Aminoheteroaryl kinase inhibitors

Abstract

Provided herein are novel compounds, pharmaceutical compositions and methods of use related to cyclin-dependent kinases (CDKs).The compounds herein are typically CDK2 inhibitors that can be used to treat a variety of diseases or disorders, such as cancer.

Description

[Technical field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims priority to PCT / CN2021 / 133429, filed November 26, 2021, the contents of which are incorporated by reference in their entirety for all purposes.

[0002] In various embodiments, the present disclosure relates generally to novel heteroaryl compounds, compositions comprising same, methods of preparation and methods of use, e.g., for inhibiting cyclin-dependent kinases and / or for treating or preventing various diseases or disorders described herein. [Background technology]

[0003] Cyclin-dependent kinases (CDKs) are a family of serine / threonine protein kinases that regulate cell cycle progression. Among CDKs, CDK2 is an essential driver for the transition of cells from late G1 to S and G2 phases. During late G1, CDK2 is activated upon binding of cyclin E. This cyclin E / CDK2 complex converts RB to a highly phosphorylated form, which releases E2F from Rb and initiates the transcription of genes required for the G1 / S transition. CDK2 then forms a complex with cyclin A to regulate S-phase progression by activating proteins important for DNA replication and centrosome duplication, such as the DNA replication licensing protein (CDC6) and the centrosomal protein CP110 (Tadesse et al. Targeting CDK2 in cancer: challenges and opportunities for therapy, Drug Discovery Today. 2019;25(2):406-413).

[0004] Cyclin E1 is frequently amplified and / or overexpressed in human cancers. Cyclin E1 amplification is detected in approximately 20% of patients with high-grade serous ovarian cancer, which is associated with chemotherapy resistance / refractory disease (TCGA, Integrated genomic analyses of ovarian carcinoma, Nature. 2011; 474: 609-615; Nakayama et al; Gene amplification CCNE1 is related to poor survival and potential therapeutic target in ovarian cancer, Cancer (2010) 116: 2621-34). Cyclin E1 amplified ovarian cancer cell lines are highly sensitive to agents that either inhibit CDK2 activity or reduce cellular CDK2 protein levels, suggesting CDK2 dependence in these cyclin E1 amplified cells (Au-Yeung et al. Selective targeting of cyclin E1 amplified high grade serous ovarian cancer by clin-dependent kinase 2 and AKT inhibition, Clin. Cancer Res. 2017;23(7):1862-1874).Poor outcome and drug resistance have also been associated with high expression of cyclin E1 in endometrial, gastric, breast and other cancers (Noske et al., Detection of CCNE1 / URI(19q12) amplification by in situ hybridization is common in high grade and type II endometrial cancer, Oncotarget(2017)8:14794-14805; Ooi et al., Gene amplification of CCNE1, CCND1 and CDK6 in gastric cancers detected by multiplex ligation-dependent probe amplification and fluorescence in situ hybridization, Hum Pathol.(2017)61:58-67; Keyomarsi et al., Cyclin E and survival in patients with breast cancer.N Engl J Med.(2002)347:1566-75). Estrogen receptor (ER)-positive breast cancer cell lines that exhibit acquired resistance to the CDK4 / 6 inhibitor palbociclib show increased expression of cyclin E1 and can be resensitized by knocking down CDK2 (Herrera-Abreu et al., Early adaptation and acquired resistance to CDK4 / 6 inhibition in estrogen receptor-positive breast cancer, Cancer Res. (2016) 76: 2301-2313).High cyclin E1 levels have also been reported to be associated with poor response to palbociclib plus fulvestrant combination therapy in ER+BC (high CCNE1 vs low CCNE1: median PFS 7.6 vs 14.1 months in the palbociclib plus fulvestrant arm; 4.0 vs 4.8 months in the placebo plus fulvestrant arm), further highlighting the importance of CDK2 activity in mediating resistance to CDK4 / 6 inhibitors (Turner et al.,Cyclin E1 expression and Palbociclib efficacy in previously treated hormone receptor positive metastatic breast cancer Clin Oncol.(2019)37(14):1169-1178).

[0005] It has been reported that overexpression of cyclin E2 (CCNE2) is associated with endocrine resistance in breast cancer cells, and CDK2 inhibition restores sensitivity to tamoxifen or CDK4 inhibitors in tamoxifen-resistant CCNE2-overexpressing cells (Caldon et al.,Cyclin E2 overexpression is associated with endocrine resistance but not insensitivity to CDK2 inhibition in human breast cancer cells.Mol Cancer Ther.(2012)11:1488-99;Herrera-Abreu et al.,Early Adaptation and Acquired Resistance to CDK4 / 6 Inhibition in Estrogen Receptor-Positive Breast Cancer,Cancer Res.(2016)76:2301-2313). In addition, cyclin E amplification has been reported to contribute to trastuzumab resistance in HER2+ breast cancer (Scaltriti et al. Cyclin E amplification / overexpression is a mechanism of trastuzumab resistance in HER2+ breast cancer patients, Proc Natl Acad Sci. (2011) 108: 3761-6).Furthermore, cyclin E overexpression has been reported to play a role in basal-like and triple-negative breast cancer (TNBC) as well as inflammatory breast cancer (Elsawaf & Sinn, Triple Negative Breast Cancer: Clinical and Histological Correlations, Breast Care (2011) 6:273-278; Alexander et al., Cyclin E overexpression as a biomarker for combination treatment strategies in inflammatory breast cancer, Oncotarget (2017) 8:14897-14911). Summary of the Invention

[0006] The importance of CDK2 in proliferation pathways and the high frequency of altered CDK2 / cyclin E1 activity in tumors highlights CDK2 as a target for cancer therapy. CDK2 knockout mice exhibit minimal defects in viability, suggesting that CDK2 is not essential for normal cell proliferation (Berthet et al., CDK2 knock out mice are viable. Curr Biol. (2003) 13(20): 1775-85). In addition, selective CDK2 inhibitors can be active in treating patients with high tumor cyclin E1 and / or E2 expression while minimizing clinical toxicity. However, in some embodiments, inhibition of CDK2 and other CDKs may also be clinically beneficial.

[0007] In various embodiments, the disclosure relates to novel heteroaryl compounds that can selectively inhibit CDK2 relative to, for example, other CDKs and / or other kinases. The compounds and compositions herein are useful for treating a variety of diseases or disorders, including cancer, for example, cancers characterized by amplification or overexpression of cyclin E1 (CCNE1) and / or cyclin E2 (CCNE2).

[0008] In some embodiments, the disclosure provides specific compounds as disclosed herein in Table 1, or pharma- ceutically acceptable salts thereof. In some embodiments, the disclosure provides specific compounds according to E1-E7, or pharma- ceutically acceptable salts thereof, as described herein.

[0009] In some embodiments, the present disclosure provides a pharmaceutical composition comprising one or more compounds of the present disclosure and, optionally, a pharma- ceutical acceptable excipient. The pharmaceutical composition may typically be formulated for oral administration.

[0010] In some embodiments, the disclosure also provides methods of inhibiting CDK activity, such as CDK2 activity, in a subject or biological sample. In some embodiments, the methods include contacting the subject or biological sample with an effective amount of one or more compounds of the disclosure, such as any of Examples E1-E7 or any of the specific compounds disclosed in Table 1 herein, or a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition comprising same.

[0011] In some embodiments, the disclosure provides a method of treating or preventing a CDK-mediated disease or disorder in a subject in need thereof. In some embodiments, the method comprises administering to the subject an effective amount of one or more compounds of the disclosure or a pharmaceutical composition herein. In some embodiments, the method comprises administering to the subject an effective amount of any of Examples E1-E7 or any of the specific compounds disclosed in Table 1 herein, or a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition comprising same.

[0012] In some embodiments, the disclosure also provides a method of treating or preventing cancer in a subject in need thereof, comprising administering to the subject an effective amount of a compound of the disclosure (e.g., any of Examples E1-E7 or any of the specific compounds disclosed in Table 1 herein or a pharma- ceutically acceptable salt thereof) or an effective amount of a pharmaceutical composition described herein. In some embodiments, the cancer is characterized by amplification or overexpression of CCNE1 and / or CCNE2. In some embodiments, the cancer is selected from breast cancer, ovarian cancer, bladder cancer, uterine cancer, prostate cancer, lung cancer (including NSCLC, SCLC, squamous cell carcinoma or adenocarcinoma), esophageal cancer, head and neck cancer, colorectal cancer, renal cancer (including RCC), liver cancer (including HCC), pancreatic cancer, stomach cancer (i.e., gastric cancer), thyroid cancer, and combinations thereof. In some embodiments, the cancer is a breast cancer selected from ER positive / HR positive, HER2 negative breast cancer; ER positive / HR positive, HER2 positive breast cancer; triple negative breast cancer (TNBC); and inflammatory breast cancer. In some embodiments, the cancer is breast cancer. In some embodiments, the cancer is a breast cancer selected from endocrine resistant breast cancer, trastuzumab resistant breast cancer, or breast cancer that exhibits primary or acquired resistance to CDK4 / CDK6 inhibition. In some embodiments, the cancer is advanced or metastatic breast cancer. In some embodiments, the cancer is ovarian cancer.

[0013] The administration in the method herein is not limited to any particular administration route.For example, in some embodiments, the administration can be orally, nasally, transdermally, intrapulmonary, by inhalation, buccal, sublingually, intraperitoneally, subcutaneously, intramuscularly, intravenously, rectally, intrapleurally, intrathecally and parenterally.In some embodiments, the administration is orally.In some embodiments, the administration is parenterally, such as intravenous injection.

[0014] The compounds of the present disclosure can be used as monotherapy or in combination therapy.In some embodiments of the methods described herein, one or more compounds of the present disclosure can be administered as one or more sole active ingredients.In some embodiments, the methods herein further comprise administering to the subject an additional therapeutic agent, such as an additional anticancer agent as described herein.

[0015] It is to be understood that both the foregoing general description and the following detailed description are exemplary and explanatory only and are not restrictive of the invention herein. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0016] In various embodiments, the present disclosure provides compounds and compositions useful for inhibiting CDKs, such as CDK2, and / or treating or preventing various diseases or disorders described herein, such as cancer.

[0017] The compounds herein are typically capable of inhibiting CDK2. In some embodiments, the compounds herein are capable of selectively inhibiting CDK2 relative to other CDKs. In some specific embodiments, the present disclosure provides a compound selected from Table 1 below, a deuterated analog thereof, a stereoisomer thereof, or a pharma- ceutically acceptable salt thereof.

[0018] Table 1. Compound list [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka]

[0019] The compounds in Table 1 may exist in various stereoisomeric forms, such as individual isomers, individual enantiomers and / or diastereomers, if applicable, or mixtures of stereoisomers, including racemic mixtures and mixtures enriched in one or more stereoisomers. In some embodiments, if applicable, the compounds shown in Table 1 may exist as isolated individual enantiomers that are substantially free (e.g., less than 20%, less than 10%, less than 5%, less than 1%, or undetectable amounts by weight, HPLC or SFC area basis, or both) of the other enantiomer. In some embodiments, if applicable, the compounds shown in Table 1 may also exist as mixtures of stereoisomers in any ratio, such as racemic mixtures.

[0020] In some embodiments, the disclosure provides a compound of 4-((4-(((3S,4R)-3-hydroxytetrahydro-2H-pyran-4-yl)oxy)-5-(trifluoromethyl)pyrimidin-2-yl)amino)-N-(methyl-d3)benzenesulfonamide.

[0021] In some embodiments, the disclosure provides a compound of 4-((4-(((3R,4R)-3-hydroxytetrahydro-2H-pyran-4-yl)oxy)-5-(trifluoromethyl)pyrimidin-2-yl)amino)-N-(methyl-d3)benzenesulfonamide.

[0022] In some embodiments, the disclosure provides the compound 4-((4-(((3S,4R)-3-hydroxytetrahydro-2H-pyran-4-yl)oxy)-5-(trifluoromethyl)pyrimidin-2-yl)amino)-N-methylbenzenesulfonamide.

[0023] In some embodiments, the disclosure provides the compound N-ethyl-4-((4-(((3S,4R)-3-hydroxytetrahydro-2H-pyran-4-yl)oxy)-5-(trifluoromethyl)pyrimidin-2-yl)amino)benzenesulfonamide.

[0024] In some embodiments, the disclosure provides a compound of 4-((4-(((3S,4R)-3-hydroxytetrahydro-2H-pyran-4-yl)oxy)-5-(trifluoromethyl)pyrimidin-2-yl)amino)benzenesulfonamide.

[0025] The compounds of the present disclosure can be readily synthesized by one of ordinary skill in the art in light of the present disclosure. Exemplary syntheses are also shown in the Examples section. The novel synthetic intermediates described herein are also an aspect of the present disclosure. For example, in some embodiments, the present disclosure provides a method for the synthesis of 4-((4-(((3S,4R)-3-((4-methoxybenzyl)oxy)tetrahydro-2H-pyran-4-yl)oxy)-5-(trifluoromethyl)pyrimidin-2-yl)amino)benzenesulfonamide; 4-((4-(((3S,4R)-3-((4-methoxybenzyl)oxy)tetrahydro-2H-pyran-4-yl)oxy)-5-(trifluoromethyl)pyrimidine- 2-yl)amino)-N-methylbenzenesulfonamide;N-ethyl-4-((4-(((3S,4R)-3-((4-methoxybenzyl)oxy)tetrahydro-2H-pyran-4-yl)oxy)-5-(trifluoromethyl)pyrimidin-2-yl)amino)benzenesulfonamide;4-((4-(((3S,4R)-3-((4-methoxybenzyl)oxy)tetrahydro-2H-pyran-4-yl)oxy)-5-(trifluoromethyl)pyrimidin-2-yl)amino)benzenesulfonamide 4-((4-(((3R,4R)-3-((4-methoxybenzyl)oxy)tetrahydro-2H-pyran-4-yl)oxy)-5-(trifluoromethyl)pyrimidin-2-yl)amino)-N-(methyl-d3)benzenesulfonamide;4-((4-(((3S,4S)-3-((4-methoxybenzyl)oxy)tetrahydro-2H-pyran-4-yl)oxy)-5-(trifluoromethyl)pyrimidin-2-yl)amino)-N-(methyl-d3)benzenesulfonamide;4-((4-(((3S,4S)-3-((4-methoxybenzyl)oxy)tetrahydro and 4-((4-(((3R,4S)-3-((4-methoxybenzyl)oxy)tetrahydro-2H-pyran-4-yl)oxy)-5-(trifluoromethyl)pyrimidin-2-yl)amino)-N-(methyl-d3)benzenesulfonamide.

[0026] Pharmaceutical Compositions Certain embodiments relate to pharmaceutical compositions comprising one or more compounds of the present disclosure.

[0027] The pharmaceutical composition may optionally contain a pharma- ceutically acceptable excipient. In some embodiments, the pharmaceutical composition comprises a compound of the present disclosure (e.g., any of Examples E1-E7 or any of the specific compounds disclosed in Table 1 herein or a pharma- ceutically acceptable salt thereof) and a pharma- ceutically acceptable excipient. Pharmaceutically acceptable excipients are known in the art. Non-limiting suitable excipients include, for example, encapsulating materials or additives, such as antioxidants, binders, buffers, carriers, coating agents, colorants, diluents, disintegrants, emulsifiers, bulking agents, fillers, flavoring agents, humectants, lubricants, fragrances, preservatives, propellants, release agents, sterilizing agents, sweeteners, solubilizers, wetting agents, and mixtures thereof. See also Remington's The Science and Practice of Pharmacy, 21st Edition, A.R. Gennaro (Lippincott, Williams & Wilkins, Baltimore, Md., 2005; incorporated herein by reference), which discloses various excipients used in formulating pharmaceutical compositions and known techniques for their preparation.

[0028] The pharmaceutical composition may include any one or more of the compounds of the present disclosure. For example, in some embodiments, the pharmaceutical composition includes, for example, a therapeutically effective amount of any of Examples E1-E7 or any of the specific compounds disclosed in Table 1 herein, or a pharma- ceutically acceptable salt thereof. In any of the embodiments described herein, the pharmaceutical composition may include a therapeutically effective amount (e.g., for the treatment of breast cancer or ovarian cancer) of a compound selected from any of Examples E1-E7 or any of the specific compounds disclosed in Table 1 herein, or a pharma- ceutically acceptable salt thereof. In some preferred embodiments, the pharmaceutical composition may include a compound according to Examples E1-E7 or a compound selected from those in Table 1 herein, that has a CDK2 / cyclin E1 IC50 level of less than 100 nM, more preferably less than 10 nM, when tested as per Biological Example 1 as described in WO2022 / 111621.

[0029] The pharmaceutical compositions herein may be formulated for delivery by any of the known delivery routes, including, but not limited to, orally, nasally, transdermally, intrapulmonary, by inhalation, buccally, sublingually, intraperitoneally, subcutaneously, intramuscularly, intravenously, rectally, intrapleurally, intrathecally or parenterally.

[0030] In some embodiments, pharmaceutical composition can be formulated for oral administration.Oral formulation can be in the form of individual units, such as capsules, pills, cachets, lozenges or tablets, each containing a predetermined amount of active compound; in the form of powder or granules; in the form of a solution or suspension in aqueous or non-aqueous liquid; or in the form of oil-in-water or water-in-oil emulsion.Excipients for preparing compositions for oral administration are known in the art. Non-limiting examples of suitable excipients include agar, alginic acid, aluminum hydroxide, benzyl alcohol, benzyl benzoate, 1,3-butylene glycol, carbomer, castor oil, cellulose, cellulose acetate, cocoa butter, corn starch, corn oil, cottonseed oil, crospovidone, diglycerides, ethanol, ethylcellulose, ethyl laurate, ethyl oleate, fatty acid esters, gelatin, germ oil, glucose, glycerol, peanut oil, hydroxypropylmethylcellulose, isopropanol, isotonic saline, lactose, and water. Magnesium oxide, magnesium stearate, malt, mannitol, monoglycerides, olive oil, peanut oil, potassium phosphates, potato starch, povidone, propylene glycol, Ringer's solution, safflower oil, sesame oil, sodium carboxymethylcellulose, sodium phosphates, sodium lauryl sulfate, sodium sorbitol, soybean oil, stearic acid, stearyl fumarate, sucrose, surfactants, talc, tragacanth, tetrahydrofurfuryl alcohol, triglycerides, water and mixtures thereof.

[0031] In some embodiments, the pharmaceutical composition is formulated for parenteral administration (intravenous injection or infusion, subcutaneous or intramuscular injection, etc.). Parenteral formulations can be, for example, aqueous solutions, suspensions or emulsions. Excipients for the preparation of parenteral formulations are known in the art. Non-limiting suitable excipients include, for example, 1,3-butanediol, castor oil, corn oil, cottonseed oil, dextrose, germ oil, peanut oil, liposomes, oleic acid, olive oil, peanut oil, Ringer's solution, safflower oil, sesame oil, soybean oil, USP or isotonic saline solution, water and mixtures thereof.

[0032] The compounds of the present disclosure may be used alone, in combination with each other or in combination with one or more additional therapeutic agents, such as, for example, mitotic inhibitors, alkylating agents, antimetabolites, antitumor antibiotics, antiangiogenic agents, topoisomerase I and II inhibitors, plant alkaloids, hormone agonists and antagonists, growth factor inhibitors, radiation, signal transduction inhibitors such as protein tyrosine kinase and / or serine / threonine kinase inhibitors, cell cycle inhibitors, biological response modifiers, enzyme inhibitors, antisense oligonucleotides or oligonucleotide derivatives, cytotoxic agents, immuno-oncological agents, and the like. In some embodiments, one or more compounds of the present disclosure may be used in combination with one or more targeted agents, such as inhibitors of PI3 kinase, mTOR, PARP, IDO, TDO, ALK, ROS, MEK, VEGF, FLT3, AXL, ROR2, EGFR, FGFR, Src / Abl, RTK / Ras, Myc, Raf, PDGF, AKT, c-Kit, erbB, CDK4 / CDK6, CDK5, CDK7, CDK9, SMO, CXCR4, HER2, GLS1, EZH2, or Hsp90, or an immunomodulatory agent, such as a PD-1 or PD-L1 antagonist, an OX40 agonist, or a 4-1BB agonist. In some embodiments, one or more compounds of the present disclosure can be used in combination with standard of care agents, such as tamoxifen, docetaxel, paclitaxel, cisplatin, capecitabine, gemcitabine, vinorelbine, exemestane, letrozole, fulvestrant, anastrozole, or trastuzumab. Suitable additional anti-cancer therapeutic agents include any of those known in the art, such as those approved for the appropriate cancer by a regulatory agency, such as the U.S. Food and Drug Administration. Some examples of suitable additional anti-cancer therapeutic agents include those described in WO 2020 / 157652, U.S. Patent Application Publication No. 2018 / 0044344, WO 2008 / 122767, and the like, the contents of each of which are incorporated herein by reference in their entirety.

[0033] When used in combination with one or more additional therapeutic agents, the compounds of the present disclosure or pharmaceutical compositions herein may be administered to a subject simultaneously with such additional therapeutic agents or sequentially in any order. In some embodiments, the pharmaceutical composition may comprise one or more compounds of the present disclosure and one or more additional therapeutic agents in a single composition. In some embodiments, the pharmaceutical composition comprising one or more compounds of the present disclosure may be included in a kit that also comprises another pharmaceutical composition comprising one or more additional therapeutic agents.

[0034] A pharmaceutical composition may contain various amounts of the disclosed compound depending on various factors, such as the purpose of use and the potency and selectivity of the compound. In some embodiments, the pharmaceutical composition contains a therapeutically effective amount of the disclosed compound. In some embodiments, the pharmaceutical composition contains a therapeutically effective amount of the disclosed compound and a pharma- ceutical acceptable excipient. As used herein, a therapeutically effective amount of the disclosed compound is an amount effective to treat a disease or disorder as described herein, such as breast cancer or ovarian cancer, and may depend on the recipient of the treatment, the disorder, the condition or disease under treatment and its severity, the composition containing the compound, the time of administration, the route of administration, the duration of treatment, the potency of the compound, its clearance rate, and whether another drug is co-administered.

[0035] Treatment / Usage The compounds of the present disclosure have various uses.For example, the compounds of the present disclosure can be used as therapeutic active substances for treating and / or preventing CDK2-mediated diseases or disorders.Therefore, some embodiments of the present disclosure also relate to the method of using one or more compounds of the present disclosure or pharmaceutical compositions herein for treating or preventing CDK2-mediated diseases or disorders in a subject in need thereof, such as treating cancer in a subject in need thereof.

[0036] In some embodiments, the disclosure provides a method of inhibiting abnormal cell growth in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of the disclosure or a pharmaceutical composition described herein. In some embodiments, the abnormal cell growth is a cancer characterized by amplification or overexpression of cyclin E1 (CCNE1) and / or cyclin E2 (CCNE2). In some embodiments, the subject is identified as having a cancer characterized by amplification or overexpression of CCNE1 and / or CCNE2.

[0037] In some embodiments, the disclosure also provides a method of inhibiting CDK activity in a subject or biological sample. In some embodiments, the disclosure provides a method of inhibiting CDK2 activity in a subject or biological sample, comprising contacting the subject or biological sample with an effective amount of a compound of the disclosure (e.g., any of Examples E1-E7 or any of the specific compounds disclosed in Table 1 herein, or a pharma- ceutical acceptable salt thereof) or a pharmaceutical composition described herein.

[0038] In some embodiments, the disclosure provides a method of treating or preventing a CDK-mediated, particularly CDK2-mediated, disease or disorder in a subject in need thereof. In some embodiments, the method comprises administering to the subject an effective amount of a compound of the disclosure (e.g., any of Examples E1-E7 or any of the specific compounds disclosed in Table 1 herein, or a pharma- ceutically acceptable salt thereof) or an effective amount of a pharmaceutical composition described herein. In some embodiments, the CDK2-mediated disease or disorder is cancer. In some embodiments, the cancer is characterized by amplification or overexpression of CCNE1 and / or CCNE2.

[0039] In some embodiments, the disclosure also provides a method of treating or preventing cancer in a subject in need thereof, comprising administering to the subject an effective amount of a compound of the disclosure (e.g., any of Examples E1-E7 or any of the specific compounds disclosed in Table 1 herein or a pharma- ceutically acceptable salt thereof) or an effective amount of a pharmaceutical composition described herein. In some embodiments, the cancer is characterized by amplification or overexpression of CCNE1 and / or CCNE2. In some embodiments, the subject is identified as having a cancer characterized by amplification or overexpression of CCNE1 and / or CCNE2. In some embodiments, the cancer is selected from breast cancer, ovarian cancer, bladder cancer, uterine cancer, prostate cancer, lung cancer (including NSCLC, SCLC, squamous cell carcinoma or adenocarcinoma), esophageal cancer, head and neck cancer, colorectal cancer, renal cancer (including RCC), liver cancer (including HCC), pancreatic cancer, stomach cancer (i.e., gastric cancer), thyroid cancer, and combinations thereof. In some embodiments of the methods herein, the cancer is breast cancer, ovarian cancer, bladder cancer, uterine cancer, prostate cancer, lung cancer, esophageal cancer, liver cancer, pancreatic cancer, and / or gastric cancer.

[0040] In some embodiments of the methods herein, the cancer is breast cancer, such as ER positive / HR positive, HER2 negative breast cancer; ER positive / HR positive, HER2 positive breast cancer; triple negative breast cancer (TNBC); or inflammatory breast cancer. In some embodiments, the breast cancer can be endocrine resistant breast cancer, trastuzumab resistant breast cancer, or breast cancer that exhibits primary or acquired resistance to CDK4 / CDK6 inhibition. In some embodiments, the breast cancer can be advanced or metastatic breast cancer. In some embodiments, the breast cancer described herein is characterized by amplification or overexpression of CCNE1 and / or CCNE2.

[0041] In some embodiments of the methods herein, the cancer is ovarian cancer. In some embodiments, the ovarian cancer is characterized by amplification or overexpression of CCNE1 and / or CCNE2.

[0042] In some embodiments of the methods herein, the cancer is a hematological cancer, such as leukemia. In some embodiments of the methods herein, the cancer is a chronic lymphocytic leukemia, such as relapsed or refractory chronic lymphocytic leukemia (CLL).

[0043] In some embodiments of the methods herein, the cancer is acute myeloid leukemia. In some embodiments of the methods herein, the cancer is relapsed or refractory acute myeloid leukemia or myelodysplastic syndrome.

[0044] In any embodiment described herein, unless otherwise specified or contradictory, the cancers herein can be characterized by amplification or overexpression of CCNE1 and / or CCNE2.

[0045] In some embodiments, the disclosure also provides a method of treating breast cancer in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of the disclosure (e.g., any of Examples E1-E7 or any of the specific compounds disclosed in Table 1 herein or a pharma- ceutically acceptable salt thereof) or an effective amount of a pharmaceutical composition described herein. In some embodiments, the breast cancer is selected from ER positive / HR positive, HER2 negative breast cancer; ER positive / HR positive, HER2 positive breast cancer; triple negative breast cancer (TNBC); and inflammatory breast cancer. In some embodiments, the breast cancer is selected from endocrine resistant breast cancer, trastuzumab resistant breast cancer, or breast cancer exhibiting primary or acquired resistance to CDK4 / CDK6 inhibition. In some embodiments, the breast cancer is advanced or metastatic breast cancer. In some embodiments, the breast cancer is characterized by amplification or overexpression of CCNE1 and / or CCNE2.

[0046] In some embodiments, the disclosure also provides a method of treating ovarian cancer in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of the disclosure (e.g., any of Examples E1-E7 or any of the specific compounds disclosed in Table 1 herein, or a pharma- ceutically acceptable salt thereof) or an effective amount of a pharmaceutical composition described herein. In some embodiments, the ovarian cancer is characterized by amplification or overexpression of CCNE1 and / or CCNE2.

[0047] In some embodiments, the disclosure also provides a method of treating leukemia in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of the disclosure (e.g., any of Examples E1-E7 or any of the specific compounds disclosed in Table 1 herein, or a pharma- ceutically acceptable salt thereof) or an effective amount of a pharmaceutical composition described herein. In some embodiments, the leukemia is characterized by amplification or overexpression of CCNE1 and / or CCNE2.

[0048] In some embodiments, the disclosure also provides a method of treating chronic lymphocytic leukemia, such as relapsed or refractory chronic lymphocytic leukemia (CLL), in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of the disclosure (e.g., any of Examples E1-E7 or any of the specific compounds disclosed in Table 1 herein, or a pharma- ceutically acceptable salt thereof) or an effective amount of a pharmaceutical composition described herein.

[0049] In some embodiments, the disclosure also provides a method of treating acute myeloid leukemia, such as relapsed or refractory acute myeloid leukemia, in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of the disclosure (e.g., any of Examples E1-E7 or any of the specific compounds disclosed in Table 1 herein, or a pharma- ceutically acceptable salt thereof) or an effective amount of a pharmaceutical composition described herein.

[0050] In some embodiments, the disclosure also provides a method of treating myelodysplastic syndrome in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of the disclosure (e.g., any of Examples E1-E7 or any of the specific compounds disclosed in Table 1 herein, or a pharma- ceutically acceptable salt thereof) or an effective amount of a pharmaceutical composition described herein.

[0051] In some preferred embodiments, the compounds disclosed herein for the methods described herein have a CDK2 / Cyclin E1 IC50 of less than 100 nM, more preferably less than 10 nM, measured / calculated by Biological Example 1 as described in WO 2022 / 111621.

[0052] The administration in the method herein is not limited to any particular administration route.For example, in some embodiments, the administration can be orally, nasally, transdermally, intrapulmonary, by inhalation, buccal, sublingually, intraperitoneally, subcutaneously, intramuscularly, intravenously, rectally, intrapleurally, intrathecally and parenterally.In some embodiments, the administration is orally.In some embodiments, the administration is parenterally, such as intravenous injection.

[0053] The compounds of the present disclosure can be used as monotherapy or in combination therapy. In some embodiments of the methods described herein, one or more compounds of the present disclosure can be administered as one or more sole active ingredients. In some embodiments of the methods described herein, one or more compounds of the present disclosure can be co-administered simultaneously or sequentially in any order with an additional therapeutic agent to a subject in need thereof. The additional therapeutic agent can typically be an additional anti-cancer therapeutic agent, such as mitotic inhibitors, alkylating agents, antimetabolites, antitumor antibiotics, antiangiogenic agents, topoisomerase I and II inhibitors, plant alkaloids, hormone agonists and antagonists, growth factor inhibitors, radiation, signal transduction inhibitors such as protein tyrosine kinase and / or serine / threonine kinase inhibitors, cell cycle inhibitors, biological response modifiers, enzyme inhibitors, antisense oligonucleotides or oligonucleotide derivatives, cytotoxic agents, immuno-oncological agents, and the like. In some embodiments, the additional anti-cancer agent is an endocrine agent, such as an aromatase inhibitor, a SERD or a SERM. In some embodiments, one or more compounds of the present disclosure may be administered in combination with one or more targeted agents, such as inhibitors of PI3 kinase, mTOR, PARP, IDO, TDO, ALK, ROS, MEK, VEGF, FLT3, AXL, ROR2, EGFR, FGFR, Src / Abl, RTK / Ras, Myc, Raf, PDGF, AKT, c-Kit, erbB, CDK4 / CDK6, CDK5, CDK7, CDK9, SMO, CXCR4, HER2, GLS1, EZH2 or Hsp90 or an immunomodulatory agent, such as a PD-1 or PD-L1 antagonist, an OX40 agonist or a 4-1BB agonist. In some embodiments, one or more compounds of the present disclosure can be administered in combination with a standard of care agent, such as tamoxifen, docetaxel, paclitaxel, cisplatin, capecitabine, gemcitabine, vinorelbine, exemestane, letrozole, fulvestrant, anastrozole, or trastuzumab. Suitable additional anti-cancer therapeutic agents include any of those known in the art, such as those approved for the appropriate cancer by a regulatory agency, such as the U.S. Food and Drug Administration.Some examples of suitable additional anti-cancer therapeutic agents include those described in WO 2020 / 157652, U.S. Patent Application Publication No. 2018 / 0044344, WO 2008 / 122767, and the like, the contents of each of which are incorporated herein by reference in their entirety.

[0054] Dosage regimens, including doses, of the methods described herein can vary and be adjusted depending on the recipient of the treatment, the disorder, condition or disease being treated and its severity, the composition containing the compound, the time of administration, the route of administration, the duration of treatment, the potency of the compound, its clearance rate, and whether another drug is co-administered.

[0055] definition It is intended that all moieties and combinations thereof be understood as meaning that appropriate valences are maintained.

[0056] It is also intended to be understood that a specific embodiment of a variable moiety herein can be the same or different from another specific embodiment having the same identifier.

[0057] symbol [ka] Whether utilized as a bond or displayed perpendicular to (or otherwise across) a bond, indicates the point at which the displayed moiety is attached to the remainder of the molecule. As will be understood by one of ordinary skill in the art, the symbol [ka] It should be noted that the above information may be presented on the other side of the

[0058] The definitions of specific functional groups and chemical terms are described in more detail below. Chemical elements are defined in the Periodic Table of the Elements, CAS version, Handbook of Chemistry and Physics, 75 th Ed., and specific functional groups are generally defined as described therein. In addition, general principles of organic chemistry and specific functional moieties and reactivities are described in Thomas Sorrell, Organic Chemistry, University Science Books, Sausalito, 1999; Smith and March, March's Advanced Organic Chemistry, 5 th Edition, John Wiley&Sons, Inc., New York, 2001; Larock, Comprehensive Organic Transformations, VCH Publishers, Inc., New York, 1989; and Carruthers, Some Modern Methods of Organic Synthesis, 3 rd Edition, Cambridge University Press, Cambridge, 1987. It is not intended that the disclosure be limited in any way by the exemplary substituents described herein.

[0059] The compounds described herein may contain one or more asymmetric centers, and therefore may exist in various stereoisomeric forms, such as enantiomers and / or diastereomers.For example, the compounds described herein may be in the form of individual enantiomers, diastereomers, or geometric isomers, or may be in the form of a mixture of stereoisomers, including racemic mixtures and mixtures enriched in one or more stereoisomers.Isomers can be isolated from mixtures by methods known to those skilled in the art, including chiral high performance liquid chromatography (HPLC), chiral supercritical fluid chromatography (SFC), and the formation and crystallization of chiral salts; or preferred isomers can be prepared by asymmetric synthesis. See, for example, Jacques et al., Enantiomers, Racemates and Resolutions (Wiley Interscience, New York, 1981); Wilen et al., Tetrahedron 33:2725 (1977); Eliel, Stereochemistry of Carbon Compounds (McGraw-Hill, NY, 1962); and Wilen, Tables of Resolving Agents and Optical Resolutions p. 268 (EL Eliel, Ed., Univ. of Notre Dame Press, Notre Dame, IN 1972). The present disclosure additionally encompasses the compounds described herein as individual isomers substantially free of other isomers, and instead as mixtures of various isomers, including racemic mixtures. When stereochemistry is specifically depicted, it is to be understood that with respect to that particular chiral center or axial chirality, the compound may exist predominantly as the stereoisomer depicted, such as with less than 20%, less than 10%, less than 5%, less than 1%, or undetectable amounts of the other stereoisomer or stereoisomers by weight, HPLC or SFC area basis, or both, unless the context contradicts otherwise. The presence and / or amount of stereoisomers can be determined by one of skill in the art in light of the present disclosure, including using chiral HPLC or chiral SFC. As will be understood by one of skill in the art, the term "stereoisomer" may be used herein to refer to a chemical structure. *" is shown, unless the context specifically contradicts, it is intended to indicate that the corresponding chiral center is enantiomerically pure or enriched in one of the configurations, or enantiomerically pure or enriched in the configuration as depicted, such that the other stereoisomer or stereoisomers are present in less than 20%, less than 10%, less than 5%, less than 1%, or undetectable amounts by weight, HPLC or SFC area basis, or both. When stereochemistry is not specifically depicted and " is not included in a chemical structure, * " is not used, unless the context specifically contradicts, such structures are also understood to include the corresponding compounds in any stereoisomeric form, including individual isomers substantially free of other isomers and mixtures of various isomers, including racemic mixtures.

[0060] When a range of values ​​is recited, it is intended that each value and subrange within the range is encompassed. For example, "C 1~6 " includes C1, C2, C3, C4, C5, C6, C 1~6 , C 1~5 , C 1~4 , C 1~3 , C 1~2 , C 2~6 , C 2~5 , C 2~4 , C 2~3 , C 3~6 , C 3~5 , C 3~4 , C 4~6 , C 4~5 and C 5~6 is intended to be encompassed.

[0061] As used herein, the term "one or more compounds of the present disclosure" refers to any of the compounds described herein according to any of Examples E1-E7 or any of the specific compounds disclosed in Table 1 herein, one or more isotopically labeled compounds thereof (such as deuterated analogs in which one or more of the hydrogen atoms are replaced by deuterium atoms in abundance above their natural abundance, e.g., CD3 analogs when the compound has a CH3 group), possible positional isomers thereof, possible geometric isomers, possible stereoisomers (including diastereoisomers, enantiomers and racemic mixtures), tautomers thereof, conformers thereof, pharmaceutically acceptable esters thereof and / or possible pharmaceutically acceptable salts thereof (e.g., acid addition salts such as HCl salts or base addition salts such as Na salts). For clarity, the compounds of Examples E1-E7 refer to the compounds designated in the Examples section by the symbol E, E1, E2, etc. through E7, followed by an integer. Hydrates and solvates of the compounds of the present disclosure are considered to be compositions of the present disclosure in which one or more compounds are in association with water or solvent, respectively.

[0062] The compounds of the present disclosure may exist in isotopically labeled or isotopically enriched forms containing one or more atoms with atomic masses or mass numbers different from the atomic masses or mass numbers most abundantly found in nature. The isotopes may be radioactive or non-radioactive isotopes. Isotopes of atoms such as, but not limited to, hydrogen, carbon, phosphorus, sulfur, fluorine, chlorine and iodine include: 2 H, 3 H, 13 C. 14 C. 15 N, 18 O. 32 P, 35 S, 18 F, 36 Cl and 125 I. Compounds that contain other isotopes of these and / or other atoms are within the scope of this invention.

[0063] As used herein, the phrases "administration" of a compound, "administering" a compound, or other variations thereof, mean providing a compound or a prodrug of a compound to an individual in need of treatment.

[0064] The term "pharmaceutically acceptable salt" refers to salts that are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response, and the like, and are commensurate with a reasonable benefit-to-risk ratio. Pharmaceutically acceptable salts are well known in the art.

[0065] The term "tautomer" or "tautomeric" refers to two or more interconvertible compounds resulting from tautomerization. The exact ratio of tautomers depends on several factors, including, for example, temperature, solvent, and pH. Tautomerization is known to those skilled in the art. Exemplary tautomerizations include keto to enol, amide to imide, lactam to lactim, enamine to imine, and enamine to (another enamine) tautomerization.

[0066] The term "subject" (alternatively referred to herein as "patient"), as used herein, refers to an animal, preferably a mammal, most preferably a human, who has been the object of treatment, observation or experiment.

[0067] As used herein, the terms "treat", "treating", "treatment" and the like refer to the elimination, reduction or amelioration of a disease or condition and / or symptoms associated therewith. Although not excluded, when referring to treating a disease or condition, it is not necessary that the disease, condition or symptoms associated therewith be completely eliminated. As used herein, the terms "treat", "treating", "treatment" and the like may include "prophylactic treatment", which refers to reducing the likelihood of a disease or condition reoccurring or a previously controlled disease or condition reoccurring in a subject who has not yet reoccurred or has a disease or condition recurrence, but who is at risk or susceptible to such a disease or condition. The term "treat" and synonyms contemplate administering a therapeutically effective amount of a compound described herein to a subject in need of such treatment.

[0068] The term "effective amount" refers to an amount of a compound or combination of compounds as described herein sufficient to achieve the intended application, including, but not limited to, prevention or treatment of disease. A therapeutically effective amount may vary depending on the intended application (in vitro or in vivo) or subject and disease state under treatment (e.g., subject's weight, age, and sex), the severity of the disease state, the method of administration, etc., and can be readily determined by one of ordinary skill in the art. The term also applies to a dose that will elicit a particular response in target cells and / or tissues. The specific dose will vary depending on the particular compound selected, the administration regimen to be followed, whether the compound is administered in combination with other compounds, the timing of administration, the tissue to which it is administered, and the physical delivery system in which the compound is loaded.

[0069] As used herein, the singular forms "a," "an," and "the" include plural references unless expressly stated or unless it is clear without ambiguity from the context that this is not intended.

[0070] The term "and / or," when used herein in phrases such as "A and / or B," is intended to include both A and B; A or B; A (alone); and B (alone). Similarly, the term "and / or," when used in phrases such as "A, B and / or C," is intended to encompass each of the following embodiments: A, B and C; A, B or C; A or C; A or B; B or C; A and C; A and B; B and C; A (alone); B (alone); and C (alone).

[0071] Headings and subheadings are used for convenience and / or formal correspondence only, are not intended to limit the subject technology, and are not to be referenced in connection with the interpretation of the description of the subject technology. Features described under one heading or one subheading of the subject disclosure may be combined with features described under other headings or subheadings in various embodiments. Moreover, not all features under a single heading or a single subheading may be used together in an embodiment. EXAMPLES

[0072] Various starting materials, intermediates and compounds of the embodiments herein can be isolated and purified, if necessary, using conventional techniques such as precipitation, filtration, crystallization, evaporation, distillation and chromatography. Characterization of these compounds can be performed using conventional methods, such as by melting point, mass spectrum, nuclear magnetic resonance and various other spectroscopic analyses. Abbreviations used in this example section should be understood to have their ordinary meaning in the art, unless otherwise specifically indicated or clearly contrary in context. These examples are merely illustrative and do not limit the claimed invention in any way.

[0073] The synthetic procedures for representative compounds of the present disclosure were described in detail in PCT / CN2021 / 133429, published as International Publication No. WO 2022 / 111621 on June 2, 2022 (the contents of which are incorporated herein by reference in their entirety). Additional synthetic procedures using chiral starting materials / intermediates are described below herein.

[0074] Synthesis of (3S,4R)-3-((4-methoxybenzyl)oxy)tetrahydro-2H-pyran-4-ol (Intermediate I) [ka] Acetic anhydride (328.5 g) was added dropwise to a mixture of (3R,4S,5S)-tetrahydro-2H-pyran-2,3,4,5-tetraol (Intermediate IA, 100 g, 0.67 mol) and 4-dimethylaminopyridine (8.18 g) in tetrahydrofuran (400 mL) at 10-20° C. under nitrogen atmosphere and the reaction mixture was stirred at 20-30° C. for 20 h. The reaction mixture was concentrated under reduced pressure and then diluted with ethyl acetate (800 mL) and ice water (800 mL). The organic phase was washed with saturated aqueous sodium bicarbonate solution (5%, 800 mL) and brine (15%, 800 mL) and then concentrated under reduced pressure. The residue was dissolved in dichloromethane (800 mL) and cooled to −5-5° C. Hydrobromic acid (33% in acetic acid, 328 g) was added to the above solution and it was stirred at −5-5° C. for 18 h. The reaction mixture was diluted with ice water (800 mL) at <10° C., and the organic phase was washed with brine (15%, 800 mL) and concentrated under reduced pressure to give (3R,4S,5S)-2-bromotetrahydro-2H-pyran-3,4,5-triyl triacetate (Intermediate IB, 124 g, 55%) as a pale yellow solid.

[0075] To a mixture of copper acetate (53.6 g, 0.29 mol) in acetic acid (200 mL) and tetrahydrofuran (200 mL) was added zinc dust (115 g, 1.77 mol) in small portions at 40-50° C. under nitrogen atmosphere. The mixture was then cooled to 0-5° C., and tetrahydrofuran (1.30 L), sodium acetate (24.2 g, 0.29 mol) and (3R,4S,5S)-2-bromotetrahydro-2H-pyran-3,4,5-triyl triacetate (Intermediate IB, 100 g, 0.29 mol) were added thereto. The resulting mixture was stirred at 15-20° C. for 16 hours under nitrogen atmosphere. The reaction mixture was filtered, and the filtrate was washed with saturated aqueous sodium carbonate solution (2.0 L) and water (500 mL). The organic phase was concentrated under reduced pressure to give (3S,4R)-3,4-dihydro-2H-pyran-3,4-diyl diacetate (Intermediate IC, 48.4 g, 82%) as a colorless oil.

[0076] Palladium (50 g, 5% on carbon) was added to a solution of (3S,4R)-3,4-dihydro-2H-pyran-3,4-diyl diacetate (Intermediate IC, 500 g, 2.50 mol) in methyl alcohol (3.5 L) under nitrogen atmosphere, and the mixture was then stirred at 25° C. under hydrogen atmosphere (1 atm) for 26 h. The reaction mixture was filtered and the filter cake was washed with methyl alcohol (500 mL). The filtrate was concentrated under reduced pressure to give (3S,4R)-tetrahydro-2H-pyran-3,4-diyl diacetate (Intermediate ID, 480 g, 95%) as a colorless oil.

[0077] To a solution of (3S,4R)-tetrahydro-2H-pyran-3,4-diyl diacetate (Intermediate ID, 100 g, 0.49 mol) in methyl alcohol (1.0 L) was added sodium methoxide (2.70 g, 0.05 mol) at 0-10 °C, then the mixture was warmed to 20-25 °C and stirred for 3 h. The reaction mixture was adjusted to pH 6-8 with aqueous sulfuric acid (6 mol / L) and then filtered. The filter cake was washed with methyl alcohol (50 mL) and the filtrate was concentrated under reduced pressure to give (3S,4R)-tetrahydro-2H-pyran-3,4-diol (Intermediate IE, 53.7 g, 92%, crude) as a pale yellow oil.

[0078] A mixture of (3S,4R)-tetrahydro-2H-pyran-3,4-diol (intermediate IE, 30.0 g, crude), (4-fluorophenyl)boronic acid (35.5 g, 0.02 mol), 4-methoxybenzyl chloride (47.8 g, 0.30 mol), potassium carbonate (42.1 g, 0.30 mol) and potassium iodide (42.1 g, 0.25 mol) in acetonitrile (300 mL) was stirred at 70-80 °C for 16 h. The reaction mixture was concentrated under reduced pressure and the residue was dissolved in ethyl acetate (300 mL) and water (300 mL). The aqueous phase was extracted with ethyl acetate (150 mL) and the combined organic phase was washed with brine (15%, 300 mL x 2), dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to give (3S,4R)-3-((4-methoxybenzyl)oxy)tetrahydro-2H-pyran-4-ol (Intermediate I, 15.2 g) as a yellow oil. 1 H NMR(400MHz,CDCl3)δ 7.23-7.14(m,2H),6.87-6.75(m,2H),4.58-4.47(m,2H),3.91(dt,J=6.4,3.3Hz,1H),3 .77-3.60(m,5H),3.54-3.39(m,3H),2.32(s,1H),1.90-1.83(m,1H),1.78-1.70(m,1H).

[0079] Example 1. 4-((4-(((3S,4R)-3-hydroxytetrahydro-2H-pyran-4-yl)oxy)-5-(trifluoromethyl)pyrimidin-2-yl)amino)-N-(methyl-d 3 ) Synthesis of benzenesulfonamide (E1) [ka] To a solution of 2,4-dichloro-5-(trifluoromethyl)pyrimidine (72.9 g, 0.34 mol) in dichloromethane (290 mL) and tert-butanol (290 mL) was added dropwise a solution of zinc chloride (364 mL, 13% in tetrahydrofuran) over 30 min at 0-10 °C under nitrogen atmosphere. The mixture was stirred at 0-10 °C for 1 h, followed by dropwise addition of a solution of 4-amino-N-(methyl-d3)benzenesulfonamide (1.1, 52.9 g, 0.28 mol) and triethylamine (36.8 g, 50 mL, 0.36 mol) in dichloromethane / tert-butanol (214 mL, v / v=1 / 1,) over 30 min. The resulting mixture was stirred at 25-30 °C for 40 h under nitrogen atmosphere. The reaction mixture was cooled to 0-10 °C and slowly quenched with water (800 mL). The mixture was allowed to warm to 10-20° C. and stirred for 30 min, then it was filtered. The filter cake was washed with dichloromethane (100 mL) and dried in vacuum to give 4-((4-chloro-5-(trifluoromethyl)pyrimidin-2-yl)amino)-N-(methyl-d3)benzenesulfonamide as a yellow solid (1.2, 79.0 g, 77%).

[0080] To a mixture of 4-((4-chloro-5-(trifluoromethyl)pyrimidin-2-yl)amino)-N-(methyl-d3)benzenesulfonamide (1.2, 4.08 g, 11.0 mmol) and (3S,4R)-3-((4-methoxybenzyl)oxy)tetrahydro-2H-pyran-4-ol (3.42 g, 14.3 mmol, intermediate I) in tetrahydrofuran (80 mL) was added lithium hexamethyldisilazide (27.5 mL, 24% in tetrahydrofuran) dropwise under nitrogen atmosphere and the mixture was stirred at 55-60 °C for 16 h. The reaction mixture was cooled to 0-10 °C and quenched with 20% aqueous NH4Cl solution (16 mL) and water (16 mL). The aqueous phase was extracted with 2-methyltetrahydrofuran (30 mL x 2) and the combined organic phase was washed with brine (30 mL) and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (petroleum ether:ethyl acetate=4:1 to 1:1) to give 4-((4-(((3S,4R)-3-((4-methoxybenzyl)oxy)tetrahydro-2H-pyran-4-yl)oxy)-5-(trifluoromethyl)pyrimidin-2-yl)amino)-N-(methyl-d3)benzenesulfonamide as a yellow solid (1.3, 4.38 g, 70%).

[0081] To a solution of 4-((4-(((3S,4R)-3-((4-methoxybenzyl)oxy)tetrahydro-2H-pyran-4-yl)oxy)-5-(trifluoromethyl)pyrimidin-2-yl)amino)-N-(methyl-d3)benzenesulfonamide (1.3, 3.50 g, 6.12 mmol) in dichloromethane (70 mL) and water (10 mL) was added 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (1.81 g, 7.97 mmol) and the mixture was stirred at 15-20 °C for 5 h. The reaction mixture was concentrated under vacuum below 30 °C. The residue was redissolved in 2-methyltetrahydrofuran (35 mL) followed by the addition of 20% aqueous sodium thiosulfate solution (35 mL) and the mixture was stirred at 15-20 °C for 30 min. The organic phase was washed with 5% aqueous sodium bicarbonate solution (35 mL x 2) and brine (35 mL), and then it was concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (heptane:ethyl acetate = 1:1 to 1:2) to give 4-((4-(((3S,4R)-3-hydroxytetrahydro-2H-pyran-4-yl)oxy)-5-(trifluoromethyl)pyrimidin-2-yl)amino)-N-(methyl-d3)benzenesulfonamide (E1, 3.36 g, 83%). LC-MS (ESI): m / z 452.2 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δ 10.50(s,lH),8.60(s,lH),7.92(d,J=8.8Hz,2H),7.73(d,J=8.7Hz,2H),7.27(s,lH),5.62- 5.56(m,lH),5.05(d,J=4.9Hz,lH),3.94-3.85(m,lH),3.69-3.49(m,4H),2.10-1.81(m,2H).

[0082] LC-MS and NMR spectroscopy for additional exemplary compounds prepared with chiral starting materials / intermediates using similar synthetic methodologies (with different starting materials, intermediates or stereoisomers) and routes to this example. 1 The H NMR is provided in Table A below.

[0083] [Table 1]

[0084] [Table 2]

[0085] [Table 3]

[0086] Representative compounds of the present disclosure were tested for biological activity as described in Biological Example 1 of PCT / CN2021 / 133429, published as WO 2022 / 111621 on June 2, 2022. Exemplary results are shown in IC 50 The values ​​are presented as calculated values ​​and are presented in Table 2 below. In Table 2, "A" denotes an IC of less than 10 nM. 50 "B" represents IC of 10 nM or more but less than 100 nM. 50 represents the calculated value; "C" is IC ≥ 100 nM < 1 µM 50 represents the calculated value; and "D" indicates an IC of 1 µM or higher. 50 Represents the calculated value.

[0087] [Table 4]

[0088] The Summary and Abstract sections may set forth one or more, but not all, exemplary embodiments of the invention as contemplated by the inventor(s) and are therefore not intended to be in any way limiting of the scope of the invention and the appended claims.

[0089] The present invention is described above using functional building blocks that illustrate the implementation of the specified functional groups and their relationships. The boundaries of these functional building blocks are arbitrarily defined herein for convenience of description. Alternative boundaries can be defined as long as the specified functional groups and their relationships are properly implemented.

[0090] For aspects of the invention described as genus, each individual species is considered individually as a separate aspect of the invention. When an aspect of the invention is described as "comprising" a certain feature, embodiments "consisting of" or "consisting essentially of" that feature are also contemplated.

[0091] From the foregoing description of specific embodiments, the general nature of the present invention will be fully and completely clear, so that others, by applying knowledge within the skill of the art, can easily modify and / or adapt such specific embodiments for various applications without departing from the general concept of the present invention without undue experimentation. Such adaptations and modifications are therefore intended to be within the meaning and range of equivalents of the disclosed embodiments, based on the teaching and guidance provided herein. It should be understood that the phraseology or terminology used herein is for the purpose of description, not limitation, and thus the terminology or terminology used herein should be interpreted by those of skill in the art in light of this teaching and guidance.

[0092] The breadth and scope of the present invention should not be limited by the exemplary embodiments described above.

[0093] All of the various aspects, embodiments and options described herein may be combined in any and all variations.

[0094] All publications, patents, and patent applications mentioned in this specification are incorporated herein by reference to the same extent as if each individual publication, patent, or patent application was specifically and individually indicated to be incorporated by reference. To the extent that any meaning or definition of a term in this specification conflicts with any meaning or definition of the same term in a document incorporated by reference, the meaning or definition assigned to that term in this specification shall control.

Claims

1. A method for producing 4-((4-(((3S,4R)-3-((4-methoxybenzyl)oxy)tetrahydro-2H-pyran-4-yl)oxy)-5-(trifluoromethyl)pyrimidin-2-yl)amino)-N-(methyl-d 3 )benzenesulfonamide, which comprises reacting 4-((4-(((3S,4R)-3-((4-methoxybenzyl)oxy)tetrahydro-2H-pyran-4-yl)oxy)-5-(trifluoromethyl)pyrimidin-2-yl)amino)-N-(methyl-d 3 )benzenesulfonamide with 2,3-dichloro-5,6-dicyano-1,4-benzoquinone.

2. The method of claim 1, further comprising reacting 4-((4-chloro-5-(trifluoromethyl)pyrimidin-2-yl)amino)-N-(methyl-d3)benzenesulfonamide with (3S,4R)-3-((4-methoxybenzyl)oxy)tetrahydro-2H-pyran-4-ol and lithium hexamethyldisilazide to produce 4-((4-(((3S,4R)-3-((4-methoxybenzyl)oxy)tetrahydro-2H-pyran-4-yl)oxy)-5-(trifluoromethyl)pyrimidin-2-yl)amino)-N-(methyl-d3)benzenesulfonamide.

3. The method of claim 2, further comprising reacting 4-amino-N-(methyl-d3)benzenesulfonamide with 2,4-dichloro-5-(trifluoromethyl)pyrimidine, zinc chloride, and triethylamine to produce 4-((4-chloro-5-(trifluoromethyl)pyrimidin-2-yl)amino)-N-(methyl-d3)benzenesulfonamide.

4. A compound which is 4-((4-(((3S,4R)-3-((4-methoxybenzyl)oxy)tetrahydro-2H-pyran-4-yl)oxy)-5-(trifluoromethyl)pyrimidin-2-yl)amino)-N-(methyl-d 3 )benzenesulfonamide.

5. A compound which is (3S,4R)-3-((4-methoxybenzyl)oxy)tetrahydro-2H-pyran-4-ol.

6. A method for producing (3S,4R)-3-((4-methoxybenzyl)oxy)tetrahydro-2H-pyran-4-ol by reacting (3S,4R)-tetrahydro-2H-pyran-3,4-diol with (4-fluorophenyl)boronic acid and 4-methoxybenzyl chloride, optionally in the presence of potassium carbonate and potassium iodide.

7. The method of claim 1, further comprising reacting (3S,4R)-tetrahydro-2H-pyran-3,4-diyl diacetate with sodium methoxide to produce (3S,4R)-tetrahydro-2H-pyran-3,4-diol; Optionally, (3S,4R)-tetrahydro-2H-pyran-3,4-diyl diacetate is produced by a process comprising reacting (3S,4R)-3,4-dihydro-2H-pyran-3,4-diyl diacetate with a palladium catalyst and hydrogen; The method of claim 6.

8. The method of claim 7, further comprising reacting (3R,4S,5S)-2-bromotetrahydro-2H-pyran-3,4,5-triyl triacetate with sodium acetate and a mixture of copper acetate, acetic acid, and zinc dust to produce (3S,4R)-3,4-dihydro-2H-pyran-3,4-diyl diacetate; Optionally, (3R,4S,5S)-2-bromotetrahydro-2H-pyran-3,4,5-triyl triacetate is produced by a process comprising reacting (3R,4S,5S)-tetrahydro-2H-pyran-2,3,4,5-tetraol with 4-dimethylaminopyridine and acetic anhydride. The method of claim 7.

9. 4-((4-(((3S,4R)-3-((4-methoxybenzyl)oxy)tetrahydro-2H-pyran-4-yl)oxy)-5-(trifluoromethyl)pyrimidin-2-yl)amino)benzenesulfonamide; 4-((4-(((3S,4R)-3-((4-methoxybenzyl)oxy)tetrahydro-2H-pyran-4-yl)oxy)-5-(trifluoromethyl)pyrimidin-2-yl)amino)-N-methylbenzenesulfonamide; N-ethyl-4-((4-(((3S,4R)-3-((4-methoxybenzyl)oxy)tetrahydro-2H-pyran-4-yl)oxy)-5-(trifluoromethyl)pyrimidin-2-yl)amino)benzenesulfonamide; 4-((4-(((3S,4R)-3-((4-methoxybenzyl)oxy)tetrahydro-2H-pyran-4-yl)oxy)-5-(trifluoromethyl)pyrimidin-2-yl)amino)-N-(methyl-d3)benzenesulfonamide; 4-((4-(((3R,4R)-3-((4-methoxybenzyl)oxy)tetrahydro-2H-pyran-4-yl)oxy)-5-(trifluoromethyl)pyrimidin-2-yl)amino)-N-(methyl-d3)benzenesulfonamide; 4-((4-(((3S,4S)-3-((4-methoxybenzyl)oxy)tetrahydro-2H-pyran-4-yl)oxy)-5-(trifluoromethyl)pyrimidin-2-yl)amino)-N-(methyl-d3)benzenesulfonamide; and 4-((4-(((3R,4S)-3-((4-methoxybenzyl)oxy)tetrahydro-2H-pyran-4-yl)oxy)-5-(trifluoromethyl)pyrimidin-2-yl)amino)-N-(methyl-d3)benzenesulfonamide A compound selected from:

10. below: 【Chemistry 1】 A compound selected from Examples E1-E7, selected from: or a pharmaceutically acceptable salt thereof.

11. 11. A pharmaceutical composition comprising the compound of claim 10 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient.

12. A compound according to claim 10 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 11, for use in the treatment of cancer.

13. 13. The compound or pharmaceutically acceptable salt thereof, or pharmaceutical composition according to claim 12, wherein the cancer is selected from the group consisting of breast cancer, ovarian cancer, bladder cancer, uterine cancer, prostate cancer, lung cancer, esophageal cancer, head and neck cancer, colorectal cancer, kidney cancer, liver cancer, pancreatic cancer, gastric cancer, and thyroid cancer.

14. the cancer is a breast cancer selected from ER positive / HR positive, HER2 negative breast cancer; ER positive / HR positive, HER2 positive breast cancer; triple negative breast cancer (TNBC); and inflammatory breast cancer; and / or The compound or pharmaceutically acceptable salt thereof, or pharmaceutical composition according to claim 12, for treating breast cancer selected from endocrine-resistant breast cancer, trastuzumab-resistant breast cancer, or breast cancer exhibiting primary or acquired resistance to CDK4 / CDK6 inhibition.

15. 13. The compound or a pharmaceutically acceptable salt thereof, or pharmaceutical composition according to claim 12, wherein the cancer is characterized by amplification or overexpression of cyclin E1 and / or cyclin E2.

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