Cyclin-dependent kinase 2 inhibitors for medical treatment

Abstract

1. The constructs described herein for the treatment of disorders characterized by abnormal cell division with amplified cyclin E activation and / or expression, i.e., disorders characterized by abnormal cell division disorders, CDK4 / 6 resistance, and / or endocrine therapy resistance (including, but not limited to, the treatment of tumors and cancers): Use of a pyrimidine-based selective cyclin-dependent kinase 2 (CDK2) inhibitor of TIFF2025525376000146.tif74170 (Compound I) or a pharmaceutically acceptable salt or morphic form thereof.

Description

[Technical Field]

[0001] [CROSS-REFERENCE TO RELATED APPLICATIONS] This application claims the benefit of U.S. Provisional Patent Application No. 63 / 353,729, filed June 20, 2022, U.S. Provisional Patent Application No. 63 / 444,523, filed February 9, 2023, U.S. Provisional Patent Application No. 63 / 460,201, filed April 18, 2023, and U.S. Provisional Patent Application No. 63 / 470,621, filed June 2, 2023, the entireties of which are incorporated herein by reference for all purposes.

[0002] The present invention is in the area of the use of certain heterocyclic compounds that 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 technology]

[0003] Adult tissues are primarily composed of terminally differentiated, quiescent cells that have exited the cell cycle. Physiological cues in response to extracellular stimuli, including tissue injury, can trigger some cells to re-enter the cell cycle and divide to replenish damaged or dead cells (Non-Patent Document 1). A finely tuned balance exists between cell division and programmed cell death (apoptosis).

[0004] Cell division is regulated by the cell cycle, which is divided into four phases: G1 (cell growth and machinery synthesis), S (DNA replication to generate two identical sets of chromosomes), G2 (cell growth and auxiliary machinery synthesis), and M (a single cell divides into two identical daughter cells). Progression between cell cycle phases is primarily governed by cyclins and cyclin-dependent kinases (CDKs) (Non-Patent Document 2), which are activated or inhibited in response to a complex system of cell signaling networks that interpret extracellular signals.

[0005] Cyclins bind to and activate CDKs, which preferentially phosphorylate the tumor suppressor retinoblastoma (Rb) protein. When dephosphorylated, Rb binds to and represses E2 factor (E2F) transcription factors, recruiting corepressors and suppressing the transcription of E2F-regulated cell cycle genes. However, when Rb is phosphorylated by the CDK / cyclin complex, it dissociates from the E2F transcription factors and transcribes a series of genes involved in cell cycle control, including cyclin E (CCNE), cyclin A (CCNA), and cyclin B1 (CCNB1), allowing the cell to progress to the next stage of the cell cycle (Non-Patent Document 3). Following cell division during mitosis (M), cells shut off the expression of machinery required for gene replication and segregation and exit the cell cycle.

[0006] Uncontrolled cell proliferation leads to the development of various neoplastic disorders. The development of broad-spectrum anti-neoplastic agents has been utilized to treat various cell proliferation disorders, including ovarian, breast, and lung cancers (see, e.g., Non-Patent Document 4). Organometallic-based chemotherapeutic agents, such as cisplatin, are used to treat cancers including lymphomas, sarcomas, and germ cell tumors, as well as carcinomas such as small cell lung cancer (SCLC), bladder cancer, and ovarian cancer. Cisplatin, one such organometallic agent, binds to nitrogenous bases and induces significant DNA cross-linking, leading to apoptosis (see, e.g., Non-Patent Document 5). Separately, agents that intercalate or alkylate DNA have been extensively tested in clinical settings for the treatment of cancer. The toxicity associated with these drugs is a major concern for patients requiring long-term treatment.

[0007] Dysregulation of cyclin-dependent kinases and cyclins promotes excessive neoplastic growth and tumor development, ultimately leading to cell division disorders such as cancer (Non-Patent Document 6). Recently, targeted approaches involving the use of compounds that inhibit CDKs have been used to treat cancer, reducing adverse events associated with broad-spectrum anti-neoplastic agents (Non-Patent Document 7). For example, researchers at Pfizer discovered that palbociclib (PD-033299; IBRANCE™) transiently inhibits cell cycle progression in CDK4 / 6-dependent cells (Non-Patent Document 8). In February 2015, the FDA approved IBRANCE™ (palbociclib) for the treatment of estrogen receptor-positive (ER+), human epidermal growth factor receptor 2-negative (HER2-) breast cancer in combination with letrozole. The structure of palbociclib is: [ka]

[0008] Ribociclib (Lee011; KISQALI™) is a CDK4 / 6 inhibitor approved by the FDA for use in combination with aromatase inhibitors for the treatment of metastatic breast cancer. Ribociclib is currently being tested in clinical trials for the treatment of various other cancers. The structure of ribociclib is as follows: [ka]

[0009] Abemaciclib (LY2835219; VERZENIO™) is a CDK4 / 6 inhibitor that has been approved by the FDA for use in combination with endocrine therapy (tamoxifen or aromatase inhibitors) 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 either anastrozole or letrozole for the first-line treatment of breast cancer. The structure of abemaciclib is as follows: [ka]

[0010] Despite the demonstrated antitumor efficacy and generally favorable safety profile of the aforementioned compounds, treatment-related side effects remain (Non-Patent Document 9), with neutropenia being the most commonly observed adverse effect. Novel CDK4 / 6 inhibitors have been demonstrated to preserve bone marrow cells during cancer treatment and are expected to soon be approved by the FDA for cancer treatment.

[0011] Trilaciclib (COSELA™) is an FDA-approved selective CDK4 / 6 inhibitor manufactured by G1 Therapeutics, Inc., and is used as a first-in-class bone marrow-sparing therapy designed to improve the quality of life and outcomes of patients with advanced-stage small cell lung cancer (SCLC) undergoing chemotherapy by preserving hematopoietic stem and progenitor cells (HSPCs). Trilaciclib is a short-acting CDK4 / 6 inhibitor administered intravenously prior to chemotherapy and has been studied in four randomized phase II clinical trials, including first-line combination therapy with carboplatin / etoposide chemotherapy regimens and the checkpoint inhibitor Tecentriq™ (atezolizumab) for the treatment of SCLC. Trilaciclib has the following structure: [ka]

[0012] Relociclib is a selective CDK4 / 6 inhibitor in clinical development by EQRx, Inc., an exclusive licensee of G1 Therapeutics, Inc., for the treatment of multiple oncology indications in combination with other anti-cancer agents. Relociclib is being investigated in two clinical trials (NCT02983071) for patients with estrogen receptor-positive (ER+), HER2- breast cancer, including relociclib in combination with fulvestrant (Faslodex™), and for patients with epidermal growth factor receptor-mutant (EGFR) breast cancer.mut Two Phase 1 / 2 clinical trials are underway, including a trial in combination with osmiltinib (Tagrisso™) for the treatment of non-small cell lung cancer. Relociclib has the following structure: [ka]

[0013] Other pyrimidine anti-CDK2 agents include those with the following structure: [ka] The compound and the process for its preparation are described in US Pat. No. 6,233,999, assigned to G1 Therapeutics, Inc.

[0014] Despite progress in the development of cell cycle inhibitory compounds for treating disorders of abnormal cell proliferation in subjects, e.g., humans, there remains an unmet need for new strategies to combat these fatal disorders.

[0015] It is an object of the present invention to provide new uses and combinations for preventing uncontrolled cell cycling in a subject, such as a human. [Prior art documents] [Patent documents]

[0016] [Patent Document 1] International Publication No. 2021 / 236650 [Non-patent literature]

[0017] [Non-Patent Document 1] Matthews et al. Nat Rev Mol Cell Biol. 23:74-88(2022) [Non-patent document 2] Asghar et al. Nat Rev Drug Discov. 14(2):130-46(2015)

Non-Patent Document 3

Non-Patent Document 4

Non-Patent Document 5

Non-Patent Document 6

Non-Patent Document 7

Non-Patent Document 8

Non-Patent Document 9

Summary of the Invention

[0018] Compound I, a selective CDK2 inhibitor described herein, or a pharmaceutically acceptable salt or morphic form thereof, has been discovered to be a potent therapeutic agent useful for treating neoplasias associated with increased cyclin E expression or cyclin E amplification. Compound I, a pharmaceutically acceptable salt or morphic form described herein, may also be used to treat cancers that have developed resistance to CDK4 / 6 inhibitors. Furthermore, Compound I, a pharmaceutically acceptable salt or morphic form described herein, may also be used to treat cancers that have developed resistance to estrogen receptor degraders (SERDs), including but not limited to selective estrogen receptor degraders (SERDs), such as fulvestrant or elacestrant. Compound I, a pharmaceutically acceptable salt or morphic form described herein, may also be used to treat small cell lung cancer (SCLC), a retinoblastoma-null cancer for which no approved targeted therapy exists. As further described below, new, more stable morphic forms and salts of Compound I have also been discovered. [ka]

[0019] Compound I, or a pharmaceutically acceptable salt thereof, or a morphic form thereof, described herein has several advantageous properties that may be used to treat cyclin E overexpressed or amplified cancers, 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., Figures 1A and 1B and 2A-2C in Example 1); (ii) inhibition of CDK2 complexed with several cyclin binding partners (see, e.g., Figures 1A and 1B in Example 1); (iii) significantly longer residence time when complexed with CDK2 (see, e.g., Figure 1B in Example 1); (iv) a robust safety profile when administered to healthy, non-cancer cells (see, e.g., Figures 3 and 4, 5A-5C, and 6 in Example 2); (v) synergistic effects with chemotherapeutic agents for greater anti-tumor efficacy (see, e.g., Figures 29A-29C, 30A-30C in Example 5); (vi) inhibition of CDK4 / 6 inhibitor-resistant cells when administered in combination with CDK4 / 6 inhibitors. (vii) enhanced anti-tumor efficacy in cells with amplified cyclin E activation and / or expression (see, e.g., Figures 7-7D, 8A-8I, 9A-9B, and 149 in Examples 3 and 45); (vii) enhanced anti-tumor efficacy in cells with amplified cyclin E activation and / or expression (see, e.g., Figures 10A-10E, 11A-11B, 12, 13A-13C, 14A-14B, 16A-16B, 17A-17B, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100, 101, 102, 103, 10 (viii) induction of changes in the expression and post-translational modification of cell cycle-related proteins (see, e.g., Figures 7C, 8B, 10E, 11A and 11B, 12, 20, 26A-26C, 146E and 146F, and 147L in Examples 4, 5, 6, and 45); (ix) induction of a targeted DNA damage response in neoplastic cells (see, e.g., Figures 22D and 22E, 25, 27A-27D, and 28C in Example 5);(x) robust cell cycle arrest in naive and therapy-resistant cells (see, e.g., Figures 9A and 9B, 10C and 10D, 13A-13C, 14B, 15A-15D, 21B, 23, 24, 28B, and 147D-147J in Examples 3-5 and 45); (xi) development of cellular senescence following cell cycle arrest in therapy-resistant cells (see, e.g., Figures 148A-148F in Example 45); (xii) persistent in vivo cell cycle arrest in subjects with cell proliferation disorders, e.g., cancer. (xiii) improved overall survival in subjects with a cell proliferation disorder, e.g., cancer, as demonstrated by animal studies (see, e.g., Figure 19B in Example 4); (xiv) prolonged time to resistance to other anticancer agents, e.g., SERDs (see, e.g., Figure 145, Example 43); (xv) little or no inhibition of human drug transporters, suggesting low risk of drug-drug interaction toxicity (see, e.g., Figures 127-143 in Example 41); and / or (xvi) good tolerability to daily administration in multiple animal models (see, e.g., Examples 42 and 45).

[0020] In addition to its potent anticancer activity, compound I, or a pharmaceutically acceptable salt or morphic form thereof, described herein can be used to resensitize relapsed 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 represents a significant advance in the state of the art in cancer treatment. In certain embodiments, compound I, or a pharmaceutically acceptable salt or morphic form thereof, described herein, causes resensitization by favorably altering the gene expression profile within the cell, resulting in a tumor microenvironment suitable for treatment with the previously resistant therapeutic agent. The net result of this effect on the tumor microenvironment, in some non-limiting examples, is an improved response of the subject to therapeutic agents (i.e., tumor resensitization), including therapeutic agents previously administered to the subject and to which the subject subsequently became resistant, to effectively combat the cancer or tumor and enhance its ability to achieve a short-term response (up to approximately 1 month, 2 months, 3 months, 4 months, 5 months, or 6 months), a long-term response (up to more than 7 months, 8 months, 9 months, 10 months, 11 months, or 12 months), or a complete response.

[0021] As a result of the pronounced CDK2 inhibitor properties of Compound I, a new and advantageous method for the treatment of disorders mediated by cyclin E overexpression / amplification, CDK4 / 6 inhibitor resistance, estrogen receptor degrader resistance, and / or Rb-independent mechanisms, such as small cell lung cancer, has been discovered. In non-limiting embodiments of the present invention, Compound I or a pharmaceutically acceptable salt, morphic form, or pharmaceutical composition thereof can be used, for example, for the following non-limiting indications: (a) the use of Compound I, or a pharmaceutically acceptable salt, or morphic form thereof, as described herein for the treatment of a human having an abnormal cell proliferation disorder in which cyclin E is amplified or overexpressed, including, but not limited to, ovarian, gastric, breast, bladder, lung, or gynecological cancer in which cyclin E is amplified or overexpressed; (b) use of Compound I, or a pharmaceutically acceptable salt thereof, or a morphic form thereof, as described herein, for treating a subject having an abnormal cell proliferation disorder, e.g., cancer, comprising obtaining a sample from the human, detecting whether cyclin E1 and / or E2 (CCNE1 / CCNE2) are overexpressed in the sample compared to a control sample, and, if CCNE1 and / or CCNE2 are determined to be overexpressed, administering to the human an effective amount of a selective CDK2 inhibitor having the structure of Compound I, or a pharmaceutically acceptable salt thereof, or a morphic form thereof, as described herein; (c) Use of Compound I or a pharmaceutically acceptable salt or morphic form thereof as described herein for the treatment of a human having small cell lung cancer, wherein an additional therapeutic agent, such as doxorubicin or camptothecin, is further administered to the human in combination with Compound I. (d) the use of compound I as described herein or a pharmaceutically acceptable salt or morphic form thereof in combination with a CDK4 / 6 inhibitor, such as relociclib, palbociclib, abemaciclib, or ribociclib, for the treatment of a subject with acquired CDK4 / 6 inhibitor-resistant cancer; (e) the use of compound I as described herein or a pharmaceutically acceptable salt or morphic form thereof in combination with a CDK4 / 6 inhibitor, such as relociclib, palbociclib, abemaciclib, or ribociclib, for the treatment of a subject with an endogenous CDK4 / 6 inhibitor-resistant cancer; (f) the use of compound I as described herein or a pharmaceutically acceptable salt or morphic form thereof in combination with an estrogen inhibitor, such as an estrogen receptor degrader, e.g., fulvestrant or elacestrant, for the treatment of a subject with estrogen inhibitor-resistant cancer; (g) Use of compound I as described herein or a pharmaceutically acceptable salt or morphic form thereof in combination with a CDK4 / 6 inhibitor, such as relociclib, palbociclib, abemaciclib, or ribociclib, and an estrogen inhibitor, such as fulvestrant or elacestrant, for the treatment of a subject with CDK4 / 6 inhibitor-resistant and / or estrogen inhibitor-resistant cancer; (h) Use of (d to f), wherein the CDK4 / 6 inhibitor-resistant cancer is cyclin E amplified or overexpressed; (i) the use of (d) or (f), wherein the CDK4 / 6 inhibitor-resistant cancer is estrogen receptor-positive (ER+) breast cancer; (j) The use of any one of (a) to (h), wherein the abnormal cell proliferation disorder is unresectable cancer; (k) the use of any one of (a) to (i), wherein the abnormal cell proliferation disorder is advanced cancer; (l) the use of any one of (a) to (j), wherein the abnormal cell proliferation disorder is a solid tumor; (m) the use of any one of (a) to (k), wherein the abnormal cell proliferation disorder is advanced cancer; (n) Use of any one of (i) to (l), wherein the cancer is metastatic; (o) Use of any one of (i) to (l), wherein the cancer is platinum-resistant or platinum-refractory; (p) Use of any one of (i) to (l), wherein the cancer is CCNE1 amplified; (q) a morphic form of Compound I described herein; (r) a pharmaceutical composition comprising a morphic form of Compound I and a pharmaceutically acceptable excipient; (s) a pharmaceutical composition comprising Compound I and a pharmaceutically acceptable excipient, the pharmaceutical composition being prepared from a morphic form of Compound I, e.g., a spray-dried dispersion; (t) the pharmaceutical composition of (q) or (r), wherein the pharmaceutically acceptable excipient is a diluent, e.g., polyethylene glycol; (u) Use of any one of (a) to (o), wherein compound I is a morphic form or pharmaceutical composition of any one of (q) to (s); or (v) Use of a morphic form or pharmaceutical composition of any one of (q) to (s) in the treatment of CDK2-mediated abnormal cell growth, such as CDK2-mediated cancer.

[0022] In certain aspects, Compound I, or a pharmaceutically acceptable salt or morphic form thereof, described herein is used to treat an Rb-dependent cancer, where the cancer has overexpressed or amplified cyclin E expression. For example, in certain embodiments, Compound I, or a pharmaceutically acceptable salt or morphic form thereof, described herein is used to treat other cancers of the reproductive system, such as breast cancer, prostate cancer (including androgen-resistant prostate cancer), colon cancer (including metastatic colon cancer), endometrial cancer, ovarian cancer, or testicular cancer, where these cancers have overexpressed or amplified cyclin E expression. Cancers with overexpressed or amplified cyclin E expression may have overexpression or amplification of CCNE1 and / or CCNE2. In certain embodiments, cyclin E-amplified or overexpressing cancers have amplification or overexpression of CCNE1. In certain embodiments, cyclin E-amplified or overexpressing cancers have amplification or overexpression of CCNE2.

[0023] In yet another embodiment, Compound I, or a pharmaceutically acceptable salt or morphic form thereof, described herein is administered in an effective amount in combination or alternation with an effective amount of an estrogen inhibitor, including, but not limited to, a SERM (selective estrogen receptor modulator), a SERD (selective estrogen receptor degrader), a full estrogen receptor degrader, or another form of partial or full estrogen antagonist, for the treatment of abnormal tissues with overexpressed or amplified cyclin E expression in the female reproductive tract, such as breast cancer, ovarian cancer, endometrial cancer, or uterine cancer. In some embodiments, Compound I, or a pharmaceutically acceptable salt or morphic form thereof, described herein, is administered to a subject at least once daily, wherein an effective amount of the estrogen inhibitor is administered according to the label. In some embodiments, Compound I, or a pharmaceutically acceptable salt or morphic form thereof, described herein, is administered to a subject at least twice daily, wherein an effective amount of the estrogen inhibitor is administered according to the label.

[0024] In some embodiments, the abnormal cell proliferation disorder in which Cyclin E is amplified or aberrantly expressed is selected from the group consisting of ovarian cancer, uterine cancer, uterine carcinosarcoma (UCS), uterine 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, and esophageal adenocarcinoma (ESCA). carcinoma), adrenocortical carcinoma, breast cancer, invasive breast cancer (BRCA), pancreatic cancer, pancreatic adenocarcinoma (PAAD), fallopian tube cancer, primary peritoneal cancer, liver cancer, liver hepatocellular carcinoma (LIHC), cervical cancer, cervical squamous cell carcinoma (CESC), cervical adenocarcinoma, mesothelioma (MESO), head and neck squamous cell carcinoma (HSNC), colon cancer, colon adenocarcinoma (COAD), skin cancer, melanoma, skin cutaneous melanoma (SKCM), glioblastoma multiforme (GBM), renal cancer, and chromophobe renal cell carcinoma (KICH). In some embodiments, the cyclin E amplified or overexpressing cancer is ovarian cancer. In some embodiments, the cyclin E amplified cancer is resistant to CDK4 / 6 inhibitors. 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 has progressed after a prior standard of care regimen. In certain embodiments, the cancer has progressed after a prior standard systemic therapy. In certain embodiments, the cancer has progressed after a prior systemic anti-cancer therapy. In certain embodiments, the cancer has progressed after a prior regimen comprising a platinum analog. In certain embodiments, the cancer has progressed after a prior regimen comprising a CDK4 / 6 inhibitor. In some embodiments, the cyclin E amplified or overexpressing cancer is uterine cancer. In some embodiments, the cyclin E amplified or overexpressing cancer is ovarian cancer. In some embodiments, the cyclin E amplified or overexpressing cancer is breast cancer. In some embodiments, the cyclin E amplified or overexpressing cancer is prostate cancer.In some embodiments, the cyclin E amplified or overexpressing cancer is bladder cancer. In some embodiments, the cyclin E amplified or overexpressing cancer is sarcoma.

[0025] In certain embodiments, the methods further comprise administering an effective amount of one or more additional anti-cancer therapies. In some embodiments, the anti-cancer therapies are selected from radiation, surgery, immune checkpoint inhibitors, estrogen inhibitors, androgen inhibitors, PARP inhibitors, or combinations thereof. In certain embodiments, the methods 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 full estrogen receptor degrader, a full 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, the SERD comprises fulvestrant. In some embodiments, the SERD comprises elacestrant (RAD1901). In some embodiments, Compound I, or a pharmaceutically acceptable salt or morphic form thereof, as described herein, is administered to a subject at least once daily, where an effective amount of the anti-cancer therapy is administered according to the label. In some embodiments, Compound I, or a pharmaceutically acceptable salt or morphic form thereof, as described herein, is administered to a subject at least twice daily, where an effective amount of the anti-cancer therapy is administered according to the label.

[0026] In another aspect, Compound I, or a pharmaceutically acceptable salt or morphic form thereof, described herein, is used to treat small cell lung cancer (Rb null cancer). In certain embodiments, Compound I inhibits the CDK2 / A axis, resulting in growth inhibition or amelioration of small cell lung cancer. In other embodiments, Compound I induces DNA damage in small cell lung cancer cells, resulting in growth arrest or amelioration.

[0027] For example, in certain embodiments, there is provided a use for treating a subject having CDK4 / 6 inhibitor-resistant small cell lung cancer (SCLC), comprising: (i) administering to the subject an effective amount of Compound I, or a pharmaceutically acceptable salt or morphic form thereof, as described herein; and (ii) administering to the subject an effective amount of a chemotherapeutic agent, wherein Compound I, or a pharmaceutically acceptable salt or morphic form thereof, as described herein, is administered to the subject within 24 hours prior to or simultaneously 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, 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, the subject is administered Compound I, or a pharmaceutically acceptable salt or morphic form thereof, as described herein, within 6 hours prior to administration of the chemotherapeutic agent. In some embodiments, the subject is administered Compound I, or a pharmaceutically acceptable salt or morphic form thereof, as described herein, within three hours prior to administration of a chemotherapeutic agent. In some embodiments, the subject is administered Compound I, or a pharmaceutically acceptable salt or morphic form thereof, as described herein, at least once daily, where an effective amount of the chemotherapeutic agent is administered according to its label or standard of care. In some embodiments, the subject is administered Compound I, or a pharmaceutically acceptable salt or morphic form thereof, as described herein, at least twice daily, where an effective amount of the chemotherapeutic agent is administered according to its label or standard of care.

[0028] In another aspect, disclosed herein are methods for treating a subject with a CDK4 / 6 inhibitor-resistant cancer, comprising administering to the subject an effective amount of Compound I, or a pharmaceutically acceptable salt or morphic form thereof, as described herein, 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 a CDK4 / 6 inhibitor. In certain embodiments, the CDK4 / 6 inhibitor-resistant cancer has progressed after a prior regimen comprising a CDK4 / 6 inhibitor. In some embodiments, the CDK4 / 6 inhibitor of the prior regimen is selected from palbociclib, ribociclib, abemaciclib, trilaciclib, lerociclib, SHR6390 (dalpiciclib), or a combination thereof. In some embodiments, the CDK4 / 6 inhibitor of the preceding regimen is selected from BPI-16350, nalazaciclib (ON-123300), FLX-925 (AMG-925), UCT-03-008, GLR2007, vilociclib (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-resistant cancer is retinoblastoma (Rb) protein null (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 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 amplified or overexpressed. In some embodiments, Compound I, or a pharmaceutically acceptable salt or morphic form thereof, described herein, is administered to a subject at least once daily, wherein an effective amount of a CDK4 / 6 inhibitor is administered according to a label. In some embodiments, Compound I, or a pharmaceutically acceptable salt thereof, is administered to a subject at least twice daily, wherein an effective amount of a CDK4 / 6 inhibitor is administered according to a label. In some embodiments, the CDK4 / 6 inhibitor-resistant cancer is also resistant to endocrine therapy or an estrogen inhibitor, e.g., a SERD.

[0029] In another aspect, disclosed herein are methods 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 I, or a pharmaceutically acceptable salt or morphic form thereof, as described herein, 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 tyrosine kinase cell surface receptor HER2-negative. In some embodiments, Compound I, or a pharmaceutically acceptable salt or morphic form thereof, as described herein, is administered to the subject at least once daily, wherein an effective amount of the CDK4 / 6 inhibitor is administered according to labeling or standard of care. In some embodiments, Compound I, or a pharmaceutically acceptable salt or morphic form thereof, as described herein, is administered to the subject at least twice daily, wherein an effective amount of the CDK4 / 6 inhibitor is administered according to labeling or standard of care.

[0030] In certain embodiments, the treatment results in a reduction in the incidence of treatment-emergent adverse events compared to the expected incidence of treatment-emergent adverse events in subjects receiving treatment that does not include Compound I. In certain embodiments, the treatment results in a reduction in the incidence of laboratory abnormalities compared to the expected incidence of laboratory abnormalities in subjects receiving treatment that does not include Compound I. In certain embodiments, the treatment results in improved overall survival (OS) compared to subjects receiving treatment that does not include Compound I. In certain embodiments, the treatment results in an improved overall response rate (ORR) compared to subjects receiving treatment that does not include Compound I. In certain embodiments, the treatment results in an improved disease control rate (DCR) compared to subjects receiving treatment that does not include Compound I. In certain embodiments, the treatment results in improved progression-free survival (PFS). In certain embodiments, the treatment results in an improved duration of response (DOR) compared to subjects receiving treatment that does not include Compound I. In certain embodiments, the treatment results in an increase in time to disease progression (TTP) compared to subjects receiving treatment that does not include Compound I.

[0031] In another aspect, advantageous morphic forms of Compound I are described that have improved solubility, stability, crystallinity, flowability, and / or purity. Eight advantageous salts were identified under various solvent conditions and temperatures, resulting in the discovery and testing of over 20 morphic forms of Compound I and various salts of Compound I. Salts of Compound I have been prepared with counterions selected from sulfate, methanesulfonate, maleate, phosphate, L-(+)-tartarate, citrate, hydrobromide, and benzenesulfonate. Some of these salts have multiple morphic forms, as described herein.

[0032] The free base pattern 1 of Compound I is a highly crystalline and stable morphic form that can be used to treat CDK2-mediated disorders or to prepare amorphous forms of Compound I (e.g., by spray-drying dispersion) for the treatment of CDK2-mediated disorders.

[0033] HCl Pattern 1 of Compound I is a particularly stable crystalline morphic form of Compound I, distinguished from other salts by its high purity, enhanced morphological stability at 40° C. / 75% RH for 7 days, enhanced morphological stability at 80° C. for 7 days, and only moderate hygroscopicity. HCl Pattern 1 of Compound I can be used to treat CDK2-mediated disorders or can be used to prepare amorphous forms of Compound I or pharmaceutically acceptable salts thereof (e.g., by spray-drying dispersion) for the treatment of CDK2-mediated disorders.

[0034] In certain aspects, pharmaceutical compositions are provided comprising Compound I or a pharmaceutically acceptable salt thereof, or a morphic form of Compound I 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.

[0035] In another aspect, a pharmaceutical composition is provided comprising amorphous Compound I or a pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable excipients, wherein the pharmaceutical composition is prepared from a morphic form of Compound I or a pharmaceutically acceptable salt thereof as described herein. In certain embodiments, the prepared pharmaceutical composition comprises polyethylene glycol (PEG). In certain embodiments, the prepared pharmaceutical composition comprises hydroxypropyl methylcellulose.

[0036] When referenced on the drawings, PF-07104091 is [ka] is. [Brief explanation of the drawings]

[0037] [Figure 1] Figures 1A and 1B are a set of tables showing that Compound I CDK2 / E selectively inhibits CDK2 / E to a greater extent than Pfizer's CDK2 inhibitor compound PF-07104091. The experimental conditions for these experiments can be found in Example 1. Figure 1A is a table showing the biochemical profile of a novel and potent CDK2 inhibitor against a panel of CDKs and their respective binding partners. Assays were completed in a 12-point dose-response format. Results are presented as nanomolar IC50 concentrations for each target. Pfizer's selective CDK2 inhibitor, PF-07104091, was included as a reference compound. ND, not specified. The compound was shown to bind preferentially to CDK2 / E over CDK1 / B and CDK9 / T. Furthermore, Compound I is four times more potent against CDK2 / E than PF-07104091. Figure 1B is a table showing the compound I residence times, i.e., the duration of compound-target interaction, with several CDK / cyclin complex partners in a TR-FRET binding assay. Compound I complexes with CDK2 / E and CDK2 / A are longer than those with CDK1 / B and CDK9 / T. [Figure 2]Figures 2A-2C show that Compound I demonstrates robust intracellular selectivity for CDK2 / E, limiting CDK1 / B or CDK9 / T activity. The experimental conditions for these experiments can be found in Example 1. Figure 2A is a collection of line graphs showing the normalized percent bioluminescence resonance energy transfer (NanoBRET) response on the y-axis and Compound I concentration as log(M) on the x-axis. Results from the NanoBRET target engagement intracellular kinase assay demonstrate potent inhibition of CDK2 / E (circles) but not CDK1 / B1 (squares) or CDK9 / T1 (triangles) by Compound I. This experiment was performed in HEK-293 cells transiently expressing CDK2-Nluc, CDK1-Nluc, or CDK9-Nluc fusions. Figure 2B is a table showing the intracellular inhibitory IC50 values of Compound I for CDK2 / E, CDK1 / B, and CDK9 / T. IC50 values are also expressed as the fold change relative to CDK2 / E of the IC50 values observed for Compound I. Figure 2C is a table showing the NanoBRET target engagement intracellular kinase assay IC50 values of Compound I against CDK2 / E, CDK1 / B, CDK2 / A, CDK4 / D1, CDK6 / D3, and CDK9 / T. IC50 values are also expressed as the fold change relative to CDK2 / E of the IC50 values observed for Compound I. IC50, half maximal inhibitory concentration. [Figure 3] 1 is a bar graph showing that Compound I exhibits limited cytotoxicity in normal H68 human fibroblasts. The experimental conditions for these experiments can be found in Example 2. The cell proliferation IC50 values for each treatment of normal human fibroblast Hs68 cells are shown on the y-axis for various CDK inhibitors, including dinaciclib, palbociclib, and Compound I on the x-axis. Limited cytotoxic activity was observed with Compound I in Hs68 cells. IC50, half maximal inhibitory concentration. [Figure 4]4 shows that administration of Compound I alone or in combination with cisplatin induces little cell cycle changes in normal H68 human fibroblasts. The experimental conditions for these experiments can be found in Example 2. FIG. 4 is a bar graph showing the percentage of Hs68 cells, shown on the y-axis, measured in different cell cycle states, including DNA content <2N, G0 / G1, S, or G2 / M, for different treatment conditions, shown on the x-axis. [Figure 5] Figures 5A-5C show that Compound I does not induce caspase 3 / 7 activation in normal human fibroblast Hs68 cells after long-term administration. The experimental methods for these experiments can be found in Example 2. Figure 5A is a collection of line plots showing the cell ratio to the control value on the y-axis for cells treated for 24 hours with different molar concentrations of staurosporine (circles), Compound I (squares), and PF-07104091 (triangles) on the x-axis. Figure 5B is a collection of line plots showing the cell ratio to the control value on the y-axis for cells treated for 48 hours with different molar concentrations of staurosporine (circles), Compound I (squares), and PF-07104091 (triangles) on the x-axis. Figure 5C is a collection of line plots showing the cell ratio to the control value on the y-axis for cells treated for 72 hours with different molar concentrations of staurosporine (circles), Compound I (squares), and PF-07104091 (triangles) on the x-axis. [Figure 6] Figure 6 shows that Compound I, alone or in combination with cisplatin, does not induce γ-H2AX formation in normal Hs68 human fibroblasts. The experimental conditions for these experiments can be found in Example 2. Figure 6 is a bar graph showing the percentage of cells positive for the γ-H2AX marker on the y-axis for various treatment conditions involving administration of cisplatin and / or Compound I to Hs68 fibroblasts. The symbol ">" indicates staggered co-administration of the indicated molecules in sequence. The symbol "+" indicates that the two molecules were administered simultaneously. [Figure 7]Figures 7A-7D show the generation and validation of palbociclib-resistant breast cancer model MCF7 cells. The experimental methods for these experiments can be found in Example 3. Figure 7A shows photographs of cultured cells exhibiting similar morphology and growth to the breast cancer model MCF7 parental cells (MCF7 Parent) and cells cultured for 4 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 is a bar graph showing the Log2 fold change on the x-axis for genes of interest indicated on the y-axis (*p-value < 0.05). MCF7 Palbo-R cells showed upregulation of CDK6, CCNE1, and CCNE2 transcripts, markers of acquired CDK4 / 6 inhibitor resistance. Figure 7C is a Western blot of retinoblastoma protein (Rb), cyclin E, and the input loading control, GAPDH, in palbociclib-sensitive (Palbo-S) MCF7 parental control cells (left) and MCF7 Palbo-R daughter cells. Figure 7D is a bar graph analysis showing quantified immunoblot signals, shown on the y-axis, of Rb and cyclin E proteins, displayed on the x-axis, normalized to the GAPDH loading control in MCF7 Palbo-S parental (open squares) and MCF7 Palbo-R daughter (closed squares) cell lines. Cyclin E levels are increased in MCF7 Palbo-R cells. [Figure 8]Figures 8A-8I show that palbociclib-resistant (Palbo-R) breast cancer model MCF7 cells are highly sensitive to combination treatment involving administration of both Compound I and palbociclib. The experimental methods for these experiments can be found in Example 3. Figure 8A is a bar graph showing cell proliferation IC50 values in nanomolar (nM) on the y-axis and different treatment regimens on the x-axis. MCF7 Palbo-R cells are highly sensitive to combined inhibition of CDK2 and CDK4 / 6, involving administration of both Compound I and palbociclib, compared to either agent administered alone. Figure 8B is a Western blot showing levels of phosphorylated residues 807 and 811 of retinoblastoma protein (pRb 807 / 811) and beta-tubulin as an input loading control, without PD-0332991 (palbociclib) or with 1 μM palbociclib administered in combination with increasing concentrations of Compound I. Compound I potently inhibited Rb phosphorylation in MCF7 Palbo-R cells when combined with PD-0332991 (palbociclib). IC50, half maximal inhibitory concentration. Figure 8C is a line graph showing the ratio of viable MCF7 PDRCL5-1 cells without PD cells to the control on the y-axis and the concentration of Compound I in molar concentrations on the x-axis. For maintenance, MCF7 PDRCL5-1 cells were grown in the presence of 1 μM palbociclib. Figure 8D is a line graph showing the ratio of viable MCF7 PDRCL5-1 cells without PD cells to the control on the y-axis and the concentration of Compound I in molar concentrations on the x-axis. Figures 8F-8I are bar graphs showing the mean colony area and percent size for different treatment conditions, including control (black bars); 300 nM palbociclib (white bars); 300 nM palbociclib in combination with Compound I (vertical bars); 300 nM Compound I (diagonal bars); and palbociclib followed by palbociclib in combination with Compound I (checkered bars). Figure 8E is an image of a culture plate containing T47D human breast cancer cell colonies under different treatment conditions at weeks 2, 3, 5, or 8. Figure 8F is a bar graph showing the mean colony size for the different treatment conditions on the y-axis compared to the control at weeks 2, 3, 5, or 8, as indicated on the x-axis.Figure 8G is a bar graph showing on the y-axis the percent colony area for the different treatment conditions compared to the control at weeks 2, 3, 5, or 8, as indicated on the x-axis. Figure 8H is a bar graph showing on the y-axis the average colony size for the different treatment conditions at weeks 2, 3, 5, or 8, as indicated on the x-axis. Figure 81 is a bar graph showing on the y-axis the percent colony area for the different treatment conditions at weeks 2, 3, 5, or 8, as indicated on the x-axis. The symbol ">" indicates staggered co-administration of the indicated molecules in sequence. The symbol "+" indicates that two molecules were administered simultaneously. [Figure 9] Figures 9A and 9B show 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 can be found in Example 3. Figure 9A is a bar graph showing the percentage of MCF7 parental cells at different cell stages on the y-axis for different concentrations of Compound I, as shown on the x-axis. Figure 9B is a bar graph showing the percentage of Palbo-R MCF7 daughter cells at different cell stages on the y-axis for different concentrations of Compound I, as shown on the x-axis. [Figure 10]Figures 10A-10E show that Compound I preferentially inhibits several independent CCNEhigh-expressing ovarian cancer model cell lines. Experimental methods for these experiments can be found in Example 4. Figure 10A is a bar graph showing on the y-axis the percentage of tumors that exhibit increased cyclin E1 expression and / or activation compared to controls for different 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 endometrial carcinoma; BLCA: bladder urothelial carcinoma; LUAD: lung adenocarcinoma; ESCA: esophageal carcinoma; ACC: adrenocortical carcinoma; BRCA: invasive breast carcinoma; PAAD: pancreatic adenocarcinoma; LIHC: liver hepatocellular carcinoma; CESC: cervical squamous cell carcinoma and adenocarcinoma; MESO: mesothelioma; HNSC: head and neck squamous cell carcinoma; COAD: colon adenocarcinoma; SKCM: cutaneous melanoma; GBM: glioblastoma multiforme; KICH: chromophobe renal cell carcinoma. Figure 10B is a bar graph showing the IC50 values for cell proliferation on the y-axis for different ovarian model cancer cell lines indicated on the x-axis. The cyclin E1 (CCNE1) status (amplified, increased, or unamplified) of each cell line is indicated above the graph. Figure 10C is a bar graph showing the percentage of ovarian OVCAR-3 cells in G0-G1, S, 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 G0-G1, S, or G2-M phase on the y-axis at different concentrations of Compound I on the x-axis. Figure 10E is an image of a Western blot showing the levels of phosphorylated threonine residue 821 of the retinoblastoma protein (pRb T821) in OVCAR-3 or COV318 cells treated with vehicle (C) or increasing concentrations of Compound I (30 nM, 100 nM, 300 nM, 10 mM). The blot is further labeled for CDK2 and β-tubulin as loading controls. [Figure 11]Figures 11A and 11B show that Compound I reduces phosphorylated retinoblastoma (pRb) in ovarian OVCAR3 cells in a dose- and time-dependent manner. The experimental methods for these experiments can be found in Example 4. Figure 11A is a Western blot showing the levels of cell cycle inhibitor proteins (p130, p27, p16), retinoblastoma protein (Rb), markers of phosphorylated Rb protein (pRb 807 / 811, pRb T821), cyclin-dependent kinase 2 (CDK2), and cyclin proteins (CCNE1, CCNE2, CCNA2) in OVCAR-3 cells treated with vehicle (C) or increasing concentrations (30 nM, 100 nM, 300 nM, 10 mM) of Compound I. β-Actin is included as an input loading control. Figure 11B is a Western blot showing levels of pRb at residues 807 and 811, and the cell cycle inhibitor protein p27, upon extended incubation of OVCAR-3 cells with Compound I. β-actin is included as an input loading control. [Figure 12]Figures 12A and 12B show that Compound I dose-dependently reduces phosphorylated pRb in ovarian cancer model cells. The experimental conditions for these experiments are described in Example 4. Figure 12A shows that Compound I dose-dependently reduces phosphorylated pRb in ovarian cancer model cells FUOV1 and Kuramochi. The experimental conditions for these experiments are described in Example 4. Figure 12A is a Western blot showing the levels of cell cycle inhibitor proteins (p130, p27, p16), retinoblastoma protein (Rb), markers of phosphorylated Rb protein (pRb 807 / 811, pRb T821, pRb S780), cyclin-dependent kinase 2 (CDK2), and cyclin proteins (CCNE1, CCNE2, CCNA2) in FUOV1 cells treated with vehicle (C) or increasing concentrations (30 nM, 100 nM, 300 nM, 1000 nM) of Compound I. Figure 12B is a Western blot showing levels of retinoblastoma protein (Rb), markers of phosphorylated Rb protein (pRb 807 / 811, pRb T821), and cyclin A2 (CCNA2) in Kuramochi cells treated with vehicle (0) or increasing concentrations (30 nM, 100 nM, 300 nM, 1000 nM) of Compound I. [Figure 13]Figures 13A-13C show cell cycle changes observed over time in ovarian cancer model OVCAR-3 cells treated with Compound I or the reference CDK2 inhibitor, Pfizer's compound PF-07104091. The experimental methods for these experiments can be found in Example 4. Figure 13A is a composite bar graph showing the percentage of OVCAR-3 cells, shown on the x-axis, measured in different cell cycle states, including G1, S, or G2 / M, for different treatment conditions, shown on the right y-axis, over different lengths of time (24 or 48 hours of treatment), as shown on the left y-axis. Figure 13B is a composite bar graph showing the percentage of OVCAR-3 cells, shown on the lower x-axis, measured in different cell cycle states, including G1, S, or G2 / M, for different concentrations (100 nM, 300 nM, or 600 nM) listed on the upper x-axis for different treatment conditions, shown on the right y-axis, over different lengths of time (24 or 48 hours of treatment), as shown on the left y-axis. FIG. 13C is a composite bar graph showing the percentage of OVCAR-3 cells, shown on the x-axis, measured in different cell cycle states including G1, S, or G2 / M for different treatment conditions, shown on the right y-axis, over different lengths of time (24 or 48 hours of treatment), shown on the left y-axis. [Figure 14] Figures 14A and 14B show cell cycle changes observed in ovarian cancer model OVCAR-3 cells at increasing times after washout of Compound I. The experimental conditions for these experiments can be found in Example 4. Figure 14A is a flow diagram showing the sequence of experiments performed. Figure 14B is a bar graph showing the percentage of OVCAR-3 cells, shown on the y-axis, measured in different cell cycle states, including DNA content <2N (black bars), G0 / G1 phase (white bars), S phase (dark dotted bars), or G2 / M phase (light dotted bars), for different treatment conditions, shown on the x-axis. Compound I was administered at 300 nM for 0, 6, 18, 24, 30, or 48 hours. [Figure 15]Figures 15A-15D show APC histograms with Edu gating from 1 hour to 48 hours of treatment. Treatment conditions included DMSO control, 300 nM Compound I, or 300 nM PF-07104091. The experimental methods for these experiments can be found in Example 4. Figure 15A shows a histogram showing the number of cells in different cell cycle phases, including G1, S, and G2, on the y-axis, and the magnitude of the staining signal on the x-axis. The graph shows EdU traces from 1 hour to 48 hours. Figure 15B shows a histogram showing the number of cells in different cell cycle phases, including G1, S, and G2, on the y-axis, and the magnitude of the staining signal on the x-axis. The graph shows EdU traces from 6 hours to 48 hours. Figure 15C shows a histogram showing the number of cells in different cell cycle phases, including G1, S, and G2, on the y-axis, and the magnitude of the staining signal on the x-axis. The graph shows the EdU trace from 24 to 48 hours. Figure 15D is a histogram showing the number of cells in different cell cycle phases, including G1, S, and G2, on the y-axis, and the magnitude of the staining signal on the x-axis. The graph shows data collected at 48 hours (no trace). [Figure 16] Figures 16A and 16B show that Compound I is more cytotoxic than the reference CDK2 inhibitor, Pfizer's compound PF-07104091, in Kuramochi cells and FUOV1 cells, CCNEhigh ovarian cancer models. The experimental methods for these experiments can be found in Example 4. Figure 16A is a set of line plots showing the cell ratios relative to the control value at different concentrations of Compound I (circles) and palbociclib (squares) on the x-axis in Kuramochi cells, an ovarian cancer cell model. Figure 16B is a set of line plots showing the cell ratios relative to the control value at different concentrations of Compound I (circles) and Pfizer's compound PF-07104091 (squares) on the x-axis in FUOV1 cells, an ovarian cancer cell model. The cell proliferation IC50 values in molar (M) for Compound I and PF-07104091 are listed below the graphs. [Figure 17]Figures 17A and 17B show that Compound I more potently inhibits CCNEhigh ovarian cancer model OVCAR-3 cells than the reference CDK2 inhibitor, Pfizer's compound PF-07104091. The experimental conditions for these experiments can be found in Example 4. Figure 17A is a set of line graphs showing the ratio of OVCAR-3 cell numbers to control on the y-axis and the molar concentration of either Compound I (squares) or PF-07104091 (triangles) on the x-axis. Figure 17B is a table listing the OVCAR-3 cell proliferation IC50 values for Compound I and PF-07104091 in nanomolar (nM). [Figure 18] Figure 1 shows that Compound I is effective as a single agent in reducing tumor size. Tumor size (mm) is displayed on the y-axis over a 28-day treatment series, indicated on the x-axis, in a CCNE-high ovarian OVCAR-3 tumor xenograft mouse model. The experimental conditions for these experiments are found in Example 4. OVCAR-3 xenograft tumor fragments were harvested from host animals and implanted into immunodeficient mice (CR1:NU(NCr)-Fox1nu). QD, once daily; BID, twice daily; mpk, milligrams per kilogram. [Figure 19] Figures 19A and 19B show an in vivo comparison of tumor efficacy and survival benefit of Compound I versus a reference CDK2 inhibitor, Pfizer's compound PF-07104091, in a CCNE-high 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)-Fox1nu). The experimental conditions for these experiments can be found in Example 4. Figure 19A is a collection of line graphs showing tumor volume (mm) on the y-axis and treatment days on the x-axis. Treatment conditions include vehicle (circles), Compound I 100 mpk BID (open squares), and PF-07104091 100 mpk BID (triangles). Figure 19B is a survival plot showing the percentage of mice alive on the treatment days indicated on the x-axis. Treatment conditions included vehicle (dotted line), Compound I 100 mpk BID (solid line), and PF-07104091 100 mpk BID (checkered line). [Figure 20] This figure shows that Compound I dose-dependently reduces phosphorylated retinoblastoma (pRb) in the gastric cancer model MKN1 cells. The experimental conditions for these experiments are described in Example 4. Figure 20 is a Western blot showing the levels of cell cycle inhibitor proteins (p130, p27, p21, p16), retinoblastoma protein (Rb), markers of phosphorylated Rb protein (pRb 807 / 811, pRb T821), cyclin-dependent kinase 2 (CDK2), and cyclin proteins (CCNE1, CCNE2, CCNA2) in MKN1 cells treated with 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 21] Figures 21A and 21B show that cell cycle changes are observed in gastric cancer model MKN1 cells at increasing times after washout of Compound I. The experimental conditions for these experiments can be found in Example 4. Figure 21A is a flow diagram showing the sequence of experiments performed. Figure 21B is a bar graph showing the percentage of MKN1 cells, shown on the y-axis, measured in different cell cycle states, including DNA content <2N (black bars), G0 / G1 phase (white bars), S phase (dark dotted bars), or G2 / M phase (light dotted bars), for different treatment conditions, shown on the x-axis. Compound I was administered at 300 nM for 0, 6, 18, 24, 30, or 48 hours. [Figure 22]Figures 22A-22E show that Compound I potently inhibits several independent small cell lung cancer (SCLC) model cell lines. The experimental methods for these experiments can be found in Example 5. Figure 22A is a bar graph showing the cell proliferation IC50 values of palbociclib or Compound I administered to SCLC models H526, SHP77, NCIH82, and NCIH69 cells, as indicated on the x-axis. Figure 22B is a collection of line graphs showing the ratio of H526 cell numbers to control on the y-axis and the molar (M) treatment concentration of either Compound I (squares) or PF-07104091 (triangles) on the x-axis. Figure 22C is a table listing the H526 cell proliferation IC50 values for Compound I and PF-07104091 in nanomolar (nM) units. Figure 22D is a collection of line graphs showing caspase 3 / 7 activation ratios relative to control in H526 cells on the y-axis and molar (M) concentrations of staurosporine (circles), compound I (squares), or PF-07104091 (triangles) on the x-axis at 72 hours. The caspase 3 / 7 activation IC50 values for each administered compound are listed below the graphs. Figure 22E is a table listing the caspase 3 / 7 activation IC50 concentration values in nanomolar (nM) for compound I and PF-07104091. [Figure 23] Figure 23 shows the cell cycle changes exhibited by nocodazole-synchronized and released H526 cells in the presence or absence of Compound I. The experimental conditions for these experiments can be found in Example 5. Figure 23 is a bar graph showing the percentage of H526 cells, shown on the y-axis, measured in different cell cycle states, including DNA content <2N (black bars), G0 / G1 phase (white bars), S phase (dark dotted bars), or G2 / M phase (light dotted bars), for different treatment conditions, shown on the x-axis. Compound I was administered at 300 nM for 6, 12, 24, 30, or 48 hours. [Figure 24]Figure 24 shows the time course of H526 cell cycle progression after incubation with Compound I or PF-07104091. The experimental conditions for these experiments can be found in Example 5. Figure 24 is a composite bar graph showing the percentage of H526 cells, shown on the x-axis, measured in different cell cycle states including G1, S, G2, or M phase for different treatment conditions, shown on the right y-axis, over different lengths of time (1 hour, 6 hours, 24 hours, or 48 hours of treatment), shown on the left y-axis. [Figure 25] Figure 25 shows that Compound I induces DNA damage in small cell lung cancer (SCLC) model H526 cells, and that the DNA damage is even greater when Compound I is administered in combination with cisplatin. The experimental conditions for these experiments can be found in Example 5. Figure 25 is a bar graph showing the percentage of cells positively immunolabeled with anti-γ-H2AX antibody on the y-axis for different treatment conditions listed on the x-axis. The symbol ">" indicates staggered co-administration of the indicated molecules in sequence. The symbol "+" indicates that the two molecules were administered simultaneously. [Figure 26]Figures 26A-C show that Compound I increases cyclin E (CCNE1 / CCNE2) levels and causes a dose-dependent increase in DNA damage markers in H69 and H526 cells, models of small cell lung cancer (SCLC). The experimental methods for these experiments can be found in Example 5. Figure 26A is a Western blot showing the levels of cell cycle inhibitor proteins (p130, p27, p21, p16), retinoblastoma protein (Rb), and cyclin proteins (CCNE1, CCNE2, CCNA2) in H69 cells, a model of small cell lung cancer (SCLC), treated with 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 26B is a Western blot showing the levels of cell cycle inhibitor proteins (p130, p27, p21, p16), cyclin-dependent kinase 2 (CDK2), and cyclin proteins (CCNE1, CCNE2, CCNA2) in small cell lung cancer (SCLC) model H526 cells treated with vehicle (control) or increasing concentrations (30 nM, 100 nM, 300 nM, 10 mM) of Compound I. β-Actin is included as an input loading control. Figure 29C is a Western blot showing the levels of cell cycle inhibitor proteins (p130, p27, p21, p16), cyclin-dependent kinase 2 (CDK2), and cyclin proteins (CCNE1, CCNE2, CCNA2) in small cell lung cancer (SCLC) model Hs68 cells treated with vehicle (control) or increasing concentrations (30 nM, 100 nM, 300 nM, 10 mM) of Compound I. β-Actin is included as an input loading control. [Figure 27]Figures 27A-27D show 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 can be found in Example 5. Figure 27A is a collection of line graphs showing the caspase 3 / 7 activation ratio relative to the control in H526 cells on the y-axis and the molar (M) concentration of staurosporine (circles), Compound I (squares), or PF-07104091 (triangles) on the x-axis at 24 hours. The caspase 3 / 7 activation IC50 values for each administered compound are listed below the graphs. Figure 27B is a collection of line graphs showing the caspase 3 / 7 activation ratio relative to the control in H526 cells on the y-axis and the molar (M) concentration of staurosporine (circles), Compound I (squares), or PF-07104091 (triangles) on the x-axis at 48 hours. The caspase 3 / 7 activation IC50 values for each compound administered are listed below the graphs. Figure 27C is a collection of line graphs showing the caspase 3 / 7 activation ratio relative to control in H526 cells on the y-axis and the molar (M) concentration of staurosporine (circles), Compound I (squares), or PF-07104091 (triangles) on the x-axis at 72 hours. The caspase 3 / 7 activation IC50 values for each compound administered are listed below the graphs. Figure 27D is a table listing the caspase 3 / 7 activation IC50 values in nanomolar (nM) for each compound administered. [Figure 28] Figures 28A-28C show H526 cell cycle changes and caspase 3 / 7 activation following co-administration of Compound I and cisplatin. The symbol ">" indicates staggered co-administration of the indicated molecules. The symbol "+" indicates that the two molecules were administered simultaneously. The experimental methods for these experiments can be found in Example 5. Figure 28A is a flow diagram showing the experimental sequence. Figure 28B is a bar graph showing the percentage of cells in different cell cycle stages, including DNA content <2N, G0 / G1, S, or G2 / M, for different treatment conditions, as indicated on the x-axis. Figure 28C is a bar graph showing the ratio of yH2AX to control levels, as indicated on the y-axis, for different treatment conditions, as indicated on the x-axis. [Figure 29]Figures 29A-29C show that Compound I synergizes with doxorubicin to inhibit certain small cell lung cancer (SCLC) model cells. The experimental methods for these experiments can be found in Example 5. Figure 29A is a collection of line graphs showing the ratio of H526 cell numbers to control on the y-axis and the molar (M) treatment concentration of either Compound I (squares), doxorubicin (triangles), or doxorubicin in combination with Compound I (diamonds) on the x-axis. Figure 29B is a collection of line graphs showing the ratio of H69 cell numbers to control on the y-axis and the molar (M) treatment concentration of either Compound I (squares), doxorubicin (triangles), or doxorubicin in combination with Compound I (diamonds) on the x-axis. Figure 29C is a collection of line graphs showing the ratio of SHP77 cell numbers to control on the y-axis and the molar (M) treatment concentration of either Compound I (squares), doxorubicin (triangles), or doxorubicin in combination with Compound I (diamonds) on the x-axis. [Figure 30] Figures 30A-30C show that Compound I synergizes with camptothecin to inhibit small cell lung cancer (SCLC) model H526, H69, and SHP77 cells. The experimental methods for these experiments can be found in Example 5. Figure 30A is a collection of line graphs showing the ratio of H526 cell counts to control on the y-axis and the molar (M) treatment concentration of either Compound I (squares), camptothecin (triangles), or camptothecin in combination with Compound I (inverted triangles) on the x-axis. Figure 30B is a collection of line graphs showing the ratio of H69 cell counts to control on the y-axis and the molar (M) treatment concentration of either Compound I (squares), camptothecin (triangles), or camptothecin in combination with Compound I (inverted triangles) on the x-axis. FIG. 30C is a collection of line graphs showing the ratio of SHP77 cell numbers to control on the y-axis and the molar (M) treatment concentration of either Compound I (squares), camptothecin (triangles), or camptothecin in combination with Compound I (inverted triangles) on the x-axis. [Figure 31]Figures 31A-31G show the in vivo efficacy of Compound I in a mouse hollow fiber assay involving three tumor cell lines, including OVCAR-3 (ovarian), MKN-1 (gastric), and HCC-1569 (breast). Different treatment groups of mice were administered: Group 1 (G1) received vehicle at 10 ml / kg twice daily; Group 2 (G2) received Compound I at 75 mg / kg, 10 ml / kg twice daily; Group 3 (G3) received Compound I at 100 mg / kg, 10 ml / kg twice daily; and Group 4 (G4) received Compound I at 150 mg / kg, 10 ml / kg twice daily. The experimental methods for these experiments can be found in Example 6. Figure 31A is a set of line graphs showing the mean animal weight in grams (g) on the y-axis for a range of treatment schedules involving the administration of different concentrations of Compound I. Female NMRI nude mice were implanted with hollow fibers loaded with HCC-1569, MKN1, and OVCAR3 tumor cells both subcutaneously and intraperitoneally on day 0. Data are expressed as mean ± SEM. The number of surviving animals in each group on days 0 (implantation) and 16 (necropsy) is shown in parentheses in the legend. Figures 31B and 31C show that compound I induces changes in cancer cell viability in mice implanted with HCC-1569 cells, a breast cancer tumor model. Female NMRI nude mice were implanted with hollow fibers loaded with HCC-1569 cells both subcutaneously (left part of the graph) and intraperitoneally (right part of the graph) on day 0. Hollow fibers were collected during necropsy on day 16 and analyzed using the CellTiter Glo assay. Figure 31B shows the mean photons / second of Celltiter-GLO reagent captured from HCC-1569 hollow fibers on day 16 on the y-axis and the different treatment groups on the x-axis. Figure 31C shows the individual replicate photons / second values on the y-axis for the different treatment groups on the x-axis. Error bars indicate the interquartile range. Figures 31D and 31E show that Compound I induces changes in cancer cell viability in mice implanted with MKN-1 cells, a gastric cancer tumor model. MKN-1 cell-loaded hollow fibers were implanted both subcutaneously (left part of the graph) and intraperitoneally (right part of the graph) 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 31D shows the mean photons / second of Celltiter-GLO reagent captured from MKN-1 hollow fibers on day 16, with the different treatment groups on the x-axis. Figure 31E shows the individual replicate photons / second values on the y-axis for the different treatment groups on the x-axis. Error bars indicate the interquartile range. Figures 31F and 31G show that Compound I induces changes in cancer cell viability in mice implanted with ovarian cancer tumor model OVCAR-3 cells. Hollow fibers loaded with OVCAR-3 cells were implanted both subcutaneously (left part of the graph) and intraperitoneally (right part of the graph) 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 31F shows the mean photons / second of Celltiter-GLO reagent captured from OVCAR-3 hollow fibers on day 16, with the different treatment groups on the x-axis. Figure 31G shows the individual replication photons / second values on the y-axis for different treatment groups on the x-axis. Error bars indicate the interquartile range. [Figure 32] 1 is an XRPD diffractogram of crystalline free base Pattern 1. The diffractogram was obtained as described in Example 10, and the 2-theta values along with relative intensities are shown in Table 14. [Figure 33] 1 is an XRPD diffractogram of crystalline free base Pattern 2. The diffractogram was obtained as described in Example 10, and the 2-theta values along with relative intensities are shown in Table 15. [Figure 34] 16 is an XRPD diffractogram of crystalline free base Pattern 3. The diffractogram was obtained as described in Example 10, and the 2-theta values along with relative intensities are shown in Table 16. [Figure 35] 1 is an XRPD diffractogram of the crystalline HCl salt Pattern 1. The diffractogram was obtained as described in Example 10, and the 2-theta values along with the relative intensities are shown in Table 17. [Figure 36] 18 is an XRPD diffractogram of the crystalline HCl salt Pattern 2. The diffractogram was obtained as described in Example 10 and the 2-theta values along with the relative intensities are shown in Table 18. [Figure 37]1 is an XRPD diffractogram of the crystalline HCl salt Pattern 3. The diffractogram was obtained as described in Example 10, and the 2-theta values along with the relative intensities are shown in Table 19. [Figure 38] 2 is an XRPD diffractogram of crystalline sulfate salt Pattern 1. The diffractogram was obtained as described in Example 10, and the 2-theta values along with the relative intensities are shown in Table 20. [Figure 39] 2 is an XRPD diffractogram of crystalline sulfate salt Pattern 1*. The diffractogram was obtained as described in Example 10, and the 2-theta values along with relative intensities are shown in Table 21. [Figure 40] 2 is an XRPD diffractogram of crystalline sulfate salt Pattern 2. The diffractogram was obtained as described in Example 10, and the 2-theta values along with relative intensities are shown in Table 22. [Figure 41] 2 is an XRPD diffractogram of crystalline sulfate salt Pattern 3. The diffractogram was obtained as described in Example 10, and the 2-theta values along with the relative intensities are shown in Table 23. [Figure 42] 2 is an XRPD diffractogram of crystalline sulfate salt Pattern 4. The diffractogram was obtained as described in Example 10, and the 2-theta values along with relative intensities are shown in Table 24. [Figure 43] 2 is an XRPD diffractogram of crystalline sulfate salt Pattern 5. The diffractogram was obtained as described in Example 10, and the 2-theta values along with the relative intensities are shown in Table 25. [Figure 44] 2 is an XRPD diffractogram of crystalline sulfate salt Pattern 6. The diffractogram was obtained as described in Example 10, and the 2-theta values along with the relative intensities are shown in Table 26. [Figure 45] 2 is an XRPD diffractogram of crystalline sulfate salt Pattern 7. The diffractogram was obtained as described in Example 10, and the 2-theta values along with the relative intensities are shown in Table 27. [Figure 46]2 is an XRPD diffractogram of the crystalline methanesulfonate salt Pattern 1. The diffractogram was obtained as described in Example 10, and the 2-theta values along with the relative intensities are shown in Table 28. [Figure 47] 2 is an XRPD diffractogram of the crystalline methanesulfonate salt Pattern 2. The diffractogram was obtained as described in Example 10, and the 2-theta values along with the relative intensities are shown in Table 29. [Figure 48] 3 is an XRPD diffractogram of the crystalline methanesulfonate salt Pattern 3. The diffractogram was obtained as described in Example 10, and the 2-theta values along with the relative intensities are shown in Table 30. [Figure 49] 3 is an XRPD diffractogram of the crystalline methanesulfonate salt Pattern 4. The diffractogram was obtained as described in Example 10, and the 2-theta values along with the relative intensities are shown in Table 31. [Figure 50] 3 is an XRPD diffractogram of the crystalline methanesulfonate salt pattern 5. The diffractogram was obtained as described in Example 10, and the 2-theta values along with the relative intensities are shown in Table 32. [Figure 51] 3 is an XRPD diffractogram of the crystalline maleate salt Pattern 1. The diffractogram was obtained as described in Example 10, and the 2-theta values along with the relative intensities are shown in Table 33. [Figure 52] 3 is an XRPD diffractogram of the crystalline maleate salt Pattern 1*. The diffractogram was obtained as described in Example 10, and the 2-theta values along with the relative intensities are shown in Table 34. [Figure 53] 3 is an XRPD diffractogram of the crystalline maleate salt Pattern 2. The diffractogram was obtained as described in Example 10, and the 2-theta values along with the relative intensities are shown in Table 35. [Figure 54] 3 is an XRPD diffractogram of crystalline maleate salt Pattern 3. The diffractogram was obtained as described in Example 10, and the 2-theta values along with the relative intensities are shown in Table 36. [Figure 55]3 is an XRPD diffractogram of the crystalline maleate salt Pattern 3*. The diffractogram was obtained as described in Example 10, and the 2-theta values along with the relative intensities are shown in Table 37. [Figure 56] 3 is an XRPD diffractogram of crystalline maleate salt Pattern 4. The diffractogram was obtained as described in Example 10, and the 2-theta values along with relative intensities are shown in Table 38. [Figure 57] 3 is an XRPD diffractogram of crystalline maleate salt pattern 5. The diffractogram was obtained as described in Example 10, and the 2-theta values along with the relative intensities are shown in Table 39. [Figure 58] 4 is an XRPD diffractogram of crystalline phosphate pattern 1. The diffractogram was obtained as described in Example 10, and the 2-theta values along with the relative intensities are shown in Table 40. [Figure 59] 4 is an XRPD diffractogram of crystalline phosphate pattern 2. The diffractogram was obtained as described in Example 10, and the 2-theta values along with the relative intensities are shown in Table 41. [Figure 60] 4 is an XRPD diffractogram of crystalline phosphate pattern 3. The diffractogram was obtained as described in Example 10 and the 2-theta values along with relative intensities are shown in Table 42. [Figure 61] 4 is an XRPD diffractogram of crystalline phosphate pattern 4. The diffractogram was obtained as described in Example 10, and the 2-theta values along with the relative intensities are shown in Table 43. [Figure 62] 4 is an XRPD diffractogram of crystalline phosphate pattern 5. The diffractogram was obtained as described in Example 10, and the 2-theta values along with the relative intensities are shown in Table 44. [Figure 63] 4 is an XRPD diffractogram of crystalline phosphate pattern 6. The diffractogram was obtained as described in Example 10, and the 2-theta values along with the relative intensities are shown in Table 45. [Figure 64]4 is an XRPD diffractogram of crystalline phosphate pattern 6*. The diffractogram was obtained as described in Example 10, and the 2-theta values along with the relative intensities are shown in Table 46. [Figure 65] 4 is an XRPD diffractogram of crystalline phosphate pattern 7. The diffractogram was obtained as described in Example 10, and the 2-theta values along with the relative intensities are shown in Table 47. [Figure 66] 48 is an XRPD diffractogram of crystalline phosphate pattern 7*. The diffractogram was obtained as described in Example 10 and 2-theta values along with relative intensities are shown in Table 48. [Figure 67] 4 is an XRPD diffractogram of crystalline phosphate pattern 8. The diffractogram was obtained as described in Example 10, and the 2-theta values along with the relative intensities are shown in Table 49. [Figure 68] 5 is an XRPD diffractogram of crystalline phosphate pattern 8*. The diffractogram was obtained as described in Example 10, and the 2-theta values along with the relative intensities are shown in Table 50. [Figure 69] 5 is an XRPD diffractogram of the crystalline (+)-L-tartrate salt, Pattern 1. The diffractogram was obtained as described in Example 10, and the 2-theta values along with the relative intensities are shown in Table 51. [Figure 70] 5 is an XRPD diffractogram of the crystalline (+)-L-tartrate salt Pattern 1*. The diffractogram was obtained as described in Example 10, and the 2-theta values along with the relative intensities are shown in Table 52. [Figure 71] 5 is an XRPD diffractogram of the crystalline (+)-L-tartrate salt, Pattern 2. The diffractogram was obtained as described in Example 10, and the 2-theta values along with the relative intensities are shown in Table 53. [Figure 72] 5 is an XRPD diffractogram of the crystalline citrate salt pattern 1. The diffractogram was obtained as described in Example 10, and the 2-theta values along with the relative intensities are shown in Table 54. [Figure 73]5 is an XRPD diffractogram of crystalline citrate salt pattern 2. The diffractogram was obtained as described in Example 10, and the 2-theta values along with relative intensities are shown in Table 55. [Figure 74] 5 is an XRPD diffractogram of crystalline citrate salt pattern 4. The diffractogram was obtained as described in Example 10, and the 2-theta values along with relative intensities are shown in Table 56. [Figure 75] 5 is an XRPD diffractogram of the crystalline hydrobromide salt Pattern 1. The diffractogram was obtained as described in Example 10, and the 2-theta values along with the relative intensities are shown in Table 57. [Figure 76] 5 is an XRPD diffractogram of the crystalline hydrobromide salt Pattern 2. The diffractogram was obtained as described in Example 10 and 2-theta values along with relative intensities are shown in Table 58. [Figure 77] 5 is an XRPD diffractogram of the crystalline benzenesulfonate salt Pattern 1. The diffractogram was obtained as described in Example 10, and the 2-theta values along with the relative intensities are shown in Table 59. [Figure 78] 6 is an XRPD diffractogram of the crystalline benzenesulfonate salt Pattern 2. The diffractogram was obtained as described in Example 10, and the 2-theta values along with the relative intensities are shown in Table 60. [Figure 79] 6 is an XRPD diffractogram of the crystalline benzenesulfonate salt Pattern 3. The diffractogram was obtained as described in Example 10, and the 2-theta values along with the relative intensities are shown in Table 61. [Figure 80] 6 is an XRPD diffractogram of the crystalline benzenesulfonate salt Pattern 3*. The diffractogram was obtained as described in Example 10, and 2-theta values along with relative intensities are shown in Table 62. [Figure 81] 6 is a thermogravimetric / differential scanning calorimetry (TG / DSC) thermogram of sulfuric acid pattern 1. The TG / DSC thermogram was obtained as described in Example 13, and the results are shown in Table 63. [Figure 82]6 is a thermogravimetric / differential scanning calorimetry (TG / DSC) thermogram of sulfuric acid pattern 2. The TG / DSC thermogram was obtained as described in Example 13, and the results are shown in Table 63. [Figure 83] 6 is a thermogravimetry / differential scanning calorimetry (TG / DSC) thermogram of sulfuric acid pattern 3. The TG / DSC thermogram was obtained as described in Example 13, and the results are shown in Table 63. [Figure 84] 6 is a thermogravimetry / differential scanning calorimetry (TG / DSC) thermogram of sulfuric acid pattern 4. The TG / DSC thermogram was obtained as described in Example 13, and the results are shown in Table 63. [Figure 85] 6 is a thermogravimetric / differential scanning calorimetry (TG / DSC) thermogram of sulfuric acid pattern 5. The TG / DSC thermogram was obtained as described in Example 13, and the results are shown in Table 63. [Figure 86] 6 is a thermogravimetry / differential scanning calorimetry (TG / DSC) thermogram of sulfuric acid pattern 6. The TG / DSC thermogram was obtained as described in Example 13, and the results are shown in Table 63. [Figure 87] 1 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 shown in Example 23 and Table 64. [Figure 88] 1 is a thermogravimetry / 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 shown in Example 23 and Table 64. [Figure 89] 1 is a thermogravimetry / 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 shown in Example 23 and Table 64. [Figure 90] 1 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 shown in Example 23 and Table 64. [Figure 91] 1 is a thermogravimetry / 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 shown in Example 24 and Table 65. [Figure 92] 1 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 shown in Example 24 and Table 65. [Figure 93] 1 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 shown in Example 24 and Table 65. [Figure 94] 1 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 shown in Example 24 and Table 65. [Figure 95] 1 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 shown in Example 24 and Table 65. [Figure 96] 1 is a thermogravimetry / differential scanning calorimetry (TG / DSC) thermogram of Phosphate Pattern 1. The TG / DSC thermogram was obtained as described in Example 13, and the results are shown in Example 25 and Table 66. [Figure 97] 1 is a thermogravimetry / differential scanning calorimetry (TG / DSC) thermogram of phosphate pattern 2. The TG / DSC thermogram was obtained as described in Example 13, and the results are shown in Example 25 and Table 66. [Figure 98] 1 is a thermogravimetry / differential scanning calorimetry (TG / DSC) thermogram of phosphate pattern 3. The TG / DSC thermogram was obtained as described in Example 13, and the results are shown in Example 25 and Table 66. [Figure 99]1 is a thermogravimetric / differential scanning calorimetry (TG / DSC) thermogram of phosphate pattern 4. The TG / DSC thermogram was obtained as described in Example 13, and the results are shown in Example 25 and Table 66. [Figure 100] 1 is a thermogravimetry / differential scanning calorimetry (TG / DSC) thermogram of Phosphate Pattern 7*. The TG / DSC thermogram was obtained as described in Example 13, and the results are shown in Example 25 and Table 66. [Figure 101] 1 is a thermogravimetry / differential scanning calorimetry (TG / DSC) thermogram of phosphate pattern 8*. The TG / DSC thermogram was obtained as described in Example 13, and the results are shown in Example 25 and Table 66. [Figure 102] 1 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 shown in Example 26 and Table 67. [Figure 103] 1 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 shown in Example 26 and Table 67. [Figure 104] 1 is a thermogravimetric / differential scanning calorimetry (TG / DSC) thermogram of citric acid Pattern 1. The TG / DSC thermogram was obtained as described in Example 13, and the results are shown in Example 27 and Table 68. [Figure 105] 1 is a thermogravimetric / differential scanning calorimetry (TG / DSC) thermogram of citric acid Pattern 1. The TG / DSC thermogram was obtained as described in Example 13, and the results are shown in Example 27 and Table 68. [Figure 106] 1 is a thermogravimetric / differential scanning calorimetry (TG / DSC) thermogram of citric acid Pattern 1. The TG / DSC thermogram was obtained as described in Example 13, and the results are shown in Example 27 and Table 68. [Figure 107]1 is a thermogravimetric / differential scanning calorimetry (TG / DSC) thermogram of hydrobromic acid Pattern 1. The TG / DSC thermogram was obtained as described in Example 13, and the results are shown in Example 28 and Table 69. [Figure 108] 1 is a thermogravimetric / differential scanning calorimetry (TG / DSC) thermogram of hydrobromic acid Pattern 1. The TG / DSC thermogram was obtained as described in Example 13, and the results are shown in Example 28 and Table 69. [Figure 109] 1 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 shown in Example 29 and Table 70. [Figure 110] 1 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 shown in Example 29 and Table 70. [Figure 111] 1 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 shown in Example 29 and Table 70. [Figure 112] 1 is a thermogravimetric / differential scanning calorimetry (TG / DSC) thermogram of HCl salt Pattern 1. The TG / DSC thermogram was obtained as described in Example 13, and the results are shown in Example 30. [Figure 113] 1 is a thermogravimetric / differential scanning calorimetry (TG / DSC) thermogram of HCl salt Pattern 2. The TG / DSC thermogram was obtained as described in Example 13, and the results are shown in Example 30 and Table 72. [Figure 114] 1 is a differential scanning calorimetry (DSC) thermogram of HCl salt Pattern 1. The DSC thermogram was obtained as described in Example 14, and the results are shown in Example 30. [Figure 115]1 is a dynamic vapor sorption (DVS) analysis showing the results of a moisture sorption experiment for HCl Pattern 1. The DVS analysis of HCl Pattern 1 was performed as described in Example 15. The DVS analysis revealed that the material was moderately hygroscopic, with absorption rates of 5.15% and 5.10% for the first and second sorption cycles, respectively. The results of the study are shown in Example 30. [Figure 116] Figure 1 is a dynamic vapor sorption (DVS) kinetic plot of HCl Pattern 1. DVS of HCl Pattern 1 was obtained as described in Example 15. DVS analysis revealed that the material was moderately hygroscopic, with absorption rates of 5.15% and 5.10% for the first and second sorption cycles, respectively. The results of the study are shown in Example 30. [Figure 117] 1 is a thermogravimetry / differential scanning calorimetry (TG / DSC) thermogram of sulfuric acid pattern 7. The TG / DSC thermogram was obtained as described in Example 13, and the results are shown in Example 34. [Figure 118] 7 is a thermogravimetry / differential scanning calorimetry (TG / DSC) thermogram of Phosphate Pattern 7*. The TG / DSC thermogram was obtained as described in Example 13, and the results are shown in Table 79. [Figure 119] 7 is a differential scanning calorimetry (DSC) thermogram of phosphate pattern 7*. The DSC thermogram was obtained as described in Example 14, and the results are shown in Table 79. [Figure 120]

[0033] Figure 79 is a dynamic vapor sorption (DVS) analysis showing the results of a moisture sorption experiment on Phosphate Pattern 7*. DVS analysis of Phosphate Pattern 7* was performed as described in Example 15. DVS analysis revealed that the material was moderately hygroscopic, with absorption rates of 4.76% and 5.18% in the first and second sorption cycles, respectively. The results of the study are shown in Table 79. [Figure 121] 7 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 shown in Table 79. [Figure 122] This is a PLM image of HCl pattern 1. [Figure 123] PLM image of phosphate pattern 7*. [Figure 124] 1 is a plot showing the effect of Compound I on hERG currents. The experimental conditions for this experiment can be found in Example 40. Data points (triangles) represent the percent hERG block value, shown on the y-axis, at a particular concentration of Compound I, shown on the x-axis. [Figure 125] 1 is a plot showing Compound I inhibition of COX1. The experimental conditions for this experiment can be found in Example 40. Data points (triangles) represent the percent of control enzyme inhibition of diclofenac ligand binding to COX1, shown on the y-axis, at a particular concentration of Compound I, shown on the x-axis. [Figure 126] 1 is a plot showing Compound I inhibition of COX2. The experimental conditions for this experiment can be found in Example 40. Data points (triangles) represent the percent of control enzyme inhibition of NS398 ligand binding to COX2, shown on the y-axis, at a particular concentration of Compound I, shown on the x-axis. [Figure 127] 1 is a plot showing Compound I inhibition of CYP1A2. The experimental conditions for this experiment can be found in Example 41. Data points (triangles) represent the percent of control enzyme inhibition of the formation of hydroxytacrine relative to the CYP1A2-catalyzed metabolism of tacrine, shown on the y-axis, at a particular concentration of Compound I, shown on the x-axis. [Figure 128] 1 is a plot showing Compound I inhibition of CYP2B6. The experimental conditions for this experiment can be found in Example 41. Data points (triangles) represent percent of control enzyme inhibition of the formation of hydroxybuproprion for CYP2B6-catalyzed metabolism of buproprion, shown on the y-axis, at a particular concentration of Compound I, shown on the x-axis. [Figure 129]1 is a plot showing Compound I inhibition of CYP2C8. The experimental conditions for this experiment can be found in Example 41. Data points (triangles) represent percent of control enzyme inhibition of the formation of desethylamodiquine for CYP2C8-catalyzed metabolism of amodiaquine, shown on the y-axis, at a particular concentration of Compound I, shown on the x-axis. [Figure 130] 1 is a plot showing Compound I inhibition of CYP2C9. The experimental conditions for this experiment can be found in Example 41. Data points (triangles) represent the percent of control enzyme inhibition of the formation of 4-hydroxytolbutamide for CYP2C9-catalyzed metabolism of tolbutamide, shown on the y-axis, at a particular concentration of Compound I, shown on the x-axis. [Figure 131] 1 is a plot showing Compound I inhibition of CYP2C19. The experimental conditions for this experiment can be found in Example 41. Data points (triangles) represent the percent of control enzyme inhibition of the formation of 4-hydroxymephenytoin for CYP2C19-catalyzed metabolism of mephenytoin, shown on the y-axis, at a particular concentration of Compound I, shown on the x-axis. [Figure 132] 1 is a plot showing Compound I inhibition of CYP2D6. The experimental conditions for this experiment can be found in Example 41. Data points (triangles) represent percent of control enzyme inhibition of the formation of dextrorphan for CYP2D6-catalyzed metabolism of dextromethorphan, shown on the y-axis, at a particular concentration of Compound I, shown on the x-axis. [Figure 133] 1 is a plot showing Compound I inhibition of CYP3A4. The experimental conditions for this experiment can be found in Example 41. Data points (triangles) represent the percent of control enzyme inhibition of the formation of 1-hydroxymidazolam for CYP3A4-catalyzed metabolism of midazolam, shown on the y-axis, at a particular concentration of Compound I, shown on the x-axis. [Figure 134]1 is a plot showing Compound I inhibition of CYP3A4. The experimental conditions for this experiment can be found in Example 41. Data points (triangles) represent the percent of control enzyme inhibition of the formation of 6β-hydroxy-testosterone relative to CYP3A4-catalyzed metabolism of testosterone, shown on the y-axis, at a particular concentration of Compound I, shown on the x-axis. [Figure 135] 1 is a plot showing Compound I inhibition of BCRP. The experimental conditions for this experiment can be found in Example 41. Data points (triangles) represent the percent of control enzyme inhibition of BCRP-mediated estrone-3-sulfate transport, shown on the y-axis, at a particular concentration of Compound I, shown on the x-axis. [Figure 136] 1 is a plot showing Compound I inhibition of MATE1. The experimental conditions for this experiment can be found in Example 41. Data points (triangles) represent the percent of control enzyme inhibition of MATE1-mediated metformin transport, shown on the y-axis, at a particular concentration of Compound I, shown on the x-axis. [Figure 137] 1 is a plot showing Compound I inhibition of MATE2-K. The experimental conditions for this experiment can be found in Example 41. Data points (triangles) represent the percent of control enzyme inhibition of MATE2-K-mediated metformin transport, shown on the y-axis, at a particular concentration of Compound I, shown on the x-axis. [Figure 138] 1 is a plot showing Compound I inhibition of OAT1. The experimental conditions for this experiment can be found in Example 41. Data points (triangles) represent the percent of control enzyme inhibition of OAT1-mediated tenofovir transport, shown on the y-axis, at a particular concentration of Compound I, shown on the x-axis. [Figure 139] 1 is a plot showing Compound I inhibition of OAT3. The experimental conditions for this experiment can be found in Example 41. Data points (triangles) represent the percent of control enzyme inhibition of OAT3-mediated estrone-3-sulfate transport, shown on the y-axis, at a particular concentration of Compound I, shown on the x-axis. [Figure 140]1 is a plot showing Compound I inhibition of OAT1P1B1. The experimental conditions for this experiment can be found in Example 41. Data points (triangles) represent the percent of control enzyme inhibition of estradiol-17-β-glucuronide transport mediated by OAT1P1B1, shown on the y-axis, at a particular concentration of Compound I, shown on the x-axis. [Figure 141] 1 is a plot showing Compound I inhibition of OAT1P1B3. The experimental conditions for this experiment can be found in Example 41. Data points (triangles) represent the percent of control enzyme inhibition of cholecystokinin octapeptide transport mediated by OAT1P1B3, shown on the y-axis, at a particular concentration of Compound I, shown on the x-axis. [Figure 142] 1 is a plot showing Compound I inhibition of OCT1. The experimental conditions for this experiment can be found in Example 41. Data points (triangles) represent the percent of control enzyme inhibition of OCT1-mediated sumatriptan transport, shown on the y-axis, at a particular concentration of Compound I, shown on the x-axis. [Figure 143] 1 is a plot showing Compound I inhibition of OCT2. The experimental conditions for this experiment can be found in Example 41. Data points (triangles) represent the percent of control enzyme inhibition of OCT2-mediated metformin transport, shown on the y-axis, at a particular concentration of Compound I, shown on the x-axis. [Figure 144] 1 is a plot showing the phototoxicity of Compound I in Balb-c3T3 mice. The experimental conditions for this experiment can be found in Example 42. Cell viability was measured as the percent of viable cells on the y-axis for different concentrations of Compound I (μg / mL) shown on the x-axis in the dark (filled circles) and light (open squares). [Figure 145]

[0023] Figure 1 shows images of culture plates taken during a crystal violet colony assay, demonstrating that Compound I extends the time to CDK4 / 6 inhibitor resistance in ER+ breast cancer. The experimental conditions for this experiment can be found in Example 43. From week 3 to week 8, T47D 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. [Figure 146]Figures 146A-146H show that Compound I reduces Rb phosphorylation and cyclin A2 levels in tumors and induces tumor regression and stasis in CCNE1-amplified animal preclinical cancer models of the ovary and stomach. The experimental conditions for these experiments can be found in Example 44. Figure 146A is a plot showing the cell line-derived tumor xenograft (CDX) OVCAR3 ovarian mouse preclinical model treated with vehicle (circles), or Compound I at 200 mg / kg once daily (QD) (squares) or 100 mg / kg twice daily (BID) (triangles). Tumor volume (mm3) is displayed on the y-axis, and days of study are displayed 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. Body weight loss did not exceed 5% at any time point. Figure 146B is a plot showing the patient-derived tumor xenograft (PDX) OV5398 ovarian mouse preclinical model treated with vehicle (circles) or Compound I at 200 mg / kg once daily (QD) (triangles) or 100 mg / kg twice daily (BID) (diamonds). Tumor volume (mm) is displayed on the y-axis, and the number of days on the study is displayed on the x-axis. Mice were treated for 56 days and showed tumor regression in both treatment groups. n=10, body weight loss did not exceed 5% at any time point. Figure 146C is a plot showing 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). Tumor volume (mm) is displayed on the y-axis, and the number of days on the x-axis. Mice were treated for 56 days and showed tumor stasis with 100 BID treatment. n=8, weight loss did not exceed 5% at any time point. Figure 146D is a plot showing a patient-derived tumor xenograft (PDX) GA0114 gastric mouse preclinical model treated with vehicle (circles) or 100 mg / kg Compound I twice daily (BID) (triangles). Tumor volume (mm3) is displayed on the y-axis and study days are displayed on the x-axis. Mice were treated for 35 days and showed 95% TGI with 100 BID treatment. N=8, weight loss did not exceed 5% at any time point.Figure 146E is a 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 or 24 hours after the final dose of control or Compound I. Figure 146F is a Western blot showing the levels of retinoblastoma protein (Rb), markers of phosphorylated Rb protein (pRb 807 / 811, pRb T821), and cyclin A2 (CCNA2) in OV5398 tumors extracted from the patient-derived tumor xenograft (PDX) OV5398 ovarian mouse model 2 or 24 hours after the final dose of control or Compound I. Figure 146G is a plot showing relative thymidine kinase (TK) activity levels calculated by ELISA. TK activity is plotted on the y-axis relative to vehicle control or GA0103 PDX model mice receiving 100 mpk BID of Compound I. Figure 146H is a plot showing relative TK activity levels calculated by ELISA. TK activity levels are plotted on the y-axis relative to vehicle control or GA0114 PDX model mice receiving 100 mpk BID of Compound I. [Figure 147]Figures 147A-L show that Compound I in combination with a CDK4 / 6 inhibitor (CDK4 / 6i) restores sensitivity in cell lines resistant to CDK4 / 6i and / or anti-estrogen therapy. The experimental conditions for these experiments can be found in Example 45. Figure 147A is a bar graph showing that multiple cell lines resistant to CDK4 / 6 inhibitor and / or estrogen therapy are sensitive to the combination of Compound I and a CDK4 / 6 inhibitor. The bar graph shows cell proliferation IC50 values in nanomolar (nM) on the y-axis and different treatment-resistant daughter MCF7 cells or T47D luminal breast cancer cells on the x-axis. PAR: non-4 / 6i-resistant parental cell line; LYR: abemaciclib-resistant cell line; FR: fulvestrant-resistant cell line; LYFR: abemaciclib and fulvestrant-resistant cell line; PAR+LY: parental cell line treated with 500 nM abemaciclib; PDR: palbociclib-resistant cell line. Figure 147B is a set of line graphs showing the fold change in cell number of the breast cancer model T47D 2xDT 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). Parental cell lines (PAR+LY) previously treated with 500 nM abemaciclib were treated with abemaciclib in combination with Compound I (diamonds). Abemaciclib-resistant (LYR) cells were treated with abemaciclib in combination with Compound I (squares). Fulvestrant-resistant (FR) cells were treated with fulvestrant in combination with Compound I (upward-pointing triangles). Abemaciclib- and fulvestrant-resistant (LYFR) cells were treated with abemaciclib in combination with fulvestrant and Compound I (inverted triangles). Figure 147C is a set of line graphs showing the fold change in cell number of the breast cancer model MCF7-M 2xDT 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). Parental cell lines (PAR+LY) previously treated with 500 nM abemaciclib were treated with abemaciclib in combination with Compound I (diamonds). Abemaciclib-resistant (LYR) cells were treated with abemaciclib in combination with Compound I (squares). Fulvestrant-resistant (FR) cells were treated with fulvestrant in combination with Compound I (upward-pointing triangles).Abemaciclib- and fulvestrant-resistant (LYFR) cells were treated with abemaciclib in combination with fulvestrant and Compound I (inverted triangles). Figure 147D is a bar graph showing that T47D cells resistant to abemaciclib arrest in G1 when combined with Compound I. The bar graph shows the percentage of cells in different cell phases on the y-axis relative to the different treatment-resistant daughter T47D cells shown on the x-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 147E is a flow cytometry plot quantifying the percentage of non-resistant parental (PAR) cells in S, G1, or G2M phase after treatment with DMSO control. FITC quantification: BrdU staining intensity is displayed on the y-axis and PI-A staining intensity is displayed on the x-axis. Figure 147F is a flow cytometry plot quantifying the percentage of non-resistant parental (PAR) cells in S, G1, or G2M phase after treatment with abemaciclib. FITC quantification: BrdU staining intensity is displayed on the y-axis and PI-A staining intensity is displayed on the x-axis. Figure 147G is a flow cytometry plot quantifying the percentage of abemaciclib-resistant (LYR) cells in S, G1, or G2M phase after treatment with abemaciclib. FITC quantification: BrdU staining intensity is displayed on the y-axis and PI-A staining intensity is displayed on the x-axis. Figure 147H is a flow cytometry plot quantifying the percentage of abemaciclib- and fulvestrant-resistant (LYFR) cells in S, G1, or G2M phase after treatment with abemaciclib and fulvestrant. FITC quantification: BrdU staining intensity is displayed on the y-axis and PI-A staining intensity is displayed on the x-axis. Figure 147I is a flow cytometry plot quantifying the percentage of abemaciclib-resistant (LYR) cells in S, G1, or G2M phase after treatment with abemaciclib in combination with Compound I. FITC quantification: BrdU staining intensity is displayed on the y-axis and PI-A staining intensity is displayed on the x-axis.Figure 147J is a flow cytometry plot quantifying the percentage of abemaciclib- and fulvestrant-resistant (LYFR) cells in S, G1, or G2M phase after treatment with abemaciclib in combination with fulvestrant and Compound I. FITC quantification: BrdU staining intensity is displayed on the y-axis, and PI-A staining intensity is displayed on the x-axis. Figure 147K is a Western blot showing that Compound I in combination with CDK4 / 6i prevents Rb phosphorylation in treatment-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 either DMSO or abemaciclib and Compound I alone or in combination. Parental: non-4 / 6i-resistant parental line; LYR: abemaciclib-resistant cell line; FR: fulvestrant-resistant cell line; LYFR: abemaciclib and fulvestrant-resistant cell line. Figure 147L is a Western blot showing the levels of phosphorylated retinoblastoma protein (pRb) and vinculin loading control in treatment-resistant cells. Treatment-resistant cells were treated with DMSO, abemaciclib, fulvestrant, and / or Compound I. 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; +: drug treatment; -: no drug treatment. [Figure 148]Figures 148A-148F show beta-galactosidase staining of treatment-resistant cells treated with abemaciclib, fulvestrant, and / or Compound I. The experimental conditions for these experiments can be found in Example 45. Figure 148A is a photomicrograph showing beta-galactosidase staining of abemaciclib-resistant (LYR) cells treated with abemaciclib. Figure 148B is a photomicrograph showing beta-galactosidase staining of abemaciclib-resistant (LYR) cells treated with a combination of abemaciclib and Compound I. Figure 148C is a photomicrograph showing beta-galactosidase staining of abemaciclib and fulvestrant-resistant (LYFR) cells treated with a combination of abemaciclib and fulvestrant. Figure 148D is a photomicrograph showing beta-galactosidase staining of abemaciclib and fulvestrant-resistant (LYFR) cells treated with a combination of abemaciclib, fulvestrant, and Compound I. Figure 148E is a plot showing beta-galactosidase activity in abemaciclib-resistant (LYR) cells. The y-axis shows quantification of the ratio of beta-galactosidase stained area to cell area in different treatment groups, including abemaciclib + DMSO or abemaciclib + Compound I, as shown on the x-axis. Figure 148F is a plot showing beta-galactosidase activity in abemaciclib and fulvestrant-resistant (LYFR) cells. The y-axis shows quantification of the ratio of beta-galactosidase stained area to cell area in different treatment groups, including abemaciclib + fulvestrant + DMSO or abemaciclib + fulvestrant + Compound I, as shown on the x-axis. [Figure 149]Figure 1 is a plot showing the fold change in tumor volume in HER2-overexpressing mice (MMTV-rtTA / tetO-HER2) pretreated with the CDK4 / 6 inhibitor abemaciclib until resistance to treatment was observed. The experimental conditions for this experiment are found in Example 45. Mice were randomized and then administered vehicle control (squares), 50 mg / kg Compound I twice daily (BID) (inverted triangles), 50 mg / kg abemaciclib twice daily (BID) (upward-pointing triangles), or a combination of abemaciclib and Compound I (diamonds) at the doses and frequencies listed above. The fold change in tumor volume is displayed on the y-axis, and the number of days of treatment is displayed on the x-axis. *Compound I was initially dosed at 75 mg / kg BID and was tapered on day 9. [Figure 150] Figures 150A-150C show that estrogen receptor-positive (ER+) breast cancer model T47D cells are sensitive to combination treatment including administration of both Compound I and fulvestrant. The experimental conditions for these experiments can be found in Example 46. Figure 150A shows images of culture plates containing T47D human breast cancer cell colonies under Compound I and / or fulvestrant treatment conditions relative to vehicle control at weeks 2 and 3. Figure 150B shows a bar graph on the y-axis depicting the average colony size for the different treatment conditions compared to the control at weeks 2 and 3, as shown on the x-axis. Figure 150C shows a bar graph on the y-axis depicting the percent colony area for the different treatment conditions compared to the control at weeks 2 and 3, as shown on the x-axis. [Figure 151]This figure shows the potent and selective CDK2 inhibitor compound I, which demonstrates robust anticancer activity in CCNE1-amplified and CDK4 / 6 inhibitor-resistant cancers. Cyclins E1 (CCNE1) and E2 (CCNE2) are key cell cycle regulators that bind to CDK2 and phosphorylate retinoblastoma (Rb), driving cancer cell proliferation through the G1 to S phase transition of the cell cycle. Dysregulation of CDK2 activity occurs frequently in various human cancers, and amplification / overexpression of CCNE1 and CCNE2 is the most frequent mechanism of dysregulation of CDK2 activity and CDK4 / 6 inhibitor resistance. Compound I is a selective and potent CDK2 inhibitor that may provide clinical benefit in patients with CDK2 / cyclin E-driven cancers and delay resistance to conventional therapies. In CCNE1-amplified human ovarian and gastric cancer cell lines, compound I potently inhibits retinoblastoma (Rb) phosphorylation, induces G1 cell cycle arrest, and inhibits cell proliferation. Compound I also exhibits potent antiproliferative activity in long-term cultured luminal breast cancer cell lines that develop drug resistance in the presence of CDK4 / 6 inhibitors. In CCNE1-amplified models of breast, ovarian, and gastric cancer, compound I inhibits Rb phosphorylation and induces tumor regression and long-term tumor stasis. DETAILED DESCRIPTION OF THE INVENTION

[0038] It has been surprisingly and unexpectedly discovered that compound I, or a pharmaceutically acceptable salt thereof, or a morphic form thereof, e.g., Pattern 1, described herein, is particularly effective in treating cancers that amplify or overexpress cyclin E and are resistant to CDK4 / 6 inhibitors due to either acquired or intrinsic resistance (e.g., SCLC) and / or are resistant to endocrine therapy, e.g., estrogen receptor degraders. Compound I 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. Non-limiting examples of favorable properties exhibited by Compound I include selective inhibition of CDK2, inhibition of CDK2 across multiple cyclin complex partners, significantly longer residence time when complexed with CDK2, a robust safety profile when administered to healthy, non-cancerous cells, synergy with chemotherapeutic agents to enhance antitumor efficacy, antitumor efficacy in CDK4 / 6 inhibitor-resistant cells, antitumor efficacy in endocrine inhibitor-resistant cells, antitumor efficacy in cells with amplified cyclin E activation and / or expression, altered expression of cell cycle-related proteins, induction of a targeted DNA damage response in neoplastic cells, sustained tumor suppression, and / or improved overall survival. The altered steady-state levels of proteins involved in the cell cycle indicate that administration of Compound I leads to modulation of gene expression, resulting in a tumor microenvironment favorable for tumor resensitization to other therapeutic agents, including, but not limited to, CDK4 / 6 inhibitors, endocrine therapies such as SERDs, chemotherapeutic agents, immune checkpoint inhibitors, or combinations thereof. This improvement represents a significant advance in the state of the art in cancer treatment.

[0039] It is well known that host cells begin to circumvent CDK4 / 6 inhibition by activating and / or upregulating other cyclins and / or CDKs to again promote uncontrolled cell division. Of the CDK4 / 6 inhibitor trials that led to FDA approval, at least 33% of patients developed recurrent disease within just two years of CDK4 / 6 inhibitor treatment. In the PALOMA-2 trial, more than 70% of subjects receiving palbociclib in combination with letrozole for the treatment of advanced breast cancer experienced disease progression within three years of initiating initial treatment (Finn et al. Lancet Oncol. 16:25-35(2016)).

[0040] The proportion of patients with advanced ER+ breast cancer with deleted or mutated retinoblastoma (Rb) genes is extremely rare (3.9%) (Ciriello et al. Cell. 163:506-19(2015)), suggesting that an intact CDK / Rb axis is required for patients to respond to CDK4 / 6 inhibition. Indeed, patients with advanced ER+ breast cancer are selected for CDK4 / 6 inhibitor treatment based on their cancer's expression of Rb. Studies in preclinical models have demonstrated that low or no 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 treated with palbociclib, two non-responding samples lacked Rb expression (Dean et al. Cell Cycle. 11:2756-61(2012)). Similar studies on pancreatic and glioblastoma cancer models demonstrate similar results, with the efficacy of CDK4 / 6 inhibition being related to an intact CDK / Rb axis (Michaud et al. Canc Res. 70:3228-38(2010); Chou et al. Gut. 67(12):2142-55(2017)).

[0041] CDK2 plays a key role in promoting the G1 / S transition and S-phase progression. In complex with cyclin E, CDK2 phosphorylates retinoblastoma pocket protein family members (p107, p130, and pRb), leading to derepression of E2F transcription factors, expression of G1 / S transition-related genes, and progression from G1 to S phase. This allows activation of CDK2 / cyclin A, which phosphorylates endogenous substrates that enable DNA synthesis, replication, and centrosome duplication. Another important adaptation for cancer cell development is the activation or overexpression of cyclin E (CCNE1 or CCNE2). Increased CCNE1 / 2 levels or activity abolishes 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)). Dysregulation of CDK2 activity typically occurs through amplification of CCNE1 (the gene encoding the cyclin E1 protein) and / or overexpression of cyclin E1, and mutations that inactivate endogenous CDK2 inhibitors (e.g., p27), respectively. In certain embodiments, Compound I is used to treat some cancers with increased CCNE1 / 2 levels or activity.

[0042] I. Terminology Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. Although the present invention can be practiced using methods and materials similar or equivalent to those described herein, suitable methods and materials are described below. All publications, patent applications, patents, and other references mentioned herein are incorporated by reference in their entirety. In the case of conflict, the present specification, including definitions, will control. Furthermore, the materials, methods, and examples are illustrative only and not intended to be limiting.

[0043] All references cited herein are incorporated by reference in their entirety.

[0044] The terms "a" and "an" do not denote a limitation of quantity, but rather denote the presence of at least one of the referenced items. The term "or" means "and / or." The recitation of ranges of values, unless otherwise stated herein, is merely intended to serve as a shorthand method of referring individually to each separate value falling within the range, and each separate value is incorporated into the specification as if it were individually recited herein. The endpoints of all ranges are included within the range and are independently combinable. All methods described herein can be performed in any suitable order unless otherwise stated herein or clearly contradicted by context. The use of examples or illustrative language (e.g., "such as") is intended merely to better describe the invention and does not denote a limitation on the scope of the invention unless otherwise stated. Unless otherwise defined, technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs.

[0045] In certain embodiments, the term "about" means ±10%.

[0046] A "patient" or "subject" or "participant" to be treated is typically a human patient, unless otherwise specified. In alternative embodiments, the methods described herein can be used to treat or test mammals such as those used in preclinical trials, including, but not limited to, mice, rats, monkeys, dogs, pigs, and rabbits, as well as other similarly responsive animals such as domestic pigs and hogs, ruminants, horses, poultry, felines, cattle, mice, dogs, and the like.

[0047] As used herein, "effective amount" means an amount that provides a therapeutic benefit.

[0048] "Treating" a disease, as that term is used herein, means reducing the frequency or severity of at least one sign or symptom of a disease or disorder experienced by a patient (i.e., palliative treatment), or reducing the cause or effect of a disease, disorder, or side effect experienced by a patient (i.e., disease-modifying treatment), as a result of administration of a therapeutic agent.

[0049] As used herein, the term "treatment-emergent adverse event" means an adverse event that occurs or worsens after initial dosing or during treatment.

[0050] As used herein, the term "overall survival (OS)" means the time from first dose to death from any cause.

[0051] As used herein, the term "overall response rate (ORR)" means a best confirmed overall response of CR or PR as determined by RECIST v1.1 criteria.

[0052] As used herein, the term "disease control rate (DCR)" means the best confirmed overall response of CR, PR, or SD as determined by RECIST v1.1 criteria.

[0053] As used herein, the term "progression-free survival (PFS)" means the time from first dose to first recorded disease progression or death from any cause, whichever occurs first.

[0054] As used herein, the term "duration of response (DOR)" means the time from the first documented best overall response of confirmed CR or PR to the first documented disease progression or death from any cause, whichever occurs first.

[0055] As used herein, the term "time to disease progression (TTP)" means the time from first dose to first documented disease progression.

[0056] As used herein, the term "MTD" refers to the maximum tolerated dose of Compound I.

[0057] As used herein, the term "AUC" refers to the area under the Compound I concentration-time curve.

[0058] As used herein, "AUC 0-t The term " refers to the AUC up to the time of the last measurable concentration of Compound I.

[0059] As used herein, "AUC 0-∞ The term " refers to the AUC of Compound I to time infinity.

[0060] As used herein, the term "Cl" refers to the clearance of Compound I.

[0061] As used herein, "C max The term " refers to the maximum concentration of Compound I.

[0062] As used herein, "IC 50 The term "" refers to the half maximal inhibitory concentration of compound I. The IC, a measure of drug potency, 50 indicates the concentration of compound I that inhibits a particular biological process by half compared to a control compound.

[0063] As used herein, the term "nH" refers to the IC between the minimum and maximum plateaus. 50 Refers to the Hill slope coefficient, which represents the slope of the sigmoid curve fitted to the data.

[0064] As used herein, "t 1 / 2 " refers to the half-life of Compound I.

[0065] As used herein, "t 1 / 2α " refers to the initial elimination half-life of Compound I.

[0066] As used herein, "t 1 / 2β " refers to the terminal half-life of Compound I.

[0067] As used herein, "t max The term "C" refers to the C max It refers to the time it takes to reach

[0068] As used herein, "t last The term "time to reach the last measurable concentration of Compound I" refers to the time to reach the last measurable concentration of Compound I.

[0069] As used herein, "v d " refers to the volume of distribution of Compound I.

[0070] As used herein, "intrinsic resistance," also referred to as primary resistance, refers to a condition in which a cancer does not respond or does not adequately respond to the inhibitory effects of an initial anti-cancer treatment, for example, but not limited to, a CDK4 / 6 inhibitor treatment or an endocrine therapy treatment. In some embodiments of the treatment methods described herein, the cancer being treated exhibits intrinsic resistance to a CDK4 / 6 inhibitor. Mutations and conditions associated with 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, deletion, or absence (Rb null) of the retinoblastoma tumor suppressor protein (Rb); 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 may be characterized by reduced expression of retinoblastoma tumor suppressor protein or retinoblastoma family member protein(s) (such as, but not limited to, p107 and p130). In certain embodiments, tumors or cancers that are intrinsically resistant to inhibition of a selective CDK4 / 6 inhibitor are tumors or cancers whose cell population as a whole does not undergo substantial G1 cell cycle arrest when exposed to a selective CDK4 / 6 inhibitor. In certain embodiments, tumors or cancers that are intrinsically resistant to inhibition of a CDK4 / 6 inhibitor are tumors or cancers having a cell population in which less than 25%, 20%, 15%, 10%, or 5% of the cells undergo G1 cell cycle arrest when exposed to a selective CDK4 / 6 inhibitor. In some alternative embodiments of the treatment methods described herein, the cancer being treated is intrinsically resistant to endocrine therapy, e.g., 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 the bioactive agent or other anti-cancer therapy.

[0071] As used herein, "acquired resistance" refers to a condition in which a cancer that was initially sensitive or sensitive to the inhibitory effects of an anticancer therapy becomes unresponsive or hyporesponsive over time to the effects of administering that anticancer therapy. In some embodiments of the methods described herein, the cancer being treated has acquired resistance to a selective CDK4 / 6 inhibitor. Without wishing to be bound by any theory, acquired resistance to a CDK4 / 6 inhibitor is believed to occur due to one or more additional mutations or genetic alterations in bypass signaling that develop after initiation of a CDK4 / 6 inhibitor treatment regimen. For example, a non-limiting exemplary cause of acquired resistance to a CDK4 / 6 inhibitor can be the result of the development of one or more genetic abnormalities associated with "intrinsic resistance." Further, other non-limiting exemplary causes of acquired resistance to CDK4 / 6 inhibitors 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 deficiency; HDAC activation; FGFR pathway activation; PI3K / AKT / mTOR pathway activation; loss of ER or PR expression; increased AP-1 transcriptional activity; epithelial-mesenchymal transition; Smad3 suppression; autophagy activation; Rb1 deficiency or inactivating RB1 mutation; or combinations thereof. A review of CDK4 / 6 resistance mechanisms can be found, for example, in 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 inhibition by a selective CDK4 / 6 inhibitor is a tumor or cancer whose cell population as a whole no longer undergoes substantial G1 cell cycle arrest upon exposure to a selective CDK4 / 6 inhibitor, resulting in disease progression.In certain embodiments, a tumor or cancer that has acquired resistance to inhibition of a CDK4 / 6 inhibitor is a tumor or cancer having a cell population in which less than 50%, 40%, 30%, 20%, 15%, 10%, or 5% of its cells undergo G1 cell cycle arrest when exposed to a selective CDK4 / 6 inhibitor, leading to disease progression. In some embodiments, the cancer has progressed after a prior treatment regimen including administration of a CDK4 / 6 inhibitor. In some alternative embodiments of the treatment methods described herein, the cancer being treated has acquired resistance to estrogen inhibitor therapy, such as, for example, a SERD, including, but not limited to, fulvestrant or elacestrant. In some alternative embodiments of the treatment methods described herein, the cancer being treated has acquired resistance to a bioactive agent or other anti-cancer therapy.

[0072] II. Treatment method In certain aspects, provided herein are methods 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 I, as described herein, or a pharmaceutically acceptable salt, deuterated derivative, or morphic 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.

[0073] In another aspect, 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 morphic form of Compound I, a pharmaceutical composition comprising the morphic form of Compound I, or a pharmaceutical composition prepared from the morphic form of Compound I, or a pharmaceutically acceptable salt, deuterated derivative thereof, as described herein. Non-limiting examples of disorders mediated by CDK2 include tumors, cancers, disorders associated with abnormal cell proliferation, inflammatory disorders, immune disorders, and autoimmune disorders.

[0074] In another aspect, provided herein are methods for treating a subject with a CDK4 / 6 inhibitor-resistant cancer, comprising administering to the subject an effective amount of Compound I or a pharmaceutically acceptable salt or morphic form thereof as described herein, and administering to the subject an effective amount of a CDK4 / 6 inhibitor. In certain embodiments, the CDK4 / 6 inhibitor-resistant cancer has intrinsic resistance 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 has progressed after a prior regimen comprising a CDK4 / 6 inhibitor. In some embodiments, the CDK4 / 6 inhibitor of the prior regimen is selected from palbociclib, ribociclib, abemaciclib, trilaciclib, relociclib, SHR6390 (dalpiciclib), or a combination thereof. In some embodiments, the CDK4 / 6 inhibitor of the preceding regimen is selected from BPI-16350, narazaciclib (ON-123300), FLX-925 (AMG-925), UCT-03-008, GLR2007, vilociclib (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.

[0075] In certain embodiments, the method of treatment comprises administering a pharmaceutical composition prepared from a morphic form described herein. In other embodiments, the method of treatment comprises administering a morphic form described herein.

[0076] In certain aspects, disclosed herein are methods for treating a subject with CDK4 / 6 inhibitor-resistant small cell lung cancer (SCLC), comprising administering to the subject an effective amount of Compound I, or a pharmaceutically acceptable salt or morphic form thereof, as described herein. 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, trilaciclib, relociclib, and SHR6390 (dalpiciclib). In some embodiments, the CDK4 / 6 inhibitor is selected from BPI-16350, nalazaciclib (ON-123300), FLX-925 (AMG-925), UCT-03-008, GLR2007, virociclib (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 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, the chemotherapeutic agent is selected from a protein synthesis inhibitor, a DNA damaging chemotherapeutic agent, an alkylating agent, a topoisomerase inhibitor, an RNA synthesis inhibitor, a DNA complex binder, a thiolate alkylating agent, a guanine alkylating agent, a tubulin binder, a DNA polymerase inhibitor, an anti-cancer enzyme, a RAC1 inhibitor, a thymidylate synthase inhibitor, an oxazophosphorine compound, an integrin inhibitor, an antifolate, an antifolate, or a combination thereof.

[0077] In certain aspects, disclosed herein are methods of treating a subject having abnormal cell proliferation, 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 comprises an abnormal cell proliferation disorder of cyclin E amplification or overexpression; and, if the subject is determined to have an abnormal cell proliferation disorder of cyclin E amplification or overexpression, administering to the subject an effective amount of Compound I or a pharmaceutically acceptable salt thereof. In certain embodiments, cyclin E1 (CCNE1) and / or cyclin E2 (CCNE2) are overexpressed and / or activated by at least 1.5-fold, at least 2.0-fold, at least 2.5-fold, at least 3.0-fold, at least 3.5-fold, at least 4.0-fold, at least 4.5-fold, at least 5.0-fold, or more than 5.0-fold in a sample from a treated subject compared to a 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, trilaciclib, relociclib, or SHR6390 (dalpiciclib). In some embodiments, the additional CDK4 / 6 inhibitor is selected from BPI-16350, nalazaciclib (ON-123300), FLX-925 (AMG-925), UCT-03-008, GLR2007, vilociclib (XZP-3287), LY5219, PF-07220060, or ON-123300. 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 One™ CDx, Foundation One™ Liquid CDx, Tempus xT (solid tumors), Tempus xF (liquid biopsy), Caris™ 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.

[0078] In a primary embodiment, the cancer treated by Compound I or a pharmaceutically acceptable salt thereof, or a morphic form described herein is a cyclin E amplified or overexpressed cancer or small cell lung cancer.

[0079] In some embodiments, the abnormal cell proliferation disorder in which Cyclin E is amplified or aberrantly expressed that is treated according to the methods detailed above is selected from the group consisting of uterine cancer, uterine carcinosarcoma (UCS), uterine 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 carcinoma (ESCA), adrenal gland cancer, and the like. The cancer is selected from cortical 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), cervical adenocarcinoma, mesothelioma (MESO), head and neck squamous cell carcinoma (HSNC), colon cancer, colon adenocarcinoma (COAD), skin cancer, melanoma, cutaneous melanoma (SKCM), glioblastoma multiforme (GBM), kidney cancer, and chromophobe renal cell carcinoma (KICH). In some embodiments, the cyclin E amplified or overexpressed cancer is retinoblastoma (Rb) protein positive. In some embodiments, the cyclin E amplified or overexpressed cancer is resistant to a CDK4 / 6 inhibitor. In certain embodiments, the CDK4 / 6 inhibitor-resistant cancer is intrinsically resistant to a CDK4 / 6 inhibitor. In certain embodiments, the CDK4 / 6 inhibitor-resistant cancer has acquired resistance to the CDK4 / 6 inhibitor. In some embodiments, the cyclin E amplified or overexpressing cancer is endocrine therapy resistant. In certain embodiments, the endocrine therapy resistant cancer is intrinsically resistant to endocrine therapy. In certain embodiments, the endocrine therapy resistant cancer has acquired resistance to endocrine therapy. In some embodiments, the endocrine therapy comprises an estrogen inhibitor as described herein. In certain embodiments, the cancer is advanced and / or metastatic cancer. In certain embodiments, the cancer is unresectable. In certain embodiments, the cancer is advanced unresectable. In certain embodiments, the cancer is platinum-refractory and / or platinum-resistant. In certain embodiments, the cancer has progressed after a prior standard treatment regimen. In certain embodiments, the cancer has progressed after a prior standard systemic therapy. In certain embodiments, the cancer has progressed after a prior systemic anti-cancer therapy.In certain embodiments, the cancer has progressed after a prior regimen including a platinum analog. In certain embodiments, the cancer has progressed after a prior regimen including a CDK4 / 6 inhibitor. In certain embodiments, the cancer has progressed after a prior regimen including an estrogen inhibitor.

[0080] In certain embodiments, the methods described herein are useful for treating cyclin E overexpressing and / or amplified ovarian cancer, wherein the ovarian cancer has CCNE1 amplification. In certain embodiments, the ovarian cancer is advanced and / or metastatic. In certain embodiments, the ovarian cancer is advanced unresectable. In certain embodiments, the ovarian cancer is platinum-refractory and / or platinum-resistant. In certain embodiments, the ovarian cancer has progressed after a prior standard treatment regimen. In certain embodiments, the ovarian cancer has progressed after a prior standard systemic therapy. In certain embodiments, the ovarian cancer has progressed after a prior systemic anti-cancer therapy. In certain embodiments, the ovarian cancer has progressed after a prior regimen comprising a platinum analog. In certain embodiments, the ovarian cancer has progressed after a prior regimen comprising a CDK4 / 6 inhibitor. In certain embodiments, the ovarian cancer has progressed after a prior regimen comprising an estrogen inhibitor.

[0081] 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. In some embodiments, the cyclin E amplified or overexpressing cancer is uterine cancer. In some embodiments, the cyclin E amplified or overexpressing cancer is ovarian cancer. In some embodiments, the cyclin E amplified or overexpressing cancer is breast cancer. In certain embodiments, the method further comprises 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 full estrogen receptor degrader, a full 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, the SERD comprises fulvestrant. In some embodiments, the SERD comprises elacestrant (RAD1901). In some embodiments, the cyclin E amplified or overexpressing cancer is prostate cancer. In some embodiments, the cyclin E amplified or overexpressing cancer is bladder cancer. In some embodiments, the cyclin E amplified or overexpressing cancer is sarcoma.

[0082] Compound I, or a pharmaceutically acceptable salt or morphic form thereof, as described herein, when administered in an effective amount to a subject, including a human, is effective in treating tumors, cancers (including solid, non-solid, diffuse, and hematological cancers), abnormal cell proliferation, immune disorders, inflammatory disorders, hematological disorders, myeloproliferative or lymphoproliferative disorders such as B-cell or T-cell lymphomas, multiple myeloma, breast cancer, prostate cancer, AML, ALL, CLL, myelodysplastic syndromes (MDS), mesothelioma, renal cell carcinoma (RCC), cholangiocarcinoma, lung cancer, pancreatic cancer, colon cancer, skin cancer, melanoma, Waldenstrom's disease, and the like. They are useful as therapeutic agents for treating Rehm's macroglobulinemia, 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; diseases of cardiac dysfunction, including hypercholesterolemia; infectious diseases, including viral and / or bacterial infections; inflammatory conditions, including asthma, chronic peptic ulcer, tuberculosis, rheumatoid arthritis, periodontitis, ulcerative colitis, or hepatitis.

[0083] In certain embodiments, compound I or a pharmaceutically acceptable salt or morphic form thereof described herein is used to treat cyclin E-overexpressing or amplified breast cancer. 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 HER2-overexpressing breast cancer. In certain embodiments, the breast cancer comprises HER2 gene amplification. In some embodiments, compound I or a pharmaceutically acceptable salt thereof is administered in combination with an antibody-drug conjugate (ADC). In some embodiments, Compound I, or a pharmaceutically acceptable salt thereof, is administered in combination with an ADC selected from ado-trastuzumab emtansine (KADCYLA™), trastuzumab deruxtecan (ENHERTU™), or sacituzumab govitecan (TRODELVY™).

[0084] In certain embodiments, compound I or its pharmaceutically acceptable salt or morphic form as described herein is used to treat cyclin E overexpression or amplification non-small cell lung cancer (NSCLC). In certain embodiments, the NSCLC has an EGFR mutation. In certain embodiments, the NSCLC has an EGFR mutation and has failed an EGFR inhibitor (e.g., second-line therapy). In certain embodiments, the NSCLC has failed an ALK inhibitor (e.g., second-line therapy). In certain embodiments, the NSCLC has a KRAS mutation.

[0085] In certain embodiments, Compound I or a pharmaceutically acceptable salt or morphic form thereof described herein is used to treat cyclin E-overexpressing or -amplified prostate cancer. In certain embodiments, the prostate cancer is castration-resistant. In certain embodiments, prior chemotherapy has already failed (e.g., second-line therapy).

[0086] In certain embodiments, compound I or a pharmaceutically acceptable salt or morphic form thereof described herein is used to treat cyclin E-overexpressing or -amplified lymphoma. 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 chemotherapy has already failed (e.g., second-line therapy).

[0087] In certain embodiments, Compound I or a pharmaceutically acceptable salt or morphic form thereof described herein is used to treat cyclin E-overexpressing or -amplified melanoma. In certain embodiments, the melanoma has a BRAF mutation.

[0088] In certain embodiments, Compound I or its pharmaceutically acceptable salt or morphic form described herein is used to treat cyclin E overexpression or amplification RAS mutant cancer. 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 cholangiocarcinoma.

[0089] In certain embodiments, Compound I or a pharmaceutically acceptable salt or morphic form thereof described herein is used to treat cyclin E-overexpressing or -amplified gastrointestinal stromal tumors (GISTs), in certain embodiments, where treatment with imatinib or sunitinib has already failed (e.g., second-line therapy).

[0090] Exemplary proliferative disorders treated by the detailed methods, compounds, and morphic forms described herein include, but are not limited to, benign proliferations, neoplasms, tumors, cancers (Rb positive or Rb negative), autoimmune disorders, inflammatory disorders, graft-versus-host rejection, and fibrotic disorders where the disorder is mediated by overexpressed or amplified cyclin E.

[0091] Non-limiting examples of cancers that can be treated according to the detailed methods, compounds, and morphic forms described herein include acoustic neuroma, adenocarcinoma, adrenal carcinoma, anal carcinoma, angiosarcoma (e.g., lymphangiosarcoma, lymphangioendotheliosarcoma, hemangiosacroma), appendix cancer, benign monoclonal gammopathy, biliary tract cancer (e.g., cholangiocarcinoma), bladder cancer, breast cancer (e.g., adenocarcinoma of the breast, papillary carcinoma of the breast, mammary carcinoma, ovarian ... cancer), medullary carcinoma of the breast), brain cancer (e.g., meningioma; glioma, e.g., astrocytoma, oligodendroglioma; medulloblastoma), bronchial carcinoma, carcinoid tumor, cervical cancer (e.g., cervical adenocarcinoma), choriocarcinoma, chordoma, craniopharyngioma, colorectal cancer (e.g., colon cancer, rectal cancer, colorectal adenocarcinoma), epithelial carcinoma, ependymoma, endotheliosarcoma (e.g., Kaposi's sarcoma, multiple idiopathic hemorrhagic sarcoma), endometrial cancer (e.g., uterine carcinoma, uterine sarcoma), esophageal cancer (e.g., esophageal adenocarcinoma, Barrett's adenocarcinoma), Ewing's sarcoma, eye cancer (e.g., intraocular melanoma, retinoblastoma), familial hypereosinophilia hypereosinophilia), gallbladder cancer, stomach cancer (e.g., gastric adenocarcinoma), gastrointestinal stromal tumor (GIST), head and neck cancer (e.g., head and neck squamous cell carcinoma), oral cancer (e.g., oral squamous cell carcinoma (OSCC), throat cancer (e.g., laryngeal cancer, pharyngeal cancer, nasopharyngeal cancer, oropharyngeal cancer)), hematopoietic cancer (e.g., acute lymphocytic leukemia (ALL) (e.g., B-cell ALL, T-cell ALL), also known as acute lymphoblastic leukemia or acute lymphocytic leukemia), 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 leukemias such as Hodgkin's lymphoma (HL) (e.g., B-cell HL, T-cell HL) and non-Hodgkin's lymphoma (NHL) (e.g., diffuse large cell lymphoma (DLCL) (e.g., B-cell NHL such as diffuse large B-cell lymphoma (DLBCL)), follicular lymphoma, chronic lymphocytic leukemia / small lymphocytic lymphoma (CLL / SLL), mantle cell lymphoma (MCL), marginal zone B-cell lymphoma (e.g., mucosa-associated lymphoid tissue (MALT) lymphoma,lymphomas such as nodal marginal zone B-cell lymphoma, splenic marginal zone B-cell lymphoma), primary mediastinal B-cell lymphoma, Burkitt's 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 precursor T-lymphoblastic lymphoma / leukemia, peripheral T-cell lymphomas (PTCL) (e.g., cutaneous T-cell lymphoma (CTCL) (e.g., mycosis fungoides, Sézary syndrome), angioimmunoblastic T-cell lymphoma T-cell NHL, such as leukemia / lymphoma, extranodal natural killer T-cell lymphoma, enteropathic T-cell lymphoma, subcutaneous panniculitis-like T-cell lymphoma, and anaplastic large cell lymphoma; mixed leukemia / lymphomas of one or more of the above; and multiple myeloma (MM), heavy chain diseases (e.g., alpha chain disease, gamma chain disease, and mu chain disease), hemangioblastoma, inflammatory myofibroblastic tumor, immunocytic amyloidosis, kidney cancer (e.g., nephroblastoma, also known as Wilms' tumor, renal cell carcinoma), liver cancer (e.g., hepatocellular carcinoma (HCC), malignant hepatoma), lung cancer (e.g., bronchogenic carcinoma, small cell lung cancer (SCLC), non-small cell lung cancer (NSCLC), pulmonary adenocarcinoma), leiomyosarcoma (LMS), mastocytosis (e.g., systemic mastocytosis), myelodysplastic syndrome (MDS), mesothelioma, myeloproliferative disorders (MPD) (e.g., polycythemia vera (PV), essential thrombocythemia (ET), idiopathic myeloid metaplasia (AMM), also known as myelofibrosis (MF), chronic idiopathic myelofibrosis, chronic myeloid leukemia (CML), chronic neutrophilic leukemia (CNL), hypereosinophilic syndrome (HES)), neuroblastoma, neurofibroma (e.g., neurofibromatosis (NF) type 1 or 2, schwannomatosis), neuroendocrine cancer (e.g., gastrointestinal pancreatic neuroendocrine tumor (GEP-NET), carcinoid tumor), osteosarcoma, ovarian cancer (e.g., cystadenocarcinoma, ovarian embryonal carcinoma, ovarian adenocarcinoma), papillary adenocarcinoma, pancreatic cancer (e.g., pancreatic adenocarcinoma, intraductal papillary mucinous neoplasm (IPMN), pancreatic islet cell tumor), penile cancer (e.g., Paget's disease of the penis and scrotum), pinealoma, primitive neuroectodermal tumor (PNT), prostate cancer (e.g., prostatic adenocarcinoma), rectal cancer, rhabdomyosarcoma, salivary gland cancer, skin cancer (e.g., squamous cell carcinoma (SCC), keratoacanthoma (KA), melanoma, basal cell carcinoma (BCC)), small intestine cancer (e.g., appendix cancer), soft tissue sarcoma (e.g., malignant fibrous histiocytoma (MFH), liposarcoma,These cancers include, but are not limited to, malignant peripheral nerve sheath tumors (MPNST), chondrosarcoma, fibrosarcoma, myxosarcoma, sebaceous gland carcinoma, sweat gland carcinoma, synovium, testicular cancer (e.g., seminoma, testicular embryonal carcinoma), thyroid cancer (e.g., papillary thyroid carcinoma, 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 null (Rb-). In some embodiments, the cancer is resistant to endocrine therapy. In some embodiments, the endocrine therapy includes an estrogen inhibitor.

[0092] In another embodiment, the methods, compounds, and morphic forms described herein are useful for treating myelodysplastic syndromes (MDS).

[0093] In certain embodiments, the methods, compounds, and morphic forms described herein are useful for treating hematopoietic cancer. In certain embodiments, the hematopoietic cancer is lymphoma. In certain embodiments, the hematopoietic cancer is leukemia. In certain embodiments, the leukemia is acute myeloid leukemia (AML).

[0094] In certain embodiments, the methods, compounds, and morphic forms described herein are useful for treating myeloproliferative neoplasms. In certain embodiments, the myeloproliferative neoplasm (MPN) is primary myelofibrosis (PMF).

[0095] In certain embodiments, the methods, compounds, and morphic forms described herein are useful for treating solid tumors. As used herein, a solid tumor refers to an abnormal mass of tissue that typically does not contain cysts or liquid areas. Various types of solid tumors are named after the type of cells that form them. Examples of solid tumor types include, but are not limited to, sarcomas, carcinomas, and lymphomas 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.

[0096] In certain embodiments, the condition treated with Compound I or a pharmaceutically acceptable salt thereof, or a morphic form thereof, as described herein, is a disorder associated with abnormal cell proliferation. Abnormal cell proliferation, particularly hyperproliferation, can result from a wide range of factors, including genetic mutation, infection, exposure to toxins, autoimmune disorders, and the induction of benign or malignant tumors.

[0097] The methods, compounds, and morphic forms described herein are useful for treating many skin disorders associated with cell hyperproliferation.For example, psoriasis is a benign human skin disease characterized by plaques generally covered with thickened scales.This disease is caused by increased proliferation of epidermal cells for unknown reasons.Chronic eczema is also associated with significant epidermal hyperproliferation.Other diseases caused by skin cell hyperproliferation include atopic dermatitis, lichen planus, warts, pemphigus vulgaris, actinic keratosis, basal cell carcinoma, and squamous cell carcinoma.

[0098] The methods, compounds, and morphic forms described herein are useful in the treatment of other hyperproliferative cell disorders, including blood vessel proliferation disorders, fibrotic disorders, autoimmune disorders, graft-versus-host rejection, tumors, and cancers.

[0099] The methods, compounds, and morphic forms described herein are useful for treating vascular proliferation disorders, including angiogenesis and vasculogenesis disorders. Smooth muscle cell proliferation during the development of plaques in vascular tissue leads to, for example, restenosis, retinopathy, and atherosclerosis. Both cell migration and cell proliferation play a role in the formation of atherosclerotic lesions.

[0100] The methods, compounds, and morphic forms described herein are useful for treating fibrotic disorders that are often caused by abnormal formation of extracellular matrix. Examples of fibrotic disorders include liver cirrhosis and mesangial proliferative cell disorders. Liver cirrhosis is characterized by an increase in extracellular matrix components, which leads to the formation of liver scars. Liver cirrhosis can lead to diseases such as cirrhosis of the liver. The increase in extracellular matrix that leads to liver scars can also be caused by viral infections such as hepatitis. Lipid cells appear to play an important role in liver cirrhosis.

[0101] The methods, compounds, and morphic forms described herein are useful for treating mesangial disorders caused by abnormal proliferation of mesangial cells, including a variety of human kidney diseases such as glomerulonephritis, diabetic nephropathy, malignant nephrosclerosis, thrombotic microangiopathy syndrome, graft rejection, and glomerulopathy.

[0102] The methods, compounds, and morphic forms described herein are useful for treating rheumatoid arthritis, a disease with a proliferative component that is generally considered an autoimmune disease associated with the activity of autoreactive T cells and thought to result from autoantibodies produced against collagen and IgE.

[0103] The methods, compounds, and morphic forms described herein are useful for treating other disorders that may involve a component of abnormal cell proliferation selected from the group consisting of Behcet's syndrome, acute respiratory distress syndrome (ARDS), ischemic heart disease, post-dialysis syndrome, leukemia, acquired immune deficiency syndrome, vasculitis, lipid histiocytosis, septic shock, and inflammation in general.

[0104] In certain embodiments, the methods, compounds, and morphic forms described herein are useful for treating conditions associated with an immune response.

[0105] For example, skin contact hypersensitivity and asthma are just two examples of immune responses that can 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 due to arthropod stings, Crohn's disease, aphthous ulcers, iritis, conjunctivitis, keratoconjunctivitis, ulcerative colitis, cutaneous lupus erythematosus, scleroderma, vaginitis, proctitis, and drug eruptions. These conditions may produce any one or more of the following symptoms or signs: itching, swelling, redness, blisters, crusting, ulceration, pain, scaling, cracking, hair loss, scarring, or exudation of fluid from the skin, eyes, or mucous membranes.

[0106] In atopic dermatitis and eczema, immune-mediated leukocyte infiltration into the skin (particularly infiltration of monocytes, lymphocytes, neutrophils, and eosinophils) generally plays an important role in the pathogenesis of these diseases. Chronic eczema is also associated with marked hyperproliferation of the epidermis. Immune-mediated leukocyte infiltration can also occur in sites other than the skin, such as the airways in asthma and the tear-producing glands of the eye in keratoconjunctivitis sicca.

[0107] In certain non-limiting embodiments, Compound I or a pharmaceutically acceptable salt or morphic form thereof described herein is used as an external agent to treat contact dermatitis, atopic dermatitis, eczematous dermatitis, psoriasis, Sjögren's syndrome, including keratoconjunctivitis sicca secondary to Sjögren's syndrome, alopecia areata, allergic reactions due to arthropod bites, Crohn's disease, aphthous ulcers, iritis, conjunctivitis, keratoconjunctivitis, ulcerative colitis, asthma, allergic asthma, cutaneous lupus erythematosus, scleroderma, vaginitis, proctitis, and drug rash. This novel method may also be useful for reducing skin infiltration by malignant leukocytes in diseases such as mycosis fungoides. These compounds can also be used to treat aqueous-deficient dry eye conditions (such as immune-mediated keratoconjunctivitis) in patients with such conditions by topically administering the compound to the eye.

[0108] Exemplary cancers that can be treated by the methods, compounds, and morphic forms of the present disclosure, alone or in combination with at least one additional anti-cancer agent, include squamous cell carcinoma, basal cell carcinoma, adenocarcinoma, hepatocellular carcinoma, and renal cell carcinoma, cancer of the bladder, intestine, breast, cervix, colon, esophagus, head, kidney, liver, lung, neck, ovary, pancreas, prostate, and stomach; leukemia; benign and malignant lymphomas, particularly Burkitt's lymphoma and non-Hodgkin's lymphoma; benign and malignant melanoma; myeloproliferative disorders; Ewing's sarcoma, hematopoietic Sarcomas, including ductosarcoma, Kaposi's sarcoma, liposarcoma, myosarcoma, peripheral neuroepithelioma, synovial sarcoma, glioma, astrocytoma, oligodendroglioma, ependymoma, glioblastoma, neuroblastoma, ganglioneuroma, ganglioglioma, medulloblastoma, pineal cell tumor, meningioma, meningeal sarcoma, neurofibroma, and Schwannoma; intestinal cancer, breast cancer, prostate cancer, cervical cancer, uterine cancer, lung cancer, ovarian cancer, testicular cancer, thyroid cancer, astrocytoma, esophageal cancer, pancreatic cancer, gastric cancer, liver cancer, colon cancer, melanoma; carcinosarcoma, Hodgkin's disease, Wilms' tumor, and teratocarcinoma. Additional cancers that can be treated using the disclosed compounds according to the present invention include, for example, acute granulocytic leukemia, acute lymphocytic leukemia (ALL), acute myeloid leukemia (AML), adenocarcinoma, adenosarcoma, adrenal gland carcinoma, adrenocortical carcinoma, anal carcinoma, anaplastic astrocytoma, angiosarcoma, appendix carcinoma, astrocytoma, basal cell carcinoma, B-cell lymphoma, bile duct carcinoma, 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 (two of estrogen, progesterone and HER-2 are negative), single negative (one of estrogen, progesterone and HER-2 is negative) (including HER2-positive 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 cancer, gastrointestinal stromal tumor (GIST), germ cell tumor, glioblastoma multiforme (GBM), glioma, hairy cell leukemia, head and neck cancer, hemangioendothelioma, Hodgkin lymphoma, Pharyngeal cancer, invasive ductal carcinoma (IDC), invasive lobular carcinoma (ILC), inflammatory breast cancer (IBC), intestinal cancer, intrahepatic cholangiocarcinoma, invasive / invasive breast cancer, islet cell carcinoma, jaw cancer, Kaposi's sarcoma, kidney cancer, laryngeal cancer, smooth Myosarcoma, 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, mesenchymous mesothelioma, metastatic breast cancer, metastatic melanoma, metastatic squamous cell neck cancer, mixed glioma, monodermal teratoma, mouth cancer cancer), mucinous carcinoma, mucosal melanoma, multiple myeloma, mycosis fungoides, myelodysplastic syndrome, nasal cavity cancer, nasopharyngeal cancer, cervical cancer, neuroblastoma, neuroendocrine tumor (NET), non-Hodgkin's lymphoma, non-small cell lung cancer (NSCLC), oat cell carcinoma, eye cancer, intraocular melanoma, oligodendroglioma, oral cancer, oral cavity cancer, oropharyngeal cancer, osteogenic sarcoma, osteosarcoma, ovarian cancer, epithelial ovarian cancer, ovarian germ cell tumor, ovarian progenitor Primary peritoneal cancer, ovarian sex cord-stromal tumor, Paget's disease, pancreatic cancer, papillary carcinoma, sinus cancer, parathyroid cancer, pelvic cancer, penile cancer, peripheral nerve cancer, peritoneal cancer, pharyngeal cancer, pheochromocytoma, pilocytic astrocytoma, pineal 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, bone sarcoma sarcoma), sarcoma, sinus cancer, skin cancer, small cell lung cancer (SCLC), small intestine cancer, spine cancer, spinal column cancer, spinal cord cancer, squamous cell carcinoma, gastric cancer, synovial sarcoma, T-cell lymphoma, testicular cancer, throat cancer, thymoma / thymic cancer, thyroid cancer, tongue cancer, tonsil cancer, transitional cell cancer, fallopian tube cancer, tubular cancer carcinoma), undiagnosed cancer, ureteral cancer, urethral cancer, uterine adenocarcinoma, uterine cancer, uterine sarcoma, vaginal cancer, vulvar cancer, T-cell acute lymphoblastic leukemia (T-ALL), T-cell 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, nodal 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 unclassifiable; diffuse red pulp small B-cell lymphoma; lymphoplasmacytic lymphoma; heavy chain diseases, e.g., alpha heavy chain disease, gamma heavy chain disease, and mu heavy chain disease; plasmacytic myeloma These include: diffuse large B-cell lymphoma, solitary plasmacytoma of bone; extraskeletal plasmacytoma; primary cutaneous follicle center lymphoma, T-cell / histiocytocyte-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-associated multicentric Castleman disease; unclassifiable B-cell lymphoma with features intermediate to diffuse large B-cell lymphoma or unclassifiable B-cell lymphoma with features intermediate between diffuse large B-cell lymphoma and classical Hodgkin lymphoma.

[0109] In another aspect, provided is a method for increasing BIM expression (e.g., BCLC2L11 expression) to induce apoptosis in cells, comprising contacting the cells with compound I described herein or a pharmaceutically acceptable composition, salt, morphic form, or isotopic analog thereof. In certain embodiments, the method is an in vitro method. In certain embodiments, the method is an in vivo method. BCL2L11 expression is tightly regulated in cells. BCL2L11 encodes the pro-apoptotic protein BIM. 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 suppression of BCL2L11 expression confers resistance to tyrosine kinase inhibitors. See, e.g., Ng et al., Nat. Med. (2012) 18:521-528.

[0110] In yet another aspect, provided herein are methods for treating an angiogenesis-associated condition, e.g., a diabetic condition (e.g., diabetic retinopathy), an inflammatory condition (e.g., rheumatoid arthritis), macular degeneration, obesity, atherosclerosis, or a proliferative disorder, comprising administering to a subject in need thereof Compound I, or a pharmaceutically acceptable composition, salt, morphic form, or isotopic analog thereof, as described herein.

[0111] In certain embodiments, the condition associated with angiogenesis is macular degeneration. In certain embodiments, a method for treating macular degeneration is provided, comprising administering to a subject in need thereof Compound I as described herein or a pharmaceutically acceptable composition, salt, morphic form, or isotopic analog thereof.

[0112] In certain embodiments, the condition associated with angiogenesis is obesity. As used herein, "obesity" and "obese" refer to Class I obesity, Class II obesity, Class III obesity, and pre-obesity (e.g., being "overweight") as defined by the World Health Organization. In certain embodiments, provided are methods for treating obesity, comprising administering to a subject in need thereof Compound I, or a pharmaceutically acceptable composition, salt, morphic form, or isotopic analog thereof, as described herein.

[0113] In certain embodiments, the condition associated with angiogenesis is atherosclerosis. In certain embodiments, a method for treating atherosclerosis is provided, comprising administering to a subject in need thereof Compound I or a pharmaceutically acceptable composition, salt, morphic form, or isotopic analog thereof as described herein.

[0114] In certain embodiments, the condition associated with angiogenesis is a proliferative disorder. In certain embodiments, a method for treating a proliferative disorder is provided, comprising administering to a subject in need thereof Compound I or a pharmaceutically acceptable composition, salt, morphic form, or isotopic analog thereof as described herein.

[0115] The present invention provides advantageous methods for treating a subject with a cyclin E amplified or overexpressing cancer, the method 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 comprises an abnormal cell proliferation disorder of cyclin E amplification or overexpression, and administering an effective amount of Compound I, or a pharmaceutically acceptable composition, salt, morphic form, or isotopic analog thereof, as described herein, if the subject is determined to have an abnormal cell proliferation disorder of cyclin E amplification or overexpression. In certain embodiments, Compound I or a pharmaceutically acceptable salt thereof is used to treat a subject with a cyclin E amplified or overexpressing cancer. In certain aspects, Compound I, or a pharmaceutically acceptable salt or morphic form thereof, as described herein, is used to treat a subject who has been screened and determined to have an elevated level of cyclin E expression compared to a control subject. In certain aspects, Compound I, or a pharmaceutically acceptable salt or morphic form thereof, as described herein, is used to treat a subject who has been screened and determined to have an elevated level 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 One™ CDx, Foundation One™ Liquid CDx, Tempus xT (solid tumor), Tempus xF (liquid biopsy), Caris™ 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, cyclin E1 (CCNE1) and / or cyclin E2 (CCNE2) are overexpressed and / or activated by at least 1.5-fold, at least 2.0-fold, at least 2.5-fold, at least 3.0-fold, at least 3.5-fold, at least 4.0-fold, at least 4.5-fold, at least 5.0-fold, or more than 5.0-fold in a sample from a treated subject compared to a control sample. In certain aspects, compound I, or a pharmaceutically acceptable salt or morphic form thereof, as described herein, is used in combination with a CDK4 / 6 inhibitor to treat a subject with a cyclin E-amplified or overexpressed cancer. In certain aspects, compound I, or a pharmaceutically acceptable salt or morphic form thereof, as described herein, is used to treat a subject with a cyclin E-amplified or overexpressed cancer that is resistant to a CDK4 / 6 inhibitor. In certain embodiments, the CDK4 / 6 inhibitor-resistant cancer is intrinsically resistant to a CDK4 / 6 inhibitor. In certain embodiments, the CDK4 / 6 inhibitor-resistant cancer has acquired resistance to the CDK4 / 6 inhibitor. In certain aspects, Compound I or a pharmaceutically acceptable salt or morphic form thereof described herein is used in combination with a CDK4 / 6 inhibitor to resensitize a subject with a cyclin E amplified or overexpressed cancer that is resistant to the CDK4 / 6 inhibitor treatment. In some embodiments, the CDK4 / 6 inhibitor is selected from palbociclib, ribociclib, abemaciclib, trilaciclib, relociclib, or SHR6390 (dalpiciclib). In some embodiments, the CDK4 / 6 inhibitor is selected from BPI-16350, narazaciclib (ON-123300), FLX-925 (AMG-925), UCT-03-008, GLR2007, vilociclib (XZP-3287), LY5219, PF-07220060, or ON-123300.

[0116] In another aspect, disclosed herein are methods for treating a subject with a CCNE1-amplified cancer. For example, disclosed herein are methods for treating a subject with an advanced and / or metastatic solid tumor with CCNE1 amplification, comprising administering to the subject an effective amount of Compound I or a pharmaceutically acceptable salt or morphic form thereof, as described herein. In certain embodiments, the advanced and / or metastatic solid tumor with CCNE1 amplification is platinum-resistant. In certain embodiments, the advanced and / or metastatic solid tumor with CCNE1 amplification is platinum-refractory. In certain embodiments, the solid tumor has progressed after a prior standard treatment regimen. In certain embodiments, the advanced or metastatic solid tumor is intolerant to or ineligible 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, trilaciclib, relociclib, or SHR6390 (dalpiciclib). In some embodiments, the CDK4 / 6 inhibitor is selected from BPI-16350, narazaciclib (ON-123300), FLX-925 (AMG-925), UCT-03-008, GLR2007, vilociclib (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, the chemotherapeutic agent is selected from a protein synthesis inhibitor, a DNA damaging chemotherapeutic agent, an alkylating agent, a topoisomerase inhibitor, an RNA synthesis inhibitor, a DNA complex binder, a thiolate alkylating agent, a guanine alkylating agent, a tubulin binder, a DNA polymerase inhibitor, an anti-cancer enzyme, a RAC1 inhibitor, a thymidylate synthase inhibitor, an oxazophosphorine compound, an integrin inhibitor, an antifolate, an antifolate, or a combination thereof.In certain embodiments, the anticancer therapy is an estrogen inhibitor. In certain 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 certain embodiments, the estrogen inhibitor is a selective estrogen receptor degrader (SERD). In certain embodiments, the SERD is selected from fulvestrant, lintodestrant (G1T48), borestrant (ZB-716), brilanestrant (GDC0810), camizestrant (AZD9833), D00502, elacestrant (RAD1901), etaxtil (GW5638), GW7604, AZD9496, GDC-0927, giledestrant (GDC9545, RG6171), LSZ102, imrunestrant (LY3484356), SAR439859, SCR6852, or ZN-c5. In some embodiments, the SERD comprises fulvestrant. In some embodiments, the SERD comprises elacestrant (RAD1901).

[0117] 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 I or a pharmaceutically acceptable salt or morphic form thereof as described herein, 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 a CDK4 / 6 inhibitor. In certain embodiments, the CDK4 / 6 inhibitor-resistant cancer has progressed after a prior regimen comprising a CDK4 / 6 inhibitor. In some embodiments, the CDK4 / 6 inhibitor of the prior regimen is selected from palbociclib, ribociclib, abemaciclib, trilaciclib, relociclib, SHR6390 (dalpiciclib), or a combination thereof. In some embodiments, the CDK4 / 6 inhibitor of the preceding regimen is selected from BPI-16350, narazaciclib (ON-123300), FLX-925 (AMG-925), UCT-03-008, GLR2007, vilociclib (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 null (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 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 or a pharmaceutically acceptable salt or morphic form thereof described herein is administered to a subject at least once daily, wherein an effective amount of a CDK4 / 6 inhibitor is administered according to a designated label. In some embodiments, Compound I or a pharmaceutically acceptable salt thereof is administered to a subject at least twice daily, wherein an effective amount of a CDK4 / 6 inhibitor is administered according to a designated label. In some embodiments, the CDK4 / 6 inhibitor-resistant cancer is also resistant to endocrine therapy or an estrogen inhibitor, such as a SERD.

[0118] Intrinsic resistance to selective CDK4 / 6 inhibitors can be determined through any standard assay known to those skilled in the art, for example, by determining the loss or absence (Rb null) of the retinoblastoma (Rb) tumor suppressor protein. For example, Rb status in cancer can be determined by, but not limited to, Western blot, ELISA (enzyme-linked immunosorbent assay), IHC (immunohistochemistry), and FACS (fluorescence-activated cell sorting). The choice of assay depends on the tissue, cell line, or alternative tissue sample used; for example, Western blot and ELISA can be used for any type of tissue, cell line, or alternative tissue, while IHC methods may be more appropriate when the tissue used in the methods described herein is a tumor biopsy. FACS analysis is most applicable to cell lines and single-cell suspension samples, such as isolated peripheral blood mononuclear cells. See, e.g., U.S. Patent Application Publication No. 20070212736, "Functional Immunohistochemical Cell Cycle Analysis as a Prognostic Indicator for Cancer."

[0119] Alternatively, molecular genetic testing can be used to determine the status of the retinoblastoma gene, such as those 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).

[0120] Increased cyclin E activity or levels can be determined via any standard assay known to those skilled in the art, including, but not limited to, next-generation sequencing (NGS), Western blot, ELISA (enzyme-linked immunosorbent assay), IHC (immunohistochemistry), and FACS (fluorescence-activated cell sorting). The choice of assay depends on the tissue, cell line, or alternative tissue sample used. For example, Western blot and ELISA can be used for any type of tissue, cell line, or alternative tissue, while IHC methods may be more appropriate when the tissue used in the method is a tumor biopsy. FACS analysis is most applicable to cell lines and single-cell suspension samples, such as isolated peripheral blood mononuclear cells.

[0121] In some embodiments, an NGS panel test is used to confirm the overexpression or amplification status of CCNE1 or CCNE2. NGS panel tests of patient samples are known to those skilled in the art. In some embodiments, the NGS panel test for confirming the overexpression or amplification status of CCNE1 or CCNE2 is selected from Foundation One™ CDx, Foundation One™ Liquid CDx, Tempus xT (solid tumor), Tempus xF (liquid biopsy), Caris™ 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. For example, an NGS panel is an in vitro diagnostic device used to detect substitutions, insertions, deletions (such as 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). Briefly, DNA is extracted from a sample collected from a patient using a DNA extraction method. Whole-genome shotgun library construction and hybridization-based capture are performed using a next-generation sequencing platform (e.g., Illumina™ HiSeq 4000) to sequence the coding exon or intron regions of a panel of selected genes at high and uniform depth. The sequence data are then processed after collection to detect genomic alterations, including, but not limited to, base substitutions, indels, copy number changes (e.g., amplifications, homozygous gene deletions), genomic rearrangements (e.g., gene fusions), microsatellite instability (MSI), tumor mutation burden (TMB), and positive homologous recombination deficiency (HRD) status. In some embodiments, the overexpression or amplification status of CCNE1 or CCNE2 is confirmed by NGS panel testing at any time during or after initial diagnosis, but before the first administration of Compound I.

[0122] Immunohistochemistry (IHC) and immunocytochemistry (ICC) are techniques used to localize expression and rely on the interaction of specific epitopes with antibodies. IHC involves the use of tissue sections, whereas ICC involves the use of cultured cells or cell suspensions. Both methods visualize positive staining using molecular labels, which can be fluorescent or chromogenic. Briefly, samples are fixed to preserve cellular integrity and then incubated with a blocking reagent to prevent nonspecific antibody binding. The samples are then incubated with primary and secondary antibodies, and the signal is visualized by microscopic analysis.

[0123] The Western blot technique uses three components to identify specific proteins from a complex mixture of proteins extracted from cells: size separation, transfer to a solid support, and marking 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. Protein samples are first electrophoresed on SDS-PAGE to separate proteins according to molecular weight. The proteins are then transferred to a membrane, where they are probed with antibodies specific to the target protein.

[0124] 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.

[0125] 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 spatial and temporal patterns of gene expression. FISH relies on fluorescent probes that bind to complementary sequences of the RNA of interest. A series of hybridization steps achieves signal amplification of the target of interest. This amplification is then visualized by fluorescence microscopy. This technique can be used with formalin-fixed, paraffin-embedded (FFPE) tissue, frozen tissue, fresh tissue, cells, and circulating tumor cells.

[0126] Targeted RNA-sequencing (RNA-Seq) is a highly accurate method for selecting and sequencing specific transcripts of interest. RNA-Seq provides both quantitative and qualitative information. Targeted RNA-Seq can be achieved through either enrichment or amplicon-based approaches, both of which enable focused gene expression analysis of a specific gene set of interest. Furthermore, enrichment assays offer the ability to detect both known and novel gene fusion partners in many sample types, including formalin-fixed, paraffin-embedded (FFPE) tissues. RNA enrichment provides not only quantitative expression information but also the detection of small variants and gene fusions.

[0127] Microarray analysis typically involves collecting mRNA molecules from both an experimental sample and a reference sample. For example, the reference sample may be collected from a healthy individual, while the experimental sample is collected from an individual with a disease such as cancer. The two mRNA samples are then converted into complementary DNA (cDNA), and each sample is labeled with a different colored fluorescent probe. The experimental cDNA sample may be labeled with a red fluorescent dye, while the reference cDNA may be labeled with a green fluorescent dye. The two samples are then mixed and hybridized to a microarray slide. After hybridization, the microarray is scanned to measure the expression level of each gene printed on the slide. If the expression of a particular gene is higher in the experimental sample than in the reference sample, the corresponding spot on the microarray will be red. Conversely, if the expression in the experimental sample is lower than in the reference sample, the spot will be green. Finally, if the gene is expressed similarly in the two samples, the spot will be yellow. Data collected by microarrays can be used to create gene expression profiles that show simultaneous changes in the expression of many genes in response to a particular condition or treatment.

[0128] In another aspect, disclosed herein are methods for treating a subject with CDK4 / 6 inhibitor-resistant small cell lung cancer (SCLC), comprising administering to the subject an effective amount of Compound I, or a pharmaceutically acceptable salt or morphic form thereof, as described herein. 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, the chemotherapeutic agent is selected from a protein synthesis inhibitor, a DNA-damaging chemotherapeutic agent, an alkylating agent, a topoisomerase inhibitor, an RNA synthesis inhibitor, a DNA complex binder, a thiolate alkylating agent, a guanine alkylating agent, a tubulin binder, a DNA polymerase inhibitor, an anticancer enzyme, a RAC1 inhibitor, a thymidylate synthase inhibitor, an oxazophosphorine compound, an integrin inhibitor, an antifolate, an antifolate, or a combination thereof. In some embodiments, the chemotherapeutic agent is carboplatin. In some embodiments, the chemotherapeutic agent is etoposide. In some embodiments, the chemotherapeutic agent is doxorubicin. In some embodiments, the chemotherapeutic agent is camptothecin. In some embodiments, the chemotherapeutic agent is cisplatin.

[0129] In another aspect, disclosed herein is a method for treating a subject with advanced and / or metastatic ovarian cancer with CCNE1 amplification, comprising administering to the subject an effective amount of Compound I, or a pharmaceutically acceptable salt or morphic form thereof, as described herein. 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 has progressed after a prior standard treatment regimen. In certain embodiments, the ovarian cancer has progressed after a prior standard systemic therapy. In certain embodiments, the ovarian cancer has progressed after a prior systemic anti-cancer therapy. In certain embodiments, the ovarian cancer has progressed after a prior regimen containing 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, trilaciclib, relociclib, or SHR6390 (dalpiciclib). In some embodiments, the CDK4 / 6 inhibitor is selected from BPI-16350, narazaciclib (ON-123300), FLX-925 (AMG-925), UCT-03-008, GLR2007, vilociclib (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 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, the chemotherapeutic agent is selected from protein synthesis inhibitors, DNA damaging chemotherapeutic agents, alkylating agents, topoisomerase inhibitors, RNA synthesis inhibitors, DNA complex binders, thiolate alkylating agents, guanine alkylating agents, tubulin binders, DNA polymerase inhibitors, anticancer enzymes, RAC1 inhibitors, thymidylate synthase inhibitors, oxazophosphorine compounds, integrin inhibitors, antifolates, antifolates, or combinations thereof. In certain embodiments, the anticancer therapy is an estrogen inhibitor. In certain embodiments, 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. In certain embodiments, the estrogen inhibitor is a selective estrogen receptor degrader (SERD). In some embodiments, the SERD comprises fulvestrant. In some embodiments, the SERD comprises elacestrant (RAD1901).

[0130] 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 I described herein or a pharmaceutically acceptable salt or morphic form thereof. In certain embodiments, the breast cancer is hormone receptor positive (HR+). In certain embodiments, the breast cancer is HR+ / HER2- breast cancer. In certain embodiments, the breast cancer is estrogen receptor positive (ER+). In certain embodiments, the breast cancer is ER+ / HER2- breast cancer. In certain embodiments, the advanced and / or metastatic human epidermal growth factor 2-negative (HER2-) breast cancer is platinum-resistant. In certain embodiments, the advanced and / or metastatic human epidermal growth factor 2-negative (HER2-) breast cancer is platinum-refractory. In certain embodiments, the advanced and / or metastatic human epidermal growth factor 2-negative (HER2-) breast cancer has progressed after a prior standard of care regimen. 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, the chemotherapeutic agent is selected from a protein synthesis inhibitor, a DNA damaging chemotherapeutic agent, an alkylating agent, a topoisomerase inhibitor, an RNA synthesis inhibitor, a DNA complex binder, a thiolate alkylating agent, a guanine alkylating agent, a tubulin binder, a DNA polymerase inhibitor, an anti-cancer enzyme, a RAC1 inhibitor, a thymidylate synthase inhibitor, an oxazophosphorine compound, an integrin inhibitor, an antifolate, an antifolate, or a combination thereof.

[0131] In certain embodiments, Compound I or a pharmaceutically acceptable salt thereof, or a morphic form described herein 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 I is administered at a dose of about 100 mg to about 800 mg. In certain embodiments, Compound I or a pharmaceutically acceptable salt thereof, or a morphic form described herein 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 I or a pharmaceutically acceptable salt thereof, or a morphic form described herein is administered at a dose of about 100 mg. In certain embodiments, Compound I or a pharmaceutically acceptable salt thereof, or a morphic form described herein is administered at a dose of about 200 mg. In certain embodiments, Compound I or a pharmaceutically acceptable salt thereof, or a morphic form described herein is administered at a dose of about 300 mg. In certain embodiments, Compound I or a pharmaceutically acceptable salt thereof, or a morphic form described herein is administered at a dose of about 400 mg. In certain embodiments, Compound I or a pharmaceutically acceptable salt thereof, or a morphic form described herein is administered at a dose of about 500 mg. In certain embodiments, Compound I or a pharmaceutically acceptable salt thereof, or a morphic form described herein is administered at a dose of about 600 mg. In certain embodiments, Compound I or a pharmaceutically acceptable salt thereof, or a morphic form thereof described herein is administered at a dose of about 700 mg. In certain embodiments, Compound I or a pharmaceutically acceptable salt thereof, or a morphic form thereof described herein is administered at a dose of about 800 mg.

[0132] 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 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, the anti-cancer therapy comprises a chemotherapeutic agent. In some embodiments, the chemotherapeutic agent is selected from a protein synthesis inhibitor, a DNA damaging chemotherapeutic agent, an alkylating agent, a topoisomerase inhibitor, an RNA synthesis inhibitor, a DNA complex binder, a thiolate alkylating agent, a guanine alkylating agent, a tubulin binder, a DNA polymerase inhibitor, an anti-cancer enzyme, a RAC1 inhibitor, a thymidylate synthase inhibitor, an oxazophosphorine compound, an integrin inhibitor, an antifolate, an antifolate, 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, Abraxane, ifosfamide, topotecan, irinotecan, docetaxel, temozolomide, paclitaxel, doxorubicin, camptothecin, or a combination thereof. In some embodiments, Compound I, or a pharmaceutically acceptable salt or morphic form thereof, as described herein, is administered within 24 hours after the administration of the chemotherapeutic agent. In some embodiments, Compound I, or a pharmaceutically acceptable salt or morphic form thereof, as described herein, is administered within 6 hours after the administration of the chemotherapeutic agent. In some embodiments, Compound I, or a pharmaceutically acceptable salt or morphic form thereof, as described herein, is administered within 3 hours after the administration of the chemotherapeutic agent. In some embodiments, Compound I, or a pharmaceutically acceptable salt or morphic form thereof, described herein is administered to a subject at least once daily, where an effective amount of the anti-cancer therapy is administered according to the label.In some embodiments, Compound I, or a pharmaceutically acceptable salt or morphic form thereof, described herein is administered to a subject at least twice daily, where an effective amount of the anti-cancer therapy is administered according to the label.

[0133] 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 full estrogen receptor degrader, a full 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, the SERD comprises fulvestrant. In some embodiments, the SERD comprises elacestrant (RAD1901).

[0134] In certain embodiments, the methods described herein further comprise 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, Abraxane, ifosfamide, topotecan, irinotecan, docetaxel, temozolomide, paclitaxel, doxorubicin, camptothecin, or a combination thereof. In some embodiments, the CDK4 / 6 inhibitor-resistant ER+ breast cancer is luminal A breast cancer. In some embodiments, Compound I or a pharmaceutically acceptable salt or morphic form thereof described herein is administered to a subject at least once daily, wherein an effective amount of the chemotherapeutic agent is administered according to the prescribed label. In some embodiments, Compound I or a pharmaceutically acceptable salt or morphic form thereof described herein is administered to a subject at least twice daily, wherein an effective amount of a chemotherapeutic agent is administered according to the prescribed label. In certain embodiments, the cancer has progressed after a prior regimen including a CDK4 / 6 inhibitor. In certain embodiments, the cancer that has progressed after a prior regimen including a CDK4 / 6 inhibitor is CDK4 / 6 inhibitor-resistant. In some embodiments, the CDK4 / 6 inhibitor is selected from palbociclib, ribociclib, abemaciclib, trilaciclib, relociclib, or SHR6390 (dalpiciclib). In some embodiments, the CDK4 / 6 inhibitor is selected from BPI-16350, narazaciclib (ON-123300), FLX-925 (AMG-925), UCT-03-008, GLR2007, vilociclib (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).

[0135] III. Pharmaceutical Compositions and Dosage Forms Compound I, or a pharmaceutically acceptable salt thereof, or an isotopic analog or morphic form thereof, 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 approach that achieves the desired therapeutic result. The dosage and timing of administration of Compound I will, of course, depend on the host being treated, the direction of the administering physician, the time course of exposure, the method of administration, the pharmacokinetic properties, and the judgment of the prescribing physician. Therefore, due to host-to-host variability, the dosage amounts below are for guidance, and the physician can determine the dosage of the compound to achieve treatment that the physician deems appropriate for the host. In considering the degree of treatment desired, the physician can balance various factors, such as the age and weight of the host, the presence of pre-existing diseases, and the presence of other diseases.

[0136] In certain embodiments, pharmaceutical compositions are prepared from the morphic forms described herein. For example, in certain embodiments, pharmaceutical compositions are prepared from the morphic forms described herein, and in the final pharmaceutical composition, the compound is no longer in the same morphic form or is amorphous. In certain embodiments, the use of a pharmaceutical composition of Compound I or a morphic form described herein to prepare the pharmaceutical composition improves purity, yield, manufacturing control, reproducibility, and / or scalability.

[0137] The pharmaceutical compositions can be formulated in any pharmaceutically useful form, for example, as oral liquid dosage forms, oral solid dosage forms, oral semisolid dosage forms, aerosols, creams, gels, pills, injection or infusion solutions, capsules, tablets, syrups, transdermal patches, subcutaneous patches, dry powders, inhalation formulations in medical devices, suppositories, buccal or sublingual formulations, parenteral formulations, intravenous solutions, or eye drops. Some dosage forms, such as tablets and capsules, are divided into suitably sized unit doses containing an appropriate amount of the active ingredient, for example, an effective amount to achieve a desired purpose.

[0138] The compounds disclosed herein or used as described herein can be administered orally, topically, parenterally, by inhalation or spray, sublingually, by implant, including ocular implant, transdermally, buccally, rectally, as eye drops, injection, including intraocular injection, intravenously, intramuscularly, by inhalation, intraaortal, intracranial, subdermal, intraperitoneal, subcutaneous, nasal, sublingually, or rectally, or by other means in dosage unit formulations containing conventional pharmaceutically acceptable carriers. For intraocular delivery, the compounds can be administered, for example, by intravitreal, intrastromal, intracameral, sub-Tenon, subretinal, retrobulbar, peribulbar, suprachoroidal, conjunctival, subconjunctival, episcleral, periocular, transscleral, retrobulbar, posterior juxtascleral, periclinal, or lacrimal injection, as desired, or in an immediate or controlled release manner via mucus, mucin, or mucosal barriers, or by intraocular device.

[0139] In certain embodiments, a pharmaceutical composition comprising Compound I, or a pharmaceutically acceptable salt thereof, or a morphic form thereof, as described herein, is orally administered. For example, in certain embodiments, the pharmaceutical composition comprises Compound I, or a pharmaceutically acceptable salt thereof, or a morphic form thereof, as described herein, and polyethylene glycol and / or hydroxypropylmethylcellulose.

[0140] Therapeutically effective dosages of Compound I or its pharmaceutically acceptable salts or morphic forms described herein can be determined by a medical professional depending on the patient's condition, size, and age, as well as the route of delivery. In certain non-limiting embodiments, dosages of about 0.1 mg / kg to about 200 mg / kg are therapeutically effective, with all weights calculated based on the weight of Compound I, including salts. In certain embodiments, dosages are about 0.1 mg / kg, 0.5 mg / kg, 1 mg / kg, 5 mg / kg, 10 mg / kg, 25 mg / kg, 50 mg / kg, 75 mg / kg, 100 mg / kg, 125 mg / kg, 150 mg / kg, 175 mg / kg, or 200 mg / kg or more. In some embodiments, the dosage may 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.

[0141] In certain embodiments, the pharmaceutical composition is in 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 I or a pharmaceutically acceptable salt thereof, and optionally, an additional active agent in a unit dosage form 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. Exemplary dosage forms include at least about 5 mg, about 10 mg, about 15 mg, about 20 mg, about 25 mg, about 50 mg, about 75 mg, about 100 mg, about 150 mg, about 175 mg, about 200 mg, about 250 mg, about 300 mg, about 350 mg, about 400 mg, about 450 mg, about 500 mg, about 500 mg, about 600 mg, about 650 mg, about 700 mg, about 750 mg, or about 800 mg of Compound I or a salt thereof, or a morphic form described herein. In certain embodiments, the pharmaceutical composition is a dosage form comprising about 100 mg of Compound I or a pharmaceutically acceptable salt thereof, or a morphic form described herein. In certain embodiments, the pharmaceutical composition is a dosage form comprising about 200 mg of Compound I or a pharmaceutically acceptable salt thereof, or a morphic form described herein. In certain embodiments, the pharmaceutical composition is in a dosage form containing about 300 mg of Compound I or a pharmaceutically acceptable salt thereof, or a morphic form as described herein. In certain embodiments, the pharmaceutical composition is in a dosage form containing about 400 mg of Compound I or a pharmaceutically acceptable salt thereof, or a morphic form as described herein. In certain embodiments, the pharmaceutical composition is in a dosage form containing about 500 mg of Compound I or a pharmaceutically acceptable salt thereof, or a morphic form as described herein. In certain embodiments, the pharmaceutical composition is in a dosage form containing about 600 mg of Compound I or a pharmaceutically acceptable salt thereof, or a morphic form as described herein. In certain embodiments, the pharmaceutical composition is in a dosage form containing about 700 mg of Compound I or a pharmaceutically acceptable salt thereof, or a morphic form as described herein.In certain embodiments, the pharmaceutical composition is in a dosage form containing about 800 mg of Compound I or a pharmaceutically acceptable salt thereof, or a morphic form described herein. The pharmaceutical composition may contain a molar ratio of Compound I or a pharmaceutically acceptable salt thereof to the additional active agent that achieves the desired result.

[0142] In some embodiments, a compound disclosed herein or a pharmaceutically acceptable salt thereof, or a morphic form thereof, as described or used as described herein, is administered once daily (QD), twice daily (BID), or three times daily (TID). In some embodiments, compound I described herein or a pharmaceutically acceptable salt thereof, or a morphic form thereof, is administered once daily (QD). In some embodiments, compound I described herein or a pharmaceutically acceptable salt thereof, or a morphic form thereof, is administered twice daily (BID). In some embodiments, compound I described herein or a pharmaceutically acceptable salt thereof, or a morphic form thereof, is administered three times daily (TID). In some embodiments, Compound I or a pharmaceutically acceptable salt or morphic form thereof described herein is administered at least once daily 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 medical professional determines that the drug is no longer needed.

[0143] According to the methods of the present disclosure, 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 by inhalation, intravenously, or intramuscularly as a liposomal suspension. When administered by inhalation, Compound I or a salt or morphic form described herein can be in the form of a plurality of solid particles or droplets having any desired particle size, e.g., from about 0.01 microns, 0.1 microns, or 0.5 microns to about 5 microns, 10 microns, 20 microns, or greater, optionally from about 1 micron to about 2 microns. The compounds disclosed herein have demonstrated favorable pharmacokinetic and pharmacodynamic properties when administered, for example, by oral or intravenous routes.

[0144] Pharmaceutical formulations can contain Compound I or its pharmaceutically acceptable salts or morphic forms described herein in any pharmaceutically acceptable carrier. When a solution is desired, water may be the carrier of choice 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 significant amount of water. In either case, the solution can be sterilized by any suitable method known to those skilled in the art, for example, by filtration through a 0.22 micron filter. Following sterilization, the solution can be dispensed into suitable containers, such as depyrogenated glass vials. Dispensing is optionally performed using aseptic methods. A sterile closure can then be attached to the vial, and the contents of the vial can be lyophilized, if desired.

[0145] Carriers include excipients and diluents and must be of sufficiently high purity and sufficiently low toxicity to be suitable for administration to the patient being treated. Carriers may be inert or may have their own medicinal properties. The amount of carrier used in conjunction with the compound is sufficient to provide a practical amount of material for administration per unit dose of the compound.

[0146] Types of carriers include, but are not limited to, binders, buffers, coloring agents, diluents, disintegrants, emulsifiers, flavoring agents, glidants, lubricants, preservatives, stabilizers, surfactants, tableting agents, and wetting agents. Some carriers may be classified into more than one category; for example, vegetable oils can be used as lubricants in some formulations and as diluents in other formulations. Exemplary pharmaceutically acceptable carriers include sugars, starches, cellulose, powdered tragacanth, malt, gelatin; talc, and vegetable oils. Any active agent that does not substantially interfere with the activity of the compound may be included in the pharmaceutical composition.

[0147] Additionally, auxiliary substances such as wetting or emulsifying agents, physiological buffer substances, surfactants, etc. may be present in such vehicles. The physiological buffer can be any solution that is pharmacologically acceptable and that results in the formulation having a desired pH, i.e., a pH in the physiologically acceptable range. Examples of buffer solutions include saline, phosphate buffered saline, Tris buffered saline, Hank's buffered saline, etc.

[0148] Depending on the intended method of administration, the pharmaceutical composition may be in solid, semi-solid, or liquid dosage form, such as tablets, suppositories, pills, capsules, powders, liquids, suspensions, creams, ointments, lotions, etc., preferably in unit dosage form suitable for single administration of a precise dosage. The composition will contain an effective amount of the selected drug in combination with a pharmaceutically acceptable carrier, and may, in addition, include other medicinal agents, adjuvants, diluents, buffers, etc.

[0149] Thus, the compositions of the present disclosure may 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 method of administration is intravenous or oral, using a convenient daily dosing regimen that can be adjusted according to the level of pain.

[0150] For solid compositions, conventional non-toxic solid carriers include, for example, pharmaceutical grades of 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 or dispersing Compound I described herein or a pharmaceutically acceptable salt or morphic form thereof, and any pharmaceutical adjuvants, in an excipient such as water, saline, aqueous dextrose, glycerol, ethanol, or the like, to form a solution or suspension. If desired, the pharmaceutical composition to be administered may contain minor amounts of non-toxic auxiliary substances such as wetting or emulsifying agents, pH buffering agents, and the like, e.g., sodium acetate, sorbitan monolaurate, triethanolamine sodium acetate, triethanolamine oleate, and the like. Actual methods for preparing such dosage forms are known or will be apparent to those skilled in the art. See, for example, Remington's Pharmaceutical Sciences, supra.

[0151] In yet another embodiment, permeation-enhancing excipients are used, including polymers such as polycations (chitosan and its quaternary ammonium derivatives, poly-L-arginine, aminated gelatin); polyanions (N-carboxymethylchitosan, poly-acrylic acid); and thiolated polymers (carboxymethylcellulose-cysteine, polycarbophil-cysteine, chitosan-thiobutylamidine, chitosan-thioglycolic acid, chitosan-glutathione conjugates).

[0152] For oral administration, the compositions generally take the form of tablets, capsules, softgel capsules, or can be aqueous or non-aqueous solutions, suspensions, or syrups. Tablets and capsules are preferred oral dosage forms. Oral tablets and capsules may contain one or more commonly used carriers, such as lactose and corn starch. Lubricants, such as magnesium stearate, are also commonly added. Typically, the compositions 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, and the like. Furthermore, if desired or necessary, suitable binders, lubricants, disintegrating agents, and coloring agents may be incorporated into the mixture. Suitable binders include starch, gelatin, natural sugars such as glucose or β-lactose, corn sweeteners, natural and synthetic gums such as gum arabic and tragacanth, or sodium alginate, carboxymethylcellulose, polyethylene glycol, waxes, and the like. 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.

[0153] When liquid suspensions are used, the active agent can be combined with any oral, non-toxic, pharmaceutically acceptable inert carrier, such as ethanol, glycerol, water, etc., as well as emulsifying and suspending agents. Flavoring, coloring, and / or sweetening agents can also be added as needed. Other optional ingredients that may be incorporated into the oral formulations herein include, but are not limited to, preservatives, suspending agents, thickening agents, etc.

[0154] Parenteral formulations can be prepared in conventional forms, either as liquid solutions or suspensions, solid forms suitable for solubilization or suspension in liquid prior to injection, or as emulsions. Sterile injectable suspensions are preferably formulated using suitable carriers, dispersing or wetting agents, and suspending agents according to techniques known in the art. Sterile injectable formulations may also be sterile injectable solutions or suspensions in non-toxic parenterally acceptable diluents or solvents. Acceptable vehicles and solvents that can be used include water, Ringer's solution, and isotonic sodium chloride solution. In addition, sterile fixed oils, fatty acid esters, or polyols are commonly used as solvents or suspending media. In addition, parenteral administration may involve the use of a sustained-release or sustained-release system to maintain a constant level of dosage.

[0155] Parenteral administration includes intraarticular, intravenous, intramuscular, intradermal, intraperitoneal, and subcutaneous routes, and includes aqueous and non-aqueous isotonic sterile injection solutions, which may contain antioxidants, buffers, bacteriostats, and solutes that render the formulation isotonic with the blood of the intended recipient, as well as aqueous and non-aqueous sterile suspensions, which may contain suspending agents, solubilizers, thickeners, stabilizers, and preservatives. Administration by certain parenteral routes may involve introducing the formulations of the present disclosure into the patient's body through a needle or catheter, propelled by a sterile syringe or some other mechanical device, such as a continuous infusion system. The formulations provided by the present disclosure can be administered using a syringe, infuser, pump, or any other device recognized in the art for parenteral administration.

[0156] In addition to Compound I or its pharmaceutically acceptable salts or morphic forms described herein, the pharmaceutical formulation may contain other additives, such as pH-adjusting additives. Particularly 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. Furthermore, the formulation may contain an antimicrobial preservative. Useful antimicrobial preservatives include methylparaben, propylparaben and benzyl alcohol. Antimicrobial preservatives are typically used when the formulation is packaged in a vial designed for multiple doses. The pharmaceutical formulations described herein can be lyophilized using techniques known in the art.

[0157] For oral administration, pharmaceutical compositions can take the form of solutions, suspensions, tablets, pills, capsules, powders, and the like. Tablets containing various excipients, such as sodium citrate, calcium carbonate, and calcium phosphate, can be used in conjunction with various disintegrants, such as starch (e.g., potato or tapioca starch) and certain complex silicates, along with binders, such as polyvinylpyrrolidone, sucrose, gelatin, and gum arabic. Additionally, lubricants, such as magnesium stearate, sodium lauryl sulfate, and talc, are often very useful for tableting purposes. Solid compositions of a similar type can be used as fillers in soft and hard gelatin capsules. Related materials also include lactose, i.e., milk sugar, and high molecular weight polyethylene glycols. When aqueous suspensions and / or elixirs are desired for oral administration, the compounds of the presently disclosed subject matter can be combined with various sweeteners, flavorings, colorings, emulsifying and / or suspending agents, and diluents, such as water, ethanol, propylene glycol, glycerin, and various similar combinations thereof.

[0158] In another embodiment of the subject matter described herein, a stable sterile formulation for injection is provided, comprising an active compound or a salt thereof described herein in a unit dosage form in a sealed container. The compound or salt is provided in the form of a lyophilizate that can be reconstituted with a suitable pharmaceutically acceptable carrier to form a liquid formulation suitable for injection into a host. If the compound or salt is substantially water-insoluble, a sufficient amount of a physiologically acceptable emulsifying agent can be used in an amount sufficient to emulsify the compound or salt in an aqueous carrier. Particularly useful emulsifying agents include phosphatidylcholine and lecithin.

[0159] Additional embodiments include liposomal formulations of the active compounds disclosed herein. Techniques for forming liposomal suspensions are known in the art. When the compound is an aqueous-soluble salt, it can be incorporated into lipid vesicles using conventional liposome technology. In such cases, the active compound's water solubility allows the active compound to be substantially entrapped in the hydrophilic center or core of the liposome. The lipid layers used can be of any conventional composition and may or may not contain cholesterol. When the active compound of interest is water-insoluble, conventional liposome formation techniques can also be used to substantially entrap the salt in the hydrophobic lipid bilayer that forms the liposome structure. In either case, the resulting liposomes can be reduced in size, such as by using standard sonication and homogenization techniques. Liposomal formulations containing the active compounds disclosed herein can be lyophilized to produce a lyophilizate, which can be reconstituted with a pharmaceutically acceptable carrier, such as water, to regenerate the liposomal suspension.

[0160] Pharmaceutical formulations suitable for administration as aerosols via inhalation are also provided. These formulations comprise a solution or suspension of the desired compound described herein or a salt thereof, or a plurality of solid particles of the compound or salt. The desired formulation can be placed in a small chamber and nebulized. Nebulization can be achieved by using compressed air or ultrasonic energy to form a plurality of liquid droplets or solid particles comprising the compound or salt. The liquid droplets or solid particles can have a particle size ranging, for example, from about 0.5 microns to about 10 microns, optionally from about 0.5 microns to about 5 microns. In certain embodiments, the solid particles provide controlled release through the use of degradable polymers. The solid particles can be obtained by processing the solid compound or a salt thereof by any suitable method known in the art, such as micronization. Optionally, the size of the solid particles or droplets can be from about 1 micron to about 2 microns. In this regard, commercially available nebulizers are available for this purpose. The compounds can be administered by an aerosol suspension of respirable particles as described in U.S. Pat. No. 5,628,984, the disclosure of which is incorporated herein by reference in its entirety.

[0161] Also provided are pharmaceutical formulations that provide controlled release of the compounds described herein, for example, through the use of degradable polymers known in the art.

[0162] When a pharmaceutical formulation suitable for administration as an aerosol is in liquid form, the formulation may contain a water-soluble active compound in a carrier that includes water. A surfactant may be present that sufficiently reduces the surface tension of the formulation to result in the formation of droplets within the desired size range when hosted by nebulization.

[0163] As used herein, the term "pharmaceutically acceptable salts" 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, within the scope of sound medical judgment, and that are effective for those uses at a reasonable benefit / risk ratio.

[0164] Thus, the term "salts" refers to the relatively non-toxic inorganic and organic acid addition salts of the compounds of the present disclosure. These salts can be prepared during the final isolation and purification of the compounds, or by separately reacting the purified compound in its free base form with a suitable organic or inorganic acid and isolating the salt formed thereby. Basic compounds are capable of forming a wide variety of salts with various inorganic and organic acids. Acid addition salts of basic compounds are prepared in the conventional manner by contacting the free base form with a sufficient amount of the desired acid to produce a salt. The free base form can be regenerated by contacting the salt form with a base in the conventional manner and isolating the free base. Free base forms may differ from their respective salt forms in certain physical properties, such as solubility in polar solvents.

[0165] Salts can be prepared from inorganic acids including hydrochloric acid, sulfuric acid, pyrosulfuric acid, bisulfite, sulfurous acid, bisulfite, nitric acid, phosphoric acid, monohydrogenphosphate, dihydrogenphosphate, metaphosphoric acid, pyrophosphate, chloride, bromide, iodide, such as hydrochloric acid, nitric acid, phosphoric acid, sulfuric acid, hydrobromic acid, hydroiodic acid, phosphorous acid, etc. Representative salts include hydrobromide, hydrochloride, sulfate, bisulfate, nitrate, acetate, oxalate, valerate, oleate, palmitate, stearate, laurate, borate, benzoate, lactate, phosphate, tosylate, citrate, maleate, fumarate, succinate, tartrate, naphthylate, mesylate, glucoheptonate, lactobionate, laurylsulfonate, isethionate, and the like. 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, etc. Representative salts include acetate, propionate, caprylate, isobutyrate, oxalate, malonate, succinate, suberate, sebacate, fumarate, maleate, mandelate, benzoate, chlorobenzoate, methylbenzoate, dinitrobenzoate, phthalate, benzenesulfonate, toluenesulfonate, phenylacetate, citrate, lactate, maleate, tartrate, methanesulfonate, etc. Pharmaceutically acceptable salts may include cations based on alkali and alkaline earth metals such as sodium, lithium, potassium, calcium, magnesium, etc., as well as non-toxic ammonium, quaternary ammonium, and amine cations, including, but not limited to, ammonium, tetramethylammonium, tetraethylammonium, methylamine, dimethylamine, trimethylamine, triethylamine, ethylamine, etc. Also contemplated are salts of amino acids such as arginate, gluconate, galacturonate, etc. See, e.g., Berge et al., J. Pharm. Sci., 1977, 66, 1-19 (incorporated herein by reference).

[0166] Pharmaceutically acceptable base addition salts can be formed with metals or amines, such as alkali and alkaline earth metal hydroxides, or organic amines. Examples of metals used as cations include, but are not limited to, sodium, potassium, magnesium, calcium, etc. 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 the conventional manner. The free acid form can be regenerated by contacting the salt form with an acid and isolating the free acid in the conventional manner. Free acid forms may differ somewhat from their respective salt forms in certain physical properties, such as solubility in polar solvents.

[0167] Sterile injectable suspensions are preferably formulated using suitable carriers, dispersing or wetting agents, and suspending agents according to techniques known in the art. Sterile injectable formulations may be sterile injectable solutions or suspensions in non-toxic parenterally acceptable diluents or solvents. Acceptable vehicles and solvents that can be used include water, Ringer's solution, and isotonic sodium chloride solution. In addition, sterile fixed oils, fatty acid esters, or polyols are commonly used as solvents or suspending media. In addition, parenteral administration may involve the use of a sustained-release or sustained-release system to maintain a constant level of dosage.

[0168] Preparations for parenteral administration according to the present disclosure include sterile aqueous or non-aqueous solutions, suspensions, or emulsions. Examples of non-aqueous solvents or vehicles are 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 may contain adjuvants such as preservatives, wetting agents, emulsifying agents, and dispersing agents. They can be sterilized, for example, by filtration through a bacteria-retaining filter, incorporating a sterilizing agent into the composition, irradiating the composition, or heating the composition. They can also be prepared immediately before use using sterile water or some other sterile injectable medium.

[0169] Sterile injectable solutions are prepared by incorporating the required amount of one or more compounds of the present disclosure into a suitable solvent, optionally with various other ingredients listed above, followed by filtration and sterilization. Generally, dispersions are prepared by incorporating various sterilized active ingredients into a sterile vehicle containing a basic dispersion medium and the required other ingredients listed above. In the case of sterile powders for preparing sterile injectable solutions, the preferred preparation methods are vacuum drying and freeze-drying, which yield a powder of the active ingredient and any additional desired ingredients from the solution previously sterile-filtered. Thus, for example, a parenteral composition suitable for administration by injection is prepared by stirring 1.5% by weight of the active ingredient in 10% by volume of propylene glycol and water. The solution is made isotonic with sodium chloride and sterilized.

[0170] Formulations suitable for rectal administration are typically presented as unit-dose suppositories, which may be prepared by admixing the active compound disclosed herein with one or more conventional solid carriers, for example, cocoa butter, and then shaping the resulting mixture.

[0171] Formulations suitable for topical application to the skin preferably take the form of an ointment, cream, lotion, paste, gel, spray, aerosol, or oil. Carriers that can be used include petrolatum, lanolin, polyethylene glycols, alcohols, transdermal enhancers, and combinations of two or more thereof.

[0172] Formulations suitable for transdermal administration can be provided as individual patches adapted to remain in intimate contact with the recipient's epidermis for an extended period of time. Formulations suitable for transdermal administration can also be delivered by iontophoresis (see, for example, Pharmaceutical Research 3 (6):318 (1986)), and typically take the form of an aqueous solution of the active compound, optionally buffered. In certain embodiments, microneedle patches or devices are provided for the delivery of drugs across or into biological tissues, particularly skin. Microneedle patches or devices allow drug delivery across or into skin or other tissue barriers at clinically relevant rates with little or no tissue damage, pain, or irritation.

[0173] Formulations suitable for pulmonary administration can be delivered by a wide range of passively and actively powered single / multiple dose dry powder inhalers (DPIs). The most commonly used devices 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.

[0174] IV. Combination Therapy In certain aspects, there is provided compound I, or a pharmaceutically acceptable salt or morphic form thereof, as described herein, used in an effective amount, alone or in combination with another biologically active agent (therapeutic agent), to treat a subject, such as a human, having a cyclin E overexpression or amplification disorder, or small cell lung cancer, as described herein.

[0175] In another aspect, there is provided a pharmaceutical composition comprising a morphic form of Compound I or a pharmaceutically acceptable salt thereof, used in an effective amount, alone or in combination with another bioactive agent (therapeutic agent), to treat a subject, such as a human, having a CDK2-mediated cancer or small cell lung cancer described herein.

[0176] In yet another aspect, there is provided a pharmaceutical composition comprising Compound I or a pharmaceutically acceptable salt thereof, or a morphic form as described herein, used alone or in combination with another bioactive agent (therapeutic agent) in an effective amount to treat a subject, such as a human, having a CDK2-mediated cancer or small cell lung cancer as described herein, wherein the pharmaceutical composition is a morphic form of Compound I or a pharmaceutically acceptable salt thereof as described herein, or prepared from a morphic form (e.g., by spray drying or dissolving the morphic form and then mixing it with one or more pharmaceutically acceptable excipients).

[0177] The terms "bioactive agent" or "therapeutic agent" or "anti-cancer therapy" are used to refer to an agent other than Compound I that can be used in combination with or in place of Compound I to achieve a desired therapeutic outcome. In certain embodiments, Compound I and the bioactive agent are administered to exert their activity in vivo during overlapping time periods, e.g., overlapping C max , T max , AUC, or other pharmacokinetic parameters. In another embodiment, Compound I and a bioactive agent that do not have overlapping pharmacokinetic parameters (but one has a therapeutic effect on the therapeutic effect of the other) are administered to a subject in need thereof.

[0178] Despite the successful treatment of many patients with CDK4 / 6 inhibitors, a major problem in cancer treatment is that a significant number of patients essentially fail to respond to treatment, and a significant proportion of the remaining patients ultimately 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. Furthermore, 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 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, despite intact Rb. 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 selective CDK4 / 6 inhibitor therapy, for example, due to upregulation of cyclin E, which allows cell cycle progression from G1 to S via CDK2. In certain embodiments, Compound I effectively inhibits cell cycle progression in cancer cells that are intrinsically resistant, susceptible to acquiring resistance, or have become resistant to selective CDK4 / 6 inhibitors. In certain embodiments, Compound I effectively inhibits cell cycle progression in cancer cells of a subject whose cancer has progressed after a prior regimen comprising a CDK4 / 6 inhibitor.

[0179] In one aspect, disclosed herein are methods for treating a subject with a CDK4 / 6 inhibitor-resistant cancer, comprising administering to the subject an effective amount of Compound I or a pharmaceutically acceptable salt or morphic form thereof as described herein, 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, trilaciclib, relociclib, or SHR6390 (dalpiciclib). In some embodiments, the CDK4 / 6 inhibitor is selected from BPI-16350, narazaciclib (ON-123300), FLX-925 (AMG-925), UCT-03-008, GLR2007, vilociclib (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 null (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 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, the breast cancer is human epidermal growth factor receptor 2-negative (HER2-). In certain embodiments, the breast cancer is ER+ / HER2- breast cancer. In certain embodiments, the 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, lintodestrant (G1T48), borestrant (ZB-716), brilanestrant (GDC0810), camizestrant (AZD9833), D00502, elacestrant (RAD1901), etaxtil (GW5638), GW7604, AZD9496, GDC-0927, giledestrant (GDC9545, RG6171), LSZ102, imurnestrant (LY3484356), SAR439859, SCR6852, or ZN-c5. In some embodiments, the SERD comprises fulvestrant. In some embodiments, the SERD comprises elacestrant (RAD1901).

[0180] In certain embodiments, the methods specifically described above further comprise 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, the anti-cancer therapy comprises a chemotherapeutic agent. In some embodiments, the chemotherapeutic agent is selected from a protein synthesis inhibitor, a DNA damaging chemotherapeutic agent, an alkylating agent, a topoisomerase inhibitor, an RNA synthesis inhibitor, a DNA complex binder, a thiolate alkylating agent, a guanine alkylating agent, a tubulin binder, a DNA polymerase inhibitor, an anti-cancer enzyme, a RAC1 inhibitor, a thymidylate synthase inhibitor, an oxazophosphorine compound, an integrin inhibitor, an antifolate, an antifolate, 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, Abraxane, ifosfamide, topotecan, irinotecan, docetaxel, temozolomide, paclitaxel, doxorubicin, camptothecin, or a combination thereof. In some embodiments, Compound I and the CDK4 / 6 inhibitor are administered within 24 hours of the administration of the chemotherapeutic agent. In some embodiments, Compound I and the CDK4 / 6 inhibitor are administered within 6 hours of the administration of the chemotherapeutic agent. In some embodiments, Compound I and the CDK4 / 6 inhibitor are administered within 3 hours of the administration of the chemotherapeutic agent. In some embodiments, Compound I, or a pharmaceutically acceptable salt or morphic form thereof, described herein, is administered to a subject at least once daily, wherein an effective amount of a CDK4 / 6 inhibitor and a chemotherapeutic agent are administered according to the label. In some embodiments, Compound I, or a pharmaceutically acceptable salt or morphic form thereof, described herein, is administered to a subject at least twice daily, wherein an effective amount of a CDK4 / 6 inhibitor and a chemotherapeutic agent are administered according to the label.

[0181] 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 I or a pharmaceutically acceptable salt or morphic form thereof as described herein, 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 tyrosine kinase cell surface receptor HER2-negative. 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, the SERD comprises fulvestrant. In some embodiments, the SERD comprises elacestrant (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 an ADC selected from ado-trastuzumab emtansine (KADCYLA™), trastuzumab deruxtecan (ENHERTU™), or sacituzumab govitecan (TRODELVY™).

[0182] In some embodiments, disclosed herein are methods for treating a human having a CDK4 / 6 inhibitor-resistant and optionally endocrine therapy-resistant cancer, comprising administering an effective amount of Compound I or a pharmaceutically acceptable salt or morphic form thereof as described herein 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, the SERD comprises fulvestrant. In some embodiments, the SERD comprises elacestrant (RAD1901). Additional non-limiting examples of anti-estrogen compounds include SERMs such as anordrin, arzoxifene, bazedoxifene, broparestriol, clomiphene citrate, cyclophenyl, droloxifene, endoxifene, 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 leuprorelin, cetrorelix, allylestrenol, chlormadinone acetate, delmadinone acetate, dydrogesterone, medroxyprogesterone acetate, megestrol acetate, nomegestrol acetate, norethisterone acetate, progesterone, and spironolactone.Additional non-limiting examples of anti-estrogen compounds include SERDs such as fulvestrant, lintodestrant (G1T48), borestrant (ZB-716), brilanestrant (GDC0810), camizestrant (AZD9833), D00502, elacestrant (RAD1901), etaxtil (GW5638), GW7604, AZD9496, GDC-0927, gildestrant (GDC9545, RG6171), LSZ102, imrunestrant (LY3484356), SAR439859, SCR6852, and ZN-c5. In some embodiments, the SERD is elacestrant (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 has progressed after a prior regimen comprising a CDK4 / 6 inhibitor. 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, a CDK4 / 6 inhibitor, an estrogen inhibitor, an androgen inhibitor, a PARP inhibitor, or a combination thereof. In some 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, trilaciclib, relociclib, or SHR6390 (dalpiciclib). In some embodiments, the CDK4 / 6 inhibitor is selected from BPI-16350, narazaciclib (ON-123300), FLX-925 (AMG-925), UCT-03-008, GLR2007, vilociclib (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 CDK4 / 6 inhibitor-resistant and / or estrogen inhibitor-resistant breast cancer is luminal A breast cancer.

[0183] In some embodiments, disclosed herein is a method for treating a human with advanced, unresectable or metastatic breast cancer, comprising administering to the subject an effective amount of Compound I or a pharmaceutically acceptable salt or morphic form thereof as described herein, 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 full estrogen receptor degrader, a full 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, the SERD is selected from fulvestrant, lintodestrant (G1T48), brilanestrant (GDC0810), elacestrant (RAD1901), etaxtil (GW5638), GW7604, AZD9496, GDC-0927, GDC9545 (RG6171), LSZ102, or SAR439859. In some embodiments, the SERD comprises fulvestrant. In some embodiments, the SERD comprises elacestrant (RAD1901). In some embodiments, the estrogen inhibitor is a selective estrogen receptor modulator (SERM).In some embodiments, the SERMS is selected from anordrin, arzoxifene, bazedoxifene, broparestriol, clomiphene citrate, cyclophenyl, droloxifene, endoxifene, idoxifene, lasofoxifene, ormeloxifene, pipendoxifene, raloxifene, tamoxifen, toremifene, aminoglutethimide, testolactone, anastrozole, exemestane, fadrozole, formestane, letrozole, leuprorelin, cetrorelix, allylestrenol, chlormadinone acetate, delmadinone acetate, dydrogesterone, medroxyprogesterone acetate, megestrol acetate, nomegestrol acetate, norethisterone acetate, progesterone, or spironolactone. In some embodiments, the SERD comprises fulvestrant. In some embodiments, the SERD comprises elacestrant (RAD1901). Selective CDK4 / 6 inhibitors for use in combination with Compound I include, but are not limited to, palbociclib, abemaciclib, ribociclib, trilaciclib, SHR6390 (dalpiciclib), and relociclib. In some embodiments, the CDK4 / 6 inhibitor is selected from BPI-16350, narazaciclib (ON-123300), FLX-925 (AMG-925), UCT-03-008, GLR2007, vilociclib (XZP-3287), LY5219, PF-07220060, or ON-123300. In some embodiments, the CDK4 / 6 inhibitor for use in combination with Compound I is palbociclib. In some embodiments, the CDK4 / 6 inhibitor for use 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, the patient has advanced unresectable and / or metastatic ER+ / HER2- breast cancer that has progressed after treatment with a CDK4 / 6 inhibitor. In certain embodiments, the previously administered CDK4 / 6 inhibitor is selected from palbociclib, abemaciclib, ribociclib, trilaciclib, SHR6390 (dalpiciclib), or relociclib.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, vilociclib (XZP-3287), LY5219, PF-07220060, or ON-123300.

[0184] In another aspect, disclosed herein is a method of treating a subject with breast cancer, comprising administering to the subject an effective amount of Compound I or a pharmaceutically acceptable salt or morphic form thereof as described herein, and administering to the subject an effective amount of an estrogen inhibitor. 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 certain embodiments, the breast cancer is HR+HER2- breast cancer. In certain embodiments, the method is administered as first-line therapy (1L). In some embodiments, 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. In some embodiments, the estrogen inhibitor is a selective estrogen receptor degrader (SERD). In certain embodiments, the SERD is selected from fulvestrant, lintodestrant (G1T48), borestrant (ZB-716), brilanestrant (GDC0810), camizestrant (AZD9833), D00502, elacestrant (RAD1901), etaxtil (GW5638), GW7604, AZD9496, GDC-0927, giledestrant (GDC9545, RG6171), LSZ102, imrunestrant (LY3484356), SAR439859, SCR6852, or ZN-c5. In some embodiments, the SERD comprises fulvestrant. In some embodiments, the SERD comprises elacestrant (RAD1901). In some embodiments, the estrogen inhibitor is a selective estrogen receptor modulator (SERM).In some embodiments, the SERMS is selected from anordrin, arzoxifene, bazedoxifene, broparestriol, clomiphene citrate, cyclophenyl, droloxifene, endoxifene, idoxifene, lasofoxifene, ormeloxifene, pipendoxifene, raloxifene, tamoxifen, toremifene, aminoglutethimide, testolactone, anastrozole, exemestane, fadrozole, formestane, letrozole, leuprorelin, cetrorelix, allylestrenol, chlormadinone acetate, delmadinone acetate, dydrogesterone, medroxyprogesterone acetate, megestrol acetate, nomegestrol acetate, norethisterone acetate, progesterone, or spironolactone. In some embodiments, the SERM is selected from anastrozole, exemestane, or letrozole. 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, trilaciclib, relociclib, or SHR6390 (dalpiciclib). In some embodiments, the CDK4 / 6 inhibitor is selected from BPI-16350, narazaciclib (ON-123300), FLX-925 (AMG-925), UCT-03-008, GLR2007, vilociclib (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 inhibitors are palbociclib and abemaciclib. In certain embodiments, the method extends the time to acquired resistance to estrogen inhibitors compared to methods lacking Compound I. In certain embodiments, the method extends the time to acquired resistance to CDK4 / 6 inhibitors compared to methods 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 has 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.

[0185] In another aspect, disclosed herein is a method for treating a subject with advanced estrogen receptor-positive (ER+) breast cancer, comprising administering to the subject an effective amount of Compound I or a pharmaceutically acceptable salt or morphic form thereof as described herein, and administering to the subject an effective amount of fulvestrant. In certain embodiments, the HR+ advanced breast cancer is human epidermal growth factor 2-negative (HER2-). In certain embodiments, the method is administered as first-line therapy (1L). In certain embodiments, the method extends the time to acquired resistance to fulvestrant compared to methods lacking Compound I. In certain embodiments, the subject has previously received at least one prior line of endocrine therapy. In certain embodiments, the ER+ or ER+ / HER2- breast cancer has progressed after a prior 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, trilaciclib, relociclib, or SHR6390 (dalpiciclib). In some embodiments, the CDK4 / 6 inhibitor is selected from BPI-16350, narazaciclib (ON-123300), FLX-925 (AMG-925), UCT-03-008, GLR2007, vilociclib (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 inhibitors are palbociclib and abemaciclib.

[0186] 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 or a pharmaceutically acceptable salt or morphic form thereof as described herein, and administering to the subject an effective amount of fulvestrant. In certain embodiments, the HR+ advanced breast cancer is human epidermal growth factor 2-negative (HER2-). In certain embodiments, the method is administered as first-line therapy (1L). In certain embodiments, the method extends the time to acquired resistance to fulvestrant compared to methods lacking Compound I. In certain embodiments, the subject has previously received at least one prior line of endocrine therapy. In certain embodiments, the HR+ or HR+ / HER2- breast cancer has progressed after a prior 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, trilaciclib, relociclib, or SHR6390 (dalpiciclib). In some embodiments, the CDK4 / 6 inhibitor is selected from BPI-16350, narazaciclib (ON-123300), FLX-925 (AMG-925), UCT-03-008, GLR2007, vilociclib (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 inhibitors are palbociclib and abemaciclib.

[0187] In another aspect, fully disclosed herein is a method of treating a subject having unresectable cancer by administering to the subject a morphic form of Compound I described herein. In another aspect, fully disclosed herein is a method of treating a subject having advanced cancer by administering to the subject a morphic form of Compound I described herein. In another aspect, fully disclosed herein is a method of treating a subject having metastatic cancer by administering to the subject a morphic form of Compound I described herein. In another aspect, fully disclosed herein is a method of treating a subject having advanced unresectable and / or metastatic cancer by administering to the subject a morphic form of Compound I described herein. In certain embodiments, the advanced unresectable and / or metastatic cancer is selected from the group consisting of uterine cancer, uterine carcinosarcoma (UCS), uterine 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. The cancer is selected from BRCA, pancreatic cancer, pancreatic adenocarcinoma (PAAD), fallopian tube cancer, primary peritoneal cancer, liver cancer, liver hepatocellular carcinoma (LIHC), cervical cancer, cervical squamous cell carcinoma (CESC), cervical adenocarcinoma, mesothelioma (MESO), head and neck squamous cell carcinoma (HSNC), colon cancer, colon adenocarcinoma (COAD), skin cancer, melanoma, cutaneous melanoma (SKCM), glioblastoma multiforme (GBM), renal cancer, or chromophobe renal cell carcinoma (KICH). In some embodiments, the cyclin E amplified or overexpressing cancer is retinoblastoma (Rb) protein positive. In some embodiments, the cyclin E amplified or overexpressing cancer 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 has progressed after a prior standard of care regimen. In certain embodiments, the cancer has progressed after a prior standard of care systemic therapy.In certain embodiments, the cancer has progressed after a prior systemic anticancer therapy. In certain embodiments, the cancer has progressed after a prior regimen including a platinum analog. In certain embodiments, the cancer has progressed after a prior 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, trilaciclib, relociclib, or SHR6390 (dalpiciclib). In some embodiments, the CDK4 / 6 inhibitor is selected from BPI-16350, narazaciclib (ON-123300), FLX-925 (AMG-925), UCT-03-008, GLR2007, virociclib (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, the chemotherapeutic agent is selected from protein synthesis inhibitors, DNA damaging chemotherapeutic agents, alkylating agents, topoisomerase inhibitors, RNA synthesis inhibitors, DNA complex binders, thiolate alkylating agents, guanine alkylating agents, tubulin binders, DNA polymerase inhibitors, anticancer enzymes, RAC1 inhibitors, thymidylate synthase inhibitors, oxazophosphorine compounds, integrin inhibitors, antifolates, antifolates, or combinations thereof. In certain embodiments, the anticancer therapy is an estrogen inhibitor. In certain 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 certain embodiments, the estrogen inhibitor is a selective estrogen receptor degrader (SERD).In some embodiments, the SERD comprises fulvestrant. In some embodiments, the SERD comprises elacestrant (RAD1901).

[0188] Disclosed herein are methods for treating a human 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 I, or a pharmaceutically acceptable salt or morphic form thereof, as described herein. 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 advanced, unresectable or metastatic ER+ / HER2- breast cancer has progressed after a prior regimen comprising 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, trilaciclib, relociclib, or SHR6390 (dalpiciclib). In some embodiments, the CDK4 / 6 inhibitor is selected from BPI-16350, narazaciclib (ON-123300), FLX-925 (AMG-925), UCT-03-008, GLR2007, vilociclib (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, the chemotherapeutic agent is selected from protein synthesis inhibitors, DNA damaging chemotherapeutic agents, alkylating agents, topoisomerase inhibitors, RNA synthesis inhibitors, DNA complex binders, thiolate alkylating agents, guanine alkylating agents, tubulin binders, DNA polymerase inhibitors, anticancer enzymes, RAC1 inhibitors, thymidylate synthase inhibitors, oxazophosphorine compounds, integrin inhibitors, antifolates, antifolates, or combinations thereof. In certain embodiments, the anticancer therapy is an estrogen inhibitor. In certain embodiments, 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. In certain embodiments, the estrogen inhibitor is a selective estrogen receptor degrader (SERD). In some embodiments, the SERD comprises fulvestrant. In some embodiments, the SERD comprises elacestrant (RAD1901). In some embodiments, disclosed herein are methods of treating a human with advanced, unresectable or metastatic ER+ / HER2- breast cancer, comprising administering to the subject an effective amount of Compound I described herein or a pharmaceutically acceptable salt or morphic form thereof, administering to the subject an effective amount of a CDK4 / 6 inhibitor, and administering to the subject an effective amount of a selective estrogen receptor degrader (SERD). In some embodiments, the SERD comprises fulvestrant. In some embodiments, the SERD comprises elacestrant (RAD1901). In certain embodiments, the advanced, unresectable and / or metastatic ER+ / HER2- breast cancer has progressed after treatment with a CDK4 / 6 inhibitor. In certain embodiments, the previously administered CDK4 / 6 inhibitor is selected from palbociclib, abemaciclib, ribociclib, trilaciclib, SHR6390 (dalpiciclib), or lerociclib.Selective CDK4 / 6 inhibitors for use in combination with Compound I include, but are not limited to, palbociclib, abemaciclib, ribociclib, trilaciclib, SHR6390 (dalpiciclib), and relociclib. In alternative embodiments, the CDK4 / 6 inhibitor for use in combination with Compound I is selected from BPI-16350, narazaciclib (ON-123300), FLX-925 (AMG-925), UCT-03-008, GLR2007, vilociclib (XZP-3287), LY5219, PF-07220060, or ON-123300.

[0189] In certain embodiments, the methods described herein further comprise administering an effective amount of an estrogen inhibitor, hi some embodiments, 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.

[0190] In certain embodiments, the methods described herein further comprise 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, Abraxane, ifosfamide, topotecan, irinotecan, docetaxel, temozolomide, paclitaxel, doxorubicin, camptothecin, or a combination thereof. In some embodiments, the CDK4 / 6 inhibitor-resistant ER+ breast cancer is luminal A breast cancer. In some embodiments, Compound I or a pharmaceutically acceptable salt thereof is administered to the subject at least once daily, wherein an effective amount of the chemotherapeutic agent is administered according to the prescribed label. In some embodiments, Compound I or a pharmaceutically acceptable salt thereof is administered to a subject at least twice daily, where an effective amount of a chemotherapeutic agent is administered according to its label.

[0191] In some embodiments, disclosed herein are methods for treating a human having a CDK4 / 6 inhibitor-resistant cancer, comprising administering Compound I, a pharmaceutically acceptable salt thereof, or a morphic form thereof, as described herein, in combination with a CDK4 / 6 inhibitor. In some embodiments, the CDK4 / 6 inhibitor is selected from palbociclib, ribociclib, abemaciclib, trilaciclib, relociclib, or SHR6390 (dalpiciclib). In some embodiments, the CDK4 / 6 inhibitor is selected from BPI-16350, narazaciclib (ON-123300), FLX-925 (AMG-925), UCT-03-008, GLR2007, vilociclib (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).

[0192] In another aspect, disclosed herein are methods for treating a subject with CDK4 / 6 inhibitor-resistant small cell lung cancer (SCLC), comprising administering to the subject an effective amount of Compound I, or a pharmaceutically acceptable salt or morphic form thereof, as described herein, and administering to the subject an effective amount of a chemotherapeutic agent, wherein Compound I is administered to the subject within 24 hours 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, 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, the chemotherapeutic agent is carboplatin. In some embodiments, the chemotherapeutic agent is etoposide. In some embodiments, Compound I is administered to the subject within 6 hours of administering the chemotherapeutic agent. In some embodiments, Compound I is administered to the subject within 3 hours of administering the chemotherapeutic agent. In some embodiments, Compound I or a pharmaceutically acceptable salt thereof is administered to the subject at least once daily, wherein an effective amount of the chemotherapeutic agent is administered according to a designated label. In some embodiments, Compound I or a pharmaceutically acceptable salt thereof is administered to the subject at least twice daily, wherein an effective amount of the chemotherapeutic agent is administered according to a designated label.

[0193] In certain embodiments, the methods described herein further comprise administering an effective amount of an additional anti-cancer therapy, hi 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.

[0194] In another aspect, disclosed herein are methods for treating a subject with CDK4 / 6 inhibitor-resistant small cell lung cancer (SCLC), comprising administering to the subject an effective amount of Compound I, or a pharmaceutically acceptable salt or morphic form thereof, as described herein, and administering to the subject an effective amount of doxorubicin, wherein Compound I is administered to the subject within 24 hours prior to or simultaneously with administration of doxorubicin. In some embodiments, Compound I is administered to the subject within 6 hours prior to or simultaneously with administration of doxorubicin. In some embodiments, Compound I is administered to the subject within 3 hours prior to or simultaneously with administration of doxorubicin.

[0195] In certain aspects of this embodiment, the bioactive agent is a chemotherapeutic agent.

[0196] In another aspect of this embodiment, the bioactive agent is a growth factor.

[0197] In certain aspects of this embodiment, the bioactive agent is an immunomodulatory agent, including, but not limited to, checkpoint inhibitors, including, by way of non-limiting example, PD-1 inhibitors, PD-L1 inhibitors, PD-L2 inhibitors, CTLA-4 inhibitors, LAG-3 inhibitors, TIM-3 inhibitors, V-domain Ig suppressor of T-cell activation (VISTA) inhibitors, small molecules, peptides, nucleotides, or other inhibitors. In certain aspects, the immunomodulatory agent is an antibody, such as a monoclonal antibody.

[0198] Immune checkpoint inhibitors In an alternative embodiment, the selective CDK2 inhibitor Compound I described herein, or a pharmaceutically acceptable salt or morphic 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 antigen (CTA) inhibitors, and PD-L1 inhibitors. and combinations thereof. In some embodiments, an immune checkpoint inhibitor is administered in an effective amount in combination with a compound described herein to treat cancer, including, but not limited to, Hodgkin's 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, colon 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.

[0199] PD-1 inhibitors 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, thus inhibiting immunosuppression. In certain embodiments, the immune checkpoint inhibitor is selected from the group consisting of nivolumab (Opdivo™), pembrolizumab (Keytruda™), pidilizumab, AMP-224 (Amplimmune), sasanlimab (PF-06801591, Pfizer), MEDI0680 (AstraZeneca), spartalizumab (PDR001, Novartis), cemiplimab (Libtayo™, REGN2810, Regeneron), retifanlimab (MGA012, MacroGenics), tislelizumab (BGB-A317; BeiGene), camrelizumab (SHR-12-1, Jiangsu Hengrui Medicine Company and Incyte Corporation), CS1003 (Cstone and PD-1 immune checkpoint inhibitors selected from the group consisting of dostallimab (TSR-042, Tesaro), PD-L1 / VISTA inhibitor CA-170 (Curis Inc.).

[0200] In certain embodiments, the immune checkpoint inhibitor is the PD-1 immune checkpoint inhibitor nivolumab (Opdivo™), administered in an effective amount with a compound 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, colon cancer, hepatocellular carcinoma, or ovarian cancer. Nivolumab is FDA-approved for use in 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, advanced classical Hodgkin lymphoma (cHL), colorectal cancer, urothelial carcinoma, head and neck squamous cell carcinoma, or ovarian cancer. In some embodiments, nivolumab is administered at 240 mg every two weeks or 480 mg every four weeks. In some embodiments, the PD-1 inhibitor is pembrolizumab (Keytruda™) administered in an effective amount. In some embodiments, pembrolizumab is administered at 200 mg every three weeks or 400 mg every six weeks. In another aspect of this embodiment, the immune checkpoint inhibitor is the PD-1 immune checkpoint inhibitor pembrolizumab (Keytruda™) administered 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 a further aspect of this embodiment, the immune checkpoint inhibitor is the PD-1 immune checkpoint inhibitor pidilizumab (Medivation) administered in an amount effective for refractory diffuse large B-cell lymphoma (DLBCL) or metastatic melanoma. In a further aspect of this embodiment, the immune checkpoint inhibitor is the PD-1 immune checkpoint inhibitor cemiplimab (Libtayo / Regeneron) administered in an amount effective for cutaneous squamous cell carcinoma.

[0201] PD-L1 inhibitors 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, thus inhibiting immunosuppression. PD-L1 inhibitors include atezolizumab (Tecentriq™, Genentech), durvalumab (Imfinzi™, AstraZeneca), avelumab (Bavencio™, Merck), embafolimab (KN035, Alphamab), BMS-936559 (Bristol-Myers Squibb), lodapolimab (LY3300054, Eli Lilly), cosibelimab (CK-301, Checkpoint Therapeutics), sugemalimab (CS-1001, Cstone Pharmaceuticals), adebrelimab (SHR-1316, Jiangsu HengRui Medicine), CBT-502 (CBT Pharma), and BGB-A333 (BeiGene). In certain embodiments, the PD-L1 inhibitor is atezolizumab. In certain embodiments, the PD-L1 inhibitor is durvalumab. In certain embodiments, the PD-L1 inhibitor is avelumab. In certain embodiments, the PD-L1 inhibitor blocks the interaction of PD-L1 with CD80, thereby inhibiting immunosuppression.

[0202] In certain embodiments, the immune checkpoint inhibitor is the PD-L1 immune checkpoint inhibitor atezolizumab (Tecentriq™) 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 two weeks, 1200 mg every three weeks, or 1680 mg every four weeks. In some embodiments, atezolizumab is administered prior to chemotherapy. In another aspect of this embodiment, the immune checkpoint inhibitor is durvalumab (Imfinzi™; AstraZeneca and MedImmune) administered in an effective amount for the treatment of small cell lung cancer, non-small cell lung cancer, or bladder cancer. In some embodiments, durvalumab is administered at 10 mg / kg every two weeks or 1500 mg every four weeks for patients weighing over 30 kg, and at 10 mg / kg every two weeks for patients weighing less than 30 kg. In certain embodiments, the immune checkpoint inhibitor is the PD-L1 immune checkpoint inhibitor avelumab (Bavencio™; EMD Serono / Pfizer) administered in an amount effective for the treatment of Merkel cell carcinoma or urothelial carcinoma. In some embodiments, avelumab is administered at 800 mg every two weeks. In yet another aspect of the embodiment, the immune checkpoint inhibitor is KN035 (alfamab) administered in an amount effective for the treatment of PD-L1-positive solid tumors.

[0203] CTLA-4 inhibitors In certain aspects of this embodiment, the immune checkpoint inhibitor is a CTLA-4 immune checkpoint inhibitor that binds to CTLA-4 and inhibits immunosuppression. CTLA-4 is a glycoprotein of the immunoglobulin superfamily (Brunet et al. Nature. 328(6127):267-70 (1987)), which suppresses T cell responses through several converging mechanisms (Guntermann et al. J Immunol. 168(9);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).

[0204] In certain embodiments, the CTLA-4 immune checkpoint inhibitor is ipilimumab (Yervoy™) administered in an amount effective to treat metastatic melanoma, adjuvant melanoma, or non-small cell lung cancer.

[0205] LAG-3 inhibitors 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) that regulates many aspects of T cell function (Triebel et al. J Exp Med. 171:1393-405 (1990)). LAG-3 is expressed on the cell membrane 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. 168:874-80 (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 binds to regulatory T cells (T reg LAG-3 is an immune checkpoint receptor that is upregulated in both neutrophilic and anergic T cells. Simultaneous blockade of LAG-3 receptors enhances the reversal of this anergic state compared to blockade of a single receptor (Grosso et al. J Immunol. 182:6659-69 (2009)). The LAG-3 / MHC class II complex leads to downregulation of CD4+ Ag-specific T cell clonal expansion and cytokine secretion (Huard et al. Eur J Immunol. 26:1180-6 (1996)).

[0206] In some embodiments, the checkpoint inhibitor is a LAG-3 inhibitor that blocks the interaction of LAG-3 with MHC class II by binding to the LAG-3 receptor, thereby inhibiting immunosuppression. Examples of LAG-3 immune checkpoint inhibitors include, but are not limited to, leratolimab (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 Co. Ltd. (Suzhou)), EMB-02 (Shanghai EpimAb Biotherapeutics Co., Ltd.), SNA03 (Microbio Group), and AVA021 (Avacta).

[0207] T cell immunoreceptor (TIGIT) inhibitors containing immunoglobulin and ITIM domains In some embodiments, the immune checkpoint inhibitor is T cell immunoreceptor with immunoglobulin and ITIM domains (TIGIT). TIGIT is a promising new target for cancer immunotherapy. TIGIT levels are associated with the proliferation and proliferation of activated T cells, natural killer cells, and regulatory T cells (T regTIGIT is upregulated in several immune cell subtypes, including leukocytes (e.g., leukocytes), and binds to two ligands, CD155 (PVR) and CD112 (PVRL2, nectin-2), which are expressed by tumor cells and antigen-presenting cells (APCs) within the tumor microenvironment (Stanietsky et al. Proc Natl Acad Sci. 106:17858-63 (2009)).

[0208] TIGIT (also known as WUCAM, Vstm3, and VSIG9) is an Ig superfamily receptor that suppresses 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), one competitive costimulatory receptor (DNAM-1 / CD226), and multiple ligands (e.g., CD155 (PVR / NECL-5) and CD112 (Nectin-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)).

[0209] In humans, TIGIT is involved in the activation of activated CD4+ T cells, CD8+ T cells, natural killer (NK) cells, and regulatory T cells (T regTIGIT is expressed by T cells, including follicular T helper cells (Joller et al. J Immunol. 186:1338-42 (2011), Wu et al. Eur J Immunol. 46:1152-61 (2016)), while it is weakly expressed by 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) from healthy donors and cancer patients. reg TIGIT is highly expressed by tumors and is 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 within tumors (Chauvin et al. J Clin Invest. 125:2046-58 (2015), Johnston et al. Cancer Cell. 26:923-37 (2014)).

[0210] In some embodiments, the immune checkpoint inhibitor is a TIGIT inhibitor that blocks the interaction between TIGIT and CD155 by binding to the TIGIT receptor, thereby inhibiting immunosuppression. 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), osipelimab (BGB-A1217, BeiGene), EOS884448 (iTeos Therapeutics), SEA-TGT (Seattle Genetics), COM902 (Compugen), MPH-313 (Mereo Biopharma), M6223 (EMD Serono), HLX53 (Shanghai Henlius Biotech), JS006 (Junshi Bio), mAb-7 (Stanwei Biotech), SHR-1708 (Hengrui Medicine), BAT6005 (Bio-Thera Solutions), 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).

[0211] T-cell immunoglobulin and mucin domain 3 (TIM-3) inhibitor 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-expressed molecule containing immunoglobulin (Ig) and mucin domains that naturally inhibits interferon gamma (IFN-γ)-producing CD4 + T helper 1 (Th1) and CD8 + TIM-3 was discovered as a cell surface marker specific to T cytotoxic 1 (Tc1) cells (Monney et al. Nature. 415:536-41 (2002)). + and CD8 + It is co-regulated and co-expressed with other immune checkpoint receptors (PD-1, LAG-3, and TIGIT) on T cells (Chihara et al. Nature. 558:454-9 (2018), DeLong et al. ImmunoHorizons. 3:13-25 (2019)). TIM-3 expression is associated with substantially dysfunctional or terminally exhausted CD8 T cells in cancer. + It is a marker for 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 protein B1 (HMGB1), and CEACAM-1.

[0212] 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 protein B1 (HMGB1), and / or CEACAM-1 by binding to the TIM-3 receptor, thereby inhibiting immunosuppression. TIM-3 inhibitors include, but are not limited to, sabatolimab (MGB453, Novartis Pharmaceuticals), covolimab (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).

[0213] Alternative immune checkpoint inhibitors In some embodiments, the patient is administered a B7-H3 / CD276 immune checkpoint inhibitor such as enoblituzumab (MGA217, Macrogenics), MGD009 (Macrogenics), I-8H9 / omburtamab (Y-mabs), and I-8H9 / omburtamab (Y-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); or a carcinoembryonic antigen-related 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, such as monoclonal antibodies 34B1, 26H7, and 5F4, or recombinant forms thereof (e.g., as described in U.S. Patent Application Publication No. 2004 / 0047858, U.S. Patent No. 7,132,255, and WO 99 / 052552). In other embodiments, the anti-CEACAM antibody binds to CEACAM-5 (e.g., as described 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 (e.g., as described in WO 2013 / 054331 and U.S. Patent Application Publication No. 2014 / 0271618).

[0214] In some embodiments, the patient is 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 (ImmuneOnco Biopharma), 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 (KAHR Medical), CTX-5861 (Compass Therapeutics), BAT6004 (Bio-Thera), AUR-105 (Aurigene), AUR-104 (Aurigene), ANTI-CD47 (Biocad), ABP-500 (Abpro), ABP-160 (Abpro), TJC4 (I-MAB Biopharma), TJC4-CK (I-MAB Biopharma), SY102 (Saiyuan), SL-172154 (Shattuck Labs), PSTx-23 (Paradigm ShiftTherapeutics), PDL1 / CD47 BsAb (Hanmi Pharmaceuticals), NI-1801 (Novimmune), MBT-001 (Morphiex), LYN00301 (LynkCell), and BH-29xx (Beijing Hanmi).

[0215] In some embodiments, the ICI is an inhibitor directed 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).

[0216] In some embodiments, the immune checkpoint inhibitor is an inhibitor directed against B and T lymphocyte attenuator molecule (BTLA) (described in Zhang et al. Clin Exp Immunol. 163(1):77-87 (2011)), and TAB004 / JS004 (Junshi Biosciences).

[0217] 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).

[0218] chemotherapy drugs As contemplated herein, the CDK inhibitors described herein can be used in combination with any standard chemotherapeutic treatment modality, hi certain embodiments, the CDK inhibitors described herein can be used in combination with any standard chemotherapeutic treatment modality, and can further be used in combination with an immune checkpoint inhibitor.

[0219] In certain embodiments, the chemotherapeutic agent is toxic to immune effector cells. In certain embodiments, the chemotherapeutic agent inhibits cell proliferation. In certain embodiments, the administered cytotoxic chemotherapeutic agent is a DNA-damaging chemotherapeutic agent. In certain embodiments, the chemotherapeutic agent is a protein synthesis inhibitor, a DNA-damaging chemotherapeutic agent, an alkylating agent, a topoisomerase inhibitor, an RNA synthesis inhibitor, a DNA complex binder, a thiolate alkylating agent, a guanine alkylating agent, a tubulin binder, a DNA polymerase inhibitor, an anti-cancer enzyme, a RAC1 inhibitor, a thymidylate synthase inhibitor, an oxazophosphorine compound, a cilengitide, an integrin inhibitor such as camptothecin or homocamptothecin, an antifolate, or an antifolate.

[0220] In some embodiments, the additional therapeutic agent is selected from elotuzumab, rituximab, lenalidomide, cytarabine, daratumumab, adalimumab, idelalisib, gilteritinib, glasdegib, valacyclovir, acalabrutinib, ibrutinib, midostaurin, ruxolitinib, bortezomib, lapatinib, bendamustine, enzalutamide, azacitadine, obinutuzumab, decitabine, erdafitinib, or venetoclax.

[0221] In certain embodiments, the additional therapeutic agent is trastuzumab. In certain embodiments, the additional therapeutic agent is lapatinib. In certain embodiments, Compound I is administered with two, three, or four additional therapeutic agents. In certain embodiments, two additional therapeutic agents are present. In certain embodiments, the two additional therapeutic agents are lapatinib and trastuzumab.

[0222] In certain embodiments, the additional therapeutic agent is osimertinib mesylate (Tagrisso™).

[0223] In certain embodiments, the additional therapeutic agent is alectinib (Alecensa™).

[0224] In certain embodiments, the additional therapeutic agent is a MEK inhibitor.

[0225] In certain embodiments, the additional therapeutic agent is an androgen receptor ligand.

[0226] In certain embodiments, the additional therapeutic agent is a BTK inhibitor, such as, but not limited to, ibrutinib (Imbruvica™) or acalabrutinib (Calquence™).

[0227] In certain embodiments, the additional therapeutic agents are a MEK inhibitor and a RAF inhibitor.

[0228] In certain embodiments, the additional therapeutic agent is a RAF inhibitor.

[0229] In certain embodiments, the additional therapeutic agent is regorafenib.

[0230] Cytotoxic chemotherapy agents Cytotoxic, DNA-damaging chemotherapeutic agents are nonspecific and tend to be toxic to normal, rapidly dividing cells, such as HSPCs and immune effector cells, especially at high doses. As used herein, the term "DNA-damaging" chemotherapy or chemotherapeutic agent refers to treatment with a cytostatic or cytotoxic agent (i.e., a compound) to reduce or eliminate the growth or proliferation of unwanted cells, e.g., cancer cells, whose cytotoxic effects may be the result of one or more of nucleic acid intercalation or binding, DNA or RNA alkylation, inhibition of RNA or DNA synthesis, inhibition of another nucleic acid-associated activity (e.g., protein synthesis), or any other cytotoxic effect. Such compounds include, but are not limited to, DNA-damaging compounds capable of killing cells. "DNA-damaging" chemotherapeutic agents include, but are not limited to, alkylating agents, DNA intercalators, protein synthesis inhibitors, inhibitors of DNA or RNA synthesis, DNA base analogs, topoisomerase inhibitors, telomerase inhibitors, and telomeric DNA-binding compounds. For example, alkylating agents include alkylsulfonates such as busulfan, improsulfan, and piposulfan; aziridines such as benzodizepa, carboquone, meturedepa, and uredepa; ethylenimines and methylmelamines such as altretamine, triethylenemelamine, triethylenephosphoramide, triethylenethiophosphoramide, and triethylolmelamine; nitrogen mustards such as chlorambucil, chlornaphazine, cyclophosphamide, estramustine, mechlorethamine, mechlorethamine oxide hydrochloride, melphalan, nobembicine, phenesterine, 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 streptozocin.Chemotherapeutic antimetabolites include gemcitabine, mercaptopurine, thioguanine, cladribine, fludarabine phosphate, fluorouracil (5-FU), floxuridine, cytarabine, pentostatin, methotrexate, azathioprine, acyclovir, adenine β-1-D-arabinoside, amethopterin, aminopterin, 2-aminopurine, aphidicolin, 8-azaguanine, azaserine, 6-azauracil, 2'-azido-2'-deoxynucleosides, 5-bromodeoxycytidine, cytosine β-1-D-arabinoside, diazoxynorsine, dideoxynucleosides, 5-fluorodoxycytidine, 5-fluorodexuridine, and hydroxyurea.

[0231] Chemotherapeutic protein synthesis inhibitors include abrin, aurintricarboxylic acid, chloramphenicol, colicin E3, cycloheximide, diphtheria toxin, edeine A, emetine, erythromycin, ethionine, fluoride, 5-fluorotryptophan, fusidic acid, guanylylmethylene diphosphate and guanylyl imidodiphosphate, kanamycin, kasugamycin, kirromycin, and O-methylthreonine. Additional protein synthesis inhibitors include modeccin, neomycin, norvaline, pactamycin, paromomycin, puromycin, ricin, Shiga toxin, showdomycin, sparsomycin, spectinomycin, streptomycin, tetracycline, thiostrepton, and trimethoprim.

[0232] Inhibitors of DNA synthesis include alkylating agents such as dimethyl sulfate, nitrogen mustard, and sulfur mustard; intercalating agents such as acridine dyes, actinomycin, anthracene, benzopyrene, ethidium bromide, and propidium diiodide intertwining; and other agents such as distamycin and netropsin. Topoisomerase inhibitors such as irinotecan, teniposide, coumamycin, nalidixic acid, novobiocin, and oxolinic acid; inhibitors of cell division including colcemid, mitoxantrone, colchicine, vinblastine, and vincristine; and RNA synthesis inhibitors including actinomycin D, α-amanitin and other fungal amatoxins, cordycepin (3'-deoxyadenosine), dichlororibofuranosylb...

Claims

1. A pharmaceutical composition for use in the treatment of human patients with abnormal cell proliferation, The aforementioned pharmaceutical composition 【Chemistry 1】 (Compound I) contains a compound or a pharmaceutically acceptable salt thereof, The aforementioned treatment, (i) Obtaining a sample from the aforementioned human patient, (ii) To detect whether cyclin E1 (CCNE1) and / or cyclin E2 (CCNE2) are overexpressed and / or amplified in the sample compared to a control sample, (iii) If cyclin E1 (CCNE1) and / or cyclin E2 (CCNE2) are overexpressed and / or amplified, administer an effective amount of the pharmaceutical composition to the human patient, The pharmaceutical composition comprising the above.

2. The pharmaceutical composition according to claim 1, wherein the abnormal cell proliferation is lung cancer or gastric cancer.

3. The pharmaceutical composition according to claim 2, wherein the lung cancer is small cell lung cancer, squamous cell carcinoma of the lung, or adenocarcinoma of the lung.

4. The pharmaceutical composition according to claim 1, wherein the abnormal cell proliferation is breast cancer.

5. The pharmaceutical composition according to claim 4, wherein the breast cancer is hormone receptor positive (HR+).

6. The pharmaceutical composition according to claim 4, wherein the breast cancer is estrogen receptor positive (ER+).

7. The pharmaceutical composition according to claim 4, wherein the breast cancer is progesterone receptor positive (PR+).

8. The pharmaceutical composition according to claim 4, wherein the breast cancer is human epidermal growth factor receptor (HER2) 2-negative (HER2-).

9. The pharmaceutical composition according to claim 4, wherein the breast cancer is estrogen receptor positive (ER+) and human epidermal growth factor receptor 2 negative (HER2-).

10. The pharmaceutical composition according to claim 1, wherein the abnormal cell proliferation is ovarian cancer.

11. The pharmaceutical composition according to claim 10, wherein the ovarian cancer is ovarian serous cystadenocarcinoma.

12. The pharmaceutical composition according to claim 1, wherein the abnormal cell proliferation is platinum-refractory or platinum-resistant.

13. The pharmaceutical composition according to claim 1, wherein the abnormal cell proliferation is occurring after a prior regimen containing a CDK4 / 6 inhibitor.

14. The pharmaceutical composition according to any one of claims 1 to 13, wherein the treatment further comprises administering an effective amount of a CDK4 / 6 inhibitor.

15. The pharmaceutical composition according to claim 14, wherein the CDK4 / 6 inhibitor is selected from palbociclib, ribociclib, abemaciclib, trilaciclib, rerocyclib, SHR6390 (darpiciclib), BPI-16350, narazaciclib (ON-123300), FLX-925 (AMG-925), UCT-03-008, GLR2007, bilociclib (XZP-3287), LY5219, PF-07220060, and ON-123300.

16. The pharmaceutical composition according to any one of claims 1 to 13, wherein the treatment further comprises administering an effective amount of anticancer therapy.

17. The pharmaceutical composition according to claim 16, wherein the anticancer therapy is selected from radiation, surgery, immune checkpoint inhibitors, estrogen inhibitors, androgen inhibitors, and PARP inhibitors, or a combination thereof.

18. The pharmaceutical composition according to claim 17, wherein the anticancer therapy is an estrogen inhibitor selected from selective estrogen receptor modulators (SERMs), selective estrogen receptor degraders (SERDs), complete estrogen receptor degraders, complete estrogen antagonists, and partial estrogen antagonists, or combinations thereof.

19. The pharmaceutical composition according to claim 18, wherein the estrogen inhibitor is a selective estrogen receptor degrader (SERD).

20. The pharmaceutical composition according to claim 19, wherein SERD is selected from fulvestrant, lint destrant (G1T48), bolistrant (ZB-716), brillanestrant (GDC0810), camizestrant (AZD9833), D00502, elastrant (RAD1901), etuxtil (GW5638), GW7604, AZD9496, GDC-0927, giledestrant (GDC9545, RG6171), LSZ102, imulnestrant (LY3484356), SAR439859, SCR6852, and ZN-c5.

21. The pharmaceutical composition according to claim 18, wherein the estrogen inhibitor is a selective estrogen receptor modulator (SERM).

22. The pharmaceutical composition according to claim 21, wherein the SERM is letrozole.

23. The pharmaceutical composition according to any one of claims 1 to 13, further comprising administering 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 binder, a thiolate alkylating agent, a guanine alkylating agent, a tubulin binder, a DNA polymerase inhibitor, an anticancer enzyme, a RAC1 inhibitor, a thymidylate synthase inhibitor, an oxazophosphorine compound, an integrin inhibitor, an antifolic acid agent, and a folic acid antimetabolite, or a combination thereof, for the treatment.

24. The pharmaceutical composition according to claim 23, wherein the chemotherapeutic agent is selected from cisplatin, carboplatin, etoposide, oxaliplatin, 5-fluorouracil, floxuridine, capecitabine, gemcitabine, mitomycin, methotrexate, vinblastine, cyclophosphamide, dacarbazine, abraxane, ifosfamide, topotecan, irinotecan, docetaxel, temozolomide, paclitaxel, doxorubicin, and camptothecin, or a combination thereof.

25. The pharmaceutical composition according to claim 24, wherein the chemotherapeutic agent is doxorubicin, camptothecin, cisplatin, carboplatin, or etoposide.

26. The pharmaceutical composition according to any one of claims 1 to 13, wherein compound I is administered in a dosage form of about 100 mg to about 800 mg.

27. The pharmaceutical composition according to any one of claims 1 to 13, wherein compound I is administered once a day.

28. The pharmaceutical composition according to any one of claims 1 to 13, wherein compound I is administered twice a day.

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