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Fig. 1C Fig. 1A Fig. Ib ) ( (51) International Patent Classification: DZ, EC, EE, EG, ES, FI, GB, GD, GE, GH, GM, GT, HN, A61K 31/4045 (2006.01) C07D 471/04 (2006.01) HR, HU, ID, IL, IN, IR, IS, JO, JP, KE, KG, KH, KN, KP, A61K 31/519 (2006.01) KR, KW, KZ, LA, LC, LK, LR, LS, LU, LY, MA, MD, ME, MG, MK, MN, MW, MX, MY, MZ, NA, NG, NI, NO, NZ, (21) International Application Number: OM, PA, PE, PG, PH, PL, PT, QA, RO, RS, RU, RW, SA, PCT/US20 19/0272 17 SC, SD, SE, SG, SK, SL, SM, ST, SV, SY, TH, TJ, TM, TN, (22) International Filing Date: TR, TT, TZ, UA, UG, US, UZ, VC, VN, ZA, ZM, ZW. 12 April 2019 (12.04.2019) (84) Designated States (unless otherwise indicated, for every (25) Filing Language: English kind of regional protection available) . ARIPO (BW, GH, GM, KE, LR, LS, MW, MZ, NA, RW, SD, SL, ST, SZ, TZ, (26) Publication Language: English UG, ZM, ZW), Eurasian (AM, AZ, BY, KG, KZ, RU, TJ, (30) Priority Data: TM), European (AL, AT, BE, BG, CH, CY, CZ, DE, DK, 62/657,563 13 April 2018 (13.04.2018) US EE, ES, FI, FR, GB, GR, HR, HU, IE, IS, IT, LT, LU, LV, 62/657,540 13 April 2018 (13.04.2018) US MC, MK, MT, NL, NO, PL, PT, RO, RS, SE, SI, SK, SM, 62/743,469 09 October 2018 (09. 10.2018) US TR), OAPI (BF, BJ, CF, CG, Cl, CM, GA, GN, GQ, GW, 62/753,025 30 October 2018 (30. 10.2018) US KM, ML, MR, NE, SN, TD, TG). 62/753,023 30 October 2018 (30. 10.2018) US Declarations under Rule 4.17: (71) Applicant: TOLERO PHARMACEUTICALS, INC. — of inventorship (Rule 4.17(iv)) [US/US]; 3900 N Traverse Mountain Blvd, Lehi, Utah 84043 (US). Published: — with international search report (Art. 21(3)) (72) Inventors: FOULKS, Jason Marc; 3900 N Traverse Mountain Blvd, Lehi, Utah 84043 (US). WARNER, Steven L.; 3900 N Traverse Mountain Blvd, Lehi, Utah 84043 (US). (74) Agent: LIGON, Toby, J. et al.; Seed Intellectual Proper¬ ty Law Group LLP, Suite 5400, 701 Fifth Avenue, Seattle, Washington 98104-7064 (US). (81) Designated States (unless otherwise indicated, for every kind of national protection available) : AE, AG, AL, AM, AO, AT, AU, AZ, BA, BB, BG, BH, BN, BR, BW, BY, BZ, CA, CH, CL, CN, CO, CR, CU, CZ, DE, DJ, DK, DM, DO, (54) Title: PIM KINASE INHIBITORS FOR TREATMENT OF MYELOPROLIFERATIVE NEOPLASMS AND FIBROSIS ASSOCIATED WITH CANCER FIG. 1C FIG. 1A FIG. IB (57) Abstract: Methods for treatment of myeloproliferative neoplasms and/or fibrosis associated with cancer are provided. The dis¬ closed methods comprise administering a PIM kinase inhibitor, and optionally a JAK kinase inhibitor or other therapeutic agent, to a mammal in need thereof. PIM KINASE INHIBITORS FOR TREATMENT OF MYELOPROLIFERATIVE NEOPLASMS AND FIBROSIS ASSOCIATED WITH CANCER RELATED APPLICATIONS [0001] This application claims the benefit of U.S. Provisional Application No. 62/657,540, filed on April 13, 2018, U.S. Provisional Application No. 62/657,563, filed on April 13, 2018, U.S. Provisional Application No. 62/743,469, filed on October 9, 2018, U.S. Provisional Application No. 62/753,023, filed on October 30, 2018, and U.S. Provisional Application No. 62/753,025, filed on October 30, 2018. The entire teachings of the above applications are incorporated herein by reference. BACKGROUND [0002] Despite meaningful advancements in the treatment of many hematological malignancy indications, significant unmet needs persist. Drug resistance and poor overall survival remain a substantial challenge that will require the development and evaluation of novel therapeutic agents. [0003] PIM kinases are frequently overexpressed in various hematologic and solid tumors, allowing cancer cells to evade apoptosis and promoting tumor growth. In inflammatory disorders, PIM-l kinase has been shown to mediate interleukin-22 signaling in cell-based and animal models. [0004] Thus, there is a need for treatment regimens that exploit the activity of PIM kinase inhibitors to treat hematological malignancies. SUMMARY [0005] This disclosure is based, at least in part, on the discovery that the compound of structural formula l is a PIM kinase inhibitor, and demonstrates profound preclinical activity in models of leukemia and myeloproliferative disorders (e.g., myelofibrosis). [0006] Accordingly, provided herein is a method for treating a myeloproliferative neoplasm (e.g., myelofibrosis) in a mammal in need thereof. The method comprises administering to the mammal from about 250 mg to about 2.5 g (e.g, from about 300 mg to about 1.5 g, from about 450 mg to about 1.5 g) per day of a compound represented by structural formula 1: or a pharmaceutically acceptable salt thereof; and an effective amount of ruxolitinib, or a pharmaceutically acceptable salt thereof. [0007] Also provided herein is a pharmaceutical composition comprising a pharmaceutically acceptable carrier or excipient; a compound of structural formula 1, or a pharmaceutically acceptable salt thereof; and ruxolitinib, or a pharmaceutically acceptable salt thereof. [0008] Also provided herein is a kit comprising a compound of structural formula 1, or a pharmaceutically acceptable salt thereof; ruxolitinib, or a pharmaceutically acceptable salt thereof; and written instructions for administering the compound of structural formula 1, or a pharmaceutically acceptable salt thereof, in combination with ruxolitinib, or a pharmaceutically acceptable salt thereof, to treat a myeloproliferative neoplasm (e.g ., myelofibrosis). [0009] These and other aspects of embodiments of the disclosure will be apparent upon reference to the following detailed description. To this end, various references are set forth herein which describe in more detail certain background information, procedures, compounds and/or compositions, and are each hereby incorporated by reference in their entirety. BRIEF DESCRIPTION OF THE DRAWINGS [0010] In the figures, identical reference numbers identify similar elements. The sizes and relative positions of elements in the figures are not necessarily drawn to scale and some of these elements are enlarged and positioned to improve figure legibility. Further, the particular shapes of the elements as drawn are not intended to convey any information regarding the actual shape of the particular elements, and have been solely selected for ease of recognition in the figures. [0011] FIGs. 1A-C show increased expression of PIM1 mRNA in myeloproliferative neoplasm hematopoietic progenitors and long-term hematopoietic stem cells. [0012] FIGs. 2A-C show PIM1 protein expression in myelofibrosis patients as immunoblotting results. [0013] FIGs. 3A-C show inhibition of hematopoietic cells for PIM1 knockdown compared to wild-type JAK2 expressing cells. [0014] FIGs. 4A-E illustrate Compound 1 inducing selective inhibition of proliferation in cells expressing JAK2 V617F. [0015] FIGs. 5A-B depict myeloproliferative neoplasm inhibition in CK34+ cells when treated with Compound 1. [0016] FIGs. 6A-6F show a synergistic relationship between Compound 1 (a PIM kinase inhibitor) and ruxolitinib (a JAK2 inhibitor) for inducing apoptosis in hematopoietic cells expressing JAK2 V617F. [0017] FIGs. 7A-C illustrate that Compound 1 overcomes resistance to a JAK2 inhibitor (ruxolitinib) in cells expressing JAK2 V617F. [0018] FIG. 8 presents spleen and bone marrow samples of knock-in mice expressing JAK2 V617F that develop high-grade myelofibrosis. [0019] FIG. 9A-E are histograms comparing treatment with Compound 1 alone or in combination with ruxolitinib to improve blood cell counts (white blood cells and neutrophils) and spleen size in a myelofibrosis mouse model. [0020] FIG. 10 is a depiction of tissue samples for comparing treatment using Compound 1 alone or in combination with ruxolitinib and the related reduction of fibrosis in myelofibrosis mouse models. [0021] FIGs. 11A-E show genes related to TNFa and WNT signaling pathways are downregulated in JAK2 V617F expressing hematopoietic progenitors after treatment with Compound 1 alone or in combination with ruxolitinib. [0022] FIG. 12 shows a plot of Compound 1 having anti-proliferative activity against prostate cancer cells in a colony formation assay. [0023] FIG. 13 shows the actual results from the colony formation assay. [0024] FIG. 14 is a plot of tumor volume against the number of days for a prostate adenocarcinoma xenograft model. [0025] FIG. 15 illustrates the potency of Compound 1 compared to Compound A with respect to inhibition of p-BAD. DETAILED DESCRIPTION [0026] In the following description, certain specific details are set forth in order to provide a thorough understanding of various embodiments of the disclosure. However, one skilled in the art will understand that embodiments of the disclosure may be practiced without these details. [0027] ETnless the context requires otherwise, throughout the present specification and claims, the word "comprise" and variations thereof, such as "comprises" and "comprising," are to be construed in an open, inclusive sense (i.e., as "including, but not limited to"). [0028] Reference throughout this specification to "one embodiment" or "an embodiment" means that a particular feature, structure or characteristic described in connection with the embodiment is included in at least one embodiment of the present disclosure. Thus, the appearances of the phrases "in one embodiment" or "in an embodiment" in various places throughout this specification are not necessarily all referring to the same embodiment. Furthermore, the particular features or characteristics may be combined in any suitable manner in one or more embodiments. [0029] Amino" refers to the -NH2 radical. [0030] "Cyano" refers to the
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