Cyclin-dependent kinase inhibiting compounds for treatment of medical conditions

Abstract

The present invention is in the field of cell cycle inhibiting compounds for the treatment of conditions involving abnormal cell proliferation, and includes selective CDK2 inhibitors and pharmaceutically acceptable salts and compositions thereof for medical treatment.

Description

[0001] This application is a divisional application of the invention patent application filed on May 18, 2021, with application number 202180036868.5 and invention title "Cyclic protein-dependent kinase inhibitory compound for treating medical conditions".

[0002] Cross-references to related applications

[0003] This application claims the benefits of U.S. Provisional Application No. 63 / 027,113, filed May 19, 2020, and U.S. Provisional Application No. 63 / 085,672, filed September 30, 2020. The entire contents of these applications are incorporated herein by reference for all purposes. Technical Field

[0004] This invention belongs to the field of pyrimidine-based compounds for treating conditions involving abnormal cell proliferation, including but not limited to the treatment of cancer and tumors. Background Technology

[0005] In normal tissues, cell proliferation is typically limited to replenishing the cells needed by the tissue. Once cells have terminally differentiated, they acquire specialized functions and cease dividing. Most tissues are composed of non-dividing cells. Therefore, normal cell proliferation is strictly controlled to ensure that only necessary cells divide. A careful balance also exists between cell division and programmed cell death (apoptosis).

[0006] Cell division—sometimes called the cell cycle—has four phases: G1 phase (synthesis of various enzymes required for DNA replication), S phase (DNA replication produces two identical sets of chromosomes), G2 phase (synthesis of important proteins, including microtubules), and M phase (nuclear division, cytoplasmic division, and formation of a new cell membrane). Cell division also involves a complex network of cell signaling systems that allow cells to interpret information from a multitude of extracellular signals, including those from receptor proteins, inflammatory factors, and pro- and anti-apoptotic signals. Dysfunctional signals include those from gene mutations, infection, exposure to environmental factors including toxins, systemic stress, autoimmune diseases, and inflammation.

[0007] When the cell proliferation process becomes disordered, a range of conditions can occur, including benign growth, tumors, tumorigenesis, carcinogenesis, autoimmune diseases, inflammatory diseases, graft-versus-host rejection, and fibrosis.

[0008] Many broad-spectrum antitumor agents have been developed. Cytoskeletal drugs, such as paclitaxel, target microtubules to arrest mitotic cell division and are used to treat a variety of cancers, including ovarian, breast, lung, pancreatic, and testicular tumors (see, for example, Jordan, Wilson, Nature Reviews Cancer (2004) 4:253-265). Organometallic drugs, such as cisplatin, have been used to treat lymphomas, sarcomas, germ cell tumors, and some cancers, including bladder, small cell lung, and ovarian cancer. Cisplatin has the ability to bind nitrogenous bases and induce extensive DNA cross-linking that ultimately leads to apoptosis (see, for example, Siddick, Oncogene (2003) 22:7265-7279). Intercalating agents and alkylating agents have also been widely used clinically to treat a variety of tumors; however, the overall toxicity associated with these drugs is a critical concern for patients requiring long-term treatment.

[0009] Palbociclib (PD-033299; Ibrance), marketed by Pfizer, is used 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:

[0010]

[0011] Pomazenil (LY2835219) is a CDK 4 / 6 inhibitor currently undergoing human clinical trials for the treatment of various types of cancer. It is in a phase III trial for non-small cell lung cancer (a phase IV trial); in combination with fulvestrant for women with breast cancer; and in combination with anastrozole or letrozole for first-line treatment of breast cancer. The structure of pomazenil is:

[0012]

[0013] Ribociclib (Lee011; Kisqali) is a CDK 4 / 6 inhibitor approved for use in combination with aromatase inhibitors to treat some metastatic breast cancers and is currently in clinical trials for the treatment of certain other tumors. The structure of Ribociclib is as follows:

[0014]

[0015] Lerociclib is an oral selective CDK4 / 6 inhibitor under clinical development by G1 Therapeutics, intended for use in combination with other targeted therapies for various oncology indications. Lerociclib is currently being evaluated in two Phase 1 / 2 clinical trials: one in combination with fulvestrant. In combination with osimertinib, one trial involved the use of osimertinib in patients with estrogen receptor-positive, HER2-negative (ER+, HER2-) breast cancer (NCT02983071). It is used in combination for the treatment of EGFRm non-small cell lung cancer. Lerociclib has the following structure:

[0016]

[0017] Trilacinib is a selective CDK4 / 6 inhibitor under clinical development by G1 Therapeutics as a first-in-class myeloprotective therapy designed to improve outcomes in chemotherapy-receiving patients by protecting hematopoietic stem cell and progenitor cell (HSPC) and immune system function. Trilacinib is a short-acting, intravenously administered CDK4 / 6 inhibitor administered before chemotherapy and is currently being evaluated in four randomized phase 2 clinical trials, including the first-line SCLC trial (NCT02499770) in combination with etoposide and carboplatin chemotherapy; and in combination with the same chemotherapy regimen and checkpoint inhibitor. (Azepam) in combination with first-line SCLC trials. Trilacizumab has the following structure:

[0018]

[0019] Various other pyrimidine-based agents have been developed to treat hyperproliferative disorders. U.S. Patent Nos. 8,822,683, 8,598,197, 8,598,186, 8,691,830, 8,829,102, 8,822,683, 9,102,682, 9,260,442, 9,481,691, 9,499,564, 9,957,276, 10,189,849, 10,189,850, and 10,189,851, filed by Tavares and Strum and assigned to G1 Therapeutics, describe a class of N-(heteroaryl)-pyrrolo[3,2-d]pyrimidine-2-amine cyclin-dependent kinase inhibitors, including those of the following formula (with variables as defined therein):

[0020]

[0021] U.S. Patent Nos. 9,464,092, 9,487,530, 9,527,857, 10,076,523, 10,085,992 and 10,434,104, also assigned to G1 Therapeutics, describe the use of the aforementioned pyrimidine-based agents in the treatment of cancer.

[0022] WO 2013 / 148748 (USSN61 / 617,657) entitled “Lactam Kinase Inhibitors”, WO 2013 / 163239 (USSN61 / 638,491) entitled “Synthesis of Lactams”, and WO 2015 / 061407, submitted by Tavares and also assigned to G1 Therapeutics, describe the synthesis of N-(heteroaryl)-pyrrolo[3,2-d]pyrimidine-2-amine and its use as a lactam kinase inhibitor.

[0023] Other patent publications include the following: WO 2014 / 144326, filed and assigned to G1 Therapeutics by Strum et al., describes compounds and methods for protecting normal cells during chemotherapy using pyrimidine-based CDK4 / 6 inhibitors. WO 2014 / 144596, filed and assigned to G1 Therapeutics by Strum et al., describes compounds and methods for protecting hematopoietic stem cells and progenitor cells from ionizing radiation using pyrimidine-based CDK4 / 6 inhibitors. WO 2014 / 144847, filed and assigned to G1 Therapeutics by Strum et al., describes HSPC preservation therapy for abnormal cell proliferation using pyrimidine-based CDK4 / 6 inhibitors. WO 2014 / 144740, filed and assigned to G1 Therapeutics by Strum et al., describes highly active antitumor and antiproliferative pyrimidine-based CDK4 / 6 inhibitors. Strum et al.'s WO 2015 / 161285, submitted and assigned to G1 Therapeutics, describes a tricyclic pyrimidine-based CDK inhibitor for radiation protection. Strum et al.'s WO 2015 / 161287, submitted and assigned to G1 Therapeutics, describes a tricyclic pyrimidine-based CDK inhibitor for protecting cells during chemotherapy. Strum et al.'s WO 2015 / 161283, submitted and assigned to G1 Therapeutics, describes a tricyclic pyrimidine-based CDK inhibitor for HSPC retention therapy in the treatment of RB-positive abnormal cell proliferation. Strum et al.'s WO 2015 / 161288, submitted and assigned to G1 Therapeutics, describes a tricyclic pyrimidine-based CDK inhibitor used as an antitumor and antiproliferative agent. Strum et al.'s WO 2016 / 040858, submitted and assigned to G1 Therapeutics, describes the use of pyrimidine-based CDK4 / 6 inhibitors in combination with other antitumor agents. Strum et al.'s WO 2016 / 040848, submitted and assigned to G1 Therapeutics, describes compounds and methods for treating certain Rb-negative cancers with CDK4 / 6 inhibitors and topoisomerase inhibitors. Strum et al.'s WO 2018 / 005860, WO 2018 / 005533, and WO 2018 / 005863, submitted and assigned to G1 Therapeutics, describe various CDK inhibitors. Sorrentino et al.'s WO 2018 / 106739, submitted and assigned to G1 Therapeutics, describes the use of CDK4 / 6 inhibitors with specific dosing regimens.Strum et al.'s WO 2018 / 156812, submitted and transferred to G1 Therapeutics, describes the use of CDK4 / 6 inhibitors for the treatment of EGFR-driven cancers. Strum et al.'s WO 2019 / 199883, submitted and transferred to G1 Therapeutics, describes compounds and methods for treating chemotherapy-resistant cancers. Beelen et al.'s WO 2019 / 136451, submitted and transferred to G1 Therapeutics, describes a dosage regimen for the administration of G1T38. Strum et al.'s WO 2019 / 136244, submitted and transferred to G1 Therapeutics, describes additional compounds for CDK inhibition. Strum et al.'s WO 2019 / 222521, submitted and transferred to G1 Therapeutics, describes additional compounds for CDK inhibition. Schneider et al.'s WO 2020 / 041770, submitted and transferred to G1 Therapeutics, describes a synthetic method for preparing CDK-inhibiting compounds. Schneider et al.'s WO 2020 / 097625, submitted and transferred to G1 Therapeutics, describes the use of a combination of CDK4 / 6 inhibitors and eribulin. Strum et al.'s WO 2020 / 206034, submitted and transferred to G1 Therapeutics, describes other compounds for CDK inhibition. Jung et al.'s WO 2020 / 206035, submitted and transferred to G1 Therapeutics, describes other compounds for CDK inhibition. Roberts et al.'s WO 2020 / 257536, submitted and transferred to G1 Therapeutics, describes enhancing patient selection for cancer treatment with CDK4 / 6 inhibitors. Strum et al.'s WO 2021 / 072319, submitted and transferred to G1 Therapeutics, describes the use of CDK4 / 6 inhibitors for the treatment of fibroblast growth factor-mediated cancers.

[0024] Although research has been conducted in the field of cell cycle inhibitory compounds to treat abnormal cell proliferation in hosts (e.g., humans), given the severity of these diseases, there is still a need to find new compounds that can meet this medical need.

[0025] Therefore, one object of the present invention is to provide novel compounds, methods, compositions, and manufacturing methods to inhibit unwanted cell cycle in a host (e.g., a human), wherein said compounds can be used to treat abnormal cell proliferation. Another aspect of the present invention is to provide compounds, methods, and compositions that can be used to treat cell cycle disorders in cells that are naturally occurring or have become resistant to other therapies. Summary of the Invention

[0026] This invention provides therapeutically active compounds of formula I, II, III, IV, V, VI, VII, VIII, IX, or X, or pharmaceutically acceptable salts thereof, or combinations thereof. In some embodiments, the active compound, its salt, composition, or isotope analogue thereof is used in an effective amount to treat a medical condition involving abnormal cell proliferation in a host (typically, a human), including tumors or cancer.

[0027] In some embodiments, the compounds of the present invention are active against a variety of cyclin-dependent kinases, including, for example, preferential activity against CDK2. In some embodiments, the inhibitory selectivity of the compounds of the present invention against CDK2 is superior to that against CDK1, CDK3, CDK4, CDK5, CDK6, CDK7, and / or CDK9. Based on this finding, compounds and methods are provided for treating patients suffering from proliferative disorders, including tumors or cancer, comprising administering to a patient in need an effective amount of one or a combination of the compounds described herein or pharmaceutically acceptable salts thereof, optionally in a pharmaceutically acceptable carrier. In some embodiments, the antiproliferative disorder is selected from cancer, tumors, cysts, benign growths, autoimmune disorders, inflammatory disorders, graft-versus-host rejection, and fibrotic disorders. In a typical embodiment, the patient is a human being.

[0028] In some embodiments, the compounds of the present invention have high oral bioavailability, for example, oral bioavailability greater than about 50%, 60%, 70%, 80%, 90%, or 95% F (as the fraction of the drug that reaches systemic circulation intact). In some embodiments, the compounds of the present invention have high metabolic stability, for example, the compounds of the present invention can exhibit stability in human microsomes greater than about 30 minutes, 45 minutes, 1 hour, 1.5 hours, or 2 hours.

[0029] This invention also provides an advantageous method for treating patients with selective CDK4 / 6 inhibitor-resistant proliferative disorders such as tumors or cancers, comprising administering an effective amount of a compound of formula I, II, III, IV, V, VI, VII, VIII, IX, or X, or a pharmaceutically acceptable combination, salt, or isotope analog thereof. Despite the development of selective CDK4 / 6 inhibitors, MYC-driven tumor types with retinoblastoma (Rb) protein deficiency or high cyclin E expression levels, such as triple-negative breast cancer (TNBC) and small cell lung cancer (SCLC), are difficult to treat due to intrinsic or primary resistance to existing selective CDK4 / 6 inhibitors. Additionally, some cancers, although Rb-positive, exhibit intrinsic resistance to the effects of selective CDK4 / 6 inhibitors. Furthermore, some cancers with intact Rb pathways may exhibit intrinsic resistance to selective CDK4 / 6 inhibitors in other ways due to the presence of other genetic or phenotypic abnormalities. For example, it is estimated that despite Rb integrity, 40% of uterine cancers, 20% of ovarian cancers, 15% of bladder cancers, 20% of prostate cancers, and 15% of breast cancers may be intrinsically resistant to selective CDK4 / 6 inhibition due to upregulation of cyclin E. See, 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, certain cancers, such as ER+ breast cancer, are able to acquire resistance to selective CDK4 / 6 inhibitors during selective CDK4 / 6 inhibitor therapy, for example, by upregulating cyclin E, which allows cell cycle progression from G1 to S via CDK2. In some embodiments, the compounds described herein effectively inhibit cell cycle progression in cancer cells that are intrinsically resistant to selective CDK4 / 6 inhibitors, readily acquire resistance to selective CDK4 / 6 inhibitors, or have become resistant to selective CDK4 / 6 inhibitors.

[0030] The active compounds described herein act as inhibitors of cyclin-dependent kinases (CDKs), providing cell cycle inhibition in replicating cells, for example, by inhibiting CDK2 and / or CDK4 and / or CDK6, or combinations thereof. However, unlike selective CDK4 / 6 inhibitors, some of the active compounds described herein are capable of inhibiting cells resistant to or having become resistant to selective CDK4 / 6 inhibitors by preferentially inhibiting another CDK (e.g., CDK2), thereby providing an additional cell cycle inhibition mechanism. In one embodiment, the present invention provides a selective CDK2 inhibitor. This property is particularly useful in inhibiting cell cycle progression in cancer or other Rb-negative or Rb-negative proliferative diseases that evade CDK4 / 6 cell cycle control.

[0031] In certain aspects of the invention, compounds of formula I, II, III, IV or V:

[0032]

[0033] Or a pharmaceutically acceptable salt, N-oxide, isotope analog, and / or a pharmaceutically acceptable composition thereof;

[0034] in:

[0035] X 1 X 2 X 3 X 4 and X 5 Independently selected from N, CH, CR 2 and CR 4 ;where X 1 X 2 X 3 X 4 and X 5 At least one of them is CR 2 ; and X 1 X 2 X 3 X 4 and X 5 There are no more than two choices N;

[0036] Each R 1 Independently selected from hydrogen, halogen, -OR 14 NR 14 R 15 Alkyl, aryl, cycloalkyl, haloalkyl, heteroaryl, alkyl-hydroxyl, and heterocyclic, wherein two R 1They can optionally form 3, 4, 5, 6, 7, or 8-membered cycloalkyl groups or 4, 5, 6, 7, or 8-membered heterocycles having 1, 2, or 3 heteroatoms selected from N, O, and S; wherein the two R groups are connected together. 1 The cycloalkyl or heterocyclic rings formed by the bonding of the atoms to which they are attached may optionally be composed of one or two independently selected from R 50 The substituents are replaced;

[0037] Each R 2 Independently selected from -NR 14 C(O)R 6 -NR 14 S(O)R 6 -NR 14 S(O)2R 6 -NR 14 C(S)R 6 -OC(O)R 6 -OS(O)R 6 -OS(O)2R 6 -OC(S)R 6 -C(O)R 6 ;-C(S)R 6 -S(O)R 6 and -S(O)2R 6 ;

[0038] Or each R 2 Independently selected from -NR 14 C(O)R 6 -NR 14 S(O)R 6 -NR 14 S(O)2R 6 -NR 14 C(S)R 6 -OC(O)R 6 -OS(O)R 6 -OS(O)2R 6 -OC(S)R 6 -C(O)R 6 ;-C(S)R 6 -S(O)R 6 -S(=NR) 14 )2R 6 -S(=NR) 14 )(O)R 6 and -S(O)2R 6 ;

[0039] R 3 Selected from hydrogen, -OR 14 -NR14 R 15 alkyl, alkenyl, ynyl, –C(O)R 6 -C(O)alkyl, -C(S)alkyl, aryl, -SO2alkyl, heteroaryl, heterocyclic, -alkyl-aryl and -alkyl-heteroaryl;

[0040] Each R 4 Independently selected from 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 ;

[0041] R 5 Hydrogen, alkyl, haloalkyl, halogen, cyano, -OR 14 or -NR 14 R 15 ;

[0042] Each R 6 Independently selected from hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, heteroaryl, NR 7 R 7 and OR 7 ; except for hydrogen, NR 7 R 7 and OR 7 Each R outside 6 Can be arbitrarily divided by 1, 2, 3 or 4 Rs 8 Substituted by groups;

[0043] Each R 7 Independently selected from hydrogen, alkyl, alkenyl, ynyl, cycloalkyl, heterocyclic, aryl, alkyl-aryl, alkyl-heteroaryl, and heteroaryl; each R except hydrogen 7 Can be arbitrarily divided by 1, 2, 3 or 4 Rs 8 Substituted by groups;

[0044] Each R 8 Independently selected from hydrogen, halogen, haloalkyl, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, heteroaryl, -S(O)2alkyl, NR 12 R 13 alkyl-heteroaryl, alkyl-aryl and OR 12 ;

[0045] Each R 12 and R 13 Independently selected from hydrogen, alkyl, alkenyl, ynyl, -C(O)alkyl, -C(S)alkyl, aryl, -SO2alkyl, -S(O)alkyl, heteroaryl, alkyl-aryl, cycloalkyl, heterocyclic and alkyl-heteroaryl;

[0046] Each R 14 and R 15 Independently selected from hydrogen, alkyl, alkenyl, ynyl, –C(O)R 6 -C(O)alkyl, -C(S)alkyl, aryl, -SO2alkyl, heteroaryl, heterocyclic, -alkyl-aryl and -alkyl-heteroaryl; and

[0047] Each R 50 Independently selected from hydrogen, -NR 14 R 15 OR 14 and R 4 .

[0048] In an alternative implementation, Equation I is:

[0049]

[0050] Or a pharmaceutically acceptable salt, N-oxide, isotope analog, and / or a pharmaceutically acceptable composition thereof;

[0051] Each R 5 Independently selected from hydrogen, alkyl, haloalkyl, halogen, cyano, -OR 14 and -NR 14 R 15 All other variables are as defined in this document.

[0052] In certain aspects of the invention, compounds of formula VI, VII, VIII, IX or X are provided:

[0053]

[0054]

[0055] Or a pharmaceutically acceptable salt, N-oxide, isotope analog, and / or a pharmaceutically acceptable composition thereof;

[0056] in:

[0057] X 11 X 12 X 13 X 14 and X 15 Independently selected from N, CH and CR 4 , where X 11 X 12 X 13 X 14 and X 15 There are no more than two choices N;

[0058] R 17 and R 18 Independently selected from hydrogen, alkyl, alkenyl, ynyl, cycloalkyl, heterocyclic, aryl, alkyl-aryl, alkyl-heteroaryl, and heteroaryl, each of which except hydrogen is optionally marked by 1, 2, 3, or 4 R's. 8 Substituted by groups; and

[0059] R 19 Hydrogen, alkyl, haloalkyl, halogen, cyano, -OR 14 or -NR 14 R 15 .

[0060] In some embodiments, the compounds of the present invention inhibit CDK2 or CDK9 more effectively than CDK4 and / or CDK6. In some embodiments, the compounds of the present invention are CDK inhibitors with increased activity against CDK2.

[0061] These compounds can be used to treat patients with abnormal cell proliferation in a host (typically, a human) who require this treatment.

[0062] In another embodiment, a method for treating fibrosis in a host is provided, comprising administering an effective amount of the compound of the present invention or a pharmaceutically acceptable salt thereof, optionally in a pharmaceutically acceptable carrier.

[0063] In another embodiment, a method for treating rheumatoid arthritis or psoriasis in a host is provided, comprising administering an effective amount of the compound of the present invention or a pharmaceutically acceptable salt thereof, optionally in a pharmaceutically acceptable carrier.

[0064] In another embodiment, a method for treating an autoimmune disease in a host is provided, comprising administering an effective amount of the compound of the present invention or a pharmaceutically acceptable salt thereof, optionally in a pharmaceutically acceptable carrier.

[0065] In some embodiments, a method of treating a tumor or cancer in a host is provided, comprising administering an effective amount of the compound of the present invention or a pharmaceutically acceptable salt thereof, optionally in a pharmaceutically acceptable carrier. In one aspect of this embodiment, the cancer is an Rb-positive tumor or cancer. In another aspect of this embodiment, the cancer is an Rb-negative tumor or cancer. In some aspects, the cancer is selected from breast cancer, prostate cancer (including anti-androgen prostate cancer), colon cancer (including metastatic colon cancer), another reproductive system cancer such as endometrial cancer, ovarian cancer or testicular cancer, small cell lung cancer, glioblastoma, and head and / or neck cancer.

[0066] In another embodiment, a method for treating a disease of abnormal cell proliferation in a host such as a human is provided, comprising administering, in combination with or alternately with, an effective amount of one or more of the active compounds described herein. In some aspects of the invention, the second compound is a chemotherapeutic agent. In another aspect of this embodiment, the second active compound is an immunomodulatory agent, including but not limited to checkpoint inhibitors such as antibodies, small molecules, peptides, nucleotides, or other inhibitors such as anti-PD1, Ant-PD-L1, anti-CTLA, anti-LAG-3, and anti-Tim, including but not limited to ipilimumab (Yervoy), pembrolizumab (Keytruda), nivolumab (Opdivo), cimiprimab (Libtayo), atezolizumab (Tecentriq), avelumab (Bavencio), and durvalumab (Imfinzi).

[0067] In another embodiment, one of the active compounds described herein is combined with or alternated with an effective amount of an estrogen inhibitor to treat abnormal tissues of the female reproductive system such as breast cancer, ovarian cancer, endometrial cancer, or uterine cancer, said estrogen inhibitor including, but not limited to, SERM (selective estrogen receptor modulator), SERD (selective estrogen receptor degrader), complete estrogen receptor degrader, or another form of partial or complete estrogen antagonist.

[0068] In another embodiment, one of the active compounds described herein is administered in combination with or alternately with an effective amount of an androgen (such as testosterone) inhibitor to treat abnormal tissues of the male reproductive system, such as prostate cancer or testicular cancer. The androgen inhibitor includes, but is not limited to, selective androgen receptor modulators, selective androgen receptor degraders, complete androgen receptor degraders, or other forms of partial or complete androgen antagonists. In some embodiments, the prostate cancer or testicular cancer is androgen-resistant.

[0069] In some embodiments, the compounds described herein inhibit cyclin-dependent kinases (“CDKs”). For example, the compounds described in this invention provide dose-dependent G1 blockade against CDK replication-dependent healthy cells in a subject, such as HSPCs or renal epithelial cells. The methods provided herein are sufficient to provide chemical protection to targeted CDK replication-dependent healthy cells during chemotherapeutic agent exposure, for example, during the period when DNA-damaging chemotherapeutic agents can cause DNA damage to CDK replication-dependent healthy cells in a subject.

[0070] In some embodiments, the application of the compound using the methods described herein is combined with the use of hematopoietic growth factors, including but not limited to granulocyte colony-stimulating factor (G-CSF), granulocyte-macrophage colony-stimulating factor (GM-CSF), thrombopoietin, interleukin (IL)-12, steel factor, and erythropoietin (EPO) or derivatives thereof. In some embodiments, the compound is applied prior to the application of the hematopoietic growth factor. In some embodiments, the application of the hematopoietic growth factor is timed so that the effect of the compound on HSPC has dissipated.

[0071] In some embodiments, the compounds described herein are administered in combination with a BTK inhibitor. In another embodiment, the compounds described herein are administered in combination with an EGFR inhibitor.

[0072] The present invention also provides an advantageous method for treating patients with cancers resistant to selective CDK4 / 6 inhibitors, comprising administering an effective amount of a compound of formula I, II, III, IV, V, VI, VII, VIII, IX, or X, or a pharmaceutically acceptable combination, salt, or isotope analog thereof. In some aspects, the compounds of the present invention are used to treat patients with cancers exhibiting intrinsic resistance to selective CDK4 / 6 inhibition. In some aspects, the compounds of the present invention are used to treat patients with cancers exhibiting acquired resistance to one or more selective CDK4 / 6 inhibitors. In some aspects, the compounds of the present invention are administered in combination with a selective CDK4 / 6 inhibitor to patients with CDK4 / 6 inhibition-responsive cancers to prolong the therapeutic efficacy of cell cycle inhibition in the cancer.

[0073] Similarly, cancers initially sensitive to selective CDK4 / 6 inhibitors, such as ER+ breast cancer, may acquire resistance to selective CDK4 / 6 inhibition by upregulating cyclin E, which allows cell cycle progression from G1 to S via CDK2. Therefore, the compounds of the present invention can be used in effective amounts to treat patients with cancers that have developed resistance to selective CDK4 / 6 inhibitors over time, either due to prior exposure to CDK4 / 6 inhibitors or through natural tumor progression. Therefore, the present invention includes a method of administering an effective amount of the compounds of the present invention to treat patients with cancers that were initially responsive to or sensitive to selective CDK4 / 6 inhibition, the method prolonging the efficacy of selective CDK4 / 6 inhibitor treatment for CDK4 / 6-responsive cancers by delaying the acquisition of resistance to selective CDK4 / 6 inhibitor inhibition.

[0074] In one particular aspect, the present invention provides a method for treating a patient with cancer that has developed acquired resistance to a selective CDK4 / 6 inhibitor by administering to the patient an effective amount of the compound of the present invention. In some embodiments, the selective CDK4 / 6 inhibitor to which the cancer has developed resistance is selected from palbociclib, pomacinib, lerociclib, triacinib, SH6390, and ribociclib.

[0075] In some aspects, the present invention is a method of 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 treatment-naïve with selective CDK4 / 6 inhibitors. By administering the compound of the present invention 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, pomazenil, rebociclib, triazenil, SHR6390, and lerociclib.

[0076] In certain aspects of the invention, a method of treating a patient with cancer is provided, comprising administering a therapeutically effective amount of a compound of the 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 invention, the present method allows for continued treatment of the cancer using cell cycle inhibition after the development of selective CDK4 / 6 inhibitor resistance. In some embodiments, the selective CDK4 / 6 inhibitor to which the cancer has become resistant is selected from palbociclib, pomazenil, ribociclib, triazenil, SHR6390, and lerociclib.

[0077] In an alternative aspect, the present invention is a method for treating a patient with Rb-positive cancer, comprising:

[0078] a) Administering selective CDK4 / 6 inhibitors to the patient;

[0079] b) Monitor cyclin E levels in patients with cancer; and

[0080] c) Upon detection of elevated cyclin E levels, administer to the patient a compound of formula I, II, III, IV, V, VI, VII, VIII, IX, or X, wherein the elevated cyclin E levels confuse the cancer with resistance to the inhibitory effects of a selective CDK4 / 6 inhibitor. In some embodiments, the selective CDK4 / 6 inhibitor administered is selected from palbociclib, pomazenil, ribociclib, triazenil, SHR6390, and lerociclib.

[0081] In an alternative aspect, the present invention is a method for treating a patient suffering from cancer, comprising:

[0082] a) Determine the Rb status of the cancer;

[0083] b) If the Rb status is positive, a selective CDK4 / 6 inhibitor is administered to the patient in combination with a compound of formula I, II, III, IV, V, VI, VII, VIII, IX or X.

[0084] c) If the Rb status is negative, administer a compound of formula I, II, III, IV, V, VI, VII, VIII, IX or X to the patient without administering a selective CDK4 / 6 inhibitor.

[0085] In some embodiments, the selective CDK4 / 6 inhibitors administered in combination with compounds of formula I, II, III, IV, V, VI, VII, VIII, IX, or X are selected from palbociclib, bumasinib, ribociclib, triazolamiclib, SHR6390, and lerociclib.

[0086] In an alternative aspect, the present invention is a method for treating a patient suffering from abnormal cell proliferation, such as cancer, comprising:

[0087] a) Administering selective CDK4 / 6 inhibitors to the patient;

[0088] b) Monitor the patient's cancer response to selective CDK4 / 6 inhibitors;

[0089] c) After detecting that a patient’s cancer has become unresponsive to a selective CDK4 / 6 inhibitor, administer a compound of formula I, II, III, IV, V, VI, VII, VIII, IX or X to the patient.

[0090] In some embodiments, the CDK4 / 6 inhibitor administered in combination with compounds of formula I, II, III, IV, V, VI, VII, VIII, IX, or X is selected from palbociclib, pomacinib, ribociclib, triazolamiclib, SHR6390, and lerociclib. In some embodiments, non-responsiveness is disease progression.

[0091] In another alternative aspect, the present invention is a method for treating a patient suffering from abnormal cell proliferation, such as cancer, comprising:

[0092] a) Administering selective CDK4 / 6 inhibitors to the patient;

[0093] b) Monitor one or more cellular signals that indicate the development of resistance to selective CDK4 / 6 inhibitors in cancer;

[0094] c) If one or more cellular signals indicate the development of selective CDK4 / 6 inhibitor resistance in cancer, administer a compound of formula I, II, III, IV, V, VI, VII, VIII, IX, or X to the patient. In some embodiments, the selective CDK4 / 6 inhibitor administered is selected from palbociclib, bumarazine, ribociclib, triazolamiclib, SHR6390, and lerociclib.

[0095] In some implementations, one or more cellular signals indicating the development of selective CDK4 / 6 inhibitor resistance in cancer are selected from increased expression of cyclin E, CCNE1 / 2 amplification, E2F amplification, CDK2 amplification, CDK6 amplification, CDK4 amplification, p16 amplification, WEE1 overexpression, DM2 overexpression, CDK7 overexpression, FZR1 loss, HDAC activation, FGFR pathway activation, PI3K / AKT / mTOR pathway activation, loss of ER or PR expression, higher AP-1 transcriptional activity, epithelial-mesenchymal transition, Smad3 inhibition, autophagy activation, Rb1 loss, and RB1 mutation inactivation.

[0096] In another alternative aspect, 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, such as, but not limited to, one selected from palbociclib, buboramiclib, ribociclib, triazolamiclib, SHR6390, and lerociclib.

[0097] In another embodiment, a method for treating a disease of abnormal cell proliferation in a host such as a human is provided, comprising administering, in combination with or alternately with an effective amount of a compound of formula I, II, III, IV, or a compound of formula V, VI, VII, VIII, IX, or X, and a selective CDK4 / 6 inhibitor. In some aspects of the invention, the additional active compound is a chemotherapeutic agent. In another aspect of this embodiment, the additional active compound is an immunomodulator, including but not limited to checkpoint inhibitors such as antibodies, small molecules, peptides, nucleotides, or other inhibitors such as anti-PD1, anti-PD-L1, anti-CTLA, anti-LAG-3, and anti-Tim, including but not limited to ipilimumab (Yervoy), pembrolizumab (Keytruda), nivolumab (Opdivo), cimiprimab (Libtayo), atezolizumab (Tecentriq), avelumab (Bavencio), and durvalumab (Imfinzi).

[0098] In another embodiment, the compounds of the present invention are combined with a selective CDK4 / 6 inhibitor and an effective amount of an estrogen inhibitor, or alternately administered in an effective amount, to treat abnormal tissues of the female reproductive system such as breast cancer, ovarian cancer, endometrial cancer, or uterine cancer, wherein the estrogen inhibitor includes, but is not limited to, SERM (selective estrogen receptor modulator), SERD (selective estrogen receptor degrader), complete estrogen receptor degrader, or another form of partial or complete estrogen antagonist.

[0099] In another embodiment, the compounds of the present invention are combined with a selective CDK4 / 6 inhibitor and an effective amount of an androgen (e.g., testosterone) inhibitor, or administered alternately in an effective amount, to treat abnormal tissues of the male reproductive system such as prostate cancer or testicular cancer. The androgen inhibitor includes, but is not limited to, selective androgen receptor modulators, selective androgen receptor degraders, complete androgen receptor degraders, or other forms of partial or complete androgen antagonists. In some embodiments, the prostate cancer or testicular cancer is androgen-resistant.

[0100] In some embodiments, the compounds of the present invention are administered in combination with a CDK4 / 6 inhibitor at an effective amount in combination with a BTK inhibitor. In another embodiment, the compounds of the present invention are administered in combination with a CDK4 / 6 inhibitor at an effective amount in combination with an EGFR inhibitor.

[0101] In some embodiments, the compounds of the present invention inhibit CDK2, CDK4, CDK6, and / or CDK9. In some embodiments, the compound is a CDK2 inhibitor. In some embodiments, the compound is a CDK4 inhibitor. In some embodiments, the compound is a CDK6 inhibitor. In some embodiments, the compound is a CDK9 inhibitor.

[0102] Therefore, the present invention includes at least the following features:

[0103] (a) The compounds of the present invention as described herein, or pharmaceutically acceptable salts thereof;

[0104] (b) The compounds of the present invention as described herein, or pharmaceutically acceptable salts thereof, can be used in effective amounts to treat abnormal cell proliferation disorders, including tumors or cancer;

[0105] (c) The compounds of the present invention as described herein, or pharmaceutically acceptable salts thereof, may be used to treat cancers resistant to treatment with compounds used as CDK4 / 6 inhibitors, such as palbociclib, buboramiclib, or rebociclib.

[0106] (d) Use of the compounds of the present invention or pharmaceutically acceptable salts thereof in the manufacture of medicaments for treating abnormal cell proliferation conditions such as tumors or cancer;

[0107] (e) Use of the compounds of the present invention or pharmaceutically acceptable salts thereof in the manufacture of a medicament for treating cancers resistant to compounds used as CDK4 / 6 inhibitors, such as palbociclib, bubomashinib or rebociclib.

[0108] (f) A method of manufacturing a medicament intended for therapeutic use in treating abnormal cell proliferation disorders, including tumors or cancer, characterized in that a compound of the present invention as described herein is used in the manufacturing process;

[0109] (q) A pharmaceutical formulation comprising an effective therapeutic amount of the compound of the present invention or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or diluent;

[0110] (r) The compounds of the present invention as described herein, as mixtures of enantiomers or diastereomers (as relevant), including as racemates;

[0111] (s) The compounds of the present invention as described herein are in the form of enantiomers or diastereomers (as applicable), including as isolated enantiomers or diastereomers (i.e., with a purity greater than 85%, 90%, 95%, 97% or 99%).

[0112] (t) A method for preparing a therapeutic product containing an effective amount of the compound of the present invention as described herein;

[0113] (u) A solid dosage form for oral delivery of the compound of the present invention or a pharmaceutically acceptable salt thereof in a pharmaceutically acceptable carrier;

[0114] (v) Parenteral dosage forms of the compounds of the present invention or pharmaceutically acceptable salts thereof in pharmaceutically acceptable carriers for systemic delivery (including delivery via intravenous injection); and

[0115] (w) A method of manufacturing a medicament intended for use in antitumor therapy, characterized in that a compound of the present invention as described herein is used in the manufacturing process.

[0116] This invention also relates to the following items.

[0117] 1. A compound of the following formula:

[0118]

[0119]

[0120] Or a pharmaceutically acceptable salt, N-oxide, isotope analog, and / or a pharmaceutically acceptable composition thereof;

[0121] in:

[0122] X 1 X 2 X 3 X 4 and X 5 Independently selected from N, CH, CR 2 and CR 4 ;where X 1 X 2 X 3 X 4 and X 5 At least one of them is CR 2 ; and X 1 X 2 X 3 X 4 and X 5 There are no more than two choices N;

[0123] X 11 X12 X 13 X 14 and X 15 Independently selected from N, CH, CR 2 and CR 4 ;where X 11 X 12 X 13 X 14 and X 15 There are no more than two choices N;

[0124] Each R 1 Independently selected from hydrogen, halogen, -OR 14 NR 14 R 15 Alkyl, aryl, cycloalkyl, haloalkyl, heteroaryl, alkyl-hydroxyl, and heterocyclic, wherein two R 1 They can optionally form 3, 4, 5, 6, 7, or 8-membered cycloalkyl groups or 4, 5, 6, 7, or 8-membered heterocycles having 1, 2, or 3 heteroatoms selected from N, O, and S; wherein the two R groups are connected together. 1 The cycloalkyl or heterocyclic rings formed by the bonding of the atoms to which they are attached may optionally be composed of one or two independently selected from R 50 The substituents are replaced;

[0125] Each R 2 Independently selected from -NR 14 C(O)R 6 -NR 14 S(O)R 6 -NR 14 S(O)2R 6 -NR 14 C(S)R 6 -OC(O)R 6 -OS(O)R 6 -OS(O)2R 6 -OC(S)R 6 -C(O)R 6 ;-C(S)R 6 -S(O)R 6 -S(=NR) 14 )2R 6 -S(=NR) 14 )(O)R 6 and -S(O)2R 6 ;

[0126] R 3 Selected from hydrogen, -OR 14 -NR 14 R 15alkyl, alkenyl, ynyl, –C(O)R 6 -C(O)alkyl, -C(S)alkyl, aryl, -SO2alkyl, heteroaryl, heterocyclic, -alkyl-aryl and -alkyl-heteroaryl;

[0127] Each R 4 Independently selected from 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 ;

[0128] R 5 Hydrogen, alkyl, haloalkyl, halogen, cyano, -OR 14 or -NR 14 R 15 ;

[0129] Each R 6 Independently selected from hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, heteroaryl, NR 7 R 7 and OR 7 Except for hydrogen, NR 7 R 7 and OR 7 Each R outside 6 Can be arbitrarily divided by 1, 2, 3 or 4 Rs 8 Substituted by groups;

[0130] Each R 7 Independently selected from hydrogen, alkyl, alkenyl, ynyl, cycloalkyl, heterocyclic, aryl, alkyl-aryl, alkyl-heteroaryl, and heteroaryl, each R except hydrogen 7 Can be arbitrarily divided by 1, 2, 3 or 4 Rs 8 Substituted by groups;

[0131] Each R8 Independently selected from hydrogen, halogen, haloalkyl, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, heteroaryl, -S(O)2alkyl, NR 12 R 13 alkyl-heteroaryl, alkyl-aryl and OR 12 ;

[0132] Each R 12 and R 13 Independently selected from hydrogen, alkyl, alkenyl, ynyl, -C(O)alkyl, -C(S)alkyl, aryl, -SO2alkyl, -S(O)alkyl, heteroaryl, alkyl-aryl, cycloalkyl, heterocyclic and alkyl-heteroaryl;

[0133] Each R 14 and R 15 Independently selected from hydrogen, alkyl, alkenyl, ynyl, –C(O)R 6 -C(O)alkyl, -C(S)alkyl, aryl, -SO2alkyl, heteroaryl, heterocyclic, -alkyl-aryl and -alkyl-heteroaryl;

[0134] R 17 and R 18 Independently selected from hydrogen, alkyl, alkenyl, ynyl, cycloalkyl, heterocyclic, aryl, alkyl-aryl, alkyl-heteroaryl, and heteroaryl, each of which except hydrogen is optionally marked by 1, 2, 3, or 4 R's. 8 Substituted by groups; and

[0135] R 19 Hydrogen, alkyl, haloalkyl, halogen, cyano, -OR 14 or -NR 14 R 15 ;and

[0136] Each R 50 Independently selected from hydrogen, -NR 14 R 15 OR 14 and R 4 .

[0137] 2. The compound according to Project 1, the compound having the formula:

[0138]

[0139] Or a pharmaceutically acceptable salt, N-oxide, isotope analog, and / or a pharmaceutically acceptable composition thereof;

[0140] Each R 2 Independently selected from -NR 14 C(O)R 6 -NR 14 S(O)R6 -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 .

[0141] 3. The compound according to Project 1, the compound having the formula:

[0142]

[0143] Or its pharmaceutically acceptable salt.

[0144] 4. The compound according to Project 1, wherein R 5 It is a hydroxyl group.

[0145] 5. The compound according to Project 1, wherein the compound has the formula:

[0146]

[0147] Or its pharmaceutically acceptable salt.

[0148] 6. According to the compound described in Project 1, one of R... 1 It is hydrogen.

[0149] 7. According to the compound described in Project 1, wherein two R... 1 Both are hydrogen.

[0150] 8. The compound according to Project 1, wherein any one of R 1 None of them are hydrogen.

[0151] 9. The compound according to Project 1, wherein the compound has the formula:

[0152]

[0153] Or its pharmaceutically acceptable salt.

[0154] 10. The compound according to Project 1, wherein the compound has the formula:

[0155]

[0156] Or its pharmaceutically acceptable salt.

[0157] 11. The compound according to Project 1, wherein the compound has the formula:

[0158]

[0159] Or its pharmaceutically acceptable salt.

[0160] 12. The compound according to Project 1, wherein the compound has the formula:

[0161]

[0162] Or its pharmaceutically acceptable salt.

[0163] 13. The compound according to any one of items 10-12, wherein X 11 For CH.

[0164] 14. The compound according to any one of items 10-12, wherein X 11 Let N be the number of elements in the array.

[0165] 15. The compound according to any one of items 10-12, wherein X 11 For CR 4 .

[0166] 16. The compound according to any one of items 10-15, wherein X 12 For CH.

[0167] 17. The compound according to any one of items 10-15, wherein X 12 Let N be the number of elements in the array.

[0168] 18. The compound according to any one of items 10-15, wherein X 12 For CR 4 .

[0169] 19. The compound according to any one of items 10-18, wherein X 13 For CH.

[0170] 20. The compound according to any one of items 10-18, wherein X 13 Let N be the number of elements in the array.

[0171] 21. The compound according to any one of items 10-18, wherein X 13 For CR 4 .

[0172] 22. The compound according to any one of items 10-21, wherein X 14 For CH.

[0173] 23. The compound according to any one of items 10-21, wherein X 14 Let N be the number of elements in the array.

[0174] 24. The compound according to any one of items 10-21, wherein X 14 For CR 4 .

[0175] 25. The compound according to any one of items 10-24, wherein X 15 For CH.

[0176] 26. A compound according to any one of items 10-24, wherein X 15 Let N be the number of elements in the array.

[0177] 27. The compound according to any one of items 10-24, wherein X 15 For CR 4 .

[0178] 28. The compound according to Project 1, the compound having the formula:

[0179]

[0180] Or its pharmaceutically acceptable salt.

[0181] 29. The compound according to any one of items 1-28, wherein R 3 It is hydrogen.

[0182] 30. The compound according to any one of items 1-28, wherein R 3 It is an alkyl group.

[0183] 31. The compound according to any one of items 1-28, wherein R 3 For -NR 14 R 15 .

[0184] 32. The compound according to any one of items 1-28, wherein R 3 It is -NH2.

[0185] 33. The compound according to Project 1, the compound having the formula:

[0186]

[0187] Or its pharmaceutically acceptable salt.

[0188] 34. The compound according to Project 1, the compound having the formula:

[0189]

[0190] Or its pharmaceutically acceptable salt.

[0191] 35. The compound according to Project 1, the compound having the formula:

[0192]

[0193] Or its pharmaceutically acceptable salt.

[0194] 36. The compound according to Project 1, the compound having the formula:

[0195]

[0196] Or its pharmaceutically acceptable salt.

[0197] 37. The compound according to Project 1, the compound having the formula:

[0198]

[0199] Or its pharmaceutically acceptable salt.

[0200] 38. A compound according to any one of Item 1 or Items 33-37, wherein two R... 1 Together with the carbon atoms they are attached to, they form 3-8 membered rings.

[0201] 39. A compound according to any one of Item 1 or Items 33-37, wherein two R... 1 Together with the carbon atoms they are attached to, they form a 6-membered carbon ring.

[0202] 40. A compound according to any one of Item 1 or Items 33-37, wherein one of R 1 It is a halogen.

[0203] 41. A compound according to any one of Item 1 or Items 33-37, wherein one of R 1 It is a haloalkyl group.

[0204] 42. A compound according to any one of Item 1 or Items 33-37, wherein one of R 1 It is a hydroxyl group.

[0205] 43. A compound according to any one of Item 1 or Items 33-37, wherein R 1 It is selected from alkyl, aryl, cycloalkyl and haloalkyl.

[0206] 44. The compound according to any one of items 1-43, wherein R 2 -C(O)R 6 ;-C(S)R 6 -S(O)R6 or -S(O)2R 6 .

[0207] 45. The compound according to any one of items 1-43, wherein R 2 -C(O)R 6 .

[0208] 46. ​​The compound according to any one of items 1-43, wherein R 2 is -S(O)2R 6 .

[0209] 47. The compound according to any one of items 1-46, wherein each R 6 It is independently selected from hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl and heteroaryl.

[0210] 48. The compound according to any one of items 1-46, wherein each R 6 Independently selected from NR 7 R 7 and OR 7 .

[0211] 49. The compound according to any one of items 1-43, wherein R 2 It is -S(O)2NH2.

[0212] 50. The compound according to any one of items 1-49, wherein for

[0213] 51. The compound according to any one of items 1-50, wherein X 1 For CH.

[0214] 52. The compound according to any one of items 1-50, wherein X 1 Let N be the number of elements in the array.

[0215] 53. The compound according to any one of items 1-50, wherein X 1 For CR 2 .

[0216] 54. The compound according to any one of items 1-50, wherein X 1 For CR 4 .

[0217] 55. The compound according to any one of items 1-54, wherein X 2 For CH.

[0218] 56. The compound according to any one of items 1-54, wherein X 2 Let N be the number of elements in the array.

[0219] 57. The compound according to any one of items 1-54, wherein X 2 For CR 2 .

[0220] 58. The compound according to any one of items 1-54, wherein X 2 For CR 4 .

[0221] 59. The compound according to any one of items 1-58, wherein for

[0222] 60. The compound according to any one of items 1-58, wherein X 3 For CH.

[0223] 61. The compound according to any one of items 1-58, wherein X 3 Let N be the number of elements in the array.

[0224] 62. The compound according to any one of items 1-58, wherein X 3 For CR 2 .

[0225] 63. The compound according to any one of items 1-58, wherein X 3 For CR 4 .

[0226] 64. The compound according to any one of items 60-63, wherein for

[0227] 65. The compound according to any one of items 1-64, wherein X 4 For CH.

[0228] 66. The compound according to any one of items 1-64, wherein X 4 Let N be the number of elements in the array.

[0229] 67. The compound according to any one of items 1-64, wherein X 4 For CR 2 .

[0230] 68. The compound according to any one of items 1-64, wherein X 4 For CR 4 .

[0231] 69. The compound according to any one of items 1-68, wherein X 5 For CH.

[0232] 70. The compound according to any one of items 1-68, wherein X 5 Let N be the number of elements in the array.

[0233] 71. The compound according to any one of items 1-68, wherein X 5 For CR 2 .

[0234] 72. The compound according to any one of items 1-68, wherein X 5 For CR 4 .

[0235] 73. The compound according to any one of items 1-72, wherein at least one R 4 OR 14 .

[0236] 74. The compound according to any one of items 1-72, wherein at least one R 4 It is a halogen.

[0237] 75. The compound according to any one of items 1-72, wherein at least one R 4 It is an alkyl group.

[0238] 76. The compound according to any one of items 1-72, wherein at least one R 3 It is an alkyl group.

[0239] 77. In some projects, the compound is selected from:

[0240]

[0241]

[0242] Or its pharmaceutically acceptable salt.

[0243] 78. The compound according to item 77, the compound having the following structure:

[0244]

[0245] Or its pharmaceutically acceptable salt.

[0246] 79. The compound according to item 77, wherein the compound has the following structure:

[0247]

[0248] Or its pharmaceutically acceptable salt.

[0249] 80. The compound according to item 77, wherein the compound has the following structure:

[0250]

[0251] Or its pharmaceutically acceptable salt.

[0252] 81. The compound according to item 77, the compound having the following structure:

[0253]

[0254] Or its pharmaceutically acceptable salt.

[0255] 82. The compound according to item 77, the compound having the following structure:

[0256]

[0257] Or its pharmaceutically acceptable salt.

[0258] 83. The compound according to item 77, the compound having the following structure:

[0259]

[0260] Or its pharmaceutically acceptable salt.

[0261] 84. The compound according to item 77, wherein the compound has the following structure:

[0262]

[0263] Or its pharmaceutically acceptable salt.

[0264] 85. The compound according to item 77, wherein the compound has the following structure:

[0265]

[0266] Or its pharmaceutically acceptable salt.

[0267] 86. The compound according to item 77, wherein the compound has the following structure:

[0268]

[0269] Or its pharmaceutically acceptable salt.

[0270] 87. The compound according to item 77, wherein the compound has the following structure:

[0271]

[0272] Or its pharmaceutically acceptable salt.

[0273] 88. The compound according to Project 1, the compound having the following structure:

[0274]

[0275]

[0276]

[0277]

[0278]

[0279] Or its pharmaceutically acceptable salt.

[0280] 89. A method for treating a condition associated with abnormal cell proliferation, the method comprising administering to a host in need an effective amount of a compound according to any one of items 1-88, optionally in a pharmaceutically acceptable carrier.

[0281] 90. The method according to item 89, wherein the host is a human being.

[0282] 91. The method described in item 89 or 90, wherein the condition is an inflammatory condition.

[0283] 92. The method according to item 89 or 90, wherein the condition is a fibrotic condition.

[0284] 93. The method described in item 89 or 90, wherein the condition is an autoimmune disease.

[0285] 94. The method described in item 89 or 90, wherein the condition is a tumor.

[0286] 95. The method described in item 89 or 90, wherein the condition is cancer.

[0287] 96. The method according to item 89 or 90, wherein the condition is rheumatoid arthritis.

[0288] 97. A method for reducing the effect of chemotherapy on healthy cells in a person being treated for cancer or abnormal cell proliferation, wherein the healthy cells are hematopoietic stem cells or hematopoietic progenitor cells, the method comprising administering to the person an effective amount of a compound or a pharmaceutically acceptable salt thereof according to any one of items 1-88, optionally in a pharmaceutically acceptable carrier.

[0289] 98. A pharmaceutical composition comprising a compound according to any one of items 1-88 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient.

[0290] 99. The pharmaceutical composition according to item 98, said pharmaceutical composition for treating a condition associated with abnormal cell proliferation.

[0291] 100. The pharmaceutical composition according to item 99, wherein the condition is an inflammatory condition.

[0292] 101. The pharmaceutical composition according to item 99, wherein the condition is a fibrotic condition.

[0293] 102. The pharmaceutical composition according to item 99, wherein the condition is an autoimmune disease.

[0294] 103. The pharmaceutical composition according to item 99, wherein the condition is a tumor.

[0295] 104. The pharmaceutical composition according to item 99, wherein the condition is cancer.

[0296] 105. The pharmaceutical composition according to item 99, wherein the condition is rheumatoid arthritis.

[0297] 106. The pharmaceutical composition according to item 98, the pharmaceutical composition being used to reduce the effect of chemotherapy on healthy cells in a person being treated for cancer or abnormal cell proliferation, wherein the healthy cells are hematopoietic stem cells or hematopoietic progenitor cells.

[0298] 107. A compound or a pharmaceutically acceptable salt thereof according to any one of items 1-88, used to manufacture a medicament for treating a condition associated with abnormal cell proliferation.

[0299] 108. The compound according to item 107, wherein the condition is an inflammatory condition.

[0300] 109. The compound according to item 107, wherein the condition is a fibrotic condition.

[0301] 110. The compound according to item 107, wherein the condition is an autoimmune disease.

[0302] 111. The compound according to item 107, wherein the condition is a tumor.

[0303] 112. The compound according to item 107, wherein the condition is cancer.

[0304] 113. The compound according to item 107, wherein the condition is rheumatoid arthritis.

[0305] 114. Use of any compound of any one of items 1-88 or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for reducing the effect of chemotherapy on healthy cells in a person being treated for cancer or abnormal cell proliferation, wherein said healthy cells are hematopoietic stem cells or hematopoietic progenitor cells.

[0306] 115. Use of any compound of any one of items 1-88 or a pharmaceutically acceptable salt thereof in the treatment of a condition associated with abnormal cell proliferation.

[0307] 116. As described in item 115, the condition is an inflammatory condition.

[0308] 117. The use as described in item 115, wherein the condition is a fibrotic condition.

[0309] 118. As described in item 115, the condition is an autoimmune disease.

[0310] 119. The use described in item 115, wherein the condition is a tumor.

[0311] 120. As described in item 115, the condition is cancer.

[0312] 121. The use as described in item 115, wherein the condition is rheumatoid arthritis.

[0313] 122. Use of any compound of any one of items 1-88 or a pharmaceutically acceptable salt thereof in reducing the effect of chemotherapy on healthy cells in a person being treated for cancer or abnormal cell proliferation, wherein said healthy cells are hematopoietic stem cells or hematopoietic progenitor cells. Detailed Implementation

[0314] I. Compounds

[0315] In some embodiments, the compounds of the present invention have the following formula:

[0316]

[0317]

[0318] Or a pharmaceutically acceptable salt, N-oxide, isotope analog, and / or pharmaceutically acceptable composition thereof; wherein y is 0, 1, 2, 3, or 4 and the remaining variables are as defined herein.

[0319] In some embodiments, the compounds of the present invention have the following formula:

[0320]

[0321]

[0322] Or a pharmaceutically acceptable salt, N-oxide, isotope analog, and / or pharmaceutically acceptable composition thereof; wherein the variables are as defined herein.

[0323] In some embodiments, the compounds of the present invention have the following formula:

[0324]

[0325] Or a pharmaceutically acceptable salt, N-oxide, isotope analog, and / or pharmaceutically acceptable composition thereof; wherein the variables are as defined herein.

[0326] In some embodiments, the compounds of the present invention have the following formula:

[0327]

[0328] Or a pharmaceutically acceptable salt, N-oxide, isotope analog, and / or pharmaceutically acceptable composition thereof; wherein the variables are as defined herein.

[0329] In some embodiments, the compounds of the present invention have the following formula:

[0330]

[0331]

[0332] Or a pharmaceutically acceptable salt, N-oxide, isotope analog, and / or pharmaceutically acceptable composition thereof; wherein the variables are as defined herein.

[0333] In some embodiments, the compounds of the present invention have the following formula:

[0334]

[0335] Or a pharmaceutically acceptable salt, N-oxide, isotope analog, and / or pharmaceutically acceptable composition thereof; wherein the variables are as defined herein.

[0336] In some embodiments, the compounds of the present invention are selected from:

[0337]

[0338] Or its pharmaceutically acceptable salt.

[0339] In some embodiments, the compounds of the present invention are selected from:

[0340]

[0341]

[0342] Or its pharmaceutically acceptable salt.

[0343] In some embodiments, the compounds of the present invention are selected from:

[0344]

[0345]

[0346] Or its pharmaceutically acceptable salt.

[0347] Implementation scheme of "alkyl"

[0348] In some embodiments, "alkyl" is C1-C 10 Alkyl, C1-C9 alkyl, C1-C8 alkyl, C1-C7 alkyl, C1-C6 alkyl, C1-C5 alkyl, C1-C4 alkyl, C1-C3 alkyl, or C1-C2 alkyl.

[0349] In some implementations, "alkyl" has one carbon atom.

[0350] In some implementations, "alkyl" has two carbon atoms.

[0351] In some implementations, "alkyl" has three carbon atoms.

[0352] In some implementations, "alkyl" has four carbon atoms.

[0353] In some implementations, "alkyl" has five carbon atoms.

[0354] In some implementations, "alkyl" has six carbon atoms.

[0355] Non-limiting examples of "alkyl" include: methyl, ethyl, propyl, butyl, pentyl, and hexyl.

[0356] Other non-limiting examples of "alkyl" include isopropyl, isobutyl, isopentyl, and isohexyl.

[0357] Other non-limiting examples of "alkyl" include sec-butyl, sec-pentyl, and sec-hexyl.

[0358] Other non-limiting examples of "alkyl" include tert-butyl, tert-pentyl, and tert-hexyl.

[0359] Other non-limiting examples of "alkyl" include neopentyl, 3-pentyl, and reactive pentyl.

[0360] In some implementations, "alkyl" means "substituted alkyl".

[0361] In some implementations, "alkenyl" means "substituted alkenyl".

[0362] In some implementations, "alkynyl" is "substituted alkynyl".

[0363] Implementation scheme of "halogenated alkyl"

[0364] In some embodiments, "haloalkyl" is C1-C 10 Halogenated alkyl, C1-C9 halogenated alkyl, C1-C8 halogenated alkyl, C1-C7 halogenated alkyl, C1-C6 halogenated alkyl, C1-C5 halogenated alkyl, C1-C4 halogenated alkyl, C1-C3 halogenated alkyl and C1-C2 halogenated alkyl.

[0365] In some implementations, the "halogenated alkyl" has one carbon atom.

[0366] In some implementations, the "halogenated alkyl" has one carbon atom and one halogen.

[0367] In some implementations, the "halogenated alkyl" has one carbon atom and two halogens.

[0368] In some implementations, the "halogenated alkyl" has one carbon atom and three halogens.

[0369] In some implementations, the "halogenated alkyl" has two carbon atoms.

[0370] In some implementations, the "halogenated alkyl" has three carbons.

[0371] In some implementations, the "halogenated alkyl" has four carbons.

[0372] In some implementations, the "halogenated alkyl" has five carbons.

[0373] In some implementations, the "halogenated alkyl" has six carbons.

[0374] Non-limiting examples of “halogenated alkyl” include:

[0375] Other non-limiting examples of “haloalkyl” include:

[0376] Other non-limiting examples of “haloalkyl” include:

[0377] Other non-limiting examples of “haloalkyl” include:

[0378] Implementation plan for "Aryl"

[0379] In some implementations, "aryl" is a 6-carbon aromatic group (phenyl).

[0380] In some implementations, "aryl" is a 10-carbon aromatic group (naphthyl).

[0381] In some embodiments, "aryl" is a 6-carbon aromatic group fused with a heterocycle; wherein the linking point is an aryl ring. Non-limiting examples of "aryl" include dihydroindole, tetrahydroquinoline, tetrahydroisoquinoline, and dihydrobenzofuran; and wherein the linking point of each group is on an aromatic ring.

[0382] For example, It is an "aryl" group.

[0383] However, It is a "heterocyclic" group.

[0384] In some embodiments, "aryl" is a 6-carbon aromatic group fused with a cycloalkyl group, wherein the linking point is an aryl ring. Non-limiting examples of "aryl" include dihydroindene and tetrahydronaphthalene, wherein the linking point of each group is on an aromatic ring.

[0385] For example, It is an "aryl" group.

[0386] However, It is a "cycloalkyl" group.

[0387] In some implementations, "aryl" means "substituted aryl".

[0388] Implementation plan of "hybrid aromatics"

[0389] In some embodiments, "heteroaryl" is a 5-membered aromatic group containing 1, 2, 3 or 4 nitrogen atoms.

[0390] In some embodiments, "heteroaryl" is a 5-membered aromatic group containing 1, 2, 3 or 4 atoms independently selected from nitrogen and oxygen.

[0391] Non-limiting examples of 5-membered "heteroaryl" groups include pyrrole, furan, thiophene, pyrazole, imidazole, triazole, tetraazole, isoxazole, oxazole, oxadiazole, oxtriazole, isothiazole, thiazole, thiazolium, and thiatriazole.

[0392] Other non-limiting examples of 5-membered "heteroaryl" groups include:

[0393]

[0394]

[0395] In some embodiments, "heteroaryl" is a 6-membered aromatic group containing 1, 2 or 3 nitrogen atoms (i.e., pyridinyl, pyridazinyl, triazinyl, pyrimidinyl and pyrazinyl).

[0396] Non-limiting examples of 6-membered "heteroaryl" groups having one or two nitrogen atoms include:

[0397]

[0398] In some embodiments, "heteroaryl" is a 9-membered bicyclic aromatic group containing one or two atoms selected from nitrogen, oxygen and sulfur.

[0399] Non-limiting examples of bicyclic "heteroaryl" groups include indole, benzofuran, isoindole, indazole, benzimidazole, azaindole, azaindazole, purine, isobenzofuran, benzothiophene, benzoisoxazole, benzoisothiazol, benzoxazole and benzothiazol.

[0400] Other non-limiting examples of bicyclic "heteroaryl" groups include:

[0401]

[0402] Other non-limiting examples of bicyclic "heteroaryl" groups include:

[0403]

[0404] Other non-limiting examples of bicyclic "heteroaryl" groups include:

[0405]

[0406] In some embodiments, "heteroaryl" is a 10-membered bicyclic aromatic group containing one or two atoms selected from nitrogen, oxygen and sulfur.

[0407] Non-limiting examples of bicyclic "heteroaryl" groups include quinoline, isoquinoline, quinoxaline, phthalazine, quinazoline, cyclophosphine, and naphthidine.

[0408] Other non-limiting examples of bicyclic "heteroaryl" groups include:

[0409]

[0410] In some implementations, "heteroaryl" means "substituted heteroaryl".

[0411] "Cycloalkyl" implementation scheme

[0412] In some embodiments, "cycloalkyl" is C3-C8 cycloalkyl, C3-C7 cycloalkyl, C3-C6 cycloalkyl, C3-C5 cycloalkyl, C3-C4 cycloalkyl, C4-C8 cycloalkyl, C5-C8 cycloalkyl, or C6-C8 cycloalkyl.

[0413] In some implementations, "cycloalkyl" has three carbons.

[0414] In some implementations, "cycloalkyl" has four carbons.

[0415] In some implementations, "cycloalkyl" has five carbons.

[0416] In some implementations, "cycloalkyl" has six carbons.

[0417] In some implementations, "cycloalkyl" has seven carbons.

[0418] In some implementations, "cycloalkyl" has eight carbons.

[0419] In some implementations, "cycloalkyl" has nine carbons.

[0420] In some implementations, "cycloalkyl" has ten carbons.

[0421] Non-limiting examples of "cycloalkyl" include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, and cyclodecyl.

[0422] Other non-limiting examples of "cycloalkyl" include dihydroindene and tetrahydronaphthalene, wherein the linking point of each group is on the cycloalkyl ring.

[0423] For example, It is a "cycloalkyl" group.

[0424] However, It is an "aryl" group.

[0425] In some implementations, "cycloalkyl" means "substituted cycloalkyl".

[0426] Implementation plan of "heterocyclic"

[0427] In some implementations, a "heterocycle" refers to a cyclic ring having one nitrogen atom and 3, 4, 5, 6, 7, or 8 carbon atoms.

[0428] In some implementations, a "heterocycle" refers to a cyclic ring having one nitrogen atom, one oxygen atom, and 3, 4, 5, 6, 7, or 8 carbon atoms.

[0429] In some implementations, a "heterocycle" refers to a cyclic ring having two nitrogen atoms and 3, 4, 5, 6, 7, or 8 carbon atoms.

[0430] In some implementations, a "heterocycle" refers to a cyclic ring having one oxygen atom and 3, 4, 5, 6, 7, or 8 carbon atoms.

[0431] In some implementations, a "heterocycle" refers to a cyclic ring having one sulfur atom and 3, 4, 5, 6, 7, or 8 carbon atoms.

[0432] Non-limiting examples of "heterocycles" include azirropropane, ethylene oxide, cyclothioethane, azirrobutane, 1,3-diazaheterobutane, oxoheterobutane, and thioheterobutane.

[0433] Other non-limiting examples of "heterocyclic" compounds include pyrrolidine, 3-pyrrolidine, 2-pyrrolidine, pyrazolidine, and imidazoline.

[0434] Other non-limiting examples of "heterocyclic rings" include tetrahydrofuran, 1,3-dioxolane, tetrahydrothiophene, 1,2-oxothiocyclopentane, and 1,3-oxothiocyclopentane.

[0435] Other non-limiting examples of "heterocyclic" compounds include piperidine, piperazine, tetrahydropyran, 1,4-dioxane, thiazide, 1,3-dithiazide, 1,4-dithiazide, morpholine, and thiomorpholine.

[0436] Other non-limiting examples of "heterocyclic" include dihydroindole, tetrahydroquinoline, tetrahydroisoquinoline, and dihydrobenzofuran, wherein the connection point of each group is on a heterocyclic ring.

[0437] For example, It is a "heterocyclic" group.

[0438] However, It is an "aryl" group.

[0439] Non-limiting examples of "heterocycles" also include:

[0440]

[0441]

[0442] Other non-limiting examples of "heterocycles" include:

[0443]

[0444] Other non-limiting examples of "heterocycles" include:

[0445]

[0446] Non-limiting examples of "heterocycles" also include:

[0447]

[0448] Non-limiting examples of "heterocycles" also include:

[0449]

[0450] Other non-limiting examples of "heterocycles" include:

[0451]

[0452] Other non-limiting examples of "heterocycles" include:

[0453]

[0454] In some implementations, "heterocyclic ring" refers to "substituted heterocyclic ring".

[0455] Implementation schemes of "-alkyl-aryl"

[0456] In some embodiments, "-alkyl-aryl" refers to a 1-carbon alkyl group that has been replaced by an aryl group.

[0457] Non-limiting examples of “-alkyl-aryl” include:

[0458]

[0459] In some implementations, "-alkyl-aryl" is

[0460] In some implementations, "-alkyl-aryl" refers to a 2-carbon alkyl group that has been replaced by an aryl group.

[0461] Non-limiting examples of “-alkyl-aryl” include:

[0462]

[0463] In some implementations, "alkyl-aryl" refers to a 3-carbon alkyl group that has been replaced by an aryl group.

[0464] Optional substituents

[0465] In some embodiments, the groups described herein that can be replaced by one or two substituents are replaced by one substituent.

[0466] In some embodiments, the groups described herein that can be replaced by one or two substituents are replaced by two substituents.

[0467] In some embodiments, the groups described herein that can be replaced by 1, 2, 3 or 4 substituents are replaced by a single substituent.

[0468] In some embodiments, the groups described herein that can be replaced by 1, 2, 3 or 4 substituents are replaced by two substituents.

[0469] In some embodiments, the groups described herein that can be replaced by 1, 2, 3 or 4 substituents are replaced by three substituents.

[0470] In some embodiments, the groups described herein that can be replaced by 1, 2, 3 or 4 substituents are replaced by four substituents.

[0471] R 1 Implementation plan

[0472] In some implementations, an R 1 For H, another R 1 It is an aryl group.

[0473] In some implementations, an R 1 For H, another R 1 It is a phenyl group.

[0474] In some implementations, an R 1 For H, another R 1 It is an alkyl group.

[0475] In some implementations, at least one R 1 It is a hydroxyl group.

[0476] In some implementations, at least one R 1 It is a halogen.

[0477] In some implementations, at least one R 1 It is a haloalkyl group.

[0478] In some implementations, at least one R 1 It is fluorine.

[0479] In some implementations, at least two R 1 It is fluorine.

[0480] In some implementations, at least two R 1 It is an alkyl group.

[0481] In some implementations, two R 1 They combine to form a 5-membered cycloalkyl group. In some embodiments, the cycloalkyl group is formed by an R... 50 Substituents. In some embodiments, the cycloalkyl group is replaced by two R groups. 50 Substituents. In some embodiments, the cycloalkyl group is replaced by NH2. In some embodiments, the cycloalkyl group is replaced by OR. 14The cycloalkyl group is substituted with OH in some embodiments. In some embodiments, the cycloalkyl group is substituted with alkyl groups. In some embodiments, the cycloalkyl group is substituted with CH3.

[0482] In some implementations, two R 1 This combination forms a 6-membered cycloalkyl group. In some embodiments, the cycloalkyl group is formed by an R... 50 Substituents. In some embodiments, the cycloalkyl group is replaced by two R groups. 50 Substituents. In some embodiments, the cycloalkyl group is replaced by NH2. In some embodiments, the cycloalkyl group is replaced by OR. 14 The cycloalkyl group is substituted with OH in some embodiments. In some embodiments, the cycloalkyl group is substituted with alkyl groups. In some embodiments, the cycloalkyl group is substituted with CH3.

[0483] In some implementations, two R 1 They combine to form a 5-membered heterocycle. In some embodiments, the heterocycle is bound by an R 50 Substituents are used to replace the heterocycle. In some embodiments, the heterocycle is replaced by two R groups. 50 The heterocycle is substituted by a substituent. In some embodiments, the heterocycle is substituted by NH2. In some embodiments, the heterocycle is substituted by OR. 14 The heterocycle is substituted. In some embodiments, the heterocycle is substituted with OH. In some embodiments, the heterocycle is substituted with alkyl groups. In some embodiments, the heterocycle is substituted with CH3.

[0484] In some implementations, two R 1 They combine to form a 6-membered heterocycle. In some embodiments, the heterocycle is bound by an R 50 Substituents are used to replace the heterocycle. In some embodiments, the heterocycle is replaced by two R groups. 50 The heterocycle is substituted by a substituent. In some embodiments, the heterocycle is substituted by NH2. In some embodiments, the heterocycle is substituted by OR. 14 The heterocycle is substituted. In some embodiments, the heterocycle is substituted with OH. In some embodiments, the heterocycle is substituted with alkyl groups. In some embodiments, the heterocycle is substituted with CH3.

[0485] In some implementations, two R 1 The following 5-membered helical rings are combined to form:

[0486]

[0487] In some implementations, two R 1 The following 6-membered spirorings are combined to form:

[0488]

[0489] In some implementations, an R 1 It is hydrogen.

[0490] In some implementations, an R 1 It is an alkyl group.

[0491] In some implementations, an R 1 For -NR 12 R 13 .

[0492] In some implementations, an R 1 It is a cycloalkyl group.

[0493] In some implementations, an R 1 It is a heterocyclic ring.

[0494] In some implementations, an R 1 It is an aryl group.

[0495] In some implementations, an R 1 It is a heteroaryl group.

[0496] In some implementations, R 1 Independently hydrogen, halogen, -OR 14 or NR 14 R 15 , where R 14 Independently selected from hydrogen, alkyl, -C(O)R 6 and -C(O)alkyl; and wherein R 15 It is independently selected from hydrogen and alkyl groups.

[0497] In some implementations, R 1 For -OR 14 , where R 14 Independently selected from hydrogen, alkyl, and –C(O)R 6 ;where R 6 It is independently selected from hydrogen and alkyl groups.

[0498] In some implementations, R 1 For NR 14 R 15 ;where R 14 Independently selected from hydrogen, alkyl, –C(O)R 6 and -C(O)alkyl; and wherein R 15 It is independently selected from hydrogen and alkyl groups.

[0499] In some implementations, two R 1Together with the ring atoms to which they are attached, they form 3, 4, 5, 6, 7 or 8-membered cycloalkyl groups or 4, 5, 6, 7 or 8-membered heterocycles having 1, 2 or 3 heteroatoms selected from N, O and S.

[0500] In some implementations, two R 1 Together with the ring atoms to which they are attached, they form 3, 4, 5, 6, 7, or 8-membered cycloalkyl groups or 4, 5, 6, 7, or 8-membered heterocycles having 1, 2, or 3 heteroatoms selected from N, O, and S; and wherein the two R groups are connected together to form cycloalkyl groups. 1 The cycloalkyl or heterocyclic rings formed by the bonding of the atoms to which they are attached may optionally be composed of one or two independently selected from R 50 The substituents are replaced by the substituents.

[0501] R 2 Implementation plan:

[0502] In some implementations, R 2 For -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 .

[0503] In some implementations, R 2 -C(O)R 6 ;-C(S)R 6 -S(O)R 6 or -S(O)2R 6 .

[0504] In some implementations, R 2 -C(O)R 6 .

[0505] In some implementations, R 2 It is -C(O)NH2.

[0506] In some implementations, R 2 It is -C(O)CH3.

[0507] In some implementations, R 2 is -S(O)2R 6 .

[0508] In some implementations, R 2 It is -S(O)2NH2.

[0509] In some implementations, R 2 for

[0510] In some implementations, R 2 for

[0511] In some implementations, R 2 for

[0512] In some implementations, R 2 for

[0513] In some implementations, R 2 for

[0514] In some implementations, R 2 for

[0515] In some implementations, R 2 for

[0516] In some implementations, R 2 for

[0517] In some implementations, R 2 for

[0518] In some implementations, R 2 for

[0519] In some implementations, R 2 for

[0520] In some implementations, R 2 for

[0521] In some implementations, R 2 for

[0522] In some implementations, R 2 for

[0523] In some implementations, R 2 for

[0524] In some implementations, R 2 for

[0525] In some implementations, R 2 for

[0526] In some implementations, R 2 for

[0527] In some implementations, R 2 for

[0528] In some implementations, R 2 for

[0529] In some implementations, R 2 for

[0530] In some implementations, R 2 for

[0531] In some implementations, R 2 for

[0532] In some implementations, R 2 for

[0533] In some implementations, R 2 for

[0534] In some implementations, R 2 for

[0535] In some implementations, R 2 for

[0536] In some implementations, R 2 for

[0537] In some implementations, R 2 for

[0538] In some implementations, R 2 for

[0539] In some implementations, R 2 for

[0540] In some implementations, R 2 for

[0541] In some implementations, R 2 for

[0542] In some implementations, R 2 for

[0543] In some implementations, R 2 for

[0544] In some implementations, R 2 for

[0545] In some implementations, R 2 for

[0546] In some implementations, R 2 for

[0547] In some implementations, R 2 for R 3 Implementation plan:

[0548] In some implementations, R 3 It is hydrogen.

[0549] In some implementations, R 3 It is an alkyl group.

[0550] In some implementations, R 3 For -NR 12 R 13 .

[0551] In some implementations, R 3 It is an -S(O) alkyl group.

[0552] In some implementations, R 3 It is an -SO2 alkyl group.

[0553] In some implementations, R 3 It is a cycloalkyl group.

[0554] In some implementations, R 3 It is a heterocyclic ring.

[0555] In some implementations, R 3 It is an aryl group.

[0556] In some implementations, R 3 It is a heteroaryl group.

[0557] In some implementations, R 3 It is alkyl-aryl.

[0558] In some implementations, R 3 It is an alkyl-heteroaryl group.

[0559] R 4 Implementation plan:

[0560] In some implementations, R 4 It is hydrogen.

[0561] In some implementations, R 4 It is an alkyl group.

[0562] In some implementations, R 4 For -NR 12 R 13 .

[0563] In some implementations, R 4 It is an -S(O) alkyl group.

[0564] In some implementations, R 4 It is an -SO2 alkyl group.

[0565] In some implementations, R 4 It is a cycloalkyl group.

[0566] In some implementations, R 4 It is a heterocyclic ring.

[0567] In some implementations, R 4 It is an aryl group.

[0568] In some implementations, R 4 It is a heteroaryl group.

[0569] R 5 Implementation plan:

[0570] In some implementations, R 5 It is hydrogen.

[0571] In some implementations, R 5 It is an alkyl group.

[0572] In some implementations, R5 It is a haloalkyl group.

[0573] In some implementations, R 5 It is a halogen.

[0574] In some implementations, R 5 It is a cyano group.

[0575] In some implementations, R 5 For -OR 14 .

[0576] In some implementations, R 5 For -NR 14 R 15 .

[0577] R 6 Implementation plan:

[0578] In some implementations, R 6 It is hydrogen.

[0579] In some implementations, R 6 It is an alkyl group.

[0580] In some implementations, R 6 It is an alkenyl or ynyl group.

[0581] In some implementations, R 6 For any 1, 2, 3 or 4 Rs 8 Cycloalkyl groups substituted by the radical.

[0582] In some implementations, R 6 It is a cycloalkyl group.

[0583] In some implementations, R 6 For any 1, 2, 3 or 4 Rs 8 Heterocyclic rings substituted by groups.

[0584] In some implementations, R 6 It is a heterocyclic ring.

[0585] In some implementations, R 6 For any 1, 2, 3 or 4 Rs 8 The aryl group substituted by the group.

[0586] In some implementations, R 6 It is an aryl group.

[0587] In some implementations, R 6 For any 1, 2, 3 or 4 Rs 8 The heteroaryl group substituted by the group.

[0588] In some implementations, R 6 For NR 7 R 7 .

[0589] In some implementations, R 6 It is NH2.

[0590] In some implementations, R 6 It is OH.

[0591] In some implementations, R 6 It is OCH3.

[0592] R 7 Implementation plan:

[0593] In some implementations, each R 7 It is independently selected from hydrogen and alkyl groups.

[0594] In some implementations, R 7 It is hydrogen.

[0595] In some implementations, R 7 It is an alkyl group.

[0596] In some implementations, R 7 It is an alkenyl or ynyl group.

[0597] In some implementations, R 7 For any 1, 2, 3 or 4 Rs 8 Cycloalkyl groups substituted by the radical.

[0598] In some implementations, R 7 It is a cycloalkyl group.

[0599] In some implementations, R 7 For any 1, 2, 3 or 4 Rs 8 Heterocyclic rings substituted by groups.

[0600] In some implementations, R 7 It is a heterocyclic ring.

[0601] In some implementations, R 7 For any 1, 2, 3 or 4 Rs 8 The aryl group substituted by the group.

[0602] In some implementations, R 7 It is an aryl group.

[0603] In some implementations, R 7 For any 1, 2, 3 or 4 Rs 8 The heteroaryl group substituted by the group.

[0604] R 8 Implementation plan:

[0605] In some implementations, each R 8 Independently selected from halogens, haloalkyl groups, alkyl groups, and NR. 12 R 13 and OR 12 .

[0606] In some implementations, each R 8 It is a halogen.

[0607] In some implementations, each R 8 It is a haloalkyl group.

[0608] In some implementations, each R 8 It is an alkyl group.

[0609] In some implementations, at least one R 8 It is a halogen.

[0610] In some implementations, at least one R 8 It is a haloalkyl group.

[0611] In some implementations, at least one R 8 It is an alkyl group.

[0612] In some implementations, each R 8 It is a cycloalkyl group.

[0613] In some implementations, at least one R 8 It is a heterocyclic ring.

[0614] In some implementations, at least one R 8 It is an aryl group.

[0615] In some implementations, at least one R 8 It is a heteroaryl group.

[0616] In some implementations, at least one R 8 It is an -S(O)2 alkyl group.

[0617] In some implementations, at least one R 8 For NR 12 R 13 .

[0618] In some implementations, at least one R 8 It is an alkyl-heteroaryl group.

[0619] In some implementations, at least one R 8 It is alkyl-aryl.

[0620] In some implementations, at least one R 8 OR 12 .

[0621] In some implementations, each R 8 Independently selected from hydrogen, halogen, haloalkyl, alkyl, cycloalkyl, heterocyclic, aryl, heteroaryl, -S(O)2alkyl, NR 12 R 13 alkyl-heteroaryl, alkyl-aryl and OR 12 .

[0622] In some implementations, each R 8 Independently selected from hydrogen, alkyl, NR 12 R 13 alkyl-heteroaryl, alkyl-aryl and OR 12 .

[0623] R 12 and R 13 Implementation plan:

[0624] In some implementations, each R 12 and R 13 It is independently selected from hydrogen and alkyl groups.

[0625] In some implementations, R 12 and R 13 Both are hydrogen.

[0626] In some implementations, R 12 and R 13 Both are alkyl groups.

[0627] In some implementations, R 12 and R 13 One of them is hydrogen.

[0628] In some implementations, R 12 and R 13 One of them is an alkyl group.

[0629] In some implementations, R 12 and R 13 One of them is -C(O) alkyl.

[0630] In some implementations, R 12 and R 13 One of them is -C(S) alkyl.

[0631] In some implementations, R 12 and R 13 One of them is aryl.

[0632] In some implementations, R 12 and R 13 One of them is -SO2 alkyl.

[0633] In some implementations, R 12 and R 13 One of them is -S(O) alkyl.

[0634] In some implementations, R 12 and R 13 One of them is a heteroaryl group.

[0635] In some implementations, R 12 and R 13 One of them is alkyl-aryl.

[0636] In some implementations, R 12 and R 13 One of them is a cycloalkyl group.

[0637] In some implementations, R 12 and R 13 One of them is a heterocyclic ring.

[0638] In some implementations, R 12 and R 13 One of them is alkyl-heteroaryl.

[0639] R 14 and R 15 Implementation plan:

[0640] In some implementations, each R 14 and R 15 It is independently selected from hydrogen and alkyl groups.

[0641] In some implementations, R 14 and R 15 Both are hydrogen.

[0642] In some implementations, R 14 and R 15 Both are alkyl groups.

[0643] In some implementations, R 14 and R 15 One of them is hydrogen.

[0644] In some implementations, R 14 and R 15 One of them is an alkyl group.

[0645] In some implementations, R 14 and R 15 One of them is -C(O) alkyl.

[0646] In some implementations, R 14 and R 15 One of them is -C(S) alkyl.

[0647] In some implementations, R 14 and R 15 One of them is aryl.

[0648] In some implementations, R 14 and R 15 One of them is -SO2 alkyl.

[0649] In some implementations, R 14 and R 15 One of them is -S(O) alkyl.

[0650] In some implementations, R 14 and R 15 One of them is a heteroaryl group.

[0651] In some implementations, R 14 and R 15 One of them is alkyl-aryl.

[0652] In some implementations, R 14 and R 15 One of them is a cycloalkyl group.

[0653] In some implementations, R 14 and R 15 One of them is a heterocyclic ring.

[0654] In some implementations, R 14 and R 15 One of them is alkyl-heteroaryl.

[0655] R 17 and R 18 Implementation plan:

[0656] In some implementations, each R 17 It is independently selected from hydrogen and alkyl groups.

[0657] In some implementations, R 17 It is hydrogen.

[0658] In some implementations, R 17 It is an alkyl group.

[0659] In some implementations, R 17 It is an alkenyl or ynyl group.

[0660] In some implementations, R 17 For any 1, 2, 3 or 4 Rs8 Cycloalkyl groups substituted by the radical.

[0661] In some implementations, R 17 It is a cycloalkyl group.

[0662] In some implementations, R 17 For any 1, 2, 3 or 4 Rs 8 Heterocyclic rings substituted by groups.

[0663] In some implementations, R 17 It is a heterocyclic ring.

[0664] In some implementations, R 17 For any 1, 2, 3 or 4 Rs 8 The aryl group substituted by the group.

[0665] In some implementations, R 17 It is an aryl group.

[0666] In some implementations, R 17 For any 1, 2, 3 or 4 Rs 8 The heteroaryl group substituted by the group.

[0667] In some implementations, each R 18 It is independently selected from hydrogen and alkyl groups.

[0668] In some implementations, R 18 It is hydrogen.

[0669] In some implementations, R 18 It is an alkyl group.

[0670] In some implementations, R 18 It is an alkenyl or ynyl group.

[0671] In some implementations, R 18 For any 1, 2, 3 or 4 Rs 8 Cycloalkyl groups substituted by the radical.

[0672] In some implementations, R 18 It is a cycloalkyl group.

[0673] In some implementations, R 18 For any 1, 2, 3 or 4 Rs 8 Heterocyclic rings substituted by groups.

[0674] In some implementations, R 18 It is a heterocyclic ring.

[0675] In some implementations, R 18 For any 1, 2, 3 or 4 Rs8 The aryl group substituted by the group.

[0676] In some implementations, R 18 It is an aryl group.

[0677] In some implementations, R 18 For any 1, 2, 3 or 4 Rs 8 The heteroaryl group substituted by the group.

[0678] R 19 Implementation plan:

[0679] In some implementations, R 19 It is hydrogen.

[0680] In some implementations, R 19 It is an alkyl group.

[0681] In some implementations, R 19 It is a haloalkyl group.

[0682] In some implementations, R 19 It is a halogen.

[0683] In some implementations, R 19 It is a cyano group.

[0684] In some implementations, R 19 For -OR 14 .

[0685] In some implementations, R 19 For -NR 14 R 15 .

[0686] R 50 Implementation plan:

[0687] In some implementations, each R 50 Independently selected from amino, -NHR 14 -NR 14 R 15 hydroxyl group, OR 14 and R 4 .

[0688] In some implementations, there exists an R 50 The group is -NR 14 R 15 .

[0689] In some implementations, there exists an R 50 Group and it is OR 14 .

[0690] In some implementations, there exists an R 50 Group and it is R 4 .

[0691] X 1 X 2 X 3 X 4 and X 5 Implementation plan

[0692] In some implementations, X 1 X 2 X 3 X 4 and X 5 Each of them is independently CH.

[0693] In some implementations, X 1 X 2 X 3 X 4 and X 5 At least one of them is N.

[0694] In some implementations, X 1 X 2 X 3 X 4 and X 5 The two in the equation are N.

[0695] In some implementations, X 1 X 2 X 3 X 4 and X 5 At least one of them is CR 4 ;where R 4 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 or -S(O)2R 6 .

[0696] In some implementations, X 1 X 2 X 3 X 4 and X 5 At least one of them is CR 4 ;where R 4 OR 14 -NR 14 R 15 -NR 14 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 .

[0697] In some implementations, X 1 X 2 X 3 X 4 and X 5 At least one of them is CR 4 ;where R 4 OR 14 -NR 14 R 15 -NR 14 S(O)2R 6 S(O)R 6 or -S(O)2R 6 .

[0698] In some implementations, X 1 X 2 X 3 X 4 and X 5 At least one of them is CR 4 ;where R 4 It is hydrogen, haloalkyl, or halogen.

[0699] X 11 X 12 X 13 X 14 and X 15 Implementation plan

[0700] In some implementations, X 11 X 12 X 13 X14 and X 15 Each of them is independently CH.

[0701] In some implementations, X 11 X 12 X 13 X 14 and X 15 At least one of them is N.

[0702] In some implementations, X 11 X 12 X 13 X 14 and X 15 The two in the equation are N.

[0703] In some implementations, X 11 X 12 X 13 X 14 and X 15 At least one of them is CR 4 ;where R 4 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 or -S(O)2R 6 .

[0704] In some implementations, X 11 X 12 X 13 X 14 and X 15 At least one of them is CR 4 ;where R 4 OR 14 -NR 14 R15 -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 .

[0705] In some implementations, X 11 X 12 X 13 X 14 and X 15 At least one of them is CR 4 ;where R 4 OR 14 -NR 14 R 15 -NR 14 S(O)2R 6 S(O)R 6 or -S(O)2R 6 .

[0706] In some implementations, X 11 X 12 X 13 X 14 and X 15 At least one of them is CR 4 ;where R 4 It is hydrogen, haloalkyl, or halogen.

[0707] Other implementation plans

[0708] 1. In some embodiments, compounds of the following formula are provided:

[0709]

[0710]

[0711] Or a pharmaceutically acceptable salt, N-oxide, isotope analog, and / or a pharmaceutically acceptable composition thereof;

[0712] in:

[0713] X 1 X 2 X 3 X 4 and X 5 Independently selected from N, CH, CR 2 and CR 4 ;where X 1 X2 X 3 X 4 and X 5 At least one of them is CR 2 ; and X 1 X 2 X 3 X 4 and X 5 There are no more than two choices N;

[0714] X 11 X 12 X 13 X 14 and X 15 Independently selected from N, CH, CR 2 and CR 4 ;where X 11 X 12 X 13 X 14 and X 15 There are no more than two choices N;

[0715] Each R 1 Independently selected from hydrogen, halogen, -OR 14 NR 14 R 15 Alkyl, aryl, cycloalkyl, haloalkyl, heteroaryl, alkyl-hydroxyl, and heterocyclic, wherein two R 1 They can optionally form 3, 4, 5, 6, 7, or 8-membered cycloalkyl groups or 4, 5, 6, 7, or 8-membered heterocycles having 1, 2, or 3 heteroatoms selected from N, O, and S; wherein the two R groups are connected together. 1 The cycloalkyl or heterocyclic rings formed by the bonding of the atoms to which they are attached may optionally be composed of one or two independently selected from R 50 The substituents are replaced;

[0716] Each R 2 Independently selected from -NR 14 C(O)R 6 -NR 14 S(O)R 6 -NR 14 S(O)2R 6 -NR 14 C(S)R 6 -OC(O)R 6 -OS(O)R 6 -OS(O)2R 6 -OC(S)R 6 -C(O)R 6 ;-C(S)R6 -S(O)R 6 -S(=NR) 14 )2R 6 -S(=NR) 14 )(O)R 6 and -S(O)2R 6 ;

[0717] R 3 Selected from hydrogen, -OR 14 -NR 14 R 15 alkyl, alkenyl, ynyl, –C(O)R 6 -C(O)alkyl, -C(S)alkyl, aryl, -SO2alkyl, heteroaryl, heterocyclic, -alkyl-aryl and -alkyl-heteroaryl;

[0718] Each R 4 Independently selected from 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 ;

[0719] R 5 Hydrogen, alkyl, haloalkyl, halogen, cyano, -OR 14 or -NR 14 R 15 ;

[0720] Each R 6 Independently selected from hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, heteroaryl, NR 7 R 7 and OR 7 Except for hydrogen, NR 7 R 7 and OR 7Each R outside 6 Can be arbitrarily divided by 1, 2, 3 or 4 Rs 8 Substituted by groups;

[0721] Each R 7 Independently selected from hydrogen, alkyl, alkenyl, ynyl, cycloalkyl, heterocyclic, aryl, alkyl-aryl, alkyl-heteroaryl, and heteroaryl, each R except hydrogen 7 Can be arbitrarily divided by 1, 2, 3 or 4 Rs 8 Substituted by groups;

[0722] Each R 8 Independently selected from hydrogen, halogen, haloalkyl, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, heteroaryl, -S(O)2alkyl, NR 12 R 13 alkyl-heteroaryl, alkyl-aryl and OR 12 ;

[0723] Each R 12 and R 13 Independently selected from hydrogen, alkyl, alkenyl, ynyl, -C(O)alkyl, -C(S)alkyl, aryl, -SO2alkyl, -S(O)alkyl, heteroaryl, alkyl-aryl, cycloalkyl, heterocyclic and alkyl-heteroaryl;

[0724] Each R 14 and R 15 Independently selected from hydrogen, alkyl, alkenyl, ynyl, –C(O)R 6 -C(O)alkyl, -C(S)alkyl, aryl, -SO2alkyl, heteroaryl, heterocyclic, -alkyl-aryl and -alkyl-heteroaryl;

[0725] R 17 and R 18 Independently selected from hydrogen, alkyl, alkenyl, ynyl, cycloalkyl, heterocyclic, aryl, alkyl-aryl, alkyl-heteroaryl, and heteroaryl, each of which except hydrogen is optionally marked by 1, 2, 3, or 4 R's. 8 Substituted by groups; and

[0726] R 19 Hydrogen, alkyl, haloalkyl, halogen, cyano, -OR 14 or -NR 14 R 15 ;and

[0727] Each R 50 Independently selected from hydrogen, -NR 14 R 15 OR 14 and R 4 .

[0728] 2. In some embodiments, compounds of the following formula are provided:

[0729]

[0730]

[0731] Or a pharmaceutically acceptable salt, N-oxide, isotope analog, and / or a pharmaceutically acceptable composition thereof;

[0732] Each R 2 Independently selected from -NR 14 C(O)R 6 -NR 14 S(O)R 6 -NR 14 S(O)2R 6 -NR 14 C(S)R 6 -OC(O)R 6 -OS(O)R 6 -OS(O)2R 6 -OC(S)R 6 -C(O)R 6 ;-C(S)R 6 -S(O)R 6 and -S(O)2R 6 .

[0733] 3. Compounds according to the following formula in Scheme 1:

[0734]

[0735] Or its pharmaceutically acceptable salt.

[0736] 4. The compound of embodiment 1, wherein R 5 It is a hydroxyl group.

[0737] 5. Compounds according to the following formula in Scheme 1:

[0738]

[0739] Or its pharmaceutically acceptable salt.

[0740] 6. The compound of embodiment 1, wherein one of R 1 It is hydrogen.

[0741] 7. The compound of embodiment 1, wherein two R 1 Both are hydrogen.

[0742] 8. A compound according to Scheme 1, wherein any one of R 1 None of them are hydrogen.

[0743] 9. Compounds according to the following formula of Scheme 1:

[0744]

[0745] Or its pharmaceutically acceptable salt.

[0746] 10. Compounds according to the following formula of Scheme 1:

[0747]

[0748] Or its pharmaceutically acceptable salt.

[0749] 11. Compounds according to the following formula in Scheme 1:

[0750]

[0751] Or its pharmaceutically acceptable salt.

[0752] 12. Compounds according to the following formula of Scheme 1:

[0753]

[0754] Or its pharmaceutically acceptable salt.

[0755] 13. A compound according to any one of embodiments 10-12, wherein X 11 For CH.

[0756] 14. A compound according to any one of embodiments 10-12, wherein X 11 Let N be the number of elements in the array.

[0757] 15. A compound according to any one of embodiments 10-12, wherein X 11 For CR 4 .

[0758] 16. A compound according to any one of embodiments 10-15, wherein X 12 For CH.

[0759] 17. A compound according to any one of embodiments 10-15, wherein X 12 Let N be the number of elements in the array.

[0760] 18. A compound according to any one of embodiments 10-15, wherein X 12 For CR 4 .

[0761] 19. A compound according to any one of embodiments 10-18, wherein X 13 For CH.

[0762] 20. A compound according to any one of embodiments 10-18, wherein X 13 Let N be the number of elements in the array.

[0763] 21. A compound according to any one of embodiments 10-18, wherein X 13 For CR 4 .

[0764] 22. A compound according to any one of embodiments 10-21, wherein X 14 For CH.

[0765] 23. A compound according to any one of embodiments 10-21, wherein X 14 Let N be the number of elements in the array.

[0766] 24. A compound according to any one of embodiments 10-21, wherein X 14 For CR 4 .

[0767] 25. A compound of any one of embodiments 10-24, wherein X 15 For CH.

[0768] 26. A compound of any one of embodiments 10-24, wherein X 15 Let N be the number of elements in the array.

[0769] 27. A compound of any one of embodiments 10-24, wherein X 15 For CR 4 .

[0770] 28. Compounds according to the following formula of Scheme 1:

[0771]

[0772] Or its pharmaceutically acceptable salt.

[0773] 29. A compound of any one of embodiments 1-28, wherein R 3 It is hydrogen.

[0774] 30. A compound of any one of embodiments 1-28, wherein R 3 It is an alkyl group.

[0775] 31. A compound of any one of embodiments 1-28, wherein R 3 For -NR 14 R 15 .

[0776] 32. A compound of any one of embodiments 1-28, wherein R 3 It is -NH2.

[0777] 33. Compounds according to the following formula of Scheme 1:

[0778]

[0779] Or its pharmaceutically acceptable salt.

[0780] 34. Compounds according to the following formula of Scheme 1:

[0781]

[0782] Or its pharmaceutically acceptable salt.

[0783] 35. Compounds according to the following formula of Scheme 1:

[0784]

[0785] Or its pharmaceutically acceptable salt.

[0786] 36. Compounds according to the following formula of Scheme 1:

[0787]

[0788] Or its pharmaceutically acceptable salt.

[0789] 37. Compounds according to the following formula of Scheme 1:

[0790]

[0791] Or its pharmaceutically acceptable salt.

[0792] 38. A compound of embodiment 1 or any one of embodiments 33-37, wherein two R 1 Together with the carbon atoms they are attached to, they form 3-8 membered rings.

[0793] 39. A compound of embodiment 1 or any one of embodiments 33-37, wherein two R 1 Together with the carbon atoms they are attached to, they form a 6-membered carbon ring.

[0794] 40. A compound of any one of embodiments 1 or 33-37, wherein one of the R 1 It is a halogen.

[0795] 41. A compound of any one of embodiments 1 or 33-37, wherein one of the R 1 It is a haloalkyl group.

[0796] 42. A compound of any one of embodiments 1 or 33-37, wherein one of the R 1 It is a hydroxyl group.

[0797] 43. A compound of any one of embodiments 1 or 33-37, wherein R 1 It is selected from alkyl, aryl, cycloalkyl and haloalkyl.

[0798] 44. A compound of any one of embodiments 1-43, wherein R 2 -C(O)R 6 ;-C(S)R 6 -S(O)R 6 or -S(O)2R 6 .

[0799] 45. A compound of any one of embodiments 1-43, wherein R 2 -C(O)R 6 .

[0800] 46. ​​A compound of any one of embodiments 1-43, wherein R 2 is -S(O)2R 6 .

[0801] 47. A compound of any one of embodiments 1-46, wherein each R 6 It is independently selected from hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl and heteroaryl.

[0802] 48. A compound of any one of embodiments 1-46, wherein each R 6 Independently selected from NR 7 R 7 and OR 7 .

[0803] 49. A compound of any one of embodiments 1-43, wherein R 2 It is -S(O)2NH2.

[0804] 50. A compound of any one of embodiments 1-49, wherein for

[0805] 51. A compound of any one of embodiments 1-50, wherein X 1 For CH.

[0806] 52. A compound of any one of embodiments 1-50, wherein X 1 Let N be the number of elements in the array.

[0807] 53. A compound of any one of embodiments 1-50, wherein X 1 For CR 2 .

[0808] 54. A compound of any one of embodiments 1-50, wherein X1 For CR 4 .

[0809] 55. A compound of any one of embodiments 1-54, wherein X 2 For CH.

[0810] 56. A compound of any one of embodiments 1-54, wherein X 2 Let N be the number of elements in the array.

[0811] 57. A compound of any one of embodiments 1-54, wherein X 2 For CR 2 .

[0812] 58. A compound of any one of embodiments 1-54, wherein X 2 For CR 4 .

[0813] 59. A compound of any one of embodiments 1-58, wherein for

[0814] 60. A compound of any one of embodiments 1-58, wherein X 3 For CH.

[0815] 61. A compound of any one of embodiments 1-58, wherein X 3 Let N be the number of elements in the array.

[0816] 62. A compound of any one of embodiments 1-58, wherein X 3 For CR 2 .

[0817] 63. A compound of any one of embodiments 1-58, wherein X 3 For CR 4 .

[0818] 64. A compound according to any one of embodiments 60-63, wherein for

[0819] 65. A compound according to any one of embodiments 1-64, wherein X 4 For CH.

[0820] 66. A compound according to any one of embodiments 1-64, wherein X 4 Let N be the number of elements in the array.

[0821] 67. A compound according to any one of embodiments 1-64, wherein X 4 For CR 2 .

[0822] 68. A compound of any one of embodiments 1-64, wherein X 4 For CR 4 .

[0823] 69. A compound of any one of embodiments 1-68, wherein X 5 For CH.

[0824] 70. A compound of any one of embodiments 1-68, wherein X 5 Let N be the number of elements in the array.

[0825] 71. A compound of any one of embodiments 1-68, wherein X 5 For CR 2 .

[0826] 72. A compound of any one of embodiments 1-68, wherein X 5 For CR 4 .

[0827] 73. A compound of any one of embodiments 1-72, wherein at least one R 4 OR 14 .

[0828] 74. A compound of any one of embodiments 1-72, wherein at least one R 4 It is a halogen.

[0829] 75. A compound of any one of embodiments 1-72, wherein at least one R 4 It is an alkyl group.

[0830] 76. A compound of any one of embodiments 1-72, wherein at least one R 3 It is an alkyl group.

[0831] 77. In some embodiments, the compound is selected from:

[0832]

[0833]

[0834] Or its pharmaceutically acceptable salt.

[0835] 78. Compounds with the following structures according to implementation scheme 77:

[0836]

[0837] Or its pharmaceutically acceptable salt.

[0838] 79. Compounds with the following structures according to embodiment 77:

[0839]

[0840] Or its pharmaceutically acceptable salt.

[0841] 80. Compounds with the following structures according to embodiment 77:

[0842]

[0843] Or its pharmaceutically acceptable salt.

[0844] 81. Compounds with the following structures according to embodiment 77:

[0845]

[0846] Or its pharmaceutically acceptable salt.

[0847] 82. Compounds with the following structures according to implementation scheme 77:

[0848]

[0849] Or its pharmaceutically acceptable salt.

[0850] 83. Compounds with the following structures according to implementation scheme 77:

[0851]

[0852] Or its pharmaceutically acceptable salt.

[0853] 84. Compounds with the following structures according to implementation scheme 77:

[0854]

[0855] Or its pharmaceutically acceptable salt.

[0856] 85. Compounds with the following structures according to embodiment 77:

[0857]

[0858] Or its pharmaceutically acceptable salt.

[0859] 86. Compounds with the following structures according to implementation scheme 77:

[0860]

[0861] Or its pharmaceutically acceptable salt.

[0862] 87. Compounds with the following structures according to embodiment 77:

[0863]

[0864] Or its pharmaceutically acceptable salt.

[0865] 88. Compounds with the following structures according to Scheme 1:

[0866]

[0867]

[0868]

[0869]

[0870] Or its pharmaceutically acceptable salt.

[0871] 89. A method for treating a condition associated with abnormal cell proliferation is provided, comprising administering to a host in need an effective amount of any one of embodiments 1-88, optionally in a pharmaceutically acceptable carrier.

[0872] 90. The method of implementation scheme 89, wherein the host is a human being.

[0873] 91. The method of implementation scheme 89 or 90, wherein the condition is an inflammatory condition.

[0874] 92. The method of implementation scheme 89 or 90, wherein the condition is a fibrotic condition.

[0875] 93. The method of implementing 89 or 90, wherein the disease is an autoimmune disease.

[0876] 94. The method of implementation scheme 89 or 90, wherein the condition is a tumor.

[0877] 95. The method of implementation scheme 89 or 90, wherein the condition is cancer.

[0878] 96. The method of implementation scheme 89 or 90, wherein the condition is rheumatoid arthritis.

[0879] 97. In some embodiments, a method is provided for reducing the effect of chemotherapy on healthy cells in a person being treated for cancer or abnormal cell proliferation, wherein the healthy cells are hematopoietic stem cells or hematopoietic progenitor cells, the method comprising administering to the person an effective amount of a compound of any one of embodiments 1-88, optionally in a pharmaceutically acceptable carrier.

[0880] 98. A pharmaceutical composition is provided in which a compound of any one of embodiments 1-88 or a pharmaceutically acceptable salt thereof is contained in a pharmaceutically acceptable carrier.

[0881] 99. The pharmaceutical composition of embodiment 98, used for treating a condition associated with abnormal cell proliferation.

[0882] 100. The pharmaceutical composition of embodiment 99, wherein the condition is an inflammatory condition.

[0883] 101. The pharmaceutical composition of embodiment 99, wherein the condition is fibrosis.

[0884] 102. The pharmaceutical composition of embodiment 99, wherein the condition is an autoimmune disease.

[0885] 103. The pharmaceutical composition of embodiment 99, wherein the condition is a tumor.

[0886] 104. The pharmaceutical composition of embodiment 99, wherein the condition is cancer.

[0887] 105. The pharmaceutical composition of embodiment 99, wherein the condition is rheumatoid arthritis.

[0888] 106. The pharmaceutical composition of embodiment 98, used to reduce the effect of chemotherapy on healthy cells in a person being treated for cancer or abnormal cell proliferation, wherein the healthy cells are hematopoietic stem cells or hematopoietic progenitor cells.

[0889] 107. In some embodiments, compounds are provided for manufacturing medicaments for treating conditions associated with abnormal cell proliferation, wherein said compounds are selected from any one of embodiments 1-88 or their pharmaceutically acceptable salts.

[0890] 108. The compound of embodiment 107, wherein the condition is an inflammatory condition.

[0891] 109. The compound of embodiment 107, wherein the condition is fibrotic condition.

[0892] 110. The compound of embodiment 107, wherein the condition is an autoimmune disease.

[0893] 111. The compound of embodiment 107, wherein the condition is a tumor.

[0894] 112. The compound of embodiment 107, wherein the condition is cancer.

[0895] 113. The compound of embodiment 107, wherein the condition is rheumatoid arthritis.

[0896] 114. In some embodiments, a compound is provided for use in manufacturing a medicament for reducing the effect of chemotherapy on healthy cells in a person being treated for cancer or abnormal cell proliferation, wherein said healthy cells are hematopoietic stem cells or hematopoietic progenitor cells, and said compound is selected from any one of embodiments 1-88 or a pharmaceutically acceptable salt thereof.

[0897] 115. In some embodiments, the use of a compound in the treatment of a condition associated with abnormal cell proliferation is provided, wherein the compound is selected from any one of embodiments 1-88 or a pharmaceutically acceptable salt thereof.

[0898] 116. The use of implementation scheme 115, wherein the condition is an inflammatory condition.

[0899] 117. The use of implementation scheme 115, wherein the condition is a fibrotic condition.

[0900] 118. The use of implementation scheme 115, wherein the disease is an autoimmune disease.

[0901] 119. The use of implementation scheme 115, wherein the condition is a tumor.

[0902] 120. The use of implementation scheme 115, wherein the condition is cancer.

[0903] 121. The use of implementation scheme 115, wherein the condition is rheumatoid arthritis.

[0904] 122. In some embodiments, the use of the compound is provided in reducing the effect of chemotherapy on healthy cells in a person being treated for cancer or abnormal cell proliferation, wherein the healthy cells are hematopoietic stem cells or hematopoietic progenitor cells, and wherein the compound is selected from any one of embodiments 1-88 or a pharmaceutically acceptable salt thereof.

[0905] Core implementation plan

[0906] In some implementations, Selected from:

[0907]

[0908]

[0909] In some implementations, Selected from

[0910]

[0911] In some implementations, Selected from:

[0912]

[0913]

[0914] In some implementations, Selected from:

[0915]

[0916] In some implementations, Selected from:

[0917]

[0918]

[0919] In some implementations, Selected from:

[0920]

[0921]

[0922]

[0923] In some implementations, Selected from:

[0924]

[0925] In some implementations, Selected from:

[0926]

[0927] In some implementations, Selected from:

[0928]

[0929]

[0930] In some implementations, Selected from:

[0931]

[0932] Other implementation plans

[0933] In some embodiments, the compounds of the present invention are selected from:

[0934]

[0935] Or its pharmaceutically acceptable salt.

[0936] In some embodiments, the compounds of the present invention are selected from:

[0937]

[0938] Or its pharmaceutically acceptable salt.

[0939] In some embodiments, the compounds of the present invention are selected from:

[0940]

[0941]

[0942] Or its pharmaceutically acceptable salt.

[0943] In some embodiments, the compounds of the present invention are selected from:

[0944]

[0945]

[0946] Or its pharmaceutically acceptable salt.

[0947] In some embodiments, the compounds of the present invention are selected from:

[0948]

[0949] Or its pharmaceutically acceptable salt.

[0950] In some embodiments, the compounds of the present invention are selected from:

[0951]

[0952] Or its pharmaceutically acceptable salt.

[0953] In some embodiments, the compounds of the present invention are selected from:

[0954]

[0955]

[0956] Or its pharmaceutically acceptable salt.

[0957] In some embodiments, the compounds of the present invention are selected from:

[0958]

[0959]

[0960] Or its pharmaceutically acceptable salt.

[0961] Non-limiting examples of compounds of the present invention

[0962] In some embodiments, the compounds of the present invention are selected from:

[0963]

[0964]

[0965] Or its pharmaceutically acceptable salt.

[0966] In some embodiments, the compounds of the present invention are selected from:

[0967]

[0968] Or its pharmaceutically acceptable salt.

[0969] In some embodiments, the compounds of the present invention are selected from:

[0970] Or its pharmaceutically acceptable salt.

[0971] In some embodiments, the compounds of the present invention are selected from:

[0972]

[0973]

[0974] Or its pharmaceutically acceptable salt.

[0975] In some embodiments, the compounds of the present invention are selected from:

[0976]

[0977]

[0978] Or its pharmaceutically acceptable salt.

[0979] In some embodiments, the compounds of the present invention are selected from:

[0980]

[0981]

[0982] Or its pharmaceutically acceptable salt.

[0983] In some embodiments, the compounds of the present invention are selected from:

[0984]

[0985]

[0986]

[0987] Or its pharmaceutically acceptable salt.

[0988] In some embodiments, the compounds of the present invention are selected from:

[0989]

[0990]

[0991] Or its pharmaceutically acceptable salt.

[0992] In some embodiments, the compounds of the present invention are selected from:

[0993]

[0994]

[0995]

[0996]

[0997]

[0998] Or its pharmaceutically acceptable salt.

[0999] In some embodiments, the compounds of the present invention are selected from:

[1000]

[1001]

[1002]

[1003]

[1004] Or its pharmaceutically acceptable salt.

[1005] In some embodiments, the compounds of the present invention are selected from:

[1006]

[1007]

[1008] Or its pharmaceutically acceptable salt.

[1009] In some embodiments, the compounds of the present invention are selected from:

[1010]

[1011] Or its pharmaceutically acceptable salt.

[1012] In some embodiments, the compounds of the present invention are selected from:

[1013]

[1014] Or its pharmaceutically acceptable salt.

[1015] In some embodiments, the compounds of the present invention are selected from:

[1016]

[1017]

[1018]

[1019] Or its pharmaceutically acceptable salt.

[1020] In some embodiments, the compounds of the present invention are selected from:

[1021]

[1022]

[1023] Or its pharmaceutically acceptable salt.

[1024] In some embodiments, the compounds of the present invention are selected from:

[1025]

[1026]

[1027] Or its pharmaceutically acceptable salt.

[1028] II. Terminology

[1029] Compounds are described using standard nomenclature. Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention pertains.

[1030] Any compound described herein includes racemic compounds, enantiomers, mixtures of enantiomers, diastereomers, mixtures of diastereomers, tautomers, N-oxides, isomers; such as rotational isomers, as each is explicitly described.

[1031] The term "a / an" does not indicate a limitation of quantity, but rather the presence of at least one of the mentioned items. The term "or" means "and / or". Unless otherwise indicated herein, the description of ranges of values ​​is intended only as a shorthand method for referring one by one to each individual value falling within the range, and each individual value is incorporated into this specification as if it were described one by one herein. The endpoints of all ranges are included within the range and can be combined independently. Unless otherwise indicated herein or clearly contradicted by the context, all methods described herein may be performed in a suitable order. Unless otherwise stated, the use of examples or exemplary language (e.g., "such as") is intended only to better illustrate the invention and does not constitute a limitation on the scope of the invention. Unless otherwise defined, the technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention pertains.

[1032] The term "isotope analog" refers to a compound having at least one atomic isotope substitution in an amount higher than the natural abundance of that isotope. An isotope is an atom with the same atomic number but different mass numbers, i.e., atoms with the same number of protons but different numbers of neutrons. Non-limiting examples of isotope analogs of compound 1 include:

[1033] This invention includes compounds of formula I, II, III, IV, V, VI, VII, VIII, IX, or X, having at least one desired isotopic substitution of an atom to an amount exceeding the natural abundance of that isotope, i.e., enrichment. In some embodiments, the atom is substituted with its isotope at or near a metabolic region in vivo, producing an α, β, or γ effect.

[1034] Examples of isotopes that can be incorporated into the compounds of this invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine, chlorine, and iodine, respectively, as follows: 2 H, 3 H, 11 C 13 C 14 C 15 N、 17 O、 18 O、 18 F, 31 P, 32 P, 35 S, 36 Cl and 125 I. In one non-limiting embodiment, the isotope-labeled compound can be used for metabolic studies (using...) 14 C) Reaction kinetic studies (using, for example) 2 H or 3H) Detection or imaging techniques such as positron emission tomography (PET) or single-photon emission computed tomography (SPECT), including drug or substrate tissue distribution assays, or for use in patient radiation therapy. In particular, 18 F-labeled compounds may be particularly ideal for PET and SPECT studies. The isotopically labeled compounds of this invention can generally be prepared by replacing non-isotopically labeled reagents with readily available isotopically labeled reagents, using the procedures disclosed in the embodiments or examples and the preparation methods described below.

[1035] As a general example, but not a limitation, isotopes of hydrogen, such as deuterium (… 2 H) and tritium ( 3 H) can be used anywhere in the structure to achieve the desired result. Alternatively, carbon isotopes, such as 13C and 14 C.

[1036] Isotope substitution, such as deuterium substitution, can be partial or complete. Partial deuterium substitution refers to the substitution of at least one hydrogen atom with deuterium. In some embodiments, an isotope is enriched at any target location by 90, 95, or 99% or more. In a non-limiting embodiment, deuterium is enriched at the desired location by 90, 95, or 99%.

[1037] In one non-limiting embodiment, the substitution of one or more hydrogen atoms by a deuterium atom may be provided in any of Formula I, II, III, IV, V, VI, VII, VIII, IX, or X. In one non-limiting embodiment, the substitution of hydrogen atoms by a deuterium atom occurs in a process selected from R... 1 R 2 R 3 R 4 R 5 R 6 R 7 R 8 R 11 R 12 R 13 R 14 R 15 R 17 R 18 and R 19Within any of the substituents. For example, when any substituent is or contains (e.g., by substitution) a methyl, ethyl, or methoxy group, the alkyl residue may be deuterated (in a non-limiting embodiment, CDH2, CD2H, CD3, CH2CD3, CD2CD3, CHDCH2D, CH2CD3, CHDCHD2, OCDH2, OCD2H, or OCD3, etc.). In some other embodiments, when two substituents combine to form a ring, the unsubstituted carbon may be deuterated.

[1038] The compounds of the present invention can form solvates with solvents, including water. Therefore, in a non-limiting embodiment, the present invention includes the solvated form of the compounds. The term "solvate" refers to a molecular complex of a compound of the present invention (including its salts) with one or more solvent molecules. Non-limiting examples of solvents are water, ethanol, dimethyl sulfoxide, acetone, and other common organic solvents. The term "hydrate" refers to a molecular complex comprising a compound of the present invention and water. Pharmaceutically acceptable solvates according to the present invention include those in which the solvent can be substituted with an isotope (e.g., D2O, d6-acetone, d6-DMSO). Solvates may be in liquid or solid form.

[1039] A hyphen ("-") not between two letters or symbols is used to indicate the connection point of a substituent. For example, -(C=O)NH2 is connected to the carbon atom of a ketone (C=O) group.

[1040] "alkyl" refers to a branched or straight-chain saturated aliphatic hydrocarbon group. In one non-limiting embodiment, the alkyl group contains 1 to about 12 carbon atoms, more typically 1 to about 6 carbon atoms or 1 to about 4 carbon atoms. In one non-limiting embodiment, the alkyl group contains 1 to about 8 carbon atoms. In some embodiments, the alkyl group is C1-C2, C1-C3, C1-C4, C1-C5, or C1-C6. Specific ranges as used herein indicate alkyl groups having each member of the range, each member of which is described as a separate substance. For example, the term C1-C6 alkyl as used herein indicates a straight-chain or branched alkyl group having 1, 2, 3, 4, 5, or 6 carbon atoms and is intended to mean that each of these is described as a separate substance. For example, the term C1-C4 alkyl as used herein indicates a straight-chain or branched alkyl group having 1, 2, 3, or 4 carbon atoms and is intended to mean that each of these is described as a separate substance. Examples of alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, tert-pentyl, neopentyl, n-hexyl, 2-methylpentane, 3-methylpentane, 2,2-dimethylbutane, and 2,3-dimethylbutane. In an alternative embodiment, the alkyl group may optionally be substituted. The term "alkyl" also encompasses cycloalkyl or carbocyclic groups. For example, when the term includes "alk," "cycloalkyl" or "carbocyclic" may be considered part of this definition unless the context explicitly excludes it. For example, but not limited to, the terms alkyl, -O-alkyl, haloalkyl, etc., may be considered to include cyclic forms of alkyl groups unless the context explicitly excludes it.

[1041] As used herein, “substituted alkyl” refers to an alkyl group substituted by the described substituent. Where no substituent is explicitly described, “substituted alkyl” refers to an alkyl group substituted by one, two, three, or four independently selected substituents from the following: F, Cl, Br, I, cyano, hydroxy, -O-alkyl, -SH, -S-alkyl, -COOH, -COOalkyl, -COalkyl, -COH, -CONH2, -CONHalkyl, -CON(alkyl)2, -OC(O)alkyl, -NHC(O)alkyl, -NalkylC(O)alkyl, nitro, amino, -NHalkyl, N(alkyl)2, cyano, haloalkyl, aryl, heteroaryl, alkenyl, ynyl, haloalkyl, cycloalkyl, alkyl-aryl, alkyl -heteroaryl, alkyl-cycloalkyl, alkyl-heterocyclic, heterocyclic, -COO aryl, -CO aryl, -CONH aryl, -CON(alkyl)(aryl), -OC(O) aryl, -NHC(O) aryl, -NalkylC(O) aryl, -COO heteroaryl, -CO heteroaryl, -CONH heteroaryl, -CON(alkyl)(heteroaryl), -OC(O) heteroaryl, -NHC(O) heteroaryl, -NalkylC(O) heteroaryl, -COO heterocyclic, -CO heterocyclic, -CONH heterocyclic, -CON(alkyl)(heterocyclic), -OC(O) heterocyclic, -NHC(O) heterocyclic and -NalkylC(O) heterocyclic.

[1042] "Alkenyl" is a straight-chain or branched aliphatic hydrocarbon group having one or more carbon-carbon double bonds, which may be present at a stable point along the chain. The specific range used herein refers to an alkenyl group having each member of the range, each member of which is described as an independent substance, as described above with respect to the alkyl portion. Examples of alkenyl groups include, but are not limited to, vinyl, propenyl, allyl, propenyl, butenyl, and 4-methylbutenyl. The term "alkenyl" also embodies "cis" and "trans" alkenyl geometries, or alternatively, "E" and "Z" alkenyl geometries. In an alternative embodiment, the alkenyl group may optionally be substituted. The term "alkenyl" also covers cycloalkyl or carbon cyclic groups having at least one unsaturation point. As used herein, "substituted alkenyl" may be replaced by a group described above with respect to alkyl.

[1043] "Alynyl" is a branched or straight-chain aliphatic hydrocarbon group having one or more carbon-carbon triple bonds, which may be present at any stable point along the chain. The specific ranges used herein refer to alkynyl groups having each member of the range, each member of which is described as an independent substance as described above with respect to the alkyl portion. Examples of alkynyl groups include, but are not limited to, ethynyl, propynyl, 1-butynyl, 2-butynyl, 3-butynyl, 1-pentynyl, 2-pentynyl, 3-pentynyl, 4-pentynyl, 1-hexynyl, 2-hexynyl, 3-hexynyl, 4-hexynyl, and 5-hexynyl. In an alternative embodiment, the alkynyl group may optionally be substituted. The term "alkynyl" also covers cycloalkyl or carbon cyclic groups having at least one unsaturation point. As used herein, "substituted alkynyl" may be replaced by a group described above with respect to the alkyl portion.

[1044] "Halogen" refers to fluorine, chlorine, bromine, or iodine.

[1045] "Haloalkyl" refers to a branched or straight-chain alkyl group that is replaced by one or more of the aforementioned halogen atoms, up to a maximum permitted number of halogen atoms. Examples of haloalkyl groups include, but are not limited to, fluoromethyl, difluoromethyl, trifluoromethyl, chloromethyl, dichloromethyl, trichloromethyl, pentafluoroethyl, heptafluoropropyl, difluorochloromethyl, dichlorofluoromethyl, difluoroethyl, difluoropropyl, dichloroethyl, and dichloropropyl. "Hyperhaloalkyl" means an alkyl group in which all hydrogen atoms are replaced by halogen atoms. Examples include, but are not limited to, trifluoromethyl and pentafluoroethyl.

[1046] As used in this article, "aryl" refers to a compound in the aromatic ring system ("C"). 6–14 The aryl group provides a monocyclic or polycyclic (e.g., bicyclic or tricyclic) 4n+2 aromatic ring system (e.g., sharing 6, 10, or 14 π electrons in a ring array) having 6-14 ring carbon atoms and zero heteroatoms. In some embodiments, the aryl group has 6 ring carbon atoms (“C6 aryl”; e.g., phenyl). In some embodiments, the aryl group has 10 ring carbon atoms (“C…”). 10 Aryl; 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, anthracene). "Aryl" also includes a ring system in which an aryl ring as defined above is fused with one or more cycloalkyl or heterocyclic groups, wherein the group or linking point is located on the aryl ring, and in such cases, the number of carbon atoms still specifies the number of carbon atoms in the aryl ring system. The one or more fused cycloalkyl or heterocyclic groups may be 4 to 7-membered saturated or partially unsaturated cycloalkyl or heterocyclic groups. As used herein, "substituted aryl" means an aryl group substituted by the described substituent. If the substituent is not explicitly described, "substituted aryl" means an aryl group substituted by 1, 2, 3 or 4 substituents independently selected from the following: F, Cl, Br, I, cyano, hydroxyl, -O-alkyl, -SH, -S-alkyl, -COOH, -COOalkyl, -COalkyl, -COH, -CONH2, -CONHalkyl, -CON(alkyl)2, -O C(O)alkyl, -NHC(O)alkyl, -NalkylC(O)alkyl, nitro, amino, -NHalkyl, N(alkyl)2, cyano, haloalkyl, aryl, heteroaryl, alkyl, alkenyl, alkynyl, haloalkyl, cycloalkyl, alkyl-aryl, alkyl-heteroaryl, alkyl-cycloalkyl, alkyl-heterocyclic, heterocyclic, -COOaryl, -COaryl, -CONHaryl, -CON(alkyl)(aryl), -OC(O)aryl, -N HC(O) aryl, -N alkyl C(O) aryl, -COO heteroaryl, -CO heteroaryl, -CONH heteroaryl, -CON(alkyl)(heteroaryl), -OC(O) heteroaryl, -NHC(O) heteroaryl, -N alkyl C(O) heteroaryl, -COO heterocyclic, -CO heterocyclic, -CONH heterocyclic, -CON(alkyl)(heterocyclic), -OC(O) heterocyclic, -NHC(O) heterocyclic and -N alkyl C(O) heterocyclic.

[1047] The terms "heterocyclic group" and "heterocycle" include saturated and partially saturated cyclic groups containing heteroatoms, wherein the heteroatoms may be selected from nitrogen, sulfur, boron, silicon, and oxygen. Heterocyclic rings include monocyclic 3- to 10-membered rings and 5- to 16-membered bicyclic ring systems (which may include bridged fused and spirofused bicyclic ring systems). They do not include rings containing -OO-, -OS-, or -SS- motifs. Examples of saturated heterocyclic groups include saturated 3- to 6-membered heteromonocyclic groups containing 1 to 4 nitrogen atoms [e.g., pyrrolyl, imidazolyl, piperidinyl, pyrrololinyl, piperazinel]; saturated 3- to 6-membered heteromonocyclic groups containing 1 to 2 oxygen atoms and 1 to 3 nitrogen atoms [e.g., morpholinyl]; and saturated 3- to 6-membered heteromonocyclic groups containing 1 to 2 sulfur atoms and 1 to 3 nitrogen atoms [e.g., thiazolyl]. Examples of partially saturated heterocyclic groups include, but are not limited to, dihydrothiophene, dihydropyrano, dihydrofurano, and dihydrothiazolyl. Examples of partially saturated and saturated heterocyclic groups include, but are not limited to, pyrrolyl, imidazolyl, piperidinyl, pyrrololino, pyrazolyl, piperazinyl, morpholino, tetrahydropyrano, thiazolyl, dihydrothiophene, 2,3-dihydro-benzo[1,4]dioxyl, dihydroindolyl, isodihydroindolyl, dihydrobenzothiophene, dihydrobenzofurano, isochromyl, chromyl, 1,2-dihydroquinolino, and 1,2,3,4-tetrahydro-isoquinolino. The terms include 1,2,3,4-tetrahydro-quinolinyl, 2,3,4,4a,9,9a-hexahydro-1H-3-azafluorenyl, 5,6,7-trihydro-1,2,4-triazolo[3,4-a]isoquinolinyl, 3,4-dihydro-2H-benzo[1,4]oxazinyl, benzo[1,4]dioxalkyl, 2,3-dihydro-1H-1λ'-benzo[d]isothiazolyl-6-yl, dihydropyranyl, dihydrofuranyl, and dihydrothiazolyl. As used herein, "substituted heterocycle" refers to a heterocyclic group substituted by the described substituent.Unless otherwise specified, “substituted heterocycle” refers to a heterocyclic group substituted by one, two, three, or four independent substituents selected from the following: oxo, F, Cl, Br, I, cyano, hydroxyl, -O-alkyl, -SH, -S-alkyl, -COOH, -COOalkyl, -COalkyl, -COH, -CONH2, -CONHalkyl, -CON(alkyl)2, -OC(O)alkyl, -NHC(O)alkyl, -NalkylC(O)alkyl, nitro, amino, -NHalkyl, N(alkyl)2, cyano, haloalkyl, aryl, heteroaryl, alkyl, alkenyl, ynyl, haloalkyl, cycloalkyl, alkyl-aryl Alkyl-heteroaryl, alkyl-cycloalkyl, alkyl-heterocyclic, heterocyclic, -COO aryl, -CO aryl, -CONH aryl, -CON(alkyl)(aryl), -OC(O) aryl, -NHC(O) aryl, -NalkylC(O) aryl, -COO heteroaryl, -CO heteroaryl, -CONH heteroaryl, -CON(alkyl)(heteroaryl), -OC(O) heteroaryl, -NHC(O) heteroaryl, -NalkylC(O) heteroaryl, -COO heterocyclic, -CO heterocyclic, -CONH heterocyclic, -CON(alkyl)(heterocyclic), -OC(O) heterocyclic, -NHC(O) heterocyclic and -NalkylC(O) heterocyclic.

[1048] "Heterocycle" also includes groups in which a heterocyclic group is fused / condensed with an aryl or carbocyclic group, wherein the connection point is a heterocyclic ring. For example, partially unsaturated condensed heterocyclic groups containing 1 to 5 nitrogen atoms, such as indoline and isoindoline; partially unsaturated condensed heterocyclic groups containing 1 to 2 oxygen atoms and 1 to 3 nitrogen atoms; partially unsaturated condensed heterocyclic groups containing 1 to 2 sulfur atoms and 1 to 3 nitrogen atoms; and saturated condensed heterocyclic groups containing 1 to 2 oxygen or sulfur atoms.

[1049] The term "heteroaryl" refers to a stable aromatic ring system containing one or more heteroatoms selected from O, N, and S, wherein the cyclic nitrogen and sulfur atoms are optionally oxidized, and the nitrogen atom is optionally quaternized. Examples include, but are not limited to, unsaturated 5- to 6-membered heteromonocyclic groups containing 1 to 4 nitrogen atoms, such as pyrroloyl, imidazolyl, pyrazolyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazolyl [e.g., 4H-1,2,4-triazolyl, 1H-1,2,3-triazolyl, 2H-1,2,3-triazolyl]; unsaturated 5- to 6-membered heteromonocyclic groups containing oxygen atoms, such as pyranyl, 2-furanyl, 3-furanyl, etc.; and unsaturated 5- to 6-membered heteromonocyclic groups containing sulfur atoms. Examples include 2-thienyl, 3-thienyl, etc.; unsaturated 5- to 6-membered heterocyclic groups containing 1 to 2 oxygen atoms and 1 to 3 nitrogen atoms, such as oxazolyl, isoxazolyl, oxadiazolyl [e.g., 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,5-oxadiazolyl]; and unsaturated 5- to 6-membered heterocyclic groups containing 1 to 2 sulfur atoms and 1 to 3 nitrogen atoms, such as thiazolyl, thiadiazolyl [e.g., 1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl, 1,2,5-thiadiazolyl]. In some embodiments, the "heteroaryl" group is an 8, 9, or 10-membered bicyclic ring system. Examples of 8, 9, or 10-membered bicyclic heteroaryl groups include benzofuranyl, benzothiopheneyl, benzothiazolyl, benzoxazolyl, quinazolinyl, quinoxalinyl, naphthidyl, quinolinyl, isoquinolinyl, benzofuranyl, indolyl, indazoleyl, and benzotriazolyl. As used herein, "substituted heteroaryl" refers to a heteroaryl group substituted by the described substituent.Unless otherwise specified, “substituted heteroaryl” refers to a heteroaryl group substituted by one, two, three, or four independent substituents selected from the following: F, Cl, Br, I, cyano, hydroxyl, -O-alkyl, -SH, -S-alkyl, -COOH, -COOalkyl, -COalkyl, -COH, -CONH2, -CONHalkyl, -CON(alkyl)2, -OC(O)alkyl, -NHC(O)alkyl, -NalkylC(O)alkyl, nitro, amino, -NHalkyl, N(alkyl)2, cyano, haloalkyl, aryl, heteroaryl, alkyl, alkenyl, ynyl, haloalkyl, cycloalkyl, alkyl-aryl Alkyl-heteroaryl, alkyl-cycloalkyl, alkyl-heterocyclic, heterocyclic, -COO aryl, -CO aryl, -CONH aryl, -CON(alkyl)(aryl), -OC(O) aryl, -NHC(O) aryl, -NalkylC(O) aryl, -COO heteroaryl, -CO heteroaryl, -CONH heteroaryl, -CON(alkyl)(heteroaryl), -OC(O) heteroaryl, -NHC(O) heteroaryl, -NalkylC(O) heteroaryl, -COO heterocyclic, -CO heterocyclic, -CONH heterocyclic, -CON(alkyl)(heterocyclic), -OC(O) heterocyclic, -NHC(O) heterocyclic and -NalkylC(O) heterocyclic.

[1050] The term "sulfonyl", whether used alone or in combination with other terms such as alkylsulfonyl, refers to the divalent group -SO2-.

[1051] "alkyl-heterocyclic" refers to an alkyl group as defined herein that has a heterocyclic substituent. Examples include, but are not limited to, piperidinylmethyl and morpholinylethyl.

[1052] "alkyl-aryl" refers to an alkyl group as defined herein that has an aryl substituent. Non-limiting examples of alkyl-aryl groups include:

[1053] "alkyl-heteroaryl" is an alkyl group as defined herein that has a heteroaryl substituent. Non-limiting examples of alkyl-heteroaryl groups include:

[1054] As used herein, “carbocyclic,” “carbocyclic,” “carbocyclic,” or “cycloalkyl” refers to a compound containing all carbon ring atoms and 3 to 14 ring carbon atoms (“C…”). 3–14 The cycloalkyl group is a saturated or partially unsaturated (i.e., not aromatic) group containing zero heteroatoms in a non-aromatic ring system. In some embodiments, the cycloalkyl group has 3 to 10 cyclic carbon atoms (“C”). 3–10 cycloalkyl group (“Cycloalkyl”). In some embodiments, the cycloalkyl group has 3 to 9 cyclic carbon atoms (“C”).3–9 cycloalkyl group (“Cycloalkyl”). In some embodiments, the cycloalkyl group has 3 to 8 cyclic carbon atoms (“C”). 3–8 cycloalkyl group (“Cycloalkyl”). In some embodiments, the cycloalkyl group has 3 to 7 cyclic carbon atoms (“C”). 3–7 cycloalkyl group (“Cycloalkyl”). In some embodiments, the cycloalkyl group has 3 to 6 cyclic carbon atoms (“C”). 3–6 cycloalkyl group (“Cycloalkyl”). In some embodiments, the cycloalkyl group has 4 to 6 cyclic carbon atoms (“C”). 4–6 cycloalkyl group (“Cycloalkyl”). In some embodiments, the cycloalkyl group has 5 to 6 cyclic carbon atoms (“C”). 5–6 cycloalkyl group (“Cycloalkyl”). In some embodiments, the cycloalkyl group has 5 to 10 cyclic carbon atoms (“C”). 5–10 Cycloalkyl). Exemplary C 3–6 Cycloalkyl groups include, but are not limited to, cyclopropyl (C3), cyclopropenyl (C3), cyclobutyl (C4), cyclobutenyl (C4), cyclopentyl (C5), cyclopentenyl (C5), cyclohexyl (C6), cyclohexenyl (C6), and cyclohexadienyl (C6). An example is C... 3–8 Cycloalkyl groups include, but are not limited to, the aforementioned C 3–6 Cycloalkyl groups, including cycloheptyl (C7), cycloheptenyl (C7), cycloheptadienyl (C7), cycloheptanetrienyl (C7), cyclooctyl (C8), cyclooctenyl (C8), etc. An example is C... 3–10 Cycloalkyl groups include, but are not limited to, the aforementioned C 3–8 Cycloalkyl groups and cyclononyl (C9), cyclononenyl (C9), cyclodecyl (C9) 10 ), cyclodecenyl (C 10 As illustrated in the foregoing examples, in some embodiments, the cycloalkyl group may be saturated or may contain one or more carbon-carbon double or triple bonds. In an alternative embodiment, "cycloalkyl" further includes a ring system in which the cycloalkyl ring as defined above is fused with a heterocyclic, aryl, or heteroaryl ring, wherein the bonding point is on the cycloalkyl ring, and in such a case, the number of carbons still specifies the number of carbons in the carbocyclic ring system. In an alternative embodiment, each cycloalkyl example is optionally substituted with one or more substituents. In some embodiments, the cycloalkyl group is an unsubstituted C14 group. 3-14 Cycloalkyl.

[1055] "alkyl-cycloalkyl" refers to an alkyl group as defined herein that has a cycloalkyl substituent. Non-limiting examples of alkyl-cycloalkyl groups include:

[1056] As used in this article, the term "oxo" refers to the oxygen atom connected to the double bond.

[1057] As used herein, “intrinsic resistance,” also known as “primary resistance,” refers to a condition in which cancer does not respond to the inhibitory effect of initial CDK4 / 6 inhibitor treatment. Mutations and conditions associated with intrinsic resistance to CDK4 / 6 inhibitors include, but are not limited to: increased activity of cyclin-dependent kinase 1 (CDK1); increased activity of cyclin-dependent kinase 2 (CDK2); loss, absence, 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 one or more retinoblastoma family member proteins (such as, but not limited to, p107 and p130). In some embodiments, tumors or cancers with intrinsic resistance to selective CDK4 / 6 inhibitors are those whose cell population as a whole does not undergo substantial G1 cell cycle arrest upon exposure to the selective CDK4 / 6 inhibitor. In some implementations, the tumor or cancer that is intrinsically resistant to CDK4 / 6 inhibitors is a tumor or cancer having a cell population in which less than 25%, 20%, 15%, 10%, or 5% of its cells undergo G1 cell cycle arrest when exposed to a selective CDK4 / 6 inhibitor.

[1058] As used herein, “acquired resistance” refers to a condition in which cancers that were initially sensitive to or sensitive to the action of at least one selective CDK4 / 6 inhibitor become unresponsive or less responsive over time. Without wishing to be bound by any single theory, it is believed that acquired resistance to CDK4 / 6 inhibitors results from one or more additional mutations or genetic alterations in bypass signaling that occur after the initiation of a CDK4 / 6 inhibitor treatment regimen. For example, a non-limiting exemplary cause of acquired resistance to CDK4 / 6 inhibitors might be the development of one or more genetic aberrations associated with “intrinsic resistance.” Other non-limiting exemplary causes of acquired resistance to CDK4 / 6 inhibitors may include increased expression of cyclin E; CCNE1 / 2 amplification; E2F amplification; CDK2 amplification; CDK6 amplification; CDK4 amplification; p16 amplification; WEE1 overexpression; MDM2 overexpression; CDK7 overexpression; FZR1 deletion; HDAC activation; FGFR pathway activation; PI3K / AKT / mTOR pathway activation; loss of ER or PR expression; increased AP-1 transcriptional activity; epithelial-mesenchymal transition; Smad 3 inhibition; autophagy activation; Rb1 deletion or RB1 mutation inactivation; or combinations thereof. A general review of the mechanisms of CDK4 / 6 resistance 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 some embodiments, acquired resistance to selective CDK4 / 6 inhibitors is defined as tumors or cancers whose cell population as a whole no longer undergoes substantial G1 cell cycle arrest upon exposure to the selective CDK4 / 6 inhibitor, thus preventing disease progression. In some embodiments, acquired resistance to CDK4 / 6 inhibitors is defined as tumors or cancers having a cell population in which less than 50%, 40%, 30%, 20%, 15%, 10%, or 5% of the cells undergo G1 cell cycle arrest upon exposure to the selective CDK4 / 6 inhibitor, thus preventing disease progression.

[1059] Intrinsic resistance to selective CDK4 / 6 inhibitors can be determined by any standard assay known to those skilled in the art, such as by measuring the absence or absence (Rb-null) of tumor suppressor proteins in retinoblastoma (Rb). For example, Rb status in cancer can be determined by, for example, but not limited to, Western blotting, ELISA (enzyme-linked immunosorbent assay), IHC (immunohistochemistry), and FACS (fluorescence-activated cell sorting). The choice of assay will depend on the tissue, cell line, or substitute tissue sample used; for example, Western blotting and ELISA can be used for any or all types of tissue, cell line, or substitute tissue, while IHC is more suitable when the tissue used in the methods described herein is a tumor biopsy. FACs analysis is best suited for samples that are single-cell suspensions, such as cell lines and isolated peripheral blood mononuclear cells. See, for example, US20070212736, “Functional Immunohistochemical Cell Cycle Analysis as a Prognostic Indicator for Cancer”.

[1060] Alternatively, molecular genetic testing can be used to determine the gene status of retinoblastoma. Molecular genetic testing for retinoblastoma includes the following, as described in Lohmann and Gallie, “Retinoblastoma. Gene Reviews” (2010) or Parsam et al., “A comprehensive, sensitive and economical approach for the detection of mutations in the RB1 gene in retinoblastoma”, Journal of Genetics, 88(4), 517-527 (2009).

[1061] Increased CDK1 or CDK2 activity, high levels of MYC expression, increased cyclin E, and increased cyclin A can be measured by 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 will depend on the tissue, cell line, or substitute tissue sample used. For example, Western blotting and ELISA can be used for any or all types of tissue, cell line, or substitute tissue, while IHC is more suitable when the tissue used in the method is a tumor biopsy. FACs analysis is best suited for samples that are single-cell suspensions, such as cell lines and isolated peripheral blood mononuclear cells.

[1062] Many methods can be used to measure biomarkers believed to contribute to acquired resistance to CDK4 / 6 inhibitors. Current methods include immunohistochemistry (IHC), immunocytochemistry, and mass spectrometry. An alternative approach includes using immunofluorescence (IF) and image analysis to determine the relative abundance of proteins of interest in formalin-fixed, paraffin-embedded (FFPE) tissue samples. Immunohistochemistry (IHC) is the most commonly used method for determining gene expression levels, but Western blotting allows for the assessment of total expression as well as subtype-specific expression. Reverse transcription polymerase chain reaction (RT-PCR) can also be used to measure mRNA from genes of interest.

[1063] Immunohistochemistry (IHC) and immunocytochemistry (ICC) are techniques for localizing expression and rely on specific epitope-antibody interactions. IHC refers to the use of tissue sections, while ICC describes the use of cultured cells or cell suspensions. In both methods, positive staining is visualized using molecular markers, which can be fluorescent or chromogenic. In short, the sample is fixed to maintain cell integrity and then incubated with a blocking reagent to prevent non-specific antibody binding. The sample is then incubated with primary and secondary antibodies, and the signal is visualized for microscopic analysis.

[1064] Western blotting techniques use three elements to identify specific proteins in a complex mixture of proteins extracted from cells: separation by size, transfer to a solid support, and labeling the target protein with appropriate primary and secondary antibodies for visualization. The most common form of this method is immunoblotting. This technique is used to detect specific proteins in a given tissue homogenate or extract sample. The protein sample is first subjected to SDS-PAGE electrophoresis to separate proteins based on molecular weight. The proteins are then transferred to a membrane, where they are detected using antibodies specific to the target protein.

[1065] Genomic alterations and mRNA expression can be determined using fluorescence in situ hybridization (FISH), targeted sequencing, and microarray analysis. Common mutated genes, as well as differentially expressed and co-expressed genes, can be identified.

[1066] Fluorescence in situ hybridization (FISH) is a cytogenetic technique used to detect and locate RNA sequences within tissues or cells. This is particularly important for defining spatiotemporal patterns of gene expression. FISH relies on fluorescent probes that bind to complementary sequences of the RNA of interest. A series of hybridization steps are performed to amplify the signal from the target of interest. This amplification is then observed using a fluorescence microscope. This technique can be used with formalin-fixed paraffin-embedded (FFPE) tissues, frozen tissues, fresh tissues, cells, and circulating tumor cells.

[1067] Targeted RNA sequencing (RNA-Seq) is a highly precise method for selecting and sequencing specific transcripts of interest. It provides both quantitative and qualitative information. Targeted RNA-Seq can be performed via enrichment or amplicon-based methods, both of which allow for gene expression analysis within a concentrated set of genes of interest. Enrichment assays also provide the ability to detect known and novel gene fusion pairings in many sample types, including formalin-fixed paraffin-embedded (FFPE) tissue. RNA enrichment provides quantitative expression information as well as the detection of minor variations and gene fusions.

[1068] In microarray analysis, mRNA molecules are typically collected from both experimental and reference samples. For example, reference samples can be collected from healthy individuals, and experimental samples can be collected from individuals with diseases such as cancer. The two mRNA samples are then converted into complementary DNA (cDNA), and each sample is labeled with a different colored fluorescent probe. The experimental cDNA sample is labeled with a red fluorescent dye, while the reference cDNA is labeled with a green fluorescent dye. The two samples are then mixed together and allowed to hybridize with a microarray slide. After hybridization, the microarray is scanned to measure the expression of each gene printed on the slide. If the expression of a particular gene in the experimental sample is higher than in the reference sample, the corresponding point on the microarray is displayed in red. Conversely, if the expression in the experimental sample is lower than in the reference sample, the point is displayed in green. Finally, if the expression in both samples is the same, the point is displayed in yellow. The data collected through the microarray can be used to create gene expression profiles that show the simultaneous changes in the expression of many genes in response to specific conditions or treatments.

[1069] The term “selective CDK4 / 6 inhibitor” as used in the context of the compounds described herein includes compounds that inhibit CDK4 activity, CDK6 activity, or both CDK4 and CDK6 activity at an IC50 molar concentration at least about 300, 400, 500, 1000, 1500, 1800, 2000, 5000, or 10,000 times lower than the IC50 molar concentration required to inhibit the same degree of CDK2 activity in a standard phosphorylation assay.

[1070] In the context of the compounds described herein, the term "N-oxide" refers to the oxidized form of a molecule in which nitrogen is oxidized. Any nitrogen on any molecule described herein can be oxidized.

[1071] As a non-limiting embodiment, the N-oxide of compound 1 can be:

[1072]

[1073] In some embodiments, any active compound may be provided to the patient in need in N-oxide form. In some embodiments, the N-oxide of the active compound or a precursor of the active compound is used in the manufacturing process. In other embodiments, the N-oxide is an administered metabolite of one of the active compounds described herein and may have independent activity. Using techniques known to those skilled in the art, N-oxides can be formed by treating the compound of interest with an oxidizing agent (e.g., a suitable peroxyacid or peroxide) to generate an N-oxide compound. For example, an N-oxide compound can be generated by treating a heteroaryl group, such as a pyrimidine group, with an oxidizing agent such as sodium percarbonate under mild reaction conditions in the presence of a metal catalyst. Those skilled in the art will understand that carrying out this chemical reaction may require appropriate protecting groups. 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.

[1074] III. Treatment Methods

[1075] In some aspects, a method of treating proliferative disorders in a host (including humans) is provided, 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, optionally in a 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 some embodiments, the disorder is mediated by CDK2, CDK4, CDK6, or CDK9. In some embodiments, the disorder is mediated by CDK2. In some embodiments, the disorder is mediated by CDK4. In some embodiments, the disorder is mediated by CDK6. In some embodiments, the disorder is mediated by CDK9.

[1076] When administered in an effective amount to a host (including humans), compounds of formulas I, II, III, IV, V, VI, VII, VIII, IX, or X may be used as therapeutic agents to treat tumors, cancers (solid cancers, non-solid cancers, diffuse cancers, hematologic cancers, etc.), abnormal cell proliferation, immune disorders, inflammatory disorders, hematologic disorders, myeloproliferative disorders, or lymphoproliferative disorders such as B- or T-cell lymphoma, multiple myeloma, breast cancer, prostate cancer, AML, ALL, CLL, myelodysplastic syndromes (MDS), mesothelioma, renal cell carcinoma (RCC), cholangiocarcinoma, and lung cancer. Pancreatic cancer, colon cancer, skin cancer, melanoma, Waldenström macroglobulinemia, Wiskott-Aldrich syndrome, or post-transplant lymphoproliferative disorders; autoimmune diseases such as lupus, Crohn's disease, Addison's disease, celiac disease, dermatomyositis, Graves' disease, thyroiditis, multiple sclerosis, pernicious anemia, reactive arthritis, or type 1 diabetes; cardiac dysfunction, including hypercholesterolemia; infectious diseases, including viral and / or bacterial infections; inflammatory diseases, including asthma, chronic peptic ulcers, tuberculosis, rheumatoid arthritis, periodontitis, ulcerative colitis, or hepatitis.

[1077] In some embodiments, the compounds of the present invention are used to treat breast cancer. In some embodiments, the breast cancer is HR+ and HER2-.

[1078] In some embodiments, the compounds of the present invention are used to treat non-small cell lung cancer (NSCLC). In some embodiments, the NSCLC has an EGFR mutation. In some embodiments, the NSCLC has an EGFR mutation and an EGFR inhibitor has failed (e.g., second-line treatment). In some embodiments, an ALK inhibitor has failed (e.g., second-line treatment). In some embodiments, the NSCLC has a KRAS mutation.

[1079] In some embodiments, the compounds of the present invention are used to treat prostate cancer. In other embodiments, the prostate cancer is castration-resistant. In some embodiments, prior chemotherapy has failed (e.g., second-line treatment).

[1080] In some embodiments, the compounds of the present invention are used to treat lymphoma. In some 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 some embodiments, prior chemotherapy has failed (e.g., second-line treatment).

[1081] In some embodiments, the compounds of the present invention are used to treat melanoma. In some embodiments, the melanoma has a BRAF mutation.

[1082] In some embodiments, the compounds of the present invention are used to treat RAS-mutated cancers. In some embodiments, the RAS-mutated cancer is colorectal cancer (CLC). In some embodiments, the RAS-mutated cancer is pancreatic cancer. In some embodiments, the RAS-mutated cancer is cholangiocarcinoma.

[1083] In some embodiments, the compounds of the present invention are used to treat gastrointestinal stromal tumors (GIST). In some embodiments, treatment with imatinib or sunitinib has failed (e.g., second-line treatment).

[1084] Exemplary proliferative disorders include, but are not limited to, benign growths, tumors, necrotic tumors, cancers (Rb positive or Rb negative), autoimmune disorders, inflammatory disorders, graft-versus-host rejection, and fibrotic disorders.

[1085] Non-limiting examples of cancers treatable according to the present invention include, but are not limited to, acoustic neuroma, adenocarcinoma, adrenal carcinoma, anal cancer, angiosarcoma (e.g., lymphangiosarcoma, lymphangioendothelial sarcoma, angiosarcoma), appendix cancer, benign monoclonal gammopathy, biliary tract cancer (e.g., bile duct cancer), bladder cancer, breast cancer (e.g., breast adenocarcinoma, breast papillary carcinoma, breast cancer, medullary breast cancer), brain cancer (e.g., meningioma; glioma, e.g., astrocytoma, oligodendroglioma; medulloblastoma), bronchial cancer, carcinoid tumor, cervical cancer (e.g., cervical adenocarcinoma), chordoma, craniopharyngioma, colon cancer, etc. Rectal cancer (e.g., colon cancer, rectal cancer, colorectal adenocarcinoma), epithelial cancer, ependymoma, endothelial sarcoma (e.g., Kaposi's sarcoma, multiple idiopathic hemorrhagic sarcomas), endometrial cancer (e.g., uterine cancer, uterine sarcoma), esophageal cancer (e.g., esophageal adenocarcinoma, Barrett's adenocarcinoma), Ewing's sarcoma, ocular cancer (e.g., intraocular melanoma, retinoblastoma), familial eosinophilia, gallbladder cancer, gastric cancer (e.g., gastric adenocarcinoma), gastrointestinal stromal tumor (GIST), head and neck cancer (e.g., head and neck squamous cell carcinoma), oral cancer (e.g., oral squamous cell carcinoma (OSCC), pharyngeal cancer (e.g., laryngeal cancer) Cancer, pharyngeal carcinoma, nasopharyngeal carcinoma, oropharyngeal carcinoma), hematopoietic cancers (e.g., leukemia such as 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 (CLL) (e.g., B-cell CLL, T-cell CLL); lymphomas such as Hodgkin lymphoma (HL) (e.g., B-cell HL, ... T-cell lymphomas (HL) and non-Hodgkin lymphomas (NHL) (e.g., B-cell NHL such as diffuse large cell lymphoma (DLCL) (e.g., diffuse large B-cell lymphoma (DLBCL)), follicular lymphoma, chronic lymphocytic leukemia / small lymphocytic lymphoma (CLL / SLL), mantle cell lymphoma (MCL), marginal zone B-cell lymphoma (e.g., mucosa-associated lymphoid tissue (MALT) lymphoma, lymph node marginal zone B-cell lymphoma, spleen marginal zone B-cell lymphoma), primary mediastinal B-cell lymphoma, Burkitt lymphoma, lymphoplasmacytic lymphoma (i.e., " Macroglobulinemia, hairy cell leukemia (HCL), immunoblastic large cell lymphoma, precursor B-lymphoblastic lymphoma, and primary central nervous system (CNS) lymphoma; and T-cell NHL such as precursor T-lymphoblastic lymphoma / leukemia, peripheral T-cell lymphoma (PTCL) (e.g., cutaneous T-cell lymphoma (CTCL) (e.g., mycosis fungoides, Sezary syndrome), angioimmunoblastic T-cell lymphoma, extranodal natural killer T-cell lymphoma, enteropathy-type T-cell lymphoma, subcutaneous panniculitis-like T-cell lymphoma, anaplastic large cell lymphoma); a mixture of one or more of the above-mentioned leukemia / lymphomas; and multiple myeloma (MM), heavy chain disease Diseases (e.g., alpha chain disease, gamma chain disease, μ chain disease), angioblastoma, inflammatory myofibroblastoma, immune cell amyloidosis, renal cell carcinoma (e.g., nephroblastoma, also known as Wilms' tumor, renal cell carcinoma), liver cancer (e.g., hepatocellular carcinoma (HCC), malignant hepatocellular carcinoma), lung cancer (e.g., bronchial carcinoma, small cell lung cancer (SCLC), non-small cell lung cancer (NSCLC), lung adenocarcinoma), leiomyosarcoma (LMS), mastocytosis (e.g., systemic mastocytosis), myelodysplastic syndrome (MDS), mesothelioma, myeloproliferative disorders (MPD) (e.g., polycythemia vera (PV), essential thrombocythemia (ET), idiopathic myelochemical exophytosis (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., gastrointestinal pancreatic neuroendometrial tumor (GEP-NET), carcinoid tumor), osteosarcoma, ovarian cancer (e.g., cystadenocarcinoma, ovarian embryonal carcinoma, ovarian adenocarcinoma), papillary adenocarcinoma, pancreatic cancer (e.g., pancreatic adenocarcinoma, intraductal papillary mucinous tumor (IPMN), islet cell tumor), penile cancer (e.g., Paget's disease of the penis and scrotum), pineal tumor, primary neuroectodermal tumor ( PNT (prostate cancer), prostate cancer (e.g., prostate adenocarcinoma), rectal cancer, rhabdomyosarcoma, salivary gland cancer, skin cancer (e.g., squamous cell carcinoma (SCC), keratoacanthoma (KA), melanoma, basal cell carcinoma (BCC)), small bowel cancer (e.g., appendix cancer), soft tissue sarcoma (e.g., malignant fibrous histiocytoma (MFH), liposarcoma, malignant peripheral nerve sheath tumor (MPNST), chondrosarcoma, fibrosarcoma, myxosarcoma), sebaceous gland cancer, sweat gland cancer, synovial tumor, testicular cancer (e.g., seminoma, embryonal testis), thyroid cancer (e.g., papillary thyroid carcinoma, papillary thyroid carcinoma (PTC), medullary thyroid carcinoma), urethral cancer, vaginal cancer, and vulvar cancer (e.g., vulvar Paget's disease).

[1086] In another implementation, the condition is myelodysplastic syndrome (MDS).

[1087] In some implementations, the cancer is a hematopoietic carcinoma. In some implementations, the hematopoietic carcinoma is a lymphoma. In some implementations, the hematopoietic carcinoma is leukemia. In some implementations, the leukemia is acute myeloid leukemia.

[1088] In some implementations, the proliferative condition is myeloproliferative neoplasm. In some implementations, myeloproliferative neoplasm (MPN) is primary myelofibrosis (PMF).

[1089] In some implementations, cancer is defined as a solid tumor. As used herein, a solid tumor is an abnormal mass of tissue that does not typically contain cysts or fluid-filled areas. Different types of solid tumors are named after the type of cells that form them. Examples of solid tumor categories include, but are not limited to, sarcomas, carcinomas, and lymphomas, as described above herein. Other 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.

[1090] In some implementations, patients treated with Formula I, Formula II, Formula III, Formula IV, Formula V, Formula VI, Formula VII, Formula VIII, Formula IX, or Formula X are patients with conditions related to abnormal cell proliferation.

[1091] Abnormal cell proliferation, especially excessive proliferation, can be the result of a wide range of factors, including gene mutations, infection, exposure to toxins, autoimmune diseases, and induction by benign or malignant tumors.

[1092] Many skin conditions are associated with excessive cell proliferation. For example, psoriasis is a benign skin disease characterized by plaques typically covered with thickened scales. This disease is caused by an unexplained increase in the proliferation of epidermal cells. Chronic eczema is also associated with significant excessive proliferation of the epidermis. Other conditions caused by excessive proliferation of skin cells include atopic dermatitis, lichen planus, warts, pemphigus vulgaris, actinic keratosis, basal cell carcinoma, and squamous cell carcinoma.

[1093] Other proliferative cell disorders include angiogenesis disorders, fibrosis disorders, autoimmune disorders, graft-versus-host rejection, tumors, and cancer.

[1094] Angiogenic disorders include both angiogenesis and vascularization disorders. The proliferation of smooth muscle cells during plaque development 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.

[1095] Fibrotic disorders are often caused by abnormal formation of the extracellular matrix. Examples of fibrotic disorders include cirrhosis and mesangial proliferative cell disease. Cirrhosis is characterized by an increase in extracellular matrix components leading to liver scarring. Cirrhosis can cause diseases such as liver cirrhosis. The increase in extracellular matrix leading to liver scarring can also be caused by viral infections such as hepatitis. Adipocytes appear to play a major role in cirrhosis.

[1096] Mesangial disorders are caused by the abnormal proliferation of mesangial cells. Mesangial hyperproliferative cell disorders include various human kidney diseases such as glomerulonephritis, diabetic nephropathy, malignant nephrocisic nephropathy, thrombotic microangiopathy syndrome, transplant rejection, and glomerulonephropathy.

[1097] Another disease with a proliferative component is rheumatoid arthritis. Rheumatoid arthritis is generally considered an autoimmune disease, believed to be associated with the activity of autoreactive T cells and caused by autoantibodies produced against collagen and IgE.

[1098] Other conditions that may include abnormal cell proliferation components include Bechet syndrome, acute respiratory distress syndrome (ARDS), ischemic heart disease, postdialysis syndrome, leukemia, acquired immunodeficiency syndrome, vasculitis, lipohistiocytosis, septic shock, and general inflammation.

[1099] In some embodiments, the compounds of the present invention and their pharmaceutically acceptable derivatives, or pharmaceutically acceptable formulations containing these compounds, may also be used for the prevention and treatment of HBV infection and other related conditions such as anti-HBV antibody-positive and HBV-positive patients, chronic liver inflammation caused by HBV, cirrhosis, acute hepatitis, fulminant hepatitis, chronic persistent hepatitis, and fatigue. These compounds or formulations may also be used prophylactically to prevent or delay the clinical progression of disease in individuals who are positive for anti-HBV antibodies or HBV-antigens, or individuals who have been exposed to HBV.

[1100] In some implementations, the patient is associated with an immune response.

[1101] Skin contact hypersensitivity and asthma are just two examples of immune responses that may be associated with a significant incidence rate. Others 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 cause any one or more of the following symptoms or signs: itching, swelling, redness, blisters, crusting, ulceration, pain, scaling, cracking, hair loss, scarring, or fluid exudation involving the skin, eyes, or mucous membranes.

[1102] In atopic dermatitis and eczema general, immune-mediated leukocyte infiltration (particularly monocytes, lymphocytes, neutrophils, and eosinophils) into the skin is a significant factor in the pathogenesis of these diseases. Chronic eczema is also associated with significant epidermal hyperplasia. Immune-mediated leukocyte infiltration also occurs in sites outside the skin, such as in the airways of asthmatic patients and in the lacrimal glands of the eyes of patients with keratoconjunctivitis sicca.

[1103] In one non-limiting embodiment, the compounds of the present invention are used as topical medications for treating contact dermatitis, atopic dermatitis, eczematous dermatitis, psoriasis, 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, asthma, allergic asthma, cutaneous lupus erythematosus, scleroderma, vaginitis, proctitis, and drug eruptions. This novel approach can also be used to reduce the infiltration of malignant leukocytes into the skin in diseases such as mycosis fungoides. By applying the compounds topically to the eyes, these compounds can also be used to treat dehydrated dry eye syndrome (such as immune-mediated keratoconjunctivitis) in patients with dehydrated dry eye syndrome.

[1104] Throughout this document, the terms “tumor formation” or “cancer” refer to the pathological process leading to the formation and growth of a cancerous or malignant tumor. Specifically, through cell proliferation, abnormal tissue (solid) or cells (non-solid) often grows faster than normal tissue or cells and continues to grow after the stimulus that initiated new growth ceases. Malignant tumors are characterized by a partial or complete lack of structural tissue and functional coordination with normal tissue, and most invade surrounding tissues, can metastasize to multiple sites, are likely to recur after attempted removal, and can lead to patient death unless adequately treated. As used herein, the term tumor formation is used to describe all cancerous disease states and includes or encompasses the pathological processes associated with malignant hematogenous, ascites, and solid tumors. Exemplary cancers that can be treated alone or in combination with at least one other anticancer agent by the compounds of this disclosure include squamous cell carcinoma, basal cell carcinoma, adenocarcinoma, hepatocellular carcinoma and renal cell carcinoma, bladder cancer, head cancer, kidney cancer, neck cancer, leukemia; benign and malignant lymphomas, particularly Burkitt lymphoma and non-Hodgkin lymphoma; benign and malignant melanomas; myeloproliferative disorders; sarcomas, including Ewing's sarcoma, angiosarcoma, Kaposi's sarcoma, liposarcoma, myxosarcoma, peripheral neuroepithelial tumor, synovial sarcoma, and glioma. Plasma, astrocytoma, oligodendroglioma, ependymoma, glioblastoma, neuroblastoma, ganglioneuroma, ganglioglioma, medulloblastoma, pineal cell carcinoma, meningioma, meningeal sarcoma, neurofibroma and schwannoma; colorectal cancer, breast cancer, prostate cancer, cervical cancer, uterine cancer, lung cancer, ovarian cancer, testicular cancer, thyroid cancer, astrocytoma, esophageal cancer, pancreatic cancer, gastric cancer, liver cancer, colon cancer, melanoma; carcinosarcoma, Hodgkin's lymphoma, nephroblastoma and teratoma.

[1105] Other cancers that can be treated with the compounds disclosed in this invention include, for example, acute myeloid leukemia, acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), adenocarcinoma, adenosarcoma, adrenal carcinoma, adrenocortical carcinoma, anal cancer, anaplastic astrocytoma, angiosarcoma, appendiceal cancer, astrocytoma, basal cell carcinoma, B-cell lymphoma, bile duct cancer, bladder cancer, bone cancer, bone marrow cancer, colorectal cancer, brain cancer, brainstem glioma, breast cancer, triple (estrogen, progesterone, and HER-2) negative breast cancer, double-negative breast cancer (two of estrogen, progesterone, and HER-2 are negative), single-negative (one of estrogen, progesterone, and HER-2 is negative), estrogen receptor-positive HER2-negative breast cancer, estrogen receptor-negative breast cancer, estrogen receptor-positive breast cancer, metastatic breast cancer, luminal type A breast cancer, luminal Type 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 tumors, cervical cancer, hepatobiliary carcinoma, chondrosarcoma, chronic lymphocytic leukemia (CLL), chronic myeloid leukemia (CML), colon cancer, colorectal cancer, craniopharyngioma, cutaneous lymphoma, cutaneous melanoma, diffuse astrocytoma, ductal carcinoma in situ (DCIS), uterus Endometrial cancer, ependymoma, epithelioid sarcoma, esophageal cancer, Ewing sarcoma, extrahepatic bile duct cancer, ocular cancer, fallopian tube cancer, fibrosarcoma, gallbladder cancer, gastric cancer, gastrointestinal cancer, gastrointestinal carcinoid tumor, gastrointestinal stromal tumor (GIST), germ cell tumors, glioblastoma multiforme (GBM), glioma, hairy cell leukemia, head and neck cancer, hemangioendothelioma, Hodgkin's lymphoma, hypopharyngeal cancer, invasive ductal carcinoma (IDC), invasive lobular carcinoma (ILC), inflammatory breast cancer (I... BC), colorectal cancer, intrahepatic cholangiocarcinoma, invasive / invasive breast cancer, islet cell tumor, jaw cancer, Kaposi's sarcoma, kidney cancer, laryngeal cancer, leiomyosarcoma, meningeal metastasis, leukemia, lip cancer, liposarcoma, liver cancer, lobular carcinoma in situ, low-grade astrocytoma, lung cancer, lymph node cancer, lymphoma, male breast cancer, medullary carcinoma, medulloblastoma, melanoma, meningioma, Merkel cell carcinoma, mesenchymal chondrosarcoma, mesenchymal tumor, mesothelioma, metastatic breast cancer Cancer, metastatic melanoma, metastatic squamous neck cancer, mixed glioma, monoblastic teratoma, oral cancer, mucinous carcinoma, mucinous melanoma, multiple myeloma, mycosis fungoides, myelodysplastic syndrome, nasal cavity cancer, nasopharyngeal carcinoma, neck cancer, neuroblastoma, neuroendocrine tumors (NETs), non-Hodgkin's lymphoma, non-small cell lung cancer (NSCLC), oat cell carcinoma, eye cancer, ocular melanoma, oligodendroglioma, oral cancer (oral cavity)Cancer, oropharyngeal cancer, bone-derived sarcoma, osteosarcoma, ovarian cancer, ovarian epithelial cancer, ovarian germ cell tumor, primary ovarian peritoneal cancer, ovarian sex cord-stromal tumor, Paget's disease, pancreatic cancer, papillary carcinoma, sinus cancer, parathyroid cancer, pelvic cancer, penile cancer, peripheral nerve cancer, peritoneal cancer, pharyngeal cancer, pheochromocytoma, pilocytic astrocytoma, pineal region tumor, pineal cell carcinoma, pituitary adenoma, primary central nervous system (CNS) lymphoma, prostate cancer, rectal cancer, renal cell carcinoma, renal pelvis cancer, rhabdomyosarcoma, salivary gland cancer, soft tissue sarcoma, osteosarcoma, sarcoma, sinus cancer, skin cancer, small cell lung cancer (SCLC), small bowel cancer, spinal cancer (spinal cancer / spinal column) Cancer), spinal cord cancer, squamous cell carcinoma, gastric cancer, synovial sarcoma, T-cell lymphoma, testicular cancer, pharyngeal cancer, thymoma / thymic carcinoma, thyroid cancer, tongue cancer, tonsil cancer, transitional cell carcinoma, fallopian tube cancer, tubular carcinoma, undiagnosed cancer, ureteral cancer, uterine adenocarcinoma, uterine cancer, uterine sarcoma, vaginal cancer, vulvar cancer, T-cell lineage acute lymphoblastic leukemia (T-ALL), T-cell lineage lymphoblastic lymphoma (T-LL), peripheral T-cell lymphoma, adult T-cell leukemia, Pre-B...ALL, Pre-B lymphoma, Large B-cell lymphoma, Burkitt's lymphoma, B-cell ALL, Philadelphia chromosome-positive ALL, Philadelphia chromosome-positive CML, Juvenile myeloid monocytic 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, 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; Splenic lymphoma / leukemia, Unclassifiable, Diffuse red pulp small B-cell lymphoma of the spleen Lymphoplasmacytic lymphoma; heavy chain diseases (e.g., alpha heavy chain disease, gamma heavy chain disease, μ heavy chain disease), plasmacytic myeloma, solitary osteoplasmacytoma; extraosseous plasmacytoma; primary cutaneous follicular center lymphoma, T-cell / histiocytic abundant large B-cell lymphoma, DLBCL associated with chronic inflammation; EBV-positive elderly DLBCL; primary mediastinal (thymic) large B-cell lymphoma, primary cutaneous DLBCL, leg type, ALK+ large B-cell lymphoma, plasmablastic lymphoma; large B-cell lymphoma in HHV8-associated multicentric Castleman disease; B-cell lymphoma, unclassifiable, with features between diffuse large B-cell lymphoma; or B-cell lymphoma, unclassifiable, with features between diffuse large B-cell lymphoma and classical Hodgkin lymphoma.

[1106] In another aspect, 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 some embodiments, the method is an in vitro method. In some 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, BIM is inhibited in many cancers, including chronic myeloid leukemia (CML) and non-small cell lung cancer (NSCLC), and inhibition of BCL2L11 expression can confer resistance to tyrosine kinase inhibitors. See, for example, Ng et al., Nat. Med. (2012) 18:521–528.

[1107] In another aspect, a method is provided for treating patients with angiogenesis-related conditions such as diabetic patients (e.g., diabetic retinopathy), inflammatory patients (e.g., rheumatoid arthritis), macular degeneration, obesity, atherosclerosis, or proliferative disorders, comprising administering to a subject in need a compound of the invention or a pharmaceutically acceptable composition, salt, or isotope analog thereof.

[1108] In some embodiments, the patient associated with angiogenesis has macular degeneration. In some embodiments, a method of treating macular degeneration is provided, comprising administering to a subject in need a compound of the present invention or a pharmaceutically acceptable composition, salt, or isotope analog thereof.

[1109] In some embodiments, the patient associated with angiogenesis is obese. As used herein, “obesity” and “obesity” as used herein refer to Group I obesity, Group II obesity, Group III obesity, and pre-obesity (e.g., “overweight”) as defined by the World Health Organization. In some embodiments, a method of treating obesity is provided, comprising administering to a subject in need of the compound of the present invention or a pharmaceutically acceptable composition, salt, or isotope analog thereof.

[1110] In some embodiments, the patient associated with angiogenesis is atherosclerosis. In some embodiments, a method of treating atherosclerosis is provided, comprising administering to a subject in need of the compound of the present invention or a pharmaceutically acceptable composition, salt, or isotope analog thereof.

[1111] In some embodiments, the condition associated with angiogenesis is a proliferative disorder. In some embodiments, a method of treating a proliferative disorder is provided, comprising administering to a subject in need a compound of the present invention or a pharmaceutically acceptable composition, salt, or isotope analog thereof.

[1112] IV. Methods to reduce chemotherapy-related side effects

[1113] In some embodiments, the compounds of the present invention reduce the effects of chemotherapeutic agent toxicity on CDK4 / 6 replication-dependent healthy cells, such as hematopoietic stem cells and hematopoietic progenitor cells (collectively, HSPCs) and / or renal epithelial cells, in subjects (typically, humans) that will be, are, or have been exposed to chemotherapeutic agents (typically DNA-damaging agents).

[1114] In some embodiments, the subject has been exposed to a chemotherapeutic agent, and using the compound described herein, the subject's CDK4 / 6-replication-dependent healthy cells are placed in G1 blockade after exposure to mitigate, for example, DNA damage. In some embodiments, the compound is administered at least 1 / 2 hour, at least 1 hour, at least 2 hours, at least 3 hours, at least 4 hours, at least 5 hours, at least 6 hours, at least 7 hours, at least 8 hours, at least 10 hours, at least 12 hours, at least 14 hours, at least 16 hours, at least 18 hours, at least 20 hours, or longer after exposure to the chemotherapeutic agent.

[1115] In some embodiments, the compound may allow for dose intensification in medically relevant chemotherapy (e.g., more treatment can be administered over a fixed period of time), which translates into better efficacy. Therefore, the currently disclosed methods can produce chemotherapy regimens that are less toxic and more effective.

[1116] In some embodiments, the use of the compounds described herein may result in reduced or substantially no off-target effects, for example, in connection with the inhibition of kinases other than CDK4 and / or CDK6 and / or CDK2. Furthermore, in some embodiments, the use of the compounds described herein should not induce cell cycle arrest in CDK4 / 6 replication-independent cells.

[1117] 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 estrogenic effects. Antioxidant effects can be determined by standard assays known in the art. For example, a compound without significant antioxidant effects is one that does not significantly scavenge free radicals such as oxygen free radicals. The antioxidant effect of a compound can be compared to that of a compound with known antioxidant activity, such as genistein. Therefore, a compound without significant antioxidant activity can be one with antioxidant activity less than about 2, 3, 5, 10, 30, or 100 times that of genistein. Estrogenic activity can also be determined by known assays. For example, a non-estrogenous compound is one that does not significantly bind to and activate estrogen receptors. A compound with substantially no estrogenic effect can be one with estrogenic activity less than about 2, 3, 5, 10, 20, or 100 times that of a compound with estrogenic activity, such as genistein.

[1118] V. Methods for treating abnormal proliferation of T cells, B cells, and / or NK cells

[1119] In some aspects, the present invention includes optionally using an effective amount of the compounds described herein, or pharmaceutically acceptable salts thereof, or isotope analogs thereof, in a pharmaceutical composition to treat a host (typically, a human) suffering from selected cancers, tumors, hyperproliferative disorders, or inflammatory or immune conditions. Some of the disclosed compounds are highly active against T-cell proliferation. Given the lack of drugs targeting T-cell cancers and abnormal proliferation, the determination of such use represents a substantial improvement in the medical treatment of these diseases.

[1120] Abnormal proliferation of T cells, B cells, and / or NK cells can lead to a wide range of diseases, such as cancer, proliferative disorders, and inflammatory / immune diseases. Hosts (e.g., humans) suffering from any of these conditions can be treated with effective amounts of compounds as described herein to achieve symptom relief (palliative agents) or reduction of underlying disease (disease modulators).

[1121] Examples include T-cell or NK-cell lymphomas, such as, but not limited to: peripheral T-cell lymphoma; anaplastic large cell lymphoma, such as anaplastic lymphoma kinase (ALK) positive, ALK negative anaplastic large cell lymphoma, or primary cutaneous anaplastic large cell lymphoma; autoimmune blastic lymphoma; cutaneous T-cell lymphoma, such as mycosis fungoides, Sézary syndrome, primary cutaneous anaplastic large cell lymphoma, primary cutaneous CD30+ T-cell lymphoproliferative disorder; primary cutaneous aggressive epidermophilic CD8+ cytotoxic T-cell lymphoma; primary cutaneous γ-δ T-cell lymphoma; primary cutaneous small / medium CD4+ T-cell lymphoma and lymphomatoid papulosis; adult T-cell leukemia / lymphoma. ATLL; blastoblastic NK-cell lymphoma; enteropathic T-cell lymphoma; hepatosplenic γ-δ T-cell lymphoma; lymphoblastic lymphoma; nasal NK / T-cell lymphoma; treatment-associated T-cell lymphoma, such as lymphoma following solid organ or bone marrow transplantation; T-cell prolymphocytic leukemia; T-cell large granular lymphocytic leukemia; NK-cell chronic lymphoproliferative disorder; aggressive NK-cell leukemia; systemic EBV+ T-cell lymphoproliferative disorder in childhood (associated with chronic active EBV infection); vaccinia-like vesicular lymphoma; adult T-cell leukemia / lymphoma; enteropathic T-cell lymphoma; hepatosplenic T-cell lymphoma; or subcutaneous panniculitis-like T-cell lymphoma.

[1122] In some embodiments, the compounds disclosed herein, or their salts or isotope analogs thereof, can be used in effective amounts to treat a host (e.g., a human) suffering from lymphoma or a lymphocytic or myeloid cell proliferation disorder or abnormality. For example, compounds as described herein can be administered to a host suffering from Hodgkin lymphoma or non-Hodgkin lymphoma. For example, the host may have non-Hodgkin's lymphoma, such as, but not limited to: AIDS-related lymphoma; anaplastic large cell lymphoma; autoimmune blastic lymphoma; blastic NK cell lymphoma; Burkitt lymphoma; Burkitt-like lymphoma (small non-cleaved cell lymphoma); chronic lymphocytic leukemia / small lymphocytic leukemia; cutaneous T-cell lymphoma; diffuse large B-cell lymphoma; enteropathy-type T-cell lymphoma; follicular lymphoma; hepatosplenic 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; transformed lymphoma; treatment-associated T-cell lymphoma; or Waldenström macroglobulinemia.

[1123] Alternatively, the compounds disclosed herein, or their salts or isotope analogs thereof, may be used in effective amounts to treat a host (e.g., a human) with Hodgkin lymphoma, such as, but not limited to: tuberous sclerosis classical Hodgkin lymphoma (CHL); mixed cellularity CHL; lymphocyte-depleted CHL; lymphocyte-rich CHL; lymphocyte-dominant Hodgkin lymphoma; or nodular lymphocyte-dominant HL.

[1124] Alternatively, the compounds disclosed herein, or their salts or isotope analogs thereof, may be used in effective amounts to treat hosts (e.g., humans) with specific B-cell lymphomas or proliferative disorders, such as, but not limited to: multiple myeloma; diffuse large B-cell lymphoma; follicular lymphoma; mucosa-associated lymphoid tissue lymphoma (MALT); small cell lymphocytic lymphoma; mediastinal large B-cell lymphoma; lymph node marginal zone B-cell lymphoma (NMZL); spleen 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 of the spleen; hairy cell leukemia-variant; lymphoplasmacytic lymphoma; heavy chain disease; For example, alpha heavy chain disease, gamma heavy chain disease, μ heavy chain disease; plasma cell myeloma; solitary osteoplasmacytoma; extraosseous plasmacytoma; primary cutaneous follicular center lymphoma; T-cell / histiocytic abundant large B-cell lymphoma; DLBCL associated with chronic inflammation; EBV-positive elderly DLBCL; primary mediastinal (thymic) large B-cell lymphoma; primary cutaneous DLBCL, leg type; ALK+ large B-cell lymphoma, plasmablastic lymphoma; large B-cell lymphoma in HHV8-associated multicentric Castleman disease; B-cell lymphoma, unclassifiable, with features between diffuse large B-cell lymphoma; or B-cell lymphoma, unclassifiable, with features between diffuse large B-cell lymphoma and classical Hodgkin lymphoma.

[1125] In some embodiments, the compounds disclosed herein, or their salts or isotope analogs thereof, can be used in effective amounts to treat a host (e.g., a human) suffering from leukemia. For example, the host may be suffering from acute or chronic leukemia of lymphocytic or bone marrow origin, such as, but not limited to: acute lymphoblastic leukemia (ALL); acute myeloid leukemia (AML); chronic lymphocytic leukemia (CLL); chronic myeloid leukemia (CML); juvenile myelomonocytic leukemia (JMML); hairy cell leukemia (HCL); acute promyelocytic leukemia (a subtype of AML); large granular lymphocytic leukemia; or adult T-cell chronic leukemia. In some implementations, the patient has acute myeloid leukemia, such as undifferentiated AML (M0); myeloblastic leukemia (M1; with / without minimum cell maturation); myeloblastic leukemia (M2; with cell maturation); promyelocytic leukemia (M3 or M3 variant [M3V]); myelomonocytic leukemia (M4 or M4 variant [M4E] with eosinophilia); monocytic leukemia (M5); erythroleukemia (M6); or megakaryoblastic leukemia (M7).

[1126] VI. Pharmaceutical Compositions and Dosage Forms

[1127] The active compounds described herein, or their salts or isotopic analogs, may be administered to the host in an effective amount using any suitable method to achieve the desired therapeutic outcome to treat any of the conditions described herein. Of course, the dosage and timing of administration of the active compound will depend on the host being treated, the instructions of the attending medical professional, the duration of exposure, the method of administration, the pharmacokinetic properties of the specific active compound, and the judgment of the prescribing physician. Therefore, due to variability among hosts, the dosages given below are guidelines, and physicians may adjust the dosage of the compound to achieve the treatment deemed appropriate for the host by the physician. In considering the required level of treatment, physicians may balance various factors such as the host's age and weight, pre-existing conditions, and the presence of other illnesses.

[1128] Pharmaceutical compositions can be formulated into any pharmaceutically useful form, such as aerosols, creams, gels, pills, injectable or infusion solutions, capsules, tablets, syrups, transdermal patches, subcutaneous patches, dry powders, inhaled formulations, medical devices, suppositories, buccal or sublingual formulations, parenteral formulations, or ophthalmic solutions. Some dosage forms, such as tablets and capsules, are subdivided into appropriately sized unit doses containing a suitable amount of the active ingredient, such as an effective amount to achieve the desired purpose.

[1129] The therapeutically effective dose of any active compound described herein will be determined by a healthcare professional based on the patient's condition, body type, age, and route of delivery. In one non-limiting embodiment, a dose of about 0.1 to about 200 mg / kg is therapeutically effective, all weights being calculated based on the weight of the active compound, including in the case of saline. In some embodiments, the dose is about or greater than 0.1, 0.5, 1, 5, 10, 25, 50, 75, 100, 125, 150, 175, or 200 mg / kg. In some embodiments, the dose may be the amount of compound required to provide a serum concentration of the active compound up to about 10 nM, 50 nM, 100 nM, 200 nM, 300 nM, 400 nM, 500 nM, 600 nM, 700 nM, 800 nM, 900 nM, 1 μM, 5 μM, 10 μM, 20 μM, 30 μM, or 40 μM.

[1130] In some embodiments, the pharmaceutical composition is a dosage form containing, in a unit dosage form, 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 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 have at least 5, 10, 15, 20, 25, 50, 100, 200, 250, 300, 400, 500, 600, 700, or 750 mg of the active compound or a salt thereof. The pharmaceutical composition may also contain a molar ratio of the active compound and the additional active agent to achieve the desired result.

[1131] In some embodiments, the compounds disclosed herein or used as described are administered once daily (QD), twice daily (BID), or three times daily (TID). In some embodiments, the compounds disclosed herein or used as described are administered at least once daily for at least 21 days, at least 24 days, at least 28 days, at least 35 days, at least 45 days, at least 60 days, at least 75 days, at least 90 days, at least 120 days, at least 180 days, or longer.

[1132] The compounds disclosed herein or used as described herein may be administered orally, topically, parenterally, by inhalation or spray, sublingually, via implants (including ocular implants), percutaneously, via buccal administration, rectally, as ocular solutions, by injection (including ocular injection), intravenously, intramuscularly, by inhalation, intra-aortic, intracranial, subdermal, intraperitoneal, subcutaneous, nasal, sublingual, or rectal administration, or by other means in dosage units containing conventionally pharmaceutically acceptable carriers. For ocular delivery, the compounds may be administered as needed, for example via intravitreal, intrastromal, anterior chamber, subfascial, subretinal, retrobulbar, peribulbar, suprachorodial, conjunctival, subconjunctival, suprascleral, periocular, transscleral, retrobulbar, posterior juxtascleral, pericardial, or lacrimal duct injection, or via mucus, mucin, or mucosal barriers, in an immediate or controlled release manner or via ocular devices.

[1133] According to the currently disclosed methods, oral administration can be in any desired form, such as solid, gel, or liquid, including solutions, suspensions, or emulsions. In some embodiments, the compound or salt is administered as a liposome suspension via inhalation, intravenous, or intramuscular administration. When administered by inhalation, the active compound or salt can be in the form of multiple solid particles or droplets having any desired particle size, for example, from about 0.01, 0.1, or 0.5 to about 5, 10, 20 micrometers or larger, and optionally from about 1 to about 2 micrometers. The compounds disclosed in this invention have demonstrated favorable pharmacokinetic and pharmacodynamic properties, for example, when administered via oral or intravenous routes.

[1134] Pharmaceutical formulations may contain the active compound described herein or a pharmaceutically acceptable salt thereof in any pharmaceutically acceptable carrier. If a solution is required, water may sometimes be the preferred carrier for water-soluble compounds or salts. For water-soluble compounds or salts, organic mediators such as glycerol, propylene glycol, polyethylene glycol, or mixtures thereof may be suitable. In the latter case, the organic mediator may contain a significant amount of water. The solution in either case may then be sterilized in a manner known to those skilled in the art, for example, by filtration through a 0.22-micron filter. After sterilization, the solution may be dispensed into appropriate containers, such as pyrogen-free glass vials. Dispensing may optionally be performed aseptically. A sterile cap may then be placed on the vial, and the contents of the vial may be lyophilized if necessary.

[1135] The carrier comprises excipients and diluents and must possess sufficiently high purity and low toxicity to be suitable for administration to the treated patient. The carrier may be inert or possess its own pharmaceutical benefits. The amount of carrier used in conjunction with the compound is sufficient to provide a practical amount of application material per unit dose of the compound.

[1136] Carriers include, but are not limited to, binders, buffers, colorants, diluents, disintegrants, emulsifiers, flavoring agents, gliding agents, lubricants, preservatives, stabilizers, surfactants, tableting agents, and wetting agents. Some carriers may be listed in more than one category; for example, vegetable oils may be used as lubricants in some formulations and as diluents in others. Exemplary pharmaceutically acceptable carriers include sugars, starches, cellulose, powdered tragacanth gum, malt, gelatin; talc, and vegetable oils. Pharmaceutical compositions may contain optional active agents that do not substantially interfere with the activity of the compounds of the present invention.

[1137] In addition, auxiliary substances, such as wetting agents or emulsifiers, biological buffers, and surfactants, can be present in such media. Biological buffers can be any pharmacologically acceptable solution, and they provide the required pH for the formulation, i.e., a pH within a physiologically acceptable range. Examples of buffer solutions include saline, phosphate-buffered saline, Tris-buffered saline, Hank's buffered saline, etc.

[1138] Depending on the intended mode of administration, the pharmaceutical composition may be in the form of a solid, semi-solid, or liquid dosage form, such as tablets, suppositories, pills, capsules, powders, liquids, suspensions, creams, ointments, lotions, etc., preferably a single-dose unit dosage form suitable for precise dosing. The composition will contain an effective amount of the selected drug combined with a pharmaceutically acceptable carrier, and may also contain other pharmaceutical agents, adjuvants, diluents, buffers, etc.

[1139] Therefore, the compositions disclosed herein can be administered as pharmaceutical preparations, including those suitable for oral (including buccal and sublingual), rectal, nasal, topical, pulmonary, vaginal, or parenteral (including intramuscular, intra-arterial, intrathecal, subcutaneous, and intravenous) administration, or in forms suitable for inhalation or insufflation. Preferred administration methods are intravenous or oral, using convenient daily dosing regimens that can be adjusted according to the degree of discomfort.

[1140] For solid compositions, conventional non-toxic solid carriers include, for example, pharmaceutical-grade mannitol, lactose, starch, magnesium stearate, sodium saccharin, talc, cellulose, glucose, sucrose, magnesium carbonate, etc. Compositions suitable for liquid pharmaceutical administration can be prepared, for example, by dissolving, dispersing, etc., the active compound as described herein and optional adjuvants in an excipient such as water, saline, dextran aqueous solution, glycerol, ethanol, etc., to form a solution or suspension. If desired, the pharmaceutical composition to be administered may also contain small amounts of non-toxic excipients, such as wetting agents or emulsifiers, pH buffers, etc., for example, sodium acetate, sorbitol monolaurate, triethanolamine acetate sodium, triethanolamine oleate, etc. Practical methods for preparing such dosage forms are known or will be obvious to those skilled in the art; see, for example, Remington's Pharmaceutical Sciences cited above.

[1141] In another embodiment, for the use of a penetration enhancer excipient, the penetration enhancer excipient includes polymers such as: polycationic (chitosan and its quaternary ammonium derivatives, poly-L-arginine, amination gelatin); polyanionic (N-carboxymethyl chitosan, polyacrylic acid); and thiolized polymers (carboxymethyl cellulose-cysteine, polycarbofil-cysteine, chitosan-thiobutylamidine, chitosan-thioglycolic acid, chitosan-glutathione conjugate).

[1142] For oral administration, the compositions are typically in the form of tablets, capsules, soft gel capsules, or may be aqueous or non-aqueous solutions, suspensions, or syrups. Tablets and capsules are preferred forms for 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 often also added. Typically, the compositions of this disclosure can be combined with oral, non-toxic, pharmaceutically acceptable inert carriers such as lactose, starch, sucrose, glucose, methylcellulose, magnesium stearate, dicalcium phosphate, calcium sulfate, mannitol, sorbitol, etc. In addition, suitable binders, lubricants, disintegrants, and colorants may be introduced into the mixture when desired or necessary. Suitable binders include starch, gelatin, natural sugars such as glucose or β-lactose, corn sweeteners, natural and synthetic gums such as gum arabic, tragacanth, or sodium alginate, carboxymethyl cellulose, polyethylene glycol, waxes, etc. The lubricants used in these formulations 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.

[1143] When using liquid suspensions, the active agent may be combined with any orally administered, non-toxic, pharmaceutically acceptable inert carrier such as ethanol, glycerol, water, etc., as well as with emulsifiers and suspending agents. Flavoring agents, coloring agents, and / or sweeteners may also be added if desired. Other optional components introduced into the oral formulations herein include, but are not limited to, preservatives, suspending agents, thickeners, etc.

[1144] Parenteral formulations can be prepared in conventional forms, or in the form of liquid solutions or suspensions, solid forms suitable for dissolution or suspension in a liquid prior to injection, or emulsions. Preferably, sterile injectable suspensions are formulated using suitable carriers, dispersants or wetting agents, and suspending agents according to techniques known in the art. Sterile injectable formulations can also be sterile injectable solutions or suspensions in non-toxic parenteral diluents or solvents. Acceptable media and solvents that can be used include water, Ringer's solution, and isotonic sodium chloride solution. In addition, sterile non-volatile oils, fatty esters, or polyols are commonly used as solvents or suspension media. Furthermore, parenteral administration may involve the use of slow-release or sustained-release systems to maintain a constant dose level.

[1145] Parenteral administration includes intra-articular, intravenous, intramuscular, intradermal, intraperitoneal, and subcutaneous routes, and includes aqueous and non-aqueous isotonic sterile injectable 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 via certain parenteral routes may involve introducing the formulations of this disclosure into the patient through a needle or catheter propelled by a sterile syringe or some other mechanical device such as a continuous infusion system. The formulations provided in this disclosure can be administered using a syringe, injector, pump, or any other device recognized in the art for parenteral administration.

[1146] In addition to the active compound or its salts, pharmaceutical formulations may contain other additives, such as pH-adjusting additives. Specifically, available pH adjusters include acids such as hydrochloric acid, bases, or buffers such as sodium lactate, sodium acetate, sodium phosphate, sodium citrate, sodium borate, or sodium gluconate. Furthermore, formulations may contain antimicrobial preservatives. Available antimicrobial preservatives include methylparaben, propylparaben, and benzyl alcohol. Antimicrobial preservatives are typically used when formulations are packaged in vials designed for multiple-dose administration. The pharmaceutical formulations described herein may be lyophilized using techniques well known in the art.

[1147] For oral administration, pharmaceutical compositions can be in the form of solutions, suspensions, tablets, pills, capsules, powders, etc. Tablets containing various excipients such as sodium citrate, calcium carbonate, and calcium phosphate can be used with various disintegrants such as starch (e.g., potato or cassava starch) and certain complex silicates, as well as binders such as polyvinylpyrrolidone, sucrose, gelatin, and gum arabic. Additionally, lubricants such as magnesium stearate, sodium lauryl sulfate, and talc are often very useful for tableting purposes. Similar types of solid compositions can be used as fillers in soft and hard-filled gelatin capsules. Materials in this regard also include lactose or milk sugar and high molecular weight polyethylene glycol. When aqueous suspensions and / or elixirs are required for oral administration, the compounds of the disclosed subject matter can be used in combination with various sweeteners, flavoring agents, coloring agents, emulsifiers and / or suspending agents, as well as diluents such as water, ethanol, propylene glycol, glycerin, and various similar combinations thereof.

[1148] In another embodiment of the subject matter described herein, an injectable, stable, sterile formulation in a sealed container, in unit dosage form, is provided, comprising an active compound or a salt thereof as described herein. The compound or salt is provided in lyophilized form, which can be reconstituted with a suitable pharmaceutically acceptable carrier to form a liquid formulation suitable for injection into a host. When the compound or salt is substantially insoluble in water, a physiologically acceptable sufficient amount of emulsifier can be used to emulsify the compound or salt in an aqueous carrier. Particularly useful emulsifiers include phosphatidylcholine and lecithin.

[1149] Other embodiments include liposome formulations of the active compounds disclosed herein. Techniques for forming liposome suspensions are well known in the art. When the compound is a water-soluble salt, it can be incorporated into lipid vesicles using conventional liposome techniques. In this case, due to the water solubility of the active compound, it can be substantially encased within the hydrophilic center or core of the liposome. The lipid layer used can be of any conventional composition and may or may not contain cholesterol. When the active compound of interest is water-insoluble, conventional liposome formation techniques are also used, and the salt can be substantially encased within a hydrophobic lipid bilayer forming the liposome structure. In either case, the resulting liposomes can be reduced in size, such as by using standard sonication and homogenization techniques. Liposome formulations containing the active compounds disclosed herein can be lyophilized to produce lyophilized products, which can be reconstituted using pharmaceutically acceptable carriers such as water to regenerate the liposome suspension.

[1150] Pharmaceutical formulations suitable for aerosol administration via inhalation are also provided. These formulations comprise a solution or suspension of a desired compound or salt thereof described herein, or multiple solid particles of said compound or salt. The desired formulation can be placed in a chamber and nebulized. Nebulization can be accomplished by compressed air or by ultrasonic energy to form multiple liquid droplets or solid particles containing said compound or salt. The liquid droplets or solid particles may, for example, have a particle size in the range of about 0.5 to about 10 micrometers, optionally about 0.5 to about 5 micrometers. In some embodiments, the solid particles provide controlled release by using a biodegradable polymer. The solid particles can be obtained by processing a solid compound or salt thereof in any suitable manner known in the art, such as by micronization. Optionally, the size of the solid particles or droplets may be about 1 to about 2 micrometers. In this regard, commercial nebulizers can be used to achieve this purpose. The compound can be administered via an aerosol suspension of breathable particles in the manner set forth in U.S. Patent No. 5,628,984, the disclosure of which is incorporated herein by reference in its entirety.

[1151] Pharmaceutical formulations that provide controlled release of the compounds described herein are also provided, including by using biodegradable polymers as known in the art.

[1152] When a pharmaceutical formulation suitable for aerosol application is in liquid form, the formulation may contain a water-soluble active compound in a water-containing carrier. A surfactant may be present, which sufficiently reduces the surface tension of the formulation to form droplets within the desired size range upon atomization.

[1153] As used herein, the term "pharmaceutically acceptable salt" means those salts that are suitable for use in contact with a host (e.g., a human host) without excessive toxicity, irritation, allergic reactions, etc., within the bounds of reasonable medical judgment, and that are effective for their intended use, in proportion to a reasonable benefit / risk ratio, and, where possible, in the zwitterionic form of the subject matter currently disclosed.

[1154] Therefore, the term "salt" refers to the relatively non-toxic inorganic and organic acid addition salts of currently disclosed compounds. These salts can be prepared during the final separation and purification of the compound, or by reacting the purified compound, in its free base form, with a suitable organic or inorganic acid and separating the salt thus formed. Basic compounds are capable of forming a wide variety of salts with various inorganic and organic acids. Acid addition salts of basic compounds are prepared by contacting the free base form with a sufficient amount of the desired acid in a conventional manner to produce the salt. The free base form can be regenerated by contacting the salt form with a base in a conventional manner and separating the free base. The free base form may differ from its corresponding salt form in certain physical properties, such as solubility in polar solvents. Pharmaceutically acceptable base addition salts can be formed from metals or amines such as alkali metal and alkaline earth metal hydroxides or organic amines. Examples of metals used as cations include, but are not limited to, sodium, potassium, magnesium, calcium, etc. Examples of suitable amines include, but are not limited to, N,N'-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, ethylenediamine, N-methylglucosamine, and procaine. Base addition salts of acidic compounds are prepared by contacting the free acid form with a sufficient amount of the desired base in a conventional manner to produce the salt. The free acid form can be regenerated by contacting the salt form with an acid in a conventional manner and then separating the free acid. The free acid form and its corresponding salt form may differ in some physical properties, such as solubility in polar solvents.

[1155] Salts can be prepared from inorganic acids such as sulfates, pyrosulfates, bisulfates, sulfites, nitrates, phosphates, monohydrogen phosphates, dihydrogen phosphates, metaphosphates, pyrophosphates, chlorides, bromides, and iodides, including hydrochloric acid, nitric acid, phosphoric acid, sulfuric acid, hydrobromic acid, hydroiodic acid, and phosphoric acid. Representative salts include hydrobromide, hydrochloride, sulfate, bisulfate, nitrate, acetate, oxalate, valerate, oleate, palmitate, stearate, laurate, borate, benzoate, lactate, phosphate, toluenesulfonate, citrate, maleate, fumarate, succinate, tartrate, naphthylmethanesulfonate, gluconate, lactobionate, laurylsulfonate, and hydroxyethylsulfonate. Salts can also be prepared from organic acids, such as aliphatic monocarboxylic acids and dicarboxylic acids, phenyl-substituted alkanes, hydroxyalkanes, alkanedioic acids, aromatic acids, and aliphatic and aromatic sulfonic acids. Representative salts include acetates, propionates, caprylates, isobutyrates, oxalates, malonates, succinates, caprylates, sebacic acid salts, fumarates, maleates, mandelates, benzoates, chlorobenzoates, methylbenzoates, dinitrobenzoates, phthalates, benzenesulfonates, toluenesulfonates, phenylacetates, citrates, lactates, maleates, tartrates, and methanesulfonates. Pharmaceutically acceptable salts may include cations based on alkali metals and alkaline earth metals such as sodium, lithium, potassium, calcium, and magnesium, as well as non-toxic ammonium, quaternary ammonium, and amine cations, including but not limited to ammonium, tetramethylammonium, tetraethylammonium, methylamine, dimethylamine, trimethylamine, triethylamine, and ethylamine. Salts of amino acids are also included, such as arginine salts, gluconates, and galacturonic acids. See, for example, Berge et al., J. Pharm. Sci., 1977, 66, 1-19, which are incorporated herein by reference.

[1156] Preferably, sterile injectable suspensions are formulated using suitable carriers, dispersants or wetting agents and suspending agents according to techniques known in the art. Sterile injectable formulations can also be sterile injectable solutions or suspensions in non-toxic, parenteral diluents or solvents. Acceptable media and solvents include water, Ringer's solution, and isotonic sodium chloride solution. Additionally, sterile, non-volatile oils, fatty esters, or polyols are typically used as solvents or suspension media. Furthermore, parenteral administration may involve the use of slow-release or sustained-release systems to maintain a constant dose level.

[1157] The parenteral formulations according to this disclosure include sterile aqueous or non-aqueous solutions, suspensions, or emulsions. Examples of non-aqueous solvents or media 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 also contain adjuvants such as preservatives, wetting agents, emulsifiers, and dispersants. They can be sterilized, for example, by filtration through a bacteria retaining filter, by introducing a sterilizing agent into the composition, by irradiating the composition, or by heating the composition. They can also be manufactured using sterile water or some other sterile injectable media just before use.

[1158] Sterile injectable solutions are prepared by introducing a desired amount of one or more of the disclosed compounds, along with various other ingredients listed above, into a suitable solvent and then filtering and sterilizing. Typically, dispersions are prepared by introducing various sterilized active ingredients into a sterile medium containing a base dispersion medium and desired other ingredients from those listed above. In the case of sterile powders used to prepare sterile injectable solutions, preferred methods of preparation are vacuum drying and freeze-drying techniques, which produce powders of the active ingredient plus any other desired ingredients from their previously sterile filtered solutions. Thus, for example, a parenteral composition suitable for injection is prepared by stirring 10% by volume of propylene glycol and water with 1.5% by weight of the active ingredient. The solution is isotonicized with sodium chloride and sterilized.

[1159] Formulations suitable for rectal administration are typically available as unit-dose suppositories. These suppositories are prepared by mixing the disclosed active compound with one or more conventional solid carriers, such as cocoa butter, and then molding the resulting mixture.

[1160] Formulations suitable for topical application to the skin are preferably in the form of ointments, creams, lotions, pastes, gels, sprays, aerosols, or oils. Carriers that can be used include petrolatum, lanolin, polyethylene glycol, alcohols, transdermal penetration enhancers, and combinations of two or more of these.

[1161] Formulations suitable for transdermal application may be in the form of discrete patches adapted to maintain close contact with the recipient's epidermis for extended periods. Formulations suitable for transdermal application may also be delivered via iontophoresis (see, for example, Pharmaceutical Research 3(6):318(1986)) and are typically in the form of an optional buffered aqueous solution of the active compound. In some embodiments, microneedle patches or devices are provided to deliver drugs through or into biological tissues, particularly the skin. Microneedle patches or devices allow for the delivery of drugs across or into the skin or other tissue barriers at clinically relevant rates with minimal or no damage, pain, or irritation to the tissue.

[1162] Suitable formulations for lung delivery can be delivered via a wide range of passively driven and actively powered single / multi-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 screen nebulizers. The selection of a suitable lung delivery device depends on parameters such as the nature and formulation of the drug, the site of action, and the pathophysiology of the lungs.

[1163] Other non-limiting examples of drug delivery devices and methods include, for example, US20090203709 (Abbott Laboratories) entitled "Pharmaceutical Dosage Form For Oral Administration Of Tyrosine Kinase Inhibitor"; US20050009910 entitled "Delivery of an active drug to the posterior part of the eye via subconjunctival or periocular delivery of aprodrug"; US20130071349 entitled "Biodegradable polymers for lowering intraocular pressure"; US8,481,069 entitled "Tyrosine kinase microspheres"; US8,465,778 entitled "Method of making tyrosine kinase microspheres"; and US8,465,778 entitled "Sustained release intraocular implants containing tyrosine kinase inhibitors and related methods". US 8,409,607, US 8,512,738 and US2014 / 0031408 titled "Biodegradable intravitreal tyrosine kinase implants", US2014 / 0294986 titled "Microsphere Drug Delivery System for Sustained Intraocular Release", US 8,911,768 (Allergan, Inc.) titled "Methods For Treating Retinopathy With Extended Therapeutic Effect", and US 6,495,164 (Alkermes Controlled Therapeutics, Inc.) titled "Preparation of injectable supplements having improved injectability".); WO 2014 / 047439 (Akina, Inc.) entitled "Biodegradable Microcapsules Containing Filling Material"; WO 2010 / 132664 (Baxter International Inc., Baxter Healthcare SA) entitled "Compositions And Methods For Drug Delivery"; US20120052041 (The Brigham and Women's Hospital, Inc.) entitled "Polymeric nanoparticles with enhanced drug loading and methods of use thereof"; US20140178475, US20140248358, and US20140249158 (BIND Therapeutics, Inc.) entitled "Therapeutic Nanoparticles Comprising a Therapeutic Agent and Methods of Making and Using Same"; US20140178475, US20140248358, and US20140249158 (BIND Therapeutics, Inc.) entitled "Polymer microparticles for drug delivery"; US 5,869,103 (Danbiosyst UK Ltd.); US 8628801 (Universidad de Navarra) titled "Pegylated Nanoparticles"; US2014 / 0107025 (Jade Therapeutics, LLC) titled "Ocular drug delivery system"; titled "Agent delivery system comprised of microparticles and biodegradable gel with an improved releasing profile and methods of use US 6,287,588 entitled "Bioactive agent delivering system comprised of microparticles within abiodegradable to improve release profiles" (Macromed, Inc.); US 6,007,845 and US 5,578,325 (Massachusetts Institute of Technology) entitled “Nanoparticles and microparticles of non-linear hydrophilic hydrophobic multiblock copolymers”; US 20040234611, US 20080305172, US 20120269894 and US 20130122064 (Novartis Ag) entitled “Ophthalmic depot formulations for periocular or subconjunctival administration”; US 6,413,539 (Poly-Med, Inc.) entitled “Block polymer”; US 20070071756 (Peyman) entitled “Delivery of an agent to ameliorate inflammation”; and “Injectable Depot Formulations And Methods For Providing Sustained Release Of Poorly US 20080166411 (Pfizer, Inc.) titled "Soluble Drugs Comprising Nanoparticles"; US 6,706,289 (PR Pharmaceuticals, Inc.) titled "Methods and compositions for enhanced delivery of bioactive molecules"; and US 8,663,674 (Surmodics) titled "Microparticle containing matrices for drug delivery".

[1164] VII. Combination therapy

[1165] The compounds of formula I, II, III, IV, V, VI, VII, VIII, IX or X disclosed herein may be used in effective amounts alone or in combination with another compound of the present invention or another bioactive agent (therapeutic agent) to treat a host, such as a human, suffering from a condition as described herein.

[1166] The disclosed compounds described herein can be used in effective amounts, alone or in combination with another compound of the present invention or another bioactive agent, to treat a host, such as a human, suffering from a condition as described herein.

[1167] The terms "bioactive agent" or "therapeutic agent" are used to describe agents, not selected according to the invention, that can be used in combination with or alternately with compounds of the invention to achieve a desired therapeutic outcome. In some embodiments, the compounds and bioactive agents of the invention are administered in such a manner that they have in vivo activity over overlapping time periods, for example, C with overlapping time periods. max T max AUC or other pharmacokinetic parameters. In another embodiment, the compounds and bioactive agents of the present invention are administered to a host in need of treatment, which do not have overlapping pharmacokinetic parameters, however, one has a therapeutic effect on the therapeutic efficacy of the other.

[1168] In some aspects of this implementation scheme, the bioactive agent is a chemotherapeutic agent.

[1169] In another aspect of this implementation scheme, the bioactive agent is a growth factor.

[1170] In some aspects of this embodiment, the bioactive agent is an immunomodulatory agent, including but not limited to checkpoint inhibitors, such as, as non-limiting examples, PD-1 inhibitors, PD-L1 inhibitors, PD-L2 inhibitors, CTLA-4 inhibitors, LAG-3 inhibitors, TIM-3 inhibitors, T-cell activation V-domain Ig inhibitor (VISTA) inhibitors, small molecules, peptides, nucleotides, or other inhibitors. In some aspects, the immunomodulatory agent is an antibody, such as a monoclonal antibody.

[1171] Immune checkpoint inhibitors

[1172] Immune checkpoint inhibitors used 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 inhibitors of T-cell-activating V-domain Ig inhibitors (VISTA), or combinations thereof. In some embodiments, immune checkpoint inhibitors are administered in an effective amount in combination with the compounds described herein to treat cancers, including but not limited to Hodgkin's lymphoma, melanoma, non-small cell lung cancer (including NSCLC with EGFR or ALK genomic tumor aberrations), head and neck squamous cell carcinoma, small cell lung cancer, hepatocellular carcinoma, renal cell carcinoma, urothelial carcinoma, colorectal cancer, colorectal cancer, hepatocellular carcinoma, renal cell carcinoma, small cell lung cancer, bladder cancer, B-cell lymphoma, gastric cancer, cervical cancer, liver cancer, advanced Merkel cell carcinoma, esophageal squamous cell carcinoma, or ovarian cancer.

[1173] In some embodiments, the immune checkpoint inhibitor is a PD-1 inhibitor that blocks the interaction between PD-1 and PD-L1 by binding to the PD-1 receptor, thereby inhibiting immunosuppression. In some embodiments, the immune checkpoint inhibitor is a PD-1 immune checkpoint inhibitor selected from the following: nivolumab Pembrolizumab Pidilizumab (AMP-224 (AstraZeneca and MedImmune), PF-06801591 (Pfizer), MEDI0680 (AstraZeneca), PDR001 (Novartis), cemiplimad / REGN2810 ( Regeneron), MGA012 (MacroGenics), BGB-A317 (BeiGene), SHR-12-1 (Jiangsu Hengrui Medicine Company and Incyte Corporation), TSR-042 (Tesaro), and PD-L1 / VISTA inhibitor CA-170 (Curis Inc.).

[1174] In some implementations, the immune checkpoint inhibitor is the PD-1 immune checkpoint inhibitor nivolumab. It is administered in an effective amount, together with the compounds described herein, to treat Hodgkin lymphoma, melanoma, non-small cell lung cancer (including NSCLC with EGFR or ALK genomic tumor aberrations), head and neck squamous cell carcinoma, small cell lung cancer, hepatocellular carcinoma, renal cell carcinoma, squamous cell carcinoma, urothelial carcinoma, colorectal cancer, hepatocellular carcinoma, or ovarian cancer. Nivolumab has been approved by the FDA for Hodgkin lymphoma, melanoma, non-small cell lung cancer (including NSCLC with EGFR or ALK genomic tumor aberrations), head and neck squamous cell carcinoma, small cell lung cancer, hepatocellular carcinoma, renal cell carcinoma, squamous cell carcinoma, urothelial carcinoma, colorectal cancer, progressive classical Hodgkin lymphoma (cHL), colorectal cancer, urothelial carcinoma, head and neck squamous cell carcinoma, or ovarian cancer. In another aspect of this implementation, the immune checkpoint inhibitor is the PD-1 immune checkpoint inhibitor pembrolizumab. It is administered in effective doses to treat melanoma, non-small cell lung cancer, small cell lung cancer, head and neck cancer, bladder cancer, urothelial carcinoma, renal cell carcinoma, classical Hodgkin lymphoma, gastric cancer, cervical cancer, liver cancer, primary mediastinal B-cell lymphoma, advanced Merkel cell carcinoma, esophageal squamous cell carcinoma, or urothelial carcinoma. In another aspect of this embodiment, the immune checkpoint inhibitor is the PD-1 immune checkpoint inhibitor pildizumab (Medivation), administered in effective doses for refractory diffuse large B-cell lymphoma (DLBCL) or metastatic melanoma. In another aspect of this embodiment, the immune checkpoint inhibitor is the PD-1 immune checkpoint inhibitor cimipril (Libtayo / Regeneron), administered in effective doses for cutaneous squamous cell carcinoma.

[1175] In some embodiments, the immune checkpoint inhibitor is a PD-L1 inhibitor that blocks the interaction between PD-1 and PD-L1 by binding to the PD-L1 receptor, thereby inhibiting immunosuppression. PD-L1 inhibitors include, but are not limited to, atezolizumab, durvalumab, KN035CA-170 (Curis Inc.), and LY3300054 (Eli Lilly). In some embodiments, the PD-L1 inhibitor is atezolizumab. In some embodiments, the PD-L1 inhibitor blocks the interaction between PD-L1 and CD80 to inhibit immunosuppression.

[1176] In some implementations, the immune checkpoint inhibitor is the PD-L1 immune checkpoint inhibitor atezolizumab. It is administered in an effective dose to treat metastatic bladder cancer, small cell lung cancer, metastatic melanoma, metastatic non-small cell lung cancer, or metastatic renal cell carcinoma. In another aspect of this protocol, the immune checkpoint inhibitor is durvalumab (…). AstraZeneca and MedImmune, administered in effective doses, are used to treat small cell lung cancer, non-small cell lung cancer, or bladder cancer. In some embodiments, the immune checkpoint inhibitor is the PD-L1 immune checkpoint inhibitor avelumab (…). EMD Serono / Pfizer, administered in an effective dose, is used to treat Merkel cell carcinoma or urothelial carcinoma. In another aspect of this implementation, the immune checkpoint inhibitor KN035 (Alphamab), administered in an effective dose, is used to treat PD-L1-positive solid tumors.

[1177] In some aspects of this implementation scheme, the immune checkpoint inhibitor is a CTLA-4 immune checkpoint inhibitor that binds to CTLA-4 and inhibits immunosuppression. CTLA-4 inhibitors include, but are not limited to, ipilimumab, trimemumab (AstraZeneca and MedImmune), AGEN1884, and AGEN2041 (Agenus).

[1178] In some implementations, the CTLA-4 immune checkpoint inhibitor is ipilimumab. It is used in effective doses to treat metastatic melanoma, helper melanoma, or non-small cell lung cancer.

[1179] In another embodiment, the immune checkpoint inhibitor is a LAG-3 immune checkpoint inhibitor. Examples of LAG-3 immune checkpoint inhibitors include, but are not limited to, BMS-986016 (Bristol-Myers Squibb), GSK2831781 (GlaxoSmithKline), IMP321 (Prima BioMed), LAG525 (Novartis), and the dual PD-1 and LAG-3 inhibitor MGD013 (MacroGenics). In another aspect of this embodiment, the immune checkpoint inhibitor is a TIM-3 immune checkpoint inhibitor. Specific TIM-3 inhibitors include, but are not limited to, TSR-022 (Tesaro).

[1180] Other immune checkpoint inhibitors used in the inventions described herein include, but are not limited to, B7-H3 / CD276 immune checkpoint inhibitors such as MGA217, indoleamine 2,3-dioxygenase (IDO) immune checkpoint inhibitors such as Indoximod and INCB024360, cytotoxic immunoglobulin-like receptor (KIR) immune checkpoint inhibitors such as Lirilumab (BMS-986015), and carcinoembryonic antigen cell adhesion molecule (CEACAM) inhibitors (e.g., CEACAM-1, -3, and / or -5). Exemplary anti-CEACAM-1 antibodies are described in WO 2010 / 125571, WO 2013 / 082366 and WO 2014 / 022332, for example, monoclonal antibodies 34B1, 26H7 and 5F4; or recombinant forms thereof, as described, for example, in US2004 / 0047858, US Patent No. 7,132,255 and WO 99 / 052552. In other embodiments, the anti-CEACAM antibody binds to CEACAM-5, as described, for example, in Zheng et al., PLoS One. 2010 September 2; 5(9). pii:e12529 (DOI:10:1371 / journal.pone.0021146), or cross-reacts with CEACAM-1 and CEACAM-5, as described, for example, in WO 2013 / 054331 and US2014 / 0271618. Other checkpoint inhibitors may be molecules targeting B and T lymphocyte attenuating factor molecules (BTLA), such as monoclonal antibodies against B and T lymphocyte attenuating factor (BTLA) as described in Zhang et al., which have no effect on B cell proliferation in vitro and inhibit T cell proliferation in vitro when presented in cis rather than trans form relative to activating stimuli. Clin Exp Immunol. 2011 Jan; 163(1):77–87.

[1181] Chemotherapy

[1182] As covered herein, the CDK inhibitors described herein can be used in combination with any standard chemotherapy regimen. In some embodiments, the CDK inhibitors described herein can be used in combination with any standard chemotherapy regimen and also with immune checkpoint inhibitors.

[1183] In some embodiments, the chemotherapeutic agent is toxic to immune effector cells. In some embodiments, the chemotherapeutic agent inhibits cell growth. In some embodiments, the administered cytotoxic chemotherapeutic agent is a DNA-damaging chemotherapeutic agent. In some embodiments, the chemotherapeutic agent is a protein synthesis inhibitor, a DNA-damaging chemotherapeutic agent, an alkylating agent, a topoisomerase inhibitor, an RNA synthesis inhibitor, a DNA complex binding agent, a thiolate alkylating agent, a guanine alkylating agent, a microtubule binding agent, a DNA polymerase inhibitor, an anticancer enzyme, a RAC1 inhibitor, a thymidylate synthase inhibitor, an oxazophosphorine compound, an integrin inhibitor such as silengiptide, camptothecin or holocorostachysine, or an antifolate or folic acid antimetabolite.

[1184] In some implementations, additional therapeutic agents are selected from erlotinumab, rituximab, lenalidomide, cytarabine, daratumumab, adalimumab, idealisib, giratetinib, glasdegib, valacyclovir, acalatinib, ibrutinib, midotutolin, ruxotinib, bortezomib, lapatinib, bendamustine, enzalutamide, azacitidine, oxotinumab, decitabine, erdatinib, and venetoclax.

[1185] In some embodiments, the additional therapeutic agent is trastuzumab. In some embodiments, the additional therapeutic agent is lapatinib. In some embodiments, the compound of the present invention is administered together with two, three, or four additional therapeutic agents. In some embodiments, there are two additional therapeutic agents. In some embodiments, the two additional therapeutic agents are lapatinib and trastuzumab.

[1186] In some implementations, the additional treatment agent is osimertinib mesylate.

[1187] In some implementations, the additional treatment agent is alectinib.

[1188] In some implementations, the additional therapeutic agent is a MEK inhibitor.

[1189] In some implementations, the additional therapeutic agent is an androgen receptor ligand.

[1190] In some implementations, the additional therapeutic agent is a BTK inhibitor, such as, but not limited to, ibrutinib. Or acalatinib

[1191] In some implementations, additional therapeutic agents are MEK inhibitors and RAF inhibitors.

[1192] In some implementations, the additional therapeutic agent is a RAF inhibitor.

[1193] In some implementations, the additional treatment agent is regorafenib.

[1194] Cytotoxic chemotherapy agents

[1195] Cytotoxic, DNA-damaging chemotherapeutic agents are often nonspecific, particularly toxic to normal, rapidly dividing cells such as HSPCs and immune effector cells at high doses. As used herein, the term “DNA-damaging” chemotherapy or chemotherapeutic agent refers to treatment with a cell inhibitor or cytotoxic agent (i.e., a compound) to reduce or eliminate the growth or proliferation of unwanted cells, such as cancer cells, where the cytotoxic effect of said agent 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, cell-killing DNA-damaging compounds. “DNA-damaging” chemotherapeutic agents include, but are not limited to, alkylating agents, DNA intercalating agents, protein synthesis inhibitors, DNA or RNA synthesis inhibitors, DNA base analogs, topoisomerase inhibitors, telomerase inhibitors, and telomere DNA-binding compounds. For example, alkylating agents include alkyl sulfonates such as busulfan, indomethacin, and piperosulfan; azacyclopropanes such as benzodizepa, carboquinone, meturedepa, and uredepa; ethyleneimines and methylmelamines such as hexamethylmelamine, triethylenemelamine, triethylenephosphoramide, triethylenethiophosphoramide, and tris(hydroxymethylmelamine); nitrogen mustards such as chlorambucil, naphthalenemus, cyclophosphamide, estradiol, nitrogen mustard, oxynitrogen mustard hydrochloride, melphalan, novobichine, phenesterine, prednimustine, trofosfamide, and uracil mustard; and nitrosoureas such as carmustine, chloramphenicol, formustine, lomustine, nimustine, and ramustine. Other DNA-damaging chemotherapeutic agents include ruminoplasmin, doxorubicin, idarubicin, epirubicin, mitomycin, and strepzotocin. Chemoantimes include gemcitabine, mercaptopurine, thioguanine, cladribine, fludarabine phosphate, fluorouracil (5-FU), fluorouridine, cytarabine, pentostatin, methotrexate, azathioprine, acyclovir, adenine β-1-D-arabinoside, methotrexate, aminopterin, 2-aminopurine, afenidemycin, 8-azaguanine, diazoserine, 6-azauracil, 2′-azido-2′-deoxynucleoside, 5-bromodeoxycytidine, cytosine β-1-D-arabinoside, diazooxynorleucine, dideoxynucleoside, 5-fluorodeoxycytidine, 5-fluorodeoxyuridine, and hydroxyurea.

[1196] Chemotherapy protein synthesis inhibitors include absinthecin, styracin tricarboxylic acid, chloramphenicol, colibacin E3, actinomycin, diphtheria toxin, ileocetin A, ipecacin, erythromycin, ethionine, fluoride, 5-fluorotryptophan, fusobionic acid, guanylate methylene diphosphate and guanylate imine diphosphate, kanamycin, kasugamycin, flavomycin, and O-methylthreonine. Other protein synthesis inhibitors include salicylic acid, neomycin, valine, salicylic acid, paromomycin, puromycin, ricin, shigatoxin, pyroxine, salicylic acid, spectinomycin, streptomycin, tetracycline, thiomycin, and trimethoprim.

[1197] DNA synthesis inhibitors include alkylating agents such as dimethyl sulfate, nitrogen mustard, and sulfur mustard; intercalating agents such as acridine dyes, actinomycin, anthracene, benzo[a]pyrene, ethidium bromide, and propidium diiodide-intertwining; and other agents such as acromycin and fusiformin. Topoisomerase inhibitors, such as irinotecan, teniposide, coumarin, nalidixic acid, neomycin, and oxoridic acid; cell division inhibitors, including colchicine, mitoxantrone, colchicine, vincristine, and vinblastine; and RNA synthesis inhibitors, including actinomycin D, α-amanitin and other fungal amatoxins, cordycepin (3′-deoxyadenosine), dichlorofuranosylbenzimidazole, rifampin, streptomycin, and lidistreptin, can also be used as DNA-damaging compounds.

[1198] In some implementations, the chemotherapeutic agents are DNA complex binding agents such as camptothecin or etoposide; thiolate alkylating agents such as nitrosoureas, BCNU, CCNU, ACNU, or formustin; guanine alkylating agents such as temozolomide; microtubule binding agents such as vincristine, vinorelbine, vinflunine, cryptophyte 52; and halichondrin, such as halichondrin B. B); Dolatasstatins, such as dolasstatin 10 and dolasstatin 15; hemiasterlins, such as hemiasterlin A and hemiasterlin B, colchicine, cobustatin, 2-methoxyestradiol, E7010, paclitaxel, docetaxel, epothilone, spongiol; 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; oxonium, nitrogen, phosphorus, and benzene compounds such as Cytoxan; integrin inhibitors such as silengiptide; antifolate such as pralatrexate; folic acid antimetabolites such as pemetrexed; or camptothecin or high camptothecin such as diflutamide.

[1199] In some embodiments, the topoisomerase inhibitor is a type I inhibitor. In another embodiment, the topoisomerase inhibitor is a type II inhibitor.

[1200] 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, procainoxane, paclitaxel, antiplatinum, thiotepa, oxaliplatin, and similar agents. In some embodiments, the DNA-damaging chemotherapeutic agent is selected from cisplatin, carboplatin, camptothecin, and etoposide.

[1201] Other suitable chemotherapeutic agents include, but are not limited to, radioactive molecules, toxins (also known as cytotoxic agents or cytotoxic agents), which include any agent harmful to cell viability, and liposomes or other vesicles containing chemotherapeutic compounds. Common anticancer drugs include vincristine. Liposome vincristine Cytarabine (cytosine arabinoside, ara-C or...) L-asparaginase Or PEG-L-asparaginase (pegaspargase or Etoposide (VP-16), Teniposide 6-Mercaptopurine (6-MP or Prednisone and dexamethasone (decatelon). Other suitable chemotherapeutic agents include, but are not limited to, 5-fluorouracil, dacarbazine, alkylating agents, atrazomycin (AMC), antimitotic agents, cis-dichlorodiamineplatin(II) (DDP), diaminodichloroplatin, anthracyclines, antibiotics, antimetabolites, asparaginase, and BCG. Live (intrabladder), Bleomycin sulfate, Kazimidycin, Cytochalasin B, Dermatomycin (formerly Actinomycin), Daunorubicin HCl, Daunorubicin Citrate, Dinnisin-toxin conjugate, Dihydroxyanthradin, Docetaxel, Doxorubicin HCl, Escherichia coli L-asparaginase, Erwinia L-asparaginase, Etoposide Citrate Factor, Etoposide Phosphate, Gemcitabine HCl, Idarubicin HCl, Interferon α-2b, Irinotecan HCl, Maytansinoid, Nitrogen Mustard Hydrochloride, Melphalan HCl, Glechomycosis, Mitomycin C, Mitotan, Polyphenylpropanol 20 with Carmustine Implant, Procarbazine HCl, Streptozotocin, Teniposide, Thiotepa, Topotecan HCl, Pentorubicin, Vincristine Sulfate, Vincristine Sulfate, and Vinorelbine Tartrate.

[1202] Other cytotoxic chemotherapeutic agents used in this invention include: epirubicin, abraxane, taxotere, epothilone, tafluposide, vemodigine, azacitidine, deoxyfluorouridine, vinorelbine, and vinorelbine.

[1203] In some embodiments, the chemotherapeutic agent is not an aromatase inhibitor. In some embodiments, the chemotherapeutic agent is not a steroid. In some embodiments, the chemotherapeutic agent is not a BCR-ABL inhibitor.

[1204] In some embodiments, the chemotherapeutic agent is a DNA complex binder. In some embodiments, the chemotherapeutic agent is a microtubule binder. In some embodiments, the chemotherapeutic agent is an alkylating agent. In some embodiments, the chemotherapeutic agent is a thiolate alkylating agent.

[1205] Other chemotherapy agents

[1206] Other chemotherapeutic agents that may be used as described herein may include 2-methoxyestradiol or 2ME2, finasunate, edazolizumab (MEDI-522), HLL1, huN901-DM1, atemod, saquinavir mesylate, ritonavir, nelfinavir mesylate, indinavir sulfate, plitidepsin, P276-00, tepifenabine, lenalidomide, thalidomide, pomalidomide, simvastatin, and celecoxib. Chemotherapeutic agents that may be used in this invention include, but are not limited to, trastuzumab. Pertuzumab (Perjeta) TM Lapatinib Gefitinib Erlotinib cetuximab Panitumumab Van der Thani Vimofini Vorinostat Romidesin Besarodine Alivitamin Acid Retinoic acid Kyprolis TM ), Prattria bevacizumab Abersipu Sorafenib Sunitinib Pazopanib Regorafenib and Cabozantinib (Cometriq) TM ).

[1207] Other chemotherapy agents covered include, but are not limited to, calcineurin inhibitors such as cyclosporine or ascomycin, such as cyclosporine A. FK506 (tacrolimus), pimecrolimus; mTOR inhibitors, such as rapamycin or its derivatives, such as sirolimus. Everolimus Tesirolimus, zotacolimus, emelemus-7, emelemus-9; rapamycin analogues, such as lidafolimus, campath 1H; S1P receptor modulators; dual mTORC1 and mTORC2 inhibitors, such as vistusertib (AZD2014), such as fingolimod or analogues thereof; anti-IL-8 antibodies, mycophenolic acid or its salts, such as sodium salts, or their prodrugs, such as morphifenzitrate. OKT3(Orthoclone Prednisone Buquina sodium, OKT4, T10B9.A-3A, 33B3.1, 15-deoxyguanidine, tropelimus, leflunomide Anti-CD25, anti-IL2R, baliximab Dalizumab Imidazolidin, dexamethasone, ISAtx-247, SDZASM 981 (pimecrix) Abasiput, Belasip, LFA3lg, Enarip (by ImmuneXcite) (For Sale) Adalimumab Infliximab Anti-LFA-1 antibody, nastatin Enmumab, Garvicumab, Golimumab, Anti-thymocyte Immunoglobulin, Cializumab, Alfacinol, Efalizumab, Podesan, Mesalazine, Alexantin, Codeine Phosphate, Benorilate, Fenbufen, Naproxen, Diclofenac, Etodoxime, Indomethacin, Dasatinib Nilotinib Bosutinib Imatinib Mesylate and punatinib (Iclusig) TM Amifostine, dolasetron mesylate, dronabinol, epollin-α, etidronate, filgrastim, fluconazole, goserelin acetate, bacitracin D, granisetron, leucovorin calcium, lidocaine, mesna, ondansetron HCl, pilocarpine HCl, porphyrin sodium, vatalani, 1-dehydrotestosterone, allopurinol sodium, betamethasone sodium phosphate and betamethasone acetate, calcium formyltetrahydroacetate, Conjugated estrogens, dextromethorphan, dibromomannitol, esterified estrogens, estradiol, sodium estradiol phosphate, ethinyl estradiol, flutamide, leucovorin, glucocorticoids, leuprolide acetate, levamisole HCl, medroxyprogesterone acetate, megestrol acetate, methyltestosterone, nilumet, octreotide acetate, disodium pamidronate, procaine, propranolol, testosterone lactone, tetracaine, toremifene citrate, and samoxicillin.

[1208] In some implementations, the chemotherapeutic agents are estrogen receptor ligands such as tamoxifen, raloxifene, fulvestrant, diacetylcholine, bardoxifene, broparestriol, chlorestradiol, clomiphene citrate, cyclofennig, lasoxifene, olmexifen, or toremifene; and androgen receptor ligands such as bicalutamide, enzalutamide, apalutamide, cyproterone acetate, chlormadinone acetate, spironolactone, canrone, drospirenone, ketoconazole, and topilutam. Ideonium chloride, abiraterone acetate or cimetidine; aromatase inhibitors such as letrozole, anastrozole or exemestane; anti-inflammatory agents such as prednisone; oxidase inhibitors such as allopurinol; anticancer antibodies; anticancer monoclonal antibodies; antibodies against CD40 such as rucamumab or dasizumab; antibodies against CD20 such as rituximab; antibodies binding CD52 such as alemtuzumab; antibodies binding integrins such as voloximab or natezumab; antibodies against interleukin-6 receptors such as tocilizumab. Interleukin-2 mimics such as adeleukin; antibodies targeting IGF1 such as fentuximab; antibodies targeting DR4 such as mapamumumab; antibodies targeting TRAIL-R2 such as lexaamumumab or dulanamine; fusion proteins such as acecept; B-cell inhibitors such as acecept; proteasome inhibitors such as carfilzomib, bortezomib, or marizomib; HSP90 inhibitors such as tanspiramycin; HDAC inhibitors such as vorinostat, belitistat, or pabistat; MAPK ligands such as... Tapimod; PKC inhibitors such as enzatolin; HER2 receptor ligands such as trastuzumab, lapatinib, or pertuzumab; EGFR inhibitors such as gefitinib, erlotinib, cetuximab, panitumumab, or vandetanib; natural products such as romidixin; retinoids such as bexarotin, tretinoin, or retinoic acid; receptor tyrosine kinase (RTK) inhibitors such as sunitinib, regorafenib, or pazopanib; or VEGF inhibitors such as aflibercept, bevacizumab, or dovirtinib.

[1209] In some implementations, the combination of CDK4 / 6 inhibitors, chemotherapeutic agents, and immune checkpoint inhibitors is further combined with the use of hematopoietic growth factors, including but not limited to granulocyte colony-stimulating factor (G-CSF, e.g., γ-CSF). For Sale (Fegristatin); (peg-filgrastim); or levofloxacin), granulocyte-macrophage colony-stimulating factor (GM-CSF), for example sold as morasiltin and samosiltin. M-CSF (macrophage colony-stimulating factor), thrombopoietin (megakaryocyte growth and development factor (MGDF), for example...) and (For sale), interleukin (IL)-12, interleukin-3, interleukin-11 (adipogenesis inhibitor or Opti-L), SCF (steel factor, kit-ligand or KL) and erythropoietin (EPO) and their derivatives (epoterin-α, sold as, for example, Darbepoetin, Epocept, Nanokine, Epofit, Epogen, Eprex and Procrit; epoterin-β, sold as, for example, NeoRecormon, Recordon and Micera), epoterin-δ (sold as, for example, Dynepo), epoterin-ω (sold as, for example, Epomax), epoterin-ζ (sold as, for example, Silapo and Retacrit), and, for example, Epocept, Epotrust, Erypro Safe, Repoitin, Vintor, Epofit, Erykine, Wepox, Espogen, Relipoietin, Shanpoietin, Zyrop and EPIAO).

[1210] Other active compounds covered in this article, particularly in the treatment of abnormal tissues of the female reproductive system such as breast cancer, ovarian cancer, endometrial cancer, or uterine cancer, include combinations of CDK9 inhibitors and estrogen inhibitors described herein, including but not limited to SERMs (selective estrogen receptor modulators), SERDs (selective estrogen receptor degraders), complete estrogen receptor degraders, or other forms of partial or complete estrogen antagonists. Partial anti-estrogens, including raloxifene and tamoxifen, retain some estrogen-like activity. Complete anti-estrogens include fulvestrant. Non-limiting examples of anti-estrogenic compounds are provided in the following: WO 2014 / 19176 assigned to Astra Zeneca; WO2013 / 090921, WO 2014 / 203129, WO 2014 / 203132 and US2013 / 0178445 assigned to Olema Pharmaceuticals; WO2017 / 100712, WO2017 / 100715, WO2018 / 081168 and WO2018 / 148576 assigned to G1 Therapeutics; U.S. Patents 9,078,871, 8,853,423 and 8,703,810; and US2015 / 0005286, WO 2014 / 205136 and WO 2014 / 205138. Other non-limiting examples of anti-estrogenic compounds include: SERMS such as diacetylcholine, azoxifen, bardoxifene, bromhexine, clomiphene citrate, cyclofennig, traloxifen, indoxifene, edoxifene, lasoxifene, olmexifen, piperfenoxifene, raloxifene, tamoxifen, toremifene, and fulvestrant; aromatase inhibitors such as aminoglutethimide, testosterone, anastrozole, exemestane, fazodazole, formexane, and letrozole; and anti-gonadotropic hormones such as leuprorelin, cetrexate, allylestradiol, chlormedrone acetate, dimagesterone acetate, dydrogesterone, medroxyprogesterone acetate, megestrol acetate, norethindrone acetate, progesterone, and spironolactone. Other non-limiting examples of anti-estrogenic compounds include: SERDS such as fulvestrant, rintodestrant (G1T48), brilanestrant (GDC0810), ellastrant (RAD1901), etacstil (GW5638), GW7604, AZD9496, GDC-0927, GDC9545 (RG6171), LSZ102, and SAR439859.

[1211] In some embodiments, SERD compounds of the formula described in WO 2017 / 100712

[1212]

[1213] Or its pharmaceutically acceptable salt.

[1214] in:

[1215] m 4 It can be 0, 1, 2, 3, or 4;

[1216] n 4 It can be 0, 1, 2, 3, or 4;

[1217] X A Selected from -O-, -CH2-, -S-, -NH-, -NMe-, -CF2- and C3 cycloalkyl groups;

[1218] Ring B is a phenyl, naphthyl, quinolinyl, 5- or 6-membered monocyclic heteroaryl or a 7-, 8-, 9- or 10-membered bicyclic heterocycle;

[1219] The ring C is phenyl, thienyl, 5- or 6-membered monocyclic heteroaryl, or 7-, 8-, 9- or 10-membered bicyclic heterocycle;

[1220] R 41 Selected from hydroxyl, hydrogen, halogen, –O (C1-C6 alkyl), –OC(O) (C1-C6 alkyl), –OC(O)C6H5, –OC(O)O (C1-C6 alkyl), –OC(O)OC6H5 and –OSO2 (C2-C6 alkyl);

[1221] R 42 Selected from –CH=CHCOOH, –NH(CO)COOH, –COOH, -C2-C6 alkenyl-COOH and -C2-C6 alkyne-COOH;

[1222] R 43 Each time it appears, it is independently selected from hydrogen, halogen, –CN, –NO2, -C1-C6 alkyl, and -C1-C6 fluoroalkyl; and

[1223] R 44 Each time it appears, it is independently selected from hydrogen, halogen, hydroxyl, -C1-C6 alkyl, -C1-C6 fluoroalkyl, –CN, –O(C1-C6 alkyl) and –O(C1-C6 fluoroalkyl).

[1224] Non-limiting examples of SERDS used in this invention include:

[1225]

[1226]

[1227]

[1228] Or its pharmaceutically acceptable salt.

[1229] In some implementations, SERD is:

[1230]

[1231] Or its pharmaceutically acceptable salt.

[1232] In some implementations, SERD is:

[1233]

[1234] Or its pharmaceutically acceptable salt.

[1235] In some implementations, SERD is:

[1236]

[1237] Or its pharmaceutically acceptable salt.

[1238] Other chemotherapeutic agents covered herein, particularly in the treatment of abnormal tissues of the male reproductive system such as prostate or testicular cancer, include, but are not limited to, androgen (e.g., testosterone) inhibitors, including, but not limited to, selective androgen receptor modulators, selective androgen receptor degraders, complete androgen receptor degraders, or other forms of partial or complete androgen antagonists. In some embodiments, the prostate or testicular cancer is androgen-resistant. Non-limiting examples of antiandrogen compounds are provided in WO 2011 / 156518 and U.S. Patent Nos. 8,455,534 and 8,299,112. Further non-limiting examples of antiandrogen compounds include: chlormadinone acetate, spironolactone, allesterone, drospirenone, ketoconazole, topilutamide, abiraterone acetate, and cimetidine.

[1239] Chemotherapy agents may include kinase inhibitors, including but not limited to phosphoinositol 3-kinase (PI3K) inhibitors, Bruton's tyrosine kinase (BTK) inhibitors, or spleen tyrosine kinase (Syk) inhibitors or combinations thereof.

[1240] PI3k inhibitors are well known. Examples of PI3 kinase inhibitors include, but are not limited to, Wortmannin, demethylamphenicol, pireflactin, idelalisib, pictilisib, Palomid 529, ZSTK474, PWT33597, CUDC-907 and AEZS-136, duvelisib, GS-9820, GDC-0032(2-[4-[2-(2-isopropyl-5-methyl-1,2,4-triazol-3-yl)-5,6-dihydroimidazo[1,2-d][1,4]benzoxazine). -9-yl]pyrazol-1-yl]-2-methylpropionamide), MLN-1117 ((2R)-1-phenoxy-2-butylhydro(S)-methylphosphonate; or methyl(oxo){[(2R)-l-phenoxy-2-butyl]oxy}phosphonium), BYL-719 ((2S)-N1-[4-methyl-5-[2-(2,2,2-trifluoro-1,1-dimethylethyl)-4-pyridinyl]-2-thiazolyl]-1,2-pyrrolidinedicarboxamide), GSK2126458 (2,4-difluoro-N-{2- (methoxy)-5-[4-(4-pyridazinyl)-6-quinolinyl]-3-pyridyl}benzenesulfonamide), TGX-221((±)-7-methyl-2-(morpholin-4-yl)-9-(l-phenylaminoethyl)-pyrido[l,2-a]pyrimidin-4-one), GSK2636771(2-methyl-1-(2-methyl-3-(trifluoromethyl)benzyl)-6-morpholino-lH-benzo[d]imidazolium-4-carboxylic acid dihydrochloride), KIN-193((R)-2-((l-(7-methyl-2-morpholinyl) Lino-4-oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid), TGR-1202 / RP5264, GS-9820((S)-l-(4-((2-(2-aminopyrimidin-5-yl)-7-methyl-4-hydroxypropane-1-one), GS-1101(5-fluoro-3-phenyl-2-([S)]-1-[9H-purin-6-ylamino]-propyl)-3H-quinazolin-4-one), AMG-319, GSK-2269557, SAR245 409(N-(4-(N-(3-((3,5-dimethoxyphenyl)amino)quinoxalin-2-yl)aminosulfonyl)phenyl)-3-methoxy-4-methylbenzamide), BAY80-6946(2-amino-N-(7-methoxy-8-(3-morpholinopropoxy)-2,3-dihydroimidazo[l,2-c]quinaz), AS252424(5-[l-[5-(4-fluoro-2-hydroxy-phenyl)-furan-2-yl]-methyl-(Z)-ylidene]-thiazolidin-2,4-dione), CZ 24832(5-(2-amino-8-fluoro-[l,2,4]triazolo[l,5-a]pyridin-6-yl)-N-tert-butylpyridine-3-sulfonamide), buparlisib(5-[2,6-di(4-morpholinyl)-4-pyrimidinyl]-4-(trifluoromethyl)-2-pyridinylamine), GDC-0941(2-(lH-indazol-4-yl)-6-[[4-(methylsulfonyl)-l-piperazinyl]methyl]-4-(4-morpholinyl)thieno[3,2-d]pyrimidine), GDC-0980((S)-1-(4-((2-(2-aminopyrimidin-5-yl)-7-methyl-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)piperazin-l-yl)-2-hydroxypropane-l-one (also known as RG7422)), SF1126((8S,14S,17S)-14-(carboxymethyl)-8-(3-guanidinopropyl)-17-(hydroxymethyl)-3,6,9,12,15-pentoxo-1-(4-(4-oxo-8-phenyl-4H-chromen-2-yl)morpholine-4-onthium)-2-oxa-7,10, 13,16-Tetraazaoctadecane-18-ester), PF-05212384 (N-[4-[[4-(dimethylamino)-1-piperidinyl]carbonyl]phenyl]-N'-[4-(4,6-di-4-morpholino-1,3,5-triazin-2-yl)phenyl]urea), LY3023414, BEZ235 (2-methyl-2-{4-[3-methyl-2-oxo-8-(quinolin-3-yl)-2,3-di- Hydrogen-lH-imidazo[4,5-c]quinolin-l-yl]phenyl}propionitrile), XL-765(N-(3-(N-(3-(3,5-dimethoxyphenylamino)quinoxalino-2-yl)aminosulfonyl)phenyl)-3-methoxy-4-methylbenzamide) and GSK1059615(5-[[4-(4-pyridyl)-6-quinolinyl]methylene]-2,4-thiazolidinedione), PX886([(3aR,6E ,9S,9aR,10R,11aS)-6-[[bis(prop-2-enyl)amino]methylene]-5-hydroxy-9-(methoxymethyl)-9a,11a-dimethyl-1,4,7-trioxo-2,3,3a,9,10,11-hexahydroindo[4,5h]isocyanen-10-yl]acetate (also known as sonolisib) and the structure described in WO2014 / 071109 having the following formula:

[1241] BTK inhibitors are well-known. Examples of BTK inhibitors include ibrutinib (also known as PCI-32765). TM (1-[(3R)-3-[4-amino-3-(4-phenoxy-phenyl)pyrazolo[3,4-d]pyrimidin-1-yl]piperidin-1-yl]prop-2-en-1-one), acalabrutinib Inhibitors based on diphenylaminopyrimidines, such as AVL-101 and AVL-291 / 292 (N-(3-((5-fluoro-2-((4-(2-methoxyethoxy)phenyl)amino)pyrimidin-4-yl)amino)phenyl)acrylamide) (Avila) Therapeutics (see U.S. Patent Publication No. 2011 / 0117073, the entire contents of which are incorporated herein by reference), dasatinib ([N-(2-chloro-6-methylphenyl)-2-(6-(4-(2-hydroxyethyl)piperazin-1-yl)-2-methylpyrimidin-4-ylamino)thiazolyl-5-carboxamide], LFM-A13 (α-cyano-β-hydroxy-β-methyl-N-(2,5-dibromophenyl)acrylamide), GDC-0834 ([RN-(3-(6-(4-(1,4-dimethyl-3-oxopiperazin-2-yl)phenylamino)-4-methyl-5-oxo-4,5-dihydropyrazin-2-yl)-2-methylphenyl)-4,5,6,7-tetrahydrobenzo[b]thiophene-2-carboxamide], CGI-560 4-(tert-butyl)-N-(3-(8-(phenylamino)imidazo[1,2-a]pyrazin-6-yl)phenyl)benzamide, CGI-1746(4-(tert-butyl)-N-(2-methyl-3-(4-methyl-6-((4-(morpholin-4-carbonyl)phenyl)amino)-5-oxo-4,5-dihydropyrazin-2-yl)phenyl)benzamide), CNX-774(4-(4-((4-((3-acrylamidophenyl)amino)-5-fluoropyrimidin-2-yl)amino)phenoxy)-N-methylpyridinamide), CTA056(7-benzyl-1-(3-(piperidin-1-yl)propyl)-2-(4-(pyridin-4-yl)phenyl)-1H-imidazo[4,5-g]quinoxaline- 6(5H)-ketone), GDC-0834((R)-N-(3-(6-((4-(1,4-dimethyl-3-oxopiperazin-2-yl)phenyl)amino)-4-methyl-5-oxo-4,5-dihydropyrazin-2-yl)-2-methylphenyl)-4,5,6,7-tetrahydrobenzo[b]thiophene-2-carboxamide), GDC-0837((R)-N-(3-(6-((4-(1,4-dimethyl-3-oxopiperazin-2-yl)phenyl)amino)-4-methyl-5-oxo-4,5-dihydropyrazin-2-yl)-2-methylphenyl)-4,5,6,7-tetrahydrobenzo[b]thiophene-2-carboxamide), HM-71224, ACP-196, ONO-4059(Ono Pharmaceuticals), PRT062607 (4-((3-(2H-1,2,3-triazol-2-yl)phenyl)amino)-2-(((1R,2S)-2-aminocyclohexyl)amino)pyrimidine-5-carboxamide hydrochloride), QL-47 (1-(1-acryloylindoline-6-yl)-9-(1-methyl-1H-pyrazol-4-yl)benzo[h][1,6]naphthidin-2(1H)-one), and RN486 (6-cyclopropyl-8-fluoro-2-(2-hydroxymethyl-3-{1-methyl-5-[5-(4-methyl-piperazin-1-yl)-pyridin-2-ylamino]-6-oxo-1,6-dihydro-pyridin-3-yl}-phenyl)-2H-isoquinoline-1-one), BGB-3111, and other molecules capable of inhibiting BTK activity, such as those BTK inhibitors disclosed in Akinleye et al., Journal of Hematology & Oncology, 2013, 6:59, the entire contents of which are incorporated herein by reference.

[1242] Syk inhibitors are well known and include, for example, cerdulatinib (4-(cyclopropylamino)-2-((4-(4-(ethylsulfonyl)piperazin-1-yl)phenyl)amino)pyrimidine-5-carboxamide), entospletinib (6-(1H-indazol-6-yl)-N-(4-morpholinophenyl)imidazo[1,2-a]pyrazin-8-amine), and fostamatinib ([6-({5-fluoro-2-[(3,4,5-trimethylammonium trioxide)). [Methoxyphenyl)amino]-4-pyrimidinyl)amino)-2,2-dimethyl-3-oxo-2,3-dihydro-4H-pyrido[3,2-b][1,4]oxazin-4-yl]methyl dihydrophosphate), fotentinib disodium salt ((6-((5-fluoro-2-((3,4,5-trimethoxyphenyl)amino)pyrimidin-4-yl)amino)-2,2-dimethyl-3-oxo-2H-pyrido[3,2-b][1,4]oxazin-4(3H)-yl)methyl phosphate), BAY 61-3606 (2-(7-(3,4-dimethoxyphenyl)-imidazo[1,2-c]pyrimidin-5-ylamino)-nicotinamide HCl), RO9021 (6-[(1R,2S)-2-amino-cyclohexylamino]-4-(5,6-dimethyl-pyridin-2-ylamino)-pyridazine-3-carboxamide), imatinib (Gleevac; 4-[(4-methylpiperazin-1-yl)methyl] -N-(4-methyl-3-{[4-(pyridin-3-yl)pyrimidin-2-yl]amino}phenyl)benzamide), cruciferine, GSK143(2-(((3R,4R)-3-aminotetrahydro-2H-pyran-4-yl)amino)-4-(p-tolylamino)pyrimidin-5-carboxamide), PP2(1-(tert-butyl)-3-(4-chlorophenyl)-1H-pyrazolo[3,4-d]pyrimidin- 4-amine), PRT-060318(2-(((1R,2S)-2-aminocyclohexyl)amino)-4-(m-tolylamino)pyrimidine-5-carboxamide), PRT-062607(4-((3-(2H-1,2,3-triazol-2-yl)phenyl)amino)-2-(((1R,2S)-2-aminocyclohexyl)amino)pyrimidine-5-carboxamide hydrochloride), R112(3,3' -((5-fluoropyrimidin-2,4-diyl)bis(azanediyl))diol), R348(3-ethyl-4-methylpyridine), R406(6-((5-fluoro-2-((3,4,5-trimethoxyphenyl)amino)pyrimidin-4-yl)amino)-2,2-dimethyl-2H-pyrido[3,2-b][1,4]oxazine-3(4H)-one), YM193306(see Singh et al.,Compounds containing 7-azaindole, leucine, ER-27319 (see Singh et al., Discovery and Development of Spleen Tyrosine Kinase (SYK) Inhibitors, J. Med. Chem. 2012, 55, 3614-3643, the full text of which is incorporated herein by reference), compound D (see Singh et al., Discovery and Development of Spleen Tyrosine Kinase (SYK) Inhibitors, J. Med. Chem. 2012, 55, 3614-3643, the full text of which is incorporated herein by reference), and PRT060318 (see Singh et al., Discovery and Development of Spleen Tyrosine Kinase (SYK) Inhibitors, J. Med. Chem. 2012, 55, 3614-3643, the full text of which is incorporated herein by reference), and PRT060318 (see Singh et al., Discovery and Development of Spleen Tyrosine Kinase (SYK) Inhibitors, J. Med. Chem. 2012, 55, 3614-3643, the full text of which is incorporated herein by reference), are also mentioned. Spleen Tyrosine Kinase (SYK) Inhibitors, J. Med. Chem. 2012, 55, 3614-3643 (the full text of which is incorporated herein by reference), luteolin (see Singh et al., Discovery and Development of Spleen Tyrosine Kinase (SYK) Inhibitors, J. Med. Chem. 2012, 55, 3614-3643 (the full text of which is incorporated herein by reference), apigenin (see Singh et al., Discovery and Development of Spleen Tyrosine Kinase (SYK) Inhibitors, J. Med. Chem. 2012, 55, 3614-3643 (the full text of which is incorporated herein by reference), quercetin ... Tyrosine Kinase (SYK) Inhibitors, J. Med. Chem. 2012, 55, 3614-3643, the full text of which is incorporated herein by reference), squalene (see Singh et al., Discovery and Development of Spleen Tyrosine Kinase (SYK) Inhibitors, J. Med. Chem. 2012, 55, 3614-3643, the full text of which is incorporated herein by reference), myricetin (see Singh et al.,Discovery and Development of Spleen Tyrosine Kinase (SYK) Inhibitors, J. Med. Chem. 2012, 55, 3614-3643 (the full text of which is incorporated herein by reference), and linalool (see Singh et al., Discovery and Development of Spleen Tyrosine Kinase (SYK) Inhibitors, J. Med. Chem. 2012, 55, 3614-3643 (the full text of which is incorporated herein by reference).

[1243] Chemotherapy agents can also be B-cell lymphoma 2 (Bcl-2) protein inhibitors. BCL-2 inhibitors are known in the art and include, for example, ABT-199 (4-[4-[[2-(4-chlorophenyl)-4,4-dimethylcyclohexyl-1-en-1-yl]methyl]piperazin-1-yl]-N-[[[3-nitro-4-[[(tetrahydro-2H-pyran-4-yl)methyl]amino]phenyl]sulfonyl]-2-[(1H-pyrrolo[2,3-b]pyridin-5-yl)oxy]benzamide) and ABT-737 (4-[4-[[2-(4-chlorophenyl)phenyl]methyl]piperazin-1-yl]-N-[4-[[( 2R)-4-(dimethylamino)-1-phenylsulfonylbutane-2-yl]amino]-3-nitrophenyl]sulfonylbenzamide), ABT-263((R)-4-(4-((4'-chloro-4,4-dimethyl-3,4,5,6-tetrahydro-[l,l'-biphenyl]-2-yl)methyl)piperazin-1-yl)-N-((4-((4-morpholino-1-(phenylthio)butane-2-yl)amino)-3((trifluoromethyl)sulfonyl)phenyl)sulfonyl)benzamide), GX15-070(obatoclax methanesulfonate) mesylate), (2Z)-2-[(5Z)-5-[(3,5-dimethyl-1H-pyrrolo-2-yl)methylene]-4-methoxypyrrolo-2-yl]indolemethanesulfonic acid), 2-methoxy-antimycin A3, YC137(4-(4,9-dioxo-4,9-dihydronaphtho[2,3-d]thiazolyl-2-ylamino)-phenyl ester), pogosin, 2-amino-6-bromo-4-( Ethyl 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).

[1244] Other chemotherapeutic agents used in the methods covered herein include, but are not limited to, midazolam, MEK inhibitors, RAS inhibitors, ERK inhibitors, ALK inhibitors, HSP inhibitors (e.g., HSP70 and HSP90 inhibitors or combinations thereof), RAF inhibitors, apoptosis compounds, topoisomerase inhibitors, AKT inhibitors (including but not limited to MK-2206, GSK690693, perifolfenoxam, (KRX-0401), GDC-0068, tricerebroside, AZD5363, honokiol, PF-04691502, and mitefolfenoxam), or FLT-3 inhibitors (including but not limited to P406, dovirtinib, quezatinib (AC220), amuvatinib (MP-470), tandutinib (MLN518), ENMD-2076, and KW-2449) or combinations thereof.Examples of MEK inhibitors include, but are not limited to, trametinib / GSKl120212 (N-(3-{3-cyclopropyl-5-[(2-fluoro-4-iodophenyl)amino]-6,8-dimethyl-2,4,7-trioxo-3,4,6,7-tetrahydropyrido[4,3-d]pyrimidin-l(2H-yl}phenyl)acetamide), sumetinib (6-(4-bromo-2-chloroanilino)-7-fluoro-N-(2-hydroxyethoxy)-3-methylbenzimidazole-5-carboxamide), and pimasertib / AS703026 / MSC1935369 ((S)-N-(2,3-dihydroxypropyl)-3 -((2-fluoro-4-iodophenyl)amino)isonicotinamide), XL-518 / GDC-0973(l-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-[(2S)-piperidin-2-yl]azacyclobutane-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-dihydroxypropyl)cyclopropane-1-sulfonamide) [[3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]-benzamide), TAK733 ((R)-3-(2,3-dihydroxypropyl)-6-fluoro-5-(2-fluoro-4-iodophenylamino)-8-methylpyridino[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-(methylaminosulfonylamino)-4-pyridine]-3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino] ...-[[3-fluoro-2-(methylaminosulfonyl)amino]-4-pyridine]-3-[[3-fluoro-2-(methylaminosulfonyl)amino]-4-pyridine]-3-[[[3-fluoro-2-(methylaminosulfonyl)amino]-4-pyridine]-3-[[[3-fluoro-2-(methylaminosulfonyl)amino]-4-pyridine]-3-[[[3-fluoro-2-(methylamino [Methyl]-4-methyl-7-pyrimidin-2-yloxychromene-2-one), WX-554, R04987655 / CH4987655 (3,4-difluoro-2-((2-fluoro-4-iodophenyl)amino)-N-(2-hydroxyethoxy)-5-((3-oxo-1,2-oxazin-2-yl)methyl)benzamide) or AZD8330 (2-((2-fluoro-4-iodophenyl)amino)-N-(2-hydroxyethoxy)-1,5-dimethyl-6-oxo-1,6-dihydropyridine-3-carboxamide). Examples of RAS inhibitors include, but are not limited to, Reolysin and siG12D. LODER. Examples of ALK inhibitors include, but are not limited to, crizotinib, AP26113, and LDK378. HSP inhibitors include, but are not limited to, geldmycin or 17-N-allylamino-17-demethoxygeldmycin (17AAG) and Radicicol.

[1245] Known ERK inhibitors include SCH772984 (Merck / Schering-Plough), VTX-11e (Vertex), DEL-22379, Ulixertinib (BVD-523, VRT752271), GDC-0994, FR 180204, XMD8-92, and ERK5-IN-1.

[1246] Raf inhibitors are well known and include, for example, vemurafinib (N-[3-[[5-(4-chlorophenyl)-1H-pyrrolo[2,3-b]pyridin-3-yl]carbonyl]-2,4-difluorophenyl]-1-propanesulfonamide), sorafenib tosylate (4-[4-[[4-chloro-3-(trifluoromethyl)phenyl]carbamoylamino]phenoxy]-N-methylpyridin-2-carboxamide 4-methylbenzenesulfonate), and AZ628 (3-(2-cyanopropane-2-yl)-N-(4-methyl-3-(3-methyl-4-oxo-3,4-dihydroquinazolino)). -6-ylamino)phenyl)benzamide), NVP-BHG712 (4-methyl-3-(1-methyl-6-(pyridin-3-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-ylamino)-N-(3-(trifluoromethyl)phenyl)benzamide), RAF-265 (1-methyl-5-[2-[5-(trifluoromethyl)-1H-imidazol-2-yl]pyridin-4-yl]oxy-N-[4-(trifluoromethyl)phenyl]benzimidazol-2-amine), 2-Bromoaldisine (2-bromo-6,7-dihydro-1H,5H-pyrrolo[2,3-c]aza) -4,8-dione), Raf kinase inhibitor IV (2-chloro-5-(2-phenyl-5-(pyridin-4-yl)-1H-imidazol-4-yl)phenol) and sorafenib N-oxide (4-[4-[[[[[4-chloro-3(trifluoromethyl)phenyl]amino]carbonyl]amino]phenoxy]-N-methyl-2-pyridinecarboxamide 1-oxide).

[1247] Known topoisomerase I inhibitors that can be used in this invention include (S)-10-[(dimethylamino)methyl]-4-ethyl-4,9-dihydroxy-1H-pyrano[3',4':6,7]indolazin[1,2-b]quinoline-3,14(4H,12H)-dione hydrochloride (topotecan), (S)-4-ethyl-4-hydroxy-1H-pyrano[3',4':6,7]indolazin[1,2-b]quinoline-3,14-(4H,12H)-dione (camptothecin), and (1S,9S)-1-amino-9-ethyl-5-fluoro-1,2,3,9,12,15-hexahydro-9-hydroxy-4-methyl- 10H,13H-Benzo(de)pyrano(3',4':6,7)indolazino(1,2-b)quinoline-10,13-dione (Ecinotecan), (7-(4-methylpiperazinomethylene)-10,11-ethylenedioxy-20(S)-camptothecin (Letopecan) or (S)-4,11-diethyl-3,4,12,14-tetrahydro-4-hydroxy-3,14-dioxo-1H-pyrano[3',4':6,7]-indolazino[1,2-b]quinoline-9-yl-[1,4'-bipiperidine]-1'-carboxylate (Irinotecan), (R)-5-ethyl-9,10-difluoro-5-hydroxy-4,5-dihydrooxane [3',4':6,7]indolazino[1,2-b]quinoline-3,15(1H,13H)-dione (diflutecan), (4S)-11-((E)-((1,1-dimethylethoxy)imino)methyl)-4-ethyl-4-hydroxy-1,12-dihydro-14H-pyrano(3',4':6,7)indolazino(1,2-b)quinoline-3,14(4H)-dione (gematocan), (S)-8-ethyl-8-hydroxy-15-((4-methylpiperazin-1-yl)methyl)-11,14-dihydro-2H-[1,4]dioxinno[2,3-g]pyrano [3',4':6,7]Indolazin[1,2-b]quinoline-9,12(3H,8H)-dione (letotecan), (4S)-4-ethyl-4-hydroxy-11-[2-[(1-methylethyl)amino]ethyl]-1H-pyrano[3,4:6,7]indolazin[1,2-b]quinoline-3,14(4H,12H)-dione (belotecan), 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-indolo[2,3-a]pyrrolo[3,4-c]carbazole-5,7(6H)-dione (edotecarin), 8,9-dimethoxy-5-(2-N,N-dimethylaminoethyl)-2,3-methylenedioxy-5H-dibenzo(c,h)(1,6)naphthidium-6-one (topovale), benzo[6,7]indolazino[1,2-b]quinoline-11(13H)-one (rosettacin), (S)-4-ethyl-4-hydroxy-11-(2-(trimethylsilyl)ethyl)-1H-pyrano[3' [4':6,7]Indolinazino[1,2-b]quinoline-3,14(4H,12H)-dione (cositecan), tetra{(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]indolinazino[1,2-b]quinoline-4-yl}N,N',N”,N”'-{methanetetra[methylene poly(oxyethylene)oxy(1-oxoethylene)]}tetraglycine tetrahydrochloride (etirinotecan) pegol), 10-hydroxy-camptothecin (HOCPT), 9-nitrocamptothecin (rubitecan), SN38 (7-ethyl-10-hydroxycamptothecin) and 10-hydroxy-9-nitrocamptothecin (CPT109), (R)-9-chloro-5-ethyl-5-hydroxy-10-methyl-12-((4-methylpiperidin-1-yl)methyl)-4,5-dihydrooxane [3',4':6,7]indorazine[1,2-b]quinoline-3,15(1H,13H)-dione (elmotecan).

[1248] In some implementations, the chemotherapeutic agent is not an aromatase inhibitor. In some implementations, the chemotherapeutic agent is not an estrogen or androgen receptor agonist or antagonist.

[1249] growth factors

[1250] In some implementations, the combination of CDK4 / 6 inhibitors, chemotherapeutic agents, and checkpoint inhibitors is further combined with the use of the following factors: hematopoietic growth factors, including but not limited to granulocyte colony-stimulating factor (G-CSF, e.g., sold as Neupogen (filgrastim); Neulasta (peg-filgrastim); or lequamab), granulocyte-macrophage colony-stimulating factor (GM-CSF, e.g., sold as moraxillamine and samoxetine (Leukine)), M-CSF (macrophage colony-stimulating factor), thrombopoietin (megakaryocyte growth and development factor (MGDF), e.g., sold as romimista and eltrombopag), interleukin (IL)-12, interleukin-3, and interleukin-11 (adipogenesis inhibitors). Factors or interleukin), SCF (stem cell factor, steel factor, kit-ligand or KL) and erythropoietin (EPO) and their derivatives (epotine-α, sold as, for example, Darbepoetin, Epocept, Nanokine, Epofit, Epogen, Eprex and Procrit; epotine-β, sold as, for example, NeoRecormon, Recordon and Micera), epotine-δ (sold as, for example, Dynepo), epotine-ω (sold as, for example, Epomax), epotine-ζ (sold as, for example, Silapo and Retacrit), and, for example, Epocept, Epotrust, Erypro Safe, Repoitin, Vintor, Epofit, Erykine, Wepox, Espogen, Relipoietin, Shanpoietin, Zyrop and EPIAO).

[1251] CDK4 / 6 inhibitors

[1252] The present invention also provides an advantageous method for treating patients with selective CDK4 / 6 inhibitor-resistant cancer, comprising administering an effective amount of a compound of formula I, II, III, IV, V, VI, VII, VIII, IX, or X, or a pharmaceutically acceptable combination, salt, or isotope analog thereof. In some aspects, the compounds of the present invention are used to treat patients with cancer having intrinsic resistance to selective CDK4 / 6 inhibition. In some aspects, the compounds of the present invention are used to treat patients with cancer having acquired resistance to one or more selective CDK4 / 6 inhibitors. In some aspects, the compounds of the present invention are administered in combination with a selective CDK4 / 6 inhibitor to patients with selective CDK4 / 6 inhibition-responsive cancer to prolong the therapeutic efficacy of the selective CDK4 / 6 inhibitor. In some aspects, the compounds of the present invention are administered in combination with a selective CDK4 / 6 inhibitor to patients with selective CDK4 / 6 inhibition-responsive cancer, wherein the patients are selective CDK4 / 6 inhibitor-naïve. Selective CDK4 / 6 inhibitors for use in combination with the compounds of the present invention include, but are not limited to, palbociclib, bumarazine, ribociclib, triazolamiclib, SHR6390, and lerociclib.

[1253] In some implementations, the selective CDK4 / 6 inhibitor is palbociclib:

[1254] Or its pharmaceutically acceptable salt.

[1255] In some implementations, the selective CDK4 / 6 inhibitor is poumacinib:

[1256] Or its pharmaceutically acceptable salt.

[1257] In some implementations, the selective CDK4 / 6 inhibitor is ribociclib:

[1258] Or its pharmaceutically acceptable salt.

[1259] In some implementations, the selective CDK4 / 6 inhibitor is lerociclib:

[1260] Or its pharmaceutically acceptable salt.

[1261] In some implementations, the selective CDK4 / 6 inhibitor is triaseni:

[1262] Or its pharmaceutically acceptable salt.

[1263] In some implementations, the selective CDK4 / 6 inhibitor is SHR 6390.

[1264] In some embodiments, the selective CDK4 / 6 inhibitor is selected from, for example, the inhibitors described in U.S. Patent Nos. 8,822,683, 8,598,197, 8,598,186, 8,691,830, 8,829,102, 8,822,683, 9,102,682, 9,499,564, 9,481,591, and 9,260,442, which were filed by Tavares and Strum and assigned to G1 Therapeutics, describing a class of N-(heteroaryl)-pyrrolo[3,2-d]pyrimidine-2-amine cyclin-dependent kinase inhibitors, including those of the following formula (having variables as defined therein):

[1265]

[1266] In some embodiments, the selective CDK4 / 6 inhibitor is selected from, for example, the inhibitors described in U.S. Patent Nos. 9,464,092, 9,487,530, and 9,527,857, which are also assigned to G1 Therapeutics and describe the use of the aforementioned pyrimidine-based agents in the treatment of cancer.

[1267] In some embodiments, the selective CDK4 / 6 inhibitor is selected from, for example, the inhibitors described in WO 2013 / 148748 (USSN61 / 617,657) entitled "Lactam Kinase Inhibitors", WO 2013 / 163239 (USSN61 / 638,491) entitled "Synthesis of Lactams" and WO 2015 / 061407, which were filed by Tavares and also assigned to G1 Therapeutics, describing the synthesis of N-(heteroaryl)-pyrrolo[3,2-d]pyrimidine-2-amine and its use as a lactam kinase inhibitor.

[1268] In some embodiments, the selective CDK4 / 6 inhibitor is selected from, for example, the inhibitors described below. WO 2014 / 144326, submitted by Strum et al. and assigned to G1 Therapeutics, describes compounds and methods for protecting normal cells during chemotherapy using pyrimidine-based CDK4 / 6 inhibitors. WO 2014 / 144596, submitted by Strum et al. and assigned to G1 Therapeutics, describes compounds and methods for protecting hematopoietic stem cells and progenitor cells from ionizing radiation using pyrimidine-based CDK4 / 6 inhibitors. WO 2014 / 144847, submitted by Strum et al. and assigned to G1 Therapeutics, describes HSPC preservation therapy for abnormal cell proliferation using pyrimidine-based CDK4 / 6 inhibitors. WO 2014 / 144740, submitted by Strum et al. and assigned to G1 Therapeutics, describes highly active antitumor and antiproliferative pyrimidine-based CDK4 / 6 inhibitors. Strum et al.'s WO 2015 / 161285, submitted and assigned to G1 Therapeutics, describes a tricyclic pyrimidine-based CDK inhibitor for radiation protection. Strum et al.'s WO 2015 / 161287, submitted and assigned to G1 Therapeutics, describes a tricyclic pyrimidine-based CDK inhibitor for protecting cells during chemotherapy. Strum et al.'s WO 2015 / 161283, submitted and assigned to G1 Therapeutics, describes a tricyclic pyrimidine-based CDK inhibitor for HSPC retention therapy for RB-positive abnormal cell proliferation. Strum et al.'s WO 2015 / 161288, submitted and assigned to G1 Therapeutics, describes a tricyclic pyrimidine-based CDK inhibitor used as an antitumor and antiproliferative agent. Strum et al.'s WO 2016 / 040858, submitted and assigned to G1 Therapeutics, describes the use of pyrimidine-based CDK4 / 6 inhibitors in combination with other antitumor agents. Strum et al. submitted and transferred to G1 Therapeutics WO 2016 / 040848, describing compounds and methods for treating certain Rb-negative cancers with CDK4 / 6 inhibitors and topoisomerase inhibitors.

[1269] VIII. Examples

[1270] Example 1

[1271] General method:

[1272] For convenience, the compounds of the present invention having a stereocenter are drawn as racemic. Those skilled in the art will recognize that pure enantiomers can be prepared by methods known in the art. Examples of methods for obtaining optically active materials include at least the following.

[1273] i) Physical separation of crystals – a technique for manually separating macroscopic crystals of individual enantiomers. This technique can be used if individual enantiomers exist, i.e., the material is conglomerate and the crystals are visually distinct;

[1274] ii) Simultaneous crystallization—a technique for separately crystallizing individual enantiomers from a solution of a racemic compound, which is only possible when the latter is a solid aggregate;

[1275] iii) Enzymatic resolution – a technique for partially or completely separating racemic compounds by using the different reaction rates of enantiomers with enzymes;

[1276] iv) Enzymatic asymmetric synthesis – a synthetic technique in which at least one step of the synthesis uses an enzymatic reaction to obtain enantiomerically pure desired enantiomer or an enriched synthetic precursor of desired enantiomer.

[1277] v) Chemical asymmetric synthesis – a synthetic technique in which the desired enantiomers are synthesized from achiral precursors under conditions that produce asymmetry (i.e., chirality) in the product, which can be achieved using chiral catalysts or chiral auxiliaries.

[1278] vi) Diastereomer Separation – A technique that converts a single enantiomer into a diastereomer by reacting a racemic compound with an enantiomer-pure reagent (chiral auxiliary agent). The resulting diastereomers are then separated by chromatography or crystallization based on their now more pronounced structural differences, followed by removal of the chiral auxiliary agent to obtain the desired enantiomer;

[1279] vii) Primary and secondary asymmetric transformations—the diastereomers from the racemic product reach equilibrium and produce a quantitative advantage in a solution of the diastereomer from the desired enantiomer, or the preferential crystallization of the diastereomer from the desired enantiomer perturbs this equilibrium so that, in principle, all materials are eventually converted from the desired enantiomer to the crystalline diastereomer. The desired enantiomer is then released from the diastereomer.

[1280] viii) Kinetic resolution – This technique refers to the partial or complete resolution of racemic compounds (or further resolution of partially resolved compounds) by means of different reaction rates of enantiomers with chiral non-racemic reagents or catalysts under kinetic conditions.

[1281] ix) Enantiospecific synthesis from non-racemic precursors—synthetic techniques in which the desired enantiomers are obtained from achiral starting materials and in which the stereochemical integrity is not compromised or is only minimally compromised during synthesis;

[1282] x) Chiral liquid chromatography—a technique for separating enantiomers of racemic compounds in a liquid mobile phase by means of their different interactions with the stationary phase (including via chiral HPLC). The stationary phase may be made of a chiral material, or the mobile phase may contain other chiral materials to stimulate different interactions;

[1283] xi) Chiral gas chromatography – a technique for volatilizing racemic compounds and separating enantiomers by means of their different interactions with a column containing a fixed non-racemic chiral adsorbent phase in a gaseous mobile phase.

[1284] xii) Chiral solvent extraction – a technique for separating enantiomers by means of the preferential dissolution of an enantiomer in a specific chiral solvent;

[1285] xiii) Transchiral membrane transport—a technique that places a racemic compound in contact with a membrane barrier. This barrier typically separates two miscible fluids, one of which contains the racemic compound, and driving forces such as concentration or pressure differential cause preferential transport across the membrane barrier. Separation occurs due to the non-racemic chiral nature of the membrane, which allows only one enantiomer of the racemic compound to pass through.

[1286] Chiral chromatography, including simulated moving bed chromatography, is used in some implementations. A wide variety of commercially available chiral stationary phases are available.

[1287] Representative Synthesis

[1288] Overview

[1289] Unless otherwise stated, all reagents were used without further purification. 1 ¹H NMR spectra were obtained at room temperature on a Bruker 300 MHz instrument in DMSO-d6 or CD3OD. When more than one conformational isomer was detected, the chemical shift of the most abundant conformational isomer was reported. 1 Chemical shifts in the 1H NMR spectra were recorded in parts per million (ppm) based on the delta scale from the residual solvent internal standard. Splitting modes were indicated as: s, singlet; d, doublet; t, triplet; q, quartet; m, multiplet; brs, broad peak. LC-MS conditions are described below:

[1290] General LC / MS method:

[1291] Column: Agilent Zorbax XDB C18 4.6×50mm, 3.5μm

[1292] Mobile phase: Solvent A: 0.1% formic acid / water

[1293] Solvent B: MeOH

[1294] Flow rate: 1.0 mL / min

[1295] Runtime / gradient: 2 minutes (20%-90% B), then 3 minutes @ 90% B

[1296] Temperature: 30℃.

[1297] General HPLC methods:

[1298] Column: Agilent SB-C18 4.6×150mm, 3.5μm

[1299] Mobile phase: Solvent A: 0.02% TFA / water

[1300] Solvent B: MeOH

[1301] Flow rate: 1.0 mL / min

[1302] Runtime / gradient: 0.5 minutes @ 10% B, 9.5 minutes gradient @ 10% - 90% B, then 10 minutes @ 90% B.

[1303] Temperature: 30℃.

[1304] General preparative HPLC method:

[1305] Column: Phenomenex Luna 5u 100A, 21.2×250mm, 5μm

[1306] Mobile phase: Solvent A: Water

[1307] Solvent B: MeOH

[1308] Flow rate: 10 mL / min

[1309] Runtime / gradient: 1 minute @ 20% B, 30-minute gradient @ 20%-80% B, then 10 minutes @ 90% B

[1310] Temperature: Ambient temperature

[1311] The following abbreviations are used: 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(pinacol)diboron, AcOK = potassium acetate, N2 = nitrogen, Pd(OAc)2 = palladium(II) acetate, EtOAc = ethyl acetate, Na2SO4 = sodium sulfate, SOCl2 = thionyl chloride, NaHCO3 = carbonic acid Sodium hydrogen, Na2CO3 = sodium carbonate, NaS2O3 = sodium thiosulfate, MgSO4 = magnesium sulfate, RT = room temperature, THF = tetrahydrofuran, DMAC = dimethylacetamide, t-BuOH = tert-butanol, DBU = 1,8-diazabicyclo[5.4.0]undec-7-ene, CuI = copper iodide (I), TBAF = tetra-n-butylammonium fluoride, Pd(PPh3)2Cl2 = bis(triphenylphosphine)palladium dichloride (II), Pd(OAc)2 = palladium acetate (II), n-BuLi = n-butyllithium, NH4Cl = ammonium chloride, Cs2CO3 = cesium carbonate, EA = ethyl acetate, MeCN = acetonitrile, NBS = N-bromosuccinimide, K2CO3 = potassium carbonate, CPBA = m-chloroperoxybenzoic acid.

[1312] 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]pyrimidin]-2'-yl)amino)benzenesulfonamide—Synthesis of Compound 1

[1313]

[1314] Step 1: 4-Aminobenzenesulfonamide (67.3 mg, 0.39 mmol), AcOK (95.8 mg, 0.98 mmol), Pd(OAc)2 (7.3 mg, 0.03 mmol), and X-phos (62.2 mg, 0.13 mmol) were added to a solution of intermediate 1 (100 mg, 0.33 mmol) in DMF (4 mL) under N2 atmosphere. The solution was stirred at 80 °C for 3 hours, then the reaction mixture was cooled to room temperature, quenched with water (10 mL), and extracted with EtOAc (10 mL × 3). The organic phases were combined, washed with brine (5 mL × 2), dried over Na2SO4, and concentrated under vacuum. The residue was purified by preparative TLC to give compound 1 (2.5 mg, 0.006 mmol). MS (ESI+): m / z 443 [M+H]+ . 1 H NMR (300MHz, DMSO-d6): 9.97(s,1H),8.82(s,1H),8.75(d,J=3.9Hz,1H),8.02(d,J=9.0Hz,2H),7.73(d,J=9.0Hz,2H),7.1 9(s,2H),6.55(d,J=6.6Hz,1H),6.50(s,1H),5.90-5.85(m,1H),2.75-2.65(m,2H),2.31-2.17(m,2H),1.95-1.62(m,6H).

[1315] Scheme 2.4-((7'-oxo-7',8'-dihydro-6'H-spiro[cyclohexane-1,9'-pyrrolo[1,5-a:2,3-d']diamycin]-2'-yl)amino)benzenesulfonamide—Synthesis of Compound 2

[1316]

[1317] Step 1: SOCl2 (10 mL) was added dropwise to a mixture of intermediate 1 (12 g, 76.33 mmol) and MeOH (120 mL). The reaction was stirred overnight at 40 °C. The reaction was concentrated under vacuum. The resulting residue was neutralized to pH ~8 with aqueous Na2CO3 solution and extracted with DCM (50 mL × 5). The organic phases were combined and concentrated to give intermediate 2 (12 g, 70.08 mmol). LC-MS (ESI+): m / z 172 [M+H]+.

[1318] Step 2: DBU (23 g, 151.08 mmol) was added dropwise to a solution of intermediate 3 (10 g, 142.76 mmol) in DCM (150 mL) at 0 °C over 30 minutes. After the addition was complete, the reaction solution was stirred at room temperature for 2 hours. Then, 1-(chloromethyl)-4-methoxybenzene (20 g, 127.71 mmol) was added to the reaction solution. The reaction was stirred at room temperature for 2 days. The reaction was quenched with a saturated sodium bicarbonate aqueous solution (100 mL). The organic phase was dried over Na₂SO₄, filtered, and concentrated under vacuum. The residue was purified by silica gel column chromatography to give intermediate 4 (14 g, 73.61 mmol).

[1319] Step 3: Intermediate 2 (12 g, 70.08 mmol) and NaHCO3 (20 g, 238.07 mmol) were added to a solution of intermediate 5 (25 g, 90.95 mmol) in DMAc (100 mL). 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 EtOAc (100 mL × 2). The organic layer was separated, washed with brine, dried over anhydrous MgSO4, filtered, and concentrated under vacuum. The crude product was purified by column chromatography to give intermediate 6 (14 g, 34.17 mmol). LC-MS (ESI+): m / z 410 [M+H]+.

[1320] Step 4: 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 to a solution of intermediate 6 (14 g, 34.17 mmol) in THF (200 mL) under 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. The mixture was stirred overnight at room temperature, and then the reaction mixture was concentrated under vacuum. The resulting residue was purified by silica gel column chromatography to give intermediate 7 (5 g, 10.59 mmol). LC-MS (ESI+): m / z 472 [M+H]+.

[1321] Step 5: TBAF (30 mL, 1 M, in THF) was added to a solution of intermediate 7 (5 g, 10.59 mmol) in THF (30 mL) under N2 atmosphere at 60 °C. The mixture was stirred at 60 °C for 2 hours, then quenched with water (100 mL) and extracted with EtOAc (50 mL × 2). The organic phases were combined, washed with brine (50 mL), dried over Na2SO4, filtered, and concentrated under vacuum. The residue was purified by silica gel column chromatography to give intermediate 8 (1 g, 2.12 mmol). LC-MS (ESI+): m / z 472 [M+H]+.

[1322] Step 6: Add TFA (3 mL) to a solution of intermediate 8 (1 g, 2.12 mmol) in DCM (9 mL) at room temperature. Stir the reaction solution overnight at room temperature. Concentrate the reaction solution under vacuum. Purify the residue by silica gel column chromatography to give intermediate 9 (380 mg, 1.08 mmol). LC-MS (ESI+): m / z 352 [M+H] + .

[1323] Step 7: Add 100 mg of 4A molecular sieve to a solution of intermediate 9 (160 mg, 0.46 mmol) in t-BuOH (5 mL). Stir the mixture at room temperature for 30 minutes. Then add triethylamine (90 mg, 0.89 mmol) and diphenyl azidophosphate (240 mg, 0.87 mmol) to the mixture. Stir the mixture at 80 °C for 4 hours, then filter the reaction mixture and concentrate the filtrate under vacuum. Purify the residue by silica gel column chromatography to give intermediate 10 (30 mg, 0.10 mmol). LC-MS (ESI+): m / z 291 [M+H]+.

[1324] Step 8: 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) under N2 atmosphere. The mixture was stirred at 80 °C for 4 hours, the reaction mixture was cooled to room temperature, quenched with water (5 mL), and extracted with EtOAc / THF = 1 / 1 (5 mL × 3). The organic phases were combined, dried over Na2SO4, and concentrated under vacuum. The residue was purified by preparative TLC to give compound 2 (4.2 mg, 0.01 mmol). LC-MS(ESI+):m / z 427[M+H]+; 1H NMR (300MHz, DMSO-d6): 11.05(s,1H),9.72(s,1H),8.53(s,1H),7.91(d,J=9.0Hz,2H),7.69(d,J=9.0Hz,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).

[1325] Scheme 3.4-((3'-oxo-2',3'-dihydro-1'H-spiro[cyclohexane-1,4'-pyrimidino[5',4':4,5]pyrrolo[2,1-c][1,2,4]triazine]-7'-yl)amino)benzenesulfonamide—Synthesis of Compound 3

[1326]

[1327] Step 1: n-BuLi (147 mL, 2.5 mol, in THF, 367.5 mmol) was added dropwise over 30 minutes to a solution of ethynyltrimethylsilane (30 g, 305.94 mmol) in anhydrous THF (500 mL) under a nitrogen atmosphere at -78 °C. After the addition was complete, the reaction was stirred at -78 °C for 20 minutes. Then, intermediate 1 (105 g, 456.26 mmol) in anhydrous THF (300 mL) was added dropwise over 60 minutes. After the addition was complete, the reaction was gradually heated to -20 °C and stirred at -20 °C for 30 minutes. The reaction was quenched with saturated NH4Cl solution (100 mL) and water (300 mL), and extracted with EA (200 mL × 2). The organic phases were combined, washed with brine (100 mL), dried over Na2SO4, filtered, and concentrated under vacuum. The residue was purified by silica column chromatography to give intermediate 2 (60 g, 182.83 mmol) in the form of oil.

[1328] Step 2: At -20°C, a solution of TBAF trihydrate (72 g, 228.20 mmol) in THF (300 mL) was added to a solution of intermediate 2 (60 g, 182.83 mmol) in THF (300 mL). After the addition was complete, 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 × 2). The organic phases were combined, dried over Na2SO4, filtered, and concentrated under vacuum. The residue was purified by silica column chromatography to give intermediate 3 (36 g, 140.55 mmol).

[1329] Step 3: A solution of intermediates 3 and 4, CuI (1.1 g, 5.79 mmol), Pd(PPh3)2Cl2 (4.1 g, 5.86 mmol), and diisopropylamine (17.6 g, 174.05 mmol) in DMF was mixed overnight at room temperature. The reaction was quenched with water (500 mL) and extracted with EA (500 mL × 3). The organic phases were combined, washed with water (500 mL × 3), dried over Na2SO4, filtered, and concentrated under vacuum. The residue was purified by silica column chromatography to give intermediate 5 (28 g, 69.64 mmol). LC-MS (ESI+): m / z 403 [M+H]+.

[1330] Step 4: Intermediate 6 (1.2 g, 7.64 mmol) and NaHCO3 (1.25 g, 14.93 mmol) were added to a solution of intermediate 5 (2 g, 4.97 mmol) in DMF (20 mL) under N2 atmosphere. 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 × 3). The organic phases were combined, dried over Na2SO4, filtered, and concentrated under vacuum. The residue was purified by silica column chromatography to give intermediate 7 (1.2 g, 2.29 mmol). LC-MS (ESI+): m / z 524 [M+H]+.

[1331] Step 5: Add a solution of TBAF (1.2 mL, 1 mol, in THF, 1.2 mmol) to a solution of intermediate 7 (1.2 g, 2.29 mmol) in THF (15 mL). Stir the reaction mixture at 60 °C for 1 hour. Cool the reaction mixture to room temperature, quench with water (30 mL), and extract with EA (30 mL × 3). Combine the organic phases, dry with Na₂SO₄, filter, and concentrate under vacuum. Purify the residue by silica column chromatography to give intermediate 8 (300 mg, 0.57 mmol). LC-MS (ESI+): m / z 524 [M+H]+.

[1332] Step 6: Add Cs₂CO₃ (4 g, 12.28 mmol) to a solution of intermediate 8 (2 g, 3.82 mmol) in DMAc (30 mL). Stir the reaction mixture at 100 °C for 5 hours. Cool the reaction mixture to room temperature, quench with water (60 mL), and extract with EA (20 mL × 3). Combine the organic phases, dry with Na₂SO₄, filter, and concentrate under vacuum. Purify the residue by silica column chromatography to give intermediate 9 (320 mg, 0.82 mmol). LC-MS (ESI+): m / z 392 [M+H]⁺.

[1333] Step 7: 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 to a solution of intermediate 9 (50 mg, 0.13 mmol) in DMF (2 mL) under N2 atmosphere. 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 × 3). The organic phases were combined, dried over MgSO4, filtered, and concentrated under vacuum. The residue was purified by preparative TLC to give intermediate 11 (43 mg, 0.082 mmol). LC-MS (ESI+): m / z 528 [M+H]+.

[1334] Step 8: Add TFA (0.2 mL) to a solution of intermediate 11 (20 mg, 0.038 mmol) in DCM (2 mL). Stir the reaction mixture at room temperature for 2 hours. Quench the reaction mixture with saturated NaHCO3 solution (10 mL) and extract with DCM:MeOH = 10:1 (10 mL × 3). Combine the organic phases, dry with MgSO4, filter, and concentrate under vacuum. The residue was purified by preparative TLC to give compound 3 (2.1 mg, 0.005 mmol). LC-MS(ESI+):m / z 428[M+H]+; 1HNMR(300MHz,CD3OD):8.48(s,1H),7.92(d,J=9.0Hz,2H),7.80(d,J=9.0Hz,2H ),5.80(s,1H),2.49-2.38(m,2H),2.15-1.97(m,6H),1.90-1.81(m,1H),1.70-1.61(m,1H).

[1335] Scheme 4.4-((1'H-spiro[cyclohexane-1,4'-pyrimidino[5',4':4,5]pyrrolo[2,1-c][1,2,4]triazine]-7'-yl)amino)benzenesulfonamide—Synthesis of Compound 4

[1336]

[1337] Step 1: TBAF trihydrate (50 mg, 0.16 mmol) was added to a solution of intermediate 1 (300 mg, 0.89 mmol) in THF (20 mL) at -10 °C. After the addition was complete, 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 × 2). The organic phases were combined, dried over Na2SO4, filtered, and concentrated under vacuum to give intermediate 2 (220 mg, 0.83 mmol). LC-MS (ESI+): m / z 266 [M+H] + .

[1338] Step 2: At room temperature, NBS (200 mg, 1.12 mmol) and DBU (170 mg, 1.12 mmol) were added to a solution of intermediate 2 (200 mg, 0.83 mmol) in MeCN (20 mL). After the addition was complete, 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 × 2). The organic phases were combined, dried over Na2SO4, filtered, and concentrated under vacuum. The residue was purified by column chromatography to give intermediate 3 (200 mg, 0.58 mmol). LC-MS (ESI+): m / z 344 / 346 [M+H] + .

[1339] Step 3: At room temperature, Dess-Martin reagent (100 mg, 0.24 mmol) was added to a solution of intermediate 3 (75 mg, 0.22 mmol) in DCM (5 mL). After the addition was complete, 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 × 2). The organic phases were combined, dried over Na₂SO₄, filtered, and concentrated under vacuum. The residue was purified by silica column chromatography to give intermediate 4 (50 mg, 0.15 mmol). LC-MS (ESI+): m / z 342 / 344 [M+H]⁺.

[1340] Step 4: At room temperature, TBAF trihydrate (1 g, 3.17 mmol) was added to a solution of intermediate 4 (400 mg, 1.17 mmol) in THF (40 mL). After the addition was complete, 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 × 2). The organic phases were combined, dried over Na2SO4, filtered, and concentrated under vacuum. The residue was purified by silica column chromatography to give intermediate 5 (260 mg, 0.77 mmol) as a white solid.

[1341] Step 5: Add hydrazine hydrate (2 mL) and K₂CO₃ (200 mg, 1.45 mmol) to a solution of intermediate 5 (300 mg, 0.88 mmol) in THF (5 mL). After the addition is complete, stir the reaction mixture at 40 °C for 1 hour. Quench the reaction mixture with water (20 mL) and extract with EA (20 mL × 3). Combine the organic phases, dry with Na₂SO₄, filter, and concentrate under vacuum. Purify the residue by silica column chromatography to give intermediate 6 (200 mg, 0.73 mmol). LC-MS (ESI+): m / z 276 / 278 [M+H]⁺.

[1342] Step 6: 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) under N2 atmosphere. 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 × 3). The organic phases were combined, dried over MgSO4, filtered, and concentrated under vacuum. The residue was purified by preparative TLC to give compound 4 (3.9 mg, 0.01 mmol). LC-MS(ESI+):m / z 412[M+H]+; 1H NMR (300MHz, DMSO-d6): 10.71(s,1H),9.77(s,1H),8.45(s,1H),7.95(d,J=8.7Hz,2H),7.70(d,J=8.7H z,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).

[1343] Scheme 5.4-((9'-oxo-8',9'-dihydrospiro[cyclohexane-1,10'-pyrimidino[5',4':4,5]pyrrolo[2,1-d][1,2,5]triaza) Synthesis of Compound 6: 2'-yl)amino)benzenesulfonamide

[1344]

[1345] Step 1: Add thionyl chloride to a methanol solution of intermediate 1 (10 g) and stir the reaction overnight. After purification, intermediate 2 (5.47 g) is obtained.

[1346] Step 2: Sodium ...

Claims

1. A compound of the following formula: Or a pharmaceutically acceptable salt, N-oxide, isotope analog, and / or a pharmaceutically acceptable composition thereof; in: X 1 X 2 X 3 X 4 and X 5 Independently selected from N, CH, CR 2 and CR 4 ;where X 1 X 2 X 3 X 4 and X 5 At least one of them is CR 2 ; and X 1 X 2 X 3 X 4 and X 5 There are no more than two choices, N; X 11 X 12 X 13 X 14 and X 15 Independently selected from N, CH, CR 2 and CR 4 ;where X 11 X 12 X 13 X 14 and X 15 There are no more than two choices, N; Each R 1 Independently selected from hydrogen, halogen, -OR 14 NR 14 R 15 Alkyl, aryl, cycloalkyl, haloalkyl, heteroaryl, alkyl-hydroxyl, and heterocyclic, wherein two R 1 They can optionally form 3, 4, 5, 6, 7, or 8-membered cycloalkyl groups or 4, 5, 6, 7, or 8-membered heterocycles having 1, 2, or 3 heteroatoms selected from N, O, and S; wherein the two R groups are connected together. 1 The cycloalkyl or heterocyclic rings formed by the bonding of the atoms to which they are attached may optionally be composed of one or two independently selected from R 50 The substituents are replaced; Each R 2 Independently selected from -NR 14 C(O)R 6 -NR 14 S(O)R 6 -NR 14 S(O)2R 6 -NR 14 C(S)R 6 -OC(O)R 6 -OS(O)R 6 -OS(O)2R 6 -OC(S)R 6 -C(O)R 6 ;-C(S)R 6 -S(O)R 6 -S(=NR) 14 )2R 6 -S(=NR) 14 )(O)R 6 and -S(O)2R 6 ; R 3 Selected from hydrogen, -OR 14 -NR 14 R 15 alkyl, alkenyl, ynyl, –C(O)R 6 -C(O)alkyl, -C(S)alkyl, aryl, -SO2alkyl, heteroaryl, heterocyclic, -alkyl-aryl and -alkyl-heteroaryl; Each R 4 Independently selected from 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 ; R 5 Hydrogen, alkyl, haloalkyl, halogen, cyano, -OR 14 or -NR 14 R 15 ; Each R 6 Independently selected from hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, heteroaryl, NR 7 R 7 and OR 7 Except for hydrogen, NR 7 R 7 and OR 7 Each R outside 6 Optionally divided by 1, 2, 3 or 4 R 8 Substituted by groups; Each R 7 Independently selected from hydrogen, alkyl, alkenyl, ynyl, cycloalkyl, heterocyclic, aryl, alkyl-aryl, alkyl-heteroaryl, and heteroaryl, each R except hydrogen 7 Optionally divided by 1, 2, 3 or 4 R 8 Substituted by groups; Each R 8 Independently selected from hydrogen, halogen, haloalkyl, alkyl, alkenyl, ynyl, cycloalkyl, heterocyclic, aryl, heteroaryl, -S(O)2alkyl, NR 12 R 13 alkyl-heteroaryl, alkyl-aryl and OR 12 ; Each R 12 and R 13 Independently selected from hydrogen, alkyl, alkenyl, ynyl, -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 Independently selected from hydrogen, alkyl, alkenyl, ynyl, –C(O)R 6 -C(O)alkyl, -C(S)alkyl, aryl, -SO2alkyl, heteroaryl, heterocyclic, -alkyl-aryl and -alkyl-heteroaryl; R 17 and R 18 Independently selected from hydrogen, alkyl, alkenyl, ynyl, cycloalkyl, heterocyclic, aryl, alkyl-aryl, alkyl-heteroaryl, and heteroaryl, each of which except hydrogen is optionally marked by 1, 2, 3, or 4 R's. 8 Substituted by groups; and R 19 Hydrogen, alkyl, haloalkyl, halogen, cyano, -OR 14 or -NR 14 R 15 ;and Each R 50 Independently selected from hydrogen, -NR 14 R 15 OR 14 and R 4 .

2. The compound according to claim 1, wherein the compound has the formula: Or a pharmaceutically acceptable salt, N-oxide, isotope analog, and / or a pharmaceutically acceptable composition thereof; Each R 2 Independently selected from -NR 14 C(O)R 6 -NR 14 S(O)R 6 -NR 14 S(O)2R 6 -NR 14 C(S)R 6 -OC(O)R 6 -OS(O)R 6 -OS(O)2R 6 -OC(S)R 6 -C(O)R 6 ;-C(S)R 6 -S(O)R 6 and -S(O)2R 6 .

3. The compound according to claim 1, wherein the compound has the formula: Or its pharmaceutically acceptable salt.

4. The compound according to claim 1, wherein R 5 It is a hydroxyl group.

5. The compound according to claim 1, wherein the compound has the formula: Or its pharmaceutically acceptable salt.

6. The compound according to claim 1, wherein one of R... 1 It is hydrogen.

7. The compound according to claim 1, wherein the two Rs 1 Both are hydrogen.

8. The compound according to claim 1, wherein any one of R... 1 None of them are hydrogen.

9. The compound according to claim 1, wherein the compound has the formula: Or its pharmaceutically acceptable salt.

10. The compound according to claim 1, wherein the compound has the formula: Or its pharmaceutically acceptable salt.

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