Cyclin-dependent kinase inhibitory compounds for treating medical conditions

Abstract

The present invention pertains to the field of cell cycle inhibitory compounds for treating disorders involving abnormal cell proliferation and encompasses selective CDK2 inhibitors for medical treatment, as well as their pharmaceutically acceptable salts and compositions.

Description

[0001] Cross - Reference to Related Applications

[0002] This application claims the benefit of U.S. Provisional Application No. 63 / 027,113, filed May 19, 2020, and U.S. Provisional Application No. 63 / 085,672, filed Sep. 30, 2020. The entire contents of these applications are incorporated herein by reference for all purposes. Field of the Invention

[0003] The present invention pertains to the field of pyrimidine-based compounds for treating disorders involving abnormal cell proliferation, including but not limited to treating cancer and tumors. Background of the Invention

[0004] In normal tissues, cell proliferation is generally restricted to replenishing the cells required by the tissue. Once cells have terminally differentiated, they have a specialized function and no longer divide. Most tissues consist of non-dividing cells. Thus, normal cell proliferation is tightly controlled to ensure that only necessary cells divide. There is also a delicate balance between cell division and programmed cell death (apoptosis).

[0005] Cell division - sometimes referred to as the cell cycle - has four stages: G1 phase (synthesis of various enzymes required for DNA replication), S phase (DNA replication to produce two identical sets of chromosomes), G2 (synthesis of important proteins, including the production of microtubules), and M phase (nuclear division, cytoplasmic division, and formation of new cell membranes). Cell division also includes a complex system of cell signaling networks that allows cells to interpret information from numerous extracellular signals, including through receptor proteins, inflammatory factors, and pro-apoptotic and anti-apoptotic signals. Dysregulated signals include signals from gene mutations, infections, exposure to environmental factors including toxins, systemic stress, autoimmune disorders, and inflammation.

[0006] When the process of cell proliferation becomes dysregulated, a series of disorders occur, including benign growths, tumors, tumorigenesis, carcinogenesis, autoimmune disorders, inflammatory disorders, graft-versus-host rejection, and fibrotic disorders.

[0007] Numerous broad-spectrum anti-tumor agents have been developed. Cytoskeletal drugs such as paclitaxel target tubulin to block mitotic cell division and are used to treat a variety of cancers, including ovarian tumors, breast tumors, lung tumors, pancreatic tumors, and testicular tumors (see, e.g., Jordan, Wilson, Nature Reviews Cancer (2004) 4:253-265). Organometallic-based drugs such as cisplatin have been used to treat lymphomas, sarcomas, germ cell tumors, and some carcinomas, including bladder cancer, small cell lung cancer, and ovarian cancer. Cisplatin has the ability to bind to nitrogenous bases and cause extensive DNA cross-linking that ultimately leads to apoptosis (see, e.g., Siddick, Oncogene (2003) 22:7265-7279). Intercalating agents and alkylating agents have also been widely used clinically to treat various tumors. However, the overall toxicity associated with these drugs is a key issue for patients who require long-term treatment.

[0008] Palbociclib (PD-033299; Ibrance) is sold by Pfizer for use in combination with letrozole to treat estrogen-positive, HER2-negative breast cancer. The compound inhibits CDK4 and CDK6. The structure of palbociclib is:

[0009]

[0010] Abemaciclib (LY2835219) is a CDK 4 / 6 inhibitor that is currently in human clinical trials for the treatment of various types of cancer. It is in a Phase III trial for non-small cell lung cancer in Phase IV; is used in combination with fulvestrant for women with breast cancer; and is used in combination with anastrozole or letrozole for first-line treatment of breast cancer. The structure of abemaciclib is:

[0011]

[0012] Ribociclib (Lee011; Kisqali) is a CDK 4 / 6 inhibitor approved for use in combination with an aromatase inhibitor to treat some metastatic breast cancers and is currently in clinical trials for the treatment of certain other tumors. The structure of ribociclib is:

[0013]

[0014] Lerociclib is an oral selective CDK4 / 6 inhibitor in clinical development by G1 Therapeutics that can be used in combination with other targeted therapies in a variety of oncology indications. Lerociclib is currently being evaluated in two Phase 1 / 2 clinical trials: one trial is in combination with fulvestrant Combined for use in patients with estrogen receptor-positive, HER2-negative (ER+, HER2-) breast cancer (NCT02983071), one trial is with osimertinib Combined for use in the treatment of EGFRm non-small cell lung cancer. Lerociclib has the structure:

[0015]

[0016] Trilaciclib is a selective CDK4 / 6 inhibitor in clinical development by G1 Therapeutics, used as a first-in-class myeloprotective therapy designed to improve the prognosis of patients receiving chemotherapy by protecting hematopoietic stem and progenitor cells (HSPC) and immune system function. Trilaciclib is a short-acting intravenous CDK4 / 6 inhibitor administered before chemotherapy and is currently being evaluated in four randomized Phase 2 clinical trials, including a first-line SCLC trial in combination with etoposide and carboplatin chemotherapy regimens (NCT02499770); and a first-line SCLC trial in combination with the same chemotherapy regimen and checkpoint inhibitor (atezolizumab). Trilaciclib has the structure:

[0017]

[0018] A variety of other pyrimidine-based agents have been developed for the treatment of hyperproliferative diseases. U.S. Patent Nos. 8,822,683, 8,598,197, 8,598,186, 8,691,830, 8,829,102, 8,822,683, 9,102,682, 9,260,442, 9,481,691, 9,499,564, 9,957,276, 10,189,849, 10,189,850, and 10,189,851, filed by Tavares and Strum and assigned to G1 Therapeutics, describe a class of N-(heteroaryl)-pyrrolo[3,2-d]pyrimidin-2-amine cyclin-dependent kinase inhibitors, including those of the following formula (with variables as defined therein):

[0019]

[0020] U.S. Patent Nos. 9,464,092, 9,487,530, 9,527,857, 10,076,523, 10,085,992, and 10,434,104, also assigned to G1 Therapeutics, describe the use of the above pyrimidine-based agents in the treatment of cancer.

[0021] WO 2013 / 148748 (U.S.S.N. 61 / 617,657) entitled "Lactam Kinase Inhibitors", WO 2013 / 163239 (U.S.S.N. 61 / 638,491) entitled "Synthesis of Lactams", and WO 2015 / 061407, all filed by Tavares and also assigned to G1 Therapeutics, describe the synthesis of N-(heteroaryl)-pyrrolo[3,2-d]pyrimidin-2-amines and their use as lactam kinase inhibitors.

[0022] Other patent publications include the following. WO 2014 / 144326, filed by Strum et al. and assigned to G1 Therapeutics, describes compounds and methods for using pyrimidine-based CDK4 / 6 inhibitors to protect normal cells during chemotherapy. WO 2014 / 144596, filed by Strum et al. and assigned to G1 Therapeutics, describes compounds and methods for using pyrimidine-based CDK4 / 6 inhibitors to protect hematopoietic stem and progenitor cells from the effects of ionizing radiation. WO 2014 / 144847, filed by Strum et al. and assigned to G1 Therapeutics, describes the retention therapy of HSPC for abnormal cell proliferation using pyrimidine-based CDK4 / 6 inhibitors. WO 2014 / 144740, filed by Strum et al. and assigned to G1 Therapeutics, describes highly active antitumor and antiproliferative pyrimidine-based CDK 4 / 6 inhibitors. WO 2015 / 161285, filed by Strum et al. and assigned to G1 Therapeutics, describes tricyclic pyrimidine-based CDK inhibitors for radiation protection. WO 2015 / 161287, filed by Strum et al. and assigned to G1 Therapeutics, describes tricyclic pyrimidine-based CDK inhibitors for protecting cells during chemotherapy. WO 2015 / 161283, filed by Strum et al. and assigned to G1 Therapeutics, describes tricyclic pyrimidine-based CDK inhibitors for use in the retention therapy of HSPC for RB-positive abnormal cell proliferation. WO 2015 / 161288, filed by Strum et al. and assigned to G1 Therapeutics, describes tricyclic pyrimidine-based CDK inhibitors used as antitumor and antiproliferative agents. WO 2016 / 040858, filed by Strum et al. and assigned to G1 Therapeutics, describes the use of combinations of pyrimidine-based CDK4 / 6 inhibitors with other antitumor agents. WO 2016 / 040848, filed by Strum et al. and assigned to G1 Therapeutics, describes compounds and methods for treating certain Rb-negative cancers with CDK4 / 6 inhibitors and topoisomerase inhibitors. WO 2018 / 005860, WO 2018 / 005533, and WO 2018 / 005863, filed by Sorrentino et al. and assigned to G1 Therapeutics, describe various CDK inhibitors. WO 2018 / 106739, filed by Sorrentino et al. and assigned to G1 Therapeutics, describes the use of CDK4 / 6 inhibitors in conjunction with a specific dosing regimen.WO 2018 / 156812, filed by Strum et al. and assigned to G1 Therapeutics, describes the use of CDK4 / 6 inhibitors to treat EGFR-driven cancers. WO 2019 / 199883, filed by Strum et al. and assigned to G1 Therapeutics, describes compounds and methods for treating chemotherapy-resistant cancers. WO2019 / 136451, filed by Beelen et al. and assigned to G1 Therapeutics, describes a dosing regimen for the administration of G1T38. WO 2019 / 136244, filed by Strum et al. and assigned to G1 Therapeutics, describes additional compounds for inhibiting CDK. WO 2019 / 222521, filed by Strum et al. and assigned to G1 Therapeutics, describes additional compounds for inhibiting CDK. WO 2020 / 041770, filed by Schneider et al. and assigned to G1 Therapeutics, describes a synthetic method for preparing CDK inhibitory compounds. WO 2020 / 097625, filed by Schneider et al. and assigned to G1 Therapeutics, describes the use of a combination of a CDK4 / 6 inhibitor and eribulin. WO 2020 / 206034, filed by Strum et al. and assigned to G1 Therapeutics, describes additional compounds for inhibiting CDK. WO2020 / 206035, filed by Jung et al. and assigned to G1 Therapeutics, describes additional compounds for inhibiting CDK. WO 2020 / 257536, filed by Roberts et al. and assigned to G1 Therapeutics, describes enhancing patient selection for treating tumors with CDK4 / 6 inhibitors. WO 2021 / 072319, filed by Strum et al. and assigned to G1 Therapeutics, describes the use of CDK4 / 6 inhibitors to treat fibroblast growth factor-mediated cancers.

[0023] Although research has been conducted in the field of cell cycle inhibitory compounds for treating abnormal cell proliferation in a host (e.g., a human), given the severity of these diseases, there remains a need to identify new compounds that can meet this medical need.

[0024] Accordingly, an object of the present invention is to provide new compounds, methods, compositions, and manufacturing methods for inhibiting an unwanted cell cycle in a host (e.g., a human), wherein the compounds can be used to treat abnormal cell proliferation. Another aspect of the present invention is to provide compounds, methods, and compositions that can be used to treat cell cycle disorders in cells that are naturally or have become resistant to other therapies. SUMMARY OF THE INVENTION

[0025] The present invention provides a therapeutically active compound of formula I, formula II, formula III, formula IV, formula V, formula VI, formula VII, formula VIII, formula IX or formula X, or a pharmaceutically acceptable salt thereof, or a composition thereof. In certain embodiments, the active compound or its salt, composition or its isotopic analogue is used in an effective amount to treat a medical condition involving abnormal cell proliferation in a host (generally, a human) in need thereof, including tumors or cancers.

[0026] In certain embodiments, the compounds of the present invention are active against various cyclin-dependent kinases, including, for example, preferential activity against CDK2. In certain embodiments, the compounds of the present invention have a better inhibitory selectivity for CDK2 than for CDK1, CDK3, CDK4, CDK5, CDK6, CDK7 and / or CDK9. Based on this finding, compounds and methods for treating patients suffering from proliferative disorders including tumors or cancers are provided, which comprise administering to a patient in need thereof an effective amount of one or a combination of the compounds described herein or a pharmaceutically acceptable salt thereof, optionally in a pharmaceutically acceptable carrier. In certain embodiments, the anti-proliferative disorder is selected from cancer, tumor, neoplasm, benign growth, autoimmune disorder, inflammatory disorder, graft-versus-host rejection and fibrotic disorder. In a typical embodiment, the patient is a human.

[0027] In certain embodiments, the compounds of the present invention have high oral bioavailability, for example, an oral bioavailability of greater than about 50%, 60%, 70%, 80%, 90% or 95% F (the fraction of the drug reaching the systemic circulation as the intact drug). In certain embodiments, the compounds of the present invention have high metabolic stability, for example, the compounds of the present invention can exhibit a stability of greater than about 30 minutes, 45 minutes, 1 hour, 1.5 hours or 2 hours in human microsomes.

[0028] The present invention also provides an advantageous method of treating a patient suffering from a selective CDK4 / 6 inhibitor-resistant proliferative disorder such as a tumor or cancer, which comprises administering an effective amount of a compound of formula I, formula II, formula III, formula IV, formula V, formula VI, formula VII, formula VIII, formula IX or formula X or a pharmaceutically acceptable composition, salt or isotopic analogue thereof. Despite the development of selective CDK4 / 6 inhibitors, MYC-driven tumor types such as triple-negative breast cancer (TNBC) and small cell lung cancer (SCLC) with retinoblastoma (Rb) protein deletion or high cyclin E expression levels are difficult to treat due to intrinsic or primary resistance to existing selective CDK4 / 6 inhibitors. Additionally, certain cancers, although Rb-positive, are intrinsically resistant to the action of selective CDK4 / 6 inhibitors. Additionally, due to the presence of other genetic or phenotypic abnormalities, certain cancers with an intact Rb pathway may otherwise be intrinsically resistant to selective CDK4 / 6 inhibitors. 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 cyclin E upregulation, despite having an 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. Furthermore, certain cancers, such as ER+ breast cancer, are able to acquire resistance to selective CDK4 / 6 inhibitors during selective CDK4 / 6 inhibitor therapy, e.g., by upregulating cyclin E, which permits progression from G1 to S cell cycle via CDK2. In certain embodiments, the compounds described herein effectively inhibit cell cycle progression in cancer cells that are intrinsically resistant to selective CDK4 / 6 inhibitors, prone to acquiring resistance to selective CDK4 / 6 inhibitors, or have become resistant to selective CDK4 / 6 inhibitors.

[0029] The active compounds described herein act as inhibitors of cyclin-dependent kinases (CDKs), for example, by inhibiting CDK2 and / or CDK4 and / or CDK6 or a combination thereof and providing cell cycle inhibition in replicating cells. However, unlike selective CDK4 / 6 inhibitors, some active compounds herein can inhibit cells that are resistant to or have become resistant to selective CDK4 / 6 inhibitors by the ability of the active compound to preferentially inhibit another CDK (e.g., CDK2), thereby providing additional cell-cycle inhibition mechanisms. In one embodiment, the invention provides a selective CDK2 inhibitor. This feature is particularly useful in suppressing the cell cycle progression of proliferative disorders in cancer or other Rb negatives or that have become Rb negatives to escape CDK4 / 6 cell cycle control.

[0030] In certain aspects of the invention, the compound of Formula I, Formula II, Formula III, Formula IV, or Formula V:

[0031]

[0032] or a pharmaceutically acceptable salt, N-oxide, isotope analog and / or pharmaceutically acceptable composition thereof;

[0033] in:

[0034] X 1 , X 2 , X 3 , X 4 and X 5 Independently selected from N, CH, CR 2 and CR 4 ; where X 1 , X 2 , X 3 , X 4 and X 5 At least one of them is CR 2 ; and where X 1 , X 2 , X 3 , X 4 and X 5 No more than 2 choices are N;

[0035] Each R 1 are independently selected from hydrogen, halogen, -OR 14 NR 14 R 15 , alkyl, aryl, cycloalkyl, haloalkyl, heteroaryl, alkyl-hydroxyl and heterocycle, wherein two R 1may optionally form, together with the ring atoms to which they are attached, a 3-, 4-, 5-, 6-, 7- or 8-membered cycloalkyl or a 4-, 5-, 6-, 7- or 8-membered heterocycle having 1, 2 or 3 heteroatoms selected from N, O and S; wherein the cycloalkyl or heterocycle formed by bonding through two R 1 to the atoms to which they are attached may optionally be substituted by 1 or 2 substituents independently selected from R 50 ;

[0036] Each R 2 is independently selected from -NR 14 C(O)R 6 , -NR 14 S(O)R 6 , -NR 14 S(O)2R 6 , -NR 14 C(S)R 6 , -OC(O)R 6 , -OS(O)R 6 , -OS(O)2R 6 , -OC(S)R 6 , -C(O)R 6 ; -C(S)R 6 , -S(O)R 6 and -S(O)2R 6 ;

[0037] Or each R 2 is independently selected from -NR 14 C(O)R 6 , -NR 14 S(O)R 6 , -NR 14 S(O)2R 6 , -NR 14 C(S)R 6 , -OC(O)R 6 , -OS(O)R 6 , -OS(O)2R 6 , -OC(S)R 6 , -C(O)R 6 ; -C(S)R 6 , -S(O)R 6 , -S(=NR 14 )(O)R 6 , -S(=NR 14 )(O)R 6 and -S(O)2R 6 ;

[0038] R 3 is selected from hydrogen, -OR 14 , -NR14 R 15 , alkyl, alkenyl, alkynyl, –C(O)R 6 , -C(O)alkyl, -C(S)alkyl, aryl, -SO2alkyl, heteroaryl, heterocycle, -alkyl-aryl, and -alkyl-heteroaryl;

[0039] Each R 4 are independently selected from hydrogen, alkyl, aryl, cycloalkyl, haloalkyl, heteroaryl, heterocycle, halogen, cyano, -OR 14 、-NR 14 R 15 、-NR 14 C(O)R 6 、-NR 14 S(O)R 6 、-NR 14 S(O)2R 6 、-NR 14 C(S)R 6 、-OC(O)R 6 、-OS(O)R 6 、-OS(O)2R 6 、-OC(S)R 6 、-C(O)R 6 ;-C(S)R 6 、-S(O)R 6 and -S(O)2R 6 ;

[0040] R 5 is hydrogen, alkyl, haloalkyl, halogen, cyano, -OR 14 or -NR 14 R 15 ;

[0041] Each R 6 are independently selected from hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocycle, aryl, heteroaryl, NR 7 R 7 and OR 7 ; Hydrogen removal, NR 7 R 7 and OR 7 Each R outside 6 Optionally 1, 2, 3 or 4 R 8 substituted by a group;

[0042] Each R 7 is independently selected from hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocycle, aryl, alkyl-aryl, alkyl-heteroaryl, and heteroaryl; each R except hydrogen is 7 Optionally 1, 2, 3 or 4 R 8 substituted by a group;

[0043] Each R 8 is independently selected from hydrogen, halogen, haloalkyl, alkyl, alkenyl, alkynyl, cycloalkyl, heterocycle, aryl, heteroaryl, -S(O)2alkyl, NR 12 R 13 , alkyl-heteroaryl, alkyl-aryl and OR 12 ;

[0044] Each R 12 and R 13 are independently selected from hydrogen, alkyl, alkenyl, alkynyl, -C(O)alkyl, -C(S)alkyl, aryl, -SO2alkyl, -S(O)alkyl, heteroaryl, alkyl-aryl, cycloalkyl, heterocycle and alkyl-heteroaryl;

[0045] Each R 14 and R 15 are independently selected from hydrogen, alkyl, alkenyl, alkynyl, –C(O)R 6 , -C(O)alkyl, -C(S)alkyl, aryl, -SO2alkyl, heteroaryl, heterocycle, -alkyl-aryl and -alkyl-heteroaryl; and

[0046] Each R 50 is independently selected from hydrogen, -NR 14 R 15 , OR 14 and R 4 .

[0047] In an alternative embodiment, Formula I is:

[0048]

[0049] or a pharmaceutically acceptable salt, N-oxide, isotopic analogue and / or pharmaceutically acceptable composition thereof;

[0050] wherein each R 5 is independently selected from hydrogen, alkyl, haloalkyl, halogen, cyano, -OR 14 and -NR 14 R 15 while all other variables are as defined herein.

[0051] In certain aspects of the invention, there are provided compounds of Formula VI, Formula VII, Formula VIII, Formula IX or Formula X:

[0052]

[0053]

[0054] or a pharmaceutically acceptable salt, N-oxide, isotopically-labelled analogue and / or pharmaceutically acceptable composition thereof;

[0055] wherein:

[0056] X 11 、X 12 、X 13 、X 14 and X 15 are independently selected from N, CH and CR 4 , where no more than two of X 11 , X 12 , X 13 , X 14 and X 15 are selected as N;

[0057] R 17 and R 18 are independently selected from hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocycle, aryl, alkyl-aryl, alkyl-heteroaryl and heteroaryl, each of which other than hydrogen is optionally substituted by 1, 2, 3 or 4 R 8 groups; and

[0058] R 19 is hydrogen, alkyl, haloalkyl, halogen, cyano, -OR 14 or -NR 14 R 15 .

[0059] In certain embodiments, the compounds of the invention inhibit CDK2 or CDK9 more potently than CDK4 and / or CDK6. In certain embodiments, the compounds of the invention are CDK inhibitors with increased activity against CDK2.

[0060] These compounds can be used to treat diseases of abnormal cell proliferation in a host (usually a human) in need thereof.

[0061] In another embodiment, there is provided a method of treating a fibrotic disorder in a host, which comprises administering an effective amount of a compound of the invention or a pharmaceutically acceptable salt thereof, optionally in a pharmaceutically acceptable carrier.

[0062] In another embodiment, there is provided a method of treating rheumatoid arthritis or psoriasis in a host, which comprises administering an effective amount of a compound of the invention or a pharmaceutically acceptable salt thereof, optionally in a pharmaceutically acceptable carrier.

[0063] In another embodiment, there is provided a method of treating an autoimmune disorder in a host, which comprises administering an effective amount of a compound of the invention or a pharmaceutically acceptable salt thereof, optionally in a pharmaceutically acceptable carrier.

[0064] In certain embodiments, a method of treating a tumor or cancer in a host is provided, which comprises administering an effective amount of a compound of the invention or a pharmaceutically acceptable salt thereof, optionally in a pharmaceutically acceptable carrier. In one aspect of this embodiment, the cancer is an Rb-positive tumor or cancer. In another aspect of this embodiment, the cancer is an Rb-negative tumor or cancer. In certain aspects, the cancer is selected from breast cancer, prostate cancer (including anti-androgen prostate cancer), colon cancer (including metastatic colon cancer), another reproductive system cancer such as endometrial cancer, ovarian cancer or testicular cancer, small cell lung cancer, glioblastoma, and head and / or neck cancer.

[0065] In another embodiment, a method of treating a disorder of abnormal cell proliferation in a host such as a human is provided, which comprises administering in combination with or alternately with another active compound an effective amount of a combination of one or more active compounds described herein. In certain aspects of the invention, the second compound is a chemotherapeutic agent. In another aspect of this embodiment, the second active compound is an immunomodulator, including but not limited to checkpoint inhibitors such as anti-PD1, Ant-PD-L1, anti-CTLA, anti-LAG-3, anti-Tim and other antibodies, small molecules, peptides, nucleotides or other inhibitors, including but not limited to ipilimumab (Yervoy), pembrolizumab (Keytruda), nivolumab (Opdivo), cemiplimab (Libtayo), atezolizumab (Tecentriq), avelumab (Bavencio) and durvalumab (Imfinzi).

[0066] In another embodiment, one of the active compounds described herein is administered in combination with or alternately with an effective amount of an estrogen inhibitor in an effective amount to treat abnormal tissues of the female reproductive system such as breast cancer, ovarian cancer, endometrial cancer or uterine cancer, and the estrogen inhibitor includes but not limited to SERM (selective estrogen receptor modulator), SERD (selective estrogen receptor degrader), complete estrogen receptor degrader or another form of partial or complete estrogen antagonist.

[0067] In another embodiment, one of the active compounds described herein is administered in combination with or alternately with an effective amount of an androgen (such as testosterone) inhibitor in an effective amount to treat abnormal tissues of the male reproductive system such as prostate cancer or testicular cancer, and the androgen inhibitor includes but not limited to selective androgen receptor modulator, selective androgen receptor degrader, complete androgen receptor degrader or another form of partial or complete androgen antagonist. In certain embodiments, the prostate cancer or testicular cancer is androgen-resistant.

[0068] In certain embodiments, the compounds described herein inhibit cyclin-dependent kinases (“CDKs”). For example, the compounds described in the present invention provide a dose-dependent G1 arrest to CDK replication-dependent healthy cells of a subject, such as HSPCs or renal epithelial cells. The methods provided herein are sufficient to provide chemoprotection to targeted CDK replication-dependent healthy cells during exposure to chemotherapeutic agents, e.g., during the time period in which a DNA-damaging chemotherapeutic agent is capable of exerting a DNA-damaging effect on CDK replication-dependent healthy cells in a subject.

[0069] In certain embodiments, the compounds described herein are administered in combination with the use of hematopoietic growth factors, including but not limited to granulocyte colony-stimulating factor (G-CSF), granulocyte-macrophage colony-stimulating factor (GM-CSF), thrombopoietin, interleukin (IL)-12, steel factor, and erythropoietin (EPO) or derivatives thereof. In certain embodiments, the compound is administered prior to the administration of the hematopoietic growth factor. In certain embodiments, the administration of the hematopoietic growth factor is timed such that the effect of the compound on HSPCs has dissipated.

[0070] In certain embodiments, the compounds described herein are administered in combination with a BTK inhibitor. In another embodiment, the compounds described herein are administered in combination with an EGFR inhibitor.

[0071] The present invention also provides an advantageous method for treating a patient suffering from a cancer resistant to a selective CDK4 / 6 inhibitor, which comprises administering an effective amount of a compound of Formula I, Formula II, Formula III, Formula IV, Formula V, Formula VI, Formula VII, Formula VIII, Formula IX, or Formula X, or a pharmaceutically acceptable composition, salt, or isotopic analogue thereof. In certain aspects, the compounds of the present invention are used to treat a patient suffering from a cancer that is intrinsically resistant to selective CDK4 / 6 inhibition. In certain aspects, the compounds of the present invention are used to treat a patient suffering from a cancer that has acquired resistance to one or more selective CDK4 / 6 inhibitors. In certain aspects, the compounds of the present invention are administered in combination with a selective CDK4 / 6 inhibitor to a patient suffering from a CDK4 / 6-inhibitor-responsive cancer to extend the therapeutic efficacy of cell cycle inhibition in the cancer.

[0072] Similarly, cancers that are initially sensitive to inhibition by selective CDK4 / 6 inhibitors, such as ER+ breast cancer, may acquire resistance to selective CDK4 / 6 inhibition by upregulating cyclin E, which permits progression from G1 to S phase of the cell cycle through CDK2. Accordingly, the compounds of the present invention can be used in an effective amount to treat patients having a cancer that has developed resistance to a selective CDK4 / 6 inhibitor over time, said resistance being due to prior exposure to a CDK 4 / 6 inhibitor or through natural progression of the tumor. Accordingly, the present invention encompasses methods of administering an effective amount of a compound of the present invention to treat patients having a cancer that is initially responsive or sensitive to selective CDK4 / 6 inhibition, said methods prolonging the efficacy of selective CDK4 / 6 inhibitor treatment of CDK4 / 6-responsive cancers by delaying the acquisition of resistance to the inhibitory effects of the selective CDK4 / 6 inhibitor.

[0073] In a particular aspect, the present invention provides methods of treating a patient having a cancer that has developed acquired resistance to a selective CDK4 / 6 inhibitor by administering to the patient an effective amount of a compound of the present invention. In some embodiments, the selective CDK4 / 6 inhibitor to which the cancer has developed resistance is selected from palbociclib, abemaciclib, leroiciclib, trilaciclib, SH6390, and ribociclib.

[0074] In certain aspects, the present invention is a method of treating a patient having a cancer by administering a therapeutically effective amount of a compound of the present invention in combination with a selective CDK 4 / 6 inhibitor, wherein the patient is treatment-naive to the selective CDK4 / 6 inhibitor. By administering the compound of the present invention in combination with a selective CDK 4 / 6 inhibitor, a delay in the occurrence of acquired resistance to the selective CDK4 / 6 inhibitor can be achieved. In some embodiments, the selective CDK4 / 6 inhibitor administered in combination with the compound of the present invention is selected from palbociclib, abemaciclib, ribociclib, trilaciclib, SHR6390, and leroiciclib.

[0075] In certain aspects of the present invention, there is provided a method of treating a patient having a cancer, which comprises administering a therapeutically effective amount of a compound of the present invention, wherein the patient has previously received a selective CDK4 / 6 inhibitor and the cancer has become resistant to the selective CDK4 / 6 inhibitor. By administering the compound of the present invention, the present method permits continued treatment of the cancer with cell cycle inhibition following the development of resistance to the selective CDK 4 / 6 inhibitor. In some embodiments, the selective CDK4 / 6 inhibitor to which the cancer has developed resistance is selected from palbociclib, abemaciclib, ribociclib, trilaciclib, SHR6390, and leroiciclib.

[0076] In an alternative aspect, the present invention is a method for treating a patient suffering from Rb-positive cancer, which comprises:

[0077] a) administering to the patient a selective CDK4 / 6 inhibitor;

[0078] b) monitoring the cyclin E level in the patient's cancer; and

[0079] c) after detecting an increase in the cyclin E level, administering to the patient a compound of formula I, formula II, formula III, formula IV, formula V, formula VI, formula VII, formula VIII, formula IX or formula X, wherein the increase in the cyclin E level confers resistance of the cancer to the inhibitory effect of the selective CDK4 / 6 inhibitor. In some embodiments, the selective CDK4 / 6 inhibitor administered is selected from palbociclib, abemaciclib, ribociclib, trilaciclib, SHR6390 and lero ciclib.

[0080] In an alternative aspect, the present invention is a method for treating a patient suffering from cancer, which comprises:

[0081] a) determining the Rb status of the cancer;

[0082] b) if the Rb status is positive, administering to the patient a selective CDK4 / 6 inhibitor in combination with a compound of formula I, formula II, formula III, formula IV, formula V, formula VI, formula VII, formula VIII, formula IX or formula X;

[0083] c) if the Rb status is negative, administering to the patient a compound of formula I, formula II, formula III, formula IV, formula V, formula VI, formula VII, formula VIII, formula IX or formula X without administering a selective CDK4 / 6 inhibitor.

[0084] In some embodiments, the selective CDK4 / 6 inhibitor administered in combination with a compound of formula I, formula II, formula III, formula IV, formula V, formula VI, formula VII, formula VIII, formula IX or formula X is selected from palbociclib, abemaciclib, ribociclib, trilaciclib, SHR6390 and lero ciclib.

[0085] In an alternative aspect, the present invention is a method for treating a patient suffering from abnormal cell proliferation such as cancer, which comprises:

[0086] a) administering to the patient a selective CDK4 / 6 inhibitor;

[0087] b) monitoring the response of the patient's cancer to the selective CDK4 / 6 inhibitor;

[0088] c) Administering a compound of formula I, formula II, formula III, formula IV, formula V, formula VI, formula VII, formula VIII, formula IX or formula X to a patient after detecting that the patient's cancer has become unresponsive to a selective CDK4 / 6 inhibitor.

[0089] In some embodiments, the CDK4 / 6 inhibitor administered in combination with a compound of formula I, formula II, formula III, formula IV, formula V, formula VI, formula VII, formula VIII, formula IX or formula X is selected from palbociclib, abemaciclib, ribociclib, trilaciclib, SHR6390 and leroiciclib. In some embodiments, the non-responsiveness is disease progression.

[0090] In another alternative aspect, the present invention is a method of treating a patient suffering from abnormal cell proliferation such as cancer, comprising:

[0091] a) Administering a selective CDK4 / 6 inhibitor to the patient;

[0092] b) Monitoring one or more cellular signals indicative of the development of resistance to a selective CDK4 / 6 inhibitor in the cancer;

[0093] c) If one or more cellular signals indicate the development of resistance to a selective CDK4 / 6 inhibitor in the cancer, administering a compound of formula I, formula II, formula III, formula IV, formula V, formula VI, formula VII, formula VIII, formula IX or formula X to the patient. In some embodiments, the selective CDK4 / 6 inhibitor administered is selected from palbociclib, abemaciclib, ribociclib, trilaciclib, SHR6390 and leroiciclib.

[0094] In some embodiments, the one or more cellular signals indicative of the development of resistance to a selective CDK4 / 6 inhibitor in the cancer are selected from an increase in cyclin E expression, CCNE1 / 2 amplification, E2F amplification, CDK2 amplification, CDK6 amplification, CDK4 amplification, p16 amplification, WEE1 overexpression, DM2 overexpression, CDK7 overexpression, deletion of FZR1, HDAC activation, activation of the FGFR pathway, activation of the PI3K / AKT / mTOR pathway, deletion of ER or PR expression, higher AP-1 transcriptional activity, epithelial-mesenchymal transition, Smad 3 inhibition, autophagy activation, Rb1 deletion and RB1 mutational inactivation.

[0095] In another alternative aspect, the present invention provides a pharmaceutically acceptable composition comprising a compound of Formula I, Formula II, Formula III, Formula IV, Formula V, Formula VI, Formula VII, Formula VIII, Formula IX or Formula X and a selective CDK4 / 6 inhibitor, such as but not limited to one selected from palbociclib, abemaciclib, ribociclib, trilaciclib, SHR6390 and leroiciclib.

[0096] In another embodiment, there is provided a method of treating a disorder of abnormal cell proliferation in a host such as a human, which comprises administering in combination or alternately with another active compound an effective amount of a combination of compounds of Formula I, Formula II, Formula III, Formula IV, a combination of compounds of Formula V, Formula VI, Formula VII, Formula VIII, Formula IX or Formula X with a selective CDK4 / 6 inhibitor. In certain aspects of the present invention, the said another active compound is a chemotherapeutic agent. In another aspect of this embodiment, the said another active compound is an immunomodulator, including but not limited to checkpoint inhibitors such as anti-PD1, anti-PD-L1, anti-CTLA, anti-LAG-3, anti-Tim and other antibodies, small molecules, peptides, nucleotides or other inhibitors, including but not limited to ipilimumab (Yervoy), pembrolizumab (Keytruda), nivolumab (Opdivo), cemiplimab (Libtayo), atezolizumab (Tecentriq), avelumab (Bavencio) and durvalumab (Imfinzi).

[0097] In another embodiment, the compounds of the present invention are combined with a selective CDK4 / 6 inhibitor and combined or alternately administered in an effective amount with an estrogen inhibitor to treat abnormal tissues of the female reproductive system such as breast cancer, ovarian cancer, endometrial cancer or uterine cancer, and the estrogen inhibitors include but not limited to SERM (selective estrogen receptor modulator), SERD (selective estrogen receptor degrader), complete estrogen receptor degrader or another form of partial or complete estrogen antagonist.

[0098] In another embodiment, the compounds of the present invention are combined with a selective CDK4 / 6 inhibitor and combined or alternately administered in an effective amount with an androgen (such as testosterone) inhibitor to treat abnormal tissues of the male reproductive system such as prostate cancer or testicular cancer, and the androgen inhibitors include but not limited to selective androgen receptor modulators, selective androgen receptor degraders, complete androgen receptor degraders or another form of partial or complete androgen antagonists. In some embodiments, the prostate cancer or testicular cancer is androgen-resistant.

[0099] In some embodiments, the compounds of the invention are administered in an effective amount in combination with a CDK4 / 6 inhibitor and in combination with a BTK inhibitor. In another embodiment, the compounds of the invention are administered in an effective amount in combination with a CDK4 / 6 inhibitor and in combination with an EGFR inhibitor.

[0100] In certain embodiments, the compounds of the invention inhibit CDK2, CDK4, CDK6, and / or CDK9. In certain embodiments, the compound is a CDK2 inhibitor. In certain embodiments, the compound is a CDK4 inhibitor. In certain embodiments, the compound is a CDK6 inhibitor. In certain embodiments, the compound is a CDK9 inhibitor.

[0101] Accordingly, the invention includes at least the following features:

[0102] (a) A compound of the invention as described herein or a pharmaceutically acceptable salt thereof;

[0103] (b) A compound of the invention as described herein or a pharmaceutically acceptable salt thereof, which can be used in an effective amount for treating disorders of abnormal cell proliferation, including tumors or cancers;

[0104] (c) A compound of the invention as described herein or a pharmaceutically acceptable salt thereof, which can be used for treating cancers resistant to treatment with a compound that is a CDK4 / 6 inhibitor, such as treatment with palbociclib, abemaciclib, or ribociclib;

[0105] (d) Use of a compound of the invention or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for treating disorders of abnormal cell proliferation such as tumors or cancers;

[0106] (e) Use of a compound of the invention or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for treating cancers resistant to treatment with a compound that is a CDK4 / 6 inhibitor, such as treatment with palbociclib, abemaciclib, or ribociclib;

[0107] (f) A method of manufacturing a medicament for therapeutic use for treating disorders of abnormal cell proliferation including tumors or cancers, characterized in that a compound of the invention as described herein is used in the manufacture;

[0108] (q) A pharmaceutical formulation comprising an effective therapeutically amount of a compound of the invention or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier or diluent;

[0109] (r) A compound of the invention as described herein, as a mixture of enantiomers or diastereomers (as relevant), including as a racemate;

[0110] (s) The compounds of the invention as described herein, in enantiomerically or diastereomerically (as appropriate) enriched form, including as isolated enantiomers or diastereomers (i.e., with a purity greater than 85%, 90%, 95%, 97% or 99%);

[0111] (t) A method for preparing a therapeutic product containing an effective amount of a compound of the invention as described herein;

[0112] (u) A solid dosage form for oral delivery of a compound of the invention or a pharmaceutically acceptable salt thereof in a pharmaceutically acceptable carrier;

[0113] (v) A parenteral dosage form for systemic delivery (including delivery via intravenous injection) of a compound of the invention or a pharmaceutically acceptable salt thereof in a pharmaceutically acceptable carrier; and

[0114] (w) A method for manufacturing a medicament intended for antitumor therapy, characterized in that a compound of the invention as described herein is used in the manufacturing. Detailed Description

[0115] I. Compounds

[0116] In certain embodiments, the compounds of the invention have the following formula:

[0117]

[0118] or a pharmaceutically acceptable salt, N-oxide, isotopic analogue and / or pharmaceutically acceptable composition thereof; wherein y is 0, 1, 2, 3 or 4 and the remaining variables are as defined herein.

[0119] In certain embodiments, the compounds of the invention have the following formula:

[0120]

[0121]

[0122] or a pharmaceutically acceptable salt, N-oxide, isotopic analogue and / or pharmaceutically acceptable composition thereof; wherein the variables are as defined herein.

[0123] In certain embodiments, the compounds of the invention have the following formula:

[0124]

[0125]

[0126] or a pharmaceutically acceptable salt, N-oxide, isotopically labeled analogue, and / or pharmaceutically acceptable composition thereof; wherein the variables are as defined herein.

[0127] In certain embodiments, the compounds of the invention have the following formula:

[0128]

[0129] or a pharmaceutically acceptable salt, N-oxide, isotopically labeled analogue, and / or pharmaceutically acceptable composition thereof; wherein the variables are as defined herein.

[0130] In certain embodiments, the compounds of the invention have the following formula:

[0131]

[0132] or a pharmaceutically acceptable salt, N-oxide, isotopically labeled analogue, and / or pharmaceutically acceptable composition thereof; wherein the variables are as defined herein.

[0133] In certain embodiments, the compounds of the invention have the following formula:

[0134]

[0135] or a pharmaceutically acceptable salt, N-oxide, isotopically labeled analogue, and / or pharmaceutically acceptable composition thereof; wherein the variables are as defined herein.

[0136] In certain embodiments, the compounds of the invention are selected from:

[0137]

[0138]

[0139] or a pharmaceutically acceptable salt thereof.

[0140] In certain embodiments, the compounds of the invention are selected from:

[0141]

[0142]

[0143] or a pharmaceutically acceptable salt thereof.

[0144] In certain embodiments, the compounds of the invention are selected from:

[0145]

[0146] or a pharmaceutically acceptable salt thereof.

[0147] Embodiments of "alkyl"

[0148] In certain embodiments, "alkyl" is C1-C 10 alkyl, C1-C9 alkyl, C1-C8 alkyl, C1-C7 alkyl, C1-C6 alkyl, C1-C5 alkyl, C1-C4 alkyl, C1-C3 alkyl or C1-C2 alkyl.

[0149] In certain embodiments, "alkyl" has one carbon.

[0150] In certain embodiments, "alkyl" has two carbons.

[0151] In certain embodiments, "alkyl" has three carbons.

[0152] In certain embodiments, "alkyl" has four carbons.

[0153] In certain embodiments, "alkyl" has five carbons.

[0154] In certain embodiments, "alkyl" has six carbons.

[0155] Non-limiting examples of "alkyl" include: methyl, ethyl, propyl, butyl, pentyl and hexyl.

[0156] Additional non-limiting examples of "alkyl" include: isopropyl, isobutyl, isopentyl and isohexyl.

[0157] Additional non-limiting examples of "alkyl" include: sec-butyl, sec-pentyl and sec-hexyl.

[0158] Additional non-limiting examples of "alkyl" include: tert-butyl, tert-pentyl and tert-hexyl.

[0159] Additional non-limiting examples of "alkyl" include: neopentyl, 3-pentyl and active pentyl.

[0160] In certain embodiments, "alkyl" is "substituted alkyl".

[0161] In certain embodiments, "alkenyl" is "substituted alkenyl".

[0162] In certain embodiments, "alkynyl" is "substituted alkynyl".

[0163] Embodiments of "haloalkyl"

[0164] In certain embodiments, "haloalkyl" is C1-C 10Halogenated alkyl, C1-C9 halogenated alkyl, C1-C8 halogenated alkyl, C1-C7 halogenated alkyl, C1-C6 halogenated alkyl, C1-C5 halogenated alkyl, C1-C4 halogenated alkyl, C1-C3 halogenated alkyl, and C1-C2 halogenated alkyl.

[0165] In certain embodiments, "halogenated alkyl" has one carbon.

[0166] In certain embodiments, "halogenated alkyl" has one carbon and one halogen.

[0167] In certain embodiments, "halogenated alkyl" has one carbon and two halogens.

[0168] In certain embodiments, "halogenated alkyl" has one carbon and three halogens.

[0169] In certain embodiments, "halogenated alkyl" has two carbons.

[0170] In certain embodiments, "halogenated alkyl" has three carbons.

[0171] In certain embodiments, "halogenated alkyl" has four carbons.

[0172] In certain embodiments, "halogenated alkyl" has five carbons.

[0173] In certain embodiments, "halogenated alkyl" has six carbons.

[0174] Non-limiting examples of "halogenated alkyl" include:

[0175] Additional non-limiting examples of "halogenated alkyl" include:

[0176] Additional non-limiting examples of "halogenated alkyl" include:

[0177] Additional non-limiting examples of "halogenated alkyl" include:

[0178] Embodiments of "aryl"

[0179] In certain embodiments, "aryl" is a 6-carbon aromatic group (phenyl).

[0180] In certain embodiments, "aryl" is a 10-carbon aromatic group (naphthyl).

[0181] In certain embodiments, "aryl" is a 6-carbon aromatic group fused to a heterocycle; wherein the point of attachment is the aryl ring. Non-limiting examples of "aryl" include indoline, tetrahydroquinoline, tetrahydroisoquinoline, and dihydrobenzofuran; and wherein the point of attachment of each group is on the aromatic ring.

[0182] For example, is an "aryl" group.

[0183] However, is a "heterocycle" group.

[0184] In certain embodiments, "aryl" is a 6-carbon aromatic group fused to a cycloalkyl, wherein the point of attachment is the aryl ring. Non-limiting examples of "aryl" include indane and tetralin, wherein the point of attachment of each group is on the aromatic ring.

[0185] For example, is an "aryl" group.

[0186] However, is a "cycloalkyl" group.

[0187] In certain embodiments, "aryl" is "substituted aryl".

[0188] Embodiments of "heteroaryl"

[0189] In certain embodiments, "heteroaryl" is a 5-membered aromatic group containing 1, 2, 3, or 4 nitrogen atoms.

[0190] In certain embodiments, "heteroaryl" is a 5-membered aromatic group containing 1, 2, 3, or 4 atoms independently selected from nitrogen and oxygen.

[0191] Non-limiting examples of 5-membered "heteroaryl" groups include pyrrole, furan, thiophene, pyrazole, imidazole, triazole, tetrazole, isoxazole, oxazole, oxadiazole, oxatriazole, isothiazole, thiazole, thiadiazole, and thiatriazole.

[0192] Additional non-limiting examples of 5-membered "heteroaryl" groups include:

[0193]

[0194] In certain embodiments, "heteroaryl" is a 6-membered aromatic group containing 1, 2, or 3 nitrogen atoms (i.e., pyridyl, pyridazinyl, triazinyl, pyrimidinyl, and pyrazinyl).

[0195] Non-limiting examples of 6-membered "heteroaryl" groups having 1 or 2 nitrogen atoms include:

[0196]

[0197] In certain embodiments, "heteroaryl" is a 9-membered bicyclic aromatic group containing 1 or 2 atoms selected from nitrogen, oxygen, and sulfur.

[0198] Non-limiting examples of bicyclic "heteroaryl" groups include indole, benzofuran, isoindole, indazole, benzimidazole, azaindole, azaindazole, purine, isobenzofuran, benzothiophene, benzisoxazole, benzisothiazole, benzoxazole, and benzothiazole.

[0199] Additional non-limiting examples of bicyclic "heteroaryl" groups include:

[0200]

[0201] Additional non-limiting examples of bicyclic "heteroaryl" groups include:

[0202]

[0203] Additional non-limiting examples of bicyclic "heteroaryl" groups include:

[0204]

[0205] In certain embodiments, "heteroaryl" is a 10-membered bicyclic aromatic group containing 1 or 2 atoms selected from nitrogen, oxygen, and sulfur.

[0206] Non-limiting examples of bicyclic "heteroaryl" groups include quinoline, isoquinoline, quinoxaline, phthalazine, quinazoline, cinnoline, and naphthyridine.

[0207] Additional non-limiting examples of bicyclic "heteroaryl" groups include:

[0208]

[0209] In certain embodiments, "heteroaryl" is "substituted heteroaryl".

[0210] Embodiments of "cycloalkyl"

[0211] In certain embodiments, "cycloalkyl" is C3-C8 cycloalkyl, C3-C7 cycloalkyl, C3-C6 cycloalkyl, C3-C5 cycloalkyl, C3-C4 cycloalkyl, C4-C8 cycloalkyl, C5-C8 cycloalkyl, or C6-C8 cycloalkyl.

[0212] In certain embodiments, "cycloalkyl" has three carbons.

[0213] In certain embodiments, "cycloalkyl" has four carbons.

[0214] In certain embodiments, "cycloalkyl" has five carbons.

[0215] In certain embodiments, "cycloalkyl" has six carbons.

[0216] In certain embodiments, "cycloalkyl" has seven carbons.

[0217] In certain embodiments, "cycloalkyl" has eight carbons.

[0218] In certain embodiments, "cycloalkyl" has nine carbons.

[0219] In certain embodiments, "cycloalkyl" has ten carbons.

[0220] Non-limiting examples of "cycloalkyl" include: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, and cyclodecyl.

[0221] Additional non-limiting examples of "cycloalkyl" include indane and tetralin, where the point of attachment of each group is on the cycloalkyl ring.

[0222] For example, is a "cycloalkyl" group.

[0223] However, is an "aryl" group.

[0224] In certain embodiments, "cycloalkyl" is "substituted cycloalkyl".

[0225] Embodiments of "heterocycle"

[0226] In certain embodiments, "heterocycle" refers to a cyclic ring having one nitrogen and 3, 4, 5, 6, 7, or 8 carbon atoms.

[0227] In certain embodiments, "heterocycle" refers to a cyclic ring having one nitrogen and one oxygen and 3, 4, 5, 6, 7, or 8 carbon atoms.

[0228] In certain embodiments, "heterocycle" refers to a cyclic ring having two nitrogens and 3, 4, 5, 6, 7, or 8 carbon atoms.

[0229] In certain embodiments, "heterocycle" refers to a cyclic ring having one oxygen and 3, 4, 5, 6, 7, or 8 carbon atoms.

[0230] In certain embodiments, "heterocycle" refers to a cyclic ring having one sulfur and 3, 4, 5, 6, 7, or 8 carbon atoms.

[0231] Non-limiting examples of "heterocycle" include aziridine, ethylene oxide, ethylene sulfide, azetidine, 1,3-diazetidine, oxetane, and thietane.

[0232] Additional non-limiting examples of "heterocycle" include pyrrolidine, 3-pyrroline, 2-pyrroline, pyrazolidine, and imidazolidine.

[0233] Additional non-limiting examples of "heterocycle" include tetrahydrofuran, 1,3-dioxolane, tetrahydrothiophene, 1,2-oxathiolane, and 1,3-oxathiolane.

[0234] Additional non-limiting examples of "heterocycle" include piperidine, piperazine, tetrahydropyran, 1,4-dioxane, thiane, 1,3-dithiane, 1,4-dithiane, morpholine, and thiomorpholine.

[0235] Additional non-limiting examples of "heterocycle" include indoline, tetrahydroquinoline, tetrahydroisoquinoline, and dihydrobenzofuran, wherein the point of attachment of each group is on the heterocyclic ring.

[0236] For example, is a "heterocyclic" group.

[0237] However, is an "aryl" group.

[0238] Non-limiting examples of "heterocycle" also include:

[0239]

[0240] Additional non-limiting examples of "heterocycle" include:

[0241]

[0242] Additional non-limiting examples of "heterocycle" include:

[0243]

[0244] Non-limiting examples of "heterocycle" also include:

[0245]

[0246] Non-limiting examples of "heterocycle" also include:

[0247]

[0248] Additional non-limiting examples of "heterocycle" include:

[0249]

[0250] Additional non-limiting examples of "heterocycle" include:

[0251]

[0252] In certain embodiments, the "heterocycle" is a "substituted heterocycle".

[0253] Embodiments of "-alkyl-aryl"

[0254] In certain embodiments, "-alkyl-aryl" refers to a 1-carbon alkyl group substituted with an aryl group.

[0255] Non-limiting examples of "-alkyl-aryl" include:

[0256]

[0257] In certain embodiments, "-alkyl-aryl" is

[0258] In certain embodiments, "-alkyl-aryl" refers to a 2-carbon alkyl group substituted with an aryl group.

[0259] Non-limiting examples of "-alkyl-aryl" include:

[0260]

[0261] In certain embodiments, "alkyl-aryl" refers to a 3-carbon alkyl group substituted with an aryl group.

[0262] Optional substituents

[0263] In certain embodiments, a group described herein that may be substituted with 1 or 2 substituents is substituted with one substituent.

[0264] In certain embodiments, a group described herein that may be substituted with 1 or 2 substituents is substituted with two substituents.

[0265] In certain embodiments, a group described herein that may be substituted with 1, 2, 3, or 4 substituents is substituted with one substituent.

[0266] In certain embodiments, a group described herein that may be substituted with 1, 2, 3, or 4 substituents is substituted with two substituents.

[0267] In certain embodiments, a group described herein that may be substituted with 1, 2, 3, or 4 substituents is substituted with three substituents.

[0268] In certain embodiments, a group described herein that may be substituted with 1, 2, 3, or 4 substituents is substituted with four substituents.

[0269] R 1 Embodiments of

[0270] In certain embodiments, one R 1is H and the other R 1 is aryl.

[0271] In certain embodiments, one R 1 is H and the other R 1 is phenyl.

[0272] In certain embodiments, one R 1 is H and the other R 1 is alkyl.

[0273] In certain embodiments, at least one R 1 is hydroxy.

[0274] In certain embodiments, at least one R 1 is halogen.

[0275] In certain embodiments, at least one R 1 is haloalkyl.

[0276] In certain embodiments, at least one R 1 is fluorine.

[0277] In certain embodiments, at least two Rs 1 are fluorine.

[0278] In certain embodiments, at least two Rs 1 are alkyl.

[0279] In certain embodiments, two Rs 1 combine to form a 5-membered cycloalkyl. In certain embodiments, the cycloalkyl is substituted by one R 50 substituent. In certain embodiments, the cycloalkyl is substituted by two R 50 substituents. In certain embodiments, the cycloalkyl is substituted by NH2. In certain embodiments, the cycloalkyl is substituted by OR 14 substituent. In certain embodiments, the cycloalkyl is substituted by OH. In certain embodiments, the cycloalkyl is substituted by alkyl. In certain embodiments, the cycloalkyl is substituted by CH3.

[0280] In certain embodiments, two Rs 1 combine to form a 6-membered cycloalkyl. In certain embodiments, the cycloalkyl is substituted by one R 50 substituent. In certain embodiments, the cycloalkyl is substituted by two R 50 substituents. In certain embodiments, the cycloalkyl is substituted by NH2. In certain embodiments, the cycloalkyl is substituted by OR 14is replaced. In certain embodiments, the cycloalkyl is replaced by OH. In certain embodiments, the cycloalkyl is replaced by alkyl. In certain embodiments, the cycloalkyl is replaced by CH3.

[0281] In certain embodiments, two Rs 1 combine to form a 5-membered heterocycle. In certain embodiments, the heterocycle is replaced by one R 50 substituent. In certain embodiments, the heterocycle is replaced by two R 50 substituents. In certain embodiments, the heterocycle is replaced by NH2. In certain embodiments, the heterocycle is replaced by OR 14 . In certain embodiments, the heterocycle is replaced by OH. In certain embodiments, the heterocycle is replaced by alkyl. In certain embodiments, the heterocycle is replaced by CH3.

[0282] In certain embodiments, two Rs 1 combine to form a 6-membered heterocycle. In certain embodiments, the heterocycle is replaced by one R 50 substituent. In certain embodiments, the heterocycle is replaced by two R 50 substituents. In certain embodiments, the heterocycle is replaced by NH2. In certain embodiments, the heterocycle is replaced by OR 14 . In certain embodiments, the heterocycle is replaced by OH. In certain embodiments, the heterocycle is replaced by alkyl. In certain embodiments, the heterocycle is replaced by CH3.

[0283] In certain embodiments, two Rs 1 combine to form a 5-membered spiro ring selected from the following:

[0284]

[0285]

[0286] In certain embodiments, two Rs 1 combine to form a 6-membered spiro ring selected from the following:

[0287]

[0288] In certain embodiments, one R 1 is hydrogen.

[0289] In certain embodiments, one R 1 is alkyl.

[0290] In certain embodiments, one R 1 is -NR 12 R 13 .

[0291] In certain embodiments, one R 1 is cycloalkyl.

[0292] In certain embodiments, one R 1 is heterocyclic.

[0293] In certain embodiments, one R 1 is aryl.

[0294] In certain embodiments, one R 1 is heteroaryl.

[0295] In certain embodiments, R 1 is independently hydrogen, halogen, -OR 14 or NR 14 R 15 wherein R 14 is independently selected from hydrogen, alkyl, -C(O)R 6 and -C(O)alkyl; and wherein R 15 is independently selected from hydrogen and alkyl.

[0296] In certain embodiments, R 1 is -OR 14 wherein R 14 is independently selected from hydrogen, alkyl and –C(O)R 6 ; wherein R 6 is independently selected from hydrogen and alkyl.

[0297] In certain embodiments, R 1 is NR 14 R 15 ; wherein R 14 is independently selected from hydrogen, alkyl, –C(O)R 6 and -C(O)alkyl; and wherein R 15 is independently selected from hydrogen and alkyl.

[0298] In certain embodiments, two Rs 1 together with the ring atom to which they are attached form a 3-, 4-, 5-, 6-, 7- or 8-membered cycloalkyl or a 4-, 5-, 6-, 7- or 8-membered heterocycle having 1, 2 or 3 heteroatoms selected from N, O and S.

[0299] In certain embodiments, two Rs 1 together with the ring atom to which they are attached form a 3-, 4-, 5-, 6-, 7- or 8-membered cycloalkyl or a 4-, 5-, 6-, 7- or 8-membered heterocycle having 1, 2 or 3 heteroatoms selected from N, O and S; and wherein the cycloalkyl or heterocycle formed by the combination of two Rs 1 with the atoms to which they are attached may optionally be substituted by 1 or 2 substituents independently selected from R 50 .

[0300] R 2 embodiments of:

[0301] In certain embodiments, R 2 is -NR 14 C(O)R 6 、-NR 14 S(O)R 6 、-NR 14 S(O)2R 6 、-NR 14 C(S)R 6 、-OC(O)R 6 、-OS(O)R 6 、-OS(O)2R 6 、-OC(S)R 6 、-C(O)R 6 ; -C(S)R 6 、-S(O)R 6 or -S(O)2R 6 .

[0302] In certain embodiments, R 2 is -C(O)R 6 ; -C(S)R 6 、-S(O)R 6 or -S(O)2R 6 .

[0303] In certain embodiments, R 2 is -C(O)R 6 .

[0304] In certain embodiments, R 2 is -C(O)NH2.

[0305] In certain embodiments, R 2 is -C(O)CH3.

[0306] In certain embodiments, R 2 is -S(O)2R 6 .

[0307] In certain embodiments, R 2 is -S(O)2NH2.

[0308] In certain embodiments, R 2 is

[0309] In certain embodiments, R 2 is

[0310] In certain embodiments, R 2 is

[0311] In certain embodiments, R 2 is

[0312] In certain embodiments, R 2 is

[0313] In certain embodiments, R 2 is

[0314] In certain embodiments, R 2 is

[0315] In certain embodiments, R 2 is

[0316] In certain embodiments, R 2 is

[0317] In certain embodiments, R 2 is

[0318] In certain embodiments, R 2 is

[0319] In certain embodiments, R 2 is

[0320] In certain embodiments, R 2 is

[0321] In certain embodiments, R 2 is

[0322] In certain embodiments, R 2 is

[0323] In certain embodiments, R 2 is

[0324] In certain embodiments, R 2 is

[0325] In certain embodiments, R 2 is

[0326] In certain embodiments, R 2 is

[0327] In certain embodiments, R 2 is

[0328] In certain embodiments, R 2 is

[0329] In certain embodiments, R 2 is

[0330] In certain embodiments, R 2 is

[0331] In certain embodiments, R 2 is

[0332] In certain embodiments, R 2 is

[0333] In certain embodiments, R 2 is

[0334] In certain embodiments, R 2 is

[0335] In certain embodiments, R 2 is

[0336] In certain embodiments, R 2 is

[0337] In certain embodiments, R 2 is

[0338] In certain embodiments, R 2 is

[0339] In certain embodiments, R 2 is

[0340] In certain embodiments, R 2 is

[0341] In certain embodiments, R 2 is

[0342] In certain embodiments, R 2 is

[0343] In certain embodiments, R 2 is

[0344] In certain embodiments, R 2 is

[0345] In certain embodiments, R 2 is

[0346] In certain embodiments, R 2 is

[0347] R 3 embodiments:

[0348] In certain embodiments, R 3 is hydrogen.

[0349] In certain embodiments, R 3 is alkyl.

[0350] In certain embodiments, R 3 is -NR 12 R 13 .

[0351] In certain embodiments, R 3 is -S(O)alkyl.

[0352] In certain embodiments, R 3 is -SO2alkyl.

[0353] In certain embodiments, R 3 is cycloalkyl.

[0354] In certain embodiments, R 3 is heterocycle.

[0355] In certain embodiments, R 3 is aryl.

[0356] In certain embodiments, R 3 is heteroaryl.

[0357] In certain embodiments, R 3 is alkyl-aryl.

[0358] In certain embodiments, R 3 is alkyl-heteroaryl.

[0359] R 4 Embodiments of

[0360] In certain embodiments, R 4 is hydrogen.

[0361] In certain embodiments, R 4 is alkyl.

[0362] In certain embodiments, R 4 is -NR 12 R 13 .

[0363] In certain embodiments, R 4 is -S(O)alkyl.

[0364] In certain embodiments, R 4 is -SO2alkyl.

[0365] In certain embodiments, R 4 is cycloalkyl.

[0366] In certain embodiments, R 4 is heterocycle.

[0367] In certain embodiments, R 4 is aryl.

[0368] In certain embodiments, R 4 is heteroaryl.

[0369] R 5 Embodiments of

[0370] In certain embodiments, R 5 is hydrogen.

[0371] In certain embodiments, R 5 is alkyl.

[0372] In certain embodiments, R 5 is haloalkyl.

[0373] In certain embodiments, R 5 is halogen.

[0374] In certain embodiments, R 5 is cyano.

[0375] In certain embodiments, R 5 is -OR 14 .

[0376] In certain embodiments, R 5 is -NR14 R 15 。

[0377] R 6 of the embodiments:

[0378] In certain embodiments, R 6 is hydrogen.

[0379] In certain embodiments, R 6 is alkyl.

[0380] In certain embodiments, R 6 is alkenyl or alkynyl.

[0381] In certain embodiments, R 6 is cycloalkyl optionally substituted with 1, 2, 3, or 4 R 8 groups.

[0382] In certain embodiments, R 6 is cycloalkyl.

[0383] In certain embodiments, R 6 is heterocycle optionally substituted with 1, 2, 3, or 4 R 8 groups.

[0384] In certain embodiments, R 6 is heterocycle.

[0385] In certain embodiments, R 6 is aryl optionally substituted with 1, 2, 3, or 4 R 8 groups.

[0386] In certain embodiments, R 6 is aryl.

[0387] In certain embodiments, R 6 is heteroaryl optionally substituted with 1, 2, 3, or 4 R 8 groups.

[0388] In certain embodiments, R 6 is NR 7 R 7 。

[0389] In certain embodiments, R 6 is NH2.

[0390] In certain embodiments, R 6 is OH.

[0391] In certain embodiments, R 6 is OCH3.

[0392] R7 Embodiments:

[0393] In certain embodiments, each R 7 is independently selected from hydrogen and alkyl.

[0394] In certain embodiments, R 7 is hydrogen.

[0395] In certain embodiments, R 7 is alkyl.

[0396] In certain embodiments, R 7 is alkenyl or alkynyl.

[0397] In certain embodiments, R 7 is cycloalkyl optionally substituted with 1, 2, 3, or 4 R 8 groups.

[0398] In certain embodiments, R 7 is cycloalkyl.

[0399] In certain embodiments, R 7 is heterocycle optionally substituted with 1, 2, 3, or 4 R 8 groups.

[0400] In certain embodiments, R 7 is heterocycle.

[0401] In certain embodiments, R 7 is aryl optionally substituted with 1, 2, 3, or 4 R 8 groups.

[0402] In certain embodiments, R 7 is aryl.

[0403] In certain embodiments, R 7 is heteroaryl optionally substituted with 1, 2, 3, or 4 R 8 groups.

[0404] Embodiments of R 8 :

[0405] In certain embodiments, each R 8 is independently selected from halogen, haloalkyl, alkyl, NR 12 R 13 and OR 12 .

[0406] In certain embodiments, each R 8 is halogen.

[0407] In certain embodiments, each R 8is a haloalkyl group.

[0408] In certain embodiments, each R 8 is an alkyl group.

[0409] In certain embodiments, at least one R 8 is a halogen.

[0410] In certain embodiments, at least one R 8 is a haloalkyl group.

[0411] In certain embodiments, at least one R 8 is an alkyl group.

[0412] In certain embodiments, each R 8 is a cycloalkyl group.

[0413] In certain embodiments, at least one R 8 is a heterocycle.

[0414] In certain embodiments, at least one R 8 is an aryl group.

[0415] In certain embodiments, at least one R 8 is a heteroaryl group.

[0416] In certain embodiments, at least one R 8 is -S(O)2alkyl.

[0417] In certain embodiments, at least one R 8 is NR 12 R 13 .

[0418] In certain embodiments, at least one R 8 is an alkyl-heteroaryl.

[0419] In certain embodiments, at least one R 8 is an alkyl-aryl.

[0420] In certain embodiments, at least one R 8 is OR 12 .

[0421] In certain embodiments, each R 8 is independently selected from hydrogen, halogen, haloalkyl, alkyl, cycloalkyl, heterocycle, aryl, heteroaryl, -S(O)2alkyl, NR 12 R 13 , alkyl-heteroaryl, alkyl-aryl, and OR 12 .

[0422] In certain embodiments, each R 8Independently selected from hydrogen, alkyl, NR 12 R 13 , alkyl - heteroaryl, alkyl - aryl, and OR 12 .

[0423] R 12 and R 13 embodiments:

[0424] In certain embodiments, each R 12 and R 13 is independently selected from hydrogen and alkyl.

[0425] In certain embodiments, both R 12 and R 13 are hydrogen.

[0426] In certain embodiments, both R 12 and R 13 are alkyl.

[0427] In certain embodiments, one of R 12 and R 13 is hydrogen.

[0428] In certain embodiments, one of R 12 and R 13 is alkyl.

[0429] In certain embodiments, one of R 12 and R 13 is - C(O)alkyl.

[0430] In certain embodiments, one of R 12 and R 13 is - C(S)alkyl.

[0431] In certain embodiments, one of R 12 and R 13 is aryl.

[0432] In certain embodiments, one of R 12 and R 13 is - SO2alkyl.

[0433] In certain embodiments, one of R 12 and R 13 is - S(O)alkyl.

[0434] In certain embodiments, one of R 12 and R 13 is heteroaryl.

[0435] In certain embodiments, one of R 12 and R 13One of them is alkyl-aryl.

[0436] In certain embodiments, R 12 and R 13 One of them is cycloalkyl.

[0437] In certain embodiments, R 12 and R 13 One of them is heterocycle.

[0438] In certain embodiments, R 12 and R 13 One of them is alkyl-heteroaryl.

[0439] R 14 and R 15 Embodiments:

[0440] In certain embodiments, each R 14 and R 15 is independently selected from hydrogen and alkyl.

[0441] In certain embodiments, R 14 and R 15 are both hydrogen.

[0442] In certain embodiments, R 14 and R 15 are both alkyl.

[0443] In certain embodiments, one of R 14 and R 15 is hydrogen.

[0444] In certain embodiments, one of R 14 and R 15 is alkyl.

[0445] In certain embodiments, one of R 14 and R 15 is -C(O)alkyl.

[0446] In certain embodiments, one of R 14 and R 15 is -C(S)alkyl.

[0447] In certain embodiments, one of R 14 and R 15 is aryl.

[0448] In certain embodiments, one of R 14 and R 15 is -SO2alkyl.

[0449] In certain embodiments, R 14 and R15 One of them is -S(O)alkyl.

[0450] In certain embodiments, R 14 and R 15 One of them is heteroaryl.

[0451] In certain embodiments, R 14 and R 15 One of them is alkyl-aryl.

[0452] In certain embodiments, R 14 and R 15 One of them is cycloalkyl.

[0453] In certain embodiments, R 14 and R 15 One of them is heterocycle.

[0454] In certain embodiments, R 14 and R 15 One of them is alkyl-heteroaryl.

[0455] R 17 and R 18 Embodiments:

[0456] In certain embodiments, each R 17 is independently selected from hydrogen and alkyl.

[0457] In certain embodiments, R 17 is hydrogen.

[0458] In certain embodiments, R 17 is alkyl.

[0459] In certain embodiments, R 17 is alkenyl or alkynyl.

[0460] In certain embodiments, R 17 is cycloalkyl optionally substituted with 1, 2, 3, or 4 R 8 groups.

[0461] In certain embodiments, R 17 is cycloalkyl.

[0462] In certain embodiments, R 17 is heterocycle optionally substituted with 1, 2, 3, or 4 R 8 groups.

[0463] In certain embodiments, R 17 is heterocycle.

[0464] In certain embodiments, R 17is an aryl optionally substituted with 1, 2, 3 or 4 R 8 groups.

[0465] In certain embodiments, R 17 is an aryl.

[0466] In certain embodiments, R 17 is a heteroaryl optionally substituted with 1, 2, 3 or 4 R 8 groups.

[0467] In certain embodiments, each R 18 is independently selected from hydrogen and alkyl.

[0468] In certain embodiments, R 18 is hydrogen.

[0469] In certain embodiments, R 18 is alkyl.

[0470] In certain embodiments, R 18 is alkenyl or alkynyl.

[0471] In certain embodiments, R 18 is a cycloalkyl optionally substituted with 1, 2, 3 or 4 R 8 groups.

[0472] In certain embodiments, R 18 is cycloalkyl.

[0473] In certain embodiments, R 18 is a heterocycle optionally substituted with 1, 2, 3 or 4 R 8 groups.

[0474] In certain embodiments, R 18 is heterocycle.

[0475] In certain embodiments, R 18 is an aryl optionally substituted with 1, 2, 3 or 4 R 8 groups.

[0476] In certain embodiments, R 18 is aryl.

[0477] In certain embodiments, R 18 is a heteroaryl optionally substituted with 1, 2, 3 or 4 R 8 groups.

[0478] Embodiments of R 19 :

[0479] In certain embodiments, R 19 is hydrogen.

[0480] In certain embodiments, R 19 is an alkyl group.

[0481] In certain embodiments, R 19 is a haloalkyl group.

[0482] In certain embodiments, R 19 is a halogen.

[0483] In certain embodiments, R 19 is a cyano group.

[0484] In certain embodiments, R 19 is -OR 14 .

[0485] In certain embodiments, R 19 is -NR 14 R 15 .

[0486] Embodiments of R 50 :

[0487] In certain embodiments, each R 50 is independently selected from amino, -NHR 14 , -NR 14 R 15 , hydroxy, OR 14 and R 4 .

[0488] In certain embodiments, there is one R 50 group and it is -NR 14 R 15 .

[0489] In certain embodiments, there is one R 50 group and it is OR 14 .

[0490] In certain embodiments, there is one R 50 group and it is R 4 .

[0491] Embodiments of X 1 , X 2 , X 3 , X 4 and X 5 :

[0492] In certain embodiments, X 1 , X 2 , X 3 , X 4 and X 5Each of them is independently CH.

[0493] In certain embodiments, X 1 , X 2 , X 3 , X 4 and X 5 at least one of which is N.

[0494] In certain embodiments, X 1 , X 2 , X 3 , X 4 and X 5 two of which are N.

[0495] In certain embodiments, X 1 , X 2 , X 3 , X 4 and X 5 at least one of which is CR 4 ; wherein R 4 is independently hydrogen, alkyl, aryl, cycloalkyl, haloalkyl, heteroaryl, heterocycle, halogen, cyano, -OR 14 , -NR 14 R 15 , -NR 14 C(O)R 6 , -NR 14 S(O)R 6 , -NR 14 S(O)2R 6 , -NR 14 C(S)R 6 , -OC(O)R 6 , -OS(O)R 6 , -OS(O)2R 6 , -OC(S)R 6 , -C(O)R 6 ; -C(S)R 6 , -S(O)R 6 or -S(O)2R 6 .

[0496] In certain embodiments, X 1 , X 2 , X 3 , X 4 and X 5 at least one of which is CR 4 ; wherein R 4 is OR 14 , -NR 14 R 15 , -NR 14 C(O)R6 、-NR 14 S(O)R 6 、-NR 14 S(O)2R 6 、S(O)R 6 or -S(O)2R 6 .

[0497] In certain embodiments, X 1 , X 2 , X 3 , X 4 and X 5 At least one of them is CR 4 ; where R 4 OR 14 、-NR 14 R 15 、-NR 14 S(O)2R 6 、S(O)R 6 or -S(O)2R 6 .

[0498] In certain embodiments, X 1 , X 2 , X 3 , X 4 and X 5 At least one of them is CR 4 ; where R 4 is hydrogen, haloalkyl or halogen.

[0499] X 11 , X 12 , X 13 , X 14 and X 15 Implementation plan

[0500] In certain embodiments, X 11 , X 12 , X 13 , X 14 and X 15 Each of is independently CH.

[0501] In certain embodiments, X 11 , X 12 , X 13 , X 14 and X 15 At least one of them is N.

[0502] In certain embodiments, X 11 , X 12 , X 13 , X 14 and X15 Two of them are N.

[0503] In certain embodiments, X 11 , X 12 , X 13 , X 14 and X 15 at least one of which is CR 4 ; wherein R 4 is independently hydrogen, alkyl, aryl, cycloalkyl, haloalkyl, heteroaryl, heterocycle, halogen, cyano, -OR 14 , -NR 14 R 15 , -NR 14 C(O)R 6 , -NR 14 S(O)R 6 , -NR 14 S(O)2R 6 , -NR 14 C(S)R 6 , -OC(O)R 6 , -OS(O)R 6 , -OS(O)2R 6 , -OC(S)R 6 , -C(O)R 6 ; -C(S)R 6 , -S(O)R 6 or -S(O)2R 6 .

[0504] In certain embodiments, X 11 , X 12 , X 13 , X 14 and X 15 at least one of which is CR 4 ; wherein R 4 is OR 14 , -NR 14 R 15 , -NR 14 C(O)R 6 , -NR 14 S(O)R 6 , -NR 14 S(O)2R 6 , S(O)R 6 or -S(O)2R 6 .

[0505] In certain embodiments, X 11 , X 12 , X 13 , X 14 and X15 at least one of them is CR 4 ; wherein R 4 is OR 14 , -NR 14 R 15 , -NR 14 S(O)2R 6 , S(O)R 6 or -S(O)2R 6 .

[0506] In certain embodiments, X 11 , X 12 , X 13 , X 14 and X 15 at least one of them is CR 4 ; wherein R 4 is hydrogen, haloalkyl or halogen.

[0507] Additional embodiments

[0508] 1. In certain embodiments, a compound of the following formula is provided:

[0509]

[0510]

[0511] or a pharmaceutically acceptable salt, N-oxide, isotopically labeled analogue and / or pharmaceutically acceptable composition thereof;

[0512] wherein:

[0513] X 1 , X 2 , X 3 , X 4 and X 5 are independently selected from N, CH, CR 2 and CR 4 ; wherein X 1 , X 2 , X 3 , X 4 and X 5 at least one of them is CR 2 ; and wherein X 1 , X 2 , X 3 , X 4 and X 5 no more than 2 of them are selected as N;

[0514] X 11 , X 12 , X 13 , X 14 and X15 independently selected from N, CH, CR 2 and CR 4 ; wherein X 11 , X 12 , X 13 , X 14 and X 15 no more than 2 of which are selected as N;

[0515] Each R 1 is independently selected from hydrogen, halogen, -OR 14 , NR 14 R 15 , alkyl, aryl, cycloalkyl, haloalkyl, heteroaryl, alkyl-hydroxy and heterocycle, wherein two Rs 1 may optionally form, together with the ring atoms to which they are attached, a 3-, 4-, 5-, 6-, 7- or 8-membered cycloalkyl or a 4-, 5-, 6-, 7- or 8-membered heterocycle having 1, 2 or 3 heteroatoms selected from N, O and S; wherein the cycloalkyl or heterocycle formed by the combination of two Rs 1 with the atoms to which they are attached may optionally be substituted by 1 or 2 substituents independently selected from R 50 ;

[0516] Each R 2 is independently selected from -NR 14 C(O)R 6 , -NR 14 S(O)R 6 , -NR 14 S(O)2R 6 , -NR 14 C(S)R 6 , -OC(O)R 6 , -OS(O)R 6 , -OS(O)2R 6 , -OC(S)R 6 , -C(O)R 6 ; -C(S)R 6 , -S(O)R 6 , -S(=NR 14 )2R 6 , -S(=NR 14 )(O)R 6 and -S(O)2R 6 ;

[0517] R 3 is selected from hydrogen, -OR 14 , -NR 14 R 15 , alkyl, alkenyl, alkynyl, –C(O)R 6, -C(O)alkyl, -C(S)alkyl, aryl, -SO2alkyl, heteroaryl, heterocycle, -alkyl-aryl, and -alkyl-heteroaryl;

[0518] Each R 4 are independently selected from hydrogen, alkyl, aryl, cycloalkyl, haloalkyl, heteroaryl, heterocycle, halogen, cyano, -OR 14 、-NR 14 R 15 、-NR 14 C(O)R 6 、-NR 14 S(O)R 6 、-NR 14 S(O)2R 6 、-NR 14 C(S)R 6 、-OC(O)R 6 、-OS(O)R 6 、-OS(O)2R 6 、-OC(S)R 6 、-C(O)R 6 ;-C(S)R 6 、-S(O)R 6 and -S(O)2R 6 ;

[0519] R 5 is hydrogen, alkyl, haloalkyl, halogen, cyano, -OR 14 or -NR 14 R 15 ;

[0520] Each R 6 are independently selected from hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocycle, aryl, heteroaryl, NR 7 R 7 and OR 7 , hydrogen removal, NR 7 R 7 and OR 7 Each R outside 6 Optionally 1, 2, 3 or 4 R 8 substituted by a group;

[0521] Each R 7 Each R except hydrogen is independently selected from hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocycle, aryl, alkyl-aryl, alkyl-heteroaryl and heteroaryl. 7 Optionally 1, 2, 3 or 4 R 8 substituted by a group;

[0522] Each R 8Independently selected from hydrogen, halogen, haloalkyl, alkyl, alkenyl, alkynyl, cycloalkyl, heterocycle, aryl, heteroaryl, -S(O)2alkyl, NR 12 R 13 、alkyl - heteroaryl, alkyl - aryl and OR 12 ;

[0523] Each R 12 and R 13 is independently selected from hydrogen, alkyl, alkenyl, alkynyl, -C(O)alkyl, -C(S)alkyl, aryl, -SO2alkyl, -S(O)alkyl, heteroaryl, alkyl - aryl, cycloalkyl, heterocycle and alkyl - heteroaryl;

[0524] Each R 14 and R 15 is independently selected from hydrogen, alkyl, alkenyl, alkynyl, –C(O)R 6 、-C(O)alkyl, -C(S)alkyl, aryl, -SO2alkyl, heteroaryl, heterocycle, -alkyl - aryl and -alkyl - heteroaryl;

[0525] R 17 and R 18 is independently selected from hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocycle, aryl, alkyl - aryl, alkyl - heteroaryl and heteroaryl, each of which other than hydrogen is optionally substituted by 1, 2, 3 or 4 R 8 groups; and

[0526] R 19 is hydrogen, alkyl, haloalkyl, halogen, cyano, -OR 14 or -NR 14 R 15 ; and

[0527] Each R 50 is independently selected from hydrogen, -NR 14 R 15 、OR 14 and R 4 .

[0528] 2. In certain embodiments, a compound of the following formula is provided:

[0529]

[0530] or a pharmaceutically acceptable salt, N - oxide, isotopic analogue and / or pharmaceutically acceptable composition thereof;

[0531] wherein each R 2 is independently selected from -NR 14 C(O)R 6 、-NR 14 S(O)R 6, -NR 14 S(O)2R 6 , -NR 14 C(S)R 6 , -OC(O)R 6 , -OS(O)R 6 , -OS(O)2R 6 , -OC(S)R 6 , -C(O)R 6 ; -C(S)R 6 , -S(O)R 6 and -S(O)2R 6 .

[0532] 3. A compound of the following formula according to Embodiment 1:

[0533]

[0534] or a pharmaceutically acceptable salt thereof.

[0535] 4. The compound according to Embodiment 1, wherein R 5 is a hydroxyl group.

[0536] 5. A compound of the following formula according to Embodiment 1:

[0537]

[0538] or a pharmaceutically acceptable salt thereof.

[0539] 6. The compound according to Embodiment 1, wherein one R 1 is hydrogen.

[0540] 7. The compound according to Embodiment 1, wherein both Rs 1 are hydrogen.

[0541] 8. The compound according to Embodiment 1, wherein any one of Rs 1 is not hydrogen.

[0542] 9. A compound of the following formula according to Embodiment 1:

[0543]

[0544] or a pharmaceutically acceptable salt thereof.

[0545] 10. A compound of the following formula according to Embodiment 1:

[0546]

[0547] or a pharmaceutically acceptable salt thereof.

[0548] 11. A compound of the following formula according to Embodiment 1:

[0549]

[0550] or a pharmaceutically acceptable salt thereof.

[0551] 12. A compound of the following formula according to embodiment 1:

[0552] or a pharmaceutically acceptable salt thereof.

[0553] 13. The compound according to any one of embodiments 10 - 12, wherein X 11 is CH.

[0554] 14. The compound according to any one of embodiments 10 - 12, wherein X 11 is N.

[0555] 15. The compound according to any one of embodiments 10 - 12, wherein X 11 is CR 4 .

[0556] 16. The compound according to any one of embodiments 10 - 15, wherein X 12 is CH.

[0557] 17. The compound according to any one of embodiments 10 - 15, wherein X 12 is N.

[0558] 18. The compound according to any one of embodiments 10 - 15, wherein X 12 is CR 4 [[ID=4⑤]]].

[0559] 19. The compound according to any one of embodiments 10 - 18, wherein X 13 is CH.

[0560] 20. The compound according to any one of embodiments 10 - 18, wherein X 13 is N.

[0561] 21. The compound according to any one of embodiments 10 - 18, wherein X 13 is CR 4 .

[0562] 22. The compound according to any one of embodiments 10 - 21, wherein X 14 is CH.

[0563] 23. The compound according to any one of embodiments 10 - 21, wherein X 14 is N.

[0564] 24. The compound according to any one of embodiments 10 - 21, wherein X 14 is CR4 .

[0565] 25. The compound of any one of embodiments 10 - 24, wherein X 15 is CH.

[0566] 26. The compound of any one of embodiments 10 - 24, wherein X 15 is N.

[0567] 27. The compound of any one of embodiments 10 - 24, wherein X 15 is CR 4 .

[0568] 28. The compound of the following formula of embodiment 1:

[0569]

[0570] or a pharmaceutically acceptable salt thereof.

[0571] 29. The compound of any one of embodiments 1 - 28, wherein R 3 is hydrogen.

[0572] 30. The compound of any one of embodiments 1 - 28, wherein R 3 is alkyl.

[0573] 31. The compound of any one of embodiments 1 - 28, wherein R 3 is -NR 14 R 15 .

[0574] 32. The compound of any one of embodiments 1 - 28, wherein R 3 is -NH2.

[0575] 33. The compound of the following formula of embodiment 1:

[0576]

[0577] or a pharmaceutically acceptable salt thereof.

[0578] 34. The compound of the following formula of embodiment 1:

[0579]

[0580] or a pharmaceutically acceptable salt thereof.

[0581] 35. The compound of the following formula of embodiment 1:

[0582]

[0583] or a pharmaceutically acceptable salt thereof.

[0584] 36. The compound of the following formula according to Embodiment 1:

[0585]

[0586] or a pharmaceutically acceptable salt thereof.

[0587] 37. The compound of the following formula according to Embodiment 1:

[0588]

[0589] or a pharmaceutically acceptable salt thereof.

[0590] 38. The compound according to Embodiment 1 or any one of Embodiments 33 - 37, wherein two Rs 1 together with the carbon to which they are attached form a 3 - 8 - membered ring.

[0591] 39. The compound according to Embodiment 1 or any one of Embodiments 33 - 37, wherein two Rs 1 together with the carbon to which they are attached form a 6 - membered carbon ring.

[0592] 40. The compound according to Embodiment 1 or any one of Embodiments 33 - 37, wherein one R 1 is a halogen.

[0593] 41. The compound according to Embodiment 1 or any one of Embodiments 33 - 37, wherein one R 1 is a haloalkyl.

[0594] 42. The compound according to Embodiment 1 or any one of Embodiments 33 - 37, wherein one R 1 is a hydroxyl group.

[0595] 43. The compound according to Embodiment 1 or any one of Embodiments 33 - 37, wherein R 1 is selected from alkyl, aryl, cycloalkyl and haloalkyl.

[0596] 44. The compound according to any one of Embodiments 1 - 43, wherein R 2 is -C(O)R 6 ; -C(S)R 6 , -S(O)R 6 or -S(O)2R 6 .

[0597] 45. The compound according to any one of Embodiments 1 - 43, wherein R 2 is -C(O)R 6 .

[0598] 46. The compound according to any one of Embodiments 1 - 43, wherein R 2-S(O)2R 6 。

[0599] 47. A compound according to any one of embodiments 1-46, wherein each R 6 is independently selected from hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocycle, aryl and heteroaryl.

[0600] 48. A compound according to any one of embodiments 1-46, wherein each R 6 is independently selected from NR 7 R 7 and OR 7 。

[0601] 49. A compound according to any one of embodiments 1-43, wherein R 2 is -S(O)2NH2.

[0602] 50. A compound according to any one of embodiments 1-49, wherein

[0603] 51. A compound according to any one of embodiments 1-50, wherein X 1 is CH.

[0604] 52. A compound according to any one of embodiments 1-50, wherein X 1 is N.

[0605] 53. A compound according to any one of embodiments 1-50, wherein X 1 is CR 2 。

[0606] 54. A compound according to any one of embodiments 1-50, wherein X 1 is CR 4 。

[0607] 55. A compound according to any one of embodiments 1-54, wherein X 2 is CH.

[0608] 56. A compound according to any one of embodiments 1-54, wherein X 2 is N.

[0609] 57. A compound according to any one of embodiments 1-54, wherein X 2 is CR 2 。

[0610] 58. A compound according to any one of embodiments 1-54, wherein X 2 is CR 4 。

[0611] The compound of any one of embodiments 1-58, wherein is

[0612] 60. The compound of any one of embodiments 1-58, wherein X 3 is CH.

[0613] 61. The compound of any one of embodiments 1-58, wherein X 3 is N.

[0614] 62. The compound of any one of embodiments 1-58, wherein X 3 is CR 2 .

[0615] 63. The compound of any one of embodiments 1-58, wherein X 3 is CR 4 .

[0616] 64. The compound of any one of embodiments 60-63, wherein is

[0617] 65. The compound of any one of embodiments 1-64, wherein X 4 is CH.

[0618] 66. The compound of any one of embodiments 1-64, wherein X 4 is N.

[0619] 67. The compound of any one of embodiments 1-64, wherein X 4 is CR 2 .

[0620] 68. The compound of any one of embodiments 1-64, wherein X 4 is CR 4 .

[0621] 69. The compound of any one of embodiments 1-68, wherein X 5 is CH.

[0622] 70. The compound of any one of embodiments 1-68, wherein X 5 is N.

[0623] 71. The compound of any one of embodiments 1-68, wherein X 5 is CR 2 .

[0624] 72. The compound of any one of embodiments 1-68, wherein X 5 is CR 4 .

[0625] The compound of any one of embodiments 1-72, wherein at least one R 4 is OR 14 .

[0626] The compound of any one of embodiments 1-72, wherein at least one R 4 is a halogen

[0627] The compound of any one of embodiments 1-72, wherein at least one R 4 is an alkyl

[0628] The compound of any one of embodiments 1-72, wherein at least one R 3 is an alkyl

[0629] 77. In certain embodiments, the compound is selected from:

[0630]

[0631]

[0632] or a pharmaceutically acceptable salt thereof

[0633] 78. The compound of the following structure of embodiment 77:

[0634]

[0635] or a pharmaceutically acceptable salt thereof

[0636] 79. The compound of the following structure of embodiment 77:

[0637]

[0638] or a pharmaceutically acceptable salt thereof

[0639] 80. The compound of the following structure of embodiment 77:

[0640]

[0641] or a pharmaceutically acceptable salt thereof

[0642] 81. The compound of the following structure of embodiment 77:

[0643]

[0644] or a pharmaceutically acceptable salt thereof

[0645] 82. The compound of the following structure of embodiment 77:

[0646]

[0647] or a pharmaceutically acceptable salt thereof.

[0648] 83. A compound of the following structure according to embodiment 77:

[0649]

[0650] or a pharmaceutically acceptable salt thereof.

[0651] 84. A compound of the following structure according to embodiment 77:

[0652]

[0653] or a pharmaceutically acceptable salt thereof.

[0654] 85. A compound of the following structure according to embodiment 77:

[0655]

[0656] or a pharmaceutically acceptable salt thereof.

[0657] 86. A compound of the following structure according to embodiment 77:

[0658]

[0659] or a pharmaceutically acceptable salt thereof.

[0660] 87. A compound of the following structure according to embodiment 77:

[0661]

[0662] or a pharmaceutically acceptable salt thereof.

[0663] 88. A compound of the following structure according to embodiment 1:

[0664]

[0665]

[0666]

[0667]

[0668]

[0669] or a pharmaceutically acceptable salt thereof.

[0670] 89. A method for treating a disorder associated with abnormal cell proliferation is provided, which comprises administering to a host in need thereof an effective amount of a compound of any one of embodiments 1-88, optionally in a pharmaceutically acceptable carrier.

[0671] 90. The method of embodiment 89, wherein the host is a human.

[0672] 91. The method of embodiment 89 or 90, wherein the disorder is an inflammatory disorder.

[0673] 92. The method of embodiment 89 or 90, wherein the disorder is a fibrotic disorder.

[0674] 93. The method of embodiment 89 or 90, wherein the disorder is an autoimmune disorder.

[0675] 94. The method of embodiment 89 or 90, wherein the disorder is a tumor.

[0676] 95. The method of embodiment 89 or 90, wherein the disorder is cancer.

[0677] 96. The method of embodiment 89 or 90, wherein the disorder is rheumatoid arthritis.

[0678] 97. In certain embodiments, a method for reducing the effect of chemotherapy on healthy cells in a human being being treated for cancer or abnormal cell proliferation is provided, wherein the healthy cells are hematopoietic stem cells or hematopoietic progenitor cells, and the method comprises administering to the human an effective amount of a compound of any one of embodiments 1-88, optionally in a pharmaceutically acceptable carrier.

[0679] 98. A pharmaceutical composition is provided which comprises a compound of any one of embodiments 1-88 or a pharmaceutically acceptable salt thereof in a pharmaceutically acceptable carrier.

[0680] 99. The pharmaceutical composition of embodiment 98 for treating a disorder associated with abnormal cell proliferation.

[0681] 100. The pharmaceutical composition of embodiment 99, wherein the disorder is an inflammatory disorder.

[0682] 101. The pharmaceutical composition of embodiment 99, wherein the disorder is a fibrotic disorder.

[0683] 102. The pharmaceutical composition of embodiment 99, wherein the disorder is an autoimmune disorder.

[0684] 103. The pharmaceutical composition of embodiment 99, wherein the disorder is a tumor.

[0685] 104. The pharmaceutical composition of embodiment 99, wherein the disease is cancer.

[0686] 105. The pharmaceutical composition of embodiment 99, wherein the disease is rheumatoid arthritis.

[0687] 106. The pharmaceutical composition of embodiment 98, which is used to reduce the effect of chemotherapy on healthy cells in a person being treated for cancer or abnormal cell proliferation, wherein the healthy cells are hematopoietic stem cells or hematopoietic progenitor cells.

[0688] 107. In certain embodiments, there is provided a compound for use in the manufacture of a medicament for treating a disease associated with abnormal cell proliferation, wherein the compound is selected from any one of embodiments 1-88 or is a pharmaceutically acceptable salt thereof.

[0689] 108. The compound of embodiment 107, wherein the disease is an inflammatory disease.

[0690] 109. The compound of embodiment 107, wherein the disease is a fibrotic disease.

[0691] 110. The compound of embodiment 107, wherein the disease is an autoimmune disease.

[0692] 111. The compound of embodiment 107, wherein the disease is a tumor.

[0693] 112. The compound of embodiment 107, wherein the disease is cancer.

[0694] 113. The compound of embodiment 107, wherein the disease is rheumatoid arthritis.

[0695] 114. In certain embodiments, there is provided a compound for use in the manufacture of a medicament for reducing the effect of chemotherapy on healthy cells in a person being treated for cancer or abnormal cell proliferation, wherein the healthy cells are hematopoietic stem cells or hematopoietic progenitor cells, and wherein the compound is selected from any one of embodiments 1-88 or is a pharmaceutically acceptable salt thereof.

[0696] 115. In certain embodiments, there is provided the use of a compound in the treatment of a disease associated with abnormal cell proliferation, wherein the compound is selected from any one of embodiments 1-88 or is a pharmaceutically acceptable salt thereof.

[0697] 116. The use of embodiment 115, wherein the disease is an inflammatory disease.

[0698] 117. The use of embodiment 115, wherein the disease is a fibrotic disease.

[0699] Use according to embodiment 115, wherein the disease is an autoimmune disease.

[0700] Use according to embodiment 115, wherein the disease is a tumor.

[0701] Use according to embodiment 115, wherein the disease is cancer.

[0702] Use according to embodiment 115, wherein the disease is rheumatoid arthritis.

[0703] In certain embodiments, there is provided the use of a compound in reducing the effect of chemotherapy on healthy cells in a person being treated for cancer or abnormal cell proliferation, wherein the healthy cells are hematopoietic stem cells or hematopoietic progenitor cells, and wherein the compound is selected from any one of embodiments 1-88 or a pharmaceutically acceptable salt thereof.

[0704] Embodiments of the core

[0705] In certain embodiments, Selected from:

[0706]

[0707] In certain embodiments, Selected from

[0708]

[0709] In certain embodiments, Selected from:

[0710]

[0711]

[0712] In certain embodiments, Selected from:

[0713]

[0714]

[0715] In certain embodiments, Selected from:

[0716]

[0717] In certain embodiments, Selected from:

[0718]

[0719] In certain embodiments, selected from:

[0720]

[0721] In certain embodiments, selected from:

[0722]

[0723]

[0724] In certain embodiments, selected from:

[0725]

[0726] In certain embodiments, selected from:

[0727]

[0728] Additional embodiments

[0729] In certain embodiments, the compounds of the present invention are selected from:

[0730]

[0731]

[0732] or a pharmaceutically acceptable salt thereof.

[0733] In certain embodiments, the compounds of the present invention are selected from:

[0734]

[0735]

[0736] or a pharmaceutically acceptable salt thereof.

[0737] In certain embodiments, the compounds of the present invention are selected from:

[0738]

[0739]

[0740] or a pharmaceutically acceptable salt thereof.

[0741] In certain embodiments, the compounds of the present invention are selected from:

[0742]

[0743]

[0744] or a pharmaceutically acceptable salt thereof.

[0745] In certain embodiments, the compounds of the invention are selected from:

[0746]

[0747]

[0748] or a pharmaceutically acceptable salt thereof.

[0749] In certain embodiments, the compounds of the invention are selected from:

[0750]

[0751]

[0752] or a pharmaceutically acceptable salt thereof.

[0753] In certain embodiments, the compounds of the invention are selected from:

[0754]

[0755]

[0756] or a pharmaceutically acceptable salt thereof.

[0757] In certain embodiments, the compounds of the invention are selected from:

[0758]

[0759]

[0760] or a pharmaceutically acceptable salt thereof.

[0761] Non-limiting examples of the compounds of the invention

[0762] In certain embodiments, the compounds of the invention are selected from:

[0763]

[0764]

[0765] or a pharmaceutically acceptable salt thereof.

[0766] In certain embodiments, the compounds of the invention are selected from:

[0767]

[0768]

[0769] or a pharmaceutically acceptable salt thereof.

[0770] In certain embodiments, the compounds of the present invention are selected from:

[0771]

[0772]

[0773] or a pharmaceutically acceptable salt thereof.

[0774] In certain embodiments, the compounds of the present invention are selected from:

[0775]

[0776]

[0777] or a pharmaceutically acceptable salt thereof.

[0778] In certain embodiments, the compounds of the present invention are selected from:

[0779]

[0780]

[0781] or a pharmaceutically acceptable salt thereof.

[0782] In certain embodiments, the compounds of the present invention are selected from:

[0783]

[0784]

[0785] or a pharmaceutically acceptable salt thereof.

[0786] In certain embodiments, the compounds of the present invention are selected from:

[0787]

[0788]

[0789]

[0790] or a pharmaceutically acceptable salt thereof.

[0791] In certain embodiments, the compounds of the present invention are selected from:

[0792]

[0793]

[0794] or a pharmaceutically acceptable salt thereof.

[0795] In certain embodiments, the compounds of the invention are selected from:

[0796]

[0797]

[0798]

[0799]

[0800] or a pharmaceutically acceptable salt thereof.

[0801] In certain embodiments, the compounds of the invention are selected from:

[0802]

[0803]

[0804]

[0805]

[0806] or a pharmaceutically acceptable salt thereof.

[0807] In certain embodiments, the compounds of the invention are selected from:

[0808]

[0809]

[0810] or a pharmaceutically acceptable salt thereof.

[0811] In certain embodiments, the compounds of the invention are selected from:

[0812]

[0813]

[0814] or a pharmaceutically acceptable salt thereof.

[0815] In certain embodiments, the compounds of the invention are selected from:

[0816]

[0817] or a pharmaceutically acceptable salt thereof.

[0818] In certain embodiments, the compounds of the present invention are selected from:

[0819]

[0820]

[0821]

[0822]

[0823] or a pharmaceutically acceptable salt thereof.

[0824] In certain embodiments, the compounds of the present invention are selected from:

[0825]

[0826]

[0827] or a pharmaceutically acceptable salt thereof.

[0828] In certain embodiments, the compounds of the present invention are selected from:

[0829]

[0830] or a pharmaceutically acceptable salt thereof.

[0831] II. Terms

[0832] Compounds are described using standard nomenclature. 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.

[0833] Compounds of any of the formulas described herein include racemates, enantiomers, mixtures of enantiomers, diastereomers, mixtures of diastereomers, tautomers, N-oxides, isomers; such as rotamers, as if each were specifically described.

[0834] The term "a / an" does not denote a limitation of quantity but rather the presence of at least one of the item(s) mentioned. The term "or" refers to "and / or". Unless otherwise indicated herein, the recitation of a range of values is merely intended to be a shorthand method of referring individually to each value falling within the range, and each individual value is incorporated into the specification as if it were individually recited herein. All endpoints of a range are included within the range and may be combined independently. Unless otherwise indicated herein or clearly contradicted by context, all methods described herein can be performed in a suitable order. Unless otherwise stated, the use of instance or exemplary language (e.g., "such as") is only intended to better illustrate the invention and does not limit the scope of the invention. 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 pertains.

[0835] The term "isotope analogue" refers to a compound having at least one atomic isotope substitution in an amount greater than the natural abundance of that isotope. Isotopes are atoms having the same atomic number but different mass numbers, i.e., atoms having the same number of protons but different numbers of neutrons. Non-limiting examples of isotope analogues of Compound 1 include:

[0836] The present invention encompasses compounds of Formula I, Formula II, Formula III, Formula IV, Formula V, Formula VI, Formula VII, Formula VIII, Formula IX or Formula X, which have at least one desired isotope substitution of an atom in an amount greater than the natural abundance of that isotope, i.e., enriched. In some embodiments, the atom is replaced by its isotope at or near the in vivo metabolic region, resulting in an α, β or γ effect.

[0837] Examples of isotopes that can be incorporated into the compounds of the present invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine, chlorine and iodine, such as 2 H, 3 H, 11 C, 13 C, 14 C, 15 N, 17 O, 18 O, 18 F, 31 P, 32 P, 35 S, 36 Cl and 125 I. In a non-limiting embodiment, the isotope-labeled compounds can be used for metabolic studies (with 14 C), reaction kinetics studies (with, for example, 2 H or 3H), detection or imaging techniques such as positron emission tomography (PET) or single photon emission computed tomography (SPECT), including determination of drug or substrate tissue distribution, or for radiotherapy of patients. In particular, 18 F-labeled compounds may be particularly desirable for PET and SPECT studies. The isotopically labeled compounds of the present invention can generally be prepared by replacing non-isotopically labeled reagents with readily available isotopically labeled reagents by the procedures disclosed in the embodiments or in the examples and the preparation methods described below.

[0838] As a general example but not limitation, isotopes of hydrogen, such as deuterium ( 2 H) and tritium ( 3 H), can be used anywhere in the structure to achieve the desired results. Alternatively or additionally, isotopes of carbon, such as 13C and 14 C.

[0839] Isotope substitution, such as deuterium substitution, can be partial or complete. Partial deuterium substitution means that at least one hydrogen is replaced by deuterium. In certain embodiments, an isotope is enriched at 90, 95 or 99% or more of that isotope at any target position. In a non-limiting embodiment, deuterium is enriched at 90, 95 or 99% at the desired position.

[0840] In a non-limiting embodiment, substitution of deuterium atoms for one or more hydrogen atoms can be provided in any of Formula I, Formula II, Formula III, Formula IV, Formula V, Formula VI, Formula VII, Formula VIII, Formula IX or Formula X. In a non-limiting embodiment, substitution of deuterium atoms for hydrogen atoms occurs at a position selected from R 1 、R 2 、R 3 、R 4 、R 5 、R 6 、R 7 、R 8 、R 11 、R 12 、R 13 、R 14 、R 15 、R 17 、R 18 and R 19within the group of any one of them. For example, when any group is or contains (e.g., by substitution) methyl, ethyl, or methoxy, the alkyl residue can be deuterated (in non-limiting embodiments, CDH2, CD2H, CD3, CH2CD3, CD2CD3, CHDCH2D, CH2CD3, CHDCHD2, OCDH2, OCD2H, or OCD3, etc.). In some other embodiments, when two substituents combine to form a ring, the unsubstituted carbon can be deuterated.

[0841] The compounds of the present invention can form solvates with solvents (including water). Thus, in a non-limiting embodiment, the present invention includes solvated forms of the compounds. The term "solvate" refers to a molecular complex of a compound of the present invention (including its salts) with one or more solvent molecules. Non-limiting examples of solvents are water, ethanol, dimethyl sulfoxide, acetone, and other common organic solvents. The term "hydrate" refers to a molecular complex containing a compound of the present invention and water. Pharmaceutically acceptable solvates according to the present invention include those in which the solvent can be isotopically substituted (e.g., D2O, d6-acetone, d6-DMSO). Solvates can be in liquid or solid form.

[0842] A dash ("-") not between two letters or symbols is used to indicate the point of attachment of a substituent. For example, -(C=O)NH2 is attached through the carbon of the keto (C=O) group.

[0843] "Alkyl" is a branched or straight-chain saturated aliphatic hydrocarbon group. In one non-limiting embodiment, the alkyl group contains from 1 to about 12 carbon atoms, more typically from 1 to about 6 carbon atoms or from 1 to about 4 carbon atoms. In one non-limiting embodiment, the alkyl contains from 1 to about 8 carbon atoms. In certain embodiments, the alkyl is C1-C2, C1-C3, C1-C4, C1-C5 or C1-C6. As used herein, a specific range indicates an alkyl group having each member of the range, and each member of the range is described as an independent substance. For example, as used herein, the term C1-C6 alkyl indicates a straight-chain or branched-chain alkyl group having 1, 2, 3, 4, 5 or 6 carbon atoms and is intended to mean that each of these is described as an independent substance. For example, as used herein, the term C1-C4 alkyl indicates a straight-chain or branched-chain alkyl group having 1, 2, 3 or 4 carbon atoms and is intended to mean that each of these is described as an independent substance. Examples of alkyl include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, tert-pentyl, neopentyl, n-hexyl, 2-methylpentane, 3-methylpentane, 2,2-dimethylbutane and 2,3-dimethylbutane. In an alternative embodiment, the alkyl group is optionally substituted. The term "alkyl" also encompasses cycloalkyl or carbocyclic groups. For example, when using a term including "alk", "cycloalkyl" or "carbocyclic" may be considered part of this definition, unless the context clearly excludes it. By way of example and not limitation, terms such as alkyl, -O-alkyl, haloalkyl, etc. may all be considered to include the cyclic forms of alkyl, unless the context clearly excludes them.

[0844] As used herein, "substituted alkyl" refers to an alkyl group substituted with the substituents described. If the substituents are not explicitly described, "substituted alkyl" refers to an alkyl group substituted with 1, 2, 3, or 4 substituents independently selected from: F, Cl, Br, I, cyano, hydroxy, -O-alkyl, -SH, -S-alkyl, -COOH, -COO-alkyl, -CO-alkyl, -COH, -CONH2, -CONH-alkyl, -CON(alkyl)2, -OC(O)-alkyl, -NHC(O)-alkyl, -N-alkylC(O)-alkyl, nitro, amino, -NH-alkyl, N(alkyl)2, cyano, haloalkyl, aryl, heteroaryl, alkenyl, alkynyl, haloalkyl, cycloalkyl, alkyl-aryl, alkyl-heteroaryl, alkyl-cycloalkyl, alkyl-heterocycle, heterocycle, -COO-aryl, -CO-aryl, -CONH-aryl, -CON(alkyl)(aryl), -OC(O)-aryl, -NHC(O)-aryl, -N-alkylC(O)-aryl, -COO-heteroaryl, -CO-heteroaryl, -CONH-heteroaryl, -CON(alkyl)(heteroaryl), -OC(O)-heteroaryl, -NHC(O)-heteroaryl, -N-alkylC(O)-heteroaryl, -COO-heterocycle, -CO-heterocycle, -CONH-heterocycle, -CON(alkyl)(heterocycle), -OC(O)-heterocycle, -NHC(O)-heterocycle, and -N-alkylC(O)-heterocycle.

[0845] "Alkenyl" is a straight-chain or branched-chain aliphatic hydrocarbon group having one or more carbon-carbon double bonds, which may occur at stable points along the chain. As used herein, a specific range indicates an alkenyl group having each member of the range, and each member of the range is described as an independent substance, as described above for the alkyl moiety. Examples of alkenyl groups include, but are not limited to, vinyl, propenyl, allyl, propenyl, butenyl, and 4-methylbutenyl. The term "alkenyl" also encompasses "cis" and "trans" alkenyl geometries, or alternatively, "E" and "Z" alkenyl geometries. In an alternative embodiment, the alkenyl group is optionally substituted. The term "alkenyl" also encompasses a cycloalkyl or carbocyclic group having at least one unsaturation point. As used herein, "substituted alkenyl" may be substituted with the groups described above for alkyl.

[0846] "Alkynyl" is a branched or straight-chain aliphatic hydrocarbon group having one or more carbon-carbon triple bonds, which can occur at any stable point along the chain. As used herein, a specific range indicates an alkynyl group having each member of the range, and each member of the range is described as an independent substance, as described above for the alkyl moiety. Examples of alkynyl include, but are not limited to, ethynyl, propynyl, 1-butynyl, 2-butynyl, 3-butynyl, 1-pentynyl, 2-pentynyl, 3-pentynyl, 4-pentynyl, 1-hexynyl, 2-hexynyl, 3-hexynyl, 4-hexynyl, and 5-hexynyl. In an alternative embodiment, the alkynyl group is optionally substituted. The term "alkynyl" also encompasses a cycloalkyl or carbocyclic group having at least one unsaturation point. As used herein, "substituted alkynyl" may be substituted by the groups described above for alkyl.

[0847] "Halo / halogen" is fluorine, chlorine, bromine, or iodine.

[0848] "Haloalkyl" is a branched or straight-chain alkyl group substituted by one or more of the above halogen atoms, up to the maximum permitted number of halogen atoms. Examples of haloalkyl include, but are not limited to, fluoromethyl, difluoromethyl, trifluoromethyl, chloromethyl, dichloromethyl, trichloromethyl, pentafluoroethyl, heptafluoropropyl, difluorochloromethyl, dichlorofluoromethyl, difluoroethyl, difluoropropyl, dichloroethyl, and dichloropropyl. "Perhaloalkyl" means an alkyl group in which all hydrogen atoms have been replaced by halogen atoms. Examples include, but are not limited to, trifluoromethyl and pentafluoroethyl.

[0849] As used herein, "aryl" refers to a group having 6 to 14 ring carbon atoms and zero heteroatoms in an aromatic ring system ("C 6–14 aryl"), which is a monocyclic or polycyclic (e.g., bicyclic or tricyclic) 4n+2 aromatic ring system (e.g., sharing 6, 10, or 14 π electrons in a cyclic array). In some embodiments, the aryl group has 6 ring carbon atoms ("C6 aryl"; e.g., phenyl). In some embodiments, the aryl group has 10 ring carbon atoms ("C 10 aryl"; e.g., naphthyl such as 1-naphthyl and 2-naphthyl). In some embodiments, the aryl group has 14 ring carbon atoms ("C 14"Aryl"; for example, anthryl). "Aryl" also includes a ring system in which an aryl ring as defined above is fused to one or more cycloalkyl or heterocyclic groups, where the group or point of attachment is on the aryl ring, and in such cases, the number of carbon atoms still designates the number of carbon atoms in the aryl ring system. The one or more fused cycloalkyl or heterocyclic groups may be 4- to 7-membered saturated or partially unsaturated cycloalkyl or heterocyclic groups. As used herein, "substituted aryl" means an aryl group substituted with the described substituents. If the substituents are not explicitly described, "substituted aryl" means an aryl group substituted with 1, 2, 3, or 4 substituents independently selected from: F, Cl, Br, I, cyano, hydroxy, -O-alkyl, -SH, -S-alkyl, -COOH, -COO-alkyl, -CO-alkyl, -COH, -CONH2, -CONH-alkyl, -CON(alkyl)2, -OC(O)-alkyl, -NHC(O)-alkyl, -N-alkylC(O)-alkyl, nitro, amino, -NH-alkyl, N(alkyl)2, cyano, haloalkyl, aryl, heteroaryl, alkyl, alkenyl, alkynyl, haloalkyl, cycloalkyl, alkyl-aryl, alkyl-heteroaryl, alkyl-cycloalkyl, alkyl-heterocycle, heterocycle, -COO-aryl, -CO-aryl, -CONH-aryl, -CON(alkyl)(aryl), -OC(O)-aryl, -NHC(O)-aryl, -N-alkylC(O)-aryl, -COO-heteroaryl, -CO-heteroaryl, -CONH-heteroaryl, -CON(alkyl)(heteroaryl), -OC(O)-heteroaryl, -NHC(O)-heteroaryl, -N-alkylC(O)-heteroaryl, -COO-heterocycle, -CO-heterocycle, -CONH-heterocycle, -CON(alkyl)(heterocycle), -OC(O)-heterocycle, -NHC(O)-heterocycle, and -N-alkylC(O)-heterocycle.

[0850] The terms "heterocyclic group" and "heterocycle" include saturated and partially saturated ring groups containing heteroatoms, where the heteroatoms are independently selected from nitrogen, sulfur, boron, silicon, and oxygen. Heterocyclic rings include monocyclic 3- to 10-membered rings, as well as 5- to 16-membered bicyclic ring systems (which may include bridged fused and spiro fused bicyclic ring systems). It does not include rings containing -O-O-, -O-S-, or -S-S- moieties. Examples of saturated heterocyclic groups include saturated 3- to 6-membered heteromonocyclic groups containing 1 to 4 nitrogen atoms [e.g., pyrrolidinyl, imidazolidinyl, piperidinyl, pyrroline, piperazinyl]; saturated 3- to 6-membered heteromonocyclic groups containing 1 to 2 oxygen atoms and 1 to 3 nitrogen atoms [e.g., morpholinyl]; saturated 3- to 6-membered heteromonocyclic groups containing 1 to 2 sulfur atoms and 1 to 3 nitrogen atoms [e.g., thiazolidinyl]. Examples of partially saturated heterocyclic groups include, but are not limited to, dihydrothienyl, dihydropyranyl, dihydrofuranyl, and dihydrothiazolyl. Examples of partially saturated and saturated heterocyclic groups include, but are not limited to, pyrrolidinyl, imidazolidinyl, piperidinyl, pyrroline, pyrazolidinyl, piperazinyl, morpholinyl, tetrahydropyranyl, thiazolidinyl, dihydrothienyl, 2,3-dihydro-benzo[l,4]dioxolanyl, dihydroindolyl, iso-dihydroindolyl, dihydrobenzothienyl, dihydrobenzofuranyl, isochromanyl, chromanyl, 1,2-dihydroquinolinyl, 1,2,3,4-tetrahydro-isoquinolinyl, 1,2,3,4-tetrahydroquinolinyl, 2,3,4,4a,9,9a-hexahydro-1H-3-aza-fluorenyl, 5,6,7-trihydro-1,2,4-triazolo[3,4-a]isoquinolinyl, 3,4-dihydro-2H-benzo[l,4]oxazinyl, benzo[l,4]dioxolanyl, 2,3-dihydro-1H-1λ6-benzo[d]isothiazol-6-yl, dihydropyranyl, dihydrofuranyl, and dihydrothiazolyl. As used herein, "substituted heterocycle" means a heterocyclic group substituted with the described substituents.If a substituent is not explicitly described, "substituted heterocycle" means a heterocyclic group substituted with 1, 2, 3 or 4 substituents independently selected from the following: oxo, F, Cl, Br, I, cyano, hydroxy, -O-alkyl, -SH, -S-alkyl, -COOH, -COO-alkyl, -CO-alkyl, -COH, -CONH2, -CONH-alkyl, -CON(alkyl)2, -OC(O)-alkyl, -NHC(O)-alkyl, -N-alkylC(O)-alkyl, nitro, amino, -NH-alkyl, N(alkyl)2, cyano, haloalkyl, aryl, heteroaryl, alkyl, alkenyl, alkynyl, haloalkyl, cycloalkyl, alkyl-aryl, alkyl-heteroaryl, alkyl-cycloalkyl, alkyl-heterocycle, heterocycle, -COO-aryl, -CO-aryl, -CONH-aryl, -CON(alkyl)(aryl), -OC(O)-aryl, -NHC(O)-aryl, -N-alkylC(O)-aryl, -COO-heteroaryl, -CO-heteroaryl, -CONH-heteroaryl, -CON(alkyl)(heteroaryl), -OC(O)-heteroaryl, -NHC(O)-heteroaryl, -N-alkylC(O)-heteroaryl, -COO-heterocycle, -CO-heterocycle, -CONH-heterocycle, -CON(alkyl)(heterocycle), -OC(O)-heterocycle, -NHC(O)-heterocycle and -N-alkylC(O)-heterocycle.

[0851] "Heterocycle" also includes groups in which the heterocyclic group is fused / condensed with an aryl or carbocyclic group, where the point of attachment is the heterocyclic ring. For example, partially unsaturated condensed heterocyclic groups containing 1 to 5 nitrogen atoms, such as indoline, isoindoline; partially unsaturated condensed heterocyclic groups containing 1 to 2 oxygen atoms and 1 to 3 nitrogen atoms; partially unsaturated condensed heterocyclic groups containing 1 to 2 sulfur atoms and 1 to 3 nitrogen atoms; and saturated condensed heterocyclic groups containing 1 to 2 oxygen or sulfur atoms.

[0852] The term "heteroaryl" denotes a stable aromatic ring system containing one or more heteroatoms selected from O, N, and S, wherein the ring nitrogen and sulfur atoms are optionally oxidized, and the nitrogen atoms are optionally quaternized. Examples include, but are not limited to, unsaturated 5- to 6-membered hetero-monocyclic groups containing 1 to 4 nitrogen atoms, such as pyrrolyl, imidazolyl, pyrazolyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazolyl [e.g., 4H-1,2,4-triazolyl, 1H-1,2,3-triazolyl, 2H-1,2,3-triazolyl]; unsaturated 5- to 6-membered hetero-monocyclic groups containing an oxygen atom, such as pyranyl, 2-furyl, 3-furyl, etc.; unsaturated 5- to 6-membered hetero-monocyclic groups containing a sulfur atom, such as 2-thienyl, 3-thienyl, etc.; unsaturated 5- to 6-membered hetero-monocyclic groups containing 1 to 2 oxygen atoms and 1 to 3 nitrogen atoms, such as oxazolyl, isoxazolyl, oxadiazolyl [e.g., 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,5-oxadiazolyl]; unsaturated 5- to 6-membered hetero-monocyclic groups containing 1 to 2 sulfur atoms and 1 to 3 nitrogen atoms, such as thiazolyl, thiadiazolyl [e.g., 1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl, 1,2,5-thiadiazolyl]. In certain embodiments, the "heteroaryl" group is an 8-, 9- or 10-membered bicyclic ring system. Examples of 8-, 9- or 10-membered bicyclic heteroaryl groups include benzofurazan, benzothienyl, benzothiazolyl, benzoxazolyl, quinazolinyl, quinoxalinyl, naphthyridinyl, quinolinyl, isoquinolinyl, benzofuranyl, indolyl, indazolyl, and benzotriazolyl. As used herein, "substituted heteroaryl" means a heteroaryl group substituted with the described substituents.If a substituent is not explicitly described, "substituted heteroaryl" means a heteroaryl group substituted with 1, 2, 3, or 4 substituents independently selected from: F, Cl, Br, I, cyano, hydroxy, -O-alkyl, -SH, -S-alkyl, -COOH, -COO-alkyl, -CO-alkyl, -COH, -CONH2, -CONH-alkyl, -CON(alkyl)2, -OC(O)-alkyl, -NHC(O)-alkyl, -N-alkylC(O)-alkyl, nitro, amino, -NH-alkyl, N(alkyl)2, cyano, haloalkyl, aryl, heteroaryl, alkyl, alkenyl, alkynyl, haloalkyl, cycloalkyl, alkyl-aryl, alkyl-heteroaryl, alkyl-cycloalkyl, alkyl-heterocycle, heterocycle, -COO-aryl, -CO-aryl, -CONH-aryl, -CON(alkyl)(aryl), -OC(O)-aryl, -NHC(O)-aryl, -N-alkylC(O)-aryl, -COO-heteroaryl, -CO-heteroaryl, -CONH-heteroaryl, -CON(alkyl)(heteroaryl), -OC(O)-heteroaryl, -NHC(O)-heteroaryl, -N-alkylC(O)-heteroaryl, -COO-heterocycle, -CO-heterocycle, -CONH-heterocycle, -CON(alkyl)(heterocycle), -OC(O)-heterocycle, -NHC(O)-heterocycle, and -N-alkylC(O)-heterocycle.

[0853] The term "sulfonyl", whether used alone or in combination with other terms such as alkylsulfonyl, represents the divalent group -SO2-.

[0854] "Alkyl-heterocycle" is an alkyl group as defined herein having a heterocyclic substituent. Examples include, but are not limited to, piperidinylmethyl and morpholinylethyl.

[0855] "Alkyl-aryl" is an alkyl group as defined herein having an aryl substituent. Non-limiting examples of alkyl-aryl groups include:

[0856] "Alkyl-heteroaryl" is an alkyl group as defined herein having a heteroaryl substituent. Non-limiting examples of alkyl-heteroaryl groups include:

[0857] As used herein, "carbocyclic", "carbocyclic ring", "carbocycle", or "cycloalkyl" is a saturated or partially unsaturated (i.e., not aromatic) group containing all carbon ring atoms and having 3 to 14 ring carbon atoms ("C 3–14 cycloalkyl") and containing zero heteroatoms in a non-aromatic ring system. In some embodiments, the cycloalkyl group has 3 to 10 ring carbon atoms ("C 3–10 cycloalkyl"). In some embodiments, the cycloalkyl group has 3 to 9 ring carbon atoms ("C3–9 cycloalkyl”). In some embodiments, the cycloalkyl group has 3 to 8 ring carbon atoms (“C 3–8 cycloalkyl”). In some embodiments, the cycloalkyl group has 3 to 7 ring carbon atoms (“C 3–7 cycloalkyl”). In some embodiments, the cycloalkyl group has 3 to 6 ring carbon atoms (“C 3–6 cycloalkyl”). In some embodiments, the cycloalkyl group has 4 to 6 ring carbon atoms (“C 4–6 cycloalkyl”). In some embodiments, the cycloalkyl group has 5 to 6 ring carbon atoms (“C 5–6 cycloalkyl”). In some embodiments, the cycloalkyl group has 5 to 10 ring carbon atoms (“C 5–10 cycloalkyl”). Exemplary C 3–6 cycloalkyl groups include, but are not limited to, cyclopropyl (C3), cyclopropenyl (C3), cyclobutyl (C4), cyclobutenyl (C4), cyclopentyl (C5), cyclopentenyl (C5), cyclohexyl (C6), cyclohexenyl (C6), cyclohexadienyl (C6), etc. Exemplary C 3–8 cycloalkyl groups include, but are not limited to, the foregoing C 3–6 cycloalkyl groups and cycloheptyl (C7), cycloheptenyl (C7), cycloheptadienyl (C7), cycloheptatrienyl (C7), cyclooctyl (C8), cyclooctenyl (C8), etc. Exemplary C 3–10 cycloalkyl groups include, but are not limited to, the foregoing C 3–8 cycloalkyl groups and cyclononyl (C9), cyclononenyl (C9), cyclodecyl (C 10 ), cyclodecenyl (C 10 ), etc. As illustrated by the foregoing examples, in certain embodiments, the cycloalkyl group can be saturated or can contain one or more carbon-carbon double or triple bonds. In an alternative embodiment, “cycloalkyl” also includes ring systems in which a cycloalkyl ring as defined above is fused to a heterocyclic, aryl, or heteroaryl ring, where the point of attachment is on the cycloalkyl ring, and in such cases, the carbon number still designates the carbon atoms in the carbocyclic ring system. In an alternative embodiment, each cycloalkyl instance is optionally substituted with one or more substituents. In certain embodiments, the cycloalkyl group is unsubstituted C 3-14 cycloalkyl.

[0858] “alkyl-cycloalkyl” is an alkyl group as defined herein having a cycloalkyl substituent. Non-limiting examples of alkyl-cycloalkyl groups include:

[0859] As used herein, the term “oxo” encompasses an oxygen atom attached to a double bond.

[0860] As used herein, “intrinsic resistance,” also referred to as “primary resistance,” refers to a situation in which cancer does not respond to the inhibitory effect of an initial CDK4 / 6 inhibitor treatment. 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); deletion, lack, or absence of the retinoblastoma tumor suppressor protein (Rb) (Rb-null); high levels of p16Ink4a expression; high levels of MYC expression; increased expression of cyclin E1, cyclin E2, and cyclin A; and combinations thereof. The cancer may be characterized by decreased expression of the retinoblastoma tumor suppressor protein or one or more retinoblastoma family member proteins such as, but not limited to, p107 and p130. In certain embodiments, a tumor or cancer that is intrinsically resistant to selective CDK4 / 6 inhibitor inhibition is a tumor or cancer whose cell population as a whole does not undergo substantial G1 cell cycle arrest upon exposure to the selective CDK4 / 6 inhibitor. In certain embodiments, a tumor or cancer that is intrinsically resistant to CDK4 / 6 inhibitor inhibition is a tumor or cancer having a cell population in which fewer than 25%, 20%, 15%, 10%, or 5% of its cells undergo G1 cell cycle arrest upon exposure to the selective CDK4 / 6 inhibitor.

[0861] As used herein, “acquired resistance” refers to a situation in which a cancer that is sensitive or initially sensitive to the inhibitory effects of at least one selective CDK4 / 6 inhibitor becomes unresponsive or less responsive over time to the effects of that CDK4 / 6 inhibitor. Without wishing to be bound by any one theory, it is believed that acquired resistance to CDK4 / 6 inhibitors occurs as a result of one or more additional mutations or genetic alterations in bypass signaling that arise after the start of a CDK4 / 6 inhibitor treatment regimen. For example, non-limiting exemplary causes of acquired resistance to CDK4 / 6 inhibitors may be the result of the generation of one or more genetic aberrations associated with “intrinsic resistance”. Additionally, other non-limiting exemplary causes of acquired resistance to CDK4 / 6 inhibitors may include increased cyclin E expression; CCNE1 / 2 amplification; E2F amplification; CDK2 amplification; CDK6 amplification; CDK4 amplification; p16 amplification; WEE1 overexpression; MDM2 overexpression; CDK7 overexpression; deletion of FZR1; HDAC activation; activation of the FGFR pathway; activation of the PI3K / AKT / mTOR pathway; loss of ER or PR expression; higher AP-1 transcriptional activity; epithelial-mesenchymal transition; Smad 3 inhibition; autophagy activation; Rb1-deletion or RB1 mutational inactivation; or combinations thereof. A general 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 the inhibition of a selective CDK4 / 6 inhibitor is a tumor or cancer in which its cell population as a whole no longer undergoes substantial G1 cell cycle arrest upon exposure to the selective CDK4 / 6 inhibitor, resulting in disease progression. In certain embodiments, a tumor or cancer that has acquired resistance to the 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 upon exposure to the selective CDK4 / 6 inhibitor, resulting in disease progression.

[0862] Intrinsic resistance to a selective CDK4 / 6 inhibitor can be determined by any standard assay known to one of ordinary skill in the art, for example, by determining the absence or non - existence of the retinoblastoma (Rb) tumor suppressor protein (Rb - null). For example, the Rb status in cancer can be determined by, for example but not limited to, Western blotting, ELISA (enzyme - linked immunosorbent assay), IHC (immunohistochemistry), and FACS (fluorescence - activated cell sorting). The choice of assay will depend on the tissue, cell line, or alternative tissue sample being used. For example, Western blotting and ELISA can be used for any or all types of tissues, cell lines, or alternative tissues, while the IHC method will be more appropriate when the tissue used in the methods described herein is a tumor biopsy. FACS analysis is most suitable for samples that are single - cell suspensions, such as cell lines and isolated peripheral blood mononuclear cells. See, for example, US 20070212736 “Functional Immunohistochemical Cell Cycle Analysis as a Prognostic Indicator for Cancer”.

[0863] Alternatively, molecular genetic testing can be used to determine the retinoblastoma gene status. Molecular genetic testing for retinoblastoma includes, for example, 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).

[0864] Increased activity of CDK1 or CDK2, high levels of MYC expression, increased cyclin E, and increased cyclin A can be determined by any standard assay known to one of ordinary skill in the art, including but not limited to Western blotting, ELISA (enzyme - linked immunosorbent assay), IHC (immunohistochemistry), and FACS (fluorescence - activated cell sorting). The choice of assay will depend on the tissue, cell line, or alternative tissue sample being used. For example, Western blotting and ELISA can be used for any or all types of tissues, cell lines, or alternative tissues, while the IHC method will be more appropriate when the tissue used in the method is a tumor biopsy. FACS analysis is most suitable for samples that are single - cell suspensions, such as cell lines and isolated peripheral blood mononuclear cells.

[0865] Many methods can be employed to measure markers that are thought to contribute to acquired resistance to CDK4 / 6 inhibitors. Current methods include immunohistochemistry (IHC), immunocytochemistry, and mass spectrometry. An alternative method involves using immunofluorescence (IF) and image analysis to determine the relative abundance of proteins of interest in formalin-fixed, paraffin-embedded (FFPE) tissue samples. The most commonly used method for determining gene expression levels is immunohistochemistry (IHC), but western blotting allows for the assessment of total expression as well as subtype-specific expression. mRNA from genes of interest can also be measured by reverse transcription polymerase chain reaction (RT-PCR).

[0866] Immunohistochemistry (IHC) and immunocytochemistry (ICC) are techniques used to localize expression and rely on specific epitope-antibody interactions. IHC refers to the use of tissue sections, while ICC describes the use of cultured cells or cell suspensions. In both methods, positive staining is visualized using a molecular label, which can be fluorescent or chromogenic. Briefly, the sample is fixed to preserve cell integrity and then incubated with a blocking reagent to prevent non-specific binding of antibodies. Subsequently, the sample is incubated with a primary and a secondary antibody, and the signal is visualized for microscopic analysis.

[0867] The western blotting technique uses three elements to identify a specific protein in a complex mixture of proteins extracted from cells: separation by size, transfer to a solid support, and labeling of the target protein with appropriate primary and secondary antibodies for visualization. The most common form of this method is immunoblotting. This technique is used to detect a specific protein in a given tissue homogenate or extract sample. Protein samples are first electrophoresed by SDS-PAGE to separate proteins based on molecular weight. The proteins are then transferred to a membrane, where they are probed with an antibody specific for the target protein.

[0868] Genomic alterations and mRNA expression can be determined by fluorescence in situ hybridization (FISH), targeted sequencing, and microarray analysis. Common mutated genes, as well as differentially expressed and co-expressed genes, can be identified.

[0869] Fluorescence in situ hybridization (FISH) is a cytogenetic technique used to detect and localize RNA sequences within tissues or cells. This is particularly important for defining the spatio-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 are performed to achieve signal amplification of the target of interest. This amplification is then visualized using a fluorescence microscope. This technique can be used on formalin-fixed paraffin-embedded (FFPE) tissue, frozen tissue, fresh tissue, cells, and circulating tumor cells.

[0870] Targeted RNA sequencing (RNA-Seq) is a highly accurate method for selecting and sequencing specific transcripts of interest. It provides both quantitative and qualitative information. Targeted RNA-Seq can be achieved via enrichment or amplicon-based methods, both of which allow gene expression analysis in a focused set of genes of interest. Enrichment assays also provide the ability to detect known and novel gene fusion partners in many sample types, including formalin-fixed paraffin-embedded (FFPE) tissues. RNA enrichment provides quantitative expression information as well as the detection of small variants and gene fusions.

[0871] In microarray analysis, mRNA molecules are typically collected from both an experimental sample and a reference sample. For example, a reference sample can be collected from a healthy individual, and an experimental sample can be collected from an individual with a disease such as cancer. The two mRNA samples are then converted to complementary DNA (cDNA), and each sample is labeled with a fluorescent probe of a different color. The experimental cDNA sample can be labeled with a red fluorescent dye, while the reference cDNA can be labeled with a green fluorescent dye. The two samples are then mixed together and allowed to hybridize to a microarray slide. After hybridization, the microarray is scanned to measure the expression of each gene printed on the slide. If the expression of a particular gene in the experimental sample is higher than in the reference sample, the corresponding spot on the microarray appears red. Conversely, if the expression in the experimental sample is lower than in the reference sample, the spot appears green. Finally, if the expression is the same in both samples, the spot appears yellow. The data collected via microarray can be used to create a gene expression profile that shows the simultaneous changes in the expression of many genes in response to a specific condition or treatment.

[0872] The term "selective CDK4 / 6 inhibitor" as used in the context of the compounds described herein includes compounds that inhibit CDK4 activity, CDK6 activity, or both CDK4 and CDK6 activities at an IC50 molar concentration that is at least about 300-fold, or 400-fold, or 500-fold, or 1000-fold, or 1500-fold, or 1800-fold, or 2000-fold, or 5000-fold, or 10,000-fold lower than the IC50 molar concentration required to inhibit CDK2 activity to the same extent in a standard phosphorylation assay.

[0873] The term "N-oxide" as used in the context of the molecules described herein refers to the oxidized form of a molecule in which oxidation has occurred at nitrogen. Any nitrogen on any of the molecules described herein can be oxidized.

[0874] As a non-limiting embodiment, the N-oxide of Compound 1 can be:

[0875]

[0876] In certain embodiments, any active compound can be provided to a patient in need thereof in the N-oxide form. In certain embodiments, the N-oxide of the active compound or a precursor of the active compound is used in a manufacturing process. In other embodiments, the N-oxide is a metabolite of the administration of one of the active compounds herein and can have independent activity. Using techniques known to those of ordinary skill in the art, the N-oxide can be formed by treating the compound of interest with an oxidizing agent (e.g., a suitable peroxy acid or peroxide) to generate the N-oxide compound. For example, a heteroaryl group such as a pyrimidine group can be treated with an oxidizing agent such as sodium percarbonate in the presence of a metal catalyst under mild reaction conditions to generate the N-oxide compound. Those skilled in the art will understand that appropriate protecting groups may be required for carrying out this chemical reaction. See Jain, S.L. et al., “Rhenium-Catalyzed Highly Efficient Oxidations of Tertiary Nitrogen Compounds to N-Oxides Using Sodium Percarbonate as Oxygen Source, Synlett, 2261-2663, 2006.

[0877] III. Methods of Treatment

[0878] In certain aspects, provided is a method of treating a proliferative disorder in a host (including a human), which comprises administering an effective amount of a compound of formula I, formula II, formula III, formula IV, formula V, formula VI, formula VII, formula VIII, formula IX or formula X as described herein or a pharmaceutically acceptable salt, N-oxide, deuterated derivative and / or a pharmaceutically acceptable composition thereof, optionally in a pharmaceutically acceptable carrier. Non-limiting examples of the disorder include tumors, cancers, disorders associated with abnormal cell proliferation, inflammatory disorders, immune disorders and autoimmune disorders. In certain embodiments, the disorder is mediated by CDK2, CDK4, CDK6 or CDK9. In certain embodiments, the disorder is mediated by CDK2. In certain embodiments, the disorder is mediated by CDK4. In certain embodiments, the disorder is mediated by CDK6. In certain embodiments, the disorder is mediated by CDK9.

[0879] When administered to a host (including a human) in an effective amount, the compounds of Formula I, Formula II, Formula III, Formula IV, Formula V, Formula VI, Formula VII, Formula VIII, Formula IX or Formula X can be used as therapeutic agents to treat tumors, cancers (solid cancers, non-solid cancers, diffuse cancers, blood cancers, etc.), abnormal cell proliferation, immune disorders, inflammatory disorders, blood disorders, myeloid or lymphoproliferative disorders such as B- or T-cell lymphoma, multiple myeloma, breast cancer, prostate cancer, AML, ALL, CLL, myelodysplastic syndrome (MDS), mesothelioma, renal cell carcinoma (RCC), cholangiocarcinoma, lung cancer, pancreatic cancer, colon cancer, skin cancer, melanoma, Waldenström 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 I diabetes; cardiac dysfunction diseases including hypercholesterolemia; infectious diseases including viral and / or bacterial infections; inflammatory diseases including asthma, chronic peptic ulcer, tuberculosis, rheumatoid arthritis, periodontitis, ulcerative colitis or hepatitis.

[0880] In certain embodiments, the compounds of the present invention are used to treat breast cancer. In certain embodiments, the breast cancer is HR+ and HER2-. In certain embodiments, the breast cancer is HR- and HER2+.

[0881] In certain embodiments, the compounds of the present invention are used to treat non-small cell lung cancer (NSCLC). In certain embodiments, NSCLC has an EGFR mutation. In certain embodiments, NSCLC has an EGFR mutation and an EGFR inhibitor has failed (e.g., second-line treatment). In certain embodiments, an ALK inhibitor has failed (e.g., second-line treatment). In certain embodiments, NSCLC has a KRAS mutation.

[0882] In certain embodiments, the compounds of the present invention are used to treat prostate cancer. In other embodiments, the prostate cancer is castration-resistant. In certain embodiments, a previous chemotherapeutic agent has failed (e.g., second-line treatment).

[0883] In certain embodiments, the compounds of the present invention are used to treat 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, a previous chemotherapeutic agent has failed (e.g., second-line treatment). <>

[0884] In certain embodiments, the compounds of the invention are used for treating melanoma. In certain embodiments, the melanoma has a BRAF mutation.

[0885] In certain embodiments, the compounds of the invention are used for treating cancers with RAS mutations. In certain embodiments, the cancer with RAS mutations is colon cancer (CLC). In certain embodiments, the cancer with RAS mutations is pancreatic cancer. In certain embodiments, the cancer with RAS mutations is cholangiocarcinoma.

[0886] In certain embodiments, the compounds of the invention are used for treating gastrointestinal stromal tumors (GIST). In certain embodiments, treatment with imatinib or sunitinib has failed (e.g., second-line treatment).

[0887] Exemplary proliferative disorders include, but are not limited to, benign growths, tumors, cancers (Rb-positive or Rb-negative), autoimmune disorders, inflammatory disorders, graft-versus-host rejection, and fibrotic disorders.

[0888] Non-limiting examples of cancers treatable according to the present invention include, but are not limited to, acoustic neuroma, adenocarcinoma, adrenal cancer, anal cancer, angiosarcoma (e.g., lymphangiosarcoma, lymphangioendotheliosarcoma, angiosarcoma), appendiceal cancer, benign monoclonal gammopathy, biliary tract cancer (e.g., cholangiocarcinoma), bladder cancer, breast cancer (e.g., breast adenocarcinoma, breast papillary carcinoma, breast cancer, breast medullary carcinoma), brain cancer (e.g., meningioma; glioma, e.g., astrocytoma, oligodendroglioma; medulloblastoma), bronchial cancer, carcinoid tumor, cervical cancer (e.g., cervical adenocarcinoma), choriocarcinoma, chordoma, craniopharyngioma, colorectal cancer (e.g., colon cancer, rectal cancer, colorectal adenocarcinoma), epithelial cancer, ependymoma, endothelial sarcoma (e.g., Kaposi sarcoma, multiple idiopathic hemorrhagic sarcoma), endometrial cancer (e.g., uterine cancer, uterine sarcoma), esophageal cancer (e.g., esophageal adenocarcinoma, Barrett adenocarcinoma), Ewing sarcoma, eye cancer (e.g., intraocular melanoma, retinoblastoma), familial eosinophilia, gallbladder cancer, gastric 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., leukemia such as acute lymphoblastic leukemia (ALL) – also known as acute lymphocytic leukemia or acute lymphoid leukemia (e.g., B-cell ALL, T-cell ALL), acute myeloid leukemia (AML) (e.g., B-cell AML, T-cell AML), chronic myeloid leukemia (CML) (e.g., B-cell CML, T-cell CML) and chronic lymphocytic leukemia (CLL) (e.g., B-cell CLL, T-cell CLL); lymphoma such as Hodgkin lymphoma (HL) (e.g., B-cell HL, T-cell HL) and non-Hodgkin lymphoma (NHL) (e.g., B-cell NHL such as diffuse large cell lymphoma (DLCL) (e.g., diffuse large B-cell lymphoma (DLBCL)), follicular lymphoma, chronic lymphocytic leukemia / small lymphocytic lymphoma (CLL / SLL), mantle cell lymphoma (MCL), marginal zone B-cell lymphoma (e.g., mucosa-associated lymphoid tissue (MALT) lymphoma, nodal marginal zone B-cell lymphoma, splenic marginal zone B-cell lymphoma), primary mediastinal B-cell lymphoma, Burkitt lymphoma, lymphoplasmacytic lymphoma (i.e., " macroglobulinemia”), hairy cell leukemia (HCL), immunoblastic large cell lymphoma, precursor B-lymphoblastic lymphoma, and primary central nervous system (CNS) lymphoma; and T-cell NHL such as precursor T-lymphoblastic lymphoma / leukemia, peripheral T-cell lymphoma (PTCL) (e.g., cutaneous T-cell lymphoma (CTCL) (e.g., mycosis fungoides, Sézary syndrome), angioimmunoblastic T-cell lymphoma, extranodal natural killer T-cell lymphoma, enteropathy-type T-cell lymphoma, subcutaneous panniculitis-like T-cell lymphoma, anaplastic large cell lymphoma); a mixture of one or more of the leukemias / lymphomas described above; and multiple myeloma (MM)), heavy chain disease (e.g., alpha chain disease, gamma chain disease, mu chain disease), hemangioblastoma, inflammatory myofibroblastic tumor, immunocyte amyloidosis, kidney cancer (e.g., nephroblastoma also known as Wilms tumor, renal cell carcinoma), liver cancer (e.g., hepatocellular carcinoma (HCC), malignant liver tumor), lung cancer (e.g., bronchial carcinoma, small cell lung cancer (SCLC), non-small cell lung cancer (NSCLC), lung adenocarcinoma), leiomyosarcoma (LMS), mastocytosis (e.g., systemic mastocytosis), myelodysplastic syndrome (MDS), mesothelioma, myeloproliferative disorder (MPD) (e.g., polycythemia vera (PV), essential thrombocythemia (ET), idiopathic myelofibrosis with myeloid metaplasia (AMM) also known as myelofibrosis (MF), chronic idiopathic myelofibrosis, chronic myelocytic leukemia (CML), chronic neutrophilic leukemia (CNL), hypereosinophilic syndrome (HES)), neuroblastoma, neurofibroma (e.g., neurofibromatosis type 1 or 2 (NF), schwannomatosis), neuroendocrine carcinoma (e.g., gastroenteropancreatic 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), islet cell tumor), penile cancer (e.g., penile and scrotal Paget's disease), pinealoma, primary neuroectodermal tumor (PNT), prostate cancer (e.g., prostatic adenocarcinoma), rectal cancer, rhabdomyosarcoma, salivary gland carcinoma, skin cancer (e.g., squamous cell carcinoma (SCC), keratoacanthoma (KA), melanoma, basal cell carcinoma (BCC)), small intestine cancer (e.g., appendiceal cancer), soft tissue sarcoma (e.g., malignant fibrous histiocytoma (MFH), liposarcoma, malignant peripheral nerve sheath tumor (MPNST), chondrosarcoma, fibrosarcoma, myxosarcoma), sebaceous gland carcinoma, sweat gland carcinoma, synovioma, testicular cancer (e.g., seminoma, testicular embryonal carcinoma), thyroid cancer (e.g., papillary thyroid carcinoma, papillary thyroid cancer (PTC), medullary thyroid carcinoma), urethral cancer, vaginal cancer, and vulvar cancer (e.g., vulvar Paget's disease).

[0889] In another embodiment, the disorder is myelodysplastic syndrome (MDS).

[0890] In certain embodiments, the cancer is a 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.

[0891] In certain embodiments, the proliferative disorder is a myeloproliferative neoplasm. In certain embodiments, the myeloproliferative neoplasm (MPN) is primary myelofibrosis (PMF).

[0892] In certain embodiments, the cancer is a solid tumor. As used herein, a solid tumor refers to an abnormal mass of tissue that typically does not contain cysts or liquid areas. Different types of solid tumors are named after the type of cells that form them. Examples of solid tumor categories include, but are not limited to, sarcomas, carcinomas, and lymphomas, as described above herein. 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.

[0893] In certain embodiments, the patient being treated with Formula I, Formula II, Formula III, Formula IV, Formula V, Formula VI, Formula VII, Formula VIII, Formula IX, or Formula X has a disorder associated with abnormal cell proliferation.

[0894] Abnormal cell proliferation, particularly hyperproliferation, can be the result of a wide range of factors, including genetic mutations, infections, exposure to toxins, autoimmune disorders, and benign or malignant tumor induction.

[0895] There are many skin disorders associated with excessive cell proliferation. For example, psoriasis is a benign disease of the human skin, typically characterized by plaques covered with thickened scales. The disease is caused by an increase in epidermal cell proliferation of unknown origin. Chronic eczema is also associated with significant hyperproliferation of the epidermis. Other diseases caused by excessive proliferation of skin cells include atopic dermatitis, lichen planus, warts, pemphigus vulgaris, actinic keratosis, basal cell carcinoma, and squamous cell carcinoma.

[0896] Other hyperproliferative cell disorders include vascular proliferative disorders, fibrotic disorders, autoimmune disorders, graft-versus-host rejection, tumors, and cancers.

[0897] Vascular proliferative disorders include angiogenesis and vasculogenesis disorders. Proliferation of smooth muscle cells during the development of plaques in vascular tissue results in, for example, restenosis, retinopathy, and atherosclerosis. Both cell migration and cell proliferation play a role in the formation of atherosclerotic lesions.

[0898] Fibrotic disorders are often due to the abnormal formation of the extracellular matrix. Examples of fibrotic disorders include cirrhosis and mesangial proliferative cell disorders. Cirrhosis is characterized by an increase in extracellular matrix components leading to the formation of liver scars. Cirrhosis can cause diseases such as liver cirrhosis. The increase in extracellular matrix leading to liver scars may also be caused by viral infections such as hepatitis. Adipocytes seem to play a major role in cirrhosis.

[0899] Mesangial disorders are caused by the abnormal proliferation of mesangial cells. Mesangial hyperproliferative cell disorders include various human kidney diseases such as glomerulonephritis, diabetic nephropathy, malignant nephrosclerosis, thrombotic microangiopathy syndrome, transplant rejection, and glomerulopathy.

[0900] Another disease with a proliferative component is rheumatoid arthritis. Rheumatoid arthritis is generally considered an autoimmune disease, believed to be associated with the activity of autoreactive T cells and caused by autoantibodies produced against collagen and IgE.

[0901] Other disorders that may include an abnormal cell proliferation component include Bechet syndrome, acute respiratory distress syndrome (ARDS), ischemic heart disease, post-dialysis syndrome, leukemia, acquired immunodeficiency syndrome, vasculitis, lipid histiocytosis, septic shock, and general inflammation.

[0902] In certain embodiments, the compounds of the present invention, their pharmaceutically acceptable derivatives, or pharmaceutically acceptable formulations containing these compounds can also be used for the prevention and treatment of HBV infection and other related diseases such as anti-HBV antibody-positive and HBV-positive patients, chronic liver inflammation caused by HBV, cirrhosis, acute hepatitis, fulminant hepatitis, chronic persistent hepatitis, and fatigue. These compounds or formulations can also be prophylactically used to prevent or delay the progression of clinical diseases in individuals who are anti-HBV antibody or HBV-antigen positive or who have been exposed to HBV.

[0903] In certain embodiments, the disease is associated with an immune response.

[0904] Cutaneous contact hypersensitivity and asthma are just two examples of immune responses that may be associated with significant morbidity. Others include atopic dermatitis, eczema, Sjogren's syndrome (including keratoconjunctivitis sicca secondary to Sjogren's syndrome), alopecia areata, allergic reactions caused by arthropod bites, Crohn's disease, aphthous ulcers, iritis, conjunctivitis, keratoconjunctivitis, ulcerative colitis, cutaneous lupus erythematosus, scleroderma, vaginitis, proctitis, and drug eruptions. These diseases may result in any one or more of the following symptoms or signs: itching, swelling, redness, blisters, crusting, ulcers, pain, desquamation, cracking, hair loss, scarring, or fluid exudation involving the skin, eyes, or mucous membranes.

[0905] In atopic dermatitis and common eczema, immune-mediated leukocyte infiltration (especially infiltration of monocytes, lymphocytes, neutrophils, and eosinophils) into the skin is an important cause of the pathogenesis of these diseases. Chronic eczema is also associated with marked hyperproliferation of the epidermis. Immune-mediated leukocyte infiltration also occurs at sites outside the skin, such as in the airways of asthma patients and in the lacrimal glands of the eyes of patients with keratoconjunctivitis sicca.

[0906] In a non-limiting embodiment, the compounds of the present invention are used as topical medicaments for treating contact dermatitis, atopic dermatitis, eczematous dermatitis, psoriasis, Sjogren's syndrome (including keratoconjunctivitis sicca secondary to Sjogren's syndrome), alopecia areata, allergic reactions caused by arthropod bite reactions, Crohn's disease, aphthous ulcers, iritis, conjunctivitis, keratoconjunctivitis, ulcerative colitis, asthma, allergic asthma, cutaneous lupus erythematosus, scleroderma, vaginitis, proctitis, and drug eruptions. The novel method can also be used to reduce the infiltration of malignant leukocytes into the skin in diseases such as mycosis fungoides. By topically applying the compounds to the eyes, these compounds can also be used to treat aqueous dry eye in patients suffering from aqueous dry eye (such as immune-mediated keratoconjunctivitis).

[0907] As used throughout the specification, the term "neoplasia" or "cancer" refers to the pathological process that results in the formation and growth of a cancerous or malignant tumor, i.e., through cell proliferation, abnormal tissue (solid) or cells (non-solid) often grow faster than normal tissue or cells and continue to grow after the stimulus for initiating new growth has ceased. Malignant tumors exhibit partial or complete lack of structural organization and functional coordination with normal tissue, and most invade surrounding tissues, can metastasize to multiple sites, are likely to recur after attempted removal, and can cause death of the patient unless adequately treated. As used herein, the term neoplasia is used to describe all cancerous disease states and includes or encompasses the pathological processes associated with malignant hematogenous, ascitic, and solid tumors. Exemplary cancers that can be treated by the compounds 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, bladder cancer, head cancer, kidney cancer, cervical cancer, leukemia; benign and malignant lymphomas, particularly Burkitt lymphoma and non-Hodgkin lymphoma; benign and malignant melanomas; myeloproliferative disorders; sarcomas, including Ewing's sarcoma, angiosarcoma, Kaposi's sarcoma, liposarcoma, myxosarcoma, peripheral neuroepithelioma, synovial sarcoma, glioma, astrocytoma, oligodendroglioma, ependymoma, glioblastoma multiforme, neuroblastoma, ganglioneuroma, gangliocytoma, medulloblastoma, pineocytoma, meningioma, meningeal sarcoma, neurofibroma and schwannoma; bowel 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 lymphoma, Wilms tumor and teratoma.

[0908] Additional cancers that can be treated using the compounds disclosed in the present invention include, for example, acute granulocytic leukemia, acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), adenocarcinoma, adenosarcoma, adrenal cancer, adrenocortical carcinoma, anal cancer, anaplastic astrocytoma, angiosarcoma, appendiceal cancer, astrocytoma, basal cell carcinoma, B-cell lymphoma, cholangiocarcinoma, bladder cancer, bone cancer, myeloma, bowel cancer, brain cancer, brainstem 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), estrogen receptor positive HER2-negative breast cancer, estrogen receptor negative breast cancer, estrogen receptor positive breast cancer, metastatic breast cancer, luminal A breast cancer, luminal B 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, intrahepatic cholangiocarcinoma, 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 sarcoma, extrahepatic bile duct cancer, eye cancer, fallopian tube cancer, fibrosarcoma, gallbladder cancer, gastric cancer, gastrointestinal cancer, gastrointestinal carcinoid, gastrointestinal stromal tumor (GIST), germ cell tumor, glioblastoma multiforme (GBM), glioma, hairy cell leukemia, head and neck cancer, hemangioendothelioma, Hodgkin lymphoma, hypopharyngeal cancer, invasive ductal carcinoma (IDC), invasive lobular carcinoma (ILC), inflammatory breast cancer (IBC), intestinal cancer, intrahepatic bile duct cancer, invasive / infiltrating breast cancer, islet cell tumor, jaw cancer, Kaposi sarcoma, kidney cancer, laryngeal cancer, leiomyosarcoma, meningeal metastatic carcinoma, leukemia, lip cancer, liposarcoma, liver cancer, lobular carcinoma in situ, low-grade astrocytoma, lung cancer, lymph node cancer, lymphoma, male breast cancer, medullary carcinoma, medulloblastoma, melanoma, meningioma, Merkel cell carcinoma, mesenchymal chondrosarcoma, mesenchymal tumor, mesothelioma, metastatic breast cancer, metastatic melanoma, metastatic squamous neck cancer, mixed glioma, monodermal teratoma, oral cancer, mucinous carcinoma, mucinous melanoma, multiple myeloma, mycosis fungoides, myelodysplastic syndrome, nasal cancer, nasopharyngeal cancer, neck cancer, neuroblastoma, neuroendocrine tumors (NETs), non-Hodgkin lymphoma, non-small cell lung cancer (NSCLC), oat cell carcinoma, ocular cancer, ocular melanoma, oligodendroglioma, oral cancer (oral cancer / oral cavitycancer), oropharyngeal cancer, osteogenic sarcoma, osteosarcoma, ovarian cancer, ovarian epithelial cancer, ovarian germ cell tumor, primary peritoneal cancer of the ovary, 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 region tumor, pineoblastoma, pituitary tumor, primary central nervous system (CNS) lymphoma, prostate cancer, rectal cancer, renal cell carcinoma, renal pelvic carcinoma, rhabdomyosarcoma, salivary gland cancer, soft tissue sarcoma, osteosarcoma, sarcoma, sinus cancer, skin cancer, small cell lung cancer (SCLC), small intestine cancer, spinal cancer (spinalcancer / spinal column cancer), spinal cord cancer, squamous cell carcinoma, gastric cancer, synovial sarcoma, T-cell lymphoma, testicular cancer, throat cancer, thymoma / thymic carcinoma, thyroid cancer, tongue cancer, tonsil cancer, transitional cell carcinoma, fallopian tube cancer, tubular carcinoma, undiagnosed cancer, ureteral cancer, urethral cancer, uterine adenocarcinoma, uterine cancer, uterine sarcoma, vaginal cancer, vulvar cancer, T-cell lineage acute lymphoblastic leukemia (T-ALL), T-cell line lymphoblastic lymphoma (T-LL), peripheral T-cell lymphoma, adult T-cell leukemia, Pre-BALL, 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, splenic diffuse red pulp small B-cell lymphoma; lymphoplasmacytic lymphoma; heavy chain disease (e.g., alpha heavy chain disease, gamma heavy chain disease, mu heavy chain disease), plasma cell myeloma, solitary plasmacytoma of bone; extramedullary plasmacytoma; primary cutaneous follicle center lymphoma, T-cell / histiocyte-rich large B-cell lymphoma, DLBCL associated with chronic inflammation; EBV-positive elderly DLBCL; 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; B-cell lymphoma, unclassifiable, with features intermediate between diffuse large B-cell lymphoma; or B-cell lymphoma, unclassifiable, with features intermediate between diffuse large B-cell lymphoma and classical Hodgkin lymphoma.

[0909] In another aspect, a method of increasing BIM expression (e.g., BCL2L11 expression) to induce apoptosis in a cell is provided, which comprises contacting a compound of the invention or a pharmaceutically acceptable composition, salt or isotopic analogue thereof with the cell. 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 BIM, a pro-apoptotic protein. BCL2L11 is downregulated in many cancers, and BIM is inhibited in many cancers, including chronic myeloid leukemia (CML) and non-small cell lung cancer (NSCLC), and inhibition of BCL2L11 expression can confer resistance to tyrosine kinase inhibitors. See, e.g., Ng et al., Nat. Med. (2012) 18:521–528.

[0910] In another aspect, there is provided a method of treating a disease associated with angiogenesis such as a diabetic patient (e.g., diabetic retinopathy), an inflammatory patient (e.g., rheumatoid arthritis), macular degeneration, obesity, atherosclerosis or a proliferative disorder, which comprises administering to a subject in need thereof a compound of the present invention or a pharmaceutically acceptable composition, salt or isotopic analogue thereof.

[0911] In certain embodiments, the disease associated with angiogenesis is macular degeneration. In certain embodiments, there is provided a method of treating macular degeneration, which comprises administering to a subject in need thereof a compound of the present invention or a pharmaceutically acceptable composition, salt or isotopic analogue thereof.

[0912] In certain embodiments, the disease associated with angiogenesis is obesity. As used herein, "obesity" and "obese" as used herein refer to class I obesity, class II obesity, class III obesity and pre-obesity (e.g., "overweight") as defined by the World Health Organization. In certain embodiments, there is provided a method of treating obesity, which comprises administering to a subject in need thereof a compound of the present invention or a pharmaceutically acceptable composition, salt or isotopic analogue thereof.

[0913] In certain embodiments, the disease associated with angiogenesis is atherosclerosis. In certain embodiments, there is provided a method of treating atherosclerosis, which comprises administering to a subject in need thereof a compound of the present invention or a pharmaceutically acceptable composition, salt or isotopic analogue thereof.

[0914] In certain embodiments, the disease associated with angiogenesis is a proliferative disorder. In certain embodiments, there is provided a method of treating a proliferative disorder, which comprises administering to a subject in need thereof a compound of the present invention or a pharmaceutically acceptable composition, salt or isotopic analogue thereof.

[0915] IV. Method of reducing side effects associated with chemotherapy

[0916] In certain embodiments, the compounds of the present invention reduce the effect of chemotherapeutic agent toxicity on CDK4 / 6 replication-dependent healthy cells such as hematopoietic stem cells and hematopoietic progenitor cells (collectively referred to as HSPC) and / or renal epithelial cells in a subject (generally, a human) who will be, is or has been exposed to a chemotherapeutic agent (generally a DNA-damaging agent).

[0917] In certain embodiments, a subject has been exposed to a chemotherapeutic agent, and the CDK4 / 6-replication-dependent healthy cells of the subject are placed in G1 arrest after exposure using the compounds described herein to mitigate, for example, DNA damage. In certain embodiments, the compound is administered at least 1 / 2 hour, at least 1 hour, at least 2 hours, at least 3 hours, at least 4 hours, at least 5 hours, at least 6 hours, at least 7 hours, at least 8 hours, at least 10 hours, at least 12 hours, at least 14 hours, at least 16 hours, at least 18 hours, at least 20 hours or longer after exposure to the chemotherapeutic agent.

[0918] In certain embodiments, the compound allows for dose intensification in medically relevant chemotherapy (e.g., more treatment can be given over a fixed time period), which would translate to better efficacy. Thus, the presently disclosed methods can result in less toxic and more effective chemotherapy regimens.

[0919] In some embodiments, the use of the compounds described herein can result in a reduction or substantially no off-target effects, e.g., related to the inhibition of kinases other than CDK4 and / or CDK6 and / or CDK2. Additionally, in certain embodiments, the use of the compounds described herein should not induce cell cycle arrest in CDK4 / 6 replication-independent cells.

[0920] In some embodiments, the use of the compounds described herein reduces the risk of unwanted off-target effects, including but not limited to long-term toxicity, antioxidant effects, and estrogenic effects. Antioxidant effects can be determined by standard assays known in the art. For example, a compound without significant antioxidant effects is a compound that does not significantly scavenge free radicals such as oxygen free radicals. The antioxidant effects of a compound can be compared to a compound with known antioxidant activity such as genistein. Thus, a compound without significant antioxidant activity can be a compound that has less than about 2, 3, 5, 10, 30, or 100-fold antioxidant activity relative to genistein. Estrogenic activity can also be determined via known assays. For example, a non-estrogenic compound is a compound that does not significantly bind and activate estrogen receptors. A compound with substantially no estrogenic effects can be a compound that has less than about 2, 3, 5, 10, 20, or 100-fold estrogenic activity relative to a compound with estrogenic activity such as genistein.

[0921] V. Methods of Treating Abnormal Proliferation of T-Cells, B-Cells, and / or NK-Cells

[0922] In some aspects, the invention includes the use, optionally in a pharmaceutical composition, of an effective amount of a compound described herein or a pharmaceutically acceptable salt or isotopically labeled analogue thereof to treat a host (generally, a human) suffering from a selected cancer, tumor, proliferative disorder, or inflammatory or immune condition. Some of the disclosed compounds are highly active against T-cell proliferation. Given the lack of drugs directed against T-cell cancers and abnormal proliferation, the identification of such uses represents a substantial improvement in the medical treatment of these diseases.

[0923] Abnormal proliferation of T-cells, B-cells, and / or NK-cells can lead to a wide range of diseases, such as cancer, proliferative disorders, and inflammatory / immune diseases. A host (e.g., a human) suffering from any of these conditions can be treated with an effective amount of a compound as described herein to effect symptom relief (palliative agent) or reduction of the underlying disease (disease modifier).

[0924] Examples include T-cell or NK-cell lymphomas, such as, but not limited to: peripheral T-cell lymphoma; anaplastic large cell lymphoma, such as anaplastic lymphoma kinase (ALK)-positive, ALK-negative anaplastic large cell lymphoma, or primary cutaneous anaplastic large cell lymphoma; immunoblastic lymphoma; cutaneous T-cell lymphoma, such as mycosis fungoides, Sézary syndrome, primary cutaneous anaplastic large cell lymphoma, primary cutaneous CD30+ T-cell lymphoproliferative disorder; primary cutaneous aggressive epidermotropic CD8+ cytotoxic T-cell lymphoma; primary cutaneous gamma-delta T-cell lymphoma; primary cutaneous small / medium CD4+ T-cell lymphoma, and lymphomatoid papulosis; adult T-cell leukemia / lymphoma (ATLL); blastic NK-cell lymphoma; enteropathy-type T-cell lymphoma; hepatosplenic gamma-delta T-cell lymphoma; lymphoblastic lymphoma; nasal NK / T-cell lymphoma; therapy-related T-cell lymphoma, such as lymphoma that appears after solid organ or bone marrow transplantation; T-cell prolymphocytic leukemia; T-cell large granular lymphocyte leukemia; chronic lymphoproliferative disorders of NK-cells; aggressive NK-cell leukemia; systemic EBV+ T-cell lymphoproliferative disease in childhood (associated with chronic active EBV infection); hydroa vacciniforme-like lymphoma; adult T-cell leukemia / lymphoma; enteropathy-associated T-cell lymphoma; hepatosplenic T-cell lymphoma; or subcutaneous panniculitis-like T-cell lymphoma.

[0925] In certain embodiments, the compounds or salts or isotopically labeled analogs thereof disclosed herein can be used in an effective amount to treat a host (e.g., a human) suffering from lymphoma or lymphocytic or myelocytic proliferative disorders or abnormalities. For example, the compounds as described herein can be administered to a host suffering from Hodgkin lymphoma or non-Hodgkin lymphoma. For example, the host may have non-Hodgkin lymphoma, such as but not limited to: AIDS-related lymphoma; anaplastic large cell lymphoma; immunoblastic lymphoma; blastic NK cell lymphoma; Burkitt lymphoma; Burkitt-like lymphoma (small non-cleaved cell lymphoma); chronic lymphocytic leukemia / small lymphocytic leukemia; cutaneous T-cell lymphoma; diffuse large B-cell lymphoma; enteropathy-type T-cell lymphoma; follicular lymphoma; hepatosplenic gamma-delta T-cell lymphoma; lymphoblastic lymphoma; mantle cell lymphoma; marginal zone lymphoma; nasal T-cell lymphoma; pediatric lymphoma; peripheral T-cell lymphoma; primary central nervous system lymphoma; T-cell leukemia; transformed lymphoma; therapy-related T-cell lymphoma; or Waldenström macroglobulinemia.

[0926] Alternatively, the compounds or salts or isotopically labeled analogs thereof disclosed herein can be used in an effective amount to treat a host (e.g., a human) suffering from Hodgkin lymphoma, such as but not limited to: nodular sclerosis classical Hodgkin lymphoma (CHL); mixed cellularity CHL; lymphocyte depletion CHL; lymphocyte-rich CHL; lymphocyte-predominant Hodgkin lymphoma; or nodular lymphocyte-predominant HL.

[0927] Alternatively, the compounds, salts or isotopically-labelled analogues thereof disclosed herein may be used in an effective amount to treat a host (e.g., a human) suffering from a particular B-cell lymphoma or proliferative disorder, such as, but not limited to: multiple myeloma; 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; hairy cell leukemia; splenic lymphoma / leukemia, unclassifiable; splenic diffuse red pulp small B-cell lymphoma; hairy cell leukemia - variant; lymphoplasmacytic lymphoma; heavy chain disease, e.g., alpha heavy chain disease, gamma heavy chain disease, mu heavy chain disease; plasma cell myeloma; solitary plasmacytoma of bone; extramedullary plasmacytoma; primary cutaneous follicle center lymphoma; T-cell / histiocyte-rich large B-cell lymphoma; DLBCL associated with chronic inflammation; EBV-positive elderly DLBCL; 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; B-cell lymphoma, unclassifiable, with features intermediate between diffuse large B-cell lymphoma; or B-cell lymphoma, unclassifiable, with features intermediate between diffuse large B-cell lymphoma and classical Hodgkin lymphoma.

[0928] In certain embodiments, the compounds, salts or isotopically-labelled analogues thereof disclosed herein may be used in an effective amount to treat a host (e.g., a human) suffering from leukemia. For example, the host may be suffering from acute or chronic leukemia of lymphocytic or myelogenous origin, such as, but not limited to: acute lymphoblastic leukemia (ALL); acute myeloid leukemia (AML); chronic lymphocytic leukemia (CLL); chronic myeloid leukemia (CML); juvenile myelomonocytic leukemia (JMML); hairy cell leukemia (HCL); acute promyelocytic leukemia (a subtype of AML); large granular lymphocytic leukemia; or adult T-cell chronic leukemia. In certain embodiments, the patient has acute myeloid leukemia, e.g., undifferentiated AML (M0); myeloblastic leukemia (M1; with / without minimal cell maturation); myeloblastic leukemia (M2; with cell maturation); promyelocytic leukemia (M3 or M3 variant [M3V]); myelomonocytic leukemia (M4 or M4 variant with eosinophilia [M4E]); monocytic leukemia (M5); erythroleukemia (M6); or megakaryoblastic leukemia (M7).

[0929] VI. Pharmaceutical Compositions and Dosage Forms

[0930] The active compounds, salts, or isotopically-labelled analogues thereof described herein can be administered to a host in an effective amount by any suitable method to achieve the desired therapeutic outcome for treating any of the disorders described herein. Of course, the dosage and timing of the active compounds will depend on the host being treated, the directions of the attending medical professional, the time course of exposure, the mode of administration, the pharmacokinetic properties of the particular active compound, and the judgment of the prescribing physician. Accordingly, due to variability between hosts, the dosages given below are guidelines and the physician may adjust the dosage of the compound to achieve a treatment that the physician deems suitable for the host. In considering the desired degree of treatment, the physician may balance various factors such as the age and weight of the host, pre-existing diseases, and the presence of other diseases.

[0931] The pharmaceutical compositions can be formulated into any pharmaceutically useful form, for example, formulated into aerosols, creams, gels, pills, injection or infusion solutions, capsules, tablets, syrups, transdermal patches, subcutaneous patches, dry powders, inhalation preparations, medical devices, suppositories, buccal or sublingual preparations, parenteral preparations, or ophthalmic solutions. Some dosage forms, such as tablets and capsules, are subdivided into suitable unit dosages containing a suitable amount of the active ingredient, for example, an effective amount to achieve the desired purpose.

[0932] The therapeutically effective dose of any of the active compounds described herein will be determined by the healthcare provider based on the patient's illness, body size and age, and the route of delivery. In a non-limiting embodiment, a dose of about 0.1 to about 200 mg / kg has therapeutic efficacy, all weights being calculated based on the weight of the active compound, including in the case of using salts. In certain embodiments, the dose is about or greater than 0.1, 0.5, 1, 5, 10, 25, 50, 75, 100, 125, 150, 175, or 200 mg / kg. In some embodiments, the dose can be the amount of the compound required to provide a serum concentration of the active compound 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.

[0933] In certain embodiments, the pharmaceutical composition is in a dosage form containing from about 0.1 mg to about 2000 mg, from about 10 mg to about 1000 mg, from about 100 mg to about 800 mg, or from about 200 mg to about 600 mg of the active compound and optionally from about 0.1 mg to about 2000 mg, from about 10 mg to about 1000 mg, from about 100 mg to about 800 mg, or from about 200 mg to about 600 mg of additional active agent in a unit dosage form. Examples of dosage forms have at least 5, 10, 15, 20, 25, 50, 100, 200, 250, 300, 400, 500, 600, 700 or 750 mg of the active compound or a salt thereof. The pharmaceutical composition may also contain a certain molar ratio of the active compound and the additional active agent in a ratio that achieves the desired result.

[0934] In some embodiments, the compounds disclosed herein or used as described are administered once daily (QD), twice daily (BID) or three times daily (TID). In some embodiments, the compounds disclosed herein or used as described are 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.

[0935] The compounds disclosed herein or used as described herein may be administered orally, topically, parenterally, by inhalation or spray, sublingually, via implants (including ocular implants), transdermally, via buccal administration, rectally, as an ophthalmic solution, by injection (including intraocular injection), intravenously, intramuscularly, by inhalation, intra-aortically, intracranially, subdermally, intraperitoneally, subcutaneously, intranasally, sublingually or rectally or by other means in dosage unit formulations containing conventional pharmaceutically acceptable carriers. For ocular delivery, the compound may be administered as needed, for example, via intravitreal, intrastromal, intracameral, subtenon's, subretinal, retrobulbar, peribulbar, suprachorodial, conjunctival, subconjunctival, episcleral, periorbital, transscleral, retrobulbar, posterior juxtascleral, perikeratomal or lacrimal duct injection, or through mucus, mucin or mucosal barriers, in an immediate or controlled release manner or via an ocular device.

[0936] According to the presently disclosed methods, oral administration can be in any desired form, such as solid, gel or liquid, including solutions, suspensions or emulsions. In some embodiments, the compound or salt is administered by inhalation, intravenously or intramuscularly as a liposome suspension. When administered by inhalation, the active compound or salt can be in the form of multiple solid particles or droplets having any desired particle size, e.g., from about 0.01, 0.1 or 0.5 to about 5, 10, 20 microns or greater, and optionally from about 1 to about 2 microns. The compounds disclosed in the present invention have demonstrated good pharmacokinetic and pharmacodynamic properties, e.g., when administered by oral or intravenous routes.

[0937] The pharmaceutical formulation can contain the active compound described herein or a pharmaceutically acceptable salt thereof in any pharmaceutically acceptable carrier. If a solution is desired, water can sometimes be the preferred carrier for water-soluble compounds or salts. For water-soluble compounds or salts, organic vehicles such as glycerol, propylene glycol, polyethylene glycol or mixtures thereof may be suitable. In the latter case, the organic vehicle can contain a substantial amount of water. The solution can then be sterilized in a manner known to those skilled in the art, e.g., by filtration through a 0.22 micron filter. After sterilization, the solution can be dispensed into suitable containers, such as pyrogen-free glass vials. Dispensing is optionally carried out by aseptic methods. A sterilized closure can then be placed on the vial, and if desired, the vial contents can be lyophilized.

[0938] The carrier includes excipients and diluents and must have a sufficiently high purity and a sufficiently low toxicity such that it is suitable for administration to the patient being treated. The carrier can be inert or can have its own pharmaceutical benefits. The amount of carrier used in combination with the compound is sufficient to provide a practical amount of the administration material per unit dose of the compound.

[0939] The classes of carriers include, but are not limited to, binders, buffers, coloring agents, diluents, disintegrants, emulsifiers, flavoring agents, glidants, lubricants, preservatives, stabilizers, surfactants, tabletting agents and wetting agents. Some carriers may be listed in more than one class, e.g., vegetable oils can be used as lubricants in some formulations and as diluents in other formulations. Exemplary pharmaceutically acceptable carriers include sugars, starches, celluloses, powdered tragacanth, malt, gelatin; talc and vegetable oils. Optionally, active agents can be included in the pharmaceutical composition that do not substantially interfere with the activity of the compounds of the present invention.

[0940] In addition, auxiliary substances, such as wetting agents or emulsifiers, biological buffer substances, surfactants, etc., may be present in such a medium. The biological buffer can be any pharmaceutically acceptable solution, and it provides the required pH for the preparation, that is, the pH within the physiologically acceptable range. Examples of buffer solutions include saline, phosphate buffered saline, Tris buffered saline, Hank's buffered saline, etc.

[0941] Depending on the intended mode of administration, the pharmaceutical composition can be in the form of solid, semi-solid or liquid dosage forms, such as tablets, suppositories, pills, capsules, powders, liquids, suspensions, creams, ointments, lotions, etc., preferably in unit dosage forms suitable for single administration of precise doses. The composition will comprise a combination of an effective amount of the selected drug and a pharmaceutically acceptable carrier, and additionally, other medicaments, adjuvants, diluents, buffers, etc. may also be included.

[0942] Thus, the compositions of the present disclosure can be administered as pharmaceutical formulations, including those suitable for oral (including buccal and sublingual), rectal, nasal, topical, pulmonary, vaginal or parenteral (including intramuscular, intraarterial, intrathecal, subcutaneous and intravenous) administration or in forms suitable for administration by inhalation or insufflation. Preferred modes of administration are intravenous or oral administration, with a convenient daily dosing regimen that can be adjusted according to the degree of affliction.

[0943] For solid compositions, conventional non-toxic solid carriers include, for example, pharmaceutical grade mannitol, lactose, starch, magnesium stearate, sodium saccharin, talc, cellulose, glucose, sucrose, magnesium carbonate, etc. Compositions that can be administered in liquid form can be prepared, for example, by dissolving, dispersing, etc. the active compounds as described herein and optionally pharmaceutical adjuvants in excipients such as water, saline, dextrose aqueous solution, glycerol, ethanol, etc. to form a solution or suspension. If desired, the pharmaceutical composition to be administered may also contain small amounts of non-toxic auxiliary substances, such as wetting agents or emulsifiers, pH buffers, etc., such as sodium acetate, sorbitan monolaurate, triethanolamine acetate, triethanolamine oleate, etc. The actual methods for preparing such dosage forms are known or will be apparent to those skilled in the art; for example, see Remington’s Pharmaceutical Sciences cited above.

[0944] In another embodiment, the use of penetration enhancer excipients is provided, and the penetration enhancer excipients include polymers such as: polycations (chitosan and its quaternary ammonium derivatives, poly-L-arginine, aminated gelatin); polyanions (N-carboxymethyl chitosan, polyacrylic acid); and thiolated polymers (carboxymethyl cellulose-cysteine, polycarbophil-cysteine, chitosan-thiobutylamidine, chitosan-mercaptoacetic acid, chitosan-glutathione conjugate).

[0945] For oral administration, the compositions are generally in the form of tablets, capsules, soft gel capsules, or may be aqueous or non-aqueous solutions, suspensions or syrups. Tablets and capsules are the preferred forms for oral administration. Tablets and capsules for oral use may contain one or more common carriers such as lactose and corn starch. Lubricants such as magnesium stearate are usually also added. Generally, 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, dibasic calcium phosphate, calcium sulfate, mannitol, sorbitol, etc. In addition, when needed or necessary, suitable binders, lubricants, disintegrants and colorants can also be introduced 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, tragacanth or sodium alginate, carboxymethyl cellulose, polyethylene glycol, waxes, etc. Lubricants used in these dosage forms include sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, sodium chloride, etc. Disintegrants include, but are not limited to, starch, methylcellulose, agar, bentonite, xanthan gum, etc.

[0946] When using a liquid suspension, the active agent can be combined with any oral, non-toxic, pharmaceutically acceptable inert carrier such as ethanol, glycerol, water, etc., as well as with emulsifying agents and suspending agents. If desired, flavoring agents, colorants and / or sweetening agents can also be added. Other optional components introduced into the oral formulations herein include, but are not limited to, preservatives, suspending agents, thickening agents, etc.

[0947] Parenteral formulations can be prepared in conventional forms, or as liquid solutions or suspensions, solid forms suitable for dissolving or suspending in a liquid prior to injection, or as emulsions. Preferably, sterile injectable suspensions are formulated using suitable carriers, dispersing or wetting agents and suspending agents according to techniques known in the art. Sterile injectable formulations can also be sterile injectable solutions or suspensions in a non-toxic parenterally acceptable diluent or solvent. Acceptable vehicles and solvents that can be employed are water, Ringer's solution, and isotonic sodium chloride solution. Additionally, sterile non-volatile oils, fatty esters or polyols are commonly used as solvents or suspending media. Additionally, parenteral administration can involve the use of slow-release or sustained-release systems to maintain a constant dosage level.

[0948] Parenteral administration includes intra-articular, intravenous, intramuscular, intradermal, intraperitoneal, and subcutaneous routes, and includes aqueous and non-aqueous isotonic sterile injection solutions, which may contain antioxidants, buffers, bacteriostatic agents, and solutes that render the preparation isotonic with the blood of the intended recipient, as well as aqueous and non-aqueous sterile suspensions, which may contain suspending agents, solubilizers, thickening agents, stabilizers, and preservatives. Administration via certain parenteral routes may involve introducing the preparation of the present disclosure into a patient's body through a needle or catheter, which is propelled by a sterile syringe or some other mechanical device such as a continuous infusion system. The preparation provided by the present disclosure may be administered using a syringe, jet injector, pump, or any other device recognized in the art for parenteral administration.

[0949] In addition to the active compound or its salt, the pharmaceutical preparation may also contain other additives such as pH-adjusting additives. In particular, useful pH regulators include acids such as hydrochloric acid, bases, or buffers such as sodium lactate, sodium acetate, sodium phosphate, sodium citrate, sodium borate, or sodium gluconate. In addition, the preparation may contain antimicrobial preservatives. Useful antimicrobial preservatives include methylparaben, propylparaben, and benzyl alcohol. Antimicrobial preservatives are typically employed when the preparation is placed in a vial designed for multi-dose use. The pharmaceutical preparations described herein may be lyophilized using techniques well known in the art.

[0950] For oral administration, the pharmaceutical composition may be in the form of solutions, suspensions, tablets, pills, capsules, powders, etc. Tablets containing various excipients such as sodium citrate, calcium carbonate, and calcium phosphate may be used with various disintegrants such as starch (e.g., potato or tapioca starch) and certain complex silicates, as well as 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 may be used as fillers in soft and hard gelatin capsules. Materials in this regard also include lactose or milk sugar, as well as high molecular weight polyethylene glycols. When aqueous suspensions and / or elixirs are desired for oral administration, the compounds of the presently disclosed subject may be used in combination with various sweetening agents, flavoring agents, coloring agents, emulsifying agents, and / or suspending agents, as well as diluents such as water, ethanol, propylene glycol, glycerol, and various similar combinations thereof.

[0951] In yet another embodiment of the subject matter described herein, there is provided an injectable, stable, sterile preparation in unit dosage form in a sealed container, which contains the active compound or its salt as described herein. The compound or salt is provided in the form of a lyophilizate, which is capable of being reconstituted with a suitable pharmaceutically acceptable carrier to form a liquid preparation suitable for injection into a host. When the compound or salt is substantially insoluble in water, a sufficient amount of a physiologically acceptable emulsifier may be employed in an amount sufficient to emulsify the compound or salt in an aqueous carrier. Particularly useful emulsifiers include phosphatidylcholine and lecithin.

[0952] Additional embodiments include liposomal formulations of the active compounds disclosed herein. Techniques for forming liposomal suspensions are well known in the art. When the compound is a water-soluble salt, it can be incorporated into lipid vesicles using conventional liposome techniques. In such cases, due to the water solubility of the active compound, the active compound can be substantially entrapped within the hydrophilic center or core of the liposome. The lipid layer employed can be of any conventional composition and can contain cholesterol or can be cholesterol-free. When the active compound of interest is water-insoluble, again using conventional liposome-forming techniques, the salt can be substantially entrapped within 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. The 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.

[0953] Also provided are pharmaceutical formulations suitable for administration by inhalation as an aerosol. These formulations comprise a solution or suspension of the desired compound or its salt described herein, or multiple solid particles of the compound or salt. The desired formulation can be placed in a chamber and atomized. Atomization can be accomplished by compressed air or by ultrasonic energy to form multiple liquid droplets or solid particles containing the compound or salt. The liquid droplets or solid particles can, for example, have a particle size in the range of about 0.5 to about 10 microns, optionally about 0.5 to about 5 microns. In certain embodiments, the solid particles provide controlled release by using a biodegradable polymer. The solid particles can be obtained by treating the solid compound or its salt in any suitable manner known in the art (such as by micronization). Optionally, the size of the solid particles or droplets can be about 1 to about 2 microns. In this regard, commercial atomizers can be used to achieve this purpose. The compound can be administered via an aerosol suspension of respirable particles in the manner set forth in U.S. Patent No. 5,628,984, the disclosure of which is incorporated herein by reference in its entirety.

[0954] Also provided are pharmaceutical formulations that provide controlled release of the compounds described herein, including by using biodegradable polymers known in the art.

[0955] When the pharmaceutical formulation suitable for administration as an aerosol is in liquid form, the formulation can contain a water-soluble active compound in a carrier comprising water. A surfactant can be present, which sufficiently reduces the surface tension of the formulation so that droplets of the desired size range are formed upon atomization.

[0956] As used herein, the term "pharmaceutically acceptable salt" refers to those salts of the presently disclosed compounds that are relatively non-toxic inorganic and organic acid addition salts that are suitable for use in contact with a host (e.g., a human host) within the scope of reasonable medical judgment, without undue toxicity, irritation, allergic response, etc., commensurate with a reasonable benefit / risk ratio and effective for their intended use, as well as zwitterionic forms of the compounds of the presently disclosed subject matter where possible.

[0957] Accordingly, the term "salt" refers to relatively non-toxic inorganic and organic acid addition salts of the presently disclosed compounds. 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 so formed. Basic compounds are capable of forming a wide variety of different salts with various inorganic and organic acids. Acid addition salts of basic compounds are prepared by contacting the free base form in a conventional manner with a sufficient amount of the desired acid to produce the salt. The free base form can be regenerated by contacting the salt form with a base in a conventional manner and isolating the free base. The free base form may differ from their corresponding salt forms in certain physical properties such as solubility in polar solvents. 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 in a conventional manner with a sufficient amount of the desired base to produce the salt. The free acid form can be regenerated by contacting the salt form with an acid in a conventional manner and isolating the free acid. The free acid form may differ from their corresponding salt forms in certain physical properties such as solubility in polar solvents.

[0958] Salts can be prepared from inorganic acid sulfates, pyrosulfates, bisulfates, sulfites, bisulfites, nitrates, phosphates, monohydrogen phosphates, dihydrogen phosphates, metaphosphates, pyrophosphates, chlorides, bromides, iodides such as hydrochloric acid, nitric acid, phosphoric acid, sulfuric acid, hydrobromic acid, hydroiodic acid, 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, naphthalenesulfonate, glucoheptonate, lactobionate, laurylsulfonate, and hydroxyethylsulfonate, etc. Salts can also be prepared from organic acids such as aliphatic mono- and dicarboxylic acids, phenyl-substituted alkanoic acids, hydroxyalkanoic acids, alkanedioic acids, aromatic acids, aliphatic and aromatic sulfonic acids, etc. Representative salts include acetate, propionate, octanoate, isobutyrate, oxalate, malonate, succinate, suberate, sebacate, fumarate, maleate, mandelate, benzoate, chlorobenzoate, methylbenzoate, dinitrobenzoate, phthalate, benzenesulfonate, tosylate, phenylacetate, citrate, lactate, maleate, tartrate, mesylate, etc. Pharmaceutically acceptable salts can include cations based on alkali metals 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 covered are salts of amino acids such as arginine salt, gluconate, galacturonate, etc. See, for example, Berge et al., J. Pharm. Sci., 1977, 66, 1-19, which is incorporated herein by reference.

[0959] Preferably, the sterile injectable suspension is formulated using suitable carriers, dispersing or wetting agents, and suspending agents according to techniques known in the art. The sterile injectable preparation can also be a sterile injectable solution or suspension in a non-toxic parenterally acceptable diluent or solvent. Acceptable vehicles and solvents that can be employed are water, Ringer's solution, and isotonic sodium chloride solution. Additionally, sterile non-volatile oils, fatty esters, or polyols are commonly used as solvents or suspending media. Additionally, parenteral administration can involve the use of slow-release or sustained-release systems to maintain a constant dosage level.

[0960] Formulations 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 also contain adjuvants such as preservatives, wetting agents, emulsifying agents and dispersing agents. They may be sterilized, for example, by filtration through a bacteria retaining filter, by introducing a sterilizing agent into the composition, by irradiating the composition or by heating the composition. They may also be manufactured using sterile water or some other sterile injectable medium immediately before use.

[0961] Sterile injectable solutions are prepared by introducing the required amount of one or more compounds of the present disclosure, as needed, into a suitable solvent along with the various other ingredients enumerated above and then filtering the solution sterilize. Generally, dispersions are prepared by introducing the various sterilized active ingredients into a sterile vehicle that contains a basic dispersion medium and the required other ingredients from those enumerated above. In the case of sterile powders for the preparation of sterile injectable solutions, the preferred methods of preparation are vacuum drying and freeze-drying techniques, which yield a powder of the active ingredient plus any additional required ingredients from its previously sterile-filtered solution. 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.

[0962] Formulations suitable for rectal administration are generally presented as unit dose suppositories. These suppositories may be prepared by mixing the disclosed active compound with one or more conventional solid carriers such as cocoa butter and then shaping the resulting mixture.

[0963] Formulations suitable for topical administration to the skin preferably take the form of ointments, creams, lotions, pastes, gels, sprays, aerosols or oils. Carriers that may be used include petrolatum, lanolin, polyethylene glycol, alcohols, transdermal penetration enhancers, and combinations of two or more of them.

[0964] Formulations suitable for transdermal administration may be in the form of discrete patches adapted to remain in intimate contact with the epidermis of the recipient for an extended period of time. Formulations suitable for transdermal administration may also be delivered by iontophoresis (see, for example, Pharmaceutical Research 3(6):318 (1986)) and are generally in the form of an optionally buffered aqueous solution of the active compound. In certain embodiments, microneedle patches or devices are provided to deliver the drug through or into biological tissue, particularly the skin. Microneedle patches or devices allow the drug to be delivered through or into the skin or other tissue barrier at a clinically relevant rate with minimal or no tissue damage, pain or irritation.

[0965] Preparations suitable for administration to the lungs can be delivered by a wide range of passive breath-actuated and active power-actuated single / multi-dose dry powder inhalers (DPIs). The devices most commonly used for respiratory delivery include nebulizers, metered-dose inhalers, and dry powder inhalers. There are several types of nebulizers available, including jet nebulizers, ultrasonic nebulizers, and vibrating mesh nebulizers. The choice of a suitable lung delivery device depends on parameters such as the nature of the drug and its formulation, the site of action, and the pathophysiology of the lungs.

[0966] Additional non-limiting examples of drug delivery devices and methods include, for example, US20090203709 (Abbott Laboratories) titled "Pharmaceutical Dosage Form For Oral Administration Of Tyrosine Kinase Inhibitor"; US20050009910 titled "Delivery of an active drug to the posterior part of the eye via subconjunctival or periocular delivery of a prodrug", US20130071349 titled "Biodegradable polymers for lowering intraocular pressure", US 8,481,069 titled "Tyrosine kinase microspheres", US 8,465,778 titled "Method of making tyrosine kinase microspheres", US 8,409,607 titled "Sustained release intraocular implants containing tyrosine kinase inhibitors and related methods", US 8,512,738 and US 2014 / 0031408 titled "Biodegradable intravitreal tyrosine kinase implants", US2014 / 0294986 titled "Microsphere Drug Delivery System for Sustained Intraocular Release", US 8,911,768 (Allergan, Inc.) titled "Methods For Treating Retinopathy With Extended Therapeutic Effect"; US 6,495,164 (Alkermes Controlled Therapeutics, Inc.) titled "Preparation of injectable suspensions having improved injectability"); WO 2014 / 047439 (Akina, Inc.) titled "Biodegradable Microcapsules Containing Filling Material"; WO 2010 / 132664 (Baxter International Inc., Baxter Healthcare SA) titled "Compositions And Methods For Drug Delivery"; US20120052041 (The Brigham and Women’s Hospital, Inc.) titled "Polymeric nanoparticles with enhanced drug loading and methods of use thereof"; US20140178475, US20140248358 and US20140249158 (BIND Therapeutics, Inc.) titled "Therapeutic Nanoparticles Comprising a Therapeutic Agent and Methods of Making and Using Same"; US 5,869,103 (Danbiosyst UK Ltd.); US 8628801 (Universidad de Navarra) titled "Pegylated Nanoparticles"; US2014 / 0107025 (Jade Therapeutics, LLC) titled "Ocular drug delivery system"; US 6,287,588 titled "Agent delivering system comprised of microparticle and biodegradable gel with an improved releasing profile and methods of use thereof", US 6,589,549 (Macromed, Inc.) titled "Bioactive agent delivering system comprised of microparticles within a biodegradable to improve release profiles"; US 6,007,845 and US 5,578,325 (Massachusetts Institute of Technology) titled "Nanoparticles and microparticles of non-linear hydrophilic hydrophobic multiblock copolymers"; US20040234611, US20080305172, US20120269894 and US20130122064 (Novartis Ag) titled "Ophthalmic depot formulations for periocular or subconjunctival administration; US 6,413,539 (Poly-Med, Inc.) titled "Block polymer");US 20070071756 (Peyman) entitled “Delivery of an agent to ameliorate inflammation”; US 20080166411 (Pfizer, Inc.) entitled “Injectable Depot Formulations And Methods For Providing Sustained Release Of Poorly Soluble Drugs Comprising Nanoparticles”; US 6,706,289 (PR Pharmaceuticals, Inc.) entitled “Methods and compositions for enhanced delivery of bioactive molecules”; and US 8,663,674 (Surmodics) entitled “Microparticle containing matrices for drug delivery”.

[0967] VII. COMBINATION THERAPY

[0968] The compounds of formula I, formula II, formula III, formula IV, formula V, formula VI, formula VII, formula VIII, formula IX or formula X as disclosed may be used, either alone or in combination with another compound of the present invention or another bioactive agent (therapeutic agent), in an effective amount to treat a host, such as a human, suffering from a disorder as described herein.

[0969] The disclosed compounds described herein may be used, either alone or in combination with another compound of the present invention or another bioactive agent, in an effective amount to treat a host, such as a human, suffering from a disorder as described herein.

[0970] The term “bioactive agent” or “therapeutic agent” is used to describe an agent that may be used in combination with or in place of a compound of the present invention to achieve a desired therapeutic outcome, which is a compound not selected according to the present invention. In certain embodiments, the compounds of the present invention and the bioactive agent are administered in such a way that they have in vivo activity during overlapping time periods, e.g., having overlapping time periods of C max 、T max 、AUC or other pharmacokinetic parameters. In another embodiment, the compounds of the present invention and the bioactive agent are administered to a host in need thereof, and they do not have overlapping pharmacokinetic parameters; however, one has a therapeutic impact on the therapeutic efficacy of the other.

[0971] In certain aspects of this embodiment, the bioactive agent is a chemotherapeutic agent.

[0972] In another aspect of this embodiment, the bioactive agent is a growth factor.

[0973] In certain aspects of this embodiment, the bioactive agent is an immunomodulator, including but not limited to checkpoint inhibitors, which include, as non-limiting examples, PD-1 inhibitors, PD-L1 inhibitors, PD-L2 inhibitors, CTLA-4 inhibitors, LAG-3 inhibitors, TIM-3 inhibitors, T-cell activation V-domain Ig suppressor (VISTA) inhibitors, small molecules, peptides, nucleotides, or another inhibitor. In certain aspects, the immunomodulator is an antibody, such as a monoclonal antibody.

[0974] Immune checkpoint inhibitor

[0975] Immune checkpoint inhibitors for use in the methods described herein include but are not limited to PD-1 inhibitors, PD-L1 inhibitors, PD-L2 inhibitors, CTLA-4 inhibitors, LAG-3 inhibitors, TIM-3 inhibitors, and T-cell activation V-domain Ig suppressor (VISTA) inhibitors or combinations thereof. In some embodiments, the 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 lymphoma, melanoma, non-small cell lung cancer (including NSCLC with EGFR or ALK genomic tumor aberrations), head and neck squamous cell carcinoma, small cell lung cancer, hepatocellular carcinoma, renal cell carcinoma, urothelial carcinoma, colorectal cancer, colorectal cancer, hepatocellular carcinoma, renal cell carcinoma, small cell lung cancer, bladder cancer, B-cell lymphoma, gastric cancer, cervical cancer, liver cancer, advanced Merkel cell carcinoma, esophageal squamous cell carcinoma, or ovarian cancer.

[0976] In certain embodiments, the immune checkpoint inhibitor is a PD-1 inhibitor that blocks the interaction of PD-1 and PD-L1 by binding to the PD-1 receptor, and thereby inhibits immunosuppression. In certain embodiments, the immune checkpoint inhibitor is a PD-1 immune checkpoint inhibitor selected from: nivolumab pembrolizumab pidilizumab (AMP-224 (AstraZeneca and MedImmune), PF-06801591 (Pfizer), MEDI0680 (AstraZeneca), PDR001 (Novartis), cemiplimad / REGN2810 ( Regeneron), MGA012 (MacroGenics), BGB-A317 (BeiGene), SHR-12-1 (Jiangsu Hengrui Medicine Company and Incyte Corporation), TSR-042 (Tesaro), and the PD-L1 / VISTA inhibitor CA-170 (Curis Inc.).

[0977] In certain embodiments, the immune checkpoint inhibitor is the PD-1 immune checkpoint inhibitor nivolumab which is administered in an effective amount together with the compounds described herein to treat Hodgkin lymphoma, melanoma, non-small cell lung cancer (including NSCLC with EGFR or ALK genomic tumor aberrations), head and neck squamous cell carcinoma, small cell lung cancer, hepatocellular carcinoma, renal cell carcinoma, squamous cell carcinoma, urothelial carcinoma, colorectal cancer, colorectal cancer, hepatocellular carcinoma, or ovarian cancer. Nivolumab has been approved by the FDA for Hodgkin lymphoma, melanoma, non-small cell lung cancer (including NSCLC with EGFR or ALK genomic tumor aberrations), head and neck squamous cell carcinoma, small cell lung cancer, hepatocellular carcinoma, renal cell carcinoma, squamous cell carcinoma, urothelial carcinoma, colorectal cancer, progressive classical Hodgkin lymphoma (cHL), colorectal cancer, urothelial carcinoma, head and neck squamous cell carcinoma, or ovarian cancer. In another aspect of this embodiment, the immune checkpoint inhibitor is the PD-1 immune checkpoint inhibitor pembrolizumab which is administered in an effective amount to treat 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), which is administered in an effective amount to 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), which is administered in an effective amount to cutaneous squamous cell carcinoma.

[0978] In certain embodiments, the immune checkpoint inhibitor is a PD-L1 inhibitor, which blocks the interaction between PD-1 and PD-L1 by binding to the PD-L1 receptor, thereby inhibiting immunosuppression. PD-L1 inhibitors include, but are not limited to, atezolizumab, durvalumab, KN035 CA-170 (Curis Inc.), and LY3300054 (Eli Lilly). In certain embodiments, the PD-L1 inhibitor is atezolizumab. In certain embodiments, the PD-L1 inhibitor blocks the interaction between PD-L1 and CD80 to inhibit immunosuppression.

[0979] In certain embodiments, the immune checkpoint inhibitor is the PD-L1 immune checkpoint inhibitor atezolizumab which is administered in an effective amount to treat metastatic bladder cancer, small cell lung cancer, metastatic melanoma, metastatic non-small cell lung cancer, or metastatic renal cell carcinoma. In another aspect of this embodiment, the immune checkpoint inhibitor is durvalumab ( AstraZeneca and MedImmune), which is administered in an effective amount to treat small cell lung cancer, non-small cell lung cancer, or bladder cancer. In certain embodiments, the immune checkpoint inhibitor is the PD-L1 immune checkpoint inhibitor avelumab ( EMD Serono / Pfizer), which is administered in an effective amount to treat Merkel cell carcinoma or urothelial carcinoma. In yet another aspect of this embodiment, the immune checkpoint inhibitor is KN035 (Alphamab), which is administered in an effective amount to treat PD-L1 positive solid tumors.

[0980] 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 inhibitors include, but are not limited to, ipilimumab, tremelimumab (AstraZeneca and MedImmune), AGEN1884, and AGEN2041 (Agenus).

[0981] In certain embodiments, the CTLA-4 immune checkpoint inhibitor is ipilimumab which is administered in an effective amount to treat metastatic melanoma, adjuvant melanoma, or non-small cell lung cancer.

[0982] In another embodiment, the immune checkpoint inhibitor is a LAG-3 immune checkpoint inhibitor. Examples of LAG-3 immune checkpoint inhibitors include, but are not limited to, BMS-986016 (Bristol-Myers Squibb), GSK2831781 (GlaxoSmithKline), IMP321 (Prima BioMed), LAG525 (Novartis), and the PD-1 and LAG-3 dual inhibitor MGD013 (MacroGenics). In another aspect of this embodiment, the immune checkpoint inhibitor is a TIM-3 immune checkpoint inhibitor. Specific TIM-3 inhibitors include, but are not limited to, TSR-022 (Tesaro).

[0983] Other immune checkpoint inhibitors for use in the inventions described herein include, but are not limited to, B7-H3 / CD276 immune checkpoint inhibitors such as MGA217, indoleamine 2,3-dioxygenase (IDO) immune checkpoint inhibitors such as Indoximod and INCB024360, killer immunoglobulin-like receptor (KIRs) immune checkpoint inhibitors such as lirilumab (BMS-986015), carcinoembryonic antigen cell adhesion molecule (CEACAM) inhibitors (e.g., CEACAM-1, -3, and / or -5). Exemplary anti-CEACAM-1 antibodies are described in WO 2010 / 125571, WO 2013 / 082366, and WO 2014 / 022332, e.g., monoclonal antibodies 34B1, 26H7, and 5F4; or recombinant forms thereof, as described, e.g., in US 2004 / 0047858, U.S. Patent No. 7,132,255, and WO 99 / 052552. In other embodiments, the anti-CEACAM antibody binds to CEACAM-5, as described, e.g., in Zheng et al., PLoS One. 2010 September 2; 5(9). pii: e12529 (DOI: 10:1371 / journal.pone.0021146), or cross-reacts with CEACAM-1 and CEACAM-5, as described, e.g., in WO 2013 / 054331 and US 2014 / 0271618. Still other checkpoint inhibitors can be molecules directed against the B and T lymphocyte attenuator molecule (BTLA), e.g., as described in Zhang et al., monoclonal antibodies directed against the B and T lymphocyte attenuator (BTLA) have no effect on in vitro B cell proliferation and inhibit in vitro T cell proliferation when presented in cis rather than trans form relative to the activating stimulus. Clin Exp Immunol. 2011 Jan; 163(1): 77–87.

[0984] Chemotherapeutic agent

[0985] As covered herein, the CDK inhibitors described herein can be used in combination with any standard chemotherapy treatment regimen. In certain embodiments, the CDK inhibitors described herein can be used in combination with any standard chemotherapy treatment regimen and further in combination with an immune checkpoint inhibitor.

[0986] In certain embodiments, the chemotherapeutic agent is toxic to immune effector cells. In certain embodiments, the chemotherapeutic agent inhibits cell growth. In certain embodiments, the cytotoxic chemotherapeutic agent administered 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-binding agent, a thiolate alkylating agent, a guanine alkylating agent, a tubulin-binding agent, a DNA polymerase inhibitor, an anticancer enzyme, a RAC1 inhibitor, a thymidylate synthase inhibitor, an oxazophosphorine compound, an integrin inhibitor such as cilengitide, camptothecin or homocamptothecin, an antifolate or a folic acid antimetabolite.

[0987] 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, azacitidine, obinutuzumab, decitabine, erdafitinib and venetoclax.

[0988] In certain embodiments, the additional therapeutic agent is trastuzumab. In certain embodiments, the additional therapeutic agent is lapatinib. In certain embodiments, the compounds of the invention are administered together with 2, 3 or 4 additional therapeutic agents. In certain embodiments, there are 2 additional therapeutic agents. In certain embodiments, the two additional therapeutic agents are lapatinib and trastuzumab.

[0989] In certain embodiments, the additional therapeutic agent is osimertinib mesylate

[0990] In certain embodiments, the additional therapeutic agent is alectinib

[0991] In certain embodiments, the additional therapeutic agent is a MEK inhibitor.

[0992] In certain embodiments, the additional therapeutic agent is an androgen receptor ligand.

[0993] In certain embodiments, the additional therapeutic agent is a BTK inhibitor, such as but not limited to ibrutinib or acalabrutinib

[0994] In certain embodiments, the additional therapeutic agents are MEK inhibitors and RAF inhibitors.

[0995] In certain embodiments, the additional therapeutic agent is a RAF inhibitor.

[0996] In certain embodiments, the additional therapeutic agent is regorafenib.

[0997] Cytotoxic chemotherapeutic agent

[0998] Cytotoxic, DNA-damaging chemotherapeutic agents are often non-specific and are toxic, especially at high doses, to normal, rapidly dividing cells such as HSPCs and immune effector cells. 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 undesired cells such as cancer cells, wherein the cytotoxic effect of the agent 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-related activity (e.g., protein synthesis), or any other cytotoxic effect. Such compounds include, but are not limited to, DNA-damaging compounds that can kill cells. "DNA-damaging" chemotherapeutic agents include, but are not limited to, alkylating agents, DNA intercalating agents, protein synthesis inhibitors, DNA or RNA synthesis inhibitors, DNA base analogs, topoisomerase inhibitors, telomerase inhibitors, and telomeric DNA-binding compounds. For example, alkylating agents include alkyl sulfonates such as busulfan, improsulfan, and piposulfan; aziridines such as benzodizepa, carboquone, meturedepa, and uredepa; ethyleneimines and methylmelamines such as hexamethylmelamine, triethylenemelamine, triethylenephosphoramide, triethylenethiophosphoramide, and trimethylolmelamine; nitrogen mustards such as chlorambucil, chlornaphazine, cyclophosphamide, estramustine, mechlorethamine, mechlorethamine hydrochloride, melphalan, novembichine, 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. Chemotherapy antimetabolites include gemcitabine, mercaptopurine, thioguanine, cladribine, fludarabine phosphate, fluorouracil (5-FU), floxuridine, cytarabine, pentostatin, methotrexate, azathioprine, acyclovir, adenine β-1-D-arabinofuranoside, amethopterin, aminopterin, 2-aminopurine, aphidicolin, 8-azaguanine, diazo serine, 6-azauracil, 2'-azido-2'-deoxynucleoside, 5-bromodeoxycytidine, cytosine β-1-D-arabinofuranoside, diazooxynorleucine, dideoxynucleoside, 5-fluorodeoxycytidine, 5-fluorodeoxyuridine, and hydroxyurea.

[0999] Chemotherapeutic protein synthesis inhibitors include abrin, aurintricarboxylic acid, chloramphenicol, colicin E3, cycloheximide, diphtheria toxin, edeine A, emetine, erythromycin, ethionine, fluoride, 5-fluorotryptophan, fusidic acid, guanylylmethylenediphosphate and guanylylimidodiphosphate, kanamycin, kasugamycin, flavomycin and O-methylthreonine. Additional protein synthesis inhibitors include agrostin, neomycin, norvaline, pactamycin, paromomycin, puromycin, ricin, shiga toxin, terramycin, sparsomycin, spectinomycin, streptomycin, tetracycline, thiostrepton and trimethoprim.

[1000] 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, propidium diiodide-intertwining; and other agents such as distamycin and netropsin. Topoisomerase inhibitors such as irinotecan, teniposide, coumermycin, nalidixic acid, novobiocin and oxolinic acid; cell division inhibitors including colchicine, mitoxantrone, colchicine, vinblastine and vincristine; and RNA synthesis inhibitors including actinomycin D, α-amanitin and other amatoxins, cordycepin (3′-deoxyadenosine), dichlororibosylbenzimidazole, rifampicin, streptothricin and streptolydigin can also be used as DNA-damaging compounds.

[1001] In certain embodiments, the chemotherapeutic agent is a DNA complex binder such as camptothecin or etoposide; a thiolate alkylating agent such as nitrosoureas, BCNU, CCNU, ACNU or fotemustine; a guanine alkylating agent such as temozolomide, a tubulin binder such as vinblastine, vincristine, vinorelbine, vinflunine, cryptophycin 52; a spongistatin such as halichondrin B; a dolastatin such as dolastatin 10 and dolastatin 15; a hemiasterlin such as hemiasterlin A and hemiasterlin B, colchicine, combretastatin, 2-methoxyestradiol, E7010, paclitaxel, docetaxel, epothilone, discodermolide; a DNA polymerase inhibitor such as cytarabine; an anticancer enzyme such as asparaginase; a Rac1 inhibitor such as 6-thioguanine; a thymidylate synthase inhibitor such as capecitabine or 5-FU; an oxazaphosphorine compound such as Cytoxan; an integrin inhibitor such as cilengitide; an antifolate such as pralatrexate; a folate antimetabolite such as pemetrexed; or a camptothecin or homocamptothecin such as diflomotecan.

[1002] In certain embodiments, the topoisomerase inhibitor is a type I inhibitor. In another embodiment, the topoisomerase inhibitor is a type II inhibitor.

[1003] Other DNA-damaging chemotherapeutic agents whose toxic effects can be mitigated by currently disclosed selective CDK4 / 6 inhibitors include, but are not limited to, cisplatin, hydrogen peroxide, carboplatin, procarbazine, ifosfamide, bleomycin, plicamycin, paclitaxel, transplatin, thiotepa, oxaliplatin, and the like, as well as agents of similar mode of action. In certain embodiments, the DNA-damaging chemotherapeutic agent is selected from cisplatin, carboplatin, camptothecin, and etoposide.

[1004] Other suitable chemotherapeutic agents include, but are not limited to, radiomolecules, toxins (also referred to as cytotoxins or cytotoxic agents), which include any agent that is detrimental to cell viability, and liposomes or other vesicles containing chemotherapeutic compounds. General anticancer drugs include: vincristine liposomal vincristine cytarabine (cytosine arabinoside, ara-C, or ), L-asparaginase or PEG-L-asparaginase (pegaspargase or ), etoposide (VP-16), teniposide 6-mercaptopurine (6-MP or ), prednisone, and dexamethasone (decadron). Examples of additional suitable chemotherapeutic agents include, but are not limited to, 5-fluorouracil, dacarbazine, alkylating agents, anthramycin (AMC), antimitotic agents, cis-dichlorodiammineplatinum(II) (DDP, cisplatin), diaminodichloroplatinum, anthracyclines, antibiotics, antimetabolites, asparaginase, BCG live (intravesical), bleomycin sulfate, calicheamicin, cytochalasin B, dactinomycin (formerly actinomycin), daunorubicin HCl, daunorubicin citrate, denileukin-diftitox, mitoxantrone, docetaxel, doxorubicin HCl, Escherichia coli L-asparaginase, Erwinia L-asparaginase, etoposide phthalate, etoposide phosphate, gemcitabine HCl, idarubicin HCl, interferon alpha-2b, irinotecan HCl, maytansinoid, mechlorethamine HCl, melphalan HCl, mithramycin, mitomycin C, mitotane, polylactide-co-glycolide 20 with carmustine implant, procarbazine HCl, streptozotocin, teniposide, thiotepa, topotecan HCl, valrubicin, vinblastine sulfate, vincristine sulfate, and vinorelbine tartrate.

[1005] Additional cytotoxic chemotherapeutic agents for use in the present invention include: epirubicin, abraxane, taxotere, epothilone, tafluposide, vismodegib, azacitidine, capecitabine, vindesine, and vinorelbine.

[1006] In certain embodiments, the chemotherapeutic agent is not an aromatase inhibitor. In certain embodiments, the chemotherapeutic agent is not a steroid. In certain embodiments, the chemotherapeutic agent is not a BCR-ABL inhibitor.

[1007] In certain embodiments, the chemotherapeutic agent is a DNA complex binding agent. In certain embodiments, the chemotherapeutic agent is a tubulin binding agent. In certain embodiments, the chemotherapeutic agent is an alkylating agent. In certain embodiments, the chemotherapeutic agent is a thiolate alkylating agent.

[1008] Additional chemotherapeutic agents

[1009] Additional chemotherapeutic agents that can be used as described herein can include 2-methoxyestradiol or 2ME2, finasunate, edaravone (MEDI-522), HLL1, huN901-DM1, atimolide, saquinavir mesylate, ritonavir, nelfinavir mesylate, indinavir sulfate, plitidepsin, P276-00, tipifarnib, lenalidomide, thalidomide, pomalidomide, simvastatin, and celecoxib. Chemotherapeutic agents that can be used in the present invention include, but are not limited to, trastuzumab pertuzumab (Perjeta TM )、lapatinib gefitinib erlotinib cetuximab panitumumab vandetanib vemurafenib vorinostat romidepsin bexarotene alitretinoin tretinoin carfilzomib (Kyprolis TM )、pralatrexate bevacizumab aflibercept sorafenib sunitinib pazopanib regorafenib and cabozantinib (Cometriq TM ).

[1010] Additional chemotherapeutic agents encompassed include, but are not limited to, calcineurin inhibitors such as cyclosporine or ascomycin, such as cyclosporine A FK506 (tacrolimus), pimecrolimus; mTOR inhibitors such as rapamycin or its derivatives such as sirolimus everolimus Temsirolimus, zotarolimus, everolimus-7, everolimus-9; rapamycin analogs such as ridaforolimus, campath 1H; S1P receptor modulators; dual mTORC1 and mTORC2 inhibitors such as Vistusertib (AZD2014), such as fingolimod or its analogs; anti-IL-8 antibodies, mycophenolic acid or its salts such as sodium salt, or its prodrugs such as mycophenolate mofetil OKT3 (Orthoclone ), prednisone, buquinolate sodium, OKT4, T10B9.A-3A, 33B3.1, 15-deoxyspergualin, trepoimus, leflunomide anti-CD25, anti-IL2R, basiliximab daclizumab mizoribine, dexamethasone, ISAtx-247, SDZASM 981 (pimecrolimus, ), abatacept, belatacept, LFA3lg, etanercept (sold by ImmuneXcite as ), adalimumab infliximab anti-LFA-1 antibody, natalizumab enlimomab, gevokizumab, golimumab, antithymocyte immunoglobulin, siltuximab, alefacept, efalizumab, pentasa, mesalazine, asacol tablets, codeine phosphate, benorilate, fenbufen, naproxen, diclofenac, etodolac, indomethacin, dasatinib nilotinib bosutinib imatinib mesylate and ponatinib (Iclusig TM ), amifostine, dolasetron mesylate, dronabinol, epoetin-α, etidronate, filgrastim, fluconazole, goserelin acetate, gramicidin D, granisetron, leucovorin calcium, lidocaine, mesna, ondansetron HCl, pilocarpine HCl, porfimer sodium, vatalanib, 1-dehydrotestosterone, allopurinol sodium, betamethasone phosphate sodium and betamethasone acetate, calcium folinate, conjugated estrogens, dexrazoxane, dibromomannitol, esterified estrogens, estradiol, estramustine phosphate sodium, ethinyl estradiol, flutamide, folinic acid, glucocorticoids, leuprorelin acetate, levamisole HCl, medroxyprogesterone acetate, megestrol acetate, methyltestosterone, nilutamide, octreotide acetate, pamidronate disodium, procaine, propranolol, testolactone, tetracaine, toremifene citrate and sargramostim.

[1011] In certain embodiments, the chemotherapeutic agent is an estrogen receptor ligand such as tamoxifen, raloxifene, fulvestrant, anordrin, bazedoxifene, broparestriol, chlorotrianisene, clomiphene citrate, cyclofenil, lasofoxifene, ormeloxifene, or toremifene; an androgen receptor ligand such as bicalutamide, enzalutamide, apalutamide, cyproterone acetate, chlormadinone acetate, spironolactone, canrenone, drospirenone, ketoconazole, topilutamide, abiraterone acetate, or cimetidine; an aromatase inhibitor such as letrozole, anastrozole, or exemestane; an anti-inflammatory agent such as prednisone; an oxidase inhibitor such as allopurinol; an anti-cancer antibody; an anti-cancer monoclonal antibody; an antibody against CD40 such as lucatumumab or daratumumab; an antibody against CD20 such as rituximab; an antibody that binds CD52 such as alemtuzumab; an antibody that binds integrin such as volociximab or natalizumab; an antibody against the interleukin-6 receptor such as tocilizumab; an interleukin-2 mimetic such as aldesleukin; an antibody that targets IGF1 such as figitumumab; an antibody that targets DR4 such as mapatumumab; an antibody that targets TRAIL-R2 such as lexatumumab or dulaimumab; a fusion protein such as abatacept; a B cell inhibitor such as abatacept; a proteasome inhibitor such as carfilzomib, bortezomib, or marizomib; an HSP90 inhibitor such as tanespimycin; an HDAC inhibitor such as vorinostat, belinostat, or panobinostat; a MAPK ligand such as tapomulin; a PKC inhibitor such as enzastaurin; a HER2 receptor ligand such as trastuzumab, lapatinib, or pertuzumab; an EGFR inhibitor such as gefitinib, erlotinib, cetuximab, panitumumab, or vandetanib; a natural product such as romidepsin; a retinoid such as bexarotene, tretinoin, or alitretinoin; a receptor tyrosine kinase (RTK) inhibitor such as sunitinib, regorafenib, or pazopanib; or a VEGF inhibitor such as aflibercept, bevacizumab, or dovitinib.

[1012] In certain embodiments, the combination of a CDK4 / 6 inhibitor, a chemotherapeutic agent, and an immune checkpoint inhibitor is further combined with the use of the following factors: hematopoietic growth factors, including but not limited to granulocyte colony-stimulating factor (G-CSF, e.g., sold as (filgrastim); (peg-filgrastim); or lenograstim), granulocyte-macrophage colony-stimulating factor (GM-CSF, e.g., sold as molgramostim and sargramostim ), M-CSF (macrophage colony-stimulating factor), thrombopoietin (megakaryocyte growth and development factor (MGDF), e.g., sold as and Interleukin (IL)-12, interleukin-3, interleukin-11 (adipogenesis inhibitory factor or oprelvekin), SCF (stem cell factor, steel factor, kit-ligand or KL), and erythropoietin (EPO) and its derivatives (epoetin-α, sold, for example, as Darbepoetin, Epocept, Nanokine, Epofit, Epogen, Eprex, and Procrit; epoetin-β, sold, for example, as NeoRecormon, Recormon, and Micera), epoetin-δ (sold, for example, as Dynepo), epoetin-ω (sold, for example, as Epomax), epoetin ζ (sold, for example, as Silapo and Retacrit), and, for example, Epocept, Epotrust, Erypro Safe, Repoitin, Vintor, Epofit, Erykine, Wepox, Espogen, Relipoietin, Shanpoietin, Zyrop, and EPIAO).

[1013] Additional active compounds covered herein, particularly in the treatment of abnormal tissues of the female reproductive system such as breast cancer, ovarian cancer, endometrial cancer or uterine cancer, include combinations of the CDK9 inhibitors described herein with estrogen inhibitors, said estrogen inhibitors including but not limited to SERMs (selective estrogen receptor modulators), SERDs (selective estrogen receptor degraders), complete estrogen receptor degraders or another form of partial or complete estrogen antagonist. Partial antiestrogens, including raloxifene and tamoxifen, retain some estrogen-like effects. Complete antiestrogens include fulvestrant. Non-limiting examples of antiestrogenic compounds are provided in the following: WO 2014 / 19176 assigned to Astra Zeneca; WO2013 / 090921, WO 2014 / 203129, WO 2014 / 203132 and US2013 / 0178445 assigned to Olema Pharmaceuticals; WO2017 / 100712, WO2017 / 100715, WO2018 / 081168 and WO2018 / 148576 assigned to G1 Therapeutics; U.S. Patent Nos. 9,078,871, 8,853,423 and 8,703,810; and US2015 / 0005286, WO 2014 / 205136 and WO 2014 / 205138. Additional non-limiting examples of antiestrogenic compounds include: SERMs such as anordrin, asoxifene, bazedoxifene, bromoparestrol, clomiphene citrate, cyclofenil, trioxifene, indoxifene, idoxifene, lasofoxifene, oremoxifene, pipendoxifene, raloxifene, tamoxifen, toremifene and fulvestrant; aromatase inhibitors such as aminoglutethimide, testolactone, anastrozole, exemestane, fadrozole, formestane and letrozole; and antigonadotropins such as leuprolide, cetrorelix, allylestrenol, chlormadinone acetate, demegestone acetate, dydrogesterone, medroxyprogesterone acetate, megestrol acetate, nomegestrol acetate, norethisterone acetate, progesterone and spironolactone. Additional non-limiting examples of antiestrogenic compounds include: SERDs such as fulvestrant, rintodestrant (G1T48), brilanestrant (GDC0810), elacestrant (RAD1901), etacstil (GW5638), GW7604, AZD9496, GDC-0927, GDC9545 (RG6171), LSZ102 and SAR439859.

[1014] In certain embodiments, SERD compounds of the formula described in WO 2017 / 100712

[1015]

[1016] or a pharmaceutically acceptable salt thereof.

[1017] Wherein:

[1018] m 4 is 0, 1, 2, 3 or 4;

[1019] n 4 is 0, 1, 2, 3 or 4;

[1020] X A is selected from -O-, -CH2-, -S-, -NH-, -NMe-, -CF2- and C3 cycloalkyl;

[1021] Ring B is phenyl, naphthyl, quinolinyl, 5- or 6-membered monocyclic heteroaryl or 7-, 8-, 9- or 10-membered bicyclic heterocycle;

[1022] Ring C is phenyl, thienyl, 5- or 6-membered monocyclic heteroaryl or 7-, 8-, 9- or 10-membered bicyclic heterocycle;

[1023] R 41 is selected from hydroxy, hydrogen, halogen, –O(C1-C6 alkyl), –OC(O)(C1-C6 alkyl), –OC(O)C6H5, –OC(O)O(C1-C6 alkyl), –OC(O)OC6H5 and –OSO2(C2-C6 alkyl);

[1024] R 42 is selected from –CH=CHCOOH, –NH(CO)COOH, –COOH, -C2-C6 alkenylene-COOH and -C2-C6 alkynylene-COOH;

[1025] R 43 is independently selected from hydrogen, halogen, –CN, –NO2, -C1-C6 alkyl and -C1-C6 fluoroalkyl each time it appears; and

[1026] R 44 is independently selected from hydrogen, halogen, hydroxy, -C1-C6 alkyl, -C1-C6 fluoroalkyl, –CN, –O(C1-C6 alkyl) and –O(C1-C6 fluoroalkyl) each time it appears.

[1027] Non-limiting examples of SERDS for use in the present invention include:

[1028]

[1029]

[1030] or a pharmaceutically acceptable salt thereof.

[1031] In certain embodiments, the SERD is:

[1032]

[1033] or a pharmaceutically acceptable salt thereof.

[1034] In certain embodiments, the SERD is:

[1035]

[1036] or a pharmaceutically acceptable salt thereof.

[1037] In certain embodiments, the SERD is:

[1038]

[1039] or a pharmaceutically acceptable salt thereof.

[1040] Additional chemotherapeutic agents covered herein, particularly in the treatment of abnormal tissues of the male reproductive system such as prostate cancer or testicular cancer, include but are not limited to androgen (such as testosterone) inhibitors, including but not limited to selective androgen receptor modulators, selective androgen receptor degraders, complete androgen receptor degraders, or another form of partial or complete androgen antagonist. In certain embodiments, the prostate cancer or testicular cancer is androgen resistant. Non-limiting examples of antiandrogen compounds are provided in WO 2011 / 156518 and U.S. Patent Nos. 8,455,534 and 8,299,112. Additional non-limiting examples of antiandrogen compounds include: chlormadinone acetate, spironolactone, epitiostanol, drospirenone, ketoconazole, topilutamide, abiraterone acetate, and cimetidine.

[1041] The chemotherapeutic agent may include kinase inhibitors, including but not limited to phosphoinositide 3-kinase (PI3K) inhibitors, Bruton's tyrosine kinase (BTK) inhibitors, or spleen tyrosine kinase (Syk) inhibitors or combinations thereof.

[1042] PI3k inhibitors are well known. Examples of PI3 kinase inhibitors include but are not limited to Wortmannin, demethoxycuracin A, perifosine, idelalisib, pictilisib, Palomid529, ZSTK474, PWT33597, CUDC-907, and AEZS-136, duvelisib, GS-9820, GDC-0032 (2-[4-[2-(2-isopropyl-5-methyl-1,2,4-triazol-3-yl)-5,6-dihydroimidazo[1,2-d][1,4]benzoxazepin -9-yl]pyrazol-1-yl]-2-methylpropanamide), MLN-1117 ((2R)-1-phenoxy-2-butanyl hydrogen (S)-methylphosphonate; or methyl(oxo){[(2R)-1-phenoxy-2-butanyl]oxy}phosphonium), BYL-719 ((2S)-N1-[4-methyl-5-[2-(2,2,2-trifluoro-1,1-dimethylethyl)-4-pyridinyl]-2-thiazolyl]-1,2-pyrrolidinedicarboxamide), GSK2126458 (2,4-difluoro-N-{2-(methyloxy)-5-[4-(4-pyridazinyl)-6-quinolinyl]-3-pyridinyl}benzenesulfonamide), TGX-221 ((±)-7-methyl-2-(morpholin-4-yl)-9-(1-phenylaminoethyl)-pyrido[1,2-a]-pyrimidin-4-one), GSK2636771 (2-methyl-1-(2-methyl-3-(trifluoromethyl)benzyl)-6-morpholino-1H-benzo[d]imidazole-4-carboxylic acid dihydrochloride), KIN-193 ((R)-2-((1-(7-methyl-2-morpholino-4-oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid), TGR-1202 / RP5264, GS-9820 ((S)-1-(4-((2-(2-aminopyrimidin-5-yl)-7-methyl-4-hydroxypropan-1-one), GS-1101 (5-fluoro-3-phenyl-2-([S)]-1-[9H-purin-6-ylamino]-propyl)-3H-quinazolin-4-one), AMG-319, GSK-2269557, SAR245409 (N-(4-(N-(3-((3,5-dimethoxyphenyl)amino)quinoxalin-2-yl)sulfamoyl)phenyl)-3-methoxy-4-methylbenzamide), BAY80-6946 (2-amino-N-(7-methoxy-8-(3-morpholinopropoxy)-2,3-dihydroimidazo[1,2-c]quinaz), AS 252424 (5-[1-[5-(4-fluoro-2-hydroxyphenyl)-furan-2-yl]-methyl-(Z)-ylidene]-thiazolidine-2,4-dione), CZ 24832 (5-(2-amino-8-fluoro-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-N-tert-butylpyridine-3-sulfonamide), buparlisib (5-[2,6-bis(4-morpholinyl)-4-pyrimidinyl]-4-(trifluoromethyl)-2-pyridinamine), GDC-0941 (2-(1H-indazol-4-yl)-6-[[4-(methylsulfonyl)-1-piperazinyl]methyl]-4-(4-morpholinyl)thieno[3,2-d]pyrimidine), GDC-0980 ((S)-1-(4-((2-(2-aminopyrimidin-5-yl)-7-methyl-4-morpholinothieno[3,(2-d)pyrimidin-6-yl)methyl)piperazin-1-yl)-2-hydroxypropan-1-one (also known as RG7422)), SF1126 ((8S,14S,17S)-14-(carboxymethyl)-8-(3-guanidinopropyl)-17-(hydroxymethyl)-3,6,9,12,15-pentaoxo-1-(4-(4-oxo-8-phenyl-4H-chromen-2-yl)morpholin-4-ium)-2-oxa-7,10,13,16-tetraazaoctadecane-18-carboxylate), PF-05212384 (N-[4-[[4-(dimethylamino)-1-piperidinyl]carbonyl]phenyl]-N'-[4-(4,6-di-4-morpholinyl-1,3,5-triazin-2-yl)phenyl]urea), LY3023414, BEZ235 (2-methyl-2-{4-[3-methyl-2-oxo-8-(quinolin-3-yl)-2,3-dihydro-1H-imidazo[4,5-c]quinolin-1-yl]phenyl}propanenitrile), XL-765 (N-(3-(N-(3-(3,5-dimethoxyphenylamino)quinoxalin-2-yl)sulfamoyl)phenyl)-3-methoxy-4-methylbenzamide) and GSK1059615 (5-[[4-(4-pyridyl)-6-quinolinyl]methylene]-2,4-thiazolidinedione), PX886 ([(3aR,6E,9S,9aR,10R,11aS)-6-[[bis(prop-2-enyl)amino]methylene]-5-hydroxy-9-(methoxymethyl)-9a,11a-dimethyl-1,4,7-trioxo-2,3,3a,9,10,11-hexahydroindeno[4,5h]isochromen-10-yl]acetate (also known as sonolisib)) and the structure of the following formula described in WO2014 / 071109:

[1043] BTK inhibitors are well known. Examples of BTK inhibitors include ibrutinib (also known as PCI-32765) (Imbruvica TM )(1-[(3R)-3-[4-amino-3-(4-phenoxyphenyl)pyrazolo[3,4-d]pyrimidin-1-yl]piperidin-1-yl]prop-2-en-1-one), acalabrutinib Diphenylaminopyrimidine-based inhibitors such as AVL-101 and AVL-291 / 292 (N-(3-((5-fluoro-2-((4-(2-methoxyethoxy)phenyl)amino)pyrimidin-4-yl)amino)phenyl)acrylamide) (Avila Therapeutics) (see U.S. Patent Publication No. 2011 / 0117073, which is incorporated herein by reference in its entirety), dasatinib ([N-(2-chloro-6-methylphenyl)-2-(6-(4-(2-hydroxyethyl)piperazin-1-yl)-2-methylpyrimidin-4-ylamino)thiazole-5-carboxamide]), LFM-A13 (α-cyano-β-hydroxy-β-methyl-N-(2,5-dibromophenyl)acrylamide), GDC-0834 ([R-N-(3-(6-(4-(1,4-dimethyl-3-oxopiperazin-2-yl)phenylamino)-4-methyl-5-oxo-4,5-dihydropyrazin-2-yl)-2-methylphenyl)-4,5,6,7-tetrahydrobenzo[b]thiophene-2-carboxamide]), CGI-560 4-(tert-butyl)-N-(3-(8-(phenylamino)imidazo[1,2-a]pyrazin-6-yl)phenyl)benzamide, CGI-1746 (4-(tert-butyl)-N-(2-methyl-3-(4-methyl-6-((4-(morpholine-4-carbonyl)phenyl)amino)-5-oxo-4,5-dihydropyrazin-2-yl)phenyl)benzamide), CNX-774 (4-(4-((4-((3-acrylamidophenyl)amino)-5-fluoropyrimidin-2-yl)amino)phenoxy)-N-methylpyridinecarboxamide), CTA056 (7-benzyl-1-(3-(piperidin-1-yl)propyl)-2-(4-(pyridin-4-yl)phenyl)-1H-imidazo[4,5-g]quinoxalin-6(5H)-one), GDC-0834 ((R)-N-(3-(6-((4-(1,4-dimethyl-3-oxopiperazin-2-yl)phenyl)amino)-4-methyl-5-oxo-4,5-dihydropyrazin-2-yl)-2-methylphenyl)-4,5,6,7-tetrahydrobenzo[b]thiophene-2-carboxamide), GDC-0837 ((R)-N-(3-(6-((4-(1,4-dimethyl-3-oxopiperazin-2-yl)phenyl)amino)-4-methyl-5-oxo-4,5-dihydropyrazin-2-yl)-2-methylphenyl)-4,5,6,7-tetrahydrobenzo[b]thiophene-2-carboxamide), HM-71224, ACP-196, ONO-4059 (Ono Pharmaceuticals), PRT062607 (4-((3-(2H-1,2,3-triazol-2-yl)phenyl)amino)-2-(((1R,((2S)-2-aminocyclohexyl)amino)pyrimidine-5-carboxamide hydrochloride), QL-47 (1-(1-acryloylindolin-6-yl)-9-(1-methyl-1H-pyrazol-4-yl)benzo[h][1,6]naphthyridin-2(1H)-one), and RN486 (6-cyclopropyl-8-fluoro-2-(2-hydroxymethyl-3-{1-methyl-5-[5-(4-methylpiperazin-1-yl)pyridin-2-ylamino]-6-oxo-1,6-dihydro-pyridin-3-yl}-phenyl)-2H-isoquinolin-1-one), BGB-3111, and other molecules capable of inhibiting BTK activity, e.g., those BTK inhibitors disclosed in Akinleye et al., Journal of Hematology & Oncology, 2013, 6:59, the entire content of which is incorporated herein by reference.,

[1044] Syk inhibitors are well-known and include, for example, Cerdulatinib (4-(cyclopropylamino)-2-((4-(4-(ethylsulfonyl)piperazin-1-yl)phenyl)amino)pyrimidine-5-carboxamide), Entospletinib (6-(1H-indazol-6-yl)-N-(4-morpholinophenyl)imidazo[1,2-a]pyrazin-8-amine), Fostamatinib ([6-({5-fluoro-2-[(3,4,5-trimethoxyphenyl)amino]-4-pyrimidinyl}amino)-2,2-dimethyl-3-oxo-2,3-dihydro-4H-pyrido[3,2-b][1,4]oxazin-4-yl]methyl dihydrogen phosphate), Fostamatinib disodium ((6-((5-fluoro-2-((3,4,5-trimethoxyphenyl)amino)pyrimidin-4-yl)amino)-2,2-dimethyl-3-oxo-2H-pyrido[3,2-b][1,4]oxazin-4(3H)-yl)methyl sodium phosphate), BAY 61-3606 (2-(7-(3,4-dimethoxyphenyl)-imidazo[1,2-c]pyrimidin-5-ylamino)-nicotinamide HCl), RO9021 (6-[(1R,2S)-2-aminocyclohexylamino]-4-(5,6-dimethyl-pyridin-2-ylamino)-pyridazine-3-carboxamide), Imatinib (Gleevac; 4-[(4-methylpiperazin-1-yl)methyl]-N-(4-methyl-3-{[4-(pyridin-3-yl)pyrimidin-2-yl]amino}phenyl)benzamide), Staurosporine, GSK143 (2-(((3R,4R)-3-aminotetrahydro-2H-pyran-4-yl)amino)-4-(p-tolylamino)pyrimidine-5-carboxamide), PP2 (1-(tert-butyl)-3-(4-chlorophenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine), PRT-060318 (2-(((1R,2S)-2-aminocyclohexyl)amino)-4-(m-tolylamino)pyrimidine-5-carboxamide), PRT-062607 (4-((3-(2H-1,2,3-triazol-2-yl)phenyl)amino)-2-(((1R,2S)-2-aminocyclohexyl)amino)pyrimidine-5-carboxamide hydrochloride), R112 (3,3'-((5-fluoropyrimidine-2,4-diyl)bis(azanediyl))diphenol), R348 (3-ethyl-4-methylpyridine), R406 (6-((5-fluoro-2-((3,4,5-trimethoxyphenyl)amino)pyrimidin-4-yl)amino)-2,2-dimethyl-2H-pyrido[3,2-b][1,4]oxazin-3(4H)-one), YM193306 (see Singh et al.,Discovery and Development of Spleen Tyrosine Kinase(SYK)Inhibitors, J.Med.Chem.2012, 55, 3614 - 3643), 7 - azaindole, piceatannol, ER - 27319 (see Singh et al., Discovery and Development of Spleen Tyrosine Kinase(SYK)Inhibitors, J.Med.Chem.2012, 55, 3614 - 3643, the full text of which is incorporated herein), compound D (see Singh et al., Discovery and Development of Spleen Tyrosine Kinase(SYK)Inhibitors, J.Med.Chem.2012, 55, 3614 - 3643, the full text of which is incorporated herein), PRT060318 (see Singh et al., Discovery and Development of Spleen Tyrosine Kinase(SYK)Inhibitors, J.Med.Chem.2012, 55, 3614 - 3643, the full text of which is incorporated herein), luteolin (see Singh et al., Discovery and Development of Spleen Tyrosine Kinase(SYK)Inhibitors, J.Med.Chem.2012, 55, 3614 - 3643, the full text of which is incorporated herein), apigenin (see Singh et al., Discovery and Development of Spleen Tyrosine Kinase(SYK)Inhibitors, J.Med.Chem.2012, 55, 3614 - 3643, the full text of which is incorporated herein), quercetin (see Singh et al., Discovery and Development of Spleen Tyrosine Kinase(SYK)Inhibitors, J.Med.Chem.2012, 55, 3614 - 3643, the full text of which is incorporated herein), fisetin (see Singh et al., Discovery and Development of Spleen Tyrosine Kinase(SYK)Inhibitors, J.Med.Chem.2012, 55, 3614 - 3643, the full text of which is incorporated herein), myricetin (see Singh et al.,Discovery and Development of Spleen Tyrosine Kinase (SYK) Inhibitors, J. Med. Chem. 2012, 55, 3614 - 3643 (the full text of which is incorporated herein by reference), morin (see Singh et al., Discovery and Development of Spleen Tyrosine Kinase (SYK) Inhibitors, J. Med. Chem. 2012, 55, 3614 - 3643, the full text of which is incorporated herein by reference).

[1045] The chemotherapeutic agent can also be a B - cell lymphoma 2 (Bcl - 2) protein inhibitor. BCL - 2 inhibitors are known in the art and include, for example, ABT - 199 (4 - [4 - [[2 - (4 - chlorophenyl)-4,4 - dimethylcyclohex - 1 - en - 1 - yl]methyl]piperazin - 1 - yl]-N - [[3 - nitro - 4 - [[(tetrahydro - 2H - pyran - 4 - yl)methyl]amino]phenyl]sulfonyl]-2 - [(1H - pyrrolo[2,3 - b]pyridin - 5 - yl)oxy]benzamide), ABT - 737 (4 - [4 - [[2 - (4 - chlorophenyl)phenyl]methyl]piperazin - 1 - yl]-N - [4 - [[(2R)-4 - (dimethylamino)-1 - phenylsulfonylbutan - 2 - yl]amino]-3 - nitrophenyl]sulfonylbenzamide), ABT - 263 ((R)-4 - (4 - ((4'-chloro - 4,4 - dimethyl - 3,4,5,6 - tetrahydro - [1,1'-biphenyl]-2 - yl)methyl)piperazin - 1 - yl)-N - ((4 - ((4 - morpholino - 1 - (phenylthio)butan - 2 - yl)amino)-3((trifluoromethyl)sulfonyl)phenyl)sulfonyl)benzamide), GX15 - 070 (obatoclax mesylate, (2Z)-2 - [(5Z)-5 - [(3,5 - dimethyl - 1H - pyrrol - 2 - yl)methylene]-4 - methoxypyrrole - 2 - ylidene]indole methanesulfonate)), 2 - methoxy - antimycin A3, YC137 (4 - (4,9 - dioxo - 4,9 - dihydronaphtho[2,3 - d]thiazol - 2 - ylamino)-phenyl ester), pogosin, ethyl 2 - amino - 6 - bromo - 4 - (1 - cyano - 2 - ethoxy - 2 - oxoethyl)-4H - chromene - 3 - carboxylate, nilotinib - d3, TW - 37 (N - [4 - [[2 - (1,1 - dimethylethyl)phenyl]sulfonyl]phenyl]-2,3,4 - trihydroxy - 5 - [[2 - (1 - methylethyl)phenyl]methyl]benzamide), Apogossypolone (ApoG2) or G3139 (Oblimersen).

[1046] Additional chemotherapeutic agents for use in the methods covered herein include, but are not limited to, midazolam, MEK inhibitors, RAS inhibitors, ERK inhibitors, ALK inhibitors, HSP inhibitors (e.g., HSP70 and HSP 90 inhibitors or combinations thereof), RAF inhibitors, apoptosis compounds, topoisomerase inhibitors, AKT inhibitors (including but not limited to MK-2206, GSK690693, perifosine, (KRX-0401), GDC-0068, troxacitabine, AZD5363, honokiol, PF-04691502, and miltefosine), or FLT-3 inhibitors (including but not limited to P406, dovitinib, quizartinib (AC220), amuvatinib (MP-470), tandutinib (MLN518), ENMD-2076, and KW-2449) or combinations thereof.Examples of MEK inhibitors include, but are not limited to, trametinib / GSK1120212 (N-(3-{3-cyclopropyl-5-[(2-fluoro-4-iodophenyl)amino]-6,8-dimethyl-2,4,7-trioxo-3,4,6,7-tetrahydropyrido[4,3-d]pyrimidin-1(2H-yl)phenyl)acetamide), selumetinib (6-(4-bromo-2-chloroanilino)-7-fluoro-N-(2-hydroxyethoxy)-3-methylbenzimidazole-5-carboxamide), pimasertib / AS703026 / MSC1935369 ((S)-N-(2,3-dihydroxypropyl)-3-((2-fluoro-4-iodophenyl)amino)isonicotinamide), XL-518 / GDC-0973 (1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-[(2S)-piperidin-2-yl]azetidin-3-ol), refametinib / BAY869766 / RDEA119 (N-(3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-6-methoxyphenyl)-1-(2,3-dihydroxypropyl)cyclopropane-1-sulfonamide), PD-0325901 (N-[(2R)-2,3-dihydroxypropoxy]-3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]-benzamide), TAK733 ((R)-3-(2,3-dihydroxypropyl)-6-fluoro-5-(2-fluoro-4-iodophenylamino)-8-methylpyrido[2,3-d]pyrimidine-4,7(3H,8H)-dione), MEK162 / ARRY438162 (5-[(4-bromo-2-fluorophenyl)amino]-4-fluoro-N-(2-hydroxyethoxy)-1-methyl-1H-benzimidazole-6-carboxamide), RO5126766 (3-[[3-fluoro-2-(methylsulfamoylamino)-4-pyridyl]methyl]-4-methyl-7-pyrimidin-2-yloxychromen-2-one), WX-554, RO4987655 / CH4987655 (3,4-difluoro-2-((2-fluoro-4-iodophenyl)amino)-N-(2-hydroxyethoxy)-5-((3-oxo-1,2-oxazinan-2-yl)methyl)benzamide) or AZD8330 (2-((2-fluoro-4-iodophenyl)amino)-N-(2-hydroxyethoxy)-1,5-dimethyl-6-oxo-1,6-dihydropyridine-3-carboxamide). Examples of RAS inhibitors include, but are not limited to, Reolysin and siG12D LODER. Examples of ALK inhibitors include, but are not limited to, crizotinib, AP26113 and LDK378. HSP inhibitors include, but are not limited to, geldanamycin or 17-N-allylamino-17-demethoxygeldanamycin (17AAG) and Radicicol.

[1047] Known ERK inhibitors include SCH772984 (Merck / Schering-Plough), VTX-11e (Vertex), DEL-22379, Ulixertinib (BVD-523, VRT752271), GDC-0994, FR 180204, XMD8-92, and ERK5-IN-1.

[1048] Raf inhibitors are well-known and include, for example, Vemurafinib (N-[3-[[5-(4-chlorophenyl)-1H-pyrrolo[2,3-b]pyridin-3-yl]carbonyl]-2,4-difluorophenyl]-1-propanesulfonamide), Sorafenib tosylate (4-[4-[[4-chloro-3-(trifluoromethyl)phenyl]carbamoylamino]phenoxy]-N-methylpyridine-2-carboxamide 4-methylbenzenesulfonate), AZ628 (3-(2-cyanopropan-2-yl)-N-(4-methyl-3-(3-methyl-4-oxo-3,4-dihydroquinazolin-6-ylamino)phenyl)benzamide), NVP-BHG712 (4-methyl-3-(1-methyl-6-(pyridin-3-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-ylamino)-N-(3-(trifluoromethyl)phenyl)benzamide), RAF-265 (1-methyl-5-[2-[5-(trifluoromethyl)-1H-imidazol-2-yl]pyridin-4-yl]oxy-N-[4-(trifluoromethyl)phenyl]benzimidazol-2-amine), 2-Bromoaldisine (2-bromo-6,7-dihydro-1H,5H-pyrrolo[2,3-c]azepin-4,8-dione), Raf kinase inhibitor IV (2-chloro-5-(2-phenyl-5-(pyridin-4-yl)-1H-imidazol-4-yl)phenol), and Sorafenib N-oxide (4-[4-[[[[4-chloro-3(trifluoromethyl)phenyl]amino]carbonyl]amino]phenoxy]-N-methyl-2-pyridinecarboxamide 1-oxide). -4,8-dione), Raf kinase inhibitor IV (2-chloro-5-(2-phenyl-5-(pyridin-4-yl)-1H-imidazol-4-yl)phenol), and Sorafenib N-oxide (4-[4-[[[[4-chloro-3(trifluoromethyl)phenyl]amino]carbonyl]amino]phenoxy]-N-methyl-2-pyridinecarboxamide 1-oxide).

[1049] Known topoisomerase I inhibitors that can be used in the present invention include (S)-10-[(dimethylamino)methyl]-4-ethyl-4,9-dihydroxy-1H-pyrano[3',4':6,7]indolizino[1,2-b]quinoline-3,14(4H,12H)-dione monohydrochloride (topotecan), (S)-4-ethyl-4-hydroxy-1H-pyrano[3',4':6,7]indolizino[1,2-b]quinoline-3,14-(4H,12H)-dione (camptothecin), (1S,9S)-1-amino-9-ethyl-5-fluoro-1,2,3,9,12,15-hexahydro-9-hydroxy-4-methyl-10H,13H-benzo(de)pyrano(3',4':6,7)indolizino(1,2-b)quinoline-10,13-dione (exatecan), (7-(4-methylpiperazinomethylene)-10,11-ethylenedioxy-20(S)-camptothecin (letotecan) or (S)-4,11-diethyl-3,4,12,14-tetrahydro-4-hydroxy-3,14-dioxo-1H-pyrano[3’,4’:6,7]-indolizino[1,2-b]quinolin-9-yl-[1,4’-bipiperidin]-1’-carboxylate (irinotecan), (R)-5-ethyl-9,10-difluoro-5-hydroxy-4,5-dihydrooxa Benzo[3',4':6,7]indolizino[1,2-b]quinoline-3,15(1H,13H)-dione (diflomotecan), (4S)-11-((E)-((tert-butoxy)imino)methyl)-4-ethyl-4-hydroxy-1,12-dihydro-14H-pyrano(3',4':6,7)indolizino(1,2-b)quinoline-3,14(4H)-dione (gemcitabine), (S)-8-ethyl-8-hydroxy-15-((4-methylpiperazin-1-yl)methyl)-11,14-dihydro-2H-[1,4]dioxino[2,3-g]pyrano[3',4':6,7]indolizino[1,2-b]quinoline-9,12(3H,8H)-dione (leucototecan), (4S)-4-ethyl-4-hydroxy-11-[2-[(isopropylamino)ethyl]]-1H-pyrano[3,4:6,7]indolizino[1,2-b]quinoline-3,14(4H,12H)-dione (belotecan), 6-((1,3-dihydroxypropan-2-yl)amino)-2,10-dihydroxy-12-((2R,3R,4S,5S,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-2-yl)-12,13-dihydro-5H-indolo[2,3-a]pyrrolo[3,4-c]carbazole-5,7(6H)-dione (edotecarin), 8,9-dimethoxy-5-(2-N,N-dimethylaminoethyl)-2,3-methylenedioxy-5H-dibenzo(c,h)(1,6)naphthyridin-6-one (topovale), benzo[6,7]indolizino[1,2-b]quinolin-11(13H)-one (rosettacin), (S)-4-ethyl-4-hydroxy-11-(2-(trimethylsilyl)ethyl)-1H-pyrano[3',4':6,7]indolizino[1,2-b]quinoline-3,14(4H,12H)-dione (cositecan), tetra{(4S)-9-[([1,4'-bipiperidinyl]-1'-carbonyloxy)]-4,11-diethyl-3,14-dioxo-3,4,12,14-tetrahydro-1H-pyrano[3',4':6,7]indolizino[1,2-b]quinolin-4-yl} N,N',N'',N'''-{methanetetrayltetra[methylene poly(oxyethyleneoxy(1-oxoethylene))]}tetraglycine tetrahydrochloride (etirinotecan pegol), 10-hydroxy-camptothecin (HOCPT), 9-nitro-camptothecin (rubitecan), SN38 (7-ethyl-10-hydroxycamptothecin) and 10-hydroxy-9-nitro-camptothecin (CPT109), (R)-9-chloro-5-ethyl-5-hydroxy-10-methyl-12-((4-methylpiperazin-1-yl)methyl)-4,5-dihydrooxa [3',4':6,7]Indolizino[1,2-b]quinoline-3,15(1H,13H)-dione (elmotecan).

[1050] In certain embodiments, the chemotherapeutic agent is not an aromatase inhibitor. In certain embodiments, the chemotherapeutic agent is not an estrogen or androgen receptor agonist or antagonist.

[1051] Growth factor

[1052] In certain embodiments, the combination of a CDK4 / 6 inhibitor, a chemotherapeutic agent, and a checkpoint inhibitor is further combined with the use of the following factors: hematopoietic growth factors, including but not limited to granulocyte colony-stimulating factor (G-CSF, such as sold as Neupogen (filgrastim); Neulasta (peg-filgrastim); or lenograstim), granulocyte macrophage colony-stimulating factor (GM-CSF, such as sold as molgramostim and sargramostim (Leukine)), M-CSF (macrophage colony-stimulating factor), thrombopoietin (megakaryocyte growth and development factor (MGDF), such as sold as romiplostim and eltrombopag), interleukin (IL)-12, interleukin-3, interleukin-11 (adipogenesis inhibitory factor or oprelvekin), SCF (stem cell factor, steel factor, kit-ligand or KL), and erythropoietin (EPO) and its derivatives (epoetin-α, sold as, for example, Darbepoetin, Epocept, Nanokine, Epofit, Epogen, Eprex, and Procrit; epoetin-β, sold as, for example, NeoRecormon, Recormon, and Micera), epoetin-δ (sold as, for example, Dynepo), epoetin-ω (sold as, for example, Epomax), epoetin ζ (sold as, for example, Silapo and Retacrit), and, for example, Epocept, Epotrust, Erypro Safe, Repoitin, Vintor, Epofit, Erykine, Wepox, Espogen, Relipoietin, Shanpoietin, Zyrop, and EPIAO).

[1053] CDK4 / 6 inhibitor

[1054] The present invention also provides an advantageous method for treating a patient suffering from a selective CDK4 / 6 inhibitor-resistant cancer, which comprises administering an effective amount of a compound of Formula I, Formula II, Formula III, Formula IV, Formula V, Formula VI, Formula VII, Formula VIII, Formula IX or Formula X, or a pharmaceutically acceptable composition, salt or isotopic analogue thereof. In certain aspects, the compounds of the present invention are used for treating a patient suffering from a cancer having intrinsic resistance to selective CDK4 / 6 inhibition. In certain aspects, the compounds of the present invention are used for treating a patient suffering from a cancer having acquired resistance to one or more selective CDK4 / 6 inhibitors. In certain aspects, the compounds of the present invention are administered in combination with a selective CDK4 / 6 inhibitor to a patient suffering from a selective CDK4 / 6 inhibitor-responsive cancer to extend the therapeutic efficacy of the selective CDK4 / 6 inhibitor. In certain aspects, the compounds of the present invention are administered in combination with a selective CDK4 / 6 inhibitor to a patient suffering from a selective CDK4 / 6 inhibitor-responsive cancer, wherein the patient is naive to the selective CDK4 / 6 inhibitor. Selective CDK4 / 6 inhibitors for use in combination with the compounds of the present invention include, but are not limited to, palbociclib, abemaciclib, ribociclib, trilaciclib, SHR6390 and leroiciclib.

[1055] In certain embodiments, the selective CDK4 / 6 inhibitor is palbociclib:

[1056] or a pharmaceutically acceptable salt thereof.

[1057] In certain embodiments, the selective CDK4 / 6 inhibitor is abemaciclib:

[1058] or a pharmaceutically acceptable salt thereof.

[1059] In certain embodiments, the selective CDK4 / 6 inhibitor is ribociclib:

[1060] or a pharmaceutically acceptable salt thereof.

[1061] In certain embodiments, the selective CDK4 / 6 inhibitor is leroiciclib:

[1062] or a pharmaceutically acceptable salt thereof.

[1063] In certain embodiments, the selective CDK4 / 6 inhibitor is trilaciclib:

[1064] or a pharmaceutically acceptable salt thereof.

[1065] In certain embodiments, the selective CDK4 / 6 inhibitor is SHR 6390.

[1066] In certain embodiments, the selective CDK4 / 6 inhibitor is selected from, for example, the inhibitors described in U.S. Patent Nos. 8,822,683, 8,598,197, 8,598,186, 8,691,830, 8,829,102, 8,822,683, 9,102,682, 9,499,564, 9,481,591, and 9,260,442, which were filed by Tavares and Strum and assigned to G1 Therapeutics and describe a class of N-(heteroaryl)-pyrrolo[3,2-d]pyrimidin-2-amine cyclin-dependent kinase inhibitors, including those of the following formula (with variables as defined therein):

[1067]

[1068] In certain embodiments, the selective CDK4 / 6 inhibitor is selected from, for example, the inhibitors described in U.S. Patent Nos. 9,464,092, 9,487,530, and 9,527,857, which are also assigned to G1 Therapeutics and describe the use of the above-described pyrimidine-based agents in the treatment of cancer.

[1069] In certain embodiments, the selective CDK4 / 6 inhibitor is selected from, for example, the inhibitors described in WO 2013 / 148748 (U.S.S.N. 61 / 617,657) entitled "Lactam Kinase Inhibitors", WO 2013 / 163239 (U.S.S.N. 61 / 638,491) entitled "Synthesis of Lactams", and WO 2015 / 061407, which were filed by Tavares and also assigned to G1 Therapeutics and describe the synthesis of N-(heteroaryl)-pyrrolo[3,2-d]pyrimidin-2-amine and its use as a lactam kinase inhibitor.

[1070] In certain embodiments, the selective CDK4 / 6 inhibitor is selected from, for example, the inhibitors described in the following. WO 2014 / 144326, filed by Strum et al. and assigned to G1 Therapeutics, describes compounds and methods for using pyrimidine-based CDK4 / 6 inhibitors to protect normal cells during chemotherapy. WO 2014 / 144596, filed by Strum et al. and assigned to G1 Therapeutics, describes compounds and methods for using pyrimidine-based CDK4 / 6 inhibitors to protect hematopoietic stem and progenitor cells from the effects of ionizing radiation. WO 2014 / 144847, filed by Strum et al. and assigned to G1 Therapeutics, describes the use of pyrimidine-based CDK4 / 6 inhibitors for the retention therapy of HSPCs with abnormal cell proliferation. WO 2014 / 144740, filed by Strum et al. and assigned to G1 Therapeutics, describes highly active antitumor and antiproliferative pyrimidine-based CDK 4 / 6 inhibitors. WO 2015 / 161285, filed by Strum et al. and assigned to G1 Therapeutics, describes tricyclic pyrimidine-based CDK inhibitors for radiation protection. WO 2015 / 161287, filed by Strum et al. and assigned to G1 Therapeutics, describes tricyclic pyrimidine-based CDK inhibitors for protecting cells during chemotherapy. WO 2015 / 161283, filed by Strum et al. and assigned to G1 Therapeutics, describes tricyclic pyrimidine-based CDK inhibitors for the retention therapy of HSPCs with RB-positive abnormal cell proliferation. WO 2015 / 161288, filed by Strum et al. and assigned to G1 Therapeutics, describes tricyclic pyrimidine-based CDK inhibitors used as antitumor and antiproliferative agents. WO 2016 / 040858, filed by Strum et al. and assigned to G1 Therapeutics, describes the use of combinations of pyrimidine-based CDK4 / 6 inhibitors with other antitumor agents. WO 2016 / 040848, filed by Strum et al. and assigned to G1 Therapeutics, describes compounds and methods for treating certain Rb-negative cancers with CDK4 / 6 inhibitors and topoisomerase inhibitors.

[1071] VIII. Examples

[1072] Example 1

[1073] General methods:

[1074] For convenience, the compounds of the invention having a stereocenter are depicted as racemic. Those skilled in the art will recognize that the pure enantiomers can be prepared by methods known in the art. Examples of methods for obtaining optically active materials include at least the following.

[1075] i) Physical separation of crystals - a technique for manually separating the macroscopic crystals of the individual enantiomers. This technique can be used if there are crystals of the individual enantiomers, i.e., the material is a conglomerate and the crystals are visually different;

[1076] ii) Simultaneous crystallization - a technique in which the individual enantiomers crystallize separately from a solution of the racemate, which is only possible if the latter is a conglomerate in the solid state;

[1077] iii) Enzymatic resolution - a technique for partially or completely separating a racemate by the different reaction rates of the enantiomers with an enzyme;

[1078] iv) Enzymatic asymmetric synthesis - a synthetic technique in which at least one step of the synthesis uses an enzymatic reaction to obtain the enantiomerically pure desired enantiomer or an enriched synthetic precursor of the desired enantiomer;

[1079] v) Chemical asymmetric synthesis - a synthetic technique in which the desired enantiomer is synthesized from achiral precursors under conditions that generate asymmetry (i.e., chirality) in the product, which can be achieved using a chiral catalyst or a chiral auxiliary;

[1080] vi) Diastereoisomer separation - a technique in which a racemic compound reacts with an enantiomerically pure reagent (chiral auxiliary) to convert the individual enantiomers into diastereoisomers. The resulting diastereoisomers are then separated by chromatography or crystallization by virtue of their now more distinct structural differences, and the chiral auxiliary is then removed to obtain the desired enantiomer;

[1081] vii) Primary and secondary asymmetric transformation - an excess in quantity is generated in a solution of the diastereoisomers from the desired enantiomer from the diastereoisomer equilibrium of the racemate, or the preferential crystallization of the diastereoisomers from the desired enantiomer disturbs the equilibrium such that ultimately in principle all the material is converted from the desired enantiomer into crystalline diastereoisomers. The desired enantiomer is then released from the diastereoisomers;

[1082] viii) Kinetic resolution - this technique refers to the partial or complete resolution of a racemate (or further resolution of a partially resolved compound) by virtue of the different reaction rates of the enantiomers with a chiral non-racemic reagent or catalyst under kinetic conditions;

[1083] ix) Enantioselective synthesis from non-racemic precursors - a synthetic technique in which the desired enantiomer is obtained from achiral starting materials and in which the stereochemical integrity is not compromised or is only minimally compromised during the synthesis;

[1084] x) Chiral liquid chromatography - a technique for separating the enantiomers of a racemate in a liquid mobile phase by virtue of their different interactions with a stationary phase (including via chiral HPLC). The stationary phase may be made of a chiral material, or the mobile phase may contain additional chiral material to elicit different interactions;

[1085] xi) Chiral gas chromatography - a technique for volatilizing a racemate and separating the enantiomers by virtue of their different interactions with a column containing a fixed non-racemic chiral adsorbent phase in a gaseous mobile phase;

[1086] xii) Extraction with chiral solvents - a technique for separating enantiomers by virtue of the preferential dissolution of one enantiomer into a specific chiral solvent;

[1087] xiii) Transport across chiral membranes - a technique in which a racemate is placed in contact with a thin film barrier. The barrier typically separates two miscible fluids, one of which contains the racemate, and a driving force such as a concentration or pressure difference causes preferential transport across the membrane barrier. Separation occurs due to the non-racemic chiral nature of the membrane, which allows only one enantiomer of the racemate to pass through.

[1088] Chiral chromatography, including simulated moving bed chromatography, is used in certain embodiments. There is a wide variety of commercially available chiral stationary phases.

[1089] Representative synthesis

[1090] Overview

[1091] Unless otherwise stated, all reagents were used without further purification. 1 1H NMR spectra were obtained at room temperature on a Bruker 300 MHz instrument in DMSO-d6 or CD3OD. When more than one conformational isomer was detected, the chemical shifts of the conformational isomer with the highest abundance were reported. 1 The chemical shifts of the 1H NMR spectra were recorded in parts per million (ppm) based on the δ scale from the residual solvent internal standard. The splitting patterns were designated as: s, singlet; d, doublet; t, triplet; q, quartet; m, multiplet; brs, broad peak. The LC-MS conditions are described below:

[1092] General LC / MS method:

[1093] Column: Agilent Zorbax XDB C18 4.6×50 mm, 3.5 μm

[1094] Mobile phase: Solvent A: 0.1% formic acid / water

[1095] Solvent B: MeOH

[1096] Flow rate: 1.0 mL / min

[1097] Run time / gradient: 2 minutes (20%-90% B), then 3 minutes @ 90% B

[1098] Temperature: 30 °C

[1099] General HPLC method:

[1100] Column: Agilent SB-C18 4.6×150 mm, 3.5 μm

[1101] Mobile phase: Solvent A: 0.02% TFA / water

[1102] Solvent B: MeOH

[1103] Flow rate: 1.0 mL / min

[1104] Run time / gradient: 0.5 minute @ 10% B, 9.5 minutes gradient @ 10%-90% B, then 10 minutes @ 90% B

[1105] Temperature: 30 °C

[1106] General preparative HPLC method:

[1107] Column: Phenomenex Luna 5u 100A, 21.2×250 mm, 5 μm

[1108] Mobile phase: Solvent A: water

[1109] Solvent B: MeOH

[1110] Flow rate: 10 mL / min

[1111] Run time / gradient: 1 minute @ 20% B, 30 minutes gradient @ 20%-80% B, then 10 minutes @ 90% B

[1112] Temperature: Ambient temperature

[1113] The following abbreviations are used below: PE = petroleum ether, EA = ethyl acetate, DMSO = dimethyl sulfoxide, DMP = Dess-Martin reagent, DMF = N,N-dimethylacetamide, MeOH = methanol, MTBE = methyl tert-butyl ether, DCM = dichloromethane, TEA = triethylamine, DIPEA = diisopropylethylamine, DIEA = N,N-diisopropylethylamine, N2H4.H2O = hydrazine hydrate, TFA = trifluoroacetic acid, TLC = thin layer chromatography, B2Pin2 = bis(pinacolato)diboron, AcOK = potassium acetate, N2 = nitrogen, Pd(OAc)2 = palladium(II) acetate, EtOAc = ethyl acetate, Na2SO4 = sodium sulfate, SOCl2 = thionyl chloride, NaHCO3 = sodium bicarbonate, Na2CO3 = sodium carbonate, NaS2O3 = sodium thiosulfate, MgSO4 = magnesium sulfate, RT = room temperature, THF = tetrahydrofuran, DMAC = dimethylacetamide, t-BuOH = tert-butanol, DBU = 1,8-diazabicyclo[5.4.0]undec-7-ene, CuI = copper(I) iodide, TBAF = tetrabutylammonium fluoride, Pd(PPh3)2Cl2 = bis(triphenylphosphine)palladium(II) dichloride, Pd(OAc)2 = palladium(II) acetate, n-BuLi = n-butyllithium, NH4Cl = ammonium chloride, Cs2CO3 = cesium carbonate, EA = ethyl acetate, MeCN = acetonitrile, NBS = N-bromosuccinimide, K2CO3 = potassium carbonate, CPBA = m-chloroperoxybenzoic acid.

[1114] Scheme 1. Synthesis of 4-((6'-hydroxy-8'-oxo-7',8'-dihydro-6'H-spiro[cyclohexane-1,9'-pyrazino[1',2':1,5]pyrrolo[2,3-d]pyrimidine]-2'-yl)amino)benzenesulfonamide - Compound 1

[1115]

[1116] Step 1: To a solution of Intermediate 1 (100 mg, 0.33 mmol) in DMF (4 mL) under N2 atmosphere was added 4-aminobenzenesulfonamide (67.3 mg, 0.39 mmol), AcOK (95.8 mg, 0.98 mmol), Pd(OAc)2 (7.3 mg, 0.03 mmol) and X-phos (62.2 mg, 0.13 mmol). The solution was stirred at 80 °C for 3 hours, then the reaction mixture was cooled to room temperature, quenched with water (10 mL) and extracted with EtOAc (10 mL × 3). The combined organic phases were washed with brine (5 mL × 2), dried over Na2SO4 and concentrated in vacuo. The resulting residue was purified by preparative TLC to give Compound 1 (2.5 mg, 0.006 mmol). MS (ESI+): m / z 443 [M+H]+ 。 1 1H NMR (300 MHz, DMSO-d6): 9.97 (s, 1H), 8.82 (s, 1H), 8.75 (d, J = 3.9 Hz, 1H), 8.02 (d, J = 9.0 Hz, 2H), 7.73 (d, J = 9.0 Hz, 2H), 7.19 (s, 2H), 6.55 (d, J = 6.6 Hz, 1H), 6.50 (s, 1H), 5.90 - 5.85 (m, 1H), 2.75 - 2.65 (m, 2H), 2.31 - 2.17 (m, 2H), 1.95 - 1.62 (m, 6H).

[1117] Scheme 2. 4 - ((7'-oxo - 7',8'-dihydro - 6'H - spiro[cyclohexane - 1,9'-pyrrolo[1,5 - a:2,3 - d']dipyrimidin]-2'-yl)amino)benzenesulfonamide - Synthesis of Compound 2

[1118]

[1119] Step 1: SOCl2 (10 mL) was added dropwise to a mixture of Intermediate 1 (12 g, 76.33 mmol) in MeOH (120 mL). The reaction was stirred overnight at 40 °C. The reaction was concentrated in vacuo. The resulting residue was neutralized to pH ~ 8 with aqueous Na2CO3 and extracted with DCM (50 mL × 5). The combined organic phases were concentrated to give Intermediate 2 (12 g, 70.08 mmol). LC - MS (ESI+): m / z 172 [M + H]+.

[1120] Step 2: DBU (23 g, 151.08 mmol) was added dropwise to a solution of Intermediate 3 (10 g, 142.76 mmol) in DCM (150 mL) at 0 °C over 30 minutes. After addition, the reaction solution was stirred at room temperature for 2 hours. Then 1-(chloromethyl)-4 - methoxybenzene (20 g, 127.71 mmol) was added to the reaction solution. The reaction was stirred at room temperature for 2 days. The reaction was quenched with saturated aqueous sodium bicarbonate (100 mL). The organic phase was dried over Na2SO4, filtered, and concentrated in vacuo. The resulting residue was purified by silica gel column chromatography to give Intermediate 4 (14 g, 73.61 mmol).

[1121] Step 3: To a solution of intermediate 5 (25 g, 90.95 mmol) in DMAc (100 mL) was added intermediate 2 (12 g, 70.08 mmol) and NaHCO3 (20 g, 238.07 mmol). The reaction mixture was stirred at 60 °C for 12 h. After cooling to room temperature, the reaction mixture was quenched with water (200 mL) and extracted with EtOAc (100 mL × 2). The organic layer was separated, washed with brine, dried over anhydrous MgSO4, filtered, and concentrated in vacuo. The resulting crude product was purified by column chromatography to give intermediate 6 (14 g, 34.17 mmol). LC-MS (ESI+): m / z 410 [M+H]+.

[1122] Step 4: To a solution of intermediate 6 (14 g, 34.17 mmol) in THF (200 mL) under N2 atmosphere was added CuI (647 mg, 3.40 mmol), Pd(PPh3)2Cl2 (1.2 g, 1.71 mmol), and TEA (6.9 g, 68.19 mmol). Then a solution of intermediate 4 (8 g, 42.06 mmol) in THF (20 mL) was added dropwise to the reaction mixture over 15 min. The mixture was stirred at room temperature overnight and then the reaction mixture was concentrated in vacuo. The resulting residue was purified by silica gel column chromatography to give intermediate 7 (5 g, 10.59 mmol). LC-MS (ESI+): m / z 472 [M+H]+.

[1123] Step 5: To a solution of intermediate 7 (5 g, 10.59 mmol) in THF (30 mL) under N2 atmosphere at 60 °C was added TBAF (30 mL, 1 M in THF). The mixture was stirred at 60 °C for 2 h and then the reaction was quenched with water (100 mL) and extracted with EtOAc (50 mL × 2). The combined organic phases were washed with brine (50 mL), dried over Na2SO4, filtered, and concentrated in vacuo. The resulting residue was purified by silica gel column chromatography to give intermediate 8 (1 g, 2.12 mmol). LC-MS (ESI+): m / z 472 [M+H]+.

[1124] Step 6: To a solution of intermediate 8 (1 g, 2.12 mmol) in DCM (9 mL) at room temperature was added TFA (3 mL). The reaction was stirred at room temperature overnight. The reaction solution was concentrated in vacuo. The resulting residue was purified by silica gel column chromatography to give intermediate 9 (380 mg, 1.08 mmol). LC-MS (ESI+): m / z 352 [M+H] + 。

[1125] Step 7: To a solution of intermediate 9 (160 mg, 0.46 mmol) in t-BuOH (5 mL) was added 4A molecular sieves (100 mg). The mixture was stirred at room temperature for 30 minutes. Then triethylamine (90 mg, 0.89 mmol) and diphenylphosphoryl azide (240 mg, 0.87 mmol) were added to the mixture. The mixture was stirred at 80 °C for 4 hours, then the reaction mixture was filtered and the filtrate was concentrated in vacuo. The resulting residue was purified by silica gel column chromatography to give intermediate 10 (30 mg, 0.10 mmol). LC-MS (ESI+): m / z 291 [M+H]+.

[1126] Step 8: To a solution of 4-aminobenzenesulfonamide (40 mg, 0.23 mmol) in DMF (4 mL) under N2 atmosphere was added intermediate 10 (57 mg, 0.20 mmol), Pd(OAc)2 (8 mg, 0.036 mmol), X-Phos (20 mg, 0.042 mmol) and AcOK (50 mg, 0.51 mmol). The mixture was stirred at 80 °C for 4 hours, the reaction mixture was cooled to room temperature, quenched with water (5 mL) and extracted with EtOAc / THF = 1 / 1 (5 mL × 3). The combined organic phases were dried over Na2SO4 and concentrated in vacuo. The resulting residue was purified by preparative TLC to give compound 2 (4.2 mg, 0.01 mmol). LC-MS (ESI+): m / z 427 [M+H]+; 1H NMR (300 MHz, DMSO-d6): 11.05 (s, 1H), 9.72 (s, 1H), 8.53 (s, 1H), 7.91 (d, J = 9.0 Hz, 2H), 7.69 (d, J = 9.0 Hz, 2H), 7.15 (s, 1H), 5.68 (s, 1H), 5.32 (s, 1H), 3.02 - 2.95 (m, 4H), 2.05 - 1.95 (m, 2H), 1.85 - 1.81 (m, 2H), 1.60 - 1.50 (m, 4H).

[1127] Scheme 3. Synthesis of 4-((3'-oxo-2',3'-dihydro-1'H-spiro[cyclohexane-1,4'-pyrimido[5',4':4,5]pyrrolo[2,1-c][1,2,4]triazin]-7'-yl)amino)benzenesulfonamide - Compound 3

[1128]

[1129] Step 1: At -78 °C, n-BuLi (147 ml, 2.5 mol, in THF, 367.5 mmol) was added dropwise to a solution of ethynyltrimethylsilane (30 g, 305.94 mmol) in anhydrous THF (500 mL) under a N2 atmosphere over 30 minutes. After addition, the reaction was stirred at -78 °C for 20 minutes. Then, a solution of intermediate 1 (105 g, 456.26 mmol) in anhydrous THF (300 mL) was added dropwise to the reaction solution over 60 minutes. After addition, the reaction was allowed to warm gradually to -20 °C and the reaction was stirred at -20 °C for 30 minutes. The reaction was quenched with saturated NH4Cl solution (100 mL) and water (300 mL), and extracted with EA (200 mL × 2). The organic phases were combined, washed with brine (100 mL), dried over Na2SO4, filtered, and concentrated in vacuo. The resulting residue was purified by silica column chromatography to give intermediate 2 (60 g, 182.83 mmol) as an oil.

[1130] Step 2: At -20 °C, a solution of TBAF trihydrate (72 g, 228.20 mmol) in THF (300 mL) was added to a solution of intermediate 2 (60 g, 182.83 mmol) in THF (300 mL). After addition, the reaction was stirred at -20 °C for 60 minutes. The reaction mixture was quenched with saturated NH4Cl solution (100 mL) and water (400 mL), and extracted with EA (300 mL × 2). The organic phases were combined, dried over Na2SO4, filtered, and concentrated in vacuo. The resulting residue was purified by silica column chromatography to give intermediate 3 (36 g, 140.55 mmol).

[1131] Step 3: A solution of intermediate 3, intermediate 4, CuI (1.1 g, 5.79 mmol), Pd(PPh3)2Cl2 (4.1 g, 5.86 mmol), and diisopropylamine (17.6 g, 174.05 mmol) in DMF was mixed at room temperature overnight. The reaction was quenched with water (500 ml) and extracted with EA (500 mL × 3). The organic phases were combined, washed with water (500 mL × 3), dried over Na2SO4, filtered, and concentrated in vacuo. The resulting residue was purified by silica column chromatography to give intermediate 5 (28 g, 69.64 mmol). LC-MS (ESI+): m / z 403 [M+H]+.

[1132] Step 4: To a solution of intermediate 5 (2 g, 4.97 mmol) in DMF (20 mL) under N2 atmosphere was added intermediate 6 (1.2 g, 7.64 mmol) and NaHCO3 (1.25 g, 14.93 mmol). The reaction mixture was stirred at 60 °C overnight. Then the reaction mixture was cooled to room temperature, quenched with water (100 mL), and extracted with EA (30 mL×3). The combined organic phases were dried over Na2SO4, filtered, and concentrated in vacuo. The resulting residue was purified by silica gel column chromatography to give intermediate 7 (1.2 g, 2.29 mmol). LC-MS (ESI+): m / z 524 [M+H]+.

[1133] Step 5: To a solution of intermediate 7 (1.2 g, 2.29 mmol) in THF (15 mL) was added a solution of TBAF (1.2 mL, 1 mol in THF, 1.2 mmol). The reaction mixture was stirred at 60 °C for 1 h. The reaction mixture was cooled to room temperature, quenched with water (30 mL), and extracted with EA (30 mL×3). The combined organic phases were dried over Na2SO4, filtered, and concentrated in vacuo. The resulting residue was purified by silica gel column chromatography to give intermediate 8 (300 mg, 0.57 mmol). LC-MS (ESI+): m / z 524 [M+H]+.

[1134] Step 6: To a solution of intermediate 8 (2 g, 3.82 mmol) in DMAc (30 mL) was added Cs2CO3 (4 g, 12.28 mmol). The reaction mixture was stirred at 100 °C for 5 h. The reaction mixture was cooled to room temperature, quenched with water (60 mL), and extracted with EA (20 mL×3). The combined organic phases were dried over Na2SO4, filtered, and concentrated in vacuo. The resulting residue was purified by silica gel column chromatography to give intermediate 9 (320 mg, 0.82 mmol). LC-MS (ESI+): m / z 392 [M+H]+.

[1135] Step 7: To a solution of intermediate 9 (50 mg, 0.13 mmol) in DMF (2 mL) under N2 atmosphere was added intermediate 10 (24 mg, 0.14 mmol), Pd(OAc)2 (2.8 mg, 0.013 mmol), X-Phos (24 mg, 0.05 mmol) and AcOK (38 mg, 0.38 mmol). The reaction was stirred at 80 °C for 5 h. The reaction mixture was cooled to room temperature, quenched with water (20 mL), and extracted with DCM:MeOH = 10:1 (20 mL × 3). The combined organic phases were dried over MgSO4, filtered and concentrated in vacuo. The resulting residue was purified by preparative TLC to give intermediate 11 (43 mg, 0.082 mmol). LC-MS (ESI+): m / z 528 [M+H]+.

[1136] Step 8: To a solution of intermediate 11 (20 mg, 0.038 mmol) in DCM (2 mL) was added TFA (0.2 mL). The reaction was stirred at room temperature for 2 h. The reaction mixture was quenched with saturated NaHCO3 solution (10 mL) and extracted with DCM:MeOH = 10:1 (10 mL × 3). The combined organic phases were dried over MgSO4, filtered and concentrated in vacuo. The resulting residue was purified by preparative TLC to give compound 3 (2.1 mg, 0.005 mmol). LC-MS (ESI+): m / z 428 [M+H]+; 1H NMR (300 MHz, CD3OD): δ 8.48 (s, 1H), 7.92 (d, J = 9.0 Hz, 2H), 7.80 (d, J = 9.0 Hz, 2H), 5.80 (s, 1H), 2.49 - 2.38 (m, 2H), 2.15 - 1.97 (m, 6H), 1.90 - 1.81 (m, 1H), 1.70 - 1.61 (m, 1H).

[1137] Scheme 4. Synthesis of 4-((1'H-spiro[cyclohexane-1,4'-pyrimido[5',4':4,5]pyrrolo[2,1-c][1,2,4]triazin]-7'-yl)amino)benzenesulfonamide - Compound 4

[1138]

[1139] Step 1: To a solution of Intermediate 1 (300 mg, 0.89 mmol) in THF (20 mL) at -10 °C was added TBAF trihydrate (50 mg, 0.16 mmol). After addition, the reaction was stirred at -10 °C for 5 minutes. The reaction mixture was quenched with saturated NH4Cl solution (30 mL) and extracted with EA (20 mL × 2). The combined organic phases were dried over Na2SO4, filtered and concentrated in vacuo to give Intermediate 2 (220 mg, 0.83 mmol). LC-MS (ESI+): m / z 266 [M+H] + .

[1140] Step 2: To a solution of Intermediate 2 (200 mg, 0.83 mmol) in MeCN (20 mL) at room temperature was added NBS (200 mg, 1.12 mmol) and DBU (170 mg, 1.12 mmol). After addition, the reaction was stirred at room temperature for 30 minutes. The reaction mixture was quenched with water (100 mL) and extracted with EA (50 mL × 2). The combined organic phases were dried over Na2SO4, filtered and concentrated in vacuo. The resulting residue was purified by column chromatography to give Intermediate 3 (200 mg, 0.58 mmol). LC-MS (ESI+): m / z344 / 346 [M+H] + .

[1141] Step 3: To a solution of Intermediate 3 (75 mg, 0.22 mmol) in DCM (5 mL) at room temperature was added Dess-Martin reagent (100 mg, 0.24 mmol). After addition, the reaction was stirred at room temperature for 10 minutes. The reaction mixture was quenched with saturated Na2S2O3 solution (10 mL) and saturated NaHCO3 solution (10 mL) and extracted with DCM (20 mL × 2). The combined organic phases were dried over Na2SO4, filtered and concentrated in vacuo. The resulting residue was purified by silica column chromatography to give Intermediate 4 (50 mg, 0.15 mmol). LC-MS (ESI+): m / z 342 / 344 [M+H]+.

[1142] Step 4: To a solution of Intermediate 4 (400 mg, 1.17 mmol) in THF (40 mL) at room temperature was added TBAF trihydrate (1 g, 3.17 mmol). After addition, the reaction was stirred at room temperature for 30 minutes. The reaction mixture was quenched with water (100 mL) and extracted with EA (50 mL × 2). The combined organic phases were dried over Na2SO4, filtered and concentrated in vacuo. The resulting residue was purified by silica column chromatography to give Intermediate 5 as a white solid (260 mg, 0.77 mmol).

[1143] Step 5: To a solution of intermediate 5 (300 mg, 0.88 mmol) in THF (5 mL) was added hydrazine hydrate (2 mL) and K2CO3 (200 mg, 1.45 mmol). After addition, the reaction was stirred at 40 °C for 1 h. The reaction mixture was quenched with water (20 mL) and extracted with EA (20 mL×3). The combined organic phases were dried over Na2SO4, filtered and concentrated in vacuo. The resulting residue was purified by silica column chromatography to give intermediate 6 (200 mg, 0.73 mmol). LC-MS (ESI+): m / z 276 / 278 [M+H]+.

[1144] Step 6: To a solution of intermediate 6 (20 mg, 0.07 mmol) in DMF (2 mL) under N2 atmosphere was added intermediate 7 (15 mg, 0.09 mmol), Pd(OAc)2 (1.9 mg, 0.01 mmol), X-Phos (14 mg, 0.03 mmol) and AcOK (21 mg, 0.22 mmol). The reaction was stirred at 80 °C for 5 h. The reaction mixture was cooled to room temperature, quenched with water (5 mL), and extracted with DCM:MeOH = 10:1 (5 mL×3). The combined organic phases were dried over MgSO4, filtered and concentrated in vacuo. The resulting residue was purified by preparative TLC to give compound 4 (3.9 mg, 0.01 mmol). LC-MS (ESI+): m / z 412 [M+H]+; 1H NMR (300 MHz, DMSO-d6): 10.71 (s, 1H), 9.77 (s, 1H), 8.45 (s, 1H), 7.95 (d, J = 8.7 Hz, 2H), 7.70 (d, J = 8.7 Hz, 2H), 7.20 (s, 1H), 7.16 (s, 1H), 5.41 (s, 1H), 3.12 - 3.05 (m, 2H), 1.98 - 1.87 (m, 4H), 1.85 - 1.75 (m, 4H).

[1145] Scheme 5. 4-((9'-oxo-8',9'-dihydrospiro[cyclohexane-1,10'-pyrimido[5',4':4,5]pyrrolo[2,1-d][1,2,5]triazepin -2'-yl)amino)benzenesulfonamide - Synthesis of Compound 6

[1146]

[1147] Step 1: Thionyl chloride was added to a solution of intermediate 1 (10 g) in methanol and then the reaction was stirred overnight. Intermediate 2 (5.47 g) was obtained after purification.

[1148] Step 2: Sodium bicarbonate was added to a solution of Intermediate 2 (5.47 g) in DMAC and then the reaction was stirred overnight at 90 °C. After purification, Intermediate 3 (6.25 g) was obtained.

[1149] Step 3: DIEA was added to a solution of Intermediate 3 (500 mg) in THF, then Compound b, PdCl2(PPh3)2 and CuI were added. Then the reaction was stirred overnight at 30 °C. After purification, Intermediate 4 (410 mg) was obtained.

[1150] Step 4: TBAF was added to a solution of Intermediate 4 (20 mg) in THF and then the reaction was stirred overnight at 60 °C. After purification, Intermediate 5 (8 g) was obtained.

[1151] Step 5: Compound c, Pd(OAc)2, X-phos and AcOK were added to a solution of Intermediate 5 (50 mg) in DMF. Then the reaction was stirred at 70 °C for 4 hours. The MS peak of the desired product was detected by LC-MS. After purification, Intermediate 6 (10 mg) was obtained.

[1152] Scheme 6. Synthesis of cyclic imine intermediate and Compound 24

[1153]

[1154] Scheme 7. Synthesis of 4-((1'-Methyl-3'-oxo-2',3'-dihydro-1'H-spiro[cyclohexane-1,4'-pyrimido[5',4':4,5]pyrrolo[2,1-c][1,2,4]triazin]-7'-yl)amino)benzenesulfonamide - Compound 12

[1155]

[1156] Step 1: 200 mg of 1 was converted to 2 using Cbz-Cl / NaH / THF / 0 °C / 0.5 h. After purification, 220 mg of 2 was obtained.

[1157] Step 2: 210 mg of 2 was converted to 3 using TFA / DCM / RT / 30 min. After purification, 150 mg of 3 was obtained.

[1158] Step 3: 130 mg of 3 was converted to 4 using NaH / THF / 0 °C / 2 h. The starting material was consumed. After purification, 80 mg of 4 was obtained.

[1159] Steps 4 and 5: 20 mg of 4 was converted to 5 using Pd(OAc)2 / x-phos / AcOK / DMF / 85 °C / 4 h. The starting material was consumed. TLC was clean. The MS peak of compound 12 was significantly detected by LC-MS. After purification, 7.3 mg of compound 12 was obtained.

[1160] Scheme 8. Synthesis of (R)-4-((6'-(fluoromethyl)-8'-oxo-7',8'-dihydro-6'H-spiro[cyclohexane-1,9'-pyrazino[1',2':1,5]pyrrolo[2,3-d]pyrimidin]-2'-yl)amino)benzenesulfonamide - Compound 18

[1161]

[1162] Step 6: 500 mg of 6 was converted to 7 using Pd(OAc)2 / X-Phos / KOAc / DMF / 80 °C / 4 h. After purification, 315 mg of 7 was obtained.

[1163] Step 7: 70 mg of 7 was converted to compound 18 using DAST / THF / 0 °C to RT / 3 h. After purification by the above method, 3.0 mg of compound 18 was obtained.

[1164] Scheme 9. Synthesis of (S)-4-((6'-methyl-8'-oxo-7',8'-dihydro-6'H-spiro[cyclohexane-1,9'-pyrazino[1',2':1,5]pyrrolo[2,3-d]pyrimidin]-2'-yl)amino)benzenesulfonamide - Compound 19

[1165]

[1166] Step 1: 20 g of 1 was converted to 2 using SOCl2 / MeOH / reflux to RT / overnight. After purification, 17.7 g of 2 was obtained.

[1167] Step 2: 17.7 g of 2 was converted to 3 using NaHCO3 / DMAc / 70 °C / overnight. After purification, 22 g of 3 was obtained.

[1168] Step 3: 5.5 g of 3 was converted to 4 using CuI / PdCl2(PPh3)2 / TEA / THF / RT / overnight. After purification, 4.5 g of 4 was obtained.

[1169] Step 4: 500 mg of 4 was converted to 5 using Cs2CO3 / DMF / RT / overnight. After purification, 195 mg of 5 was obtained.

[1170] Step 5: 165 mg of 5 was converted to 6 using TFA / DCM / RT / 30 min. After purification, 100 mg of 6 was obtained.

[1171] Step 6: 30 mg of 6 was converted to compound 19 using Pd(OAc)2 / x-phos / AcOK / DMF / 80 °C / 3 h. A major new spot was observed by TLC. After purification, 3.4 mg of compound 19 was obtained. H-NMR and LC-MS were both good.

[1172] Scheme 10. R-4-((6’-Methyl-8’-oxo-7’,8’-dihydro-6’H-spiro[cyclohexane-1,9’-pyrazino[1’,2’:1,5]pyrrolo[2,3-d]pyrimidine]-2’-yl)amino)benzenesulfonamide - Synthesis of Compound 22

[1173]

[1174] Compound 22 was prepared in a similar manner to compound 19, but using the R-enantiomer of the propargylamine reagent in step 3.

[1175] Scheme 11. 4-((6’-Amino-8’H-spiro[cyclohexane-1,9’-pyrazino[1’,2’:1,5]pyrrolo[2,3-d]pyrimidine]-2’-yl)amino)benzenesulfonamide - Synthesis of Compound 40

[1176]

[1177] Step 1: 2.6 g of 1 was converted to 2 using HOAc / THF / H2O / 60 °C / overnight. After purification, 2 g of 2 was obtained.

[1178] Step 2: 2 g of 2 was converted to 3 using NaCl2O / THF / H2O / RT / overnight. Some starting material remained. After purification, 1.5 g of 3 was obtained.

[1179] Step 3: 1.5 g of 3 was converted to 4 using TFA / DCM / RT / 0.5 h. After purification, 1.0 g of 4 was obtained.

[1180] Step 4: 500 mg of 4 was converted to 5 using Lawesson's reagent / THF / reflux / 2 h. The starting material was consumed. After purification, 200 mg of 5 was obtained.

[1181] Step 5: 240 mg of 5 was converted to 6 using MeI / K2CO3 / acetone / RT / overnight. After purification, 100 mg of 6 was obtained.

[1182] Step 6: Convert 90 mg of 6 to 7 using a / Pd(OAc)2 / X-Phos / AcOK / DMF / 90 °C / 3 h. After purification, 60 mg of 7 was obtained.

[1183] Step 7: Convert 40 mg of 7 to compound 40 using NH3 / EtOH / 70 °C / 8 h. After purification, 13.5 mg of compound 40 was obtained.

[1184] Scheme 12. Synthesis of 4-((8’-amino-6’H-spiro[cyclohexane-1,9’-pyrazino[1’,2’:1,5]pyrrolo[2,3-d]pyrimidin]-2’-yl)amino)benzenesulfonamide - compound 41

[1185]

[1186] Step 1: Convert 50 g of impure 1 to 2 using SOCl2 / MeOH / RT / overnight. After purification, 45 g of 2 was obtained.

[1187] Step 2: Convert 15 g of 2 to 3 using a / DMF / NaHCO3 / 60 °C / overnight. After purification, 13 g of 3 was obtained.

[1188] Step 3: Convert 13 g of 3 to 4 using b / CuI / Pd(PPh3)2Cl2 / TEA / THF / RT / 3 h. After purification, 12 g of 4 was obtained.

[1189] Step 4: Convert 6 g of 4 to 5 using TBAF / THF / 60 °C / 3 h. After purification, 3 g of 5 was obtained.

[1190] Step 5: Convert 3 g of 5 to 6 using SOCl2 / DCM / RT / 3 h. After purification, 1 g of 6 was obtained.

[1191] Step 6: Convert 950 mg of 6 to 7 using Lawesson’s reagent / toluene / reflux / 4 h. After purification, 250 mg of 7 was obtained.

[1192] Step 7: Convert 250 mg of 7 to 8 using MeI / K2CO3 / acetone / room temperature / overnight. After purification, 200 mg of 8 was obtained.

[1193] Step 8: Convert 100 mg of 8 to 9 using a / Pd(OAc)2 / Xphos / KOAc / DMF / 90 °C / 4 h. After purification, 60 mg of 9 was obtained.

[1194] Step 9: Convert 30 mg of 9 to compound 41 using NH3 / EtOH / 80 °C / overnight. After purification, 5.2 mg of compound 41 was obtained.

[1195] Scheme 13 4-((6’,8’-Dimethyl-7’,8’-dihydro-6’H-spiro[cyclohexane-1,9’-pyrazino[1’,2’:1,5]pyrrolo[2,3-d]pyrimidine]-2’-yl)amino)benzenesulfonamide - Synthesis of Compound 85

[1196]

[1197] Step 1: Convert 50 g of 1 to 2 using LiAlH4 / THF / RT / overnight. After purification, 42.7 g of 2 was obtained.

[1198] Step 2: Convert 42.7 g of 2 to 3 using a / NaHCO3 / DMAC / 60 °C / overnight. After purification, 76.5 g of 3 was obtained.

[1199] Step 3: Convert 14.4 g of 3 to 4 using b / CuI / PdCl2(PPh3)2 / Et3N / THF / room temperature / overnight. After purification, 16.3 g of 4 was obtained.

[1200] Step 4: Convert 5 g of 4 to 5 using Dess-Martin reagent / DCM / 0 °C–RT / 2 h. After purification, 3.6 g of 5 was obtained.

[1201] Step 5: Convert 3.8 g of 5 to 6 using CH3MgBr / THF / -78 °C–RT / 2 h. After purification, 3.86 g of 6 was obtained.

[1202] Step 6: Convert 400 mg of 6 to 7 using Dess-Martin reagent / DCM / 0 °C–RT / 2 h. After purification, 310 mg of 7 was obtained.

[1203] Step 7: Convert 310 mg of 7 to 8 using Cs2CO3 / DMSO / RT / 40 °C / 4 h. After purification, 180 mg of 8 was obtained.

[1204] Step 8: Convert 180 mg of 8 to 9 using a (1.2 equiv) / AcOK (3 equiv) / Pd(OAc)2 (0.1 equiv) / X-phos (0.4 equiv) / DMF / 85 °C / 3.5 h. After purification, 290 mg of 9 was obtained.

[1205] Step 9: Convert 290 mg of 9 to 10 using TFA / DCM / RT / 2 h. After purification, 100 mg of 10 was obtained.

[1206] Step 10: Convert 80 mg of 10 to compound 85 using NaBH4 / THF / MeOH / RT / 0.5 h. After purification, 19.3 mg of compound 85 was obtained.

[1207] Scheme 14 Synthesis of 4-((8’-Methyl-7’-oxo-7’,8’-dihydro-6’H-spiro[cyclohexane-1,9’-pyrrolo[1,5-a:2,3-d’]dipyrimidin]-2’-yl)amino)benzenesulfonamide - Compound 42

[1208]

[1209] Step 1: Convert 20 g of 1 to 2 using a / NH4OAc / t-BuOH / 135 °C / 3.5 h. After purification, 19.7 g of 2 was obtained.

[1210] Step 2: Convert 20 g of 2 to 3 using Boc2O / NaOH / H2O / THF / RT / 4 h. After purification, 21 g of 3 was obtained.

[1211] Step 3: Convert 21 g of 3 to 4 using Na2CO3 / MeI / DMF / RT / 2 h. After purification, 19 g of 4 was obtained.

[1212] Step 4: Convert 14 g of 4 to 5 using MeI / LDA / HMPA / THF / -78 °C - RT / 3 h. After purification, 14 g of impure 5 (mixed with some starting material 4 and dimethyl by-products) was obtained.

[1213] Step 5: Convert 14 g of impure 5 to 6 using TFA / DCM / RT / 3 h. After simple work-up, 7.1 g of crude 6 was obtained.

[1214] Step 6: Convert 7.1 g of 6 to 7 using b / NaHCO3 / DMAc / 60 °C / overnight. After purification, 3.0 g of 7 was obtained.

[1215] Step 7: Convert 2.87 g of 7 to 8 using c / Pd(PPh3)2Cl2 / CuI / DIEA / THF / RT / 2 h. After purification, 1.78 g of 8 was obtained.

[1216] Step 8: Convert 1.7 g of 8 to 9 using TBAF / THF / 0 °C / 5 min. After purification, 1.4 g of 9 was obtained.

[1217] Step 9: Convert 1.15 g of 9 to 10 using DBU / NBS / acetonitrile / 0 °C / 10 min. After work-up, 1.5 g of crude 10 was obtained.

[1218] Step 10: Convert 1.5 g of crude product 10 to 11 using TBAF / THF / 10 °C / 1 hour. After purification, 430 mg of pure 11 and 350 mg of impure 11 were obtained.

[1219] Step 11: Convert 400 mg of 11 to 12 using HCl (10 N) / 70 °C / 6 hours. After purification, 150 mg of 12 was obtained.

[1220] Step 12: Convert 150 mg of 12 to 13 using oxalyl chloride / DCM / RT / 1 hour. Then concentrate the reaction and treat with NH3(g). After purification, 155 mg of 13 was obtained.

[1221] Step 13: Convert 155 mg of 13 to 14 using NaH / DMAc / 0 °C - RT / 30 minutes. After purification, 85 mg of 14 was obtained.

[1222] Step 14: Convert 10 mg of 14 to compound 42 using d / Pd(OAc)2 / X-phos / KOAc / DMF / 60 °C / 4 hours. After purification, 3.2 mg of compound 42 was obtained.

[1223] Scheme 15 Synthesis of 4-((6’,8’-dimethyl-7’-oxo-7’,8’-dihydro-6’H-spiro[cyclohexane-1,9’-pyrrolo[1,5-a:2,3-d’]dipyrimidin]-2’-yl)amino)benzenesulfonamide - Compound 42

[1224]

[1225]

[1226] Step 1: Convert 20 g of 1 to 2 using a / NH4OAc / t-BuOH / 135 °C / 3.5 hours. After purification, 19.7 g of 2 was obtained.

[1227] Step 2: Convert 20 g of 2 to 3 using Boc2O / NaOH / H2O / THF / RT / 4 hours. After purification, 21 g of 3 was obtained.

[1228] Step 3: Convert 21 g of 3 to 4 using Na2CO3 / MeI / DMF / RT / 2 hours. After purification, 19 g of 4 was obtained.

[1229] Step 4: Convert 14 g of 4 to 5 using MeI / LDA / HMPA / THF / -78 °C - RT / 3 hours. After purification, 14 g of impure 5 (mixed with some starting material 4 and dimethyl by-products) was obtained.

[1230] Step 5: Convert 14 g of impure 5 to 6 using TFA / DCM / RT / 3 h. After simple workup, 7.1 g of crude 6 was obtained.

[1231] Step 6: Convert 7.1 g of 6 to 7 using b / NaHCO3 / DMAc / 60 °C / overnight. After purification, 3.0 g of 7 was obtained.

[1232] Step 7: Convert 2.87 g of 7 to 8 using c / Pd(PPh3)2Cl2 / CuI / DIEA / THF / RT / 2 h. After purification, 1.78 g of 8 was obtained.

[1233] Step 8: Convert 1.7 g of 8 to 9 using TBAF / THF / 0 °C / 5 min. After purification, 1.4 g of 9 was obtained.

[1234] Step 9: Convert 1.15 g of 9 to 10 using DBU / NBS / acetonitrile / 0 °C / 10 min. After workup, 1.5 g of crude 10 was obtained.

[1235] Step 10: Convert 1.5 g of crude 10 to 11 using TBAF / THF / 10 °C / 1 h. After purification, 430 mg of pure 11 and 350 mg of impure 11 were obtained.

[1236] Step 11: Convert 400 mg of 11 to 12 using HCl (10 N) / 70 °C / 6 h. After purification, 150 mg of 12 was obtained.

[1237] Step 12: Convert 150 mg of 12 to 13 using oxalyl chloride / DCM / RT / 1 h. Then concentrate the reaction and treat with NH3(g). After purification, 155 mg of 13 was obtained.

[1238] Step 13: Convert 155 mg of 13 to 14 using NaH / DMAc / 0 °C - RT / 30 min. After purification, 85 mg of 14 was obtained.

[1239] Step 14: Convert 40 mg of 14 to 15 using CH3I / NaH / DMAc / 0 °C - RT / 30 min. After purification, 30 mg of 15 was obtained.

[1240] Step 15: Convert 30 mg of 15 to compound 42 using d / Pd(OAc)2 / X - phos / KOAc / DMF / 60 °C / 4 h. After purification, 5 mg of compound 42 was obtained.

[1241] Scheme 16 4-((1’,3’-Dimethyl-1’H-spiro[cyclohexane-1,4’-pyrimido[5’,4’:4,5]pyrrolo[2,1-c][1,2,4]triazin]-7’-yl)amino)benzenesulfonamide - Synthesis of Compound 46

[1242]

[1243]

[1244] Step 1: 100.0 g of 1 was converted to 2 using LiAlH4 / THF / 40 °C - room temperature / overnight. After workup, 89 g of 2 was obtained.

[1245] Step 2: 42.7 g of 2 was converted to 3 using a / NaHCO3 / DMAC / 60 °C / overnight. After purification, 76.5 g of 3 was obtained.

[1246] Step 3: 20 g of 3 was converted to 4 using b / TEA / PdCl2(PPh3)2 / CuI / THF / room temperature / 3 h. After purification, 13 g of 4 was obtained.

[1247] Step 4: 14.39 g of 4 was converted to 5 using Dess-Martin reagent / DCM / RT / 1 h. After purification, 11 g of 5 was obtained.

[1248] Step 5: 11.0 g of 5 was converted to 6 using CH3MgI / THF / -75 °C – RT / 2 h. After purification, 9.0 g of 6 was obtained.

[1249] Step 6: 9.0 g of 6 was converted to 7 using TBAF / THF / -20 °C / 20 min. After purification, 6.8 g of 7 was obtained.

[1250] Step 7: 6.8 g of 7 was converted to 8 using NBS / DBU / MeCN / RT / 20 min. After purification, 8.7 g of 8 was obtained.

[1251] Step 8: 8.7 g of 8 was converted to 9 using Dess-Martin reagent / DCM / RT / 1 h. After purification, 5.8 g of 9 was obtained.

[1252] Step 9: 4.2 g of 9 was converted to 10 using Cs2CO3 / DMSO / RT / 15 min. After purification, 1.4 g of 10 was obtained.

[1253] Step 10: 1.4 g of 10 was converted to 11 using NH2NH2.H2O / THF / K2CO3 / RT / overnight. After purification, 700 mg of 11 was obtained.

[1254] Step 11: Convert 100 mg of 11 to 12 using CH3I / NaH / DMF / 30 °C / 1 hour. After purification, 107 mg of 12 was obtained.

[1255] Step 12: Convert 40 mg of 12 to compound 46 using c / Pd(OAc)2 / X-Phos / KOAc / DMF / 80 °C / overnight. After purification, 24.7 mg of compound 46 was obtained.

[1256] Scheme 17 Synthesis of N-((1r,4r)-4-(4-(cyclopropylmethyl)piperazin-1-yl)cyclohexyl)-7’,8’-dihydro-6’H-spiro[cyclohexane-1,9’-pyrazino[1’,2’:1,5]pyrrolo[2,3-d]pyrimidine]-2’-amine - Compound 47

[1257]

[1258] Step 1: Convert 25.0 g of 1 to 2 using BnBr / K2CO3 / DMF / room temperature / overnight. After purification, 43 g of 2 was obtained.

[1259] Step 2: Convert 42 g of 2 to 3 using PCC / DCM / RT / overnight. After purification, 35.4 g of 3 was obtained.

[1260] Step 3: Convert 25.0 g of 4 to 5 using a / K2CO3 / DCM / RT / overnight. After purification, 26.8 g of 5 was obtained.

[1261] Step 4: Convert 26.8 g of 5 to 6 using TFA / DCM / RT / 2.5 hours. After purification, 12.0 g of 6 was obtained.

[1262] Step 5: Convert 660 mg of 3 to 7 using 6 / NaBH(OAc)3 / HOAc / DCM / RT / overnight. After purification, 240 mg of 7 and 160 mg of impure 8 were obtained.

[1263]

[1264] Step 6: Convert 100.0 g of 1’ to 2’ using LiAlH4 / THF / 40 °C - room temperature / overnight. After work-up, 89 g of 2’ was obtained.

[1265] Step 7: Convert 42.7 g of 2’ to 3’ using b / NaHCO3 / DMAC / 60 °C / overnight. After purification, 76.5 g of 3’ was obtained.

[1266] Step 8: Convert 5.0 g of 3’ to 4’ using c / PdCl2(PPh3)2 / CuI / TEA / THF / RT / overnight. After purification, 4.8 g of 4’ was obtained.

[1267] Step 9: Convert 4.8 g of 4’ to 5’ using Dess-Martin reagent / DCM / RT / overnight. After purification, 4.0 g of 5’ was obtained.

[1268] Step 10: Convert 3.5 g of 5’ to 6’ using TBAF / THF / 60 °C / 1.5 h. After purification, 600 mg of 6’ was obtained.

[1269] Step 11: Convert 600 mg of 6’ to 7’ using TFA / DCM / RT / 2 h. After purification, 200 mg of 7’ was obtained.

[1270] Step 12: Convert 1.3 g of 7’ (TLC showed that the purity decreased slightly within a week) to 8’ using NaBH4 / MeOH / THF / room temperature / 3 h. After purification, 300 mg of 8’ was obtained.

[1271] Step 13: Convert 300 mg of 8’ to d using Cbz-Cl / NaHCO3 / THF / RT / 30 min. After purification, 300 mg of d was obtained.

[1272]

[1273] Step 14: Convert 200 mg of 7 to 9 using H2 / Pd / C / RT / overnight. After purification, 100 mg of 9 was obtained.

[1274] Step 15: Convert 50 mg of 9 to 11 using d / t-BuONa / X-phos / Pd(OAc)2 / 60 °C / 1 h. The MS peak of the desired product was detected by LC-MS. After purification, 14.7 mg of 11 was obtained.

[1275] Step 16: Convert 14.7 mg of 11 to compound 47 using H2 / Pd / C / MeOH / RT / 1 h. After purification, 2.7 mg of compound 47 was obtained.

[1276] Scheme 18 Synthesis of N-((1s,4s)-4-(4-(cyclopropylmethyl)piperazin-1-yl)cyclohexyl)-7’,8’-dihydro-6’H-spiro[cyclohexane-1,9’-pyrazino[1’,2’:1,5]pyrrolo[2,3-d]pyrimidine]-2’-amine - Compound 48

[1277]

[1278] Step 1: Convert 25.0 g of 1 to 2 using BnBr / K2CO3 / DMF / room temperature / overnight. After purification, 43 g of 2 was obtained.

[1279] Step 2: Convert 42 g of 2 to 3 using PCC / DCM / RT / overnight. After purification, 35.4 g of 3 was obtained.

[1280] Step 3: Convert 25.0 g of 4 to 5 using a / K2CO3 / DCM / RT / overnight. After purification, 26.8 g of 5 was obtained.

[1281] Step 4: Convert 26.8 g of 5 to 6 using TFA / DCM / RT / 2.5 h. After purification, 12.0 g of 6 was obtained.

[1282] Step 5: Convert 660 mg of 3 to 7 using 6 / NaBH(OAc)3 / HOAc / DCM / RT / overnight. After purification, 240 mg of 7 and 160 mg of impure 8 were obtained.

[1283]

[1284] Step 6: Convert 100.0 g of 1’ to 2’ using LiAlH4 / THF / 40 °C - room temperature / overnight. After work-up, 89 g of 2’ was obtained.

[1285] Step 7: Convert 42.7 g of 2’ to 3’ using b / NaHCO3 / DMAC / 60 °C / overnight. After purification, 76.5 g of 3’ was obtained.

[1286] Step 8: Convert 5.0 g of 3’ to 4’ using c / PdCl2(PPh3)2 / CuI / TEA / THF / RT / overnight. After purification, 4.8 g of 4’ was obtained.

[1287] Step 9: Convert 4.8 g of 4’ to 5’ using Dess-Martin reagent / DCM / RT / overnight. After purification, 4.0 g of 5’ was obtained.

[1288] Step 10: Convert 3.5 g of 5’ to 6’ using TBAF / THF / 60 °C / 1.5 h. After purification, 600 mg of 6’ was obtained.

[1289] Step 11: Convert 600 mg of 6’ to 7’ using TFA / DCM / RT / 2 h. After purification, 200 mg of 7’ was obtained.

[1290] Step 12: 1.3 g 7’ (TLC showed that its purity slightly decreased within one week) was converted to 8’ using NaBH4 / MeOH / THF / room temperature / 3 hou...

Claims

1. A compound of the following formula: or a pharmaceutically acceptable salt thereof; Wherein: R 2 selected from -S(O)2NH2, -C(O)(1-piperazinyl), -C(O)(1-morpholinyl), -C(O)N(CH3)2, -C(O)NH2, -C(O)NHCH3, -NHC(O)NHCH3 and -S(=NH)(O)CH3; and R 3 Selected from hydrogen and methyl.

2. The compound according to claim 1, wherein R 2 is selected from -S(O)2NH2, -C(O)(1-piperazinyl), -C(O)(1-morpholinyl), -C(O)N(CH3)2, -C(O)NH2, -C(O)NHCH3, and -S(=NH)(O)CH3.

3. The compound according to claim 1, wherein R 3 is hydrogen.

4. The compound according to claim 1, wherein R 3 is methyl.

5. The compound according to claim 1, which has the following formula: or a pharmaceutically acceptable salt thereof.

6. The compound according to any one of claims 1-5, wherein R 2 is -S(O)2NH2, -C(O)(1-piperazinyl), -C(O)(1-morpholinyl), -C(O)N(CH3)2, -C(O)NH2 or -C(O)NHCH3.

7. The compound according to any one of claims 1-5, wherein R 2 is -C(O)(1-piperazinyl), -C(O)(1-morpholinyl), -C(O)N(CH3)2, -C(O)NH2 or -C(O)NHCH3.

8. The compound according to any one of claims 1-5, wherein R 2 is -S(O)2NH2 or -S(=NH)(O)CH3.

9. The compound according to any one of claims 1-5, wherein R 2 is -S(O)2NH2.

10. A compound having the structure: or a pharmaceutically acceptable salt thereof.

11. A compound having the structure: or a pharmaceutically acceptable salt thereof.

12. A compound having the structure: or a pharmaceutically acceptable salt thereof.

13. A compound having the structure: or a pharmaceutically acceptable salt thereof.

14. A pharmaceutical composition comprising the compound according to any one of claims 1-13 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient.

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