[0001] This application claims benefit of and priority to US Patent Application No. 13/798,394 filed March 13, 2013.

[0002] The foregoing applications, and all documents cited therein or during their prosecution ("appln cited documents") and all documents cited or referenced in the appin cited documents, and all documents cited or referenced herein (" ^' herein cited documents"), and ail documents cited or referenced in herein cited documents, together with any manufacturer's instructions, descriptions, product specifications, and product sheets for any products mentioned herein or in any document incorporated by reference herein, are hereby incorporated herein by reference, and may be employed in the practice of the invention. More specifically, all referenced documents are incorporated by reference to the same extent as if each individual document was specifically and individually indicated to be incorporated by reference.

FIELD OF THE INVENTION

[0003] The invention is directed to compounds of formula (I):

(I),

and to pharmaceutical compositions comprising the compounds. The compounds and compositions disclosed herein protect against calcium- and oxidative-stress mediated damage to mitochondrial function and are useful for the treatment of degenerative diseases and disord ers.

[0004] All documents cited or relied upon below are expressly incorporated herein by reference.

BACKGROUND OF THE INVENTION

[0005] Mitochondri $. 3XC CC llular organelles present in most eukaryotic cells. One of their primary functions is oxidative phosphorylation, a process through which energy derived from metabolism of fuels like glucose or fatty acids is converted to ATP, which is then used to drive various energy-requiring biosynthetic reactions and other metabolic activities. Mitochondria have their own genomes, separate from nuclear DNA, comprising rings of DNA with about 16,000 base pairs in human cells. Each mitochondrion may have multiple copies of its genome, and individual cells may have hundreds of mitochondria. In addition to supplying cellular energy, mitochondria are involved in a range of other processes, such as signaling, cellular differentiation, cell death, as well as the control of the cel l cycle and cell growth (McBride et a!., Curr. Biol, 2006, 16 (14): R551).

[0006] As mitochondria produce ATP, they simultaneously yield reactive oxygen species (ROS), which are harmful free radicals that circulate throughout the cell, the mitochondria, and the body, causing more damage. The circulation of ROS leads to the activation of reactive nitrogen compounds, which in turn induce, or activate, genes in the DNA that are associated with many degenerative diseases. The DNA for each mitochondrion (mtDNA) remains unprotected within the membrane of the mitochondrion itself. In comparison to the DNA in the nucleus of the ceil (iiDNA), mtDNA is easily damaged by free radicals and the ROS that it produces. Freely floating mtDNA lacks protective measures associated with nD ^' NA, and therefore suffers from multiple mutations. It has been estimated that the lack of protective measures results in mutations to mtDN A occurring 10 to 20 times more frequently than mutations to iiDNA.

[0ΘΘ7] Mitochondrial damage and/or dysfunction contribute to various disease states. Some diseases are due to mutations or deletions in the mitochondrial genome. Mitochondria divide and proliferate with a faster turnover rate than their host cells, and their replication is under control of the nuclear genome. If a threshold proportion of mitochondria in a ceil is defective, and if a threshold proportion of such cells within a tissue have defective mitochondria, symptoms of tissue or organ dysfunction can result. Practically any tissue can be affected, and a large variety of symptoms can be present, depending on the extent to which different tissues are involved.

[0008] A fertilized ovum might contain both normal and genetical ly defective mitochondria.

The segregation of defective mitochondria into different tissues during division of this ovum is a stochastic process, as will be the ratio of defective to normal mitochondria within a given tissue or cell (although there can be positive or negative selection for defective mitochondrial genomes during mitochondrial turnover within cells). Thus, a variety of different pathologic phenotypes

9 can emerge out of a particular point mutation in mitochondrial DNA. Conversely, similar phenotypes can emerge from mutations or deletions affecting different genes within mitochondrial DNA. Clinical symptoms in congenital mitochondrial diseases often manifest in postmitotic tissues with high energy demands like brain, muscle, optic nerve, and myocardium, but other tissues including endocrine glands, liver, gastrointestinal tract, kidney, and hematopoietic tissue are also involved, again depending in part on the segregation of mitochondria during development, and on the dynamics of mitochondrial turnover over time.

[0Θ09] In addition to congenital disorders involving inherited defective mitochondria, acquired mitochondrial damage and/or dysfunction contribute to diseases, particularly neurodegenerative disorders associated with aging like Parkinson's, Alzheimer's, Huntington's Diseases. The incidence of somatic mutations in mitochondrial DNA rises exponentially with age; and diminished respiratory chain activity is found universally in aging people. Mitochondrial dysfunction is also implicated in excitotoxic neuronal injury, such as that associated with seizures or ischemia.

[0010] Other pathologies with etiology involving mitochondrial damage and/or dysfunction include schizophrenia, bipolar disorder, dementia, epilepsy, stroke, cardiovascular disease, retinal degenerative disease (e.g., age-related macular degeneration, Stargardt's disease, glaucoma, retinitis pigmentosa, and optic nerve degeneration), and diabetes meilitus. A common thread thought to link these seemingly-unrelated conditions is cellular damage causing oxidative stress. Oxidative stress is caused by an imbalance between the production of reactive oxygen and a biological system's ability to readily detoxify the reactive intermediates or easily repair the resulting damage. All forms of life maintain a reducing environment within their ceils. This reducing environment is preserved by enzymes that maintain the reduced state through a constant input of metabolic energy. Disturbances in this normal redox state can cause toxic effects through the production of peroxides and free radicals that damage all components of the cell, including proteins, lipids, and DNA.

[001 ί J Mitochondrial damage and/or dysfunction particularly contribute to degenerative disesaes. Degenerative diseases are diseases in which the function or structure of the affected tissues or organs will progressively deteriorate over time. Some examples of degenerative diseases are retinal degenerative disease, e.g., age-related macular degeneration, Stargardt's disease, glaucoma, retinitis pigmentosa, and optic nerve degeneration; amyotrophic lateral sclerosis (ALS), e.g., Lou Gehrig's Disease; Alzheimer's disease; Parkinson's Disease; multiple system atrophy; Niemann Pick disease; atherosclerosis; progressive supranuclear palsy; cancer; Tay-Saehs disease; diabetes; heart disease; keratoconus; inflammatory bowel disease (IBD); prostatitis; osteoarthritis; osteoporosis; rheumatoid arthritis; and Huntington's disease.

[0012] Treatment of degenerative diseases involving mitochondrial damage and/or dysfunction has heretofore involved administration of vitamins and cofactors used by particular elements of the mitochondrial respirator)' chain. Coenzyme Q (ubiquinone), nicotinamide, riboflavin, carnitine, bioti , and lipoic acid are used in patients with occasional benefit, especially in disorders directly stemming from primary deficiencies of one of these cofactors. However, while useful in isolated cases, no such metabolic cofactors or vitamins have been shown to have general utility in clinical practice in treating degenerative diseases involving mitochondrial damage and/or dysfunction.

[0013] Therefore, a need exists for new drug therapies for the treatment of subjects suffering from or susceptible to the above disorders or conditions associated with mitochondrial damage and/or dysfunction. In particular, a need exists for new drugs having one or more improved properties (such as safety profile, efficacy or physical properties) relative to those currently available.

SUMMARY OF THE INVENTION [0014] The present invention is directed to compounds of formula I:

wherein;

Ri is lower alkyl, trimethylsilyl or pyridinyl;

one of R.2 or R ₂ - is absent and the other is -CH2R3 or -CH ₂ C(0)R.3; and

Rj is pyridinyl, l H-indol-3-yl, unsubstituted phenyl or phenyl mono-, bi- or tri- substituted independently with aikoxy, or a pharmaceutically acceptable salt thereof.

[0015] The present invention is also directed to pharmaceutical compositions containing the above compounds, method of using the compounds and to methods of treating degenerative diseases and disorders.

[0016] Accordingly, it is an object of the invention to not encompass within the invention any previously known product, process of making the product, or method of using the product such that Applicants reserve the right and hereby disclose a disciaimer of any previously known product, process, or method. It is further noted that the invention does not intend to encompass within the scope of the invention any product, process, or making of the product or method of using the product, which does not meet the written description and enablement requirements of the USPTO (35 U.S.C. § 112, first paragraph) or the EPO (Article 83 of the EPC), such that Applicants reserve the right and hereby disclose a disciaimer of any previously described product, process of making the product, or method of using the product.

[0017] it is noted that in this disclosure and particularly in the claims and/or paragraphs, terms such as "comprises", "comprised", "comprising" and the like can have the meaning attributed to it in U.S. Patent law; e.g., they can mean "includes", "included", "including", and the like; and that terms such as "consisting essentially of and "consists essentially of have the meaning ascribed to them in U.S. Patent law, e.g., they allow for elements not explicitly recited, but exclude elements that are found in the prior art or that affect a basic or novel characteristic of the invention.

[0018] These and other embodiments are disclosed or are obvious from and encompassed by, the following Detailed Description.

DETAILED DESCRIPTION OF THE INVENTION

[0019] It is to be understood that the terminology employed herein is for the purpose of describing particular embodiments, and is not intended to be limiting. Further, although any methods, devices and materials similar or equivalent to those described herein can be used in the practice or testing of the invention, the preferred methods, devices and materials are now described. [0020] As used herein, the term "alkyl", alone or in combination with other groups, refers to a branched or straight-chain monovalent saturated aliphatic hydrocarbon radical of one to twenty carbon atoms, preferably one to sixteen carbon atoms, more preferably one to ten carbon atoms.

[0021 J As used herein, the term "alkenyl", alone or in combination with other groups, refers to a straight-chain or branched hydrocarbon residue having an olefinic bond.

[0022] The term ''cyeloalkyl" refers to a monovalent mono- or poiycarbocyclic radical of three to ten, pref erably three to six carbon atoms. This term is further exemplified by radicals such as cyclopropyi, cyclobutyi, cyciopentyl, cyclohexyl, cycloheptyl, norbomyl, adamantyi, indanyl and the like. In a preferred embodiment, the "cyeloalkyl" moieties can optionally be substituted with one, two, three or four substituents. Each substituent can independently be, alkyl, alkoxy, halogen, amino, hydroxy! or oxygen unless otherwise specifically indicated. Examples of cyeloalkyl moieties include, but are not limited to, optionally substituted cyclopropyi, optionally substituted cyclobutyi, optionally substituted cyciopentyl, optionally substituted cyclopentenyl, optionally substituted cyclohexyl, optionally substituted cyclohexylene, optionally substituted cycloheptyl, and the like or those which are specifically exemplified herein.

[0023] The term "heterocycloaikyl" denotes a mono- or polycyclic alkyl ring, wherein one, two or three of the carbon ring atoms is replaced by a heteroatom such as N, O or S. Examples of heterocycloaikyl groups include, but are not limited to, morpholinyl, thiomorpholinyl, piperazinyl, piperidmyl, pyrrolidinyl, tetrahydropyranyl, tetrahydrofuranyl, 1 ,3-dioxanyl and the like. The heterocycloaikyl groups may be unsubstituted or substituted and attachment may be through their carbon frame or through their heteroatom(s) where appropriate.

[0024] The term 'lower alley! ", alone or in combination with other groups, refers to a branched or straight-chain alkyl radical of one to nine carbon atoms, preferably one to six carbon atoms, more preferably one to four carbon atoms. This term is further exemplified by radicals such as methyl, ethyl, n-propyl, isopropyl, n-butyl, s-butyl, isobutyl, t-butyl, n-pentyl, 3- methylbutyl, n-hexyl, 2-eth.ylbutyl and the like.

[0025] The term "aryi" refers to an aromatic mono- or poiycarbocyclic radical of 6 to 12 carbon atoms having at least one aromatic ring. Examples of such groups include, but are not limited to, phenyl, naphthyl, 1 ,2,3,4-tetrahydronaphthalene, 1 ,2-dihydronaphthalene, indanyl, IH-indenyl and the like, [0026] The alkyl, lower aikyl and aryl groups may be substituted or unsubstituted. When substituted, there will generally be, for example, 1 to 4 substituents present. These substituents may optionally form a ring with the alkyl, lower alkyl or aryl group with which they are connected. Substituents may include, for example: carbon-containing groups such as alkyl, aryl, arylalkyi (e.g. substituted and unsubstituted phenyl, substituted and unsubstituted benzyl); halogen atoms and halogen-containing groups such as haloaikyi (e.g. trifluoromethyl); oxygen- containing groups such as alcohols (e.g. hydroxyl, hydroxyalkyl aryl(hydroxyl)alkyl), ethers (e.g. alkoxy, aryloxy, aikoxyaikyi, aryloxyaikyi, more preferably, for example, methoxy and ethoxy), aldehydes (e.g. carboxaldehyde), ketones (e.g. alkylcarbonyl, alkylcarbonylalkyl, aryicarbonyl, aryialkylcarbonyl, arycarbonyl alkyl), acids (e.g. carboxy, carboxyaikyi), acid derivatives such as esters (e.g. alkoxyearbonyl, alkoxycarbonylalkyl, alkylearbonyloxy, alkylcarbonyloxyaikyi), amides (e.g. aminocarbonyi, mono- or di-alkylaminocarbonyi, aminocarbonylalkyl, mono- or di-alkyiaminocarbonylaikyi, aryiaminocarbonyl), carbamates (e.g. alkoxycarbonylamino, atyloxycarbonylaniino, aminocarbonyloxy, mono- or di- alkylaminocarbonyloxy, arylminocarbonloxy) and ureas (e.g. mono- or di- aikyiammoearbonylaniino or arylaminocarbonjd amino); nitrogen-containing groups such as amines (e.g. amino, mono- or di-alkylamino, aminoalkyl, mono- or di-alkylaminoalkyl), azides, nitriles (e.g. cyano, cyanoalkyl), nitro; sulfur-containing groups such as thiols, thioethers, sulfoxides and sulfones (e.g. alkylthio, alkylsulfinyl, alkylsuifonyl, alkylthioalkyl, alkylsultinylalkyl, alkylsulfonylalkyl, ai lthio, arysulfinyl, arysulfonyl, arythioalkyl, aryisulfinylalkyl, arylsulfonylalkyl); and heterocyclic groups containing one or more heteroatoms, (e.g. thienyl, furanyl, pyrroiyi, imidazolyl, pyrazolyl, thiazolyi, isothiazoiyl, oxazolyl, oxadiazolyl, thiadiazolyl, aziridinyl, azetidinyi, pyrrolidinyi, pyrrolinyl, imidazolidinyl, imidazolinyl, pyrazoiidinyl, tetrahydrofuranyi, pyranyl, pyronyl, pyridyi, pyrazinyl, pyridazinyl, piperidyl, hexahydroazepinyl, piperazinyl, morpholinyl, thianaphthyl, benzofuranyl, isobenzofuranyl, indolyi, isoindolyl, indazoiyl, indolinyl, 7-azaindolyi, benzopyranyl, coumarinyl, isocoumarinyl, quinolinyl, isoquinolmyl, naphthridinyl, cinnolinyl, quinazolinyl, pyridopyTidyl, benzoxazinyl, quinoxalinyl, chromenyl, chromanyl, isochromanyl, phthaiazinyl and carboiinyl).

[0027] The term "heteroaryi," refers to an aromatic mono- or polycyclic radical of 5 to 12 atoms having at least one aromatic ring containing one, two, or three ring heteroatoms selected from N, O, and 8, with the remaining ring atoms being C. One or two ring carbon atoms of the heteroaryl group may be replaced with a carbonyl group.

[0028] The heteroaryl group described above may be substituted independently with one, two, or three substituents. Substituents may include, for example: carbon-containing groups such as alkyi, aryl, arylalkyl (e.g. substituted and unsubstituted phenyl, substituted and unsubstituted benzyl); halogen atoms and halogen-containing groups such as haloaikyi (e.g. trifluoromethyl); oxygen-containing groups such as alcohols (e.g. hydroxy [, hydroxyalkyl, aryl(hydroxyl)alkyl), ethers (e.g. alkoxy, aryloxy, alkoxyalkyl, aryloxyalkyl), aldehydes (e.g. carboxaldehyde), ketones (e.g. alkylcarbonyl, alkylcarbonylalkyl, arylearbonyl, arylalkyl carbonyl, arycarbonylalkyl), acids (e.g. carboxy, carboxyalkyl), acid derivatives such as esters (e.g. alkoxycarbonyl, alkoxycarbonylalkyl, alkylcarbonyloxy, alkylcarbonyloxyalkyl), amides (e.g. aminocarbonyl, mono- or di-alkylaminocarbonyi, aminocarbonylalkyl, mono- or di- alkylaminocarbonylalkyl, aryiaminocarboiiyi), carbamates (e.g. alkoxycarbonylamino, aryloxycarbonylamino, aminocarbonyloxy, mono- or di-alkylaminocarbonyloxy, arylminocarbonloxy) and ureas (e.g. mono- or di- alkylaminocarbonylammo or aryl aminocarbonyiamino); nitrogen-containing groups such as amines (e.g. amino, mono- or di- alkylamino, aminoalkyl, mono- or di-alkylammoalkyl), azides, nitriles (e.g. cyano, cyanoaikyl), nitro; sulfur-containing groups such as thiols, thioethers, sulfoxides and sulfones (e.g. alkyltbio, alkylsulfinyl, alkylsuifonyl, aikylthioalkyl, aikylsulfinyialkyi, alkylsulfonylalkyl, arylthio, arysulfinyl, arysulfonyl, arythioalkyl, arylsulfmylaikyl, arylsulfonyialkyl); and heterocyclic groups containing one or more heteroatoms, (e.g. thienyl, furanyi, pyrrolyl, imidazolyl, pyrazoivl, tliiazolyi, isotiiiazolyl, oxazolyi, oxadiazoivl, thiadiazolvl, aziridinyl, azetidinyi, pyrrolidinyl, pyrrolinyl, imidazolidinyl, imidazolinyl, pyrazolidinyl, tetrahydrofuranyl, pyranyl, pyronyl, pyridyi, pyrazinyi, pyridazinyl, piperidyl, hexahydroazepmyl, piperazmyl, morpholinyl, thianaphthyl, benzofuranyl, isobenzofuranyl, indolyl, oxyi.ndol.yl, isoindolyl, indazolyl, indoiinyl, 7-azaindolyi, benzopyranyl, coumarinyl, isocoumarinyl, quinoiinyl, isoquinolinyl, naphthridinyi, cirmolinyl, quinazolinyl, pyridopyridyl, benzoxazinyl, quinoxalinyl, chromenyl, chromanyl, isochromanyl, phthalazinyl, benzothiazoyl and carbolinyi).

[0Θ29] As used herein, the term "alkoxy" means a kyl-O-; and "alkoyl" means alkyl-CO— . Alkoxy substituent groups or alkoxy-containing substituent groups may be substituted by, for example, one or more alkyl groups. [0030] As used herein, the term "halogen" means a fluorine, chlorine, bromine or iodine radical, preferably a fluorine, chlorine or bromine radical, and more preferably a bromine or chlorine radical.

[0031 J Compounds of formula I can have one or more asymmetric carbon atoms and can exist in the form of optical!)' pure enantiomers, mixtures of enantiomers such as, for example, racemates, optically pure diastereoisomers, mixtures of diastereoisomers, diastereoisomeric racemates or mixtures of diastereoisomeric racemates. The optically active forms can be obtained for example by resolution of the racemates, by asymmetric synthesis or asymmetric chromatography (chromatography with a ehiral adsorbents or eluant). The invention embraces all of these forms.

[0032] As used herein, the term "pharmaceutically acceptable salt" means any pharmaceutically acceptable salt of the compound of formula (I). Salts may be prepared from pharmaceutically acceptable non-toxic acids and bases including inorganic and organic acids and bases. Such acids include, for example, acetic, benzenes lfonic, benzoic, camphorsulfonic, citric, ethenesuifonic, dichloroacetic, formic, fumaric, gluconic, glutamic, hippuric, hydrobromic, hydrochloric, isethionic, lactic, maieic, malic, mandeiic, niethanesulfonic, mucic, nitric, oxalic, pamoic, pantothenic, phosphoric, succinic, sulfuric, tartaric, oxalic, p-toluenesulfonic and the like. Particularly preferred are fumaric, hydrochloric, hydrobromic, phosphoric, succinic, sulfuric and niethanesulfonic acids. Acceptable base salts include alkali metal (e.g. sodium, potassium), alkaline earth metal (e.g. calcium, magnesium) and aluminum salts.

[ 0033] in one embodiment of the invention, provided is a compound of formula (I):

wherein:

Ri is lower alkyl, trimethylsilyl or pyridinyl ;

one of R ₂ or R ₂ - is absent and the other is -CH ₂ R.3 or -CH ₂ C(0)R3; and

R ₃ is pyridinyl, l.H-indol-3-yl, unsubstituted phenyl or phenyl mono

substituted independently with alkoxy, or a pharmaceutically acceptable salt thereof.

[0034] In another embodiment of the invention, provided is a compound according to formula (I), wherein Ri is lower alkyl.

[0035] In another embodiment of the invention, provided is a compound according to formula (Γ), wherein i is trimethylsilyl.

[0036] In another embodiment of the invention, provided is a compound according to formula (I), wherein Ri is pyridinyl.

[0037] In another embodiment of the invention, provided is a compound according to formula (I), wherein one of R ₂ or R ₂ - is absent and the other is -CH ₂ R ₃ .

[0038] In another embodiment of the invention, provided is a compound according to formula (I), wherein one of R? or R ₂ - is absent and the other is -CH ₂ C(0)R. ₃ .

[0039] In another embodiment of the invention, provided is a compound according to formula (I), wherein R ₃ is pyridinyl.

[0040] in another embodiment of the invention, provided is a compound according to formula (I), wherein R ₃ is lH-iiidol-3-yi.

[0041] in another embodiment of the invention, provided is a compound according to formula (I), wherein R ₃ is phenyl mono-substituted with methoxy.

[0042] In another embodiment of the invention, provided is a compound according to formula (I), wherein R ₃ is phenyl bi-substituted with methoxy.

[0043] In another embodiment of the invention, provided is a compound according to formula (I), wherein R is phenyl tri-substituted with methoxy.

[0044] In another embodiment of the invention, provided is a compound according to formula (I), wherein R ₂ is absent, R ₂ - is -CH ₂ C(0)R ₃ and R ₃ is phenyl bi-substituted with methoxy.

[0045] In another embodiment of the invention, provided is a compound according to formula (I), wherem Ri is lower alkyl, R ₂ is lower alkyl, one of R ₂ or R ' is absent and the other is -CH ₂ R ₃ , or -CH ₂ C(0) and R ₃ is pyridinyl or l H-mdol-3-yl.

[0046] in another embodiment of the invention, provided is a compound according to formula (I), wherein Rj is trimethylsilyl, R ₂ is lower alkyl, one of R ₂ or R ₂ ' is absent and the other is ~-CH ₂ R ₃ , or --CH ₂ C(0)R ₃ and R ₃ is pyri.dinyl or 1 H-indol-3-yl. [0047] In another embodiment of the mvention, provided is a compound according to formula (I), wherein Ri is pyridinyi, R ₂ is lower alkyl, one of R ₂ or R ₂ ^' is absent and the other is -CH ₂ R ₃ , or ( Ί !;( ^' ( () ;·!< ;. and R ₃ is pyridinyi or lH-indol-3-yl.

[0048] In another embodiment of the invention, provided is a compound according to formula (Ϊ), wherein Ri is lower alkyl, R ₂ is lower alkyl, one of R. ₂ or R ₂ ^' is absent and the other is -CH2R3, or -CH ₂ C(0)R ₃ , and R3 is substituted or unsubstituted phenyl.

[0049] In another embodiment of the invention, provided is a compound according to formula (I), wherein R _} is trimethylsiiyi, R ₂ is lower alkyl, one of R ₂ or R ₂ ^' is absent and the other is -CH ₂ R. ₃ , or -CfI ₂ C(0)R. ₃ , and R. ₃ is substituted or unsubstituted phenyl.

[0050] In another embodiment of the mvention, provided is a compound according to formula (I), wherein j is pyridinyi, R ₂ is lower alkyl, one of R ₂ or R ₂ ^' is absent and the other is -CH ₂ R ₃ , or ( Ί !;( ^' ( () ;·!< ;. and R ₃ is substituted or unsubstituted phenyl.

[0Θ51] In another embodiment of the invention, provided is a compound according to formula (Γ), wherein the compound is:

Emyl-l-(2-(2,4-dimethoxyphenyl)-2-oxoethyl)-3-(pyridm-2-yl)- lH-pyrazole-5- carboxylate;

Ethyl- 1 -(2-(2 ,4-dimethoxyp henyl)-2-oxoethyl)-5 -(pyridin-2-yl .)- 1 H-pyrazole-3 - carboxylate;

Ethyl- 1 -(2-(2,5-dimethoxyphenyl)-2-oxoethy[)-3-(pyridm-3-yl)- lH-pyrazole-5- carboxylate;

Ethyl- 1 -(2-(2,4-dimethoxyphenyl)-2-oxoethyl)-3-(trimethylsi lyl)~ lH-pyrazole-5- carboxylate;

Ethyl- l -(2-(2,5-dimethoxyphenyl)-2-oxoethyi)-3-(trimethylsilyl)-l H-pyrazole-5- carboxylate;

Ethyl 3-(pyridm~2- !)- 1 -(pyridin-3-yImethyi)- l/f-pyrazole-5-carboxylate; Ethyl 1 -(3,4,5-trimethoxybenzyl)-3-(trimethylsilyl)- lH-pyrazole-5-earboxylate;

Ethyl- ] -(2-(2,4-dimethoxyphenyl)-2-oxoethyi)-3-(pyridin-3-yl)- lH-pyrazole-5- carboxylate;

Ethyl l-(2-oxo-2-(pyridin-3-yl)ethyl)-5-(1iimethylsilyl)-lH-pyrazo le-3-carboxylate; Ethyl l -(2-oxo-2-(pyridin-3-yi)ethyl)-3-(trimethyisiiyl)-lH-pyrazol e-5-carboxylate; Ethyl- 1 -(2-(2,5-dimethoxyphenyl)-2-oxoethyl)-3-(pyridm-2-yl)- lH-pyrazole-5- earboxylate; or

Ethyl l -((lH-mdol-3-yl)methyl)-3-isopropyl-lH-pyrazole-5-carboxylat e.

[0052] In a further embodiment of the invention, provided is a pharmaceutical composition, comprising a therapeutically effective amount of a compound according to formula (I) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier,

[0053] in a further embodiment of the invention, provided is a method for treating a degenerative disease or disorder, comprising the step of administering a therapeutically effective amount of a compound according to formula (I) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier to a patient in need thereof. The degenerative diseases and disorders include, for example, retinitis pigmentosa.

[0054] In another embodiment of the mvention, provided is a method of treating a retinal degenerative disease in a subject in need thereof, comprising administering to said subject a therapeutically effective amount of a compound or a pharmaceutically acceptable salt thereof according to formula (I).

[0055] In a yet further embodiment of the invention, provided is a method for preventing calcium-induced or oxidant-induced mitochondrial damage preventing or loss of mitochondrial respiratory capacity in a cell susceptible thereof wherein the calcium-induced or oxidant-induced mitochondrial damage or loss of mitochondrial respiratory capacity comprises excess of cGMP that increases the number of cGMP-gated cation channels in an open configuration, allowing an influx of Ca2+ into the cell, said method comprising contacting the cell with an effective amount of a compound or a pharmaceutically acceptable salt thereof according to formula (I),

[0056] In the practice of the method of the present invention, an effective amount of any one of the compounds of this invention or a combination of any of the compoimds of this invention or a pharmaceu tically acceptable salt thereof, is administered via any of the usual and acceptabl e methods known in the art, either singly or in combination. The compounds or compositions can thus be administered, for example, ocularly, orally (e.g., buccal cavity), sublingually, parenterally (e.g., intramuscularly, intravenously, or subcutaneously), rectally (e.g., by suppositories or washings), transdermaily (e.g., skin electroporation) or by inhalation (e.g., by aerosol), and in the form or solid, liquid or gaseous dosages, including tablets and suspensions. The administration can be conducted in a single unit dosage form with continuous therapy or in a single dose therapy ad libitum. The therapeutic composition can also be in the form of an oil emulsion or dispersion in conjunction with a lipophilic salt such as pamoic acid, or in the form of a biodegradable sustained-release composition for subcutaneous or intramuscular administration.

[0057] Useful pharmaceutical carriers for the preparation of the compositions hereof, can be solids, liquids or gases. Thus, the compositions can take the form of tablets, pills, capsules, suppositories, powders, enterically coated or other protected formulations (e.g. binding on ion- exchange resins or packaging in lipid-protein vesicles), sustained release formulations, solutions, suspensions, elixirs, aerosols, and the like. The carrier can be selected from the various oils including those of petroleum, animal, vegetable or synthetic origin, e.g., peanut oil, soybean oil, mineral oil, sesame oil, and the like. Water, saline, aqueous dextrose, and glycols are preferred liquid carriers, particularly (when isotonic with the blood) for injectable solutions. For example, formulations for intravenous administration comprise sterile aqueous solutions of the active ingredient(s) which are prepared by dissolving solid active ingredient(s) in water to produce an aqueous soiution, and rendering the solution sterile. Suitable pharmaceutical excipients include starch, cellulose, talc, glucose, lactose, talc, gelatin, malt, rice, flour, chalk, silica, magnesium stearate, sodium stearate, glycerol monostearate, sodium chloride, dried skim milk, glycerol, propylene glycol, water, ethanol, and the like. The compositions may be subjected to conventional pharmaceutical additives such as preservatives, stabilizing agents, wetting or emulsifying agents, salts for adjusting osmotic pressure, buffers and the like. Suitable pharmaceutical carriers and their formulation are described in Remington's Pharmaceutical Sciences by E. W. Martin. Such compositions will, in any event, contain an effective amount of the active compound together with a suitable carrier so as to prepare the proper dosage form for proper administration to the recipient.

[0Θ58] The dose of a compound of the present invention depends on a number of factors, such as, for example, the manner of administration, the age and the body weight of the subject, and the condition of the subject to be treated, and ultimately will be decided by the attending physician or veterinarian. Such an amount of the active compound as determined by the attending physician or veterinarian is referred to herein, and in the claims, as a "therapeutically effective amount". For example, the dose of a compound of the present invention is typically in the range of about 1 to about 1000 mg per day. Preferably, the therapeutically effective amount is in an amount of from about 1 mg to about 500 mg per day. [0059] It will be appreciated, that the compounds of general formula I in this invention may be derivatized at functional groups to provide derivatives which are capable of conversion back to the parent compound in vivo. Physiologically acceptable and metaboiically labile derivatives, which are capable of producing the parent compounds of general formula ] in vivo are also within the scope of this invention.

[0060] Compounds of the present invention can be prepared beginning with commercially available starting materials and utilizing general synthetic techniques and procedures known to those skilled in the art. Chemicals may be purchased from companies such as for example Aldrich, Argonaut Technologies, VWR and Lancaster. Chromatography supplies and equipment may be purchased from such companies as for example AnaLogix, Inc, Burlington, Wis.; Biotage AB, Charlottesville, Va.; Analytical Sales and Sendees, Inc., Pompton Plains, N.J.; Teledyne Isco, Lincoln, Nebr.; VWR International, Bridgeport, N.J.; Varian Inc., Palo Alto, Calif, and Multigram II Mettler Toledo Instrument Newark, Del. Biotage, ISCO and Analogix columns are pre-packed silica gel columns used in standard chromatography,

[0061] The compounds of formula I can be prepared according to the following scheme:

Scheme 1

[0062] As seen in Scheme 1, compounds of formula I and II (collectively "formula (I)") may be made using intermediate i. Intermediate i may be made from reacting an acetylene where Rj can be, for example, aryl, phenyl, 2-pyridyl, or 3-pyridyl, methyl, tert-butyl, trim ethyl, silyl, trialkyl silyl, dialkylphenylsilyl, diphenylalkylsilyl, or triphenylsilyl with the appropriately commercially available diazoethyl acetate (purchased from Aldrich) at the appropriate temperature (such as 95 °C) for the appropriate time (such as 24 hours) (Cheung, K.M.J. ; Reynissoii, J.; McDonald, E. Tetrahedron Lett. 2010, 51 5915 - 5918). Formation of compounds of formula Ϊ may then be made by reacting intermediates of formula i with a base such as LiHMDS, KHMDS, NaHMDS, LDA, BuLi, t-BuMgCl, any alkyl lithium, any aryl lithium, any alkyl Grignard, or any aryl Gri guard, that may or may not be in the presence of 18~crow ^r n-6, or compounds analogous thereto, in a solvent such as DMF, THF, or 1,4 dioxane at the appropriate temperature with any commercially available R ₂ ~X to afford compounds of formulation I or I I as either a mixture, or exclusive. R ₂ and R ₂ >, independently of each other, may be, for example, benzyl, aryl, aryl keto, 2,4-dimethoxvphenyl)~2-oxoethyl, (2,5-d.imethoxyphenyl)-2-oxoeth.yl, pyridrn-3-yimethyl, 3,4,5-trimethoxybenzyl, 2-oxo-2-(pyridm-3-yl)ethyl, -(lH-indol-3- yi)methyl. X may be any halogen such as chlorine, bromine, or iodine.

[0063] The invention will now be further described in the Examples below, which are intended as an illustration only and do not limit the scope of the invention.

Examples

/. Preparation of Certain Intermediates of the Invention

ihyi 3-(innicthylsllyl )- i //-pyra ulc-5- ar[x¾xyiatc

[0064] To a flame dried sealed tube equipped with a stir bar that was cooled under argon was added trimethylsilylacetylene (l .OmL, 9.56 mmol) and ethyldiazoacetate (1.5 mL, 9.6 mmol). The tube was then sealed and heated to 95 °C over night. The next day the reaction was cooled to room temperature and the resulting mixture diluted with hexanes. it was then filtered. The precipitate was then washed with hexanes twice. It was then used without any further purification.

Ethyl 3-(pyridm-2-yl)- lH-pyrazole-5-carboxylate

[0Θ65] Was prepared in a similar way as ethyl 3-(trimethylsilyl)-IH-pyrazole-5-carboxylate using diazoethyl acetate (Purchased from Aldrich) and 2-ethynyl -pyridine (Purchased from Aldrich). Ethyl 3-(p>Tidm-3-yl)-lH-pyrazole-5-carboxylate

[0066] Was prepared in a similar way to ethyl 3-(tTimeth.yisilyl)-lH-pyrazole-5-carboxylate using diazoethyl acetate (Purchased from Aidrich) and 2-ethynyl-pyridine (Purchased from Aldrich)

I -Bcn/o i- 1 //-lndol-3-yl imcthvl bcn oaic

[0067] To an oven dried flask that cooled under argon was added the (lH-indol-3- yl)methanol (1.0 grams, 6.8 mmol, 0.1 M in dry dichloromethane, purchased from Fisher Scientific, stored over 4 angstrom molecular sieves) and DMAP (0.083 grams, 0.68 mmol). While stirring at 0°C, triethyl amine (2.0 mL, 14.3 mmol, purchased from Fisher Scientific) was added followed by benzoyl ch loride (0.96 mL, 8.2 mmol, purchased from Fisher Scientific). Once the reaction was complete it was diluted with water, and the organic layer removed. The aqueous layer was then washed with dichloromethane twice and the organic material combined. The organic material was dried with sodium sulfate, filtered, and concentrated. Purification using a Teledyne ISCO on silica support, (hexanes/ethyl acetate gradient) afforded the desired 1- benzoyl-lH-indol-3-yl)methyl benzoate . 42% yield. 1 H-NMR δ 8.42 (d, i l l ). 8.02 (dd, 2H), 7.76 (m, 3H), 7.62 (dd, i l l ), 7.54 (m, M l ⁾ . 7.47 - 7.37 (m, 5H), 5.50 (s, 2H).

Ethyl 3-isopropyl-1 H-pyrazole-5-carboxyiate [0068] To a clean round bottom flask equipped with a stir bar, Dean-Stark trap, and reflux condenser was added 3-isopropyl-l H-pyrazoie-5~carboxyIic acid (1 gram, 6.49 mmol, purchased from Fisher Scientific). 30 mL of ethanol (95%, purchased from Fisher Scientific) was added followed by 30 mL of benzene. 43 μ,Ε of acetyl chloride was then added and the solution reflux ed over the three days. The solvent was then removed using a Buehi rotoevaporator. The residue was then taken up in ethyl acetate and washed with NaHCOS (saturated). It was then dried with sodium sulfate, filtered and concentrated. Purification using a Teledyne ISCO silica chromatography (hexanes/ ethyl acetate gradient) afforded the desired ester. Yield, 85% 1H- NMR.5 6.7 (s, f i n, 5.1 (bs, N i l ). 4.41 (q, 2H), 3.13 (septet, ! M h 1 .38 (t, M l ⁾ . 1 .33 (d, 6H).

IL Preparation of Certain Embodiments of the invention

Examples 1 and 2

Ethyl l-(2-(2,4-dimethoxyplienyl)-2-oxoethyl)-3-(pyridin-2-yl)-l/ --pyrazoie-5- carboxylate and Ethyl l-(2-(2,4-dimethoxyphenyl.)-2-oxoethyl)-5-(pyridin-2-yl)-l.H - p yrazol.e-3 -carboxyl ate

[0069] To an oven dried flask equipped with a stir bar cooled under argon was added ethyl 3- (pyridin-2-yl)- lH-pyrazole-5-carboxylate (0.03 grams, 0.14 mmol, 0.1 M in 1 ,4 dioxane (anhydrous Sure Seal, purchased from Aldrich)). While stirring at room temperature, a solution of KHMDS (0.17 mL, 0.15 mmol, 0.87 M in toluene, purchased from Fisher Scientific) was added slowly. In a separate oven dried flask cooled under argon was added 2-bromo-l-(2,4- dim.ethoxyphenyl)ethanone (0.04 grams, 0.154 mmol, 0.1 M in 1 ,4 dioxane (anhydrous Sure Seal, purchased from Aldrich)).

[0070] After stirring for one hour at room temperature the solution of dimethoxyphenylethanone was added to the ethyl 3-(pyridin-2-yl)-lH-pyrazole-5-carboxylate and the reaction continued to stir at room temperature over night. The next day, the reaction was diluted with 0.1 M HCl and ethyl acetate. The organic material was extracted. The aqueous layer was salted out with sodium chloride and washed twice with ethyl acetate. The combined organic material was then dried with sodium sulfate, filtered and concentrated. Purification using a Teledyne ISCO on a silica support (hexanes, ethyl acetate gradient) affords the two regioisomers in a 1 : 1 ratio. Further purification can be done using a Teledyne ISCO C I 8 reverse phase column using water with 0.1% formic acid, acetonitrile gradient. Combined yield, 60%. l-(2-(2,4-dimethoxyphenyl)-2-oxoethyl)-3-( yridrn-2-yl)-lH-pyrazole-5-carboxylate 1.H-NMR δ

8.34 (ddd, lH), 7.81 (d, I B), 7.69 (m, 2H), 7.29 (s, 1H), 7.14 (m, 1H), 6.54 (dd, I H), 6.51 (d, 1H), 6.23 (s, 2H), 4.4 (q, 2H), 3.97 (s, 3H), 3.88 (s, 3H), 1.43 (t, 3H). calculated mass for C21 H21 N305, 395.15, observed, 396.2 (M + 1).

[0071] l -(2-(2,4-dimethoxyphenyl)-2-oxoethyl)-5-{pyridme-2-yl)-l H-pyrazole-3- carboxylate. 1H-NMR. δ 8.33 (dd, 1H), 7.81 (d, IH), 7.69 (m, 2H), 7.28 (s, 1H), 7.14 (t, 1H), 6.54 (dd . I I I ), 6.50 (d, I H), 6.22 (s, 2H), 4.44 (d, 2H), 3.96 (s, 3H), 3.88 (s, M l ⁾ . 1.42 (t, 3H). Calculated mass for C21H21N305, 395.15, observed, 418.1 (M + Na).

Example 3

Ethyl 1 -(2-(2,5-dimethoxyphenyl)-2-oxoethyl -3-(pyridin-3-yl)- 1 H-pyrazole-5- carboxylate

[0Θ72] To a flame dried flask equipped with a stirbar cooled under argon was added ethyl 3- (pyriditi-3-yl)-lH-pyrazole-5-carboxylate (0.02 grams, 0.092 mmol, 0.1 M in THF). While stirring at room temperature NaH (0.0055 grams, 1.8 mmol, 60% in mineral oil, purchase from Aldrich) was added. After fifteen minutes 2-bromo-l -(2,5-dimethoxyphenyl)ethanone (0.047 grams, 0.14 mmol, purchased from Aldrich) was added as a solid. The reaction was stirred overnight. The next day, the reaction was quenched with 0.1 M HCl and the organic material extracted using ethyl acetate. The aqueous layer was salted out using sodium chloride and washed twice with ethyl acetate. The combined organic material was then dried with sodium sulfate, filtered, and concentrated. Purification was done on preparative thin layer chromatography using hexanes/ethyl acetate (1 :2) to afford the desired compound. Yield, 10%. 1 H-NMR δ 9.07 (bs, 1 H), 8.58 (bs, 1H), 8.13 (d, 1 1 1 ). 7.47 (d, I H h 7.31 (bs, 1H), 7.29 (s, 1H), 7.14 (dd, 1H), 7.00 (d, H I ). 6.03 (s, 2H), 4.32 (q, 2H), 3.99 (s, 3H), 3.79 (s, M l ). 1.35 (t, 31 ! ) Calculated mass for C21 H21N305, 395.15, observed, 396.3 (M + 1 ).

Example 4

Ethyl l-(2-(2.,4-dimethox phenyl)-2-oxoethyl)-3-(trimetliylsilyl)-lH-pyrazoie-5- carboxylate

This compound was prepared in a similar method to ethyl l-(2-(2,5- dimethox phenyl)-2-oxoethyl)-3-(p idin-3-yl)-lH-p Tazole-5-carboxylate using ethyl 3- (trimethy[silyl)-lH-pyrazole-5-carboxylate and 2-bromo-l-(2,4-dimethoxyphenyl)ethanone (purchased from Aldrich). 1H-NMR δ 9.92 (d, 1H), 7.02 (s. l l f ). 6.57 (dd, 1H), 6.51 (d, 1H), 5.67 (s, 2i l 4.39 (quartet, 2H), 3.98 (s, M i l 3.89 (s, M i l 1.38 (t, 3H), 0.27 (s, 9H).

Example 5

Ethyl l-(2-(2,5-dimethoxyphmyl)-2-oxoethyl)-3-(trimethy

carboxylate

This compound was prepared in a similar method to ethyl l-(2-(2,5- dimethoxyphenyl)-2-oxoethy[)-3-(pyridm-3-yl)-lH-pyrazole-5-c arboxyiate using ethyl 3- (trimethylsilyl)-lH-pyrazole-5-carboxylate and 2-bromo-l-(2,5-dimethoxyphenyl)ethanone (Purchased from Aldrich). IH-NMR δ 7.40 (d, IH), 7.12 (dd,lH), 7.02 (dd, IH), 6.96 (d, IH), 5.72 (s, 2H), 4.40 (q, 2H), 3.96 (s, 3H), 3.78 (s, 3H), 1.39 (t, l ). 0.28 (s, 9H).

Exam.plle 6

Ethyl

[0075] To a flame dried flask equipped with a stir bar cooled under argon was added ethyl 3- (pyridin~3-yl)-I/f-pyrazole-5~carboxyiate (0.02 grams, 0.092 mmol), 3-bromo-methylene- pyridine-H Br (0.0466 grams, 0,18 mmol, purchased from Aldrich) and ImL of THF (anhydrous, Sure Seal purchased from Aldrich). While stirring at room temperature sodium hydride (0.011 grams, 0.28 mmol, 60% in mineral oil, purchased from Aldrich), was added and the reaction continued to stir over night at room temperature. The next day, the reaction was quenched with 0.1M HQ, and the organic material extracted using ethyl acetate. The aqueous layer was then salted out using sodium chloride, and washed twice with ethyl acetate. The combined organic material was then dried with sodium sulfate, filtered, and concentrated. Purification was done on preparative thin layer chromatography using hexanes/ethyl acetate (1 :2) to afford the desired compound. Yield, 9.4%. IH-NMR δ 8.67 (m, 2H), 8.56 (m, I H), 8.00 (d, IH), 7.80 - 7.72 (m, 2H), 7.56 (m, I H), 7.35 - 7.24 (m, 2H), 5.88 (s, 2H), 4.34 (q, 2FI), 1.36 (t, 3H).

Example 7

Ethyl l-(3,4,5-trimethoxybenzyl)-3-(trimethyisilyl)-lH-p Tazole--5-carboxylate

[0076] This compound was made in an analogous fashion to ethyl l-(2-(2,5- dimethoxyphenyi)-2-oxoet^ using ethyl 3-

(trimethylsilyl)-lH-pyrazole-5-carboxylate and 3,4,5-trimethoxy benzyl chloride (purchased from Aldrich), lH-NMR δ 6.98 (s, 1H), 6.21 (s, 2H), 5.44 (s, 2H), 4.41 (q, 2H), 3.81 (s, 3H), 3.76 (s, 6H), 1 .40 (t, 3H), 0.22 (s, 9). Calculated mass for C19H28N205Si, 392.18, observed, 393.0 (M + 1), 415.1 (M+Na).

Example 8

ihyi 1 -(2-(2.4Hiimcl iu)xyphcnvl )-2-ox<)C;hyi )- -(pyndisi- -yl )- l //-pyra/oic-5- carboxvlate

[0077] This compound was made in an analogous fashion to ethyl l-(2-(2,5- dimethoxyphenyl)-2-oxoethyl)-3-^yridin-3-yl)-lH-pyrazole-5- using ethyl 3-

(pyridin-3-yl)- lH-pyrazole-5-carboxyIate and 2-bromo- 1 -(2,4-dimethoxyphenyl)ethanone (purchased from Aldrich). 1H-NMR δ 9.08 (s, 8.58 (d. 1H), 8.14 (d, 1H), 8.00 (d. 1 1 1 ). 7.33 (m, H i ). 7.27 (s, ! i ! ). 6.58 (dd, I I I ), 6.49 (d, 1H), 5.98 (s, 2H), 4.31 (q, 2H), 4.00, (s, 3H), 3.88 (s, 3H), 1.34 (t, 3H). Calculated mass for C21H21N305, 395.15, observed, 396.2 (M + 1).

Example 9

Ethyl l -(2-oxo-2-(pvridin-3-vDethyl)-5-(^^

[0078] This compound was made in an analogous fashion to ethyl l-(2-(2,5- dimethoxyphenyl)-2-oxoethyl)-3-( yridin-3-yl)- lH-pyrazole-5-carboxylate using ethyl 3- (trimethylsilyi)-lH-pyrazole-5-carboxylate and 2-bromo-l -(pyridm-3-yl)ethanoiie- HBr (purchased from Aldrich). 1H-NMR δ 9.17 (d, IH), 8.88 (dd, IH), 8.24 (ddd, IH), 7.50 (td, I H), 7.03 (s, IH), 5.73 (s, 2H), 4.40 (q, 2H), 1 .39 (t, M i l 0.28 (s, 9H). Calculated mass for C16H21N303Si, 331.14, observed, 332.0 (M + 1 ).

Example 10

Ethyl l-(2-oxo-2-(pyridm-3-yl)ethyl)-3-(trimethylsilyl)-lH-pyrazol e-5-carboxylate

[0079] This compound was made in an analogous fashion to ethyl l -(2-(2,5- dimethoxyphenyl)-2-ox«el ^' hyl)-3-(pyri.dm-3-yl)-l.H-pyTazole-5-carbox.yiate using ethyl 3- (trimethy[silyl)-lH-pyrazoIe-5-carboxylate and 2-bromo-l -(pyridin-3-yl)ethanone-HBr

(purchased from Aldrich). 1H-NMR δ 9.20 (d, IH), 8.84 (dd, IH), 8.25 (dt, IH), 7.46 (dd, IH), 7.07 (s, 1 H), 6.05 (s, 2H), 4.26 (q, 2H), 1.31 (t, 3H), 0.32 (s, 9H). Calculated mass for C16H21N303Si, 331.14, observed. 332.0 (M + 1).

Example 11

carboxylate

[0080] This compound was made in an analogous fashion to ethyl l -(2-(2,5- dimethox phenyl)-2-oxoethyl)-3-(p idin-3-yl)-lH-p Tazole-5-carboxylate using ethyl 3-

(trimethyIsilyl)-lH-pyrazole-5-carboxylate and 2-bromo- 1 -(2,5-dimethoxyphenyi)ethanone

(purchased from Aldrich). lH-NMR δ 8.65 (dt, IH), 7.94 (d, IH), 7.72 (dd, IH), 7.57(s, I H),

7.47 (d, I H), 7.22 (dd, I I I ), 7.13 (dd, IH), 6.98 (s, I H), 6.05 (s, 2H), 4.28 (q, 2H), 3.98 (s, 3H),

3.78 (s, 3H), 1.33 (t, 3H). Calculated mass for C21H21 N305, 395.15, observed, 396.2 (M + 1). Example 12

Ethyl l-((lH-mdol-3-yl)methyl)-3-isopropyl-lH-pyrazole-5-carboxyla te

[0Θ81] To an oven dried flask cooled under argon equipped with a stir bar was added ethyl 3- isopropyl-.l H-pyrazoie-5-carboxylate (0.044 grams, 0.24 mmol, 0.1 in anhydrous 1,4 dioxane). While stirrmg at room temperature KHMDS (0.3 mL, 0.261 mmol, 0.87 M in toluene) was added. After stirrmg for 45 minutes, a solution of (l-benzoyl-lH~mdol~3-yi)methyl. benzoate (0.02 grams, 0.056 mmol, in l .OmL of anhydrous 1,4 dioxane) was added and the reaction mixture stirred over night. The next day, the reaction was quenched with 0.1M HC1 and the organic material extracted with ethyl acetate. The aqueous solution was then salted out using sodium chloride and washed twice with ethyl acetate. The combined organic material was then dried with sodium sulfate, filtered, and concentrated. Purification using a Teledyne ISCO chromatography on silica gel (hexanes/ethyl acetate gradient) followed by a Teledyne ISCO chromatography using CI 8 reverse phase (water with 0.1% formic acid, acetonitrile gradient) afforded the desired compound. Yield, 63%.1H NMR δ 8.29 fbs, IH), 7.58 (d, IH), 7.36 (d, I I f ). 7.20 (t, IH), 7.1 1 it. I I I ). 6.96 (s, IH), 6.62 (s, IH), 5.58 (s, 2H), 4.41 (q, 2H), 3.03 (m, IH), 1.39 (t, 31 Π. 1.16 (d, 6H). Calculated mass for C18H21N302, 31 1.16. Observed 334.1 (M-H).

Example 13

Biological Assays of Certain Compounds of the Invention

[0Θ82] The compounds of the invention were tested in various biological assays. The results of these assays indicated that the compounds of the invention ameliorated dysregulated bioenergetics and are, thus, useful for treatment of degenerative diseases and disorders, such as retinal damage. MTT Assay

[0Θ83] The compound 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) is a tetrazolium ion that is reduced to a blue formazan dye via several families of NAD(P)H- dependent oxidoreductases. Formation of the formazan dye from MTT or other related tetrazolium dyes are commonly used as a viability assay even though, in fact, the assay is a metabolic capacity assay. While it is true that dead cells cannot produce NAD(P)H, very sick cells in the throes of death can exhibit extremely high levels of metabolic capacity as they attempt to overcome stress and it is well known that the MTT and related assays report on the ability of cells to produce reducing equivalents, and not live-dead ratios (Sumantran 2011). As shown below, it was found that the MTT assay was a useful metabolic assay when linked to more specific bioenergetic assays.

[0084] In this assay, 661 W or C6 cells were maintained, in DMEM supplemented with 10% FBS. 100 iiL of 70,000 cells/mL cells were seeded into each w ^r ell of 96 well plates using DMEM supplemented with 5% FBS. Cells were then allowed to grow to confluency for 48 hours. The compounds of the invention were added in 2 μΐ, media and calcium-ionophore A23187 was then added in 1 μΐ. for a final concentration of 1 μΜ and after 24 h, 20 uL of 2 p.g/mL MTT were added to each well and the cells were incubated for another 4 h after which 100 uL of 1% SDS in 0.01 M aqueous HC1 were added to each well and the plates were incubated overnight, Absorbance was measured at 640 and 570 ti (background correction). The 1 μΜ ionophore A23187 caused about 50%s loss in MTT signal at 24 h. Protection was calculated as the increase in absorbance of treatment groups normalized to the vehicle control. As shown in Table 1 , the compounds of the invention gave significant protection at low concentrations:

Table ί

Uncoupled Oxygen Consumption Rate Assay

[0085] The XF FCCP-uncoupled oxygen consumption rate assay assesses mitochondrial capacity by measuring cellular respiration. It was shown that the maximum FCCP-uncoupled oxygen consumption rate (OCR) was a good estimate of maximal mitochondrial capacity (Beeson 2010) and that IBMX treatment of 661W or C6 cells for 24 h caused a loss in maximal uncoupled OCR (Perron 2013). Thus, cells were pretreated with the exemplified compounds for 1 h, added 600 μΜ IBMX and then measured the uncoupled rate after 24 h. The OCR measurements were performed using a Seahorse Bioscience XF instrument (Seahorse Bioscience, Billerica, MD), as previously pubiished (Perron 2013). 0 ₂ leakage through the plastic sides and bottom of the plate was accounted for using the AKOS algorithm in the XF software package. Ceils were plated on 96- or 24-well custom plates designed for use in the XF and grown to confluency in DMEM + 5 % FBS (48 h). The medium was then replaced with DMEM + 1% FBS for 24 h, along with any treatments. The IBMX treatment alone typically caused about a 50% decrease in the uncoupled rate and protection was calculated as the increase in absorbance of treatment groups normalized to the vehicle control. As shown in Table 2, below, the compounds of the invention gave significant protection in the concentration ranges that gave maximal protection in the MTT assay:

Table 2

Retinal Degeneration Assay

[0Θ86] The in vitro data demonstrated that the compounds of the invention mitigated oxidative- and calcium-induced loss of mitochondrial metabolic capacity. It was reasoned that the compounds' activities would enable them to protect against loss of photoreceptors in retinal degenerative animal models. As a translational bridge between the cell line-based assays and in vivo animal studies, mouse retina organ cultures were utilized. These retinal explants were a powerful ex vivo screening tool, which al lowed the testing of photoreceptor cell survival within the retinal network, and the effects of a specific compound were tested like in an in vitro system, without systemic interference. In this assay, the rdl mouse was utilized. The genotype of the rdl mouse has a mutation in the β-subunit of the phosphodiesterase gene. This mutation resulted in high levels of cGMP, leaving an increased number of the cGMP-gated channels in the open state, allowing intracellular calcium to rise to toxic levels and rapid rod degeneration.The genetic deficit and the retinal pathology were very similar to that observed in the patients with βΡΟΕ- dependent RP. In these mice, rod photoreceptor degeneration started after postnatal day 10 (PIO), progressing rapidly, such that at P2 1 , only 1 -2 rows of photoreceptor remained, mainly representing cones. Finally, the rdl mouse retina was amenable to culturhig, replicating both retinal development and degeneration, following the same time course as in vivo. The retinal explants were cultured for 1 1 days ex vivo. Explants were treated with compounds of the invention. Additives were replaced with fresh medium in every alternate day. At the end of the experiments, tissues were fixed, sectioned and stained with 0.1% toluidine and the numbers of rows of photoreceptors remaining in the outer nuclear layer (ONL) were counted. Rdl explants treated with vehicle only were found to contain 1.2 ± 0.19 cells in the ONL. This was in contrast to cultures treated with the compounds of the invention that showed significant protection (Table 3 below):

Table 3

Light Model Assay

[0Θ87] The light model assay is generally accepted as a model of age related macular degeneration (AMD). Light as an environmental factor has been shown to be toxic to rod photoreceptors if the retina was exposed to high light levels over a long period of time ; and oxidative stress has been implicated as the main trigger for cell death. In particular, oxidative damage has been detected by immunohistochemistry, detecting the presence of oxidized and tyrosme-phosphorylated proteins as well as the upregttlation of endogenous antioxidants such as thioredoxin and glutathione peroxidase. Likewise, exogenous antioxidants have been found to protect the rodent retina from light damage. Additional indirect evidence for the involvement of oxidative stress in photoreceptor degeneration has been provided by treatment of photodamaged retinas with antioxidants such as dimethylthiourea, or the treatment of N-methyl-N-nitrosourea (MNU)-challenged rats with the antioxidant DHA.

[0088] The light model assay was used to further test the therapeutic potential of the compounds of the invention. Photoreceptors from albino animals are very sensitive to constant light, lacking the RPE pigment to protect them. Thus, Balb/c mice were exposed to continuous light for 7 days, which caused loss of about 50% of the photoreceptor ceils as measured via histology. To test the potential therapeutic efficacy, eyedrops were formulated in 0.1% Bij 35 in 9% saline, applied once or twice daily throughout the period of light exposure, and assessed their effect on the light-induced degeneration of photoreceptor cells morphologically and electrophysiologically, 10 days after the onset of the CL exposure. In control BALB/c mice, constant light resulted in the elimination of -50% of the photoreceptors (average retina score: 4.3 ± 0.25 rows of photoreceptors), whereas the mice treated with compound eyedrops once per day retained significantly more photoreceptors cells (Table 4).

Ta le 4

[0089] As seen above, the compounds of the invention mitigate oxidative- and calcium- mediated loss of mitochondrial capacity in cell lines and protect photoreceptors from cell death in several models of retinal degeneration. References

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* * * [0090] It is to he understood that the invention is not limited to the particular embodiments of the invention described above, as variations of the particular embodiments may be made and still fall within the scope of the appended claims.