Pyridone amides as modulators of sodium channels

This application is a continuation of U.S. patent application Ser. No. 14/699,437, filed Apr. 29, 2015, which is a continuation of U.S. patent application Ser. No. 14/167,759, filed Jan. 29, 2014, which claims the benefit of U.S. Provisional Patent Application No. 61/759,059, filed Jan. 31, 2013, all of which are incorporated herein by reference in their entireties.

The invention relates to compounds useful as inhibitors of sodium channels. The invention also provides pharmaceutically acceptable compositions comprising the compounds of the invention and methods of using the compositions in the treatment of various disorders including pain.

Pain is a protective mechanism that allows healthy animals to avoid tissue damage and to prevent further damage to injured tissue. Nonetheless there are many conditions where pain persists beyond its usefulness, or where patients would benefit from inhibition of pain. Neuropathic pain is a form of chronic pain caused by an injury to the sensory nerves (Dieleman, J. P., 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 damage to the nerve and pain caused by a discrete nerve injury. The metabolic neuropathies include post herpetic neuropathy, diabetic neuropathy, and drug-induced neuropathy. Discrete nerve injuries indications include post amputation pain, post-surgical nerve injury pain, and nerve entrapment injuries like neuropathic back pain.

Voltage-gated sodium channels (Na V 's) play a critical role in pain signaling. Na V 's are key biological mediators of electrical signaling as they are the primary mediators of the rapid upstroke of the action potential of many excitable cell types (e.g. neurons, skeletal myocytes, cardiac myocytes). The evidence for the role of these channels in normal physiology, the pathological states 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 the central role of Na V 's in pain sensation (Rush, A. M. and T. R. Cummins, Painful Research: Identification of a Small - Molecule Inhibitor that Selectively Targets Na V 1.8 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., Sodium channels and nociception: recent concepts and therapeutic opportunities. Curr Opin Pharmacol 8 (1), p. 50-56 (2008)). Na V 's are the primary mediators of the rapid upstroke of the action potential of many excitable cell types (e.g. neurons, skeletal myocytes, cardiac myocytes), and thus are critical for the initiation of signaling in those cells (Hille, Bertil, Ion Channels of Excitable Membranes , Third ed. (Sinauer Associates, Inc., Sunderland, Mass., 2001)). Because of the role Na V 's play in the initiation and propagation of neuronal signals, antagonists that reduce Na V currents can prevent or reduce neural signaling and Na V channels have long been considered likely targets to reduce pain in conditions where hyper-excitability is observed (Chahine, M., Chatelier, A., Babich, O., and Krupp, J. J., Voltage-gated sodium channels in neurological disorders. CNS Neurol Disord Drug Targets 7 (2), p. 144-58 (2008)). Several clinically useful analgesics have been identified as inhibitors of Na V channels. The local anesthetic drugs such as lidocaine block pain by inhibiting Na V channels, and other compounds, such as carbamazepine, lamotrigine, and tricyclic antidepressants that have proven effective at reducing pain have also been suggested to act by sodium channel inhibition (Soderpalm, B., Anticonvulsants: aspects of their mechanisms of action. Eur J Pain 6 Suppl A, p. 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), p. 79-90 (2008)).

The Na V 's form a subfamily of the voltage-gated ion channel super-family and comprises 9 isoforms, designated Na V 1.1-Na V 1.9. The tissue localizations of the nine isoforms vary greatly. Na V 1.4 is the primary sodium channel of skeletal muscle, and Na V 1.5 is primary sodium channel of cardiac myocytes. Na V 's 1.7, 1.8 and 1.9 are primarily localized to the peripheral nervous system, while Na V 's 1.1, 1.2, 1.3, and 1.6 are neuronal channels found in both the central and peripheral nervous systems. The functional behaviors of the nine isoforms are similar but distinct in the specifics of their voltage-dependent and kinetic behavior (Catterall, W. A., Goldin, A. L., and Waxman, S. G., International Union of Pharmacology. XLVII. Nomenclature and structure-function relationships of voltage-gated sodium channels. Pharmacol Rev 57 (4), p. 397 (2005)).

Immediately upon their discovery, Na V 1.8 channels were identified as likely targets for analgesia (Akopian, A. N., L. Sivilotti, and J. N. Wood, A tetrodotoxin-resistant voltage-gated 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 the sodium current that maintains action potential firing in small DRG neurons (Blair, N. T. and B. P. 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 spontaneous firing in damaged neurons, like those that drive neuropathic pain (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; Jarvis, M. F., 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, S. K., et al., Involvement of the TTX-resistant sodium channel Nav1.8 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, J. A., 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-gated 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). The small DRG neurons where Na V 1.8 is expressed include the nociceptors critical for pain signaling. Na V 1.8 is the primary channel that mediates large amplitude action potentials in small neurons of the dorsal root ganglia (Blair, N. T. and B. P. 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 necessary for rapid repetitive action potentials in nociceptors, and for spontaneous activity of damaged neurons. (Choi, J. S. and S. G. 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., T. R. Cummins, and S. G. 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 DRG neurons, Na V 1.8 appears to be the primary driver of hyper-excitablility (Rush, A. M., 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 some animal pain models, Na V 1.8 mRNA expression levels have been shown to increase in the DRG (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): p. 359-75; Strickland, I. T., et al., Changes in the expression of NaV1.7, 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 primary drawback to the known Na V inhibitors is their poor therapeutic window, and this is likely a consequence of their lack of isoform selectivity. Since Na V 1.8 is primarily restricted to the neurons that sense pain, selective Na V 1.8 blockers are unlikely to induce the adverse events common to non-selective Na V blockers. Accordingly, there remains a need to develop additional Na V channel antagonists preferably those that are more Nav1.8 selective and more potent with increased metabolic stability and with fewer side effects.

It has now been found that compounds of this invention, and pharmaceutically acceptable compositions thereof, are useful as inhibitors of voltage-gated sodium channels. 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 lessening the severity of a variety of diseases, disorders, or conditions, including, but not limited to, chronic pain, gut pain, neuropathic pain, musculoskeletal pain, acute pain, inflammatory pain, cancer pain, idiopathic pain, multiple sclerosis, Charcot-Marie-Tooth syndrome, incontinence or cardiac arrhythmia.

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

or a pharmaceutically acceptable salt thereof,

wherein, independently for each occurrence:

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, wherein up to two non-adjacent CH 2 units of said C 1 -C 6 alkyl may be replaced with —O—;

R X is absent, H, or C 3 -C 8 cycloaliphatic, wherein up to two non-adjacent CH 2 units of said C 3 -C 8 cycloaliphatic may be replaced with —O— and said C 3 -C 8 cycloaliphatic is substituted with 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 and wherein up to two non-adjacent CH 2 units of said C 1 -C 6 alkyl may be replaced with —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, wherein up to two non-adjacent CH 2 units of said C 1 -C 6 alkyl may be replaced with —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, wherein up to two non-adjacent CH 2 units of said C 1 -C 6 alkyl may be replaced with —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, wherein up to two non-adjacent CH 2 units of said C 1 -C 6 alkyl may be replaced with —O—;

R 5 is H, halogen, CN, or —X—R X ;

R 5′ is H, halogen, CN, or —X—R X ;

R 6 is H, halogen, CN, or —X—R X ;

R 6′ is H, halogen, CN, or —X—R X ;

R 7 is H, halogen, CN, or —X—R X ;

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

p is an integer from 0 to 3 inclusive; and

R 9 is H, or C 1 -C 6 alkyl wherein up to two non-adjacent CH 2 units of said C 1 -C 6 alkyl may be replaced with —O—.

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

As described herein, compounds of the invention can optionally be substituted with one or more substituents, such as are illustrated generally above, or as exemplified by particular classes, subclasses, and species of the invention. As described herein, the variables R 1 -R 9 in formula I or I′ encompass specific groups, such as, for example, alkyl and cycloalkyl. As one of ordinary skill in the art will recognize, combinations of substituents envisioned by this invention are those combinations that result in the formation of stable or chemically feasible compounds. The term “stable,” as used herein, refers to compounds that are not substantially altered when subjected to conditions to allow for their production, detection, and preferably their recovery, purification, and use for one or more of the purposes disclosed herein. In some embodiments, a stable compound or chemically feasible compound is one that is not substantially altered when kept at a temperature of 40° C. or less, in the absence of moisture or other chemically 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,” whether preceded by the term “optionally” or not, refers to the replacement of hydrogen radicals in a given structure with the radical of a specified substituent. Specific substituents are described above in the definitions and below in the description of compounds and examples thereof. Unless otherwise indicated, an optionally substituted group can have a substituent at each substitutable position of the group, and when more than one position in any given structure can be substituted with more than one substituent selected from a specified group, the substituent can be either the same or different at every position. A ring substituent, such as a heterocycloalkyl, can be bound to another ring, such as a cycloalkyl, to form a spiro-bicyclic ring system, e.g., both rings share one common atom. As one of ordinary skill in the art will recognize, combinations of substituents envisioned by this invention are those combinations that result in the formation of stable or chemically feasible compounds.

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

The term “aliphatic,” “aliphatic group” or “alkyl” as used herein, means a straight-chain (i.e., unbranched) or branched, substituted or unsubstituted hydrocarbon chain that is completely saturated or that contains one or more units of unsaturation. Unless otherwise specified, aliphatic groups contain 1-20 aliphatic carbon atoms. In some embodiments, aliphatic groups contain 1-10 aliphatic carbon atoms. In other embodiments, aliphatic groups contain 1-8 aliphatic carbon atoms. In still other embodiments, aliphatic groups contain 1-6 aliphatic carbon atoms, and in yet other embodiments 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 a polycyclic hydrocarbon ring system that is completely saturated or that contains one or more units of unsaturation, but which is not aromatic and has a single point of attachment to the rest 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, wherein the two rings have 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 non-aromatic, monocyclic, bicyclic, or tricyclic ring systems in which one or more ring atoms in one or more ring members is an independently selected heteroatom. Heterocyclic ring can be saturated or can contain one or more unsaturated bonds. In some embodiments, the “heterocycle,” “heterocyclyl,” “heterocycloaliphatic,” “heterocycloalkyl,” or “heterocyclic” group has three to fourteen ring members in which one or more ring members is a heteroatom independently selected from oxygen, sulfur, nitrogen, or phosphorus, and each ring in the ring system contains 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 substitutable nitrogen of a heterocyclic ring, for example N (as in 3,4-dihydro-2H-pyrrolyl), NH (as in pyrrolidinyl) or NR + (as in N-substituted pyrrolidinyl)).

The term “unsaturated,” as used herein, means that a moiety has one or more units of unsaturation but is not aromatic.

The term “alkoxy,” or “thioalkyl,” as used herein, refers to an alkyl group, as previously defined, attached to the principal carbon chain through an oxygen (“alkoxy”) or sulfur (“thioalkyl”) atom.

The term “aryl” used alone or as part of a larger moiety as in “aralkyl,” “aralkoxy,” or “aryloxyalkyl,” refers to monocyclic, bicyclic, and tricyclic ring systems having a total of five to fourteen ring carbon atoms, wherein at least one ring in the system is aromatic and wherein each ring in the system contains 3 to 7 ring carbon atoms. The term “aryl” may be used interchangeably with the term “aryl ring.”

The term “heteroaryl,” used alone or as part of a larger moiety as in “heteroaralkyl” or “heteroarylalkoxy,” refers to monocyclic, bicyclic, and tricyclic ring systems having a total of five to fourteen ring members, wherein at least one ring in the system is aromatic, at least one ring in the system contains one or more heteroatoms, and wherein each ring in the system contains 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 stated, structures depicted herein are also meant to include all isomeric (e.g., enantiomeric, diastereomeric, and geometric (or conformational)) forms of the structure; for example, the R and S configurations for each asymmetric center, (Z) and (E) double bond isomers, and (Z) and (E) conformational isomers. Therefore, single stereochemical isomers as well as enantiomeric, diastereomeric, and geometric (or conformational) mixtures of the present compounds are within the scope of the invention. Unless otherwise stated, all tautomeric forms of the compounds of the invention are within the scope of the invention. Thus, included within the scope of the invention are tautomers of compounds of formula I and I′. The structures also include zwitterioinc forms of the compounds or salts of formula I and formula I′ where appropriate.

Additionally, unless otherwise stated, structures depicted herein are also meant to include compounds that differ only in the presence of one or more isotopically enriched or isotopically-labeled atoms. The isotopically-labeled compounds may have one or more atoms replaced by an atom having an atomic mass or mass number usually found in nature. Examples of isotopes present in compounds of formula I and formula I′ include isotopes of hydrogen, carbon, nitrogen, 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 or formula I′, in addition to being useful as therapuetic agents, are also useful in drug and/or substrate tissue distribution assays, as analytical tools or as probes in other biological assays. In one aspect of the present invention, tritiated (e.g., 3 H) and carbon-14 (e.g., 14 C) isotopes are useful given their ease of detectability. In another aspect of the present invention, replacement of one or more hydrogen atoms with heavier isotopes such as deuterium, (e.g., 2 H) can afford certain therapeutic advantages.

In the formulas and drawings, a line transversing a ring and bonded to an R group such as in

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

Within a definition of a term as, for example, X, R X , R 1 , R 2 , R 3 , R 4 , R 8 , or R 9 when a CH 2 unit or, interchangeably, methylene unit may be replaced by —O—, it is meant to include any CH 2 unit, including a CH 2 within a terminal methyl group. For example, CH 2 CH 2 CH 2 OH is within the definition of C 1 -C 6 alkyl wherein up to two non-adjacent CH 2 units may be replaced by —O— because the CH 2 unit of the terminal methyl group has been replaced by —O—.

In another embodiment, the invention features a compound of formula I or I′ and the attendant 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. In another embodiment, R 1 is CF 3 .

In another embodiment, the invention features a compound of formula I or I′ and the attendant 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. 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 substituted with 0-6 halogen wherein one CH 2 unit of said C 1 -C 6 alkyl is replaced with —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 invention features a compound of formula I or I′ and the attendant 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. In another embodiment, R 3 is t-butyl. In another embodiment, R 3 is CF 3 . In another embodiment, R 3 is CF 2 CF 3 .

In another embodiment, the invention features a compound of formula I or I′ and the attendant 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. In another embodiment, R 4 is CF 3 .

In another embodiment, the invention features a compound of formula I or I′ and the attendant definitions, wherein p is zero. In another embodiment, p is an integer from 1 to 3 and R 8 is 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 C 1 -C 6 alkyl wherein said C 1 -C 6 alkyl is substituted with 0-6 halogen wherein one CH 2 unit of said C 1 -C 6 alkyl is replaced with —O—. In another embodiment, p is an integer from 1 to 3 and R 8 is CH 3 .

In another embodiment, the invention features a compound of formula I or I′ and the attendant 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 substituted with 0-6 halogen wherein one CH 2 unit of said C 1 -C 6 alkyl is replaced with —O—. In another embodiment, R 9 is CH 2 CH 2 OH.

In another embodiment, the invention features a compound of formula I or I′ and the attendant definitions, wherein G is

wherein:

R 5 is H, halogen, CN, or —X—R X ;

R 5′ is H, halogen, CN, or —X—R X ;

R 6 is H, halogen, CN, or —X—R X ;

R 6′ is H, halogen, CN, or —X—R X ;

R 7 is H, halogen, CN, or —X—R X ;

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

R X is absent, H, or C 3 -C 8 cycloaliphatic, wherein up to two non-adjacent CH 2 units of said C 3 -C 8 cycloaliphatic may be replaced with —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, the invention features a compound of formula I or I′ and the attendant definitions, wherein G is

wherein:

R 5 is H or —X—R X ;

R 5′ is H or —X—R X ;

R 6 is H, halogen, CN, or —X—R X ;

R 7 is H or —X—R X ;

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

R X is absent, H, or C 3 -C 8 cycloaliphatic, wherein up to two non-adjacent CH 2 units of said C 3 -C 8 cycloaliphatic may be replaced with —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, the invention features a compound of formula I or I′ and the attendant 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 —X—R X . In another embodiment, R 5 is —X—R X wherein R X is absent. In another embodiment, R 5 is —X—R X wherein 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. In another embodiment, R 5 is CH 3 . In another embodiment, R 5 is —X—R X wherein 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 wherein 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, the invention features a compound of formula I or I′ and the attendant definitions, wherein G is

In one embodiment, R 5 is H. In another embodiment, R 5 is —X—R X . In another embodiment, R 5 is —X—R X wherein R X is absent. In another embodiment, R 5 is —X—R X wherein 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. In another embodiment, R 5 is CH 3 . In another embodiment, R 5 is —X—R X wherein 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 wherein 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, the invention features a compound of formula I or I′ and the attendant 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 —X—R X . In another embodiment, R 5′ is —X—R X wherein R X is absent. In another embodiment, R 5′ is —X—R X wherein 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. In another embodiment, R 5′ is CH 3 . In another embodiment, R 5′ is —X—R X wherein 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 wherein 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, the invention features a compound of formula I or I′ and the attendant definitions, wherein G is

In one embodiment, R 5 is H. In another embodiment, R 5 is —X—R X . In another embodiment, R 5 is —X—R X wherein R X is absent. In another embodiment, R 5 is —X—R X wherein 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. In another embodiment, R 5 is CH 3 . In another embodiment, R 5 is —X—R X wherein 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 wherein 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, the invention features a compound of formula I or I′ and the attendant 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 —X—R X . In another embodiment, R 6 is —X—R X wherein R X is absent. In another embodiment, R 6 is —X—R X wherein 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. In another embodiment, R 6 is CH 3 . In another embodiment, R 6 is —X—R X wherein 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 wherein 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, the invention features a compound of formula I or I′ and the attendant 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 —X—R X . In another embodiment, R 6′ is —X—R X wherein R X is absent. In another embodiment, R 6′ is —X—R X wherein 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. In another embodiment, R 6′ is CH 3 . In another embodiment, R 6′ is —X—R X wherein 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 wherein 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, the invention features a compound of formula I or I′ and the attendant 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 —X—R X . In another embodiment, R 7 is —X—R X wherein R X is absent. In another embodiment, R 7 is —X—R X wherein 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. 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 —X—R X wherein 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 wherein two non-adjacent CH 2 units of said C 1 -C 6 alkyl are replaced with —O—. In another embodiment, R 7 is OCH 2 CH 2 OCH 3 . In another embodiment, R 7 is —X—R X wherein 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 wherein one CH 2 unit of said C 1 -C 6 alkyl is replaced with —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 invention features a compound of formula I or I′ and the attendant definitions, wherein G is

In one embodiment, R 7 is H In another embodiment, R 7 is —X—R X . In another embodiment, R 7 is —X—R X wherein R X is absent. In another embodiment, R 7 is —X—R X wherein 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. 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 —X—R X wherein 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 wherein two non-adjacent CH 2 units of said C 1 -C 6 alkyl are replaced with —O—. In another embodiment, R 7 is OCH 2 CH 2 OCH 3 . In another embodiment, R 7 is —X—R X wherein 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 wherein one CH 2 unit of said C 1 -C 6 alkyl is replaced with —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 invention features a compound of formula I or I′ and the attendant definitions, wherein G is

In one embodiment, R 7 is —X—R X wherein X is a bond and R X is C 3 -C 8 cycloaliphatic 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 —X—R X wherein X is a bond and R X is cyclopropyl.

In another embodiment, the invention features a compound of formula I or I′ and the attendant definitions, wherein G is

In one embodiment, R 7 is —X—R X wherein X is C 1 -C 6 alkyl wherein said C 1 -C 6 alkyl is substituted with 0-6 halogen wherein one CH 2 unit of said C 1 -C 6 alkyl is replaced with —O— and R X is C 3 -C 8 cycloaliphatic and said C 3 -C 8 cycloaliphatic is substituted with up 0-3 substituents selected from halogen and C 1 -C 4 alkyl. In another embodiment, R 7 is —X—R X wherein X is OCH 2 and R X is cyclopropyl.

In another embodiment, the invention features a compound of formula I or I′ and the attendant definitions, wherein G is:

and G is selected from:

In another embodiment, the invention features a compound of formula I or I′ and the attendant definitions, wherein G is:

and G is selected from

In another embodiment, the invention features a compound of formula I or I′ and the attendant definitions, wherein G is

wherein:

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

R X is absent, H, or C 3 -C 8 cycloaliphatic, wherein up to two non-adjacent CH 2 units of said C 3 -C 8 cycloaliphatic may be replaced with —O— and said C 3 -C 8 cycloaliphatic is substituted with up 0-3 substituents selected from halogen and C 1 -C 4 alkyl.

In another embodiment, the invention features a compound of formula I or I′ and the attendant definitions, wherein G is —X—R X wherein X is C 1 -C 6 alkyl wherein said C 1 -C 6 alkyl is substituted with 0-6 halogen wherein up to two non-adjacent CH 2 units of said C 1 -C 6 alkyl may be replaced with —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 invention features a compound of formula I or I′ and the attendant definitions, wherein G is —X—R X wherein X is a bond and R X is C 3 -C 8 cycloaliphatic wherein up to two non-adjacent CH 2 of said C 3 -C 8 cycloaliphatic may be replaced with —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 a bond and R X is cyclobutane, cyclohexane, bicyclo[2.2.1]heptane, or bicyclo[3.1.0]hexane.

In another embodiment, the invention features a compound of formula I or I′ and the attendant definitions, wherein G is —X—R X wherein X is C 1 -C 6 alkyl wherein said C 1 -C 6 alkyl is substituted with 0-6 halogen wherein up to two non-adjacent CH 2 units of said C 1 -C 6 alkyl may be replaced with —O— and R X is C 3 -C 8 cycloaliphatic wherein up to two non-adjacent CH 2 units of said C 3 -C 8 cycloaliphatic may be replaced with —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 C 3 -C 8 cycloaliphatic. 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 C 3 -C 8 cycloaliphatic 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-methylcylopropyl, 2,2-dimethylcyclopropyl or 2,2-difluorocyclopropyl.

In another embodiment, the invention features a compound of formula I or I′ and the attendant definitions, wherein G is —X—R X wherein X is C 1 -C 6 alkyl wherein said C 1 -C 6 alkyl is substituted with 0-6 halogen wherein up to two non-adjacent CH 2 units of said C 1 -C 6 alkyl are replaced with —O— and R X is C 3 -C 8 cycloaliphatic wherein up to two non-adjacent CH 2 of said C 3 -C 8 cycloaliphatic may be replaced with —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 C 3 -C 8 cycloaliphatic wherein one CH 2 unit of said C 3 -C 8 cycloaliphatic is replaced with —O—. In another embodiment, X is CH 2 and R X is 3-tetrahydrofuran.

In another embodiment, the invention features a compound of formula I or I′ and the attendant definitions, wherein G is —X—R X and —X—R X is selected from:

In another aspect, the invention provides a compound of formula I-A or I′-A:

or a pharmaceutically acceptable salt thereof,

wherein, independently for each occurrence:

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, wherein up to two non-adjacent CH 2 units of said C 1 -C 6 alkyl may be replaced with —O—;

R X is absent, H, or C 3 -C 8 cycloaliphatic, wherein up to two non-adjacent CH 2 units of said C 3 -C 8 cycloaliphatic may be replaced with —O— and said C 3 -C 8 cycloaliphatic is substituted with 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 with 0-6 halogen and wherein up to two non-adjacent CH 2 units of said C 1 -C 6 alkyl may be replaced with —O—;

R 5 is H, halogen, CN, or —X—R X ;

R 5′ is H, halogen, CN, or —X—R X ;

R 6 is H, halogen, CN, or —X—R X ;

R 6′ is H, halogen, CN, or —X—R X ;

R 7 is H, halogen, CN, or —X—R X ;

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

p is an integer from 0 to 3 inclusive; and

R 9 is H, or C 1 -C 6 alkyl wherein up to two non-adjacent CH 2 units of said C 1 -C 6 alkyl may be replaced with —O—.

In another embodiment, the invention features a compound of formula I-A or I′-A and the attendant 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. 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 substituted with 0-6 halogen wherein one CH 2 unit of said C 1 -C 6 alkyl is replaced with —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 invention features a compound of formula I-A or I′-A and the attendant definitions, wherein p is zero. In another embodiment, p is an integer from 1 to 3 and R 8 is 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 C 1 -C 6 alkyl wherein said C 1 -C 6 alkyl is substituted with 0-6 halogen wherein one CH 2 unit of said C 1 -C 6 alkyl is replaced with —O—. In another embodiment, p is an integer from 1 to 3 and R 8 is CH 3 .

In another embodiment, the invention features a compound of formula I-A or I′-A and the attendant 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 substituted with 0-6 halogen wherein one CH 2 unit of said C 1 -C 6 alkyl is replaced with —O—. In another embodiment, R 9 is CH 2 CH 2 OH.

In another embodiment, the invention features a compound of formula I-A or I′-A and the attendant definitions, wherein G is

wherein:

R 5 is H, halogen, CN, or —X—R X ;

R 5′ is H, halogen, CN, or —X—R X ;

R 6 is H, halogen, CN, or —X—R X ;

R 6′ is H, halogen, CN, or —X—R X ;

R 7 is H, halogen, CN, or —X—R X ;

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

R X is absent, H, or C 3 -C 8 cycloaliphatic, wherein up to two non-adjacent CH 2 units of said C 3 -C 8 cycloaliphatic may be replaced with —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, the invention features a compound of formula I-A or I′-A and the attendant definitions, wherein G is

wherein:

R 5 is H, or —X—R X ;

R 5′ is H, or —X—R X ;

R 6 is H, halogen, CN, or —X—R X ;

R 7 is H, or —X—R X ;

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

R X is absent, H, or C 3 -C 8 cycloaliphatic, wherein up to two non-adjacent CH 2 units of said C 3 -C 8 cycloaliphatic may be replaced with —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, the invention features a compound of formula I-A or I′-A and the attendant 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 —X—R X . In another embodiment, R 5 is —X—R X wherein R X is absent. In another embodiment, R 5 is —X—R X wherein 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. In another embodiment, R 5 is CH 3 . In another embodiment, R 5 is —X—R X wherein 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 wherein 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, the invention features a compound of formula I-A or I′-A and the attendant definitions, wherein G is

In one embodiment, R 5 is H. In another embodiment, R 5 is —X—R X . In another embodiment, R 5 is —X—R X wherein R X is absent. In another embodiment, R 5 is —X—R X wherein 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. In another embodiment, R 5 is CH 3 . In another embodiment, R 5 is —X—R X wherein 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 wherein 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, the invention features a compound of formula I-A or I′-A and the attendant 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 —X—R X . In another embodiment, R 5′ is —X—R X wherein R X is absent. In another embodiment, R 5′ is —X—R X wherein 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. In another embodiment, R 5′ is CH 3 . In another embodiment, R 5′ is —X—R X wherein 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 wherein 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, the invention features a compound of formula I-A or I′-A and the attendant definitions, G is

In one embodiment R 5′ is H. In another embodiment, R 5′ is —X—R X . In another embodiment, R 5′ is —X—R X wherein R X is absent. In another embodiment, R 5′ is —X—R X wherein 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. In another embodiment, R 5′ is CH 3 . In another embodiment, R 5′ is —X—R X wherein 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 wherein 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, the invention features a compound of formula I-A or I′-A and the attendant 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 —X—R X . In another embodiment, R 6 is —X—R X wherein R X is absent. In another embodiment, R 6 is —X—R X wherein 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. In another embodiment, R 6 is CH 3 . In another embodiment, R 6 is —X—R X wherein 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 wherein 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, the invention features a compound of formula I-A or I′-A and the attendant 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 —X—R X . In another embodiment, R 6′ is —X—R X wherein R X is absent. In another embodiment, R 6′ is —X—R X wherein 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. In another embodiment, R 6′ is CH 3 . In another embodiment, R 6′ is —X—R X wherein 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 wherein 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, the invention features a compound of formula I-A or I′-A and the attendant 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 —X—R X . In another embodiment, R 7 is —X—R X wherein R X is absent. In another embodiment, R 7 is —X—R X wherein 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. 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 —X—R X wherein 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 wherein two non-adjacent CH 2 units of said C 1 -C 6 alkyl are replaced with —O—. In another embodiment, R 7 is OCH 2 CH 2 OCH 3 . In another embodiment, R 7 is —X—R X wherein 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 wherein one CH 2 unit of said C 1 -C 6 alkyl is replaced with —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 invention features a compound of formula I-A or I′-A and the attendant definitions, wherein G is

In one embodiment, R 7 is H. In another embodiment, R 7 is —X—R X . In another embodiment, R 7 is —X—R X wherein R X is absent. In another embodiment, R 7 is —X—R X wherein 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. 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 —X—R X wherein 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 wherein two non-adjacent CH 2 units of said C 1 -C 6 alkyl are replaced with —O—. In another embodiment, R 7 is OCH 2 CH 2 OCH 3 . In another embodiment, R 7 is —X—R X wherein 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 wherein one CH 2 unit of said C 1 -C 6 alkyl is replaced with —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 invention features a compound of formula I-A or I′-A and the attendant definitions, wherein G is

In one embodiment, R 7 is —X—R X wherein X is a bond and R X is C 3 -C 8 cycloaliphatic 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 —X—R X wherein X is a bond and R X is cyclopropyl.

In another embodiment, the invention features a compound of formula I-A or I′-A and the attendant definitions, wherein G is

In one embodiment, R 7 is —X—R X wherein X is C 1 -C 6 alkyl wherein said C 1 -C 6 alkyl is substituted with 0-6 halogen wherein one CH 2 unit of said C 1 -C 6 alkyl is replaced with —O— and R X is C 3 -C 8 cycloaliphatic 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 —X—R X wherein X is OCH 2 and R X is cyclopropyl.

In another embodiment, the invention features a compound of formula I-A or I′-A and the attendant definitions, wherein G is:

and G is selected from:

In another embodiment, the invention features a compound of formula I-A or I′-A and the attendant definitions, wherein G is:

and G is selected from

In another embodiment, the invention features a compound of formula I-A or I′-A and the attendant definitions, wherein G is

wherein:

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

R X is absent, H, or C 3 -C 8 cycloaliphatic, wherein up to two non-adjacent CH 2 units of said C 3 -C 8 cycloaliphatic may be replaced with —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, the invention features a compound of formula I-A or I′-A and the attendant definitions, wherein G is —X—R X wherein X is C 1 -C 6 alkyl wherein said C 1 -C 6 alkyl is substituted with 0-6 halogen wherein up to two non-adjacent CH 2 units of said C 1 -C 6 alkyl may be replaced with —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 invention features a compound of formula I-A or I′-A and the attendant definitions, wherein G is —X—R X wherein X is a bond and R X is C 3 -C 8 cycloaliphatic wherein up to two non-adjacent CH 2 of said C 3 -C 8 cycloaliphatic may be replaced with —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 a bond and R X is cyclobutane, cyclohexane, bicyclo[2.2.1]heptane, or bicyclo[3.1.0]hexane.

In another embodiment, the invention features a compound of formula I-A or I′-A and the attendant definitions, wherein G is —X—R X wherein X is C 1 -C 6 alkyl wherein said C 1 -C 6 alkyl is substituted with 0-6 halogen wherein up to two non-adjacent CH 2 units of said C 1 -C 6 alkyl may be replaced with —O— and R X is C 3 -C 8 cycloaliphatic wherein up to two non-adjacent CH 2 units of said C 3 -C 8 cycloaliphatic may be replaced with —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 C 3 -C 8 cycloaliphatic. 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 C 3 -C 8 cycloaliphatic 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-methylcylopropyl, 2,2-dimethylcyclopropyl or 2,2-difluorocyclopropyl.

In another embodiment, the invention features a compound of formula I-A or I′-A and the attendant definitions, wherein G is —X—R X wherein X is C 1 -C 6 alkyl wherein said C 1 -C 6 alkyl is substituted with 0-6 halogen wherein up to two non-adjacent CH 2 units of said C 1 -C 6 alkyl are replaced with —O— and R X is C 3 -C 8 cycloaliphatic wherein up to two non-adjacent CH 2 of said C 3 -C 8 cycloaliphatic may be replaced with —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 C 3 -C 8 cycloaliphatic wherein one CH 2 unit of said C 3 -C 8 cycloaliphatic is replaced with —O—. In another embodiment, X is CH 2 and R X is 3-tetrahydrofuran.

In another embodiment, the invention features a compound of formula I-A or I′-A and the attendant definitions, wherein G is —X—R X and —X—R X is selected from:

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

or a pharmaceutically acceptable salt thereof,

wherein, independently for each occurrence:

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 and wherein up to two non-adjacent CH 2 units of said C 1 -C 6 alkyl may be replaced with —O—;

R X is absent, H, or C 3 -C 8 cycloaliphatic, wherein up to two non-adjacent CH 2 units of said C 3 -C 8 cycloaliphatic may be replaced with —O— and said C 3 -C 8 cycloaliphatic is substituted with 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 with 0-6 halogen and wherein up to two non-adjacent CH 2 units of said C 1 -C 6 alkyl may be replaced with —O—;

R 5 is H, halogen, CN, or —X—R X ;

R 5′ is H, halogen, CN, or —X—R X ;

R 6 is H, halogen, CN, or —X—R X ;

R 6′ is H, halogen, CN, or —X—R X ;

R 7 is H, halogen, CN, or —X—R X ;

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

p is an integer from 0 to 3 inclusive; and

R 9 is H, or C 1 -C 6 alkyl wherein up to two non-adjacent CH 2 units of said C 1 -C 6 alkyl may be replaced with —O—.

In another embodiment, the invention features a compound of formula I-B or I′-B and the attendant 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. In another embodiment, R 3 is t-butyl. In another embodiment, R 3 is CF 3 . In another embodiment, R 3 is CF 2 CF 3 .

In another embodiment, the invention features a compound of formula I-B or I′-B and the attendant definitions, wherein p is zero. In another embodiment, p is an integer from 1 to 3 and R 8 is 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 C 1 -C 6 alkyl wherein said C 1 -C 6 alkyl is substituted with 0-6 halogen wherein one CH 2 unit of said C 1 -C 6 alkyl is replaced with —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 invention features a compound of formula I-B or I′-B and the attendant 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 substituted with 0-6 halogen wherein one CH 2 unit of said C 1 -C 6 alkyl is replaced with —O—. In another embodiment, R 9 is CH 2 CH 2 OH.

In another embodiment, the invention features a compound of formula I-B or I′-B and the attendant definitions, wherein G is

wherein:

R 5 is H, halogen, CN, or —X—R X ;

R 5′ is H, halogen, CN, or —X—R X ;

R 6 is H, halogen, CN, or —X—R X ;

R 6′ is H, halogen, CN, or —X—R X ;

R 7 is H, halogen, CN, or —X—R X ;

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

R X is absent, H, or C 3 -C 8 cycloaliphatic, wherein up to two non-adjacent CH 2 units of said C 3 -C 8 cycloaliphatic may be replaced with —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, the invention features a compound of formula I-B or I′-B and the attendant definitions, wherein G is

wherein:

R 5 is H, or —X—R X ;

R 5′ is H, or —X—R X ;

R 6 is H, halogen, CN, or —X—R X ;

R 7 is H, or —X—R X ;

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

R X is absent, H, or C 3 -C 8 cycloaliphatic, wherein up to two non-adjacent CH 2 units of said C 3 -C 8 cycloaliphatic may be replaced with —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, the invention features a compound of formula I-B or I′-B and the attendant 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 —X—R X . In another embodiment, R 5 is —X—R X wherein R X is absent. In another embodiment, R 5 is —X—R X wherein 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. In another embodiment, R 5 is CH 3 . In another embodiment, R 5 is CD 3 . In another embodiment, R 5 is —X—R X wherein 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 wherein 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, the invention features a compound of formula I-B or I′-B and the attendant definitions, wherein G is

In one embodiment, R 5 is H. In another embodiment, R 5 is —X—R X . In another embodiment, R 5 is —X—R X wherein R X is absent. In another embodiment, R 5 is —X—R X wherein 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. In another embodiment, R 5 is CH 3 . In another embodiment, R 5 is CD 3 . In another embodiment, R 5 is —X—R X wherein 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 wherein 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, the invention features a compound of formula I-B or I′-B and the attendant 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 —X—R X . In another embodiment, R 5′ is —X—R X wherein R X is absent. In another embodiment, R 5′ is —X—R X wherein 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. In another embodiment, R 5′ is CH 3 . In another embodiment, R 5′ is —X—R X wherein 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 wherein 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, the invention features a compound of formula I-B or I′-B and the attendant definitions, wherein G is

In one embodiment, R 5′ is H. In another embodiment, R 5′ is D. In another embodiment, R 5′ is —X—R X . In another embodiment, R 5′ is —X—R X wherein R X is absent. In another embodiment, R 5′ is —X—R X wherein 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. In another embodiment, R 5′ is CH 3 . In another embodiment, R 5′ is —X—R X wherein 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 wherein 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, the invention features a compound of formula I-B or I′-B and the attendant 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 —X—R X . In another embodiment, R 6 is —X—R X wherein R X is absent. In another embodiment, R 6 is —X—R X wherein 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. In another embodiment, R 6 is CH 3 . In another embodiment, R 6 is —X—R X wherein 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 wherein 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, the invention features a compound of formula I-B or I′-B and the attendant 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 —X—R X . In another embodiment, R 6′ is —X—R X wherein R X is absent. In another embodiment, R 6′ is —X—R X wherein 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. In another embodiment, R 6′ is CH 3 . In another embodiment, R 6′ is —X—R X wherein 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 wherein 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, the invention features a compound of formula I-B or I′-B and the attendant 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 —X—R X . In another embodiment, R 7 is —X—R X wherein R X is absent. In another embodiment, R 7 is —X—R X wherein 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. 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 —X—R X wherein 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 wherein two non-adjacent CH 2 units of said C 1 -C 6 alkyl are replaced with —O—. In another embodiment, R 7 is OCH 2 CH 2 OCH 3 . In another embodiment, R 7 is —X—R X wherein 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 wherein one CH 2 unit of said C 1 -C 6 alkyl is replaced with —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 invention features a compound of formula I-B or I′-B and the attendant definitions, wherein G is

In one embodiment, R 7 is H. In another embodiment, R 7 is —X—R X . In another embodiment, R 7 is —X—R X wherein R X is absent. In another embodiment, R 7 is —X—R X wherein 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. 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 —X—R X wherein 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 wherein two non-adjacent CH 2 units of said C 1 -C 6 alkyl are replaced with —O—. In another embodiment, R 7 is OCH 2 CH 2 OCH 3 . In another embodiment, R 7 is —X—R X wherein 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 wherein one CH 2 unit of said C 1 -C 6 alkyl is replaced with —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 invention features a compound of formula I-B or I′-B and the attendant definitions, wherein G is

In one embodiment, R 7 is —X—R X wherein X is a bond and R X is C 3 -C 8 cycloaliphatic 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 —X—R X wherein X is a bond and R X is cyclopropyl.

In another embodiment, the invention features a compound of formula I-B or I′-B and the attendant definitions, wherein G is

In one embodiment, R 7 is —X—R X wherein X is C 1 -C 6 alkyl wherein said C 1 -C 6 alkyl is substituted with 0-6 halogen and wherein one CH 2 unit of said C 1 -C 6 alkyl is replaced with —O— and R X is C 3 -C 8 cycloaliphatic 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 —X—R X wherein X is OCH 2 and R X is cyclopropyl.

In another embodiment, the invention features a compound of formula I-B or I′-B and the attendant definitions, wherein G is selected from:

In another embodiment, the invention features a compound of formula I-B or I′-B and the attendant definitions, wherein G is:

and G is selected from

In another embodiment, the invention features a compound of formula I-B or I′-B and the attendant definitions, wherein G is

wherein:

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

R X is absent, H, or C 3 -C 8 cycloaliphatic, wherein up to two non-adjacent CH 2 units of said C 3 -C 8 cycloaliphatic may be replaced with —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, the invention features a compound of formula I-B or I′-B and the attendant definitions, wherein G is —X—R X wherein X is C 1 -C 6 alkyl wherein said C 1 -C 6 alkyl is substituted with 0-6 halogen wherein up to two non-adjacent CH 2 units of said C 1 -C 6 alkyl may be replaced with —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 invention features a compound of formula I-B or I′-B and the attendant definitions, wherein G is —X—R X wherein X is a bond and R X is C 3 -C 8 cycloaliphatic wherein up to two non-adjacent CH 2 of said C 3 -C 8 cycloaliphatic may be replaced with —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 a bond and R X is cyclobutane, cyclohexane, bicyclo[2.2.1]heptane, or bicyclo[3.1.0]hexane.

In another embodiment, the invention features a compound of formula I-B or I′-B and the attendant definitions, wherein G is —X—R X wherein X is C 1 -C 6 alkyl wherein said C 1 -C 6 alkyl is substituted with 0-6 halogen wherein up to two non-adjacent CH 2 units of said C 1 -C 6 alkyl may be replaced with —O— and R X is C 3 -C 8 cycloaliphatic wherein up to two non-adjacent CH 2 units of said C 3 -C 8 cycloaliphatic may be replaced with —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 C 3 -C 8 cycloaliphatic. 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 C 3 -C 8 cycloaliphatic 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-methylcylopropyl, 2,2-dimethylcyclopropyl or 2,2-difluorocyclopropyl.

In another embodiment, the invention features a compound of formula I-B or I′-B and the attendant definitions, wherein G is —X—R X wherein X is C 1 -C 6 alkyl wherein said C 1 -C 6 alkyl is substituted with 0-6 halogen wherein up to two non-adjacent CH 2 units of said C 1 -C 6 alkyl are replaced with —O— and R X is C 3 -C 8 cycloaliphatic wherein up to two non-adjacent CH 2 of said C 3 -C 8 cycloaliphatic may be replaced with —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 C 3 -C 8 cycloaliphatic wherein one CH 2 unit of said C 3 -C 8 cycloaliphatic is replaced with —O—. In another embodiment, X is CH 2 and R X is 3-tetrahydrofuran.

In another embodiment, the invention features a compound of formula I-B or I′-B and the attendant definitions, wherein G is selected from:

In another aspect, the invention provides a compound of formula I-C or I′-C:

or a pharmaceutically acceptable salt thereof,

wherein, independently for each occurrence:

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, wherein up to two non-adjacent CH 2 units of said C 1 -C 6 alkyl may be replaced with —O—;

R X is absent, H, or C 3 -C 8 cycloaliphatic, wherein up to two non-adjacent CH 2 units of said C 3 -C 8 cycloaliphatic may be replaced with —O— and said C 3 -C 8 cycloaliphatic is substituted with 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 with 0-6 halogen and wherein up to two non-adjacent CH 2 units of said C 1 -C 6 alkyl may be replaced with —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 and wherein up to two non-adjacent CH 2 units of said C 1 -C 6 alkyl may be replaced with —O—;

R 5 is H, halogen, CN, or —X—R X ;

R 5′ is H, halogen, CN, or —X—R X ;

R 6 is H, halogen, CN, or —X—R X ;

R 6′ is H, halogen, CN, or —X—R X ;

R 7 is H, halogen, CN, or —X—R X ;

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

p is an integer from 0 to 3 inclusive; and

R 9 is H, or C 1 -C 6 alkyl wherein up to two non-adjacent CH 2 units of said C 1 -C 6 alkyl may be replaced with —O—.

In another embodiment, the invention features a compound of formula I-C or I′-C and the attendant 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. 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 substituted with 0-6 halogen wherein one CH 2 unit of said C 1 -C 6 alkyl is replaced with —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 invention features a compound of formula I-C or I′-C and the attendant 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. In another embodiment, R 3 is t-butyl. In another embodiment, R 3 is CF 3 . In another embodiment, R 3 is CF 2 CF 3 .

In another embodiment, the invention features a compound of formula I-C or I′-C and the attendant definitions, wherein p is zero. In another embodiment, p is an integer from 1 to 3 and R 8 is 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 C 1 -C 6 alkyl wherein said C 1 -C 6 alkyl is substituted with 0-6 halogen wherein one CH 2 unit of said C 1 -C 6 alkyl is replaced with —O—. In another embodiment, p is an integer from 1 to 3 and R 8 is CH 3 .

In another embodiment, the invention features a compound of formula I-C or I′-C and the attendant 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 substituted with 0-6 halogen wherein one CH 2 unit of said C 1 -C 6 alkyl is replaced with —O—. In another embodiment, R 9 is CH 2 CH 2 OH.

In another embodiment, the invention features a compound of formula I-C or I′-C and the attendant definitions, wherein G is

wherein:

R 5 is H, halogen, CN, or —X—R X ;

R 5′ is H, halogen, CN, or —X—R X ;

R 6 is H, halogen, CN, or —X—R X ;

R 6′ is H, halogen, CN, or —X—R X ;

R 7 is H, halogen, CN, or —X—R X ;

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

R X is absent, H, or C 3 -C 8 cycloaliphatic, wherein up to two non-adjacent CH 2 units of said C 3 -C 8 cycloaliphatic may be replaced with —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, the invention features a compound of formula I-C or I′-C and the attendant definitions, wherein G is

wherein:

R 5 is H, or —X—R X ;

R 5′ is H, or —X—R X ;

R 6 is H, halogen, CN, or —X—R X ;

R 7 is H, or —X—R X ;

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

R X is absent, H, or C 3 -C 8 cycloaliphatic, wherein up to two non-adjacent CH 2 units of said C 3 -C 8 cycloaliphatic may be replaced with —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, the invention features a compound of formula I-C or I′-C and the attendant 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 —X—R X . In another embodiment, R 5 is —X—R X wherein R X is absent. In another embodiment, R 5 is —X—R X wherein 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. In another embodiment, R 5 is CH 3 . In another embodiment, R 5 is —X—R X wherein 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 wherein 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, the invention features a compound of formula I-C or I′-C and the attendant definitions, wherein G is

In one embodiment R 5 is H. In another embodiment, R 5 is —X—R X . In another embodiment, R 5 is —X—R X wherein R X is absent. In another embodiment, R 5 is —X—R X wherein 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. In another embodiment, R 5 is CH 3 . In another embodiment, R 5 is —X—R X wherein 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 wherein 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, the invention features a compound of formula I-C or I′-C and the attendant 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 —X—R X . In another embodiment, R 5′ is —X—R X wherein R X is absent. In another embodiment, R 5′ is —X—R X wherein 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. In another embodiment, R 5′ is CH 3 . In another embodiment, R 5′ is —X—R X wherein 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 wherein 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, the invention features a compound of formula I-C or I′-C and the attendant 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 —X—R X . In another embodiment, R 5′ is —X—R X wherein R X is absent. In another embodiment, R 5′ is —X—R X wherein 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. In another embodiment, R 5′ is CH 3 . In another embodiment, R 5′ is —X—R X wherein 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 wherein 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, the invention features a compound of formula I-C or I′-C and the attendant 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 —X—R X . In another embodiment, R 6 is —X—R X wherein R X is absent. In another embodiment, R 6 is —X—R X wherein 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. In another embodiment, R 6 is CH 3 . In another embodiment, R 6 is —X—R X wherein 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 wherein 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, the invention features a compound of formula I-C or I′-C and the attendant definitions, wherein G is

In another 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 —X—R X . In another embodiment, R 6′ is —X—R X wherein R X is absent. In another embodiment, R 6′ is —X—R X wherein 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. In another embodiment, R 6′ is CH 3 . In another embodiment, R 6′ is —X—R X wherein 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 wherein 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, the invention features a compound of formula I-C or I′-C and the attendant 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 —X—R X . In another embodiment, R 7 is —X—R X wherein R X is absent. In another embodiment, R 7 is —X—R X wherein 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. 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 —X—R X wherein 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 wherein two non-adjacent CH 2 units of said C 1 -C 6 alkyl are replaced with —O—. In another embodiment, R 7 is OCH 2 CH 2 OCH 3 . In another embodiment, R 7 is —X—R X wherein 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 wherein one CH 2 unit of said C 1 -C 6 alkyl is replaced with —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 invention features a compound of formula I-C or I′-C and the attendant definitions, wherein G is

In one embodiment, R 7 is H. In another embodiment, R 7 is —X—R X . In another embodiment, R 7 is —X—R X wherein R X is absent. In another embodiment, R 7 is —X—R X wherein 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. 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 —X—R X wherein 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 wherein two non-adjacent CH 2 units of said C 1 -C 6 alkyl are replaced with —O—. In another embodiment, R 7 is OCH 2 CH 2 OCH 3 . In another embodiment, R 7 is —X—R X wherein 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 wherein one CH 2 unit of said C 1 -C 6 alkyl is replaced with —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 invention features a compound of formula I-C or I′-C and the attendant definitions, wherein G is

In one embodiment, R 7 is —X—R X wherein X is a bond and R X is C 3 -C 8 cycloaliphatic 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 —X—R X wherein X is a bond and R X is cyclopropyl.

In another embodiment, the invention features a compound of formula I-C or I′-C and the attendant definitions, wherein G is

In one embodiment, R 7 is —X—R X wherein X is C 1 -C 6 alkyl wherein said C 1 -C 6 alkyl is substituted with 0-6 halogen wherein one CH 2 unit of said C 1 -C 6 alkyl is replaced with —O— and R X is C 3 -C 8 cycloaliphatic 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 —X—R X wherein X is OCH 2 and R X is cyclopropyl.

In another embodiment, the invention features a compound of formula I-C or I′-C and the attendant definitions, wherein G is:

and G is selected from:

In another embodiment, the invention features a compound of formula I-C or I′-C and the attendant definitions, wherein G is:

and G is selected from

In another embodiment, the invention features a compound of formula I-C or I′-C and the attendant definitions, wherein G is

wherein:

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

R X is absent, H, or C 3 -C 8 cycloaliphatic, wherein up to two non-adjacent CH 2 units of said C 3 -C 8 cycloaliphatic may be replaced with —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, the invention features a compound of formula I-C or I′-C and the attendant definitions, wherein G is —X—R X wherein X is C 1 -C 6 alkyl wherein said C 1 -C 6 alkyl is substituted with 0-6 halogen wherein up to two non-adjacent CH 2 units of said C 1 -C 6 alkyl may be replaced with —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 invention features a compound of formula I-C or I′-C and the attendant definitions, wherein G is —X—R X wherein X is a bond and R X is C 3 -C 8 cycloaliphatic wherein up to two non-adjacent CH 2 of said C 3 -C 8 cycloaliphatic may be replaced with —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 a bond and R X is cyclobutane, cyclohexane, bicyclo[2.2.1]heptane, or bicyclo[3.1.0]hexane.

In another embodiment, the invention features a compound of formula I-C or I′-C and the attendant definitions, wherein G is —X—R X wherein X is C 1 -C 6 alkyl wherein said C 1 -C 6 alkyl is substituted with 0-6 halogen wherein up to two non-adjacent CH 2 units of said C 1 -C 6 alkyl may be replaced with —O— and R X is C 3 -C 8 cycloaliphatic wherein up to two non-adjacent CH 2 units of said C 3 -C 8 cycloaliphatic may be replaced with —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 C 3 -C 8 cycloaliphatic. 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 C 3 -C 8 cycloaliphatic 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-methylcylopropyl, 2,2-dimethylcyclopropyl or 2,2-difluorocyclopropyl.

In another embodiment, the invention features a compound of formula I-C or I′-C and the attendant definitions, wherein G is —X—R X wherein X is C 1 -C 6 alkyl wherein said C 1 -C 6 alkyl is substituted with 0-6 halogen wherein up to two non-adjacent CH 2 units of said C 1 -C 6 alkyl are replaced with —O— and R X is C 3 -C 8 cycloaliphatic wherein up to two non-adjacent CH 2 of said C 3 -C 8 cycloaliphatic may be replaced with —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 C 3 -C 8 cycloaliphatic wherein one CH 2 unit of said C 3 -C 8 cycloaliphatic is replaced with —O—. In another embodiment, X is CH 2 and R X is 3-tetrahydrofuran.

In another embodiment, the invention features a compound of formula I-C or I′-C and the attendant definitions, wherein G is selected from:

In another aspect, the invention provides a compound of formula I-D or I′-D:

or a pharmaceutically acceptable salt thereof,

wherein, independently for each occurrence:

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 and wherein up to two non-adjacent CH 2 units of said C 1 -C 6 alkyl may be replaced with —O—;

R X is absent, H, or C 3 -C 8 cycloaliphatic, wherein up to two non-adjacent CH 2 units of said C 3 -C 8 cycloaliphatic may be replaced with —O— and said C 3 -C 8 cycloaliphatic 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 with 0-6 halogen and wherein up to two non-adjacent CH 2 units of said C 1 -C 6 alkyl may be replaced with —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 and wherein up to two non-adjacent CH 2 units of said C 1 -C 6 alkyl may be replaced with —O—;

R 5 is H, halogen, CN, or —X—R X ;

R 5′ is H, halogen, CN, or —X—R X ;

R 6 is H, halogen, CN, or —X—R X ;

R 6′ is H, halogen, CN, or —X—R X ;

R 7 is H, halogen, CN, or —X—R X ;

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

p is an integer from 0 to 3 inclusive; and

R 9 is H, or C 1 -C 6 alkyl wherein up to two non-adjacent CH 2 units of said C 1 -C 6 alkyl may be replaced with —O—.

In another embodiment, the invention features a compound of formula I-D or I′-D and the attendant 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. In another embodiment, R 1 is CF 3 .

In another embodiment, the invention features a compound of formula I-D or I′-D and the attendant 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. In another embodiment, R 3 is t-butyl. In another embodiment, R 3 is CF 3 . In another embodiment, R 3 is CF 2 CF 3 .

In another embodiment, the invention features a compound of formula I-D or I′-D and the attendant definitions, wherein p is zero. In another embodiment, p is an integer from 1 to 3 and R 8 is 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 C 1 -C 6 alkyl wherein said C 1 -C 6 alkyl wherein said C 1 -C 6 alkyl is substituted with 0-6 halogen wherein one CH 2 unit of said C 1 -C 6 alkyl is replaced with —O—. In another embodiment, p is an integer from 1 to 3 and R 8 is CH 3 .

In another embodiment, the invention features a compound of formula I-D or I′-D and the attendant 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 substituted with 0-6 halogen wherein one CH 2 unit of said C 1 -C 6 alkyl is replaced with —O—. In another embodiment, R 9 is CH 2 CH 2 OH.

In another embodiment, the invention features a compound of formula I-D or I′-D and the attendant definitions, wherein G is

wherein:

R 5 is H, halogen, CN, or —X—R X ;

R 5′ is H, halogen, CN, or —X—R X ;

R 6 is H, halogen, CN, or —X—R X ;

R 6′ is H, halogen, CN, or —X—R X ;

R 7 is H, halogen, CN, or —X—R X ;

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

R X is absent, H, or C 3 -C 8 cycloaliphatic, wherein up to two non-adjacent CH 2 units of said C 3 -C 8 cycloaliphatic may be replaced with —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, the invention features a compound of formula I-D or I′-D and the attendant definitions, wherein G is

wherein:

R 5 is H, or —X—R X ;

R 5′ is H, or —X—R X ;

R 6 is H, halogen, CN, or —X—R X ;

R 7 is H, or —X—R X ;

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

R X is absent, H, or C 3 -C 8 cycloaliphatic, wherein up to two non-adjacent CH 2 units of said C 3 -C 8 cycloaliphatic may be replaced with —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, the invention features a compound of formula I-D or I′-D and the attendant 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 —X—R X . In another embodiment, R 5 is —X—R X wherein R X is absent. In another embodiment, R 5 is —X—R X wherein 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. In another embodiment, R 5 is CH 3 . In another embodiment, R 5 is —X—R X wherein 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 wherein 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, the invention features a compound of formula I-D or I′-D and the attendant definitions, wherein G is

In one embodiment, R 5 is H. In another embodiment, R 5 is —X—R X . In another embodiment, R 5 is —X—R X wherein R X is absent. In another embodiment, R 5 is —X—R X wherein 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. In another embodiment, R 5 is CH 3 . In another embodiment, R 5 is —X—R X wherein 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 wherein 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, the invention features a compound of formula I-D or I′-D and the attendant 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 —X—R X . In another embodiment, R 5′ is —X—R X wherein R X is absent. In another embodiment, R 5′ is —X—R X wherein 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. In another embodiment, R 5′ is CH 3 . In another embodiment, R 5′ is —X—R X wherein 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 wherein 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, the invention features a compound of formula I-D or I′-D and the attendant definitions, wherein G is

In one embodiment R 5′ is H. In another embodiment, R 5′ is —X—R X . In another embodiment, R 5′ is —X—R X wherein R X is absent. In another embodiment, R 5′ is —X—R X wherein 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. In another embodiment, R 5′ is CH 3 . In another embodiment, R 5′ is —X—R X wherein 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 wherein 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, the invention features a compound of formula I-D or I′-D and the attendant 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 —X—R X . In another embodiment, R 6 is —X—R X wherein R X is absent. In another embodiment, R 6 is —X—R X wherein 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. In another embodiment, R 6 is CH 3 . In another embodiment, R 6 is —X—R X wherein 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 wherein 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, the invention features a compound of formula I-D or I′-D and the attendant 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 —X—R X . In another embodiment, R 6′ is —X—R X wherein R X is absent. In another embodiment, R 6′ is —X—R X wherein 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. In another embodiment, R 6′ is CH 3 . In another embodiment, R 6′ is —X—R X wherein 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 wherein 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, the invention features a compound of formula I-D or I′-D and the attendant 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 —X—R X . In another embodiment, R 7 is —X—R X wherein R X is absent. In another embodiment, R 7 is —X—R X wherein 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. 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 —X—R X wherein 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 wherein two non-adjacent CH 2 units of said C 1 -C 6 alkyl are replaced with —O—. In another embodiment, R 7 is OCH 2 CH 2 OCH 3 . In another embodiment, R 7 is —X—R X wherein 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 wherein one CH 2 unit of said C 1 -C 6 alkyl is replaced with —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 invention features a compound of formula I-D or I′-D and the attendant definitions, wherein G is

In one embodiment, R 7 is H. In another embodiment, R 7 is —X—R X . In another embodiment, R 7 is —X—R X wherein R X is absent. In another embodiment, R 7 is —X—R X wherein 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. 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 —X—R X wherein 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 wherein two non-adjacent CH 2 units of said C 1 -C 6 alkyl are replaced with —O—. In another embodiment, R 7 is OCH 2 CH 2 OCH 3 . In another embodiment, R 7 is —X—R X wherein 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 wherein one CH 2 unit of said C 1 -C 6 alkyl is replaced with —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 invention features a compound of formula I-D or I′-D and the attendant definitions, wherein G is

In one embodiment, R 7 is —X—R X wherein X is a bond and R X is C 3 -C 8 cycloaliphatic 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 —X—R X wherein X is a bond and R X is cyclopropyl.

In another embodiment, the invention features a compound of formula I-D or I′-D and the attendant definitions, wherein G is

In one embodiment, R 7 is —X—R X wherein X is C 1 -C 6 alkyl wherein said C 1 -C 6 alkyl is substituted with 0-6 halogen wherein one CH 2 unit of said C 1 -C 6 alkyl is replaced with —O— and R X is C 3 -C 8 cycloaliphatic 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 —X—R X wherein X is OCH 2 and R X is cyclopropyl.

In another embodiment, the invention features a compound of formula I-D or I′-D and the attendant definitions, wherein G is:

and G is selected from:

In another embodiment, the invention features a compound of formula I-D or I′-D and the attendant definitions, wherein G is:

and G is selected from

In another embodiment, the invention features a compound of formula I-D or I′-D and the attendant definitions, wherein G is

wherein:

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

R X is absent, H, or C 3 -C 8 cycloaliphatic, wherein up to two non-adjacent CH 2 units of said C 3 -C 8 cycloaliphatic may be replaced with —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, the invention features a compound of formula I-D or I′-D and the attendant definitions, wherein G is —X—R X wherein X is C 1 -C 6 alkyl wherein said C 1 -C 6 alkyl is substituted with 0-6 halogen wherein up to two non-adjacent CH 2 units of said C 1 -C 6 alkyl may be replaced with —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 invention features a compound of formula I-D or I′-D and the attendant definitions, wherein G is —X—R X wherein X is a bond and R X is C 3 -C 8 cycloaliphatic wherein up to two non-adjacent CH 2 of said C 3 -C 8 cycloaliphatic may be replaced with —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 a bond and R X is cyclobutane, cyclohexane, bicyclo[2.2.1]heptane, or bicyclo[3.1.0]hexane.

In another embodiment, the invention features a compound of formula I-D or I′-D and the attendant definitions, wherein G is —X—R X wherein X is C 1 -C 6 alkyl wherein said C 1 -C 6 alkyl is substituted with 0-6 halogen wherein up to two non-adjacent CH 2 units of said C 1 -C 6 alkyl may be replaced with —O— and R X is C 3 -C 8 cycloaliphatic wherein up to two non-adjacent CH 2 units of said C 3 -C 8 cycloaliphatic may be replaced with —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 C 3 -C 8 cycloaliphatic. 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 C 3 -C 8 cycloaliphatic 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-methylcylopropyl, 2,2-dimethylcyclopropyl or 2,2-difluorocyclopropyl.

In another embodiment, the invention features a compound of formula I-D or I′-D and the attendant definitions, wherein G is —X—R X wherein X is C 1 -C 6 alkyl wherein said C 1 -C 6 alkyl is substituted with 0-6 halogen wherein up to two non-adjacent CH 2 units of said C 1 -C 6 alkyl are replaced with —O— and R X is C 3 -C 8 cycloaliphatic wherein up to two non-adjacent CH 2 of said C 3 -C 8 cycloaliphatic may be replaced with —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 C 3 -C 8 cycloaliphatic wherein one CH 2 unit of said C 3 -C 8 cycloaliphatic is replaced with —O—. In another embodiment, X is CH 2 and R X is 3-tetrahydrofuran.

In another embodiment, the invention features a compound of formula I-D or I′-D and the attendant definitions, wherein G is selected from:

In another aspect, the invention provides a compound of formula I-E or I′-E

or a pharmaceutically acceptable salt thereof,

wherein, independently for each occurrence:

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

R 5 is halogen, CN, or —X—R X ;

R 7 is halogen, CN, or —X—R X ;

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

R X is absent, H, or C 3 -C 8 cycloaliphatic, wherein up to two non-adjacent CH 2 units of said C 3 -C 8 cycloaliphatic may be replaced with —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 halogen or C 1 -C 6 alkyl wherein said C 1 -C 6 alkyl is substituted with 0-6 halogen and wherein up to two non-adjacent CH 2 units of said C 1 -C 6 alkyl may be replaced with —O—;

p is an integer from 0 to 3 inclusive; and

R 9 is H, or C 1 -C 6 alkyl wherein up to two non-adjacent CH 2 units of said C 1 -C 6 alkyl may be replaced with —O—.

In another embodiment, the invention features a compound of formula I-E or I′-E and the attendant 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. 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 substituted with 0-6 halogen wherein one CH 2 unit of said C 1 -C 6 alkyl is replaced with —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 invention features a compound of formula I-E or I′-E and the attendant 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 —X—R X . In another embodiment, R 5 is —X—R X wherein R X is absent. In another embodiment, R 5 is —X—R X wherein 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. In another embodiment, R 5 is CH 3 . In another embodiment, R 5 is —X—R X wherein 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 wherein 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, the invention features a compound of formula I-E or I′-E and the attendant 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 —X—R X . In another embodiment, R 7 is —X—R X wherein R X is absent. In another embodiment, R 7 is —X—R X wherein 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. 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 —X—R X wherein 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 wherein two non-adjacent CH 2 units of said C 1 -C 6 alkyl are replaced with —O—. In another embodiment, R 7 is OCH 2 CH 2 OCH 3 . In another embodiment, R 7 is —X—R X wherein 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 wherein one CH 2 unit of said C 1 -C 6 alkyl is replaced with —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 invention features a compound of formula I-E or I′-E and the attendant definitions, wherein R 7 is —X—R X wherein X is a bond and R X is C 3 -C 8 cycloaliphatic 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 —X—R X wherein X is a bond and R X is cyclopropyl.

In another embodiment, the invention features a compound of formula I-E or I′-E and the attendant definitions, wherein R 7 is —X—R X wherein X is C 1 -C 6 alkyl wherein said C 1 -C 6 alkyl is substituted with 0-6 halogen wherein one CH 2 unit of said C 1 -C 6 alkyl is replaced with —O— and R X is C 3 -C 8 cycloaliphatic 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 —X—R X wherein X is OCH 2 and R X is cyclopropyl.

In another embodiment, the invention features a compound of formula I-E or I′-E and the attendant definitions, wherein p is zero. In another embodiment, p is an integer from 1 to 3 and R 8 is 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 C 1 -C 6 alkyl wherein said C 1 -C 6 alkyl is substituted with 0-6 halogen wherein one CH 2 unit of said C 1 -C 6 alkyl is replaced with —O—. In another embodiment, p is an integer from 1 to 3 and R 8 is CH 3 .

In another embodiment, the invention features a compound of formula I-E or I′-E and the attendant 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 substituted with 0-6 halogen wherein one CH 2 unit of said C 1 -C 6 alkyl is replaced with —O—. In another embodiment, R 9 is CH 2 CH 2 OH.

In another embodiment, the invention features a compound of formula I-E or I′-E and the attendant definitions, wherein ring A is selected from:

In another aspect, the invention provides a compound of formula I-F or I′-F:

or a pharmaceutically acceptable salt thereof,

wherein, independently for each occurrence:

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

R 5 is halogen, CN, or —X—R X ;

R 7 is halogen, CN, or —X—R X ;

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

R X is absent, H, or C 3 -C 8 cycloaliphatic, wherein up to two non-adjacent CH 2 units of said C 3 -C 8 cycloaliphatic may be replaced with —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 halogen or C 1 -C 6 alkyl wherein said C 1 -C 6 alkyl is substituted with 0-6 halogen and wherein up to two non-adjacent CH 2 units of said C 1 -C 6 alkyl may be replaced with —O—;

p is an integer from 0 to 3 inclusive; and

R 9 is H, or C 1 -C 6 alkyl wherein up to two non-adjacent CH 2 units of said C 1 -C 6 alkyl may be replaced with —O—.

In another embodiment, the invention features a compound of formula I-F or I′-F and the attendant 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. In another embodiment, R 3 is t-butyl. In another embodiment, R 3 is CF 3 . In another embodiment, R 3 is CF 2 CF 3 .

In another embodiment, the invention features a compound of formula I-F or I′-F and the attendant 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 —X—R X . In another embodiment, R 5 is —X—R X wherein R X is absent. In another embodiment, R 5 is —X—R X wherein 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. In another embodiment, R 5 is CH 3 . In another embodiment, R 5 is CD 3 . In another embodiment, R 5 is —X—R X wherein 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 wherein 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, the invention features a compound of formula I-F or I′-F and the attendant definitions, wherein R 1 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 —X—R X . In another embodiment, R 7 is —X—R X wherein R X is absent. In another embodiment, R 7 is —X—R X wherein 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. 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 —X—R X wherein 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 wherein two non-adjacent CH 2 units of said C 1 -C 6 alkyl are replaced with —O—. In another embodiment, R 7 is OCH 2 CH 2 OCH 3 . In another embodiment, R 7 is —X—R X wherein 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 wherein one CH 2 unit of said C 1 -C 6 alkyl is replaced with —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 invention features a compound of formula I-F or I′-F and the attendant definitions, wherein R 7 is —X—R X wherein X is a bond and R X is C 3 -C 8 cycloaliphatic 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 —X—R X wherein X is a bond and R X is cyclopropyl.

In another embodiment, the invention features a compound of formula I-F or I′-F and the attendant definitions, wherein R 7 is —X—R X wherein X is C 1 -C 6 alkyl wherein said C 1 -C 6 alkyl is substituted with 0-6 halogen wherein one CH 2 unit of said C 1 -C 6 alkyl is replaced with —O— and R X is C 3 -C 8 cycloaliphatic 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 —X—R X wherein X is OCH 2 and R X is cyclopropyl.

In another embodiment, the invention features a compound of formula I-F or I′-F and the attendant definitions, wherein p is zero. In another embodiment, p is an integer from 1 to 3 and R 8 is 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 C 1 -C 6 alkyl wherein said C 1 -C 6 alkyl is substituted with 0-6 halogen wherein one CH 2 unit of said C 1 -C 6 alkyl is replaced with —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 invention features a compound of formula I-F or I′-F and the attendant 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 substituted with 0-6 halogen wherein one CH 2 unit of said C 1 -C 6 alkyl is replaced with —O—. In another embodiment, R 9 is CH 2 CH 2 OH.

In another embodiment, the invention features a compound of formula I-F or I′-F and the attendant definitions, wherein ring A is selected from:

In another aspect, the invention provides a compound of formula I-G or I′-G:

or a pharmaceutically acceptable salt thereof,

wherein, independently for each occurrence:

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

R 5 is halogen, CN, or —X—R X ;

R 7 is halogen, CN, or —X—R X ;

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

R X is absent, H, or C 3 -C 8 cycloaliphatic, wherein up to two non-adjacent CH 2 units of said C 3 -C 8 cycloaliphatic may be replaced with —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 halogen or C 1 -C 6 alkyl wherein said C 1 -C 6 alkyl is substituted with 0-6 halogen and wherein up to two non-adjacent CH 2 units of said C 1 -C 6 alkyl may be replaced with —O—;

p is an integer from 0 to 3 inclusive; and

R 9 is H, or C 1 -C 6 alkyl wherein up to two non-adjacent CH 2 units of said C 1 -C 6 alkyl may be replaced with —O—.

In another embodiment, the invention features a compound of formula I-G or I′-G and the attendant 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. 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 substituted with 0-6 halogen wherein one CH 2 unit of said C 1 -C 6 alkyl is replaced with —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 invention features a compound of formula I-G or I′-G and the attendant 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. In another embodiment, R 3 is t-butyl. In another embodiment, R 3 is CF 3 . In another embodiment, R 3 is CF 2 CF 3 .

In another embodiment, the invention features a compound of formula I-G or I′-G and the attendant 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 —X—R X . In another embodiment, R 5 is —X—R X wherein R X is absent. In another embodiment, R 5 is —X—R X wherein 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. In another embodiment, R 5 is CH 3 . In another embodiment, R 5 is —X—R X wherein 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 wherein 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, the invention features a compound of formula I-G or I′-G and the attendant 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 —X—R X . In another embodiment, R 7 is —X—R X wherein R X is absent. In another embodiment, R 7 is —X—R X wherein 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. 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 —X—R X wherein 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 wherein two non-adjacent CH 2 units of said C 1 -C 6 alkyl are replaced with —O—. In another embodiment, R 7 is OCH 2 CH 2 OCH 3 . In another embodiment, R 7 is —X—R X wherein 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 wherein one CH 2 unit of said C 1 -C 6 alkyl is replaced with —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 invention features a compound of formula I-G or I′-G and the attendant definitions, wherein R 7 is —X—R X wherein X is a bond and R X is C 3 -C 8 cycloaliphatic 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 —X—R X wherein X is a bond and R X is cyclopropyl.

In another embodiment, the invention features a compound of formula I-G or I′-G and the attendant definitions, wherein R 7 is —X—R X wherein X is C 1 -C 6 alkyl wherein said C 1 -C 6 alkyl is substituted with 0-6 halogen and wherein one CH 2 unit of said C 1 -C 6 alkyl is replaced with —O— and R X is C 3 -C 8 cycloaliphatic 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 —X—R X wherein X is OCH 2 and R X is cyclopropyl.

In another embodiment, the invention features a compound of formula I-G or I′-G and the attendant definitions, wherein p is zero. In another embodiment, p is an integer from 1 to 3 and R 8 is 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 C 1 -C 6 alkyl wherein said C 1 -C 6 alkyl is substituted with 0-6 halogen wherein one CH 2 unit of said C 1 -C 6 alkyl is replaced with —O—. In another embodiment, p is an integer from 1 to 3 and R 8 is CH 3 .

In another embodiment, the invention features a compound of formula I-G or I′-G and the attendant 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 substituted with 0-6 halogen wherein one CH 2 unit of said C 1 -C 6 alkyl is replaced with —O—. In another embodiment, R 9 is CH 2 CH 2 OH.

In another embodiment, the invention features a compound of formula I-G or I′-G and the attendant definitions, wherein ring A is selected from:

In another aspect, the invention provides a compound of formula I-H or I′-H:

or a pharmaceutically acceptable salt thereof,

wherein, independently for each occurrence:

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

R 5 is halogen, CN, or —X—R X ;

R 7 is halogen, CN, or —X—R X ;

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

R X is absent, H, or C 3 -C 8 cycloaliphatic, wherein up to two non-adjacent CH 2 units of said C 3 -C 8 cycloaliphatic may be replaced with —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 halogen or C 1 -C 6 alkyl wherein said C 1 -C 6 alkyl is substituted with 0-6 halogen and wherein up to two non-adjacent CH 2 units of said C 1 -C 6 alkyl may be replaced with —O—;

p is an integer from 0 to 3 inclusive; and

R 9 is H, or C 1 -C 6 alkyl wherein up to two non-adjacent CH 2 units of said C 1 -C 6 alkyl may be replaced with —O—.

In another embodiment, the invention features a compound of formula I-H or I′-H and the attendant 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. In another embodiment, R 1 is CF 3 .

In another embodiment, the invention features a compound of formula I-H or I′-H and the attendant 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. In another embodiment, R 3 is t-butyl. In another embodiment, R 3 is CF 3 . In another embodiment, R 3 is CF 2 CF 3 .

In another embodiment, the invention features a compound of formula I-H or I′-H and the attendant 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 —X—R X . In another embodiment, R 5 is —X—R X wherein R X is absent. In another embodiment, R 5 is —X—R X wherein 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. In another embodiment, R 5 is CH 3 . In another embodiment, R 5 is —X—R X wherein 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 wherein 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, the invention features a compound of formula I-H or I′-H and the attendant 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 —X—R X . In another embodiment, R 7 is —X—R X wherein R X is absent. In another embodiment, R 7 is —X—R X wherein 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. 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 —X—R X wherein 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 wherein two non-adjacent CH 2 units of said C 1 -C 6 alkyl are replaced with —O—. In another embodiment, R 7 is OCH 2 CH 2 OCH 3 . In another embodiment, R 7 is —X—R X wherein 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 wherein one CH 2 unit of said C 1 -C 6 alkyl is replaced with —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 invention features a compound of formula I-H or I′-H and the attendant definitions, wherein R 7 is —X—R X wherein X is a bond and R X is C 3 -C 8 cycloaliphatic 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 —X—R X wherein X is a bond and R X is cyclopropyl.

In another embodiment, the invention features a compound of formula I-H or I′-H and the attendant definitions, wherein R 7 is —X—R X wherein X is C 1 -C 6 alkyl wherein said C 1 -C 6 alkyl is substituted with 0-6 halogen wherein one CH 2 unit of said C 1 -C 6 alkyl is replaced with —O— and R X is C 3 -C 8 cycloaliphatic 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 —X—R X wherein X is OCH 2 and R X is cyclopropyl.

In another embodiment, the invention features a compound of formula I-H or I′-H and the attendant definitions, wherein p is zero. In another embodiment, p is an integer from 1 to 3 and R 8 is 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 C 1 -C 6 alkyl wherein said C 1 -C 6 alkyl is substituted with 0-6 halogen wherein one CH 2 unit of said C 1 -C 6 alkyl is replaced with —O—. In another embodiment, p is an integer from 1 to 3 and R 8 is CH 3 .

In another embodiment, the invention features a compound of formula I-H or I′-H and the attendant 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 substituted with 0-6 halogen wherein one CH 2 unit of said C 1 -C 6 alkyl is replaced with —O—. In another embodiment, R 9 is CH 2 CH 2 OH.

In another embodiment, the invention features a compound of formula I-H or I′-H and the attendant definitions, wherein ring A is selected from:

In another aspect, the invention provides a compound of formula I-J or I′-J:

or a pharmaceutically acceptable salt thereof,

wherein, independently for each occurrence:

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

R 7 is halogen, CN, or —X—R X ;

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

R X is absent, H, or C 3 -C 8 cycloaliphatic, wherein up to two non-adjacent CH 2 units of said C 3 -C 8 cycloaliphatic may be replaced with —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 and wherein up to two non-adjacent CH 2 units of said C 1 -C 6 alkyl may be replaced with —O—;

p is an integer from 0 to 3 inclusive; and

R 9 is H, or C 1 -C 6 alkyl wherein up to two non-adjacent CH 2 units of said C 1 -C 6 alkyl may be replaced with —O—.

In another embodiment, the invention features a compound of formula I-J or I′-J and the attendant 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. 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 substituted with 0-6 halogen wherein one CH 2 unit of said C 1 -C 6 alkyl is replaced with —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 invention features a compound of formula I-J or I′-J and the attendant 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 —X—R X . In another embodiment, R 7 is —X—R X wherein R X is absent. In another embodiment, R 7 is —X—R X wherein 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. 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 —X—R X wherein 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 wherein two non-adjacent CH 2 units of said C 1 -C 6 alkyl are replaced with —O—. In another embodiment, R 7 is OCH 2 CH 2 OCH 3 . In another embodiment, R 7 is —X—R X wherein 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 wherein one CH 2 unit of said C 1 -C 6 alkyl is replaced with —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 invention features a compound of formula I-J or I′-J and the attendant definitions, wherein R 7 is —X—R X wherein X is a bond and R X is C 3 -C 8 cycloaliphatic 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 —X—R X wherein X is a bond and R X is cyclopropyl.

In another embodiment, the invention features a compound of formula I-J or I′-J and the attendant definitions, wherein R 7 is —X—R X wherein X is C 1 -C 6 alkyl wherein said C 1 -C 6 alkyl is substituted with 0-6 halogen wherein one CH 2 unit of said C 1 -C 6 alkyl is replaced with —O— and R X is C 3 -C 8 cycloaliphatic 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 —X—R X wherein X is OCH 2 and R X is cyclopropyl.

In another embodiment, the invention features a compound of formula I-J or I′-J and the attendant definitions, wherein p is zero. In another embodiment, p is an integer from 1 to 3 and R 8 is 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 C 1 -C 6 alkyl wherein said C 1 -C 6 alkyl is substituted with 0-6 halogen wherein one CH 2 unit of said C 1 -C 6 alkyl is replaced with —O—. In another embodiment, p is an integer from 1 to 3 and R 8 is CH 3 .

In another embodiment, the invention features a compound of formula I-J or I′-J and the attendant 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 substituted with 0-6 halogen wherein one CH 2 unit of said C 1 -C 6 alkyl is replaced with —O—. In another embodiment, R 9 is CH 2 CH 2 OH.

In another embodiment, the invention features a compound of formula I-J or I′-J and the attendant definitions, wherein ring B is selected from:

In another aspect, the invention provides a compound of formula I-K or I′-K:

or a pharmaceutically acceptable salt thereof,

wherein, independently for each occurrence:

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

R 7 is halogen, CN, or —X—R X ;

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

R X is absent, H, or C 3 -C 8 cycloaliphatic, wherein up to two non-adjacent CH 2 units of said C 3 -C 8 cycloaliphatic may be replaced with —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 halogen or C 1 -C 6 alkyl wherein said C 1 -C 6 alkyl is substituted with 0-6 halogen and wherein up to two non-adjacent CH 2 units of said C 1 -C 6 alkyl may be replaced with —O—;

p is an integer from 0 to 3 inclusive; and

R 9 is H, or C 1 -C 6 alkyl wherein up to two non-adjacent CH 2 units of said C 1 -C 6 alkyl may be replaced with —O—.

In another embodiment, the invention features a compound of formula I-K or I′-K and the attendant 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. In another embodiment, R 3 is t-butyl. In another embodiment, R 3 is CF 3 . In another embodiment, R 3 is CF 2 CF 3 .

In another embodiment, the invention features a compound of formula I-K or I′-K and the attendant 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 —X—R X . In another embodiment, R 7 is —X—R X wherein R X is absent. In another embodiment, R 7 is —X—R X wherein 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. 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 —X—R X wherein 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 wherein two non-adjacent CH 2 units of said C 1 -C 6 alkyl are replaced with —O—. In another embodiment, R 7 is OCH 2 CH 2 OCH 3 . In another embodiment, R 7 is —X—R X wherein 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 wherein one CH 2 unit of said C 1 -C 6 alkyl is replaced with —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 invention features a compound of formula I-K or I′-K and the attendant definitions, wherein R 7 is —X—R X wherein X is a bond and R X is C 3 -C 8 cycloaliphatic 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 —X—R X wherein X is a bond and R X is cyclopropyl.

In another embodiment, the invention features a compound of formula I-K or I′-K and the attendant definitions, wherein R 7 is —X—R X wherein X is C 1 -C 6 alkyl wherein said C 1 -C 6 alkyl is substituted with 0-6 halogen wherein one CH 2 unit of said C 1 -C 6 alkyl is replaced with —O— and R X is C 3 -C 8 cycloaliphatic 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 —X—R X wherein X is OCH 2 and R X is cyclopropyl.

In another embodiment, the invention features a compound of formula I-K or I′-K and the attendant definitions, wherein p is zero. In another embodiment, p is an integer from 1 to 3 and R 8 is halogen. In another embodiment, wherein p is an integer from 1 to 3 and R 8 is Cl. In another embodiment, wherein p is an integer from 1 to 3 and R 8 is C 1 -C 6 alkyl wherein said C 1 -C 6 alkyl is substituted with 0-6 halogen wherein 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 invention features a compound of formula I-K or I′-K and the attendant 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 substituted with 0-6 halogen wherein one CH 2 unit of said C 1 -C 6 alkyl is replaced with —O—. In another embodiment, R 9 is CH 2 CH 2 OH.

In another embodiment, the invention features a compound of formula I-K or I′-K and the attendant definitions, wherein ring B is selected from:

In another aspect, the invention provides a compound of formula I-L or I′-L:

or a pharmaceutically acceptable salt thereof,

wherein, independently for each occurrence:

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

R 7 is halogen, CN, or —X—R X ;

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

R X is absent, H, or C 3 -C 8 cycloaliphatic, wherein up to two non-adjacent CH 2 units of said C 3 -C 8 cycloaliphatic may be replaced with —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 halogen or C 1 -C 6 alkyl wherein said C 1 -C 6 alkyl is substituted with 0-6 halogen and wherein up to two non-adjacent CH 2 units of said C 1 -C 6 alkyl may be replaced with —O—;

p is an integer from 0 to 3 inclusive; and

R 9 is H, or C 1 -C 6 alkyl wherein up to two non-adjacent CH 2 units of said C 1 -C 6 alkyl may be replaced with —O—.

In another embodiment, the invention features a compound of formula I-L or I′-L and the attendant 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. 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 substituted with 0-6 halogen wherein one CH 2 unit of said C 1 -C 6 alkyl is replaced with —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 invention features a compound of formula I-L or I′-L and the attendant 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. In another embodiment, R 3 is t-butyl. In another embodiment, R 3 is CF 3 . In another embodiment, R 3 is CF 2 CF 3 .

In another embodiment, the invention features a compound of formula I-L or I′-L and the attendant 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 —X—R X . In another embodiment, R 7 is —X—R X wherein R X is absent. In another embodiment, R 7 is —X—R X wherein 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. 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 —X—R X wherein 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 wherein two non-adjacent CH 2 units of said C 1 -C 6 alkyl are replaced with —O—. In another embodiment, R 7 is OCH 2 CH 2 OCH 3 . In another embodiment, R 7 is —X—R X wherein 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 wherein one CH 2 unit of said C 1 -C 6 alkyl is replaced with —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 invention features a compound of formula I-L or I′-L and the attendant definitions, wherein R 7 is —X—R X wherein X is a bond and R X is C 3 -C 8 cycloaliphatic 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 —X—R X wherein X is a bond and R X is cyclopropyl.

In another embodiment, the invention features a compound of formula I-L or I′-L and the attendant definitions, wherein R 7 is —X—R X wherein X is C 1 -C 6 alkyl wherein said C 1 -C 6 alkyl is substituted with 0-6 halogen wherein one CH 2 unit of said C 1 -C 6 alkyl is replaced with —O— and R X is C 3 -C 8 cycloaliphatic 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 —X—R X wherein X is OCH 2 and R X is cyclopropyl.

In another embodiment, the invention features a compound of formula I-L or I′-L and the attendant definitions, wherein p is zero. In another embodiment, p is an integer from 1 to 3 and R 8 is 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 C 1 -C 6 alkyl wherein said C 1 -C 6 alkyl is substituted with 0-6 halogen wherein one CH 2 unit of said C 1 -C 6 alkyl is replaced with —O—. In another embodiment, p is an integer from 1 to 3 and R 8 is CH 3 .

In another embodiment, the invention features a compound of formula I-L or I′-L and the attendant 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 substituted with 0-6 halogen wherein one CH 2 unit of said C 1 -C 6 alkyl is replaced with —O—. In another embodiment, R 9 is CH 2 CH 2 OH.

In another embodiment, the invention features a compound of formula I-L or I′-L and the attendant definitions, wherein ring B is selected from:

In another aspect, the invention provides a compound of formula I-M or I′-M:

or a pharmaceutically acceptable salt thereof,

wherein, independently for each occurrence:

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

R 7 is halogen, CN, or —X—R X ;

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

R X is absent, H, or C 3 -C 8 cycloaliphatic, wherein up to two non-adjacent CH 2 units of said C 3 -C 8 cycloaliphatic may be replaced with —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 and wherein up to two non-adjacent CH 2 units of said C 1 -C 6 alkyl may be replaced with —O—;

p is an integer from 0 to 3 inclusive; and

R 9 is H, or C 1 -C 6 alkyl wherein up to two non-adjacent CH 2 units of said C 1 -C 6 alkyl may be replaced with —O—.

In another embodiment, the invention features a compound of formula I-M or I′-M and the attendant 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. In another embodiment, R 1 is CF 3 .

In another embodiment, the invention features a compound of formula I-M or I′-M and the attendant 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. In another embodiment, R 3 is t-butyl. In another embodiment, R 3 is CF 3 . In another embodiment, R 3 is CF 2 CF 3 .

In another embodiment, the invention features a compound of formula I-M or I′-M and the attendant 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 —X—R X . In another embodiment, R 7 is —X—R X wherein R X is absent. In another embodiment, R 7 is —X—R X wherein 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. 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 —X—R X wherein 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 wherein two non-adjacent CH 2 units of said C 1 -C 6 alkyl are replaced with —O—. In another embodiment, R 7 is OCH 2 CH 2 OCH 3 . In another embodiment, R 7 is —X—R X wherein 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 wherein one CH 2 unit of said C 1 -C 6 alkyl is replaced with —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 invention features a compound of formula I-M or I′-M and the attendant definitions, wherein R 7 is —X—R X wherein X is a bond and R X is C 3 -C 8 cycloaliphatic 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 —X—R X wherein X is a bond and R X is cyclopropyl.

In another embodiment, the invention features a compound of formula I-M or I′-M and the attendant definitions, wherein R 7 is —X—R X wherein X is C 1 -C 6 alkyl wherein said C 1 -C 6 alkyl is substituted with 0-6 halogen wherein one CH 2 unit of said C 1 -C 6 alkyl is replaced with —O— and R X is C 3 -C 8 cycloaliphatic 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 —X—R X wherein X is OCH 2 and R X is cyclopropyl.

In another embodiment, the invention features a compound of formula I-M or I′-M and the attendant definitions, wherein p is zero. In another embodiment, p is an integer from 1 to 3 and R 8 is 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 C 1 -C 6 alkyl wherein said C 1 -C 6 alkyl is substituted with 0-6 halogen wherein one CH 2 unit of said C 1 -C 6 alkyl is replaced with —O—. In another embodiment, p is an integer from 1 to 3 and R 8 is CH 3 .

In another embodiment, the invention features a compound of formula I-M or I′-M and the attendant 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 substituted with 0-6 halogen wherein one CH 2 unit of said C 1 -C 6 alkyl is replaced with —O—. In another embodiment, R 9 is CH 2 CH 2 OH.

In another embodiment, the invention features a compound of formula I-M or I′-M and the attendant definitions, wherein ring B is selected from:

In another aspect, the invention provides a compound of formula I-N or I′-N:

or a pharmaceutically acceptable salt thereof,

wherein, independently for each occurrence:

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

R 5 is halogen, CN, or —X—R X ;

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

R X is absent, H, or C 3 -C 8 cycloaliphatic, wherein up to two non-adjacent CH 2 units of said C 3 -C 8 cycloaliphatic may be replaced with —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 halogen, or C 1 -C 6 alkyl wherein said C 1 -C 6 alkyl is substituted with 0-6 halogen and wherein up to two non-adjacent CH 2 units of said C 1 -C 6 alkyl may be replaced with —O—;

p is an integer from 0 to 3 inclusive; and

R 9 is H, or C 1 -C 6 alkyl wherein up to two non-adjacent CH 2 units of said C 1 -C 6 alkyl may be replaced with —O—.

In another embodiment, the invention features a compound of formula I-N or I′-N and the attendant 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. 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 substituted with 0-6 halogen wherein one CH 2 unit of said C 1 -C 6 alkyl is replaced with —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 invention features a compound of formula I-N or I′-N and the attendant 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 —X—R X . In another embodiment, R 5 is —X—R X wherein R X is absent. In another embodiment, R 5 is —X—R X wherein 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. In another embodiment, R 5 is CH 3 . In another embodiment, R 5 is —X—R X wherein 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 wherein 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, the invention features a compound of formula I-N or I′-N and the attendant definitions, wherein p is zero. In another embodiment, p is an integer from 1 to 3 and R 8 is 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 C 1 -C 6 alkyl wherein said C 1 -C 6 alkyl is substituted with 0-6 halogen wherein one CH 2 unit of said C 1 -C 6 alkyl is replaced with —O—. In another embodiment, p is an integer from 1 to 3 and R 8 is CH 3 .

In another embodiment, the invention features a compound of formula I-N or I′-N and the attendant 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 substituted with 0-6 halogen wherein one CH 2 unit of said C 1 -C 6 alkyl is replaced with —O—. In another embodiment, R 9 is CH 2 CH 2 OH.

In another embodiment, the invention features a compound of formula I-N or I′-N and the attendant definitions, wherein ring C is selected from:

In another aspect, the invention provides a compound of formula I-O or I′-O:

or a pharmaceutically acceptable salt thereof,

wherein, independently for each occurrence:

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

R 5 is halogen, CN, or —X—R X ;

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

R X is absent, H, or C 3 -C 8 cycloaliphatic, wherein up to two non-adjacent CH 2 units of said C 3 -C 8 cycloaliphatic may be replaced with —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 halogen, or C 1 -C 6 alkyl wherein said C 1 -C 6 alkyl is substituted with 0-6 halogen and wherein up to two non-adjacent CH 2 units of said C 1 -C 6 alkyl may be replaced with —O—;

p is an integer from 0 to 3 inclusive; and

R 9 is H, or C 1 -C 6 alkyl wherein up to two non-adjacent CH 2 units of said C 1 -C 6 alkyl may be replaced with —O—.

In another embodiment, the invention features a compound of formula I-O or I′-O and the attendant 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. In another embodiment, R 3 is t-butyl. In another embodiment, R 3 is CF 3 . In another embodiment, R 3 is CF 2 CF 3 .

In another embodiment, the invention features a compound of formula I-O or I′-O and the attendant 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 —X—R X . In another embodiment, R 5 is —X—R X wherein R X is absent. In another embodiment, R 5 is —X—R X wherein 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. In another embodiment, R 5 is CH 3 . In another embodiment, R 5 is —X—R X wherein 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 wherein 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, the invention features a compound of formula I-O or I′-O and the attendant definitions, wherein p is an integer from 1 to 3 and R 8 is 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 C 1 -C 6 alkyl wherein said C 1 -C 6 alkyl is substituted with 0-6 halogen wherein one CH 2 unit of said C 1 -C 6 alkyl is replaced with —O—. In another embodiment, p is an integer from 1 to 3 and R 8 is CH 3 .

In another embodiment, the invention features a compound of formula I-O or I′-O and the attendant 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 substituted with 0-6 halogen wherein one CH 2 unit of said C 1 -C 6 alkyl is replaced with —O—. In another embodiment, R 9 is CH 2 CH 2 OH.

In another embodiment, the invention features a compound of formula I-O or I′-O and the attendant definitions, wherein ring C is selected from:

In another aspect, the invention provides a compound of formula I-P or I′-P:

or a pharmaceutically acceptable salt thereof,

wherein, independently for each occurrence:

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

R 5 is halogen, CN, or —X—R X ;

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

R X is absent, H, or C 3 -C 8 cycloaliphatic, wherein up to two non-adjacent CH 2 units of said C 3 -C 8 cycloaliphatic may be replaced with —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, wherein up to two non-adjacent CH 2 units of said C 1 -C 6 alkyl may be replaced with —O—;

p is an integer from 0 to 3 inclusive; and

R 9 is H, or C 1 -C 6 alkyl wherein up to two non-adjacent CH 2 units of said C 1 -C 6 alkyl may be replaced with —O—.

In another embodiment, the invention features a compound of formula I-P or I′-P and the attendant 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. 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 substituted with 0-6 halogen wherein one CH 2 unit of said C 1 -C 6 alkyl is replaced with —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 invention features a compound of formula I-P or I′-P and the attendant 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. In another embodiment, R 3 is t-butyl. In another embodiment, R 3 is CF 3 . In another embodiment, R 3 is CF 2 CF 3 .

In another embodiment, the invention features a compound of formula I-P or I′-P and the attendant 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 —X—R X . In another embodiment, R 5 is —X—R X wherein R X is absent. In another embodiment, R 5 is —X—R X wherein 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. In another embodiment, R 5 is CH 3 . In another embodiment, R 5 is —X—R X wherein 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 wherein 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, the invention features a compound of formula I-P or I′-P and the attendant definitions, wherein p is zero. In another embodiment, p is an integer from 1 to 3 and R 8 is 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 C 1 -C 6 alkyl wherein said C 1 -C 6 alkyl is substituted with 0-6 halogen wherein one CH 2 unit of said C 1 -C 6 alkyl is replaced with —O—. In another embodiment, p is an integer from 1 to 3 and R 8 is CH 3 .

In another embodiment, the invention features a compound of formula I-P or I′-P and the attendant 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 substituted with 0-6 halogen wherein one CH 2 unit of said C 1 -C 6 alkyl is replaced with —O—. In another embodiment, R 9 is CH 2 CH 2 OH.

In another embodiment, the invention features a compound of formula I-P or I′-P and the attendant definitions, wherein ring C is selected from:

In another aspect, the invention provides a compound of formula I-Q or I′-Q:

or a pharmaceutically acceptable salt thereof,

wherein, independently for each occurrence:

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

R 6 is halogen, CN, or —X—R X ;

R 7 is halogen, CN, or —X—R X ;

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

R X is absent, H, or C 3 -C 8 cycloaliphatic, wherein up to two non-adjacent CH 2 units of said C 3 -C 8 cycloaliphatic may be replaced with —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 and wherein up to two non-adjacent CH 2 units of said C 1 -C 6 alkyl may be replaced with —O—;

p is an integer from 0 to 3 inclusive; and

R 9 is H, or C 1 -C 6 alkyl wherein up to two non-adjacent CH 2 units of said C 1 -C 6 alkyl may be replaced with —O—.

In another embodiment, the invention features a compound of formula I-Q or I′-Q and the attendant 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. 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 substituted with 0-6 halogen wherein one CH 2 unit of said C 1 -C 6 alkyl is replaced with —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 invention features a compound of formula I-Q or I′-Q and the attendant 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 —X—R X . In another embodiment, R 6 is —X—R X wherein R X is absent. In another embodiment, R 6 is —X—R X wherein 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. In another embodiment, R 6 is CH 3 . In another embodiment, R 6 is —X—R X wherein 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 wherein 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, the invention features a compound of formula I-Q or I′-Q and the attendant 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 —X—R X . In another embodiment, R 7 is —X—R X wherein R X is absent. In another embodiment, R 7 is —X—R X wherein 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. 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 —X—R X wherein 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 wherein two non-adjacent CH 2 units of said C 1 -C 6 alkyl are replaced with —O—. In another embodiment, R 7 is OCH 2 CH 2 OCH 3 . In another embodiment, R 7 is —X—R X wherein 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 wherein one CH 2 unit of said C 1 -C 6 alkyl is replaced with —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 invention features a compound of formula I-Q or I′-Q and the attendant definitions, wherein R 7 is —X—R X wherein X is a bond and R X is C 3 -C 8 cycloaliphatic 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 —X—R X wherein X is a bond and R X is cyclopropyl.

In another embodiment, the invention features a compound of formula I-Q or I′-Q and the attendant definitions, wherein R 7 is —X—R X wherein X is C 1 -C 6 alkyl wherein said C 1 -C 6 alkyl is substituted with 0-6 halogen wherein one CH 2 unit of said C 1 -C 6 alkyl is replaced with —O— and R X is C 3 -C 8 cycloaliphatic 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 —X—R X wherein X is OCH 2 and R X is cyclopropyl.

In another embodiment, the invention features a compound of formula I-Q or I′-Q and the attendant definitions, wherein p is zero. In another embodiment, p is an integer from 1 to 3 and R 8 is 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 C 1 -C 6 alkyl wherein said C 1 -C 6 alkyl is substituted with 0-6 halogen wherein one CH 2 unit of said C 1 -C 6 alkyl is replaced with —O—. In another embodiment, p is an integer from 1 to 3 and R 8 is CH 3 .

In another embodiment, the invention features a compound of formula I-Q or I′-Q and the attendant 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 substituted with 0-6 halogen wherein one CH 2 unit of said C 1 -C 6 alkyl is replaced with —O—. In another embodiment, R 9 is CH 2 CH 2 OH.

In another embodiment, the invention features a compound of formula I-Q or I′-Q and the attendant definitions, wherein ring D is selected from:

In another aspect, the invention provides a compound of formula I-R or I′-R:

or a pharmaceutically acceptable salt thereof,

wherein, independently for each occurrence:

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

R 6 is halogen, CN, or —X—R X ;

R 7 is halogen, CN, or —X—R X ;

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

R X is absent, H, or C 3 -C 8 cycloaliphatic, wherein up to two non-adjacent CH 2 units of said C 3 -C 8 cycloaliphatic may be replaced with —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 and wherein up to two non-adjacent CH 2 units of said C 1 -C 6 alkyl may be replaced with —O—;

p is an integer from 0 to 3 inclusive; and

R 9 is H, or C 1 -C 6 alkyl wherein up to two non-adjacent CH 2 units of said C 1 -C 6 alkyl may be replaced with —O—.

In another embodiment, the invention features a compound of formula I-R or I′-R and the attendant 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. In another embodiment, R 3 is t-butyl. In another embodiment, R 3 is CF 3 . In another embodiment, R 3 is CF 2 CF 3 .

In another embodiment, the invention features a compound of formula I-R or I′-R and the attendant 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 —X—R X . In another embodiment, R 6 is —X—R X wherein R X is absent. In another embodiment, R 6 is —X—R X wherein 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. In another embodiment, R 6 is CH 3 . In another embodiment, R 6 is —X—R X wherein 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 wherein 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, the invention features a compound of formula I-R or I′-R and the attendant 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 —X—R X . In another embodiment, R 7 is —X—R X wherein R X is absent. In another embodiment, R 7 is —X—R X wherein 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. 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 —X—R X wherein 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 wherein two non-adjacent CH 2 units of said C 1 -C 6 alkyl are replaced with —O—. In another embodiment, R 7 is OCH 2 CH 2 OCH 3 . In another embodiment, R 7 is —X—R X wherein 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 wherein one CH 2 unit of said C 1 -C 6 alkyl is replaced with —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 invention features a compound of formula I-R or I′-R and the attendant definitions, wherein R 7 is —X—R X wherein X is a bond and R X is C 3 -C 8 cycloaliphatic 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 —X—R X wherein X is a bond and R X is cyclopropyl.

In another embodiment, the invention features a compound of formula I-R or I′-R and the attendant definitions, wherein R 7 is —X—R X wherein X is C 1 -C 6 alkyl wherein said C 1 -C 6 alkyl is substituted with 0-6 halogen wherein one CH 2 unit of said C 1 -C 6 alkyl is replaced with —O— and R X is C 3 -C 8 cycloaliphatic 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 —X—R X wherein X is OCH 2 and R X is cyclopropyl.

In another embodiment, the invention features a compound of formula I-R or I′-R and the attendant definitions, wherein p is zero. In another embodiment, p is an integer from 1 to 3 and R 8 is 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 C 1 -C 6 alkyl wherein said C 1 -C 6 alkyl is substituted with 0-6 halogen wherein one CH 2 unit of said C 1 -C 6 alkyl is replaced with —O—. In another embodiment, p is an integer from 1 to 3 and R 8 is CH 3 .

In another embodiment, the invention features a compound of formula I-R or I′-R and the attendant 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 substituted with 0-6 halogen wherein one CH 2 unit of said C 1 -C 6 alkyl is replaced with —O—. In another embodiment, R 9 is CH 2 CH 2 OH.

In another embodiment, the invention features a compound of formula I-R or I′-R and the attendant definitions, wherein ring D is selected from:

In another aspect, the invention provides a compound of formula I-S or I′-S:

or a pharmaceutically acceptable salt thereof,

wherein, independently for each occurrence:

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

R 6 is halogen, CN, or —X—R X ;

R 7 is halogen, CN, or —X—R X ;

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

R X is absent, H, or C 3 -C 8 cycloaliphatic, wherein up to two non-adjacent CH 2 units of said C 3 -C 8 cycloaliphatic may be replaced with —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 halogen, or C 1 -C 6 alkyl wherein said C 1 -C 6 alkyl is substituted with 0-6 halogen and wherein up to two non-adjacent CH 2 units of said C 1 -C 6 alkyl may be replaced with —O—;

p is an integer from 0 to 3 inclusive; and

R 9 is H, or C 1 -C 6 alkyl wherein up to two non-adjacent CH 2 units of said C 1 -C 6 alkyl may be replaced with —O—.

In another embodiment, the invention features a compound of formula I-S or I′-S and the attendant 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. 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 substituted with 0-6 halogen wherein one CH 2 unit of said C 1 -C 6 alkyl is replaced with —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 invention features a compound of formula I-S or I′-S and the attendant 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. In another embodiment, R 3 is t-butyl. In another embodiment, R 3 is CF 3 . In another embodiment, R 3 is CF 2 CF 3 .

In another embodiment, the invention features a compound of formula I-S or I′-S and the attendant 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 —X—R X . In another embodiment, R 6 is —X—R X wherein R X is absent. In another embodiment, R 6 is —X—R X wherein 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. In another embodiment, R 6 is CH 3 . In another embodiment, R 6 is —X—R X wherein 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 wherein 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, the invention features a compound of formula I-S or I′-S and the attendant 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 —X—R X . In another embodiment, R 7 is —X—R X wherein R X is absent. In another embodiment, R 7 is —X—R X wherein 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. 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 —X—R X wherein 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 wherein two non-adjacent CH 2 units of said C 1 -C 6 alkyl are replaced with —O—. In another embodiment, R 7 is OCH 2 CH 2 OCH 3 . In another embodiment, R 7 is —X—R X wherein 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 wherein one CH 2 unit of said C 1 -C 6 alkyl is replaced with —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 invention features a compound of formula I-S or I′-S and the attendant definitions, wherein R 7 is —X—R X wherein X is a bond and R X is C 3 -C 8 cycloaliphatic 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 —X—R X wherein X is a bond and R X is cyclopropyl.

In another embodiment, the invention features a compound of formula I-S or I′-S and the attendant definitions, wherein R 7 is —X—R X wherein X is C 1 -C 6 alkyl wherein said C 1 -C 6 alkyl is substituted with 0-6 halogen wherein one CH 2 unit of said C 1 -C 6 alkyl is replaced with —O— and R X is C 3 -C 8 cycloaliphatic 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 —X—R X wherein X is OCH 2 and R X is cyclopropyl.

In another embodiment, the invention features a compound of formula I-S or I′-S and the attendant definitions, wherein p is zero. In another embodiment, p is an integer from 1 to 3 and R 8 is 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 C 1 -C 6 alkyl wherein said C 1 -C 6 alkyl is substituted with 0-6 halogen wherein one CH 2 unit of said C 1 -C 6 alkyl is replaced with —O—. In another embodiment, p is an integer from 1 to 3 and R 8 is CH 3 .

In another embodiment, the invention features a compound of formula I-S or I′-S and the attendant 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 substituted with 0-6 halogen wherein one CH 2 unit of said C 1 -C 6 alkyl is replaced with —O—. In another embodiment, R 9 is CH 2 CH 2 OH.

In another embodiment, the invention features a compound of formula I-S or I′-S and the attendant definitions, wherein ring D is selected from:

In another embodiment, the invention features a compound of formula I or I′, wherein the compound or a pharmaceutically acceptable salt thereof, is selected from Table 1. Compounds names in Table 1 were generated using ChemBioDrawUltra version 12.0 from Cambridge Soft/Chem Office 2010.

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-(2,4-difluorophenoxy)-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-methylphenoxy)-N- (2-oxo-1,2-dihydropyridin-4-yl)-4- (trifluoromethyl)benzamide

11

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

30

2-(4-fluoro-2-methoxyphenoxy)- N-(2-oxo-1,2-dihydropyridin-4- yl)-5-(trifluoromethoxy)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-(trifluoromethyl)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)-4- (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)-4-(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- (perfluoroethyl)benzamide

89

2-(3-fluoro-4-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-(cyclopentylmethoxy)-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- N-(2-oxo-1,2-dihydropyridin-4-yl) (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.

Salts, Compositions, Uses, Formulation, Administration and Additional Agents

Pharmaceutically Acceptable Salts and Compositions

As discussed herein, the invention provides compounds that are inhibitors of voltage-gated sodium channels, and thus the present compounds are useful for the treatment of diseases, disorders, and conditions including, but not limited to chronic pain, gut pain, neuropathic pain, musculoskeletal pain, acute pain, inflammatory pain, cancer pain, idiopathic pain, multiple sclerosis, Charcot-Marie-Tooth syndrome, incontinence or cardiac arrhythmia. Accordingly, in another aspect of the invention, pharmaceutically acceptable compositions are provided, wherein these compositions comprise any of the compounds as described herein, and optionally comprise a pharmaceutically acceptable carrier, adjuvant or vehicle. In certain embodiments, these compositions optionally further comprise one or more additional therapeutic agents.

It will also be appreciated that certain of the compounds of invention can exist in free form for treatment, or where appropriate, as a pharmaceutically acceptable derivative thereof. According to the invention, a pharmaceutically acceptable derivative includes, but is not limited to, pharmaceutically acceptable salts, esters, salts of such esters, or any other adduct or derivative which upon administration to a subject in need is capable of providing, directly or indirectly, a compound as otherwise described herein, or a metabolite or residue thereof.

As used herein, the term “pharmaceutically acceptable salt” refers to those salts which are, within the scope of sound medical judgement, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response and the like, and are commensurate with a reasonable benefit/risk ratio. A “pharmaceutically acceptable salt” means any non-toxic salt or salt of an ester of a compound of this invention that, upon administration to a recipient, is capable of providing, either directly or indirectly, a compound of this invention or an inhibitorily active metabolite or residue thereof. As used herein, the term “inhibitorily active metabolite or residue thereof” means that a metabolite or residue thereof is also an inhibitor of a voltage-gated sodium channel.

Pharmaceutically acceptable salts are well known in the art. For example, S. M. Berge, et al. describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 1977, 66, 1-19, incorporated herein by reference. Pharmaceutically acceptable salts of the compounds of this invention include those derived from suitable inorganic and organic acids and bases. Examples of pharmaceutically acceptable, nontoxic acid addition salts are salts of an amino group 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 by 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, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, undecanoate, valerate salts, and the like. Salts derived from appropriate bases include alkali metal, alkaline earth metal, ammonium and N + (C 1-4 alkyl) 4 salts. This invention also envisions the quaternization of any basic nitrogen-containing groups of the compounds disclosed herein. Water or oil-soluble or dispersable products may be obtained by such quaternization. Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like. Further pharmaceutically acceptable salts include, when appropriate, nontoxic ammonium, quaternary ammonium, and amine cations formed using counterions such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, lower alkyl sulfonate and aryl sulfonate.

As described herein, the pharmaceutically acceptable compositions of the invention additionally comprise a pharmaceutically acceptable carrier, adjuvant, or vehicle, which, as used herein, includes any and all solvents, diluents, or other liquid vehicle, dispersion or suspension aids, surface active agents, isotonic agents, thickening or emulsifying agents, preservatives, solid binders, lubricants and the like, as suited to the particular dosage form desired. Remington's Pharmaceutical Sciences, Sixteenth Edition, E. W. Martin (Mack Publishing Co., Easton, Pa., 1980) discloses various carriers used in formulating pharmaceutically acceptable compositions and known techniques for the preparation thereof. Except insofar as any conventional carrier medium is incompatible with the compounds of the invention, such as by producing any undesirable biological effect or otherwise interacting in a deleterious manner with any other component(s) of the pharmaceutically acceptable composition, its use is contemplated to be within the scope of this invention. Some examples of materials which can serve as pharmaceutically acceptable carriers include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, serum proteins, such as human serum albumin, buffer substances such as phosphates, glycine, sorbic acid, or potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes, such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinyl pyrrolidone, polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers, wool fat, sugars such as lactose, glucose and sucrose; starches such as corn starch and potato starch; cellulose and its derivatives such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; powdered tragacanth; malt; gelatin; talc; excipients 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; such a 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; 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 coloring agents, releasing agents, coating agents, sweetening, flavoring and perfuming agents, preservatives and antioxidants can also be present in the composition, according to the judgment of the formulator.

In another aspect, the invention features a pharmaceutical composition comprising the compound of the invention and a pharmaceutically acceptable carrier.

In another aspect, the invention features a pharmaceutical composition comprising a therapeutically effective amount of the compound or a pharmaceutically acceptable salt thereof of the compounds of formula I or formula I′ and one or more pharmaceutically acceptable carriers or vehicles.

Uses of Compounds and Pharmaceutically Acceptable Salts and Compositions

In another aspect, the invention features a method of inhibiting a voltage-gated sodium channel in a subject comprising administering to the subject 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 Nav1.8.

In yet another aspect, the invention features a method of treating or lessening the severity in a subject of chronic pain, gut pain, neuropathic pain, musculoskeletal pain, acute pain, inflammatory pain, cancer pain, idiopathic pain, multiple sclerosis, Charcot-Marie-Tooth syndrome, incontinence or cardiac arrhythmia comprising administering an effective amount of a compound, a pharmaceutically acceptable salt thereof or a pharmaceutical composition of the compounds of formula I or formula I′.

In yet another aspect, the invention features a method of treating or lessening the severity in a subject of gut pain, wherein gut pain comprises inflammatory bowel disease pain, Crohn's disease pain or interstitial cystitis pain wherein said method comprises administering an effective amount of a compound, a pharmaceutically acceptable salt thereof or a pharmaceutical composition of the compounds of formula I or formula I′.

In yet another aspect, the invention features a method of treating or lessening the severity in a subject of neuropathic pain, wherein neuropathic pain comprises post-herpetic neuralgia, diabetic neuralgia, painful HIV-associated sensory neuropathy, trigeminal neuralgia, burning mouth syndrome, post-amputation pain, phantom pain, painful neuroma; traumatic neuroma; Morton's neuroma; nerve entrapment injury, spinal stenosis, carpal tunnel syndrome, radicular pain, sciatica pain; nerve avulsion injury, brachial plexus avulsion injury; complex regional pain syndrome, drug therapy induced neuralgia, cancer chemotherapy induced neuralgia, anti-retroviral therapy induced neuralgia; post spinal cord injury pain, idiopathic small-fiber neuropathy, idiopathic sensory neuropathy or trigeminal autonomic cephalalgia wherein said method comprises administering an effective amount of a compound, a pharmaceutically acceptable salt thereof or a pharmaceutical composition of the compounds of formula I or formula I′.

In yet another aspect, the invention features a method of treating or lessening the severity in a subject of musculoskeletal pain, wherein musculoskeletal pain comprises osteoarthritis pain, back pain, cold pain, burn pain or dental pain wherein said method comprises administering an effective amount of a compound, a pharmaceutically acceptable salt thereof or a pharmaceutical composition of the compounds of formula I or formula I′.

In yet another aspect, the invention features a method of treating or lessening the severity in a subject of inflammatory pain, wherein inflammatory pain comprises rheumatoid arthritis pain or vulvodynia wherein said method comprises administering an effective amount of a compound, a pharmaceutically acceptable salt thereof or a pharmaceutical composition of the compounds of formula I or formula I′.

In yet another aspect, the invention features a method of treating or lessening the severity in a subject of idiopathic pain, wherein idiopathic pain comprises fibromyalgia pain wherein said method comprises administering an effective amount of a compound, a pharmaceutically acceptable salt thereof or a pharmaceutical composition of the compounds of formula I or formula I′.

In yet another aspect, the invention features a method wherein the subject is treated with one or more additional therapeutic agents administered concurrently with, prior to, or subsequent to treatment with an effective amount of a compound, a pharmaceutically acceptable salt thereof or a pharmaceutical composition of the compounds of formula I or formula I′.

In another aspect, the invention features a method of inhibiting a voltage-gated sodium channel in a subject comprising administering to the subject an effective amount of a compound, a pharmaceutically acceptable salt thereof or a pharmaceutical composition of the compounds of formula I or formula I′. In another aspect, the voltage-gated sodium channel is Nav1.8.

In another aspect, the invention features 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 of the compounds of formula I or formula I′. In another aspect, the voltage-gated sodium channel is Nav1.8.

In another aspect, the invention features a method of treating or lessening the severity in a subject of acute pain, chronic pain, neuropathic pain, inflammatory pain, arthritis, migraine, cluster headaches, trigeminal neuralgia, herpetic neuralgia, general neuralgias, epilepsy, epilepsy conditions, neurodegenerative disorders, psychiatric disorders, anxiety, depression, dipolar disorder, myotonia, arrhythmia, movement disorders, neuroendocrine disorders, ataxia, multiple sclerosis, irritable bowel syndrome, incontinence, visceral pain, osteoarthritis pain, postherpetic neuralgia, diabetic neuropathy, radicular pain, sciatica, back pain, head pain, neck pain, severe pain, intractable pain, nociceptive pain, breakthrough pain, postsurgical pain, cancer pain, stroke, cerebral ischemia, traumatic brain injury, amyotrophic lateral sclerosis, stress induced angina, exercise induced angina, palpitations, hypertension, or abnormal gastro-intestinal motility, comprising administering an effective amount of a compound, a pharmaceutically acceptable salt thereof or a pharmaceutical composition of the compounds of formula I or formula I′.

In another aspect, the invention features a method of treating or lessening the severity in a subject of femur cancer pain; non-malignant chronic bone pain; rheumatoid arthritis; osteoarthritis; spinal stenosis; neuropathic low back pain; myofascial pain syndrome; fibromyalgia; temporomandibular joint pain; chronic visceral pain, abdominal pain; pancreatic pain; IBS pain; chronic and acute headache pain; migraine; tension headache; cluster headaches; chronic and acute neuropathic pain, post-herpetic neuralgia; diabetic neuropathy; HIV-associated neuropathy; trigeminal neuralgia; Charcot-Marie Tooth neuropathy; hereditary sensory neuropathies; peripheral nerve injury; painful neuromas; ectopic proximal and distal discharges; radiculopathy; chemotherapy induced neuropathic pain; radiotherapy-induced neuropathic pain; post-mastectomy pain; central pain; spinal cord injury pain; post-stroke pain; thalamic pain; complex regional pain syndrome; phantom pain; intractable pain; acute pain, acute post-operative pain; acute musculoskeletal pain; joint pain; mechanical low back pain; neck pain; tendonitis; injury/exercise pain; acute visceral pain; pyelonephritis; appendicitis; cholecystitis; intestinal obstruction; hernias; chest pain, cardiac pain; pelvic pain, renal colic pain, acute obstetric pain, labor pain; cesarean section pain; acute inflammatory, burn and trauma pain; acute intermittent pain, endometriosis; acute herpes zoster pain; sickle cell anemia; acute pancreatitis; breakthrough pain; orofacial pain; sinusitis pain; dental pain; multiple sclerosis (MS) pain; pain in depression; leprosy pain; Behcet's disease pain; adiposis dolorosa; phlebitic pain; Guillain-Barre pain; painful legs and moving toes; Haglund syndrome; erythromelalgia pain; Fabry's disease pain; bladder and urogenital disease; urinary incontinence; hyperactivity bladder; painful bladder syndrome; interstitial cyctitis (IC); prostatitis; complex regional pain syndrome (CRPS), type I and type II; widespread pain, paroxysmal extreme pain, pruritis, tinnitis, or angina-induced pain, comprising administering an effective amount of a compound, a pharmaceutically acceptable salt thereof or a pharmaceutical composition of the compounds of formula I or formula I′.

In another aspect, the invention features a method of treating or lessening the severity in a subject of neuropathic pain comprising administering an effective amount of a compound, a pharmaceutically acceptable salt thereof or a pharmaceutical composition of the compounds of formula I or formula I′. In one aspect, the neuropathic pain is selected from post-herpetic neuralgia, diabetic neuralgia, painful HIV-associated sensory neuropathy, trigeminal neuralgia, burning mouth syndrome, post-amputation pain, phantom pain, painful neuroma, traumatic neuroma, Morton's neuroma, nerve entrapment injury, spinal stenosis, carpal tunnel syndrome, radicular pain, sciatica pain, nerve avulsion injury, brachial plexus avulsion, complex regional pain syndrome, drug therapy induced neuralgia, cancer chemotherapy induced neuralgia, anti-retroviral therapy induced neuralgia, post spinal cord injury pain, idiopathic small-fiber neuropathy, idiopathic sensory neuropathy or trigeminal autonomic cephalalgia.

Manufacture of Medicaments

In one aspect, the invention provides the use of a compound or pharmaceutical composition described herein for the manufacture of a medicament for use in inhibiting a voltage-gated sodium channel. In another aspect, the voltage-gated sodium channel is Nav1.8.

In yet another aspect, the invention provides the use of a compound or pharmaceutical composition described herein for the manufacture of a medicament for use in treating or lessening the severity in a subject of chronic pain, gut pain, neuropathic pain, musculoskeletal pain, acute pain, inflammatory pain, cancer pain, idiopathic pain, multiple sclerosis, Charcot-Marie-Tooth syndrome, incontinence or cardiac arrhythmia.

In yet another aspect, the invention provides the use of a compound or pharmaceutical composition described herein for the manufacture of a medicament for use in treating or lessening the severity in a subject of gut pain, wherein gut pain comprises inflammatory bowel disease pain, Crohn's disease pain or interstitial cystitis pain.

In yet another aspect, the invention provides the use of a compound or pharmaceutical composition described herein for the manufacture of a medicament for use in a treating or lessening the severity in a subject of neuropathic pain, wherein neuropathic pain comprises post-herpetic neuralgia, diabetic neuralgia, painful HIV-associated sensory neuropathy, trigeminal neuralgia, burning mouth syndrome, post-amputation pain, phantom pain, painful neuroma; traumatic neuroma; Morton's neuroma; nerve entrapment injury, spinal stenosis, carpal tunnel syndrome, radicular pain, sciatica pain; nerve avulsion injury, brachial plexus avulsion injury; complex regional pain syndrome, drug therapy induced neuralgia, cancer chemotherapy induced neuralgia, anti-retroviral therapy induced neuralgia; post spinal cord injury pain, idiopathic small-fiber neuropathy, idiopathic sensory neuropathy or trigeminal autonomic neuropathy.

In yet another aspect, the invention provides the use of a compound or pharmaceutical composition described herein for the manufacture of a medicament for use in treating or lessening the severity in a subject of musculoskeletal pain, wherein musculoskeletal pain comprises osteoarthritis pain, back pain, cold pain, burn pain or dental pain.

In yet another aspect, the invention the invention provides the use of a compound or pharmaceutical composition described herein for the manufacture of a medicament for use in treating or lessening the severity in a subject of inflammatory pain, wherein inflammatory pain comprises rheumatoid arthritis pain or vulvodynia.

In yet another aspect, the invention provides the use of a compound or pharmaceutical composition described herein for the manufacture of a medicament for use in treating or lessening the severity in a subject of idiopathic pain, wherein idiopathic pain comprises fibromyalgia pain.

In yet another aspect, the invention provides the use of a compound or pharmaceutical composition described herein for the manufacture of a medicament in combination with one or more additional therapeutic agents administered concurrently with, prior to, or subsequent to treatment with the compound or pharmaceutical composition.

In another aspect, the invention provides the use of a compound or pharmaceutical composition described herein for the manufacture of a medicament for use in treating or lessening the severity of acute pain, chronic pain, neuropathic pain, inflammatory pain, arthritis, migraine, cluster headaches, trigeminal neuralgia, herpetic neuralgia, general neuralgias, epilepsy, epilepsy conditions, neurodegenerative disorders, psychiatric disorders, anxiety, depression, dipolar disorder, myotonia, arrhythmia, movement disorders, neuroendocrine disorders, ataxia, multiple sclerosis, irritable bowel syndrome, incontinence, visceral pain, osteoarthritis pain, postherpetic neuralgia, diabetic neuropathy, radicular pain, sciatica, back pain, head pain, neck pain, severe pain, intractable pain, nociceptive pain, breakthrough pain, postsurgical pain, cancer pain, stroke, cerebral ischemia, traumatic brain injury, amyotrophic lateral sclerosis, stress induced angina, exercise induced angina, palpitations, hypertension, or abnormal gastro-intestinal motility.

In another aspect, the invention provides the use of a compound or pharmaceutical composition described herein for the manufacture of a medicament for use in treating or lessening the severity of femur cancer pain; non-malignant chronic bone pain; rheumatoid arthritis; osteoarthritis; spinal stenosis; neuropathic low back pain; myofascial pain syndrome; fibromyalgia; temporomandibular joint pain; chronic visceral pain, abdominal pain; pancreatic pain; IBS pain; chronic and acute headache pain; migraine; tension headache; cluster headaches; chronic and acute neuropathic pain, post-herpetic neuralgia; diabetic neuropathy; HIV-associated neuropathy; trigeminal neuralgia; Charcot-Marie Tooth neuropathy; hereditary sensory neuropathies; peripheral nerve injury; painful neuromas; ectopic proximal and distal discharges; radiculopathy; chemotherapy induced neuropathic pain; radiotherapy-induced neuropathic pain; post-mastectomy pain; central pain; spinal cord injury pain; post-stroke pain; thalamic pain; complex regional pain syndrome; phantom pain; intractable pain; acute pain, acute post-operative pain; acute musculoskeletal pain; joint pain; mechanical low back pain; neck pain; tendonitis; injury/exercise pain; acute visceral pain; pyelonephritis; appendicitis; cholecystitis; intestinal obstruction; hernias; chest pain, cardiac pain; pelvic pain, renal colic pain, acute obstetric pain, labor pain; cesarean section pain; acute inflammatory, burn and trauma pain; acute intermittent pain, endometriosis; acute herpes zoster pain; sickle cell anemia; acute pancreatitis; breakthrough pain; orofacial pain; sinusitis pain; dental pain; multiple sclerosis (MS) pain; pain in depression; leprosy pain; Behcet's disease pain; adiposis dolorosa; phlebitic pain; Guillain-Barre pain; painful legs and moving toes; Haglund syndrome; erythromelalgia pain; Fabry's disease pain; bladder and urogenital disease; urinary incontinence; hyperactivity bladder; painful bladder syndrome; interstitial cyctitis (IC); prostatitis; complex regional pain syndrome (CRPS), type I and type II; widespread pain, paroxysmal extreme pain, pruritis, tinnitis, or angina-induced pain.

In another aspect, the invention provides the use of a compound or pharmaceutical composition described herein for the manufacture of a medicament for use in treating or lessening the severity of neuropathic pain. In one aspect, the neuropathic pain is selected from post-herpetic neuralgia, diabetic neuralgia, painful HIV-associated sensory neuropathy, trigeminal neuralgia, burning mouth syndrome, post-amputation pain, phantom pain, painful neuroma, traumatic neuroma, Morton's neuroma, nerve entrapment injury, spinal stenosis, carpal tunnel syndrome, radicular pain, sciatica pain, nerve avulsion injury, brachial plexus avulsion, complex regional pain syndrome, drug therapy induced neuralgia, cancer chemotherapy induced neuralgia, anti-retroviral therapy induced neuralgia, post spinal cord injury pain, idiopathic small-fiber neuropathy, idiopathic sensory neuropathy or trigeminal autonomic cephalalgia.

Administration of Pharmaceutically Acceptable Salts and Compositions.

In certain embodiments of the invention an “effective amount” of the compound, a pharmaceutically acceptable salt thereof or pharmaceutically acceptable composition is that amount effective for treating or lessening the severity of one or more of chronic pain, gut pain, neuropathic pain, musculoskeletal pain, acute pain, inflammatory pain, cancer pain, idiopathic pain, multiple sclerosis, Charcot-Marie-Tooth syndrome, incontinence or cardiac arrhythmia.

The compounds and compositions, according to the method of the invention, may be administered using any amount and any route of administration effective for treating or lessening the severity of one or more of the pain or non-pain diseases recited herein. The exact amount required will vary from subject to subject, depending on the species, age, and general condition of the subject, the severity of the infection, the particular agent, its mode of administration, and the like. The compounds of the invention are preferably formulated in dosage unit form for ease of administration and uniformity of dosage. The expression “dosage unit form” as used herein refers to a physically discrete unit of agent appropriate for the subject to be treated. It will be understood, however, that the total daily usage of the compounds and compositions of the invention will be decided by the attending physician within the scope of sound medical judgment. The specific effective dose level for any particular subject or organism will depend upon a variety of factors including the disorder being treated and the severity of the disorder; the activity of the specific compound employed; the specific composition employed; the age, body weight, general health, sex and diet of the subject; the time of administration, route of administration, and rate of excretion of the specific compound employed; the duration of the treatment; drugs used in combination or coincidental with the specific compound employed, and like factors well known in the medical arts. The term “subject” or “patient,” as used herein, means an animal, preferably a mammal, and most preferably a human.

The pharmaceutically acceptable compositions of this invention can be administered to humans and other animals orally, rectally, parenterally, intracisternally, intravaginally, intraperitoneally, topically (as by powders, ointments, or drops), bucally, as an oral or nasal spray, or the like, depending on the severity of the infection being treated. In certain embodiments, the compounds of the invention may be administered orally or parenterally at dosage levels of about 0.01 mg/kg to about 50 mg/kg and preferably from about 1 mg/kg to about 25 mg/kg, of subject body weight per day, one or more times a 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, the 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 (in particular, cottonseed, groundnut, corn, germ, olive, castor, and sesame oils), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, and mixtures thereof. Besides inert diluents, the oral compositions can also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.

Injectable preparations, for example, sterile injectable aqueous or oleaginous suspensions may be formulated according to the known art using suitable dispersing or wetting agents and suspending agents. The sterile injectable preparation may also be a sterile injectable solution, suspension or emulsion in a nontoxic parenterally acceptable diluent or solvent, for example, as a solution in 1,3-butanediol. Among the acceptable vehicles and solvents that may be employed are water, Ringer's solution, U.S.P. and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose any bland fixed oil can be employed including synthetic mono- or diglycerides. In addition, fatty acids such as oleic acid are used in the preparation of injectables.

The injectable formulations can be sterilized, for example, by filtration through a bacterial-retaining filter, or by incorporating sterilizing agents in the form of sterile solid compositions which can be dissolved or dispersed in sterile water or other sterile injectable medium prior to use.

In order to prolong the effect of a compound of the invention, it is often desirable to slow the absorption of the compound from subcutaneous or intramuscular injection. This may be accomplished by the use of a liquid suspension of crystalline or amorphous material with poor water solubility. The rate of absorption of the compound then depends upon its rate of dissolution that, in turn, may depend upon crystal size and crystalline form. Alternatively, delayed absorption of a parenterally administered compound form is accomplished by dissolving or suspending the compound in an oil vehicle. Injectable depot forms are made by forming microencapsule matrices of the compound in biodegradable polymers such as polylactide-polyglycolide. Depending upon the ratio of compound to polymer and the nature of the particular polymer employed, the rate of compound release can be controlled. Examples of other biodegradable polymers include poly(orthoesters) and poly(anhydrides). Depot injectable formulations are also prepared by entrapping the compound in liposomes or microemulsions that are compatible with body tissues.

Compositions for rectal or vaginal administration are preferably 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 a suppository wax which are solid at ambient temperature but liquid at body temperature and therefore melt in the rectum or vaginal cavity and 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) fillers or extenders such as starches, lactose, sucrose, glucose, mannitol, and silicic acid, b) binders such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidinone, sucrose, and acacia, c) humectants such as glycerol, d) disintegrating agents such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate, e) solution 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 comprise buffering agents.

Solid compositions of a similar type may also be employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polyethylene glycols and the like. The solid dosage forms of tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings and other coatings well known in the pharmaceutical formulating art. They may optionally contain opacifying agents and can also be of a composition that they release the active ingredient(s) only, or preferentially, in a certain part of the intestinal tract, optionally, in a delayed manner. Examples of embedding compositions that can be used include polymeric substances and waxes. Solid compositions of a similar type may also be employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polyethylene glycols and the like.

The active compounds can also be in microencapsulated form with one or more excipients as noted above. The solid dosage forms of tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings, release controlling coatings and other coatings well known in the pharmaceutical formulating art. In such solid dosage forms the active compound may be admixed with at least one inert diluent such as sucrose, lactose or starch. Such dosage forms may also comprise, as is normal practice, additional substances other than inert diluents, e.g., tableting lubricants and other tableting aids such a magnesium stearate and microcrystalline cellulose. In the case of capsules, tablets and pills, the dosage forms may also comprise buffering agents. They may optionally contain opacifying agents and can also be of a composition that they release the active ingredient(s) only, or preferentially, in a certain part of the intestinal tract, optionally, in a delayed manner. Examples of embedding compositions that can be used include polymeric substances and waxes.

Dosage forms for topical or transdermal administration of a compound of this invention include ointments, pastes, creams, lotions, gels, powders, solutions, sprays, inhalants or patches. The active component is admixed under sterile conditions with a pharmaceutically acceptable carrier and any needed preservatives or buffers as may be required. Ophthalmic formulation, eardrops, and eye drops are also contemplated as being within the scope of this invention. Additionally, the invention contemplates the use of transdermal patches, which have the added advantage of providing controlled delivery of a compound to the body. Such dosage forms are prepared by dissolving or dispensing the compound in the proper medium. Absorption enhancers can also be used to increase the flux of the compound across the skin. The rate can be controlled by either providing a rate controlling membrane or by dispersing the compound in a polymer matrix or gel.

As described generally above, the compounds of the invention are useful as inhibitors of voltage-gated sodium channels. In one embodiment, the compounds and compositions of the invention are inhibitors of Na V 1.8 and thus, without wishing to be bound by any particular theory, the compounds and compositions are particularly useful for treating or lessening the severity of a disease, condition, or disorder where activation or hyperactivity of Na V 1.8 is implicated in the disease, condition, or disorder. When activation or hyperactivity of Na V 1.8 is implicated in a particular 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.” Accordingly, in another aspect, the invention provides a method for treating or lessening the severity of a disease, condition, or disorder where activation or hyperactivity of Na V 1.8 is implicated in the disease state.

The activity of a compound utilized in this invention as an inhibitor of Na V 1.8 may be assayed according to methods described generally in the Examples herein, or according to methods available to one of ordinary skill in the art.

Additional Therapeutic Agents

It will also be appreciated that the compounds and pharmaceutically acceptable compositions of the invention can be employed in combination therapies, that is, the compounds and pharmaceutically acceptable compositions can be administered concurrently with, prior to, or subsequent to, one or more other desired therapeutics or medical procedures. The particular combination of therapies (therapeutics or procedures) to employ in a combination regimen will take into account compatibility of the desired therapeutics and/or procedures and the desired therapeutic effect to be achieved. It will also be appreciated that the therapies employed may achieve a desired effect for the same disorder (for example, an inventive compound may be administered concurrently with another agent used to treat the same disorder), or they may achieve different effects (e.g., control of any adverse effects). As used herein, additional therapeutic agents that are normally administered to treat or prevent a particular disease, or condition, are known as “appropriate for the disease, or condition, being treated.” For example, exemplary additional therapeutic agents include, but are not limited to: nonopioid analgesics (indoles such as Etodolac, Indomethacin, Sulindac, Tolmetin; naphthylalkanones such sa 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 (such as Codeine, Fentanyl, Hydromorphone, Levorphanol, Meperidine, Methadone, Morphine, Oxycodone, Oxymorphone, Propoxyphene, Buprenorphine, Butorphanol, Dezocine, Nalbuphine, and Pentazocine). Additionally, nondrug analgesic approaches may be utilized in conjunction with administration of one or more compounds of the invention. For example, anesthesiologic (intraspinal infusion, neural blockade), neurosurgical (neurolysis of CNS pathways), neurostimulatory (transcutaneous electrical nerve stimulation, dorsal column stimulation), physiatric (physical therapy, orthotic devices, diathermy), or psychologic (cognitive methods-hypnosis, biofeedback, or behavioral methods) approaches may also be utilized. Additional appropriate 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 the Food and Drug Administration website, www.fda.gov, the entire contents of which are hereby incorporated by reference.

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

(1) an opioid analgesic, e.g. 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 antiinflammatory drug (NSAID), e.g. aspirin, diclofenac, diflunisal, etodolac, fenbufen, fenoprofen, flufenisal, flurbiprofen, ibuprofen, indomethacin, ketoprofen, ketorolac, meclofenamic acid, mefenamic acid, meloxicam, nabumetone, naproxen, nimesulide, nitroflurbiprofen, olsalazine, oxaprozin, phenylbutazone, piroxicam, sulfasalazine, sulindac, tolmetin or zomepirac;

(3) a barbiturate sedative, e.g. amobarbital, aprobarbital, butabarbital, butalbital, mephobarbital, metharbital, methohexital, pentobarbital, phenobarbital, secobarbital, talbutal, thiamylal or thiopental;

(4) a benzodiazepine having a sedative action, e.g. chlordiazepoxide, clorazepate, diazepam, flurazepam, lorazepam, oxazepam, temazepam or triazolam;

(5) a histamine (H 1 ) antagonist having a sedative action, e.g. diphenhydramine, pyrilamine, promethazine, chlorpheniramine or chlorcyclizine;

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

(7) a skeletal muscle relaxant, e.g. baclofen, carisoprodol, chlorzoxazone, cyclobenzaprine, methocarbamol or orphenadrine;

(8) an NMDA receptor antagonist, e.g. dextromethorphan ((+)-3-hydroxy-N-methylmorphinan) or its metabolite dextrorphan ((+)-3-hydroxy-N-methylmorphinan), ketamine, memantine, pyrroloquinoline quinine, cis-4-(phosphonomethyl)-2-piperidinecarboxylic acid, budipine, EN-3231 (MorphiDex®), a combination formulation of morphine and dextromethorphan), topiramate, neramexane or perzinfotel including an NR2B antagonist, e.g. ifenprodil, traxoprodil or (−)-(R)-6-{2-[4-(3-fluorophenyl)-4-hydroxy-1-piperidinyl]-1-hydroxyethyl-3,4-dihydro-2(1H)-quinolinone;

(9) an alpha-adrenergic, e.g. doxazosin, tamsulosin, clonidine, guanfacine, dexmedetomidine, modafinil, or 4-amino-6,7-dimethoxy-2-(5-methane-sulfonamido-1, 2,3,4-tetrahydroisoquinolin-2-yl)-5-(2-pyridyl) quinazoline;

(10) a tricyclic antidepressant, e.g. desipramine, imipramine, amitriptyline or nortriptyline;

(11) an anticonvulsant, e.g. carbamazepine (Tegretol®), lamotrigine, topiramate, lacosamide (Vimpat®) or valproate;

(12) a tachykinin (NK) antagonist, particularly an NK-3, NK-2 or NK-1 antagonist, e.g. (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, e.g oxybutynin, tolterodine, propiverine, tropsium chloride, darifenacin, solifenacin, temiverine and ipratropium;

(14) a COX-2 selective inhibitor, e.g. celecoxib, rofecoxib, parecoxib, valdecoxib, deracoxib, etoricoxib, or lumiracoxib;

(15) a coal-tar analgesic, in particular paracetamol;

(16) a neuroleptic such as droperidol, chlorpromazine, haloperidol, perphenazine, thioridazine, mesoridazine, trifluoperazine, fluphenazine, clozapine, olanzapine, risperidone, ziprasidone, quetiapine, sertindole, aripiprazole, sonepiprazole, blonanserin, iloperidone, perospirone, raclopride, zotepine, bifeprunox, asenapine, lurasidone, amisulpride, balaperidone, palindore, eplivanserin, osanetant, rimonabant, meclinertant, Miraxion® or sarizotan;

(17) a vanilloid receptor agonist (e.g. resinferatoxin or civamide) or antagonist (e.g. capsazepine, GRC-15300);

(18) a beta-adrenergic such as propranolol;

(19) a local anaesthetic such as mexiletine;

(20) a corticosteroid such as dexamethasone;

(21) a 5-HT receptor agonist or antagonist, particularly 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-dimethoxy-phenyl)-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-piperazinyl-sulphonyl)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 (IC-351 or tadalafil), 2-[2-ethoxy-5-(4-ethyl-piperazin-1-yl-1-sulphonyl)-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-7H-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-ylsulphonyl)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)pyrimidine-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) an alpha-2-delta ligand such as gabapentin (Neurontin®), gabapentin GR (Gralise®), gabapentin, enacarbil (Horizant®), pregabalin (Lyrica®), 3-methyl gabapentin, (1[alpha],3[alpha],5[alpha])(3-amino-methyl-bicyclo[3.2.0]hept-3-yl)-acetic acid, (3S,5R)-3-aminomethyl-5-methyl-heptanoic acid, (3 S,5R)-3-amino-5-methyl-heptanoic acid, (3 S,5R)-3-amino-5-methyl-octanoic 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-aminomethyl-cyclohexylmethyl)-4H-[1,2,4]oxadiazol-5-one, C-[1-(1H-tetrazol-5-ylmethyl)-cycloheptyl]-methylamine, (3S,4S)-(1-aminomethyl-3,4-dimethyl-cyclopentyl)-acetic acid, (3S,5R)-3-aminomethyl-5-methyl-octanoic acid, (3 S,5R)-3-amino-5-methyl-nonanoic acid, (3 S,5R)-3-amino-5-methyl-octanoic acid, (3R,4R,5R)-3-amino-4,5-dimethyl-heptanoic acid and (3R,4R,5R)-3-amino-4,5-dimethyl-octanoic acid;

(27) a cannabinoid such as KHK-6188;

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

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

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

(31) a dual serotonin-noradrenaline 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]-L-homocysteine, S-[2-[(l-iminoethyl)-amino]ethyl]-4,4-dioxo-L-cysteine, S-[2-[(1-iminoethyl)amino]ethyl]-2-methyl-L-cysteine, (2S,5Z)-2-amino-2-methyl-7-[(l-iminoethyl)amino]-5-heptenoic acid, 2-[[(1R,3S)-3-amino-4-hydroxy-1-(5-thiazolyl)-butyl]thio]-S-chloro-S-pyridinecarbonitrile; 2-[[(1R,3 S)-3-amino-4-hydroxy-1-(5-thiazolyl)butyl]thio]-4-chlorobenzonitrile, (2S,4R)-2-amino-4-[[2-chloro-5-(trifluoromethyl)phenyl]thio]-5-thiazolebutanol, 2-[[(1R,3 S)-3-amino-4-hydroxy-1-(5-thiazolyl) butyl]thio]-6-(trifluoromethyl)-3-pyridinecarbonitrile, 2-[[(1R,3S)-3-amino-4-hydroxy-1-(5-thiazolyl)butyl]thio]-5-chlorobenzonitrile, N-[4-[2-(3-chlorobenzylamino)ethyl]phenyl]thiophene-2-carboxamidine, NXN-462, or guanidinoethyldisulfide;

(33) an acetylcholinesterase inhibitor 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-methylbenzenesulfonamide 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-hydroxy-chroman-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])phenoxy-methyl]-1-methyl-2-quinolone (ZD-2138), or 2,3,5-trimethyl-6-(3-pyridylmethyl)-1,4-benzoquinone (CV-6504);

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

(38) an Na V 1.7 blocker, such as XEN-402 and such as those disclosed in WO2011/140425; WO2012/106499; WO2012/112743; WO2012/125613 or PCT/US2013/21535 the entire contents of each application hereby incorporated by reference.

(39) an Na V 1.8 blocker, such as those disclosed in WO2008/135826 and WO2006/011050 the entire contents of each application hereby incorporated 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 ondansetron;

(42) a TPRV 1 receptor agonist, such as capsaicin (NeurogesX®, Qutenza®); and the pharmaceutically acceptable salts and solvates thereof;

(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 stimulant, such as senrebotase;

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

In one embodiment, the additional appropriate therapeutic agents are selected from V-116517, Pregabalin, controlled release Pregabalin, Ezogabine (Potiga®). Ketamine/amitriptyline topical 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 will be no more than the amount that would normally be administered in a composition comprising that therapeutic agent as the only active agent. The amount of additional therapeutic agent in the presently disclosed compositions will range from about 10% to 100% of the amount normally present in a composition comprising that agent as the only therapeutically active agent.

The compounds of this invention or pharmaceutically acceptable compositions thereof may also be incorporated into compositions for coating an implantable medical device, such as prostheses, artificial valves, vascular grafts, stents and catheters. Accordingly, the invention, in another aspect, includes a composition for coating an implantable device comprising a compound of the invention as described generally above, and in classes and subclasses herein, and a carrier suitable for coating said implantable device. In still another aspect, the invention includes an implantable device coated with a composition comprising a compound of the invention as described generally above, and in classes and subclasses herein, and a carrier suitable for coating said implantable device. Suitable coatings and the general preparation of coated implantable devices are described in U.S. Pat. Nos. 6,099,562; 5,886,026; and 5,304,121. The coatings are typically biocompatible polymeric materials such as a hydrogel polymer, polymethyldisiloxane, polycaprolactone, polyethylene glycol, polylactic acid, ethylene vinyl acetate, and mixtures thereof. The coatings may optionally be further covered by a suitable topcoat of fluorosilicone, polysaccarides, polyethylene glycol, phospholipids or combinations thereof to impart controlled release characteristics in the composition.

Another aspect of the invention relates to inhibiting Na V 1.8 activity in a biological sample or a subject, which method comprises administering to the subject, or contacting said biological sample with a compound of formula I or formula I′ or a composition comprising said compound. The term “biological sample,” as used herein, includes, without limitation, cell cultures or extracts thereof, biopsied material obtained from a mammal 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 useful for a variety of purposes that are known to one of skill in the art. Examples of such purposes include, but are not limited to, the study of sodium channels in biological and pathological phenomena; and the comparative evaluation of new sodium channel inhibitors.

The compounds of the invention may be prepared readily using the following methods. Illustrated below in Scheme 1 through Scheme 3 are general methods for preparing the compounds of the present invention.

General Methods

1 H NMR (400 MHz) spectra were obtained as solutions in an appropriate 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 times were determined by reverse phase HPLC using a Kinetix C18 column (50×2.1 mm, 1.7 μm particle) from Phenomenex (pn: 00B-4475-AN)), and a dual gradient run from 1-99% mobile phase B over 3 minutes. Mobile phase A=H 2 0 (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 was performed 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 were from Baker or Aldrich and in some cases the reagents were Aldrich Sure-Seal bottles kept under dry nitrogen. All reactions were stirred magnetically unless otherwise noted.