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WO 2017/197240 Al O (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 2017/197240 Al 16 November 2017 (16.11.2017) W !P O PCT (51) International Patent Classification: mon; 1600 Huron Parkway, 2nd Floor, Ann Arbor, Michi A61P 35/02 (2006.01) C07D 209/00 (2006.01) gan 48109 (US). ZHUANG, Jin; 1600 Huron Parkway, A61K 31/395 (2006.01) C07D 213/83 (2006.01) 2nd Floor, Ann Arbor, Michigan 48109 (US). MONT¬ A61P 35/00 (2006.01) GOMERY, Deanna; 1600 Huron Parkway, 2nd Floor, Ann Arbor, Michigan 48109 (US). DENG, Jing; 1600 Huron (21) International Application Number: Parkway, 2nd Floor, Ann Arbor, Michigan 48109 (US). PCT/US2017/032365 SZEWCZYK, Marta; 1600 Huron Parkway, 2nd Floor, (22) International Filing Date: Ann Arbro, Michigan 48109 (US). LI, Hao; 1600 Huron 12 May 2017 (12.05.2017) Parkway, 2nd Floor, Ann Arbor, Michigan 48109 (US). (25) Filing Language: English (74) Agent: STAPLE, David W.; 2275 Deming Way, Ste 310, Middleton, Wisconsin 53562 (US). (26) Publication Langi English (81) Designated States (unless otherwise indicated, for every (30) Priority Data: kind of national protection available): AE, AG, AL, AM, 62/335,160 12 May 2016 (12.05.2016) US AO, AT, AU, AZ, BA, BB, BG, BH, BN, BR, BW, BY, BZ, (71) Applicant: THE REGENTS OF THE UNIVERSITY OF CA, CH, CL, CN, CO, CR, CU, CZ, DE, DJ, DK, DM, DO, MICHIGAN [US/US]; 1600 Huron Parkway, 2nd Floor, DZ, EC, EE, EG, ES, FI, GB, GD, GE, GH, GM, GT, HN, Ann Arbor, Michigan 48109 (US). HR, HU, ID, IL, IN, IR, IS, JP, KE, KG, KH, KN, KP, KR, KW, KZ, LA, LC, LK, LR, LS, LU, LY, MA, MD, ME, MG, (72) Inventors: GREMBECKA, Jolanta; 1600 Huron Park MK, MN, MW, MX, MY, MZ, NA, NG, NI, NO, NZ, OM, way, 2nd Floor, Ann Arbor, Michigan 48109 (US). CIER- PA, PE, PG, PH, PL, PT, QA, RO, RS, RU, RW, SA, SC, PICKI, Tomasz; 1600 Huron Parkway, 2nd Floor, Ann SD, SE, SG, SK, SL, SM, ST, SV, SY,TH, TJ, TM, TN, TR, Arbor, Michigan 48109 (US). ROGAWSKI, David; 1600 TT, TZ, UA, UG, US, UZ, VC, VN, ZA, ZM, ZW. Huron Parkway, 2nd Floor, Ann Arbor, Michigan 48109 (US). BORKIN, Dmitry; 1600 Huron Parkway, 2nd Floor, (84) Designated States (unless otherwise indicated, for every Ann Arbor, Michigan 48109 (US). KLOSSOWSKI, Szy- kind of regional protection available): ARIPO (BW, GH, (54) Title: ASH1L INHIBITORS AND METHODS OF TREATMENT THEREWITH FIG. 1 Cp. f€ ¾ i i V1 00- o C g C rr} µ )) - (57) Abstract: Provided herein are small molecule inhibitors of ASH 1L activity and small molecules that facilitate ASH 1L degradation and methods of use thereof for the treatment of disease, including acute leukemia, solid cancers and other diseases dependent on activity of ASH1L. [Continued on nextpage] WO 2017/197240 Al llll II II 11III I II I II I III I II II III II I II GM, KE, LR, LS, MW, MZ, NA, RW, SD, SL, ST, SZ, TZ, UG, ZM, ZW), Eurasian (AM, AZ, BY, KG, KZ, RU, TJ, TM), European (AL, AT, BE, BG, CH, CY, CZ, DE, DK, EE, ES, FI, FR, GB, GR, HR, HU, IE, IS, IT, LT, LU, 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, GW, KM, ML, MR, NE, SN, TD, TG). 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)) ASHIL INHIBITORS AND METHODS OF TREATMENT THEREWITH CROSS-REFERENCE TO RELATED APPLICATIONS The present application claims the priority benefit of U.S. Provisional Patent Application 62/335,160, filed May 12, 2016, which is incorporated by reference in its entirety. FIELD Provided herein are small molecule inhibitors of ASHIL activity and small molecules that facilitate ASHIL degradation and methods of use thereof for the treatment of disease, including acute leukemia, solid cancers and other diseases dependent on activity of ASHIL. BACKGROUND ASHIL (Absent small and hoiiieotic disks protein 1 homolog; EC:2. 1.1.43) is a histone-lysine N-methyltransferase (KMTase), which methylates histone 3, lysine 36 (H3K36). ASHIL is required for chromatin association of MLL fusion proteins at crucial leukemia target genes and for MLL fusion protein mediated oncogenic transformation, implying that ASHIL represents a therapeutic target in MLL leukemias and possibly other leukemias with high HOX expression (ref. 1; incorporated by reference in their entireties). ASHIL is also overexpressed in a variety of solid tumors, including thyroid and breast cancer (refs. 2, 3; incorporated by reference in their entireties). In thyroid cancer, ASHIL is overexpressed in tumor-specific truncated forms. The tumor suppressor microRNA miR-142- 3p inhibits ASHIL protein expression by binding to the ASHIL 3'UTR, an effect correlated with inhibition of colony formation and slowing of thyroid cancer cell growth (ref. 2; incorporated by reference in its entirety). In addition, the ASHIL gene frequently undergoes copy number amplification in aggressive basal-like breast cancer, and high expression of ASHIL mRNA is associated with shorter survival of breast cancer patients (ref. 3; incorporated by reference in its entirety). Finally, in hepatocellular carcinoma (HCC), structural variations are found near the ASHIL gene, and knockdown of ASHIL in HCC cells slows proliferation (ref. 4; incorporated by reference in its entirety). In multiple developmental and oncogenic contexts, ASHIL activates HOXA -B, -C, and -D genes MEIS (refs. 5-8; incorporated by reference in their entireties). ASHlL's KMTase activity is required for at least some of its gene activating function, as deletion of the ASHIL SET domain in differentiating mouse embryonic stem cells leads to loss of expression of 152 genes, including members of the Hox and Wnt familes (ref. 8; incorporated by reference in its entirety). These findings are highly relevant because H genes are oncogenic drivers in many different blood and solid tumors (ref. 9; incorporated by reference in its entirety). For example, overexpression of HOXA9 is highly associated with a poor prognosis in AML (ref. 10; incorporated by reference in its entirety), and HOXA9 and its collaborator MEIS1 are required for survival of MLL-rearranged leukemia cells (refs. 11, 12; incorporated by reference in their entireties). ASH1L deficiency causes a major reduction in long-term hematopoietic stem cells (HSC) in mouse bone marrow, but has very modest effects on peripheral blood counts due to increased proliferation of progenitors downstream of HSCs (ref. 5; incorporated by reference in its entirety). ASHlL-deficient HSCs are also unable to reconstitute bone marrow output when transplanted into lethally irradiated mice (ref. 5; incorporated by reference in its entirety). These findings indicate that ASH1L maintains quiescence and self-renewal potential of long-term HSCs. ASH1L also plays important roles in diseases beyond cancer. For example, in facioscapulohumeral muscular dystrophy, ASH1L is recruited by a noncoding RNA to chromosome region 4q35, where it causes H3K36 dimethylation, chromatin remodeling, and abnormal transcription of 4q35 genes (ref. 13; incorporated by reference in its entirety). In liver fibrosis, during the transdifferentiation of hepatic stellate cells to fibrogenic myofibroblasts, ASH1L is upregulated and binds to and activates profibrogenic genes (ref. 14; incorporated by reference in its entirety). SUMMARY Provided herein are small molecule inhibitors of ASH1L activity and small molecules that facilitate ASH1L degradation and methods of use thereof for the treatment of disease, including acute leukemia, solid cancers and other diseases dependent on activity of ASH1L. In some embodiments, provided herein are compounds comprising a structure of Formula (I): wherein X is S, O, NH or CH2; wherein R1 is selected from H, alkyl, substituted alkyl, hydroxy, alkoxy, amine, thioalkyl, halogen, ketone, amide, cyano, sulfonyl, dialkylphosphine oxide, a carbocyclic ring, an aromatic ring, a substituted aromatic ring, a heterocyclic aromatic ring, a substituted heterocyclic aromatic ring, a substituted or non-substituted heterocyclic non-aromatic ring, carbocyclic or heterocyclic aromatic ring fused to another aromatic ring, a hydrogen bond donor, a hydrogen bond acceptor, and combinations thereof; wherein L is 0-3 C, S, O, and/or N members, and wherein if L is 0 members there is no bond at L; wherein is a 4-7 member aryl, heteroaryl, carbocyclic (e.g., cycloalkyl ring or unsaturated non-aromatic carbocyclic ring) or heterocyclic ring, optionally substituted at 0-5 positons by RD 1-RD5 substituents; wherein RD 1-RD5, when present, are independently selected from H, alkyl, substituted alkyl, hydroxy, alkoxy, amine, substituted amine, thioalkyl, halogen, ketone, amide, substituted amide, cyano, sulfonyl, carboxy, dialkylphosphine oxide, a carbocyclic ring, a substituted carbocyclic ring, an aromatic ring, a substituted aromatic ring, a heterocyclic aromatic ring, a substituted heterocyclic aromatic ring, a substituted or non-substituted heterocyclic non-aromatic ring, carbocyclic or heterocyclic aromatic ring fused to another aromatic ring, a hydrogen bond donor, a hydrogen bond acceptor, and combinations thereof; wherein s an optionally present 4-7 member carbocyclic, heterocyclic, aryl, or heteroaryl ring which forms a ring system with , and is optionally substituted at 0-5 positons by RG 1-RG5 substituents; wherein R -R , when present, are independently selected
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