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WO2020264398A1.Pdf ( (51) International Patent Classification: (71) Applicant: NURIX THERAPEUTICS, INC. [US/US]; A61P35/00 (2006.01) C07D 413/14 (2006.01) 1700 Owens Street, Suite 205, San Francisco, California C07D 401/14 (2006.01) C07D 471/04 (2006.01) 94158 (US). C07D 403/10 (2006.01) A61P 37/00 (2006.01) (72) Inventors: SANDS, Arthur T.; c/o Nurix Therapeutics, C07D 403/12 (2006.01) A61K 31/506 (2006.01) Inc., 1700 Owens Street, Suite 205, San Francisco, Califor¬ C07D 405/14 (2006.01) nia 94158 (US). BENCE, Neil F.; c/o Nurix Therapeutics, (21) International Application Number: Inc., 1700 Owens Street, Suite 205, San Francisco, Califor¬ PCT/US2020/039957 nia 94158 (US). ZAPF, Christoph W.; c/o Nurix Thera¬ peutics, Inc., 1700 Owens Drive, Suite 205, San Francis¬ (22) International Filing Date: co, California 94158 (US). COHEN, Frederick; c/o Nurix 26 June 2020 (26.06.2020) Therapeutics, Inc., 1700 Owens Drive, Suite 205, San Fran¬ (25) Filing Language: English cisco, California 94158 (US). WANG, Chenbo; c/o Nurix Therapeutics, Inc., 1700 Owens Drive, Suite 205, San Fran¬ (26) Publication Language: English cisco, California 94158 (US). CUMMINS, Thomas; c/o (30) Priority Data: Nurix Therapeutics, Inc., 1700 Owens Drive, Suite 205, San 62/866,914 26 June 2019 (26.06.2019) US Francisco, California 94158 (US). TANAKA, Hiroko; c/ 62/880,285 30 July 2019 (30.07.2019) US o Nurix Therapeutics, Inc., 1700 Owens Drive, Suite 205, 62/888,845 19 August 2019 (19.08.2019) US San Francisco, California 94158 (US). SHUNATONA, 62/888,870 19 August 2019 (19.08.2019) US Hunter; c/o Nurix Therapeutics, Inc., 1700 Owens Street, (54) Title: SUBSTITUTED BENZYL-TRIAZOLE COMPOUNDS FOR CBL-B INHIBITION, AND FURTHER USES THEREOF FIG. Conditional Survival Days post implant (57) Abstract: Compounds of formula (I), compositions, and methods for use in inhibiting the E3 enzyme Cbl-b in the ubiquitin proteasome pathway are disclosed. The compounds, compositions, and methods can be used to modulate the immune system, to treat diseases amenable to immune system modulation, and for treatment of cells in vivo, in vitro, or ex vivo. Also disclosed are pharmaceutical compositions comprising a Cbl-b inhibitor and a cancer vaccine, as well as methods for treating cancer using a Cbl-b inhibitor and a cancer vaccine; and pharmaceutical compositions comprising a Cbl-b inhibitor and an oncolytic vims, as well as methods for treating cancer using a Cbl-b inhibitor and an oncolytic vims. [Continued on next page] Suite 205, San Francisco, California 94158 (US). CAR- DOZO, Mario; c/o Nurix Therapeutics, Inc., 1700 Owens Street, Suite 205, San Francisco, California 94158 (US). WEISS, Dahlia; c/o Nurix Therapeutics, Inc., 1700 Owens Street, Suite 205, San Francisco, California 94158 (US). GOSLING, Jennifa; c/o Nurix Therapeutics, Inc., 1700 Owens Street, Suite 205, San Francisco, California 94158 (US). (74) Agent: NOSON, Kevin et al.; Squire Patton Boggs (US) LLP, 275 Battery Street, Suite 2600, San Francisco, Cali¬ fornia 941 11 (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, ST, SV, SY, TH, TJ, TM, TN, TR, TT, TZ, UA, UG, US, UZ, VC, VN, WS, 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, Cl, CM, GA, GN, GQ, GW, KM, ML, MR, NE, SN, TD, TG). Declarations under Rule 4.17: — as to applicant's entitlement to apply for and be granted a patent (Rule 4.17(H)) — as to the applicant's entitlement to claim the priority of the earlier application (Rule 4.17(iii)) Published: SUBSTITUTED BENZYL-TRIAZOLE COMPOUNDS FOR CBL-B INHIBITION, AND FURTHER USES THEREOF CROSS-REFERENCE TO RELATED APPLICATIONS [1] This application claims the benefit under 35 U.S.C. § 119 of U.S. provisional application numbers: 62/866,914, filed June 26, 2019; 62/880,285, filed July 30, 2019; 62/888,845, filed August 19, 2019; and 62/888,870, filed August 19, 2019, wherein the contents of each are incorporated herein by reference in their entirety. FIELD [2] Provided herein are compounds and compositions for inhibition of the Cbl-b enzyme and methods of use thereof in modulating the immune system, treatment of diseases, and treatment of cells in vivo, in vitro, or ex vivo. Also provided herein are pharmaceutical compositions, kits, and methods of treating cancer comprising a combination of an inhibitor of the Cbl-b enzyme and a cancer vaccine; and pharmaceutical compositions, kits, and methods of treating cancer comprising a combination of an inhibitor of the Cbl-b enzyme and an oncolytic virus. BACKGROUND [3] The ubiquitin proteasome pathway is a complex system involved in the regulation of protein function and catabolism. Proteins in eukaryotic cells are conjugated with ubiquitin, a 76 amino acid, 8.5 kilodalton protein. This conjugation, known as ubiquitination, results in altered function or degradation of the target protein. Ubiquitination of the target protein occurs via a coupled series of reactions involving ubiquitin and a set of enzymes known as E1, E2, and E3 enzymes. Ubiquitin is activated by the ubiquitin-activating enzyme, or E1 enzyme. Ubiquitin is then transferred to a ubiquitin-conjugating enzyme, or E2 enzyme. Finally, a ubiquitin ligase, or E3 enzyme, promotes the transfer of ubiquitin from the E2 enzyme to the target protein. Polyubiquitination of the target protein predominantly serves as a signal leading to degradation of the ubiquitin-conjugated protein by the proteasome, where it undergoes proteolysis. Ubiquitination by E3 ligases can also result in altered protein activity, interactions, or localization. Ubiquitination regulates diverse biology including cell division, DNA repair, and cellular signaling. [4] The synthesis and degradation of proteins in the cell is critical for cell cycle regulation, cell proliferation, apoptosis, and many other cellular processes. Thus, the ability to modulate the ubiquitin proteasome pathway offers a wealth of opportunities to intervene in disease processes. Mechanisms for intervention can include enhanced degradation of oncogene products, reduced degradation of tumor-suppressor proteins, modulation of immune cell response, and modulation of anti-tumor immune responses. [5] Therapeutic cancer vaccines have been evaluated in numerous clinical trials. However, only two therapeutic cancer vaccines have been licensed for use in the United States. In particular, the Bacillus of Calmette and Guerin strain of Mycobacterium bovis has been approved for treatment of bladder cancer, and an ex vivo-activated, autologous cell vaccine has been approved for treatment of prostate cancer. Even so, the response rates and overall survival of patients treated with cancer vaccines are considerably lower than desirable. Thus, what is needed in the art are methods of improving the efficacy of cancer vaccines. [6] Although numerous clinical trials employing an oncolytic virus to treat cancer have been conducted, only one oncolytic virus has been licensed for use in the United States and Europe. In particular, talimogene laherparepvec is a genetically modified herpes simplex virus approved for treatment of melanoma. However, even talimogene laherparepvec has not been shown to improve overall survival or to benefit patients with visceral metastases. Thus, what is needed in the art are methods of improving the efficacy of oncolytic virus therapy. [7] Approximately 35 E2 enzymes and over 500 E3 enzymes are encoded in the human genome. Casitas B-lineage lymphoma proto-oncogene-b (Cbl-b) is an E3 ubiquitin ligase that negatively regulates T-cell activation (Wallner et al., Clin Dev Immunol, 2012: 692639). Discovery of agents that modulate E2 or E3 enzymes accordingly provides the potential for therapies directed against disease processes involving a particular E2 or E3 enzyme. This patent application is directed to agents that inhibit one such E3 enzyme, Casitas B-lineage lymphoma proto-oncogene-b (Cbl-b); agents that inhibit Cbl-b, for use in combination with cancer vaccines, and to pharmaceutical compositions comprising Cbl-b inhibitors and cancer vaccines; and agents that inhibit Cbl-b, for use in combination with oncolytic viruses, and to pharmaceutical compositions comprising Cbl-b inhibitors and oncolytic viruses. SUMMARY [8] Disclosed herein are compounds and compositions for inhibition of the Cbl-b enzyme and methods of use thereof in modulating the immune system, treatment of diseases, and treatment of cells in vivo, in vitro, or ex vivo. Also disclosed herein are methods for use of a Cbl-b inhibitor in treating cancer. In brief, the Cbl-b inhibitor may be administered to an individual with cancer, either alone or as part of a combination therapy with one or more of an immune checkpoint inhibitor, an anti-neoplastic agent, and radiation therapy. Additionally, cells treated in vivo and/or in vitro with a compound or composition as disclosed herein may be used in adoptive cell therapy for treating cancer.
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