NZ710293B2 - Amides as modulators of sodium channels - Google Patents

Amides as modulators of sodium channels Download PDF

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NZ710293B2
NZ710293B2 NZ710293A NZ71029314A NZ710293B2 NZ 710293 B2 NZ710293 B2 NZ 710293B2 NZ 710293 A NZ710293 A NZ 710293A NZ 71029314 A NZ71029314 A NZ 71029314A NZ 710293 B2 NZ710293 B2 NZ 710293B2
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New Zealand
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alkyl
halogen
another embodiment
benzamido
pain
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NZ710293A
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NZ710293A (en
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Corey Anderson
Vijayalaksmi Arumugam
Iuliana Luci Asgian
Brian Richard Bear
Sara Sabina Hadidaruah
James Philip Johnson
Andreas P Termin
Ruah Sara Sabina Hadida
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Vertex Pharmaceuticals Incorporated
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Priority claimed from PCT/US2014/013667 external-priority patent/WO2014120820A1/en
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Publication of NZ710293B2 publication Critical patent/NZ710293B2/en

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/192—Carboxylic acids, e.g. valproic acid having aromatic groups, e.g. sulindac, 2-aryl-propionic acids, ethacrynic acid 
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/04—Centrally acting analgesics, e.g. opioids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/06—Antiarrhythmics
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C235/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms
    • C07C235/42—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings and singly-bound oxygen atoms bound to the same carbon skeleton
    • C07C235/44—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings and singly-bound oxygen atoms bound to the same carbon skeleton with carbon atoms of carboxamide groups and singly-bound oxygen atoms bound to carbon atoms of the same non-condensed six-membered aromatic ring
    • C07C235/58—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings and singly-bound oxygen atoms bound to the same carbon skeleton with carbon atoms of carboxamide groups and singly-bound oxygen atoms bound to carbon atoms of the same non-condensed six-membered aromatic ring with carbon atoms of carboxamide groups and singly-bound oxygen atoms, bound in ortho-position to carbon atoms of the same non-condensed six-membered aromatic ring
    • C07C235/64—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings and singly-bound oxygen atoms bound to the same carbon skeleton with carbon atoms of carboxamide groups and singly-bound oxygen atoms bound to carbon atoms of the same non-condensed six-membered aromatic ring with carbon atoms of carboxamide groups and singly-bound oxygen atoms, bound in ortho-position to carbon atoms of the same non-condensed six-membered aromatic ring having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a six-membered aromatic ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D213/79—Acids; Esters

Abstract

The invention relates to amide compounds of formula I and For pharmaceutically acceptable salts thereof, useful as inhibitors of sodium channels: (I), (I') 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. ions in the treatment of various disorders, including pain.

Description

AMIDES AS MODULATORS OF SODIUM CHANNELS CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit of US. Provisional Patent Application No. 61/759,062, filed January 31, 2013, the entire ts of which are incorporated herein by reference.
TECHNICAL FIELD OF THE INVENTION 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.
BACKGROUND OF THE INVENTION Pain is a protective mechanism that allows healthy animals to avoid tissue damage and to t further damage to injured tissue. Nonetheless there are many conditions where pain ts beyond its usefulness, or where patients would benefit from inhibition of pain. athic 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 tion.
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 tions include post amputation pain, post-surgical nerve injury pain, and nerve entrapment injuries like athic back pain.
Voltage-gated sodium channels (NaV’s) play a critical role in pain signaling.
NaV’s are key biological mediators of electrical ing 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 es). The evidence for the role of these ls in normal physiology, the pathological states arising from mutations in sodium channel genes, preclinical work in animal , and the clinical pharmacology ofknown sodium channel modulating agents all point to the central role ofNaV’s in pain sensation (Rush, A.M. and TR. s, Painful Research: fication ofa Small-Molecule Inhibitor that Selectively Targets NaV1.8 Sodium ls. Mol Interv, 2007. 7(4): p. 192-5); England, 8., Voltage-gated sodium ls: 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)). NaV’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, , Ion Channels OfExcz'table Membranes, Third ed. (Sinauer Associates, Inc., Sunderland, MA, 2001)). Because of the role NaV’s play in the initiation and propagation of neuronal signals, antagonists that reduce NaV currents can prevent or reduce neural signaling and NaV channels have long been considered likely targets to reduce pain in conditions where hyper-excitability is observed (Chahine, M., Chatelier, A., Babich, 0., and Krupp, J. J., Voltage-gated sodium channels in neurological disorders. CNS Neural Disord Drug Targets 7 (2), p. 144-58 (2008)). Several clinically useful analgesics have been fied as inhibitors ofNaV channels. The local anesthetic drugs such as lidocaine block pain by inhibiting NaV channels, and other compounds, such as carbamazepine, lamotrigine, and tricyclic antidepressants that have proven effective at reducing pain have also been ted 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. JMembr Biol 222 (2), p. 79-90 (2008)).
The NaV’s form a subfamily of the e-gated ion channel super-family and ses 9 ms, designated Nav1.1 — Nav1.9. The tissue localizations of the nine isoforms vary greatly. Nav1.4 is the primary sodium channel of skeletal muscle, and Nav1.5 is primary sodium channel of cardiac myocytes. NaV’s 1.7, 1.8 and 1.9 are ily localized to the peripheral nervous system, while NaV’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 ics of their voltage-dependent and c behavior (Catterall, W.
A., Goldin, A. L., and Waxman, S. G., International Union of cology. XLVII.
Nomenclature and structure-function relationships of voltage-gated sodium channels. col Rev 57 (4), p. 397 (2005)).
Immediately upon their discovery, NaV1.8 channels were identified as likely targets for analgesia (Akopian, A.N., L. tti, and J.N. Wood, A tetrodotoxin-resistant voltage- gated sodium l expressed by sensory neurons. Nature, 1996. 379(6562): p. 257-62). Since then, NaV1.8 has been shown to be the most significant carrier of the sodium current that ins action potential firing in small DRG neurons (Blair, NT. and B.P. Bean, Roles of otoxin (TTX)-sensitive Na+ current, TTX-resistant Na+ current, and Ca2+ current in the action potentials of nociceptive sensory s. J Neurosci., 2002. 22(23): p. 10277-90). NaV1.8 is essential for spontaneous firing in damaged neurons, like those that drive neuropathic pain (Roza, C., et al., The tetrodotoxin-resistant Na+ channel NaV1.8 is essential for the expression of spontaneous activity in damaged sensory axons ofmice. J. Physiol., 2003. 550(Pt 3): p. 921-6; Jarvis, M.F., et al., A- 803467, a potent and selective NaV1.8 sodium channel blocker, ates neuropathic and inflammatory pain in the rat. Proc Natl Acad Sci. U S A, 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 athic pain by decreased expression of the tetrodotoxin-resistant sodium channel, NaVl .8.
Pain, 2002. 95(1-2): p. 143-52; Dong, X.W., et al., Small interfering RNA-mediated selective knockdown of Na(V)l .8 tetrodotoxin-resistant sodium channel reverses mechanical allodynia in athic rats. Neuroscience, 2007. 146(2): p. 812-21; Huang, H.L., et al., Proteomic profiling of neuromas reveals tions in protein composition and local protein synthesis in hyper- excitable nerves. M01 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. ; Coward, K., et al., Immunolocalization of SNS/PN3 and NaN/SNSZ sodium ls 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. ; ri, S., et al., Relationship of axonal voltage- gated sodium channel 1.8 (NaVl .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 NaV1.8 is expressed include the nociceptors critical for pain signaling. NaV1.8 is the primary channel that mediates large amplitude action potentials in small neurons of the dorsal root ganglia (Blair, NT. and B.P. Bean, Roles of tetrodotoxin (TTX)-sensitive Na+ current, TTX-resistant Na+ t, and Ca2+ current in the action potentials of nociceptive sensory neurons. JNeurosci., 2002. 22(23): p. 10277-90). Navl .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 NaVl .7 and NaVl .8 sodium channels: a computer simulation study. J hysiol. 106(6): p. 3173-84; Renganathan, M., T.R. s, and S.G. Waxman, Contribution ofNa(V)1.8 sodium channels to action ial electrogenesis in DRG neurons. J Neurophysiol., 2001. 86(2): p. 629-40; Roza, C., et al., The tetrodotoxin-resistant Na+ channel NaVl .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 rized or damaged DRG neurons, NaV1.8 appears to be the primary driver of hyper-excitablility (Rush, A.M., et al., A single sodium channel on produces hyper- or citability in ent types of neurons. Proc Natl Acad Sci USA, 2006. 103(21): p. 8245-50). In some animal pain models, NaV1.8 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 ofNaVl .7, NaVl.8 and NaVl .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., sed sion of tetrodotoxin-resistant sodium ls NaVl .8 and NaVl .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 NaV inhibitors is their poor eutic window, and this is likely a consequence of their lack of isoform selectivity. Since NaV1.8 is primarily restricted to the neurons that sense pain, selective NaV1.8 blockers are unlikely to induce the adverse events common to non-selective NaV blockers. Accordingly, there remains a need to develop additional NaV channel antagonists preferably those that are more Nav1.8 selective, more potent and with fewer side s.
SUMMARY OF THE INVENTION It has now been found that compounds of this invention, and pharmaceutically acceptable salts and compositions thereof, are useful as inhibitors of voltage-gated sodium channels. These compounds have the general formula I or formula I′: (R8)p (R8)p R1 O OH R1 O Y R2 Y R2 OH N N H H R3 O R3 O R4 R4 R5 R5' R5 R5' A A R6 R6' R6 R6' R7 R7 I I′; or a pharmaceutically acceptable salt thereof. [007A]In a particular aspect, the present invention es a compound of a I or I′ (R8)p (R8)p R1 O OH R1 O Y R2 Y R2 OH N N H H R3 O R3 O R4 R4 R5 R5' R5 R5' A A R6 R6' R6 R6' R7 R7 I I′; or a pharmaceutically acceptable salt thereof, wherein, independently for each ence: Y is CH or N R1 is H, halogen, CN, or C1-C6 alkyl wherein said C1-C6 alkyl is tuted with 0-6 halogen and [FOLLOWED BY PAGE 4a] wherein up to two jacent CH2 units of said C1-C6 alkyl may be replaced with -O-; R2 is H, halogen, CN, or C1-C6 alkyl wherein said C1-C6 alkyl is substituted with 0-6 halogen, wherein up to two non-adjacent CH2 units of said C1-C6 alkyl may be replaced with -O-; R3 is H, halogen, CN, or C1-C6 alkyl wherein said C1-C6 alkyl is substituted with 0-6 halogen, wherein up to two non-adjacent CH2 units of said C1-C6 alkyl may be replaced with -O-; R4 is H, n, CN, or C1-C6 alkyl wherein said C1-C6 alkyl is substituted with 0-6 n, wherein up to two non-adjacent CH2 units of said C1-C6 alkyl may be ed with -O-; R5 is H, halogen, CN, or –X-RX; R5′ is H, halogen, CN, or –X-RX; R6 is H, halogen, CN, or –X-RX; R6′ is H, halogen, CN, or –X-RX; R7 is H, halogen, CN, or –X-RX; X is a bond or C1-C6 alkyl wherein said C1-C6 alkyl is substituted with 0-6 halogen, wherein up to two non-adjacent CH2 units of said C1-C6 alkyl may be replaced with -O-; RX is absent, H, or C3-C8 cycloaliphatic, wherein up to two non-adjacent CH2 units of said C3-C8 liphatic may be replaced with -O- and said C3-C8 cycloaliphatic is substituted with 0-3 substituents selected from halogen and C1-C4 alkyl; R8 is halogen, or C1-C6 alkyl wherein said C1-C6 alkyl is substituted with 0-6 halogen, wherein up to two non-adjacent CH2 units of said C1-C6 alkyl may be replaced with -O-; p is an integer from 0 to 4 inclusive; and provided the following compounds are excluded: 4-methyl(2-phenoxybenzamido)benzoic acid; 3-(2-phenoxybenzamido)benzoic acid; 4-chloro(2-phenoxybenzamido)benzoic acid; 3-methyl[(2-phenoxybenzoyl)amino]-benzoic acid; 4-[(2-phenoxybenzoyl)amino]-benzoic acid; and -chloromethoxy[(2-phenoxybenzoyl)amino]-benzoic acid. [007B] In another particular aspect, the present invention provides a compound of a (R8)p R1 O OH R2 Y R3 O R5 R5' R6 R6' -4a- [FOLLOWED BY PAGE 4b] or a pharmaceutically acceptable salt thereof, wherein, independently for each ence: Y is C or N R1 is H, halogen, CN, or C1-C6 alkyl n said C1-C6 alkyl is substituted with 0-6 halogen and wherein up to two non-adjacent CH2 units of said C1-C6 alkyl may be replaced with -O-; R2 is H, halogen, CN, or C1-C6 alkyl wherein said C1-C6 alkyl is substituted with 0-6 halogen, wherein up to two non-adjacent CH2 units of said C1-C6 alkyl may be ed with -O-; R3 is H, halogen, CN, or C1-C6 alkyl wherein said C1-C6 alkyl is substituted with 0-6 halogen, wherein up to two non-adjacent CH2 units of said C1-C6 alkyl may be replaced with -O-; R4 is H, halogen, CN, or C1-C6 alkyl wherein said C1-C6 alkyl is substituted with 0-6 n, wherein up to two jacent CH2 units of said C1-C6 alkyl may be replaced with -O-; R5 is H, halogen, CN, or –X-RX; R5′ is H, halogen, CN, or –X-RX; R6 is H, halogen, CN, or –X-RX; R6′ is H, halogen, CN, or –X-RX; R7 is H, halogen, CN, or –X-RX; X is a bond or C1-C6 alkyl wherein said C1-C6 alkyl is substituted with 0-6 halogen, wherein up to two non-adjacent CH2 units of said C1-C6 alkyl may be ed with -O-; RX is absent, H, or C3-C8 cycloaliphatic, wherein up to two non-adjacent CH2 units of said C3-C8 cycloaliphatic may be replaced with -O- and said C3-C8 cycloaliphatic is substituted with 0-3 substituents selected from halogen and C1-C4 alkyl; R8 is halogen, or C1-C6 alkyl wherein said C1-C6 alkyl is substituted with 0-6 halogen, n up to two non-adjacent CH2 units of said C1-C6 alkyl may be replaced with -O-; p is an integer from 0 to 4 inclusive; and provided the following compounds are excluded: 3-methyl[(2-phenoxybenzoyl)amino]-benzoic acid; 4-[(2-phenoxybenzoyl)amino]-benzoic acid; and -chloromethoxy[(2-phenoxybenzoyl)amino]-benzoic acid.
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 d 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.
[FOLLOWED BY PAGE 4c] -4b- Detailed Description of the Invention In one aspect, the invention provides nds of formula I or formula I′: (R8)p (R8)p R1 O OH R1 O Y R2 Y R2 OH N N H H R3 O R3 O R4 R4 R5 R5' R5 R5' A A R6 R6' R6 R6' R7 R7 [FOLLOWED BY PAGE 5] -4c- I I'; or a pharmaceutically able salt f, wherein, independently for each occurrence: Y is C or N R1 is H, halogen, CN, or C1-C6 alkyl wherein said C1-C6 alkyl is substituted with 0-6 halogen and wherein up to two non-adjacent CH2 units of said C1-C6 alkyl may be replaced with -O-; R2 is H, halogen, CN, or C1-C6 alkyl wherein said C1-C6 alkyl is substituted with 0-6 halogen, n up to two non-adjacent CH2 units of said C1-C6 alkyl may be replaced with -O-; R3 is H, halogen, CN, or C1-C6 alkyl wherein said C1-C6 alkyl is substituted with 0-6 halogen, wherein up to two non-adjacent CH2 units of said C1-C6 alkyl may be replaced with -O-; R4 is H, halogen, CN, or C1-C6 alkyl wherein said C1-C6 alkyl is substituted with 0-6 halogen, wherein up to two non-adjacent CH2 units of said C1-C6 alkyl may be replaced with -O-; R5 is H, n, CN, or —X-RX; R5, is H, halogen, CN, or —X-RX; R6 is H, halogen, CN, or —X-RX; R6, is H, halogen, CN, or —X-RX; R7 is H, halogen, CN, or —X-RX; X is a bond or C1-C6 alkyl wherein said C1-C6 alkyl is substituted with 0-6 halogen, wherein up to two jacent CH2 units of said C1-C6 alkyl may be replaced with -O-; RX is absent, H, or C3-C3 cycloaliphatic, wherein up to two non-adjacent CH2 units of said C3-C3 cycloaliphatic may be replaced with -O- and said C3-C3 cycloaliphatic is substituted with 0-3 substituents selected from halogen and C1-C4 alkyl; R8 is halogen, or C1-C6 alkyl wherein said C1-C6 alkyl is substituted with 0-6 halogen, wherein up to two non-adjacent CH2 units of said C1-C6 alkyl may be replaced with -O-; p is an integer from 0 to 4 inclusive; and provided the following nds are excluded: 3-methyl[(2-phenoxybenzoyl)amino]-benzoic acid; phenoxybenzoyl)amino]-benzoic acid; and -chloromethoxy[(2-phenoxybenzoyl)amino]-benzoic acid.
In another aspect, the invention provides nds of formula I or formula I': (Rex, (Ran, R1 \’ I OH R1 0 Y R2 \ Y R2 \ OH R3 0 R3 0 R4 R4 R5 R5 R5 R5 G @ R6 R6 R6 R6 R7 R7 I I'; or a ceutically acceptable salt thereof, wherein, independently for each occurrence: Y is C or N R1 is H, halogen, CN, or C1-C6 alkyl wherein said C1-C6 alkyl is substituted with 0-6 halogen and wherein up to two jacent CH2 units of said C1-C6 alkyl may be replaced with -O-; R2 is H, halogen, CN, or C1-C6 alkyl wherein said C1-C6 alkyl is substituted with 0-6 halogen, wherein up to two non-adjacent CH2 units of said C1-C6 alkyl may be replaced with -O-; R3 is H, halogen, CN, or C1-C6 alkyl wherein said C1-C6 alkyl is substituted with 0-6 halogen, wherein up to two non-adjacent CH2 units of said C1-C6 alkyl may be replaced with -O-; R4 is H, halogen, CN, or C1-C6 alkyl n said C1-C6 alkyl is substituted with 0-6 halogen, wherein up to two non-adjacent CH2 units of said C1-C6 alkyl may be replaced with -O-; R5 is H, halogen, CN, or —X-RX; R5, is H, halogen, CN, or —X-RX; R6 is H, halogen, CN, or —X-RX; R6, is H, halogen, CN, or —X-RX; R7 is H, halogen, CN, or —X-RX; X is a bond or C1-C6 alkyl wherein said C1-C6 alkyl is tuted with 0-6 halogen, n up to two non-adjacent CH2 units of said C1-C6 alkyl may be replaced with -O-; RX is absent, H, or C3-C3 cycloaliphatic, wherein up to two non-adjacent CH2 units of said C3-C3 liphatic may be replaced with -O- and said C3-C3 cycloaliphatic is substituted with 0-3 substituents selected from halogen and C1-C4 alkyl; R8 is halogen, or C1-C6 alkyl wherein said C1-C6 alkyl is substituted with 0-6 halogen, wherein up to two non-adjacent CH2 units of said C1-C6 alkyl may be replaced with -O-; and p is an integer from 0 to 4 inclusive.
WO 20820 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, 75th Ed. Additionally, general principles of organic chemistry are described in “Organic Chemistry,” Thomas Sorrell, University Science Books, Sausalito: 1999, and “March’s ed Organic try,” 5th Ed., Ed.: Smith, MB. 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 lly above, or as ified by particular classes, subclasses, and species of the invention. As described herein, the variables R1 — R8 in a I or formula I’encompass specific groups, such as, for example, alkyl and cycloalkyl.
As one of ordinary skill in the art will ize, 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 ably their recovery, purification, and use for one or more of the purposes disclosed . In some embodiments, a stable compound or chemically le 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,” r 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 tuent, such as a heterocycloalkyl, can be bound to another ring, such as a lkyl, to form a spiro-bicyclic ring , e.g., both rings share one common atom. As one of ordinary skill in the art will recognize, combinations of substituents oned 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, l, 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 embodi ments aliphatic groups contain 1 — 4 aliphatic carbon atoms.
Suitable aliphatic groups include, but are not d to, linear or branched, substituted or tituted alkyl, alkenyl, alkynyl groups.
The terms “cycloaliphatic” or “cycloalkyl” mean a monocyclic hydrocarbon ring, or a polycyclic arbon 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 ted or can contain one or more rated bonds. In some ments, the “heterocycle,” “heterocyclyl,” "heterocycloaliphatic,” “heterocycloalkyl,” or “heterocyclic” group has three to en 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, en, phosphorus, or silicon (including, any oxidized form of nitrogen, sulfur, phosphorus, or silicon; the quatemized 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 , refers to an alkyl group, as previously defined, ed to the principal carbon chain through an oxygen (“alkoxy”) or sulfur alkyl”) atom.
The term “aryl” used alone or as part of a larger moiety as in “aralkyl,” “aralkoxy,” or “aryloxyalkyl,” refers to clic, bicyclic, and tricyclic ring systems haVing a total of five to en 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 ns one or more atoms, 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.” Unless otherwise stated, structures depicted herein are also meant to include all isomeric (e.g., enantiomeric, diastereomeric, and geometric (or mational)) forms of the structure; for example, the R and S configurations for each tric , (Z) and (E) double bond isomers, and (Z) and (E) conformational isomers. Therefore, single stereochemical isomers as well as enantiomeric, diastereomeric, and ric (or conformational) mixtures of the t compounds are within the scope of the invention. Unless otherwise stated, all tautomeric forms of the nds 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 or formula I’. The ures 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. es of isotopes t in compounds of formula I and formula I’ include isotopes of hydrogen, carbon, nitrogen, oxygen, orus, fluorine and chlorine, such as, but not limited to, 2H, 3 13C, 14C, 15N, 18O, 17O, 3 5 S and 18F. Certain isotopically-labeled compounds of formula I or formula I’, in addition to being useful as 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 3H) and carbon-14 (e. present invention, tritiated (e.g., g., 14C) 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., 2H) can afford certain therapeutic advantages.
In the formulas and gs, a line transversing a ring and bonded to an R group such as in (Rex.
R1 XI OH R2 \ Y R3 0 R5 R5' R6 R6 means that the R group, i.e. the R8 group can be bonded to any carbon of that ring as valency allows.
Within a definition of a term as, for example, X, RX, R1, R2, R3, R4 or R8 when a CH2 unit or, interchangeably, methylene unit may be replaced by -O-, it is meant to include any CH2 unit, including a CH2 within a terminal methyl group. For example, CHZCHZCHZOH is within the definition of C1-C6 alkyl wherein up to two jacent CH2 units may be replaced by because the CH2 unit of the terminal methyl group has been replaced by -O-.
In one embodiment, the invention features a compound of formula I or formula I’ and the attendant definitions, Y is C. In another embodiment, Y is N.
In another embodiment, the invention features a compound of formula I or formula I’ and the attendant definitions, wherein R1 is H. In another embodiment, R1 is halogen.
In another embodiment, R1 is CN. In another embodiment, R1 is C1-C6 alkyl n said C1-C6 alkyl is substituted with 0-6 halogen. In another embodiment, R1 is CF3. In another embodiment, the invention features a compound of formula I or formula I’ and the attendant definitions, wherein R2 is H. In another embodiment, R2 is halogen. In another ment, R2 is Cl. In another embodiment, R2 is F. In another embodiment, R2 is CN. In another embodiment, R2 is C1-C6 alkyl wherein said C1-C6 alkyl is substituted with 0-6 halogen. In another embodiment, R2 is CF3. In another embodiment, R2 is C1-C6 alkyl wherein said C1-C6 alkyl is substituted with 0-6 halogen wherein one CH2 unit of said C1-C6 alkyl is replaced with -O-. In another embodiment, R2 is OCF3. In another embodiment, R2 is F, Cl, CN, CF3 or OCF3. In another ment, R2 is H, halogen, or C1-C6 alkyl wherein said C1-C6 alkyl is substituted with 0-6 halogen and wherein one CH2 unit of said C1-C6 alkyl is replaced with -O-. In r embodiment, R2 is F, Cl, CF3 or OCF3.
In r ment, the invention features a compound of formula I or a I’ and the attendant definitions, wherein R3 is H. In another embodiment, R3 is halogen.
In another embodiment, R3 is Cl. In another embodiment, R3 is F. In another ment, R3 is CN. In r embodiment, R3 is C1-C6 alkyl wherein said C1-C6 alkyl is substituted with 0-6 halogen. In another embodiment, R3 is t—butyl. In another ment, R3 is CF3. In another embodiment, R3 is CFZCF3. In another embodiment, R3 is t—butyl, Cl, CF3 or CFZCF3.
In another embodiment, the invention es a compound of formula I or formula I’ and the attendant definitions, n R4 is H. In another embodiment, R4 is halogen.
In another embodiment, R4 is CN. In another embodiment, R4 is C1-C6 alkyl wherein said C1-C6 alkyl is substituted with 0-6 halogen. In another ment, R4 is CF3.
In another ment, the invention features a compound of a I or formula I’ and the attendant definitions, wherein R5 is H. In another embodiment, R5 is halogen.
In another embodiment, R5 is Cl. In another embodiment, R5 is F. In another embodiment, R5 is CN. In another embodiment, R5 is -X-RX. In r ment, R5 is -X-RX wherein RX is absent. In another embodiment, R5 is -X-RX wherein RX is absent and X is C1-C6 alkyl wherein said C1-C6 alkyl is substituted with 0-6 halogen. In another embodiment, R5 is CH3. In another embodiment, R5 is -X-RX wherein RX is absent and X is C1-C6 alkyl wherein said C1-C6 alkyl is substituted with 0-6 halogen wherein one CH2 unit of said C1-C6 alkyl is ed with -O-. In another embodiment, R5 is OCH3, OCHZCH3, OCHZCHZCH3, or OCH(CH3)2. In another embodiment, R5 is OCH3. In another embodiment, R5 is CHZOH. In another embodiment, R5 is OCF3. In another ment, R5 is OCHFZ.
In another embodiment, the ion features a compound of formula I or formula I’ and the attendant definitions, wherein R5, is H. In r embodiment, R5, is n.
In another embodiment, R5, is Cl. In another embodiment, R5, is F. In another embodiment, R5, is CN. In another embodiment, R5, is -X-RX. In another embodiment, R5, is -X-RX wherein RX is absent. In another embodiment, R5, is -X-RX wherein RX is absent and X is C1-C6 alkyl wherein said C1-C6 alkyl is substituted with 0-6 halogen. In another embodiment, R5, is CH3. In r embodiment, R5, is -X-RX wherein RX is absent and X is C1-C6 alkyl wherein said C1-C6 alkyl is substituted with 0-6 halogen wherein one CH2 unit of said C1-C6 alkyl is replaced with -O-. In another embodiment, R5, is OCH3, OCHZCH3, OCHZCHZCH3, or 3)2. In another embodiment, R5, is OCH3. In another embodiment, R5, is CHZOH. In another embodiment, R5, is OCF3. In another embodiment, R5, is OCHFZ.
In another embodiment, the invention features a compound of formula I or formula I’ and the attendant definitions, R6 is H. In another embodiment, R6 is n. In another embodiment, R6 is Cl. In another embodiment, R6 is F. In another ment, R6 is CN. In another embodiment, R6 is -X-RX. In another embodiment, R6 is -X-RX wherein RX is . In another embodiment, R6 is -X-RX wherein RX is absent and X is C1-C6 alkyl wherein said C1-C6 alkyl is substituted with 0-6 halogen. In another embodiment, R6 is CH3. In another embodiment, R6 is -X-RX wherein RX is absent and X is C1-C6 alkyl wherein said C1-C6 alkyl is substituted with 0-6 n wherein one CH2 unit of said C1-C6 alkyl is replaced with -O-. In another embodiment, R6 is OCH3.
In another embodiment, the invention features a compound of formula I or formula I’ and the attendant definitions, wherein R6, is H. In r ment, R6, is halogen.
In another embodiment, R6, is Cl. In another embodiment, R6, is F. In another embodiment, R6, is CN. In another embodiment, R6, is -X-RX. In another embodiment, R6, is -X-RX wherein RX is absent. In r embodiment, R6, is -X-RX wherein RX is absent and X is C1-C6 alkyl wherein said C1-C6 alkyl is substituted with 0-6 halogen. In another embodiment, R6, is CH3. In another embodiment, R6, is -X-RX wherein RX is absent and X is C1-C6 alkyl wherein said C1-C6 alkyl is substituted with 0-6 halogen wherein one CH2 unit of said C1-C6 alkyl is replaced with -O-. In r embodiment, R6, is OCH3.
In another ment, the ion es a nd of formula I or formula I’ and the attendant tions, wherein R7 is H. In another embodiment, R7 is halogen.
In r embodiment, R7 is Cl. In another ment, R7 is F. In another embodiment, R7 is CN. In r embodiment, R7 is -X-RX. In another embodiment, R7 is -X-RX wherein RX is absent. In another ment, R7 is -X-RX n RX is absent and X is C1-C6 alkyl wherein said C1-C6 alkyl is substituted with 0-6 halogen. In another embodiment, R7 is CH3, CH2CH3, CH2CH2CH3 or isopropyl. In another embodiment, R7 is CF3. In another embodiment, R7 is -X- RX wherein RX is absent and X is C1-C6 alkyl wherein said C1-C6 alkyl is substituted with 0-6 halogen wherein two non-adjacent CH2 units of said C1-C6 alkyl are replaced with -O-. In another embodiment, R7 is OCHZCHZOCHg. In another embodiment, R7 is -X-RX wherein RX is absent and X is C1-C6 alkyl wherein said C1-C6 alkyl is substituted with 0-6 halogen wherein one CH2 unit of said C1-C6 alkyl is replaced with -O-. In another embodiment, R7 is OCH3, OCH2CH3, OCHZCHZCHg, OC(CH3)3, OCHZCHZCH(CH3)2, or CHZCHZOCHg. In another embodiment, R7 is OCFg, OCH2CF3, OCHZCHZCHZCFg, or OCHFZ.
In r embodiment, the invention features a compound of formula I or formula I’ wherein R7 is -X-RX n X is a bond and RX is C3-C3 cycloaliphatic and said C3-C3 cycloaliphatic is substituted with 0-3 substituents selected from halogen and C1-C4 alkyl. In another embodiment, R7 is -X-RX wherein X is a bond and RX is cyclopropyl.
In another embodiment, the invention features a compound of formula I or formula I’ and the attendant definitions, wherein R7 is -X-RX wherein X is C1-C6 alkyl wherein said C1-C6 alkyl is substituted with 0-6 halogen wherein one CH2 unit of said C1-C6 alkyl is replaced with -O- and RX is C3-C3 cycloaliphatic and said C3-C3 cycloaliphatic is substituted with up 0-3 substituents selected from halogen and C1-C4 alkyl. In another embodiment, R7 is -X-RX wherein X is OCHZ and RX is cyclopropyl.
In another embodiment, the invention features a compound of formula I or formula I’ and the attendant definitions, n p is zero. In another embodiment, p is an integer from 1 to 4 and R8 is halogen. In another embodiment, p is an integer from 1 to 4 and R8 is Cl. In another embodiment, p is an integer from 1 to 4 and R8 is C1-C6 alkyl wherein said C1-C6 alkyl is substituted with 0-6 n wherein one CH2 unit of said C1-C6 alkyl is replaced with -O-. In another embodiment, p is an integer from 1 to 4 and R8 is CH3. In another embodiment, p is an integer from 1 to 4 and R8 is OH.
In r embodiment, the invention features a compound of formula I or formula I’ and the attendant tions, wherein ring A is selected from: ' ' ' | F CI 0 I m] I ml 0 O F F CI CI , , , , F,F , /O \\ ,or o F.
In another embodiment, the invention features a compound of formula I or formula I’ and the attendant definitions, wherein ring A is selected from: CI 0 F><O F, F, CI F ,,O C|,F F or F 9 9 In another ment, the invention features a compound of formula I or formula I’ and the ant definitions, wherein R5 and R7 are each ndently halogen, or —X- RX and R5,, R6, and R6, are each hydrogen. In another embodiment, R5 and R7 are each independently F, Cl, CH3 or OCHg.
In another embodiment, the invention features a compound of formula I or formula I’ and the ant definitions, wherein Y is N. In another embodiment, Y is C.
In another aspect, the invention es a compound of formula I-A or formula I'-A: (R8)p\7\|HkOH (R8) o p\4\ R2 \ Y OH N RficfikN \ H H o 0 R5 R5 G @ R6 R6' R6 R6 R7 R7 I-A I'-A or a pharmaceutically acceptable salt thereof, wherein, ndently for each occurrence: Y is C or N R2 is halogen, CN, or C1-C6 alkyl wherein said C1-C6 alkyl is substituted with 0-6 halogen, wherein up to two non-adjacent CH2 units of said C1-C6 alkyl may be replaced with -O-; R5 is H, halogen, CN, or —X-RX; R5, is H, halogen, CN, or —X-RX; R6 is H, halogen, CN, or —X-RX; R6, is H, halogen, CN, or —X-RX; R7 is H, halogen, CN, or —X-RX; X is a bond or C1-C6 alkyl wherein said C1-C6 alkyl is substituted with 0-6 halogen, wherein up to two non-adjacent CH2 units of said C1-C6 alkyl may be replaced with -O-; RX is absent, H, or C3-C3 cycloaliphatic, wherein up to two non-adjacent CH2 units of said C3-C3 cycloaliphatic may be replaced with -O- and said C3-C3 cycloaliphatic is substituted with 0-3 substituents selected from halogen and C1-C4 alkyl; R8 is halogen, or C1-C6 alkyl wherein said C1-C6 alkyl is substituted with 0-6 halogen, wherein up to two non-adjacent CH2 units of said C1-C6 alkyl may be replaced with -O-; and p is an integer from 0 to 4 inclusive.
In one ment, the invention es a nd of formula I-A or a I’-A and the attendant definitions, Y is C. In another embodiment, Y is N.
In another embodiment, the invention features a compound of formula I-A or formula I’-A and the attendant definitions, wherein R2 is halogen. In r embodiment, R2 is Cl. In another embodiment, R2 is F. In another embodiment, R2 is CN. In r embodiment, R2 is C1-C6 alkyl wherein said C1-C6 alkyl is substituted with 0-6 halogen. In another embodiment, R2 is CF3. In another embodiment, R2 is C1-C6 alkyl wherein said C1-C6 alkyl is substituted with 0-6 halogen wherein one CH2 unit of said C1-C6 alkyl is replaced with -O-. In another embodiment, R2 is OCF3. In another embodiment, R2 is F, Cl, CN, CF3 or OCF3.
In another ment, the ion features a compound of formula I-A or a I’-A and the attendant definitions, wherein R5 is H. In another ment, R5 is halogen.
In another embodiment, R5 is Cl. In another embodiment, R5 is F. In another ment, R5 is CN. In another embodiment, R5 is -X-RX. In another embodiment, R5 is -X-RX wherein RX is absent. In another embodiment, R5 is -X-RX wherein RX is absent and X is C1-C6 alkyl wherein said C1-C6 alkyl is substituted with 0-6 halogen. In another embodiment, R5 is CH3. In another embodiment, R5 is -X-RX wherein RX is absent and X is C1-C6 alkyl n said C1-C6 alkyl is substituted with 0-6 n wherein one CH2 unit of said C1-C6 alkyl is replaced with -O-. In another embodiment, R5 is OCH3, OCH2CH3, OCHZCHZCHg, or OCH(CH3)2. In another embodiment, R5 is OCH3. In another embodiment, R5 is CHZOH. In another embodiment, R5 is OCF3. In another embodiment, R5 is OCHFZ.
In another embodiment, the invention features a compound of formula I-A or formula I’-A and the attendant definitions, wherein R5, is H. In another embodiment, R5, is halogen. In another embodiment, R5, is Cl. In another embodiment, R5, is F. In another embodiment, R5, is CN. In another ment, R5, is -X-RX. In another embodiment, R5, is -X- RX wherein RX is absent. In another embodiment, R5, is -X-RX n RX is absent and X is C1- C6 alkyl wherein said C1-C6 alkyl is substituted with 0-6 halogen. In another embodiment, R5, is CH3. In another embodiment, R5, is -X-RX wherein RX is absent and X is C1-C6 alkyl wherein said C1-C6 alkyl is substituted with 0-6 halogen wherein one CH2 unit of said C1-C6 alkyl is replaced with -O-. In another embodiment, R5, is OCH3, OCH2CH3, OCHZCHZCHg, or OCH(CH3)2. In another embodiment, R5, is OCH3. In another embodiment, R5, is CHZOH. In r embodiment, R5, is OCF3. In another ment, R5, is OCHFZ.
In another ment, the ion features a compound of formula I-A or formula I’-A and the attendant definitions, R6 is H. In another embodiment, R6 is halogen. In r embodiment, R6 is Cl. In r embodiment, R6 is F. In r embodiment, R6 is CN.
In another embodiment, R6 is -X-RX. In another embodiment, R6 is -X-RX wherein RX is absent.
In another embodiment, R6 is -X-RX wherein RX is absent and X is C1-C6 alkyl wherein said C1-C6 alkyl is substituted with 0-6 halogen. In another embodiment, R6 is CH3. In another embodiment, R6 is -X-RX wherein RX is absent and X is C1-C6 alkyl wherein said C1-C6 alkyl is substituted with 0-6 halogen wherein one CH2 unit of said C1-C6 alkyl is replaced with -O-. In another WO 20820 embodiment, R6 is OCH3.
In another embodiment, the invention features a nd of a I-A or a I’-A and the attendant tions, wherein R6, is H. In r embodiment, R6, is halogen. In r ment, R6, is Cl. In another ment, R6, is F. In another embodiment, R6, is CN. In another embodiment, R6, is -X-RX. In another embodiment, R6, is -X- RX wherein RX is absent. In another embodiment, R6, is -X-RX wherein RX is absent and X is C1- C6 alkyl wherein said C1-C6 alkyl is substituted with 0-6 halogen. In another embodiment, R6, is CH3. In r embodiment, R6, is -X-RX wherein RX is absent and X is C1-C6 alkyl wherein said C1-C6 alkyl is substituted with 0-6 halogen wherein one CH2 unit of said C1-C6 alkyl is replaced with -O-. In another embodiment, R6, is OCH3.
In another embodiment, the invention features a compound of a I-A or formula I’-A and the attendant definitions, wherein R7 is H. In another embodiment, R7 is halogen.
In another embodiment, R7 is Cl. In another embodiment, R7 is F. In another embodiment, R7 is CN. In another embodiment, R7 is -X-RX. In another embodiment, R7 is -X-RX wherein RX is absent. In another embodiment, R7 is -X-RX n RX is absent and X is C1-C6 alkyl wherein said C1-C6 alkyl is substituted with 0-6 n. In another embodiment, R7 is CH3, CH2CH3, CH2CH2CH3 or isopropyl. In another embodiment, R7 is CF3. In another embodiment, R7 is -X- RX wherein RX is absent and X is C1-C6 alkyl wherein said C1-C6 alkyl is substituted with 0-6 halogen wherein two jacent CH2 units of said C1-C6 alkyl are ed with -O-. In another embodiment, R7 is OCHZCHZOCHg. In another embodiment, R7 is -X-RX wherein RX is absent and X is C1-C6 alkyl wherein said C1-C6 alkyl is substituted with 0-6 halogen wherein one CH2 unit of said C1-C6 alkyl is replaced with -O-. In another embodiment, R7 is OCH3, OCH2CH3, OCHZCHZCHg, OC(CH3)3, ZCH(CH3)2, or CHZCHZOCHg. In another embodiment, R7 is OCF3, OCH2CF3, OCHZCHZCHZCFg, or OCHFZ.
In another embodiment, the invention features a compound of formula I-A or a I’-A wherein R7 is -X-RX wherein X is a bond and RX is C3-C3 cycloaliphatic and said C3- C3 cycloaliphatic is substituted with 0-3 substituents selected from halogen and C1-C4 alkyl. In another embodiment, R7 is -X-RX wherein X is a bond and RX is cyclopropyl.
In another embodiment, the invention features a compound of formula I-A or formula I’-A and the attendant definitions, wherein R7 is -X-RX wherein X is C1-C6 alkyl wherein said C1-C6 alkyl is substituted with 0-6 halogen wherein one CH2 unit of said C1-C6 alkyl is replaced with -O- and RX is C3-C3 cycloaliphatic and said C3-C3 cycloaliphatic is substituted with up 0-3 substituents selected from halogen and C1-C4 alkyl. In another embodiment, R7 is -X-RX wherein X is OCHZ and RX is cyclopropyl.
In another embodiment, the invention features a compound of formula I-A or formula I’-A and the attendant definitions, wherein p is zero. In another embodiment, p is an integer from 1 to 4 and R8 is n. In another embodiment, p is an r from 1 to 4 and R8 is Cl. In another embodiment, p is an r from 1 to 4 and R8 is C1-C6 alkyl wherein said C1-C6 alkyl is substituted with 0-6 halogen wherein one CH2 unit of said C1-C6 alkyl is replaced with -O-.
In another embodiment, p is an integer from 1 to 4 and R8 is CH3. In another embodiment, p is an integer from 1 to 4 and R8 is OH.
In another embodiment, the invention features a compound of formula I-A or formula I’-A and the attendant definitions, wherein ring A is selected from: In another aspect, the invention provides a compound of formula LB or formula I'-B: (Ran. o WOH o \AIY H H R3 o R3 0 R5 R5 R5 G G R6 R6 R6 R6 R7 R7 I-B I'-B or a pharmaceutically acceptable salt thereof, wherein, independently for each occurrence: Y is C or N; R3 is halogen, CN, or C1-C6 alkyl wherein said C1-C6 alkyl is tuted with 0-6 halogen, wherein up to two non-adjacent CH2 units of said C1-C6 alkyl may be replaced with -O-; R5 is H, halogen, CN, or —X-RX; R5, is H, n, CN, or —X-RX; R6 is H, halogen, CN, or —X-RX; R6, is H, halogen, CN, or —X-RX; R7 is H, halogen, CN, or —X-RX; X is a bond or C1-C6 alkyl wherein said C1-C6 alkyl is substituted with 0-6 halogen, wherein up to two non-adjacent CH2 units of said C1-C6 alkyl may be replaced with -O-; RX is absent, H, or C3-C3 cycloaliphatic, n up to two non-adjacent CH2 units of said C3-C3 cycloaliphatic may be replaced with -O- and said C3-C3 cycloaliphatic is substituted with 0-3 substituents selected from halogen and C1-C4 alkyl; R8 is halogen, or C1-C6 alkyl wherein said C1-C6 alkyl is substituted with 0-6 halogen, wherein up to two non-adjacent CH2 units of said C1-C6 alkyl may be replaced with -O-; and p is an integer from 0 to 4 inclusive.
In one embodiment, the invention features a compound of a LB or formula I’-B and the attendant definitions, Y is C. In another embodiment, Y is N.
In another embodiment, the invention features a nd of formula LB or formula I’-B and the attendant definitions, wherein R3 is halogen. In another embodiment, R3 is Cl. In another embodiment, R3 is F. In another embodiment, R3 is CN. In another embodiment, R3 is C1-C6 alkyl wherein said C1-C6 alkyl is substituted with 0-6 halogen. In another embodiment, R3 is t—butyl. In another embodiment, R3 is CF3. In another embodiment, R3 is CF2CF3. In another embodiment, R3 is l, Cl, CF3 or CF2CF3.
In another embodiment, the invention features a compound of formula LB or formula I’-B and the attendant definitions, wherein R5 is H. In another embodiment, R5 is halogen.
In another embodiment, R5 is Cl. In another embodiment, R5 is F. In another embodiment, R5 is CN. In r ment, R5 is -X-RX. In r embodiment, R5 is -X-RX wherein RX is absent. In another embodiment, R5 is -X-RX wherein RX is absent and X is C1-C6 alkyl wherein said C1-C6 alkyl is substituted with 0-6 n. In r embodiment, R5 is CH3. In another embodiment, R5 is -X-RX wherein RX is absent and X is C1-C6 alkyl wherein said C1-C6 alkyl is substituted with 0-6 halogen wherein one CH2 unit of said C1-C6 alkyl is replaced with -O-. In another embodiment, R5 is OCH3, OCH2CH3, OCHZCHZCHg, or OCH(CH3)2. In r embodiment, R5 is OCH3. In another embodiment, R5 is CHZOH. In another embodiment, R5 is OCF3. In another embodiment, R5 is OCHFZ. In another embodiment, R5 is F, Cl, CH3 or OCH3.
In another embodiment, the invention features a compound of formula LB or formula I’-B and the attendant definitions, wherein R5, is H. In another embodiment, R5, is halogen. In r ment, R5, is Cl. In another embodiment, R5, is F. In another ment, R5, is CN. In another embodiment, R5, is -X-RX. In another ment, R5, is -X- RX wherein RX is absent. In another embodiment, R5, is -X-RX wherein RX is absent and X is C1- C6 alkyl n said C1-C6 alkyl is substituted with 0-6 halogen. In r embodiment, R5, is CH3. In another embodiment, R5, is -X-RX wherein RX is absent and X is C1-C6 alkyl wherein said C1-C6 alkyl is substituted with 0-6 halogen wherein one CH2 unit of said C1-C6 alkyl is replaced with -O-. In another embodiment, R5, is OCH3, OCH2CH3, OCHZCHZCHg, or OCH(CH3)2. In another embodiment, R5, is OCH3. In another embodiment, R5, is CHZOH. In another embodiment, R5, is OCF3. In another embodiment, R5, is OCHFZ.
In another embodiment, the invention features a compound of formula LB or formula I’-B and the attendant definitions, R6 is H. In another embodiment, R6 is n. In another embodiment, R6 is Cl. In another embodiment, R6 is F. In r embodiment, R6 is CN.
In another embodiment, R6 is -X-RX. In another embodiment, R6 is -X-RX wherein RX is absent.
In r embodiment, R6 is -X-RX wherein RX is absent and X is C1-C6 alkyl wherein said C1-C6 alkyl is tuted with 0-6 halogen. In another embodiment, R6 is CH3. In another ment, R6 is -X-RX wherein RX is absent and X is C1-C6 alkyl wherein said C1-C6 alkyl is substituted with 0-6 halogen wherein one CH2 unit of said C1-C6 alkyl is replaced with -O-. In another embodiment, R6 is OCH3.
In another embodiment, the invention features a compound of formula LB or formula I’-B and the attendant definitions, wherein R6, is H. In another embodiment, R6, is halogen. In another embodiment, R6, is Cl. In another embodiment, R6, is F. In another embodiment, R6, is CN. In another embodiment, R6, is -X-RX. In another ment, R6, is -X- RX wherein RX is absent. In another embodiment, R6, is -X-RX wherein RX is absent and X is C1- C6 alkyl wherein said C1-C6 alkyl is substituted with 0-6 halogen. In another ment, R6, is CH3. In another ment, R6, is -X-RX wherein RX is absent and X is C1-C6 alkyl wherein said C1-C6 alkyl is substituted with 0-6 halogen wherein one CH2 unit of said C1-C6 alkyl is ed with -O-. In another embodiment, R6, is OCH3.
In r embodiment, the invention features a compound of formula LB or formula I’-B and the attendant definitions, wherein R7 is H. In another embodiment, R7 is halogen.
In another embodiment, R7 is Cl. In another embodiment, R7 is F. In another embodiment, R7 is CN. In another embodiment, R7 is -X-RX. In another embodiment, R7 is -X-RX n RX is absent. In r embodiment, R7 is -X-RX wherein RX is absent and X is C1-C6 alkyl wherein said C1-C6 alkyl is substituted with 0-6 halogen. In another ment, R7 is CH3, CH2CH3, CH3 or isopropyl. In another embodiment, R7 is CF3. In another embodiment, R7 is -X- RX wherein RX is absent and X is C1-C6 alkyl wherein said C1-C6 alkyl is substituted with 0-6 halogen wherein two non-adjacent CH2 units of said C1-C6 alkyl are replaced with -O-. In another embodiment, R7 is OCHZCHZOCHg. In r embodiment, R7 is -X-RX wherein RX is absent and X is C1-C6 alkyl wherein said C1-C6 alkyl is substituted with 0-6 halogen wherein one CH2 unit of said C1-C6 alkyl is replaced with -O-. In another embodiment, R7 is OCH3, OCHZCHg, OCHZCHZCHg, OC(CH3)3, OCHZCHZCH(CH3)2, or CHZCHZOCHg. In another embodiment, R7 is OCFg, OCH2CF3, OCHZCHZCHZCFg, or OCHFZ. In another ment, R7 is F, Cl, CH3 or OCHg.
In r embodiment, the invention features a compound of formula LB or a I’-B wherein R7 is -X-RX wherein X is a bond and RX is C3-C3 cycloaliphatic and said C3- C3 cycloaliphatic is substituted with 0-3 substituents selected from halogen and C1-C4 alkyl. In r embodiment, R7 is -X-RX wherein X is a bond and RX is cyclopropyl.
In another embodiment, the invention features a compound of formula LB or formula I’-B and the attendant definitions, wherein R7 is -X-RX wherein X is C1-C6 alkyl wherein said C1-C6 alkyl is tuted with 0-6 halogen wherein one CH2 unit of said C1-C6 alkyl is replaced with -O- and RX is C3-C3 cycloaliphatic and said C3-C3 cycloaliphatic is substituted with up 0-3 substituents selected from halogen and C1-C4 alkyl. In another ment, R7 is -X-RX wherein X is OCHZ and RX is cyclopropyl.
In another embodiment, the invention features a compound of formula LB or formula I’-B and the attendant definitions, wherein p is zero. In another embodiment, p is an integer from 1 to 4 and R8 is halogen. In r embodiment, p is an integer from 1 to 4 and R8 is Cl. In r embodiment, p is an integer from 1 to 4 and R8 is C1-C6 alkyl wherein said C1-C6 alkyl is substituted with 0-6 halogen wherein one CH2 unit of said C1-C6 alkyl is replaced with -O-.
In another embodiment, p is an integer from 1 to 4 and R8 is CH3. In another embodiment, p is an integer from 1 to 4 and R8 is OH.
In another embodiment, the invention features a compound of formula LB or formula I’-B and the attendant definitions, wherein ring A is selected from: JVI\N .m‘vv .N'vv 70f) CI PTO© FFXFO F /O 9 9 9 9 9 MN NW MAI MN W W l W CI F /o o F~PF 1 F /O /O /O /O F F 9 9 9 9 9 9 9 9 NW .N'vv MN I .Iv'vv F CI 0 I m I m 0 O F, F, CI, CI, F,F ,/O, or O F In another ment, ring A is selected from: CI 0 O / F F><O F, F, CI, F, /0, C|,FFor F In another embodiment, R5 and R7 are each independently F, Cl, CH3 or OCH3.
In another aspect, the invention provides a compound of formula LC or formula I'-C: / (R8)p I OH O ’ R2 \ Y R2 \ OH N N R3 0 R3 0 R5 R5 G @ R6 R6 R6 R6 R7 R7 I—C I'-C or a pharmaceutically acceptable salt thereof, wherein, independently for each occurrence: YisCorN; R2 is halogen, CN, or C1-C6 alkyl wherein said C1-C6 alkyl is substituted with 0-6 halogen, wherein up to two non-adjacent CH2 units of said C1-C6 alkyl may be replaced with -O-; R3 is halogen, CN, or C1-C6 alkyl wherein said C1-C6 alkyl is substituted with 0-6 halogen, wherein up to two non-adjacent CH2 units of said C1-C6 alkyl may be ed with -O-; R5 is H, halogen, CN, or —X-RX; R5, is H, halogen, CN, or —X-RX; R6 is H, halogen, CN, or —X-RX; R6, is H, halogen, CN, or —X-RX; R7 is H, halogen, CN, or —X-RX; X is a bond or C1-C6 alkyl wherein said C1-C6 alkyl is substituted with 0-6 halogen, wherein up to two jacent CH2 units of said C1-C6 alkyl may be replaced with -O-; RX is absent, H, or C3-C3 cycloaliphatic, wherein up to two non-adjacent CH2 units of said C3-C3 cycloaliphatic may be ed with -O- and said C3-C3 cycloaliphatic is substituted with 0-3 substituents selected from halogen and C1-C4 alkyl; R8 is halogen, or C1-C6 alkyl wherein said C1-C6 alkyl is substituted with 0-6 halogen, n up to two non-adjacent CH2 units of said C1-C6 alkyl may be replaced with -O-; and p is an integer from 0 to 4 inclusive.
In one embodiment, the invention features a compound of formula LC or formula I’-C and the attendant definitions, Y is C. In another ment, Y is N.
In another embodiment, the invention es a compound of formula LC or formula I’-C and the attendant definitions, wherein R2 is halogen. In another embodiment, R2 is Cl. In r embodiment, R2 is F. In another embodiment, R2 is CN. In another embodiment, R2 is C1-C6 alkyl wherein said C1-C6 alkyl is substituted with 0-6 halogen. In another embodiment, R2 is CF3. In another embodiment, R2 is C1-C6 alkyl wherein said C1-C6 alkyl is substituted with 0-6 halogen n one CH2 unit of said C1-C6 alkyl is replaced with -O-. In another embodiment, R2 is OCF3. In another embodiment, R2 is F, Cl, CN, CF3 or OCF3. In another embodiment, R2 is H, halogen, or C1-C6 alkyl wherein said C1-C6 alkyl is substituted with 0-6 halogen and wherein one CH2 unit of said C1-C6 alkyl is replaced with -O-. In another embodiment, R2 is F, C1, CF3 or 001:3.
In another embodiment, the ion es a compound of a LC or formula I’-C and the attendant definitions, wherein R3 is halogen. In another embodiment, R3 is Cl. In r embodiment, R3 is F. In another embodiment, R3 is CN. In another embodiment, R3 is C1-C6 alkyl n said C1-C6 alkyl is substituted with 0-6 halogen. In another embodiment, R3 is t—butyl. In another embodiment, R3 is CF3. In another embodiment, R3 is CF2CF3. In WO 20820 another embodiment, R3 is t—butyl, Cl, CF3 or CF2CF3.
In another embodiment, the ion features a compound of formula LC or formula I’-C and the attendant definitions, wherein R5 is H. In another ment, R5 is halogen.
In another embodiment, R5 is Cl. In r embodiment, R5 is F. In another embodiment, R5 is CN. In another embodiment, R5 is -X-RX. In another embodiment, R5 is -X-RX wherein RX is . In another embodiment, R5 is -X-RX n RX is absent and X is C1-C6 alkyl wherein said C1-C6 alkyl is substituted with 0-6 n. In another embodiment, R5 is CH3. In another embodiment, R5 is -X-RX wherein RX is absent and X is C1-C6 alkyl wherein said C1-C6 alkyl is substituted with 0-6 n wherein one CH2 unit of said C1-C6 alkyl is replaced with -O-. In another embodiment, R5 is OCH3, OCH2CH3, ZCHg, or OCH(CH3)2. In r embodiment, R5 is OCH3. In another embodiment, R5 is CHZOH. In another embodiment, R5 is OCF3. In another embodiment, R5 is OCHFZ. In another embodiment, R5 is F, Cl, CH3 or OCH3.
In another embodiment, the ion features a compound of formula LC or formula I’-C and the attendant definitions, n R5, is H. In another embodiment, R5, is halogen. In another embodiment, R5, is Cl. In another embodiment, R5, is F. In another embodiment, R5, is CN. In another embodiment, R5, is -X-RX. In another embodiment, R5, is -X- RX wherein RX is absent. In another embodiment, R5, is -X-RX wherein RX is absent and X is C1- C6 alkyl wherein said C1-C6 alkyl is substituted with 0-6 halogen. In another embodiment, R5, is CH3. In another embodiment, R5, is -X-RX wherein RX is absent and X is C1-C6 alkyl wherein said C1-C6 alkyl is substituted with 0-6 halogen wherein one CH2 unit of said C1-C6 alkyl is replaced with -O-. In another embodiment, R5, is OCH3, OCH2CH3, OCHZCHZCHg, or OCH(CH3)2. In another embodiment, R5, is OCH3. In another embodiment, R5, is CHZOH. In another embodiment, R5, is OCF3. In another embodiment, R5, is OCHFZ.
In another embodiment, the ion features a nd of formula LC or a I’-C and the attendant definitions, R6 is H. In another embodiment, R6 is halogen. In another embodiment, R6 is Cl. In another embodiment, R6 is F. In another ment, R6 is CN.
In another embodiment, R6 is -X-RX. In another embodiment, R6 is -X-RX wherein RX is absent.
In another embodiment, R6 is -X-RX wherein RX is absent and X is C1-C6 alkyl wherein said C1-C6 alkyl is substituted with 0-6 halogen. In another embodiment, R6 is CH3. In another embodiment, R6 is -X-RX wherein RX is absent and X is C1-C6 alkyl wherein said C1-C6 alkyl is substituted with 0-6 halogen wherein one CH2 unit of said C1-C6 alkyl is replaced with -O-. In another embodiment, R6 is OCH3.
In another embodiment, the invention features a compound of formula LC or formula I’-C and the attendant definitions, n R6, is H. In another embodiment, R6, is halogen. In another embodiment, R6, is Cl. In another embodiment, R6, is F. In another embodiment, R6, is CN. In another embodiment, R6, is -X-RX. In another embodiment, R6, is -X- WO 20820 RX wherein RX is absent. In another ment, R6, is -X-RX wherein RX is absent and X is C1- C6 alkyl wherein said C1-C6 alkyl is substituted with 0-6 halogen. In another embodiment, R6, is CH3. In another embodiment, R6, is -X-RX wherein RX is absent and X is C1-C6 alkyl wherein said C1-C6 alkyl is substituted with 0-6 halogen wherein one CH2 unit of said C1-C6 alkyl is replaced with -O-. In another embodiment, R6, is OCH3.
In another embodiment, the invention features a compound of formula LC or formula I’-C and the attendant definitions, wherein R7 is H. In another embodiment, R7 is halogen.
In another ment, R7 is Cl. In another embodiment, R7 is F. In another embodiment, R7 is CN. In another embodiment, R7 is -X-RX. In another embodiment, R7 is -X-RX wherein RX is absent. In another embodiment, R7 is -X-RX wherein RX is absent and X is C1-C6 alkyl wherein said C1-C6 alkyl is substituted with 0-6 halogen. In another embodiment, R7 is CH3, , CH2CH2CH3 or isopropyl. In another embodiment, R7 is CF3. In another embodiment, R7 is -X- RX wherein RX is absent and X is C1-C6 alkyl wherein said C1-C6 alkyl is substituted with 0-6 n wherein two non-adjacent CH2 units of said C1-C6 alkyl are replaced with -O-. In another embodiment, R7 is OCHZCHZOCHg. In r embodiment, R7 is -X-RX wherein RX is absent and X is C1-C6 alkyl wherein said C1-C6 alkyl is substituted with 0-6 halogen wherein one CH2 unit of said C1-C6 alkyl is replaced with -O-. In r embodiment, R7 is OCH3, OCH2CH3, OCHZCHZCHg, )3, OCHZCHZCH(CH3)2, or CHZCHZOCHg. In another embodiment, R7 is OCF3, OCH2CF3, OCHZCHZCHZCFg, or OCHFZ. In another embodiment, R7 is F, Cl, CH3 or OCH3.
In another embodiment, the ion es a compound of formula LC or a I’-C wherein R7 is -X-RX wherein X is a bond and RX is C3-C3 cycloaliphatic and said C3- C3 cycloaliphatic is substituted with 0-3 substituents selected from halogen and C1-C4 alkyl. In another embodiment, R7 is -X-RX wherein X is a bond and RX is cyclopropyl.
In another embodiment, the invention features a compound of formula LC or formula I’-C and the attendant definitions, wherein R7 is -X-RX n X is C1-C6 alkyl wherein said C1-C6 alkyl is substituted with 0-6 halogen wherein one CH2 unit of said C1-C6 alkyl is replaced with -O- and RX is C3-C3 cycloaliphatic and said C3-C3 cycloaliphatic is substituted with up 0-3 tuents selected from n and C1-C4 alkyl. In another embodiment, R7 is -X-RX wherein X is OCHZ and RX is cyclopropyl.
In another embodiment, the invention features a compound of formula LC or formula I’-C and the attendant definitions, wherein p is zero. In another ment, p is an integer from 1 to 4 and R8 is halogen. In another embodiment, p is an integer from 1 to 4 and R8 is Cl. In another embodiment, p is an integer from 1 to 4 and R8 is C1-C6 alkyl wherein said C1-C6 alkyl is substituted with 0-6 halogen wherein one CH2 unit of said C1-C6 alkyl is replaced with -O-.
In another embodiment, p is an integer from 1 to 4 and R8 is CH3. In another embodiment, p is an integer from 1 to 4 and R8 is OH.
In r embodiment, the invention features a compound of formula LC or formula I’-C and the attendant definitions, wherein ring A is selected from: F‘PF F \Q/ /O /O /O /O F F 9 9 9 9 9 9 9 9 vav .N'vv W I .N'vv F CI 0 I .N'vv I .N'vv O O F, F, CI, CI, F,F ,/O, or O F In another embodiment, ring A is selected from: CI 0 O / F F><O F, F, CI, F, /0, C|,FFor F In another embodiment, R5 and R7 are each independently F, Cl, CH3 or OCHg.
In another aspect, the invention provides a compound of a LB or formula I'-D: (Ran, (R8)p R1 WOH R1 o YWY \ Y OH H H R3 o R3Cb \0 R5 R5 6 G R6 R6 R6 R6 R7 R7 I-D I'-D or a pharmaceutically acceptable salt thereof, wherein, independently for each occurrence: Y is C or N; R1 is halogen, CN, or C1-C6 alkyl wherein said C1-C6 alkyl is substituted with 0-6 halogen and wherein up to two non-adjacent CH2 units of said C1-C6 alkyl may be replaced with -O-; R3 is halogen, CN, or C1-C6 alkyl n said C1-C6 alkyl is substituted with 0-6 halogen, n up to two non-adjacent CH2 units of said C1-C6 alkyl may be replaced with -O-; R5 is H, halogen, CN, or —X-RX; R5, is H, halogen, CN, or —X-RX; R6 is H, halogen, CN, or —X-RX; R6, is H, halogen, CN, or —X-RX; R7 is H, halogen, CN, or —X-RX; X is a bond or C1-C6 alkyl wherein said C1-C6 alkyl is substituted with 0-6 halogen, n up to two non-adjacent CH2 units of said C1-C6 alkyl may be replaced with -O-; RX is absent, H, or C3-C3 liphatic, wherein up to two non-adjacent CH2 units of said C3-C3 cycloaliphatic may be replaced with -O- and said C3-C3 cycloaliphatic is substituted with 0-3 substituents ed from halogen and C1-C4 alkyl; R8 is halogen, or C1-C6 alkyl wherein said C1-C6 alkyl is substituted with 0-6 halogen, wherein up to two non-adjacent CH2 units of said C1-C6 alkyl may be replaced with -O-; and p is an integer from 0 to 4 inclusive.
In one embodiment, the invention features a nd of formula I-D or formula I’-D and the attendant definitions, Y is C. In another embodiment, Y is N.
In another embodiment, the invention features a compound of formula I-D or formula I’-D and the attendant definitions, wherein R1 is halogen. In another embodiment, R1 is CN. In r embodiment, R1 is C1-C6 alkyl wherein said C1-C6 alkyl is substituted with 0-6 halogen. In another embodiment, R1 is CF3.
In another embodiment, the invention features a compound of formula I-D or formula I’-D and the attendant definitions, wherein R3 is halogen. In r embodiment, R3 is Cl. In another embodiment, R3 is F. In another embodiment, R3 is CN. In another embodiment, R3 is C1-C6 alkyl wherein said C1-C6 alkyl is substituted with 0-6 halogen. In another embodiment, R3 is t—butyl. In another ment, R3 is CF3. In another embodiment, R3 is CFZCF3.
In another embodiment, the invention features a compound of formula I-D or formula I’-D and the attendant definitions, wherein R5 is H. In another embodiment, R5 is halogen.
In another embodiment, R5 is Cl. In another embodiment, R5 is F. In another embodiment, R5 is CN. In another embodiment, R5 is -X-RX. In another embodiment, R5 is -X-RX wherein RX is . In another embodiment, R5 is -X-RX n RX is absent and X is C1-C6 alkyl wherein said C1-C6 alkyl is substituted with 0-6 n. In r embodiment, R5 is CH3. In another embodiment, R5 is -X-RX wherein RX is absent and X is C1-C6 alkyl wherein said C1-C6 alkyl is substituted with 0-6 halogen wherein one CH2 unit of said C1-C6 alkyl is replaced with -O-. In another embodiment, R5 is OCH3, OCH2CH3, OCHZCHZCHg, or OCH(CH3)2. In another ment, R5 is OCH3. In another embodiment, R5 is CHZOH. In another embodiment, R5 is OCF3. In another embodiment, R5 is OCHFZ.
In another embodiment, the invention features a compound of formula I-D or a I’-D and the attendant definitions, wherein R5, is H. In another embodiment, R5, is halogen. In another embodiment, R5, is Cl. In another ment, R5, is F. In another embodiment, R5, is CN. In another embodiment, R5, is -X-RX. In another embodiment, R5, is -X- RX wherein RX is absent. In r embodiment, R5, is -X-RX wherein RX is absent and X is C1- C6 alkyl wherein said C1-C6 alkyl is substituted with 0-6 halogen. In another embodiment, R5, is CH3. In r embodiment, R5, is -X-RX wherein RX is absent and X is C1-C6 alkyl wherein said C1-C6 alkyl is substituted with 0-6 halogen wherein one CH2 unit of said C1-C6 alkyl is ed with -O-. In another embodiment, R5, is OCH3, OCH2CH3, OCHZCHZCHg, or 3)2. In another embodiment, R5, is OCH3. In another ment, R5, is CHZOH. In another embodiment, R5, is OCF3. In another embodiment, R5, is OCHFZ.
In another embodiment, the invention features a compound of a I-D or formula I’-D and the attendant definitions, R6 is H. In another embodiment, R6 is halogen. In another embodiment, R6 is Cl. In another embodiment, R6 is F. In another ment, R6 is CN.
In another embodiment, R6 is -X-RX. In another embodiment, R6 is -X-RX wherein RX is absent.
In another ment, R6 is -X-RX wherein RX is absent and X is C1-C6 alkyl wherein said C1-C6 alkyl is substituted with 0-6 halogen. In another embodiment, R6 is CH3. In another embodiment, 6is -X-Rx wherein RX')8 absent and X15 C1-C13 alkyl n said C1-C5 all(ylIS substituted with 0-6 halogenwherein one CH2 unit of said C1-C6 alkylIS replaced with -O- In another embodiment,R515 OCHJ.
In another embodiment, the invention features a compound of a I-D or formula I’-D and the attendant definitions, wherein R6, is H. In another embodiment, IRS is n. In another ment, R615 Cl. In another embodiment, R6 is F In another embodiment, R6 is CN In another embodiment, R615 -X-RX. In another embodiment, R6.IS. -X- Rx wherein RX15 absent. In another embodiment, R6 is--X—RX wherein RX15absent and X15 (31- 'Cé alkyl wherein said C1-C6 alkylis substituted with ()-6 halogen. In another embodiment, R6.'1s CH3. In another embodiment, .R6 is--X-RX n RX15 absent and X15 C1—C6 alkyl.wherein said.
C1--C6 alkyl15 substituted. with 0-6 halogen wherein one CH2 unit of said C1-Cg alkylis replaced with O--. In another embodiment, R615 OCH3.
In another embodiment, the invention features a compound of formula I-D or formula I’-D and the attendant definitions, wherein R7is H In another embodiment, R7 is halogen In anotherembodiment, R715 Cl In another embodiment, R7 is F. In another embodiment, R715 CN. In another embodiment, R715 -X-Rx In another embodiment, R7IS -X-Rx n RX15 . In another embodiment, R715 -X-Rx wherein Rx1s absent and X1s C1-C6 alkyl wherein said C1-C5 alkylIS substituted with 0-6 halogen. In r embodiment, R7'IS CH3, CH2CH3, 2Cl-I3 or pyl. In another embodiment, 'R71s CF21. In another embodiment,R715 -X- Rx wherein RXIS absent and X15 C1-C6 alkyl wherein said C1-C6 alkylis substituted with 0-6 halogen wherein two non-adjacent CH2 units of said C1—C5 alkyl are replaced with O--. In another ment, R7 is OCH2CH2OCH1 In another embodiment, X-Rx whereinRX15 absent and.
X'IS C1-C6 alkyl wherein said C1-C6 alkyl1ssubstituted with 0-6 halogen wherein one CH2 unit of said C1-C6 alkyl15 replaced with -O-. -In another embodiment, R7IS OCHg, 0Cl-I2CH3, OCH2CH2CH2, OC(CH3)3, -I2CI-I(CH3)2, or CH2CH2OCH3. In another embodiment R715 OCFg, OCH2CF3‘, OCH2CH2CH2CF3, or OCHF2 In another ment, the invention features a compound of formula 1-D or formula I'-D wherein R'715-X-RX n X15 a bond and RX is C3-C11 cycloaliphatic and said C2- C11 liphatic1s substituted with 0—3 substituents selected from halogen and C1-C4 alkyl. In another embodiment, R7_is —X-Rx wherein X is a bond and R)c is cyclopropyl.
In another embodiment, the invention features a compound of formula 1-D or formula I'-D and the attendant definitions, wherein R7 isr-VX-Rx wherein X is C1-C5 alkyl wherein said C1-C5 alkyl is substituted'withi 0-6 halogen wherein one'CHz unit of said C12C5 alkyl is replaced with 9.0- and Rx is C3-C3 cycloaliphatic and said C3-C1; cycloaliphatic is tuted with up 0-3 substituents selected from halogen and C1—C4 alkyl. In another embodiment, R7 is -X-RX wherein X is OCH2 and RX is cyclopropyl.
RECTIFIED SHEET (RULE 91) ISA/EP In another embodiment, the invention features a compound of a I-D or a I’-D and the attendant definitions, wherein p is zero. In another embodiment, p is an integer from 1 to 4 and R8 is halogen. In another ment, p is an integer from 1 to 4 and R8 is Cl. In another embodiment, p is an integer from 1 to 4 and R8 is C1-C6 alkyl wherein said C1-C6 alkyl is substituted with 0-6 halogen wherein one CH2 unit of said C1-C6 alkyl is ed with -O-.
In another embodiment, p is an integer from 1 to 4 and R8 is CH3. In another embodiment, p is an integer from 1 to 4 and R8 is OH.
In another embodiment, the invention features a compound of formula I-D or formula I’-D and the attendant definitions, wherein ring A is selected from: F F 9 9 9 9 9 9 9/0 9 © JWV MN JWV JVW W W I W F‘PF 1 F /O /O /O /O F F 9 9 9 9 9 9 9 9 WW .N'vv Jwv I .N'w F CI 0 I .N'vv I WW 0 O F F CI CI /0 , , , F, F , , , or O F In another aspect, the invention provides a nd of formula I-E or formula I'-E: 8 o (R)p (R)p8 \’ /\ I OH 0 k R2 \ Y R2 \ OH N N o o Fifi R5 R7 R7 I-E I'-E or a pharmaceutically acceptable salt thereof, wherein, ndently for each occurrence: Y is C or N; R2 is halogen, CN, or C1-C6 alkyl wherein said C1-C6 alkyl is substituted with 0-6 halogen, wherein up to two non-adjacent CH2 units of said C1-C6 alkyl may be replaced with -O-; R5 is halogen, CN, or —X-RX; R7 is halogen, CN, or —X-RX; X is a bond or C1-C6 alkyl wherein said C1-C6 alkyl is substituted with 0-6 n, wherein up to two non-adjacent CH2 units of said C1-C6 alkyl may be replaced with -O-; RX is absent, H, or C3-C3 cycloaliphatic, wherein up to two non-adjacent CH2 units of said C3-C3 cycloaliphatic may be replaced with -O- and said C3-C3 cycloaliphatic is substituted with 0-3 substituents selected from halogen and C1-C4 alkyl; R8 is halogen, or C1-C6 alkyl wherein said C1-C6 alkyl is substituted with 0-6 halogen, wherein up to two non-adjacent CH2 units of said C1-C6 alkyl may be ed with -O-; and p is an integer from 0 to 4 inclusive.
In one embodiment, the invention features a compound of formula LB or a I’-E and the attendant definitions, Y is C. In another embodiment, Y is N.
In another ment, the invention features a compound of formula LB or formula I’-E and the attendant tions, wherein R2 is n. In another embodiment, R2 is Cl. In another embodiment, R2 is F. In another embodiment, R2 is CN. In another embodiment, R2 is C1-C6 alkyl wherein said C1-C6 alkyl is substituted with 0-6 n. In another ment, R2 is CF3. In another embodiment, R2 is C1-C6 alkyl wherein said C1-C6 alkyl is substituted with 0-6 halogen wherein one CH2 unit of said C1-C6 alkyl is replaced with -O-. In another embodiment, R2 is OCF3. In another embodiment, R2 is F, Cl, CN, CF3 or OCF3.
In r embodiment, the invention features a compound of formula LB or formula I’-E and the attendant definitions, wherein R5 is halogen. In another embodiment, R5 is Cl. In another embodiment, R5 is F. In another embodiment, R5 is CN. In another embodiment, R5 is -X-RX. In another embodiment, R5 is -X-RX wherein RX is . In another embodiment, R5 is -X-RX wherein RX is absent and X is C1-C6 alkyl wherein said C1-C6 alkyl is tuted with 0-6 halogen. In another embodiment, R5 is CH3. In another embodiment, R5 is -X-RX wherein RX is absent and X is C1-C6 alkyl wherein said C1-C6 alkyl is substituted with 0-6 halogen wherein one CH2 unit of said C1-C6 alkyl is replaced with -O-. In another embodiment, R5 is OCH3, OCH2CH3, OCHZCHZCHg, or OCH(CH3)2. In another embodiment, R5 is OCH3. In another embodiment, R5 is CHZOH. In another embodiment, R5 is OCF3. In another embodiment, R5 is OCHFZ.
In another embodiment, the invention features a compound of formula I-E or formula I’-E and the attendant definitions, wherein R7 is halogen. In another embodiment, R7 is Cl. In another embodiment, R7 is F. In another embodiment, R7 is CN. In another embodiment, R7 is -X-RX. In r embodiment, R7 is -X-RX wherein RX is absent. In r embodiment, R7 is -X-RX wherein RX is absent and X is C1-C6 alkyl wherein said C1-C6 alkyl is substituted with 0-6 halogen. In another ment, R7 is CH3, CHZCH3, CHZCHZCH3 or isopropyl. In another ment, R7 is CF3. In another ment, R7 is -X-RX n RX is absent and X is C1-C6 alkyl wherein said C1-C6 alkyl is substituted with 0-6 halogen wherein two non-adjacent CH2 units of said C1-C6 alkyl are replaced with -O-. In another embodiment, R7 is ZOCH3. In another embodiment, R7 is -X-RX wherein RX is absent and X is C1-C6 alkyl wherein said C1-C6 alkyl is substituted with 0-6 halogen wherein one CH2 unit of said C1-C6 alkyl is replaced with -O-.
In another embodiment, R7 is OCH3, OCHZCH3, OCHZCHZCH3, OC(CH3)3, OCHZCHZCH(CH3)2, or CHZCHZOCH3. In another embodiment, R7 is OCF3, OCHZCF3, OCHZCHZCHZCF3, or OCHFZ.
In another embodiment, the invention es a compound of formula I-E or formula I’-E wherein R7 is -X-RX wherein X is a bond and RX is C3-C3 liphatic and said C3-C3 cycloaliphatic is substituted with 0-3 substituents selected from halogen and C1-C4 alkyl. In another embodiment, R7 is -X-RX wherein X is a bond and RX is cyclopropyl.
In another ment, the invention features a compound of formula I-E or formula I’-E and the attendant definitions, wherein R7 is -X-RX wherein X is C1-C6 alkyl wherein said C1-C6 alkyl is substituted with 0-6 halogen n one CH2 unit of said C1-C6 alkyl is replaced with -O- and RX is C3-C3 cycloaliphatic and said C3-C3 liphatic is substituted with up 0-3 substituents selected from halogen and C1-C4 alkyl. In another embodiment, R7 is -X- RX wherein X is OCHZ and RX is cyclopropyl.
] In another embodiment, the invention features a compound of formula I-E or formula I’-E and the attendant definitions, wherein p is zero. In r embodiment, p is an integer from 1 to 4 and R8 is halogen. In another embodiment, p is an integer from 1 to 4 and R8 is Cl. In another embodiment, p is an integer from 1 to 4 and R8 is C1-C6 alkyl wherein said C1-C6 alkyl is substituted with 0-6 halogen wherein one CH2 unit of said C1-C6 alkyl is replaced with -O-.
In another embodiment, p is an integer from 1 to 4 and R8 is CH3. In another embodiment, p is an integer from 1 to 4 and R8 is OH.
In another embodiment, the invention features a compound of formula I-E or a I’-E and the attendant definitions, wherein ring A is selected from: C' F /0 o F CI /0 /O /O /O F F F F 9 9 9 9 9 9 9 9 MN I .Iv'vv CI or CI In another aspect, the invention provides a compound of formula I-F or formula I'-F: (R8)p (R8 O ’ I OH O )p\Vf\’ IY \ Y \ OH R3 0 R3 0 R5 R5 G G R7 R7 I-F I'-F or a pharmaceutically acceptable salt thereof, wherein, independently for each occurrence: Y is C or N; R3 is halogen, CN, or C1-C6 alkyl wherein said C1-C6 alkyl is substituted with 0-6 halogen, wherein up to two non-adjacent CH2 units of said C1-C6 alkyl may be ed with -O-; R5 is halogen, CN, or —X-RX; R7 is halogen, CN, or —X-RX; X is a bond or C1-C6 alkyl wherein said C1-C6 alkyl is substituted with 0-6 halogen, wherein up to two non-adjacent CH2 units of said C1-C6 alkyl may be replaced with -O-; RX is absent, H, or C3-C3 cycloaliphatic, wherein up to two non-adjacent CH2 units of said C3-C3 liphatic may be replaced with -O- and said C3-C3 liphatic is substituted with 0-3 substituents selected from halogen and C1-C4 alkyl; R8 is n, or C1-C6 alkyl wherein said C1-C6 alkyl is substituted with 0-6 halogen, wherein up to two jacent CH2 units of said C1-C6 alkyl may be replaced with -O-; and p is an integer from 0 to 4 inclusive.
In one embodiment, the ion features a compound of formula I-F or formula I’-F and the attendant definitions, Y is C. In another embodiment, Y is N.
In r embodiment, the invention features a compound of formula I-F or formula I’-F and the attendant definitions, wherein R3 is n. In another embodiment, R3 is Cl. In another embodiment, R3 is F. In another embodiment, R3 is CN. In another embodiment, R3 is C1-C6 alkyl wherein said C1-C6 alkyl is substituted with 0-6 halogen. In another embodiment, R3 is t—butyl. In another embodiment, R3 is CF3. In r embodiment, R3 is .
In another embodiment, the invention features a compound of formula I-F or formula I’-F and the attendant definitions, wherein R5 is halogen. In another embodiment, R5 is Cl. In another embodiment, R5 is F. In another embodiment, R5 is CN. In r ment, R5 is -X-RX. In another embodiment, R5 is -X-RX wherein RX is absent. In another ment, R5 is -X-RX wherein RX is absent and X is C1-C6 alkyl wherein said C1-C6 alkyl is substituted with 0-6 halogen. In another embodiment, R5 is CH3. In another embodiment, R5 is -X-RX wherein RX is absent and X is C1-C6 alkyl wherein said C1-C6 alkyl is substituted with 0-6 halogen wherein one CH2 unit of said C1-C6 alkyl is replaced with -O-. In another embodiment, R5 is OCH3, OCH2CH3, ZCHg, or OCH(CH3)2. In another embodiment, R5 is OCH3. In another embodiment, R5 is CHZOH. In another embodiment, R5 is OCF3. In another embodiment, R5 is OCHFZ.
In another ment, the invention features a compound of formula I-F or formula I’-F and the ant definitions, wherein R7 is halogen. In another embodiment, R7 is Cl. In another embodiment, R7 is F. In another embodiment, R7 is CN. In another embodiment, R7 is -X-RX. In another ment, R7 is -X-RX wherein RX is absent. In another embodiment, R7 is -X-RX wherein RX is absent and X is C1-C6 alkyl wherein said C1-C6 alkyl is substituted with 0-6 halogen. In another embodiment, R7 is CH3, CH2CH3, CH2CH2CH3 or isopropyl. In another embodiment, R7 is CF3. In another embodiment, R7 is -X-RX wherein RX is absent and X is C1-C6 alkyl wherein said C1-C6 alkyl is substituted with 0-6 halogen wherein two non-adjacent CH2 units of said C1-C6 alkyl are replaced with -O-. In another embodiment, R7 is OCHZCHZOCHg. In another embodiment, R7 is -X-RX n RX is absent and X is C1-C6 alkyl wherein said C1-C6 alkyl is tuted with 0-6 halogen wherein one CH2 unit of said C1-C6 alkyl is replaced with -O-.
In another embodiment, R7 is OCH3, OCH2CH3, OCHZCHZCHg, OC(CH3)3, OCHZCHZCH(CH3)2, or CHZCHZOCHg. In another embodiment, R7 is OCF3, OCH2CF3, ZCHZCFg, or OCHFZ.
In another embodiment, the invention features a nd of formula I-F or formula I’-F wherein R7 is -X-RX wherein X is a bond and RX is C3-C3 cycloaliphatic and said C3-C3 liphatic is substituted with 0-3 substituents selected from halogen and C1-C4 alkyl. In another embodiment, R7 is -X-RX wherein X is a bond and RX is cyclopropyl.
In another embodiment, the invention features a compound of formula I-F or formula I’-F and the attendant definitions, wherein R7 is -X-RX wherein X is C1-C6 alkyl wherein said C1-C6 alkyl is tuted with 0-6 halogen wherein one CH2 unit of said C1-C6 alkyl is replaced with -O- and RX is C3-C3 cycloaliphatic and said C3-C3 cycloaliphatic is substituted with up 0-3 substituents selected from halogen and C1-C4 alkyl. In another embodiment, R7 is -X- RX wherein X is OCHZ and RX is cyclopropyl.
In another embodiment, the invention features a compound of formula I-F or formula I’-F and the attendant definitions, wherein p is zero. In another embodiment, p is an integer from 1 to 4 and R8 is halogen. In another embodiment, p is an integer from 1 to 4 and R8 is Cl. In r embodiment, p is an integer from 1 to 4 and R8 is C1-C6 alkyl wherein said C1-C6 alkyl is tuted with 0-6 halogen wherein one CH2 unit of said C1-C6 alkyl is replaced with -O-.
In another embodiment, p is an r from 1 to 4 and R8 is CH3. In another ment, p is an integer from 1 to 4 and R8 is OH.
] In another embodiment, the invention features a compound of formula I-F or formula I’-F and the attendant definitions, wherein ring A is selected from: .N'IVV | WIVV Jv'vv w'vv C' F /0 o F CI /0 /O /O /O F F F F 9 9 9 9 9 9 9 9 MN I Jv'vv CI or CI In another aspect, the invention provides a compound of formula LC or a I'-G: (Ran. (R8)p o WOH o k R2 \ Y R2 \ OH H H R3 O R3 O R5 R5 G @ R7 R7 I-G I'-G or a pharmaceutically acceptable salt thereof, wherein, independently for each occurrence: YisCorN; 2014/013667 R2 is halogen, CN, or C1-C6 alkyl n said C1-C6 alkyl is substituted with 0-6 halogen, wherein up to two non-adjacent CH2 units of said C1-C6 alkyl may be replaced with -O-; R3 is halogen, CN, or C1-C6 alkyl wherein said C1-C6 alkyl is substituted with 0-6 halogen, wherein up to two non-adjacent CH2 units of said C1-C6 alkyl may be replaced with -O-; R5 is halogen, CN, or —X-RX; R7 is halogen, CN, or —X-RX; X is a bond or C1-C6 alkyl wherein said C1-C6 alkyl is substituted with 0-6 halogen, wherein up to two non-adjacent CH2 units of said C1-C6 alkyl may be replaced with -O-; RX is absent, H, or C3-C3 cycloaliphatic, wherein up to two non-adjacent CH2 units of said C3-C3 cycloaliphatic may be replaced with -O- and said C3-C3 cycloaliphatic is substituted with 0-3 substituents ed from halogen and C1-C4 alkyl; R8 is halogen, or C1-C6 alkyl wherein said C1-C6 alkyl is substituted with 0-6 halogen, wherein up to two non-adjacent CH2 units of said C1-C6 alkyl may be replaced with -O-; and p is an integer from 0 to 4 inclusive.
In one ment, the invention features a compound of formula I-G or formula I’-G and the attendant definitions, Y is C. In another embodiment, Y is N.
In another embodiment, the invention features a compound of formula I-G or formula I’-G and the attendant definitions, wherein R2 is halogen. In another embodiment, R2 is Cl. In another ment, R2 is F. In r ment, R2 is CN. In another embodiment, R2 is C1-C6 alkyl wherein said C1-C6 alkyl is substituted with 0-6 halogen. In r embodiment, R2 is CF3. In another embodiment, R2 is C1-C6 alkyl wherein said C1-C6 alkyl is substituted with 0-6 halogen wherein one CH2 unit of said C1-C6 alkyl is replaced with -O-. In another embodiment, R2 is OCF3. In another embodiment, R2 is F, Cl, CN, CF3 or OCF3.
In another ment, the invention features a compound of formula I-G or formula I’-G and the attendant tions, wherein R3 is halogen. In another embodiment, R3 is Cl. In another embodiment, R3 is F. In r embodiment, R3 is CN. In another embodiment, R3 is C1-C6 alkyl wherein said C1-C6 alkyl is substituted with 0-6 halogen. In another embodiment, R3 is t—butyl. In another embodiment, R3 is CF3. In another embodiment, R3 is CF2CF3.
In another embodiment, the invention features a nd of formula I-G or a I’-G and the attendant definitions, wherein R5 is halogen. In another embodiment, R5 is Cl. In another ment, R5 is F. In another embodiment, R5 is CN. In another embodiment, R5 is -X-RX. In another embodiment, R5 is -X-RX wherein RX is absent. In another embodiment, R5 is -X-RX wherein RX is absent and X is C1-C6 alkyl wherein said C1-C6 alkyl is substituted with 0-6 halogen. In another embodiment, R5 is CH3. In another embodiment, R5 is -X-RX wherein RX is absent and X is C1-C6 alkyl wherein said C1-C6 alkyl is substituted with 0-6 n wherein one CH2 unit of said C1-C6 alkyl is replaced with -O-. In another embodiment, R5 is OCH3, OCH2CH3, OCHZCHZCHg, or OCH(CH3)2. In another embodiment, R5 is OCH3. In r embodiment, R5 is CHZOH. In another embodiment, R5 is OCF3. In another embodiment, R5 is OCHFZ.
In another ment, the invention features a compound of formula I-G or formula I’-G and the attendant definitions, wherein R7 is halogen. In another embodiment, R7 is Cl. In another embodiment, R7 is F. In another ment, R7 is CN. In another embodiment, R7 is -X-RX. In another embodiment, R7 is -X-RX wherein RX is absent. In r ment, R7 is -X-RX wherein RX is absent and X is C1-C6 alkyl wherein said C1-C6 alkyl is substituted with 0-6 halogen. In another embodiment, R7 is CH3, CH2CH3, CH3 or isopropyl. In r embodiment, R7 is CF3. In another embodiment, R7 is -X-RX wherein RX is absent and X is C1-C6 alkyl wherein said C1-C6 alkyl is substituted with 0-6 halogen wherein two non-adjacent CH2 units of said C1-C6 alkyl are replaced with -O-. In another embodiment, R7 is OCHZCHZOCHg. In another embodiment, R7 is -X-RX wherein RX is absent and X is C1-C6 alkyl wherein said C1-C6 alkyl is substituted with 0-6 halogen wherein one CH2 unit of said C1-C6 alkyl is replaced with -O-.
In another embodiment, R7 is OCH3, OCH2CH3, ZCHg, OC(CH3)3, OCHZCHZCH(CH3)2, or CHZCHZOCHg. In another embodiment, R7 is OCF3, OCH2CF3, OCHZCHZCHZCFg, or OCHFZ.
In r embodiment, the invention features a compound of formula I-G or formula I’-G wherein R7 is -X-RX wherein X is a bond and RX is C3-C3 liphatic and said C3-C3 cycloaliphatic is substituted with 0-3 substituents ed from halogen and C1-C4 alkyl. In another embodiment, R7 is -X-RX wherein X is a bond and RX is cyclopropyl.
In another embodiment, the ion features a compound of formula I-G or formula I’-G and the attendant definitions, wherein R7 is -X-RX wherein X is C1-C6 alkyl wherein said C1-C6 alkyl is substituted with 0-6 halogen wherein one CH2 unit of said C1-C6 alkyl is replaced with -O- and RX is C3-C3 cycloaliphatic and said C3-C3 cycloaliphatic is substituted with up 0-3 substituents selected from halogen and C1-C4 alkyl. In another embodiment, R7 is -X- RX wherein X is OCHZ and RX is cyclopropyl.
In another embodiment, the invention features a compound of formula I-G or formula I’-G and the attendant definitions, wherein p is zero. In another embodiment, p is an r from 1 to 4 and R8 is halogen. In r ment, p is an integer from 1 to 4 and R8 is Cl. In another embodiment, p is an integer from 1 to 4 and R8 is C1-C6 alkyl wherein said C1-C6 alkyl is substituted with 0-6 halogen wherein one CH2 unit of said C1-C6 alkyl is replaced with -O-.
In another embodiment, p is an integer from 1 to 4 and R8 is CH3. In another embodiment, p is an integer from 1 to 4 and R8 is OH.
In another embodiment, the invention features a compound of formula I-G or a I’-G and the attendant definitions, wherein ring A is selected from: -3 6- C' F /0 o F CI /0 /O /O /O F F F F 9 9 9 9 9 9 9 9 MN I .Iv'vv CI or CI In another aspect, the invention provides a compound of formula I-H or a I'-H: (R8)p (R8)p R1 / A o , | OH R1 o , IY \ Y \ OH H H R3 0 R3 0 R7 R7 1-H I'-H or a pharmaceutically acceptable salt thereof, wherein, independently for each occurrence: Y is C or N; R1 is halogen, CN, or C1-C6 alkyl wherein said C1-C6 alkyl is substituted with 0-6 halogen and wherein up to two jacent CH2 units of said C1-C6 alkyl may be replaced with -O-; R3 is halogen, CN, or C1-C6 alkyl wherein said C1-C6 alkyl is substituted with 0-6 halogen, wherein up to two non-adjacent CH2 units of said C1-C6 alkyl may be ed with -O-; R5 is halogen, CN, or —X-RX; R7 is halogen, CN, or —X-RX; X is a bond or C1-C6 alkyl wherein said C1-C6 alkyl is substituted with 0-6 halogen, wherein up to two jacent CH2 units of said C1-C6 alkyl may be replaced with -O-; RX is absent, H, or C3-C3 cycloaliphatic, wherein up to two non-adjacent CH2 units of said C3-C3 cycloaliphatic may be replaced with -O- and said C3-C3 cycloaliphatic is substituted with 0-3 substituents selected from halogen and C1-C4 alkyl; R8 is halogen, or C1-C6 alkyl wherein said C1-C6 alkyl is substituted with 0-6 halogen, wherein up to two non-adjacent CH2 units of said C1-C6 alkyl may be replaced with -O-; and p is an integer from 0 to 4 inclusive.
In one embodiment, the invention features a compound of formula I-H or formula I’-H and the attendant definitions, Y is C. In another embodiment, Y is N.
In another embodiment, the invention features a compound of formula I-H or formula I’-H and the attendant definitions, n R1 is n. In another ment, R1 is CN. In r embodiment, R1 is C1-C6 alkyl wherein said C1-C6 alkyl is substituted with 0-6 halogen. In another embodiment, R1 is CF3.
In another embodiment, the ion features a compound of formula I-H or formula I’-H and the ant definitions, wherein R3 is halogen. In another embodiment, R3 is Cl. In another embodiment, R3 is F. In another embodiment, R3 is CN. In another embodiment, R3 is C1-C6 alkyl n said C1-C6 alkyl is substituted with 0-6 halogen. In another ment, R3 is t—butyl. In another ment, R3 is CF3. In another embodiment, R3 is CF2CF3.
In another embodiment, the invention features a compound of formula I-H or a I’-H and the attendant definitions, wherein R5 is halogen. In another embodiment, R5 is Cl. In another embodiment, R5 is F. In another embodiment, R5 is CN. In r embodiment, R5 is -X-RX. In another embodiment, R5 is -X-RX n RX is absent. In r embodiment, R5 is -X-RX n RX is absent and X is C1-C6 alkyl wherein said C1-C6 alkyl is substituted with 0-6 halogen. In another embodiment, R5 is CH3. In another embodiment, R5 is -X-RX n RX is absent and X is C1-C6 alkyl wherein said C1-C6 alkyl is substituted with 0-6 halogen wherein one CH2 unit of said C1-C6 alkyl is replaced with -O-. In another embodiment, R5 is OCH3, OCH2CH3, OCHZCHZCHg, or OCH(CH3)2. In another embodiment, R5 is OCH3. In another ment, R5 is CHZOH. In another embodiment, R5 is OCF3. In another embodiment, R5 is OCHFZ.
In another embodiment, the invention features a compound of formula I-H or formula I’-H and the attendant definitions, wherein R7 is halogen. In another embodiment, R7 is Cl. In another embodiment, R7 is F. In another embodiment, R7 is CN. In another ment, R7 is -X-RX. In r embodiment, R7 is -X-RX wherein RX is absent. In another embodiment, R7 is -X-RX wherein RX is absent and X is C1-C6 alkyl wherein said C1-C6 alkyl is substituted with 0-6 halogen. In another embodiment, R7 is CH3, CH2CH3, CH2CH2CH3 or isopropyl. In another embodiment, R7 is CF3. In another embodiment, R7 is -X-RX wherein RX is absent and X is C1-C6 alkyl wherein said C1-C6 alkyl is substituted with 0-6 halogen wherein two non-adjacent CH2 units of said C1-C6 alkyl are replaced with -O-. In another embodiment, R7 is OCHZCHZOCHg. In another embodiment, R7 is -X-RX wherein RX is absent and X is C1-C6 alkyl wherein said C1-C6 alkyl is substituted with 0-6 halogen n one CH2 unit of said C1-C6 alkyl is replaced with -O-.
In another embodiment, R7 is OCH3, OCH2CH3, OCHZCHZCHg, OC(CH3)3, OCHZCHZCH(CH3)2, or CHZCHZOCHg. In another embodiment, R7 is OCF3, OCH2CF3, OCHZCHZCHZCFg, or OCHFZ.
In another embodiment, the invention features a compound of formula I-H or formula I’-H n R7 is -X-RX wherein X is a bond and RX is C3-C3 cycloaliphatic and said C3-C3 cycloaliphatic is substituted with 0-3 substituents selected from halogen and C1-C4 alkyl. In another embodiment, R7 is -X-RX wherein X is a bond and RX is cyclopropyl.
In another embodiment, the invention features a compound of formula I-H or formula I’-H and the attendant definitions, wherein R7 is -X-RX wherein X is C1-C6 alkyl wherein said C1-C6 alkyl is substituted with 0-6 halogen wherein one CH2 unit of said C1-C6 alkyl is replaced with -O- and RX is C3-C3 cycloaliphatic and said C3-C3 cycloaliphatic is tuted with up 0-3 substituents selected from halogen and C1-C4 alkyl. In another embodiment, R7 is -X- RX wherein X is OCHZ and RX is cyclopropyl.
In r embodiment, the invention es a compound of a I-H or formula I’-H and the attendant definitions, wherein p is zero. In another embodiment, p is an integer from 1 to 4 and R8 is halogen. In another embodiment, p is an integer from 1 to 4 and R8 is Cl. In another ment, p is an r from 1 to 4 and R8 is C1-C6 alkyl n said C1-C6 alkyl is substituted with 0-6 halogen wherein one CH2 unit of said C1-C6 alkyl is replaced with -O-.
In another embodiment, p is an integer from 1 to 4 and R8 is CH3. In another ment, p is an integer from 1 to 4 and R8 is OH.
In another embodiment, the invention features a compound of formula I-H or formula I’-H and the attendant definitions, n ring A is selected from: .N'IVV | WIVV Jv'vv w'vv C' F /0 o F CI /0 /O /O /O F F F F 9 9 9 9 9 9 9 9 MN I .N'w CI or CI In another aspect, the invention provides a compound of formula I-J or formula I'-J: (Ran.MW (Ran.
/ \//\ R2 \ Y R2 \ OH o o R7 R7 I-J I'-J or a pharmaceutically acceptable salt thereof, wherein, ndently for each occurrence: Y is C or N; R2 is halogen, CN, or C1-C6 alkyl wherein said C1-C6 alkyl is substituted with 0-6 halogen, wherein up to two non-adjacent CH2 units of said C1-C6 alkyl may be replaced with -O-; R7 is halogen, CN, or —X-RX; X is a bond or C1-C6 alkyl wherein said C1-C6 alkyl is substituted with 0-6 halogen, wherein up to two non-adjacent CH2 units of said C1-C6 alkyl may be replaced with -O-; RX is absent, H, or C3-C3 cycloaliphatic, wherein up to two non-adjacent CH2 units of said C3-C3 cycloaliphatic may be replaced with -O- and said C3-C3 cycloaliphatic is tuted with 0-3 substituents selected from halogen and C1-C4 alkyl; R8 is halogen, or C1-C6 alkyl wherein said C1-C6 alkyl is substituted with 0-6 halogen, wherein up to two non-adjacent CH2 units of said C1-C6 alkyl may be replaced with -O-; and p is an integer from 0 to 4 inclusive.
In one embodiment, the invention features a compound of formula I-J or formula I’-J and the attendant definitions, Y is C. In another embodiment, Y is N.
In another embodiment, the invention features a nd of formula I-J or formula I’-J and the attendant definitions, wherein R2 is halogen. In r embodiment, R2 is Cl. In another ment, R2 is F. In another embodiment, R2 is CN. In another embodiment, R2 is C1-C6 alkyl wherein said C1-C6 alkyl is tuted with 0-6 halogen. In another embodiment, R2 is CF3. In another embodiment, R2 is C1-C6 alkyl wherein said C1-C6 alkyl is substituted with 0-6 n n one CH2 unit of said C1-C6 alkyl is replaced with -O-. In another embodiment, R2 is OCFg. In another embodiment, R2 is F, Cl, CN, CF3 or OCFg.
In another embodiment, the invention features a compound of formula I-J or formula I’-J and the attendant definitions, wherein R7 is halogen. In another embodiment, R7 is 2014/013667 Cl. In another embodiment, R7 is F. In another embodiment, R7 is CN. In another ment, R7 is -X-RX. In another embodiment, R7 is -X-RX wherein RX is absent. In another embodiment, R7 is -X-RX wherein RX is absent and X is C1-C6 alkyl wherein said C1-C6 alkyl is substituted with 0-6 halogen. In another embodiment, R7 is CH3, CH2CH3, CH2CH2CH3 or isopropyl. In another embodiment, R7 is CF3. In another embodiment, R7 is -X-RX wherein RX is absent and X is C1-C6 alkyl wherein said C1-C6 alkyl is substituted with 0-6 halogen wherein two non-adjacent CH2 units of said C1-C6 alkyl are replaced with -O-. In another embodiment, R7 is OCHZCHZOCHg. In another embodiment, R7 is -X-RX wherein RX is absent and X is C1-C6 alkyl wherein said C1-C6 alkyl is tuted with 0-6 halogen wherein one CH2 unit of said C1-C6 alkyl is replaced with -O-.
In another ment, R7 is OCH3, OCH2CH3, OCHZCHZCHg, OC(CH3)3, OCHZCHZCH(CH3)2, or CHZCHZOCHg. In another embodiment, R7 is OCFg, OCH2CF3, OCHZCHZCHZCFg, or OCHFZ.
In another embodiment, the invention features a compound of a I-J or formula I’-J wherein R7 is -X-RX wherein X is a bond and RX is C3-C3 cycloaliphatic and said C3-C3 cycloaliphatic is substituted with 0-3 substituents selected from halogen and C1-C4 alkyl. In another embodiment, R7 is -X-RX wherein X is a bond and RX is cyclopropyl.
In another embodiment, the invention features a compound of formula I-J or formula I’-J and the attendant tions, wherein R7 is -X-RX wherein X is C1-C6 alkyl wherein said C1-C6 alkyl is substituted with 0-6 halogen wherein one CH2 unit of said C1-C6 alkyl is replaced with -O- and RX is C3-C3 cycloaliphatic and said C3-C3 cycloaliphatic is substituted with up 0-3 substituents selected from halogen and C1-C4 alkyl. In r embodiment, R7 is -X-RX wherein X is OCHZ and RX is cyclopropyl.
In another ment, the invention features a compound of formula I-J or a I’-J and the attendant definitions, wherein p is zero. In another embodiment, p is an integer from 1 to 4 and R8 is halogen. In another ment, p is an integer from 1 to 4 and R8 is Cl. In r embodiment, p is an r from 1 to 4 and R8 is C1-C6 alkyl wherein said C1-C6 alkyl is substituted with 0-6 halogen wherein one CH2 unit of said C1-C6 alkyl is replaced with -O-.
In another embodiment, p is an integer from 1 to 4 and R8 is CH3. In r embodiment, p is an r from 1 to 4 and R8 is OH.
In another embodiment, the invention features a compound of formula I-J or formula I’-J and the attendant definitions, wherein ring A is selected from: In another aspect, the ion provides a compound of formula I-K or formula I'-K: (R8)p (R8)P o / ' OH 0 \ Y \ Y \ OH N M R3 0 R3 0 R7 R7 I-K I'-K or a pharmaceutically acceptable salt f, wherein, independently for each ence: Y is C or N; R3 is halogen, CN, or C1-C6 alkyl wherein said C1-C6 alkyl is substituted with 0-6 halogen, wherein up to two non-adjacent CH2 units of said C1-C6 alkyl may be replaced with -O-; R7 is halogen, CN, or —X-RX; X is a bond or C1-C6 alkyl wherein said C1-C6 alkyl is substituted with 0-6 halogen, wherein up to two non-adjacent CH2 units of said C1-C6 alkyl may be replaced with -O-; RX is absent, H, or C3-C3 cycloaliphatic, n up to two non-adjacent CH2 units of said C3-C3 cycloaliphatic may be replaced with -O- and said C3-C3 cycloaliphatic is substituted with 0-3 substituents selected from halogen and C1-C4 alkyl; R8 is halogen, or C1-C6 alkyl wherein said C1-C6 alkyl is substituted with 0-6 halogen, wherein up to two non-adjacent CH2 units of said C1-C6 alkyl may be replaced with -O-; and p is an integer from 0 to 4 inclusive.
In one embodiment, the invention features a compound of formula I-K or formula I’-K and the attendant definitions, Y is C. In r embodiment, Y is N.
In another ment, the invention features a compound of a I-K or formula I’-K and the attendant definitions, wherein R3 is halogen. In another embodiment, R3 is Cl. In another embodiment, R3 is F. In another embodiment, R3 is CN. In another embodiment, R3 is C1-C6 alkyl wherein said C1-C6 alkyl is substituted with 0-6 halogen. In another embodiment, R3 is l. In another embodiment, R3 is CF3. In another embodiment, R3 is CF2CF3.
In another embodiment, the invention features a compound of formula I-K or formula I’-K and the attendant definitions, wherein R7 is halogen. In another embodiment, R7 is Cl. In another embodiment, R7 is F. In another embodiment, R7 is CN. In another embodiment, R7 is -X-RX. In another ment, R7 is -X-RX wherein RX is absent. In another embodiment, R7 is -X-RX wherein RX is absent and X is C1-C6 alkyl wherein said C1-C6 alkyl is substituted with 0-6 halogen. In another embodiment, R7 is CH3, CH2CH3, CH2CH2CH3 or isopropyl. In another embodiment, R7 is CF3. In another embodiment, R7 is -X-RX wherein RX is absent and X is C1-C6 alkyl wherein said C1-C6 alkyl is substituted with 0-6 halogen wherein two non-adjacent CH2 units of said C1-C6 alkyl are replaced with -O-. In another embodiment, R7 is ZOCHg. In another ment, R7 is -X-RX wherein RX is absent and X is C1-C6 alkyl n said C1-C6 alkyl is substituted with 0-6 halogen wherein one CH2 unit of said C1-C6 alkyl is replaced with -O-.
In r embodiment, R7 is OCH3, OCH2CH3, OCHZCHZCHg, OC(CH3)3, ZCH(CH3)2, or CHZCHZOCHg. In another embodiment, R7 is OCF3, OCH2CF3, OCHZCHZCHZCFg, or OCHFZ.
In another embodiment, the invention features a compound of formula I-K or formula I’-K wherein R7 is -X-RX wherein X is a bond and RX is C3-C3 cycloaliphatic and said C3-C3 cycloaliphatic is substituted with 0-3 substituents ed from halogen and C1-C4 alkyl. In another embodiment, R7 is -X-RX wherein X is a bond and RX is cyclopropyl.
In another embodiment, the invention features a compound of formula I-K or formula I’-K and the attendant definitions, wherein R7 is -X-RX wherein X is C1-C6 alkyl wherein said C1-C6 alkyl is substituted with 0-6 halogen wherein one CH2 unit of said C1-C6 alkyl is replaced with -O- and RX is C3-C3 liphatic and said C3-C3 cycloaliphatic is substituted with up 0-3 substituents selected from halogen and C1-C4 alkyl. In another ment, R7 is -X- RX wherein X is OCHZ and RX is cyclopropyl.
In another ment, the invention features a compound of formula I-K or formula I’-K and the attendant definitions, wherein p is zero. In another embodiment, p is an integer from 1 to 4 and R8 is halogen. In another embodiment, p is an integer from 1 to 4 and R8 is Cl. In another embodiment, p is an integer from 1 to 4 and R8 is C1-C6 alkyl wherein said C1-C6 alkyl is substituted with 0-6 halogen wherein one CH2 unit of said C1-C6 alkyl is replaced with -O-.
In another embodiment, p is an integer from 1 to 4 and R8 is CH3. In another embodiment, p is an integer from 1 to 4 and R8 is OH.
In r embodiment, the invention features a compound of a I-K or formula I’-K and the ant definitions, wherein ring A is selected from: o 0 o , F . x0 .. 4F 1 F ' 0 F F /O , F' , , , or in another aspect, the invention provides a nd of formula I-L or formula l'-'L (Rah, ‘ .\’\/ OH > I R2- '1 'OH \ Y {:11 .
R3 I g , l-L ‘ l L or a pharmaceutically acceptable salt thereof, wherein, independently for eachloccurrence: Y15 C or N; 2is halogen, CN, or C1-C6 alkyl wherein said C.-C6 alkyl18 substituted With 0-6 halogen, wherein up to two non-adjacent CH; units of said C1-C5 alkyl may be replaced with -O-; ' R3 is halogen, CN, or C1-C6 alkyl wherein said C1¥C5 alkyl is tuted with 0-6 halogen, ' 'wherein up to two non-adjacent CH2 units of said C1-C5 alkylimay be replaced with -O-; R7 is.hal0gen, CN, or —X-Rx; X'rs a bond or C1-C6 alkyl wherein said C.-C6 alkyl15 subStituted with 0—6 halogen, n up to two non-adjacent CH2 units of said C1-C6 alkyl may be replaced with -;O- Rx is absent, H, or C3-C3 cycloaliphatic, whereinup to tWo non-adjacent CH2 units of said C3-C5 cycloali'phatic may be replaced with -O- and said C1—C3 cycloaliphatic1s substituted with 0-3 substituents selected from n and C.-C4 alkyl; R? is halogen, or C1-C5 alkyl n saidC1-C6 5 substituted with 046 halogen, wherein up - to two non-adjaCent CH2 units of said Cl-C6 alkyl may be replaced with -O-; and pis an integer from Oito 4 inclusive. . 1 In one embodiment,«the invention features a compound offormula I-L‘ or RECTIFIED SHEET (RULE 91) ISA/EP formula I’-L and the attendant definitions, Y is C. In another embodiment, Y is N.
In r embodiment, the invention features a compound of formula I-L or formula I’-L and the attendant definitions, wherein R2 is halogen. In another embodiment, R2 is Cl. In another embodiment, R2 is F. In another embodiment, R2 is CN. In another embodiment, R2 is C1-C6 alkyl wherein said C1-C6 alkyl is substituted with 0-6 halogen. In another embodiment, R2 is CF3. In r embodiment, R2 is C1-C6 alkyl wherein said C1-C6 alkyl is substituted with 0-6 halogen wherein one CH2 unit of said C1-C6 alkyl is replaced with -O-. In another ment, R2 is OCF3. In another embodiment, R2 is F, Cl, CN, CF3 or OCF3.
] In another embodiment, the invention features a compound of formula I-L or formula I’-L and the attendant tions, wherein R3 is halogen. In another embodiment, R3 is Cl. In another embodiment, R3 is F. In another embodiment, R3 is CN. In another embodiment, R3 is C1-C6 alkyl n said C1-C6 alkyl is substituted with 0-6 halogen. In another embodiment, R3 is t—butyl. In another embodiment, R3 is CF3. In another embodiment, R3 is CFZCF3.
In another embodiment, the invention features a nd of formula I-L or formula I’-L and the attendant definitions, wherein R7 is halogen. In another embodiment, R7 is Cl. In another embodiment, R7 is F. In another ment, R7 is CN. In another embodiment, R7 is -X-RX. In another embodiment, R7 is -X-RX wherein RX is absent. In another embodiment, R7 is -X-RX wherein RX is absent and X is C1-C6 alkyl wherein said C1-C6 alkyl is substituted with 0-6 halogen. In another embodiment, R7 is CH3, CHZCH3, CHZCHZCH3 or isopropyl. In another embodiment, R7 is CF3. In another embodiment, R7 is -X-RX wherein RX is absent and X is C1-C6 alkyl wherein said C1-C6 alkyl is substituted with 0-6 halogen wherein two non-adjacent CH2 units of said C1-C6 alkyl are replaced with -O-. In r embodiment, R7 is ZOCH3. In r embodiment, R7 is -X-RX wherein RX is absent and X is C1-C6 alkyl wherein said C1-C6 alkyl is substituted with 0-6 halogen n one CH2 unit of said C1-C6 alkyl is replaced with -O-.
In another ment, R7 is OCH3, OCHZCH3, OCHZCHZCH3, OC(CH3)3, OCHZCHZCH(CH3)2, or CHZCHZOCH3. In another ment, R7 is OCF3, OCHZCF3, OCHZCHZCHZCF3, or OCHFZ.
In another embodiment, the invention features a compound of formula I-L or formula I’-L wherein R7 is -X-RX wherein X is a bond and RX is C3-C3 cycloaliphatic and said C3-C3 cycloaliphatic is substituted with 0-3 substituents selected from halogen and C1-C4 alkyl. In another embodiment, R7 is -X-RX wherein X is a bond and RX is cyclopropyl.
In another embodiment, the invention features a compound of formula I-L or formula I’-L and the attendant definitions, wherein R7 is -X-RX wherein X is C1-C6 alkyl wherein said C1-C6 alkyl is substituted with 0-6 halogen n one CH2 unit of said C1-C6 alkyl is replaced with -O- and RX is C3-C3 cycloaliphatic and said C3-C3 cycloaliphatic is tuted with up 0-3 substituents selected from halogen and C1-C4 alkyl. In another embodiment, R7 is -X- RX wherein X is OCHZ and RX is cyclopropyl.
In another embodiment, the invention es a compound of formula I-L or a I’-L and the attendant definitions, wherein p is zero. In another embodiment, p is an integer from 1 to 4 and R8 is halogen. In r embodiment, p is an integer from 1 to 4 and R8 is Cl. In another embodiment, p is an integer from 1 to 4 and R8 is C1-C6 alkyl wherein said C1-C6 alkyl is substituted with 0-6 halogen wherein one CH2 unit of said C1-C6 alkyl is replaced with -O-.
In another embodiment, p is an integer from 1 to 4 and R8 is CH3. In another embodiment, p is an integer from 1 to 4 and R8 is OH.
In another embodiment, the invention features a compound of a I-L or formula I’-L and the attendant definitions, wherein ring A is selected from: X0 F~PF 1 FF,F,/O,F,or 0.
In r aspect, the invention provides a compound of formula I-M or formula I'-M: (R8)p ( )p%R8 R1 / o , OH R1 o , I IY \ Y \ OH H H R3 0 R3 0 R7 R7 I-M I'-M or a pharmaceutically acceptable salt thereof, wherein, independently for each occurrence: Y is C or N; R1 is halogen, CN, or C1-C6 alkyl wherein said C1-C6 alkyl is tuted with 0-6 halogen and wherein up to two jacent CH2 units of said C1-C6 alkyl may be replaced with -O-; R3 is halogen, CN, or C1-C6 alkyl wherein said C1-C6 alkyl is substituted with 0-6 halogen, wherein up to two non-adjacent CH2 units of said C1-C6 alkyl may be replaced with -O-; R7 is halogen, CN, or —X-RX; X is a bond or C1-C6 alkyl wherein said C1-C6 alkyl is substituted with 0-6 halogen, wherein up to two non-adjacent CH2 units of said C1-C6 alkyl may be replaced with -O-; RX is absent, H, or C3-C3 cycloaliphatic, wherein up to two non-adjacent CH2 units of said C3-C3 cycloaliphatic may be replaced with -O- and said C3-C3 cycloaliphatic is substituted with 0-3 substituents selected from halogen and C1-C4 alkyl; R8 is halogen, or C1-C6 alkyl wherein said C1-C6 alkyl is substituted with 0-6 halogen, wherein up to two non-adjacent CH2 units of said C1-C6 alkyl may be ed with -O-; and p is an integer from 0 to 4 inclusive.
In one embodiment, the invention features a compound of formula I-M or formula I’-M and the attendant definitions, Y is C. In another embodiment, Y is N.
In another embodiment, the ion es a compound of formula IM or formula I’-M and the attendant definitions, wherein R1 is halogen. In r embodiment, R1 is CN. In another embodiment, R1 is C1-C6 alkyl wherein said C1-C6 alkyl is substituted with 0- 6 halogen. In another embodiment, R1 is CF3.
In another embodiment, the invention features a compound of formula I- M or formula I’-M and the attendant definitions, n R3 is halogen. In another embodiment, R3 is Cl. In r ment, R3 is F. In r embodiment, R3 is CN. In another embodiment, R3 is C1-C6 alkyl wherein said C1-C6 alkyl is tuted with 0-6 halogen. In r embodiment, R3 is t—butyl. In another embodiment, R3 is CF3. In another embodiment, R3 is CF2CF3.
In another embodiment, the invention features a nd of a I- M or formula I’-M and the attendant definitions, wherein R7 is n. In another embodiment, R7 is Cl. In another embodiment, R7 is F. In another embodiment, R7 is CN. In another embodiment, R7 is -X-RX. In another embodiment, R7 is -X-RX wherein RX is absent. In another embodiment, R7 is -X-RX wherein RX is absent and X is C1-C6 alkyl wherein said C1-C6 alkyl is substituted with 0-6 halogen. In another embodiment, R7 is CH3, CH2CH3, CH2CH2CH3 or pyl. In another embodiment, R7 is CF3. In another ment, R7 is -X-RX wherein RX is absent and X is C1-C6 alkyl wherein said C1-C6 alkyl is substituted with 0-6 halogen wherein two non-adjacent CH2 units of said C1-C6 alkyl are replaced with -O-. In another embodiment, R7 is OCHZCHZOCHg. In another embodiment, R7 is -X-RX wherein RX is absent and X is C1-C6 alkyl wherein said C1-C6 alkyl is substituted with 0-6 halogen wherein one CH2 unit of said C1-C6 alkyl is replaced with -O-. In another embodiment, R7 is OCH3, OCH2CH3, OCHZCHZCHg, OC(CH3)3, OCHZCHZCH(CH3)2, or CHZCHZOCHg. In another embodiment, R7 is OCF3, OCH2CF3, OCHZCHZCHZCFg, or OCHFZ.
In another embodiment, the invention features a compound of formula I- M or formula I’-M wherein R7 is -X-RX wherein X is a bond and RX is C3-C3 cycloaliphatic and said C3-C3 cycloaliphatic is substituted with 0-3 substituents selected from halogen and C1-C4 alkyl. In another embodiment, R7 is -X-RX wherein X is a bond and RX is cyclopropyl.
In another embodiment, the invention features a compound of formula IM or formula I’-M and the attendant definitions, wherein R7 is -X-RX wherein X is C1-C6 alkyl wherein said C1-C6 alkyl is substituted with 0-6 halogen wherein one CH2 unit of said C1-C6 alkyl is replaced with -O- and RX is C3-C3 cycloaliphatic and said C3-C3 liphatic is substituted with up 0-3 substituents selected from halogen and C1-C4 alkyl. In another embodiment, R7 is -X- RX wherein X is OCHZ and RX is cyclopropyl.
In another embodiment, the invention es a compound of a IM or a I’-M and the ant definitions, wherein p is zero. In another embodiment, p is an integer from 1 to 4 and R8 is n. In another ment, p is an integer from 1 to 4 and R8 is Cl. In another embodiment, p is an integer from 1 to 4 and R8 is C1-C6 alkyl wherein said C1-C6 alkyl is substituted with 0-6 halogen wherein one CH2 unit of said C1-C6 alkyl is replaced with -O-.
In another embodiment, p is an integer from 1 to 4 and R8 is CH3. In another ment, p is an integer from 1 to 4 and R8 is OH.
In another embodiment, the invention features a compound of formula I- M or formula I’-M and the attendant definitions, wherein ring A is selected from: X0 F‘PF F \QO F /O F or 9 9 9 9 ' In another aspect, the invention provides a compound of formula I-N or a I'-N: or a pharmaceutically acceptable salt thereof, wherein, independently for each occurrence: Y is C or N; R2 is halogen, CN, or C1-C6 alkyl wherein said C1-C6 alkyl is substituted with 0-6 halogen, wherein up to two non-adjacent CH2 units of said C1-C6 alkyl may be replaced with -O-; R5 is n, CN, or —X-RX; X is a bond or C1-C6 alkyl wherein said C1-C6 alkyl is substituted with 0-6 n, wherein up to two non-adjacent CH2 units of said C1-C6 alkyl may be replaced with -O-; RX is absent, H, or C3-C3 cycloaliphatic, wherein up to two non-adjacent CH2 units of said C3-C3 cycloaliphatic may be replaced with -O- and said C3-C3 liphatic is substituted with 0-3 substituents selected from halogen and C1-C4 alkyl; R8 is halogen, or C1-C6 alkyl wherein said C1-C6 alkyl is tuted with 0-6 halogen, n up to two non-adjacent CH2 units of said C1-C6 alkyl may be replaced with -O-; and p is an integer from 0 to 4 inclusive.
In one embodiment, the invention es a compound of formula I-N or formula I’-N and the attendant tions, Y is C. In another embodiment, Y is N.
In another embodiment, the invention features a compound of formula I-N or formula I’-N and the attendant definitions, wherein R2 is halogen. In another embodiment, R2 is Cl. In another embodiment, R2 is F. In another embodiment, R2 is CN. In another embodiment, R2 is C1-C6 alkyl wherein said C1-C6 alkyl is substituted with 0-6 halogen. In r ment, R2 is CF3. In another embodiment, R2 is C1-C6 alkyl wherein said C1-C6 alkyl is substituted with 0-6 halogen wherein one CH2 unit of said C1-C6 alkyl is ed with -O-. In another embodiment, R2 is OCF3. In another embodiment, R2 is F, Cl, CN, CF3 or OCF3.
In another embodiment, the invention features a compound of a I-N or formula I’-N and the attendant definitions, wherein R5 is halogen. In another embodiment, R5 is Cl. In another embodiment, R5 is F. In another embodiment, R5 is CN. In another embodiment, R5 is -X-RX. In r embodiment, R5 is -X-RX wherein RX is absent. In another ment, R5 is -X-RX wherein RX is absent and X is C1-C6 alkyl wherein said C1-C6 alkyl is substituted with 0-6 halogen. In another embodiment, R5 is CH3. In another embodiment, R5 is -X-RX wherein RX is absent and X is C1-C6 alkyl wherein said C1-C6 alkyl is substituted with 0-6 halogen wherein one CH2 unit of said C1-C6 alkyl is replaced with -O-. In another embodiment, R5 is OCH3, OCH2CH3, OCHZCHZCHg, or OCH(CH3)2. In another embodiment, R5 is OCH3. In another embodiment, R5 is CHZOH. In another embodiment, R5 is OCF3. In another embodiment, R5 is OCHFZ.
In another embodiment, the invention features a compound of formula I-N or formula I’-N and the ant definitions, n p is zero. In another embodiment, p is an r from 1 to 4 and R8 is halogen. In another embodiment, p is an integer from 1 to 4 and R8 is Cl. In another embodiment, p is an integer from 1 to 4 and R8 is C1-C6 alkyl wherein said C1-C6 alkyl is substituted with 0-6 n wherein one CH2 unit of said C1-C6 alkyl is replaced with -O-.
In another embodiment, p is an integer from 1 to 4 and R8 is CH3. In another embodiment, p is an integer from 1 to 4 and R8 is OH.
In another embodiment, the invention features a nd of formula I-N or formula I’-N and the attendant definitions, wherein ring A is selected from: ' I W I W'vv JVVV \(ob CI 0 ,or FYO\© , , .
In another aspect, the invention provides a compound of formula 1-0 or formula I'-O: (R8) (R8) 0 p\/ NA L/I OH O ’ \ Y \ OH R3 0 R3 0 R5 R5 O G 1-0 I'-O or a pharmaceutically able salt thereof, wherein, independently for each occurrence: Y is C or N; R3 is halogen, CN, or C1-C6 alkyl wherein said C1-C6 alkyl is substituted with 0-6 halogen, wherein up to two non-adjacent CH2 units of said C1-C6 alkyl may be replaced with -O-; R5 is halogen, CN, or —X-RX; X is a bond or C1-C6 alkyl n said C1-C6 alkyl is substituted with 0-6 halogen, wherein up to two non-adjacent CH2 units of said C1-C6 alkyl may be replaced with -O-; RX is absent, H, or C3-C3 liphatic, n up to two non-adjacent CH2 units of said C3-C3 cycloaliphatic may be replaced with -O- and said C3-C3 cycloaliphatic is substituted with 0-3 substituents selected from halogen and C1-C4 alkyl; R8 is halogen, or C1-C6 alkyl wherein said C1-C6 alkyl is substituted with 0-6 halogen, wherein up to two non-adjacent CH2 units of said C1-C6 alkyl may be replaced with -O-; and WO 20820 p is an integer from 0 to 4 inclusive.
In one embodiment, the invention features a compound of formula 1-0 or formula I’-O and the attendant ions, Y is C. In another ment, Y is N.
In another embodiment, the ion features a compound of formula 1-0 or formula I’-O and the attendant definitions, wherein R3 is halogen. In another embodiment, R3 is Cl. In another embodiment, R3 is F. In another embodiment, R3 is CN. In another embodiment, R3 is C1-C6 alkyl wherein said C1-C6 alkyl is substituted with 0-6 halogen. In r embodiment, R3 is t—butyl. In another embodiment, R3 is CF3. In another embodiment, R3 is CF2CF3.
In another ment, the ion features a compound of formula 1-0 or formula I’-O and the attendant definitions, wherein R5 is halogen. In another embodiment, R5 is Cl. In another embodiment, R5 is F. In another embodiment, R5 is CN. In another embodiment, R5 is -X-RX. In another embodiment, R5 is -X-RX wherein RX is absent. In another embodiment, R5 is -X-RX wherein RX is absent and X is C1-C6 alkyl wherein said C1-C6 alkyl is substituted with 0-6 halogen. In another embodiment, R5 is CH3. In another embodiment, R5 is -X-RX wherein RX is absent and X is C1-C6 alkyl wherein said C1-C6 alkyl is substituted with 0-6 n wherein one CH2 unit of said C1-C6 alkyl is replaced with -O-. In another embodiment, R5 is OCH3, OCH2CH3, OCHZCHZCHg, or OCH(CH3)2. In another embodiment, R5 is OCHg. In another embodiment, R5 is CHZOH. In another embodiment, R5 is OCF3. In r embodiment, R5 is OCHFZ.
In another embodiment, the invention es a compound of formula 1-0 or a I’-O and the ant definitions, wherein p is zero. In another embodiment, p is an integer from 1 to 4 and R8 is halogen. In another embodiment, p is an integer from 1 to 4 and R8 is Cl. In another embodiment, p is an integer from 1 to 4 and R8 is C1-C6 alkyl wherein said C1-C6 alkyl is substituted with 0-6 halogen wherein one CH2 unit of said C1-C6 alkyl is replaced with -O-.
In r embodiment, p is an integer from 1 to 4 and R8 is CH3. In another embodiment, p is an integer from 1 to 4 and R8 is OH.
In another embodiment, the invention features a nd of formula 1-0 or formula I’-O and the attendant definitions, wherein ring A is selected from: uv'vv ' W I W'vv .nm \rob CI 0 FYO 9 9 9 In another aspect, the invention provides a compound of formula LP or formula I'-P: (R8)kaOH (R8) l 0 p\4\ R2 \ Y R2 \ OH N N R3 O R3 O Rfifi R5 I-P I'-P or a pharmaceutically acceptable salt thereof, wherein, independently for each occurrence: Y is C or N; R2 is halogen, CN, or C1-C6 alkyl wherein said C1-C6 alkyl is substituted with 0-6 halogen, wherein up to two jacent CH2 units of said C1-C6 alkyl may be replaced with -O-; R3 is halogen, CN, or C1-C6 alkyl wherein said C1-C6 alkyl is substituted with 0-6 halogen, wherein up to two non-adjacent CH2 units of said C1-C6 alkyl may be replaced with -O-; R5 is halogen, CN, or —X-RX; X is a bond or C1-C6 alkyl wherein said C1-C6 alkyl is substituted with 0-6 halogen, wherein up to two jacent CH2 units of said C1-C6 alkyl may be replaced with -O-; RX is absent, H, or C3-C3 cycloaliphatic, wherein up to two non-adjacent CH2 units of said C3-C3 liphatic may be replaced with -O- and said C3-C3 cycloaliphatic is substituted with 0-3 substituents selected from halogen and C1-C4 alkyl; R8 is halogen, or C1-C6 alkyl n said C1-C6 alkyl is substituted with 0-6 halogen, n up to two non-adjacent CH2 units of said C1-C6 alkyl may be replaced with -O-; and p is an r from 0 to 4 inclusive.
In one embodiment, the invention features a compound of formula LP or formula I’-P and the attendant definitions, Y is C. In r embodiment, Y is N.
In another embodiment, the invention features a compound of formula I-P or formula I’-P and the attendant definitions, wherein R2 is halogen. In another embodiment, R2 is Cl. In another embodiment, R2 is F. In another embodiment, R2 is CN. In another embodiment, R2 is C1-C6 alkyl wherein said C1-C6 alkyl is substituted with 0-6 halogen. In another embodiment, R2 is CF3. In another ment, R2 is C1-C6 alkyl wherein said C1-C6 alkyl is substituted with 0-6 halogen wherein one CH2 unit of said C1-C6 alkyl is ed with -O-. In another embodiment, R2 is OCF3. In another embodiment, R2 is F, Cl, CN, CF3 or OCF3. 2014/013667 In another embodiment, the invention features a compound of formula I-P or formula I’-P and the attendant definitions, wherein R3 is halogen. In another embodiment, R3 is Cl. In another embodiment, R3 is F. In another embodiment, R3 is CN. In another ment, R3 is C1-C6 alkyl wherein said C1-C6 alkyl is substituted with 0-6 halogen. In another embodiment, R3 is t—butyl. In another embodiment, R3 is CF3. In another embodiment, R3 is CF2CF3.
In r embodiment, the invention features a compound of formula I-P or formula I’-P and the attendant definitions, wherein R5 is halogen. In another embodiment, R5 is Cl. In another embodiment, R5 is F. In another embodiment, R5 is CN. In another embodiment, R5 is -X-RX. In another embodiment, R5 is -X-RX wherein RX is absent. In another embodiment, R5 is -X-RX wherein RX is absent and X is C1-C6 alkyl wherein said C1-C6 alkyl is tuted with 0-6 halogen. In another embodiment, R5 is CH3. In another embodiment, R5 is -X-RX wherein RX is absent and X is C1-C6 alkyl wherein said C1-C6 alkyl is substituted with 0-6 halogen wherein one CH2 unit of said C1-C6 alkyl is replaced with -O-. In another ment, R5 is OCH3, OCH2CH3, OCHZCHZCHg, or OCH(CH3)2. In another embodiment, R5 is OCH3. In another embodiment, R5 is CHZOH. In another embodiment, R5 is OCF3. In another embodiment, R5 is OCHFZ.
In another embodiment, the invention features a compound of formula I-P or formula I’-P and the ant definitions, wherein p is zero. In another embodiment, p is an integer from 1 to 4 and R8 is halogen. In another embodiment, p is an integer from 1 to 4 and R8 is Cl. In another ment, p is an integer from 1 to 4 and R8 is C1-C6 alkyl wherein said C1-C6 alkyl is substituted with 0-6 halogen wherein one CH2 unit of said C1-C6 alkyl is replaced with -O-.
In r embodiment, p is an r from 1 to 4 and R8 is CH3. In another embodiment, p is an integer from 1 to 4 and R8 is OH.
In another ment, the invention features a compound of formula I-P or formula I’-P and the attendant definitions, wherein ring A is selected from: MN I W'vv .nm \rob CI 0 FYO , , , In another aspect, the ion es a compound of formula I-Q or formula I'-Q: 2014/013667 (Rap\“HoH (Rap 0 \fi R2 \ Y Rficfik \ OH N N H H o o 3 a R7 R7 I-Q I'-Q or a pharmaceutically acceptable salt thereof, wherein, independently for each occurrence: Y is C or N; R2 is halogen, CN, or C1-C6 alkyl wherein said C1-C6 alkyl is substituted with 0-6 halogen, wherein up to two non-adjacent CH2 units of said C1-C6 alkyl may be replaced with -O-; R6 is halogen, CN, or —X-RX; R7 is halogen, CN, or —X-RX; X is a bond or C1-C6 alkyl wherein said C1-C6 alkyl is substituted with 0-6 halogen, wherein up to two non-adjacent CH2 units of said C1-C6 alkyl may be replaced with -O-; RX is absent, H, or C3-C3 cycloaliphatic, wherein up to two non-adjacent CH2 units of said C3-C3 cycloaliphatic may be replaced with -O- and said C3-C3 cycloaliphatic is substituted with 0-3 substituents selected from halogen and C1-C4 alkyl; R8 is halogen, or C1-C6 alkyl wherein said C1-C6 alkyl is substituted with 0-6 n, wherein up to two non-adjacent CH2 units of said C1-C6 alkyl may be replaced with -O-; and p is an integer from 0 to 4 inclusive.
In one embodiment, the invention es a compound of formula I-Q or formula I’-Q and the attendant definitions, Y is C. In another embodiment, Y is N.
In another embodiment, the invention features a compound of formula I-Q or formula I’-Q and the attendant definitions, wherein R2 is halogen. In another embodiment, R2 is Cl. In r embodiment, R2 is F. In r embodiment, R2 is CN. In another embodiment, R2 is C1-C6 alkyl wherein said C1-C6 alkyl is substituted with 0-6 halogen. In another ment, R2 is CF3. In another embodiment, R2 is C1-C6 alkyl n said C1-C6 alkyl is tuted with 0-6 halogen n one CH2 unit of said C1-C6 alkyl is replaced with -O-. In another embodiment, R2 is OCF3. In another embodiment, R2 is F, Cl, CN, CF3 or OCF3.
In another embodiment, the invention features a compound of formula I-Q or formula I’-Q and the attendant definitions, R6 is halogen. In r embodiment, R6 is Cl. In r embodiment, R6 is F. In another embodiment, R6 is CN. In another embodiment, R6 is -X- RX. In another embodiment, R6 is -X-RX wherein RX is absent. In another embodiment, R6 is -X- RX wherein RX is absent and X is C1-C6 alkyl wherein said C1-C6 alkyl is substituted with 0-6 halogen. In another embodiment, R6 is CH3. In another embodiment, R6 is -X-RX wherein RX is absent and X is C1-C6 alkyl wherein said C1-C6 alkyl is tuted with 0-6 halogen wherein one CH2 unit of said C1-C6 alkyl is replaced with -O-. In another embodiment, R6 is OCH3.
In another embodiment, the invention features a compound of a I-Q or formula I’-Q and the attendant definitions, wherein R7 is halogen. In another ment, R7 is Cl. In another embodiment, R7 is F. In another embodiment, R7 is CN. In another embodiment, R7 is -X-RX. In another embodiment, R7 is -X-RX wherein RX is absent. In another embodiment, R7 is -X-RX wherein RX is absent and X is C1-C6 alkyl wherein said C1-C6 alkyl is substituted with 0-6 halogen. In another embodiment, R7 is CH3, CH2CH3, CH2CH2CH3 or isopropyl. In another embodiment, R7 is CF3. In another embodiment, R7 is -X-RX wherein RX is absent and X is C1-C6 alkyl wherein said C1-C6 alkyl is substituted with 0-6 halogen wherein two non-adjacent CH2 units of said C1-C6 alkyl are replaced with -O-. In r embodiment, R7 is OCHZCHZOCHg. In another embodiment, R7 is -X-RX wherein RX is absent and X is C1-C6 alkyl wherein said C1-C6 alkyl is substituted with 0-6 halogen wherein one CH2 unit of said C1-C6 alkyl is replaced with -O-.
In another embodiment, R7 is OCH3, OCH2CH3, OCHZCHZCHg, )3, OCHZCHZCH(CH3)2, or CHZCHZOCHg. In r embodiment, R7 is OCFg, OCH2CF3, OCHZCHZCHZCFg, or OCHFZ.
] In r embodiment, the invention features a compound of formula I-Q or formula I’-Q wherein R7 is -X-RX wherein X is a bond and RX is C3-C3 cycloaliphatic and said C3-C3 cycloaliphatic is substituted with 0-3 tuents selected from halogen and C1-C4 alkyl. In another ment, R7 is -X-RX wherein X is a bond and RX is cyclopropyl.
In another embodiment, the invention features a compound of formula I-Q or formula I’-Q and the attendant definitions, wherein R7 is -X-RX wherein X is C1-C6 alkyl wherein said C1-C6 alkyl is substituted with 0-6 halogen wherein one CH2 unit of said C1-C6 alkyl is replaced with -O- and RX is C3-C3 cycloaliphatic and said C3-C3 liphatic is substituted with up 0-3 substituents selected from n and C1-C4 alkyl. In another embodiment, R7 is -X- RX n X is OCHZ and RX is cyclopropyl.
] In another embodiment, the invention features a compound of formula I-Q or formula I’-Q and the attendant definitions, wherein p is zero. In another embodiment, p is an integer from 1 to 4 and R8 is halogen. In another embodiment, p is an r from 1 to 4 and R8 is Cl. In another embodiment, p is an integer from 1 to 4 and R8 is C1-C6 alkyl wherein said C1-C6 alkyl is substituted with 0-6 halogen wherein one CH2 unit of said C1-C6 alkyl is replaced with -O-.
WO 20820 In another embodiment, p is an integer from 1 to 4 and R8 is CH3. In another embodiment, p is an integer from 1 to 4 and R8 is OH.
In another embodiment, the ion features a compound of formula I-Q or formula I’-Q and the attendant definitions, wherein ring A is selected from: Jv'vv In another aspect, the invention provides a compound of formula I-R or formula I'-R: (R8)p\/ (R8 I OH O )p\4\’ \ Y \ OH H H R3 0 R3 0 R,‘ a R7 R7 I-R I'-R or a pharmaceutically acceptable salt thereof, wherein, independently for each occurrence: Y is C or N; R3 is halogen, CN, or C1-C6 alkyl wherein said C1-C6 alkyl is substituted with 0-6 n, wherein up to two non-adjacent CH2 units of said C1-C6 alkyl may be replaced with -O-; R6 is halogen, CN, or —X-RX; R7 is halogen, CN, or —X-RX; X is a bond or C1-C6 alkyl wherein said C1-C6 alkyl is substituted with 0-6 halogen, wherein up to two non-adjacent CH2 units of said C1-C6 alkyl may be replaced with -O-; RX is , H, or C3-C3 cycloaliphatic, wherein up to two jacent CH2 units of said C3-C3 cycloaliphatic may be replaced with -O- and said C3-C3 liphatic is substituted with 0-3 substituents selected from halogen and C1-C4 alkyl; R8 is halogen, or C1-C6 alkyl wherein said C1-C6 alkyl is substituted with 0-6 halogen, wherein up to two non-adjacent CH2 units of said C1-C6 alkyl may be replaced with -O-; and —56— 2014/013667 p is an r from 0 to 4 inclusive.
In one embodiment, the invention features a compound of formula I-R or formula I’-R and the attendant definitions, Y is C. In r embodiment, Y is N.
In another embodiment, the invention features a compound of formula I-R or formula I’-R and the attendant definitions, wherein R3 is halogen. In another embodiment, R3 is Cl. In r embodiment, R3 is F. In another embodiment, R3 is CN. In another embodiment, R3 is C1-C6 alkyl wherein said C1-C6 alkyl is substituted with 0-6 halogen. In r ment, R3 is t—butyl. In another embodiment, R3 is CF3. In another embodiment, R3 is .
In another embodiment, the invention features a compound of formula I-R or formula I’-R and the attendant definitions, R6 is halogen. In another embodiment, R6 is Cl. In another embodiment, R6 is F. In another embodiment, R6 is CN. In another embodiment, R6 is -X- RX. In another embodiment, R6 is -X-RX wherein RX is absent. In another embodiment, R6 is -X- RX wherein RX is absent and X is C1-C6 alkyl n said C1-C6 alkyl is substituted with 0-6 halogen. In another embodiment, R6 is CH3. In another embodiment, R6 is -X-RX wherein RX is absent and X is C1-C6 alkyl wherein said C1-C6 alkyl is substituted with 0-6 halogen wherein one CH2 unit of said C1-C6 alkyl is replaced with -O-. In another ment, R6 is OCH3.
In another embodiment, the invention es a compound of formula I-R or formula I’-R and the ant definitions, wherein R7 is halogen. In another embodiment, R7 is Cl. In another embodiment, R7 is F. In another embodiment, R7 is CN. In another embodiment, R7 is -X-RX. In another embodiment, R7 is -X-RX wherein RX is absent. In another embodiment, R7 is -X-RX wherein RX is absent and X is C1-C6 alkyl wherein said C1-C6 alkyl is substituted with 0-6 halogen. In another ment, R7 is CH3, CH2CH3, CH2CH2CH3 or isopropyl. In another embodiment, R7 is CF3. In another embodiment, R7 is -X-RX wherein RX is absent and X is C1-C6 alkyl n said C1-C6 alkyl is substituted with 0-6 halogen wherein two non-adjacent CH2 units of said C1-C6 alkyl are replaced with -O-. In another embodiment, R7 is OCHZCHZOCHg. In r ment, R7 is -X-RX wherein RX is absent and X is C1-C6 alkyl wherein said C1-C6 alkyl is substituted with 0-6 halogen wherein one CH2 unit of said C1-C6 alkyl is replaced with -O-.
In another embodiment, R7 is OCH3, OCHZCHg, OCHZCHZCHg, OC(CH3)3, OCHZCHZCH(CH3)2, or OCHg. In another embodiment, R7 is OCF3, OCH2CF3, OCHZCHZCHZCFg, or OCHFZ.
In another embodiment, the invention features a compound of formula I-R or formula I’-R wherein R7 is -X-RX wherein X is a bond and RX is C3-C3 cycloaliphatic and said C3-C3 cycloaliphatic is substituted with 0-3 substituents selected from halogen and C1-C4 alkyl. In another embodiment, R7 is -X-RX wherein X is a bond and RX is cyclopropyl.
In another embodiment, the invention features a compound of formula I-R or formula I’-R and the attendant definitions, wherein R7 is -X-RX wherein X is C1-C6 alkyl wherein said C1-C6 alkyl is substituted with 0-6 halogen wherein one CH2 unit of said C1-C6 alkyl 2014/013667 is replaced with -O- and RX is C3-C3 cycloaliphatic and said C3-C3 cycloaliphatic is substituted with up 0-3 substituents ed from halogen and C1-C4 alkyl. In another embodiment, R7 is -X- RX wherein X is OCHZ and RX is cyclopropyl.
In another embodiment, the invention features a nd of formula I-R or formula I’-R and the attendant definitions, n p is zero. In another embodiment, p is an integer from 1 to 4 and R8 is halogen. In another embodiment, p is an integer from 1 to 4 and R8 is Cl. In another embodiment, p is an integer from 1 to 4 and R8 is C1-C6 alkyl wherein said C1-C6 alkyl is substituted with 0-6 halogen wherein one CH2 unit of said C1-C6 alkyl is replaced with -O-.
In another embodiment, p is an integer from 1 to 4 and R8 is CH3. In another embodiment, p is an integer from 1 to 4 and R8 is OH.
In another embodiment, the invention features a compound of formula I-R or formula I’-R and the attendant definitions, wherein ring A is selected from: Jv'vv In another aspect, the invention provides a compound of a 1-8 or a I'-S: (Ran, (Ran, o WOH o VIY R2 \ Y R2 \ OH N N R3 O R3 O R6 *3 R6 *3 R7 R7 I-S I'-S or a ceutically acceptable salt thereof, wherein, independently for each occurrence: Y is C or N; R2 is halogen, CN, or C1-C6 alkyl wherein said C1-C6 alkyl is substituted with 0-6 halogen, wherein up to two non-adjacent CH2 units of said C1-C6 alkyl may be replaced with -O-; R3 is halogen, CN, or C1-C6 alkyl wherein said C1-C6 alkyl is substituted with 0-6 halogen, wherein up to two non-adjacent CH2 units of said C1-C6 alkyl may be replaced with -O-; —58— R6 is n, CN, or —X-RX; R7 is halogen, CN, or —X-RX; X is a bond or C1-C6 alkyl wherein said C1-C6 alkyl is substituted with 0-6 halogen, wherein up to two non-adjacent CH2 units of said C1-C6 alkyl may be replaced with -O-; RX is absent, H, or C3-C3 cycloaliphatic, wherein up to two non-adjacent CH2 units of said C3-C3 cycloaliphatic may be ed with -O- and said C3-C3 cycloaliphatic is substituted with 0-3 substituents ed from halogen and C1-C4 alkyl; R8 is halogen, or C1-C6 alkyl wherein said C1-C6 alkyl is substituted with 0-6 halogen, n up to two non-adjacent CH2 units of said C1-C6 alkyl may be replaced with -O-; and p is an integer from 0 to 4 inclusive.
In one embodiment, the invention es a compound of formula 1-8 or a I’-S and the ant definitions, Y is C. In another embodiment, Y is N.
In another ment, the ion features a compound of a 1-8 or formula I’-S and the attendant definitions, wherein R2 is halogen. In another embodiment, R2 is Cl. In another embodiment, R2 is F. In another embodiment, R2 is CN. In another ment, R2 is C1-C6 alkyl wherein said C1-C6 alkyl is substituted with 0-6 halogen. In another embodiment, R2 is CF3. In another embodiment, R2 is C1-C6 alkyl wherein said C1-C6 alkyl is substituted with 0-6 halogen wherein one CH2 unit of said C1-C6 alkyl is replaced with -O-. In another embodiment, R2 is OCF3. In another embodiment, R2 is F, Cl, CN, CF3 or OCF3.
In another embodiment, the invention features a compound of a 1-8 or formula I’-S and the attendant definitions, wherein R3 is halogen. In another embodiment, R3 is Cl. In another embodiment, R3 is F. In another embodiment, R3 is CN. In another ment, R3 is C1-C6 alkyl wherein said C1-C6 alkyl is tuted with 0-6 halogen. In another embodiment, R3 is t—butyl. In another embodiment, R3 is CF3. In another embodiment, R3 is CFZCF3.
In another embodiment, the invention features a compound of formula 1-8 or formula I’-S and the attendant definitions, R6 is halogen. In another embodiment, R6 is Cl. In another embodiment, R6 is F. In another embodiment, R6 is CN. In another embodiment, R6 is -X- RX. In another embodiment, R6 is -X-RX wherein RX is absent. In another embodiment, R6 is -X- RX wherein RX is absent and X is C1-C6 alkyl wherein said C1-C6 alkyl is substituted with 0-6 halogen. In another embodiment, R6 is CH3. In another embodiment, R6 is -X-RX wherein RX is absent and X is C1-C6 alkyl wherein said C1-C6 alkyl is substituted with 0-6 halogen wherein one CH2 unit of said C1-C6 alkyl is replaced with -O-. In another embodiment, R6 is OCH3.
In another embodiment, the invention features a compound of formula 1-8 or a I’-S and the ant definitions, wherein R7 is halogen. In another embodiment, R7 is Cl. In another embodiment, R7 is F. In r embodiment, R7 is CN. In another embodiment, R7 is -X-RX. In another embodiment, R7 is -X-RX wherein RX is absent. In another ment, R7 is -X-RX wherein RX is absent and X is C1-C6 alkyl wherein said C1-C6 alkyl is substituted with 0-6 halogen. In another embodiment, R7 is CH3, CH2CH3, CH2CH2CH3 or isopropyl. In another embodiment, R7 is CF3. In another embodiment, R7 is -X-RX wherein RX is absent and X is C1-C6 alkyl wherein said C1-C6 alkyl is substituted with 0-6 halogen wherein two non-adjacent CH2 units of said C1-C6 alkyl are replaced with -O-. In another embodiment, R7 is OCHZCHZOCHg. In another embodiment, R7 is -X-RX wherein RX is absent and X is C1-C6 alkyl wherein said C1-C6 alkyl is substituted with 0-6 halogen wherein one CH2 unit of said C1-C6 alkyl is replaced with -O-.
In another embodiment, R7 is OCH3, OCH2CH3, OCHZCHZCHg, OC(CH3)3, OCHZCHZCH(CH3)2, or CHZCHZOCHg. In another embodiment, R7 is OCFg, OCH2CF3, OCHZCHZCHZCFg, or OCHFZ.
In another embodiment, the invention features a compound of formula 1-8 or formula I’-S wherein R7 is -X-RX wherein X is a bond and RX is C3-C3 cycloaliphatic and said C3-C3 cycloaliphatic is substituted with 0-3 substituents selected from halogen and C1-C4 alkyl. In another embodiment, R7 is -X-RX wherein X is a bond and RX is cyclopropyl.
In another embodiment, the invention features a nd of formula 1-8 or a I’-S and the attendant definitions, wherein R7 is -X-RX wherein X is C1-C6 alkyl n said C1-C6 alkyl is substituted with 0-6 halogen wherein one CH2 unit of said C1-C6 alkyl is replaced with -O- and RX is C3-C3 liphatic and said C3-C3 cycloaliphatic is substituted with up 0-3 substituents selected from halogen and C1-C4 alkyl. In another embodiment, R7 is -X- RX wherein X is OCHZ and RX is cyclopropyl.
In another embodiment, the invention features a compound of formula 1-8 or formula I’-S and the attendant definitions, wherein p is zero. In another ment, p is an integer from 1 to 4 and R8 is halogen. In another embodiment, p is an integer from 1 to 4 and R8 is Cl. In another embodiment, p is an integer from 1 to 4 and R8 is C1-C6 alkyl wherein said C1-C6 alkyl is substituted with 0-6 halogen wherein one CH2 unit of said C1-C6 alkyl is replaced with -O-.
In r embodiment, p is an integer from 1 to 4 and R8 is CH3. In another ment, p is an integer from 1 to 4 and R8 is OH.
In r ment, the invention features a compound of formula 1-8 or formula I’-S and the attendant definitions, n ring A is selected from: Jv'vv In another embodiment, the compound or a pharmaceutically able salt thereof is selected from Table 1. 2014/013667 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 ted using ChemBioDrawUltra version 12.0 from Cambridge Soft/Chem Office 2010.
Table 1 Compound Numbers, Structures and Chemical Names O OH 0: EOH HN O HN 0 0| F CF F3C F 4-(2-(2-ch10r0flu0r0phen0xy) ometh 1 benzamldo benzmc ac1d 4-(2—(2-ch10r0fluorophenoxy) O OH oerfluoroeth 1 benzamido c acid 2 FFOZOH: HN 0 4-(2-(4-flu0r0methylphen0xy) (trifluoromethy1)benzamid0)benzoic acid 4-(2-(2,4-difluorophenoxy}4- 3 (perfluoroethyl)benzamid02)benzoic acid 4-(2—(2,4-diflu0r0phen0xy) trifluorometh 1 benzamido benzoic acid 4-(2-(4-flu0r0methy1phen0xy) oerfluoroeth 1 benzamido benzoic acid -62— 7 O: EOH 10 O: EOH HN o HN 0 OCH3 00 O CF3 F3CO F CFs CF3 4-(2-(4-(trifluoromethoxy)phen0xy) 4-(2-(4-flu0r0meth0xyphen0xy)-4,6- trifluorometh 1 benzamido benzoic acid iflu0r0methyl)benzamid0)benzoic 8 O OH acid : l l O OH HN O F i HN o O CF3 O CF3 CF3 F 4-(2-(2,4-difluorophenoxy)-4,6- CF3 bis(triflu0r0methyl)benzamid0)benzoic 4-(2-(4-flu0r0phen0xy)-4,6- acid bis(triflu0r0methyl)benzamid0)benzoic 9 O: EOH acid 12 O: EOH HN 0 CH3 HN O 0 CF3 OCH3 CF3 F CI 4-(2—(4-fluoro-Z-methylphenoxy)-4,6- CI bis(triflu0r0methyl)benzamid0)benzoic 4-(4,5-dich10r0(4-flu0r0 acid methoxyphenoxy)benzamid0)benzoic acid 13 0: EOH 16 O: EOH HN o HN O 00 0 F CI H300 CI 4-(4,5-dich10r0—2-(4_ 4-(4,5-dich10r0(2-flu0r0 fluorOohenox benzamido benzoic acid yphenoxy)benzamid0)benzoic acid : E0H HN o CF30 CI ko CI 4-(4,5-dich10r0-2—(4-flu0r0-2— CI methylphenoxy)benzamid0)benz0ic acid 4-(4,5-dich10r0(4-(2,2,2- if trifluoroethoxy)phen0xy)benzamid0)benz oic acid G? mi? 4-(4,5-dich10r0 ohenox benzamido benzoic acid ”76? 4-(4,5-dich10r0(4-ch10r0 methoxyphenoxy)benzamid0)benzoic acid 19 O OH EOH F é O: x HN O H300 CI F CI 4-(4,5-dich10r0(2- 4-(4,5-dich10r0(3-flu0r0 (difluoromethoxy)phenoxy)benzamid0)be methoxyphenoxy)benzamid0)benzoic nzoic acid acid : EOH HN O CI CI 4-(4,5-dich10r0(4-ch10r0 4-(4,5-dich10r0(2-ch10r0 methylphenoxy)benzaomid0)benz0ic acid fluorophenoxy)benzamid0)l_lbenzoic acid HN E0: OCH30 H3CO -dichloro(2,4- 4-(4,5-dich10r0(2,4- dimethoxyphenoxy)benzamid0)benzoic difluoro henox benzamido benzoic acid acid O: EOH 28 O: EOH HN 0 HN 0 CI CH3 0 0 H300 CI F CF3 CI 4-(2-(4-flu0r0methylphen0xy) 4-(4,5-dich10r0(2-ch10r0 trifluorometh 1 benzamido benzoic acid yphenoxy)benzamid0)benz0ic acid 26 O OH HN o 00 4-(2-(4-flu0r0methylphen0xy)-5 - F300 CI (trifluoromethy1)benzamid0)benzoic acid CI O OH 4-(4,5-dich10r0—2-(4_ (trifluoromethoxy)phen0xy)benzamido)be \ N nzoic acid 27 O: EOH HN O HN O F00 CI OCH3 '(4,5-dich10r0-2.(4_ fluoro henox benzamido icolinic acid 4-(2-(4-fluorometh0xyphen0xy) (perfluoroethyl)benzamid0)benzoic acid 31 O OH 34 O OH \N \ N / / HN o HN O 00 0 0 CI H300 CI K/A CI CI -dich10r0(2-flu0r0 -(4,5-dich10r0—2-(4_ methoxyphenoxy)benzamid0)pic01inic (isopentyloxy)phen0xy)benzamid0)pic01i acid nic acid 0 OH 0 OH | / HN O HN 0 000 CI F CI k CI CI CF3 -(4,5-dich10r0(4-flu0r0 5 -(4, 5 -dich10r0 (4-(2,2,2- ohenox benzamido oicolinic acid trifluoroethoxy)phen0xy)benzamid0)pic01 inic acid 0 OH HN O OCH3 CI CI -(4,5-dich10r0 CI ohenox benzamido oicolinic acid 5-(4,5-dich10r0(4-ch10r0 methoxyphenoxy)benzamid0)pic01inic acid 37 O 40 O OH HN 0 H3CO F00 CI -(4,5-dich10r0(2- 5-(4,5-dich10r0(3-flu0r0 (difluoromethoxy)phen0xy)benzamid0)pi yphenoxy)benzamid0)pic01inic colinic acid acid HN O CI CI -(4,5-dich10r0(4-ch10r0 5 -(4, 5 -dich10r0(2-ch10r0 methylphenoxy)benzamid0)pic01inic acid fluorophenoxy)benéamidogpic01inic acid OCH30 H3CO 50:0HN -(4,5-dich10r0(2,4- 5-(4,5-dich10r0(2,4- dimethoxyphenoxy)benzamid0)pic01inic difluorophenoxy)benzamid0)pic01inic acid acid 43 O OH 46 O OH \ N \ N / / HN 0 HN O 0 o CF3 H300 CI H300” : CI CF3 -(4,5-dich10r0(2-ch10r0 5-(2-(4-meth0xyphen0xy)-4,6- methoxyphenoxy)benzamid0)pic01inic bis(trifluoromethyl)benzamid0)pic01inic acid acid 0 OH 0 OH \ N \N / / HN o HN 0 00 0 CF3 F3CO CI F CI CF3 -(4,5-dich10r0—2-(4_ 5-(2-(4-fluoro-Z-methylphenoxy)-4,6- (trifluoromethoxy)phen0xy)benzamid0)pi bis(trifluoromethyl)benzamid0)pic01inic c acid acid 0 OH HN o OCH3 o CF3 -(2-(2-meth0xyphen0xy)-4,6- 5-(2-(4-flu0r0meth0xyphen0xy)-4,6- bis(triflu0r0methyl)benzamid0)pic01inic bis(trifluoromethyl)benzamid0)pic01inic acid acid 2014/013667 49 0 OH 52 HN o OCH3 of? 0 CF H300 CF {a -(2-(2,4-dimethoxyphenoxy)-4,6- 5- (4-(tert-buty1)(4-fluoro bis(triflu0r0methyl)benzamid0)pic01inic methoxyphenoxy)benzamid0)pic01inic acid acid OH OH \ N \N / / HN 0 HN O CF3 0 EN; -(2-(4-flu0r0phen0xy)-4,6- 5-(4-(tert-butyl)(4-flu0r0 bis(triflu0r0methyl)benzamid0)pic01inic acid methylphenoxy)benzaomido)piHc01inic acid 51 OH HN o OCH3 -(4,5-dich10r0(4-flu0r0 5-(4-(tert—butyl)(4- methoxyphenoxy)benzamid0)pic01inic fluoro henox benzamido icolinic acid acid 2014/013667 55 58 O OH \ N \ N / / HN O HN O F OéCF -(2-(4- 5-(2-(2-ch10r0flu0r0phen0xy) fluorophenoxy)benzamid0)pic01inic acid trifluorometh 1 lgenzamido icolinic acid 56 5 OH 05 HN OCH30 -(2-(4-flu0r0phen0xy) 5-(2-(5-fluoromethoxyphenoxy) trifluorometh 1 benzamido oicolinic acid rometh 1 benzamido icolinic acid OCH3O -(2-(4-fluoromethoxyphenoxy}5- 5-(2-(2-(difluoromethoxy)phen0xy)-5 - trifluorometh 1 benzamido oicolinic acid (trifluoromethyl)benzamid0)pic01inic acid 61 O OH 5-(2-(2-isopr0p0xyphen0xy) (trifluoromethyl)benzamid0)pic01inic acid \ N 65 HN O OéCF $0:HN OCHgo0003 -(2-(4-ch10r0methylphen0xy) trifluorometh 1 boenzamido oicolinic acid H300 -(2- (2,4-dimethoxyphenoxy}5- trifluorometh 1 benozamido icolinic acid OCHgoOHNOCFE OCH30om: -(2-(2-meth0xyphen0xyF) (trifluoromethyl)boenzamoid0)pic01inic acid 5-(2-C(4-ch10r0methoxyphenf):3y) (trifluoromethyl)benzamid0)pic01inic acid {EL OHS: -(2-(2-ch10r0phen0xy) CHOHNOE\CF3 orometh 1 benzamido oicolinic acid H300 - (2-(4-methoxymethylphenoxy}5- trifluorometh 1 benzamido icolinic acid 68 O OH 5-(2-(4-flu0r0phen0xy) (trifluoromethyl)benzamid0)pic01inic acid \ N 72 HN 0 CI 5H 0 HN OCH30 H3CO CF32 -(2-(2-ch10r0meth0xyphen0xy) trifluorometh 1 ido oicolinic acid -(2-(4-fluoromethoxyphenoxy) oeth 1 benzamido icolinic acid OCH3O -(2-(3-fluoromethoxyphenoxy}5- (trifluoromethyl)benzamid0)pic01inic acid 5H 5-(2-(4-flu0r0phen0xy) (perfluoroethy1)benozamid0)pic01inic acid ©§H 74 5H -(2-phenoxy trifluorometh 1 benzamido oicolinic acid {50“ -(2F- (2-ch10r0fluorophenoxy}6- (trifluoromethyl)benzamid0)pic01inic acid 75 0 OH HN 0 F CF3 -(2-(4-fluoromethy1phenoxy) trifluorometh 1 benzamido icolinic acid -dichloro(4-fluoro methoxyphenoxy)benzamido)picolinic acid In one embodiment, the compound is 5-(4,5-dichloro(4-fluoro methoxyphenoxy)benzamido)picolinic acid.
In r embodiment, the compound is 2,4-dimethoxyphenoxy)-4,6- bis(trifluoromethy1)benzamido)picolinic acid.
In another embodiment, the compound is 4-(4,5-dichloro(4-fluoro methoxyphenoxy)benzamido)benzoic acid.
In another embodiment, the compound is 5-(2-(4-fluoromethoxyphenoxy)- 4,6-bis(trifluoromethy1)benzamido)picolinic acid.
In another embodiment, the compound is 4-(2-(4-fluoromethoxyphenoxy)- 4-(perfluoroethy1)benzamido)benzoic acid.
In another embodiment, the nd is 5-(2-(4-fluoromethoxyphenoxy)- 4-(perfluoroethy1)benzamido)picolinic acid.
In another embodiment, the compound is 4-(2-(4-fluoromethy1phenoxy) oromethy1)benzamido)benzoic acid.
In another embodiment, the compound is -dichloro(4-fluoro yphenoxy)benzamido)picolinic acid.
In another embodiment, the compound is 4-(2-(2-chlorofluorophenoxy) uoroethy1)benzamido)benzoic acid.
In another embodiment, the compound is 4-fluoromethy1phenoxy) uoroethy1)benzamido)benzoic acid.
In another embodiment, the compound is 4-(4,5-dichloro(4- (trifluoromethoxy)phenoxy)benzamido)benzoic acid.
In another embodiment, the compound is -dichloro(4-chloro methylphenoxy)benzamido)benzoic acid.
In another embodiment, the compound is 5-(4-(tert-buty1)(4-fluoro methoxyphenoxy)benzamido)picolinic acid.
In another embodiment, the compound is 5-(4,5-dichloro(4- (trifluoromethoxy)phenoxy)benzamido)picolinic acid.
In another embodiment, the compound is 4-(4,5-dichloro(4-fluoro methylphenoxy)benzamido)benzoic acid.
In another embodiment, the compound is 5-(4,5-dichloro(2,4- dimethoxyphenoxy)benzamido)picolinic acid.
In another embodiment, the compound is 5-(4,5-dichloro(2-chloro fluorophenoxy)benzamido)picolinic acid.
In another embodiment, the compound is 5-(4,5-dichloro(4-fluoro methylphenoxy)benzamido)picolinic acid.
In another embodiment, the compound is 4-(4,5-dichloro(4-chloro methoxyphenoxy)benzamido)benzoic acid.
In another embodiment, the compound is 5-(4,S-dichlorQ(2,4—'.' difluorophenoxy)benzamido)picolinic acid. . salts, Compositions, Uses, Formulation,Administration and onal ‘Agents .PharmaceuticallyI acceptable salts and compositions - ,As discussed herein, the invention provides nds that are inhibitors of voltage—gated sodium channels, and thus the present compounds are useful for the treatmentof diseases, disorders, and conditions ing, 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 a1e provided, wherein these . compositions comprise any of the compounds as described herein, and optionally comprise a pha1maceutlcally acceptablecIa1rier,--adJ'uvant-or vehicle. in nembod1ments:these compositions" optiOnally further comprise one ormore additional therapeutic agents. In one embediment, the pharmaceutical composition comprises a eutically effective amount of a compound of the present invention or a pharmaceutically acceptable salt thereof and one or more pharmaceutically able carriers or vehicles It will also be appreciated that n ofthe compounds of1nvention can exist . in free form for treatment, or where appropriate, as a pharmaceutically aCceptable tive thereof According to the invention, a pharmaceutically able derivative includes, butIS not limited to; pharmaceutically acceptable salts, esters, salts of such esters" or any 'other addu‘ct or derivative which upon administration to a subject'1n need15 capable of providing, directly or ctly, a compound as otherwise described herein, or a metabolite or residue thereof . As used herein, the harmaceutically acceptable salt” refers to those salts which are, within the scope of sound ljudgement, suitableforuse in obntact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response and the like, and are surate With a reasonable beneft/r1sk ratio. A‘phatmaceut1cally acceptable salt” ny non-toxic salt or salt of an ester of a compound ofthis invention that, upon administration to a recipient, is capable of providing, either directly or indirectly, a compoundof this invention or an Iinhibitorily 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.
RECTlFlED SHEET (RULE 91) ISA/EP Pharmaceutically acceptable salts are well known in the art. For example, S.
M. Berge, et al. describe pharmaceutically acceptable salts in detail in J. ceutical Sciences, 1977, 66, 1-19, orated herein by reference. Pharmaceutically able salts of the nds 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 ceutically acceptable salts include adipate, alginate, ascorbate, ate, 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, enesulfonate, noate, valerate salts, and the like. Salts derived from appropriate bases include alkali metal, alkaline earth metal, ammonium and N+(C1_4 alkyl)4 salts.
This invention also envisions the quatemization of any basic nitrogen-containing groups of the nds disclosed herein. Water or oil-soluble or sable ts may be obtained by such quatemization. Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like. Further ceutically acceptable salts include, when appropriate, nontoxic ammonium, quaternary ammonium, and amine cations formed using counterions such as , ide, 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, ts, or other liquid e, 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 ceutically acceptable compositions and known techniques for the preparation thereof Except r 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 als which can serve as ceutically acceptable carriers include, but are not d 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 es of saturated vegetable fatty acids, water, salts or electrolytes, such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium de, zinc salts, colloidal silica, magnesium trisilicate, nyl 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 ible lubricants such as sodium lauryl sulfate and magnesium stearate, as well as coloring agents, releasing agents, coating agents, sweetening, ng and perfuming agents, preservatives and idants 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 , the invention features a pharmaceutical composition comprising a therapeutically effective amount of the compound or a pharmaceutically acceptable salt thereof of the compounds of a I or formula I’ and one or more pharmaceutically acceptable carriers or vehicles.
Uses ounds and Pharmaceutically Acceptable Salts and Compositions In r aspect, the invention features a method of inhibiting a voltage- gated sodium channel in a subject comprising administering to the subject a compound of a I or formula I’ or a pharmaceutically able salt thereof or a pharmaceutical composition thereof In another , the voltage-gated sodium channel is Navl .8.
In yet another aspect, the invention features a method of treating or lessening the ty 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 c 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 a I’.
In yet another aspect, the invention es a method of ng or lessening the severity in a t 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 r embodiment, the present invention provides a method of treating or lessening the ty in a t 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 of the present invention or a pharmaceutically acceptable salt thereof or a pharmaceutical composition f.
In another embodiment, the present invention provides a method of treating or lessening the severity in a subject of gut pain, wherein the gut pain comprises inflammatory bowel disease pain, Crohn’s disease pain or interstitial cystitis pain.
In another embodiment, the present invention es a method of treating or lessening the severity in a subject of neuropathic pain, wherein the neuropathic pain comprises post- ic neuralgia, diabetic neuralgia, painful HIV-associated sensory neuropathy, trigeminal neuralgia, burning mouth syndrome, post-amputation pain, m pain, painful neuroma; traumatic neuroma; Morton’s neuroma; nerve entrapment injury, spinal stenosis, carpal tunnel syndrome, lar pain, sciatica pain; nerve avulsion injury, brachial plexus avulsion ; complex regional pain syndrome, drug therapy d 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.
In another embodiment, the t invention provides a method of treating or lessening the ty in a subject of musculoskeletal pain wherein said musculoskeletal pain comprises osteoarthritis pain, back pain, cold pain, burn pain or dental pain.
] In r embodiment, the present invention provides a method of treating or lessening the severity in a subject of inflammatory pain wherein said inflammatory pain comprises rheumatoid arthritis pain or vulvodynia.
In another embodiment, the present invention provides a method of treating or lessening the severity in a subject of idiopathic pain wherein said thic pain comprises flbromyalgia pain.
In another embodiment, the t invention provides a method of treating or lessening the severity in a subject 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 wherein said t is treated with one or more additional therapeutic agents administered concurrently with, prior to, or subsequent to ent with the nd or pharmaceutical composition of the present invention.
In yet another aspect, the ion features a method of ng or lessening the severity in a t of neuropathic pain, wherein neuropathic pain comprises erpetic neuralgia, ic neuralgia, painful HIV-associated sensory neuropathy, trigeminal neuralgia, burning mouth syndrome, post-amputation pain, phantom pain, painful neuroma, traumatic a, Morton’s neuroma; nerve ment 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, etroviral therapy induced neuralgia; post spinal cord injury pain, idiopathic small-fiber neuropathy, idiopathic sensory athy or trigeminal mic 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 ses 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 , 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 , the invention features a method of ng or lessening the severity in a subject of thic pain, wherein idiopathic pain comprises flbromyalgia pain n said method ses administering an effective amount of a compound, a pharmaceutically acceptable salt thereof or a pharmaceutical composition of the nds 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 eutic agents administered concurrently with, prior to, or subsequent to treatment with an effective amount of a compound, a pharmaceutically able 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 t comprising administering to the subject an effective amount of a compound, a pharmaceutically acceptable salt thereof or a pharmaceutical ition of the compounds of formula I or formula I’. In another aspect, the voltage-gated sodium channel is Navl .8.
In another aspect, the invention features a method of inhibiting a voltage- gated sodium l in a biological sample sing ting 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 Navl .8.
In another aspect, the invention features a method of treating or lessening the ty in a subject of acute pain, c pain, neuropathic pain, inflammatory pain, arthritis, migraine, cluster headaches, trigeminal neuralgia, herpetic neuralgia, general neuralgias, epilepsy, epilepsy conditions, neurodegenerative ers, psychiatric disorders, anxiety, depression, dipolar disorder, myotonia, arrhythmia, nt disorders, neuroendocrine disorders, ataxia, le 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 l sclerosis, stress induced angina, exercise induced , ations, hypertension, or abnormal gastro-intestinal motility, comprising administering an effective amount of a compound, a pharmaceutically acceptable salt thereof or a ceutical composition of the compounds of formula I or formula I’.
In r 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; f1bromyalgia; temporomandibular joint pain; chronic visceral pain, abdominal pain; pancreatic pain; IBS pain; chronic and acute headache pain; migraine; n headache, cluster headaches; chronic and acute neuropathic pain, post-herpetic gia; 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 d 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; table 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 ittent pain, endometriosis; acute herpes zoster pain; sickle cell anemia; acute pancreatitis; breakthrough pain; orofacial pain including sinusitis pain, dental pain; multiple sclerosis (MS) pain; pain in depression; leprosy pain; Behcet's disease pain; adiposis dolorosa; phlebitic pain; Guillain-Barre pain; l legs and moving toes; Haglund syndrome; erythromelalgia pain; Fabry's disease pain; bladder and urogenital disease, including, urinary incontinence; hyperactivity bladder; painful bladder syndrome; interstitial is (1C); prostatitis; complex regional pain me , type I and type II; widespread pain, smal extreme pain, pruritis, is, 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 1’.
In another aspect, the ion features a method of ng 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 ceutical composition of the compounds of formula I or formula I’. In one aspect, the athic pain is selected from post-herpetic neuralgia, diabetic neuralgia, painful HIV-associated sensory athy, trigeminal neuralgia, burning mouth syndrome, post-amputation pain, phantom pain, painful a, tic 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-f1ber neuropathy, idiopathic sensory athy or inal autonomic cephalalgia. -82— Manufacture ofMedicaments 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 e-gated sodium channel. In another aspect, the voltage-gated sodium channel is Navl .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 ng 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 , 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 athic pain, wherein athic pain comprises post- herpetic gia, diabetic neuralgia, painful HIV-associated sensory neuropathy, inal 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 on injury, brachial plexus on injury; complex regional pain syndrome, drug therapy induced neuralgia, cancer chemotherapy induced neuralgia, anti- retroviral therapy induced gia; post spinal cord injury pain, idiopathic small-f1ber neuropathy, idiopathic sensory neuropathy or trigeminal autonomic cephalalgia.
In yet another aspect, the invention es 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 oskeletal pain comprises osteoarthritis pain, back pain, cold pain, burn pain or dental pain.
In yet another aspect, the invention the invention es the use of a compound or pharmaceutical composition described herein for the manufacture of a ment for use in treating or lessening the ty in a subject of inflammatory pain, wherein atory pain comprises rheumatoid arthritis pain or vulvodynia.
WO 20820 ] 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 f1bromyalgia 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 stered concurrently with, prior to, or subsequent to treatment with the nd or pharmaceutical composition.
In r , the invention provides the use of a compound or pharmaceutical composition bed herein for the manufacture of a medicament for use in ng or ing the severity of acute pain, chronic pain, neuropathic pain, inflammatory pain, arthritis, migraine, r headaches, trigeminal neuralgia, ic gia, general neuralgias, epilepsy, epilepsy conditions, neurodegenerative disorders, psychiatric disorders, anxiety, sion, dipolar disorder, myotonia, arrhythmia, movement ers, 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 al 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; f1bromyalgia; omandibular joint pain; chronic visceral pain, abdominal pain; pancreatic pain; IBS pain; chronic and acute headache pain; migraine; tension he, including, cluster hes; chronic and acute neuropathic pain, post-herpetic gia; 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 athic 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 atory, burn and trauma pain; acute intermittent pain, endometriosis; acute herpes zoster pain; sickle cell anemia; acute pancreatitis; breakthrough pain; orofacial pain including 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 e pain; bladder and urogenital disease, including, urinary inence; ctivity 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 ment for use in treating or lessening the severity of neuropathic pain. In one aspect, the neuropathic pain is ed from post- herpetic neuralgia, ic neuralgia, painful HIV-associated sensory neuropathy, trigeminal gia, burning mouth syndrome, mputation 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 me, drug therapy induced neuralgia, cancer chemotherapy induced neuralgia, anti-retroviral y induced neuralgia, post spinal cord injury pain, idiopathic small-f1ber neuropathy, idiopathic sensory neuropathy or inal autonomic cephalalgia. stration ofPharmaceutically acceptable salts and compositions In certain embodiments of the invention an “effective ” 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, atory pain, cancer pain, idiopathic pain, multiple sclerosis, Charcot—Marie-Tooth me, incontinence or cardiac hmia.
The compounds and compositions, according to the method of the invention, may be administered using any amount and any route of stration 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 ion 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 c 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 s orally, rectally, parenterally, intracistemally, intravaginally, intraperitoneally, topically (as by powders, nts, or drops), bucally, as an oral or nasal spray, or the like, depending on the severity of the ion being treated. In certain embodiments, the nds 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 l, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, oils (in particular, seed, 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, fying and suspending agents, sweetening, flavoring, and perfuming agents.
Injectable preparations, for example, sterile injectable s or nous suspensions may be formulated according to the known art using suitable sing or g agents and suspending . The sterile inj ectable preparation may also be a sterile injectable on, suspension or emulsion in a ic parenterally acceptable diluent or solvent, for example, as a on in 1,3-butanediol. Among the acceptable vehicles and solvents that may be employed are water, ’s solution, U.S.P. and isotonic sodium chloride solution. In addition, sterile, fixed oils WO 20820 are conventionally employed as a t 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 inj ectable formulations can be sterilized, for example, by filtration through a bacterial-retaining filter, or by incorporating izing agents in the form of sterile solid compositions which can be dissolved or dispersed in sterile water or other sterile able medium prior to use.
In order to prolong the effect of a compound of the ion, it is often desirable to slow the absorption of the compound from subcutaneous or intramuscular injection. This may be lished by the use of a liquid suspension of crystalline or amorphous material with poor water solubility. The rate of tion 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 stered compound form is accomplished by dissolving or suspending the compound in an oil vehicle. able 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 radable polymers include poly(orthoesters) and poly(anhydrides). Depot inj ectable formulations are also prepared by entrapping the compound in liposomes or mulsions 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 ore melt in the rectum or vaginal cavity and e 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 ers such as starches, lactose, sucrose, e, 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 rators such as quaternary ammonium 2014/013667 compounds, g) wetting agents such as, for example, cetyl alcohol and glycerol earate, h) absorbents such as kaolin and bentonite clay, and i) lubricants such as talc, calcium. te, 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 .l Solid compositions ofa similar type may also be employed as fillers in sofi and hard-filled n 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 c coatings and other coatings well n the ceutical formulating art They may optionallycontain opacifying' agents and can also be of a composition that they release the active ingredient(s) only, or entially,1n a n 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 ed as fillers"1n 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 microen‘capsulated form with'one or, more excipients as notedabovei The solid dosage forms of tablets, dragees, capsules, pills, and granules Can be ed with gs and shells such as enteric coatings, release controllingcoatings and other coatings well known1n the pharmaceutical formulating art in such solid dosage f01ms the ‘ activecompound may be admixed with at least one inert diluent such as suc1ose, 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 stea1ate 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 fircompositiOn that they release the active ingredient(s) only, or prefe1ent1ally,1n a n part of the 1 intestinal tract, optionally,1n a delayed manner. Examples of embedding compositions that can be used include polymeric substances and waxes.
]. Dosage forms for topical or transdermal stration of a compound of this invention include ointments, pastes, creams, lotions, gels, powders, solutions, sprays, inhalants or patches. The active ent is admixed under sterile conditions'with a pharmaceutically acceptable . ' carrier and any needed pres'erVatives 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 ion contemplates the use oftransdermal patches, which have the added advantage of providing RECTIFIED SHEET (RULE 91) lSA/EP controlled delivery of a compound to the body. Such dosage forms are ed 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 itions of the invention are inhibitors ofNaVl .8 and thus, without g 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 ctivity ofNaVl .8 is implicated in the disease, condition, or disorder. When activation or hyperactivity of NaVl.8 is implicated in a particular disease, condition, or disorder, the disease, condition, or disorder may also be referred to as a “NaV1.8 ted e, ion 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 NaV1.8 is implicated in the disease state.
The activity of a compound utilized in this ion as an inhibitor ofNaVl .8 may be assayed according to methods described generally in the es herein, or according to s available to one of ry skill in the art.
Additional Therapeutic Agents It will also be appreciated that the compounds and ceutically 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 ation 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 er (for e, 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 , additional therapeutic agents that are normally administered to treat or t a particular disease, or condition, are known as “appropriate for the disease, or condition, being treated.” For example, exemplary onal therapeutic agents include, but are not limited to: nonopioid analgesics (indoles such as Etodolac, lndomethacin, Sulindac, Tolmetin; naphthylalkanones such sa Nabumetone; oxicams such as Piroxicam; para-aminophenol derivatives, such as Acetaminophen; propionic acids such as Fenoprofen, profen, Ibuprofen, Ketoprofen, Naproxen, Naproxen , Okaproiin; salicylates such as Aspirin, Choline magnesium icylate, Diflunisal; fen‘ama'tes such as meclofenami‘c acid, Mefenamic acid; and pyrazolesv such as Phenylbutazone); or opio-id.(narcotic)lagonists (such as Codeine, Fentanyl, Hydromorphone, Levorphanol, Meperidine, Methadone, Morphine, Oxycodone, Oxymorphone, Propoxyphene, orphine, Butorphanol, Dezocine, Nalbuphine, and Pentazocine). onally, nondrug. sic approaches may be utilized in conjunction with administration of one or more compounds of the invention. For eXample, anesthesiologicll(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 tive methods-hypnosis, biofeedback, or oral methods) approaches may also be utili7ed.
Additional appropriate therapeutic agents or approaches are described gene1-ally'in The Merck Manual Nineteenth Edition, Ed Robert S. Porter and JUStin L.l<aplan-, Merck Sharp &Dohme Corp, a subsidiary of Merck & Co., Inc. 201 land the Food and Drug Administration Website, www.-fdagov, the entire contents Of which are hereby orated by reference.
In another embodiment, additional appropriate therapeutic agents are selected- from the following: (1)an opioid analgesic, e..g ne, heroin, hydromorphone, oxym‘orphone, ,,levorpl1anol, levallorphan, one, meperidine, fentanyl, coCaine, codeine, dihydrocodeine, oxycodone,hydrocodone propoxyphene,i1almefene,nalorphi'ne, naloxone,naltrexone, buprenorphine, butorphanol, nalbuphine or pentazocine; (2) a nonsteroidal'antiinflammatory drug (NSAID), e.g. aspirin, diclofenac, diflunisal, etodolac, fenbufen, fenOprofen, flufenisal, flurbiprofen, ibuprofen, thacin, ofen, ketorolac, meclo'fenamic'aCid, mic acid, meloxicam, nab‘umetone, naproxen, lide, nitroflurbiprofen, olsavlabine, oxaprozin, phenylbu'tazo’ne, piroxicam, sulfasalazine, sulindac, tolmetin or rac; (3) a barbiturate sedative, e.g. amobarbital, aprobarbital, butabarbital, butalbital, mephobarbital, metharbital, exital, arbital, phenobarbital, secobarbital, talbutal, thiamylal or thiopental; (4) a benzodiazepine having a sedatiVe action, eg. chlordiazepoxide, clorazepate, diazepam, flurazepam, lorazepam, oxazepam, temazepam or triazolam; ”[00298] (5) a histamine (H1) antagonist having a sedative action, e.g.
» RECTIFIED SHEET (RULE 91) ISA/EP diphenhydra'mine, pyrilamine, promethazine, chlorpheniramine or chlorcyclizine; (6) a sedatiye such as himi'de, meprobamate, methaqualone Or dichloralphenazone; (7) a skeletal muscle relaxant, 'e.g. baclovfen, carisoprodol, chlorzoxazone, cyclobenzaprine, methocarbamol or. orphenadrine; (8)Ian NMDA receptor antagonist, e.g. dextromethorphan ((+)—3-hydr0xy-N- methylmorphinan) or its metabolite dextrorphan ((+)hydroxy-N-methylmorphinan), ketamine, memantine, pyrroloquinoline quinine, cis(phosphonomethyl)——2- piperidinecarboxylic acid, budipine, EN-323] (MorphiDex®), a combination formulation of morphine and dextromethorphan), topiramate, xane or perzinfotel including an NRZB antagonist, eg. ifenprodil, traxoprodil o1 (- )-(R){2-[4-(3-flu0rophenyl)hydroxy—l- piper1d1nyl]-l-hyd1oxyethyl-9,4-,d1hydro2(IH)- quinolinoney ' (9) an alpha-adrenergic, eg. doxazosin, tam‘sulosin, clonidine, guanfaeine', dexmedetomidine, modaflnil, or 4--a1nino--6,7-dimethoxy-(methane—sulfona1nido-l, 2",9,4— ’tetrahydroisoquinolinyl)(2-pyridyl) quinazoline; I (1 O) a tricyclic antidepressant, e.g. desiprainine, imipramine, amitriptyline or» nonriptyline; ' (1 1) an anticonvulsant, eLg. carbamazepine (Tegretol®), lamotrigine, > [00304] topifamate, laeosamide (>Vimpat®) or valproate; ' (I 2) a tachykinin (NK) antagonist, particularly an INK-3, NK—2 or NK-l nist, eg (alphaR,9R)[3,5-bis(trifluoromethyl)benzyl]-8,9, 10, 11 hydromethyl--(4-- methylphenyl)--7H-[l,4]dia‘zoci_no[2,l-g][l,7]-naphthyridinee6- 13-dione (TAK-637), 5- 3S)2- [(IR)--l-[3,5-bis(trifluoromethyl)phenyl]ethoxy-3——-(4fluorophenyl)morph‘olinyl]--methyl]-1,2- dihydro-3H-l,2,4-triazolone (MK--869), aprepitant, lanepitant, dapitant or 3-[[2-methoxy—5- (tr1fluoromethoxy)phenylJ-methylam1no]-_2-phenylp1per1d1ne (28,38); ] (13) a muscarinic antagonist, e.g oxybutynin, od1ne propiverine, tropsium chloride, darifenacin, solifenacin,temive1ine and ipratropium'; ] ‘(14)_ a COX-2 selective inhibitor, e.g. celecoxib, xib, parecoxib, valdecoxib, deracoxib, etoricoxib, ‘or lumiracoxib; (15) a coal-tar sic, in particular tamol; RECTIFIED SHEET (RULE 91) ISA/EP (16) a neuroleptic such as droperidol, romazine, haloperido1, perphenazjne, thioridazine, dazine, trifluopcrazine, fluphenazine, clozapin'e, oianzapine, _ risperidone, ziprasidone, quetiapine, dole, aripiprazole, sonepiprazole, blonanserin, iloperidone, perospirone, ride, zotepine, bifeprunox, asenapine, done, amisulpride, ba1aperidone, palindore, ep‘livanserin, osanetant, rimonabant, nertant, Miraxion® or sari-zotan, (17) a oid receptor agonist (e. g. resinferatoxin or civamide) or antagonist (e.g. capsazepine, ORG-15300); . (18) a beta:adrenerg1c such as propianoldl; (1 9) a local hetic such as 1nexiletine; ] . (20) a corticosteroid such as 'dexamethasone; (21) aj-HT receptor agonist or antagonist, particularly a154HTlg/19agonist 's,uch :as eletriptan, sUmatriptan, naKratrsiptan, .zolmitriptan o'r riiatriptan; (22) a 517sz receptor antagonist such as -R(+)j—a1pha'—(2,3—dimethoxy-phenyl)— 1-[2-(4;fluoiophenyiethyl)]piperidinemethanol (mm-100907); . (23’) a cholinergic- (nico’tinic) analgesic, such‘asispronicline (TC—17.34,), (E)- 'N-1nethylf4~(3fpyridiny1)buten—i-amine (MR-24031), (R)—5-(2'-aze1idinylmethoxy)—2-chloropyridine (ABT-Sf9'4) of nicotine; ' ' (24) Tramadol®, Tramadol ER (Ultiam_ER®), Tapentado‘l ER (Nucynta®); (25)a PDES inhibitor; such as 5-[2-ethoxy—5-(4-methy1-l-piperazinyl-‘-- ny1)pheny1]‘--l-methyl-n--prcpy1-1,-6ldihydro-7H-pyrazolo[4,"3-d]pyrimidin-one (sildenafil), (6R, 12aR)- 2,3 ,,67, 12, 12a-hexahydro-Z-methyl6(3,4—methyienedioxypheny1)-pyrazino[2‘, 1':6,1]- pyrido[3,4-b]indo1e-l,4-dione (IC--351 or tadalafil), 2--[-2ethoxy-(4-ethyl-piperazin—l-yl- honyl) phenyl]5-methy1propyl-3H-imidazo[5,l-f][1,2,4]triazinone (vardenafil), 5—(5-accty1butoxyr"3—- pyridiny1)ethyl(1-ethy1—3-azetidiny1)—2,6Hdihydro--7H- pyrazolo[_4,3 -a']pyrimidin--one, 5-(5- acetyl-propoxy-pyridiny1)---ethy1(1-isopiopy1;3-azetidiny1)--2,‘6dihydro--7H-pyrazolo[4,3~ d]pyrimidin—7-one, 5-[2-ethoxy—5-(4~ethy1piperazin-l--ylsu1phonyl)pyridin-3—yl]-ethy1- [2~ 1nethoxyethyl]-2,6--dihydro--7H- pyrazolo‘[4,3d]pyrimidin--one, 4- [(3-chloro—4— methoxybenzy1)amino][(2$)--(hydroxymethy1)pyr1'01idin--y1]-N--(py-rimidin- y1methyl)pyrimidine-S-carboxamide, 3-(1~ methyloxo-3—propy1—6,7~dihydr6|—lH-pyrazolo[4,3- d]pyrimidiny1)-N-'[2-(l-methylpyrrolid‘inyl)ethy'1]jpropoxybenzen‘esulfonamide; .92- RECTIFIED SHEET (RULE 91) lSA/EP 2014/013667 ] (26) an alpha-Z-delta ligand'such as gabapenti'n min®), gabapcntin GR (Gralise®), ntin, enacarbil (Horizant®), pregabalin (Lyrica®), 3-methyl'gabapentin, (l[alpha],3[alpha],5[alpha])(3—amino-methyl-bicyclo[3.2.0]hept—3-yl)-acetic acid, (3 S,5R) aminomethyl-S-methyl-heptanoic acid, (38,5R)aminomethyl-'heptanoic acid, (3S,5R)am'ino methyl-octanoic acid, (28,4S)(3-chlorophenbxy)proline, (2S,4‘S)—4~(3—fluorobenzyl)—proline, R,6S)—6-(aminomethyl)bicyclo[3.2.’0]hept—6-yl]acctic acid, 3-(l-aminomethyl-cyclohexylmethyl)-- '4H-[l ,2,4]oxadiazo,lone, C-[l -(lH-tetrazolylmethyl)-cycloheptyl]-methyla'min'c, (3 S,4S)—(l- aminomethyl-3,4—dimethyl-cyclopentyvl)-acetic acid, (38,5R)—3-_aminomethylé—methyl«octafioic acid, (3S,5R)---3amino-S-methyl-nonanoic acid, (SS,5R)—3--amino-methyl--octanoic acid, (3R,4R,5R amino-4,5-dimethyl-heptanoic acid and (3R,4R,5R)amino-4, 5-dimethyl-octanoic acid; (27) a cannabinoid such as KHK-6188; ] ' (28) tropic glutamate subtype 1 receptor (rinGluRl) antagonist; ] (29) a serotonin ke inhibitor suchassertraline, sertraline metabolite demethylsertraline, fluoxetine, norfluoxetine (fluoxetinc desmethyl metabolite), mine, paroxetine, citalopram, citaloprammetabolite desmethylcitalopram, escitalopram, dl-fenfluramine, femoxetine, ifoxetine, cyanodothiepin, litoxetine, dapoxetine, nefazodone, cericlamine and one; ‘ (30) a noradrenaline (norepinephrine) reuptake inhibitor, such as mapro'tilinc,- lofepramine, mirtazepi-ne, oxaprotiline, fezolamine, tomoxetine, mianseIin, bupropion, bupropion metabolite hydroxybupropion, nomifensine and .viloxa'zine (Vivalan®), especially‘a selective- noradrenaline reuptake inhibitor such as reboxetine, in particular rebc‘>xetine; (31) a dual serotonin-noradrenaline reuptake inhibitor, such as yenlafaxirie, venlafaxine lite O—desmethylvenlafakine, clomipramine, clomipramine metabolite desmethyl'clomipramine, duloxetine (cy'mbalta®), milnacipran and imipramine; .[00325] (32) an inducible nitric onide synthase (iNOS) inhibitor such as"S—[2-[(lj _ .iminoethyl)amino]'cthyl]-L-hbmocysteine' S- [2-[(l-iminoethyl)-amino]ethyl]——4,dioxo-L-cystcine, S- [2- [(l-iminoethyl)amino]ethyl]methyl--L--cysteine, (ZS,SZ)--amino--2—methyl—7- [(1- iminoethyl)amino]heptenoic acid, 2-[[(lR,3S)aminohydroxy-l--(5-thiazolyl)--butyl]thio]- S- chloro—S--pyridinecarbonitrile; R,SS)aminohydroxy-l-(5- thiazolyl)butyl]thio]- . chlorobenzonitrile, (2S,4R)—2-‘amino[[2‘-chloro (trifluoromethyl)phenyl]thio]-5‘-thiazolebutanol, 2-[[(lR,3 S)—3-arninohydroxy-l-(S-thiazolyl) butyl]thio](trifluoromethyl)-3 -pyridinecarbonitrile, 2-[[(lR,3S)aminohydroxy(5-thiazolyl)butyl]thio]—5-chlorobenzonitrile, N-[4-[2-(3- RECTIFIED SHEET (RULE 91) ISA/EP chlorobenzylamino)ethyl]phenyl]thiophenecarboxamidine, 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-lH-imidazo[4,5-c]pyridin-l-yl)phenyl]ethyl} -carbonyl] methylbenzenesulfonamide or 4-[(15)-l-({[5-chloro(3-fluorophenoxy)pyridin yl]carbonyl} amino)ethyl]benzoic acid; (35) a leukotriene B4 antagonist; such as l-(3-biphenylylmethylhydroxy- chromanyl)-cyclopentanecarboxylic acid (CP- 105696), 5-[2-(2-Carboxyethyl)[6-(4- methoxyphenyl)-5E-hexenyl]oxyphenoxy]-valeric acid (ONO-4057) or DPC-l 1870; (36) a 5-lipoxygenase inhibitor, such as zileuton, 6-[(3-fluoro[4-methoxy- 3,4,5,6- tetrahydro-2H-pyranyl])phenoxy-methyl]-l-methylquinolone (ZD-2138), or 2,3,5- hyl(3-pyridylmethyl)-l,4-benzoquinone (CV-6504); (3 7) a sodium channel blocker, such as lidocaine, lidocaine plus tetracaine cream 01) or eslicarbazepine acetate; (38) an NaV1.7 blocker, such as XEN—402 and such as those disclosed in /140425; /106499; W02012/112743; W02012/125613 0r ZOl3/21535 the entire contents of each application hereby incorporated by reference. (39) an NaV1.8 blocker, such as those sed in W02008/ 135 826 and W02006/011050 the entire contents of each application hereby incorporated by reference. (40) a combined NaV1.7 and NaV1.8 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 mab; (46)_an ptidase ant, such as senrebotase; ] (47) an angiotensin II antagonist, such as EMA-401; ] ' In one embodiment, the additionalappropriate therapeutic agents are selected from V— 116517, Pregabalin, controlled release Pregabalin, Ezogabine (Potiga®). Ketainine/ amitriptyline topical cream (Amiket®), AVP-923, Perampanel (E—2007), Ralfina1nide;'transdermal caine (Eladur®), CNV1014802, JNJ-10234094 (Carisbamate), BMS-9545610r ARC24558.}, The amount of additional therapeutic agent presentin‘ the compositions of this invention will be no more than the amountthat would normally be administered in a ition 1 comprising that therapeutic agent as the only active agent. The amount of onal 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 th1s invention or pharmaceutically acceptable compositions f may also be incorporated into compositions for coating an implantable l device, suchas prostheses, artificial valves, vascular grafts, stents and ers. Accordingly, the invention, in '- another aspect, includes a composition for coating an implantabledevice comprising a compound of the invention as described generally above, and1n classes andsubclasses herein,- and a carrier suitable for coating said table device In still r aspect, the invention includes an implantable devicelcoated with a composition comprising a compound of the invention as described lly“ above, and in es 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 US Patents 6,099,562; 5,886,026, and 5,304,121. The coatingsare typically biocompatibie polymeric mate1ials such as a hydrogel polymer, polymethyldisiloxane, polycaprolactone, polyethylene glycol, actic acid, ethylene vinyl acetate, and mixtures thereof. The coatings may optionally be further covered by a.suitable to'pcoat 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 Navl .8 activity in a biological sample or a subject, which method comprises" administering to_ the subject, or ting said biological sample with a compound of formula I or formula 1' or a ition comprising said compound. The term “biological sample,” as used herein, includes, without limitation, cell cultures or extracts thereof; ed material obtained from a mammal or extracts thereof; and blood, saliva, urine, feces, semen, tears, or other body fluids or extracts thereof.
Inhibition of Navl .8 activity in a biological sample is useful for a variety of es that are known to one of skill in the art. es of such purposes include, but are not limited‘to, the study of sodium ls in biological land'pathological phenomena; and the -95, RECTIFIED SHEET (RULE 91) ISA/EP' comparative tion ofnew sodium channel inhibitors.
SCHEMES AND EXAMPLES The compounds of the invention may be prepared readily using the following methods. Illustrated below in Scheme 1 is a general method for preparing the compounds of the present invention.
Scheme 1: General ation of Compounds of Formula I or Formula _ 2A R10 H2N\XO _ R2 -- R2 2 T< OH (8) R10/CxORN\XO R (c) R10/CXORN\XO —> H —> H R3 F R3 F R3 9 R4 R4 R4 RingA R2 2 0' (b) (e) R3 F OH R1 0 / X OH R4 RingA R3 o R4 RingA X: N, C Ring A, R1, R2, R3, R4 are as defined herein. R2A is defined below. (a) Coupling agent (i.e. HATU, EDCI, HOBT), base (i.e. N—methyl-morpholine), solvent (i.e. DMF, romethane); (b) base (i.e. pyridine), t (i.e. dichloromethane, DMF); (c) RingA-OH, base (i.e.Cs2C03, K2C03), AT; (d) ester hydrolysis R2A= alkyl (i.e. Me, Et) aqueous base (i.e. NaOH, LiOH), solvent (i.e. MeOH, dioxane); R2A= tBu, acid (i.e. trifluoroacetic acid), solvent (i.e. dichloromethane); (e) Coupling agent (i.e. HATU, EDCI, HOBT), base (i.e. N—methyl-morpholine), solvent (i.e. DMF, dichloromethane) EXAMPLES General methods. 1H NMR (400 MHz) a were obtained as solutions in an appropriate deuterated solvent such as dimethyl sulfoxide-d6 (DMSO). Mass a (MS) were obtained using an Applied Biosystems API EX LC/MS system. Compound purity and retention times were ined by reverse phase HPLC using a Kinetix C18 column (50 X 2.1 mm, 1.7 um particle) from Phenomenex (pn: OOBAN)), and a dual gradient run from 1-99% mobile phase B over 3 minutes. Mobile phase A= H20 (0.05 % CF3C02H). Mobile phase B= CH3CN (0.05 % CF3IC02H).
Flow rate= 2 mL/min, injection volume= 3 uL, and column temperature—= 50 °C_. Silica gel chromatography was performed using silica gel-60 with a particle size of230-400 mesh Pyridine, dichloromethane (CHzClz), tetrahydrofuran (THF), dimethylformamide (DMF), ac’etonitrile (ACN), methanol (MeOl-l), and 1,4-dioxane were from Baker or Aldrich and'1n some cases the reagents were Aldrich Sure-Seal bottles kept under dry nitrogen. All reactions were stirred magnetically unless ise noted.
EXAMPLE 1 Preparation of 5-(2-(2,4-dime‘thexyphenoxy)(trifluoromethyl)benzamido)p_‘icolinic-acid.‘(65) .
. O o OH . ; / %N \ I N , . ,' ' A solution of 2-fluoro-5—(trifluoromethy1)benzoyl chloride (2.9.8 mL,I1-9.72- mmol) in dichloromethane (22.3 mL) was added drop-wise to a mixture of methyl Sraminopyridihe-Z: .I carboxylate (3.0 g, 19.72 mmol), pyridine (4280 mL, 59.16 mmol) and dichloromethane (89.4 11113) at ‘0 °C. The mixture was removed from the ice bath after 1.5 hours and was Stirred at room temperature for 0.5 hours. The mixture was poured into 1N HCl (50 mL) and dichloromethane (50' mL). The - layers were separated and the organic layer was dried over sodium sulfate, d and concentrated under reduced pressure. The product was slurried in hexanes- to ‘imp‘urities. The solid was isolated by filtration rinsing with s to yield methy1"5-[[2-fluoro (trifluoromethyl)benzoyl]amino]pyridine-Z-carboxylate (5.16 g, 76%) as an off-white solid. ll-lINMR (400 MHz, DMSO-d6) 511.18 (s, 1H), 8.95 (d, J.= 2.5 Hz, 1H), 8.38 (dd, J = 8.6, 2.5Hz, 1H), 8.16 (dd, .1 = 6.1,‘2.4 Hz, 1H), 8.13 (d, J = 8.6 Hz, 1H), 8.09 - 7.98 (m, lH),7.67 (t, J .= 9.2 Hz, 1H1, 3.88 (s, 311) ppm. ESI-MS m/z calc. 342.06, found 343.2 (M+l )+; Retention time: 1.54 minutes,(3 minutes run).
To, methyl 5-[[2-fluoro(trifluoromethyl)b‘enzoyl]amino]pyridine-2— carboxylate (51.3 mg, 0.15 mmol) in N-methylpyrrolidinone (1 mL) was added 2,4-dimethoxyphenol (23.1 mg, 0.45 mmol), cesiumcarbonate (146.6 mg,.0.45 mmol) and the mixture was heated 'at 100 °C RECTIIFIED SHEET (RULE 91) ISA/EP for 50 minutes to yield methyl 5-(2-(2,4-dimethoxyphenoxyj—S-(trifluoromethyl)benzamido)picolinate that was taken into the next step without further purification, Sodium hydroitide (150 uL, 3M) and methanol(150' uL) were added to the methyl 5-(2-(2,4-dimethoxyphenoxy)(trifluoromethyl)benzamido)pico‘linate prepared~ in the previous step; and the reaction was stirred at 50 °C for 3 hours. The on mixture was filtered and purified by reverse phase preparative chromatography utilizing a gradient of 10-99% acetonitrile'in water containing HCl as a r to yield 2,4-dimethoxyphenoxy)—5- (trifluoromethyl)benzamido)picolinic acid hydrochloric acid (65).(37.3 mg, 49%). 'H NMR (400 MHz, DMSO-d6) 6 10.97 (s, 1H), 3.97 (d, J =‘2'.5 Hz, 1H), 8.35 (dd, J = 8.8, 2.5 Hz, 1H), 8.09 (d, J ? 8.6 Hz, 1H), 8.00 (d, .l = 2.3 Hz, 1.1-1), 7.78 (dd, J = 8.9, 2.4 Hz, 1H), 7.24 (d, J = 8.8 Hz, 1H), 6.92 - 6.69 (m, 2H),. 6.61 (dd, J = 8.8,.2.8 Hz, 1H), 3.79 (s, 3H), 3.73 (5,; 3H) ppm. ESI-MS m/z calc. 462.10, found 463.5 (M+l)+_; Retention time: 1.81 minutes (3 minutes run).
The fellowing compounds were prepared using a procedure similar to the One described above for compound 65’ from the following alcohols. '5-(2-(4-chloroniethoxyphenoxy)—5- ' 4—chloro-Z-methoxy-phenol trifluorometh l benzamido ic acid ' 67 5-(2.-(4~methoxymethylphenoxy) oxymethyl-phenol " trifluorometh l benzamido icolinic acid -(2-(2-chloroflu0rophenoxy)-5; , 2-chloroJ4-fluoro-phenol trifluorometh l benzamido oicolinic acid 57 4~fl‘uoro~2'-methoxyphenoxy)é5‘- trifluorometh l benzamido icolinic acid -(2—(4-fluoro-Z-methylphenoxy)—54 , trifluorometh l‘benzamido nicolinic acid -(2-(3-flupro’Z-methoxyphenoxy) trifluorometh l benzamido uicolinic acid _ -(2—(2—chl0romethoxyphenoxy)—S— trifluorometh l benzamido icolinic acid — -(2-(4~chloromethylphenoxy,) 4-chloro 2-methyl phenol trifluorometh l benzamido aicolinic acid 71 5-(2-(4~fluorophenoxy) 4 fluorophenol trifluorometh l benzamido nic acid 62 5-(2-(2-methoxyphenoxy) 2-methoxyphenol trifluorometh l benzamido icolinic acid 63 5-(2-(2-chlorophenoxy) 2-chlorophenol trifluorometh l benzamido icolinic acid 2-(difluoromethdxy)phenoxy)-S- 2-(difluoromethoxy)phenol rometh l benzamido nicolinic acid -(2-(5-fluoromethoxyphenoxy) S-fluoro 2 methoxy phenol trifluorometh l benzamido icolinic acid - 2- crooxl nhenox oroox nhenol ' RECTIFIED SHEET (RULE 91) ISA/EP (trifiuoromethyl)benzamido)picolinic acid 70 henoxy-5 - phenol (trifiuoromethyl)benzamido)picolinic acid EXAMPLE 2 Preparation of 5-(4,5-dichloro(4-fiuoromethoxyphenoxy)benzamido)picolinic acid (51) O / OH CI \ N CI 0 A solution of 4,5-dichlorofiuoro-benzoyl chloride (4.35 g, 19.13 mmol) in dichloromethane (40 mL) was added drop-wise to a mixture of methyl 5-aminopyridinecarboxylate (2.91 g, 19.13 mmol), pyridine (4.64 mL, 57.39 mmol) and dichloromethane (60 mL) at 0 OC. The reaction was stirred and allowed to warm up to room temperature over 2 hours. The mixture was poured into 1N HCl (50 mL) and romethane (50 mL). The two layers were separated. The aqueous layer was ted with dichloromethane (3 x 200 mL). The combined organic layer was washed with water (1 x 150 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure. The product was slurried in hexanes to remove impurities. The solid was isolated by filtration using hexane to yield methyl 5-[(4,5-dichlorofiuoro-benzoyl)amino]pyridine carboxylate (5.33 g, 81%) as a cream color solid. 1H NMR (400 MHz, DMSO-d6) 8 11.11 (s, 1H), 8.94 (d, J = 2.5 Hz, 1H), 8.36 (dd, J = 8.6, 2.5 Hz, 1H), 8.12 (d, J = 8.6 Hz, 1H), 8.08 (d, J = 6.6 Hz, 1H), 7.95 (d, J = 9.6 Hz, 1H), 3.87 (s, 3H) ppm. ESI-MS m/z calc. 342.00, found 343.1 (M+1)+; Retention time: 1.72 minutes (3 minutes run).
Methyl 5-[(4,5-dichlorofluoro-benzoyl)amino]pyridinecarboxylate (50 mg, 0.14 mmol), romethoxy-phenol (18.27 ”L, 0.16 mmol) and K2CO3 (60.41 mg, 0.44 mmol) were combined in DMF (0.5 mL) and heated at 70 °C for 1.5 hours to form methyl 5-[[4,5- dichloro(4-fiuoromethoxy-phenoxy)benzoyl]amino]pyridinecarboxylate. Aqueous NaOH (145.7 ”L of 3 M, 0.44 mmol) was then added and heating continued for 30 min. HPLC purification (1-99% CH3CN / 5mM HCl) ed 5-(4,5-dichloro(4-fluoro yphenoxy)benzamido)picolinic acid (51) (35.28 mg, 54%) as a white solid. 1H NMR (400 MHz, DMSO-d6) 8 13.05 (s, 1H), 10.96 (s, 1H), 8.93 (d, J = 2.4 Hz, 1H), 8.30 (dd, J = 8.7, 2.5 Hz, 1H), 8.08 (d, J = 8.6 Hz, 1H), 7.97 (s, 1H), 7.27 (dd, J = 8.9, 5.8 Hz, 1H), 7.12 (dd, J = 10.7, 2.9 Hz, 1H), 6.91 (s, 1H), 6.84 (td, J = 8.5, 2.9 Hz, 1H), 3.75 (s, 3H) ppm. ESl-MS m/z calc. 450.02, found 451.1 (M+1)+; Retention time: 1.61 minutes (3 minutes run).
] The following compounds were prepared using a procedure similar to the one described above for compound 51 from the ing alcohols.
Cmpd Product name Alcohol 32 5-(4,5-dichloro(4-fluoro 4-fluoromethyl- methylphenoxy)benzamido)picolinic acid phenol 41 5-(4,5-dichloro(2-chloro 2-chlorofluoro- henoxy)benzamido)picolinic acid phenol 39 5-(4,5-dichloro(2,4- 2,4-dimethoxyphenol dimethoxyphenoxy)benzamido)picolinic acid 44 5-(4,5-dichloro(4- 4- oromethoxy)phenoxy)benzamido)picolinic acid oromethoxy)phen 42 5-(4,5-dichloro(2,4- 2,4-difluorophenol difluorophenoxy)benzamido)picolinic acid 40 5-(4,5-dichloro(3-fluoro 3-fluoromethoxy- methoxyphenoxy)benzamido)picolinic acid phenol 5-(4,5-dichloro(4-fluorophenoxy)benzamido)picolinic 4-fluorophenol acid 36 5-(4,5-dichloro(4-chloro 4-chloromethoxy- methoxyphenoxy)benzamido)picolinic acid phenol 37 5-(4,5-dichloro(2- 2- (difluoromethoxy)phenoxy)benzamido)picolinic acid (difluoromethoxy)phen 5-(4,5-dichloro(4-(2,2,2- 4-(2,2,2- trifluoroethoxy)phenoxy)benzamido)picolinic acid trifluoroethoxy)phenol 34 5-(4,5-dichloro(2-fluoro 2-fluoromethoxy- methoxyphenoxy)benzamido)picolinic acid phenol 43 5-(4,5-dichloro(2-chloro 2-chloromethoxy- methoxyphenoxy)benzamido)picolinic acid phenol 38 5-(4,5-dichloro(4-chloro 4-chloromethyl- methylphenoxy)benzamido)picolinic acid phenol 33 5- 4,5-dichloro ohenox benzamido oicolinic acid ohenol -(4,5-dichloro(4- 2-isopentanol iso oent lox ohenox benzamido oicolinic acid EXAMPLE 3 Preparation of 5-(2-(2,4-dimethoxyphenoxy)-4,6-bis(trifluoromethyl)benzamido)picolinic acid (49) CF3 o / OH F3C o A on of 2-fiuoro-4,6-bis(trifiuoromethyl)benzoyl chloride (1.0 g, 3.39 mmol) and dichloromethane (5.0 mL) was added drop-wise to a mixture of methyl 5-aminopyridine carboxylate (619.9 mg, 4.07 mmol), pyridine (824.1 ”L, 10.18 mmol) in dichloromethane (20.00 mL) at 0 OC. The mixture was allowed to warm to room temperature and was stirred at that temperature overnight. The mixture was poured into 1N HCl and dichloromethane. The layers were separated and the organic layer was dried over sodium sulfate, filtered and concentrated under reduced pressure to give a tan solid. The product was purified on column tography eluting with 10-100% ethyl acetate in hexanes to obtain methyl 5-[[2-fluoro-4,6-bis(trifiuoromethyl)benzoyl]amino]pyridine carboxylate (850 mg, 61%) as a white solid. ESl-MS m/z calc. 410.05, found 411.0 (M+1)+; Retention time: 0.62 minutes (3 minutes run). 1H NMR (400 MHz, DMSO-d6) 5 11.59 (s, 1H), 8.86 (d, J = 2.4 Hz, 1H), 8.48 = 8.6, 2.6 Hz, 1H), 8.20 (s, 1H), 8.15 (d, J = 8.6 - 8.41 (m, 1H), 8.34 (dd, J Hz, 1H), 3.89 (s, 3H) ppm.
Methyl 5-[[2-fluoro-4,6-bis(trifiuoromethyl)benzoyl] amino]pyridine ylate (60 mg, 0.15 mmol), 2,4-dimethoxyphenol (24.80 mg, 0.16 mmol) and K2C03 (60.66 mg, 0.44 mmol) were combined in DMF (0.4 mL) and heated at 70°C. Once the reaction was completed (by HPLC), aqueous 5 M NaOH (87.8 uL, 0.44 mmol) was added and the reaction was heated to 50 OC and monitored by HPLC until the on was complete. The reaction was cooled to 25 OC, filtered and purified by reverse phase HPLC using a nt of 1-99% ACN in Water and HCl as a r to yield 5-(2-(2,4-dimethoxyphenoxy)-4,6-bis(trifluoromethyl)benzamido)picolinic acid (49) (18 mg, 22%). ESI-MS m/z calc. 530.09, found 531.3 ; Retention time: 1.54 minutes (3 minutes run). 1H NMR (400 MHz, DMSO-d6) 8 11.41 (s, 1H), 8.89 (d, J = 2.5 Hz, 1H), 8.32 (dd, J = 8.6, 2.5 Hz, 1H), 8.10 (d, J = 8.5 Hz, 1H), 7.90 (s, 1H), 7.17 (d, J = 8.8 Hz, 1H), 7.07 (s, 1H), 6.79 (d, J = 2.8 Hz, 1H), 6.61 (dd, J = 8.9, 2.8 Hz, 1H), 3.78 (d, J = 14.3 Hz, 6H) ppm.
The following compounds were prepared using a procedure r to the one described above for compound 49 from the following alcohols.
Cmpd. Product name Alcohol 50 5-(2-(4-fluorophenoxy)-4,6- 4-fluorophenol bis(trifiuoromethyl)benzamido)picolinic acid 48 5-(2-(4-fluoromethoxyphenoxy)-4,6- 4-fluoromethoxy-phenol bis(trifiuoromethyl)benzamido)picolinic acid 47 5-(2-(4-fluoromethylphenoxy)-4,6- 4-fluoromethyl-phenol bis(trifiuoromethyl)benzamido)picolinic acid 46 5-(2-(4-methoxyphenoxy)-4,6- 4-methoxyphenol bis(trifiuoromethyl)benzamido)picolinic acid 45 5-(2-(2-methoxyphenoxy)-4,6- 2-methoxyphenol bis(trifiuoromethyl)benzamido)picolinic acid EXAMPLE 4 Preparation of 4-fiuoromethoxyphenoxy)(perfiuoroethyl)benzamido)picolinic acid (72) O / OH F3C H F F o\ A solution of 2-fluoro(1,1,2,2,2-pentafluoroethyl)benzoic acid (80.48 mg, 0.31 mmol), ethyl 5-aminopyridinecarboxylate (57.0 mg, 0.34 mmol), HATU (130.4 mg, 0.34 mmol) and N—methylmorpholine (68.57 “L, 0.62 mmol) in DMF (1 mL) was stirred at 25 0C for 16 hours. The reaction mixture was poured into water and extracted with ethyl acetate (3x). The cs were combined, washed with water, brine, dried over Na2S04, filtered and evaporated to give ethyl 5 - [[2-fiuoro(1,1,2,2,2-pentafiuoroethyl)benzoyl]amino]pyridinecarboxylate (110 mg, 87%) as an orange waxy solid. ESl-MS m/z calc. 406.07, found 407.3 (M+1)+; Retention time: 1.64 minutes (3 minutes run).
] Ethyl 5-[[2-fluoro(1,1,2,2,2-pentafiuoroethyl)benzoyl]amino]pyridine carboxylate (40.63 mg, 0.10 mmol), 4-fluoromethoxyphenol (42.64 mg, 0.30 mmol) and Cs2C03 (97.75 mg, 0.30 mmol) in NMP (0.4 mL) was stirred at 90 0C for 1 hour. Aqueous 3M NaOH (100 uL) and MeOH (0.2 mL) were added and the mixture was stirred at 40 0C for 1h. The mixture was diluted with methanol, filtered and purified by reverse phase HPLC using a gradient ofACN in Water ) and HCl as a modifier to give 4-fiuoromethoxyphenoxy) (perfluoroethyl)benzamido)picolinic acid (72) (20.42 mg, 36%). ESl-MS m/z calc. , found 501.3 (M+1)+; Retention time: 1.69 minutes (3 minutes run). 1H NMR (400 MHZ, DMSO) 5 11.08 (s, 1H), 8.95 (d, J = 2.4 Hz, 1H), 8.33 (dd, J = 8.6, 2.5 Hz, 1H), 8.08 (d, J = 8.6 Hz, 1H), 7.90 (d, J = 8.0 Hz, 1H), 7.54 (d, J = 8.0 Hz, 1H), 7.31 (dd, J = 8.8, 5.9 Hz, 1H), 7.16 (dd, J = 10.7, 2.9 Hz, 1H), 6.98 - 6.85 (m, 1H), 6.80 (s, 1H), 3.72 (s, 3H) ppm. 4-Fluorophenoxy)(perfluoroethyl)benzamido)picolinic acid (73) was prepared as described above for compound 72 from 4-fluorophenol.
EXAMPLE 5 Preparation of 5-(2-(2-chlorofluorophenoxy)(trifluoromethyl)benzamido)picolinic acid (74) CF30 /| OH To a on of 2-chlorofluoro-phenol (20.97 g, 143.10 mmol) and 2- 6-(trifluoromethyl)benzaldehyde (25 g, 130.1 mmol) in DMF (125.0 mL) was added Cs2C03 (46.62 g, 143.1 mmol) and the reaction mixture was stirred at 100 0C for 1 hour. The reaction mixture was poured into water (500 ml) and extracted with ethyl acetate (3 x 150 ml). The organics were combined, washed with water, brine (2x), dried over Na2S04, filtered and evaporated to give a red oil which solidified after standing over night. The material was then triturated with hot hexanes and cooled to 25 °C. The slurry was filtered and washed with cold hexanes to give 2-(2-chlorofluoro- phenoxy)(trifluoromethyl)benzaldehyde (32.7 g, 79%) as an off white solid. 1H NMR (400 MHz, DMSO) 8 10.61 (s, 1H), 7.84 = 7.9 Hz, 1H), 7.47 (dd, J = 9.0, 5.3 Hz, 1H), - 7.70 (m, 2H), 7.66 (d, J 7.42 = 8.3 Hz, 1H) ppm. - 7.32 (m, 1H), 7.12 (d, J To a solution of 2-(2-chlorofluoro-phenoxy) (trifluoromethyl)benzaldehyde (31 g, 97.29 mmol) in tBuOH (155.0 mL), water (100.8 mL), CH3CN ( 155 .0 mL) and 2-methylbutene (51.45 mL, 486.4 mmol) was added sodium ogen phosphate (35.02 g, 291.9 mmol) and the mixture was cooled to 0 OC. Sodium te (26.40 g, 291.9 mmol) was added in one portion and the mixture was stirred at 25 0C for 1 hour. The pH of the on was adjusted to 2-3 with 1N HCl and the layers were separated. The aqueous layer was extracted with EtOAc (3x). All the organic layers were combined, and solid sodium sulfite (~5 g) was added followed by brine (50 ml) and 1N NaOH (10 ml) and the mixture was shaken until the yellow color disappeared. The layers were separated and the organic was washed with brine, dried over Na2S04, filtered h a short plug of silica and evaporated to s to give 2-(2-chlorofluoro-phenoxy)- 6-(trifiuoromethyl)benzoic acid (40 g, 98%) as an oil that was used in the next step without further purification. ESI-MS m/z calc. 334.00, found 335.1 (M+1)+; Retention time: 1.58 minutes (3 minutes run).
A solution of 2-(2-chlorofiuoro-phenoxy)(trifiuoromethyl)benzoic acid (33.46 mg, 0.10 mmol), ethyl 5-aminopyridinecarboxylate (19.94 mg, 0.12 mmol), HATU (41.83 mg, 0.11 mmol) and N—methylmorpholine (21.99 uL, 0.20 mmol) was stirred at 100 0C for 8 hours.
NaH (16.00 mg, 0.40 mmol) was added and the e was stirred at 100 0C for 10 min. The mixture was d and purified by reverse phase HPLC using a gradient of acetonitrile in Water (1-99% ) and HCl as a modifier, to give 5-[[2-(2-chlorofluoro-phenoxy) (trifiuoromethyl)benzoyl]amino]pyridinecarboxylic acid (74) (2.52 mg, 5%) as a white solid. ESI- MS m/z calc. 454.03, found 455.3 (M+l)+; ion time: 1.42 minutes (3 s run).
EXAMPLE 6 Preparation of 5-(2-(4-fiuorophenoxy)(trifluoromethyl)benzamido)picolinic acid (56) O OH To a solution of 2-fluoro(trifluoromethyl)benzaldehyde (1.0 g, 5.20 mmol) and 4-fluorophenol (583.5 mg, 5 .20 mmol) in DMF (5.0 mL) was added dicesium carbonate (1.7 g, .20 mmol) and the mixture was heated at 100 0C for 1 hour. The reaction was cooled to room temperature. The reaction was diluted with ethyl acetate (5 ml) and water (10 ml). The organic layer was washed with water (2 x 10 mL), dried with MgSO4 filtered and evaporated to yield a brown oil that was purified by column chromatography using a gradient of ethyl acetate in hexanes (0-25%) to yield 2-(4-fiuorophenoxy)(trifluoromethyl)benzaldehyde (1.16 g, 78%). 1H NMR (400 MHz, CDCl3) 8 10.58 (s, 1H), 8.04 (d, J = 8.0 Hz, 1H), 7.42 (d, J = 7.5 Hz, 1H), 7.18-7.04 (m, 5H) ppm.
To a solution of 2-(4-fluorophenoxy)(trifluoromethyl)benzaldehyde (1.16 g, 4.08 mmol) in tBuOH (11.60 mL), water (7.30 mL), itrile (7.30 mL) was added sodium dihydrogen phosphate (1.47 g, 12.25 mmol), 2-methylbutene (2.16 mL, 20.42 mmol) and sodium —104— chlorite (1.11 g, 12.25 mmol) and the reaction mixture was stirred at 25 0C for 2 hours. The reaction was acidified with 1N HCl and diluted with ethyl acetate. Sodium sulfide was added to remove the slightly yellow color. The 2 layers were separated and the s layer extracted 2 additional times with ethyl acetate. The organics were combined, dried with MgSO4, filtered and evaporated to give 2- (4-fluorophenoxy)(trifluoromethyl)benzoic acid (1.0 g, 82%) as a yellow solid that was used in the next step without further purification. 1H NMR (400 MHz, DMSO) 5 8.01 (d, J = 8.0 Hz, 1H), 7.62 (d, J = 7.9 Hz, 1H), 7.33 - 7.18 (m, 3H), 7.14 - 7.01 (m, 2H) ppm.
A solution of methyl 5-aminopicolinate (15.2 mg, 0.1 mmol), 2-(4- fluorophenoxy)(trifluoromethyl)benzoic acid (33.0 mg, 0.12 mmol), N—methylmorpholine (22 uL, 0.2 mmol) and HATU (45.6 mg, 0.12 mmol) in DMF (0.4 mL) was stirred at 40 0C for 16 hours.
Aqueous NaOH (166.7 uL, 3M) and methanol (0.2 mL) were added and the e was stirred at 40 0C for 1 hour. The reaction mixture was diluted with MeOH, filtered and purification by reverse phase HPLC using a gradient ofACN in Water (1-99%) and HCl as a modifier to give 5-(2-(4- fluorophenoxy)(trifluoromethyl)benzamido)picolinic acid (56) (9.95 mg, 33%). ESl-MS m/z calc. 420.07, found 421.29 (M+1)+; ion time: 1.60 minutes (3 minutes run). 1H NMR (400 MHz, DMSO)813.15 = 8.8 - 12.96 (m, 1H), 11.09 (s, 1H), 8.90 (s, 1H), 8.28 (d, J= 8.0 Hz, 1H), 8.07 (d, J Hz, 1H), 7.92 (d, J = 7.8 Hz, 1H), 7.66 (d, J = 7.9 Hz, 1H), 7.36 - 7.13 (m, 5H) ppm.
EXAMPLE 7 Preparation of 4-(4,5-dichloro(4-fluoromethoxyphenoxy)benzamido)picolinic acid (76) O / IN CI \ OH CI 0 ] 4,5-Dichlorofluoro-benzoic acid (50 mg, 0.24 mmol), HATU (100.0 mg, 0.26 mmol) and N—methoxymethanamine (hydrochloric acid) (23.33 mg, 0.24 mmol) were combined in DMF (1.0 mL) and treated with DIEA (83.33 uL, 0.48 mmol). After 10 min, the reaction was complete. The reaction was d with diethyl ether and washed with 50% sat. NaHCO3 (2x) and brine, dried over Na2S04, filtered and concentrated. Silica gel chromatography using a nt of ethyl acetate/hexanes from 0 to 30% provided 4,5-dichlorofluoro-N-methoxy-N-methyl-benzamide (50 mg, 83%) as a colorless oil. 1H NMR (400 MHz, CDCl3) 8 7.54 (d, J = 6.3 Hz, 1H), 7.26 (d, J = 8.6 Hz, 1H), 3.56 (s, 3H), 3.35 (s, 3H) ppm.
To a stirring on of chlorofluoro-N-methoxy-N—methyl- benzamide (5.1 g, 20.23 mmol) in THF (100 mL) at -780 was added a solution of lithium aluminum hydride in THF (12.14 mL of 2 M, 24.28 mmol). After 3 h at -78°C, 50 mL water was added ed by 50 mL of 1N HCl. The reaction was allowed to warm to 25 oC and d for 1h. The on was diluted with water and extracted with diethyl ether. The ether was dried over Na2S04, filtered, and concentrated to provide crude 4,5-dichlorofluoro-benzaldehyde that was taken directly into the next step without further purification.
Crude 4,5-dichlorofluoro-benzaldehyde, 4-fluoromethoxy-phenol (2.31 mL, 20.23 mmol) and K2CO3 (5.59 g, 40.46 mmol) were combined in DMF (100 mL) and heated for ~30 min at 70 °C, then at 55 °C overnight. The reaction was cooled, diluted with water (500 mL) and extracted with diethyl ether. The ether layer was dried over , filtered, and concentrated. Silica gel tography using a gradient of ethyl acetate/hexane (0-40%) provided 4,5-dichloro(4- fiuoromethoxy-phenoxy)benzaldehyde (3.30 g, 51%) as a crystalline white solid. 1H NMR (400 MHz, DMSO-d6) 8 10.39 (s, 1H), 7.93 (s, 1H), 7.35 (dd, J = 8.8, 5.8 Hz, 1H), 7.19 (dd, J = 10.7, 2.9 Hz, 1H), 6.92 - 6.85 (m, 2H), 3.78 (s, 3H) ppm.
To a solution of 4,5-dichloro(4-fiuoromethoxy-phenoxy)benzaldehyde (3.3 g, 10.47 mmol) in tBuOH (33.00 mL), water (19.80 mL) and acetonitrile ( 19.80 mL) was added sodium dihydrogen phosphate (655.9 uL, 10.47 mmol), 2-methylbutene (5.54 mL, 52.35 mmol) and sodium chlorite (2.84 g, 31.41 mmol). The reaction mixture was d at 25 0C for 1h. The reaction mixture was acidified with 1N HCl and diluted with ethyl acetate. Sodium sulfite was added to remove the faint yellow color. The two layers were separated and the aqueous layer was extracted with ethyl e (3 x 25 mL). The combined organics were washed with brine, dried over sodium sulfate, filtered and concentrated. The solid was triturated with hexanes and filtered to provide 4,5 - dichloro(4-fiuoromethoxy-phenoxy)benzoic acid (2.94 g, 85%) as a white solid. 1H NMR (400 MHz, DMSO-d6) 8 13.37 (br s, 1H), 7.96 (s, 1H), 7.18 - 7.12 (m, 2H), 6.86 - 6.80 (m, 2H), 3.76 (s, 3H) ppm. 4,5-Dichloro(4-fiuoromethoxy-phenoxy)benzoic acid (40 mg, 0.12 mmol), methyl 4-aminopicolinate (36.5 mg, 0.24 mmol) and HATU (45.9 mg, 0.12 mmol) were combined in DMF (1 mL) and heated at 50 0c for 2 hours. The reaction was treated with 10 drops of 3 M NaOH and heated at 50 °C for 16 h. The reaction was filtered and purified by reverse phase HPLC using a gradient of acetonitrile in water containing HCl (5 mM) as a modifier (10-99%) to yield 4-(4,5- dichloro(4-fluoromethoxyphenoxy)benzamido)picolinic acid (76) (3.80 mg, 7%). ESl-MS m/z calc. 450.02, found 451.1 (M+1)+; ion time: 1.47 minutes (3 minutes run).
EXAMPLE 8 2014/013667 Preparation of 4-(2-(4-fluoromethoxyphenoxy)(perfluoroethyl)benzamido)benzoic acid (27) O OH F H F C3 F O\ To a solution of 2-(4-fluoromethoxy-phenoxy)(1,1,2,2,2- pentafluoroethyl)benzoic acid (152.1 mg, 0.10 mmol), tert—butyl 4-aminobenzoate (21.26 mg, 0.11 mmol) and HATU (41.83 mg, 0.11 mmol) in DMF (0.5 mL) was added N—methylmorpholine (24.18 uL, 0.22 mmol) and the mixture was stirred at 25°C for 16 hours. The mixture was poured into water and extracted with ethyl e (3x). The organics were combined, evaporated and taken up in dichloromethane (0.25 mL). TFA (0.25 mL, 3.245 mmol) was added and the reaction mixture was stirred at 25 0C for 1h. The mixture was diluted with MeOH, filtered and purified by reverse phase HPLC using a gradient of acetonitrile in water (1-99%) containing HCl as a modifier to give 4-[[2-(4- fluoromethoxy-phenoxy)(1,1,2,2,2-pentafluoroethyl)benzoyl]amino]benzoic acid (27) (5.16 mg, %) as a white solid. ESl-MS m/z calc. 499.07, found 500.3 (M+1)+; Retention time: 1.82 minutes (3 minutes run). 1H NMR (400 MHz, DMSO) 8 12.80 (s, 1H), 10.84 (s, 1H), 7.94 (d, J = 8.6 Hz, 2H), 7.87 (d, J = 8.0 Hz, 1H), 7.83 (d, J = 8.8 Hz, 2H), 7.52 (d, J = 7.9 Hz, 1H), 7.40 - 7.27 (m, 1H), 7.16 (dd, J = 10.6, 2.8 Hz, 1H), 6.98 - 6.82 (m, 1H), 6.77 (s, 1H), 3.73 (s, 3H) ppm.
EXAMPLE 9 ation of 4-(2-(2,4-difluorophenoxy)(perfluoroethyl)benzamido)benzoic acid (2) O OH F H F F ] 4-Bromofluoro-benzoic acid (3.5 g, 15.98 mmol) was dissolved in DMSO (70.00 mL) at 25 0C under N2 atmosphere. The 1,1,1,2,2,2-pentafluoroiodoethane tank was cooled and then excess poured into a reaction flask under N2. A mixture of activated copper (nanoparticles < 100nM) (8.528 g, 134.2 mmol) was added and the reaction flask was sealed under N2 and heated in an oil bath for 30 minutes at 100 0C, then the temperature was raised to 120 oC and stirred for 48 hrs.
After 48 hours, the reaction mixture was cooled to 25 OC. The reaction mixture was d and the copper filter cake was washed with 40 ml DMSO. The filtrate was diluted with ethyl acetate (450 ml) and re-filtered to get rid of any remaining copper salt. To the filtrate was added 1000 ml water and the mixture was ted 3 times with ethyl acetate. The organic layer was washed 3 times with water and brine, dried over Na2S04, filtered and evaporated to dryness to give 2.8 g of crude product that was purified by column chromatography on silica gel using a gradient of ethyl acetate and hexanes (0- 40%). 2-Fluoro(1,1,2,2,2-pentafiuoroethyl)benzoic acid (1.80 g, 44%) was ed as an as off- white solid.
] To 2-fluoro(1,1,2,2,2-pentafluoroethyl)benzoic acid (1 g, 3.87 mmol) was added thionyl chloride (3.67 mL, 50.36 mmol) and the reaction was d at 60 0C for 22 hours.
Excess thionyl chloride was removed in vacuo to yield 2-fluoro(1,1,2,2,2-pentafluoroethyl)benzoyl chloride (1 g, 93%) a s a viscous yellow liquid.
A solution of 2-fluoro(1,1,2,2,2-pentafiuoroethyl)benzoyl chloride (0.46 g, 1.66 mmol) in dichloromethane (6.34 mL) was added dropwise to a mixture of tert-butyl 4- aminobenzoate (321.4 mg, 1.66 mmol), pyridine (403.5 uL, 4.99 mmol) and dichloromethane (4.2 mL) at 0 OC. The reaction was d and allowed to warm up to room temperature over 18 hours. To this reaction, water (5 mL) was added. The two layers were separated. The organic layer was washed with water (2 x 10 mL), dried over , filtered and evaporated under reduced pressure to yield tert- butyl 4-[[2-fiuoro(1,1,2,2,2-pentafiuoroethyl)benzoyl]amino]benzoate (0.7 g, 97%) that was used in the next step without further purification. ESI-MS m/z calc. 433.11, found 434.3 (M+1)+; Retention time: 2.27 minutes (3 minutes run). 1H NMR (400 MHz, DMSO-d6) 5 10.96 (s, 1H), 7.99 - 7.90 (m, 3H), 7.90 = 8.1, 1.7 Hz, 1H), 1.55 (s, 9H) ppm. - 7.80 (m, 3H), 7.71 (dd, J A mitxture of tert-butyl 4-[[2-fiuoro(1,1,2,2,2- pentafluoroethyl)benzoyl]amino]benzoate (130 mg, 0.30 mmol), 2,4-difluorophenol (39.03 mg, 0.3 mmol), potassium carbonate (41.16 mg, 0.3 mmol) and N—methylpyrrolidinone (2 mL) was stirred at 100 0C for 3 hours. The reaction was filtered and taken to the next step without r purification.
The ester obtained in the previous step was dissolved in dichloromethane (1 mL). 2,2,2-Trifiuoroacetic acid (4 mL, 52.50 mmol) was added and the reaction was stirred at 40 0C for 18 hours. The excess TFA and dichloromethane was evaporated under reduced pressure. The crude product was d and purified by reverse phase preparative chromatography utilizing a gradient of 30-99% acetonitrile in water containing HCl as a modifier to yield 2,4- difiuorophenoxy)(perfiuoroethyl)benzamido)benzoic acid (2) (31.8 mg, 22%). ESI-MS m/z calc. 487.07, found 488.5 (M+1)+; Retention time: 2.01 minutes (3 minutes run). 1H NMR (400 MHz, DMSO-d6) 8 12.80 (s, 1H), 10.92 (s, 1H), 7.98 - 7.87 (m, 3H), 7.87 - 7.75 (m, 2H), 7.68 - 7.59 (m, 1H), 7.57 - 7.45 (m, 1H), 7.44 - 7.31 (m, 1H), 7.22 - 7.13 (m, 1H), 7.11 (s, 1H) ppm. 4-(2-(4-fluoromethylphenoxy)(perfiuoroethyl)benzamido)benzoic acid (3) was prepared following a procedure similar to the one reported above for compound 2 from 4- fluoromethylphenol.
EXAMPLE 10 Preparation of 4-(2-(4-(trifiuoromethoxy)phenoxy)(trifiuoromethyl)benzamido)benzoic acid (7) o /[::]/fl\OH 11%N F4: 0 OCF3 A solution of 2-fluoro(trifiuoromethyl)benzoyl chloride (3 g, 13.24 mmol) in romethane (27.6 mL) was added dropwise to a e of methyl obenzoate (2.0 g, 13.24 mmol), pyridine (3.21 mL, 39.72 mmol) and dichloromethane (41.4 mL) at 0 OC. The on was stirred and allowed to warm up to room temperature over 2 hours. To the reaction, water (30 mL) was added. The solid was isolated by filtration, washed with water (2 x 30 mL) and hexane (2 x 30 mL) to yield methyl 4-[[2-fiuoro(trifluoromethyl)benzoyl]amino]benzoate (3.811 g, 84%) as a white solid. ESl-MS m/z calc. 341.07, found 342.2 (M+1)+; Retention time: 1.64 minutes (3 minutes run). 1H NMR (400 MHz, DMSO-d6) 8 10.97 (s, 1H), 8.02 - 7.96 (m, 2H), 7.96 - 7.89 (m, 2H), 7.89 - 7.83 (m, 2H), 7.76 (dd, J = 8.0, 1.6 Hz, 1H), 3.85 (s, 3H) ppm.
To methyl 4-[[2-fiuoro(trifiuoromethyl)benzoyl]amino]benzoate (102.4 mg, 0.3 mmol),4-trifiuoromethoxyphenol (38.9 ul, 0.3 mmol), potassium ate (41.46 mg, 0.3 mmol) and ylpyrrolidinone (2 mL) were added and the reaction was stirred at 100 0C for 3 hours. The reaction was filtered and used in the next step without further purification.
To the ester from the previous step were added lithium hydroxide (2M, 450 ”L, 0.9 mmol) and methanol (300 uL) and the on was stirred at 50 0C for 3 hours. The reaction was filtered and purified by reverse phase preparative chromatography utilizing a gradient of 3 0-99% acetonitrile in water containing HCl as a modifier to yield 4-(2-(4-(trifiuoromethoxy)phenoxy) (trifiuoromethyl)benzamido)benzoic acid (7) (53.8 mg, 37%). ESl-MS m/z calc. 485.07, found 486.3 (M+1)+; Retention time: 2.05 minutes (3 minutes run). 1H NMR (400 MHz, DMSO-d6) 5 12.80 (s, 1H), 10.85 (s, 1H), 7.96 - 7.86 (m, 3H), 7.78 - 7.67 (m, 3H), 7.45 - 7.35 (m, 3H), 7.24 - 7.17 (m, 2H) The following compounds were prepared using a procedure r to the one described above for nd 7 from the following alcohols.
Cmpd Product name Alcohol 4-(2-(2-chlorofluorophenoxy) 2-chlorofluoro-phenol (trifluoromethyl)benzamido)benzoic acid 4-(2-(4-fluoromethylphenoxy) 4-fluoromethyl-phenol (trifluoromethyl)benzamido)benzoic acid 4-(2-(2,4-difluorophenoxy) 2,4-difluorophenol (trifluoromethyl)benzamido)benzoic acid EXAMPLE 1 1 Preparation of 4-(4,5-dichloro(4-chloromethoxyphenoxy)benzamido)benzoic acid (18) 0 @0H CI 0 A solution of 4,5-dichlorofluoro-benzoyl chloride (794.5 mg, 3.49 mmol) in dichloromethane (7.3 mL) was added drop-wise to a e of methyl 4-aminobenzoate (528.0 mg, 3.49 mmol), pyridine (847.6 ”L, 10.48 mmol) and dichloromethane (11.0 mL) at 0 OC. The reaction was d and allowed to warm up to room temperature over 1.5 hours. To the reaction, water (10 mL) was added. The solid was isolated by filtration, washed with water (2 x 10 mL) and hexane (2 x mL) to yield methyl 4-[(4,5-dichlorofluoro-benzoyl)amino]benzoate (955 mg, 80%) as a light pink solid. ESl-MS m/z calc. 341.00, found 342.2 (M+1)+; Retention time: 1.75 minutes (3 minutes run). 1H NMR (400 MHz, DMSO-d6) 8 10.90 (s, 1H), 8.03 (d, J = 6.7 Hz, 1H), 8.02 - 7.95 (m, 2H), 7.93 (d, J = 9.4 Hz, 1H), 7.88 - 7.76 (m, 2H), 3.84 (s, 3H) ppm.
A mixture of methyl 5-dichlorofluoro-benzoyl)amino]benzoate (34.21 mg, 0.1 mmol), 4-chloromethoxyphenol (12.16 ul, 0.1 mmol), potassium carbonate 13.82 mg, 0.1 mmol) and N—methyl pyrrolidinone (1 mL) were heated at 80 0C for 2.5 hours. Methanol (100 uL) and sodium ide (3M, 100 uL, 0.3 mmol) were added and the reaction was stirred at 50 0C for 2 hours. An additional 100 ”L ofMeOH and 100 ”L of 3M NaOH were added and the reactions were heated for another hour. The reaction mixture was filtered and purified by reverse phase preparative chromatography utilizing a nt of 10-99% acetonitrile in water containing HCl as a modifier to yield 4-(4,5-dichloro(4-chloromethoxyphenoxy)benzamido)benzoic acid (18) (11.78 mg, 25%).
ESI-MS m/z calc. , found 466.3 (M+l)+; Retention time: 2.20 minutes (3 minutes run).
The following compounds were prepared using a procedure similar to the one bed above for compound 18 from the following alcohols.
Cmpd. Product name Alcohol 4-(4,5-dichloro(4-fluoro 4-fluoromethoxy-phenol omethyl-phenol H .l; 4'(4,5-dichloro-2.(4_ 4-(trifluoromethoxy)phenol trifluoromethox ohenox benzamido benzoic acid 4{4,5-dichloro(4-chloro-2— 4-chloromethyl-phenol meth l henox benzamido benzoic acid 4-(4,5-dichlor0(2a4' 2,4-dimethoxyphenol dimethox phenox ido benzoic acid -dichloro(2-chloro 2-chlorofluoro-phenol N(a) fluoro.henox benzamido benzoic acid 4-(4,5-dichlor0(2a4' 2,4-difluorophenol difluoro.henox benzamido c acid 4'(4,5-dichloro-2.(4_ 4-fluorophenol H (a) fluoro.henox benzamido benzoic acid 4-(4,5-dichloro(4-(2,2,2- H \l trifluoroethox ohenox benzamido benzoic acid 4-(4,5-dichloro(2- 2-(difluoromethoxy)phenol H \O difluoromethox ohenox benzamido benzoic acid 4-(4,5-dichloro(3-fluoro 3-fluoromethoxy-phenol ohenox benzamido benzoic acid 4-(4,5-dichloro(2-chloro 2-chloromethoxy-phenol ohenox benzamido benzoic acid 4-(4,5-dichloro(2-fluoro 2-fluoromethoxy-phenol ohenox ido benzoic acid _15 4-(4,5-dichlorophenoxybenzamido)benzoic acid phenol E l2 Preparation of 4-(2-(4-fluorophenoxy)-4,6-bis(trifluoromethyl)benzamido)benzoic acid (11) CF3 O mam F3C O To a solution of methyl 4-aminobenzoate (514.6 mg, 3.40 mmol) and di- isopropylethyl amine (1.77 mL, 10.18 mmol) in DMF (10 mL) at 0 °C was added a solution of 2- fluoro-4,6-bis(trifluoromethyl)benzoyl chloride (1 g, 3.39 mmol) in dichloromethane. The reaction was complete after 10 min. The reaction mixture was diluted with ethyl acetate and washed with water (2 x 200 mL), 1 N HCl (2 x 50 mL), and brine then dried over Na2S04, filtered and concentrated.
Silica gel chromatography using a gradient of ethyl acetate/hexane (0-100%) ed methyl 4-[[2- fluoro-4,6-bis(trifluoromethyl)benzoyl]amino]benzoate (459 mg, 33%) as an off-white solid. ESl-MS m/z calc. 409.05, found 410.3 (M+1)+; Retention time: 1.86 minutes. 1H NMR (400 MHz, 6) 8 11.22 (s, 1H), 8.36 (s, 1H), 7.62 - 7.57 (m, 2H), 7.56 - 7.51 (m, 2H), 7.51 - 7.46 (m, 1H), 3.42 (s, 3H) ppm. 4-Fluorophenol (12.05 mg, 0.1075 mmol), methyl 4-[[2-fluoro-4,6- bis(trifluoromethyl)benzoyl]amino]benzoate (40 mg, 0.09774 mmol), and K2CO3 (40.52 mg, 0.29 mmol) were combined in DMF (0.5 mL) and heated at 90 °C for 10 min resulting in complete conversion to methyl 4-[[2-(4-fluorophenoxy)-4,6-bis(trifluoromethyl)benzoyl]amino]benzoate.
NaOH (97.73 “L of 3 M, 0.29 mmol) was added and the on heated at 90 °C for 2 hours, then at 50°C for ght. Additional NaOH was added [2 x NaOH (97.73 uL of 3 M, 0.29 mmol), 6 eq] and the reaction heated at 90°C for 5 hours. HPLC purif1cation using a gradient of itrile in water (10-99%) with 5mM HCl as a modif1er ed 4-(2-(4-fluorophenoxy)-4,6- bis(trifluoromethyl)benzamido)benzoic acid (11) as a white solid. ESl-MS m/z calc. 487.06, found 488.3 (M+1)+; Retention time: 1.84 minutes (3 minutes run). 1H NMR (400 MHz, DMSO-d6) 5 12.83 (s, 1H), 11.14 (s, 1H), 7.99 (s, 1H), 7.94 (d, J = 8.7 Hz, 2H), 7.73 (d, J = 8.7 Hz, 2H), 7.48 (s, 1H), 7.36 - 7.22 (m, 4H) ppm.
The following compounds were prepared using a procedure similar to the one bed above for compound 11 from the following alcohols. 4-(2-(4-fluoromethoxyphenoxy)-4,6- 4-fluoromethoxy-phenol WO 20820 bis(trifiuoromethyl)benzamido)benzoic acid 4-fluoromethylphenoxy)-4,6- 4-fiuoromethyl-phenol bis(trifiuoromethyl)benzamido)benzoic acid 4-(2-(2,4-difiuorophenoxy)-4,6- 2,4-difiuorophenol bis(trifiuoromethyl)benzamido)benzoic acid EXAMPLE 13 Preparation of 4-fiuoromethylphenoxy)(trifiuoromethyl)benzamido)benzoic acid (28) o @OH F3C\©5LO NH ] Triethylamine (177.4 ml, 1.27 mmol) was added to a solution of 2-(4-fluoro- 2-methylphenoxy)(trifluoromethyl)benzoic acid (100 mg, 0.32 mmol), HATU (121 mg, 0.32 mmol) and tert—butyl 4-aminobenzoate (61.49 mg, 0.32 mmol) in DMF (1 mL) and the reaction was stirred at room temperature overnight. The reaction was filtered and purified by reverse phase LC-MS using a gradient of acetonitrile in water ( 10-99%) and HCl as a modifier to yield tert-butyl 4-(2-(4-fluoro methylphenoxy)(trifiuoromethyl)benzamido)benzoate (43.8 mg, 28%). ESl-MS m/z calc. 489.16, found 490.3 (M+l)+; Retention time: 2.46 s (3 minutes run). tert-Butyl 4-[[2-(4-fiuoromethyl-phenoxy) (trifiuoromethyl)benzoyl]amino]benzoate (43.8 mg, 0.09 mmol) was suspended in dichloromethane (1.45 mL) and TFA (1.45 mL) was added and the mixture stirred 0.5 h at room temperature. The on mixture was filtered and purified by reverse phase HPLC using a gradient of acetonitrile and water ( 10-99%) and HCl as a modifier to yield 4-(2-(4-fiuoromethylphenoxy) oromethyl)benzamido)benzoic acid (28) (24.71 mg, 67%). ESI-MS m/z calc. 433.09, found 434.3 (M+l)+; Retention time: 2.00 minutes (3 minutes run). 1H NMR (400 MHZ, DMSO) 5 12.78 (s, 1H), 10.83 (s, 1H), 8.01 (d, J = 2.1 Hz, 1H), 7.94 (d, J = 8.7 Hz, 2H), 7.80 (dd, J = 15.4, 5.6 Hz, 3H), 7.18 (m, 3H), 6.83 (d, J = 8.7 Hz, 1H), 2.14 (s, 3H) ppm.
Analytical data for the compounds of the t invention is provided below in Table 2. Mass Spec (e. g., M+l data in Table 2), final purity and retention times were determined by reverse phase HPLC using a Kinetix C18 column (50 X 2.1 mm, 1.7 um particle) from Phenomenex Pn: 00BAN and a dual radient run from 1-99% mobile phase B over 3 minutes. Mobile , g -ll3- phase A = H20 (0.05 % CF3C02H). Mobile phase B = CH3CN (0.05 % CF3C02H). Flow rate = 2 mL/min, injection volume = 3 uL, and column temperature = 50 OC.
] Table 2. Analytical Data LCMS CmNEd Ret. MS 1H-NMR (400 MHz) ° Time in (M+1) minutes (DMSO-d6) 8 12.80 (s, 1H), 10.90 (s, 1H), 7.98 - 7.89 (m, 1 2.08 504.1 3H), 7.83 - 7.74 (m, 2H), 7.68 - 7.60 (m, 2H), 7.40 - 7.27 (m, 2H), 7.02 (s, 1H) ppm.
(DMSO-d6) 5 12.80 (s, 1H), 10.92 (s, 1H), 7.98 - 7.87 (m, 3H), 7.87 - 7.75 (m, 2H), 7.68 - 7.59 (m, 1H), 7.57 - 7.45 2 2.02 488.5 (m, 1H), 7.44 - 7.31 (m, 1H), 7.22 - 7.13 (m, 1H), 7.11 (s, 1H) ppm.
(DMSO-d6) 5 12.80 (s, 1H), 10.89 (s, 1H), 8.02 - 7.87 (m, 3H), 7.87 = 8.1, 1.7 Hz, 1H), 7.33 - 7.69 (m, 2H), 7.57 (dd, J - 7.16 (m, 1H), 7.16 - 7.03 (m, 2H), 6.90 (s, 1H), 2.15 (s, 3H), 7.84 = 8.1, 1.6 Hz, 1H), 7.64 - 7.73 (m, 2H), 7.67 (dd, J (dd, J = 8.4, 2.8 Hz, 1H), 7.41 — 7.26 (m, 2H), 7.11 (s, 1H) I Om.
(DMSO-d6) 5 12.80 (s, 1H), 10.85 (s, 1H), 7.97 - 7.90 (m, 2H), 7.87 (d, J = 7.9 Hz, 1H), 7.83 - 7.75 (m, 2H), 7.61 (dd, J = 7.9, 1.5 Hz, 1H), 7.25 - 7.17 (m, 1H), 7.15 - 7.05 (m, 2H,6.98 d,J= 1.7 Hz, 1H ,2.16 s, 3H .
(DMSO-d6) 5 12.80 (s, 1H), 10.89 (s, 1H), 7.99 - 7.84 (m, 3H), 7.84 = 8.0, 1.6 Hz, 1H), 7.56 - 7.74 (m, 2H), 7.66 (dd, J — 7.44 (m, 1H), 7.44 — 7.28 (m, 1H), 7.25 — 7.10 (m, 2H) I Om. d6) 5 12.80 (s, 1H), 10.85 (s, 1H), 7.96 - 7.86 (m, 3H), 7.78 - 7.67 (m, 3H), 7.45 - 7.35 (m, 3H), 7.24 - 7.17 Hz, 1H), 7.95 (d, J = 8.7 Hz, 2H), 7.74 (d, J = 8.7 Hz, 2H), 7.58 (s, 1H), 7.54 (ddd, J = 11.5, 8.8, 3.0 Hz, 1H), 7.42 (td, J 7.11 m,2H,2.15 s, 3H .
(DMSO-d6) 5 12.82 (s, 1H), 11.11 (s, 1H), 7.95 (d, J = 8.7 Hz, 2H), 7.91 (s, 1H), 7.77 (d, J = 8.8 Hz, 2H), 7.26 (dd, J = 8.9, 5.8 Hz, 1H), 7.19 (dd, J = 10.7, 2.9 Hz, 1H), 7.15 (s, (DMSO-d6) 5 12.83 (s, 1H), 11.14 (s, 1H), 7.99 (s, 1H), 7.94 d, J = 8.7 Hz, 2H 7.73 , d, J = 8.7 Hz, 2H 7.48 , s, —114— LCMS Cmpd.
Ret. MS 1H-NMR (400 MHz) Time in (M+1) minutes 1H), 7.36 - 7.22 (m, 4H) ppm.
(DMSO-d6) 5 12.80 (s, 1H), 10.70 (s, 1H), 7.94 (s, 1H), 7.92 (d, J = 2.7 Hz, 2H), 7.80 (d, J = 8.4 Hz, 2H), 7.37 — 12 2.08 450.3 7.21 (m, 1H), 7.13 (dd, J = 10.7, 2.9 Hz, 1H), 6.87 (s, 1H), 6.84 (dd, J = 8.6, 2.9 Hz, 1H), 3.75 (s, 3H) ppm.
(DMSO-d6) 5 12.79 (s, 1H), 10.77 (s, 1H), 7.98 (s, 1H), 13 2.07 420.1 7.92 (d, J = 8.6 Hz, 2H), 7.76 (d, J = 8.4 Hz, 2H), 7.30 - 7.21 (m, 2H), 7.21 - 7.14 (m, 3H) ppm.
(DMSO-d6) 5 12.79 (s, 1H), 10.78 (s, 1H), 7.97 (s, 1H), 7.96 - 7.88 (m, 2H), 7.77 (d, J = 8.4 Hz, 2H), 7.19 (dd, J = 14 2.1 434.3 9.3, 2.4 Hz, 1H), 7.14 - 7.04 (m, 2H), 6.97 (s, 1H), 2.16 (s, 3H) ppm. d6) 5 12.78 (s, 1H), 10.77 (s, 1H), 7.99 (s, 1H), 7.91 (d, J = 8.7 Hz, 2H), 7.75 (d, J = 8.4 Hz, 2H), 7.41 (t, J = 2.04 402.3 7.9 Hz, 2H), 7.23 - 7.16 (m, 2H), 7.12 (d, J = 8.0 Hz, 2H) ppm.
(DMSO-d6) 5 12.80 (s, 1H), 10.80 (s, 1H), 7.96 (s, 1H), 7.93 (d, J = 8.6 Hz, 2H), 7.80 (d, J = 8.4 Hz, 2H), 7.29 (t, J = 16 2.08 450.3 9.2 Hz, 1H), 7.05 (dd, J = 12.6, 2.9 Hz, 1H), 7.02 (s, 1H), 6.87 - 6.81 (m, 1H), 3.77 (s, 3H) ppm.
(DMSO-d6) 5 12.79 (s, 1H), 10.76 (s, 1H), 7.96 (s, 1H), 7.92 (d, J = 8.6 Hz, 2H), 7.78 (d, J = 8.4 Hz, 2H), 7.20 - 17 2.18 500.1 7.14 (m, 2H), 7.14 - 7.09 (m, 2H), 7.06 (s, 1H), 4.75 (q, J = 8.9 Hz, 2H) ppm.
(DMSO-d6) 5 12.79 (s, 1H), 10.71 (s, 1H), 8.02 - 7.85 (m, 3H), 7.78 (d, J = 8.4 Hz, 2H), 7.26 (d, J = 2.4 Hz, 1H), 7.23 18 2.2 466.3 (d, J = 8.5 Hz, 1H), 7.06 (dd, J = 8.6, 2.4 Hz, 1H), 6.98 (s, 1H), 3.76 (s, 3H) ppm.
(DMSO-d6) 5 12.78 (s, 1H), 10.76 (s, 1H), 8.01 (s, 1H), 19 2.06 468.1 7.91 (d, J = 8.6 Hz, 2H), 7.75 (d, J = 8.4 Hz, 2H), 7.39 - 7.14 (m, 6H) ppm.
(DMSO-d6) 5 12.79 (s, 1H), 10.78 (s, 1H), 7.99 (s, 1H), 7.91 (d, J = 8.4 Hz, 2H), 7.74 (d, J = 8.4 Hz, 2H), 7.38 (d, J 2.24 450.5 = 2.6 Hz, 1H), 7.27 (dd, J = 8.7, 2.6 Hz, 1H), 7.14 (s, 1H), 7.01 (d, J = 8.7 Hz, 1H), 2.17 (s, 3H) ppm.
(DMSO-d6) 5 12.79 (s, 1H), 10.67 (s, 1H), 8.02 - 7.89 (m, 3H), 7.81 (d, J = 8.5 Hz, 2H), 7.22 (d, J = 8.7 Hz, 1H), 6.86 21 2.14 462.3 = 8.7, 2.8 Hz, 1H), 3.79 - 6.65 (m, 2H), 6.59 (dd, J (s, 3H), 3.74 (s, 3H) ppm.
(DMSO-d6) 5 12.79 (s, 1H), 10.74 (s, 1H), 7.96 (s, 1H), 22 2.06 450.3 7.92 (d, J = 8.6 Hz, 2H), 7.77 (d, J = 8.5 Hz, 2H), 7.27 - 7.05 (m, 3H), 7.07 - 6.82 (m, 1H), 3.82 (s, 3H) ppm.
(DMSO-d6) 5 12.79 (s, 1H), 10.79 (s, 1H), 8.01 (s, 1H), 23 2.1 454.3 7.92 (d, J = 8.4 Hz, 2H), 7.77 (d, J = 8.6 Hz, 2H), 7.61 (dd, J = 8.4, 2.8 Hz, 1H), 7.42 — 7.24 (m, 2H), 7.17 (s, 1H) ppm. 24 2.06 438.1 DMSO-d6 5 12.80 s, 1H 10.82 , s, 1H 7.99 , s, 1H , WO 20820 LCMS Cmpd 1 Ret. MS H-NMR (400 MHz) Time in (M+1) minutes 7.96 - 7.88 (m, 2H), 7.83 - 7.71 (m, 2H), 7.54 - 7.42 (m, 1H), 7.42 - 7.29 (m, 1H), 7.25 (s, 1H), 7.22 - 7.07 (m, 1H) ppm.
(DMSO-d6) 8 12.80 (s, 1H), 10.77 (s, 1H), 7.98 (s, 1H), 7.93 (d, J = 8.6 Hz, 2H), 7.80 (d, J = 8.4 Hz, 2H), 7.31 (d, J 215 466.3 = 9.0 Hz, 1H), 7.20 (d, J = 3.0 Hz, 1H), 7.01 (dd, J = 9.1, 3.0 Hz, 1H), 6.91 (s, 1H), 3.79 (s, 3H) ppm.
(DMSO-d6) 8 12.78 (s, 1H), 10.78 (s, 1H), 8.02 (s, 1H), 26 2.18 486.5 7.90 (d, J = 8.4 Hz, 2H), 7.72 (d, J = 8.4 Hz, 2H), 7.42 (s, 1H), 7.39 (d, J = 8.5 Hz, 2H), 7.31 - 7.05 (m, 2H) ppm.
(DMSO-d6) 8 12.80 (s, 1H), 10.84 (s, 1H), 7.94 (d, J = 8.6 Hz, 2H), 7.87 (d, J = 8.0 Hz, 1H), 7.83 (d, J = 8.8 Hz, 2H), 27 1.82 500.3 7.52 (d, J = 7.9 Hz, 1H), 7.40 = - 7.27 (m, 1H), 7.16 (dd, J .6, 2.8 Hz, 1H), 6.98 - 6.82 (m, 1H), 6.77 (s, 1H), 3.73 (s, 3H) ppm.
(DMSO-d6) 5 12.78 (s, 1H), 10.83 (s, 1H), 8.01 (d, J = 2.1 Hz, 1H), 7.94 (d, J = 8.7 Hz, 2H), 7.80 (dd, J = 15.4, 5.6 Hz, 3H), 7.18 (m, 3H), 6.83 (d, J = 8.7 Hz, 1H), 2.14 (s, 3H) I Om.
(DMSO-d6) 5 11.05 (s, 1H), 8.89 (d, J = 2.6 Hz, 1H), 8.27 (dd, J = 8.7, 2.6 Hz, 1H), 8.07 (d, J = 8.6 Hz, 1H), 8.03 (s, (DMSO-d6) 5 13.03 (s, 1H), 11.01 (s, 1H), 8.86 (d, J = 2.4 Hz, 1H), 8.24 (dd, J = 8.6, 2.6 Hz, 1H), 8.09 — 7.99 (m, 2H), 7.41 (t, J = 7.9 Hz, 2H), 7.26 (s, 1H), 7.18 (t, J = 7.4 Hz, (DMSO-d6) 5 10.98 (s, 1H), 8.91 (d, J = 2.5 Hz, 1H), 8.28 (dd, J = 8.6, 2.5 Hz, 1H), 8.07 (d, J = 8.5 Hz, 1H), 7.98 (s, 1H), 7.25 (d, J = 2.4 Hz, 1H), 7.21 (d, J = 8.6 Hz, 1H), 7.06 (DMSO-d6) 5 11.06 (s, 1H), 8.89 (d, J = 2.4 Hz, 1H), 8.27 (dd, J = 8.7, 2.5 Hz, 1H), 8.15 - 7.95 (m, 2H), 7.61 (dd, J = LCMS Cmpd 1 Ret. MS H-NMR (400 MHz) Time in (M+1) minutes d6) 5 11.44 (s, 1H), 8.89 (d, J = 2.5 Hz, 1H), 8.32 (dd, J = 8.6, 2.5 Hz, 1H), 8.10 (d, J = 8.6 Hz, 1H), 7.94 (s, 1H), 7.33 (td, J = 7.9, 1.6 Hz, 1H), 7.24 (ddd, J = 7.9, 5.0, 1.5 Hz, 2H), 7.12 (d, J = 1.4 Hz, 1H), 7.08 — 7.00 (m, 1H), (dd, J = 8.6, 2.5 Hz, 1H), 8.10 (d, J = 8.6 Hz, 1H), 7.96 (s, 1H), 7.33 (d, J = 1.4 Hz, 1H), 7.27 — 7.14 (m, 2H), 7.12 — 6.98 m, 2H 3.77 , s, 3H .
(DMSO-d6) 5 11.45 (s, 1H), 8.85 (d, J = 2.4 Hz, 1H), 8.29 (dd, J = 8.6, 2.5 Hz, 1H), 8.10 (d, J = 8.6 Hz, 1H), 7.98 (d, J = 1.3 Hz, 1H), 7.30 (d, J = 1.4 Hz, 1H), 7.26 (dd, J = 9.4, 2.9 (DMSO-d6) 5 11.42 (s, 1H), 8.88 (d, J = 2.5 Hz, 1H), 8.31 (dd, J = 8.7, 2.5 Hz, 1H), 8.10 (d, J = 8.6 Hz, 1H), 7.94 (s, 1H), 7.28 (dd, J = 8.9, 5.8 Hz, 1H), 7.22 — 7.12 (m, 2H), 6.88 8.5, 2.9 Hz, 1H 3.78 , s, 3H . [1] (DMSO-d6) 5 11.41 (s, 1H), 8.89 (d, J = 2.5 Hz, 1H), 8.32 (dd, J = 8.6, 2.5 Hz, 1H), 8.10 (d, J = 8.5 Hz, 1H), 7.90 (s, 1H), 7.17 (d, J = 8.8 Hz, 1H), 7.07 (s, 1H), 6.79 (d, J = 2.8 Hz, 1H), 6.61 (dd, J = 8.9, 2.8 Hz, 1H), 3.78 (d, J = 14.3 Hz, 7.91 m, 3H ,7.51 s,1H,7.39-7.14 m, 4H .
(DMSO-d6) 8 13.05 (s, 1H), 10.96 (s, 1H), 8.93 (d, J = 2.4 Hz, 1H), 8.30 (dd, J = 8.7, 2.5 Hz, 1H), 8.08 (d, J = 8.6 Hz, 1H), 7.97 (s, 1H), 7.27 (dd, J = 8.9, 5.8 Hz, 1H), 7.12 (dd, J = 10.7, 2.9 Hz, 1H), 6.91 (s, 1H), 6.84 (td, J = 8.5, 2.9 Hz, 1H), 3.75 (s, 3H). [1], 1H NMR (400 MHz, DMSO-d6) ? .68 (s, 1H), 8.77 (d, J = 2.5 Hz, 1H), 8.04 (dd, J = 8.5, 2.4 Hz, 1H), 7.94 (s, 1H), 7.89 (d, J = 8.5 Hz, 1H), 7.30 (dd, J = 8.9, 5.8 Hz, 1H), 7.13 (dd, J =10.7, 2.9 Hz, 1H), 6.92 - 6.78 (m, 2H), 3.76 (s, 3H) ppm. (For Sodium Salt) (DMSO-d6) 8 13.05 (s, 1H), 10.96 (s, 1H), 8.93 (d, J = 2.4 Hz, 1H), 8.30 (dd, J = 8.7, 2.5 Hz, 1H), 8.08 (d, J = 8.6 Hz, 1H), 7.98 (s, 1H), 7.27 (dd, J = 8.9, 5.8 Hz, 1H), 7.13 (dd, J = 10.7, 2.9 Hz, 1H), 6.91 (s, 1H), 6.85 (td, J = 8.5, 2.9 Hz, (DMSO-d6) 5 13.00 (s, 1H), 10.80 (s, 1H), 8.88 (d, J = 2.3 54 1.79 409.39 Hz, 1H), 8.24 (dd, J = 8.6, 2.4 Hz, 1H), 8.03 (d, J = 8.6 Hz, 1H), 7.64 (d, J = 8.1 Hz, 1H), 7.35 (dd, J = 81,18 Hz, 1H), 2014/013667 LCMS Cmpd 1 Ret. MS H-NMR (400 MHz) Time in (M+1) minutes 7.24 = 1.7 Hz, - 7.14 (m, 2H), 7.09 - 7.02 (m, 2H), 7.00 (d, J 1H), 1.25 (s, 9H) ppm. 55 1.27 353.1 (DMSO-d6) 5 13.15 — 12.96 (m, 1H), 11.09 (s, 1H), 8.90 (s, 1H), 8.28 (d, J = 8.0 Hz, 1H), 8.07 (d, J = 8.8 Hz, 1H), 7.92 (d, J = 7.8 Hz, 1H), 7.66 (d, J = 7.9 Hz, 1H), 7.36 — 7.13 (m, (dd, J = 8.7, 2.5 Hz, 1H), 8.09 (d, J = 8.6 Hz, 1H), 8.06 — 7.91 (m, 1H), 7.91 — 7.69 (m, 1H), 7.42 — 7.27 (m, 1H), 7.17 (dd, J = 10.7, 2.9 Hz, 1H), 6.92 = — 6.84 (m, 1H), 6.82 (d, J (dd, J = 8.6, 2.5 Hz, 1H), 8.23 = — 8.00 (m, 2H), 7.85 (dd, J 8.8, 2.4 Hz, 1H), 7.68 (dd, J = 8.4, 3.0 Hz, 1H), 7.54 — 7.42 7.42 — , . -d6) 5 11.01 (s, 1H), 8 (dd, J = 8.7, 2.5 Hz, 1H), 8.09 (d, J = 8.6 Hz, 1H), 8.04 (d, J = 2.4 Hz, 1H), 7.82 (dd, J = 8.8, 2.4 Hz, 1H), 7.27 — 7.19 (m, 2H), 7.19 — 7.10 (m, 1H), 6.91 (d, J = 8.8 Hz, 1H), 3.72 (5, Hz, 1H), 8.31 (dd, J = 8.6, 2.5 Hz, 1H), 8.17 - 7.99 (m, 2H), 7.84 (dd, J = 8.7, 2.4 Hz, 1H), 7.45 (d, J = 2.5 Hz, 1H), 7.34 (dd, J = 8.7, 2.7 Hz, 1H), 7.12 (d, J = 8.6 Hz, 1H), 6.95 (d, J (dd, J = 8.6, 2.5 Hz, 1H), 8.09 (d, J = 8.6 Hz, 1H), 8.02 (d, J = 2.3 Hz, 1H), 7.80 (dd, J = 8.8, 2.3 Hz, 1H), 7.35 — 7.25 (m, 2H), 7.25 — 7.18 (m, 1H), 7.10 — 7.01 (m, 1H), 6.81 (d, J = (dd, J = 8.6, 2.5 Hz, 1H), 8.10 (d, J = 2.4 Hz, 1H), 8.08 (d, J = 8.6 Hz, 1H), 7.87 (dd, J = 8.8, 2.4 Hz, 1H), 7.63 (dd, J = 8.0, 1.5 Hz, 1H), 7.50 - 7.40 (m, 1H), 7.40 — 7.26 (m, 2H), Hz, 1H), 8.35 (dd, J = 8.6, 2.5 Hz, 1H), 8.09 (d, J = 8.6 Hz, 1H), 8.04 (d, J = 2.3 Hz, 1H), 7.81 (dd, J = 9.0, 2.4 Hz, 1H), 7.34 — 7.27 (m, 1H), 7.27 — 7.17 (m, 2H), 7.14 — 6.94 (m, 1H), 6.85 (d, J = 8.7 Hz, 1H), 4.65 — 4.46 (m, 1H), 1.07 (d, J LCMS Cmpd.
Ret. MS 1H-NMR (400 MHz) Time in (M+1) minutes (dd, J = 8.8, 2.5 Hz, 1H), 8.09 (d, J = 8.6 Hz, 1H), 8.00 (d, J = 2.3 Hz, 1H), 7.78 (dd, J = 8.9, 2.4 Hz, 1H), 7.24 (d, J = 8.8 Hz, 1H), 6.92 = 8.8, 2.8 Hz, 1H), - 6.69 (m, 2H), 6.61 (dd, J 3.79 (s, 3H), 3.73 (s, 3H) ppm. d6) 5 11.01 (s, 1H), 8.95 (d, J = 2.5 Hz, 1H), 8.33 (dd, J = 8.6, 2.6 Hz, 1H), 8.08 (d, J = 8.6 Hz, 1H), 8.03 (d, J 66 1.88 467.3 = 2.3 Hz, 1H), 7.80 (dd, J = 8.8, 2.4 Hz, 1H), 7.39 - 7.24 (m, 2H), 7.10 (dd, J = 8.6, 2.4 Hz, 1H), 6.87 (d, J = 8.8 Hz, 1H), 3.76 (s, 3H) ppm.
(DMSO-d6) 5 13.04 (s, 1H), 11.05 (s, 1H), 8.96 (d, J = 2.5 Hz, 1H), 8.35 (dd, J = 8.6, 2.5 Hz, 1H), 8.09 (d, J = 8.6 Hz, 1H), 8.04 (d, J = 2.3 Hz, 1H), 7.80 (dd, J = 8.8, 2.4 Hz, 1H), 67 1.87 447.3 7.11 (d, J = 8.8 Hz, 1H), 6.94 (d, J = 3.1 Hz, 1H), 6.86 (dd, J = 8.8, 3.1 Hz, 1H), 6.78 (d, J = 8.8 Hz, 1H), 3.75 (s, 3H), 2.11 (s, 3H) ppm.
(DMSO-d6) 5 13.07 (s, 1H), 11.06 (s, 1H), 8.96 (d, J = 2.5 Hz, 1H), 8.34 (dd, J = 8.6, 2.5 Hz, 1H), 8.09 (d, J = 8.5 Hz, 1H), 8.07 (d, J = 2.3 Hz, 1H), 7.83 (dd, J = 8.8, 2.3 Hz, 1H), 68 1.85 467.3 7.38 (d, J = 9.0 Hz, 1H), 7.23 (d, J = 3.0 Hz, 1H), 7.05 (dd, J = 9.0, 3.0 Hz, 1H), 6.84 (d, J = 8.7 Hz, 1H), 3.80 (s, 3H) ppm.
(DMSO-d6) 5 11.12 (s, 1H), 8.95 (d, J = 2.5 Hz, 1H), 8.34 (dd, J = 8.6, 2.5 Hz, 1H), 8.16 = - 8.03 (m, 2H), 7.84 (dd, J 69 1.78 451.3 8.8, 2.4 Hz, 1H), 7.30 - 7.13 (m, 2H), 7.13 - 7.04 (m, 1H), 7.01 (d, J = 8.7 Hz, 1H), 3.77 (d, J = 1.0 Hz, 3H) ppm.
(DMSO-d6) 8 11.09 (s, 1H), 8.93 (d, J = 2.4 Hz, 1H), 8.31 (dd, J = 8.6, 2.5 Hz, 1H), 8.12 = - 8.01 (m, 2H), 7.87 (dd, J 70 1.76 403.5 8.7, 2.3 Hz, 1H), 7.51 - 7.41 (m, 2H), 7.30 — 7.22 (m, 1H), 7.22 = 8.7 Hz, 1H) ppm. - 7.15 (m, 2H), 7.06 (d, J (DMSO-d6) 5 11.08 (s, 1H), 8.94 (d, J = 2.5 Hz, 1H), 8.32 (dd, J = 8.6, 2.5 Hz, 1H), 8.14 = - 8.02 (m, 2H), 7.86 (dd, J 71 1.78 421.3 8.8, 2.4 Hz, 1H), 7.37 - 7.20 (m, 4H), 7.03 (d, J = 8.7 Hz, 1H) ppm.
(DMSO-d6) 5 11.08 (s, 1H), 8.95 (d, J = 2.4 Hz, 1H), 8.33 (dd, J = 8.6, 2.5 Hz, 1H), 8.08 (d, J = 8.6 Hz, 1H), 7.90 (d, J 72 1.69 501.3 = 8.0 Hz, 1H), 7.54 (d, J = 8.0 Hz, 1H), 7.31 (dd, J = 8.8, 5.9 Hz, 1H), 7.16 (dd, J = 10.7, 2.9 Hz, 1H), 6.98 - 6.85 (m, 1H), 6.80 (s, 1H), 3.72 (s, 3H) ppm. 73 1.65 471.5 1.42 455.3 1.62 435.3 76 1.48 451.1 ASSAYS FOR DETECTING AND MEASURING NaKINHIBITIONPROPERTIES OF COMPOUNDS E-VIPR l membrane potential assay method with electrical stimulation Sodium channels are voltage-dependent proteins that can be activated by inducing membrane voltage changes by applying electric fields. The electrical stimulation instrument and methods of use are described in Ion Channel Assay Methods PCT/US01/21652, herein incorporated by reference and are referred to as . The instrument comprises a microtiter plate r, an optical system for exciting the coumarin dye while simultaneously recording the coumarin and oxonol emissions, a waveform generator, a current- or e-controlled amplifier, and a device for inserting electrodes in well. Under integrated computer control, this instrument passes user- programmed electrical stimulus protocols to cells within the wells of the microtiter plate. 24 hours before the assay on E-VIPR, HEK cells expressing human Nav1.8 were seeded in 384-well poly-lysine coated plates at 15,000-20,000 cells per well. HEK cells were grown in media (exact composition is specific to each cell type and NaV e) supplemented with % FBS (Fetal Bovine Serum, qualified; GibcoBRL #16140-071) and 1% Pen-Strep (Penicillin- Streptomycin; GibcoBRL #15140-122). Cells were grown in vented cap flasks, in 90% ty and % C02. ts and Solutions: 100 mg/mL Pluronic F-127 (Sigma #P2443), in dry DMSO Compound Plates: 384-well round bottom plate, e.g. Corning 384-well Polypropylene Round Bottom #3656 Cell : 384-well tissue culture treated plate, e. g. r #781091-1B ] 10 mM 6(3) (Aurora #00010) in dry DMSO 10 mM CC2—DMPE (Aurora #00008) in dry DMSO 200 mM ABSCl in H20 Bathl buffer: Glucose 10mM (1.8g/L), Magnesium Chloride (Anhydrous), lmM (0.095g/L), Calcium Chloride, 2mM (0.222g/L), HEPES 10mM (2.3 8g/L), ium de, 4.5mM (0.335g/L), Sodium Chloride 160mM (9.35g/L).
Hexyl Dye Solution: Bathl Buffer + 0.5% B-cyclodextrin (make this prior to use, Sigma #C4767), 8 uM CC2-DMPE + 2.5 uM DiSBAC6(3). To make the solution added volume of 10% Pluronic F127 stock equal to volumes of CC2-DMPE + DiSBAC6(3). The order of preparation was first mix Pluronic and CC2-DMPE, then added 6(3) while vortexing, then added Bathl + odextrin.
Assay Protocol: 1) otted compounds (in neat DMSO) into compound plates. Vehicle control (neat DMSO), the ve control (20mM DMSO stock tetracaine, 125 uM final in assay) and test compounds were added to each well at 160x desired final concentration in neat DMSO. Final compound plate volume was 80 uL (80-fold intermediate dilution from 1 [LL DMSO spot; 160-fold final dilution after transfer to cell plate). Final DMSO concentration for all wells in assay was 0.625%. 2) Prepared Hexyl Dye Solution. 3) Prepared cell plates. On the day of the assay, medium was aspirated and cells were washed three times with 100 uL of Bath] Solution, maintaining 25 [LL residual volume in each well. 4) Dispensed 25 uL per well of Hexyl Dye Solution into cell . ted for 20-35 minutes at room temp or ambient conditions. 5) Dispensed 8O uL per well of Bathl into compound plates. Acid Yellow-17 (1 mM) was added and Potassium Chloride was altered from 4.5 to 20 mM depending on the NaV subtype and assay sensitivity. 6) Washed cell plates three times with 100 uL per well of Bath], g 25 uL of residual volume. Then transfered 25uL per well from Compound Plates to Cell Plates. lncubated for 20-35 minutes at room temp/ambient condition. 7) Read Plate on E-VIPR. Used the t-controlled amplifier to deliver ation wave pulses for 10 seconds and a scan rate of 200Hz. A pre-stimulus recording was med for 0.5 seconds to obtain the un-stimulated intensities baseline. The stimulatory waveform was followed by 0.5 seconds of post-stimulation recording to examine the relaxation to the resting state.
Data Analysis Data was analyzed and reported as normalized ratios of emission ities measured in the 460 nm and 580 nm channels. The response as a function of time was reported as the ratios obtained using the following formula:: -l2l- (intensity 460 nm - background 460 nm) R(t) = --------------------------------------------- (intensity 580 nm - background 580 nm) The data was further reduced by calculating the l (R) and final (Rf) ratios. These were the average ratio values during part or all of the pre-stimulation period, and during sample points during the stimulation period. The response to the stimulus R= Rf/Ri was then calculated and reported as a function of time.
Control responses were obtained by performing assays in the presence of a compound with the desired properties ive control), such as tetracaine, and in the absence of cological agents (negative control). Responses to the negative (N) and ve (P) ls were calculated as above. The compound antagonist activity A is defined as: A _R—P *100.
N — P where R is the ratio response of the test compound ELECTROPHYSIOLOGYASSAYSFOR NaZACTIVITYAND INHIBITION OF TEST COMPOUNDS Patch clamp electrophysiology was used to assess the efficacy and selectivity of sodium channel blockers in dorsal root ganglion neurons. Rat neurons were isolated from the dorsal root ganglions and maintained in e for 2 to 10 days in the presence ofNGF (50 ng/ml) re media consisted obasalA supplemented with B27, glutamine and antibiotics). Small diameter neurons (nociceptors, 8- 12 pm in diameter) were visually fied and probed with fine tip glass electrodes connected to an amplifier (Axon Instruments). The “voltage clamp” mode was used to assess the compound’s IC50 holding the cells at — 60 mV. In addition, the “current clamp” mode was employed to test the efficacy of the compounds in blocking action potential generation in response to current injections. The s of these experiments contributed to the definition of the efficacy profile of the compounds.
The exemplified compounds in Table 1 herein are active against Navl.8 sodium channels as measured using the assays bed herein and as presented in Table 3 below.
Table 3. Navl.8 IC50 activity Cmpd. NaV1.8 IC50 (HM) Cmpd. NaV1.8 IC50 (HM) 2 0.032 6 0.145 0.037 14 0.015 18 0.011 22 0.078 26 0.024 0.034 34 0.052 38 0.074 ] IonWorks assays. This assay was performed to determine the activity for the compounds of the present invention against non NaV1.8 channels. Sodium currents were recorded using the automated patch clamp system, IonWorks (Molecular Devices Corporation, Inc.). Cells expressing NaV subtypes were harvested from tissue culture and placed in suspension at 0.5-4 million cells per mL Bath]. The IonWorks ment measured changes in sodium currents in response to applied voltage clamp similarly to the ional patch clamp assay, except in a 384-well format.
Using the IonWorks, dose-response relationships were determined in voltage clamp mode by depolarizing the cell from the experiment specif1c holding potential to a test potential of about 0 mV before and following addition of the test compound. The influence of the compound on currents were measured at the test potential.
Many cations and variations of the embodiments described herein may be made without departing from the scope, as is apparent to those skilled in the art. The specific ments bed herein are offered by way of example only. —124—

Claims (52)

We claim:
1. A nd of formula I or I′ (R8)p (R8)p R1 O OH R1 O Y R2 Y R2 OH N N H H R3 O R3 O R4 R4 R5 R5' R5 R5' A A R6 R6' R6 R6' R7 R7 I I′; or a pharmaceutically acceptable salt thereof, wherein, independently for each occurrence: Y is CH or N R1 is H, halogen, CN, or C1-C6 alkyl wherein said C1-C6 alkyl is substituted with 0-6 halogen and n up to two non-adjacent CH2 units of said C1-C6 alkyl may be replaced with -O-; R2 is H, halogen, CN, or C1-C6 alkyl wherein said C1-C6 alkyl is substituted with 0-6 halogen, wherein up to two non-adjacent CH2 units of said C1-C6 alkyl may be replaced with -O-; R3 is H, halogen, CN, or C1-C6 alkyl wherein said C1-C6 alkyl is substituted with 0-6 halogen, n up to two non-adjacent CH2 units of said C1-C6 alkyl may be replaced with -O-; R4 is H, halogen, CN, or C1-C6 alkyl wherein said C1-C6 alkyl is substituted with 0-6 halogen, wherein up to two non-adjacent CH2 units of said C1-C6 alkyl may be ed with -O-; R5 is H, halogen, CN, or –X-RX; R5′ is H, halogen, CN, or –X-RX; R6 is H, halogen, CN, or –X-RX; R6′ is H, halogen, CN, or –X-RX; R7 is H, halogen, CN, or –X-RX; X is a bond or C1-C6 alkyl wherein said C1-C6 alkyl is substituted with 0-6 halogen, wherein up to two non-adjacent CH2 units of said C1-C6 alkyl may be replaced with -O-; RX is absent, H, or C3-C8 cycloaliphatic, wherein up to two non-adjacent CH2 units of said C3-C8 cycloaliphatic may be replaced with -O- and said C3-C8 liphatic is substituted with 0-3 substituents selected from halogen and C1-C4 alkyl; R8 is n, or C1-C6 alkyl wherein said C1-C6 alkyl is substituted with 0-6 halogen, wherein up to two non-adjacent CH2 units of said C1-C6 alkyl may be replaced with -O-; p is an integer from 0 to 4 inclusive; and provided the following compounds are ed: 4-methyl(2-phenoxybenzamido)benzoic acid; 3-(2-phenoxybenzamido)benzoic acid; 4-chloro(2-phenoxybenzamido)benzoic acid; 3-methyl[(2-phenoxybenzoyl)amino]-benzoic acid; phenoxybenzoyl)amino]-benzoic acid; and 5-chloromethoxy[(2-phenoxybenzoyl)amino]-benzoic acid.
2. A compound of formula I (R8)p R1 O OH R2 Y R3 O R5 R5' R6 R6' or a pharmaceutically acceptable salt thereof, wherein, independently for each occurrence: Y is C or N R1 is H, n, CN, or C1-C6 alkyl wherein said C1-C6 alkyl is substituted with 0-6 halogen and wherein up to two non-adjacent CH2 units of said C1-C6 alkyl may be replaced with -O-; R2 is H, halogen, CN, or C1-C6 alkyl wherein said C1-C6 alkyl is tuted with 0-6 halogen, wherein up to two non-adjacent CH2 units of said C1-C6 alkyl may be replaced with -O-; R3 is H, halogen, CN, or C1-C6 alkyl wherein said C1-C6 alkyl is substituted with 0-6 halogen, wherein up to two non-adjacent CH2 units of said C1-C6 alkyl may be replaced with -O-; R4 is H, halogen, CN, or C1-C6 alkyl wherein said C1-C6 alkyl is substituted with 0-6 halogen, wherein up to two non-adjacent CH2 units of said C1-C6 alkyl may be replaced with -O-; R5 is H, halogen, CN, or –X-RX; R5′ is H, halogen, CN, or –X-RX; R6 is H, halogen, CN, or –X-RX; R6′ is H, halogen, CN, or –X-RX; R7 is H, halogen, CN, or –X-RX; X is a bond or C1-C6 alkyl n said C1-C6 alkyl is substituted with 0-6 halogen, wherein up to two jacent CH2 units of said C1-C6 alkyl may be replaced with -O-; RX is absent, H, or C3-C8 cycloaliphatic, wherein up to two non-adjacent CH2 units of said C3-C8 cycloaliphatic may be replaced with -O- and said C3-C8 cycloaliphatic is substituted with 0-3 tuents selected from halogen and C1-C4 alkyl; R8 is n, or C1-C6 alkyl wherein said C1-C6 alkyl is substituted with 0-6 halogen, wherein up to two non-adjacent CH2 units of said C1-C6 alkyl may be replaced with -O-; p is an integer from 0 to 4 inclusive; and provided the following compounds are excluded: 3-methyl[(2-phenoxybenzoyl)amino]-benzoic acid; 4-[(2-phenoxybenzoyl)amino]-benzoic acid; and 5-chloromethoxy[(2-phenoxybenzoyl)amino]-benzoic acid.
3. The compound or pharmaceutically acceptable salt according to claim 1 or 2, wherein R1 is H or C1-C6 alkyl wherein said C1-C6 alkyl is substituted with 0-6 halogen.
4. The compound or pharmaceutically acceptable salt according to claim 3, wherein R1 is CF3.
5. The compound or pharmaceutically acceptable salt according to claim 1 or 2, wherein R2 is H, n, or C1-C6 alkyl wherein said C1-C6 alkyl is substituted with 0-6 halogen and wherein one CH2 unit of said C1-C6 alkyl is replaced with -O.
6. The compound or pharmaceutically acceptable salt ing to claim 5, wherein R2 is F, Cl, CF3 or OCF3.
7. The compound or pharmaceutically acceptable salt according to claim 1 or 2, wherein R3 is halogen or C1-C6 alkyl wherein said C1-C6 alkyl is substituted with 0-6 n.
8. The compound or pharmaceutically acceptable salt according to claim 7, n R3 is t-butyl, Cl, CF3 or CF2CF 3.
9. The compound or pharmaceutically acceptable salt according to any one of claims 1, 2, 7 or 8, wherein R5 and R7 are each independently halogen, or –X-RX and R5′, R6, and R6′ are each hydrogen.
10. The compound or pharmaceutically acceptable salt ing to claim 9, wherein R5 and R7 are each independently F, Cl, CH3 or OCH3.
11. The compound or ceutically acceptable salt according to claim 1 or 2, n ring A is: O Cl O F O F O F F , , , , F , F F , F , , O , F , Cl F O O F , O , O , O , O , F , F , F , Cl O O O F , Cl , Cl , F , F , O ,or O F.
12. The compound or pharmaceutically acceptable salt according to claim 11, wherein ring A is: Cl O O O F F , F , Cl , F , O , F Cl , F or F .
13. The compound or pharmaceutically acceptable salt according to any one of claims 1 to 12, wherein p is 0.
14. The compound or pharmaceutically acceptable salt according to any one of claims 1 to 13, wherein Y is N.
15. The compound or pharmaceutically acceptable salt according to any one of claims 1 to 13, wherein Y is CH.
16. The nd of claim 1, wherein the compound has formula I-B or I′-B: (R8)p (R8)p O OH O Y Y OH N N H H R3 O R3 O R5 R5' R5 R5' A A R6 R6' R6 R6' R7 R7 I-B I′-B or a pharmaceutically acceptable salt thereof, wherein, ndently for each occurrence: Y is CH or N; R3 is halogen, CN, or C1-C6 alkyl wherein said C1-C6 alkyl is substituted with 0-6 halogen, wherein up to two jacent CH2 units of said C1-C6 alkyl may be replaced with -O-; R5 is H, halogen, CN, or –X-RX; R5′ is H, halogen, CN, or –X-RX; R6 is H, halogen, CN, or –X-RX; R6′ is H, halogen, CN, or –X-RX; R7 is H, halogen, CN, or –X-RX; X is a bond or C1-C6 alkyl wherein said C1-C6 alkyl is substituted with 0-6 halogen, wherein up to two non-adjacent CH2 units of said C1-C6 alkyl may be replaced with -O-; RX is absent, H, or C3-C8 cycloaliphatic, wherein up to two non-adjacent CH2 units of said C3-C8 cycloaliphatic may be replaced with -O- and said C3-C8 cycloaliphatic is substituted with 0-3 substituents selected from halogen and C1-C4 alkyl; R8 is halogen, or C1-C6 alkyl wherein said C1-C6 alkyl is tuted with 0-6 halogen, wherein up to two non-adjacent CH2 units of said C1-C6 alkyl may be replaced with -O-; and p is an integer from 0 to 4 inclusive.
17. The compound or ceutically acceptable salt according to claim 16, wherein R3 is C1-C6 alkyl n said C1-C6 alkyl is substituted with 0-6 halogen.
18. The compound or pharmaceutically acceptable salt according to claim 16 or 17, wherein R3 is tbutyl , Cl, CF3 or CF2CF3.
19. The compound or pharmaceutically acceptable salt according to any one of claims 16 to 18, wherein R5 and R7 are each independently F, Cl, CH3 or OCH3.
20. The compound or pharmaceutically acceptable salt according to claim 16, wherein ring A is: Cl O O O F F , F , Cl , , O , Cl , F F F or F .
21. The nd or pharmaceutically acceptable salt according to any one of claims 16 to 20, wherein p is 0.
22. The compound according to claim 1, wherein the compound has formula I-C or I′-C: (R8)p (R8)p O OH O Y R2 Y R2 OH N N H H R3 O R3 O R5 R5' R5 R5' A A R6 R6' R6 R6' R7 R7 I-C I′-C or a pharmaceutically able salt thereof, wherein, independently for each occurrence: Y is CH or N; R2 is halogen, CN, or C1-C6 alkyl wherein said C1-C6 alkyl is substituted with 0-6 halogen, wherein up to two non-adjacent CH2 units of said C1-C6 alkyl may be replaced with -O-; R3 is halogen, CN, or C1-C6 alkyl wherein said C1-C6 alkyl is substituted with 0-6 halogen, wherein up to two non-adjacent CH2 units of said C1-C6 alkyl may be replaced with -O-; R5 is H, halogen, CN, or –X-RX; R5′ is H, halogen, CN, or –X-RX; R6 is H, halogen, CN, or –X-RX; R6′ is H, halogen, CN, or –X-RX; R7 is H, halogen, CN, or –X-RX; X is a bond or C1-C6 alkyl n said C1-C6 alkyl is substituted with 0-6 halogen, wherein up to two non-adjacent CH2 units of said C1-C6 alkyl may be ed with -O-; RX is absent, H, or C3-C8 cycloaliphatic, wherein up to two non-adjacent CH2 units of said C3-C8 cycloaliphatic may be replaced with -O- and said C3-C8 cycloaliphatic is substituted with 0-3 substituents selected from halogen and C1-C4 alkyl; R8 is halogen, or C1-C6 alkyl wherein said C1-C6 alkyl is substituted with 0-6 halogen, wherein up to two non-adjacent CH2 units of said C1-C6 alkyl may be replaced with -O-; and p is an integer from 0 to 4 inclusive.
23. The compound or pharmaceutically able salt according to claim 22, wherein R2 is H, halogen, or C1-C6 alkyl wherein said C1-C6 alkyl is tuted with 0-6 halogen and wherein one CH2 unit of said C1-C6 alkyl is replaced with -O-.
24. The compound or pharmaceutically acceptable salt according to claim 23, wherein R2 is F, Cl, CF 3 or OCF3.
25. The compound or pharmaceutically acceptable salt according to any one of claims 22 to 24, wherein R3 is C1-C6 alkyl wherein said C1-C6 alkyl is tuted with 0-6 halogen.
26. The compound or ceutically acceptable salt according to claim 25, wherein R3 is l, Cl, CF3 or CF2CF 3.
27. The compound or pharmaceutically acceptable salt according to any one of claims 22 to 26, wherein R5 and R7 are each independently F, Cl, CH3 or OCH3.
28. The compound or pharmaceutically able salt according to claim 22, wherein ring A is: Cl O O O F , , , , O , , F F F Cl F Cl F or F .
29. The compound or pharmaceutically acceptable salt according to any one of claims 22 to 28, wherein p is 0.
30. The compound or ceutically acceptable salt of claim 1, wherein the compound or pharmaceutically acceptable salt, is selected from the group consisting of: 4-(2-(2-chlorofluorophenoxy)(perfluoroethyl)benzamido)benzoic acid; 4-(2-(2,4-difluorophenoxy)(perfluoroethyl)benzamido)benzoic acid; 4-fluoromethylphenoxy)(perfluoroethyl)benzamido)benzoic acid; 4-(2-(2-chlorofluorophenoxy)(trifluoromethyl)benzamido)benzoic acid; 4-(2-(4-fluoromethylphenoxy)(trifluoromethyl)benzamido)benzoic acid; 4-(2-(2,4-difluorophenoxy)(trifluoromethyl)benzamido)benzoic acid; 4-(trifluoromethoxy)phenoxy)(trifluoromethyl)benzamido)benzoic acid; 4-(2-(2,4-difluorophenoxy)-4,6-bis(trifluoromethyl)benzamido)benzoic acid; 4-(2-(4-fluoromethylphenoxy)-4,6-bis(trifluoromethyl)benzamido)benzoic acid; 4-fluoromethoxyphenoxy)-4,6-bis(trifluoromethyl)benzamido)benzoic acid; 4-(2-(4-fluorophenoxy)-4,6-bis(trifluoromethyl)benzamido)benzoic acid; 4-(4,5-dichloro(4-fluoromethoxyphenoxy)benzamido)benzoic acid; -dichloro(4-fluorophenoxy)benzamido)benzoic acid; 4-(4,5-dichloro(4-fluoromethylphenoxy)benzamido)benzoic acid; -dichlorophenoxybenzamido)benzoic acid; 4-(4,5-dichloro(2-fluoromethoxyphenoxy)benzamido)benzoic acid; 4-(4,5-dichloro(4-(2,2,2-trifluoroethoxy)phenoxy)benzamido)benzoic acid; -dichloro(4-chloromethoxyphenoxy)benzamido)benzoic acid; 4-(4,5-dichloro(2-(difluoromethoxy)phenoxy)benzamido)benzoic acid; 4-(4,5-dichloro(4-chloromethylphenoxy)benzamido)benzoic acid; -dichloro(2,4-dimethoxyphenoxy)benzamido)benzoic acid; 4-(4,5-dichloro(3-fluoromethoxyphenoxy)benzamido)benzoic acid; 4-(4,5-dichloro(2-chlorofluorophenoxy)benzamido)benzoic acid; -dichloro(2,4-difluorophenoxy)benzamido)benzoic acid; 4-(4,5-dichloro(2-chloromethoxyphenoxy)benzamido)benzoic acid; 4-(4,5-dichloro(4-(trifluoromethoxy)phenoxy)benzamido)benzoic acid; 4-fluoromethoxyphenoxy)(perfluoroethyl)benzamido)benzoic acid; 4-(2-(4-fluoromethylphenoxy)(trifluoromethyl)benzamido)benzoic acid; 4-(2-(4-fluoromethylphenoxy)(trifluoromethyl)benzamido)benzoic acid; -dichloro(4-fluorophenoxy)benzamido)picolinic acid; 5-(4,5-dichloro(4-(isopentyloxy)phenoxy)benzamido)picolinic acid; 5-(4,5-dichloro(4-fluoromethylphenoxy)benzamido)picolinic acid; -dichlorophenoxybenzamido)picolinic acid; 5-(4,5-dichloro(2-fluoromethoxyphenoxy)benzamido)picolinic acid; 5-(4,5-dichloro(4-(2,2,2-trifluoroethoxy)phenoxy)benzamido)picolinic acid; -dichloro(4-chloromethoxyphenoxy)benzamido)picolinic acid; 5-(4,5-dichloro(2-(difluoromethoxy)phenoxy)benzamido)picolinic acid; 5-(4,5-dichloro(4-chloromethylphenoxy)benzamido)picolinic acid; 5-(4,5-dichloro(2,4-dimethoxyphenoxy)benzamido)picolinic acid; -dichloro(3-fluoromethoxyphenoxy)benzamido)picolinic acid; 5-(4,5-dichloro(2-chlorofluorophenoxy)benzamido)picolinic acid; -dichloro(2,4-difluorophenoxy)benzamido)picolinic acid; 5-(4,5-dichloro(2-chloromethoxyphenoxy)benzamido)picolinic acid; 5-(4,5-dichloro(4-(trifluoromethoxy)phenoxy)benzamido)picolinic acid; 5-(2-(2-methoxyphenoxy)-4,6-bis(trifluoromethyl)benzamido)picolinic acid; 4-methoxyphenoxy)-4,6-bis(trifluoromethyl)benzamido)picolinic acid; 5-(2-(4-fluoromethylphenoxy)-4,6-bis(trifluoromethyl)benzamido)picolinic acid; 4-fluoromethoxyphenoxy)-4,6-bis(trifluoromethyl)benzamido)picolinic acid; 5-(2-(2,4-dimethoxyphenoxy)-4,6-bis(trifluoromethyl)benzamido)picolinic acid; 5-(2-(4-fluorophenoxy)-4,6-bis(trifluoromethyl)benzamido)picolinic acid; 5-(4,5-dichloro(4-fluoromethoxyphenoxy)benzamido)picolinic acid; tert-butyl)(4-fluoromethoxyphenoxy)benzamido)picolinic acid; 5-(4-(tert-butyl)(4-fluoromethylphenoxy)benzamido)picolinic acid; tert-butyl)(4-fluorophenoxy)benzamido)picolinic acid; 5-(2-(4-fluorophenoxy)benzamido)picolinic acid; 5-(2-(4-fluorophenoxy)(trifluoromethyl)benzamido)picolinic acid; 5-(2-(4-fluoromethoxyphenoxy)(trifluoromethyl)benzamido)picolinic acid; 2-chlorofluorophenoxy)(trifluoromethyl)benzamido)picolinic acid; 5-(2-(5-fluoromethoxyphenoxy)(trifluoromethyl)benzamido)picolinic acid; 5-(2-(2-(difluoromethoxy)phenoxy)(trifluoromethyl)benzamido)picolinic acid; 4-chloromethylphenoxy)(trifluoromethyl)benzamido)picolinic acid; 5-(2-(2-methoxyphenoxy)(trifluoromethyl)benzamido)picolinic acid; 5-(2-(2-chlorophenoxy)(trifluoromethyl)benzamido)picolinic acid; 2-isopropoxyphenoxy)(trifluoromethyl)benzamido)picolinic acid; 5-(2-(2,4-dimethoxyphenoxy)(trifluoromethyl)benzamido)picolinic acid; 5-(2-(4-chloromethoxyphenoxy)(trifluoromethyl)benzamido)picolinic acid; 5-(2-(4-methoxymethylphenoxy)(trifluoromethyl)benzamido)picolinic acid; 2-chloromethoxyphenoxy)(trifluoromethyl)benzamido)picolinic acid; 5-(2-(3-fluoromethoxyphenoxy)(trifluoromethyl)benzamido)picolinic acid; 5-(2-phenoxy(trifluoromethyl)benzamido)picolinic acid; 5-(2-(4-fluorophenoxy)(trifluoromethyl)benzamido)picolinic acid; 4-fluoromethoxyphenoxy)(perfluoroethyl)benzamido)picolinic acid; 5-(2-(4-fluorophenoxy)(perfluoroethyl)benzamido)picolinic acid; 5-(2-(2-chlorofluorophenoxy)(trifluoromethyl)benzamido)picolinic acid; 5-(2-(4-fluoromethylphenoxy)(trifluoromethyl)benzamido)picolinic acid; and -dichloro(4-fluoromethoxyphenoxy)benzamido)picolinic acid; or a pharmaceutically acceptable salt thereof.
31. A pharmaceutical composition comprising a therapeutically effective amount of a compound or a pharmaceutically acceptable salt thereof of any one of claims 1 to 30 and one or more pharmaceutically acceptable carriers or vehicles.
32. A pharmaceutical composition comprising a compound or a pharmaceutically acceptable salt thereof of any one of claims 1 to 30 and one or more pharmaceutically acceptable rs or vehicles.
33. Use of a compound or a pharmaceutically acceptable salt thereof of any one of claims 1 to 30 or a pharmaceutical composition according to claim 31 or 32 in the manufacture of a medicament for ting a voltage-gated sodium channel in a subject.
34. The use of claim 33, wherein the voltage-gated sodium l is Nav1.8.
35. Use a compound or a pharmaceutically acceptable salt thereof of any one of claims 1 to 30 or a pharmaceutical composition of claim 31 or 32 in the manufacture of a medicament for treating or lessening the severity of chronic pain, gut pain, neuropathic pain, oskeletal pain, acute pain, inflammatory pain, cancer pain, idiopathic pain, postsurgical pain, visceral pain, multiple sclerosis, Charcot-Marie-Tooth syndrome, incontinence or cardiac arrhythmia in a subject.
36. The use of claim 35, wherein the medicament is for treating or ing the severity in a subject of gut pain,wherein gut pain comprises inflammatory bowel disease pain, Crohn’s disease pain or interstitial cystitis pain.
37. The use of claim 35, wherein the medicament is for treating or lessening the severity in a t of neuropathic pain, n neuropathic pain comprises post-herpetic neuralgia, diabetic neuralgia, painful sociated sensory neuropathy, trigeminal neuralgia, burning mouth syndrome, postamputation 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 herapy induced neuralgia, etroviral therapy induced neuralgia; post spinal cord injury pain, idiopathic small-fiber neuropathy, idiopathic sensory neuropathy or trigeminal mic cephalalgia.
38. The use of claim 37, wherein athic pain comprises idiopathic fiber neuropathy.
39. The use of claim 37, wherein neuropathic pain comprises post-herpetic neuralgia.
40. The use of claim 35, n the medicament is for treating or lessening the severity in a patient of musculoskeletal pain, wherein musculoskeletal pain comprises osteoarthritis pain, back pain, cold pain, burn pain or dental pain.
41. The use of claim 40, wherein musculoskeletal pain comprises rthritis pain.
42. The use of claim 35, wherein the medicament is for treating or lessening the severity in a t of inflammatory pain, wherein inflammatory pain comprises rheumatoid arthritis pain or vulvodynia.
43. The use of claim 35, wherein the medicament is for treating or lessening the severity in a subject of idiopathic pain, wherein idiopathic pain comprises fibromyalgia pain.
44. The use of claim 35, wherein the medicament is for ng or lessening the severity in a t of acute pain.
45. The use of claim 44, wherein acute pain comprises acute post-operative pain.
46. The use of claim 35, wherein the medicament is for treating or lessening the ty in a subject of postsurgical pain.
47. The use of claim 35, wherein the medicament is for treating or ing the severity in a subject of visceral pain.
48. The use of claim 35, n the medicament is for treating or lessening the severity in a subject of neuropathic pain, wherein neuropathic pain comprises diabetic neuropathy.
49. The use of a compound or a pharmaceutically acceptable salt thereof of any one of claims 1 to 30 or a pharmaceutical composition of claim 31 or 32 in the manufacture of a medicament for treating or lessening the severity in a subject of a disease, disorder, or condition.
50. The use ing to any one of claims 33 to 49, wherein the medicament is for administration with one or more additional therapeutic agents administered concurrently with, prior to, or subsequent to administration of the medicament.
51. A compound or a pharmaceutically acceptable salt f of any one of claims 1 to 30 or a pharmaceutical composition of claim 31 or 32 for use as a medicament.
52. The compound of claim 1 or 2, substantially as herein described with reference to any one of the Examples thereof.
NZ710293A 2013-01-31 2014-01-29 Amides as modulators of sodium channels NZ710293B2 (en)

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US201361759062P 2013-01-31 2013-01-31
US61/759,062 2013-01-31
PCT/US2014/013667 WO2014120820A1 (en) 2013-01-31 2014-01-29 Amides as modulators of sodium channels

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