Cyclin dependent kinase 2 inhibitors for medical treatment

Abstract

A pyrimidine-based selective cyclin dependent kinase 2 (CDK2) of the following structure described herein is used: (Compound I), or a pharmaceutically acceptable salt or morphological form thereof, the compounds are useful for treating disorders characterized by aberrant cell division or aberrant cell division disorders with expanded cyclin E activation and / or expression, CDK4 / 6 resistance, and / or endocrine therapy resistance, including but not limited to the treatment of tumors and cancers. # imgabs0 #

Description

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS

[0002] This application claims the benefit of U.S. Provisional Application No. 63 / 353,729, filed June 20, 2022, U.S. Provisional Application No. 63 / 444,523, filed February 9, 2023, U.S. Provisional Application No. 63 / 460,201, filed April 18, 2023, and U.S. Provisional Application No. 63 / 470,621, filed June 2, 2023. The entire contents of these applications are hereby incorporated by reference herein for all purposes. Technical Field

[0003] The present invention is in the field of using specific heterocyclic-based compounds to selectively inhibit cyclin-dependent kinase 2 (CDK2) for the treatment of medical disorders characterized by abnormal cell division, including but not limited to the treatment of tumors and cancer. Background Art

[0004] Adult tissues are mainly composed of terminally differentiated, quiescent cells that have exited the cell cycle. Physiological signals in response to extracellular stimuli (including, for example, tissue damage) can trigger some cells to re-enter the cell cycle and divide to replenish damaged or dead cells (Matthews et al. Nat Rev Mol Cell Biol. 23: 74-88 (2022)). There is a fine regulatory balance between cell division and programmed cell death (apoptosis).

[0005] Cell division is regulated by the cell cycle, which is divided into four phases: G1 (cell growth and machinery synthesis), S (DNA replication to produce two identical sets of chromosomes), G2 (cell growth and replenishment machinery synthesis), and M (a single cell divides into two identical daughter cells). Progression between cell cycle phases is primarily controlled by cyclins and cyclin-dependent kinases (CDKs) (Asghar et al. Nat Rev Drug Discov. 14(2):130-46 (2015)), which are activated or inhibited in a complex cellular signaling network system that interprets extracellular signals.

[0006] Cyclin binds and activates CDK, which preferentially phosphorylates the tumor suppressor retinoblastoma (Rb) protein. Rb protein binds and represses E2 factor (E2F) transcription factors when dephosphorylated, recruits corepressors, and represses the transcription of cell cycle genes regulated by E2F. However, when Rb is phosphorylated by the CDK / cyclin complex, it separates from the E2F transcription factor and then transcribes a group of genes involved in cell cycle control, including, for example, cyclin E (CCNE), cyclin A (CCNA), and cyclin B1 (CCNB1), and causes cells to progress to subsequent stages of the cell cycle (Hochegger et al. Nat Rev Mol Cell Biol. 9:910-16 (2008)). After cell division during mitosis (M), cells shut down the expression of the machinery required for gene replication and separation and exit the cell cycle.

[0007] When there is uncontrolled cell proliferation, a series of tumor disorders will occur. The development of broad-spectrum anti-tumor agents has been used to treat various cell proliferative disorders, including ovarian cancer, breast cancer and lung cancer (see, for example, Jordan & Wilson, Nat Rev Canc. 4: 253-65 (2004)). Organometallic-based chemotherapy agents such as cisplatin have been used to treat cancers, including lymphomas, sarcomas, germ cell tumors and cancers, such as small cell lung cancer (SCLC), bladder cancer, and ovarian cancer. One such organometallic agent, cisplatin, binds to nitrogenous bases and induces deep DNA cross-linking, leading to apoptosis (see, for example, Siddick et al. Oncogene. 22: 7265-79 (2003)). In addition, agents that insert or alkylate DNA have been extensively tested in the clinic for cancer treatment. For patients who require long-term therapy, the toxicity associated with these drugs is a primary concern.

[0008] The dysregulation of cyclin-dependent kinases and cyclins provides the driving force for the excessive growth of neoplasms and the development of tumors, ultimately leading to cell division disorders such as cancer (Otto & Sicinski. Nat Rev Canc. 17: 93-115 (2017)). Recently, targeted approaches involving the use of compounds to inhibit CDKs have been used to treat cancer and limit adverse events associated with broad-spectrum anti-tumor agents (O'Leary et al. Nat Rev Clin Oncol. 13: 417-30 (2016)). For example, Pfizer researchers found that palbociclib (PD-033299; ) transiently inhibits cell cycle progression in CDK4 / 6-dependent cells (Roberts et al. JNCI. 104(6):476-87(2012)). In February 2015, FDA approved (Palbociclib) is used in combination with letrozole to treat estrogen receptor-positive (ER+), human epidermal growth factor receptor 2-negative (HER2-) breast cancer. The structure of Palbociclib is:

[0009]

[0010] Ribociclib (Lee011; ) is a CDK4 / 6 inhibitor that is FDA-approved for use in combination with an aromatase inhibitor for the treatment of metastatic breast cancer. Ribociclib is currently being tested in clinical trials for the treatment of a variety of other cancers. The structure of ribociclib is:

[0011]

[0012] Abemaciclib (LY2835219; ) is a CDK4 / 6 inhibitor that is FDA-approved for use in combination with endocrine therapy (tamoxifen or an aromatase inhibitor) for the adjuvant treatment of hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2-) breast cancer. The compound is also in a series of clinical trials, including a Phase III trial for the treatment of stage IV non-small cell lung cancer and another trial with anastrozole or letrozole for the treatment of breast cancer in the first-line setting. The structure of abemaciclib is:

[0013]

[0014] Although the above compounds exhibit antitumor efficacy and generally favorable safety profiles, there are still treatment-related side effects (Thill et al. Ther Adv Med Oncol. 10:1758835918793326 (2018)), the most common of which is neutropenia. New CDK4 / 6 inhibitors have been shown to protect myeloid cells during cancer treatment and are expected to receive FDA approval for cancer treatment soon.

[0015] Trilaciclib (COSELA) TM ) is an FDA-approved selective CDK4 / 6 inhibitor from G1 Therapeutics, Inc., used as a first-in-class bone marrow preservation therapy, designed to improve the quality of life and prognosis of patients with extensive-stage small cell lung cancer (SCLC) receiving chemotherapy by protecting hematopoietic stem and progenitor cells (HSPCs). Triraciclib is a short-acting CDK4 / 6 inhibitor administered intravenously before chemotherapy and is being studied in four randomized Phase II clinical trials, including as a first-line therapy with carboplatin / etoposide chemotherapy and checkpoint inhibitors. (atezolizumab) is used in combination with trexacillin to treat SCLC. The structure of trexacillin is as follows:

[0016]

[0017] Lerociclib is a selective CDK4 / 6 inhibitor being clinically developed by EQRx, Inc. (the exclusive licensee of G1 Therapeutics, Inc.) for use in combination with other anticancer agents for the treatment of multiple oncology indications. Lerociclib is undergoing two Phase 1 / 2 clinical trials, including a future Phase 1 / 2 study comparing Lerociclib with fulvestrant. A trial in combination with osimertinib in patients with estrogen receptor-positive (ER+), HER2- breast cancer (NCT02983071) is underway. Combination for the treatment of epidermal growth factor receptor mutant (EGFR mut ) non-small cell lung cancer trial. The structure of leloxilim is as follows:

[0018]

[0019] Additional pyrimidine-based anti-CDK2 agents are described in WO 2021 / 236650, assigned to G1 Therapeutics, Inc., and include compounds of the following structures:

[0020] and a preparation method thereof.

[0021] Despite progress in developing cell cycle inhibitory compounds to treat abnormal cell proliferative disorders in subjects (eg, humans), there remains an unmet need for new strategies to combat these fatal disorders.

[0022] It is an object of the present invention to provide novel uses and combinations for preventing uncontrolled cell cycling in a subject, such as a human. Summary of the Invention

[0023] It has been found that the selective CDK2 inhibitor compound 1 described herein or its pharmaceutically acceptable salt or morphological form is a potent therapeutic agent that can be used to treat abnormal proliferation with increased cyclin E expression or cyclin E amplification. Compound 1 described herein or its pharmaceutically acceptable salt or morphological form can also be used to treat cancers that have developed resistance to CDK4 / 6 inhibitors. Still further, compound 1 described herein or its pharmaceutically acceptable salt or morphological form can also be used to treat cancers that have developed resistance to estrogen receptor degraders (such as, but not limited to, selective estrogen receptor degraders (SERDs), such as fulvestrant or elacestrant). Compound 1 described herein or its pharmaceutically acceptable salt or morphological form can also be used to treat small cell lung cancer (SCLC), which is a retinoblastoma-null cancer for which there is currently no approved targeted therapy. As further described below, new and highly stable morphological forms and salts of compound 1 have also been found.

[0024]

[0025] Compound 1, or a pharmaceutically acceptable salt or morphological form thereof, as described herein has several advantageous properties and may be used to treat cancers that overexpress or amplify cyclin E, CDK4 / 6 inhibitor-resistant cancers, estrogen receptor degrader-resistant cancers, and / or small cell lung cancer (see, e.g., Figure 151 Non-limiting examples of these advantageous properties include (i) selective inhibition of CDK2 (see, e.g., Example 1 Figures 1A-1B and 2A-2C); (ii) inhibiting CDK2 in complex with several cyclin binding partners (see, e.g., Example 1 Figures 1A-1B ); (iii) substantially long residence time when complexed with CDK2 (see, e.g., Example 1 Figure 1B (iv) a robust safety profile when administered to healthy, non-cancerous cells (see, e.g., Example 2 Figure 3-4 , 5A-5C and 6); (v) synergistic effects with chemotherapeutic agents for greater anti-tumor efficacy (see, e.g., Example 5 Figures 29A-29C 、 Figures 30A-30C ); (vi) enhanced anti-tumor efficacy in CDK4 / 6 inhibitor-resistant cells when administered in combination with a CDK4 / 6 inhibitor (see, e.g., Examples 3 and 45). Figures 7A-7D , 8A-8I, 9A-9B, 149); (vii) anti-tumor efficacy in cells with enhanced cyclin E activation and / or expression (see, e.g., Example 4 Figures 10A-10E, 11A-11B, 12, 13A-13C, 14A-14B, 16A-16B, 17A-17B, 18, 19A-19B, 20 and 21A-21B); (viii) inducing changes in the expression and post-translational modification of cell cycle-related proteins (see, e.g., Examples 4, 5, 6 and 45). Figure 7C 、 8B , 10E, 11A-11B, 12, 20, 26A-26C, 146E-146F, 147L); (ix) inducing a targeted DNA damage response in tumor cells (see, e.g., 22D-22E, 25, 27A-27D, and 28C of Example 5); (x) at the initial Robust cell cycle arrest in cells and therapy-resistant cells (see, e.g., Examples 3-5 and 45) Figures 9A-9B , 10C-10D, 13A-13C, 14B, 15A-15D, 21B, 23, 24, 28B, 147D-147J) (xi) cellular senescence following cell cycle arrest in therapy-resistant cells (see, e.g., Example 45 Figures 148A-148F (xii) durable in vivo tumor inhibition and tumor stasis in subjects with cell proliferative disorders such as cancer (see, e.g., Examples 4, 6, 44, and 45). Figure 18 、 19A , 31A-31G, 146A-146D, 149); (xiii) improved overall survival in subjects with a cell proliferative disorder, such as cancer, as demonstrated by animal studies (see, e.g., Example 4 of Figure 19B ); (xiv) prolonging resistance to other anticancer agents such as SERDs (see e.g. Figure 145 , Example 43); (xv) little to no inhibition of human drug transporters, indicating a low risk of toxic drug-drug interactions (see, e.g., Example 41). Figures 127-143 ); and / or (xvi) excellent tolerability for daily administration in various animal models (see, e.g., Examples 42 and 45).

[0026] In addition to its potent anticancer activity, Compound 1 described herein or its pharmaceutically acceptable salt or morphological form can be used to re-sensitize recurrent and / or refractory cancers to other anticancer therapies, including but not limited to CDK4 / 6 inhibitors, estrogen receptor degraders and inhibitors, chemotherapeutic agents, immune checkpoint inhibitors, or combinations thereof. This improvement provides a significant advancement in the state of the art for cancer treatment. In certain embodiments, Compound 1 described herein or its pharmaceutically acceptable salt or morphological form causes re-sensitization by advantageously changing the gene expression profile in the cell, thereby producing a tumor microenvironment that is easily treated with a therapeutic agent that was previously resistant to it. The net result of this effect on the tumor microenvironment is to improve the subject's response to the therapeutic agent, including in certain non-limiting cases, previously administered to the subject and the subject subsequently produces a resistant therapeutic agent (i.e., resensitizing the tumor), to effectively combat cancer or tumors, improving the ability to achieve short-term (up to about 1, 2, 3, 4, 5, or 6 months), long-term (up to 7, 8, 9, 10, 11, or 12 months or longer) or complete response.

[0027] Due to the significant CDK2 inhibitor properties of Compound 1, new and advantageous treatments have been found for disorders mediated by cyclin E overexpression / amplification, CDK4 / 6 inhibitor resistance, estrogen receptor degrader resistance, and / or Rb-independent mechanisms (e.g., small cell lung cancer). In non-limiting embodiments of the present invention, Compound 1 or a pharmaceutically acceptable salt, morphological form, or pharmaceutical composition thereof can be used in the following non-limiting indications, for example:

[0028] (a) Use of Compound 1 as described herein, or a pharmaceutically acceptable salt or morphological form thereof, for treating a human suffering from an abnormal cell proliferative disorder characterized by cyclin E amplification or overexpression, including but not limited to ovarian cancer, gastric cancer, breast cancer, bladder cancer, lung cancer, or gynecological cancer characterized by cyclin E amplification or overexpression;

[0029] (b) Use of Compound 1 as described herein, or a pharmaceutically acceptable salt or morphological form thereof, for treating a subject suffering from an abnormal cell proliferative disorder, such as cancer, comprising obtaining a sample from the human, detecting whether cyclin E1 and / or E2 (CCNE1 / CCNE2) is overexpressed in the sample compared to a control sample, and, after determining that CCNE1 and / or CCNE2 are overexpressed, administering to the human an effective amount of a selective CDK2 inhibitor having the structure of Compound 1 as described herein, or a pharmaceutically acceptable salt or morphological form thereof;

[0030] (c) Use of Compound 1, or a pharmaceutically acceptable salt or morphological form thereof, as described herein, for treating a human suffering from small cell lung cancer, wherein the human is further administered an additional therapeutic agent, such as doxorubicin or camptothecin, in combination with Compound 1;

[0031] (d) Use of Compound 1 described herein, or a pharmaceutically acceptable salt or morphological form thereof, in combination with a CDK4 / 6 inhibitor (e.g., leloxilim, palbociclib, abemaciclib, or ribociclib) for treating a subject with an acquired CDK4 / 6 inhibitor-resistant cancer;

[0032] (e) Use of Compound 1 described herein, or a pharmaceutically acceptable salt or morphological form thereof, in combination with a CDK4 / 6 inhibitor (e.g., leloxilim, palbociclib, abemaciclib, or ribociclib) for treating a subject with an intrinsically CDK4 / 6 inhibitor-resistant cancer;

[0033] (f) Use of Compound 1 as described herein, or a pharmaceutically acceptable salt or morphological form thereof, in combination with an estrogen inhibitor, such as an estrogen receptor degrader (e.g., fulvestrant or elastrant), for treating a subject with an estrogen inhibitor-resistant cancer;

[0034] (g) Use of Compound 1 as described herein, or a pharmaceutically acceptable salt or morphological form thereof, in combination with a CDK4 / 6 inhibitor (e.g., leloxicil, palbociclib, abemaciclib, or ribociclib) and an estrogen inhibitor (e.g., fulvestrant or elastostat) for treating a subject having a CDK4 / 6 inhibitor-resistant and / or estrogen inhibitor-resistant cancer;

[0035] (h)(df) The use of, wherein the CDK4 / 6 inhibitor-resistant cancer is cyclin E amplified or overexpressed;

[0036] (i) The use of (d) or (f), wherein the CDK4 / 6 inhibitor-resistant cancer is estrogen receptor-positive (ER+) breast cancer;

[0037] (j) The use of any one of (a) to (h), wherein the abnormal cell proliferative disorder is an unresectable cancer;

[0038] (k) The use of any one of (a)-(i), wherein the abnormal cell proliferative disorder is advanced cancer;

[0039] (l) The use of any one of (a)-(j), wherein the abnormal cell proliferative disorder is a solid tumor;

[0040] (m) The use of any one of (a)-(k), wherein the abnormal cell proliferative disorder is advanced cancer;

[0041] (n) The use of any one of (i)-(l), wherein the cancer is metastatic;

[0042] (o) The use of any one of (i)-(l), wherein the cancer is platinum-resistant or platinum-refractory;

[0043] (p) The use of any one of (i)-(l), wherein the cancer is CCNE1 amplified;

[0044] (q) the morphological form of Compound 1 is as described herein;

[0045] (r) a pharmaceutical composition comprising a morphological form of Compound 1 and a pharmaceutically acceptable excipient;

[0046] (s) a pharmaceutical composition comprising Compound 1 and a pharmaceutically acceptable excipient, wherein the pharmaceutical composition is prepared from a morphological form of Compound 1, such as a spray-dried dispersion;

[0047] (t) the pharmaceutical composition of (q) or (r), wherein the pharmaceutically acceptable excipient is a diluent, such as polyethylene glycol;

[0048] (u) The use of any one of (a)-(o), wherein Compound I is the morphological form or pharmaceutical composition of any one of (q)-(s); or

[0049] (v) Use of the morphological form or pharmaceutical composition of any one of (q) to (s) for treating CDK2-mediated abnormal cell proliferation (eg, CDK2-mediated cancer).

[0050] In certain aspects, Compound 1 as described herein, or a pharmaceutically acceptable salt or morphological form thereof, is used to treat an Rb-dependent cancer, wherein the cancer has overexpressed or amplified expression of cyclin E. For example, in certain embodiments, Compound 1 as described herein, or a pharmaceutically acceptable salt or morphological form thereof, is used to treat breast cancer, prostate cancer (including androgen-resistant prostate cancer), colon (including metastatic colon), another reproductive system cancer (e.g., endometrial cancer, ovarian cancer, or testicular cancer), which has overexpressed or amplified expression of cyclin E. Cancers with overexpressed or amplified expression of cyclin E may have overexpression or amplification of CCNE1 and / or CCNE2. In certain embodiments, cancers with amplified or overexpressed cyclin E have amplification or overexpression of CCNE1. In certain embodiments, cancers with amplified or overexpressed cyclin E have amplification or overexpression of CCNE2.

[0051] In yet another embodiment, an effective amount of Compound 1 as described herein, or a pharmaceutically acceptable salt or morphological form thereof, is used to treat abnormal tissue (e.g., breast cancer, ovarian cancer, endometrial cancer, or uterine cancer) with overexpressed or amplified cyclin E expression in the female reproductive system in combination or alternating administration with an effective amount of an estrogen inhibitor, including but not limited to SERMs (selective estrogen receptor modulators), SERDs (selective estrogen receptor degraders), complete estrogen receptor degraders, or another form of partial or complete estrogen antagonists. In some embodiments, Compound 1 as described herein, or a pharmaceutically acceptable salt or morphological form thereof, is administered to a subject at least once a day, and wherein an effective amount of an estrogen inhibitor is administered according to its prescribed label. In some embodiments, Compound 1 as described herein, or a pharmaceutically acceptable salt or morphological form thereof, is administered to a subject at least twice a day, and wherein an effective amount of an estrogen inhibitor is administered according to its prescribed label.

[0052] In some embodiments, the abnormal cell proliferative disorder in which cyclin E is amplified or overexpressed is selected from ovarian cancer, uterine cancer, uterine carcinosarcoma (UCS), uterine corpus endometrial cancer (UCEC), ovarian cancer, ovarian serous cystadenocarcinoma (OV), sarcoma (SARC), lung cancer, lung squamous cell carcinoma (LUSC), lung adenocarcinoma (LUAD), gastric cancer, gastric adenocarcinoma (STAD), bladder cancer, bladder urothelial carcinoma (BLCA), esophageal cancer, esophageal carcinoma (ESCA), adrenocortical carcinoma, breast cancer , invasive breast cancer (BRCA), pancreatic cancer, pancreatic adenocarcinoma (PAAD), fallopian tube cancer, primary peritoneal cancer, liver cancer, hepatocellular carcinoma (LIHC), cervical cancer, cervical squamous cell carcinoma (CESC), endocervical adenocarcinoma, mesothelioma (MESO), head and neck squamous cell carcinoma (HSNC), colon cancer, colon adenocarcinoma (COAD), skin cancer, melanoma, cutaneous melanoma of the skin (SKCM), glioblastoma multiforme (GBM), renal cancer or renal chromophobe cell (KICH). In some embodiments, the cancer with cyclin E amplification or overexpression is ovarian cancer. In some embodiments, the cancer with cyclin E amplification is CDK4 / 6 inhibitor resistant. In certain embodiments, the cancer is advanced and / or metastatic cancer. In certain embodiments, the cancer is advanced unresectable cancer. In certain embodiments, the cancer is platinum refractory and / or platinum resistant. In certain embodiments, the cancer progresses after a previous standard of care regimen. In certain embodiments, the cancer progresses after a previous standard systemic therapy. In certain embodiments, the cancer progresses after a previous systemic anticancer therapy. In certain embodiments, the cancer progresses after a previous regimen that includes a platinum analog. In certain embodiments, the cancer progresses after a previous regimen that includes a CDK4 / 6 inhibitor. In some embodiments, the cancer in which cyclin E is amplified or overexpressed is uterine cancer. In some embodiments, the cancer in which cyclin E is amplified or overexpressed is ovarian cancer. In some embodiments, the cancer in which cyclin E is amplified or overexpressed is breast cancer. In some embodiments, the cancer in which cyclin E is amplified or overexpressed is prostate cancer. In some embodiments, the cancer in which cyclin E is amplified or overexpressed is bladder cancer. In some embodiments, the cancer in which cyclin E is amplified or overexpressed is sarcoma.

[0053] In certain embodiments, the above method further includes administering an effective amount of one or more additional anticancer therapies. In certain embodiments, anticancer therapy is selected from radiation, surgery, immune checkpoint inhibitors, estrogen inhibitors, androgen inhibitors, PARP inhibitors, or a combination thereof. In certain embodiments, the method further includes administering an effective amount of an estrogen inhibitor. In certain embodiments, the estrogen inhibitor is selected from selective estrogen receptor modulators (SERMs), selective estrogen receptor degraders (SERDs), complete estrogen receptor degraders, complete estrogen antagonists, partial estrogen antagonists, or a combination thereof. In some embodiments, the estrogen inhibitor is a selective estrogen receptor degrader (SERD). In some embodiments, SERD includes Fulvestrant. In some embodiments, SERD includes Alastrant (RAD1901). In some embodiments, Compound 1 described herein or its pharmaceutically acceptable salt or morphological form is administered to the subject at least once a day, and wherein an effective amount of anticancer therapy is administered according to its prescribed label. In some embodiments, Compound 1 described herein or its pharmaceutically acceptable salt or morphological form is administered to the subject at least twice a day, and wherein an effective amount of anticancer therapy is administered according to its prescribed label.

[0054] In other aspects, Compound 1 described herein, or a pharmaceutically acceptable salt or morphological form thereof, is used to treat small cell lung cancer (Rb-deficient cancer). In certain embodiments, Compound 1 inhibits the CDK2 / A axis, resulting in inhibition of growth or remission of small cell lung cancer. In other embodiments, Compound 1 causes DNA damage in small cell lung cancer cells, arrests growth, or causes remission.

[0055] For example, in certain embodiments, there is provided a method for treating a subject with CDK4 / 6 inhibitor-resistant small cell lung cancer (SCLC), comprising administering to the subject an effective amount of Compound 1 as described herein, or a pharmaceutically acceptable salt or morphological form thereof; and (ii) administering to the subject an effective amount of a chemotherapeutic agent, wherein Compound 1 as described herein, or a pharmaceutically acceptable salt or morphological form thereof, is administered to the subject within 24 hours or less prior to administration of the chemotherapeutic agent or concomitantly with administration of the chemotherapeutic agent. In some embodiments, the chemotherapeutic agent is selected from cisplatin, carboplatin, etoposide, oxaliplatin, 5-fluorouracil, floxuridine, capecitabine, gemcitabine, mitomycin, methotrexate, vinblastine, cyclophosphamide, dacarbazine, albumin-bound paclitaxel (abraxane), ifosfamide, topotecan, irinotecan, docetaxel, temozolomide, paclitaxel, doxorubicin, camptothecin, or a combination thereof. In some embodiments, the chemotherapeutic agent is doxorubicin. In some embodiments, the chemotherapeutic agent is camptothecin. In some embodiments, the chemotherapeutic agent is cisplatin. In some embodiments, Compound 1 described herein, or a pharmaceutically acceptable salt or morphological form thereof, is administered to a subject within 6 hours or less of the administration of the chemotherapeutic agent. In some embodiments, Compound 1 described herein, or a pharmaceutically acceptable salt or morphological form thereof, is administered to a subject within 3 hours or less of the administration of the chemotherapeutic agent. In some embodiments, Compound 1 described herein, or a pharmaceutically acceptable salt or morphological form thereof, is administered to a subject at least once a day, and wherein an effective amount of the chemotherapeutic agent is administered according to its prescribed label or standard of care. In some embodiments, Compound 1 described herein, or a pharmaceutically acceptable salt or morphological form thereof, is administered to a subject at least twice a day, and wherein an effective amount of the chemotherapeutic agent is administered according to its prescribed label or standard of care.

[0056] In another aspect, disclosed herein is a method for treating a subject with a CDK4 / 6 inhibitor-resistant cancer, comprising administering to the subject an effective amount of Compound 1 as described herein, or a pharmaceutically acceptable salt or morphological form thereof; and administering to the subject an effective amount of a CDK4 / 6 inhibitor. In certain embodiments, the CDK4 / 6 inhibitor-resistant cancer has acquired resistance to the CDK4 / 6 inhibitor. In certain embodiments, the CDK4 / 6 inhibitor-resistant cancer progresses after a previous regimen including a CDK4 / 6 inhibitor. In some embodiments, the CDK4 / 6 inhibitor of the previous regimen is selected from palbociclib, ribociclib, abemaciclib, traxilib, leloxilib, SHR6390 (dalpiciclib), or a combination thereof. In some embodiments, the CDK4 / 6 inhibitor of the previous regimen is selected from BPI-16350, narazaciclib (ON-123300), FLX-925 (AMG-925), UCT-03-008, GLR2007, birociclib (XZP-3287), LY5219, PF-07220060 or ON-123300. In some embodiments, the CDK4 / 6 inhibitor is palbociclib. In some embodiments, the CDK4 / 6 inhibitor is ribociclib. In some embodiments, the CDK4 / 6 inhibitor is abemaciclib. In some embodiments, the CDK4 / 6 inhibitor-resistant cancer is retinoblastoma (Rb) protein positive (Rb+). In some embodiments, the CDK4 / 6 inhibitor-resistant cancer has intrinsic CDK4 / 6 inhibitor resistance. In some embodiments, the CDK4 / 6 inhibitor cancer is retinoblastoma (Rb) protein deficient (Rb-). In some embodiments, the CDK4 / 6 inhibitor resistant cancer is selected from breast cancer, lung cancer, uterine cancer, endometrial cancer, ovarian cancer, prostate cancer, bladder cancer, testicular cancer, glioblastoma, head and / or neck cancer or prostate cancer. In some embodiments, the CDK4 / 6 inhibitor resistant cancer is breast cancer. In some embodiments, the CDK4 / 6 inhibitor resistant breast cancer is estrogen receptor positive (ER+) breast cancer. In certain embodiments, the CDK4 / 6 inhibitor resistant cancer is hormone receptor positive (HR+) breast cancer. In certain embodiments, the CDK4 / 6 inhibitor resistant cancer is cyclin E amplification or overexpression. In some embodiments, Compound 1 described herein or a pharmaceutically acceptable salt or morphological form thereof is administered to a subject at least once a day, and wherein an effective amount of a CDK4 / 6 inhibitor is administered according to its prescribed label. In some embodiments, Compound 1 or a pharmaceutically acceptable salt thereof is administered to a subject at least twice a day, and wherein an effective amount of a CDK4 / 6 inhibitor is administered according to its prescribed label.In some embodiments, the CDK4 / 6 inhibitor-resistant cancer is also resistant to endocrine therapy or estrogen inhibitors (eg, SERDs).

[0057] In another aspect, disclosed herein is a method for treating a subject with CDK4 / 6 inhibitor-resistant estrogen receptor-positive (ER+) breast cancer, comprising administering to the subject an effective amount of Compound 1 as described herein, or a pharmaceutically acceptable salt or morphological form thereof; and administering to the subject an effective amount of a CDK4 / 6 inhibitor. In some embodiments, the CDK4 / 6 inhibitor-resistant ER+ breast cancer is negative for tyrosine kinase-type cell surface receptor HER2. In some embodiments, Compound 1 as described herein, or a pharmaceutically acceptable salt or morphological form thereof, is administered to the subject at least once a day, and wherein an effective amount of a CDK4 / 6 inhibitor is administered according to its prescribed label or standard of care. In some embodiments, Compound 1 as described herein, or a pharmaceutically acceptable salt or morphological form thereof, is administered to the subject at least twice a day, and wherein an effective amount of a CDK4 / 6 inhibitor is administered according to its prescribed label or standard of care.

[0058] In certain embodiments, the number of events of adverse events caused by treatment is reduced compared to the number of events of adverse events predicted in subjects receiving treatment without Compound I. In certain embodiments, the number of events of laboratory abnormalities caused by treatment is reduced compared to the number of events of laboratory abnormalities predicted in subjects receiving treatment without Compound I. In certain embodiments, treatment results in improved overall survival (OS) compared to subjects receiving treatment without Compound I. In certain embodiments, treatment results in improved overall response rate (ORR) compared to subjects receiving treatment without Compound I. In certain embodiments, treatment results in improved disease control rate (DCR) compared to subjects receiving treatment without Compound I. In certain embodiments, treatment results in improved progression-free survival (PFS). In certain embodiments, treatment results in improved duration of response (DOR) compared to subjects receiving treatment without Compound I. In certain embodiments, treatment results in prolonged time to progression (TTP) compared to subjects receiving treatment without Compound I.

[0059] Among other aspects, favorable morphological forms of Compound 1 are described by improved solubility, stability, crystallinity, flowability, and / or purity. Over twenty morphological forms of Compound 1 and various salts of Compound 1 were discovered and tested under various solvent conditions and temperatures, with the goal of identifying eight favorable salts. Salts of Compound 1 were prepared using counterions selected from sulfuric acid, methanesulfonic acid, maleic acid, phosphoric acid, L-(+)-tartaric acid, citric acid, hydrobromic acid, and benzenesulfonic acid. Several of these salts have various morphological forms, which are described herein.

[0060] Compound 1 free base Pattern 1 is a highly crystalline and stable morphological form that can be used to treat CDK2-mediated disorders or to prepare amorphous forms of Compound 1 (e.g., dispersion by spray drying) to treat CDK2-mediated disorders.

[0061] Compound 1 HCl Pattern 1 is a particularly stable, crystalline morphological form of Compound 1 that, unlike other salts, is highly pure and has improved 7-day indicative stability at 40°C / 75% RH, 7-day form stability at 80°C, and only moderate hygroscopicity. Compound 1 HCl Pattern 1 can be used to treat CDK2-mediated disorders or to manufacture an amorphous form of Compound 1 or a pharmaceutically acceptable salt thereof (e.g., dispersion by spray drying) for use in treating CDK2-mediated disorders.

[0062] In certain aspects, a pharmaceutical composition is provided comprising Compound 1 or a pharmaceutically acceptable salt thereof or a morphological form of Compound 1 or a pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable excipients. In certain embodiments, the pharmaceutical composition comprises polyethylene glycol (PEG). In certain embodiments, the pharmaceutical composition comprises hydroxypropyl methylcellulose.

[0063] In other aspects, pharmaceutical compositions are provided, comprising amorphous Compound 1 or a pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable excipients, wherein the pharmaceutical composition is made from a morphological form of Compound 1 or a pharmaceutically acceptable salt thereof as described herein. In certain embodiments, the prepared pharmaceutical composition includes polyethylene glycol (PEG). In certain embodiments, the prepared pharmaceutical composition includes hydroxypropyl methylcellulose. BRIEF DESCRIPTION OF THE DRAWINGS

[0064] As shown in the figure, PF-07104091 is

[0065]

[0066] Figure 1A-B is a set of tables showing that Compound I selectively inhibits CDK2 / E to a greater extent than Pfizer CDK2 inhibitor compound PF-07104091. The experimental conditions for these experiments are described in Example 1. Figure 1A Table 1 shows the biochemical profiles of novel and potent CDK2 inhibitors against a panel of CDKs and their respective binding partners. The assay was performed in a 12-point dose-response format. Results are shown as nanomolar IC values ​​for each target. 50 concentration. Pfizer's selective CDK2 inhibitor PF-07104091 was listed as a reference compound. ND, not determined. The compound showed preferential binding to CDK2 / E over CDK1 / B and CDK9 / T. Furthermore, Compound I was four-fold more potent against CDK2 / E compared to PF-07104091. Figure 1B TABLE 1 is a table illustrating the residence time, i.e., the lifetime of compound-target interactions with several CDK / cyclin complex partners in TR-FRET binding assays, of Compound 1. Compound 1 complexes longer with CDK2 / E and CDK2 / A than with CDK1 / B and CDK9 / T.

[0067] Figure 2A-C Compound I was shown to exhibit strong intracellular selectivity for CDK2 / E and limited activity against CDK1 / B or CDK9 / T. The experimental conditions for these experiments are described in Example 1. Figure 2A is a grouped line graph showing the normalized percent bioluminescence resonance energy transfer (NanoBRET) response (on the y-axis) and the log (M) concentration of Compound I (on the x-axis). NanoBRET target-engaged intracellular kinase assay results show potent inhibition of CDK2 / E (circles) by Compound I, but no inhibition of CDK1 / B1 (squares) or CDK9 / T1 (triangles). Experiments were performed in HEK-293 cells transiently expressing CDK2-Nluc, CDK1-Nluc, or CDK9-Nluc fusions. Figure 2B Compound I showed intracellular inhibition IC against CDK2 / E, CDK1 / B and CDK9 / T 50 Table of values. IC 50 Values ​​are also expressed as the IC observed for compound 1 against CDK2 / E 50 Fold change in value. Figure 2C Compounds are shown to be active against CDK2 / E, CDK1 / B, CDK2 / A, CDK4 / D1, CDK6 / D3, and CDK9 / T in the InanoBRET target engagement intracellular kinase assay IC 50 Table of values. IC 50 Values ​​are also expressed as the IC observed for compound 1 against CDK2 / E 50Fold change of IC 50 , half-maximal inhibitor concentration.

[0068] Figure 3 The bar graph shows that Compound I exhibits limited cytotoxicity in normal H68 human fibroblasts. The experimental conditions for these experiments are shown in Example 2. For different CDK inhibitors (including dinaciclib, palbociclib and Compound I) (on the x-axis), the IC values ​​for each treatment of Hs68 cells (which are normal human fibroblasts) were calculated. 50 The values ​​are shown on the y-axis. Limited cytotoxic activity of compound I was observed in Hs68 cells. IC 50 , half-maximal inhibitor concentration.

[0069] Figure 4 It was shown that compound I alone or in combination with cisplatin caused little cell cycle change in normal H68 human fibroblasts. The experimental conditions for these experiments are shown in Example 2. Figure 4 is a bar graph showing the percentage of Hs68 cells (indicated on the y-axis) measured in different cell cycle states, including DNA content <2N, G0 / G1 phase, S phase, or G2 / M phase, for different treatment conditions (indicated on the x-axis).

[0070] Figure 5A-C Compound I was shown to not induce caspase 3 / 7 activation in normal human fibroblast Hs68 cells during long-term administration. The experimental methods for these experiments are described in Example 2. Figure 5A is a grouped line graph showing the cell ratio (on the y-axis) of cells treated with staurosporine (circles), Compound I (squares), and PF-07104091 (triangles) at various molar concentrations (on the x-axis) for 24 hours compared to control values. Figure 5B is a grouped line graph showing the cell ratio (on the y-axis) of cells treated with staurosporine (circles), Compound I (squares), and PF-07104091 (triangles) at various molar concentrations (on the x-axis) for 48 hours compared to control values. Figure 5C is a grouped line graph showing the cell ratio (on the y-axis) of cells treated with staurosporine (circles), Compound I (squares), and PF-07104091 (triangles) at various molar concentrations (on the x-axis) for 72 hours compared to control values.

[0071] Figure 6 It was shown that Compound I alone or in combination with cisplatin did not induce γ-H2AX formation in normal Hs68 human fibroblasts. The experimental conditions for these experiments are shown in Example 2. Figure 6is a bar graph showing the percentage of cells positive for γ-H2AX labeling (on the y-axis) for different treatment conditions, including administration of cisplatin and / or Compound I to Hs68 fibroblasts. The symbol ">" indicates sequential, staggered co-administration of the indicated molecules. The symbol "+" indicates simultaneous administration of both molecules.

[0072] Figure 7A -D shows the generation and validation of the palbociclib-resistant breast cancer model MCF7 cells. The experimental methods for these experiments are shown in Example 3. Figure 7A Shown are pictures of cultured cells depicting similar morphology and growth of breast cancer model MCF7 parental cells (MCF7 Parental) and cells cultured for four months in the presence of Palbociclib (MCF7 Palbo-R). The MCF7 cell line is a well-characterized model system for estrogen receptor-positive (ER+) breast cancer. Figure 7B Bar graph showing the Log2 fold change (on the x-axis) of the indicated genes of interest (on the y-axis) (*p-value < 0.05). MCF7 Palbo-R cells exhibit upregulation of CDK6, CCNE1, and CCNE2 transcripts, a hallmark of acquired resistance to CDK4 / 6 inhibitors. Figure 7C Western blot of retinoblastoma protein (Rb), cyclin E, and input loading control GAPDH in palbociclib-sensitive (Palbo-S) MCF7 parental control cells (left) and MCF7 Palbo-R daughter cells. Figure 7D Figure 2 is a bar graph showing quantitative immunoblot signals (indicated on the y-axis) of Rb and cyclin E proteins (shown on the x-axis) normalized to the GAPDH loading control in MCF7 Palbo-S parental (open squares) and MCF7 Palbo-R daughter cells (black squares). Cyclin E levels are elevated in MCF7 Palbo-R cells.

[0073] Figure 8A Compound I showed that Palbociclib-resistant (Palbo-R) breast cancer model MCF7 cells were highly sensitive to a combination treatment comprising administration of Compound I and Palbociclib. The experimental methods for these experiments are described in Example 3. Figure 8A is a bar graph showing the IC values ​​of cell proliferation in nanomolar (nM) 50 Values ​​(on the y-axis), and different treatment regimens (on the x-axis). MCF7 Palbo-R cells were extremely sensitive to combined CDK2 and CDK4 / 6 inhibition comprising administration of Compound I and palbociclib compared to either agent alone. Figure 8Bis a Western blot showing the levels of phosphorylated residues 807 and 811 of the retinoblastoma protein (pRb 807 / 811) and β-tubulin as an input loading control in the absence of PD-0332991 (palbociclib) or at 1 uM palbociclib administered in combination with increasing concentrations of Compound I. Compound I potently inhibits Rb phosphorylation in MCF7 Palbo-R cells when combined with PD-0332991 (palbociclib). 50 , half-maximal inhibitor concentration. Figure 8C is a line graph showing the ratio of viable MCF7 PDRCL5-1 PD-free cells to control (on the y-axis) and the molar concentration of Compound I (on the x-axis). MCF7PDRC15-1 cells were grown in the presence of 1 uM palbociclib for maintenance. Figure 8D is a line graph showing the ratio of viable MCF7PDRCL5-1 PD-free cells to control (on the y-axis) and the molar concentration of Compound I (on the x-axis). Figure 8F -I is a bar graph illustrating the mean colony area and percent size for different treatment conditions including: control (black bars); 300 nM palbociclib (white bars); palbociclib in combination with 300 nM Compound I (vertical bar graph); 300 nM Compound I (diagonal bar graph); and palbociclib followed by palbociclib in combination with Compound I (checkerboard bar graph). Figure 8E Images of culture plates containing T47D human breast cancer cell colonies at 2, 3, 5, or 8 weeks under different treatment conditions. Figure 8F is a bar graph showing the mean colony size (on the y-axis) for the different treatment conditions compared to the control (on the x-axis) at 2, 3, 5, or 8 weeks as indicated. Figure 8G is a bar graph showing the percentage of colony area (on the y-axis) for the different treatment conditions compared to the control (on the x-axis) at 2, 3, 5, or 8 weeks as indicated. Figure 8H are bar graphs showing the average colony size (on the y-axis) for the different treatment conditions at week 2, 3, 5, or 8 (on the x-axis) as indicated. Figure 8I is a bar graph showing the percentage of colony area (on the y-axis) for the different treatment conditions at the indicated weeks 2, 3, 5, or 8 (on the x-axis). The symbol ">" indicates sequential, staggered co-administration of the indicated molecules. The symbol "+" indicates simultaneous administration of two molecules.

[0074] Figure 9A -B shows that compound I potently arrests palbociclib-resistant (Palbo-R) breast cancer model MCF7 cells in the G0 / G1 phase. The experimental methods for these experiments are described in Example 3. Figure 9Ais a bar graph showing the percentage of MCF7 parental cells in different cell stages (on the y-axis) for different concentrations of Compound I (on the x-axis) as indicated. Figure 9B is a bar graph showing the percentage of Palbo-R MCF7 daughter cells (on the y-axis) in different cell stages for different concentrations of Compound I (on the x-axis) as indicated.

[0075] Figure 10A -E shows that compound I preferentially inhibits several independent CCNEs 高 Expression of ovarian cancer model cell lines. The experimental methods for these experiments are shown in Example 4. Figure 10A is a bar graph showing the percentage of tumors that exhibit increased expression and / or activation of cyclin E1 (on the y-axis) compared to controls for the various cancer types indicated (on the x-axis). UCS: uterine carcinosarcoma; OV: ovarian serous cystadenocarcinoma; SARC: sarcoma; LUSC: lung squamous cell carcinoma; STAD: gastric adenocarcinoma; UCEC: uterine corpus endometrial carcinoma; BLCA: bladder urothelial carcinoma; LUAD: lung adenocarcinoma; ESCA: esophageal carcinoma; ACC: adrenocortical carcinoma; BRCA: invasive breast carcinoma; PAAD: pancreatic adenocarcinoma; LIHC: hepatocellular carcinoma of the liver; CESC: cervical squamous cell carcinoma and endocervical adenocarcinoma; MESO: mesothelioma; HNSC: head and neck squamous cell carcinoma; COAD: colon adenocarcinoma; SKCM: cutaneous melanoma; GBM: glioblastoma multiforme; KICH: kidney chromophobe. Figure 10B is a bar graph showing the IC values ​​for cell proliferation for the different ovarian model cancer cell lines (on the x-axis) as shown. 50 The CCNE1 expression status of each cell line (amplified, increased, not amplified) is indicated above the graph. Figure 10C is a bar graph showing the percentage of ovarian OVCAR-3 cells in the G0-G1 phase, S phase, or G2-M phase (on the y-axis) at different concentrations of Compound I (on the x-axis). Figure 10D is a bar graph showing the percentage of ovarian COV318 cells in the G0-G1 phase, S phase, or G2-M phase (on the y-axis) at different concentrations of Compound I (on the x-axis). Figure 10E (C) is a Western blot image showing the levels of phosphorylated threonine residue 821 of the retinoblastoma protein (pRb T821) in OVCAR-3 or COV318 cells administered vehicle (C) or increasing concentrations (30 nM, 100 nM, 300 nM, 10 mM) of Compound I. The blot was further labeled for CDK2 and β-tubulin as a loading control.

[0076] Figure 11A-B shows that Compound I reduces phosphorylated retinoblastoma (pRb) in ovarian OVCAR3 cells in a dose- and time-dependent manner. The experimental methods for these experiments are described in Example 4. Figure 11A Figure 1 is a Western blot showing the levels of cell cycle inhibitory proteins (p130, p27, p16), retinoblastoma protein (Rb), markers of phosphorylated Rb protein (pRb807 / 811, pRb T821), cyclin-dependent kinase 2 (CDK2), and cell cycle proteins (CCNE1, CCNE2, CCNA2) in OVCAR-3 cells administered vehicle (C) or increasing concentrations (30 nM, 100 nM, 300 nM, 10 mM) of Compound I. β-actin was included as an input loading control. Figure 11B is a Western blot showing the levels of pRb at residues 807 and 811 and the cell cycle inhibitory protein p27 following increasing lengths of incubation of OVCAR-3 cells with Compound I. β-actin was included as an input loading control.

[0077] Figure 12A -B shows that compound I reduces phosphorylated retinoblastoma (pRb) in ovarian cancer model cells in a dose-dependent manner. The experimental conditions for these experiments are shown in Example 4. Figure 12A Compound I was shown to reduce phosphorylated retinoblastoma (pRb) in the ovarian cancer models FUOV1 and Kuramochi cells in a dose-dependent manner. The experimental conditions for these experiments are described in Example 4. Figure 12A is a Western blot showing the levels of cell cycle inhibitory proteins (p130, p27, p16), retinoblastoma protein (Rb), markers of phosphorylated Rb protein (pRb807 / 811, pRb T821, pRbS780), cyclin-dependent kinase 2 (CDK2), cyclins (CCNE1, CCNE2, CCNA2) in FUOV1 cells administered vehicle (C) or increasing concentrations (30 nM, 100 nM, 300 nM, 1000 nM) of compound I. Figure 12B is a Western blot showing the levels of retinoblastoma protein (Rb), markers of phosphorylated Rb protein (pRb807 / 811, pRbT821), and cyclin A2 (CCNA2) in Kuramochi cells administered vehicle (0) or increasing concentrations (30 nM, 100 nM, 300 nM, 1000 nM) of compound I.

[0078] Figure 13A-CShown are the cell cycle changes observed over time in ovarian cancer model OVCAR-3 cells treated with Compound I or the reference CDK2 inhibitor Pfizer compound PF-07104091. The experimental methods for these experiments are described in Example 4. Figure 13A is a composite bar graph showing the percentage of OVCAR-3 cells (represented on the x-axis) measured in different cell cycle states, including G1, S, or G2 / M phases, for different treatment conditions (represented on the right y-axis) and for different lengths of time (24 or 48 hours of treatment) (represented on the left y-axis). Figure 13B is a composite bar graph showing the percentage of OVCAR-3 cells (indicated on the bottom x-axis) measured in different cell cycle states, including G1, S, or G2 / M phases, for different concentrations (100 nM, 300 nM, or 600 nM) (listed on the top x-axis) for different treatment conditions (indicated on the right y-axis) for different lengths of time (24 or 48 hours treatment) (illustrated on the left y-axis). Figure 13C is a composite bar graph showing the percentage of OVCAR-3 cells (indicated on the bottom x-axis) measured in different cell cycle states, including G1, S, or G2 / M phases, for different treatment conditions (indicated on the right y-axis) for different lengths of time (24 or 48 hours of treatment) (indicated on the left y-axis).

[0079] Figure 14A -B shows the cell cycle changes observed in ovarian cancer model OVCAR-3 cells after increasing lengths of time following washout of Compound I. The experimental conditions for these experiments are described in Example 4. Figure 14A is a flow chart showing the sequence of experiments performed. Figure 14B It is a bar graph showing the percentage of OVCAR-3 cells (expressed on the y-axis) measured at different cell cycle states (including DNA content <2N (black bars), G0 / G1 phase (white bars), S phase (dark dotted line) or G2 / M phase (light dotted line)) for different treatment conditions (expressed on the x-axis). Compound I was applied at 300 nM for 0, 6, 18, 24, 30 or 48 hours.

[0080] Figures 15A-15D EdU-gated APC histograms are shown between 1 hour and 48 hours of treatment. Treatment conditions included DMSO control, 300 nM Compound I, or 300 nM PF-07104091. The experimental procedures for these experiments are described in Example 4. Figure 15A Is a histogram showing the cell count (on the y-axis) at different cell cycle stages (including G1, S and G2 phases) represented by the staining signal amplitude (shown on the x-axis). The graph shows EdU tracking from 1h to 48h. Figure 15B15 is a histogram showing the cell count (on the y-axis) at different cell cycle stages (including G1, S, and G2), as indicated by the staining signal amplitude (shown on the x-axis). The graph shows EdU tracking from 6 h to 48 h. FIG. 15C is a histogram showing the cell count (on the y-axis) at different cell cycle stages (including G1, S, and G2), as indicated by the staining signal amplitude (shown on the x-axis). The graph shows EdU tracking from 24 h to 48 h. Figure 15D Is a histogram showing the cell count (on the y-axis) at different cell cycle stages (including G1, S and G2 phases) as represented by the staining signal amplitude (shown on the x-axis). The graph shows data collected at 48h (no chase).

[0081] Figure 16A -B Display in CCNE 高 In ovarian cancer models Kuramochi and FUOV1 cells, Compound I was more cytotoxic than the reference CDK2 inhibitor Pfizer compound PF-07104091. The experimental methods for these experiments are shown in Example 4. Figure 16A is a grouped line graph showing the cell ratio (on the y-axis) to the control value at various concentrations of Compound I (circles) and Palbociclib (squares) (on the x-axis) in the ovarian cancer cell model Kuramochi cells. Figure 16B is a grouped line graph showing the cell ratio (on the y-axis) to the control value at different concentrations of Compound I (circles) and the reference CDK2 inhibitor Pfizer compound PF-07104091 (squares) (on the x-axis) in ovarian cancer cell model FUOV1 cells. IC values ​​of cell proliferation of Compound I and PF-07104091 50 The values ​​(in molar (M) units) are listed below the graph.

[0082] Figure 17A -B shows that compound I inhibits CCNE more potently than the reference CDK2 inhibitor Pfizer compound PF-07104091 高 Ovarian cancer model OVCAR-3 cells. The experimental conditions for these experiments are shown in Example 4. Figure 17A is a grouped line graph showing the ratio of OVCAR-3 cell number to control (on the y-axis) and the molar concentration of Compound I (squares) or PF-07104091 (triangles) (on the x-axis). Figure 17B is a table listing the IC values ​​of Compound I and PF-07104091 for OVCAR-3 cell proliferation in nanomolar (nM) units. 50 value.

[0083] Figure 18 Compound I was shown to be effective in reducing tumor size as a single agent.高 Tumor size (mm) during 28 days of administration (indicated on the x-axis) in the ovarian OVCAR-3 tumor xenograft mouse model 3 ) (indicated on the y-axis). The experimental conditions for these experiments are described in Example 4. OVCAR-3 xenograft tumor fragments were harvested from host animals and implanted into immunodeficient mice (CR1:NU(NCr)-Fox1 nu ). QD, once daily; BID, twice daily; mpk, mg / kg.

[0084] Figure 19A -B Display in CCNE 高 In vivo comparison of the tumor efficacy and survival benefit of Compound 1 relative to the reference CDK2 inhibitor Pfizer compound PF-07104091 in the ovarian OVCAR-3 tumor xenograft mouse model. OVCAR-3 xenograft tumor fragments were harvested from host animals and implanted into immunodeficient mice (CR1:NU(NCr)-Fox1 nu The experimental conditions of these experiments are shown in Example 4. Figure 19A is a grouped line graph showing tumor volume (mm 3 ) (on the y-axis) and treatment days (shown on the x-axis). Treatment conditions included: vehicle (circles); Compound I 100 mpk BID (open squares); and PF-07104091 100 mpk BID (triangles). Figure 19B is a survival line graph showing the percentage of mice that survived on the days of treatment (indicated on the x-axis). Treatment conditions include: vehicle (dashed line); Compound I 100 mpk BID (solid line); and PF-07104091 100 mpk BID (checkered line).

[0085] Figure 20 Compound I was shown to reduce phosphorylated retinoblastoma (pRb) in a dose-dependent manner in MKN1 gastric cancer model cells. The experimental conditions for these experiments are described in Example 4. Figure 20 Figure 1 is a Western blot showing the levels of cell cycle inhibitory proteins (p130, p27, p21, p16), retinoblastoma protein (Rb), markers of phosphorylated Rb protein (pRb807 / 811, pRbT821), cyclin-dependent kinase 2 (CDK2), and cell cycle proteins (CCNE1, CCNE2, CCNA2) in MKN1 cells administered vehicle (C) or increasing concentrations (30 nM, 100 nM, 300 nM, 10 mM) of Compound I. β-actin was included as an input loading control.

[0086] Figure 21A-B shows the cell cycle changes observed in gastric cancer model MKN1 cells after increasing lengths of time following washout of Compound I. The experimental conditions for these experiments are described in Example 4. Figure 21A is a flow chart showing the sequence of experiments performed. Figure 21B Is a bar graph showing the percentage of MKN1 cells measured in different cell cycle states, including DNA content <2N (black bars), G0 / G1 phase (white bars), S phase (dark dashed bar), or G2 / M phase (light dashed bar) for different treatment conditions (indicated on the x-axis). Compound I was applied at 300 nM for 0, 6, 18, 24, 30, or 48 hours.

[0087] Figure 22A -E shows that compound I potently inhibits several independent small cell lung cancer (SCLC) model cell lines. The experimental methods for these experiments are shown in Example 5. Figure 22A is a bar graph showing the IC values ​​of cell proliferation after administration of palbociclib or compound I to SCLC models H526, SHP77, NCIH82, and NCIH69 cells (indicated on the x-axis). 50 value. Figure 22B is a grouped line graph showing the ratio of H526 cell number to control (on the y-axis) and the molar (M) treatment concentration of Compound I (squares) or PF-07104091 (triangles) (on the x-axis). Figure 22C is a table listing the IC values ​​of Compound I and PF-07104091 for H526 cell proliferation in nanomolar (nM) units. 50 value. Figure 22D is a grouped line graph showing the ratio of caspase 3 / 7 activation to control in H526 cells (on the y-axis) and the molar (M) concentration of staurosporine (circles), compound I (squares), or PF-07104091 (triangles) at 72 hours (on the x-axis). The IC value of caspase 3 / 7 activation for each administered compound is listed below the graph. 50 value. Figure 22E is a table listing the caspase 3 / 7 activation IC values ​​of Compound I and PF-07104091 in nanomolar (nM) values. 50 Concentration value.

[0088] Figure 23 Shown are cell cycle changes exhibited by H526 cells subjected to nocodazole synchronization and release in the presence or absence of Compound I. The experimental conditions for these experiments are described in Example 5. Figure 23Is a bar graph showing the percentage of H526 cells measured at different cell cycle states (including DNA content <2N (black bars), G0 / G1 phase (white bars), S phase (dark dashed bar) or G2 / M phase (light dashed bar) for different treatment conditions (represented on the x-axis). Compound I was applied at 300 nM for 6, 12, 24, 30 or 48 hours.

[0089] Figure 24 The changes in the H526 cell cycle over time after incubation with Compound I or PF-07104091 are shown. The experimental conditions for these experiments are described in Example 5. Figure 24 is a composite bar graph showing the percentage of H526 cells (represented on the x-axis) measured in different cell cycle states, including G1, S, G2, or M phase, for different treatment conditions (represented on the right y-axis) for different lengths of time (1, 6, 24, or 48 hours of treatment) (represented on the left y-axis).

[0090] Figure 25 Compound I was shown to induce DNA damage in H526 cells, a small cell lung cancer (SCLC) model, and the DNA damage was even greater when Compound I was used in combination with cisplatin. The experimental conditions for these experiments are shown in Example 5. Figure 25 is a bar graph showing the percentage of cells positively immunolabeled with the antibody anti-γ-H2AX (on the y-axis) for different treatment conditions (listed on the x-axis). The symbol ">" indicates sequential, staggered co-administration of the indicated molecules. The symbol "+" indicates simultaneous administration of both molecules.

[0091] Figure 26A-C Compound I was shown to increase cyclin E (CCNE1 / CCNE2) levels and trigger an increase in DNA damage markers in small cell lung cancer (SCLC) model H69 and H526 cells in a dose-dependent manner. The experimental methods for these experiments are shown in Example 5. Figure 26A Figure 1 is a Western blot showing the levels of cell cycle inhibitors (p130, p27, p21, p16), retinoblastoma protein (Rb), and cyclins (CCNE1, CCNE2, CCNA2) in H69 cells, a small cell lung cancer (SCLC) model, administered vehicle (control) or increasing concentrations (30 nM, 100 nM, 300 nM, 10 mM) of Compound I. β-actin was included as an input loading control. Figure 26BFigure 1 is a Western blot showing the levels of cell cycle inhibitors (p130, p27, p21, p16), cyclin-dependent kinase 2 (CDK2), and cyclins (CCNE1, CCNE2, CCNA2) in H526 cells, a small cell lung cancer (SCLC) model, administered vehicle (control) or increasing concentrations (30 nM, 100 nM, 300 nM, 10 mM) of Compound I. β-actin was included as an input loading control. Figure 29C Figure 1 is a Western blot showing the levels of cell cycle inhibitors (p130, p27, p21, p16), cyclin-dependent kinase 2 (CDK2), and cyclins (CCNE1, CCNE2, CCNA2) in Hs68 cells, a small cell lung cancer (SCLC) model, administered vehicle (control) or increasing concentrations (30 nM, 100 nM, 300 nM, 10 mM) of Compound I. β-actin was included as an input loading control.

[0092] Figure 27A -D shows that compound I activates caspase 3 / 7 in a time-dependent manner in small cell lung cancer (SCLC) model H526 cells. The experimental methods for these experiments are shown in Example 5. Figure 27A is a grouped line graph showing the ratio of caspase 3 / 7 activation to control in H526 cells (on the y-axis) and the molar (M) concentration of staurosporine (circles), Compound I (squares), or PF-07104091 (triangles) at 24 hours (on the x-axis). The IC value for caspase 3 / 7 activation for each compound administered is listed below the graph. 50 value. Figure 27B is a grouped line graph showing the ratio of caspase 3 / 7 activation to control in H526 cells (y-axis) and the molar (M) concentration of staurosporine (circles), compound I (squares), or PF-07104091 (triangles) at 48 hours (on the x-axis). Listed below the graph is the IC value for caspase 3 / 7 activation for each compound administered. 50 value. Figure 27C is a grouped line graph showing the ratio of caspase 3 / 7 activation to control (on the y-axis) in H526 cells and the molar (M) concentration of staurosporine (circles), compound 1 (squares), or PF-07104091 (triangles) at 72 hours (on the x-axis). Listed below the graph are the IC50 values ​​for caspase 3 / 7 activation for each compound administered. Figure 27D is a table listing the caspase 3 / 7 activation IC values ​​for each compound administered in nanomolar (nM) units. 50 value.

[0093] Figure 28A-CShown are H526 cell cycle changes and caspase 3 / 7 activation following co-administration of Compound I and cisplatin. The symbol ">" indicates sequential, staggered co-administration of the indicated molecules. The symbol "+" indicates simultaneous administration of both molecules. The experimental procedures for these experiments are described in Example 5. Figure 28A is a flow chart showing the experimental sequence. Figure 28B is a bar graph showing the percentage of cells in different cell cycle phases (indicated on the y-axis), including DNA content <2N, G0 / G1 phase, S phase, or G2 / M phase, for different treatment conditions (indicated on the x-axis). Figure 28C is a bar graph showing the ratio of yH2AX to control levels (indicated on the y-axis) for different treatment conditions (indicated on the x-axis).

[0094] Figure 29A-C Compound I was shown to synergize with doxorubicin to inhibit certain small cell lung cancer (SCLC) model cells. The experimental methods for these experiments are shown in Example 5. Figure 29A is a grouped line graph showing the ratio of H526 cell number to control (on the y-axis) and the molar (M) treatment concentration (on the x-axis) of Compound I (squares), doxorubicin (triangles), or the combination of Compound I and doxorubicin (diamonds). Figure 29B is a grouped line graph showing the ratio of H69 cell number to control (on the y-axis) and the molar (M) treatment concentration (on the x-axis) of Compound I (squares), doxorubicin (triangles), or the combination of Compound I and doxorubicin (diamonds). Figure 29C is a grouped line graph showing the ratio of SHP77 cell number to control (on the y-axis) and the molar (M) treatment concentration (on the x-axis) of Compound I (squares), doxorubicin (triangles), or the combination of Compound I and doxorubicin (diamonds).

[0095] Figure 30A-C Compound I was shown to synergize with camptothecin to inhibit the growth of small cell lung cancer (SCLC) models H526, H69, and SHP77 cells. The experimental methods for these experiments are described in Example 5. Figure 30A is a grouped line graph showing the ratio of H526 cell number to control (on the y-axis) and the molar (M) treatment concentration (on the x-axis) of Compound I (squares), camptothecin (triangles), or the combination of Compound I and camptothecin (inverted triangles). Figure 30B is a grouped line graph showing the ratio of H69 cell number to control (on the y-axis) and the molar (M) treatment concentration (on the x-axis) of Compound I (squares), camptothecin (triangles), or the combination of Compound I and camptothecin (inverted triangles). Figure 30Cis a grouped line graph showing the ratio of SHP77 cell number to control (on the y-axis) and the molar (M) treatment concentration (on the x-axis) of Compound I (squares), camptothecin (triangles), or the combination of Compound I and camptothecin (inverted triangles).

[0096] Figure 31A -G shows that compound I has in vivo efficacy in a mouse hollow fiber assay including three tumor cell lines, including OVCAR-3 (ovary), MKN-1 (stomach), and HCC-1569 (breast). Mice were administered in different treatment groups: Group 1 (G1) was administered with vehicle at 10 ml / kg twice a day; Group 2 (G2) was administered with compound I at 75 mg / kg, 10 ml / kg twice a day; Group 3 (G3) was administered with compound I at 100 mg / kg, 10 ml / kg twice a day; Group 4 (G4) was administered with compound I at 150 mg / kg, 10 ml / kg twice a day. The experimental methods for these experiments are shown in Example 6. Figure 31A : is a grouped line graph showing the average animal weight (on the y-axis) in grams (g) during the treatment regimen including the administration of different concentrations of Compound I. Female NMRI nude mice were implanted subcutaneously and intraperitoneally with hollow fibers loaded with HCC-1569, MKN1, and OVCAR3 tumor cells at day 0. Data are shown as mean ± SEM. The number of animals surviving at day 0 (implantation) and day 16 (necropsy) is shown in brackets in the legend. Figure 31B-C Compound I is shown to induce changes in cancer cell viability in mice implanted with HCC-1569 cells, a breast cancer tumor model. Hollow fibers loaded with HCC-1569 cells were implanted subcutaneously (left side of the figure) and intraperitoneally (right side of the figure) into female NMRI nude mice on day 0. Hollow fibers were collected during necropsy on day 16 and analyzed using the CellTiter Glo assay. Figure 31B Shown are the average photons / second captured by the CellTiter-Glo reagent from the HCC-1569 hollow fibers on day 16 (on the y-axis) and for the different treatment groups (on the x-axis). Figure 31C Individual replicate photon / second values ​​(on the y-axis) for the different treatment groups (on the x-axis) are shown. Error bars represent the interquartile range. Figure 31D -E shows the changes in cancer cell viability induced by Compound I in mice implanted with MKN-1 cells, a gastric cancer tumor model. On day 0, hollow fibers loaded with MKN-1 cells were implanted subcutaneously (left panel) and intraperitoneally (right panel) into female NMRI nude mice. Hollow fibers were harvested during necropsy on day 16 and analyzed using the CellTiter Glo assay. Figure 31DShown are the average photons / second captured by the CellTiter-Glo reagent from the MKN-1 hollow fibers on day 16 (on the y-axis) and for the different treatment groups (on the x-axis). Figure 31E Individual replicate photon / second values ​​(on the y-axis) for the different treatment groups (on the x-axis) are shown. Error bars represent the interquartile range. Figure 31F -G shows that compound I induces cancer cell viability change in ovarian cancer tumor model OVCAR-3 cells implanted in mice.At day 0, the hollow fiber of load OVCAR-3 cells is subcutaneously (left part of figure) and intraperitoneally (right part of figure) implanted into female NMRI nude mice.Hollow fiber is collected during autopsy on day 16 and analyzed using CellTiter Glo assay. Figure 31F Shown are the average photons / second captured by the CellTiter-Glo reagent from the OVCAR-3 hollow fibers on day 16 (on the y-axis) and for the different treatment groups (on the x-axis). Figure 31G Individual replicate photon / second values ​​(on the y-axis) for the different treatment groups (on the x-axis) are shown. Error bars represent the interquartile range.

[0097] Figure 32 is the XRPD diffraction pattern of the crystalline free base, Pattern 1. The diffraction pattern was obtained as described in Example 10, and the 2-theta values ​​and relative intensities are given in Table 14.

[0098] Figure 33 is the XRPD diffraction pattern of the crystalline free base, Pattern 2. The diffraction pattern was obtained as described in Example 10, and the 2-theta values ​​and relative intensities are given in Table 15.

[0099] Figure 34 is the XRPD diffraction pattern of the crystalline free base, Pattern 3. The diffraction pattern was obtained as described in Example 10, and the 2-theta values ​​and relative intensities are given in Table 16.

[0100] Figure 35 is the XRPD diffraction pattern of crystalline HCl salt Pattern 1. The diffraction pattern was obtained as described in Example 10, and the 2-theta values ​​and relative intensities are given in Table 17.

[0101] Figure 36 is the XRPD diffraction pattern of crystalline HCl salt Pattern 2. The diffraction pattern was obtained as described in Example 10, and the 2-theta values ​​and relative intensities are given in Table 18.

[0102] Figure 37 is the XRPD diffraction pattern of crystalline HCl salt Pattern 3. The diffraction pattern was obtained as described in Example 10, and the 2-theta values ​​and relative intensities are given in Table 19.

[0103] Figure 38is the XRPD diffraction pattern of the crystalline sulfate salt, Pattern 1. The diffraction pattern was obtained as described in Example 10, and the 2-theta values ​​and relative intensities are given in Table 20.

[0104] Figure 39 is the XRPD diffraction pattern of the crystalline sulfate salt, pattern 1*. This diffraction pattern was obtained as described in Example 10, and the 2-theta values ​​and relative intensities are given in Table 21.

[0105] Figure 40 is the XRPD diffraction pattern of the crystalline sulfate salt, Pattern 2. The diffraction pattern was obtained as described in Example 10, and the 2-theta values ​​and relative intensities are given in Table 22.

[0106] Figure 41 is the XRPD diffraction pattern of the crystalline sulfate salt, Pattern 3. The diffraction pattern was obtained as described in Example 10, and the 2-theta values ​​and relative intensities are given in Table 23.

[0107] Figure 42 is the XRPD diffraction pattern of the crystalline sulfate salt, Pattern 4. This diffraction pattern was obtained as described in Example 10, and the 2-theta values ​​and relative intensities are given in Table 24.

[0108] Figure 43 is the XRPD diffraction pattern of the crystalline sulfate salt, Pattern 5. The diffraction pattern was obtained as described in Example 10, and the 2-theta values ​​and relative intensities are given in Table 25.

[0109] Figure 44 is the XRPD diffraction pattern of the crystalline sulfate salt, Pattern 6. This diffraction pattern was obtained as described in Example 10, and the 2-theta values ​​and relative intensities are given in Table 26.

[0110] Figure 45 is the XRPD diffraction pattern of the crystalline sulfate salt, Pattern 7. This diffraction pattern was obtained as described in Example 10, and the 2-theta values ​​and relative intensities are given in Table 27.

[0111] Figure 46 is the XRPD diffraction pattern of the crystalline mesylate salt, Pattern 1. The diffraction pattern was obtained as described in Example 10, and the 2-theta values ​​and relative intensities are given in Table 28.

[0112] Figure 47 is the XRPD diffraction pattern of the crystalline mesylate salt, Pattern 2. The diffraction pattern was obtained as described in Example 10, and the 2-theta values ​​and relative intensities are given in Table 29.

[0113] Figure 48 is the XRPD diffraction pattern of the crystalline mesylate salt, Pattern 3. The diffraction pattern was obtained as described in Example 10, and the 2-theta values ​​and relative intensities are given in Table 30.

[0114] Figure 49 is the XRPD diffraction pattern of the crystalline mesylate salt, Pattern 4. This diffraction pattern was obtained as described in Example 10, and the 2-theta values ​​and relative intensities are given in Table 31.

[0115] Figure 50 is the XRPD diffraction pattern of the crystalline mesylate salt, Pattern 5. This diffraction pattern was obtained as described in Example 10, and the 2-theta values ​​and relative intensities are given in Table 32.

[0116] Figure 51 is the XRPD diffraction pattern of the crystalline maleate salt, Pattern 1. The diffraction pattern was obtained as described in Example 10, and the 2-theta values ​​and relative intensities are given in Table 33.

[0117] Figure 52 is the XRPD diffraction pattern of the crystalline maleate salt, Pattern 1*. This diffraction pattern was obtained as described in Example 10, and the 2-theta values ​​and relative intensities are given in Table 34.

[0118] Figure 53 is the XRPD diffraction pattern of the crystalline maleate salt, Pattern 2. The diffraction pattern was obtained as described in Example 10, and the 2-theta values ​​and relative intensities are given in Table 35.

[0119] Figure 54 is the XRPD diffraction pattern of the crystalline maleate salt, Pattern 3. The diffraction pattern was obtained as described in Example 10, and the 2-theta values ​​and relative intensities are given in Table 36.

[0120] Figure 55 is the XRPD diffraction pattern of the crystalline maleate salt, pattern 3*. This diffraction pattern was obtained as described in Example 10, and the 2-theta values ​​and relative intensities are given in Table 37.

[0121] Figure 56 is the XRPD diffraction pattern of the crystalline maleate salt, Pattern 4. The diffraction pattern was obtained as described in Example 10, and the 2-theta values ​​and relative intensities are given in Table 38.

[0122] Figure 57 is the XRPD diffraction pattern of the crystalline maleate salt, Pattern 5. The diffraction pattern was obtained as described in Example 10, and the 2-theta values ​​and relative intensities are given in Table 39.

[0123] Figure 58 is the XRPD diffraction pattern of crystalline phosphate pattern 1. The diffraction pattern was obtained as described in Example 10, and the 2-theta values ​​and relative intensities are given in Table 40.

[0124] Figure 59is the XRPD diffraction pattern of crystalline phosphate pattern 2. The diffraction pattern was obtained as described in Example 10, and the 2-theta values ​​and relative intensities are given in Table 41.

[0125] Figure 60 is the XRPD diffraction pattern of crystalline phosphate pattern 3. The diffraction pattern was obtained as described in Example 10, and the 2-theta values ​​and relative intensities are given in Table 42.

[0126] Figure 61 is the XRPD diffraction pattern of crystalline phosphate pattern 4. The diffraction pattern was obtained as described in Example 10, and the 2-theta values ​​and relative intensities are given in Table 43.

[0127] Figure 62 is the XRPD diffraction pattern of crystalline phosphate pattern 5. The diffraction pattern was obtained as described in Example 10, and the 2-theta values ​​and relative intensities are given in Table 44.

[0128] Figure 63 is the XRPD diffraction pattern of crystalline phosphate pattern 6. The diffraction pattern was obtained as described in Example 10, and the 2-theta values ​​and relative intensities are given in Table 45.

[0129] Figure 64 is the XRPD diffraction pattern of the crystalline phosphate pattern 6*. This diffraction pattern was obtained as described in Example 10, and the 2-theta values ​​and relative intensities are given in Table 46.

[0130] Figure 65 is the XRPD diffraction pattern of crystalline phosphate pattern 7. The diffraction pattern was obtained as described in Example 10, and the 2-theta values ​​and relative intensities are given in Table 47.

[0131] Figure 66 is the XRPD diffraction pattern of the crystalline phosphate pattern 7*. This diffraction pattern was obtained as described in Example 10, and the 2-theta values ​​and relative intensities are given in Table 48.

[0132] Figure 67 is the XRPD diffraction pattern of crystalline phosphate pattern 8. The diffraction pattern was obtained as described in Example 10, and the 2-theta values ​​and relative intensities are given in Table 49.

[0133] Figure 68 is the XRPD diffraction pattern of the crystalline phosphate pattern 8*. This diffraction pattern was obtained as described in Example 10, and the 2-theta values ​​and relative intensities are given in Table 50.

[0134] Figure 69is the XRPD diffraction pattern of the crystalline (+)-L-tartrate salt, Pattern 1. The diffraction pattern was obtained as described in Example 10, and the 2-theta values ​​and relative intensities are given in Table 51.

[0135] Figure 70 is the XRPD diffraction pattern of the crystalline (+)-L-tartrate salt, Pattern 1*. This diffraction pattern was obtained as described in Example 10, and the 2-theta values ​​and relative intensities are given in Table 52.

[0136] Figure 71 is the XRPD diffraction pattern of the crystalline (+)-L-tartrate salt, Pattern 2. This diffraction pattern was obtained as described in Example 10, and the 2-theta values ​​and relative intensities are given in Table 53.

[0137] Figure 72 is the XRPD diffraction pattern of the crystalline citrate salt, Pattern 1. The diffraction pattern was obtained as described in Example 10, and the 2-theta values ​​and relative intensities are given in Table 54.

[0138] Figure 73 is the XRPD diffraction pattern of the crystalline citrate salt, Pattern 2. The diffraction pattern was obtained as described in Example 10, and the 2-theta values ​​and relative intensities are given in Table 55.

[0139] Figure 74 is the XRPD diffraction pattern of the crystalline citrate salt, Pattern 4. The diffraction pattern was obtained as described in Example 10, and the 2-theta values ​​and relative intensities are given in Table 56.

[0140] Figure 75 is the XRPD diffraction pattern of the crystalline hydrobromide salt, Pattern 1. This diffraction pattern was obtained as described in Example 10, and the 2-theta values ​​and relative intensities are given in Table 57.

[0141] Figure 76 is the XRPD diffraction pattern of the crystalline hydrobromide salt, Pattern 2. This diffraction pattern was obtained as described in Example 10, and the 2-theta values ​​and relative intensities are given in Table 58.

[0142] Figure 77 is the XRPD diffraction pattern of the crystalline benzenesulfonate salt, Pattern 1. The diffraction pattern was obtained as described in Example 10, and the 2-theta values ​​and relative intensities are given in Table 59.

[0143] Figure 78 is the XRPD diffraction pattern of the crystalline benzenesulfonate salt, Pattern 2. The diffraction pattern was obtained as described in Example 10, and the 2-theta values ​​and relative intensities are given in Table 60.

[0144] Figure 79is the XRPD diffraction pattern of the crystalline benzenesulfonate salt, Pattern 3. The diffraction pattern was obtained as described in Example 10, and the 2-theta values ​​and relative intensities are given in Table 61.

[0145] Figure 80 is the XRPD diffraction pattern of the crystalline benzenesulfonate salt, Pattern 3*. This diffraction pattern was obtained as described in Example 10, and the 2-theta values ​​and relative intensities are given in Table 62.

[0146] Figure 81 is a thermogravimetric / differential scanning calorimetry (TG / DSC) thermogram of sulfuric acid mode 1. The TG / DSC thermogram was obtained as described in Example 13, and the results are presented in Table 63.

[0147] Figure 82 is a thermogravimetric / differential scanning calorimetry (TG / DSC) thermogram of sulfuric acid mode 2. The TG / DSC thermogram was obtained as described in Example 13, and the results are presented in Table 63.

[0148] Figure 83 is a thermogravimetric / differential scanning calorimetry (TG / DSC) thermogram of sulfuric acid mode 3. The TG / DSC thermogram was obtained as described in Example 13, and the results are presented in Table 63.

[0149] Figure 84 is a thermogravimetric / differential scanning calorimetry (TG / DSC) thermogram of sulfuric acid mode 4. The TG / DSC thermogram was obtained as described in Example 13, and the results are presented in Table 63.

[0150] Figure 85 is a thermogravimetric / differential scanning calorimetry (TG / DSC) thermogram of sulfuric acid mode 5. The TG / DSC thermogram was obtained as described in Example 13, and the results are presented in Table 63.

[0151] Figure 86 is a thermogravimetric / differential scanning calorimetry (TG / DSC) thermogram of sulfuric acid mode 6. The TG / DSC thermogram was obtained as described in Example 13, and the results are presented in Table 63.

[0152] Figure 87 is a thermogravimetric / differential scanning calorimetry (TG / DSC) thermogram of methanesulfonic acid pattern 1. The TG / DSC thermogram was obtained as described in Example 13, and the results are presented in Example 23 and Table 64.

[0153] Figure 88 is a thermogravimetric / differential scanning calorimetry (TG / DSC) thermogram of methanesulfonic acid pattern 2. The TG / DSC thermogram was obtained as described in Example 13, and the results are presented in Example 23 and Table 64.

[0154] Figure 89 is a thermogravimetric / differential scanning calorimetry (TG / DSC) thermogram of methanesulfonic acid pattern 3. The TG / DSC thermogram was obtained as described in Example 13, and the results are presented in Example 23 and Table 64.

[0155] Figure 90 is a thermogravimetric / differential scanning calorimetry (TG / DSC) thermogram of methanesulfonic acid pattern 4. The TG / DSC thermogram was obtained as described in Example 13, and the results are presented in Example 23 and Table 64.

[0156] Figure 91 is a thermogravimetric / differential scanning calorimetry (TG / DSC) thermogram of maleic acid pattern 1. The TG / DSC thermogram was obtained as described in Example 13, and the results are presented in Example 24 and Table 65.

[0157] Figure 92 is a thermogravimetric / differential scanning calorimetry (TG / DSC) thermogram of maleic acid pattern 2. The TG / DSC thermogram was obtained as described in Example 13, and the results are presented in Example 24 and Table 65.

[0158] Figure 93 is a thermogravimetric / differential scanning calorimetry (TG / DSC) thermogram of maleic acid pattern 3. The TG / DSC thermogram was obtained as described in Example 13, and the results are presented in Example 24 and Table 65.

[0159] Figure 94 is a thermogravimetric / differential scanning calorimetry (TG / DSC) thermogram of maleic acid pattern 4. The TG / DSC thermogram was obtained as described in Example 13, and the results are presented in Example 24 and Table 65.

[0160] Figure 95 is a thermogravimetric / differential scanning calorimetry (TG / DSC) thermogram of maleic acid pattern 5. The TG / DSC thermogram was obtained as described in Example 13, and the results are presented in Example 24 and Table 65.

[0161] Figure 96 is a thermogravimetric / differential scanning calorimetry (TG / DSC) thermogram of phosphoric acid pattern 1. The TG / DSC thermogram was obtained as described in Example 13, and the results are presented in Example 25 and Table 66.

[0162] Figure 97 is a thermogravimetric / differential scanning calorimetry (TG / DSC) thermogram of phosphoric acid pattern 2. The TG / DSC thermogram was obtained as described in Example 13, and the results are presented in Example 25 and Table 66.

[0163] Figure 98is a thermogravimetric / differential scanning calorimetry (TG / DSC) thermogram of phosphoric acid pattern 3. The TG / DSC thermogram was obtained as described in Example 13, and the results are presented in Example 25 and Table 66.

[0164] Figure 99 is a thermogravimetric / differential scanning calorimetry (TG / DSC) thermogram of phosphoric acid pattern 4. The TG / DSC thermogram was obtained as described in Example 13, and the results are presented in Example 25 and Table 66.

[0165] Figure 100 is the thermogravimetric / differential scanning calorimetry (TG / DSC) thermogram of phosphoric acid pattern 7*. The TG / DSC thermogram was obtained as described in Example 13, and the results are presented in Example 25 and Table 66.

[0166] Figure 101 is the thermogravimetric / differential scanning calorimetry (TG / DSC) thermogram of phosphoric acid pattern 8. The TG / DSC thermogram was obtained as described in Example 13, and the results are presented in Example 25 and Table 66.

[0167] Figure 102 is a thermogravimetric / differential scanning calorimetry (TG / DSC) thermogram of (+)-L-tartaric acid Pattern 1. The TG / DSC thermogram was obtained as described in Example 13, and the results are presented in Example 26 and Table 67.

[0168] Figure 103 is a thermogravimetric / differential scanning calorimetry (TG / DSC) thermogram of (+)-L-tartaric acid Pattern 2. The TG / DSC thermogram was obtained as described in Example 13, and the results are presented in Example 26 and Table 67.

[0169] Figure 104 is a thermogravimetric / differential scanning calorimetry (TG / DSC) thermogram of citric acid Model 1. The TG / DSC thermogram was obtained as described in Example 13, and the results are presented in Example 27 and Table 68.

[0170] Figure 105 is a thermogravimetric / differential scanning calorimetry (TG / DSC) thermogram of citric acid Model 1. The TG / DSC thermogram was obtained as described in Example 13, and the results are presented in Example 27 and Table 68.

[0171] Figure 106 is a thermogravimetric / differential scanning calorimetry (TG / DSC) thermogram of citric acid Model 1. The TG / DSC thermogram was obtained as described in Example 13, and the results are presented in Example 27 and Table 68.

[0172] Figure 107is a thermogravimetric / differential scanning calorimetry (TG / DSC) thermogram of hydrobromic acid mode 1. The TG / DSC thermogram was obtained as described in Example 13, and the results are presented in Example 28 and Table 69.

[0173] Figure 108 is a thermogravimetric / differential scanning calorimetry (TG / DSC) thermogram of hydrobromic acid mode 1. The TG / DSC thermogram was obtained as described in Example 13, and the results are presented in Example 28 and Table 69.

[0174] Figure 109 is a thermogravimetric / differential scanning calorimetry (TG / DSC) thermogram of benzenesulfonic acid pattern 1. The TG / DSC thermogram was obtained as described in Example 13, and the results are presented in Example 29 and Table 70.

[0175] Figure 110 is a thermogravimetric / differential scanning calorimetry (TG / DSC) thermogram of benzenesulfonic acid pattern 2. The TG / DSC thermogram was obtained as described in Example 13, and the results are presented in Example 29 and Table 70.

[0176] Figure 111 is a thermogravimetric / differential scanning calorimetry (TG / DSC) thermogram of benzenesulfonic acid pattern 3. The TG / DSC thermogram was obtained as described in Example 13, and the results are presented in Example 29 and Table 70.

[0177] Figure 112 is a thermogravimetric / differential scanning calorimetry (TG / DSC) thermogram of HCl salt Model 1. The TG / DSC thermogram was obtained as described in Example 13, and the results are presented in Example 30.

[0178] Figure 113 is the thermogravimetric / differential scanning calorimetry (TG / DSC) thermogram of HCl salt Model 2. The TG / DSC thermogram was obtained as described in Example 13, and the results are presented in Example 30 and Table 72.

[0179] Figure 114 is the differential scanning calorimetry (DSC) thermogram of HCl salt Model 1. The DSC thermogram was obtained as described in Example 14, and the results are presented in Example 30.

[0180] Figure 115 Figure 1 is a dynamic vapor sorption (DVS) analysis showing the results of a moisture sorption experiment for HCl Model 1. DVS analysis of HCl Model 1 was performed as described in Example 15. DVS analysis showed that the material was moderately hygroscopic, with uptakes of 5.15% and 5.10% in the first and second sorption cycles, respectively. The results of this study are presented in Example 30.

[0181] Figure 116Figure 1 is a dynamic vapor sorption (DVS) kinetic plot of HCl Model 1. The DVS for HCl Model 1 was obtained as described in Example 15. DVS analysis indicated that the material was moderately hygroscopic, with uptakes of 5.15% and 5.10% in the first and second adsorption cycles, respectively. The results of this study are presented in Example 30.

[0182] Figure 117 is a thermogravimetric / differential scanning calorimetry (TG / DSC) thermogram of sulfuric acid mode 7. The TG / DSC thermogram was obtained as described in Example 13, and the results are presented in Example 34.

[0183] Figure 118 is the thermogravimetric / differential scanning calorimetry (TG / DSC) thermogram of phosphate mode 7*. The TG / DSC thermograms were obtained as described in Example 13, and the results are presented in Table 79.

[0184] Figure 119 is the differential scanning calorimetry (DSC) thermogram of phosphate mode 7*. The DSC thermograms were obtained as described in Example 14, and the results are presented in Table 79.

[0185] Figure 120 Table 79 shows the results of a dynamic vapor sorption (DVS) analysis of water sorption experiments for Phosphate Pattern 7*. DVS analysis of Phosphate Pattern 7* was performed as described in Example 15. DVS analysis showed that the material was moderately hygroscopic, with uptakes of 4.76% and 5.18% in the first and second sorption cycles, respectively. The results are presented in Table 79.

[0186] Figure 121 is a dynamic vapor sorption (DVS) kinetic plot of phosphate pattern 7*. The DVS of phosphate pattern 7* was obtained as described in Example 15. The results of the study are presented in Table 79.

[0187] Figure 122 is the PLM image of HCl mode 1.

[0188] Figure 123 is the PLM image of phosphate mode 7*.

[0189] Figure 124 A graph showing the effect of Compound I on hERG currents. The experimental conditions for this experiment are described in Example 40. The data points (triangles) represent the percent hERG blockade values ​​(indicated on the y-axis) at certain concentrations of Compound I (indicated on the x-axis).

[0190] Figure 125is a graph showing the inhibitory effect of Compound I on COX1. The experimental conditions for this experiment are shown in Example 40. The data points (triangles) show the percentage inhibition of the control enzyme (indicated on the y-axis) of diclofenac ligand binding to COX1 at certain concentrations of Compound I (indicated on the x-axis).

[0191] Figure 126 is a graph showing the inhibitory effect of Compound I on COX2. The experimental conditions for this experiment are shown in Example 40. The data points (triangles) show the percentage inhibition of the control enzyme (indicated on the y-axis) by NS398 ligand binding to COX2 at certain concentrations of Compound I (indicated on the x-axis).

[0192] Figure 127 is a graph showing the inhibitory effect of Compound I on CYP1A2. The experimental conditions for this experiment are described in Example 41. The data points (triangles) represent the percentage inhibition of the control enzyme (indicated on the y-axis) in the CYP1A2-catalyzed metabolism of tacrine at certain concentrations of Compound I (indicated on the x-axis) of hydroxytacrine formation.

[0193] Figure 128 is a graph showing the inhibitory effect of Compound I on CYP2B6. The experimental conditions for this experiment are shown in Example 41. The data points (triangles) show the percentage inhibition of the control enzyme (represented on the y-axis) in the formation of hydroxybupropion in the CYP2B6-catalyzed metabolism of buproprion at certain concentrations of Compound I (represented on the x-axis).

[0194] Figure 129 is a graph showing the inhibitory effect of Compound I on CYP2C8. The experimental conditions for this experiment are shown in Example 41. The data points (triangles) represent the percentage inhibition of the control enzyme (indicated on the y-axis) in the formation of desethylamodiaquine in the CYP2C8-catalyzed amodiaquine metabolism at certain concentrations of Compound I (indicated on the x-axis).

[0195] Figure 130 is a graph showing the inhibitory effect of Compound I on CYP2C9. The experimental conditions for this experiment are shown in Example 41. The data points (triangles) represent the percentage inhibition of the control enzyme (indicated on the y-axis) in the CYP2C9-catalyzed metabolism of tolbutamide at certain concentrations of Compound I (indicated on the x-axis) of 4-hydroxytolbutamide formation.

[0196] Figure 131 is a graph showing the inhibitory effect of Compound I on CYP2C19. The experimental conditions for this experiment are shown in Example 41. The data points (triangles) represent the percentage inhibition of the control enzyme (indicated on the y-axis) in the formation of 4-hydroxymephenytoin in the CYP2C19-catalyzed metabolism of mephenytoin at certain concentrations of Compound I (indicated on the x-axis).

[0197] Figure 132 is a graph showing the inhibitory effect of Compound I on CYP2D6. The experimental conditions for this experiment are described in Example 41. The data points (triangles) represent the percent inhibition of control enzyme (indicated on the y-axis) of dextrorphan formation in the CYP2D6-catalyzed metabolism of dextromethorphan at certain concentrations of Compound I (indicated on the x-axis).

[0198] Figure 133 is a graph showing the inhibitory effect of Compound I on CYP3A4. The experimental conditions for this experiment are shown in Example 41. The data points (triangles) represent the percentage inhibition of the control enzyme (indicated on the y-axis) in the CYP3A4-catalyzed metabolism of midazolam at certain concentrations of Compound I (indicated on the x-axis) of 1-hydroxymidazolam formation.

[0199] Figure 134 is a graph showing the inhibitory effect of Compound I on CYP3A4. The experimental conditions for this experiment are shown in Example 41. The data points (triangles) represent the percentage inhibition of the control enzyme (indicated on the y-axis) in the formation of 6β-hydroxy-testosterone in the CYP3A4-catalyzed testosterone metabolism at certain concentrations of Compound I (indicated on the x-axis).

[0200] Figure 135 is a graph showing the inhibitory effect of Compound I on BCRP. The experimental conditions for this experiment are shown in Example 41. The data points (triangles) represent the percentage inhibition of the control enzyme (indicated on the y-axis) of estrone-3-sulfate transport mediated by BCRP at certain concentrations of Compound I (indicated on the x-axis).

[0201] Figure 136 is a graph showing the inhibitory effect of Compound I on MATE1. The experimental conditions for this experiment are shown in Example 41. The data points (triangles) represent the percentage inhibition of the control enzyme (indicated on the y-axis) of metformin transport mediated by MATE1 at certain concentrations of Compound I (indicated on the x-axis).

[0202] Figure 137 is a graph showing the inhibitory effect of Compound I on MATE2-K. The experimental conditions for this experiment are shown in Example 41. The data points (triangles) represent the percentage inhibition of the control enzyme (indicated on the y-axis) of metformin transport mediated by MATE2-K at certain concentrations of Compound I (indicated on the x-axis).

[0203] Figure 138 is a graph showing the inhibitory effect of Compound I on OAT1. The experimental conditions for this experiment are shown in Example 41. The data points (triangles) represent the percentage inhibition of the control enzyme (indicated on the y-axis) of tenofovir transport mediated by OAT1 at certain concentrations of Compound I (indicated on the x-axis).

[0204] Figure 139 is a graph showing the inhibitory effect of Compound I on OAT3. The experimental conditions for this experiment are shown in Example 41. The data points (triangles) represent the percentage inhibition of the control enzyme (indicated on the y-axis) of estrone-3-sulfate transport mediated by OAT3 at certain concentrations of Compound I (indicated on the x-axis).

[0205] Figure 140 Graph showing the inhibitory effect of Compound I on OAT1P1B1. The experimental conditions for this experiment are shown in Example 41. The data points (triangles) represent the percentage inhibition of the control enzyme (indicated on the y-axis) of estradiol-17-β-glucuronide transport mediated by OAT1P1B1 at certain concentrations of Compound I (indicated on the x-axis).

[0206] Figure 141 Graph showing the inhibitory effect of Compound I on OAT1P1B3. The experimental conditions for this experiment are shown in Example 41. The data points (triangles) represent the percentage inhibition of the control enzyme (indicated on the y-axis) of cholecystokinin octapeptide transport mediated by OAT1P1B3 at certain concentrations of Compound I (indicated on the x-axis).

[0207] Figure 142 is a graph showing the inhibitory effect of Compound I on OCT1. The experimental conditions for this experiment are shown in Example 41. The data points (triangles) represent the percentage inhibition of the control enzyme (indicated on the y-axis) of sumatriptan transport mediated by OCT1 at certain concentrations of Compound I (indicated on the x-axis).

[0208] Figure 143 is a graph showing the inhibitory effect of Compound I on OCT2. The experimental conditions for this experiment are shown in Example 41. The data points (triangles) represent the percentage inhibition of the control enzyme of metformin transport mediated by OCT2 at certain concentrations of Compound I (indicated on the x-axis).

[0209] Figure 144 is a graph showing the phototoxicity of Compound 1 in Balb-c3T3 mice. The experimental conditions for this experiment are shown in Example 42. Cell viability was measured as the percentage of live cells (represented on the y-axis) in the dark (filled circles) and in the light (open squares) at different concentrations of Compound 1 (μg / mL) (represented on the x-axis).

[0210] Figure 145Images of culture plates taken during the crystal violet colony assay are shown, demonstrating that Compound I prolongs the duration of CDK4 / 6 inhibitor resistance in ER+ breast cancer. The experimental conditions for this experiment are described in Example 43. From week 3-8, T47D human ER+ breast cancer cell colonies and BT474 human ER+ breast cancer cell colonies were treated with Compound I alone or in combination with the CDK4 / 6 inhibitors (CDK4 / 6i) palbociclib or abemaciclib.

[0211] Figures 146A-146H Compound I was shown to reduce Rb phosphorylation and cyclin A2 levels in tumors and induce tumor regression and arrest in animal preclinical cancer models of ovarian and gastric CCNE1 amplification. The experimental conditions for these experiments are described in Example 44. Figure 146A Figure 2 is a graph showing the cell line derived tumor xenograft (CDX) OVCAR3 ovarian mouse preclinical model administered with vehicle (circles) or Compound I at 200 mg / kg once daily (QD) (squares) or 100 mg / kg twice daily (BID) (triangles). 3 ) is indicated on the y-axis and the number of study days is indicated on the x-axis. Mice were treated for 42 days and showed tumor stasis with 100 BID treatment or 89% TGI with 200 QD treatment. n=10, weight loss was not >5% at any point. Figure 146B Figure 3 shows the administration of vehicle (circles) or Compound I at 200 mg / kg once daily (QD) (triangles) or 100 mg / kg twice daily (BID) (diamonds) to the patient-derived tumor xenograft (PDX) OV5398 ovarian mouse preclinical model. 3 ) is indicated on the y-axis and the number of study days is indicated on the x-axis. Mice were treated for 56 days and both treatment groups showed tumor regression. n=10, weight loss was not >5% at any point. Figure 146C Figure 3 shows the patient-derived tumor xenograft (PDX) GA0103 gastric mouse preclinical model treated with vehicle (circles) or Compound I at 100 mg / kg twice daily (BID) (triangles). 3 ) is indicated on the y-axis and the number of study days is indicated on the x-axis. Mice were treated for 56 days and showed tumor stasis with 100 BID treatment. n=8, no weight loss >5% at any point. Figure 146D Graph showing administration of vehicle (circles) or Compound I at 100 mg / kg twice daily (BID) (triangles) to the patient-derived tumor xenograft (PDX) GA0114 gastric mouse preclinical model. 3) is indicated on the y-axis and the number of study days is indicated on the x-axis. Mice were treated for 35 days and showed 95% TGI with 100 BID treatment. N=8, weight loss was not >5% at any point. Figure 146E Western blot showing the levels of retinoblastoma protein (Rb), markers of phosphorylated Rb protein (pRb 807 / 811, pRb T821), and cyclin A2 (CCNA2) in OVCAR3 tumors extracted from the cell line-derived tumor xenograft (CDX) OVCAR3 ovarian mouse model 2 hours or 24 hours after the last dose of control or Compound I. Figure 146F Western blot showing the levels of retinoblastoma protein (Rb), markers of phosphorylated Rb protein (pRb807 / 811, pRb T821), and cyclin A2 (CCNA2) in OV5398 tumors extracted from the patient-derived tumor xenograft (PDX) OV5398 ovarian mouse model 2 hours or 24 hours after the last dose of control or Compound I. Figure 146G Figure 2 is a graph showing relative thymidine kinase (TK) activity levels calculated by ELISA. TK activity (shown on the y-axis) is relative to GA0103 PDX model mice that received vehicle control or Compound 1 100 mpk BID. Figure 146H Graph showing relative TK activity levels calculated by ELISA. TK activity (indicated on the y-axis) relative to GA0114 PDX model mice receiving vehicle control or Compound I 100 mpk BID.

[0212] Figures 147A-147L The combination of Compound I and a CDK4 / 6 inhibitor (CDK4 / 6i) was shown to restore sensitivity in cell lines resistant to CDK4 / 6i and / or anti-estrogen therapy. The experimental conditions for these experiments are shown in Example 45. Figure 147A The bar graph shows that multiple cell lines resistant to CDK4 / 6 inhibitors and / or estrogen therapy are sensitive to the combination of Compound I and a CDK4 / 6 inhibitor. The bar graph illustrates the nanomolar (nM) IC of cell proliferation. 50 Figure 3. Responses of MCF7 or T47D luminal breast cancer cells to different therapies (on the y-axis). PAR: non-4 / 6i resistant parental line; LYR: abemaciclib-resistant cell line; FR: fulvestrant-resistant cell line; LYFR: abemaciclib- and fulvestrant-resistant cell line; PAR+LY: parental line treated with 500 nM abemaciclib; PDR: palbociclib-resistant cell line. Figure 147B: It is a grouped line graph showing the breast cancer model T47D 2xDT cell number fold change (on the y-axis) and compound I nanomolar (nM) treatment concentration (on the x-axis). Non-resistant parental (PAR) cell lines were treated with compound I (circles). The parental cell line (PAR+LY) previously administered 500nM abemaciclib was administered in combination with abemaciclib and compound I (diamonds). Abemaciclib-resistant (LYR) cells were administered in combination with abemaciclib and compound I (squares). Fulvestrant-resistant (FR) cells were administered in combination with Fulvestrant and compound I (equilateral triangles). Abemaciclib and Fulvestrant-resistant (LYFR) cells were administered in combination with abemaciclib and compound I (inverted triangles). Figure 147C : is a grouped line graph illustrating the breast cancer model MCF7-M2xDT cell number fold change (on the y-axis) and the nanomolar (nM) treatment concentration of Compound I (on the x-axis). Non-resistant parental (PAR) cell lines were treated with Compound I (circles). The parental cell line (PAR+LY) previously administered 500nM abemaciclib was administered in combination with abemaciclib and Compound I (diamonds). Abemaciclib-resistant (LYR) cells were administered in combination with abemaciclib and Compound I (squares). Fulvestrant-resistant (FR) cells were administered in combination with Fulvestrant and Compound I (equilateral triangles). Abemaciclib and Fulvestrant-resistant (LYFR) cells were administered in combination with abemaciclib and Compound I (inverted triangles). Figure 147D : is a bar graph showing that T47D cells resistant to abemaciclib are arrested in G1 when combined with compound I. The bar graph shows the percentage of cells (on the y-axis) in different cell phases for different therapy-resistant progeny T47D cells (shown on the x-axis). PAR: non-4 / 6i resistant parental line; LYR: cell line resistant to abemaciclib; FR: cell line resistant to fulvestrant; LYFR: cell line resistant to abemaciclib and fulvestrant; PAR+LY: parental line with 500nM abemaciclib; PDR: cell line resistant to palbociclib. Figure 147E Flow cytometry graphs quantifying the percentage of non-resistant parental (PAR) cells in S phase, G1 phase, or G2M phase after treatment with DMSO control. Quantification of FITC:BrdU staining intensity is shown on the y-axis, and PI-A staining intensity is shown on the x-axis. Figure 147F Flow cytometry graphs quantifying the percentage of non-resistant parental (PAR) cells in S phase, G1 phase, or G2M phase after treatment with abemaciclib. Quantification of FITC:BrdU staining intensity is shown on the y-axis, and PI-A staining intensity is shown on the x-axis. Figure 147GFlow cytometry graphs quantifying the percentage of abemaciclib-resistant (LYR) cells in S phase, G1 phase, or G2M phase after abemaciclib treatment. Quantification of FITC:BrdU staining intensity is shown on the y-axis, and PI-A staining intensity is shown on the x-axis. Figure 147H Figure 1 is a flow cytometry graph quantifying the percentage of abemaciclib and fulvestrant-resistant (LYFR) cells in S phase, G1 phase, or G2M phase after treatment with abemaciclib and fulvestrant. Quantification of FITC:BrdU staining intensity is shown on the y-axis, and PI-A staining intensity is shown on the x-axis. Figure 147I is a flow cytometry graph quantifying the percentage of abemaciclib-resistant (LYR) cells in S phase, G1 phase, or G2M phase after treatment with abemaciclib in combination with Compound I. Quantification of FITC:BrdU staining intensity is represented on the y-axis, and PI-A staining intensity is represented on the x-axis. Figure 147J is a flow cytometry graph quantifying the percentage of abemaciclib and fulvestrant-resistant (LYFR) cells in S phase, G1 phase, or G2M phase after treatment with the combination of abemaciclib and fulvestrant and Compound I. Quantification of FITC:BrdU staining intensity is represented on the y-axis, and PI-A staining intensity is represented on the x-axis. Figure 147K It is a Western blot showing that the combination of Compound I and CDK4 / 6i prevents the phosphorylation of Rb in therapy-resistant cells. The Western blot shows the levels of retinoblastoma protein (Rb), a marker for phosphorylated Rb protein (pRb S780), and histone H3 loading control in response to DMSO or abemaciclib and Compound I alone or in combination. Parent: non-4 / 6i resistant parental line; LYR: cell line resistant to abemaciclib; FR: cell line resistant to fulvestrant; LYFR: cell line resistant to abemaciclib and fulvestrant. Figure 147L Figure 2 is a Western blot showing the levels of phosphorylated retinoblastoma protein (pRb) and focal adhesion protein loading control in therapy-resistant cells. DMSO, abemaciclib, fulvestrant, and / or Compound I were administered to therapy-resistant cells. PAR: non-4 / 6i resistant parental line; LYR: abemaciclib-resistant cell line; FR: fulvestrant-resistant cell line; LYFR: abemaciclib- and fulvestrant-resistant cell line; PAR+LY: parental line with 500 nM abemaciclib; +: drug administered; -: no drug administered.

[0213] Figures 148A-148F Shown are β-galactosidase staining of therapy-resistant cells treated with abemaciclib, fulvestrant, and / or Compound I. The experimental conditions for these experiments are described in Example 45. Figure 148Aare micrographs showing β-galactosidase staining of abemaciclib-resistant (LYR) cells treated with abemaciclib. Figure 148B are micrographs showing β-galactosidase staining of abemaciclib-resistant (LYR) cells treated with abemaciclib in combination with Compound I. Figure 148C are micrographs showing β-galactosidase staining of abemaciclib and fulvestrant-resistant (LYFR) cells treated with abemaciclib in combination with fulvestrant. Figure 148D are photomicrographs showing β-galactosidase staining of abemaciclib and fulvestrant-resistant (LYFR) cells treated with the combination of abemaciclib and fulvestrant and Compound I. Figure 148E Graph showing β-galactosidase activity in abemaciclib-resistant (LYR) cells. Quantification of the ratio of β-galactosidase staining area to cell area (shown on the y-axis) in different treatment groups including abemaciclib + DMSO or abemaciclib + Compound I (shown on the x-axis). Figure 148F Graph showing β-galactosidase activity in abemaciclib and fulvestrant-resistant (LYFR) cells. Quantification of the ratio of β-galactosidase staining area to cell area (shown on the y-axis) in different treatment groups including abemaciclib + fulvestrant + DMSO or abemaciclib + fulvestrant + Compound I (shown on the x-axis).

[0214] Figure 149 Graph showing the fold change in tumor volume in mice that were pre-treated with the CDK4 / 6 inhibitor abemaciclib until treatment-resistant HER2-overexpressing (MMTV-rtTA / tetO-HER2) was observed. The experimental conditions for this experiment are shown in Example 45. Mice were randomized and then administered vehicle control (squares), Compound I 50* mg / kg twice daily (BID) (inverted triangles), abemaciclib 50 mg / kg twice daily (BID) (equilateral triangles), or a combination of abemaciclib and Compound I at the dose and frequency described above (diamonds). The fold change in tumor volume is shown on the y-axis, and the number of days of treatment is shown on the x-axis. *Compound I was initially dosed at 75 mg / kg BID, but was reduced on day 9.

[0215] Figures 150A-150C Estrogen receptor positive (ER+) breast cancer model T47D cells were shown to be sensitive to the combined treatment comprising administration of Compound I and fulvestrant. The experimental conditions for these experiments are described in Example 46. Figure 150A Images of culture plates containing T47D human breast cancer cell colonies at weeks 2 and 3 under Compound I and / or fulvestrant treatment conditions relative to vehicle control. Figure 150Bis a bar graph showing the mean colony size of the different treatment conditions (on the y-axis) compared to the control (on the x-axis) at weeks 2 and 3. Figure 150C is a bar graph showing the percentage of colony area for different treatment conditions (on the y-axis) compared to the control (on the x-axis) at weeks 2 and 3.

[0216] Figure 151 Compound I, a potent and selective CDK2 inhibitor, was shown to exhibit strong anticancer activity in CCNE-amplified and CDK4 / 6 inhibitor-resistant cancers. Cyclin E1 (CCNE1) and E2 (CCNE2) are key cell cycle regulators that bind to CDK2, which phosphorylates retinoblastoma (Rb) to drive cancer cell proliferation by transitioning from the G1 phase to the S phase of the cell cycle. Dysregulated CDK2 activity frequently occurs in a variety of human cancers, with amplification / overexpression of CCNE1 and CCNE2 being the most common mechanism of dysregulated CDK2 activity and resistance to CDK4 / 6 inhibitors. Compound I is a selective and potent CDK2 inhibitor that may provide clinical benefits to patients with CDK2 / cyclin E-driven cancers and delay the onset of resistance to conventional therapies. In CCNE1-amplified human ovarian and gastric cancer cell lines, Compound I potently inhibited retinoblastoma (Rb) phosphorylation, induced G1 cell cycle arrest, and inhibited cell proliferation. Compound I also exhibited potent antiproliferative activity in luminal breast cancer cell lines that had been cultured for extended periods in the presence of CDK4 / 6 inhibitors, leading to drug resistance. In CCNE1-amplified breast, ovarian, and gastric cancer models, Compound I inhibited Rb phosphorylation and induced tumor regression and prolonged tumor stasis. Detailed Description of the Invention

[0218] Surprisingly and unexpectedly, Compound 1 described herein, or a pharmaceutically acceptable salt or morphological form thereof, such as Pattern 1, has been found to be particularly effective in treating cancers with amplified or overexpressed cyclin E, resistance to CDK4 / 6 inhibitors (e.g., SCLC) through acquired or intrinsic resistance, and / or resistance to endocrine therapy (e.g., estrogen receptor degraders). Compound 1 can be used to treat difficult-to-treat cyclin E amplified cancers, including CCNE1 amplified unresectable solid tumors and CCNE1 amplified platinum-resistant or platinum-refractory cancers. The non-limiting examples of the favorable properties shown by Compound I include selective inhibition of CDK2, inhibition of CDK2 across several cyclin complex partners, considerable residence time when compounded with CDK2, robust safety characteristics when applied to healthy non-cancerous cells, synergy with chemotherapeutics for greater anti-tumor efficacy, anti-tumor efficacy in CDK4 / 6 inhibitor-resistant cells, anti-tumor efficacy in endocrine inhibitor-resistant cells, anti-tumor efficacy in cells with amplified cyclin E activation and / or expression, changes in cell cycle-related protein expression, induction of targeted DNA damage response in tumor cells, persistent tumor suppression and / or improvement of overall survival. Changes in the steady-state levels of proteins involved in the cell cycle indicate that the administration of Compound I leads to regulation of gene expression, thereby generating a tumor microenvironment that is conducive to resensitizing the tumor to other therapeutic agents, including but not limited to CDK4 / 6 inhibitors, endocrine therapies (such as SERD), chemotherapeutics, immune checkpoint inhibitors, or combinations thereof. This improvement provides a significant advancement in the state-of-the-art for cancer treatment.

[0219] It is well known that host cells begin to escape CDK4 / 6 inhibition by activating and / or upregulating other cell cycle proteins and / or CDKs, thereby promoting uncontrolled cell division again. In FDA-approved CDK4 / 6 inhibitor trials, at least 33% of patients developed recurrent disease within only 2 years of using CDK4 / 6 inhibitors. In the PALOMA-2 trial, more than 70% of subjects were treated with a combination of palbociclib and letrozole for the treatment of advanced breast cancer with disease progression within 3 years of the start of the first therapy (Finn et al. Lancet Oncol. 16:25-35 (2016)).

[0220] The proportion of patients with advanced ER+ breast cancer who have deletions or mutations in the retinoblastoma (Rb) gene is extremely rare (3.9%) (Ciriello et al. Cell. 163:506-19 (2015)), suggesting that an intact CDK / Rb axis is necessary for patients to respond to CDK4 / 6 inhibition. In fact, patients with advanced ER+ breast cancer are selected for CDK4 / 6 inhibitor treatment based on the expression of Rb in their cancer. Studies in preclinical models have shown that low or absent Rb expression renders tumors unresponsive to CDK4 / 6 inhibition (Konecny ​​et al. Clin Canc Res. 17:1591-1602 (2011); Thangavel et al. Endocr Relat Canc. 18:333-45 (2011)). For example, in a study of 13 ex vivo tumor explant breast cancer models administered palbociclib, two samples that did not respond lacked Rb expression (Dean et al. Cell Cycle. 11:2756-61 (2012)). Similar studies in pancreatic and glioblastoma cancer models demonstrated similar results, indicating that the efficacy of CDK4 / 6 inhibition was associated with an intact CDK / Rb axis (Michaud et al. Canc Res. 70:3228-38 (2010); Chou et al. Gut. 67(12):2142-55 (2017)).

[0221] CDK2 plays a crucial role in promoting the G1 / S transition and S phase progression. In complex with cyclin E, CDK2 phosphorylates members of the retinoblastoma pocket protein family (p107, p130, pRb), leading to derepression of E2F transcription factors, expression of G1 / S transition-related genes, and transition from G1 to S phase. This, in turn, leads to CDK2 / cyclin A activation, which phosphorylates endogenous substrates, thereby allowing DNA synthesis, replication, and centrosome duplication. Another key adaptation in cancer cell development is the activation or overexpression of cyclin E (CCNE1 or CCNE2). Increased levels or activity of CCNE1 / 2 disrupt the cell cycle arrest induced by CDK4 / 6 inhibitors by activating alternative CDKs (Taylor-Harding et al. (2015); Herrera-Abreu et al. (2016); Bollard et al. (2017); Martin et al. (2017); Yang et al. (2017)). Dysregulated CDK2 activity typically occurs through amplification of CCNE1 (the gene encoding the cyclin E1 protein) and / or overexpression of cyclin E1, as well as mutations that inactivate endogenous inhibitors of CDK2 (e.g., p27), respectively. In certain embodiments, Compound 1 is used to treat a subset of cancers with increased CCNE1 / 2 levels or activity.

[0222] I. Terminology

[0223] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as those generally understood by those skilled in the art to which the present invention belongs. Although methods and materials similar or equivalent to the methods and materials described herein can be used to practice the present invention, suitable methods and materials are described below. All publications, patent applications, patents and other references mentioned herein are incorporated herein by reference in their entirety. In the event of any conflict, this specification (including definitions) shall prevail. In addition, materials, methods and examples are for illustrative purposes only and are not intended to be limiting.

[0224] Each reference cited herein is incorporated by reference in its entirety.

[0225] The terms "a" and "an" do not represent a limit to quantity, but rather represent the presence of at least one cited item. The term "or" means "and / or". Unless otherwise specified herein, the recording of a numerical range is only intended to serve as a shorthand method for quoting each individual numerical value falling within the range individually, and each individual numerical value is incorporated into the specification as if it were individually recorded herein. The endpoints of all ranges are included within the range and are independently combinable. Unless otherwise specified herein or the context is clearly contradictory, all methods described herein can be performed in a suitable order. The use of examples or exemplary language (e.g., "for example") is only intended to better illustrate the present invention, and unless otherwise stated, will not limit the scope of the present invention. Unless otherwise defined, the technical and scientific terms used herein have the same meanings as those generally understood by those skilled in the art to which the present invention belongs.

[0226] In certain embodiments, the term "about" means ± 10%.

[0227] Unless otherwise indicated, the "patient" or "subject" or "participant" being treated is typically a human patient. In alternative embodiments, the methods described herein can be used to treat or test other animals that respond similarly, such as mammals, such as animals used in preclinical testing, including but not limited to mice, rats, monkeys, dogs, pigs, and rabbits; as well as domestic swine (pigs and hogs), ruminants, horses, poultry, felines, cattle, rats, canines, and the like.

[0228] As used herein, an "effective amount" refers to an amount that provides a therapeutic benefit.

[0229] As used herein, the term "treating" a disease refers to reducing the frequency or severity of at least one sign or symptom of the disease or disorder experienced by a patient (i.e., palliative treatment) or reducing the cause or effect of the disease, disorder (i.e., disease-modifying treatment) or side effects experienced by a patient as a result of the administration of a therapeutic agent.

[0230] As used herein, the term "treatment-emergent adverse event" refers to an adverse event that occurs or worsens after the first dose or during treatment.

[0231] As used herein, the term "overall survival (OS)" refers to the time from the first dose until death from any cause.

[0232] As used herein, the term "overall response rate (ORR)" refers to the occurrence of a best overall response of confirmed CR or PR as determined by RECIST v1.1 criteria.

[0233] As used herein, the term "disease control rate (DCR)" refers to the occurrence of a best overall response of confirmed CR, PR, or SD, as determined by RECIST v1.1 criteria.

[0234] As used herein, the term "progression-free survival (PFS)" refers to the period of time from the first dose until the first documented disease progression or death from any cause, whichever occurs first.

[0235] As used herein, the term "duration of response (DOR)" refers to the time from the first documented confirmed best overall response of CR or PR to the first documented disease progression or death from any cause, whichever occurs first.

[0236] As used herein, the term "time to progression (TTP)" refers to the time from the first dose until the first documented disease progression.

[0237] As used herein, the term "MTD" refers to the maximum tolerated dose of Compound 1.

[0238] As used herein, the term "AUC" refers to the area under the Compound I concentration-time curve.

[0239] As used herein, the term "AUC 0-t ” refers to the AUC at the time of the last measurable concentration of Compound I.

[0240] As used herein, the term "AUC 0-∞ ” refers to the AUC of Compound 1 at unlimited time.

[0241] As used herein, the term "Cl" refers to the clearance of Compound I by Compound I.

[0242] As used herein, the term "C max ” refers to the maximum concentration of Compound 1.

[0243] As used herein, the term "IC 50 ” refers to the half-maximal inhibitory concentration of compound I. IC 50 It is a measure of drug potency and represents the concentration of compound I that inhibits a selected biological process by half compared to a control compound.

[0244] As used herein, the term "nH" refers to the Hill slope factor, which describes the fit between the minimum and maximum plateaus of the IC 50 The slope of the sigmoid curve of the data.

[0245] As used herein, the term " 1 / 2 ” refers to the half-life of Compound 1.

[0246] As used herein, the term " 1 / 2α ” refers to the initial elimination half-life of Compound 1.

[0247] As used herein, the term " 1 / 2β ” refers to the terminal elimination half-life of Compound 1.

[0248] As used herein, the term " max ” refers to the C of compound I max time.

[0249] As used herein, the term " last ” refers to the time at which the last measurable concentration of Compound I is reached.

[0250] As used herein, the term “ d ” refers to the volume of distribution of Compound 1.

[0251] As used herein, "intrinsic resistance" is also called primary resistance and refers to a situation in which the cancer does not respond or responds insufficiently to the inhibitory effects of the initial anti-cancer treatment, such as, but not limited to, CDK4 / 6 inhibitor treatment or endocrine therapy treatment. In some embodiments of the methods of treatment described herein, the cancer being treated is intrinsically resistant to CDK4 / 6 inhibitors. Mutations and situations associated with, for example, intrinsic resistance to CDK4 / 6 inhibitors include, but are not limited to: increased activity of cyclin-dependent kinase 1 (CDK1); increased activity of cyclin-dependent kinase 2 (CDK2); loss, deficiency or deletion of retinoblastoma tumor suppressor protein (Rb) (Rb deficiency); high levels of p16Ink4a expression; high levels of MYC expression; increased expression of cyclin E1, cyclin E2 and cyclin A; and combinations thereof. Cancers that are intrinsically resistant to CDK4 / 6 inhibitors are characterized by reduced expression of retinoblastoma tumor suppressor protein or one or more retinoblastoma family member proteins (such as, but not limited to, p107 and p130). In certain embodiments, the tumor or cancer inhibited by the intrinsic resistance selective CDK4 / 6 inhibitor is a tumor or cancer whose cell population as a whole does not undergo significant G1 cell cycle arrest when exposed to a selective CDK4 / 6 inhibitor. In certain embodiments, the tumor or cancer inhibited by the intrinsic resistance CDK4 / 6 inhibitor is a tumor or cancer in which less than 25%, 20%, 15%, 10% or 5% of the cells in the cell population undergo G1 cell cycle arrest when exposed to a selective CDK4 / 6 inhibitor. In some alternative embodiments of the methods of treatment described herein, the cancer being treated is intrinsically resistant to endocrine therapy, such as estrogen inhibitor therapy, such as SERD. In some alternative embodiments of the methods of treatment described herein, the cancer being treated is intrinsically resistant to biologically active agents or other anti-cancer therapies.

[0252] As used herein, "acquired resistance" refers to a situation in which a cancer that was initially sensitive to the inhibitory effects of an anticancer therapy becomes unresponsive or less responsive over time to the administration of that therapy. In some embodiments of the methods described herein, the cancer to be treated has acquired resistance to a selective CDK4 / 6 inhibitor. Without wishing to be bound by any one theory, it is believed that acquired resistance to CDK4 / 6 inhibitors occurs due to one or more additional mutations or genetic alterations in bypass signaling that occur after initiation of a CDK4 / 6 inhibitor treatment regimen. For example, a non-limiting exemplary cause of acquired resistance to CDK4 / 6 inhibitors may be due to the presence of one or more genetic aberrations associated with "intrinsic resistance." In addition, other non-limiting exemplary causes of acquired resistance to CDK4 / 6 inhibitors may include increased expression of cyclin E; CCNE1 / 2 amplification; E2F amplification; CDK2 amplification; CDK6 amplification; CDK4 amplification; p16 amplification; WEE1 overexpression; MDM2 overexpression; CDK7 overexpression; FZR1 loss; HDAC activation; FGFR pathway activation; PI3K / AKT / mTOR pathway activation; loss of ER or PR expression; higher AP-1 transcriptional activity; epithelial-mesenchymal transition; Smad 3 inhibition; autophagy activation; Rb1 loss or inactivating RB1 mutation; or a combination thereof. A general review of CDK4 / 6 resistance mechanisms can be found in, for example, Pandey et al., Molecular mechanisms of resistance to CDK4 / 6 inhibitors in breast cancer: A review. Int. J. Cancer: 00, 1–10 (2019), which is incorporated herein by reference. In certain embodiments, a tumor or cancer that has acquired resistance to selective CDK4 / 6 inhibitor inhibition is a tumor or cancer cell population (as a whole) that no longer experiences significant G1 cell cycle arrest when exposed to a selective CDK4 / 6 inhibitor, thereby leading to a tumor or cancer that progresses with the disease. In certain embodiments, a tumor or cancer that has acquired resistance to CDK4 / 6 inhibitor inhibition is a tumor or cancer cell population that has less than 50%, 40%, 30%, 20%, 15%, 10% or 5% of cells that undergo G1 cell cycle arrest when exposed to a selective CDK4 / 6 inhibitor, thereby leading to a tumor or cancer that progresses with the disease. In some embodiments, cancer progresses after a previous treatment regimen including administration of a CDK4 / 6 inhibitor. In some alternative embodiments of the methods of treatment described herein, the cancer treated has acquired resistance, such as resistance to estrogen inhibitor therapy (e.g., SERD) (e.g., but not limited to fulvestrant or alastrant).In some alternative embodiments of the treatment methods described herein, the cancer being treated has acquired resistance to the bioactive agent or other anti-cancer therapy.

[0253] II. Treatment Methods

[0254] In certain aspects, methods described herein are provided for treating a proliferative disorder mediated by overexpression or amplification of cyclin E in a subject (including a human), comprising administering an effective amount of Compound 1 as described herein, or a pharmaceutically acceptable salt, deuterated derivative, or morphological form thereof, and / or a pharmaceutically acceptable composition thereof. Non-limiting examples of disorders mediated by overexpression or amplification of cyclin E include tumors and cancers mediated by overexpression or amplification of cyclin E.

[0255] In other aspects, provided herein are methods for treating a proliferative disorder mediated by CDK2 in a subject (including a human) comprising administering an effective amount of a morphological form of Compound 1 as described herein; a pharmaceutical composition comprising a morphological form of Compound 1; or a pharmaceutical composition made from a morphological form of Compound 1; or a pharmaceutically acceptable salt or deuterated derivative thereof. Non-limiting examples of disorders mediated by CDK2 include tumors, cancers, disorders associated with abnormal cell proliferation, inflammatory disorders, immune disorders, and autoimmune disorders.

[0256] In another aspect, there is provided a method as described herein for treating a subject with a CDK4 / 6 resistant cancer, comprising administering to the subject an effective amount of Compound 1 as described herein or a pharmaceutically acceptable salt or morphological form thereof; and administering to the subject an effective amount of a CDK4 / 6 inhibitor. In certain embodiments, the CDK4 / 6 inhibitor resistant cancer is intrinsically resistant to the CDK4 / 6 inhibitor. In certain embodiments, the CDK4 / 6 inhibitor resistant cancer has acquired resistance to the CDK4 / 6 inhibitor. In certain embodiments, the CDK4 / 6 inhibitor resistant cancer progresses after a previous regimen including a CDK4 / 6 inhibitor. In some embodiments, the CDK4 / 6 inhibitor of the previous regimen is selected from palbociclib, ribociclib, abemaciclib, tracillin, leloxilib, SHR6390 (Dalxilib), or a combination thereof. In some embodiments, the CDK4 / 6 inhibitor of the prior regimen is selected from BPI-16350, narazaciclib (ON-123300), FLX-925 (AMG-925), UCT-03-008, GLR2007, biroxicam (XZP-3287), LY5219, PF-07220060, or ON-123300. In some embodiments, the CDK4 / 6 inhibitor is palbociclib. In some embodiments, the CDK4 / 6 inhibitor is ribociclib. In some embodiments, the CDK4 / 6 inhibitor is abemaciclib.

[0257] In certain embodiments, the methods of treatment comprise administering a pharmaceutical composition made from a morphological form described herein. In other embodiments, the methods of treatment comprise administering a morphological form described herein.

[0258] In certain aspects, disclosed herein is a method for treating a subject with CDK4 / 6 inhibitor-resistant small cell lung cancer (SCLC), comprising administering to the subject an effective amount of Compound 1 as described herein, or a pharmaceutically acceptable salt or morphological form thereof. In certain embodiments, the method further comprises administering an effective amount of a CDK4 / 6 inhibitor. In some embodiments, the CDK4 / 6 inhibitor is selected from palbociclib, ribociclib, abemaciclib, traxilib, leloxilib, SHR6390 (dalcili). In some embodiments, the CDK4 / 6 inhibitor is selected from BPI-16350, narazaciclib (ON-123300), FLX-925 (AMG-925), UCT-03-008, GLR2007, pyroxilib (XZP-3287), LY5219, PF-07220060, or ON-123300. In some embodiments, the CDK4 / 6 inhibitor is palbociclib. In some embodiments, the CDK4 / 6 inhibitor is ribociclib. In some embodiments, the CDK4 / 6 inhibitor is abemaciclib. In certain embodiments, the method further comprises administering an effective amount of another anticancer therapy. In some embodiments, anticancer therapy is selected from chemotherapeutics, radiation, surgery, immune checkpoint inhibitors, estrogen inhibitors, androgen inhibitors, PARP inhibitors, or a combination thereof. In some embodiments, chemotherapeutics are selected from protein synthesis inhibitors, DNA damaging chemotherapeutics, alkylating agents, topoisomerase inhibitors, RNA synthesis inhibitors, DNA complex binding agents, thiol alkylating agents, guanine alkylating agents, tubulin binding agents, DNA polymerase inhibitors, anticancer enzymes, RAC1 inhibitors, thymidylate synthase inhibitors, oxazophosphorine compounds, integrin inhibitors, antifolates, folic acid antimetabolites, or a combination thereof.

[0259] In certain aspects, disclosed herein are methods for treating subjects with abnormal cell proliferation, comprising monitoring the overexpression and / or activation of cyclin E1 (CCNE1) and / or cyclin E2 (CCNE2) in a sample of the subject compared to a control sample, wherein the overexpression and / or activation of CCNE1 and / or CCNE2 includes abnormal cell proliferative disorders in which cyclin E is amplified or overexpressed; and, after determining that the subject has an abnormal cell proliferative disorder in which cyclin E is amplified or overexpressed, administering an effective amount of Compound 1 or a pharmaceutically acceptable salt thereof to the subject. In certain embodiments, cyclin E1 (CCNE1) and / or cyclin E2 (CCNE2) are overexpressed and / or activated in the sample of the subject to be treated by at least 1.5 times, at least 2.0 times, at least 2.5 times, at least 3.0 times, at least 3.5 times, at least 4.0 times, at least 4.5 times, at least 5.0 times, or greater than 5.0 times, compared to the control sample. In certain embodiments, the method further comprises administering an effective amount of an additional CDK4 / 6 inhibitor. In some embodiments, the additional CDK4 / 6 inhibitor is selected from palbociclib, ribociclib, abemaciclib, triclasiclib, leloxilib, or SHR6390 (dalcili). In some embodiments, the additional CDK4 / 6 inhibitor is selected from BPI-16350, narazaciclib (ON-123300), FLX-925 (AMG-925), UCT-03-008, GLR2007, pyroximate (XZP-3287), LY5219, PF-07220060, or ON-123300. In some embodiments, an NGS panel test is used to confirm the overexpression or amplification status of CCNE1 or CCNE2. In some embodiments, the NGS panel test for confirming the overexpression or amplification status of CCNE1 or CCNE2 is selected from Foundation CDx, Foundation Liquid CDx, Tempus xT (solid tumors), Tempus xF (liquid biopsy), Life Sciences Molecular Profiling or OncoHelix Solid Tumor NGS. In some embodiments, the patient sample is selected from tumor tissue, formalin-fixed paraffin-embedded (FFPE) tumor tissue, blood, or plasma.

[0260] In a primary embodiment, the cancer treated by Compound I described herein, or a pharmaceutically acceptable salt or morphological form thereof, is a cyclin E amplified or overexpressing cancer or small cell lung cancer.

[0261] In some embodiments, the abnormal cell proliferative disorder with amplification or overexpression of cyclin E treated according to the above detailed methods is selected from uterine cancer, uterine carcinosarcoma (UCS), uterine corpus endometrial cancer (UCEC), ovarian cancer, ovarian serous cystadenocarcinoma (OV), sarcoma (SARC), lung cancer, lung squamous cell carcinoma (LUSC), lung adenocarcinoma (LUAD), gastric cancer, gastric adenocarcinoma (STAD), bladder cancer, bladder urothelial carcinoma (BLCA), esophageal cancer, esophageal carcinoma (ESCA), adrenocortical carcinoma. , breast cancer, invasive breast cancer (BRCA), pancreatic cancer, pancreatic adenocarcinoma (PAAD), fallopian tube cancer, primary peritoneal cancer, liver cancer, hepatocellular carcinoma (LIHC), cervical cancer, cervical squamous cell carcinoma (CESC), endocervical adenocarcinoma, mesothelioma (MESO), head and neck squamous cell carcinoma (HSNC), colon cancer, colon adenocarcinoma (COAD), skin cancer, melanoma, cutaneous melanoma of the skin (SKCM), glioblastoma multiforme (GBM), renal cancer or renal chromophobe cell (KICH). In some embodiments, the cancer with cyclin E amplification or overexpression is retinoblastoma (Rb) protein positive. In some embodiments, the cancer with cyclin E amplification or overexpression is CDK4 / 6 inhibitor resistant. In certain embodiments, the CDK4 / 6 inhibitor resistant cancer is intrinsically resistant to CDK4 / 6 inhibitors. In certain embodiments, the CDK4 / 6 inhibitor resistant cancer has acquired resistance to CDK4 / 6 inhibitors. In some embodiments, the cancer with cyclin E amplification or overexpression is resistant to endocrine therapy. In certain embodiments, the cancer resistant to endocrine therapy is intrinsically resistant to endocrine therapy. In certain embodiments, the cancer resistant to endocrine therapy has acquired resistance to endocrine therapy. In some embodiments, endocrine therapy includes an estrogen inhibitor as described herein. In certain embodiments, the cancer is advanced and / or metastatic cancer. In certain embodiments, the cancer is unresectable cancer. In certain embodiments, the cancer is advanced unresectable cancer. In certain embodiments, the cancer is platinum-refractory and / or platinum-resistant. In certain embodiments, the cancer progressed after a previous standard of care regimen. In certain embodiments, the cancer progressed after a previous standard systemic therapy. In certain embodiments, the cancer progressed after a previous systemic anticancer therapy. In certain embodiments, the cancer progressed after a previous regimen including a platinum analog. In certain embodiments, the cancer progressed after a previous regimen including a CDK4 / 6 inhibitor. In certain embodiments, the cancer progressed after a previous regimen including an estrogen inhibitor.

[0262] In certain embodiments, the methods described herein can be used to treat ovarian cancer with overexpression and / or amplification of cyclin E, wherein the ovarian cancer has CCNE1 amplification. In certain embodiments, the ovarian cancer is advanced and / or metastatic cancer. In certain embodiments, the ovarian cancer is advanced, unresectable cancer. In certain embodiments, the ovarian cancer is platinum-refractory and / or platinum-resistant. In certain embodiments, the ovarian cancer progresses after a previous standard of care regimen. In certain embodiments, the ovarian cancer progresses after a previous standard systemic therapy. In certain embodiments, the ovarian cancer progresses after a previous systemic anticancer therapy. In certain embodiments, the ovarian cancer progresses after a previous regimen including a platinum analog. In certain embodiments, the ovarian cancer progresses after a previous regimen including a CDK4 / 6 inhibitor. In certain embodiments, the ovarian cancer progresses after a previous regimen including an estrogen inhibitor.

[0263] In certain embodiments, the method described herein as a whole further includes administering an effective amount of another anti-cancer therapy. In some embodiments, anti-cancer therapy is selected from radiation, surgery, immune checkpoint inhibitors, estrogen inhibitors, androgen inhibitors, PARP inhibitors, or a combination thereof. In some embodiments, the cancer of cyclin E amplification or overexpression is uterine cancer. In some embodiments, the cancer of cyclin E amplification or overexpression is ovarian cancer. In some embodiments, the cancer of cyclin E amplification or overexpression is breast cancer. In certain embodiments, the method further includes administering an effective amount of an estrogen inhibitor. In some embodiments, the estrogen inhibitor is selected from selective estrogen receptor modulators (SERMs), selective estrogen receptor degraders (SERDs), complete estrogen receptor degraders, complete estrogen antagonists, partial estrogen antagonists, or a combination thereof. In some embodiments, the estrogen inhibitor is a selective estrogen receptor degrader (SERD). In some embodiments, SERD includes fulvestrant. In some embodiments, SERD includes elastomeric (RAD1901). In some embodiments, the cancer of cyclin E amplification or overexpression is prostate cancer. In some embodiments, the cancer in which cyclin E is amplified or overexpressed is bladder cancer. In some embodiments, the cancer in which cyclin E is amplified or overexpressed is a sarcoma.

[0264] Compound 1 described herein, or a pharmaceutically acceptable salt or morphological form thereof, can be used as a therapeutic agent when administered in an effective amount to a subject, including a human, to treat tumors, cancers (solid, non-solid, diffuse, hematological, etc.), abnormal cell proliferation, immune disorders, inflammatory disorders, blood disorders, myeloproliferative or lymphoproliferative disorders such as B-cell or T-cell lymphoma, multiple myeloma, breast cancer, prostate cancer, AML, ALL, CLL, myelodysplastic syndrome (MDS), mesothelioma, renal cell carcinoma (RCC), bile duct cancer, lung cancer, pancreatic cancer, colon cancer, skin cancer, melanoma, Waldenstrom's macroglobulinemia, Wiskott-Aldrich syndrome (Wiskott-Aldrich), syndrome) or post-transplant lymphoproliferative disorder; autoimmune disorders such as lupus, Crohn's disease, Addison's disease, celiac disease, dermatomyositis, Graves' disease, thyroiditis, multiple sclerosis, pernicious anemia, reactive arthritis, or type 1 diabetes; cardiological dysfunction including hypercholesterolemia; infectious diseases including viral and / or bacterial infections; inflammatory conditions including asthma, chronic peptic ulcers, tuberculosis, rheumatoid arthritis, periodontitis, ulcerative colitis, or hepatitis.

[0265] In certain embodiments, Compound 1 or a pharmaceutically acceptable salt or morphological form thereof described herein is used to treat breast cancer in which cyclin E is overexpressed or amplified. In certain embodiments, the breast cancer is HR+ and HER2-. In certain embodiments, the breast cancer is HR- and HER2+. In certain embodiments, the breast cancer is ER+ and HER2-. In certain embodiments, the breast cancer is ER- and HER2+. In certain embodiments, the breast cancer is breast cancer in which HER2 is overexpressed. In certain embodiments, the breast cancer includes HER2 gene amplification. In some embodiments, Compound 1 or a pharmaceutically acceptable salt thereof is administered in combination with an antibody drug conjugate (ADC). In some embodiments, Compound 1 or a pharmaceutically acceptable salt thereof is administered in combination with an antibody drug conjugate (ADC) selected from ado-trastuzumab emtansine. trastuzumab deruxtecan or sacituzumab govetican ADCs are administered in combination.

[0266] In certain embodiments, Compound 1 described herein, or a pharmaceutically acceptable salt or morphological form thereof, is used to treat non-small cell lung cancer (NSCLC) in which cyclin E is overexpressed or amplified. In certain embodiments, the NSCLC has an EGFR mutation. In certain embodiments, the NSCLC has an EGFR mutation and an EGFR inhibitor has failed (e.g., a second-line therapy). In certain embodiments, an ALK inhibitor has failed (e.g., a second-line therapy). In certain embodiments, the NSCLC has a KRAS mutation.

[0267] In certain embodiments, Compound 1 as described herein, or a pharmaceutically acceptable salt or morphological form thereof, is used to treat prostate cancer in which cyclin E is overexpressed or amplified. In certain embodiments, the prostate cancer is castration-resistant. In certain embodiments, previous chemotherapy agents have failed (e.g., second-line therapy).

[0268] In certain embodiments, Compound 1 described herein, or a pharmaceutically acceptable salt or morphological form thereof, is used to treat a lymphoma that overexpresses or amplifies cyclin E. In certain embodiments, the lymphoma is mantle cell lymphoma (MCL), marginal zone lymphoma (MZL), chronic lymphocytic leukemia (CLL), follicular lymphoma (FL), or diffuse large B-cell lymphoma (DLBCL). In certain embodiments, prior chemotherapeutic agents have failed (e.g., second-line therapy).

[0269] In certain embodiments, Compound 1 described herein, or a pharmaceutically acceptable salt or morphological form thereof, is used to treat a melanoma that overexpresses or amplifies cyclin E. In certain embodiments, the melanoma has a BRAF mutation.

[0270] In certain embodiments, Compound 1 described herein, or a pharmaceutically acceptable salt or morphological form thereof, is used to treat a RAS mutant cancer with overexpression or amplification of cyclin E. In certain embodiments, the RAS mutant cancer is colon cancer (CLC). In certain embodiments, the RAS mutant cancer is pancreatic cancer. In certain embodiments, the RAS mutant cancer is bile duct cancer.

[0271] In certain embodiments, Compound 1 described herein, or a pharmaceutically acceptable salt or morphological form thereof, is used to treat gastrointestinal stromal tumors (GIST) that overexpress or amplify cyclin E. In certain embodiments, treatment with imatinib or sunitinib has failed (e.g., second-line therapy).

[0272] Exemplary proliferative disorders treated by the detailed methods, compounds, and morphological forms described herein include, but are not limited to, benign growths, neoplasms, tumors, cancers (Rb positive or Rb negative), autoimmune disorders, inflammatory disorders, graft-versus-host rejection, and fibrotic disorders, wherein the disorder is mediated by overexpression or amplification of cyclin E.

[0273] Non-limiting examples of cancers that can be treated according to the detailed methods, compounds, and morphological forms described herein include, but are not limited to, acoustic neuroma, adenocarcinoma, adrenal cancer, anal cancer, angiosarcoma (e.g., lymphangiosarcoma, lymphangioendothelial sarcoma, angiosarcoma), appendix cancer, benign monoclonal gammopathy, biliary cancer (e.g., cholangiocarcinoma), bladder cancer, breast cancer (e.g., adenocarcinoma of the breast, papillary carcinoma of the breast, mammary carcinoma), ovarian cancer, ovarian cancer, ovarian cancer, ovarian cancer, bladder cancer, ovarian ... cancer), medullary carcinoma of the breast), brain cancer (e.g., meningioma; gliomas, such as astrocytomas, oligodendrogliomas; medulloblastomas), bronchogenic carcinoma, carcinoid tumors, cervical cancer (e.g., cervical adenocarcinoma), choriocarcinoma, chordoma, craniopharyngioma, colorectal cancer (e.g., colon cancer, rectal cancer, colorectal adenocarcinoma), epithelial carcinoma, ependymoma, endothelial sarcoma (e.g., Kaposi's sarcoma, multiple idiopathic hemorrhagic sarcoma), endometrial cancer (e.g., uterine cancer, uterine sarcoma), esophageal cancer (e.g., esophageal adenocarcinoma, Barrett's adenocarcinoma), Ewing's Sarcomas, eye cancers (e.g., intraocular melanoma, retinoblastoma), familial hypereosinophilia, gallbladder cancer, stomach cancer (e.g., gastric adenocarcinoma), gastrointestinal stromal tumors (GIST), head and neck cancers (e.g., head and neck squamous cell carcinoma, oral cancers (e.g., oral squamous cell carcinoma (OSCC)), pharyngeal cancers (e.g., larynx, pharynx, nasopharynx, oropharynx)), hematopoietic cancers (e.g., leukemias such as acute lymphoblastic leukemia (ALL) – also called acute lymphoblastic leukemia or acute lymphocytic leukemia (e.g., B-cell ALL, T-cell ALL), acute myeloid leukemia (AML) (e.g., B-cell AML, T-cell AML), chronic myeloid leukemia (CML) (e.g., B-cell CML, T-cell CML), and chronic lymphocytic leukemia (CLL) (e.g., B-cell CLL, T-cell CLL); lymphomas, such as Hodgkin lymphoma (HL) (e.g., B-cell HL, T-cell HL) and non-Hodgkin lymphoma (NHL) (e.g., B-cell NHL, such as diffuse large cell lymphoma (DLCL) (e.g., diffuse large B-cell lymphoma (DLBCL)), follicular lymphoma , chronic lymphocytic leukemia / small lymphocytic lymphoma (CLL / SLL), mantle cell lymphoma (MCL), marginal zone B-cell lymphomas (e.g., mucosa-associated lymphoid tissue (MALT) lymphoma, nodal marginal zone B-cell lymphoma, splenic marginal zone B-cell lymphoma), primary mediastinal B-cell lymphoma, Burkitt lymphoma, lymphoplasmacytic lymphoma (i.e., "Waldenstrom's macroglobulinemia"), hairy cell leukemia (HCL), immunoblastic large cell lymphoma, precursor B-lymphoblastic lymphoma, and primary central nervous system (CNS) lymphoma;and T-cell NHL, such as precursor T-cell blastic lymphoma / leukemia, peripheral T-cell lymphoma (PTCL) (e.g., cutaneous T-cell lymphoma (CTCL) (e.g., mycosis fungoides, Sézary syndrome), angioimmunoblastic T-cell lymphoma, extranodal natural killer T-cell lymphoma, enteropathy-type T-cell lymphoma, subcutaneous panniculitis-like T-cell lymphoma, anaplastic large cell lymphoma); mixtures of one or more leukemias / lymphomas as described above;and multiple myeloma (MM)), heavy chain diseases (e.g., alpha chain disease, gamma chain disease, mu chain disease), hemangioblastoma, inflammatory myofibroblastic tumor, immune cell amyloidosis, kidney cancer (e.g., Wilms' tumor, renal cell carcinoma), liver cancer (e.g., hepatocellular carcinoma (HCC), malignant liver tumor), lung cancer (e.g., bronchogenic carcinoma, small cell lung cancer (SCLC), non-small cell lung cancer (NSCLC), lung adenocarcinoma), leiomyosarcoma (LMS), mastocytosis (e.g., systemic mastocytosis), bone marrow dysplasia (BMD), hepatitis B virus (HV), hepatitis C virus (HIV), hepatitis B ... Myelodysplastic syndrome (MDS), mesothelioma, myeloproliferative disorders (MPDs) (e.g., polycythemia vera (PV), essential thrombocythemia (ET), myeloid metaplasia of unknown cause (AMM) also known as myelofibrosis (MF), chronic idiopathic myelofibrosis, chronic myeloid leukemia (CML), chronic neutrophilic leukemia (CNL), hypereosinophilic syndrome (HES)), neuroblastoma, neurofibromas (e.g., neurofibromatosis (NF) type 1 or type 2, schwannomatosis), neuroendocrine carcinomas (e.g., gastroenteropancreatic neuroendocrine tumors (GEP-NETs), carcinoid tumors), osteosarcoma, ovarian cancer (e.g., cystadenocarcinoma, ovarian embryonal carcinoma, ovarian adenocarcinoma), papillary adenocarcinoma, pancreatic cancer (e.g., pancreatic adenocarcinoma, intraductal papillary mucinous neoplasms (IPMNs), islet cell tumors), penile cancer (e.g., Paget's disease of the penis and scrotum), pinealoma, primitive neuroectodermal tumors (PNTs), prostate cancer (e.g., prostate adenocarcinoma), rectal cancer, rhabdomyosarcoma, salivary gland cancer, skin cancer (e.g., squamous cell carcinoma (SCC), keratoacanthoderma), In some embodiments, the cancer comprises adenocarcinoma (e.g., sarcoma, melanoma, basal cell carcinoma (BCC)), small intestinal cancer (e.g., appendix cancer), soft tissue sarcoma (e.g., malignant fibrous histiocytoma (MFH), liposarcoma, malignant peripheral nerve sheath tumor (MPNST), chondrosarcoma, fibrosarcoma, myxosarcoma), sebaceous gland cancer, sweat gland cancer, synovioma, testicular cancer (e.g., seminoma, testicular embryonal carcinoma), thyroid cancer (e.g., papillary carcinoma of the thyroid, papillary thyroid carcinoma (PTC), medullary thyroid carcinoma), urethral cancer, vaginal cancer, and vulvar cancer (e.g., Paget's disease of the vulva). In some embodiments, the cancer has overexpression and / or amplification of CCNE1 and / or CCNE2. In some embodiments, the cancer is CDK4 / 6 inhibitor-resistant. In some embodiments, the CDK4 / 6 inhibitor-resistant cancer is retinoblastoma (Rb) protein positive (Rb+). In some embodiments, the CDK4 / 6 inhibitor-resistant cancer is retinoblastoma (Rb) protein deficient (Rb-). In some embodiments, the cancer is resistant to endocrine therapy. In some embodiments, the endocrine therapy comprises an estrogen inhibitor.

[0274] In another embodiment, the methods, compounds, and morphological forms described herein can be used to treat myelodysplastic syndrome (MDS).

[0275] In certain embodiments, the methods, compounds, and morphological forms described herein can be used to treat hematopoietic cancers. In certain embodiments, the hematopoietic cancer is a lymphoma. In certain embodiments, the hematopoietic cancer is a leukemia. In certain embodiments, the leukemia is acute myeloid leukemia (AML).

[0276] In certain embodiments, the methods, compounds, and morphological forms described herein can be used to treat myeloproliferative neoplasms. In certain embodiments, the myeloproliferative neoplasm (MPN) is primary myelofibrosis (PMF).

[0277] In certain embodiments, the methods, compounds, and morphological forms described herein can be used to treat solid tumors. As used herein, a solid tumor refers to an abnormal mass of tissue that generally does not contain cysts or fluid areas. Different types of solid tumors are named after the cell types that form them. Examples of solid tumor categories include, but are not limited to, sarcomas, carcinomas, and lymphomas, as described herein above. Additional examples of solid tumors include, but are not limited to, squamous cell carcinoma, colon cancer, breast cancer, prostate cancer, lung cancer, liver cancer, pancreatic cancer, and melanoma.

[0278] In certain embodiments, the condition treated with Compound 1 as described herein, or a pharmaceutically acceptable salt or morphological form thereof, is a disorder associated with abnormal cell proliferation. Abnormal cell proliferation, particularly hyperproliferation, may be the result of a variety of factors, including genetic mutations, infection, exposure to toxins, autoimmune disorders, and the induction of benign or malignant tumors.

[0279] The methods, compounds, and morphological forms described herein can be used to treat a variety of skin disorders associated with excessive cell proliferation. For example, psoriasis is a benign disease of the human skin typically characterized by plaques covered with thickened scales. The disease is caused by an unexplained increase in the proliferation of epidermal cells. Chronic eczema is also associated with significant excessive proliferation of the epidermis. Other diseases caused by excessive proliferation of skin cells include atopic dermatitis, lichen planus, warts, pemphigus vulgaris, actinic keratosis, basal cell carcinoma, and squamous cell carcinoma.

[0280] The methods, compounds, and morphological forms described herein can be used to treat other hyperproliferative cellular disorders, including angiogenic disorders, fibrotic disorders, autoimmune disorders, graft-versus-host rejection, tumors, and cancer.

[0281] The methods, compounds, and morphological forms described herein can be used to treat vascular proliferative disorders, including angiogenic disorders and vasculogenic disorders. Smooth muscle cell proliferation during plaque formation in vascular tissue can lead to, for example, restenosis, retinopathy, and atherosclerosis. Both cell migration and cell proliferation play a role in the formation of atherosclerotic lesions.

[0282] The methods, compounds, and morphological forms described herein can be used to treat fibrotic disorders that are generally caused by abnormal formation of the extracellular matrix. Examples of fibrotic disorders include cirrhosis of the liver and mesangial proliferative cell disorders. Cirrhosis of the liver is characterized by an increase in extracellular matrix components, leading to scarring of the liver. Cirrhosis of the liver can lead to diseases such as cirrhosis of the liver. Increased extracellular matrix that leads to liver scarring can also be caused by viral infections (e.g., hepatitis). Adipocytes appear to play a major role in cirrhosis of the liver.

[0283] The methods, compounds, and morphological forms described herein are useful for treating mesangial disorders caused by abnormal proliferation of mesangial cells. Mesangial hyperproliferative cell disorders include various human kidney diseases, such as glomerulonephritis, diabetic nephropathy, malignant nephrosclerosis, thrombotic microangiopathy syndrome, transplant rejection, and glomerulopathy.

[0284] The methods, compounds, and morphological forms described herein can be used to treat rheumatoid arthritis, a disease with a proliferative component. Rheumatoid arthritis is generally considered an autoimmune disease that is thought to be associated with the activity of autoreactive T cells and is caused by autoantibodies produced against collagen and IgE.

[0285] The methods, compounds, and morphological forms described herein can be used to treat other disorders that may include an abnormal cellular proliferative component selected from Bechet syndrome, acute respiratory distress syndrome (ARDS), ischemic heart disease, post-dialysis syndrome, leukemia, acquired immunodeficiency syndrome, vasculitis, lipid histiocytosis, septic shock, and general inflammation.

[0286] In certain embodiments, the methods, compounds, and morphological forms described herein are useful for treating disorders associated with an immune response.

[0287] For example, contact allergies and asthma are just two examples of immune responses that may be associated with significant morbidity. Others include atopic dermatitis, eczema, Sjögren's syndrome (including keratoconjunctivitis sicca secondary to Sjögren's syndrome), alopecia areata, allergic reactions caused by arthropod bite reactions, Crohn's disease, aphthous ulcers, iritis, conjunctivitis, keratoconjunctivitis, ulcerative colitis, lupus erythematosus of the skin, scleroderma, vaginitis, proctitis, and drug eruptions. These conditions may cause any one or more of the following symptoms or signs: itching, swelling, redness, blisters, crusting, ulcers, pain, scaling, cracking, hair loss, scarring, or fluid exudation involving the skin, eyes, or mucous membranes.

[0288] In atopic dermatitis and eczema in general, immune-mediated leukocyte infiltration (particularly of monocytes, lymphocytes, neutrophils, and eosinophils) into the skin contributes significantly to the pathogenesis of these diseases. Chronic eczema is also associated with significant hyperproliferation of the epidermis. Immune-mediated leukocyte infiltration also occurs in sites other than the skin, such as the airways in asthma and the tear-producing glands of the eye in keratoconjunctivitis sicca.

[0289] In certain non-limiting embodiments, Compound 1 as described herein, or a pharmaceutically acceptable salt or morphological form thereof, is used as a topical agent for the treatment of contact dermatitis, atopic dermatitis, eczematous dermatitis, psoriasis, Sjögren's syndrome (including keratoconjunctivitis sicca secondary to Sjögren's syndrome), alopecia areata, allergic reactions caused by arthropod bite reactions, Crohn's disease, aphthous ulcers, iritis, conjunctivitis, keratoconjunctivitis, ulcerative colitis, asthma, allergic asthma, lupus erythematosus of the skin, scleroderma, vaginitis, proctitis, and drug eruptions. The novel method can also be used to reduce the infiltration of malignant leukocytes into the skin in diseases such as mycosis fungoides. These compounds can also be used to treat dehydrated dry eye conditions (e.g., immune-mediated keratoconjunctivitis) in patients suffering from dehydrated dry eye conditions by topical administration of the compound to the eye.

[0290] Exemplary cancers that can be treated by the methods, compounds, and morphological forms disclosed herein, alone or in combination with at least one additional anticancer agent, include squamous cell carcinoma, basal cell carcinoma, adenocarcinoma, hepatocellular carcinoma, and renal cell carcinoma, bladder cancer, intestinal cancer, breast cancer, cervical cancer, colon cancer, esophageal cancer, head cancer, kidney cancer, liver cancer, lung cancer, neck cancer, ovarian cancer, pancreatic cancer, prostate cancer, and stomach cancer; leukemias; benign and malignant lymphomas, particularly Burkitt's lymphoma and non-Hodgkin's lymphoma; benign and malignant melanomas; myeloproliferative disorders; sarcomas, including Ewing's sarcoma, angiosarcoma, Kaposi's sarcoma, and leukemia. tumors, liposarcoma, myosarcoma, peripheral neuroepithelioma, synovial sarcoma, glioma, astrocytoma, oligodendroglioma, ependymoma, glioblastoma, neuroblastoma, ganglioneuroma, ganglioglioma, medulloblastoma, pineal cell tumor, meningioma, meningiosarcoma, neurofibroma, and schwannoma; colorectal cancer, breast cancer, prostate cancer, cervical cancer, uterine cancer, lung cancer, ovarian cancer, testicular cancer, thyroid cancer, astrocytoma, esophageal cancer, pancreatic cancer, stomach cancer, liver cancer, colon cancer, melanoma; carcinosarcoma, Hodgkin's disease, Wilms' tumor, and teratoma. Additional cancers that can be treated using the disclosed compounds according to the present invention include, for example, acute myeloid leukemia, acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), adenocarcinoma, adenosarcoma, adrenal cancer, adrenocortical cancer, anal cancer, anaplastic astrocytoma, angiosarcoma, appendix cancer, astrocytoma, basal cell carcinoma, B cell lymphoma, bile duct cancer, bladder cancer, bone cancer, bone marrow cancer, intestinal cancer, brain cancer, brain stem glioma, breast cancer, triple (estrogen, progesterone and HER-2) negative breast cancer, double negative breast cancer (negative for two of estrogen, progesterone and HER-2), single negative (negative for one of estrogen, progesterone and HER-2), estrogen receptor positive, HER2 negative breast cancer, estrogen receptor negative breast cancer, estrogen receptor positive breast cancer, metastatic breast cancer, luminal A breast cancer, luminal B Type 1 breast cancer, HER2-negative breast cancer, HER2-positive or -negative breast cancer, progesterone receptor-negative breast cancer, progesterone receptor-positive breast cancer, recurrent breast cancer, carcinoid tumor, cervical cancer, bile duct cancer, chondrosarcoma, chronic lymphocytic leukemia (CLL), chronic myeloid leukemia (CML), colon cancer, colorectal cancer, craniopharyngioma, cutaneous lymphoma, cutaneous melanoma, diffuse astrocytoma, ductal carcinoma in situ (DCIS), endometrial cancer, ependymoma, epithelioid sarcoma, esophageal cancer, Ewing's sarcoma, extrahepatic bile duct cancer, eye cancer, fallopian tube cancer, fibrosarcoma, gallbladder cancer, gastric cancer, gastrointestinal cancer, gastrointestinal carcinoid, gastrointestinal stromal tumor (GIST), germ cell tumor glioblastoma multiforme (GBM), glioma, hairy cell leukemia, head and neck cancer, hemangioendothelioma, Hodgkin's lymphoma, hypopharyngeal cancer, infiltrating ductal carcinoma (IDC), infiltrating lobular carcinoma (ILC),Inflammatory breast cancer (IBC), colorectal cancer, intrahepatic bile duct cancer, invasive breast cancer, pancreatic islet cell carcinoma, jaw cancer, Kaposi's sarcoma, kidney cancer, laryngeal cancer, leiomyosarcoma, leptomeningeal metastasis, leukemia, lip cancer, liposarcoma, liver cancer, lobular carcinoma in situ, low-grade astrocytoma, lung cancer, lymph node cancer, lymphoma, male breast cancer, medullary carcinoma, medulloblastoma, melanoma, meningioma, Merkel cell carcinoma, mesenchymal chondrosarcoma, mesenchymal us), mesothelioma, metastatic breast cancer, metastatic melanoma, metastatic squamous neck cancer, mixed glioma, monodermal teratoma, oral cancer, mucinous carcinoma, mucosal melanoma, multiple myeloma, mycosis fungoides, myelodysplastic syndrome, nasal cancer, nasopharyngeal cancer, cervical cancer, neuroblastoma, neuroendocrine tumor (NET), non-Hodgkin lymphoma, non-small cell lung cancer (NSCLC), oat cell carcinoma, eye cancer, ocular melanoma, oligodendroglioma, oral cancer cancer), oral cavity cancer, oropharyngeal cancer, osteogenic sarcoma, osteosarcoma, ovarian cancer, ovarian epithelial cancer, ovarian germ cell tumor, primary ovarian peritoneal cancer, ovarian sex cord-stromal tumor, Paget's disease, pancreatic cancer, papillary carcinoma, paranasal sinus cancer, parathyroid cancer, pelvic cancer, penile cancer, peripheral nerve cancer, peritoneal cancer, pharyngeal cancer, pheochromocytoma, pilocytic astrocytoma, pineal region tumor, pineoblastoma, pituitary cancer, primary central nervous system (CNS) lymphoma, prostate cancer, rectal cancer, renal cell carcinoma, renal pelvis cancer, rhabdomyosarcoma, salivary gland cancer, soft tissue sarcoma, osteosarcoma, sarcoma, paranasal sinus cancer, skin cancer, small cell lung cancer (SCLC), small intestine cancer, spinal cancer, spinal column cancer cancer), spinal cord cancer, squamous cell carcinoma, gastric cancer, synovial sarcoma, T-cell lymphoma, testicular cancer, pharyngeal cancer, thymoma / thymic carcinoma, thyroid cancer, tongue cancer, tonsil cancer, transitional cell carcinoma, fallopian tube cancer, tubular cancer, undiagnosed cancer, ureteral cancer, urethral cancer, uterine adenocarcinoma, uterine cancer, uterine sarcoma, vaginal cancer, vulvar cancer, T-cell lineage acute lymphoblastic leukemia (T-ALL), T-cell lineage lymphoblastic lymphoma (T-LL), peripheral T-cell lymphoma, adult T-cell leukemia, pre-B ALL, pre-B lymphoma, large B-cell lymphoma, Burkitt lymphoma, B-cell ALL, Philadelphia chromosome-positive ALL, Philadelphia chromosome-positive CML, juvenile myelomonocytic leukemia (JMML), acute promyelocytic leukemia (a subtype of AML), large granular lymphocytic leukemia, adult T-cell chronic leukemia, diffuse large B-cell lymphoma, follicular lymphoma; mucosa-associated lymphoid tissue lymphoma (MALT), small cell lymphocytic lymphoma, mediastinal large B-cell lymphoma,Nodular marginal zone B-cell lymphoma (NMZL); splenic marginal zone lymphoma (SMZL); intravascular large B-cell lymphoma; primary effusion lymphoma; or lymphomatoid granulomatosis; B-cell prolymphocytic leukemia; splenic lymphoma / leukemia, undifferentiated type, splenic diffuse red pulp small B-cell lymphoma; lymphoplasmacytic lymphoma; heavy chain disorders, e.g., alpha heavy chain disease, gamma heavy chain disease, mu heavy chain disease, plasma cell myeloma, solitary plasmacytoma of bone; extraskeletal plasmacytoma; primary cutaneous follicle center lymphoma, T cell / histiocyte-rich large B-cell lymphoma, DLBCL associated with chronic inflammation; Epstein-Barr virus (EBV)+ DLBCL in the elderly; primary mediastinal (thymic) large B-cell lymphoma, primary cutaneous DLBCL, leg type, ALK+ large B-cell lymphoma, plasmablastic lymphoma; large B-cell lymphoma arising in HHV8-related multicentric settings, Castleman disease; B-cell lymphoma, undifferentiated type, with features intermediate between diffuse large B-cell lymphoma or B-cell lymphoma, undifferentiated type, with features intermediate between diffuse large B-cell lymphoma and classical Hodgkin lymphoma.

[0291] In another aspect, a method of increasing BIM expression (e.g., BCLC2L11 expression) to induce apoptosis in a cell is provided, comprising contacting a cell with Compound 1 or a pharmaceutically acceptable composition, salt, morphological form, or isotopic analog thereof described herein. In certain embodiments, the method is an in vitro method. In certain embodiments, the method is an in vivo method. BCL2L11 expression is strictly regulated in cells. BCL2L11 encodes BIM (a pro-apoptotic protein). BCL2L11 is downregulated in many cancers, and BIM is inhibited in many cancers, including chronic myeloid leukemia (CML) and non-small cell lung cancer (NSCLC), and inhibition of BCL2L11 expression can confer resistance to tyrosine kinase inhibitors. See, e.g., Ng et al., Nat. Med. (2012) 18: 521–528.

[0292] In yet another aspect, methods described herein are provided for treating angiogenesis-related conditions. For example, provided herein are methods for treating angiogenesis-related conditions selected from diabetic conditions (e.g., diabetic retinopathy), inflammatory conditions (e.g., rheumatoid arthritis), macular degeneration, obesity, atherosclerosis, or a proliferative disorder, comprising administering to a subject in need thereof Compound 1 as described herein, or a pharmaceutically acceptable composition, salt, morphological form, or isotopic analog thereof.

[0293] In certain embodiments, the angiogenesis-related disorder is macular degeneration. In certain embodiments, methods of treating macular degeneration are provided, comprising administering Compound 1 or a pharmaceutically acceptable composition, salt, morphological form, or isotopic analog thereof as described herein to a subject in need thereof.

[0294] In certain embodiments, the condition associated with angiogenesis is obesity. As used herein, "obesity" and "obesity" refer to Class I obesity, Class II obesity, Class III obesity, and pre-obesity (e.g., "overweight") as defined by the World Health Organization. In certain embodiments, a method of treating obesity is provided, comprising administering Compound 1 or a pharmaceutically acceptable composition, salt, morphological form, or isotopic analog thereof as described herein to a subject in need thereof.

[0295] In certain embodiments, the condition associated with angiogenesis is atherosclerosis. In certain embodiments, methods of treating atherosclerosis are provided, comprising administering Compound 1 or a pharmaceutically acceptable composition, salt, morphological form, or isotopic analog thereof as described herein to a subject in need thereof.

[0296] In certain embodiments, the condition associated with angiogenesis is a proliferative disorder. In certain embodiments, methods of treating a proliferative disorder are provided, comprising administering Compound 1 or a pharmaceutically acceptable composition, salt, morphological form, or isotopic analog thereof as described herein to a subject in need thereof.

[0297] The present invention provides advantageous methods for treating subjects with cancers in which cyclin E is amplified or overexpressed, comprising monitoring a sample from the subject for overexpression and / or activation of cyclin E1 (CCNE1) and / or cyclin E2 (CCNE2) compared to a control sample, wherein overexpression and / or activation of CCNE1 and / or CCNE2 includes a dysproliferative disorder in which cyclin E is amplified or overexpressed, and upon determining that the subject has a dysproliferative disorder in which cyclin E is amplified or overexpressed, administering an effective amount of Compound 1 or a pharmaceutically acceptable composition, salt, morphological form, or isotopic analog thereof as described herein. In certain aspects, Compound 1 or a pharmaceutically acceptable salt thereof is used to treat subjects with cancers in which cyclin E is amplified or overexpressed. In certain aspects, Compound 1 or a pharmaceutically acceptable salt or morphological form thereof as described herein is used to treat subjects who have been screened and determined to have elevated cyclin E expression levels compared to a control subject. In certain aspects, Compound 1 described herein, or a pharmaceutically acceptable salt or morphological form thereof, is used to treat a subject screened and determined to have elevated levels of cyclin E activation compared to a control subject. In some embodiments, an NGS panel test is used to confirm CCNE1 or CCNE2 overexpression or amplification status. In some embodiments, the NGS panel test for confirming CCNE1 or CCNE2 overexpression or amplification status is selected from Foundation CDx, Foundation Liquid CDx, Tempus xT (solid tumors), Tempus xF (liquid biopsy), Life Sciences Molecular Profiling or OncoHelix Solid Tumor NGS. In some embodiments, the patient sample is selected from tumor tissue, formalin-fixed paraffin-embedded (FFPE) tumor tissue, blood or plasma. In certain embodiments, compared to the control sample, cyclin E1 (CCNE1) and / or cyclin E2 (CCNE2) are overexpressed and / or activated in the sample of the subject to be treated by at least 1.5 times, at least 2.0 times, at least 2.5 times, at least 3.0 times, at least 3.5 times, at least 4.0 times, at least 4.5 times, at least 5.0 times or more than 5.0 times. In some aspects, Compound 1 described herein, or a pharmaceutically acceptable salt thereof, or a morphological form thereof, is used in combination with a CDK4 / 6 inhibitor to treat a subject with a cancer having amplified or overexpressed cyclin E. In some aspects, Compound 1 described herein, or a pharmaceutically acceptable salt thereof, or a morphological form thereof, is used to treat a subject with a cancer having amplified or overexpressed cyclin E (which is CDK4 / 6 inhibitor-resistant). In certain embodiments, CDK4 / 6 inhibitor resistant cancer is intrinsically resistant to CDK4 / 6 inhibitors. In certain embodiments, CDK4 / 6 inhibitor resistant cancer has acquired resistance to CDK4 / 6 inhibitors. In some aspects, Compound 1 described herein or its pharmaceutically acceptable salt or morphological form is used in combination with CDK4 / 6 inhibitors to resensitize subjects with cyclin E amplification or overexpressed cancer (which has CDK4 / 6 inhibitor resistance to treatment). In some embodiments, CDK4 / 6 inhibitors are selected from palbociclib, ribociclib, abemaciclib, triclasiclib, leloxilib or SHR6390 (dalcili). In some embodiments, the CDK4 / 6 inhibitor is selected from BPI-16350, narazaciclib (ON-123300), FLX-925 (AMG-925), UCT-03-008, GLR2007, bilociclib (XZP-3287), LY5219, PF-07220060, or ON-123300.

[0298] In another aspect, disclosed herein are methods for treating subjects with CCNE1 amplified cancer. For example, disclosed herein are methods for treating subjects with advanced and / or metastatic solid tumors with CCNE1 amplification, comprising administering to the subject an effective amount of Compound 1 described herein, or a pharmaceutically acceptable salt or morphological form thereof. In certain embodiments, advanced and / or metastatic solid tumors with CCNE1 amplification are platinum-resistant. In certain embodiments, advanced and / or metastatic solid tumors with CCNE1 amplification are platinum-refractory. In certain embodiments, the solid tumor progresses after a previous standard of care regimen. In certain embodiments, advanced or metastatic solid tumors are intolerant or unsuitable for standard therapy. In certain embodiments, the method further comprises administering an effective amount of a CDK4 / 6 inhibitor. In certain embodiments, the CDK4 / 6 inhibitor is selected from palbociclib, ribociclib, abemaciclib, tracillin, lelocillin, or SHR6390 (Dalsilil). In certain embodiments, the CDK4 / 6 inhibitor is selected from BPI-16350, narazaciclib (ON-123300), FLX-925 (AMG-925), UCT-03-008, GLR2007, bilociclib (XZP-3287), LY5219, PF-07220060, or ON-123300. In certain embodiments, the method further comprises administering an effective amount of an additional anticancer therapy. In some embodiments, the anticancer therapy is selected from a chemotherapeutic agent, radiation, surgery, an immune checkpoint inhibitor, an estrogen inhibitor, an androgen inhibitor, a PARP inhibitor, or a combination thereof. In some embodiments, chemotherapeutic agents are selected from protein synthesis inhibitors, DNA damaging chemotherapeutic agents, alkylating agents, topoisomerase inhibitors, RNA synthesis inhibitors, DNA complex binding agents, thiol alkylating agents, guanine alkylating agents, tubulin binding agents, DNA polymerase inhibitors, anticancer enzymes, RAC1 inhibitors, thymidylate synthase inhibitors, oxazaphosphorus compounds, integrin inhibitors, antifolates, folic acid antimetabolites, or combinations thereof. In certain embodiments, anticancer therapy is an estrogen inhibitor. In certain embodiments, estrogen inhibitors are selected from selective estrogen receptor modulators (SERMs), selective estrogen receptor degraders (SERDs), complete estrogen receptor degraders, complete estrogen antagonists, partial estrogen antagonists, or combinations thereof. In certain embodiments, estrogen inhibitors are selective estrogen receptor degraders (SERDs).In certain embodiments, the SERD is selected from fulvestrant, rintodestrant (G1T48), borestrant (ZB-716), brilanestrant (GDC0810), camizestrant (AZD9833), D00502, elastostat (RAD1901), etacstil (GW5638), GW7604, AZD9496, GDC-0927, giredestrant (GDC9545, RG6171), LSZ102, imlunestrant (LY3484356), SAR439859, SCR6852, or ZN-c5. In some embodiments, the SERD includes fulvestrant. In some embodiments, the SERD includes elastostat (RAD1901).

[0299] In another aspect, disclosed herein is a method for treating a subject with a CDK4 / 6 resistant cancer, comprising administering to the subject an effective amount of Compound 1 as described herein, or a pharmaceutically acceptable salt or morphological form thereof; and administering to the subject an effective amount of a CDK4 / 6 inhibitor. In certain embodiments, the CDK4 / 6 inhibitor resistant cancer has acquired resistance to the CDK4 / 6 inhibitor. In certain embodiments, the CDK4 / 6 inhibitor resistant cancer progresses after a previous regimen including a CDK4 / 6 inhibitor. In some embodiments, the CDK4 / 6 inhibitor of the previous regimen is selected from palbociclib, ribociclib, abemaciclib, triclasiclib, leloxilib, SHR6390 (dalcili), or a combination thereof. In some embodiments, the CDK4 / 6 inhibitor of the previous regimen is selected from BPI-16350, narazaciclib (ON-123300), FLX-925 (AMG-925), UCT-03-008, GLR2007, biroxicam (XZP-3287), LY5219, PF-07220060 or ON-123300. In some embodiments, the CDK4 / 6 inhibitor is palbociclib. In some embodiments, the CDK4 / 6 inhibitor is ribociclib. In some embodiments, the CDK4 / 6 inhibitor is abemaciclib. In certain embodiments, the CDK4 / 6 inhibitor-resistant cancer is intrinsically resistant to the CDK4 / 6 inhibitor. In some embodiments, the CDK4 / 6 inhibitor-resistant cancer is retinoblastoma (Rb) protein positive (Rb+). In some embodiments, the CDK4 / 6 inhibitor-resistant cancer has intrinsic CDK4 / 6 inhibitor resistance. In some embodiments, the CDK4 / 6 inhibitor-resistant cancer is retinoblastoma (Rb) protein deficiency (Rb-). In some embodiments, the CDK4 / 6 inhibitor-resistant cancer is selected from breast cancer, lung cancer, small cell lung cancer, uterine cancer, endometrial cancer, ovarian cancer, prostate cancer, bladder cancer, testicular cancer, glioblastoma, head and / or neck cancer or prostate cancer. In some embodiments, the CDK4 / 6 inhibitor-resistant cancer is breast cancer. In some embodiments, the CDK4 / 6 inhibitor-resistant breast cancer is estrogen receptor positive (ER+) breast cancer. In certain embodiments, the CDK4 / 6 inhibitor-resistant cancer is hormone receptor positive (HR+) breast cancer. In some embodiments, the CDK4 / 6 inhibitor-resistant cancer is small cell lung cancer (SCLC). In certain embodiments, the CDK4 / 6 inhibitor-resistant cancer is cyclin E amplified or overexpressed. In some embodiments, Compound I described herein or a pharmaceutically acceptable salt or morphological form thereof is administered to a subject at least once a day, and wherein an effective amount of a CDK4 / 6 inhibitor is administered according to its prescribed label.In some embodiments, Compound 1 or a pharmaceutically acceptable salt thereof is administered to a subject at least twice daily, and an effective amount of a CDK4 / 6 inhibitor is administered according to its prescribed label. In some embodiments, the CDK4 / 6 inhibitor-resistant cancer is also resistant to endocrine therapy or estrogen inhibitors (e.g., SERDs).

[0300] For example, intrinsic resistance to selective CDK4 / 6 inhibitors is determined by determining the loss or deletion of retinoblastoma (Rb) tumor suppressor protein (Rb deficiency). For example, the Rb status of cancer can be determined by, for example, but not limited to, Western blotting, ELISA (enzyme-linked immunosorbent assay), IHC (immunohistochemistry) and FACS (fluorescence-activated cell sorting). The choice of assay will depend on the tissue, cell line or alternative tissue sample used, for example, Western blotting and ELISA can be used for any or all types of tissue, cell line or alternative tissue, while the IHC method is more suitable for the tissue used in the methods described herein is a tumor biopsy. FAC analysis is most suitable for samples that are single cell suspensions, such as cell lines and isolated peripheral blood mononuclear cells. See, for example, US20070212736 "Functional Immunohistochemical Cell Cycle Analysis as a Prognostic Indicator for Cancer".

[0301] Alternatively, molecular genetic testing can be used to determine retinoblastoma gene status. Molecular genetic testing for retinoblastoma includes the following, as described in Lohmann and Gallie "Retinoblastoma. Gene Reviews" (2010) or Parsam et al. "A comprehensive, sensitive and economical approach for the detection of mutations in the RB1 gene in retinoblastoma" Journal of Genetics, 88(4), 517-527 (2009).

[0302] The activity of cyclin E or the increase of level can be determined by any standard assay known to those skilled in the art, including but not limited to next generation sequencing (NGS), Western blotting, ELISA (enzyme-linked immunosorbent assay), IHC (immunohistochemistry) and FACS (fluorescence activated cell sorting). The selection of assay depends on the tissue, cell line or alternative tissue sample used, for example, Western blotting and ELISA can be used for any or all types of tissue, cell line or alternative tissue, while the IHC method is more suitable for the tissue used in the method is tumor biopsy. FAC analysis is most suitable for samples that are single cell suspensions, such as cell lines and isolated peripheral blood mononuclear cells.

[0303] In some embodiments, an NGS panel test is used to confirm the overexpression or amplification status of CCNE1 or CCNE2. NGS panel tests for patient samples are known to those skilled in the art. In some embodiments, an NGS panel test for confirming the overexpression or amplification status of CCNE1 or CCNE2 is selected from the Foundation CDx, Foundation LiquidCDx, Tempus xT (solid tumors), Tempus xF (liquid biopsy), Life SciencesMolecular Profiling or OncoHelix Solid Tumor NGS. In some embodiments, the patient sample is selected from tumor tissue, formalin-fixed paraffin-embedded (FFPE) tumor tissue, blood, or plasma. For example, an NGS panel is an in vitro diagnostic device for detecting substitutions, insertions, deletions (e.g., insertion-deletions (indels)), and copy number changes in a panel of selected genes using DNA isolated from a sample (e.g., formalin-fixed paraffin-embedded (FFPE) tumor tissue). In short, DNA is extracted from a sample obtained from the patient using a DNA extraction method. Using a next-generation sequencing platform (e.g., The HiSeq 4000) performs whole-genome shotgun library construction and hybridization-based capture to sequence the coding exon or intron regions of the panel of selected genes at a high uniform depth. The sequence data is then processed after collection to detect genomic changes, including but not limited to base substitutions, indels, copy number changes (e.g., amplification, homozygous gene deletion), genomic rearrangements (e.g., gene fusions), microsatellite instability (MSI), tumor mutation burden (TMB), and positive homologous recombination deficiency (HRD) status. In some embodiments, the NGS panel test confirms CCNE1 or CCNE2 overexpression or amplification status at any time during or after the original diagnosis but before the first administration of Compound I.

[0304] Immunohistochemistry (IHC) and immunocytochemistry (ICC) are techniques used to localize expression and rely on specific epitope-antibody interactions. IHC refers to the use of tissue sections, while ICC refers to the use of cultured cells or cell suspensions. In both methods, positive staining is visualized using molecular markers, which can be fluorescent or chromogenic. Briefly, the sample is fixed to maintain cell integrity and then incubated with a blocking reagent to prevent nonspecific binding of antibodies. The sample is then incubated with primary and secondary antibodies, and the signal is visualized for microscopic analysis.

[0305] Western blotting uses three elements to identify specific proteins from a complex mixture of proteins extracted from cells: separation by size, transfer to a solid support, and labeling of the target protein with appropriate primary and secondary antibodies for visualization. The most common version of this method is immunoblotting. This technique is used to detect specific proteins in a given sample of tissue homogenate or extract. The protein sample is first electrophoresed using SDS-PAGE to separate the proteins according to their molecular weight. The proteins are then transferred to a membrane, where they are probed with antibodies specific for the target protein.

[0306] Genomic alterations and mRNA expression can be determined by fluorescence in situ hybridization (FISH), targeted sequencing, and microarray analysis. Commonly mutated genes as well as differentially expressed and co-expressed genes can be identified.

[0307] Fluorescence in situ hybridization (FISH) is a cytogenetic technique used to detect and localize RNA sequences within tissues or cells. It is particularly important for defining spatiotemporal patterns of gene expression. FISH relies on fluorescent probes that bind to complementary RNA sequences of interest. A series of hybridization steps are performed to achieve signal amplification of the target of interest. This amplification is then observed using fluorescence microscopy. The technique can be used on formalin-fixed, paraffin-embedded (FFPE) tissues, frozen tissues, fresh tissues, cells, and circulating tumor cells.

[0308] Targeted RNA sequencing (RNA-Seq) is a highly accurate method for selecting and sequencing specific transcripts of interest. It provides both quantitative and qualitative information. Targeted RNA-Seq can be achieved using either enrichment or amplicon-based approaches, both of which allow gene expression analysis within a focused set of genes of interest. Enrichment assays also provide the ability to detect known and novel gene fusion partners in many sample types, including formalin-fixed paraffin-embedded (FFPE) tissues. RNA enrichment provides quantitative expression information as well as detection of small variants and gene fusions.

[0309] In microarray analysis, mRNA molecules are usually collected from experimental samples and reference samples. For example, reference samples can be collected from healthy individuals, while experimental samples can be collected from individuals with diseases (such as cancer). The two mRNA samples are then converted into complementary DNA (cDNA), and each sample is labeled with a fluorescent probe of a different color. The experimental cDNA sample can be labeled with a red fluorescent dye, while the reference cDNA can be labeled with a green fluorescent dye. The two samples are then mixed together and allowed to mix onto a microarray slide. After hybridization, the microarray is scanned to measure the expression of each gene printed on the slide. If the expression of a particular gene in the experimental sample is higher than that in the reference sample, the corresponding point on the microarray is displayed in red. Conversely, if the expression in the experimental sample is lower than that in the reference sample, the point is displayed in green. Finally, if the expression in the two samples is equal, the point is displayed in yellow. The data collected by microarrays can be used to create gene expression profiles, which show that the expression of many genes changes simultaneously in response to specific conditions or treatments.

[0310] In another aspect, disclosed herein is a method for treating a subject with CDK4 / 6 inhibitor-resistant small cell lung cancer (SCLC), comprising administering to the subject an effective amount of Compound 1 as described herein or a pharmaceutically acceptable salt or morphological form thereof. In certain embodiments, the method further comprises administering an effective amount of another anticancer therapy. In some embodiments, the anticancer therapy is selected from chemotherapeutics, radiation, surgery, immune checkpoint inhibitors, estrogen inhibitors, androgen inhibitors, PARP inhibitors, or a combination thereof. In some embodiments, chemotherapeutics are selected from protein synthesis inhibitors, DNA damage chemotherapeutics, alkylating agents, topoisomerase inhibitors, RNA synthesis inhibitors, DNA complex binding agents, thiol alkylating agents, guanine alkylating agents, microtubule binding agents, DNA polymerase inhibitors, anticancer enzymes, RAC1 inhibitors, thymidylate synthase inhibitors, oxazaphosphorus compounds, integrin inhibitors, antifolates, folic acid antimetabolites, or a combination thereof. In some embodiments, the chemotherapeutics are carboplatin. In some embodiments, the chemotherapeutics are etoposide. In some embodiments, the chemotherapeutics are doxorubicin. In some embodiments, the chemotherapeutics are camptothecin. In some embodiments, the chemotherapeutic agent is cisplatin.

[0311] In another aspect, disclosed herein is a method for treating a subject having advanced and / or metastatic ovarian cancer with CCNE1 amplification, comprising administering to the subject an effective amount of Compound 1 as described herein, or a pharmaceutically acceptable salt or morphological form thereof. In certain embodiments, the advanced and / or metastatic ovarian cancer with CCNE1 amplification is platinum-resistant. In certain embodiments, the advanced and / or metastatic ovarian cancer with CCNE1 amplification is platinum-refractory. In certain embodiments, the ovarian cancer is epithelial ovarian cancer. In certain embodiments, the ovarian cancer is fallopian tube cancer. In certain embodiments, the ovarian cancer is primary peritoneal cancer. In certain embodiments, the ovarian cancer progresses after a previous standard of care regimen. In certain embodiments, the ovarian cancer progresses after a previous standard systemic therapy. In certain embodiments, the ovarian cancer progresses after a previous systemic anticancer therapy. In certain embodiments, the ovarian cancer progresses after a previous regimen including a platinum analog. In certain embodiments, the method further comprises administering an effective amount of a CDK4 / 6 inhibitor. In certain embodiments, the CDK4 / 6 inhibitor is selected from palbociclib, ribociclib, abemaciclib, triclasiclib, leloxilib or SHR6390 (dalcili). In some embodiments, the CDK4 / 6 inhibitor is selected from BPI-16350, narazaciclib (ON-123300), FLX-925 (AMG-925), UCT-03-008, GLR2007, pyroxilib (XZP-3287), LY5219, PF-07220060 or ON-123300. In certain embodiments, the method further comprises administering an effective amount of another anticancer therapy. In some embodiments, the anticancer therapy is selected from chemotherapeutics, radiation, surgery, immune checkpoint inhibitors, estrogen inhibitors, androgen inhibitors, PARP inhibitors, or a combination thereof. In some embodiments, chemotherapeutic agents are selected from protein synthesis inhibitors, DNA damaging chemotherapeutic agents, alkylating agents, topoisomerase inhibitors, RNA synthesis inhibitors, DNA complex binding agents, thiol alkylating agents, guanine alkylating agents, tubulin binding agents, DNA polymerase inhibitors, anticancer enzymes, RAC1 inhibitors, thymidylate synthase inhibitors, oxazaphosphorus compounds, integrin inhibitors, antifolates, folic acid antimetabolites, or combinations thereof. In certain embodiments, anticancer therapy is an estrogen inhibitor. In certain embodiments, estrogen inhibitors are selected from selective estrogen receptor modulators (SERMs), selective estrogen receptor degraders (SERDs), complete estrogen receptor degraders, complete estrogen antagonists, partial estrogen antagonists, or combinations thereof. In certain embodiments, estrogen inhibitors are selective estrogen receptor degraders (SERDs). In some embodiments, SERDs include fulvestrant. In some embodiments, SERDs include elastomeric (RAD1901).

[0312] In another aspect, disclosed herein is a method for treating a subject with advanced and / or metastatic human epidermal growth factor 2 negative (HER2-) breast cancer, comprising administering to the subject an effective amount of Compound 1 as described herein, or a pharmaceutically acceptable salt or morphological form thereof. In certain embodiments, breast cancer is hormone receptor positive (HR+). In certain embodiments, breast cancer is HR+ / HER2- breast cancer. In certain embodiments, breast cancer is estrogen receptor positive (ER+). In certain embodiments, breast cancer is ER+ / HER2- breast cancer. In certain embodiments, advanced and / or metastatic human epidermal growth factor 2 negative (HER2-) breast cancer is platinum-resistant. In certain embodiments, advanced and / or metastatic human epidermal growth factor 2 negative (HER2-) breast cancer is platinum-refractory. In certain embodiments, advanced and / or metastatic human epidermal growth factor 2 negative (HER2-) breast cancer progresses after a previous standard of care regimen. In certain embodiments, the method further comprises administering an effective amount of another anticancer therapy. In some embodiments, the anticancer therapy is selected from chemotherapeutic agents, radiation, surgery, immune checkpoint inhibitors, estrogen inhibitors, androgen inhibitors, PARP inhibitors, or a combination thereof. In some embodiments, the chemotherapeutic agent is selected from protein synthesis inhibitors, DNA damaging chemotherapeutic agents, alkylating agents, topoisomerase inhibitors, RNA synthesis inhibitors, DNA complex binding agents, thiol alkylating agents, guanine alkylating agents, tubulin binding agents, DNA polymerase inhibitors, anticancer enzymes, RAC1 inhibitors, thymidylate synthase inhibitors, oxazaphosphorus compounds, integrin inhibitors, antifolates, folic acid antimetabolites, or a combination thereof.

[0313] In certain embodiments, Compound 1 as described herein, or a pharmaceutically acceptable salt or morphological form thereof, is administered at a dose of about 0.1 mg to about 2000 mg, about 10 mg to about 1000 mg, about 100 mg to about 800 mg, or about 200 mg to about 600 mg. In certain embodiments, Compound 1 is administered at a dose of about 100 mg to about 800 mg. In certain embodiments, Compound 1 as described herein, or a pharmaceutically acceptable salt or morphological form thereof, is administered at a dose of about 100 mg, about 150 mg, about 200 mg, about 250 mg, about 300 mg, about 350 mg, about 400 mg, about 450 mg, about 500 mg, about 550 mg, about 600 mg, about 650 mg, about 700 mg, about 750 mg, or about 800 mg. In certain embodiments, Compound 1 as described herein, or a pharmaceutically acceptable salt or morphological form thereof, is administered at a dose of about 100 mg. In certain embodiments, Compound 1 as described herein, or a pharmaceutically acceptable salt or morphological form thereof, is administered at a dose of about 200 mg. In certain embodiments, Compound 1 as described herein, or a pharmaceutically acceptable salt or morphological form thereof, is administered at a dose of about 300 mg. In certain embodiments, Compound 1 as described herein, or a pharmaceutically acceptable salt or morphological form thereof, is administered at a dose of about 400 mg. In certain embodiments, Compound 1 as described herein, or a pharmaceutically acceptable salt or morphological form thereof, is administered at a dose of about 500 mg. In certain embodiments, Compound 1 as described herein, or a pharmaceutically acceptable salt or morphological form thereof, is administered at a dose of about 600 mg. In certain embodiments, Compound 1 as described herein, or a pharmaceutically acceptable salt or morphological form thereof, is administered at a dose of about 700 mg. In certain embodiments, Compound 1 as described herein, or a pharmaceutically acceptable salt or morphological form thereof, is administered at a dose of about 800 mg.

[0314] In certain embodiments, the methods described herein further include administering an effective amount of another anticancer therapy. In some embodiments, the anticancer therapy is selected from chemotherapeutics, radiation, surgery, immune checkpoint inhibitors, estrogen inhibitors, androgen inhibitors, PARP inhibitors, or a combination thereof. In some embodiments, the anticancer therapy includes chemotherapeutics. In some embodiments, the chemotherapeutics are selected from protein synthesis inhibitors, DNA damaging chemotherapeutics, alkylating agents, topoisomerase inhibitors, RNA synthesis inhibitors, DNA complex binders, thiol alkylating agents, guanine alkylating agents, tubulin binders, DNA polymerase inhibitors, anticancer enzymes, RAC1 inhibitors, thymidylate synthase inhibitors, oxazaphosphorus compounds, integrin inhibitors, antifolates, folic acid antimetabolites, or a combination thereof. In some embodiments, the chemotherapeutic agent is selected from cisplatin, carboplatin, etoposide, oxaliplatin, 5-fluorouracil, floxuridine, capecitabine, gemcitabine, mitomycin, methotrexate, vinblastine, cyclophosphamide, dacarbazine, albumin-bound paclitaxel, ifosfamide, topotecan, irinotecan, docetaxel, temozolomide, paclitaxel, doxorubicin, camptothecin, or a combination thereof. In some embodiments, Compound 1 as described herein, or a pharmaceutically acceptable salt or morphological form thereof, is administered within 24 hours or less of the administration of the chemotherapeutic agent. In some embodiments, Compound 1 as described herein, or a pharmaceutically acceptable salt or morphological form thereof, is administered within 6 hours or less of the administration of the chemotherapeutic agent. In some embodiments, Compound 1 as described herein, or a pharmaceutically acceptable salt or morphological form thereof, is administered within 3 hours or less of the administration of the chemotherapeutic agent. In some embodiments, Compound 1 as described herein, or a pharmaceutically acceptable salt or morphological form thereof, is administered to a subject at least once daily, and wherein an effective amount of the anticancer therapy is administered according to its prescribed label. In some embodiments, Compound 1, or a pharmaceutically acceptable salt or morphological form thereof, as described herein is administered to a subject at least twice daily, and wherein an effective amount of the anti-cancer therapy is administered in accordance with its prescribed label.

[0315] In certain embodiments, the methods described herein further include administering an effective amount of an estrogen inhibitor. In some embodiments, the estrogen inhibitor is selected from a selective estrogen receptor modulator (SERM), a selective estrogen receptor degrader (SERD), a complete estrogen receptor degrader, a complete estrogen antagonist, a partial estrogen antagonist, or a combination thereof. In some embodiments, the estrogen inhibitor is a selective estrogen receptor degrader (SERD). In some embodiments, SERD includes fulvestrant. In some embodiments, SERD includes elastomeric (RAD1901).

[0316] In certain embodiments, the methods described herein further include administering an effective amount of a chemotherapeutic agent. In some embodiments, the chemotherapeutic agent is selected from cisplatin, carboplatin, etoposide, oxaliplatin, 5-fluorouracil, floxuridine, capecitabine, gemcitabine, mitomycin, methotrexate, vinblastine, cyclophosphamide, dacarbazine, albumin-bound paclitaxel, ifosfamide, topotecan, irinotecan, docetaxel, temozolomide, paclitaxel, doxorubicin, camptothecin, or a combination thereof. In some embodiments, CDK4 / 6 inhibitor-resistant ER+ breast cancer is luminal A breast cancer. In some embodiments, Compound 1 as described herein, or a pharmaceutically acceptable salt or morphological form thereof, is administered to a subject at least once a day, and wherein an effective amount of the chemotherapeutic agent is administered according to its prescribed label. In some embodiments, Compound 1 as described herein, or a pharmaceutically acceptable salt or morphological form thereof, is administered to a subject at least twice a day, and wherein an effective amount of the chemotherapeutic agent is administered according to its prescribed label. In certain embodiments, the cancer progresses after a previous regimen including a CDK4 / 6 inhibitor. In certain embodiments, the cancer that progressed after a previous regimen including a CDK4 / 6 inhibitor is CDK4 / 6 inhibitor-resistant. In some embodiments, the CDK4 / 6 inhibitor is selected from palbociclib, ribociclib, abemaciclib, traxacil, leloxilib or SHR6390 (dalcili). In some embodiments, the CDK4 / 6 inhibitor is selected from BPI-16350, narazaciclib (ON-123300), FLX-925 (AMG-925), UCT-03-008, GLR2007, pyroxilib (XZP-3287), LY5219, PF-07220060 or ON-123300. In some embodiments, the CDK4 / 6 inhibitor is palbociclib. In some embodiments, the CDK4 / 6 inhibitor is ribociclib. In some embodiments, the CDK4 / 6 inhibitor is abemaciclib. In some embodiments, the CDK4 / 6 inhibitor-resistant cancer is lung cancer. In some embodiments, the CDK4 / 6 inhibitor-resistant lung cancer is small cell lung cancer (SCLC).

[0317] III. Pharmaceutical Compositions and Dosage Forms

[0318] Compound 1 or a pharmaceutically acceptable salt thereof, or an isotopic analog thereof, or a morphological form described herein, can be administered to a host in an effective amount according to the methods described herein to treat any of the disorders described herein using any suitable method to achieve the desired therapeutic outcome. The amount and timing of Compound 1 administration will, of course, depend on the host being treated, the instructions of the supervising medical professional, the time course of exposure, the mode of administration, the pharmacokinetic properties, and the judgment of the prescribing physician. Therefore, due to host-to-host variability, the dosages given below are guidelines, and the physician can titrate the dosage of the compound to achieve the treatment that the physician deems appropriate for the host. In considering the desired degree of treatment, the physician can balance various factors, such as the age and weight of the host, the presence of pre-existing disease, and the presence of other diseases.

[0319] In certain embodiments, pharmaceutical compositions are prepared from the morphological forms described herein. For example, in certain embodiments, pharmaceutical compositions are prepared from the morphological forms described herein, and in the final pharmaceutical composition, the compound is no longer in the same morphological form or is amorphous. In certain embodiments, the use of the morphological forms described herein provides improved purity, yield, manufacturing control, reproducibility, and / or scalability for the manufacture of pharmaceutical compositions of Compound 1 or pharmaceutical compositions thereof.

[0320] The pharmaceutical composition can be formulated into any pharmaceutically useful form, such as a liquid oral dosage form, a solid oral dosage form, a semisolid oral dosage form, as an aerosol, a cream, a gel, a pill, an injectable or infusible solution, a capsule, a tablet, a syrup, a transdermal patch, a subcutaneous patch, a dry powder, an inhalation formulation, a medical device, a suppository, a buccal or sublingual formulation, a parenteral formulation, an intravenous solution, or an ophthalmic solution. Some dosage forms, such as tablets and capsules, are subdivided into suitably sized unit doses containing an appropriate amount of the active ingredient, such as an effective amount to achieve the desired purpose.

[0321] The compounds disclosed herein or used as described herein can be administered orally, topically, parenterally, by inhalation or spray, sublingually, by implant (including ocular implants), transdermally, by buccal application, rectally, as an ophthalmic solution, by injection (including ocular injection), intravenously, intramuscularly, by inhalation, intraaortically, intracranially, subdermally, intraperitoneally, subcutaneously, nasally, sublingually, or rectally, or by other means, in dosage unit formulations containing conventional pharmaceutically acceptable carriers. For ocular delivery, the compounds can be administered as desired, for example, by intravitreal, intrastromal, intracameral, sub-tenon, subretinal, retrobulbar, peribulbar, suprachorodial, conjunctival, subconjunctival, suprascleral, periocular, transscleral, retrobulbar, posterior juxtascleral, pericorneal, or canaliculus injection, or through mucus, mucin, or mucosal barriers, in an immediate or controlled release manner or via an ocular device.

[0322] In certain embodiments, pharmaceutical compositions comprising Compound 1 as described herein, or a pharmaceutically acceptable salt or morphological form thereof, are administered orally. For example, in certain embodiments, pharmaceutical compositions comprise Compound 1 as described herein, or a pharmaceutically acceptable salt or morphological form thereof, and polyethylene glycol and / or hydroxypropyl methylcellulose.

[0323] A healthcare practitioner can determine the therapeutically effective dose of Compound I described herein, or a pharmaceutically acceptable salt or morphological form thereof, based on the patient's condition, size, and age, and the route of delivery. In certain non-limiting embodiments, a dose of about 0.1 to about 200 mg / kg has therapeutic efficacy, with all weights calculated based on the weight of Compound I, including the use of salts. In certain embodiments, the dose is about or greater than 0.1, 0.5, 1, 5, 10, 25, 50, 75, 100, 125, 150, 175, or 200 mg / kg. In some embodiments, the dose can be the amount of compound required to provide a serum concentration of Compound I of up to about 10 nM, 50 nM, 100 nM, 200 nM, 300 nM, 400 nM, 500 nM, 600 nM, 700 nM, 800 nM, 900 nM, 1 μM, 5 μM, 10 μM, 20 μM, 30 μM, or 40 μM.

[0324] In certain embodiments, the pharmaceutical composition is a dosage form containing about 0.1 mg to about 2000 mg, about 10 mg to about 1000 mg, about 100 mg to about 800 mg, or about 200 mg to about 600 mg of Compound 1, or a pharmaceutically acceptable salt thereof, and optionally about 0.1 mg to about 2000 mg, about 10 mg to about 1000 mg, about 100 mg to about 800 mg, or about 200 mg to about 600 mg of an additional active agent in a unit dosage form. Examples of dosage forms include at least about 5, about 10, about 15, about 20, about 25, about 50, about 75, about 100, about 150, about 175, about 200, about 250, about 300, about 350, about 400, about 450, about 500, about 500, about 600, about 650, about 700, about 750 mg, or about 800 mg of Compound 1, or a salt thereof, or a morphological form described herein. In certain embodiments, the pharmaceutical composition is a dosage form containing about 100 mg of Compound 1, or a pharmaceutically acceptable salt or morphological form thereof, as described herein. In certain embodiments, the pharmaceutical composition is a dosage form containing about 200 mg of Compound 1, or a pharmaceutically acceptable salt or morphological form thereof, as described herein. In certain embodiments, the pharmaceutical composition is a dosage form containing about 300 mg of Compound 1, or a pharmaceutically acceptable salt or morphological form thereof, as described herein. In certain embodiments, the pharmaceutical composition is a dosage form containing about 400 mg of Compound 1 as described herein, or a pharmaceutically acceptable salt or morphological form thereof. In certain embodiments, the pharmaceutical composition is a dosage form containing about 500 mg of Compound 1 as described herein, or a pharmaceutically acceptable salt or morphological form thereof. In certain embodiments, the pharmaceutical composition is a dosage form containing about 600 mg of Compound 1 as described herein, or a pharmaceutically acceptable salt or morphological form thereof. In certain embodiments, the pharmaceutical composition is a dosage form containing about 700 mg of Compound 1 as described herein, or a pharmaceutically acceptable salt or morphological form thereof. In certain embodiments, the pharmaceutical composition is a dosage form containing about 800 mg of Compound 1 as described herein, or a pharmaceutically acceptable salt or morphological form thereof. The pharmaceutical composition may also contain a molar ratio of Compound 1, or a pharmaceutically acceptable salt thereof, and an additional active agent in a ratio to achieve the desired result.

[0325] In some embodiments, a compound disclosed herein, or a pharmaceutically acceptable salt thereof, or a morphological form described herein or used as described, is administered once a day (QD), twice a day (BID), or three times a day (TID). In some embodiments, Compound 1 described herein, or a pharmaceutically acceptable salt thereof, or a morphological form thereof, is administered once a day (QD). In some embodiments, Compound 1 described herein, or a pharmaceutically acceptable salt thereof, or a morphological form thereof, is administered twice a day (BID). In some embodiments, Compound 1 described herein, or a pharmaceutically acceptable salt thereof, or a morphological form thereof, is administered three times a day (TID). In some embodiments, Compound 1 described herein, or a pharmaceutically acceptable salt thereof, or a morphological form thereof, is administered at least once a day for at least 21 days, at least 24 days, at least 28 days, at least 35 days, at least 45 days, at least 60 days, at least 75 days, at least 90 days, at least 120 days, at least 180 days, or longer, indefinitely, or until a healthcare provider determines that the drug is no longer needed.

[0326] According to the currently disclosed methods, oral administration can be in any desired form, such as a solid, gel or liquid, including a solution, suspension or emulsion. In some embodiments, the compound or salt is administered as a liposomal suspension by inhalation, intravenously or intramuscularly. When administered by inhalation, Compound 1 or a salt or a morphological form described herein can be in the form of a plurality of solid particles or droplets having any desired particle size, for example, from about 0.01, 0.1 or 0.5 to about 5, 10, 20 or more microns, and optionally from about 1 to about 2 microns. The compounds disclosed herein have shown good pharmacokinetic and pharmacodynamic properties, for example, when administered by oral or intravenous routes.

[0327] The pharmaceutical formulation may comprise Compound 1 described herein, or a pharmaceutically acceptable salt or morphological form thereof, in any pharmaceutically acceptable carrier. If a solution is desired, water may sometimes be the preferred carrier for water-soluble compounds or salts. For water-soluble compounds or salts, organic vehicles, such as glycerol, propylene glycol, polyethylene glycol, or mixtures thereof, may be suitable. In the latter case, the organic vehicle may contain a large amount of water. The solution in either case may then be sterilized in a suitable manner known to those skilled in the art and, for example, filtered through a 0.22 micron filter. After sterilization, the solution may be dispensed into appropriate containers, such as depyrogenated glass vials. Distribution is optionally performed by aseptic methods. Sterilized closures may then be placed on the vials, and the vial contents may be lyophilized if desired.

[0328] The carrier includes an excipient and a diluent and must be of sufficiently high purity and sufficiently low toxicity to make it suitable for administration to a patient being treated. The carrier may be inert, or it may have its own pharmaceutical benefits. The amount of carrier used with the compound is an amount sufficient to provide the actual material for administration of the compound per unit dose.

[0329] The types of carriers include, but are not limited to, binders, buffers, colorants, diluents, disintegrants, emulsifiers, flavorings, glidants, lubricants, preservatives, stabilizers, surfactants, tableting agents, and wetting agents. Some carriers may be listed in multiple categories; for example, vegetable oils may be used as lubricants in some formulations and as diluents in other formulations. Exemplary pharmaceutically acceptable carriers include sugars, starches, cellulose, tragacanth powder, malt, gelatin, talc, and vegetable oils. Optional active agents may be included in the pharmaceutical composition that do not substantially interfere with the activity of the compound.

[0330] In addition, auxiliary substances, such as wetting agents or emulsifiers, biological buffer substances, surfactants, etc., may be present in such vehicles. The biological buffer can be any pharmacologically acceptable solution that provides the desired pH for the formulation, i.e., a pH within a physiologically acceptable range. Examples of buffer solutions include saline, phosphate-buffered saline, Tris-buffered saline, Hank's buffered saline, and the like.

[0331] Depending on the intended mode of administration, the pharmaceutical composition may be in the form of a solid, semisolid, or liquid dosage form, such as a tablet, suppository, pill, capsule, powder, liquid, suspension, cream, ointment, lotion, etc., preferably in a unit dosage form suitable for single administration of a precise dose. The composition will include an effective amount of the selected drug in combination with a pharmaceutically acceptable carrier and may also include other agents, adjuvants, diluents, buffers, etc.

[0332] Thus, the compositions of the present disclosure can be administered as pharmaceutical formulations, including those suitable for oral (including buccal and sublingual), rectal, nasal, topical, pulmonary, vaginal or parenteral (including intramuscular, intraarterial, intrathecal, subcutaneous and intravenous) administration, or in a form suitable for administration by inhalation or insufflation. The preferred route of administration is intravenous or oral, which allows for a convenient daily dosage regimen that can be adjusted according to the degree of affliction.

[0333] For solid compositions, conventional non-toxic solid carriers include, for example, pharmaceutical grade mannitol, lactose, starch, magnesium stearate, sodium saccharin, talc, cellulose, glucose, sucrose, magnesium carbonate, and the like. Liquid pharmaceutically administrable compositions can be prepared, for example, by dissolving, dispersing, or the like Compound I described herein, or a pharmaceutically acceptable salt or morphological form thereof, and optional pharmaceutical adjuvants, in an excipient (e.g., water, saline, aqueous dextrose, glycerol, ethanol, and the like) to form a solution or suspension. If desired, the pharmaceutical composition to be administered may also contain small amounts of non-toxic auxiliary substances, such as wetting agents or emulsifiers, pH buffers, and the like, such as sodium acetate, sorbitan monolaurate, triethanolamine sodium acetate, triethanolamine oleate, and the like. The actual methods for preparing such dosage forms are known or readily apparent to those skilled in the art; for example, see Remington's Pharmaceutical Sciences cited above.

[0334] In yet another embodiment, penetration enhancer excipients are used, including polymers such as: polycations (chitosan and its quaternary ammonium derivatives, poly-L-arginine, aminated gelatin); polyanions (N-carboxymethylchitosan, polyacrylic acid); and, thiolated polymers (carboxymethylcellulose-cysteine, polycarbophil-cysteine, chitosan-thiobutylamidine, chitosan-thioglycolic acid, chitosan-glutathione conjugates).

[0335] For oral administration, the composition is usually in the form of tablets, capsules, soft gel capsules, or can be an aqueous or non-aqueous solution, suspension or syrup. Tablets and capsules are preferred oral administration forms. Tablets and capsules for oral use can include one or more commonly used carriers, such as lactose and corn starch. Lubricants, such as magnesium stearate, are usually also added. Usually, the composition of the present disclosure can be combined with oral, non-toxic, pharmaceutically acceptable inert carriers (such as lactose, starch, sucrose, glucose, methylcellulose, magnesium stearate, dicalcium phosphate, calcium sulfate, mannitol, sorbitol, etc.). In addition, when needed or necessary, suitable binders, lubricants, disintegrants and colorants can also be incorporated into the mixture. Suitable binders include starch, gelatin, natural sugars (such as glucose or beta-lactose), corn sweeteners, natural and synthetic gums (such as gum arabic, tragacanth or sodium alginate), carboxymethyl cellulose, polyethylene glycol, waxes, etc. Lubricants used in these dosage forms include sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, sodium chloride, etc. Disintegrants include, but are not limited to, starch, methylcellulose, agar, bentonite, xanthan gum, etc.

[0336] When a liquid suspension is used, the active agent can be combined with any oral, non-toxic, pharmaceutically acceptable inert carrier (e.g., ethanol, glycerol, water, etc.) and with an emulsifier and suspending agent. If desired, flavorings, colorants, and / or sweeteners may also be added. Other optional ingredients for incorporation into oral formulations herein include, but are not limited to, preservatives, suspending agents, thickening agents, and the like.

[0337] Parenteral preparations can be prepared in conventional form (as liquid solution or suspension, suitable for dissolving or being suspended in the solid form in the liquid before injection or as emulsion). Preferably, sterile injectable suspensions are prepared using suitable carriers, dispersants or wetting agents and suspending agents according to technology known in the art. Sterile injectable preparations can also be sterile injectable solutions or suspensions in non-toxic parenteral acceptable diluents or solvents. Among acceptable vehicles and solvents, water, Ringer's solution and isotonic sodium chloride solution can be used. In addition, sterile, fixed oils, fatty esters or polyols are typically used as solvents or suspension media. In addition, parenteral administration can relate to and use slow-release or sustained-release systems so as to maintain a constant dosage level.

[0338] Parenteral administration includes intra-articular, intravenous, intramuscular, intradermal, intraperitoneal and subcutaneous routes, and includes aqueous and non-aqueous isotonic sterile injection solutions, which may contain antioxidants, buffers, antibacterial agents and solutes that make the preparation isotonic with the blood of the intended recipient, and aqueous and non-aqueous sterile suspensions, which may include suspending agents, solubilizers, thickeners, stabilizers and preservatives. Administration by certain parenteral routes may involve the introduction of the preparation of the present disclosure into the patient's body by propelling it by a sterile syringe or some other mechanical device (e.g., continuous infusion system) through a needle or catheter. The preparation provided by the present disclosure can be administered using a syringe, an injector, a pump or any other device generally recognized in the art for parenteral administration.

[0339] In addition to Compound 1 described herein or its pharmaceutically acceptable salt or morphological form, the pharmaceutical formulations may contain other additives, such as pH adjusting additives. Specifically, useful pH adjusting agents include acids, such as hydrochloric acid, bases or buffers, such as sodium lactate, sodium acetate, sodium phosphate, sodium citrate, sodium borate or sodium gluconate. In addition, the formulations may contain antimicrobial preservatives. Useful antimicrobial preservatives include methylparaben, propylparaben and benzyl alcohol. When the formulation is placed in a vial designed for multi-dose use, an antimicrobial preservative is generally used. The pharmaceutical formulations described herein can be lyophilized using techniques well known in the art.

[0340] For oral administration, pharmaceutical compositions can be in the form of solutions, suspensions, tablets, pills, capsules, powders, etc. Tablets containing various excipients (e.g., sodium citrate, calcium carbonate, and calcium phosphate) can be used with various disintegrants (e.g., starch (e.g., potato starch or tapioca starch) and certain complex silicates) and binders (e.g., polyvinyl pyrrolidone, sucrose, gelatin, and gum arabic). In addition, lubricants (e.g., magnesium stearate, sodium lauryl sulfate, and talc) are generally very useful for tableting purposes. Similar types of solid compositions can be used as fillers in soft and hard-filled gelatin capsules. Related materials also include lactose or milk sugar and high molecular weight polyethylene glycol. When aqueous suspensions and / or elixirs are needed for oral administration, the compounds of the subject matter disclosed herein can be combined with various sweeteners, flavorings, coloring agents, emulsifiers, and / or suspending agents and diluents such as water, ethanol, propylene glycol, glycerol, and various similar combinations thereof.

[0341] In another embodiment of the subject matter described herein, an injectable, stable, sterile formulation is provided, which comprises an active compound as described herein or a salt thereof in a unit dose form in a sealed container. The compound or salt is provided in the form of a lyophilizate, which can be reconstituted with a suitable pharmaceutically acceptable carrier to form a liquid formulation suitable for injection into a host. When the compound or salt is substantially insoluble in water, a sufficient amount of a physiologically acceptable emulsifier can be used in sufficient amounts to emulsify the compound or salt in an aqueous carrier. Particularly useful emulsifiers include phosphatidylcholine and lecithin.

[0342] Other embodiments include liposome formulations of active compounds disclosed herein. The technology of forming liposome suspensions is well known in the art. When the compound is a water-soluble salt, conventional liposome technology is used, which can be incorporated into lipid vesicles. In this case, due to the water solubility of the active compound, the active compound can be substantially entrained in the hydrophilic center or core of the liposome. The lipid layer used can have any conventional composition and can contain cholesterol, or can be cholesterol-free. When the active compound of interest is insoluble in water, conventional liposome formation technology is also used, and salts can be substantially entrained in the hydrophobic lipid bilayer forming the liposome structure. In either case, the size of the liposomes produced can be reduced by using standard ultrasonic treatment and homogenization techniques. The liposome formulations comprising active compounds disclosed herein can be lyophilized to produce a lyophilized product, which can be reconstituted with a pharmaceutically acceptable carrier (e.g., water) to regenerate the liposome suspension.

[0343] Also provided are pharmaceutical preparations suitable for administration by inhalation as an aerosol. These preparations include solutions or suspensions of the desired compound or its salt as described herein, or multiple solid particles of the compound or salt. The desired preparation can be placed in a chamber and atomized. Atomization can be achieved by compressed air or ultrasonic energy to form multiple liquid droplets or solid particles comprising the compound or salt. The liquid droplets or solid particles can, for example, have a range of about 0.5 to about 10 microns, and optionally a particle size of about 0.5 to about 5 microns. In certain embodiments, the solid particles provide controlled release by using a degradable polymer. The solid particles can be obtained by treating the solid compound or its salt in any appropriate manner known in the art (e.g., by micronization). Optionally, the size of the solid particles or droplets can be about 1 to about 2 microns. In this regard, commercial nebulizers can be used to achieve this purpose. The compound can be administered by an aerosol suspension of respirable particles in the manner described in U.S. Patent No. 5,628,984, the disclosure of which is incorporated herein by reference in its entirety.

[0344] Also provided are pharmaceutical formulations that provide controlled release of the compounds described herein, including through the use of degradable polymers known in the art.

[0345] When the pharmaceutical formulation suitable for administration as an aerosol is in liquid form, the formulation may comprise a water-soluble active compound in a carrier including water. A surfactant may be present which sufficiently reduces the surface tension of the formulation to result in the formation of droplets within the desired size range when aerosolized.

[0346] As used herein, the term "pharmaceutically acceptable salt" refers to salts, and where possible, zwitterionic forms of the compounds of the presently disclosed subject matter, that are suitable for use in contact with a host (e.g., a human host) without undue toxicity, irritation, allergic response, and the like, commensurate with a reasonable benefit / risk ratio, and effective for their intended use.

[0347] Therefore, the term "salt" refers to the relatively nontoxic inorganic and organic acid addition salts of the currently disclosed compounds. These salts can be prepared during the final separation and purification of the compound, or by reacting the free base form of the purified compound with a suitable organic or inorganic acid and separating the salt thus formed. Basic compounds can form various salts with various inorganic and organic acids. The acid addition salts of basic compounds are prepared by contacting the free base form with a sufficient amount of the desired acid to produce a salt in a conventional manner. The free base form can be regenerated by contacting the salt form with a base and separating the free base in a conventional manner. The free base form may differ from its respective salt form in certain physical properties (e.g., solubility in polar solvents).

[0348] Salts that can be prepared from inorganic acids include hydrochlorides, sulfates, pyrosulfates, bisulfates, sulfites, bisulfites, nitrates, phosphates, monohydrogen phosphates, dihydrogen phosphates, metaphosphates, pyrophosphates, chlorides, bromides, iodides, such as hydrochloric acid, nitric acid, phosphoric acid, sulfuric acid, hydrobromic acid, hydroiodic acid, phosphorus, etc. Representative salts include hydrobromide, hydrochloride, sulfate, bisulfate, nitrate, acetate, oxalate, valerate, oleate, palmitate, stearate, laurate, borate, benzoate, lactate, phosphate, toluenesulfonate, citrate, maleate, fumarate, succinate, tartrate, naphthoate, methanesulfonate, gluconate, lactobionate, dodecylsulfonate, and isethionate, etc. Salts can also be prepared from organic acids such as aliphatic mono- and dicarboxylic acids, phenyl-substituted alkanoic acids, hydroxyalkanoic acids, alkanedioic acids, aromatic acids, aliphatic and aromatic sulfonic acids, and the like. Representative salts include acetate, propionate, octanoate, isobutyrate, oxalate, malonate, succinate, suberate, sebacate, fumarate, maleate, mandelate, benzoate, chlorobenzoate, methylbenzoate, dinitrobenzoate, phthalate, benzenesulfonate, toluenesulfonate, phenylacetate, citrate, lactate, maleate, tartrate, methanesulfonate, and the like. Pharmaceutically acceptable salts can include cations based on alkali and alkaline earth metals, such as sodium, lithium, potassium, calcium, magnesium, and the like, as well as non-toxic ammonium, quaternary ammonium, and amine cations, including, but not limited to, ammonium, tetramethylammonium, tetraethylammonium, methylamine, dimethylamine, trimethylamine, triethylamine, ethylamine, and the like. Also contemplated are salts of amino acids, such as argininate, gluconate, galacturonate, etc. See, for example, Berge et al., J. Pharm. Sci., 1977, 66, 1-19, which is incorporated herein by reference.

[0349] Pharmaceutically acceptable base addition salts can be formed with metals or amines (e.g., alkali metal and alkaline earth metal hydroxides) or organic amines. Examples of metals used as cations include, but are not limited to, sodium, potassium, magnesium, calcium, and the like. Examples of suitable amines include, but are not limited to, N,N'-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, ethylenediamine, N-methylglucamine, and procaine. Base addition salts of acidic compounds are prepared by contacting the free acid form with a sufficient amount of the desired base to produce the salt in a conventional manner. The free acid form can be regenerated by contacting the salt form with an acid and isolating the free acid in a conventional manner. The free acid form may differ slightly from its respective salt form in certain physical properties (e.g., solubility in polar solvents).

[0350] Preferably, sterile injectable suspensions are prepared using suitable carriers, dispersants or wetting agents and suspending agents according to technology known in the art. Sterile injectable preparations can also be sterile injectable solutions or suspensions in nontoxic parenteral acceptable diluents or solvents. Among acceptable vehicles and solvents, water, Ringer's solution and isotonic sodium chloride solution can be used. In addition, sterile, fixed oils, fatty esters or polyols are typically used as solvents or suspension media. In addition, parenteral administration can relate to and use slow-release or sustained-release systems so as to maintain a constant dosage level.

[0351] According to the present disclosure, the preparation for parenteral administration includes sterile aqueous or non-aqueous solutions, suspensions or emulsions. The example of non-aqueous solvents or vehicles is propylene glycol, polyethylene glycol, vegetable oils (such as olive oil and corn oil), gelatin and injectable organic esters (such as ethyl oleate). Such dosage forms can also contain adjuvants, such as preservatives, wetting agents, emulsifiers and dispersants. They can be sterilized by, for example, filtering by bacteria-retaining filters, by incorporating sterilizing agents into the compositions, by irradiating compositions or by heating compositions. They can also be manufactured using sterilized water or some other sterile injectable media immediately before use.

[0352] Sterile injectable solution is by one or more compounds of the present invention being mixed in suitable solvent with the various other compositions (as required) listed above with the required amount, then filter sterilize and prepare.Usually, dispersion is prepared by mixing various sterilization active ingredients into sterile vehicle, and this vehicle contains basic dispersion medium and the required other compositions listed above.For the sterile powder for the preparation of sterile injectable solution, preferred preparation method is vacuum drying and freeze drying technology, and the powder of active ingredient is obtained from its previous sterile filtered solution plus any other desired composition.Therefore, for example, by stirring the active ingredient of 1.5 % by weight in 10 % by volume propylene glycol and water, prepare the parenteral composition suitable for being used by injection.Make solution isotonic and sterilize with sodium chloride.

[0353] Formulations suitable for rectal administration are generally presented as unit-dose suppositories. These suppositories can be prepared by mixing the active disclosed compound with one or more conventional solid carriers, such as cocoa butter, and then shaping the resulting mixture.

[0354] Formulations suitable for topical application to the skin are preferably in the form of ointments, creams, lotions, pastes, gels, sprays, aerosols or oils. Useful carriers include petrolatum, lanolin, polyethylene glycol, alcohol, skin penetration enhancers and combinations of two or more thereof.

[0355] The preparation that is suitable for transdermal administration can exist as discrete patches, and these patches are suitable for keeping close contact for a long time with the epidermis of recipient.The preparation that is suitable for transdermal administration can also be sent by iontophoresis (referring to, for example, Pharmaceutical Research 3 (6): 318 (1986)), and the form of the optional buffered aqueous solution of active compound is generally adopted.In certain embodiments, microneedle patch or device are provided for drug delivery through or into biological tissue, particularly skin.Microneedle patch or device allow to pass or enter skin or other tissue barriers with the rate delivery drug of clinical relevance, simultaneously to the damage of tissue, pain or stimulation minimum or without damage, pain or stimulation.

[0356] Preparations suitable for administration to the lungs can be delivered by a variety of passive breath-driven and active power-driven single-dose / multi-dose dry powder inhalers (DPIs). The devices most commonly used for respiratory delivery include nebulizers, metered dose inhalers, and dry powder inhalers. Several types of nebulizers are available, including jet nebulizers, ultrasonic nebulizers, and vibrating mesh nebulizers. The selection of a suitable pulmonary delivery device depends on parameters such as the properties of the drug and its formulation, the site of action, and the pathophysiology of the lungs.

[0357] IV. Combination Therapy

[0358] In certain aspects, provided are Compound 1 described herein, or a pharmaceutically acceptable salt or morphological form thereof, for use in an effective amount, alone or in combination with another biologically active agent (therapeutic agent), to treat a subject (e.g., a human) having a cyclin E overexpression or amplification disorder or small cell lung cancer described herein.

[0359] In other aspects, pharmaceutical compositions comprising a morphological form of Compound 1 or a pharmaceutically acceptable salt thereof are provided for use alone or in combination with another biologically active agent (therapeutic agent) in an effective amount for treating a subject (e.g., a human) having a CDK2-mediated cancer or small cell lung cancer as described herein.

[0360] In yet other aspects, provided are pharmaceutical compositions comprising Compound 1 or a pharmaceutically acceptable salt or morphological form thereof described herein, for use alone or in combination with another biologically active agent (therapeutic agent) in an effective amount to treat a subject (e.g., a human) having a CDK2-mediated cancer or small cell lung cancer described herein, wherein the pharmaceutical composition is prepared from a morphological form of Compound 1 or a pharmaceutically acceptable salt thereof, or a morphological form described herein (e.g., by spray drying or dissolving the morphological form and then mixing it with one or more pharmaceutically acceptable excipients).

[0361] The term "biologically active agent" or "therapeutic agent" or "anti-cancer therapy" is used to describe an agent other than Compound I that can be used in combination or alternating with Compound I to achieve the desired effect of therapy. In certain embodiments, Compound I and the biologically active agent are administered in a manner that is active in vivo for overlapping time periods, e.g., with C max 、T max , AUC or other pharmacokinetic parameters. In another embodiment, Compound 1 and a biologically active agent are administered to a subject in need thereof that do not have overlapping pharmacokinetic parameters, however, one has a therapeutic impact on the therapeutic efficacy of the other.

[0362] Although many patients are successfully cured with CDK4 / 6 inhibitors, a major problem in cancer treatment is that a significant number of patients are inherently unresponsive to treatment, and a significant proportion of the remaining patients eventually develop resistance to CDK4 / 6 inhibition (Xu et al. Cureus. 9:e1408 (2017); Condorelli et al. Annals of Oncology. 29:640-5 (2018)). For example, MYC-type tumors, such as triple-negative breast cancer (TNBC) and small cell lung cancer (SCLC), exhibit loss of retinoblastoma (Rb) protein expression. Certain cancers, despite being Rb-positive, are intrinsically resistant to the effects of selective CDK4 / 6 inhibitors. In addition, certain cancers with an intact Rb pathway may be intrinsically resistant to selective CDK4 / 6 inhibitors due to the presence of other genetic or phenotypic abnormalities. For example, it is estimated that despite intact Rb, 40% of uterine cancers, 20% of ovarian cancers, 15% of bladder cancers, 20% of prostate cancers, and 15% of breast cancers may be intrinsically resistant to selective CDK4 / 6 inhibition due to upregulation of cyclin E. See, e.g., Knudsen et al., The Strange Case of CDK4 / 6 Inhibitors: Mechanisms, Resistance, and Combination Strategies. Trends Cancer. 2017 Jan;3(1):39–55. Other cancers, such as ER+ breast cancer, acquire resistance to selective CDK4 / 6 inhibitors during a course of selective CDK4 / 6 inhibitor therapy, for example, by upregulating cyclin E, which allows G1 to S cell cycle progression via CDK2. In certain embodiments, Compound I effectively inhibits cell cycle progression in cancer cells that are intrinsically resistant to, are prone to acquiring resistance to, or have developed resistance to selective CDK4 / 6 inhibitors. In certain embodiments, Compound 1 is effective in inhibiting cell cycle progression of cancer cells in a subject having a cancer that progressed following a prior regimen that included a CDK4 / 6 inhibitor.

[0363] On the one hand, disclosed herein is a method for treating a subject with a CDK4 / 6 resistant cancer, comprising administering to the subject an effective amount of Compound 1 as described herein or a pharmaceutically acceptable salt or morphological form thereof; and administering to the subject an effective amount of a CDK4 / 6 inhibitor. In some embodiments, the CDK4 / 6 inhibitor is selected from palbociclib, ribociclib, abemaciclib, traxilib, leloxilib, or SHR6390 (dalcili). In some embodiments, the CDK4 / 6 inhibitor is selected from BPI-16350, narazaciclib (ON-123300), FLX-925 (AMG-925), UCT-03-008, GLR2007, pyroxilib (XZP-3287), LY5219, PF-07220060, or ON-123300. In some embodiments, the CDK4 / 6 inhibitor is palbociclib. In some embodiments, the CDK4 / 6 inhibitor is ribociclib. In some embodiments, the CDK4 / 6 inhibitor is abemaciclib. In some embodiments, the CDK4 / 6 inhibitor-resistant cancer is retinoblastoma (Rb) protein positive (Rb+). In some embodiments, the CDK4 / 6 inhibitor-resistant cancer is retinoblastoma (Rb) protein defective (Rb-). In some embodiments, the CDK4 / 6 inhibitor-resistant cancer is selected from breast cancer, lung cancer, uterine cancer, endometrial cancer, ovarian cancer, prostate cancer, bladder cancer, testicular cancer, glioblastoma, head and / or neck cancer or prostate cancer. In some embodiments, the CDK4 / 6 inhibitor-resistant cancer is breast cancer. In some embodiments, the CDK4 / 6 inhibitor-resistant breast cancer is estrogen receptor positive (ER+) breast cancer. In some embodiments, the CDK4 / 6 inhibitor-resistant breast cancer is hormone receptor positive (HR+) breast cancer. In certain embodiments, breast cancer is human epidermal growth factor receptor 2 negative (HER2-). In certain embodiments, breast cancer is ER+ / HER2- breast cancer. In certain embodiments, breast cancer is HR+ / HER2- breast cancer. In certain embodiments, the CDK4 / 6 inhibitor-resistant cancer is ovarian cancer. In certain embodiments, the ovarian cancer has CCNE1 amplification. In certain embodiments, the method further comprises administering an effective amount of an estrogen inhibitor. In certain embodiments, the estrogen inhibitor is a selective estrogen receptor degrader (SERD).In certain embodiments, the SERD is selected from fulvestrant, rintodestrant (G1T48), borestrant (ZB-716), brilanestrant (GDC0810), camizestrant (AZD9833), D00502, elastostat (RAD1901), etacstil (GW5638), GW7604, AZD9496, GDC-0927, giredestrant (GDC9545, RG6171), LSZ102, imlunestrant (LY3484356), SAR439859, SCR6852, or ZN-c5. In some embodiments, the SERD includes fulvestrant. In some embodiments, the SERD includes elastostat (RAD1901).

[0364] In certain embodiments, the methods specifically described above further include administering an effective amount of another anticancer therapy. In some embodiments, the anticancer therapy is selected from chemotherapeutics, radiation, surgery, immune checkpoint inhibitors, estrogen inhibitors, androgen inhibitors, PARP inhibitors, or a combination thereof. In some embodiments, the anticancer therapy includes chemotherapeutics. In some embodiments, the chemotherapeutics are selected from protein synthesis inhibitors, DNA damaging chemotherapeutics, alkylating agents, topoisomerase inhibitors, RNA synthesis inhibitors, DNA complex binders, thiol alkylating agents, guanine alkylating agents, microtubule binding agents, DNA polymerase inhibitors, anticancer enzymes, RAC1 inhibitors, thymidylate synthase inhibitors, oxazaphosphorus compounds, integrin inhibitors, antifolates, folic acid antimetabolites, or a combination thereof. In some embodiments, the chemotherapeutic agent is selected from cisplatin, carboplatin, etoposide, oxaliplatin, 5-fluorouracil, floxuridine, capecitabine, gemcitabine, mitomycin, methotrexate, vinblastine, cyclophosphamide, dacarbazine, albumin-bound paclitaxel, ifosfamide, topotecan, irinotecan, docetaxel, temozolomide, paclitaxel, doxorubicin, camptothecin, or a combination thereof. In some embodiments, Compound 1 and the CDK4 / 6 inhibitor are administered within 24 hours or less of the administration of the chemotherapeutic agent. In some embodiments, Compound 1 and the CDK4 / 6 inhibitor are administered within 6 hours or less of the administration of the chemotherapeutic agent. In some embodiments, Compound 1 and the CDK4 / 6 inhibitor are administered within 3 hours or less of the administration of the chemotherapeutic agent. In some embodiments, Compound 1 or a pharmaceutically acceptable salt thereof or a morphological form as described herein is administered to a subject at least once a day, and wherein an effective amount of the CDK4 / 6 inhibitor and the chemotherapeutic agent are administered according to their prescribed label. In some embodiments, Compound 1 as described herein, or a pharmaceutically acceptable salt or morphological form thereof, is administered to a subject at least twice daily, and wherein effective amounts of a CDK4 / 6 inhibitor and a chemotherapeutic agent are administered in accordance with their prescribed labeling.

[0365] In another aspect, disclosed herein is a method for treating a subject with estrogen receptor-positive (ER+) breast cancer that is resistant to CDK4 / 6 inhibitors, comprising administering to the subject an effective amount of Compound I described herein, or a pharmaceutically acceptable salt or morphological form thereof; and administering to the subject an effective amount of a CDK4 / 6 inhibitor. In some embodiments, the ER+ breast cancer that is resistant to CDK4 / 6 inhibitors is negative for the tyrosine kinase-type cell surface receptor HER2. In certain embodiments, the method further comprises administering an effective amount of an estrogen inhibitor. In certain embodiments, the estrogen inhibitor is a selective estrogen receptor degrader (SERD). In some embodiments, SERD includes Fulvestrant. In some embodiments, SERD includes Alastrazumab (RAD1901). In some embodiments, the method further comprises administering an effective amount of an antibody-drug conjugate (ADC). In some embodiments, the method further comprises administering an effective amount of a trastuzumab selected from Trastuzumab or sacituzumab govetican ADC.

[0366] In some embodiments, disclosed herein are methods for treating people with cancer that is resistant to CDK4 / 6 inhibitors and optionally resistant to endocrine therapy, comprising administering an effective amount of Compound 1 as described herein or a pharmaceutically acceptable salt or morphological form thereof, and administering an effective amount of an estrogen inhibitor. In some embodiments, the estrogen inhibitor is selected from a selective estrogen receptor modulator (SERM), a selective estrogen receptor degrader (SERD), a complete estrogen receptor degrader, a complete estrogen antagonist, a partial estrogen antagonist, or a combination thereof. In some embodiments, the estrogen inhibitor is a selective estrogen receptor degrader (SERD). In some embodiments, SERD includes Fulvestrant. In some embodiments, SERD includes Alastrant (RAD1901). Additional non-limiting examples of anti-estrogen compounds include: SERMS, such as anordrin, arzoxifene, bazedoxifene, broparestriol, clomiphene citrate, cyclofenil, droloxifene, tamoxifen, idoxifene, lasofoxifene, ormeloxifene, pipendoxifene, raloxifene, tamoxifen, toremifene, and fulvestrant; aromatase inhibitors, such as aminoglutethimide, testolactone, anastrozole, exemestane, fadrozole, formestane, and letrozole; and antigonadotropins, such as leuprolide, cetrorelix, allylestradiol, chlormadinone acetate, delmadinone acetate, dydrogesterone acetate, medroxyprogesterone acetate, megestrol acetate, nomegestrol acetate, norethisterone acetate, progesterone, and spironolactone. Additional non-limiting examples of anti-estrogen compounds include SERDs such as fulvestrant, rintodestrant (G1T48), borestrant (ZB-716), brilanestrant (GDC0810), camizestrant (AZD9833), D00502, elastodestran (RAD1901), etacstil (GW5638), GW7604, AZD9496, GDC-0927, giredestrant (GDC9545, RG6171), LSZ102, imlunestrant (LY3484356), SAR439859, SCR6852, and ZN-c5. In some embodiments, the SERD is elastodestran (RAD1901). In some embodiments, the SERD is fulvestrant. In some embodiments, the human has previously received at least one prior line of endocrine therapy. In some embodiments, the human has previously received at least one prior line of CDK4 / 6 inhibitor therapy. In some embodiments, the human has previously received at least one prior line of chemotherapy. In some embodiments, the human has previously received at least two prior lines of chemotherapy. In some embodiments, the cancer progressed after a prior regimen that included a CDK4 / 6 inhibitor.In certain embodiments, the method further includes administering an effective amount of another anticancer therapy. In some embodiments, anticancer therapy is selected from chemotherapeutics, radiation, surgery, immune checkpoint inhibitors, CDK4 / 6 inhibitors, estrogen inhibitors, androgen inhibitors, PARP inhibitors, or a combination thereof. In some embodiments, the method further includes administering an effective amount of a CDK4 / 6 inhibitor. In some embodiments, the CDK4 / 6 inhibitor is selected from palbociclib, ribociclib, abemaciclib, traxacil, leloxilib or SHR6390 (dalcili). In some embodiments, the CDK4 / 6 inhibitor is selected from BPI-16350, narazaciclib (ON-123300), FLX-925 (AMG-925), UCT-03-008, GLR2007, pyroxilib (XZP-3287), LY5219, PF-07220060 or ON-123300. In some embodiments, the cancer is selected from breast cancer, ovarian cancer, endometrial cancer, prostate cancer, or uterine cancer. In some embodiments, the cancer is breast cancer. In some embodiments, the breast cancer is ER+ breast cancer. In some embodiments, the breast cancer is HR+ breast cancer. In some embodiments, the breast cancer is PR+ breast cancer. In some embodiments, the breast cancer is HER2- breast cancer. In some embodiments, the breast cancer is ER+HER2- breast cancer. In some embodiments, the breast cancer is ER+PR+HER2- breast cancer. In some embodiments, the breast cancer is HR+HER2- breast cancer. In some embodiments, the breast cancer is HR+HER2- breast cancer. In some embodiments, the CDK4 / 6 inhibitor-resistant and / or estrogen inhibitor-resistant breast cancer is luminal A breast cancer.

[0367] In some embodiments, disclosed herein is a method for treating a person with advanced unresectable or metastatic breast cancer, comprising: administering to a subject an effective amount of Compound 1 as described herein, or a pharmaceutically acceptable salt or morphological form thereof; administering to the subject an effective amount of an estrogen inhibitor; and optionally, administering to the subject an effective amount of a CDK4 / 6 inhibitor. In some embodiments, the estrogen inhibitor is selected from a selective estrogen receptor modulator (SERM), a selective estrogen receptor degrader (SERD), a complete estrogen receptor degrader, a complete estrogen antagonist, a partial estrogen antagonist, or a combination thereof. In some embodiments, the estrogen inhibitor is a selective estrogen receptor degrader (SERD). In some embodiments, SERD is selected from fulvestrant, rintodestrant (G1T48), brilanestrant (GDC0810), elastostrant (RAD1901), etacstil (GW5638), GW7604, AZD9496, GDC-0927, GDC9545 (RG6171), LSZ102, or SAR439859. In some embodiments, SERD includes fulvestrant. In some embodiments, SERD includes elastrant (RAD1901). In some embodiments, estrogen inhibitor is selective estrogen receptor modulator (SERM). In some embodiments, SERM is selected from anordrin, arzoxifene, bazedoxifene, broparestriol, clomiphene citrate, cyclofenil, droloxifene, tamoxifen, idoxifene, lasofoxifene, ormeloxifene, pipenoxifene, raloxifene, tamoxifen, toremifene, aminoglutethimide, testolactone, anastrozole, exemestane, fadrozole, formestane, letrozole, leuprorelin, cetrorelix, allylestradiol, chlormadinone acetate, delmadinone acetate, dydrogesterone, medroxyprogesterone acetate, megestrol acetate, nomegestrol acetate, norethisterone acetate, progesterone or spironolactone. In some embodiments, SERD includes fulvestrant. In some embodiments, SERD includes elastatin (RAD1901). Selective CDK4 / 6 inhibitors used in combination with Compound I include but are not limited to palbociclib, abemaciclib, ribociclib, tricaciclib, SHR6390 (darsilili) and leroxicillin. In some embodiments, the CDK4 / 6 inhibitor is selected from BPI-16350, narazaciclib (ON-123300), FLX-925 (AMG-925), UCT-03-008, GLR2007, pyroxicillin (XZP-3287), LY5219, PF-07220060 or ON-123300. In some embodiments, the CDK4 / 6 inhibitor used in combination with Compound I is palbociclib. In some embodiments, the CDK4 / 6 inhibitor used in combination with Compound I is ribociclib.In some embodiments, the CDK4 / 6 inhibitor used in combination with Compound I is abemaciclib. In certain embodiments, advanced unresectable and / or metastatic ER+ / HER2- breast cancer progresses after treatment with a CDK4 / 6 inhibitor. In certain embodiments, the previously administered CDK4 / 6 inhibitor is selected from palbociclib, abemaciclib, ribociclib, triclasiclib, SHR6390 (darsild) or leloxilib. In some embodiments, the previously administered CDK4 / 6 inhibitor is selected from BPI-16350, narazaciclib (ON-123300), FLX-925 (AMG-925), UCT-03-008, GLR2007, pyroximate (XZP-3287), LY5219, PF-07220060 or ON-123300.

[0368] In another aspect, disclosed herein is a method for treating a subject with breast cancer, comprising administering to the subject an effective amount of Compound 1 as described herein, or a pharmaceutically acceptable salt or morphological form thereof, and administering to the subject an effective amount of an estrogen inhibitor. In some embodiments, breast cancer is ER+ breast cancer. In some embodiments, breast cancer is HR+ breast cancer. In some embodiments, breast cancer is PR+ breast cancer. In some embodiments, breast cancer is HER2- breast cancer. In some embodiments, breast cancer is ER+HER2- breast cancer. In some embodiments, breast cancer is ER+PR+HER2- breast cancer. In some embodiments, breast cancer is HR+HER2- breast cancer. In certain embodiments, the method is administered as a first-line (1L) therapy. In some embodiments, the estrogen inhibitor is selected from a selective estrogen receptor modulator (SERM), a selective estrogen receptor degrader (SERD), a complete estrogen receptor degrader, a complete estrogen antagonist, a partial estrogen antagonist, or a combination thereof. In some embodiments, the estrogen inhibitor is a selective estrogen receptor degrader (SERD). In certain embodiments, the SERD is selected from fulvestrant, rintodestrant (G1T48), borestrant (ZB-716), brilanestrant (GDC0810), camizestrant (AZD9833), D00502, elastostat (RAD1901), etacstil (GW5638), GW7604, AZD9496, GDC-0927, giredestrant (GDC9545, RG6171), LSZ102, imlunestrant (LY3484356), SAR439859, SCR6852, or ZN-c5. In some embodiments, the SERD includes fulvestrant. In some embodiments, the SERD includes elastostat (RAD1901). In some embodiments, the estrogen inhibitor is a selective estrogen receptor modulator (SERM). In some embodiments, SERM is selected from anordrin, arzoxifene, bazedoxifene, broparestriol, clomiphene citrate, cyclofenil, droloxifene, tamoxifen, idoxifene, lasofoxifene, ormeloxifene, pipendoxifene, raloxifene, tamoxifen, toremifene, aminoglutethimide, testolactone, anastrozole, exemestane, fadrozole, formestane, letrozole, leuprorelin, cetrorelix, allylestradiol, chlormadinone acetate, delmadinone acetate, dydrogesterone, medroxyprogesterone acetate, megestrol acetate, nomegestrol acetate, norethisterone acetate, progesterone or spironolactone.In some embodiments, SERM is selected from anastrozole, exemestane or letrozole.In certain embodiments, the method further comprises the CDK4 / 6 inhibitor using effective dose.In some embodiments, the CDK4 / 6 inhibitor is selected from palbociclib, ribociclib, abemaciclib, traxacil, leloxacil, or SHR6390 (dalcili). In some embodiments, the CDK4 / 6 inhibitor is selected from BPI-16350, narazaciclib (ON-123300), FLX-925 (AMG-925), UCT-03-008, GLR2007, pironiclib (XZP-3287), LY5219, PF-07220060, or ON-123300. In some embodiments, the CDK4 / 6 inhibitor is palbociclib. In some embodiments, the CDK4 / 6 inhibitor is ribociclib. In some embodiments, the CDK4 / 6 inhibitor is abemaciclib. In some embodiments, the CDK4 / 6 inhibitor is palbociclib and abemaciclib. In certain embodiments, the method prolongs the time of acquired resistance to estrogen inhibitors compared to a method lacking Compound I. In certain embodiments, the method prolongs the time of acquired resistance to CDK4 / 6 inhibitors compared to a method lacking Compound I. In certain embodiments, the subject has previously received at least one prior line of endocrine therapy. In certain embodiments, the breast cancer progressed after a prior standard of care regimen. In some embodiments, the CDK4 / 6 inhibitor-resistant and / or estrogen inhibitor-resistant breast cancer is luminal A breast cancer.

[0369] In another aspect, disclosed herein is a method for treating a subject with estrogen receptor positive (ER+) advanced breast cancer, comprising administering to the subject an effective amount of Compound I described herein or a pharmaceutically acceptable salt or morphological form thereof, and administering to the subject an effective amount of Fulvestrant. In certain embodiments, HR+ advanced breast cancer is human epidermal growth factor 2 negative (HER2-). In certain embodiments, the method is administered as a first-line (1L) therapy. In certain embodiments, the method prolongs the time of acquired resistance to Fulvestrant compared to a method lacking Compound I. In certain embodiments, the patient has previously received at least one previous line of endocrine therapy. In certain embodiments, ER+ or ER+ / HER2- breast cancer progresses after a previous standard of care regimen. In certain embodiments, the method further comprises administering an effective amount of a CDK4 / 6 inhibitor. In some embodiments, the CDK4 / 6 inhibitor is selected from palbociclib, ribociclib, abemaciclib, tremaciclib, leloxilib or SHR6390 (Dalxilib). In some embodiments, the CDK4 / 6 inhibitor is selected from BPI-16350, narazaciclib (ON-123300), FLX-925 (AMG-925), UCT-03-008, GLR2007, biroxicam (XZP-3287), LY5219, PF-07220060, or ON-123300. In some embodiments, the CDK4 / 6 inhibitor is palbociclib. In some embodiments, the CDK4 / 6 inhibitor is ribociclib. In some embodiments, the CDK4 / 6 inhibitor is abemaciclib. In some embodiments, the CDK4 / 6 inhibitor is palbociclib and abemaciclib.

[0370] In another aspect, disclosed herein is a method for treating a subject with hormone receptor positive (HR+) advanced breast cancer, comprising administering to the subject an effective amount of Compound I as described herein, or a pharmaceutically acceptable salt or morphological form thereof, and administering to the subject an effective amount of Fulvestrant. In certain embodiments, HR+ advanced breast cancer is human epidermal growth factor 2 negative (HER2-). In certain embodiments, the method is administered as a first-line (1L) therapy. In certain embodiments, the method prolongs the time of acquired resistance to Fulvestrant compared to a method lacking Compound I. In certain embodiments, the subject has previously received at least one previous line of endocrine therapy. In certain embodiments, HR+ or HR+ / HER2- breast cancer progresses after a previous standard of care regimen. In certain embodiments, the method further comprises administering an effective amount of a CDK4 / 6 inhibitor. In some embodiments, the CDK4 / 6 inhibitor is selected from palbociclib, ribociclib, abemaciclib, tremaciclib, leloxilib, or SHR6390 (Dalxilib). In some embodiments, the CDK4 / 6 inhibitor is selected from BPI-16350, narazaciclib (ON-123300), FLX-925 (AMG-925), UCT-03-008, GLR2007, biroxicam (XZP-3287), LY5219, PF-07220060, or ON-123300. In some embodiments, the CDK4 / 6 inhibitor is palbociclib. In some embodiments, the CDK4 / 6 inhibitor is ribociclib. In some embodiments, the CDK4 / 6 inhibitor is abemaciclib. In some embodiments, the CDK4 / 6 inhibitor is palbociclib and abemaciclib.

[0371] In another aspect, methods of treating a subject having unresectable cancer by administering to the subject a morphological form of Compound 1 as described herein are fully disclosed herein. In another aspect, methods of treating a subject having advanced cancer by administering to the subject a morphological form of Compound 1 as described herein are fully disclosed herein. In another aspect, methods of treating a subject having metastatic cancer by administering to the subject a morphological form of Compound 1 as described herein are disclosed herein. In another aspect, methods of treating a subject having advanced unresectable and / or metastatic cancer by administering to the subject a morphological form of Compound 1 as described herein are disclosed herein. In certain embodiments, the advanced unresectable and / or metastatic cancer is selected from uterine cancer, uterine carcinosarcoma (UCS), uterine corpus endometrial cancer (UCEC), ovarian cancer, ovarian serous cystadenocarcinoma (OV), sarcoma (SARC), lung cancer, lung squamous cell carcinoma (LUSC), lung adenocarcinoma (LUAD), gastric cancer, gastric adenocarcinoma (STAD), bladder cancer, bladder urothelial carcinoma (BLCA), esophageal cancer, esophageal tumor (ESCA), adrenocortical carcinoma, breast cancer, invasive breast carcinoma (BRCA), pancreatic cancer, pancreatic adenocarcinoma (PAAD), fallopian tube cancer, primary peritoneal cancer, liver cancer, hepatocellular carcinoma of the liver (LIHC), cervical cancer, cervical squamous cell carcinoma (CESC), endocervical adenocarcinoma, mesothelioma (MESO), head and neck squamous cell carcinoma (HSNC), colon cancer, colon adenocarcinoma (COAD), skin cancer, melanoma, cutaneous melanoma of the skin (SKCM), glioblastoma multiforme (GBM), kidney cancer, or kidney chromophobe cell (KICH). In some embodiments, the cancer of cyclin E amplification or overexpression is retinoblastoma (Rb) protein positive. In some embodiments, the cancer of cyclin E amplification or overexpression is CDK4 / 6 inhibitor resistant. In certain embodiments, the cancer is advanced and / or metastatic cancer. In certain embodiments, the cancer is advanced unresectable cancer. In certain embodiments, the cancer is platinum refractory and / or platinum resistant. In certain embodiments, the cancer progresses after the previous standard of care regimen. In certain embodiments, the cancer progresses after the previous standard systemic therapy. In certain embodiments, the cancer progresses after the previous systemic anticancer therapy. In certain embodiments, the cancer progresses after the previous scheme including platinum analogs. In certain embodiments, the cancer progresses after the previous scheme including CDK4 / 6 inhibitors. In certain embodiments, the method further comprises administering an effective amount of a CDK4 / 6 inhibitor. In certain embodiments, the CDK4 / 6 inhibitor is selected from palbociclib, ribociclib, abemaciclib, trexacil, leloxicil or SHR6390 (dalcili).In some embodiments, the CDK4 / 6 inhibitor is selected from BPI-16350, narazaciclib (ON-123300), FLX-925 (AMG-925), UCT-03-008, GLR2007, bilociclib (XZP-3287), LY5219, PF-07220060 or ON-123300. In certain embodiments, the method further comprises administering an effective amount of an additional anti-cancer therapy. In some embodiments, the anti-cancer therapy is selected from a chemotherapeutic agent, radiation, surgery, an immune checkpoint inhibitor, an estrogen inhibitor, an androgen inhibitor, a PARP inhibitor, or a combination thereof. In some embodiments, chemotherapeutic agents are selected from protein synthesis inhibitors, DNA damaging chemotherapeutic agents, alkylating agents, topoisomerase inhibitors, RNA synthesis inhibitors, DNA complex binding agents, thiol alkylating agents, guanine alkylating agents, tubulin binding agents, DNA polymerase inhibitors, anticancer enzymes, RAC1 inhibitors, thymidylate synthase inhibitors, oxazaphosphorus compounds, integrin inhibitors, antifolates, folic acid antimetabolites, or combinations thereof. In certain embodiments, anticancer therapy is an estrogen inhibitor. In certain embodiments, estrogen inhibitors are selected from selective estrogen receptor modulators (SERMs), selective estrogen receptor degraders (SERDs), complete estrogen receptor degraders, complete estrogen antagonists, partial estrogen antagonists, or combinations thereof. In certain embodiments, estrogen inhibitors are selective estrogen receptor degraders (SERDs). In some embodiments, SERDs include fulvestrant. In some embodiments, SERDs include elastomeric (RAD1901).

[0372] In some embodiments, disclosed herein is a method for treating a person with advanced unresectable and / or metastatic estrogen receptor-positive (ER+) epidermal growth factor receptor 2-negative (HER2-) breast cancer, comprising administering an effective amount of Compound 1 as described herein, or a pharmaceutically acceptable salt or morphological form thereof. In some embodiments, the person has previously received at least one previous line of endocrine therapy. In some embodiments, the person has previously received at least one previous line of CDK4 / 6 inhibitor therapy. In some embodiments, the person has previously received at least one previous line of chemotherapy. In some embodiments, the person has previously received at least two previous lines of chemotherapy. In some embodiments, advanced unresectable or metastatic ER+ / HER2- breast cancer progresses after a previous regimen including a CDK4 / 6 inhibitor. In certain embodiments, the method further comprises administering an effective amount of a CDK4 / 6 inhibitor. In certain embodiments, the CDK4 / 6 inhibitor is selected from palbociclib, ribociclib, abemaciclib, tricaciclib, leloxilib, or SHR6390 (dalcili). In certain embodiments, the CDK4 / 6 inhibitor is selected from BPI-16350, narazaciclib (ON-123300), FLX-925 (AMG-925), UCT-03-008, GLR2007, bilociclib (XZP-3287), LY5219, PF-07220060, or ON-123300. In certain embodiments, the method further comprises administering an effective amount of an additional anticancer therapy. In some embodiments, the anticancer therapy is selected from a chemotherapeutic agent, radiation, surgery, an immune checkpoint inhibitor, an estrogen inhibitor, an androgen inhibitor, a PARP inhibitor, or a combination thereof. In some embodiments, chemotherapeutic agents are selected from protein synthesis inhibitors, DNA damaging chemotherapeutic agents, alkylating agents, topoisomerase inhibitors, RNA synthesis inhibitors, DNA complex binding agents, thiol alkylating agents, guanine alkylating agents, tubulin binding agents, DNA polymerase inhibitors, anticancer enzymes, RAC1 inhibitors, thymidylate synthase inhibitors, oxazaphosphorus compounds, integrin inhibitors, antifolates, folic acid antimetabolites, or combinations thereof. In certain embodiments, anticancer therapy is an estrogen inhibitor. In certain embodiments, estrogen inhibitors are selected from selective estrogen receptor modulators (SERMs), selective estrogen receptor degraders (SERDs), complete estrogen receptor degraders, complete estrogen antagonists, partial estrogen antagonists, or combinations thereof. In certain embodiments, estrogen inhibitors are selective estrogen receptor degraders (SERDs). In some embodiments, SERDs include fulvestrant. In some embodiments, SERDs include elastomeric (RAD1901).In some embodiments, disclosed herein is a method for treating a person with advanced unresectable or metastatic ER+ / HER2- breast cancer, comprising: administering to a subject an effective amount of Compound I described herein, or a pharmaceutically acceptable salt or morphological form thereof; administering to a subject an effective amount of a CDK4 / 6 inhibitor; and administering to a subject an effective amount of a selective estrogen receptor degrader (SERD). In some embodiments, SERD includes Fulvestrant. In some embodiments, SERD includes elastomeric (RAD1901). In certain embodiments, advanced unresectable and / or metastatic ER+ / HER2- breast cancer progresses after treatment with a CDK4 / 6 inhibitor. In certain embodiments, the previously administered CDK4 / 6 inhibitor is selected from palbociclib, abemaciclib, ribociclib, trexacil, SHR6390 (Darsilib), or lerocillib. Selective CDK4 / 6 inhibitors used in combination with Compound I include, but are not limited to, palbociclib, abemaciclib, ribociclib, trexacil, SHR6390 (Darsilib), and lerocillib. In alternative embodiments, the CDK4 / 6 inhibitor used in combination with Compound 1 is selected from BPI-16350, narazaciclib (ON-123300), FLX-925 (AMG-925), UCT-03-008, GLR2007, bilociclib (XZP-3287), LY5219, PF-07220060, or ON-123300.

[0373] In certain embodiments, the methods described herein further comprise administering an effective amount of an estrogen inhibitor. In some embodiments, the estrogen inhibitor is selected from a selective estrogen receptor modulator (SERM), a selective estrogen receptor degrader (SERD), a complete estrogen receptor degrader, a complete estrogen antagonist, a partial estrogen antagonist, or a combination thereof.

[0374] In certain embodiments, the methods described herein further include administering an effective amount of a chemotherapeutic agent. In some embodiments, the chemotherapeutic agent is selected from cisplatin, carboplatin, etoposide, oxaliplatin, 5-fluorouracil, floxuridine, capecitabine, gemcitabine, mitomycin, methotrexate, vinblastine, cyclophosphamide, dacarbazine, albumin-bound paclitaxel, ifosfamide, topotecan, irinotecan, docetaxel, temozolomide, paclitaxel, doxorubicin, camptothecin, or a combination thereof. In some embodiments, CDK4 / 6 inhibitor-resistant ER+ breast cancer is luminal A breast cancer. In some embodiments, Compound 1 or a pharmaceutically acceptable salt thereof is administered to a subject at least once a day, wherein an effective amount of the chemotherapeutic agent is administered according to its prescribed label. In some embodiments, Compound 1 or a pharmaceutically acceptable salt thereof is administered to a subject at least twice a day, wherein an effective amount of the chemotherapeutic agent is administered according to its prescribed label.

[0375] In some embodiments, disclosed herein are methods for treating people with CDK4 / 6 inhibitor-resistant cancers, comprising administering a combination of Compound I, a pharmaceutically acceptable salt thereof, or a morphological form thereof, and a CDK4 / 6 inhibitor as described herein. In some embodiments, the CDK4 / 6 inhibitor is selected from palbociclib, ribociclib, abemaciclib, traxilib, leloxilib, or SHR6390 (dalcili). In some embodiments, the CDK4 / 6 inhibitor is selected from BPI-16350, narazaciclib (ON-123300), FLX-925 (AMG-925), UCT-03-008, GLR2007, pyroxilib (XZP-3287), LY5219, PF-07220060, or ON-123300. In some embodiments, the CDK4 / 6 inhibitor is palbociclib. In some embodiments, the CDK4 / 6 inhibitor is ribociclib. In some embodiments, the CDK4 / 6 inhibitor is abemaciclib. In some embodiments, the CDK4 / 6 inhibitor-resistant cancer is lung cancer. In some embodiments, the CDK4 / 6 inhibitor-resistant lung cancer is small cell lung cancer (SCLC).

[0376] In another aspect, disclosed herein are methods for treating subjects with CDK4 / 6 inhibitor-resistant small cell lung cancer (SCLC), comprising administering to the subject an effective amount of Compound 1 as described herein, or a pharmaceutically acceptable salt or morphological form thereof; and administering to the subject an effective amount of a chemotherapeutic agent, wherein Compound 1 is administered to the subject within 24 hours or less of administering the chemotherapeutic agent. In some embodiments, the chemotherapeutic agent is selected from cisplatin, carboplatin, etoposide, oxaliplatin, 5-fluorouracil, floxuridine, capecitabine, gemcitabine, mitomycin, methotrexate, vinblastine, cyclophosphamide, dacarbazine, albumin-bound paclitaxel, ifosfamide, topotecan, irinotecan, docetaxel, temozolomide, paclitaxel, doxorubicin, camptothecin, or a combination thereof. In some embodiments, the chemotherapeutic agent is doxorubicin. In some embodiments, the chemotherapeutic agent is camptothecin. In some embodiments, the chemotherapeutic agent is cisplatin. In some embodiments, the chemotherapeutic agent is carboplatin. In some embodiments, the chemotherapeutic agent is etoposide. In some embodiments, Compound 1 is administered to a subject within 6 hours or less of the administration of a chemotherapeutic agent. In some embodiments, Compound 1 is administered to a subject within 3 hours or less of the administration of a chemotherapeutic agent. In some embodiments, Compound 1 or a pharmaceutically acceptable salt thereof is administered to a subject at least once daily, and wherein an effective amount of the chemotherapeutic agent is administered in accordance with its prescribed labeling. In some embodiments, Compound 1 or a pharmaceutically acceptable salt thereof is administered to a subject at least twice daily, and wherein an effective amount of the chemotherapeutic agent is administered in accordance with its prescribed labeling.

[0377] In certain embodiments, the methods described herein further comprise administering an effective amount of an additional anti-cancer therapy. In some embodiments, the anti-cancer therapy is selected from radiation, surgery, an immune checkpoint inhibitor, an estrogen inhibitor, an androgen inhibitor, a PARP inhibitor, or a combination thereof.

[0378] In another aspect, disclosed herein are methods for treating subjects with CDK4 / 6 inhibitor-resistant small cell lung cancer (SCLC), comprising administering to the subject an effective amount of Compound 1 as described herein, or a pharmaceutically acceptable salt or morphological form thereof; and administering to the subject an effective amount of doxorubicin, wherein Compound 1 is administered to the subject 24 hours or less prior to the administration of doxorubicin or concomitantly with the administration of doxorubicin. In some embodiments, Compound 1 is administered to the subject 6 hours or less prior to the administration of doxorubicin or concomitantly with the administration of doxorubicin. In some embodiments, Compound 1 is administered to the subject 3 hours or less prior to the administration of doxorubicin or concomitantly with the administration of doxorubicin.

[0379] In certain aspects of this embodiment, the bioactive agent is a chemotherapeutic agent.

[0380] In another aspect of this embodiment, the bioactive agent is a growth factor.

[0381] In some aspects of this embodiment, bioactive agent is an immunomodulator, including but not limited to checkpoint inhibitors, including (as non-limiting examples) PD-1 inhibitors, PD-L1 inhibitors, PD-L2 inhibitors, CTLA-4 inhibitors, LAG-3 inhibitors, TIM-3 inhibitors, V domain Ig inhibitory factor (VISTA) inhibitors of T cell activation, small molecules, peptides, nucleotides or other inhibitors. In some aspects, immunomodulator is an antibody, such as a monoclonal antibody.

[0382] Immune checkpoint inhibitors

[0383] In alternative aspects, the selective CDK2 inhibitor Compound 1 described herein, or a pharmaceutically acceptable salt or morphological form thereof, is administered to a subject in combination with an effective amount of an immune checkpoint inhibitor. Immune checkpoint inhibitors for use in the methods described herein include, but are not limited to, programmed cell death-1 (PD-1) inhibitors, programmed cell death ligand 1 (PD-L1) inhibitors, programmed cell death ligand 2 (PD-L2) inhibitors, cytotoxic T lymphocyte-associated protein 4 (CTLA-4) inhibitors, lymphocyte activation gene 3 (LAG-3) inhibitors, T cell immunoglobulin mucin-3 (TIM-3) inhibitors, T cell immunoreceptor with Ig and ITIM domains (TIGIT) inhibitors, V-domain Ig inhibitory factor of T cell activation (VISTA) inhibitors, B7-H3 / CD276 inhibitors, indoleamine 2,3-dioxygenase (IDO) inhibitors, killer immunoglobulin-like receptor (KIR) inhibitors, carcinoembryonic antigen cell adhesion molecule (CEACAM) inhibitors, sialic acid-binding immunoglobulin-like lectin 15 (Siglec-15) inhibitors, CD47 inhibitors, CD39 inhibitors, B and T lymphocyte attenuator (BTLA) protein inhibitors, or combinations thereof. In some embodiments, immune checkpoint inhibitors are administered in effective amounts in combination with the compounds described herein to treat cancer, including but not limited to Hodgkin lymphoma, melanoma, non-small cell lung cancer, including NSCLC with EGFR or ALK genomic tumor aberrations, head and neck squamous cell carcinoma, small cell lung cancer, hepatocellular carcinoma, renal cell carcinoma, urothelial carcinoma, colorectal cancer, colorectal cancer, hepatocellular carcinoma, renal cell carcinoma, small cell lung cancer, bladder cancer, B-cell lymphoma, gastric cancer, cervical cancer, liver cancer, advanced Merkel cell carcinoma, esophageal squamous cell carcinoma, or ovarian cancer.

[0384] PD-1 inhibitors

[0385] In certain embodiments, the immune checkpoint inhibitor is a PD-1 inhibitor, which blocks the interaction between PD-1 and PD-L1 by binding to the PD-1 receptor, thereby inhibiting immunosuppression. In certain embodiments, the immune checkpoint inhibitor is a PD-1 immune checkpoint inhibitor selected from the following: nivolumab Pembrolizumab pidilizumab, AMP-224 (Amplimmune), sasanlimab (PF-06801591; Pfizer), MEDI0680 (AstraZeneca), spartalizumab (PDR001; Novartis), cemiplimad ( REGN2810; Regeneron), retifanlimab (MGA012; MacroGenics), islelizumab (BGB-A317; BeiGene), carrelizumab (SHR-12-1; Jiangsu Hengrui Medicine Company and Incyte Corporation), CS1003 (Cstone Pharmaceuticals), dostarlimab (TSR-042; Tesaro), and the PD-L1 / VISTA inhibitor CA-170 (Curis Inc.).

[0386] In certain embodiments, the immune checkpoint inhibitor is the PD-1 immune checkpoint inhibitor nivolumab. It is administered in an effective amount with the compounds described herein for the treatment of Hodgkin lymphoma, melanoma, non-small cell lung cancer, including NSCLC with EGFR or ALK genomic tumor aberrations, head and neck squamous cell carcinoma, small cell lung cancer, hepatocellular carcinoma, renal cell carcinoma, squamous cell carcinoma, urothelial carcinoma, colorectal cancer, colorectal cancer, hepatocellular carcinoma or ovarian cancer. The FDA has approved nivolumab for Hodgkin lymphoma, melanoma, non-small cell lung cancer, including NSCLC with EGFR or ALK genomic tumor aberrations, head and neck squamous cell carcinoma, small cell lung cancer, hepatocellular carcinoma, renal cell carcinoma, squamous cell carcinoma, urothelial carcinoma, colorectal cancer, progressive classical Hodgkin lymphoma (cHL), colorectal cancer, urothelial cancer, head and neck squamous cell carcinoma or ovarian cancer. In some embodiments, nivolumab is administered at 240 mg every 2 weeks or 480 mg every 4 weeks. In some embodiments, the PD-1 inhibitor is pembrolizumab administered in an effective amount. In some embodiments, pembrolizumab is administered at 200 mg every 3 weeks or 400 mg every 6 weeks. In another aspect of this embodiment, the immune checkpoint inhibitor is the PD-1 immune checkpoint inhibitor pembrolizumab. It is used in an effective amount for the treatment of melanoma, non-small cell lung cancer, small cell lung cancer, head and neck cancer, bladder cancer, urothelial carcinoma, renal cell carcinoma, classical Hodgkin lymphoma, gastric cancer, cervical cancer, liver cancer, primary mediastinal B cell lymphoma, advanced Merkel cell carcinoma, esophageal squamous cell carcinoma or urothelial carcinoma. In another aspect of this embodiment, immune checkpoint inhibitors are PD-1 immune checkpoint inhibitors pidilizumab (Medivation), which are used in an effective amount for refractory diffuse large B cell lymphoma (DLBCL) or metastatic melanoma. In another aspect of this embodiment, immune checkpoint inhibitors are PD-1 immune checkpoint inhibitors cemiplizumab (Libtayo / Regeneron), which are used in an effective amount for cutaneous squamous cell carcinoma.

[0387] PD-L1 inhibitors

[0388] In certain embodiments, the immune checkpoint inhibitor is a PD-L1 inhibitor, which blocks the interaction between PD-1 and PD-L1 by binding to the PD-L1 receptor, thereby inhibiting immunosuppression. PD-L1 inhibitors include atezolizumab ( Genentech, durvalumab ( AstraZeneca; avelumab ( In some embodiments, the PD-L1 inhibitor is atezolizumab. In some embodiments, the PD-L1 inhibitor is durvalumab. In some embodiments, the PD-L1 inhibitor is avelumab. In some embodiments, the PD-L1 inhibitor blocks the interaction between PD-L1 and CD80 to inhibit immunosuppression.

[0389] In certain embodiments, the immune checkpoint inhibitor is the PD-L1 immune checkpoint inhibitor atezolizumab It is administered in an effective amount for the treatment of metastatic bladder cancer, small cell lung cancer, metastatic melanoma, metastatic non-small cell lung cancer, or metastatic renal cell carcinoma. In some embodiments, atezolizumab is administered at 840 mg every 2 weeks, 1200 mg every 3 weeks, or 1680 mg every 4 weeks. In some embodiments, atezolizumab is administered prior to chemotherapy. In another aspect of this embodiment, the immune checkpoint inhibitor is durvalumab ( AstraZeneca and MedImmune), which are administered in an effective amount for the treatment of small cell lung cancer, non-small cell lung cancer, or bladder cancer. In some embodiments, for patients weighing more than 30 kg, durvalumab is administered at 10 mg / kg every 2 weeks or 1500 mg every 4 weeks, and for patients weighing less than 30 kg, durvalumab is administered at 10 mg / kg every 2 weeks. In certain embodiments, the immune checkpoint inhibitor is the PD-L1 immune checkpoint inhibitor avelumab ( In some embodiments, avelumab is administered at 800 mg every 2 weeks. In another embodiment, the immune checkpoint inhibitor is KN035 (Alphamab), which is administered in an effective amount for the treatment of PD-L1 positive solid tumors.

[0390] CTLA-4 inhibitors

[0391] In some aspects of this embodiment, immune checkpoint inhibitors are CTLA-4 immune checkpoint inhibitors, which bind to CTLA-4 and suppress immunosuppression. CTLA-4 is a glycoprotein of the immunoglobulin superfamily (Brunet et al. Nature. 328 (6127): 267-70 (1987)), which inhibits T cell responses (Guntermann et al. J Immunol. 168 (9) by several convergent mechanisms; 4420-9 (2002); Kong et al. Nat Immunol. 15 (5): 465-72 (2014); Qureshi et al. J Biol Chem. 287 (12): 9429-40 (2012)). CTLA-4 inhibitors include but are not limited to ipilimumab, tremelimumab (AstraZeneca and MedImmune), AGEN1884 and AGEN2041 (Agenus).

[0392] In certain embodiments, the CTLA-4 immune checkpoint inhibitor is ipilimumab. It is administered in an effective amount for treating metastatic melanoma, adjuvant melanoma or non-small cell lung cancer.

[0393] LAG-3 inhibitors

[0394] In another embodiment, the immune checkpoint inhibitor is a LAG-3 immune checkpoint inhibitor. LAG-3 (CD223) is encoded by the lymphocyte activation gene 3 (LAG-3) gene. LAG-3 is a member of the immunoglobulin superfamily (IgSF), which regulates multiple aspects of T cell function (Triebel et al. J Exp Med. 171: 1393-405 (1990)). LAG-3 is expressed on the cell membranes of natural killer (NK) cells, B cells, tumor-infiltrating lymphocytes (TILs), T cell subsets, and dendritic cells (DCs) (Triebel et al. J Exp Med. 171: 1393-405 (1990); KIsielow et al. Eur J Immunol. 35: 2081-8 (2005); Grosso et al. J Clin Invest. 117: 3383-92 (2009); Workman et al. J Immunol. 182: 1885-91 (2009); Andreae et al. J Immunol. 168: 3874-80 (2002)). LAG-3 binds to the nonholomorphic region of the major histocompatibility complex 2 (MHC class II) with higher affinity than CD4 (Baixeras et al. J Exp Med. 176: 27-37 (1992)). LAG-3 is a key regulator of Treg cells (T regs ) and anergic T cells. Blocking the LAG-3 receptor simultaneously can enhance the reversal of this anergic state compared to blocking either receptor alone (Grosso et al. J Immunol. 182:6659–69 (2009)). The LAG-3 / MHC class II complex leads to the expansion of CD4+ Ag-specific T cell clones and downregulation of cytokine secretion (Huard et al. Eur J Immunol. 26:1180–6 (1996)).

[0395] In some embodiments, the checkpoint inhibitor is a LAG-3 inhibitor, which inhibits immunosuppression by binding to the LAG-3 receptor to block the interaction of LAG-3 with MHC class II. Examples of LAG-3 immune checkpoint inhibitors include, but are not limited to, relatlimab (BMS 986016 / Ono 4482; Bristol-Myers Squibb); tebotelimab (MGD013; Macrogenics); LAG525 (Immutep, Novartis); TSR-033 (Tesaro, GlaxoSmithKline); Eftilagimod alpha (IMP321, Immutep); REGN3767 (Regeneron); INCAGN02385 (Incyte); RO7247669 (Hoffman-LaRoche); Favezelimab (Merck Sharp & Dohme); CB213 (Crescendo Biologics); FS118 (F-star Therapeutics); SYM022 (Symphogen); GSK2831781 (GlaxoSmithKline); IBI323 (Innovent Biologics (Suzhou) Co. Ltd.); EMB-02 (Shanghai EpimAb Biotherapeutics Co., Ltd.); SNA03 (MicrobioGroup); and AVA021 (Avacta).

[0396] T cell immunoreceptor with inhibitor of immunoglobulin and ITIM domains (TIGIT)

[0397] In some embodiments, the immune checkpoint inhibitor is a T cell immune receptor with immunoglobulin and ITIM domains (TIGIT). TIGIT is a promising new target for cancer immunotherapy. TIGIT levels are significantly increased in several immune cell subtypes, including activated T cells, natural killer cells, and regulatory T cells (Tregs). regs TIGIT binds to two ligands, CD155 (PVR) and CD112 (PVRL2, connexin-2), which are expressed by tumor cells and antigen-presenting cells (APCs) in the tumor microenvironment (Stanietsky et al. Proc Natl Acad Sci. 106:17858–63 (2009)).

[0398] TIGIT (also known as WUCAM, Vstm3, VSIG9) is an Ig superfamily receptor that inhibits adaptive and innate immunity (Boles et al. Eur J Immunol. 39:695-703 (2009)). TIGIT is a member of a complex regulatory network involving multiple inhibitory receptors (e.g., CD96 / TACTILE, CD112R / PVRIG), a competitive co-stimulatory receptor (DNAM-1 / CD226), and multiple ligands (e.g., CD155 (PVR / NECL-5), CD112 (connexin-2 / PVRL2)) (Levin et al. Eur J Immunol. 41:902–15 (2011); Bottino et al. J Exp Med. 198:557–67 (2003); Seth et al. Biochem Biophys Res Commun. 364:959–65 (2007); Zhu et al. J Exp Med 213:167–76 (2016)).

[0399] In humans, TIGIT is activated by activated CD4+ T cells and CD8+ T cells, natural killer (NK) cells, regulatory T cells (Tregs), and regs ) and follicular helper T cells (Joller et al. J Immunol. 186: 1338–42 (2011); Wu et al. Eur J Immunol. 46: 1152–61 (2016)), while TIGIT is weakly expressed in naive T cells. In cancer, TIGIT is co-expressed with PD-1 on tumor antigen-specific CD8+ T cells and CD8+ tumor-infiltrating lymphocytes (TILs) in mice and humans (Chauvin et al. J Clin Invest. 125: 2046–58 (2015); Johnston et al. Cancer Cell. 26: 923–37 (2014)). TIGIT is expressed by T cells in peripheral blood mononuclear cells (PBMCs) of healthy donors and cancer patients. regs Highly expressed and upregulated in the TME (Joller et al. Immunity. 40: 569–81 (2014); Zhang et al. Blood. 122: 2823–36 (2013)). TIGIT is also co-expressed with other inhibitory receptors (including TIM-3 and LAG-3) on exhausted CD8+ T cell subsets in tumors (Chauvin et al. J Clin Invest. 125: 2046–58 (2015); Johnston et al. Cancer Cell. 26: 923–37 (2014)).

[0400] In some embodiments, the immune checkpoint inhibitor is a TIGIT inhibitor, which blocks the interaction of TIGIT with CD155 by binding to the TIGIT receptor to inhibit immune suppression. TIGIT inhibitors include, but are not limited to, etigilimab (OMP-313M32; Oncomed Pharmaceuticals); tiragolumab (MTIG7192A; RG6058; Roche / Genentech); vibostolimab (MK-7684; Merck); BMS-986207 (Bristol-Myers Squibb); AZD2936 (AstraZeneca); ASP8374 (Astellas / Potenza Therapeutics); domvanalimab (AB154; Arcus Biosciences); IBI939 (Innovent Biologics); ociperlimab (BGB-A1217; BeiGene); EOS884448 (iTeos Therapeutics); SEA-TGT (Seattle Biosciences); Genetics); COM902 (Compugen); MPH-313 (MereoBiopharma); M6223 (EMD Serono); HLX53 (Shanghai Henlius Biotech); JS006 (JunshiBio); mAb-7 (Stanwei Biotech); SHR-1708 (Hengrui Medicine); BAT6005 (Bio-TheraSolutions); GS02 (Suzhou Zelgen / Qilu Pharma); RXI-804 (Rxi Pharmaceuticals); NB6253 (Northern Biologics); ENUM009 (Enumreal Biomedical); CASC-674 (Cascadian Therapeutics); AJUD008 (AJUD Biopharma); and AGEN1777 (Agenus, Bristol-Myers Squibb).

[0401] T cell immunoglobulin and mucin domain 3 (TIM-3) inhibitor

[0402] In some embodiments, the immune checkpoint inhibitor is a T cell immunoglobulin and mucin domain 3 (TIM-3) inhibitor. TIM-3 is a cell surface molecule containing immunoglobulin (Ig) and mucin domains that was originally discovered as a target for CD4 T cells that produce interferon gamma (IFN-γ). + T helper 1 (Th1) and CD8 + TIM-3 is a cell surface marker unique to T-cell cytotoxic 1 (Tc1) cells (Monney et al. Nature. 415:536–41 (2002)). + and CD8 + TIM-3 expression is a key factor in the regulation and co-expression of other immune checkpoint receptors on T cells (PD-1, LAG-3, and TIGIT) (Chihara et al. Nature. 558:454–9 (2018); DeLong et al. ImmunoHorizons. 3:13–25 (2019)). + TIM-3 is a marker of T cell subsets (Fourcade et al. J Exp Med. 207:2175–86 (2010); Sakuishi et al. J Exp Med. 207:2187–94 (2010)). Several TIM-3 ligands have been identified, including galectin-9, phosphatidylserine (PtdSer), high-mobility group box 1 protein (HMGB1), and CEACAM-1.

[0403] In some embodiments, the immune checkpoint inhibitor is a TIM-3 inhibitor that blocks the interaction of TIM-3 with galectin-9, phosphatidylserine (PtdSer), high mobility group box 1 protein (HMGB1) and / or CEACAM-1 by binding to the TIM-3 receptor to inhibit immunosuppression. TIM-3 inhibitors include, but are not limited to, sabatolimab (MGB453; Novartis Pharmaceuticals); cobolimab (TSR-022; Tesaro / GSK); RG7769 (Genentech); MAS-825 (Novartis); Sym023 (Symphogen A / S); BGBA425 (BeiGene); R07121661 (Hoffmann-La Roche); LY3321367 (Eli Lilly and Company); INCAGN02390 (Incyte Corporation); BMS-986258 (ONO7807, Bristol-Myers Squibb); AZD7789 (AstraZeneca); TQB2618 (Chia Tai Tianqing Pharmaceutical Group Co., Ltd.); and NB002 (Neologics Bioscience).

[0404] Alternative immune checkpoint inhibitors

[0405] In some embodiments, the patient is administered a B7-H3 / CD276 immune checkpoint inhibitor, such as enoblituzumab (MGA217, Macrogenics) MGD009 (Macrogenics), 131I-8H9 / omburtamab (γ-mabs) and I-8H9 / omburtamab (γ-mabs), an indoleamine 2,3-dioxygenase (IDO) immune checkpoint inhibitor, such as Indoximod and INCB024360, a killer immunoglobulin-like receptor (KIR) immune checkpoint inhibitor, such as Lirilumab (BMS-986015), a carcinoembryonic antigen cell adhesion molecule (CEACAM) inhibitor (e.g., CEACAM-1, -3 and / or -5). Exemplary anti-CEACAM-1 antibodies are described in WO 2010 / 125571, WO 2013 / 082366, and WO 2014 / 022332, e.g., monoclonal antibodies 34B1, 26H7, and 5F4; or recombinant forms thereof (as described in, e.g., US 2004 / 0047858, U.S. Pat. No. 7,132,255, and WO 99 / 052552). In other embodiments, the anti-CEACAM antibody binds to CEACAM-5 (as described, e.g., in Zheng et al. PloS One. 2:5(9). Pii:e12529 (DOI: 10:1371 / journal.pone.0021146, 2010)), or cross-reacts with CEACAM-1 and CEACAM-5 (as described, e.g., in WO 2013 / 054331 and US 2014 / 0271618).

[0406] In some embodiments, patients are administered an ICI directed against CD47, including but not limited to Hu5F9-G4 (Stanford University / Forty Seven), TI-061 (Arch Oncology), TTI-622 (Trillum Therapeutics), TTI-621 (Trillum Therapeutics), SRF231 (Surface Oncology), SHR-1603 (Hengrui), OSE-172 (Boehringer Ingelheim / OSE Immunotherapeutics), NI-1701 (Novimmune TG Therapeutics), IBI188 (Innovent Biologics);CC-95251 (Celgene), CC-90002 (Celgene / Inibrx), AO-176 (Arch Oncology), ALX148 (ALX Oncology), IMM01 (ImmuneOnco Biopharma), IMM2504 (ImmuneOnco Biopharma), IMM2502 (ImmuneOncoBiopharma), IMM03 (ImmuneOnco Biopharma), IMC-002 (ImmuneOncia Therapeutics), IBI322 (Innovent Biologics), HMBD-004B (Hummingbird Bioscience), HMBD-004A (Hummingbird Bioscience), HLX24 (Henlius), FSI-189 (Forty Seven), DSP107 (KAHRMedical), CTX-5861 (Compass) Therapeutics), BAT6004 (Bio-Thera), AUR-105 (Aurigene), AUR-104 (Aurigene), ANTI-CD47 (Biocad), ABP-500 (Abpro), ABP-160 (Abpro), TJC4 (I-MABBiopharma), TJC4-CK (I-MAB Biopharma), SY102 (Saiyuan), SL-172154 (Shattuck Labs), PSTx-23 (Paradigm Shift Therapeutics), PDL1 / CD47BsAb (Hanmi Pharmaceuticals), NI-1801 (Novimmune), MBT-001 (Morphiex), LYN00301 (LynkCell) and BH-29xx (Beijing) Hanmi). ;

[0407] In some embodiments, the ICI is an inhibitor against CD39, including but not limited to TTX-030 (Tizona Therapeutics), IPH5201 (Innate Pharma / AstraZeneca), SRF-617 (Surface Oncology), ES002 (Elpisciences), 9-8B (Igenica), and antisense oligonucleotides (Secarna)

[0408] In some embodiments, the immune checkpoint inhibitor is an inhibitor of B and T lymphocyte attenuator (BTLA), as described in Zhang et al. Clin Exp Immunol. 163(1):77–87 (2011), and TAB004 / JS004 (Junshi Biosciences).

[0409] In some embodiments, the immune checkpoint inhibitor is a sialic acid-binding immunoglobulin-like lectin 15 (Siglec-15) inhibitor, including but not limited to NC318 (anti-Siglec-15 mAb).

[0410] Chemotherapeutic agents

[0411] As contemplated herein, the CDK inhibitors described herein can be combined with any standard chemotherapeutic treatment modality. In certain embodiments, the CDK inhibitors described herein can be combined with any standard chemotherapeutic treatment modality and further combined with immune checkpoint inhibitors.

[0412] In certain embodiments, chemotherapeutics are toxic to immune effector cells. In certain embodiments, chemotherapeutics inhibit cell growth. In certain embodiments, the cytotoxic chemotherapeutics administered are DNA damaging chemotherapeutics. In certain embodiments, chemotherapeutics are protein synthesis inhibitors, DNA damaging chemotherapeutics, alkylating agents, topoisomerase inhibitors, RNA synthesis inhibitors, DNA complex binding agents, thiol alkylating agents, guanine alkylating agents, tubulin binding agents, DNA polymerase inhibitors, anticancer enzymes, RAC1 inhibitors, thymidylate synthase inhibitors, oxazaphosphorus compounds, integrin inhibitors (such as cilengitide), camptothecin or homocamptothecin, antifolates or folic acid antimetabolites.

[0413] In some embodiments, the additional therapeutic agent is selected from elotuzumab, rituximab, lenalidomide, cytarabine, daratumumab, adalimumab, idealisib, gilteritinib, glasdegib, valacyclovir, acalabrutinib, ibrutinib, midostaurin, ruxolitinib, bortezomib, lapatinib, bendamstine, enzalutamide, azacitidine, obinutuzumab, decitabine, erdafitinib, or venetoclax.

[0414] In certain embodiments, the additional therapeutic agent is trastuzumab. In certain embodiments, the additional therapeutic agent is lapatinib. In certain embodiments, Compound 1 is administered with 2, 3, or 4 additional therapeutic agents. In certain embodiments, there are 2 additional therapeutic agents. In certain embodiments, the two additional therapeutic agents are lapatinib and trastuzumab.

[0415] In certain embodiments, the additional therapeutic agent is osimertinib mesylate

[0416] In certain embodiments, the additional therapeutic agent is alectinib

[0417] In certain embodiments, the additional therapeutic agent is a MEK inhibitor.

[0418] In certain embodiments, the additional therapeutic agent is an androgen receptor ligand.

[0419] In certain embodiments, the additional therapeutic agent is a BTK inhibitor, such as, but not limited to, ibrutinib or acalabrutinib

[0420] In certain embodiments, the additional therapeutic agent is a MEK inhibitor and a RAF inhibitor.

[0421] In certain embodiments, the additional therapeutic agent is a RAF inhibitor.

[0422] In certain embodiments, the additional therapeutic agent is regorafenib.

[0423] Cytotoxic chemotherapy drugs

[0424] Cytotoxicity, DNA damaging chemotherapeutics are often non-specific, and particularly at high doses, are toxic to normal, rapidly dividing cells (such as HSPC and immune effector cells). As used herein, the term "DNA damaging" chemotherapy or chemotherapeutics refers to treatment with cytostatics or cytotoxic agents (i.e., compounds) to reduce or eliminate the growth or proliferation of undesirable cells (such as cancer cells), wherein the cytotoxic effect of the agent may be one or more results of nucleic acid insertion or combination, DNA or RNA alkylation, RNA or DNA synthesis inhibition, another nucleic acid related activity (such as protein synthesis) inhibition or any other cytotoxic effect. Such compounds include but are not limited to DNA damaging compounds that can kill cells." DNA damaging" chemotherapeutics include but are not limited to alkylating agents, DNA intercalators, protein synthesis inhibitors, DNA or RNA synthesis inhibitors, DNA base analogs, topoisomerase inhibitors, telomerase inhibitors and telomeric DNA binding compounds. For example, alkylating agents include alkyl sulfonates, such as busulfan, improsulfan, and piposulfan; aziridines, such as benzodizepa, carboquinone, metodepa, and uredepa; ethyleneimines and methylmelamines, such as hexamethylmelamine, triethylenemelamine, triethylenephosphamide, triethylenethiophosphamide, and trishydroxymethylmelamine; nitrogen mustards, such as chlorambucil, naphthyl mustard, cyclophosphamide, estramustine, mechlorethamine, mechlorethamine oxide hydrochloride, melphalan, novembichine, phenylephrine, prednimustine, trofosfamide, and uracil mustard; and nitrosoureas, such as carmustine, chlorozotocin, fotemustine, lomustine, nimustine, and ranimustine. Other DNA damaging chemotherapeutic agents include daunorubicin, doxorubicin, idarubicin, epirubicin, mitomycin, and streptozotocin. Chemotherapeutic antimetabolites include gemcitabine, mercaptopurine, thioguanine, cladribine, fludarabine phosphate, fluorouracil (5-FU), floxuridine, cytarabine, pentostatin, me...

Claims

1. A method for treating a human suffering from abnormal cell proliferation mediated by cyclin E1 (CCNE1) and / or cyclin E2 (CCNE2), wherein CCNE1 and / or CCNE2 is amplified or overexpressed, the method comprising administering an effective amount of a compound of the following structure: or a pharmaceutically acceptable salt thereof.

2. A method of treating a subject suffering from abnormal cell proliferation, comprising: (i) obtaining a sample from a human patient; (ii) detecting whether cyclin E1 (CCNE1) and / or cyclin E2 (CCNE2) are overexpressed in the sample compared with a control sample; (iii) if cyclin E1 (CCNE1) and / or cyclin E2 (CCNE2) are overexpressed, administering to the human patient an effective amount of a compound of the following structure: or a pharmaceutically acceptable salt thereof.

3. The method of claim 1 or 2, wherein the abnormal cell proliferation is cancer or a tumor.

4. The method of any one of claims 1-3, wherein the abnormal cell proliferation is selected from the group consisting of uterine cancer, uterine carcinosarcoma (UCS), uterine corpus endometrial carcinoma (UCEC), ovarian cancer, ovarian serous cystadenocarcinoma (OV), sarcoma (SARC), lung cancer, lung squamous cell carcinoma (LUSC), lung adenocarcinoma (LUAD), gastric cancer, gastric adenocarcinoma (STAD), bladder cancer, bladder urothelial carcinoma (BLCA), esophageal cancer, esophageal tumor (ESCA), adrenocortical carcinoma, breast cancer, breast invasive carcinoma (BRCA), pancreatic cancer, pancreatic adenocarcinoma (PAAD), liver cancer, liver hepatocellular carcinoma (LIHC), cervical cancer, cervical squamous cell carcinoma (CESC), endocervical adenocarcinoma, mesothelioma (MESO), head and neck squamous cell carcinoma (HSNC), colon cancer, colon adenocarcinoma (COAD), skin cancer, melanoma, cutaneous melanoma of the skin (SKCM), glioblastoma multiforme (GBM), kidney cancer, and kidney chromophobe cell (KICH).

5. The method of claim 3 or 4, wherein the cancer is retinoblastoma (Rb) protein positive (Rb+).

6. The method of claim 3 or 4, wherein the cancer is retinoblastoma (Rb) protein deficient (Rb-).

7. The method of claim 3, wherein the cancer is small cell lung cancer.

8. The method of claim 3, wherein the cancer is breast cancer.

9. The method of claim 8, wherein the breast cancer is hormone receptor positive (HR+).

10. The method of claim 8 or 9, wherein the breast cancer is estrogen receptor positive (ER+).

11. The method of any one of claims 8-10, wherein the breast cancer is progesterone receptor positive (PR+).

12. The method of any one of claims 8-11, wherein the breast cancer is HER2 negative (HER2-).

13. The method of claim 3, wherein the cancer is ovarian cancer.

14. The method of claim 3, wherein the cancer is prostate cancer.

15. The method of claim 3, wherein the cancer is bladder cancer.

16. The method of claim 3, wherein the cancer is a sarcoma.

17. The method of claim 3, wherein the cancer is uterine cancer. E 18. The method of any one of E 3-17, wherein the cancer is recurrent. E 19. The method of any one of E 3-18, wherein the cancer progresses following standard of care therapy.

20. The method of any one of claims 3-19, wherein the cancer is intolerant to or unsuitable for standard or care therapy.

21. The method of any one of claims 3-20, wherein the cancer is refractory.

22. The method of any one of claims 3-21, wherein the cancer is platinum-refractory or platinum-resistant.

23. The method of any one of claims 3-22, wherein the cancer progressed following a prior regimen comprising a CDK4 / 6 inhibitor.

24. The method of any one of claims 3-23, wherein the cancer is CDK4 / 6 inhibitor-resistant.

25. The method of any one of claims 3-24, wherein the cancer is intrinsically resistant to a CDK4 / 6 inhibitor.

26. The method of any one of claims 3-24, wherein the cancer has acquired resistance to a CDK4 / 6 inhibitor.

27. The method of any one of claims 3-26, further comprising administering an effective amount of a CDK4 / 6 inhibitor.

28. The method of claim 27, wherein the CDK4 / 6 inhibitor is selected from palbociclib, ribociclib, abemaciclib, triclasiclib, leloxicil, or SHR6390 (dalcili).

29. The method of claim 27, wherein the CDK4 / 6 inhibitor is selected from BPI-16350, narazaciclib (ON-123300), FLX-925 (AMG-925), UCT-03-008, GLR2007, bilociclib (XZP-3287), LY5219, PF-07220060, or ON-123300.

30. The method of any one of claims 3-29, further comprising administering an effective amount of an anti-cancer therapy.

31. The method of claim 30, wherein the anti-cancer therapy is selected from radiation, surgery, immune checkpoint inhibitors, estrogen inhibitors, androgen inhibitors, PARP inhibitors, or a combination thereof.

32. The method of claim 31, wherein the anti-cancer therapy is an estrogen inhibitor.

33. The method of claim 32, wherein the estrogen inhibitor is selected from a selective estrogen receptor modulator (SERM), a selective estrogen receptor degrader (SERD), a complete estrogen receptor degrader, a complete estrogen antagonist, a partial estrogen antagonist, or a combination thereof.

34. The method of claim 32 or 33, wherein the estrogen inhibitor is a selective estrogen receptor degrader (SERD).

35. The method of claim 34, wherein the SERD is selected from fulvestrant, rintodestrant (G1T48), borestrant (ZB-716), brilanestrant (GDC0810), camizestrant (AZD9833), D00502, elastodestran (RAD1901), etacstil (GW5638), GW7604, AZD9496, GDC-0927, giredestrant (GDC9545, RG6171), LSZ102, imlunestrant (LY3484356), SAR439859, SCR6852, or ZN-c5.

36. The method of claim 35, wherein the SERD is fulvestrant.

37. The method of claim 35, wherein the SERD is elastatin (RAD1901).

38. The method of claim 32 or 33, wherein the estrogen inhibitor is a selective estrogen receptor modulator (SERM).

39. The method of claim 38, wherein the SERM is letrozole.

40. The method of any one of claims 1-39, further comprising administering a chemotherapeutic agent selected from the group consisting of a protein synthesis inhibitor, a DNA damaging chemotherapeutic agent, an alkylating agent, a topoisomerase inhibitor, an RNA synthesis inhibitor, a DNA complex binding agent, a thiol alkylating agent, a guanine alkylating agent, a tubulin binding agent, a DNA polymerase inhibitor, an anticancer enzyme, a RAC1 inhibitor, a thymidylate synthase inhibitor, an oxazaphosphorus compound, an integrin inhibitor, an antifolate, a folate antimetabolite, or a combination thereof.

41. The method of claim 40, wherein the chemotherapeutic agent is selected from cisplatin, carboplatin, etoposide, oxaliplatin, 5-fluorouracil, floxuridine, capecitabine, gemcitabine, mitomycin, methotrexate, vinblastine, cyclophosphamide, dacarbazine, nab-paclitaxel, ifosfamide, topotecan, irinotecan, docetaxel, temozolomide, paclitaxel, doxorubicin, camptothecin, or a combination thereof.

42. The method of claim 41, wherein the chemotherapeutic agent is doxorubicin.

43. The method of claim 42, wherein the chemotherapeutic agent is camptothecin.

44. The method of claim 43, wherein the chemotherapeutic agent is cisplatin.

45. The method of claim 41, wherein the chemotherapeutic agent is carboplatin.

46. ​​The method of claim 41, wherein the chemotherapeutic agent is etoposide.

47. The method of claims 1-46, wherein Compound I is administered in a dosage form of between about 100 mg and about 800 mg.

48. The method of claims 1-47, wherein Compound I is administered in a dosage form selected from about 100 mg, about 200 mg, about 300 mg, about 400 mg, about 600 mg, or about 800 mg.

49. The method of claims 1-48, wherein Compound I is administered at least once a day.

50. The method of claims 1-48, wherein Compound I is administered at least twice a day.

51. The method of claims 1-50, wherein Compound I is administered for at least 21 days.

52. The method of claims 1-50, wherein Compound I is administered for at least 24 days.

53. The method of claims 1-50, wherein Compound I is administered for at least 28 days.

54. The method of claims 1-50, wherein Compound I is administered for at least 35 days.

55. The method of any one of claims 1-54, wherein a next generation sequencing (NGS) panel test is used to confirm the CCNE1 and / or CCNE2 overexpression or amplification status.

56. A method of treating a subject having CDK4 / 6 inhibitor-resistant small cell lung cancer (SCLC), comprising: (i) administering to the subject an effective amount of the following structural compound: or a pharmaceutically acceptable salt thereof; and (ii) administering to the subject an effective amount of one or more chemotherapeutic agents.

57. The method of claim 56, wherein the chemotherapeutic agent is selected from cisplatin, carboplatin, etoposide, oxaliplatin, 5-fluorouracil, floxuridine, capecitabine, gemcitabine, mitomycin, methotrexate, vinblastine, cyclophosphamide, dacarbazine, nab-paclitaxel, ifosfamide, topotecan, irinotecan, docetaxel, temozolomide, paclitaxel, doxorubicin, camptothecin, or a combination thereof.

58. The method of claim 56 or 57, wherein the chemotherapeutic agent is doxorubicin.

59. The method of claim 56 or 57, wherein the chemotherapeutic agent is camptothecin.

60. The method of claim 56 or 57, wherein the chemotherapeutic agent is cisplatin.

61. The method of claim 56 or 57, wherein the chemotherapeutic agent is etoposide.

62. The method of claim 56 or 57, wherein the chemotherapeutic agent is carboplatin.

63. A method of treating a subject having CDK4 / 6 inhibitor-resistant sex hormone receptor-positive (HR+) breast cancer, comprising: (i) administering to the subject an effective amount of the following structural compound or a pharmaceutically acceptable salt thereof; and, (ii) administering an effective amount of a CDK4 / 6 inhibitor to the subject.

64. The method of claim 63, wherein the hormone receptor positive (HR+) breast cancer is intrinsically resistant to a CDK4 / 6 inhibitor.

65. The method of claim 63, wherein the hormone receptor positive (HR+) breast cancer has acquired resistance to a CDK4 / 6 inhibitor.

66. The method of any one of claims 63-65, wherein the CDK4 / 6 inhibitor-resistant HR+ breast cancer is HER2-negative.

67. The method of any one of claims 63 to 66, further comprising administering to the subject an effective amount of an estrogen inhibitor.

68. The method of claim 67, wherein the estrogen inhibitor is selected from a selective estrogen receptor modulator (SERM), a selective estrogen receptor degrader (SERD), a full estrogen receptor degrader, a full estrogen antagonist, a partial estrogen antagonist, or a combination thereof.

69. The method of claim 68, wherein the estrogen inhibitor is a selective estrogen receptor modulator (SERM).

70. The method of claim 68, wherein the estrogen inhibitor is a selective estrogen receptor degrader (SERD).

71. The method of any one of E 63-70, further comprising administering an effective amount of a chemotherapeutic agent.

72. The method of claim 71, wherein the chemotherapeutic agent is selected from cisplatin, carboplatin, etoposide, oxaliplatin, 5-fluorouracil, floxuridine, capecitabine, gemcitabine, mitomycin, methotrexate, vinblastine, cyclophosphamide, dacarbazine, nab-paclitaxel, ifosfamide, topotecan, irinotecan, docetaxel, temozolomide, paclitaxel, doxorubicin, camptothecin, or a combination thereof.

73. The method of any one of claims 63-72, wherein the CDK4 / 6 inhibitor is selected from palbociclib, ribociclib, abemaciclib, triclasiclib, leloxicil, SHR6390 (Darcili).

74. The method of claim 73, wherein the CDK4 / 6 inhibitor is palbociclib.

75. The method of claim 73, wherein the CDK4 / 6 inhibitor is ribociclib.

76. The method of claim 73, wherein the CDK4 / 6 inhibitor is abemaciclib.

77. The method of any one of claims 63-72, wherein the CDK4 / 6 inhibitor is selected from BPI-16350, narazaciclib (ON-123300), FLX-925 (AMG-925), UCT-03-008, GLR2007, bilociclib (XZP-3287), LY5219, PF-07220060, or ON-123300.

78. The method of any one of Es 63-77, wherein the hormone receptor-positive (HR+) breast cancer is progesterone receptor-positive (PR+).

79. The method of any one of Es 63-78, wherein the hormone receptor-positive (HR+) breast cancer is estrogen receptor-positive (ER+).

80. The method of any one of Es 63-79, wherein the hormone receptor-positive (HR+) breast cancer is HER2-negative.

81. The method of any one of Es 63-80, wherein the hormone receptor-positive (HR+) breast cancer is resistant to endocrine therapy.

82. The method of claim 81, wherein the hormone receptor positive (HR+) breast cancer has acquired resistance to endocrine therapy.

83. The method of any one of claims 81-82, wherein the hormone receptor-positive (HR+) breast cancer is resistant to SERDs.

84. The method of any one of Es 81-83, wherein the hormone receptor-positive (HR+) breast cancer is resistant to fulvestrant.

85. The method of any one of E81-83, wherein the hormone receptor positive (HR+) breast cancer is resistant to elastomeric.

86. A method of treating a subject having CDK4 / 6 inhibitor-resistant estrogen receptor-positive (ER+) breast cancer, comprising: (i) administering to the subject an effective amount of the following structural compound or a pharmaceutically acceptable salt thereof; and, (ii) administering an effective amount of a CDK4 / 6 inhibitor to the subject.

87. The method of claim 86, wherein the ER+ breast cancer is intrinsically resistant to CDK4 / 6 inhibitors.

88. The method of claim 86, wherein the ER+ breast cancer has acquired resistance to a CDK4 / 6 inhibitor.

89. The method of any one of claims 86-88, wherein the CDK4 / 6 inhibitor-resistant ER+ breast cancer is HER2-negative.

90. The method of any one of claims 86-89, further comprising administering an effective amount of an estrogen inhibitor.

91. The method of claim 90, wherein the estrogen inhibitor is selected from a selective estrogen receptor modulator (SERM), a selective estrogen receptor degrader (SERD), a full estrogen receptor degrader, a full estrogen antagonist, a partial estrogen antagonist, or a combination thereof.

92. The method of claim 91, wherein the estrogen inhibitor is a selective estrogen receptor modulator (SERM).

93. The method of claim 91, wherein the estrogen inhibitor is a selective estrogen receptor degrader (SERD).

94. The method of any one of E 86-93, further comprising administering an effective amount of a chemotherapeutic agent.

95. The method of claim 94, wherein the chemotherapeutic agent is selected from cisplatin, carboplatin, etoposide, oxaliplatin, 5-fluorouracil, floxuridine, capecitabine, gemcitabine, mitomycin, methotrexate, vinblastine, cyclophosphamide, dacarbazine, nab-paclitaxel, ifosfamide, topotecan, irinotecan, docetaxel, temozolomide, paclitaxel, doxorubicin, camptothecin, or a combination thereof.

96. The method of any one of claims 86-95, wherein the CDK4 / 6 inhibitor-resistant ER+ breast cancer is luminal A breast cancer.

97. The method of any one of claims 86-96, wherein the CDK4 / 6 inhibitor is selected from palbociclib, ribociclib, abemaciclib, triclasiclib, leloxicil, SHR6390 (Darcili).

98. The method of claim 97, wherein the CDK4 / 6 inhibitor is palbociclib.

99. The method of claim 97, wherein the CDK4 / 6 inhibitor is ribociclib.

100. The method of claim 97, wherein the CDK4 / 6 inhibitor is abemaciclib.

101. The method of any one of Es 86-100, wherein the ER+ breast cancer is resistant to endocrine therapy.

102. The method of claim 101, wherein the ER+ breast cancer has acquired resistance to endocrine therapy.

103. The method of any one of claims 101-102, wherein the ER+ breast cancer is resistant to SERDs.

104. The method of any one of Es 101-103, wherein the ER+ breast cancer is resistant to fulvestrant.

105. The method of any one of E101-103, wherein the ER+ breast cancer is resistant to elastostat.

106. The method of any one of claims 1-105, wherein Compound 1 is crystalline and characterized in that The X-ray powder diffraction (XRPD) pattern comprises at least three 2θ values ​​selected from 10.3±0.2°, 11.9±0.2°, 16.3±0.2°, 17.8±0.2°, 19.3±0.2°, 22.4±0.2°, 23.0±0.2°, 24.1±0.2°, 24.7±0.2°, and 30.0±0.

2.

107. The method of claim 106, wherein the XRPD pattern comprises at least four 2θ values ​​selected from 10.3±0.2°, 11.9±0.2°, 16.3±0.2°, 17.8±0.2°, 19.3±0.2°, 22.4±0.2°, 23.0±0.2°, 24.1±0.2°, 24.7±0.2°, and 30.0±0.

2.

108. The method of claim 106, wherein the XRPD pattern comprises at least five 2θ values ​​selected from 10.3±0.2°, 11.9±0.2°, 16.3±0.2°, 17.8±0.2°, 19.3±0.2°, 22.4±0.2°, 23.0±0.2°, 24.1±0.2°, 24.7±0.2°, and 30.0±0.

2.

109. The method of claim 106, wherein the XRPD pattern comprises at least six 2θ values ​​selected from 10.3±0.2°, 11.9±0.2°, 16.3±0.2°, 17.8±0.2°, 19.3±0.2°, 22.4±0.2°, 23.0±0.2°, 24.1±0.2°, 24.7±0.2°, and 30.0±0.

2.

110. The method of any one of claims 106-109, wherein said XRPD pattern comprises a 2-θ value of at least 22.4 ± 0.2°.

111. The method of any one of claims 106-110, wherein said XRPD pattern comprises a 2θ value of at least 23.0±0.2°.

112. The method of any one of claims 106-111, wherein said XRPD pattern comprises a 2θ value of at least 17.8±0.2°.

113. A crystalline compound of the following structure: Features The X-ray powder diffraction (XRPD) pattern comprises at least three 2θ values ​​selected from 10.3±0.2°, 11.9±0.2°, 16.3±0.2°, 17.8±0.2°, 19.3±0.2°, 22.4±0.2°, 23.0±0.2°, 24.1±0.2°, 24.7±0.2°, and 30.0±0.

2.

114. The crystalline compound of claim 113, wherein the XRPD pattern comprises at least four 2θ values ​​selected from 10.3±0.2°, 11.9±0.2°, 16.3±0.2°, 17.8±0.2°, 19.3±0.2°, 22.4±0.2°, 23.0±0.2°, 24.1±0.2°, 24.7±0.2°, and 30.0±0.

2.

115. The crystalline compound of claim 113, wherein the XRPD pattern comprises at least five 2θ values ​​selected from 10.3±0.2°, 11.9±0.2°, 16.3±0.2°, 17.8±0.2°, 19.3±0.2°, 22.4±0.2°, 23.0±0.2°, 24.1±0.2°, 24.7±0.2°, and 30.0±0.

2.

116. The crystalline compound of claim 113, wherein the XRPD pattern comprises at least six 2θ values ​​selected from 10.3±0.2°, 11.9±0.2°, 16.3±0.2°, 17.8±0.2°, 19.3±0.2°, 22.4±0.2°, 23.0±0.2°, 24.1±0.2°, 24.7±0.2°, and 30.0±0.

2.

117. The crystalline compound of any one of claims 113-116, wherein the XRPD pattern comprises a 2θ value of at least 22.4 ± 0.2°.

118. The crystalline compound of any one of claims 113-117, wherein the XRPD pattern comprises a 2θ value of at least 23.0 ± 0.2°.

119. The crystalline compound of any one of claims 113-118, wherein the XRPD pattern comprises a 2θ value of at least 17.8 ± 0.2°.

120. Crystalline compounds of the following structure: Features The X-ray powder diffraction (XRPD) pattern comprises at least three 2θ values ​​selected from 7.3±0.2°, 10.7±0.2°, 15.5±0.2°, 15.6±0.2°, 16.6±0.2°, 16.9±0.2°, 19.3±0.2°, 20.0±0.2°, 24.0±0.2°, 25.1±0.2°, 25.9±0.2°, and 27.9±0.2°.

121. The crystalline compound of claim 120, wherein the XRPD pattern comprises at least four 2θ values ​​selected from 7.3±0.2°, 10.7±0.2°, 15.5±0.2°, 15.6±0.2°, 16.6±0.2°, 16.9±0.2°, 19.3±0.2°, 20.0±0.2°, 24.0±0.2°, 25.1±0.2°, 25.9±0.2°, and 27.9±0.2°.

122. The crystalline compound of claim 120, wherein the XRPD pattern comprises at least five 2θ values ​​selected from 7.3±0.2°, 10.7±0.2°, 15.5±0.2°, 15.6±0.2°, 16.6±0.2°, 16.9±0.2°, 19.3±0.2°, 20.0±0.2°, 24.0±0.2°, 25.1±0.2°, 25.9±0.2°, and 27.9±0.2°.

123. The crystalline compound of claim 120, wherein the XRPD pattern comprises at least six 2θ values ​​selected from 7.3±0.2°, 10.7±0.2°, 15.5±0.2°, 15.6±0.2°, 16.6±0.2°, 16.9±0.2°, 19.3±0.2°, 20.0±0.2°, 24.0±0.2°, 25.1±0.2°, 25.9±0.2°, and 27.9±0.2°.

124. The crystalline compound of any one of claims 120-123, wherein the XRPD pattern comprises a 2-θ value of at least 7.3 ± 0.2°.

125. The crystalline compound of any one of claims 120-124, wherein the XRPD pattern comprises a 2-θ value of at least 15.6 ± 0.2°.

126. The crystalline compound of any one of claims 120-125, wherein the XRPD pattern comprises a 2-θ value of at least 16.6 ± 0.2°.

127. A pharmaceutical composition comprising the crystalline compound of any one of claims 113-127 and one or more pharmaceutically acceptable excipients.

128. A pharmaceutical composition comprising Compound 1 or a pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable excipients, wherein the pharmaceutical composition is prepared from the crystalline compound of any one of claims 113-127.

129. The pharmaceutical composition of claim 128, wherein the composition is prepared by spray drying the crystalline compound of any one of claims 113-127.

130. The pharmaceutical composition of claim 128, wherein the composition is prepared by dissolving the crystalline compound of any one of claims 113-127 and mixing it with a pharmaceutically acceptable excipient.

131. The pharmaceutical composition of any one of claims 127-130, wherein the composition comprises polyethylene glycol.

132. The pharmaceutical composition of any one of claims 127-131, wherein the composition comprises hydroxypropyl methylcellulose.

133. The pharmaceutical composition of any one of claims 127-131, wherein the composition is in a dosage form of between about 100 mg to about 800 mg of Compound 1 or a pharmaceutically acceptable salt thereof.

134. The pharmaceutical composition of any one of claims 127-132, wherein the composition is in a dosage form selected from about 100 mg, about 200 mg, about 300 mg, about 400 mg, about 600 mg, or about 800 mg of Compound 1 or a pharmaceutically acceptable salt thereof.

135. A method for treating abnormal cell proliferation mediated by CDK2, comprising administering to a human in need thereof an effective amount of a crystalline compound of any one of claims 113-126 or a pharmaceutical composition of any one of claims 127-135.

136. The method of claim 135, wherein the abnormal cell proliferation is mediated by CDK2 and is cancer.

137. The method of claim 136, wherein the cancer has amplified or overexpressed cyclin E1 (CCNE1) and / or cyclin E2 (CCNE2).

138. The method of claim 136 or 137, wherein the cancer is retinoblastoma (Rb) protein positive (Rb+).

139. The method of claim 136 or 137, wherein the cancer is retinoblastoma (Rb) protein deficient (Rb-).

140. The method of any one of Es 136-139, wherein the cancer is an advanced unresectable and / or metastatic cancer.

141. The method of any one of Es 136-140, wherein the cancer is platinum-refractory and / or platinum-resistant. E 142. The method of any one of E 136-141, wherein the cancer progressed following a prior standard of care regimen. E 143. The method of any one of E 136-142, wherein the cancer progressed after prior standard systemic therapy.

144. The method of any one of Es 136-143, wherein the cancer progressed following prior systemic anticancer therapy.

145. The method of any one of Es 136-144, wherein the cancer progressed following a prior regimen comprising a platinum analog.

146. The method of any one of claims 136-145, wherein the cancer progressed following a prior regimen comprising a CDK4 / 6 inhibitor.

147. The method of any one of claims 135-146, wherein the abnormal cell proliferation is selected from the group consisting of uterine cancer, uterine carcinosarcoma (UCS), uterine corpus endometrial carcinoma (UCEC), ovarian cancer, ovarian serous cystadenocarcinoma (OV), sarcoma (SARC), lung cancer, lung squamous cell carcinoma (LUSC), lung adenocarcinoma (LUAD), gastric cancer, gastric adenocarcinoma (STAD), bladder cancer, bladder urothelial carcinoma (BLCA), esophageal cancer, esophageal tumor (ESCA), adrenocortical carcinoma, breast cancer, breast invasive carcinoma (BRCA), gastric cancer, pancreatic cancer, pancreatic adenocarcinoma (PAAD), liver cancer, hepatocellular carcinoma of the liver (LIHC), cervical cancer, cervical squamous cell carcinoma (CESC), endocervical adenocarcinoma, mesothelioma (MESO), head and neck squamous cell carcinoma (HSNC), colon cancer, colon adenocarcinoma (COAD), skin cancer, melanoma, cutaneous melanoma of the skin (SKCM), glioblastoma multiforme (GBM), kidney cancer, and kidney chromophobe cell (KICH).

148. The method of any one of claims 135-146, wherein the abnormal cell proliferation is fallopian tube cancer or primary peritoneal cancer.

149. The method of any one of Es 135-146, wherein the cancer is small cell lung cancer.

150. The method of any one of claims 135-146, wherein the cancer is breast cancer.

151. The method of claim 150, wherein the breast cancer is hormone receptor positive (HR+).

152. The method of claim 150 or 151, wherein the breast cancer is estrogen receptor positive (ER+).

153. The method of any one of claims 150-152, wherein the breast cancer is estrogen receptor positive (ER+).

154. The method of any one of claims 150-153, wherein the breast cancer is human epidermal growth factor receptor 2 negative (HER2-).

155. The method of claim 154, wherein the breast cancer is HR+ / HER2- breast cancer.

156. The method of claim 154, wherein the breast cancer is ER+ / HER2- breast cancer.

157. The method of any one of claims 135-146, wherein the cancer is ovarian cancer.

158. The method of claim 157, wherein the ovarian cancer has an amplification of CCNE1.

159. The method of any one of claims 135-146, wherein the cancer is prostate cancer.

160. The method of any one of claims 135-146, wherein the cancer is bladder cancer.

161. The method of any one of claims 135-146, wherein the cancer is a sarcoma.

162. The method of any one of claims 135-146, wherein the cancer is uterine cancer.

163. The method of any one of claims 135-162, wherein the cancer is recurrent.

164. The method of any one of claims 135-163, wherein the cancer is refractory.

165. The method of any one of claims 135-164, wherein the cancer is resistant to a CDK4 / 6 inhibitor.

166. The method of any one of claims 135-165, wherein the cancer is intrinsically resistant to a CDK4 / 6 inhibitor.

167. The method of any one of claims 135-165, wherein the cancer has acquired resistance to a CDK4 / 6 inhibitor.

168. The method of any one of claims 135-167, wherein the cancer is platinum-resistant or platinum-refractory.

169. The method of any one of claims 135-168, further comprising administering an effective amount of a CDK4 / 6 inhibitor.

170. The method of claim 169, wherein the CDK4 / 6 inhibitor is selected from palbociclib, ribociclib, abemaciclib, triclasiclib, leloxicil, or SHR6390 (dalcili).

171. The method of claim 169, wherein the CDK4 / 6 inhibitor is selected from BPI-16350, narazaciclib (ON-123300), FLX-925 (AMG-925), UCT-03-008, GLR2007, bilociclib (XZP-3287), LY5219, PF-07220060, or ON-123300.

172. The method of any one of Es 135-171, further comprising administering an effective amount of an additional anti-cancer therapy.

173. The method of claim 172, wherein the anti-cancer therapy is selected from radiation, surgery, an immune checkpoint inhibitor, an estrogen inhibitor, an androgen inhibitor, a PARP inhibitor, or a combination thereof.

174. The method of claim 172, wherein the anti-cancer therapy is an estrogen inhibitor.

175. The method of claim 175, wherein the estrogen inhibitor is selected from a selective estrogen receptor modulator (SERM), a selective estrogen receptor degrader (SERD), a full estrogen receptor degrader, a full estrogen antagonist, a partial estrogen antagonist, or a combination thereof.

176. The method of claim 175, wherein the estrogen inhibitor is a selective estrogen receptor degrader (SERD).

177. The method of claim 176, wherein the SERD is selected from fulvestrant, rintodestrant (G1T48), borestrant (ZB-716), brilanestrant (GDC0810), camizestrant (AZD9833), D00502, elastodestran (RAD1901), etacstil (GW5638), GW7604, AZD9496, GDC-0927, giredestrant (GDC9545, RG6171), LSZ102, imlunestrant (LY3484356), SAR439859, SCR6852 or ZN-c5.

178. The method of claim 177, wherein the SERD comprises fulvestrant.

179. The method of claim 177, wherein the SERD comprises elastostat (RAD1901).

180. The method of claim 175, wherein the estrogen inhibitor is a selective estrogen receptor modulator (SERM).

181. The method of claim 180, wherein the SERM is letrozole.

182. The method of any one of claims 135-181, further comprising administering an effective amount of a chemotherapeutic agent selected from a protein synthesis inhibitor, a DNA damaging chemotherapeutic agent, an alkylating agent, a topoisomerase inhibitor, an RNA synthesis inhibitor, a DNA complex binding agent, a thiol alkylating agent, a guanine alkylating agent, a tubulin binding agent, a DNA polymerase inhibitor, an anticancer enzyme, a RAC1 inhibitor, a thymidylate synthase inhibitor, an oxazaphosphorus compound, an integrin inhibitor, an antifolate, a folate antimetabolite, or a combination thereof.

183. The method of claim 182, wherein the chemotherapeutic agent is selected from cisplatin, carboplatin, etoposide, oxaliplatin, 5-fluorouracil, floxuridine, capecitabine, gemcitabine, mitomycin, methotrexate, vinblastine, cyclophosphamide, dacarbazine, nab-paclitaxel, ifosfamide, topotecan, irinotecan, docetaxel, temozolomide, paclitaxel, doxorubicin, camptothecin, or a combination thereof.

184. The method of claim 183, wherein the chemotherapeutic agent is doxorubicin.

185. The method of claim 183, wherein the chemotherapeutic agent is camptothecin.

186. The method of claim 183, wherein the chemotherapeutic agent is cisplatin.

187. The method of claim 183, wherein the chemotherapeutic agent is carboplatin.

188. The method of claim 183, wherein the chemotherapeutic agent is etoposide.

189. The method of any of E135-188, wherein Compound I is administered in combination with a standard of care chemotherapeutic treatment regimen.

190. The method of any one of claims 135-189, wherein the crystalline compound is administered at a dose of between about 100 mg to about 800 mg.

191. The method of any one of claims 135-189, wherein the crystalline compound is administered at a dose selected from about 100 mg, about 200 mg, about 300 mg, about 400 mg, about 600 mg, or about 800 mg.

192. A method of treating a human having advanced unresectable or metastatic ER+ / HER2- breast cancer comprising: (i) administering an effective amount of a CDK2 inhibitor of the following structure: or a pharmaceutically acceptable salt thereof; (ii) administering an effective amount of a CDK4 / 6 inhibitor; and, (iii) administering an effective amount of an estrogen inhibitor, The ER+ / HER2- breast cancer has acquired resistance to CDK4 / 6 inhibitors and SERDs.

193. The method of claim 192, wherein the CDK4 / 6 inhibitor is selected from palbociclib, ribociclib, abemaciclib, triclasiclib, leloxicil, or SHR6390 (Darcili).

194. The method of claim 192, wherein the CDK4 / 6 inhibitor is selected from BPI-16350, narazaciclib (ON-123300), FLX-925 (AMG-925), UCT-03-008, GLR2007, bilociclib (XZP-3287), LY5219, PF-07220060 or ON-123300.

195. The method of any one of claims 192-194, wherein the estrogen inhibitor is selected from a selective estrogen receptor modulator (SERM), a selective estrogen receptor degrader (SERD), a full estrogen receptor degrader, a full estrogen antagonist, a partial estrogen antagonist, or a combination thereof.

196. The method of claim 195, wherein the estrogen inhibitor is a selective estrogen receptor modulator (SERM).

197. The method of claim 195, wherein the estrogen inhibitor is a selective estrogen receptor degrader (SERD).

198. A method of treating a human with advanced unresectable or metastatic ER+ / HER2- breast cancer comprising administering an effective amount of a CDK2 inhibitor of the structure: or a pharmaceutically acceptable salt thereof; wherein Compound 1 is crystalline and is characterized by an X-ray powder diffraction (XRPD) pattern comprising at least three 2θ values ​​selected from 10.3±0.2°, 11.9±0.2°, 16.3±0.2°, 17.8±0.2°, 19.3±0.2°, 22.4±0.2°, 23.0±0.2°, 24.1±0.2°, 24.7±0.2°, and 30.0±0.

2.

199. The method of claim 198, further comprising administering an effective amount of a CDK4 / 6 inhibitor.

200. The method of claim 198, wherein the CDK4 / 6 inhibitor is selected from palbociclib, ribociclib, abemaciclib, triclasiclib, leloxicil, or SHR6390 (dalcili).

201. The method of claim 199, wherein the CDK4 / 6 inhibitor is selected from BPI-16350, narazaciclib (ON-123300), FLX-925 (AMG-925), UCT-03-008, GLR2007, bilociclib (XZP-3287), LY5219, PF-07220060 or ON-123300.

202. The method of any one of claims 198-201, further comprising administering an effective amount of an estrogen inhibitor.

203. The method of claim 202, wherein the estrogen inhibitor is selected from a selective estrogen receptor modulator (SERM), a selective estrogen receptor degrader (SERD), a full estrogen receptor degrader, a full estrogen antagonist, a partial estrogen antagonist, or a combination thereof.

204. The method of claim 203, wherein the estrogen inhibitor is a selective estrogen receptor modulator (SERM).

205. The method of claim 203, wherein the estrogen inhibitor is a selective estrogen receptor degrader (SERD). E 206. The method of any one of E 192-205, wherein the human has previously received at least one prior line of endocrine therapy.

207. The method of any one of claims 192-206, wherein the human has previously received at least one prior line of CDK4 / 6 inhibitor therapy. E 208. The method of any one of E 192-207, wherein the human has previously received at least one prior line of chemotherapy. E 209. The method of any one of E 192-208, wherein the human has previously received at least two prior lines of chemotherapy.

210. The method of any one of claims 192-209, wherein the advanced unresectable or metastatic ER+ / HER2- breast cancer has progressed following a prior regimen comprising a CDK4 / 6 inhibitor.

211. The method of any of E191-210, wherein Compound I is administered in combination with a standard of care chemotherapeutic treatment regimen.

212. A method of treating a human having advanced or metastatic epithelial ovarian cancer with CCNE1 amplification comprising administering an effective amount of a CDK2 inhibitor of the structure: or a pharmaceutically acceptable salt thereof; wherein Compound 1 is crystalline and is characterized by an X-ray powder diffraction (XRPD) pattern comprising at least three 2θ values ​​selected from 10.3±0.2°, 11.9±0.2°, 16.3±0.2°, 17.8±0.2°, 19.3±0.2°, 22.4±0.2°, 23.0±0.2°, 24.1±0.2°, 24.7±0.2°, and 30.0±0.

2.

213. The method of claim 212, wherein the advanced or metastatic epithelial ovarian cancer with CCNE1 amplification is platinum-resistant or platinum-refractory.

214. The method of claim 212 or 213, wherein the advanced or metastatic epithelial ovarian cancer comprises fallopian tube cancer.

215. The method of claim 212 or 213, wherein the advanced or metastatic epithelial ovarian cancer comprises primary peritoneal cancer.

216. A method of treating a human having advanced or metastatic fallopian tube cancer with CCNE1 amplification, comprising administering an effective amount of a CDK2 inhibitor of the structure: or a pharmaceutically acceptable salt thereof; wherein Compound 1 is crystalline and is characterized by an X-ray powder diffraction (XRPD) pattern comprising at least three 2θ values ​​selected from 10.3±0.2°, 11.9±0.2°, 16.3±0.2°, 17.8±0.2°, 19.3±0.2°, 22.4±0.2°, 23.0±0.2°, 24.1±0.2°, 24.7±0.2°, and 30.0±0.

2.

217. The method of claim 216, wherein the advanced or metastatic fallopian tube cancer with CCNE1 amplification is platinum-resistant or platinum-refractory.

218. The method of claim 216 or 217, further comprising administering an effective amount of one or more additional biologically active agents.

219. A method of treating a human having advanced or metastatic primary peritoneal cancer with CCNE1 amplification comprising administering an effective amount of a CDK2 inhibitor of the structure: or a pharmaceutically acceptable salt thereof; wherein Compound 1 is crystalline and is characterized by an X-ray powder diffraction (XRPD) pattern comprising at least three 2θ values ​​selected from 10.3±0.2°, 11.9±0.2°, 16.3±0.2°, 17.8±0.2°, 19.3±0.2°, 22.4±0.2°, 23.0±0.2°, 24.1±0.2°, 24.7±0.2°, and 30.0±0.

2.

220. The method of claim 219, wherein the advanced or metastatic primary peritoneal cancer with CCNE1 amplification is platinum-resistant or platinum-refractory.

221. The method of claim 219 or 220, further comprising administering an effective amount of one or more additional biologically active agents.

222. The method of any one of claims 212-221, wherein the cancer progressed following prior standard of care therapy.

223. The method of any one of claims 212-222, wherein the cancer progressed following prior anti-cancer therapy.

224. The method of any one of claims 212-223, wherein the cancer progressed after a prior regimen comprising a platinum analog.

225. The method of any one of claims 212-224, wherein Compound I is administered in combination with a standard of care chemotherapeutic treatment regimen.

226. A method of treating a human having an advanced or metastatic solid tumor comprising administering an effective amount of a CDK2 inhibitor of the structure: or a pharmaceutically acceptable salt thereof; wherein Compound 1 is crystalline and is characterized by an X-ray powder diffraction (XRPD) pattern comprising at least three 2θ values ​​selected from 10.3±0.2°, 11.9±0.2°, 16.3±0.2°, 17.8±0.2°, 19.3±0.2°, 22.4±0.2°, 23.0±0.2°, 24.1±0.2°, 24.7±0.2°, and 30.0±0.

2.

227. The method of claim 226, wherein the advanced or metastatic solid tumor has progressed following a prior standard of care regimen.

228. The method of claim 226 or 227, wherein the advanced or metastatic solid tumor is intolerant or unsuitable for standard therapy.

229. The method of any one of claims 226-228, wherein the advanced or metastatic solid tumor comprises amplification of CCNE1.

230. The method of any one of claims 226-229, further comprising administering an effective amount of a CDK4 / 6 inhibitor.

231. The method of claim 230, wherein the CDK4 / 6 inhibitor is selected from palbociclib, ribociclib, abemaciclib, triclasiclib, leloxicil, or SHR6390 (Darcili).

232. The method of claim 230, wherein the CDK4 / 6 inhibitor is selected from BPI-16350, narazaciclib (ON-123300), FLX-925 (AMG-925), UCT-03-008, GLR2007, bilociclib (XZP-3287), LY5219, PF-07220060, or ON-123300.

233. The method of any one of claims 226-232, further comprising administering an effective amount of an anti-cancer therapy.

234. The method of claim 233, wherein the anti-cancer therapy is selected from a chemotherapeutic agent, radiation, surgery, an immune checkpoint inhibitor, an estrogen inhibitor, an androgen inhibitor, a PARP inhibitor, or a combination thereof.

235. The method of claim 234, wherein the anti-cancer therapy is an estrogen inhibitor.

236. The method of claim 235, wherein the estrogen inhibitor is selected from a selective estrogen receptor modulator (SERM), a selective estrogen receptor degrader (SERD), a full estrogen receptor degrader, a full estrogen antagonist, a partial estrogen antagonist, or a combination thereof.

237. The method of claim 236, wherein the estrogen inhibitor is a selective estrogen receptor degrader (SERD).

238. The method of claim 237, wherein the SERD is selected from fulvestrant, rintodestrant (G1T48), borestrant (ZB-716), brilanestrant (GDC0810), camizestrant (AZD9833), D00502, elastodestran (RAD1901), etacstil (GW5638), GW7604, AZD9496, GDC-0927, giredestrant (GDC9545, RG6171), LSZ102, imlunestrant (LY3484356), SAR439859, SCR6852 or ZN-c5.

239. The method of claim 238, wherein the SERD comprises fulvestrant.

240. The method of claim 238, wherein the SERD comprises elastostat (RAD1901).

241. The method of claim 236, wherein the estrogen inhibitor is a selective estrogen receptor modulator (SERM).

242. The method of claim 241, wherein the SERM comprises letrozole.

243. The method of any one of claims 226-242, wherein Compound I is administered in combination with a standard of care chemotherapeutic treatment regimen.

244. A method of treating a patient with hormone receptor positive (HR+) advanced breast cancer, comprising: (i) administering an effective amount of a CDK2 inhibitor of the following structure: or a pharmaceutically acceptable salt thereof; and (ii) administering an effective amount of fulvestrant; wherein Compound 1 is crystalline and is characterized by an X-ray powder diffraction (XRPD) pattern comprising at least three 2θ values ​​selected from 10.3±0.2°, 11.9±0.2°, 16.3±0.2°, 17.8±0.2°, 19.3±0.2°, 22.4±0.2°, 23.0±0.2°, 24.1±0.2°, 24.7±0.2°, and 30.0±0.

2.

245. The method of claim 244, further comprising administering an effective amount of a CDK4 / 6 inhibitor.

246. The method of claim 245, wherein the CDK4 / 6 inhibitor is selected from palbociclib, ribociclib, abemaciclib, triclasiclib, leloxicil, or SHR6390 (Darcili).

247. The method of claim 245, wherein the CDK4 / 6 inhibitor is selected from BPI-16350, narazaciclib (ON-123300), FLX-925 (AMG-925), UCT-03-008, GLR2007, bilociclib (XZP-3287), LY5219, PF-07220060, or ON-123300.

248. A method of treating a patient with hormone receptor positive (HR+) advanced breast cancer, comprising: (i) administering an effective amount of a CDK2 inhibitor of the following structure: or a pharmaceutically acceptable salt thereof; and (ii) administering an effective amount of fulvestrant; and, (iii) administering an effective amount of a CDK4 / 6 inhibitor.

249. The method of claim 248, wherein the CDK4 / 6 inhibitor is selected from palbociclib, ribociclib, abemaciclib, triclasiclib, leloxicil, or SHR6390 (Darcili).

250. The method of claim 249, wherein the CDK4 / 6 inhibitor is selected from BPI-16350, narazaciclib (ON-123300), FLX-925 (AMG-925), UCT-03-008, GLR2007, bilociclib (XZP-3287), LY5219, PF-07220060, or ON-123300.

251. The method of any one of claims 244-250, wherein the HR+ advanced breast cancer is HER2-.

252. The method of any one of E244-251, wherein the method is administered as first-line (1L) therapy.

253. The method of any one of claims 244-251, wherein the human has previously received at least one prior line of endocrine therapy.

254. The method of any one of claims 244-251 or 253, wherein the HR+ advanced breast cancer has progressed following a prior standard of care regimen.

255. A method of treating a human having a CDK4 / 6 inhibitor-resistant and endocrine therapy-resistant cancer, comprising: (i) administering an effective amount of a CDK2 inhibitor of the following structure: or a pharmaceutically acceptable salt thereof; and (ii) administering an effective amount of an estrogen inhibitor.

256. The method of claim 255, wherein the estrogen inhibitor is selected from a selective estrogen receptor modulator (SERM), a selective estrogen receptor degrader (SERD), a full estrogen receptor degrader, a full estrogen antagonist, a partial estrogen antagonist, or a combination thereof.

257. The method of claim 256, wherein the estrogen inhibitor is a selective estrogen receptor degrader (SERD).

258. The method of claim 256, wherein the SERD is selected from fulvestrant, rintodestrant (G1T48), borestrant (ZB-716), brilanestrant (GDC0810), camizestrant (AZD9833), D00502, elastodestran (RAD1901), etacstil (GW5638), GW7604, AZD9496, GDC-0927, giredestrant (GDC9545, RG6171), LSZ102, imlunestrant (LY3484356), SAR439859, SCR6852, or ZN-c5.

259. The method of claim 258, wherein the SERD comprises fulvestrant.

260. The method of claim 258, wherein the SERD comprises elastostat (RAD1901).

261. The method of claim 256, wherein the estrogen inhibitor is a selective estrogen receptor modulator (SERM).

262. The method of claim 261, wherein the SERM comprises letrozole.

263. The method of any one of claims 255-262, further comprising administering an effective amount of a CDK4 / 6 inhibitor.

264. The method of claim 263, wherein the CDK4 / 6 inhibitor is selected from palbociclib, ribociclib, abemaciclib, triclasiclib, leloxicil, or SHR6390 (Darcili).

265. The method of claim 263, wherein the CDK4 / 6 inhibitor is selected from BPI-16350, narazaciclib (ON-123300), FLX-925 (AMG-925), UCT-03-008, GLR2007, bilociclib (XZP-3287), LY5219, PF-07220060 or ON-123300.

266. The method of any one of claims 255-265, wherein the cancer is selected from breast cancer, ovarian cancer, endometrial cancer, prostate cancer, or uterine cancer.

267. The method of claim 266, wherein the cancer is breast cancer.

268. The method of claim 267, wherein the breast cancer is hormone receptor positive (HR+).

269. The method of any one of claims 267 or 268, wherein the breast cancer is estrogen receptor positive (ER+).

270. The method of any one of claims 266-269, wherein the breast cancer is progesterone receptor positive (PR+).

271. The method of any one of claims 266-270, wherein the breast cancer is human epidermal growth factor receptor 2 negative (HER2-).

272. The method of claim 271, wherein the breast cancer is ER+ / HER2- breast cancer.

273. The method of claim 271, wherein the breast cancer is HR+ / HER2- breast cancer.

274. The method of claim 267, wherein the breast cancer is luminal A breast cancer.

275. The method of any one of claims 255-274, wherein the human has previously received at least one prior line of CDK4 / 6 inhibitor therapy.

276. The method of any one of claims 255-275, wherein the human has previously received at least one prior line of endocrine therapy.

277. The method of any one of claims 255-276, wherein the cancer progressed after prior standard systemic therapy.

278. The method of any one of claims 255-277, wherein the cancer progressed following a prior regimen comprising a CDK4 / 6 inhibitor.

279. The method of any one of claims 255-278, wherein Compound I is administered in combination with a standard of care chemotherapeutic treatment regimen.

280. The method of any one of claims 135-279, wherein Compound I is administered at least once a day.

281. The method of any one of claims 135-279, wherein Compound I is administered at least twice a day.

282. The method of claim 280 or 281, wherein Compound I is administered for at least 21 days, at least 24 days, at least 28 days, or longer than 28 days.

283. The method of claim 282, wherein Compound I is administered at least once a day for at least 28 days.

284. The method of any one of claims 1-112 or 135-283, wherein the treatment results in a reduction in the number of events of treatment-emergent adverse events compared to the predicted number of events of treatment-emergent adverse events in subjects receiving treatment without Compound I.

285. The method of any one of claims 1-112 or 135-284, wherein said treatment results in a reduction in the number of events of laboratory abnormalities compared to the predicted number of events of laboratory abnormalities in a subject receiving treatment without Compound I.

286. The method of any one of claims 1-112 or 135-285, wherein said treatment results in improved overall survival (OS) compared to predicted overall survival (OS) in a subject receiving treatment without Compound I.

287. The method of any one of claims 1-112 or 135-286, wherein said treatment results in an improved overall response rate (ORR) compared to the predicted overall response rate (ORR) in subjects receiving treatment without Compound I.

288. The method of any one of claims 1-112 or 135-287, wherein said treatment results in an improved disease control rate (DCR) compared to the predicted disease control rate (DCR) in subjects receiving treatment without Compound I.

289. The method of any one of claims 1-112 or 135-288, wherein said treatment results in improved progression-free survival (PFS) compared to predicted progression-free survival (PFS) in a subject receiving treatment without Compound I.

290. The method of any one of claims 1-112 or 135-289, wherein said treatment results in an improved duration of response (DOR) compared to the predicted duration of response (DOR) in a subject receiving treatment without Compound I.

291. The method of any one of claims 1-112 or 135-290, wherein the treatment results in a prolonged time to progression (TTP) compared to the predicted time to progression (TTP) in a subject receiving treatment without Compound I.

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