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WO 2017/223229 Al 28 December 2017 (28.12.2017) W !P O PCT

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WO 2017/223229 Al 28 December 2017 (28.12.2017) W !P O PCT (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 2017/223229 Al 28 December 2017 (28.12.2017) W !P O PCT (51) International Patent Classification: (74) Agent: RED), Andrea L.C. et al; One International A61K 31/445 (2006.01) C07D 221/00 (2006.01) Place, 40th Floor, 100 Oliver Street, Boston, Massachusetts A61K 31/451 (2006.01) C07D 227/04 (2006.01) 021 10-2605 (US). A61K 31/4523 (2006.01) C07D 235/06 (2006.01) (81) Designated States (unless otherwise indicated, for every (21) International Application Number: kind of national protection available): AE, AG, AL, AM, PCT/US2017/038590 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, (22) International Filing Date: DZ, EC, EE, EG, ES, FI, GB, GD, GE, GH, GM, GT, HN, 2 1 June 2017 (21 .06.2017) HR, HU, ID, IL, IN, IR, IS, JO, JP, KE, KG, KH, KN, KP, (25) Filing Language: English 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, (26) Publication Language: English OM, PA, PE, PG, PH, PL, PT, QA, RO, RS, RU, RW, SA, (30) Priority Data: SC, SD, SE, SG, SK, SL, SM, ST, SV, SY,TH, TJ, TM, TN, 62/352,816 2 1 June 2016 (21 .06.2016) US TR, TT, TZ, UA, UG, US, UZ, VC, VN, ZA, ZM, ZW. 62/456,536 08 February 2017 (08.02.2017) US (84) Designated States (unless otherwise indicated, for every (71) Applicant: X4 PHARMACEUTICALS, INC. [US/US]; kind of regional protection available): ARIPO (BW, GH, 955 Massachusetts Avenue; 4th Floor, Cambridge, Massa GM, KE, LR, LS, MW, MZ, NA, RW, SD, SL, ST, SZ, TZ, chusetts 02139 (US). UG, ZM, ZW), Eurasian (AM, AZ, BY, KG, KZ, RU, TJ, TM), European (AL, AT, BE, BG, CH, CY, CZ, DE, DK, (72) Inventors: BOURQUE, Elyse Marie Josee; 3115 Racine EE, ES, FI, FR, GB, GR, HR, HU, IE, IS, IT, LT, LU, LV, Street, Unit 214, Bellingham, Washington 98226 (US). SK- MC, MK, MT, NL, NO, PL, PT, RO, RS, SE, SI, SK, SM, ERLJ, Renato; 12 Crocker Circle, West Newton, Massa TR), OAPI (BF, BJ, CF, CG, CI, CM, GA, GN, GQ, GW, chusetts 02465 (US). KM, ML, MR, NE, SN, TD, TG). (54) Title: CXCR4 INHIBITORS AND USES THEREOF Figure 1 30 Group 1, PO-vehicle 29 28 Group 2 , PO-10mg/kg, 27 26 Group 3, PO-30mg/kg 25 24 Group 4 , PO-100mg/kg 23 22 2 1 20 o 19 18 17 16 15 3 Time(da^) (57) Abstract: The present invention provides compounds, compositions thereof, and methods of using the same. o [Continued on nextpage] WO 2017/223229 Al llll II II 11III I II I II III I II II I III II I II Published: — with international search report (Art. 21(3)) — before the expiration of the time limit for amending the claims and to be republished in the event of receipt of amendments (Rule 48.2(h)) CXCR4 INHIBITORS AND USES THEREOF CROSS-REFERENCE TO RELATED APPLICATIONS [0001] This application claims the benefit under 35 U.S.C . § 119(e) of U.S. Provisional Application nos. 62/352,816, filed June 21, 2016, and 62/456,536, filed February 8, 2017, the contents of all of which are incorporated herein in their entireties by reference. TECHNICAL FIELD OF THE INVENTION [0002] The present invention relates to compounds and methods useful for inhibition of C-X- C receptor type 4 (CXCR4). The invention also provides pharmaceutically acceptable compositions comprising compounds of the present invention and methods of using said compositions in the treatment of various disorders. BACKGROUND OF THE INVENTION [0003] C-X-C chemokine receptor type 4 (CXCR4), also known as fusin or cluster of differentiation 184 (CD 184), is a seven transmembrane G-protein coupled receptor (GPCR) belonging to Class I GPCR or rhodopsin-like GPCR family. Under normal physiological conditions, CXCR4 carries out multiple roles and is principally expressed in the hematopoietic and immune systems. CXCR4 was initially discovered as one of the co-receptors involved in human immunodeficiency virus (HIV) cell entry. Subsequent studies showed that it is expressed in many tissues, including brain, thymus, lymphatic tissues, spleen, stomach, and small intestine, and also specific cell types such as hematopoietic stem cells (HSC), mature lymphocytes, and fibroblasts. CXCL12, previously designated SDF- Ια, is the only known ligand for CXCR4. CXCR4 mediates migration of stem cells during embryonic development as well as in response to injury and inflammation. Multiple roles have been demonstrated for CXCR4 in human diseases such as cellular proliferative disorders, Alzheimer's disease, HIV, rheumatoid arthritis, pulmonary fibrosis, and others. For example, expression of CXCR4 and CXCL12 have been noted in several tumor types. CXCL12 is expressed by cancer-associated fibroblast (CAFs) and is often present at high levels in the tumor microenvironment (TME). In clinical studies of a wide range of tumor types, including breast, ovarian, renal, lung, and melanoma, expression of CXCR4/CXCL12 has been associated with a poor prognosis and with an increased risk of metastasis to lymph nodes, lung, liver, and brain, which are sites of CXCL12 expression. CXCR4 is frequently expressed on melanoma cells, particularly the CD133+ population that is considered to represent melanoma stem cells; in vitro experiments and murine models have demonstrated that CXCL12 is chemotactic for such cells. [0004] Furthermore, there is now evidence implicating the CXCL12/CXCR4 axis in contributing to the loss or lack of tumor responsiveness to angiogenesis inhibitors (also referred to as "angiogenic escape"). In animal cancer models, interference with CXCR4 function has been demonstrated to alter the TME and sensitize the tumor to immune attack by multiple mechanisms such as elimination of tumor re-vascularization and increasing the ratio of CD8+ T cells to Treg cells. These effects result in significantly decreased tumor burden and increased overall survival in xenograft, syngeneic, and transgenic cancer models. See Vanharanta et al. (2013) Nat Med 19: 50-56; Gale and McColl (1999) BioEssays 21: 17-28; Highfill et al. (2014) Sci Transl Med 6 : ra67; Facciabene et al. (201 1) Nature 475: 226-230. [0005] These data underscore the significant, unmet need for CXCR4 inhibitors to treat the many diseases and conditions mediated by aberrant or undesired expression of the receptor, for example in cellular proliferative disorders. SUMMARY OF THE INVENTION [0006] It has now been found that compounds of the present invention, and pharmaceutically acceptable compositions thereof, are effective as CXCR4 inhibitors. In one aspect, the present invention provides a compound of Formula I : or a pharmaceutically acceptable salt thereof, wherein each variable is as defined and described herein. [0007] In another aspect, the present invention provides a compound of Formula XII: or a pharmaceutically acceptable salt thereof, wherein each variable is as defined and described herein. [0008] Compounds of the present invention, and pharmaceutically acceptable compositions thereof, are useful for treating a variety of diseases, disorders or conditions, associated with CXC receptor type 4 (CXCR4). Such diseases, disorders, or conditions include cellular proliferative disorders (e.g., cancer) such as those described herein. BRIEF DESCRIPTION OF THE DRAWINGS [0009] FIG. 1 shows the results of a 7-day toxicology study in male C57BL/6 mice who were administered up to 100 mg/kg/day of compound 1-3 by oral gavage. All mouse body weights remained stable over the study period and no overt signs of toxicity were observed. [0010] FIG. 2 shows food consumption measurements of a 7-day toxicology study in male C57BL/6 mice who were administered up to 100 mg/kg/day of compound 1-3 by oral gavage. [0011] FIG. 3 shows mean plasma, brain and cerebrospinal fluid (CSF) concentration-time profiles of 1-3 after a single PO administration at 30 mg/kg in male C57BL/6 mice (5 weeks old) (N=3/time point). [0012] FIG. 4 shows mean plasma, brain and CSF concentration-time profiles of 1-3 after repeat PO administrations at 30 mg/kg in male C57BL/6 mice on day 7 (5 weeks old) (N=3/time point). DETAILED DESCRIPTION OF CERTAIN EMBODIMENTS 1. General Description of Certain Embodiments of the Invention: [0013] Compounds of the present invention, and pharmaceutical compositions thereof, are useful as inhibitors of CXCR4. Without wishing to be bound by any particular theory, it is believed that compounds of the present invention, and pharmaceutical compositions thereof, may inhibit the activity of CXCR4 and thus treat certain diseases, such as cancer. [0014] It has now been found that compounds of this invention, and pharmaceutically acceptable compositions thereof, are effective as CXCR4 inhibitors. In one aspect, the present invention provides a compound of Formula I : or a pharmaceutically acceptable salt thereof, wherein: Ring A is a 3-8 membered saturated or partially unsaturated monocyclic carbocyclic ring, phenyl, an 8-10 membered bicyclic aromatic carbocyclic ring, a 4-8 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, a 5-6 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or an 8-10 membered bicyclic heteroaromatic ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur; 6 each R is independently R, halogen, -CN, -OR, -N(R)2, -N0 2, -N3, -SR, or -I^-R
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