WO 2016/003886 Al 7 January 2016 (07.01.2016) P O P C T
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(12) INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT) (19) World Intellectual Property Organization I International Bureau (10) International Publication Number (43) International Publication Date WO 2016/003886 Al 7 January 2016 (07.01.2016) P O P C T (51) International Patent Classification: (81) Designated States (unless otherwise indicated, for every A61K 31/4706 (2006.01) kind of national protection available): AE, AG, AL, AM, AO, AT, AU, AZ, BA, BB, BG, BH, BN, BR, BW, BY, (21) International Application Number: BZ, CA, CH, CL, CN, CO, CR, CU, CZ, DE, DK, DM, PCT/US20 15/038287 DO, DZ, EC, EE, EG, ES, FI, GB, GD, GE, GH, GM, GT, (22) International Filing Date: HN, HR, HU, ID, IL, IN, IR, IS, JP, KE, KG, KN, KP, KR, 29 June 2015 (29.06.2015) KZ, LA, LC, LK, LR, LS, LU, LY, MA, MD, ME, MG, MK, MN, MW, MX, MY, MZ, NA, NG, NI, NO, NZ, OM, (25) Filing Language: English PA, PE, PG, PH, PL, PT, QA, RO, RS, RU, RW, SA, SC, (26) Publication Language: English SD, SE, SG, SK, SL, SM, ST, SV, SY, TH, TJ, TM, TN, TR, TT, TZ, UA, UG, US, UZ, VC, VN, ZA, ZM, ZW. (30) Priority Data: 62/020,167 2 July 2014 (02.07.2014) (84) Designated States (unless otherwise indicated, for every kind of regional protection available): ARIPO (BW, GH, (71) Applicant: LAM THERAPEUTICS, INC. [US/US]; 530 GM, KE, LR, LS, MW, MZ, NA, RW, SD, SL, ST, SZ, Old Whitfield Street, Guilford, CT 06437 (US). TZ, UG, ZM, ZW), Eurasian (AM, AZ, BY, KG, KZ, RU, TJ, TM), European (AL, AT, BE, BG, CH, CY, CZ, DE, (72) Inventors: BEEHARRY, Neil; 530 Old Whitfield Street, DK, EE, ES, FI, FR, GB, GR, HR, HU, IE, IS, IT, LT, LU, Guilford, CT 06437 (US). BECKETT, Paul; 530 Old LV, MC, MK, MT, NL, NO, PL, PT, RO, RS, SE, SI, SK, Whitfield Street, Guilford, CT 06437 (US). ROTHBERG, SM, TR), OAPI (BF, BJ, CF, CG, CI, CM, GA, GN, GQ, Jonathan, M.; 530 Old Whitfield Street, Guilford, CT GW, KM, ML, MR, NE, SN, TD, TG). 06437 (US). LICHENSTEIN, Henri; 530 Old Whitfield Street, Guilford, CT 06437 (US). HERNANDEZ, Published: Marylens; 530 Old Whitfield Street, Guilford, CT 06437 — with international search report (Art. 21(3)) (US). (74) Agents: ASHRAF, Shovon et al; Mintz Levin Cohn Fer ris Glovsky and Popeo, P.C., Chrysler Center, 666 Third Avenue, New York, NY 10017 (US). 00 00 ©o v o (54) Title: 4-AMINOQUINOLINE COMPOSITIONS AND METHODS FOR USING SAME (57) Abstract: The present disclosure relates to 4-aminoquinoline compositions (an exemplary compound being JTC-801 ) having cytotoxic and/or anti-proliferative activity and methods of using same for treating and/or preventing proliferative diseases, disorders o or conditions in a subject in need of such treatment. The diseases could be cancer, neurodegenerative diseases, or those characterized by abnormal mTO signaling. Also described are methods of inhibiting ACOX3 (peroxisomal acyl coenzyme- A oxidase) activity. 4-AMINOQUINOLINE COMPOSITIONS AND METHODS FOR USING SAME CROSS-REFERENCE TO RELATED APPLICATION [01] This application claims priority to U.S. Provisional Patent Application Serial Number 62/020, 167, titled "4-Aminoquinoline Compositions and Methods for Using Same," filed July 2, 2014, the disclosure of which is hereby incorporated by reference in its entirety. FIELD OF THE DISCLOSURE [02] The present disclosure relates to compositions and methods for the treatment of mTOR diseases, disorders or conditions, and for the treatment of proliferative disorders including cancer. BACKGROUND OF THE DISCLOSURE [03] The mammalian target of rapamycin (mTOR) pathway is an important cellular signaling pathway that is involved in multiple physiological functions, including cell growth, cell proliferation, metabolism, protein synthesis, and autophagy. mTOR is a kinase that integrates intracellular and extracellular cues that signal the levels of amino acids, stress, oxygen, energy, and growth factors and regulates the cellular response to these environment cues. mTOR deregulation has been implicated in a wide range of disorders and diseases, including cancer, obesity, diabetes, and neurodegeneration. Certain components of the mTOR pathway have been explored as drug targets for treating some of these diseases. However, therapeutic efficacy has been limited, for example, in the treatment of some cancers, and some mTOR inhibitors have been shown to have an adverse effect on metabolism. [04] Lymphangioleiomyomatosis (LAM) is a multisystem disease affecting 30-40% of women with tuberous sclerosis complex (TSC), an often-fatal disease which is characterized by the widespread proliferation of abnormal smooth muscle-like cells that grow aberrantly in the lung. The proliferation of these cells (referred to as LAM cells) leads to the formation of cysts in the lungs and fluid-filled cystic structures in the axial lymphatics (referred to as lymphangioleiomyomas). In addition, LAM cells can form tumors. The abnormal proliferation of LAM cells is caused at least in part by an inactivating mutation in one of the tuberous sclerosis complex tumor suppressor genes, TSC1 or TSC2. The TSC genes are negative regulators of mTOR. As a consequence of the inactivation of TSC genes, LAM cells show constitutive activation of mTOR and many of the mTOR-related kinases such as Akt, Erk, S6K1 and S6. SUMMARY OF THE DISCLOSURE [05] The present disclosure relates to methods of treating an mTOR-related disease, disorder or condition and methods for treating proliferative diseases, disorders, and conditions using 4-aminoquinoline compounds identified herein as having cytotoxic and/or anti-proliferative activity. [06] In one embodiment, the 4-aminoquinoline compound is referred to as JTC-801. In one aspect, the present disclosure provides methods for treating an mTOR disease, disorder or condition in a subject in need thereof, the method including administering to the subject a therapeutically effective amount of a pharmaceutical composition comprising JTC-801, or a pharmaceutically acceptable salt, solvate, clathrate, hydrate, polymorph, metabolite, prodrug, analog or derivative thereof. In one embodiment, the pharmaceutical composition includes JTC-801. [07] The mTOR disease, disorder or condition can be selected from genetic tumor syndromes, neurological diseases, fragile X syndrome, Down syndrome, Rett syndrome, epilepsy, autism/neurodevelopmental disorders, neurodegenerative diseases, metabolic diseases or proliferative disorders, including cancer. In one embodiment, the proliferative disorder is a cancer that is not known to be mediated by hyper activation of mTOR. [08] The neurodegenerative disease can be Alzheimer's, Parkinson's, Huntington's disease, amyotrophic lateral sclerosis, or frontotemporal dementia. [09] The metabolic disease can be obesity, diabetes such as Type I or Type II diabetes, lipotoxicity, hyperlipidemia, hyperglycemia, insulin resistance, hyperglycemia, hyperinsulinemia, hypoinsulinemic, fatty liver disease, or cirrhosis. [10] The proliferative disorder can be cancer. In one embodiment, the cancer has not previously been linked to constitutive activation of mTOR. The cancer can be brain cancer, glioma, sarcoma, breast cancer, lung cancer, non-small-cell lung cancer, mesothelioma, appendiceal cancer, genitourinary cancers, renal cell carcinoma, prostate cancer, bladder cancer, testicular cancer, penile cancer, cervical cancer, ovarian cancer, von Hippel Lindau disease, head and neck cancer, gastrointestinal cancer, hepatocellular carcinoma, gallbladder cancer, esophageal cancer, gastric cancer, colorectal cancer, pancreatic cancer, neuroendocrine tumors, thyroid tumor, pituitary tumor, adrenal tumor, hematological malignancy, Hodgkin's lymphoma, Non-Hodgkin's lymphoma, mantle cell lymphoma, myeloma, B-cell lymphoma, leukemia or melanoma. [11] The mTOR disease, disorder or condition can be Tuberous Sclerosis (TSC) and/or Lymphangioleiomyomatosis (LAM). [12] In one embodiment, the disclosure provides methods of treating cancer in a subject in need thereof, the methods comprising administering to the subject JTC-801 . In one embodiment the cancer is selected from the group consisting of colon cancer, prostate cancer, lung cancer, breast cancer, pancreatic cancer, a leukemia, and a neuroglioma. In one embodiment an amount of JTC-80 1 is administered effective alleviate one or more symptoms of the cancer, for example an amount effective to inhibit the proliferation of the cancer cells and/or to slow the growth or reduce the size of a solid tumor, or to prevent the spread or further spread of the cancer to other tissues of the subject. [13] The method can further include administering to the subject one or more additional therapies or therapeutic agents as part of a therapeutic regimen. [14] The one or more additional therapeutic agents can be selected from the group consisting of an mTOR inhibitor, a statin, preferably simvastatin, an anti-estrogen therapy, doxycycline, a tyrosine kinase inhibitor, a src inhibitor, an autophagy inhibitor (e.g. hydroxychloroquine), a Bcr-ABL ligand, a VEGF-C or -D inhibitor, and a VEGF receptor inhibitor. Preferably, the one or more additional therapeutic agents is a tyrosine kinase inhibitor. Preferably, the tyrosine kinase inhibitor is selected from imatinib and pazopanib. [15] The one or more additional therapies can be selected from chemotherapy, radiation therapy, hormonal therapy, anti-estrogen therapy, biological response modifier treatment, bone marrow transplantation, gene therapy, and surgery. Preferably, the one or more additional therapies is selected from anti-estrogen