ZA200503469B - Methods for the treatment, prevention and management of macular degeneration - Google Patents

Description

METHODS FOR THE TREATMENT, PREVENTION AND

MANAGEMENT OF MACULAR DEGENERATI ON

This application claims the benefit of U.S. provisional application no. 60/422,89¢, filed October 31, 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 and/or managing macular degeneration (MD) and related syndromes, which comprise the administration of a JNK Inhibitor alone or in combination with a known therapeutic.

The invention also relates to pharmaceutical compositions and dosing regimens. In particular, the invention encompasses the use of a JNK Inhibitor in conjunction with surgical imtervention, and/or another standard therapy for macular degeneration. 2. BACKGROUND OF THE INVENTION 2.1 PATHOBIOLOGY OF MACULAR DEGENERATION

Macular degeneration (MD), which is also referred to as age-related macular degeneration (AMD), is an eye disease that destroys central wision by damaging the macula. The macula is part of the retina, a thin layer of nerve cells that lines most of the inside of the eyeball. The nerve cells in the retina detect light and send to the brain signals abeout what the eye sees. The macula is near the center of the retina at the back of the eyeball and provides the clear, sharp central vision that an animal uses for focusing on what iss in front of it. The rest of the retina provides side (peripher-al) vision.

There are two forms of MD: exudative (wet) and atrophic (dry).

Riordan-E8va, P., Eye, in Current Medical Diagnosis and Treatment, 41 ed. 210-211 (2002). Ninety percent of patients have the dry form, while only ten percent have the wetform. However, patients with the wet form can lose up to ninety percent of their vision. DuBosar, R., J. of Ophthalmic Nursing and Technology, 18: 60-64 (1998).

Macular degeneration results in the presence of choroidal neovascul arisation (CNVM) and/or geographic atrophy of retinal pigment epithelium

(RPE) in an eye: with drusen. Bird, A.C., Surv. Ophthamol. 39:367-74 (1995). Drusen are rounded whritish-yellowish spots in the fundus, located external to the neuroretina..

Additional sym-ptoms of MD include RPE detachment (PED) and submacular discifoam scar tissue. Algyvere, P.V., Acta Ophthalmologica Scandinavica 80:136-143 (2002). «Choroidal neovascularisation is a problem that is related to a wide variety of retinal diseases, but is most commonly associated with MD. CNVM is characterized by abnormal bl ood vessels stemming from the choroid (the blood vessel-rich tissue 1 ayer just beneath thee retina) growing up through the retinal layers. These new vessels ares very fragile and break easily, causing blood and fluid to pool within the layers of thes retina. As the vessels leak, they disturb the delicate retinal tissue, causing the visiom to deteriorate. The severity of the symptoms depends on the size of the CNVM and its proximity to the macula. Patients’ symptoms may be very mild, such as a blurry or distorted area -of vision, or more severe, such as a central blind spot.

Patients having drusen and possibly pigmentary abnormalities, but no

CNVM or geographic atrophy, are generally diagnosed as having age-related maculopathy ARM). Jd. The histopathological hallmark of ARM and MD is a continuous layer of fine granular material deposited in the inner part of Bruch’s membrane at the base of the RPE cells. Sarks, J.P., et al., Eye 2(Pt. 5):552-77 (198 8).

These basal d_eposits are though to be accumulated as waste products from the continuing

RPE phagocy=tosis or photoreceptor outer segment material. The basal deposits lead to a thickening ard decreased permeability of Bruch’s membrane. It has been hypothesized that decreased water permeability impairs an exchange of nutrients, traps water and enhances the development of soft drusen and PED and eventually leads to atrophy of

RPE cells. Id However, the current overall understanding of ARM and MD pathogenesis. is incomplete. Cour, M., ef al., Drugs Aging 19:101-133 (2002).

Because MD is most prevalent in the elderly, the fastest growing sesgment of the population, MD is destined to become a major problem economicaily and socially.

Macular degeneration is the most common cause of visual loss in developed countries in individuals over the age of 60. Macular degeneration has obliterated the central vision of 1.7 million Americans and another 11 million are at risk. DuBosar, R., J. of Ophthalmic

Nursing and Technology, 18: 60-64 (1998). Currently, there is no known cure.

Rhoodhoeoft, I., Bull. Soc. belge Ophtalmol. 276:83-92 (2000). Thus, theres is an urgent need for -effective treatments for MD. 22 TREATMENT OF MACULAR DEGENERATI®ON

Until recently, laser photocoagulation was the only treatment routinely used for ‘MD, and it provides only modest results. Laser photocoagulatior is a type of laser surgery that uses an intense beam of light to burn small areas of the retina and the abnormael blood vessels beneath the macula. The burns form scar tissue amd seal the blood ve=ssels, keeping them from leaking under the macula. Laser photocoagulation is effectives only for patients having wet MD. Furthermore, laser photocoagulation is a viable opotion for only about 13% of those patients. Joffe, L. ef al., International Ophthalanology Clinics 36(2): 99-116 (1996). Laser photocoagulation does not cure wet

MD, rather it sometimes slows down or prevents further loss of central vi sion. Without treatmernt, however, vision loss from wet MD may progress until a persora has no remainirmg central vision.

The most serious drawback to laser surgery is that the lasesr damages some of the nerve cells in the macula that react to light, causing some vision loss. Sometimes, the vision loss resulting from surgery is as severe or worse than the visiom loss resulting from no treatment. In some patients, however, laser surgery initially worsens vision, but prevents more severe loss of vision over time.

Verteporfin has recently been used to treat wet MD. Cour, M.,, et al.,

Drugs Aging 19:101-133 (2002). Verteporfin is a blood-vessel-blocking photoreactive dye thak is administered via injection. The dye moves to the blood vessels that are respons-ible for the loss of sight and is then activated by shining a non-bumrning beam of light into the eye in the presence of oxygen. Verteporfin is transported ir the plasma primarily by lipoproteins. Activated verteporfin generates highly reactiv=e, short-lived singlet «oxygen and reactive oxygen radicals, resulting in local damage tow neovascular endothelium. This causes vessel occlusion. Damaged endothelium is krmown to release procoagulant and vasoactive factors through the lipo-oxygenase (leukotr-iene) and cyclo- oxygen ase (eicosanoids such as thromboxane) pathways, resulting in plautelet aggregation, fibrin clot formation and vasoconstriction. Verteporfin app-ears to somewhat preferentially accumulate in neovasculature, including choroidal neocovasculature. However, animal models indicate that verteporfin also accumulates in the retina. Therefore, verteporfin admimistration might collaterally damage retinal structures, including the retinal pigmented epithelium and outer nuclear layer of the retina.

Another strategy currently being investigated for the treatment of MD is pharmacological antiangiogenic therapy. Cour, M., et al., Drugs Aging 19:101-133 (2002). However, a first clinical trial with an antiangiogenic agent, interferon-¢, showed - that it was ineffective at treating MD awd resulted in a high rate of adverse effects. Arch.

Ophthalmol. 115:865-72 (1997).

Intravitreal injection of triamcinolone reportedly inhibits the growth of laser-induced CNVM in monkeys, but fails to prevent severe visual loss over a one-year period in patients with MD in a randormized trial. Gillies, M.C,, et al., Invest.

Ophthalmol. Vis. Sci. 42:3522 (2001). A number of other antiangiogenic drugs are in various stages of development for use in patients with MD, including angiostatic steroids (e.g., anecortave acetate, Alcon) and v-ascular epidermal growth factor (VEGF) antibodies or fragments thereof. Guyer, D.R., et al., Invest. Ophthalmol. Vis. Sci. 42:8522 (2001). One such VEGF antibody is rhuFab. Additional new drugs for the treatment of MD include EYE101 (Eyvetech Pharmaceuticals), L'Y333531 (Eli Lilly),

Miravant and RETISERT implant (Bausch & Lomb), which exudes a steroid into the eye for up to three years.

Although new and proamising strategies for the treatment of MD and related macular degenerative diseases: are being investigated, there is still no effective treatment available. Accordingly, there remains a need in the art for an effective treatment for MD. 23 C-JUN N-TERMINAL KINASE

Three c-Jun N-terminal kinase (JNK) enzymes have been identified.

These represent alternatively spliced forms of three different genes: INK 1, INK2, and

INK3 (Hibi M.,, Lin A., Smeal T., Minden A., Karin M. Genes Dev. 7:2135-2148, 1993;

Mohit A.A., Martin M.H., and Millex- C.A. Neuron 14:67-78, 1995; Gupta, S., Barrett,

T., Whitmarsh, A.J., Cavanagh, J., SHuss, H.X., Derijard, B. and Davis, R.J. The EMBO

J. 15:2760-2770, 1996). Activation «of the JNK pathway has been documented in a . a.

number of disease settings, providing the rationale for targeting this pathway for drug discovery. In addition, molecular genetic approaches have validated the pathogenic role of the JNK pathway in several diseases. Many genes are regulated by the INK pathway through activation of the transcription factors AP-1 and ATF-2, including TNF-alpha,

II.-2, E-selectin, and matrix metalloproteinases such as collagenase-1 (Mzanning A.M. and Mercurio F. , Exp Opin Invest Drugs, 6: 555-567, 1997). 3. SUMMARY OF THE INVENTION

This invention encompasses methods for treating and/or preventing MD, which comprise admin istering to a patient in need thereof an effective amount ofa JNK

Inhibitor. The invention also encompasses methods for managing MD (e-g., lengthening the time of remi ssion), which comprise administering to a patient in need of such management an effective amount of a JNK Inhibitor.

Another embodiment of the invention encompasses the use of an effective amount of a JNK Inhibitor in combination with another therapeutic agent useful to treat, prevent and/or rmanage MD such as, but not limited to, a steroid, a light seensitizer, an integrin, an anti oxidant, an interferon, a xanthine derivative, a growth hormone, a neutrotrophic factor, a regulator of neovascularization, an anti-VEGF antibody, a prostaglandin, an antibiotic, a phytoestrogen, an anti-inflammatory comp-ound, an

IMiD®, a SelCID®, or an antiangiogenesis compound, or a combination thereof.

Yet another embodiment of the invention encompasses methods for treating, preventing and/-or managing MD, comprising administering to a patient im need thereof an effective ameount of a INK Inhibitor in combination with a convention_al therapy used to treat or prevesnt MD such as, but not limited to, surgical intervention (e.g., laser photocoagulation therapy and photodynamic therapy).

The invention further encompasses pharmaceutical compositions, single unit dosage forrms, and kits suitable for use in treating, preventing and/or managing MD, which comprises an effective amount of a JNK Inhibitor. "The following Detailed Description and Examples illustra_te non-limiting embodiments of the invention. 3.1 DEFINITIONS

As used herein, the term “macular degeneration” or “MD” encompasses all forms of macular degenerative diseases regardless of a patient’s age, although some macular degenerative diseases are more common in certain age groups. These include, but are not Ximited to, Best’s disease or vitelliform (most common in patients under about seven years of age); Stargardt’s disease, juvenile macular dystrophy or fundus flavimaculatus (most common in patients between about five and about 20 years of age);

Behr’s dise ase, Sorsby’s disease, Doyne’s disease or honeycomb dystrophy (most common in. patients between about 30 and about 50 years of age); and age-related macular de generation (most common in patients of about 60 years of age or older). In one embod iment, the cause of the macular degenerative disease is genetic. In another embodiment, the cause of the macular degenerative disease is physical tratama. In another embodiment, the cause of the macular degenerative disease is diabetes. In another embodiment, the cause of the macular degenerative disease is malmutrition. In another embodiment, the cause of the macular degenerative disease is infection.

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 or human), most preferably a human. “Alkyl” means a saturated straight chain or branched non-cyclic hydrocarb on having from 1 to 10 carbon atoms. “Lower alkyl” means allyl, 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- methylpemtyl, 4-methylpentyl, 2-methylhexyl, 3-methylhexyl, 4-methylh exyl, 5- methylhexyl, 2,3-dimethylbutyl, 2,3-dimethylpentyl, 2,4-dimethylpentyl, 2,3- dimethylkexyl, 2,4-dimethylhexyl, 2,5-dimethylhexyl, 2,2-dimethylpents/1, 2,2- dimethylhexyl, 3,3-dimtheylpentyl, 3,3-dimethylhexyl, 4,4-dimethylhex yl, 2-ethylpentyl, 3-ethylpentyl, 2-ethylhexyl, 3-ethylhexyl, 4-ethylhexyl, 2-methyl-2-ethyIpentyl, 2- methyl-3 ~ethylpentyl, 2-methyl-4-ethylpentyl, 2-methyl-2-ethylbexyl, 2—methyl-3-

ethylhexyl, 2-methyl-d-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,-

Cyp)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-nonen yl, -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 cara 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 chair and branched -(C,-Co)alkynyls include -acetylenyl, -propynyl, -1-butynyl, -2-buttynyl, -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-octymyl, -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 iodine. “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)allkyl group, wherein alkyl is defined above, including -C(O)CHa, ~-C(O)CH,CH3, -C{0)(CH;)CH3, -C(0O)(CH>);CHs, -C(O)(CH.)4CH3, -C(O)(CH;)sCH3, andl the like. “Acyloxy” means an -OC(O)alkyl group, wherein alkyl is defined above, including -OC(O)CHs, -OC(O)CH,CHj , -OC(0)(CH,),CH3, -OC(O)CH,);CHs, -OC(O)(CH;)4CHs, -OC(O)(CH;)sCH3, and the like.

“Ester” means and -C(O)Oalkyl group, wherein alkyl is defined above, including -C(C»)OCH;, -C(0)OCH,CHj, ~C(0)O(CH,),CH;, -C(0O)O(CH,):CH, -C(O)O(CH2)4«CH3, -C(O)O(CH,)sCHs, and the like. “Alkoxy” means -O-(alkyl), wherein alkyl is defined above, incluading -OCHj3, -OCH=CH, -O(CH2):CHs, -O(CH,);CHa, -O(CH;)4CHs, -O(CH,)sCHs, =and the like. “Lower alkoxy” means -O-(lower alkyl), wherein lower alkyl is as describexd above. “Alkoxyalkoxy” means -O-(alkyl)-O-(alkyl), wherein each alkyl &s independently an alkyl group defined above, including -OCH,OCH3;, -OCH,CH=0CH;, -OCH,;CH,;0OCH,CHa, and the like. : “Alkoxycarbonyl” means -C(=0)O-(alkyl), wherein alkyl is defiraed above, including -C(=0)O-CHj, -C(=0)0-CH,CH3, -C(=0)0-(CH,),CHs, -C(=€0)0- (CH;)sCH3, -C(=0)0O-(CH,)sCHj, -C(=0)0-(CH,)sCH3, and the like. “Alkoxycarbonylalky!l” means -(alkyl)-C(=0)O-(alkyl), wherein each alkyl is indepeendently defined above, including ~CH,-C(=0)O-CHj;, -CH,-C(=0)0O-

CH,CH3, -CHL,-C(=0)0-(CH;),CHj, -CH,-C(=0)0-(CH,)3CHj3, -CH,-C(=0)O— (CH2)4CHjs, -&€CH;-C(=0)0-(CH,)sCHs, and the like. “Alkoxyalkyl” means -(alkyl)-O-(alkyl), wherein each alkyl is independently an alkyl group defined above, including -CH,;OCHj3, ~CH,OCH,CCH3, -(CH;),OCHCHj, -(CH;),0(CH,),CHj, and the like. “Aryl” means a carbocyclic aromatic group containing from 5 toe 10 ring atoms. Representative examples include, but are not limited to, phenyl, tolyl, anthracenyl, fluorenyl, indenyl, azulenyl, pyridiny! and naphthyl, as well as berzo-fused carbocyclic rmoieties including $,6,7,8-tetrahydronaphthyl. A carbocyclic aromatic group can be= unsubstituted or substituted. In one embodiment, the carbocyclic aromatic group is a plenyl group. “Aryloxy” means -O-aryl group, wherein aryl is as defined abowe. An aryloxy growmp can be unsubstituted or substituted. In one embodiment, the ary-1ring of an aryloxy group is a phenyl group “Arylalkyl” means -(alkyl)-(aryl), wherein alkyl and aryl are as defined above, including -(CH;)phenyl, -(CH;);phenyl, -(CH,);phenyl, -CH(phenyl)s, _8-

-CH(phenyl)s, (CHy)tolwl, -(CH,)anthracenyl, -(CH,)fluorenyl, -(CH,)indenyl, -(CHz)azulenyl, -(CH;)p-yridinyl, -(CHz)naphthyl, and the like. “Arylalky’loxy” means -O-(alkyl)-(aryl), wherein alkyl and aryl are defined above, including: -O-(CHz);phenyl, -O-(CH,)sphenyl, -O-CH(phenyl);, -O-

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

O-azulenyl, -(CH,)-O-pwridinyl, -(CH;)-O-naphthyl, and the like. “Cycloalky]l” 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—Cy)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 ab ove, including -O-CH,-cyclopropyl, -O-(CHz),-cyclopropyl, -O- (CH,)s-cyclopropyl, -O—(CHa)s-cyclopropyl, O-CH,-cyclobutyl, O-CH,-cyclopentyl, O-

CHa-cyclohexyl, O-CH.,-cycloheptyl, and the like. “Aminoalkoxy” means -O-(alkyl)-NH,, wherein alkyl is defined above, such as -O-CH;-NH>, -O-(CH,);-NH,, -0-(CH;)3-NH,, -O-(CH2)s-NH3, -O-(CH,)s-NH,, and the like. “Mono-alkylamino” means -NH(alkyl), wherein alkyl is defined above, such as -NHCH;, -NHCH,CHj3, -NH(CH:),CH3, -NH(CH;);CH3, -NH(CH,)sCHa, -NH(CH_;)sCH3, and the like.

“Di-alkylamino” means -N(alkyl)(alkyl), wherein each alkyl is independently an alkyl group defined above, including -N(CHa)z, -N(CH2CHs)z, “N((CH2)2CHas),, -N(CH1)(CH2CHj), and the like. “Mono-alkylaminoalkoxy” means -O-(alk-yl)-NH(alkyl), wherein each alkyl is independently an alkyl group defined above, including -O-(CH;)-NHCHj3, -O- (CHp)-NHCH,CHs, -O~(CH;)-NH(CH,),CH3, -O~(CHz)-NH(CH,);CHj, -O-(CHz)-

NH(CH,)4CH3, -0-(CH;)-NH(CH;)sCHj, -O-(CH2),-NH_CH3, and the like. “Di-alkylaminoalkoxy” means -O-(alkyl)~N(alkyl)(alkyl), wherein each alkyl is independently an alkyl group defined above, incRuding -O-(CH;)-N(CH3),, -O- (CH2)-N(CH,CH3,),, ~O-~(CH,)-N((CH,).CH3)3, -O-(CH2.)-N(CH;)(CH,CH3), and the like. “Arylamino”means -NH(aryl), wherein azryl is defined above, including -NH(pbenyl), -NH(tolyl), -NH(anthracenyl), -NH(fluoresnyl), -NH(indenyl), “NH(azulenyl), -NH(pyridinyl), -NH(naphthyl), and the like. “Arylalkylamino” means -NH-(alkyl)-(axyl), wherein alkyl and aryl are defined above, including -NH-CH,-(phenyl), -NH-CH,—(tolyl), -NH-CH;-(anthracenyl), -NH-CH,~(fluorenyl), -NH-CH;-(indenyl), -NH-CH,-(a_zulenyl), -NH-CH,-(pyridinyl), -NH-CH;-(naphthyl), -NH-(CH,),-(phenyl) and the likes. “Alkylamino’” means mono-alkylamino eor di-alkylamino as defined above, such as -N(alkyl)(alkyl), wherein each alkyl is imdependently an alkyl group defined above, including -N(CH;),, -N(CH,CHj3),, -N(CCH,),CH3)s, -N(CH3)(CH2CHz) and -N(alkyl)(alkyl), wherein each alkyl is independently an alkyl group defined above, including -N(CHa);, -N(CH,CH3),, -N((CHz)2CHs),, -I™N(CH3)(CH>CH3;) and the like. “Cycloalkylamino” means -NH-(cycloadkyl), wherein cycloalkyl is as defined above, including -NH-cyclopropyl, -NH-cyclo®butyl, -NH-cyclopentyl, -NH- cyclohexyl, -NH-cycloheptyl, and the like. “Carboxyl” and “carboxy” mean -COOTH. “Cycloalkylalkylamino” means -NH-(aJkyl)-(cycloalkyl), wherein alkyl and cycloalkyl are defined above, including -NH-CH,—cyclopropyl, -NH-CH,- cyclobutyl, -NH-CHj,-cyclopentyl, -NH-CH,-cyclohex:yl, -NH-CHz-cycloheptyl, -NH- (CHa);-cyclopropyl and the like.

“Aminoalkyl” means -(alkyl)-NH,, wherein alkyl is defined above, including CHz-NHp, -(CH3),-NH,, ~(CHz)3-NH3, -(CHa)4-NH,, -(CH:)s-NH; and the like. “Mono-alkylaminoalkyl” means -(alkyl)-NH(alkyl),wherein each alkyl is independently an alkyl group defined above, including -CH,-NH-CH;, -CH,-

NHCH;CH3;, -CH;-NH(CH;),CHs, -CH,-NH(CH,);CH3, -CH,-NH(CH,),CH3, -CH,- NH(CH_)sCHj, (CH,),-NH-CHj, and the like. “Di-alkylaminoalkyl” means -(alkyl)-N(alkyl)(alkyl),wherein each alkyl is independently an alkyl group defined above, including -CH,-N(CH3),, -CHa-

N(CH;CHz);, -CH;-N((CH;), CH3);, -CH2-N(CH;3)(CH,;CHj), -(CH;,);-N(CH3);, 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, -CHa-tetrazolyl, -CH,- oxadiazolyl, -CH,-pyridyl, -CH,-furyl, -CH;-benzofuranyl, -CHj-thiophenyl, -CH,- benzothiophenyl, -CH;~quinolinyl, -CH,-pyrrolyl, -CH,-indolyl, -CH;-oxazolyl, -CH,- benzoxazolyl, -CHz-imidazolyl, -CH,-benzimidazolyl, -CH,-thiazolyl, -CH,- benzothiazolyl, -CH;-isoxazolyl, -CH,-pyrazolyl, -CHa-isothiazolyl, -CH,-pyridazinyl, -CH,-pyrimidinyl, -CHy-pyrazinyl, -CH;-triazinyl, -CH,-cinnolinyl, -CH,-phthalazinyl, -CH;-quinazolinyl, -CH,-pyrimidyl, -CH,-oxetanyl, -CH,-azepinyl, -CH,-piperazinyl, -CH;-morpholinyl, -CHz-dioxanyl, -CHa-thietanyl, -CH,-oxazolyl, -(CHz),-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 optiomally 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, pyrrolidino nyl, pyrrolidinyl, piperidinyl,. hydantoinyl, valerolactamyl, oxiranyl, oxetanyl, tetrahydrofuranyl, tetrahydrop~yranyl, tetrahydropyridinyl, tetrahydroprimidinyl, tetrahycrothiophenyl, tetrahydrothiopyranyl, tetrahydropyrimidinyl, tetrahydrothiophenyl, tetrahydrothiopyranyl, and the like. “Heterocycle fused to phenyl” means a heterocycle, wherein heterocycle : is defined ams above, that is attached to a phenyl ring at two adjacent carbon atoms of the phenyl rings. “Heterocycloalkyl” means -(alkyl)-(heterocycle), wherein alkyl and heterocycles are defined above, including -CH,-morpholinyl, ~-CH,-pysrrolidinonyl, -CHa- pyrrolidiny-1, -CH,-piperidinyl, -CH,-hydantoinyl, -CH,-valerolactamayl, -CH;-oxiranyl, -CH,-oxetanyl, -CH;-tetrahydrofuranyl, -CH,-tetrahydropyranyl, -CE,- tetrahydropyridinyl, -CH,-tetrahydroprimidinyl, -CH,-tetrahydrothio phenyl, -CH,- tetrahydrotthiopyranyl, -CHj-tetrahydropyrimidinyl, -CH,-tetrahydrothiophenyl, -CH,- tetrahydrothiopyranyl, and the like.

The term “substituted” as used herein means any of tne 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 ermbodiment, each carbon atorm of the group being substituted is substituted with no mo re 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 aminoalkyll, alkyloxyalkyl, aryl, arylalkyl, heterocycle, heterocycloalkyl, -NR,Rs, -NR.C(=O)Ry, -NR.C(=0)NRRy, -NR,C(=0)OR}, -NR,SO;R, -OR _, -C(=0O)R,

C(=0)ORa -C(=O)NR.R, -OC(=O)R,, -OC(=0)OR,, -OC(=O)NR,R;, -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(Ry)~, -C(=0)-, -C(=0)0-, -OC(=0)-, -NR,)C(=0)-, -C(=0)N(Rp)- or a direct bond, wherein R, and Ry, are the same or different and indegpendently hydrogen, amino, alkyl, haloalkyl, aryl, arylalkyl, heterocycle, or heterocylea Ikyl, or wherein R,; and Ry, taken together with the nitrogen atom to which they are attached form a heterocycle. “Haloalkyl” means alkyl, wherein alk-yl is defined as above, having one or more hydro gen atoms replaced with halogen, whereim halogen is as defined above, including -CFs, -CHF,, -CH,F, -CBr3, -CHBr;, -CH, Br, -CCl;, -CHCl,, -CH2Cl, -Cl3, -CHI,, -CH,]I, -CH,-CF3, -CH,-CHF,, -CH,-CH,F, -€H,-CBr3, -CH;-CHBr,, -CH;-

CH;Br, -CH,-CCl;, -CH;-CHCI,, -CH>-CH,Cl, -CHo-CI3, -CH,-CHI,, -CH,-CHol, and thelike. “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;);CH;0H, -(CH;),CH,OH, -(«CH,)sCH,OH, -CH(OH)-CH3, -CH,CH(OH)CHj3, and the like. “Hydroxy” means -OH. “Sulfonyl” means -SO;H. “Sulfonylalkyl” means -SO,-(alkyl), wherein alkyl is defined above, including -SO,-CHj, -SO2-CH;CHj, -SO2-(CH2)CH, -80,-(CHz);CH;, -SO;- (CH,)4+CHjs, -SO2-(CH3)sCHs, and the like. “Sulfinylalky!” means -SO-(alkyl), wherein alkyl is defined above, including -SO-CHa, -SO-CH,CHj, -SO-(CH>)2CHa,. -SO-(CH,);CH, -SO-(CHz2)4CHs, -SO-(CH,)sCHj, and the like. “Sulfonamidoalkyl” means -NHSO,~(alkyl), wherein aklyl is defined above, including -NHSO,-CHj, -NHSO,-CH,CH3, —NHSO,-(CH,),CH3, -NHSO»- (CH);CHs, -NHSO,;~(CH;)4CHs, -NHSO,-(CH,)sCH;, and the like. “Thioalkyl” means -S-(alkyl), wheresin alkyl is defined above, including -S-CHs, -S-CH,CH3, -S-(CHz),CHj, -S-(CH,)3CH3_ -S-(CH2)4CHs, -S-(CH2)sCH3, 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 are capable of inhibiting the activity of INK in vitro or in vivo. The JNK

Inhibitor can be in the form of a pharmaceutically acceptable salt ., free base, solvate, hydrates, stereoisomer, clathrate or prodrug thereof. Such inhibitory activity can be determined by an assay or animal model well-known in the art in_cluding those set forth in Section 5. In one embodiment, the INK Inhibitor is a compoumd of structure (I)-(11I).

As used herein, unless otherwise specified, the terms “prevent”, “prevemting” or “prevention” include, but are not limited to, inhibiting MD or a symptom of MD». The symptoms of with MD include, but are not limited to, blindness, loss of central vision, blurred vision, wavy vision and blind spots.

As used herein, unless otherwise specified, the temms “treat”, “treating” or “treatrment” refer to the eradication of MD or a symptom of MD _ [n one embodiment, “treat’>, “treating” or “treatment” refer to minimizing the spread or minimizing the worseming of MD or a symptom of MD.

As used herein, the term “manage”, “managing” or “management” when used im connection with MD refer to providing beneficial effects to a patient being admimmistered a INK Inhibitor, which does not result in a cure of” MD. In certain embocliments, a patient is administered one or more JNK Inhibitors to manage MD so as to pre-vent the progression or worsening of MD. “JNK” means a protein or an isoform thereof expressed by a JNK 1, INK 2, or INK 3 gene (Gupta, S., Barrett, T., Whitmarsh, A.J., Cavanagh, J., Sluss, HK, Derijaud, 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 sa JNK Inhibitor means an amount of the JNK Inhibitor thaat is useful for treating or preventing MD.

As used herein, the phrase “an effective amount™’ when used in connection with asecond active agent means an amount of the second acti~ve agent that is useful for for treating or preventing MD.

As used herein, the term “pharmaceutically acceptable salt(s)” refers to a salt prepared from a pharmaceutically acceptable non-toxic ack d or base including an inorganic acid and base and an organic acid and base. Suitabl e pharmaceutically acceptable base addition salts of the JNK Inhibitor include, bust 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" edls., Mack Publishing, Baston PA. (1990) or

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

PA (1995).

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, biohydrolyzabie esters, biohydrolyzabie carbarnates, biohydrolyzable carbonates, biohydrolyzable ureides, and biohydrolyzable phosphate analogues. Preferably, prodrugs of compoumds 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. “stereoisomer” or “stereomerically pure” means one stereoisomer of a compound that 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 opgposite enantiomer of the comp ound. 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 prefer-ably greater than about 90% by weight of one stereoisomesr of the compound and less than about 10% by weight of the other stereoisomers of the compound, even more prefexably greater than about 95% by weight of one stereoisomesr 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 albbout 3% by weight of the other stereoisomers of the compound. 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 and/or managing MD, comprising administering an effective amount of” a INK Inhibitor to a patient in need thereof. Illustrative JINK Inhibitors are set forth below.

In one embodiment, the JNK Inhibitor has the follow-ing structure (I): \

Qu,

R27 o “TR wherein:

A is a direct bond, -(CHz),-, -(CH,),CH=CH(CH3),-, or - (CH),C =C(CHy).~;

R; is aryl, heteroaryl or heterocycle fus-ed to phenyl, each being optionally substituted with one to four substituents independentlsy selected from Rs;

Ry is -Rs, -Ry, -(CH,)5C(=0)Rs, -(CH2 )sC(=0)ORs, -(CH,)»C(=0)NRsRs, -(CHz2),C(=O)NR5(CH2).C(=O)Rs, (CH,):NRsC(=O)Rs, (CH, );NRsC(=O)NR¢R7, -(CHz)sNRsRs, -(CHz2);0Rs, «(CH2)»SO4Rs or ~(CH2)»SO.NR;R; ais 1,2,3,4,5or6; b and c are the same or different and aft 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, sualfonylalkyl, hydroxyalkyl, aryl, arylalkyl, heterocycle, heterocycloalkyl, -C(=0)ORs, -OC(=O)Rs, -C(=O)NRgRo, - C(=O)NRgORsy, -SO2NRgRg, -NRsSO;Ry, -CN, -NO, , -NRgRy, -NR;C(=0)Rg, -

NRgC(=0)(CH,),ORs, ~NRsC(=0)(CHa)sRs, -O(CHz):NRgRy, or heterocycle fused to phenyl;

Rais alkyl, aryl, arylalkyl, heterocycles or heterocycloalkyl, each being optionally substituted with one to four substituents imdependently selected from Rs, or Ry is halogen or hydroxy;

Rs, Rs and R; 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 Rs; and :

Rg and Ry are the same or different an d at each occurrence independently hydrogen, alkyl, aryl, arylalkyl, heterocycle, or heter-ocycloalkyl, or Rg and Re 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 Rs.

In one embodiment, -A-R; is phenyl, optionally substituted with one to four substituents independently selected from halogen, alkoxy, -NRgC(=O)R, -C(=C€)NR3Ry, and -O(CH;)sNRgRo, wherein b is 2 or 3 and wherein Rg and Ry are defin ed above.

In another embodiment, R; is -R4, (CH2),C(=Q)Rs, -(CH2);C(=0)ORs, «(CHI2),C(=O)NRsRs, -(CH2)sC(=O)NRs(CH2).C(=O)Rs, -(CEL)sNRsC(=O)Rs, -(CHI2)sNRsC(=O)NRsR7, -(CH2)sNRsRs, -(CH2)s0Rs, -(CH2D)sSO4Rs or -(CH;)5SO;NR;sRg, and b is an integer ranging from 0-4.

In another embodiment, R; is -(CH;),C(=0)NIRsR;, -(CH,):NR5C(=0)Rs, 3-tri azolyl or 5-tetrazolyl, wherein b is 0 and wherein Rg and “Ry are defined above.

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

In another embodiment: (2) -A-R; is phenyl, optionally substituted wit"h one to four substituents independently selected from halogen, alkoxy, -NReC(=0)Rs, -C(=0)NRgRy, and -O(CH,),NRgRg, wherein b is 2 or 3; and (b) R; is -(CH2),C(=O)NRsRs, (CH2)sNRsCa(=0)Rs, 3-triazolyl or 5- tetrazolyl, wherein 4 is 0 and wherein Rg and Ry are defined above.

In another embodiment: (a) -A-R; is phenyl, optionally substituted with one to four substituents ind ependently selected from halogen, alkoxy, -NRsC(=0)Ry., -C(=0)NRgRy, and -OCCH,);NRgRy, wherein bis 2 or 3; and (b) R3 is 3-triazolyl or 5-tetrazolyl.

In another embodiment, Ry is R4, and Ry4 is 3- triazolyl, optionally substituted at its 5-position with: (a) a Cy-C4 straight or branched chain alkyl group optionally substituted with a hydroxyl, methylamino, dimethylamino or 1-pyrrolidiinyl group; or (b) a2-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- hy~droxypropyl, methylaminomethyl, dimethylaminomethyl , 1-(dimethylamino)ethyl, 1- pymolidinylmethyl or 2-pyrrolidinyl. )

In another embodiment, the compounds Of structure (I) have structure (TA) when A is a direct bond, or have structure (IB) when A is -(CHgz),~:

H H

Ne N, / / N

Rg R2

R1 (CH2)a-R1 (IA) (IB)

In other embodiments, the compounds off structure (I) have structure (IC) when A is a -CH,),CH=CH(CH,).-, and have structure ID) when A is -(CH,),C =

C(CH,),~ \ §

N

/ N / N

Rs Rs (CHR) CHECH(CH) Ry (CH),CH=CH(CHp)sR (8) «D)

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

RJ he

UX

(Rs)o4 | | (IE)

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

H

.0 N

NK /

Re

Rs A—Ry (IF)

Representative R; 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 -NHCH;, -N(CH3), and -NHCH, CH), -NHC(=O)R, wherein Rs 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 -NHCHj(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(=O)NH_, -C(=0)NHCH3, -C(=0)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), alky! (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 methylsulfonyl), sulfonamidoalkyl (such as -NHSO,CHj), -NRgC(=0)(CH),ORy (such as NHC(=O)CH,OCH;), NHC(=O)R; (such as -NHC(=0)CHs, -NHC(=0)CH,C4Hs, -N'HC(=0)(2-furanyl)), and -O(CH,)sNRgRs (such as -O(CH;);N(CHj3),).

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 (I) are:

H

N

N a ¢

HG

F

3~(4-Fluoro-phenyl)-5-(1H- {1.2,4]triazol-3-yI)-1#-indazole,

H

A

/ ¢ ; N .

Od 3-[3-(2-Piperidin-1-yl-ethoxy)-phenyl]-5-(1H- . [1,2,4]triazol-3-yl)-1H-indazole :

N

0)

A

~TN

ER

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

H hy

HaN %

J 3 4 3-[3~(3-Piperidin-1-yl-propionylamino)-phenyl}-1H- indazole-5-carboxylic acid amide :

H yy ‘SE

Gq . 0] . o 3-Benzo[1,3]dioxol-5-yl-5-(2H-tetrazol- 5-yl)-1H-indazole ;

H qe 0. /

HC

Rae

F

3-(4-Fluoro-phenyl)-5-(5- methyl-[1,3 4)oxadiazol-2-yl)- 1Fi-indazole :

H gw

N { HsG_ CHa <0 H

Ry = at oO .

N-tert-Butyl-3-{5-C1H-{1,2,4]triazol-3-y1)-1H- indazol—3-yl]-benzamide ;

H

N a

N a ¢ I py et 3-[3-(2-Morpholin—4-yl-ethoxy)-phenyl}-5-(1H- [1,2,4]triazzo0]-3-y1)-1 H-indazole ;

N

\

N J 7 ¢ ]

M8 ee o—/ Nero

Dimethyl-(2- {4-[ S-(1H-[1,2 4]triazol-3-yl)-1H- indazol-3-y1§-phenoxy }-ethyl)-amine :

H

N,

H, Han Y, 7

F

5-[5-(1,1—Dimethyl-propyl)-1H-{1,2,4]triazol-3- yl]-3-(4-fluoro-phenyl)-1H-indazole :

H

Ne

N / ~~]

SEAR

F

3-(4—Fluoro-phenyl)-5-(5-pyrrolidin-1- ~ ylmethyl-1H-[1,2 4]triazol-3-y])-1H- indazole :

H

N,

N 7a ~~ oo Ue 0—CHgs 3-(6-Methoxy-naphthalen-2-yl)-5-(5-pyrrolidin-1- ylmethy1-LH-{1,2,4]triazol-3-yl)-1 H-indazole

H

N,

HoN ¢ oN

RY

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

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

Ri A = Rg

Im 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;

Ra 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 differerat and independently -Rg, -(CH2).C(=0)Ry, -(CH2).C(=0)ORy, -(CH;).C(=0)NRgR 0, ~(CH2),C(=O)NRg(CH2)sC(=O)R 0, -(CH2),NRg«C(=O)R 0, (CHz)sNR;C(=O)NRR 5, ~(CH2)sNRsR 10, ~(CH2),0Rg, -(CH2).SORs or -(CHy),SO:NRgR 10; or Rs and Rg 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, thioa kyl, sulfinylalkyl, sulfonylalkyl, hydroxyalkyl, aryl, arylalkyl, heterocycle, substi tuted heterocycle, heterocycloalkyl, _C(=0)ORs, -OC(=O)Rs, -C(=0)NRsRy, -C(=0)NRsORs, -SOcRs, -SO:NRsRy, -NRgSOcRs, -NRgRs, -NRC(=0)R9, -NR¢C(=0)(CH,);0Rg, -NRsC(=0)(CHz)sRy, _O(CH;z)sNRgRy, or heterocycle fused to phenyl ;

Rs, Rg, 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 is 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,Rg or -SO2RsRo.

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, tri azinyl, 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 suabstituted with a halogen, -SO2R;g or -SO;RsRs.

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 halogen, -SO,R;s or -SO;RgRs.

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

When Rs and Rg, taken together with the nitrogen atom to which they areattached form substituted piperazinyl, piperadinyl or morpkolinyl, 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, Rj is hydrogen and Ry is mot present, and the INK

Inhibitor has the following structure (ILA):

oN Rs

Je L

Ri H (A) and pharmaceutically acceptable salts thereof.

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

Ry, and having the following structure (IIB):

N Rs . Ry H (IIB) and pharmaceutically acceptable salts thereof.

In still a further embodiment, R7is at the para position of the phenyl group relative to the pyrimidine, as represented by the following structure (IIC):

NN Rs

Jo

H

R

’ @o) 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, lime 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. :

Nlustrative examples of INK Inhibitors of structure (II) are:

8 Ne

FZ

H

Cl 4-[4-(4-Chloro-phenyl)-pyrinnidin-2-ylamino]- benzamide : . ES CH;

A CH3

H cl 4-[4-(4-Chloro-phenyl)-pyrimidin-2--ylamino]-N,N-dimethyl- : benzamide :

H

PR

H

Cl 4-[4-(4-Chloro-phenyl)-pyrimidin-2-ylamin=o]-N-(3-piperidin-1-yl-propyl)- benzamide : x

CX 1

H

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

AS

. H 0 cl 1-(4- {4-[4-(4-Chloro-phenyl)-pyrimidin-2-ylamino_}-benzoyl}~ piperazin-1-yl)-ethanone .

AS

BN N CH

N TY

Ho "Ng 1-{4-(4-{4-[4-(3-Hydroxy-propylsulfanyl)-phenyl]-pyrimidin—2-ylamino} -benzoyl)- piperazin-1-yl]-ethanone : =

L ae 0 cl {4-[4-(4-Chloro-pheny!)-pyrimidin-2-ylamino}-pheny!} -C4-pyrrolidin-1-yl- piperidin-1-yl)-methanone ; an-d pharmaceutically acceptable salts thereof.

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

N——R, 10 9 3

LI

7 6. 5 v, [0] , : (IIT)

wherein Rg is -O-, -S-, -S(0)-, -S(0),-, NH or -CH,-; the compound of structure (IIT) being: (i) unsubstituted, (ii) monosubstituted and having a first substituent, or (iii) disubstituted amd 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, cycloalkyl-oxy, alkoxyalkyl, alkoxyalkoxy, aminoalkoxy, mono-alkylaminoalkoxy, di-alkylamino-alkoxy, or a group represented. by structure (a), (b), (¢), (d), (e), or (f):

Q Q

R

VAT J a 0p, —N\ AN —N NG = ® © @ oo i

Pe Rs ’ S Ra °

Rs Ra © 0 wherein Rj; and Ry are taken together and represent all<ylidene or a heteroatom—containing cyclic alkylidene or R3 and Ry are independen-tly hydrogen, alkyl, cycloalkyl, aryl, arylalkyl, cycloalkylalkyl, aryloxyalkyl, alkoxyalkyl, aminoalkyl, mono-alkyl aminoalkyl, or di-alkylaminoalkyl; and

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

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

N———CH, l 9 3 8 4 7 6 5 bo) 2H-Dibenzo[cd,glindol-6-one (IIA) being: (i) unsubstituted, (ii) monosubstituted andl having a first 10 substituent, or (iii) disubstituted and having a first substituent arid 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, cycloalkylalkylox y, cycloalkyloxy, alkoxyalkyl, alkoxyalkoxy, aminoalkoxy, mono- alkylaminoalkexy, di- alkylaminoalkoxy, or a group represented by structure (a), (b), (<c), (d), (e), or (f): (0) 'e}

R

VA Vai — 03s —N —N—(alkyh—N —N rl

S \ \ \ 4 Rs H H (8) (®) (0) @ 0 (0) oe NT ~~ SN °

Rs R4 (e) . ® wherein Rj and Ry are taken together and represent alkylidene or a heteroatom-containing cyclic alkylidene or R3; and Ry are indeperadently hydrogen, alkyl,

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

Rsis hydrogen, alkyl, cycloalkyl, aryl, arylalkyl, cycloalkylalkyl, alkoxy, alkoxyalkyl, alkoxycarbony/lalkyl, 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 preserat 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 i s present at the 5, 7, or 9 position; the first or second substituent is independently alkoxy, aryloxy, aminoalkyl, mono-alkylam-inoalkyl, di-alkylaminoalkyl, or a group represented by the structure (a), (c), (d), (€), ox (£);

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

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

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

[0] } — 2 . ’ 8 4

E 7 8 5 4) 2-Ox0-2H-214-anthra[9,1-cd] isothiazol-6-one (IIIB) being (i) un substituted, (ii) 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, or 10 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 lo] / Ho Va Mrs o=3 —Rs

IN —N— (alkyl)—N —_ NG

R4 AY \ \, (a) ®) (©) (d)

I I oy —Ra “Ty Rs :

R4 Ry4 © ® wherein R; and R4 are taken together and represent alkylidene or a heteroatom-containing cyclic alkylidene or Rj; and R, 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.

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);

Rj and R, are independently Thydrogen, 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 ac): 1 2 0 9 8 4 7 6 5 0 2-Oxa-1-aza-aceanthrylen-6-one

Ic) being (i) monosubstituted amd having a first substituent or (ii) disubstituted and having a first substituent zand 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, halogen, hydroxy, nitro, trifluoromethyl, sulfonyl, carboxyl, alkoxycarbonyl, alkoxy, aryl, aryloxy, arylalkyloxy, arylalkyl, cycloalkylalkyloxy, cycloalkyloxy, alkoxyalkyl, alkoxyalkoxy, aminoalkoxy, mmono-alkylaminoalkoxy, di-alkylaminoalkoxy, or a group represented by structure (a), (b), (c) (d), (e), or (f):

Q lo} / 2 H Se rs 0 —rs

RN —N— (alkyl) —N — _N

R4 “ M \, (2) ®) © (0 i i

PN ise °

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

Rs is hydrogen, alkyl, cycloalkyl, aryl, arylalkyl, cycloalkylalkyl, alkoxy, alkoxyalkyl, alkoxycarbonylalkyl, amino, mono-alkyJdamino, di-alkylamino, arylamino, arylalkylamino, cycloalkylamino, cycloalkylalkylami-no, aminoalkyl, mono- alkylaminoalkyl, or di-alkylaminoalkyl.

A subclass of the compounds of structwre (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, ar-yloxy, aminoalkyl, mono- alkylaminoalkyl, di-alkylaminoalky}, 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

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

In another embodiment, the JNK Inhibwitor has the following structure (ID):

o 1 2 Fl

N——S=—0 10 0 3 8 4 7 6 5 lo) 2,2-Diox0-2H-21%-anthra [9,1-cd]isothiazol—6-0ne (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, (ii) disubstituted and having a first substituent present at the 5 position and a secondl 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, cy<cloalkylalkyloxy, cycloalkyloxy, alkoxyalkyl, alkoxyalkoxy, aminoalkoxy, mono—alkylaminoalkoxy, di-alkylaminoalkoxy, or a group represented by structure (a), (b), (c), (d), (e), or ®:

Q 0)

Rs R ) \ / H / 3 Rs NY —~ NEN —N N

Ra Rs H H @®@ ®) (©) @

Cs ;

PY Ra : S Ra

WT | “TN

Te

Ra : Ra (e) ® wherein Rj and Ry are taken together and represent alkylidene ora heteroatom- containing cyclic alkylidene or Rj and Ry are independently hydroggen, alkyl, cycloalkyl, aryl, arylalkyl, cycloalkylalkyl, aryloxyalkyl, alkoxyalkyl, aminoalky], mono-alkylaminoalkyl, or di-alkylaminoalkyl; and

Rsis hydrogen, alkyl, cycloalkyl, aryl, arylalkyl, cycloalkylalkyl, alkoxy, alkoxyalkyl, alkoxycarbonylalkyl, amino, mono-alkylamino, di-alkylamino, ar-ylarnino, arylalkylam3no, cycloalkylamino, cycloalkylalkylamino, aminoalkyl, mono- alkylaminoaclkyl, or di-alkylaminoalkyl.

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

A second subclass of the compounds of structure (IIID) is that wherein the first or seecond substituent is independently alkyl, trifluoromethyl, sulfonyl, carboxyl, alkoxycarbo nyl, alkoxy, aryl, aryloxy, arylalkyloxy, arylalkyl, cycloalkylalkyl-oxy, cycloalkyloxy, alkoxyalkyl, alkoxyalkoxy, aminoalkoxy, mono-alkylaminoalk-oxy, di- alkylaminoa_ lkoxy, or a group represented by structure (a), (c), (d), (e), or (£).

Another subclass of the compounds of structure (IID) is that wherein the first and seceond substituent are independently alkoxy, aryloxy, or a group represented by the structure (2), (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, alkoxycarbonwl, or cycloalkylalkyl.

In another embodiment, the JNK Inhibitor has the following strmicture (IIE): 1 2 w J]

CLI

8 4 7 6 5 0

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

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, trifluorometinyl, sulfonyl, carboxyl, alkoxycarbonyl, alkoxy, aryl, aryloxy, arylalkyloxy, arylalkyl, cycloalkylalkyloxy, cycloalkyloxy, alkoxyalkyl, alkoxyalkoxy, aminoalkoxy, mmono-alkylaminoalkoxy, di-alkylaminoalkoxy, or a group represented by structure (a), (b), €c), (d), (e), or (f):

Q lo}

Jo y J Vrs 03g, ™N —N—(alky)—N —N —

Ra hY \ M @) ®) | (©) @

I i = Rs “Ty Rs

Rs Rq (e) 0 wherein R3 and Ry are taken together and represent alkylidene or a heteroatom-containing cyclic alkylidene or Rj and R,4 are independently hydrogen, alkyl, cycloalkyl, aryl, arylalkyl, cycloalkylalkyl, aryloxyalkyl, alkoxyalkyl, aminoalkyl, : mono-alkylaminoalkyl, or di-alkylaminoalksyl; and

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

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

A second subclass of the compounds of structure (IIE) is that wherein the compound of structure (ITE) is disubstituted and at least one of the substituents is a group represented by the structure (d) or (f).

Another subclass of the compounds of structure (IIE) is that wherein the compounds are monosubstituted. Yet another subclass of compounds is that wherein the compounds are monosubstituted at the 5 or 7 position with a group represented by the structure (e) or (f).

In another embodiment, the INK Inhibitor has the following structure (OIF): : 1 2 i” He 3 - 9 : 7 6 5 o - 2H-Dibenz o[cd,g]indazol-6-one (IF) being (i) unsubstituted, (if) 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 structure (a), (b), (c), (d), (e), or (£):

Claims (37)

What is claimed is:

1. Use of an effective amount 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 or preventing MD in a patient.

2. Use of an effective amount of a compound having the following formula: H N N / RZ A~re, or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, wherein: A is a direct bond, -(CH3),-, -(CH2),CH=CH(CH3)c-, or -(CH; );C=C(CH;).-; Ris aryl, heteroaryl or heterocycle fused to phenyl, each bein g optionally substituted with one to four substituents independently from Rj; R; is -R3, —R4, -(CH,)»C(=O)Rs, -(CH,),C(=0)ORs, -(CH,),C (FO)NRsRG, -(CH2),C(=0)NRs(CH;).C(=O)Rs, -(CH2),NRsC(=O)Rs, -(CH2)sNRsC(=O)NRsR7, -(CH,),NRsRg, -(CH32),ORs,-(CH1)5SOuRs or -(CH2),SO,NRs Ry, aisl,2,3.4,50r16; b and ¢ ares the same or different and at each occurrence indep endently 0, 1, 2, 3 or 4; d is at each occurrence 0, 1 or 2; R; is at each occurrence independently halogen, hydroxy, carboxy, alkyl, alkoxy, haloalkyl, acyloxy, thioalkyl, sulfinylalkyl, sulfonylalkyl, hyd roxyalkyl, aryl, substituted aryl, arylalkyl, heterocycle, heterocycloalkyl, -C(=O)ORs, -O«C(=0)Rg, -C(=O)NRgRG, -C(=0)NR_3ORy, -SO;NRgRg, -NRgSOR9, -CN, -NO;, -NRgR.9, -NRgC(=O)R, -63- . Amended sheet: 2 June 2006

-NRgC(=0)(CH,);ORy, -NRsC(=0)(CH,),Ro, -O(CH,),NRgR, or hetexocycle fused to phenyl; Ryis alkyl, aryl, arylalkyl, heterocycle or heterocycloalkyl, each being optionally substituted with one to four substituents independently from Rj, or R41 s halogen or hydroxy; Rs, Rgand 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 from Rj; and Rgand Re are the same or different and at each occurrence independently hydrogen, alkyl, aryl, aryla_lkyl, heterocycle, or heterocycloalkyl, or Rg and Ry taken together with the atom or atom. sto which they are bonded form a heterocycle, wherein each of Rg, Ro, and Rg and Ro ta_ken together to form a heterocycle are optionally substituted with ne to four substituents independently from R,, in the manufacture of a medicament for use in a method for treating or preventing MD in a patient.

3. Use of an effective amount of a compound having the followin g formula: R; 0 R R 4 R ’e Try s PY Rj N N ZZ Re H or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, wherein: R, is aryl or heteroaryl optionally substituted with one to four substituemts independently from Ry; R; 1s "hydrogen; - 64 - Amended sheet: 2 June 2006

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)Ry, -(CH2 ),C(=0)ORy, -(CH2),C(=0)NR9R 1, -(CH2).C(=O)NRo(CH2),L(=O)R 0, -(CH2).NRyC(=0)R 0, (CH2).NR;C(=0)NRgR 0, -(CH2).NRoR 10, -CCH2)cOR, -(CH; ).SO.Ry or -(CH3),SO;NRyR ;; or Rs and Rg taken together with the nitrogen atom to which they are attached to form a hetero cycle 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)ORs, -OC(=0)Rs, -C(=O)NRgRy, -C(=0O INRgORGg, -SO.R;, -SONRgRy, -NRgSO.Ro, -NRgRo, -NRgC(=0)Rg, -NR3C(=0)(CH;),0Ro, -NR3C(=0)(CH,);R9, -O(CH2)sNR3Ry, or heterocycle fused to phenyl; Rs, Ro, Rip and Ry; are the same or different and at each occurrence irdependently hydrogzen, alkyl, substituted alkyl, aryl, arylalkyl, heterocycle or hetexocycloalkyl; 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 independentl y 0, 1, 2, 3 or 4; and cis at each occurrence 0, 1 or 2, in the manufacture of a medicament for use in a method for treating o r preventing MD in a patient. - 65 - Amended sheet: 2 June 2006 J

4. Use of an effective amount of a comp ound having the following formula: 1 2 N——R,

DPS 8 6 4 7 5 0) or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, wherein Ry is -O-, -S-, -S(0)-, -S(0O),-, NH or -CH-; 10 the compound being (1) unsubstituted, (ii) 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 atthe 3,4, 5, 7, 8, 9, or 10 position, wherein the first and second substituent, whem present, are independently alkyl, hydroxy, : halogen, nitro, trifluoromethyl, sulfonyl, carb oxyl, alkoxycarbonyl, alkoxy, aryl, aryloxy, arylalkyloxy, arylalkyl, cycloalkylalkyloxy, cycloalkyloxy, alkoxyalkyl, alkoxyalkoxy, aminoalkoxy, mono-alkylaminoalkoxy, di-allkkylaminoalkoxy, or a group represented by formula (a), (b), (¢), (d), (e), or (f): -66 - Amended sheet: 2 June 2006

0 0} R a ’ Se N— 0-8 rs —™ — N— (alkyl) + _N N R, R, \, \ (a) (b) (c) (d) i i PS Rs S Rs NT “INT ° R4 Ry (e) () =wherein R; and R; are taken together and represent alkylidene or a heteroatom- containing cyclic alkylidene or Rj; and Ry are independently hy-drogen, alkyl, cycloalkyl, aryl, arylalkyl, cycloalkylalkyl, aryloxyalkyl, alkoxyalkyl, amanoalkyl, mono- alkylaminoalkyl, or di-alkylaminoalkyl; and IRR; is hydrogen, alkyl, cycloalkyl, aryl, arylalkyl, cycloalkylalkyl, alkoxy, alkoxyalkyl, alkoxycarbonylalkyl, amino, mono-alkylamino, di-alkylamino , arylamino, arylalkylamino, cycloalkylamino, cycloalkylalkylamino, amin oalkyl, mono- alkylaminoalkyl, or di-alkylaminoalkyl, an the manufacture of a medicament for use in a method for treating or preventing MD in a patient.

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

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

7. The use of claim 2 wherein A is -(CH,),CH=CH(CH;) ~.

s. The use of claim 2 wherein A is -(CH;),C=C(CH,).-.

9. The use of claim 2 wherein the compound has the follwing formula: -67 - Acmended sheet: 2 June 2006

H N

\ . N Rz AQ XX (R3)0-4 or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, wherein: A is a direct bond, -(CH;),-, -(CH,),CH=CH(CH,),-, or -(CH 3),C=C(CH),-; R| 1s aryl, heteroaryl or heterocycle fused to phenyl, each beirg optionally substituted with one to four substituents independently from Rj; R; is -R3, -Ry, -(CH2)C(=0O)Rs, -(CH2),C(=0)ORs, -(CH2),C(=O)NRsRs, -(CH>),C(=0O)NR;s(CH,).C(=O)Rg, -(CH;),NRsC(=O)R¢, -(CH;),NRsC(=0O)NR¢R7, -(CHz )sNRsRg, -(CH2),0Rs, -(CH),SO4Rs or -(CH2),SO2NR sR, aisl,2,3,4,50r6; band care 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, hyd roxyalkyl, aryl, arylalkyl, hetero cycle, heterocycloalkyl, -C(=0)ORg, -OC(=0)Rg, -C(=O)NRgRy, -C(=O)NR3ORy, -SO,NIRgRg, -NRgSO2R,, -CN, -NO,, -NRgRg, -NRsC(=0)Ry, -NRgC(=0)(CH1),ORo, -NRzC(=0)(CHy)sR9, -O(CH3),NRgRo, or heterocycle fused to phenyl, Rs is alkyl, aryl, arylalkyl, heterocycle or heterocycloalkyl, each being optionally substit uted with one to four substituents independently from R3, or R4is halogen or hydroxy; - 68 - Aamended sheet: 2 June 2006

Rs, Rgand 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 from Rj; and Rs and Ry are the same or different and at each occurrence independently hydrogen, alkyl, aryl, arylalkyl, heterocycle, or lmeterocycloalkyl, 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 from R;.

10. The use of claim 2 wherein the compound has the following formula: H o N, JL Rg N Rs A—R1 or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, wherein: A is a direct bond, -(CH3)4-, -(CH,),CH=CH(CH,),-, or -(CH,),C=C(CH;).; Ris aryl, heteroaryl or heterocycle fu sed to phenyl, each being optionally substituted with one to four substituents independently from Rs; R; is -R3, -R4, -(CH2)»C(=O)Rs, -(CH 2),C(=0)ORs, -(CH2),C(=O)NR;Rg, -(CH2)»C(=0)NR5(CH2).C(=O)Rs, -(CH2),NRsC(=O)Rs, -(CH,),NRsC(=O)NR¢R7, -(CH;),NRsRg, -(CH;),ORs, -(CH3)pS O4Rs or -(CH3),SO2NRsRg. aisl,2,3,4,5o0r6; b and c are the same or different and at each occurrence independently 0, 1, 2, 3 or 4; - 69 - Amended sheet: 2 June 2006 d is 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, arylalkyl, heterocycle, heterocycloalkyl, -C(=0)ORg, -OC(=0)Rg, -€C(=0)NRgRs, -C(=0)NR3ORy, -SO,NRgRg, -NRgSO,Rg, -CN, -NO,, -NRgRo, -NRgC(=0 )Rg, -NRC(=0)(CH;),ORo, -NR3C(=0)(CH:),R9, -O(CH,),NRgRy, or heterocycle fus ed to phenyl; Ry is alkyl, aryl, arylalkyl, heterocycle or heterocycloalky1, each being optionally substituted with one to four substituents independently from Rj, or R4 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, Rs and R; are optionally substituted with one to four substituents independently 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 Re 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 from Rj.

11. The use of claim 2 wherein the compound has the following formula: H ge N N / ¢ IR F or a pharmaceutically acceptable salt, solvate or stereoiso mer thereof.

12. The use of claim 3, wherein the compound has the following formula: -70 - Amended sheet: 2 June 2006

Oo R 2 Ory PY Ri N N 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 from Ry;

Rsand Ry are the same or different and independently -Rg, -(CH3),C(=O)Ro, -(CH,).C(=0)ORy, -(CH,),C(=O)NRgR 9, -(CH;),C(=0)NRo(CH;),C(=O)Rq, -(CH;).NRoC(=O)R 9, (CH2) NR; C(=0)NRgR 0, -(CH2)sNR9R 1p, -(CH),ORo, -(CH;).SO:Rg or -(CH2),SO;NR<R |g; 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 indepemdently halogen, hydroxy, cyano, nitro, carboxy, alkyl, alkoxy, haloalkyl, acyloxy, thioalkyl, sulfinylalkyl, sulfonylalkyl, hydroxyalkyl, aryl, arylalkyl, heterocycle, heterocycloalkyl, -C(=0)ORg, -OC(=O)Rg, -C(=O)NR3Ry, -C(=0)NR3ORy, -SORs, -SON RgRy, -NRgSO.Ry, -NRgRy, -NRsC(=O)Ro,

-NRyC(=0)(CH;),ORyg, -NRgC(=0)(CH;)sRg, -O(CH2)sNRgRy, or heterocycle fused to phenyl;

Rs, Ry, 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 71 - Amended sheet: 2 June 200 6

5S cis at each occurrence 0, 1 or 2.

13. The use of claim 3, wherein the compound has the following formula: 0 F A Re R—— | H AN or a pharmaceutically acceptable salt, solwate or stereoisomer thereof, wherein: Rs and Rg are the same or different and imdependently -Rg, -(CH»),C(=O)Ro, -(CH;),C(=0)ORy, -(CH3),C(=0O)NRyR 0, -(CH2),C(=O)NRy(CH,)»C(=O)R 0, -(CH3),NRyC(=0)R 0, (CH3).NR, 1C(=O)»NRgR 9p, -(CH3,).NRygR 0, -(CH3), ORs, -(CH,),SO.Ry or -(CH),SO2NRyR 0; or Rs and R; taken together with the nitro gen 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, sul finylalkyl, sulfonylalkyl, hydroxyalkyl, aryl, arylalkyl, heterocycle, heterocycloalkyl, ~C(=0)ORg, -OC(=0)Rs, -C(=O)NRgRg, -C(=0)NR3ORy, -SO.Rs, -SO:-NRgRg, -NRgSOR9, -NRgRy, -NRgC(=0)Ro, -NR3C(=0)(CH;),ORy, -NRgC(=0)(CH2);sRo, -O(CH,),NRgRy, or heterocycle fused to phenyl; Ry, Rg, 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; -72- Amended sheet: 2 June 2006 a and b are the same or different and at each occurrence independently 0, 1, 2, 3 or 4; and cis at each occurrence 0, 1 or 2.

14. The use of claim 3, wherein the compound has the followdng formula: O PY N N Ro H Ry or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, wh erein: Rs and Rg are the same or different and independently -Rg, -(CH=),C(=O)Ro, -(CH,),C(=0)ORy, -(CH),C(=O)NRgR,(, -(CH2),C(=O0)NRo(CH,),C(=O)Ro, -(CH,) ,NRyC(=O)R ig, (CH2)aNR | C(=O)NRoR 0, -(CH2)aNRgR ¢, -(CH2),ORo, -(CH,).SORo or -(CH2).SO2NRgR 0; or Rs and 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, alkzoxy, haloalkyl, acyloxy, thioalkyl, sulfinylalkyl, sulfonylalkyl, hydroxyalkyl, aryl, arylalkyl, heterocycle, heterocycloalkyl, -C(=O)ORg, -OC(=O)R_s, -C(=O)NRgRo, -Cq(=0O)NR3ORo, -SORg, -SO.NRgRo, -NR3SORo, -NRsgRo, -NR_sC(=0)Rg, -N RgC(=0)(CH;)5ORq, -NRsC(=0)(CH;)sRg, -O(CH;);NRgRy, Or heterocycle fused to phenyl; Rg , Ro, Rio and Ry; are the same or different and at each occurrerice independently hydrogen, alkyl, substituted alkyl, aryl, arylalkyl, heterocycle, hesterocycloalkyl; -73- Anmended sheet: 2 June 2006 orRgand Ro 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.

15. The use of claim 0, wherein Rg is -O-.

16. The -use of claim 0, wherein Ry is -S-.

17. The use of claim 0, wherein Rg is-S(O)-.

18. The use of claim 0, wherein Rg is -S(O),-.

19. The use of claim 0, wherein Rg is NH.

20. The use of claim 0, wherein Rgi1s CHj-.

21. The use of claim 0, wherein the compound has the followings formula: TI 0] or a pharmaceutically acceptable salt, solvate or stereoisomer thereof.

22. The use of claim 1, wherein the method further comprises aedministering an effective ammount of a steroid, a light sensitizer, an integrin, an antioxidant, an interferon, -74 - Amenaded sheet: 2 June 2006 a xanthine derivative, a growth hormone, a n.eutrotrophic factor, a regulator of neovascularization, an anti-VEGF antibody, a prostaglandin, an antibiotic, a phytoestrogen, an anti-inflammatory compound, an IMiD®, a SelCID®, an antiangiogenesis compound, or a combination thereof.

23. The use of claim 2, wherein the method further comprises administering an effective amount of a steroid, a light sensitizer, an integrin, an antioxidant, an interferon, a xanthine derivative, a growth hormone, a neutrotrophic factor, a regulator of neovascularization, an anti-VEGF antibody, a prostaglandin, an antibiotic, a phytoestrogen, an anti-inflammatory compound, an IMiD®, a SelCID®, an antiangiogenesis compound, or a combination thereof.

24. The use of claim 3, wherein the method further comprises administering an effective amount of a steroid, a light sensitizer, an integrin, an antioxidant, an interferon, a xanthine derivative, a growth hormone, a meutrotrophic factor, a regulator of neovascularization, an anti-VEGF antibody. a prostaglandin, an antibiotic, a phytoestrogen, an anti-inflammatory compound, an IMiD®, a SelCID®, an antiangiogenesis compound, or a combinati on thereof.

25. The use of claim 0, wherein the method further comprises administering an effective amount of a steroid, a light sensiti zer, an integrin, an antioxidant, an interferon, a xanthine derivative, a growth hormone, a neutrotrophic factor, a regulator of neovascularization, an anti-VEGF antibody, a prostaglandin, an antibiotic, a phytoestrogen, an anti-inflammatory compound, an IMiD®, a SelCID®, an antiangiogenesis compound, or a combination thereof.

26. The use of claim 1, wherein the MID is wet MD.

27. The use of claim 1, wherein the MID is dry MD.

28. The use of claim 1, wherein the method further comprises the administration of verteporfin. -75- Amended sheet: 2 June 2006

29. The use of claim 22, wherein antiangiogenesis compound is thalidomide.

30. The use of claim 22, wherein the anti-VEGF antibody is rthuFab.

31. The use of claim 22, wherein the xanthine derivative is pentoxifylline.

32. The use of claim 22, wherein the interferon is inter feron-2o.

33. The use of claim 1, wherein the method further coamprises administering laser photocoagulation therapy.

34. The use of claim 1, wherein the method further co mprises administering photodynamic therapy. :

35. Use of an effective amount of a JNK inhibitor or & pharmaceutically acceptable salt, solvate or stereoisomer thereof in the manufacture o fa medicament for use in a method for treating or preventing ARM, CNVM, PED or atrophy of RPE.

36. The use of claim 35, wherein the method further comprises administering an effective amount of a steroid, a light sensitizer, an integrin, an antioxidant, an interferon, a xanthine derivative, a growth hormone, a neutrotrophic factor, a regulator of neovascularization, an anti-VEGF antibody, a prostaglandin, an antibiotic, a phytoestrogen, an anti-inflammatory compound or an ant iangiogenesis compound.

37. A pharmaceutical composition comprising an effective amount of a JNK Inhibitor and a steroid, a light sensitizer, an integrin, an antioxidant, an interferon, a xanthine derivative, a growth hormone, a neutrotrophic factor, a regulator of neovascularization, an anti-VEGF antibody, a prostaglan din, an antibiotic, a phytoestrogen, an antiangiogenesis compound, or a combination thereof. -76 - Amended sheet: 2 June 2006