ZA200503242B

ZA200503242B - Treatment of pain with JNK inhibitors

Info

Publication number: ZA200503242B
Application number: ZA200503242A
Authority: ZA
Inventors: Jerome B Zeldis; Faleck Herbert; Donald C Manning
Original assignee: Celgene Corp
Priority date: 2002-10-24
Filing date: 2003-10-24
Publication date: 2006-10-25
Also published as: CN1732004A

Description

) METHODS OF USING AND COMPOSITIONS COMPRISING

A JNK INHIBITOR FOR THE TREATMENT, . PREVENTION, MANAGEMENT AND/OR MODIFICATION OF PAIN

This application claims the benefit of U.S. provisional application no. 60/421,104, filed October 24, 2002, the contents of which are incorporated by reference herein in their entirety. 1. FIELD OF INVENTION

This invention relates to methods for treating, preventing, modifying and/or managing pain and related syndromes, which comprise the administration of a

INK Inhibitor alone or in combination with known therapeutics or therapies. The invention also relates to pharmaceutical compositions comprising a JNK Inhibitor and dosing regimens. 2. BACKGROUND OF THE INVENTION

Pain is the leading symptom of many different disorders and is defined as an unpleasant sensory and emotional experience associated with actual or potential tissue damage or described in terms of such damage. Classification of Chronic Pain,

International Association for the Study of Pain (IASP) Task Force on Taxonomy,

Merskey H, Bogduk N, eds., IASP Press: Seattle, 209-214, 1994. Becase the perception of pain is highly subjective, it is one of the most difficult pathologies to diagnose and treat effectively. Pain leads to severe impairment of functional ability, which compromises the working, social, and family lives of sufferers. Around five percent of the adult population is estimated to suffer from pain sufficiently severe to cause significant disability. Chojnowska E , Stannard C. Epidemiology of Chronic Pain,

Chapter 2, pp 15-26: T.S. Jensen, P.R. Wilson, A.S.C. Rice eds., Clinical Pain . Management Chronic Pain, Amold, London, 2003.

In most pain conditions, there is increased neural input from the . 30 periphery. Sensory nerve impulses travel via the axons of primary afferent neurons to the dorsal horn of the spinal cord, where they propagate nerve impulses to dorsal horn neurons by releasing excitatory amino acids and neuropeptides at synapses. Dorsal horn projection neurons process and transfer the information about a peripheral stimuli to the brain via ascending spinal pathways. Mannion, R.J. and Woolf, C.J., Clin. J. of Pain ‘ 16:S144-S156 (2000).

The firing of dorsal hom projection neurons is determined not only by the excitatory input they receive, but also by inhibitory input from the spinal cord and higher nerve centers. Several brain regions contribute to descending inhibitory pathways. Nerve fibers from these pathways release inhibitory substances such as endogenous opioids, y- aminobutyric acid (GABA), and serotonin at synapses with other neurons in the dorsal horn or primary afferent neurons and inhibit nociceptive transmission. Peripheral nerve injury can produce changes in dorsal hom excitability by down-regulating the amount of inhibitory control over dorsal horn neurons through various mechanisms.

Repeated or prolonged stimulation of dorsal horn neurons due to C- nociceptor activation or damaged nerves can cause a prolonged increase in dorsal hom neuron excitability and responsiveness that can last hours longer than the stimulus.

Sensitization of the dorsal hom neurons increases their excitability such that they respond to normal input in an exaggerated and extended way. It is now known that such sustained activity in primary afferent C-fibers leads to both morphological and biochemical changes in the dorsal horn which may be difficult to reverse. Several changes in the dorsal horn have been noted to occur with central sensitization: (i) an expansion of the dorsal hom receptive field size so that a spinal neuron will respond to noxious stimuli outside the region normally served by that neuron ; (ii) an increase in the magnitude and duration of the response to a given noxious stimulus (hyperalgesia); (iii) a painful response to a normally innocuous stimulus, for example, from a mechanoreceptive primary afferent AB-fibre (allodynia); and (iv) the spread of pain to uninjured tissue (referred pain). Koltzenburg, M. Clin. J. of Pain 16:S131-S138 (2000;

Mannion, R.J. and Woolf, C.J., Clin. J. of Pain 16:3144-S156 (2000).

Central sensitization may explain, in part, the continuing pain and ) hyperalgesia that occurs following an injury and may serve an adaptive purpose by encouraging protection of the injury, during the healing phase. Central sensitization however can persist long after the injury has healed thereby supporting chronic pain.

Sensitization also plays a key role in chronic pain, helping to explain why it often exceeds the provoking stimulus, both spatially and temporally, and may help explain why established pain is more difficult to suppress than acute pain. Koltzenburg, M. Clin. ’ J. of Pain 16:S131-S138 (2000).

Accordingly, safe and effective methods for the treatment, prevention, modification or management of pain are needed. 2.1 TYPES OF PAIN 2.1.1 Nociceptive Pain

Nociceptive pain is elicited when noxious stimuli such as inflammatory chemcial mediators are released following tissue injury, disease, or inflammation and are detected by normally functioning sensory receptors (nociceptors) at the site of injury.

Koltzenburg, M. Clin. J. of Pain 16:S131-S138 (2000). Clinical examples of nociceptive pain include, but are not limited to, pain associated with chemical or thermal burns, cuts and contusions of the skin, osteoarthritis, rheumatoid arthritis, tendonitis, and myofascial pain.

Nociceptors (sensory receptors) are distributed throughout the periphery of tissue. They are sensitive to noxious stimuli (e.g., thermal, mechanical, or chemical) which would damage tissue if prolonged. Activation of peripheral nociceptors by such stimuli excites discharges in two distinct types of primary afferent neurons: slowly conducting unmyelinated c-fibers and more rapidly conducting, thinly myelinated A$ fibers. C-fibers are associated with burning pain and AS fibers with stabbing pain.

Koltzenburg, M. Clin. J. of Pain 16:S131-S138 (2000); Besson, J.M. Lancet 353:1610- 15 (1999); Johnson, B.-W. Pain Mechanisms: Anatomy, Physiology and Neurochemistry,

Chapter 11 in Practical Management of Pain ed. P. Prithvi Raj. (3 Ed., Mosby, Inc.. St

Louis, 2000). Most nociceptive pain involves signaling from both AS and c-types of primary afferent nerve fibers.

Peripheral nociceptors are sensitized by inflammatory mediators such as . 30 prostaglandin, substance P, bradykinin, histamine, and serotonin, as well as by intense, repeated, or prolonged noxious stimulation. In addition, cytokines and growth factors : (e.g., nerve growth factor) can influence neuronal phenotype and function. Besson, J.M.

Lancet 353:1610-15 (1999).

When sensitized, nociceptors exhibit a lower activation threshold and an increased rate of firing, which means that they generate nerve impulses more readily and more frequently. Peripheral sensitization of nociceptors plays an important role inspinal ’ cord dorsal horn central sensitization and clinical pain states such as hyperalgesia and allodynia. ) Inflammation also appears to have another important effect on peripheral nociceptors. Some C-nociceptors do not normally respond to any level of mechanical or thermal stimuli, and are only activated in the presence of inflammation or in response to tissue injury. Such nociceptors are called “silent” nociceptors, and have been identified in visceral and cutaneous tissue. Besson, J.M. Lancet 353:1610-15 (1999); Koltzenburg,

M. Clin. J. of Pain 16:S131-S138 (2000).

Differences in how noxious stimuli are processed across different tissues contribute to the varying characteristics of nociceptive pain. For example, cutaneous pain is often described as a well-localized sharp, prickling, or burning sensation whereas deep somatic pain may be described as diffuse, dull, or an aching sensation. In general, there is a variable association between pain perception and stimulus intensity, as the central nervous system and general experience influence the perception of pain. 2.1.2 Neuropathic Pain

Neuropathic pain reflects injury or impairment of the nervous system, and has been defined by the IASP as “pain initiated or caused by a primary lesion or dysfunction in the nervous system”. Classification of Chronic Pain, International

Association for the Study of Pain (IASP) Task Force on Taxonomy, Merskey H, Bogduk

NN, eds., IASP Press: Seattle, 209-214, 1994. Some neuropathic pain is caused by injury or dysfunction of the peripheral nervous system. As a resultof injury, changes in the expression of key transducer molecules, transmitters, and ion channels occur, leading to altered excitability of peripheral neurons. Johnson, B.W. Pain Mechanisms: Anatomy,

Physiology and Neurochemistry, Chapter 11 in Practical Management of Pain ed. P.

Prithvi Raj. (3 Ed, Mosby, Inc., St Louis, 2000). Clinical examples of neuropathic pain include, but are not limited to, pain associated with diabetic neuropathy, postherpetic neuralgia, trigeminal neuralgia, and post-stroke pain.

Neuropathic pain is commonly associated with several distinct characteristics, such as pain which may be continuous or episodic and is described in many ways, such as bumning, tingling, prickling, shooting, electric-shock-like, jabbing,

squeezing, deep aching, or spasmodic. Paradoxically partial or complete sensory deficit : is often present in patients with neuropathic pain who experience diminished perception of thermal and mechanical stimuli. Abnormal or unfamiliar unpleasant sensations (dysaesthesias) may also be present and contribute to suffering. Other features are the ability of otherwise non-noxious stimuli to produce pain (allodynia) or the disproportionate perception of pain in response to supra-threshold stimuli (hyperalgesia).

Johnson, B.W. Pain Mechanisms: Anatomy, Physiology and Neurochemistry, Chapter 11 in Practical Management of Pain ed. P. Prithvi Raj. (3 Ed., Mosby, Inc., St Louis, 2000(; Attal, N. Clin. J. of Pain 16:S118-S130 (2000).

Complex regional pain syndrome (CRPS) is a type of neuropathic pain which usually affects the extremities in the absence (CRPS type I) or presence (CRPS type II) of a nerve injury. CRPS type I encompasses the condition known as reflex sympathetic dystrophy (RSD), CRPS type II encompasses the condition known as causalgia and both types have subsets consistent with sympathetic maintained pain syndrome. In 1993, a special consensus conference of the IASP addressed diagnosis and terminology of the disease, and endorsed the term CRPS with the two subtypes.

Subsequent studies and conferences have refined the definitions such that the current guidelines give high sensitivity (0.70) with very high specificity (0.95). Bruehl, et al.

Pain 81:147-154 (1999). However, there is still no general agreement on what causes the disease, or how best to treat it. Paice, E., British Medical Journal 310: 1645-1648 (1995).

CRPS is a multi-symptom and multi-system syndrome affecting multiple neural, bone and soft tissues, including one or more extremities, which is characterized by an intense pain. Although it was first described 130 years ago, CRPS remains poorly understood. For example, changes in peripheral and central somatosensory, autonomic, and motor processing, and a pathologic interaction of sympathetic and afferent systems ) have been proposed as underlying mechanisms. Wasner et al. demonstrated a complete functional loss of cutaneous sympathetic vasoconstrictor activity in an early stage of

CRPS with recovery. Wasner G., Heckmann K., Maier C., Arch Neurol 56(5): 613-20 (1999). Kurvers et al. suggested a spinal component to microcirculatory abnormalities at stage I of CRPS, which appeared to manifest itself through a neurogenic inflammatory mechanism. Kurvers H.A., Jacobs M.J., Beuk R.J., Pain 60(3): 333-40 (1995). The ) cause of vascular abnormalities is unknown, and debate still surrounds the question of whether the sympathetic nervous system (SNS) is involved in the generation of these changes.

The actual incidence of CRPS in the U.S. is unknown, and limited information is available about the epidemiology of the disease. Both sexes are affected, but the incidence of the syndrome is higher in women. The syndrome may occur in any age group, including the pediatric population. Schwartzman R.J., Curr Opin Neurol

Neurosurg 6(4): 531-6 (1993). Various causes that have led to CRPS include, but are not limited to, head injury, stroke, polio, tumor, trauma, amylotrophic lateral sclerosis (ALS), myocardial infarction, polymyalgia rheumatica, operative procedure, brachial plexopathy, cast/splint immobilization, minor extremity injury and malignancy.

Symptoms of CRPS include, but are not limited to, pain, autonomic dysfunction, edema, movement disorder, dystrophy, and atrophy. Schwartzman R.J., N

Engl J Med 343(9): 654-6 (2000). The pain is described as extremely severe and unrelenting, often with a burning character. Ninety percent of all CRPS patients complain of spontaneous burning pain and allodynia, which refers to pain with light touch. Much of the difficulty clinicians have with this syndrome is the fact that pain may be far worse than what would be expected based on physical findings. Jd. Pain is also accompanied by swelling and joint tenderness, increased sweating, sensitivity to temperature and light touch, as well as color change to the skin. In fact, the diagnosis of

CRPS cannot be made on reports of pain alone. Patients must have signs and symptoms of sensory abnormalities as well as vascular dysfunction accompanied by excessive sweating, edema or trophic changes to the skin.

As metnioned above, the IASP has divided CRPS into two types, namely CRPS type I (also referred to as RSD) and CRPS type II (also referred to as causalgia).

These two types are differentiated mainly based upon whether the inciting incident included a definable nerve injury. CRPS type I occurs after an initial noxious event other than a nerve injury. CRPS type II occurs after nerve injury. CRPS is further divided into distinct stages in its development and manifestation. However, the course of the disease seems to be so unpredictable between various patients that staging is not always clear or helpful in treatment. Schwartzman R.J., N Engl J Med 343(9): 654

In stage I, or “early RSD,” pain is more severe than would be expected ' from the injury, and it has a burning or aching quality. It may be increased by dependency of the limb, physical contact, or emotional upset. The affected area typically becomes edematous, may be hyperthermic or hypothermic, and may show increased nail and hair growth. Radiographs may show early bony changes. Id.

In stage II, or “established RSD,” edematous tissue becomes indurated.

Skin typically becomes cool and hyperhidrotic with livedo reticularis or cyanosis. Hair may be lost, and nails become ridged, cracked, and brittle. Hand dryness becomes prominent, and atrophy of skin and subcutaneous tissues becomes noticeable. Pain remains the dominant feature. It is usually constant and is increased by any stimulus to the affected area. Stiffness develops at this stage. Radiographs may show diffuse osteoporosis. Id.

In stage III, or “late RSD,” pain spreads proximally. Although it may diminish in intensity, pain remains a prominent feature. Flare-ups may occur spontaneously. Irreversible tissue damage occurs, and the skin is typically thin and shiny.

Edema is absent, but contractures may occur. X-ray films typically indicate marked bone demineralization. Id.

In all stages of CRPS, patients endure severe chronic pain and most patients are sleep deprived. CRPS has significant morbidity and thus raising awareness of the disease is important. Early and effective treatment may lessen the effect of CRPS in some individuals. William D. Dzwierzynski et al., Hand Clinics Vol 10 (1): 29-44 (1994). 2.1.3 Other Types of Pain

Visceral pain has been conventionally viewed as a variant of somatic pain, but may differ in neurological mechanisms. Visceral pain is also thought to involve . silent nociceptors, visceral afferent fibers that only become activated in the presence of inflammation. Cervero, F. and Laird J.M.A., Lancet 353:2145-48 ( 1999).

Certain clinical characteristics are peculiar to visceral pain: (i) it is not evoked from all viscera and not always linked to visceral injury; (ii) it is ofien diffuse and poorly localized, due to the organization of visceral nociceptive pathways in the central nervous system (CNS), particularly the absence of a separate visceral sensory pathway and the low proportion of visceral afferent nerve fibers; (iii) it is sometimes referred to other non-visceral structures; and (iv) it is associated with motor and ~ autonomic reflexes, such as nausea. Johnson, B.W. Pain Mechanisms: Anatomy,

Prithvi Raj. 3™ Ed., Mosby, Inc., St Louis, 2000); Cervero, F. and Laird J.M.A., Lancet 353:2145-48 (1999).

Headaches can be classified as primary and secondary headache disorders.

The pathophysiology of the two most common primary disorders, migraine and tension- type headache, is complex and not fully understood. Recent studies indicate that nociceptive input to the CNS may be increased due to the activation and sensitization of peripheral nociceptors, and the barrage of nociceptive impulses results in the activation and sensitization of second- and third-order neurons in the CNS. Thus, it is likely that central sensitization plays a role in the initiation and maintenance of migraine and tension-type headache. Johnson, B.W. Pain Mechanisms: Anatomy, Physiology and

Neurochemistry, Chapter 11 in Practical Management of Pain ed. P. Prithvi Raj. (3 Ed,

Mosby, Inc., St Louis, 2000).

Post-operative pain, such as that resulting: from trauma to tissue caused during surgery, produces a barrage of nociceptive input. Following surgery, there is an inflammatory response at the site of injury involving cytokines, neuropeptides and other inflammatory mediators. These chemical are responsible for the sensitization and increased responsiveness to external stimuli, resulting in, for example, lowering of the threshold and an increased response to supra-threshold stimuli. Together, these processes result in peripheral and central sensitization. Johnson, B.W. Pain Mechanisms:

Anatomy, Physiology and Neurochemistry, Chapter 11 in Practical Management of Pain ed. P. Prithvi (Raj. 3" Ed., Mosby, Inc., St Louis, 2000).

Mixed pain is chronic pain that has nociceptive and neuropathic components. For example, a particular pain can be initiated through one pain pathway and sustained through a different pain pathway. Examples of mixed pain states include, but are not limited to, cancer pain and low back pain.

2.2 CURRENT TREATMENTS FOR PAIN

Current treatment for CRPS related pain in particular and chronic pain in general includes pain management and extensive physical therapy, which can help to prevent edema and joint contractures and can also help to minimize pain. Often, medication and neural blockade are used to help with the severe pain. Regional neural blockade is performed using Bier blocks with a variety of agents, including local anesthetics, bretylium, steroids, calcitonin, reserpine, and guanethidine. Perez, R.S., ef al., J. Pain Symptom Manage 21(6): 511-26 (2001). Specific, selective sympathetic ganglia neural blockade is performed for both diagnostic and therapeutic purposes. The rationale for selective neural blockade is to interrupt the sympathetic nervous system and reduce the activation of the sensory nerves. Patients who fail well-controlled neural blockade treatment may have pain that is sympathetic-independent Once refractory to neural blockade, pain is typically lifelong and may be severe enough to be debilitating.

Id.

Medications presently used during the treatment of chronic pain in general include calcium channel blockers, muscle relaxants, non-narcotic analgesics, opioid analgesics, and systemic corticosteroids. However, patients rarely obtain complete pain relief. Moreover, because the mechanisms of pain and autonomic dysfunction are poorly understood, the treatments are completely empirical. Therefore, there remains a need for safe and effective methods of treating and managing pain. 3. SUMMARY OF THE INVENTION

The present invention relates to methods for treating or preventing pain, comprising administering to a patient in need thereof a therapeutically or prophylactically effective amount of a JNK Inhibitor. The invention also relates to methods for managing (e.g., lengthening the time of remission) pain, which comprise administering to a patient in need of such management a therapeutically or prophylactically effective amount of a JNK Inhibitor. The invention further relates to : methods for modifying pain, which comprise administering to a patient in need thereof a therapeutically or prophylactically effective amount of a JNK Inhibitor.

Another embodiment of the invention encompasses the use of one or more

JNK Inhibitors with another therapeutic useful for the treatment, prevention,

management and/or modification of pain such as, but not limited to, an antidepressant, ’ antihypertensive, anxiolytic, calcium channel blocker, muscle relaxant, non-narcotic analgesic, anti-inflammatory agent, cox-2 inhibitor, alpha-adrenergic receptor agonist or antagonist, ketamine, anesthetics, immunomodulatory agent, Immunosuppressive agent, corticosteroid, hyperbaric oxygen, anticonvulsant, an IMiD®, a SelCID®, or a combination thereof.

Yet another embodiment of the invention encompasses the use of one or more JNK Inhibitors in combination with conventional therapies used to treat, prevent, manage and/or modify pain including, but not limited to, surgery, interventional procedures (e.g., neural blockade), physical therapy, and psychological therapy.

The mvention further encompasses pharmaceutical compositions, single unit dosage forms, and kits suitable for use in treating, preventing, managing and/or modifying pain, which comprise a therpeutically or prophylactically effective amount of a JNK Inhibitor. 3.1 DEFINITIONS

As used herein, the term “patient” means an animal (e. g., cow, horse, sheep, pig, chicken, turkey, quail, cat, dog, mouse, rat, rabbit or guinea pig), preferably a mammal such as a non-primate and a primate (e.g., monkey and human), most preferably a human. “Alkyl” means a saturated straight chain or branched non-cyclic hydrocarbon having from 1 to 10 carbon atoms. “Lower alkyl” means alkyl, as defined above, having from 1 to 4 carbon atoms. Representative saturated straight chain alkyls include -methyl, -ethyl, -n-propyl, -n-butyl, -n-pentyl, -n-hexyl, -n-heptyl, -n-octyl, -n- nonyl and -n-decyl; while saturated branched alkyls include isopropyl, -sec-butyl, - isobutyl, -fert-butyl, -isopentyl, 2-methylbutyl, 3-methylbutyl, 2-methylpentyl, 3- methylpentyl, 4-methylpentyl, 2-methylhexyl, 3-methylhexyl, 4-methylhexyl, 5- methylhexyl, 2,3-dimethylbutyl, 2,3-dimethylpentyl, 2,4-dimethylpentyl, 2,3- dimethylhexyl, 2,4-dimethylhexyl, 2,5-dimethythexyl, 2,2-dimethylpentyl, 2,2- dimethylhexyl, 3,3-dimtheylpentyl, 3,3-dimethylhexyl, 4,4-dimethylhexyl, 2-ethylpentyl, 3-ethylpentyl, 2-ethylhexyl, 3-ethylhexyl, 4-ethylhexyl, 2-methyl-2-ethylpentyl, 2- methyl-3-ethylpentyl, 2-methyl-4-ethylpentyl, 2-methyl-2-ethylhexyl, 2-methyl-3-

ethylhexyl, 2-methyl-4-ethylhexyl, 2,2-diethylpentyl, 3,3-diethylhexyl, 2,2-diethylhexyl, 3,3-diethylhexyl and the like.

An “alkenyl group” or “alkylidene” mean a straight chain or branched non-cyclic hydrocarbon having from 2 to 10 carbon atoms and including at least one carbon-carbon double bond. Representative straight chain and branched (C,-

Cjg)alkenyls include -vinyl, -allyl, -1-butenyl, -2-butenyl, -isobutylenyl, -1-pentenyl, -2- pentenyl, -3-methyl-1-butenyl, -2-methyl-2-butenyl, -2,3-dimethyl-2-butenyl, -1- hexenyl, -2-hexenyl, -3-hexenyl, -1-heptenyl, -2-heptenyl, -3-heptenyl, -1-octenyl, -2- octenyl, -3-octenyl, -1-nonenyl, -2-nonenyl, -3-nonenyl, -1-decenyl, -2-decenyl, -3- decenyl and the like. An alkenyl group can be unsubstituted or substituted. A “cyclic alkylidene” is a ring having from 3 to 8 carbon atoms and including at least one carbon- carbon double bond, wherein the ring can have from 1 to 3 heteroatoms.

An “alkynyl group” means a straight chain or branched non-cyclic . hydrocarbon having from 2 to 10 carbon atoms and including at lease one carbon-carbon triple bond. Representative straight chain and branched -(C,-Cjg)alkynyls include - acetylenyl, -propynyl, -1-butynyl, -2-butynyl, -1-pentynyl, -2-pentynyl, -3-methyl-1- butynyl, -4-pentynyl, -1-hexynyl, -2-hexynyl, -5-hexynyl, -1-heptynyl, -2-heptynyl, -6- heptynyl, -1-octynyl, -2-octynyl, -7-octynyl, -1-nonynyl, -2-nonynyl, -8-nonynyl, -1- decynyl, -2-decynyl, -9-decynyl, and the like. An alkynyl group can be unsubstituted or substituted.

The terms “Halogen” and “Halo” mean fluorine, chlorine, bromine or 10dine. “Haloalkyl” means an alkyl group, wherein alkyl is defined above, substituted with one or more halogen atoms. “Keto” means a carbonyl group (i.e.,C=0). “Acyl” means an -C(O)alkyl group, wherein alkyl is defined above, including -C(O)CHj, -C(O)CH,CHs, -C(O)(CH;),CHs, -C(O)(CH,);CHs, -

C(O)(CH_2)4CHs, -C(O)(CH3)sCH3, and the like. “Acyloxy” means an -OC(O)alkyl group, wherein alkyl is defined above, including -OC(O)CHj;, -OC(O)CH,CHs, -OC(O)(CH,),CH3, -OC(0)(CH,);CHs, -

OC(O)(CH2)4CHs;, -OC(O)(CH,)sCHs3, and the like.

“Ester” means and -C(O)Oalkyl group, wherein alkyl is defined above, including -C(O)OCH3, -C(O)OCH,CHs, -C(0)O(CH,),CH3, -C(0)O(CH,);CHj, -

C(O)O(CH;)4CH3, -C(0)O(CH;)sCH3, and the like. “Alkoxy” means -O-(alkyl), wherein alkyl is defined above, including -

OCH, -OCH,CH3, -O(CH,),CHjs, -O(CHz);CHj;, -O(CH,)4,CHj3, -O(CH»)sCHj3, and the like. “Lower alkoxy” means -O-(lower alkyl), wherein lower alkyl is as described above. “Alkoxyalkoxy” means -O-(alkyl)-O-(alkyl), wherein each alkyl is independently an alkyl group defined above, including -OCH,OCHa, -OCH,CH,OCHS, -

OCH,CH,OCH,CH3, and the like. “Alkoxycarbonyl” means -C(=0)O-(alkyl), wherein alkyl is defined above, including -C(=0)O-CHj3, -C(=0)0-CH,CHs, -C(=0)0-(CH;),CHs, -C(=0)O- (CH2)3:CHs, -C(=0)0O-(CH2)4CH3, -C(=0)O-(CH,)sCHs, and the like. “Alkoxycarbonylalkyl” means -(alkyl)-C(=0)O-(alkyl), wherein each alkyl is independently defined above, including -CH,-C(=0)0-CHj3, -CH,-C(=0)0-

CH,CH3, -CH,-C(=0)0-(CH_),CHj3, -CH,-C(=0)0-(CH,);CH3, -CH,-C(=0)O- (CH3)sCHjs, -CH,-C(=0)O-(CH,)sCHs, and the like. “Alkoxyalkyl” means -(alkyl)-O-(alkyl), wherein each alkyl is independently an alkyl group defined above, including -CH,OCH3, -CH,OCH,CHs, - (CH,)20CH,CH3, -(CH;),0O(CH,),CHj3, and the like. “Aryl” means a carbocyclic aromatic group containing from 5 to 10 ring atoms. Representative examples include, but are not limited to, phenyl, tolyl, anthracenyl, fluorenyl, indenyl, azulenyl, pyridinyl and naphthyl, as well as benzo-fused carbocyclic moieties including 5,6,7,8-tetrahydronaphthyl. A carbocyclic aromatic group can be unsubstituted or substituted. In one embodiment, the carbocyclic aromatic group is a phenyl group. “Aryloxy” means -O-aryl group, wherein aryl is as defined above. An aryloxy group can be unsubstituted or substituted. In one embodiment, the aryl ring of an aryloxy group is a phenyl group “Arylalkyl” means -(alkyl)-(aryl), wherein alkyl and aryl are as defined above, including ~(CHz)phenyl, -(CHz).phenyl, -(CH,)sphenyl, -CH(phenyl),, -

CH(phenyl)s, -(CH,)tolyl, -(CHy)anthracenyl, -(CH,)fluorenyl, -(CH;)indenyl, - (CHz)azulenyl, -(CH,)pyridinyl, -(CH)naphthyl, and the like. “Arylalkyloxy” means -O-(alkyl)-(aryl), wherein alkyl and aryl are defined above, including -O-(CH,);phenyl, -O-(CH;);phenyl, -O-CH(phenyl),, -O-

CH(phenyl), -O-(CHa)tolyl, -O-(CHz)anthracenyl, -O-(CHy)fluorenyl, -O- (CHp)indenyl, -O-(CH;)azulenyl, -O-(CH,)pyridinyl, -O-(CH,)naphthyl, and the like. “Aryloxyalkyl” means -(alkyl)-O-(aryl), wherein alkyl and aryl are defined above, including -CHa-O-(phenyl), -(CH,),-O-phenyl, -(CH;);-O-phenyl, - (CHy)-O-tolyl, -(CHy)-O-anthracenyl, -(CH,)-O-fluorenyl, -(CH,)-O-indenyl, -(CH,)-O- azulenyl, -(CH,)-O-pyridinyl, -(CH,)-O-naphthyl, and the like. “Cycloalkyl” means a monocyclic or polycyclic saturated ring having carbon and hydrogen atoms and having no carbon-carbon multiple bonds. Examples of cycloalkyl groups include, but are not limited to, (C3—C;)cycloalkyl groups, including cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl, and saturated cyclic and bicyclic terpenes. A cycloalkyl group can be unsubstituted or substituted. In one embodiment, the cycloalkyl group is a monocyclic ring or bicyclic ring. “Cycloalkyloxy” means -O-(cycloalkyl), wherein cycloalkyl is defined above, including -O-cyclopropyl, -O-cyclobutyl, -O-cyclopentyl, -O-cyclohexyl, -O- cycloheptyl and the like. “Cycloalkylalkyloxy” means -O-(alkyl)-(cycloalkyl), wherein cycloalkyl and alkyl are defined above, including -O-CH,-cyclopropyl, -O-(CH,),-cyclopropyl, -O- (CHa)s-cyclopropyl, -O-(CHz)s-cyclopropyl, O-CH,-cyclobutyl, O-CH,-cyclopentyl, O-

CH;-cyclohexyl, O-CH,-cycloheptyl, and the like. “Aminoalkoxy” means -O-(alkyl)-NH,, wherein alkyl is defined above, such as -0-CH-NH,, -O-(CHz),-NH3, -O-(CH,)3-NHy, -O-(CHy)4-NH,, -O-(CHy)s-NH, and the like. “Mono-alkylamino” means -NH(alkyl), wherein alkyl is defined above, such as -NHCH3;, -NHCH,CHj3, -NH(CH,),CHj3, -NH(CH,);CH3s, -NH(CH;),CHi, -

NH(CH;)sCHs, and the like.

“Di-alkylamino” means -N(alkyl)(alkyl), wherein each alkyl is } independently an alkyl group defined above, including -N(CHj),, -N(CH,CH3),, -

N((CH,),CH3s),, -N(CH3)(CH,CH3), and the like. “Mono-alkylaminoalkoxy” means -O-(alkyl)-NH(alkyl), wherein each alkyl is independently an alkyl group defined above, including -O-(CH,)-NHCHj, -O- (CH2)-NHCH,CHs, -O-(CH;)-NH(CH,),CHj, -O-(CH,)-NH(CH,);CH3, -O-(CH,)-

NH(CH_)4sCH3, -O-(CH;)-NH(CH_)sCH3, -O-(CH,),-NHCH3, and the like. “Di-alkylaminoalkoxy”” means -O-(alkyl)-N(alkyl)(alkyl), wherein each alkyl is independently an alkyl group defined above, including -O-(CH,)-N(CHs),, -O- (CH2)-N(CH>CH3),, -O-(CH»)-N((CH,),CHs),, -O-(CH,)-N(CH3)(CH,CH3), and the like. “Arylamino”means -NH(aryl), wherein aryl is defined above, including -

NH(phenyl), -NH(tolyl), -NH(anthracenyl), -NH(fluorenyl), -NH(indenyl), -

NH(azulenyl), -NH(pyridinyl), -NH (naphthyl), and the like. “Arylalkylamino” means -NH-(alkyl)~(aryl), wherein alkyl and aryl are defined above, including -NH-CH»-(phenyl), -NH-CHa-(tolyl), -NH-CH)-(anthracenyl), -

NH-CH,-(fluorenyl), -NH-CH,-(indenyl), -NH-CH,-(azulenyl), -NH-CH,-(pyridiny1), -

NH-CHz-(naphthyl), -NH-(CH,),-(phenyl) and the like. “Alkylamino” means mono-alkylamino or di-alkylamino as defined above, such as -N(alkyl)(alkyl), wherein each alkyl is independently an alkyl group defined above, including -N(CH3),, -N(CH,CHj),, -N((CH;)2CH3),, -N(CH;3)(CH,CH3) and -N(alkyl)(alkyl), wherein each alkyl is independently an alkyl group defined above, including -N(CHj3)z, -N(CH>CH3);, -N((CH>),CHz),, -N(CH;3)(CH,CHa) and the like. “Cycloalkylamino” means -NH-(cycloalkyl), wherein cycloalkyl is as defined above, including -NH-cyclopropyl, -NH-cyclobutyl, -NH-cyclopentyl, -NH- cyclohexyl, -NH-cycloheptyl, and the like. “Carboxyl” and “carboxy” mean -COOH. “Cycloalkylalkylamino” means -NH-(alkyl)-(cycloalkyl), wherein alkyl and cycloalkyl are defined above, including -NH-CH,-cyclopropyl, -NH-CH,- cyclobutyl, -NH-CH,-cyclopentyl, -NH-CH;-cyclohexyl, -NH-CH,-cycloheptyl, -NH- (CHaz)z-cyclopropyl and the like.

“Aminoalkyl” means -(alkyl)-NH,, wherein alkyl is defined above, including CH;,-NHp, -(CHz),-NH, -(CH,)3-NH,, -(CH,)s-NH,, -(CH,)s-NH, and the like. “Mono-alkylaminoalkyl” means -(alky!)-NH(alkyl),wherein each alkyl is independently an alkyl group defined above, including -CH,-NH-CHj, -CH,- } NHCH,CHs, -CH,-NH(CH,),CHs, -CH,-NH(CH,);CHj3, -CH,-NH(CH,)4CHj3, -CH,-

NH(CH;)sCHj;, -(CH,),-NH-CHj3, and the like. “Di-alkylaminoalkyl” means -(alkyl)-N(alkyl)(alkyl),wherein each alkyl is independently an alkyl group defined above, including -CH,-N(CHs),, -CH,-

N(CH>CHj),, -CH;-N((CH2),CH3),, -CH,-N(CH;)(CH,;CHj3), -(CH3),-N(CHa),, and the like. “Heteroaryl” means an aromatic heterocycle ring of 5- to 10 members and having at least one heteroatom selected from nitrogen, oxygen and sulfur, and containing at least 1 carbon atom, including both mono- and bicyclic ring systems. Representative heteroaryls are triazolyl, tetrazolyl, oxadiazolyl, pyridyl, furyl, benzofuranyl, thiophenyl, benzothiophenyl, quinolinyl, pyrrolyl, indolyl, oxazolyl, benzoxazolyl, imidazolyl, benzimidazolyl, thiazolyl, benzothiazolyl, isoxazolyl, pyrazolyl, isothiazolyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, cinnolinyl, phthalazinyl, quinazolinyl, pyrimidyl, oxetanyl, azepinyl, piperazinyl, morpholinyl, dioxanyl, thietanyl and oxazolyl. “Heteroarylalkyl” means -(alkyl)-(heteroaryl), wherein alkyl and heteroaryl are defined above, including -CH,-triazolyl, -CH,-tetrazolyl, -CH,- oxadiazolyl, -CHy-pyridyl, -CH,-furyl, -CH,-benzofuranyl, -CH,-thiophenyl, -CH,- benzothiophenyl, -CH;-quinolinyl, -CH,-pyrrolyl, -CH,-indolyl, -CH,-oxazolyl, -CH,- benzoxazolyl, -CH,-imidazolyl, -CH,-benzimidazolyl, -CH,-thiazolyl, -CH,- benzothiazolyl, -CH,-1soxazolyl, -CH,-pyrazolyl, -CH,-isothiazolyl, -CH,-pyridazinyl, -

CH,-pyrimidinyl, -CH,-pyrazinyl, -CH,-triazinyl, -CH,-cinnolinyl, -CH,-phthalazinyl, -

CH,-quinazolinyl, -CHa-pyrimidyl, -CH,-oxetanyl, -CH,-azepinyl, -CH,-piperazinyl, -

CHz-morpholinyl, -CH,-dioxanyl, -CHy-thietanyl, -CH,-oxazolyl, -(CH,),-triazolyl, and the like. “Heterocycle” means a 5- to 7-membered monocyclic, or 7- to 10- membered bicyclic, heterocyclic ring which is either saturated, unsaturated, and which contains from 1 to 4 heteroatoms independently selected from nitrogen, oxygen and sulfur, and wherein the nitrogen and sulfur heteroatoms can be optionally oxidized, and the nitrogen heteroatom can be optionally quaternized, including bicyclic rings in which any of the above heterocycles are fused to a benzene ring. The heterocycle can be attached via any heteroatom or carbon atom. Heterocycles include heteroaryls as defined above. Representative heterocycles include morpholinyl, pyrrolidinonyl, pyrrolidinyl, piperidinyl, hydantoinyl, valerolactamyl, oxiranyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydropyridinyl, tetrahydroprimidinyl, tetrahydrothiophenyl, tetrahydrothiopyranyl, tetrahydropyrimidinyl, tetrahydrothiophenyl, tetrahydrothiopyranyl, and the like. “Heterocycle fused to phenyl” means a heterocycle, wherein heterocycle is defined as above, that is attached to a phenyl ring at two adjacent carbon atoms of the phenyl ring. “Heterocycloalkyl” means -(alkyl)-(heterocycle), wherein alkyl and heterocycle are defined above, including -CH,-morpholinyl, -CH;-pyrrolidinonyl, -CH,- pyrrolidinyl, -CH,-piperidinyl, -CH;-hydantoinyl, -CH,-valerolactamyl, -CH,-oxiranyl, -

CH;-oxetanyl, -CH,-tetrahydrofuranyl, -CH,-tetrahydropyranyl, -CH,- tetrahydropyridinyl, -CH,-tetrahydroprimidinyl, -CH,-tetrahydrothiophenyl, -CH,- tetrahydrothiopyranyl, -CH,-tetrahydropyrimidinyl, -CH,-tetrahydrothiophenyl, -CH,- tetrabydrothiopyranyl, and the like.

The term “substituted” as used herein means any of the above groups (i.e., aryl, arylalkyl, heterocycle and heterocycloalkyl) wherein at least one hydrogen atom of the moiety being substituted is replaced with a substituent. In one embodiment, each carbon atom of the group being substituted is substituted with no more that two substituents. In another embodiment, each carbon atom of the group being substituted is substituted with no more than one substituent. In the case of a keto substituent, two hydrogen atoms are replaced with an oxygen which is attached to the carbon via a double bond. Substituents include halogen, hydroxyl, alkyl, haloalkyl, mono- or di-substituted aminoalkyl, alkyloxyalkyl, aryl, arylalkyl, heterocycle, heterocycloalkyl, -NR Ry, -

NR.C(=O)Rs, -NR,C(=O)NR:Rs, -NR,C(=0)OR;, -NR,SO2Ry, -OR., -C(=O)R,

C(=0)OR; -C(=0)NRaRy, -OC(=O)R,, -OC(=0)OR,, -OC(=0)NR.Ry, -NR,SO,R,, or a radical of the formula -Y-Z-R, where Y is alkanediyl, or a direct bond, Z is -O-, -S-, - ) N(Rp)-, -C(=0)-, -C(=0)0-, -OC(=0)-, -N(Rp)C(=0)-, -C(=0)N(Ry)- or a direct bond, wherein R, and Ry are the same or different and independently hydro gen, amino, alkyl, haloalkyl, aryl, arylalkyl, heterocycle, or heterocylealkyl, or wherein R, and Ry, taken together with the nitrogen atom to which they are attached form a heterocycle. “Haloalkyl” means alkyl, wherein alkyl is defined as above, having one or more hydrogen atoms replaced with halogen, wherein halogen is as defined above, including -CF3, -CHF,, -CH}F, -CBr3, -CHBTI3, -CH,Br, -CCls, -CHCl,, -CH,Cl, -CL, -

CHL, -CH,L, -CH»-CFs, -CH,-CHF,, -CH,-CH,F, -CH,-CBr3, -CH,-CHBr,, -CH,-

CH;Br, -CH,-CCls, -CH,-CHCl,, -CH,-CH,Cl, -CH,-Cls, -CH,-CHI,, -CH,-CH,I, and the like. “Hydroxyalkyl” means alkyl, wherein alkyl is as defined above, having one or more hydrogen atoms replaced with hydroxy, including -CH, OH, -CH,CH,OH, - (CH,),CH, OH, -(CH,);CH20H, -(CH;)4CH, OH, -(CH,)sCH,0H, -CH(OH)-CH, -

CH,CH(OH)CHy3, and the like. “Hydroxy” means -OH. “Sulfonyl” means -SOzH. “Sulfonylalkyl” means -SO,-(alkyl), wherein alkyl is defined above, including -SO,-CHj3, -SO,-CH,CHj, -SO,-(CH,),CHs, -SO,-(CH,);CH, -S0O,- (CH2)4CH3, -SO,-(CH,)sCH3, and the like. “Sulfinylalky]l” means -SO-(alkyl), wherein alkyl is defined above, including -SO-CHj, -SO-CH,CH3, -SO-(CH,),CHs, -SO-(CH,);CHa, -SO-(CH,)4CH;, -

SO-(CH3)sCH3, and the like. “Sulfonamidoalkyl” means -NHSO,-(alkyl), wherein aklyl is defined above, including -NHSO,-CH3, -NHSO,-CH,CHjs, -NHSO,-(CH,),CHs, -NHSO,- (CHy);CHjs, -NHSO,-(CH,)4CHs, -NHSO,-(CH,)sCHs, and the like. “Thioalkyl” means -S-(alkyl), wherein alkyl is defined above, including -

S-CHs, -S-CH,CHa, -S-(CH2),CHs, -S-(CH.)3CHj, -S-(CH:)4CHj, -S-(CH,)sCHs, and the like.

As used herein, the term “JNK Inhibitor” encompasses , but is not limited to, compounds disclosed herein. Without being limited by theory, specific INK

Inhibitors capable of inhibiting the activity of JNK in vitro or in vivo. The JNK ] Inhibitor can be in the form of a pharmaceutically acceptable salt, free base, solvate, hydrate, stereoisomer, clathrate or prodrug thereof. Such inhibitory activity can be determined by an assay or animal model well-known in the art including those set forth in Section 5. In one embodiment, the JNK Inhibitor is a compound of structure (I)-(IIL). “JNK” means a protein or an isoform thereof expressed by a JNK 1, INK 2, or JNK 3 gene (Gupta, S., Barrett, T., Whitmarsh, A.J, Cavanagh, J., Sluss, HK.,

Dernjard, B. and Davis, R.J. The EMBO J. 15:2760-2770 (1996)).

As used herein, the phrase “an effective amount” when used in connection with a JNK Inhibitor means an amount of the JNK Inhibitor that is useful for for treating, preventing, managing and/or modifying pain.

As used herein, the phrase “an effective amount” when used in connection with another therpeutic or prophylactic agent means an amount of the other therapeutic or prophylactic agent that is useful for for treating, preventing, managing and/or modifying pain when administered while the JNK Inhibitor exerts its therapeutic or prophylactic activity.

As used herein, the term “pharmaceutically acceptable salt(s)” refers to a salt prepared from a pharmaceutically acceptable non-toxic acid or base including an inorganic acid and base and an organic acid and base. Suitable pharmaceutically acceptable base addition salts of the JNK Inhibitor include, but are not limited to metallic salts made from aluminum, calcium, lithium, magnesium, potassium, sodium and zinc or organic salts made from lysine, N,N’-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, ethylenediamine, meglumine (N-methylglucamine) and procaine.

Suitable non-toxic acids include, but are not limited to, inorganic and organic acids such as acetic, alginic, anthranilic, benzenesulfonic, benzoic, camphorsulfonic, citric, ethenesulfonic, formic, fumaric, furoic, galacturonic, gluconic, glucuronic, glutamic, glycolic, hydrobromic, hydrochloric, isethionic, lactic, maleic, malic, mandelic, methanesulfonic, mucic, nitric, pamoic, pantothenic, phenylacetic, phosphoric, propionic, salicylic, stearic, succinic, sulfanilic, sulfuric, tartaric acid, and p- : toluenesulfonic acid. Specific non-toxic acids include hydrochloric, hydrobromic, phosphoric, sulfuric, and methanesulfonic acids. Examples of specific salts thus include hydrochloride and mesylate salts. Others are well-known in the art, see for example, ’ Remington's Pharmaceutical Sciences, 18" eds., Mack Publishing, Easton PA (1990) or

Remington: The Science and Practice of Pharmacy, 19™ eds., Mack Publishing, Easton

PA (1995). 3 As used herein and unless otherwise indicated, the term “polymorph” means a particular crystalline arrangement of the JNK Inhibitor. Polymorphs can be obtained through the use of different work-up conditions and/or solvents. In particular, polymorphs can be prepared by recrystallization of a JNK Inhibitor in a particular solvent.

As used herein and unless otherwise indicated, the term “prodrug” means a JNK Inhibitor derivative that can hydrolyze, oxidize, or otherwise react under biological conditions (in vitro or in vivo) to provide an active compound, particularly a

JNK Inhibitor. Examples of prodrugs include, but are not limited to, derivatives and metabolites of a JNK Inhibitor that include biohydrolyzable moieties such as biohydrolyzable amides, biohydrolyzable esters, biohydrolyzable carbamates, biohydrolyzable carbonates, biohydrolyzable ureides, and biohydrolyzable phosphate analogues. Preferably, prodrugs of compounds with carboxyl functional groups are the lower alkyl esters of the carboxylic acid. The carboxylate esters are conveniently formed by esterifying any of the carboxylic acid moieties present on the molecule. Prodrugs can typically be prepared using well-known methods, such as those described by Burger's

Medicinal Chemistry and Drug Discovery 6™ ed. (Donald J. Abraham ed., 2001, Wiley) and Design and Application of Prodrugs (H. Bundgaard ed., 1985, Harwood Academic

Publishers Gmfh).

As used herein and unless otherwise indicated, the term “optically pure” or “‘stercomerically pure” means one stereoisomer of a compound is substantially free of other stereoisomers of that compound. For example, a stereomerically pure compound having one chiral center will be substantially free of the opposite enantiomer of the compound. A stereomerically pure a compound having two chiral centers will be substantially free of other diastereomers of the compound. A typical stereomerically pure compound comprises greater than about 80% by weight of one stereoisomer of the compound and less than about 20% by weight of other stereoisomers of the compound,

more preferably greater than about 90% by weight of one stereoisomer of the compound ’ and less than about 10% by weight of the other stereoisomers of the compound, even more preferably greater than about 95% by weight of one stereoisomer of the compound and less than about 5% by weight of the other stereoisomers of the compound, and most preferably greater than about 97% by weight of one stereoisomer of the compound and less than about 3% by weight of the other stereoisomers of the compound.

As used herein, the terms “complex regional pain syndrome,” “CRPS” and “CRPS and related syndromes” mean a chronic pain disorder characterized by one or more of the following: pain, whether spontaneous or evoked, including allodynia (painful response to a stimulus that is not usually painful) and hyperalgesia (exaggerated response to a stimulus that is usually only mildly painful); pain that is disproportionate to the inciting event (e.g., years of severe pain after an ankle sprain); regional pain that is not limited to a single peripheral nerve distribution; and autonomic dysregulation (e.g., edema, alteration in blood flow and hyperhidrosis) associated with trophic skin changes (hair and nail growth abnormalities and cutaneous ulceration). Unless otherwise indicated, the terms “complex regional pain syndrome” and “CRPS” include: type I, encompassing the condition known as reflex sympathetic dystrophy (RSD), which occurs after an initial noxious event other than a nerve injury; type II, encompassing the condition known as causalgia, which occurs after nerve injury; acute stage (usually hyperthermic phase of 2-3 months); dystrophic phase (showing vasomotor instability for several months); atrophic phase (usually cold extremity with atrophic changes); reflex neurovascular dystrophy; reflex dystrophy; sympathetic maintained pain syndrome;

Sudeck atrophy of bone; algoneurodystrophy; shoulder hand syndrome; post-traumatic dystrophy; trigeminal neuralgia; post herpetic neuralgia; cancer related pain; phantom limb pain; fibromyalgia; chronic fatigue syndrome; radiculopathy; and other painful neuropathic conditions, e.g., diabetic neuropathy, luetic neuropathy, painful neuropathy induced iatrogenically by drugs such as vincristine, velcade or thalidomide.

As used herein, unless otherwise specified, the term “treating pain” refers to the administration of a JNK Inhibitor, optionally in combination with another active agent or other therapy, after the onset of a symptom of pain, whereas “preventing pain”refers to the administration of a JNK Inhibitor, optionally in combination with another active agent or other therapy, prior to the onset of a symptom of pain, ‘ particularly to patients at risk of experiencing pain. Examples of patients at risk of experiencing pain include, but are not limited to, those who have incidents of trauma, neurologic disorder, genetic disorder, myocardial infarction, surgery, muscoskeletal disorder or malignancy. Patients with familial history of pain are also preferred candidates for preventive regimens. As used herein, unless otherwise indicated, the term “managing pain” encompasses preventing the recurrence of pain in a patient who has suffered from pain, and/or lengthening the time that a patient who has suffered from pain remains in remission. As used herein, unless otherwise specified, the term “modifying pain” means changing the way that a patient responds to pain. In one embodiment, “modifying pain” means bringing a patient’s pain threshold from an elevated level (i.e, a level at which a patient experiences greater than normal pain in response to a particular stimulus) back to a normal level. In another embodiment, “modifying pain” means reducing a patient’s pain response to a stimulus of a particular intensity. In another embodiment, modifying pain” means increasing a patient’s pain threshold relative to the patient’s pain threshold prior to the administration of an effective amount of a JNK

Inhibitor. 4. DETAILED DESCRIPTION OF THE INVENTION 4.1 ILLUSTRATIVE JNK INHIBITORS

As mentioned above, the present invention is directed to methods useful for treating, preventing, managing and/or modifying pain, comprising administering an effective amount of a JNK Inhibitor to a patient in need thereof. Illustrative JNK

Inhibitors are set forth below.

In one embodiment, the JNK Inhibitor has the following structure (I):

H

N,

Qu,

R3 on “TR wherein:

A is a direct bond, -(CHy),-, -(CH,),CH=CH(CH,).-, or -(CH,),C =

C(CHa)c-;

R; is aryl, heteroaryl or heterocycle fused to phenyl, each being optionally substituted with one to four substituents independently selected from Rj;

Rg is -Rs, -Ry, (CH2),C(=O)Rs, -(CH,)5C(=0)ORs, -(CH2)sC(=O)NR Rs, -(CH,),C(=0)NRs(CH,).C(=O)Rs, -(CH,)sNRsC(=O)Rs, -(CH2)sNRsC(=O)NR¢Rs, (CH,);NRsRs, -(CHy),0Rs, -(CH2)5SO4R 5 or -(CH,),SO,NRsRs, ais 1,2,3,4,5 or 6; . b and c are the same or different and at each occurrence independently selected from 0, 1, 2, 3 or 4; d is at each occurrence 0, 1 or 2;

Rj is at each occurrence independently halogen, hydroxy, carboxy, alkyl, alkoxy, haloalkyl, acyloxy, thioalkyl, sulfinylalkyl, sulfonylalkyl, hydroxyalkyl, aryl, arylalkyl, heterocycle, heterocycloalkyl, -C(=0)ORg, -OC(=0)R3, -C(=0)NR;zRo, -C(=O)NRsORy, -SO;NR3Ry, -NRgSO;Ry, -CN, -NO,, -NRsR, -NR3sC(=0)Ro, -NRsC(=0)(CH;),ORyg, -NRsC(=0)(CH,);R, -O(CH2)sNRgRy, or heterocycle fused to phenyl;

Ryis alkyl, aryl, arylalkyl, heterocycle or heterocycloalkyl, each being optionally substituted with one to four substituents independently selected from Rj, or Ry 1s halogen or hydroxy;

Rs, Rg and R; are the same or different and at each occurrence independently hydrogen, alkyl, aryl, arylalkyl, heterocycle or heterocycloalkyl, wherein each of Rs, Rs and R; are optionally substituted with one to four substituents independently selected from Rj; and

Rg and Ry are the same or different and at each occurrence independently ‘ hydrogen, alkyl, aryl, arylalkyl, heterocycle, or heterocycloalkyl, or Rg and Ro taken together with the atom or atoms to which they are bonded form a heterocycle, wherein each of Rg, Ro, and Rg and Ry taken together to form a heterocycle are optionally substituted with one to four substituents independently selected from Rs.

In one embodiment, -A-R; is phenyl, optionally substituted with one to ; four substituents independently selected from halogen, alkoxy, -NRgC(=0)Ro, -C(=0O)NR;gRy, and -O(CH;),NRgRg, wherein 4 is 2 or 3 and wherein Rg and Ry are defined above. ] In another embodiment, R; is -R4, -(CH,),C(=0)Rs, -(CH,),C(=0)ORs, «(CH2),C(=O)NRsRs, -(CH2)sC(=O)NRs5(CH,).C(=O)Rs, -(CH,),NRsC(=O)Rs, -(CH2)sNRsC(=O)NReR7, -(CH2),NR Rg, -(CH,),ORs, -(CH,),SO.Rs or -(CH»)»SO:NRsRg, and b is an integer ranging from 0-4.

In another embodiment, R; is -(CH,),C(=0)NRsRs, -(CH,)sNRsC(=0O)Rs, 3-triazolyl or 5-tetrazolyl, wherein 5 is 0 and wherein Rs and Ry are defined above.

In another embodiment, R, is 3-triazolyl or 5-tetrazolyl.

In another embodiment: (a) -A-R; is phenyl, optionally substituted with one to four substituents independently selected from halogen, alkoxy, -NRgC(=O)Ry, -C(=O)NRgRg, and -O(CH,);NRgRg, wherein b is 2 or 3; and (b) Ry is -(CH2),C(=O)NRsRs, -(CH,),NRsC(=O)Rs, 3-triazolyl or 5- tetrazolyl, wherein b is 0 and wherein Rg and Rg are defined above.

In another embodiment: (a) -A-R; is phenyl, optionally substituted with one to four substituents independently selected from halogen, alkoxy, -NRgC(=0)Ry, -C(=0)NRzRy, and -O(CH;);NRgRy, wherein b is 2 or 3; and (b) R; is 3-triazolyl or 5-tetrazolyl.

In another embodiment, R; is Ry, and Ry is 3-triazolyl, optionally substituted at its 5-position with: (a) a C,-C; straight or branched chain alkyl group optionally substituted with a hydroxyl, methylamino, dimethylamino or 1-pyrrolidinyl group; or (b) a 2-pyrrolidinyl group.

In another embodiment, R; is Ry, and Ry is 3-triazolyl, optionally substituted at its 5-position with: methyl, n-propyl, isopropyl, 1-hydroxyethyl, 3- hydroxypropyl, methylaminomethyl, dimethylaminomethyl, 1-(dimethylamino)ethyl, 1- pyrrolidinylmethyl or 2-pyrrolidinyl.

In another embodiment, the compounds of structure (I) have structure (IA) when A is a direct bond, or have structure (IB) when A is -(CH,),-:

H H

N N

AN AY

) N N

R2 R27

R1 (CH2)aRy (IA) (IB)

In other embodiments, the compounds of structure (I) have structure (IC) when A is a -CH;),CH=CH(CH3),-, and have structure (ID) when A is -(CH,),C = C(CHy).-:

H

N N

'N \ / / N

Rs Rs (CH2),CH=CH(CH)-R; (CHp)sCH=CH(CHy)Rq

Io (ID)

In further embodiments of this invention, R; of structure (I) is aryl or substituted aryl, such as phenyl or substituted phenyl as represented by the following structure (IE):

H

N

\ y N

R7 0

XX

(Ra)o-4 (IE)

In another embodiment, R; of structure (I) is -(CH;),NR4(C=0)R5. In one aspect of this embodiment, b =0 and the compounds have the following structure (IF):

H : 0 N

PN 4

Re N

Rs A—Rq (IF)

Representative Ry groups of the compounds of structure (I) include alkyl (such as methyl and ethyl), halo (such as chloro and fluoro), haloalkyl (such as trifluoromethyl), hydroxy, alkoxy (such as methoxy and ethoxy), amino, arylalkyloxy (such as benzyloxy), mono- or di-alkylamine (such as -NHCHj, -N(CH3); and -

NHCH,CH3), -NHC(=0O)R, wherein Rg is a substituted or unsubstituted phenyl or heteroaryl (such as phenyl or heteroaryl substituted with hydroxy, carboxy, amino, ester, alkoxy, alkyl, aryl, haloalkyl, halo, -CONH, and -CONH alkyl), -NH(heteroarylalkyl) (such as -NHCH,(3-pyridyl), -NHCH,(4-pyridyl), heteroaryl (such as pyrazolo, triazolo and tetrazolo), -C(=O)NHR¢ wherein Rg is hydrogen, alkyl, or as defined above (such as -C(=0)NHo, -C(=0)NHCH3, -C(=O)NH(H-carboxyphenyl), -C(=O)N(CH,),), arylalkenyl (such as phenylvinyl, 3-nitrophenylvinyl, 4-carboxyphenylvinyl), heteroarylalkenyl (such as 2-pyridylvinyl, 4-pyridylvinyl).

Representative R; groups of the compounds of structure (I) include halogen (such as chloro and fluoro), alkyl (such as methyl, ethyl and isopropyl), haloalkyl (such as trifluoromethyl), hydroxy, alkoxy (such as methoxy, ethoxy, n- propyloxy and isobutyloxy), amino, mono- or di-alkylamino (such as dimethylamine), aryl (such as phenyl), carboxy, nitro, cyano, sulfinylalkyl (such as methylsulfinyl), sulfonylalkyl (such as methylsulfony!), sulfonamidoalkyl (such as -NHSO,CH3), -NRgC(=0)(CH,),ORy (such as NHC(=0)CH,0OCHj), NHC(=0)Ry (such as -NHC(=0)CHj, -NHC(=0)CH,C¢Hs, -NHC(=0)(2-furanyl)), and -O(CH3)sNRgRs (such as -O(CH.)N(CHs),).

The compounds of structure (I) can be made using organic synthesis techniques known to those skilled in the art, as well as by the methods described in

International Publication No. WO 02/10137 (particularly in Examples 1-430, at page 35, line 1 to page 396, line 12), published February 7, 2002, which is incorporated herein by reference in its entirety. Further, specific examples of these compounds are found in this publication.

Illustrative examples of JNK Inhibitors of structure (D are:

H

N, . N / N ¢

Re

F

3-(4-Fluoro-phenyl)-5-(1 H- [1 2,4]triazol-3-yl)-1H-indazole,

H

N yr / ) wv

Oe 3-[3-(2-Piperidin-1-yl-ethoxy)-phenyl]-5-(1H- [1,2,4]triazol-3-yl)-1H-indazole ; § _ H N

NPL PN %

TY

F

3-(4-Fluoro-phenyl)-1H-indazole-5-carboxylic acid (3-morpholin-4-yl-propyl)-amide ;

H gw eo

HaN % o N o W

Oi 3-[3-(3-Piperidin-1-yl-propionylamino)-phenyl]-1 H- indazole-5-carboxylic acid amide ;

H

N

\

N <¢ MN /,

N’ “0 Q ; 0 o 3-Benzo[1,3]dioxol-5-yl-5-(2H-tetrazol- 5-yl)-1H-indazole ;

H

N

\ : 0) 4g AN

HaC—(

W

F

3-(4-Fluoro-phenyl)-5-(5- methyl-[1,3,4]oxadiazol-2-yl)- 1H-indazole ;

H

N ge;

N / ¢ H3C CHj

NE HN

8

Oo

N-teri-Butyl-3-[5-(1H-[1,2,4]triazol-3-y1)-1H- indazol-3-yl]-benzamide ;

N q

N { ¢ Cl 7 N !

RA

3-[3-(2-Morpholin-4-yl-cthoxy)-phenyl]-5-(1 H- [1,2,4]triazol-3-yl)-1H-indazole ; . H ’

N

N %a

CA

He

SN fo! CHj

Dimethyl-(2-{4-[5-(1H-[1,2,4]triazol-3-yl)-1 H- : indazol-3-yl]-phenoxy}-ethyl)-amine :

H

N

\ . ) H3C CH, N 4g / N

Dad

F

5-[5-(1,1-Dimethyl-propyl)-1H-[1,2,4]triazol-3- i 5 yl]-3-(4-fluoro-phenyl)- 1 H-indazole ;

H

N,

N a ~~

Ele

F

3-(4-Fluoro-phenyl)-5-(5-pyrrolidin-1- ylmethyl-1H-[1,2 4]triazol-3-y1)-1H- indazole ;

H

N,

N 7a ~~

SEAS

0—CHs 3-(6-Methoxy-naphthalen-2-y1)-5-(5 -pyrrolidin-1- ylmethyl-1H-[1,2,4]triazol-3-yl)-1H-indazole ;

H

N

HoN g %

RY,

F

3-(4-Fluoro-phenyl)-1H-indazole-5-carboxylic acid and pharmaceutically acceptable salts thereof.

In another embodiment, the INK Inhibitor has the following structure dD:

3 0)

AAAI ay wherein:

R, is aryl or heteroaryl optionally substituted with one to four substituents independently selected from Ry;

R; is hydrogen;

Rj is hydrogen or lower alkyl;

R, represents one to four optional substituents, wherein each substituent is the same or different and independently selected from halogen, hydroxy, lower alkyl and lower alkoxy;

Rs and Rg are the same or different and independently -Rg, -(CH2)sC(=O)Ry, -(CH2),C(=0)ORo, -(CH,),C(=O)NRR q, ~(CH2)aC(=O)NRy(CH,),C(=0)R 0, -(CH2),NRyC(=O)R,, (CH2)oNR;;C(=0)NRoR;o, -(CH2)aNRgR 0, -(CH2),ORs, -(CH,),SO.Rg or -(CH3),SO;NRgR 0; or Rs and Re taken together with the nitrogen atom to which they are attached to form a heterocycle or substituted heterocycle;

Ry is at each occurrence independently halogen, hydroxy, cyano, nitro, carboxy, alkyl, alkoxy, haloalkyl, acyloxy, thioalkyl, sulfinylalkyl, sulfonylalkyl, hydroxyalkyl, aryl, arylalkyl, heterocycle, substituted heterocycle, heterocycloalkyl, -C(=0)ORs, -OC(=O)Rs, -C(=0)NRgRy, -C(=O)NRgORy, -SO.Rs, -SO:NRgRg, -NRgSOcRy, -NRgRy, -NRsC(=O)Ry, -NRgC(=0)(CH,),ORy, -NRC(=0)(CH,)sRs, -O(CH)sNRgRy, or heterocycle fused to phenyl; . Rg, Ro, Rip and Ry; are the same or different and at each occurrence independently hydrogen, alkyl, aryl, arylalkyl, heterocycle, heterocycloalkyl; : or Rg and Ry taken together with the atom or atoms to which they are attached to form a heterocycle; a and b are the same or different and at each occurrence independently selected from 0, 1, 2, 3 or 4; and c 1s at each occurrence 0, 1 or 2.

In one embodiment, R; is a substituted or unsubstituted aryl or heteroaryl.

When R; is substituted, it is substituted with one or more substituents defined below. In one embodiment, when substituted, R; is substituted with a halogen, -SO,R; or -SO,R3R,.

In another embodiment, R; is substituted or unsubstituted aryl, furyl, benzofuranyl, thiophenyl, benzothiophenyl, quinolinyl, pyrrolyl, indolyl, oxazolyl, benzoxazolyl, imidazolyl, benzimidazolyl, thiazolyl, benzothiazolyl, isoxazolyl, pyrazolyl, isothiazolyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, cinnolinyl, phthalazinyl or quinazolinyl.

In another embodiment R, is substituted or unsubstituted aryl or heteroaryl. When R,; is substituted, it is substituted with one or more substituents defined below. In one embodiment, when substituted, R; is substituted with a halogen, -SO,R3 or -SO;RgRo.

In another embodiment, R; is substituted or unsubstituted aryl, preferably phenyl. When R; is a substituted aryl, the substituents are defined below. In one embodiment, when substituted, R; is substituted with a halo gen, -SO;R;3 or -SO,RzRs.

In another embodiment, Rs and Rg, taken to gether with the nitrogen atom to which they are attached form a substituted or unsubstituted nitrogen-containing non- aromatic heterocycle, in one embodiment, piperazinyl, piperidinyl or morpholinyl.

When Rs and Rg, taken together with the nitro gen atom to which they areattached form substituted piperazinyl, piperadinyl or morpholinyl, the piperazinyl, piperadinyl or morpholinyl is substituted with one or more substituents defined below.

In one embodiment, when substituted, the substituent is alkyl, amino, alkylamino, alkoxyalkyl, acyl, pyrrolidinyl or piperidinyl.

In one embodiment, R3 is hydrogen and Ry is not present, and the INK

Inhibitor has the following structure (ILA):

0

Rs ’® \ or if

Va

R; A Rg

H . : (a) : and pharmaceutically acceptable salts thereof,

In a more specific embodiment, R; is phenyl optionally substituted with

R7, and having the following structure (IIB):

R

7) r

Ry— | . H

XN

(IIB) and pharmaceutically acceptable salts thereof.

In still a further embodiment, Ryis at the para position of the phenyl group relative to the pyrimidine, as represented by the following structure (IC): 0]

R. gi i

A Re

H

R- ’ mo) and pharmaceutically acceptable salts thereof.

The JNK Inhibitors of structure (II) can be made using organic synthesis techniques known to those skilled in the art, as well as by the methods described in

International Publication No. WO 02/46170 (particularly Examples 1-27 at page 23, line : 5 to page 183, line 25), published June 13, 2002, which is hereby incorporated by reference in itsr entirety. Further, specific examples of these compounds are found in the publication.

Ilustrative examples of JNK Inhibitors of structure (II) are:

0

SN NH,

PN

H

) Cl 4-[4-(4-Chloro-phenyl)-pyrimidin-2-ylamino]- benzamide :

CH.

Ny N 3

A CHj

H

Cl 4-[4-(4-Chloro-phenyl)-pyrimidin-2-ylamino]-N,N-dimethyl- benzamide .

NN NTN

A

H

Cl 4-[4-(4-Chloro-pheny!)-pyrimidin-2-ylamino]-N-(3-piperidin-1-yl-propyl)- benzamide :

SN NT

: H

Cl : {4-[4-(4-Chloro-phenyl)-pyrimidin-2-ylamino]-phenyl} - piperazin-1-yl-methanone :

. AN N NY

N hg 0 ] Cl 1-(4-{4-[4-(4-Chloro-phenyl)-pyrimidin-2-ylamino]-benzoyl} - piperazin-1-yl)-ethanone : 0)

SN NT

N Y

(0) u 0 Ng 1-{4-(4-{4-[4-(3-Hydroxy-propylsulfanyl)-phenyl] -pyrimidin-2-ylamino}-benzoyl)- piperazin-1-yl]-ethanone : (7

AA

¥ 0) a {4-[4-(4-Chloro-phenyl)-pyrimidin-2-ylamino]-phenyl} -(4-pyrrolidin-1-y1- piperidin-1-yl)-methanone ; and pharmaceutically acceptable salts thereof.

In another embodiment, the INK Inhibitor has the following structure (II): 1 2 . N—-—R, 10 9 3 8 CLC 4 7 6 5 0 (IIT)

wherein Rp is -O-, -S-, -S(O)-, -S(0),-, NH or -CH;-; the compound of structure (IIT) being: (i) unsubstituted, (11) monosubstituted and having a first substituent, or (iii) disubstituted and having a first substituent and a second substituent; the first or second substituent, when present, is at the 3, 4, 5,7,8,9,0r 10 position, wherein the first and second substituent, when present, are independently alkyl, hydroxy, halogen, nitro, trifluoromethyl, sulfonyl, carboxyl, alkoxycarbonyl, alkoxy, aryl, aryloxy, arylalkyloxy, arylalkyl, cycloalkylalkyloxy, cycloalkyloxy, alkoxyalkyl, alkoxyalkoxy, aminoalkoxy, mono-alkylaminoalkoxy, di-alkylaminoalkoxy, or a group represented by structure (a), (b), (c), (d), (¢), or (f):

Q 0

Ra . Ja Hr 0=3—r, ™N NEN —N —

Rs " AY \, (a) (b) (c) (d)

I i a “he

R4 R4 (e) (H wherein R3 and Ry are taken together and represent alkylidene or a heteroatom-containing cyclic alkylidene or R3 and Ry are independently hydrogen, alkyl, cycloalkyl, aryl, arylalkyl, cycloalkylalkyl, aryloxyalkyl, alkoxyalkyl, aminoalkyl, mono-alkylaminoalkyl, or di-alkylaminoalkyl; and

Rsis hydrogen, alkyl, cycloalkyl, aryl, arylalkyl, cycloalkylalkyl, alkoxy, . alkoxyalkyl, alkoxycarbonylalkyl, amino, mono-alkylamino, di-alkylamino, arylamino, arylalkylamino, cycloalkylamino, cycloalkylalkylamino, aminoalkyl, mono- alkylaminoalkyl, or di-alkylaminoalkyl.

In another embodiment, the JNK Inhibitor has the following structure (IIIA): 1 2

N———CH, o 3 8 4 7 6 5 0 2H-Dibenzo[cd,glindol-6-one (IIIA) being: (i) unsubstituted, (ii) monosubstituted and having a first 10 substituent, or (iii) disubstituted and having a first substituent and a second substituent; the first or second substituent, when present, is at the 3, 4, 5,7,8,9,0or 10 position; wherein the first and second substituent, when present, are independently alkyl, hydroxy, halogen, nitro, trifluoromethyl, sulfonyl, carboxyl, alkoxycarbonyl, alkoxy, aryl, aryloxy, arylalkyloxy, arylalkyl, cycloalkylalkyloxy, cycloalkyloxy, alkoxyalkyl, alkoxyalkoxy, aminoalkoxy, mono- alkylaminoalkoxy, di- alkylaminoalkoxy, or a group represented by structure (a), (b), (c), (d), (e), or (f):

Q 0

R a H Va Mrs 03g, ™ EN —N _

Raq Ra \ \, (2) (b) (© @

I I

PY Rs S Rs

N ~~ pd I N pr °

Rs Ry © ® wherein R3 and Ry are taken together and represent alkylidene or a heteroatom-containing cyclic alkylidene or R3 and Ry are independently hydrogen, alkyl,

cycloalkyl, aryl, arylalkyl, cycloalkylalkyl, aryloxyalkyl, alkoxyalkyl, aminoalkyl, mono-alkylaminoalkyl, or di-alkylaminoalkyl; and

Rs 1s hydrogen, alkyl, cycloalkyl, aryl, arylalkyl, cycloalkylalkyl, alkoxy, alkoxyalkyl, alkoxycarbonylalkyl, amino, mono-alkylamino, di-alkylamino, arylamino, arylalkylamino, cycloalkylamino, cycloalkylalkylamino, aminoalkyl, mono- alkylaminoalkyl, or di-alkylaminoalkyl.

A subclass of the compounds of structure (IIIA) is that wherein the first or second substituent is present at the 5, 7, or 9 position. In one embodiment, the first or second substituent is present at the 5 or 7 position.

A second subclass of compounds of structure (IIIA) is that wherein the first or second substituent is present at the 5, 7, or 9 position; the first or second substituent is independently alkoxy, aryloxy, aminoalkyl, mono-alkylaminoalkyl, di-alkylaminoalkyl, or a group represented by the structure (a), (c), (d), (e), or (f);

Rj and Ry are independently hydrogen, alkyl, cycloalkyl, aryl, arylalkyl, or cycloalkylalkyl; and

Rsis hydrogen, alkyl, cycloalkyl, aryl, arylalkyl, or cycloalkylalkyl.

In another embodiment, the JNK Inhibitor has the following structure (IIB): 0 10 — i

CL

8 4 7 8 5 [eo] 2-Ox0-2H-21%-anthra[9,1-cd] isothiazol-6-one (IIIB) . 25 being (i) unsubstituted, (ii) monosubstituted and having a first substituent, or (it) disubstituted and having a first substituent and a second substituent; the first or second substituent, when present, is at the 3, 4, 5, 7, 8, 9,0r10 position;

wherein the first and second substituent, when present, are independently ’ alkyl, halogen, hydroxy, nitro, trifluoromethyl, sulfonyl, carboxyl, alkoxycarbonyl, alkoxy, aryl, aryloxy, arylalkyloxy, arylalkyl, cycloalkylalkyloxy, cycloalkyloxy, alkoxyalkyl, alkoxyalkoxy, aminoalkoxy, mono-alkylaminoalkoxy, di-alkylaminoalkoxy, ] or a group represented by structure (a), (b) (c), (d), (e), or (f):

Q 0

R

J H a rs 0} —r 5

EN NEN N Nd \

I I

Py Rs S Rs

N ~~ ~~ | I N ~~ °

R4 R4 (e) ® wherein R; and Ry are taken together and represent alkylidene or a heteroatom-containing cyclic alkylidene or R3 and R, are independently hydrogen, alkyl, cycloalkyl, aryl, arylalkyl, cycloalkylalkyl, aryloxyalkyl, alkoxyalkyl, aminoalkyl, mono-alkylaminoalkyl, or di-alkylaminoalkyl; and

A subclass of the compounds of structure (IIIB) is that wherein the first or second substituent is present at the 5, 7, or 9 position. In one embodiment, the first or second substituent is present at the 5 or 7 position.

A second subclass of the compounds of structure (IIIB) is that wherein the first or second substituent is independently alkoxy, aryloxy, or a group represented by the structure (a), (c), (d), (e), or (f);

Rs and Rs are independently hydrogen, alkyl, cycloalkyl, aryl, arylalkyl, or ’ cycloalkylalkyl; and

Rs is hydrogen, alkyl, cycloalkyl, aryl, arylalkyl, or cycloalkylalkyl.

In another embodiment, the JNK Inhibitor has the following structure (IC): 1 2 0 he

COO

8 4 7 6 5 0 2-Oxa-1-aza-aceanthrylen-6-one (Ic being (i) monosubstituted and having a first substituent or (ii) disubstituted and having a first substituent and a second substituent; the first or second substituent, when present, is at the 3,4,5,7,8,9,0r 10 position; wherein the first and second substituent, when present, are dependently alkyl, halogen, hydroxy, nitro, trifluoromethyl, sulfonyl, carboxyl, alkoxycarbonyl, alkoxy, aryl, aryloxy, arylalkyloxy, arylalkyl, cycloalkylalkyloxy, cycloalkyloxy, alkoxyalkyl, alkoxyalkoxy, aminoalkoxy, mono-alkylaminoalkoxy, di-alkylaminoalkoxy, or a group represented by structure (a), (b), (c) (d), (e), or (f):

Q 0

Jo y Rs Hrs 0=3—r,

EN NEN —_N VN

Rq R, \ \, (a) (b) (c) (d)

I I

- Ra “1 Rs

Ra R4 (e) th] wherein R3 and Ry are taken together and represent alkylidene or a heteroatom-containing cyclic alkylidene or R3 and Ry are independently hydrogen, alkyl, cycloalkyl, aryl, arylalkyl, cycloalkylalkyl, aryloxyalkyl, alkoxyalkyl, aminoalkyl, mono-alkylaminoalkyl, or di-alkylaminoalkyl; and

Rs is hydrogen, alkyl, cycloalkyl, aryl, arylalkyl, cycloalkylalkyl, alkoxy, alkoxyalkyl, alkoxycarbonylalkyl, amino, mono-alkylamino, di-alkylamino, arylamino, arylalkylamino, cycloalkylamino, cycloalkylalkylamino, aminoalkyl, mono- alkylaminoalkyl, or di-alkylaminoalkyl.

A subclass of the compounds of structure (IIIC) is that wherein the first or second substituent is present at the 5, 7, or 9 position. In one embodiment, the first or second substituent is present at the 5 or 7 position.

A second subclass of the compounds of structure (IIIC) is that wherein the first or second substituent is independently alkoxy, aryloxy, aminoalkyl, mono- alkylaminoalkyl, di-alkylaminoalkyl, or a group represented by the structure (a), (c), (d), . (e), or (f);

R; and Ry are independently hydrogen, alkyl, cycloalkyl, aryl, arylalkyl, or cycloalkylalkyl; and

Rs is hydrogen, alkyl, cycloalkyl, aryl, arylalkyl, or cycloalkylalkyl.

In another embodiment, the JNK Inhibitor has the following structure (IID):

o) 1 2)

N——S=—/0 : 10 ° 3 7 6 5 o) 2,2-Dioxo-2H-21%anthra [9,1-cd]isothiazol-6-0one (IIID) being (i) monosubstituted and having a first substituent present at the 5, 7, or 9 position, (ii) disubstituted and having a first substituent present at the 5 position and a second substituent present at the 7 position, (iii) disubstituted and having a first substituent present at the 5 position and a second substituent present at the 9 position, or (iv) disubstituted and having a first substituent present at the 7 position and a second substituent present at the 9 position; wherein the first and second substituent, when present, are independently alkyl, halogen, hydroxy, nitro, trifluoromethyl, sulfonyl, carboxyl, alkoxycarbonyl, alkoxy, aryl, aryloxy, arylalkyloxy, arylalkyl, cycloalkylalkyloxy, cycloalkyloxy, alkoxyalkyl, alkoxyalkoxy, aminoalkoxy, mono-alkylaminoalkoxy, di-alkylaminoalkoxy, or a group represented by structure (a), (b), (c), (d), (¢), or (f):

Q 0)

Ra R \ / H a Mery obs, —N —N— (alkyl) — — \ (alkyl) "\ \ N

PS Rs S Rs

NT ed Sn °

Raq Rs (e) ® wherein R; and R, are taken together and represent alkylidene or a ' heteroatom-containing cyclic alkylidene or R3 and R, are independently hydrogen, alkyl, cycloalkyl, aryl, arylalkyl, cycloalkylalkyl, aryloxyalkyl, alkoxyalkyl, aminoalkyl, mono-alkylaminoalkyl, or di-alkylaminoalkyl; and

A subclass of the compounds of structure (IIID) is that wherein the first or second substituent is present at the 5 or 7 position.

A second subclass of the compounds of structure (IID) is that wherein the first or second substituent is independently alkyl, trifluoromethyl, sulfonyl, carboxyl, alkoxycarbonyl, alkoxy, aryl, aryloxy, arylalkyloxy, arylalkyl, cycloalkylalkyloxy, cycloalkyloxy, alkoxyalkyl, alkoxyalkoxy, aminoalkoxy, mono-alkylaminoalkoxy, di- alkylaminoalkoxy, or a group represented by structure (a), (c), (d), (e), or (9).

Another subclass of the compounds of structure (IID) is that wherein the first and second substituent are independently alkoxy, aryloxy, or a group represented by the structure (a), (c), (d), (e), or (f);

R3 and Ry are independently hydrogen, alkyl, cycloalkyl, aryl, arylalkyl, or cycloalkylalkyl; and

Rs is hydrogen, alkyl, cycloalkyl, aryl, arylalkyl, alkoxycarbonyl, or cycloalkylalkyl.

In another embodiment, the JNK Inhibitor has the following structure (IIE): 1 2 10 TI : 8 4 - 7 6 5 lo}

Anthra[9,1-cd]isothiazol-6-one (UIE)

being (i) monosubstituted and having a first substituent present at the 5, 7, or 9 position, (ii) disubstituted and having a first substituent present at the 5 position and ] a second substituent present at the 9 position, (iii) disubstituted and having a first substituent present at the 7 position and a second substituent present at the 9 position, or (iv) disubstituted and having a first substituent present at the 5 position and a second substituent present at the 7 position; wherein the first and second substituent, when present, are independently alkyl, halogen, hydroxy, nitro, trifluoromethyl, sulfonyl, carboxyl, alkoxycarbonyl, alkoxy, aryl, aryloxy, arylalkyloxy, arylalkyl, cycloalkylalkyloxy, cycloalkyloxy, alkoxyalkyl, alkoxyalkoxy, aminoalkoxy, mono-alkylaminoalkoxy, di-alkylaminoalkoxy, or a group represented by structure (a), (b), (c), (d), (e), or (f):

Q 0

Fa ! Vi Mrs 0=N—r,

AN —N—(alkyl)—N —N —

I I

- Rs “Ty Ra

Rs Rs (e) ® wherein Rj and Ry are taken together and represent alkylidene or a heteroatom-containing cyclic alkylidene or R3 and Ry are independently hydrogen, alkyl, cycloalkyl, aryl, arylalkyl, cycloalkylalkyl, aryloxyalkyl, alkoxyalkyl, aminoalkyl, } mono-alkylaminoalkyl, or di-alkylaminoalkyl; and

Rs is hydrogen, alkyl, cycloalkyl, aryl, arylalkyl, cycloalkylalkyl, alkoxy, ’ alkoxyalkyl, alkoxycarbonylalkyl, amino, mono-alkylamino, di-alkylamino, arylamino, arylalkylamino, cycloalkylamino, cycloalkylalkylamino, aminoalkyl, mono- alkylaminoalkyl, or di-alkylaminoalkyl.

Claims

1. A JNK Inhibitor or a pharmaceutically acceptable salt, solvate or stereoisomer thereof for use in a method for treating, preventing, managing and/or modifying pain in a patient, wherein the method comprises administering to a patient in need thereof an effective amount of the JNK Inhibitor or salt, solvate or stereoisomer.

2. A compound having the following formula: H N N / RZ A~R, or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, wherein: A is a direct bond, -(CH,),-, -(CH2)sCH=CH(CH,).-, or -(CH,);C=C(CH,).-; Rj is aryl, heteroaryl or heterocycle fused to phenyl, each being optionally substituted with one to four substituents independently from Rj; Ry is -R3, -R4, -(CH2)sC(=O)Rs, -(CH2),C(=0)ORs, -(CH,),C(=O)NR;sRs, -(CH2)sC(=0)NRs(CH2):C(=O)Rs, -(CH,)sNRsC(=O)Rs, -(CH,)sNRsC(=0)NReR7, -(CH2)sNR;sRs, -(CH3),0Rs,-(CH2)5SO4R s or -(CH3),SO,NRsR, ais 1,2,3,4,5o0r6; b and c are the same or different and at each occurrence independently 0, 1, 2, 3 or 4; d is at each occurrence 0, 1 or 2; Rj is at each occurrence independently halogen, hydroxy, carboxy, alkyl, alkoxy, haloalkyl, acyloxy, thioalkyl, sulfinylalkyl, sulfonylalkyl, hydroxyalkyl, aryl, substituted aryl, arylalkyl, heterocycle, heterocycloalkyl, -C(=0)ORs, -OC(=0)Rg, -C(=O)NRgR,, -C(=O)NR3ORy, -SO:NRgRy, -NR3SOzRg, -CN, -NO,, -NRgRy, -NR3C(=0)Rg, -77 - Amended sheet: 19 October 2006

-NRgC(=0)(CH2),ORy, -NR3C(=0)(CH2)sR9, -O(CH,)sNRgRo, or heterocycle fused to phenyl; Ry is alkyl, aryl, arylalkyl, heterocycle or heterocycloalkyl, each being optionally substituted with one to four substituents independently from Rj, or Ry is halogen or hydroxy; Rs, Reand Rj are the same or different and at each occurrence independently hydrogen, alkyl, aryl, arylalkyl, heterocycle or heterocycloalkyl, wherein each of Rs, Rgand R; are optionally substituted with one to four substituents independently selected from Rj; and Rg and Ry are the same or different and at each occurrence independently hydrogen, alkyl, aryl, arylalkyl, heterocycle, or heterocycloalkyl, or Rg and Rg taken together with the atom or atoms to which they are bonded form a heterocycle, wherein each of Rg, Rg, and Rg and Ry taken together to form a heterocycle are optionally substituted with one to four substituents independently selected from Rs, for use in a method for treating, preventing, managing and/or modifying pain in a patient, wherein the method comprises administering to a patient in need thereof an effective amount of the compound.

3. A compound having the following formula: R3 0 R Rq R )e TY 5 PY Rj N N 7 Re H or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, wherein: R; is aryl or heteroaryl optionally substituted with one to four substituents independently selected from Ry; -78 - Amended sheet: 19 October 2006

R; is hydrogen; Rs is hydrogen or lower alkyl; R4 represents one to four optional substituents, wherein each substituent is the same or ] different and independently halogen, hydroxy, lower alkyl or lower alkoxy; Rs and Rg are the same or different and independently -Rg, -(CH,),C(=O)Ry, -(CH2),C(=0)ORy, -(CH2),C(=O)NRyR 9, -(CH,),C(=O)NRy(CH;),C(=O)R 9, -(CH2)aNRyC(=O)R10, (CH;)aNR11C(=O)NR9R 0, -(CH2)sNR4R 10, -(CH2), ORs, -(CH2),SO(Ry or -(CH3),SONRyR 0; or Rs and Rg taken together with the nitrogen atom to which they are attached to form a heterocycle or substituted heterocycle; Rj; is at each occurrence independently halogen, hydroxy, cyano, nitro, carboxy, alkyl, alkoxy, haloalkyl, acyloxy, thioalkyl, sulfinylalkyl, sulfonylalkyl, hydroxyalkyl, aryl, arylalkyl, heterocycle, heterocycloalkyl, -C(=0)ORg, -OC(=0)Rgs, -C(=O)NRgRy, -C(=0O)NR3ORy, -SO.Rg, -SO.NRgRy, -NRgSO.

Ry, -NRgRg, -NR3C(=0)Ry, -NR3C(=0)(CH>)sORg, -NRsC(=0)(CH2)sR9, -O(CH1)sNRsRy, or heterocycle fused to phenyl; Rs, Ro, Rig and Ry; are the same or different and at each occurrence independently hydrogen, alkyl, substituted alkyl, aryl, arylalkyl, heterocycle or heterocycloalkyl, or Rg and Ry taken together with the atom or atoms to which they are attached to form a heterocycle; a and b are the same or different and at each occurrence independently 0, 1, 2, 3 or 4; and c is at each occurrence 0, 1 or 2, for use in a method for treating, preventing, managing and/or modifying pain in a patient, wherein the method comprises administering to a patient in need thereof an effective amount of the compound. -79 - Amended sheet: 19 October 2006

4. A compound having the following formula: 1 2 N——R,

PoP 8 5 4 7 5 oO or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, wherein Ry is -O-, -S-, -S(0)-, -S(0)»-, NH or -CH;-; the compound being (i) unsubstituted, (ii) monosubstituted and having a first substituent, or (iii) disubstituted and having a first substituent and a second substituent; the first or second substituent, when present, is at the 3, 4, 5, 7, 8, 9, or 10 position, wherein the first and second substituent, when present, are independently alkyl, hydroxy, halogen, nitro, trifluoromethyl, sulfonyl, carboxyl, alkoxycarbonyl, alkoxy, aryl, aryloxy, arylalkyloxy, arylalkyl, cycloalkylalkyloxy, cycloalkyloxy, alkoxyalkyl, alkoxyalkoxy, aminoalkoxy, mono-alkylaminoalkoxy, di-alkylaminoalkoxy, or a group represented by formula (a), (b), (c), (d), (e), or (f): -80 - Amended sheet: 19 October 2006

Q 0 R Ro , Fo Nr A aN — N—(alkyl) + —N N Ry 2, \, \, (a) (b) (© (d) i I PS Rs; S Rs NT rd I SN ° Ry Rs (e) 6) wherein Rj; and Ry are taken together and represent alkylidene or a heteroatom-containing cyclic alkylidene or Rj; and R4 are independently hydrogen, alkyl, cycloalkyl, aryl, arylalkyl, cycloalkylalkyl, aryloxyalkyl, alkoxyalkyl, aminoalkyl, mono-alkylaminoalkyl, or di-alkylaminoalkyl; and Rs is hydrogen, alkyl, cycloalkyl, aryl, arylalkyl, cycloalkylalkyl, alkoxy, alkoxyalkyl, alkoxycarbonylalkyl, amino, mono-alkylamino, di-alkylamino, arylamino, arylalkylamino, cycloalkylamino, cycloalkylalkylamino, aminoalkyl, mono- alkylaminoalkyl, or di-alkylaminoalkyl, for use in a method for treating, preventing, managing and/or modifying pain in a patient, wherein the method comprises administering to a patient in need thereof an effective amount of the compound.

5. The compound of claim 2 wherein A is a direct bond.

6. The compound of claim 2 wherein A is -(CH;),-.

7. The compound of claim 2 wherein A is -(CH),CH=CH(CH,),-.

8. The compound of claim 2 wherein A is -(CH,),C = C(CH;),-. -81- Amended sheet: 19 October 2006

9. The compound of claim 2 which has the following formula:

H

N

\ N RZ AQ XX (Ra)o4 or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, wherein: A is a direct bond, -(CH3),-, -(CH3),CH=CH(CH,),-, or -(CH;),C=C(CH;),-; Rj is aryl, heteroaryl or heterocycle fused to phenyl, each being optionally substituted with one to four substituents independently from Rj; Ry is -R3, -R4, -(CH2)sC(=O)Rs, -(CH2)»C(=0)ORs, -(CH2)»C(=O)NR;sRs, -(CH2)sC(=O)NRs(CH,).C(=O)Rs, -(CH2)sNRsC(=O)Rs, -(CH2),NRsC(=O)NRgR, -(CH3)sNRsRg, -(CH»);ORs5, -(CH»),SORs or -(CH,),SO;NRsR ais1,2,3,4,50r6; b and c are the same or different and at each occurrence independently selected from 0, 1, 2,3 or4; d is at each occurrence 0, 1 or 2; Rj is at each occurrence independently halogen, hydroxy, carboxy, alkyl, alkoxy, haloalkyl, acyloxy, thioalkyl, sulfinylalkyl, sulfonylalkyl, hydroxyalkyl, aryl, arylalkyl, heterocycle, heterocycloalkyl, -C(=0)ORgs, -OC(=0)Ry, -C(=0)NR3Rg, -C(=O)NR3ORy, -SO,;NRgRg, -NRgSO;Ry, -CN, -NO,, -NRgRg, -NRsC(=0)Ry, -NR3C(=0)(CH,);ORy, -NR3C(=O)(CHz)sRo, -O(CH,)sNRgRy, or heterocycle fused to phenyl, -82- Amended sheet: 19 October 2006

R4is alkyl, aryl, arylalkyl, heterocycle or heterocycloalkyl, each being optionally substituted with one to four substituents independently from Rj, or R4 is halogen or hydroxy; Rs, Rg and R; are the same or different and at each occurrence independently hydrogen, alkyl, aryl, arylalkyl, heterocycle or heterocycloalkyl, wherein each of Rs, Rg and R; are optionally substituted with one to four substituents independently selected from Rj; and Rg and Ry are the same or different and at each occurrence independently hydrogen, alkyl, aryl, arylalkyl, heterocycle, or heterocycloalkyl, or Rg and Rg taken together with the atom or atoms to which they are bonded form a heterocycle, wherein each of Rg, Rg, and Rg and Ry taken together to form a heterocycle are optionally substituted with one to four substituents independently selected from Rj.

10. The compound of claim 2 which has the following formula: H o “ J 7 Rg N Rs A—R; or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, wherein: A is a direct bond, -(CHa),-, -(CH,),CH=CH(CH,),.-, or -(CH,),C=C(CH;).; Rj is aryl, heteroaryl or heterocycle fused to phenyl, each being optionally substituted with one to four substituents independently from Rj; Ry is -R3, -R4, -(CH2)sC(=O)Rs, -(CH2)sC(=0)ORs, -(CH,)»C(=O)NRsRs, -(CH2)C(=O)NRs(CH2).C(=0)Rs, -(CH,)sNR5C(=0O)Rs, -(CH)sNRsC(=0)NR¢R7, -(CH2)sNR;sRs, -(CH2),0Rs, -(CH;,)sSORs or -(CH2),SO2NR sR. -83- Amended sheet: 19 October 2006

- . ais 1,2,3,4,5o0r6; b and c are the same or different and at each occurrence independently 0, 1, 2, 3 or 4; d is at each occurrence 0, 1 or 2; Rj; is at each occurrence independently halogen, hydroxy, carboxy, alkyl, alkoxy, haloalkyl, acyloxy, thioalkyl, sulfinylalkyl, sulfonylalkyl, hydroxyalkyl, aryl, arylalkyl, heterocycle, heterocycloalkyl, -C(=0)ORg, -OC(=0)Rg, -C(=0)NRgRy, -C(=0)NR3ORy, -SO,;NRgRg, -NRgSO;R, -CN, -NO,, -NRgRy, -NR3C(=0)Ry, -NRgC(=0)(CH,);ORg, -NR3C(=O)(CH,)sR9, -O(CH3),NR3gRy, or heterocycle fused to phenyl; Rs is alkyl, aryl, arylalkyl, heterocycle or heterocycloalkyl, each being optionally substituted with one to four substituents independently from Rj, or R4is halogen or hydroxy; Rs, Rg and Ry are the same or different and at each occurrence independently hydrogen, alkyl, aryl, arylalkyl, heterocycle or heterocycloalkyl, wherein each of Rs, Rg and Ry are optionally substituted with one to four substituents independently selected from Rj; and Rg and Ry are the same or different and at each occurrence independently hydrogen, alkyl, aryl, arylalkyl, heterocycle, or heterocycloalkyl, or Rg and Rg taken together with the atom or atoms to which they are bonded form a heterocycle, wherein each of Rg, Ry, and Rg and Ry taken together to form a heterocycle are optionally substituted with one to four substituents independently selected from Rj.

11. The compound of claim 2 which has the following formula: H ge N N / ¢ Se F -84 - Amended sheet: 19 October 2006 or a pharmaceutically acceptable salt, solvate or stereoisomer thereof.

12. The compound of claim 3, which has the following formula: 0 R ASE N 5 PY Rg Rj N N H or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, wherein: R; is aryl or heteroaryl optionally substituted with one to four substituents independently selected from Ry; R; is hydrogen; Rs is hydrogen or lower alkyl; R4 represents one to four optional substituents, wherein each substituent is the same or different and independently halogen, hydroxy, lower alkyl or lower alkoxy; Rs and Rg are the same or different and independently -Rg, -(CH,),C(=O)Ry, -(CH),C(=0)ORg, -(CH2),C(=O)NRyR 1, -(CH2),C(=O)NRg(CH2),C(=O)R 10, -(CH2)aNRgC(=0)R 1g, (CH2)aNR 1 C(=O)NR4R 9, -(CH;)aNRgR 19, -(CH2)sORG, «(CH2)aSOcRg or -(CH2)2SO;NRgR 10; or Rs and Rg taken together with the nitrogen atom to which they are attached to form a heterocycle or substituted heterocycle; R5 is at each occurrence independently halogen, hydroxy, cyano, nitro, carboxy, alkyl, alkoxy, haloalkyl, acyloxy, thioalkyl, sulfinylalkyl, sulfonylalkyl, hydroxyalkyl, aryl, arylalkyl, heterocycle, heterocycloalkyl, -C(=0)ORj3, -OC(=0O)R3, -C(=O)NRgRo, -C(=0)NR3ORy, -SOR3, -SO.NR;gRy, -NRgSO.Ry, -NRgRy, -NR3C(=0)Rs, -85- Amended sheet: 19 October 2006

-NRC(=0)(CH2),ORy, -NRsC(=O0)(CH,)sR9, -O(CH,),NR3Ro, or heterocycle fused to phenyl; Rs, Rg, Rig and R;; are the same or different and at each occurrence independently hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, heterocycle, heterocycloalkyl; or Rg and Ry taken together with the atom or atoms to which they are attached to form a heterocycle; a and b are the same or different and at each occurrence independently 0, 1, 2, 3 or 4; and c is at each occurrence 0, 1 or 2.

13. The compound of claim 3, which has the following formula: 0 Ny NO AA k R; | H x or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, wherein: R is aryl or heteroaryl optionally substituted with one to four substituents independently from Ry; R; is hydrogen; Rj is hydrogen or lower alkyl; R4 represents one to four optional substituents, wherein each substituent is the same or different and independently halogen, hydroxy, lower alkyl or lower alkoxy; Rs and Rg are the same or different and independently -Rg, -(CH,),C(=O)Rg -86- Amended sheet: 19 October 2006

-(CH2),C(=0)ORy, -(CH2)dC(=O)NRgR jg, -(CH,),C(=O)NRy(CH2);C(=O)R 0, -(CH2)aNRoC(=0)R 19, (CH2)aNR11C(=0)NRgR , -(CH2),NR9R 9, -(CH;),OR, -(CH2),SORy or -(CH;),SO;NRgR jg; or Rs and Rg taken together with the nitrogen atom to which they are attached to form a heterocycle or substituted heterocycle; R7 is at each occurrence independently halogen, hydroxy, cyano, nitro, carboxy, alkyl, alkoxy, haloalkyl, acyloxy, thioalkyl, sulfinylalkyl, sulfonylalkyl, hydroxyalkyl, aryl, arylalkyl, heterocycle, heterocycloalkyl, -C(=0)ORs3, -OC(=0)Rs, -C(=O)NRgRy, -C(=O)NR3ORy, -SO.R3, -SO-NRgRy, -NR3SO.Rg, -NRgRg, -NRgC(=O)Ry, -NR3C(=O)(CH_)sORy, -NR3C(=0)(CH,)sR9, -O(CH,);NRgR, or heterocycle fused to phenyl; Rg, Ro, Ro and Ry; are the same or different and at each occurrence independently hydrogen, alkyl, aryl, arylalkyl, heterocycle, heterocycloalkyl; or Rg and Ry taken together with the atom or atoms to which they are attached to form a heterocycle; a and b are the same or different and at each occurrence independently 0, 1, 2, 3 or 4; and c is at each occurrence 0, 1 or 2.

14. The compound of claim 3, which has the following formula: 0] NN ons . Re H Rj or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, wherein: -87- Amended sheet: 19 October 2006

R is aryl or heteroaryl optionally substituted with one to four substituents independently from Ry; R; is hydrogen; Rj is hydrogen or lower alkyl; R4 represents one to four optional substituents, wherein each substituent is the same or different and independently from halogen, hydroxy, lower alkyl or lower alkoxy; Rs and Rg are the same or different and independently -Rg, -(CH;),C(=O)Ry, “(CH2)sC(=0)ORy, -(CH2)aC(=0)NRgR gp, -(CH2),C(=O0)NRy(CH,),C(=O)R 0, -(CH2).NRoC(=0)R 9, (CH3),NR;C(=O)NRgR 9, -(CH2),NR9R jg, -(CH3),ORy, -(CH;),SORy or -(CH,),SO;NRgR yg; or Rsand Rg taken together with the nitrogen atom to which they are attached to form a heterocycle; R; is at each occurrence independently halogen, hydroxy, cyano, nitro, carboxy, alkyl, alkoxy, haloalkyl, acyloxy, thioalkyl, sulfinylalkyl, sulfonylalkyl, hydroxyalkyl, aryl, arylalkyl, heterocycle, heterocycloalkyl, -C(=0)ORgs, -OC(=0)Rs, -C(=O)NR3Ry, -C(=0)NR3ORy, -SO:R3, -SO.NR3Ry, -NR3SO.Ry, -NR3Rg, -NRgC(=0)Ry, -NR3C(=O)(CH1),ORy, -NRgC(=O)(CH;)sR9, -O(CH2),NRgRy, or heterocycle fused to phenyl; Rs, Rg, Rip and Rj; are the same or different and at each occurrence independently hydrogen, alkyl, substituted alkyl, aryl, arylalkyl, heterocycle, heterocycloalkyl, or Rg and Ry taken together with the atom or atoms to which they are attached to form a heterocycle; a and b are the same or different and at each occurrence independently 0, 1, 2, 3 or 4; and c¢ is at each occurrence 0, 1 or 2. -88- Amended sheet: 19 October 2006

15. The compound of claim 4, wherein Ry is -O-.

16. The compound of claim 4, wherein Ry is -S-.

17. The compound of claim 4, wherein Rg is-S(O)-.

18. The compound of claim 4, wherein Ry is -S(O);,-.

19. The compound of claim 4, wherein Rgis NH.

20. The compound of claim 4, wherein Rg is CHa-.

21. The compound of claim 4, which has the following formula: TA 0) or a pharmaceutically acceptable salt, solvate or stereoisomer thereof.

22. The compound of claim 1, wherein the method further comprises administering a second active agent.

23. The compound of claim 2, wherein the method further comprises administering a second active agent.

24. The compound of claim 3, wherein the method further comprises administering a second active agent.

25. The compound of claim 4, wherein the method further comprises administering a second active agent.

26. The compound of claim 22, wherein the second active agent is an antidepressant, antihypertensive, anxiolytic, calcium channel blocker, muscle relaxant, non-narcotic -89- Amended sheet: 19 October 2006

- i analgesic, anti-inflammatory agent, cox-2 inhibitor, alpha-adrenergic receptor agonist or antagonist, ketamine, anesthetics, immunomodulatory agent, immunosuppressive agent, corticosteroid, hyperbaric oxygen, anticonvulsant, an IMiD®, a SelCID®, or a combination thereof.

27. The compound of claim 22, wherein the second active agent is gabapentin, thalidomide, salicyclic acid acetate, ketamine, celocoxib, carbamazepine, oxcarbazepine, phenytoin, sodium valproate, prednisone, nifedipine, clonidine, oxycodone, meperidine, morphine sulfate, hydromorphone, fentanyl, acetaminophen, ibuprofen, naproxen sodium, griseofulvin, amitriptyline, imipramine, doxepin, or a pharmaceutically acceptable salt, solvate or stereoisomer thereof.

28. The compound of claim 1, wherein the pain is complex regional pain syndrome.

29. The compound of claim 28, wherein the complex regional pain syndrome is type I or type II.

30. The compound of claim 28, wherein the complex regional pain syndrome is stage I, stage II or stage III of complex regional pain syndrome type I.

31. The compound of claim 28, wherein the complex regional pain syndrome is pain, autonomic dysfunction, trigeminal neuralgia, post-herpetic neuralgia, cancer-related pain, phantom limb pain, fibromyalgia, chronic fatigue syndrome, radiculopathy, inability to initiate movement, weakness, tremor, muscle spasm, dytonia, dystrophy, atrophy, edema, stiffness, joint tenderness, increased sweating, sensitivity to temperature, light touch (allodynia), color change to the skin, hyperthermic or hypothermic, increased nail and hair growth, early bony changes, hyperhidrotic with livedo reticularis or cyanosis, lost hair, ridged, cracked or brittle nails, dry hand, diffuse osteoporosis, irreversible tissue damage, thin and shiny skin, joint contractures, marked bone demineralization, diabetic neuropathy, luetic neuropathy, painful neuropathy induced iatrogenically by a drug, or another painful neuropathic condition.

32. The compound of claim 1, wherein the pain is nociceptive pain. -90- Amended sheet: 19 October 2006 a .

33. The compound of claim 32, wherein the nociceptive pain is associated with a cut or contusion of the skin; a chemical or thermal burn; osteoarthritis; rheumatoid arthritis; or tendonitis.

34. The compound of claim 1, wherein the pain is neuropathic pain.

35. The compound of claim 34, wherein the neuropathic pain is associated with stroke, diabetic neuropathy, luetic neuropathy, postherpetic neuralgia, trigeminal neuralgia, fibromyalgia, or painful neuropathy induced iatrogenically by a drug.

36. Use of a JNK Inhibitor or a pharmaceutically acceptable salt, solvate or stereoisomer thereof in the manufacture of a medicament for use in a method for treating, preventing, managing and/or modifying pain in a patient.

37. Use of a compound having the following formula: H N N / R32 A~R, or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, wherein: A is a direct bond, -(CH3),~, -(CH,),CH=CH(CH,),-, or -(CH3),C=C(CH;)-; Ris aryl, heteroaryl or heterocycle fused to phenyl, each being optionally substituted with one to four substituents independently from Rj; R; is -R3, -R4, -(CH2)sC(=O)Rs, -(CH2)sC(=0)ORs, -(CH,),C(=O)NRsRs, ~(CH2),C(=0)NR5(CH2).C(=O)Rs, -(CH2)sNRsC(=O)Rs, -(CH:)sNRsC(=O)NR¢R7, -(CH2)sNR;sRs, -(CH2)sORs,-(CH;)5SOR 5 or -(CH2),SO2NRsRs, ais 1,2,3,4,5 or 6; b and c are the same or different and at each occurrence independently 0, 1, 2, 3 or 4; -9] - Amended sheet: 19 October 2006 dis at each occurrence 0, 1 or 2; R3 is at each occurrence independently halogen, hydroxy, carboxy, alkyl, alkoxy, haloalkyl, acyloxy, thioalkyl, sulfinylalkyl, sulfonylalkyl, hydroxyalkyl, aryl, substituted aryl, arylalkyl, heterocycle, heterocycloalkyl, -C(=0)ORg, -OC(=0)Rg, -C(=O)NRgRy, -C(=0)NR3ORy, -SO,NR3Rg, -NR3gSO,Rg, -CN, -NO,, -NRgRy, -NR3C(=0O)Ry, -NR3C(=0)(CH2),ORy, -NR3C(=0)(CH3);R9, -O(CH;),NRgRy, or heterocycle fused to phenyl; Rs is alkyl, aryl, arylalkyl, heterocycle or heterocycloalkyl, each being optionally substituted with one to four substituents independently from Rj, or R4 is halogen or hydroxy; Rs, Rgand R7 are the same or different and at each occurrence independently hydrogen, alkyl, aryl, arylalkyl, heterocycle or heterocycloalkyl, wherein each of Rs, Rg and Ry are optionally substituted with one to four substituents independently selected from R3; and Rg and Ry are the same or different and at each occurrence independently hydrogen, alkyl, aryl, arylalkyl, heterocycle, or heterocycloalkyl, or Rg and Rg taken together with the atom or atoms to which they are bonded form a heterocycle, wherein each of Rg, Ry, and Rg and Ry taken together to form a heterocycle are optionally substituted with one to four substituents independently selected from Rj, in the manufacture of a medicament for use in a method for treating, preventing, managing and/or modifying pain in a patient.

38. Use of a compound having the following formula: R; 0 Ry PQ Ry N N 7 Re H or a pharmaceutically acceptable salt, solvate or stereoisomer thereof,

-92. Amended sheet: 19 October 2006 wherein: R| is aryl or heteroaryl optionally substituted with one to four substituents independently selected from R+; R; is hydrogen; Rj is hydrogen or lower alkyl; R4 represents one to four optional substituents, wherein each substituent is the same or different and independently halogen, hydroxy, lower alkyl or lower alkoxy; Rs and Rg are the same or different and independently -Rg, -(CH2),C(=O)Ry, -(CH3),C(=0)ORy, -(CH;),C(=0)NRyR ¢, -(CH3),C(=O)NRo(CH;),C(=O)R 9, “(CH2)aNR9C(=0)R 10, (CH2)aNR11C(=0)NRgR 19, (CH2)sNRgR 10, -(CH2),ORy, -(CH,),SO.Ry or -(CH;),SO.NRgR 1; or Rs and Rg taken together with the nitrogen atom to which they are attached to form a heterocycle or substituted heterocycle; R; is at each occurrence independently halogen, hydroxy, cyano, nitro, carboxy, alkyl, alkoxy, haloalkyl, acyloxy, thioalkyl, sulfinylalkyl, sulfonylalkyl, hydroxyalkyl, aryl, arylalkyl, heterocycle, heterocycloalkyl, -C(=0)ORjs, -OC(=0)Rg, -C(=O)NR3Ro, -C(=O)NRgORy, -SO:R3, -SO-NR3gRo, -NRgSO.Rg, -NRgRg, -NRgC(=0)R, -NRsC(=0)(CH2)s0Ry, -NRC(=0)(CH)sRy, -O(CH2);NRsRy, or heterocycle fused to phenyl; Rs, Ro, Rig and Ry; are the same or different and at each occurrence independently hydrogen, alkyl, substituted alkyl, aryl, arylalkyl, heterocycle or heterocycloalkyl; or Rg and Ry taken together with the atom or atoms to which they are attached to form a heterocycle; a and b are the same or different and at each occurrence independently 0, 1, 2, 3 or 4; and

-93. Amended sheet: 19 October 2006 c is at each occurrence 0, 1 or 2, in the manufacture of a medicament for use in a method for treating, preventing, managing and/or modifying pain in a patient.

39. Use of a compound having the following formula: 1 2 POP 8 5 4 7 5 0 or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, wherein Ry is -O-, -S-, -S(0)-, -S(O);-, NH or -CH,-; the compound being (i) unsubstituted, (ii) monosubstituted and having a first substituent, or (iii) disubstituted and having a first substituent and a second substituent; the first or second substituent, when present, is at the 3, 4, 5, 7, 8, 9, or 10 position, wherein the first and second substituent, when present, are independently alkyl, hydroxy, halogen, nitro, trifluoromethyl, sulfonyl, carboxyl, alkoxycarbonyl, alkoxy, aryl, aryloxy, arylalkyloxy, arylalkyl, cycloalkylalkyloxy, cycloalkyloxy, alkoxyalkyl, alkoxyalkoxy, aminoalkoxy, mono-alkylaminoalkoxy, di-alkylaminoalkoxy, or a group represented by formula (a), (b), (¢), (d), (e), or (f):

-94. Amended sheet: 19 October 2006

0 0 R Va } Vi Nr \ — —N—(alky}) + — N R, " \, \, @ (b) © @ i I PS Rs S Rs ° R4 Rs (e ® wherein Rj and Ry are taken together and represent alkylidene or a heteroatom-containing cyclic alkylidene or R; and R4 are independently hydrogen, alkyl, cycloalkyl, aryl, arylalkyl, cycloalkylalkyl, aryloxyalkyl, alkoxyalkyl, aminoalkyl, mono-alkylaminoalkyl, or di-alkylaminoalkyl; and Rs is hydrogen, alkyl, cycloalkyl, aryl, arylalkyl, cycloalkylalkyl, alkoxy, alkoxyalkyl, alkoxycarbonylalkyl, amino, mono-alkylamino, di-alkylamino, arylamino, arylalkylamino, cycloalkylamino, cycloalkylalkylamino, aminoalkyl, mono- alkylaminoalkyl, or di-alkylaminoalkyl, in the manufacture of a medicament for use in a method for treating, preventing, managing and/or modifying pain in a patient.

40. The use of claim 37 wherein A is a direct bond.

41. The use of claim 37 wherein A is -(CH,),-.

42. The use of claim 37 wherein A is -(CH,),CH=CH(CH,).-.

43. The use of claim 37 wherein A is -(CH;),C=C(CH;).-. :

44. The use of claim 37 wherein the compound has the following formula: -95- Amended sheet: 19 October 2006

H

N

\ / N R2 AQ XX (Ra)o-4 or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, wherein: A is a direct bond, -(CH,),-, -(CH,),CH=CH(CH,),.-, or -(CH;),C=C(CH,).-; Riis aryl, heteroaryl or heterocycle fused to phenyl, each being optionally substituted with one to four substituents independently from Rj; R; is -R3, -R4, -(CH,)sC(=O)Rs, -(CH,),C(=0)ORs, -(CH),C(=O)NRsRs, -(CH2)sC(=O)NRs(CH;).C(=O)Rs, -(CH2)sNRsC(=O)Rg, -(CH2);NRsC(=O)NR4R3, -(CH2),NR;sRg, -(CH,),0Rs, -(CH,)sSOR 5 or -(CH2)sSO;NRsRs: ais 1,2,3,4,50r6; b and c are the same or different and at each occurrence independently selected from 0, 1, 2,3 ord; d is at each occurrence 0, 1 or 2; Rj is at each occurrence independently halogen, hydroxy, carboxy, alkyl, alkoxy, haloalkyl, acyloxy, thioalkyl, sulfinylalkyl, sulfonylalkyl, hydroxyalkyl, aryl, arylalkyl, heterocycle, heterocycloalkyl, -C(=0)ORg3, -OC(=0)Rs, -C(=0)NRgRg, -C(=O)NRgORy, -SO;NRgRg, -NRgSOsRy, -CN, -NO,, -NRgRy, -NR3C(=0)Ry, -NR3C(=0)(CH,),ORy, -NRgC(=0)(CH3)sRo9, -O(CH3),NR3Ry, or heterocycle fused to phenyl; -96- Amended sheet: 19 October 2006

Pl » Ry is alkyl, aryl, arylalkyl, heterocycle or heterocycloalkyl, each being optionally substituted with one to four substituents independently from Rs, or R4 is halogen or hydroxy; Rs, Rs and Ry are the same or different and at each occurrence independently hydrogen, alkyl, aryl, arylalkyl, heterocycle or heterocycloalkyl, wherein each of Rs, Rg and Rare optionally substituted with one to four substituents independently selected from Rj; and Rg and Ry are the same or different and at each occurrence independently hydrogen, alkyl, aryl, arylalkyl, heterocycle, or heterocycloalkyl, or Rgand Rg taken together with the atom or atoms to which they are bonded form a heterocycle, wherein each of Rg, Rg, and Rg and Ry taken together to form a heterocycle are optionally substituted with one to four substituents independently selected from Rj.

45. The use of claim 37 wherein the compound has the following formula: H o) “ J % Rg N Rs A—R; or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, wherein: A is a direct bond, -(CH,),-, -(CH,),CH=CH(CH,),-, or -(CH;),C=C(CH).; Rj is aryl, heteroaryl or heterocycle fused to phenyl, each being optionally substituted with one to four substituents independently from Rs; R; is -R3, -R4, -(CH2),C(=O)Rs, -(CH,),C(=0)ORs, -(CH2),C(=O)NR;sRs, -(CH3),C(=0)NRs(CH).C(=0O)R¢, -(CH2)sNRsC(=0O)Rg, -(CH2)sNR5sC(=O)NRsR7, -(CH3)sNRsRs, -(CH2)50Rs, -(CH2)sSO4R;s or -(CH2),SO2NRsRg; -97- Amended sheet: 19 October 2006 ais1,2,3,4,5 or 6; b and c are the same or different and at each occurrence independently 0, 1, 2, 3 or 4; d is at each occurrence 0, 1 or 2; Rj; is at each occurrence independently halogen, hydroxy, carboxy, alkyl, alkoxy, haloalkyl, acyloxy, thioalkyl, sulfinylalkyl, sulfonylalkyl, hydroxyalkyl, aryl, arylalkyl, heterocycle, heterocycloalkyl, -C(=0)ORg, -OC(=0)Rg, -C(=O)NRgRg, -C(=O)NRgORg, -SO,NRgRo, -NRzSO;R,, -CN, -NO,, -NRgRy, -NR3C(=0O)Ry, -NR3C(=0)(CH;);,ORo, -NR3C(=0)(CH2)sR9, -O(CH,);NR3Ry, or heterocycle fused to phenyl; Rs is alkyl, aryl, arylalkyl, heterocycle or heterocycloalkyl, each being optionally substituted with one to four substituents independently from Rj, or Ry4 is halogen or hydroxy; Rs, Rg and Ry are the same or different and at each occurrence independently hydrogen, alkyl, aryl, arylalkyl, heterocycle or heterocycloalkyl, wherein each of Rs, Rgand Ry are optionally substituted with one to four substituents independently selected from Rj; and Rs and Ry are the same or different and at each occurrence independently hydrogen, alkyl, aryl, arylalkyl, heterocycle, or heterocycloalkyl, or Rg and Rg taken together with the atom or atoms to which they are bonded form a heterocycle, wherein each of Rg, Ro, and Rg and Ry taken together to form a heterocycle are optionally substituted with one to four substituents independently selected from Rs.

46. The use of claim 37 wherein the compound has the following formula: H N N N ¢ % ¢ MY F -98- Amended sheet: 19 October 2006 or a pharmaceutically acceptable salt, solvate or stereoisomer thereof.

47. The use of claim 38, wherein the compound has the following formula: O R JO ory 5 Al Rj N N Re H or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, wherein: Rj is aryl or heteroaryl optionally substituted with one to four substituents independently selected from Ry; R, is hydrogen; Rj is hydrogen or lower alkyl; R4 represents one to four optional substituents, wherein each substituent is the same or different and independently halogen, hydroxy, lower alkyl or lower alkoxy; Rs and Rg are the same or different and independently -Rg, -(CH2),C(=O)Ry, -(CH3),C(=0)ORy, -(CH,),C(=0)NRgR q, -(CH;),C(=O)NRy(CH;),C(=O)R q, -(CH2)aNRyC(=O)R 9, (CH2)aNR 11 C(=O)NRyR 0, -(CH2)aNRgR 10, -(CH2),ORg, -(CH2)4SOcR9 or -(CH2),SO,NRgR 0; or Rsand Rg taken together with the nitrogen atom to which they are attached to form a heterocycle or substituted heterocycle; R7 is at each occurrence independently halogen, hydroxy, cyano, nitro, carboxy, alkyl, alkoxy, haloalkyl, acyloxy, thioalkyl, sulfinylalkyl, sulfonylalkyl, hydroxyalkyl, aryl, arylalkyl, heterocycle, heterocycloalkyl, -C(=0)ORs, -OC(=0)Rs, -C(=0)NRgRs, -C(=O)NR;3ORy, -SOR3, -SO-NRgRy, -NRgSO(Ry, -NRgRg, -NRgC(=O)Ro,

-99. Amended sheet: 19 October 2006

® . -NR3C(=0)(CH;),ORy, -NRgC(=0)(CH,)sRy, -O(CH,),NR3Ry, or heterocycle fused to phenyl; Rg, Rg, Rig and Ry; are the same or different and at each occurrence independently hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, heterocycle, heterocycloalkyl, or Rg and Ry taken together with the atom or atoms to which they are attached to form a heterocycle; a and b are the same or different and at each occurrence independently 0, 1, 2, 3 or 4; and c is at each occurrence 0, 1 or 2.

48. The use of claim 38, wherein the compound has the following formula: 0 R XN y 5

PE. k R— | H x or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, wherein: Rj is aryl or heteroaryl optionally substituted with one to four substituents independently from Ry; R; is hydrogen; Rj is hydrogen or lower alkyl; R4 represents one to four optional substituents, wherein each substituent is the same or different and independently halogen, hydroxy, lower alkyl or lower alkoxy; Rs and Re are the same or different and independently -Rg, -(CH,),C(=O)Ry, - 100 - Amended sheet: 19 October 2006

CA . ~(CH2)sC(=0)ORy, -(CH2)aC(=O)NRgR 19, -(CH2),C(=O)NRy(CH2),C(=O)R 10, -(CH3).NRoC(=0O)R 9, (CH2),NR1C(=O)NRgR 9, -(CH3),NRgR 1g, -(CH2),ORo, -(CH3)aSORg or -(CH,),SO2NRgR 1; or Rs and Rg taken together with the nitrogen atom to which they are attached to form a heterocycle or substituted heterocycle; R7 is at each occurrence independently halogen, hydroxy, cyano, nitro, carboxy, alkyl, alkoxy, haloalkyl, acyloxy, thioalkyl, sulfinylalkyl, sulfonylalkyl, hydroxyalkyl, aryl, arylalkyl, heterocycle, heterocycloalkyl, -C(=0)ORgs, -OC(=O)Rg, -C(=O)NRgRy, -C(=0)NRORy, -SORs, -SO:-NRgRg, -NRgSO.Rg, -NR3Rg, -NRsC(=O)Ry, -NR3C(=0)(CH,),0Rg, -NRzC(=0)(CH;)sRg, -O(CH;),NRgRy, or heterocycle fused to phenyl; Rs, Ro, Rig and Ry; are the same or different and at each occurrence independently hydrogen, alkyl, aryl, arylalkyl, heterocycle, heterocycloalkyl; or Rg and Ry taken together with the atom or atoms to which they are attached to form a heterocycle; a and b are the same or different and at each occurrence independently 0, 1, 2, 3 or 4; and c is at each occurrence 0, 1 or 2.

49. The use of claim 38, wherein the compound has the following formula: oO R Fee jon if a N N Re H R7 or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, wherein: - 101 - Amended sheet: 19 October 2006

AT

R| is aryl or heteroaryl optionally substituted with one to four substituents independently from Ry; R; is hydrogen; Rj is hydrogen or lower alkyl; R4 represents one to four optional substituents, wherein each substituent is the same or different and independently from halogen, hydroxy, lower alkyl or lower alkoxy; Rs and Rg are the same or different and independently -Rs, -(CH,),C(=O)Ry, -(CH2),C(=0)ORy, -(CH,),C(=O)NRyR 9, -(CH2),C(=O)NRo(CH,),C(=O)R 0, -(CH2)aNRyC(=O)R 10, (CH2)sNR 1 C(=0)NRgR 19, -(CH2)sNR9R 19, -(CH2), ORs, -(CH1),SO.Ry or -(CH,),SO2NRgR 0; or Rsand Rg taken together with the nitrogen atom to which they are attached to form a heterocycle; Ry is at each occurrence independently halogen, hydroxy, cyano, nitro, carboxy, alkyl, alkoxy, haloalkyl, acyloxy, thioalkyl, sulfinylalkyl, sulfonylalkyl, hydroxyalkyl, aryl, arylalkyl, heterocycle, heterocycloalkyl, -C(=0)ORs, -OC(=0)Rs, -C(=O)NRgRo, -C(=O)NRgORy, -SOcRs, -SO:NRgRg, -NR3SO Rg, -NRgRg, -NRsC(=0)Ry, -NR3C(=0)(CH;)50Ry, -NR3C(=O)(CH,)sR9, -O(CH;)sNRgRy, or heterocycle fused to phenyl; Rg, Ro, Rig and Ry; are the same or different and at each occurrence independently hydrogen, alkyl, substituted alkyl, aryl, arylalkyl, heterocycle, heterocycloalkyl, or Rg and Ry taken together with the atom or atoms to which they are attached to form a heterocycle; a and b are the same or different and at each occurrence independently 0, 1, 2, 3 or 4; and c¢ is at each occurrence 0, 1 or 2. -102 - Amended sheet: 19 October 2006

Nn >» , R

50. The use of claim 39, wherein Rg is -O-.

51. The use of claim 39, wherein Rg is -S-.

52. The use of claim 39, wherein Rg is-S(O)-.

53. The use of claim 39, wherein Rg is -S(O);-.

54. The use of claim 39, wherein Rgis NH.

55. The use of claim 39, wherein Rgis CH-.

56. The use of claim 39, wherein the compound has the following formula: i NH oO or a pharmaceutically acceptable salt, solvate or stereoisomer thereof.

57. The use of claim 36, wherein the medicament further comprises a second active agent.

58. The use of claim 37, wherein the medicament further comprises a second active agent.

59. The use of claim 38, wherein the medicament further comprises a second active agent.

60. The use of claim 39, wherein the medicament further comprises a second active agent.

61. The use of claim 57, wherein the second active agent is an antidepressant, antihypertensive, anxiolytic, calcium channel blocker, muscle relaxant, non-narcotic - 103 - Amended sheet: 19 October 2006 o> analgesic, anti-inflammatory agent, cox-2 inhibitor, alpha-adrenergic receptor agonist or antagonist, ketamine, anesthetics, immunomodulatory agent, immunosuppressive agent, corticosteroid, hyperbaric oxygen, anticonvulsant, an IMiD®, a SelCID®, or a combination thereof.

62. The use of claim 57, wherein the second active agent is gabapentin, thalidomide, salicyclic acid acetate, ketamine, celocoxib, carbamazepine, oxcarbazepine, phenytoin, sodium valproate, prednisone, nifedipine, clonidine, oxycodone, meperidine, morphine sulfate, hydromorphone, fentanyl, acetaminophen, ibuprofen, naproxen sodium, griseofulvin, amitriptyline, imipramine, doxepin, or a pharmaceutically acceptable salt, solvate or stereoisomer thereof.

63. The use of claim 36, wherein the pain is complex regional pain syndrome.

64. The use of claim 63, wherein the complex regional pain syndrome is type I or type

IL.

65. The use of claim 63, wherein the complex regional pain syndrome is stage I, stage IT or stage III of complex regional pain syndrome type I.

66. The use of claim 63, wherein the complex regional pain syndrome is pain, autonomic dysfunction, trigeminal neuralgia, post-herpetic neuralgia, cancer-related pain, phantom limb pain, fibromyalgia, chronic fatigue syndrome, radiculopathy, inability to initiate movement, weakness, tremor, muscle spasm, dytonia, dystrophy, atrophy, edema, stiffness, joint tenderness, increased sweating, sensitivity to temperature, light touch (allodynia), color change to the skin, hyperthermic or hypothermic, increased nail and hair growth, early bony changes, hyperhidrotic with livedo reticularis or cyanosis, lost hair, ridged, cracked or brittle nails, dry hand, diffuse osteoporosis, irreversible tissue damage, thin-and shiny skin; joint contractures, marked bone demineralization, diabetic’ neuropathy, luetic neuropathy, painful neuropathy induced iatrogenically by a drug, or another painful neuropathic condition.

67. The use of claim 36, wherein the pain is nociceptive pain. - 104 - Amended sheet: 19 October 2006

“ue ’ vy

68. The use of claim 67, wherein the nociceptive pain is associated with a cut or contusion of the skin; a chemical or thermal burn; osteoarthritis; rheumatoid arthritis; or tendonitis.

69. The use of claim 36, wherein the pain is neuropathic pain.

70. The use of claim 69, wherein the neuropathic pain is associated with stroke, diabetic neuropathy, luetic neuropathy, postherpetic neuralgia, trigeminal neuralgia, fibromyalgia, or painful neuropathy induced iatrogenically by a drug.

71. A pharmaceutical composition comprising an effective amount of a JNK Inhibitor and an antidepressant, antihypertensive agent, anxiolytic agent, calcium channel blocker, muscle relaxant, non-narcotic analgesic, anti-inflammatory agent, cox-2 inhibitor, alpha- adrenergic receptor agonist or antagonist, ketamine, an anesthetic, an immunomodulatory agent, an immunosuppressive agent, a corticosteroid, hyperbaric oxygen, an anticonvulsant, an IMiD®, a SelCID®, or a combination thereof. - 105 - Amended sheet: 19 October 2006