Compounds that mediate protein degradation and methods of use thereof

Abstract

Described herein are compounds that mediate the degradation of cyclin-dependent kinase 2 (CDK2) and are therefore useful in the treatment of various disorders, such as cancer.

Description

COMPOUNDS THAT MEDIATE PROTEIN DEGRADATION AND METHODS OF USE THEREOF CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] The application claims the benefit of, and priority to, International Patent Application no. PCT / US2023 / 077781 filed on 25th October 2023, and U.S. Patent Application no.63 / 638,704 filed 25th April 2024, the contents of which is incorporated herein by reference. BACKGROUND

[0002] The ubiquitin proteasome system can be manipulated with different small molecules to trigger targeted degradation of specific proteins of interest. Promoting the targeted degradation of pathogenic proteins using small molecule degraders is emerging as a new modality in the treatment of diseases. One such modality relies on redirecting the activity of E3 ligases such as cereblon (a phenomenon known as E3 reprogramming) using low molecular weight compounds, which have been termed molecular glues, to promote the poly-ubiquitination and ultimately proteasomal degradation of new protein substrates involved in the development of diseases. The molecular glues bind to both the E3 ligase and the target protein, thereby mediating an alteration of the ligase surface and enabling an interaction with the target protein.

[0003] WO 2023 / 069700, WO 2023 / 069720, and WO2024 / 092039 describe compounds that mediate the degradation of cyclin-dependent kinase 2 (CDK2) and are thus useful in treating diseases. There exists a need for further therapeutics that mediate the degradation of CDK2. SUMMARY

[0004] Described herein are novel compounds that modulate cereblon to mediate the targeted degradation of the protein CDK2 and are therefore useful in the treatment of various disorders, such as cancer.

[0005] Thus, in a first aspect, described herein is a compound selected from the group consisting of: Compound 1 Compound 2 Compound 3 Compound 4 FFO F O O O N O N N HN N N HN N HN N HN N N N N N FFF F F F O F F O O O NH NH NH NH O O O O Compound 5 Compound 6 Compound 7 Compound 8 F FFFFFFFO F F F F O O O O N N N N HN N HN N HN N HN N N N N N F FF FFFFFO O O O (R) (S) NH NH NH NH O O O O or a pharmaceutically acceptable salt thereof.

[0006] In a second aspect, described herein is a pharmaceutical composition comprising a compound or pharmaceutically acceptable salt described herein and one or more pharmaceutically acceptable excipients.

[0007] In a third aspect, described herein is a method of treating a disease or condition, such as cancer, in a subject in need thereof, wherein the method comprises administering to the subject a therapeutically effective amount of a compound, pharmaceutically acceptable salt, or pharmaceutical composition described herein.BRIEF DESCRIPTION OF THE FIGURES

[0008] Figure 1 shows effect of various doses of compound 6 on CDK2 protein levels by western blot cell and on proliferation in MDA-MB-157 breast cancer cells.

[0009] Figure 2 shows the effect of various doses of compound 6 on the cell cycle in MDA-MB- 157 breast cancer cells.

[0010] Figure 3 shows the in vivo antitumor effect of Compound 6 in MKN1, a gastric cancer CDX mouse model. DETAILED DESCRIPTION

[0011] The features and other details of the disclosure will now be more particularly described. Certain terms employed in the specification, examples and appended claims are collected here. These definitions should be read in light of the remainder of the disclosure and as understood by a person of skill in the art. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by a person of ordinary skill in the art.Compounds

[0012] In one aspect, described herein is a compound selected from the group consisting of: Compound 1 Compound 2 Compound 3 Compound 4 FFO F O O O N O N N HN N N HN N HN N HN N N N N N FFF F F F O F F O O O NH NH NH NH O O O O Compound 5 Compound 6 Compound 7 Compound 8 F FFFFFFFO F F F F O O O O N N N N HN N HN N HN N HN N N N N N F FF FFFFFO O O O (R) (S) NH NH NH NH O O O O or a pharmaceutically acceptable salt thereof.

[0013] In some embodiments, the compound is selected from the group consisting of: Compound 6 Compound 7 Compound 8 FFFFFFF F F O O O N N N HN N HN N HN N N N N FFFFFFO O O (R) (S) NH NH NH O O O or a pharmaceutically acceptable salt thereof.

[0014] In some embodiments, the compound is selected from the group consisting of: Compound 7 Compound 8 FFFFF F O O N N HN N HN N N N FFFFO O (R) (S) NH NH O O or a pharmaceutically acceptable salt thereof.

[0015] In some embodiments, the compound is: Compound 6 FFF O N HN N N FFO NH O or a pharmaceutically acceptable salt thereof.

[0016] In some embodiments, the compound is a racemic mixture of compound 7 or a pharmaceutically acceptable salt thereof and compound 8 or a pharmaceutically acceptable salt thereof: Compound 7 Compound 8 .

[0017] In some embodiments, the compound is: Compound 7 FFF O N HN N N FFO (R) NH O or a pharmaceutically acceptable salt thereof.

[0018] In some embodiments, the compound is: Compound 8 FFF O N HN N N FFO (S) NH O or a pharmaceutically acceptable salt thereof.

[0019] In some embodiments, the compound is selected from the group consisting of: Compound 1 Compound 2 Compound 3 Compound 4 Compound 5 FFF O F O F F O O O N O N N O HN N N HN N HN N N HN NHNNN N N N N FFF FFO F FFO O F F O O NH NH NH NH NH O O O O O or a pharmaceutically acceptable salt thereof.

[0020] In some embodiments, the compound is: Compound 1 O O N HN N N FFO NH O or a pharmaceutically acceptable salt thereof.

[0021] In some embodiments, the compound is: Compound 2 FFF O N HN N N F F O NH O or a pharmaceutically acceptable salt thereof.

[0022] In some embodiments, the compound is: Compound 3 O N HN N N F F O NH O or a pharmaceutically acceptable salt thereof.

[0023] In some embodiments, the compound is: Compound 4 O N HN N N FFO NH O or a pharmaceutically acceptable salt thereof.

[0024] In some embodiments, the compound is: Compound 5 F O F F O N HNNN F F O NH O or a pharmaceutically acceptable salt thereof.

[0025] The compounds of the invention may be provided in any suitable form. For instance, the compounds may be provided in crystalline, or amorphous form. The compounds may be provided as salts, solvates (including hydrates), clathrates, eutectics, co-crystals, solid solutions, or solid dispersions. Pharmaceutical Compositions

[0026] In one aspect, described herein is a pharmaceutical composition comprising a compound or pharmaceutically acceptable salt described herein and one or more pharmaceutically acceptable excipients. In some embodiments, the pharmaceutical composition comprises an effective amount of the compound or pharmaceutically acceptable salt. In some embodiments, the pharmaceutical composition comprises a therapeutically effective amount of the compound or pharmaceutically acceptable salt.

[0027] The pharmaceutical compositions described herein may be administered by a variety of routes including, but not limited to, oral (enteral) administration, parenteral (by injection) administration, rectal administration, transdermal administration, intradermal administration, intrathecal administration, subcutaneous (SC) administration, intravenous (IV) administration, intramuscular (IM) administration, and intranasal administration. Advantageously, the compounds of the invention are suitable for oral administration.

[0028] Compositions for oral administration may take the form of bulk liquid solutions or suspensions, or bulk powders. In some embodiments, the compositions are presented in unit dosage forms to facilitate accurate dosing. The term “unit dosage forms” refers to physically discrete units suitable as unitary dosages for human subjects and other mammals, each unit containing a predetermined quantity of active material calculated to produce the desired therapeutic effect, in association with a suitable pharmaceutical excipient. Typical unit dosage forms include prefilled, premeasured ampules or syringes of the liquid compositions or pills, tablets, capsules or the like in the case of solid compositions. In such compositions, the compound is usually a minor component with the remainder being various vehicles or excipients and processing aids helpful for forming the desired dosing form. Methods of Treatment and Uses

[0029] The compounds described herein can be used to degrade CDK2.

[0030] In some embodiments of the disclosure, a compound described herein is used to degrade CDK2 in an ex vivo or in vitro system. In some embodiments, a compound described herein is used to degrade CDK2 in an ex vivo system. In some embodiments, a compound described herein is used to degrade CDK2 in an in vitro system.

[0031] Described herein is a method of degrading CDK2 comprising combining CDK2 and cereblon with a compound described herein in an ex vivo system or in vitro system. In some embodiments, the method comprises combining CDK2 and cereblon with a compound described herein in an ex vivo system. In some embodiments, the method comprises combining CDK2 and cereblon with a compound described herein in an in vitro system.

[0032] Cyclin dependent kinases (CDKs) are a family of closely related kinases that regulate progression through the cell cycle. CDK activity is further modulated by levels of specific cyclins; for example, cyclin E1 activates cyclin dependent kinase 2 (CDK2). Mechanisms activating CDK2 in tumors are (i) amplification of cyclin E1 or cyclin E2, and (ii) loss of the AMBRA1 gene. Elimination of CDK2 is contemplated to treat such disorders.

[0033] Accordingly, the compounds, pharmaceutically acceptable salts, and pharmaceutical compositions described herein are contemplated as useful in the treatment or prevention of disorders in subjects in need thereof. In some embodiments, a compound or pharmaceutical composition described herein is used to degrade CDK2 in a subject. In some embodiments, a compound, pharmaceutically acceptable salt, or pharmaceutical composition described herein is used to degrade CDK2 for the treatment or prevention of a disorder.

[0034] Where methods for treatment of the human or animal body by surgery or therapy, or diagnostic methods practiced on the human or animal body, are described herein, this corresponds to the compounds, pharmaceutically acceptable salts, and pharmaceutical compositions described herein for use in such methods.

[0035] In one aspect, described herein is a method of treating or preventing a disorder in a subject in need thereof, wherein the method comprises administering to the subject a therapeutically effective amount of a compound, pharmaceutically acceptable salt, or pharmaceutical composition described herein. In some embodiments, the compound, pharmaceutically acceptable salt, or pharmaceutical composition is administered to degrade CDK2 in the subject.

[0036] In one aspect, described herein is a method of degrading CDK2 in a subject suffering from a disorder, wherein the method comprises administering to the subject a therapeutically effective amount of a compound, pharmaceutically acceptable salt thereof, or pharmaceutical composition described herein. In some embodiments, the compound binds to cereblon and a CDK2 protein to induce ubiquitination and subsequent proteasomal degradation of the CDK2 protein.

[0037] Exemplary disorders that can be treated or prevented by the methods of the present disclosure include, but are not limited to, cancer of the bladder, bone, brain, breast, cervix, chest, colon, endometrium, esophagus, eye, head, kidney, liver, lymph nodes, lung, upper aerodigestive tract (including nasal cavity and paranasal sinuses, nasopharynx or cavum, oral cavity, oropharynx, larynx, hypopharynx, and salivary glands), neck, ovaries, pancreas, prostate, rectum, skin, stomach, testis, throat, and uterus. Other exemplary disorders include, but are not limited to, amyloidosis, neuroblastoma, meningioma, hemangiopericytoma, multiple brain metastases, glioblastoma multiforms, glioblastoma, brain stemglioma, poor prognosis malignant brain tumor, malignant glioma, recurrent malignant glioma, anaplastic astrocytoma, anaplastic oligodendroglioma, neuroendocrine tumor, e.g., neuroendocrine prostate cancer such as castration-resistant neuroendocrine prostate cancer (NEPC) and lung neuroendocrine tumors (Lu- NETs), rectal adenocarcinoma, colorectal cancer, including stage 3 and stage 4 colorectal cancer, unresectable colorectal carcinoma, metastatic hepatocellular carcinoma, Kaposi's sarcoma, malignant melanoma, malignant mesothelioma, malignant pleural effusion mesothelioma syndrome, peritoneal carcinoma, papillary serous carcinoma, gynecologic sarcoma, soft tissue sarcoma, scleroderma, cutaneous vasculitis, Langerhans cell histiocytosis, leiomyosarcoma, fibrodysplasia ossificans progressive, hormone refractory prostate cancer, resected high-risk soft tissue sarcoma, unrescectable hepatocellular carcinoma, fallopian tube cancer, androgen independent prostate cancer, androgen dependent stage IV non-metastatic prostate cancer, hormone-insensitive prostate cancer, chemotherapy-insensitive prostate cancer, papillary thyroid carcinoma, follicular thyroid carcinoma, medullary thyroid carcinoma, and leiomyoma; and blood bourne (liquid) or hematological cancers, including but not limited to leukemias, lymphomas, and myelomas, such as diffuse large B-cell lymphoma (DLBCL), B-cell immunoblastic lymphoma, small non-cleaved cell lymphoma, human lymphotropic virus-type 1 (HTLV-1) leukemia / lymphoma, adult T- cell lymphoma, peripheral T-cell lymphoma (PTCL), cutaneous T-cell lymphoma (CTCL), mantle cell lymphoma (MCL), Hodgkin’s lymphoma (HL), non-Hodgkin’s lymphoma (NHL), AIDS-related lymphoma, follicular lymphoma, small lymphocytic lymphoma, T-cell / histiocyte rich large B-cell lymphoma, transformed lymphoma, primary mediastinal (thymic) large B-cell lymphoma, splenic marginal zone lymphoma, Richter's transformation, nodal marginal zone lymphoma, ALK-positive large B-cell lymphoma, indolent lymphoma (for example, DLBCL, follicular lymphoma, or marginal zone lymphoma), acute myelogenous leukemia (AML), acute lymphocytic leukemia (ALL), adult T-cell leukemia, chronic lymphocytic leukemia (CLL), small lymphocytic lymphoma (SLL), hairy cell leukemia, myelodysplasia, myeloproliferative disorders, chronic myelogenous leukemia (CML), acute monocytic leukemia (AMoL), myelodysplastic syndrome (MDS), human lymphotropic virus-type 1 (HTLV-1) leukemia, mastocytosis, B-cell acute lymphoblastic leukemia, Non-Hodgkin's Lymphoma, Hodgkin's Lymphoma, and multiple myeloma (MM).

[0038] In some embodiments, the disorder is cancer.

[0039] In some embodiments, the disorder is cancer that comprises a solid tumor. In some embodiments, the solid tumor is at least one of the group consisting of: uterine cancer (such as uterine carcinosarcoma and uterine corpus endometrial carcinoma), endometrial cancer, breast cancer, (such as breast invasive carcinoma and triple negative breast cancer, ER+ HER2- breast cancer, and HER2+ breast cancer), ovarian cancer (such as ovarian serous cystadenocarcinoma), stomach cancer (such as stomachadenocarcinoma), gastric cancer (such as gastrointestinal stromal cancer), colorectal cancer, pancreatic cancer, kidney cancer, head and neck cancer, liver cancer, prostate cancer, skin cancer, lymphoma (such as B-cell lymphoma), sarcoma, esophageal cancer (such as esophageal carcinoma), bladder cancer (such as bladder urothelial carcinoma), lung cancer (such as lung squamous carcinoma and non-small cell lung cancer including EGFRm+ (epidermal growth factor receptor mutant positive) non-small cell lung cancer), cholangiocarcinoma, adrenocortical carcinoma, mesothelioma, and malignant melanoma. In some embodiments, the solid tumor is at least one of the group consisting of: prostate cancer, colon cancer, esophageal cancer, endometrial cancer, ovarian cancer, uterine cancer, renal cancer, hepatic cancer, pancreatic cancer, gastric cancer, breast cancer, lung cancer, cancers of the head and neck, thyroid cancer, glioblastoma, sarcoma, bladder cancer, and melanoma.

[0040] In some embodiments, the disorder is cancer that is selected from the group consisting of: ovarian cancer, endometrial cancer, gastric cancer, esophaegeal cancer, breast cancer (such as triple negative breast cancer), and lung adenosarcoma. In some embodiments, the disorder is breast cancer or ovarian cancer. In some embodiments, the disorder is ovarian cancer. In some embodiments, the cancer is gastric cancer.

[0041] In some embodiments, the disorder is breast cancer. In some embodiments, the breast cancer is HR+ (hormone receptor positive) breast cancer. In some embodiments, the breast cancer is ER+ (estrogen receptor positive) breast cancer. In some embodiments, the breast cancer is HR+ HER2- (human epidermal growth factor receptor 2 negative) breast cancer. In some embodiments, the breast cancer is ER+ HER2- breast cancer. In some embodiments, the cancer is triple negative breast cancer.

[0042] In some embodiments, the disorder is cancer that comprises a liquid tumor. In some embodiments, the liquid tumor is at least one of the group consisting of: diffuse large B-cell lymphoma (DLBCL), B-cell immunoblastic lymphoma, small non-cleaved cell lymphoma, human lymphotropic virus-type 1 (HTLV-1) leukemia / lymphoma, adult T-cell lymphoma, peripheral T-cell lymphoma (PTCL), cutaneous T-cell lymphoma (CTCL), mantle cell lymphoma (MCL), Hodgkin’s lymphoma (HL), non-Hodgkin’s lymphoma (NHL), AIDS-related lymphoma, follicular lymphoma, small lymphocytic lymphoma, T-cell / histiocyte rich large B-cell lymphoma, transformed lymphoma, primary mediastinal (thymic) large B-cell lymphoma, splenic marginal zone lymphoma, Richter's transformation, nodal marginal zone lymphoma, ALK-positive large B-cell lymphoma, indolent lymphoma (for example, DLBCL, follicular lymphoma, or marginal zone lymphoma), acute myelogenous leukemia (AML), acute lymphocytic leukemia (ALL), adult T-cell leukemia, chronic lymphocytic leukemia (CLL), small lymphocytic lymphoma (SLL), hairy cell leukemia, myelodysplasia, myeloproliferative disorders, chronic myelogenous leukemia (CML), acute monocytic leukemia (AMoL), myelodysplastic syndrome (MDS),human lymphotropic virus- type 1 (HTLV-1) leukemia, mastocytosis, B-cell acute lymphoblastic leukemia, Non-Hodgkin's Lymphoma, Hodgkin's Lymphoma, and multiple myeloma (MM). In some embodiments, the liquid tumor is at least one of the group consisting of: acute lymphoblastic leukemia (ALL), acute myelogenous leukemia (AML), chronic lymphocytic leukemia (CLL), chronic myelogenous leukemia (CML), DLBCL, mantle cell lymphoma, Non-Hodgkin lymphoma (such as follicular lymphoma, including relapsed or refractory NHL and recurrent follicular), Hodgkin lymphoma, and multiple myeloma.

[0043] In one aspect, described herein is a method of treating cancer (e.g., a cancer described herein) in a subject in need thereof, wherein the method comprises administering to the subject a therapeutically effective amount of a compound, pharmaceutically acceptable salt, or pharmaceutical composition described herein.

[0044] In one aspect, described herein is a method of degrading CDK2 in a subject suffering from cancer (e.g., a cancer described herein), wherein the method comprises administering to the subject a therapeutically effective amount of a compound, pharmaceutically acceptable salt, or pharmaceutical composition described herein.

[0045] In one aspect, described herein is a method of treating a solid tumor (e.g., a solid tumor described herein) in a subject in need thereof, wherein the method comprises administering to the subject a therapeutically effective amount of a compound, pharmaceutically acceptable salt, or pharmaceutical composition described herein.

[0046] In one aspect, described herein is a method of treating a liquid tumor (e.g., a liquid tumor described herein) in a subject in need thereof, wherein the method comprises administering to the subject a therapeutically effective amount of a compound, pharmaceutically acceptable salt, or pharmaceutical composition described herein. In some embodiments, the liquid tumor is that of a haematological cancer (e.g., a haematological cancer described herein).

[0047] In one aspect, described herein is a method of treating a cancer with a CCNE1 (cyclin E1) amplification. In some embodiments, the cancer is a cancer listed above. CCNE1 amplification can be determined by identifying an increase in the number of copies of the CCNE1 gene in cancer cells. This can be done routinely through a variety of molecular techniques that analyze DNA and gene expression levels. Such techniques include fluorescence in situ hybridisation (FISH), quantitative polymerase chain reaction (qPCR), and immunohistochemistry (IHC).

[0048] In some embodiments, the compound, pharmaceutically acceptable salt, or pharmaceutical composition is administered as a first-line therapy. In some embodiments, the subject towhich the compound, pharmaceutically acceptable salt, or pharmaceutical composition is administered is a treatment-naïve subject, i.e. a subject that has not yet been treated with the standard of care. Combinations

[0049] The compounds, pharmaceutically acceptable salts, and pharmaceutical compositions described herein can be administered as single agents or in combination with one or more additional therapeutic agents such as additional anticancer agents, in particular standard of care agents appropriate for the particular disorder (e.g., the particular cancer) to be treated. Therefore, in some embodiments, the compound, pharmaceutically acceptable salt, or pharmaceutical composition is administered in combination with an additional therapeutic agent, for example an additional anticancer agent. In other words, the compounds, salts, or compositions of the invention may be for use in therapy in combination with an additional therapeutic agent, for example an additional anticancer agent. Similarly, a therapeutic agent, for example an anticancer agent, may be for use in therapy with the compounds, salts, or compositions of the invention.

[0050] The additional therapeutic agent may be administered at the same time or at a different time (for example, sequentially) to the compounds, pharmaceutically acceptable salts, and pharmaceutical compositions described herein.

[0051] In some embodiments, the additional therapeutic agent is a CDK4 / 6 inhibitor. In some embodiments, CDK4 / 6 inhibitor is palbociclib, ribociclib, abemaciclib, or in each case a pharmaceutically acceptable salt thereof. In some embodiments, the CDK4 / 6 inhibitor is palbociclib or a pharmaceutically acceptable salt thereof, or ribociclib or a pharmaceutically acceptable salt thereof. In some embodiments, the CDK4 / 6 inhibitor is palbociclib or a pharmaceutically acceptable salt thereof. In some embodiments, the CDK4 / 6 inhibitor is ribociclib or a pharmaceutically acceptable salt thereof such as ribociclib succinate. In some embodiments, the CDK4 / 6 inhibitor is abemaciclib or a pharmaceutically acceptable salt thereof. These additional therapeutic agents are particularly suitable when the disorder to be treated is breast cancer (such as HR+ breast cancer, ER+ breast cancer, HR+ HER2- breast cancer, or ER+ HER2- breast cancer). In some embodiments, the breast cancer has progressed despite treatment with a CDK4 / 6 inhibitor. In some embodiments, the breast cancer is resistant to treatment with a CDK4 / 6 inhibitor. In some embodiments, the subject with breast cancer is a treatment-naïve subject. In some embodiments, the CDK4 / 6 inhibitor is administered in combination with endocrine therapy. In some embodiments, the CDK4 / 6 inhibitor is administered in combination with endocrine therapy and the endocrine therapy is administered in combination with a luteinising hormone-releasing hormone (LHRH) agonist. In some embodiments, the endocrine therapy is an estrogen receptor antagonist such as fulvestrant, or anaromatase inhibitor such as letrozole. In some embodiments, the endocrine therapy is fulvestrant. In some embodiments, the CDK4 / 6 inhibitor is palbociclib or a pharmaceutically acceptable salt thereof, or ribociclib or a pharmaceutically acceptable salt thereof, and is administered in combination with fulvestrant. In some embodiments, the CDK4 / 6 inhibitor is ribociclib or a pharmaceutically acceptable salt thereof and is administered in combination with fulvestrant. In any of the preceding embodiments, the CDK4 / 6 inhibitor may be present in the form of a pharmaceutically acceptable salt. For example, ribociclib, if present, may be in the form of a succinate salt, i.e. as ribociclib succinate. Definitions

[0052] As used herein, the term “pharmaceutically acceptable salt” refers to those salts which 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 / risk ratio. Pharmaceutically acceptable salts are well known in the art. For example, Berge et al., describes pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences (1977) 66:1–19. Pharmaceutically acceptable salts of the compounds of the present disclosure include those derived from suitable inorganic and organic acids and bases. Examples of pharmaceutically acceptable, nontoxic acid addition salts are salts of an amino group formed with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid or with organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid or malonic acid or by using other methods used in the art such as ion exchange. Other pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2–hydroxy–ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2–naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3–phenylpropionate, phosphate, picrate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p–toluenesulfonate, undecanoate, valerate salts, and the like. Pharmaceutically acceptable salts derived from appropriate bases include alkali metal, alkaline earth metal, ammonium, and N+(C1–4alkyl)4salts. Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like. Further pharmaceutically acceptable salts include, when appropriate, nontoxic ammonium, quaternary ammonium, and amine cations formed using counterions such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, lower alkyl sulfonate, and aryl sulfonate.

[0053] A “subject” to which administration is contemplated includes, but is not limited to, humans (i.e., a male or female of any age group, e.g., a pediatric subject (e.g, infant, child, or adolescent) or adult subject (e.g., young adult, middle–aged adult or senior adult)) and / or non-human animals, e.g., mammals such as primates (e.g., cynomolgus monkeys and rhesus monkeys), cattle, pigs, horses, sheep, goats, rodents, cats, and / or dogs. In some embodiments, the subject is a human. In some embodiments, the subject is a non-human animal. The terms “human,” “patient,” and “subject” are used interchangeably herein.

[0054] The terms “disease,” “disorder,” and “condition” are used interchangeably herein.

[0055] As used herein, and unless otherwise specified, the terms “treat,” “treating” and “treatment” contemplate an action that occurs while a subject is suffering from the specified disease, disorder or condition, which reduces the severity of the disease, disorder or condition, or retards or slows the progression of the disease, disorder or condition. In some embodiments, the present disclosure contemplates administration of the compounds described herein as a prophylactic before a subject begins to suffer from the specified disease, disorder or condition.

[0056] In general, the “effective amount” of a compound as used herein refers to an amount sufficient to elicit the desired biological response. As will be appreciated by those of ordinary skill in this art, the effective amount of a compound of the present disclosure may vary depending on factors such as the desired biological endpoint, the pharmacokinetics of the compound, the disease being treated, the mode of administration, and the age, health, and condition of the subject.

[0057] As used herein, and unless otherwise specified, a “therapeutically effective amount” of a compound is an amount sufficient to provide a therapeutic benefit in the treatment of a disease, disorder or condition, or to delay or minimize one or more symptoms associated with the disease, disorder or condition. A therapeutically effective amount of a compound means an amount of therapeutic agent, alone or in combination with other therapies, which provides a therapeutic benefit in the treatment of the disease, disorder or condition. The term “therapeutically effective amount” can encompass an amount that improves overall therapy, reduces or avoids symptoms or causes of disease or condition, or enhances the therapeutic efficacy of another therapeutic agent.

[0058] It is to be understood that compounds that have the same molecular formula but differ in the nature or sequence of bonding of their atoms or the arrangement of their atoms in space are termed “isomers.” Isomers that differ in the arrangement of their atoms in space are termed “stereoisomers.” Stereoisomers that are not mirror images of one another are termed “diastereomers” and those that are non–superimposable mirror images of each other are termed “enantiomers.” When a compound has anasymmetric center, for example, it is bonded to four different groups, a pair of enantiomers is possible. An enantiomer can be characterized by the absolute configuration of its asymmetric center and is described by the R– and S–sequencing rules of Cahn and Prelog, or by the manner in which the molecule rotates the plane of polarized light and designated as dextrorotatory or levorotatory (i.e., as (+) or (–)– isomers respectively). A chiral compound can exist as either individual enantiomer or as a mixture thereof. A mixture containing equal proportions of the enantiomers is called a “racemic mixture”.

[0059] Isomers, e.g., stereoisomers, can be isolated from mixtures by methods known to those skilled in the art, including chiral high pressure liquid chromatography (HPLC) and the formation of chiral salts; or preferred isomers can be prepared by asymmetric syntheses. 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 (E.L. Eliel, Ed., Univ. of Notre Dame Press, Notre Dame, IN 1972). The present disclosure additionally encompasses compounds and pharmaceutically acceptable salts described herein as individual isomers substantially free of other isomers, and alternatively, as mixtures of various isomers.

[0060] The compounds and pharmaceutically acceptable salts described herein can be administered as the sole active agent, or they can be administered in combination with other active agents. In some embodiments, the present invention provides a combination of a compound of the present invention or a pharmaceutically acceptable salt thereof and another pharmacologically active agent. Administration in combination can proceed by any technique apparent to those of skill in the art including, for example, separate, sequential, concurrent, and alternating administration.

[0061] The present disclosure, in an alternative embodiment, also embraces isotopically labeled compounds and pharmaceutically acceptable salts which are identical to those recited herein, except that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature. Examples of isotopes that can be incorporated into compounds described herein include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur,fluorine and chlorine, such as 2H,3H,13C,14C,15N,18O,17O,31P,32P,35S,18F, and36Cl, respectively. For example, the compounds and pharmaceutically acceptable salts of the present disclosure may have one or more, or all H atoms replaced with or enriched with deuterium.EXEMPLARY EMBODIMENTS

[0061] Various exemplary embodiments are set out below. 1. A compound selected from the group consisting of: Compound 1 Compound 2 Compound 3 Compound 4 FFO F O O O N O N N HN N N HN N HN N HN N N N N N FFF F F F O F F O O O NH NH NH NH O O O O Compound 5 Compound 6 Compound 7 Compound 8 F FFFFFFFO F F F F O O O O N N N N HN N HN N HN N HN N N N N N F FF FFFFFO O O O (R) (S) NH NH NH NH O O O O or a pharmaceutically acceptable salt thereof.The compound of embodiment 1, wherein the compound is selected from the group consisting of: Compound 6 Compound 7 Compound 8 FFFFFFF F F O O O N N N HN N HN N HN N N N N FFFFFFO O O (R) (S) NH NH NH O O O or a pharmaceutically acceptable salt thereof. The compound of embodiment 1 or 2, wherein the compound is: Compound 6 FFF O N HN N N FFO NH O or a pharmaceutically acceptable salt thereof.The compound of embodiment 3, wherein the compound is a racemic mixture of compound 7 or a pharmaceutically acceptable salt thereof and compound 8 or a pharmaceutically acceptable salt thereof: Compound 7 Compound 8 FFFFF F O O N N HN N HN N N N FFFFO O (R) (S) NH NH O O . The compound of any one of embodiments 1 to 3, wherein the compound is: Compound 7 FFF O N HN N N F F O (R) NH O or a pharmaceutically acceptable salt thereof.The compound of any one of embodiments 1-3, wherein the compound is: Compound 8 FFF O N HN N N FFO (S) NH O or a pharmaceutically acceptable salt thereof. The compound of embodiment 1, wherein the compound is selected from the group consisting of: Compound 1 Compound 2 Compound 3 Compound 4 Compound 5 FFF O F O F F O O O N O N N O HN N N HN N HN N N HN NHNNN N N N N FFF F F F O F F O O F F O O NH NH NH NH NH O O O O O or a pharmaceutically acceptable salt thereof.he compound of embodiment 7, wherein the compound is: Compound 1 O O N HN N N FFO NH O or a pharmaceutically acceptable salt thereof. he compound of embodiment 7, or the salt thereof, wherein the compound is: Compound 2 FFF O N HN N N F F O NH O or a pharmaceutically acceptable salt thereof.The compound of embodiment 7, wherein the compound is: Compound 3 O N HN N N F F O NH O or a pharmaceutically acceptable salt thereof. The compound of embodiment 7, wherein the compound is: Compound 4 O N HN N N F F O NH O or a pharmaceutically acceptable salt thereof.The compound of embodiment 7, wherein the compound is: Compound 5 F O F F O N HNNN F F O NH O or a pharmaceutically acceptable salt thereof. A pharmaceutical composition comprising the compound or pharmaceutically acceptable salt of any one of embodiments 1-12 and one or more pharmaceutically acceptable excipients. A method of treating a disease or condition in a subject in need thereof, wherein the method comprises administering to the subject a therapeutically effective amount of the compound or pharmaceutically acceptable salt of any one of embodiments 1-12, or the pharmaceutical composition of embodiment 13. A method of treating cancer in a subject in need thereof, wherein the method comprises administering to the subject a therapeutically effective amount of the compound or pharmaceutically acceptable salt of any one of embodiments 1-12, or the pharmaceutical composition of embodiment 13. The method of embodiment 15, wherein the cancer comprises a solid tumor. The method of embodiment 16, wherein the solid tumor is at least one of the group consisting of: uterine cancer (such as uterine carcinosarcoma and uterine corpus endometrial carcinoma), endometrial cancer, breast cancer (such as breast invasive carcinoma and triple negative breastcancer, ER+ HER2- breast cancer, and HER2+ breast cancer), ovarian cancer (such as ovarian serous cystadenocarcinoma), stomach cancer (such as stomach adenocarcinoma), gastric cancer (such as gastrointestinal stromal cancer), colorectal cancer, pancreatic cancer, kidney cancer, head and neck cancer, liver cancer, prostate cancer, skin cancer, lymphoma (such as B-cell lymphoma), sarcoma, esophageal cancer (such as esophageal carcinoma), bladder cancer (such as bladder urothelial carcinoma), lung cancer (such as lung squamous carcinoma and non-small cell lung cancer including EGFRm+ (epidermal growth factor receptor mutant positive) non-small cell lung cancer), cholangiocarcinoma, adrenocortical carcinoma, mesothelioma, and malignant melanoma. The method of any one of embodiments 15-17, wherein the cancer is selected from the group consisting of: ovarian cancer, endometrial cancer, gastric cancer, esophaegeal cancer, breast cancer (such as triple negative breast cancer), and lung adenosarcoma. The method of embodiment 18, wherein the cancer is breast cancer. The method of embodiment 19, wherein the breast cancer is HR+ (hormone receptor positive) breast cancer. The method of embodiment 19 or embodiment 20, wherein the breast cancer is ER+ (estrogen receptor positive) breast cancer. The method of embodiment 20, wherein the breast cancer is HR+ HER2- (human epidermal growth factor receptor 2 negative) breast cancer. The method of embodiment 21, wherein the breast cancer is ER+ HER2- (human epidermal growth factor receptor 2 negative) breast cancer. The method of embodiment 19, wherein the breast cancer is triple negative breast cancer. The method of embodiment 15, wherein the cancer comprises a liquid tumor. The method of embodiment 25, wherein the liquid tumor is at least one of the group consisting of: diffuse large B-cell lymphoma (DLBCL), B-cell immunoblastic lymphoma, small non-cleaved cell lymphoma, human lymphotropic virus-type 1 (HTLV-1) leukemia / lymphoma, adult T-celllymphoma, peripheral T-cell lymphoma (PTCL), cutaneous T-cell lymphoma (CTCL), mantle cell lymphoma (MCL), Hodgkin’s lymphoma (HL), non-Hodgkin’s lymphoma (NHL), AIDS-related lymphoma, follicular lymphoma, small lymphocytic lymphoma, T-cell / histiocyte rich large B-cell lymphoma, transformed lymphoma, primary mediastinal (thymic) large B-cell lymphoma, splenic marginal zone lymphoma, Richter's transformation, nodal marginal zone lymphoma, ALK-positive large B-cell lymphoma, indolent lymphoma (e.g., DLBCL, follicular lymphoma, or marginal zone lymphoma), acute myelogenous leukemia (AML), acute lymphocytic leukemia (ALL), adult T-cell leukemia, chronic lymphocytic leukemia (CLL), small lymphocytic lymphoma (SLL), hairy cell leukemia, myelodysplasia, myeloproliferative disorders, chronic myelogenous leukemia (CML), acute monocytic leukemia (AMoL), myelodysplastic syndrome (MDS), human lymphotropic virus- type 1 (HTLV-1) leukemia, mastocytosis, B-cell acute lymphoblastic leukemia, Non-Hodgkin's Lymphoma, Hodgkin's Lymphoma, and multiple myeloma (MM). ^^^ The method of any one of embodiments 14-26, wherein the method further comprises^ administering to the subject a CDK4 / 6 inhibitor, for example wherein the CDK4 / 6 inhibitor is^ ribociclib, palbociclib, abemaciclib, or in each case a pharmaceutically acceptable salt thereof,^ optionally wherein the CDK4 / 6 inhibitor is administered in combination with endocrine therapy^ such as a luteinising hormone-releasing hormone (LHRH) agonist, an estrogen receptor antagonist^ such as fulvestrant, or an aromatase inhibitor such as letrozole. ^^^ The method of any one of embodiments 1^-27, wherein the cancer is a cancer with a CCNE1 (cyclin E1) amplification. ^^^ The method of embodiment 14, wherein the disease or condition is cancer of the bladder, bone,^ brain, breast, cervix, chest, colon, endrometrium, esophagus, eye, head, kidney, liver, lymph nodes,^ lung, upper aerodigestive tract (including nasal cavity and paranasal sinuses, nasopharynx or^ cavum, oral cavity, oropharynx, larynx, hypopharynx and salivary glands, neck, ovaries, pancreas,^ prostate, rectum, skin, stomach, testis, throat, or uterus. ^^^ The method of embodiment 14, wherein the disease or condition is selected from the group^ consisting of amyloidosis, neuroblastoma, meningioma, hemangiopericytoma, multiple brain^ metastases, glioblastoma multiforms, glioblastoma, brain stem glioma, poor prognosis malignant^ brain tumor, malignant glioma, recurrent malignant glioma, anaplastic astrocytoma, anaplastic^ oligodendroglioma, neuroendocrine tumor, e.g., neuroendocrine prostate cancer such as castration-resistant neuroendocrine prostate cancer (NEPC) and lung neuroendocrine tumors (Lu-NETs), rectal adenocarcinoma, colorectal cancer, including stage 3 and stage 4 colorectal cancer, unresectable colorectal carcinoma, metastatic hepatocellular carcinoma, Kaposi's sarcoma, malignant melanoma, malignant mesothelioma, malignant pleural effusion mesothelioma syndrome, peritoneal carcinoma, papillary serous carcinoma, gynecologic sarcoma, soft tissue sarcoma, scleroderma, cutaneous vasculitis, Langerhans cell histiocytosis, leiomyosarcoma, fibrodysplasia ossificans progressive, hormone refractory prostate cancer, resected high-risk soft tissue sarcoma, unrescectable hepatocellular carcinoma, fallopian tube cancer, androgen independent prostate cancer, androgen dependent stage IV non-metastatic prostate cancer, hormone-insensitive prostate cancer, chemotherapy -insensitive prostate cancer, papillary thyroid carcinoma, follicular thyroid carcinoma, medullary thyroid carcinoma, and leiomyoma; and blood bourne (liquid) or hematological cancers, including but not limited to leukemias, lymphomas, and myelomas, such as diffuse large B-cell lymphoma (DLBCL), B-cell immunoblastic lymphoma, small non-cleaved cell lymphoma, human lymphotropic virus-type 1 (HTLV-1) leukemia / lymphoma, adult T-cell lymphoma, peripheral T-cell lymphoma (PTCL), cutaneous T- cell lymphoma (CTCL), mantle cell lymphoma (MCL), Hodgkin’s lymphoma (HL), non- Hodgkin’s lymphoma (NHL), AIDS-related lymphoma, follicular lymphoma, small lymphocytic lymphoma, T-cell / histiocyte rich large B-cell lymphoma, transformed lymphoma, primary mediastinal (thymic) large B-cell lymphoma, splenic marginal zone lymphoma, Richter's transformation, nodal marginal zone lymphoma, ALK-positive large B-cell lymphoma, indolent lymphoma (for example, DLBCL, follicular lymphoma, or marginal zone lymphoma), acute myelogenous leukemia (AML), acute lymphocytic leukemia (ALL), adult T-cell leukemia, chronic lymphocytic leukemia (CLL), small lymphocytic lymphoma (SLL), hairy cell leukemia, myelodysplasia, myeloproliferative disorders, chronic myelogenous leukemia (CML), acute monocytic leukemia (AMoL), myelodysplastic syndrome (MDS), human lymphotropic virus- type 1 (HTLV-1) leukemia, mastocytosis, B-cell acute lymphoblastic leukemia, Non-Hodgkin's Lymphoma, Hodgkin's Lymphoma, and multiple myeloma (MM). The method of any one of embodiments 14-30, wherein the subject is a treatment-naïve subject.EXAMPLES Synthesis of Exemplary Compounds

[0062] The compounds provided herein can be prepared from readily available starting materials using the following methods and procedures. It will be appreciated that where typical or preferred process conditions (i.e., reaction temperatures, times, mole ratios of reactants, solvents, pressures, etc.) are given, other process conditions can also be used unless otherwise stated. Optimum reaction conditions may vary with the particular reactants or solvent used, but such conditions can be determined by a person of ordinary skill in the art by routine optimization.

[0062] Abbreviations: ACN: acetonitrile; AIBN: 2,2-azobis(2-methylpropionitrile); Boc: tert- butyloxycarbonyl; brd: broad doublet; brdd: broad doublet of doublet; brs: broad singlet; brt: broad triplet; eq: equivalents; CDI: carbonyldiimidazole; CuBr: copper bromide; CuBr2: copper(II) bromide; d: doublet; dd: doublet of doublet; ddd: doublet of doublet of doublet; DCM: dichloromethane; DIEA: diisopropyethylamine; DMA: dimethylacetamide; DMSO: dimethyl sulfoxide; EDCI: 1-Ethyl-3-(3- dimethylaminopropyl)carbodiimide; ESI: electrospray ionization; EtOAc: ethyl acetate; EtOH: ethanol; h: hours; HCl: hydrochloric acid; HPLC: high-performance liquid chromatography; K2CO3: potassium carbonate; m: multiplet; MeOH: methanol; MS: mass spectrometry; NH4Cl: ammonium chloride; NMR: nuclear magnetic resonance; q: quartet; s: singlet; Pd PEPPSI-IHept Cl: 1,3-bis[2,6-bis(heptan-4- yl)phenyl]-4,5-dichloro-1,2-didehydro-1^^-imidazole 3-chloropyridine palladium(II) dichloride; PyClOP: chlorotripyrrolidinophosphonium hexafluorophosphate; quin: quintet; t: triplet; td: triplet of doublet; TEA: triethylamine; TFA: trifluoroacetic acid; tt: triplet of triplet.Example 1: Synthesis of Compound 1 O O O O SOCl NH -NH •H O CDI, TEA O^^^^^^HT^^^LQ^PHWKDQRO^^^^^^^P / ^^ZDV^DGGHG^WKLRQ\O^FKORULGH^^^^^^PJ^^^^^^^PPRO^^^^^^^ / ^^^^^^^^HT^^^DW^ 0°C. The mixture was stirred at 25°C for 12 h. The reaction mixture was concentrated under reduced pressure to afford methyl 3-methoxybicyclo[1.1.1]pentane-1-carboxylate (548 mg, crude) as a colourless liquid.

[0064] Step 2. To a solution of methyl 3-methoxybicyclo[1.1.1]pentane-1-carboxylate (548 mg, 3.51 mmol, 1.00 eq.) in methanol (6.00 mL) was added hydrazine monohydrate (2.07 g, 35.1 mmol, 2.00 mL, 85% purity, 10.0 eq.). The reaction was stirred at 60 °C for 2 h. The mixture was concentrated under reduced pressure to afford 3-methoxybicyclo[1.1.1]pentane-1-carbohydrazide (548 mg, crude) as a white solid.

[0065] Step 3. To a solution of 3-methoxybicyclo[1.1.1]pentane-1-carbohydrazide (548 mg, 3.51 mmol, 1.00 eq.) in dichloromethane (5.00 mL) was added 1,1'-carbonyldiimidazole (683 mg, 4.21 mmol, 1.20 HT^^^DW^^^&^DQG^WULHWK\ODPLQH^^^^^^PJ^^^^^^^PPRO^^^^^^^ / ^^^^^^^^HT^^^^The mixture was stirred at 25 °C for 12 h. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (formic acid FRQGLWLRQ^^FROXPQ^^3KHQRPHQH[^OXQD^&^^^^^^^^^PP^^^^P^^ mobile phase: [water(formic acid)- acetonitrile]; gradient: 8%-38% B over 15 min) and lyophilized toafford 5-(3-methoxybicyclo[1.1.1]pentan-1-yl)-1,3,4-oxadiazol-2-RO^^^^^^PJ^^^^^^^PRO^^^^^^\LHOG^^DV^D^ brown oil.

[0066] Step 4. To a solution of 5-bromo-1,3-difluoro-2-methylbenzene (19.3 g, 93.1 mmol, 1.00 eq.) in tetrachloromethane 190 mL) was added N-bromosuccinimide (16.6 g, 93.1 mmol, 1.00 eq.) and (E)-3,3'- (diazene-1,2-diyl)bis(2-methylpropanenitrile) (764 mg, 4.65 mmol, 0.05 eq.). The mixture was stirred at 80 °C for 2 h. The mixture was filtered, and the filtrate was concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 1 / 0) to afford 5-bromo-2-(bromomethyl)-1,3-difluorobenzene (21.2 g, 74.2 mmol, 80% yield) as a yellow oil.

[0067] Step 5. To a solution of 5-bromo-2-(bromomethyl)-1,3-difluorobenzene (21.2 g, 74.2 mmol, 1.00 eq.) in ethanol (150 mL) and water (50.0 mL) was added potassium cyanide (5.79 g, 89.0 mmol, 3.81 mL, 1.20 eq.). The reaction was stirred at 60 °C for 2 h. The mixture was diluted with water (400 mL) and extracted with ethyl acetate (3 × 300 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 1 / 0 to 20 / 1) to afford 2-(4- bromo-2,6-difluorophenyl)acetonitrile (12.2 g, 52.6 mmol, 71% yield) as a white solid.

[0068] Step 6. To a solution of 2-(4-bromo-2,6-difluorophenyl)acetonitrile (12.2 g, 52.6 mmol, 1.00 eq.), methyl acrylate (4.53 g, 52.6 mmol, 4.73 mL, 1.00 eq.) in tetrahydrofuran (120 mL) was added sodium methoxide (284.06 mg, 5.26 mmol, 0.10 eq.) at 0 °C. The reaction was stirred at 20 °C for 1 h. The reaction was quenched with saturated ammonium chloride aqueous solution (50 mL) and extracted with ethyl acetate (3 × 50 mL). The combined organic layers were washed with brine (2 × 300 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 1 / 0 to 10 / 1) to afford methyl 4-(4-bromo-2,6-difluorophenyl)-4-cyanobutanoate (13.5 g, 42.4 mmol, 81% yield) as a yellow oil.

[0069] Step 7. To a solution of methyl 4-(4-bromo-2,6-difluorophenyl)-4-cyanobutanoate (13.5 g, 42.4 mmol, 1.00 eq.) in acetic acid (135 mL) was added sulfuric acid (24.8 g, 253 mmol, 13.5 mL, 5.97 eq.). The reaction was stirred at 90 °C for 2 h. The mixture was poured into ice water (400 mL) and filtered. The filter cake was lyophilized to afford 3-(4-bromo-2,6-difluorophenyl)piperidine-2,6-dione (15.0 g, crude) as a white solid.

[0070] Step 8. To a solution of 3-(4-bromo-2,6-difluorophenyl)piperidine-2,6-dione (1.37 g, 4.49 mmol, 1.00 eq.) in dioxane (8.00 mL) was added tert-butyl ((2R,3S)-2-methylazetidin-3-yl)carbamate (1.00 g, 4.49 mmol, 1.00 eq., hydrochloride), caesium carbonate (4.39 g, 13.5 mmol, 3.00 eq.) and 1,3-bis[2,6-bis(1-propylbutyl)phenyl]-4,5-dichloro-2H-imidazol-1-ium-2-ide;3-chloropyridine;dichloropalladium ^^^^^PJ^^^^^^^PRO^^^^^^^ eq.) under nitrogen atmosphere. The mixture was stirred at 100 °C for 1 h under nitrogen atmosphere. Two batches were combined, filtered, and the filtrate was concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 5 / 1 to 1 / 1) to afford tert-butyl ((2R, 3S)-1-(4-(2, 6-dioxopiperidin-3-yl)-3, 5- difluorophenyl)-2-methylazetidin-3-yl) carbamate (3.50 g, 7.61 mmol, 84% yield) as a yellow solid.

[0071] Step 9. A solution of tert-butyl ((2R,3S)-1-(4-(2,6-dioxopiperidin-3-yl)-3,5-difluorophenyl)-2- methylazetidin-3-yl) carbamate (1.50 g, 3.66 mmol, 1.00 eq.) in trifluoroacetic acid (15.0 mL) was stirred at 25 °C for 1 h. The mixture was concentrated under reduced pressure to give a residue. The residue was purified by reverse phase column chromatography (C18, 40 g; condition: water / acetonitrile = 100 / 0 to 0 / 100, 0.1% formic acid) and lyophilized to afford 3-(4-((2R,3S)-3-amino-2-methylazetidin-1-yl)-2,6- difluorophenyl)piperidine-2,6-dione (1.10 g, 2.52 mmol, 68% yield, trifluoroacetate) as a white solid.

[0072] Step 10. To a solution of 5-(3-methoxybicyclo[1.1.1]pentan-1-yl)-1,3,4-oxadiazol-2-ol (50.0 mg, ^^^^^PRO^^^^^^ eq.) and 3-(4-((2R,3S)-3-amino-2-methylazetidin-1-yl)-2,6-difluorophenyl)piperidine- 2,6-GLRQH^^^^^^^PJ^^^^^^^PRO^^^^^^^^HT^^^LQ^N,N-dimethylacetamide (1.00 mL) was added chloro(tripyrrolidin-1-\O^SKRVSKRQLXP^KH[DIOXRURSKRVSKDWH^^^^^^PJ^^^^^^^PRO^^^^^^^^HT^^^DQG^N,N- GLLVRSURS\OHWK\ODPLQH^^^^^^PJ^^^^^^^PRO^^^^^^^^ / ^^^^^^^^HT^^^^7KH^UHDFWLRQ^ZDV^VWLUUHG^DW^^^^^&^IRU^^^^^K^^ then at 60 °C for 11.5 h. The mixture was concentrated under reduced pressure to give a residue. The residue was purified by prep-+3 / &^^QHXWUDO^FRQGLWLRQ^^FROXPQ^^:DWHUV^;EULGJH^^^^^^^PP^^^P^^ mobile phase: [water(ammonium bicarbonate)-acetonitrile]; gradient: 25%-55% B over 9 min) and lyophilized to afford Compound 13-(2,6-difluoro-4-((2R,3S)-3-((5-(3-methoxybicyclo[1.1.1]pentan-1- yl)-1,3,4-oxadiazol-2-yl)amino)-2-methylazetidin-1-yl)phenyl)piperidine-2,6-dione (11.83 mg, 24.74^PRO^^^^^^^^\LHOG^^DV^D^ZKLWH^VROLG^^1H NMR (400 MHz, DMSO-d6) į = 10.87 (br s, 1H), 8.13 (d, J = 7.2Hz, 1H), 6.22 (d, J = 11.2 Hz, 2H), 4.21 (t, J = 7.4 Hz, 1H), 4.08 - 3.93 (m, 3H), 3.48 (br t, J = 6.6 Hz, 1H), 3.24 (s, 3H), 2.85 - 2.71 (m, 1H), 2.54 - 2.51 (m, 1H), 2.21 (s, 6H), 2.13 - 2.02 (m, 1H), 1.99 - 1.90 (m, 1H), 1.46 (d, J = 5.8 Hz, 3H). MS (ESI) m / z 474.2 [M+H]+Example 2: Synthesis of Compound 2 FFFFFFNHFFF F N F F N N NH NHBoc, EDCI DCM / TFA (5:1) Na g, dichloromethane (10.0mL) were added tert-butyl N-aminocarbamate (716 mg, 5.42 mmol, 1.03 eq.) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (1.03 g, 5.37 mmol, 1.02 eq.). The mixture was stirred at 25 °C for 12 h. The reaction was quenched by addition of water (30 mL), then extracted with ethyl acetate (3 × 25 mL). The combined organic layers were washed with brine (20 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure to afford tert-butyl 2-(4- (trifluoromethyl)benzoyl)hydrazine-1-carboxylate (1.30 g, 4.27 mmol, 81.2% yield) as a white solid.

[0074] Step 2. A solution of tert-butyl 2-(4-(trifluoromethyl)benzoyl)hydrazine-1-carboxylate (1.30 g, 4.27 mmol, 1.00 eq.) in dichloromethane (10.0 mL) and trifluoroacetic acid (3.07 g, 26.9 mmol, 2.00 mL, 6.30 eq.) was stirred at 25 °C for 2 h. The reaction mixture was concentrated under reduced pressure to afford 4-(trifluoromethyl)benzohydrazide (1.30 g, crude) as a white solid.

[0075] Step 3. To a solution of 4-(trifluoromethyl)benzohydrazide (1.30 g, 6.37 mmol, 1.00 eq.) in tetrahydrofuran (13.0 mL) was added di(1H-imidazol-1-yl)methanimine (1.03 g, 6.37 mmol, 1.00 eq.). The mixture was stirred at 60 °C for 2 h. The reaction mixture was concentrated under reduced pressure to give a residue. The crude product was triturated with ethyl acetate at 25 °C for 30 min and filtered toafford 5-(4-(trifluoromethyl)phenyl)-1,3,4-oxadiazol-2-amine (750 mg, 3.27 mmol, 51.4% yield) as a white solid.

[0076] Step 4. To a solution of 5-(4-(trifluoromethyl)phenyl)-1,3,4-oxadiazol-2-amine (1.60 g, 6.98 mmol, 1.00 eq.) LQ^DFHWRQLWULOH^^^^^^^P / ^^ZDV^DGGHG^FRSSHU^,^^EURPLGH^^^^^^^J^^^^^^^PPRO^^^^^^^ / ^^^^^^ eq.) and tert-butyl nitrite (1.08 g, 10.5 mmol, 1.25 mL, 1.50 eq.). The mixture was stirred at 60 °C for 1h. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 1 / 0 to 5 / 1) to afford 2-bromo-5-(4- (trifluoromethyl)phenyl)-1,3,4-oxadiazole (1.40 g, 4.73 mmol, 33.9% yield) as a yellow solid.

[0077] Step 5.3-(4-((2R,3S)-3-amino-2-methylazetidin-1-yl)-2,6-difluorophenyl)piperidine-2,6-dione can be prepared according to Example 1, steps 4 to 9. To a solution of 2-bromo-5-(4- (trifluoromethyl)phenyl)-1,3,4-R[DGLD]ROH^^^^^^^PJ^^^^^^^PRO^^^^^^^^HT^^^LQ^N,N-dimethylacetamide (1.00 mL) were added N,N-GLLVRSURS\OHWK\ODPLQH^^^^^^^PJ^^^^^^^PRO^^^^^^^^ / ^^^^^^^^HT^^^DQG^^-(4-((2R,3S)-3- amino-2-methylazetidin-1-yl)-2,6-difluorophenyl)piperidine-2,6-GLRQH^^^^^^^PJ^^^^^^^PRO^^^^^^^^HT^^. The mixture was stirred at 110 °C for 1h. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (formic acid condition; column: Phenomenex OXQD^&^^^^^^^^^PP^^^^P^^PRELOH^SKDVH^^>ZDWHU^formic acid)- acetonitrile]; gradient: 45%-75% B over 9 min) and lyophilized to afford Compound 23-(2,6-difluoro-4-((2R,3S)-2-methyl-3-((5-(4- (trifluoromethyl)phenyl)-1,3,4-oxadiazol-2-yl)amino)azetidin-1-yl)phenyl)piperidine-2,6-dione (67.95 PJ^^^^^^^^^^PRO^^^^^^^^^\LHOG^^DV^D^ZKLWH^VROLG^^1H NMR (400 MHz, DMSO-d6) į = 10.88 (s, 1H), 8.57 (d, J = 7.4 Hz, 1H), 8.04 - 7.98 (m, 2H), 7.91 (d, J = 8.6 Hz, 2H), 6.25 (d, J = 11.0 Hz, 2H), 4.33 - 4.23 (m, 1H), 4.21 - 4.11 (m, 1H), 4.10 - 4.01 (m, 2H), 3.65 - 3.53 (m, 1H), 2.86 - 2.72 (m, 1H), 2.52 (br d, J = 3.2 Hz, 1H), 2.16 - 2.02 (m, 1H), 2.01 - 1.90 (m, 1H), 1.52 (d, J = 6.0 Hz, 3H). MS (ESI) m / z 522.2 [M+H]+Example 3: Synthesis of Compound 3 NH Nin dichloromethane (40.0 mL) were added hydrazine carbothioamide (2.08 g, 22.8 mmol, 1.60 eq.) and 1- (3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (8.21 g, 42.8 mmol, 3.00 eq.). The reaction was stirred at 20 °C for 12 h under nitrogen atmosphere. The mixture was concentrated under reduced pressure to give a residue. The residue was diluted with dimethylformamide (30 mL) and filtered. The filtrate was purified by reverse phase column chromatography (C18, 330 g; condition: water / acetonitrile = 100:0 to 90:10, 0.1% ammonium hydroxide) and concentrated under reduced pressure to afford 5- (spiro[3.3]heptan-2-yl)-1,3,4-oxadiazol-2-amine (2.70 g, crude) as a black oil.

[0079] Step 2. To a solution of 5-(spiro[3.3]heptan-2-yl)-1,3,4-oxadiazol-2-amine (2.40 g, 13.4 mmol, 1.00 eq.) LQ^DFHWRQLWULOH^^^^^^^P / ^^ZHUH^DGGHG^FRSSHU^EURPLGH^^^^^^^J^^^^^^^PPRO^^^^^^^ / ^^^^^^^ eq.) and tert-butyl nitrite (2.07 g, 20.1 mmol, 2.39 mL, 1.50 eq.). The reaction was stirred at 60 °C for 3 h under nitrogen atmosphere. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, petroleumether / ethyl acetate = 1 / 0 to 20 / 1) to afford 2-bromo-5-(spiro[3.3]heptan-2-yl)-1,3,4-oxadiazole (800 mg, 3.29 mmol, 25% yield) as a pink oil.

[0080] Step 3. 3-(4-((2R,3S)-3-amino-2-methylazetidin-1-yl)-2,6-difluorophenyl)piperidine-2,6-dione can be prepared according to Example 1, steps 4 to 9. To a solution of 2-bromo-5-(spiro[3.3]heptan-2-yl)- 1,3,4-R[DGLD]ROH^^^^^^^PJ^^^^^^^PRO^^^^^^^^HT^^^LQ^N,N-dimethylacetamide (1.00 mL) were added N,N- GLLVRSURS\OHWK\ODPLQH^^^^^^PJ^^^^^^^PRO^^^^^^^ / ^^^^^^^^HT^^^DQG^^-(4-((2R,3S)-3-amino-2- methylazetidin-1-yl)-2,6-difluorophenyl)piperidine-2,6-GLRQH^^^^^^^PJ^^^^^^^PRO^^^^^^^^HT^^. Thereaction was stirred at 110 °C for 1 h. The mixture was concentrated under reduced pressure to give a residue. The residue was purified by Prep-+3 / &^^FROXPQ^^:DWHUV^;EULGJH^^^^^^^^PP^^^P^^PRELOH^ phase: [water(ammonium bicarbonate)-acetonitrile]; gradient: 38%-68% B over 9 min) and lyophilized to afford Compound 33-(2,6-difluoro-4-((2R,3S)-2-methyl-3-((5-(spiro[3.3]heptan-2-yl)-1,3,4-oxadiazol-2- yl)amino)azetidin-1-yl)phenyl)piperidine-2,6-GLRQH^^^^^^^^PJ^^^^^^^^^PRO^^^^^^^^\LHOG^^DV^DQ^RII-white solid.1H NMR (400 MHz, DMSO-d6) į = 10.88 (s, 1H), 8.01 (d, J = 7.0 Hz, 1H), 6.23 (d, J = 11.0 Hz, 2H), 4.27 - 4.16 (m, 1H), 4.09 - 3.95 (m, 3H), 3.54 - 3.46 (m, 1H), 3.42 - 3.37 (m, 1H), 2.84 - 2.74 (m, 1H), 2.49 (br s, 1H), 2.38 - 2.32 (m, 2H), 2.24 - 2.15 (m, 2H), 2.12 - 2.03 (m, 3H), 1.99 - 1.89 (m, 3H), 1.82 - 1.74 (m, 2H), 1.52 - 1.43 (m, 3H). MS (ESI) m / z 472.2 [M+H]+Example 4: Synthesis of Compound 4 NH2-NH2•H2O BrCN, NaHCO3tBuONO, CuBr

[0081] Step 1. To a solution of methyl 4-methylbenzoate (1.00 g, 6.66 mmol, 1.00 eq.) in methanol (10.0 mL) was added hydrazine hydrate (3.92 g, 66.5 mmol, 3.80 mL, 85% purity, 10.0 eq.). The reaction was stirred at 60 °C for 12 h. The mixture was concentrated under reduced pressure to afford 4- methylbenzohydrazide (988 mg, 6.58 mmol, 98% yield) as a white solid.

[0082] Step 2. To a solution of 4-methylbenzohydrazide (988 mg, 6.58 mmol, 1.00 eq.) in dioxane (5.00 P / ^^DQG^ZDWHU^^^^^^^P / ^^ZHUH^DGGHG^VDWXUDWHG^VRGLXP^ELFDUERQDWH^^^^^^PJ^^^^^^^PPRO^^^^^^^ / ^^^^^^^ eq.) DQG^F\DQRJHQ^EURPLGH^^^^^^PJ^^^^^^^PPRO^^^^^^^ / ^^^^^^^ eq.). The reaction was stirred at 25 °C for12 h. The mixture was filtered, and the filter cake was washed with 10 mL of petroleum ether and dried under reduced pressure to afford 5-(p-tolyl)-1,3,4-oxadiazol-2-amine (1.02 g, 5.82 mmol, 88% yield) as a white solid.

[0083] Step 3. To a solution of 5-(p-tolyl)-1,3,4-oxadiazol-2-amine (510 mg, 2.91 mmol, 1.00 eq.) in DFHWRQLWULOH^^^^^^^P / ^^ZHUH^DGGHG^FXSURXV^EURPLGH^^^^^^PJ^^^^^^^PPRO^^^^^^^ / ^^^^^^^ eq.) and tert-butyl QLWULWH^^^^^^^^^^^^PPRO^^^^^^^ / ^^^^^^^ eq.) at 0 °C. The reaction was stirred at 65 °C for 3 h. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 1 / 0 to 0 / 1) to afford 2-bromo-5-(p-tolyl)-1,3,4- R[DGLD]ROH^^^^^^PJ^^^^^^^PRO^^^^^^^\LHOG^^DV^D^ZKLWH^VROLG^

[0084] Step 4.3-(4-((2R,3S)-3-amino-2-methylazetidin-1-yl)-2,6-difluorophenyl)piperidine-2,6-dione can be prepared according to Example 1, steps 4 to 9. To a solution of 2-bromo-5-(p-tolyl)-1,3,4- R[DGLD]ROH^^^^^^^PJ^^^^^^^PRO^^^^^^^ eq.) and 3-(4-((2R,3S)-3-amino-2-methylazetidin-1-yl)-2,6- difluorophenyl)piperidine-2,6-GLRQH^^^^^^^PJ^^^^^^^PRO^^^^^^^ eq.) in dimethylformamide (1.00 mL) was added N,N-GLLVRSURS\OHWK\ODPLQH^^^^^^^PJ^^^^^^^PRO^^^^^^^ / ^^^^^^^ eq.). The reaction was stirred at 80 °C for 3 h. The mixture was filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-+3 / &^^FROXPQ^^3KHQRPHQH[^OXQD^&^^^^^^^^^PP^^^^P^^PRELOH^SKDVH^^ [water(formic acid)-acetonitrile]; gradient: 40%-70% B over 9 min) to afford Compound 43-(2,6- difluoro-4-((2R,3S)-2-methyl-3-((5-(p-tolyl)-1,3,4-oxadiazol-2-yl)amino)azetidin-1-yl)phenyl)piperidine- 2,6-GLRQH^^^^^^^PJ^^^^^^^^PRO^^^^^^\LHOG^^DV^D^ZKLWH^VROLG^^1H NMR (400 MHz, DMSO-d6) į = 10.89 (s, 1H), 8.36 (d, J = 7.2 Hz, 1H), 7.70 (d, J = 8.0 Hz, 2H), 7.35 (br d, J = 8.0 Hz, 2H), 6.25 (br d, J = 11.2 Hz, 2H), 4.30 - 4.24 (m, 1H), 4.17 - 4.11 (m, 1H), 4.09 - 4.03 (m, 2H), 3.57 (br t, J = 6.8 Hz, 1H), 2.84 - 2.75 (m, 1H), 2.53 (br s, 1H), 2.37 (s, 3H), 2.15 - 2.04 (m, 1H), 2.01 - 1.93 (m, 1H), 1.52 (d, J = 6.0 Hz, 3H). MS (ESI) m / z 490.3 [M+H]+Example 5: Synthesis of Compound 5 F F F F F F F O F O O O F F SOCl F NH NH •H O F BrCN NHa g, methanol (30.0 mL) was added thionyl chloride (2.60 g, 21.8 mmol, 1.58 mL, 1.50 eq.) at 0 °C. The reaction was stirred at 60 °C for 3 h. The mixture was concentrated under reduced pressure to give methyl 4-(trifluoromethoxy)benzoate (2.6 g, crude) as a white solid.

[0086] Step 2. To a solution of methyl 4-(trifluoromethoxy)benzoate (2.60 g, 11.8 mmol, 1.00 eq.) in ethanol (30.0 mL) was added hydrazine hydrate (1.39 g, 23.6 mmol, 1.35 mL, 85% purity, 2.00 eq.). The reaction was stirred at 80 °C for 8 h. The mixture was cooled to 25 °C and concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 0 / 1) to afford 4-(trifluoromethoxy)benzohydrazide (1.95 g, 8.24 mmol, 69% yield) as a white solid.

[0087] Step 3. To a solution of 4-(trifluoromethoxy)benzohydrazide (1.20 g, 5.45 mmol, 1.00 eq.) in PHWKDQRO^^^^^^^P / ^^ZDV^DGGHG^F\DQLF^EURPLGH^^^^^^PJ^^^^^^^PPRO^^^^^^^ / ^^^^^^^ eq.). The reaction was stirred at 65 °C for 4 h. The mixture was cooled to 25 °C, poured into water (60.0 mL), and extracted with ethyl acetate (2 × 50.0 mL). The combined organic layers were washed with brine (50.0 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure to give a residue. The residue was triturated with ethyl acetate (30.0 mL) at 25 °C for 15 min, and the solid was filtered. The solid waswashed with saturated sodium bicarbonate solution to give 5-(4-(trifluoromethoxy)phenyl)-1,3,4- oxadiazol-2-amine (800 mg, 3.23 mmol, 59% yield) as a white solid.

[0088] Step 4. To a solution of 5-(4-(trifluoromethoxy)phenyl)-1,3,4-oxadiazol-2-amine (800 mg, 3.26 mmol, 1.00 eq.) LQ^DFHWRQLWULOH^^^^^^^P / ^^ZHUH^DGGHG^FXSURXV^EURPLGH^^^^^^PJ^^^^^^^PPRO^^^^^^^ / ^^ 2.00 eq.) and tert-EXW\O^QLWULWH^^^^^^PJ^^^^^^^PPRO^^^^^^^ / ^^^^^^^ eq.) at 0 °C. The reaction was stirred at 65 °C for 3 h. The mixture was concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 9 / 1) to give 2-bromo-5-(4- (trifluoromethoxy)phenyl)-1,3,4-oxadiazole (400 mg, 1.23 mmol, 37% yield) as a white solid.

[0089] Step 5.3-(4-((2R,3S)-3-amino-2-methylazetidin-1-yl)-2,6-difluorophenyl)piperidine-2,6-dione can be prepared according to Example 1, steps 4 to 9. To a solution of 3-(4-((2R,3S)-3-amino-2- methylazetidin-1-yl)-2,6-difluorophenyl)piperidine-2,6-dione (1.10 g, 2.60 mmol, 1.00 eq., trifluoroacetate) in dimethylformamide (10.0 mL) was added N,N-diisopropylethylamine (1.01 g, 7.80 mmol, 1.36 mL, 3.00 eq.) and 2-bromo-5-(4-(trifluoromethoxy)phenyl)-1,3,4-oxadiazole (883 mg, 2.86 mmol, 1.10 eq.). The reaction was stirred at 80 °C for 3 h under nitrogen atmosphere. The mixture was concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 10 / 1 to 1 / 1) and lyophilized to afford Compound 53-(2,6-difluoro-4-((2R,3S)-2-methyl-3-((5-(4-(trifluoromethoxy)phenyl)-1,3,4-oxadiazol-2- yl)amino)azetidin-1-yl)phenyl)piperidine-2,6-dione (1.032 g, 1.90 mmol, 73.16% yield) as a white solid.1H NMR (400 MHz, DMSO-d6) į = 10.86 (s, 1H), 8.47 (d, J = 7.1 Hz, 1H), 7.93 (d, J = 8.8 Hz, 2H), 7.54 (d, J = 8.4 Hz, 2H), 6.25 (d, J = 11.1 Hz, 2H), 4.31 - 4.24 (m, 1H), 4.18 - 4.10 (m, 1H), 4.09 - 4.02 (m, 2H), 3.58 (br t, J = 6.6 Hz, 1H), 2.84 - 2.72 (m, 1H), 2.53 (br s, 1H), 2.13 - 2.04 (m, 1H), 2.00 - 1.91 (m, 1H), 1.52 (d, J = 6.1 Hz, 3H). MS (ESI) m / z 538.2 [M+H]+Example 6: Synthesis of Compound 6 F F F FFF FFFF F FNH2a g, 5.00 mmol, 1.00 eq.) LQ^PHWKDQRO^^^^^^^P / ^^ZDV^DGGHG^WKLRQ\O^FKORULGH^^^^^^^J^^^^^^^PPRO^^^^^^^ / ^^^^^^^ eq.) at 0 °C. The reaction was stirred at 25 °C for 12 h. The mixture was concentrated under reduced pressure to afford methyl 3-(trifluoromethyl)bicyclo[1.1.1]pentane-1-carboxylate (970 mg, 5.00 mmol, 99% yield) as a yellow oil.

[0091] Step 2. To a solution of methyl 3-(trifluoromethyl)bicyclo[1.1.1]pentane-1-carboxylate (970 mg, 5.00 mmol, 1.00 eq.) in methanol (9.00 mL) was added hydrazine hydrate (4.41 g, 74.9 mmol, 4.28 mL, 85% purity, 15.0 eq.). The reaction was stirred at 60 °C for 2 h. The mixture was diluted with water (30 mL) and extracted with ethyl acetate (3 × 30 mL). The combined organic layers were washed with brine (10 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure to afford 3- (trifluoromethyl)bicyclo[1.1.1]pentane-1-carbohydrazide (700 mg, 3.61 mmol, 72% yield) as a white solid.

[0092] Step 3. To a solution of 3-(trifluoromethyl)bicyclo[1.1.1]pentane-1-carbohydrazide (3.23 g, 16.6 mmol, 1.00 eq.) in methanol (30.0 mL) was added cyanogen bromide (2.11 g, 20.0 mmol, 1.47 mL, 1.20eq.). The reaction was stirred at 65 °C for 3 h. The reaction was quenched by addition of water (30 mL) and extracted with ethyl acetate (3 × 40 mL). The combined organic layers were washed with brine (30 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure to afford 5-(3- (trifluoromethyl)bicyclo[1.1.1]pentan-1-yl)-1,3,4-oxadiazol-2-amine (1.10 g, 5.02 mmol, 30 % yield) as a white solid.

[0093] Step 4. To a solution of 5-(3-(trifluoromethyl)bicyclo[1.1.1]pentan-1-yl)-1,3,4-oxadiazol-2-amine (2.20 g, 10.0 mmol, 1.00 eq.) in acetonitrile (22.0 mL) was added tert-butyl nitrite (2.07 g, 20.1 mmol, 2.39 mL, 2.00 eq.) DQG^FRSSHU^,^^EURPLGH^^^^^^^J^^^^^^^PPRO^^^^^^^ / ^^^^^^^ eq.). The reaction was stirred at 80 °C for 2 h. The mixture was filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (Petroleum ether / Ethyl acetate = 5 / 1) to afford 2-bromo-5-(3-(trifluoromethyl)bicyclo[1.1.1]pentan-1-yl)-1,3,4-oxadiazole (1.10 g, 3.89 mmol, 39% yield) as a white solid.

[0094] Step 5.3-(4-((2R,3S)-3-amino-2-methylazetidin-1-yl)-2,6-difluorophenyl)piperidine-2,6-dione can be prepared according to Example 1, steps 4 to 9. To a solution of 3-(4-((2R,3S)-3-amino-2- methylazetidin-1-yl)-2,6-difluorophenyl)piperidine-2,6-GLRQH^^^^^^^PJ^^^^^^^PRO^^^^^^^ eq.) and 5-(3- (trifluoromethyl)bicyclo[1.1.1]pentan-1-yl)-1,3,4-oxadiazol-2-RO^^^^^^^PJ^^^^^^^PRO^^^^^^^ eq.) in N,N- dimethylacetamide (1.50 mL) were added N,N-eq.) and chloro(tripyrrolidin-1-\O^SKRVSKRQLXP^KH[DIOXRURSKRVSKDWH^^^^^^PJ^^^^^^^PRO^^^^^^^ eq.) at 25 °C. After 1h, the reaction was heated to 60 °C, and stirring was continued for 11 h. The mixture was filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep- +3 / &^^FROXPQ^^:DWHUV^;EULGJH^^^^^^^PP^^^P^^PRELOH^SKDVH^^>ZDWHU^DPPRQLXP^K\GURJHQ^ carbonate)-acetonitrile]; gradient: 26%-56% B over 9 min) to afford Compound 63-(2,6-difluoro-4- ((2R,3S)-2-methyl-3-((5-(3-(trifluoromethyl)bicyclo[1.1.1]pentan-1-yl)-1,3,4-oxadiazol-2- yl)amino)azetidin-1-yl)phenyl)piperidine-2,6-GLRQH^^^^^^^^PJ^^^^^^^^^PRO^^^^^^^^\LHOG^^DV^D^ZKLWH^VROLG^^1H NMR (400 MHz, DMSO-d6) į = 10.87 (br s, 1H), 8.23 (d, J = 7.2 Hz, 1H), 6.23 (d, J = 11.2 Hz, 2H), 4.22 (t, J = 7.4 Hz, 1H), 4.09 - 4.02 (m, 2H), 4.00 - 3.96 (m, 1H), 3.49 (br s, 1H), 2.83 - 2.76 (m, 1H), 2.55 (br s, 1H), 2.40 (s, 6H), 2.14 - 2.05 (m, 1H), 1.99 - 1.93 (m, 1H), 1.47 (d, J = 6.0 Hz, 3H). MS (ESI) m / z 512.2 [M+H]+Example 7: Synthesis of Compound 7 and Compound 8 FFFFFFFF F

[0095] ( / ^ &+,5$ / 3$.^$'^^^^^^PP^^^^PP^^^^P^^^PRELOH^SKDVH^^>FDUERQ^GLR[LGH-ethyl alcohol]; B%: 35%, isocratic elution mode) and concentrated under reduced pressure to give two solids.

[0096] Peak 1 (Rt = 1.682 min) was lyophilized to afford Compound 7 (R)-3-(2,6-difluoro-4-((2R,3S)-2- methyl-3-((5-(3-(trifluoromethyl)bicyclo[1.1.1]pentan-1-yl)-1,3,4-oxadiazol-2-yl)amino)azetidin-1- yl)phenyl)piperidine-2,6-GLRQH^^^^^PJ^^^^^^^^^PRO^^^^^^^^\LHOG^^DV^D^ZKLWH^VROLG^^1H NMR (400 MHz, DMSO-d6) į = 10.87 (s, 1H), 8.22 (br d, J = 6.8 Hz, 1H), 6.22 (d, J = 11.0 Hz, 2H), 4.22 (t, J = 7.6 Hz, 1H), 4.09 - 4.01 (m, 2H), 4.00 - 3.94 (m, 1H), 3.49 (t, J = 7.0 Hz, 1H), 2.84 - 2.72 (m, 1H), 2.47 (br s, 1H), 2.39 (s, 6H), 2.08 (dq, J = 3.2, 13.0 Hz, 1H), 1.99 - 1.91 (m, 1H), 1.47 (d, J = 6.0 Hz, 3H). MS (ESI) m / z 512.2 [M+H]+

[0097] Peak 2 (Rt = 1.917 min) was lyophilized to afford Compound 8 (S)-3-(2,6-difluoro-4-((2R,3S)-2- methyl-3-((5-(3-(trifluoromethyl)bicyclo[1.1.1]pentan-1-yl)-1,3,4-oxadiazol-2-yl)amino)azetidin-1- yl)phenyl)piperidine-2,6-GLRQH^^^^^^PJ^^^^^^^^^PRO^^^^^^^^\LHOG^^DV^D^ZKLWH^VROLG^^1H NMR (400 MHz, DMSO-d6) į = 10.87 (s, 1H), 8.22 (d, J = 7.0 Hz, 1H), 6.22 (d, J = 11.0 Hz, 2H), 4.22 (t, J = 7.4 Hz, 1H), 4.08 - 4.01 (m, 2H), 4.00 - 3.94 (m, 1H), 3.49 (t, J = 7.0 Hz, 1H), 2.85 - 2.73 (m, 1H), 2.54 - 2.52 (m, 1H), 2.39 (s, 6H), 2.11 - 2.05 (m, 1H), 1.97 -(m, 1H), 1.47 (d, J = 6.0 Hz, 3H). MS (ESI) m / z 512.2 [M+H]+Example 8: Determination of Absolute Configuration of Compound 7 and Compound 8 FFF F F F F F

[0099] 3-(4-((2R,3S)-3-amino-2-methylazetidin-1-yl)-2,6-difluorophenyl)piperidine-2,6-dione can be prepared according to Example 1, steps 4 to 9.3-(4-((2R,3S)-3-amino-2-methylazetidin-1-yl)-2,6- difluorophenyl)piperidine-2,6-dione was purified by chiral SFC (column: DAICEL CHIRALPAK AD ^^^^^PP^^^^PP^^^^^P^^^PRELOH^SKDVH^^>FDUERQ^GLR[LGH-isopropyl alcohol]; B%: 32%, isocratic elution mode) and concentrated under reduced pressure to give two solids: Enantiomer 1 (eluting first), and Enantiomer 2 (eluting second).

[0100] Enantiomer 1 was crystallized from Ethyl alcohol-Methyl tert-butyl ether (1:1). A suitable crystal 0.40×0.20×0.02 mm3was selected for testing. Data collection temperature: T = 150.01(10) K. A total of 20842 reflections were collected in the 2^ range from 8.604 to 133.174. The limiting indices were: -^^^^^K^^^^^^^-^^^^^N^^^^^^^-^^^^O^^^^^^ZKLFK^\LHOGHG^^^^^^XQLTXH^UHIOHFWLRQV^^5int= 0.0575). Thestructure was solved using SHELXT (Sheldrick, G. M.2015. Acta Cryst. A71, 3-8) and refined using SHELXL (against F2) (Sheldrick, G. M.2015. Acta Cryst. C71, 3-8). The total number of refined parameters was 210, compared with 2461 data. All reflections were included in the refinement. The goodness of fit on F2was 1.056 with a final R value for [I >= 2ı (I)] R1= 0.0279 and wR2= 0.0717. The largest differential peak and hole were 0.12 and -0.17 eÅ-3.

[0101] The symmetry of the crystal structure was assigned the monoclinic space group C2 with the following parameters: a = 20.6346(2) Å, b = 9.65220(12) Å, c = 7.22562(8) Å, Į = 90°, ȕ = 95.0670(9)°, Ȗ = 90°, V = 1433.50(3) Å3, Z = 4, Dc = 1.433 g / cm3, ^^&X^.Į^^ ^^^^^^^PP–1, and F(000) = 648.0.

[0102] The absolute configuration structure is judged by the value of the Flack parameter: 0.02(9), indicating that Enantiomer 1 has the (R) configuration. Therefore, Enantiomer 2 is (S).

[0103] Table 1. Summary of X-ray crystallographic data for Enantiomer 1 Temperature / K 150.01(10) Crystal system monoclinic Space group C2 a / Å 20.6346(2) b / Å 9.65220(12) c / Å 7.22562(8) ɲ^Σ 90 ɴ^Σ 95.0670(9) ɶ^Σ 90 Volume / Å31433.50(3) Z 4 ʌcalcg / cm31.433 ʅ^ŵŵ-10.972 F(000) 648.0Crystal size / mm30.40 × 0.20 × 0.02 Radiation ^Ƶ^<ɲ^;ʄ^с^ϭ^ϱϰϭ^ϰ^ Ϯ^^ƌĂŶŐĞ^ĨŽƌ^ĚĂƚĂ^ĐŽůůĞĐƚŝŽŶ^Σ 8.604 to 133.174 Index ranges -Ϯϰ^ч^Ś^ч^Ϯϰ^^-ϭϬ^ч^Ŭ^ч^ϭϭ^^-^^ч^ů^ч^^ ZĞĨůĞĐƚŝŽŶƐ^ĐŽůůĞĐƚĞĚ 20842 / ŶĚĞƉĞŶĚĞŶƚ^ƌĞĨůĞĐƚŝŽŶƐ 2461 [Rint с^Ϭ^Ϭϱϳϱ^^Zsigma с^Ϭ^ϬϯϬϰ^ Data / restraints / parameters 2461 / 1 / 210 Goodness-ŽĨ-Ĩŝƚ^ŽŶ^&21.056 &ŝŶĂů^Z^ŝŶĚĞdžĞƐ^^ / хсϮʍ^; / ^^ R1 с^Ϭ^ϬϮϳ^^^ǁZ2 с^Ϭ^Ϭϳϭϳ &ŝŶĂů^Z^ŝŶĚĞdžĞƐ^^Ăůů^ĚĂƚĂ^ R1 с^Ϭ^ϬϮ^ϳ^^ǁZ2 с^Ϭ^ϬϳϮϯ >ĂƌŐĞƐƚ^ĚŝĨĨ^^ƉĞĂŬ^ŚŽůĞ^^^Ğ^^-30.12 / -0.17 &ůĂĐŬ^ƉĂƌĂŵĞƚĞƌ 0.02(9)

[0104] Compound 7 was synthesized from (R)-Enantiomer 1 (for reaction conditions, see the synthesis of Compound 6), and its properties were identical to those of Compound 7 obtained from the chiral separation of Compound 6. This confirms that the absolute configuration of Compound 7 is (R).

[0105] Compound 8 was synthesized from (S)-Enantiomer 2 (for reaction conditions, see the synthesis of Compound 6), and its properties were identical to those of Compound 8 obtained from the chiral separation of Compound 6. This confirms that the absolute configuration of Compound 8 is (S). Example: 9 CDK2 Live-cell HiBiT Assay

[0106] CDK2-HiBiT luminescence live-cell abundance measurements were performed using a genetically modified HEK293 clonal cell line containing a C-terminal HiBiT tag knock-in on the CDK2 endogenous locus and stably expressing LgBiT protein. This was obtained from Promega (Madison, WI). Cells were plated in 384-well white bottom plates (Corning, 3570) using a Biotek MultiFlo FX (BioTek) at 5000 cells per well in 25 µl DMEM without phenol red (ThermoFisher Scientific, 21063029) supplemented with 10% FBS (Corning, 35-016-CV), 1% Penicillin / Streptomycin (ThermoFisherScientific, 15140-163), and 0.5% Nano-Glo Endurazine Live Cell Substrate (Promega, N2571). Cells were incubated for 16 hours at 37°C and 5% CO2. Compound dosing was performed using a Labcyte Echo 650 acoustic dispenser (Beckman Coulter) as follows: first, 10-point 3-fold serial dilutions of the indicated compounds were pre-prepared in DMSO from a 10 mM stock directly on Echo qualified 384LDV plates (Beckman Coulter) and a fixed volume of 2.5 nL was then transferred to the cells. The cells were subsequently incubated at 37°C and 5% CO2 for 24 hours, after which the HiBiT-LgBiT luminescence signal was directly read on a Pherastar FSX using the “LUM plus” optic module. Two repeats were carried out (n = 2).

[0107] Analysis was performed using Genedata (Genedata, Basel, Switzerland). Luminescence response (R) was calculated using the formula: R = 100 * (S - N) / (P - N) where S is the signal in each well, and N and P are the mean negative and positive control values on the same plate. In other words, the signal in each well was normalized between 100% (DMSO treated cells) and 0% (dead cells or empty wells). Dose response curves in Genedata were fit to the Hill equation (four-parameter logistic equation): where:S0is the fitted activity level at zero concentration of test sample ("zero activity"). Sinfis the fitted activity level at infinite concentration of test sample ("infinite activity"). n is the Hill coefficient for the curve, i.e. the measure of the slope at AC50. DC50 is the concentration at which the activity reaches 50% of its maximum level. Sometimes, the terms EC50 ("half maximal effective concentration") or IC50 ("half maximal inhibitory concentration") are used as well: EC50 implies activation (increasing curves), IC50 is used for inhibition (decreasing curves). It is a measure of potency where low values indicate high potency. C is the concentration in logarithmic units corresponding to the values on the x-axis of the dose-response curve plot.

[0108] n was restricted to between 0.5 and 2. The span (S0– Sinf) was restricted to between 25% and 125%. If the span was less than 25%, a constant fit was applied to the curve.

[0109] The span (S0– Sinf, i.e. the difference between the top and bottom plateaus on the dose response curve) is also referred to herein as the Dspan. It represents the maximal percentage decrease in theamount of CDK2 over the doses tested at the measured time-point. A greater Dspanvalue therefore indicates that the compound mediates greater levels of protein degradation. Example 10: GSPT1 Live-cell HiBiT Assay

[0110] HiBiT-GSPT1 luminescence live-cell abundance measurements were performed as for CDK2, except that 1) a genetically modified HEK293 pooled cell line with a N-terminal HiBiT tag knock-in on GSPT1 endogenous locus and stably expressing LgBiT protein was used instead of the genetically modified HEK293 clonal cell line containing a C-terminal HiBiT tag knock-in on the CDK2 endogenous locus and stably expressing LgBiT protein, 2) the Nano-Glo Endurazine Live Cell Substrate was used at 0.2% instead of 0.5%, and 3) 2000 cells / well were seeded instead of 5000 as for CDK2. Example 11: Assay Data

[0111] As can be seen from the data in Table 2, the compounds provided herein are effective in mediating the degradation of CDK2. In addition, the compounds provided herein can selectively mediate the degradation of CDK2 over GSPT1. Table 2. Assay Data CDK2 HiBiT 24h CDK2 HiBiT GSPT1 HiBiT Compound No. Dspan(%) 24h DC50 (nM) 24h Dspan(%) 1 47.5 785.1 0.4 2 67.6 97.4 18.8 3 65 52.6 11.2 4 59.4 87.4 4.8 5 63.5 181.5 19.6 6 62.0 46.5 9.9 7 62.2 27.0 3.7 8 62.6 166.7 6.9 Example 12: In vitro effect of Compound 6 in MDA-MB-157 breast cancer cells Proliferation

[0112] The MDA-MB-157 breast cancer cell line was acquired by ATCC and maintained by Monte Rosa in vitro as monolayer culture in Leibovitz's L-15 Medium with 10% heat inactivated fetal bovine serumand at 37 °C in CO2free air. Cells were plated at a density of 500 cells / well in quadruplicate in 96-well plates in the presence of DMSO or under an 8-point dose response curve (DRC) with a starting concentration of 1000 nM, intermediate concentrations of 316 nM, 100 nM, 31.6 nM, 10 nM, 3.16 nM, 1 nM and a lowest concentration of 0.316 nM of Compound 6. After 7 days, the anti-proliferative effect of Compound 6 relative to day zero (D0) and DMSO treated cells was assessed using a CyQuant assay.

[0113] In the proliferation assay, a 7-day treatment with Compound 6 resulted in 81% reduction relative to DMSO and D0 on MDA-MB-157 cells (Emax= 81%, EC50 = 10 nM). The results are shown in Figure 1. CDK2 Protein levels by Western Blot

[0114] In parallel to the proliferation assay, MDA-MB-157 cells were plated as monolayer at a density of 0.5 x 106cells / well in a 6-well plate in the presence of DMSO or under an 8-point dose response curve (DRC) with a starting concentration of 1000 nM followed by 3-fold dilutions to a lowest concentration of 152 nM of Compound 6. After a 24-hour treatment the degradation effect on CDK2 protein levels was assessed by western blot (WB).

[0115] In the WB assay, a gradual reduction in the CDK2 protein levels was observed, reaching a maximal 84% protein degradation and a DC50 of 4 nM. The results are shown in Figure 1. Cell cycle: MDA-MB-157 cells were maintained in vitro as described above, plated at a density of 1 x 105cells / well in triplicate in 24-well plates and allowed to settle overnight. The cells were then treated with DMSO or 10 nM, 100 nM or 1000 nM of Compound 6. After a 24-hour treatment, compound effects on the cell cycle were assessed using an EdU incorporation assay for flow cytometry (Click-iT™ EdU Alexa Fluor™ ^^^^)ORZ^&\WRPHWU\^$VVD\^.LW^^^DQG^D^'$3,^^^ƍ^^-diamidino-2-phenylindole) counterstain to measure DNA content.

[0117] As shown in Figure 2, 24h treatment resulted in a dose dependent accumulation of cells in the G1 phase, from 56.3% in the DMSO treated conditions to 65.4% at the 1000 nM concentration of Compound 6. Similarly, a gradual reduction of cells in the S phase of cell cycle was observed, from 15.8% in DMSO versus 3.1% at the highest 1000 nM treatment concentration of Compound 6.Example 13: In vivo effect of Compound 6 in MKN1, a gastric cancer CDX mouse model

[0118] The MKN1 tumor cell line was maintained in vitro as monolayer culture in RPMI 1640 medium supplemented with 10% heat inactivated fetal bovine serum at 37°C in an atmosphere of 5% CO2 in air. The tumor cells were routinely sub-cultured twice weekly by trypsin-EDTA treatment, not to exceed 4-5 passages. The cells growing in an exponential growth phase were harvested and counted for tumor inoculation. Each mouse was inoculated subcutaneously on the right flank with 1 × 107MKN1 tumor cells in 0.1 mL of RPMI 1640 and Matrigel mixture (1:1 ratio) for tumor development. The treatments were initiated when the average tumor size reached approximately 200 (180-220) mm3. n=6, i.e.6 mice per group were inoculated for this efficacy study for Group1 and n=8 mice for Groups 2 and 3: x Group 1: Vehicle PO BID (vehicle = 10% Capsitol in water) x Group 2: Compound 630 mpk PO BID x Group 3: Compound 6100 mpk PO BID

[0119] Where mpk: milligram per kilogram, PO: per os, for oral administration, and BID: bis in die, for administration twice a day.

[0120] Dosing was continued for 21 days. Tumor volume and body weight were measured twice a week, with tumor volume being calculated using the [(Length x Width x Width) / 2)] formula.

[0121] Tumor Growth Inhibition (TGI) on day 21 was calculated as 100*(1 -AT / AC). The AC was obtained by subtracting the mean tumor burden in the vehicle group on the first day of treatment (Day 0) from the mean tumor burden in the vehicle group on Day 21. The AT was obtained by subtracting the mean tumor burden in the treated group on the first day of treatment (Day 0) from the mean tumor burden in the treated group on Day 21.

[0122] Statistical analysis was performed using t-test analysis with Graph Pad Prism software 10.1.0 (Graph Pad Software Inc, San Diego). Day 21 results are shown in Figure 3.

[0123] As shown in Figure 3, oral (PO) administration of compound 6 at 30 and 100 mpk, twice a day (BID) for 21 days, resulted in a significant (p < 0.05 versus vehicle) antitumor activity with 45% and 47% TGI respectively.EQUIVALENTS

[0124] While specific embodiments have been discussed, the above specification is illustrative and not restrictive. Many variations of the embodiments will become apparent to those skilled in the art upon review of this specification. The full scope of what is disclosed should be determined by reference to the claims, along with the full scope of their equivalents, and the specification, along with such variations.

Claims

CLAIMS 1. A compound selected from the group consisting of: Compound 1 Compound 2 Compound 3 Compound 4 FFO F O O O N O N N HN N N HN N HN N HN N N N N N FFF F F F O F F O O O NH NH NH NH O O O O Compound 5 Compound 6 Compound 7 Compound 8 F FFFFFFFO F F F F O O O O N N N N HN N HN N HN N HN N N N N N F FF FFFFFO O O O (R) (S) NH NH NH NH O O O O or a pharmaceutically acceptable salt thereof.

2. The compound of claim 1, wherein the compound is selected from the group consisting of: Compound 6 Compound 7 Compound 8 FFFFFFF F F O O O N N N HN N HN N HN N N N N FFFFFFO O O (R) (S) NH NH NH O O O or a pharmaceutically acceptable salt thereof.

3. The compound of claim 1 or 2, wherein the compound is: Compound 6 FFF O N HN N N FFO NH O or a pharmaceutically acceptable salt thereof.

4. The compound of claim 3, wherein the compound is a racemic mixture of compound 7 or a pharmaceutically acceptable salt thereof and compound 8 or a pharmaceutically acceptable salt thereof:Compound 7 Compound 8 FFFFF F O O N N HN N HN N N N FFFFO O (R) (S) NH NH O O .

5. The compound of any one of claims 1 to 3, wherein the compound is: Compound 7 FFF O N HN N N F F O (R) NH O or a pharmaceutically acceptable salt thereof.The compound of any one of claims 1-3, wherein the compound is: Compound 8 FFF O N HN N N FFO (S) NH O or a pharmaceutically acceptable salt thereof.

7. The compound of claim 1, wherein the compound is selected from the group consisting of: 1 Compound 2 Compound 3 Compound 4 Compound 5 FFF O F O F F O O O N O N N O HN N N HN N HN N N HN NHNNN N N N N FFF F F F O F F O O F F O O NH NH NH NH NH O O O O Oor a pharmaceutically acceptable salt thereof.

8. A pharmaceutical composition comprising the compound or pharmaceutically acceptable salt of any one of claims 1-7 and one or more pharmaceutically acceptable excipients.

9. A method of treating a disease or condition in a subject in need thereof, wherein the method comprises administering to the subject a therapeutically effective amount of the compound or pharmaceutically acceptable salt of any one of claims 1-7 or the pharmaceutical composition of claim 8.

10. A method of treating cancer in a subject in need thereof, wherein the method comprises administering to the subject a therapeutically effective amount of the compound or pharmaceutically acceptable salt of any one of claims 1-7 or the pharmaceutical composition of claim 8.

11. The method of claim 10, wherein the cancer comprises a solid tumor, for example wherein the solid tumor is at least one of the group consisting of: uterine cancer (such as uterine carcinosarcoma and uterine corpus endometrial carcinoma), endometrial cancer, breast cancer, (such as breast invasive carcinoma and triple negative breast cancer, ER+ HER2- breast cancer, and HER2+ breast cancer), ovarian cancer (such as ovarian serous cystadenocarcinoma), stomach cancer (such as stomach adenocarcinoma), gastric cancer (such as gastrointestinal stromal cancer), colorectal cancer, pancreatic cancer, kidney cancer, head and neck cancer, liver cancer, prostate cancer, skin cancer, lymphoma (such as B-cell lymphoma), sarcoma, esophageal cancer (such as esophageal carcinoma), bladder cancer (such as bladder urothelial carcinoma), lung cancer (such as lung squamous carcinoma and non-small cell lung cancer including EGFRm+ (epidermal growth factor receptor mutant positive) non-small cell lung cancer), cholangiocarcinoma, adrenocortical carcinoma, mesothelioma, and malignant melanoma; or 12. The method of claim 10, wherein the cancer comprises a liquid tumor, for example wherein the liquid tumor is at least one of the group consisting of: diffuse large B-cell lymphoma (DLBCL), B-cell immunoblastic lymphoma, small non-cleaved cell lymphoma, human lymphotropic virus- type 1 (HTLV-1) leukemia / lymphoma, adult T-cell lymphoma, peripheral T-cell lymphoma (PTCL), cutaneous T-cell lymphoma (CTCL), mantle cell lymphoma (MCL), Hodgkin’s lymphoma (HL), non-Hodgkin’s lymphoma (NHL), AIDS-related lymphoma, follicular lymphoma, small lymphocytic lymphoma, T-cell / histiocyte rich large B-cell lymphoma,transformed lymphoma, primary mediastinal (thymic) large B-cell lymphoma, splenic marginal zone lymphoma, Richter's transformation, nodal marginal zone lymphoma, ALK-positive large B-cell lymphoma, indolent lymphoma (e.g., DLBCL, follicular lymphoma, or marginal zone lymphoma), acute myelogenous leukemia (AML), acute lymphocytic leukemia (ALL), adult T- cell leukemia, chronic lymphocytic leukemia (CLL), small lymphocytic lymphoma (SLL), hairy cell leukemia, myelodysplasia, myeloproliferative disorders, chronic myelogenous leukemia (CML), acute monocytic leukemia (AMoL), myelodysplastic syndrome (MDS), human lymphotropic virus-type 1 (HTLV-1) leukemia, mastocytosis, B-cell acute lymphoblastic leukemia, Non-Hodgkin's Lymphoma, Hodgkin's Lymphoma, and multiple myeloma (MM).

13. The method of claim 11, wherein the cancer is selected from the group consisting of: ovarian cancer, endometrial cancer, gastric cancer, esophaegeal cancer, breast cancer, and lung adenosarcoma.

14. The method of claim 13, wherein the cancer is breast cancer, for example wherein the breast cancer is HR+ (hormone receptor positive) breast cancer, ER+ (estrogen receptor positive) breast cancer, HR+ HER2- (human epidermal growth factor receptor 2 negative) breast cancer, ER+ HER2- (human epidermal growth factor receptor 2 negative) breast cancer, or triple negative breast cancer, for example HR+ HER2- (human epidermal growth factor receptor 2 negative) breast cancer.

15. The method of any one of claims 10-14, wherein the cancer is a cancer with a CCNE1 (cyclin E1) amplification.

16. The method of claim 9, wherein the disease or condition is cancer of the bladder, bone, brain, breast, cervix, chest, colon, endrometrium, esophagus, eye, head, kidney, liver, lymph nodes, lung, upper aerodigestive tract (including nasal cavity and paranasal sinuses, nasopharynx or cavum, oral cavity, oropharynx, larynx, hypopharynx and salivary glands, neck, ovaries, pancreas, prostate, rectum, skin, stomach, testis, throat, or uterus.

17. The method of claim 9, wherein the disease or condition is selected from the group consisting of amyloidosis, neuroblastoma, meningioma, hemangiopericytoma, multiple brain metastases, glioblastoma multiforms, glioblastoma, brain stem glioma, poor prognosis malignant brain tumor, malignant glioma, recurrent malignant glioma, anaplastic astrocytoma, anaplastic oligodendroglioma, neuroendocrine tumor, e.g., neuroendocrine prostate cancer such ascastration-resistant neuroendocrine prostate cancer (NEPC) and lung neuroendocrine tumors (Lu- NETs), rectal adenocarcinoma, colorectal cancer, including stage 3 and stage 4 colorectal cancer, unresectable colorectal carcinoma, metastatic hepatocellular carcinoma, Kaposi's sarcoma, malignant melanoma, malignant mesothelioma, malignant pleural effusion mesothelioma syndrome, peritoneal carcinoma, papillary serous carcinoma, gynecologic sarcoma, soft tissue sarcoma, scleroderma, cutaneous vasculitis, Langerhans cell histiocytosis, leiomyosarcoma, fibrodysplasia ossificans progressive, hormone refractory prostate cancer, resected high-risk soft tissue sarcoma, unrescectable hepatocellular carcinoma, fallopian tube cancer, androgen independent prostate cancer, androgen dependent stage IV non-metastatic prostate cancer, hormone-insensitive prostate cancer, chemotherapy -insensitive prostate cancer, papillary thyroid carcinoma, follicular thyroid carcinoma, medullary thyroid carcinoma, and leiomyoma; and blood bourne (liquid) or hematological cancers, including but not limited to leukemias, lymphomas, and myelomas, such as diffuse large B-cell lymphoma (DLBCL), B-cell immunoblastic lymphoma, small non-cleaved cell lymphoma, human lymphotropic virus-type 1 (HTLV-1) leukemia / lymphoma, adult T-cell lymphoma, peripheral T-cell lymphoma (PTCL), cutaneous T- cell lymphoma (CTCL), mantle cell lymphoma (MCL), Hodgkin’s lymphoma (HL), non- Hodgkin’s lymphoma (NHL), AIDS-related lymphoma, follicular lymphoma, small lymphocytic lymphoma, T-cell / histiocyte rich large B-cell lymphoma, transformed lymphoma, primary mediastinal (thymic) large B-cell lymphoma, splenic marginal zone lymphoma, Richter's transformation, nodal marginal zone lymphoma, ALK-positive large B-cell lymphoma, indolent lymphoma (for example, DLBCL, follicular lymphoma, or marginal zone lymphoma), acute myelogenous leukemia (AML), acute lymphocytic leukemia (ALL), adult T-cell leukemia, chronic lymphocytic leukemia (CLL), small lymphocytic lymphoma (SLL), hairy cell leukemia, myelodysplasia, myeloproliferative disorders, chronic myelogenous leukemia (CML), acute monocytic leukemia (AMoL), myelodysplastic syndrome (MDS), human lymphotropic virus- type 1 (HTLV-1) leukemia, mastocytosis, B-cell acute lymphoblastic leukemia, Non-Hodgkin's Lymphoma, Hodgkin's Lymphoma, and multiple myeloma (MM).

18. The method of any one of claims 9-17, wherein the subject is a treatment-naïve subject.

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