Cyclin-dependent kinase inhibitor compounds for treating medical disorders

Abstract

The present invention provides novel compounds, methods, compositions, and manufacturing processes for inhibiting undesirable cell cycles in a host, such as humans. [Solution] For example, compounds represented by formula (I), or pharmaceutically acceptable salts, N-oxides, isotopic analogs, and / or pharmaceutically acceptable compositions thereof are provided. This includes selective CDK2 inhibitors for medical treatment, as well as pharmaceutically acceptable salts and compositions thereof. TIFF2026076261000306.tif47170

Description

Technical Field

[0001] [Cross - Reference to Related Applications] This application claims the benefit of U.S. Provisional Patent Application No. 63 / 027,113, filed May 19, 2020, and U.S. Provisional Patent Application No. 63 / 085,672, filed September 30, 2020. The entire disclosures of these applications are hereby incorporated by reference in their entirety for all purposes.

[0002] The present invention lies in the area of pyrimidine - based compounds for the treatment of disorders associated with abnormal cell proliferation, including but not limited to the treatment of cancer and tumors.

Background Art

[0003] In normal tissues, cell proliferation is generally limited to the cells necessary for tissue replenishment. When cells finally differentiate, they have special functions and no longer divide. Most tissues are made up of non - dividing cells. Thus, normal cell proliferation is tightly regulated to ensure that only the necessary cells divide. There is also a careful balance between cell division and programmed cell death (apoptosis).

[0004] Cell division, also sometimes called the cell cycle, has four stages: the G1 phase (synthesis of various enzymes necessary for DNA replication), the S phase (DNA replication resulting in two identical sets of chromosomes), the G2 phase (synthesis of important proteins including microtubule formation), and the M phase (nuclear division, cytokinesis, and formation of new cell membranes). Cell division also involves a complex system of cell signaling networks that enable cells to interpret information from numerous extracellular signals via receptor proteins, inflammatory factors, and apoptosis - promoting and anti - apoptosis signals, etc. Dysfunctional signals include those due to gene mutations, infections, exposure to environmental factors including toxins, system stress, autoimmune disorders, and inflammation.

[0005] When the cell proliferation process malfunctions, a variety of disorders can occur, including benign tumors, neoplasms, tumorigenesis, carcinogenesis, autoimmune disorders, inflammatory disorders, graft-versus-host rejection, and fibrous disorders.

[0006] Numerous broad-spectrum anti-neoplastic agents have been developed. Cytoskeletal agents such as paclitaxel target tubulin to halt mitotic cell division and are used to treat a variety of cancers, including ovarian, breast, lung, pancreatic, and testicular tumors (see, for example, Non-Patent Document 1). Organometallic drugs such as cisplatin are used to treat lymphoma, sarcoma, germ cell tumors, and several cancers, including bladder, small cell lung, and ovarian cancer. Cisplatin has the ability to bind nitrogenous bases and induce large-scale DNA crosslinking, ultimately leading to apoptosis (see, for example, Non-Patent Document 2). Intercalation and alkylating agents are also widely used clinically to treat a variety of neoplasms, but the overall toxicity associated with these drugs raises significant concerns for patients requiring long-term therapy.

[0007] Palbociclib (PD-033299; Ibrance) is marketed by Pfizer in combination with letrozole for the treatment of estrogen-positive, HER2-negative breast cancer. This compound inhibits CDK4 and CDK6. The structure of palbociclib is as follows: [ka]

[0008] Abemaciclib (LY2835219) is a CDK4 / 6 inhibitor currently undergoing human clinical trials as a treatment for various types of cancer. Phase III trials are being conducted for stage IV non-small cell lung cancer, in combination with fulvestrant in women with breast cancer, and as a first-line treatment for breast cancer in combination with either anastrozole or letrozole. The structure of abemaciclib is as follows: [ka]

[0009] Ribociclib (Lee011; Kisqali) is a CDK4 / 6 inhibitor approved for use in combination with aromatase inhibitors in the treatment of some metastatic breast cancers, and is currently undergoing clinical trials for the treatment of other specific tumors. The structure of ribociclib is as follows: [ka]

[0010] Lerocyclib is an orally selective CDK4 / 6 inhibitor currently in clinical development by G1 Therapeutics for use in combination with other targeted therapies in multiple oncological indications. Lerocyclib is currently being evaluated in two Phase 1 / 2 clinical trials: a combination study with fulvestrant (Faslodex®) in patients with estrogen receptor-positive, HER2-negative (ER+, HER2-) breast cancer (NCT02983071), and a combination study with osmirtinib (Tagrisso®) in patients with EGFRm non-small cell lung cancer. Lerocyclib has the following structure: [ka]

[0011] Trilasiclib is a selective CDK4 / 6 inhibitor and is being clinically developed by G1 Therapeutics as a first-in-class bone marrow preservation therapy designed to improve the prognosis of patients undergoing chemotherapy by preserving the function of hematopoietic stem cells and progenitor cells (HSPCs) and the immune system. It is a short-acting intravenous CDK4 / 6 inhibitor administered prior to therapy and is currently being evaluated in four randomized phase 2 clinical trials, including the first-line SCLC trial (NCT02499770) in combination with the etoposide and carboplatin chemotherapy regimen, and the first-line SCLC trial in combination with the same chemotherapy regimen and the checkpoint inhibitor Tecentriq® (atezolizumab). Trilaciclib has the following structure: [ka]

[0012] Various other pyrimidine-based drugs have been developed for the treatment of hyperproliferative disorders. Patent documents 1, 2, 3, 4, 5, 1, 6, 7, 8, 9, 10, 11, 12, and 13, filed by Tavares and Strum and assigned to G1 Therapeutics, describe a group of N-(heteroaryl)-pyrrolo[3,2-d]pyrimidine-2-aminecyclin-dependent kinase inhibitors comprising the following formula (variable parts are defined in their specifications): [ka]

[0013] Patent documents 14, 15, 16, 17, 18, and 19 have also been transferred to G1 Therapeutics, and describe the above pyrimidine-based drugs in the treatment of cancer. This document describes how to use it.

[0014] Patent documents 20, titled “Lactam Kinase Inhibitors,” 21, and 22, titled “Synthesis of Lactams,” filed by Tavares and similarly transferred to G1 Therapeutics, describe the synthesis of N-(heteroaryl)-pyrrolo[3,2-d]pyrimidine-2-amines and their use as lactam kinase inhibitors.

[0015] Other patent publications include: Patent document 23, filed by Strum et al. and assigned to G1 Therapeutics, describes a chemotherapy using a pyrimidine-based CDK4 / 6 inhibitor. The law describes compounds and methods for protecting normal cells. Patent document 24, filed by Strum et al. and assigned to G1 Therapeutics, describes pyrimidine CDK4 / 6 inhibitors. This document describes compounds and methods for protecting hematopoietic stem cells and progenitor cells from ionizing radiation. Patent Document 2, filed by Strum et al. and assigned to G1 Therapeutics. 5 describes the HSPC-preserving treatment of abnormal cell proliferation using a pyrimidine-based CDK4 / 6 inhibitor. Patent application filed by Strum et al. and assigned to G1 Therapeutics. Reference 26 describes a highly active antineoplastic and antiproliferative pyrimidine-based CDK4 / 6 inhibitor. Patent Document 2, filed by Strum et al. and assigned to G1 Therapeutics. Patent document 7 describes a tricyclic pyrimidine CDK inhibitor for use in radiation protection. Patent document 28, filed by Strum et al. and assigned to G1 Therapeutics, describes chemical This article describes tricyclic pyrimidine CDK inhibitors for cell protection during therapy. (Strum et al.) Patent document 29, filed by al. and assigned to G1 Therapeutics, describes RB-positive abnormalities. This patent document describes a tricyclic pyrimidine CDK inhibitor for use in HSPC-preserving therapy for cell proliferation. Filed by Strum et al. and assigned to G1 Therapeutics. Patent document 30 describes a tricyclic pyrimidine CDK inhibitor for use as an antineoplastic and antiproliferative agent. The patent application was filed by Strum et al. and assigned to G1 Therapeutics. Reference 31 describes the combination of pyrimidine CDK4 / 6 inhibitors with other antineoplastic agents. Patent document 32, filed by Strum et al. and assigned to G1 Therapeutics, describes CDK This document describes compounds and methods for treating certain Rb-negative cancers with 4 / 6 inhibitors and topoisomerase inhibitors. Patent Document 3, filed by Strum and assigned to G1 Therapeutics. 3. Patent documents 34 and 35 describe various CDK inhibitors. Patent document 36, filed by Sorrentino et al. and assigned to G1 Therapeutics, describes the use of CDK4 / 6 inhibitors in specific dose regimens. Patent document 37, filed by Strum et al. and assigned to G1 Therapeutics, describes a method for treating EGFR-driven cancers. The use of CDK4 / 6 inhibitors is described. Patent document 38, filed by Strum et al. and assigned to G1 Therapeutics, describes compounds and methods for treating chemotherapy-resistant cancer. Patent document 39, filed by Beelen et al. and assigned to G1 Therapeutics, describes a method of administration for G1T38. Patent document 40, filed by Strum et al. and assigned to G1 Therapeutics, describes additional compounds that inhibit CDK. Patent document 41, filed by Strum and assigned to G1 Therapeutics, describes additional compounds that inhibit CDK. Patent document 41, filed by Schneider et al. and assigned to G1 Patent document 42, transferred to Therapeutics, describes a synthetic method for preparing CDK inhibitor compounds. The following describes the methods. Patent document 43, filed by Sorrentino et al. and assigned to G1 Therapeutics, describes the combined use of a CDK4 / 6 inhibitor and eribulin. Patent document 44, filed by Strum and assigned to G1 Therapeutics, describes additional compounds that inhibit CDK. Patent document 45, filed by Jung et al. and assigned to G1 Therapeutics, describes additional compounds that inhibit CDK. Patent document 46, filed by Roberts et al. and assigned to G1 Therapeutics, describes CDK4 / 6 inhibitors. This document describes patient selection for enhancing tumor treatment with agents. Patent document 47, filed by Strum et al. and transferred to G1 Therapeutics, describes the treatment of fibroblast growth factor-mediated cancer. The use of CDK4 / 6 inhibitors for this purpose is described. [Prior art documents] [Patent Documents]

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[0017] [Non-Patent Document 1] Jordan, Wilson, Nature Reviews Cancer (2004) 4:253-265 [Non-Patent Document 2] Siddick, Oncogene (2003) 22: 7265-7279 [Overview of the project] [Problems that the invention aims to solve]

[0018] Despite research in the field of cell cycle inhibitors for treating abnormal cell proliferation in hosts, such as humans, given the severity of these diseases, there is still a need to identify new compounds that can meet this medical need.

[0019] Therefore, an object of the present invention is to provide novel compounds, methods, compositions and manufacturing processes for inhibiting undesirable cell cycles in a host, such as humans, the compounds which can be used to treat abnormal cell proliferation. Another aspect of the present invention is to provide compounds, methods and compositions which can be used to treat cell cycle disorders in cells that are spontaneously resistant or have become resistant to other treatments. [Means for solving the problem]

[0020] The present invention provides therapeutically active compounds of formulas I, II, III, IV, V, VI, VII, VIII, IX, or X, or pharmaceutically acceptable salts or compositions thereof. In certain embodiments, the active compounds or salts, compositions thereof, or isotopic analogs thereof are used in effective amounts in a host requiring them, typically a human, to treat medical disorders involving abnormal cell proliferation, including tumors or cancer.

[0021] In certain embodiments, the compounds of the present invention are active against various cyclin-dependent kinases, for example, having preferential activity against CDK2. In certain embodiments, the compounds of the present invention are active against CDK1, CDK3, CDK4, C It is more selective for inhibiting CDK2 than DK5, CDK6, CDK7, and / or CDK9. Based on this finding, compounds and methods for the treatment of patients with proliferative disorders, including tumors or cancer, are presented, which comprises administering to patients in need one or more effective amounts of one or a combination of the compounds described herein or pharmaceutically acceptable salts thereof in an optionally pharmaceutically acceptable carrier. In certain embodiments, the antiproliferative disorder is selected from cancer, tumors, neoplasms, benign tumors, autoimmune disorders, inflammatory disorders, graft-versus-host rejection, and fibrous disorders. In a typical embodiment, the patient is human.

[0022] In certain embodiments, the compounds of the present invention have high oral bioavailability, for example, oral bioavailability exceeding about 50%, 60%, 70%, 80%, 90%, or 95%F (the percentage of the drug that reaches systemic circulation as intact drug). In certain embodiments, the compounds of the present invention have high metabolic stability, for example, the compounds of the present invention may exhibit stability in human microsomes for more than about 30 minutes, 45 minutes, 1 hour, 1.5 hours, or 2 hours.

[0023] The present invention also provides a favorable method for treating patients with proliferative disorders resistant to selective CDK4 / 6 inhibitors, such as tumors or cancers, which comprises administering an effective amount of a compound of formula I, II, III, IV, V, VI, VII, VIII, IX, or X, or a pharmaceutically acceptable composition, salt, or isotope analog 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), which involve loss of retinoblastoma (Rb) protein or high levels of cyclin E expression, remain difficult to treat due to intrinsic or primary resistance to existing selective CDK4 / 6 inhibitors. Furthermore, certain cancers, despite being Rb-positive, are intrinsically resistant to the effects of selective CDK4 / 6 inhibitors. In addition, certain cancers with an intact Rb pathway may be intrinsically resistant to selective CDK4 / 6 inhibitors due to the presence of other genetic or phenotypic abnormalities. For example, it is estimated that 40% of uterine cancers, 20% of ovarian cancers, 15% of bladder cancers, 20% of prostate cancers, and 15% of breast cancers may develop endogenous resistance to selective CDK4 / 6 inhibition due to squirin E upregulation, even if Rb is intact. See, for example, Knudsen et al., The Strange Case of CDK4 / 6 Inhibitors: Mechanisms, Resistance, and Combination Strategies. Trends Cancer. 2017 Jan; 3(1): 39-55. Furthermore, in certain specific cancers, for example... For example, ER+ breast cancer can acquire resistance to selective CDK4 / 6 inhibitors during the course of selective CDK4 / 6 inhibitor therapy, for instance, by upregulation of cyclin E, which enables cell cycle progression from G1 to S via CDK2. In certain embodiments, the compounds described herein effectively inhibit cell cycle progression in cancer cells that are endogenously resistant, susceptible to resistance, or have become resistant to selective CDK4 / 6 inhibitors.

[0024] The active compounds described herein act as inhibitors of cyclin-dependent kinases (CDKs), and provide, for example, inhibition of the cell cycle in replicating cells through inhibition of CDK2 and / or CDK4 and / or CDK6, or combinations thereof. However, unlike selective CDK4 / 6 inhibitors, certain active compounds herein are resistant to selective CDK4 / 6 inhibitors, or are able to inhibit cells that have become so, by virtue of the ability of the active compound to preferentially inhibit another CDK, such as CDK2, and thus provide an additional cell cycle inhibition mechanism. In one embodiment, the invention provides a selective CDK2 inhibitor. This property is particularly useful for inhibiting the cell cycle progression of cancers or other proliferative disorders that are Rb-negative or have become Rb-negative and thus escape cell cycle control by CDK4 / 6.

[0025] In certain embodiments of the invention, Formula I, Formula II, Formula III, Formula IV, or Formula V:

Chemical formula

[0026] In the alternative embodiment, formula I is as follows: [ka] (In the formula, each R 5 These are independently hydrogen, alkyl, haloalkyl, halogen, cyano, and -O R 14 , and -NR 14 R 15 The variable parts are selected from (and all other variable parts are as specified herein), or are pharmaceutically acceptable salts, N-oxides, isotopic analogs, and / or pharmaceutically acceptable compositions thereof.

[0027] In a particular embodiment of the present invention, formulas VI, VII, VIII, IX, or X: [ka] (In the formula, X 11 , X 12 , X 13 , X 14 , and X 15 These are independently N, CH, and CR 4 Selected from, X 11 , X 12 , X 13 , X 14 , and X 15 Two or fewer of these are selected such that the total is N. R 17 and R 18 Each of the following is independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, alkyl-aryl, alkyl-heteroaryl, and heteroaryl, and each except hydrogen has 1, 2, 3, or 4 R 8 It is arbitrarily substituted in the base, R 19 These are hydrogen, alkyl, haloalkyl, halogen, cyano, -OR 14 , or -NR 14 R 15 (is) Compounds of or pharmaceutically acceptable salts, N-oxides, isotopic analogs, and / or pharmaceutically acceptable compositions thereof are provided.

[0028] In certain embodiments, the compounds of the present invention preferentially inhibit CDK2 or CDK9 over CDK4 and / or CDK6. In certain embodiments, the compounds of the present invention are CDK inhibitors with increased activity against CDK2.

[0029] These compounds can be used to treat conditions of abnormal cell proliferation in hosts that require them, typically in humans.

[0030] In another embodiment, a method for treating fibrous disorders in a host is provided, comprising administering an effective amount of the compound of the present invention or a pharmaceutically acceptable salt thereof in an optionally pharmaceutically acceptable carrier.

[0031] In another embodiment, a method for treating rheumatoid arthritis and psoriasis in a host is provided, comprising administering an effective amount of the compound of the present invention or a pharmaceutically acceptable salt thereof in an optionally pharmaceutically acceptable carrier.

[0032] In yet another embodiment, a method for treating an autoimmune disorder in a host is provided, comprising administering an effective amount of the compound of the present invention or a pharmaceutically acceptable salt thereof in an optionally pharmaceutically acceptable carrier.

[0033] In certain embodiments, a method is provided for treating a tumor or cancer in a host, comprising administering an effective amount of the compound of the present invention or a pharmaceutically acceptable salt thereof in an optionally pharmaceutically acceptable carrier. In one embodiment of this embodiment, the cancer is an Rb-positive tumor or cancer. In another embodiment of this embodiment, the cancer is an Rb-negative tumor or cancer. In certain embodiments, the cancer is selected from breast cancer, prostate cancer (including androgen-resistant prostate cancer), colon cancer including metastatic colon cancer, endometrial cancer, other cancers of the reproductive system such as ovarian cancer or testicular cancer, small cell lung cancer, glioblastoma, and cancers of the head and / or neck.

[0034] In yet another embodiment, a method is provided for treating impaired abnormal cell proliferation in a host such as a human, comprising administering an effective amount of a combination of one or more active compounds described herein, either in combination with or alternately with another active compound. In a particular embodiment of the present invention, the second compound is a chemotherapeutic agent. In another embodiment of this embodiment, the second active compound is an immunomodulator, including, but not limited to, checkpoint inhibitors such as anti-PD1, anti-PD-L1, anti-CTLA, anti-LAG-3, and anti-Tim, antibodies, small molecules, peptides, nucleotides, or other inhibitors (including, but not limited to, ipilimumab (Yervoy), pembrolizumab (Keytruda), nivolumab (Opdivo), semiprimab (Libtayo), atezolizumab (Tecentriq), avelumab (Bavencio), and durvalumab (Imfinzi)).

[0035] In yet another embodiment, one of the active compounds described herein is administered in an effective dose in combination with or alternately with an effective dose of an estrogen inhibitor, including but not limited to a SERM (selective estrogen receptor modulator), SERD (selective estrogen receptor degrader), complete estrogen receptor degrader, or another form of partial or complete estrogen antagonist, for the treatment of abnormal tissues of the female reproductive system, such as breast cancer, ovarian cancer, endometrial cancer, or uterine cancer.

[0036] In another embodiment, one of the active compounds described herein is administered in an effective dose in combination with or alternately with an effective dose of an androgen (such as testosterone) inhibitor, including but not limited to a selective androgen receptor modulator, a selective androgen receptor degrader, a complete androgen receptor degrader, or another form of partial or complete androgen antagonist, for the treatment of abnormal tissue of the male reproductive system, such as prostate cancer or testicular cancer. In a particular embodiment, the prostate cancer or testicular cancer is androgen-resistant.

[0037] In certain embodiments, the compounds described herein inhibit cyclin-dependent kinases ("CDKs"). For example, the compounds described herein provide a dose-dependent G1 phase arrest effect to subject CDK replication-dependent healthy cells, 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 a chemotherapeutic agent, for example, during the period in which a DNA-damaging chemotherapeutic agent can exert a DNA-damaging effect on subject CDK replication-dependent healthy cells.

[0038] In certain embodiments, the administration of compounds using the methods described herein may be combined with, but are not limited to, the use of hematopoietic growth factors including 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 compounds may be administered before the administration of hematopoietic growth factors. In certain embodiments, the administration of hematopoietic growth factors may be timed to eliminate the effect of the compounds on HSPCs.

[0039] In certain embodiments, the compounds described herein are administered in combination with a BTK inhibitor. In other embodiments, the compounds described herein are administered in combination with an EGFR inhibitor.

[0040] The present invention also provides an advantageous method for treating patients with selective CDK4 / 6 inhibitor-resistant cancer, which comprises administering an effective amount of a compound of formula I, II, III, IV, V, VI, VII, VIII, IX, or X, or a pharmaceutically acceptable composition, salt, or isotopic analog thereof. In certain embodiments, the compounds of the present invention are used to treat patients with cancer that has endogenous resistance to selective CDK4 / 6 inhibition. In certain embodiments, the compounds of the present invention are used to treat patients with cancer that has acquired resistance to one or more selective CDK4 / 6 inhibitors. In certain embodiments, the compounds of the present invention are administered in combination with a selective CDK4 / 6 inhibitor to patients with CDK4 / 6 inhibition-responsive cancer in order to extend the therapeutic effect of cell cycle inhibition in cancer.

[0041] Similarly, cancers that were initially sensitive to selective inhibition of CDK4 / 6 inhibitors, such as ER+ breast cancer, may acquire resistance to selective CDK4 / 6 inhibition through the upregulation of cyclin E, which enables cell cycle progression from G1 to S via CDK2. Therefore, the compounds of the present invention can be used in effective doses to treat patients with cancer that has developed resistance to selective CDK4 / 6 inhibitors over time, either due to prior exposure to CDK4 / 6 inhibitors or natural tumor progression. Accordingly, the present invention includes a method of administering an effective dose of the compounds of the present invention to treat patients with cancer that was initially responsive to or sensitive to selective CDK4 / 6 inhibition, thereby extending the therapeutic effect of selective CDK4 / 6 inhibitors on CDK4 / 6-responsive cancers by delaying acquired resistance to the inhibitory effect of selective CDK4 / 6 inhibitors.

[0042] In certain embodiments, the present invention provides a method for treating patients with cancer that has developed acquired resistance to a selective CDK4 / 6 inhibitor by administering an effective amount of the compound of the present invention to the patient. In some embodiments, the selective CDK4 / 6 inhibitor to which the cancer has developed resistance is selected from palbociclib, abemaciclib, rerocyclib, trilaciclib, SH6390, and ribociclib.

[0043] In certain embodiments, the present invention is a method for treating a patient with cancer by administering a therapeutically effective amount of the compound of the present invention in combination with a selective CDK4 / 6 inhibitor, wherein the patient is selective CDK4 / 6 inhibitor-naive. By administering this compound in combination with a selective CDK4 / 6 inhibitor, the development of acquired resistance to the selective CDK4 / 6 inhibitor can be delayed. 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 rerocyclib.

[0044] In certain embodiments of the present invention, a method is provided for treating a patient with cancer, comprising administering a therapeutically effective amount of the 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 after the development of selective CDK4 / 6 inhibitor resistance, the method enables the continued use of cell cycle inhibition in the treatment of cancer. In some embodiments, the selective CDK4 / 6 inhibitor to which the cancer has developed resistance is selected from palbociclib, abemaciclib, ribociclib, trilaciclib, SHR6390, and rerocyclib.

[0045] In an alternative embodiment, the present invention is a method for treating a patient having Rb-positive cancer, a) Administer selective CDK4 / 6 inhibitors to the patient. b) Monitoring cyclin E levels in patients with cancer, and c) A method comprising 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 upon detection of an increase in cyclin E levels that confers resistance to the inhibitory effect of a selective CDK4 / 6 inhibitor to cancer. In some embodiments, the selective CDK4 / 6 inhibitor administered is selected from palbociclib, abemaciclib, ribociclib, trilaciclib, SHR6390, and rerocyclib.

[0046] In an alternative embodiment, the present invention is a method for treating a patient having cancer, a) To determine the Rb status of cancer, b) If the Rb- status is positive, administer a selective CDK4 / 6 inhibitor to the patient in combination with a compound of formula I, II, III, IV, V, VI, VII, VIII, IX, or X. c) A method comprising administering to a 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, which does not contain a selective CDK4 / 6 inhibitor, if the Rb- status is negative.

[0047] In some embodiments, the selective CDK4 / 6 inhibitor administered in combination with a compound of formula I, II, III, IV, V, VI, VII, VIII, IX, or X is selected from palbociclib, abemaciclib, ribociclib, trilaciclib, SHR6390, and rerocyclib.

[0048] In an alternative embodiment, the present invention relates to a method for treating a patient with abnormal cell proliferation such as cancer, a) Administer selective CDK4 / 6 inhibitors to the patient. b) Monitoring the patient's cancer response to selective CDK4 / 6 inhibitors. c) A method comprising 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 upon detection that the patient's cancer has become unresponsive to a selective CDK4 / 6 inhibitor.

[0049] In some embodiments, CDK4 / 6 is administered in combination with compounds of formula I, II, III, IV, V, VI, VII, VIII, IX, or X. The inhibitor is selected from palbociclib, abemaciclib, ribociclib, trilaciclib, SHR6390, and rerocyclib. In some embodiments, non-responsiveness is disease progression.

[0050] In another alternative embodiment, the present invention relates to a method for treating a patient having abnormal cell proliferation, such as cancer, a) Administer selective CDK4 / 6 inhibitors to the patient. b) Monitoring one or more cellular signals that indicate the development of selective CDK4 / 6 inhibitor resistance in cancer. c) A method comprising 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 if one or more cellular signals indicate the development of selective CDK4 / 6 inhibitor resistance in cancer. In some embodiments, the selective CDK4 / 6 inhibitor administered is selected from palbociclib, abemaciclib, ribociclib, trilaciclib, SHR6390, and rerocyclib.

[0051] In some embodiments, one or more cellular signals indicating the development of selective CDK4 / 6 inhibitor resistance in cancer are selected from increased cyclin E expression, CCNE1 / 2 amplification, E2F amplification, CDK2 amplification, CDK6 amplification, CDK4 amplification, p16 amplification, WEE1 overexpression, DM2 overexpression, CDK7 overexpression, FZR1 deficiency, HDAC activation, FGFR pathway activation, PI3K / AKT / mTOR pathway activation, loss of ER or PR expression, increased AP-1 transcriptional activity, epithelial-mesenchymal transition, Smad3 suppression, autophagy activation, Rb1 deficiency, and inactivating RB1 mutations.

[0052] In another alternative embodiment, the present invention is a pharmaceutically acceptable composition comprising a compound of formula I, II, III, IV, V, VI, VII, VIII, IX, or X, and a selective CDK4 / 6 inhibitor, for example, one selected from, but not limited to, palbociclib, abemaciclib, ribociclib, trilaciclib, SHR6390, and rerocyclib.

[0053] In yet another embodiment, a method is provided for treating impaired abnormal cell proliferation in a host such as a human, comprising administering an effective dose of a combination of a compound of formula I, II, III, IV, V, VI, VII, VIII, IX, or X and a selective CDK4 / 6 inhibitor, either in combination with or alternately with an additional active compound. In certain embodiments of the present invention, the additional active compound is a chemotherapeutic agent. In another embodiment of this embodiment, the additional active compound is an immunomodulator, including, but not limited to, checkpoint inhibitors such as anti-PD1, anti-PD-L1, anti-CTLA, anti-LAG-3, and anti-Tim, antibodies, small molecules, peptides, nucleotides, or other inhibitors (including, but not limited to, ipilimumab (Yervoy), pembrolizumab (Keytruda), nivolumab (Opdivo), semiprimab (Libtayo), atezolizumab (Tecentriq), avelumab (Bavencio), and durvalumab (Imfinzi)).

[0054] In yet another embodiment, the compounds of the present invention are administered in an effective dose in combination with or alternately with an effective dose of an estrogen inhibitor, including but not limited to a SERM (selective estrogen receptor modulator), SERD (selective estrogen receptor degrader), complete estrogen receptor degrader, or another form of partial or complete estrogen antagonist, for the treatment of abnormal tissues of the female reproductive system, such as breast cancer, ovarian cancer, endometrial cancer, or uterine cancer.

[0055] In another embodiment, the compound of the present invention is combined with a selective CDK4 / 6 inhibitor. For the treatment of abnormal tissues of the male reproductive system, such as prostate cancer or testicular cancer, an effective dose of an androgen (testosterone, etc.) inhibitor, including but not limited to a selective androgen receptor modulator, a selective androgen receptor degrader, a complete androgen receptor degrader, or another form of partial or complete androgen antagonist, is administered in combination with or alternately with an effective dose. In some embodiments, prostate cancer or testicular cancer is androgen-resistant.

[0056] In some embodiments, the compound of the present invention, combined with a CDK4 / 6 inhibitor, is administered in an effective dose in combination with a BTK inhibitor. In other embodiments, the compound of the present invention, combined with a CDK4 / 6 inhibitor, is administered in an effective dose in combination with an EGFR inhibitor.

[0057] In certain embodiments, the compounds of the present 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.

[0058] Therefore, the present invention includes at least the following features: (a) Compounds of the present invention as described herein, or pharmaceutically acceptable salts thereof; (b) A compound of the present invention described herein or a pharmaceutically acceptable salt thereof, useful in an effective amount for treating a disorder of abnormal cell proliferation, including tumors or cancer; (c) Compounds of the present invention as described herein, or pharmaceutically acceptable salts thereof, useful for treating cancers that are resistant to treatment with CDK4 / 6 inhibitor compounds, such as palbociclib, abemaciclib, or ribociclib; (d) Use of the compound of the present invention or a pharmaceutically acceptable salt thereof in the manufacture of a pharmaceutical product for the treatment of abnormal cell proliferation disorders such as tumors or cancer; (e) Use of the compound of the present invention, or a pharmaceutically acceptable salt thereof, in the manufacture of a pharmaceutical product for the treatment of cancer resistant to treatment with a CDK4 / 6 inhibitor compound, such as palbociclib, abemaciclib, or ribociclib; (f) A method for manufacturing a pharmaceutical product intended for therapeutic use in treating disorders of abnormal cell proliferation, including tumors or cancer, characterized in that the manufacturing process uses the compounds of the present invention described herein; (q) A pharmaceutical formulation comprising an effective host therapeutic dose of the compound of the present invention or a pharmaceutically acceptable salt thereof, together with a pharmaceutically acceptable carrier or diluent; (r) The compounds of the present invention as described herein as a mixture of enantiomers or diastereomers (where appropriate), including a racemic mixture; (s) as an enantiomer or diastereomer (including as an isolated enantiomer or diastereomer (i.e., with a purity greater than 85%, 90%, 95%, 97%, or 99%)) (where appropriate) a concentrated form of the compounds of the present invention described herein; (t) A process for preparing a therapeutic product comprising an effective amount of the compound of the present invention as described herein; (u) A solid dosage form of the compound of the present invention or a pharmaceutically acceptable salt thereof in a pharmaceutically acceptable carrier for oral delivery; (v) Parenteral dosage forms of the compound of the present invention or a pharmaceutically acceptable salt thereof in a pharmaceutically acceptable carrier for systemic delivery, including intravenous delivery; and, (w) A method for manufacturing a pharmaceutical product intended for antineoplastic therapy, characterized in that the manufacturing of the product involves using a compound of the present invention as described herein. [Modes for carrying out the invention]

[0059] 1.Compound In a particular embodiment, the compound of the present invention is of formula: [ka] The substance thereof, or a pharmaceutically acceptable salt thereof, N-oxide, isotope analogue, and / or a pharmaceutically acceptable composition thereof, where y is 0, 1, 2, 3, or 4, and the remaining variable part is as specified herein.

[0060] In a particular embodiment, the compound of the present invention is of formula: [ka] The formula is a pharmaceutically acceptable salt, N-oxide, isotope analog, and / or pharmaceutically acceptable composition thereof, wherein the variable part is as defined herein.

[0061] In a particular embodiment, the compound of the present invention is of formula: [ka] The formula is a pharmaceutically acceptable salt, N-oxide, isotope analog, and / or pharmaceutically acceptable composition thereof, wherein the variable part is as defined herein.

[0062] In a particular embodiment, the compound of the present invention is of formula: [ka] The formula is a pharmaceutically acceptable salt, N-oxide, isotope analog, and / or pharmaceutically acceptable composition thereof, wherein the variable part is as defined herein.

[0063] In a particular embodiment, the compound of the present invention is of formula: [ka] The formula is a pharmaceutically acceptable salt, N-oxide, isotope analog, and / or pharmaceutically acceptable composition thereof, wherein the variable part is as defined herein.

[0064] In a particular embodiment, the compound of the present invention is of formula: [ka] The formula is a pharmaceutically acceptable salt, N-oxide, isotope analog, and / or pharmaceutically acceptable composition thereof, wherein the variable part is as defined herein.

[0065] In certain embodiments, the compound of the present invention is [ka] Alternatively, a pharmaceutically acceptable salt thereof is selected.

[0066] In certain embodiments, the compound of the present invention is [ka] Alternatively, a pharmaceutically acceptable salt thereof is selected.

[0067] In certain embodiments, the compound of the present invention is [ka] Alternatively, a pharmaceutically acceptable salt thereof is selected.

[0068] "alkyl" embodiment In certain embodiments, "alkyl" is C1-C 10 It is alkyl, C1-C9 alkyl, C1-C8 alkyl, C1-C7 alkyl, C1-C6 alkyl, C1-C5 alkyl, C1-C4 alkyl, C1-C3 alkyl, or C1 or C2 alkyl.

[0069] In certain embodiments, the "alkyl" contains one carbon atom.

[0070] In certain embodiments, the "alkyl" contains two carbon atoms.

[0071] In certain embodiments, the "alkyl" contains three carbon atoms.

[0072] In certain embodiments, the "alkyl" contains four carbon atoms.

[0073] In certain embodiments, the "alkyl" contains five carbon atoms.

[0074] In certain embodiments, the "alkyl" contains six carbon atoms.

[0075] Non-limiting examples of "alkyl" include methyl, ethyl, propyl, butyl, pentyl, and hexyl.

[0076] Additional, non-limiting examples of "alkyl" include isopropyl, isobutyl, isopentyl, and isohexyl.

[0077] Additional, non-limiting examples of "alkyl" include sec-butyl, sec-pentyl, and sec-hexyl.

[0078] Additional, non-limiting examples of "alkyl" include tert-butyl, tert-pentyl, and tert-hexyl.

[0079] Additional, non-limiting examples of "alkyl" include neopentyl, 3-pentyl, and active pentyl.

[0080] In certain embodiments, "alkyl" is "substituted alkyl".

[0081] In certain embodiments, the "alkenyl" is a "substituted alkenyl".

[0082] In certain embodiments, "alkynyl" is "substituted alkynyl".

[0083] "Haloalkyl" embodiment In certain embodiments, "haloalkyl" is C1-C 10 These include haloalkyl, C1-C9 haloalkyl, C1-C8 haloalkyl, C1-C7 haloalkyl, C1-C6 haloalkyl, C1-C5 haloalkyl, C1-C4 haloalkyl, C1-C3 haloalkyl, and C1 or C2 haloalkyl.

[0084] In certain embodiments, the "haloalkyl" has one carbon atom.

[0085] In certain embodiments, the "haloalkyl" has one carbon atom and one halogen atom.

[0086] In certain embodiments, the "haloalkyl" has one carbon atom and two halogen atoms.

[0087] In certain embodiments, the "haloalkyl" has one carbon atom and three halogen atoms.

[0088] In certain embodiments, the "haloalkyl" has two carbon atoms.

[0089] In certain embodiments, the "haloalkyl" has three carbon atoms.

[0090] In certain embodiments, the "haloalkyl" has four carbon atoms.

[0091] In certain embodiments, the "haloalkyl" has five carbon atoms.

[0092] In a particular embodiment, the "haloalkyl" has six carbon atoms.

[0093] Non-specific examples of "haloalkyl" include: [ka] These are some examples.

[0094] Additional, non-limiting examples of "haloalkyl" include: [ka] These are some examples.

[0095] Additional, non-limiting examples of "haloalkyl" include: [ka] These are some examples.

[0096] Additional, non-limiting examples of "haloalkyl" include: [ka] These are some examples.

[0097] "Aryl" embodiment In certain embodiments, "aryl" is a six-carbon aromatic group (phenyl).

[0098] In certain embodiments, "aryl" is a 10-carbon aromatic group (naphthyl).

[0099] In certain embodiments, "aryl" is a six-carbon aromatic group fused to a heterocycle, with an aryl ring as its bonding site. Non-limiting examples of "aryl" include indoline, tetrahydroquinoline, tetrahydroisoquinoline, and dihydrobenzofuran, where the bonding site of each group is on an aromatic ring.

[0100] for example, [ka] This is an "aryl" group.

[0101] however, [ka] This is a "heterocyclic" group.

[0102] In certain embodiments, "aryl" is a six-carbon aromatic group condensed with a cycloalkyl group, with the bonding site being an aryl ring. Non-limiting examples of "aryl" include dihydroindene and tetrahydronaphthalene, where the bonding site of each group is on an aromatic ring.

[0103] for example, [ka] This is an "aryl" group.

[0104] however, [ka] This is a "cycloalkyl" group.

[0105] In certain embodiments, "aryl" is a "substitutional aryl".

[0106] "Heteroaryl" Embodiment In certain embodiments, the "heteroaryl" is a five-membered aromatic group containing one, two, three, or four nitrogen atoms.

[0107] In certain embodiments, the "heteroaryl" is a five-membered aromatic group containing one, two, three, or four atoms independently selected from nitrogen and oxygen.

[0108] Non-exclusive examples of five-membered "heteroaryl" groups include pyrrole, furan, thiophene, pyrazole, imidazole, triazole, tetrazole, isoxazole, oxazole, oxadiazole, oxatriazole, isothiazole, thiazole, thiadiazole, and thiatriazole.

[0109] Additional non-limiting examples of five-membered "heteroaryl" groups include: [ka] These are some examples.

[0110] In certain embodiments, the "heteroaryl" is a six-membered aromatic group containing one, two, or three nitrogen atoms (i.e., pyridinyl, pyridazinyl, triazinyl, pyrimidinyl, and pyrazinyl).

[0111] Non-limiting examples of six-membered "heteroaryl" groups having one or two nitrogen atoms include: [ka] These are some examples.

[0112] In certain embodiments, the "heteroaryl" is a nine-membered bicyclic aromatic group containing one or two atoms selected from nitrogen, oxygen, and sulfur.

[0113] Non-exclusive examples of bicyclic "heteroaryl" groups include indole, benzofuran, isoindole, indazole, benzimidazole, azaindole, azaindazole, purine, isobenzofuran, benzothiophene, benzoisoxazole, benzoisothiazole, benzoxazole, and benzothiazole.

[0114] Additional non-limiting examples of bicyclic "heteroaryl" groups include: [ka] These are some examples.

[0115] Additional non-limiting examples of bicyclic "heteroaryl" groups include: [ka] These are some examples.

[0116] Additional non-limiting examples of bicyclic "heteroaryl" groups include: [ka] These are some examples.

[0117] In certain embodiments, the "heteroaryl" is a 10-membered bicyclic aromatic group containing one or two atoms selected from nitrogen, oxygen, and sulfur.

[0118] Non-exclusive examples of bicyclic "heteroaryl" groups include quinoline, isoquinoline, quinoxaline, phthalazine, quinazoline, cinnoline, and naphthyridine.

[0119] Additional non-limiting examples of bicyclic "heteroaryl" groups include: [ka] These are some examples.

[0120] In certain embodiments, the "heteroaryl" is a "substituted heteroaryl."

[0121] "Cycloalkyl" Embodiment In certain embodiments, "cycloalkyl" is a C3-C8 cycloalkyl, C3-C7 cycloalkyl, C3-C6 cycloalkyl, C3-C5 cycloalkyl, C3 or C4 cycloalkyl, C4-C8 cycloalkyl, C5-C8 cycloalkyl, or C6-C8 cycloalkyl.

[0122] In certain embodiments, the "cycloalkyl" has three carbon atoms.

[0123] In certain embodiments, the "cycloalkyl" has four carbon atoms.

[0124] In certain embodiments, the "cycloalkyl" has five carbon atoms.

[0125] In certain embodiments, the "cycloalkyl" has six carbon atoms.

[0126] In certain embodiments, the "cycloalkyl" has seven carbon atoms.

[0127] In certain embodiments, the "cycloalkyl" has eight carbon atoms.

[0128] In certain embodiments, the "cycloalkyl" has nine carbon atoms.

[0129] In a particular embodiment, the "cycloalkyl" has 10 carbon atoms.

[0130] Non-limiting examples of "cycloalkyl" include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, and cyclodecyl.

[0131] Additional, non-limiting examples of "cycloalkyl" include dihydroindene and tetrahydronaphthalene, where the bonding sites of each group are located on the cycloalkyl ring.

[0132] for example, [ka] This is a "cycloalkyl" group.

[0133] however, [ka] This is an "aryl" group.

[0134] In certain embodiments, "cycloalkyl" is "substituted cycloalkyl".

[0135] "Hybrid Algebra" Embodiment In certain embodiments, “heterocycle” refers to a cyclic ring having one nitrogen atom and three, four, five, six, seven, or eight carbon atoms.

[0136] In certain embodiments, “heterocycle” refers to a cyclic ring having one nitrogen atom, one oxygen atom, and three, four, five, six, seven, or eight carbon atoms.

[0137] In certain embodiments, “heterocycle” refers to a cyclic ring having two nitrogen atoms and three, four, five, six, seven, or eight carbon atoms.

[0138] In certain embodiments, "heterocycle" refers to a cyclic ring having one oxygen atom and three, four, five, six, seven, or eight carbon atoms.

[0139] In certain embodiments, “heterocycle” refers to a cyclic ring having one sulfur atom and three, four, five, six, seven, or eight carbon atoms.

[0140] Non-restrictive examples of "heterocyclic compounds" include aziridine, oxirane, thiirane, azetidine, 1,3-diazetidine, oxetane, and thiethane.

[0141] Additional, non-restrictive examples of "heterocyclic compounds" include pyrrolidines, 3-pyrroline, 2-pyrroline, pyrazolidines, and imidazolidines.

[0142] Additional, non-restrictive examples of "heterocyclic" compounds include tetrahydrofuran, 1,3-dioxolane, tetrahydrothiophene, 1,2-oxathiolane, and 1,3-oxathiolane.

[0143] Additional, non-restrictive examples of "heterocyclic compounds" include piperidine, piperazine, tetrahydropyran, 1,4-dioxane, thiane, 1,3-dithiane, 1,4-dithiane, morpholine, and thiomorpholine.

[0144] Additional, non-restrictive examples of "heterocyclic" structures include indoline, tetrahydroquinoline, tetrahydroisoquinoline, and dihydrobenzofuran, where the bonding sites of each group lie on the heterocyclic ring.

[0145] for example, [ka] This is a "heterocyclic" group.

[0146] however, [ka] This is an "aryl" group.

[0147] An unrestricted example of a "complex algebra" is: [ka] This can also be mentioned.

[0148] An additional, non-restrictive example of a "complex algebra" is: [ka] These are some examples.

[0149] An additional, non-restrictive example of a "complex algebra" is: [ka] These are some examples.

[0150] An unrestricted example of a "complex algebra" is: [ka] This can also be mentioned.

[0151] An unrestricted example of a "complex algebra" is: [ka] This can also be mentioned.

[0152] An additional, non-restrictive example of a "complex algebra" is: [ka] These are some examples.

[0153] An additional, non-restrictive example of a "complex algebra" is: [ka] These are some examples.

[0154] In certain embodiments, the "complex ring" is a "substitutional complex ring".

[0155] Embodiments of "-alkyl-aryl" In certain embodiments, "-alkyl-aryl" refers to a C1 alkyl group substituted with an aryl group.

[0156] Non-limiting examples of "-alkyl-aryl" include the following: [ka]

[0157] In certain embodiments, "-alkyl-aryl" is, [ka] That is the case.

[0158] In certain embodiments, "-alkyl-aryl" refers to a C2 alkyl group substituted with an aryl group.

[0159] Non-limiting examples of "alkyl-aryl" include the following: [ka]

[0160] In certain embodiments, "alkyl-aryl" refers to a C3 alkyl group substituted with an aryl group.

[0161] Any substituent In certain embodiments, a group described herein that may be substituted with one or two substituents is substituted with one substituent.

[0162] In certain embodiments, a group described herein that may be substituted with one or two substituents is substituted with two substituents.

[0163] In certain embodiments, a group described herein, which may be substituted with one, two, three, or four substituents, is substituted with one substituent.

[0164] In certain embodiments, the groups described herein, which may be substituted with one, two, three, or four substituents, are substituted with two substituents.

[0165] In certain embodiments, the groups described herein, which may be substituted with one, two, three, or four substituents, are substituted with three substituents.

[0166] In certain embodiments, the groups described herein, which may be substituted with one, two, three, or four substituents, are substituted with four substituents.

[0167] R 1 Embodiment In a particular embodiment, one R 1 H is the other R 1 That is Ariel.

[0168] In a particular embodiment, one R 1 H is the other R 1 It is phenyl.

[0169] In a particular embodiment, one R 1 H is the other R 1 It is alkyl.

[0170] In a particular embodiment, at least one R 1 It is a hydroxyl group.

[0171] In a particular embodiment, at least one R 1 That is a halogen.

[0172] In a particular embodiment, at least one R 1 It is a haloalkyl.

[0173] In a particular embodiment, at least one R 1 That is fluorine.

[0174] In a particular embodiment, at least two R 1 That is fluorine.

[0175] In a particular embodiment, at least two R 1 It is alkyl.

[0176] In a particular embodiment, two R 1 These combine to form a 5-membered cycloalkyl group. In certain embodiments, the cycloalkyl group has one R 50 Substituting with substituents. In certain embodiments, the cycloalkyl is substituted with two R 50 Substituting with a substituent. In certain embodiments, the cycloalkyl is substituted with NH2. In certain embodiments, the cycloalkyl is OR 14 It is substituted with. In certain embodiments, the cycloalkyl is substituted with OH. In certain embodiments, the cycloalkyl is substituted with alkyl. In certain embodiments, the cycloalkyl is substituted with CH3.

[0177] In a particular embodiment, two R 1 These combine to form a 6-membered cycloalkyl group. In certain embodiments, the cycloalkyl group has one R 50 Substituting with substituents. In certain embodiments, the cycloalkyl is substituted with two R 50 Substituting with a substituent. In certain embodiments, the cycloalkyl is substituted with NH2. In certain embodiments, the cycloalkyl is OR 14 It is substituted with. In certain embodiments, the cycloalkyl is substituted with OH. In certain embodiments, the cycloalkyl is substituted with alkyl. In certain embodiments, the cycloalkyl is substituted with CH3.

[0178] In a particular embodiment, two R 1 These combine to form a 5-membered heterocycle. In a particular embodiment, the heterocycle is formed by one R 50 Substituting with substituents. In certain embodiments, the heterocycle has two R 50Substituting with substituents. In certain embodiments, the heterocycle is substituted with NH2. In certain embodiments, the heterocycle is OR 14 It is substituted with. In certain embodiments, the heterocycle is substituted with OH. In certain embodiments, the heterocycle is substituted with alkyl. In certain embodiments, the heterocycle is substituted with CH3.

[0179] In a particular embodiment, two R 1 These combine to form a six-membered heterocycle. In a particular embodiment, the heterocycle is formed by one R 50 Substituting with substituents. In certain embodiments, the heterocycle has two R 50 Substituting with substituents. In certain embodiments In this case, the heterocycle is substituted with NH2. In a particular embodiment, the heterocycle is OR 14 It is substituted with. In certain embodiments, the heterocycle is substituted with OH. In certain embodiments, the heterocycle is substituted with alkyl. In certain embodiments, the heterocycle is substituted with CH3.

[0180] In a particular embodiment, two R 1 These combine to form a 5-membered spiro ring selected from the following: [ka]

[0181] In a particular embodiment, two R 1 These combine to form a 6-membered spiro ring selected from the following: [ka]

[0182] In a particular embodiment, one R 1 It is hydrogen.

[0183] In a particular embodiment, one R 1It is alkyl.

[0184] In a particular embodiment, one R 1 -NR 12 R 13 That is the case.

[0185] In a particular embodiment, one R 1 It is a cycloalkyl group.

[0186] In a particular embodiment, one R 1 It is a complex algebra.

[0187] In a particular embodiment, one R 1 That is Ariel.

[0188] In a particular embodiment, one R 1 It is a heteroaryl compound.

[0189] In a particular embodiment, R 1 These are independently hydrogen, halogen, and -OR 14 , or NR 14 R 15 And R 14 These are independently hydrogen, alkyl, and -C(O)R 6 Selected from , and -C(O)alkyl, R 15 These are independently selected from hydrogen and alkyl.

[0190] In a particular embodiment, R 1 は-OR 14 And R 14 These are independently hydrogen, alkyl, and -C(O)R 6 Selected from, R 6 These are independently selected from hydrogen and alkyl.

[0191] In a particular embodiment, R 1 , NR 14 R 15 And R 14 These are independently hydrogen, alkyl, and -C(O)R6 Selected from , and -C(O)alkyl, R 15 These are independently selected from hydrogen and alkyl.

[0192] In a particular embodiment, two R 1 However, together with the rifling atoms to which they are bonded, they form a 3-membered, 4-membered, 5-membered, 6-membered, 7-membered, or 8-membered cycloalkyl group, or a 4-membered, 5-membered, 6-membered, 7-membered, or 8-membered heterocycle having one, two, or three heteroatoms selected from N, O, and S.

[0193] In a particular embodiment, two R 1 However, together with the red atoms to which they are bonded, they form a cycloalkyl group with 3, 4, 5, 6, 7, or 8 members, or a heterocycle with 4, 5, 6, 7, or 8 members having 1, 2, or 3 heteroatoms selected from N, O, and S, and two R 1 However, the cycloalkyl or heterocycle formed by bonding with the atoms to which they are bonded is R 50 It may be optionally substituted with one or two substituents independently selected from the above.

[0194] R 2 Embodiment: In a particular embodiment, R 2 -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 That is the case.

[0195] In a particular embodiment, R 2 is -C(O)R 6 ,-C(S)R 6 ,-S(O)R 6 , or -S(O)2R 6 That is the case.

[0196] In a particular embodiment, R 2 is -C(O)R 6 That is the case.

[0197] In a particular embodiment, R 2 It is -C(O)NH2.

[0198] In a particular embodiment, R 2 It is -C(O)CH3.

[0199] In a particular embodiment, R 2 is -S(O)2R 6 That is the case.

[0200] In a particular embodiment, R 2 It is -S(O)2NH2.

[0201] In a particular embodiment, R 2 teeth, [ka] That is the case.

[0202] In a particular embodiment, R 2 teeth, [ka] That is the case.

[0203] In a particular embodiment, R 2 teeth, [ka] That is the case.

[0204] In a particular embodiment, R 2 teeth, [ka] That is the case.

[0205] In a particular embodiment, R 2 teeth, [ka] That is the case.

[0206] In a particular embodiment, R 2 teeth, [ka] That is the case.

[0207] In a particular embodiment, R 2 teeth, [ka] That is the case.

[0208] In a particular embodiment, R 2 teeth, [ka] That is the case.

[0209] In a particular embodiment, R 2 teeth, [ka] That is the case.

[0210] In a particular embodiment, R 2 teeth, [ka] That is the case.

[0211] In a particular embodiment, R 2 teeth, [ka] That is the case.

[0212] In a particular embodiment, R 2 teeth, [ka] That is the case.

[0213] In a particular embodiment, R 2 teeth, [ka] That is the case.

[0214] In a particular embodiment, R 2 teeth, [ka] That is the case.

[0215] In a particular embodiment, R 2 teeth, [ka] That is the case.

[0216] In a particular embodiment, R 2 teeth, [ka] That is the case.

[0217] In a particular embodiment, R 2 teeth, [ka] That is the case.

[0218] In a particular embodiment, R 2 teeth, [ka] That is the case.

[0219] In a particular embodiment, R 2 teeth, [ka] That is the case.

[0220] In a particular embodiment, R 2 teeth, [ka] That is the case.

[0221] In a particular embodiment, R 2 teeth, [ka] That is the case.

[0222] In a particular embodiment, R 2 teeth, [ka] That is the case.

[0223] In a particular embodiment, R 2 teeth, [ka] That is the case.

[0224] In a particular embodiment, R 2 teeth, [ka] That is the case.

[0225] In a particular embodiment, R 2 teeth, [ka] That is the case.

[0226] In a particular embodiment, R 2 teeth, [ka] That is the case.

[0227] In a particular embodiment, R 2 teeth, [ka] That is the case.

[0228] In a particular embodiment, R 2 teeth, [ka] That is the case.

[0229] In a particular embodiment, R 2 teeth, [ka] That is the case.

[0230] In a particular embodiment, R 2 teeth, [ka] That is the case.

[0231] In a particular embodiment, R 2 teeth, [ka] That is the case.

[0232] In a particular embodiment, R 2 teeth, [ka] That is the case.

[0233] In a particular embodiment, R 2 teeth, [ka] That is the case.

[0234] In a particular embodiment, R 2 teeth, [ka] That is the case.

[0235] In a particular embodiment, R 2 teeth, [ka] That is the case.

[0236] In a particular embodiment, R 2 teeth, [ka] That is the case.

[0237] In a particular embodiment, R 2 teeth, [ka] That is the case.

[0238] In a particular embodiment, R 2 teeth, [ka] That is the case.

[0239] In a particular embodiment, R 2 teeth, [ka] That is the case.

[0240] R 3 Embodiment: In a particular embodiment, R 3 It is hydrogen.

[0241] In a particular embodiment, R 3 It is alkyl.

[0242] In a particular embodiment, R 3 -NR 12 R 13 That is the case.

[0243] In a particular embodiment, R 3 It is a -S(O) alkyl group.

[0244] In a particular embodiment, R 3 It is an -SO2 alkyl group.

[0245] In a particular embodiment, R 3 It is a cycloalkyl group.

[0246] In a particular embodiment, R 3 It is a complex algebra.

[0247] In a particular embodiment, R 3 That is Ariel.

[0248] In a particular embodiment, R 3 It is a heteroaryl compound.

[0249] In a particular embodiment, R 3 It is an alkyl-aryl compound.

[0250] In a particular embodiment, R 3 It is an alkyl-heteroaryl compound.

[0251] R 4 Embodiment: In a particular embodiment, R 4 It is hydrogen.

[0252] In a particular embodiment, R 4 It is alkyl.

[0253] In a particular embodiment, R 4 -NR 12 R 13 That is the case.

[0254] In a particular embodiment, R 4 It is a -S(O) alkyl group.

[0255] In a particular embodiment, R 4 It is an -SO2 alkyl group.

[0256] In a particular embodiment, R 4 It is a cycloalkyl group.

[0257] In a particular embodiment, R 4 It is a complex algebra.

[0258] In a particular embodiment, R 4 That is Ariel.

[0259] In a particular embodiment, R 4 It is a heteroaryl compound.

[0260] R 5 Embodiment: In a particular embodiment, R 5 It is hydrogen.

[0261] In a particular embodiment, R 5 It is alkyl.

[0262] In a particular embodiment, R 5 It is a haloalkyl compound.

[0263] In a particular embodiment, R 5 It is a halogen.

[0264] In a particular embodiment, R 5 It is cyano.

[0265] In a particular embodiment, R 5 は-OR 14 That is the case.

[0266] In a particular embodiment, R 5 ga-NR 14 R 15 That is the case.

[0267] R 6 Embodiment: In a particular embodiment, R 6 It is hydrogen.

[0268] In a particular embodiment, R 6 It is alkyl.

[0269] In a particular embodiment, R 6 This is alkenyl or alkinyl.

[0270] In a particular embodiment, R 6 This is 1, 2, 3, or 4 R 8 It is a cycloalkyl group that is optionally substituted with a group.

[0271] In a particular embodiment, R 6 It is a cycloalkyl group.

[0272] In a particular embodiment, R 6 This is 1, 2, 3, or 4 R 8It is a complex ring arbitrarily substituted with a base.

[0273] In a particular embodiment, R 6 It is a complex algebra.

[0274] In a particular embodiment, R 6 This is 1, 2, 3, or 4 R 8 This is an aryl that has been arbitrarily substituted with the base.

[0275] In a particular embodiment, R 6 It is Ariel.

[0276] In a particular embodiment, R 6 This is 1, 2, 3, or 4 R 8 It is a heteroaryl compound that has been arbitrarily substituted with a base compound.

[0277] In a particular embodiment, R 6 , NR 7 R 7 That is the case.

[0278] In a particular embodiment, R 6 It is NH2.

[0279] In a particular embodiment, R 6 It is OH.

[0280] In a particular embodiment, R 6 This is OCH3.

[0281] R 7 Embodiment: In a particular embodiment, each R 7 These are independently selected from hydrogen and alkyl.

[0282] In a particular embodiment, R 7 It is hydrogen.

[0283] In a particular embodiment, R7 It is alkyl.

[0284] In a particular embodiment, R 7 This is alkenyl or alkinyl.

[0285] In a particular embodiment, R 7 This is 1, 2, 3, or 4 R 8 It is a cycloalkyl group that is optionally substituted with a group.

[0286] In a particular embodiment, R 7 It is a cycloalkyl group.

[0287] In a particular embodiment, R 7 This is 1, 2, 3, or 4 R 8 It is a complex ring arbitrarily substituted with a base.

[0288] In a particular embodiment, R 7 It is a complex algebra.

[0289] In a particular embodiment, R 7 This is 1, 2, 3, or 4 R 8 This is an aryl that has been arbitrarily substituted with the base.

[0290] In a particular embodiment, R 7 It is Ariel.

[0291] In a particular embodiment, R 7 This is 1, 2, 3, or 4 R 8 It is a heteroaryl compound that has been arbitrarily substituted with a base compound.

[0292] R 8 Embodiment: In a particular embodiment, each R 8 These are independently halogens, haloalkyls, alkyls, and NRs. 12 R 13 , and OR 12 Selected from.

[0293] In a particular embodiment, each R 8 It is a halogen.

[0294] In a particular embodiment, each R 8 It is a haloalkyl.

[0295] In a particular embodiment, each R 8 It is alkyl.

[0296] In a particular embodiment, at least one R 8 It is a halogen.

[0297] In a particular embodiment, at least one R 8 It is a haloalkyl.

[0298] In a particular embodiment, at least one R 8 It is alkyl.

[0299] In a particular embodiment, each R 8 It is a cycloalkyl group.

[0300] In a particular embodiment, at least one R 8 It is a complex algebra.

[0301] In a particular embodiment, at least one R 8 It is Ariel.

[0302] In a particular embodiment, at least one R 8 It is a heteroaryl compound.

[0303] In a particular embodiment, at least one R 8 It is a -S(O)2 alkyl group.

[0304] In a particular embodiment, at least one R 8 is NR 12R 13 That is the case.

[0305] In a particular embodiment, at least one R 8 It is an alkyl-heteroaryl compound.

[0306] In a particular embodiment, at least one R 8 It is an alkyl-aryl compound.

[0307] In a particular embodiment, at least one R 8 is OR 12 That is the case.

[0308] In a particular embodiment, each R 8 These are independently hydrogen, halogen, haloalkyl, alkyl, cycloalkyl, heterocyclic, aryl, heteroaryl, -S(O)2alkyl, and NR. 12 R 13 , alkyl-heteroaryl, alkyl-aryl and OR 12 Selected from.

[0309] In a particular embodiment, each R 8 These are independently hydrogen, alkyl, and NR 12 R 13 , alkyl-heteroaryl, alkyl-aryl, and OR 12 Selected from.

[0310] R 12 and R 13 Embodiment: In a particular embodiment, each R 12 and R 13 These are independently selected from hydrogen and alkyl.

[0311] In a particular embodiment, R 12 and R 13 Both are hydrogen.

[0312] In a particular embodiment, R 12 and R13 All of them are alkyl groups.

[0313] In a particular embodiment, R 12 and R 13 One of them is hydrogen.

[0314] In a particular embodiment, R 12 and R 13 One of them is alkyl.

[0315] In a particular embodiment, R 12 and R 13 One of them is -C(O)alkyl.

[0316] In a particular embodiment, R 12 and R 13 One of them is -C(S)alkyl.

[0317] In a particular embodiment, R 12 and R 13 One of them is Ariel.

[0318] In a particular embodiment, R 12 and R 13 One of them is -SO2 alkyl.

[0319] In a particular embodiment, R 12 and R 13 One of them is -S(O)alkyl.

[0320] In a particular embodiment, R 12 and R 13 One of them is a heteroaryl.

[0321] In a particular embodiment, R 12 and R 13 One of them is alkyl-aryl.

[0322] In a particular embodiment, R 12 and R 13 One of them is cycloalkyl.

[0323] In a particular embodiment, R 12 and R 13 One of them is a complex algebra.

[0324] In a particular embodiment, R 12 and R 13 One of them is alkyl-heteroaryl.

[0325] R 14 and R 15 Embodiment: In a particular embodiment, each R 14 and R 15 These are independently selected from hydrogen and alkyl.

[0326] In a particular embodiment, R 14 and R 15 Both are hydrogen.

[0327] In a particular embodiment, R 14 and R 15 All of them are alkyl groups.

[0328] In a particular embodiment, R 14 and R 15 One of them is hydrogen.

[0329] In a particular embodiment, R 14 and R 15 One of them is alkyl.

[0330] In a particular embodiment, R 14 and R 15 One of them is -C(O)alkyl.

[0331] In a particular embodiment, R 14 and R15 One of them is -C(S)alkyl.

[0332] In a particular embodiment, R 14 and R 15 One of them is Ariel.

[0333] In a particular embodiment, R 14 and R 15 One of them is -SO2 alkyl.

[0334] In a particular embodiment, R 14 and R 15 One of them is -S(O)alkyl.

[0335] In a particular embodiment, R 14 and R 15 One of them is a heteroaryl.

[0336] In a particular embodiment, R 14 and R 15 One of them is alkyl-aryl.

[0337] In a particular embodiment, R 14 and R 15 One of them is cycloalkyl.

[0338] In a particular embodiment, R 14 and R 15 One of them is a complex algebra.

[0339] In a particular embodiment, R 14 and R 15 One of them is alkyl-heteroaryl.

[0340] R 17 and R 18 Embodiment: In a particular embodiment, each R 17 These are independently selected from hydrogen and alkyl.

[0341] In a particular embodiment, R 17 It is hydrogen.

[0342] In a particular embodiment, R 17 It is alkyl.

[0343] In a particular embodiment, R 17 This is alkenyl or alkinyl.

[0344] In a particular embodiment, R 17 This is 1, 2, 3, or 4 R 8 It is a cycloalkyl group that is optionally substituted with a group.

[0345] In a particular embodiment, R 17 It is a cycloalkyl group.

[0346] In a particular embodiment, R 17 This is 1, 2, 3, or 4 R 8 It is a complex ring arbitrarily substituted with a base.

[0347] In a particular embodiment, R 17 It is a complex algebra.

[0348] In a particular embodiment, R 17 This is 1, 2, 3, or 4 R 8 This is an aryl that has been arbitrarily substituted with the base.

[0349] In a particular embodiment, R 17 It is Ariel.

[0350] In a particular embodiment, R 17 This is 1, 2, 3, or 4 R 8 It is a heteroaryl compound that has been arbitrarily substituted with a base compound.

[0351] In a particular embodiment, each R18 These are independently selected from hydrogen and alkyl.

[0352] In a particular embodiment, R 18 It is hydrogen.

[0353] In a particular embodiment, R 18 It is alkyl.

[0354] In a particular embodiment, R 18 This is alkenyl or alkinyl.

[0355] In a particular embodiment, R 18 This is 1, 2, 3, or 4 R 8 It is a cycloalkyl group that is optionally substituted with a group.

[0356] In a particular embodiment, R 18 It is a cycloalkyl group.

[0357] In a particular embodiment, R 18 This is 1, 2, 3, or 4 R 8 It is a complex ring arbitrarily substituted with a base.

[0358] In a particular embodiment, R 18 It is a complex algebra.

[0359] In a particular embodiment, R 18 This is 1, 2, 3, or 4 R 8 This is an aryl that has been arbitrarily substituted with the base.

[0360] In a particular embodiment, R 18 It is Ariel.

[0361] In a particular embodiment, R 18 This is 1, 2, 3, or 4 R 8 It is a heteroaryl compound that has been arbitrarily substituted with a base compound.

[0362] R 19 Embodiment: In a particular embodiment, R 19 It is hydrogen.

[0363] In a particular embodiment, R 19 It is alkyl.

[0364] In a particular embodiment, R 19 It is a haloalkyl.

[0365] In a particular embodiment, R 19 It is a halogen.

[0366] In a particular embodiment, R 19 It is cyano.

[0367] In a particular embodiment, R 19 は-OR 14 That is the case.

[0368] In a particular embodiment, R 19 -NR 14 R 15 That is the case.

[0369] R 50 Embodiment: In a particular embodiment, each R 50 These are, independently, amino, -NHR 14 , -NR 14 R 15 hydroxyl, OR 14 , and R 4 Selected from.

[0370] In a particular embodiment, R 50 There is only one base, and it is -NR 14 R 15 That is the case.

[0371] In a particular embodiment, R 50 There is only one base, and that is OR 14 That is the case.

[0372] In a particular embodiment, R 50 There is only one base, and that is R 4 That is the case.

[0373] X 1 , X 2 , X 3 , X 4 , and X 5 Embodiment In a particular embodiment, X 1 , X 2 , X 3 , X 4 , and X 5 Each of these is independently a CH.

[0374] In a particular embodiment, X 1 , X 2 , X 3 , X 4 , and X 5 At least one of them is N.

[0375] In a particular embodiment, X 1 , X 2 , X 3 , X 4 , and X 5 Two of them are N.

[0376] In a particular embodiment, X 1 , X 2 , X 3 , X 4 , and X 5 At least one of them is CR 4 And R 4 These are independently hydrogen, alkyl, aryl, cycloalkyl, haloalkyl, heteroaryl, heterocyclic, halogen, cyano, -OR 14 , -NR 14 R 15 , -NR 14 C(O)R 6 , -NR 14 S(O)R 6 , -NR 14 S(O)2R6 , -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 That is the case.

[0377] In a particular embodiment, X 1 , X 2 , X 3 , X 4 , and X 5 At least one of them is CR 4 And 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 That is the case.

[0378] In a particular embodiment, X 1 , X 2 , X 3 , X 4 , and X 5 At least one of them is CR 4 And R 4 is OR 14 , -NR 14 R 15 , -NR 14 S(O)2R 6 , S(O)R 6 , or -S(O)2R 6 That is the case.

[0379] In a particular embodiment, X 1 , X 2 , X 3 , X4 , and X 5 At least one of them is CR 4 And R 4 is hydrogen, a haloalkyl, or a halogen.

[0380] X 11 , X 12 , X 13 , X 14 , and X 15 Embodiment In a particular embodiment, X 11 , X 12 , X 13 , X 14 , and X 15 Each of these is independently a CH.

[0381] In a particular embodiment, X 11 , X 12 , X 13 , X 14 , and X 15 At least one of them is N.

[0382] In a particular embodiment, X 11 , X 12 , X 13 , X 14 , and X 15 Two of them are N.

[0383] In a particular embodiment, X 11 , X 12 , X 13 , X 14 , and X 15 At least one of them is CR 4 And R 4 These are independently hydrogen, alkyl, aryl, cycloalkyl, haloalkyl, heteroaryl, heterocyclic, halogen, cyano, -OR 14 , -NR 14 R 15 , -NR 14 C(O)R 6 , -NR 14 S(O)R 6 , -NR 14 S(O)2R6 , -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 That is the case.

[0384] In a particular embodiment, X 11 , X 12 , X 13 , X 14 , and X 15 among At least one is CR 4 And 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 That is the case.

[0385] In a particular embodiment, X 11 , X 12 , X 13 , X 14 , and X 15 At least one of them is CR 4 And R 4 is OR 14 , -NR 14 R 15 , -NR 14 S(O)2R 6 , S(O)R 6 , or -S(O)2R 6 That is the case.

[0386] In a particular embodiment, X 11 , X 12 , X13 , X 14 , and X 15 At least one of them is CR 4 And R 4 is hydrogen, a haloalkyl, or a halogen.

[0387] Additional Embodiments 1. In a particular embodiment, formula: [ka] TIFF2026076261000089.tif92170 (in the formula, X 1 , X 2 , X 3 , X 4 , and X 5 These are independently N, CH, CR 2 , and CR 4 Selected from, X 1 , X 2 , X 3 , X 4 , and X 5 At least one of them is CR 2 X 1 , X 2 , X 3 , X 4 , and X 5 Two or fewer of these are selected such that the total is N. X 11 , X 12 , X 13 , X 14 , and X 15 These are independently N, CH, and CR. 2 , and CR 4 Selected from, X 11 , X 12 , X 13 , X 14 , and X 15 Two or fewer of these are selected such that the total is N. Each R 1 These are independently hydrogen, halogen, and -OR 14 , NR 14 R 15Selected from the group consisting of alkyl, aryl, cycloalkyl, haloalkyl, heteroaryl, alkyl-hydroxyl, and heterocyclic, with 2 R 1 These can optionally form a 3-membered, 4-membered, 5-membered, 6-membered, 7-membered, or 8-membered cycloalkyl group, or a 4-membered, 5-membered, 6-membered, 7-membered, or 8-membered heterocycle having one, two, or three heteroatoms selected from N, O, and S, together with the ring atoms to which they are bonded, and two R 1 However, the cycloalkyl or heterocycle formed by bonding with the atoms to which they are bonded is R 50 They may be optionally substituted with one or two substituents independently selected from them. Each R 2 -NR is independent. 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 Selected from the group consisting of, R 3 is hydrogen, -OR 14 , -NR 14 R 15 , alkyl, alkenyl, alkynyl, -C(O)R 6 Selected from the group consisting of -C(O)alkyl, -C(S)alkyl, aryl, -SO2alkyl, heteroaryl, heterocyclic, -alkyl-aryl, and -alkyl-heteroaryl, Each R 4These are independently hydrogen, alkyl, aryl, cycloalkyl, haloalkyl, heteroaryl, heterocyclic, 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 Selected from the group consisting of, R 5 These are hydrogen, alkyl, haloalkyl, halogen, cyano, -OR 14 , or -NR 14 R 15 And, Each R 6 These are independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, heteroaryl, and NR. 7 R 7 , and OR 7 Selected from the group consisting of hydrogen, NR 7 R 7 , and OR 7 Other than R 6 Each of them has 1, 2, 3, or 4 R 8 It is arbitrarily substituted in the base, Each R 7 R is independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, alkyl-aryl, alkyl-heteroaryl, and heteroaryl, and R other than hydrogen. 7 Each of these consists of 1, 2, 3, or 4 R 8 It is arbitrarily substituted in the base, Each R 8These are independently hydrogen, halogen, haloalkyl, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, heteroaryl, -S(O)2alkyl, and NR. 12 R 13 , alkyl-heteroaryl, alkyl-aryl, and OR 12 Selected from the group consisting of, Each R 12 and R 13 These are independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, -C(O)alkyl, -C(S)alkyl, aryl, -SO2alkyl, -S(O)alkyl, heteroaryl, alkyl-aryl, cycloalkyl, heterocyclic, and alkyl-heteroaryl. Each R 14 and R 15 These are independently hydrogen, alkyl, alkenyl, alkynyl, and -C(O)R 6 Selected from the group consisting of -C(O)alkyl, -C(S)alkyl, aryl, -SO2alkyl, heteroaryl, heterocyclic, -alkyl-aryl, and -alkyl-heteroaryl, R 17 and R 18 Each of the following is independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, alkyl-aryl, alkyl-heteroaryl, and heteroaryl, and each except hydrogen has 1, 2, 3, or 4 R 8 It is arbitrarily substituted in the base, R 19 These are hydrogen, alkyl, haloalkyl, halogen, cyano, -OR 14 , or -NR 14 R 15 and Each R 50 Independently, hydrogen, -NR 14 R 15 , OR 14 , and R 4 (Selected from the group consisting of) Compounds thereof, or pharmaceutically acceptable salts, N-oxides, isotopic analogs, and / or pharmaceutically acceptable compositions thereof are provided.

[0388] 2. In a particular embodiment, formula: [ka] (In the formula, each R 2 -NR is independent. 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 (Selected from the group consisting of) Compounds thereof, or pharmaceutically acceptable salts, N-oxides, isotopic analogs, and / or pharmaceutically acceptable compositions thereof are provided.

[0389] 3.Formula: [ka] The compound described in Embodiment 1, or a pharmaceutically acceptable salt thereof.

[0390] 4.R 5 The compound according to Embodiment 1, wherein the compound is a hydroxyl group.

[0391] 5.Formula: [ka] The compound described in Embodiment 1, or a pharmaceutically acceptable salt thereof.

[0392] 6.1 R 1 The compound according to Embodiment 1, wherein the compound is hydrogen.

[0393] 7.R1 The compound according to Embodiment 1, wherein all of the atoms are hydrogen.

[0394] 8.R 1 The compound described in Embodiment 1, wherein none of the compounds are hydrogen.

[0395] 9.Formula: [ka] The compound described in Embodiment 1, or a pharmaceutically acceptable salt thereof.

[0396] 10.Formula: [ka] The compound described in Embodiment 1, or a pharmaceutically acceptable salt thereof.

[0397] 11.Formula: [ka] The compound described in Embodiment 1, or a pharmaceutically acceptable salt thereof.

[0398] 12.Formula: [ka] The compound described in Embodiment 1, or a pharmaceutically acceptable salt thereof.

[0399] 13.X 11 A compound according to any one of embodiments 10 to 12, wherein is CH.

[0400] 14.X 11 A compound according to any one of embodiments 10 to 12, wherein is N.

[0401] 15.X 11 CR 4 The compound according to any one of embodiments 10 to 12.

[0402] 16.X12 A compound according to any one of embodiments 10 to 15, wherein is CH.

[0403] 17.X 12 A compound according to any one of embodiments 10 to 15, wherein is N.

[0404] 18.X 12 CR 4 The compound described in any one of embodiments 10 to 15.

[0405] 19.X 13 A compound according to any one of embodiments 10 to 18, wherein CH is present.

[0406] 20.X 13 A compound according to any one of embodiments 10 to 18, wherein is N.

[0407] 21.X 13 CR 4 The compound described in any one of embodiments 10 to 18.

[0408] 22.X 14 A compound according to any one of embodiments 10 to 21, wherein is CH.

[0409] 23.X 14 A compound according to any one of embodiments 10 to 21, wherein is N.

[0410] 24.X 14 CR 4 The compound according to any one of embodiments 10 to 21.

[0411] 25.X 15 A compound according to any one of embodiments 10 to 24, wherein is CH.

[0412] 26.X 15 A compound according to any one of embodiments 10 to 24, wherein is N.

[0413] 27.X 15CR 4 The compound described in any one of embodiments 10 to 24.

[0414] 28.Formula: [ka] The compound described in Embodiment 1, or a pharmaceutically acceptable salt thereof.

[0415] 29.R 3 A compound according to any one of Embodiments 1 to 28, wherein the compound is hydrogen.

[0416] 30.R 3 A compound according to any one of Embodiments 1 to 28, wherein the parent molecule is alkyl.

[0417] 31.R 3 ga-NR 14 R 15 The compound described in any one of Embodiments 1 to 28.

[0418] 32.R 3 A compound according to any one of Embodiments 1 to 28, wherein -NH2.

[0419] 33.Formula: [ka] The compound described in Embodiment 1, or a pharmaceutically acceptable salt thereof.

[0420] 34.Formula: [ka] The compound described in Embodiment 1, or a pharmaceutically acceptable salt thereof.

[0421] 35.Formula: [ka] The compound described in Embodiment 1, or a pharmaceutically acceptable salt thereof.

[0422] 36.Formula: [ka] The compound described in Embodiment 1, or a pharmaceutically acceptable salt thereof.

[0423] 37.Formula: [ka] The compound described in Embodiment 1, or a pharmaceutically acceptable salt thereof.

[0424] 38.2 R 1 The compound according to Embodiment 1 or any one of Embodiments 33 to 37, wherein they form a 3-membered ring to an 8-membered ring together with the carbon atoms to which they are bonded.

[0425] 39.2 R 1 The compound according to Embodiment 1 or any one of Embodiments 33 to 37, wherein they form a six-membered carbon ring together with the carbons to which they are bonded.

[0426] 40.1 R 1 A compound according to Embodiment 1 or any one of Embodiments 33 to 37, wherein the compound is a halogen.

[0427] 41.1 R 1 A compound according to Embodiment 1 or any one of Embodiments 33 to 37, wherein the compound is a haloalkyl group.

[0428] 42.1 R 1 The compound according to Embodiment 1 or any one of Embodiments 33 to 37, wherein the compound is hydroxyl.

[0429] 43.R 1 A compound according to Embodiment 1 or any one of Embodiments 33 to 37, wherein is selected from alkyl, aryl, cycloalkyl, and haloalkyl.

[0430] 44.R 2 -C(O)R6 ,-C(S)R 6 ,-S(O)R 6 , or -S(O)2R 6 The compound described in any one of Embodiments 1 to 43.

[0431] 45.R 2 -C(O)R 6 The compound described in any one of Embodiments 1 to 43.

[0432] 46.R 2 -S(O)2R 6 The compound described in any one of Embodiments 1 to 43.

[0433] 47.Each R 6 The compounds according to any one of Embodiments 1 to 46, which are independently selected from hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, and heteroaryl.

[0434] 48.Each R 6 However, independently, NR 7 R 7 and OR 7 A compound according to any one of embodiments 1 to 46, selected from the above.

[0435] 49.R 2 A compound according to any one of Embodiments 1 to 43, wherein is -S(O)2NH2.

[0436] 50. [ka] but, [ka] The compound described in any one of Embodiments 1 to 49.

[0437] 51.X 1 A compound according to any one of Embodiments 1 to 50, wherein is CH.

[0438] 52.X 1 A compound according to any one of Embodiments 1 to 50, wherein is N.

[0439] 53.X 1 CR 2 The compound described in any one of Embodiments 1 to 50.

[0440] 54.X 1 CR 4 The compound described in any one of Embodiments 1 to 50.

[0441] 55.X 2 A compound according to any one of Embodiments 1 to 54, wherein is CH.

[0442] 56.X 2 A compound according to any one of Embodiments 1 to 54, wherein is N.

[0443] 57.X 2 CR 2 The compound described in any one of Embodiments 1 to 54.

[0444] 58.X 2 CR 4 The compound described in any one of Embodiments 1 to 54.

[0445] 59. [ka] but, [ka] The compound described in any one of Embodiments 1 to 58.

[0446] 60.X 3 A compound according to any one of Embodiments 1 to 58, wherein CH is present.

[0447] 61.X 3A compound according to any one of Embodiments 1 to 58, wherein is N.

[0448] 62.X 3 CR 2 The compound described in any one of Embodiments 1 to 58.

[0449] 63.X 3 CR 4 The compound described in any one of Embodiments 1 to 58.

[0450] 64. [ka] but, [ka] The compound according to any one of embodiments 60 to 63.

[0451] 65.X 4 A compound according to any one of embodiments 1 to 64, wherein is CH.

[0452] 66.X 4 A compound according to any one of embodiments 1 to 64, wherein is N.

[0453] 67.X 4 CR 2 The compound according to any one of Embodiments 1 to 64.

[0454] 68.X 4 CR 4 The compound according to any one of Embodiments 1 to 64.

[0455] 69.X 5 A compound according to any one of Embodiments 1 to 68, wherein CH is present.

[0456] 70.X 5 A compound according to any one of Embodiments 1 to 68, wherein is N.

[0457] 71.X 5 CR 2 The compound described in any one of Embodiments 1 to 68.

[0458] 72.X 5 CR 4 The compound described in any one of Embodiments 1 to 68.

[0459] 73.R 4 is OR 14 The compound described in any one of Embodiments 1 to 72.

[0460] 74.R 4 A compound according to any one of embodiments 1 to 72, wherein is a halogen.

[0461] 75.R 4 A compound according to any one of Embodiments 1 to 72, wherein the parent is alkyl.

[0462] 76.R 3 A compound according to any one of Embodiments 1 to 72, wherein the parent is alkyl.

[0463] 77. In a particular embodiment, the above compound is [ka] Alternatively, a pharmaceutically acceptable salt thereof is selected.

[0464] 78. Structure: [ka] The compound described in Embodiment 77, or a pharmaceutically acceptable salt thereof.

[0465] 79. Structure: [ka] The compound described in Embodiment 77, or a pharmaceutically acceptable salt thereof.

[0466] 80. Structure: [ka] The compound described in Embodiment 77, or a pharmaceutically acceptable salt thereof.

[0467] 81. Structure: [ka] The compound described in Embodiment 77, or a pharmaceutically acceptable salt thereof.

[0468] 82. Structure: [ka] The compound described in Embodiment 77, or a pharmaceutically acceptable salt thereof.

[0469] 83. Structure: [ka] The compound described in Embodiment 77, or a pharmaceutically acceptable salt thereof.

[0470] 84. Structure: [ka] The compound described in Embodiment 77, or a pharmaceutically acceptable salt thereof.

[0471] 85. Structure: [ka] The compound described in Embodiment 77, or a pharmaceutically acceptable salt thereof.

[0472] 86. Structure: [ka] The compound described in Embodiment 77, or a pharmaceutically acceptable salt thereof.

[0473] 87. Structure: [ka] The compound described in Embodiment 77, or a pharmaceutically acceptable salt thereof.

[0474] 88. Structure: [ka] A compound described in Embodiment 1 of TIFF2026076261000121.tif207170TIFF2026076261000122.tif194170TIFF2026076261000123.tif226170, or a pharmaceutically acceptable salt thereof.

[0475] 89. A method is provided for the treatment of a disorder related to abnormal cell proliferation, comprising administering to a host in need of the treatment an effective amount of a compound described in any one of Embodiments 1 to 88 in an optionally pharmaceutically acceptable carrier.

[0476] 90. The method according to Embodiment 89, wherein the host is a human.

[0477] 91. The method according to Embodiment 89 or 90, wherein the above-mentioned disorder is an inflammatory disorder.

[0478] 92. The method according to Embodiment 89 or 90, wherein the above-mentioned disorder is a fibrous disorder.

[0479] 93. The method according to Embodiment 89 or 90, wherein the above-mentioned disorder is an autoimmune disorder.

[0480] 94. The method according to Embodiment 89 or 90, wherein the above-mentioned disorder is a tumor.

[0481] 95. The method according to Embodiment 89 or 90, wherein the above-mentioned disorder is cancer.

[0482] 96. The method according to Embodiment 89 or 90, wherein the above-mentioned disorder is rheumatoid arthritis.

[0483] 97. In a particular embodiment, a method is provided for reducing the effects 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 the method comprises administering to the person an effective amount of a compound described in any one of Embodiments 1 to 88 in an optionally pharmaceutically acceptable carrier.

[0484] 98. A pharmaceutical composition is provided comprising a compound described in any one of Embodiments 1 to 88 or a pharmaceutically acceptable salt thereof in a pharmaceutically acceptable carrier.

[0485] 99. A pharmaceutical composition according to Embodiment 98 for treating disorders related to abnormal cell proliferation.

[0486] 100. The pharmaceutical composition according to Embodiment 99, wherein the above-mentioned disorder is an inflammatory disorder.

[0487] 101. The pharmaceutical composition according to Embodiment 99, wherein the above-mentioned disorder is a fibrous disorder.

[0488] 102. The pharmaceutical composition according to Embodiment 99, wherein the above-mentioned disorder is an autoimmune disorder.

[0489] 103. The pharmaceutical composition according to Embodiment 99, wherein the above-mentioned disorder is a tumor.

[0490] 104. The pharmaceutical composition according to Embodiment 99, wherein the above-mentioned disorder is cancer.

[0491] 105. The pharmaceutical composition according to Embodiment 99, wherein the above-mentioned disorder is rheumatoid arthritis.

[0492] 106. A pharmaceutical composition according to Embodiment 98 for reducing the effects of chemotherapy on healthy cells in a person undergoing treatment for cancer or abnormal cell proliferation, wherein the healthy cells are hematopoietic stem cells or hematopoietic progenitor cells.

[0493] 107. In a particular embodiment, a compound is provided for use in the manufacture of a pharmaceutical product for treating a disorder associated with abnormal cell proliferation, wherein the compound is selected from any of Embodiments 1 to 88 or is a pharmaceutically acceptable salt thereof.

[0494] 108. The compound according to Embodiment 107, wherein the above-mentioned disorder is an inflammatory disorder.

[0495] 109. The compound according to Embodiment 107, wherein the above-mentioned disorder is a fibrous disorder.

[0496] 110. The compound according to Embodiment 107, wherein the above-mentioned disorder is an autoimmune disorder.

[0497] 111. The compound according to Embodiment 107, wherein the above-mentioned disorder is a tumor.

[0498] 112. The compound according to Embodiment 107, wherein the above-mentioned disorder is cancer.

[0499] 113. The compound according to Embodiment 107, wherein the above-mentioned disorder is rheumatoid arthritis.

[0500] 114. In certain embodiments, a compound is provided for use in the manufacture of a pharmaceutical product for reducing the effects 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 the compound is selected from any of Embodiments 1 to 88, or is a pharmaceutically acceptable salt thereof.

[0501] 115. In certain embodiments, a use is provided of a compound in the treatment of a disorder related to abnormal cell proliferation, wherein the compound is selected from any of Embodiments 1 to 88 or is a pharmaceutically acceptable salt thereof.

[0502] 116. The use according to Embodiment 115, wherein the above-mentioned disorder is an inflammatory disorder.

[0503] 117. The use described in Embodiment 115, wherein the above-mentioned disorder is a fibrous disorder.

[0504] 118. The use according to Embodiment 115, wherein the above-mentioned disorder is an autoimmune disorder.

[0505] 119. The use according to Embodiment 115, wherein the above-mentioned disorder is a tumor.

[0506] 120. The use described in Embodiment 115, wherein the above-mentioned disorder is cancer.

[0507] 121. The use according to Embodiment 115, wherein the above-mentioned disorder is rheumatoid arthritis.

[0508] 122. In certain embodiments, the use of a compound in reducing the effects 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 the compound is selected from any of Embodiments 1 to 88, or a pharmaceutically acceptable salt thereof.

[0509] Core Embodiment In a particular embodiment, [ka] teeth, [ka] Selected from.

[0510] In a particular embodiment, [ka] teeth, [ka] Selected from.

[0511] In a particular embodiment, [ka] teeth, [ka] Selected from.

[0512] In a particular embodiment, [ka] teeth, [ka] Selected from.

[0513] In a particular embodiment, [ka] teeth, [ka] Selected from.

[0514] In a particular embodiment, [ka] teeth, [ka] Selected from.

[0515] In a particular embodiment, [ka] teeth, [ka] Selected from.

[0516] In a particular embodiment, [ka] teeth, [ka] Selected from.

[0517] In a particular embodiment, [ka] teeth, [ka] Selected from.

[0518] In a particular embodiment, [ka] teeth, [ka] Selected from.

[0519] Additional Embodiments In certain embodiments, the compound of the present invention is [ka] Alternatively, a pharmaceutically acceptable salt thereof is selected.

[0520] In certain embodiments, the compound of the present invention is [ka] Alternatively, a pharmaceutically acceptable salt thereof is selected.

[0521] In certain embodiments, the compound of the present invention is [ka] Alternatively, a pharmaceutically acceptable salt thereof is selected.

[0522] In certain embodiments, the compound of the present invention is [ka] Alternatively, a pharmaceutically acceptable salt thereof is selected.

[0523] In certain embodiments, the compound of the present invention is [ka] Alternatively, a pharmaceutically acceptable salt thereof is selected.

[0524] In certain embodiments, the compound of the present invention is [ka] Alternatively, a pharmaceutically acceptable salt thereof is selected.

[0525] In certain embodiments, the compound of the present invention is [ka] Alternatively, a pharmaceutically acceptable salt thereof is selected.

[0526] In certain embodiments, the compound of the present invention is [ka] Alternatively, a pharmaceutically acceptable salt thereof is selected.

[0527] Non-limiting examples of the compounds of the present invention In certain embodiments, the compound of the present invention is [ka] Alternatively, a pharmaceutically acceptable salt thereof is selected.

[0528] In certain embodiments, the compound of the present invention is [ka] Alternatively, a pharmaceutically acceptable salt thereof is selected.

[0529] In certain embodiments, the compound of the present invention is [ka] Alternatively, a pharmaceutically acceptable salt thereof is selected.

[0530] In certain embodiments, the compound of the present invention is [ka] Alternatively, a pharmaceutically acceptable salt thereof is selected.

[0531] In certain embodiments, the compound of the present invention is [ka] Selected from TIFF2026076261000157.tif88170 or a pharmaceutically acceptable salt thereof.

[0532] In certain embodiments, the compound of the present invention is [ka] Selected from TIFF2026076261000159.tif222170 or a pharmaceutically acceptable salt thereof.

[0533] In certain embodiments, the compound of the present invention is [ka] Selected from TIFF2026076261000161.tif197170 or a pharmaceutically acceptable salt thereof.

[0534] In certain embodiments, the compound of the present invention is [ka] Alternatively, a pharmaceutically acceptable salt thereof is selected.

[0535] In certain embodiments, the compound of the present invention is [ka] Selected from TIFF2026076261000164.tif203170, TIFF2026076261000165.tif204170, TIFF2026076261000166.tif152170, or a pharmaceutically acceptable salt thereof.

[0536] In certain embodiments, the compound of the present invention is [ka] Selected from TIFF2026076261000168.tif203170, TIFF2026076261000169.tif203170, or a pharmaceutically acceptable salt thereof.

[0537] In certain embodiments, the compound of the present invention is [ka] Alternatively, a pharmaceutically acceptable salt thereof is selected.

[0538] In certain embodiments, the compound of the present invention is [ka] Alternatively, a pharmaceutically acceptable salt thereof is selected.

[0539] In certain embodiments, the compound of the present invention is [ka] Alternatively, a pharmaceutically acceptable salt thereof is selected.

[0540] In certain embodiments, the compound of the present invention is [ka] Selected from TIFF2026076261000174.tif228170, TIFF2026076261000175.tif182170, TIFF2026076261000176.tif118170, or a pharmaceutically acceptable salt thereof.

[0541] In certain embodiments, the compound of the present invention is [ka] Alternatively, a pharmaceutically acceptable salt thereof is selected.

[0542] In certain embodiments, the compound of the present invention is [ka] Alternatively, a pharmaceutically acceptable salt thereof is selected.

[0543] II. Technical Terms Compounds are described using standard nomenclature. Unless otherwise specified, all technical and scientific terms used herein have the same meaning as those generally understood by those skilled in the art to which this invention pertains.

[0544] Any compound of any of the formulas described herein is a racemic mixture, an enantiomer, or an enantiomer This includes isomers such as mixtures, diastereomers, mixtures of diastereomers, tautomers, N-oxides, and rotational isomers, each described as specifically.

[0545] The terms "a" and "an" do not indicate a limit on quantity, but rather indicate the presence of at least one of the items mentioned. The term "or" means "and / or". Unless otherwise specified herein, the enumeration of value ranges is intended merely as a simple way to refer individually to each distinct value contained within that range, and each distinct value constitutes part of this specification as if they were individually listed herein. The endpoints of all ranges are contained within that range and can be combined independently. All methods described herein can be performed in a preferred order unless otherwise specified herein or clearly rejected by the context. The use of example or illustrative words (e.g., "such as") is intended merely to better illustrate the invention, and not otherwise. Unless otherwise specified, this does not indicate a limitation of the scope of the present invention. Unless otherwise specified, the technical and scientific terms used herein have the same meanings as those generally understood by those skilled in the art to which the present invention pertains.

[0546] The term "isotope analog" refers to a compound in which at least one isotopic substitution of an atom is present in greater quantities than the natural abundance of that isotope. An isotope is an atom with the same atomic number but a different mass number; that is, an atom with the same number of protons but a different number of neutrons. Non-restrictive examples of isotopic analogs of compound 1 include: [ka]

[0547] The present invention includes compounds of Formula I, Formula II, Formula III, Formula IV, Formula V, Formula VI, Formula VII, Formula VIII, Formula IX, or Formula X having at least one desired isotope substitution of an atom in an amount greater than its natural abundance of that isotope, i.e., in a concentrated state. In some embodiments, the atom is replaced with its isotope in the region of or near in vivo metabolism to produce an alpha, beta, or gamma effect.

[0548] 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, respectively. In one non-limiting embodiment, the isotope-labeled compound can be used in metabolic studies ( 14 using 2 H or 3 H), kinetic studies (e.g., 18 F-labeled compounds may be particularly desirable for PET or SPECT studies. The isotope-labeled compounds of the present invention can generally be prepared by replacing the non-isotope-labeled reagent with an isotope-labeled reagent readily available and performing the schemes or procedures disclosed in the following examples and preparations.

[0549] As a general example, but not limited to, isotopes of hydrogen such as deuterium ( 2 H) and tritium ( <000H) can be used in any part of the described structure in which the desired result is achieved. Alternatively or additionally, carbon isotopes, for example 13 C and 14 You can use C.

[0550] Isotope substitution, such as deuterium substitution, may be partial or complete. Partial deuterium substitution means that at least one hydrogen atom is replaced by deuterium. In certain embodiments, the isotope is concentrated to 90%, 95%, or 99% or more at any desired position. In one non-limiting embodiment, deuterium is concentrated to 90%, 95%, or 99% at a desired position.

[0551] In one non-limiting embodiment, the substitution of one or more hydrogen atoms for a deuterium atom may be provided in any of formulas I, II, III, IV, V, VI, VII, VIII, IX, or X. In one non-limiting embodiment, the substitution of hydrogen atoms for a deuterium atom is 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 19 Select from one of the following: Deuteration occurs within the group. For example, if any of these groups is, or contains, methyl, ethyl, or methoxy, for example by substitution, the alkyl residue can be deuterated (in non-limiting embodiments, CDH2, CD2H, CD3, CH2CD3, CD2CD3, CHDCH2D, CH2CD3, CHDCHD2, OCDH2, OCD2H, or OCD3, etc.). In certain other embodiments, if two substituents combine to form a cycle, the unsubstituted carbon can be deuterated.

[0552] The compounds of the present invention can form solvates with a solvent (including water). Therefore, in one non-limiting embodiment, the present invention includes compounds in solvated form. The term "solvate" refers to a molecular complex of the compound of the present invention (including its salts) with one or more solvent molecules. Non-limiting examples of solvents include water, ethanol, dimethyl sulfoxide, acetone, and other common organic solvents. The term "hydrate" refers to a molecular complex containing the compound of the present invention and water. Pharmaceutically acceptable solvates according to the present invention include those in which the solvent can be isotope-substituted, such as D2O, d6-acetone, and d6-DMSO. Solvates may be in liquid or solid form.

[0553] A horizontal line ("-") between two letters or symbols is used to indicate a bonding point to a substituent. For example, -(C=O)NH2 is bonded by the carbon of the keto (C=O) group.

[0554] "Alkyl" refers to a branched or linear saturated aliphatic hydrocarbon group. In one non-limiting embodiment, an alkyl group contains 1 to about 12 carbon atoms, more commonly 1 to about 6 carbon atoms, or 1 to about 4 carbon atoms. In one non-limiting embodiment, an alkyl group contains 1 to about 8 carbon atoms. In certain embodiments, an alkyl group is C1-C2, C1-C3, C1-C4, C1-C5, or C1-C6. The designations used herein refer to alkyl groups having members in each range that are described as independent species. For example, the term C1-C6 alkyl as used herein refers to linear or branched alkyl groups having 1, 2, 3, 4, 5, or 6 carbon atoms, and is intended to mean that these are each described as independent species. For example, the term C1-C4 alkyl as used herein refers to linear or branched alkyl groups having 1, 2, 3, or 4 carbon atoms, and is intended to mean that these are each described as independent species. Examples of alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, t-butyl, n-pentyl, isopentyl, tert-pentyl, neopentyl, n-hexyl, 2-methylpentane, 3-methylpentane, 2,2-dimethylbutane, and 2,3-dimethylbutane. However, it is not limited to these. In alternative embodiments, alkyl groups are optionally substituted. The term "alkyl" also includes cycloalkyl or carbocyclic groups. For example, when a term containing "alk" is used, it is not clearly excluded by context. To the extent that it is defined, "cycloalkyl" or "carbocyclic" may be part of the definition. For example, without limitation, terms such as alkyl, -O-alkyl, and haloalkyl may all be considered to include the cyclic form of alkyl unless clearly excluded by the context.

[0555] As used herein, “substituted alkyl” refers to an alkyl group substituted with the substituents listed. If no substituent is explicitly listed, “substituted alkyl” refers to 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-heterocyclic, heterocyclic, -COO-aryl This refers to alkyl groups substituted with one, two, three, or four substituents independently selected from -CO aryl, -CONH aryl, -CON(alkyl)(aryl), -OC(O) aryl, -NHC(O) aryl, -NalkylC(O) aryl, -CO heteroaryl, -CO heteroaryl, -CONH heteroaryl, -CON(alkyl)(heteroaryl), -OC(O) heteroaryl, -NHC(O) heteroaryl, -NalkylC(O) heteroaryl, -CO heterocycle, -CO heterocycle, -CONH heterocycle, -CON(alkyl)(heterocycle), -OC(O) heterocycle, -NHC(O) heterocycle, and -NalkylC(O) heterocycle.

[0556] An "alkenyl" is a linear or branched aliphatic hydrocarbon group having one or more carbon-carbon double bonds that can occur at stable points along the chain. The specified range as used herein refers to an alkenyl group having each member in the range described above as an independent species for the alkyl moiety. Examples of alkenyl radicals include, but are not limited to, ethenyl, propenyl, allyl, propenyl, butenyl, and 4-methylbutenyl. The term "alkenyl" also includes "cis" and "trans" alkenyl configurations, or alternatively, "E" and "Z" alkenyl configurations. In alternative embodiments, the alkenyl group is optionally substituted. The term "alkenyl" also includes cycloalkyl or carbocyclic groups having at least one unsaturated point. As used herein, "substituted alkenyl" may be substituted with the groups described above for the alkyl.

[0557] An "alkynyl" is a branched or linear aliphatic hydrocarbon group having one or more carbon-carbon triple bonds that can occur at any stable point along the chain. The specified range as used herein refers to an alkynyl group having each member of the range described above as an independent species for the alkyl moiety. Examples of alkynyls 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 alternative embodiments, the alkynyl group may be optionally substituted. The term "alkynyl" also encompasses cycloalkyl or carbocyclic groups having at least one unsaturated point. As used herein, "substituted alkynyl" may be substituted with the groups described above for the alkyl.

[0558] "Halo" and "halogen" refer to fluorine, chlorine, bromine, or iodine.

[0559] A "haloalkyl" is a branched or linear alkyl group substituted with one or more of the above-mentioned halo atoms up to the maximum allowable number of halogen atoms. An example of a haloalkyl group is fluoromethyl. Examples include, but are not limited to, difluoromethyl, trifluoromethyl, chloromethyl, dichloromethyl, trichloromethyl, pentafluoroethyl, heptafluoropropyl, difluorochloromethyl, dichlorofluoromethyl, difluoroethyl, difluoropropyl, dichloroethyl, and dichloropropyl. "Perhaloalkyl" means an alkyl group in which all hydrogen atoms are replaced by halogen atoms. Examples include, but are not limited to, trifluoromethyl and pentafluoroethyl.

[0560] As used herein, "aryl" refers to a radical ("C") of a monocyclic or polycyclic (e.g., bicyclic or tricyclic) 4n+2 aromatic ring system having 6 to 14 ring carbon atoms and 0 heteroatoms within the aromatic ring system (e.g., 6, 10, or 14 π electrons shared in a cyclic configuration). 6~14 This refers to "aryl". In some embodiments, the aryl group has six ring carbon atoms ("C6 aryl", e.g., phenyl). In some embodiments, the aryl group has ten ring carbon atoms ("C6 aryl"). 10 "Aryl" (for example, naphthyl such as 1-naphthyl and 2-naphthyl). In some embodiments, the aryl group has 14 ring carbon atoms ("C"). 14 "Aryl," for example, anthracyl. "aryl" includes ring systems in which the above-specified aryl ring is fused with one or more cycloalkyl or heterocyclic groups, and the radical or bond site is on the aryl ring, in which case the number of carbon atoms continues to specify 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" refers to an aryl group substituted with the substituents described. If a substituent is not explicitly stated, "substituted aryl" refers to 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-heterocyclic, heterocyclic, -COO-alkyl This refers to an aryl group substituted with one, two, three, or four substituents independently selected from the following: aryl, -CO aryl, -CONH aryl, -CON(alkyl)(aryl), -OC(O) aryl, -NHC(O) aryl, -NalkylC(O) aryl, -CO heteroaryl, -CO heteroaryl, -CONH heteroaryl, -CON(alkyl)(heteroaryl), -OC(O) heteroaryl, -NHC(O) heteroaryl, -NalkylC(O) heteroaryl, -CO heterocycle, -CO heterocycle, -CONH heterocycle, -CON(alkyl)(heterocycle), -OC(O) heterocycle, -NHC(O) heterocycle, and -NalkylC(O) heterocycle.

[0561] The terms "heterocyclyl" and "heterocycle" include saturated and partially saturated heteroatom-containing ring radicals, where the heteroatom may be selected from nitrogen, sulfur, boron, silicon, and oxygen. Heterocycles include monocyclic rings with 3 to 10 members and bicyclic ring systems with 5 to 16 members (which may include bridged fusion and spirofused bicyclic ring systems). Heterocycles do not include rings containing -OO-, -OS-, or -SS- 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, pyrrolidinyl, piperazinyl), saturated 3- to 6-membered heteromonocyclic groups containing 1 or 2 oxygen atoms and 1 to 3 nitrogen atoms (e.g., morpholinyl), and saturated 3- to 6-membered heteromonocyclic groups containing 1 or 2 sulfur atoms and 1 to 3 nitrogen atoms (e.g., thiazolidinyl). Examples of partially saturated heterocyclic radicals include, but are not limited to, dihydrothienyl, dihydropyranyl, dihydrofuryl, and dihydrothiazolyl. Examples of partially saturated and saturated heterocyclic groups include pyrrolidinyl, imidazolidinyl, piperidinyl, pyrrolidinyl, pyrazolidinyl, piperazinyl, morpholinyl, tetrahydropyranyl, thiazolidinyl, dihydrothienyl, 2,3-dihydro-benzo[1,4]dioxanyl, indolinyl, isoindolinyl, dihydrobenzothienyl, dihydrobenzofuryl, isochromanil, chromanil, 1,2-dihydroquinolyl, 1,2,3,4-tetrahydro-isoquinolyl, Examples include, but are not limited to, 1,2,3,4-tetrahydroquinolyl, 2,3,4,4a,9,9a-hexahydro-1H-3-azafluorenyl, 5,6,7-trihydro-1,2,4-triazolo[3,4-a]isoquinolyl, 3,4-dihydro-2H-benzo[1,4]oxazinyl, benzo[1,4]dioxanyl, 2,3-dihydro-1H-1λ'-benzo[d]isothiazolyl-6-yl, dihydropyranyl, dihydrofuryl, and dihydrothiazolyl. As used herein, "substituted heterocycle" means a heterocyclic group substituted with any of the substituents described.Unless a substituent is explicitly stated, "substituted heterocycle" refers to 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, -CO This refers to a heterocyclic group substituted with one, two, three, or four substituents independently selected from O-aryl, -CO-aryl, -CONH-aryl, -CON(alkyl)(aryl), -OC(O)-aryl, -NHC(O)-aryl, -N-alkylC(O)-aryl, -CO-heteroaryl, -CONH-heteroaryl, -CON(alkyl)(heteroaryl), -OC(O)-heteroaryl, -NHC(O)-heteroaryl, -N-alkylC(O)-heteroaryl, -CO-heterocyclic, -CO-heterocyclic, -CONH-heterocyclic, -CON(alkyl)(heterocyclic), -OC(O)-heterocyclic, -NHC(O)-heterocyclic, and -N-alkylC(O)-heterocyclic.

[0562] "Heterocyclic groups" also include groups in which a heterocyclic radical is fused / condensed with an aryl or carbocyclic radical, with the bonding site being the heterocyclic ring. Examples include partially unsaturated condensed heterocyclic groups containing 1 to 5 nitrogen atoms, such as indoline and isoindoline; partially unsaturated condensed heterocyclic groups containing 1 or 2 oxygen atoms and 1 to 3 nitrogen atoms; partially unsaturated condensed heterocyclic groups containing 1 or 2 sulfur atoms and 1 to 3 nitrogen atoms; and saturated condensed heterocyclic groups containing 1 or 2 oxygen or sulfur atoms.

[0563] The term "heteroaryl" refers to a stable aromatic ring system containing one or more heteroatoms selected from O, N, and S, where the ring nitrogen and sulfur atoms (may be multiple) are optionally oxidized, and the nitrogen atoms (may be multiple) are optionally quaternarixated. Examples include unsaturated 5- or 6-membered heteromonocyclyl groups containing one to four nitrogen atoms, such as pyrrolyl, imidazolyl, pyrazolyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, pyrimidyl, pyrazinyl, pyridadinyl, and triazolyl (e.g., 4H-1,2,4-triazolyl, 1H-1,2,3-triazolyl, 2H-1,2,3-triazolyl); unsaturated 5- or 6-membered heteromonocyclic groups containing an oxygen atom, such as pyranyl, 2-furyl, 3-furyl, etc.; and unsaturated 5- or This includes six-membered heteromonocyclic groups, e.g., 2-thienyl, 3-thienyl; unsaturated five- or six-membered heteromonocyclic groups containing one or two oxygen atoms and one to three nitrogen atoms, e.g., oxazolyl, isoxazolyl, oxadiazolyl (e.g., 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,5-oxadiazolyl); unsaturated five- or six-membered heteromonocyclic groups containing one or two sulfur atoms and one to three nitrogen atoms, e.g., thiazolyl, thiadiazolyl (e.g., 1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl Examples include, but are not limited to, 1,2,5-thiazolyl. In certain embodiments, the "heteroaryl" group is an 8-membered, 9-membered, or 10-membered bicyclic ring system. Examples of 8-membered, 9-membered, or 10-membered bicyclic heteroaryl groups include benzoflazanyl, benzothiophenyl, benzothiazolyl, benzoxazolyl, quinazolinyl, quinoxalinyl, naphthilidinyl, quinolinyl, isoquinolinyl, benzofuranyl, indolyl, indazolyl, and benzotriazolyl. As used herein, "substituted heteroaryl" refers to a heteroaryl group substituted with one of the substituents described. If the substituent is not explicitly stated, "substituted heteroaryl" refers to 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-heterocyclic, heterocyclic, -COO- This refers to a heteroaryl group substituted with one, two, three, or four substituents independently selected from the following: riel, -CO aryl, -CONH aryl, -CON(alkyl)(aryl), -OC(O) aryl, -NHC(O) aryl, -NalkylC(O) aryl, -CO heteroaryl, -CONH heteroaryl, -CON(alkyl)(heteroaryl), -OC(O) heteroaryl, -NHC(O) heteroaryl, -NalkylC(O) heteroaryl, -CO heterocycle, -CO heterocycle, -CONH heterocycle, -CON(alkyl)(heterocycle), -OC(O) heterocycle, -NHC(O) heterocycle, and -NalkylC(O) heterocycle.

[0564] The term "sulfonyl," whether used alone or in conjunction with other terms such as alkylsulfonyl, represents a divalent radical -SO2-.

[0565] "Alkyl-heterocyclic" refers to an alkyl group as defined herein having a heterocyclic substituent. Examples, but not limited to, include piperidylmethyl and morpholinylethyl.

[0566] "Alkyl-aryl" refers to an alkyl group as defined herein, having an aryl substituent. Non-limiting examples of alkyl-aryl groups include: [ka]

[0567] "Alkyl-heteroaryl" refers to an alkyl group as defined herein having a heteroaryl substituent. Non-limiting examples of alkyl-heteroaryl groups include: [ka]

[0568] As used herein, "carbocykyl," "carbocyclic," "carbocyclic," or "cycloalkyl" refers to a non-aromatic ring system containing all carbocyclic atoms and 3 to 14 ring carbon atoms ("C"). 3~14 A saturated or partially unsaturated (i.e., non-aromatic) group containing 3 to 10 ring carbon atoms ("C"). In some embodiments, the cycloalkyl group contains 3 to 10 ring carbon atoms ("C"). 3~10 The cycloalkyl group has 3 to 9 ring carbon atoms ("C"). In some embodiments, the cycloalkyl group has 3 to 9 ring carbon atoms ("C"). 3~9 The cycloalkyl group has 3 to 8 ring carbon atoms ("C"). In some embodiments, the cycloalkyl group has 3 to 8 ring carbon atoms ("C"). 3~8 The cycloalkyl group has 3 to 7 ring carbon atoms ("C"). In some embodiments, the cycloalkyl group has 3 to 7 ring carbon atoms ("C"). 3~7 The cycloalkyl group has 3 to 6 ring carbon atoms ("C"). In some embodiments, the cycloalkyl group has 3 to 6 ring carbon atoms ("C"). 3~6The cycloalkyl group has 4 to 6 ring carbon atoms ("C"). In some embodiments, the cycloalkyl group has 4 to 6 ring carbon atoms ("C"). 4~6 The cycloalkyl group has 5 to 6 ring carbon atoms ("C"). In some embodiments, the cycloalkyl group has 5 to 6 ring carbon atoms ("C"). 5~6 The cycloalkyl group has 5 to 10 ring carbon atoms ("C"). In some embodiments, the cycloalkyl group has 5 to 10 ring carbon atoms ("C"). 5~10 It has a cycloalkyl compound. Exemplary C 3~6 Examples of cycloalkyl groups include, but are not limited to, cyclopropyl (C3), cyclopropenyl (C3), cyclobutyl (C4), cyclobutenyl (C4), cyclopentyl (C5), cyclopentenyl (C5), cyclohexyl (C6), cyclohexenyl (C6), and cyclohexadienyl (C6). 3~8 The cycloalkyl group is not limited to the above C 3~6 Examples of cycloalkyl groups include cycloheptyl (C7), cycloheptenyl (C7), cycloheptadienyl (C7), cycloheptatrienyl (C7), cyclooctyl (C8), and cyclooctenyl (C8). 3~10 The cycloalkyl group is not limited to the above C 3~8 Alongside cycloalkyl groups, there are cyclononyl (C9), cyclononenyl (C9), and cyclodecyl (C9). 10 ), cyclodecenyl (C 10 Examples include the above. As illustrated in the above examples, in certain embodiments, the cycloalkyl group may be saturated or contain one or more carbon-carbon double or triple bonds. In alternative embodiments, "cycloalkyl" also includes ring systems in which the cycloalkyl ring is fused with one heterocycle, aryl, or heteroaryl ring as defined above, and the bonding site is on the cycloalkyl ring, in which case the number of carbon atoms remains the number of carbon atoms in the carbocyclic ring system. In alternative embodiments, the cycloalkyl group is optionally substituted with one or more substituents in any case. In certain embodiments, the cycloalkyl group is unsubstituted C 3~14 It is a cycloalkyl group.

[0569] "Alkyl-cycloalkyl" refers to an alkyl group as defined herein having a cycloalkyl substituent. Non-limiting examples of alkyl-cycloalkyl groups include: [ka]

[0570] As used herein, the term "oxo" refers to an oxygen atom bonded by a double bond.

[0571] As used herein, "intrinsic resistance," also known as primary resistance, refers to a condition in which cancer does not respond to the inhibitory effects of initial CDK4 / 6 inhibitor treatment. Mutations and conditions associated with intrinsic resistance to CDK4 / 6 inhibitors include, but are not limited to, cyclin-dependent kinase 1 (CDK1) activity. Examples include increased sex; increased activity of cyclin-dependent kinase 2 (CDK2); loss, deficiency, or absence (Rb null) of retinoblastoma tumor suppressor protein (Rb); high levels of p16Ink4a expression; high levels of MYC expression; increased expression of cyclin E1, cyclin E2, and cyclin A; and combinations thereof. Cancer may be characterized by decreased expression of retinoblastoma tumor suppressor protein or retinoblastoma family member proteins (one or more) (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 experience substantial G1 cell cycle arrest upon exposure to a selective CDK4 / 6 inhibitor. In certain embodiments, a tumor or cancer that is endogenously resistant to CDK4 / 6 inhibitor inhibition is a tumor or cancer having a cell population in which less than 25%, 20%, 15%, 10%, or 5% of its cells experience G1 cell cycle arrest when exposed to a selective CDK4 / 6 inhibitor.

[0572] As used herein, “acquired resistance” refers to a condition in which cancer that was initially sensitive to or sensitive to the inhibitory effect of at least one selective CDK4 / 6 inhibitor becomes unresponsive or poorly responsive to the effect of that selective CDK4 / 6 inhibitor over time. While we do not wish to be bound by any theory, acquired resistance to CDK4 / 6 inhibitors is thought to result from one or more additional mutations or genetic changes in bypass signaling that develop after the initiation of a CDK4 / 6 inhibitor treatment regimen. For example, non-exclusive exemplary causes of acquired resistance to CDK4 / 6 inhibitors may be the result of the development of one or more genetic abnormalities associated with “endogenous resistance.” Furthermore, other non-limiting exemplary causes of acquired resistance to CDK4 / 6 inhibitors include increased cyclin E expression; CCNE1 / 2 amplification; E2F amplification; CDK2 amplification; CDK6 amplification; CDK4 amplification; p16 amplification; WEE1 overexpression; MDM2 overexpression; CDK7 overexpression; FZR1 deficiency; HDAC activation; FGFR pathway activation; PI3K / AKT / mTOR pathway activation; loss of ER or PR expression; increased AP-1 transcriptional activity; epithelial-mesenchymal transition; Smad3 suppression; autophagy activation; Rb1 deficiency or inactivated RB1 mutation; or combinations thereof. A review of CDK4 / 6 resistance mechanisms can be found, for example, in Pandey et al., Molecular mechanisms of resistance to CDK4 / 6 inhibitors in breast cancer: A review. Int. J. Cancer:00,1-10 (2019), which is incorporated herein by reference. In certain embodiments, a tumor or cancer that has acquired resistance to the inhibition of a selective CDK4 / 6 inhibitor is a tumor or cancer in which the cell population as a whole no longer experiences 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 in which 50%, 40%, 30%, 20%, 15%, 10%, or less than 5% of its cells experience G1 cell cycle arrest upon exposure to the selective CDK4 / 6 inhibitor, leading to disease progression.

[0573] The determination of endogenous resistance to selective CDK4 / 6 inhibitors can be made via any of the standard assays known to those skilled in the art, for example, by determining the loss or absence (Rb null) of retinoblastoma (Rb) tumor suppressor protein. For example, the Rb status in cancer can be determined by, but is not limited to, Western blotting, ELISA (enzyme-linked immunosorbent assay), IHC (immunohistochemistry), and FACS (fluorescence-activated cell sorting). The choice of assay depends on the tissue, cell line, or alternative tissue sample used; for example, Western blotting and ELISA can be used for, for example, any type of tissue, cell line, or alternative tissue, while IHC methods may be more appropriate when the tissue used in the methods described herein is a tumor biopsy. FACs analysis is most applicable to single-cell suspension samples such as cell lines and isolated peripheral blood mononuclear cells. For example, U.S. Patent Application Publication No. 20070212736, "Functional Immunohistochemical Cell Cycle Analysis as a Prognostic Indicator for Cancer" Please refer to "Ognostic Indicator for Cancer."

[0574] Alternatively, the state of the retinoblastoma gene can be determined through molecular genetic testing. Examples of molecular genetic testing for retinoblastoma include Lohmann and Gallie's "Retinoblastoma. Gene Examples include those described in "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).

[0575] Increased CDK1 or CDK2 activity, high levels of MYC expression, increased cyclin E, and increased cyclin A can be determined via any standard assay known to those skilled 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 depends on the tissue, cell line, or alternative tissue sample used; for example, Western blotting and ELISA can be used for any type of tissue, cell line, or alternative tissue, while IHC methods may be more appropriate if the tissue used in the method is a tumor biopsy. FACs analysis is most applicable to cell lines and single-cell suspension samples such as isolated peripheral blood mononuclear cells.

[0576] Many methods are available to measure markers thought to contribute to acquired resistance to CDK4 / 6 inhibitors. Current methods include immunohistochemistry (IHC), immunocytochemistry, and mass spectrometry. Alternative methods include immunofluorescence (IF) and image analysis to determine the relative amount of the target protein in formalin-fixed, paraffin-embedded (FFPE) tissue samples. Immunohistochemistry (IHC) is the most frequently used method for determining gene expression levels, but Western blotting can assess not only total expression but also isoform-specific expression. mRNA derived from the target gene can also be measured by reverse transcription polymerase chain reaction (RT-PCR).

[0577] Immunohistochemistry (IHC) and immunocytochemistry (ICC) are techniques used to localize expression and rely on the interaction of specific epitopes with antibodies. IHC refers to the use of tissue sections, while ICC refers to the use of cultured cells or cell suspensions. In both methods, positive staining is visualized using molecular labels that may be fluorescent or chromogenic. Briefly, the sample is fixed to maintain cellular integrity and then incubated with a blocking reagent to prevent nonspecific binding of antibodies. Subsequently, the sample is incubated with primary and secondary antibodies, and the signal is visualized for microscopic analysis.

[0578] Western blotting is a technique that uses three elements—size-based separation, transfer to a solid support, and visualization of the target protein using appropriate primary and secondary antibodies—to identify specific proteins from a complex mixture of proteins extracted from cells. The most common version of this method is immunoblotting. This technique is used to detect specific proteins in a given sample of tissue homogenates or extracts. The protein sample is first subjected to electrophoresis using SDS-PAGE to separate proteins according to their molecular weight. Then, the proteins are transferred to a membrane and probed using antibodies specific to the target protein.

[0579] Genomic alterations and mRNA expression can be determined by fluorescence in situ hybridization (FISH), targeted sequencing, and microarray analysis. Common mutant genes, as well as differentially expressed and co-expressed genes, can be identified.

[0580] Fluorescence in situ hybridization (FISH) is used to analyze RNA in tissues or cells. FISH is a cytogenetic technique used for sequence detection and localization. It is particularly important for defining the spatial-temporal patterns of gene expression. FISH relies on a fluorescent probe that binds to the complementary sequence of the target RNA. A series of hybridization steps are performed to achieve signal amplification of the target. This amplification is then observed using a fluorescence microscope. This technique can be used with formalin-fixed paraffin-embedded (FFPE) tissue, frozen tissue, fresh tissue, cells, and circulating tumor cells.

[0581] Targeted RNA sequencing (RNA-Seq) is a highly accurate method for selecting and sequencing specific transcripts of interest. RNA-Seq provides both quantitative and qualitative information. Targeted RNA-Seq can be achieved through either enrichment or amplicon-based approaches, both of which enable gene expression analysis focused on a target gene set. Furthermore, enrichment assays offer the ability to detect both known and novel gene fusion partners in many sample types, including formalin-fixed paraffin-embedded (FFPE) tissues. RNA enrichment provides not only quantitative expression information but also the detection of small variants and gene fusions.

[0582] Microarray analysis typically involves collecting mRNA molecules from both experimental and reference samples. For example, the reference sample might be collected from a healthy individual, while the experimental sample is collected from an individual with a disease such as cancer. The two mRNA samples are then converted to complementary DNA (cDNA), and each sample is labeled with a different colored fluorescent probe. The experimental cDNA sample may be labeled with a red fluorescent dye, while the reference cDNA may be labeled with a green fluorescent dye. The two samples are then mixed and hybridized onto a microarray slide. After hybridization, the microarray is scanned, and the expression levels of each gene printed on the slide are measured. If the expression of a particular gene is higher in the experimental sample than in the reference sample, the corresponding spot on the microarray turns red. Conversely, if the expression in the experimental sample is lower than in the reference sample, the spot turns green. Finally, if the two samples are expressed similarly, the spot turns yellow. The data collected by the microarray can be used to create gene expression profiles that show how the expression of many genes changes simultaneously in response to specific conditions or treatments.

[0583] The term “selective CDK4 / 6 inhibitor” as used in relation to the compounds described herein includes compounds that inhibit CDK4 activity, CDK6 activity, or the activity of both CDK4 and CDK6 at an IC50 molar concentration at least about 300-fold, 400-fold, 500-fold, 1000-fold, 1500-fold, 1800-fold, 2000-fold, 5000-fold, or 10000-fold lower than the IC50 molar concentration required to similarly inhibit CDK2 activity in a standard phosphorylation assay.

[0584] The term "N-oxide" as used in relation to the compounds described herein refers to the oxidation form of a molecule in which oxidation occurs at a nitrogen atom. Any nitrogen atom in any of the molecules described herein can be oxidized.

[0585] In non-limiting embodiments, the N-oxide of compound 1 may be: [ka]

[0586] In certain embodiments, any of the active compounds may be provided to patients in need in the form of an N-oxide. In certain embodiments, an N-oxide of the active compound or a precursor of the active compound is used in the manufacturing scheme. In other embodiments, the N-oxide may be a metabolite of one dose of the active compound herein and may have independent activity. By methods known to those skilled in the art, an N-oxide compound can be produced by treating the compound of interest with an oxidizing agent, such as a suitable peroxy acid or peroxide. For example, an N-oxide compound can be produced by treating a heteroaryl group, such as a pyrimidine group, with an oxidizing agent such as sodium percarbonate in the presence of a metal catalyst under mild reaction conditions. Those skilled in the art will understand that a suitable protecting group may be required to carry out the chemistry. See Jain, SL et al., "Rhenium-Catalyzed Highly Efficient Oxidations of Tertiary Nitrogen Compounds to N-Oxides Using Sodium Percarbonate as Oxygen Source," Synlett, 2261-2663, 2006. .

[0587] III. Treatment method In certain embodiments, a method is provided for treating proliferative disorders in a host, including a human, comprising administering an effective amount of a compound of formula I, II, III, IV, V, VI, VII, VIII, IX, or X as described herein, or a pharmaceutically acceptable salt, N-oxide, deuterated derivative, and / or a pharmaceutically acceptable composition thereof, in an optionally pharmaceutically acceptable carrier. Non-limiting examples of disorders 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.

[0588] When administered in an effective dose to a host including humans, the compounds of formula I, II, III, IV, V, VI, VII, VIII, IX, or X are effective in treating tumors, cancers (solid tumors, non-solid tumors, diffuse cancers, hematological cancers, etc.), abnormal cell proliferation, immune disorders, inflammatory disorders, hematological disorders, myeloproliferative disorders or lymphoproliferative disorders such as B-cell lymphoma or T-cell lymphoma, multiple myeloma, breast cancer, prostate cancer, AML, ALL, CLL, myelodysplastic syndrome (MDS), mesothelioma, renal cell carcinoma (RCC), cholangiocarcinoma, lung cancer, and pancreatic cancer. Colon cancer, skin cancer, melanoma, Waldenström macroglobulinemia, Wiscott-Aldrich syndrome, or post-transplant lymphoproliferative disorders; autoimmune disorders, such as lupus, Crohn's disease, Addison's disease, celiac disease, dermatomyositis, Graves' disease, thyroiditis, multiple sclerosis, pernicious anemia, reactive arthritis, type 1 diabetes; cardiac dysfunction, including hypercholesterolemia; infectious diseases, including viral and / or bacterial infections; asthma, chronic peptic ulcer, tuberculosis, rheumatoid arthritis, periodontitis, ulcerative colitis It is useful as a therapeutic agent for treating inflammatory conditions, including colitis or hepatitis.

[0589] 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+.

[0590] 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 EGFR inhibitors have failed (e.g., second-line therapy). In certain embodiments, ALK inhibitors have failed (e.g., second-line therapy). In certain embodiments, NSCLC has a KRAS mutation.

[0591] In certain embodiments, the compounds of the present invention are used to treat prostate cancer. In certain embodiments, the prostate cancer is castration-resistant. In certain embodiments, prior chemotherapy agents have already failed (e.g., second-line therapy).

[0592] 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, prior chemotherapy agents have already failed (e.g., second-line therapy).

[0593] In certain embodiments, the compounds of the present invention are used to treat melanoma. In certain embodiments, the melanoma has a BRAF mutation.

[0594] In certain embodiments, the compounds of the present invention are used to treat RAS-mutated cancer. In certain embodiments, the RAS-mutated cancer is colon cancer (CLC). In certain embodiments, the RAS-mutated cancer is pancreatic cancer. In certain embodiments, the RAS-mutated cancer is bile duct cancer.

[0595] In certain embodiments, the compounds of the present invention are used to treat gastrointestinal stromal tumors (GISTs). In certain embodiments, treatment with imatinib or sunitinib has already failed (e.g., second-line therapy).

[0596] Examples of proliferative disorders include, but are not limited to, benign tumors, neoplasms, tumors, cancer (Rb-positive or Rb-negative), autoimmune disorders, inflammatory disorders, graft-versus-host rejection, and fibrous disorders.

[0597] Non-limiting examples of cancers that can be treated according to the present invention include acoustic neuroma, adenocarcinoma, adrenal carcinoma, anal cancer, angiosarcoma (e.g., lymphangiosarcoma, lymphangioendotheliosarcoma), appendiceal cancer, benign monoclonal gammaglobulinemia, and biliary tract cancer. (e.g., bile duct cancer), bladder cancer, breast cancer (e.g., adenocarcinoma of the breast, papillary carcinoma of the breast, breast cancer, medullary carcinoma of the breast), brain cancer (e.g., meningioma; glioma, e.g., astrocytoma, oligodendroglioma; medulloblastoma), bronchial cancer, carcinoid tumors, cervical cancer (e.g., cervical adenocarcinoma), choriocarcinoma, chordoma, craniopharyngioma, colorectal cancer (e.g., colon cancer, rectal cancer, colorectal adenocarcinoma), epithelial carcinoma, ependymoma, endotheliosarcoma (e.g., Kaposi's sarcoma, multiple idiopathic hemorrhagic sarcoma), endometrial cancer (e.g., uterine cancer, uterine sarcoma), esophageal cancer (e.g., esophageal adenocarcinoma, Barrett's adenocarcinoma), Ewing's sarcoma, eye cancer (e.g., intraocular melanoma, retinoblastoma), familial hypereosinophilia, gallbladder cancer, gastric cancer (e.g., gastric adenocarcinoma), gastrointestinal stromal tumor (GIST), brain Neck cancer (e.g., head and neck squamous epithelial cancer), oral cancer (e.g., oral squamous epithelial cancer) (OSCC), pharyngeal cancer (e.g., laryngeal cancer, pharyngeal cancer, nasopharyngeal cancer, oropharyngeal cancer)), hematopoietic cancer (e.g., acute lymphoblastic leukemia (ALL), also known as acute lymphoblastic leukemia or acute lymphoblastic 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 Leukemias such as (CLL) (e.g., B-cell CLL, T-cell CLL); Hodgkin lymphoma (HL) (e.g., B-cell HL, T-cell HL) and non-Hodgkin lymphoma (NHL) (e.g., diffuse large cell lymphoma (DLCL) (e.g., B-cell NHL such as diffuse large B-cell lymphoma (DLBCL)), follicular lymphoma, chronic lymphocytic leukemia / small lymphocytic lymphoma (CLL / SLL), mantle cell lymphoma (MC) L) 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., "Waldenstrem macroglobulinemia"), hairy cell leukemia (HCL), immunoblastic large cell lymphoma, precursor B-lymphoblastic lymphoma, and primary central nervous system (CNS) lymphoma. Lymphomas such as leukemia; and T-cell NHLs such as progenitor 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); and mixtures of one or more of the above leukemia / lymphomas;Also, multiple myeloma (MM), heavy chain disease (e.g., alpha chain disease, gamma chain disease, μ chain disease), hemangioblastoma, inflammatory myofibroblastic neoplasm, immunocytic amyloidosis, renal cancer (e.g., nephroblastoma, also known as Wilms' tumor, renal cell carcinoma), liver cancer (e.g., hepatocellular carcinoma (HCC), malignant hepatoma), lung cancer (e.g., bronchogenic carcinoma, small cell lung cancer (SCLC), non-small cell lung cancer (NSCLC), adenocarcinoma of the lung), leiomyosarcoma (LMS), mastocytosis (e.g., systemic mastocytosis), myelodysplastic syndromes Myeloproliferative disorders (MDS), mesothelioma, myeloproliferative disorders (MPD) (e.g., polycythemia vera (PV), essential thrombocythemia (ET), idiopathic myelometropia (AMM), also known as myelofibrosis (MF), chronic idiopathic myelofibrosis, chronic myeloid leukemia (CML), chronic neutrophilic leukemia (CNL), eosinophilic syndrome (HES)), neuroblastoma, neurofibroma (e.g., neurofibromatosis type 1 or 2, schwannoma), neuroendocrine carcinoma (e.g., pancreatic gastrointestinal neuroendocrine tumor (GEP-N)) ET), carcinoid tumors, osteosarcoma, ovarian cancer (e.g., cystadenocarcinoma, ovarian embryonic carcinoma, ovarian adenocarcinoma), papillary adenocarcinoma, pancreatic cancer (e.g., pancreatic adenocarcinoma, intraductal papillary mucinous neoplasm (IPMN), islet cell tumor), penile cancer (e.g., Paget's disease of the penis and scrotum), pineal gland tumor, primitive neuroectodermal tumor (PNT), prostate cancer (e.g., prostatic adenocarcinoma), rectal cancer, rhabdomyosarcoma, salivary gland cancer, skin cancer (e.g., squamous cell carcinoma (SCC), keratoacanthoma (KA), melanoma, basal cell carcinoma) Examples of cancers that fall under this category include, but are not limited to, BCC (biocracytoma), small intestine cancer (e.g., appendiceal cancer), soft tissue sarcomas (e.g., malignant fibrous histiocytoma (MFH), liposarcoma, malignant peripheral nerve sheath tumor (MPNST), chondrosarcoma, fibrosarcoma, myxosarcoma), sebaceous gland cancer, sweat gland cancer, synoviomas, testicular cancer (e.g., seminomas, embryonal testicular cancer), thyroid cancer (e.g., papillary thyroid carcinoma, papillary thyroid carcinoma (PTC), medullary thyroid carcinoma), urethral cancer, vaginal cancer, and vulvar cancer (e.g., Paget's disease of the vulva).

[0598] In another embodiment, the disorder is myelodysplastic syndrome (MDS).

[0599] In certain embodiments, cancer is hematopoietic cancer. In certain embodiments, hematopoietic cancer is lymphoma. In certain embodiments, hematopoietic cancer is leukemia. In certain embodiments, leukemia is acute myeloid leukemia (AML).

[0600] In certain embodiments, the proliferative disorder is a myeloproliferative neoplasm. In certain embodiments, the myeloproliferative neoplasm (MPN) is primary myelofibrosis (PMF).

[0601] In certain embodiments, cancer is a solid tumor. As used herein, a solid tumor refers to an abnormal mass of tissue that does not typically contain cysts or fluid areas. Various types of solid tumors are named after the type of cells that form them. Examples of types of solid tumors include, but are not limited to, sarcomas, carcinomas and lymphomas as described 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.

[0602] In certain embodiments, the condition treated with formulas I, II, III, IV, V, VI, VII, VIII, IX, or X is a disorder related to abnormal cell proliferation.

[0603] Abnormal cell proliferation, particularly hyperproliferation, can result from a wide range of factors, including gene mutations, infections, exposure to toxins, autoimmune disorders, and the induction of benign or malignant tumors.

[0604] Numerous skin disorders are associated with cell overgrowth. For example, psoriasis is a benign disease of human skin generally characterized by plaques covered with thickened scales. This disease is caused by an increase in the proliferation of epidermal cells of unknown origin. Chronic eczema is also associated with marked epidermal overgrowth. 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.

[0605] Other hyperproliferative cell disorders include vascular disorders, fibrotic disorders, autoimmune disorders, graft-versus-host rejection, tumors, and cancers.

[0606] Vascular proliferative disorders include neovascularization and vascular disorders. The proliferation of smooth muscle cells during plaque formation in vascular tissue leads to conditions such as restenosis, retinopathy, and atherosclerosis. Both cell migration and cell proliferation play a role in the formation of atherosclerotic lesions.

[0607] Fibrotic disorders are often caused by abnormal formation of the extracellular matrix. Examples of fibrotic disorders include cirrhosis and mesangial proliferative cytotoxicity. Cirrhosis is characterized by an increase in extracellular matrix components that lead to the formation of liver scars. Cirrhosis can lead to diseases such as liver cirrhosis. The increase in extracellular matrix that leads to liver scars may also be due to viral infections such as hepatitis. Lipid cells appear to play an important role in liver cirrhosis.

[0608] Mesangial disorders are caused by the abnormal proliferation of mesangial cells. Mesangial hyperproliferative cytotoxicity includes various human kidney diseases such as glomerulonephritis, diabetic nephropathy, malignant nephrosclerosis, thrombotic microangiopathy syndrome, graft rejection, and glomerulopathy.

[0609] Another disease caused by proliferative components is rheumatoid arthritis. Rheumatoid arthritis is generally considered an autoimmune disease associated with the activity of autoreactive T cells and caused by autoantibodies produced against collagen and IgE.

[0610] Other disorders that may contain abnormal cell proliferation components include Behçet's syndrome, acute respiratory distress syndrome (ARDS), ischemic heart disease, post-dialysis syndrome, leukemia, acquired immunodeficiency syndrome, vasculitis, lipid histiocytosis, septic shock, and general inflammation.

[0611] In certain embodiments, the compounds of the present invention and their pharmaceutically acceptable derivatives, or pharmaceutically acceptable formulations containing these compounds, are also useful for the prevention and treatment of HBV infection, as well as anti-HBV antibody positivity and HBV-positive conditions, chronic hepatitis, cirrhosis, acute hepatitis, fulminant hepatitis, chronic persistent hepatitis, and other related conditions such as fatigue caused by HBV. These compounds or formulations are anti-HBV antibody or HBV antigen positive, or HBV It can also be used prophylactically to prevent or slow the progression of clinical disease in individuals exposed to it.

[0612] In certain embodiments, the pathological condition is related to an immune response.

[0613] Skin contact hypersensitivity and asthma are just two examples of immune responses that may have a significant prevalence. Other examples include atopic dermatitis, eczema, Sjögren's syndrome including keratoconjunctivitis sicca secondary to Sjögren's syndrome, alopecia areata, allergic reactions to arthropod bites, Crohn's disease, aphthous ulcers, iritis, conjunctivitis, keratoconjunctivitis, ulcerative colitis, cutaneous lupus erythematosus, scleroderma, vaginitis, proctitis, and drug eruptions. These conditions may present with one or more of the following symptoms or signs: itching, swelling, redness, blistering, crusting, ulceration, pain, desquamation, cracking, hair loss, scarring, or exudation of fluid from the skin, eyes, or mucous membranes.

[0614] In atopic dermatitis and eczema, immune-mediated leukocyte infiltration into the skin (particularly mononuclear cells, lymphocytes, neutrophils, and eosinophils) generally plays a significant role in the development of these diseases. Chronic eczema is also associated with marked epidermal hyperplasia. Immune-mediated leukocyte infiltration can occur in areas other than the skin, such as the airways in asthma and the tear-producing glands in keratoconjunctivitis sicca.

[0615] In one non-limiting embodiment, the compounds of the present invention are used as topical agents for the treatment of contact dermatitis, atopic dermatitis, eczematous dermatitis, psoriasis, Sjögren's syndrome including keratoconjunctivitis sicca secondary to Sjögren's syndrome, alopecia areata, allergic reactions due to arthropod bites, Crohn's disease, aphthous ulcers, iritis, conjunctivitis, keratoconjunctivitis, ulcerative colitis, asthma, allergic asthma, cutaneous lupus erythematosus, scleroderma, vaginitis, proctitis, and drug eruptions. This novel method may also be useful in reducing skin infiltration by malignant leukocytes in diseases such as mycosis fungoides. These compounds can also be used to treat patients suffering from tear-deficient dry eye conditions (such as immune-mediated keratoconjunctivitis) by topical administration of the compounds to the eyes.

[0616] The terms “neoplasia” or “cancer” are used throughout this specification to mean malignant or cancerous. Malignant neoplasms are used to refer to pathological processes that result in the formation and growth of abnormal tissues (solid) or cells (non-solid) that grow more rapidly than normal through cell proliferation and continue to grow even after the stimulus that initiated new growth has ceased. Malignant neoplasms exhibit a partial or complete lack of structural organization and functional coordination with normal tissue, are prone to invading surrounding tissues, may metastasize to several sites, may recur after attempted removal, and can lead to patient death if not properly treated. As used herein, the term neoplasia is used to describe all cancerous disease conditions and includes or encompasses pathological processes associated with malignant hematological malignancies, ascites tumors, and solid tumors. Exemplary cancers that can be treated with the disclosed compounds alone or in combination with at least one additional anticancer agent include squamous cell carcinoma, basal cell carcinoma, adenocarcinoma, hepatocellular carcinoma, and renal cell carcinoma, cancers of the bladder, head, kidney, and neck; leukemia; benign and malignant lymphomas, particularly Burkitt lymphoma and non-Hodgkin lymphoma; benign and malignant melanoma; myeloproliferative disorders; Ewing's sarcoma, angiosarcoma, Kaposi's sarcoma, liposarcoma, myosarcoma, peripheral nerves Sarcomas including transepithelial tumors, synovial sarcomas, gliomas, astrocytomas, oligodendrogliomas, ependymomas, glioblastomas, neuroblastomas, gangliocytomas, gangliogliomas, medulloblastomas, pineal cell tumors, meningiomas, meningiosarcomas, neurofibromas, and Schwann cell tumors; intestinal cancers, breast cancers, prostate cancers, cervical cancers, uterine cancers, lung cancers, ovarian cancers, testicular cancers, thyroid cancers, astrocytomas, esophageal cancers, pancreatic cancers, gastric cancers, liver cancers, colon cancers, melanomas; carcinosarcomas, Hodgkin's disease, Wilms' tumors, and teratomas.

[0617] Additional cancers that can be treated with the compounds disclosed according to the present invention include, for example, acute granulocytic leukemia, acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), Adenocarcinoma, adenosarcoma, adrenal carcinoma, adrenocortical carcinoma, anal carcinoma, undifferentiated astrocytoma, angiosarcoma, appendiceal carcinoma, astrocytoma, basal cell carcinoma, B-cell lymphoma, cholangiocarcinoma, bladder cancer, bone cancer, bone marrow cancer, intestinal cancer, brain cancer, brainstem glioma, breast cancer, triple (estrogen, progesterone, and HER-2) negative breast cancer, double negative breast cancer (negative for two of estrogen, progesterone, and HER-2), single negative (negative for one of estrogen, progesterone, and HER-2) (Yes), 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, cholangiocarcinoma, chondrosarcoma, chronic lymphocytic leukemia (CLL), chronic myeloid leukemia (CML), colon cancer, colorectal cancer, craniopharyngioma, cutaneous lymphoma, skin Melanoma, diffuse astrocytoma, ductal carcinoma in situ (DCIS), endometrial cancer, ependymoma, epithelioid sarcoma, esophageal cancer, Ewing's sarcoma, extrahepatic bile duct cancer, eye cancer, fallopian tube cancer, fibrosarcoma, gallbladder cancer, gastric cancer, gastrointestinal cancer, gastrointestinal carcinoid cancer, Gastrointestinal stromal tumor (GIST), germ cell tumor, glioblastoma multiforme (GBM), glioma, hairy cell leukemia, head and neck cancer, hemangioendothelioma, Hodgkin lymphoma, hypopharyngeal carcinoma, invasive ductal carcinoma (IDC), invasive lobular carcinoma (ILC), inflammatory breast cancer (IBC) Intestinal cancer, intrahepatic cholangiocarcinoma, invasive breast cancer, islet cell carcinoma, jaw cancer, Kaposi's sarcoma, kidney cancer, laryngeal cancer, leiomyosarcoma, 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 mesothelioma, metastatic breast cancer, metastatic melanoma, metastatic squamous cell carcinoma of the neck, mixed glioma, monodermal teratoma, mouth cancer, mucinous carcinoma Mucosal melanoma, multiple myeloma, mycosis fungoides, myelodysplastic syndrome, nasal cavity cancer, nasopharyngeal cancer, cervical cancer, neuroblastoma, neuroendocrine tumor (NET), non-Hodgkin lymphoma, non-small cell lung cancer (NSCLC), ophthalmic cancer, intraocular melanoma, oligodendroglioma, oral cancer, oral cancer, oropharyngeal cancer, osteogenic sarcoma, osteosarcoma, ovarian cancer, epithelial ovarian cancer, ovarian germ cell tumor, primary peritoneal cancer of the ovary Ovarian cord-stromal tumor, Paget's disease, pancreatic cancer, papillary carcinoma, paranasal sinus cancer, parathyroid cancer, pelvic cancer, penile cancer, peripheral nerve cancer, peritoneal cancer, pharyngeal cancer, pheochromocytoma, pilocytic astrocytoma, pineal gland tumor, pineoblastoma, pituitary cancer, primary central nervous system (CNS) lymphoma, prostate cancer, rectal cancer, renal cell carcinoma, renal pelvis cancer, rhabdomyosarcoma, salivary gland cancer, soft tissue sarcoma, bone sarcoma sarcoma), sarcoma, sinus cancer, skin cancer, small cell lung cancer (SCLC), small intestine cancer, spine cancer, spinal column cancer, spinal cord cancer, squamous cell carcinoma, gastric cancer, synovial sarcoma, T-cell lymphoma, testicular cancer, throat cancer, thymoma / thymic cancer, thyroid cancer, tongue cancer, tonsil cancer, transitional cell carcinoma, fallopian tube cancer, tubular carcinoma, undiagnosed certain cancers, ureteral cancer, urethral cancer, uterine adenocarcinoma, uterine cancer, uterine sarcoma, vaginal cancer, vulvar cancer, T-cell acute lymphoblastic leukemia (T-ALL), T-cell lymphoblastic lymphoma (T-LL), peripheral T-cell lymphoma, adult T-cell leukemia, Pre-B ALL, Pre-B lymphoma, Large B-cell lymphoma, Burkitt lymphoma, B-cell ALL, Philadelphia chromosome-positive ALL, Philadelphia chromosome-positive CML, Juvenile myelomonocytic leukemia (JMML), Acute promyelocytic leukemia (a subtype of AML), Large granular lymphocytic leukemia, Adult T-cell chronic leukemia, Diffuse large B-cell lymphoma, Follicular lymphoma; Mucosa-associated lymphoid tissue lymphoma (MALT), Small cell lymphocytic lymphoma, Mediastinal large B-cell lymphoma, Nodal marginal zone B-cell lymphoma (NMZL); Splenic marginal zone lymphoma (SMZL); Intravascular large B-cell lymphoma; Primary exudative lymphoma; or Lymphomatoid granulomatosis; B-cell prelymphocytic leukemia; Unclassified splenic lymphoma / leukemia Hematological diseases, diffuse red pulp small B-cell lymphoma; lymphoplasmacytic lymphoma; heavy chain diseases, e.g., α-heavy chain disease, γ-heavy chain disease, μ-heavy chain disease, plasmacytogenic myeloma, solitary plasmacytoma of bone; extraskeletal plasmacytoma; primary cutaneous follicular lymphoma, T-cell / histiocyte-rich large B-cell lymphoma, DLBCL associated with chronic inflammation; Epstein-Barr virus (EBV) + DLBCL in the elderly; primary mediastinal (thymic) large B-cell lymphoma, primary cutaneous DLBCL lower extremity type, ALK + large B-cell lymphoma, plasmablastic lymphoma; large B-cell lymphoma arising in HHV8-associated multicentric Castleman disease; unclassifiable B-cell lymphoma with intermediate features of diffuse large B-cell lymphoma, or diffuse large B-cell lymphoma One example is unclassifiable B-cell lymphoma, which has characteristics intermediate between follicular lymphoma and classical Hodgkin lymphoma.

[0618] In another embodiment, a method is provided for increasing BIM expression (e.g., BCLC2L11 expression) to induce apoptosis in cells, comprising contacting cells with a compound of the present invention, or a pharmaceutically acceptable composition, salt, or isotope analog thereof. In certain embodiments, the method is an in vitro method. In certain embodiments, the method is an in vivo method. BCL2L11 expression is tightly regulated in cells. BCL2L11 encodes 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 suppression of BCL2L11 expression confers resistance to tyrosine kinase inhibitors. See, for example, Ng et al., Nat. Med. (2012) 18:521-528.

[0619] In another embodiment, a method is provided for treating conditions associated with angiogenesis, such as diabetic conditions (e.g., diabetic retinopathy), inflammatory conditions (e.g., rheumatoid arthritis), macular degeneration, obesity, atherosclerosis, or proliferative disorders, comprising administering the compound of the present invention, or a pharmaceutically acceptable composition, salt, or isotope analog thereof, to a subject in need of treatment.

[0620] In certain embodiments, the condition associated with angiogenesis is macular degeneration. In certain embodiments, a method for treating macular degeneration is provided, comprising administering the compound of the present invention, or a pharmaceutically acceptable composition, salt, or isotope analog thereof, to a subject in need of treatment.

[0621] In certain embodiments, the condition associated with angiogenesis is obesity. As used herein, “obesity” and “obese” refer to Class I obesity, Class II obesity, Class III obesity, and pre-obesity (e.g., “overweight”) as defined by the World Health Organization. In certain embodiments, treatment is necessary A method for treating obesity is provided, comprising administering the compound of the present invention, or a pharmaceutically acceptable composition, salt, or isotope analog thereof, to a subject.

[0622] In certain embodiments, the pathological condition associated with angiogenesis is atherosclerosis. In certain embodiments, a method for treating atherosclerosis is provided, comprising administering the compound of the present invention, or a pharmaceutically acceptable composition, salt, or isotope analog thereof, to a subject in need of treatment.

[0623] In certain embodiments, the pathological condition associated with angiogenesis is a proliferative disorder. In certain embodiments, a method is provided for treating a proliferative disorder, comprising administering the compound of the present invention, or a pharmaceutically acceptable composition, salt, or isotope analog thereof, to a subject in need.

[0624] IV. Methods to reduce side effects related to chemotherapy In certain embodiments, the compounds of the present invention reduce the toxic effects of chemotherapeutic agents on subjects exposed to, having been exposed to, or having been exposed to chemotherapeutic agents (typically DNA damaging agents), typically hematopoietic stem cells and hematopoietic progenitor cells (both referred to as HSPCs) in humans, and / or CDK4 / 6 replication-dependent healthy cells such as renal epithelial cells.

[0625] In certain embodiments, the subject is exposed to a chemotherapeutic agent, and to mitigate DNA damage, for example, the compounds described herein are used to modify the subject's CDK4 / 6 polymorphism. 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 more after exposure to the chemotherapeutic agent.

[0626] In certain embodiments, the compound can enable dose intensification in medical-related chemotherapy (e.g., allowing more therapy to be administered over a period of time), which leads to better efficacy. Therefore, the methods of the present disclosure can result in less toxic and more effective chemotherapy regimens.

[0627] In some embodiments, the use of the compounds described herein can reduce or substantially eliminate off-target effects related to the inhibition of kinases other than CDK4 and / or CDK6 and / or CDK2, for example. Furthermore, in certain embodiments, the use of the compounds described herein does not induce cell cycle arrest in CDK4 / 6 replication-independent cells.

[0628] In some embodiments, the use of the compounds described herein reduces the risk of undesirable off-target effects, including but not limited to long-term toxicity, antioxidant effects, and estrogen-like effects. Antioxidant effects can be determined by standard assays known in the art. For example, compounds with no significant antioxidant effect are those that do not significantly remove free radicals such as oxygen radicals. The antioxidant effect of a compound can be compared to known antioxidant compounds such as genistein. Therefore, compounds with no significant antioxidant activity may have antioxidant activity that is about 2, 3, 5, 10, 30, or 100 times less than genistein. Estrogen-like activity can also be determined by known assays. For example, non-estrogen compounds are those that do not significantly bind to or activate estrogen receptors. Compounds with substantially no estrogen-like effect may have estrogen-like activity that is about 2, 3, 5, 10, 20, or 100 times less than compounds with estrogen-like activity, such as genistein.

[0629] V. Methods for treating abnormal proliferation of T cells, B cells, and / or NK cells. In certain embodiments, the present invention involves the use of an effective amount of a compound described herein, or a pharmaceutically acceptable salt thereof or an isotopic analog thereof, in an optionally pharmaceutically appropriate composition for treating a host, typically human, having selected cancer, tumor, hyperproliferative condition, or inflammatory or immunodeficiency. Some of the compounds disclosed are highly active against T-cell proliferation. Given the scarcity of drugs for T-cell cancer and hyperproliferation, such use would represent a significant improvement in the pharmacotherapy of these diseases.

[0630] Abnormal proliferation of T cells, B cells, and / or NK cells can lead to a wide range of diseases, including cancer, proliferative disorders, and inflammatory / immune diseases. Treating a host suffering from any of these disorders, such as a human, with an effective amount of the compounds described herein can reduce (palliative) the symptoms. Achieve a reduction in underlying disease (disease-modifying agent) It is possible.

[0631] Examples include T-cell or NK-cell lymphomas, such as peripheral T-cell lymphomas (but not limited to these); anaplastic large cell lymphomas, such as anaplastic lymphoma kinase (ALK)-positive, ALK-negative, or primary cutaneous anaplastic large cell lymphomas; angioimmunoblastic lymphomas; and cutaneous T-cell lymphomas, such as mycosis fungoides, Sézary syndrome, and primary cutaneous lymphomas. Cutaneous anaplastic large cell lymphoma, primary cutaneous CD30+ T-cell lymphoproliferative disorder; primary cutaneous progressive epidermotropic CD8+ cytotoxic T-cell lymphoma; primary cutaneous γ-δ T-cell lymphoma; primary cutaneous small / medium-cell CD4+ T-cell lymphoma, and adult T-cell leukemia / lymphoma (ATLL); blastic NK-cell lymphoma; enteropathic T-cell lymphoma; hepatosplenic γ-δ T-cell lymphoma; lymphoblastic lymphoma; nasal NK / T-cell Lymphoma; treatment-related T-cell lymphoma; for example, lymphoma occurring after solid organ or bone marrow transplantation; T-cell pre-lymphocytic leukemia; T-cell macrogranular lymphocytic leukemia; chronic lymphoproliferative disorder of NK cells; rapidly progressive NK-cell leukemia; systemic EBV + T-cell lymphoproliferative disorder in children (associated with chronic active EBV infection); vaccinia-like varicella-like lymphoma; adult T-cell leukemia / lymphoma; enteropathy-associated T-cell lymphoma; hepatosplenic T-cell lymphoma; or subcutaneous panniculitis-like T-cell lymphoma.

[0632] In certain embodiments, the compounds disclosed herein, or their salts or isotopic analogs thereof, can be used in effective amounts to treat a host, such as a human, with lymphoma or lymphocytic or myeloid proliferative disorders or abnormalities. For example, the compounds described herein can be administered to a host suffering from Hodgkin lymphoma or non-Hodgkin lymphoma. For example, the host may have, but is not limited to, AIDS-related lymphoma; anaplastic large cell lymphoma; angioimmunoblastic lymphoma; blastic NK cell lymphoma; Burkitt lymphoma; Burkitt-like lymphoma (small, non-incisional nuclear cell lymphoma); chronic lymphocytic leukemia / small lymphocytic lymphoma; cutaneous T-cell lymphoma; diffuse large B-cell lymphoma; enteropathy-type T-cell lymphoma; follicular lymphoma; hepatosplenic γ-δ 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; transforming lymphoma; treatment-related T-cell lymphoma; or non-Hodgkin lymphoma such as Waldenström macroglobulinemia.

[0633] Alternatively, the compounds disclosed herein, or their salts or isotopic analogs thereof, can be used in effective amounts to treat hosts, such as humans, who have Hodgkin lymphomas including tuberous sclerosis classical Hodgkin lymphoma (CHL); mixed cell type CHL; lymphopenic CHL; lymphocyte-rich CHL; lymphocyte-dominant Hodgkin lymphoma; or nodular lymphocyte-dominant HL.

[0634] Alternatively, the compounds disclosed herein, or their salts or isotopic analogs, may include, but are 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 exudative lymphoma; or lymphomatoid granulomatosis; B-cell prelymphocytic leukemia; hairy cell leukemia; unclassifiable splenic lymphoma / leukemia; diffuse red pulp small B-cell lymphoma; hairy cell leukemia subtype; lymphoplasmacytic lymphoma; heavy chain disease, e.g., α-heavy chain disease, γ-heavy chain disease, μ-heavy chain disease; plasmacytic myeloma; solitary plasmacytoma of bone; extraosseous It can be used in effective doses to treat specific B-cell lymphomas or proliferative disorders in hosts, such as humans, including plasmacytoma; primary cutaneous follicular lymphoma; T-cell / histiocyte-rich large B-cell lymphoma; DLBCL associated with chronic inflammation; Epstein-Barr virus (EBV) + DLBCL in the elderly; primary mediastinal (thymic) large B-cell lymphoma; primary cutaneous DLBCL (lower extremity type); ALK + large B-cell lymphoma; plasmablastic lymphoma; large B-cell lymphoma occurring in HHV8-associated multicentric Castleman disease; unclassifiable B-cell lymphoma with intermediate characteristics between diffuse large B-cell lymphoma; or unclassifiable B-cell lymphoma with intermediate characteristics between diffuse large B-cell lymphoma and classical Hodgkin lymphoma.

[0635] In certain embodiments, the compounds disclosed herein, or their salts or isotopic analogs thereof, can be used in effective amounts to treat a host having leukemia, such as a human. For example, the host may have, but is 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); macrogranular lymphocytic leukemia; or acute or chronic leukemia of lymphocyte or myeloid origin, such as adult T-cell chronic leukemia. In certain embodiments, the patient suffers from acute myeloid leukemia, such as undifferentiated AML (M0); myeloblastic leukemia (M1; with / without minimal cellular maturation); myeloblastic leukemia (M2; with cellular maturation); promyelocytic leukemia (M3 or subtype M3 (M3V)); myelomonocytic leukemia (M4 or subtype M4 with eosinophilia (M4E)); monocytic leukemia (M5); erythroleukemia (M6); or megakaryoblastic leukemia (M7).

[0636] VI. Pharmaceutical compositions and dosage forms The active compounds described herein, or their salts or isotopic analogs thereof, may be administered to a host in an effective dose to treat any of the disorders described herein using any preferred approach to achieve the desired therapeutic outcome. The amount and timing of administration of the active compound will naturally depend on the host being treated, the instructions of the attending physician, the time course of exposure, the method of administration, the pharmacokinetic properties of the specific active compound, and the judgment of the prescribing physician. Therefore, due to inter-host variability, the following dosages are guidelines, and the physician can determine the dosage of the compound and achieve the treatment that the physician deems appropriate for the host. In considering the desired degree of treatment, the physician can balance various factors such as the host's age and weight, the presence of pre-existing diseases, and the presence of other diseases.

[0637] Pharmaceutical compositions can be formulated in any pharmaceutically useful form, such as aerosols, creams, gels, pills, injections or infusions, capsules, tablets, syrups, transdermal patches, subcutaneous patches, dry powders, inhalation formulations in medical devices, suppositories, oral or sublingual formulations, parenteral formulations, or eye drops. Some dosage forms, such as tablets and capsules, can be divided into appropriate-sized unit doses containing an appropriate amount of the active ingredient, for example, an effective amount to achieve the desired purpose.

[0638] The therapeutically effective dose of any active compound described herein is determined by a healthcare professional in accordance with the patient's condition, size and age, and route of delivery. In one non-limiting embodiment, doses ranging from about 0.1 mg / kg to about 200 mg / kg are therapeutically effective, and all weights, including those using salts, are calculated based on the weight of the active compound. In certain embodiments, doses are about 0.1 mg / kg, 0.5 mg / kg, 1 mg / kg, 5 mg / kg, 10 mg / kg, 25 mg / kg, 50 mg / kg, 75 mg / kg, 100 mg / kg, 125 mg / kg, 150 mg / kg, 175 mg / kg, or 200 mg / kg or more. In some embodiments, the dose may be the amount of compound required to produce serum concentrations of the active compound up to approximately 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.

[0639] In certain embodiments, the pharmaceutical composition is in a dosage form containing about 0.1 mg to about 2000 mg, about 10 mg to about 1000 mg, about 100 mg to about 800 mg, or about 200 mg to about 600 mg of an active compound in a unit dosage form, and optionally about 0.1 mg to about 2000 mg, about 10 mg to about 1000 mg, about 100 mg to about 800 mg, or about 200 mg to about 600 mg of an additional active agent. Examples of dosage forms include at least 5 mg, 10 mg, 15 mg, 20 mg, 25 mg, 50 mg, 100 mg, 200 mg, 250 mg, The pharmaceutical composition may also contain 300 mg, 400 mg, 500 mg, 600 mg, 700 mg, or 750 mg of the active compound or a salt thereof.

[0640] In some embodiments, the compounds used as disclosed or described herein are administered once daily (QD), twice daily (BID), or three times daily (TID). In some embodiments, the compounds used as disclosed or described herein 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.

[0641] Compounds disclosed herein or used as described herein may be administered orally, topically, parenterally, by inhalation or spray, sublingually, by implant including ocular implants, percutaneously, by oral administration, rectally, as injections including ophthalmic solutions and intraocular injections, intravenously, intramuscularly, by inhalation, intra-aortal, intracranial, subdermally, intraperitoneally, subcutaneously, nasally, sublingually or rectally, or by other means in drug formulations containing conventionally pharmaceutically acceptable carriers. For intraocular delivery, compounds may be administered as desired, for example, intravitreous, intramammary, anterior chamber, sub-Tenon's capsule, subretinal, retrobulbar, peribulbar, superchoroidal, conjunctival, subconjunctival, superscleral, periocular, transscleral, retrobulbar, near the posterior sclera, periclora, or lacrimal duct injection, or via mucus, mucin, or the mucosal barrier in an immediate or controlled release manner, or by an intraocular device.

[0642] According to the methods of this disclosure, oral administration can be in any desired form, such as a solid, gel, or liquid including a solution, suspension, or emulsion. In some embodiments, the compound or salt is administered by inhalation, intravenously, or intramuscularly as a liposome suspension. When administered by inhalation, the active compound or salt may be in the form of a plurality of solid particles or droplets having any desired particle size, for example, about 0.01 microns, 0.1 microns, or 0.5 microns to about 5 microns, 10 microns, 20 microns or more, or optionally about 1 micron to about 2 microns. The compounds disclosed in this invention have shown good pharmacokinetic and pharmacodynamic properties when administered, for example, by oral or intravenous routes.

[0643] Pharmaceutical formulations may contain the active compounds described herein or pharmaceutically acceptable salts thereof in any pharmaceutically acceptable carrier. Where a solution is desired, water may be the optimal 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 preferred. In the latter case, the organic vehicle may contain a substantial amount of water. In either case, the solution can be sterilized by a preferred method known to those skilled in the art, for example, by filtration through a 0.22 micron filter. Following sterilization, the solution can be dispensed into a suitable container, such as a depyrogenated glass vial. Dispensing is optionally performed using a sterile method. A sterile closure is then attached to the vial, and the contents of the vial can be freeze-dried if necessary.

[0644] The carrier, containing excipients and diluents, must be sufficiently pure and sufficiently low in toxicity to be suitable for administration to the patient being treated. The carrier may be inert or may have its own pharmaceutically active properties. The amount of carrier used in combination with the compound is sufficient to provide a practical amount of material for administration per unit dose of the compound.

[0645] Examples of carriers include binders, buffers, colorants, diluents, disintegrants, emulsifiers, flavorings, glidentifiers, lubricants, preservatives, stabilizers, surfactants, tableting agents, and wetting agents. However, it is not limited to these. Some carriers may be of two or more types; for example, vegetable oil can be used as a lubricant in some formulations and as a diluent in others. Exemplary pharmaceutically acceptable carriers include sugars, starches, cellulose, tragacanth powder, malt, gelatin; talc and vegetable oils. Any active agent that does not substantially interfere with the activity of the compounds of the present invention may be included in the pharmaceutical composition.

[0646] Additionally, auxiliary substances such as wetting agents or emulsifiers, physiological buffers, and surfactants may be present in the vehicle. The physiological buffer can be any solution that is pharmacologically acceptable and yields a formulation with a desired pH, i.e., a physiologically acceptable pH range. Examples of buffer solutions include physiological saline, phosphate-buffered saline, Tris-buffered saline, and Hanks-buffered saline.

[0647] Depending on the intended method of administration, the pharmaceutical composition may be in solid, semi-solid, or liquid dosage form, such as tablets, suppositories, pills, capsules, powders, liquids, suspensions, creams, ointments, lotions, etc., preferably in a unit dosage form suitable for precise single-dose administration. The composition may contain an effective amount of a selected drug combined with a pharmaceutically acceptable carrier, and may also contain other pharmaceuticals, adjuvants, diluents, buffers, etc.

[0648] Therefore, the compositions of this disclosure can be administered as pharmaceutical formulations suitable for oral (including oral and sublingual), rectal, nasal, local, pulmonary, vaginal, or parenteral (including intramuscular, intra-arterial, intrathecal, subcutaneous, and intravenous) administration, or in forms suitable for inhalation or insufflation. A preferred method of administration is intravenous or oral administration using a simple daily administration regimen that can be adjusted according to the degree of discomfort.

[0649] Examples of conventional non-toxic solid carriers for solid compositions include pharmaceutical-grade mannitol, lactose, starch, magnesium stearate, sodium saccharin, talc, cellulose, glucose, sucrose, and magnesium carbonate. Liquid pharmaceutically administerable compositions can be prepared, for example, by dissolving and dispersing the active compounds and any pharmaceutical adjuvants described herein in an excipient such as water, physiological saline, aqueous dextrose, glycerol, or ethanol, thereby forming a solution or suspension. Optionally, the administered pharmaceutical composition may contain small amounts of non-toxic auxiliary substances such as wetting agents or emulsifiers, pH buffers, etc., such as sodium acetate, sorbitan monolaurate, sodium triethanolamine acetate, or triethanolamine oleate. Practical methods for preparing such dosage forms are known or apparent to those skilled in the art. See, for example, Remington's Pharmaceutical Sciences mentioned above. sea ​​bream.

[0650] In another embodiment, permeation-promoting excipients are used that include polycations (chitosan and its quaternary ammonium derivatives, poly-L-arginine, amination gelatin); polyanions (N-carboxymethyl chitosan, polyacrylic acid); and polymers such as thiolated polymers (carboxymethylcellulose-cysteine, polycarbophil-cysteine, chitosan-thiobutylamidine, chitosan-thioglycolic acid, chitosan-glutathione conjugate).

[0651] For oral administration, the composition generally takes the form of tablets, capsules, softgel capsules, or can be aqueous or non-aqueous solutions, suspensions, or syrups. Tablets and capsules are preferred forms of oral administration. Tablets and capsules for oral use may contain one or more commonly used carriers, such as lactose and corn starch. Lubricants such as magnesium stearate are also typically added. Typically, the compositions of this disclosure consist of lactose, starch, sucrose, glucose, methylcellulose, and magnesium stearate. It can be combined with oral, non-toxic, pharmaceutically acceptable, inert carriers such as dicalcium phosphate, calcium sulfate, mannitol, and sorbitol. Furthermore, suitable binders, lubricants, disintegrants, and colorants may be incorporated into the mixture as desired or required. Suitable binders include natural sugars such as starch, gelatin, glucose, or β-lactose, corn sweeteners, natural and synthetic gums such as gum arabic and tragacanth, or sodium alginate, carboxymethylcellulose, polyethylene glycol, and wax. Lubricants used in these dosage forms include sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, and sodium chloride. Disintegrants include, but are not limited to, starch, methylcellulose, agar, bentonite, and xanthan gum.

[0652] When using a liquid suspension, the active agent can be combined with any oral, non-toxic, pharmaceutically acceptable, inert carrier such as ethanol, glycerol, or water, as well as emulsifiers and suspending agents. Flavorings, colorings, and / or sweeteners may also be added as needed. Other optional components incorporated into the oral formulations herein include, but are not limited to, preservatives, suspending agents, and thickeners.

[0653] Parenteral formulations can be prepared in conventional forms as liquid solutions or suspensions, solid forms suitable for solubilization or suspension in liquids before injection, or emulsions. Sterile injection suspensions are preferably formulated using suitable carriers, dispersants or wetting agents, and suspending agents according to techniques known in the art. Sterile injection formulations may also be sterile injection solutions or suspensions in non-toxic, parenterally acceptable diluents or solvents. Acceptable vehicles and solvents that can be used include water, Ringer's solution, and isotonic sodium chloride solution. In addition, sterile non-volatile oils, fatty acid esters, or polyols are commonly used as solvents or suspension media. Furthermore, parenteral administration may involve the use of sustained-release or continuous-release systems to maintain a constant dose level.

[0654] Parenteral administration includes intra-articular, intravenous, intramuscular, intradermal, intraperitoneal, and subcutaneous routes and includes aqueous and non-aqueous isotonic sterile injection solutions that may contain antioxidants, buffers, antibacterial agents, and solutes that make the formulation isotonic with the blood of the intended recipient, as well as aqueous and non-aqueous sterile suspensions that may contain suspending agents, solubilizers, thickeners, stabilizers, and preservatives. Administration by certain parenteral routes may involve introducing the formulation of the Disclosure into the patient's body by needle or catheter, and may be promoted by a sterile syringe or several other mechanical devices such as a continuous infusion system. The formulations provided by the Disclosure may be administered using syringes, injectors, pumps, or any other devices permitted in the art for parenteral administration.

[0655] In addition to the active compound or its salts, the pharmaceutical formulation may contain other additives such as pH adjusting additives. Particularly useful pH adjusting agents include acids such as hydrochloric acid, and bases or buffers such as sodium lactate, sodium acetate, sodium phosphate, sodium citrate, sodium borate, or sodium gluconate. Furthermore, the formulation may contain antimicrobial preservatives. Useful antimicrobial preservatives include methylparaben, propylparaben, and benzyl alcohol. Antimicrobial preservatives are typically used when the formulation is placed in a vial designed for multiple doses. The pharmaceutical formulations described herein can be freeze-dried using techniques known in the art.

[0656] For oral administration, pharmaceutical compositions can take the form of solutions, suspensions, tablets, pills, capsules, powders, etc. Tablets containing various excipients such as sodium citrate, calcium carbonate, and calcium phosphate can be used together with binders such as polyvinylpyrrolidone, sucrose, gelatin, and gum arabic, along with various disintegrants such as starch (e.g., potato or tapioca starch) and certain complex silicates. Yes, it is possible. Additionally, lubricants such as magnesium stearate, sodium lauryl sulfate, and talc are often extremely useful for tableting purposes. Similar types of solid compositions can be used as fillers in soft and hard gelatin capsules. Related materials include lactose and high molecular weight polyethylene glycol. If an aqueous suspension and / or elixir is desired for oral administration, the host matter of this disclosure is... The compounds can be combined with various sweeteners, flavorings, colorants, emulsifiers and / or suspending agents, as well as diluents such as water, ethanol, propylene glycol, glycerin, and various similar combinations thereof.

[0657] In yet another embodiment of the subject matter described herein, a stable, sterile formulation for injection containing the active compound or a salt thereof described herein in a unit dose form in a sealed container is provided. The compound or salt is provided in the form of a lyophilized product that can be reconstituted with a suitable pharmaceutically acceptable carrier to form a liquid formulation suitable for injection into a host. If the compound or salt is substantially water-insoluble, a sufficient amount of physiologically acceptable emulsifier can be used in an amount sufficient to emulsify the compound or salt in an aqueous carrier. Particularly useful emulsifiers include phosphatidylcholine and lecithin.

[0658] Additional embodiments include liposome formulations of the active compounds disclosed herein. Techniques for forming liposome suspensions are known in the art. When the compound is an aqueous salt, conventional liposome techniques are used to incorporate it into lipid vesicles. This is possible. In such cases, the active compound can be substantially incorporated into the hydrophilic center or core of the liposome for water solubility. The lipid layer used can have any conventional composition and may or may not contain cholesterol. Even if the target active compound is water-insoluble, the salt can be substantially incorporated into the hydrophobic lipid bilayer forming the liposome structure using conventional liposome formation techniques. In either case, the size of the resulting liposomes can be reduced, as can be achieved using standard sonication and homogenization techniques. A liposome formulation containing the active compound disclosed herein can be freeze-dried to produce a lyophilized product, which can then be reconstituted with a pharmaceutically acceptable carrier such as water to regenerate a liposome suspension.

[0659] Pharmaceutical formulations suitable for administration as an aerosol by inhalation are also provided. These formulations comprise a desired compound or salt thereof, or a solution or suspension of a plurality of solid particles of the compound or salt. The desired formulation can be placed in a small chamber and atomized. Atomization can be achieved by forming a plurality of droplets or solid particles containing the compound or salt using compressed air or ultrasonic energy. The droplets or solid particles may have a particle size in the range of, for example, about 0.5 microns to about 10 microns, and optionally about 0.5 microns to about 5 microns. In certain embodiments, the solid particles are provided with controlled release by the use of a biodegradable polymer. The solid particles can be obtained by processing a solid compound or salt thereof by any suitable method known in the art, such as micronization. Optionally, the size of the solid particles or droplets may be about 1 micron to about 2 microns. In this regard, commercially available nebulizers are available to achieve this purpose. The compounds can be administered by aerosol suspension of inhalable particles as described in U.S. Patent No. 5,628,984 (whose entire disclosure is by reference to this specification).

[0660] For example, pharmaceutical formulations are also provided that result in the controlled release of the compounds described herein by the use of biodegradable polymers known in the art.

[0661] When a pharmaceutical formulation suitable for aerosol administration is in liquid form, the formulation may contain a water-soluble active compound in a water-containing carrier. When subjected to spraying (hosted), the desired spraying occurs. A surfactant may be present that sufficiently reduces the surface tension of the formulation to cause the formation of droplets within the IZ range.

[0662] As used herein, the term “pharmaceutically acceptable salt” refers to a salt that is suitable for use in contact with a host (e.g., a human host) without excessive toxicity, irritation, allergic response, etc., within the bounds of sound medical judgment, that is effective for such use and that has a reasonable benefit-risk ratio, and, if possible, a zwitterionic form of the compound of the subject matter of this disclosure.

[0663] Therefore, the term “salt” refers to relatively non-toxic inorganic and organic acid addition salts of the compounds of this disclosure. These salts can be prepared during the final isolation and purification of the compounds, or by reacting the purified compound in its free base form separately with a suitable organic or inorganic acid and isolating the salt formed thereby. Basic compounds can form a wide range of salts with various inorganic and organic acids. Acid addition salts of basic compounds are prepared by conventional methods by contacting the free base form with a sufficient amount of the desired acid to produce a salt. The free base form can be regenerated by conventional methods by contacting the salt form with a base and isolating the free base. The free base form may differ from their respective 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, and calcium. 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 conventional methods by contacting the free acid form with a sufficient amount of the desired base to produce a salt. The free acid form can be regenerated by contacting the salt form with an acid and isolating the free acid by conventional methods. The free acid forms may differ somewhat from their respective salt forms in certain physical properties, such as solubility in polar solvents.

[0664] Salts are inorganic acid sulfates, pyrosulfates, bisulfates, sulfites, bisulfites, nitrates, phosphates, monohydrogen phosphates, dihydrogen phosphates, metaphosphates, pyro These salts can be prepared from phosphates, chlorides, bromides, iodides, such as hydrochloric acid, nitric acid, phosphoric acid, sulfuric acid, hydrobromic acid, hydroiodic acid, and phosphorous acid. Typical salts include hydrobromide, hydrochloride, sulfate, bisulfate, nitrate, acetate, oxalate, valerate, oleate, palmitate, stearate, laurate, borate, benzoate, lactate, phosphate, tosylate, citrate, maleate, fumarate, succinate, tartrate, naphthylate, mesylate, glucoheptonate, lactobionate, laurylsulfonate, and isethionate. Salts can also be prepared from organic acids, such as aliphatic monocarboxylic acids and dicarboxylic acids, phenyl-substituted alkanes, hydroxyalkanoates, alkanedioates, aromatic acids, aliphatic and aromatic sulfonic acids, and the like. Representative salts include acetate, propionate, caprylate, isobutyrate, oxalate, malonate, succinate, suberate, sebacinate, fumarate, maleate, mandelate, benzoate, chlorobenzoate, methylbenzoate, dinitrobenzoate, phthalate, benzenesulfonate, toluenesulfonate, phenylacetate, citrate, lactate, maleate, tartrate, and methanesulfonate. Pharmaceutically acceptable salts include, but are not limited to, cations based on alkali and alkaline earth metals such as sodium, lithium, potassium, calcium, and magnesium, as well as ammonium, tetramethylammonium, tetraethylammonium, methylamine, dimethylamine, trimethylamine, triethylamine, and ethylamine, and may also include non-toxic ammonium, quaternary ammonium, and amine cations. Salts of amino acids such as arginate, gluconate, and galacturonate are also considered. For example, Berge et al., J. Pharm. Sci., 19 See 77, 66, 1-19 (which by reference constitute part of this specification).

[0665] Sterile injection suspensions are preferably formulated using suitable carriers, dispersants or wetting agents, and suspending agents according to techniques known in the art. Sterile injection formulations may be sterile injection solutions or suspensions in non-toxic, parenterally acceptable diluents or solvents. Acceptable vehicles and solvents that can be used include water, Ringer's solution, and isotonic sodium chloride solution. In addition, sterile non-volatile oils, fatty acid esters, or polyols are commonly used as solvents or suspension media. Furthermore, parenteral administration may involve the use of sustained-release or continuous-release systems that maintain a certain level of dose.

[0666] Preparations for parenteral administration according to this disclosure include sterile aqueous or non-aqueous solutions, suspensions, or emulsions. Examples of non-aqueous solvents or vehicles include propylene glycol, polyethylene glycol, vegetable oils such as olive oil and corn oil, gelatin, and injectable organic esters such as ethyl oleate. Such dosage forms may contain adjuvants such as preservatives, wetting agents, emulsifiers, and dispersants. These can be sterilized, for example, by filtration through a bacterial-retaining filter, by incorporating a sterilizing agent into the composition, by irradiating the composition, or by heating the composition. These can also be prepared immediately before use using sterile water or several other sterile injectable media.

[0667] Sterile injectable solutions are prepared by incorporating one or more of the compounds of this disclosure in required amounts, along with various other components listed above as needed, into a suitable solvent, followed by filtration sterilization. Generally, dispersions are prepared by incorporating various sterilizing active ingredients into a sterile vehicle containing a basic dispersion medium and other required components from those listed above. For sterile powders for the preparation of sterile injectable solutions, preferred preparation methods are vacuum drying and freeze-drying, which yield a powder of the active ingredient and any additional desired components from the previously sterile filtered solution. For example, a parenteral composition suitable for administration by injection is prepared by stirring 1.5% by weight of the active ingredient with 10% by volume of propylene glycol and water. The solution is isotonicized with sodium chloride and sterilized.

[0668] Formulations suitable for rectal administration are typically provided as unit-dose suppositories. These can be prepared by mixing the disclosed active compound with one or more conventional solid carriers, such as cocoa butter, and then molding the resulting mixture.

[0669] Formulations suitable for topical application to the skin are preferably in the form of ointments, creams, lotions, pastes, gels, sprays, aerosols, or oils. Suitable carriers include petrolatum, lanolin, polyethylene glycol, alcohol, transdermal enhancers, and combinations of two or more thereof.

[0670] Formulations suitable for transdermal administration can be provided as individual patches adapted to remain in close contact with the recipient's epidermis for extended periods. Formulations suitable for transdermal administration can also be delivered by iontophoresis (see, e.g., Pharmaceutical Research 3 (6):318 (1986)), typically in the form of an optionally buffered aqueous solution of the active compound. In certain embodiments, microneedle patches or devices are provided for the delivery of drugs across or into biological tissues, particularly the skin. Microneedle patches or devices enable drug delivery across or into the barriers of the skin or other tissues at clinically relevant rates with little or no tissue damage, pain, or irritation.

[0671] Formulations suitable for pulmonary administration can be delivered by a wide range of passive and active single / multiple dose dry powder inhalers (DPIs). The most commonly used devices for respiratory delivery include nebulizers, metered-dose inhalers, and dry powder inhalers. Several types of nebulizers are available, including jet nebulizers, ultrasonic nebulizers, and vibrating mesh nebulizers. The selection of a suitable lung delivery device depends on parameters such as the properties of the drug and its formulation, the site of action, and the pathophysiology of the lung.

[0672] An additional, non-limiting example of a drug delivery device and method is, for example, U.S. Patent Application Publication 20090 entitled "Pharmaceutical Dosage Form For Oral Administration Of Tyrosine Kinase Inhibitor". No. 203709 (Abbott Laboratories); "Subconjunctival or periocular delivery of prodrugs" A US publication titled "Delivery of an active drug to the posterior part of the eye via subconjunctival or periocular delivery of a prodrug" U.S. Patent Application Publication No. 20050009910, titled "Biodegradable polymers for lowering intraocular pressure," U.S. Patent No. 20130071349, titled "Tyrosine kinase microspheres," and U.S. Patent No. 8,481,069, titled "Method of making tyrosine kinase microspheres." U.S. Patent No. 8,465,778, titled "Sustained release intraocular implants containing tyrosine kinase inhibitors and related methods," U.S. Patent No. 8,409,607, titled "Biodegradable intravitreal tyrosine kinase implants," and U.S. Patent No. 8,512,738, titled "Biodegradable intravitreal tyrosine kinase implants," and U.S. Patent No. 2014 U.S. Patent No. / 0031408, entitled "Microsphere Drug Delivery System for Sustained Intraocular Release", U.S. Patent No. 2014 / 0294986, entitled "Methods For Treating Retinopathy With Extended Therapeutic Effect", Patent No. 911,768 (Allergan, Inc.); entitled "Preparation of injectable suspensions having improved injectability" U.S. Patent No. 6,495,164 (Alkermes Controlled Therapeutics, Inc.); International Publication No. 2014 / 047439 (Akina, Inc.) entitled "Biodegradable Microcapsules Containing Filling Material"; International Publication No. 2010 / 132664 (Baxter International Inc. Baxter Healthcare SA) entitled "Compositions And Methods For Drug Delivery"; Patent Application Publication No. 20120052041 (The Brigham and Women's Hospital, Inc.); "Therapeutic Nanoparticles Comprising a Therapeutic Agent and Methods of Making and Using Same" U.S. Patent Application Publication No. 20140178475, U.S. Patent Application Publication No. 20140248358, and U.S. Patent Application Publication No. 20140249158 (BIND Therapeutics, Inc.); U.S. Patent No. 5,869,103 (Danbiosyst UK Ltd.) titled "Polymer microparticles for drug delivery"; U.S. Patent No. 8628801, titled "Pegylated Nanoparticles" (University of Navarra); United States, titled "Ocular drug delivery system" U.S. Patent Publication No. 2014 / 0107025 (Jade Therapeutics, LLC); U.S. Patent No. 6,287,588 titled "Agent delivering system comprised of microparticle and biodegradable gel with an improved releasing profile and methods of use thereof"; U.S. Patent No. 6,589,549 (Macromed, Inc.) titled "Bioactive agent delivering system comprised of microparticles within a biodegradable to improve release profiles"; "Nonlinear hydrophilic phosphating" Titled "Nanoparticles and microparticles of non-linear hydrophilichydrophobic multiblock copolymers" U.S. Patent No. 6,007,845 and U.S. Patent No. 5,578,325 (Massachusetts Institute of Technology); "Ophthalmic depot formulations for periocular or subconjunctival administration" U.S. Patent Application Publication Nos. 20040234611, 20080305172, 20120269894 and 20130122064 (Novartis Ag); U.S. Patent No. 6,413,539 (Poly-Med, Inc.) titled "Block polymer";. 6,413,539 (Poly-Med, Inc.) titled "Delivery of an agent to ameliorate inflammation" U.S. Patent Application Publication No. 20070071756 (Peyman); U.S. Patent Application Publication No. 20080166411 (Pfizer, Inc.) entitled "Injectable Depot Formulations And Methods For Providing Sustained Release Of Poorly Soluble Drugs Comprising Nanoparticles"; U.S. Patent No. 6,706,289 (PR Pharmaceuticals, Inc.) entitled "Methods and compositions for enhanced delivery of bioactive molecules"; and "Microparticles containing a matrix for drug delivery" (Microparticle containing matrices for drug delivery)" U.S. 8, Numbers 663 and 674 (Surmodics) are cited.

[0673] VII. Combination Therapy Compounds of formulas I, II, III, IV, V, VI, VII, VIII, IX, or X disclosed herein may be used alone or in combination with other compounds of the present invention or other bioactive agents (therapeutic agents) in effective amounts to treat a host such as a human having the disorders described herein.

[0674] The compounds disclosed herein may be used alone or in combination with other compounds of the present invention or other bioactive agents in effective amounts to treat a host such as a human having the disorders described herein.

[0675] The terms “bioactive agent” or “therapeutic agent” are used to describe active substances other than the selected compounds of the present invention that can be used in combination with or alternately with the compounds of the present invention to achieve a desired therapeutic outcome. In certain embodiments, the compounds of the present invention and the bioactive agent are active in vivo during the period in which they overlap, for example, C max , T max The compounds and bioactive agents of the present invention are administered to a host in need, such that there is an overlapping period in AUC or another pharmacokinetic parameter. In another embodiment, the compounds and bioactive agents of the present invention are administered to a host in need, such that there is no overlapping pharmacokinetic parameter, but one has a therapeutic effect on the therapeutic efficacy of the other.

[0676] In a particular embodiment of this design, the bioactive agent is a chemotherapeutic agent.

[0677] In another embodiment of this design, the bioactive agent is a growth factor.

[0678] In certain embodiments of this embodiment, the bioactive agent is, in non-limiting examples, a checkpoint inhibitor including a PD-1 inhibitor, a PD-L1 inhibitor, a PD-L2 inhibitor, a CTLA-4 inhibitor, a LAG-3 inhibitor, a TIM-3 inhibitor, and a V-domain Ig suppressor of T-cell activation (VISTA) inhibitor. An immunomodulator includes, but is not limited to, a molecule, peptide, nucleotide, or another inhibitor. In certain embodiments, the immunomodulator is an antibody, such as a monoclonal antibody.

[0679] Immune checkpoint inhibitors 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 V-domain Ig suppressor (VISTA) inhibitors for T-cell activation, or combinations thereof. In some embodiments, the immune checkpoint inhibitor is administered in an effective dose in combination with the compounds described herein to treat cancers including, but are not limited to, Hodgkin lymphoma, melanoma, non-small cell lung cancer including NSCLC with EGFR or ALK genomic tumor abnormalities, head and neck squamous cell carcinoma, small cell lung cancer, hepatocellular carcinoma, renal cell carcinoma, urothelial carcinoma, colorectal cancer, bladder cancer, B-cell lymphoma, gastric cancer, cervical cancer, liver cancer, advanced Merkel cell carcinoma, esophageal squamous cell carcinoma, or ovarian cancer.

[0680] In certain embodiments, the immune checkpoint inhibitor is a PD-1 inhibitor that inhibits immunosuppression by blocking the interaction between PD-1 and PD-L1 by binding to the PD-1 receptor. In certain embodiments, the immune checkpoint inhibitor is nivolumab (Opdivo®), pembrolizumab (Keytruda®), pidilizumab, AMP-224 (AstraZeneca and MedImmune), PF-06801591 (Pfizer), MEDI0680 (AstraZeneca), PDR001 (Novartis). Semiprimab / REGN2810 (Libtayo(trademark) Regeneron), MGA01 It is a PD-1 immune checkpoint inhibitor selected from 2 (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.).

[0681] In certain embodiments, the immune checkpoint inhibitor is nivolumab (Opdivo®), a PD-1 immune checkpoint inhibitor administered in an effective dose together with the compounds described herein for the treatment of Hodgkin lymphoma, melanoma, non-small cell lung cancer including NSCLC with EGFR or ALK genomic tumor abnormalities, head and neck squamous cell carcinoma, small cell lung cancer, hepatocellular carcinoma, renal cell carcinoma, squamous cell carcinoma, urothelial carcinoma, colorectal cancer, colon cancer, hepatocellular carcinoma, or ovarian cancer. Nivolumab is FDA approved for use in Hodgkin lymphoma, melanoma, non-small cell lung cancer including NSCLC with EGFR or ALK genomic tumor abnormalities, head and neck squamous cell carcinoma, small cell lung cancer, hepatocellular carcinoma, renal cell carcinoma, squamous cell carcinoma, urothelial carcinoma, colorectal cancer, advanced classical Hodgkin lymphoma (cHL), colorectal cancer, urothelial carcinoma, head and neck squamous cell carcinoma, or ovarian cancer. In another embodiment of this design, the immune checkpoint inhibitor is pembrolizumab (Keytruda®), a PD-1 immune checkpoint inhibitor administered in an effective dose for the treatment of melanoma, non-small cell lung cancer, small cell lung cancer, head and neck cancer, bladder cancer, urothelial carcinoma, renal cell carcinoma, classical Hodgkin lymphoma, gastric cancer, cervical cancer, liver cancer, primary mediastinal B-cell lymphoma, advanced Merkel cell carcinoma, esophageal squamous cell carcinoma, or urothelial carcinoma. In an additional embodiment of this design, the immune checkpoint inhibitor is pidilizumab (Medivation), a PD-1 immune checkpoint inhibitor administered in an effective dose for refractory diffuse large B-cell lymphoma (DLBCL) or metastatic melanoma. In an additional embodiment of this design, the immune checkpoint inhibitor is cemiprimab (Libtayo / Regeneron), a PD-1 immune checkpoint inhibitor administered in an effective dose for cutaneous squamous cell carcinoma. That is the case.

[0682] In certain embodiments, the immune checkpoint inhibitor is a PD-L1 inhibitor that inhibits immunosuppression by blocking the interaction between PD-1 and PD-L1 by binding to the PD-L1 receptor. Examples of PD-L1 inhibitors, but not limited to, include atezolizumab, durvalumab, KN035CA-170 (Curis Inc.), and LY3300054 (Eli Lilly). In certain embodiments, PD-L One inhibitor is atezolizumab. In certain embodiments, the PD-L1 inhibitor inhibits immunosuppression by blocking the interaction between PD-L1 and CD80.

[0683] In certain embodiments, the immune checkpoint inhibitor is the PD-L1 immune checkpoint inhibitor atezolizumab (Tecentriq®) administered in an effective dose for the treatment of metastatic bladder cancer, small cell lung cancer, metastatic melanoma, metastatic non-small cell lung cancer, or metastatic renal cell carcinoma. In another embodiment of this embodiment, the immune checkpoint inhibitor is durvalumab (Imfinzi®; AstraZeneca and MedImmune) administered in an effective dose for the treatment of 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 (Bavencio®; EMD Serono / Pfizer) administered in an effective dose for the treatment of Merkel cell carcinoma or urothelial carcinoma. In yet another embodiment of this embodiment, the immune checkpoint inhibitor is KN035 (alphamab) administered in an effective dose for the treatment of PD-L1-positive solid tumors.

[0684] In certain embodiments of this embodiment, the immune checkpoint inhibitor is a CTLA-4 immune checkpoint inhibitor that binds to CTLA-4 and inhibits immunosuppression. Examples of CTLA-4 inhibitors, but not limited to, include ipilimumab, tremelimumab (AstraZeneca and MedImmune), AGEN1884, and AGEN2041 (Agenus).

[0685] In certain embodiments, the CTLA-4 immune checkpoint inhibitor is ipilimumab (Yervoy®) administered in an effective dose for the treatment of metastatic melanoma, adjuvant melanoma, or non-small cell lung cancer.

[0686] 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), One example is MGD013 (MacroGenics), a dual inhibitor of PD-1 and LAG-3. In yet another embodiment of the 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).

[0687] Other immune checkpoint inhibitors for use in the present invention as 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 (KIR) immune checkpoint inhibitors such as lirilumab (BMS-986015) and carcinoembryonic antigen-associated cell adhesion molecule (CEACAM) inhibitors (e.g., CEACAM-1, -3 and / or -5). Exemplary anti-CEACAM-1 antibodies are described in International Publication Nos. 2010 / 125571, 2013 / 082366, and 2014 / 022332, and are, for example, monoclonal antibodies 34B1, 26H7, and 5F4, or their recombinants described in, for example, U.S. Patent Application Publication No. 2004 / 0047858, U.S. Patent No. 7,132,255, and International Publication No. 99 / 052552. In other embodiments, the anti-CEACAM antibody binds to CEACAM-5, for example, as described 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, for example, as described in International Publication No. 2013 / 054331 and U.S. Patent Application Publication No. 2014 / 0271618. Further other checkpoint inhibitors include, for example, Zh ang et al., Monoclonal antibodies to B and T lymphocyte attenuator (BTLA) have no effect on in vitro B cell proliferation and act to inhibit in vitro T cell proliferation when presented in a cis, but not trans, format relative to the activating stimulus, Clin Exp Immunol. 2011 Jan; 163(1):77-87. It may be a molecule directed towards the Pacyl Atenuator molecule (BTLA).

[0688] Chemotherapy agents As intended herein, the CDK inhibitors described herein can be used in combination with any standard chemotherapy regimen. In certain embodiments, the CDK inhibitors described herein can be used in combination with any standard chemotherapy regimen and further in combination with immune checkpoint inhibitors.

[0689] In certain embodiments, the chemotherapeutic agent is toxic to immune effector cells. In certain embodiments, the chemotherapeutic agent inhibits cell proliferation. In certain embodiments, the administered cytotoxic chemotherapeutic agent is a DNA-damaging chemotherapeutic agent. In certain embodiments, the chemotherapeutic agent is a protein synthesis inhibitor, a DNA-damaging chemotherapeutic agent, an alkylating agent, a topoisomerase inhibitor, an RNA synthesis inhibitor, a DNA complex binder, a thiolate alkylating agent, a guanine alkylating agent, a tubulin binder, a DNA polymerase inhibitor, an anti-cancer enzyme, an RAC1 inhibitor, a thymidylate synthase inhibitor, an oxazophosphorine compound, a silendide, an integrin inhibitor such as camptothecin or homocamptothecin, an antifolate agent, or a folate antimetabolite.

[0690] In some embodiments, additional therapeutic agents are selected from elotuzumab, rituximab, lenalidomide, cytarabine, daratumumab, adalimumab, idialicib, gilteritinib, glasdecib, valacyclovir, acalabrutinib, ibrutinib, midostaurine, ruxolitinib, bortezomib, lapatinib, bendamustine, enzalutamide, azacitadine, obinutuzumab, decitabine, erdafitinib, and venetoclax.

[0691] In certain embodiments, the additional therapeutic agent is trastuzumab. In certain embodiments, the additional therapeutic agent is lapatinib. In certain embodiments, the compound of the present invention is administered together with two, three, or four additional therapeutic agents. In certain embodiments, there are two additional therapeutic agents. In certain embodiments, the two additional therapeutic agents are lapatinib and trastuzumab.

[0692] In certain embodiments, the additional therapeutic agent is osimertinib mesylate (Tagrisso®).

[0693] In certain embodiments, the additional therapeutic agent is alectinib (Alecensa®).

[0694] In certain embodiments, the additional therapeutic agent is a MEK inhibitor.

[0695] In certain embodiments, the additional therapeutic agent is an androgen receptor ligand.

[0696] In certain embodiments, the additional therapeutic agent is a BTK inhibitor, such as, but not limited to, ibrutinib (Imbruvica®) or acalabrutinib (Calquence®).

[0697] In certain embodiments, additional therapeutic agents are MEK inhibitors and RAF inhibitors.

[0698] In certain embodiments, the additional therapeutic agent is an RAF inhibitor.

[0699] In certain embodiments, the additional therapeutic agent is regorafenib.

[0700] Cytotoxic chemotherapeutic agents Cytotoxic and DNA-damaging chemotherapeutic agents are nonspecific and tend to be toxic to normal, rapidly dividing cells such as HSPCs and immune effector cells, especially at high doses. As used herein, the terms "DNA-damaging" chemotherapy or chemotherapeutic agent refer to treatment with cell proliferation inhibitors or cytotoxic agents (i.e., compounds) for reducing or eliminating the growth or proliferation of undesirable cells, such as cancer cells, and the cytotoxic effect of such agents may be the result of one or more of the following: 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. Examples of "DNA-damaging" chemotherapeutic agents include, but are not limited to, alkylating agents, DNA intercalators, protein synthesis inhibitors, DNA or RNA synthesis inhibitors, DNA base analogs, topoisomerase inhibitors, telomerase inhibitors, and telomere DNA binding compounds. Examples of alkylating agents include alkyl sulfonates such as busulfan, improsulfan, and biposulfan; aziridines such as benzodizepa, carboquan, metuledepa, and uredepa; ethyleneimines and methylmelamines such as altretamine, triethylenemelamine, triethylenephosphoramide, triethylenethiophosphoramide, and triethylolmelamine; nitrogen mustards such as chlorambucil, chlornafadin, cyclophosphamide, estramustine, mechloretamine, mechloretamine oxide hydrochloride, melphalan, nobenbicin, phenesterine, prednimustine, trophosphamide, and uracil mustard; and nitrosoureas such as carmustine, chlorozotosine, fotemustine, lomustine, nimustine, and ranimustine. Other DNA-damaging chemotherapeutic agents include daunorubicin, doxorubicin, idarubicin, epirubicin, mitomycin, and streptozocin.Antimetabolites for chemotherapy include gemcitabine, mercaptopurine, thioguanine, cladribine, fludarabine phosphate, fluorouracil (5-FU), phloxlysine, cytarabine, pentostatin, methotrexate, azathioprine, acyclovir, adenine β-1-D-arabinoside, ametopterin, aminopterin, 2-aminopurine, aphydicolin, 8-azaguanine, azaserin, 6-azauracil, 2'-azido-2'-deoxynucleoside, 5-bromodeoxycytidine, cytosine β-1-D-arabinoside, diazoxynorsine, dideoxynucleoside, 5-fluorodexycytidine, 5-fluorodexyuridine, and hydroxyurea.

[0701] Examples of chemotherapy protein synthesis inhibitors include abrin, oulintricarboxylic acid, chloramphenicol, cholin E3, cycloheximide, diphtheria toxin, edine A, emetine, erythromycin, ethionine, fluoride, 5-fluorotryptophan, fusidic acid, guanylylmethylene diphosphate and guanylylimide diphosphate, kanamycin, kasugamycin, chilomycin, and O-methylthreonine. Additional protein synthesis inhibitors include modexin, neomycin, norvaline, patamycin, paromomycin, promycin, lysine, Shiga toxin, shodomycin, sparsomycin, spectinomycin, streptomycin, tetracycline, thiostrepton, and trimethoprim.

[0702] Inhibitors of DNA synthesis include alkylating agents such as dimethyl sulfate, nitrogen mustard, and sulfa mustard; intercalating agents such as acridine dyes, actinomycin, anthracene, benzopyrene, ethidium bromide, and propidium iodide intertwining; and other agents such as dystamycin and netropsin. Topoisomerase inhibitors such as irinotecan, teniposide, coumamycin, nalidixic acid, novobiocin, and oxolinic acid; cell division inhibitors including colsemid, mitoxantrone, colchicine, vinblastine, and vincristine; and RNA synthesis inhibitors including actinomycin D, α-amanitin, and other fungal amatoxins, cordycepin (3'-deoxyadenosine), dichlororibofuranosylbenzimidazole, rifampicin, streptovaricin, and streptorizidine can also be used as DNA damage compounds.

[0703] In certain embodiments, the chemotherapeutic agent is a DNA complex binder such as camptothecin or etoposide; a thiolate alkylating agent such as nitrosourea, BCNU, CCNU, ACNU, or fotesmustine; a guanine alkylating agent such as temozolomide; a tubulin binder such as vinblastine, vincristine, vinorelbine, vinflunin, or cryptophycin 52; halichondrin such as halichondrin B; drastatin such as drastatin 10 and drastatin 15; hemiastalin such as hemiastalin A and hemiastalin B; colchicine; corn These include prestatin, 2-methoxyestradiol, E7010, paclitaxel, docetaxel, epotilon, discodermolide; DNA polymerase inhibitors such as cytarabine; anticancer enzymes such as asparaginase; Rac1 inhibitors such as 6-thioguanine; thymidylate synthase inhibitors such as capecitabine or 5-FU; oxazophosphorine compounds such as cytoxane; integrin inhibitors such as silendide; antifolic acid agents such as pralatrexate; folic acid antimetabolites such as pemetrexed; or camptothecin or homocamptothecin such as diflomotecan.

[0704] In a particular embodiment, the topoisomerase inhibitor is a type I inhibitor. In another embodiment, the topoisomerase inhibitor is a type II inhibitor.

[0705] 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, taxol, transplatin, thiotepa, oxaliplatin, and similar agents. In certain embodiments, the DNA-damaging chemotherapeutic agent is selected from the group consisting of cisplatin, carboplatin, camptothecin, and etoposide.

[0706] Other suitable chemotherapeutic agents include, but are not limited to, any agents harmful to cell viability, also known as radiomolecules, toxins, cytotoxins or cytotoxic agents, and agents containing chemotherapeutic compounds and liposomes or other vesicles. Common anticancer drugs include: vincristine (Oncovin®), liposomal vincristine (Marqibo®), cytarabine (cytosine arabinoside, ala C, or Cytosar®), L-asparaginase (Elspar®) or PEG-L-asparaginase (Pegaspargase, or Oncaspar®), etoposide (VP-16), teniposide (Vumon®), 6-mercaptopurine (6-MP or Purinethol®), prednisone, and dexamethasone (Decadron). Examples of additional appropriate chemotherapeutic agents include, but are not limited to, 5-fluorouracil, dacarbazine, alkylating agents, anthramycin (AMC), antimitotic agents, cis-dichlorodiamine platinum(II) (DDP) cisplatin, diaminodichloroplatin, anthracyclines, antibiotics, antimetabolites, asparaginase, live BCG (intravesical), bleomycin sulfate, calicheamicin, cytochalasin B, dactinomycin (previously Examples include actinomycin, daunorubicin HCl, daunorubicin triphosphate, denileukin difuticox, dihydroxyanthracine dione, docetaxel, doxorubicin HCl, Escherichia coli (E. coli) L-asparaginase, Ervinya L-asparaginase, etoposide citroborum factor, etoposide phosphate, gemcitabine HCl, idarubicin HCl, interferon α-2b, irinotecan HCl, meitansinoid, mechloretamine HCl, melphalan HCl, mitramycin, mitomycin C, mitotan, polyfeprosan 20 containing carmustine implant, procarbazine HCl, streptozotocin, teniposide, thiotepa, topotecan HCl, barbicin, vinblastine sulfate, vincristine sulfate, and vinorelbine tartrate.

[0707] Additional cytotoxic chemotherapeutic agents for use in the present invention include epirubicin, abraxane, taxotere, epotilon, tafluposide, bismodegib, azacitidine, doxifluridine, vindesine, and vinorelbine.

[0708] 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.

[0709] In certain embodiments, the chemotherapeutic agent is a DNA complex binder. In certain embodiments, the chemotherapeutic agent is a tubulin binder. In certain embodiments, the chemotherapeutic agent is an alkylating agent. In certain embodiments, the chemotherapeutic agent is a thiolate alkylating agent.

[0710] Other chemotherapeutic agents Additional chemotherapeutic agents that may be used as described herein include 2-methoxyestradiol or 2ME2, finasnate, etalacizumab (MEDI-522), HLL1, huN901-DM1, atiprimoid, saquinavir mesylate, ritonavir, nelfinavir mesylate, indinavir sulfate, pritidecin, P276-00, tipifarnib, lenalidomide, thalidomide, pomalidomide, simvastatin, and celecoxib. The chemotherapy agents useful in this invention are not limited to, but include trastuzumab (Herceptin®), pertuzumab (Perjeta®), lapatinib (Tykerb®), gefitinib (Iressa®), erlotinib (Tarceva®), cetuximab (Erbitux®), panitumumab (Vectibix®), vandetanib (Caprelsa®), vemurafenib (Zelboraf®), vorinostat (Zolinza®), romidepsin (Istodax®), and bexarotene. Examples include Targretin (Trademark), Alitretinoin (Panretin (Trademark)), Tretinoin (Vesanoid (Trademark)), Carfilzomib (Kyprolis (Trademark)), Plalatrexate (Folotyn (Trademark)), Bevacizumab (Avastin (Trademark)), Ziv-Aflibercept (Zaltrap (Trademark)), Sorafenib (Nexavar (Trademark)), Sunitinib (Sutent (Trademark)), Pazopanib (Votrient (Trademark)), Regorafenib (Stivarga (Trademark)), and Cabozantinib (Cometriq (Trademark)).

[0711] Additional chemotherapeutic agents that may be considered include, but are not limited to, calcineurin inhibitors such as cyclosporine or ascomycin, such as cyclosporine A (Neoral®), FK506 (tacrolimus), pimecrolimus; mTOR inhibitors such as rapamycin or its derivatives, such as sirolimus (Rapamune®), everolimus (Certican®), temsirolimus, zotarolimus, biolimus-7, biolimus-9, rapalog, such as ridafolimus, campas 1H, and S1P receptor mo Dehydrators, mTORC1 and mTORC2 dual inhibitors, e.g., vistacertib (AZD2014), e.g., fingolimod or its analogues, anti-IL-8 antibodies, mycophenolic acid or its salts (e.g., sodium salt), or its prodrugs, e.g., mycophenolate mofetil (CellCept®), OKT3 (Orthoclone OKT3®), prednisone, ATGAM®, Thymoglobulin®, Brekiner sodium, OKT4, T10B9.A-3A, 33B3.1, 15-deoxysperguarine, tresperimus, leflunomid e Arava (trademark), anti-CD25, anti-IL2R, basiliximab (Simulect (trademark)), daclizumab (Zenapax (trademark)), mizoribine, dexamethasone, ISAtx-247, SDZ ASM 981 (pimecrolimus, Elidel (trademark)), abatacept, beratacept, LFA3lg, etanercept (by ImmuneXcite) Enbrel (trademark), adalimumab (Humira (trademark)), infliximab (Remicade (trademark)), anti-LFA-1 antibody, natalizumab (Antegren (trademark)), enrimomab, gabirimomab, golimumab, anti-thymocyte immunoglobulin, cyprizumab, alefecept, efalizumab, pentasa, mesalazine, asacol, codeine phosphate, benolilate, fenbufen, naprosin, di Clofenac, etodolac, indomethacin, dasatinib (Sprycel®), nilotinib (Tasigna®), bosutinib (Bosulif®), imatinib mesylate (Gleevec®), and ponatinib (Iclusig®), amifostin, drasetron mesylate, dronabinol, epoetin-α, etidronic acid, filgrastim, fluconazole, goserelin acetate, gramicidin Examples include lin-D, granisetron, leucovorin calcium, lidocaine, mesna, ondansetron HCl, pilocarpine HCl, porfimer sodium, batalanib, 1-dehydrotestosterone, allopurinol sodium, betamethasone, sodium phosphate and betamethasone acetate, calcium leucovorin, conjugated estrogen, dexrazoxane, dibromomannitol, esterified estrogen, estradiol, estramustine sodium phosphate, ethinylestradiol, flutamide, folinic acid, glucocorticoid, leuprolid acetate, levamisole hydrochloride, medroxyprogesterone acetate, megestrol acetate, methyltestosterone, nilutamide, octreotide acetate, pamidronate disodium, procaine, propranolol, testactone, tetracaine, toremifene citrate, and salglamostim.

[0712] In certain embodiments, the chemotherapeutic agent is an estrogen receptor ligand such as tamoxifen, raloxifen, fulvestrant, anoldrin, bazedoxifen, bpropalestriol, chlorotrianicene, clomiphene citrate, cyclophenyl, rasofoxifen, olmeroxifen, 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 anticancer antibody; an anticancer monoclonal antibody; lucatumumab or Antibodies against CD40 such as daketuzumab; antibodies against CD20 such as rituximab; antibodies that bind to CD52 such as alemtuzumab; antibodies that bind to integrins such as borocikimab or natalizumab; antibodies against interleukin-6 receptors such as tocilizumab; interleukin-2 mimes such as aldesleukin; antibodies that target IGF1 such as figtumumab; antibodies that target DR4 such as mapatumumab; antibodies that target TRAIL-R2 such as lexatumumab or duranermin; fusion proteins such as atacicept; B cell inhibitors such as atacicept; proteasome inhibitors such as carfilzomib, bortezomib, or marizomib; HSP90 inhibitors such as tanespimycin; HDAC inhibitors such as vorinostat, belinostat, or panobinostat; MAs such as talmapimod These include PK ligands; PKC inhibitors such as enzastaurin; HER2 receptor ligands such as trastuzumab, lapatinib, or pertuzumab; EGFR inhibitors such as gefitinib, erlotinib, cetuximab, panitumumab, or vandetanib; natural products such as romidepsin; retinoids such as besarotene, tretinoin, or alitretinoin; receptor tyrosine kinase (RTK) inhibitors such as sunitinib, regorafenib, or pazopanib; or VEGF inhibitors such as ziv-aflibercept, bevacizumab, or dovitinib.

[0713] In certain embodiments, the combination of CDK4 / 6 inhibitors, chemotherapeutic agents, and immune checkpoint inhibitors is not limited to, but may include, granulocyte colony-stimulating factor (G-CSF, e.g., marketed as Neupogen® (filgrastim), Neulasta® (pegfilgrastim), or lenograstim), granulocyte-macrophage colony-stimulating factor (GM-CSF, e.g., marketed as Morglamostim and Salglamostim (Leukine®)), M-CSF (macrophage colony-stimulating factor), thrombopoietin (megakaryocyte growth factor (MGDF), e.g., marketed as Romiplostim® and Eltrombopag®), interleukin (IL)-12, interleukin-3, interleukin-11 (lipidogenesis inhibitor or opioid inhibitor). Further combined use of hematopoietic growth factors including Levequin), SCF (Stem Cell Factor, Steel Factor, Kit Ligand, or KL), and erythropoietin (EPO), and their derivatives (marketed as epoetin-α, e.g., Darbepoetin, Epocept, Nanokin, Epofit, Epogen, Eplex, and Procrit; marketed as epoetin-β, e.g., Neorecomon, Recomon, and Micella), epoetin delta (marketed as e.g., Dynepo), epoetin omega (marketed as e.g., Epomax), epoetin zeta (marketed as e.g., Silapo and Retacrete), and e.g., Epocept, Epotrust, Eriprosafe, Lepoitin, Vintol, Epofit, Eriquin, Wepox, Espogen, Relipoitin, Champoetin, Zilup, and EPIAO).

[0714] Additional active compounds intended 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, but are not limited to, CDK9 inhibitors described herein in combination with estrogen inhibitors, including SERMs (selective estrogen receptor modulators), SERDs (selective estrogen receptor degraders), complete estrogen receptor degraders, or other forms of partial or complete estrogen antagonists. Examples of partial antiestrogens include raloxifene and tamoxifene, which retain some estrogen-like effects. Examples of complete antiestrogens include fulvestrant. Non-limited examples of antiestrogens are provided to AstraZeneca. International Publication No. 2014 / 19176, International Publication No. 2, transferred to Olema Pharmaceuticals. Publication No. 013 / 090921, International Publication No. 2014 / 203129, International Publication No. 2014 / 203132, and U.S. Patent Application Publication No. 2013 / 0178445, International Publication No. 2017 / 100712 and International Publication No. 2017 / 10071 assigned to G1 Therapeutics. Provided in Patent No. 5, International Publication Nos. 2018 / 081168 and 2018 / 148576, and U.S. Patent Nos. 9,078,871, 8,853,423 and 8,703,810, and U.S. Patent Application Publication Nos. 2015 / 0005286, International Publication Nos. 2014 / 205136 and 2014 / 205138. Additional non-limiting examples of anti-estrogen compounds include: SERMS such as anoldrin, aldoxifen, bazedoxifen, propalestriol, clomiphene citrate, cyclophenyl, droxifen, endoxifen, idoxifen, rasofoxifen, olmeroxifen, pipendoxifen, raloxifen, tamoxifen, toremifene, and fulvestrant; aromatase inhibitors such as aminoglutethimide, testolactone, anastrozole, exemestane, fadrozol, formestan, and letrozole; and leuprorelin, cetrorelix, allylestreno Antigonadotropins such as chloromadinone acetate, dermadinone acetate, didrogesterone, medroxyprogesterone acetate, megestrol acetate, nomegestrol acetate, norethisterone acetate, progesterone, and spironolactone. Additional non-limiting examples of antiestrogenic compounds include: fulvestrant, lintodestrant (G1T48), brillanestrant (GDC0810), elastrant (RAD1901), ethactyl (GW5638), GW7604, AZD9496, GDC-0927, GDC9545 (RG6171), LSZ102, and SERDS such as SAR439859.

[0715] In a particular embodiment, the SERD compound of the following formula is described in International Publication No. 2017 / 100712: [ka] (In the formula, m 4 0, 1, 2, 3, and 4 are, n 4 is 0, 1, 2, 3, or 4, X A These are selected from -O-, -CH2-, -S-, -NH-, -NMe-, -CF2-, and C3 cycloalkyl groups. Ring B is a phenyl, naphthyl, quinolinyl, a 5- or 6-membered monocyclic heteroaryl, or a 7-, 8-, 9- or 10-membered bicyclic heterocycle. Ring C is a phenyl, thienyl, a 5- or 6-membered monocyclic heteroaryl, or a 7-, 8-, 9- or 10-membered bicyclic heterocycle. R 41 These are selected from hydroxyl, hydrogen, halogen, -O(C1~C6alkyl), -OC(O)(C1~C6alkyl), -OC(O)C6H5, -OC(O)O(C1~C6alkyl), -OC(O)OC6H5, and -OSO2(C2~C6alkyl). R 42It is selected from -CH=CHCOOH, -NH(CO)COOH, -COOH, -C2~C6 alkenylene-COOH, and -C2~C6 alkynylene-COOH. R 43 In each case, the following are independently selected from hydrogen, halogen, -CN, -NO2, -C1~C6 alkyl and -C1~C6 fluoroalkyl, R 44 In each case, the following are independently described: hydrogen, halogen, hydroxyl, -C1-C6 alkyl, -C1-C6 fluoroalkyl, -CN, -O(C1-C6 alkyl) and -O(C1-C6 fluoroalkyl)) or a pharmaceutically acceptable salt thereof.

[0716] Non-limiting examples of SERDS for use in the present invention include: [ka] TIFF2026076261000186.tif218170 TIFF2026076261000187.tif43170 or a pharmaceutically acceptable salt thereof.

[0717] In a particular embodiment, SERD is as follows: [ka] or a pharmaceutically acceptable salt thereof.

[0718] In a particular embodiment, SERD is as follows: [ka] or a pharmaceutically acceptable salt thereof.

[0719] In a particular embodiment, SERD is as follows: [ka] or a pharmaceutically acceptable salt thereof.

[0720] In this specification, additional chemotherapeutic agents intended for the treatment of abnormal tissues of the male reproductive system, particularly prostate cancer or testicular cancer, include, but are not limited to, androgen (testosterone, etc.) inhibitors, including, selective androgen receptor modulators, selective androgen receptor degraders, complete androgen receptor degraders, or other forms of partial or complete androgen antagonists. In certain embodiments, prostate cancer or testicular cancer is androgen-resistant. Non-limiting examples of antiandrogen compounds are presented in International Publication No. 2011 / 156518, and U.S. Patents No. 8,455,534 and 8,299,112. Further non-limiting examples of antiandrogen compounds include chlormadinone acetate, spironolactone, canrenone, drospirenone, ketoconazole, topilutamide, abiraterone acetate, and cimetidine.

[0721] The chemotherapeutic agents may include, but are not limited to, kinase inhibitors, such as phosphoinositide 3-kinase (PI3K) inhibitors, Bruton's tyrosine kinase (BTK) inhibitors, or splenic tyrosine kinase (Syk) inhibitors, or combinations thereof.

[0722] PI3k inhibitors are well known. Examples of PI3 kinase inhibitors include, but are not limited to, wartmannin, demethoxypyridine, perifosine, idelalisib, pictilisib, paromide 529, ZSTK474, PWT33597, CUDC-907 and AEZS-136, duberisib, GS-9820, and GDC-0032 (2-[4-[2-(2-isopropyl-5-methyl-1,2,4-triazole-3-yl)-5,6-dihydroimidazo[1,2-d][1,4]benzoxazepine-9 (-yl]pyrazole-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-pyrrolidinedicarba Mido), GSK2126458 (2,4-difluoro-N-{2-(methyloxy)-5-[4-(4-pyridazinyl)-6-quinolinyl]-3-pyridinyl}benzenesulfonamide), TGX-221 ((±)-7-methyl-2-(morpholine-4-yl)-9-(1-phenylaminoethyl)-pyrido[1,2-a]-pyrimidine-4-one), GSK2636771 (2-methyl-1-(2-methyl-3-(trifluoromethyl)benzyl)-6-mol (Folino-1H-benzo[d]imidazole-4-carboxylic acid dihydrochloride), KIN-193((R)-2-((1-(7-methyl-2-morpholino-4-oxo-4H-pyrido[1,2-a]pyrimidine-9-yl)ethyl)amino)benzoic acid), TGR-1202 / RP5264, GS-9820((S)-(1-(4-((2-(2-aminopyrimidine-5-yl)-7-methyl-4-mohydroxypropane(mohydroxypropan)-1- 0), GS-1101(5-fluoro-3-phenyl-2-([S)]-1-[9H-purine-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), AS25 2424(5-[1-[5-(4-fluoro-2-hydroxyphenyl)-furan-2-yl]-meth-(Z)-ylidene]-thiazolidin-2,4-dione), CZ24832(5-(2-amino-8-fluoro-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-N-tert-butylpyridin-3-sulfonamide), Buparlicib(5-[2,6-di(4-morpholinyl)-4-pyrimidinyl]-4-(trifluoromethyl)-2-pyridinamine), GDC-0941(2-(1H-indazole-4-yl)-6-[[4-(methylsulfonyl)-1- [Piperadinyl]methyl]-4-(4-morpholinyl)thieno[3,2-d]pyrimidine), GDC-0980((S)-1-(4-((2-(2-aminopyrimidine-5-yl)-7-methyl-4-morpholinothieno[3,2-d]pyrimidine-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)morpholino-4-ium)-2-oxa-7,10,13,16-tetraazaoctadecane-18-oate), PF-05212384(N-[4-[[4-(dimethylamino)-1-piperidinyl]carbonyl]phenyl]N'-[4-(4,6-di-4-morpholinyl-1,3,5-triazine-2-yl)phenyl]urea), LY302341 4. BEZ235 (2-methyl-2-{4-[3-methyl-2-oxo-8-(quinoline-3-yl)-2,3-dihydro-1H-imidazo[4,5-c]quinoline-1-yl]phenyl}propanenitrile), XL-765 (N-(3-(N-(3-(3,5-dimethoxyphenylamino)quinoxaline-2-yl)sulfamoyl)phenyl)-3-methoxy-4-methylbenzamide), and GSK1059615 (5-[[4-(4-pyridinyl)-6-quinolinyl]methylene]-2 ,4-thiazolidendione), PX886 ([(3aR,6E,9S,9aR,10R,11aS)-6-[[bis(propa-2-enyl)amino]methylidene]-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 described in International Publication No. 2014 / 071109 A structure having the formula can be given.

[0723] BTK inhibitors are well known. Examples of BTK inhibitors include ibrutinib (also known as PCI-32765) (Imbruvica®) (1-[(3R)-3-[4-amino-3-(4-phenoxyphenyl)pyrazolo[3,4-d]pyrimidine-1-yl]piperidine-1-yl]propa-2-en-1-one), acalabrutinib (Calquence®), AVL-101 and AVL-291 / 292 (N-(3-((5-fluoro-2-((4-(2-methoxyethoxy)phenyl)amino)pyrimidine-4-yl)amino)phenyl)acrylamide) (Avila Dianilinopyrimidine inhibitors such as Therapeutics (see U.S. Patent Application Publication No. 2011 / 0117073, which in whole forms part of this specification), dasatinib ([N-(2-chloro-6-methylphenyl)-2-(6-(4-(2-hydroxyethyl)piperazine-1-yl)-2-methylpyrimidine-4-ylamino)thiazole-5-carboxamide]), LFM-A13 (alpha-cyano-beta-hydroxy-beta-methyl-N-(2,5-ibromopenyne)propenamide), GDC-0834 ([RN-(3-(6-(4-(1,4-dimethyl-3-oxopiperazine-2-yl)phenylamino)-4-methyl-5-oxo-4,5-dihydropyrazine-2-yl)-2-methylphenyl)-4,5,6,7-tetrahydro [Robenzo[b]thiophene-2-carboxamide]), CGI-560 (4-(tert-butyl)-N-(3-(8-(phenylamino)imidazo[1,2-a]pyrazine-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 -Dihydropyrazine-2-yl)phenyl)benzamide), CNX-774(4-(4-((4-((3-acrylamidophenyl)amino)-5-fluoropyrimidine-2-yl)amino)phenoxy)-N-methylpicolinamide), CTA056(7-benzyl-1-(3-(piperidine-1-yl)propyl)-2-(4-(pyridine-4-yl)phenyl)-1H-imidazo[4,5-g]Quinoxaline-6(5H)-one), GDC-0834((R)-N-(3-(6-((4-(1,4-dimethyl-3-oxopiperazine-, 2-yl)phenyl)amino)-4-methyl-5-oxo-4,5-dihydropyrazine-2-yl)-2-methylphenyl)-4,5,6,7-tetrahydrobenzo[b]thiophene-2-carboxamide), GDC-0837((R)-N-(3-(6-((4-(1,4-dimethyl-3-oxopiperazine-2-yl)phenyl)amino)-4-methyl-5- Xo-4,5-dihydropyrazine-2-yl)-2-methylphenyl)-4,5,6,7-tetrahydrobenzo[b]thiophene-2-carboxamide), HM-71224, ACP-196, ONO-4059 (Ono Pharmaceutical Co., Ltd.), PRT062607 (4-((3-(2H-1,2,3-triazole-2-yl)phenyl)amino)-2-(((1R, 2S)-2-aminocyclohexyl)amino)pyrimidine-5-carboxamide hydrochloride), QL-47(1-(1-acroylindolin-6-yl)-9-(1-methyl-1H-pyrazole-4-yl)benzo[h][1,6]naphthyridine-2(1H)-one), and RN486(6-cyclopropyl-8-fluoro-2-(2-hydroxymethyl-3-{1-methyl-5-[5-(4-methyl-piperazine-1-yl)-pyridine-2-ylamino]-6-oxo-1,6-dihydropyridine-3-yl}phenyl)-2H-isoquinoline-1-one), BGB-3111, and other molecules that can inhibit BTK activity, for example, Akinleye, whose entirety forms part of this specification by reference. These BTK inhibitors are disclosed in et al, Journal of Hematology & Oncology, 2013, 6:59.

[0724] Syk inhibitors are well known, for example, celduratinib (4-(cyclopropylamino)-2-((4-(4-(ethylsulfonyl)piperazine-1-yl)phenyl)amino)pyrimidine-5-carboxamide), entospretinib (6-(1H-indazole-6-yl)-N-(4-morpholinophenyl)imidazo[1,2-a]pyrazine-8-amine), hostamatinib ([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]oxazine-4-yl]methyldihydrogen phosphate), Stamatinib disodium salt (sodium (6-((5-fluoro-2-((3,4,5-trimethoxyphenyl)amino)pyrimidine-4-yl)amino)-2,2-dimethyl-3-oxo-2H-pyrido[3,2-b][1,4]oxazine-4(3H)-yl)methylphosphate), BAY61-3606 (2-(7-(3,4-dimethoxyphenyl)-imidazo[1,2-c]pyrimidine-5-ylamino)-nicotinamide HCl), RO9021 (6-[(1R,2S)-2-amino-cyclohexylamino]-4-(5,6-dimethyl-pyridine-2-ylamino)-pyridazine-3-carboxylic acid amide), Imatinib (Gleevec;4-[(4-methylpiperazine-1-yl)methyl]-N-(4-methyl-3-{[4-(pyridine-3-yl)pyrimidine-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]pyrimidine-4-amine), PRT-060318(2-(((1R,2S)-2-aminocyclohexyl)amino)-4-(m-tolylamino)pyrimidine-5-carboxamide ), PRT-062607 (4-((3-(2H-1,2,3-triazole-2-yl)phenyl)amino)-2-(((1R,2S)-2-aminocyclohexyl)amino)pyrimidine-5-carboxamide hydrochloride), R112 (3,3'-((5-fluoropyrimidine-2,4-diyl)bis(azandiyl))diphenol), R348 (3-ethyl-4-methylpyridine), R406 (6-((5-fluoro-2-((3,4,5-trimethoxyphenyl)amino)pyrimidine-4-yl)amino)-2,2-dimethyl-2H-pyrido[3,2-b][1,4]oxazine-3(4H)-one), YM193306 (Singh et al. Discovery and Development of Spleen Tyrosine Kinase; (See (SYK) Inhibitors, J. Med. Chem. 2012, 55, 3614-3643), 7-Azai Ndol, piceatannol, ER-27319 (the entire text of which forms part of this specification by reference, Singh et al. Discovery and Development of Spleen Tyrosine Kinase) See (SYK) Inhibitors, J. Med. Chem. 2012, 55, 3614-3643), Compound D (the whole compound is incorporated herein by reference; see Singh et al. Discovery and Development of Spleen Tyrosine Kinase (SYK) Inhibitors, J. Med. Chem. 2012, 55, 3614-3643), PRT060318 (the whole compound is incorporated herein by reference; see Singh et al. Discovery and Development of Spleen Tyrosine Kinase (SYK) Inhibitors, J. Med. Chem. 2012, 55, 3614-3643), Luteolin (the whole compound is incorporated herein by reference; see Singh et al. Discovery and Development of Spleen Tyrosine Kinase (SYK) Inhibitors, J. Med. See Chem. 2012, 55, 3614-3643), apigenin (the entire text is incorporated herein by reference; see Singh et al. Discovery and Development of Spleen Tyrosine Kinase (SYK) Inhibitors, J. Med. Chem. 2012, 55, 3614-3643), quercetin (the entire text is incorporated herein by reference; see Singh et al. Discovery and Development See of Spleen Tyrosine Kinase (SYK) Inhibitors, J. Med. Chem. 2012, 55, 3614-3643), fisetin (the entire article is incorporated herein by reference, Singh et al. Discovery and Development of Spleen Tyrosine Kinase (SYK) Inhibitors, Examples include myricetin (see J. Med. Chem. 2012, 55, 3614-3643, which is entirely cited herein), and morin (see Singh et al. Discovery and Development of Spleen Tyrosine Kinase (SYK) Inhibitors, J. Med. Chem. 2012, 55, 3614-3643, which is entirely cited herein).

[0725] Chemotherapy agents can also be B-cell lymphoma 2 (Bcl-2) protein inhibitors. BCL-2 inhibitors are known in the art, for example, ABT-199 (4-[4-[[2-(4-chlorophenyl)-4,4-dimethylcyclohexa-1-en-1-yl]methyl]piperazine-1-yl]-N-[[3-nitro-4-[[(tetrahydro-2H-pyran-4-yl)methyl]amino]phenyl]sulfonyl]-2-[(1H-pyrrolo[2,3-b]pyridine-5-yl)oxy]benzamide), ABT-737 (4-[4-[[2-(4-chlorophenyl)phenyl]methyl]piperazine-1-yl]-N-[4-[[(2R)-4-(dimethylamino)-1-phenylsulfanylbutan-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)piperazine-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-pyrrole-2-yl)methylidene]-4-methoxypyrrole-2-ylidene]indole; methanesulfonic acid)), 2-methoxy-antimycin A3, YC137(4-(4,9-dioxo-4,9-dihydronaphtho[2,3-d]thiazole-2-ylamino)-phenyl ester), pogosin, ethyl 2-amino-6- Examples include rom-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).

[0726] In the methods intended herein, additional chemotherapeutic agents used include, but are limited to: Examples of prohibited substances include midazolam, MEK inhibitors, RAS inhibitors, ERK inhibitors, ALK inhibitors, HSP inhibitors (e.g., HSP70 and HSP90 inhibitors, or combinations thereof), RAF inhibitors, apoptotic compounds, topoisomerase inhibitors, AKT inhibitors including but not limited to MK-2206, GSK690693, perifosine (KRX-0401), GDC-0068, trisirivine, AZD5363, honokiol, PF-04691502, and miltefosine, or FLT-3 inhibitors including but not limited to P406, dovitinib, quizartinib (AC220), amvatinib (MP-470), tandutinib (MLN518), ENMD-2076, and KW-2449, or combinations thereof. Examples of MEK inhibitors, though not limited to them, include trametinib / GSK120212 (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]pyrimidine-1(2H-yl}phenyl)acetamide), selmetinib (6-(4-bromo-2-chloroanilino)-7-fluoro-N-(2-hydroxyethoxy)-3-methylbenzimidazole-5-carboxamide), and pimacertib / AS703026 / MSC1935369 ((S)-N-(2,3-dihydroxypropyl)-3-((2-fluoro-4-iodophenyl)amino)isonicotinamide Mid), XL-518 / GDC-0973 (1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-[(2S)-piperidine-2-yl]azetidine-3-ol), refametinib / BAY869766 / RDEAl19 (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[2,3d]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), R05126766(3-[[3-Fluoro-2-(methylsulfamoylamino)-4-pyridyl]methyl]-4-methyl-7- Examples of inhibitors include pyrimidine-2-yloxychromen-2-one, WX-554, R04987655 / CH4987655 (3,4-difluoro-2-((2-fluoro-4-iodophenyl)amino)-N-(2-hydroxyethoxy)-5-((3-oxo-1,2-oxadinan-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. Examples of HSP inhibitors, though not limited to them, include geldanamycin, i.e., 17-N-allylamino-17-demethoxygeldanamycin (17AAG), and radicicol.

[0727] Known ERK inhibitors include SCH772984 (Merck / Schering-Plough), VTX-11e (Vertex), DEL-22379, Ulixertinib (BVD-523, VRT752271), GDC-0994, FR180204, XMD8-92, and ERK5-IN-1.

[0728] Raf inhibitors are well known, such as vemurafenib (N-[3-[[5-(4-chlorophenyl)-1H-pyrrolo[2,3-b]pyridine-3-yl]carbonyl]-2,4-difluorophenyl]-1-propanesulfonamide) and sorafenib tosylate. Salt (4-[4-[[4-chloro-3-(trifluoromethyl)phenyl]carbamoylamino]phenoxy]-N-methylpyridine-2-carboxamide; 4-methylbenzenesulfonic acid), AZ628 (3-(2-cyanopropan-2-yl)-N-(4-methyl-3-(3-methyl-4-oxo-3,4-dihydroquinazoline-6-ylamino)phenyl)benzamide), NVP-BHG712 (4-methyl-3-(1-methyl-6-(pyridine-3-yl)-1H-pyrazolo[3,4-d]pyrimidine-4-ylamino)-N-(3-(trifluoromethyl)phenyl)benzamide), RAF-265 (1-methyl-5-[2-[5-(trifluoro Examples include (-methyl)-1H-imidazole-2-yl]pyridine-4-yl]oxy-N-[4-(trifluoromethyl)phenyl]benzimidazole-2-amine), 2-bromoardicine (2-bromo-6,7-dihydro-1H,5H-pyrrolo[2,3-c]azepine-4,8-dione), Raf kinase inhibitor IV (2-chloro-5-(2-phenyl-5-(pyridine-4-yl)-1H-imidazole-4-yl)phenol), and sorafenib N-oxide (4-[4-[[[[4-chloro-3(trifluoromethyl)phenyl]amino]carbonyl]amino]phenoxy]-N-methyl-2-pyridinecarboxamide-1-oxide).

[0729] Known topoisomerase I inhibitors useful in the present invention include (S)-10-[(dimethylamino)methyl]-4-ethyl-4,9-dihydroxy-1H-pyrano[3',4':6,7]indolidino[1,2-b]quinoline-3,14(4H,12H)-dione monohydrochloride (topotecan), (S)-4-ethyl-4-hydroxy-1H-pyrano[3',4':6,7]indolidino[1,2-b]quinoline-3,14-(4H,12H)-dione (camptothecin), and (1S,9S)-1-amino-9-ethyl-5-fluoro-1,2,3,9,1 2,15-Hexahydro-9-hydroxy-4-methyl-10H,13H-benzo(de)pyrano(3',4':6,7)indolidino(1,2-b)quinoline-10,13-dione (exatecan), (7-(4-methylpiperazinomethylene)-10,11-ethylenedioxy-20(S)-camptothecin (lulutotecan), or (S)-4,11-diethyl-3,4,12,14-tetrahydro-4-hydroxy-3,14-dioxo1H-pyrano[3',4':6,7]-indolidino[1,2-b]quinoline-9-yl-[1,4'-bipiperidine ]-1'-carboxylate (irinotecan), (R)-5-ethyl-9,10-difluoro-5-hydroxy-4,5-dihydrooxepino[3',4':6,7]indolidino[1,2-b]quinoline-3,15(1H,13H)-dione (diflomothecan), (4S)-11-((E)-((1,1-dimethylethoxy)imino)methyl)-4-ethyl-4-hydroxy-1,12-dihydro-14H-pyrano(3',4':6,7)indolidino(1,2-b)quinoline-3,14(4H)-dione (dimatecan), (S)-8-ethyl-8-hydr Roxy-15-((4-methylpiperazine-1-yl)methyl)-11,14-dihydro-2H-[1,4]dioxyno[2,3-g]pyrano[3',4':6,7]indolidino[1,2-b]quinoline-9,12(3H,8H)-dione(rulutotecan), (4S)-4-ethyl-4-hydroxy-11-[2-[(1-methylethyl)amino]ethyl]-1H-pyrano[3,4:6,7]indolidino[1,2-b]quinoline-3,14(4H,12H)-dione(berotecan), 6-((1,3-dihydroxypropane-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-Indro[2,3-a]pyrrolo[3,4-c]carbazole-5,7(6H)-dione(edotecarin),8,9-Dimethoxy-5-(2-N,N-dimethylaminoethyl)-2,3-methylenediol Xy-5H-dibenzo(c,h)(1,6)naphthyrizin-6-one (Topoveil), benzo[6,7]indolidino[1,2-b]quinoline-11(13H)-one (Rosettacin), (S)-4-ethyl-4-hydroxy-11-(2-(trimethylsilyl)ethyl)-1H-pyrano[3',4':6,7]indolidino[1,2-b]quinoline-3,14(4H,12H)-dione (Cositeca, N), Tetrakis{(4S)-9-[([1,4'-bipiperidinyl]-1'-carbonyl)oxy]-4,11-diethyl-3,14-dioxo-3,4,12,14-tetrahydro-1H-pyrano[3',4':6,7]indolidino[1,2-b]quinoline-4-yl}N,N',N'',N'''-{methanetetrayltetrakis[methylenepoly(oxyethylene)oxy(1-oxoethylene)]}tetraglycinate tetrahydrochloride (ethilinotecan pegol), 10-hydroxy- Examples include camptothecin (HOCPT), 9-nitrocamptothecin (rubitecan), SN38 (7-ethyl-10-hydroxycamptothecin), and 10-hydroxy-9-nitrocamptothecin (CPT109), and (R)-9-chloro-5-ethyl-5-hydroxy-10-methyl-12-((4-methylpiperidine-1-yl)methyl)-4,5-dihydrooxepino[3',4':6,7]indolidino[1,2-b]quinoline-3,15(1H,13H)-dione (ermothecan).

[0730] 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.

[0731] growth factors In certain embodiments, the combination of CDK4 / 6 inhibitors, chemotherapeutic agents, and checkpoint inhibitors is not limited to, but may include: granulocyte colony-stimulating factor (G-CSF, e.g., marketed as Neupogen (filgrastim), Neulasta (pegfilgrastim), or lenograstim), granulocyte-macrophage colony-stimulating factor (GM-CSF, e.g., marketed as morglamostim and salglamostim (Leukine)), M-CSF (macrophage colony-stimulating factor), thrombopoietin (megakaryocyte growth factor (MGDF), e.g., marketed as Romiplostim and Eltrombopag), interleukin (IL)-12, interleukin-3, interleukin-11 (lipidogenesis inhibitor or oprevekin), SCF ( Further combined with the use of hematopoietic growth factors, including stem cell factors, steel factors, kit ligands, or KL) and erythropoietin (EPO), and their derivatives (marketed as epoetin-α, e.g., Darbepoetin, Epocept, Nanokin, Epofit, Epogen, Eplex, and Procrit; marketed as epoetin-β, e.g., Neorecomon, Recomon, and Micella), epoetin delta (marketed as e.g., Dynepo), epoetin omega (marketed as e.g., Epomax), epoetin zeta (marketed as e.g., Silapo and Retacrete), and hematopoietic growth factors, e.g., Epocept, Epotrust, Eriprosafe, Lepoitin, Vintol, Epofit, Erikin, Wepox, Espogen, Relipoitin, Champoetin, Zilop, and EPIAO).

[0732] CDK4 / 6 inhibitors The present invention also provides an advantageous method for treating patients with selective CDK4 / 6 inhibitor-resistant cancer, which comprises administering an effective amount of a compound of formula I, II, III, IV, V, VI, VII, VIII, IX, or X, or a pharmaceutically acceptable composition, salt, or isotopic analog thereof. In certain embodiments, the compounds of the present invention are used to treat patients with cancer that has endogenous resistance to selective CDK4 / 6 inhibition. In certain embodiments, the compounds of the present invention are used to treat patients with cancer that has acquired resistance to one or more selective CDK4 / 6 inhibitors. In certain embodiments, the compounds of the present invention are administered in combination with a selective CDK4 / 6 inhibitor to patients with cancer that responds to selective CDK4 / 6 inhibition in order to extend the therapeutic effect of the selective CDK4 / 6 inhibitor. In certain embodiments, the compounds of the present invention are administered in combination with a selective CDK4 / 6 inhibitor to patients with selective CDK4 / 6 inhibitor-responsive cancer, the patients being selective CDK4 / 6 inhibitor-naive. Selective CDK4 / 6 inhibitors for use in this context include, but are not limited to, palbociclib, abemaciclib, ribociclib, trilaciclib, SHR6390, and rerocyclib.

[0733] In certain embodiments, the selective CDK4 / 6 inhibitor is palbociclib: [ka] or a pharmaceutically acceptable salt thereof.

[0734] In certain embodiments, the selective CDK4 / 6 inhibitor is abemaciclib: [ka] or a pharmaceutically acceptable salt thereof.

[0735] In certain embodiments, the selective CDK4 / 6 inhibitor is ribociclib: [ka] or a pharmaceutically acceptable salt thereof.

[0736] In certain embodiments, the selective CDK4 / 6 inhibitor is rerocyclib: [ka] or a pharmaceutically acceptable salt thereof.

[0737] In certain embodiments, the selective CDK4 / 6 inhibitor is trilaciclib: [ka] or a pharmaceutically acceptable salt thereof.

[0738] In certain embodiments, the selective CDK4 / 6 inhibitor is SHR6390.

[0739] In certain embodiments, selective CDK4 / 6 inhibitors are selected from, for example, the inhibitors described in Patent Documents 1, 2, 3, 4, 5, 1, 6, 9, U.S. Patent No. 9,481,591, and 7, filed by Tavares and Strum and assigned to G1 Therapeutics, which describe a group of N-(heteroaryl)-pyrrolo[3,2-d]pyrimidine-2-aminecyclin-dependent kinase inhibitors comprising the following formula (variable parts are defined in their specifications): [ka]

[0740] In certain embodiments, selective CDK4 / 6 inhibitors are, for example, described in Patent Documents 14, 15, and 16 (also transferred to G1 Therapeutics, for cancer treatment). The inhibitors are selected from those listed in the section on the use of pyrimidine-based drugs in treatment.

[0741] In certain embodiments, the selective CDK4 / 6 inhibitor is, for example, Tavares The inhibitors described in Patent Document 20, titled "Lactam Kinase Inhibitors," Patent Document 21, titled "Synthesis of Lactams," and Patent Document 22, which were filed and similarly transferred to G1 Therapeutics, are selected from these. They describe the synthesis of N-(heteroaryl)-pyrrolo[3,2-d]pyrimidine-2-amines and their use as lactam kinase inhibitors.

[0742] In certain embodiments, the selective CDK4 / 6 inhibitor is derived, for example, from the inhibitor described in Patent Document 23, filed by Strum et al. and assigned to G1 Therapeutics. Selected, this describes compounds and methods for protecting normal cells during chemotherapy using pyrimidine CDK4 / 6 inhibitors. Patent document 24, filed by Strum et al. and assigned to G1 Therapeutics, describes compounds and methods for protecting normal cells during chemotherapy using pyrimidine CDK4 / 6 inhibitors. This document describes compounds and methods for protecting hematopoietic stem cells and progenitor cells from radiation. Patent document 25, filed by Strum et al. and assigned to G1 Therapeutics, describes pyrimidine Patent document 26, filed by Strum et al. and assigned to G1 Therapeutics, describes the HSPC-preserving treatment of abnormal cell proliferation using a CDK4 / 6 inhibitor. This document describes active antineoplastic and antiproliferative pyrimidine-based CDK4 / 6 inhibitors. Patent document 27, filed by Strum et al. and assigned to G1 Therapeutics, describes radiation protection This describes tricyclic pyrimidine CDK inhibitors for use in [specific context]. Patent document 28, filed by Strum et al. and assigned to G1 Therapeutics, describes the maintenance of cells during chemotherapy. This document describes a tricyclic pyrimidine CDK inhibitor for rheumatoid arthritis. Patent document 29, filed by Strum et al. and transferred to G1 Therapeutics, describes rheumatoid arthritis for abnormal cell proliferation in RB-positive cells. This document describes tricyclic pyrimidine CDK inhibitors for use in PC-preserving therapy. Patent document 30, filed by Strum et al. and transferred to G1 Therapeutics, describes antineoplastic This document describes tricyclic pyrimidine CDK inhibitors for use as physical agents and antiproliferative agents. Patent document 31, filed by Strum et al. and assigned to G1 Therapeutics, describes other The combination of antineoplastic agents and pyrimidine CDK4 / 6 inhibitors is described. Patent document 32, filed by Strum et al. and transferred to G1 Therapeutics, describes CDK4 / 6 inhibitors The paper also describes compounds and methods for treating certain Rb-negative cancers with topoisomerase inhibitors. [Examples]

[0743] VIII. Examples Example 1 General method: For convenience, the compounds of the present invention having stereocenters are depicted as racemates. It will be recognized by those skilled in the art that pure enantiomers can be prepared by methods known in the art. Examples of methods for obtaining optically active substances include, at least, the following: i) Physical separation of crystals - A technique for manually separating macroscopic crystals of individual enantiomers. This technique can be used when distinct enantiomer crystals exist, i.e., when the substance is an aggregate and the crystals are visually distinct; ii) Simultaneous crystallization - A technique for separately crystallizing individual enantiomers from a racemic solution, which is only possible when the racemic mixture exists as an aggregate in its solid state; iii) Enzymatic resolution - A technique for the partial or complete separation of racemates by the difference in reaction rates with enantiomer enzymes; iv) Enzymatic asymmetric synthesis - A synthetic technique that uses an enzymatic reaction in at least one synthetic step to obtain a pure or concentrated synthetic precursor as an enantiomer of a desired enantiomer; v) Chemical asymmetric synthesis - A synthetic technique for synthesizing a desired enantiomer from an achiral precursor under conditions that produce asymmetry (i.e., chirality) in the product, which can be achieved using a chiral catalyst or chiral auxiliary agent; vi) Diastereomer separation - A technique in which a racemic compound is reacted with a pure reagent (a chiral auxiliary) to convert individual enantiomers into diastereomers. The resulting diastereomers are then separated by chromatography or crystallization based on their more distinct structural differences, and the chiral auxiliary is subsequently removed to obtain the desired enantiomers; vii) Primary and secondary asymmetric conversion - Equilibrium conversion of diastereomers derived from racemates A technique in which, in principle, all substances are converted into crystalline diastereomers derived from the desired enantiomer by either creating a dominant solution of the diastereomer derived from the desired enantiomer, or by disrupting the equilibrium through the selective crystallization of the diastereomer derived from the desired enantiomer. The desired enantiomer is then released from the diastereomer; viii) Kinetic resolution - This technique refers to achieving partial or complete resolution of a racemate (or further resolution of a partially resolved compound) by unequal reaction rates of enantiomers with chiral, non-racemic reagents or catalysts under dynamic conditions; ix) Enantioselective synthesis from non-racemic precursors - synthetic techniques in which the desired enantiomer is obtained from non-chiral starting materials, and in which stereochemical integrity is lost completely or minimally during the synthesis process; x) Chiral liquid chromatography - A technique (including chiral HPLC) for separating enantiomers of a racemic mixture in a liquid mobile phase based on differences in their interactions with the stationary phase. The stationary phase may be composed of chiral substances, or the mobile phase may contain additional chiral substances, to induce different interactions. xi) Chiral gas chromatography - A technique for separating enantiomers by volatilizing a racemic mixture and observing the differences in its interaction with a column containing a stationary non-racemic chiral adsorbent phase in the gas mobile phase; xii) Extraction using chiral solvents - A technique for separating enantiomers by selective dissolution of a particular enantiomer in a specific chiral solvent; xiii) Transport through chiral membranes - a technique for placing racemates in contact with a thin membrane barrier. The barrier typically separates two miscible fluids, one of which contains a racemate, and a driving force such as a concentration difference or pressure difference causes selective transport through the membrane barrier. The separation occurs as a result of the non-racemic chiral properties of the membrane, which allow only one enantiomer of the racemate to pass through.

[0744] Chiral chromatography, including pseudo-moving-bed chromatography, is used in certain embodiments. A wide range of chiral stationary phases are commercially available.

[0745] Typical synthesis examples general Unless otherwise specified, all reagents were used without further purification. 1 1H NMR spectra were obtained at room temperature using a Bruker 300 MHz instrument in DMSO-d6 or CD3OD. If multiple conformers were detected, the chemical shift of the most abundant conformer was reported. 1 The chemical shifts of the 1H NMR spectra were recorded in parts per million (ppm) on a delta scale from the internal standard of the residual solvent. Splitting patterns are shown as s (singlet), d (doublet), t (triplet), q (quartet), m (multiplet), brs (broad). The LC-MS conditions were as follows:

[0746] General LC / MS method: Column: Agilent Zorbax XDB C18 4.6×50mm, 3.5μm Mobile phase: Solvent A: 0.1% formic acid in water Solvent B: MeOH Flow rate: 1.0mL / min Runtime / Gradient: 2 minutes (20%~90%B), then 3 minutes at 90%B Temperature: 30℃.

[0747] Common HPLC method: Column: Agilent SB-C18 4.6×150mm, 3.5μm Mobile phase: Solvent A: 0.02% TFA in water Solvent B: MeOH Flow rate: 1.0mL / min Runtime / Gradient: 0.5 minutes at 10%B, 9.5 minutes at gradients 10% to 90%B, then 10 minutes at 90%B. Temperature: 30℃.

[0748] Common preparative HPLC method: Column: Phenomenex Luna 5u 100A, 21.2 × 250 mm, 5 μm Mobile phase: Solvent A: Water Solvent B: MeOH Flow rate: 10mL / min Runtime / Gradient: 1 minute at 20%B, 30 minutes at 20%~80%B, then 10 minutes at 90%B. Temperature: Ambient

[0749] The following abbreviations will be 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(pinacorato)diborone, AcOK = potassium acetate, N2 = nitrogen gas, Pd(OAc)2 = palladium(II) acetate, siRNA = 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-butyl alcohol, DBU = 1,8-disabicyclo[5.4.0]undec-7-ene, CuI = copper iodide, TBAF = tetra-n-butylammonium 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 = meta-chloroperbenzoic acid.

[0750] Scheme 1.4-((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 Synthesis of Compound 1 [ka]

[0751] Step 1: In a solution of intermediate 1 (100 mg, 0.33 mmol) in DMF (4 mL), 4-aminobenzenesulfonamide (67.3 mg, 0.39 mmol), AcOK (95.8 mg, 0.98 mmol), and Pd(OAc)2 (7.3 mg, 0.0 mmol) are added under an N2 atmosphere. 3 mmol) and X-phos (62.2 mg, 0.13 mmol) were added. 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 ₹ (10 mL × 3). The combined organic phase was washed with brine (5 mL × 2), dried over Na₂SO₄, and concentrated under vacuum. The resulting residue was purified by preparative TLC to obtain compound 1 (2.5 mg, 0.006 mmol). MS (ESI+): m / z 443 [M + H] + . 1 H NMR (300 MHz, DMSO-d6):δ 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, 2 H), 1.95 - 1.62 (m, 6 H).

[0752] Scheme 2.4-((7'-Oxo-7',8'-Dihydro-6'H-Spiro[Cyclohexane-1,9'-Pyrrolo[1,5-a:2,3-d']Dipyrimidine]-2'-yl)amino)benzenesulfonamide Synthesis of Compound 2 [ka]

[0753] Step 1: To a mixture of intermediate 1 (12 g, 76.33 mmol) in MeOH (120 mL), SOCl2 (10 mL) was added dropwise. The reaction mixture was stirred overnight at 40°C. The reaction mixture was concentrated under vacuum. The resulting residue was neutralized to approximately pH 8 with Na2CO3 aqueous solution and extracted using DCM (50 mL x 5). The combined organic phase was concentrated to obtain intermediate 2 (12 g, 70.08 mmol). LC-MS (ESI+): m / z 172 [M + H]+.

[0754] Step 2: Add the solution of intermediate 3 (10 g, 142.76 mmol) to DCM (150 mL). DBU (23 g, 151.08 mmol) was added dropwise over 30 minutes at 0°C. After addition, the reaction solution was stirred at room temperature for 2 hours. Next, 1-(chloromethyl)-4-methoxybenzene (20 g, 127.71 mmol) was added to the reaction solution. The reaction mixture was stirred at room temperature for 2 days. The reaction mixture was quenched with saturated sodium bicarbonate aqueous solution (100 mL). The organic phase was dried over Na₂SO₄, filtered, and concentrated under vacuum. The resulting residue was purified by silica gel column chromatography to obtain intermediate 4 (14 g, 73.61 mmol).

[0755] Step 3: To a solution of intermediate 5 (25 g, 90.95 mmol) in DMAc (100 mL), intermediate 2 (12 g, 70.08 mmol) and NaHCO3 (20 g, 238.07 mmol) were added. The reaction mixture was stirred at 60 °C for 12 hours. After cooling to room temperature, the reaction mixture was quenched with water (200 mL) and extracted with SiO2 (100 mL x 2). The organic layer was separated, washed with brine, dried over MgSO4, filtered, and concentrated under vacuum. The resulting crude product was purified by column chromatography to obtain intermediate 6 (14 g, 34.17 mmol). LC-MS (ESI+): m / z 410 [M + H]+.

[0756] Step 4: To a solution of intermediate 6 (14 g, 34.17 mmol) in THF (200 mL), CuI (647 mg, 3.40 mmol), Pd(PPh3)2Cl2 (1.2 g, 1.71 mmol), and TEA (6.9 g, 68.19 mmol) were added under an N2 atmosphere. Then, a solution of intermediate 4 (8 g, 42.06 mmol) in THF (20 mL) was added dropwise to the reaction mixture over 15 minutes. After stirring the mixture overnight at room temperature, the reaction mixture was concentrated under vacuum. The resulting residue was purified by silica gel column chromatography to obtain intermediate 7 (5 g, 10.59 mmol). LC-MS (ESI+): m / z 472 [M + H]+.

[0757] Step 5: To a solution of intermediate 7 (5 g, 10.59 mmol) in THF (30 mL), TBAF (30 mL, 1 M in THF) was added at 60°C under an N2 atmosphere. The mixture was stirred at 60°C for 2 hours, then the reaction product was quenched with water (100 mL) and extracted with SiO2 (50 mL x 2). The combined organic phase was washed with brine (50 mL), dried over Na2SO4, filtered, and concentrated under vacuum. The resulting residue was purified by silica gel column chromatography to obtain intermediate 8 (1 g, 2.12 mmol). LC-MS (ESI+): m / z 472 [M+H]+.

[0758] Step 6: To a solution of intermediate 8 (1 g, 2.12 mmol) in DCM (9 mL), TFA (3 mL) was added at room temperature. The reaction mixture was stirred overnight at room temperature. The reaction solution was concentrated under vacuum. The resulting residue was purified by silica gel column chromatography to obtain intermediate 9 (380 mg, 1.08 mmol). LC-MS (ESI+): m / z 352 [M+H] + .

[0759] Step 7: To a solution of intermediate 9 (160 mg, 0.46 mmol) in t-BuOH (5 mL), 4A molecular sieve (100 mg) was added. The mixture was stirred at room temperature for 30 minutes. Then, triethylamine (90 mg, 0.89 mmol) and diphenyl phosphate azide (240 mg, 0.0.87 mmol) were added to the mixture. After stirring the mixture at 80°C for 4 hours, the reaction mixture was filtered, and the filtrate was concentrated under vacuum. The resulting residue was purified by silica gel column chromatography to obtain intermediate 10 (30 mg, 0.10 mmol). LC-MS (ESI+): m / z 291 [M+H]+.

[0760] Step 8: Under an N2 atmosphere, 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) were added to a solution of 4-aminobenzenesulfonamide (40 mg, 0.23 mmol) in DMF (4 mL). 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 siRNA / THF = 1 / 1 (5 mL × 3). The combined organic phase was dried over Na2SO4 and concentrated under vacuum. The resulting residue was purified by preparative TLC, and compound 2 (4.2 mg, 0.01 mmol) was obtained. ol) was obtained. LC-MS (ESI+): m / z 427 [M + H]+; 1H NMR (300 MHz, DMSO-d6): δ 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).

[0761] Scheme 3.4-((3'-Oxo-2',3'-Dihydro-1'H-Spiro[Cyclohexane-1,4'-Pyrimido[5',4':4,5]Pyrrolo[2,1-c][1,2,4]Triadin]-7'-Il)amino)Benzenolsulfonamide Synthesis of Compound 3 [ka]

[0762] Step 1: Under an N2 atmosphere, n-BuLi (147 ml, 2.5 mol in THF, 367.5 mmol) was added dropwise to a solution of ethynyltrimethylsilane (305.94 mmol) in anhydrous THF (500 mL) over 30 minutes at -78°C. After addition, the reaction mixture was stirred at -78°C for 20 minutes. Next, a solution of intermediate 1 (105 g, 456.26 mmol) in anhydrous THF (300 mL) was added dropwise to this reaction solution over 60 minutes. After addition, the reaction mixture was gradually warmed to -20°C and stirred at -20°C for 30 minutes. The reaction mixture was quenched with saturated NH4Cl solution (100 mL) and water (300 mL), and extracted with EA (200 mL x 2). The combined organic phases were washed with brine (100 mL), dried over Na2SO4, filtered, and concentrated under vacuum. The resulting residue was purified by silica column chromatography to obtain intermediate 2 (60 g, 182.83 mmol) as oil.

[0763] Step 2: To a solution of intermediate 2 (60 g, 182.83 mmol) in THF (300 mL), a solution of TBAF trihydrate (72 g, 228.20 mmol) in THF (300 mL) was added at -20°C. After addition, the reaction mixture 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 x 2). The combined organic phase was dried over Na2SO4, filtered, and concentrated under vacuum. The resulting residue was purified by silica column chromatography to obtain intermediate 3 (36 g, 140 mmol). 55 mmol was obtained.

[0764] Step 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) were mixed overnight in DMF at room temperature. The reaction mixture was quenched with water (500 mL) and extracted with EA (500 mL x 3). The combined organic phase was washed with water (500 mL x 3), dried over Na2SO4, filtered, and concentrated under vacuum. The resulting residue was purified by silica column chromatography to obtain intermediate 5 (28 g, 69.64 mmol). LC-MS (ESI+): m / z 403 [M + H]+.

[0765] Step 4: Under an N2 atmosphere, intermediate 6 (1.2g, 7.64 mmol) and NaHCO3 (1.25g, 14.93 mmol) were added to a solution of intermediate 5 (2g, 4.97 mmol) in DMF (20 mL). The reaction mixture was stirred overnight at 60°C. The reaction mixture was then cooled to room temperature, quenched with water (100 mL), and extracted with EA (30 mL x 3). The combined organic phase was dried over Na2SO4, filtered, and concentrated under vacuum. The resulting residue was purified by silica column chromatography to obtain intermediate 7 (1.2g, 2.29 mmol). LC-MS (ESI+): m / z 524 [M + H]+.

[0766] Step 5: To a solution of intermediate 7 (1.2 g, 2.29 mmol) in THF (15 mL), a solution of TBAF (1.2 mL, 1 mol in THF, 1.2 mmol) was added. The reaction mixture was stirred at 60°C for 1 hour. The reaction mixture was cooled to room temperature, quenched with water (30 mL), and extracted with EA (30 mL x 3). The combined organic phase was dried over Na2SO4, filtered, and concentrated under vacuum. The resulting residue was purified by silica column chromatography to obtain intermediate 8 (300 mg, 0.57 mmol). LC-MS (ESI+): m / z 524 [M + H]+.

[0767] Step 6: To a solution of intermediate 8 (2 g, 3.82 mmol) in DMAc (30 mL), Cs2CO3 (4 g, 12.28 mmol) was added. The reaction mixture was stirred at 100 °C for 5 hours. The reaction mixture was cooled to room temperature, quenched with water (60 mL), and extracted with EA (20 mL x 3). The combined organic phase was dried over Na2SO4, filtered, and concentrated under vacuum. The resulting residue was purified by silica column chromatography to obtain intermediate 9 (320 mg, 0.82 mmol). LC-MS (ESI+): m / z 392 [M + H]+.

[0768] Step 7: Under an N2 atmosphere, intermediate 9 (50 mg, 0.13 mmol) was dissolved in DMF (2 mL), to which 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) were added. The reaction mixture was stirred at 80°C for 5 hours. The reaction mixture was cooled to room temperature, quenched with water (20 mL), and extracted with DCM:MeOH = 10:1 (20 mL x 3). The combined organic phase was dried over MgSO4, filtered, and concentrated under vacuum. The resulting residue was purified by preparative TLC to obtain intermediate 11 (43 mg, 0.082 mmol). LC-MS (ESI+): m / z 528 [M + H]+.

[0769] Step 8: To the solution of intermediate 11 (20 mg, 0.038 mmol) in DCM (2 mL), TFA (0.2 mL) was added. The reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was quenched with saturated NaHCO3 solution (10 mL) and extracted with DCM:MeOH = 10:1 (10 mL × 3). The combined organic phase was dried over MgSO4, filtered, and concentrated under vacuum. The resulting residue was purified by preparative TLC to obtain 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, 1 H), 1.70 - 1.61 (m, 1H).

[0770] Scheme 4.4-((1'H-spiro[cyclohexane-1,4'-pyrimido[5',4':4,5]pyrrolo[2,1-c][1,2,4]triazine]-7'-yl)amino)benzenesulfonamide Synthesis of Compound 4 [ka]

[0771] Step 1: To a solution of intermediate 1 (300 mg, 0.89 mmol) in THF (20 mL), TBAF trihydrate (50 mg, 0.16 mmol) was added at -10°C. After addition, the reaction mixture 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 x 2). The combined organic phase was dried over Na2SO4, filtered, and concentrated under vacuum to obtain intermediate 2 (220 mg, 0.83 mmol). LC-MS (ESI+): m / z 266 [M + H] + .

[0772] Step 2: To a solution of intermediate 2 (200 mg, 0.83 mmol) in MeCN (20 mL), NBS (200 mg, 1.12 mmol) and DBU (170 mg, 1.12 mmol) were added at room temperature. After addition, the reaction mixture was stirred at room temperature for 30 minutes. The reaction mixture was quenched with water (100 mL) and extracted with EA (50 mL x 2). The combined organic phase was dried over Na2SO4, filtered, and concentrated under vacuum. The resulting residue was purified by column chromatography to obtain intermediate 3 (200 mg, 0.58 mmol). LC-MS (ESI+): m / z 344 / 346 [M + H] + .

[0773] Step 3: To a solution of intermediate 3 (75 mg, 0.22 mmol) in DCM (5 mL), Dess-Martin reagent (100 mg, 0.24 mmol) was added at room temperature. After addition, the reaction mixture 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 x 2). The combined organic phase was dried over Na2SO4, filtered, and concentrated under vacuum. The resulting residue was purified by silica column chromatography to obtain intermediate 4 (50 mg, 0.15 mmol). LC-MS (ESI+): m / z 342 / 344 [M + H]+.

[0774] Step 4: Add the solution of intermediate 4 (400 mg, 1.17 mmol) in THF (40 mL) TBAF trihydrate (1 mg, 3.17 mmol) was added at room temperature. After addition, the reaction mixture was stirred at room temperature for 30 minutes. The reaction mixture was quenched with water (100 mL) and extracted with EA (50 mL x 2). The combined organic phase was dried over Na2SO4, filtered, and concentrated under vacuum. The resulting residue was purified by silica column chromatography to obtain intermediate 5 (260 mg, 0.77 mmol) as a white solid.

[0775] Step 5: To a solution of intermediate 5 (300 mg, 0.88 mmol) in THF (5 mL), hydrazine hydrate diamide hydrate (2 mL) and K2CO3 (200 mg, 1.45 mmol) were added. After addition, the reaction mixture was stirred at 40°C for 1 hour. The reaction mixture was quenched with water (20 mL) and extracted with EA (20 mL x 3). The combined organic phase was dried over Na2SO4, filtered, and concentrated under vacuum. The resulting residue was purified by silica column chromatography to obtain intermediate 6 (200 mg, 0.73 mmol). LC-MS (ESI+): m / z 276 / 278 [M + H]+.

[0776] Step 6: Under an N2 atmosphere, 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) were added to a solution of intermediate 6 (20 mg, 0.07 mmol) in DMF (2 mL). The reaction mixture was stirred at 80°C for 5 hours. The reaction mixture was cooled to room temperature, quenched with water (5 mL), and extracted with DCM:MeOH = 10:1 (5 mL x 3). The combined organic phase was dried over MgSO4, filtered, and concentrated under vacuum. The resulting residue was purified by preparative TLC to obtain compound 4 (3.9 mg, 0.01 mmol). LC-MS (ESI+): m / z 412 [M + H]+; 1H NMR (300 MHz, DMSO-d6): δ 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).

[0777] Scheme 5.4-((9'-oxo-8',9'-dihydrospiro[cyclohexane-1,10'-pyrimido[5',4':4,5]pyrrolo[2,1-d][1,2,5]triazepine]-2'-yl)amino)benzenesulfonamide Synthesis of Compound 6 [ka]

[0778] Step 1: Thionyl chloride was added to a solution of intermediate 1 (10 g) in methanol, and the reaction mixture was stirred overnight. After purification, intermediate 2 (5.47 g) was obtained.

[0779] Step 2: Sodium bicarbonate was added to the solution of intermediate 2 (5.47 g) in DMAC, and the reaction mixture was stirred overnight at 90°C. After purification, intermediate 3 (6.25 g) was obtained.

[0780] Step 3: DIEA was added to a solution of intermediate 3 (500 mg) in THF, followed by compound b, PdCl2(PPh3)2, and CuI. The reaction mixture was then stirred overnight at 30°C. After purification, intermediate 4 (410 mg) was obtained.

[0781] Step 4: TBAF was added to the solution of intermediate 4 (20 mg) in THF, and the reaction mixture was stirred overnight at 60°C. After purification, intermediate 5 (8 mg) was obtained.

[0782] Step 5: Compound c, Pd(OAc)2, X-phos, and AcOK were added to a solution of intermediate 5 (50 mg) in DMF. The reaction mixture was then 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.

[0783] Scheme 6 Synthesis of cyclic imine intermediate and compound 24 [ka]

[0784] Scheme 7.4-((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]triazine]-7'-yl)amino)benzenesulfonamide Synthesis of Compound 12 [ka]

[0785] Step 1: 200 mg of compound 1 was converted to compound 2 using Cbz-Cl / NaH / THF / 0°C / 0.5 hours. After purification, 220 mg of compound 2 was obtained.

[0786] Step 2: 210 mg of compound 2 was converted to compound 3 using TFA / DCM / room temperature / 30 minutes. After purification, 150 mg of compound 3 was obtained.

[0787] Step 3: 130 mg of compound 3 was converted to compound 4 using NaH / THF / 0°C / 2 hours. The starting material was consumed. After purification, 80 mg of compound 4 was obtained.

[0788] Steps 4 and 5: 20 mg of compound 4 was converted to compound 5 using Pd(OAc)2 / x-phos / AcOK / DMF / 85°C / 4 hours. The starting material was consumed. TLC was clean. LC-MS detected a significant MS peak for compound 12. After purification... 7.3 mg of compound 12 was obtained.

[0789] Scheme 8. Synthesis of Compound 18: (R)-4-((6'-(fluoromethyl)-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 [ka]

[0790] Step 6: 500 mg of compound 6 was converted to compound 7 using Pd(OAc)2 / X-Phos / KOAc / DMF / 80°C / 4 hours. After purification, 315 mg of compound 7 was obtained.

[0791] Step 7: 70 mg of compound 7 was converted to compound 18 using DAST / THF / 0°C to room temperature / 3 hours. After purification with the above method, 3.0 mg of compound 18 was obtained.

[0792] Scheme 9. Synthesis of Compound 19: (S)-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 [ka]

[0793] Step 1: 20 g of compound 1 was converted to compound 2 using SOCl2 / MeOH / reflux at room temperature overnight. After purification, 17.7 g of compound 2 was obtained.

[0794] Step 2: 17.7 g of compound 2 was converted to compound 3 using NaHCO3 / DMAc / 70°C / overnight. After purification, 22 g of compound 3 was obtained.

[0795] Step 3: 5.5g of compound 3 was converted to compound 4 using CuI / PdCl2(PPh3)2 / TEA / THF / room temperature / overnight. After purification, 4.5g of compound 4 was obtained.

[0796] Step 4: 500 mg of compound 4 was converted to compound 5 using Cs2CO3 / DMF / room temperature / overnight. After purification, 195 mg of compound 5 was obtained.

[0797] Step 5: 165 mg of compound 5 was converted to compound 6 using TFA / DCM / room temperature / 30 minutes. After purification, 100 mg of compound 6 was obtained.

[0798] Step 6: 30 mg of compound 6 was converted to compound 19 using Pd(OAc)2 / x-phos / AcOK / DMF / 80°C / 3 hours. Major new spots were observed on TLC. After purification, 3.4 mg of compound 19 was obtained. 1H-NMR and LC-MS were good.

[0799] Scheme 10: Synthesis of Compound 22 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 [ka]

[0800] Compound 22 is prepared in the same manner as compound 19, but instead uses the R-enantiomer of the propargylamine reagent in step 3.

[0801] Scheme 11: Synthesis of Compound 40, 4-((6'-amino-8'H-spiro[cyclohexane-1,9'-pyrazino[1',2':1,5]pyrrolo[2,3-d]pyrimidine]-2'-yl)amino)benzenesulfonamide [ka]

[0802] Step 1: 2.6 g of compound 1 was converted to compound 2 using HOAc / THF / H2O / 60°C / overnight. After purification, 2 g of compound 2 was obtained.

[0803] Step 2: 2g of compound 2 was converted to compound 3 using NaCl2O / THF / H2O / room temperature / overnight. Some of the starting material remained. After purification, 1.5g of compound 3 was obtained.

[0804] Step 3: 1.5 g of compound 3 was converted to...

Claims

1. formula: 【Chemistry 1】 【change】 (In the formula, X １ 、 X ２ 、 X ３ 、 X ４ 、 and X ５ are, independently, selected from N, CH, CR ２ 、 and CR ４ and at least one of X １ 、 X ２ 、 X ３ 、 X ４ 、 and X ５ is CR ２ and no more than two of X １ 、 X ２ 、 X ３ 、 X ４ 、 and X ５ are selected to be N, X １１ , X １２ , X １３ , X １４ , and X １５ These are N, CH, and CR independently. ２ , and CR ４ Selected from, X １１ , X １２ , X １３ , X １４ , and X １５ Two or fewer of these are selected such that the total is N. Each R １ These are independently hydrogen, halogen, -OR １４ , NR １４ R １５ Selected from the group consisting of alkyl, aryl, cycloalkyl, haloalkyl, heteroaryl, alkyl-hydroxyl, and heterocyclic, with two R １ These can optionally form a 3-membered, 4-membered, 5-membered, 6-membered, 7-membered, or 8-membered cycloalkyl group, or a 4-membered, 5-membered, 6-membered, 7-membered, or 8-membered heterocycle having one, two, or three heteroatoms selected from N, O, and S, together with the ring atoms to which they are bonded, and two R １ However, the cycloalkyl or heterocycle formed by bonding with the atom to which they bond is R ５０ They may be optionally substituted with one or two substituents independently selected from them. Each R ２ It is independently, -NR １４ C(O)R ６ , -NR １４ S(O)R ６ , -NR １４ S(O) ２ R ６ , -NR １４ C(S)R ６ , -OC(O)R ６ , -OS(O)R ６ , -OS(O) ２ R ６ , -OC(S)R ６ , -C(O)R ６ , -C(S)R ６ , -S(O)R ６ , -S(=NR １４ ) ２ R ６ , -S(=NR １４ ) (O)R ６ and -S(O) ２ R ６ Selected from the group consisting of, R ３ is hydrogen, -OR １４ , -NR １４ R １５ Alkyl, alkenyl, alkynyl, -C(O)R ６ -C(O)alkyl, -C(S)alkyl, aryl, -SO ２ Selected from the group consisting of alkyl, heteroaryl, heterocyclic, -alkyl-aryl and -alkyl-heteroaryl, Each 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) ２ R ６ , -NR １４ C(S)R ６ , -OC(O)R ６ , -OS(O)R ６ , -OS(O) ２ R ６ , -OC(S)R ６ , -C(O)R ６ , -C(S)R ６ , -S(O)R ６ , and -S(O) ２ R ６ from the group Selected from, R ５ is hydrogen, alkyl, haloalkyl, halogen, cyano, -OR １４ , or -NR １４ R １５ And, Each R ６ is independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocycle, aryl, heteroaryl, NR ７ R ７ , and OR ７ ; and each R ７ R ７ , and OR ７ other than hydrogen, NR ６ is optionally substituted with one, two, three or four R ８ groups; Each R ７ R is independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, alkyl-aryl, alkyl-heteroaryl, and heteroaryl, and R other than hydrogen. ７ Each of these consists of 1, 2, 3, or 4 R ８ It is arbitrarily substituted in the base, Each R ８ These are independently hydrogen, halogen, haloalkyl, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, heteroaryl, and -S(O). ２ Alkyl, NR １２ R １３ , alkyl-heteroaryl, alkyl-aryl, and OR １２ Selected from the group consisting of, Each R １２ and R １３ These are independently hydrogen, alkyl, alkenyl, alkynyl, -C(O)alkyl, -C(S)alkyl, aryl, and -SO ２ Selected from the group consisting of alkyl, -S(O)alkyl, heteroaryl, alkyl-aryl, cycloalkyl, heterocyclic, and alkyl-heteroaryl, Each R １４ and R １５ These are independently hydrogen, alkyl, alkenyl, alkynyl, and -C(O)R ６ -C(O)alkyl, -C(S)alkyl, aryl, -SO ２ Selected from the group consisting of alkyl, heteroaryl, heterocyclic, -alkyl-aryl, and -alkyl-heteroaryl, R １７ and R １８ Each of the following is independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, alkyl-aryl, alkyl-heteroaryl, and heteroaryl, and each except hydrogen has 1, 2, 3, or 4 R ８ It is arbitrarily substituted in the base, R １９ is hydrogen, alkyl, haloalkyl, halogen, cyano, -OR １４ , or -NR １４ R １５ and Each R ５０ Independently, hydrogen, -NR １４ R １５ , OR １４ , and R ４ (Selected from the group consisting of) Compounds thereof, or pharmaceutically acceptable salts, N-oxides, isotopic analogs thereof, and / or pharmaceutically acceptable compositions thereof.

2. formula: 【Chemistry 2】 (In the formula, each R ２ It is independently, -NR １４ C(O)R ６ , -NR １４ S(O)R ６ , -NR １４ S(O) ２ R ６ , -NR １４ C(S)R ６ , -OC(O)R ６ , -OS(O)R ６ , -OS(O) ２ R ６ , -OC(S)R ６ , -C(O)R ６ , -C(S)R ６ , -S(O)R ６ , and -S(O) ２ R ６ (Selected from the group consisting of) A compound according to claim 1, or a pharmaceutically acceptable salt, N-oxide, isotope analog thereof, and / or a pharmaceutically acceptable composition thereof.

3. formula: 【Transformation 3】 The compound according to claim 1, or a pharmaceutically acceptable salt thereof.

4. R ５ The compound according to claim 1, wherein the compound is a hydroxyl group.

5. formula: 【Chemistry 4】 The compound according to claim 1, or a pharmaceutically acceptable salt thereof.

6. One R １ The compound according to claim 1, wherein the compound is hydrogen.

7. R １ The compound according to claim 1, wherein all of them are hydrogen.

8. R １ The compound according to claim 1, wherein none of the compounds are hydrogen.

9. formula: 【Transformation 5】 The compound according to claim 1, or a pharmaceutically acceptable salt thereof.

10. formula: 【Transformation 6】 The compound according to claim 1, or a pharmaceutically acceptable salt thereof.

11. formula: 【Transformation 7】 The compound according to claim 1, or a pharmaceutically acceptable salt thereof.

12. formula: 【Transformation 8】 The compound according to claim 1, or a pharmaceutically acceptable salt thereof.

13. X １１ The compound according to any one of claims 10 to 12, wherein is CH.

14. X １１ The compound according to any one of claims 10 to 12, wherein is N.

15. X １１ CR ４ The compound according to any one of claims 10 to 12.

16. X １２ The compound according to any one of claims 10 to 15, wherein is CH.

17. X １２ The compound according to any one of claims 10 to 15, wherein is N.

18. X １２ CR ４ The compound according to any one of claims 10 to 15.

19. X １３ The compound according to any one of claims 10 to 18, wherein is CH.

20. X １３ The compound according to any one of claims 10 to 18, wherein is N.

21. X １３ CR ４ The compound according to any one of claims 10 to 18.

22. X １４ The compound according to any one of claims 10 to 21, wherein is CH.

23. X １４ The compound according to any one of claims 10 to 21, wherein is N.

24. X １４ CR ４ The compound according to any one of claims 10 to 21.

25. X １５ The compound according to any one of claims 10 to 24, wherein is CH.

26. X １５ The compound according to any one of claims 10 to 24, wherein is N.

27. X １５ CR ４ The compound according to any one of claims 10 to 24.

28. formula: 【Chemistry 9】 The compound according to claim 1, or a pharmaceutically acceptable salt thereof.

29. R ３ The compound according to any one of claims 1 to 28, wherein is hydrogen.

30. R ３ The compound according to any one of claims 1 to 28, wherein the parent is alkyl.

31. R ３ ga-NR １４ R １５ The compound according to any one of claims 1 to 28.

32. R ３ ga-NH ２ The compound according to any one of claims 1 to 28.

33. formula: 【Chemistry 10】 The compound according to claim 1, or a pharmaceutically acceptable salt thereof.

34. formula: 【Chemistry 11】 The compound according to claim 1, or a pharmaceutically acceptable salt thereof.

35. formula: 【Chemistry 12】 The compound according to claim 1, or a pharmaceutically acceptable salt thereof.

36. formula: 【Chemistry 13】 The compound according to claim 1, or a pharmaceutically acceptable salt thereof.

37. formula: 【Chemistry 14】 The compound according to claim 1, or a pharmaceutically acceptable salt thereof.

38. Two R １ The compound according to claim 1 or any one of claims 33 to 37, wherein they form a 3-membered ring to an 8-membered ring together with the carbon atoms to which they are bonded.

39. Two R １ The compound according to claim 1 or any one of claims 33 to 37, wherein they form a six-membered carbon ring together with the carbons to which they are bonded.

40. One R １ The compound according to claim 1 or any one of claims 33 to 37, wherein is a halogen.

41. One R １ The compound according to claim 1 or any one of claims 33 to 37, wherein is a haloalkyl.

42. One R １ The compound according to claim 1 or any one of claims 33 to 37, wherein the compound is hydroxyl.

43. R １ The compound according to claim 1 or any one of claims 33 to 37, wherein is selected from alkyl, aryl, cycloalkyl, and haloalkyl.

44. R ２ ga-C(O)R ６ , -C(S)R ６ , -S(O)R ６ , or -S(O) ２ R ６ The compound is as described in any one of claims 1 to 43.

45. R ２ ga-C(O)R ６ The compound according to any one of claims 1 to 43.

46. R ２ ga-S(O) ２ R ６ The compound according to any one of claims 1 to 43.

47. Each R ６ The compound according to any one of claims 1 to 46, wherein the compound is independently selected from hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, and heteroaryl.

48. Each R ６ However, it became independent, NR ７ R ７ and OR ７ A compound according to any one of claims 1 to 46, selected from the above.

49. R ２ ga-S(O) ２ NH ２ The compound according to any one of claims 1 to 43. 【Request Item 50】 【Chemistry 15】 but, 【Chemistry 16】 The compound according to any one of claims 1 to 49.

51. X １ The compound according to any one of claims 1 to 50, wherein is CH.

52. X １ A compound according to any one of claims 1 to 50, wherein is N.

53. X １ CR ２ The compound according to any one of claims 1 to 50.

54. X １ CR ４ The compound according to any one of claims 1 to 50.

55. X ２ The compound according to any one of claims 1 to 54, wherein is CH.

56. X ２ A compound according to any one of claims 1 to 54, wherein is N.

57. X ２ CR ２ The compound according to any one of claims 1 to 54.

58. X ２ CR ４ The compound according to any one of claims 1 to 54. 【Request Item 59】 【Chemistry 17】 but, [Chemistry 18] The compound according to any one of claims 1 to 58.

60. X ３ The compound according to any one of claims 1 to 58, wherein is CH.

61. X ３ A compound according to any one of claims 1 to 58, wherein is N.

62. X ３ CR ２ The compound according to any one of claims 1 to 58.

63. X ３ CR ４ The compound according to any one of claims 1 to 58. 【Request Item 64】 【Chemistry 19】 but, 【Chemistry 20】 The compound according to any one of claims 60 to 63.

65. X ４ The compound according to any one of claims 1 to 64, wherein is CH.

66. X ４ A compound according to any one of claims 1 to 64, wherein is N.

67. X ４ CR ２ The compound according to any one of claims 1 to 64.

68. X ４ CR ４ The compound according to any one of claims 1 to 64.

69. X ５ The compound according to any one of claims 1 to 68, wherein is CH.

70. X ５ A compound according to any one of claims 1 to 68, wherein is N.

71. X ５ CR ２ The compound according to any one of claims 1 to 68.

72. X ５ CR ４ The compound according to any one of claims 1 to 68.

73. at least one R ４ OR １４ The compound according to any one of claims 1 to 72.

74. at least one R ４ The compound according to any one of claims 1 to 72, wherein is a halogen.

75. at least one R ４ The compound according to any one of claims 1 to 72, wherein is alkyl.

76. at least one R ３ The compound according to any one of claims 1 to 72, wherein is alkyl.

77. In a particular claim, the compound is: 【Chemistry 21】 Alternatively, a pharmaceutically acceptable salt thereof is selected.

78. structure: 【Chemistry 22】 The compound according to claim 77, or a pharmaceutically acceptable salt thereof.

79. structure: 【Chemistry 23】 The compound according to claim 77, or a pharmaceutically acceptable salt thereof.

80. structure: 【Chemistry 24】 The compound according to claim 77, or a pharmaceutically acceptable salt thereof.

81. structure: 【Chemistry 25】 The compound according to claim 77, or a pharmaceutically acceptable salt thereof.

82. structure: 【Chemistry 26】 The compound according to claim 77, or a pharmaceutically acceptable salt thereof.

83. structure: 【Chemistry 27】 The compound according to claim 77, or a pharmaceutically acceptable salt thereof.

84. structure: 【Chemistry 28】 The compound according to claim 77, or a pharmaceutically acceptable salt thereof.

85. structure: 【Chemistry 29】 The compound according to claim 77, or a pharmaceutically acceptable salt thereof.

86. structure: 【Transformation 30】 The compound according to claim 77, or a pharmaceutically acceptable salt thereof.

87. structure: 【Chemistry 31】 The compound according to claim 77, or a pharmaceutically acceptable salt thereof.

88. structure: 【Chemistry 32】 【change】 【change】 【change】 or The compound according to claim 1, or a pharmaceutically acceptable salt thereof.

89. A method for treating a disorder related to abnormal cell proliferation, comprising administering an effective amount of a compound according to any one of claims 1 to 88 in an optionally pharmaceutically acceptable carrier to a host in need thereof.

90. The method according to claim 89, wherein the host is human.

91. The method according to claim 89 or 90, wherein the disorder is an inflammatory disorder.

92. The method according to claim 89 or 90, wherein the disorder is a fibrous disorder.

93. The method according to claim 89 or 90, wherein the disorder is an autoimmune disorder.

94. The method according to claim 89 or 90, wherein the disorder is a tumor.

95. The method according to claim 89 or 90, wherein the disorder is cancer.

96. The method according to claim 89 or 90, wherein the disorder is rheumatoid arthritis.

97. A method for reducing the effects 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 the method is described in any one of claims 1 to 88, wherein the human is optionally pharmaceutically acceptable in A method comprising administering an effective amount of the compound or a pharmaceutically acceptable salt thereof.

98. A pharmaceutical composition comprising a compound according to any one of claims 1 to 88 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

99. A pharmaceutical composition according to claim 98 for treating disorders related to abnormal cell proliferation.

100. The pharmaceutical composition according to claim 99, wherein the disorder is an inflammatory disorder.

101. The pharmaceutical composition according to claim 99, wherein the disorder is a fibrous disorder.

102. The pharmaceutical composition according to claim 99, wherein the disorder is an autoimmune disorder.

103. The pharmaceutical composition according to claim 99, wherein the disorder is a tumor.

104. The pharmaceutical composition according to claim 99, wherein the disorder is cancer.

105. The pharmaceutical composition according to claim 99, wherein the disorder is rheumatoid arthritis.

106. A pharmaceutical composition according to claim 98 for reducing the effects of chemotherapy on healthy cells in a person undergoing treatment for cancer or abnormal cell proliferation, wherein the healthy cells are hematopoietic stem cells or hematopoietic progenitor cells.

107. A compound according to any one of claims 1 to 88 or a pharmaceutically acceptable salt thereof, for use in the manufacture of a pharmaceutical product for treating a disorder related to abnormal cell proliferation.

108. The compound according to claim 107, wherein the disorder is an inflammatory disorder.

109. The compound according to claim 107, wherein the disorder is a fibrous disorder.

110. The compound according to claim 107, wherein the disorder is an autoimmune disorder.

111. The compound according to claim 107, wherein the disorder is a tumor.

112. The compound according to claim 107, wherein the disorder is cancer.

113. The compound according to claim 107, wherein the disorder is rheumatoid arthritis.

114. Use of a compound according to any one of claims 1 to 88 or a pharmaceutically acceptable salt thereof in the manufacture of a pharmaceutical product for reducing the effects 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.

115. Use of a compound according to any one of claims 1 to 88 or a pharmaceutically acceptable salt thereof in the treatment of a disorder related to abnormal cell proliferation.

116. The use according to claim 115, wherein the disorder is an inflammatory disorder.

117. The use according to claim 115, wherein the disorder is a fibrous disorder.

118. The use according to claim 115, wherein the disorder is an autoimmune disorder.

119. The use according to claim 115, wherein the disorder is a tumor.

120. The use according to claim 115, wherein the disorder is cancer.

121. The use according to claim 115, wherein the disorder is rheumatoid arthritis.

122. Use of a compound according to any one of claims 1 to 88 or a pharmaceutically acceptable salt thereof in reducing the effects 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.

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