₃ -C ₈ cycloaliphatic group is substituted up to up to 0-3 substituents selected from halogen and C ₁ -C ₄ alkyl.

In another embodiment, this invention includes a compound of formula I or I' and accompanying definitions, wherein G is -XR ^x , wherein X is _C1 - _C6 alkyl, wherein said _C1 - _C6 alkyl is substituted with 0-6 halogen atoms, wherein up to two non-adjacent CH ₂ units of said C ₁ -C ₆ alkyl may be replaced by -O- and R ^x is absent. In another embodiment, X is CH ₂ CH ₂ CH(CH ₃ ) ₃ or CH ₂ CH(CH ₃ ) ₂ and R ^x is absent. In another embodiment, X is CH ₂ CH ₂ CH ₂ CF ₃ or CH ₂ CH ₂ CF ₃ and R ^x is absent.

In another embodiment, the present invention includes a compound of formula I or I' and the accompanying definitions, wherein G is -XR ^x , where X is a bond and R ^x is a C ₃ -C ₈ cycloaliphatic group, wherein up to two non-adjacent CH ₂ units of said C _{The 3} -C ₈ cycloaliphatic group may be replaced by -O-, and said C ₃ -C ₈ cycloaliphatic group is substituted with 0-3 substituents selected from halogen and C ₁ -C ₄ alkyl. In another embodiment, X is a bond and R ^x is cyclobutane, cyclohexane, bicyclo[2.2.1]heptane or bicyclo[3.1.0]hexane.

In another embodiment, this invention includes a compound of formula I or I' and accompanying definitions, wherein G is -XR ^x , wherein X is _C1 - _C6 alkyl, wherein said _C1 - _C6 alkyl is substituted with 0-6 halogen atoms, wherein up to two non-adjacent CH ₂ units of said C ₁ -C ₆ alkyl may be replaced by -O-, and R ^x is a C ₃ -C ₈ cycloaliphatic group, wherein up to two non-adjacent CH ₂ units of said C ₃ -C ₈ cycloaliphatic group may be replaced by -O-, and said C ₃ -C ₈ cycloaliphatic group is substituted with 0-3 substituents selected from halogen and C ₁ -C ₄ alkyl. In another embodiment, X is CH ₂ and R ^x is a C ₃ -C ₈ cycloaliphatic group. In another embodiment, X is CH ₂ and R ^x is cyclopropyl or cyclopentyl. In another embodiment, X is CH ₂ and R ^x is a C ₃ -C ₈ cycloaliphatic group substituted with up to 3 substituents selected from halogen and C ₁ -C ₄ alkyl. In another embodiment, X is CH ₂ and R ^x is 1-methylcyclopropyl, 2,2-dimethylcyclopropyl or 2,2-difluorocyclopropyl.

In another embodiment, this invention includes a compound of formula I or I' and accompanying definitions, wherein G is -XR ^x , wherein X is _C1 - _C6 alkyl, wherein said _C1 - _C6 alkyl is substituted with 0-6 halogen atoms, wherein up to two non-adjacent CH ₂ units of said C ₁ -C ₆ alkyl may be replaced by -O-, and R ^x is a C ₃ -C ₈ cycloaliphatic group, wherein up to two non-adjacent CH ₂ units of said C ₃ -C ₈ cycloaliphatic group may be replaced by -O-, and said C ₃ -C ₈ cycloaliphatic group is substituted with 0-3 substituents selected from halogen and C ₁ -C ₄ alkyl. In another embodiment, X is CH ₂ and R ^x is a C ₃ -C ₈ cycloaliphatic group, where one CH ₂ unit of said C ₃ -C ₈ cycloaliphatic group is replaced by -O-. In another embodiment, X is CH ₂ and R ^x is 3-tetrahydrofuran.

In another embodiment, the present invention includes a compound of formula I or I' and the accompanying definitions, wherein G is -XR ^x and -XR ^x is selected from:

In another embodiment, this invention includes a compound of formula I or I':

or a pharmaceutically acceptable salt thereof,

where, independently for each case:

G is

X is a bond or C ₁ -C ₆ alkyl, wherein said C ₁ -C ₆ alkyl is substituted with 0-6 halogen atoms, where up to two non-adjacent CH ₂ units of said C ₁ -C ₆ alkyl may be replaced by -O-;

R ^x is absent, is H or a C ₃ -C ₈ cycloaliphatic group, where up to two non-adjacent CH ₂ units of the specified C ₃ -C ₈ cycloaliphatic group can be replaced by -O-, and the specified C ₃ -C ₈ cycloaliphatic group is replaced by 0 -3 substituents selected from halogen and C ₁ -C ₄ alkyl;

R ² is halogen, CN or C ₁ -C ₆ alkyl, wherein said C ₁ -C ₆ alkyl is substituted by 0-6 halogen atoms, and where up to two non-adjacent CH ₂ units of said C ₁ -C ₆ alkyl may be replaced by - O-;

R ⁵ is H, halogen, CN or -XR ^x ;

R ^5' is H, halogen, CN or -XR ^x ;

R ⁶ is H, halogen, CN or -XR ^x ;

R ^6' is H, halogen, CN or -XR ^x ;

R ⁷ is H, halogen, CN or -XR ^x ;

R ⁸ is halogen or C ₁ -C ₆ alkyl, wherein said C ₁ -C ₆ alkyl is substituted with 0-6 halogen atoms, and where up to two non-adjacent CH ₂ units of said C ₁ -C ₆ alkyl may be replaced by -O- ;

p is an integer from 0 to 3 inclusive; And

R ⁹ is H or C ₁ -C ₆ alkyl, where up to two non-adjacent CH ₂ units of said C ₁ -C ₆ alkyl can be replaced by -O-.

In another embodiment, this invention includes a compound of formula IA or I'-A and the accompanying definitions, wherein R ² is halogen. In another embodiment, R ² is Cl. In another embodiment, R ² is F. In another embodiment, R ² is CN. In another embodiment, R ² is C ₁ -C ₆ alkyl, wherein said C ₁ -C ₆ alkyl is substituted with 0-6 halogen atoms. In another embodiment, R ² is CF ₃ . In another embodiment, R ² is C ₁ -C ₆ alkyl, wherein said C ₁ -C ₆ alkyl is replaced by 0-6 halogen atoms, wherein one CH ₂ unit of said C ₁ -C ₆ alkyl is replaced by -O-. In another embodiment, R ² is OCF ₃ . In another embodiment, R ² is F, Cl, CN, CF ₃ or OCF ₃ .

In another embodiment, the present invention includes a compound of formula IA or I'-A and accompanying definitions, where p is zero. In another embodiment, p is an integer from 1 to 3 and R ⁸ is a halogen. In another embodiment, p is an integer from 1 to 3 and R ⁸ is Cl. In another embodiment, p is an integer from 1 to 3 and R ⁸ is a C ₁ -C ₆ alkyl, wherein said C ₁ -C ₆ alkyl is substituted with 0-6 halogen atoms, where one CH ₂ unit of said C ₁ -C ₆ alkyl replaced by -O-. In another embodiment, p is an integer from 1 to 3 and R ⁸ is CH ₃ .

In another embodiment, the present invention includes a compound of formula IA or I'-A and the accompanying definitions, wherein R ⁹ is H. In another embodiment, R ⁹ is C ₁ -C ₆ alkyl. In another embodiment, R ⁹ is CH ₃ . In another embodiment, R ⁹ is C ₁ -C ₆ alkyl, wherein said C ₁ -C ₆ alkyl is replaced by 0-6 halogen atoms, wherein one CH ₂ unit of said C ₁ -C ₆ alkyl is replaced by -O-. In another embodiment, R ⁹ is CH ₂ CH ₂ OH.

In another embodiment, this invention includes a compound of formula I-A or I'-A and accompanying definitions, wherein G is

,

Where:

R ⁵ is H, halogen, CN or -XR ^x ;

R ^5' is H, halogen, CN or -XR ^x ;

R ⁶ is H, halogen, CN or -XR ^x ;

R ^6' is H, halogen, CN or -XR ^x ;

R ⁷ is H, halogen, CN or -XR ^x ;

X is a bond or C ₁ -C ₆ alkyl, wherein said C ₁ -C ₆ alkyl is substituted with 0-6 halogen atoms, where up to two non-adjacent CH ₂ units of said C ₁ -C ₆ alkyl may be replaced by -O-; And

R ^x is absent, is H or a C ₃ -C ₈ cycloaliphatic group, where up to two non-adjacent CH ₂ units of the specified C ₃ -C ₈ cycloaliphatic group can be replaced by -O-, and the specified C ₃ -C ₈ cycloaliphatic group is replaced by 0 -3 substituents selected from halogen and C ₁ -C ₄ alkyl.

In another embodiment, this invention includes a compound of formula I-A or I'-A and accompanying definitions, wherein G is

,

Where:

R ⁵ is H or -XR ^x ;

R ^5' is H or -XR ^x ;

R ⁶ is H, halogen, CN or -XR ^x ;

R ⁷ is H or -XR ^x ;

X is a bond or C ₁ -C ₆ alkyl, wherein said C ₁ -C ₆ alkyl is substituted with 0-6 halogen atoms, where up to two non-adjacent CH ₂ units of said C ₁ -C ₆ alkyl may be replaced by -O-; And

R ^x is absent, is H or a C ₃ -C ₈ cycloaliphatic group, where up to two non-adjacent CH ₂ units of the specified C ₃ -C ₈ cycloaliphatic group can be replaced by -O-, and the specified C ₃ -C ₈ cycloaliphatic group is replaced by 0 -3 substituents selected from halogen and C ₁ -C ₄ alkyl.

In another embodiment, this invention includes a compound of formula I-A or I'-A and accompanying definitions, wherein G is

.

In one embodiment, R ⁵ is H. In another embodiment, R ⁵ is halogen. In another embodiment, R ⁵ is Cl. In another embodiment, R ⁵ is F. In another embodiment, R ⁵ is CN. In another embodiment, R ⁵ is -XR ^x . In another embodiment, R ⁵ is -XR ^x where R ^x is absent. In another embodiment, R ⁵ is -XR ^x , where R ^x is absent and X is C ₁ -C ₆ alkyl, wherein said C ₁ -C ₆ alkyl is substituted with 0-6 halogen atoms. In another embodiment, R ⁵ is CH ₃ . In another embodiment, R ⁵ is -XR ^x , where R ^x is absent and X is a C ₁ -C ₆ alkyl, wherein said C ₁ -C ₆ alkyl is substituted with 0-6 halogen atoms, where one CH ₂ unit of said C ₁ -C ₆ alkyl is replaced by -O-. In another embodiment, R ⁵ is OCH ₃ , OCH ₂ CH ₃ , OCH ₂ CH ₂ CH ₃ or OCH(CH ₃ ) ₂ . In another embodiment, R ⁵ is OCH ₃ . In another embodiment, R ⁵ is CH ₂ OH. In another embodiment, R ⁵ is OCF ₃ . In another embodiment, R ⁵ is OCHF ₂ .

In another embodiment, this invention includes a compound of formula I-A or I'-A and accompanying definitions, wherein G is

.

In one embodiment, R ⁵ is H. In another embodiment, R ⁵ is -XR ^x . In another embodiment, R ⁵ is -XR ^x where R ^x is absent. In another embodiment, R ⁵ is -XR ^x , where R ^x is absent and X is C ₁ -C ₆ alkyl, wherein said C ₁ -C ₆ alkyl is substituted with 0-6 halogen atoms. In another embodiment, R ⁵ is CH ₃ . In another embodiment, R ⁵ is -XR ^x , where R ^x is absent and X is a C ₁ -C ₆ alkyl, wherein said C ₁ -C ₆ alkyl is substituted with 0-6 halogen atoms, where one CH ₂ unit of said C ₁ -C ₆ alkyl is replaced by -O-. In another embodiment, R ⁵ is OCH ₃ , OCH ₂ CH ₃ , OCH ₂ CH ₂ CH ₃ or OCH(CH ₃ ) ₂ . In another embodiment, R ⁵ is OCH ₃ . In another embodiment, R ⁵ is CH ₂ OH. In another embodiment, R ⁵ is OCF ₃ . In another embodiment, R ⁵ is OCHF ₂ .

In another embodiment, this invention includes a compound of formula I-A or I'-A and the accompanying definitions, G is

.

In one embodiment, R ^5' is H. In another embodiment, R ^5' is halogen. In another embodiment, R ^5' is Cl. In another embodiment, R ^5' is F. In another embodiment, R ^5' is CN. In another embodiment, R ^5' is -XR ^x . In another embodiment, R ^5' is -XR ^x , where R ^x is absent. In another embodiment, R ^5' is -XR ^x , where R ^x is absent and X is C ₁ -C ₆ alkyl, wherein said C ₁ -C ₆ alkyl is substituted with 0-6 halogen atoms. In another embodiment, R ^5' is CH ₃ . In another embodiment, R ^5' is -XR ^x , where R ^x is absent and X is a C ₁ -C ₆ alkyl, wherein said C ₁ -C ₆ alkyl is substituted with 0-6 halogen atoms, where one CH ₂ unit of said C ₁ - C ₆ alkyl is replaced with -O-. In another embodiment, R ^5' is OCH ₃ , OCH ₂ CH ₃ , OCH ₂ CH ₂ CH ₃ or OCH(CH ₃ ) ₂ . In another embodiment, R ^5' is OCH ₃ . In another embodiment, R ^5' is CH ₂ OH. In another embodiment, R ^5' is OCF ₃ . In another embodiment, R ^5' is OCHF ₂ .

In another embodiment, this invention includes a compound of formula I-A or I'-A and the accompanying definitions, G is

.

In one embodiment, R ^5' is H. In another embodiment, R ^5' is -XR ^x . In another embodiment, R ^5' is -XR ^x , where R ^x is absent. In another embodiment, R ^5' is -XR ^x , where R ^x is absent and X is C ₁ -C ₆ alkyl, wherein said C ₁ -C ₆ alkyl is substituted with 0-6 halogen atoms. In another embodiment, R ^5' is CH ₃ . In another embodiment, R ^5' is -XR ^x , where R ^x is absent and X is a C ₁ -C ₆ alkyl, wherein said C ₁ -C ₆ alkyl is substituted with 0-6 halogen atoms, where one CH ₂ unit of said C ₁ - C ₆ alkyl is replaced with -O-. In another embodiment, R ^5' is OCH ₃ , OCH ₂ CH ₃ , OCH ₂ CH ₂ CH ₃ or OCH(CH ₃ ) ₂ . In another embodiment, R ^5' is OCH ₃ . In another embodiment, R ^5' is CH ₂ OH. In another embodiment, R ^5' is OCF ₃ . In another embodiment, R ^5' is OCHF ₂ .

In another embodiment, this invention includes a compound of formula I-A or I'-A and accompanying definitions, wherein G is

.

In one embodiment, R ⁶ is H. In another embodiment, R ⁶ is halogen. In another embodiment, R ⁶ is Cl. In another embodiment, R ⁶ is F. In another embodiment, R ⁶ is CN. In another embodiment, R ⁶ is -XR ^x . In another embodiment, R ⁶ is -XR ^x where R ^x is absent. In another embodiment, R ⁶ is -XR ^x where R ^x is absent and X is C ₁ -C ₆ alkyl, wherein said C ₁ -C ₆ alkyl is substituted with 0-6 halogen atoms. In another embodiment, R ⁶ is CH ₃ . In another embodiment, R ⁶ is -XR ^x , where R ^x is absent and X is a C ₁ -C ₆ alkyl, wherein said C ₁ -C ₆ alkyl is substituted with 0-6 halogen atoms, where one CH ₂ unit of said C ₁ -C ₆ alkyl is replaced by -O-. In another embodiment, R ⁶ is OCH ₃ .

In another embodiment, this invention includes a compound of formula I-A or I'-A and accompanying definitions, wherein G is

.

In one embodiment, R ^6' is H. In another embodiment, R ^6' is halogen. In another embodiment, R ^6' is Cl. In another embodiment, R ^6' is F. In another embodiment, R ^6' is CN. In another embodiment, R ^6' is -XR ^x . In another embodiment, R ^6' is -XR ^x where R ^x is absent. In another embodiment, R ^6' is -XR ^x , where R ^x is absent and X is C ₁ -C ₆ alkyl, wherein said C ₁ -C ₆ alkyl is substituted with 0-6 halogen atoms. In another embodiment, R ^6' is CH ₃ . In another embodiment, R ^6' is -XR ^x , where R ^x is absent and X is a C ₁ -C ₆ alkyl, wherein said C ₁ -C ₆ alkyl is substituted with 0-6 halogen atoms, where one CH ₂ unit of said C ₁ - C ₆ alkyl is replaced with -O-. In another embodiment, R ^6' is OCH ₃ .

In another embodiment, this invention includes a compound of formula I-A or I'-A and accompanying definitions, wherein G is

.

In one embodiment, R ⁷ is H. In another embodiment, R ⁷ is halogen. In another embodiment, R ⁷ is Cl. In another embodiment, R ⁷ is F. In another embodiment, R ⁷ is CN. In another embodiment, R ⁷ is -XR ^x . In another embodiment, R ⁷ is -XR ^x where R ^x is absent. In another embodiment, R ⁷ is -XR ^x , where R ^x is absent and X is C ₁ -C ₆ alkyl, wherein said C ₁ -C ₆ alkyl is substituted with 0-6 halogen atoms. In another embodiment, R ⁷ is CH ₃ , CH ₂ CH ₃ , CH ₂ CH ₂ CH ₃ or isopropyl. In another embodiment, R ⁷ is CF ₃ . In another embodiment, R ⁷ is -XR ^x , where R ^x is absent and X is a C ₁ -C ₆ alkyl, wherein said C ₁ -C ₆ alkyl is substituted with 0-6 halogen atoms, where two non-adjacent CH ₂ units of said C ₁ - C ₆ alkyl is replaced with -O-. In another embodiment, R ⁷ is OCH ₂ CH ₂ OCH ₃ . In another embodiment, R ⁷ is -XR ^x , where R ^x is absent and X is a C ₁ -C ₆ alkyl, wherein said C ₁ -C ₆ alkyl is substituted with 0-6 halogen atoms, where one CH ₂ unit of said C ₁ -C ₆ alkyl is replaced by -O-. In another embodiment, R ⁷ is OCH ₃ , OCH ₂ CH ₃ OCH ₂ CH ₂ CH ₃ , OC(CH ₃ ) ₃ , CH ₂ CH ₂ OCH ₃ . In another embodiment, R ⁷ is OCF ₃ , OCH ₂ CF ₃ , OCH ₂ CH ₂ CH ₂ CF ₃ or OCHF ₂ .

In another embodiment, this invention includes a compound of formula I-A or I'-A and accompanying definitions, wherein G is

.

In one embodiment, R ⁷ is H. In another embodiment, R ⁷ is -XR ^x . In another embodiment, R ⁷ is -XR ^x where R ^x is absent. In another embodiment, R ⁷ is -XR ^x , where R ^x is absent and X is C ₁ -C ₆ alkyl, wherein said C ₁ -C ₆ alkyl is substituted with 0-6 halogen atoms. In another embodiment, R ⁷ is CH ₃ , CH ₂ CH ₃ , CH ₂ CH ₂ CH ₃ or isopropyl. In another embodiment, R ⁷ is CF ₃ . In another embodiment, R ⁷ is -XR ^x , where R ^x is absent and X is a C ₁ -C ₆ alkyl, wherein said C ₁ -C ₆ alkyl is substituted with 0-6 halogen atoms, where two non-adjacent CH ₂ units of said C ₁ - C ₆ alkyl is replaced with -O-. In another embodiment, R ⁷ is OCH ₂ CH ₂ OCH ₃ . In another embodiment, R ⁷ is -XR ^x , where R ^x is absent and X is a C ₁ -C ₆ alkyl, wherein said C ₁ -C ₆ alkyl is substituted with 0-6 halogen atoms, where one CH ₂ unit of said C ₁ -C ₆ alkyl is replaced by -O-. In another embodiment, R ⁷ is OCH ₃ , OCH ₂ CH ₃ , OCH ₂ CH ₂ CH ₃ , OC(CH ₃ ) ₃ , CH ₂ CH ₂ OCH ₃ . In another embodiment, R ⁷ is OCF ₃ , OCH ₂ CF ₃ , OCH ₂ CH ₂ CH ₂ CF ₃ or OCHF ₂ .

In another embodiment, this invention includes a compound of formula I-A or I'-A and accompanying definitions, wherein G is

In one embodiment, R ⁷ is -XR ^x where X is a bond and R ^x is a C ₃ -C ₈ cycloaliphatic group, and said C ₃ -C ₈ cycloaliphatic group is substituted with 0-3 substituents selected from halogen and C ₁ -C ₄ alkyl. In another embodiment, R ⁷ is -XR ^x , where X is a bond and R ^x is cyclopropyl.

In another embodiment, this invention includes a compound of formula I-A or I'-A and accompanying definitions, wherein G is

In one embodiment, R ⁷ is -XR ^x where X is a C ₁ -C ₆ alkyl, wherein said C ₁ -C ₆ alkyl is replaced by 0-6 halogen atoms, wherein one CH ₂ unit of said C ₁ -C ₆ alkyl is replaced by -O- and R ^x is a C ₃ -C ₈ cycloaliphatic group, and said C ₃ -C ₈ cycloaliphatic group is substituted with 0-3 substituents selected from halogen and C ₁ -C ₄ alkyl. In another embodiment, R ⁷ is -XR ^x where X is OCH ₂ and R ^x is cyclopropyl.

In another embodiment, the invention includes a compound of formula I-A or I'-A and accompanying definitions, wherein G is:

and G are selected from:

In another embodiment, the invention includes a compound of formula I-A or I'-A and accompanying definitions, wherein G is:

and G are selected from:

In another embodiment, this invention includes a compound of formula I-A or I'-A and accompanying definitions, wherein G is

,

Where:

X is a bond or C ₁ -C ₆ alkyl, wherein said C ₁ -C ₆ alkyl is substituted with 0-6 halogen atoms, and where up to two non-adjacent CH ₂ units of said C ₁ -C ₆ alkyl may be replaced by -O-; And

R ^x is absent, is H or a C ₃ -C ₈ cycloaliphatic group, where up to two non-adjacent CH ₂ units of the specified C ₃ -C ₈ cycloaliphatic group can be replaced by -O-, and the specified C ₃ -C ₈ cycloaliphatic group is replaced by 0 -3 substituents selected from halogen and C ₁ -C ₄ alkyl.

In another embodiment, this invention includes a compound of formula IA or I'-A and accompanying definitions, wherein G is -XR ^x , wherein X is _C1 - _C6 alkyl, wherein said _C1 - _C6 alkyl is substituted with 0-6 halogen atoms where up to two non-adjacent CH ₂ units of said C ₁ -C ₆ alkyl may be replaced by -O- and R ^x is absent. In another embodiment, X is CH ₂ CH ₂ CH(CH ₃ ) ₃ or CH ₂ CH(CH ₃ ) ₂ and R ^x is absent. In another embodiment, X is CH ₂ CH ₂ CH ₂ CF ₃ or CH ₂ CH ₂ CF ₃ and R ^x is absent.

In another embodiment, this invention includes a compound of formula IA or I'-A and the accompanying definitions, where G is -XR ^x , where X is a bond and R ^x is a C ₃ -C ₈ cycloaliphatic group, wherein up to two non-adjacent CH ₂ specified A C ₃ -C ₈ cycloaliphatic group may be replaced by -O-, and said C ₃ -C ₈ cycloaliphatic group is substituted with 0-3 substituents selected from halogen and C ₁ -C ₄ alkyl. In another embodiment, X is a bond and R ^x is cyclobutane, cyclohexane, bicyclo[2.2.1]heptane or bicyclo[3.1.0]hexane.

In another embodiment, this invention includes a compound of formula IA or I'-A and accompanying definitions, wherein G is -XR ^x , wherein X is _C1 - _C6 alkyl, wherein said _C1 - _C6 alkyl is substituted with 0-6 halogen atoms wherein up to two non-adjacent CH ₂ units of said C ₁ -C ₆ alkyl may be replaced by -O-, and R ^x is a C ₃ -C ₈ cycloaliphatic group, wherein up to two non-adjacent CH ₂ units of said C ₃ -C ₈ cycloaliphatic group may be replaced by -O-, and said C ₃ -C ₈ cycloaliphatic group is substituted with 0-3 substituents selected from halogen and C ₁ -C ₄ alkyl. In another embodiment, X is CH ₂ and R ^x is a C ₃ -C ₈ cycloaliphatic group. In another embodiment, X is CH ₂ and R ^x is cyclopropyl or cyclopentyl. In another embodiment, X is CH ₂ and R ^x is a C ₃ -C ₈ cycloaliphatic group substituted with up to 3 substituents selected from halogen and C ₁ -C ₄ alkyl. In another embodiment, X is CH ₂ and R ^x is 1-methylcyclopropyl, 2,2-dimethylcyclopropyl or 2,2-difluorocyclopropyl.

In another embodiment, this invention includes a compound of formula IA or I'-A and accompanying definitions, wherein G is -XR ^x , wherein X is _C1 - _C6 alkyl, wherein said _C1 - _C6 alkyl is substituted with 0-6 halogen atoms wherein up to two non-adjacent CH ₂ units of said C ₁ -C ₆ alkyl are replaced by -O-, and R ^x is a C ₃ -C ₈ cycloaliphatic group, wherein up to two non-adjacent CH ₂ units of said C ₃ -C ₈ cycloaliphatic group can be replaced by -O-, and said C ₃ -C ₈ cycloaliphatic group is substituted with 0-3 substituents selected from halogen and C ₁ -C ₄ alkyl. In another embodiment, X is CH ₂ and R ^x is a C ₃ -C ₈ cycloaliphatic group, where one CH ₂ unit of said C ₃ -C ₈ cycloaliphatic group is replaced by -O-. In another embodiment, X is CH ₂ and R ^x is 3-tetrahydrofuran.

In another embodiment, the present invention includes a compound of formula IA or I'-A and the accompanying definitions, wherein G is -XR ^x and -XR ^x is selected from:

In another aspect, the invention provides a compound of formula 1-B or I'-B:

or a pharmaceutically acceptable salt thereof,

where, independently for each case:

G is

X is a bond or C ₁ -C ₆ alkyl, wherein said C ₁ -C ₆ alkyl is substituted with 0-6 halogen atoms, where up to two non-adjacent CH ₂ units of said C ₁ -C ₆ alkyl may be replaced by -O-;

R ^x is absent, is H or a C ₃ -C ₈ cycloaliphatic group, where up to two non-adjacent CH ₂ units of the specified C ₃ -C ₈ cycloaliphatic group can be replaced by -O- and the specified C ₃ -C ₈ cycloaliphatic group is replaced by 0- 3 substituents selected from halogen and C ₁ -C ₄ alkyl;

R ³ is halogen, CN or C ₁ -C ₆ alkyl, wherein said C ₁ -C ₆ alkyl is substituted by 0-6 halogen atoms, and where up to two non-adjacent CH ₂ units of said C ₁ -C ₆ alkyl may be replaced by - O-;

R ⁵ is H, halogen, CN or -XR ^x ;

R ^5' is H, halogen, CN or -XR ^x ;

R ⁶ is H, halogen, CN or -XR ^x ;

R ^6' is H, halogen, CN or -XR ^x ;

R ⁷ is H, halogen, CN or -XR ^x ;

R ⁸ is halogen or C ₁ -C ₆ alkyl, wherein said C ₁ -C ₆ alkyl is substituted with 0-6 halogen atoms, and where up to two non-adjacent CH ₂ units of said C ₁ -C ₆ alkyl may be replaced by -O- ;

p is an integer from 0 to 3 inclusive; And

R ⁹ is H or C ₁ -C ₆ alkyl, where up to two non-adjacent CH ₂ units of said C ₁ -C ₆ alkyl can be replaced by -O-.

In another embodiment, this invention includes a compound of formula IB or I'-B and the accompanying definitions, wherein R ³ is halogen. In another embodiment, R ³ is Cl. In another embodiment, R ³ is F. In another embodiment, R ³ is CN. In another embodiment, R ³ is C ₁ -C ₆ alkyl, wherein said C ₁ -C ₆ alkyl is substituted with 0-6 halogen atoms. In another embodiment, R ³ is tert-butyl. In another embodiment, R ³ is CF ₃ . In another embodiment, R ³ is CF ₂ CF ₃ .

In another embodiment, the present invention includes a compound of formula IB or I'-B and the accompanying definitions, where p is zero. In another embodiment, p is an integer from 1 to 3 and R ⁸ is a halogen. In another embodiment, p is an integer from 1 to 3 and R ⁸ is Cl. In another embodiment, p is an integer from 1 to 3 and R ⁸ is a C ₁ -C ₆ alkyl, wherein said C ₁ -C ₆ alkyl is substituted with 0-6 halogen atoms, where one CH ₂ unit of said C ₁ -C ₆ alkyl replaced by -O-. In another embodiment, p is an integer from 1 to 3 and R ⁸ is CH ₃ . In another embodiment, p is an integer from 1 to 3 and R ⁸ is D.

In another embodiment, this invention includes a compound of formula IB or I'-B and the accompanying definitions, wherein R ⁹ is H. In another embodiment, R ⁹ is C ₁ -C ₆ alkyl. In another embodiment, R ⁹ is CH ₃ . In another embodiment, R ⁹ is C ₁ -C ₆ alkyl, wherein said C ₁ -C ₆ alkyl is replaced by 0-6 halogen atoms, wherein one CH ₂ unit of said C ₁ -C ₆ alkyl is replaced by -O-. In another embodiment, R ⁹ is CH ₂ CH ₂ OH.

In another embodiment, this invention includes a compound of formula I-B or I'-B and the accompanying definitions, wherein G is

,

Where:

R ⁵ is H, halogen, CN or -XR ^x ;

R ^5' is H, halogen, CN or -XR ^x ;

R ⁶ is H, halogen, CN or -XR ^x ;

R ^6' is H, halogen, CN or -XR ^x ;

R ⁷ is H, halogen, CN or -XR ^x ;

X is a bond or C ₁ -C ₆ alkyl, wherein said C ₁ -C ₆ alkyl is substituted with 0-6 halogen atoms, and where up to two non-adjacent CH ₂ units of said C ₁ -C ₆ alkyl may be replaced by -O-; And

R ^x is absent, is H or a C ₃ -C ₈ cycloaliphatic group, where up to two non-adjacent CH ₂ units of the specified C ₃ -C ₈ cycloaliphatic group can be replaced by -O-, and the specified C ₃ -C ₈ cycloaliphatic group is replaced by 0 -3 substituents selected from halogen and C ₁ -C ₄ alkyl.

In another embodiment, this invention includes a compound of formula I-B or I'-B and the accompanying definitions, wherein G is

,

Where:

R ⁵ is H or -XR ^x ;

R ^5' is H or -XR ^x ;

R ⁶ is H, halogen, CN or -XR ^x ;

R ⁷ is H or -XR ^x ;

X is a bond or C ₁ -C ₆ alkyl, wherein said C ₁ -C ₆ alkyl is substituted with 0-6 halogen atoms, and where up to two non-adjacent CH ₂ units of said C ₁ -C ₆ alkyl may be replaced by -O-; And

R ^x is absent, is H or a C ₃ -C ₈ cycloaliphatic group, where up to two non-adjacent CH ₂ units of the specified C ₃ -C ₈ cycloaliphatic group can be replaced by -O-, and the specified C ₃ -C ₈ cycloaliphatic group is replaced by 0 -3 substituents selected from halogen and C ₁ -C ₄ alkyl.

In another embodiment, this invention includes a compound of formula I-B or I'-B and the accompanying definitions, wherein G is

.

In one embodiment, R ⁵ is H. In another embodiment, R ⁵ is halogen. In another embodiment, R ⁵ is Cl. In another embodiment, R ⁵ is F. In another embodiment, R ⁵ is CN. In another embodiment, R ⁵ is -XR ^x . In another embodiment, R ⁵ is -XR ^x where R ^x is absent. In another embodiment, R ⁵ is -XR ^x , where R ^x is absent and X is C ₁ -C ₆ alkyl, wherein said C ₁ -C ₆ alkyl is substituted with 0-6 halogen atoms. In another embodiment, R ⁵ is CH ₃ . In another embodiment, R ⁵ is CD ₃ . In another embodiment, R ⁵ is -XR ^x , where R ^x is absent and X is a C ₁ -C ₆ alkyl, wherein said C ₁ -C ₆ alkyl is substituted with 0-6 halogen atoms, where one CH ₂ unit of said C ₁ -C ₆ alkyl is replaced by -O-. In another embodiment, R ⁵ is OCH ₃ , OCH ₂ CH ₃ or OCH(CH ₃ ) ₂ . In another embodiment, R ⁵ is OCH ₃ . In another embodiment, R ⁵ is CH ₂ OH. In another embodiment, R ⁵ is OCF ₃ . In another embodiment, R ⁵ is OCHF ₂ .

In another embodiment, this invention includes a compound of formula I-B or I'-B and the accompanying definitions, wherein G is

.

In one embodiment, R ⁵ is H. In another embodiment, R ⁵ is -XR ^x . In another embodiment, R ⁵ is -XR ^x where R ^x is absent. In another embodiment, R ⁵ is -XR ^x , where R ^x is absent and X is C ₁ -C ₆ alkyl, wherein said C ₁ -C ₆ alkyl is substituted with 0-6 halogen atoms. In another embodiment, R ⁵ is CH ₃ . In another embodiment, R ⁵ is CD ₃ . In another embodiment, R ⁵ is -XR ^x , where R ^x is absent and X is a C ₁ -C ₆ alkyl, wherein said C ₁ -C ₆ alkyl is substituted with 0-6 halogen atoms, where one CH ₂ unit of said C ₁ -C ₆ alkyl is replaced by -O-. In another embodiment, R ⁵ is OCH ₃ , OCH ₂ CH ₃ or OCH(CH ₃ ) ₂ . In another embodiment, R ⁵ is OCH ₃ . In another embodiment, R ³ is CH ₂ OH. In another embodiment, R ⁵ is OCF ₃ . In another embodiment, R ⁵ is OCHF ₂ .

In another embodiment, this invention includes a compound of formula I-B or I'-B and the accompanying definitions, wherein G is

.

In one embodiment, R ^5' is H. In another embodiment, R ^5' is D. In another embodiment, R ^5' is halogen. In another embodiment, R ^5' is Cl. In another embodiment, R ^5' is F. In another embodiment, R ^5' is CN. In another embodiment, R ^5' is -XR ^x . In another embodiment, R ^5' is -XR ^x , where R ^x is absent. In another embodiment, R ^5' is -XR ^x , where R ^x is absent and X is C ₁ -C ₆ alkyl, wherein said C ₁ -C ₆ alkyl is substituted with 0-6 halogen atoms. In another embodiment, R ^5' is CH ₃ . In another embodiment, R ⁵ is -XR ^x , where R ^x is absent and X is a C ₁ -C ₆ alkyl, wherein said C ₁ -C ₆ alkyl is substituted with 0-6 halogen atoms, where one CH ₂ unit of said C ₁ -C ₆ alkyl is replaced by -O-. In another embodiment, R ^5' is OCH ₃ , OCH ₂ CH ₃ or OCH(CH ₃ ) ₂ . In another embodiment, R ^5' is OCH ₃ . In another embodiment, R ⁵ is CH ₂ OH. In another embodiment, R ^5' is OCF ₃ . In another embodiment, R ^5' is OCHF ₂ .

In another embodiment, this invention includes a compound of formula I-B or I'-B and the accompanying definitions, wherein G is

In one embodiment, R ^5' is H. In another embodiment, R ^5' is D. In another embodiment, R ^5' is -XR ^x . In another embodiment, R ^5' is -XR ^x , where R ^x is absent. In another embodiment, R ^5' is -XR ^x , where R ^x is absent and X is C ₁ -C ₆ alkyl, wherein said C ₁ -C ₆ alkyl is substituted with 0-6 halogen atoms. In another embodiment, R ^5' is CH ₃ . In another embodiment, R ^5' is -XR ^x , where R ^x is absent and X is a C ₁ -C ₆ alkyl, wherein said C ₁ -C ₆ alkyl is substituted with 0-6 halogen atoms, where one CH ₂ unit of said C ₁ - C ₆ alkyl is replaced with -O-. In another embodiment, R ^5' is OCH ₃ , OCH ₂ CH ₃ or OCH(CH ₃ ) ₂ . In another embodiment, R ^5' is OCH ₃ . In another embodiment, R ^5' is CH ₂ OH. In another embodiment, R ^5' is OCF ₃ . In another embodiment, R ^5' is OCHF ₂ .

In another embodiment, this invention includes a compound of formula I-B or I'-B and the accompanying definitions, wherein G is

In one embodiment, R ⁶ is H. In another embodiment, R ⁶ is D. In another embodiment, R ⁶ is halogen. In another embodiment, R ⁶ is Cl. In another embodiment, R ⁶ is F. In another embodiment, R ⁶ is CN. In another embodiment, R ⁶ is -XR ^x . In another embodiment, R ⁶ is -XR ^x where R ^x is absent. In another embodiment, R ⁶ is -XR ^x where R ^x is absent and X is C ₁ -C ₆ alkyl, wherein said C ₁ -C ₆ alkyl is substituted with 0-6 halogen atoms. In another embodiment, R ⁶ is CH ₃ . In another embodiment, R ⁶ is -XR ^x , where R ^x is absent and X is a C ₁ -C ₆ alkyl, wherein said C ₁ -C ₆ alkyl is substituted with 0-6 halogen atoms, where one CH ₂ unit of said C ₁ -C ₆ alkyl is replaced by -O-. In another embodiment, R ⁶ is OCH ₃ .

In another embodiment, this invention includes a compound of formula I-B or I'-B and the accompanying definitions, wherein G is

.

In one embodiment, R ^6' is H. In another embodiment, R ^6' is halogen. In another embodiment, R ^6' is D. In another embodiment, R ^6' is Cl. In another embodiment, R ^6' is F. In another embodiment, R ^6' is CN. In another embodiment, R ^6' is -XR ^x . In another embodiment, R ^6' is -XR ^x where R ^x is absent. In another embodiment, R ^6' is -XR ^x , where R ^x is absent and X is C ₁ -C ₆ alkyl, wherein said C ₁ -C ₆ alkyl is substituted with 0-6 halogen atoms. In another embodiment, R ^6' is CH ₃ . In another embodiment, R ^6' is -XR ^x , where R ^x is absent and X is a C ₁ -C ₆ alkyl, wherein said C ₁ -C ₆ alkyl is substituted with 0-6 halogen atoms, where one CH ₂ unit of said C ₁ - C ₆ alkyl is replaced with -O-. In another embodiment, R ^6' is OCH ₃ .

In another embodiment, this invention includes a compound of formula I-B or I'-B and the accompanying definitions, wherein G is

.

In one embodiment, R ⁷ is H. In another embodiment, R ⁷ is halogen. In another embodiment, R ⁷ is Cl. In another embodiment, R ⁷ is F. In another embodiment, R ⁷ is CN. In another embodiment, R ⁷ is -XR ^x . In another embodiment, R ⁷ is -XR ^x where R ^x is absent. In another embodiment, R ⁷ is -XR ^x , where R ^x is absent and X is C ₁ -C ₆ alkyl, wherein said C ₁ -C ₆ alkyl is substituted with 0-6 halogen atoms. In another embodiment, R ⁷ is CH ₃ , CH ₂ CH ₃ , CH ₂ CH ₂ CH ₃ or isopropyl. In another embodiment, R ⁷ is CF ₃ . In another embodiment, R ⁷ is -XR ^x , where R ^x is absent and X is a C ₁ -C ₆ alkyl, wherein said C ₁ -C ₆ alkyl is substituted with 0-6 halogen atoms, where two non-adjacent CH ₂ units of said C ₁ - C ₆ alkyls are replaced with -O-. In another embodiment, R ⁷ is OCH ₂ CH ₂ OCH ₃ . In another embodiment, R ⁷ is -XR ^x , where R ^x is absent and X is a C ₁ -C ₆ alkyl, wherein said C ₁ -C ₆ alkyl is substituted with 0-6 halogen atoms, where one CH ₂ unit of said C ₁ -C ₆ alkyl is replaced by -O-. In another embodiment, R ⁷ is OCH ₃ , OCH ₂ CH ₃ OCH ₂ CH ₂ CH ₃ , OC(CH ₃ ) ₃ , CH ₂ CH ₂ OCH ₃ . In another embodiment, R ⁷ is OCF ₃ , OCH ₂ CF ₃ , OCH ₂ CH ₂ CH ₂ CF ₃ or OCHF ₂ .

In another embodiment, this invention includes a compound of formula I-B or I'-B and the accompanying definitions, wherein G is

.

In one embodiment, R ⁷ is H. In another embodiment, R ⁷ is -XR ^x . In another embodiment, R ⁷ is -XR ^x where R ^x is absent. In another embodiment, R ⁷ is -XR ^x , where R ^x is absent and X is C ₁ -C ₆ alkyl, wherein said C ₁ -C ₆ alkyl is substituted with 0-6 halogen atoms. In another embodiment, R ⁷ is CH ₃ , CH ₂ CH ₃ , CH ₂ CH ₂ CH ₃ or isopropyl. In another embodiment, R ⁷ is CF ₃ . In another embodiment, R ⁷ is -XR ^x , where R ^x is absent and X is a C ₁ -C ₆ alkyl, wherein said C ₁ -C ₆ alkyl is substituted with 0-6 halogen atoms, where two non-adjacent CH ₂ units of said C ₁ - C ₆ alkyls are replaced with -O-. In another embodiment, R ⁷ is OCH ₂ CH ₂ OCH ₃ . In another embodiment, R ⁷ is -XR ^x , where R ^x is absent and X is a C ₁ -C ₆ alkyl, wherein said C ₁ -C ₆ alkyl is substituted with 0-6 halogen atoms, where one CH ₂ unit of said C ₁ -C ₆ alkyl is replaced by -O-. In another embodiment, R ⁷ is OCH ₃ , OCH ₂ CH ₃ , OCH ₂ CH ₂ CH ₃ , OC(CH ₃ ) ₃ , CH ₂ CH ₂ OCH ₃ . In another embodiment, R ⁷ is OCF ₃ , OCH ₂ CF ₃ , OCH ₂ CH ₂ CH ₂ CF ₃ or OCHF ₂ .

In another embodiment, this invention includes a compound of formula I-B or I'-B and the accompanying definitions, wherein G is

In one embodiment, R ⁷ is -XR ^x where X is a bond and R ^x is a C ₃ -C ₈ cycloaliphatic group, and said C ₃ -C ₈ cycloaliphatic group is substituted with 0-3 substituents selected from halogen and C ₁ -C ₄ alkyl. In another embodiment, R ⁷ is -XR ^x , where X is a bond and R ^x is cyclopropyl.

In another embodiment, this invention includes a compound of formula I-B or I'-B and the accompanying definitions, wherein G is

In one embodiment, R ⁷ is -XR ^x where X is a C ₁ -C ₆ alkyl, wherein said C ₁ -C ₆ alkyl is replaced by 0-6 halogen atoms, wherein one CH ₂ unit of said C ₁ -C ₆ alkyl is replaced by -O-, and R ^x is a C ₃ -C ₈ cycloaliphatic group, and said C ₃ -C ₈ cycloaliphatic group is substituted with 0-3 substituents selected from halogen and C ₁ -C ₄ alkyl. In another embodiment, R ⁷ is -XR ^x where X is OCH ₂ and R ^x is cyclopropyl.

In another embodiment, the invention includes a compound of formula I-B or I'-B and accompanying definitions, wherein G is selected from:

In another embodiment, the invention includes a compound of formula I-B or I'-B and accompanying definitions, wherein G is:

and G are selected from:

In another embodiment, this invention includes a compound of formula I-B or I'-B and the accompanying definitions, wherein G is

,

Where:

X is a bond or C ₁ -C ₆ alkyl, wherein said C ₁ -C ₆ alkyl is substituted with 0-6 halogen atoms, and where up to two non-adjacent CH ₂ units of said C ₁ -C ₆ alkyl may be replaced by -O-; And

R ^x is absent, is H or a C ₃ -C ₈ cycloaliphatic group, where up to two non-adjacent CH ₂ units of the specified C ₃ -C ₈ cycloaliphatic group can be replaced by -O-, and the specified C ₃ -C ₈ cycloaliphatic group is replaced by 0 -3 substituents selected from halogen and C ₁ -C ₄ alkyl.

In another embodiment, this invention includes a compound of formula IB or I'-B and accompanying definitions, wherein G is -XR ^x , wherein X is _C1 - _C6 alkyl, wherein said _C1 - _C6 alkyl is substituted with 0-6 halogen atoms where up to two non-adjacent CH ₂ units of said C ₁ -C ₆ alkyl may be replaced by -O- and R ^x is absent. In another embodiment, X is CH ₂ CH ₂ CH(CH ₃ ) ₃ or CH ₂ CH(CH ₃ ) ₂ and R ^x is absent. In another embodiment, X is CH ₂ CH ₂ CH ₂ CF ₃ or CH ₂ CH ₂ CF ₃ and R ^x is absent.

In another embodiment, this invention includes a compound of formula IB or I'-B and the accompanying definitions, wherein G is -XR ^x , where X is a bond and R ^x is a C ₃ -C ₈ cycloaliphatic group, wherein up to two non-adjacent CH ₂ specified A C ₃ -C ₈ cycloaliphatic group may be replaced by -O-, and said C ₃ -C ₈ cycloaliphatic group is substituted with 0-3 substituents selected from halogen and C ₁ -C ₄ alkyl. In another embodiment, X is a bond and R ^x is cyclobutane, cyclohexane, bicyclo[2.2.1]heptane or bicyclo[3.1.0]hexane.

In another embodiment, this invention includes a compound of formula IB or I'-B and accompanying definitions, wherein G is -XR ^x , wherein X is _C1 - _C6 alkyl, wherein said _C1 - _C6 alkyl is substituted with 0-6 halogen atoms wherein up to two non-adjacent CH ₂ units of said C ₁ -C ₆ alkyl may be replaced by -O-, and R ^x is a C ₃ -C ₈ cycloaliphatic group, wherein up to two non-adjacent CH ₂ units of said C ₃ -C ₈ cycloaliphatic group may be replaced by -O-, and said C ₃ -C ₈ cycloaliphatic group is substituted with 0-3 substituents selected from halogen and C ₁ -C ₄ alkyl. In another embodiment, X is CH ₂ and R ^x is a C ₃ -C ₈ cycloaliphatic group. In another embodiment, X is CH ₂ and R ^x is cyclopropyl or cyclopentyl. In another embodiment, X is CH ₂ and R ^x is a C ₃ -C ₈ cycloaliphatic group substituted with up to 3 substituents selected from halogen and C ₁ -C ₄ alkyl. In another embodiment, X is CH ₂ and R ^x is 1-methylcyclopropyl, 2,2-dimethylcyclopropyl or 2,2-difluorocyclopropyl.

In another embodiment, this invention includes a compound of formula IB or I'-B and accompanying definitions, wherein G is -XR ^x , wherein X is _C1 - _C6 alkyl, wherein said _C1 - _C6 alkyl is substituted with 0-6 halogen atoms wherein up to two non-adjacent CH ₂ units of said C ₁ -C ₆ alkyl are replaced by -O-, and R ^x is a C ₃ -C ₈ cycloaliphatic group, wherein up to two non-adjacent CH ₂ units of said C ₃ -C ₈ cycloaliphatic group can be replaced by -O-, and said C ₃ -C ₈ cycloaliphatic group is substituted with 0-3 substituents selected from halogen and C ₁ -C ₄ alkyl. In another embodiment, X is CH ₂ and R ^x is a C ₃ -C ₈ cycloaliphatic group, where one CH ₂ unit of said C ₃ -C ₈ cycloaliphatic group is replaced by -O-. In another embodiment, X is CH ₂ and R ^x is 3-tetrahydrofuran.

In another embodiment, the invention includes a compound of formula I-B or I'-B and accompanying definitions, wherein G is selected from:

In another aspect, this invention includes a compound of formula I-C or I'-C

or a pharmaceutically acceptable salt thereof,

where, independently for each case:

G is

X is a bond or C ₁ -C ₆ alkyl, wherein said C ₁ -C ₆ alkyl is substituted with 0-6 halogen atoms, where up to two non-adjacent CH ₂ units of said C ₁ -C ₆ alkyl may be replaced by -O-;

R ^x is absent, is H or a C ₃ -C ₈ cycloaliphatic group, where up to two non-adjacent CH ₂ units of the specified C ₃ -C ₈ cycloaliphatic group can be replaced by -O-, and the specified C ₃ -C ₈ cycloaliphatic group is replaced by 0 -3 substituents selected from halogen and C ₁ -C ₄ alkyl;

R ² is halogen, CN or C ₁ -C ₆ alkyl, wherein said C ₁ -C ₆ alkyl is substituted by 0-6 halogen atoms, and where up to two non-adjacent CH ₂ units of said C ₁ -C ₆ alkyl may be replaced by - O-;

R ³ is halogen, CN or C ₁ -C ₆ alkyl, wherein said C ₁ -C ₆ alkyl is substituted by 0-6 halogen atoms, and where up to two non-adjacent CH ₂ units of said C ₁ -C ₆ alkyl may be replaced by - O-;

R ⁵ is H, halogen, CN or -XR ^x ;

R ⁵ is H, halogen, CN or -XR ^x ;

R ⁶ is H, halogen, CN or -XR ^x ;

R ⁶ is H, halogen, CN or -XR ^x ;

R ⁷ is H, halogen, CN or -XR ^x ;

R ⁸ is halogen or C ₁ -C ₆ alkyl, wherein said C ₁ -C ₆ alkyl is substituted with 0-6 halogen atoms, and where up to two non-adjacent CH ₂ units of said C ₁ -C ₆ alkyl may be replaced by -O- ; p is an integer from 0 to 3 inclusive; And

R ⁹ is H or C ₁ -C ₆ alkyl, where up to two non-adjacent CH ₂ units of said C ₁ -C ₆ alkyl can be replaced by -O-.

In another embodiment, this invention includes a compound of formula IC or I'-C and the accompanying definitions, wherein R ² is halogen. In another embodiment, R ² is Cl. In another embodiment, R ² is F. In another embodiment, R ² is CN. In another embodiment, R ² is C ₁ -C ₆ alkyl, wherein said C ₁ -C ₆ alkyl is substituted with 0-6 halogen atoms. In another embodiment, R ² is CF ₃ . In another embodiment, R ² is C ₁ -C ₆ alkyl, wherein said C ₁ -C ₆ alkyl is replaced by 0-6 halogen atoms, wherein one CH ₂ unit of said C ₁ -C ₆ alkyl is replaced by -O-. In another embodiment, R ² is OCF ₃ . In another embodiment, R ² is F, Cl, CN, CF ₃ or OCF ₃ .

In another embodiment, the present invention includes a compound of formula IC or I'-C and the accompanying definitions, wherein R ³ is halogen. In another embodiment, R ³ is Cl. In another embodiment, R ³ is F. In another embodiment, R ³ is CN. In another embodiment, R ³ is C ₁ -C ₆ alkyl, wherein said C ₁ -C ₆ alkyl is substituted with 0-6 halogen atoms. In another embodiment, R ³ is tert-butyl. In another embodiment, R ³ is CF ₃ . In another embodiment, R ³ is CF ₂ CF ₃ .

In another embodiment, the present invention includes a compound of formula IC or I'-C and accompanying definitions, where p is zero. In another embodiment, p is an integer from 1 to 3 and R ⁸ is a halogen. In another embodiment, p is an integer from 1 to 3 and R ⁸ is Cl. In another embodiment, p is an integer from 1 to 3 and R ⁸ is a C ₁ -C ₆ alkyl, wherein said C ₁ -C ₆ alkyl is substituted with 0-6 halogen atoms, where one CH ₂ unit of said C ₁ -C ₆ alkyl replaced by -O-. In another embodiment, p is an integer from 1 to 3 and R ⁸ is CH ₃ .

In another embodiment, this invention includes a compound of formula IC or I'-C and the accompanying definitions, wherein R ⁹ is H. In another embodiment, R ⁹ is C ₁ -C ₆ alkyl. In another embodiment, R ⁹ is CH ₃ . In another embodiment, R ⁹ is C ₁ -C ₆ alkyl, wherein said C ₁ -C ₆ alkyl is replaced by 0-6 halogen atoms, wherein one CH ₂ unit of said C ₁ -C ₆ alkyl is replaced by -O-. In another embodiment, R ⁹ is CH ₂ CH ₂ OH.

In another embodiment, this invention includes a compound of formula I-C or I'-C and accompanying definitions, wherein G is

,

Where:

R ⁵ is H, halogen, CN or -XR ^x ;

R ^5' is H, halogen, CN or -XR ^x ;

R ⁶ is H, halogen, CN or -XR ^x ;

R ^6' is H, halogen, CN or -XR ^x ;

R ⁷ is H, halogen, CN or -XR ^x ;

X is a bond or C ₁ -C ₆ alkyl, wherein said C ₁ -C ₆ alkyl is substituted with 0-6 halogen atoms, and where up to two non-adjacent CH ₂ units of said C ₁ -C ₆ alkyl may be replaced by -O-; And

R ^x is absent, is H or a C ₃ -C ₈ cycloaliphatic group, where up to two non-adjacent CH ₂ units of the specified C ₃ -C ₈ cycloaliphatic group can be replaced by -O-, and the specified C ₃ -C ₈ cycloaliphatic group is replaced by 0 -3 substituents selected from halogen and C ₁ -C ₄ alkyl.

In another embodiment, this invention includes a compound of formula I-C or I'-C and accompanying definitions, wherein G is

,

Where:

R ⁵ is H or -XR ^x ;

R ^5' is H or -XR ^x ;

R ⁶ is H, halogen, CN or -XR ^x ;

R ⁷ is H or -XR ^x ;

X is a bond or C ₁ -C ₆ alkyl, wherein said C ₁ -C ₆ alkyl is substituted with 0-6 halogen atoms, and where up to two non-adjacent CH ₂ units of said C ₁ -C ₆ alkyl may be replaced by -O-; And

R ^x is absent, is H or a C ₃ -C ₈ cycloaliphatic group, where up to two non-adjacent CH ₂ units of the specified C ₃ -C ₈ cycloaliphatic group can be replaced by -O-, and the specified C ₃ -C ₈ cycloaliphatic group is replaced by 0 -3 substituents selected from halogen and C ₁ -C ₄ alkyl.

In another embodiment, this invention includes a compound of formula I-C or I'-C and accompanying definitions, wherein G is

In one embodiment, R ⁵ is H. In another embodiment, R ⁵ is halogen. In another embodiment, R ⁵ is Cl. In another embodiment, R ⁵ is F. In another embodiment, R ⁵ is CN. In another embodiment, R ⁵ is -XR ^x . In another embodiment, R ⁵ is -XR ^x where R ^x is absent. In another embodiment, R ⁵ is -XR ^x , where R ^x is absent and X is C ₁ -C ₆ alkyl, wherein said C ₁ -C ₆ alkyl is substituted with 0-6 halogen atoms. In another embodiment, R ⁵ is CH ₃ . In another embodiment, R ⁵ is -XR ^x , where R ^x is absent and X is a C ₁ -C ₆ alkyl, wherein said C ₁ -C ₆ alkyl is substituted with 0-6 halogen atoms, where one CH ₂ unit of said C ₁ -C ₆ alkyl is replaced by -O-. In another embodiment, R ⁵ is OCH ₃ , OCH ₂ CH ₃ , OCH ₂ CH ₂ CH ₃ or OCH(CH ₃ ) ₂ . In another embodiment, R ⁵ is OCH ₃ . In another embodiment, R ⁵ is CH ₂ OH. In another embodiment, R ⁵ is OCF ₃ . In another embodiment, R ⁵ is OCHF ₂ .

In another embodiment, this invention includes a compound of formula I-C or I'-C and accompanying definitions, wherein G is

In one embodiment, R ⁵ is H. In another embodiment, R ⁵ is -XR ^x . In another embodiment, R ⁵ is -XR ^x where R ^x is absent. In another embodiment, R ⁵ is -XR ^x , where R ^x is absent and X is C ₁ -C ₆ alkyl, wherein said C ₁ -C ₆ alkyl is substituted with 0-6 halogen atoms. In another embodiment, R ⁵ is CH ₃ . In another embodiment, R ⁵ is -XR ^x , where R ^x is absent and X is a C ₁ -C ₆ alkyl, wherein said C ₁ -C ₆ alkyl is substituted with 0-6 halogen atoms, where one CH ₂ unit of said C ₁ -C ₆ alkyl is replaced by -O-. In another embodiment, R ⁵ is OCH ₃ , OCH ₂ CH ₃ , OCH ₂ CH ₂ CH ₃ or OCH(CH ₃ ) ₂ . In another embodiment, R ⁵ is OCH ₃ . In another embodiment, R ³ is CH ₂ OH. In another embodiment, R ⁵ is OCF ₃ . In another embodiment, R ⁵ is OCHF ₂ .

In another embodiment, this invention includes a compound of formula I-C or I'-C and accompanying definitions, wherein G is

In one embodiment, R ^5' is H. In another embodiment, R ^5' is halogen. In another embodiment, R ^5' is Cl. In another embodiment, R ^5' is F. In another embodiment, R ^5' is CN. In another embodiment, R ^5' is -XR ^x . In another embodiment, R ^5' is -XR ^x , where R ^x is absent. In another embodiment, R ^5' is -XR ^x , where R ^x is absent and X is C ₁ -C ₆ alkyl, wherein said C ₁ -C ₆ alkyl is substituted with 0-6 halogen atoms. In another embodiment, R ^5' is CH ₃ . In another embodiment, R ⁵ is -XR ^x , where R ^x is absent and X is a C ₁ -C ₆ alkyl, wherein said C ₁ -C ₆ alkyl is substituted with 0-6 halogen atoms, where one CH ₂ unit of said C ₁ -C ₆ alkyl is replaced by -O-. In another embodiment, R ^5' is OCH ₃ , OCH ₂ CH ₃ , OCH ₂ CH ₂ CH ₃ or OCH(CH ₃ ) ₂ . In another embodiment, R ^5' is OCH ₃ . In another embodiment, R ⁵ is CH ₂ OH. In another embodiment, R ^5' is OCF ₃ . In another embodiment, R ^5' is OCHF ₂ .

In another embodiment, this invention includes a compound of formula I-C or I'-C and accompanying definitions, wherein G is

In one embodiment, R ^5' is H. In another embodiment, R ^5' is halogen. In another embodiment, R ^5' is Cl. In another embodiment, R ^5' is F. In another embodiment, R ^5' is CN. In another embodiment, R ^5' is -XR ^x . In another embodiment, R ^5' is -XR ^x , where R ^x is absent. In another embodiment, R ^5' is -XR ^x , where R ^x is absent and X is C ₁ -C ₆ alkyl, wherein said C ₁ -C ₆ alkyl is substituted with 0-6 halogen atoms. In another embodiment, R ^5' is CH ₃ . In another embodiment, R ^5' is -XR ^x , where R ^x is absent and X is a C ₁ -C ₆ alkyl, wherein said C ₁ -C ₆ alkyl is substituted with 0-6 halogen atoms, where one CH ₂ unit of said C ₁ - C ₆ alkyl is replaced with -O-. In another embodiment, R ^5' is OCH ₃ , OCH ₂ CH ₃ , OCH ₂ CH ₂ CH ₃ or OCH(CH ₃ ) ₂ . In another embodiment, R ^5' is OCH ₃ . In another embodiment, R ^5' is CH ₂ OH. In another embodiment, R ^5' is OCF ₃ . In another embodiment, R ^5' is OCHF ₂ .

In another embodiment, this invention includes a compound of formula I-C or I'-C and accompanying definitions, wherein G is

In one embodiment, R ⁶ is H. In another embodiment, R ⁶ is halogen. In another embodiment, R ⁶ is Cl. In another embodiment, R ⁶ is F. In another embodiment, R ⁶ is CN. In another embodiment, R ⁶ is -XR ^x . In another embodiment, R ⁶ is -XR ^x where R ^x is absent. In another embodiment, R ⁶ is -XR ^x where R ^x is absent and X is C ₁ -C ₆ alkyl, wherein said C ₁ -C ₆ alkyl is substituted with 0-6 halogen atoms. In another embodiment, R ⁶ is CH ₃ . In another embodiment, R ⁶ is -XR ^x , where R ^x is absent and X is a C ₁ -C ₆ alkyl, wherein said C ₁ -C ₆ alkyl is substituted with 0-6 halogen atoms, where one CH ₂ unit of said C ₁ -C ₆ alkyl is replaced by -O-. In another embodiment, R ⁶ is OCH ₃ .

In another embodiment, this invention includes a compound of formula I-C or I'-C and accompanying definitions, wherein G is

In one embodiment, R ^6' is H. In another embodiment, R ^6' is halogen. In another embodiment, R ^6' is Cl. In another embodiment, R ^6' is F. In another embodiment, R ^6' is CN. In another embodiment, R ^6' is -XR ^x . In another embodiment, R ^6' is -XR ^x , where R ^x is absent. In another embodiment, R ^6' is -XR ^x where R ^x is absent and X is C ₁ -C ₆ alkyl, wherein said C ₁ -C ₆ alkyl is substituted with 0-6 halogen atoms. In another embodiment, R ^6' is CH ₃ . In another embodiment, R ^6' is -XR ^x , where R ^x is absent and X is a C ₁ -C ₆ alkyl, wherein said C ₁ -C ₆ alkyl is substituted with 0-6 halogen atoms, where one CH ₂ unit of said C ₁ - C ₆ alkyl is replaced with -O-. In another embodiment, R ^6' is OCH ₃ .

In another embodiment, this invention includes a compound of formula I-C or I'-C and accompanying definitions, wherein G is

In one embodiment, R ⁷ is H. In another embodiment, R ⁷ is halogen. In another embodiment, R ⁷ is Cl. In another embodiment, R ⁷ is F. In another embodiment, R ⁷ is CN. In another embodiment, R ⁷ is -XR ^x . In another embodiment, R ⁷ is -XR ^x where R ^x is absent. In another embodiment, R ⁷ is -XR ^x , where R ^x is absent and X is C ₁ -C ₆ alkyl, wherein said C ₁ -C ₆ alkyl is substituted with 0-6 halogen atoms. In another embodiment, R ⁷ is CH ₃ , CH ₂ CH ₃ , CH ₂ CH ₂ CH ₃ or isopropyl. In another embodiment, R ⁷ is CF ₃ . In another embodiment, R ⁷ is -XR ^x , where R ^x is absent and X is a C ₁ -C ₆ alkyl, wherein said C ₁ -C ₆ alkyl is substituted with 0-6 halogen atoms, where two non-adjacent CH ₂ units of said C ₁ - C ₆ alkyls are replaced with -O-. In another embodiment, R ⁷ is OCH ₂ CH ₂ OCH ₃ . In another embodiment, R ⁷ is -XR ^x , where R ^x is absent and X is a C ₁ -C ₆ alkyl, wherein said C ₁ -C ₆ alkyl is substituted with 0-6 halogen atoms, where one CH ₂ unit of said C ₁ -C ₆ alkyl is replaced by -O-. In another embodiment, R ⁷ is OCH ₃ , OCH ₂ CH ₃ OCH ₂ CH ₂ CH ₃ , OC(CH ₃ ) ₃ , CH ₂ CH ₂ OCH ₃ . In another embodiment, R ⁷ is OCF ₃ , OCH ₂ CF ₃ , OCH ₂ CH ₂ CH ₂ CF ₃ or OCHF ₂ .

In another embodiment, this invention includes a compound of formula I-C or I'-C and accompanying definitions, wherein G is

In one embodiment, R ⁷ is H. In another embodiment, R ⁷ is -XR ^x . In another embodiment, R ⁷ is -XR ^x where R ^x is absent. In another embodiment, R ⁷ is -XR ^x , where R ^x is absent and X is C ₁ -C ₆ alkyl, wherein said C ₁ -C ₆ alkyl is substituted with 0-6 halogen atoms. In another embodiment, R ⁷ is CH ₃ , CH ₂ CH ₃ , CH ₂ CH ₂ CH ₃ or isopropyl. In another embodiment, R ⁷ is CF ₃ . In another embodiment, R ⁷ is -XR ^x , where R ^x is absent and X is a C ₁ -C ₆ alkyl, wherein said C ₁ -C ₆ alkyl is substituted with 0-6 halogen atoms, where two non-adjacent CH ₂ units of said C ₁ - C ₆ alkyls are replaced with -O-. In another embodiment, R ⁷ is OCH ₂ CH ₂ OCH ₃ . In another embodiment, R ⁷ is -XR ^x , where R ^x is absent and X is a C ₁ -C ₆ alkyl, wherein said C ₁ -C ₆ alkyl is substituted with 0-6 halogen atoms, where one CH ₂ unit of said C ₁ -C ₆ alkyl is replaced by -O-. In another embodiment, R ⁷ is OCH ₃ , OCH ₂ CH ₃ , OCH ₂ CH ₂ CH ₃ , OC(CH ₃ ) ₃ , CH ₂ CH ₂ OCH ₃ . In another embodiment, R ⁷ is OCF ₃ , OCH ₂ CF ₃ , OCH ₂ CH ₂ CH ₂ CF ₃ or OCHF ₂ .

In another embodiment, this invention includes a compound of formula I-C or I'-C and accompanying definitions, wherein G is

In one embodiment, R ⁷ is -XR ^x where X is a bond and R ^x is a C ₃ -C ₈ cycloaliphatic group, and said C ₃ -C ₈ cycloaliphatic group is substituted with 0-3 substituents selected from halogen and C ₁ -C ₄ alkyl. In another embodiment, R ⁷ is -XR ^x , where X is a bond and R ^x is cyclopropyl.

In another embodiment, this invention includes a compound of formula I-C or I'-C and accompanying definitions, wherein G is

In one embodiment, R ⁷ is -XR ^x where X is a C ₁ -C ₆ alkyl, wherein said C ₁ -C ₆ alkyl is replaced by 0-6 halogen atoms, wherein one CH ₂ unit of said C ₁ -C ₆ alkyl is replaced by -O- and R ^x is a C ₃ -C ₈ cycloaliphatic group, and said C ₃ -C ₈ cycloaliphatic group is substituted with 0-3 substituents selected from halogen and C ₁ -C ₄ alkyl. In another embodiment, R ⁷ is -XR ^x where X is OCH ₂ and R ^x is cyclopropyl.

In another embodiment, this invention includes a compound of formula I-C or I'-C and accompanying definitions, where G is:

and G are selected from:

In another embodiment, this invention includes a compound of formula I-C or I'-C and accompanying definitions, where G is:

and G are selected from:

In another embodiment, this invention includes a compound of formula I-C or I'-C and accompanying definitions, wherein G is

,

Where:

X is a bond or C ₁ -C ₆ alkyl, wherein said C ₁ -C ₆ alkyl is substituted with 0-6 halogen atoms, and where up to two non-adjacent CH ₂ units of said C ₁ -C ₆ alkyl may be replaced by -O-; And

R ^x is absent, is H or a C ₃ -C ₈ cycloaliphatic group, where up to two non-adjacent CH ₂ units of the specified C ₃ -C ₈ cycloaliphatic group can be replaced by -O-, and the specified C ₃ -C ₈ cycloaliphatic group is replaced by 0 -3 substituents selected from halogen and C ₁ -C ₄ alkyl.

In another embodiment, this invention includes a compound of formula IC or I'-C and accompanying definitions, wherein G is -XR ^x , wherein X is _C1 - _C6 alkyl, wherein said _C1 - _C6 alkyl is substituted with 0-6 halogen atoms where up to two non-adjacent CH ₂ units of said C ₁ -C ₆ alkyl may be replaced by -O- and R ^x is absent. In another embodiment, X is CH ₂ CH ₂ CH(CH ₃ ) ₃ or CH ₂ CH(CH ₃ ) ₂ and R ^x is absent. In another embodiment, X is CH ₂ CH ₂ CH ₂ CF ₃ or CH ₂ CH ₂ CF ₃ and R ^x is absent.

In another embodiment, this invention includes a compound of formula IC or I'-C and the accompanying definitions, wherein G is -XR ^x , where X is a bond and R ^x is a C ₃ -C ₈ cycloaliphatic group, wherein up to two non-adjacent CH ₂ specified The C ₃ -C ₈ cycloaliphatic group may be replaced by -O-, and said C ₃ -C ₈ cycloaliphatic group is substituted with 0-3 substituents selected from halogen and C ₁ -C ₄ alkyl. In another embodiment, X is a bond and R ^x is cyclobutane, cyclohexane, bicyclo[2.2.1]heptane or bicyclo[3.1.0]hexane.

In another embodiment, this invention includes a compound of formula IC or I'-C and accompanying definitions, wherein G is -XR ^x , wherein X is _C1 - _C6 alkyl, wherein said _C1 - _C6 alkyl is substituted with 0-6 halogen atoms wherein up to two non-adjacent CH ₂ units of said C ₁ -C ₆ alkyl may be replaced by -O-, and R ^x is a C ₃ -C ₈ cycloaliphatic group, wherein up to two non-adjacent CH ₂ units of said C ₃ -C ₈ cycloaliphatic group may be replaced by -O-, and said C ₃ -C ₈ cycloaliphatic is substituted with 0-3 substituents selected from halogen and C ₁ -C ₄ alkyl. In another embodiment, X is CH ₂ and R ^x is a C ₃ -C ₈ cycloaliphatic group. In another embodiment, X is CH ₂ and R ^x is cyclopropyl or cyclopentyl. In another embodiment, X is CH ₂ and R ^x is a C ₃ -C ₈ cycloaliphatic group substituted with up to 3 substituents selected from halogen and C ₁ -C ₄ alkyl. In another embodiment, X is CH ₂ and R ^x is 1-methylcyclopropyl, 2,2-dimethylcyclopropyl or 2,2-difluorocyclopropyl.

In another embodiment, this invention includes a compound of formula IC or I'-C and accompanying definitions, wherein G is -XR ^x , wherein X is _C1 - _C6 alkyl, wherein said _C1 - _C6 alkyl is substituted with 0-6 halogen atoms wherein up to two non-adjacent CH ₂ units of said C ₁ -C ₆ alkyl are replaced by -O-, and R ^x is a C ₃ -C ₈ cycloaliphatic group, wherein up to two non-adjacent CH ₂ units of said C ₃ -C ₈ cycloaliphatic group can be replaced by -O-, and said C ₃ -C ₈ cycloaliphatic group is substituted with 0-3 substituents selected from halogen and C ₁ -C ₄ alkyl. In another embodiment, X is CH ₂ and R ^x is a C ₃ -C ₈ cycloaliphatic group, where one CH ₂ unit of said C ₃ -C ₈ cycloaliphatic group is replaced by -O-. In another embodiment, X is CH ₂ and R ^x is 3-tetrahydrofuran.

In another embodiment, the invention includes a compound of formula I-C or I'-C and accompanying definitions, wherein G is selected from:

In another aspect, this invention includes a compound of formula I-D or I'-D:

or a pharmaceutically acceptable salt thereof,

where, independently for each case:

G is

X is a bond or C ₁ -C ₆ alkyl, wherein said C ₁ -C ₆ alkyl is substituted with 0-6 halogen atoms, and where up to two non-adjacent CH ₂ units of said C ₁ -C ₆ alkyl may be replaced by -O-;

^Rx is missing; is an H or C ₃ -C ₈ cycloaliphatic group, where up to two non-adjacent CH ₂ units of said C ₃ -C ₈ cycloaliphatic group may be replaced by -O-, and said C ₃ -C ₈ cycloaliphatic group is substituted with 0-3 substituents, selected from halogen and C ₁ -C ₄ alkyl;

R ¹ is halogen, CN or C ₁ -C ₆ alkyl, wherein said C ₁ -C ₆ alkyl is substituted by 0-6 halogen atoms, and where up to two non-adjacent CH ₂ units of said C ₁ -C ₆ alkyl may be replaced by - O-;

R ³ is halogen, CN or C ₁ -C ₆ alkyl, wherein said C ₁ -C ₆ alkyl is substituted by 0-6 halogen atoms, and where up to two non-adjacent CH ₂ units of said C ₁ -C ₆ alkyl may be replaced by - O-;

R ⁵ is H, halogen, CN or -XR ^x ;

R ^5' is H, halogen, CN or -XR ^x ;

R ⁶ is H, halogen, CN or -XR ^x ;

R ^6' is H, halogen, CN or -XR ^x ;

R ⁷ is H, halogen, CN or -XR ^x ;

R ⁸ is halogen or C ₁ -C ₆ alkyl, wherein said C ₁ -C ₆ alkyl is substituted with 0-6 halogen atoms, and where up to two non-adjacent CH ₂ units of said C ₁ -C ₆ alkyl may be replaced by -O- ;

p is an integer from 0 to 3 inclusive; And

R ⁹ is H, or C ₁ -C ₆ alkyl, where up to two non-adjacent CH ₂ units of said C ₁ -C ₆ alkyl can be replaced by -O-.

In another embodiment, this invention includes a compound of formula ID or I'-D and the accompanying definitions, wherein R ¹ is halogen. In another embodiment, R ¹ is CN. In another embodiment, R ¹ is C ₁ -C ₆ alkyl, wherein said C ₁ -C ₆ alkyl is substituted with 0-6 halogen atoms. In another embodiment, R ¹ is CF ₃ .

In another embodiment, the present invention includes a compound of formula ID or I'-D and the accompanying definitions, wherein R ³ is halogen. In another embodiment, R ³ is Cl. In another embodiment, R ³ is F. In another embodiment, R ³ is CN. In another embodiment, R ³ is C ₁ -C ₆ alkyl, wherein said C ₁ -C ₆ alkyl is substituted with 0-6 halogen atoms. In another embodiment, R ³ is tert-butyl. In another embodiment, R ³ is CF ₃ . In another embodiment, R ³ is CF ₂ CF ₃ .

In another embodiment, the present invention includes a compound of formula ID or I'-D and accompanying definitions, where p is zero. In another embodiment, p is an integer from 1 to 3 and R ⁸ is a halogen. In another embodiment, p is an integer from 1 to 3 and R ⁸ is Cl. In another embodiment, p is an integer from 1 to 3 and R ⁸ is a C ₁ -C ₆ alkyl, wherein said C ₁ -C ₆ alkyl is substituted with 0-6 halogen atoms, where one CH ₂ unit of said C ₁ -C ₆ alkyl replaced by -O-. In another embodiment, p is an integer from 1 to 3 and R ⁸ is CH ₃ .

In another embodiment, this invention includes a compound of formula ID or I'-D and the accompanying definitions, wherein R ⁹ is H. In another embodiment, R ⁹ is C ₁ -C ₆ alkyl. In another embodiment, R ⁹ is CH ₃ . In another embodiment, R ⁹ is C ₁ -C ₆ alkyl, wherein said C ₁ -C ₆ alkyl is replaced by 0-6 halogen atoms, wherein one CH ₂ unit of said C ₁ -C ₆ alkyl is replaced by -O-. In another embodiment, R ⁹ is CH ₂ CH ₂ OH.

In another embodiment, this invention includes a compound of formula I-D or I'-D and accompanying definitions, wherein G is

,

Where:

R ⁵ is H, halogen, CN or -XR ^x ;

R ^5' is H, halogen, CN or -XR ^x ;

R ⁶ is H, halogen, CN or -XR ^x ;

R ^6' is H, halogen, CN or -XR ^x ;

R ⁷ is H, halogen, CN or -XR ^x ;

X is a bond or C ₁ -C ₆ alkyl, wherein said C ₁ -C ₆ alkyl is substituted with 0-6 halogen atoms, and where up to two non-adjacent CH ₂ units of said C ₁ -C ₆ alkyl may be replaced by -O-; And

R ^x is absent, is H or a C ₃ -C ₈ cycloaliphatic group, where up to two non-adjacent CH ₂ units of said C _{3 -C 8} cycloaliphatic group may be replaced by -O-, and said C ₃ -C ₈ cycloaliphatic group is replaced by 0 -3 substituents selected from halogen and C ₁ -C ₄ alkyl.

In another embodiment, this invention includes a compound of formula I-D or I'-D and accompanying definitions, wherein G is

,

Where:

R ⁵ is H or -XR ^x ;

R ^5' is H or -XR ^x ;

R ⁶ is H, halogen, CN or -XR ^x ;

R ⁷ is H or -XR ^x ;

X is a bond or C ₁ -C ₆ alkyl, wherein said C ₁ -C ₆ alkyl is substituted with 0-6 halogen atoms, and where up to two non-adjacent CH ₂ units of said C ₁ -C ₆ alkyl may be replaced by -O-; And

R ^x is absent, is H or a C ₃ -C ₈ cycloaliphatic group, where up to two non-adjacent CH ₂ units of the specified C ₃ -C ₈ cycloaliphatic group can be replaced by -O-, and the specified C ₃ -C ₈ cycloaliphatic group is replaced by 0 -3 substituents selected from halogen and C ₁ -C ₄ alkyl.

In another embodiment, this invention includes a compound of formula I-D or I'-D and accompanying definitions, wherein G is

In one embodiment, R ⁵ is H. In another embodiment, R ⁵ is halogen. In another embodiment, R ⁵ is Cl. In another embodiment, R ⁵ is F. In another embodiment, R ⁵ is CN. In another embodiment, R ⁵ is -XR ^x . In another embodiment, R ⁵ is -XR ^x where R ^x is absent. In another embodiment, R ⁵ is -XR ^x , where R ^x is absent and X is C ₁ -C ₆ alkyl, wherein said C ₁ -C ₆ alkyl is substituted with 0-6 halogen atoms. In another embodiment, R ⁵ is CH ₃ . In another embodiment, R ⁵ is -XR ^x , where R ^x is absent and X is a C ₁ -C ₆ alkyl, wherein said C ₁ -C ₆ alkyl is substituted with 0-6 halogen atoms, where one CH ₂ unit of said C ₁ -C ₆ alkyl is replaced by -O-. In another embodiment, R ⁵ is OCH ₃ , OCH ₂ CH ₃ , OCH ₂ CH ₂ CH ₃ or OCH(CH ₃ ) ₂ . In another embodiment, R ⁵ is OCH ₃ . In another embodiment, R ⁵ is CH ₂ OH. In another embodiment, R ⁵ is OCF ₃ . In another embodiment, R ⁵ is OCHF ₂ .

In another embodiment, this invention includes a compound of formula I-D or I'-D and accompanying definitions, wherein G is

In one embodiment, R ⁵ is H. In another embodiment, R ⁵ is -XR ^x . In another embodiment, R ⁵ is -XR ^x where R ^x is absent. In another embodiment, R ⁵ is -XR ^x , where R ^x is absent and X is C ₁ -C ₆ alkyl, wherein said C ₁ -C ₆ alkyl is substituted with 0-6 halogen atoms. In another embodiment, R ⁵ is CH ₃ . In another embodiment, R ⁵ is -XR ^x , where R ^x is absent and X is a C ₁ -C ₆ alkyl, wherein said C ₁ -C ₆ alkyl is substituted with 0-6 halogen atoms, where one CH ₂ unit of said C ₁ -C ₆ alkyl is replaced by -O-. In another embodiment, R ⁵ is OCH ₃ , OCH ₂ CH ₃ , OCH ₂ CH ₂ CH ₃ or OCH(CH ₃ ) ₂ . In another embodiment, R ⁵ is OCH ₃ . In another embodiment, R ³ is CH ₂ OH. In another embodiment, R ⁵ is OCF ₃ . In another embodiment, R ⁵ is OCHF ₂ .

In another embodiment, this invention includes a compound of formula I-D or I'-D and accompanying definitions, wherein G is

In one embodiment, R ^5' is H. In another embodiment, R ^5' is halogen. In another embodiment, R ^5' is Cl. In another embodiment, R ^5' is F. In another embodiment, R ^5' is CN. In another embodiment, R ^5' is -XR ^x . In another embodiment, R ^5' is -XR ^x , where R ^x is absent. In another embodiment, R ^5' is -XR ^x , where R ^x is absent and X is C ₁ -C ₆ alkyl, wherein said C ₁ -C ₆ alkyl is substituted with 0-6 halogen atoms. In another embodiment, R ^5' is CH ₃ . In another embodiment, R ⁵ is -XR ^x , where R ^x is absent and X is a C ₁ -C ₆ alkyl, wherein said C ₁ -C ₆ alkyl is substituted with 0-6 halogen atoms, where one CH ₂ unit of said C ₁ -C ₆ alkyl is replaced by -O-. In another embodiment, R ^5' is OCH ₃ , OCH ₂ CH ₃ , OCH ₂ CH ₂ CH ₃ or OCH(CH ₃ ) ₂ . In another embodiment, R ^5' is OCH ₃ . In another embodiment, R ⁵ is CH ₂ OH. In another embodiment, R ^5' is OCF ₃ . In another embodiment, R ^5' is OCHF ₂ .

In another embodiment, this invention includes a compound of formula I-D or I'-D and accompanying definitions, wherein G is

In one embodiment, R ^5' is H. In another embodiment, R ^5' is -XR ^x . In another embodiment, R ^5' is -XR ^x , where R ^x is absent. In another embodiment, R ^5' is -XR ^x , where R ^x is absent and X is C ₁ -C ₆ alkyl, wherein said C ₁ -C ₆ alkyl is substituted with 0-6 halogen atoms. In another embodiment, R ^5' is CH ₃ . In another embodiment, R ^5' is -XR ^x , where R ^x is absent and X is a C ₁ -C ₆ alkyl, wherein said C ₁ -C ₆ alkyl is substituted with 0-6 halogen atoms, where one CH ₂ unit of said C ₁ - C ₆ alkyl is replaced with -O-. In another embodiment, R ^5' is OCH ₃ , OCH ₂ CH ₃ , OCH ₂ CH ₂ CH ₃ or OCH(CH ₃ ) ₂ . In another embodiment, R ^5' is OCH ₃ . In another embodiment, R ^5' is CH ₂ OH. In another embodiment, R ^5' is OCF ₃ . In another embodiment, R ^5' is OCHF ₂ .

In another embodiment, this invention includes a compound of formula I-D or I'-D and accompanying definitions, wherein G is

In one embodiment, R ⁶ is H. In another embodiment, R ⁶ is halogen. In another embodiment, R ⁶ is Cl. In another embodiment, R ⁶ is F. In another embodiment, R ⁶ is CN. In another embodiment, R ⁶ is -XR ^x . In another embodiment, R ⁶ is -XR ^x where R ^x is absent. In another embodiment, R ⁶ is -XR ^x where R ^x is absent and X is C ₁ -C ₆ alkyl, wherein said C ₁ -C ₆ alkyl is substituted with 0-6 halogen atoms. In another embodiment, R ⁶ is CH ₃ . In another embodiment, R ⁶ is -XR ^x , where R ^x is absent and X is a C ₁ -C ₆ alkyl, wherein said C ₁ -C ₆ alkyl is substituted with 0-6 halogen atoms, where one CH ₂ unit of said C ₁ -C ₆ alkyl is replaced by -O-. In another embodiment, R ⁶ is OCH ₃ .

In another embodiment, this invention includes a compound of formula I-D or I'-D and accompanying definitions, wherein G is

In one embodiment, R ^6' is H. In another embodiment, R ^6' is halogen. In another embodiment, R ^6' is Cl. In another embodiment, R ^6' is F. In another embodiment, R ^6' is CN. In another embodiment, R ^6' is -XR ^x . In another embodiment, R ^6' is -XR ^x where R ^x is absent. In another embodiment, R ^6' is -XR ^x where R ^x is absent and X is C ₁ -C ₆ alkyl, wherein said C ₁ -C ₆ alkyl is substituted with 0-6 halogen atoms. In another embodiment, R ^6' is CH ₃ . In another embodiment, R ^6' is -XR ^x , where R ^x is absent and X is a C ₁ -C ₆ alkyl, wherein said C ₁ -C ₆ alkyl is substituted with 0-6 halogen atoms, where one CH ₂ unit of said C ₁ - C ₆ alkyl is replaced with -O-. In another embodiment, R ^6' is OCH ₃ .

In another embodiment, this invention includes a compound of formula I-D or I'-D and accompanying definitions, wherein G is

In one embodiment, R ⁷ is H. In another embodiment, R ⁷ is halogen. In another embodiment, R ⁷ is Cl. In another embodiment, R ⁷ is F. In another embodiment, R ⁷ is CN. In another embodiment, R ⁷ is -XR ^x . In another embodiment, R ⁷ is -XR ^x where R ^x is absent. In another embodiment, R ⁷ is -XR ^x , where R ^x is absent and X is C ₁ -C ₆ alkyl, wherein said C ₁ -C ₆ alkyl is substituted with 0-6 halogen atoms. In another embodiment, R ⁷ is CH ₃ , CH ₂ CH ₃ , CH ₂ CH ₂ CH ₃ or isopropyl. In another embodiment, R ⁷ is CF ₃ . In another embodiment, R ⁷ is -XR ^x , where R ^x is absent and X is a C ₁ -C ₆ alkyl, wherein said C ₁ -C ₆ alkyl is substituted with 0-6 halogen atoms, where two non-adjacent CH ₂ units of said C ₁ - C ₆ alkyls are replaced with -O-. In another embodiment, R ⁷ is OCH ₂ CH ₂ OCH ₃ . In another embodiment, R ⁷ is -XR ^x , where R ^x is absent and X is a C ₁ -C ₆ alkyl, wherein said C ₁ -C ₆ alkyl is substituted with 0-6 halogen atoms, where one CH ₂ unit of said C ₁ -C ₆ alkyl is replaced by -O-. In another embodiment, R ⁷ is OCH ₃ , OCH ₂ CH ₃ OCH ₂ CH ₂ CH ₃ , OC(CH ₃ ) ₃ , CH ₂ CH ₂ OCH ₃ . In another embodiment, R ⁷ is OCF ₃ , OCH ₂ CF ₃ , OCH ₂ CH ₂ CH ₂ CF ₃ or OCHF ₂ .

In another embodiment, this invention includes a compound of formula I-D or I'-D and accompanying definitions, wherein G is

In one embodiment, R ⁷ is H. In another embodiment, R ⁷ is -XR ^x . In another embodiment, R ⁷ is -XR ^x where R ^x is absent. In another embodiment, R ⁷ is -XR ^x , where R ^x is absent and X is C ₁ -C ₆ alkyl, wherein said C ₁ -C ₆ alkyl is substituted with 0-6 halogen atoms. In another embodiment, R ⁷ is CH ₃ , CH ₂ CH ₃ , CH ₂ CH ₂ CH ₃ or isopropyl. In another embodiment, R ⁷ is CF ₃ . In another embodiment, R ⁷ is -XR ^x , where R ^x is absent and X is a C ₁ -C ₆ alkyl, wherein said C ₁ -C ₆ alkyl is substituted with 0-6 halogen atoms, where two non-adjacent CH ₂ units of said C ₁ - C ₆ alkyls are replaced with -O-. In another embodiment, R ⁷ is OCH ₂ CH ₂ OCH ₃ . In another embodiment, R ⁷ is -XR ^x , where R ^x is absent and X is a C ₁ -C ₆ alkyl, wherein said C ₁ -C ₆ alkyl is substituted with 0-6 halogen atoms, where one CH ₂ unit of said C ₁ -C ₆ alkyl is replaced by -O-. In another embodiment, R ⁷ is OCH ₃ , OCH ₂ CH ₃ , OCH ₂ CH ₂ CH ₃ , OC(CH ₃ ) ₃ , CH ₂ CH ₂ OCH ₃ . In another embodiment, R ⁷ is OCF ₃ , OCH ₂ CF ₃ , OCH ₂ CH ₂ CH ₂ CF ₃ or OCHF ₂ .

In another embodiment, this invention includes a compound of formula I-D or I'-D and accompanying definitions, wherein G is

In one embodiment, R ⁷ is -XR ^x , where X is a bond and R ^x is a C ₃ -C ₈ cycloaliphatic group, and said C ₃ -C ₈ cycloaliphatic is substituted with 0-3 substituents selected from halogen and C ₁ -C ₄ alkyl In another embodiment, R ⁷ is -XR ^x , where X is a bond and R ^x is cyclopropyl.

In another embodiment, this invention includes a compound of formula I-D or I'-D and accompanying definitions, wherein G is

In one embodiment, R ⁷ is -XR ^x where X is a C ₁ -C ₆ alkyl, wherein said C ₁ -C ₆ alkyl is replaced by 0-6 halogen atoms, wherein one CH ₂ unit of said C ₁ -C ₆ alkyl is replaced by -O- and R ^x is a C ₃ -C ₈ cycloaliphatic group, and said C ₃ -C ₈ cycloaliphatic group is substituted with 0-3 substituents selected from halogen and C ₁ -C ₄ alkyl. In another embodiment, R ⁷ is -XR ^x where X is OCH ₂ and R ^x is cyclopropyl.

In another embodiment, this invention includes a compound of formula I-D or I'-D and the accompanying definitions, wherein G is:

and G are selected from:

In another embodiment, this invention includes a compound of formula I-D or I'-D and the accompanying definitions, wherein G is:

and G are selected from: .

In another embodiment, this invention includes a compound of formula I-D or I'-D and accompanying definitions, wherein G is

,

Where:

X is a bond or C ₁ -C ₆ alkyl, wherein said C ₁ -C ₆ alkyl is substituted with 0-6 halogen atoms, and where up to two non-adjacent CH ₂ units of said C ₁ -C ₆ alkyl may be replaced by -O-; And

R ^x is absent, is H or a C ₃ -C ₈ cycloaliphatic group, where up to two non-adjacent CH ₂ units of the specified C ₃ -C ₈ cycloaliphatic group can be replaced by -O-, and the specified C ₃ -C ₈ cycloaliphatic group is replaced by 0 -3 substituents selected from halogen and C ₁ -C ₄ alkyl.

In another embodiment, this invention includes a compound of formula ID or I'-D and the accompanying definitions, wherein G is -XR ^x , wherein X is _C1 - _C6 alkyl, wherein said _C1 - _C6 alkyl is substituted with 0-6 halogen atoms where up to two non-adjacent CH ₂ units of said C ₁ -C ₆ alkyl may be replaced by -O- and R ^x is absent. In another embodiment, X is CH ₂ CH ₂ C(CH ₃ ) ₃ or CH ₂ CH(CH ₃ ) ₂ and R ^x is absent. In another embodiment, X is CH ₂ CH ₂ CH ₂ CF ₃ or CH ₂ CH ₂ CF ₃ and R ^x is absent.

In another embodiment, the present invention includes a compound of formula ID or I'-D and the accompanying definitions, wherein G is -XR ^x , where X is a bond and R ^x is a C ₃ -C ₈ cycloaliphatic group, wherein up to two non-adjacent CH ₂ said A C ₃ -C ₈ cycloaliphatic group may be replaced by -O-, and said C ₃ -C ₈ cycloaliphatic group is substituted with 0-3 substituents selected from halogen and C ₁ -C ₄ alkyl. In another embodiment, X is a bond and R ^x is cyclobutane, cyclohexane, bicyclo[2.2.1]heptane or bicyclo[3.1.0]hexane.

In another embodiment, this invention includes a compound of formula ID or I'-D and the accompanying definitions, wherein G is -XR ^x , wherein X is _C1 - _C6 alkyl, wherein said _C1 - _C6 alkyl is substituted with 0-6 halogen atoms wherein up to two non-adjacent CH ₂ units of said C ₁ -C ₆ alkyl may be replaced by -O-, and R ^x is a C ₃ -C ₈ cycloaliphatic group, wherein up to two non-adjacent CH ₂ units of said C ₃ -C ₈ cycloaliphatic group may be replaced by -O-, and said C ₃ -C ₈ cycloaliphatic group is substituted with 0-3 substituents selected from halogen and C ₁ -C ₄ alkyl. In another embodiment, X is CH ₂ and R ^x is a C ₃ -C ₈ cycloaliphatic group. In another embodiment, X is CH ₂ and R ^x is cyclopropyl or cyclopentyl. In another embodiment, X is CH ₂ and R ^x is a C ₃ -C ₈ cycloaliphatic group substituted with up to 3 substituents selected from halogen and C ₁ -C ₄ alkyl. In another embodiment, X is CH ₂ and R ^x is 1-methylcyclopropyl, 2,2-dimethylcyclopropyl or 2,2-difluorocyclopropyl.

In another embodiment, this invention includes a compound of formula ID or I'-D and the accompanying definitions, wherein G is -XR ^x , wherein X is _C1 - _C6 alkyl, wherein said _C1 - _C6 alkyl is substituted with 0-6 halogen atoms wherein up to two non-adjacent CH ₂ units of said C ₁ -C ₆ alkyl are replaced by -O-, and R ^x is a C ₃ -C ₈ cycloaliphatic group, wherein up to two non-adjacent CH ₂ units of said C ₃ -C ₈ cycloaliphatic group can be replaced by -O-, and said C ₃ -C ₈ cycloaliphatic group is substituted with 0-3 substituents selected from halogen and C ₁ -C ₄ alkyl. In another embodiment, X is CH ₂ and R ^x is a C ₃ -C ₈ cycloaliphatic group, where one CH ₂ unit of said C ₃ -C ₈ cycloaliphatic group is replaced by -O-. In another embodiment, X is CH ₂ and R ^x is 3-tetrahydrofuran.

In another embodiment, the present invention includes a compound of formula I-D or I'-D and accompanying definitions, wherein G is selected from:

In another aspect, this invention includes a compound of formula I-E or I'-E

or a pharmaceutically acceptable salt thereof,

where, independently for each case:

R ² is halogen, CN or C ₁ -C ₆ alkyl, wherein said C ₁ -C ₆ alkyl is replaced by 0-6 halogen atoms, where up to two non-adjacent CH ₂ units of said C ₁ -C ₆ alkyl may be replaced by -O -;

R ⁵ is halogen, CN or -XR ^x ;

R ⁷ is halogen, CN or -XR ^x ;

X is a bond or C ₁ -C ₆ alkyl, wherein said C ₁ -C ₆ alkyl is substituted with 0-6 halogen atoms, and where up to two non-adjacent CH ₂ units of said C ₁ -C ₆ alkyl may be replaced by -O-;

R ^x is absent, is H or a C ₃ -C ₈ cycloaliphatic group, where up to two non-adjacent CH ₂ units of the specified C ₃ -C ₈ cycloaliphatic group can be replaced by -O-, and the specified C ₃ -C ₈ cycloaliphatic group is replaced by 0 -3 substituents selected from halogen and C ₁ -C ₆ alkyl;

R ⁸ is halogen or C ₁ -C ₆ alkyl, wherein said C ₁ -C ₆ alkyl is substituted with 0-6 halogen atoms, and where up to two non-adjacent CH ₂ units of said C ₁ -C ₆ alkyl may be replaced by -O- ;

p is an integer from 0 to 3 inclusive; And

R ⁹ is H or C ₁ -C ₆ alkyl, where up to two non-adjacent CH ₂ units of said C ₁ -C ₆ alkyl can be replaced by -O-.

In another embodiment, this invention includes a compound of formula IE or I'-E and the accompanying definitions, wherein R ² is halogen. In another embodiment, R ² is Cl. In another embodiment, R ² is F. In another embodiment, R ² is CN. In another embodiment, R ² is C ₁ -C ₆ alkyl, wherein said C ₁ -C ₆ alkyl is substituted with 0-6 halogen atoms. In another embodiment, R ² is CF ₃ . In another embodiment, R ² is C ₁ -C ₆ alkyl, wherein said C ₁ -C ₆ alkyl is replaced by 0-6 halogen atoms, wherein one CH ₂ unit of said C ₁ -C ₆ alkyl is replaced by -O-. In another embodiment, R ² is OCF ₃ . In another embodiment, R ² is F, Cl, CN, CF ₃ or OCF ₃ .

In another embodiment, this invention includes a compound of formula IE or I'-E and the accompanying definitions, wherein R ⁵ is halogen. In another embodiment, R ⁵ is Cl. In another embodiment, R ⁵ is F. In another embodiment, R ⁵ is CN. In another embodiment, R ⁵ is -XR ^x . In another embodiment, R ⁵ is -XR ^x where R ^x is absent. In another embodiment, R ⁵ is -XR ^x , where R ^x is absent and X is C ₁ -C ₆ alkyl, wherein said C ₁ -C ₆ alkyl is substituted with 0-6 halogen atoms. In another embodiment, R ⁵ is CH ₃ . In another embodiment, R ⁵ is -XR ^x , where R ^x is absent and X is a C ₁ -C ₆ alkyl, wherein said C ₁ -C ₆ alkyl is substituted with 0-6 halogen atoms, where one CH ₂ unit of said C ₁ -C ₆ alkyl is replaced by -O-. In another embodiment, R ⁵ is OCH ₃ , OCH ₂ CH ₃ , OCH ₂ CH ₂ CH ₃ or OCH(CH ₃ ) ₂ . In another embodiment, R ⁵ is OCH ₃ . In another embodiment, R ⁵ is CH ₂ OH. In another embodiment, R ⁵ is OCF ₃ . In another embodiment, R ⁵ is OCHF ₂ .

In another embodiment, this invention includes a compound of formula IE or I'-E and the accompanying definitions, wherein R ⁷ is halogen. In another embodiment, R ⁷ is Cl. In another embodiment, R ⁷ is F. In another embodiment, R ⁷ is CN. In another embodiment, R ⁷ is -XR ^x . In another embodiment, R ⁷ is -XR ^x where R ^x is absent. In another embodiment, R ⁷ is -XR ^x , where R ^x is absent and X is C ₁ -C ₆ alkyl, wherein said C ₁ -C ₆ alkyl is substituted with 0-6 halogen atoms. In another embodiment, R ⁷ is CH ₃ , CH ₂ CH ₃ , CH ₂ CH ₂ CH ₃ or isopropyl. In another embodiment, R ⁷ is CF ₃ . In another embodiment, R ⁷ is -XR ^x , where R ^x is absent and X is a C ₁ -C ₆ alkyl, wherein said C ₁ -C ₆ alkyl is substituted with 0-6 halogen atoms, where two non-adjacent CH ₂ units of said C ₁ - C ₆ alkyls are replaced with -O-. In another embodiment, R ⁷ is OCH ₂ CH ₂ OCH ₃ . In another embodiment, R ⁷ is -XR ^x , where R ^x is absent and X is a C ₁ -C ₆ alkyl, wherein said C ₁ -C ₆ alkyl is substituted with 0-6 halogen atoms, where one CH ₂ unit of said C ₁ -C ₆ alkyl is replaced by -O-. In another embodiment, R ⁷ is OCH ₃ , OCH ₂ CH ₃ , OCH ₂ CH ₂ CH ₃ , OC(CH ₃ ) ₃ , CH ₂ CH ₂ OCH ₃ . In another embodiment, R ⁷ is OCF ₃ , OCH ₂ CF ₃ , OCH ₂ CH ₂ CH ₂ CF ₃ or OCHF ₂ .

In another embodiment, this invention includes a compound of formula IE or I'-E and the accompanying definitions, wherein R ⁷ is -XR ^x , where X is a bond and R ^x is a C ₃ -C ₈ cycloaliphatic group, and said C ₃ -C ₈ the cycloaliphatic group is substituted with 0-3 substituents selected from halogen and C ₁ -C ₄ alkyl. In another embodiment, R ⁷ is -XR ^x , where X is a bond and R ^x is cyclopropyl.

In another embodiment, this invention includes a compound of formula IE or I'-E and accompanying definitions, wherein R ⁷ is -XR ^x , wherein X is C ₁ -C ₆ alkyl, wherein said C ₁ -C ₆ alkyl is substituted with 0-6 atoms halogen, wherein one CH ₂ unit of said C ₁ -C ₆ alkyl is replaced by -O-, and R ^x is a C ₃ -C ₈ cycloaliphatic group, and said C ₃ -C ₈ cycloaliphatic group is substituted with 0-3 substituents selected from halogen and C ₁ -C ₄ alkyl. In another embodiment, R ⁷ is -XR ^x where X is OCH ₂ and R ^x is cyclopropyl.

In another embodiment, the present invention includes a compound of formula IE or I'-E and accompanying definitions, where p is zero. In another embodiment, p is an integer from 1 to 3 and R ⁸ is a halogen. In another embodiment, p is an integer from 1 to 3 and R ⁸ is Cl. In another embodiment, p is an integer from 1 to 3 and R ⁸ is a C ₁ -C ₆ alkyl, wherein said C ₁ -C ₆ alkyl is substituted with 0-6 halogen atoms, where one CH ₂ unit of said C ₁ -C ₆ alkyl replaced by -O-. In another embodiment, p is an integer from 1 to 3 and R ⁸ is CH ₃ .

In another embodiment, this invention includes a compound of formula IE or I'-E and the accompanying definitions, wherein R ⁹ is H. In another embodiment, R ⁹ is C ₁ -C ₆ alkyl. In another embodiment, R ⁹ is CH ₃ . In another embodiment, R ⁹ is C ₁ -C ₆ alkyl, wherein said C ₁ -C ₆ alkyl is replaced by 0-6 halogen atoms, wherein one CH ₂ unit of said C ₁ -C ₆ alkyl is replaced by -O-. In another embodiment, R ⁹ is CH ₂ CH ₂ OH.

In another embodiment, the present invention includes a compound of formula I-E or I'-E and accompanying definitions, wherein ring A is selected from:

In another aspect, this invention includes a compound of formula I-F or I'-F

or a pharmaceutically acceptable salt thereof,

where, independently for each case:

R ³ is halogen, CN or C ₁ -C ₆ alkyl, wherein said C ₁ -C ₆ alkyl is substituted with 0-6 halogen atoms,

wherein up to two non-adjacent CH ₂ units of said C ₁ -C ₆ alkyl can be replaced by -O-;

R ⁵ is halogen, CN or -XR ^x ;

R ⁷ is halogen, CN or -XR ^x ;

X is a bond or C ₁ -C ₆ alkyl, wherein said C ₁ -C ₆ alkyl is substituted with 0-6 halogen atoms, and where up to two non-adjacent CH ₂ units of said C ₁ -C ₆ alkyl may be replaced by -O-;

R ^x is absent, is H or a C ₃ -C ₈ cycloaliphatic group, where up to two non-adjacent CH ₂ units of the specified C ₃ -C ₈ cycloaliphatic group can be replaced by -O-, and the specified C ₃ -C ₈ cycloaliphatic group is replaced by 0 -3 substituents selected from halogen and C ₁ -C ₄ alkyl;

R ⁸ is halogen or C ₁ -C ₆ alkyl, wherein said C ₁ -C ₆ alkyl is substituted with 0-6 halogen atoms, and where up to two non-adjacent CH ₂ units of said C ₁ -C ₆ alkyl may be replaced by -O- ;

p is an integer from 0 to 3 inclusive; And

R ⁹ is H or C ₁ -C ₆ alkyl, where up to two non-adjacent CH ₂ units of said C ₁ -C ₆ alkyl can be replaced by -O-.

In another embodiment, this invention includes a compound of formula IF or I'-F and the accompanying definitions, wherein R ³ is halogen. In another embodiment, R ³ is Cl. In another embodiment, R ³ is F. In another embodiment, R ³ is CN. In another embodiment, R ³ is C ₁ -C ₆ alkyl, wherein said C ₁ -C ₆ alkyl is substituted with 0-6 halogen atoms. In another embodiment, R ³ is tert-butyl. In another embodiment, R ³ is CF ₃ . In another embodiment, R ³ is CF ₂ CF ₃ .

In another embodiment, the present invention includes a compound of formula IF or I'-F and the accompanying definitions, wherein R ⁵ is halogen. In another embodiment, R ⁵ is Cl. In another embodiment, R ⁵ is F. In another embodiment, R ⁵ is CN. In another embodiment, R ⁵ is -XR ^x . In another embodiment, R ⁵ is -XR ^x where R ^x is absent. In another embodiment, R ⁵ is -XR ^x , where R ^x is absent and X is C ₁ -C ₆ alkyl, wherein said C ₁ -C ₆ alkyl is substituted with 0-6 halogen atoms. In another embodiment, R ⁵ is CH ₃ . In another embodiment, R ⁵ is CD ₃ . In another embodiment, R ⁵ is -XR ^x , where R ^x is absent and X is a C ₁ -C ₆ alkyl, wherein said C ₁ -C ₆ alkyl is substituted with 0-6 halogen atoms, where one CH ₂ unit of said C ₁ -C ₆ alkyl is replaced by -O-. In another embodiment, R ⁵ is OCH ₃ , OCH ₂ CH ₃ , OCH ₂ CH ₂ CH ₃ or OCH(CH ₃ ) ₂ . In another embodiment, R ⁵ is OCH ₃ . In another embodiment, R ⁵ is CH ₂ OH. In another embodiment, R ⁵ is OCF ₃ . In another embodiment, R ⁵ is OCHF ₂ .

In another embodiment, the present invention includes a compound of formula IF or I'-F and the accompanying definitions, wherein R ⁷ is halogen. In another embodiment, R ⁷ is Cl. In another embodiment, R ⁷ is F. In another embodiment, R ⁷ is CN. In another embodiment, R ⁷ is -XR ^x . In another embodiment, R ⁷ is -XR ^x where R ^x is absent. In another embodiment, R is -XR ^x , where R ^x is absent and X is C ₁ -C ₆ alkyl, wherein said C ₁ -C ₆ alkyl is substituted with 0-6 halogen atoms. In another embodiment, R ⁷ is CH ₃ , CH ₂ CH ₃ , CH ₂ CH ₂ CH ₃ or isopropyl. In another embodiment, R ⁷ is CF ₃ . In another embodiment, R ⁷ is -XR ^x , where R ^x is absent and X is a C ₁ -C ₆ alkyl, wherein said C ₁ -C ₆ alkyl is substituted with 0-6 halogen atoms, where two non-adjacent CH ₂ units of said C ₁ - C ₆ alkyls are replaced with -O-. In another embodiment, R ⁷ is OCH ₂ CH ₂ OCH ₃ . In another embodiment, R ⁷ is -XR ^x , where R ^x is absent and X is a C ₁ -C ₆ alkyl, wherein said C ₁ -C ₆ alkyl is substituted with 0-6 halogen atoms, where one CH ₂ unit of said C ₁ -C ₆ alkyl is replaced by -O-. In another embodiment, R ⁷ is OCH ₃ , OCH ₂ CH ₃ , OCH ₂ CH ₂ CH ₃ , OC(CH ₃ ) ₃ , CH ₂ CH ₂ OCH ₃ . In another embodiment, R ⁷ is OCF ₃ , OCH ₂ CF ₃ , OCH ₂ CH ₂ CH ₂ CF ₃ or OCHF ₂ .

In another embodiment, the present invention includes a compound of formula IF or I'-F and the accompanying definitions, wherein R ⁷ is -XR ^x , where X is a bond and R ^x is a C ₃ -C ₈ cycloaliphatic group, and said C ₃ -C ₈ the cycloaliphatic group is substituted with 0-3 substituents selected from halogen and C ₁ -C ₄ alkyl. In another embodiment, R ⁷ is -XR ^x , where X is a bond and R ^x is cyclopropyl.

In another embodiment, this invention includes a compound of formula IF or I'-F and accompanying definitions, wherein R ⁷ is -XR ^x , where X is C ₁ -C ₆ alkyl, wherein said C ₁ -C ₆ alkyl is substituted with 0-6 atoms halogen, wherein one CH ₂ unit of said C ₁ -C ₆ alkyl is replaced by -O-, and R ^x is a C ₃ -C ₈ cycloaliphatic group, and said C ₃ -C ₈ cycloaliphatic group is substituted with 0-3 substituents selected from halogen and C ₁ -C ₄ alkyl. In another embodiment, R ⁷ is -XR ^x where X is OCH ₂ and R ^x is cyclopropyl.

In another embodiment, the present invention includes a compound of formula IF or I'-F and accompanying definitions, where p is zero. In another embodiment, p is an integer from 1 to 3 and R ⁸ is a halogen. In another embodiment, p is an integer from 1 to 3 and R ⁸ is Cl. In another embodiment, p is an integer from 1 to 3 and R ⁸ is a C ₁ -C ₆ alkyl, wherein said C ₁ -C ₆ alkyl is substituted with 0-6 halogen atoms, where one CH ₂ unit of said C ₁ -C ₆ alkyl replaced by -O-. In another embodiment, p is an integer from 1 to 3 and R ⁸ is CH ₃ . In another embodiment, p is an integer from 1 to 3 and R ⁸ is D.

In another embodiment, the present invention includes a compound of formula IF or I'-F and the accompanying definitions, wherein R ⁹ is H. In another embodiment, R ⁹ is C ₁ -C ₆ alkyl. In another embodiment, R ⁹ is CH ₃ . In another embodiment, R ⁹ is C ₁ -C ₆ alkyl, wherein said C ₁ -C ₆ alkyl is replaced by 0-6 halogen atoms, wherein one CH ₂ unit of said C ₁ -C ₆ alkyl is replaced by -O-. In another embodiment, R ⁹ is CH ₂ CH ₂ OH.

In another embodiment, the invention includes a compound of formula I-F or I'-F and accompanying definitions, wherein ring A is selected from:

In another aspect, this invention includes a compound of formula I-G or I'-G:

or a pharmaceutically acceptable salt thereof,

where, independently for each case:

R ² is halogen, CN or C ₁ -C ₆ alkyl, wherein said C ₁ -C ₆ alkyl is substituted with 0-6 halogen atoms and where up to two non-adjacent CH ₂ units of said C ₁ -C ₆ alkyl may be replaced by -O -;

R ³ is halogen, CN or C ₁ -C ₆ alkyl, wherein said C ₁ -C ₆ alkyl is substituted with 0-6 halogen atoms and where up to two non-adjacent CH ₂ units of said C ₁ -C ₆ alkyl may be replaced by -O -;

R ⁵ is halogen, CN or -XR ^x ;

R ⁷ is halogen, CN or -XR ^x ;

X is a bond or C ₁ -C ₆ alkyl, wherein said C ₁ -C ₆ alkyl is substituted with 0-6 halogen atoms and where up to two non-adjacent CH ₂ units of said C ₁ -C ₆ alkyl can be replaced by -O-;

R ^x is absent, or is H or a C ₃ -C ₈ cycloaliphatic group, wherein up to two non-adjacent CH ₂ units of said C ₃ -C ₈ cycloaliphatic group may be replaced by -O-, and said C ₃ -C ₈ cycloaliphatic group is substituted 0-3 substituents selected from halogen and C ₁ -C ₄ alkyl;

R ⁸ is halogen or C ₁ -C ₆ alkyl, wherein said C ₁ -C ₆ alkyl is substituted by 0-6 halogen atoms and where up to two non-adjacent CH ₂ units of said C ₁ -C ₆ alkyl may be replaced by -O-;

p is an integer from 0 to 3 inclusive; And

R ⁹ is H or C ₁ -C ₆ alkyl, where up to two non-adjacent CH ₂ units of said C ₁ -C ₆ alkyl can be replaced by -O-.

In another embodiment, this invention includes a compound of formula IG or I'-G and the accompanying definitions, wherein R ² is halogen. In another embodiment, R ² is Cl. In another embodiment, R ² is F. In another embodiment, R ² is CN. In another embodiment, R ² is C ₁ -C ₆ alkyl, wherein said C ₁ -C ₆ alkyl is substituted with 0-6 halogen atoms. In another embodiment, R ² is CF ₃ . In another embodiment, R ² is C ₁ -C ₆ alkyl, wherein said C ₁ -C ₆ alkyl is replaced by 0-6 halogen atoms, wherein one CH ₂ unit of said C ₁ -C ₆ alkyl is replaced by -O-. In another embodiment, R ² is OCF ₃ . In another embodiment, R ² is F, Cl, CN, CF ₃ or OCF ₃ .

In another embodiment, this invention includes a compound of formula IG or I'-G and the accompanying definitions, wherein R ³ is halogen. In another embodiment, R ³ is Cl. In another embodiment, R ³ is F. In another embodiment, R ³ is CN. In another embodiment, R ³ is C ₁ -C ₆ alkyl, wherein said C ₁ -C ₆ alkyl is substituted with 0-6 halogen atoms. In another embodiment, R ³ is tert-butyl. In another embodiment, R ³ is CF ₃ . In another embodiment, R ³ is CF ₂ CF ₃ .

In another embodiment, this invention includes a compound of formula IG or I'-G and the accompanying definitions, where R ⁵ is a halogen. In another embodiment, R ⁵ is Cl. In another embodiment, R ⁵ is F. In another embodiment, R ⁵ is CN. In another embodiment, R ⁵ is -XR ^x . In another embodiment, R ⁵ is -XR ^x where R ^x is absent. In another embodiment, R ⁵ is -XR ^x , where R ^x is absent and X is C ₁ -C ₆ alkyl, wherein said C ₁ -C ₆ alkyl is substituted with 0-6 halogen atoms. In another embodiment, R ⁵ is CH ₃ . In another embodiment, R ⁵ is -XR ^x , where R ^x is absent and X is a C ₁ -C ₆ alkyl, wherein said C ₁ -C ₆ alkyl is substituted with 0-6 halogen atoms, where one CH ₂ unit of said C ₁ -C ₆ alkyl is replaced by -O-. In another embodiment, R ⁵ is OCH ₃ , OCH ₂ CH ₃ , OCH ₂ CH ₂ CH ₃ or OCH(CH ₃ ) ₂ . In another embodiment, R ⁵ is OCH ₃ . In another embodiment, R ⁵ is CH ₂ OH. In another embodiment, R ⁵ is OCF ₃ . In another embodiment, R ⁵ is OCHF ₂ .

In another embodiment, this invention includes a compound of formula IG or I'-G and the accompanying definitions, wherein R ⁷ is halogen. In another embodiment, R ⁷ is Cl. In another embodiment, R ⁷ is F. In another embodiment, R ⁷ is CN. In another embodiment, R ⁷ is -XR ^x . In another embodiment, R ⁷ is -XR ^x where R ^x is absent. In another embodiment, R is -XR ^x , where R ^x is absent and X is C ₁ -C ₆ alkyl, wherein said C ₁ -C ₆ alkyl is substituted with 0-6 halogen atoms. In another embodiment, R ⁷ is CH ₃ , CH ₂ CH ₃ , CH ₂ CH ₂ CH ₃ or isopropyl. In another embodiment, R ⁷ is CF ₃ . In another embodiment, R ⁷ is -XR ^x , where R ^x is absent and X is a C ₁ -C ₆ alkyl, wherein said C ₁ -C ₆ alkyl is substituted with 0-6 halogen atoms, where two non-adjacent CH ₂ units of said C ₁ - C ₆ alkyls are replaced with -O-. In another embodiment, R ⁷ is OCH ₂ CH ₂ OCH ₃ . In another embodiment, R ⁷ is -XR ^x , where R ^x is absent and X is a C ₁ -C ₆ alkyl, wherein said C ₁ -C ₆ alkyl is substituted with 0-6 halogen atoms, where one CH ₂ unit of said C ₁ -C ₆ alkyl is replaced by -O-. In another embodiment, R ⁷ is OCH ₃ , OCH ₂ CH ₃ , OCH ₂ CH ₂ CH ₃ , OC(CH ₃ ) ₃ , CH ₂ CH ₂ OCH ₃ . In another embodiment, R ⁷ is OCF ₃ , OCH ₂ CF ₃ , OCH ₂ CH ₂ CH ₂ CF ₃ or OCHF ₂ .

In another embodiment, this invention includes a compound of formula IG or I'-G and the accompanying definitions, wherein R ⁷ is -XR ^x , where X is a bond and R ^x is a C ₃ -C ₈ cycloaliphatic group, and said C ₃ -C ₈ the cycloaliphatic group is substituted with 0-3 substituents selected from halogen and C ₁ -C ₄ alkyl. In another embodiment, R ⁷ is -XR ^x , where X is a bond and R ^x is cyclopropyl.

In another embodiment, this invention includes a compound of formula IG or I'-G and accompanying definitions, wherein R ⁷ is -XR ^x , wherein X is C ₁ -C ₆ alkyl, wherein said C ₁ -C ₆ alkyl is substituted with 0-6 atoms halogen, wherein one CH ₂ unit of said C ₁ -C ₆ alkyl is replaced by -O-, and R ^x is a C ₃ -C ₈ cycloaliphatic group, and said C ₃ -C ₈ cycloaliphatic group is substituted with 0-3 substituents selected from halogen and C ₁ -C ₄ alkyl. In another embodiment, R ⁷ is -XR ^x where X is OCH ₂ and R ^x is cyclopropyl.

In another embodiment, the present invention includes a compound of formula IG or I'-G and accompanying definitions, where p is zero. In another embodiment, p is an integer from 1 to 3 and R ⁸ is a halogen. In another embodiment, p is an integer from 1 to 3 and R ⁸ is Cl. In another embodiment, p is an integer from 1 to 3 and R ⁸ is a C ₁ -C ₆ alkyl, wherein said C ₁ -C ₆ alkyl is substituted with 0-6 halogen atoms, where one CH ₂ unit of said C ₁ -C ₆ alkyl replaced by -O-. In another embodiment, p is an integer from 1 to 3 and R ⁸ is CH ₃ .

In another embodiment, this invention includes a compound of formula IG or I'-G and the accompanying definitions, wherein R ⁹ is H. In another embodiment, R ⁹ is C ₁ -C ₆ alkyl. In another embodiment, R ⁹ is CH ₃ . In another embodiment, R ⁹ is C ₁ -C ₆ alkyl, wherein said C ₁ -C ₆ alkyl is replaced by 0-6 halogen atoms, wherein one CH ₂ unit of said C ₁ -C ₆ alkyl is replaced by -O-. In another embodiment, R ⁹ is CH ₂ CH ₂ OH.

In another embodiment, the present invention includes a compound of formula I-G or I'-G and accompanying definitions, wherein ring A is selected from:

In another aspect, this invention includes a compound of formula I-H or I'-H:

or a pharmaceutically acceptable salt thereof,

where, independently for each case:

R ¹ is halogen, CN or C ₁ -C ₆ alkyl, wherein said C ₁ -C ₆ alkyl is substituted with 0-6 halogen atoms and where up to two non-adjacent CH ₂ units of said C ₁ -C ₆ alkyl may be replaced by -O -;

R ³ is halogen, CN or C ₁ -C ₆ alkyl, wherein said C ₁ -C ₆ alkyl is substituted with 0-6 halogen atoms and where up to two non-adjacent CH ₂ units of said C ₁ -C ₆ alkyl may be replaced by -O -;

R ⁵ is halogen, CN or -XR ^x ;

R ⁷ is halogen, CN or -XR ^x ;

X is a bond or C ₁ -C ₆ alkyl, wherein said C ₁ -C ₆ alkyl is substituted with 0-6 halogen atoms and where up to two non-adjacent CH ₂ units of said C ₁ -C ₆ alkyl can be replaced by -O-;

R ^x is absent, or is H or a C ₃ -C ₈ cycloaliphatic group, where up to two non-adjacent CH ₂ units of said C ₃ -C ₈ cycloaliphatic group may be replaced by -O- and said C ₃ -C ₈ cycloaliphatic group is replaced by 0 -3 substituents selected from halogen and C ₁ -C ₄ alkyl;

R ⁸ is halogen or C ₁ -C ₆ alkyl, wherein said C ₁ -C ₆ alkyl is substituted by 0-6 halogen atoms and where up to two non-adjacent CH ₂ units of said C ₁ -C ₆ alkyl may be replaced by -O-;

p is an integer from 0 to 3 inclusive; And

R ⁹ is H or C ₁ -C ₆ alkyl, where up to two non-adjacent CH ₂ units of said C ₁ -C ₆ alkyl can be replaced by -O-.

In another embodiment, this invention includes a compound of formula IH or I'-H and the accompanying definitions, where R ¹ is a halogen. In another embodiment, R ¹ is CN. In another embodiment, R ¹ is C ₁ -C ₆ alkyl, wherein said C ₁ -C ₆ alkyl is substituted with 0-6 halogen atoms. In another embodiment, R ¹ is CF ₃ .

In another embodiment, this invention includes a compound of formula IH or I'-H and the accompanying definitions, wherein R ³ is halogen. In another embodiment, R ³ is Cl. In another embodiment, R ³ is F. In another embodiment, R ³ is CN. In another embodiment, R ³ is C ₁ -C ₆ alkyl, wherein said C ₁ -C ₆ alkyl is substituted with 0-6 halogen atoms. In another embodiment, R ³ is tert-butyl. In another embodiment, R ³ is CF ₃ . In another embodiment, R ³ is CF ₂ CF ₃ .

In another embodiment, this invention includes a compound of formula IH or I'-H and the accompanying definitions, wherein R ⁵ is halogen. In another embodiment, R ⁵ is Cl. In another embodiment, R ⁵ is F. In another embodiment, R ⁵ is CN. In another embodiment, R ⁵ is -XR ^x . In another embodiment, R ⁵ is -XR ^x where R ^x is absent. In another embodiment, R ⁵ is -XR ^x , where R ^x is absent and X is C ₁ -C ₆ alkyl, wherein said C ₁ -C ₆ alkyl is substituted with 0-6 halogen atoms. In another embodiment, R ⁵ is CH ₃ . In another embodiment, R ⁵ is -XR ^x , where R ^x is absent and X is a C ₁ -C ₆ alkyl, wherein said C ₁ -C ₆ alkyl is substituted with 0-6 halogen atoms, where one CH ₂ unit of said C ₁ -C ₆ alkyl is replaced by -O-. In another embodiment, R ⁵ is OCH ₃ , OCH ₂ CH ₃ , OCH ₂ CH ₂ CH ₃ or OCH(CH ₃ ) ₂ . In another embodiment, R ⁵ is OCH ₃ . In another embodiment, R ⁵ is CH ₂ OH. In another embodiment, R ⁵ is OCF ₃ . In another embodiment, R ⁵ is OCHF ₂ .

In another embodiment, this invention includes a compound of formula IH or I'-H and the accompanying definitions, wherein R ⁷ is halogen. In another embodiment, R ⁷ is Cl. In another embodiment, R ⁷ is F. In another embodiment, R ⁷ is CN. In another embodiment, R ⁷ is -XR ^x . In another embodiment, R ⁷ is -XR ^x where R ^x is absent. In another embodiment, R is -XR ^x , where R ^x is absent and X is C ₁ -C ₆ alkyl, wherein said C ₁ -C ₆ alkyl is substituted with 0-6 halogen atoms. In another embodiment, R ⁷ is CH ₃ , CH ₂ CH ₃ , CH ₂ CH ₂ CH ₃ or isopropyl. In another embodiment, R ⁷ is CF ₃ . In another embodiment, R ⁷ is -XR ^x , where R ^x is absent and X is a C ₁ -C ₆ alkyl, wherein said C ₁ -C ₆ alkyl is substituted with 0-6 halogen atoms, where two non-adjacent CH ₂ units of said C ₁ - C ₆ alkyls are replaced with -O-. In another embodiment, R ⁷ is OCH ₂ CH ₂ OCH ₃ . In another embodiment, R ⁷ is -XR ^x , where R ^x is absent and X is a C ₁ -C ₆ alkyl, wherein said C ₁ -C ₆ alkyl is substituted with 0-6 halogen atoms, where one CH ₂ unit of said C ₁ -C ₆ alkyl is replaced by -O-. In another embodiment, R ⁷ is OCH ₃ , OCH ₂ CH ₃ , OCH ₂ CH ₂ CH ₃ , OC(CH ₃ ) ₃ , CH ₂ CH ₂ OCH ₃ . In another embodiment, R ⁷ is OCF ₃ , OCH ₂ CF ₃ , OCH ₂ CH ₂ CH ₂ CF ₃ or OCHF ₂ .

In another embodiment, this invention includes a compound of formula IH or I'-H and the accompanying definitions, wherein R ⁷ is -XR ^x , where X is a bond and R ^x is a C ₃ -C ₈ cycloaliphatic group, and said C ₃ -C ₈ the cycloaliphatic group is substituted with 0-3 substituents selected from halogen and C ₁ -C ₄ alkyl. In another embodiment, R ⁷ is -XR ^x , where X is a bond and R ^x is cyclopropyl.

In another embodiment, this invention includes a compound of formula IH or I'-H and the accompanying definitions, wherein R ⁷ is -XR ^x , where X is a C ₁ -C ₆ alkyl, wherein said C ₁ -C ₆ alkyl is substituted with 0-6 atoms halogen, wherein one CH ₂ unit of said C ₁ -C ₆ alkyl is replaced by -O-, and R ^x is a C ₃ -C ₈ cycloaliphatic group, and said C ₃ -C ₈ cycloaliphatic group is substituted with 0-3 substituents selected from halogen and C ₁ -C ₄ alkyl. In another embodiment, R ⁷ is -XR ^x where X is OCH ₂ and R ^x is cyclopropyl.

In another embodiment, the present invention includes a compound of formula IH or I'-H and the accompanying definitions, where p is zero. In another embodiment, p is an integer from 1 to 3 and R ⁸ is a halogen. In another embodiment, p is an integer from 1 to 3 and R ⁸ is Cl. In another embodiment, p is an integer from 1 to 3 and R ⁸ is a C ₁ -C ₆ alkyl, wherein said C ₁ -C ₆ alkyl is substituted with 0-6 halogen atoms, where one CH ₂ unit of said C ₁ -C ₆ alkyl replaced by -O-. In another embodiment, p is an integer from 1 to 3 and R ⁸ is CH ₃ .

In another embodiment, the present invention includes a compound of formula IH or I'-H and the accompanying definitions, wherein R ⁹ is H. In another embodiment, R ⁹ is C ₁ -C ₆ alkyl. In another embodiment, R ⁹ is CH ₃ . In another embodiment, R ⁹ is C ₁ -C ₆ alkyl, wherein said C ₁ -C ₆ alkyl is replaced by 0-6 halogen atoms, wherein one CH ₂ unit of said C ₁ -C ₆ alkyl is replaced by -O-. In another embodiment, R ⁹ is CH ₂ CH ₂ OH.

In another embodiment, the present invention includes a compound of formula I-H or I'-H and accompanying definitions, wherein ring A is selected from:

In another aspect, this invention includes a compound of formula I-J or I'-J:

or a pharmaceutically acceptable salt thereof,

where, independently for each case:

R ² is halogen, CN or C ₁ -C ₆ alkyl, wherein said C ₁ -C ₆ alkyl is substituted by 0-6 halogen atoms, and where up to two non-adjacent CH ₂ units of said C ₁ -C ₆ alkyl may be replaced by - O-;

R ⁷ is halogen, CN or -XR ^x ;

X is a bond or C ₁ -C ₆ alkyl, wherein said C ₁ -C ₆ alkyl is substituted with 0-6 halogen atoms, and where up to two non-adjacent CH ₂ units of said C ₁ -C ₆ alkyl may be replaced by -O-;

R ^x is absent, is H or a C ₃ -C ₈ cycloaliphatic group, wherein up to two non-adjacent CH ₂ units of said C ₃ -Cs cycloaliphatic group may be replaced by -O-, and said C ₃ -C ₈ cycloaliphatic group is replaced by 0- 3 substituents selected from halogen and C ₁ -C ₄ alkyl;

R ⁸ is H, halogen or C ₁ -C ₆ alkyl, wherein said C ₁ -C ₆ alkyl is substituted with 0-6 halogen atoms, and where up to two non-adjacent CH ₂ units of said C ₁ -C ₆ alkyl may be replaced by - O-;

p is an integer from 0 to 3 inclusive; And

R ⁹ is H or C ₁ -C ₆ alkyl, where up to two non-adjacent CH ₂ units of said C ₁ -C ₆ alkyl can be replaced by -O-.

In another embodiment, this invention includes a compound of formula IJ or I'-J and the accompanying definitions, where R ² is halogen. In another embodiment, R ² is Cl. In another embodiment, R ² is F. In another embodiment, R ² is CN. In another embodiment, R ² is C ₁ -C ₆ alkyl, wherein said C ₁ -C ₆ alkyl is substituted with 0-6 halogen atoms. In another embodiment, R ² is CF ₃ . In another embodiment, R ² is C ₁ -C ₆ alkyl, wherein said C ₁ -C ₆ alkyl is replaced by 0-6 halogen atoms, wherein one CH ₂ unit of said C ₁ -C ₆ alkyl is replaced by -O-. In another embodiment, R ² is OCF ₃ . In another embodiment, R ² is F, Cl, CN, CF ₃ or OCF ₃ .

In another embodiment, this invention includes a compound of formula IJ or I'-J and the accompanying definitions, wherein R ⁷ is halogen. In another embodiment, R ⁷ is Cl. In another embodiment, R ⁷ is F. In another embodiment, R ⁷ is CN. In another embodiment, R ⁷ is -XR ^x . In another embodiment, R ⁷ is -XR ^x where R ^x is absent. In another embodiment, R ⁷ is -XR ^x , where R ^x is absent and X is C ₁ -C ₆ alkyl, wherein said C ₁ -C ₆ alkyl is substituted with 0-6 halogen atoms. In another embodiment, R ⁷ is CH ₃ , CH ₂ CH ₃ , CH ₂ CH ₂ CH ₃ or isopropyl. In another embodiment, R ⁷ is CF ₃ . In another embodiment, R ⁷ is -XR ^x , where R ^x is absent and X is a C ₁ -C ₆ alkyl, wherein said C ₁ -C ₆ alkyl is substituted with 0-6 halogen atoms, where two non-adjacent CH ₂ units of said C ₁ - C ₆ alkyls are replaced with -O-. In another embodiment, R ⁷ is OCH ₂ CH ₂ OCH ₃ . In another embodiment, R ⁷ is -XR ^x , where R ^x is absent and X is a C ₁ -C ₆ alkyl, wherein said C ₁ -C ₆ alkyl is substituted with 0-6 halogen atoms, where one CH ₂ unit of said C ₁ -C ₆ alkyl is replaced by -O-. In another embodiment, R ⁷ is OCH ₃ , OCH ₂ CH ₃ , OCH ₂ CH ₂ CH ₃ , OC(CH ₃ ) ₃ , CH ₂ CH ₂ OCH ₃ . In another embodiment, R ⁷ is OCF ₃ , OCH ₂ CF ₃ , OCH ₂ CH ₂ CH ₂ CF ₃ or OCHF ₂ .

In another embodiment, the present invention includes a compound of formula IJ or I'-J and the accompanying definitions, wherein R ⁷ is -XR ^x , where X is a bond and R ^x is a C ₃ -C ₈ cycloaliphatic group, and said C ₃ -C ₈ the cycloaliphatic group is substituted with 0-3 substituents selected from halogen and C ₁ -C ₄ alkyl. In another embodiment, R ⁷ is -XR ^x , where X is a bond and R ^x is cyclopropyl.

In another embodiment, this invention includes a compound of formula IJ or I'-J and accompanying definitions, wherein R ⁷ is -XR ^x , where X is C ₁ -C ₆ alkyl, wherein said C ₁ -C ₆ alkyl is substituted with 0-6 atoms halogen, wherein one CH ₂ unit of said C ₁ -C ₆ alkyl is replaced by -O- and R ^x is a C ₃ -C ₈ cycloaliphatic group, and said C ₃ -C ₈ cycloaliphatic group is substituted with 0-3 substituents selected from halogen and C ₁ -C ₄ alkyl. In another embodiment, R ⁷ is -XR ^x where X is OCH ₂ and R ^x is cyclopropyl.

In another embodiment, the present invention includes a compound of formula IJ or I'-J and the accompanying definitions, where p is zero. In another embodiment, p is an integer from 1 to 3, and R ⁸ is a halogen. In another embodiment, p is an integer from 1 to 3 and R ⁸ is Cl. In another embodiment, p is an integer from 1 to 3 and R ⁸ is a C ₁ -C ₆ alkyl, wherein said C ₁ -C ₆ alkyl is substituted with 0-6 halogen atoms, where one CH ₂ unit of said C ₁ -C ₆ alkyl replaced by -O-. In another embodiment, p is an integer from 1 to 3 and R ⁸ is CH ₃ .

In another embodiment, the present invention includes a compound of formula IJ or I'-J and the accompanying definitions, wherein R ⁹ is H. In another embodiment, R ⁹ is C ₁ -C ₆ alkyl. In another embodiment, R ⁹ is CH ₃ . In another embodiment, R ⁹ is C ₁ -C ₆ alkyl, wherein said C ₁ -C ₆ alkyl is replaced by 0-6 halogen atoms, wherein one CH ₂ unit of said C ₁ -C ₆ alkyl is replaced by -O-. In another embodiment, R ⁹ is CH ₂ CH ₂ OH.

In another embodiment, the present invention includes a compound of formula I-J or I'-J and accompanying definitions, wherein ring B is selected from:

In another aspect, this invention includes a compound of formula I-K or I'-K:

or a pharmaceutically acceptable salt thereof,

where, independently for each case:

R ³ is halogen, CN or C ₁ -C ₆ alkyl, wherein said C ₁ -C ₆ alkyl is substituted by 0-6 halogen atoms, and where up to two non-adjacent CH ₂ units of said C ₁ -C ₆ alkyl may be replaced by - O-;

R ⁷ is halogen, CN or -XR ^x ;

X is a bond or C ₁ -C ₆ alkyl, wherein said C ₁ -C ₆ alkyl is substituted with 0-6 halogen atoms, and where up to two non-adjacent CH ₂ units of said C ₁ -C ₆ alkyl may be replaced by -O-;

R ^x is absent, is H or a C ₃ -C ₈ cycloaliphatic group, where up to two non-adjacent CH ₂ units of the specified C ₃ -C ₈ cycloaliphatic group can be replaced by -O-, and the specified C ₃ -C ₈ cycloaliphatic group is replaced by 0 -3 substituents selected from halogen and C ₁ -C ₄ alkyl;

R ⁸ is halogen or C ₁ -C ₆ alkyl, wherein said C ₁ -C ₆ alkyl is substituted with 0-6 halogen atoms, and where up to two non-adjacent CH ₂ units of said C ₁ -C ₆ alkyl may be replaced by -O- ;

p is an integer from 0 to 3 inclusive; And

R ⁹ is H or C ₁ -C ₆ alkyl, where up to two non-adjacent CH ₂ units of said C ₁ -C ₆ alkyl can be replaced by -O-.

In another embodiment, this invention includes a compound of formula IK or I'-K and the accompanying definitions, where R ³ is halogen. In another embodiment, R ³ is Cl. In another embodiment, R ³ is F. In another embodiment, R ³ is CN. In another embodiment, R ³ is C ₁ -C ₆ alkyl, wherein said C ₁ -C ₆ alkyl is substituted with 0-6 halogen atoms. In another embodiment, R ³ is tert-butyl. In another embodiment, R ³ is CF ₃ . In another embodiment, R ³ is CF ₂ CF ₃ .

In another embodiment, this invention includes a compound of formula IK or I'-K and the accompanying definitions, where R ⁷ is a halogen. In another embodiment, R ⁷ is Cl. In another embodiment, R ⁷ is F. In another embodiment, R ⁷ is CN. In another embodiment, R ⁷ is -X- R ^x . In another embodiment, R ⁷ is -XR ^x where R ^x is absent. In another embodiment, R ⁷ is -XR ^x , where R ^x is absent and X is C ₁ -C ₆ alkyl, wherein said C ₁ -C ₆ alkyl is substituted with 0-6 halogen atoms. In another embodiment, R ⁷ is CH ₃ , CH ₂ CH ₃ , CH ₂ CH ₂ CH ₃ or isopropyl. In another embodiment, R ⁷ is CF ₃ . In another embodiment, R ⁷ is -XR ^x , where R ^x is absent and X is a C ₁ -C ₆ alkyl, wherein said C ₁ -C ₆ alkyl is substituted with 0-6 halogen atoms, where two non-adjacent CH ₂ units of said C ₁ - C ₆ alkyls are replaced with -O-. In another embodiment, R ⁷ is OCH ₂ CH ₂ OCH ₃ . In another embodiment, R ⁷ is -XR ^x , where R ^x is absent and X is a C ₁ -C ₆ alkyl, wherein said C ₁ -C ₆ alkyl is substituted with 0-6 halogen atoms, where one CH ₂ unit of said C ₁ -C ₆ alkyl is replaced by -O-. In another embodiment, R ⁷ is OCH ₃ , OCH ₂ CH ₃ , OCH ₂ CH ₂ CH ₃ , OC(CH ₃ ) ₃ , CH ₂ CH ₂ OCH ₃ . In another embodiment, R ⁷ is OCF ₃ , OCH ₂ CF ₃ , OCH ₂ CH ₂ CH ₂ CF ₃ or OCHF ₂ .

In another embodiment, the present invention includes a compound of formula IK or I'-K and the accompanying definitions, wherein R ⁷ is -XR ^x , where X is a bond and R ^x is a C ₃ -C ₈ cycloaliphatic group, and said C ₃ -C ₈ the cycloaliphatic group is substituted with 0-3 substituents selected from halogen and C ₁ -C ₄ alkyl. In another embodiment, R ⁷ is -XR ^x , where X is a bond and R ^x is cyclopropyl.

In another embodiment, this invention includes a compound of formula IK or I'-K and accompanying definitions, wherein R ⁷ is -XR ^x , where X is C ₁ -C ₆ alkyl, wherein said C ₁ -C ₆ alkyl is substituted with 0-6 atoms halogen, wherein one CH ₂ unit of said C ₁ -C ₆ alkyl is replaced by -O- and R ^x is a C ₃ -C ₈ cycloaliphatic group, and said C ₃ -C ₈ cycloaliphatic group is substituted with 0-3 substituents selected from halogen and C ₁ -C ₄ alkyl. In another embodiment, R ⁷ is -XR ^x where X is OCH ₂ and R ^x is cyclopropyl.

In another embodiment, the present invention includes a compound of formula IK or I'-K and the accompanying definitions, where p is zero. In another embodiment, p is an integer from 1 to 3 and R ⁸ is a halogen. In another embodiment, where p is an integer from 1 to 3 and R ⁸ is Cl. In another embodiment, where p is an integer from 1 to 3 and R ⁸ is a C ₁ -C ₆ alkyl, wherein said C ₁ -C ₆ alkyl is substituted with 0-6 halogen atoms, where one CH ₂ unit of said C ₁ -C ₆ alkyl is replaced with -O-. In another embodiment, R ⁸ is CH ₃ .

In another embodiment, the present invention includes a compound of formula IK or I'-K and the accompanying definitions, wherein R ⁹ is H. In another embodiment, R ⁹ is C ₁ -C ₆ alkyl. In another embodiment, R ⁹ is CH ₃ . In another embodiment, R ⁹ is C ₁ -C ₆ alkyl, wherein said C ₁ -C ₆ alkyl is replaced by 0-6 halogen atoms, wherein one CH ₂ unit of said C ₁ -C ₆ alkyl is replaced by -O-. In another embodiment, R ⁹ is CH ₂ CH ₂ OH.

In another embodiment, the present invention includes a compound of formula I-K or I'-K and accompanying definitions, wherein ring B is selected from:

In another aspect, this invention includes a compound of formula I-L or I'-L:

or a pharmaceutically acceptable salt thereof,

where, independently for each case:

R ² is halogen, CN or C ₁ -C ₆ alkyl, wherein said C ₁ -C ₆ alkyl is substituted with 0-6 halogen atoms and where up to two non-adjacent CH ₂ units of said C ₁ -C ₆ alkyl may be replaced by -O -;

R ³ is halogen, CN or C ₁ -C ₆ alkyl, wherein said C ₁ -C ₆ alkyl is substituted with 0-6 halogen atoms and where up to two non-adjacent CH ₂ units of said C ₁ -C ₆ alkyl may be replaced by -O -;

R ⁷ is halogen, CN or -XR ^x ;

X is a bond or C ₁ -C ₆ alkyl, wherein said C ₁ -C ₆ alkyl is substituted with 0-6 halogen atoms and where up to two non-adjacent CH ₂ units of said C ₁ -C ₆ alkyl can be replaced by -O-;

R ^x is absent, is H or a C ₃ -C ₈ cycloaliphatic group, where up to two non-adjacent CH ₂ units of the specified C ₃ -C ₈ cycloaliphatic group can be replaced by -O-, and the specified C ₃ -C ₈ cycloaliphatic group is replaced by 0 -3 substituents selected from halogen and C ₁ -C ₄ alkyl;

R ⁸ is halogen or C ₁ -C ₆ alkyl, wherein said C ₁ -C ₆ alkyl is substituted by 0-6 halogen atoms and where up to two non-adjacent CH ₂ units of said C ₁ -C ₆ alkyl may be replaced by -O-;

p is an integer from 0 to 3 inclusive; And

R ⁹ is H or C ₁ -C ₆ alkyl, where up to two non-adjacent CH ₂ units of said C ₁ -C ₆ alkyl can be replaced by -O-.

In another embodiment, this invention includes a compound of formula IL or I'-L and the accompanying definitions, wherein R ² is halogen. In another embodiment, R ² is Cl. In another embodiment, R ² is F. In another embodiment, R ² is CN. In another embodiment, R ² is C ₁ -C ₆ alkyl, wherein said C ₁ -C ₆ alkyl is substituted with 0-6 halogen atoms. In another embodiment, R ² is CF ₃ . In another embodiment, R ² is C ₁ -C ₆ alkyl, wherein said C ₁ -C ₆ alkyl is replaced by 0-6 halogen atoms, wherein one CH ₂ unit of said C ₁ -C ₆ alkyl is replaced by -O-. In another embodiment, R ² is OCF ₃ . In another embodiment, R ² is F, Cl, CN, CF ₃ or OCF ₃ .

In another embodiment, this invention includes a compound of formula IL or I'-L and the accompanying definitions, wherein R ³ is halogen. In another embodiment, R ³ is Cl. In another embodiment, R ³ is F. In another embodiment, R ³ is CN. In another embodiment, R ³ is C ₁ -C ₆ alkyl, wherein said C ₁ -C ₆ alkyl is substituted with 0-6 halogen atoms. In another embodiment, R ³ is tert-butyl. In another embodiment, R ³ is CF ₃ . In another embodiment, R ³ is CF ₂ CF ₃ .

In another embodiment, this invention includes a compound of formula IL or I'-L and the accompanying definitions, wherein R ⁷ is halogen. In another embodiment, R ⁷ is Cl. In another embodiment, R ⁷ is F. In another embodiment, R ⁷ is CN. In another embodiment, R ⁷ is -XR ^x . In another embodiment, R ⁷ is -XR ^x where R ^x is absent. In another embodiment, R ⁷ is -XR ^x , where R ^x is absent and X is C ₁ -C ₆ alkyl, wherein said C ₁ -C ₆ alkyl is substituted with 0-6 halogen atoms. In another embodiment, R ⁷ is CH ₃ , CH ₂ CH ₃ , CH ₂ CH ₂ CH ₃ or isopropyl. In another embodiment, R ⁷ is CF ₃ . In another embodiment, R ⁷ is -XR ^x , where R ^x is absent and X is a C ₁ -C ₆ alkyl, wherein said C ₁ -C ₆ alkyl is substituted with 0-6 halogen atoms, where two non-adjacent CH ₂ units of said C ₁ - C ₆ alkyls are replaced with -O-. In another embodiment, R ⁷ is OCH ₂ CH ₂ OCH ₃ . In another embodiment, R ⁷ is -XR ^x , where R ^x is absent and X is a C ₁ -C ₆ alkyl, wherein said C ₁ -C ₆ alkyl is substituted with 0-6 halogen atoms, where one CH ₂ unit of said C ₁ -C ₆ alkyl is replaced by -O-. In another embodiment, R ⁷ is OCH ₃ , OCH ₂ CH ₃ , OCH ₂ CH ₂ CH ₃ , OC(CH ₃ ) ₃ , CH ₂ CH ₂ OCH ₃ . In another embodiment, R ⁷ is OCF ₃ , OCH ₂ CF ₃ , OCH ₂ CH ₂ CH ₂ CF ₃ or OCHF ₂ .

In another embodiment, the present invention includes a compound of formula IL or I'-L and the accompanying definitions, wherein R ⁷ is -XR ^x , where X is a bond and R ^x is a C ₃ -C ₈ cycloaliphatic group, and said C ₃ -C ₈ the cycloaliphatic group is substituted with 0-3 substituents selected from halogen and C ₁ -C ₄ alkyl. In another embodiment, R ⁷ is -XR ^x , where X is a bond and R ^x is cyclopropyl.

In another embodiment, this invention includes a compound of formula IL or I'-L and accompanying definitions, wherein R ⁷ is -XR ^x , where X is C ₁ -C ₆ alkyl, wherein said C ₁ -C ₆ alkyl is substituted with 0-6 atoms halogen, wherein one CH ₂ unit of said C ₁ -C ₆ alkyl is replaced by -O- and R ^x is a C ₃ -C ₈ cycloaliphatic group, and said C ₃ -C ₈ cycloaliphatic group is substituted with 0-3 substituents selected from halogen and C ₁ -C ₄ alkyl. In another embodiment, R ⁷ is -XR ^x where X is OCH ₂ and R ^x is cyclopropyl.

In another embodiment, the present invention includes a compound of formula IL or I'-L and accompanying definitions, where p is zero. In another embodiment, p is an integer from 1 to 3 and R ⁸ is a halogen. In another embodiment, p is an integer from 1 to 3 and R ⁸ is Cl. In another embodiment, p is an integer from 1 to 3 and R ⁸ is a C ₁ -C ₆ alkyl, wherein said C ₁ -C ₆ alkyl is substituted with 0-6 halogen atoms, where one CH ₂ unit of said C ₁ -C ₆ alkyl replaced by -O-. In another embodiment, p is an integer from 1 to 3 and R ⁸ is CH ₃ .

In another embodiment, the present invention includes a compound of formula IL or I'-L and the accompanying definitions, wherein R ⁹ is H. In another embodiment, R ⁹ is C ₁ -C ₆ alkyl. In another embodiment, R ⁹ is CH ₃ . In another embodiment, R ⁹ is C ₁ -C ₆ alkyl, wherein said C ₁ -C ₆ alkyl is replaced by 0-6 halogen atoms, wherein one CH ₂ unit of said C ₁ -C ₆ alkyl is replaced by -O-. In another embodiment, R ⁹ is CH ₂ CH ₂ OH.

In another embodiment, the present invention includes a compound of formula I-L or I'-L and accompanying definitions, wherein ring B is selected from:

In another aspect, this invention includes a compound of formula I-M or I'-M:

or a pharmaceutically acceptable salt thereof,

where, independently for each case:

R ¹ is halogen, CN or C ₁ -C ₆ alkyl, wherein said C ₁ -C ₆ alkyl is substituted with 0-6 halogen atoms and where up to two non-adjacent CH ₂ units of said C ₁ -C ₆ alkyl may be replaced by -O -;

R ³ is halogen, CN or C ₁ -C ₆ alkyl, wherein said C ₁ -C ₆ alkyl is substituted with 0-6 halogen atoms and where up to two non-adjacent CH ₂ units of said C ₁ -C ₆ alkyl may be replaced by -O -;

R ⁷ is halogen, CN or -XR ^x ;

X is a bond or C ₁ -C ₆ alkyl, wherein said C ₁ -C ₆ alkyl is substituted with 0-6 halogen atoms and where up to two non-adjacent CH ₂ units of said C ₁ -C ₆ alkyl can be replaced by -O-;

R ^x is absent, is H or a C ₃ -C ₈ cycloaliphatic group, where up to two non-adjacent CH ₂ units of the specified C ₃ -C ₈ cycloaliphatic group can be replaced by -O- and the specified C ₃ -C ₈ cycloaliphatic group is replaced by 0- 3 substituents selected from halogen and C ₁ -C ₄ alkyl;

R ⁸ is H, halogen or C ₁ -C ₆ alkyl, wherein said C ₁ -C ₆ alkyl is substituted with 0-6 halogen atoms and where up to two non-adjacent CH ₂ units of said C ₁ -C ₆ alkyl may be replaced by -O -;

p is an integer from 0 to 3 inclusive; And

R ⁹ is H or C ₁ -C ₆ alkyl, where up to two non-adjacent CH ₂ units of said C ₁ -C ₆ alkyl can be replaced by -O-.

In another embodiment, the present invention includes a compound of formula IM or I'-M and the accompanying definitions, wherein R ¹ is halogen. In another embodiment, R ¹ is CN. In another embodiment, R ¹ is C ₁ -C ₆ alkyl, wherein said C ₁ -C ₆ alkyl is substituted with 0-6 halogen atoms. In another embodiment, R ¹ is CF ₃ .

In another embodiment, the present invention includes a compound of formula IM or I'-M and the accompanying definitions, wherein R ³ is halogen. In another embodiment, R ³ is Cl. In another embodiment, R ³ is F. In another embodiment, R ³ is CN. In another embodiment, R ³ is C ₁ -C ₆ alkyl, wherein said C ₁ -C ₆ alkyl is substituted with 0-6 halogen atoms. In another embodiment, R ³ is tert-butyl. In another embodiment, R ³ is CF ₃ . In another embodiment, R ³ is CF ₂ CF ₃ .

In another embodiment, this invention includes a compound of formula IM or I'-M and the accompanying definitions, wherein R ⁷ is halogen. In another embodiment, R ⁷ is Cl. In another embodiment, R ⁷ is F. In another embodiment, R ⁷ is CN. In another embodiment, R ⁷ is -XR ^x . In another embodiment, R ⁷ is -XR ^x where R ^x is absent. In another embodiment, R is -XR ^x , where R ^x is absent and X is C ₁ -C ₆ alkyl, wherein said C ₁ -C ₆ alkyl is substituted with 0-6 halogen atoms. In another embodiment, R ⁷ is CH ₃ , CH ₂ CH ₃ , CH ₂ CH ₂ CH ₃ or isopropyl. In another embodiment, R ⁷ is CF ₃ . In another embodiment, R ⁷ is -XR ^x , where R ^x is absent and X is a C ₁ -C ₆ alkyl, wherein said C ₁ -C ₆ alkyl is substituted with 0-6 halogen atoms, where two non-adjacent CH ₂ units of said C ₁ - C ₆ alkyls are replaced with -O-. In another embodiment, R ⁷ is OCH ₂ CH ₂ OCH ₃ . In another embodiment, R ⁷ is -XR ^x , where R ^x is absent and X is a C ₁ -C ₆ alkyl, wherein said C ₁ -C ₆ alkyl is substituted with 0-6 halogen atoms, where one CH ₂ unit of said C ₁ -C ₆ alkyl is replaced by -O-. In another embodiment, R ⁷ is OCH ₃ , OCH ₂ CH ₃ , OCH ₂ CH ₂ CH ₃ , OC(CH ₃ ) ₃ , CH ₂ CH ₂ OCH ₃ . In another embodiment, R ⁷ is OCF ₃ , OCH ₂ CF ₃ , OCH ₂ CH ₂ CH ₂ CF ₃ or OCHF ₂ .

In another embodiment, the present invention includes a compound of formula IM or I'-M and the accompanying definitions, wherein R ⁷ is -XR ^x , where X is a bond and R ^x is a C ₃ -C ₈ cycloaliphatic group, and said C ₃ -C ₈ the cycloaliphatic group is substituted with 0-3 substituents selected from halogen and C ₁ -C ₄ alkyl. In another embodiment, R ⁷ is -XR ^x , where X is a bond and R ^x is cyclopropyl.

In another embodiment, this invention includes a compound of formula IM or I'-M and accompanying definitions, wherein R ⁷ is -XR ^x , where X is C ₁ -C ₆ alkyl, wherein said C ₁ -C ₆ alkyl is substituted with 0-6 atoms halogen, wherein one CH ₂ unit of said C ₁ -C ₆ alkyl is replaced by -O- and R ^x is a C ₃ -C ₈ cycloaliphatic group, and said C ₃ -C ₈ cycloaliphatic group is substituted with 0-3 substituents selected from halogen and C ₁ -C ₄ alkyl. In another embodiment, R ⁷ is -XR ^x where X is OCH ₂ and R ^x is cyclopropyl.

In another embodiment, the present invention includes a compound of formula IM or I'-M and accompanying definitions, where p is zero. In another embodiment, p is an integer from 1 to 3 and R ⁸ is a halogen. In another embodiment, p is an integer from 1 to 3 and R ⁸ is Cl. In another embodiment, p is an integer from 1 to 3 and R ⁸ is a C ₁ -C ₆ alkyl, wherein said C ₁ -C ₆ alkyl is substituted with 0-6 halogen atoms, where one CH ₂ unit of said C ₁ -C ₆ alkyl replaced by -O-. In another embodiment, p is an integer from 1 to 3 and R ⁸ is CH ₃ .

In another embodiment, the present invention includes a compound of formula IM or I'-M and the accompanying definitions, wherein R ⁹ is H. In another embodiment, R ⁹ is C ₁ -C ₆ alkyl. In another embodiment, R ⁹ is CH ₃ . In another embodiment, R ⁹ is C ₁ -C ₆ alkyl, wherein said C ₁ -C ₆ alkyl is replaced by 0-6 halogen atoms, wherein one CH ₂ unit of said C ₁ -C ₆ alkyl is replaced by -O-. In another embodiment, R ⁹ is CH ₂ CH ₂ OH.

In another embodiment, the present invention includes a compound of formula I-M or I'-M and accompanying definitions, wherein ring B is selected from:

In another aspect, this invention includes a compound of formula I-N or I'-N:

or a pharmaceutically acceptable salt thereof,

where, independently for each case:

R ² is halogen, CN or C ₁ -C ₆ alkyl, wherein said C ₁ -C ₆ alkyl is substituted with 0-6 halogen atoms and where up to two non-adjacent CH ₂ units of said C ₁ -C ₆ alkyl may be replaced by -O -;

R ⁵ is halogen, CN or -XR ^x ;

X is a bond or C ₁ -C ₆ alkyl, wherein said C ₁ -C ₆ alkyl is substituted with 0-6 halogen atoms and where up to two non-adjacent CH ₂ units of said C ₁ -C ₆ alkyl can be replaced by -O-;

R ^x is absent, is H or a C ₃ -C ₈ cycloaliphatic group, where up to two non-adjacent CH ₂ units of the specified C ₃ -C ₈ cycloaliphatic group can be replaced by -O-, and the specified C ₃ -C ₈ cycloaliphatic group is replaced by 0 -3 substituents selected from halogen and C ₁ -C ₄ alkyl;

R ⁸ is halogen or C ₁ -C ₆ alkyl, wherein said C ₁ -C ₆ alkyl is substituted by 0-6 halogen atoms and where up to two non-adjacent CH ₂ units of said C ₁ -C ₆ alkyl may be replaced by -O-;

p is an integer from 0 to 3 inclusive; And

R ⁹ is H or C ₁ -C ₆ alkyl, where up to two non-adjacent CH ₂ units of said C ₁ -C ₆ alkyl can be replaced by -O-.

In another embodiment, the present invention includes a compound of formula IN or I'-N and the accompanying definitions, wherein R ² is halogen. In another embodiment, R ² is Cl. In another embodiment, R ² is F. In another embodiment, R ² is CN. In another embodiment, R ² is C ₁ -C ₆ alkyl, wherein said C ₁ -C ₆ alkyl is substituted with 0-6 halogen atoms. In another embodiment, R ² is CF ₃ . In another embodiment, R ² is C ₁ -C ₆ alkyl, wherein said C ₁ -C ₆ alkyl is replaced by 0-6 halogen atoms, wherein one CH ₂ unit of said C ₁ -C ₆ alkyl is replaced by -O-. In another embodiment, R ² is OCF ₃ . In another embodiment, R ² is F, Cl, CN, CF ₃ or OCF ₃ .

In another embodiment, this invention includes a compound of formula IN or I'-N and the accompanying definitions, where R ⁵ is a halogen. In another embodiment, R ⁵ is Cl. In another embodiment, R ⁵ is F. In another embodiment, R ⁵ is CN. In another embodiment, R ⁵ is -XR ^x . In another embodiment, R ⁵ is -XR ^x where R ^x is absent. In another embodiment, R ⁵ is -XR ^x , where R ^x is absent and X is C ₁ -C ₆ alkyl, wherein said C ₁ -C ₆ alkyl is substituted with 0-6 halogen atoms. In another embodiment, R ⁵ is CH ₃ . In another embodiment, R ⁵ is -XR ^x , where R ^x is absent and X is a C ₁ -C ₆ alkyl, wherein said C ₁ -C ₆ alkyl is substituted with 0-6 halogen atoms, where one CH ₂ unit of said C ₁ -C ₆ alkyl is replaced by -O-. In another embodiment, R ⁵ is OCH ₃ , OCH ₂ CH ₃ , OCH ₂ CH ₂ CH ₃ or OCH(CH ₃ ) ₂ . In another embodiment, R ⁵ is OCH ₃ . In another embodiment, R ⁵ is CH ₂ OH. In another embodiment, R ⁵ is OCF ₃ . In another embodiment, R ⁵ is OCHF ₂ .

In another embodiment, the present invention includes a compound of formula IN or I'-N and the accompanying definitions, where p is zero. In another embodiment, p is an integer from 1 to 3 and R ⁸ is a halogen. In another embodiment, p is an integer from 1 to 3 and R ⁸ is Cl. In another embodiment, p is an integer from 1 to 3 and R ⁸ is a C ₁ -C ₆ alkyl, wherein said C ₁ -C ₆ alkyl is substituted with 0-6 halogen atoms, where one CH ₂ unit of said C ₁ -C ₆ alkyl replaced by -O-. In another embodiment, p is an integer from 1 to 3 and R ⁸ is CH ₃ .

In another embodiment, the invention includes a compound of formula IN or I'-N and the accompanying definitions, wherein R ⁹ is H. In another embodiment, R ⁹ is C ₁ -C ₆ alkyl. In another embodiment, R ⁹ is CH ₃ . In another embodiment, R ⁹ is C ₁ -C ₆ alkyl, wherein said C ₁ -C ₆ alkyl is replaced by 0-6 halogen atoms, wherein one CH ₂ unit of said C ₁ -C ₆ alkyl is replaced by -O-. In another embodiment, R ⁹ is CH ₂ CH ₂ OH.

In another embodiment, the invention includes a compound of formula I-N or I'-N and accompanying definitions, wherein ring C is selected from:

In another aspect, this invention includes a compound of formula I-O or I'-O:

or a pharmaceutically acceptable salt thereof,

where, independently for each case:

R ³ is halogen, CN or C ₁ -C ₆ alkyl, wherein said C ₁ -C ₆ alkyl is substituted with 0-6 halogen atoms and where up to two non-adjacent CH ₂ units of said C ₁ -C ₆ alkyl may be replaced by -O -;

R ⁵ is halogen, CN or -XR ^x ;

X is a bond or C ₁ -C ₆ alkyl, wherein said C ₁ -C ₆ alkyl is substituted with 0-6 halogen atoms and where up to two non-adjacent CH ₂ units of said C ₁ -C ₆ alkyl can be replaced by -O-;

R ^x is absent, is H or a C ₃ -C ₈ cycloaliphatic group, where up to two non-adjacent CH ₂ units of the specified C ₃ -C ₈ cycloaliphatic group can be replaced by -O-, and the specified C ₃ -C ₈ cycloaliphatic group is replaced by 0 -3 substituents selected from halogen and C ₁ -C ₄ alkyl;

R ⁸ is halogen or C ₁ -C ₆ alkyl, wherein said C ₁ -C ₆ alkyl is substituted by 0-6 halogen atoms and where up to two non-adjacent CH ₂ units of said C ₁ -C ₆ alkyl may be replaced by -O-;

p is an integer from 0 to 3 inclusive; And

R ⁹ is H or C ₁ -C ₆ alkyl, where up to two non-adjacent CH ₂ units of said C ₁ -C ₆ alkyl can be replaced by -O-.

In another embodiment, this invention includes a compound of formula IO or I'-O and the accompanying definitions, where R ³ is halogen. In another embodiment, R ³ is Cl. In another embodiment, R ³ is F. In another embodiment, R ³ is CN. In another embodiment, R ³ is C ₁ -C ₆ alkyl, wherein said C ₁ -C ₆ alkyl is substituted with 0-6 halogen atoms. In another embodiment, R ³ is tert-butyl. In another embodiment, R ³ is CF ₃ . In another embodiment, R ³ is CF ₂ CF ₃ .

In another embodiment, this invention includes a compound of formula IO or I'-O and the accompanying definitions, where R ⁵ is a halogen. In another embodiment, R ⁵ is Cl. In another embodiment, R ⁵ is F. In another embodiment, R ^s is CN. In another embodiment, R ⁵ is -XR ^x . In another embodiment, R ⁵ is -XR ^x where R ^x is absent. In another embodiment, R ⁵ is -XR ^x , where R ^x is absent and X is C ₁ -C ₆ alkyl, wherein said C ₁ -C ₆ alkyl is substituted with 0-6 halogen atoms. In another embodiment, R ⁵ is CH ₃ . In another embodiment, R ⁵ is -XR ^x , where R ^x is absent and X is a C ₁ -C ₆ alkyl, wherein said C ₁ -C ₆ alkyl is substituted with 0-6 halogen atoms, where one CH ₂ unit of said C ₁ -C ₆ alkyl is replaced by -O-. In another embodiment, R ⁵ is OCH ₃ , OCH ₂ CH ₃ , OCH ₂ CH ₂ CH ₃ or OCH(CH ₃ ) ₂ . In another embodiment, R ⁵ is OCH ₃ . In another embodiment, R ⁵ is CH ₂ OH. In another embodiment, R ⁵ is OCF ₃ . In another embodiment, R ⁵ is OCHF ₂ .

In another embodiment, the present invention includes a compound of formula IO or I'-O and the accompanying definitions, where p is an integer from 1 to 3 and R ⁸ is a halogen. In another embodiment, p is an integer from 1 to 3 and R ⁸ is Cl. In another embodiment, p is an integer from 1 to 3 and R ⁸ is a C ₁ -C ₆ alkyl, wherein said C ₁ -C ₆ alkyl is substituted with 0-6 halogen atoms, where one CH ₂ unit of said C ₁ -C ₆ alkyl replaced by -O-. In another embodiment, p is an integer from 1 to 3 and R ⁸ is CH ₃ .

In another embodiment, this invention includes a compound of formula IO or I'-O and the accompanying definitions, where R ⁹ is H. In another embodiment, R ⁹ is C ₁ -C ₆ alkyl. In another embodiment, R ⁹ is CH ₃ . In another embodiment, R ⁹ is C ₁ -C ₆ alkyl, wherein said C ₁ -C ₆ alkyl is replaced by 0-6 halogen atoms, wherein one CH ₂ unit of said C ₁ -C ₆ alkyl is replaced by -O-. In another embodiment, R ⁹ is CH ₂ CH ₂ OH.

In another embodiment, the present invention includes a compound of formula I-O or I'-O and accompanying definitions, wherein ring C is selected from:

In another aspect, this invention includes a compound of formula I-P or I'-P:

or a pharmaceutically acceptable salt thereof,

where, independently for each case:

R ² is halogen, CN or C ₁ -C ₆ alkyl, wherein said C ₁ -C ₆ alkyl is substituted with 0-6 halogen atoms and where up to two non-adjacent CH ₂ units of said C ₁ -C ₆ alkyl may be replaced by -O -;

R ³ is halogen, CN or C ₁ -C ₆ alkyl, wherein said C ₁ -C ₆ alkyl is substituted with 0-6 halogen atoms and where up to two non-adjacent CH ₂ units of said C ₁ -C ₆ alkyl may be replaced by -O -;

R ⁵ is halogen, CN or -XR ^x ;

X is a bond or C ₁ -C ₆ alkyl, wherein said C ₁ -C ₆ alkyl is substituted with 0-6 halogen atoms and where up to two non-adjacent CH ₂ units of said C ₁ -C ₆ alkyl can be replaced by -O-;

R ^x is absent, is H or a C ₃ -C ₈ cycloaliphatic group, where up to two non-adjacent CH ₂ units of said C3-C8 cycloaliphatic group can be replaced by -O-, and said C ₃ -C ₈ cycloaliphatic is substituted with 0-3 substituents selected from halogen and C ₁ -C ₄ alkyl;

R ⁸ is H, halogen or C ₁ -C ₆ alkyl, wherein said C ₁ -C ₆ alkyl is substituted with 0-6 halogen atoms, where up to two non-adjacent CH ₂ units of said C ₁ -C ₆ alkyl may be replaced by -O -;

p is an integer from 0 to 3 inclusive; And

R ⁹ is H or C ₁ -C ₆ alkyl, where up to two non-adjacent CH ₂ units of said C ₁ -C ₆ alkyl can be replaced by -O-.

In another embodiment, this invention includes a compound of formula IP or I'-P and the accompanying definitions, where R ² is halogen. In another embodiment, R ² is Cl. In another embodiment, R ² is F. In another embodiment, R ² is CN. In another embodiment, R ² is C ₁ -C ₆ alkyl, wherein said C ₁ -C ₆ alkyl is substituted with 0-6 halogen atoms. In another embodiment, R ² is CF ₃ . In another embodiment, R ² is C ₁ -C ₆ alkyl, wherein said C ₁ -C ₆ alkyl is replaced by 0-6 halogen atoms, wherein one CH ₂ unit of said C ₁ -C ₆ alkyl is replaced by -O-. In another embodiment, R ² is OCF ₃ . In another embodiment, R ² is F, Cl, CN, CF ₃ or OCF _3.

In another embodiment, this invention includes a compound of formula IP or I'-P and the accompanying definitions, wherein R ³ is halogen. In another embodiment, R ³ is Cl. In another embodiment, R ³ is F. In another embodiment, R ³ is CN. In another embodiment, R ³ is C ₁ -C ₆ alkyl, wherein said C ₁ -C ₆ alkyl is substituted with 0-6 halogen atoms. In another embodiment, R ³ is tert-butyl. In another embodiment, R ³ is CF ₃ . In another embodiment, R ³ is CF ₂ CF ₃ .

In another embodiment, this invention includes a compound of formula IP or I'-P and the accompanying definitions, wherein R ⁵ is halogen. In another embodiment, R ⁵ is Cl. In another embodiment, R ⁵ is F. In another embodiment, R ⁵ is CN. In another embodiment, R ⁵ is -XR ^x . In another embodiment, R ⁵ is -XR ^x where R ^x is absent. In another embodiment, R ⁵ is -XR ^x , where R ^x is absent and X is C ₁ -C ₆ alkyl, wherein said C ₁ -C ₆ alkyl is substituted with 0-6 halogen atoms. In another embodiment, R ⁵ is CH ₃ . In another embodiment, R ⁵ is -XR ^x , where R ^x is absent and X is a C ₁ -C ₆ alkyl, wherein said C ₁ -C ₆ alkyl is substituted with 0-6 halogen atoms, where one CH ₂ unit of said C ₁ -C ₆ alkyl is replaced by -O-. In another embodiment, R ⁵ is OCH ₃ , OCH ₂ CH ₃ , OCH ₂ CH ₂ CH ₃ or OCH(CH ₃ ) ₂ . In another embodiment, R ⁵ is OCH ₃ . In another embodiment, R ⁵ is CH ₂ OH. In another embodiment, R ⁵ is OCF ₃ . In another embodiment, R ⁵ is OCHF ₂ .

In another embodiment, the present invention includes a compound of formula IP or I'-P and accompanying definitions, where p is zero. In another embodiment, p is an integer from 1 to 3 and R ⁸ is a halogen. In another embodiment, p is an integer from 1 to 3 and R ⁸ is Cl. In another embodiment, p is an integer from 1 to 3 and R ⁸ is a C ₁ -C ₆ alkyl, wherein said C ₁ -C ₆ alkyl is substituted with 0-6 halogen atoms, where one CH ₂ unit of said C ₁ -C ₆ alkyl replaced by -O-. In another embodiment, p is an integer from 1 to 3 and R ⁸ is CH ₃ .

In another embodiment, this invention includes a compound of formula IP or I'-P and the accompanying definitions, wherein R ⁹ is H. In another embodiment, R ⁹ is C ₁ -C ₆ alkyl. In another embodiment, R ⁹ is CH ₃ . In another embodiment, R ⁹ is C ₁ -C ₆ alkyl, wherein said C ₁ -C ₆ alkyl is replaced by 0-6 halogen atoms, wherein one CH ₂ unit of said C ₁ -C ₆ alkyl is replaced by -O-. In another embodiment, R ⁹ is CH ₂ CH ₂ OH.

In another embodiment, the invention includes a compound of formula I-P or I'-P and accompanying definitions, wherein ring C is selected from:

In another aspect, this invention includes a compound of formula I-Q or I'-Q:

or a pharmaceutically acceptable salt thereof,

where, independently for each case:

R ² is halogen, CN or C ₁ -C ₆ alkyl, wherein said C ₁ -C ₆ alkyl is substituted with 0-6 halogen atoms and where up to two non-adjacent CH ₂ units of said C ₁ -C ₆ alkyl may be replaced by -O -;

R ⁶ is halogen, CN or -XR ^x ;

R ⁷ is halogen, CN or -XR ^x ;

X is a bond or C ₁ -C ₆ alkyl, wherein said C ₁ -C ₆ alkyl is substituted with 0-6 halogen atoms and where up to two non-adjacent CH ₂ units of said C ₁ -C ₆ alkyl can be replaced by -O-;

R ^x is absent, is H or a C ₃ -C ₈ cycloaliphatic group, wherein up to two non-adjacent CH ₂ units of said C ₃ -C ₈ cycloaliphatic group can be replaced by -O-, and said C ₃ -C ₈ cycloaliphatic is substituted with 0- 3 substituents selected from halogen and C ₁ -C ₄ alkyl;

R ⁸ is H, halogen or C ₁ -C ₆ alkyl, wherein said C ₁ -C ₆ alkyl is substituted with 0-6 halogen atoms and where up to two non-adjacent CH ₂ units of said C ₁ -C ₆ alkyl may be replaced by -O -;

p is an integer from 0 to 3 inclusive; And

R ⁹ is H or C ₁ -C ₆ alkyl, where up to two non-adjacent CH ₂ units of said C ₁ -C ₆ alkyl can be replaced by -O-.

In another embodiment, this invention includes a compound of formula IQ or I'-Q and the accompanying definitions, wherein R ² is halogen. In another embodiment, R ² is Cl. In another embodiment, R ² is F. In another embodiment, R ² is CN. In another embodiment, R ² is C ₁ -C ₆ alkyl, wherein said C ₁ -C ₆ alkyl is substituted with 0-6 halogen atoms. In another embodiment, R ² is CF ₃ . In another embodiment, R ² is C ₁ -C ₆ alkyl, wherein said C ₁ -C ₆ alkyl is replaced by 0-6 halogen atoms, wherein one CH ₂ unit of said C ₁ -C ₆ alkyl is replaced by -O-. In another embodiment, R ² is OCF ₃ . In another embodiment, R ² is F, Cl, CN, CF ₃ or OCF ₃ .

In another embodiment, the present invention includes a compound of formula IQ or I'-Q and the accompanying definitions, wherein R ⁶ is halogen. In another embodiment, R ⁶ is Cl. In another embodiment, R ⁶ is F. In another embodiment, R ⁶ is CN. In another embodiment, R ⁶ is -XR ^x . In another embodiment, R ⁶ is -XR ^x where R ^x is absent. In another embodiment, R ⁶ is -XR ^x , where R ^x is absent and X is C ₁ -C ₆ alkyl, wherein said C ₁ -C ₆ alkyl is substituted with 0-6 halogen atoms. In another embodiment, R ⁶ is CH ₃ . In another embodiment, R ⁶ is -XR ^x , where R ^x is absent and X is a C ₁ -C ₆ alkyl, wherein said C ₁ -C ₆ alkyl is substituted with 0-6 halogen atoms, where one CH ₂ unit of said C ₁ -C ₆ alkyl is replaced by -O-. In another embodiment, R ⁶ is OCH ₃ .

In another embodiment, this invention includes a compound of formula IQ or I'-Q and the accompanying definitions, wherein R ⁷ is halogen. In another embodiment, R ⁷ is Cl. In another embodiment, R ⁷ is F. In another embodiment, R ⁷ is CN. In another embodiment, R ⁷ is -XR ^x . In another embodiment, R ⁷ is -XR ^x where R ^x is absent. In another embodiment, R is -XR ^x , where R ^x is absent and X is C ₁ -C ₆ alkyl, wherein said C ₁ -C ₆ alkyl is substituted with 0-6 halogen atoms. In another embodiment, R ⁷ is CH ₃ , CH ₂ CH ₃ , CH ₂ CH ₂ CH ₃ or isopropyl. In another embodiment, R ⁷ is CF ₃ . In another embodiment, R ⁷ is -XR ^x , where R ^x is absent and X is a C ₁ -C ₆ alkyl, wherein said C ₁ -C ₆ alkyl is substituted with 0-6 halogen atoms, where two non-adjacent CH ₂ units of said C ₁ - C ₆ alkyls are replaced with -O-. In another embodiment, R ⁷ is OCH ₂ CH ₂ OCH ₃ . In another embodiment, R ⁷ is -XR ^x , where R ^x is absent and X is a C ₁ -C ₆ alkyl, wherein said C ₁ -C ₆ alkyl is substituted with 0-6 halogen atoms, where one CH ₂ unit of said C ₁ -C ₆ alkyl is replaced by -O-. In another embodiment, R ⁷ is OCH ₃ , OCH ₂ CH ₃ , OCH ₂ CH ₂ CH ₃ , OC(CH ₃ ) ₃ , CH ₂ CH ₂ OCH ₃ . In another embodiment, R ⁷ is OCF ₃ , OCH ₂ CF ₃ , OCH ₂ CH ₂ CH ₂ CF ₃ or OCHF ₂ .

In another embodiment, the present invention includes a compound of formula IQ or I'-Q and the accompanying definitions, wherein R ⁷ is -XR ^x , where X is a bond and R ^x is a C ₃ -C ₈ cycloaliphatic group, and said C ₃ -C ₈ the cycloaliphatic group is substituted with 0-3 substituents selected from halogen and C ₁ -C ₄ alkyl. In another embodiment, R ⁷ is -XR ^x , where X is a bond and R ^x is cyclopropyl.

In another embodiment, this invention includes a compound of formula IQ or I'-Q and accompanying definitions, wherein R ⁷ is -XR ^x , where X is C ₁ -C ₆ alkyl, wherein said C ₁ -C ₆ alkyl is substituted with 0-6 atoms halogen, wherein one CH ₂ unit of said C ₁ -C ₆ alkyl is replaced by -O- and R ^x is a C ₃ -C ₈ cycloaliphatic group, and said C ₃ -C ₈ cycloaliphatic group is substituted with 0-3 substituents selected from halogen and C ₁ -C ₄ alkyl. In another embodiment, R ⁷ is -XR ^x where X is OCH ₂ and R ^x is cyclopropyl.

In another embodiment, the present invention includes a compound of formula IQ or I'-Q and accompanying definitions, where p is zero. In another embodiment, p is an integer from 1 to 3 and R ⁸ is a halogen. In another embodiment, p is an integer from 1 to 3 and R ⁸ is Cl. In another embodiment, p is an integer from 1 to 3 and R ⁸ is a C ₁ -C ₆ alkyl, wherein said C ₁ -C ₆ alkyl is substituted with 0-6 halogen atoms, where one CH ₂ unit of said C ₁ -C ₆ alkyl replaced by -O-. In another embodiment, p is an integer from 1 to 3 and R ⁸ is CH ₃ .

In another embodiment, the present invention includes a compound of formula IQ or I'-Q and accompanying definitions, wherein R ⁹ is H. In another embodiment, R ⁹ is C ₁ -C ₆ alkyl. In another embodiment, R ⁹ is CH ₃ . In another embodiment, R ⁹ is C ₁ -C ₆ alkyl, wherein said C ₁ -C ₆ alkyl is replaced by 0-6 halogen atoms, wherein one CH ₂ unit of said C ₁ -C ₆ alkyl is replaced by -O-. In another embodiment, R ⁹ is CH ₂ CH ₂ OH.

In another embodiment, the present invention includes a compound of formula I-Q or I'-Q and accompanying definitions, wherein ring D is selected from:

In another aspect, this invention includes a compound of formula I-R or I'-R:

or a pharmaceutically acceptable salt thereof,

where, independently for each case:

R ³ is halogen, CN or C ₁ -C ₆ alkyl, wherein said C ₁ -C ₆ alkyl is substituted with 0-6 halogen atoms and where up to two non-adjacent CH ₂ units of said C ₁ -C ₆ alkyl may be replaced by -O -;

R ⁶ is halogen, CN or -XR ^x ;

R ⁷ is halogen, CN or -XR ^x ;

X is a bond or C ₁ -C ₆ alkyl, wherein said C ₁ -C ₆ alkyl is substituted with 0-6 halogen atoms and where up to two non-adjacent CH ₂ units of said C ₁ -C ₆ alkyl can be replaced by -O-;

R ^x is absent, is H or a C ₃ -C ₈ cycloaliphatic group, where up to two non-adjacent CH ₂ units of the specified C ₃ -C ₈ cycloaliphatic group can be replaced by -O-, and the specified C ₃ -C ₈ cycloaliphatic group is replaced by 0 -3 substituents selected from halogen and C ₁ -C ₄ alkyl;

R ⁸ is H, halogen or C ₁ -C ₆ alkyl, wherein said C ₁ -C ₆ alkyl is substituted with 0-6 halogen atoms and where up to two non-adjacent CH ₂ units of said C ₁ -C ₆ alkyl may be replaced by -O -;

p is an integer from 0 to 3 inclusive; And

R ⁹ is H or C ₁ -C ₆ alkyl, where up to two non-adjacent CH ₂ units of said C ₁ -C ₆ alkyl can be replaced by -O-.

In another embodiment, this invention includes a compound of formula IR or I'-R and the accompanying definitions, where R ³ is a halogen. In another embodiment, R ³ is Cl. In another embodiment, R ³ is F. In another embodiment, R ³ is CN. In another embodiment, R ³ is C ₁ -C ₆ alkyl, wherein said C ₁ -C ₆ alkyl is substituted with 0-6 halogen atoms. In another embodiment, R ³ is tert-butyl. In another embodiment, R ³ is CF ₃ . In another embodiment, R ³ is CF ₂ CF ₃ .

In another embodiment, this invention includes a compound of formula IR or I'-R and the accompanying definitions, where R ⁶ is a halogen. In another embodiment, R ⁶ is Cl. In another embodiment, R ⁶ is F. In another embodiment, R ⁶ is CN. In another embodiment, R ⁶ is -XR ^x . In another embodiment, R ⁶ is -XR ^x where R ^x is absent. In another embodiment, R ⁶ is -XR ^x , where R ^x is absent and X is C ₁ -C ₆ alkyl, wherein said C ₁ -C ₆ alkyl is substituted with 0-6 halogen atoms. In another embodiment, R ⁶ is CH ₃ . In another embodiment, R ⁶ is -XR ^x , where R ^x is absent and X is a C ₁ -C ₆ alkyl, wherein said C ₁ -C ₆ alkyl is substituted with 0-6 halogen atoms, where one CH ₂ unit of said C ₁ -C ₆ alkyl is replaced by -O-. In another embodiment, R ⁶ is OCH ₃ .

In another embodiment, the present invention includes a compound of formula IR or I'-R and the accompanying definitions, wherein R ⁷ is a halogen. In another embodiment, R ⁷ is Cl. In another embodiment, R ⁷ is F. In another embodiment, R ⁷ is CN. In another embodiment, R ⁷ is -XR ^x . In another embodiment, R ⁷ is -XR ^x where R ^x is absent. In another embodiment, R is -XR ^x , where R ^x is absent and X is C ₁ -C ₆ alkyl, wherein said C ₁ -C ₆ alkyl is substituted with 0-6 halogen atoms. In another embodiment, R ⁷ is CH ₃ , CH ₂ CH ₃ , CH ₂ CH ₂ CH ₃ or isopropyl. In another embodiment, R ⁷ is CF ₃ . In another embodiment, R ⁷ is -XR ^x , where R ^x is absent and X is a C ₁ -C ₆ alkyl, wherein said C ₁ -C ₆ alkyl is substituted with 0-6 halogen atoms, where two non-adjacent CH ₂ units of said C ₁ - C ₆ alkyls are replaced with -O-. In another embodiment, R ⁷ is OCH ₂ CH ₂ OCH ₃ . In another embodiment, R ⁷ is -XR ^x , where R ^x is absent and X is a C ₁ -C ₆ alkyl, wherein said C ₁ -C ₆ alkyl is substituted with 0-6 halogen atoms, where one CH ₂ unit of said C ₁ -C ₆ alkyl is replaced by -O-. In another embodiment, R ⁷ is OCH ₃ , OCH ₂ CH ₃ , OCH ₂ CH ₂ CH ₃ , OC(CH ₃ ) ₃ , CH ₂ CH ₂ OCH ₃ . In another embodiment, R ⁷ is OCF ₃ , OCH ₂ CF ₃ , OCH ₂ CH ₂ CH ₂ CF ₃ or OCHF ₂ .

In another embodiment, the present invention includes a compound of formula IR or I'-R and the accompanying definitions, wherein R ⁷ is -XR ^x , where X is a bond and R ^x is a C ₃ -C ₈ cycloaliphatic group, and said C ₃ -C ₈ the cycloaliphatic group is substituted with 0-3 substituents selected from halogen and C ₁ -C ₄ alkyl. In another embodiment, R ⁷ is -XR ^x , where X is a bond and R ^x is cyclopropyl.

In another embodiment, this invention includes a compound of formula IR or I'-R and accompanying definitions, wherein R ⁷ is -XR ^x , where X is C ₁ -C ₆ alkyl, wherein said C ₁ -C ₆ alkyl is substituted with 0-6 atoms halogen, wherein one CH ₂ unit of said C ₁ -C ₆ alkyl is replaced by -O- and R ^x is a C ₃ -C ₈ cycloaliphatic group, and said C ₃ -C ₈ cycloaliphatic group is substituted with 0-3 substituents selected from halogen and C ₁ -C ₄ alkyl. In another embodiment, R ⁷ is -XR ^x where X is OCH ₂ and R ^x is cyclopropyl.

In another embodiment, the present invention includes a compound of formula IR or I'-R and accompanying definitions, where p is zero. In another embodiment, p is an integer from 1 to 3 and R ⁸ is a halogen. In another embodiment, p is an integer from 1 to 3 and R ⁸ is Cl. In another embodiment, p is an integer from 1 to 3 and R ⁸ is a C ₁ -C ₆ alkyl, wherein said C ₁ -C ₆ alkyl is substituted with 0-6 halogen atoms, where one CH ₂ unit of said C ₁ -C ₆ alkyl replaced by -O-. In another embodiment, p is an integer from 1 to 3 and R ⁸ is CH ₃ .

In another embodiment, this invention includes a compound of formula IR or I'-R and the accompanying definitions, wherein R ⁹ is H. In another embodiment, R ⁹ is C ₁ -C ₆ alkyl. In another embodiment, R ⁹ is CH ₃ . In another embodiment, R ⁹ is C ₁ -C ₆ alkyl, wherein said C ₁ -C ₆ alkyl is replaced by 0-6 halogen atoms, wherein one CH ₂ unit of said C ₁ -C ₆ alkyl is replaced by -O-. In another embodiment, R ⁹ is CH ₂ CH ₂ OH.

In another embodiment, the present invention includes a compound of formula I-R or I'-R and accompanying definitions, wherein ring D is selected from:

In another aspect, this invention includes a compound of formula I-S or I'-S:

or a pharmaceutically acceptable salt thereof,

where, independently for each case:

R ² is halogen, CN or C ₁ -C ₆ alkyl, wherein said C ₁ -C ₆ alkyl is substituted with 0-6 halogen atoms and where up to two non-adjacent CH ₂ units of said C ₁ -C ₆ alkyl may be replaced by -O -;

R ³ is halogen, CN or C ₁ -C ₆ alkyl, wherein said C ₁ -C ₆ alkyl is substituted with 0-6 halogen atoms and where up to two non-adjacent CH ₂ units of said C ₁ -C ₆ alkyl may be replaced by -O -;

R ⁶ is halogen, CN or -XR ^x ;

R ⁷ is halogen, CN or -XR ^x ;

X is a bond or C ₁ -C ₆ alkyl, wherein said C ₁ -C ₆ alkyl is substituted with 0-6 halogen atoms and where up to two non-adjacent CH ₂ units of said C ₁ -C ₆ alkyl can be replaced by -O-;

R ^x is absent, is H or a C ₃ -C ₈ cycloaliphatic group, where up to two non-adjacent CH ₂ units of the specified C ₃ -C ₈ cycloaliphatic group can be replaced by -O-, and the specified C ₃ -C ₈ cycloaliphatic group is replaced by 0 -3 substituents selected from halogen and C ₁ -C ₄ alkyl;

R ⁸ is halogen or C ₁ -C ₆ alkyl, wherein said C ₁ -C ₆ alkyl is substituted by 0-6 halogen atoms and where up to two non-adjacent CH ₂ units of said C ₁ -C ₆ alkyl may be replaced by -O-;

p is an integer from 0 to 3 inclusive; And

R ⁹ is H or C ₁ -C ₆ alkyl, where up to two non-adjacent CH ₂ units of said C ₁ -C ₆ alkyl can be replaced by -O-.

In another embodiment, the present invention includes a compound of formula IS or I'-S and the accompanying definitions, wherein R ² is halogen. In another embodiment, R ² is Cl. In another embodiment, R ² is F. In another embodiment, R ² is CN. In another embodiment, R ² is C ₁ -C ₆ alkyl, wherein said C ₁ -C ₆ alkyl is substituted with 0-6 halogen atoms. In another embodiment, R ² is CF ₃ . In another embodiment, R ² is C ₁ -C ₆ alkyl, wherein said C ₁ -C ₆ alkyl is replaced by 0-6 halogen atoms, wherein one CH ₂ unit of said C ₁ -C ₆ alkyl is replaced by -O-. In another embodiment, R ² is OCF ₃ . In another embodiment, R ² is F, Cl, CN, CF ₃ or OCF ₃ .

In another embodiment, the present invention includes a compound of formula IS or I'-S and the accompanying definitions, wherein R ³ is halogen. In another embodiment, R ³ is Cl. In another embodiment, R ³ is F. In another embodiment, R ³ is CN. In another embodiment, R ³ is C ₁ -C ₆ alkyl, wherein said C ₁ -C ₆ alkyl is substituted with 0-6 halogen atoms. In another embodiment, R ³ is tert-butyl. In another embodiment, R ³ is CF ₃ . In another embodiment, R ³ is CF ₂ CF ₃ .

In another embodiment, this invention includes a compound of formula IS or I'-S and the accompanying definitions, wherein R ⁶ is halogen. In another embodiment, R ⁶ is Cl. In another embodiment, R ⁶ is F. In another embodiment, R ⁶ is CN. In another embodiment, R ⁶ is -XR ^x . In another embodiment, R ⁶ is -XR ^x where R ^x is absent. In another embodiment, R ⁶ is -XR ^x , where R ^x is absent and X is C ₁ -C ₆ alkyl, wherein said C ₁ -C ₆ alkyl is substituted with 0-6 halogen atoms. In another embodiment, R ⁶ is CH ₃ . In another embodiment, R ⁶ is -XR ^x , where R ^x is absent and X is a C ₁ -C ₆ alkyl, wherein said C ₁ -C ₆ alkyl is substituted with 0-6 halogen atoms, where one CH ₂ unit of said C ₁ -C ₆ alkyl is replaced by -O-. In another embodiment, R ⁶ is OCH ₃ .

In another embodiment, this invention includes a compound of formula IS or I'-S and the accompanying definitions, wherein R ⁷ is halogen. In another embodiment, R ⁷ is Cl. In another embodiment, R ⁷ is F. In another embodiment, R ⁷ is CN. In another embodiment, R ⁷ is -XR ^x . In another embodiment, R ⁷ is -XR ^x where R ^x is absent. In another embodiment, R ⁷ is -XR ^x , where R ^x is absent and X is C ₁ -C ₆ alkyl, wherein said C ₁ -C ₆ alkyl is substituted with 0-6 halogen atoms. In another embodiment, R ⁷ is CH ₃ , CH ₂ CH ₃ , CH ₂ CH ₂ CH ₃ or isopropyl. In another embodiment, R ⁷ is CF ₃ . In another embodiment, R ⁷ is -XR ^x , where R ^x is absent and X is a C ₁ -C ₆ alkyl, wherein said C ₁ -C ₆ alkyl is substituted with 0-6 halogen atoms, where two non-adjacent CH ₂ units of said C ₁ - C ₆ alkyls are replaced with -O-. In another embodiment, R ⁷ is OCH ₂ CH ₂ OCH ₃ . In another embodiment, R ⁷ is -XR ^x , where R ^x is absent and X is a C ₁ -C ₆ alkyl, wherein said C ₁ -C ₆ alkyl is substituted with 0-6 halogen atoms, where one CH ₂ unit of said C ₁ -C ₆ alkyl is replaced by -O-. In another embodiment, R ⁷ is OCH ₃ , OCH ₂ CH ₃ , OCH ₂ CH ₂ CH ₃ , OC(CH ₃ ) ₃ , CH ₂ CH ₂ OCH ₃ . In another embodiment, R ⁷ is OCF ₃ , OCH ₂ CF ₃ , OCH ₂ CH ₂ CH ₂ CF ₃ or OCHF ₂ .

In another embodiment, the present invention includes a compound of formula IS or I'-S and the accompanying definitions, wherein R ⁷ is -XR ^x , where X is a bond and R ^x is a C ₃ -C ₈ cycloaliphatic group, and said C ₃ -C ₈ the cycloaliphatic group is substituted with 0-3 substituents selected from halogen and C ₁ -C ₄ alkyl. In another embodiment, R ⁷ is -XR ^x , where X is a bond and R ^x is cyclopropyl.

In another embodiment, this invention includes a compound of formula IS or I'-S and accompanying definitions, wherein R ⁷ is -XR ^x , where X is C ₁ -C ₆ alkyl, wherein said C ₁ -C ₆ alkyl is substituted with 0-6 atoms halogen, wherein one CH ₂ unit of said C ₁ -C ₆ alkyl is replaced by -O-, and R ^x is a C ₃ -C ₈ cycloaliphatic group, and said C ₃ -C ₈ cycloaliphatic group is substituted with 0-3 substituents selected from halogen and C ₁ -C ₄ alkyl. In another embodiment, R ⁷ is -XR ^x where X is OCH ₂ and R ^x is cyclopropyl.

In another embodiment, the present invention includes a compound of formula IS or I'-S and accompanying definitions, where p is zero. In another embodiment, p is an integer from 1 to 3 and R ⁸ is a halogen. In another embodiment, p is an integer from 1 to 3 and R ⁸ is Cl. In another embodiment, p is an integer from 1 to 3 and R ⁸ is a C ₁ -C ₆ alkyl, wherein said C ₁ -C ₆ alkyl is substituted with 0-6 halogen atoms, where one CH ₂ unit of said C ₁ -C ₆ alkyl replaced by -O-. In another embodiment, p is an integer from 1 to 3 and R ⁸ is CH ₃ .

In another embodiment, this invention includes a compound of formula IS or I'-S and the accompanying definitions, wherein R ⁹ is H. In another embodiment, R ⁹ is C ₁ -C ₆ alkyl. In another embodiment, R ⁹ is CH ₃ . In another embodiment, R ⁹ is C ₁ -C ₆ alkyl, wherein said C ₁ -C ₆ alkyl is replaced by 0-6 halogen atoms, wherein one CH ₂ unit of said C ₁ -C ₆ alkyl is replaced by -O-. In another embodiment, R ⁹ is CH ₂ CH ₂ OH.

In another embodiment, the present invention includes a compound of formula I-S or I'-S and accompanying definitions, wherein ring D is selected from:

In another embodiment, the present invention includes a compound of formula I or I', wherein the compound, or a pharmaceutically acceptable salt thereof, is selected from Table 1. Compound names in Table 1 are compiled using ChemBioDrawUltra, version 12.0 from Cambridge Soft/Chem Office 2010.

Table 1
Numbers, structures and chemical names of compounds 1
2-(4-fluorophenoxy)-N-(2-oxo-1,2-dihydropyridin-4-yl)benzamide 2
2-(4-fluorophenoxy)-N-(2-oxo-1,2-dihydropyridin-4-yl)-5-(trifluoromethyl)benzamide 3
2-(4-fluorophenoxy)-N-(6-oxo-1,6-dihydropyridin-3-yl)benzamide 4
2-(4-fluorophenoxy)-N-(6-oxo-1,6-dihydropyridin-3-yl)-5-(trifluoromethyl)benzamide 5
2-(4-fluorophenoxy)-N-(2-oxo-1,2-dihydropyridin-4-yl)-4-(trifluoromethyl)benzamide 6
2-(4-fluorophenoxy)-N-(6-oxo-1,6-dihydropyridin-3-yl)-4-(trifluoromethyl)benzamide 7
2-(4-fluorophenoxy)-N-(2-oxo-1,2-dihydropyridin-4-yl)-4-(trifluoromethyl)benzamide 8
2-(4-(2-methoxyethoxy)phenoxy)-N-(2-oxo-1,2-dihydropyridin-4-yl)-4-(trifluoromethyl)benzamide 9
N-(2-oxo-1,2-dihydropyridin-4-yl)-2-phenoxy-4-(trifluoromethyl)benzamide 10
2-(4-fluoro-2-methyl-phenoxy)-N-(2-oxo-1,2-dihydropyridin-4-yl)-4-(trifluoromethyl)benzamide eleven
N-(2-oxo-1,2-dihydropyridin-4-yl)-2-(o-tolyloxy)-4-(trifluoromethyl)benzamide 12
N-(2-oxo-1,2-dihydropyridin-4-yl)-2-(p-tolyloxy)-4-(trifluoromethyl)benzamide 13
4-chloro-2-(2,4-difluorophenoxy)-N-(2-oxo-1,2-dihydropyridin-4-yl)benzamide 14
4-chloro-2-(2-chloro-4-fluorophenoxy)-N-(2-oxo-1,2-dihydropyridin-4-yl)benzamide 15
4-chloro-2-(4-fluorophenoxy)-N-(2-oxo-1,2-dihydropyridin-4-yl)benzamide 16
4-chloro-2-(4-fluoro-2-methoxyphenoxy)-N-(2-oxo-1,2-dihydropyridin-4-yl)benzamide 17
4-chloro-2-(2-fluoro-6-methylphenoxy)-N-(2-oxo-1,2-dihydropyridin-4-yl)benzamide 18
4-chloro-2-(2-chloro-6-fluorophenoxy)-N-(2-oxo-1,2-dihydropyridin-4-yl)benzamide 19
4-chloro-2-(2,6-difluorophenoxy)-N-(2-oxo-1,2-dihydropyridin-4-yl)benzamide 20
4-chloro-2-(4-fluoro-2-methylphenoxy)-N-(2-oxo-1,2-dihydropyridin-4-yl)benzamide 21
4-cyano-2-(4-fluorophenoxy)-N-(2-oxo-1,2-dihydropyridin-4-yl)benzamide 22
4-cyano-2-(4-fluoro-2-methoxyphenoxy)-N-(2-oxo-1,2-dihydropyridin-4-yl)benzamide 23
4-cyano-2-(4-fluoro-2-methylphenoxy)-N-(2-oxo-1,2-dihydropyridin-4-yl)benzamide 24
2-(2,4-difluorophenoxy)-N-(2-oxo-1,2-dihydropyridin-4-yl)-5-(trifluoromethyl)benzamide 25
2-(4-cyanophenoxy)-N-(2-oxo-1,2-dihydropyridin-4-yl)-5-(trifluoromethyl)benzamide 26
2-(2,6-difluorophenoxy)-N-(2-oxo-1,2-dihydropyridin-4-yl)-5-(trifluoromethyl)benzamide 27
N-(2-oxo-1,2-dihydropyridin-4-yl)-2-(p-tolyloxy)-5-(trifluoromethyl)benzamide 28
N-(2-oxo-1,2-dihydropyridin-4-yl)-2-(o-tolyloxy)-5-(trifluoromethyl)benzamide 29
2-(2-chloro-4-fluorophenoxy)-N-(2-oxo-1,2-dihydropyridin-4-yl)-5-(trifluoromethyl)benzamide thirty
2-(4-fluoro-2-methoxyphenoxy)-N-(2-oxo-1,2-dihydropyridin-4-yl)-5-(trifluoromethyl)benzamide 31
2-(4-fluoro-2-methylphenoxy)-N-(2-oxo-1,2-dihydropyridin-4-yl)-5-(trifluoromethyl)benzamide 32
N-(2-oxo-1,2-dihydropyridin-4-yl)-2-phenoxy-5-(trifluoromethyl)benzamide 33
2-(2,4-difluorophenoxy)-N-(2-oxo-1,2-dihydropyridin-4-yl)-5-(trifluoromethoxy)benzamide 34
2-(2,6-difluorophenoxy)-N-(2-oxo-1,2-dihydropyridin-4-yl)-5-(trifluoromethoxy)benzamide 35
N-(2-oxo-1,2-dihydropyridin-4-yl)-2-(p-tolyloxy)-5-(trifluoromethoxy)benzamide 36
N-(2-oxo-1,2-dihydropyridin-4-yl)-2-(o-tolyloxy)-5-(trifluoromethoxy)benzamide 37
2-(2-chloro-4-fluorophenoxy)-N-(2-oxo-1,2-dihydropyridin-4-yl)-5-(trifluoromethoxy)benzamide 38
2-(4-fluorophenoxy)-N-(2-oxo-1,2-dihydropyridin-4-yl)-5-(trifluoromethoxy)benzamide 39
2-(2-fluoro-6-methylphenoxy)-N-(2-oxo-1,2-dihydropyridin-4-yl)-5-(trifluoromethoxy)benzamide 40
2-(4-fluoro-2-methylphenoxy)-N-(2-oxo-1,2-dihydropyridin-4-yl)-5-(trifluoromethoxy)benzamide 41
N-(2-oxo-1,2-dihydropyridin-4-yl)-2-phenoxy-5-(trifluoromethoxy)benzamide 42
2-(4-fluoro-2-methoxyphenoxy)-N-(2-oxo-1,2-dihydropyridin-4-yl)-5-(trifluoromethoxy)benzamide 43
2-(4-fluorophenoxy)-N-(2-oxo-1,2-dihydropyridin-4-yl)-6-(trifluoromethyl)benzamide 44
2-(4-ethoxyphenoxy)-N-(2-oxo-1,2-dihydropyridin-4-yl)-5-(trifluoromethyl)benzamide 45
2-(4-methoxyphenoxy)-N-(2-oxo-1,2-dihydropyridin-4-yl)-5-(trifluoromethyl)benzamide 46
2-(2-ethoxyphenoxy)-N-(2-oxo-1,2-dihydropyridin-4-yl)-5-(trifluoromethyl)benzamide 47
2-(2-methoxy-4-methylphenoxy)-N-(2-oxo-1,2-dihydropyridin-4-yl)-5-(trifluoromethoxy)benzamide 48
2-(2-fluoro-6-methoxyphenoxy)-N-(2-oxo-1,2-dihydropyridin-4-yl)-5-(trifluoromethyl)benzamide 49
2-(2-chloro-4-methoxyphenoxy)-N-(2-oxo-1,2-dihydropyridin-4-yl)-5-(trifluoromethyl)benzamide 50
2-(4-chloro-2-methylphenoxy)-N-(2-oxo-1,2-dihydropyridin-4-yl)-5-(trifluoromethyl)benzamide 51
2-(4-chloro-2-fluorophenoxy)-N-(2-oxo-1,2-dihydropyridin-4-yl)-5-(trifluoromethyl)benzamide 52
2-(5-fluoro-2-methoxyphenoxy)-N-(2-oxo-1,2-dihydropyridin-4-yl)-5-(trifluoromethyl)benzamide 53
N-(2-oxo-1,2-dihydropyridin-4-yl)-2-(4-propoxyphenoxy)-5-(trifluoromethyl)benzamide 54
2-(3-fluoro-2-methoxyphenoxy)-N-(2-oxo-1,2-dihydropyridin-4-yl)-5-(trifluoromethyl)benzamide 55
2-(2-fluoro-4-methoxyphenoxy)-N-(2-oxo-1,2-dihydropyridin-4-yl)-5-(trifluoromethyl)benzamide 56
2-(5-fluoro-2-methylphenoxy)-N-(2-oxo-1,2-dihydropyridin-4-yl)-5-(trifluoromethyl)benzamide 57
2-(3-fluoro-5-methoxyphenoxy)-N-(2-oxo-1,2-dihydropyridin-4-yl)-5-(trifluoromethyl)benzamide 58
2-(4-chlorophenoxy)-N-(2-oxo-1,2-dihydropyridin-4-yl)-5-(trifluoromethyl)benzamide 59
2-(3-fluoro-4-methoxyphenoxy)-N-(2-oxo-1,2-dihydropyridin-4-yl)-5-(trifluoromethyl)benzamide 60
N-(6-chloro-2-oxo-1,2-dihydropyridin-4-yl)-2-(4-fluoro-2-methylphenoxy)-5-(trifluoromethyl)benzamide 61
2-(4-fluoro-2-methylphenoxy)-N-(6-methyl-2-oxo-1,2-dihydropyridin-4-yl)-5-(trifluoromethyl)benzamide 62
N-(2-oxo-1,2-dihydropyridin-4-yl)-2-(2-propoxyphenoxy)-5-(trifluoromethyl)benzamide 63
2-(4-methoxy-2-methylphenoxy)-N-(2-oxo-1,2-dihydropyridin-4-yl)-5-(trifluoromethyl)benzamide 64
2-(2-isopropoxyphenoxy)-N-(2-oxo-1,2-dihydropyridin-4-yl)-5-(trifluoromethyl)benzamide 65
2-(2-chlorophenoxy)-N-(2-oxo-1,2-dihydropyridin-4-yl)-5-(trifluoromethyl)benzamide 66
5-chloro-2-(2-chloro-4-fluorophenoxy)-N-(2-oxo-1,2-dihydropyridin-4-yl)benzamide 67
5-chloro-2-(4-fluorophenoxy)-N-(2-oxo-1,2-dihydropyridin-4-yl)benzamide 68
5-chloro-2-(4-fluoro-2-methylphenoxy)-N-(2-oxo-1,2-dihydropyridin-4-yl)benzamide 69
5-chloro-2-(2,4-difluorophenoxy)-N-(2-oxo-1,2-dihydropyridin-4-yl)benzamide 70
5-chloro-2-(4-fluoro-2-methoxyphenoxy)-N-(2-oxo-1,2-dihydropyridin-4-yl)benzamide 71
5-chloro-2-(3-fluoro-4-methoxyphenoxy)-N-(2-oxo-1,2-dihydropyridin-4-yl)benzamide 72
N-(2-oxo-1,2-dihydropyridin-4-yl)-2-(4-(trifluoromethoxy)phenoxy)-5-(trifluoromethyl)benzamide 73
2-(4-(difluoromethoxy)phenoxy)-N-(2-oxo-1,2-dihydropyridin-4-yl)-5-(trifluoromethyl)benzamide 74
N-(2-oxo-1,2-dihydropyridin-4-yl)-5-trifluoromethyl(-2-(4-trifluoromethyl)phenoxy)benzamide 75
N-(2-oxo-1,2-dihydropyridin-4-yl)-2-(2-(trifluoromethoxy)phenoxy)-5-(trifluoromethyl)benzamide 76
2-(2-(difluoromethoxy)phenoxy)-N-(2-oxo-1,2-dihydropyridin-4-yl)-5-(trifluoromethyl)benzamide 77
2-(2-chloro-4-fluorophenoxy)-N-(2-oxo-1,2-dihydropyridin-4-yl)-5-(trifluoromethyl)benzamide 78
2-(4-chlorophenoxy)-N-(2-oxo-1,2-dihydropyridin-4-yl)-4-(trifluoromethyl)benzamide 79
N-(2-oxo-1,2-dihydropyridin-4-yl)-2-(4-trifluoromethoxy)phenoxy)-4-(trifluoromethyl)benzamide 80
N-(2-oxo-1,2-dihydropyridin-4-yl)-2-(2-trifluoromethoxy)phenoxy)-4-(trifluoromethyl)benzamide 81
2-(3-fluoro-4-methoxyphenoxy)-N-(2-oxo-1,2-dihydropyridin-4-yl)-4-(trifluoromethyl)benzamide 82
2-(4-(difluoromethoxy)phenoxy)-N-(2-oxo-1,2-dihydropyridin-4-yl)-5-(trifluoromethyl)benzamide 83
2-(2-(difluoromethoxy)phenoxy)-N-(2-oxo-1,2-dihydropyridin-4-yl)-4-(trifluoromethyl)benzamide 84
2-(2-fluoro-4-methoxyphenoxy)-N-(2-oxo-1,2-dihydropyridin-4-yl)-4-(trifluoromethyl)benzamide 85
2-(4-fluorophenoxy)-N-(1-(2-hydroxyethyl)-2-oxo-1,2-dihydropyridin-4-yl)-4-(trifluoromethyl)benzamide 86
2-(4-fluoro-2-methylphenoxy)-N-(5-methyl-2-oxo-1,2-dihydropyridin-4-yl)-4-(trifluoromethyl)benzamide 87
2-(3-fluoro-2-methoxyphenoxy)-N-(2-oxo-1,2-dihydropyridin-4-yl)-4-(trifluoromethyl)benzamide 88
2-(4-fluorophenoxy)-N-(2-oxo-1,2-dihydropyridin-4-yl)-4-(trifluoromethyl)benzamide 89
2-(3-fluoro-2-methoxyphenoxy)-N-(2-oxo-1,2-dihydropyridin-4-yl)-4-(perfluoroethyl)benzamide 90
N-(2-oxo-1,2-dihydropyridin-4-yl)-5-(trifluoromethyl)-2-(2,3,4-trifluorophenoxy)benzamide 91
N-(2-oxo-1,2-dihydropyridin-4-yl)-5-(trifluoromethyl)-2-(2,3,5-trimethylphenoxy)benzamide 92
2-(2,3-difluoro-4-methylphenoxy)-N-(2-oxo-1,2-dihydropyridin-4-yl)-5-(trifluoromethyl)benzamide 93
N-(2-oxo-1,2-dihydropyridin-4-yl)-5-(trifluoromethyl)-2-(2,4,5-trimethylphenoxy)benzamide 94
5-fluoro-N-(2-oxo-1,2-dihydropyridin-4-yl)-2-(2,3,5-trimethylphenoxy)benzamide 95
5-fluoro-N-(2-oxo-1,2-dihydropyridin-4-yl)-2-phenoxybenzamide 96
2-(4-cyclopropylphenoxy)-5-fluoro-N-(2-oxo-1,2-dihydropyridin-4-yl)benzamide 97
2-(4-(tert-butoxy)phenoxy)-5-fluoro-N-(2-oxo-1,2-dihydropyridin-4-yl)benzamide 98
2-(4-ethoxyphenoxy)-5-fluoro-N-(2-oxo-1,2-dihydropyridin-4-yl)benzamide 99
5-fluoro-2-(4-isopropylphenoxy)-N-(2-oxo-1,2-dihydropyridin-4-yl)benzamide 100
5-fluoro-N-(2-oxo-1,2-dihydropyridin-4-yl)-2-(4-propoxyphenoxy)benzamide 101
5-fluoro-N-(2-oxo-1,2-dihydropyridin-4-yl)-2-(4-(trifluoromethoxy)phenoxy)benzamide 102
5-fluoro-2-(4-(2-methoxyethyl)phenoxy)-N-(2-oxo-1,2-dihydropyridin-4-yl)benzamide 103
2-(2-chloro-4-methoxyphenoxy)-5-fluoro-N-(2-oxo-1,2-dihydropyridin-4-yl)benzamide 104
5-fluoro-2-(4-methoxyphenoxy)-N-(2-oxo-1,2-dihydropyridin-4-yl)benzamide 105
5-fluoro-N-(2-oxo-1,2-dihydropyridin-4-yl)-2-(2,4,5-trimethylphenoxy)benzamide 106
2-(4-fluoro-2-methylphenoxy)-N-(2-oxo-1,2-dihydropyridin-4-yl)-5-(trifluoromethyl)benzamide 107
5-fluoro-N-(2-oxo-1,2-dihydropyridin-4-yl)-2-(4-(2,2,2-trifluoroethoxy)phenoxy)benzamide 108
2-(4-(cyclopropylmethoxy)phenoxy)-5-fluoro-N-(2-oxo-1,2-dihydropyridin-4-yl)benzamide 109
4-chloro-2-(2-chloro-4-fluorophenoxy)-5-fluoro-N-(2-oxo-1,2-dihydropyridin-4-yl)benzamide 110
2-(2-chloro-3-fluoro-4-methoxyphenoxy)-N-(2-oxo-1,2-dihydropyridin-4-yl)-4-(trifluoromethyl)benzamide 111
2-(4-fluoro-2-methoxyphenoxy)-N-(2-oxo-1,2-dihydropyridin-4-yl)-4-(perfluoroethyl)benzamide 112
2-(4-fluoro-2-methylphenoxy)-N-(2-oxo-1,2-dihydropyridin-4-yl)-4-(perfluoroethyl)benzamide 113
4,5-dichloro-2-(4-fluorophenoxy)-N-(2-oxo-1,2-dihydropyridin-4-yl)benzamide 114
4,5-dichloro-2-(4-fluoro-2-methoxyphenoxy)-N-(2-oxo-1,2-dihydropyridin-4-yl)benzamide 115
4,5-dichloro-2-(3-fluoro-4-methoxyphenoxy)-N-(2-oxo-1,2-dihydropyridin-4-yl)benzamide 116
2-(isopentyloxy)-N-(2-oxo-1,2-dihydropyridin-4-yl)-4-(trifluoromethyl)benzamide 117
2-isobutoxy-N-(2-oxo-1,2-dihydropyridin-4-yl)-4-(trifluoromethyl)benzamide 118
2-((2R)-bicyclo[2.2.1]heptan-2-yloxy)-N-(2-oxo-1,2-dihydropyridin-4-yl)-4-(trifluoromethyl)benzamide 119
2-((1-methylcyclopropyl)methoxy)-N-(2-oxo-1,2-dihydropyridin-4-yl)-4-(trifluoromethyl)benzamide 120
2-(cyclopentylmethoxy)-N-(2-oxo-1,2-dihydropyridin-4-yl)-4-(trifluoromethyl)benzamide 121
N-(2-oxo-1,2-dihydropyridin-4-yl)-2-((tetrahydrofuran-3-yl)methoxy)-4-(trifluoromethyl)benzamide 122
2-cyclobutoxy-N-(2-oxo-1,2-dihydropyridin-4-yl)-4-(trifluoromethyl)benzamide 123
N-(2-oxo-1,2-dihydropyridin-4-yl)-2-(4,4,4-trifluorobutoxy)-4-(trifluoromethyl)benzamide 124
2-((2,2-dimethylcyclopropyl)-methoxy)-N-(2-oxo-1,2-dihydropyridin-4-yl)-4-(trifluoromethyl)benzamide 125
2-(( 1R,5S )-bicyclo[3.1.0]hexan-3-yloxy)-N-(2-oxo-1,2-dihydropyridin-4-yl)-4-(trifluoromethyl)benzamide 126
2-((2,2-difluorocyclopropyl)methoxy)-N-(2-oxo-1,2-dihydropyridin-4-yl)-4-(trifluoromethyl)benzamide 127
2-bicyclo[2.2.1]heptan-2-yloxy)-N-(2-oxo-1,2-dihydropyridin-4-yl)-4-(trifluoromethyl)benzamide 128
2-(cyclohexyloxy)-N-(2-oxo-1,2-dihydropyridin-4-yl)-4-(trifluoromethyl)benzamide 129
4-chloro-N-(2-oxo-1,2-dihydropyridin-4-yl)-2-(4,4,4-trifluorobutoxy)benzamide 130
2-(cyclomentylmethoxy)-N-(2-oxo-1,2-dihydropyridin-4-yl)-5-(trifluoromethyl)benzamide 131
2-isobutoxy-N-(2-oxo-1,2-dihydropyridin-4-yl)-5-(trifluoromethyl)benzamide 132
N-(2-oxo-1,2-dihydropyridin-4-yl)-5-(trifluoromethyl)-2-(3,3,3-trifluoropropoxy)benzamide 133
N-(2-oxo-1,2-dihydropyridin-4-yl)-2-(4,4,4-trifluorobutoxy)-5-(trifluoromethyl)benzamide 134
2-((2,2-dimethylcyclopropyl)methoxy)-N-(2-oxo-1,2-dihydropyridin-4-yl)-5-(trifluoromethyl)benzamide 135
2-(( 1R,5S )-bicyclo[3.1.0]hexan-3-yloxy)-N-(2-oxo-1,2-dihydropyridin-4-yl)-4-(trifluoromethyl)benzamide 136
2-(cyclopentylmethoxy)-N-(2-oxo-1,2-dihydropyridin-4-yl)-5-(trifluoromethoxy)benzamide 137
2-(cyclohexyloxy)-N-(2-oxo-1,2-dihydropyridin-4-yl)-5-(trifluoromethoxy)benzamide 138
N-(2-oxo-1,2-dihydropyridin-4-yl)-5-(trifluoromethoxy)-2-(3,3,3-trifluoropropoxy)benzamide 139
N-(2-oxo-1,2-dihydropyridin-4-yl)-2-(4,4,4-trifluorobutoxy)-5-(trifluoromethoxy)benzamide 140
2-((2,2-dimethylcyclopropyl)methoxy)-N-(2-oxo-1,2-dihydropyridin-4-yl)-5-(trifluoromethoxy)benzamide 141
4-(tert-butyl)-N-(2-oxo-1,2-dihydropyridin-4-yl)-2-((6-trifluoromethyl)pyridin-3-yl)oxy)benzamide 142
4-(tert-butyl)-N-(6-oxo-1,6-dihydropyridin-3-yl)-2-((6-trifluoromethyl)pyridin-3-yl)oxy)benzamide 143
4-chloro-N-(2-oxo-1,2-dihydropyridin-4-yl)-2-((6-trifluoromethyl)pyridin-3-yl)oxy)benzamide 144
N-(2-oxo-1,2-dihydropyridin-4-yl)-4-(trifluoromethyl)-2-((6-trifluoromethyl)pyridin-3-yl)oxy)benzamide 145
N-(6-oxo-1,6-dihydropyridin-3-yl)-4-(trifluoromethyl)-2-((6-trifluoromethyl)pyridin-3-yl)oxy)benzamide 146
2-((6-methylpyridin-3-yl)oxy)-N-(2-oxo-1,2-dihydropyridin-4-yl)-4-(trifluoromethyl)benzamide 147
2-((2-methylpyridin-3-yl)oxy)-N-(2-oxo-1,2-dihydropyridin-4-yl)-4-(trifluoromethyl)benzamide 148
4-(tert-butyl)-N-(1-methyl-2-oxo-1,2-dihydropyridin-4-yl)-2-((6-trifluoromethyl)pyridin-3-yl)oxy)benzamide 149
4-(tert-butyl)-N-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)-2-((6-trifluoromethyl)pyridin-3-yl)oxy)benzamide 150
2-((2-methylpyridin-3-yl)oxy)-N-(2-oxo-1,2-dihydropyridin-4-yl)-5-(trifluoromethyl)benzamide 151
2-((2-methylpyridin-3-yl)oxy)-N-(2-oxo-1,2-dihydropyridin-4-yl)-5-(trifluoromethoxy)benzamide 152
2-(2,4-difluorophenoxy)-N-(2-oxo-1,2-dihydropyridin-4-yl)-4,6-bis(trifluoromethyl)benzamide 153
2-(4-fluoro-2-methylphenoxy)-N-(2-oxo-1,2-dihydropyridin-4-yl)-4,6-bis(trifluoromethyl)benzamide 154
2-(4-fluoro-2-methoxyphenoxy)-N-(2-oxo-1,2-dihydropyridin-4-yl)-4,6-bis(trifluoromethyl)benzamide 155
2-(4-fluorophenoxy)-N-(2-oxo-1,2-dihydropyridin-4-yl)-4,6-bis(trifluoromethyl)benzamide 156
N-(2-oxo-1,2-dihydropyridin-4-yl)-2-phenoxy-4,6-bis(trifluoromethyl)benzamide 157
2-(4-fluoro-2-(hydroxymethyl)phenoxy)-N-(2-oxo-1,2-dihydropyridin-4-yl)-4-(trifluoromethyl)benzamide 158
2-(4-fluoro-2-methoxyphenoxy)-N-(2-oxo-1,2-dihydropyridin-4-yl)-4-(trifluoromethyl)benzamide 159
2-((5-fluoro-2-(hydroxybenzyl)oxy)-N-(2-oxo-1,2-dihydropyridin-4-yl)-4-(trifluoromethyl)benzamide 160
5-fluoro-N-(2-oxo-1,2-dihydropyridin-4-yl)-2-(4-(4,4,4-trifluorobutoxy)phenoxy)benzamide

In one embodiment, the compound is 4,5-dichloro-2-(4-fluoro-2-methoxyphenoxy)-N-(2-oxo-1,2-dihydropyridin-4-yl)benzamide or a pharmaceutically acceptable salt thereof.

In another embodiment, the compound is 2-(4-fluoro-2-methoxyphenoxy)-N-(2-oxo-1,2-dihydropyridin-4-yl)-4-(perfluoroethyl)benzamide or a pharmaceutically acceptable salt thereof.

In another embodiment, the compound is 4,5-dichloro-2-(4-fluorophenoxy)-N-(2-oxo-1,2-dihydropyridin-4-yl)benzamide 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-dihydropyridin-4-yl)benzamide or a pharmaceutically acceptable salt thereof.

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 acceptable salt thereof.

In another embodiment, the compound is N-(2-oxo-1,2-dihydropyridin-4-yl)-2-(4-(trifluoromethoxy)phenoxy)-4-(trifluoromethyl)benzamide or a pharmaceutically acceptable salt thereof.

In another embodiment, the compound is 2-(4-fluorophenoxy)-N-(2-oxo-1,2-dihydropyridin-4-yl)-4-(perfluoroethyl)benzamide or a pharmaceutically acceptable salt thereof.

In another embodiment, the compound is 5-chloro-2-(4-fluoro-2-methoxyphenoxy)-N-(2-oxo-1,2-dihydropyridin-4-yl)benzamide or a pharmaceutically acceptable salt thereof.

In another embodiment, the compound is N-(2-oxo-1,2-dihydropyridin-4-yl)-2-(4-(trifluoromethoxy)phenoxy)-5-(trifluoromethyl)benzamide or a pharmaceutically acceptable salt thereof.

In another embodiment, the compound is 2-(4-fluoro-2-methylphenoxy)-N-(2-oxo-1,2-dihydropyridin-4-yl)-4-(trifluoromethyl)benzamide or a pharmaceutically acceptable salt thereof.

In another embodiment, the compound is 2-(4-fluoro-2-methylphenoxy)-N-(2-oxo-1,2-dihydropyridin-4-yl)-5-(trifluoromethyl)benzamide or a pharmaceutically acceptable salt thereof.

In another embodiment, the compound is 2-(2-chloro-4-fluorophenoxy)-N-(2-oxo-1,2-dihydropyridin-4-yl)-5-(trifluoromethyl)benzamide or a pharmaceutically acceptable salt thereof.

In another embodiment, the compound is 5-chloro-2-(4-fluoro-2-methylphenoxy)-N-(2-oxo-1,2-dihydropyridin-4-yl)benzamide or a pharmaceutically acceptable salt thereof.

In another embodiment, the compound is 4-chloro-2-(4-fluoro-2-methylphenoxy)-N-(2-oxo-1,2-dihydropyridin-4-yl)benzamide or a pharmaceutically acceptable salt thereof.

In another embodiment, the compound is 5-chloro-2-(2-chloro-4-fluorophenoxy)-N-(2-oxo-1,2-dihydropyridin-4-yl)benzamide or a pharmaceutically acceptable salt thereof.

In another embodiment, the compound is 2-((5-fluoro-2-hydroxybenzyl)oxy)-N-(2-oxo-1,2-dihydropyridin-4-yl)-4-(trifluoromethyl)benzamide or a pharmaceutically acceptable salt thereof .

In another embodiment, the compound is N-(2-oxo-1,2-dihydropyridin-4-yl)-2-(o-tolyloxy)-5-(trifluoromethyl)benzamide or a pharmaceutically acceptable salt thereof.

In another embodiment, the compound is 2-(2,4-difluorophenoxy)-N-(2-oxo-1,2-dihydropyridin-4-yl)-4-(trifluoromethyl)benzamide or a pharmaceutically acceptable salt thereof.

In another embodiment, the compound is N-(2-oxo-1,2-dihydropyridin-4-yl)-2-(2-(trifluoromethoxy)phenoxy)-5-(trifluoromethyl)benzamide or a pharmaceutically acceptable salt thereof.

In another embodiment, the compound is 2-(4-fluorophenoxy)-N-(2-oxo-1,2-dihydropyridin-4-yl)-5-(trifluoromethyl)benzamide or a pharmaceutically acceptable salt thereof.

Salt. Compositions. Application. Compound. Introduction and Additional Agents

Pharmaceutically acceptable salts and compositions

As described herein, this invention provides compounds that are voltage-gated sodium channel inhibitors and, thus, these compounds are useful for the treatment of diseases, disorders and conditions, including, but not limited to, chronic pain, bowel pain, neuropathic pain, muscle -skeletal pain, acute pain, inflammatory pain, cancer pain, idiopathic pain, multiple sclerosis, Charcot-Marie-Tooth syndrome, urinary incontinence or cardiac arrhythmia. Therefore, in another aspect of the present invention, pharmaceutically acceptable compositions are provided, wherein the compositions contain any compound such as described herein, and optionally contain a pharmaceutically acceptable carrier, adjuvant or excipient. In certain embodiments, these compositions optionally also include one or more additional therapeutic agents.

It is also understood that certain compounds in accordance with this invention may exist in free form for treatment or, where applicable, in the form of pharmaceutically acceptable derivatives thereof.

In accordance with this invention, a pharmaceutically acceptable derivative includes, but is not limited to, pharmaceutically acceptable salts, esters, salts of such esters, or any other product or derivative that, when administered to a patient in need thereof, is capable of providing, directly or indirectly, a compound described herein or a metabolite or residue thereof.

As used herein, the term "pharmaceutically acceptable salt" refers to salts that, from a medical point of view, can be used in contact with tissues of humans and lower animals without causing toxicity, irritation, allergic reaction, or the like, and are commensurate with a reasonable benefit/risk ratio. "Pharmaceutically acceptable salt" means any non-toxic salt or ester salt of a compound of this invention which, when administered to a patient, produces, directly or indirectly, a compound of this invention or a metabolite or residue thereof having an inhibitory effect. As used herein, the term “metabolite or residue thereof having an inhibitory effect” also means a voltage-gated sodium channel inhibitor.

Pharmaceutically acceptable salts are well known in the art. For example, S. M. Berge, et al . Pharmaceutically acceptable salts are described in detail in J. Pharmaceutical Sciences , 1977 , 66, 1-19, incorporated herein by reference. Pharmaceutically acceptable salts of the compounds of this invention include salts derived from suitable inorganic and organic acids and bases. Examples of pharmaceutically acceptable non-toxic acid addition salts include amino salts formed with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid, or with organic acids such as acetic acid, oxalic acid, maleic acid , tartaric acid, citric acid, succinic acid or malonic acid, or using other methods used in the art, such as ion exchange. Other pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentane propionate, digluconate, dodecyl sulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptano at , hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalene sulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate , phosphate, picrate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, undecanoate, valerate and the like. Salts derived from suitable bases include alkali metal, alkaline earth metal, ammonium and N ⁺ (C _1-4 alkyl) ₄ salts. This invention also provides quaternization of any basic nitrogen-containing groups in the compounds described herein. Products soluble or dispersible in water or oil can be obtained by such quaternization. Exemplary alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium or the like salts. Other pharmaceutically acceptable salts include, when applicable, non-toxic ammonium, quaternary ammonium and amine cations prepared using counterions such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, lower alkyl sulfonate and arylsulfonate.

As described herein, pharmaceutically acceptable compositions in accordance with this invention further contain a pharmaceutically acceptable carrier, adjuvant or excipient, which, as used herein, includes any and all solvents, diluents or other liquid carriers, dispersing or suspending additives, surfactants , isotonic agents, thickening or emulsifying agents, preservatives, solid binding agents, lubricants and the like, suitable for the particular dosage form desired. Remington's Pharmaceutical Sciences, Sixteenth Edition, E. W. Martin (Mack Publishing Co., Easton, Pa., 1980) describes various excipients useful in formulating pharmaceutically acceptable compositions and known methods for preparing them. s and known techniques for the preparation thereof. Except to the extent that any conventional carrier is incompatible with the compounds of this invention, eg, has an undesirable biological effect or interacts in an undesirable manner with any other components of the pharmaceutically acceptable composition, its use is included within the scope of this invention. Some examples of materials that may be pharmaceutically acceptable carriers include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, serum proteins such as human serum albumin, buffers such as phosphates, glycine, sorbic acid or sorbate potassium, mixtures of partial glycerides of saturated vegetable fatty acids, water, salts or electrolytes such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silicon dioxide, magnesium trisilicate, polyvinylpyrrolidone, polyacrylates, waxes, polyethylene-polyoxypropylene block polymers , lanolin, sugars such as lactose, glucose and sucrose; starches such as corn starch and potato starch; cellulose and its derivatives such as sodium carboxymethylcellulose, ethylcellulose and cellulose acetate; powdered tragacanth; malt; gelatin; talc; fillers such as cocoa butter and suppository waxes; oils such as peanut oil, cottonseed oil; safflower oil; Sesame oil; olive oil; corn oil and soybean oil; glycols; for example propylene glycol or polyethylene glycol; esters such as ethyl oleate and ethyl laurate; agar; buffering agents such as magnesium hydroxide and aluminum hydroxide; alginic acid; pyrogen-free water; isotonic saline solution; Ringer's solution; ethyl alcohol and phosphate buffer solutions, as well as other non-toxic compatible lubricants such as sodium lauryl sulfate and magnesium stearate, as well as dyes, release agents, coating agents, sweeteners, flavors and fragrances, preservatives and antioxidants may also be present in the composition, according to the opinion of the compiler.

In another aspect, the present invention includes pharmaceutical compositions comprising a compound of the present invention and a pharmaceutically acceptable carrier.

In another aspect, the present invention includes pharmaceutical compositions containing a therapeutically effective amount of a compound or a pharmaceutically acceptable salt thereof selected from the compounds of Formula I or Formula I', and one or more pharmaceutically acceptable carriers or excipients.

Use of compounds and pharmaceutically acceptable salts and compositions

In another aspect, the present invention includes a method of inhibiting a voltage-gated sodium channel in a patient, comprising administering to the patient a compound of Formula I or Formula I', or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof. In another aspect, the voltage-gated sodium channel is Na _v 1.8.

In yet another aspect, the invention includes a method of treating or reducing the severity of a patient's chronic pain, bowel pain, neuropathic pain, muscle pain, acute pain, inflammatory pain, cancer pain, idiopathic pain, multiple sclerosis, Charcot-Marie-Tooth syndrome, incontinence urine or cardiac arrhythmia, comprising administering an effective amount of a compound, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition selected from compounds of formula I or formula I'.

In yet another aspect, the present invention includes a method of treating or reducing the severity of bowel pain in a patient, wherein the bowel pain includes inflammatory bowel disease pain, Crohn's disease pain, or interstitial cystitis pain, wherein the method comprises administering an effective amount of a compound, a pharmaceutically acceptable amount thereof salt or pharmaceutical composition selected from compounds of formula I or formula I'.

In yet another aspect, the invention includes a method of treating or reducing the severity of neuropathic pain in a patient, wherein the neuropathic pain includes postherpetic neuralgia, diabetic neuralgia, painful HIV-associated sensory neuropathy, trigeminal neuralgia, burning mouth syndrome, post-amputation pain, phantom pain , painful neuromas; traumatic neuroma; Morton's neuroma; pinched nerve, spinal stenosis, carpal tunnel syndrome, radiculitis, inflammation of the sciatic nerve; avulsion of the nerve, avulsion of the brachial plexus; reflex sympathetic dystrophy, drug therapy-induced neuralgia, cancer chemotherapy-induced neuralgia, antiretroviral therapy-induced neuralgia; pain following spinal cord injury, idiopathic small fiber neuropathy, idiopathic sensory neuropathy, or trigeminal autonomic cephalalgia, wherein the method comprises administering an effective amount of a compound, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition selected from compounds of formula I or formula I'.

In yet another aspect, the present invention includes a method of treating or reducing the severity of musculoskeletal pain in a patient, wherein the musculoskeletal pain includes osteoarthritis pain, back pain, cold pain, burn pain, or dental pain, wherein the method includes administering an effective amount of a compound, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition selected from compounds of formula I or formula I'.

In yet another aspect, the invention includes a method of treating or reducing the severity of inflammatory pain in a patient, wherein the inflammatory pain includes pain due to rheumatoid arthritis or vulvodynia, wherein said method comprises administering an effective amount of a compound, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition selected from compounds of the formula I or formula I'.

In yet another aspect, the invention includes a method of treating or reducing the severity of idiopathic pain in a patient, wherein the idiopathic pain includes fibromyalgia, wherein said method comprises administering an effective amount of a compound, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition selected from compounds of Formula I or Formula I' .

In yet another aspect, the present invention includes a method in which a patient is treated with one or more therapeutic agents administered simultaneously with, before or after treatment, an effective amount of a compound, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition selected from compounds of Formula I or Formula I'.

In another aspect, the present invention includes a method of inhibiting a voltage-gated sodium channel in a patient, comprising administering to the patient an effective amount of a compound, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition selected from compounds of Formula I or Formula I'. In another aspect, the voltage-gated sodium channel is Na _v 1.8.

In another aspect, the present invention includes a method of inhibiting a voltage-gated sodium channel in a biological sample, comprising contacting the biological sample with an effective amount of a compound, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition selected from compounds of Formula I or Formula I'. In another aspect, the voltage-gated sodium channel is Na _v 1.8.

In another aspect, the invention includes a method of treating or reducing the severity of acute pain, chronic pain, neuropathic pain, inflammatory pain, arthritis, migraines, headaches, trigeminal neuralgia, herpetic neuralgia, general neuralgia, epilepsy, epilepsy conditions, neurodegenerative disorders in a patient. , psychiatric disorders, anxiety, depression, bipolar disorder, myotonia, arrhythmias, movement disorders, neuroendocrine disorders, ataxia, multiple sclerosis, irritable bowel syndrome, urinary incontinence, visceral pain, osteoarthritis pain, postherpetic neuralgia, diabetic neuropathy, sciatica, sciatic nerve inflammation , back pain, headache, neck pain, severe pain, intractable pain, nociceptive pain, breakthrough pain, post-operative pain, cancer pain, stroke, cerebral ischemia, traumatic brain injury, amyotrophic lateral sclerosis, stress-induced angina , exercise-induced angina, hypertension, or abnormal gastrointestinal motility, wherein the method comprises administering an effective amount of a compound, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition selected from compounds of formula I or formula I'.

In another aspect, the present invention includes a method of treating or reducing the severity of hip cancer pain in a patient; non-malignant chronic bone pain; rheumatoid arthritis; osteoarthritis; spinal canal stenosis; neuropathic lower back pain; myofascial pain syndrome; fibromyalgia; temporomandibular joint pain; chronic visceral pain, abdominal pain; pain in the pancreas; IBS pain; chronic and acute headache; migraine; tension headaches; histamine headaches; chronic and acute neuropathic pain, postherpetic neuralgia; diabetic neuropathy; HIV-associated neuropathies; trigeminal neuralgia; Charcot-Marie-Tooth neuropathies; hereditary sensory neuropathies; peripheral nerve injuries; painful neuromas; pain, ectopic proximal and distal discharge; radiculopathy; neuropathic pain caused by chemotherapy; neuropathic pain caused by radiation therapy; pain after mastectomy; central pain; pain due to spinal cord injury; pain after a stroke; thalamic pain; reflex sympathetic dystrophy; phantom pain; uncontrollable pain; acute pain, acute postoperative pain; acute musculoskeletal pain; joint pain; mechanical osteochondrosis; neck pain; tendinitis; pain from injury/exercise; acute visceral pain; pyelonephritis; appendicitis; cholecystitis; intestinal obstruction; hernias; chest pain, heart pain; pain in the pelvic area, pain due to renal colic, acute obstetric pain, labor pains; pain during caesarean section; acute pain due to inflammation, burns and injury; acute periodic pain, endometriosis; acute herpes zoster; sickle cell anemia; acute pancreatitis; pain when breaking through; maxillofacial pain; sinusitis; toothache; multiple sclerosis (MS); pain due to depression; leprosy pain; pain due to Behçet's disease; morbid obesity; phlebitic pain; Guillain-Barre pain; painful legs and toes; Haglund syndrome; erythromelalgia; pain due to Fabry disease; diseases of the bladder and genitourinary system; urinary incontinence; overactive bladder; painful bladder syndrome; interstitial cystitis (IC); prostatitis; regional pain syndrome complex (CRPS), type I and type II; generalized pain, cramping severe pain, itching, tinnitus or pain caused by angina pectoris, wherein the method comprises administering an effective amount of a compound, a pharmaceutically acceptable salt thereof or a pharmaceutical composition selected from compounds of formula I or formula I'.

In another aspect, the present invention includes a method of treating or reducing the severity of neuropathic pain in a patient, comprising administering an effective amount of a compound, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition selected from compounds of Formula I or Formula I'. In one aspect, the neuropathic pain is selected from postherpetic neuralgia, diabetic neuralgia, painful HIV-related sensory neuropathy, trigeminal neuralgia, burning mouth syndrome, post-amputation pain, phantom pain, painful neuroma, traumatic neuroma, Morton's neuroma, entrapment nerve, stenosis spinal canal, carpal tunnel syndrome, sciatica, sciatic nerve inflammation, nerve avulsion, brachial plexus avulsion, complex regional pain syndrome, drug therapy-induced neuralgia, cancer chemotherapy-induced neuralgia, antiretroviral therapy-induced neuralgia, pain after spinal cord injury, idiopathic small fiber neuropathy, idiopathic sensory neuropathy or trigeminal autonomic cephalalgia.

Production of medicines

In one aspect, this invention provides the use of a compound or pharmaceutical composition described herein for the manufacture of a medicament useful for inhibiting a voltage-gated sodium channel. In another aspect, the voltage-gated sodium channel is Na _v 1.8.

In yet another aspect, this invention provides the use of a compound or pharmaceutical composition described herein for the manufacture of a medicament used to treat or reduce severity in a patient suffering from chronic pain, bowel pain, neuropathic pain, muscle pain, acute pain, inflammatory pain , cancer pain, idiopathic pain, multiple sclerosis, Charcot-Marie-Tooth syndrome, urinary incontinence or cardiac arrhythmia.

In yet another aspect, this invention provides the use of a compound or pharmaceutical composition described herein for the manufacture of a medicament used to treat or reduce the severity of a patient suffering from bowel disease, wherein bowel pain includes inflammatory bowel disease pain, disease pain Crohn's pain or interstitial cystitis pain.

In yet another aspect, this invention provides the use of a compound or pharmaceutical composition described herein for the manufacture of a medicament used to treat or reduce severity in a patient suffering from neuropathic pain, wherein the neuropathic pain includes postherpetic neuralgia, diabetic neuralgia, HIV-related pain sensory neuropathy, trigeminal neuralgia, burning mouth syndrome, pain after amputation, phantom pain, painful neuromas; traumatic neuroma; Morton's neuroma; pinched nerve, spinal stenosis, carpal tunnel syndrome, radiculitis, inflammation of the sciatic nerve; avulsion of the nerve, avulsion of the brachial plexus; complex regional pain syndrome, drug therapy-induced neuralgia, cancer chemotherapy-induced neuralgia, antiretroviral therapy-induced neuralgia; pain after spinal cord injury, idiopathic small fiber neuropathy, idiopathic sensory neuropathy, or trigeminal autonomic neuropathy.

In yet another aspect, the present invention provides the use of a compound or pharmaceutical composition described herein for the manufacture of a medicament used to treat or reduce severity in a patient suffering from musculoskeletal pain, wherein the musculoskeletal pain includes osteoarthritis pain, pain in back, pain caused by cold, pain from burns or toothache.

In yet another aspect, the present invention provides the use of a compound or pharmaceutical composition described herein for the manufacture of a medicament used to treat or reduce the severity of a patient suffering from inflammatory pain, wherein the inflammatory pain includes rheumatoid arthritis pain or vulvodynia.

In yet another aspect, the present invention provides the use of a compound or pharmaceutical composition described herein for the manufacture of a medicament used to treat or reduce severity in a patient suffering from idiopathic pain, wherein the idiopathic pain includes fibromyalgia.

In yet another aspect, the present invention provides the use of a compound or pharmaceutical composition described herein for the manufacture of a drug in combination with one or more additional therapeutic agents administered concomitantly with, before, or after treatment with the compound or pharmaceutical composition.

In another aspect, this invention provides the use of a compound or pharmaceutical composition described herein for the manufacture of a medicament used to treat or reduce the severity of acute pain, chronic pain, neuropathic pain, inflammatory pain, arthritis, migraine, headaches, trigeminal neuralgia , herpetic neuralgia, common neuralgias, epilepsy, epilepsy conditions, neurodegenerative disorders, psychiatric disorders, anxiety, depression, bipolar disorder, myotonia, arrhythmias, movement disorders, neuroendocrine disorders, ataxia, multiple sclerosis, irritable bowel syndrome, urinary incontinence, visceral pain, osteoarthritis pain, postherpetic neuralgia, diabetic neuropathy, sciatica, sciatic nerve inflammation, back pain, headache, neck pain, severe pain, intractable pain, nociceptive pain, breakthrough pain, post-operative pain, cancer pain, stroke, cerebral ischemia , traumatic brain injury, amyotrophic lateral sclerosis, stress-induced angina, exercise-induced angina, hypertension, or abnormal gastrointestinal motility.

In another aspect, this invention provides the use of a compound or pharmaceutical composition described herein for the manufacture of a medicament used to treat or reduce the severity of pain in hip cancer; non-malignant chronic bone pain; rheumatoid arthritis; osteoarthritis; spinal canal stenosis; neuropathic lower back pain; myofascial pain syndrome; fibromyalgia; temporomandibular joint pain; chronic visceral pain, abdominal pain; pain in the pancreas; IBS pain; chronic and acute headache; migraine; tension headaches; histamine headaches; chronic and acute neuropathic pain, postherpetic neuralgia; diabetic neuropathy; HIV-associated neuropathies; trigeminal neuralgia; Charcot-Marie-Tooth neuropathies; hereditary sensory neuropathies; peripheral nerve injuries; painful neuromas; pain, ectopic proximal and distal discharge; radiculopathy; neuropathic pain caused by chemotherapy; neuropathic pain caused by radiation therapy; pain after mastectomy; central pain; pain due to spinal cord injury; pain after a stroke; thalamic pain; reflex sympathetic dystrophy; phantom pain; uncontrollable pain; acute pain, acute postoperative pain; acute musculoskeletal pain; joint pain; mechanical osteochondrosis; neck pain; tendinitis; pain from injury/exercise; acute visceral pain; pyelonephritis; appendicitis; cholecystitis; intestinal obstruction; hernias; chest pain, heart pain; pain in the pelvic area, pain due to renal colic, acute obstetric pain, labor pains; pain during caesarean section; acute pain due to inflammation, burns and injury; acute periodic pain, endometriosis; acute herpes zoster; sickle cell anemia; acute pancreatitis; pain when breaking through; maxillofacial pain; sinusitis; toothache; multiple sclerosis (MS); pain due to depression; leprosy pain; pain due to Behçet's disease; morbid obesity; phlebitic pain; Guillain-Barre pain; painful legs and toes; Haglund syndrome; erythromelalgia; pain due to Fabry disease; diseases of the bladder and genitourinary system; urinary incontinence; overactive bladder; painful bladder syndrome; interstitial cystitis (IC); prostatitis; regional pain syndrome complex (CRPS), type I and type II; widespread pain, cramping severe pain, itching, tinnitus or pain caused by angina.

In another aspect, the present invention provides the use of a compound or pharmaceutical composition described herein for the manufacture of a medicament used to treat or reduce the severity of neuropathic pain. In one aspect, the neuropathic pain is selected from postherpetic neuralgia, diabetic neuralgia, painful HIV-related sensory neuropathy, trigeminal neuralgia, burning mouth syndrome, post-amputation pain, phantom pain, painful neuroma, traumatic neuroma, Morton's neuroma, entrapment nerve, stenosis spinal canal, carpal tunnel syndrome, sciatica, sciatic nerve inflammation, nerve avulsion, brachial plexus avulsion, complex regional pain syndrome, drug therapy-induced neuralgia, cancer chemotherapy-induced neuralgia, antiretroviral therapy-induced neuralgia, pain after spinal cord injury, idiopathic small fiber neuropathy, idiopathic sensory neuropathy or trigeminal autonomic cephalalgia.

Administration of pharmaceutically acceptable salts and compositions.

In certain embodiments, an "effective amount" of a compound, a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable composition is an amount effective to treat or reduce the severity of one or more of chronic pain, bowel pain, neuropathic pain, muscle pain, acute pain, inflammatory pain, cancer pain, idiopathic pain, multiple sclerosis, Charcot-Marie-Tooth syndrome, urinary incontinence or cardiac arrhythmia.

The compounds and compositions of this invention may be administered using any amount and any route of administration effective to treat or reduce the severity of one or more of the pain or non-pain diseases listed herein. The exact amount needed may vary from patient to patient depending on the species, age and general health of the patient, severity of the infection, the specific agent, route of administration, and similar factors. The compounds of this invention are preferably formulated in unit dosage forms for ease of administration and dose uniformity. The expression "unit dosage form" as used herein refers to a physically discrete unit of agent suitable for the patient being treated. It is understood, however, that the total daily dosage of the compounds and compositions of the present invention is determined by the attending physician in accordance with medical judgment. The specific effective dose for a particular patient or organism depends on numerous factors, including the disorder being treated and the severity of the disorder; the activity of the particular compound used; the specific composition used; the patient's age, weight, general health, gender, and diet; time of administration, route of administration and rate of elimination of the particular compound used; duration of treatment; drugs used in combination or in conjunction with the particular compound used and similar factors well known in the medical field. The term "subject" or "patient" as used herein means an animal, preferably a mammal, most preferably a human.

The pharmaceutically acceptable composition in accordance with this invention can be administered to humans and other animals orally, rectally, parenterally, intracisternally, intravaginally, intraperitoneally, topically (in the form of powders, ointments or drops), buccally, as an oral or gas spray and the like, depending depending on the severity of the infection being treated. In certain embodiments, the compounds of this invention may be administered orally or parenterally in doses of from about 0.01 mg/kg to about 50 mg/kg, and preferably from about 1 mg/kg to about 25 mg/kg of the patient's body weight per day, one or more times per day, to obtain the desired therapeutic effect.

Liquid dosage forms for oral administration include, but are not limited to, pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs. In addition to the active compounds, liquid dosage forms may contain inert diluents commonly used in the art, such as, for example, water or other solvents, solubilizing agents and emulsifiers, such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate , propylene glycol, 1,3-butylene glycol, dimethylformamide, oils (especially cottonseed, peanut, corn, germ, castor and hemp oils), glycerin, tetrahydrofurfuryl alcohol, polyethylene glycols and sorbitan fatty acid esters, and mixtures thereof. In addition to inert diluents, oral compositions may also include adjuvants such as wetting agents, emulsifying and suspending agents, sweeteners, flavoring agents and fragrances.

Injectable preparations, for example, sterile aqueous or oleaginous injectable suspensions, can be formulated by methods in the art using suitable dispersing or wetting agents and suspending agents. A sterile injectable preparation may also be a sterile injectable solution, suspension or emulsion in a non-toxic parenterally acceptable diluent or solvent, for example, a solution in 1,3-butanediol. Acceptable vehicles and solvents that may be used include water, Ringer's solution, U.S.P. and isotonic sodium chloride solution. In addition, fixed oils are usually used as a solvent or suspending medium. Any soft, fixed oil can be used for this purpose, including synthetic mono- or diglycerides. In addition, fatty acids such as oleic acid are used to prepare injectable preparations.

Injectable compositions may be sterilized, for example, by filtration through a bacteria-trapping filter or by the addition of sterilizing agents in the form of sterile solid compositions that can be dissolved or dispersed in sterile water or other sterile injectable media prior to use.

To prolong the effect of a compound of the present invention, it is often desirable to slow down the absorption of the compound from subcutaneous or intramuscular injection. This can be achieved by using a liquid suspension of crystalline or amorphous materials with poor water solubility. The rate of absorption of a compound depends on the rate of its dissolution which, in turn, may depend on crystal size and crystalline form. Alternatively, delayed absorption of a parenterally administered compound is achieved by dissolving or suspending the compound in an oily vehicle. Injectable depots are prepared by forming a microencapsulating matrix of the compound in biodegradable polymers such as polylactide-polyglycolide. Depending on the ratio of the compound to the polymer and the nature of the particular polymer used, the rate of release of the compound can be controlled. Examples of other biodegradable polymers include poly(orthoesters) and poly(anhydrides). Injectable depots are also prepared by enclosing the compound in liposomes or microemulsions that are compatible with body tissues.

Compositions for rectal or vaginal administration preferably include suppositories, which can be prepared by mixing the compounds of this invention with suitable non-irritating excipients or carriers, such as cocoa butter, polyethylene glycol or suppository wax, which are solid at ambient temperature but become liquid at body temperature and melt in the rectum or vaginal cavity to release the active compound.

Solid dosage forms for oral administration include capsules, tablets, pills, powders and granules. In such solid dosage forms, the active compound is mixed with at least one inert pharmaceutically acceptable excipient or carrier such as sodium citrate or dicalcium phosphate and/or a) excipients or diluents such as starches, lactose, sucrose, glucose, mannitol and silicic acid, b) binders such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose and acacia, c) humectants such as glycerin, d) leavening agents such as agar-agar, calcium carbonate, potato starch or tapioca starch, alginic acid, certain silicates and sodium carbonate, e) dissolution retarding agents such as paraffin, f) absorption accelerators such as quaternary ammonium compounds, g) wetting agents such as, for example, cetyl alcohol and glycerol monostearate, h) absorbents such as kaolin and bentonite clay; and i) lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate and mixtures thereof. In the case of capsules, tablets and pills, the dosage form may also contain buffering agents.

Solid compositions of this type can also be used as fillers for soft and hard gelatin capsules using fillers such as lactose or milk sugar, as well as high molecular weight polyethylene glycols and the like. Solid dosage forms in the form of tablets, dragees, capsules, pills and granules can be prepared with coatings well known in the art of pharmaceutical compositions. They may optionally contain opacifying agents and may also be a composition that releases the active ingredient(s) only or preferentially in a specific part of the intestinal tract, optionally in a delayed manner. Examples of useful encapsulating compositions include polymeric substances and waxes. Solid compositions of this type can also be used as fillers for soft and hard gelatin capsules using fillers such as lactose or milk sugar, as well as high molecular weight polyethylene glycols and the like.

The active compounds may also be in microencapsulated form with one or more of the excipients listed above. Solid dosage forms in the form of tablets, dragees, capsules, pills and granules can be prepared with coatings and shells, such as enteric coatings, release control coatings and other coatings well known in the pharmaceutical field. In such solid dosage forms, the active compound may be mixed with at least one inert diluent such as sucrose, lactose or starch. Such dosage forms may also, in normal practice, contain additional substances other than inert diluents, for example, tabletting lubricants and other tabletting additives such as magnesium stearate and microcrystalline cellulose. In the case of capsules, tablets and pills, dosage forms may also contain buffering agents. They may optionally contain opacifying agents and may also be a composition that releases the active ingredient(s) only or preferentially in a specific part of the intestinal tract, optionally in a delayed manner. Examples of useful encapsulating compositions include polymeric substances and waxes.

Dosage forms for topical or transdermal administration of a compound in accordance with this invention include ointments, pastes, creams, lotions, gels, powders, solutions, sprays, inhalers or patches. The active ingredient is mixed under sterile conditions with a pharmaceutically acceptable carrier and any necessary preservatives or buffers that may be required. Ophthalmic compositions, ear drops and eye drops are also included within the scope of this invention. Additionally, the present invention includes the use of transdermal patches, which have the additional benefits of controlled delivery of the compound to the body. Such dosage forms are prepared by dissolving or dispersing the compound in a suitable medium. Absorption enhancers can also be used to increase the flux of a compound through the skin. The rate can be controlled either by a rate-controlling membrane or by dispersing the compound in a polymer matrix or gel.

As described above, the compounds of this invention are useful as inhibitors of voltage-gated sodium channels. In one embodiment, the compounds and compositions of this invention are Na _v 1.8 inhibitors and therefore, without wishing to be bound by any particular theory, the compounds and compositions are particularly useful for treating or reducing the severity of a disease, condition or disorder in which activation or Na _v 1.8 hyperactivity is involved in a disease, condition or disorder. When activation or hyperactivity of Na _v 1.8 is involved in a specific disease, condition or disorder, the disease, condition or disorder may also be referred to as a "Na _v 1.8-mediated disease, condition or disorder". Therefore, in another aspect, the invention provides a method of treating or reducing the severity of a disease, condition or disorder in which activation or hyperactivity of Na _v 1.8 is involved in the disease state.

The activity of a compound used in accordance with this invention as a Na _v 1.8 inhibitor can be assayed using the methods described in the examples herein or those available to one skilled in the art.

Additional therapeutic agents

It should also be understood that the compounds and pharmaceutically acceptable compositions of this invention may be used in combination therapy, that is, the compounds and pharmaceutically acceptable compositions may be administered concomitantly with, before, or after one or more other desired therapeutic agents or medical procedures. Specific combinations of therapies (therapeutic agents or procedures) to be used in a combination regimen must take into account the compatibility of the desired therapeutic agents and/or procedures and the desired therapeutic effect to be achieved. It will also be appreciated that the therapies used may provide the desired effect for the same disorder (e.g., a compound of the present invention may be administered concomitantly with another agent to treat the same disorder) or they may provide different effects (e.g., control which - side effects). As used herein, additional therapeutic agents that are typically administered to treat or prevent a particular disease or condition are known as “suitable for the disease or condition being treated.” For example, typical additional therapeutic agents include, but are not limited to: non-opioid analgesics (indoles such as etodolac, indomethacin, sulindac, tolmetin; naphthylalkanones such as nabumetone; oxicams such as piroxicam; para-aminophenol derivatives such as acetaminophen; propionic acids such as fenoprofen, flurbiprofen, ibuprofen, ketoprofen, naproxen, naproxen sodium, oxaprozin; salicylates such as aspirin, choline magnesium trisalicylate, diflunisal; fenamates such as meclofenamic acid, mefenamic acid; and pyrazoles such as phenylbutazone); or opioid (narcotic) agonists (eg, codeine, fentanyl, hydromorphone, levorphanol, meperidine, methadone, morphine, oxycodone, oxymorphone, propoxyphene, buprenorphine, butorphanol, dezocine, nalbuphine, and pentazocine). Additionally, non-drug analgesic approaches can be used in combination with the administration of one or more compounds in accordance with this invention. For example, anesthetic (intraspinal infusion, nerve block), neurosurgical (neurolysis of CNS tracts), neurostimulatory (transcutaneous electrical muscle stimulation, dorsal column stimulation), physical (physiotherapy, orthopedic devices, diathermy) or psychological (cognitive hypnosis techniques, biofeedback or behavioral techniques ) approaches can also be used. Additional suitable therapeutic agents or approaches are described generally in The Merck Manual, Nineteenth Edition, Ed. Robert S. Porter and Justin L. Kaplan, Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., 2011, and on the Food and Drug Administration website, www.fda.gov, the full contents of which are included herein as a reference.

In another embodiment, additional suitable therapeutic agents are selected from the following:

(1) an opioid analgesic, for example, morphine, heroin, hydromorphone, oxymorphone, levorphanol, levallorphan, methadone, meperidine, fentanyl, cocaine, codeine, dihydrocodeine, oxycodone, hydrocodone, propoxyphene, nalmefene, nalorphine, naloxone, naltrexone, buprenorphine, butorphanol, nalbuphine or pentazocine;

(2) a nonsteroidal anti-inflammatory drug (NSAID), such as aspirin; diclofenac, diflunisal, etodolac, fenbufen, fenoprofen, flufenisal, flurbiprofen, ibuprofen, indomethacin, ketoprofen, ketorolac, meclofenamic acid, mefenamic acid, meloxicam, nabumetone, naproxen, nimesulide, nitroflurbiprofen, olsalazine, oxapro zine, phenylbutazone, piroxicam, sulfasalazine, sulindac, tolmetin or zomepirac;

(3) a barbiturate sedative, for example, amobarbital, aprobarbital, butabarbital, mephobarbital, metatarbital, methohexital, pentobarbital, phenobarbital, secobarbital, talbutal, thiamylal or thiopental;

(4) a benzodiazepine having a sedative effect, for example, chlordiazepoxide, clorazepate, diazepam, lorazepam, flurazepam, oxazepam, temazepam or triazolam;

(5) a histamine antagonist (Hi) having a sedative effect, for example, diphenhydramine, pyrilamine, promethazine, chlorpheniramine or chlorcyclizine;

(6) a sedative such as glutethimide, meprobamate, methaqualone or dichloralphenazone;

(7) a muscle relaxant, for example, baclofen, carisoprodol, chlorzoxazone, cyclobenzaprine, methocarbamol or orphenadrine;

(8) an NMDA receptor antagonist, for example, dextromethorphan ((+)-3-hydroxy-N-methylmorphinan) or its metabolite dextrorphan ((+)-3-hydroxy-N-methylmorphinan), ketamine, memantine, pyrroloquinoline quinone, cis- 4-(phosphonomethyl)-2-piperidinecarboxylic acid, budipine, EN-3231 (MorphiDex®), morphine and dextromethorphan combination formulation), topiramate, neramexane or perzinoftel, including an NR2B antagonist such as ifenprodil, traxoprodil or (-)-(R )-6-{2-[4-(3-fluorophenyl)-4-hydroxy-L-piperidinyl]-L-hydroxyethyl-3,4-O-dihydro-2(1H)-quinolinone;

(9) an alpha-adrenergic agent, for example, doxazosin, tamsulosin, clonidine, guanfacine, dexmedetomidine, modafinil or 4-amino-6,7-dimethoxy-2-(5-methanesulfonamido-1,2,3,4-tetrahydroisoquinoline-2 -yl)-5-(2-pyridyl)quinazoline;

(10) a tricyclic antidepressant, for example, desipramine, imipramine, amitriptyline or nortriptyline;

(11) an anticonvulsant, for example, carbamazepine (Tegretol®), lamotrigine, topiramate, lacosamide (Vimpat®) or valproate;

(12) a tachykinin (NK) antagonist, in particular an NK-3, NK-2 or NK-1 antagonist, for example (alphaR,9R)-7-[3,5-bis(trifluoromethyl)benzyl]-8,9 ,10,11-tetrahydro-9-methyl-5-(4-methylphenyl)-7H-[1,4]diazocino[2,1-g][1,7]-naphthyridine-6-13-dione (TAK- 637), 5-[[(2R,3S)-2-[(1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethoxy-3-(4-fluorophenyl)-4-morpholinyl]-methyl] -1,2-dihydro-3H-1,2,4-triazol-3-one (MK-869), aprepitant, lanepitant, dapitant or 3-[[2-methoxy-5-(trifluoromethoxy)phenyl]-methylamino] -2-phenylpiperidine (2S,3S);

(13) a muscarinic antagonist, for example oxybutynin, tolterodine, propiverine, tropsium chloride, darifenacin, solifenacin, temiverine and ipratropium;

(14) a selective COX-2 inhibitor, for example, celecoxib, rofecoxib, parecoxib, valdecoxib, deracoxib, etoricoxib or lumiracoxib;

(15) an analgesic derived from aniline, in particular paracetamol;

(16) an antipsychotic, such as droperidol, aminazine, haloperidol, perphenazine, thioridazine, mesoridazine, trifluoroperazine, fluphenazine, clozapine, olanzapine, risperidone, ziprasidone, quetiapine, sertindole, aripiprazole, sonepiprazole, blonanserin, iloperidone, perospirone, raclopride, zotepine, bifeprunox, asenapine, lurasidone, amisulpride, balaperidone, palindor, eplivanserin, osanetant, rimonabant, meclinertant, Miraxion® or sarizotan;

(17) an agonist (eg, resinferatoxin or civamide) or antagonist (eg, capsazepine, GRC-15300) of the vanilloid receptor;

(18) a beta-adrenergic agent such as propranolol;

(19) a local anesthetic such as mexiletine;

(20) a corticosteroid such as dexamethasone;

(21) a 5-HT receptor agonist or antagonist, for example, a 5-HT _1B/1D agonist such as eletriptan, sumatriptan, naratriptan, zolmitriptan or rizatriptan;

(22) a 5-HT _2A receptor antagonist such as R(+)-alpha-(2,3-dimethoxyphenyl)-1-[2-(4-fluorophenylethyl)]-4-piperidinemethanol (MDL-100907);

(23) a cholinergic (nicotinic) analgesic such as ispronicline (TC-1734), (E)-N-methyl-4-(3-pyridinyl)-3-buten-1-amine (RJR-2403), (R) -5-(2-azetidinylmethoxy)-2-chloropyridine (ABT-594) or nicotine;

(24) Tramadol®, Tramadol ER (Ultram ER®), Tapentadol ER (Nucynta®);

(25) a PDE5 inhibitor such as 5-[2-ethoxy-5-(4-methyl-1-piperazinylsulfonyl)phenyl]-1-methyl-3-n-propyl-1,6-dihydro-7H-pyrazolo[4 ,3-d]pyrimidin-7-one (sildenafil), (6R,12aR)-2,3,6,7,12,12a-hexahydro-2-methyl-6-(3,4-methylenedioxyphenyl)pyrazino[2 ',1':6,1]pyrido[3,4-b]indole-1,4-dione (1C-351 or tadalafil), 2-[2-ethoxy-5-(4-ethylpiperazin-1-yl- 1-sulfonyl)phenyl]-5-methyl-7-propyl-3H-imidazo[5,1-f][1,2,4]triazin-4-one (vardenafil), 5-(5-acetyl-2- butoxy-3-pyridinyl)-3-ethyl-2-(1-ethyl-3-azetidinyl)-2,6-dihydro-7 H -pyrazolo[4,3- d ]pyrimidin-7-one, 5-(5 -acetyl-2-propoxy-3-pyridinyl)-3-ethyl-2-(1-isopropyl-3-azetidinyl)-2,6-dihydro- 7H- pyrazolo[4,3- d ]pyrimidin-7-one , 5-[2-ethoxy-5-(4-ethylpiperazin-1-ylsulfonyl)pyridin-3-yl]-3-ethyl-2-[2-methoxyethyl]-2,6-dihydro- 7H -pyrazolo[4 ,3-d]pyrimidin-7-one, 4-[(3-chloro-4-methoxybenzyl)amino]-2-[(2S)-2-(hydroxymethyl)pyrrolidin-1-yl]-N-(pyrimidin- 2-ylmethyl)pyrimidin-5-carboxamide, 3-(1-methyl-7-oxo-3-propyl-6,7-dihydro- 1H- pyrazolo[4,3-d]pyrimidin-5-yl)-N -[2-(1-methylpyrrolidin-2-yl)ethyl]-4-propoxybenzenesulfonamide;

(26) alpha-2-delta ligand such as gabapentin (Neuroritin®), gabapentin GR (Gralise®), gabapentin, enacarbil (Horizant®), pregabalin (Lyrica®), 3-methylgabapentin, (1[alpha],3 [alpha],5[alpha])(3-aminomethylbicyclo[3.2,0]hept-3-yl)acetic acid, (3S,5R)-3-aminomethyl-5-methylheptanoic acid, (3S,5R)-3- amino-5-methylheptanoic acid, (3S,5R)-3-amino-5-methyloctanoic acid, (2S,4S)-4-(3-chlorophenoxy)proline, (2S,4S)-4-(3-fluorobenzyl) proline, [(1R,5R,6S)-6-(aminomethyl)bicyclo[3.2,0]hept-6-yl]acetic acid, 3-(1-aminomethylcyclohexylmethyl)-4H-[1,2,4]oxadiazol- 5-one, C-[1-(1H-tetrazol-5-ylmethyl)cycloheptyl]methylamine, (3S,4S)-(1-aminomethyl-3,4-dimethylcyclopentyl)acetic acid, (3S,5R)-3- aminomethyl-5-methyloctanoic acid, (3S,5R)-3-amino-5-methylnonanoic acid, (3S,5R)-3-amino-5-methyloctanoic acid, (3R,4R,5R)-3-amino-4 ,5-dimethylheptanoic acid and (3R,4R,5R)-3-amino-4,5-dimethyloctanoic acid;

(27) a cannabinoid such as KHK-6188;

(28) metabotropic glutamate receptor subtype 1 (mGluR1) antagonist;

(29) a serotonin reuptake inhibitor such as sertraline, sertraline metabolite demethylsertraline, fluoxetine, norfluoxetine (a metabolite of fluoxetine desmethyl), fluvoxamine, paroxetine, citalopram, citalopram metabolite desmethylcitalopram, escitalopram, D,L-fenfluramine, femoxetine, ifoxetine, cyanodothiepine, litoxetine, dapoxetine, nefazodone, cericlamine and trazodone;

(30) a norepinephrine (norepinephrine) reuptake inhibitor such as maprotiline, lofepramine, mirtazepine, oxaprotiline, phesolamine, tomoxetine, mianserin, bupropion, bupropion metabolite hydroxybupropion, nomifensine and viloxazine (Vivalan®), especially a selective norepinephrine reuptake inhibitor such as reboxetine, in particular (S,S)-reboxetine;

(31) a dual serotonin-norepinephrine reuptake inhibitor such as venlafaxine, venlafaxine metabolite O-desmethylvenlafaxine, clomipramine, clomipramine metabolite desmethylclomipramine, duloxetine (Cymbalta®), milnacipran and imipramine;

(32) an inducible nitric oxide synthase (iNOS) inhibitor such as S-[2-[(1-iminoethyl)amino]ethyl]-1-homocysteine, S-[2-[(1-iminoethyl)amino]ethyl]- 4,4-dioxo-1-cysteine, S-[2-[(1-iminoethyl)amino]ethyl]-2-methyl-1-cysteine, (2S,5Z)-2-amino-2-methyl-7- [(1-iminoethyl)amino]-5-heptenoic acid, 2-[[(1R,3S)-3-amino-4-hydroxy-1-(5-thiazolyl)butyl]thio]-S-chloro-S- pyridinecarbonitrile; 2-[[(1R,3S)-3-amino-4-hydroxy-1-(5-thiazolyl)butyl]thio]-4-chlorobenzonitrile, (2S,4R)-2-amino-4-[[2- chloro-5-(trifluoromethyl)phenyl]thio]-5-thiazolbutanol, 2-[[(1R,3S)-3-amino-4-hydroxy-1-(5-thiazolyl)butyl]thio]-6-(trifluoromethyl )-3-pyridinecarbonitrile, 2-[[(1R,13S)-3-amino-4-hydroxy-1-(5-thiazolyl)butyl]thio]-5-chlorobenzonitrile, N-[4-[2-(3 -chlorobenzylamino)ethyl]phenyl]thiophene-2-carboxamidine, NXN-462 or guanidinoethyl disulfide;

(33) an acetylcholinesterase inhibitor such as a cholinesterase such as donepezil;

(34) a prostaglandin E2 subtype 4 (EP4) antagonist such as N-[({2-[4-(2-ethyl-4,6-dimethyl-1H-imidazo[4,5-c]pyridin-1-yl )phenyl]ethyl}amino)carbonyl]-4-methylbenzenesulfonmide or 4-[(15)-1-({[5-chloro-2-(3-fluorophenoxy)pyridin-3-yl]carbonyl}amino)ethyl]benzoic acid;

(35) a leukotriene B4 antagonist such as 1-(3-biphenyl-4-ylmethyl-4-hydroxychroman-7-yl)-cyclopentanecarboxylic acid (CP-105696), 5-[2-(2-carboxyethyl)-3- [6-(4-methoxyphenyl)-5E-hexenyl]oxyphenoxy]-valeric acid (ONO-4057) or DPC-11870;

(36) a 5-lipoxygenase inhibitor such as zileuton, 6-[(3-fluoro-5-[4-methoxy-3,4,5,6-tetrahydro-2H-pyran-4-yl])phenoxymethyl]-1 -methyl-2-quinolone (ZD-2138) or 2,3,5-trimethyl-6-(3-pyridylmethyl)-1,4-benzchoquinone (CV-6504);

(37) a sodium channel blocker such as lidocaine, lidocaine cream plus tetracaine (ZRS-201) or eslicarbazepine acetate;

(38) a Na _v 1.7 blocker such as XEN-402 and blockers described in WO2011/140425; WO2012/106499; WO2012/112743; WO2012/125613 or PCT/US2013/21535, the entire contents of which are incorporated herein by reference;

(39) a Na _v 1.8 blocker such as described in WO2008/135826 and WO2006/011050, the entire contents of which are incorporated herein by reference;

(40) a combined Na _v 1.7 and Na _v 1.8 blocker such as DSP-2230 or BL-1021;

(41) a 5-HT3 antagonist such as odansetron;

(42) a TPRV1 receptor agonist such as capsaicin (NeurogesX®, Qutenza®); and their pharmaceutically acceptable salts and solvates;

(43) a nicotinic receptor antagonist such as varenicline;

(44) an N-type calcium channel antagonist such as Z-160;

(45) a nerve growth factor antagonist such as tanezumab;

(46) an endopeptidase stimulator such as senrebotase;

(47) an angiotensin II antagonist such as EMA-401.

In one embodiment, additional suitable therapeutic agents are selected from V-116517, pregabalin, controlled release pregabalin, ezogabine (Potiga®), topical ketamine/amitriptyline cream (Amiket®), AVP-923, perampanel (E-2007 ), ralfinamide, transdermal bupivacaine (Eladur®), CNV1014802, JNJ-10234094 (carisbamate), BMS-954561, or ARC-4558.

The amount of additional therapeutic agent present in the compositions of this invention should not exceed the amount typically used in a composition containing such therapeutic agent as the sole active agent. The amount of additional therapeutic agent in the compositions described herein ranges from about 10% to 100% of the amount typically present in a composition containing such therapeutic agent as the sole active agent.

The compounds of this invention or pharmaceutically acceptable compositions thereof can be formulated into compositions for coating an implantable medical device such as a prosthesis, prosthetic valves, grafts, stents and vascular catheters. Therefore, the present invention, in another aspect, includes compositions for coating an implantable device, comprising a compound in accordance with the present invention described above and in classes and subclasses of the present invention, and a carrier suitable for coating such implantable devices. In yet another aspect, the present invention includes an implantable device coated with a composition comprising a compound of this invention described above and in classes and subclasses of the present invention, and a carrier suitable for coating such implantable devices. Suitable coatings and the preparation of coated implantable devices are described in US Pat. Nos. 6,099,562; 5,886,026 and 5,304,121. Coatings are typically biocompatible polymeric materials such as hydrogel polymer, polymethyldisiloxane, polycaprolactone, polyethylene glycol, polylactic acid, ethylene vinyl acetate, and mixtures thereof. The coatings may optionally be further coated with a suitable coating of fluorosilicone, polysaccharides, polyethylene glycol, phospholipids or combinations thereof to provide controlled release of the composition.

Another aspect of the present invention relates to the inhibition of the activity of Na _v 1.8 in a biological sample or in a patient, where the method includes administering to the patient or contacting such a biological sample with a compound of formula I or formula I' or a composition containing the specified compound. The term "biological sample" as used herein includes, without limitation, cell cultures or extracts thereof; material obtained by biopsy from mammals or extracts thereof; and blood, saliva, urine, feces, semen, tears or other body fluids or extracts thereof.

Inhibition of Na _v 1.8 activity in a biological sample is used for various purposes that are known to those skilled in the art. Examples of such purposes include, but are not limited to, the study of sodium channels in biological and pathological phenomena; and comparative evaluation of new sodium channel inhibitors.

DIAGRAMS AND EXAMPLES

The compounds of this invention can be easily prepared using the following methods. Schemes 1-3 below show general methods for preparing the compounds of this invention.

Scheme 1: General method for preparing compounds of formula I

(a) 2-Methoxypyridin-4-amine, coupling agent (i.e. GATU, EDCl, HOBT), base (i.e. N-methylmorpholine, Et ₃ N), solvent (i.e. DMF, dichloromethane) ; (b) SO ₂ Cl ₂ , DMF in solvent (ie dichloromethane); (c) 2-Methoxypyridin-4-amine, base (ie pyridine), solvent (ie dichloromethane, DMF); (d) TMSI or HBr, solvent (ie acetonitrile or acetic acid); (e) base (ie Cs ₂ CO ₃ , Na ₂ CO ₃ , K ₂ CO ₃ , NaHCO ₃ ), solvent (DMF, NMP, dioxane), heat.

Scheme 2: General method for preparing compounds of formula I'

(a) 6-Methoxypyridin-3-amine, coupling agent (i.e. GATU, EDCl, HOBT), base (i.e. N-methylmorpholine, Et ₃ N), solvent (i.e. DMF, dichloromethane) ; (b) SO ₂ Cl ₂ , DMF in solvent (ie dichloromethane); (c) 6-Methoxypyridin-3-amine, base (ie pyridine), solvent (ie dichloromethane, DMF); (d) TMSI or HBr, solvent (ie acetonitrile or acetic acid); (e) base (ie Cs ₂ CO ₃ , Na ₂ CO ₃ , K ₂ CO ₃ , NaHCO ₃ ), solvent (DMF, NMP, dioxane), heat.

Scheme 3: General method for preparing compounds of formula I

(a) R ⁹ -X (X=Cl, Br or I), base (i.e. NaH), solvent (i.e. DMF), heat or (b) coupling agent (i.e. HATU) , base (ie Et ₃ N), solvent (ie dichloromethane).

EXAMPLES

General methods . ¹ H NMR (400 MHz) spectrum is obtained as solutions in a suitable deuterated solvent such as dimethyl sulfoxide-d ₆ (DMSO). Mass spectra (MS) were obtained using an Applied Biosystems API EX LC/MS system. Compound purity and retention time were determined by reverse phase HPLC using a Kinetix C18 column (50 x 2.1 mm, 1.7 µm particles) from Phenomenex (pn: 00B-4475-AN)) and running a double gradient from 1-99% mobile phase B in 3 minutes. Mobile phase A = H ₂ O (0.05% CF ₃ CO ₂ H). Mobile phase B = CH ₃ CN (0.05% CF ₃ CO ₂ H). Flow rate = 2 mL/min, injection volume = 3 μL and column temperature = 50°C. Silica gel chromatography is carried out using silica gel-60 with a particle size of 230-400 mesh. Pyridine, dichloromethane (CH ₂ Cl ₂ ), tetrahydrofuran (THF), dimethylformamide (DMF), acetonitrile (ACN), methanol (MeOH) and 1,4-dioxane are obtained from Baker or Aldrich and in some cases the reagents are packaged in Aldrich Sure -Seal and stored under dry nitrogen. All reactions are stirred with a magnetic stirrer unless otherwise indicated.

EXAMPLE 1

Preparation of 2-fluoro-N-(2-oxo-1,2-dihydropyridin-4-yl)-4-(trifluoromethyl)benzamide

A solution of 2-fluoro-4-(trifluoromethyl)benzoyl chloride (25.0 g, 110.3 mmol) in dichloromethane (125.0 ml) was added dropwise to a mixture of 2-methoxypyridin-4-amine (13.7 g, 110 .3 mmol), pyridine (26.8 ml, 330.9 mmol) and dichloromethane (500.0 ml) at 0°C. The mixture is warmed to room temperature and stirred at this temperature overnight. The mixture is poured into 1N HCl (200 ml) and dichloromethane (200 ml). The layers are separated and the organic layer is dried over sodium sulfate, filtered and concentrated under reduced pressure. The product was suspended in hexane, the hexane was decanted and the product was dried under reduced pressure to give 2-fluoro-N-(2-methoxy-4-pyridyl)-4-(trifluoromethyl)benzamide (25.7 g, 74%) as a cream solid substances. ESI-MS m/z calculated 314.07, found 315.3 (M+1) ⁺ ; Hold time: 1.49 minutes (3 minute run). ^l H NMR (400 MHz, DMSO-d6) δ 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)benzamide (1.00 g, 3.18 mmol) in acetic acid (6.0 ml) add HBr (33% in acetic acid) acid) (3.9 ml 33% w/v, 15.91 mmol) and the mixture was stirred at 100°C for 6 hours. More HBr (2 mL, 33% in acetic acid) was added and the mixture was stirred at room temperature overnight. The mixture is then heated at 100°C for 2 hours, then it is cooled to room temperature. The mixture is partitioned between ethyl acetate and water. The layers are separated and the aqueous layer is extracted with ethyl acetate (3x). The combined organic layers are washed with water and brine (2x), dried over sodium sulfate, filtered and concentrated under reduced pressure. The solid was suspended in methyl t-butyl ether and filtered to give 2-fluoro-N-(2-oxo-1H-pyridin-4-yl)-4-(trifluoromethyl)benzamide (731 mg, 76%). ESI-MS m/z calculated 301.05, found 301.3 (M+1) ⁺ ; Hold time: 1.35 minutes (3 minute run). ^l H NMR (400 MHz, DMSO-d6) δ 11.33 (s, 1H), 10.70 (s, 1H), 7.96-7.85 (m, 2H), 7.75 (d, J =8.2 Hz, 1H), 7.35 (d, J=7.2 Hz, 1H), 6.81 (d, J=1.9 Hz, 1H), 6.41 (dd, J=7 ,2, 2.1 Hz, 1H) ppm

EXAMPLE 2

Preparation of 2-fluoro-N-(2-oxo-1,2-dihydropyridin-4-yl)-5-(trifluoromethyl)benzamide

A solution of 2-fluoro-5-(trifluoromethyl)benzoyl chloride (25 g, 110.3 mmol) in dichloromethane (125.0 ml) was added dropwise to a mixture of 2-methoxypyridin-4-amine (13.7 g, 110.3 mmol ), pyridine (26.8 ml, 330.9 mmol) and dichloromethane (500.0 ml) at 0°C. The mixture is warmed to room temperature and stirred at this temperature overnight. The mixture is 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 concentrated under reduced pressure to give 2-fluoro-N-(2-methoxy-4-pyridyl)-5-(trifluoromethyl)benzamide (33.6 g, 97.00% ) as a whitish solid. ESI-MS m/z calculated 314.07, found 315.2 (M+1) ⁺ ; Hold time: 1.44 minutes (3 minute run). ^l H NMR (400 MHz, DMSO-d6) δ 10.94 (s, 1H), 8.12-8.07 (m, 2H), 8.07-7.98 (m, 1H), 7.65 (t, J=9.2 Hz, 1H), 7.24 -7.19 (m, 2H), 3.85 (s, 3H) ppm

To 2-fluoro-N-(2-methoxy-4-pyridyl)-5-(trifluoromethyl)benzamide (3.54 g, 11.27 mmol) in acetonitrile (118.0 ml) add TMCI (4.0 ml, 28.18 mmol). The reaction mixture is stirred at 50°C overnight. The acetonitrile is evaporated and the crude residue is redissolved in ethyl acetate. The organic layers are washed with water, dried over sodium sulfate, filtered and concentrated. Purification by silica gel chromatography using a gradient of ethyl acetate in hexane (0-100%) followed by methanol in dichloromethane (0-20%) gives 2-fluoro-N-(2-oxo-1H-pyridin-4-yl)-5- (trifluoromethyl)benzamide (3 g, 89%) as a brown solid. ESI-MS m/z calculated 300.05, found 301.3 (M+1) ⁺ ; Hold time: 1.34 minutes (3 minute run). ^1H NMR (400 MHz, DMSO-d6) δ 10.85 (s, 1H), 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.

EXAMPLE 3

Preparation of 4-chloro-2-fluoro-N-(2-oxo-1,2-dihydropyridin-4-yl)benzamide

Solution of 4-chloro-2-fluorobenzoic acid (7.0 g, 40.10 mmol), GATU (15.25 g, 40.10 mmol), 2-methoxypyridin-4-amine (4.98 g, 40.10 mmol) and Et ₃ N (22.4 ml, 160.4 mmol) in dichloromethane (63.0 ml) were stirred at room temperature overnight. The crude mixture was purified by column chromatography, eluting with a gradient of ethyl acetate in hexane (0-50%) to give 4-chloro-2-fluoro-N-(2-methoxy-4-pyridyl)benzamide (4.35 g, 39%) in as a white solid. ESI-MS m/z calculated 280.04, found 281.3 (M+1) ⁺ ; Hold time: 1.31 minutes (3 minute run). ¹ H NMR (400 MHz, DMSO-d6) δ 10.80 (s, 1H), 8.09 (m, 1H), 7.73 (t, J=8.0 Hz, 1H), 7.66 ( dd, J=10.1, 1.9 Hz, 1H), 7.46 (dd, J=8.3, 1.9 Hz, 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) add TMCI (8.8 ml, 62. 0 mmol). The reaction mixture is stirred at 50°C overnight. The acetonitrile is evaporated and the crude solid is triturated with ethyl acetate. The solid was isolated by filtration and washed with ethyl acetate to give 4-chloro-2-fluoro-N-(2-oxo-1H-pyridin-4-yl)benzamide (3.8 g, 92%). ESI-MS m/z calculated 266.02, found 267.1 (M+1)+; Hold time: 1.23 minutes (3 minute run). ^l H NMR (400 MHz, DMSO-d6) δ 10.86 (s, 1H), 7.73 (t, J=8.0 Hz, 1H), 7.68 (dd, J=10.1, 1 .9 Hz, 1H), 7.60 (d, J=7.1 Hz, 1H), 7.47 (dd, J=8.3, 2.0 Hz, 1H), 7.11 (d, J =2.0 Hz, 1H), 6.71 (dd, J=7.1, 2.1 Hz, 1H) ppm.

EXAMPLE 4

Preparation of 5-chloro-2-fluoro-N-(2-oxo-1,2-dihydropyridin-4-yl)benzamide

Solution of 5-chloro-2-fluorobenzoic acid (5.0 g, 28.64 mmol), GATU (10.89 g, 28.64 mmol), 2-methoxypyridin-4-amine (3.6 g, 28.64 mmol) and Et ₃ N (15.98 ml, 114.60 mmol) in dichloromethane (45.0 ml) were stirred at room temperature overnight. The crude mixture was purified by column chromatography, eluting with a gradient of ethyl acetate in hexane (0-50%) to give 5-chloro-2-fluoro-N-(2-methoxy-4-pyridyl)benzamide (3.8 g, 47%) in as a white solid. ESI-MS m/z calculated 280.04, found 281.3 (M+1) ⁺ ; Hold time: 1.31 minutes (3 minute run).

To 5-chloro-2-fluoro-N-(2-methoxy-4-pyridyl)benzamide (3.8 g, 13.50 mmol) in acetonitrile (126.3 ml) add TMCI (7.7 ml, 54. 00 mmol). The reaction mixture is stirred at 50°C overnight. The acetonitrile is evaporated and the crude residue is redissolved in ethyl acetate. The organic layers are washed with water, dried over sodium sulfate, filtered and concentrated. Purification by silica gel chromatography using a gradient of ethyl acetate in hexane (0-100%) followed by methanol in dichloromethane (0-20%) gives 5-chloro-2-fluoro-N-(2-oxo-1H-pyridin-4-yl )benzamide (950 mg, 26%) as a white solid. ESI-MS m/z calculated 266.03, found 267.1 (M+1) ⁺ ; Hold time: 1.24 minutes (3 minute run).

EXAMPLE 5

Preparation of 5-chloro-2-fluoro-N-(2-oxo-1,2-dihydropyridin-4-yl)benzamide

Solution of 4-cyano-2-fluorobenzoic acid (6.7 g, 40.58 mmol), GATU (15.4 g, 40.58 mmol), 2-methoxypyridin-4-amine (5.0 g, 40.58 mmol) and Et ₃ N (22.62 ml, 162.3 mmol) in dichloromethane (60.3 ml) were stirred at room temperature overnight. The crude mixture was purified by column chromatography using a gradient of ethyl acetate in hexane (0-50%) to give 4-cyano-2-fluoro-N-(2-methoxy-4-pyridyl)benzamide (7.3 g, 66%) in as a white solid. ESI-MS m/z calculated 271.07, found 272.1 (M+1) ⁺ ; Hold time: 1.17 minutes (3 minute run).

To 4-cyano-2-fluoro-N-(2-methoxy-4-pyridyl)benzamide (7.3 g, 26.99 mmol) in acetonitrile (244.0 ml) add TMCI (9.99 ml, 70. 17 mmol). The reaction mixture is stirred at 50°C overnight. The acetonitrile is evaporated and the crude solid is triturated with ethyl acetate. The solid was 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 calculated 257.06, found 258.1 (M+1) ⁺ ; Hold time: 1.08 minutes (3 minute run). ^1H NMR (400 MHz, DMSO-d6) δ 10.94 (s, 1H), 8.11 (t, J=11.4 Hz, 1H), 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 .

EXAMPLE 6

Preparation of 2-fluoro-N-(2-oxo-1,2-dihydropyridin-4-yl)-5-(trifluoromethoxy)benzamide

A solution of 2-fluoro-5-(trifluoromethoxy)benzoic acid (5.3 g, 23.47 mmol), GATU (8.92 g, 23.47 mmol), 2-methoxypyridin-4-amine (2.9 g, 23.47 mmol) and Et ₃ N (13.09 ml, 93.88 mmol) in dichloromethane (47.4 ml) were stirred at room temperature overnight. The crude mixture was purified by column chromatography, eluting with a gradient of ethyl acetate in hexane (0-50%) to give 2-fluoro-N-(2-methoxy-4-pyridyl)-5-(trifluoromethoxy)benzamide (5.03 g, 65% ) as a white solid. ESI-MS m/z calculated 330.06, found 331.1 (M+1) ⁺ ; Hold time: 1.48 minutes (3 minute run). ^1H NMR (400 MHz, DMSO-d6) δ 10.90 (s, 1H), 8.10 (m, 1H), 7.73 (dd, J=5.1, 3.2 Hz, 1H), 7.66 (m, 1H), 7.55 (t, J=9.2 Hz, 1H), 7.21 (dd, J=3.7, 1.8 Hz, 2H), 3.84 (s , 3H) ppm

TMCI (5.6 mL, 39.60 mmol). The reaction mixture is stirred at 50°C overnight. The acetonitrile is evaporated and the crude residue is redissolved in ethyl acetate. The organic layers are washed with water, dried over sodium sulfate, filtered and concentrated. Purification by chromatography on silica gel with a gradient of ethyl acetate in hexane (0-100%) then methanol in dichloromethane (0-20%) gives 2-fluoro-N-(2-oxo-1H-pyridin-4-yl)-5-( trifluoromethoxy)benzamide (3 g, 62%) as a gray solid. ESI-MS m/z calculated 316.05, found 317.1 (M+1) ⁺ ; Hold time: 1.39 minutes (3 minute run). ^1H NMR (400 MHz, DMSO-d6) δ 10.80 (s, 1H), 7.73 (m, 1H), 7.67 (dd, J=8.7, 3.7 Hz, 1H), 7.55 (t, J=9.1 Hz, 1H), 7.48 (d, J=7.1 Hz, 1H), 6.96 (d, J=2.0 Hz, 1H), 6, 55 (dd, J=7.2, 2.1 1H) ppm

EXAMPLE 7

Preparation of 2-fluoro-N-(2-oxo-1,2-dihydropyridin-4-yl)-4-(perfluoroethyl)benzamide

A solution of 4-bromo-2-fluoro-benzoyl chloride (2 g, 8.42 mmol) in dichloromethane (10.0 ml) was added dropwise 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 is warmed to room temperature and stirred at this temperature overnight. The mixture is poured into 1N HCl (200 ml) and dichloromethane (200 ml). The layers are separated and the organic layer is dried over sodium sulfate, filtered and concentrated under reduced pressure to give 4-bromo-2-fluoro-N-(2-methoxy-4-pyridyl)benzamide (1.2 g, 44%) as an off-white solid matter. ESI-MS m/z calculated 323.99, found 325.1 (M+1) ⁺ ; Hold time: 1.37 minutes (3 minute run). ^l H NMR (400 MHz, DMSO-d6) δ 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) ppm

Through a stirred solution of 4-bromo-2-fluoro-N-(2-methoxy-4-pyridyl)benzamide (800 mg, 2.46 mmol) and copper (1.6 g, 24.61 mmol) in DMSO (15 ml ) 1,1,1,2,2-pentafluoro-2-iodoethane (4.1 g, 16.47 mmol) was bubbled into the autoclave. The vessel is sealed and heated at 120°C for 16 hours. The reaction mixture is diluted with water and filtered through a pad of silica and then extracted with ethyl acetate (4x). The organic layers are combined, washed with brine, dried over Na ₂ SO ₄ , filtered and evaporated to dryness to obtain a crude mixture, which is purified by column chromatography using a gradient of ethyl acetate in hexane (0-40%) to obtain 2-fluoro-N- (2-methoxy-4-pyridyl)-4-(1,1,2,2,2-pentafluoroethyl)benzamide (200 mg, 22%) as an off-white solid. ESI-MS m/z calculated 364.06, found 365.3 (M+1) ⁺ ; Hold time: 1.39 minutes (3 minute run). ¹ H NMR (400 MHz, DMSO-d6) δ 10.98 (s, 1H), 8.11 (d, J=6.3 Hz, 1H), 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

2-fluoro-N-(2-methoxy-4-pyridyl)-4-(1,1,2,2,2-pentafluoroethyl)benzamide (200 mg, 0.55 mmol) in HBr in acetic acid (1.3 ml 33% w/v, 5.49 mmol) is stirred at 100°C for 2 hours, at which time 1 ml of HBr in acetic acid (33% w/v) is added and the mixture is stirred at 100°C for 4 hours, then cool to room temperature. The reaction mixture is diluted with water to obtain a residue. The residue is filtered, washed with water (2x), cold methyl t-butyl ether and dried in vacuo to give 2-fluoro-N-(2-oxo-1H-pyridin-4-yl)-4-(1,1,2 ,2,2-pentafluoroethyl)benzamide (138 mg, 72%) as a light gray solid. ESI-MS m/z calculated 350.05, found 351.3 (M+1) ⁺ ; Hold time: 1.3 minutes (3 minute run).

EXAMPLE 8

Preparation of 2,5-difluoro-N-(2-oxo-1,2-dihydropyridin-4-yl)benzamide

A solution of 2,5-difluorobenzoyl chloride (2.0 ml, 16.14 mmol) and dichloromethane (14.25 ml) was added dropwise to a mixture of 2-methoxypyridin-4-amine (2.0 g, 16.14 mmol), pyridine (3.9 ml, 48.42 mmol) and dichloromethane (57.0 ml) at 0°C. The mixture is warmed to room temperature and stirred at this temperature overnight. The mixture is poured into 1N HCl and dichloromethane. The layers are separated and the organic layer is dried over sodium sulfate, filtered and concentrated under reduced pressure to give a tan solid. The solid was suspended in hexane (150 ml) and filtered to give 2,5-difluoro-N-(2-methoxy-4-pyridyl)benzamide (2.61 g, 61%) as a tan solid. ESI-MS m/z calculated 264.07, found 265.3 (M+1) ⁺ ; Hold time: 1.22 minutes (3 minute run). ^l H NMR (400 MHz, DMSO-d6) δ 10.83 (s, 1H), 8.12-8.05 (m, 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) add HBr 33% in acetic acid (12.1 ml 33% w/v, 49.20 mmol) and the mixture was stirred at 90°C for 5 hours. Add more HBr (10 ml, 33% in acetic acid) added and the mixture was stirred at 90°C overnight . The mixture is cooled to room temperature and poured into water (200 ml). The mixture is stirred and the solid is collected by filtration. The solid is washed with water (2 x 50 ml). The solid was suspended in hexane (2 x 50 ml) and filtered to give 2,5-difluoro-N-(2-oxo-1H-pyridin-4-yl)benzamide (2.30 g, 9.19 mmol, 93% ). ESI-MS m/z calculated 250.05, found 251.3 (M+1) ⁺ ; Hold time: 1.16 minutes (3 minute run). ^l H NMR (400 MHz, DMSO-d6) δ 11.31 (s, 1H), 10.59 (s, 1H), 7.56 (ddd, J=8.2, 5.4, 3.0 Hz , 1H), 7.46 (d, J=9.1, 4.4 Hz, 2H), 7.33 (d, J=7.2 Hz, 1H), 6.81 (d, J=2, 0 Hz, 1H), 6.42 (dd, J=7.2, 2.1 Hz, 1H) ppm.

EXAMPLE 9

Preparation of 4,5-dichloro-2-fluoro-N-(2-oxo-1,2-dihydropyridin-4-yl)benzamide

A solution of 2-methoxypyridin-4-amine (186.2 mg, 1.5 mmol), 4,5-dichloro-2-fluorobenzoic acid (285.1 mg, 1.36 mmol), GATU (622.4 mg, 1 .64 mmol) and n-methylmorpholine (299.9 μl, 2.73 mmol) in DMF (3 ml) were stirred at room temperature for 16 hours. The reaction mixture is poured into water and extracted with ethyl acetate (3x). The organic layers are combined, washed with water (3x), brine and dried over Na ₂ SO ₄ , filtered through a short pad of silica and evaporated to dryness. The product is taken up in HBr (in acetic acid) (6.689 ml 33% w/v, 27.28 mmol) and stirred at 95°C for 16 hours. The solution is cooled to room temperature, filtered and the solid washed with water (2x ) and then ether (2x) and dried in vacuo to give 4,5-dichloro-2-fluoro-N-(2-oxo-1H-pyridin-4-yl)benzamide (250 mg, 61%) as an off-white solid matter. ESI-MS m/z calculated 299.99, found 301.3 (M+1) ⁺ ; Hold time: 1.16 minutes (3 minute run).

EXAMPLE 10

Preparation of 4-chloro-2,5-difluoro-N-(2-oxo-1,2-dihydropyridin-4-yl)benzamide

A solution of 4-chloro-2,5-difluorobenzoyl chloride (5 g, 23.70 mmol) in dichloromethane (25 ml) was added dropwise to a mixture of 2-methoxypyridin-4-amine (2.94 g, 23.70 mmol), pyridine (5.75 ml, 71.10 mmol) and dichloromethane (100.0 ml) at 0°C. The mixture is warmed to room temperature and stirred at this temperature for 43 hours. The mixture is poured into 1N HCl (50 ml). The mixture is filtered using dichloromethane and the solid is isolated. The solid was dried in vacuo to give 4-chloro-2,5-difluoro-N-(2-methoxy-4-pyridyl)benzamide (6.2 g, 88%) as a pink solid. ^1H NMR (400 MHz, DMSO-d6) δ 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 calculated 298.03, found 299.3 (M+1) ⁺ ; Hold time: 1.43 minutes (3 minute run).

To 4-chloro-2,5-difluoro-N-(2-methoxy-4-pyridyl)benzamide (3 g, 10.04 mmol) in HOAc (15.9 ml) add HBr 33% in HOAc (12.31 ml 33% w/v, 50.20 mmol) and the mixture was stirred at 90°C for 5 hours. More HBr (10 ml, 33% in HOAc) was added and the mixture was stirred at 90°C overnight. The mixture is cooled to room temperature and poured into water (100 ml). The mixture is stirred and the solid is collected by filtration. The solid is washed with water (2 x 50 ml). The solid was suspended in hexane (2 x 50 ml) and filtered to give 4-chloro-2,5-difluoro-N-(2-oxo-1H-pyridin-4-yl)benzamide (969.7 mg, 34%) as a creamy solid. ESI-MS m/z calculated 284.02, found 285.3 (M+1) ⁺ ; Hold time: 1.36 minutes (3 min run).

EXAMPLE 11

Preparation of 2-fluoro-N-(2-oxo-1,2-dihydropyridin-4-yl)-4,6-bis(trifluoromethyl)benzamide

2-Methoxypyridin-4-amine (632.1 mg, 5.09 mmol) and DIEA (1.8 ml, 10.18 mmol) were dissolved in DMF (15 ml) and treated dropwise with a solution of 2-fluoro-4,6 -bis(trifluoromethyl)benzoyl chloride (1500 mg, 5.09 mmol) in DMF (2 ml). After 2 hours, the reaction mixture is diluted with ethyl acetate, washed with 50% saturated sodium bicarbonate solution (2 x 20 ml), water and brine. The solution is dried over anhydrous Na ₂ SO ₄ , filtered and dried to obtain a purple residue. Chromatography on silica gel using an ethyl acetate/hexane gradient (10-99%) gives 2-fluoro-N-(2-methoxypyridin-4-yl)-4,6-bis(trifluoromethyl)benzamide (1.2 g, 67%) as a beige solid. ^l H NMR (400 MHz, DMSO-d6) δ 11.29 (s, 1H), 8.42 (d, J=8.6 Hz, 1H), 8.17 (s, 1H), 8.13 ( dd, J=5.4, 0.9 Hz, 1H), 7.14-7.10 (m, 2H), 3.85 (s, 3H) ppm. ESI-MS m/z calculated 382.05, found 383.1 (M+1) ⁺ ; Hold time: 1.48 minutes (3 minute run).

To a mixture of sodium iodide (2.54 g, 16.95 mmol) in acetonitrile (75 ml) under nitrogen was added TMCCl (2.15 ml, 16.95 mmol) and the mixture was stirred at 25°C for 30 minutes. Anhydrous acetonitrile (130.0 ml) was then 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 stirring at 80°C for 5 hours and then at 60°C for 12 hours. The reaction mixture is cooled, diluted with water and extracted with ethyl acetate. The organic layer is dried over Na ₂ SO ₄ , filtered and concentrated to a dark orange solid. The solid is triturated with ethyl acetate/hexane several times to remove the dark red color, then with dichloromethane to remove the yellow color, and finally with hexane. The resulting solid was dried in vacuo to give 2-fluoro-N-(2-oxo-1H-pyridin-4-yl)-4,6-bis(trifluoromethyl)benzamide (960 mg, 83%) as an off-white solid. ^l H NMR (400 MHz, DMSO d6) δ 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 m/z calculated 368.04, found 369.1 (M+1) ⁺ ; Hold time: 1.28 minutes (3 minute run).

EXAMPLE 12

Preparation of N-(2-oxo-1,2-dihydropyridin-4-yl)-2-(4-(trifluoromethoxy)phenoxy)-4-(trifluoromethyl)benzamide ( 79 )

CS ₂ CO ₃ (651.6 mg, 2 mmol) was added to a solution of 2-fluoro-N-(2-oxo-l,2-dihydropyridin-4-yl)-4-(trifluoromethyl)benzamide (60.0 mg, 0.2 mmol) and 4-(trifluoromethoxy)phenol (259.1 μl, 2 mmol) in DMF (1 ml) and the reaction mixture was stirred at 100°C for 1 hour. The reaction mixture was filtered and purified by reverse phase HPLC using a gradient of acetonitrile in water (10-99%) and HCl modifier to give N-(2-oxo-l,2-dihydropyridin-4-yl)-2-(4 -(trifluoromethoxy)phenoxy)-4-(trifluoromethyl)benzamide ( 79 ) (25.7 mg, 28%). ESI-MS m/z calculated 458.07, found 459.5 (M+1) ⁺ ; Hold time: 1.80 minutes (run 3 minutes)

EXAMPLE 13

Preparation of 2-((5-fluoro-2-hydroxybenzyl)oxy)-N-(2-oxo-1,2-dihydropyridin-4-yl)-4-(trifluoromethyl)benzamide ( 159 )

To a solution of 2-fluoro-N-(2-oxo-1H-pyridin-4-yl)-4-(trifluoromethyl)benzamide (211.2 mg, 0.70 mmol) and 4-fluoro-2-(hydroxymethyl)phenol (100 mg, 0.70 mmol) in N-methylpyrrolidinone (3 ml) add cesium carbonate (687.8 mg, 2.1 mmol) and the mixture is heated at 100°C for 2 hours. The reaction mixture is cooled to 25°C, filtered and purified by reverse phase HPLC using an acetonitrile/water gradient (10 to 99%) and HCl as modifier to give 2-[(5-fluoro-2-hydroxyphenyl)methoxy]- N-(2-oxo-1H-pyridin-4-yl)-4-(trifluoromethyl)benzamide ( 159 ) (10.5 mg, 3%) as a yellow solid. ^l H NMR (400 MHz, DMSO-d6) δ 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 (m, 2H), 6.91 -6.79 (m, 2H), 6.61 (dd, J=7.4, 2.4 Hz, 1H), 4.96 (s, 2H) ppm. ESI-MS m/z calculated 422.09, found 423.3 (M+1) ⁺ ; Hold time: 1.83 minutes (3 minutes).

EXAMPLE 14

Preparation of 2-(4-fluoro-2-methylphenoxy)-N-(2-oxo-1,2-dihydropyridin-4-yl)-4-(trifluoromethyl)benzamide ( 10 )

A mixture of 2-fluoro-N-(2-oxo-1H-pyridin-4-yl)-4-(trifluoromethyl)-benzamide (13.6 g, 45.30 mmol), 4-fluoro-2-methylphenol (17, 1 g, 135.9 mmol), Cs ₂ CO ₃ (44.28 g, 135.9 mmol) and DMF (340.0 ml) were heated at 100°C for 1.5 hours. The mixture is cooled to room temperature and poured into water (500 ml). The mixture is stirred vigorously for 30 minutes, then filtered. The solid was washed with water (250 ml) and suspended with methyl tert-butyl ether (200 ml). The mixture is filtered and the solid is suspended in hexane (2 x 400 ml) and the filtrate is dried in vacuo to give 2-(4-fluoro-2-methylphenoxy)-N-(2-oxo-1H-pyridin-4-yl)-4 -(trifluoromethyl)benzamide ( 10 ) (13.1 g, 70%) as a solid. ESI-MS m/z calculated 406.09, found 407.5 (M+1) ⁺ ; Hold time: 1.73 minutes (3 minute run). ^l H NMR (400 MHz, DMSO-d6) δ 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 (m , 2H), 7.00-6.95 (m, 1H), 6.75 (d, J=1.8 Hz, 1H), 6.38 (dd, J=7.2, 2.1 Hz, 1H), 2.16 (s, 3H) ppm

EXAMPLE 15

Preparation of 2-(4-fluoro-2-(hydroxymethyl)phenoxy)-N-(2-oxo-1,2-dihydropyridin-4-yl)-4-(trifluoromethyl)benzamide ( 157 )

2-Fluoro-N-(2-oxo-1H-pyridin-4-yl)-4-(trifluoromethyl)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-methylpyrrolidin-2-one (3.0 ml) and the reaction mixture was stirred at 80°C for 10 minutes. The reaction mixture is filtered and the compound is purified by preparative reverse phase chromatography using a gradient of 10-99% acetonitrile in water containing HCl as a modifier to give 2-[4-fluoro-2-(hydroxymethyl)phenoxy]-N-(2- Oxo-1H-pyridin-4-yl)-4-(trifluoromethyl)benzamide ( 157 ) (10.3 mg, 1%) as a white solid. ^l H NMR (400 MHz, DMSO-d6) δ 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), 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 calculated 422.09, found 423.2 (M+1) ⁺ ; Hold time: 1.32 minutes (3 minute run).

EXAMPLE 16

Preparation of 2-(3-fluoro-4-methoxyphenoxy)-N-(2-oxo-1,2-dihydropyridin-4-yl)-4-(trifluoromethyl)benzamide ( 81 )

Cs ₂ CO ₃ (651.6 mg, 2.0 mmol) was added to a solution of 2-fluoro-N-(2-oxo-1,2-dihydropyridin-4-yl)-4-(trifluoromethyl)benzamide (60.0 mg, 0.2 mmol) and 3-fluoro-4-methoxyphenol (284.3 mg, 2.0 mmol) in DMF (1 ml), and the reaction mixture was stirred at 100°C for 1 hour. The reaction mixture is filtered and purified by reverse phase HPLC using a gradient of acetonitrile in water (10-99%) and HCl as modifier to give 2-(3-fluoro-4-methoxyphenoxy)-N-(2-oxo-1,2 -dihydropyridin-4-yl)-4-(trifluoromethyl)benzamide ( 81 ) (45.6 mg, 54%). ESI-MS m/z calculated 422.09, found 423.3 (M+1) ⁺ ; Hold time: 1.65 minutes (3 minute run).

Next, using the procedure described above for compound 81 , the following compounds are prepared from 2-fluoro-N-(2-oxo-1,2-dihydropyridin-4-yl)-4-(trifluoromethyl)benzamide in each case and using the described below alcohols.

Conn. No. Product Alcohol 144 N-(2-oxo-1,2-dihydropyridin-4-yl)-4-(trifluoromethyl)-2-((6-(trifluoromethyl)pyridin-3-yl)oxy)benzamide 6-(trifluoromethyl)pyridin-3-ol 116 2-(isopentyloxy)-N-(2-oxo-1,2-dihydropyridin-4-yl ) -4-(trifluoromethyl ) benzamide isopentanol 5 2-(4-fluorophenoxy)-N-(2-oxo-1,2-dihydropyridin-4-yl)-4-(trifluoromethyl)benzamide 4-fluorophenol 7 2-(2,4-difluorophenoxy)-N-(2-oxo-1,2-dihydropyridin-4-yl)-4-(trifluoromethyl ) benzamide 2,4-difluorophenol 117 2-isobutoxy-N-(2-oxo-1,2-dihydropyridin-4-yl)-4-(trifluoromethyl)benzamide isobutanol 146 2-((6-methylpyridin-3-yl)oxy)-N-(2-oxo-1,2-dihydropyridin-4-yl)-4-(trifluoromethyl ) benzamide 6-methyl-3-pyridinol 118 2-[(1R,2R,4S)-norbornan-2-yl]oxy-N-(2-oxo-1H-pyridin-4-yl)-4-(trifluoromethyl)benzamide (1R,2R,4S)-norbornan-2-ol 147 2-((2-methylpyridin-3-yl)oxy)-N-(2-oxo-1,2-dihydropyridin-4-yl)-4-(trifluoromethyl ) benzamide 2-methyl-3-pyridinol 119 2-((1-methylcyclopropyl)methoxy)-N-(2-oxo-1,2-dihydropyridin-4-yl)-4-(trifluoromethyl ) benzamide 1-methylcyclopropyl)methanol 120 2-(cyclopentylmethoxy)-N-(2-oxo-1,2-dihydropyridin-4-yl)-4-(trifluoromethyl ) benzamide Cyclopentylmethanol 121 N-(2-oxo-1,2-dihydropyridin-4-yl)-2-((tetrahydrofuran-3-yl)methoxy)-4-(trifluoromethyl)benzamide tetrahydrofuran-3-ylmethanol 122 2-cyclobutoxy-N-(2-oxo-1,2-dihydropyridin-4-yl)-4-(trifluoromethyl)benzamide cyclobutanol 123 N-(2-oxo-1,2-dihydropyridin-4-yl)-2-(4,4,4-trifluorobutoxy)-4-(trifluoromethyl ) benzamide 4,4,4-trifluorobutanol 124 2-((2,2-dimethylcyclopropyl)methoxy)-N-(2-oxo-1,2-dihydropyridin-4-yl)-4-(trifluoromethyl)benzamide 2,2-dimethylcyclopropyl)methanol 125 2-((1R,5S)-bicyclo[3.1.0]hexan-3-yloxy)-N-(2-oxo-1,2-dihydropyridin-4-yl)-4-(trifluoromethyl)benzamide (1R,SS)-3-bicyclo[3.1.0]hexanol 126 2-((2,2-difluorocyclopropyl)methoxy)-N-(2-oxo-1,2-dihydropyridin-4-yl)-4-(trifluoromethyl)benzamide 2,2-difluorocyclopropyl)methanol 8 2-(4-(2-methoxyethoxy)phenoxy)-N-(2-oxo-1,2-dihydropyridin-4-yl)-4-(trifluoromethyl ) benzamide 4-(2-methoxyethoxy)phenol 127 2-(bicyclo[2.2.1]heptan-2-yloxy)-N-(2-oxo-1,2-dihydropyridin-4-yl)-4-(trifluoromethyl ) benzamide norbornan-2-ol 9 N-(2-oxo-1,2-dihydropyridin-4-yl)-2-phenoxy-4-(trifluoromethyl)benzamide phenol eleven N-(2-oxo-1,2-dihydropyridin-4-yl)-2-(o-tolyloxy)-4-(trifluoromethyl)benzamide 2-methylphenol 128 2-(cyclohexyloxy)-N-(2-oxo-1,2-dihydropyridin-4-yl ) -4-(trifluoromethyl ) benzamide cyclohexanol 12 N-(2-oxo-1,2-dihydropyridin-4-yl)-2-(p-tolyloxy)-4-(trifluoromethyl)benzamide 4-methylphenol 77 2-(2-chloro-4-fluorophenoxy)-N-(2-oxo-1,2-dihydropyridin-4-yl)-4-(trifluoromethyl ) benzamide 2-chloro-4-fluorophenol 78 2-(4-chlorophenoxy)-N-(2-oxo-1,2-dihydropyridin-4-yl)-4-(trifluoromethyl)benzamide 4-chlorophenol 80 N-(2-oxo-1,2-dihydropyridin-4-yl)-2-(2-(trifluoromethoxy)phenoxy)-4-(trifluoromethyl)benzamide 2-(trifluoromethoxy)phenol 82 2-(4-(difluoromethoxy)phenoxy)-N-(2-oxo-1,2-dihydropyridin-4-yl)-4-(trifluoromethyl ) benzamide 4-(difluoromethoxy)phenol 83 2-(2-(difluoromethoxy)phenoxy)-N-(2-oxo-1,2-dihydropyridin-4-yl)-4-(trifluoromethyl ) benzamide 2-(difluoromethoxy)phenol 84 2-(2-fluoro-4-methoxyphenoxy)-N-(2-oxo-1,2-dihydropyridin-4-yl)-4-(trifluoromethyl ) benzamide 2-fluoro-4-methoxyphenol 87 2-(3-fluoro-2-methoxyphenoxy)-N-(2-oxo-1,2-dihydropyridin-4-yl)-4-(trifluoromethyl ) benzamide 3-fluoro-2-methoxyphenol 110 2-(2-chloro-3-fluoro-4-methoxyphenoxy)-N-(2-oxo-1,2-dihydropyridin-4-yl)-4-(trifluoromethyl)benzamide 2-chloro-3-fluoro-4-methoxyphenol 158 2-(4-fluoro-2-methoxyphenoxy)-N-(2-oxo-1,2-dihydropyridin-4-yl)-4-(trifluoromethyl ) benzamide 4-fluoro-2-methoxyphenol

EXAMPLE 17

Preparation of 2-(4-fluoro-2-methoxyphenoxy)-N-(2-oxo-1,2-dihydropyridin-4-yl)-5-(trifluoromethyl)benzamide ( 30 )

CS ₂ CO ₃ (651.6 mg, 2.0 mmol) was added to a solution of 2-fluoro-N-(2-oxo-1,2-dihydropyridin-4-yl)-5-(trifluoromethyl)benzamide (60.0 mg, 0.2 mmol) and 4-fluoro-3-methoxyphenol (228 μl, 2.0 mmol) in DMF (1 ml), and the reaction mixture was stirred at 100°C for 1 hour. The reaction mixture is filtered and purified by reverse phase HPLC using a gradient of acetonitrile in water (10-99%) and HCl as modifier to give 2-(4-fluoro-2-methoxyphenoxy)-N-(2-oxo-1,2 -dihydropyridin-4-yl)-5-(trifluoromethyl)benzamide ( 30 ) (67.9 mg, 80%). ESI-MS m/z calculated 422.09, found 423.2 (M+1) ⁺ ; Hold time: 1.56 minutes (3 minute run).

Using the procedure described above for compound 30 , the following compounds were then prepared from 2-fluoro-N-(2-oxo-1,2-dihydropyridin-4-yl)-5-(trifluoromethyl)benzamide and the following alcohols.

Conn. No. Product Alcohol 72 N-(2-oxo-1,2-dihydropyridin-4-yl)-2-(4-(trifluoromethoxy)phenoxy)-5-(trifluoromethyl)benzamide 4-(trifluoromethoxy)phenol 31 2-(4-fluoro-2-methylphenoxy)-N-(2-oxo-1,2-dihydropyridin-4-yl)-5-(trifluoromethyl)benzamide 4-fluoro-2-methylphenol 63 2-(4-methoxy-2-methylphenoxy)-N-(2-oxo-1,2-dihydropyridin-4-yl)-5-(trifluoromethyl)benzamide 4-methoxy-2-methylphenol 50 2-(4-chloro-2-methylphenoxy)-N-(2-oxo-1,2-dihydropyridin-4-yl)-5-(trifluoromethyl)benzamide 4-chloro-2-methylphenol 44 2-(4-ethoxyphenoxy)-N-(2-oxo-1,2-dihydropyridin-4-yl)-5-(trifluoromethyl)benzamide 4-ethoxyphenol 49 2-(2-chloro-4-methoxyphenoxy)-N-(2-oxo-1,2-dihydropyridin-4-yl)-5-(trifluoromethyl)benzamide 2-chloro-4-methoxyphenol 90 N-(2-oxo-1,2-dihydropyridin-4-yl)-5-(trifluoromethyl)-2-(2,3,4-trifluorophenoxy)benzamide 2,3,4-trifluorophenol 29 2-(2-chloro-4-fluorophenoxy)-N-(2-oxo-1,2-dihydropyridin-4-yl)-5-(trifluoromethyl)benzamide 2-chloro-4-fluorophenol 54 2-(3-fluoro-2-methoxyphenoxy)-N-(2-oxo-1,2-dihydropyridin-4-yl)-5-(trifluoromethyl)benzamide 3-fluoro-2-methoxyphenol 59 2-(3-fluoro-4-methoxyphenoxy)-N-(2-oxo-1,2-dihydropyridin-4-yl)-5-(trifluoromethyl)benzamide 3-fluoro-4-methoxyphenol 62 N-(2-oxo-1,2-dihydropyridin-4-yl)-2-(2-propoxyphenoxy)-5-(trifluoromethyl)benzamide 2-propoxyphenol 73 2-(4-(difluoromethoxy)phenoxy)-N-(2-oxo-1,2-dihydropyridin-4-yl)-5-(trifluoromethyl)benzamide 4-(difluoromethoxy)phenol 28 N-(2-oxo-1,2-dihydropyridin-4-yl)-2-(o-tolyloxy)-5-(trifluoromethyl)benzamide 2-methylphenol 53 N-(2-oxo-1,2-dihydropyridin-4-yl)-2-(4-propoxyphenoxy)-5-(trifluoromethyl)benzamide 4-propoxyphenol 75 N-(2-oxo-1,2-dihydropyridin-4-yl)-2-(2-(trifluoromethoxy)phenoxy)-5-(trifluoromethyl)benzamide 2-(trifluoromethoxy)phenol 2 2-(4-fluorophenoxy)-N-(2-oxo-1,2-dihydropyridin-4-yl)-5-(trifluoromethyl)benzamide 4-fluorophenol 76 2-(2-(difluoromethoxy)phenoxy)-N-(2-oxo-1,2-dihydropyridin-4-yl)-5-(trifluoromethyl)benzamide 2-(difluoromethoxy)phenol 58 2-(4-chlorophenoxy)-N-(2-oxo-1,2-dihydropyridin-4-yl)-5-(trifluoromethyl)benzamide 4-chlorophenol 24 2-(2,4-difluorophenoxy)-N-(2-oxo-1,2-dihydropyridin-4-yl)-5-(trifluoromethyl)benzamide 2,4-difluorophenol 46 2-(2-ethoxyphenoxy)-N-(2-oxo-1,2-dihydropyridin-4-yl)-5-(trifluoromethyl)benzamide 2-ethoxyphenol 45 2-(4-methoxyphenoxy)-N-(2-oxo-1,2-dihydropyridin-4-yl)-5-(trifluoromethyl)benzamide 4-methoxyphenoxy 56 2-(5-fluoro-2-methylphenoxy)-N-(2-oxo-1,2-dihydropyridin-4-yl)-5-(trifluoromethyl)benzamide 5-fluoro-2-methylphenol 55 2-(2-fluoro-4-methoxyphenoxy)-N-(2-oxo-1,2-dihydropyridin-4-yl)-5-(trifluoromethyl)benzamide 2-fluoro-4-methoxyphenol 51 2-(4-chloro-2-fluorophenoxy)-N-(2-oxo-1,2-dihydropyridin-4-yl)-5-(trifluoromethyl)benzamide 4-chloro-2-fluorophenol 52 2-(5-fluoro-2-methoxyphenoxy)-N-(2-oxo-1,2-dihydropyridin-4-yl)-5-(trifluoromethyl)benzamide 5-fluoro-2-methoxyphenol 65 2-(2-chlorophenoxy)-N-(2-oxo-1,2-dihydropyridin-4-yl)-5-(trifluoromethyl)benzamide 2-chlorophenol 64 2-(2-isopropoxyphenoxy)-N-(2-oxo-1,2-dihydropyridin-4-yl)-5-(trifluoromethyl)benzamide 2-isopropoxyphenol 61 2-(4-fluoro-2-methylphenoxy)-N-(6-methyl-2-oxo-1,2-dihydropyridin-4-yl)-5-(trifluoromethyl)benzamide 4-fluoro-2-methylphenol 47 2-(2-methoxy-4-methylphenoxy)-N-(2-oxo-1,2-dihydropyridin-4-yl)-5-(trifluoromethyl)benzamide 2-methoxy-4-methylphenol 92 2-(2,3-difluoro-4-methylphenoxy)-N-(2-oxo-1,2-dihydropyridin-4-yl)-5-(trifluoromethyl)benzamide 2,3-difluoro-4-methylphenol 32 N-(2-oxo-1,2-dihydropyridin-4-yl)-2-phenoxy-5-(trifluoromethyl)benzamide phenol 132 N-(2-oxo-1,2-dihydropyridin-4-yl)-5-(trifluoromethyl)-2-(3,3,3-trifluoropropoxy)benzamide 3,3,3-trifluoropropanol 27 N-(2-oxo-1,2-dihydropyridin-4-yl)-2-(p-tolyloxy)-5-(trifluoromethyl)benzamide 4-methylphenol 91 -(2-oxo-1,2-dihydropyridin-4-yl)-5-(trifluoromethyl)-2-(2,3,5-trimethylphenoxy)benzamide 2,3,5-trimethylphenol 25 2-(4-cyanophenoxy)-N-(2-oxo-1,2-dihydropyridin-4-yl)-5-(trifluoromethyl)benzamide 4-cyanophenol 93 N-(2-oxo-1,2-dihydropyridin-4-yl)-5-(trifluoromethyl)-2-(2,4,5-trimethylphenoxy)benzamide 2,4,5-trimethylphenol 131 2-isobutoxy-N-(2-oxo-1,2-dihydropyridin-4-yl)-5-(trifluoromethyl)benzamide isobutanol 135 2-[[(1R,5S)-3-bicyclo[3.1.0]hexanyl]oxy]-N-(2-oxo-1H-pyridin-4-yl)-5-(trifluoromethyl)benzamide (1R,5S)-3-bicyclo[3.1.0]
hexanol 48 2-(2-fluoro-6-methoxyphenoxy)-N-(2-oxo-1,2-dihydropyridin-4-yl)-5-(trifluoromethyl)benzamide 2-fluoro-6-methoxyphenol 86 2-(4-fluoro-2-methylphenoxy)-N-(5-methyl-2-oxo-1,2-dihydropyridin-4-yl)-4-(trifluoromethyl)benzamide 4-fluoro-2-methylphenol 130 2-(cyclopentylmethoxy)-N-(2-oxo-1,2-dihydropyridin-4-yl)-5-(trifluoromethyl)benzamide cyclopentylmethanol 74 N-(2-oxo-1,2-dihydropyridin-4-yl)-5-(trifluoromethyl)-2-(4-(trifluoromethyl)phenoxy)benzamide 4-(trifluoromethyl)phenol 133 N-(2-oxo-1,2-dihydropyridin-4-yl)-2-(4,4,4-trifluorobutoxy)-5-(trifluoromethyl)benzamide 4,4,4-trifluorobutanol 150 2-((2-methylpyridin-3-yl)oxy)-N-(2-oxo-1,2-dihydropyridin-4-yl)-5-(trifluoromethyl)benzamide 2-methyl-3-pyridinol 57 2-(3-fluoro-5-methoxyphenoxy)-N-(2-oxo-1,2-dihydropyridin-4-yl)-5-(trifluoromethyl)benzamide 3-fluoro-5-methoxyphenol 26 2-(2,6-difluorophenoxy)-N-(2-oxo-1,2-dihydropyridin-4-yl)-5-(trifluoromethyl)benzamide 2,6-difluorophenol 134 2-((2,2-dimethylcyclopropyl)methoxy)-N-(2-oxo-1,2-dihydropyridin-4-yl)-5-(trifluoromethyl)benzamide 2,2-dimethylcyclopropyl)methanol

EXAMPLE 18

Preparation of 5-chloro-2-(4-fluoro-2-methoxyphenoxy)-N-(2-oxo-1,2-dihydropyridin-4-yl)benzamide ( 70 )

Cs ₂ CO ₃ (879.9 mg, 2.7 mmol) was added to a solution of 2-fluoro-N-(2-oxo-1,2-dihydropyridin-4-yl)-5-chlorobenzamide (72.0 mg, 0 .27 mmol) and 4-fluoro-3-methoxyphenol (307.7 µl 2.7 mmol) in DMF (1 ml) and the reaction mixture was stirred at 100°C for 1 hour. The reaction mixture is filtered and purified by reverse phase HPLC using a gradient of acetonitrile in water (10-99%) and HCl modifier to give 5-chloro-2-(4-fluoro-2-methoxyphenoxy)-N-(2-oxo -1,2-dihydropyridin-4-yl)benzamide ( 70 ) (31.8 mg, 30%). ESI-MS m/z calculated 388.06, found 389.10 (M+1) ⁺ ; Hold time: 1.52 minutes (3 minute run).

Next, using the procedure described above for compound 70 , the following compounds are prepared from 5-chloro-2-(4-fluoro-2-methoxyphenoxy)-N-(2-oxo-1,2-dihydropyridin-4-yl)benzamide im the following alcohols.

Conn. No. Product Alcohol 68 5-chloro-2-(4-fluoro-2-methylphenoxy)-N-(2-oxo-1,2-dihydropyridin-4-yl)benzamide 4-fluoro-2-methylphenol 66 5-chloro-2-(2-chloro-4-fluorophenoxy)-N-(2-oxo-1,2-dihydropyridin-4-yl)benzamide 2-chloro-4-fluorophenol 67 5-chloro-2-(4-fluorophenoxy)-N-(2-oxo-1,2-dihydropyridin-4-yl)benzamide 4-fluorophenol 71 5-chloro-2-(3-fluoro-4-methoxyphenoxy)-N-(2-oxo-1,2-dihydropyridin-4-yl)benzamide 3-fluoro-4-methoxyphenol

EXAMPLE 19

Preparation of 4-chloro-2-(4-fluoro-2-methoxyphenoxy)-N-(2-oxo-1,2-dihydropyridin-4-yl)benzamide ( 16 )

Cs ₂ CO ₃ (651.6 mg, 2.0 mmol) was added to a solution of 2-fluoro-N-(2-oxo-1,2-dihydropyridin-4-yl)-4-chlorobenzamide (53.3 mg, 0 .20 mmol) and 4-fluoro-3-methoxyphenol (284.3 mg, 2.0 mmol) in DMF (1 ml) and the reaction mixture was stirred at 100°C for 1 hour. The reaction mixture is filtered and purified by reverse phase HPLC using a gradient of acetonitrile in water (10-99%) and HCl as modifier to give 4-chloro-2-(4-fluoro-2-methoxyphenoxy)-N-(2-oxo -1,2-dihydropyridin-4-yl)benzamide ( 16 ) (22.1 mg, 28%). ESI-MS m/z calculated 388.06, found 389.15 (M+1) ⁺ ; Hold time: 1.53 minutes (3 minute run).

Using the procedure described above for compound 16 , the following compounds were then prepared from 4-chloro-2-(4-fluoro-2-methoxyphenoxy)-N-(2-oxo-1,2-dihydropyridin-4-yl)benzamide and the following alcohols.

Conn. No. Product Alcohol 20 4-chloro-2-(4-fluoro-2-methylphenoxy)-N-(2-oxo-1,2-dihydropyridin-4-yl)benzamide 4-fluoro-2-methylphenol 14 4-chloro-2-(2-chloro-4-fluorophenoxy)-N-(2-oxo-1,2-dihydropyridin-4-yl)benzamide 2-chloro-4-fluorophenol 15 4-chloro-2-(4-fluorophenoxy)-N-(2-oxo-1,2-dihydropyridin-4-yl)benzamide 4-fluorophenol 13 4-chloro-2-(2,4-difluorophenoxy)-N-(2-oxo-1,2-dihydropyridin-4-yl)benzamide 2,4-difluorophenol 129 4-chloro-N-(2-oxo-1,2-dihydropyridin-4-yl)-2-(4,4,4-trifluorobutoxy)benzamide 4,4,4-trifluorobutanol 17 4-chloro-2-(2-fluoro-6-methylphenoxy)-N-(2-oxo-1,2-dihydropyridin-4-yl)benzamide 2-fluoro-6-methylphenol 143 4-chloro-N-(2-oxo-1,2-dihydropyridin-4-yl)-2-((6-(trifluoromethyl)pyridin-3-yl)oxy)benzamide 6-(trifluoromethyl)-3-pyridinol 19 4-chloro-2-(2,6-difluorophenoxy)-N-(2-oxo-1H-pyridin-4-yl)benzamide 2,6-difluorophenol 18 4-chloro-2-(2-chloro-6-fluorophenoxy)-N-(2-oxo-1,2-dihydropyridin-4-yl)benzamide 2-chloro-6-fluorophenol

EXAMPLE 20

Preparation of 4,5-dichloro-2-(4-fluoro-2-methoxyphenoxy)-N-(2-oxo-1,2-dihydropyridin-4-yl)benzamide ( 114 )

Cs ₂ CO ₃ (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-methoxyphenol (42.6 mg, 0.3 mmol) in NMP (0.5 ml) and the reaction mixture was stirred at 90°C for 2 hours. The reaction mixture was filtered and purified by reverse phase HPLC using a gradient of acetonitrile in water (1-99%) and HCl modifier to give 4,5-dichloro-2-(4-fluoro-2-methoxyphenoxy)-N-(2 -oxo-1,2-dihydropyridin-4-yl)benzamide ( 114 ) (13.2 mg, 30%). ESI-MS m/z calculated 422.02, found 423.3 (M+1) ⁺ ; Hold time: 1.57 minutes (3 minute run).

Using the procedure described above for compound 114 , the following compounds were then prepared from 4,5-dichloro-2-fluoro-N-(2-oxo-1,2-dihydropyridin-4-yl)benzamide and the following alcohols.

Conn. No. Product Alcohol 113 4,5-dichloro-2-(4-fluorophenoxy)-N-(2-oxo-1,2-dihydropyridin-4-yl)benzamide 4-fluorophenol 115 4,5-dichloro-2-(3-fluoro-4-methoxyphenoxy)-N-(2-oxo-1,2-dihydropyridin-4-yl)benzamide 3-fluoro-4-methoxyphenol

EXAMPLE 21

Preparation of 2-(4-fluoro-2-methylphenoxy)-N-(2-oxo-1,2-dihydropyridin-4-yl)-5-(trifluoromethoxy)benzamide ( 40 )

CS ₂ CO ₃ (651.6 mg, 2 mmol) was added to a solution of 2-fluoro-N-(2-oxo-1,2-dihydropyridin-4-yl)-5-(trifluoromethoxy)benzamide (63.2 mg, 0.2 mmol) and 4-fluoro-3-methylphenol (252.3 mg, 2 mmol) in DMF (1 ml) and the reaction mixture was stirred at 100°C for 1 hour. The reaction mixture is filtered and purified by reverse phase HPLC using a gradient of acetonitrile in water (10-99%) and HCl as modifier to give 2-(4-fluoro-2-methylphenoxy)-N-(2-oxo-1,2 -dihydropyridin-4-yl)-5-(trifluoromethoxy)benzamide ( 40 ) (36.3 mg, 43%). ESI-MS m/z calculated 422.09, found 423.9 (M+1) ⁺ ; Hold time: 1.64 minutes (3 minute run).

Using the procedure described above for compound 40 , the following compounds were then prepared from 2-fluoro-N-(2-oxo-1,2-dihydropyridin-4-yl)-5-(trifluoromethoxy)benzamide and the following alcohols.

Conn. No. Product Alcohol 37 2-(2-chloro-4-fluorophenoxy)-N-(2-oxo-1,2-dihydropyridin-4-yl)-5-(trifluoromethoxy)benzamide 2-chloro-4-fluorophenol 42 2-(4-fluoro-2-methoxyphenoxy)-N-(2-oxo-1,2-dihydropyridin-4-yl)-5-(trifluoromethoxy)benzamide 4-fluoro-2-methoxyphenol 38 2-(4-fluorophenoxy)-N-(2-oxo-1,2-dihydropyridin-4-yl)-5-(trifluoromethoxy)benzamide 4-fluorophenol 33 2-(2,4-difluorophenoxy)-N-(2-oxo-1,2-dihydropyridin-4-yl)-5-(trifluoromethoxy)benzamide 2,4-difluorophenol 36 N-(2-oxo-1,2-dihydropyridin-4-yl)-2-(o-tolyloxy)-5-(trifluoromethoxy)benzamide 2-methylphenol 41 N-(2-oxo-1,2-dihydropyridin-4-yl)-2-phenoxy-5-(trifluoromethoxy)benzamide phenol 35 N-(2-oxo-1,2-dihydropyridin-4-yl)-2-(p-tolyloxy)-5-(trifluoromethoxy)benzamide 4-methylphenol 39 2-(2-fluoro-6-methylphenoxy)-N-(2-oxo-1,2-dihydropyridin-4-yl)-5-(trifluoromethoxy)benzamide 2-fluoro-6-methylphenol 138 N-(2-oxo-1,2-dihydropyridin-4-yl)-5-(trifluoromethoxy)-2-(3,3,3-trifluoropropoxy)benzamide 3,3,3-trifluoropropanol 136 2-(cyclopentylmethoxy)-N-(2-oxo-1,2-dihydropyridin-4-yl)-5-(trifluoromethoxy)benzamide Cyclopentylmethanol 139 N-(2-oxo-1,2-dihydropyridin-4-yl)-2-(4,4,4-trifluorobutoxy)-5-(trifluoromethoxy)benzamide 4,4,4-trifluorobutanol 151 2-((2-methylpyridin-3-yl)oxy)-N-(2-oxo-1,2-dihydropyridin-4-yl)-5-(trifluoromethoxy)benzamide 2-methyl-3-pyridinol 34 2-(2,6-difluorophenoxy)-N-(2-oxo-1,2-dihydropyridin-4-yl)-5-(trifluoromethoxy)benzamide 2,6-difluorophenol 137 2-(cyclohexyloxy)-N-(2-oxo-1,2-dihydropyridin-4-yl)-5-(trifluoromethoxy)benzamide cyclohexanol 140 2-((2,2-dimethylcyclopropyl)methoxy)-N-(2-oxo-1,2-dihydropyridin-4-yl)-5-(trifluoromethoxy)benzamide 2,2-dimethylcyclopropyl)methanol

EXAMPLE 22

Preparation of 2-(4-fluoro-2-methoxyphenoxy)-N-(2-oxo-1,2-dihydropyridin-4-yl)-4-(perfluoroethyl)benzamide ( 111 )

Cs ₂ CO ₃ (69.8 mg, 0.21 mmol) was added to a solution of 2-fluoro-N-(2-oxo-1,2-dihydropyridin-4-yl)-4-(perfluoroethyl)benzamide (25 mg, 0.07 mmol) and 4-fluoro-2-methoxyphenol (24.4 μl, 0.2 mmol) in NMP (0.3 ml) and the reaction mixture was stirred at 100°C for 45 minutes. The reaction mixture is poured into water:ethyl acetate (9:1). The mixture is shaken and the solid is filtered off, washed with ether, then triturated with ethyl acetate and dried to obtain the desired product. The mother liquors are filtered and washed with ethyl acetate to obtain a second batch of product. Both solids are combined and dried in vacuo to give 2-(4-fluoro-2-methoxyphenoxy)-N-(2-oxo-1H-pyridin-4-yl)-4-(1,1,2,2,2 -pentafluoroethyl)benzamide ( 111 ) (15.4 mg, 45%) as a white solid. ESI-MS m/z calculated 472.08, found 473.3 (M+1) ⁺ ; Hold time: 1.62 minutes. ^l H NMR (400 MHz, DMSO) δ 11.32 (s, 1H), 10.62 (s, 1H), 7.83 (d, J=7.9 Hz, 1H), 7.51 (d, J=7.9 Hz, 1H), 7.39-7.27 (m, 2H), 7.17 (dd, J=10.7, 2.8 Hz, 1H), 6.88 (dd, J =11.3, 5.7 Hz, 1H), 6.81 (s, 1H), 6.75 (s, 1H), 6.43 (d, J=7.1 Hz, 1H), 3.73 (s, 3H) ppm

Using the procedure described above for compound 111 , the following compounds were then prepared from 2-fluoro-N-(2-oxo-1,2-dihydropyridin-4-yl)-4-(perfluoroethyl)benzamide and the following alcohols.

Conn. No. Product Alcohol 88 2-(4-fluorophenoxy)-N-(2-oxo-1,2-dihydropyridin-4-yl)-4-(perfluoroethyl)benzamide 4-fluorophenol 112 2-(4-fluoro-2-methylphenoxy)-N-(2-oxo-1,2-dihydropyridin-4-yl)-4-(perfluoroethyl)benzamide 4-fluoro-2-methylphenol 89 2-(3-fluoro-4-methoxyphenoxy)-N-(2-oxo-1,2-dihydropyridin-4-yl)-4-(perfluoroethyl)benzamide 3-fluoro-4-methoxyphenol

EXAMPLE 23

Preparation of 4-cyano-2-(4-fluoro-2-methoxyphenoxy)-N-(2-oxo-1,2-dihydropyridin-4-yl)benzamide ( 22 )

Cs ₂ CO ₃ (651.4 mg, 2.0 mmol) was added to a solution of 4-cyano-2-fluoro-N-(2-oxo-1,2-dihydropyridin-4-yl)benzamide (51.4 mg, 0.2 mmol) and 4-fluoro-2-methoxyphenol (244 μl, 2.0 mmol) in DMF (1 ml) and the reaction mixture was stirred at 100°C for 1 hour. The reaction mixture is filtered and purified by reverse phase HPLC using a gradient of acetonitrile in water (10-99%) and HCl as modifier to give 4-cyano-2-(4-fluoro-2-methoxyphenoxy)-N-(2-oxo -1,2-dihydropyridin-4-yl)benzamide ( 22 ) (26.8 mg, 35%). ESI-MS m/z calculated 379.10, found 380.17 (M+1) ⁺ ; Hold time: 1.30 minutes (run 3 minutes).

Using the procedure described above for compound 22 , the following compounds were then prepared from 2-fluoro-N-(2-oxo-1,2-dihydropyridin-4-yl)-5-(perfluoroethyl)benzamide and the following alcohols.

Conn. No. Product Alcohol 21 4-cyano-2-(4-fluorophenoxy)-N-(2-oxo-1,2-dihydropyridin-4-yl)benzamide 4-fluorophenol 23 4-cyano-2-(4-fluoro-2-methylphenoxy)-N-(2-oxo-1,2-dihydropyridin-4-yl)benzamide 4-fluoro-2-methylphenol

EXAMPLE 24

Preparation of 5-fluoro-N-(2-oxo-1,2-dihydropyridin-4-yl)-2-(4-(trifluoromethoxy)phenoxy)benzamide ( 101 )

Cs ₂ CO ₃ (146.6 mg, 0.45 mmol) was added to a solution of 2,5-difluoro-N-(2-oxo-1,2-dihydropyridin-4-yl)benzamide (37.5 mg, 0. 15 mmol) and 4-trifluoromethoxyphenol (80.1 mg, 0.45 mmol) in DMF (0.9 ml) and the reaction mixture was stirred at 100°C for 8 hours. The reaction mixture is filtered and purified by reverse phase HPLC using a gradient of acetonitrile in water (10-99%) and HCl as modifier to give 5-fluoro-N-(2-oxo-1,2-dihydropyridin-4-yl)- 2-(4-(trifluoromethoxy)phenoxy)benzamide ( 101 ) (1.9 mg, 3%). ESI-MS m/z calculated 408.07, found 409.3 (M+1) ⁺ ; Hold time: 1.68 minutes (3 minute run).

Next, using the procedure described above for compound 101 , the following compounds are prepared from 2,5-difluoro-N-(2-oxo-1,2-dihydropyridin-4-yl)benzamide and the following alcohols.

Conn. No. Product Alcohol 100 5-fluoro-N-(2-oxo-1,2-dihydropyridin-4-yl)-2-(4-propoxyphenoxy)benzamide 4-propoxyphenol 108 2-(4-(cyclopropylmethoxy)phenoxy)-5-fluoro-N-(2-oxo-1,2-dihydropyridin-4-yl)benzamide 4-(cyclopropylmethoxy)phenol 98 2-(4-ethoxyphenoxy)-5-fluoro-N-(2-oxo-1,2-dihydropyridin-4-yl)benzamide 2-(4-ethoxyphenol) 103 2-(2-chloro-4-methoxyphenoxy)-5-fluoro-N-(2-oxo-1,2-dihydropyridin-4-yl)benzamide 2-chloro-4-methoxyphenol 107 5-fluoro-N-(2-oxo-1,2-dihydropyridin-4-yl)-2-(4-(2,2,2-trifluoroethoxy)phenoxy)benzamide 4-(2,2,2-trifluoroethoxy)phenol 96 2-(4-cyclopropylphenoxy)-5-fluoro-N-(2-oxo-1,2-dihydropyridin-4-yl)benzamide 2-(4-cyclopropylphenol 97 2-(4-(tert-butoxy)phenoxy)-5-fluoro-N-(2-oxo-1,2-dihydropyridin-4-yl)benzamide 2-(4-tert-butoxyphenol 104 5-fluoro-2-(4-methoxyphenoxy)-N-(2-oxo-1,2-dihydropyridin-4-yl)benzamide 4-methoxyphenol 94 5-fluoro-N-(2-oxo-1,2-dihydropyridin-4-yl)-2-(2,3,5-trimethylphenoxy)benzamide 2,3,5-trimethylphenol 95 5-fluoro-N-(2-oxo-1,2-dihydropyridin-4-yl)-2-phenoxybenzamide phenol 105 5-fluoro-N-(2-oxo-1,2-dihydropyridin-4-yl)-2-(2,4,5-trimethylphenoxy)benzamide 2,4,5-trimethylphenol 99 5-fluoro-2-(4-isopropylphenoxy)-N-(2-oxo-1,2-dihydropyridin-4-yl)benzamide 4-isopropylphenol 102 5-fluoro-2-(4-(2-methoxyethyl)phenoxy)-N-(2-oxo-1,2-dihydropyridin-4-yl)benzamide 4-(2-methoxyethyl)phenol 160 5-fluoro-N-(2-oxo-1,2-dihydropyridin-4-yl)-2-(4-(4,4,4-trifluorobutoxy)phenoxy)benzamide 4-(4,4,4-trifluorobutoxy)phenol

EXAMPLE 25

Preparation of 4-chloro-2-(2-chloro-4-fluorophenoxy)-5-fluoro-N-(2-oxo-1,2-dihydropyridin-4-yl)benzamide ( 109 )

Cs ₂ CO ₃ (244.4 mg, 0.75 mmol) was added to a solution of 4-chloro-2,5-difluoro-N-(2-oxo-1,2-dihydropyridin-4-yl)benzamide (71.2 mg, 0.25 mmol) and 2-chloro-4-fluorophenol (109.9 mg, 0.75 mmol) in DMF (2 ml) and the reaction mixture was stirred at 100°C for 1 hour. The reaction mixture is filtered and purified by reverse phase HPLC using a gradient of acetonitrile in water (10-99%) and HCl as modifier to give 4-chloro-2-(2-chloro-4-fluorophenoxy)-5-fluoro-N- (2-oxo-1,2-dihydropyridin-4-yl)benzamide ( 109 ) (22.8 mg, 27%). ESI-MS m/z calculated 410.00, found 411.2 (M+1) ⁺ ; Hold time: 1.76 minutes (3 minute run).

EXAMPLE 26

Preparation of 2-(4-fluoro-2-methylphenoxy)-N-(6-oxo-1,6-dihydropyridin-3-yl)-5-(trifluoromethyl)benzamide ( 106 )

To a solution of 6-methoxypyridin-3-amine (20.5 mg, 0.16 mmol) in dichloromethane (0.5 ml) add 2-(4-fluoro-2-methylphenoxy)-5-(trifluoromethyl)benzoyl chloride (50 mg , 0.15 mmol), then diisopropylethylamine (26.2 μl, 0.15 mmol) and the reaction mixture was stirred at 25°C for 16 hours and then the solvent was evaporated.

The crude amide product was dissolved in HBr (in AcOH) (250 μl 33% w/v, 1.02 mmol) and heated at 80°C for 8 hours. The reaction mixture is diluted with water and extracted with ethyl acetate (3x). The organic layers are separated and evaporated to dryness. HPLC purification (1-99% ACN in water with HCl as modifier) gives 2-(4-fluoro-2-methylphenoxy)-N-(6-oxo-1H-pyridin-3-yl)-5-(trifluoromethyl) benzamide ( 106 ) (29.97 mg, 45%) as a white solid. ESI-MS m/z calculated 406.09, found 407.10 (M+1) ⁺ ; Hold time: 1.52 minutes (3 minute run).

EXAMPLE 27

Preparation of 4-(tert-butyl)-N-(2-oxo-1,2-dihydropyridin-4-yl)-2-((6-(trifluoromethyl)pyridin-3-yl)oxy)benzamide ( 141 )

Solution of 4-(tert-butyl)-2-((6-(trifluoromethyl)pyridin-3-yl)oxy)benzoic acid (169.7 mg, 0.5 mmol), GATU (190 mg, 0.5 mmol) , 2-methoxypyridin-4-amine (62.1 mg, 0.5 mmol) and triethylamine (278.8 μl, 2 mmol) in dichloromethane (5 ml) were stirred at room temperature for 72 hours. The reaction mixture was purified by chromatography on silica gel using a gradient of ethyl acetate in hexane (0-40%) to give 4-(tert-butyl)-N-(2-methoxypyridin-4-yl)-2-((6-(trifluoromethyl)pyridine -3-yl)oxy)benzamide (137 mg, 60%). ESI-MS m/z calculated 445.16, found 446.3 (M+1) ⁺ ; Hold time: 1.87 minutes (3 minute run).

To 4-(tert-butyl)-N-(2-methoxypyridin-4-yl)-2-((6-(trifluoromethyl)pyridin-3-yl)oxy)benzamide (137 mg, 0.3 mmol) in acetonitrile (4.9 ml) add TMCI (93.3 µl, 0.66 mmol). The reaction mixture is stirred at 50°C for 12 hours. The reaction mixture is cooled to 25°C, filtered and purified by reverse phase HPLC (10-99% ACN in water with HCl modifier) to give 4-(tert-butyl)-N-(2-oxo-1,2- Dihydropyridin-4-yl)-2-((6-(trifluoromethyl)pyridin-3-yl)oxy)benzamide ( 141 ) (14.4 mg, 13%). ESI-MS m/z calculated 431.15, found 432.3 (M+1) ⁺ ; Hold time: 1.78 minutes (3 minute run).

The following products are prepared using the reaction sequence described above for compound 141 .

Conn. No. Product 6 2-(4-fluorophenoxy)-N-(6-oxo-1H-pyridin-3-yl)-4-(trifluoromethyl)benzamide 4 2-(4-fluorophenoxy)-N-(6-oxo-1,6-dihydropyridin-3-yl)-5-(trifluoromethyl)benzamide 43 2-(4-fluorophenoxy)-N-(2-oxo-1,2-dihydropyridin-4-yl)-6-(trifluoromethyl)benzamide 142 4-(tert-butyl)-N-(6-oxo-1,6-dihydropyridin-3-yl)-2-((6-(trifluoromethyl)pyridin-3-yl)oxy)benzamide 1 2-(4-fluorophenoxy)-N-(2-oxo-1,2-dihydropyridin-4-yl)benzamide 145 N-(6-oxo-1,6-dihydropyridin-3-yl)-4-(trifluoromethyl)-2-((6-(trifluoromethyl)pyridin-3-yl)oxy)benzamide 3 2-(4-fluorophenoxy)-N-(6-oxo-1,6-dihydropyridin-3-yl)benzamide

EXAMPLE 28

Preparation of 4-(tert-butyl)-N-(1-methyl-2-oxo-1,2-dihydropyridin-4-yl)-2-((6-(trifluoromethyl)pyridin-3-yl)oxy)benzamide ( 148 )

Solution of 4-(tert-butyl)-2-((6-(trifluoromethyl)pyridin-3-yl)oxy)benzoic acid (67.9 mg, 0.2 mmol), GATU (66 mg, 0.2 mmol) , 5-amino-1-methylpyridyl-2-one (24.8 mg, 0.2 mmol) and triethylamine (111 µl, 0.8 mmol) in dichloromethane (0.9 ml) stirred at room temperature for 72 hours . The reaction mixture is filtered and purified by reverse phase HPLC using a gradient of acetonitrile in water (10-99%) and HCl as modifier to give 4-(tert-butyl)-N-(1-methyl-2-oxo-1,2 -dihydropyridin-4-yl)-2-((6-(trifluoromethyl)pyridin-3-yl)oxy)benzamide ( 148 ) (1.2 mg, 1%). ESI-MS m/z calculated 445.16, found 446.3 (M+1) ⁺ ; Hold time: 1.85 minutes (3 minute run).

4-tert-Butyl-N-(1-methyl-6-oxo-3-pyridyl)-2-[[6-(trifluoromethyl)-3-pyridyl]oxy]benzamide ( 149 ) was prepared using the reaction sequence described above for connection 148 .

EXAMPLE 29

Preparation of 2-(4-fluorophenoxy)-N-(1-(2-hydroxyethyl)-2-oxo-1,2-dihydropyridin-4-yl)-4-(trifluoromethyl)benzamide ( 85 )

To 2-(4-fluorophenoxy)-N-(2-oxo-1H-pyridin-4-yl)-5-(trifluoromethyl)benzamide (78.5 mg, 0.2 mmol) in DMF (1 ml) add the hydride sodium (4.8 mg, 0.20 mmol) and 2-bromoethanol (14.17 μl, 0.20 mmol) and the reaction mixture was stirred at room temperature for 16 hours. Sodium hydride (4.8 mg, 0.20 mmol) and 2-bromoethanol (14.17 0.20 mmol) were re-added to the reaction mixture and stirred for another 8 hours, then 2 more equivalents of sodium hydride and 2-bromoethanol were added and the reaction mixture is heated at 50°C overnight. 29 mg of NaH and 86 μl of 2-bromoethanol are added and the reaction mixture is heated at 50°C for 2.5 hours. Another 29 mg of NaH and 86 μl of 2-bromoethanol are added and the reaction mixture is heated at 100°C for 5 hours. The reaction mixture is quenched with methanol and the solvent is evaporated under reduced pressure. The crude product is dissolved in DMF, filtered and purified by preparative reverse phase chromatography using a gradient of 10-99% acetonitrile in water containing HCl as modifier to give 2-(4-fluorophenoxy)-N-(1-(2-hydroxyethyl) -2-oxo-1,2-dihydropyridin-4-yl)-4-(trifluoromethyl)benzamide ( 85 ) (43.6 mg, 50%). ¹ H NMR (400 MHz, DMSO-d6) δ 10.63 (s, 1H), 7.99 (d, J=2.3 Hz, 1H), 7.83 (dd, J=8.8, 2 .4 Hz, 1H), 7.54 (d, J=7.4 Hz, 1H), 7.38-7.22 (m, 4H), 6.98 (d, J=8.7 Hz, 1H ), 6.85 (d, J=2.4 Hz, 1H), 6.42 (dd, J=7.4, 2.4 Hz, 1H), 3.87 (t, J=5.5 Hz , 2H), 3.57 (t, J=5.5 Hz, 2H) ppm. ESI-MS m/z calculated 436.1, found 437.3 (M+1) ⁺ ; Hold time: 1.72 minutes (3 minute run).

EXAMPLE 30

Preparation of 2-(4-fluoro-2-methoxyphenoxy)-N-(2-oxo-1,2-dihydropyridin-4-yl)-4,6-bis(trifluoromethyl)benzamide ( 154 )

A solution of 2-fluoro-N-(2-oxo-1H-pyridin-4-yl)-4,6-bis(trifluoromethyl)benzamide (40 mg, 0.11 mmol), 4-fluoro-2-methoxyphenol (12, 4 µl, 0.11 mmol) and potassium carbonate (45 mg, 0.33 mmol) are combined in DMF (0.5 ml) and heated at 90°C for 16 hours. The reaction mixture is filtered, diluted with DMSO (0.5 ml) and purified by reverse phase HPLC using a 25-99% acetonitrile:water gradient and 5 mM HCl modifier to give 2-(4-fluoro-2-methoxyphenoxy)-N-(2-oxo-1,2- Dihydropyridin-4-yl)-4,6-bis(trifluoromethyl)benzamide ( 154 ) (17.2 mg, 32%). ^l H NMR (400 MHz, DMSO-d6) δ 11.38 (br.s, 1H), 10.91 (s, 1H), 7.91 (s, 1H), 7.35 (d, J=7 ,2 Hz, 1H), 7.26 (dd, J=8.9, 5.8 Hz, 1H), 7.20 (dd, J=10.7, 2.9 Hz, 1H), 7.15 (s, 1H), 6.88 (td, J=8.5, 2.9 Hz, 1H), 6.73 (d, J=2.1 Hz, 1H), 6.37 (dd, J= 7.2, 2.1 Hz, 1H), 3.79 (s, 3H) ppm. ESI-MS m/z calculated 490.08, found 491.3 (M+1) ⁺ ; Hold time: 1.60 minutes (3 minute run).

The following products are prepared using the reaction sequence described above for compound 154 .

Conn. No. Product Alcohol 156 N-(2-oxo-1,2-dihydropyridin-4-yl)-2-phenoxy-4,6-bis(trifluoromethyl)benzamide Phenol 155 2-(4-fluorophenoxy)-N-(2-oxo-1,2-dihydropyridin-4-yl)-4,6-bis(trifluoromethyl)benzamide 4-fluorophenol 153 2-(4-fluoro-2-methylphenoxy)-N-(2-oxo-1,2-dihydropyridin-4-yl)-4,6-bis(trifluoromethyl)benzamide 4-fluoro-2-methylphenol 152 2-(2,4-difluorophenoxy)-N-(2-oxo-1,2-dihydropyridin-4-yl)-4,6-bis(trifluoromethyl)benzamide 2,4-difluorophenol

Analytical data for compounds of this invention are presented below in Table 2. Mass spectrum (e.g. M+1 data in Table 2), final purity and retention time determined by reverse phase HPLC using a Kinetix C18 column (50 x 2.1 mm, 1.7 µm particles) from Phenomenex (pn: 00B-4475-AN)) and a double gradient run from 1-99% mobile phase B for 3 minutes. Mobile phase A = H ₂ O (0.05% CF ₃ CO ₂ H). Mobile phase B = CH ₃ CN (0.05% CF ₃ CO ₂ H). Flow rate = 2 mL/min, injection volume = 3 μL, and column temperature = 50°C.

table 2
Analytical data Conn. No. HPLC VU per min MS (M+1) ¹ H-NMR (400 MHz) 1 1.48 325.3 (DMSO-d₆) δ 11.23 (s, 1H), 10.44 (s, 1H), 7.62 (dd, J=7.6, 1.7 Hz, 1H), 7.50 (m, 1H), 7 .25 (ddd, J=9.4, 8.6, 5.3 Hz, 4H), 7.12 (t, 2H), 6.91 (d, J=8.0 Hz, 1H), 6.77 (d, J=1.9 Hz, 1H), 6.40 (dd, J=7.2, 2.0 Hz, 1H) ppm 2 1.72 393.1 (DMSO-d ₆ ) δ 11.40 (s, 1H), 10.64 (s, 1H), 8.00 (d, J=2.2 Hz, 1H), 7.83 (dd, J=8 ,8, 2.3 Hz, 1H), 7.30 (tdd, J=6.9, 5.9, 3.4 Hz, 5H), 6.99 (d, J=8.8 Hz, 1H) , 6.82 (d, J=1.8 Hz, 1H), 6.43 (dd, J=7.2, 2.0 Hz, 1H) ppm. 3 1.47 325.3 (DMSO-d ₆ ) δ 10.09 (s, 1H), 7.92 (d, J=2.8 Hz, 1H), 7.63 (dd, J=7.6, 1.7 Hz, 1H ), 7.50 (m, 2H), 7.23 (m, 3H), 7.08 (m, 2H), 6.93 (d, J=7.6 Hz, 1H), 6.38 (d , J=9.7 Hz, 1H) ppm 4 1.7 393.1 (DMSO-d ₆ ) δ 11.54 (m, 0H), 10.24 (s, 1H), 7.95 (dd, J=19.3, 2.5 Hz, 2H), 7.81 (dd , J=8.8, 2.1 Hz, 1H), 7.51 (dd, J=9.7, 2.9 Hz, 1H), 7.27 (m, 4H), 7.01 (d, J=8.6 Hz, 1H), 6.38 (d, J=9.7 Hz, 1H) ppm. 5 1.72 393.1 (DMSO-d ₆ ) δ 11.31 (s, 1H), 10.63 (s, 1H), 7.85 (d, J=7.9 Hz, 1H), 7.63 (d, J=7 ,9 Hz, 1H), 7.29 (ddd, J=8.2, 6.6, 4.6 Hz, 3H), 7.21 (m, 2H), 7.14 (s, 1H), 6 .76 (d, J=1.6 Hz, 1H), 6.39 (dd, J=7.2, 2.0 Hz, 1H) ppm. 6 1.69 393.1 (DMSO-d ₆ ) δ 11.43 (s, 1H), 10.27 (s, 1H), 7.90 (d, J=2.7 Hz, 1H), 7.84 (d, J=7 .9 Hz, 1H), 7.62 (d, J=7.1 Hz, 1H), 7.48 (dd, J=9.7, 2.9 Hz, 1H), 7.27 (dt, J =12.2, 3.0 Hz, 2H), 7.18 (m, 3H), 6.37 (d, J=9.7 Hz, 1H) ppm. 7 1.55 411.17 8 1.52 449.26 9 1.69 375.1 (DMSO-d ₆ ) δ 11.26 (s, 1H), 10.62 (s, 1H), 7.86 (d, J=7.9 Hz, 1H), 7.63 (d, J=8 ,0 Hz, 1H), 7.44 (m, 2H), 7.30 (d, J=7.2 Hz, 1H), 7.23 (t, J=7.4 Hz, 1H), 7, 15 (dd, J=7.1, 6.1 Hz, 3H), 6.75 (d, J=1.7 Hz, 1H), 6.37 (dd, J=7.2, 2.0 Hz , 1H) ppm 10 1.79 407.1 (DMSO-d ₆ ) δ 11.27 (s, 1H), 10.63 (s, 1H), 7.84 (d, J=7.8 Hz, 1H), 7.60 (d, J=7 .8 Hz, 1H), 7.31 (d, J=7.2 Hz, 1H), 7.23 (m, 1H), 7.10 (m, 2H), 6.97 (s, 1H), 6.76 (d, J=1.6 Hz, 1H), 6.38 (dd, J=7.2, 2.0 Hz, 1H), 2.16 (s, 3H) ppm. eleven 1.76 389.1 (DMSO-d ₆ ) δ 11.27 (s, 1H), 10.64 (s, 1H), 7.84 (d, J=7.8 Hz, 1H), 7.60 (d, J=7 .9 Hz, 1H), 7.30 (m, 3H), 7.16 (td, J=7.4, 1.1 Hz, 1H), 7.00 (m, 2H), 6.75 (d , J=1.8 Hz, 1H), 6.38 (dd, J=7.2, 2.1 Hz, 1H), 2.17 (s, 3H) ppm. 12 1.8 389.1 (DMSO-d ₆ ) δ 11.27 (s, 1H), 10.60 (s, 1H), 7.83 (d, J=8.0 Hz, 1H), 7.59 (d, J=8 .0 Hz, 1H), 7.31 (d, J=7.2 Hz, 1H), 7.25 (d, J=8.2 Hz, 2H), 7.05 (d, J=8.5 Hz, 3H), 6.76 (s, 1H), 6.38 (dd, J=7.2, 2.0 Hz, 1H), 2.31 (s, 3H) ppm. 13 1.48 377.1 14 1.55 393.1 15 1.48 359.2 (DMSO-d ₆ ) δ 11.25 (s, 1H), 10.48 (s, 1H), 7.65 (t, J=8.5 Hz, 1H), 7.29 (m, 4H), 7.19 (m, 2H), 6.91 (d, J=1.9 Hz, 1H), 6.75 (d, J=1.9 Hz, 1H), 6.38 (dd, J=7 ,2, 2.1 Hz, 1H) ppm 16 1.53 389.2 17 1.53 373.2 18 1.43 393.0 19 1.43 377.1 20 1.57 373.2 (DMSO-d ₆ ) δ 11.48 (s, 1H), 10.57 (s, 1H), 7.65 (d, J=8.2 Hz, 1H), 7.36 (d, J=7 .2 Hz, 1H), 7.30 (dd, J=8.2, 1.9 Hz, 1H), 7.21 (d, J=9.3 Hz, 1H), 7.10 (m, 2H ), 6.83 (d, J=1.9 Hz, 1H), 6.74 (d, J=1.9 Hz, 1H), 6.45 (dd, J=7.2, 2.1 Hz , 1H), 2.16 (s, 3H) ppm. 21 1.26 350.1 22 1.3 380.2 23 1.4 364.1 24 1.52 411.2 25 1.28 400.3 26 1.47 411.2 (DMSO-d ₆ ) δ 11.30 (s, 1H), 10.71 (d, J=7.0 Hz, 1H), 8.03 (d, J=2.1 Hz, 1H), 7, 83 (d, J=8.4 Hz, 1H), 7.39 (m, 4H), 7.03 (d, J=8.7 Hz, 1H), 6.84 (d, J=21.3 Hz, 1H), 6.46 (m, 1H) ppm. 27 1.62 389.3 28 1.58 389.3 (DMSO-d ₆ ) δ 11.28 (s, 1H), 10.62 (s, 1H), 7.99 (d, J=2.2 Hz, 1H), 7.80 (dd, J=8 ,8, 2.2 Hz, 1H), 7.31 (ddd, J=12.7, 9.2, 4.5 Hz, 3H), 7.20 (td, J=7.4, 1.2 Hz, 1H), 7.12 (m, 1H), 6.81 (dd, J=12.2, 5.3 Hz, 2H), 6.41 (dd, J=7.2, 2.1 Hz , 1H), 2.15 (s, 3H) ppm. 29 1.57 427.2 (DMSO-d ₆ ) δ 11.29 (s, 1H), 10.62 (s, 1H), 8.02 (d, J=2.2 Hz, 1H), 7.83 (dd, J=8 ,8, 2.2 Hz, 1H), 7.69 (dd, J=8.4, 3.0 Hz, 1H), 7.45 (dd, J=9.1, 5.3 Hz, 1H) , 7.40-7.30 (m, 2H), 6.92 (d, J=8.7 Hz, 1H), 6.79 (d, J=1.9 Hz, 1H), 6.42 ( dd, J=7.2, 2.1 Hz, 1H) ppm thirty 1.56 423.2 31 1.6 407.2 (DMSO-d ₆ ) δ 11.77 (s, 1H), 10.79 (s, 1H), 8.00 (d, J=2.2 Hz, 1H), 7.80 (dd, J=8 ,8, 2.3 Hz, 1H), 7.45 (d, J=7.2 Hz, 1H), 7.25 (dd, J=9.3, 3.0 Hz, 1H), 7.16 (m, 2H), 6.95 (d, J=1.9 Hz, 1H), 6.83 (d, J=8.7 Hz, 1H), 6.56 (dd, J=7.2, 2.0 Hz, 1H), 2.14 (s, 3H) ppm. 32 1.5 375.2 (DMSO-d₆) δ 11.32 (s, 1H), 10.62 (s, 1H), 7.99 (s, 1H), 7.83 (m, 1H), 7.47 (t, J=7.9 Hz , 2H), 7.29 (m, 2H), 7.19 (d, J=7.6 Hz, 2H), 7.00 (d, J=8.7 Hz, 1H), 6.79 (s , 1H), 6.41 (t, 1H) ppm 33 1.59 427.1 34 1.51 427.2 35 1.64 405.2 36 1.62 405.2 37 1.61 443.1 38 1.56 409.1 39 1.6 423.1 40 1.64 423.1 41 1.54 391.1 42 1.62 439.1 43 1.51 393.3 (DMSO-d ₆ ) δ 11.29 (s, 1H), 10.80 (s, 1H), 7.69-7.56 (m, 2H), 7.34-7.25 (m, 3H) , 7.22-7.14 (m, 3H), 6.71 (d, J=2.0 Hz, 1H), 6.34 (dd, J=7.2, 2.1 Hz, 1H) m .d. 44 1.83 419.3 (DMSO-d₆) δ 11.43 (s, 1H), 10.62 (s, 1H), 7.95 (d, J=2.4 Hz, 1H), 7.80 (dd, J=8.9, 2, 4 Hz, 1H), 7.35 (d, J=7.1 Hz, 1H), 7.22-7.10 (m, 2H), 7.07-6.95 (t, 2H), 6.95-6.80 (m, 2H), 6.45 (dd, J=7.3, 2.1 Hz, 1H), 4.03 (kv, J=6.9 Hz, 2H ), 1.33 (t, J=6.9 Hz, 3H) ppm. 45 1.73 405.4 (DMSO-d₆) δ 11.51 (s, 1H), 10.66 (s, 1H), 7.96 (d, J=2.2 Hz, 1H), 7.80 (dd, J=8.9, 2, 4 Hz, 1H), 7.38 (d, J=7.2 Hz, 1H), 7.24-7.10 (m, 2H), 7.08-6.96 (t, 2H), 6.92-6.86 (m, 2H), 6.48 (dd, J=7.2, 2.1 Hz, 1H), 3.77 (s, 3H) ppm. 46 1.81 419.3 (DMSO-d ₆ ) δ 11.31 (s, 1H), 10.50 (s, 1H), 7.95 (d, J=2.3 Hz, 1H), 7.78 (dd, J=8 ,8, 2.4 Hz, 1H), 7.33 (d, J=7.2 Hz, 1H), 7.31- 7.24 (m, 2H), 7.20 (dd, J=8, 3, 1.6 Hz, 1H), 7.04 (td, J=7.6, 1.6 Hz, 1H), 6.89- 6.74 (m, 2H), 6.43 (dd, J =7.2, 2.1 Hz, 1H), 4.02 (kv, J=7.0 Hz, 2H), 1.12 (t, J=6.9 Hz, 3H) ppm. 47 1.84 419.3 (DMSO-d ₆ ) δ 11.28 (s, 1H), 10.50 (s, 1H), 7.92 (d, J=2.3 Hz, 1H), 7.75 (dd, J=8 ,8, 2.3 Hz, 1H), 7.32 (d, J=7.1 Hz, 1H), 7.16 (d, J=8.1 Hz, 1H), 7.05 (d, J =2.1 Hz, 1H), 6.85 (dd, J=8.1, 2.1 Hz, 1H), 6.82 (d, J=2.1 Hz, 1H), 6.74 (d , J=8.7 Hz, 1H), 6.42 (dd, J=7.3, 2.1 Hz, 1H), 3.72 (s, 3H), 2.35 (s, 3H) m. d. 48 1.73 423.3 (DMSO-d ₆ ) δ 11.52 (s, 1H), 10.64 (s, 1H), 7.97 (d, J=2.3 Hz, 1H), 7.78 (dd, J=8 ,9, 2.3 Hz, 1H), 7.41-7.36 (m, 1H), 7.36-7.30 (m, 1H), 7.14-7.00 (m, 2H), 6.90 (d, J=2.0 Hz, 1H), 6.83 (d, J=8.8 Hz, 1H), 6.51 (dd, J=7.2, 2.1 Hz, 1H ), 3.79 (s, 3H) ppm. 49 1.8 439.2 50 1.89 423.3 51 1.79 427.1 52 1.74 423.3 53 1.94 433.4 54 1.73 423.3 55 1.74 423.3 (DMSO-d ₆ ) δ 11.50 (s, 1H), 10.70 (s, 1H), 7.98 (d, J=2.3 Hz, 1H), 7.81 (dd, J=8 ,8, 2.3 Hz, 1H), 7.43-7.28 (m, 2H), 7.10 (dd, J=12.7, 2.9 Hz, 1H), 6.95-6, 83 (m, 3H), 6.48 (dd, J=7.3, 2.1 Hz, 1H), 3.79 (s, 3H) ppm. 56 1.8 407.4 57 1.58 423.3 (DMSO-d ₆ ) δ 11.52 (s, 1H), 10.90 (s, 1H), 7.74 (d, J=2.3 Hz, 1H), 7.47 (dd, J=8 ,7, 2.4 Hz, 1H), 7.33 (d, J=7.2 Hz, 1H), 6.87 (d, J=8.6 Hz, 1H), 6.84-6.72 (m, 3H), 6.17 (d, J=7.2 Hz, 1H), 6.06 (d, J=2.1 Hz, 1H), 3.69 (s, 3H) ppm. 58 1.81 409.3 59 1.72 423.3 60 2.04 441.3 (DMSO-d ₆ ) δ 11.41 (s, 1H), 10.95 (s, 1H), 8.02 (d, J=2.1 Hz, 1H), 7.81 (dd, J=8 ,8, 2.3 Hz, 1H), 7.29-7.09 (m, 4H), 6.97 (s, 1H), 6.84 (d, J= 8.7 Hz, 1H), 2 .13 (s, 3H) ppm 61 1.85 421.3 (DMSO-d ₆ ) δ 11.45 (s, 1H), 10.57 (s, 1H), 7.97 (d, J=2.2 Hz, 1H), 7.79 (dd, J=8 ,8, 2.3 Hz, 1H), 7.26 (dd, J=9.4, 2.9 Hz, 1H), 7.22-7.08 (m, 2H), 6.81 (d, J=8.7 Hz, 1H), 6.67 (d, J=1.3 Hz, 1H), 6.27 (s, 1H), 2.15 (s, 3H), 2.14 (s, 3H) ppm 62 1.91 433.4 (DMSO-d ₆ ) δ 11.27 (s, 1H), 10.47 (s, 1H), 7.95 (d, J=2.2 Hz, 1H), 7.77 (dd, J=8 ,8, 2.3 Hz, 1H), 7.36-7.23 (m, 3H), 7.23-7.17 (m, 1H), 7.08-7.00 (m, 1H), 6.84-6.77 (m, 2H), 6.42 (dd, J=7.2, 2.0 Hz, 1H), 3.90 (t, J=6.3 Hz, 2H), 1 .62-1.38 (m, 2H), 0.67 (t, J=7.4 Hz, 3H) ppm. 63 1.81 419.3 (DMSO-d ₆ ) δ 11.38 (s, 1H), 10.62 (s, 1H), 7.96 (d, J=2.2 Hz, 1H), 7.77 (dd, J=8 ,8, 2.3 Hz, 1H), 7.35 (d, J=7.2 Hz, 1H), 7.11 (d, J=8.8 Hz, 1H), 6.94 (d, J =2.9 Hz, 1H), 6.90-6.80 (m, 2H), 6.74 (d, J=8.8 Hz, 1H), 6.45 (dd, J=7.2, 2.0 Hz, 1H), 3.76 (s, 3H), 2.10 (s, 3H) ppm. 64 1.87 433.4 (DMSO-d ₆ ) δ 11.29 (s, 1H), 10.46 (s, 1H), 7.96 (d, J=2.2 Hz, 1H), 7.78 (dd, J=8 ,8, 2.0 Hz, 1H), 7.40-7.12 (m, 4H), 7.12-6.93 (m, 1H), 6.86-6.73 (m, 2H), 6.42 (dd, J=7.2, 2.1 Hz, 1H), 4.69-4.41 (m, 1H), 1.07 (d, J=6.0 Hz, 6H) m. d. 65 1.74 409.3 (DMSO-d ₆ ) δ 11.30 (s, 1H), 10.62 (s, 1H), 8.02 (d, J=2.2 Hz, 1H), 7.84 (dd, J=8 ,8, 2.3 Hz, 1H), 7.65 (dd, J=7.9, 1.5 Hz, 1H), 7.54-7.39 (m, 1H), 7.39-7, 24 (m, 3H), 6.91 (d, J=8.7 Hz, 1H), 6.79 (d, J=1.8 Hz, 1H), 6.41 (dd, J=7.2 , 2.1 Hz, 1H) ppm 66 1.64 393.1 67 1.46 359.2 68 1.57 373.1 69 1.46 377.1 70 1.52 389.1 71 1.46 389.2 72 1.93 459.3 (DMSO-d ₆ ) δ 11.29 (s, 1H), 10.62 (s, 1H), 8.02 (d, J=2.3 Hz, 1H), 7.86 (dd, J=8 ,7, 2.4 Hz, 1H), 7.58-7.40 (m, 2H), 7.40-7.21 (m, 3H), 7.11 (d, J=8.7 Hz, 1H), 6.76 (d, J=2.1 Hz, 1H), 6.38 (dd, J=7.2, 2.1 Hz, 1H) ppm. 73 1.83 441.5 (DMSO-d ₆ ) δ 11.77 (s, 1H), 10.79 (s, 1H), 8.01 (d, J=2.3 Hz, 1H), 7.85 (dd, J=8 ,9, 2.4 Hz, 1H), 7.49-6.99 (t, 7H), 6.94 (d, J=2.0 Hz, 1H), 6.54 (dd, J=7, 2, 2.1 Hz, 1H) ppm 74 1.75 443.5 (DMSO-d ₆ ) δ 11.55 (s, 1H), 10.93 (s, 1H), 7.83-7.67 (m, 3H), 7.61-7.45 (m, 3H) , 7.33 (d, J=7.0 Hz, 1H), 6.88 (d, J=8.5 Hz, 1H), 6.11-5.98 (m, 2H) ppm. 75 1.83 459.3 (DMSO-d ₆ ) δ 11.28 (s, 1H), 10.63 (s, 1H), 8.04 (d, J=2.3 Hz, 1H), 7.86 (dd, J=8 ,7, 2.4 Hz, 1H), 7.60-7.54 (m, 1H), 7.54-7.43 (m, 1H), 7.43-7.34 (m, 1H), 7.34-7.28 (m, 2H), 7.05 (d, J=8.7 Hz, 1H), 6.75 (d, J=2.0 Hz, 1H), 6.38 (dd , J=7.2, 2.1 Hz, 1H) ppm 76 1.76 441.5 (DMSO-d ₆ ) δ 11.56 (s, 1H), 10.69 (s, 1H), 8.02 (d, J=2.3 Hz, 1H), 7.84 (dd, J=8 ,8, 2.4 Hz, 1H), 7.47-6.97 (m, 6H), 6.94 (d, J=8.7 Hz, 1H), 6.87 (d, J=2, 0 Hz, 1H), 6.49 (dd, J=7.2, 2.1 Hz, 1H) ppm. 77 1.78 427.3 (DMSO-d ₆ ) δ 11.29 (s, 1H), 10.64 (s, 1H), 7.87 (d, J=8.0 Hz, 1H), 7.71-7.61 (m , 2H), 7.39-7.26 (m, 3H), 7.13-7.06 (m, 1H), 6.75 (d, J=2.0 Hz, 1H), 6.39 ( dd, J=7.2, 2.1 Hz, 1H) ppm 78 1.73 409.3 (DMSO-d₆) δ 11.28 (s, 1H), 10.62 (s, 1H), 7.87 (d, J=8.0 Hz, 1H), 7.67 (d, J=7.1 Hz, 1H ), 7.48 (m, 2H), 7.30 (m, 2H), 7.13 (t, 2H), 6.73 (s, 1H), 6.36 (dd, J=7.2, 2.0 Hz, 1H) ppm. 79 1.8 459.5 80 1.74 459.3 81 1.65 423.3 82 1.71 441.3 83 1.68 441.3 84 1.67 423.3 (DMSO-d ₆ ) δ 11.34 (s, 1H), 10.67 (s, 1H), 7.83 (d, J=7.8 Hz, 1H), 7.60 (d, J=7 .9 Hz, 1H), 7.32 (m, 2H), 7.09 (dd, J=12.7, 3.0 Hz, 1H), 6.98 (s, 1H), 6.87 (m , 1H), 6.80 (d, J=1.7 Hz, 1H), 6.42 (dd, J=7.2, 2.0 Hz, 1H), 3.79 (s, 3H) m. d. 85 1.72 437.3 (DMSO-d ₆ ) δ 10.63 (s, 1H), 7.99 (d, J=2.3 Hz, 1H), 7.83 (dd, J=8.8, 2.4 Hz, 1H ), 7.54 (d, J=7.4 Hz, 1H), 7.38-7.22 (m, 4H), 6.98 (d, J=8.7 Hz, 1H), 6.85 (d, J=2.4 Hz, 1H), 6.42 (dd, J=7.4, 2.4 Hz, 1H), 3.87 (t, J=5.5 Hz, 2H), 3 .57 (t, J=5.5 Hz, 2H) ppm 86 1.89 421.2 (DMSO-d ₆ ) δ 11.66 (s, 1H), 9.91 (s, 1H), 8.22 (d, J=2.4 Hz, 1H), 7.85 (dd, J=8 ,8, 2.4 Hz, 1H), 7.45-7.28 (m, 4H), 7.20 (td, J=8.5, 3.1 Hz, 1H), 6.78 (d, J=8.8 Hz, 1H), 2.17 (s, 3H), 1.96 (s, 3H) ppm. 87 1.67 423.1 88 1.59 443.5 (DMSO-d ₆ ) δ 7.87 (d, J=7.9 Hz, 1H), 7.59 (d, J=7.6 Hz, 1H), 7.37-7.25 (m, 3H ), 7.24-7.16 (m, 2H), 7.07 (s, 1H), 6.73 (s, 1H), 6.37 (d, J=6.9 Hz, 1H) m. d. 89 1.58 473.3 (DMSO-d ₆ ) δ 11.28 (s, 1H), 10.62 (s, 1H), 7.87 (d, J=8.0 Hz, 1H), 7.58 (d, J=8 .2 Hz, 1H), 7.31 (d, J=6.9 Hz, 1H), 7.27-7.16 (m, 2H), 7.07 (s, 1H), 6.98 (d , J=8.9 Hz, 1H), 6.76 (s, 1H), 6.38 (d, J=7.1 Hz, 1H), 3.84 (s, 3H) ppm. 90 1.76 429.3 91 1.98 417.4 92 1.81 425.2 93 1.99 417.4 94 1.83 367.3 95 1.5 325.5 (DMSO-d ₆ ) δ 11.24 (s, 1H), 10.49 (s, 1H), 7.54 (dd, J=8.4, 3.2 Hz, 1H), 7.43-7 .32 (m, 3H), 7.28 (d, J=7.2 Hz, 1H), 7.12 (t, J=7.4 Hz, 1H), 7.05 (dd, J=9, 0, 4.5 Hz, 1H), 7.03-6.97 (m, 2H), 6.71 (d, J=1.9 Hz, 1H), 6.37 (dd, J=7.2 , 2.1 Hz, 1H) ppm 96 1.69 365.3 97 1.66 397.3 (DMSO-d ₆ ) δ 11.23 (s, 1H), 10.46 (s, 1H), 7.50 (dd, J=8.4, 3.2 Hz, 1H), 7.40-7 .32 (m, 1H), 7.28 (d, J=7.1 Hz, 1H), 7.00 (dd, J=9.1, 4.4 Hz, 1H), 6.98-6, 92 (m, 4H), 6.72 (d, J=1.8 Hz, 1H), 6.37 (dd, J=7.2, 2.0 Hz, 1H), 1.24 (s, 9H ) m.d. 98 1.61 369.3 99 1.74 367.3 100 1.73 383.3 101 1.68 409.3 102 1.53 383.3 103 1.61 389.5 (DMSO-d₆) δ 11.26 (s, 1H), 10.50 (s, 1H), 7.52 (dd, J=8.4, 3.2 Hz, 1H), 7.36-7.27 (t, 2H), 7.17 (dd, J=6.0, 3.0 Hz, 2H), 6.97 (dd, J=9.0, 3.0 Hz, 1H), 6.81-6.73 (m, 2H), 6.43-6.36(t, 1H), 3.77 (s, 3H) ppm. 104 1.54 355.5 105 1.85 367.3 106 1.52 407.1 107 1.74 423.3 (DMSO-d₆) δ 11.27 (s, 1H), 10.49 (s, 1H), 7.52 (dd, J=8.4, 3.2 Hz, 1H), 7.41-7.23 (t, 2H), 7.13-7.00 (t, 4H), 6.94 (dd, J=9.1, 4.3 Hz, 1H), 6.75 (d, J=2.1 Hz, 1H), 6.39 (dd, J=7.2 , 2.1 Hz, 1H), 4.73 (kv, J=8.9 Hz, 2H) ppm. 108 1.78 395.3 (DMSO-d₆) δ 11.28 (s, 1H), 10.48 (s, 1H), 7.49 (dd, J=8.4, 3.3 Hz, 1H), 7.40-7.23 (t, 2H), 7.04-6.97 (t, 2H), 6.97-6.91 (t, 2H), 6.91-6.86 (t, 1H), 6.77 (d, J=2.0 Hz, 1H), 6.40 (dd, J=7.2, 2.1 Hz, 1H), 3.77 (d, J=7.0 Hz, 2H), 1.28-1.07 (t, 1H), 0.62-0.42 (t, 2H), 0.39-0.20 (t, 2H) ppm 109 1.76 411.2 (DMSO-d₆) δ 11.39 (s, 1H), 10.60 (s, 1H), 7.88-7.79(T,1H), 7.61 (dd, J=8.4, 2.9 Hz, 1H), 7.33 (d, J=7.2 Hz, 1H), 7.31-7.16 (t, 3H), 6.74 (d, J=2.1 Hz, 1H), 6.39 (dd, J=7.3, 2.1 Hz, 1H) ppm. 110 1.52 457.3 (DMSO-d ₆ ) δ 11.48 (s, 1H), 10.66 (s, 1H), 7.86 (d, J=7.9 Hz, 1H), 7.63 (d, J=7 .9 Hz, 1H), 7.47 (d, J=8.7 Hz, 1H), 7.41 (d, J=11.6 Hz, 1H), 7.37 (d, J=7.2 Hz, 1H), 7.03 (s, 1H), 6.83 (s, 1H), 6.45 (d, J=7.1 Hz, 1H), 3.89 (s, 3H) ppm . 111 1.62 473.3 (DMSO-d₆) δ 11.32 (s, 1H), 10.62 (s, 1H), 7.83 (d, J=7.9 Hz, 1H), 7.51 (d, J=7.9 Hz, 1H ), 7.39-7.27 (t, 2H), 7.17 (dd, J=10.7, 2.8 Hz, 1H), 6.88 (dd, J=11.3, 5.7 Hz, 1H), 6.81 (s, 1H ), 6.75 (s, 1H), 6.43 (d, J=7.1 Hz, 1H), 3.73 (s, 3H) ppm. 112 1.66 457.5 (DMSO-d₆) δ 11.29 (s, 1H), 10.66 (s, 1H), 7.87 (d, J=7.9 Hz, 1H), 7.57 (d, J=7.9 Hz, 1H ), 7.31 (d, J=7.1 Hz, 1H), 7.24 (dd, J=9.2, 2.7 Hz, 1H), 7.17-7.04 (t, 2H), 6.90 (s, 1H), 6.76 (d, J=1.8 Hz, 1H), 6.38 (dd, J=7.2, 2.0 Hz, 1H), 2, 15 (s, 3H) ppm 113 1.53 393.1 (DMSO-d₆) δ 11.32 (s, 1H), 10.57 (s, 1H), 7.95 (s, 1H), 7.34-7.24 (t, 3H), 7.22-7.15 (t, 3H), 6.74 (s, 1H), 6.38 (d, J=7.2 Hz, 1H) ppm. 114 1.57 423.3 (DMSO-d₆) δ 11.27 (s, 1H), 10.49 (s, 1H), 7.90 (br.s, 1H), 7.32 (d, J=7.2 Hz, 1H), 7.28 (dd, J=8.9, 5.8 Hz, 1H), 7.14 (dd, J=10.7, 2.9 Hz, 1H), 6.89-6.82 (t, 2H), 6.77 (s, 1H), 6.39 (dd, J=7.2, 2.1 Hz, 1H), 3.76 (s, 3H) ppm. 115 1.52 423.3 (DMSO-d ₆ ) δ 11.41 (s, 1H), 10.57 (s, 1H), 7.94 (s, 1H), 7.34 (d, J=7.4 Hz, 1H), 7.30-7.12 (m, 3H), 6.96 (d, J=8.5 Hz, 1H), 6.78 (s, 1H), 6.40 (d, J=7.1 Hz , 1H), 3.83 (s, 3H) ppm. 116 1.85 369.1 (DMSO-d ₆ ) δ 11.41 (s, 1H), 10.35 (s, 1H), 7.71 (d, J=7.8 Hz, 1H), 7.49 (s, 1H), 7.39 (dd, J=15.4, 7.6 Hz, 2H), 6.83 (d, J=1.7 Hz, 1H), 6.43 (dd, J=7.2, 2, 0 Hz, 1H), 4.18 (t, J=6.4 Hz, 2H), 1.75 (td, J=13.4, 6.6 Hz, 1H), 1.62 (kv, J= 6.5 Hz, 2H), 0.90 (t, J=8.0 Hz, 6H) ppm. 117 1.58 355.2 118 1.77 393.3 119 1.62 367.2 120 1.72 381.2 121 1.33 383.2 122 1.55 353.2 123 1.57 409.2 124 1.72 381.2 125 1.6 379.2 126 1.5 389.2 127 1.72 393.2 128 1.85 381.1 (DMSO-d ₆ ) δ 11.36 (s, 1H), 10.32 (s, 1H), 7.70 (d, J=7.8 Hz, 1H), 7.48 (s, 1H), 7.36 (dd, J=14.6, 7.6 Hz, 2H), 6.81 (s, 1H), 6.42 (dd, J=7.2, 2.0 Hz, 1H), 4 .68 (m, 1H), 1.88 (m, 2H), 1.44 (t, 8H) ppm. 129 1.47 375.2 130 1.64 381.3 131 1.52 355.3 132 1.56 395.2 133 1.5 409.3 134 1.64 381.3 135 1.54 379.3 136 1.71 397.2 137 1.68 397.2 138 1.58 411.1 139 1.56 425.1 140 1.7 397.2 141 1.78 432.3 142 1.78 432.5 (DMSO-d ₆ ) δ 10.12 (s, 1H), 8.45 (d, J=2.8 Hz, 1H), 7.87 (d, J=8.7 Hz, 1H), 7, 77 (s, 1H), 7.66 (d, J=8.1 Hz, 1H), 7.44 (m, 3H), 7.32 (d, J=1.8 Hz, 1H), 6, 33 (d, J=9.6 Hz, 1H), 1.30 (s, 9H) ppm. 143 1.58 410.3 (DMSO-d ₆ ) δ 11.41 (s, 1H), 10.62 (s, 1H), 8.56 (d, J=2.7 Hz,1H), 7.92 (d, J=8 .7 Hz, 1H), 7.76 (d, J=8.2 Hz, 1H), 7.62 (dd, J=8.7, 2.7 Hz, 1H), 7.51 (m, 2H ), 7.32 (d, J=7.2 Hz, 1H), 6.72 (d, J=1.9 Hz, 1H), 6.39 (dd, J=7.2, 2.1 Hz , 1H) ppm 144 1.67 444.3 (DMSO-d ₆ ) δ 11.29 (s, 1H), 10.69 (s, 1H), 8.57 (d, J=2.8 Hz, 1H), 7.94 (t, J=8 .8 Hz, 2H), 7.82 (d, J=8.2 Hz, 1H), 7.76 (s, 1H), 7.62 (dd, J=8.7, 2.9 Hz, 1H ), 7.29 (d, J=7.0 Hz, 1H), 6.67 (s, 1H), 6.33 (d, J=7.4 Hz, 1H) ppm. 145 1.64 444.3 146 0.98 390.2 147 0.97 390.2 148 1.87 446.1 (DMSO-d ₆ ) δ 10.49 (s, 1H), 8.45 (d, J=2.8 Hz, 1H), 7.88 (d, J=8.7 Hz, 1H), 7, 66 (d, J=8.1 Hz, 1H), 7.57 (d, J=7.4 Hz, 1H), 7.49 (dd, J=8.1, 1.8 Hz, 1H), 7.42 (dd, J=8.6, 2.8 Hz, 1H), 7.32 (d, J=1.7 Hz, 1H), 6.70 (d, J=2.3 Hz, 1H ), 6.38 (dd, J=7.4, 2.3 Hz, 1H), 3.33 (s, 3H), 1.29 (s, 9H) ppm. 149 1.85 446.3 (DMSO-d₆) δ 10.15 (s, 1H), 8.45 (d, J=2.7 Hz, 1H), 8.10 (d, J=2.7 Hz, 1H), 7.88 (d, J =8.7 Hz, 1H), 7.66 (d, J=8.1 Hz, 1H), 7.48 (dd, J=8.1, 1.7 Hz, 1H), 7.39 (t , 2H), 7.32 (d, J=1.6 Hz, 1H), 6.37 (d, J=9.7 Hz, 1H), 3.39 (s, 3H), 1.30 (s, 9H) ppm 150 0.95 390.3 151 0.98 406.2 152 1.57 479.3 (DMSO-d₆) δ 11.37 (br.s, 1H), 10.96 (s, 1H), 8.02 (s, 1H), 7.59-7.52 (t, 2H), 7.41 (td, J=9.2, 5.5 Hz, 1H), 7.34 (d, J=7.1 Hz, 1H), 7.24-7.15 (t, 1H), 6.70 (d, J=2.0 Hz, 1H), 6.33 (dd, J=7.2, 2.1 Hz, 1H) ppm. 153 1.64 475.3 (DMSO-d₆) δ 11.36 (br.s, 1H), 10.94 (s, 1H), 7.95 (s, 1H), 7.34 (d, J=7.2 Hz, 1H), 7.29 -7.24 (t, 2H), 7.21-7.11(T,2H), 6.70 (d, J=2.0 Hz, 1H), 6.33 (dd, J=7.2, 2.1 Hz, 1H), 2.16 (s, 3H) ppm . 154 1.6 491.3 (DMSO-d ₆ ) δ 11.38 (br.s, 1H), 10.91 (s, 1H), 7.91 (s, 1H), 7.35 (d, J=7.2 Hz, 1H ), 7.26 (dd, J=8.9, 5.8 Hz, 1H), 7.20 (dd, J=10.7, 2.9 Hz, 1H), 7.15 (s, 1H) , 6.88 (td, J=8.5, 2.9 Hz, 1H), 6.73 (d, J=2.1 Hz, 1H), 6.37 (dd, J=7.2, 2 .1 Hz, 1H), 3.79 (s, 3H) ppm. 155 1.58 461.3 (DMSO-d₆) δ 11.34 (br.s, 1H), 10.91 (s, 1H), 7.99 (s, 1H), 7.47 (s, 1H), 7.38-7.28 (m, 3H), 7.29-7.24 (t, 2H), 6.69 (d, J=2.0 Hz, 1H), 6.31 (dd, J=7.2, 2.1 Hz, 1H) ppm. 156 1.55 443.1 (DMSO-d₆) δ 11.34 (br.s, 1H), 10.92 (s, 1H), 7.99 (d, J=1.5 Hz, 1H), 7.53-7.43 (t, 3H), 7.35-7.26 (t, 2H), 7.20 (d, J=7.6 Hz, 2H), 6.69 (d, J=2.0 Hz, 1H), 6.31 (dd, J=7.2, 2.1 Hz, 1H) ppm 157 1.32 423.2 (DMSO-d₆) δ 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 (t, 2H), 7.24-7.12 (t, 1H), 7.12-7.07 (t, 1H), 7.04 (s, 1H), 6.80 (d, J=2.1 Hz, 1H), 6.43 (dd, J=7.3, 2.2 Hz, 1H), 4, 47 (s, 2H) ppm 158 1.7 423.3 (DMSO-d₆) δ 11.33 (s, 1H), 10.58 (s, 1H), 7.81 (d, J=7.8 Hz, 1H), 7.55 (d, J=8.7 Hz, 1H ), 7.37-7.26 (t, 2H), 7.17 (dd, J=10.7, 2.9 Hz, 1H), 6.86 (t, 3H), 6.42 (dd, J=7.2, 2.0 Hz, 1H), 3.76 (s, 3H) ppm. 159 1.83 423.3 (DMSO-d₆) δ 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 (t, 2H), 7.05-6.91 (t, 2H), 6.91-6.79 (t, 2H), 6.61 (dd, J=7.4, 2.4 Hz, 1H), 4.96 (s, 2H) ppm. 160 1.45 451.2

STUDIES TO DETERMINE AND MEASURE THE Na _v INHIBITION PROPERTIES OF COMPOUNDS

Method for analyzing the optical transmembrane potential E-VIPR with electrical stimulation

Sodium channels are voltage-gated proteins that can be activated by changes in membrane potential under the influence of electric fields. The electrical stimulation instrument and methods are described in Ion Channel Assay Methods PCT/US01/21652, incorporated herein by reference, and are referred to as E-VIPR. The instrument contains a manipulator for a microtiter plate, an optical system for excitation of coumarin dye while simultaneously recording coumarin and oxonol emissions, a signal generator, a current or voltage controlled amplifier, and a device for inserting electrodes into the well. Under computer control, this instrument carries out user-programmed protocols for electrical stimulation of cells in the wells of a microtiter plate.

24 hours prior to E-VIPR assay, HEK cells expressing human Na _v 1.8 are seeded into polylysine-coated 384-well plates at 15,000-20,000 cells per well. HEK cells are grown in media (the exact composition is specific to each cell type and Na _V subtype) supplemented with 10% FBS (fetal bovine serum, prepared; GibcoBRL #16140-071) and 1% Pen-Strep (penicillin-streptomycin; GibcoBRL #15140 -122). Cells are grown in vented cap flasks at 90% humidity and 5% CO ₂ .

Reagents and solutions:

100 mg/ml Pluronic F-127 (Sigma #P2443) in dry DMSO

Connection plates: 384-well round bottom plate, such as Corning 384-well Polypropylene Round Bottom #3656

Cell plates: 384-well cell culture treated plate, e.g. Greiner #781091-1B

10 µM DiSBAC ₆ (3) (Aurora #00-100-010) in dry DMSO

10 µM CC2-DMPE (Aurora #00-100-008) in dry DMSO

200 µM ABSC1 in H ₂ O

Wash buffer 1: glucose 10 mM (1.8 g/L), magnesium chloride (anhydrous) 1 mM (0.095 g/L), calcium chloride 2 mM (0.222 g/L), HEPES 10 mM (2. 38 g/l), potassium chloride, 4.5 mmol (0.335 g/l), sodium chloride, 160 mmol (9.35 g/l).

Hexyl dye solution: wash buffer 1 + 0.5% β-cyclodextrin (prepared before use, Sigma #C4767), 8 µM CC2-DMPE + 2.5 µM DiSBAC ₆ (3). To obtain a solution, add a volume of 10% Pluronic F127 stock solution equal to the volumes of CC2-DMPE + DiSBACe(3). The preparation procedure involves first mixing Pluronic and CC2-DMPE, then adding DiSBACe(3) with vigorous stirring, then adding 1 + β-cyclodextrin wash.

Analysis protocol:

1) Pre-stain compounds (in pure DMSO) in compound plates. Vehicle control (straight DMSO), positive control (20 mM tetracaine stock in DMSO, 125 μM final assay concentration), and test compounds were added to each well at 160x the desired final concentration in neat DMSO. The final volume in the compound plate is 80 µl (80-fold intermediate dilution from 1 µl DMSO spot; 160-fold final dilution after transfer to cell plate). The final DMSO concentration for all wells in the study is 0.625%.

2) A solution of hexyl dye is obtained.

3) Prepare cell plates. On the day of the assay, the medium is aspirated and the cells are washed three times with 100 μl of wash solution 1, leaving a 25 μl residual volume in each well.

4) Disperse 25 µl per well of hexyl dye into cell plates. Incubate for 20-35 minutes at room temperature or ambient conditions.

5) Disperse 80 µl per well of wash 1 into compound plates. Acid Yellow-17 (1 mM) and potassium chloride are added and adjusted from 4.5 to 20 mM depending on Na _V subtype and assay sensitivity.

6) Wash the cell plates three times with 100 µl per well with wash 1, leaving a 25 µl residual volume. Then transfer 25 µl per well from the compound plates to the cell plates. Incubate for 20-35 minutes at room temperature/ambient conditions.

7) Read the tablet on the E-VIPR. A current-controlled amplifier is used to deliver stimulating pulses for 10 seconds and scanned at 200 Hz. Pre-stimulation recording is carried out for 0.5 seconds and a baseline intensity line without stimulation is obtained. Following the stimulation pulses, a 0.5 second post-stimulus recording is made to check for relaxation in the resting state.

Data analysis

Data are analyzed and recorded as normalized emission intensity ratios measured at the 460 nm and 580 nm channels. The response as a function of time is written as a ratio obtained using the following formula:

The data is then reduced by calculating the initial (R _i ) and final (R _f ) ratios.

These data represent the average ratio values during part or all of the pre-stimulation period and during control points during the stimulation period. The response to the impulse R = R _f /R _i is then calculated and recorded as a function of time.

Control responses are obtained by performing assays in the presence of a compound with the desired properties (positive control), such as tetracaine, and in the absence of pharmacological agents (negative control). Reactions to negative (N) and positive (P) controls were calculated as described above. The activity of compound A is determined as:

, where R is the rate of rise of the voltage of the connection under test.

ELECTROPHYSIOLOGY ANALYSIS TO DETERMINE Na ACTIVITY _v AND INHIBITION BY TEST COMPOUNDS

Patch clamp electrophysiology is used to evaluate the efficacy and selectivity of sodium channel blockers in dorsal ganglion neurons. Rat neurons are isolated from dorsal ganglions and maintained in culture for 2 to 10 days in the presence of NGF (50 ng/ml) (culture medium consisting of Neurobasa1A supplemented with B27, glutamine and antibiotics). Small diameter neurons (nociceptors, 8–12 μm in diameter) are visually identified and probed with fine-tip glass electrodes connected to an amplifier (Axon Instruments). The "potential clamp" mode is used to evaluate the IC ₅₀ of compounds contained in cells at -60 mV. In addition, the "current clamp" mode is used to test the effectiveness of compounds in blocking the generation of action potentials in response to current pulses. The results of these experiments contribute to determining the potency profile of the compounds.

Representative compounds in Table 1 are active against Na _V 1,8 sodium channels, as confirmed by the measurements described above, which are presented in Table 3 below.

Table 3
IC ₅₀ activity to Na _V 1.8 Conn. No. Na _V 1.8IC ₅₀ (µM) 1 1.09 2 0.054 3 13.5 4 0.35 5 0.039 6 0.245 7 0.05 8 0.33 9 0.093 10 0.014 eleven 0.056 12 0.106 13 0.106 14 0.065 15 0.076 16 0.014 17 1.8 18 12 19 6 20 0.03 21 0.843 22 0.1 23 1.5 24 0.058 25 1.1 26 9.65 27 0.34 28 0.044 29 0.028 thirty 0.011 31 0.017 32 0.205 33 0.095 34 12 35 0.47 36 0.101 37 0.051 38 0.069 39 0.69 40 0.04 41 0.26 42 0.068 43 0.38 44 0.02 45 0.064 46 0.064 47 0.135 48 2.7 49 0.024 50 0.019 51 0.087 52 0.094 53 0.047 54 0.03 55 0.07 56 0.069 57 6.9 58 0.054 59 0.032 60 0.126 61 0.113 62 0.034 63 0.018 64 0.108 65 0.107 66 0.037 67 0.069 68 0.03 69 0.112 70 0.013 71 0.092 72 0.013 73 0.035 74 5.175 75 0.051 76 0.054 77 0.029 78 0.031 79 0.011 80 0.105 81 0.026 82 0.036 83 0.046 84 0.046 85 2.8 86 3.55 87 0.027 88 0.012 89 0.016 90 0.026 91 0.42 92 0.135 93 1.45 94 1.4 95 3.45 96 0.4 97 0.745 98 0.3 99 5.15 100 0.155 101 0.12 102 17.1 103 0.33 104 1.15 105 3.55 106 0.099 107 0.39 108 0.285 109 0.019 110 0.89 111 0.003 112 0.016 113 0.006 114 0.001 115 0.007 116 0.488 117 1.145 118 0.765 119 14 120 0.15 121 19 122 4.2 123 0.355 124 0.485 125 17.5 126 1.4 127 1.3 128 0.56 129 0.94 130 5.1 131 1.5 132 0.33 133 5.8 134 21 135 1.65 136 2.6 137 12.65 138 1.45 139 3.05 140 15 141 0.078 142 0.653 143 3.35 144 0.615 145 5 146 4.6 147 3.8 148 0.45 149 1.65 150 6.6 151 8.4 152 0.044 153 0.01 154 0.005 155 0.011 156 0.052 157 0.058 158 0.002 159 2.6 160 1.39

IonWorks analyses. This assay is carried out to determine the activity of the compounds of this invention against non-Na_v1.8 channels. Sodium currents were recorded using an IonWorks automated voltage clamp system (Molecular Devices Corporation, Inc.). Cells expressing Na subtypes_v collected from tissue culture and placed in suspension at 0.5-4 million cells per ml Washes 1. The IonWorks instrument measures changes in sodium currents in response to an applied voltage clamp in the same way as a traditional voltage clamp assay, except for the 384-well format. Using IonWorks, the dose-response relationship is determined in voltage clamp mode using cell depolarization from an experimental specific baseline potential to a test potential of approximately 0 mV before and after addition of the test compound. The effect of the connection on the currents is measured at the test potential.

Microsomal stability assay. The compounds are incubated at 37°C and shaken for 30 minutes in phosphate buffered saline with rat or human liver microsomes and NADPH cofactor. The null control is prepared in the same way, with the exception of NADPH. Final incubation concentrations were 1 μM substrate (0.2% DMSO), 0.5 mg/ml liver microsomes, 2 mM NADPH, and 0.1 M phosphate. The reactions are quenched and the proteins are precipitated by adding 2 volume equivalents of ice-cold acetonitrile containing the internal standard. After centrifugation, aliquots from quenched incubations were further diluted with 4 volume equivalents of 50% aqueous methanol and then subjected to LC/MS/MS analysis. Microsomal stability values are calculated as the percentage of substrate remaining 30 min after the zero time control.

Microsomal stability of rat and human liver microsomes was determined for selected compounds in accordance with this invention using the above test. Table 4 presents stability data for human liver microsomes ("HLMs") and rat liver microsomes ("LMCs") as the percentage of compound remaining 30 minutes after the zero time control.

Table 4
MUF and IPC stability data Conn. No. MUF (% remaining in 30 minutes) MPK (% remaining in 30 minutes) 2 100 104 7 97 99 8 90 86 10 93 82 20 104 88 28 79 70 29 107 107 thirty 76 78 31 92 91 33 100 110 37 100 97 44 93 84 66 100 106 68 98 72 72 100 95.5 75 90 95 76 97 93 79 103 100 82 101 98 88 100 102 90 101 104 101 97 89 109 103 100 111 91 90 113 105 102 114 91 82 115 102 95 120 87 79 123 103 98 142 38 50 152 103 100 157 101.5 102

Many modifications and variations of the embodiments described herein can be made without departing from the scope, as will be apparent to one skilled in the art. The specific embodiments described are offered as examples only.

Claims (184)

1. Method for preparing the compound of formula I I or a pharmaceutically acceptable salt thereof, wherein R ¹ is H, halogen, CN or C ₁ -C ₆ alkyl, wherein said C ₁ -C ₆ alkyl is substituted with 0-6 halogen atoms, and where up to two non-adjacent CH ₂ units of said C ₁ -C ₆ alkyl may be replaced to -O-; R ² is H, halogen, CN or C ₁ -C ₆ alkyl, wherein said C ₁ -C ₆ alkyl is substituted with 0-6 halogen atoms, where up to two non-adjacent CH ₂ units of said C ₁ -C ₆ alkyl may be replaced by -O-; R ³ is H, halogen, CN or C ₁ -C ₆ alkyl, wherein said C ₁ -C ₆ alkyl is substituted with 0-6 halogen atoms, where up to two non-adjacent CH ₂ units of said C ₁ -C ₆ alkyl may be replaced by -O-; R ⁴ is H, halogen, CN or C ₁ -C ₆ alkyl, wherein said C ₁ -C ₆ alkyl is substituted with 0-6 halogen atoms, where up to two non-adjacent CH ₂ units of said C ₁ -C ₆ alkyl may be replaced by -O-; R ⁵ is H, halogen, CN or -XR ^x ; R ^5' is H, halogen, CN or -XR ^x ; R ⁶ is H, halogen, CN or -XR ^x ; R ^6' is H, halogen, CN or -XR ^x ; R ⁷ is H, halogen, CN or -XR ^x ; X is a bond or C ₁ -C ₆ alkyl, wherein said C ₁ -C ₆ alkyl is substituted with 0-6 halogen atoms, where up to two non-adjacent CH ₂ units of said C ₁ -C ₆ alkyl may be replaced by -O-; And R ^x is absent or is H or a C ₃ -C ₈ cycloaliphatic group, wherein up to two non-adjacent CH ₂ units of said C ₃ -C ₈ cycloaliphatic group may be replaced by -O-, and wherein said C ₃ -C ₈ cycloaliphatic group is substituted 0-3 substituents selected from halogen and C ₁ -C ₄ alkyl, including: interaction of a compound of formula A A with a compound of formula B B in the presence of a first base to obtain a compound of formula I; And, optionally, reacting a compound of Formula I with an acid or a second base to produce a pharmaceutically acceptable salt. 2. The method according to claim 1, where the first base is Cs ₂ CO ₃ . 3. The method according to claim 2, where the first base is K ₂ CO ₃ . 4. Method according to any one of claims 1 to 3, wherein the compound of formula A is obtained by converting the compound of formula C C into a compound of formula A. 5. The method of claim 4, wherein converting a compound of formula C to a compound of formula A involves reacting a compound of formula C with HBr. 6. Method according to any one of claims 4 or 5, wherein the compound of formula C is obtained by reacting a compound of formula D D with 2-methoxypyridin-4-amine to give the compound of formula C. 7. The method according to claim 6, wherein the compound of formula D is reacted with 2-methoxypyridin-4-amine in the presence of a base. 8. Method according to claim 7, wherein the base is pyridine. 9. Method according to claim 4 or 5, wherein the compound of formula C is obtained by reacting a compound of formula E E with 2-methoxypyridin-4-amine to give the compound of formula C. 10. The method according to claim 9, wherein the compound of formula E is reacted with 2-methoxypyridin-4-amine in the presence of a coupling agent and a base. 11. Method for preparing the compound of formula I I or a pharmaceutically acceptable salt thereof, wherein R ¹ is H, halogen, CN or C ₁ -C ₆ alkyl, wherein said C ₁ -C ₆ alkyl is substituted with 0-6 halogen atoms, and where up to two non-adjacent CH ₂ units of said C ₁ -C ₆ alkyl may be replaced to -O-; R ² is H, halogen, CN or C ₁ -C ₆ alkyl, wherein said C ₁ -C ₆ alkyl is substituted with 0-6 halogen atoms, where up to two non-adjacent CH ₂ units of said C ₁ -C ₆ alkyl may be replaced by -O-; R ³ is H, halogen, CN or C ₁ -C ₆ alkyl, wherein said C ₁ -C ₆ alkyl is substituted with 0-6 halogen atoms, where up to two non-adjacent CH ₂ units of said C ₁ -C ₆ alkyl may be replaced by -O-; R ⁴ is H, halogen, CN or C ₁ -C ₆ alkyl, wherein said C ₁ -C ₆ alkyl is substituted with 0-6 halogen atoms, where up to two non-adjacent CH ₂ units of said C ₁ -C ₆ alkyl may be replaced by -O-; R ⁵ is H, halogen, CN or -XR ^x ; R ^5' is H, halogen, CN or -XR ^x ; R ⁶ is H, halogen, CN or -XR ^x ; R ^6' is H, halogen, CN or -XR ^x ; R ⁷ is H, halogen, CN or -XR ^x ; X is a bond or C ₁ -C ₆ alkyl, wherein said C ₁ -C ₆ alkyl is substituted with 0-6 halogen atoms, where up to two non-adjacent CH ₂ units of said C ₁ -C ₆ alkyl may be replaced by -O-; And R ^x is absent or is H or a C ₃ -C ₈ cycloaliphatic group, wherein up to two non-adjacent CH ₂ units of said C ₃ -C ₈ cycloaliphatic group may be replaced by -O-, and wherein said C ₃ -C ₈ cycloaliphatic group is substituted 0-3 substituents selected from halogen and C ₁ -C ₄ alkyl, including: interaction of a compound of formula F F with TMSI (trimethylsilyl) or HBr to obtain the compound of formula I; And, optionally, reacting a compound of formula I with an acid or base to produce a pharmaceutically acceptable salt. 12. The method according to claim 11, where the compound of formula F is obtained by reacting a compound of formula G G with 2-methoxypyridin-4-amine to give the compound of formula F. 13. The method according to claim 12, wherein the compound of formula G is reacted with 2-methoxypyridin-4-amine in the presence of a coupling agent and a base. 14. Method according to any one of claims 1-13, where: R ¹ is H; R ² is H; R ³ is CF ₃ ; R ⁴ is H; R ⁵ is CH ₃ ; R ^5' is H; R ⁶ is H; R ^6' is H; And R ⁷ is F. 15. Method according to any one of claims 1-13, where: R ¹ is H; R ² is CF ₃ ; R ³ is H; R ⁴ is H; R ⁵ is H; R ^5' is H; R ⁶ is H; R ^6' is H; And R ⁷ is F. 16. Method according to any one of claims 1-13, where: R ¹ is H; R ² is H; R ³ is Cl; R ⁴ is H; R ⁵ is CH ₃ ; R ^5' is H; R ⁶ is H; R ^6' is H; And R ⁷ is F. 17. Method according to any one of claims 1-13, where: R ¹ is H; R ² is H; R ³ is CF ₂ CF ₃ ; R ⁴ is H; R ⁵ is OCH ₃ ; R ^5' is H; R ⁶ is H; R ^6' is H; And R ⁷ is F. 18. Method according to any one of claims 1-13, where: R ¹ is H; R ² is Cl; R ³ is Cl; R ⁴ is H; R ⁵ is OCH ₃ ; R ^5' is H; R ⁶ is H; R ^6' is H; And R ⁷ is F. 19. Compound of formula A , A Where: R ¹ is H, halogen, CN or C ₁ -C ₆ alkyl, wherein said C ₁ -C ₆ alkyl is substituted with 0-6 halogen atoms, and where up to two non-adjacent CH ₂ units of said C ₁ -C ₆ alkyl may be replaced to -O-; R ² is H, halogen, CN or C ₁ -C ₆ alkyl, wherein said C ₁ -C ₆ alkyl is substituted with 0-6 halogen atoms, where up to two non-adjacent CH ₂ units of said C ₁ -C ₆ alkyl may be replaced by -O-; R ³ is H, halogen, CN or C ₁ -C ₆ alkyl, wherein said C ₁ -C ₆ alkyl is substituted with 0-6 halogen atoms, where up to two non-adjacent CH ₂ units of said C ₁ -C ₆ alkyl may be replaced by -O-; R ⁴ is H, halogen, CN or C ₁ -C ₆ alkyl, wherein said C ₁ -C ₆ alkyl is substituted with 0-6 halogen atoms, where up to two non-adjacent CH ₂ units of said C ₁ -C ₆ alkyl may be replaced by -O-. 20. Connection according to claim 19, where: R ¹ is H; R ² is H; R ³ is CF ₃ ; And R ⁴ is H. 21. Connection according to claim 19, where: R ¹ is H; R ² is CF ₃ ; R ³ is H; And R ⁴ is H. 22. Connection according to claim 19, where: R ¹ is H; R ² is H; R ³ is Cl; And R ⁴ is H. 23. Connection according to claim 19, where: R ¹ is H; R ² is H; R ³ is CF ₂ CF ₃ ; And R ⁴ is H. 24. Connection according to claim 19, where: R ¹ is H; R ² is Cl; R ³ is Cl; And R ⁴ is H. 25. Compound of formula C , C Where: R ¹ is H, halogen, CN or C ₁ -C ₆ alkyl, wherein said C ₁ -C ₆ alkyl is substituted with 0-6 halogen atoms, and where up to two non-adjacent CH ₂ units of said C ₁ -C ₆ alkyl may be replaced to -O-; R ² is H, halogen, CN or C ₁ -C ₆ alkyl, wherein said C ₁ -C ₆ alkyl is substituted with 0-6 halogen atoms, where up to two non-adjacent CH ₂ units of said C ₁ -C ₆ alkyl may be replaced by -O-; R ³ is H, halogen, CN or C ₁ -C ₆ alkyl, wherein said C ₁ -C ₆ alkyl is substituted with 0-6 halogen atoms, where up to two non-adjacent CH ₂ units of said C ₁ -C ₆ alkyl may be replaced by -O-; R ⁴ is H, halogen, CN or C ₁ -C ₆ alkyl, wherein said C ₁ -C ₆ alkyl is substituted with 0-6 halogen atoms, where up to two non-adjacent CH ₂ units of said C ₁ -C ₆ alkyl may be replaced by -O-. 26. Connection according to claim 25, where: R ¹ is H; R ² is H; R ³ is CF ₃ ; And R ⁴ is H. 27. Connection according to claim 25, where: R ¹ is H; R ² is CF ₃ ; R ³ is H; And R ⁴ is H. 28. Connection according to claim 25, where: R ¹ is H; R ² is H; R ³ is Cl; And R ⁴ is H. 29. Connection according to claim 25, where: R ¹ is H; R ² is H; R ³ is CF ₂ CF ₃ ; And R ⁴ is H. 30. Connection according to claim 25, where: R ¹ is H; R ² is Cl; R ³ is Cl; And R ⁴ is H.