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WO 2017/152062 Al 8 September 2017 (08.09.2017) P O P C T

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WO 2017/152062 Al 8 September 2017 (08.09.2017) P O P C T (12) INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT) (19) World Intellectual Property Organization International Bureau (10) International Publication Number (43) International Publication Date WO 2017/152062 Al 8 September 2017 (08.09.2017) P O P C T (51) International Patent Classification: AO, AT, AU, AZ, BA, BB, BG, BH, BN, BR, BW, BY, A61K 31/435 (2006.01) A61K 35/00 (2006.01) BZ, CA, CH, CL, CN, CO, CR, CU, CZ, DE, DJ, DK, DM, DO, DZ, EC, EE, EG, ES, FI, GB, GD, GE, GH, GM, GT, (21) International Application Number: HN, HR, HU, ID, IL, IN, IR, IS, JP, KE, KG, KH, KN, PCT/US20 17/020678 KP, KR, KW, KZ, LA, LC, LK, LR, LS, LU, LY, MA, (22) International Filing Date: MD, ME, MG, MK, MN, MW, MX, MY, MZ, NA, NG, 3 March 2017 (03.03.2017) NI, NO, NZ, OM, PA, PE, PG, PH, PL, PT, QA, RO, RS, RU, RW, SA, SC, SD, SE, SG, SK, SL, SM, ST, SV, SY, (25) Filing Language: English TH, TJ, TM, TN, TR, TT, TZ, UA, UG, US, UZ, VC, VN, (26) Publication Language: English ZA, ZM, ZW. (30) Priority Data: (84) Designated States (unless otherwise indicated, for every 62/303,547 4 March 2016 (04.03.2016) US kind of regional protection available): ARIPO (BW, GH, GM, KE, LR, LS, MW, MZ, NA, RW, SD, SL, ST, SZ, (71) Applicants: GILEAD SCIENCES, INC. [US/US]; 333 TZ, UG, ZM, ZW), Eurasian (AM, AZ, BY, KG, KZ, RU, Lakeside Drive, Foster City, California 94404 (US). X-RX, TJ, TM), European (AL, AT, BE, BG, CH, CY, CZ, DE, INC. [US/US]; 430 East 29th Street, Suite 1060, New DK, EE, ES, FI, FR, GB, GR, HR, HU, IE, IS, IT, LT, LU, York, New York 10016 (US). LV, MC, MK, MT, NL, NO, PL, PT, RO, RS, SE, SI, SK, SM, TR), OAPI (BF, BJ, CF, CG, CI, CM, GA, GN, GQ, (72) Inventor: SUNDY, John; 333 Lakeside Drive, Foster City, GW, KM, ML, MR, NE, SN, TD, TG). California 94404 (US). Published: (74) Agents: TRIMBLE, Alexander R. et al; KILPATRICK TOWNSEND & STOCKTON LLP, Mailstop: IP Docket — with international search report (Art. 21(3)) ing - 22, 1100 Peachtree Street, Suite 2800, Atlanta, Geor — before the expiration of the time limit for amending the gia 30309 (US). claims and to be republished in the event of receipt of (81) Designated States (unless otherwise indicated, for every amendments (Rule 48.2(h)) kind of national protection available): AE, AG, AL, AM, (54) Title: COMPOSITIONS AND COMBINATIONS OF AUTOTAXIN INHIBITORS (57) Abstract: Pharmaceutical compositions are provided having an autotaxin inhibitor compound and an additional therapeutic agent such as anti-fibrotics, anti-inflamatory agents, anti-cancer agents, and cardiovascular agents. COMPOSITIONS AND COMBINATIONS OF AUTOTAXIN INHIBITORS CROSS-REFERENCES TO RELATED APPLICATIONS [0001] This application claims priority to U.S. Provisional Application No. 62/303,547, filed March 4, 2016, which is incorporated herein in its entirety for all purposes. BACKGROUND [0002] Autotaxin (ATX) is a secreted enzyme of the ectonucleotide pyrophosphatase/phosphodiesterase family, and is also known as Ectonucleotide Pyrophosphatase/Phosphodiesterase 2 (ENPP-2 or NPP2). ATX plays a role in driving pathological conditions, including fibrosis, arthritic inflammation, neurodegeneration, neuropathic pain, and cancer. ATX is the fundamental regulator of the conversion of Lysophosphatidylcholine (LPC) to Lysophosphatidic Acid (LPA). LPA is a bioactive lipid that affects migration, proliferation, and survival of various cell types. [0003] Inhibition of ATX has been shown to reduce LPA levels in pathological settings. Reduction of LPA may provide tlierapeutic benefits in diseases with unmet medical need, including cancer, lymphocyte homing, chronic inflammation, neuropathic pain, fibrotic diseases such as Idiopathic Pulmonary Fibrosis (IPF), thrombosis, and cholestatic pruritus which are caused, mediated and/or propagated by increased LPA levels and/or activation of ATX. [0004] Fibrotic diseases are chronic, debilitating and often lethal pathologies driven by a dysreguiated response to tissue or organ injury. Fibrosis can develop in the liver, kidney, lung, dermis, vasculature, gut and other sites. Fibrosis develops due to action of pathways including growth factors, cytokines, integrin and lipids. [0005] ATX, LPA, and LPA Receptor (LPAR) pathways have been implicated in fibrotic disease. For example, profiling studies show increased levels of ATX, LPA and LPARs in various rodent models of fibrosis and in human patient fluids and biopsy tissue. LPA can induce proliferative, survival, and chemotactic responses in transformed cell lines, indicating that LPA may exest pro-inflammatory and protibrotic responses in cells known to be critical in fibrotic disease, including: fibroblasts, smooth muscle cells, macrophages, epithelial and endothelial cells, and leukocytes. Gene-targeted mouse models have implicated LPARs in fibrosis pathogenesis. Inhibitors of LPARs indicate that antagonism of receptors within this pathway blocked or reversed fibrosis in the lung, liver, kidney and skin in rodents. Cell type- specific gene targeting studies have showed that ATX plays a role in the development of lung fibrosis and inflammatory arthritis. [0006] ATX and LPA have also been implicated in tumor progression and metastasis. ATX may be responsible for increased LPA levels in ascites and plasma of ovarian cancer patients since ATX converts LPC to LPA. Increased levels of LPA, altered receptor expression and altered responses to LPA may contribute to initiation, progression or outcome of ovarian cancer. LPA has also been linked to prostate, breast, melanoma, head and neck, bowel, brain and thyroid cancers. [0007] LPA has been shown to promote tumor cell survival, proliferation, invasion and migration into neighboring tissues, which can result in the formation of metastases. Additionally, LPA promotes cytoskeletal remodeling that may enhance migratory and invasive properties of cells, which may contribute to cancer metastasis. These biological and pathobiological processes of LPA are initiated through the activation of G-protein coupled receptors. [0008] Transcriptome analyses of more than 350 normal tissues and more than 1700 malignant tissues demonstrate that ATX is expressed in a variety of carcinomas and sarcomas, underscoring the potential contribution of LPA to metastatic disease. [0009] Accordingly, when treating patients with diseases, such as cancer, lymphocyte homing, chronic inflammation, neuropathic pain, fibrotic diseases, thrombosis, and cholestatic pruritus it is desirable to lower LPA levels. This can be accomplished through inhibition of enzymes involved in LPA biosynthesis, such as ATX. [0010] Since ATX is expressed in tumors and affects tumor cell proliferation and invasion into neighboring tissues both of which can lead to the formation of metastases, ATX is a target for anti-tumor therapy. Moreover, in angiogenesis, ATX, taken with other anti- angiogenetic factors, brings about blood vessel formation Angiogenesis supplies tumors with nutrients during tumor growth. Therefore, inhibition of angiogenesis is a target for anti-tumor therapy, leading to starvation of a tumor. [0011] ATX has also been implicated in nerve injury-induced neuropathic pain. LPA biosynthesis, through ATX, is the source of LPA for LPAl receptor-mediated neuropathic pain. Therefore, targeted inhibition of ATX-mediated LPA biosynthesis may represent a novel treatment to prevent nerve injury-induced neuropathic pain. [0012] Accordingly, there remains a need for ATX inhibitors having the potential to reach the clinic and obtain regulatory approval for use in the treatment and/or prophylaxis of physiological and/or pathophysiological conditions, such as cancer, lymphocyte homing, chronic inflammation, neuropathic pain, fibrotic diseases, thrombosis, and cholestatic pruritus which are caused, mediated and/or propagated by increased LPA levels and/or the activation of ATX. BRIEF SUMMARY [0013] In one embodiment, the present invention provides a pharmaceutical composition including a therapeutically effective amount of an autotaxm inhibitor compound of Formula I : or a pharmaceuticaliy acceptable salt thereof, an additional therapeutic agent, and a pharmaceutically acceptable carrier or excipient, wherein: X1 and X2 are each independently selected from one or more of C alkyl, C=0, NR , or O; 3 X' is independently selected from one or more of C 1-2 alkyl, C=0, NR , O, or CR ' : m and n are each independently selected from 0, 1 or 2; R is selected from Co-nalkyl-, C - cycloa kyl- Co- y - , - heterocyc oa kyi- Co- nalkyl-, aryl-Co-nalkyl-, aryl-Ca-ncycloalkyl-, heteroaryl-Co-nalkyl-, heteroaryl-Cs-ncycloalkyl-, or heteroaryl-Cs. nheterocycloalkyl-, any of which is optionally substituted with one or more independent G1 substituents; R2 is selected from Co^alkyl-, Cs-ncycloalkyl-Co-nalkyl-, C - eterocyc oa ky - C alkyl- , aryl-Co-nalkyl--, aryl-^.ncycloalkyl-, ary - heteiOcycloalky - , heteroaryl-Co-i 2alkyl-, lieteroaryl-Co^cyeloalkyl-, or heteroaiyi-Cs- nheterocycloalkyl-, any of which is optionally substituted with one or more independent G2 substituents; is selected from Co-nalkyl-, C cyc oa ky - Co- a kyi---, C 3-i2heterocycioalkyl- Co-i2alkyi-, aryl-Co-nalkyl-, aryl-C3-i2cycloalkyl-, aryl-C3- nheterocycloalkyl-, heteroaryl-Co-nalkyl-, heteroaryl-Cs^cycloalkyl---, or heteroaryl- C - heterocycloalkyl- , any of which is optionally substituted with one or more independent G substituents; 2 and R are each independently a linear structure, or, R and R are taken together with the carbon atom to which they are attached to form a 3-12
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