Mek1 inhibitors and uses thereof

Abstract

The invention relates to MEK1 inhibitors, compositions comprising an effective amount of MEK1 inhibitors and methods for treating or preventing diseases or disorders associated with MEK1 inhibition such as, for example, cancer and fibroproliferative diseases.

Description

[0001]112746-108728 (P23001) MEK1 INHIBITORS AND USES THEREOF FIELD OF THE INVENTION The invention relates to MEK1 inhibitors, compositions comprising an effective amount of a MEK1 inhibitor and methods for treating or preventing MEK1-associated diseases. All publications, patents, patent applications, and other references cited in this application are incorporated herein by reference in their entirety for all purposes and to the same extent as if each individual publication, patent, patent application or other reference was specifically and individually indicated to be incorporated by reference in its entirety for all purposes. Citation of a reference herein shall not be construed as an admission that such is prior art to the present invention. BACKGROUND OF THE INVENTION The mitogen-activated protein kinase (MAPK) / extracellular signal-regulated kinase (ERK) pathway, also known as the Ras / Raf / MEK / ERK pathway, regulates cellular processes that may include proliferation, differentiation, development, survival, and apoptosis [1]. The MEKs are an evolutionarily conserved group of three homologous isoforms, known as MEK1, MEK2, and MEK 1b, which are dual-specificity tyrosine / threonine protein kinases. Approximately 30% of all human cancers have a constitutively activated MAPK / ERK pathway, as well as several benign cutaneous proliferative tumors, most commonly through mutations in the KRAS oncogene and BRAF, and constitutive activation of MEK1 results in cellular transformation. As such, inhibition of MEK1 serves as a viable therapeutic strategy in the treatment of hyperproliferative conditions, such as melanoma, squamous cell carcinoma, dermal plexiform neurofibroma, keloid, prurigo nodularis, and cutaneous arteriovenous malformations. A need exists in the art for MEK1 inhibitory compounds in the treatment of systemic and local conditions involving aberrant cell proliferation, e.g., an injectable or topical composition for use in the treatment of benign conditions that respond best to MEK1 inhibition, such as dermal plexiform neurofibromas, keloid, prurigo nodularis, and cutaneous arteriovenous malformations. 1 3159322.1 112746-108728 (P23001) SUMMARY OF THE INVENTION In one embodiment of the present invention, provided are compounds of Formula (I): and pharmaceutically acceptable salts thereof. Other embodiments of the invention include pharmaceutical compositions comprising the compound according to Formula (I); and methods of treating cancer and fibroproliferative diseases. BRIEF DESCRIPTION OF THE DRAWINGS Figure 1 shows the chemical structures of representative NL-derivatives of the invention and the most chemically related FDA-approve MEK1 inhibitor, Cobimetinib. Figure 2 shows in vitro screening of novel NL compounds. (A) Compounds were screened at increasing concentrations to assay for activity. NL350 derivatives were as potent as FDA- approved controls, demonstrating low nanomolar range activity. (B) hERG inhibition experiments performed on CHO-cells. Cobimetinib demonstrated low nanomolar inhibition of hERG. NL350-derivatives did not inhibit hERG at the concentrations tested. DETAILED DESCRIPTION OF THE INVENTION Four FDA-approved MEK1 inhibitors exist: trametinib, cobimetinib, selumetinib, and binimetinib. These inhibitors are associated with extensive side-effect profiles, most notably 2 3159322.1 112746-108728 (P23001) rash, diarrhea, fatigue, peripheral edema, dermatitis, hypertension, and cardiomyopathy [2-4]. Additionally, MEK1 inhibitors are often associated with life threatening arrhythmias resulting from off-target hERG inhibition [2-6]. As such, we utilized artificial intelligence screening tools to preferentially select for compounds with favorable PK profiles, placing special emphasis on eliminating hERG inhibition and major cytochrome interactions. In vitro data from this study confirm computational predictions on hERG inhibition and activity. Several Norris Lab (NL)-compounds tested demonstrated activity in preventing ERK1 / 2 phosphorylation in A375 cells. NL350-139 and NL350-02 were as potent as FDA- approved controls in preventing the activation of ERK1 / 2. None of the three NL-compounds selected for hERG inhibition studies demonstrated activity. In contrast, Cobimetinib, an FDA-approved MEK1 inhibitor demonstrated low nanomolar range activity against hERG (IC50 = 52 nM). These data confirm the discovery of novel MEK1 inhibitors with retained activity in vitro and reduced liability of cardiotoxicity. These data validate publicly available PK prediction platforms and further support their use in early-stage drug discovery and development. Definitions The following definitions are used in connection with the MEK1 inhibitors: The term “MEK1 inhibitors” includes any and all possible isomers, stereoisomers, enantiomers, diastereomers, tautomers, pharmaceutically acceptable salts, hydrates, solvates, and prodrugs of the MEK1 inhibitors described herein. The articles “a” and “an” are used in this disclosure to refer to one or more than one (i.e., to at least one) of the grammatical object of the article. By way of example, “an element” means one element or more than one element. The term “and / or” is used in this disclosure to mean either “and” or “or” unless indicated otherwise. The term “aryl” refers to cyclic, aromatic hydrocarbon groups that have 1 to 2 aromatic rings, including monocyclic or bicyclic groups such as phenyl, biphenyl or naphthyl. Where containing two aromatic rings (bicyclic, etc.), the aromatic rings of the aryl group may be 3 3159322.1 112746-108728 (P23001) joined at a single point (e.g., biphenyl), or fused (e.g., naphthyl). The aryl group may be optionally substituted by one or more substituents, e.g., 1 to 5 substituents, at any point of attachment. The substituents can themselves be optionally substituted. The term “alkyl”, alternatively designated as “Ak”, refers to a mono- or multivalent, e.g., a mono- or bivalent, straight or branched saturated hydrocarbon group. “C1-C3 alkyl” refers to a straight or branched chain saturated hydrocarbon containing 1-3 carbon atoms. Examples of a C1-C3 alkyl group include, but are not limited to, methyl, ethyl, propyl and isopropyl. “C1-C4 alkyl” refers to a straight or branched chain saturated hydrocarbon containing 1-4 carbon atoms. Examples of a C1-C4 alkyl group include, but are not limited to, methyl, ethyl, propyl, butyl, isopropyl, isobutyl, sec-butyl and tert-butyl. “C1-C5 alkyl” refers to a straight or branched chain saturated hydrocarbon containing 1-5 carbon atoms. Examples of a C1-C5 alkyl group include, but are not limited to, methyl, ethyl, propyl, butyl, pentyl, isopropyl, isobutyl, sec-butyl and tert-butyl, isopentyl and neopentyl. “C1-C6 alkyl” refers to a straight or branched chain saturated hydrocarbon containing 1-6 carbon atoms. Examples of a C1-C6 alkyl group include, but are not limited to, methyl, ethyl, propyl, butyl, pentyl, hexyl, isopropyl, isobutyl, sec-butyl, tert-butyl, isopentyl, and neopentyl. The term "alkoxy" as used herein means an -O-alkyl group, wherein alkyl is as defined above such as methoxy, ethoxy, n-propyloxy, i-propyloxy, n-butyloxy, i-butyloxy, t-butyloxy, pentyloxy, hexyloxy, including their isomers. "C1-10alkoxy" as used herein refers to an-O- alkyl wherein alkyl is C1-10. The terms “aryl” or “heteroaryl” as used herein include but are not limited to, indolyl, isoindolyl, isoindolinyl, indazolyl, benzofuranyl, benzothienyl, benzothiazolyl, benzothiazolonyl, benzoxazolyl, benzoxazolonyl, benzisoxazolyl, benzisothiazolyl, benzimidazolyl, benzimidazolonyl, benztriazolyl, imidazopyridinyl, dihydropurinonyl, pyrrolopyrimidinyl, purinyl, pyrazolopyridinyl, pyrazolopyrimidinyl, phthalimidyl, phthalimidinyl, pyrazinylpyridinyl, pyridinopyrimidinyl, pyrimidinopyrimidinyl, cinnolinyl, quinoxalinyl, quinazolinyl, quinolinyl, isoquinolinyl, quinolonyl, isoquinolonyl, 4 3159322.1 112746-108728 (P23001) phthalazinyl, benzodioxyl, indolinyl, benzisobiazoline-1,1,3-trionyl, dihydroquinolinyl, tetrahydroquinolinyl, dihydroisoquinolyl, tetrahydroisoquinolinyl, benzoazepinyl, benzodiazepinyl, benzoxapinyl, benzoxazepinyl, phenyl, naphthyl, pyrrolyl, furyl, thienyl, oxazolyl, thiazolyl, isoxazolyl, isothiazolyl, imidazolyl, pyrazolyl, oxadiazolyl, thiadiazolyl, triazolyl, tetrazolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, and triazinyl. The term “cycloalkyl” refers to a cyclic hydrocarbon containing 3-8 carbon atoms (C3-C8), in one embodiment 4-6 carbon atoms (C4-C6). Examples of a cycloalkyl group include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl. It is understood that any of the substitutable hydrogens on a cycloalkyl can be substituted. The term “heterocycle” as used herein refers to a cyclic hydrocarbon containing 3-6 atoms wherein at least one of the atoms is an O, N, or S wherein a monocyclic heterocycle may contain up to two double bonds. Examples of heterocycles include, but are not limited to, aziridine, oxirane, thiirane, azetidine, oxetane, thietane, pyrrolidine, tetrahydrofuran, tetrahydrothiophene, piperidine, tetrahydropyran, thiane, imidazolidine, oxazolidine, thiazolidine, dioxolane, dithiolane, piperazine, oxazine, dithiane, and dioxane. A “subject” is a mammal, e.g., a human, mouse, rat, guinea pig, dog, cat, horse, cow, pig, or non-human primate, such as a monkey, chimpanzee, baboon or rhesus, and the terms “subject” and “patient” are used interchangeably herein. The invention also includes pharmaceutical compositions comprising an effective amount of an MEK1 inhibitor and a pharmaceutically acceptable carrier. The invention includes an MEK1 inhibitor provided as a pharmaceutically acceptable prodrug, hydrate, salt, such as a pharmaceutically acceptable salt, enantiomers, stereoisomers, or mixtures thereof. Representative “pharmaceutically acceptable salts” include, e.g., water-soluble and water- insoluble salts, such as the acetate, amsonate (4,4-diaminostilbene-2,2-disulfonate), benzenesulfonate, benzonate, bicarbonate, bisulfate, bitartrate, borate, bromide, butyrate, calcium, calcium edetate, camsylate, carbonate, chloride, citrate, clavulariate, dihydrochloride, edetate, edisylate, estolate, esylate, fiunarate, gluceptate, gluconate, glutamate, glycollylarsanilate, hexafluorophosphate, hexylresorcinate, hydrabamine, hydrobromide, hydrochloride, hydroxynaphthoate, iodide, isothionate, lactate, lactobionate, laurate, magnesium, malate, maleate, mandelate, mesylate, methylbromide, methylnitrate, 5 3159322.1 112746-108728 (P23001) methylsulfate, mucate, napsylate, nitrate, N-methylglucamine ammonium salt, 3-hydroxy-2- naphthoate, oleate, oxalate, palmitate, pamoate (1,1-methene-bis-2-hydroxy-3-naphthoate, einbonate), pantothenate, phosphate / diphosphate, picrate, polygalacturonate, propionate, p-toluenesulfonate, salicylate, stearate, subacetate, succinate, sulfate, sulfosalicylate, suramate, tannate, tartrate, teoclate, tosylate, triethiodide, and valerate salts. The term “carrier,” as used in this disclosure, encompasses carriers, excipients, and diluents and means a material, composition or vehicle, such as a liquid or solid filler, diluent, excipient, solvent or encapsulating material, involved in carrying or transporting a pharmaceutical agent from one organ, or portion of the body, to another organ, or portion of the body. The term “treating,” with regard to a subject, refers to improving at least one symptom of the subject's disorder. Treating can be curing, improving, or at least partially ameliorating the disorder. The term “disorder” is used in this disclosure to mean, and is used interchangeably with, the terms disease, condition, or illness, unless otherwise indicated. The term “administer,” “administering,” or “administration” as used in this disclosure refers to either directly administering a compound or pharmaceutically acceptable salt of the compound or a composition to a subject, or administering a prodrug derivative or analog of the compound or pharmaceutically acceptable salt of the compound or composition to the subject, which can form an equivalent amount of active compound within the subject’s body. The term “prodrug,” as used in this disclosure, means a compound which is convertible in vivo by metabolic means (e.g., by hydrolysis) to an MEK1 inhibitor. The term “optionally substituted,” as used in this disclosure, means a suitable substituent can replace a hydrogen bound to a carbon, nitrogen, or oxygen. When a substituent is oxo (i.e., = O) then 2 hydrogens on the atom are replaced by a single O. Suitable substituents are selected from the following which include, but are not limited to, hydroxyl, halogen, perfluorinated C1-C6 alkyl, amine, -C1-C12 alkyl, -C2-C12 alkene, -C2-C12 alkyne, -(C1-C3 alkyl)-(cycloalkyl), aryl, alkyl-aryl, -C(O)H, -C(O)OH, -C(O)alkyl, -C(O)-O-alkyl, -C(O)NH(alkyl), benzyl, –C(O)NH2, -C(O)N(alkyl)2, –NHC(O)H, –NHC(O)alkyl, - SO2(alkyl), -SO2NH2, -SO2NH(alkyl), -SO2N(alkyl)2, S, CN, and SCN. It will be understood 6 3159322.1 112746-108728 (P23001) by those skilled in the art, with respect to any group containing one or more substituents, that such groups are not intended to introduce any substitution or substitution patterns that are sterically impractical, synthetically non-feasible and / or inherently unstable. Furthermore, combinations of substituents and / or variables within any of the Formulae represented herein are permissible only if such combinations result in stable compounds or useful synthetic intermediates wherein stable implies a reasonable pharmologically relevant half-life at physiological conditions. General Schemes Certain embodiments of the present invention can be made using the methods and conditions as shown in the following schemes: Scheme I: Methyl 5-bromo-2,3,4-trifluorobenzoate (2) To a solution of 5-bromo-2,3,4-trifluorobenzoic acid (2.04 g, 8 mmol, 1 equiv) in DMF (20 mL) was added MeI (3.41 g, 1.5 mL, 24 mmol, 3 equiv) followed by K2CO3 (3.31 g, 24 mmol, 3 equiv). The resulting mixture was stirred at room temperature for 2 h. HPLC indicated the consumption of starting material, while LC-MS indicated the formation of desired product. The reaction mixture was diluted with 80 mL of H2O followed by 80 mL of 7 3159322.1 112746-108728 (P23001) MTBE. The layers were separated, and the aqueous layer was extracted with 80 ml of MTBE. The combined organic layers were washed with 80 ml of water followed by 40 ml of Na2SO3 aqueous solution and 40 mL of brine. The mixture was concentrated, and the crude product (2.16 g, 100%) was used directly without any further purification. Methyl 5-cyclopropyl-2,3,4-trifluorobenzoate (3) To a solution of methyl 5-bromo-2,3,4-trifluorobenzoate (2.16 g, 8.03 mmol, 1 equiv) in H2O / toluene (5%, 22 mL) was added cyclopropylboronic acid (1.035 g, 12.05 mmol, 1.5 equiv), Pd (OAc)2 (0.18 g, 0.803 mmol, 0.1 equiv), PCy3 (0.45 g, 1.61 mmol, 0.2 equiv) and K3PO4 (5.12 g, 24.1 mmol, 3 equiv). The reaction flask was sealed and was evacuated and backfilled with nitrogen for three times. The resulting mixture was stirred at 100 °C for 16 hours. HPLC indicated the consumption of starting material, while LC-MS indicated the formation of desired product. The reaction was cooled to room temperature and 20 mL water was added to the mixture. The layers were separated, and the aqueous layer was extracted with 2×20 mL EA. The combined organic layer was washed with brine and dried over Na2SO4. The mixture was concentrated, and the crude product was further purified by flash chromatography (SiO2, EA / Hep) to afford methyl 5-cyclopropyl-2,3,4-trifluorobenzoate (1.53 g, 83%). 5-Cyclopropyl-2,3,4-trifluorobenzoic acid (4) To a solution of methyl 5-cyclopropyl-2,3,4-trifluorobenzoate (1.53 g, 6.7 mmol) in H2O (9 mL) was added KOH (1.12 g, 20 mmol). The resulting mixture was stirred at room temperature for 16 hours. HPLC indicated the consumption of starting material, while LC- MS indicated the formation of desired product. 1 M HCl was then used to adjust the pH to 5 to 6. EA (15 mL) was added to the mixture. The layers were separated. The aqueous layer was extracted with EA (2×15 mL). The combined organic layer was washed with brine and dried over Na2SO4. The mixture was concentrated, and the crude product was further purified by prep HPLC to afford 5-cyclopropyl-2,3,4-trifluorobenzoic acid (1.1 g, 79%) as a faint yellow solid. 5-Cyclopropyl-3,4-difluoro-2-((2-fluoro-4-iodophenyl)amino)benzoic acid (5) Under N2 atmosphere, to a solution of 2-fluoro-4-iodoaniline (823 mg, 1.5 equiv) in THF (12 mL) was added LDA (3.24 mL, 3.5 equiv) dropwise at -78 °C. The resulting mixture was 8 3159322.1 112746-108728 (P23001) stirred at -78 °C for 20 min. Then 5-cyclopropyl-2,3,4-trifluorobenzoic acid (500 mg, 1 equiv) in THF (10 mL) was added to the mixture dropwise at -78 °C. The resulting mixture was stirred at -78 °C for 1 hour and then slowly warmed to room temperature. HPLC indicated the consumption of starting material, while LC-MS indicated the formation of desired product. The mixture was diluted with water (15 mL) and then the pH was adjusted to 6 to 7 using 1 M HCl. The layers were separated, and the aqueous layer was extracted with EA (2×30 mL). The combined organic layer was washed with brine and dried over Na2SO4. The mixture was concentrated, and the crude product was further purified by flash chromatography (SiO2, EA / Hep) to afford 5-cyclopropyl-3,4-difluoro-2-((2-fluoro-4- iodophenyl)amino)benzoic acid (400 mg, 40%) as a dark brown solid. Representative Useful Compounds for the Inventive Method In an embodiment of the invention, MEK1 inhibitors useful in the present invention include, for example: Methods for using MEK1 inhibitors In another aspect, methods of treating or preventing a disease or disorder associated with MEK1 expression is provided, which comprises administering to a subject in need thereof, a therapeutically-effective amount of an MEK1 inhibitor. In one embodiment, the disease associated with high MEK1 expression is mital valve prolapse in humans and dogs. In another embodiment, the diseases associated with aberrant MEK1 activation include cutaneous and systemic fibroproliferative diseases, such as keloids, hypertrophic scarring, prurigo nodularis, desmoid tumors, neurofibromatosis type I and II, scleroderma, morphea, dermatofibroma, Dupuytren’s contracture, Ledderhose disease, Peyronie’s disease, cutaneous 9 3159322.1 112746-108728 (P23001) leiomyoma, nephrogenic systemic sclerosis, idiopathic pulmonary fibrosis, liver cirrhosis, myelofibrosis, retroperitoneal fibrosis, cardiac fibrosis, and cardiofaciocutaneous syndrome. In another embodiment, the diseases driven by MEK1 overactivation include cancers, specifically melanoma, Merkel cell carcinoma, squamous cell carcinoma of all tissue origins, non-small cell lung cancer, colorectal cancer, pancreatic cancer, ovarian cancer, thyroid cancer, glioblastoma, hepatocellular carcinoma, acute myeloid leukemia, breast cancer, and GI stromal tumors (GIST). In another embodiment, the diseases driven by MEK1 overactivation include histiocytic conditions, such as Erdheim-Chester disease, Langerhans cell histiocytosis, and Rosai- Dorfman disease. In another embodiment, the diseases driven by MEK1 overactivation include autoimmune diseases, such as psoriasis, connective tissue diseases, rheumatoid disease, and lupus disease. In another embodiment, the diseases driven by MEK1 overactivation include vascular disorders, such as aortic and arterial aneurysms, cutaneous arterial vascular malformations (AVMs), central nervous system AVMs, capillary malformations, venous malformations, rosacea, Kaposiform hemanioendothelioma, Sturge-Weber syndrome, hereditary hemorrhagic telangiectasia, angiosarcoma, arterial manifestations of Marfan syndrome, and pulmonary artery hypertension. The invention also includes pharmaceutical compositions useful for treating or preventing an MEK1 associated disease or disorder, or for inhibiting an MEK1 associated disease, or more than one of these activities. The compositions can be suitable for internal use and comprise an effective amount of an MEK1 inhibitor and a pharmaceutically acceptable carrier. In one embodiment, the MEK1 inhibitors can each be administered in amounts that are sufficient to treat or prevent mitral valve prolapse. Administration of the MEK1 inhibitors can be accomplished via any mode of administration for therapeutic agents. These modes include systemic or local administration such as oral, nasal, parenteral (intravenous), intramuscular, intrathecal, intra-vitreal, transdermal, subcutaneous, vaginal, buccal, rectal, topical administration modes or as a drug-eluting stent. 10 3159322.1 112746-108728 (P23001) Depending on the intended mode of administration, the compositions can be in solid, semi- solid or liquid dosage form, such as, by way of non-limiting examples, injectables, tablets, suppositories, pills, time-release capsules, elixirs, tinctures, emulsions, syrups, powders, liquids, suspensions, or the like, sometimes in unit dosages and consistent with conventional pharmaceutical practices. Likewise, they can also be administered in intravenous (non- limiting examples include bolus and infusion), intraperitoneal, intrathecal, intra-vitreal injection, subcutaneous or intramuscular form, all using forms well known to those skilled in the pharmaceutical arts. Non-limiting illustrative pharmaceutical compositions are tablets and gelatin capsules comprising an MEK1 inhibitor and a pharmaceutically acceptable carrier, such as: a) a diluent, e.g., purified water, triglyceride oils, such as hydrogenated or partially hydrogenated vegetable oil, or mixtures thereof, corn oil, olive oil, sunflower oil, safflower oil, fish oils, such as EPA or DHA, or their esters or triglycerides or mixtures thereof, omega-3 fatty acids or derivatives thereof, lactose, dextrose, sucrose, mannitol, sorbitol, cellulose, sodium, saccharin, glucose and / or glycine; b) a lubricant, e.g., silica, talcum, stearic acid, its magnesium or calcium salt, sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, sodium chloride and / or polyethylene glycol; for tablets also; c) a binder, e.g., magnesium aluminum silicate, starch paste, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose, magnesium carbonate, natural sugars such as glucose or beta-lactose, corn sweeteners, natural and synthetic gums such as acacia, tragacanth or sodium alginate, waxes and / or polyvinylpyrrolidone, if desired; d) a disintegrant, e.g., starches, agar, methyl cellulose, bentonite, xanthan gum, alginic acid or its sodium salt, or effervescent mixtures; e) absorbent, colorant, flavorant and sweetener; f) an emulsifier or dispersing agent, such as Tween 80, Labrasol, HPMC, DOSS, caproyl 909, labrafac, labrafil, peceol, transcutol, capmul MCM, capmul PG-12, captex 355, gelucire, vitamin E TGPS or other acceptable emulsifier; and / or g) an agent that enhances absorption of the compound such as cyclodextrin, hydroxypropyl–cyclodextrin, PEG400, PEG200. Liquid, particularly injectable, compositions can, for example, be prepared by dissolution, dispersion, etc. For example, the MEK1 inhibitor is dissolved in or mixed with a pharmaceutically acceptable solvent such as, for example, water, saline, aqueous dextrose, glycerol, ethanol, and the like, to thereby form an injectable isotonic solution or suspension. 11 3159322.1 112746-108728 (P23001) Proteins such as albumin, chylomicron particles, or serum proteins can be used to solubilize the MEK1 inhibitors. The MEK1 inhibitors can be also formulated as a suppository that can be prepared from fatty emulsions or suspensions; using polyalkylene glycols such as propylene glycol, as the carrier. In further embodiments, the pharmaceutical formulations described herein include, but are not limited to, aqueous liquid dispersions, self-emulsifying dispersions, solid solutions, liposomal dispersions, aerosols, solid dosage forms, powders, immediate release formulations, controlled release formulations, fast melt formulations, delayed release formulations, extended release formulations, pulsatile release formulations, multiparticulate formulations, and mixed immediate and controlled release formulations The MEK1 inhibitors can also be administered in the form of liposome delivery systems, such as small unilamellar vesicles, large unilamellar vesicles and multilamellar vesicles. Liposomes can be formed from a variety of phospholipids, containing cholesterol, stearylamine or phosphatidylcholines. In some embodiments, a film of lipid components is hydrated with an aqueous solution of drug to a form lipid layer encapsulating the drug, as described in United States Patent No. 5,262,564, the contents of which are herein incorporated by reference in their entirety. MEK1 inhibitors can also be delivered by the use of monoclonal antibodies as individual carriers to which the MEK1 inhibitors are coupled. The MEK1 inhibitors can also be coupled with soluble polymers as targetable drug carriers. Such polymers can include polyvinylpyrrolidone, pyran copolymer, polyhydroxypropylmethacrylamide-phenol, polyhydroxyethylaspanamidephenol, or polyethyleneoxidepolylysine substituted with palmitoyl residues. Furthermore, the MEK1 inhibitors can be coupled to a class of biodegradable polymers useful in achieving controlled release of a drug, for example, polylactic acid, polyepsilon caprolactone, polyhydroxy butyric acid, polyorthoesters, polyacetals, polydihydropyrans, polycyanoacrylates and cross-linked or amphipathic block copolymers of hydrogels. In one embodiment, MEK1 inhibitors are not covalently bound to a polymer, e.g., a polycarboxylic acid polymer, or a polyacrylate. Parenteral injectable administration is generally used for subcutaneous, intramuscular or intravenous injections and infusions. Injectables can be prepared in conventional forms, 12 3159322.1 112746-108728 (P23001) either as liquid solutions or suspensions or solid forms suitable for dissolving in liquid prior to injection. Compositions can be prepared according to conventional mixing, granulating or coating methods, respectively, and the present pharmaceutical compositions can contain from about 0.1 % to about 80 %, from about 5 % to about 60 %, or from about 1 % to about 20 % of the MEK1 inhibitor by weight or volume. A “therapeutically effective amount” when used in connection with an MEK1 inhibitor is an amount effective for treating or preventing an MEK1-associated disease or disorder. The dosage regimen utilizing the MEK1 inhibitor is selected in accordance with a variety of factors including type, species, age, weight, sex, race, diet, concomitant medications, and medical condition of the patient; the severity of the condition to be treated; the route of administration; the renal or hepatic function of the patient; and the particular MEK1 inhibitor employed. A physician or veterinarian of ordinary skill in the art can readily determine and prescribe the effective amount of the drug required to prevent, counter or arrest the progress of the condition. Therapeutically effective amounts of the present invention, when used for the indicated effects, range from about 0.1 mg to about 5000 mg of the active ingredient per unit dose which could be administered. In one embodiment, the compositions are in the form of a tablet that can be scored. Appropriate dosages of the MEK1 inhibitors can be determined as set forth in Goodman, L. S.; Gilman, A. The Pharmacological Basis of Therapeutics, 5th ed.; MacMillan: New York, 1975, pp. 201-226, the contents of which are hereby incorporated by reference. MEK1 inhibitors can also be administered in a single daily dose, or the total daily dosage can be administered in divided doses of two, three or four times daily. Furthermore, MEK1 inhibitors can be administered in intranasal form via topical use of suitable intranasal vehicles, or via transdermal routes, using those forms of transdermal skin patches well known to those of ordinary skill in that art. To be administered in the form of a transdermal delivery system, the dosage administration can be continuous rather than intermittent throughout the dosage regimen. Other illustrative topical preparations include creams, ointments, lotions, aerosol sprays and gels, wherein the concentration of the MEK1 inhibitor ranges from about 0.1 % to about 15 %, w / w or w / v. 13 3159322.1 112746-108728 (P23001) EXAMPLES The disclosure is further illustrated by the following examples, which are not to be construed as limiting this disclosure in scope or spirit to the specific procedures herein described. It is to be understood that the examples are provided to illustrate certain embodiments and that no limitation to the scope of the disclosure is intended thereby. It is to be further understood that resort may be had to various other embodiments, modifications, and equivalents thereof which may suggest themselves to those skilled in the art without departing from the spirit of the present disclosure and / or scope of the appended claims. The methodologies described herein and below are designed to (1) quantitate and describe the nature of the physical interaction between MEK1 and candidate compounds, (2) determine the biological consequence resulting from the interaction of MEK1 with the candidate compound, (3) evaluate the impact of the candidate compound in animal models of MEK1 mediated disease. It is to be understood that any embodiments listed in the Examples section are embodiments of the MEK1 inhibitors and, as such, are suitable for use in the methods and compositions described above. Example 1 Synthesis of Representative Compounds of the Invention 14 3159322.1 112746-108728 (P23001) To a solution of 5-cyclopropyl-3,4-difluoro-2-((2-fluoro-4-iodophenyl)amino)benzoic acid (10 mg, 1 equiv) in DMF (0.25 mL) was added amine (or amine HCl salt, 2 equiv), EDC (9.7 mg, 2.2 equiv), HOBt (5.3 mg, 1.5 equiv), and DIPEA (3 to 5 equiv). The resulting mixture was stirred at 35 °C for 20 hours. HPLC indicated the consumption of starting material, while LC-MS indicated the formation of desired product. The reaction mixture was diluted with 1 mL of H2O followed by 1 mL of EA / Hep (1:1). The layers were separated, and the aqueous layer was extracted with 1 ml of EA / Hep (1:1). The combined organic layers were washed with 1 ml of water. The mixture was concentrated, and the crude product was further purified by prep HPLC to afford the final product. 15 3159322.1 112746-108728 (P23001) Example 2 Biological Assay 1. Cell Culture and Drug Treatment: Human A375 metastatic melanoma cells (ATCC (Manassas, VA, USA); No. CRL-1619IG-2) were cultured in Gibco Dulbecco’s Modified Eagle Medium (DMEM) (ATCC; No. 30-2002) using 10% fetal bovine serum and 1% Penicillin-Streptomycin. Cells were plated at a confluency of 5 × 105per 35 mm well 24 h before treatment. For initial drug screening, cells were treated with vehicle, trametinib (ChemShuttle (Burlingame, CA, USA); No. 100836, 40 nM), or NL-compounds at 10 μM for 24 h. Compounds were dissolved in DMSO and vehicle treated cells received DMSO in media. For dose response analyses, cells were treated with vehicle or drug (trametinib or NL-compounds) at varying concentrations (0.01, 0.1, 0.3, 1, 3, and 10 μM) for 24 h. Following 24-h treatment, cells were then lysed using 1× RIPA lysis buffer containing 1% protease / phosphatase inhibitor, sonicated, and stored at −80 °C until further use. 2. Western Blot Analysis: Tissue and cells were homogenized in 1× RIPA with 1% protease / phosphatase inhibitor, followed by sonication. Samples were prepared with 2× SDS Page buffer (125 mM Tris pH7, 4% SDS, 0.2% bromophenol blue, 20% glycerol, 5% β-mercaptoethanol) and boiled at 98 °C for 5 min prior to loading. Proteins were separated in 4–20% Mini-PROTEAN TGX Stain- Free Protein Gels (Bio-rad (Hercules, CA, USA), #456-8093) and transferred to Trans-Blot Turbo Mini Nitrocellulose Transfer Packs (Bio-rad, #170-4158). Membranes were blocked in 5% nonfat milk (Biorad, #170-6404) diluted in 1× Tris Buffered Saline, 0.1% Tween 20 (TBST) for 1 h and incubated in primary antibodies at 4 °C overnight with rotation. Membranes were rinsed 5 times with TBST and incubated at room temperature for 1 h in secondary antibody. The membranes were then rinsed 5 times in TBST for 10 min each and imaged on a Bio-Rad ChemiDoc MP system with SuperSignal West Femto Maximum Sensitivity Substrate (ThermoFisher (Waltham, MA, USA), #34096). Primary antibodies were used at 1:1000 and included p-p44 / p42 MAPK (t202 / y204) (phospho-ERK1 / 2) (Cell Signaling (Danvers, MA, USA); No. 4270S) and p44 / 42 MAPK (ERK1 / 2) (Cell Signaling; No. 4695S. Secondary anti-rabbit IgG HRP antibody (Sigma (Burlington, MA, USA); No: A9169) was 16 3159322.1 112746-108728 (P23001) used at 1:7500. Ponceau S (Millipore Sigma; No: P7170) was performed as need for protein normalization. 3. hERG Inhibition Assay hERG potassium channel assays were performed by Eurofins St. Charles examining six concentrations (0, 0.1, 0.3, 1, 3, and 10 μM) in CHO-cells, per their publicly available method [7]. The parameters measured were the maximum tail current evoked on stepping to 40 mV and ramping back to −80 mV from the test pulse. All data were filtered for seal quality, seal drop, and current amplitude. The peak current amplitude was calculated before and after compound addition and the amount of block was assessed by dividing the Test compound current amplitude by the Control current amplitude. Control data is the mean hERG current amplitude collected 15 s at the end of the control period; Test compound data is the mean hERG current amplitude collected 15 s at the end of test concentration application for each concentration. All compounds were tested in the presence of 0.1% Pluronic F-68 Non-Ionic Surfactant. After whole cell configuration is achieved, the cell is held at −80 mV. The cell is depolarized to +40 mV for 500 ms and then to −80 mV over a 100 ms ramp to elicit the hERG tail current. This paradigm is delivered once every 8 s to monitor the current amplitude. Results: NL compounds and controls were screened in A375 malignant melanoma cells at 10 micromolar (μM) concentrations for 24 h. Trametinib, as well as three NL compounds (NL350-02, NL350-104 and NL350-139), demonstrated significant activity at 10 μM doses. The three NL compounds with activity, as well as the four FDA-approved MEK1 inhibitors, were selected for a dose response analysis, assessing activity at 0.01, 0.1, 0.3, 1, 3, and 10 μM concentrations (Figure 32A). Trametinib, a MEK1 inhibitor with a cell-free IC50 in the picomolar range demonstrated the most potent activity of compounds tested, completely preventing MEK1-induced activation of extracellular signal-regulated protein kinase (ERK1 / 2) at 0.01 μM. Similarly, cobimetinib, a low nanomolar range inhibitor of MEK1, demonstrated significant activity at 0.01 μM. Selumetinib and binimetinib demonstrated nanomolar range activity, preventing ERK1 / 2 phosphorylation at 0.1 μM concentrations. Experimental compound NL350-139 demonstrated micromolar range activity, with NL350- 02 and NL350-139 demonstrating low nanomolar range activity. NL350-02 and NL350-139 17 3159322.1 112746-108728 (P23001) were as potent as FDA-approved controls in preventing ERK1 / 2 activation. Next, a hERG inhibition assay was performed to validate our in silico predictions. As predicted, cobimetinib inhibited hERG at low nanomolar concentrations (IC50 = 52 nM) (Figure 2B). None of the NL-compounds tested inhibited hERG. These data confirm our computational predictions, establishing a reduced cardiotoxicity potential associated with our novel NL-compounds. The invention will be further described, without limitation, by the following numbered paragraphs: 1. A compound of Formula (I): wherein: R1 is halogen; R2 is halogen, alkyl, or alkoxy; R3 is H, halogen, alkyl, or alkoxy; R4 is halogen or alkoxy; R5 is H, halogen, alkyl, or alkoxy; 18 3159322.1 112746-108728 (P23001) R6 is or a 2. The compound according to paragraph 1, wherein both R1 and R2 are, independently, halogen. 3 The compound according to paragraph 1, wherein both R3 and R4 are, independently, halogen. 4. The compound according to paragraph 1, wherein said compound is: 3159322.1 112746-108728 (P23001) or a pharmaceutically acceptable salt thereof. 5. A pharmaceutical composition, comprising a therapeutically effective amount of a compound according to paragraph 1, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier. 6. A method of treating cancer, comprising the step of administering a therapeutically effective amount of a compound according to paragraph 1, or a pharmaceutically acceptable salt thereof, to a subject in need thereof. 7. The method according to paragraph 6, wherein said cancer is melanoma, non-small cell lung cancer (NSCLC), colorectal cancer, pancreatic cancer, ovarian cancer, thyroid cancer, glioblastoma, triple-negative breast cancer, hepatocellular carcinoma, and / or neuroblastoma. 8. A method of treating fibroproliferative disease, comprising the step of administering a therapeutically effective amount of a compound according to paragraph 1, or a pharmaceutically acceptable salt thereof, to a subject in need thereof. 9. The method according to paragraph 8, wherein said fibroproliferative disease is keloid, prurigo nodularis, idiopathic pulmonary fibrosis (IPF), systemic sclerosis (scleroderma), Dupytren’s contracture, hypertrophic scars, Peyronie’s disease, myelofibrosis, retroperitoneal fibrosis, nephrogenic systemic sclerosis, scleredema, dermatofibrosarcoma protuberans. 20 3159322.1 112746-108728 (P23001) REFERENCES 1. Shaul YD, Seger R. The MEK / ERK cascade: from signaling specificity to diverse functions. Biochim Biophys Acta. 2007 Aug;1773(8):1213-26. doi: 10.1016 / j.bbamcr.2006.10.005. Epub 2006 Oct 19. PMID: 17112607. 2. Nebot, N.; Arkenau, H.T.; Infante, J.R.; Chandler, J.C.; Weickhardt, A.; Lickliter, J.D.; Sarantopoulos, J.; Gordon, M.S.; Mak, G.; St-Pierre, A.; et al. Evaluation of the effect of dabrafenib and metabolites on QTc interval in patients with BRAF V600-mutant tumours. Br J Clin Pharmacol 2018, 84, 764-775, doi:10.1111 / bcp.13488. 3. Leighton, J.K. Mekinist (Trametinib): Pharmacology / Toxicology NDA Review and Evaluation; Food and Drug Administration, 2013. 4. Leighton, J.K. Cotellic (cobimetinib): Pharmacology / Toxicology NDA Review and Evaluation; Food and Drug Administration, 2015. 5. Lamore, S.D.; Kohnken, R.A.; Peters, M.F.; Kolaja, K.L. Cardiovascular Toxicity Induced by Kinase Inhibitors: Mechanisms and Preclinical Approaches. Chem Res Toxicol 2020, 33, 125-136, doi:10.1021 / acs.chemrestox.9b00387. 6. Cotellic: Assessment Report; European Medicines Agency: 2015. Available online: https: / / www.ema.europa.eu / en / documents / assessment-report / cotellic-epar-public-assessment- report_en.pdf (accessed on 20 April 2022). 7. In Vitro Cardiac Safety Assessment Services. Available online: https: / / www.eurofinsdiscoveryservices.com / services / in-vitro-assays / ion- channels / cardiac-safety / (accessed on 10 May 2022). EQUIVALENTS Those skilled in the art will recognize, or be able to ascertain, using no more than routine experimentation, numerous equivalents to the specific embodiments described specifically herein. Such equivalents are intended to be encompassed in the scope of the following claims. 21 3159322.1

Claims

112746-108728 (P23001) CLAIMS:

1. A compound of Formula (I): wherein:R1 is halogen; R2 is halogen, alkyl, or alkoxy; R3 is H, halogen, alkyl, or alkoxy; R4 is halogen or alkoxy; R5 is H, halogen, alkyl, or alkoxy; R6 is112746-108728 (P23001) or a pharmaceutically acceptable salt thereof.

2. The compound according to claim 1, wherein both R1 and R2 are, independently, halogen. 3 The compound according to claim 1, wherein both R3 and R4 are, independently, halogen.

4. The compound according to claim 1, wherein said compound is:or a pharmaceutically acceptable salt thereof.

5. A pharmaceutical composition, comprising a therapeutically effective amount of a compound according to claim 1, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

6. A method of treating cancer, comprising the step of administering a therapeutically effective amount of a compound according to claim 1, or a pharmaceutically acceptable salt thereof, to a subject in need thereof.

7. The method according to claim 6, wherein said cancer is melanoma, non-small cell lung cancer (NSCLC), colorectal cancer, pancreatic cancer, ovarian cancer, thyroid cancer, glioblastoma, triple-negative breast cancer, hepatocellular carcinoma, and / or neuroblastoma.

8. A method of treating fibroproliferative disease, comprising the step of administering a therapeutically effective amount of a compound according to claim 1, or a pharmaceutically acceptable salt thereof, to a subject in need thereof.

9. The method according to claim 8, wherein said fibroproliferative disease is keloid, prurigo nodularis, idiopathic pulmonary fibrosis (IPF), systemic sclerosis (scleroderma), 23 3159322.1112746-108728 (P23001) Dupytren’s contracture, hypertrophic scars, Peyronie’s disease, myelofibrosis, retroperitoneal fibrosis, nephrogenic systemic sclerosis, scleredema, dermatofibrosarcoma protuberans. 24 3159322.1

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