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WO 2018/226998 Al 13 December 2018 (13.12.2018) W !P O PCT

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WO 2018/226998 Al 13 December 2018 (13.12.2018) W !P O PCT (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 2018/226998 Al 13 December 2018 (13.12.2018) W !P O PCT (51) International Patent Classification: Declarations under Rule 4.17: C07D 471/04 (2006.01) A61K 31/519 (2006.01) — as to applicant's entitlement to apply for and be granted a C07D 487/04 (2006.01) A61P 7/00 (2006.01) patent (Rule 4.1 7(H)) (21) International Application Number: — as to the applicant's entitlement to claim the priority of the PCT/US20 18/036521 earlier application (Rule 4.17(Hi)) — of inventorship (Rule 4.1 7(iv)) (22) International Filing Date: 07 June 2018 (07.06.2018) Published: — with international search report (Art. 21(3)) (25) Filing Language: English (26) Publication Language: English (30) Priority Data: 62/5 17,410 09 June 2017 (09.06.2017) US (71) Applicant: GLOBAL BLOOD THERAPEUTICS, INC. [US/US]; 171 Oyster Point Blvd., Suite 300, South San Francisco, CA 94080 (US). (72) Inventors: YU, Chul; 171 Oyster Point Blvd., Suite 300, South San Francisco, CA 94080 (US). YU, Ming; 171 Oy s ter Point Blvd., Suite 300, South San Francisco, CA 94080 (US). ZANCANELLA, Manuel; 171 Oyster Point Blvd., Suite 300, South San Francisco, CA 94080 (US). LI, Zhe; 171Oyster Point Blvd., Suite 300, South San Francisco, CA 94080 (US). (74) Agent: SKELTON, Bryan, L.; Alston & Bird LLP, Bank of America Plaza, 101 South Tryon Street, Suite 4000, Char lotte, NC 28280-4000 (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, DZ, EC, EE, EG, ES, FI, GB, GD, GE, GH, GM, GT, HN, HR, HU, ID, IL, IN, IR, IS, JO, JP, KE, KG, KH, KN, KP, 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, OM, PA, PE, PG, PH, PL, PT, QA, RO, RS, RU, RW, SA, SC, 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. (84) Designated States (unless otherwise indicated, for every kind of regional protection available): ARIPO (BW, GH, 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). (54) Title: AZAINDOLE COMPOUNDS AS HISTONE METHYLTRANSFERASE INHIBITORS (57) Abstract: The present disclosure provides certain angular tricyclic compounds that are histone methyltransferases G9a and/or GLP inhibitors and are therefore useful for the treatment of diseases treatable by inhibition of G9a and/or GLP such as cancers and hemoglobinopathies (e.g., beta-thalassemia and sickle cell disease). Also provided are pharmaceutical compositions containing such compounds and processes for preparing such compounds. AZAINDOLE COMPOUNDS AS HISTONE METHYLTRANSFERASE INHIBITORS Incorporation By Reference To Any Priority Applications Any and all applications for which a foreign or domestic priority claim is identified, for example, in the Application Data Sheet or Request as filed with the present application, are hereby incorporated by reference under 37 CFR 1.57, and Rules 4.18 and 20.6, including U.S. Provisional Application No. 62/517,410, filed June 9, 2017. Field of the disclosure The present disclosure provides certain azaindole compounds that are histone methyltransferases G9a and/or GLP inhibitors, and are therefore useful for the treatment of diseases treatable by inhibition of G9a and/or GLP such as cancers and hemoglobinopathies (e.g., beta- thalassemia and sickle cell disease). Also provided are pharmaceutical compositions containing such compounds and processes for preparing such compounds. Background Chromatin modification plays an essential role in transcriptional regulation. These modifications, including DNA methylation, histone acetylation and histone methylation, are important in a variety of biological processes including protein production and cellular differentiation, and are emerging as attractive drug targets in various human diseases. Two particular enzymes associated with histone methylation are G9a and GLP, also known as EHMT2 and EHMT1 (Euchromatic histone-lysine N-methyltransferase 2 and 1). G9a and GLP are the primary enzymes for mono- and dimethylation at Lys 9 of histone H3 (H3K9mel and H3K9me2), and exist predominantly as a G9a-GLP heteromeric complex that appears to be a functional H3K9 methyltransferase in vivo. Structurally, either G9a or GLP is composed of a catalytic SET domain, a domain containing ankyrin repeats (involved in protein-protein interactions) and nuclear localization signals on the N-terminal region. The SET domain is responsible for the addition of methyl groups on H3, whereas the ankyrin repeats have been observed to represent mono- and dimethyl lysine binding regions. The G9a-GLP complex is thus not only able to both methylate histone tails but also able to recognize this modification, and can function as a scaffold for the recruitment of other target molecules on the chromatin. See Shinkai et al., Genes Dev., 2011;25(8):781-8; and Shankar et al., Epigenetics, 2013;8(1): 16-22. Many studies have reported that G9a and GLP play critical roles in various biological processes. Several reports have highlighted its link to a variety of cancers. See Cascielle et al., Front Immunol., 2015 25;6:487. It is upregulated in hepatocellular carcinoma, B cell acute lymphoblastic leukemia, and lung cancers. In addition, elevated expression of G9a in aggressive lung cancer correlates with poor prognosis, while its knockdown in highly invasive lung cancer cells suppressed metastasis in an in vivo mouse model. In prostate cancer cells (PC3), G9a knockdown caused significant morphological changes and inhibition of cell growth. See Liu et al., J. Med Chem., 2013;56(21):8931-42.; and Sweis et al., ACS Med Chem Lett., 2014;5(2):205-9. Loss of G9a has been demonstrated to impair DNA damage repair and enhance the sensitivity of cancer cells to radiation and chemotherapeutics. See Yang et al., Proc. Natl. Acad. Sci. USA, 2017, doi: 10. 1073/pnas. 17006941 14. Interestingly, recent studies have also shown that the inhibition of G9a and GLP by either genetic depletion or pharmacological intervention increased fetal hemoglobin (HbF) gene expression in erythroid cells. See Krivega et al., Blood, 2015;126(5):665-72; and Renneville et al., Blood, 2015;126(16): 1930-9. Inducing fetal globin gene would be potentially therapeutically beneficial for the disease of hemoglobinopathies, including beta-thalassemia where the production of normal β- globin, a component of adult hemoglobin, is impaired. Similarly, induction of HbF would potentially be beneficial by diluting the concentration of hemoglobin S (HbS) molecules, thereby reducing polymerization of HbS. See Sankaran et al., Cold Spring Harb Perspect Med., 2013; 3(1): a01 1643. Moreover, G9a or GLP inhibitions may potentiate other clinically used therapies, such as hydroxyurea or HDAC inhibitors. These agents may act, at least in part, by increasing γ-globin gene expression through different mechanisms. See Charache et al., Blood, 1992;79(10):2555-65. Thus, there is a need for the development of small molecules that are capable of inhibiting the activity of G9a and/or GLP. The compounds of the present disclosure fulfill this and related needs. Summary In one aspect provided is a compound of Formula (I): wherein: X can be N (nitrogen) or CR1; Y can be N (nitrogen) or CR2; P, Q, T, and U can be independently CH, C (carbon) (when R4 or R5 is attached), or N (nitrogen); provided that at least one and not more than two of P, Q, T and U are N (nitrogen); Z can be O (oxygen), S (sulfur), or NR6, wherein R6 can be hydrogen, alkyl, or cycloalkyl; R1 can be hydrogen, alkyl, alkoxy, halo, haloalkyl, haloalkoxy, or cycloalkyl; R2 can be hydrogen, alkyl, alkoxy, halo, haloalkyl, haloalkoxy, or cycloalkyl; R3 can be -W-alkylene-R 7, wherein: W can be bond, NH, O (oxygen), or S (sulfur); alkylene can be optionally substituted with R8, wherein R8 can be halo, haloalkyl, haloalkoxy, hydroxy, or alkoxy, and one CH2 in the alkylene can be optionally replaced with NH or O (oxygen); and R7 can be -NRaR , wherein Ra and R can be independently hydrogen, alkyl, or haloalkyl; or Ra and R can be together with the nitrogen to which they are attached form heterocycloamino, bridged heterocycloamino, or spiroheterocycloamino, wherein the heterocycloamino, the bridged heterocycloamino and the spiroheterocycloamino are optionally substituted with one or two substituents independently selected from alkyl, halo, haloalkyl, hydroxy, alkoxy, and haloalkoxy; or R7 can be heterocyclyl that is attached to the alkylene at a ring carbon atom and can be optionally substituted with one or two substituents independently selected from alkyl, halo, haloalkyl, hydroxy, alkoxy and haloalkoxy; R4 and R5 can be independently alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, halo, d hydroxy, haloalkoxy, alkoxy, cyano, NH2, NR R , alkoxyalkylamino, hydroxyalkylamino, aminoalkylamino, hydroxyalkyl, alkoxyalkyl, alkylthio, alkoxyalkyloxy, phenyl, heteroaryl, heteroaryloxy, heterocyclyl, heterocyclyloxy, heterocyclylamino, 5-8 membered
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