Methods of treatment of cancer with substituted pyrrole and pyrazole compounds, and diagnosis of cancers susceptible to treatment with substituted pyrrole and pyrazole compounds

Abstract

To provide methods of treatment of cancer with substituted pyrrole and pyrazole compounds and diagnosis of cancers susceptible to treatment with substituted pyrrole and pyrazole compounds.SOLUTION: The present invention provides a pharmaceutical composition for treating a solid tumor cancer in a human individual, comprising the following formula. (L1: S, O or the like. L2: bond or CH2. L3, L4, L5: bond, C(O), S or the like. R1: unsubstituted / fluorinated C1-C8 alkyl or the like. R3, R5: substituted / unsubstituted phenyl, substituted / unsubstituted heteroaryl or the like. R4: unsubstituted, hydroxylated, C1-C4 alkoxylated or fluorinated C1-C8 alkyl or the like. Q: COOH.)SELECTED DRAWING: None

Description

[Technical Field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit of U.S. Provisional Patent Application No. 62 / 682,132, filed June 7, 2018, which is incorporated herein by reference in its entirety.

[0002] Technical Field The present disclosure relates to the diagnosis and treatment of cancer. More particularly, the present disclosure relates to the diagnosis of cancers amenable to treatment with specific compounds based on genetic profiling, and the treatment of cancers with specific compounds based on the genetic profile of the cancer. [Background technology]

[0003] In the United States, more than 1.5 million new cases of cancer are diagnosed each year, and an estimated 500,000 deaths per year are cancer-related. There are more than 200 different histopathological types of cancer, broadly classified as solid tumors and hematopoietic cancers. Current cancer treatments vary depending on the location and stage of the cancer, but generally include a combination of surgery, systemic therapy, radiation therapy, and chemotherapy. Despite the efforts that have been made to develop anti-cancer therapies, many of these remain ineffective against specific cancers.

[0004] Significant efforts have been made to develop effective treatment options for patients diagnosed with cancer. Cancer treatment options have evolved from nonspecific cytotoxic agents to molecules that target tumor-specific processes. However, the genetic complexity of cancerous tumors makes targeting specific molecular components an inefficient approach. This inefficiency is reflected by low overall success rates and the increasing need for strict patient selection criteria for clinical trials.

[0005] Therefore, approaches that target general aspects of tumor biology to provide effective treatment options that improve patient outcomes are highly desirable. Success in discovering effective cancer treatments relies on the development of novel therapeutics that target cancer hallmarks. Pathway- and marker-driven approaches place pharmacological proof-of-concept and a detailed understanding of pharmacological mechanisms of action at the heart of therapeutic innovation. Summary of the Invention

[0006] In various aspects, described herein are the identification of novel target gene biomarkers for hematopoietic and solid tumor cancers that correlate with the efficacy of treatment with therapeutic compounds; the measurement of quantitative changes in such biomarkers in hematopoietic and solid tumor cancers; and the treatment of hematopoietic and solid tumor cancers with therapeutic compounds. [Brief explanation of the drawings]

[0007] [Figure 1] 1 is a graph showing that hematological tumor cell lines ("Blood") may be more responsive to compound A197 than solid tumor cell lines ("Other") (Welch's t-test P-value -2.3e-16). [Figure 2] Graph showing that there was no significant difference in mean AUC between different solid tumor types (One-way ANOVA P value=0.54). [Figure 3] Schematic diagram of a cluster of 57 hematological tumor cell lines divided into two groups, with mean AUCs of 3.11 and 2.56, respectively. The results show that AUCs do not differ between tumor types. [Figure 4] Graph of AUC for KIAA0125 amplified ("KIAA0125_amp") and non-amplified ("KIAA0125_notamp") cell lines. Amplified and non-amplified cell lines have significantly different mean AUC (p=0.043). [Figure 5]Graph of the AUC detected between the HLA-B and HLA-C deficient ("del") and non-defective ("notdel") genes. Cell lines have significantly different AUCs (p<0.05). [Figures 6A-6B] Figure 1 shows a schematic diagram of drug efficacy prediction results using 9 signature genes and known sensitivity in 112 training solid cell lines. A total of 67 cell lines had predicted outcomes, and 61 cell lines were correctly predicted. [Figure 7] Figure 1 shows a schematic diagram of the results of drug efficacy prediction using nine signature genes and known sensitivity in 54 tested solid cell lines. A total of 28 cell lines had predicted outcomes, and 23 cell lines were correctly predicted. [Figure 8] Schematic diagram of how eIF2α phosphorylation controls translation initiation and ATF4 mRNA translation. [Figure 9] Figure 1 shows mouse pharmacokinetics graphs of single-dose escalation PK of compound A197 in female CD-1 mice. Compounds were orally administered at the indicated doses. Blood was collected from the tail at appropriate times, and the plasma concentration of compound A197 was measured by LC-MS. All values ​​are mean ± SD (n = 3 mice per group). [Figure 10] This is a collection of graphs showing the results of in vivo treatment of athymic nude mice implanted with the DLBCL line SU-DHL-10 (left panel) or the CRC line HCT-116 (right panel). After 14 days, groups of mice (n=10 per group) were randomized by tumor volume and treated with compound B19 (left panel) or compound A197 (right panel). All animals were dosed orally once daily (orally once daily). Tumor burden was measured over 21 days. Compound B19 was monitored for 21 days after the final dose, and recurrence was measured. All data are plotted as mean ± SEM, n=10 mice per group. [Figure 11]Figure 1 shows graphs of the expression of ATF4, ATF6, Xbp1, and cell cycle control genes in compound A197-responsive cell lines. All cells were treated with 5 μM compound A197 for 8 hours, after which RNA was isolated and differential gene expression was measured by qPCR. All data are expressed as Log2 Fc. *=p<0.05, n=3. [Figure 12] Figure 1 shows a set of graphs of phosphorylation of eIF2α induced by compound A197. HCT-116 cells were treated with 5 μM compound A197. The concentrations of eIF2α and p-eIF2α were measured by Western blotting. All data are mean ± SD (n=3). *=p<0.05; #=p<0.005. [Figure 13] 1 is a set of graphs showing the correlation between FAM210B expression and outcome in kidney cancer, lung cancer, and cervical cancer. [Figure 14] Graph showing Cancer Cell Line Encyclopedia (CCLE) FAM210B expression data and AUC for hematopoietic and solid tumor cell lines. Regression coefficient / Spearman correlation R value = 0.43 for solid tumors. [Figure 15] FIG. 1 is a graph showing robust multi-array average (RMA) normalized expression of FAM210B for diffuse large B-cell lymphoma (DLBCL), Burkitt's lymphoma, and myeloma. [Figure 16] FIG. 1 is a graph showing nominal logistic regression of the genes identified in Example 2, showing that two genes are responsible for the bulk of the split predicting response to compounds of the present disclosure. [Figure 17] A collection of fluorescence micrographs of HCT-116 cells transfected with vectors expressing tGFP (left) or FAM210B-GFP (right). [Figure 18] This is a graph showing ATF4 expression and GFP expression in HCT-116 cells transfected with vectors expressing tGFP or FAM210B-GFP. ATF4 expression decreases in a dose-dependent manner with increasing FAM210B expression. DETAILED DESCRIPTION OF THE INVENTION

[0008] The inventors have determined that while many cancers are responsive to certain pyrrole and pyrazole therapeutic compounds (themselves described in International Patent Application Publication No. 2015 / 196644 and International Patent Application No. PCT / US2017 / 063774, each of which is incorporated herein by reference in its entirety), many other cancers are less responsive. The inventors have identified certain cancers that are responsive to the therapeutic compounds and have further determined distinct correlates of gene expression patterns that predict responsiveness for hematopoietic cancers and solid tumors. Specifically, the present specification describes, in various aspects, the identification of novel target gene biomarkers for hematopoietic cancers and solid tumor cancers that correlate with the efficacy of treatment with therapeutic compounds; the measurement of quantitative changes in such biomarkers in hematopoietic and solid tumor cancers; and the treatment of hematopoietic cancers and solid tumor cancers with therapeutic compounds.

[0009] As discussed below, without being bound by theory, the inventors believe that the therapeutic compounds described herein act by activating the ATF4 pathway. Accordingly, another aspect of the present disclosure is a method for activating the ATF pathway in cancer cells, comprising feeding the cells with an effective amount of a therapeutic compound. In another aspect, the present disclosure provides a method for treating cancer in a human individual in which ATF4 activation is suppressed, comprising administering to the human individual an effective amount of a therapeutic compound. In another aspect, the present disclosure provides a method for treating cancer in a human individual, comprising determining whether ATF4 activation is suppressed in the cancer, and, if ATF4 activation is suppressed, administering to the human individual an effective amount of a therapeutic compound. Prostate cancer is an example of a cancer in which the ATF4 pathway is suppressed; see, for example, Y. Erzurumlu et al., Scientific Reports 7:40719 (2017); X. Sheng et al., EMBO Molecular Medicine, 7(6):788 (2015). In another aspect, the present disclosure provides a method for determining whether the ATF4 pathway is activated in a cancer by a therapeutic compound, the method comprising comparing the expression of one or more genes selected from ASNS, DDIT3, DDIT4, PP1R15A, SARS, and SLC7A11 without treatment with the therapeutic compound and with treatment with the therapeutic compound, and identifying the ATF4 pathway as activated by the therapeutic compound if one or more of the one or more genes exhibit a log2 fold change of greater than 0.5 (e.g., greater than 1). Such a method can be used for treatment. After such identification, the method can further include administering an effective amount of the therapeutic compound to a human individual suffering from cancer.

[0010] In one embodiment, the present disclosure provides a method for treating cancer in a human individual. The method includes measuring the expression levels of multiple genes in the cancer and measuring the fold change in gene expression compared to the expression levels of one or more genes in a reference cell. As used herein, "fold change in gene expression" is the quotient of the expression level of a gene in the cancer divided by the expression level of the gene in the reference cell. Thus, a fold change in gene expression of 1.5 indicates that the gene expression level in the cancer is greater than 50% compared to the reference cell. In particular, if the fold change in gene expression is significant for a first number of multiple genes, the cancer is identified as likely to be responsive to a therapeutic compound, and an effective amount of the therapeutic compound is administered to the human individual. In this embodiment of the present disclosure, the first number is 5 or more (i.e., 5 or more genes show a significant fold change in gene expression compared to the reference cell).

[0011] Those skilled in the art will determine the significance level necessary to provide the desired accuracy for the measurement. In certain embodiments described elsewhere herein, a fold change in gene expression of at least 1.2 is a significant change in gene expression. For example, in certain embodiments, a fold change in gene expression of at least 1.5 is a significant change in gene expression. In other embodiments, a fold change in gene expression of at least 2, or even at least 3, is a significant change in gene expression. Those skilled in the art will understand that a fold change in gene expression can be positive, indicating upregulation, or negative, indicating downregulation, respectively, relative to a reference cell, with a fold change in gene expression of "at least 1.2" indicating upregulation.

[0012] The methods, compounds and uses described herein may be used on a variety of different types of cancer or cells of a variety of different types of cancer.

[0013] Hematopoietic cancers are cancers of the blood, bone marrow, lymph, lymph nodes, or lymphatic system. The cyclical nature of many such cancers makes them particularly unique, resulting in over 50,000 deaths each year. Hematopoietic cancers can be broadly grouped into categories including myeloproliferative neoplasms, lymphomas, leukemias, and plasma cell neoplasms.

[0014] Solid tumor cancer is a term in the art that encompasses a large category of cancer. The majority of cancers are solid tumor cancers, with breast, lung, and prostate being common sites of solid tumor cancer. Solid tumor cancers that metastasize or spread are associated with a poor prognosis. Therefore, early detection is key, and effective drugs are key to reducing morbidity and mortality. Furthermore, new treatments are needed.

[0015] Consistent with this, a novel approach to cancer therapy is to use changes in gene expression to identify cancers that are responsive to novel drugs. In particular, hematopoietic cancers and solid tumors display genetic alterations. This application describes novel genetic alterations that can be used to identify hematopoietic and solid tumor cancers that are responsive to therapeutic compounds.

[0016] For example, in certain embodiments described elsewhere herein, the cancer is a hematopoietic cancer. In certain embodiments described elsewhere herein, the cancer is a chronic myeloproliferative neoplasm. In other embodiments described elsewhere herein, the cancer is a lymphoma (e.g., Burkitt's lymphoma, Hodgkin's lymphoma, non-Hodgkin's lymphoma, hairy cell lymphoma, mantle cell lymphoma, T-cell lymphoma, cutaneous T-cell lymphoma, B-cell lymphoma, diffuse large B-cell lymphoma, double-hit lymphoma, Waldenstrom's macroglobulinemia, primary central nervous system (CNS) lymphoma, and intravascular large B-cell lymphoma (ILBCL)). In other such embodiments, the cancer is a leukemia (e.g., acute lymphocytic leukemia (ALL), acute myeloid leukemia (AML), acute myeloblastic leukemia, chronic lymphocytic leukemia (CLL), chronic myelogenous leukemia (CML), chronic neutrophilic leukemia (CNL), chronic myelomonocytic leukemia (CMML), aggressive NK-cell leukemia, acute pleoplasmic leukemia, and polycythemia vera), acute and chronic T-cell and B-cell leukemia. In other such embodiments, the cancer is a plasma cell neoplasm (e.g., multiple myeloma).

[0017] However, one skilled in the art will understand from the disclosure provided herein that the methods, compounds, and uses described herein can be used in a variety of other types of cancer. For example, in certain embodiments of the methods, compounds, and uses otherwise described herein, the cancer is selected from appendix cancer, osteosarcoma (e.g., Ewing's sarcoma, osteosarcoma, and malignant fibrous histiocytoma), bronchial tumor, cancer of unknown primary, chronic myeloproliferative neoplasia, colon and rectal cancer, head and neck cancer (including head and neck squamous cell carcinoma (HNSCC)), leukemia (e.g., acute lymphocytic leukemia (ALL), acute myeloid leukemia (AML), acute myeloblastic leukemia, chronic lymphocytic leukemia (CLL), chronic myelogenous leukemia (CML), chronic neutrophilic leukemia (CNL), chronic myelomonocytic leukemia (CMML), aggressive NK cell leukemia, acute pleoplasmic leukemia, and polycythemia vera), acute and chronic T-cell and B-cell leukemia, The tumor is selected from lymphomas (e.g., Burkitt's lymphoma, Hodgkin's lymphoma, non-Hodgkin's lymphoma, hairy cell lymphoma, mantle cell lymphoma, T-cell lymphoma, cutaneous T-cell lymphoma, B-cell lymphoma, diffuse large B-cell lymphoma, double-hit lymphoma, Waldenstrom's macroglobulinemia, primary central nervous system (CNS) lymphoma, and intravascular large B-cell lymphoma (ILBCL)), plasma cell neoplasms (e.g., multiple myeloma), Wiskott-Aldrich syndrome, myelodysplastic / myeloproliferative neoplasia and chronic myeloproliferative neoplasia, pancreatic cancer and pancreatic neuroendocrine tumors (e.g., islet cell tumors), small intestine cancer, soft tissue sarcoma, and squamous cell carcinoma.

[0018] And in other embodiments of the methods, compounds, and uses otherwise described herein, the cancer is selected from the group consisting of adrenocortical carcinoma, adrenocortical carcinoma, AIDS-associated cancer (e.g., Kaposi's sarcoma, AIDS-associated lymphoma, Burkitt's lymphoma, and primary CNS lymphoma), anal cancer, appendix cancer, astrocytoma (e.g., childhood cerebellar or cerebral), bile duct cancer (e.g., cholangiocarcinoma), bladder cancer, osteosarcoma (e.g., Ewing's sarcoma, osteosarcoma, and malignant fibrous histiocytoma), brain tumor (e.g., glioblastoma multiforme, cerebellar astrocytoma, cerebral astrocytoma / malignant glioma, ependymoma, medulloblastoma, oligodendroglioma, Supratentorial primitive neuroectodermal tumors, and visual pathway and hypothalamic gliomas), brain stem gliomas, breast cancer, bronchial tumors, gastrointestinal carcinoid tumors, carcinoid tumors, cancer of unknown primary, cardiac (heart) tumors, central nervous system cancers (e.g., atypical teratoid / rod tumors, embryonal tumors, and germ cell tumors), cervical cancer, childhood cancers, chondrosarcoma, chronic myeloproliferative neoplasia, colon and rectal cancer, craniopharyngioma, fibrosclerosing small round cell tumor, ductal carcinoma in situ (DCIS), endometrial cancer, ependymoma, epithelioid hemangioendothelioma (EHE), esophageal cancer, nasal neuroblastoma, extracranial germ cell tumors, extragonadal germ cell tumors tumors, eye cancer (e.g., intraocular melanoma, and retinoblastoma), fallopian tube cancer, gallbladder cancer, gastric cancer, gastrointestinal stromal tumor (GIST), gestational trophoblastic disease (GTD), glioma, hairy cell leukemia, head and neck cancer (e.g., head and neck squamous cell carcinoma (HNSCC)), hepatocellular (liver) carcinoma, histiocytosis, Langerhans cell, hypopharyngeal cancer, kidney cancer, Langerhans cell histiocytosis, laryngeal cancer, laryngeal carcinoma and papillomatosis, leukemia (e.g., acute lymphocytic leukemia (ALL), acute myeloid leukemia (AML), acute myeloblastic leukemia, chronic lymphocytic leukemia (CLL), chronic myeloid leukemia (CML), chronic neutrophilic leukemia (CLL), NL), chronic myelomonocytic leukemia (CMML), aggressive NK cell leukemia, acute pleoplasmic leukemia, and polycythemia vera), acute and chronic T-cell and B-cell leukemia, lip and oral cancer, liver cancer, lung cancer (e.g., small cell lung cancer, non-small cell lung cancer (NSCLC), lung adenocarcinoma, lung carcinoma, and lung squamous cell carcinoma), pulmonary carcinoid tumors, lymphomas (e.g., Burkitt lymphoma, Hodgkin lymphoma, non-Hodgkin lymphoma, hairy cell lymphoma, mantle cell lymphoma, T-cell lymphoma, cutaneous T-cell lymphoma, B-cell lymphoma, diffuse large B-cell lymphoma, double-hit lymphoma,Waldenstrom's macroglobulinemia, primary central nervous system (CNS) lymphoma, and intravascular large B-cell lymphoma (ILBCL), male breast cancer, meningioma, mesothelioma, midline carcinoma involving the NUT gene, oral cancer, multiple endocrine neoplasia syndrome, plasma cell neoplasms (e.g., multiple myeloma), mycosis fungoides, Wiskott-Aldrich syndrome, myelodysplastic / myeloproliferative neoplasia and chronic myeloproliferative neoplasia, nasal cavity and paranasal sinus cancer, nasopharyngeal carcinoma (NPC), neuroblastoma, oral cavity cancer, lip cancer and oral and oropharyngeal cancer, ovarian cancer, pancreatic cancer, and The cancer is selected from pancreatic neuroendocrine tumors (e.g., pancreatic islet cell tumors), paraganglioma, parathyroid carcinoma, penile cancer, pharyngeal cancer, pheochromocytoma, pituitary tumor, pleuropulmonary blastoma, primary peritoneal cancer, prostate cancer, retinoblastoma, rhabdomyosarcoma, salivary gland cancer, Sezary syndrome, skin cancer (e.g., basal and squamous cell carcinoma, Merkel cell carcinoma, and melanoma), small intestine cancer, soft tissue sarcoma, squamous cell carcinoma, gastric cancer, testicular cancer, throat cancer, thymoma and thymic carcinoma, thyroid cancer, transitional cell carcinoma of the renal pelvis and ureter, urethral cancer, uterine cancer and sarcoma, vaginal cancer, vascular tumors, vulvar cancer, and Wilms' tumor.

[0019] In another embodiment, the cancer is, for example, any type of solid tumor described herein. For example, in some particular embodiments of the methods, compounds, and uses otherwise described herein, the cancer is a solid tumor. The solid tumor can be, in various embodiments, for example, lung cancer, colorectal cancer, or pancreatic cancer.

[0020] In certain embodiments of the methods, compounds, and uses otherwise described herein, the cancer is diffuse large B-cell lymphoma.

[0021] Those skilled in the art will appreciate that the above cancer classifications are broad and that some cancers may be classified in one, both, or the opposite group compared to the classifications herein. Hematopoietic or solid tumor cancer diagnoses are established by healthcare providers using commonly established criteria for cancer diagnosis.

[0022] The level of gene expression can be calculated using a variety of scientifically accepted techniques for reporting gene expression. Without being bound to any one method, in one embodiment, quantitative polymerase chain reaction is performed and gene expression is measured using real-time PCR and ΔΔC T The expression level is calculated using the .method. In an alternative embodiment, microarrays can be used to quantify RNA transcripts, providing a quantitative measure of gene expression. Those skilled in the art will understand that more than one method can be used to calculate gene expression and fold change in gene expression. Additionally, one or more housekeeping genes can be amplified as internal experimental controls. Internal experimental controls allow for internal evaluation of experimental parameters and normalization of target gene expression. Suitable housekeeping genes include 18s rRNA, 28s rRNA, α-tubulin, β-actin, ALB RPL32, TBP, CYCC, EF1A, and GAPDH. Those skilled in the art will understand that the list of housekeeping genes herein is not exclusive, and other housekeeping genes can also be amplified as dictated by the experimental conditions. Accession numbers for exemplary housekeeping genes are in the table below:

[0023] [Table 1]

[0024] Conventional sampling techniques can be used to isolate cancer cells from a human individual for analysis. For example, for solid tumor cancers, a biopsy can be obtained from the cancerous tissue. For hematopoietic cancers, cancer cells can be isolated from a blood sample, bone marrow sample, or other relevant tissue of a human individual.

[0025] The fold change in gene expression relative to a reference cell can be measured. One skilled in the art will select a suitable reference cell for a particular type of cancer. For example, in certain embodiments, the reference cell is a non-cancerous cell (e.g., of the same type as the cancer, e.g., hematopoietic cancer or solid tumor cancer) from a human individual. For example, a non-cancerous control tissue biopsy can be taken from the same organ or tissue of a human individual. In certain hematopoietic cancers, blood cell (e.g., leukocyte) lines can be cultured, and gene expression in the blood cells is used as a control. In another embodiment, the reference cell is a non-cancerous cell (e.g., of the same type as the cancer, e.g., hematopoietic cancer or solid tumor cancer) from a different human.

[0026] In other embodiments, a non-cancerous tissue-specific cell line can be used as a reference cell. Desirably, the reference cell is of the same type as the cancer, although in some cases, a reference cell of a different type can serve as a useful control. The following cell lines are exemplary control cell lines: normal human lung fibroblasts, human cervical epithelioid cell carcinoma (HeLa) cells, human umbilical vein epithelial cells, normal (non-cancerous) primary cell lines, COS7 cells, HEK cells, NIH3T3 embryonic fibroblast cells, human embryonic kidney (HEK) 293 cells, MRC-5 (PD-19) human embryonic lung cells, C2C12 mouse C3H muscle myoblasts, L929 mouse C3H / connective tissue, NIH3T3 mouse Swiss NIH embryo, MRC-5 ( PD25) Human fetal lung, ACHO-K1 Chinese hamster ovary, MDCK Canine Cocker Spaniel kidney, HUVEC Human pre-screened umbilical vein endothelial cells (HUVEC), J774A.1 Mouse BALB / c mononuclear macrophage, MC3T3-E1 Mouse C57BL / 6 calvaria, J774.2 Mouse BALB / c mononuclear macrophage, MA104 Monkey African Green kidney, BEAS-2B Human bronchial epithelium (normal), BHK 21 (clone 13) Syrian hamster kidney, MDCK-II canine cocker spaniel kidney, PNT2 human prostate (normal), immortalized COS-7 monkey African green kidney, SV40-transformed MDCK canine cocker spaniel kidney, HUVEC human umbilical vein endothelial cells (HUVEC); RK13 rabbit kidney, BVDV-negative tsA201 human embryonic kidney, SV40-transformed CHO hamster Chinese ovary, PANC-1 human Caucasian pancreas, Nthy-ori 3-1 human thyroid follicular epithelium, and WI38 human Caucasian fetal lung.

[0027] The list of possible control cells herein is not exhaustive. Those skilled in the art will understand that the control cell line requires stable expression of the gene of interest. Therefore, those skilled in the art will understand that additional cell lines can be used as controls to calculate fold changes.

[0028] In another embodiment, the reference cells have an IC of at least 30 μM for the therapeutic compound. 50As described in more detail below, the inventors have determined that the expression of certain genes correlates with sensitivity to a therapeutic compound, with non-responsive cells having different expression patterns than responsive cells. Thus, relatively non-responsive cell lines (i.e., cells with an IC of at least 30 μM to a therapeutic compound) are preferred. 50 (having the compound) can be used as a control. The data provided herein identifies a number of such cell lines. From those identified in the experimental section, one skilled in the art can select a cell line that is unresponsive to the exemplary compound for use as a reference cell.

[0029] In certain embodiments described elsewhere herein, the cancer is a hematopoietic cancer, and the plurality of genes is selected from CASP10, TMED1, PPP1CC, TMEM59, BRD7, CYB561, FAM210B, NDRG1, CTSB, MMAB, SETDB2, VPS37B, ELL3, and KIF13B. If the fold change in gene expression is greater than a first number (e.g., 5 or more) of the plurality of genes, the hematopoietic cancer is identified as likely to be sensitive to the therapeutic compound. In certain such embodiments, an effective amount of the compound is administered to a human individual to treat the cancer. However, in other embodiments, the method is used simply to identify whether the cancer is responsive to the therapeutic compound.

[0030] For hematopoietic cancers, in certain embodiments, the first number is 7 or greater, i.e., a significant fold change in gene expression in 7 or more of the 14 genes identified above indicates a likelihood of the cancer being sensitive to the therapeutic compound. For example, the first number can be 8 or greater, 9 or greater, or 10 or greater genes. In certain embodiments, the first number is 11 or greater, 12 or greater, or 13 or greater. And, in certain embodiments, the first number is 14, i.e., a significant fold change in gene expression in each of the 14 genes identified above indicates a likelihood of the cancer being sensitive to the therapeutic compound.

[0031] Those skilled in the art will understand that various combinations and permutations of the nine genes described above can be used in practicing the methods described herein. For example, in certain embodiments described elsewhere herein, at least one of the plurality of genes is CASP10 (e.g., CASP10 is one of the first number of genes). In certain embodiments described elsewhere herein, at least one of the plurality of genes is TMED1 (e.g., TMED1 is one of the first number of genes). In certain embodiments described elsewhere herein, at least one of the plurality of genes is PPP1CC (e.g., PPP1CC is one of the first number of genes). In certain embodiments described elsewhere herein, at least one of the plurality of genes is TMEM59 (e.g., TMEM59 is one of the first number of genes). In certain embodiments described elsewhere herein, at least one of the plurality of genes is BRD7 (e.g., BRD7 is one of the first number of genes). In certain embodiments described otherwise herein, at least one of the plurality of genes is CYB561 (e.g., CYB561 is one of the first number of genes). In certain embodiments described otherwise herein, at least one of the plurality of genes is FAM210B (e.g., FAM210B is one of the first number of genes). In certain embodiments described otherwise herein, at least one of the plurality of genes is NDRG1 (e.g., NDRG1 is one of the first number of genes). In certain embodiments described otherwise herein, at least one of the plurality of genes is CTSB (e.g., CTSB is one of the first number of genes). In certain embodiments described otherwise herein, at least one of the plurality of genes is MMAB (e.g., MMAB is one of the first number of genes). In certain embodiments described otherwise herein, at least one of the plurality of genes is SETDB2 (e.g., SETDB2 is one of the first number of genes).In certain embodiments described elsewhere herein, at least one of the plurality of genes is VPS37B (e.g., VPS37B is one of the first number of genes). In certain embodiments described elsewhere herein, at least one of the plurality of genes is ELL3 (e.g., ELL3 is one of the first number of genes). In certain embodiments described elsewhere herein, at least one of the plurality of genes is KIF13B (e.g., KIF13B is one of the first number of genes).

[0032] In certain embodiments described elsewhere herein, the cancer is a hematopoietic cancer and the plurality of genes is selected from LAMC3, FAM210B, SENP8, ITGB3BP, NUDT2, HNRNPCL1, C20orf43, FRMD8, and STX16. If the fold change in gene expression is large relative to a first number (e.g., 5 or more) of the plurality of genes, the solid tumor cancer is identified as likely to be sensitive to the therapeutic compound. In certain such embodiments, an effective amount of the compound is administered to a human individual to treat the cancer. However, in other embodiments, the method is used simply to identify whether the cancer is responsive to the therapeutic compound.

[0033] For solid tumor cancers, in certain embodiments, the first number is 5 or greater, i.e., a significant fold change in gene expression in five or more of the 14 genes identified above indicates a likelihood of the cancer being sensitive to the therapeutic compound. For example, the first number can be 6 or greater. In certain embodiments, the first number is 7 or greater or 8 or greater. And, in certain embodiments, the first number is 9, i.e., a significant fold change in gene expression in each of the nine genes identified above indicates a likelihood of the cancer being sensitive to the therapeutic compound.

[0034] Those skilled in the art will understand that various combinations and permutations of the nine genes described above can be used in practicing the methods described herein. For example, in certain embodiments described elsewhere herein, at least one of the plurality of genes is LAMC3 (e.g., LAMC3 is one of the first number of genes). In certain embodiments described elsewhere herein, at least one of the plurality of genes is FAM210B (e.g., FAM210B is one of the first number of genes). In certain embodiments described elsewhere herein, at least one of the plurality of genes is SENP8 (e.g., SENP8 is one of the first number of genes). In certain embodiments described elsewhere herein, at least one of the plurality of genes is ITGB3BP (e.g., ITGB3BP is one of the first number of genes). In certain embodiments described elsewhere herein, at least one of the plurality of genes is NUDT2 (e.g., NUDT2 is one of the first number of genes). In certain embodiments described otherwise herein, at least one of the plurality of genes is HNRNPCL1 (e.g., HNRNPCL1 is one of the first number of genes). In certain embodiments described otherwise herein, at least one of the plurality of genes is C20orf43 (e.g., C20orf43 is one of the first number of genes). In certain embodiments described otherwise herein, at least one of the plurality of genes is FRMD8 (e.g., FRMD8 is one of the first number of genes). In certain embodiments described otherwise herein, at least one of the plurality of genes is STX16 (e.g., STX16 is one of the first number of genes).

[0035] Another aspect of the present disclosure is a method for treating hematopoietic cancer in a human individual. The method includes determining the gene copy number for KIAA0125 in the hematopoietic cancer and identifying the hematopoietic cancer as likely to be responsive to a therapeutic compound if the gene copy number is at least a second number (e.g., at least 2, or at least 4). The method can further include administering an effective amount of the therapeutic compound to the human individual. However, in another embodiment, the method can be used to identify whether the cancer is responsive to the therapeutic compound. Such methods can otherwise be performed as described elsewhere herein. The deposit number for KIAA0125 is NM_014792.2.

[0036] Another aspect of the present disclosure is a method for treating hematopoietic cancer in a human individual. The method includes determining the gene copy number for HLA-B and / or HLA-C in the hematopoietic cancer and identifying the hematopoietic cancer as likely to be responsive to a therapeutic compound if the gene copy number is less than or equal to a third number (e.g., less than or equal to 0.4, less than or equal to 0.1, or less than or equal to 0.07). The method can further include administering an effective amount of the therapeutic compound to the human individual. However, in another embodiment, the method can be used to identify whether the cancer is responsive to the therapeutic compound. Such methods can otherwise be performed as described elsewhere herein. The accession numbers for HLA-B and HLA-C are NM_005514 and NM_001243042.1, respectively.

[0037] Another aspect of the present disclosure is a method of treating cancer in a human individual, comprising administering to said human individual an effective amount of a therapeutic compound.

[0038] In certain embodiments, the cancer is a hematopoietic cancer that exhibits a significant fold change in gene expression compared to a reference cell for a first number of a plurality of genes, wherein the first number is at least five, selected from CASP10, TMED1, PPP1CC, TMEM59, BRD7, CYB561, FAM210B, NDRG1, CTSB, MMAB, SETDB2, VPS37B, ELL3, and KIF13B. Applicable details of the fold change in gene expression, including the identity of the genes, the first number, the reference cell, the plurality of genes, and the significance level, can be as described above for the hematopoietic cancer embodiments.

[0039] In certain embodiments, the cancer is a solid tumor cancer that exhibits a significant gene expression fold change compared to a reference cell for a first number of a plurality of genes, wherein the first number is at least five, selected from LAMC3, FAM210B, SENP8, ITGB3BP, NUDT2, HNRNPCL1, C20orf43, FRMD8, and STX16. Applicable details of the gene expression fold change, including the identity of the genes, the first number, the reference cell, the plurality of genes, and the significance level, can be as described above for the solid tumor cancer embodiment.

[0040] In certain embodiments, the cancer is a hematopoietic cancer that exhibits a gene copy number for HLA-B and / or HLA-C that is 0.10 or less (eg, 0.07 or less).

[0041] In certain embodiments, the cancer is a hematopoietic cancer that exhibits a gene copy number for KIAA0125 that is at least 2 (eg, at least 4).

[0042] The data set forth in Table 1 below illustrates specific cancers for which the methods described herein may be particularly useful. Accordingly, in certain embodiments otherwise described herein, the cancer is selected from the group consisting of acute lymphocytic leukemia, acute promyelocytic leukemia, adrenocortical carcinoma, acute monocytic leukemia, acute myeloid leukemia, B-acute lymphocytic leukemia, amelanotic melanoma, anaplastic large cell lymphoma, astrocytoma, B-cell prolymphocytic leukemia, biphasic synovial sarcoma, bladder cancer, chronic myeloid leukemia, breast adenocarcinoma, breast cancer, Burkitt's lymphoma, cecal adenocarcinoma, cervical cancer, uterine squamous cell carcinoma, T-acute lymphocytic leukemia, chronic eosinophilic leukemia, chronic myeloid leukemia, and the like. Leukemia, colon adenocarcinoma, colon carcinoma, cutaneous melanoma, diffuse gastric adenocarcinoma, diffuse large B-cell lymphoma, diffuse large B-cell lymphoma (activated B-cell type), diffuse large B-cell lymphoma (germinal center B-cell type), breast ductal carcinoma, duodenal adenocarcinoma, embryonal rhabdomyosarcoma, endometrial adenocarcinoma, endometrial adenosquamous carcinoma, Epstein-Barr virus-associated Burkitt lymphoma, erythroleukemia, esophageal squamous cell carcinoma, Ewing's sarcoma, fibrosarcoma, follicular lymphoma, gallbladder carcinoma, gastric adenocarcinoma, gastric adenosquamous carcinoma, gastric carcinoma, gastric tubular adenocarcinoma, gestational choriocarcinoma, leioblastoma, squamous cell carcinoma of the head and neck, hepatoblastoma, hepatocellular carcinoma, medullary thyroid carcinoma, ovarian serous adenocarcinoma, human papillomavirus-associated cervical squamous cell carcinoma, human papillomavirus-associated cervical adenocarcinoma, hypopharyngeal squamous cell carcinoma, anaplastic (undifferentiated) thyroid carcinoma, breast cancer, inflammatory breast cancer, intrahepatic cholangiocarcinoma, invasive ductal carcinoma, large B-cell lymphoma, large cell lung carcinoma, lung adenocarcinoma, mantle cell lymphoma, melanoma, minimally invasive lung adenocarcinoma, nasopharyngeal carcinoma, natural killer cell lymphocytic leukemia / lymphoma, neuroblastoma, non-small cell lung cancer, osteosarcoma, ovarian thrombocytopenia Clear cell adenocarcinoma, ovarian endometrioid adenocarcinoma, ovarian serous cystadenocarcinoma, pancreatic adenocarcinoma, pancreatic cancer, pancreatic ductal adenocarcinoma, papillary lung adenocarcinoma, papillary renal cell carcinoma, plasma cell myeloma, plasmacytoma, pleomorphic breast cancer, pleural biphasic mesothelioma, pleural epithelioid mesothelioma, prostate cancer, rectal adenocarcinoma, rectosigmoid adenocarcinoma, renal cell carcinoma cancer, Sézary syndrome, signet ring cell gastric adenocarcinoma, small cell lung cancer, small squamous follicular cell carcinoma, follicular thyroid carcinoma, papillary thyroid carcinoma, thyroid squamous cell carcinoma, undifferentiated (reversal) thyroid carcinoma, tongue squamous cell carcinoma, uterine corpus sarcoma, or vulval squamous cell carcinoma.In certain embodiments otherwise described herein, the cancer is acute promyelocytic leukemia, acute monocytic leukemia, acute myeloid leukemia, B-acute lymphocytic leukemia, anaplastic large cell lymphoma, B-cell prolymphocytic leukemia, chronic myeloid leukemia, Burkitt's lymphoma, chronic eosinophilic leukemia, chronic myeloid leukemia, diffuse large B-cell lymphoma, diffuse large B-cell lymphoma, activated B-cell type, diffuse large B-cell lymphoma germinal center B-cell type, Epstein-Barr virus-associated Burkitt's lymphoma, erythroleukemia, follicular lymphoma, large B-cell lymphoma acute lymphocytic leukemia, mantle cell lymphoma, natural killer cell lymphocytic leukemia / lymphoma plasma cell myeloma, plasmacytoma, or Sézary syndrome.

[0043] In another aspect, the present disclosure provides methods for diagnosing and treating solid tumor cancer in a human individual. The inventors have determined that solid tumor cancers that exhibit reduced FAM210B expression are particularly amenable to treatment with the therapeutic compounds described herein.

[0044] For example, in one embodiment, a method for treating solid tumor cancer includes measuring the expression level of FAM210B in the cancer and measuring the fold change in FAM210B expression compared to the level of FAM210B expression in reference cells. In particular, if the fold change in FAM210B gene expression is significant, and if FAM210B expression in the cancer cells is lower than FAM210B expression in the reference cells, the cancer is identified as likely to be responsive to a therapeutic compound of the present disclosure, and an effective amount of the therapeutic compound is administered to the human individual. The significance of the fold change in FAM210B expression can be measured as described for other embodiments of the present disclosure.

[0045] In another embodiment, a method for treating solid tumor cancer in a human individual is provided.The solid tumor cancer exhibits a significant fold change in FAM210B expression (e.g., as otherwise described herein) compared to the expression level of FAM210B in a reference cell.The method comprises administering an effective amount of a therapeutic compound described herein to the human individual.

[0046] One of ordinary skill in the art would determine effective amounts and dosages of the compounds described herein based on this disclosure and the disclosures of International Application Publication No. 2016 / 196644 and U.S. Application Publication No. 2018 / 0100457, the disclosures of which are incorporated by reference.

[0047] Unless otherwise specified, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art. The following references provide the art with general definitions of many of the terms used in this disclosure: Singleton et al., Dictionary of Microbiology and Molecular Biology (2nd ed. 1994); The Cambridge Dictionary of Science and Technology (Walker ed., 1988); The Glossary of Genetics, 5th Ed., R. Rieger et al. (eds.), Springer Verlag (1991); and Hale & Marham, The Harper Collins Dictionary of Biology (1991). These references are intended to be exemplary and illustrative and are not limiting of the sources of information known to those of ordinary skill in the art. As used herein, the following terms have the following meanings ascribed to them unless otherwise specified.

[0048] It should be noted here that as used in this specification and the appended claims, the singular forms "a," "an," and "the" also include the plural forms unless the context clearly dictates otherwise.

[0049] As used herein, the terms "or" and "and / or" are used to describe multiple components in combination with each other or to the exclusion of each other. For example, "x, y, and / or z" can mean "x" only, "y" only, "z" only, "x, y, and z," "(x and y) or z," "x or (y and z)," or "x or y or z."

[0050] It should be noted that terms such as "preferably," "generally," and "typically" are not used herein to limit the scope of the claimed invention or to imply that particular features are critical, essential, or even essential to the structure and function of the claimed invention. Rather, these terms are merely intended to highlight alternative or additional features that may or may not be available in a particular embodiment of the invention.

[0051] A diagnostic or informative change or alteration in a biomarker is meant as an increase or decrease in the expression level or activity of a gene or gene product as detected by methods known in the art, such as those described herein.

[0052] As used herein, the term "cell" is meant to refer to a cell that is in vitro, ex vivo, or in vivo. In some embodiments, an ex vivo cell can be part of a tissue sample excised from an organism, such as a mammal. In some embodiments, an in vitro cell can be a cell in cell culture. In some embodiments, an in vivo cell is a cell that resides in an organism, such as a mammal.

[0053] As used herein, the term "housekeeping gene" refers to a gene used as an internal control in PCR experiments. Housekeeping genes show minimal variability in gene expression between blood samples from human individuals with hematopoietic cancer and blood samples from healthy individuals or cell lines. Housekeeping genes also show minimal variability in gene expression between tissues from human individuals with solid tumor cancer and non-cancerous tissue samples from healthy individuals or cell lines. Therefore, housekeeping gene expression is minimally affected by cancer.

[0054] A variety of therapeutic compounds can be used in practicing the methods of the present disclosure, generally selected from any embodiment or category of International Patent Application Publication No. WO 2015 / 196644 or WO 2018 / 102453, each of which is incorporated by reference herein in its entirety.

[0055] For example, in certain embodiments, the therapeutic compound is a compound generally described in any class, subclass, or embodiment of WO 2015 / 196644.

[0056] In certain embodiments, the therapeutic compound is of formula (I). [ka] [In formula (I), the ring system denoted by "a" is defined as a heterocyclic aromatic compound, optionally in the form of a pharmaceutically acceptable salt or N-oxide, or solvate or hydrate, wherein: A 1A is a bond, -C(O)-, -S-, -S(O) 1-2 -, -O-, -NR 6 -, -C(O)NR 6 -, -NR 6 C(O)-, -C(S)NR 6 -, -NR 6 C(S)-, -C(O)O-, -OC(O)-, -C(O)S-, -SC(O)-, -C(S)O-, -OC(S)-, -C(S)S-, -SC(S)-, -S(O) 1-2 O-, -OS(O) 1-2 -, -S(O) 1―2 NR 6 - and -NR 6 S(O) 1-2 - selected from the group consisting of L 1A is selected from the group consisting of a bond, unsubstituted C1-C4 alkylene, unsubstituted C1-C4 alkenylene, and unsubstituted C1-C4 alkynylene; A 1B is a bond, -C(O)-, -S-, -S(O) 1―2 -, -O-, -NR6 -, -C(O)NR 6 -, -NR 6 C(O)-, -C(S)NR 6 -, -NR 6 C(S)-, -C(O)O-, -OC(O)-, -C(O)S-, -SC(O)-, -C(S)O-, -OC(S)-, -C(S)S-, -SC(S)-, -S(O) 1―2 O-, -OS(O) 1―2 -, -S(O) 1―2 NR 6 - and -NR 6 S(O) 1―2 - selected from the group consisting of L 1B is selected from the group consisting of a bond, unsubstituted C1-C4 alkylene, unsubstituted C1-C4 alkenylene, and unsubstituted C1-C4 alkynylene; R 1 teeth hydrogen, optionally substituted C1-C8 alkyl, optionally substituted C1-C8 alkenyl, and optionally substituted C1-C8 alkynyl; 1-5 R 1E cycloalkyl and heterocycloalkyl substituted with Each of them can be any of 1-5 R 1E and wherein the aryl and heteroaryl are selected from the group consisting of aryl and heteroaryl substituted with During the ceremony, Each R 1E is oxo, optionally substituted C1-C4 alkyl, C1-C4 fluoroalkyl, halogen, -CN, SF5, -N3, -C(O)R 1F , -SR 1F , -S(O) 1―2 R 1F , -OR 1F , -NR 1G R 1F , -C(O)R 1F , -C(O)NR 1G R 1F , -NR 1G C(O)R 1F , -C(S)NR 1G R 1F , -NR 1G C(S)R1F , -C(O)OR 1F , -OC(O)R 1F , -C(O)SR 1F , -SC(O)R 1F , -C(S)OR 1F , -OC(S)R 1F , -C(S)SR 1F , -SC(S)R 1F , -S(O) 1―2 OR 1F , -OS(O) 1―2 R 1F , -S(O) 1―2 NR 1G R 1F , -NR 1G S(O) 1―2 R 1F are independently selected from Each R 1F is independently selected from H, C-C alkyl, C-C fluoroalkyl, C-C hydroxyalkyl, and (C-C alkoxy)C-C alkyl, (C-C alkoxy(C-C alkoxy))C-C alkyl, (C-C alkoxy(C-C alkoxy(C-C alkoxy)))C-C alkyl; Each R 1G is H, C1-C3 alkyl, C1-C3 fluoroalkyl, C1-C3 hydroxyalkyl, (C1-C3 alkoxy)C1-C3 alkyl, -S(O) 1―2 (C1-C3 alkyl), -C(O)(C1-C3 alkyl), and -C(O)O(C 1― C alkyl), L 2 is selected from the group consisting of a bond, —CH—, —CH(CH)—, or —CHCH—; Q is -H, -CH2OH, -C(O)OH, -C(O)OR 2A , -C(O)NR 2B R 2A , -C(O)NR 2B S(O)2R 2A , -C(O)NR 2B S(O)NR 2B R 2A , -C(O)R 2A, -S(O)2OH, -P(O)(OH)2, -C(OH)(CF3)2, S(O)2R 2A , -N(R 2B )S(O)2R 2A , -S(O)NR 2B R 2A , -C(O)NHOH, -C(O)NH-O(C1-C3 alkyl), -CO(NH)CN, [ka] is selected from the group consisting of During the ceremony, Each R 2A is H, C1-C3 alkyl, C1-C3 fluoroalkyl, C1-C3 hydroxyalkyl, C1-C3 aminoalkyl, C1-C3 thioalkyl, (C1-C3 alkoxy)C1-C3 alkyl, -(CH2CH2O) 2-5 -(optionally substituted C1-C3 alkyl)- and heteroaryl optionally substituted with 1 to 2 groups selected from substituents selected from C1-C3 alkyl, C1-C3 fluoroalkyl, hydroxyl, amino, thio, C1-C3 hydroxyalkyl, C1-C3 aminoalkyl, C1-C3 thioalkyl, and -C(O)C1-C3 alkyl; Each R 2B is H, C1-C3 alkyl, C1-C3 fluoroalkyl, C1-C3 hydroxyalkyl, C1-C3 aminoalkyl, C1-C3 thioalkyl, (C1-C3 alkoxy)C1-C3 alkyl, -S(O) 1―2 (C-C alkyl), —C(O)(C-C alkyl), and —C(O)O(C-C alkyl); Or R 2A and R 2B together with the nitrogen to which they are both directly attached form a heterocycloalkyl optionally substituted with 1 to 3 substituents selected from C-C alkyl, C-C fluoroalkyl, hydroxyl, amino, thio, C-C hydroxyalkyl, C-C aminoalkyl, C-C thioalkyl, and —C(O)C-C alkyl; L 3is a bond, -C(O)-, -S-, -S(O) 1―2 -, -O-, -NR 6 -, -CH2-, -CH(CH3)(OH)-, -CH(OH)-, -CH2CH2-, -C(O)NR 6 -, -NR 6 C(O)-, -C(S)NR 6 -, -NR 6 C(S)-, -C(O)O-, -OC(O)-, -S(O) 1―2 O-, -OS(O) 1―2 -, -S(O) 1―2 NR 6 - or -NR 6 S(O) 1―2 - and R 3 teeth, Each is (i)-L 3C -(1-5 R 3D aryl optionally substituted with -L 3C -(1-5 R 3D heteroaryl optionally substituted with 3C -(1-5 R 3E cycloalkyl optionally substituted with -L 3C -(1-5 R 3E (ii) 1-5 R 3E cycloalkyl and heterocycloalkyl optionally substituted with Each is (i)-L 3C -(1-5 R 3D aryl optionally substituted with -L 3C -(1-5 R 3D heteroaryl optionally substituted with 3C -(1-5 R 3E cycloalkyl optionally substituted with -L 3C -(1-5 R 3E (ii) 1-5 R 3E is selected from the group consisting of aryl and heteroaryl, optionally substituted with During the ceremony, Each L 3C is a bond, methylene, ethylene, -C(O)-, -S-, -S(O) 1―2 -, -O-, or -NR 3G - and each 3D is optionally substituted C1-C4 alkyl, C1-C4 fluoroalkyl, halogen, -CN, SF5, -N3, -C(O)R 3F , -SR 3F , -S(O) 1―2 R 3F , -OR 3F , -NR 3G R 3F , -C(O)R 3F , -C(O)NR 3G R 3F , -NR 3G C(O)R 3F , -C(S)NR 3G R 3F , -NR 3G C(S)R 3F , -C(O)OR 3F , -OC(O)R 3F , -C(O)SR 3F , -SC(O)R 3F , -C(S)OR 3F , -OC(S)R 3F , -C(S)SR 3F , -SC(S)R 3F , -S(O) 1―2 OR 3F , -OS(O) 1―2 R 3F , -S(O) 1―2 NR 3G R 3F , -NR 3G S(O) 1―2 R 3F , -OC(O)OR 3F , -OC(O)NR 3G R 3F , -NR 3G C(O)OR 3F , -NR 3G C(O)NR 3G R 3F , -SC(O)OR 3F , -OC(O)SR 3F , -SC(O)SR 3F, -SC(O)NR 3G R 3F , -NR 3G C(O)SR 3F , -OC(S)OR 3F , -OC(S)NR 3G R 3F , -NR 3G C(S)OR 3F , -NR 3G C(S)NR 3G R 3F , -SC(S)OR 3F , -OC(S)SR 3F , -SC(S)SR 3F , -SC(S)NR 3G R 3F , -NR 3G C(S)SR 3F , -NR 3G C(NR 3G )NR 3G R 3F , and -NR 3G S(O) 1―2 NR 3G R 3F are independently selected from Each R 3E is oxo, optionally substituted C1-C4 alkyl, C1-C4 fluoroalkyl, halogen, -CN, SF5, -N3, -C(O)R 3F , -SR 3F , -S(O) 1―2 R 3F , -OR 3F , -NR 3G R 3F , -C(O)R 3F , -C(O)NR 3G R 3F , -NR 3G C(O)R 3F , -C(S)NR 3G R 3F , -NR 3G C(S)R 3F , -C(O)OR 3F , -OC(O)R 3F , -C(O)SR 3F , -SC(O)R 3F , -C(S)OR 3F , -OC(S)R 3F , -C(S)SR 3F, -SC(S)R 3F , -S(O) 1―2 OR 3F , -OS(O) 1―2 R 3F , -S(O) 1―2 NR 3G R 3F , -NR 3G S(O) 1―2 R 3F , -OC(O)OR 3F , -OC(O)NR 3G R 3F , -NR 3G C(O)OR 3F , -NR 3G C(O)NR 3G R 3F , -SC(O)OR 3F , -OC(O)SR 3F , -SC(O)SR 3F , -SC(O)NR 3G R 3F , -NR 3G C(O)SR 3F , -OC(S)OR 3F , -OC(S)NR 3G R 3F , -NR 3G C(S)OR 3F , -NR 3G C(S)NR 3G R 3F , -SC(S)OR 3F , -OC(S)SR 3F , -SC(S)SR 3F , -SC(S)NR 3G R 3F , -NR 3G C(S)SR 3F , -NR 3G C(NR 3G )NR 3G R 3F , and -NR 3G S(O) 1―2 NR 3G R 3F are independently selected from Each R 3F is independently selected from H, C1-C3 alkyl, C1-C3 fluoroalkyl, and C1-C3 hydroxyalkyl; Each R 3Gis H, C1-C3 alkyl, C1-C3 fluoroalkyl, C1-C3 hydroxyalkyl, -S(O) 1―2 (C-C alkyl), —C(O)(C-C alkyl), and —C(O)O(C-C alkyl); A 4A is a bond, -C(O)-, -S-, -S(O) 1―2 -, -O-, -NR 6 -, -C(O)NR 6 -, -NR 6 C(O)-, -C(S)NR 6 -, -NR 6 C(S)-, -C(O)O-, -OC(O)-, -C(O)S-, -SC(O)-, -C(S)O-, -OC(S)-, -C(S)S-, -SC(S)-, -S(O) 1―2 O-, -OS(O) 1―2 -, -S(O) 1―2 NR 6 - and -NR 6 S(O) 1―2 - selected from the group consisting of L 4A is selected from the group consisting of a bond, unsubstituted C1-C4 alkylene, unsubstituted C1-C4 alkenylene, and unsubstituted C1-C4 alkynylene; A 4B is a bond, -C(O)-, -S-, -S(O) 1―2 -, -O-, -NR 6 -, -C(O)NR 6 -, -NR 6 C(O)-, -C(S)NR 6 -, -NR 6 C(S)-, -C(O)O-, -OC(O)-, -C(O)S-, -SC(O)-, -C(S)O-, -OC(S)-, -C(S)S-, -SC(S)-, -S(O) 1―2 O-, -OS(O) 1―2 -, -S(O) 1―2 NR 6 - and -NR 6 S(O) 1―2 - selected from the group consisting of L 4Bis selected from the group consisting of a bond, unsubstituted C1-C4 alkylene, unsubstituted C1-C4 alkenylene, and unsubstituted C1-C4 alkynylene; R 4 teeth, hydrogen, optionally substituted C1-C8 alkyl, optionally substituted C1-C8 alkenyl, and optionally substituted C1-C8 alkynyl; 1-5 R 4E and is selected from the group consisting of cycloalkyl and heterocycloalkyl substituted with During the ceremony, Each R 4E is oxo, optionally substituted C1-C4 alkyl, C1-C4 fluoroalkyl, halogen, -CN, -SF5, -N3, -C(O)R 4F , -SR 4F , -S(O) 1―2 R 4F , -OR 4F , -NR 4G R 4F , -C(O)R 4F , -C(O)NR 4G R 4F , -NR 4G C(O)R 4F , -C(S)NR 4G R 4F , -NR 1G C(S)R 4F , -C(O)OR 4F , -OC(O)R 4F , BC(O)SR 4F , -SC(O)R 4F , -C(S)OR 4F , -OC(S)R 4F , -C(S)SR 4F , -SC(S)R 4F , -S(O) 1―2 OR 4F , -OS(O) 1―2 R 4F , -S(O) 1―2 NR 4G R 4F , -NR 4G S(O) 1―2 R 4F , -OC(O)OR 4F , -OC(O)NR4G R 4F , -NR 4G C(O)OR 4F , -NR 4G C(O)NR 4G R 4F , -SC(O)OR 4F , -OC(O)SR 4F , -SC(O)SR 4F , -SC(O)NR 4G R 4F , -NR 4G C(O)SR 4F , -OC(S)OR 4F , -OC(S)NR 4G R 4F , -NR 4G C(S)OR 4F , -NR 4G C(S)NR 4G R 4F , -SC(S)OR 4F , -OC(S)SR 4F , -SC(S)SR 4F , -SC(S)NR 4G R 4F , -NR 4G C(S)SR 4F , -NR 4G C(NR 4G )NR 4G R 4F , and -NR 4G S(O) 1―2 NR 4G R 4F are independently selected from Each R 4F is independently selected from H, C1-C3 alkyl, C1-C3 fluoroalkyl, C1-C3 hydroxyalkyl, and (C1-C3 alkoxy)C1-C3 alkyl; Each R 4G is H, C1-C3 alkyl, C1-C3 fluoroalkyl, C1-C3 hydroxyalkyl, and (C1-C3 alkoxy)C1-C3 alkyl, -S(O) 1―2 (C-C alkyl), —C(O)(C-C alkyl), and —C(O)O(C-C alkyl); L 5 -C(O)-, -S-, -S(O) 1―2-, -O-, -NR 6 -, -CH2-, -CH(CH3)(OH)-, -CH(OH)-, -CH2CH2-, -C(O)NR 6 -, -NR 6 C(O)-, -C(S)NR 6 -, -NR 6 C(S)-, -C(O)O-, -OC(O)-, -S(O) 1―2 O-, -OS(O) 1―2 -, -S(O) 1―2 NR 6 - or -NR 6 S(O) 1―2 - and R 5 teeth 1-5 R 5E cycloalkyl and heterocycloalkyl substituted with 1-5 R each 5E is selected from the group consisting of aryl and heteroaryl optionally substituted with During the ceremony, Each R 5E is oxo, optionally substituted C1-C4 alkyl, C1-C4 fluoroalkyl, halogen, -CN, -SF5, -N3, -C(O)R 5F , -SR 5F , -S(O) 1-2 R 5F , -OR 5F , -NR 5G R 5F , -C(O)R 5F , -C(O)NR 5G R 5F , -NR 5G C(O)R 5F , -C(S)NR 5G R 5F , -NR 1G C(S)R 5F , -C(O)OR 5F , -OC(O)R 5F , -C(O)SR 5F , -SC(O)R 5F , -C(S)OR 5F , -OC(S)R 5F , -C(S)SR 5F , -SC(S)R 5F, -S(O) 1―2 OR 5F , -OS(O) 1―2 R 5F , -S(O) 1―2 NR 5G R 5F , -NR 5G S(O) 1―2 R 5F , -OC(O)OR 5F , -OC(O)NR 5G R 5F , -NR 5G C(O)OR 5F , -NR 5G C(O)NR 5G R 5F , -SC(O)OR 5F , -OC(O)SR 5F , -SC(O)SR 5F , -SC(O)NR 5G R 5F , -NR 5G C(O)SR 5F , -OC(S)OR 5F , -OC(S)NR 5G R 5F , -NR 5G C(S)OR 5F , -NR 5G C(S)NR 5G R 5F , -SC(S)OR 5F , -OC(S)SR 5F , -SC(S)SR 5F , -SC(S)NR 5G R 5F , -NR 5G C(S)SR 5F , -NR 5G C(NR 5G )NR 5G R 5F , and -NR 5G S(O) 1―2 NR 5G R 5F are independently selected from Each R 5F is independently selected from H, C1-C3 alkyl, C1-C3 fluoroalkyl, C1-C3 hydroxyalkyl, and (C1-C3 alkoxy)C1-C3 alkyl; Each R 5Gis H, C1-C3 alkyl, C1-C3 fluoroalkyl, C1-C3 hydroxyalkyl, and (C1-C3 alkoxy)C1-C3 alkyl, -S(O) 1―2 (C-C alkyl), —C(O)(C-C alkyl), and —C(O)O(C-C alkyl); X 1 is CR XA ,S,O,NRX B and N, X 2 is CR XA ,S,O,NRX B and N, wherein Each R XA is hydrogen, C1-C4 alkyl, C1-C4 fluoroalkyl, C1-C3 hydroalkyl, (C1-C3 alkoxy)C1-C3 alkyl, halo, -CN, oxo, -SF5, -N3, -C(O)R XC , -SR XC , -S(O) 1―2 R XC , -OR XC , -NR XD R XC wherein each R XC is independently selected from H, C-C alkyl, C-C fluoroalkyl, C-C hydroalkyl, and (C-C alkoxy)C-C alkyl; and each R XD is independently selected from H, C-C alkyl, C-C fluoroalkyl, C-C hydroxyalkyl, and (C-C alkoxy)-C alkyl, —C(O)(C-C alkyl), and —C(O)O(C-C alkyl); Each R XB is H, C1-C3 alkyl, C1-C3 fluoroalkyl, C1-C3 hydroxyalkyl, (C1-C3 alkoxy)C1-C3 alkyl, -C(O)(C1-C3 alkyl), and -C(O)O(C1-C3 alkyl and C1-C4 alkyl-S(O) 1―2 - independently selected from the group consisting of: Z 1 and Z 2 is independently selected from C and N; Y is CR Y or N, wherein R Y is hydrogen, C1-C3 alkyl, C1-C3 fluoroalkyl, C1-C3 hydroalkyl, C1-C3 aminoalkyl, C1-C3 thioalkyl, (C1-C3 alkoxy)C1-C3 alkyl, -S(O) 1―2 (C1-C3 alkyl), halogen, -CN, -SF5, -N3, -C(O)R YC , -SR YC , -S(O) 1―2 R YC , -OR YC , and -NR YD R YC wherein each R YC is independently selected from H, C-C alkyl, and C-C fluoroalkyl; and each R YD are independently selected from H, C1-C3 alkyl, and C1-C3 fluoroalkyl; During the ceremony, Each R 6 is hydrogen, C1-C3 alkyl, C1-C3 fluoroalkyl, C1-C3 hydroxyalkyl, C1-C3 aminoalkyl, C1-C3 thioalkyl, (C1-C3 alkoxy)C1-C3 alkyl, -S(O) 1―2 -(C1-C3 alkyl), -C(O)(C1-C3 alkyl), and -C(O)O(C1-C3 alkyl); Each alkyl, alkylene, alkenyl, alkenylene, alkynyl, and alkynylene is straight or branched; Each optionally substituted alkyl, alkenyl, alkynyl, alkylene, alkenylene, and alkylene may be unsubstituted or substituted with oxo, halogen, —CN, —SF, —N, —C(O)R 8 , -SR 8 , -S(O) 1―2 R 8 , -OR 8 , -NR 9 R 8 , -C(O)NR 9 R 8 , -NR 9 C(O)R 8 , -C(S)NR9 R 8 、-NR 9 C(S)R 8 、-C(O)OR 8 、-OC(O)R 8 、-C(O)SR 8 、-SC(O)R 8 、-C(S)OR 8 、-OC(S)R 8 、-C(S)SR 8 、-SC(S)R 8 、-S(O) 1―2 OR 8 、-OS(O) 1―2 R 8 、-S(O) 1―2 NR 9 R 8 、-NR 9 S(O) 1―2 R 8 、-OC(O)OR 8 、-OC(O)NR 9 R 8 、-NR 9 C(O)OR 8 、-NR 9 C(O)NR 9 R 8 、-SC(O)OR 8 、-OC(O)SR 8 、-SC(O)SR 8 、-SC(O)NR 9 R 8 、-NR 9 C(O)SR 8 、-OC(S)OR 8 、-OC(S)NR 9 R 8 、-NR 9 C(S)OR 8 、-NR 9 C(S)NR 9 R 8 、-SC(S)OR 8 、-OC(S)SR 8 、-SC(S)SR 8 、-SC(S)NR 9 R 8 、-NR 9 C(S)SR 8 、-NR 9 C(NR 9 )NR9 R 8 , and -NR 9 S(O) 1―2 NR 9 R 8 and is substituted with 1-5 substituents independently selected from: Each R 8 is independently selected from H, C1-C3 alkyl, C1-C3 fluoroalkyl, C1-C3 hydroxyalkyl, and (C1-C3 alkoxy)C1-C3 alkyl; Each R 9 is H, C1-C3 alkyl, C1-C3 fluoroalkyl, C1-C3 hydroxyalkyl, and (C1-C3 alkoxy)C1-C3 alkyl, -S(O) 1―2 (C-C alkyl), —C(O)(C-C alkyl), and —C(O)O(C-C alkyl); each cycloalkyl has 3-10 ring carbons and is unsaturated or partially unsaturated, and optionally contains one or two fused cycloalkyl rings, each having 3-8 ring members; each heterocycloalkyl has 3-10 ring members and 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and is unsaturated or partially unsaturated, and optionally contains one or two fused cycloalkyl rings, each having 3-8 ring members; each aryl is phenyl or naphthyl, and optionally contains one or two fused cycloalkyl or heterocycloalkyl rings, each having 4-8 ring members; Each heteroaryl is a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or an 8-10 membered bicyclic heteroaryl having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur, and optionally contains one or two fused cycloalkyl or heterocycloalkyl rings, each having 4-8 ring members. In certain such embodiments, each and every optionally substituted alkyl, alkylene, alkenyl, alkenylene, alkynyl, and alkynylene is unsubstituted or fluorinated, e.g., in certain such embodiments, each and every optionally substituted alkyl, alkylene, alkenyl, alkenylene, alkynyl, and alkynylene is unsubstituted.

[0057] In certain embodiments, structural formula (I) is one of formulas (Ia)-(Ic). [ka]

[0058] In certain embodiments otherwise described herein, X 1 is selected from one of the following groups (1a) to (1i): (1a)X 1 is CR XA , S, O, N, and NR XB is selected from the group consisting of (1b)X 1 are S, O, N, and NR XB is selected from the group consisting of (1c)X 1 is O, (1d)X 1 is S, (1e)X 1 is N or NR XB and (1f)X 1 is N or NR XB (In the formula, NR XB is hydrogen or optionally substituted C1-C4 alkyl; (1g)X 1 is N, (1h)X 1 is CR XA and (1i)X 1 is CR XA (In the formula, R XAis hydrogen or optionally substituted C1-C4 alkyl). In certain such embodiments, X 1 (R XA and R XB Each optionally substituted alkyl, alkenyl, and alkynyl in (including those in) can be unsubstituted or fluorinated. For example, in certain such embodiments, X 1 (R XA and R XB Each optionally substituted alkyl, alkenyl, and alkynyl in R X (including those in R X ) is unsubstituted. A and RX B is hydrogen.

[0059] In certain embodiments otherwise described herein, X 2 is selected from one of the following groups (2a) to (2i): (2a)X 2 is CR XA , S, O, N, and NR XB is selected from the group consisting of (2b)X 2 are S, O, N, and NR XB is selected from the group consisting of (2c)X 2 is O, (2d)X 2 is S, (2e)X 2 is N and NR XB is selected from (2f)X 2 is N and NR XB (In the formula, NR XB is hydrogen or optionally substituted C1-C4 alkyl; (2g)X 2 is N, (2h)X 2 is CR XA and (2i)X 2 is CR XA (In the formula, R XAis hydrogen or optionally substituted C1-C4 alkyl). In certain such embodiments, X 2 (R XA and R XB Each optionally substituted alkyl, alkenyl, and alkynyl in (including those in) can be unsubstituted or fluorinated. For example, in certain such embodiments, X 2 (R XA and R XB Each optionally substituted alkyl, alkenyl, and alkynyl in R X (including those in R X ) is unsubstituted. A and RX B is hydrogen.

[0060] In certain embodiments otherwise described herein, Z 1 is selected from one of the following groups (3a) to (3c): (3a)Z 1 is selected from C and N; (3b)Z 1 is C, (3c)Z 1 is N.

[0061] In certain embodiments otherwise described herein, Z 2 is selected from one of the following groups (4a) to (4c): (4a)Z 2 is selected from C and N; (4b)Z 2 is C, (4c)Z 2 is N.

[0062] In certain embodiments as otherwise described herein, the ring system denoted by "a" is one of the following groups (5a)-(5h): (5a) The ring system represented by "a" is a heteroaromatic compound (i.e., X 1 , X 2 , Z 1 , and Z 2 At least one of the following is C or CRXA isn't it), (5b) the ring system denoted by "a" is a thiazole; (5c) the ring system denoted by "a" is a thiazole and the compound is of formula (Id): [ka] (5d) the ring system denoted by "a" is a thiazole and the compound is of formula (Ie): [ka] (5e) the ring system denoted by "a" is a thiazole and the compound is of formula (If): [ka] (5f) the ring system denoted by "a" is a thiazole and the compound is of formula (Ig): [ka] (5g) The ring system denoted by "a" is, for example, an oxazole, imidazole, pyrazole, or triazole having one or more of the following structural formulae: [ka] or (5h) The compound is any of formulas (Ia) to (Ic), wherein the ring system denoted by "a" is a thiazole, and the thiazole moiety has the following structural formula: [ka] In certain embodiments according to embodiments (5a) and (5b), each R XA and R XB is hydrogen.

[0063] In certain embodiments otherwise described herein, the compound is of one of the following structural formulas: (Id) wherein the variables are groups (6h) (see below), (7e) (see below), (8d) (see below), (9g) (see below), (10k) (see below), (11e) (see below), (12k) (see below), (13j) (see below), (14l) (see below), (15l) (see below), (16e) (see below), (17d) (see below), (18h) (see below), (19k) (see below), (20g) (see below), and (21h) (see below), as defined herein below; (Ie) wherein the variables are groups (6h) (see below), (7e) (see below), (8d) (see below), (9g) (see below), (10k) (see below), (11e) (see below), (12k) (see below), (13j) (see below), (14l) (see below), (15l) (see below), (16e) (see below), (17d) (see below), (18h) (see below), (19k) (see below), (20g) (see below), and (21h) (see below), as defined herein below; (If) wherein the variables are groups (6h) (see below), (7e) (see below), (8d) (see below), (9g) (see below), (10k) (see below), (11e) (see below), (12k) (see below), (13j) (see below), (14l) (see below), (15l) (see below), (16e) (see below), (17d) (see below), (18h) (see below), (19k) (see below), (20g) (see below), and (21h) (see below), as defined herein below; (Ig) wherein the variables are groups (6h) (see below), (7e) (see below), (8d) (see below), (9g) (see below), (10k) (see below), (11e) (see below), (12k) (see below), (13j) (see below), (14l) (see below), (15l) (see below), (16e) (see below), (17d) (see below), (18h) (see below), (19k) (see below), (20g) (see below), and (21h) (see below), as defined herein below; (Ih) wherein the variables are groups (6h) (see below), (7e) (see below), (8d) (see below), (9g) (see below), (10k) (see below), (11e) (see below), (12k) (see below), (13j) (see below), (14l) (see below), (15l) (see below), (16e) (see below), (17d) (see below), (18h) (see below), (19k) (see below), (20g) (see below), and (21h) (see below), as defined herein below; (Ii) wherein (Ii) is formula (I) in which the ring system denoted by "a" is an oxazole, imidazole, pyrazole, or triazole (e.g., in one of the following structures: [ka] and wherein the variables are groups (6h) (see below), (7e) (see below), (8d) (see below), (9g) (see below), (10k) (see below), (11e) (see below), (12k) (see below), (13j) (see below), (14l) (see below), (15l) (see below), (16e) (see below), (17d) (see below), (18h) (see below), (19k) (see below), (20g) (see below), and (21h) (see below) as otherwise defined; (Ij) wherein (Ij) is of formula (Ic) in which the ring system denoted by "a" is an oxazole, imidazole, pyrazole, or triazole (e.g., in one of the following structures: [ka] and wherein the variables are groups (6h) (see below), (7e) (see below), (8d) (see below), (9g) (see below), (10k) (see below), (11e) (see below), (12k) (see below), (13j) (see below), (14l) (see below), (15l) (see below), (16e) (see below), (17d) (see below), (18h) (see below), (19k) (see below), (20g) (see below), and (21h) (see below) as otherwise defined. In certain embodiments, when the compound is of one of formulas (Id), (Ie), (Ih), and (Ii) above, R Y is H, —C(O)—C1-C3 alkyl, —C(O)—C1-C3 fluoroalkyl, —C1-C3 alkyl, —C1-C3 fluoroalkyl, —CN, or halogen. In certain embodiments according to Formulas (Id)-(Ij), each R A and RX B is hydrogen.

[0064] This disclosure is based on the R 1 , A 1A , L 1B , A 1B , L 1A , L 2 , Q, L 3 , R 3 , A 4A , L 4B , A 4B , L 4A , R 4 , L 5 , and R 5 are optionally independently selected from groups (6h) (see below), (7e) (see below), (8d) (see below), (9g) (see below), (10k) (see below), (11e) (see below), (12k) (see below), (13j) (see below), (14l) (see below), (15l) (see below), (16e) (see below), (17d) (see below), (18h) (see below), (19k) (see below), (20g) (see below), and (21h) (see below), as defined herein below. The definitions of the variables can be made from any combination of groups (6h) (see below), (7e) (see below), (8d) (see below), (9g) (see below), (10k) (see below), (11e) (see below), (12k) (see below), (13j) (see below), (14l) (see below), (15l) (see below), (16e) (see below), (17d) (see below), (18h) (see below), (19k) (see below), (20g) (see below), and (21h) (see below), as defined herein below, that is not theoretically or chemically inconsistent.

[0065] In certain embodiments otherwise described herein, R 1 is selected from one of the following groups (6h) to (6p): (6h)R 1 is selected from the group consisting of hydrogen, optionally substituted C1-C8 alkyl, optionally substituted C1-C8 alkenyl, optionally substituted C1-C8 alkynyl, cycloalkyl, and heterocycloalkyl, where cycloalkyl and heterocycloalkyl are selected from the group consisting of 1-5 R 1E optionally replaced by (6i)R 1 is selected from the group consisting of hydrogen, optionally substituted C1-C8 alkyl, optionally substituted C1-C8 alkenyl, and optionally substituted C1-C8 alkynyl; (6j)R 1 is selected from optionally substituted C1-C8 alkyl, optionally substituted C1-C8 alkenyl, and optionally substituted C1-C8 alkynyl; (6k)R 1 is selected from the group consisting of hydrogen, unsubstituted C1-C8 alkyl, unsubstituted C1-C8 alkenyl, and unsubstituted C1-C8 alkynyl (e.g., methyl, ethyl, propyl, or butyl); (6l)R 1 is selected from the group consisting of unsubstituted C1-C8 alkyl, unsubstituted C1-C8 alkenyl, and unsubstituted C1-C8 alkynyl (e.g., methyl, ethyl, propyl, butenyl, or butyl); (6m)R 1 are 1-5 R 1E cycloalkyl or heterocycloalkyl (e.g., cyclobutyl, cyclopentyl, cyclohexyl, or cycloheptyl), substituted with, for example, 1-5 alkyl groups; (6n)R 1 is any 1-5 R 1E is a cycloalkyl substituted with (6o)R 1 is hydrogen, optionally substituted C1-C8 alkyl, or optionally 1-5 R 1Eis a cycloalkyl substituted with (6p)R 1 is hydrogen or optionally substituted C1-C6 alkyl (e.g., ethyl, propyl, or butyl). In certain such embodiments, R 1 (R 1E Each optionally substituted alkyl, alkenyl, and alkynyl in (including those in) can be unsubstituted or fluorinated. For example, in certain such embodiments, R 1 (R 1E Each optionally substituted alkyl, alkenyl, and alkynyl in (including those in) is unsubstituted.

[0066] In certain embodiments otherwise described herein, A 1A is selected from one of the following groups (7e) to (7h): (7e)A 1A is a bond, -C(O)-, -S-, -S(O) 1-2 -, -O-, -NR 6 -, -C(O)NR 6 -, -NR 6 selected from the group consisting of -C(O)-, and -C(O)O-; (7f)A 1A is a bond, (7g)A 1A -C(O)-, -S-, -S(O) 1-2 -, -O-, and -NR 6 - selected from the group consisting of (7h)A 1A is O.

[0067] In certain embodiments otherwise described herein, L 1B is selected from one of the following groups (8d) to (8f): (8d)L 1B is selected from a bond and optionally substituted C1-C4 alkylene; (8e)L 1B is a bond, (8f)L 1B is unsubstituted C1-C4 alkylene. In certain such embodiments, L 1B and each optionally substituted alkylene is unsubstituted or fluorinated. For example, in certain such embodiments, L 1B wherein each optionally substituted alkylene is unsubstituted.

[0068] In certain embodiments otherwise described herein, A 1B is selected from one of the following groups (9g) to (9l): (9g)A 1B -C(O)-, -S-, -S(O) 1―2 -, -O-, -NR 6 -, -C(O)NR 6 -, -NR 6 is selected from the group consisting of -C(O)-, -OC(O)-, and -C(O)O-; (9h)A 1B -C(O)-, -S-, -S(O) 1―2 is selected from the group consisting of -, -O-, and -C(O)O-; (9i)A 1B is -S-, (9j)A 1B is selected from —C(O)—, —S(O)—, —S(O)2—, —OC(O)—, and —C(O)O—; (9k)A 1B is -O-, (9l)A 1B is a bond.

[0069] In certain embodiments otherwise described herein, L 1A is selected from one of the following groups (10k) to (10m): (10k)L 1A is selected from a bond and optionally substituted C1-C4 alkylene; (10l)L 1A is a bond, (10m)L 1A is an optionally substituted C1-C4 alkylene. In certain such embodiments, L 1Aand each optionally substituted alkylene is unsubstituted or fluorinated. For example, in certain such embodiments, L 1A wherein each optionally substituted alkylene is unsubstituted.

[0070] In certain embodiments otherwise described herein, A 1A -L 1A -A 1B -L 1B (i.e., -L 1 -) is selected from one of the following groups (10n) to (10v): (10n)A 1A -L 1A -A 1B -L 1B [In the formula, A 1A is a bond, -C(O)-, -S-, -S(O) 1-2 -, -O-, -NR 6 -, -C(O)NR 6 -, -NR 6 C(O)-, -C(S)NR 6 -, -NR 6 C(S)-, -C(O)O-, -OC(O)-, -C(O)S-, -SC(O)-, -C(S)O-, -OC(S)-, -C(S)S-, -SC(S)-, -S(O) 1-2 O-, -OS(O) 1-2 -, -S(O) 1―2 NR 6 - and -NR 6 S(O) 1-2 - selected from the group consisting of L 1A is selected from the group consisting of a bond, unsubstituted C1-C4 alkylene, unsubstituted C1-C4 alkenylene, and unsubstituted C1-C4 alkynylene; A 1B is a bond, -C(O)-, -S-, -S(O) 1―2 -, -O-, -NR 6 -, -C(O)NR 6 -, -NR 6 C(O)-, -C(S)NR 6 -, -NR 6C(S)-, -C(O)O-, -OC(O)-, -C(O)S-, -SC(O)-, -C(S)O-, -OC(S)-, -C(S)S-, -SC(S)-, -S(O) 1―2 O-, -OS(O) 1―2 -, -S(O) 1―2 NR 6 - and -NR 6 S(O) 1―2 - selected from the group consisting of L 1B is a bond.]; (10o)A 1A -L 1A -A 1B -L 1B [In the formula, A 1A , L 1A , and L 1B is a bond, and A 1B is as defined in formula (I) or (10n); (10p)A 1A -L 1A -A 1B -L 1B is a bond, optionally substituted C1-C4 alkylene, -C(O)-, -S-, -S(O) 1―2 -, -O-, and -NR 6 - selected from (10q)A 1A -L 1A -A 1B -L 1B is a bond, -CH2-, -CH(CH3)-, -CH2CH2-, -C(O)-, -S-, -S(O) 1―2 -, -O-, and -NR 6 - selected from (10r)A 1A -L 1A -A 1B -L 1B is -O- or -S-. (10s)A 1A -L 1A -A 1B -L 1B is unsubstituted C1-C4 alkylene; (10t)A 1A -L 1A -A 1B -L 1Bis selected from —C(O)—, —S(O)—, and —S(O)—; (10u)A 1A -L 1A -A 1B -L 1B is selected from —CH—, —CH(CH)—, and —CHCH—; (10v)A 1A -L 1A -A 1B -L 1B is a bond. In certain such embodiments, A 1A -L 1A -A 1B -L 1B and optionally substituted alkyl, alkylene, alkenyl, alkenylene, alkynyl, and alkynylene (R 6 (including those of the formula:) is unsubstituted or fluorinated. For example, in certain such embodiments, A 1A -L 1A -A 1B -L 1B and optionally substituted alkyl, alkylene, alkenyl, alkenylene, alkynyl, and alkynylene (R 6 (including those of the formula ##STR1##) are unsubstituted.

[0071] In certain embodiments otherwise described herein, L 2 is selected from one of the following groups (11e) to (11h): (11e)L 2 is selected from a bond and optionally substituted C1-C4 alkylene; (11f)L 2 is selected from unsubstituted C1-C4 alkylene; (11g)L 2 is a bond, -CH2-, -CH(CH3)-, or -CH2CH2, (11h)L 2 is a bond. In certain such embodiments, L 2and each optionally substituted alkylene is unsubstituted or fluorinated. For example, in certain such embodiments, L 2 wherein each optionally substituted alkylene is unsubstituted.

[0072] In certain embodiments as otherwise described herein, Q is selected from one of the following groups (12k)-(12t): (12k)Q is -CH2OH, -C(O)OH, -C(O)OR 2A , -C(O)NR 2B R 2A , -C(O)NR 2B S(O)2R 2A , -C(O)NR 2B S(O)NR 2B R 2A , -C(O)R 2A , -S(O)2OH, -P(O)(OH)2, -C(OH)(CF3)2, S(O)2R 2A , -N(R 2B )S(O)2R 2A , -S(O)NR 2B R 2A , -C(O)NH-O(C1-C3 alkyl), -C(O)NHOH, -CO(NH)CN, [ka] is selected from the group consisting of (12l) Q is -C(O)OH, -C(O)OR 2A , -C(O)NR 2B R 2A , -C(O)NR 2B S(O)2R 2A , -C(O)NR 2B S(O)NR 2B R 2A , -C(O)R 2A , -S(O)2OH, -P(O)(OH)2, -C(OH)(CF3)2, S(O)2R 2A , -S(O)NR 2B R 2A , -C(O)NHOH, -CO(NH)CN, [ka] is selected from the group consisting of (12m)Q is -CH2OH, -C(O)OH, -C(O)OR 2A , -C(O)NR 2B R 2A , -C(O)R 2A , -S(O)2OH, -P(O)(OH)2, -S(O)2R 2A , -S(O)NR 2B R 2A and —C(O)NHOH; (12n)Q is -C(O)OH, -C(O)OR 2A , and -C(O)NR 2B R 2A is selected from (12o) Q is selected from —C(O)OH and —C(O)O(C1-C3 alkyl); (12p) Q is -C(O)OH, (12q) Q is —C(O)O(C1-C3 alkyl), (12r)Q is -C(O)NR 2B R 2A [In the formula, R 2A is C1-C3 alkyl, C1-C3 hydroxyalkyl, C1-C3 aminoalkyl, or C1-C3 thioalkyl, and R 2B is H or C1-C3 alkyl; (12s)Q is -C(O)NR 2B R 2A [In the formula, R 2A and R 2B which together with the nitrogen to which they are both directly attached form a heterocycloalkyl optionally substituted with 1 to 3 substituents selected from C1-C3 alkyl, C1-C3 fluoroalkyl, hydroxyl, amino, thio, C1-C3 hydroxyalkyl, C1-C3 aminoalkyl, C1-C3 thioalkyl, and —C(O)C1-C3 alkyl; (12t)Q is -C(O)NR 2B R 2A [In the formula, R 2A -S(O) 1-2 (C1-C3 alkyl), -S(O)1-2 (C1-C3 fluoroalkyl), or heteroaryl optionally substituted with 1-2 groups selected from substituents selected from C1-C3 alkyl, C1-C3 fluoroalkyl, hydroxyl, amino, thio, C1-C3 hydroxyalkyl, C1-C3 aminoalkyl, C1-C3 thioalkyl, and —C(O)C1-C3 alkyl; R 2B is H or C1-C3 alkyl.

[0073] In certain embodiments otherwise described herein, L 3 is selected from one of the following groups (13j) to (13r): (13j)L 3 is a bond (i.e., L 3 Ha-L 3A -A 3A -[wherein, A 3A and L 3A are bonds], or L 3 -A 3B -L 3B -[wherein, A 3B and L 3B and both of L are bonds), and optionally substituted C1-C4 alkylene (e.g., L 3 Ha-L 3A -A 3A [In the formula, A 3A is a bond and L 3A is an optionally substituted C1-C4 alkylene; (13k)L 3 is a bond, (13l)L 3 is an optionally substituted C1-C4 alkylene (e.g., A 3A is a bond and L 3A is an optionally substituted C1-C4 alkylene; (13m)L 3 Ha-L 3A -A 3A -[wherein, A 3A is a bond and L 3Ais an optionally substituted C1-C4 alkylene, an optionally substituted C1-C4 alkenylene, or an optionally substituted C1-C4 alkynylene; (13n)L 3 is unsubstituted C1-C4 alkylene; (13o)L 3 is a C1-C3 alkylene optionally substituted with hydroxyl; (13p)L 3 -C(O)-, -S-, -S(O) 1―2 -, -O-, -NR 6 - and (13q)L 3 is —CH—, —CH(CH)—, —CHCH—, —CH(CH)(OH)—, or —CH(OH)—; (13r)L 3 is selected from —CH—, —CH(CH)—, and —CHCH—. In certain such embodiments, L 3 and optionally substituted alkyl, alkylene, alkenyl, alkenylene, alkynyl, and alkynylene (R 6 (including those of the formula:) is unsubstituted or fluorinated. For example, in certain such embodiments, L 3 and optionally substituted alkyl, alkylene, alkenyl, alkenylene, alkynyl, and alkynylene (R 6 (including those of the formula ##STR1##) are unsubstituted.

[0074] In certain embodiments otherwise described herein, R 3 is selected from one of the following groups (14l) to (14v): (14l)R 3 are (i)-L 3C -(1-5 R 3D aryl optionally substituted with -L 3C -(1-5 R 3D heteroaryl optionally substituted with 3C -(1-5 R 3E cycloalkyl optionally substituted with -L3C -(1-5 R 3E (ii) 1-5 R 3E is aryl or heteroaryl optionally substituted with (14m)R 3 is 1-5 R 3E aryl (e.g., phenyl, benzodioxole, or dihydro-1H-isoquinoline) optionally substituted with (14n)R 3 is (i)-L 3C -(1-5 R 3D aryl optionally substituted with -L 3C -(1-5 R 3D heteroaryl optionally substituted with 3C -(1-5 R 3E cycloalkyl optionally substituted with -L 3C -(1-5 R 3E (ii) 1-5 R 3E aryl (e.g., phenyl, benzodioxole, or dihydro-1H-isoquinoline), optionally substituted with (14o)R 3 is (i))-L 3C -(1-5 R 3D phenyl optionally substituted with -L 3C -(1-5 R 3D monocyclic heteroaryl optionally substituted with 3C -(1-5 R 3E monocyclic cycloalkyl optionally substituted with 3C -(1-5 R 3E and (ii) 1-5 R 3E aryl (e.g., phenyl, benzodioxole, or dihydro-1H-isoquinoline), optionally substituted with (14p)R 3is as defined in (14k) to (14n), and in the formula, aryl is any of R 3E is not replaced by (14q)R 3 is any 1-5 R 3E heteroaryl (e.g., isothiazole, pyridone, thiadiazole, pyrazine, pyrazolopyrimidine, pyrazolopyridine, imidazole, benzofuran, indole, imidazopyridine, pyridine, pyrazole, isoxazole, triazolopyridine, benzimidazole, thiophene, benzothiophene, furan, or pyrimidine) substituted with (14r)R 3 is (i)-L 3C -(1-5 R 3D aryl optionally substituted with -L 3C -(1-5 R 3D heteroaryl optionally substituted with 3C -(1-5 R 3E cycloalkyl optionally substituted with -L 3C -(1-5 R 3E and (ii) 1-5 R 3E heteroaryl (e.g., isothiazole, pyridone, thiadiazole, pyrazine, pyrazolopyrimidine, pyrazolopyridine, imidazole, benzofuran, indole, imidazopyridine, pyridine, pyrazole, isoxazole, triazolopyridine, benzimidazole, thiophene, benzothiophene, furan, or pyrimidine), optionally substituted with (14s)R 3 is (i)-L 3C -(1-5 R 3D phenyl optionally substituted with -L 3C -(1-5 R 3D monocyclic heteroaryl optionally substituted with 3C -(1-5 R 3E monocyclic cycloalkyl optionally substituted with 3C -(1-5 R 3Eand (ii) 1-5 R 3E heteroaryl (e.g., isothiazole, pyridone, thiadiazole, pyrazine, pyrazolopyrimidine, pyrazolopyridine, imidazole, benzofuran, indole, imidazopyridine, pyridine, pyrazole, isoxazole, triazolopyridine, benzimidazole, thiophene, benzothiophene, furan, or pyrimidine), optionally substituted with (14t)R 3 is as defined in (14p) to (14r), wherein heteroaryl is any of R 3E is not replaced by (14u)R 3 are (i)-L 3C -(1-5 R 3D aryl optionally substituted with -L 3C -(1-5 R 3D heteroaryl optionally substituted with 3C -(1-5 R 3E cycloalkyl optionally substituted with -L 3C -(1-5 R 3E (ii) 1-5 R 3E selected from the group consisting of phenyl, benzodioxolyl, dihydro-1H-isoquinolinyl, imidazolyl, oxazolyl, isoxazolyl, isothiazolyl, thiazolyl, pyridinyl, and pyrazinyl, pyridonyl, thiadiazolyl, pyrazolopyrimidinyl, pyrazolopyridinyl, benzofuranyl, indolyl, imidazopyridinyl, pyrazolyl, triazopyridinyl, benzimidazolyl, benzimidazolyl, thienyl, benzothienyl, furanyl, and pyrimidinyl optionally substituted with (14v)R 3 1-5 R 3E and monocyclic heteroaryl (eg, pyridyl, pyrazolyl), optionally substituted with . In certain such embodiments, R 3 (R 3D and R 3E Each optionally substituted alkyl, alkenyl, and alkynyl in (including those in) can be unsubstituted or fluorinated. For example, in certain such embodiments, R 3 (R 3D and R 3E Each optionally substituted alkyl, alkenyl, and alkynyl in (including those in) is unsubstituted.

[0075] In certain embodiments otherwise described herein, R 4 is selected from one of the following groups (15l) to (15y): (15l)R 4 is selected from hydrogen, optionally substituted C1-C8 alkyl, optionally substituted C1-C8 alkenyl, and optionally substituted C1-C8 alkynyl; (15m)R 4 is selected from hydrogen, unsubstituted C1-C8 alkyl, unsubstituted C1-C8 alkenyl, and unsubstituted C1-C8 alkynyl; (15n)R 4 is selected from hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 alkenyl, and optionally substituted C1-C6 alkynyl; (15o)R 4 is an optionally substituted C1-C8 alkyl, an optionally substituted C1-C8 alkenyl, or an optionally substituted C1-C8 alkynyl; (15p)R 4 is hydrogen, unsubstituted C1-C6 alkyl, optionally substituted C1-C8 alkenyl, and optionally substituted C1-C8 alkynyl. (15q)R 4 is selected from hydrogen, unsubstituted C1-C6 alkyl, unsubstituted C1-C6 alkenyl, and unsubstituted C1-C6 alkynyl (e.g., methyl, ethyl, propyl, butyl, or pentyl); (15r)R 4 is hydrogen or optionally substituted C1-C6 alkyl; (15s)R4 is hydrogen or unsubstituted C1-C6 alkyl; (15t)R 4 is hydrogen or optionally substituted C1-C3 alkyl; (15u)R 4 is hydrogen or unsubstituted C1-C3 alkyl; (15v)R 4 is an optionally substituted C1-C3 alkyl; (15w)R 4 is unsubstituted C1-C3 alkyl, (15x)R 4 is methyl, (15y)R 4 is hydrogen.

[0076] In certain embodiments otherwise described herein, A 4A is selected from one of the following groups (16e) to (16h): (16e)A 4A is a bond, -C(O)-, -S-, -S(O) 1―2 -, -O-, -NR 6 -, -C(O)NR 6 -, -NR 6 selected from the group consisting of -C(O)-, and -C(O)O-; (16f)A 4A is a bond, (16g)A 4A -C(O)-, -S-, -S(O) 1―2 -, -O-, and -NR 6 - selected from the group consisting of (16h)A 4A is -O-.

[0077] In certain embodiments otherwise described herein, L 4B is selected from one of the following groups (17d) to (17f): (17d)L 4B is selected from a bond, and optionally substituted C1-C4 alkylene; (17e)L 4B is a bond, (17f)L4B is an optionally substituted C1-C4 alkylene. In certain such embodiments, L 4B and each optionally substituted alkylene is unsubstituted or fluorinated. For example, in certain such embodiments, L 4B wherein each optionally substituted alkylene is unsubstituted.

[0078] In certain embodiments otherwise described herein, A 4B is selected from one of the following groups (18h) to (18n): (18h)A 4A is a bond, -C(O)-, -S-, -S(O) 1―2 -, -O-, -NR 6 -, -C(O)NR 6 -, -NR 6 is selected from the group consisting of -C(O)-, -OC(O)-, and -C(O)O-; (18i)A 4A -C(O)-, -S-, -S(O) 1―2 -, -O-, -NR 6 -, -C(O)NR 6 -, -NR 6 is selected from the group consisting of -C(O)-, -OC(O)-, and -C(O)O-; (18j)A 4A -C(O)-, -S-, -S(O) 1―2 is selected from the group consisting of -, -O-, and -C(O)O-; (18k)A 4A Ha-NR 6 -, -C(O)NR 6 - and -NR 6 C(O)-, (18l)A 4A is selected from —C(O)—, —OC(O)—, and —C(O)O—; (18m)A 4A is a bond, (18n)A 4A is -O-.

[0079] In certain embodiments otherwise described herein, L 4A is selected from one of the following groups (19k) to (19m): (19k)L 4A is selected from a bond, and optionally substituted C1-C4 alkylene; (19l)L 4A is a bond, (19m)L 4A is an optionally substituted C1-C4 alkylene. In certain such embodiments, L 4A and each optionally substituted alkylene is unsubstituted or fluorinated. For example, in certain such embodiments, L 4A wherein each optionally substituted alkylene is unsubstituted.

[0080] In certain embodiments otherwise described herein, L 4B -A 4B -L 4A -A 4A is selected from one of the following groups (19n) to (19v): (19n)L 4B -A 4B -L 4A -A 4A [In the formula, A 4A is a bond, -C(O)-, -S-, -S(O) 1―2 -, -O-, -NR 6 -, -C(O)NR 6 -, -NR 6 C(O)-, -C(S)NR 6 -, -NR 6 C(S)-, -C(O)O-, -OC(O)-, -C(O)S-, -SC(O)-, -C(S)O-, -OC(S)-, -C(S)S-, -SC(S)-, -S(O) 1―2 O-, -OS(O) 1―2 -, -S(O) 1―2 NR 6 - and -NR 6 S(O) 1―2 - selected from the group consisting of L 4Ais selected from the group consisting of a bond, unsubstituted C1-C4 alkylene, unsubstituted C1-C4 alkenylene, and unsubstituted C1-C4 alkynylene; A 4B is a bond, -C(O)-, -S-, -S(O) 1―2 -, -O-, -NR 6 -, -C(O)NR 6 -, -NR 6 C(O)-, -C(S)NR 6 -, -NR 6 C(S)-, -C(O)O-, -OC(O)-, -C(O)S-, -SC(O)-, -C(S)O-, -OC(S)-, -C(S)S-, -SC(S)-, -S(O) 1―2 O-, -OS(O) 1―2 -, -S(O) 1―2 NR 6 - and -NR 6 S(O) 1―2 - selected from the group consisting of L 4B is a bond.]; (19o)L 4B -A 4B -L 4A -A 4A [In the formula, in the formula, A 4A , L 4A , and L 4B is a bond, and A 4B is as defined in formula (I) or (19n)], (19p)L 4B -A 4B -L 4A -A 4A is a bond, optionally substituted C1-C4 alkylene, -C(O)-, -S-, -S(O) 1―2 -, -O-, and -NR 6 - selected from (19q)L 4B -A 4B -L 4A -A 4A is a bond, -CH2-, -CH(CH3)-, -CH2CH2-, -C(O)-, -S-, -S(O) 1―2 -, -O-, and -NR 6 - selected from (e.g., a bond), (19r)L 4B -A 4B -L4A -A 4A is -O- or -S-, (19s)L 4B -A 4B -L 4A -A 4A is unsubstituted C1-C4 alkylene; (19t)L 4B -A 4B -L 4A -A 4A is selected from —C(O)—, —S(O)—, and —S(O)—; (19u)L 4B -A 4B -L 4A -A 4A is selected from —CH—, —CH(CH)—, and —CHCH—; (19v)L 4B -A 4B -L 4A -A 4A is a bond. In certain such embodiments, L 4B -A 4B -L 4A -A 4A and optionally substituted alkyl, alkylene, alkenyl, alkenylene, alkynyl, and alkynylene (R 6 (including those of the formula:) is unsubstituted or fluorinated. For example, in certain such embodiments, L 4B -A 4B -L 4A -A 4A and optionally substituted alkyl, alkylene, alkenyl, alkenylene, alkynyl, and alkynylene (R 6 (including those of the formula ##STR1##) are unsubstituted.

[0081] In certain embodiments otherwise described herein, L 5 is selected from one of the following groups (20g) to (20l): (20g)L 5 is a bond (i.e., L 5 Ha-L 5A -A 5A -[wherein, A 5A and L5A are bonds], or L 5 -A 5B -L 5B -[wherein, A 5B and L 5B and both of L are bonds), and optionally substituted C1-C4 alkylene (e.g., L 5 Ha-L 5A -A 5A [In the formula, A 5A is a bond and L 5A is an optionally substituted C1-C4 alkylene; (20h)L 5 is a bond (e.g., A 5A and L 5A are bonds), (20i)L 5 -C(O)-, -S-, -S(O) 1―2 -, -O-, and -NR 6 - selected from the group consisting of (20j)L 5 is a bond, -CH2-, -CH(CH3)-, -CH2CH2-, -CH=CH-, -C≡C-, -C(O)-, -S-, -S(O) 1―2 selected from the group consisting of -, -O-, and -C(O)O- (e.g., a bond); (20k)L 5 is selected from -S- and -O-; (20l)L 5 -C(O)-, -S(O) 1―2 -, and -C(O)O-. In certain such embodiments, L 5 and optionally substituted alkyl, alkylene, alkenyl, alkenylene, alkynyl, and alkynylene (R 6 (including those of the formula:) is unsubstituted or fluorinated. For example, in certain such embodiments, L 5 and optionally substituted alkyl, alkylene, alkenyl, alkenylene, alkynyl, and alkynylene (R 6 (including those of the formula ##STR1##) are unsubstituted.

[0082] In certain embodiments otherwise described herein, R 5 is selected from one of the following groups (21h) to (21n): (21h)R 5 are (i)-L 5C -(1-5 R 5D aryl optionally substituted with -L 5C -(1-5 R 5D heteroaryl optionally substituted with -L 5C -(1-5 R 5E cycloalkyl optionally substituted with -L 5C -(1-5 R 5E (ii) 1-5 R 5E aryl (e.g., phenyl) optionally substituted with (21i)R 5 1-5 R 5E aryl (e.g., phenyl) optionally substituted with (21j)R 5 1-5 R 5E [In the formula, each R 5E is optionally substituted C1-C4 alkyl, C1-C4 fluoroalkyl, halogen, -OR 5F , and -NR 5G R 5F phenyl optionally substituted with (21k)R 5 is (i)-L 5C -(1-5 R 5D aryl optionally substituted with -L 5C -(1-5 R 5D heteroaryl optionally substituted with 5C -(1-5 R 5E cycloalkyl optionally substituted with -L 5C -(1-5 R 5E (heterocycloalkyl optionally substituted with 5Eheteroaryl (e.g., isoxazolyl, pyridyl, imidazopyridyl, pyrazolyl, benzoxazole, indolyl, pyrimidinyl), optionally substituted with (21l)R 5 1-5 R 5E heteroaryl (e.g., isoxazolyl, pyridyl, imidazopyridyl, pyrazolyl) optionally substituted with (21m)R 5 are (i)-L 5C -(1-5 R 5D aryl optionally substituted with -L 5C -(1-5 R 5D heteroaryl optionally substituted with 5C -(1-5 R 5E cycloalkyl optionally substituted with -L 5C -(1-5 R 5E (ii) 1-5 R 5E phenyl, isoxazolyl, pyridyl, imidazopyridyl, and pyrazolyl, optionally substituted with (21n)R 5 Each contains 1-5 R 5E isoxazolyl, pyridyl, imidazopyridyl, and pyrazolyl optionally substituted with In certain such embodiments, R 5 (R 5D and R 5E Each optionally substituted alkyl, alkenyl, and alkynyl in (including those in) can be unsubstituted or fluorinated. For example, in certain such embodiments, R 5 (R 5D and R 5E Each optionally substituted alkyl, alkenyl, and alkynyl in (including those in) is unsubstituted.

[0083] In certain embodiments, the therapeutic compound is of any of the following formulas (Ik), (Im), (In), or (Io): [ka] [In formula (Ik), the ring system represented by "a" is a heterocyclic aromatic compound], [ka] [In formula (Im), the ring system represented by "a" is a heterocyclic aromatic compound], [ka] These are optionally in the form of a pharmaceutically acceptable salt or N-oxide, or solvate or hydrate, wherein L 1 is a bond, -C(O)-, -S-, -S(O) 1-2 -, -O-, -NR 6 -, -C(O)NR 6 -, -NR 6 C(O)-, -C(S)NR 6 -, -NR 6 C(S)-, -C(O)O-, -OC(O)-, -C(O)S-, -SC(O)-, -C(S)O-, -OC(S)-, -C(S)S-, -SC(S)-, -S(O) 1-2 O-, -OS(O) 1-2 -, -S(O) 1―2 NR 6 - and -NR 6 S(O) 1-2 - selected from the group consisting of R 1 teeth hydrogen, C1-C8 alkyl, C1-C8 alkenyl, and C1-C8 alkynyl, each of which is unsubstituted or fluorinated; Optionally, 1-2 R 1E cycloalkyl and heterocycloalkyl substituted with Each of them can be any of 1-5 R 1E and wherein the aryl and heteroaryl are selected from the group consisting of aryl and heteroaryl substituted with During the ceremony, Each R 1Eis oxo, optionally substituted C1-C4 alkyl, C1-C4 fluoroalkyl, halogen, -CN, SF5, -N3, -C(O)R 1F , -SR 1F , -S(O) 1―2 R 1F , -OR 1F , -NR 1G R 1F , and -C(O)R 1F are independently selected from Each R 1F are independently selected from H, C1-C3 alkyl, and C1-C3 fluoroalkyl; Each R 1G are independently selected from H and C1-C3 alkyl, or Or, A 1A , L 1A , A 1B , A 1B , and R 1 does not exist, L 2 is selected from the group consisting of a bond, —CH—, —CH(CH)—, or —CHCH—; Q is -H, -CH2OH, -C(O)OH, -C(O)OR 2A , -C(O)NR 2B R 2A , -C(O)NR 2B S(O)2R 2A , -C(O)NR 2B S(O)NR 2B R 2A , -C(O)R 2A , -S(O)2OH, -P(O)(OH)2, -C(OH)(CF3)2, S(O)2R 2A , -N(R 2B )S(O)2R 2A , -S(O)NR 2B R 2A , —C(O)NHOH, —C(O)NH—O(C1-C3 alkyl), and —CO(NH)CN, wherein Each R 2A are independently selected from H and C1-C3 alkyl; Each R 2B are independently selected from H and C1-C3 alkyl; L3 is a bond, bond, -C(O)-, -S-, -S(O) 1―2 -, -O-, -NR 6 -, -CH2-, -CH(CH3)(OH)-, or -CH(OH); R 3 are (i)-L 3C -(1-5 R 3D aryl optionally substituted with -L 3C -(1-5 R 3D heteroaryl optionally substituted with 3C -(1-5 R 3E cycloalkyl optionally substituted with -L 3C -(1-5 R 3E (ii) 1-5 R 3E is aryl or heteroaryl optionally substituted with During the ceremony, Each L 3C is a bond, methylene, ethylene, -C(O)-, -S-, -S(O) 1―2 -, -O-, or -NR 3G - and Each R 3D is optionally substituted C1-C4 alkyl, C1-C4 fluoroalkyl, halogen, -CN, SF5, -N3, -C(O)R 3F , -SR 3F , -S(O) 1―2 R 3F , -OR 3F , -NR 3G R 3F , -C(O)R 3F , -C(O)NR 3G R 3F , -NR 3G C(O)R 3F , -C(S)NR 3G R 3F , -NR 3G C(S)R 3F , -C(O)OR 3F , -OC(O)R 3F , -C(O)SR 3F , -SC(O)R 3F , -C(S)OR3F , -OC(S)R 3F , -C(S)SR 3F , -SC(S)R 3F , -S(O) 1―2 OR 3F , -OS(O) 1―2 R 3F , -S(O) 1―2 NR 3G R 3F , and -NR 3G S(O) 1―2 R 3F are independently selected from Each R 3E is oxo, optionally substituted C1-C4 alkyl, C1-C4 fluoroalkyl, halogen, -CN, SF5, -N3, -C(O)R 3F , -SR 3F , -S(O) 1―2 R 3F , -OR 3F , -NR 3G R 3F , -C(O)R 3F , -C(O)NR 3G R 3F , -NR 3G C(O)R 3F , -C(S)NR 3G R 3F , -NR 3G C(S)R 3F , -C(O)OR 3F , -OC(O)R 3F , -C(O)SR 3F , -SC(O)R 3F , -C(S)OR 3F , -OC(S)R 3F , -C(S)SR 3F , -SC(S)R 3F , -S(O) 1―2 OR 3F , -OS(O) 1―2 R 3F , -S(O) 1―2 NR 3G R 3F , -NR 3G S(O) 1―2 R 3F are independently selected from Each R 3Fare independently selected from H, C1-C3 alkyl, and C1-C3 fluoroalkyl; Each R 3G are independently selected from H, C1-C3 alkyl, and C1-C3 fluoroalkyl; L 4 is a bond, -C(O)-, -S-, -S(O) 1―2 -, -O-, -NR 6 -, -C(O)NR 6 -, -NR 6 C(O)-, -C(S)NR 6 -, -NR 6 C(S)-, -C(O)O-, -OC(O)-, -C(O)S-, -SC(O)-, -C(S)O-, -OC(S)-, -C(S)S-, -SC(S)-, -S(O) 1―2 O-, -OS(O) 1―2 -, -S(O) 1―2 NR 6 - and -NR 6 S(O) 1―2 - selected from the group consisting of R 4 is selected from the group consisting of hydrogen, optionally substituted C1-C8 alkyl, optionally substituted C1-C8 alkenyl, and optionally substituted C1-C8 alkynyl; L 5 is a bond, -C(O)-, -S-, -S(O) 1―2 -, -O-, -NR 6 -, -CHCH-, -CH=CH-, -C≡C-, -CH-, -CH(CH)(OH)-, or -CH(OH)-; R 5 Each contains 1-5 R 5E aryl, heteroaryl, cycloalkyl, or heterocycloalkyl optionally substituted with During the ceremony, Each R 5E is oxo, optionally substituted C1-C4 alkyl, C1-C4 fluoroalkyl, halogen, -CN, -SF5, -N3, -C(O)R 5F , -SR 5F , -S(O) 1-2 R 5F , -OR 5F , -NR5G R 5F , -C(O)R 5F , -C(O)NR 5G R 5F , -NR 5G C(O)R 5F , -C(S)NR 5G R 5F , -NR 1G C(S)R 5F , -C(O)OR 5F , -OC(O)R 5F , -C(O)SR 5F , -SC(O)R 5F , -C(S)OR 5F , -OC(S)R 5F , -C(S)SR 5F , -SC(S)R 5F , -S(O) 1―2 OR 5F , -OS(O) 1―2 R 5F , -S(O) 1―2 NR 5G R 5F , and -NR 5G S(O) 1―2 R 5F are independently selected from Each R 5F are independently selected from H, C1-C3 alkyl, and C1-C3 fluoroalkyl; Each R 5G are independently selected from H and C1-C3 alkyl; Y is CR Y or N [wherein R Y is selected from the group consisting of hydrogen, C1-C3 alkyl, and C1-C3 fluoroalkyl; X 1 is CR XA ,S,O,NRX B and N, X 2 is CR XA ,S,O,NRX B and N, wherein Each R XA are independently selected from the group consisting of hydrogen, C1-C4 alkyl, and C1-C4 fluoroalkyl; Each RXB is hydrogen, C1-C4 alkyl, and C1-C4 fluoroalkyl, C1-C4 alkyl-C(O)-, C1-C4 alkyl-S(O) 1―2 - independently selected from the group consisting of: Z 1 and Z 2 is independently selected from C and N; During the ceremony, Z 1 is N and is attached within the ring system denoted by "A" by a double bond, A 1A , L 1A , A 1B , A 1B , and R 1 does not exist, Each R 6 is selected from the group consisting of hydrogen, C1-C3 alkyl, and —C(O)(C1-C3 alkyl); Each optionally substituted alkyl, alkenyl, and alkynyl is unsubstituted, fluorinated, or substituted with one or two hydroxyl groups. each cycloalkyl has 3-10 ring carbons and is unsaturated or partially unsaturated, and optionally contains one or two fused cycloalkyl rings, each having 3-8 ring members; each heterocycloalkyl has 3-10 ring members and 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and is unsaturated or partially unsaturated, and optionally contains one or two fused cycloalkyl rings, each having 3-8 ring members; each aryl is phenyl or naphthyl, and optionally contains one or two fused cycloalkyl or heterocycloalkyl rings, each having 4-8 ring members; Each heteroaryl is a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or an 8-10 membered bicyclic heteroaryl having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur, and optionally contains one or two fused cycloalkyl or heterocycloalkyl rings, each having 4-8 ring members. In certain such embodiments, each and every optionally substituted alkyl, alkylene, alkenyl, alkenylene, alkynyl, and alkynylene is unsubstituted or fluorinated, e.g., in certain such embodiments, each and every optionally substituted alkyl, alkylene, alkenyl, alkenylene, alkynyl, and alkynylene is unsubstituted.

[0084] The present disclosure provides various subclasses of compounds of any of formulas (1k)-(1o), wherein R 1 , L 1 , L 2 , Q, L 3 , R 3 , L 4 , R 4 , L 5 , and R 5 are optionally independently selected from groups (6q) (see below), (10w) (see below), (11i) (see below), (12u) (see below), (13s) (see below), (14w) (see below), (15z) (see below), (19w) (see below), (20m) (see below), and (21o) (see below), as defined herein below (e.g., where the compound is as defined in any combination of the following embodiments). The definitions of the variables can be made from any combination of groups (6q) (see below), (10w) (see below), (11i) (see below), (12u) (see below), (13s) (see below), (14w) (see below), (15z) (see below), (19w) (see below), (20m) (see below), and (21o) (see below), as defined herein below, that is not theoretically or chemically inconsistent.

[0085] In certain embodiments, the compound has one of the following structural formulas: (Ik); wherein the variables are defined as any combination of groups (6q) (see below), (10w) (see below), (11i) (see below), (12u) (see below), (13s) (see below), (14w) (see below), (15z) (see below), (19w) (see below), (20m) (see below), and (21o) (see below), as defined herein below; (Im); wherein the variables are defined as any combination of groups (6q) (see below), (10w) (see below), (11i) (see below), (12u) (see below), (13s) (see below), (14w) (see below), (15z) (see below), (19w) (see below), (20m) (see below), and (21o) (see below), as defined herein below; (In), wherein the variables are defined as any combination of groups (6q) (see below), (10w) (see below), (11i) (see below), (12u) (see below), (13s) (see below), (14w) (see below), (15z) (see below), (19w) (see below), (20m) (see below), and (21o) (see below), as defined herein below; (Io); wherein the variables are defined as any combination of groups (6q) (see below), (10w) (see below), (11i) (see below), (12u) (see below), (13s) (see below), (14w) (see below), (15z) (see below), (19w) (see below), (20m) (see below), and (21o) (see below), as defined herein below.

[0086] In certain embodiments otherwise described herein, R 1 is selected from one of the following groups (6q) to (6u): (6q)R 1 is hydrogen, optionally substituted C1-C8 alkyl, and 1-5 R 1E cycloalkyl optionally substituted with (6r)R 1 is hydrogen, (6s)R 1 is an optionally substituted C1-C8 alkyl; (6t)R 1 is unsubstituted C1-C8 alkyl or fluorinated C1-C8 alkyl; (6u)R 1 is an unsubstituted cycloalkyl. In certain such embodiments, R 1 (R 1E Each optionally substituted alkyl in (including that in) may be unsubstituted or fluorinated. For example, in certain such embodiments, R 1 (R 1E Each optionally substituted alkyl, alkenyl, and alkynyl in (including those in) is unsubstituted.

[0087] In certain embodiments otherwise described herein, L 1 is selected from one of the following groups (10w) to (10y): (10w)L 1 is a bond, -S-, -S(O)-, or -S(O)2-, (10x)L 1 is a bond, -CH2-, -CH(CH3)-, -CH2CH2-, -C(O)-, -S-, -S(O) 1―2 -, -O-, and -NR 6 - selected from (10y)L 1 is -O- or -S-.

[0088] In certain embodiments otherwise described herein, L 2 is selected from one of the following groups (11i) to (11k): (11i)L 2 is -CH2-, -CH(CH3)-, or -CH2CH2, (11j)L 2 is a bond, (11k)L 2 is a bond or -CH2-.

[0089] In certain embodiments as otherwise described herein, Q is selected from one of the following groups (12u)-(12x): (12u)Q is -CH2OH, -C(O)OH, -C(O)OR 2A , -C(O)NR 2B R 2A , -C(O)NR 2B S(O)2R 2A , -C(O)NR 2B S(O)NR 2B R 2A , -C(O)R 2A , -S(O)2OH, -P(O)(OH)2, -C(OH)(CF3)2, S(O)2R 2A , -N(R 2B )S(O)2R 2A , -S(O)NR 2B R 2A , —C(O)NH—O(C1-C3 alkyl), —C(O)NHOH, and —CO(NH)CN. (12v)Q is -CH2OH, -C(O)OH, -C(O)OR 2A , -C(O)NR 2B R 2A , -C(O)NR 2B S(O)2R 2A , -C(O)NR 2B S(O)NR 2B R 2A , -C(O)R 2A , —S(O)2OH, —P(O)(OH)2. (12w) Q is -CH2OH, -C(O)OH, or -C(O)OR 2A and (12x)Q is -COOH.

[0090] In certain embodiments otherwise described herein, L 3 is selected from one of the following groups (13s) to (13u): (13s)L 3 is a bond, -C(O)-, -S-, -S(O) 1―2 -, -O-, -NR 6 -, -CH2-, -CH(CH3)(OH)-, or -CH(OH); (13t)L 3 is a bond, (13u)L3 is a bond, —CH—, —CH(CH)(OH)—, or —CH(OH)—.

[0091] In certain embodiments otherwise described herein, R 3 is selected from one of the following groups (14w) to (14gg): (14w)R 3 are (i)-L 3C -(1-5 R 3D aryl optionally substituted with -L 3C -(1-5 R 3D heteroaryl optionally substituted with 3C -(1-5 R 3E cycloalkyl optionally substituted with -L 3C -(1-5 R 3E (heterocycloalkyl optionally substituted with 3E is aryl or heteroaryl optionally substituted with (14x)R 3 is 1-5 R 3E aryl (e.g., phenyl, benzodioxole, or dihydro-1H-isoquinoline) optionally substituted with (14y)R 3 is (i)-L 3C -(1-5 R 3D aryl optionally substituted with -L 3C -(1-5 R 3D heteroaryl optionally substituted with 3C -(1-5 R 3E cycloalkyl optionally substituted with -L 3C -(1-5 R 3E and (ii) 1-5 R 3E aryl (e.g., phenyl, benzodioxole, or dihydro-1H-isoquinoline), optionally substituted with (14z)R 3 is (i)-L3C -(1-5 R 3D phenyl optionally substituted with -L 3C -(1-5 R 3D monocyclic heteroaryl optionally substituted with 3C -(1-5 R 3E monocyclic cycloalkyl optionally substituted with 3C -(1-5 R 3E and (ii) 1-5 R 3E aryl (e.g., phenyl, benzodioxole, or dihydro-1H-isoquinoline), optionally substituted with (14aa)R 3 is as defined in (14u) to (14x), and in the formula, aryl is any of R 3E is not replaced by (14bb)R 3 is any 1-5 R 3E heteroaryl (e.g., isothiazole, pyridone, thiadiazole, pyrazine, pyrazolopyrimidine, pyrazolopyridine, imidazole, benzofuran, indole, imidazopyridine, pyridine, pyrazole, isoxazole, triazolopyridine, benzimidazole, thiophene, benzothiophene, furan, or pyrimidine) substituted with (14cc)R 3 is (i)-L 3C -(1-5 R 3D aryl optionally substituted with -L 3C -(1-5 R 3D heteroaryl optionally substituted with 3C -(1-5 R 3E cycloalkyl optionally substituted with -L 3C -(1-5 R 3E and (ii) 1-5 R 3Eheteroaryl (e.g., isothiazole, pyridone, thiadiazole, pyrazine, pyrazolopyrimidine, pyrazolopyridine, imidazole, benzofuran, indole, imidazopyridine, pyridine, pyrazole, isoxazole, triazolopyridine, benzimidazole, thiophene, benzothiophene, furan, or pyrimidine), optionally substituted with (14dd)R 3 is (i)-L 3C -(1-5 R 3D phenyl optionally substituted with -L 3C -(1-5 R 3D monocyclic heteroaryl optionally substituted with 3C -(1-5 R 3E monocyclic cycloalkyl optionally substituted with 3C -(1-5 R 3E and (ii) 1-5 R 3E heteroaryl (e.g., isothiazole, pyridone, thiadiazole, pyrazine, pyrazolopyrimidine, pyrazolopyridine, imidazole, benzofuran, indole, imidazopyridine, pyridine, pyrazole, isoxazole, triazolopyridine, benzimidazole, thiophene, benzothiophene, furan, or pyrimidine), optionally substituted with (14ee)R 3 is as defined in (14z) to (14bb), wherein heteroaryl is any of R 3E is not replaced by (14ff)R 3 are (i)-L 3C -(1-5 R 3D aryl optionally substituted with -L 3C -(1-5 R 3D heteroaryl optionally substituted with 3C -(1-5 R 3E cycloalkyl optionally substituted with -L 3C -(1-5 R 3E(ii) 1-5 R 3E is selected from the group consisting of phenyl, benzodioxolyl, dihydro-1H-isoquinolinyl, imidazolyl, oxazolyl, isoxazolyl, isothiazolyl, thiazolyl, pyridinyl, and pyrazinyl, pyridonyl, thiadiazolyl, pyrazolopyrimidinyl, pyrazolopyridinyl, benzofuranyl, indolyl, imidazopyridinyl, pyrazolyl, triazopyridinyl, benzimidazolyl, benzimidazolyl, thienyl, benzothienyl, furanyl, and pyrimidinyl, optionally substituted with (14gg)R 3 1-5 R 3E and monocyclic heteroaryl (eg, pyridyl, pyrazolyl), optionally substituted with . In certain such embodiments, R 3 (R 3D and R 3E Each optionally substituted alkyl, alkenyl, and alkynyl in (including those in) can be unsubstituted or fluorinated. For example, in certain such embodiments, R 3 (R 3D and R 3E Each optionally substituted alkyl, alkenyl, and alkynyl in (including those in) is unsubstituted.

[0092] In certain embodiments otherwise described herein, R 4 is selected from one of the following groups (15z) to (15cc): (15z)R 4 is hydrogen, (15aa)R 4 is an optionally substituted C1-C8 alkyl, an optionally substituted C1-C8 alkenyl, or an optionally substituted C1-C8 alkynyl; (15bb)R 4 is hydrogen or unsubstituted C1-C6 alkyl; (15cc)R 4 is unsubstituted C1-C3 alkyl. In certain such embodiments, R 4 Each optionally substituted alkyl, alkenyl, and alkynyl in 4 Each optionally substituted alkyl, alkenyl, and alkynyl is unsubstituted.

[0093] In certain embodiments, L 4 is selected from one of the following groups (19w) to (19x): (19w)L 4 is a bond, -C(O)-, -S-, -S(O) 1―2 -, -O-, and -NR 6 - selected from (19x)L 4 is a bond.

[0094] In certain embodiments, L 5 is selected from one of the following groups (20m) to (20n): (20m)L 5 is a bond, -C(O)-, -S-, -S(O) 1―2 -, -O-, -NR 6 -, -CHCH-, -CH-, -CH(CH)(OH)-, or -CH(OH)-; (20n)L 5 is a bond.

[0095] In certain embodiments otherwise described herein, R 5 is selected from one of the following groups (21o) to (21q): (21o)R 5 Each contains 1-5 R 5E aryl (e.g., phenyl) or heteroaryl (e.g., isoxazolyl, pyridyl, imidazopyridyl, pyrazolyl) optionally substituted with (21p)R 5 1-5 R 5E is phenyl optionally substituted with (21q)R 5 Each contains 1-5 R5E isoxazolyl, pyridyl, imidazopyridyl, and pyrazolyl optionally substituted with In certain such embodiments, R 5 (R 5D and R 5E Each optionally substituted alkyl, alkenyl, and alkynyl in (including those in) can be unsubstituted or fluorinated. For example, in certain such embodiments, R 5 (R 5D and R 5E Each optionally substituted alkyl, alkenyl, and alkynyl in (including those in) is unsubstituted.

[0096] In certain additional embodiments, including any of the embodiments described with reference to formulas (I)-(Io) above, each optionally substituted alkylene, alkenylene, and alkynylene recited in any one of the above embodiments is unsubstituted. In alternative additional embodiments, including any of the embodiments described with reference to formulas (I)-(Io) above, each optionally substituted alkylene, alkenylene, and alkynylene recited in any one of the above embodiments is unsubstituted or fluorinated.

[0097] In certain additional embodiments, including any of the embodiments described with reference to formulas (I)-(Io) above and any of the embodiments described in the immediately preceding paragraph, each optionally substituted alkyl, alkenyl, and alkynyl recited in any one of the above embodiments is unsubstituted. In alternative additional embodiments, including any of the embodiments described with reference to formulas (I)-(Io) above and any of the embodiments described in the immediately preceding paragraph, each optionally substituted alkyl, alkenyl, and alkynyl recited in any one of the above embodiments is unsubstituted.

[0098] In certain additional embodiments, including any of the embodiments described with reference to formulas (I)-(Io) above and any of the embodiments described in the two paragraphs immediately preceding, each cycloalkyl recited in any one of the above embodiments is a 3- to 7-membered monocyclic cycloalkyl. For example, in certain specific additional embodiments, including any of the embodiments described with reference to formulas (I)-(Io) above and any of the embodiments described in the two paragraphs immediately preceding, each cycloalkyl recited in any one of the above embodiments is cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, or cyclohexenyl.

[0099] In certain additional embodiments, including any of the embodiments described with reference to formulas (I)-(Io) above and any of the embodiments described in the three paragraphs immediately preceding, each heterocycloalkyl recited in any one of the above embodiments is a 4- to 7-membered monocyclic heterocycloalkyl having 1-2 heteroatoms selected from O, S, and N. For example, in certain specific embodiments, including any of the embodiments described with reference to formulas (I)-(Io) above and any of the embodiments described in the three paragraphs immediately preceding, each heterocycloalkyl recited in any one of the above embodiments is pyrrolidinyl, tetrahydrofuranyl, tetrahydrothienyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, tetrahydro-2H-pyranyl, or tetrahydro-2H-thiopyranyl.

[0100] In certain additional embodiments, including any of the embodiments described with reference to Formulas (I)-(Io) above and any of the embodiments described in the four paragraphs immediately preceding, each heteroaryl is a 5-6 membered monocyclic heteroaryl having 1-3 heteroatoms selected from O, S, and N. For example, in certain specific embodiments, including any of the embodiments described with reference to Formulas (I)-(Io) above and any of the embodiments described in the four paragraphs immediately preceding, each heteroaryl is furanyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, or thiazolyl.

[0101] In certain additional embodiments, including any of the embodiments described with reference to formulas (I)-(Io) above and any of the embodiments described in the four immediately preceding paragraphs, each aryl is phenyl.

[0102] In certain additional embodiments described above, including any of the embodiments described with reference to formulas (I)-(Io) above, and any of the embodiments described in the immediately preceding five paragraphs, R 5 is substituted with one, two, or three substituents selected from halogen (e.g., chloro or fluoro), and fluorinated C1-C3 alkyl (e.g., trifluoromethyl, difluoromethyl, fluoromethyl, pentafluoroethyl, trifluoroethyl). For example, in certain embodiments described above, R 5 is phenyl substituted with one or two substituents selected from trifluoromethyl, fluorine, and chlorine (e.g., trisubstituted, tetrasubstituted, 3,4-disubstituted, 2,4-disubstituted, or 2,5-disubstituted). For example, in certain embodiments, R 5 may be dichlorophenyl, such as 3,4-dichlorophenyl, or trifluoromethylphenyl, such as 4-trifluoromethylphenyl.

[0103] In certain embodiments, the therapeutic compound is one of the compounds in the following Table of Compounds: BJAB cell proliferation data is presented in the table. "A" indicates a measured EC 50 "B" indicates a measured EC value greater than 1 μM and less than or equal to 5 μM. 50 "C" indicates a measured EC value greater than 5 μM and less than or equal to 10 μM. 50 "D" indicates a measured EC value greater than 10 μM and less than or equal to 25 μM. 50 "E" indicates a measured EC value greater than 25 μM and less than or equal to 50 μM. 50 "F" indicates a measured EC greater than 50 μM and less than or equal to 100 μM. 50 "G" indicates a measured EC of 80 μM or less in the experiments performed. 50 "H" indicates that there was no measured EC below 50 μM in the experiments performed.50 "I" indicates that there was no measured EC of 40 μM or less in the experiments performed. 50 "J" indicates that there was no measured EC below 25 µM in the experiments performed. 50 "K" indicates that there was no measured EC below 20 μM in the experiments performed. 50 In certain embodiments, the therapeutic compound is a compound having activity as "A," "B," or "C" in the tables below. In certain embodiments, the therapeutic compound is a compound having activity as "A" or "B" in the tables below. In certain embodiments, the therapeutic compound is a compound having activity as "A" in the tables below.

[0104] [Table 2] JPEG2025016393000019.jpg238170 JPEG2025016393000020.jpg241170 JPEG2025016393000021.jpg240170 JPEG2025016393000022.jpg231170 JPEG2025016393000023.jpg235170 JPEG2025016393000024.jpg230170 JPEG2025016393000025.jpg240170 JPEG2025016393000026.jpg232170 JPEG2025016393000027.jpg240170 JPEG2025016393000028.jpg236170 JPEG2025016393000029.jpg233170 JPEG2025016393000030.jpg239170 JPEG2025016393000031.jpg238170 JPEG2025016393000032.jpg240170 JPEG2025016393000033.jpg240170 JPEG2025016393000034.jpg215170

[0105] And, in certain embodiments, the therapeutic compound is a compound generally described in any class, subclass, or embodiment of International Patent Application Publication No. 2018 / 012453. For example, other suitable therapeutic compounds can include compounds having any of the following formulae (IIa)-(IIe): [ka] These are optionally in the form of a pharmaceutically acceptable salt or N-oxide, and / or solvate or hydrate, wherein L 1 is a bond, -C(O)-, -S-, -S(O) 1-2 -, -O-, -NR 6 -, -C(O)NR 6 -, -NR 6 C(O)-, -C(S)NR 6 -, -NR 6 C(S)-, -C(O)O-, -OC(O)-, -C(O)S-, -SC(O)-, -C(S)O-, -OC(S)-, -C(S)S-, -SC(S)-, -S(O) 1-2 O-, -OS(O) 1-2 -, -S(O) 1―2 NR 6 - and -NR 6 S(O) 1-2 - selected from the group consisting of R 1 teeth hydrogen, C1-C8 alkyl, C1-C8 alkenyl, and C1-C8 alkynyl, each of which is unsubstituted or fluorinated; Optionally, 1-2 R 1E cycloalkyl and heterocycloalkyl substituted with Each of them can be any of 1-5 R 1Eand monocyclic heteroaryl substituted with During the ceremony, Each R 1E is oxo, optionally substituted C1-C4 alkyl, C1-C4 fluoroalkyl, halogen, -CN, SF5, -N3, -C(O)R 1F , -SR 1F , -S(O) 1―2 R 1F , -OR 1F , -(OCH2CH2O) n -R 1G [wherein n is 1 to 4], -N(R 1G )C(O)CH2-O-(CH2CH2O) n R 1G [wherein n is 0 to 3], —C(O)NR 1G (CH2CH2O) n R 1G , -NR 1G R 1F , and -C(O)R 1F are independently selected from Each R 1F are independently selected from H, C1-C3 alkyl, and C1-C3 fluoroalkyl; Each R 1G are independently selected from H and C1-C3 alkyl; L 2 is selected from the group consisting of a bond, —CH—, —CH(CH)—, or —CHCH—; Q is -H, -CH2OH, -C(O)OH, -C(O)OR 2A , -C(O)NR 2B R 2A , -C(O)NR 2B S(O)2R 2A , -C(O)NR 2B S(O)NR 2B R 2A , -C(O)R 2A , -S(O)2OH, -P(O)(OH)2, -C(OH)(CF3)2, S(O)2R 2A , -N(R 2B )S(O)2R 2A , -S(O)NR 2B R 2A, —C(O)NHOH, —C(O)NH—O(C1-C3 alkyl), and —CO(NH)CN, wherein Each R 2A are independently selected from H and C1-C3 alkyl; Each R 2B are independently selected from H and C1-C3 alkyl; L 3 is a bond, -C(O)-, -S-, -S(O) 1―2 -, -O-, -NR 6 -, -CH2-, -CH(CH3)(OH)-, or -CH(OH); R 3 are (i)-L 3C -(1-5 R 3D aryl optionally substituted with -L 3C -(1-5 R 3D heteroaryl optionally substituted with 3C -(1-5 R 3D cycloalkyl optionally substituted with -L 3C -(1-5 R 3D (ii) 1-5 R 3E is aryl or heteroaryl optionally substituted with During the ceremony, Each L 3C is a bond, methylene, ethylene, -C(O)-, -S-, -S(O) 1―2 -, -O-, or -NR 3G - and Each R 3D is oxo, optionally substituted C1-C4 alkyl, C1-C4 fluoroalkyl, halogen, -CN, SF5, -N3, -C(O)R 3F , -SR 3F , -S(O) 1―2 R 3F , -OR 3F , -NR 3G R 3F , -C(O)R 3F , -C(O)NR 3G R 3F , -NR 3G C(O)R3F , -C(S)NR 3G R 3F , -NR 3G C(S)R 3F , -C(O)OR 3F , -OC(O)R 3F , -C(O)SR 3F , -SC(O)R 3F , -C(S)OR 3F , -OC(S)R 3F , -C(S)SR 3F , -SC(S)R 3F , -S(O) 1―2 OR 3F , -OS(O) 1―2 R 3F , -S(O) 1―2 NR 3G R 3F , and -NR 3G S(O) 1―2 R 3F are independently selected from Each R 3E is oxo, optionally substituted C1-C4 alkyl, C1-C4 fluoroalkyl, halogen, -CN, SF5, -N3, -C(O)R 3F , -SR 3F , -S(O) 1―2 R 3F , -OR 3F , -NR 3G R 3F , -C(O)R 3F , -C(O)NR 3G R 3F , -NR 3G C(O)R 3F , -C(S)NR 3G R 3F , -NR 3G C(S)R 3F , -C(O)OR 3F , -OC(O)R 3F , -C(O)SR 3F , -SC(O)R 3F , -C(S)OR 3F , -OC(S)R 3F , -C(S)SR 3F , -SC(S)R 3F , -S(O) 1―2 OR 3F , -OS(O)1―2 R 3F , -S(O) 1―2 NR 3G R 3F , -NR 3G S(O) 1―2 R 3F are independently selected from Each R 3F are independently selected from H, C1-C3 alkyl, and C1-C3 fluoroalkyl; Each R 3G are independently selected from H, C1-C3 alkyl, and C1-C3 fluoroalkyl; L 4 is a bond, -C(O)-, -S-, -S(O) 1―2 -, -O-, -NR 6 -, -C(O)NR 6 -, -NR 6 C(O)-, -C(S)NR 6 -, -NR 6 C(S)-, -C(O)O-, -OC(O)-, -C(O)S-, -SC(O)-, -C(S)O-, -OC(S)-, -C(S)S-, -SC(S)-, -S(O) 1―2 O-, -OS(O) 1―2 -, -S(O) 1―2 NR 6 - and -NR 6 S(O) 1―2 - selected from the group consisting of R 4 is selected from the group consisting of hydrogen, optionally substituted C1-C8 alkyl, optionally substituted C1-C8 alkenyl, and optionally substituted C1-C8 alkynyl; L 5 is a bond, -C(O)-, -S-, -S(O) 1―2 -, -O-, -NR 6 -, -CH2-, -CH=CH-, -C≡C-, -CH2-, -CH(CH3)(OH)-, or -CH(OH)-; R 5 are (i)-L 5C -(1-5 R 5D phenyl optionally substituted with -L 5C -(1-5 R 5Dmonocyclic heteroaryl optionally substituted with 5C -(1-5 R 5D monocyclic cycloalkyl optionally substituted with 5C -(1-5 R 5D and (ii) 1-5 R 5E aryl, heteroaryl, cycloalkyl, or heterocycloalkyl optionally substituted with During the ceremony, Each L 5C is a bond, methylene, ethylene, -C(O)-, -S-, -S(O) 1―2 -, -O-, or -NR 3G - and Each R 5D is oxo, optionally substituted C1-C4 alkyl, C1-C4 fluoroalkyl, halogen, -CN, SF5, -N3, -C(O)R 3F , -SR 3F , -S(O) 1―2 R 3F , -OR 3F , -NR 3G R 3F , -C(O)R 3F , -C(O)NR 3G R 3F , -NR 3G C(O)R 3F , -C(S)NR 3G R 3F , -NR 3G C(S)R 3F , -C(O)OR 3F , -OC(O)R 3F , -C(O)SR 3F , -SC(O)R 3F , -C(S)OR 3F , -OC(S)R 3F , -C(S)SR 3F , -SC(S)R 3F , -S(O) 1―2 OR 3F , -OS(O) 1―2 R 3F , -S(O) 1―2 NR 3G R 3F , and -NR3G S(O) 1―2 R 3F are independently selected from Each R 5E is oxo, optionally substituted C1-C4 alkyl, C1-C4 fluoroalkyl, halogen, -CN, -SF5, -N3, -C(O)R 5F , -SR 5F , -S(O) 1-2 R 5F , -OR 5F , -NR 5G R 5F , -C(O)R 5F , -C(O)NR 5G R 5F , -NR 5G C(O)R 5F , -C(S)NR 5G R 5F , -NR 1G C(S)R 5F , -C(O)OR 5F , -OC(O)R 5F , -C(O)SR 5F , -SC(O)R 5F , -C(S)OR 5F , -OC(S)R 5F , -C(S)SR 5F , -SC(S)R 5F , -S(O) 1―2 OR 5F , -OS(O) 1―2 R 5F , -S(O) 1―2 NR 5G R 5F , and -NR 5G S(O) 1―2 R 5F are independently selected from Each R 5F are independently selected from H, C1-C3 alkyl, and C1-C3 fluoroalkyl; Each R 5G are independently selected from H and C1-C3 alkyl; During the ceremony, Each R 6 is selected from the group consisting of hydrogen, C1-C3 alkyl, and —C(O)(C1-C3 alkyl); Each optionally substituted alkyl, alkenyl, and alkynyl is unsubstituted, fluorinated, or substituted with one or two hydroxyl groups. each cycloalkyl has 3-10 ring carbons and is unsaturated or partially unsaturated, and optionally contains one or two fused cycloalkyl rings, each having 3-8 ring members; each heterocycloalkyl has 3-10 ring members and 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and is unsaturated or partially unsaturated, and optionally contains one or two fused cycloalkyl rings, each having 3-8 ring members; each aryl is phenyl or naphthyl, and optionally contains one or two fused cycloalkyl or heterocycloalkyl rings, each having 4-8 ring members; Each heteroaryl is a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or an 8-10 membered bicyclic heteroaryl having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur, and optionally contains one or two fused cycloalkyl or heterocycloalkyl rings, each having 4-8 ring members. In certain such embodiments, each and every optionally substituted alkyl, alkylene, alkenyl, alkenylene, alkynyl, and alkynylene is unsubstituted or fluorinated, e.g., in certain such embodiments, each and every optionally substituted alkyl, alkylene, alkenyl, alkenylene, alkynyl, and alkynylene is unsubstituted.

[0106] Such therapeutic compounds generally relate to any of the above formulas (IIa), (IIb), (IIc), and (IId), or to various subclasses of compounds [wherein R 1 , L 1 , L 2 , Q, L 3 , R 3 , L 4 , R 4, L 5 , and R 5 is optionally defined by independently selected from groups (ii-1a) (see below), (ii-2a) (see below), (ii-3a) (see below), (ii-4a) (see below), (ii-5a) (see below), (ii-6a) (see below), (ii-7a) (see below), (ii-8a) (see below), (ii-9a) (see below), and (ii-10a) (see below), as defined herein below (e.g., where the compound is of a structural formula defined in any combination of the following embodiments). The definitions of the variables can be made from any combination of groups (ii-1a) (see below), (ii-2a) (see below), (ii-3a) (see below), (ii-4a) (see below), (ii-5a) (see below), (ii-6a) (see below), (ii-7a) (see below), (ii-8a) (see below), (ii-9a) (see below), and (ii-10a) (see below) as defined herein below, that is not theoretically or chemically inconsistent.

[0107] In certain embodiments of the compounds otherwise described herein, the compounds have one of the following structural formulas: (IIa), wherein the variables are as defined in any combination of groups (ii-1a) (see below), (ii-2a) (see below), (ii-3a) (see below), (ii-4a) (see below), (ii-5a) (see below), (ii-6a) (see below), (ii-7a) (see below), (ii-8a) (see below), (ii-9a) (see below), and (ii-10a) (see below), as defined herein below; (IIb) wherein the variables are as defined in any combination of groups (ii-1a) (see below), (ii-2a) (see below), (ii-3a) (see below), (ii-4a) (see below), (ii-5a) (see below), (ii-6a) (see below), (ii-7a) (see below), (ii-8a) (see below), (ii-9a) (see below), and (ii-10a) (see below), as defined herein below; (IIc) wherein the variables are as defined in any combination of groups (ii-1a) (see below), (ii-2a) (see below), (ii-3a) (see below), (ii-4a) (see below), (ii-5a) (see below), (ii-6a) (see below), (ii-7a) (see below), (ii-8a) (see below), (ii-9a) (see below), and (ii-10a) (see below), as defined herein below; (IId) wherein the variables are as defined in any combination of groups (ii-1a) (see below), (ii-2a) (see below), (ii-3a) (see below), (ii-4a) (see below), (ii-5a) (see below), (ii-6a) (see below), (ii-7a) (see below), (ii-8a) (see below), (ii-9a) (see below), and (ii-10a) (see below), as defined herein below; (IIe) wherein the variables are as defined in any combination of groups (ii-1a) (see below), (ii-2a) (see below), (ii-3a) (see below), (ii-4a) (see below), (ii-5a) (see below), (ii-6a) (see below), (ii-7a) (see below), (ii-8a) (see below), (ii-9a) (see below), and (ii-10a) (see below), as defined herein below.

[0108] In certain embodiments of the compounds otherwise described herein, R 1 is selected from one of the following groups (ii-1a) to (ii-1k): (ii-1a)R 1 is hydrogen, optionally substituted C1-C8 alkyl, and 1-5 R 1E cycloalkyl optionally substituted with (ii-1b)R 1 is hydrogen, (ii-1c)R 1 is an optionally substituted C1-C8 alkyl; (ii-1d)R 1 is unsubstituted C1-C8 alkyl or fluorinated C1-C8 alkyl, such as propyl or butyl; (ii-1e)R 1 is unsubstituted cycloalkyl; (ii-1f)R 1 is an optionally substituted C1-C8 alkenyl; (ii-1g)R 1 1-5 R E is phenyl optionally substituted with (ii-1h)R 1 is propyl, butyl, or butenyl; (ii-1i)R 1 is trifluoromethyl-substituted phenyl, methoxy-substituted phenyl, or fluoro-substituted phenyl; (ii-1j)R 1 is -(OCH2CH2O) n -R 1G [wherein n is 1 to 4], -N(R 1G )C(O)CH2-O-(CH2CH2O) n R 1G [wherein n is 0 to 3], or —C(O)NR 1G (CH2CH2O) n R 1G is a phenyl substituted with (ii-1k)R 1 is hydroxymethyl, methoxymethyl, hydroxyethyl, or methoxyethyl. In certain such embodiments, R 1 (R 1E Each optionally substituted alkyl in (including that in) may be unsubstituted or fluorinated. For example, in certain such embodiments, R 1 (R 1E Each optionally substituted alkyl, alkenyl, and alkynyl in (including those in) is unsubstituted.

[0109] In certain embodiments of the compounds otherwise described herein, L 1 is selected from one of the following groups (ii-2a) to (ii-2e): (ii-2a)L 1 is a bond, -S-, -S(O)-, or -S(O)2-, (ii-2b)L 1 is a bond, -CH2-, -CH(CH3)--CH2CH2-, -C(O)-, -S-, -S(O) 1―2 -, -O-, and -NR 6 - selected from (ii-2c)L 1 is -O- or -S-, (ii-2d)L 1 is a bond (e.g., R 1 is (ii-1d), (ii-1f), (ii-1g), (ii-1i), (ii-1j), or (ii-1k) above), (ii-2e)L 1 Ha-NR 6 -It is.

[0110] In certain embodiments of the compounds otherwise described herein, L 2 is selected from one of the following groups (ii-3a) to (ii-3c): (ii-3a)L 2 is -CH2-, -CH(CH3)-, or -CH2CH2, (ii-3b)L 2 is a bond, (ii-3c)L 2 is a bond or -CH2-.

[0111] In certain embodiments of the compounds otherwise described herein, Q is selected from one of the following groups (ii-4a) through (ii-4d): (ii-4a)Q is -CH2OH, -C(O)OH, -C(O)OR 2A , -C(O)NR 2B R 2A , -C(O)NR 2B S(O)2R 2A , -C(O)NR 2B S(O)NR 2B R 2A , -C(O)R 2A , -S(O)2OH, -P(O)(OH)2, -C(OH)(CF3)2, S(O)2R 2A , -N(R 2B )S(O)2R2A , -S(O)NR 2B R 2A , —C(O)NH—O(C1-C3 alkyl), —C(O)NHOH, and —CO(NH)CN; (ii-4b)Q is -CH2OH, -C(O)OH, -C(O)OR 2A , -C(O)NR 2B R 2A , -C(O)NR 2B S(O)2R 2A , -C(O)NR 2B S(O)NR 2B R 2A , -C(O)R 2A , —S(O)OH, —P(O)(OH) (ii-4c) Q is -CHOH, -C(O)OH, or -C(O)OR 2A and (ii-4d) Q is —COOH.

[0112] In certain embodiments of the compounds otherwise described herein, L 3 is selected from one of the following groups (ii-5a) to (ii-5c): (ii-5a)L 3 is a bond, -C(O)-, -S-, -S(O) 1―2 -, -O-, -NR 6 -, -CH2-, -CH(CH3)(OH)-, or -CH(OH); (ii-5b)L 3 is a bond, (ii-5c)L 3 is a bond, —CH—, —CH(CH)(OH)—, or —CH(OH)—.

[0113] In certain embodiments of the compounds otherwise described herein, R 3 is selected from one of the following groups (ii-6a) to (ii-6k): (ii-6a)R 3 are (i)-L 3C -(1-5 R 3D aryl optionally substituted with -L3C -(1-5 R 3D heteroaryl optionally substituted with 3C -(1-5 R 3D cycloalkyl optionally substituted with -L 3C -(1-5 R 3D (ii) 1-5 R 3E aryl (e.g., phenyl) or heteroaryl (e.g., monocyclic heteroaryl), optionally substituted with (ii-6b)R 3 is 1-5 R 3E aryl (e.g., phenyl, benzodioxole, or dihydro-1H-isoquinoline) optionally substituted with (ii-6c)R 3 is (i)-L 3C -(1-5 R 3D aryl optionally substituted with -L 3C -(1-5 R 3D heteroaryl optionally substituted with 3C -(1-5 R 3D cycloalkyl optionally substituted with -L 3C -(1-5 R 3D and (ii) 1-5 R 3E aryl (e.g., phenyl, benzodioxole, or dihydro-1H-isoquinoline), optionally substituted with (ii-6d)R 3 is (i)-L 3C -(1-5 R 3D phenyl optionally substituted with -L 3C -(1-5 R 3D monocyclic heteroaryl optionally substituted with 3C -(1-5 R 3D monocyclic cycloalkyl optionally substituted with 3C -(1-5 R 3Dand (ii) 1-5 R 3E aryl (e.g., phenyl, benzodioxole, or dihydro-1H-isoquinoline), optionally substituted with (ii-6e)R 3 is as defined in (6a) to (6d), and in the formula, aryl is any of R 3E is not replaced by (ii-6f)R 3 is any 1-5 R 3E heteroaryl (e.g., isothiazole, pyridone, thiadiazole, pyrazine, pyrazolopyrimidine, pyrazolopyridine, imidazole, benzofuran, indole, imidazopyridine, pyridine, pyrazole, isoxazole, triazolopyridine, benzimidazole, thiophene, benzothiophene, furan, or pyrimidine) substituted with (ii-6g)R 3 is (i)-L 3C -(1-5 R 3D aryl optionally substituted with -L 3C -(1-5 R 3D heteroaryl optionally substituted with 3C -(1-5 R 3D cycloalkyl optionally substituted with -L 3C -(1-5 R 3D and (ii) 1-5 R 3E heteroaryl (e.g., isothiazole, pyridone, thiadiazole, pyrazine, pyrazolopyrimidine, pyrazolopyridine, imidazole, benzofuran, indole, imidazopyridine, pyridine, pyrazole, isoxazole, triazolopyridine, benzimidazole, thiophene, benzothiophene, furan, or pyrimidine), optionally substituted with (ii-6h)R 3 is (i)-L 3C -(1-5 R 3Dphenyl optionally substituted with -L 3C -(1-5 R 3D monocyclic heteroaryl optionally substituted with 3C -(1-5 R 3D monocyclic cycloalkyl optionally substituted with 3C -(1-5 R 3D and (ii) 1-5 R 3E heteroaryl (e.g., isothiazole, pyridone, thiadiazole, pyrazine, pyrazolopyrimidine, pyrazolopyridine, imidazole, benzofuran, indole, imidazopyridine, pyridine, pyrazole, isoxazole, triazolopyridine, benzimidazole, thiophene, benzothiophene, furan, or pyrimidine), optionally substituted with (ii-6i)R 3 is as defined in (6f) to (6h), wherein heteroaryl is any of R 3E is not replaced by (ii-6j)R 3 are (i)-L 3C -(1-5 R 3D aryl optionally substituted with -L 3C -(1-5 R 3D heteroaryl optionally substituted with 3C -(1-5 R 3D cycloalkyl optionally substituted with -L 3C -(1-5 R 3D (heterocycloalkyl optionally substituted with 3Eselected from the group consisting of phenyl, benzodioxolyl, dihydro-1H-isoquinolinyl, imidazolyl, oxazolyl, isoxazolyl, isothiazolyl, thiazolyl, pyridinyl, and pyrazinyl, pyridonyl, thiadiazolyl, pyrazolopyrimidinyl, pyrazolopyridinyl, benzofuranyl, indolyl, imidazopyridinyl, pyrazolyl, triazopyridinyl, benzimidazolyl, benzimidazolyl, thienyl, benzothienyl, furanyl, and pyrimidinyl optionally substituted with (ii-6k)R 3 1-5 R 3E and monocyclic heteroaryl (eg, pyridyl, pyrazolyl), optionally substituted with . In certain such embodiments, R 3 (R 3D and R 3E Each optionally substituted alkyl, alkenyl, and alkynyl in (including those in) can be unsubstituted or fluorinated. For example, in certain such embodiments, R 3 (R 3D and R 3E Each optionally substituted alkyl, alkenyl, and alkynyl in (including that in) is unsubstituted. In certain such embodiments, L 3C is methylene or -O-. In certain such embodiments, the optimal number of R3E substituents is 1-3, or 1-2.

[0114] In certain embodiments of the compounds otherwise described herein, R 4 is selected from one of the following groups (ii-7a) to (ii-7d): (ii-7a)R 4 is hydrogen, (ii-7b)R 4 is an optionally substituted C1-C8 alkyl, an optionally substituted C1-C8 alkenyl, or an optionally substituted C1-C8 alkynyl; (ii-7c)R 4 is hydrogen or unsubstituted C1-C6 alkyl; (ii-7d)R 4is unsubstituted C1-C3 alkyl. In certain such embodiments, R 4 Each optionally substituted alkyl, alkenyl, and alkynyl in 4 Each optionally substituted alkyl, alkenyl, and alkynyl is unsubstituted.

[0115] In certain embodiments of the compounds otherwise described herein, L 4 is selected from one of the following groups (ii-8a) to (ii-8c): ii-(8a)L 4 is a bond, -C(O)-, -S-, -S(O) 1―2 -, -O-, and -NR 6 - selected from (ii-8b)L 4 is a bond, (ii-8c)L 4 is -O- (e.g., R 4 is any of the above (ii-7a), (ii-7b), (ii-7c), or (--7d).

[0116] In certain embodiments of the compounds otherwise described herein, L 5 is selected from one of the following groups (ii-9a) to (ii-9c): (ii-9a)L 5 is a bond, -C(O)-, -S-, -S(O) 1―2 -, -O-, -NR 6 -, -CHCH-, -CH-, -CH(CH)(OH)-, or -CH(OH)-; (ii-9b)L 5 is a bond, (ii-9c)L 5 is a bond, -O-, -S-, -C(O)-, or -S(O) 1-2 -It is.

[0117] In certain embodiments of the compounds otherwise described herein, R 5is selected from one of the following groups (ii-10a) to (ii-10s): (ii-10a)R 5 Each contains 1-5 R 5E aryl (e.g., phenyl) or heteroaryl (e.g., isoxazolyl, pyridyl, imidazopyridyl, pyrazolyl) optionally substituted with (ii-10b)R 5 1-5 R 5E is phenyl optionally substituted with (ii-10c)R 5 Each contains 1-5 R 5E isoxazolyl, pyridyl, imidazopyridyl, and pyrazolyl optionally substituted with (ii-10d)R 5 -L 5C -(1-5 R 5D phenyl optionally substituted with -L 5C -(1-5 R 5D monocyclic heteroaryl optionally substituted with 5C -(1-5 R 5D monocyclic cycloalkyl optionally substituted with 5C -(1-5 R 5D and (ii) 1-5 R 5E is phenyl optionally substituted with (ii-10e)R 5 is one -L 5C -(1-5 R 5D and (ii) 1-5 R 5E is phenyl optionally substituted with (ii-10f)R 5 is one -L 5C -(1-5 R 5D and (ii) 1-5 R 5E is phenyl optionally substituted with (ii-10g) The above (ii-10d), (ii-10e), or (ii-10f) [wherein, L 5C is a bond], (ii-10h) The above (ii-10d), (ii-10e), or (ii-10f) [wherein, L 5C is —O— or —C(O)—, (ii-10h)R 5 1-5 R 5E is heterocycloalkyl optionally substituted with (ii-10i)R 5 is one -L 5C -(1-5 R 5D and (ii) 1-5 R 5E is heterocycloalkyl optionally substituted with (ii-10j) The above (ii-10h) or (ii-10i) [wherein heterocycloalkyl is -L 5 -bonded to a nitrogen-containing heterocycloalkyl; (ii-10k) (ii-10h), (ii-10i), or (ii-10j) above [wherein heterocycloalkyl is monocyclic], (ii-10l) (ii-10h), (ii-10i), or (ii-10j) above [wherein heterocycloalkyl is bicyclic], (ii-10m) any of the above (ii-10h) to (ii-10l) [wherein heterocycloalkyl is saturated]; (ii-10n)R 5 1-5 R 5E is cycloalkyl optionally substituted with (ii-10o) (ii-10n) above [wherein cycloalkyl is 1 to 5 R 5E ], (ii-10p) (ii-10n) or (ii-10o) above [wherein cycloalkyl is monocyclic], (ii-10q) Any of the above (ii-10n), (ii-10o), or (ii-10p) [wherein cycloalkyl is saturated]; (ii-10r) (ii-10n), (ii-10o), or (ii-10p) above [wherein cycloalkyl is unsaturated, for example one is unsaturated]; (ii-10s) The above (ii-10n), (ii-10o), or (ii-10p) [wherein cycloalkyl is cyclohexen-1-yl]. In certain such embodiments, R 5 (R 5D and R 5E Each optionally substituted alkyl, alkenyl, and alkynyl in (including those in) can be unsubstituted or fluorinated. For example, in certain such embodiments, R 5 (R 5D and R 5E Each optionally substituted alkyl, alkenyl, and alkynyl in (including those in) is unsubstituted.

[0118] Other embodiments of the compounds otherwise described herein include compounds represented by any of structural formulas (IIa)-(IIe) above, e.g., structural formula (IIa) 1 , R 1 , L 2 , Q, L 3 , R 3 , L 5 , and R 5 as otherwise described in any embodiment herein) with respect to any of the alternative definitions of -L 4 -R 4 has -OH or -O-(unsubstituted or fluorinated C1-C8 alkyl)], for example, methoxy.

[0119] Other embodiments of the compounds otherwise described herein include compounds represented by any of structural formulas (IIa)-(IIe) above, e.g., structural formula (IIa) 1 , R 1 , L 2 , Q, L 3 , R 3 , L 4 , and R 4as otherwise described in any embodiment herein) with respect to any of the alternative definitions of -L 5 -R 5 -L 5C -(1-5 R 5D phenyl optionally substituted with -L 5C -(1-5 R 5D monocyclic heteroaryl optionally substituted with 5C -(1-5 R 5E monocyclic cycloalkyl optionally substituted with 5C -(1-5 R 5E and (ii) 1-5 R 5E wherein R is phenyl optionally substituted with R.

[0120] Other embodiments of the compounds otherwise described herein include compounds represented by any of structural formulas (IIa)-(IIe) above, e.g., structural formula (IIa) 1 , R 1 , L 2 , Q, L 3 , R 3 , L 4 , and R 4 as otherwise described in any embodiment herein) with respect to any of the alternative definitions of -L 5 -R 5 is R 5 is one -L 5C -(1-5 R 5D and (ii) 1-5 R 5E The monocyclic heteroaryl can be, for example, oxadiazole.

[0121] Other embodiments of the compounds otherwise described herein include compounds represented by any of structural formulas (IIa)-(IIe) above, e.g., structural formula (IIa) 1 , R1 , L 2 , Q, L 3 , R 3 , L 4 , and R 4 as otherwise described in any embodiment herein) with respect to any of the alternative definitions of -L 5 -R 5 is R 5 is one -L 5C -(1-5 R 5E and (ii) 1-5 R 5E Monocyclic heterocycloalkyl can be, for example, morpholinyl, such as morpholin-1-yl, or oxetanyl, such as oxetan-3-yl.

[0122] Other embodiments of the compounds otherwise described herein include compounds represented by any of structural formulas (IIa)-(IIe) above, e.g., structural formula (IIa) 1 , R 1 , L 2 , Q, L 3 , R 3 , L 4 , and R 4 as otherwise described in any embodiment herein) with respect to any of the alternative definitions of -L 5 -R 5 1-5 R 5E Heterocycloalkyl can be, for example, heterocycloalkyl optionally substituted with -L through the nitrogen atom. 5-bonded to a nitrogen-containing heterocycloalkyl. In certain such embodiments, the heterocycloalkyl is monocyclic. In other such embodiments, the heterocycloalkyl is bicyclic. In certain such embodiments, the heterocycloalkyl is saturated. In various embodiments described otherwise herein, the heterocycloalkyl is morpholinyl (e.g., morpholin-1-yl), 1,4-dioxaspiro[4,5]decenyl (e.g., 1,4-dioxaspiro[4,5]decen-8-yl), piperidinyl (e.g., piperidin-1-yl), azabicyclo[3.2.1]octanyl (e.g., azabicyclo[3.2.1]octan-8-yl), piperazinyl (e.g., piperazin-1-yl), pyrrolidinyl (e.g., pyrrolidin-1-yl), or azaspiro[2.5]octanyl (e.g., azaspiro[2.5]octan-6-yl).

[0123] Other embodiments of the compounds otherwise described herein include compounds represented by any of structural formulas (IIa)-(IIe) above, e.g., structural formula (IIa) 1 , R 1 , L 2 , Q, L 3 , R 3 , L 4 , and R 4 as otherwise described in any embodiment herein) with respect to any of the alternative definitions of -L 5 -R 5 is one -L 5C -(1-5 R 5E and (ii) 1-5 R 5E Heterocycloalkyl is, for example, a heterocycloalkyl optionally substituted with -L through a nitrogen atom. 5-bonded to a nitrogen-containing heterocycloalkyl. In certain such embodiments, the heterocycloalkyl is monocyclic. In other such embodiments, the heterocycloalkyl is bicyclic. In certain such embodiments, the heterocycloalkyl is saturated. In various embodiments described otherwise herein, the heterocycloalkyl is morpholinyl (e.g., morpholin-1-yl), 1,4-dioxaspiro[4,5]decenyl (e.g., 1,4-dioxaspiro[4,5]decen-8-yl), piperidinyl (e.g., piperidin-1-yl), azabicyclo[3.2.1]octanyl (e.g., azabicyclo[3.2.1]octan-8-yl), piperazinyl (e.g., piperazin-1-yl), pyrrolidinyl (e.g., pyrrolidin-1-yl), or azaspiro[2.5]octanyl (e.g., azaspiro[2.5]octan-6-yl). The cycloalkyl can be, for example, a saturated cycloalkyl, such as a saturated C3-C5 cycloalkyl, for example, cyclopropyl.

[0124] Other embodiments of the compounds otherwise described herein include compounds represented by any of structural formulas (IIa)-(IIe) above, e.g., structural formula (IIa) 1 , R 1 , L 2 , Q, L 3 , R 3 , L 4 , and R 4 as otherwise described in any embodiment herein) with respect to any of the alternative definitions of -L 5 -R 5 1-5 R 5EIn certain such embodiments, the cycloalkyl is monocyclic. In other such embodiments, the cycloalkyl is bicyclic. In certain such embodiments, the cycloalkyl is saturated. In various embodiments as otherwise described herein, the cycloalkyl is cyclohexenyl (e.g., cyclohexen-1-yl, e.g., 4-trifluoromethylcyclohexen-1-yl), or cyclohexyl.

[0125] Other embodiments of the compounds otherwise described herein include compounds having any of the above structural formulas (IIa)-(IIe), e.g., structural formula (IIa), wherein the variables are (e.g., as defined herein for the variables L 1 , R 1 , L 2 , Q, L 3 , R 3 , L 4 , and R 4 as otherwise described in any embodiment herein) with respect to any of the alternative definitions of -L 5 -R 5 is phenyl substituted with 1, 2, or 3 substituents independently selected from fluoro, chloro, nitro, methyl, methoxy, ethyl, ethoxy, trifluoromethyl, difluoromethyl, fluoromethyl, trifluoromethoxy, pentafluoroethyl, and 2,2,2-trifluoroethoxy. 5 is a bond.

[0126] In certain additional embodiments, including any of the embodiments described with reference to formulas (IIa)-(IIe), each optionally substituted alkylene, alkenylene, and alkynylene recited in any one of the above embodiments is unsubstituted. In alternative additional embodiments, including any of the embodiments described with reference to formulas (IIa)-(IIe), each optionally substituted alkylene, alkenylene, and alkynylene recited in any one of the above embodiments is unsubstituted or fluorinated.

[0127] In certain additional embodiments, including any of the embodiments described with reference to Formulas (IIa)-(IIe) and any of the embodiments described in the immediately preceding paragraph, each optionally substituted alkyl, alkenyl, and alkynyl recited in any one of the above embodiments is unsubstituted. In alternative additional embodiments, including any of the embodiments described with reference to Formulas (IIa)-(IIe) and any of the embodiments described in the immediately preceding paragraph, each optionally substituted alkyl, alkenyl, and alkynyl recited in any one of the above embodiments is unsubstituted.

[0128] In certain additional embodiments, including any of the embodiments described with reference to Formulas (IIa)-(IIe) and any of the embodiments described in the two paragraphs immediately preceding, each cycloalkyl recited in any one of the above embodiments is a 3- to 7-membered monocyclic cycloalkyl. For example, in certain specific additional embodiments, including any of the embodiments described with reference to Formulas (IIa)-(IIe) and any of the embodiments described in the two paragraphs immediately preceding, each cycloalkyl recited in any one of the above embodiments is cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, or cyclohexenyl.

[0129] In certain additional embodiments, including any of the embodiments described with reference to Formulas (IIa)-(IIe) and any of the embodiments described in the three paragraphs immediately preceding, each heterocycloalkyl recited in any one of the above embodiments is a 4- to 7-membered monocyclic heterocycloalkyl having 1-2 heteroatoms selected from O, S, and N. For example, in certain specific embodiments, including any of the embodiments described with reference to Formulas (IIa)-(IIe) and any of the embodiments described in the three paragraphs immediately preceding, each heterocycloalkyl recited in any one of the above embodiments is pyrrolidinyl, tetrahydrofuranyl, tetrahydrothienyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, tetrahydro-2H-pyranyl, or tetrahydro-2H-thiopyranyl.

[0130] In certain additional embodiments, including any of the embodiments described with reference to Formulas (IIa)-(IIe) and any of the embodiments described in the four paragraphs immediately preceding, each heteroaryl is a 5-6 membered monocyclic heteroaryl having 1-3 heteroatoms selected from O, S, and N. For example, in certain specific embodiments, including any of the embodiments described with reference to Formulas (IIa)-(IIe) and any of the embodiments described in the four paragraphs immediately preceding, each heteroaryl is furanyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, or thiazolyl.

[0131] In certain additional embodiments, including any of the embodiments described with reference to Formulas (IIa)-(IIe) and any of the embodiments described in the four immediately preceding paragraphs, each aryl is phenyl.

[0132] In certain additional embodiments described above, including any of the embodiments described with reference to formulas (IIa)-(IIe) and any of the embodiments described in the immediately preceding five paragraphs, R 5 is substituted with one, two, or three substituents selected from halogen (e.g., chloro or fluoro), and fluorinated C1-C3 alkyl (e.g., trifluoromethyl, difluoromethyl, fluoromethyl, pentafluoroethyl, trifluoroethyl). For example, in certain embodiments described above, R 5 is phenyl substituted with one or two substituents selected from trifluoromethyl, fluorine, and chlorine (e.g., trisubstituted, tetrasubstituted, 3,4-disubstituted, 2,4-disubstituted, or 2,5-disubstituted). For example, in certain embodiments, R 5 may be dichlorophenyl, such as 3,4-dichlorophenyl, or trifluoromethylphenyl, such as 4-trifluoromethylphenyl.

[0133] In certain embodiments, the therapeutic compound is one of the compounds in the following Table of Compounds, optionally provided as a pharmaceutically acceptable salt or N-oxide, and / or solvate or hydrate. BJAB (a malignant human B-cell line) proliferation data is presented in the table. "A" indicates a measured EC 50 "B" indicates a measured EC value greater than 1 μM and less than or equal to 5 μM. 50 "C" indicates a measured EC value greater than 5 μM and less than or equal to 10 μM. 50 "D" indicates a measured EC value greater than 10 μM and less than or equal to 25 μM. 50 "E" indicates a measured EC value greater than 25 μM and less than or equal to 50 μM. 50 "F" indicates a measured EC greater than 50 μM and less than or equal to 100 μM. 50 "G" indicates a measured EC of 80 μM or less in the experiments performed. 50 "H" indicates that there was no measured EC below 50 μM in the experiments performed. 50 "I" indicates that there was no measured EC of 40 μM or less in the experiments performed. 50 "J" indicates that there was no measured EC below 25 µM in the experiments performed. 50 "K" indicates that there was no measured EC below 20 μM in the experiments performed. 50 "L" indicates that there was no measured EC below 5 µM in the experiments performed. 50 In certain embodiments, the therapeutic compound is a compound having activity as "A," "B," or "C" in the tables below. In certain embodiments, the therapeutic compound is a compound having activity as "A" or "B" in the tables below. In certain embodiments, the therapeutic compound is a compound having activity as "A" in the tables below.

[0134] [Table 3] JPEG2025016393000037.jpg241170 JPEG2025016393000038.jpg233170 JPEG2025016393000039.jpg194170

[0135] Terms used herein may be preceded or followed by a single line "-" or a double line "=" to indicate the bond order between the named substituent and its parent moiety. A single line indicates a single bond, and a double line indicates a double bond or, in the case of a spiro substituent, a pair of single bonds. When a single or double line is absent, a single bond is formed between the substituent and its parent moiety, and it is further understood that the substituents are intended to be read "left to right" relative to the chemical structure unless the line indicates otherwise. For example, arylalkyl, arylalkyl-, and -alkylaryl indicate the same functional group.

[0136] For simplicity, chemical moieties are defined and referred to primarily as monovalent chemical moieties (e.g., alkyl, aryl, etc.). Nevertheless, such terms are also used to convey corresponding multivalent moieties under appropriate structural circumstances clear to those of skill in the art. For example, although an "alkyl" moiety can refer to a monovalent group (e.g., CH3-CH2-), in some circumstances, a divalent linking moiety can be "alkyl," in which case one of skill will understand that alkyl is a divalent group equivalent to the term "alkylene" (e.g., -CH2-CH2-). (Similarly, in situations where a divalent moiety is required and is referred to as "aryl," one of skill will understand that the term "aryl" refers to the corresponding divalent moiety, arylene.) All atoms are understood to have their normal valences (i.e., carbon is 4, N is 3, O is 2, and S is 2, 4, or 6 depending on the oxidation state of S) for forming bonds. Nitrogen in the compounds disclosed herein can be hypervalent, e.g., an N-oxide or a tetrasubstituted ammonium salt. In some cases, the moiety can be, for example, -B-(A) awhere a is 0 or 1. In such an example, when a is 0, the moiety is -B, and when a is 1, the moiety is -BA.

[0137] As used herein, the term "alkyl" includes saturated hydrocarbons having a specified number of carbons, e.g., 1 to 10 carbons (i.e., inclusive), 1 to 8 carbons, 1 to 6 carbons, 1 to 3 carbons, or 1, 2, 3, 4, 5, or 6. An "alkyl group" can be straight-chain or branched and, depending on the context, can be a monovalent group or a divalent group (i.e., an alkylene group). For example, the moiety "-(C1-C6 alkyl)-O-" refers to the attachment of an oxygen through an alkylene bridge having 1 to 6 carbons, where C1-C3 alkyl represents methyl, ethyl, and propyl moieties. Examples of "alkyl" include, for example, methyl, ethyl, propyl, isopropyl, butyl, iso-, sec-, and tert-butyl, pentyl, and hexyl.

[0138] The term "alkoxy" represents an alkyl group having the indicated number of carbon atoms attached to the parent molecular moiety through an oxygen bridge. Examples of "alkoxy" include, for example, methoxy, ethoxy, propoxy, and isopropoxy.

[0139] As used herein, unless otherwise specified, the term "alkenyl" refers to an unsaturated hydrocarbon containing 2 to 10 carbons (i.e., inclusive), 2 to 8 carbons, 2 to 6 carbons, or 2, 3, 4, 5, or 6 carbons and containing at least one carbon-carbon double bond. Alkenyl groups can be straight or branched chain and, depending on the context, can be monovalent or divalent (i.e., alkenylene) groups. For example, the moiety "-(C2-C6 alkenyl)-O-" refers to the attachment of an oxygen through an alkenylene bridge having 2 to 6 carbons. Representative examples of alkenyl include, but are not limited to, ethenyl, 2-propenyl, 2-methyl-2-propenyl, 3-butenyl, 4-pentenyl, 5-hexenyl, 2-heptenyl, 2-methyl-1-heptenyl, 3-decenyl, and 3,7-dimethylocta-2,6-dienyl.

[0140] As used herein, unless otherwise specified, the term "alkynyl" refers to an unsaturated hydrocarbon containing 2 to 10 carbons (i.e., inclusive), 2 to 8 carbons, 2 to 6 carbons, or 2, 3, 4, 5, or 6 carbons and containing at least one carbon-carbon triple bond. Alkynyl groups can be straight-chained or branched and, depending on the context, can be monovalent or divalent (i.e., alkynylene) groups. For example, the moiety "-(C2-C6 alkynyl)-O-" refers to the attachment of oxygen via an alkynylene bridge having 2 to 6 carbons. Representative examples of alkynyl include, but are not limited to, acetylenyl, 1-propynyl, 2-propynyl, 3-butynyl, 2-pentynyl, and 1-butynyl.

[0141] The term "aryl" refers to an aromatic ring system having one ring (e.g., phenyl) optionally fused to another aromatic hydrocarbon ring, or a non-aromatic hydrocarbon or heterocyclic ring. "Aryl" includes ring systems having multiple fused rings, at least one of which is carbocyclic or aromatic (e.g., 1,2,3,4-tetrahydronaphthyl, naphthyl). Examples of aryl groups include 1-naphthyl, 2-naphthyl, indanyl, indenyl, dihydronaphthyl, fluorenyl, tetralinyl, and 6,7,8,9-tetrahydro-5H-benzo[a]cycloheptenyl. "Aryl" also includes ring systems having a first carbocyclic aromatic ring fused to a non-aromatic heterocyclic ring, such as 1H-2,3-dihydrobenzofuranyl and tetrahydroisoquinolinyl. The aryl groups herein are unsubstituted or, if specified as "optionally substituted," can be substituted in one or more substitutable positions with the various groups indicated, unless otherwise stated.

[0142] The term "halogen" or "halo" refers to fluorine, chlorine, bromine, and iodine. In certain embodiments of any of the embodiments described herein, the term "halogen" or "halo" refers to fluorine or chlorine. In certain embodiments of any of the embodiments described herein, the term "halogen" or "halo" refers to fluorine.

[0143] The term "heteroaryl" refers to an aromatic ring system containing at least one aromatic heteroatom selected from nitrogen, oxygen, and sulfur within the aromatic ring. Most commonly, heteroaryl groups have 1, 2, 3, or 4 heteroatoms. A heteroaryl can be fused to one or more non-aromatic rings, such as cycloalkyl or heterocycloalkyl rings described herein. In one embodiment of the compound, the heteroaryl group is bonded to the remainder of the structure via an atom in the aromatic ring of the heteroaryl group. In another embodiment, the heteroaryl group is bonded to the remainder of the structure via a non-aromatic ring atom.Examples of heteroaryl groups include, for example, pyridyl, pyrimidinyl, quinolinyl, benzothienyl, indolyl, indolinyl, pyridazinyl, pyrazinyl, isoindolyl, isoquinolyl, quinazolinyl, quinoxalinyl, phthalazinyl, imidazolyl, isoxazolyl, pyrazolyl, oxazolyl, thiazolyl, indolizinyl, indazolyl, benzothiazolyl, benzimidazolyl, benzofuranyl, furanyl, thienyl, pyrrolyl, oxadiazolyl, and the like. thiadiazolyl, benzo[1,4]oxazinyl, triazolyl, tetrazolyl, isothiazolyl, naphthyridinyl, isochromanyl, chromanyl, isoindolinyl, isobenzodienyl, benzoxazolyl, pyridopyridinyl, purinyl, benzodioxolyl, triazinyl, pteridinyl, benzothiazolyl, imidazopyridinyl, imidazothiazolyl, benzisoxazinyl, benzoxazinyl, benzopyranyl, benzothiopyranyl, chloro Mononyl, chromanonyl, pyridinyl N-oxide, isoindolinonyl, benzodioxanyl, benzoxazolinonyl, pyrrolyl N-oxide, pyrimidinyl N-oxide, pyridazinyl N-oxide, pyrazinyl N-oxide, quinolinyl N-oxide, indolyl N-oxide, indolinyl N-oxide, isoquinolyl N-oxide, quinazolinyl N-oxide, quinoxalinyl N-oxide, phthalazinyl N-oxide, imidazolyl N-oxide Preferred heteroaryl groups include pyridyl, pyrimidyl, quinolinyl, indolyl, pyrrolyl, furanyl, thienyl, imidazolyl, pyrazolyl, indazolyl, thiazolyl, and benzothiazolyl.In certain embodiments, each heteroaryl is selected from pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, imidazolyl, isoxazolyl, pyrazolyl, oxazolyl, thiazolyl, furanyl, thienyl, pyrrolyl, oxadiazolyl, thiadiazolyl, triazolyl, tetrazolyl, isothiazolyl, pyridinyl-N-oxide, pyrrolyl N-oxide, pyrimidinyl N-oxide, pyridazinyl N-oxide, pyrazinyl N-oxide, imidazolyl N-oxide, isoxazolyl N-oxide, oxazolyl N-oxide, thiazolyl N-oxide, pyrrolyl N-oxide, oxadiazolyl N-oxide, thiadiazolyl N-oxide, triazolyl N-oxide, and tetrazolyl N-oxide. Preferred heteroaryl groups include pyridyl, pyrimidyl, quinolinyl, indolyl, pyrrolyl, furanyl, thienyl, imidazolyl, pyrazolyl, indazolyl, thiazolyl, and benzothiazolyl. The heteroaryl groups herein can be unsubstituted or, if specified as "optionally substituted," can be substituted in one or more substitutable positions with the various groups indicated, unless otherwise stated.

[0144] The term "heterocycloalkyl" refers to a non-aromatic ring or ring system containing a heteroatom, preferably selected from nitrogen, oxygen, and sulfur, present in at least one non-aromatic ring. A heterocycloalkyl can have 1, 2, 3, or 4 heteroatoms. A heterocycloalkyl can be saturated (i.e., heterocycloalkyl) or partially unsaturated (i.e., heterocycloalkenyl). Heterocycloalkyl includes monocyclic groups of 3 to 8 ring atoms, as well as bicyclic and polycyclic ring systems, including bridged and fused systems, in which each ring contains 3 to 8 ring atoms. A heterocycloalkyl ring is optionally fused to another heterocycloalkyl ring and / or a non-aromatic hydrocarbon ring. In certain embodiments, a heterocycloalkyl group has 3 to 7 members in a ring. In other embodiments, a heterocycloalkyl group has 5 or 6 members in a ring. In some embodiments, a heterocycloalkyl group has 3, 4, 5, 6, or 7 members in a ring. Examples of heterocycloalkyl groups include, for example, azabicyclo[2.2.2]octyl (which in each case also includes "quinuclidinyl" or quinuclidine derivatives), azabicyclo[3.2.1]octyl, 2,5-diazabicyclo[2.2.1]heptyl, morpholinyl, thiomorpholinyl, thiomorpholinyl S-oxide, thiomorpholinyl S,S-dioxide, 2-oxazolidonyl, piperazinyl, homopiperazinyl, piperazinonyl, pyrrolidinyl, azepanyl, azetidinyl, pyrrolinyl, tetrahydropyranyl, piperidinyl, tetrahydropyran ... Examples include tetrahydrofuranyl, tetrahydrothienyl, 3,4-dihydroisoquinolin-2(1H)-yl, isoindolinedionyl, homopiperidinyl, homomorpholinyl, homothiomorpholinyl, homothiomorpholinyl S,S-dioxide, oxazolidinonyl, dihydropyrazolyl, dihydropyrrolyl, dihydropyrazinyl, dihydropyridinyl, dihydropyrimidinyl, dihydrofuryl, dihydropyranyl, imidazolidonyl, tetrahydrothienyl S-oxide, tetrahydrothienyl S,S-dioxide, and homothiomorpholinyl S-oxide.Particularly preferred heterocycloalkyl groups include morpholinyl, 3,4-dihydroisoquinolin-2(1H)-yl, tetrahydropyranyl, piperidinyl, aza-bicyclo[2.2.2]octyl, γ-butyrolactonyl (i.e., oxo-substituted tetrahydrofuranyl), γ-butyrolactamyl (i.e., oxo-substituted pyrrolidine), pyrrolidinyl, piperazinyl, azepanyl, azetidinyl, thiomorpholinyl, thiomorpholinyl S,S-dioxide, 2-oxazolidonyl, imidazolidonyl, isoindolinedionyl, and piperazinonyl. Heterocycloalkyl groups herein can be unsubstituted or, where specified as "optionally substituted," can be substituted in one or more substitutable positions with the various groups indicated, unless otherwise stated.

[0145] The term "cycloalkyl" refers to a non-aromatic carbocyclic ring or ring system, which can be saturated (i.e., cycloalkyl) or partially unsaturated (i.e., cycloalkenyl). Cycloalkyl rings are optionally fused to or otherwise attached (e.g., bridged) to other cycloalkyl rings. Specific examples of cycloalkyl groups present in the disclosed compounds have 3 to 7 members in a single ring, e.g., 5 or 6 members in a single ring. In some embodiments, cycloalkyl groups have 3, 4, 5, 6, or 7 members in a single ring. Examples of cycloalkyl groups include, for example, cyclohexyl, cyclopentyl, cyclobutyl, cyclopropyl, tetrahydronaphthyl, and bicyclo[2.2.1]heptane. Cycloalkyl groups herein can be unsubstituted or, if specified as "optionally substituted," can be substituted in one or more substitutable positions with the various groups indicated.

[0146] The term "ring system" includes single rings as well as fused and / or bridged multiple rings.

[0147] The term "oxo" refers to a double-bonded oxygen, sometimes depicted as =0, or "C(O)" can be used to indicate an oxo-substituted carbon, for example, in describing a carbonyl.

[0148] The term "substituted," when used to modify a particular group or radical, means that one or more hydrogen atoms of the specified group or radical are each, independently of one another, replaced with the same or different substituents, as defined below, unless otherwise specified.

[0149] As used herein, the term "pharmaceutically acceptable salts" refers to both pharmaceutically acceptable acid and base addition salts and solvates. Such pharmaceutically acceptable salts include those derived from hydrochloric, phosphoric, hydrobromic, sulfuric, sulfinic, formic, toluenesulfonic, methanesulfonic, nitric, benzoic, citric, tartaric, maleic, and hydroiodic acids; acetic acid; HOOC-(CH2) n Included are salts of acids such as alkanoic acids, such as -COOH, where n is 0-4. Non-toxic pharmaceutical base addition salts include salts of bases such as sodium, potassium, calcium, ammonium, etc. Those skilled in the art will recognize a variety of non-toxic, pharmaceutically acceptable addition salts.

[0150] Those skilled in the art of medicinal chemistry will also understand that the disclosed structures are intended to include isotopically enriched forms of the compounds. As used herein, "isotopes" include atoms having the same atomic number but different mass numbers. As known to those skilled in the art, certain atoms, such as hydrogen, occur in different isotopic forms. For example, hydrogen includes three isotopic forms: protium, deuterium, and tritium. As will be apparent to those skilled in the art upon consideration of the present compounds, a particular compound can be enriched at a given position with a particular isotope of the atom at that position. For example, a compound having a fluorine atom can be enriched with a radioactive fluorine isotope. 18 The compounds can be synthesized in a form enriched in F. Similarly, the compounds can be enriched in the heavy isotopes of hydrogen, deuterium and tritium, as well as 13The compounds can be enriched in radioactive isotopes of carbon, such as C. Such isotopically modified compounds undergo different metabolic pathways and can be useful, for example, in studying the ubiquitination pathway and its role in disease. Of course, in certain embodiments, the compounds have substantially the same isotopic character as the naturally occurring material.

[0151] As used herein, the term "cell" is meant to refer to a cell that is in vitro, ex vivo, or in vivo. In some embodiments, an ex vivo cell can be part of a tissue sample excised from an organism, such as a mammal. In some embodiments, an in vitro cell can be a cell in cell culture. In some embodiments, an in vivo cell is a cell that resides in an organism, such as a mammal.

[0152] As used herein, the terms "individual," "patient," or "subject" are used interchangeably and refer to any animal, including a mammal, preferably a mouse, rat, other rodent, rabbit, dog, cat, pig, cow, sheep, horse, or primate, and most preferably a human.

[0153] As used herein, the phrase "therapeutically effective amount" or "effective amount" means an amount of an active compound or pharmaceutical agent that elicits the biological or medical response desired in a tissue, system, animal, individual, or human by a researcher, veterinarian, medical doctor, or other clinician.

[0154] In certain embodiments, a therapeutically effective amount is (1) Disease prevention, e.g., prevention of a disease, condition, or disorder in an individual who has been previously diagnosed with or may otherwise be suspected of having a disease, condition, or disorder, but who has not yet experienced or exhibited the symptoms or full symptoms of the disease; (2) Inhibition of a disease, e.g., inhibition of a disease, condition, or disorder in an individual experiencing or exhibiting the symptoms or symptoms of the disease, condition, or disorder; (3) alleviation of a disease, condition, or disorder (including its symptoms), e.g., reduction in the severity of the disease, in an individual experiencing or exhibiting the symptoms or symptoms of the disease, condition, or disorder (i.e., reversal of the symptoms and / or symptoms); (4) Induction of the referenced biological effect, e.g., inhibition of translation initiation Such biological effect need not be complete, i.e., the inhibition of translation initiation need not be total for the amount of compound administered to be therapeutically effective.

[0155] As used herein, the terms "treatment" and "treating" mean (i) alleviating the referenced disease, condition, or disease (or symptoms thereof), such as alleviating the disease, condition, or disease (i.e., reversing or ameliorating the disease and / or symptoms) in an individual experiencing or exhibiting the disease, condition, or disease, e.g., reducing the severity of the disease or symptoms thereof, or (ii) eliciting the referenced biological effect (e.g., inhibiting translation initiation). Pharmaceutical formulation and dosage form

[0156] The compounds of the present disclosure can be administered orally, topically, parenterally, by inhalation or spray, or rectally, for example, in dosage unit forms containing one or more pharmaceutically acceptable carriers, diluents, or excipients. As used herein, the term "parenteral" includes percutaneous, subcutaneous, intravascular (e.g., intravenous), intramuscular, or intrathecal injection or infusion techniques, and the like.

[0157] Pharmaceutical compositions can be made using the compounds disclosed herein. For example, in one embodiment, the pharmaceutical composition comprises a pharmaceutically acceptable carrier, diluent, or excipient, and a compound described above with reference to any one of the structural formulas.

[0158] In the pharmaceutical compositions disclosed herein, one or more compounds of the present disclosure can be present in association with one or more pharmaceutically acceptable carriers, diluents, or excipients, and, if desired, other active ingredients. Pharmaceutical compositions containing compounds of the present disclosure can be present in a form suitable for oral use, for example, as tablets, troches, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsions, hard or soft capsules, or syrups or elixirs.

[0159] Compositions intended for oral use can be prepared according to any suitable method for preparing pharmaceutical compositions, and such compositions may contain one or more agents selected from the group consisting of sweeteners, flavoring agents, coloring agents, and preservatives to provide a pharmaceutically elegant and palatable preparation. Tablets contain the active ingredient in admixture with non-toxic, pharmaceutically acceptable excipients that are suitable for the manufacture of tablets. These excipients can be, for example, inert diluents such as calcium carbonate, sodium carbonate, lactose, calcium phosphate, or sodium phosphate; granulating and disintegrating agents such as cornstarch or alginic acid; binders such as starch, gelatin, or acacia; and lubricants such as magnesium stearate, stearic acid, or talc. Tablets can be uncoated or coated by known techniques. In some cases, such coatings can be prepared by suitable techniques to delay disintegration and absorption in the gastrointestinal tract, thereby providing a sustained action over a longer period of time. For example, a time delay material such as glyceryl monostearate or glyceryl distearate can be employed.

[0160] Formulations for oral use may also be presented as hard gelatin capsules in which the active ingredient is mixed with an inert solid diluent, such as calcium carbonate, calcium phosphate, or kaolin, or as soft gelatin capsules in which the active ingredient is mixed with water or an oil medium, such as peanut oil, liquid paraffin, or olive oil.

[0161] Formulations for oral use may also be presented as lozenges.

[0162] Aqueous suspensions contain the active material in admixture with excipients suitable for the manufacture of aqueous suspensions, such as suspending agents, for example, sodium carboxymethylcellulose, methylcellulose, hydropropylmethylcellulose, sodium alginate, polyvinylpyrrolidone, gum tragacanth, and gum acacia; dispersing or wetting agents, for example, naturally occurring phospholipids, phosphatides, such as lecithin, or condensation products of alkylene oxides with fatty acids, for example, polyoxyethylene stearate, or condensation products of ethylene oxide with long-chain aliphatic alcohols, for example, heptadecaethyleneoxycetanol, or condensation products of ethylene oxide with partial esters derived from fatty acids and hexitols, for example, polyoxyethylene sorbitol monooleate, or condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol anhydrides, for example, polyethylene sorbitan monooleate. The aqueous suspensions may also contain one or more preservatives, for example, ethyl or n-propyl p-hydroxybenzoate, one or more coloring agents, one or more flavoring agents, and one or more sweetening agents, such as sucrose or saccharin.

[0163] Oily suspensions can be formulated by suspending the active ingredient in vegetable oil, such as peanut oil, olive oil, sesame oil, or coconut oil, or mineral oil such as liquid paraffin. Oily suspensions can contain thickening agents, such as beeswax, hard paraffin, or cetyl alcohol. Sweeteners and flavoring agents can be added to provide a palatable oral preparation. These compositions can be preserved by adding antioxidants such as ascorbic acid.

[0164] Dispersible powders and granules suitable for preparation of an aqueous suspension by the addition of water provide the active ingredient in admixture with a dispersing or wetting agent, a suspending agent, and one or more preservatives. Suitable dispersing or wetting agents or suspending agents are exemplified by those already mentioned above. Additional excipients, such as sweeteners, flavoring agents, and coloring agents, can also be present.

[0165] The pharmaceutical composition can also be in the form of an oil-in-water emulsion. The oil phase can be a vegetable oil or a mineral oil, or a mixture thereof. Suitable emulsifiers can be naturally occurring gums, such as gum arabic or gum tragacanth, naturally occurring phospholipids, such as soybean, lecithin, and esters or partial esters derived from fatty acids and hexitols, anhydrides, such as sorbitan monooleate, and condensation products of the above partial esters with ethylene oxide, such as polyoxyethylene sorbitan monooleate. The emulsion can also contain sweeteners and flavoring agents.

[0166] In some embodiments, the pharmaceutically acceptable carrier, diluent, or excipient is not water. In other embodiments, water comprises less than 50% of the composition. In some embodiments, a composition containing less than 50% water has at least 1%, 2%, 3%, 4%, or 5% water. In other embodiments, the water content is present in trace amounts in the composition.

[0167] In some embodiments, the pharmaceutically acceptable carrier, diluent, or excipient is not alcohol. In other embodiments, alcohol comprises less than 50% of the composition. In some embodiments, compositions containing less than 50% alcohol have at least 1%, 2%, 3%, 4%, or 5% alcohol. In other embodiments, the alcohol content is present in trace amounts in the composition.

[0168] Syrups and elixirs can be formulated with sweetening agents, such as glycerol, propylene glycol, sorbitol, glucose, or sucrose. Such formulations may also contain demulcents, preservatives, flavoring agents, and coloring agents. The pharmaceutical compositions may be in the form of a sterile injectable aqueous or oleaginous suspension. These suspensions may be formulated according to the art using suitable dispersing or wetting agents and suspending agents, as described above. Sterile injectable preparations may also be sterile injectable solutions or suspensions in non-toxic, parenterally acceptable diluents or solvents, for example, as solutions in 1,3-butanediol. Acceptable vehicles and solvents that can be used include water, Ringer's solution, and isotonic sodium chloride solution. Additionally, sterile, fixed oils can be used as solvents or suspending media. For this purpose, any non-irritating, fixed oil can be used, including synthetic monoglycerides or diglycerides. Additionally, fatty acids, such as oleic acid, find use in the preparation of injectable solutions.

[0169] The compound of the present disclosure can also be administered in the form of suppositories, for example, for rectal administration of drugs.These compositions can be prepared by mixing the compound with a suitable non-irritating excipient that is solid at room temperature but liquid at rectal temperature, so that it melts in the rectum and releases the drug.Such materials include cocoa butter and polyethylene glycol.

[0170] The compound of the present disclosure can also be administered systemically in a sterile medium.Depending on the vehicle and concentration used, the drug can be either suspended or dissolved in the vehicle.Advantageously, adjuvants such as local anesthetics, preservatives, and buffering agents can be dissolved in the vehicle.

[0171] The compositions can be formulated in unit dosage forms of the active ingredient. The term "unit dosage form" means physically discrete units suitable as unitary dosages for human subjects and other mammals, each unit containing a predetermined amount of active material calculated to produce a desired therapeutic effect in association with a suitable pharmaceutical excipient.

[0172] The active compounds can be effective over a wide dosage range and are generally administered in a pharmaceutically effective amount. However, it will be understood that the amount of compound actually administered will usually be determined by a physician according to the relevant circumstances, including the condition being treated, the selected route of administration, the actual compound being administered, the age, weight, and response of the individual patient, the severity of the patient's symptoms, etc.

[0173] To prepare solid compositions such as tablets, the primary active ingredient is mixed with pharmaceutical excipients to form a solid preformulation composition containing a homogeneous mixture of the compounds described herein. When these preformulation compositions are referred to as homogeneous, the active ingredient is typically dispersed evenly throughout the composition, allowing the composition to be readily subdivided into equally effective unit dosage forms such as tablets, pills, and capsules. This solid preformulation is then subdivided into unit dosage forms of the type described above, containing, for example, 0.1 to about 500 mg of the active ingredient of the compounds described herein.

[0174] Tablets or pills can be coated or otherwise compounded to provide a dosage form that offers the advantage of prolonged action. For example, tablets or pills, oral contraceptives, can comprise an inner and outer component, the latter in the form of an envelope surrounding the former. The two components can be separated by an enteric layer, which serves to resist disintegration in the stomach and allow the inner component to pass intact into the duodenum or be delayed in release. A variety of materials can be used for such enteric layers or coatings, including numerous polymeric acids and mixtures of polymeric acids, including such materials, such as shellac paint, cetyl alcohol, and cellulose acetate.

[0175] The amount of compound or composition administered to a patient will vary depending on what is being administered, the purpose of the administration, e.g., prophylaxis or treatment, the condition of the patient, the method of administration, etc. In therapeutic applications, compositions can be administered to a patient already suffering from a disease in an amount sufficient to cure or at least partially arrest the symptoms of the disease and its complications. The effective dose will depend on the condition being treated and the judgment of the attending clinician, depending on factors such as the severity of the disease, the age, weight, and general condition of the patient, etc.

[0176] The compositions administered to patients can be in the form of pharmaceutical compositions described above. These compositions can be sterilized by conventional sterilization techniques, or can be sterile filtered. Aqueous solutions can be packaged for ready use or lyophilized, with the lyophilized preparation being combined with a sterile aqueous carrier prior to administration. The pH of the compound preparations is typically 3 to 11, more preferably 5 to 9, and most preferably 7 to 8. It will be understood that the use of certain of the aforementioned excipients, carriers, or stabilizers will result in the formation of pharmaceutical salts.

[0177] The therapeutic dosage of a compound can vary depending, for example, on the particular use for which the treatment is made, the method of administration of the compound, the health and condition of the patient, and the judgment of the prescribing physician. The proportion or concentration of a compound described herein in a pharmaceutical composition can vary depending on numerous factors, including dosage, chemical properties (e.g., hydrophobicity), and the route of administration. For example, for parenteral administration, the compounds described herein can be provided in an aqueous physiological buffer solution containing about 0.1 to about 10% (weight / volume) of the compound. Some typical dosage ranges are about 1 μg / kg to about 1 g / kg of body weight per day. In some embodiments, the dosage range is about 0.01 mg / kg to about 100 mg / kg of body weight per day. The dosage will likely depend on variables such as the type and progression of the disease or disorder, the overall health of the particular patient, the relative biological availability of the selected compound, the excipient formulation, and its route of administration. Effective amounts can be extrapolated from dose-response curves derived from in vitro or animal model test systems.

[0178] The compounds described herein can also be formulated in combination with one or more additional active ingredients, which can include any pharmaceutical agent, such as an antiviral agent, a vaccine, an antibody, an immunostimulant, an immunosuppressant, an anti-inflammatory agent, etc.

[0179] One skilled in the art would formulate the described compounds into pharmaceutical formulations herein based, for example, on the physicochemical properties of the compound, the amount of compound needed for a pharmaceutically effective amount, and the desired route of administration. [Example]

[0180] Example 1: Gene Quantification and Therapy Cancer can be identified using nucleic acid isolation and real-time PCR analysis. In one embodiment, blood, cell, tissue, or saliva samples are obtained from human individuals with hematopoietic cancer, solid tumor cancer, and / or healthy individuals or cell lines. Nucleic acids are isolated using standard procedures well known in the art.

[0181] The RNA or mRNA is then reverse transcribed into cDNA, and a fragment of the cDNA corresponding to the gene of interest is amplified using gene-specific primers. In one embodiment (i.e., for solid tumor cancers), primers for multiple target genes are used to amplify the gene of interest using standard PCR techniques: LAMC3, FAM210B, SENP8, ITGB3BP, NUDT2, HNRNPCL1, C20orf43, FRMD8, and STX16. In an alternative embodiment (i.e., for hematopoietic cancers), primers for the following target genes are used to amplify the gene of interest using standard PCR: CASP10, TMED1, PPP1CC, TMEM59, BRD7, CYB561, FAM210B, NDRG1, CTSB, MMAB, SETDB2, VPS37B, ELL3, and KIF13B.

[0182] Additionally, primers for one or more housekeeping genes (e.g., one or more of 18s rRNA, 28s rRNA, α-tubulin, β-actin, ALB RPL32, TBP, CYCC, EF1A, and GAPDH) can be included as internal controls in the experiment.

[0183] In certain embodiments, quantification of gene expression was followed in real time using fluorescent probes to quantify changes in gene expression.

[0184] The gene expression value is used to calculate the fold change compared to the expression of the same gene in a reference cell (e.g., from a blood sample or non-cancerous tissue from a healthy individual human or a cell line). The fold change is calculated as follows: 2- ΔΔCt , During the ceremony, ΔΔCt=ΔCt(treated sample)-ΔCt(untreated sample), and, ΔCt = Ct (gene of interest) - Ct (housekeeping gene).

[0185] Microarray analysis or alternative quantitative genetic analysis studies can also be performed.

[0186] Example 2: Predictive Biomarker Discovery in OmniScreen™ Predictive biomarkers for genes indicative of responsiveness to therapeutic compounds can be measured using cell-based screening technologies such as those offered under the OmniScreen™ (Crown Biosciences).

[0187] In an experimental study, predictive biomarkers for the efficacy of compound A197 were measured in 406 cancer cell lines, 73 hematological tumor cell lines, and 333 solid tumor cell lines. Genomic data for the cell lines was downloaded from the Cancer Cell Line Encyclopedia Project (CCLE) website. Driver mutations were predicted using the Cancer Genome Interpreter Database. Only driver mutations were used in mutation-related analyses. Spearman correlation was used to detect genes whose expression was significantly correlated with AUC.

[0188] Signature genes were selected using the Boruta package in R. The linear prediction score (LPS) for each cell line of the form was calculated as follows:

number

number

number

[0189] Welch's t-test was used to assess the association between gene amplification, deletion, mutation status, and AUC.

[0190] Dose-response curves were fitted by a four-parameter model.

number

number

number

[0191] [Table 4] JPEG2025016393000047.jpg250170 JPEG2025016393000048.jpg251170 JPEG2025016393000049.jpg252170 JPEG2025016393000050.jpg250170 JPEG2025016393000051.jpg252170 JPEG2025016393000052.jpg251170 JPEG2025016393000053.jpg171170

[0192] The 406 cancer cell lines studied included 73 hematological tumors and 333 solid tumors. The responses of hematological and solid tumor cell lines were significantly different (Welch's t-test, P value = 2.3e-16, Figure 1). Analyses of hematological tumors and solid tumors were performed separately. For solid tumor cell lines, there was no significant difference in the mean AUC between different tumor types (one-way ANOVA, P value = 0.54, Figure 2). All solid cell lines were considered together.

[0193] Of the 406 cell lines, 311 have gene expression data, 308 have gene copy number data, and 286 have mutation status detected for 1561 genes. For hematological tumor cell lines, 57, 56, and 54 have expression, copy number, and mutation data. For solid tumor cell lines, 254, 252, and 232 have expression, copy number, and mutation data. Biomarker discovery in hematopoietic cancers

[0194] After removing low-expressing cell lines (>90% of cell lines with expression levels >5) and genes with a high proportion of low expression variation, 12,822 genes were retained for correlation analysis. Gene copy numbers were converted to integers (CN <0.5 = 0; CN <1.5 = 1; CN <2.5 = 2; CN <3.5 = 3; CN <4.5 = 4; CN ≥4.5 = 5). Genes with CN ≥4 were defined as "amplified," and genes with CN = 0 were defined as "deleted." When KIAA0125 was amplified in 18 cell lines, amplified and non-amplified cell lines had significantly different mean AUCs (Welch's t-test P = 0.043, Figure 4). Cell lines with detected and non-detected HLA-B and HLA-C genes also had significantly different mean AUCs (Welch's t-test P < 0.05, Figure 5).

[0195] Cell lines were clustered into two groups according to the mutational status of each gene, and 12 genes were mutated in at least four cell lines. No genes had significantly different AUCs between the mutant and wild-type cell lines.

[0196] Gene Set Enrichment Analysis (GSEA) was performed using all genes. Correlated genes were enriched in five pathways (nominal P value < 0.01).

[0197] Fourteen genes had a Spearman rank correlation (P value less than 1e-4 (or |R|>0.493)) between their mRNA expression levels and AUC. The 14 biomarker signature genes for hematopoietic cancers are shown in the table below. Clustering of the 57 cell lines using these 14 genes shows that they cluster into two groups with average AUCs of 3.11 and 2.56, respectively (Figure 3).

[0198] [Table 5]

[0199] Biomarker discovery in solid tumor cell lines Z-score normalization of AUC was performed for 254 solid tumor cell lines. Cell lines with a normalization value greater than 0.5 (corresponding to an AUC greater than 3.49) were defined as insensitive, and cell lines with a normalization value less than -0.5 (corresponding to an AUC less than 3.05) were defined as sensitive. 77 sensitive solid cell lines and 89 insensitive solid cell lines were obtained. These 166 cell lines were randomly divided into two data sets: a training set with 52 sensitive and 60 insensitive cell lines, and a test set with 25 sensitive and 29 insensitive cell lines.

[0200] After removing genes with a high proportion of low-expressing cell lines in the training set (>90% of cell lines with expression levels <5), 13,032 genes were retained. The expression of 258 genes had a significant correlation with AUC (Spearman correlation P-value <0.001), and 9 of these (see table below) were selected as signature genes.

[0201] [Table 6]

[0202] The prediction results for the training set using these nine genes show that 61 of 67 cell lines were correctly predicted (probability in subgroups greater than 0.8), 5 cell lines were incorrectly predicted, and 45 cell lines did not yield the expected results (probability in either group less than 0.8, indicating no confidence in calling). In the test set, 23 of 28 cell lines were correctly predicted (probability in subgroups greater than 0.8), 5 cell lines were incorrectly predicted, and 26 did not yield the expected results. The accuracy of drug response prediction was 91% in the training set (Figure 6) and 82.1% in the test set (Figure 7). When the training and test sets were combined, the accuracy was 88.4%.

[0203] Gene copy numbers were converted to integers (CN < 0.5 = 0; CN < 1.5 = 1; CN < 2.5 = 2; CN < 3.5 = 3; CN < 4.5 = 4; CN ≥ 4.5 = 5). Genes with CN > 0 were defined as "deleted," and genes with CN ≥ 4 were defined as "amplified." Fourteen genes (Welch's t-test, P < 0.01) had significantly different mean AUCs between deleted and non-deleted cell lines. 84 genes had significantly different mean AUCs between amplified and non-amplified cell lines (Welch's t-test, P < 1e-5). These genes were clustered in the 20p12 and 20p13 cytobands. Amplification of regions within these cytobands is likely related to drug response.

[0204] Clustering of cell lines into two groups according to the mutational status of each gene revealed that 193 genes were mutated in at least four cell lines. For 15 genes, the mean AUC was significantly different between mutant and wild-type cell lines (Welch's t-test P value < 0.05). Gene Set Enrichment Analysis (GSEA) was performed on 254 solid cell lines. Correlated genes were enriched in 37 pathways (nominal P value < 0.01).

[0205] Those skilled in the art will understand that multiple accession numbers exist for genetic variants and can be found in publicly available databases. Thus, without being limited solely by accession number and associated sequence, genetic variants of genes in the above hematopoietic and solid tumor cancer tables with 75% or greater coverage are considered synonymous sequences.

[0206] Example 3: ATF4 pathway Activating transcription factor 4 (ATF4) is a master regulator of genes essential for the adaptation and control of gene expression in multiple cellular processes.

[0207] ATF4 encodes the transcription factor cAMP-responsive element-binding protein 2 (CREB-2). Induction of ATF4 is governed by phosphorylation of the transcription initiation factor eIF2α at Ser51 by one of four kinases. Phosphorylation of eIF2α reduces the formation of the eIF2α:GTP:tRNAmet ternary complex. Decreased ternary complex formation reduces 43S preinitiation complex formation and cap-dependent mRNA transcription, with a concomitant increase in translation of ATF4-containing mRNAs (Figure 8).

[0208] ATF4 is induced in response to a wide range of cellular stresses, including oxidative, nutritional, and endoplasmic reticulum (ER) stress. Importantly, cellular stress is a hallmark of multiple diseases, including breast, lung, colon, and prostate cancer. The residue Ser 51 Induction of ATF4 by phosphorylating the translation factor eIF2α in tumors induces changes that lead to tumor survival. ATF4 orchestrates a transcriptional program that leads to improved nutrient utilization and transport, as well as increased expression of GADD34, which leads to reduced eIF2α phosphorylation and restoration of normal protein synthesis. Thus, transient ATF4 activation may support tumor survival. ATF4 is a novel and attractive therapeutic target for cancer treatment.

[0209] However, the adaptive nature of ATF4 activation is modulated by the observation that sustained eIF2α phosphorylation and increased ATF4 recruitment activate growth arrest and pro-apoptotic pathways. A key target of ATF4 is the transcription factor C / EBP homologous protein (CHOP / DDIT3). CHOP controls apoptosis by increasing the expression of pro-apoptotic genes, such as TRB3 and BIM, while regulating the expression of anti-apoptotic genes, such as Bcl-2, XIAP, and Mcl1. Genes in the ATF4 pathway are listed in the table below. Pharmacological activation of ATF4 provides an approach to target common oncogenic pathways, which may lead to improved anti-cancer therapeutics.

[0210] [Table 7]

[0211] Antiproliferative Activity of BTM Compounds. The antiproliferative activity of compounds A197 and B19 was compared to 4EGI-1 (a known cancer cell growth inhibitor) in a panel of 99 tumor lines. Methods: The sensitivity of a panel of 96 tumor and 3 normal cells was tested against the test compounds. Cell lines were cultured in standard medium and pipetted into 96-well plates at the required plating density. Cells were allowed to acclimate for 24 hours before compound testing. Compounds were prepared as 20 mM stocks in DMSO. To prepare dose-response curves, compounds were serially diluted in DMSO and dispensed into plate wells using a Tecan D300e digital dispenser. The final DMSO concentration was 0.15%. After 72 hours of culture, cell number was measured using the CellTiter-Glo® protocol according to the manufacturer's instructions (Promega). ATP is measured in this assay as a surrogate for cell number. Compound activity is measured by comparing untreated cells to treated cells and calculating the percentage of signal retained. Compound activity is calculated as the EC 50 The activity of the two samples is then calculated as follows:

[0212] [Table 8]

[0213] Overall, the potencies of Compounds A197 and B19 were 50-100 times greater than that of 4EGI-1. Compounds A197 and B19 were active (IC<2 μM) in 40% of the cell lines tested. 50), with 90% of hematopoietic tumor lines and 28% of solid tumor lines responding. Among solid tumor lines, 80% of NSCLC tumor lines, 37% of colon tumor lines, and 40% of sarcoma tumor lines were responsive. Breast cancer and melanoma lines were largely unresponsive to the compounds (although there were instances in which certain such lines were active). In responsive cell lines, the activity range of compounds A197 and B19 was 0.1–2 μM for most compounds. Certain differences existed between tumor types: all responsive tumor lines underwent G1 growth arrest, whereas apoptosis was observed only in hematopoietic tumor lines, particularly B-cell lymphomas (data not shown). Importantly, testing of primary diploid cells (e.g., human umbilical vein epithelial cells and healthy human lung fibroblasts (NHLFs)) was negative.

[0214] [Table 9]

[0215] Compound A197 concentrations in plasma of CD-1 mice were measured and basic pharmacokinetic parameters were assessed by administering a single oral dose of the drug compared to a single intravenous dose. A197 was dissolved in 0.3% Tween-80 in 1% NMP, 0.5% methylcellulose at a dose volume of 10 ml / kg. After compound administration, blood was collected via tail vein sampling at 30 minutes, 1, 2, 4, 8, 12, 24, and 48 hours post-dose. The data are shown in the table below. Plasma drug concentrations were measured. max was observed at 6 hours. Bioavailability and half-life were estimated at 59% and 5.6 hours, respectively.

[0216] A single-dose escalation mouse pharmacokinetic (PK) study was conducted with compound A197 at 10, 20, 40, 150, and 300 mg / kg. Female CD-1 mice (20-30 g body weight) were administered A197 dissolved in 0.3% Tween-80 in 1% NMP, 0.5% methylcellulose at a dose volume of 10 ml / kg via oral gavage or intravenous injection. After compound administration, blood was collected via tail vein sampling into K2EDTA tubes at 30 min, 1, 3, 5, 7, 24, and 48 h post-dose. Plasma (5 μL) from A197-treated animals was acidified with 5 μL of 0.1% formic acid and 1% ammonium formate in methanol to precipitate proteins and delipidate the plasma. After centrifugation at 1000x, 120 μL samples of the supernatant were dried under vacuum. The deprotonated and defatted residue was resuspended in 200 μL of 1% ammonium formate in methanol, and the centrifugation and drying process was repeated. The dried material was then resuspended in 100 μL of a mixture of 2 parts methanol, 1 part acetonitrile, and 1 part water. A 10 μL sample of this material was then injected onto an Xbridge C18 2.5 μM, 3 × 30 mm, XP column attached to a TSQ Vantage LC / MS system for quantification. The results of this experiment show that dose proportionality was observed up to 300 mg / kg (Figure 9; similar results were observed with compound B19). The PK data indicate that compound A197 and compound B19 have drug-like PK properties suitable for once-daily administration.

[0217] Efficacy demonstrated in human xenograft models The positive results of the PK study led to the evaluation of compounds A197 and B19 in mouse xenograft models of human tumors. Compound A197 was tested in a human tumor xenograft model using the KRAS mutant colorectal cancer cell line HCT-116. Athymic nude mice (HSD: Athymic Nude-Foxn1 nu, Envigo) were inoculated with 5 × 10 6 HCT-116 cells were inoculated subcutaneously into the right hind flank. Animals were then wethen staged and randomized according to tumor size, each with a 150 mm3 Dose groups of 10 animals were created, with a mean tumor volume of 1000 mg / kg. Tumor-bearing mice were administered vehicle (5% NMP, 15% PEG400, 10% Solutol, and 70% D5W) or A197 dissolved in vehicle by oral gavage once daily, resulting in a dose concentration of 10 ml / kg. Compound B19 was tested in a human xenograft model using the human diffuse large B-cell lymphoma line SU-DHL-10 (ATCC). Female SCID beige mice (CB-17 / IcrHsd-PrkdcscidLystbg-J, Envigo) received 5 x 10 6 cells in Matrigel. 6 Cells were inoculated subcutaneously in the right hind flank. Animals were then staged and randomized according to tumor size, each with a 150 mm 3 Dose groups of 10 animals were created, with a mean tumor volume of 1000 mg / kg. Tumor-bearing mice were administered vehicle (5% NMP, 15% PEG400, 10% Solutol, and 70% D5W) or B19 dissolved in vehicle by oral gavage once daily, resulting in a dose concentration of 10 mL / kg. The data clearly demonstrate the antitumor activity of both compounds in hematopoietic and solid tumors (Figure 10). Compound B19 treatment resulted in dose-dependent and durable regression of DLBCL tumors by day 21 (p<0.01 for the 10 and 30 mpk doses). Compound A197 induced a similar level of regression in this model (data not shown). Compound A197 treatment resulted in significantly slower growth in the solid tumor model (p<0.01 for the 75 and 30 mpk doses). Furthermore, compound A197 treatment did not correlate well with overt signs of toxicity as measured using markers of liver function, metabolism, and myelopoiesis.

[0218] Mechanism of Action Screen A series of extensive high-content imaging, transcriptomics, and CRISPR KO screens were conducted to correlate compound A197 activity with its potential mode of action. Data from all studies are summarized in the table below. The outcomes of these screens included two notable observations. Transcriptome analysis revealed that compound A197 induced the ATF4 pathway. In turn, compound A197 induced specific changes in redox (decreased GSH), energy (decreased ATP / AMP ratio), and TCA cycle intermediates (decreased isocitrate / aconitate) in tumor cells but not in NHLF (healthy human lung fibroblast) cells.

[0219] [Table 10]

[0220] ATF4-mediated gene expression profiles are compound-induced. Activation of ATF4 is closely linked to ER stress and the activation of the related TFs ATF6, ERN1, and XBP1. To measure the role of each transcription factor, a set of 15 genes was selected to assess the specificity of the response relative to ATF4 and other transcription factors. Selected genes demonstrated the requirement for specific transcription factors in the absence of specific genes based on the use of gene deletion studies (e.g., genetic deletion of ATF6 significantly eliminates the induction of HSPA6 by ER stress inducers such as tunicamycin, whereas deletion of ATF4 has no such significant effect). Although G1 is noted in the data, cell cycle targets were also included in the panel as distinct effects on progression. These genes can be regulated in various ways, thus reflecting the compound's action: the outcome of cell cycle arrest.

[0221] [Table 11]

[0222] Four cell lines were selected for gene expression profiling. Healthy human lung fibroblasts were selected as an example of a non-responsive cell line. The colorectal cancer cell line HCT-116 and the chronic myeloid leukemia line HAP1 were selected as examples of cell lines responsive to compounds that undergo growth arrest. The diffuse large B-cell lymphoma line SU-DHL-2 was selected as a cell line that undergoes growth arrest and apoptosis. To measure the levels of expressed genes, cells (3 × 10 5 ) were plated onto coated 6-well tissue culture dishes and cultured for 24 hours. After 24 hours, the medium was replaced with medium containing compound 197 at a final concentration of 5 μM. Cells were then incubated with the compound for 8 hours, after which the medium was removed and processed for RNA isolation using the Qiagen RNAEasy Mini Kit according to the manufacturer's instructions. Briefly, cell lysis buffer was added to each well and then homogenized using a QiaShredder column. An equal volume of 70% ethanol was added to the column eluate before applying it to an RNAEasy solid-phase separation column. The column was washed twice to remove fragmented DNA and then eluted with sterile RNase-free water. RNA recovery was measured using a NanoDrop nucleic acid quantification device. RNA (400 μg) was used to generate cDNA using standard methods using ThermoFisher reagents and protocols. QPCR analysis of each gene was performed using standard methods. The probe and primer sequences for the genes are listed in the table below; ThermoFisher Scientific was the supplier of all assays. Three standard reference genes are used for data normalization. Changes in gene expression relative to vehicle are calculated using Expression Analysis software (ThermoFisher).

[0223] [Table 12]

[0224] In three responsive tumor cell lines (HCT-116, HAP-1, and SU-DHL-2), but not in primary NHLFs, compound 197 preferentially induced ATF4, but not ATF6 or IRE1 / Xbp1-regulated genes (Figure 11). Note that CDKN1A (p21 / Waf1) mRNA expression increased upon compound treatment. Recent evidence suggests that CDKN1A expression may be regulated by eIF2α phosphorylation.

[0225] Treatment induces phosphorylation of eIF2α in HCT-116 cells. The canonical pathway of ATF4 induction involves eIF2α phosphorylation. To measure the levels of eIF2α and p-eIF2α, Western blotting was used. HCT-116 cells (1.5 × 10 per well) were cultured in 10% CO2-inducible medium. 5 ) were cultured in 12-well tissue culture dishes and treated with 5 μM compound A197 dissolved in McCoy's complete medium containing 10% FBS for 30 minutes, 1, 2, or 4 hours. After treatment, the medium was removed, and the cells were washed with PBS and then lysed by adding RIPA cell lysis buffer. Cell lysates were then clarified by centrifugation at 14,000 x g for 10 minutes. The concentration of clarified lysate protein was measured using the BCA methodology. All lysates were diluted with RIPA buffer to obtain a final concentration of 200 μg / mL. As a control, starving HCT-116 cells for essential amino acids (EAAs) increased the phosphorylation of eIF2α by EIF2AAK4 (GCN2). HCT-116 cells were plated as described above, but the medium was removed and replaced with Earle's balanced saline solution. All subsequent steps for lysate preparation were identical to those described above. Increased eIF2α phosphorylation during 30 min of compound treatment indicated that eIF2 kinase was activated (FIG. 12).

[0226] Total cellular GSH levels are decreased in tumor lines treated with compound A197. The therapeutic compound causes a dose-dependent decrease in total cellular glutathione in HCT-116, BJAB, and SU-DHL-2, but not NHLF, cells. The maximum decrease in cellular GSH is in the range of 43-69%. The decrease in GSH levels appears to be independent of apoptosis. IC 50 is consistent with the activity of the compounds on cell proliferation, suggesting a correlation between cell proliferation and redox state.

[0227] Effect of Compound A197 on Whole Cell GSH Levels

[0228] NHLF, BJAB, SU-DHL-2, and HCT-116 cells were treated with compound A197 for 4 hours prior to lysate collection. Total cellular glutathione (GSH) levels were measured using a luminescence endpoint (GSH-Glo, Promega). Cell proliferation was measured 72 hours after compound treatment using Cell-Titre Glo. All data shown are the mean ± SD of three biological replicates.

[0229] [Table 13]

[0230] Example 4: ISR and metabolite biomarker prediction of tumor cell antiproliferative responses to therapeutic compounds of the present disclosure BCL tumor cell lines, six CRC lines with varying degrees of sensitivity to the therapeutic compounds, and three healthy primary cell lines with non-antiproliferative responses are tested. Compounds A197 and B19 are tested along with compound A201a, a relatively inactive positional isomer of compound A197, which serves as a control. Cells are tested over a range of concentrations from 0.01 to 10 μM. The extent of cell proliferation and apoptosis is measured using high-content cellular imaging at 24 and 72 hours. Genetic RNA profiling is performed using QPCR on RNA samples collected at 8, 24, and 72 hours. Sampling for metabolite profiling occurs at 1 and 6 hours, consistent with previous studies showing effects on ATP / AMP ratios and GSH levels.

[0231] ATP and AMP are extracted using hot ethanol and quantified by LC-MS. GSH is measured using GSH-Glo (Promega). Mitochondrial morphology and mitochondrial membrane potential are measured using confocal microscopy of cells stained with JC1 or TMRE. Mitochondrial staining studies are performed using the adherent CML line HAP1, CRC tumor lines, and NHLF. Exposure times range from 30 minutes to 72 hours. All experimental data are collected as three biological replicates and technical duplicates for each data point.

[0232] Compound-mediated changes in tumor, but not healthy, cell lines can be used as pharmacodynamic markers of compound activity, rather than as surrogates for compound efficacy. Correlations of gene response or metabolite profiles to antiproliferative activity (greater than 70% sensitivity and specificity) provide sufficient preliminary evidence of prognostic value to expand screening to more cell lines. Additional transcript or metabolite markers can be evaluated to improve results, as can the number of cells screened.

[0233] Example 5: Transcriptomic and metabolomic functional pathways and biomarkers associated with antiproliferative responses to therapeutic compounds Analysis of global gene expression and metabolite profiles in responsive KRAS mutant (HCT-116, LoVo) and non-responsive KRAS mutant (SW480) CRC cell lines identifies biomarkers associated with functional response to a single active therapeutic compound. Controls include vehicle and a negative control compound. Samples are prepared using a concentration of compound at 8 and 24 hours post-treatment. Global gene expression profiles are measured using RNASeq. Metabolite profiling samples are prepared using high-temperature extraction of metabolites followed by LC-MS detection. All data points include three biological replicates. Data are analyzed using standard statistical approaches by comparing the response to vehicle at each time point.

[0234] RNA or metabolite biomarkers discovered in responsive but not non-responsive cell lines will be identified. Identified markers will be further evaluated in a broader panel of CRC cell lines and expanded to other solid tumor types.

[0235] Example 6: Cell viability (IC50) of cancer cell lines Viability of 407 cancer cell lines was measured after treatment with compound A197, standard chemotherapy (cisplatin) as a reference control, or medium vehicle control medium containing 0.25% (vol / vol) DMSO. Viability was measured using the 50% inhibitory concentration (IC50) as measured by the CellTiter-Glo® Viability Assay (Promega). All cells were cultured under standard conditions at 37°C, 5% CO2, and 95% humidity in medium suspended with 10-15% fetal bovine serum.

[0236] The experiment began by first thawing and equilibrating the CellTiter-Glo® buffer to room temperature. The lyophilized CellTiter-Glo® substrate was also equilibrated to room temperature. The lyophilized substrate was reconstituted with the CellTiter-Glo® buffer to form the CellTiter-Glo® reagent.

[0237] Cells were harvested during the logarithmic growth phase, counted, and cultured to a cell concentration of 4.44 x 10. 4 As indicated, 4 × 10 cells / mL were added to 90 μL of cell suspension. 3 A final cell density of 100 cells / well was added to plates A and B.

[0238] [Table 14]

[0239] [Table 15]

[0240] Cells were grown overnight, and the following day, TO readings were obtained by adding 10 μL of medium to each well of Plate A. After equilibrating the plate at room temperature for 30 minutes, 50 μL of CellTiter-Glo® Reagent was added to each well. The contents were mixed on an orbital shaker for 5 minutes to induce cell lysis. The plate was incubated for 20 minutes to allow the luminescence signal to stabilize, and TO luminescence was recorded.

[0241] The IC50s of the test compounds and the reference control, Plate B, were determined by first preparing a 10x solution of compound A197 to achieve nine dose levels. A 10x reference control solution of cisplatin was also prepared. Compound A197 and cisplatin were dispensed into appropriate wells of Plate B with drug concentrations distributed in triplicate. Test Plate B was incubated for 96 hours at 37°C, 5% CO2 in a humidified incubator.

[0242] After incubation, the plate was equilibrated at room temperature for 30 minutes. CellTiter-Glo® (50 μL) was added to each well of the plate, and the contents were mixed on an orbital shaker for 5 minutes to induce cell lysis. The luminescence signal was allowed to stabilize at room temperature for 20 minutes, and luminescence was recorded.

[0243] Dose-response curves were fitted using a nonlinear regression model with a sigmoidal dose-response to determine the IC 50 (EC 50 ) was calculated. The survival rate was calculated using the following formula: Survival rate (%)=(Lum 試験物品 -Lum 培地対照 ) / (Lum 未処理 -Lum 培地対照 )×100%.

[0244] Absolute IC50 (EC50) was calculated according to the dose-response curve generated by statistical software (GraphPad Prism 5.0). The IC50 and maximum inhibition against the test cell lines are shown in Tables 6-1 to 6-16.

[0245] [Table 16]

[0246] [Table 17]

[0247] [Table 18]

[0248] [Table 19]

[0249] [Table 20]

[0250] Table 21

[0251] Table 22

[0252] Table 23

[0253] Table 24

[0254] Table 25

[0255] Table 26

[0256] Table 27

[0257] Table 28

[0258] Table 29

[0259] Table 30

[0260] [Table 31]

[0261] Example 7: Expression of FAM210B regulates the induction of ATF4 by compounds of the present disclosure FAM210B, identified in Example 2, was further investigated as a biomarker for both hematopoietic and solid tumor cancers.

[0262] Analysis of data from the Protein Atlas showed that low levels of FAM210B protein correlated with unfavorable treatment outcomes using conventional therapies in solid tumors (Figure 13). And, as shown in Figure 14, FAM210B CCLE expression data for solid tumors correlates well with AUC (see, e.g., Example 2) (for solid tumors, the regression / Spearman correlation coefficient R value = 0.43). However, FAM210B expression for hematopoietic tumors does not correlate with AUC. Furthermore, cell line profiling showed that FAM210B expression is significantly lower in hematopoietic tumors compared to solid tumors (Figure 15), with diffuse large B-cell lymphoma (DLBCL) and Burkitt's lymphoma showing the lowest FAM210B expression levels.

[0263] The inventors have determined that FAM210B is a powerful marker for predicting response to compounds of the present disclosure, such as compounds A197 and B19, in solid tumors. As shown in Figure 16, two genes—FAM210B and NUDT2—carry the bulk of the fractionation that predicts response to compounds of the present disclosure.

[0264] FAM210B transfected cells reduced compound B5-mediated ATF4 induction.

[0265] HCT-116 cells were transfected with vectors expressing tGFP or FAM210B GFP. After 48 hours, cells were treated with 3 mM Compound B5. Four hours after drug treatment, cells were fixed and permeabilized, and ATF4 levels were measured by immunofluorescence (IF), and FAM210B levels were measured by detecting GFP. Cells were discarded based on median ATF4 protein expression and ranked relative to the level of FAM210B-tGFP. As shown in Figures 17 and 18, ATF4 expression decreased in a dose-dependent manner as FAM210B expression increased. These results indicate that Compound B5 induction of ATF4 is inhibited by FAM210B expression in HCT-116 cells, demonstrating a dose-dependent effect of FAM210B expression on Compound B5-mediated ATF4 gene induction.

[0266] Selectivity of the effect of FAM210B Expression of FAM210B does not affect the induction of ATF4 by tunicamycin, arsenite, or nutrient withdrawal (see Figure 8). The lack of effect on alternative pathways of ATF4 induction suggests a lack of interaction involving at least two pathways that lead to eIF2a phosphorylation: PERK and GCN2. The lack of interaction with arsenite-mediated ATF4 expression suggests that compound B5 does not function by activating HRI.

[0267] Follow-up studies showed that PERK inhibitors had no effect on Compound B5-mediated induction of ATF4, suggesting that ER stress does not play a role in the activity of compounds of the present disclosure.

[0268] The role of the HRI and PRK pathways in the induction of ATF4 can be confirmed using knockdown studies.

[0269] Collectively, the data suggest that FAM210B expression uniquely regulates the induction of ATF4 by the therapeutic compounds of the present disclosure.

[0270] The present disclosure further provides the following enumerated embodiments, which can be combined in any number and in any manner that is not technically or logically inconsistent to form other embodiments of the present disclosure.

[0271] Embodiment 1 1. A method for treating cancer in a human individual, comprising: measuring the expression levels of multiple genes in the cancer; measuring a fold change in gene expression relative to the expression levels of the plurality of genes in a reference cell; and administering to the human individual an effective amount of a therapeutic compound of the present disclosure if the fold change in gene expression is greater for a plurality of genes in h that is 5 or greater.

[0272] Embodiment 2 2. The method of embodiment 1, wherein the cancer is a hematopoietic cancer.

[0273] Embodiment 3 3. The method of embodiment 2, wherein the hematopoietic cancer is a chronic myeloproliferative neoplasm.

[0274] Embodiment 4 3. The method of embodiment 2, wherein the hematopoietic cancer is lymphoma.

[0275] Embodiment 5 5. The method of embodiment 4, wherein the lymphoma is Burkitt lymphoma, Hodgkin lymphoma, non-Hodgkin lymphoma, hairy cell lymphoma, mantle cell lymphoma, T-cell lymphoma, cutaneous T-cell lymphoma, B-cell lymphoma, diffuse large B-cell lymphoma, double-hit lymphoma, Waldenstrom's macroglobulinemia, primary central nervous system (CNS) lymphoma, or intravascular large B-cell lymphoma (ILBCL).

[0276] Embodiment 6 3. The method of embodiment 2, wherein the hematopoietic cancer is leukemia.

[0277] Embodiment 7 7. The method of embodiment 6, wherein the leukemia is acute lymphocytic leukemia (ALL), acute myeloid leukemia (AML), acute myeloblastic leukemia, chronic lymphocytic leukemia (CLL), chronic myelogenous leukemia (CML), chronic neutrophilic leukemia (CNL), chronic myelomonocytic leukemia (CMML), aggressive NK-cell leukemia (acute pleoplasmic leukemia, and polycythemia vera), or acute and chronic T-cell and B-cell leukemia.

[0278] Embodiment 8 3. The method of embodiment 2, wherein the hematopoietic cancer is a plasma cell neoplasm.

[0279] Embodiment 9 9. The method of embodiment 8, wherein the plasma cell neoplasm is multiple myeloma, chronic myeloproliferative neoplasm, myelodysplastic syndrome, myelodysplastic / myeloproliferative neoplasia, or chronic myeloproliferative neoplasia.

[0280] Embodiment 10 10. The method of any one of embodiments 2 to 9, wherein the reference cells are non-cancerous cells (eg, of the same type as the hematopoietic cancer) of a human individual.

[0281] Embodiment 11 10. The method of any one of embodiments 2 to 9, wherein the reference cells are non-cancerous cells (eg, of the same type as the hematopoietic cancer) of a different human.

[0282] Embodiment 12 10. The method of any one of embodiments 2 to 9, wherein the reference cells are non-cancerous cells of a cell line (eg, of the same type as the hematopoietic cancer).

[0283] Embodiment 13 The reference cells have an IC of at least 30 μM for a therapeutic compound (e.g., of the same type as the hematopoietic cancer). 50 10. The method according to any one of embodiments 2 to 9, wherein the cells are derived from a cell line having the formula:

[0284] Embodiment 14 14. The method of any of embodiments 2-13, wherein a fold change in gene expression of at least 1.5 is a significant change in gene expression.

[0285] Embodiment 15 14. The method of any of embodiments 2-13, wherein a fold change in gene expression of at least 2 is a significant change in gene expression.

[0286] Embodiment 16 14. The method of any of embodiments 2-13, wherein a fold change in gene expression of at least 3 is a significant change in gene expression.

[0287] Embodiment 17 17. The method of any one of embodiments 2 to 16, wherein the plurality of genes is selected from CASP10, TMED1, PPP1CC, TMEM59, BRD7, CYB561, FAM210B, NDRG1, CTSB, MMAB, SETDB2, VPS37B, ELL3, and KIF13B.

[0288] Embodiment 18 18. The method of embodiment 17, wherein the first number is 7 or more, such as 8 or more, 9 or more, or 10 or more.

[0289] Embodiment 19 18. The method of embodiment 17, wherein the first number is 11 or more, 12 or more, or 13 or more.

[0290] Embodiment 20 20. The method of any one of embodiments 17-19, wherein at least one of the plurality of genes is CASP10 (eg, CASP10 is one of the first number of genes).

[0291] Embodiment 21 21. The method of any of embodiments 17-20, wherein at least one of the plurality of genes is TMED1 (e.g., TMED1 is one of the first number of genes).

[0292] Embodiment 22 22. The method of any of embodiments 17-21, wherein at least one of the plurality of genes is PPP1CC (eg, PPP1CC is one of the first number of genes).

[0293] Embodiment 23 23. The method of any of embodiments 17-22, wherein at least one of the plurality of genes is TMEM59 (eg, TMEM59 is one of the first number of genes).

[0294] Embodiment 24 24. The method of any one of embodiments 17-23, wherein at least one of the plurality of genes is BRD7 (e.g., BRD7 is one of the first number of genes).

[0295] Embodiment 25 25. The method of any of embodiments 17-24, wherein at least one of the plurality of genes is CYB561 (e.g., CYB561 is one of the first number of genes).

[0296] Embodiment 26 26. The method of any of embodiments 17-25, wherein at least one of the plurality of genes is FAM210B (eg, FAM210B is one of the first number of genes).

[0297] Embodiment 27 27. The method of any of embodiments 17-26, wherein at least one of the plurality of genes is NDRG1 (eg, NDRG1 is one of the first number of genes).

[0298] Embodiment 28 28. The method of any of embodiments 17-27, wherein at least one of the plurality of genes is CTSB (e.g., CTSB is one of the first number of genes).

[0299] Embodiment 29 29. The method of any of embodiments 17-28, wherein at least one of the plurality of genes is MMAB (eg, MMAB is one of the first number of genes).

[0300] Embodiment 30 30. The method of any of embodiments 17-29, wherein at least one of the plurality of genes is SETDB2 (e.g., SETDB2 is one of the first number of genes).

[0301] Embodiment 31 31. The method of any of embodiments 17-30, wherein at least one of the plurality of genes is VPS37B (e.g., VPS37B is one of the first number of genes).

[0302] Embodiment 32 32. The method of any of embodiments 17-31, wherein at least one of the plurality of genes is ELL3 (eg, ELL3 is one of the first number of genes).

[0303] Embodiment 33 33. The method of any one of embodiments 17-32, wherein at least one of the plurality of genes is KIF13B (eg, KIF13B is one of the first number of genes).

[0304] Embodiment 34 18. The method of embodiment 17, wherein the first number is 14.

[0305] Embodiment 35 2. The method of embodiment 1, wherein the cancer is a solid tumor cancer.

[0306] Embodiment 36 36. The method of embodiment 35, wherein the solid tumor cancer is adrenal gland cancer, bile duct cancer, bone or muscle cancer, cervical cancer, colorectal cancer, esophageal cancer, eye cancer, head and neck cancer (e.g., nasal cancer, tongue cancer, thyroid cancer, or submandibular gland cancer), kidney cancer, liver cancer, colon cancer, small cell lung cancer or non-small cell lung cancer, nervous system cancer, ovarian cancer, pancreatic cancer, placental cancer, prostate cancer, skin cancer, small intestine cancer, stomach cancer, or uterine cancer.

[0307] Embodiment 37 36. The method of embodiment 35, wherein the solid tumor cancer is a soft tissue cancer.

[0308] Embodiment 38 38. The method of any of embodiments 35-37, wherein the reference cells are non-cancerous cells (eg, of the same type as the solid tumor cancer) of a human individual.

[0309] Embodiment 39 39. The method of any of embodiments 35-38, wherein the reference cells are non-cancerous cells (eg, of the same type as the solid tumor cancer) of a different human.

[0310] Embodiment 40 39. The method of any of embodiments 35-38, wherein the reference cells are non-cancerous cells from a cell line (eg, of the same type as the solid tumor cancer).

[0311] Embodiment 41 The reference cells have an IC of at least 30 μM for the therapeutic compound (e.g., of the same type as the solid tumor cancer). 50 39. The method according to any one of embodiments 35 to 38, wherein the cells are derived from a cancer cell line having the following structure:

[0312] Embodiment 42 42. The method of any of embodiments 35-41, wherein a fold change in gene expression of at least 1.5 is a significant change in gene expression.

[0313] Embodiment 43 42. The method of any of embodiments 35-41, wherein a fold change in gene expression of at least 2 is a significant change in gene expression.

[0314] EMBODIMENT 44 42. The method of any of embodiments 35-41, wherein a fold change in gene expression of at least 3 is a significant change in gene expression.

[0315] Embodiment 45 45. The method of any one of embodiments 35 to 44, wherein the plurality of genes is selected from the group consisting of LAMC3, FAM210B, SENP8, ITGB3BP, NUDT2, HNRNPCL1, C20orf43, FRMD8, and STX16.

[0316] Embodiment 46 46. ​​The method of embodiment 45, wherein the first number is 5 or more, for example 6 or more.

[0317] Embodiment 47 46. ​​The method of embodiment 45, wherein the first number is 7 or more, for example 8 or more.

[0318] Embodiment 48 48. The method of any of embodiments 45-47, wherein at least one of the plurality of genes is LAMC3 (e.g., LAMC3 is one of the first number of genes).

[0319] Embodiment 49 49. The method of any of embodiments 45-48, wherein at least one of the plurality of genes is FAM210B (eg, FAM210B is one of the first number of genes).

[0320] Embodiment 50 50. The method of any of embodiments 45-49, wherein at least one of the plurality of genes is SENP8 (e.g., SENP8 is one of the first number of genes).

[0321] Embodiment 51 51. The method of any of embodiments 45-50, wherein at least one of the plurality of genes is ITGB3BP (eg, ITGB3BP is one of the first number of genes).

[0322] Embodiment 52 52. The method of any of embodiments 45-51, wherein at least one of the plurality of genes is NUDT2 (e.g., NUDT2 is one of the first number of genes).

[0323] Embodiment 53 53. The method of any of embodiments 45-52, wherein at least one of the plurality of genes is HNRNPCL1 (eg, HNRNPCL1 is one of the first number of genes).

[0324] EMBODIMENT 54 54. The method of any of embodiments 45-53, wherein at least one of the plurality of genes is C20orf43 (eg, C20orf43 is one of the first number of genes).

[0325] Embodiment 55 55. The method of any of embodiments 45-54, wherein at least one of the plurality of genes is FRMD8 (e.g., FRMD8 is one of the first number of genes).

[0326] Embodiment 56 56. The method of any of embodiments 45-55, wherein at least one of the plurality of genes is STX16 (e.g., STX16 is one of the first number of genes).

[0327] Embodiment 57 46. ​​The method of embodiment 45, wherein the first number is 9.

[0328] Embodiment 58 1. A method for treating hematopoietic cancer in a human individual, comprising: To measure the gene copy number for KIAA0125 in hematopoietic cancers, administering to the human individual an effective amount of a therapeutic compound of the present disclosure when the gene copy number is at least a second number, wherein the second number is at least two; A method comprising:

[0329] Embodiment 59 59. The method of embodiment 58, wherein the second number is at least four.

[0330] Embodiment 60 The method of embodiment 58 or embodiment 59, wherein the hematopoietic cancer is as described in any of embodiments 3 to 9.

[0331] Embodiment 61 1. A method for treating hematopoietic cancer in a human individual, comprising: Measuring the gene copy number for HLA-B and / or HLA-C of hematopoietic cancer; if the gene copy number is equal to or less than a third number, wherein the third number is equal to or less than 0.40, administering to the human individual an effective amount of a therapeutic compound of the present disclosure; A method comprising:

[0332] Embodiment 62 62. The method of embodiment 61, wherein the third number is 0.1 or less, or 0.07 or less.

[0333] Embodiment 63 The method of embodiment 61 or embodiment 62, wherein the hematopoietic cancer is as described in any of embodiments 3 to 9.

[0334] EMBODIMENT 64 1. A method of determining whether a cancer is responsive to a therapeutic compound of the present disclosure, comprising: measuring the expression levels of multiple genes in the cancer; measuring a fold change in gene expression compared to the expression level of one or more genes in a reference cell; identifying the cancer as likely to be responsive to the therapeutic compound if the fold change in gene expression is greater for a first number of genes, the first number being 5 or greater; A method comprising:

[0335] Embodiment 65 The method of embodiment 64, wherein the cancer is a hematopoietic cancer (e.g., as described with respect to any of embodiments 3-9), and the method is carried out as described in any of embodiments 10-34.

[0336] Embodiment 66 The method of embodiment 64, wherein the cancer is a solid tumor cancer (e.g., as described in any of embodiments 36 and 37), and the method is carried out as described in any of embodiments 38 to 57.

[0337] Embodiment 67 1. A method of determining whether a hematopoietic cancer (e.g., as described in any of embodiments 3-9) is responsive to a therapeutic compound of the present disclosure, comprising: To measure the gene copy number for KIAA0125 in hematopoietic cancers, identifying the cancer as likely to be responsive to the therapeutic compound if the gene copy number is at least a second number that is at least two; A method comprising:

[0338] Embodiment 68 68. The method of embodiment 67, wherein the second number is at least four.

[0339] Embodiment 69 1. A method of determining whether a hematopoietic cancer (e.g., as described in any of embodiments 3-9) is responsive to a therapeutic compound of the present disclosure, comprising: Measuring the gene copy number for HLA-B and / or HLA-C of hematopoietic cancer; identifying the cancer as likely to be responsive to the therapeutic compound if the gene copy number is less than or equal to a third number, the third number being less than or equal to 0.10; A method comprising:

[0340] Embodiment 70 70. The method of embodiment 69, wherein the third number is 0.07 or less.

[0341] Embodiment 71 A method for treating cancer in a human individual, comprising administering to the human individual an effective amount of a therapeutic compound of the present disclosure.

[0342] Embodiment 72 72. The method of embodiment 71, wherein the cancer is a hematopoietic cancer (e.g., as described in connection with any of embodiments 3-9) that exhibits a significant fold change in gene expression compared to a reference cell for a first number of genes selected from CASP10, TMED1, PPP1CC, TMEM59, BRD7, CYB561, FAM210B, NDRG1, CTSB, MMAB, SETDB2, VPS37B, ELL3, and KIF13B, and the first number is at least 5.

[0343] Embodiment 73 The method of embodiment 72, wherein the details of determining the fold change in gene expression are as described in any of embodiments 10 to 34.

[0344] EMBODIMENT 74 72. The method of embodiment 71, wherein the cancer is a solid tumor cancer (e.g., as described in connection with any of embodiments 36 and 37) that exhibits a significant fold change in gene expression compared to a reference cell for a first number of genes selected from LAMC3, FAM210B, SENP8, ITGB3BP, NUDT2, HNRNPCL1, C20orf43, FRMD8, and STX16, and the first number is at least 5.

[0345] Embodiment 75 The method of embodiment 74, wherein the details of determining the fold change in gene expression are as described in any of embodiments 38 to 57.

[0346] Embodiment 76 The method of embodiment 71, wherein the cancer is a hematopoietic cancer exhibiting a gene copy number for HLA-B and / or HLA-C of 0.10 or less (e.g., 0.07 or less), e.g., the hematopoietic cancer is as described in any of embodiments 3 to 9.

[0347] Embodiment 77 The method of embodiment 71, wherein the cancer is a hematopoietic cancer exhibiting a gene copy number for KIAA0125 that is at least 2 (e.g., at least 4), e.g., the hematopoietic cancer is as described in any of embodiments 3-9.

[0348] Embodiment 78 1. A method of treating solid tumor cancer in a human individual using a therapeutic compound of the present disclosure, comprising: measuring the expression level of FAM210B in the cancer; measuring the fold change in expression of FAM210B compared to the expression level of FAM210B in a reference cell; If the fold change in expression of FAM210B is significant and if FAM210B expression in the cancer is lower than FAM210B expression in the reference cell, administering an effective amount of a therapeutic compound to the human individual; A method comprising:

[0349] Embodiment 79 A method for treating solid tumor cancer in a human individual, comprising administering to the human individual an effective amount of a therapeutic compound of the present disclosure, wherein the solid tumor cancer exhibits significant FAM210B expression compared to the expression level of FAM210B in reference cells, and wherein FAM210B expression in the cancer is lower than FAM210B expression in the reference cells.

[0350] Embodiment 80 1. A method for determining whether a solid tumor cancer is responsive to a therapeutic compound of the present disclosure, comprising: measuring the expression level of FAM210B in the cancer; measuring the fold change in expression of FAM210B compared to the expression level of FAM210B in a reference cell; Identifying the cancer as likely to be responsive to the therapeutic compound if the fold change in expression of FAM210B is significant and if FAM210B expression in the cancer is lower than FAM210B expression in the reference cells; A method comprising:

[0351] Embodiment 80 81. The method of any of embodiments 78-80, wherein the solid tumor cancer is adrenal gland cancer, bile duct cancer, bone or muscle cancer, cervical cancer, colorectal cancer, esophageal cancer, eye cancer, head and neck cancer (e.g., nasal cancer, tongue cancer, thyroid cancer, or submandibular gland cancer), kidney cancer, liver cancer, colon cancer, small cell lung cancer or non-small cell lung cancer, nervous system cancer, ovarian cancer, pancreatic cancer, placental cancer, prostate cancer, skin cancer, small intestine cancer, stomach cancer, or uterine cancer.

[0352] Embodiment 81 The method of any of embodiments 78-80, wherein the solid tumor cancer is a soft tissue cancer.

[0353] Embodiment 82 82. The method of any of embodiments 78-81, wherein the reference cells are non-cancerous cells (eg, of the same type as the solid tumor cancer) of a human individual.

[0354] Embodiment 83 82. The method of any of embodiments 78-81, wherein the reference cells are non-cancerous cells (eg, of the same type as the solid tumor cancer) of a different human.

[0355] Embodiment 84 82. The method of any of embodiments 78-81, wherein the reference cells are non-cancerous cells from a cell line (eg, of the same type as the solid tumor cancer).

[0356] Embodiment 85 The reference cells have an IC of at least 30 μM for the therapeutic compound (e.g., of the same type as the solid tumor cancer). 50 82. The method of any one of embodiments 78 to 81, wherein the cells are derived from a cancer cell line having the following:

[0357] Embodiment 86 86. The method of any of embodiments 78-85, wherein a fold change in gene expression of at least 1.5 is a significant change in gene expression.

[0358] Embodiment 87 86. The method of any of embodiments 78-85, wherein a fold change in gene expression of at least 2 is a significant change in gene expression.

[0359] Embodiment 88 86. The method of any of embodiments 78-85, wherein a fold change in gene expression of at least 3 is a significant change in gene expression.

[0360] Embodiment 89 89. The method of any of embodiments 1-88, wherein the therapeutic compound has the formula: [ka] [In formula (I), the ring system denoted by "a" is defined as a heteroaromatic compound, optionally in the form of a pharmaceutically acceptable salt or N-oxide, or solvate or hydrate, wherein: A 1A is a bond, -C(O)-, -S-, -S(O) 1-2 -, -O-, -NR 6 -, -C(O)NR 6 -, -NR 6 C(O)-, -C(S)NR 6 -, -NR 6 C(S)-, -C(O)O-, -OC(O)-, -C(O)S-, -SC(O)-, -C(S)O-, -OC(S)-, -C(S)S-, -SC(S)-, -S(O) 1-2 O-, -OS(O) 1-2 -, -S(O) 1―2 NR 6 - and -NR 6 S(O) 1-2 - selected from the group consisting of L 1A is selected from the group consisting of a bond, unsubstituted C1-C4 alkylene, unsubstituted C1-C4 alkenylene, and unsubstituted C1-C4 alkynylene; A 1B is a bond, -C(O)-, -S-, -S(O) 1―2 -, -O-, -NR 6 -, -C(O)NR 6 -, -NR 6C(O)-, -C(S)NR 6 -, -NR 6 C(S)-, -C(O)O-, -OC(O)-, -C(O)S-, -SC(O)-, -C(S)O-, -OC(S)-, -C(S)S-, -SC(S)-, -S(O) 1―2 O-, -OS(O) 1―2 -, -S(O) 1―2 NR 6 - and -NR 6 S(O) 1―2 - selected from the group consisting of L 1B is selected from the group consisting of a bond, unsubstituted C1-C4 alkylene, unsubstituted C1-C4 alkenylene, and unsubstituted C1-C4 alkynylene; R 1 teeth hydrogen, optionally substituted C1-C8 alkyl, optionally substituted C1-C8 alkenyl, and optionally substituted C1-C8 alkynyl; 1-5 R 1E cycloalkyl and heterocycloalkyl substituted with Each of them can be any of 1-5 R 1E and wherein the aryl and heteroaryl are selected from the group consisting of aryl and heteroaryl substituted with During the ceremony, Each R 1E is oxo, optionally substituted C1-C4 alkyl, C1-C4 fluoroalkyl, halogen, -CN, SF5, -N3, -C(O)R 1F , -SR 1F , -S(O) 1―2 R 1F , -OR 1F , -NR 1G R 1F , -C(O)R 1F , -C(O)NR 1G R 1F , -NR 1G C(O)R 1F , -C(S)NR 1G R 1F , -NR 1G C(S)R 1F , -C(O)OR 1F , -OC(O)R 1F, -C(O)SR 1F , -SC(O)R 1F , -C(S)OR 1F , -OC(S)R 1F , -C(S)SR 1F , -SC(S)R 1F , -S(O) 1―2 OR 1F , -OS(O) 1―2 R 1F , -S(O) 1―2 NR 1G R 1F , -NR 1G S(O) 1―2 R 1F are independently selected from Each R 1F is independently selected from H, C-C alkyl, C-C fluoroalkyl, C-C hydroxyalkyl, and (C-C alkoxy)C-C alkyl, (C-C alkoxy(C-C alkoxy))C-C alkyl, (C-C alkoxy(C-C alkoxy(C-C alkoxy)))C-C alkyl; Each R 1G is H, C1-C3 alkyl, C1-C3 fluoroalkyl, C1-C3 hydroxyalkyl, (C1-C3 alkoxy)C1-C3 alkyl, -S(O) 1―2 (C1-C3 alkyl), -C(O)(C1-C3 alkyl), and -C(O)O(C 1― C alkyl), L 2 is selected from the group consisting of a bond, —CH—, —CH(CH)—, or —CHCH—; Q is -H, -CH2OH, -C(O)OH, -C(O)OR 2A , -C(O)NR 2B R 2A , -C(O)NR 2B S(O)2R 2A , -C(O)NR 2B S(O)NR 2B R 2A , -C(O)R 2A , -S(O)2OH, -P(O)(OH)2, -C(OH)(CF3)2, S(O)2R 2A , -N(R2B )S(O)2R 2A , -S(O)NR 2B R 2A , -C(O)NHOH, -C(O)NH-O(C1-C3 alkyl), -CO(NH)CN, [ka] wherein: Each R 2A is H, C1-C3 alkyl, C1-C3 fluoroalkyl, C1-C3 hydroxyalkyl, C1-C3 aminoalkyl, C1-C3 thioalkyl, (C1-C3 alkoxy)C1-C3 alkyl, -(CH2CH2O) 2-5 -(optionally substituted C1-C3 alkyl)- and heteroaryl optionally substituted with 1 to 2 groups selected from substituents selected from C1-C3 alkyl, C1-C3 fluoroalkyl, hydroxyl, amino, thio, C1-C3 hydroxyalkyl, C1-C3 aminoalkyl, C1-C3 thioalkyl, and -C(O)C1-C3 alkyl; Each R 2B is H, C1-C3 alkyl, C1-C3 fluoroalkyl, C1-C3 hydroxyalkyl, C1-C3 aminoalkyl, C1-C3 thioalkyl, (C1-C3 alkoxy)C1-C3 alkyl, -S(O) 1―2 (C-C alkyl), —C(O)(C-C alkyl), and —C(O)O(C-C alkyl); Or R 2A and R 2B together with the nitrogen to which they are both directly attached form a heterocycloalkyl optionally substituted with 1 to 3 substituents selected from C-C alkyl, C-C fluoroalkyl, hydroxyl, amino, thio, C-C hydroxyalkyl, C-C aminoalkyl, C-C thioalkyl, and —C(O)C-C alkyl; L 3 is a bond, -C(O)-, -S-, -S(O) 1―2 -, -O-, -NR 6-, -CH2-, -CH(CH3)(OH)-, -CH(OH)-, -CH2CH2-, -C(O)NR 6 -, -NR 6 C(O)-, -C(S)NR 6 -, -NR 6 C(S)-, -C(O)O-, -OC(O)-, -S(O) 1―2 O-, -OS(O) 1―2 -, -S(O) 1―2 NR 6 - or -NR 6 S(O) 1―2 - and R 3 teeth, Each is (i)-L 3C -(1-5 R 3D aryl optionally substituted with -L 3C -(1-5 R 3D heteroaryl optionally substituted with 3C -(1-5 R 3E cycloalkyl optionally substituted with -L 3C -(1-5 R 3E (ii) 1-5 R 3E cycloalkyl and heterocycloalkyl optionally substituted with Each is (i)-L 3C -(1-5 R 3D aryl optionally substituted with -L 3C -(1-5 R 3D heteroaryl optionally substituted with 3C -(1-5 R 3E cycloalkyl optionally substituted with -L 3C -(1-5 R 3E (ii) 1-5 R 3E is selected from the group consisting of aryl and heteroaryl, optionally substituted with During the ceremony, Each L 3Cis a bond, methylene, ethylene, -C(O)-, -S-, -S(O) 1―2 -, -O-, or -NR 3G - and each 3D is optionally substituted C1-C4 alkyl, C1-C4 fluoroalkyl, halogen, -CN, SF5, -N3, -C(O)R 3F , -SR 3F , -S(O) 1―2 R 3F , -OR 3F , -NR 3G R 3F , -C(O)R 3F , -C(O)NR 3G R 3F , -NR 3G C(O)R 3F , -C(S)NR 3G R 3F , -NR 3G C(S)R 3F , -C(O)OR 3F , -OC(O)R 3F , -C(O)SR 3F , -SC(O)R 3F , -C(S)OR 3F , -OC(S)R 3F , -C(S)SR 3F , -SC(S)R 3F , -S(O) 1―2 OR 3F , -OS(O) 1―2 R 3F , -S(O) 1―2 NR 3G R 3F , -NR 3G S(O) 1―2 R 3F , -OC(O)OR 3F , -OC(O)NR 3G R 3F , -NR 3G C(O)OR 3F , -NR 3G C(O)NR 3G R 3F , -SC(O)OR 3F , -OC(O)SR 3F , -SC(O)SR 3F , -SC(O)NR 3G R3F , -NR 3G C(O)SR 3F , -OC(S)OR 3F , -OC(S)NR 3G R 3F , -NR 3G C(S)OR 3F , -NR 3G C(S)NR 3G R 3F , -SC(S)OR 3F , -OC(S)SR 3F , -SC(S)SR 3F , -SC(S)NR 3G R 3F , -NR 3G C(S)SR 3F , -NR 3G C(NR 3G )NR 3G R 3F , and -NR 3G S(O) 1―2 NR 3G R 3F are independently selected from Each R 3E is oxo, optionally substituted C1-C4 alkyl, C1-C4 fluoroalkyl, halogen, -CN, SF5, -N3, -C(O)R 3F , -SR 3F , -S(O) 1―2 R 3F , -OR 3F , -NR 3G R 3F , -C(O)R 3F , -C(O)NR 3G R 3F , -NR 3G C(O)R 3F , -C(S)NR 3G R 3F , -NR 3G C(S)R 3F , -C(O)OR 3F , -OC(O)R 3F , -C(O)SR 3F , -SC(O)R 3F , -C(S)OR 3F , -OC(S)R 3F , -C(S)SR 3F , -SC(S)R 3F, -S(O) 1―2 OR 3F , -OS(O) 1―2 R 3F , -S(O) 1―2 NR 3G R 3F , -NR 3G S(O) 1―2 R 3F , -OC(O)OR 3F , -OC(O)NR 3G R 3F , -NR 3G C(O)OR 3F , -NR 3G C(O)NR 3G R 3F , -SC(O)OR 3F , -OC(O)SR 3F , -SC(O)SR 3F , -SC(O)NR 3G R 3F , -NR 3G C(O)SR 3F , -OC(S)OR 3F , -OC(S)NR 3G R 3F , -NR 3G C(S)OR 3F , -NR 3G C(S)NR 3G R 3F , -SC(S)OR 3F , -OC(S)SR 3F , -SC(S)SR 3F , -SC(S)NR 3G R 3F , -NR 3G C(S)SR 3F , -NR 3G C(NR 3G )NR 3G R 3F , and -NR 3G S(O) 1―2 NR 3G R 3F are independently selected from Each R 3F is independently selected from H, C1-C3 alkyl, C1-C3 fluoroalkyl, and C1-C3 hydroxyalkyl; Each R 3Gis H, C1-C3 alkyl, C1-C3 fluoroalkyl, C1-C3 hydroxyalkyl, -S(O) 1―2 (C-C alkyl), —C(O)(C-C alkyl), and —C(O)O(C-C alkyl); A 4A is a bond, -C(O)-, -S-, -S(O) 1―2 -, -O-, -NR 6 -, -C(O)NR 6 -, -NR 6 C(O)-, -C(S)NR 6 -, -NR 6 C(S)-, -C(O)O-, -OC(O)-, -C(O)S-, -SC(O)-, -C(S)O-, -OC(S)-, -C(S)S-, -SC(S)-, -S(O) 1―2 O-, -OS(O) 1―2 -, -S(O) 1―2 NR 6 - and -NR 6 S(O) 1―2 - selected from the group consisting of L 4A is selected from the group consisting of a bond, unsubstituted C1-C4 alkylene, unsubstituted C1-C4 alkenylene, and unsubstituted C1-C4 alkynylene; A 4B is a bond, -C(O)-, -S-, -S(O) 1―2 -, -O-, -NR 6 -, -C(O)NR 6 -, -NR 6 C(O)-, -C(S)NR 6 -, -NR 6 C(S)-, -C(O)O-, -OC(O)-, -C(O)S-, -SC(O)-, -C(S)O-, -OC(S)-, -C(S)S-, -SC(S)-, -S(O) 1―2 O-, -OS(O) 1―2 -, -S(O) 1―2 NR 6 - and -NR 6 S(O) 1―2 - selected from the group consisting of L 4Bis selected from the group consisting of a bond, unsubstituted C1-C4 alkylene, unsubstituted C1-C4 alkenylene, and unsubstituted C1-C4 alkynylene; R 4 teeth, hydrogen, optionally substituted C1-C8 alkyl, optionally substituted C1-C8 alkenyl, and optionally substituted C1-C8 alkynyl; 1-5 R 4E and is selected from the group consisting of cycloalkyl and heterocycloalkyl substituted with During the ceremony, Each R 4E is oxo, optionally substituted C1-C4 alkyl, C1-C4 fluoroalkyl, halogen, -CN, -SF5, -N3, -C(O)R 4F , -SR 4F , -S(O) 1―2 R 4F , -OR 4F , -NR 4G R 4F , -C(O)R 4F , -C(O)NR 4G R 4F , -NR 4G C(O)R 4F , -C(S)NR 4G R 4F , -NR 1G C(S)R 4F , -C(O)OR 4F , -OC(O)R 4F , BC(O)SR 4F , -SC(O)R 4F , -C(S)OR 4F , -OC(S)R 4F , -C(S)SR 4F , -SC(S)R 4F , -S(O) 1―2 OR 4F , -OS(O) 1―2 R 4F , -S(O) 1―2 NR 4G R 4F , -NR 4G S(O) 1―2 R 4F , -OC(O)OR 4F , -OC(O)NR4G R 4F , -NR 4G C(O)OR 4F , -NR 4G C(O)NR 4G R 4F , -SC(O)OR 4F , -OC(O)SR 4F , -SC(O)SR 4F , -SC(O)NR 4G R 4F , -NR 4G C(O)SR 4F , -OC(S)OR 4F , -OC(S)NR 4G R 4F , -NR 4G C(S)OR 4F , -NR 4G C(S)NR 4G R 4F , -SC(S)OR 4F , -OC(S)SR 4F , -SC(S)SR 4F , -SC(S)NR 4G R 4F , -NR 4G C(S)SR 4F , -NR 4G C(NR 4G )NR 4G R 4F , and -NR 4G S(O) 1―2 NR 4G R 4F are independently selected from Each R 4F is independently selected from H, C1-C3 alkyl, C1-C3 fluoroalkyl, C1-C3 hydroxyalkyl, and (C1-C3 alkoxy)C1-C3 alkyl; Each R 4G is H, C1-C3 alkyl, C1-C3 fluoroalkyl, C1-C3 hydroxyalkyl, and (C1-C3 alkoxy)C1-C3 alkyl, -S(O) 1―2 (C-C alkyl), —C(O)(C-C alkyl), and —C(O)O(C-C alkyl); L 5 -C(O)-, -S-, -S(O) 1―2-, -O-, -NR 6 -, -CH2-, -CH(CH3)(OH)-, -CH(OH)-, -CH2CH2-, -C(O)NR 6 -, -NR 6 C(O)-, -C(S)NR 6 -, -NR 6 C(S)-, -C(O)O-, -OC(O)-, -S(O) 1―2 O-, -OS(O) 1―2 -, -S(O) 1―2 NR 6 - or -NR 6 S(O) 1―2 - and R 5 teeth 1-5 R 5E cycloalkyl and heterocycloalkyl substituted with 1-5 R each 5E is selected from the group consisting of aryl and heteroaryl optionally substituted with During the ceremony, Each R 5E is oxo, optionally substituted C1-C4 alkyl, C1-C4 fluoroalkyl, halogen, -CN, -SF5, -N3, -C(O)R 5F , -SR 5F , -S(O) 1-2 R 5F , -OR 5F , -NR 5G R 5F , -C(O)R 5F , -C(O)NR 5G R 5F , -NR 5G C(O)R 5F , -C(S)NR 5G R 5F , -NR 1G C(S)R 5F , -C(O)OR 5F , -OC(O)R 5F , -C(O)SR 5F , -SC(O)R 5F , -C(S)OR 5F , -OC(S)R 5F , -C(S)SR 5F , -SC(S)R 5F, -S(O) 1―2 OR 5F , -OS(O) 1―2 R 5F , -S(O) 1―2 NR 5G R 5F , -NR 5G S(O) 1―2 R 5F , -OC(O)OR 5F , -OC(O)NR 5G R 5F , -NR 5G C(O)OR 5F , -NR 5G C(O)NR 5G R 5F , -SC(O)OR 5F , -OC(O)SR 5F , -SC(O)SR 5F , -SC(O)NR 5G R 5F , -NR 5G C(O)SR 5F , -OC(S)OR 5F , -OC(S)NR 5G R 5F , -NR 5G C(S)OR 5F , -NR 5G C(S)NR 5G R 5F , -SC(S)OR 5F , -OC(S)SR 5F , -SC(S)SR 5F , -SC(S)NR 5G R 5F , -NR 5G C(S)SR 5F , -NR 5G C(NR 5G )NR 5G R 5F , and -NR 5G S(O) 1―2 NR 5G R 5F are independently selected from Each R 5F is independently selected from H, C1-C3 alkyl, C1-C3 fluoroalkyl, C1-C3 hydroxyalkyl, and (C1-C3 alkoxy)C1-C3 alkyl; Each R 5Gis H, C1-C3 alkyl, C1-C3 fluoroalkyl, C1-C3 hydroxyalkyl, and (C1-C3 alkoxy)C1-C3 alkyl, -S(O) 1―2 (C-C alkyl), —C(O)(C-C alkyl), and —C(O)O(C-C alkyl); X 1 is CR XA ,S,O,NRX B and N, X 2 is CR XA ,S,O,NRX B and N, wherein Each R XA is hydrogen, C1-C4 alkyl, C1-C4 fluoroalkyl, C1-C3 hydroalkyl, (C1-C3 alkoxy)C1-C3 alkyl, halo, -CN, oxo, -SF5, -N3, -C(O)R XC , -SR XC , -S(O) 1―2 R XC , -OR XC , -NR XD R XC wherein each R XC is independently selected from H, C-C alkyl, C-C fluoroalkyl, C-C hydroalkyl, and (C-C alkoxy)C-C alkyl; and each R XD is independently selected from H, C-C alkyl, C-C fluoroalkyl, C-C hydroxyalkyl, and (C-C alkoxy)-C alkyl, —C(O)(C-C alkyl), and —C(O)O(C-C alkyl); Each R XB is H, C1-C3 alkyl, C1-C3 fluoroalkyl, C1-C3 hydroxyalkyl, (C1-C3 alkoxy)C1-C3 alkyl, -C(O)(C1-C3 alkyl), and -C(O)O(C1-C3 alkyl and C1-C4 alkyl-S(O) 1―2 - independently selected from the group consisting of: Z 1 and Z 2 is independently selected from C and N; Y is CR Y or N, wherein R Y is hydrogen, C1-C3 alkyl, C1-C3 fluoroalkyl, C1-C3 hydroalkyl, C1-C3 aminoalkyl, C1-C3 thioalkyl, (C1-C3 alkoxy)C1-C3 alkyl, -S(O) 1―2 (C1-C3 alkyl), halogen, -CN, -SF5, -N3, -C(O)R YC , -SR YC , -S(O) 1―2 R YC , -OR YC , and -NR YD R YC wherein each R YC is independently selected from H, C-C alkyl, and C-C fluoroalkyl; and each R YD are independently selected from H, C1-C3 alkyl, and C1-C3 fluoroalkyl; During the ceremony, Each R 6 is hydrogen, C1-C3 alkyl, C1-C3 fluoroalkyl, C1-C3 hydroxyalkyl, C1-C3 aminoalkyl, C1-C3 thioalkyl, (C1-C3 alkoxy)C1-C3 alkyl, -S(O) 1―2 -(C1-C3 alkyl), -C(O)(C1-C3 alkyl), and -C(O)O(C1-C3 alkyl); Each alkyl, alkylene, alkenyl, alkenylene, alkynyl, and alkynylene is straight or branched; Each optionally substituted alkyl, alkenyl, alkynyl, alkylene, alkenylene, and alkylene may be unsubstituted or substituted with oxo, halogen, —CN, —SF, —N, —C(O)R 8 , -SR 8 , -S(O) 1―2 R 8 , -OR 8 , -NR 9 R 8 , -C(O)NR 9 R 8 , -NR 9 C(O)R 8 , -C(S)NR9 R 8 、-NR 9 C(S)R 8 、-C(O)OR 8 、-OC(O)R 8 、-C(O)SR 8 、-SC(O)R 8 、-C(S)OR 8 、-OC(S)R 8 、-C(S)SR 8 、-SC(S)R 8 、-S(O) 1―2 OR 8 、-OS(O) 1―2 R 8 、-S(O) 1―2 NR 9 R 8 、-NR 9 S(O) 1―2 R 8 、-OC(O)OR 8 、-OC(O)NR 9 R 8 、-NR 9 C(O)OR 8 、-NR 9 C(O)NR 9 R 8 、-SC(O)OR 8 、-OC(O)SR 8 、-SC(O)SR 8 、-SC(O)NR 9 R 8 、-NR 9 C(O)SR 8 、-OC(S)OR 8 、-OC(S)NR 9 R 8 、-NR 9 C(S)OR 8 、-NR 9 C(S)NR 9 R 8 、-SC(S)OR 8 、-OC(S)SR 8 、-SC(S)SR 8 、-SC(S)NR 9 R 8 、-NR 9 C(S)SR 8 、-NR 9 C(NR 9 )NR9 R 8 , and -NR 9 S(O) 1―2 NR 9 R 8 and is substituted with 1-5 substituents independently selected from: Each R 8 is independently selected from H, C1-C3 alkyl, C1-C3 fluoroalkyl, C1-C3 hydroxyalkyl, and (C1-C3 alkoxy)C1-C3 alkyl; Each R 9 is H, C1-C3 alkyl, C1-C3 fluoroalkyl, C1-C3 hydroxyalkyl, and (C1-C3 alkoxy)C1-C3 alkyl, -S(O) 1―2 (C-C alkyl), —C(O)(C-C alkyl), and —C(O)O(C-C alkyl); each cycloalkyl has 3-10 ring carbons and is unsaturated or partially unsaturated, and optionally contains one or two fused cycloalkyl rings, each having 3-8 ring members; each heterocycloalkyl has 3-10 ring members and 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and is unsaturated or partially unsaturated, and optionally contains one or two fused cycloalkyl rings, each having 3-8 ring members; each aryl is phenyl or naphthyl, and optionally contains one or two fused cycloalkyl or heterocycloalkyl rings, each having 4-8 ring members; Each heteroaryl is a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or an 8-10 membered bicyclic heteroaryl having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur, and optionally contains one or two fused cycloalkyl or heterocycloalkyl rings, each having 4-8 ring members.

[0361] Embodiment 90 89. The method of embodiment 88, wherein Y is N.

[0362] Embodiment 91 89. The method of embodiment 88, wherein the compound has the formula: [ka]

[0363] Embodiment 92 L 2 92. The method of any of embodiments 88-91, wherein is a bond.

[0364] Embodiment 93 L 2 92. The method of any of embodiments 88-91, wherein is a bond, —CH2—, —CH(CH3)—, or —CH2CH2.

[0365] Embodiment 94 94. The method of any of embodiments 89-93, wherein Q is —C(O)OH.

[0366] Embodiment 95 Q is -C(O)OH, -CH2OH, -C(O)OR 2A , -C(O)NR 2B R 2A , -C(O)NR 2B S(O)2R 2A , -C(O)NR 2B S(O)NR 2B R 2A , -C(O)R 2A , -S(O)2OH, -P(O)(OH)2, -C(OH)(CF3)2, S(O)2R 2A , -N(R 2B )S(O)2R 2A , -S(O)NR 2B R 2A , -C(O)NH-O(C1-C3 alkyl), -CO(NH)CN, [ka] wherein: Each R 2Ais hydrogen, C1-C3 alkyl, C1-C3 fluoroalkyl, C1-C3 hydroxyalkyl, C1-C3 aminoalkyl, C1-C3 thioalkyl, (C1-C3 alkoxy)C1-C3 alkyl, -(CH2CH2O) 2-5 -(optionally substituted C1-C3 alkyl)- and heteroaryl optionally substituted with 1 to 2 groups selected from substituents selected from C1-C3 alkyl, C1-C3 fluoroalkyl, hydroxyl, amino, thio, C1-C3 hydroxyalkyl, C1-C3 aminoalkyl, C1-C3 thioalkyl, and -C(O)C1-C3 alkyl; Each R 2B is hydrogen, C1-C3 alkyl, C1-C3 fluoroalkyl, C1-C3 hydroxyalkyl, C1-C3 aminoalkyl, C1-C3 thioalkyl, (C1-C3 alkoxy)C1-C3 alkyl, -S(O) 1―2 (C-C alkyl), —C(O)(C-C alkyl), and —C(O)O(C-C alkyl); Or R 2A and R 2B are combined with the nitrogen to which they are both directly attached to form a heterocycloalkyl optionally substituted with 1 to 3 substituents selected from C1-C3 alkyl, C1-C3 fluoroalkyl, hydroxyl, amino, thio, C1-C3 hydroxyalkyl, C1-C3 aminoalkyl, C1-C3 thioalkyl, and —C(O)C1-C3 alkyl; The method of any one of embodiments 89 to 93.

[0367] Embodiment 96 Q is -C(O)O(C1-C3 alkyl); -C(O)NR 2B R 2A [In the formula, R 2A is C1-C3 alkyl, C1-C3 hydroxyalkyl, C1-C3 aminoalkyl, or C1-C3 thioalkyl, and R 2B is H or C1-C3 alkyl; -C(O)NR 2B R2A [In the formula, R 2A and R 2B together with the nitrogen to which they are both directly attached form a heterocycloalkyl optionally substituted with 1 to 3 substituents selected from C-C alkyl, C-C fluoroalkyl, hydroxyl, amino, thio, C-C hydroxyalkyl, C-C aminoalkyl, C-C thioalkyl, and —C(O)C-C alkyl; or -C(O)NR 2B R 2A [In the formula, R 2A -S(O) 1-2 (C1-C3 alkyl), -S(O) 1-2 (C1-C3 fluoroalkyl), or heteroaryl optionally substituted with 1-2 groups selected from substituents selected from C1-C3 alkyl, C1-C3 fluoroalkyl, hydroxyl, amino, thio, C1-C3 hydroxyalkyl, C1-C3 aminoalkyl, C1-C3 thioalkyl, and —C(O)C1-C3 alkyl; R 2B is H or C1-C3 alkyl] 94. The method of any one of embodiments 89 to 93, wherein

[0368] Embodiment 97 R 1 is selected from the group consisting of hydrogen, optionally substituted C1-C8 alkyl, optionally substituted C1-C8 alkenyl, and optionally substituted C1-C8 alkynyl.

[0369] Embodiment 98 R 1 is selected from the group consisting of unsubstituted C1-C8 alkyl, unsubstituted C1-C8 alkenyl, and unsubstituted C1-C8 alkynyl, such as methyl, ethyl, propyl, butenyl, or butyl.

[0370] Embodiment 99 A 1A and L 1Band each is a bond.

[0371] Embodiment 100 A 1A -L 1A -A 1B -L 1B 100. The method of embodiment 99, wherein is -S-, -S(O), or -S(O)2-.

[0372] Embodiment 101 L 3 The method of any of embodiments 89-100, wherein is a bond.

[0373] Embodiment 102 L 3 The method of any of embodiments 89-100, wherein is optionally substituted C1-C4 alkylene, optionally substituted C1-C4 alkenylene, or optionally substituted C1-C4 alkynylene.

[0374] Embodiment 103 L 3 103. The method of embodiment 102, wherein is C1-C3 alkylene optionally substituted with hydroxyl.

[0375] Embodiment 104 L 3 -C(O)-, -S-, -S(O) 1―2 -, -O-, -NR 6 101. The method of any of embodiments 89-100, wherein the aryl group is -, -CH2-, -CH(CH3)(OH)-, -CH(OH)-, or -CH2CH2.

[0376] Embodiment 105 R 3 But 1-5 R 3E The method of any of embodiments 89-104, wherein R is phenyl optionally substituted with R.

[0377] Embodiment 106 R 3 However, (i)-L 3C -(1-5 R3D aryl optionally substituted with -L 3C -(1-5 R 3D heteroaryl optionally substituted with 3C -(1-5 R 3E cycloalkyl optionally substituted with -L 3C -(1-5 R 3E and (ii) 1-5 R 3E The method of any of embodiments 89-104, wherein R is phenyl, optionally substituted with R.

[0378] Embodiment 107 R 3 are each (i) optionally -L 3C -(1-5 R 3D aryl optionally substituted with -L 3C -(1-5 R 3D heteroaryl optionally substituted with 3C -(1-5 R 3E cycloalkyl optionally substituted with -L 3C -(1-5 R 3E and (ii) 1-5 R 3E The method of any of embodiments 89-104, wherein R is aryl or heteroaryl, optionally substituted with R.

[0379] Embodiment 108 Aryl is any R 3E The method of embodiment 106 or embodiment 107, wherein the R is 0 or 1;

[0380] Embodiment 109 R 3 However, 1-5 R 3E105. The method of any of embodiments 89-104, wherein R is heteroaryl (e.g., isothiazole, pyridone, thiadiazole, pyrazine, pyrazolopyrimidine, pyrazolopyridine, imidazole, benzofuran, indole, imidazopyridine, pyridine, pyrazole, isoxazole, triazolopyridine, benzimidazole, thiophene, benzothiophene, furan, or pyrimidine) substituted with

[0381] Embodiment 110 R 3 However, (i) arbitrarily -L 3C -(1-5 R 3D aryl optionally substituted with -L 3C -(1-5 R 3D heteroaryl optionally substituted with 3C -(1-5 R 3E cycloalkyl optionally substituted with -L 3C -(1-5 R 3E and (ii) 1-5 R 3E The method of any of embodiments 89-104, wherein R is heteroaryl (e.g., isothiazole, pyridone, thiadiazole, pyrazine, pyrazolopyrimidine, pyrazolopyridine, imidazole, benzofuran, indole, imidazopyridine, pyridine, pyrazole, isoxazole, triazolopyridine, benzimidazole, thiophene, benzothiophene, furan, or pyrimidine), optionally substituted with

[0382] Embodiment 111 R 4 The method of any of embodiments 89-110, wherein is selected from the group consisting of unsubstituted C1-C8 alkyl, unsubstituted C1-C8 alkenyl, and unsubstituted C1-C8 alkynyl.

[0383] Embodiment 112 R 4The method of any of embodiments 89-110, wherein is selected from the group consisting of hydrogen, optionally substituted C1-C8 alkyl, optionally substituted C1-C8 alkenyl, and optionally substituted C1-C8 alkynyl.

[0384] Embodiment 113 A 4A , L 4B , and L 4A 113. The method of embodiment 111 or embodiment 112, wherein each is a bond.

[0385] Embodiment 114 A 4B -C(O)-, -S-, -S(O) 1―2 -, -O-, -NR 6 -, -C(O)NR 6 -, -NR 6 114. The method of embodiment 113, wherein the aryl group is —C(O)—, —C(O)O—, or —OC(O)—.

[0386] Embodiment 115 A 4B 115. The method of embodiment 114, wherein

[0387] Embodiment 116 L 5 116. The method of any of embodiments 89-115, wherein is a bond.

[0388] Embodiment 117 L 5 -C(O)-, -S-, -S(O) 1―2 -, -O-, -NR 6 The method of any one of embodiments 89 to 115, wherein the aryl group is -, -CH=CH-, -C≡C-, -CH2-, or -CH2CH2-.

[0389] Embodiment 118. R 5 are (i)-L 5C -(1-5 R 5D aryl optionally substituted with -L 5C -(1-5 R 5Dheteroaryl optionally substituted with 5C -(1-5 R 5E cycloalkyl optionally substituted with -L 5C -(1-5 R 5E (ii) 1-5 R 5E The method of any one of embodiments 89-117, wherein R is aryl (e.g., phenyl) optionally substituted with R.

[0390] Embodiment 119 R 5 But 1-5 R 5E The method of any one of embodiments 89-117, wherein R is aryl (e.g., phenyl) optionally substituted with R.

[0391] Embodiment 120 R 5 are (i)-L 5C -(1-5 R 5D aryl optionally substituted with -L 5C -(1-5 R 5D heteroaryl optionally substituted with 5C -(1-5 R 5E cycloalkyl optionally substituted with -L 5C -(1-5 R 5E (ii) 1-5 R 5E The method of any of embodiments 89-117, wherein R is heteroaryl (e.g., isoxazolyl, pyridyl, imidazopyridyl, pyrazolyl, benzoxazole, indolyl, pyrimidinyl), optionally substituted with

[0392] Embodiment 121 90. The method of embodiment 89, wherein the compound has the following structural formula: [ka] [In the formula, L 2is selected from the group consisting of a bond, —CH—, —CH(CH)—, or —CHCH—; Q is -C(O)OH, -H, -CH2OH, -C(O)OR 2A , -C(O)NR 2B R 2A , -C(O)NR 2B S(O)2R 2A , -C(O)NR 2B S(O)NR 2B R 2A , -C(O)R 2A , -S(O)2OH, -P(O)(OH)2, -C(OH)(CF3)2, S(O)2R 2A , -S(O)NR 2B R 2A , -C(O)NHOH, -CO(NH)CN, [ka] wherein: Each R 2A are independently selected from H, C-C alkyl, C-C fluoroalkyl, C-C hydroxyalkyl, C-C aminoalkyl, C-C thioalkyl, (C-C alkoxy)C-C alkyl, and heteroaryl optionally substituted with 1 to 2 groups selected from substituents selected from C-C alkyl, C-C fluoroalkyl, hydroxyl, amino, thio, C-C hydroxyalkyl, C-C aminoalkyl, C-C thioalkyl, and —C(O)C-C alkyl; Each R 2B is H, C1-C3 alkyl, C1-C3 fluoroalkyl, C1-C3 hydroxyalkyl, C1-C3 aminoalkyl, C1-C3 thioalkyl, (C1-C3 alkoxy)C1-C3 alkyl, -S(O) 1―2 (C-C alkyl), —C(O)(C-C alkyl), and —C(O)O(C-C alkyl); Or R 2A and R 2Btogether with the nitrogen to which they are both directly attached form a heterocycloalkyl optionally substituted with 1 to 3 substituents selected from C-C alkyl, C-C fluoroalkyl, hydroxyl, amino, thio, C-C hydroxyalkyl, C-C aminoalkyl, C-C thioalkyl, and —C(O)C-C alkyl; A 1A is a bond, -C(O)-, -S-, -S(O) 1-2 -, -O-, -NR 6 -, -C(O)NR 6 -, -NR 6 C(O)-, -C(S)NR 6 -, -NR 6 C(S)-, -C(O)O-, -OC(O)-, -C(O)S-, -SC(O)-, -C(S)O-, -OC(S)-, -C(S)S-, -SC(S)-, -S(O) 1-2 O-, -OS(O) 1-2 -, -S(O) 1―2 NR 6 - and -NR 6 S(O) 1-2 - selected from the group consisting of L 1A is selected from the group consisting of a bond, unsubstituted C1-C4 alkylene, unsubstituted C1-C4 alkenylene, and unsubstituted C1-C4 alkynylene; A 1B is a bond, -C(O)-, -S-, -S(O) 1―2 -, -O-, -NR 6 -, -C(O)NR 6 -, -NR 6 C(O)-, -C(S)NR 6 -, -NR 6 C(S)-, -C(O)O-, -OC(O)-, -C(O)S-, -SC(O)-, -C(S)O-, -OC(S)-, -C(S)S-, -SC(S)-, -S(O) 1―2 O-, -OS(O) 1―2 -, -S(O) 1―2 NR 6 - and -NR 6 S(O) 1―2 - selected from the group consisting of L 1Bis selected from the group consisting of a bond, unsubstituted C1-C4 alkylene, unsubstituted C1-C4 alkenylene, and unsubstituted C1-C4 alkynylene; R 1 teeth optionally substituted C1-C8 alkyl, optionally substituted C1-C8 alkenyl, and optionally substituted C1-C8 alkynyl; hydrogen, and 1-5 R 1E and is selected from the group consisting of cycloalkyl and heterocycloalkyl substituted with During the ceremony, Each R 1E is oxo, optionally substituted C1-C4 alkyl, C1-C4 fluoroalkyl, halogen, -CN, SF5, -N3, -C(O)R 1F , -SR 1F , -S(O) 1―2 R 1F , -OR 1F , -NR 1G R 1F , -C(O)R 1F , -C(O)NR 1G R 1F , -NR 1G C(O)R 1F , -C(S)NR 1G R 1F , -NR 1G C(S)R 1F , -C(O)OR 1F , -OC(O)R 1F , -C(O)SR 1F , -SC(O)R 1F , -C(S)OR 1F , -OC(S)R 1F , -C(S)SR 1F , -SC(S)R 1F , -S(O) 1―2 OR 1F , -OS(O) 1―2 R 1F , -S(O) 1―2 NR 1G R 1F , -NR 1G S(O) 1―2 R 1F are independently selected from Each R 1Fis independently selected from H, C1-C3 alkyl, C1-C3 fluoroalkyl, C1-C3 hydroxyalkyl, and (C1-C3 alkoxy)C1-C3 alkyl; Each R 1G is H, C1-C3 alkyl, C1-C3 fluoroalkyl, C1-C3 hydroxyalkyl, (C1-C3 alkoxy)C1-C3 alkyl, -S(O) 1―2 (C1-C3 alkyl), -C(O)(C1-C3 alkyl), and -C(O)O(C 1― C alkyl), L 3 is a bond, -C(O)-, -S-, -S(O) 1―2 -, -O-, -NR 6 -, -CH2-, -CH(CH3)(OH)-, -CH(OH)-, -CH2CH2-, -C(O)NR 6 -, -NR 6 C(O)-, -C(S)NR 6 -, -NR 6 C(S)-, -C(O)O-, -OC(O)-, -S(O) 1―2 O-, -OS(O) 1―2 -, -S(O) 1―2 NR 6 - or -NR 6 S(O) 1―2 - and R 3 teeth, Each is (i)-L 3C -(1-5 R 3D aryl optionally substituted with -L 3C -(1-5 R 3D heteroaryl optionally substituted with 3C -(1-5 R 3E cycloalkyl optionally substituted with -L 3C -(1-5 R 3E (heterocycloalkyl optionally substituted with 3E cycloalkyl and heterocycloalkyl optionally substituted with Each is (i)-L 3C -(1-5 R3D aryl optionally substituted with -L 3C -(1-5 R 3D heteroaryl optionally substituted with 3C -(1-5 R 3E cycloalkyl optionally substituted with -L 3C -(1-5 R 3E (ii) 1-5 R 3E is selected from the group consisting of aryl and heteroaryl, optionally substituted with During the ceremony, Each L 3C is a bond, methylene, ethylene, -C(O)-, -S-, -S(O) 1―2 -, -O-, or -NR 3G - and each 3D is optionally substituted C1-C4 alkyl, C1-C4 fluoroalkyl, halogen, -CN, SF5, -N3, -C(O)R 3F , -SR 3F , -S(O) 1―2 R 3F , -OR 3F , -NR 3G R 3F , -C(O)R 3F , -C(O)NR 3G R 3F , -NR 3G C(O)R 3F , -C(S)NR 3G R 3F , -NR 3G C(S)R 3F , -C(O)OR 3F , -OC(O)R 3F , -C(O)SR 3F , -SC(O)R 3F , -C(S)OR 3F , -OC(S)R 3F , -C(S)SR 3F , -SC(S)R 3F , -S(O) 1―2 OR 3F , -OS(O) 1―2 R 3F , -S(O) 1―2NR 3G R 3F , -NR 3G S(O) 1―2 R 3F , -OC(O)OR 3F , -OC(O)NR 3G R 3F , -NR 3G C(O)OR 3F , -NR 3G C(O)NR 3G R 3F , -SC(O)OR 3F , -OC(O)SR 3F , -SC(O)SR 3F , -SC(O)NR 3G R 3F , -NR 3G C(O)SR 3F , -OC(S)OR 3F , -OC(S)NR 3G R 3F , -NR 3G C(S)OR 3F , -NR 3G C(S)NR 3G R 3F , -SC(S)OR 3F , -OC(S)SR 3F , -SC(S)SR 3F , -SC(S)NR 3G R 3F , -NR 3G C(S)SR 3F , -NR 3G C(NR 3G )NR 3G R 3F , and -NR 3G S(O) 1―2 NR 3G R 3F are independently selected from Each R 3E is oxo, optionally substituted C1-C4 alkyl, C1-C4 fluoroalkyl, halogen, -CN, SF5, -N3, -C(O)R 3F , -SR 3F , -S(O) 1―2 R 3F , -OR 3F , -NR 3G R 3F , -C(O)R 3F、-C(O)NR 3G R 3F 、-NR 3G C(O)R 3F 、-C(S)NR 3G R 3F 、-NR 3G C(S)R 3F 、-C(O)OR 3F 、-OC(O)R 3F 、-C(O)SR 3F 、-SC(O)R 3F 、-C(S)OR 3F 、-OC(S)R 3F 、-C(S)SR 3F 、-SC(S)R 3F 、-S(O) 1―2 OR 3F 、-OS(O) 1―2 R 3F 、-S(O) 1―2 NR 3G R 3F 、-NR 3G S(O) 1―2 R 3F 、-OC(O)OR 3F 、-OC(O)NR 3G R 3F 、-NR 3G C(O)OR 3F 、-NR 3G C(O)NR 3G R 3F 、-SC(O)OR 3F 、-OC(O)SR 3F 、-SC(O)SR 3F 、-SC(O)NR 3G R 3F 、-NR 3G C(O)SR 3F 、-OC(S)OR 3F 、-OC(S)NR 3G R 3F 、-NR 3G C(S)OR 3F 、-NR 3G C(S)NR 3G R 3F 、-SC(S)OR 3F 、-OC(S)SR 3F 、-SC(S)SR 3F 、-SC(S)NR 3G R 3F, -NR 3G C(S)SR 3F , -NR 3G C(NR 3G )NR 3G R 3F , and -NR 3G S(O) 1―2 NR 3G R 3F are independently selected from Each R 3F is independently selected from H, C1-C3 alkyl, C1-C3 fluoroalkyl, and C1-C3 hydroxyalkyl; Each R 3G is H, C1-C3 alkyl, C1-C3 fluoroalkyl, C1-C3 hydroxyalkyl, -S(O) 1―2 (C-C alkyl), —C(O)(C-C alkyl), and —C(O)O(C-C alkyl); A 4A is a bond, -C(O)-, -S-, -S(O) 1―2 -, -O-, -NR 6 -, -C(O)NR 6 -, -NR 6 C(O)-, -C(S)NR 6 -, -NR 6 C(S)-, -C(O)O-, -OC(O)-, -C(O)S-, -SC(O)-, -C(S)O-, -OC(S)-, -C(S)S-, -SC(S)-, -S(O) 1―2 O-, -OS(O) 1―2 -, -S(O) 1―2 NR 6 - and -NR 6 S(O) 1―2 - selected from the group consisting of L 4A is selected from the group consisting of a bond, unsubstituted C1-C4 alkylene, unsubstituted C1-C4 alkenylene, and unsubstituted C1-C4 alkynylene; A 4B is a bond, -C(O)-, -S-, -S(O) 1―2 -, -O-, -NR 6 -, -C(O)NR 6 -, -NR 6 C(O)-, -C(S)NR6 -, -NR 6 C(S)-, -C(O)O-, -OC(O)-, -C(O)S-, -SC(O)-, -C(S)O-, -OC(S)-, -C(S)S-, -SC(S)-, -S(O) 1―2 O-, -OS(O) 1―2 -, -S(O) 1―2 NR 6 - and -NR 6 S(O) 1―2 - selected from the group consisting of L 4B is selected from the group consisting of a bond, unsubstituted C1-C4 alkylene, unsubstituted C1-C4 alkenylene, and unsubstituted C1-C4 alkynylene; R 4 teeth, optionally substituted C1-C8 alkyl, optionally substituted C1-C8 alkenyl, and optionally substituted C1-C8 alkynyl; hydrogen, and 1-5 R 4E and is selected from the group consisting of cycloalkyl and heterocycloalkyl substituted with During the ceremony, Each R 4E is oxo, optionally substituted C1-C4 alkyl, C1-C4 fluoroalkyl, halogen, -CN, -SF5, -N3, -C(O)R 4F , -SR 4F , -S(O) 1―2 R 4F , -OR 4F , -NR 4G R 4F , -C(O)R 4F , -C(O)NR 4G R 4F , -NR 4G C(O)R 4F , -C(S)NR 4G R 4F , -NR 1G C(S)R 4F , -C(O)OR 4F , -OC(O)R 4F , BC(O)SR 4F , -SC(O)R 4F , -C(S)OR 4F , -OC(S)R4F , -C(S)SR 4F , -SC(S)R 4F , -S(O) 1―2 OR 4F , -OS(O) 1―2 R 4F , -S(O) 1―2 NR 4G R 4F , -NR 4G S(O) 1―2 R 4F , -OC(O)OR 4F , -OC(O)NR 4G R 4F , -NR 4G C(O)OR 4F , -NR 4G C(O)NR 4G R 4F , -SC(O)OR 4F , -OC(O)SR 4F , -SC(O)SR 4F , -SC(O)NR 4G R 4F , -NR 4G C(O)SR 4F , -OC(S)OR 4F , -OC(S)NR 4G R 4F , -NR 4G C(S)OR 4F , -NR 4G C(S)NR 4G R 4F , -SC(S)OR 4F , -OC(S)SR 4F , -SC(S)SR 4F , -SC(S)NR 4G R 4F , -NR 4G C(S)SR 4F , -NR 4G C(NR 4G )NR 4G R 4F , and -NR 4G S(O) 1―2 NR 4G R 4F are independently selected from Each R 4Fis independently selected from H, C1-C3 alkyl, C1-C3 fluoroalkyl, C1-C3 hydroxyalkyl, and (C1-C3 alkoxy)C1-C3 alkyl; Each R 4G is H, C1-C3 alkyl, C1-C3 fluoroalkyl, C1-C3 hydroxyalkyl, and (C1-C3 alkoxy)C1-C3 alkyl, -S(O) 1―2 (C-C alkyl), —C(O)(C-C alkyl), and —C(O)O(C-C alkyl); L 5 is a bond, -C(O)-, -S-, -S(O) 1―2 -, -O-, -NR 6 -, -CH2-, -CH(CH3)(OH)-, -CH(OH)-, -CH2CH2-, -C(O)NR 6 -, -NR 6 C(O)-, -C(S)NR 6 -, -NR 6 C(S)-, -C(O)O-, -OC(O)-, -S(O) 1―2 O-, -OS(O) 1―2 -, -S(O) 1―2 NR 6 - or -NR 6 S(O) 1―2 - and R 5 teeth 1-5 R each 5E aryl and heteroaryl optionally substituted with 1-5 R 5E and is selected from the group consisting of cycloalkyl and heterocycloalkyl substituted with During the ceremony, Each R 5E is oxo, optionally substituted C1-C4 alkyl, C1-C4 fluoroalkyl, halogen, -CN, -SF5, -N3, -C(O)R 5F , -SR 5F , -S(O) 1-2 R 5F , -OR 5F , -NR 5G R 5F , -C(O)R 5F , -C(O)NR5G R 5F 、-NR 5G C(O)R 5F 、-C(S)NR 5G R 5F 、-NR 1G C(S)R 5F 、-C(O)OR 5F 、-OC(O)R 5F 、-C(O)SR 5F 、-SC(O)R 5F 、-C(S)OR 5F 、-OC(S)R 5F 、-C(S)SR 5F 、-SC(S)R 5F 、-S(O) 1―2 OR 5F 、-OS(O) 1―2 R 5F 、-S(O) 1―2 NR 5G R 5F 、-NR 5G S(O) 1―2 R 5F 、-OC(O)OR 5F 、-OC(O)NR 5G R 5F 、-NR 5G C(O)OR 5F 、-NR 5G C(O)NR 5G R 5F 、-SC(O)OR 5F 、-OC(O)SR 5F 、-SC(O)SR 5F 、-SC(O)NR 5G R 5F 、-NR 5G C(O)SR 5F 、-OC(S)OR 5F 、-OC(S)NR 5G R 5F 、-NR 5G C(S)OR 5F 、-NR 5G C(S)NR 5G R 5F 、-SC(S)OR 5F 、-OC(S)SR 5F 、-SC(S)SR 5F 、-SC(S)NR 5G R 5F 、-NR5G C(S)SR 5F , -NR 5G C(NR 5G )NR 5G R 5F , and -NR 5G S(O) 1―2 NR 5G R 5F are independently selected from Each R 5F is independently selected from H, C1-C3 alkyl, C1-C3 fluoroalkyl, C1-C3 hydroxyalkyl, and (C1-C3 alkoxy)C1-C3 alkyl; Each R 5G is H, C1-C3 alkyl, C1-C3 fluoroalkyl, C1-C3 hydroxyalkyl, and (C1-C3 alkoxy)C1-C3 alkyl, -S(O) 1―2 (C-C alkyl), —C(O)(C-C alkyl), and —C(O)O(C-C alkyl); Y is N or CR Y where R Y is hydrogen, C1-C3 alkyl, C1-C3 fluoroalkyl, C1-C3 hydroalkyl, C1-C3 aminoalkyl, C1-C3 thioalkyl, (C1-C3 alkoxy)C1-C3 alkyl, -S(O) 1―2 (C1-C3 alkyl), halogen, -CN, -SF5, -N3, -C(O)R YC , -SR YC , -S(O) 1―2 R YC , -OR YC , and -NR YD R YC wherein each R YC is independently selected from H, C-C alkyl, and C-C fluoroalkyl; and each R YD are independently selected from H, C1-C3 alkyl, and C1-C3 fluoroalkyl, Each R 6is hydrogen, C1-C3 alkyl, C1-C3 fluoroalkyl, C1-C3 hydroxyalkyl, C1-C3 aminoalkyl, C1-C3 thioalkyl, (C1-C3 alkoxy)C1-C3 alkyl, -S(O) 1―2 -(C1-C3 alkyl), -C(O)(C1-C3 alkyl), and -C(O)O(C1-C3 alkyl); Each alkyl, alkylene, alkenyl, alkenylene, alkynyl, and alkynylene is straight or branched; Each optionally substituted alkyl, alkenyl, alkynyl, alkylene, alkenylene, and alkylene may be unsubstituted or substituted with oxo, halogen, —CN, —SF, —N, —C(O)R 8 , -SR 8 , -S(O) 1―2 R 8 , -OR 8 , -NR 9 R 8 , -C(O)NR 9 R 8 , -NR 9 C(O)R 8 , -C(S)NR 9 R 8 , -NR 9 C(S)R 8 , -C(O)OR 8 , -OC(O)R 8 , -C(O)SR 8 , -SC(O)R 8 , -C(S)OR 8 , -OC(S)R 8 , -C(S)SR 8 , -SC(S)R 8 , -S(O) 1―2 OR 8 , -OS(O) 1―2 R 8 , -S(O) 1―2 NR 9 R 8 , -NR 9 S(O) 1―2 R 8 , -OC(O)OR 8 , -OC(O)NR 9 R 8 , -NR 9 C(O)OR8 , -NR 9 C(O)NR 9 R 8 , -SC(O)OR 8 , -OC(O)SR 8 , -SC(O)SR 8 , -SC(O)NR 9 R 8 , -NR 9 C(O)SR 8 , -OC(S)OR 8 , -OC(S)NR 9 R 8 , -NR 9 C(S)OR 8 , -NR 9 C(S)NR 9 R 8 , -SC(S)OR 8 , -OC(S)SR 8 , -SC(S)SR 8 , -SC(S)NR 9 R 8 , -NR 9 C(S)SR 8 , -NR 9 C(NR 9 )NR 9 R 8 , and -NR 9 S(O) 1―2 NR 9 R 8 and is substituted with 1-5 substituents independently selected from: Each R 8 is independently selected from H, C1-C3 alkyl, C1-C3 fluoroalkyl, C1-C3 hydroxyalkyl, and (C1-C3 alkoxy)C1-C3 alkyl; Each R 9 is H, C1-C3 alkyl, C1-C3 fluoroalkyl, C1-C3 hydroxyalkyl, and (C1-C3 alkoxy)C1-C3 alkyl, -S(O) 1―2 (C-C alkyl), —C(O)(C-C alkyl), and —C(O)O(C-C alkyl); each cycloalkyl has 3-10 ring carbons and is unsaturated or partially unsaturated, and optionally contains one or two fused cycloalkyl rings, each having 3-8 ring members; each heterocycloalkyl has 3-10 ring members and 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and is unsaturated or partially unsaturated, and optionally contains one or two fused cycloalkyl rings, each having 3-8 ring members; each optionally substituted aryl is phenyl or naphthyl and optionally contains one or two fused cycloalkyl or heterocycloalkyl rings, each having 4-8 ring members; Each optionally substituted heteroaryl is a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or an 8-10 membered bicyclic heteroaryl having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur, and optionally contains one or two fused cycloalkyl or heterocycloalkyl rings, each having 4-8 ring members.

[0393] Embodiment 122 122. The method of embodiment 121, wherein Y is N.

[0394] Embodiment 123 A 1A is a bond, -C(O)-, -S-, -S(O) 1-2 -, -O-, -NR 6 -, -C(O)NR 6 -, -NR 6 C(O)-, -C(S)NR 6 -, -NR 6 C(S)-, -C(O)O-, -OC(O)-, -C(O)S-, -SC(O)-, -C(S)O-, -OC(S)-, -C(S)S-, -SC(S)-, -S(O) 1-2 O-, -OS(O) 1-2 -, -S(O) 1―2 NR 6 - and -NR 6 S(O) 1-2 - selected from the group consisting of L 1A is selected from the group consisting of a bond, unsubstituted C1-C4 alkylene, unsubstituted C1-C4 alkenylene, and unsubstituted C1-C4 alkynylene; A 1B is a bond, -C(O)-, -S-, -S(O) 1―2 -, -O-, -NR 6 -, -C(O)NR 6 -, -NR 6 C(O)-, -C(S)NR 6 -, -NR 6 C(S)-, -C(O)O-, -OC(O)-, -C(O)S-, -SC(O)-, -C(S)O-, -OC(S)-, -C(S)S-, -SC(S)-, -S(O) 1―2 O-, -OS(O) 1―2 -, -S(O) 1―2 NR 6 - and -NR 6 S(O) 1―2 - selected from the group consisting of L 1B is a bond, The method of embodiment 121 or embodiment 122.

[0395] Embodiment 124 A 1A , L 1A , and L 1B 124. The method of embodiment 123, wherein:

[0396] Embodiment 125 A 1B 125. The method of embodiment 124, wherein is -S-, -S(O), or -S(O)2-.

[0397] Embodiment 126 R 1 The method of any of embodiments 121-125, wherein is optionally substituted C1-C8 alkyl, optionally substituted C1-C8 alkenyl, or optionally substituted C1-C8 alkynyl.

[0398] Embodiment 127 R 1The method of any of embodiments 121-125, wherein is unsubstituted C1-C8 alkyl, unsubstituted C1-C8 alkenyl, or unsubstituted C1-C8 alkynyl, such as methyl, ethyl, propyl, butenyl, or butyl.

[0399] Embodiment 128 L 2 128. The method of any one of embodiments 121-127, wherein is a bond.

[0400] Embodiment 129 The method of any of embodiments 121-128, wherein Q is —C(O)OH.

[0401] Embodiment 130 Q is, -C(O)O(C1-C3 alkyl); -C(O)NR 2B R 2A [In the formula, R 2A is C1-C3 alkyl, C1-C3 hydroxyalkyl, C1-C3 aminoalkyl, or C1-C3 thioalkyl, and R 2B is H or C1-C3 alkyl; -C(O)NR 2B R 2A [In the formula, R 2A and R 2B together with the nitrogen to which they are both directly attached form a heterocycloalkyl optionally substituted with 1 to 3 substituents selected from C-C alkyl, C-C fluoroalkyl, hydroxyl, amino, thio, C-C hydroxyalkyl, C-C aminoalkyl, C-C thioalkyl, and —C(O)C-C alkyl; or -C(O)NR 2B R 2A [In the formula, R 2A -S(O) 1-2 (C1-C3 alkyl), -S(O) 1-2(C1-C3 fluoroalkyl), or heteroaryl optionally substituted with 1-2 groups selected from substituents selected from C1-C3 alkyl, C1-C3 fluoroalkyl, hydroxyl, amino, thio, C1-C3 hydroxyalkyl, C1-C3 aminoalkyl, C1-C3 thioalkyl, and —C(O)C1-C3 alkyl; R 2B is H or C1-C3 alkyl] 129. The method of any one of embodiments 121 to 128, wherein

[0402] Embodiment 131 L 3 131. The method of any of embodiments 121-130, wherein is a bond.

[0403] Embodiment 132 L 3 -C(O)-, -S-, -S(O) 1―2 -, -O-, -NR 6 131. The method of any one of embodiments 121-130, wherein the aryl group is -, -CH2-, -CH(CH3)(OH)-, or -CH(OH)-.

[0404] Embodiment 133 R 3 is (i)-L 3C -(1-5 R 3D aryl optionally substituted with -L 3C -(1-5 R 3D heteroaryl optionally substituted with 3C -(1-5 R 3E cycloalkyl optionally substituted with -L 3C -(1-5 R 3E and (ii) 1-5 R 3E 133. The method of any of embodiments 121-132, wherein R is aryl (e.g., phenyl) optionally substituted with R.

[0405] Embodiment 134 R 3 But 1-5 R 3E133. The method of any of embodiments 121-132, wherein R is aryl (e.g., phenyl) optionally substituted with R.

[0406] Embodiment 135 R 3 However, (i) arbitrarily -L 3C -(1-5 R 3D aryl optionally substituted with -L 3C -(1-5 R 3D heteroaryl optionally substituted with -L 3C -(1-5 R 3E cycloalkyl optionally substituted with -L 3C -(1-5 R 3E and (ii) 1-5 R 3E 133. The method of any of embodiments 121-132, wherein R is heteroaryl (e.g., isothiazole, pyridone, thiadiazole, pyrazine, pyrazolopyrimidine, pyrazolopyridine, imidazole, benzofuran, indole, imidazopyridine, pyridine, pyrazole, isoxazole, triazolopyridine, benzimidazole, thiophene, benzothiophene, furan, or pyrimidine), optionally substituted with

[0407] Embodiment 136 A 4A is a bond, -C(O)-, -S-, -S(O) 1―2 -, -O-, -NR 6 -, -C(O)NR 6 -, -NR 6 C(O)-, -C(S)NR 6 -, -NR 6 C(S)-, -C(O)O-, -OC(O)-, -C(O)S-, -SC(O)-, -C(S)O-, -OC(S)-, -C(S)S-, -SC(S)-, -S(O) 1―2 O-, -OS(O) 1―2 -, -S(O) 1―2 NR 6 - and -NR 6 S(O) 1―2 - selected from the group consisting of L 4A is selected from the group consisting of a bond, unsubstituted C1-C4 alkylene, unsubstituted C1-C4 alkenylene, and unsubstituted C1-C4 alkynylene; A 4B is a bond, -C(O)-, -S-, -S(O) 1―2 -, -O-, -NR 6 -, -C(O)NR 6 -, -NR 6 C(O)-, -C(S)NR 6 -, -NR 6 C(S)-, -C(O)O-, -OC(O)-, -C(O)S-, -SC(O)-, -C(S)O-, -OC(S)-, -C(S)S-, -SC(S)-, -S(O) 1―2 O-, -OS(O) 1―2 -, -S(O) 1―2 NR 6 - and -NR 6 S(O) 1―2 - selected from the group consisting of L 4B is a bond, A method according to any one of embodiments 121 to 135.

[0408] Embodiment 137 A 4A , L 4A , and L 4B 136. The method of any of embodiments 121-135, wherein is a bond.

[0409] Embodiment 138 A 4B 138. The method of embodiment 137, wherein

[0410] Embodiment 139 A 4B -C(O)-, -S-, -S(O) 1―2 -, -O-, -NR 6 -, -C(O)NR 6 -, -NR 6 C(O)-, -C(O)O-, -OC(O)-, -S(O) 1―2 O-, -OS(O) 1―2 -, -S(O) 1―2 NR6 - or -NR 6 S(O) 1―2 The method of embodiment 138, wherein

[0411] Embodiment 140 R 4 is optionally substituted C1-C8 alkyl, optionally substituted C1-C8 alkenyl, or optionally substituted C1-C8 alkynyl, such as methyl, ethyl, propyl, butyl, or pentyl.

[0412] Embodiment 141 L 5 141. The method of any of embodiments 121-140, wherein is a bond.

[0413] Embodiment 142 R 5 But 1-5 R 5E 142. The method of any of embodiments 121-141, wherein R is aryl (e.g., phenyl) optionally substituted with R.

[0414] Embodiment 143 R 5 But 1-5 R 5E 142. The method of any of embodiments 121-141, wherein R is heteroaryl optionally substituted with (eg, isoxazolyl, pyridyl, imidazopyridyl, pyrazolyl).

[0415] Embodiment 144 90. The method of embodiment 89, wherein the compound has the following structural formula: [ka] [In formula (Im), the ring system represented by "a" is a heterocyclic aromatic compound], [ka] These are optionally in the form of a pharmaceutically acceptable salt or N-oxide, or solvate or hydrate, wherein L1 is a bond, -C(O)-, -S-, -S(O) 1―2 -, -O-, -NR 6 -, -C(O)NR 6 -, -NR 6 C(O)-, -C(S)NR 6 -, -NR 6 C(S)-, -C(O)O-, -OC(O)-, -C(O)S-, -SC(O)-, -C(S)O-, -OC(S)-, -C(S)S-, -SC(S)-, -S(O) 1―2 O-, -OS(O) 1―2 -, -S(O) 1―2 NR 6 - and -NR 6 S(O) 1―2 - selected from the group consisting of R 1 teeth hydrogen, C1-C8 alkyl, C1-C8 alkenyl, and C1-C8 alkynyl, each of which is unsubstituted or fluorinated; Optionally, 1-2 R 1E and is selected from the group consisting of cycloalkyl and heterocycloalkyl substituted with During the ceremony, Each R 1E is oxo, optionally substituted C1-C4 alkyl, C1-C4 fluoroalkyl, halogen, -CN, SF5, -N3, -C(O)R 1F , -SR 1F , -S(O) 1―2 R 1F , -OR 1F , -NR 1G R 1F , and -C(O)R 1F are independently selected from Each R 1F are independently selected from H, C1-C3 alkyl, and C1-C3 fluoroalkyl; Each R 1G are independently selected from H and C1-C3 alkyl; L 2 is selected from the group consisting of a bond, —CH—, —CH(CH)—, or —CHCH—; Q is -H, -CH2OH, -C(O)OH, -C(O)OR 2A , -C(O)NR 2B R 2A , -C(O)NR 2B S(O)2R 2A , -C(O)NR 2B S(O)NR 2B R 2A , -C(O)R 2A , -S(O)2OH, -P(O)(OH)2, -C(OH)(CF3)2, S(O)2R 2A , -S(O)NR 2B R 2A , —C(O)NHOH, and —CO(NH)CN, wherein Each R 2A are independently selected from H and C1-C3 alkyl; Each R 2B are independently selected from H and C1-C3 alkyl; L 3 is a bond, -C(O)-, -S-, -S(O) 1―2 -, -O-, -NR 6 -, -CH2-, -CH(CH3)(OH)-, or -CH(OH); R 3 are (i)-L 3C -(1-5 R 3D aryl optionally substituted with -L 3C -(1-5 R 3D heteroaryl optionally substituted with 3C -(1-5 R 3E cycloalkyl optionally substituted with -L 3C -(1-5 R 3E (ii) 1-5 R 3E is aryl or heteroaryl optionally substituted with During the ceremony, Each L 3C is a bond, methylene, ethylene, -C(O)-, -S-, -S(O) 1―2 -, -O-, or -NR 3G - and each3D is optionally substituted C1-C4 alkyl, C1-C4 fluoroalkyl, halogen, -CN, SF5, -N3, -C(O)R 3F , -SR 3F , -S(O) 1―2 R 3F , -OR 3F , -NR 3G R 3F , -C(O)R 3F , -C(O)NR 3G R 3F , -NR 3G C(O)R 3F , -C(S)NR 3G R 3F , -NR 3G C(S)R 3F , -C(O)OR 3F , -OC(O)R 3F , -C(O)SR 3F , -SC(O)R 3F , -C(S)OR 3F , -OC(S)R 3F , -C(S)SR 3F , -SC(S)R 3F , -S(O) 1―2 OR 3F , -OS(O) 1―2 R 3F , -S(O) 1―2 NR 3G R 3F , and -NR 3G S(O) 1―2 R 3F are independently selected from Each R 3E is oxo, optionally substituted C1-C4 alkyl, C1-C4 fluoroalkyl, halogen, -CN, SF5, -N3, -C(O)R 3F , -SR 3F , -S(O) 1―2 R 3F , -OR 3F , -NR 3G R 3F , -C(O)R 3F , -C(O)NR 3G R 3F , -NR 3G C(O)R 3F , -C(S)NR 3G R3F , -NR 3G C(S)R 3F , -C(O)OR 3F , -OC(O)R 3F , -C(O)SR 3F , -SC(O)R 3F , -C(S)OR 3F , -OC(S)R 3F , -C(S)SR 3F , -SC(S)R 3F , -S(O) 1―2 OR 3F , -OS(O) 1―2 R 3F , -S(O) 1―2 NR 3G R 3F , -NR 3G S(O) 1―2 R 3F are independently selected from Each R 3F are independently selected from H, C1-C3 alkyl, and C1-C3 fluoroalkyl; Each R 3G are independently selected from H, C1-C3 alkyl, and C1-C3 fluoroalkyl; L 4 is a bond, -C(O)-, -S-, -S(O) 1―2 -, -O-, -NR 6 -, -C(O)NR 6 -, -NR 6 C(O)-, -C(S)NR 6 -, -NR 6 C(S)-, -C(O)O-, -OC(O)-, -C(O)S-, -SC(O)-, -C(S)O-, -OC(S)-, -C(S)S-, -SC(S)-, -S(O) 1―2 O-, -OS(O) 1―2 -, -S(O) 1―2 NR 6 - and -NR 6 S(O) 1―2 - selected from the group consisting of R 4 is selected from the group consisting of hydrogen, optionally substituted C1-C8 alkyl, optionally substituted C1-C8 alkenyl, and optionally substituted C1-C8 alkynyl; L5 is a bond, -C(O)-, -S-, -S(O) 1―2 -, -O-, -NR 6 -, -CHCH-, -CH=CH-, -C≡C-, -CH-, -CH(CH)(OH)-, or -CH(OH)-; R 5 Each contains 1-5 R 5E is an aryl or heteroaryl optionally substituted with During the ceremony, Each R 5E is oxo, optionally substituted C1-C4 alkyl, C1-C4 fluoroalkyl, halogen, -CN, -SF5, -N3, -C(O)R 5F , -SR 5F , -S(O) 1-2 R 5F , -OR 5F , -NR 5G R 5F , -C(O)R 5F , -C(O)NR 5G R 5F , -NR 5G C(O)R 5F , -C(S)NR 5G R 5F , -NR 1G C(S)R 5F , -C(O)OR 5F , -OC(O)R 5F , -C(O)SR 5F , -SC(O)R 5F , -C(S)OR 5F , -OC(S)R 5F , -C(S)SR 5F , -SC(S)R 5F , -S(O) 1―2 OR 5F , -OS(O) 1―2 R 5F , -S(O) 1―2 NR 5G R 5F , and -NR 5G S(O) 1―2 R 5F are independently selected from Each R 5F are independently selected from H, C1-C3 alkyl, and C1-C3 fluoroalkyl; Each R 5G are independently selected from H and C1-C3 alkyl; Y is CR Y or N [wherein R Y is selected from the group consisting of hydrogen, C1-C3 alkyl, and C1-C3 fluoroalkyl; X 1 is CR XA ,S,O,NRX B and N, X 2 is CR XA ,S,O,NRX B and N, wherein Each R XA are independently selected from the group consisting of hydrogen, C1-C4 alkyl, and C1-C4 fluoroalkyl; Each R XB is hydrogen, C1-C4 alkyl, and C1-C4 fluoroalkyl, C1-C4 alkyl-C(O)-, C1-C4 alkyl-S(O) 1-2 - independently selected from the group consisting of: Z 1 and Z 2 is independently selected from C and N; During the ceremony, Each R 6 is selected from the group consisting of hydrogen, C1-C3 alkyl, and —C(O)O(C1-C3 alkyl); Each optionally substituted alkyl, alkenyl, and alkynyl is unsubstituted, fluorinated, or substituted with one or two hydroxyl groups. each cycloalkyl has 3-10 ring carbons and is unsaturated or partially unsaturated, and optionally contains one or two fused cycloalkyl rings, each having 3-8 ring members; each heterocycloalkyl has 3-10 ring members and 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and is unsaturated or partially unsaturated, and optionally contains one or two fused cycloalkyl rings, each having 3-8 ring members; each aryl is phenyl or naphthyl, and optionally contains one or two fused cycloalkyl or heterocycloalkyl rings, each having 4-8 ring members; Each heteroaryl is a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or an 8-10 membered bicyclic heteroaryl having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur, and optionally contains one or two fused cycloalkyl or heterocycloalkyl rings, each having 4-8 ring members.

[0416] Embodiment 145 145. The method of embodiment 144, having the formula (Io):

[0417] Embodiment 146 R 1 is hydrogen, optionally substituted C1-C8 alkyl, and 1-5 R 1E The method of embodiment 144 or embodiment 145, wherein the cycloalkyl optionally substituted with is selected from the group consisting of:

[0418] Embodiment 147 R 1 The method of any of embodiments 144-146, wherein is unsubstituted C1-C8 alkyl, or fluorinated C1-C8 alkyl.

[0419] Embodiment 148 L 1 148. The method of any one of embodiments 144-147, wherein is a bond, —O—, —S—, —S(O)—, or —S(O)2—.

[0420] Embodiment 149 L 1 The method of any of embodiments 144-147, wherein -R is -R- or -S-.

[0421] Embodiment 150 L 2 150. The method of any one of embodiments 144-149, wherein is a bond.

[0422] Embodiment 151 The method of any of embodiments 144-150, wherein Q is —C(O)OH.

[0423] Embodiment 152 L 3 152. The method of any of embodiments 144-151, wherein is a bond.

[0424] Embodiment 153. L 3 -C(O)-, -S-, -S(O) 1―2 -, -O-, -NR 6 152. The method of any one of embodiments 144-151, wherein the aryl group is -, -CH2-, -CH(CH3)(OH)-, or -CH(OH)-.

[0425] Embodiment 154 R 3 are each (i) optionally -L 3C -(1-5 R 3D aryl optionally substituted with -L 3C -(1-5 R 3D heteroaryl optionally substituted with 3C -(1-5 R 3E cycloalkyl optionally substituted with -L 3C -(1-5 R 3E and (ii) 1-5 R 3E 154. The method of any of embodiments 144-153, wherein R is aryl or heteroaryl, optionally substituted with

[0426] Embodiment 155 R 3 But 1-5 R 3E 154. The method of any of embodiments 144-153, wherein R is aryl (e.g., phenyl) optionally substituted with R.

[0427] Embodiment 156 R 3 However, 1-5 R 3E154. The method of any of embodiments 144-153, wherein R is heteroaryl (e.g., isothiazole, pyridone, thiadiazole, pyrazine, pyrazolopyrimidine, pyrazolopyridine, imidazole, benzofuran, indole, imidazopyridine, pyridine, pyrazole, isoxazole, triazolopyridine, benzimidazole, thiophene, benzothiophene, furan, or pyrimidine) substituted with

[0428] Embodiment 157 R 4 The method of any of embodiments 144-156, wherein is optionally substituted C1-C8 alkyl, optionally substituted C1-C8 alkenyl, or optionally substituted C1-C8 alkynyl.

[0429] Embodiment 158 L 4 158. The method of any one of embodiments 144-157, wherein is a bond.

[0430] Embodiment 159 L 5 The method of any of embodiments 144-158, wherein is a bond.

[0431] Embodiment 160 R 5 But 1-5 R 5E 160. The method of any of embodiments 144-159, wherein R is phenyl optionally substituted with R.

[0432] Embodiment 161 R 5 However, each has 1-5 R 5E 161. The method of any of embodiments 144-160, wherein R is heteroaryl optionally substituted with (e.g., isoxazolyl, pyridyl, imidazopyridyl, pyrazolyl).

[0433] Embodiment 162 90. The method of embodiment 89, wherein the compound has the following structural formula: [ka] These are optionally in the form of a pharmaceutically acceptable salt or N-oxide, or solvate or hydrate, wherein L 1 is -S-, -O-, -S(O)-, -S(O)2-, or a bond; R 1 is an unsubstituted or fluorinated C1-C8 alkyl, an unsubstituted or fluorinated C1-C8 alkenyl, and an unsubstituted or fluorinated C1-C8 alkynyl; L 2 is a bond or -CH2-, Q is -COOH, L 3 is a bond, bond, -C(O)-, -S-, -S(O) 1―2 -, -O-, -NR 6 -, -CH2-, -CH(CH3)(OH)-, or -CH(OH); R 3 are (i)-L 3C -(1-5 R 3D phenyl optionally substituted with -L 3C -(1-5 R 3D monocyclic heteroaryl optionally substituted with 3C -(1-5 R 3E monocyclic C3-C6 cycloalkyl optionally substituted with 3C -(1-5 R 3E (ii) 1-5 R 3E phenyl or monocyclic heteroaryl optionally substituted with During the ceremony, Each L 3C is a bond, methylene, ethylene, -C(O)-, -S-, -S(O) 1―2 -, -O-, or -NR 3G - and Each R 3D is optionally substituted C1-C4 alkyl, C1-C4 fluoroalkyl, halogen, -CN, SF5, -N3, -C(O)R 3F , -SR 3F , -S(O) 1―2 R3F , -OR 3F , -NR 3G R 3F , -C(O)R 3F , -C(O)NR 3G R 3F , -NR 3G C(O)R 3F , -C(S)NR 3G R 3F , -NR 3G C(S)R 3F , -C(O)OR 3F , -OC(O)R 3F , -C(O)SR 3F , -SC(O)R 3F , -C(S)OR 3F , -OC(S)R 3F , -C(S)SR 3F , -SC(S)R 3F , -S(O) 1―2 OR 3F , -OS(O) 1―2 R 3F , -S(O) 1―2 NR 3G R 3F , and -NR 3G S(O) 1―2 R 3F are independently selected from Each R 3E is oxo, optionally substituted C1-C4 alkyl, C1-C4 fluoroalkyl, halogen, -CN, SF5, -N3, -C(O)R 3F , -SR 3F , -S(O) 1―2 R 3F , -OR 3F , -NR 3G R 3F , -C(O)R 3F , -C(O)NR 3G R 3F , -NR 3G C(O)R 3F , -C(S)NR 3G R 3F , -NR 3G C(S)R 3F , -C(O)OR 3F , -OC(O)R 3F , -C(O)SR 3F , -SC(O)R3F , -C(S)OR 3F , -C(O)SR 3F , -SC(O)R 3F , -C(S)OR 3F , -OC(S)R 3F , -C(S)SR 3F , -SC(S)R 3F , -S(O) 1-2 OR 3F , -OS(O) 1-2 R 3F , -S(O) 1-2 NR 3G R 3F , -NR 3G S(O) 1-2 R 3F are independently selected from Each R 3F are independently selected from H, C1-C3 alkyl, and C1-C3 fluoroalkyl; Each R 3G are independently selected from H, C1-C3 alkyl, and C1-C3 fluoroalkyl; L 4 is a bond, -C(O)-, -S-, -S(O) 1―2 -, -O-, and -NR 6 - selected from the group consisting of R 4 is selected from the group consisting of unsubstituted or fluorinated C1-C8 alkyl, unsubstituted or fluorinated C1-C8 alkenyl, and unsubstituted or fluorinated C1-C8 alkynyl; L 5 is a bond, -C(O)-, -S-, -S(O) 1―2 -, -O-, or -NR 6 - and R 5 are 1-5 R 5E phenyl or monocyclic heteroaryl optionally substituted with During the ceremony, Each R 5E is oxo, optionally substituted C1-C4 alkyl, C1-C4 fluoroalkyl, halogen, -CN, -SF5, -N3, -C(O)R 5F , -SR 5F , -S(O) 1-2 R 5F, -OR 5F , -NR 5G R 5F , -C(O)R 5F , -C(O)NR 5G R 5F , -NR 5G C(O)R 5F , -C(S)NR 5G R 5F , -NR 1G C(S)R 5F , -C(O)OR 5F , -OC(O)R 5F , -C(O)SR 5F , -SC(O)R 5F , -C(S)OR 5F , -OC(S)R 5F , -C(S)SR 5F , -SC(S)R 5F , -S(O) 1―2 OR 5F , -OS(O) 1―2 R 5F , -S(O) 1―2 NR 5G R 5F , and -NR 5G S(O) 1―2 R 5F are independently selected from Each R 5F are independently selected from H, C1-C3 alkyl, and C1-C3 fluoroalkyl; Each R 5G are independently selected from H and C1-C3 alkyl; During the ceremony, Each R 6 is selected from the group consisting of hydrogen, C1-C3 alkyl, and —C(O)(C1-C3 alkyl); Each optionally substituted alkyl, alkenyl, and alkynyl is unsubstituted, fluorinated, or substituted with one or two hydroxyl groups. each cycloalkyl has 3-10 ring carbons and is unsaturated or partially unsaturated, and optionally contains one or two fused cycloalkyl rings, each having 3-8 ring members; each heterocycloalkyl has 3-10 ring members and 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and is unsaturated or partially unsaturated, and optionally contains one or two fused cycloalkyl rings, each having 3-8 ring members; each aryl is phenyl or naphthyl, and optionally contains one or two fused cycloalkyl or heterocycloalkyl rings, each having 4-8 ring members; Each heteroaryl is a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or an 8-10 membered bicyclic heteroaryl having 1-d5 heteroatoms independently selected from nitrogen, oxygen, or sulfur, and optionally contains one or two fused cycloalkyl or heterocycloalkyl rings, each having 4-8 ring members.

[0434] Embodiment 163 R 3 However, 1-5 R 3E phenyl substituted with Each L 3C is a bond, methylene, ethylene, -C(O)-, -S-, -S(O) 1―2 -, -O-, or -NR 3G - and Each R 3D is optionally substituted C1-C4 alkyl, C1-C4 fluoroalkyl, halogen, -CN, SF5, -N3, -C(O)R 3F , -SR 3F , -S(O) 1―2 R 3F , -OR 3F , -NR 3G R 3F , -C(O)R 3F , -C(O)NR 3G R 3F , -NR 3G C(O)R 3F , -C(S)NR 3G R 3F , -NR 3G C(S)R 3F , -C(O)OR 3F , -OC(O)R3F , -C(O)SR 3F , -SC(O)R 3F , -C(S)OR 3F , -OC(S)R 3F , -C(S)SR 3F , -SC(S)R 3F , -S(O) 1―2 OR 3F , -OS(O) 1―2 R 3F , -S(O) 1―2 NR 3G R 3F , and -NR 3G S(O) 1―2 R 3F are independently selected from Each R 3E is oxo, optionally substituted C1-C4 alkyl, C1-C4 fluoroalkyl, halogen, -CN, SF5, -N3, -C(O)R 3F , -SR 3F , -S(O) 1―2 R 3F , -OR 3F , -NR 3G R 3F , -C(O)R 3F , -C(O)NR 3G R 3F , -NR 3G C(O)R 3F , -C(S)NR 3G R 3F , -NR 3G C(S)R 3F , -C(O)OR 3F , -OC(O)R 3F , -C(O)SR 3F , -SC(O)R 3F , -C(S)OR 3F , -OC(S)R 3F , -C(S)SR 3F , -SC(S)R 3F , -S(O) 1―2 OR 3F , -OS(O) 1―2 R 3F , -S(O) 1―2 NR 3G R 3F , -NR 3G S(O) 1―2 R3F are independently selected from Each R 3F are independently selected from H, C1-C3 alkyl, and C1-C3 fluoroalkyl; Each R 3G are independently selected from H, C1-C3 alkyl, and C1-C3 fluoroalkyl; R 5 However, 1-5 R 5E phenyl substituted with Each R 5E is oxo, optionally substituted C1-C4 alkyl, C1-C4 fluoroalkyl, halogen, -CN, -SF5, -N3, -C(O)R 5F , -SR 5F , -S(O) 1-2 R 5F , -OR 5F , -NR 5G R 5F , -C(O)R 5F , -C(O)NR 5G R 5F , -NR 5G C(O)R 5F , -C(S)NR 5G R 5F , -NR 1G C(S)R 5F , -C(O)OR 5F , -OC(O)R 5F , -C(O)SR 5F , -SC(O)R 5F , -C(S)OR 5F , -OC(S)R 5F , -C(S)SR 5F , -SC(S)R 5F , -S(O) 1―2 OR 5F , -OS(O) 1―2 R 5F , -S(O) 1―2 NR 5G R 5F , and -NR 5G S(O) 1―2 R 5F are independently selected from Each R 5F are independently selected from H, C1-C3 alkyl, and C1-C3 fluoroalkyl; Each R 5G are independently selected from H and C1-C3 alkyl; The method of embodiment 162.

[0435] Embodiment 164 L 1 is -S-, L 2 is a bond, and L 3 is a bond, The method of embodiment 162 or embodiment 163.

[0436] Embodiment 165 L 4 is a bond, and L 5 is a bond, A method according to any one of embodiments 161 to 163.

[0437] Embodiment 166 R 5 The method according to any applicable embodiment above, wherein is trifluoromethylphenyl, halophenyl, or dihalophenyl.

[0438] Embodiment 167 R 5 is phenyl substituted with one or two substituents selected from trifluoromethyl, fluorine, and chlorine (e.g., trisubstituted, tetrasubstituted, 3,4-disubstituted, 2,4-disubstituted, or 2,5-disubstituted).

[0439] Embodiment 168 The method of any of embodiments 89-167, wherein each of the optionally substituted alkylene, alkenylene, and alkynylene is unsubstituted.

[0440] Embodiment 169 The method of any of embodiments 89-168, wherein each of the optionally substituted alkyl, alkenyl, and alkynyl is unsubstituted.

[0441] Embodiment 170 The method of any of embodiments 89-169, wherein each cycloalkyl is a 3- to 7-membered monocyclic cycloalkyl.

[0442] Embodiment 171 The method of any of embodiments 89-170, wherein each heterocycloalkyl is a 4-7 membered monocyclic heterocycloalkyl having 1-2 heteroatoms selected from O, S, and N.

[0443] Embodiment 172 The method of any of embodiments 89-171, wherein each heteroaryl is a 5-6 membered monocyclic heteroaryl having 1-3 heteroatoms selected from O, S, and N.

[0444] Embodiment 173 The method of any one of embodiments 89-172, wherein each aryl is phenyl.

[0445] Embodiment 174 Each R XA The method of any of embodiments 89-173, wherein is hydrogen or C1-C4 alkyl.

[0446] Embodiment 175 Each R XA The method of any one of embodiments 89-173, wherein is hydrogen.

[0447] Embodiment 176 Each R XB The method of any of embodiments 89-175, wherein is hydrogen or C1-C4 alkyl.

[0448] Embodiment 177 Each R XB 176. The method of any one of embodiments 89-175, wherein is hydrogen.

[0449] Embodiment 178 The method of any of embodiments 1-88, wherein the compound has any of the following structural formulas (IIa)-(IIe): [ka] These are optionally in the form of a pharmaceutically acceptable salt or N-oxide, and / or solvate or hydrate, wherein L 1 is a bond, -C(O)-, -S-, -S(O) 1-2 -, -O-, -NR 6 -, -C(O)NR 6 -, -NR 6 C(O)-, -C(S)NR 6 -, -NR 6 C(S)-, -C(O)O-, -OC(O)-, -C(O)S-, -SC(O)-, -C(S)O-, -OC(S)-, -C(S)S-, -SC(S)-, -S(O) 1-2 O-, -OS(O) 1-2 -, -S(O) 1―2 NR 6 - and -NR 6 S(O) 1-2 - selected from the group consisting of R 1 teeth hydrogen, C1-C8 alkyl, C1-C8 alkenyl, and C1-C8 alkynyl, each of which is unsubstituted or fluorinated; Optionally, 1-2 R 1E cycloalkyl and heterocycloalkyl substituted with Each of them can be any of 1-5 R 1E and monocyclic heteroaryl substituted with During the ceremony, Each R 1E is oxo, optionally substituted C1-C4 alkyl, C1-C4 fluoroalkyl, halogen, -CN, SF5, -N3, -C(O)R 1F , -SR 1F , -S(O) 1―2 R 1F , -OR 1F , -(OCH2CH2O) n -R1G [wherein n is 1 to 4], -N(R 1G )C(O)CH2-O-(CH2CH2O) n R 1G [wherein n is 0 to 3], —C(O)NR 1G (CH2CH2O) n R 1G , -NR 1G R 1F , and -C(O)R 1F are independently selected from Each R 1F are independently selected from H, C1-C3 alkyl, and C1-C3 fluoroalkyl; Each R 1G are independently selected from H and C1-C3 alkyl; L 2 is selected from the group consisting of a bond, —CH—, —CH(CH)—, or —CHCH—; Q is -H, -CH2OH, -C(O)OH, -C(O)OR 2A , -C(O)NR 2B R 2A , -C(O)NR 2B S(O)2R 2A , -C(O)NR 2B S(O)NR 2B R 2A , -C(O)R 2A , -S(O)2OH, -P(O)(OH)2, -C(OH)(CF3)2, S(O)2R 2A , -N(R 2B )S(O)2R 2A , -S(O)NR 2B R 2A , —C(O)NHOH, —C(O)NH—O(C1-C3 alkyl), —CO(NH)CN, wherein Each R 2A are independently selected from H and C1-C3 alkyl; Each R 2B are independently selected from H and C1-C3 alkyl; L 3 is a bond, -C(O)-, -S-, -S(O) 1―2 -, -O-, -NR 6-, -CH2-, -CH(CH3)(OH)-, or -CH(OH); R 3 are (i)-L 3C -(1-5 R 3D aryl optionally substituted with -L 3C -(1-5 R 3D heteroaryl optionally substituted with 3C -(1-5 R 3D cycloalkyl optionally substituted with -L 3C -(1-5 R 3D (heterocycloalkyl optionally substituted with 3E is aryl or heteroaryl optionally substituted with During the ceremony, Each L 3C is a bond, methylene, ethylene, -C(O)-, -S-, -S(O) 1―2 -, -O-, or -NR 3G - and Each R 3D is oxo, optionally substituted C1-C4 alkyl, C1-C4 fluoroalkyl, halogen, -CN, SF5, -N3, -C(O)R 3F , -SR 3F , -S(O) 1―2 R 3F , -OR 3F , -NR 3G R 3F , -C(O)R 3F , -C(O)NR 3G R 3F , -NR 3G C(O)R 3F , -C(S)NR 3G R 3F , -NR 3G C(S)R 3F , -C(O)OR 3F , -OC(O)R 3F , -C(O)SR 3F , -SC(O)R 3F , -C(S)OR 3F , -OC(S)R 3F , -C(S)SR 3F , -SC(S)R3F , -S(O) 1―2 OR 3F , -OS(O) 1―2 R 3F , -S(O) 1―2 NR 3G R 3F , and -NR 3G S(O) 1―2 R 3F are independently selected from Each R 3E is oxo, optionally substituted C1-C4 alkyl, C1-C4 fluoroalkyl, halogen, -CN, SF5, -N3, -C(O)R 3F , -SR 3F , -S(O) 1―2 R 3F , -OR 3F , -NR 3G R 3F , -C(O)R 3F , -C(O)NR 3G R 3F , -NR 3G C(O)R 3F , -C(S)NR 3G R 3F , -NR 3G C(S)R 3F , -C(O)OR 3F , -OC(O)R 3F , -C(O)SR 3F , -SC(O)R 3F , -C(S)OR 3F , -OC(S)R 3F , -C(S)SR 3F , -SC(S)R 3F , -S(O) 1―2 OR 3F , -OS(O) 1―2 R 3F , -S(O) 1―2 NR 3G R 3F , -NR 3G S(O) 1―2 R 3F are independently selected from Each R 3F are independently selected from H, C1-C3 alkyl, and C1-C3 fluoroalkyl; Each R 3Gare independently selected from H, C1-C3 alkyl, and C1-C3 fluoroalkyl; L 4 is a bond, -C(O)-, -S-, -S(O) 1―2 -, -O-, -NR 6 -, -C(O)NR 6 -, -NR 6 C(O)-, -C(S)NR 6 -, -NR 6 C(S)-, -C(O)O-, -OC(O)-, -C(O)S-, -SC(O)-, -C(S)O-, -OC(S)-, -C(S)S-, -SC(S)-, -S(O) 1―2 O-, -OS(O) 1―2 -, -S(O) 1―2 NR 6 - and -NR 6 S(O) 1―2 - selected from the group consisting of R 4 is selected from the group consisting of hydrogen, optionally substituted C1-C8 alkyl, optionally substituted C1-C8 alkenyl, and optionally substituted C1-C8 alkynyl; L 5 is a bond, -C(O)-, -S-, -S(O) 1―2 -, -O-, -NR 6 -, -CHCH-, -CH=CH-, -C≡C-, -CH-, -CH(CH)(OH)-, or -CH(OH)-; R 5 are (i)-L 5C -(1-5 R 5D phenyl optionally substituted with -L 5C -(1-5 R 5D monocyclic heteroaryl optionally substituted with 5C -(1-5 R 5D monocyclic cycloalkyl optionally substituted with 5C -(1-5 R 5D and (ii) 1-5 R 5E aryl, heteroaryl, cycloalkyl, or heterocycloalkyl optionally substituted with During the ceremony, Each L 5C is a bond, methylene, ethylene, -C(O)-, -S-, -S(O) 1―2 -, -O-, or -NR 3G - and Each R 5D is oxo, optionally substituted C1-C4 alkyl, C1-C4 fluoroalkyl, halogen, -CN, SF5, -N3, -C(O)R 3F , -SR 3F , -S(O) 1―2 R 3F , -OR 3F , -NR 3G R 3F , -C(O)R 3F , -C(O)NR 3G R 3F , -NR 3G C(O)R 3F , -C(S)NR 3G R 3F , -NR 3G C(S)R 3F , -C(O)OR 3F , -OC(O)R 3F , -C(O)SR 3F , -SC(O)R 3F , -C(S)OR 3F , -OC(S)R 3F , -C(S)SR 3F , -SC(S)R 3F , -S(O) 1―2 OR 3F , -OS(O) 1―2 R 3F , -S(O) 1―2 NR 3G R 3F , and -NR 3G S(O) 1―2 R 3F are independently selected from Each R 5E is oxo, optionally substituted C1-C4 alkyl, C1-C4 fluoroalkyl, halogen, -CN, -SF5, -N3, -C(O)R 5F , -SR ...

Claims

1. Formula (IIa): 【Chemistry 1】 [In the formula, L １ -S-, -O-, -S(O)-, -S(O) ２ - or a bond, R １ is unsubstituted or fluorinated C １ -C ８ Alkyl, unsubstituted or fluorinated C １ -C ８ Alkenyl, unsubstituted or fluorinated C １ -C ８ Alkynyl, 1-5 R １Ｅ or phenyl substituted with 1-5 R １Ｅ is a monocyclic heteroaryl substituted with Where: Each R １Ｅ is oxo, optionally substituted C １ -C ４ Alkyl, C １ -C ４ Fluoroalkyl, halogen, -CN, SF ５ , -N ３ , -C(O)R １Ｆ , -SR １Ｆ , -S(O) １―２ R １Ｆ , -OR １Ｆ , -(OCH ２ CH ２ O) ｎ -R １Ｇ [wherein n is 1 to 4], -N(R １Ｇ )C(O)CH ２ -O-(CH ２ CH ２ O) ｎ R １Ｇ [wherein n is 0 to 3], -C(O)NR １Ｇ (CH ２ CH ２ O) ｎ R １Ｇ , -NR １Ｇ R １Ｆ and -C(O)R １Ｆ are independently selected from Each R １Ｆ is H, C １ -C ３ Alkyl, and C １ -C ３ fluoroalkyl; Each R １Ｇ is H and C １ -C ３ independently selected from alkyl, L ２ is a bond or -CH ２ - and Q is -COOH; L ３ is a bond, -C(O)-, -S-, -S(O) １―２ -, -O-, -NR ６ --, --CH ２ -, -CH(CH ３ )(OH)—, or —CH(OH)—, R ３ are (i)-L ３Ｃ - (1-5 R ３Ｄ phenyl, which may be substituted with -L ３Ｃ - (1-5 R ３Ｄ -L ３Ｃ - (1-5 R ３Ｅ (monocyclic C3-C6 cycloalkyl optionally substituted with), -L ３Ｃ - (1-5 R ３Ｅ (ii) 1 to 5 R ３Ｅ phenyl or monocyclic heteroaryl, optionally substituted with Where: Each L ３Ｃ is a bond, methylene, ethylene, -C(O)-, -S-, -S(O) １―２ -, -O-, or -NR ３Ｇ - and Each R ３Ｄ is optionally substituted C １ -C ４ Alkyl, C １ -C ４ Fluoroalkyl, halogen, -CN, SF ５ , -N ３ , -C(O)R ３Ｆ , -SR ３Ｆ , -S(O) １―２ R ３Ｆ , -OR ３Ｆ , -NR ３Ｇ R ３Ｆ , -C(O)R ３Ｆ , -C(O)NR ３Ｇ R ３Ｆ , -NR ３Ｇ C(O)R ３Ｆ , -C(S)NR ３Ｇ R ３Ｆ , -NR ３Ｇ C(S)R ３Ｆ , -C(O)OR ３Ｆ , -OC(O)R ３Ｆ , -C(O)SR ３Ｆ , -SC(O)R ３Ｆ , -C(S)OR ３Ｆ , -OC(S)R ３Ｆ , -C(S)SR ３Ｆ , -SC(S)R ３Ｆ , -S(O) １―２ OR ３Ｆ , -OS(O) １―２ R ３Ｆ , -S(O) １―２ N.R. ３Ｇ R ３Ｆ , and -NR ３Ｇ S (O) １―２ R ３Ｆ are independently selected from Each R ３Ｅ is oxo, optionally substituted C １ -C ４ Alkyl, C １ -C ４ Fluoroalkyl, halogen, -CN, SF ５ , -N ３ , -C(O)R ３Ｆ , -SR ３Ｆ , -S(O) １―２ R ３Ｆ , -OR ３Ｆ , -NR ３Ｇ R ３Ｆ , -C(O)R ３Ｆ , -C(O)NR ３Ｇ R ３Ｆ , -NR ３Ｇ C(O)R ３Ｆ , -C(S)NR ３Ｇ R ３Ｆ , -NR ３Ｇ C(S)R ３Ｆ , -C(O)OR ３Ｆ , -OC(O)R ３Ｆ , -C(O)SR ３Ｆ , -SC(O)R ３Ｆ , -C(S)OR ３Ｆ , -OC(S)R ３Ｆ , -C(S)SR ３Ｆ , -SC(S)R ３Ｆ , -S(O) １―２ OR ３Ｆ , -OS(O) １―２ R ３Ｆ , -S(O) １―２ N.R. ３Ｇ R ３Ｆ , and -NR ３Ｇ S (O) １―２ R ３Ｆ are independently selected from Each R ３Ｆ is H, C １ -C ３ Alkyl, and C １ -C ３ fluoroalkyl; Each R ３Ｇ is H, C １ -C ３ Alkyl, and C １ -C ３ fluoroalkyl; L ４ is a bond, -C(O)-, -S-, -S(O) １―２ -, -O-, and -NR ６ - selected from the group consisting of R ４ is unsubstituted, hydroxylated, C １ -C ４ Alkoxylated or Fluorinated C １ -C ８ Alkyl, unsubstituted or fluorinated C １ -C ８ Alkenyl, and unsubstituted or fluorinated C １ -C ８ alkynyl, L ５ is a bond, -C(O)-, -S-, -S(O) １―２ -, -O-, or -NR ６ - and R ５ Each has 1-5 R ５Ｅ phenyl, monocyclic heteroaryl, monocyclic heterocycloalkyl or monocyclic cycloalkyl, optionally substituted with Where: Each R ５Ｅ is oxo, optionally substituted C １ -C ４ Alkyl, C １ -C ４ Fluoroalkyl, halogen, -CN, -SF ５ , -N ３ , -C(O)R ５Ｆ , -SR ５Ｆ , -S(O) １－２ R ５Ｆ , -OR ５Ｆ , -NR ５Ｇ R ５Ｆ , -C(O)R ５Ｆ , -C(O)NR ５Ｇ R ５Ｆ , -NR ５Ｇ C(O)R ５Ｆ , -C(S)NR ５Ｇ R ５Ｆ , -NR １Ｇ C(S)R ５Ｆ , -C(O)OR ５Ｆ , -OC(O)R ５Ｆ , -C(O)SR ５Ｆ , -SC(O)R ５Ｆ , -C(S)OR ５Ｆ , -OC(S)R ５Ｆ , -C(S)SR ５Ｆ , -SC(S)R ５Ｆ , -S(O) １―２ OR ５Ｆ , -OS(O) １―２ R ５Ｆ , -S(O) １―２ N.R. ５Ｇ R ５Ｆ , and -NR ５Ｇ S (O) １―２ R ５Ｆ are independently selected from Each R ５Ｆ is H, C １ -C ３ Alkyl, and C １ -C ３ fluoroalkyl; Each R ５Ｇ is H and C １ -C ３ independently selected from alkyl, Each R ６ is hydrogen, C １ -C ３ Alkyl, and -C(O)(C １ -C ３ alkyl), Each optionally substituted alkyl, alkenyl and alkynyl is unsubstituted, fluorinated or substituted with one or two hydroxyl groups; each cycloalkyl has 3-7 ring carbons and is saturated or partially unsaturated; each heterocycloalkyl has 3-7 ring members, has 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and is saturated or partially unsaturated; Each monocyclic heteroaryl is a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

1. A pharmaceutical composition for treating solid tumor cancer in a human individual comprising a therapeutic compound of The pharmaceutical composition comprises: (i) comprising the steps of: Measuring the expression level of FAM210B in the solid tumor cancer; determining the fold change in expression of FAM210B compared to the expression level of FAM210B in a reference cell; if the fold change in expression of FAM210B is significant, and if FAM210B expression in the solid tumor cancer is lower than FAM210B expression in the reference cell, administering the pharmaceutical composition to the human individual; or (ii) the steps of: measuring the expression levels of a plurality of genes in the solid tumor cancer; determining a fold change in gene expression relative to the expression level of said plurality of genes in a reference cell; administering the pharmaceutical composition to the human individual if the fold change in gene expression is greater for a first number of genes of the plurality, the first number being 5 or greater; 13. A method comprising: wherein the solid tumor cancer exhibits a significant fold change in gene expression relative to a reference cell for a first number of a plurality of genes, the first number being at least five, selected from LAMC3, FAM210B, SENP8, ITGB3BP, NUDT2, HNRNPCL1, C20orf43, FRMD8, and STX16, wherein one of the first number of a plurality of genes is FAM210B. A pharmaceutical composition for use in

2. The pharmaceutical composition of claim 1 , wherein the first number is 6 or greater.

3. The pharmaceutical composition of claim 1 , wherein the first number is 7 or greater.

4. The pharmaceutical composition according to any one of claims 1 to 3, wherein the solid tumor cancer is adrenal gland cancer, bile duct cancer, bone cancer or muscle cancer, cervical cancer, colorectal cancer, esophageal cancer, eye cancer, head and neck cancer, kidney cancer, liver cancer, colon cancer, small cell lung cancer or non-small cell lung cancer, nervous system cancer, ovarian cancer, pancreatic cancer, placental cancer, prostate cancer, skin cancer, small intestine cancer, gastric cancer, or uterine cancer.

5. Formula (IIa): 【Chemistry 2】 [In the formula, L １ -S-, -O-, -S(O)-, -S(O) ２ - or a bond, R １ is unsubstituted or fluorinated C １ -C ８ Alkyl, unsubstituted or fluorinated C １ -C ８ Alkenyl, unsubstituted or fluorinated C １ -C ８ Alkynyl, 1-5 R １Ｅ or phenyl substituted with 1-5 R １Ｅ is a monocyclic heteroaryl substituted with Where: Each R １Ｅ is oxo, optionally substituted C １ -C ４ Alkyl, C １ -C ４ Fluoroalkyl, halogen, -CN, SF ５ , -N ３ , -C(O)R １Ｆ , -SR １Ｆ , -S(O) １―２ R １Ｆ , -OR １Ｆ , -(OCH ２ CH ２ O) ｎ -R １Ｇ [wherein n is 1 to 4], -N(R １Ｇ )C(O)CH ２ -O-(CH ２ CH ２ O) ｎ R １Ｇ [wherein n is 0 to 3], -C(O)NR １Ｇ (CH ２ CH ２ O) ｎ R １Ｇ , -NR １Ｇ R １Ｆ and -C(O)R １Ｆ are independently selected from Each R １Ｆ is H, C １ -C ３ Alkyl, and C １ -C ３ fluoroalkyl; Each R １Ｇ is H and C １ -C ３ independently selected from alkyl, L ２ is a bond or -CH ２ - and Q is -COOH; L ３ is a bond, -C(O)-, -S-, -S(O) １―２ -, -O-, -NR ６ --, --CH ２ -, -CH(CH ３ )(OH)—, or —CH(OH)—, R ３ are (i)-L ３Ｃ - (1-5 R ３Ｄ phenyl, which may be substituted with -L ３Ｃ - (1-5 R ３Ｄ -L ３Ｃ - (1-5 R ３Ｅ (monocyclic C3-C6 cycloalkyl optionally substituted with), -L ３Ｃ - (1-5 R ３Ｅ (ii) 1 to 5 R ３Ｅ phenyl or monocyclic heteroaryl, optionally substituted with Where: Each L ３Ｃ is a bond, methylene, ethylene, -C(O)-, -S-, -S(O) １―２ -, -O-, or -NR ３Ｇ - and Each R ３Ｄ is optionally substituted C １ -C ４ Alkyl, C １ -C ４ Fluoroalkyl, halogen, -CN, SF ５ , -N ３ , -C(O)R ３Ｆ , -SR ３Ｆ , -S(O) １―２ R ３Ｆ , -OR ３Ｆ , -NR ３Ｇ R ３Ｆ , -C(O)R ３Ｆ , -C(O)NR ３Ｇ R ３Ｆ , -NR ３Ｇ C(O)R ３Ｆ , -C(S)NR ３Ｇ R ３Ｆ , -NR ３Ｇ C(S)R ３Ｆ , -C(O)OR ３Ｆ , -OC(O)R ３Ｆ , -C(O)SR ３Ｆ , -SC(O)R ３Ｆ , -C(S)OR ３Ｆ , -OC(S)R ３Ｆ , -C(S)SR ３Ｆ , -SC(S)R ３Ｆ , -S(O) １―２ OR ３Ｆ , -OS(O) １―２ R ３Ｆ , -S(O) １―２ N.R. ３Ｇ R ３Ｆ , and -NR ３Ｇ S (O) １―２ R ３Ｆ are independently selected from Each R ３Ｅ is oxo, optionally substituted C １ -C ４ Alkyl, C １ -C ４ Fluoroalkyl, halogen, -CN, SF ５ , -N ３ , -C(O)R ３Ｆ , -SR ３Ｆ , -S(O) １―２ R ３Ｆ , -OR ３Ｆ , -NR ３Ｇ R ３Ｆ , -C(O)R ３Ｆ , -C(O)NR ３Ｇ R ３Ｆ , -NR ３Ｇ C(O)R ３Ｆ , -C(S)NR ３Ｇ R ３Ｆ , -NR ３Ｇ C(S)R ３Ｆ , -C(O)OR ３Ｆ , -OC(O)R ３Ｆ , -C(O)SR ３Ｆ , -SC(O)R ３Ｆ , -C(S)OR ３Ｆ , -OC(S)R ３Ｆ , -C(S)SR ３Ｆ , -SC(S)R ３Ｆ , -S(O) １―２ OR ３Ｆ , -OS(O) １―２ R ３Ｆ , -S(O) １―２ N.R. ３Ｇ R ３Ｆ , and -NR ３Ｇ S (O) １―２ R ３Ｆ are independently selected from Each R ３Ｆ is H, C １ -C ３ Alkyl, and C １ -C ３ fluoroalkyl; Each R ３Ｇ is H, C １ -C ３ Alkyl, and C １ -C ３ fluoroalkyl; L ４ is a bond, -C(O)-, -S-, -S(O) １―２ -, -O-, and -NR ６ - selected from the group consisting of R ４ is unsubstituted, hydroxylated, C １ -C ４ Alkoxylated or Fluorinated C １ -C ８ Alkyl, unsubstituted or fluorinated C １ -C ８ Alkenyl, and unsubstituted or fluorinated C １ -C ８ alkynyl, L ５ is a bond, -C(O)-, -S-, -S(O) １―２ -, -O-, or -NR ６ - and R ５ Each has 1-5 R ５Ｅ phenyl, monocyclic heteroaryl, monocyclic heterocycloalkyl or monocyclic cycloalkyl, optionally substituted with Where: Each R ５Ｅ is oxo, optionally substituted C １ -C ４ Alkyl, C １ -C ４ Fluoroalkyl, halogen, -CN, -SF ５ , -N ３ , -C(O)R ５Ｆ , -SR ５Ｆ , -S(O) １－２ R ５Ｆ , -OR ５Ｆ , -NR ５Ｇ R ５Ｆ , -C(O)R ５Ｆ , -C(O)NR ５Ｇ R ５Ｆ , -NR ５Ｇ C(O)R ５Ｆ , -C(S)NR ５Ｇ R ５Ｆ , -NR １Ｇ C(S)R ５Ｆ , -C(O)OR ５Ｆ , -OC(O)R ５Ｆ , -C(O)SR ５Ｆ , -SC(O)R ５Ｆ , -C(S)OR ５Ｆ , -OC(S)R ５Ｆ , -C(S)SR ５Ｆ , -SC(S)R ５Ｆ , -S(O) １―２ OR ５Ｆ , -OS(O) １―２ R ５Ｆ , -S(O) １―２ N.R. ５Ｇ R ５Ｆ , and -NR ５Ｇ S (O) １―２ R ５Ｆ are independently selected from Each R ５Ｆ is H, C １ -C ３ Alkyl, and C １ -C ３ fluoroalkyl; Each R ５Ｇ is H and C １ -C ３ independently selected from alkyl, Each R ６ is hydrogen, C １ -C ３ Alkyl, and -C(O)(C １ -C ３ alkyl), Each optionally substituted alkyl, alkenyl and alkynyl is unsubstituted, fluorinated or substituted with one or two hydroxyl groups; each cycloalkyl has 3-7 ring carbons and is saturated or partially unsaturated; each heterocycloalkyl has 3-7 ring members, has 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and is saturated or partially unsaturated; Each monocyclic heteroaryl is a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

1. A pharmaceutical composition for treating hematopoietic cancer in a human individual comprising a therapeutic compound of The pharmaceutical composition is prepared by the steps of: Measuring the expression levels of a plurality of genes of the hematopoietic cancer; determining a fold change in gene expression relative to the expression level of said plurality of genes in a reference cell; administering the pharmaceutical composition to the human individual if the fold change in gene expression is greater for a first number of genes of the plurality, the first number being 5 or greater; used in a method comprising the hematopoietic cancer exhibits a significant fold change in gene expression relative to a reference cell for a first number of a plurality of genes, the first number being at least five, selected from CASP10, TMED1, PPP1CC, TMEM59, BRD7, CYB561, FAM210B, NDRG1, CTSB, MMAB, SETDB2, VPS37B, ELL3, and KIF13B; The pharmaceutical composition, wherein one of the first number of genes is FAM210B.

6. The pharmaceutical composition of claim 5 , wherein the first number is 7 or greater.

7. The pharmaceutical composition of claim 5 , wherein the first number is 11 or greater.

8. The pharmaceutical composition according to any one of claims 5 to 7, wherein the hematopoietic cancer is chronic myeloproliferative neoplasm, lymphoma, leukemia, or plasma cell neoplasm.

9. The hematopoietic cancer is Burkitt's lymphoma, Hodgkin's lymphoma, non-Hodgkin's lymphoma, hairy cell lymphoma, mantle cell lymphoma, T cell lymphoma, cutaneous T cell lymphoma, B cell lymphoma, diffuse large B cell lymphoma, double hit lymphoma, Waldenstrom's macroglobulinemia, primary central nervous system (CNS) lymphoma, intravascular large B cell lymphoma (ILBCL), acute lymphocytic leukemia (ALL), acute myeloid leukemia (AML).

8. The pharmaceutical composition according to any one of claims 5 to 7, wherein the leukemia is selected from the group consisting of acute myeloblastic leukemia, chronic lymphocytic leukemia (CLL), chronic myelogenous leukemia (CML), chronic neutrophilic leukemia (CNL), chronic myelomonocytic leukemia (CMML), aggressive NK cell leukemia, acute pleoplasmic leukemia, polycythemia vera, or acute and chronic T-cell and B-cell leukemia, multiple myeloma, chronic myeloproliferative neoplasms, myelodysplastic syndromes, myelodysplastic / myeloproliferative neoplasms, or chronic myeloproliferative neoplasms.

10. The pharmaceutical composition of any one of claims 1 to 9, wherein a fold change in gene expression of at least 1.5 is a significant change in gene expression.

11. The pharmaceutical composition of any one of claims 1 to 9, wherein a fold change in gene expression of at least 2 is a significant change in gene expression.

12. The pharmaceutical composition of any one of claims 1 to 9, wherein a fold change in gene expression of at least 3 is a significant change in gene expression.

13. The reference cell is a non-cancerous cell of the human individual, a non-cancerous cell of a different human, a non-cancerous cell from a cell line, or a cell that has an IC of at least 30 μM for the therapeutic compound. ５０ The pharmaceutical composition according to any one of claims 1 to 12, wherein the cell is derived from a cancer cell line having the following structure:

14. 14. The pharmaceutical composition of any one of claims 1 to 13, wherein the therapeutic compound is 4-(3-fluorophenyl)-1-(5-(isopropylthio)-4-(4-(trifluoromethyl)phenyl)thiazol-2-yl)-3-methyl-1H-pyrazole-5-carboxylic acid.

15. 14. The pharmaceutical composition of any one of claims 1 to 13, wherein the therapeutic compound is 4-(3-fluorophenyl)-1-(5-(isopropylthio)-4-(4-(trifluoromethyl)cyclohexen-1-en-1-yl)thiazol-2-yl)-3-methyl-1H-pyrazole-5-carboxylic acid, optionally in enantiopure form.

16. In the therapeutic compound of formula (IIa), (a) R １ are each unsubstituted or fluorinated, C １ -C ８ Alkyl and C １ -C ８ alkenyl; L ５ is a bond, and R ５ However, each has 1-5 R ５Ｅ or a monocyclic cycloalkyl or monocyclic heterocycloalkyl, optionally substituted with (b) L １ is a bond, and R １ However, each has 1-5 R １Ｅ and L is selected from the group consisting of phenyl and monocyclic heteroaryl, optionally substituted with ５ is a bond, and R ５ However, each is (i)-L ５Ｃ - (1-5 R ５Ｄ phenyl, which may be substituted with -L ５Ｃ - (1-5 R ５Ｄ -L ５Ｃ - (1-5 R ５Ｄ -L ５Ｃ - (1-5 R ５Ｄ phenyl, monocyclic heteroaryl, monocyclic cycloalkyl or monocyclic heterocycloalkyl, optionally substituted by one substituent selected from Where: Each R １Ｅ is oxo, optionally substituted C １ -C ４ Alkyl, C １ -C ４ Fluoroalkyl, halogen, -CN, SF ５ , -N ３ , -C(O)R １Ｆ , -SR １Ｆ , -S(O) １－２ R １Ｆ , -OR １Ｆ , -(OCH ２ CH ２ O) ｎ -R １Ｇ [wherein n is 1 to 4], -N(R １Ｇ )C(O)CH ２ -O-(CH ２ CH ２ O) ｎ R １Ｇ [wherein n is 0 to 3], -C(O)NR １Ｇ (CH ２ CH ２ O) ｎ R １Ｇ , -NR １Ｇ R １Ｆ and -C(O)R １Ｆ are independently selected from Each R １Ｆ is H, C １ -C ３ Alkyl, and C １ -C ３ fluoroalkyl; Each R １Ｇ is H and C １ -C ３ independently selected from alkyl, Each L ５Ｃ is a bond, methylene, -C(O)-, -S-, -S(O) １－２ , —O— or —NR ３Ｇ - and Each R ５Ｄ is oxo, optionally substituted C １ -C ４ Alkyl, C １ -C ４ Fluoroalkyl, halogen, -CN, SF ５ , -N ３ , -C(O)R ５Ｆ , -SR ５Ｆ , -S(O) １－２ R ５Ｆ , -OR ５Ｆ , -NR ３Ｇ R ５Ｆ , -C(O)R ５Ｆ , -C(O)NR ３Ｇ R ５Ｆ , -NR ３Ｇ C(O)R ５Ｆ , -C(S)NR ３Ｇ R ５Ｆ , -NR ３Ｇ C(S)R ５Ｆ , -C(O)OR ５Ｆ , -OC(O)R ５Ｆ , -C(O)SR ５Ｆ , -SC(O)R ５Ｆ , -C(S)OR ５Ｆ , -OC(S)R ５Ｆ , -C(S)SR ５Ｆ , -SC(S)R ５Ｆ , -S(O) １－２ OR ５Ｆ , -OS(O) １－２ R ５Ｆ , -S(O) １－２ N.R. ５Ｇ R ５Ｆ and -NR ５Ｇ S (O) １－２ R ５Ｆ are independently selected from Each R ５Ｅ is oxo, optionally substituted C １ -C ４ Alkyl, C １ -C ４ Fluoroalkyl, halogen, -CN, -SF ５ , -N ３ , -C(O)R ５Ｆ , -SR ５Ｆ , -S(O) １－２ R ５Ｆ , -OR ５Ｆ , -NR ５Ｇ R ５Ｆ , -C(O)R ５Ｆ , -C(O)NR ５Ｇ R ５Ｆ , -NR ５Ｇ C(O)R ５Ｆ , -C(S)NR ５Ｇ R ５Ｆ , -NR １Ｇ C(S)R ５Ｆ , -C(O)OR ５Ｆ , -OC(O)R ５Ｆ , -C(O)SR ５Ｆ , -SC(O)R ５Ｆ , -C(S)OR ５Ｆ , -OC(S)R ５Ｆ , -C(S)SR ５Ｆ , -SC(S)R ５Ｆ , -S(O) １－２ OR ５Ｆ , -OS(O) １－２ R ５Ｆ , -S(O) １－２ N.R. ５Ｇ R ５Ｆ and -NR ５Ｇ S (O) １－２ R ５Ｆ are independently selected from Each R ５Ｆ is H, C １ -C ３ Alkyl and C １ -C ３ fluoroalkyl; Each R ５Ｇ is H and C １ -C ３ independently selected from alkyl, L ２ is a bond and -CH ２ - selected from the group consisting of Q is selected from the group consisting of -C(O)OH; L ３ is a bond, R ３ However, each has 0-5 R ３Ｅ phenyl or monocyclic heteroaryl substituted with Where: Each R ３Ｅ is oxo, optionally substituted C １ -C ４ Alkyl, C １ -C ４ Fluoroalkyl, halogen, -CN, SF ５ , -N ３ , -C(O)R ３Ｆ , -SR ３Ｆ , -S(O) １－２ R ３Ｆ , -OR ３Ｆ , -NR ３Ｇ R ３Ｆ , -C(O)R ３Ｆ , -C(O)NR ３Ｇ R ３Ｆ , -NR ３Ｇ C(O)R ３Ｆ , -C(S)NR ３Ｇ R ３Ｆ , -NR ３Ｇ C(S)R ３Ｆ , -C(O)OR ３Ｆ , -OC(O)R ３Ｆ , -C(O)SR ３Ｆ , -SC(O)R ３Ｆ , -C(S)OR ３Ｆ , -OC(S)R ３Ｆ , -C(S)SR ３Ｆ , -SC(S)R ３Ｆ , -S(O) １－２ OR ３Ｆ , -OS(O) １－２ R ３Ｆ , -S(O) １－２ N.R. ３Ｇ R ３Ｆ , and -NR ３Ｇ S (O) １－２ R ３Ｆ are independently selected from Each R ３Ｆ is H, C １ -C ３ Alkyl, and C １ -C ３ fluoroalkyl; Each R ３Ｇ is H, C １ -C ３ Alkyl, and C １ -C ３ fluoroalkyl; L ４ is a bond, R ４ is hydrogen, optionally substituted C １ -C ８ Alkyl and optionally substituted C １ -C ８ alkenyl, each optionally substituted alkyl, alkenyl and alkynyl is unsubstituted, fluorinated or substituted with one or two hydroxyl groups; each cycloalkyl has 3-7 carbon members and is saturated or partially unsaturated; each heterocycloalkyl has 3-7 ring members, has 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and is saturated or partially unsaturated; each monocyclic heteroaryl is a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; 14. The pharmaceutical composition of any one of claims 1 to 13, wherein the therapeutic compound is not 1-(4-(cyclohexen-1-en-1-yl)-5-(isopropylthio)thiazol-2-yl)-4-(3-fluorophenyl)-3-methyl-1H-pyrazole-5-carboxylic acid or 1-(4-(cyclopent-1-en-1-yl)-5-(isopropylthio)thiazol-2-yl)-4-(3-fluorophenyl)-3-methyl-1H-pyrazole-5-carboxylic acid.

17. In the therapeutic compound of formula (IIa), L １ is a bond, -S-, -S(O) １－２ -, -O-, and -O-; R １ are each unsubstituted or fluorinated, C １ -C ８ Alkyl and C １ -C ８ alkenyl, L ５ is a bond, R ５ However, each is (i)-L ５Ｃ - (1-5 R ５Ｄ -L ５Ｃ - (1-5 R ５Ｄ (ii) is unsubstituted or substituted with one substituent selected from the group consisting of 1 to 5 R ５Ｅ The pharmaceutical composition of claim 16, wherein the aryl group is cycloalkyl or heterocycloalkyl, optionally substituted with

18. In the therapeutic compound of formula (IIa), R １ is unsubstituted C １ -C ８ Alkyl or fluorinated C １ -C ８ is alkyl; L １ is -O-, -S-, -S(O)-, or -S(O) ２ The pharmaceutical composition according to claim 17, wherein

19. In the therapeutic compound of formula (IIa), R ５ But 1-5 R ５Ｅ 19. The pharmaceutical composition of claim 17 or 18, wherein the heterocycloalkyl is optionally substituted with:

20. In the therapeutic compound of formula (IIa), L ２ The pharmaceutical composition of any one of claims 1 to 13 and 15 to 19, wherein: is a bond and Q is -C(O)OH.

21. In the therapeutic compound of formula (IIa), R ３ 0-5 R ３Ｅ The pharmaceutical composition according to any one of claims 1 to 13 and 15 to 20, wherein R is phenyl or monocyclic heteroaryl substituted with R.

22. In the therapeutic compound of formula (IIa), R ４ is hydrogen or unsubstituted C １ -C ６ The pharmaceutical composition according to any one of claims 1 to 13 and 15 to 21, wherein the aryl group is alkyl.

23. In the therapeutic compound of formula (IIa), (a) L １ is -S-, -O-, -S(O)-, -S(O) ２ - or a bond; R １ is unsubstituted or fluorinated C １ -C ８ Alkyl, or unsubstituted or fluorinated C １ -C ８ alkenyl, and L ５ is a bond, and R ５ However, each has 1-5 R ５Ｅ or a monocyclic heterocycloalkyl or monocyclic cycloalkyl, optionally substituted with (b) L １ is a bond, and R １ 0-5 R １Ｅ phenyl substituted with L ５ is a bond, and R ５ However, each has 1-5 R ５Ｅ phenyl, monocyclic heteroaryl, monocyclic heterocycloalkyl or monocyclic cycloalkyl, optionally substituted with Where: Each R １Ｅ is oxo, optionally substituted C １ -C ４ Alkyl, C １ -C ４ Fluoroalkyl, halogen, -CN, SF ５ , -N ３ , -C(O)R １Ｆ , -SR １Ｆ , -S(O) １－２ R １Ｆ , -OR １Ｆ , -(OCH ２ CH ２ O) ｎ -R １Ｇ [wherein n is 1 to 4], -N(R １Ｇ )C(O)CH ２ -O-(CH ２ CH ２ O) ｎ R １Ｇ [wherein n is 0 to 3], -C(O)NR １Ｇ (CH ２ CH ２ O) ｎ R １Ｇ , -NR １Ｇ R １Ｆ and -C(O)R １Ｆ are independently selected from Each R １Ｆ is H, C １ -C ３ Alkyl, and C １ -C ３ fluoroalkyl; Each R １Ｇ is H and C １ -C ３ independently selected from alkyl, Each R ５Ｅ is oxo, optionally substituted C １ -C ４ Alkyl, C １ -C ４ Fluoroalkyl, halogen, -CN, -SF ５ , -N ３ , -C(O)R ５Ｆ , -SR ５Ｆ , -S(O) １－２ R ５Ｆ , -OR ５Ｆ , -NR ５Ｇ R ５Ｆ , -C(O)R ５Ｆ , -C(O)NR ５Ｇ R ５Ｆ , -NR ５Ｇ C(O)R ５Ｆ , -C(S)NR ５Ｇ R ５Ｆ , -NR １Ｇ C(S)R ５Ｆ , -C(O)OR ５Ｆ , -OC(O)R ５Ｆ , -C(O)SR ５Ｆ , -SC(O)R ５Ｆ , -C(S)OR ５Ｆ , -OC(S)R ５Ｆ , -C(S)SR ５Ｆ , -SC(S)R ５Ｆ , -S(O) １－２ OR ５Ｆ , -OS(O) １－２ R ５Ｆ , -S(O) １－２ N.R. ５Ｇ R ５Ｆ and -NR ５Ｇ S (O) １－２ R ５Ｆ are independently selected from Each R ５Ｆ is H, C １ -C ３ Alkyl and C １ -C ３ fluoroalkyl; Each R ５Ｇ is H and C １ -C ３ independently selected from alkyl, L ２ is a bond or -CH ２ - and Q is -COOH; R ３ However, each has 1-5 R ３Ｅ phenyl or monocyclic heteroaryl, optionally substituted with Where: Each R ３Ｅ is oxo, optionally substituted C １ -C ４ Alkyl, C １ -C ４ Fluoroalkyl, halogen, -CN, SF ５ , -N ３ , -C(O)R ３Ｆ , -SR ３Ｆ , -S(O) １－２ R ３Ｆ , -OR ３Ｆ , -NR ３Ｇ R ３Ｆ , -C(O)R ３Ｆ , -C(O)NR ３Ｇ R ３Ｆ , -NR ３Ｇ C(O)R ３Ｆ , -C(S)NR ３Ｇ R ３Ｆ , -NR ３Ｇ C(S)R ３Ｆ , -C(O)OR ３Ｆ , -OC(O)R ３Ｆ , -C(O)SR ３Ｆ , -SC(O)R ３Ｆ , -C(S)OR ３Ｆ , -OC(S)R ３Ｆ , -C(S)SR ３Ｆ , -SC(S)R ３Ｆ , -S(O) １－２ OR ３Ｆ , -OS(O) １－２ R ３Ｆ , -S(O) １－２ N.R. ３Ｇ R ３Ｆ , and -NR ３Ｇ S (O) １－２ R ３Ｆ are independently selected from Each R ３Ｆ is H, C １ -C ３ Alkyl, and C １ -C ３ fluoroalkyl; Each R ３Ｇ is H, C １ -C ３ Alkyl, and C １ -C ３ fluoroalkyl; R ４ is unsubstituted, hydroxylated, C １ -C ４ Alkoxylated or Fluorinated C １ -C ８ Alkyl, and unsubstituted or fluorinated C １ -C ８ alkenyl, each optionally substituted alkyl, alkenyl and alkynyl is unsubstituted, fluorinated or substituted with one or two hydroxyl groups; each cycloalkyl has 3-7 ring carbons and is saturated or partially unsaturated; each heterocycloalkyl has 3-7 ring members, has 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and is saturated or partially unsaturated; 14. The pharmaceutical composition of any one of claims 1 to 13, wherein each monocyclic heteroaryl is a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

24. In the therapeutic compound of formula (IIa), R ３ But 1-5 R ３Ｅ phenyl optionally substituted with Where: Each R ３Ｅ is oxo, optionally substituted C １ -C ４ Alkyl, C １ -C ４ Fluoroalkyl, halogen, -CN, SF ５ , -N ３ , -C(O)R ３Ｆ , -SR ３Ｆ , -S(O) １－２ R ３Ｆ , -OR ３Ｆ , -NR ３Ｇ R ３Ｆ , -C(O)R ３Ｆ , -C(O)NR ３Ｇ R ３Ｆ , -NR ３Ｇ C(O)R ３Ｆ , -C(S)NR ３Ｇ R ３Ｆ , -NR ３Ｇ C(S)R ３Ｆ , -C(O)OR ３Ｆ , -OC(O)R ３Ｆ , -C(O)SR ３Ｆ , -SC(O)R ３Ｆ , -C(S)OR ３Ｆ , -OC(S)R ３Ｆ , -C(S)SR ３Ｆ , -SC(S)R ３Ｆ , -S(O) １－２ OR ３Ｆ , -OS(O) １－２ R ３Ｆ , -S(O) １－２ N.R. ３Ｇ R ３Ｆ , and -NR ３Ｇ S (O) １－２ R ３Ｆ are independently selected from Each R ３Ｆ is H, C １ -C ３ Alkyl, and C １ -C ３ fluoroalkyl; Each R ３Ｇ is H, C １ -C ３ Alkyl, and C １ -C ３ fluoroalkyl; R ５ However, each has 1-5 R ５Ｅ phenyl, morpholinyl, cyclohexyl, cyclohexenyl, piperidinyl, piperazinyl or pyrrolidinyl, optionally substituted by Where: Each R ５Ｅ is oxo, optionally substituted C １ -C ４ Alkyl, C １ -C ４ Fluoroalkyl, halogen, -CN, -SF ５ , -N ３ , -C(O)R ５Ｆ , -SR ５Ｆ , -S(O) １－２ R ５Ｆ , -OR ５Ｆ , -NR ５Ｇ R ５Ｆ , -C(O)R ５Ｆ , -C(O)NR ５Ｇ R ５Ｆ , -NR ５Ｇ C(O)R ５Ｆ , -C(S)NR ５Ｇ R ５Ｆ , -NR １Ｇ C(S)R ５Ｆ , -C(O)OR ５Ｆ , -OC(O)R ５Ｆ , -C(O)SR ５Ｆ , -SC(O)R ５Ｆ , -C(S)OR ５Ｆ , -OC(S)R ５Ｆ , -C(S)SR ５Ｆ , -SC(S)R ５Ｆ , -S(O) １―２ OR ５Ｆ , -OS(O) １―２ R ５Ｆ , -S(O) １―２ N.R. ５Ｇ R ５Ｆ , and -NR ５Ｇ S (O) １―２ R ５Ｆ are independently selected from Each R ５Ｆ is H, C １ -C ３ Alkyl, and C １ -C ３ fluoroalkyl; Each R ５Ｇ is H and C １ -C ３ 24. The pharmaceutical composition of claim 23, wherein said alkyl is independently selected from the group consisting of aryl, ... and alkyl.

25. In the therapeutic compound of formula (IIa), (a) L １ is -S-, -O-, -S(O)-, -S(O) ２ - or a bond; R １ is unsubstituted or fluorinated C １ -C ８ Alkyl, or unsubstituted or fluorinated C １ -C ８ alkenyl, and L ５ is a bond, and R ５ However, each has 1-5 R ５Ｅ or a monocyclic heterocycloalkyl or monocyclic cycloalkyl, optionally substituted with (b) L １ is a bond, and R １ 1-5 R １Ｅ phenyl optionally substituted with ５ is a bond, and R ５ However, each has 1-5 R ５Ｅ phenyl, monocyclic heteroaryl, monocyclic heterocycloalkyl or monocyclic cycloalkyl, optionally substituted with Where: Each R １Ｅ is oxo, optionally substituted C １ -C ４ Alkyl, C １ -C ４ Fluoroalkyl, halogen, -CN, SF ５ , -N ３ , -C(O)R １Ｆ , -SR １Ｆ , -S(O) １－２ R １Ｆ , -OR １Ｆ , -(OCH ２ CH ２ O) ｎ -R １Ｇ [wherein n is 1 to 4], -N(R １Ｇ )C(O)CH ２ -O-(CH ２ CH ２ O) ｎ R １Ｇ [wherein n is 0 to 3], -C(O)NR １Ｇ (CH ２ CH ２ O) ｎ R １Ｇ , -NR １Ｇ R １Ｆ and -C(O)R １Ｆ are independently selected from Each R １Ｆ is H, C １ -C ３ Alkyl, and C １ -C ３ fluoroalkyl; Each R １Ｇ is H and C １ -C ３ independently selected from alkyl, Each R ５Ｅ is oxo, optionally substituted C １ -C ４ Alkyl, C １ -C ４ Fluoroalkyl, halogen, -CN, -SF ５ , -N ３ , -C(O)R ５Ｆ , -SR ５Ｆ , -S(O) １－２ R ５Ｆ , -OR ５Ｆ , -NR ５Ｇ R ５Ｆ , -C(O)R ５Ｆ , -C(O)NR ５Ｇ R ５Ｆ , -NR ５Ｇ C(O)R ５Ｆ , -C(S)NR ５Ｇ R ５Ｆ , -NR １Ｇ C(S)R ５Ｆ , -C(O)OR ５Ｆ , -OC(O)R ５Ｆ , -C(O)SR ５Ｆ , -SC(O)R ５Ｆ , -C(S)OR ５Ｆ , -OC(S)R ５Ｆ , -C(S)SR ５Ｆ , -SC(S)R ５Ｆ , -S(O) １－２ OR ５Ｆ , -OS(O) １－２ R ５Ｆ , -S(O) １－２ N.R. ５Ｇ R ５Ｆ and -NR ５Ｇ S (O) １－２ R ５Ｆ are independently selected from Each R ５Ｆ is H, C １ -C ３ Alkyl and C １ -C ３ fluoroalkyl; Each R ５Ｇ is H and C １ -C ３ independently selected from alkyl, L ２ is a bond or -CH ２ - and Q is -COOH; R ３ However, each has 1-5 R ３Ｅ phenyl or monocyclic heteroaryl, optionally substituted with Where: Each R ３Ｅ is oxo, optionally substituted C １ -C ４ Alkyl, C １ -C ４ Fluoroalkyl, halogen, -CN, SF ５ , -N ３ , -C(O)R ３Ｆ , -SR ３Ｆ , -S(O) １－２ R ３Ｆ , -OR ３Ｆ , -NR ３Ｇ R ３Ｆ , -C(O)R ３Ｆ , -C(O)NR ３Ｇ R ３Ｆ , -NR ３Ｇ C(O)R ３Ｆ , -C(S)NR ３Ｇ R ３Ｆ , -NR ３Ｇ C(S)R ３Ｆ , -C(O)OR ３Ｆ , -OC(O)R ３Ｆ , -C(O)SR ３Ｆ , -SC(O)R ３Ｆ , -C(S)OR ３Ｆ , -OC(S)R ３Ｆ , -C(S)SR ３Ｆ , -SC(S)R ３Ｆ , -S(O) １－２ OR ３Ｆ , -OS(O) １－２ R ３Ｆ , -S(O) １－２ N.R. ３Ｇ R ３Ｆ , and -NR ３Ｇ S (O) １－２ R ３Ｆ are independently selected from Each R ３Ｆ is H, C １ -C ３ Alkyl, and C １ -C ３ fluoroalkyl; Each R ３Ｇ is H, C １ -C ３ Alkyl, and C １ -C ３ fluoroalkyl; R ４ is unsubstituted, hydroxylated, C １ -C ４ Alkoxylated or Fluorinated C １ -C ８ Alkyl, and unsubstituted or fluorinated C １ -C ８ alkenyl, each optionally substituted alkyl, alkenyl and alkynyl is unsubstituted, fluorinated or substituted with one or two hydroxyl groups; each monocyclic cycloalkyl has 3-7 ring carbons and is saturated or partially unsaturated; each monocyclic heterocycloalkyl has 3-7 ring members, has 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and is saturated or partially unsaturated; 14. The pharmaceutical composition of any one of claims 1 to 13, wherein each monocyclic heteroaryl is a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

26. In the therapeutic compound of formula (IIa), R ３ But 1-5 R ３Ｅ phenyl optionally substituted with Where: Each R ３Ｅ is oxo, optionally substituted C １ -C ４ Alkyl, C １ -C ４ Fluoroalkyl, halogen, -CN, SF ５ , -N ３ , -C(O)R ３Ｆ , -SR ３Ｆ , -S(O) １－２ R ３Ｆ , -OR ３Ｆ , -NR ３Ｇ R ３Ｆ , -C(O)R ３Ｆ , -C(O)NR ３Ｇ R ３Ｆ , -NR ３Ｇ C(O)R ３Ｆ , -C(S)NR ３Ｇ R ３Ｆ , -NR ３Ｇ C(S)R ３Ｆ , -C(O)OR ３Ｆ , -OC(O)R ３Ｆ , -C(O)SR ３Ｆ , -SC(O)R ３Ｆ , -C(S)OR ３Ｆ , -OC(S)R ３Ｆ , -C(S)SR ３Ｆ , -SC(S)R ３Ｆ , -S(O) １－２ OR ３Ｆ , -OS(O) １－２ R ３Ｆ , -S(O) １－２ N.R. ３Ｇ R ３Ｆ , and -NR ３Ｇ S (O) １－２ R ３Ｆ are independently selected from Each R ３Ｆ is H, C １ -C ３ Alkyl, and C １ -C ３ fluoroalkyl; Each R ３Ｇ is H, C １ -C ３ Alkyl, and C １ -C ３ fluoroalkyl; R ５ However, each has 0-5 R ５Ｅ phenyl, morpholinyl, cyclohexyl, cyclohexenyl, piperidinyl, piperazinyl or pyrrolidinyl, optionally substituted by Where: Each R ５Ｅ is oxo, optionally substituted C １ -C ４ Alkyl, C １ -C ４ Fluoroalkyl, halogen, -CN, -SF ５ , -N ３ , -C(O)R ５Ｆ , -SR ５Ｆ , -S(O) １－２ R ５Ｆ , -OR ５Ｆ , -NR ５Ｇ R ５Ｆ , -C(O)R ５Ｆ , -C(O)NR ５Ｇ R ５Ｆ , -NR ５Ｇ C(O)R ５Ｆ , -C(S)NR ５Ｇ R ５Ｆ , -NR １Ｇ C(S)R ５Ｆ , -C(O)OR ５Ｆ , -OC(O)R ５Ｆ , -C(O)SR ５Ｆ , -SC(O)R ５Ｆ , -C(S)OR ５Ｆ , -OC(S)R ５Ｆ , -C(S)SR ５Ｆ , -SC(S)R ５Ｆ , -S(O) １―２ OR ５Ｆ , -OS(O) １―２ R ５Ｆ , -S(O) １―２ N.R. ５Ｇ R ５Ｆ , and -NR ５Ｇ S (O) １―２ R ５Ｆ are independently selected from Each R ５Ｆ is H, C １ -C ３ Alkyl, and C １ -C ３ fluoroalkyl; Each R ５Ｇ is H and C １ -C ３ 26. The pharmaceutical composition of claim 25, wherein said aryl group is independently selected from alkyl.

27. In the therapeutic compound of formula (IIa), L １ is -S- or a bond, and L ２ 27. The pharmaceutical composition of claim 25 or 26, wherein is a bond.

28. In the therapeutic compound of formula (IIa), L １ is -S-, and R １ is unsubstituted C １ -C ８ Alkyl or fluorinated C １ -C ８ alkyl, R ５ However, each has 1-5 R ５Ｅ The pharmaceutical composition according to any one of claims 23 to 27, wherein the heterocyclic alkyl or cycloalkyl is optionally substituted with:

29. The therapeutic compound may be in the form of a pharma- ceutically acceptable salt or N-oxide, or a solvate or hydrate, of the following compounds: 4-(3-fluorophenyl)-1-(5-(isopropylthio)-4-(4-methylcyclohex-1-en-1-yl)thiazol-2-yl)-3-methyl-1H-pyrazole-5-carboxylic acid; 4-(3-fluorophenyl)-1-(5-(isopropylthio)-4-(4-(trifluoromethyl)cyclohexen-1-en-1-yl)thiazol-2-yl)-3-methyl-1H-pyrazole-5-carboxylic acid; 1-(4-(4,4-dimethylcyclohex-1-en-1-yl)-5-(isopropylthio)thiazol-2-yl)-4-(3-fluorophenyl)-3-methyl-1H-pyrazole-5-carboxylic acid; 4-(3-fluorophenyl)-1-(5-(isopropylthio)-4-(1,4-dioxaspiro[4.5]dec-7-en-8-yl)thiazol-2-yl)-3-methyl-1H-pyrazole-5-carboxylic acid; 4-(3-fluorophenyl)-1-(5-(isopropylthio)-4-(piperidin-1-yl)thiazol-2-yl)-3-methyl-1H-pyrazole-5-carboxylic acid; 4-(3-fluorophenyl)-1-(5-(isopropylthio)-4-(4-(trifluoromethyl)piperidin-1-yl)thiazol-2-yl)-3-methyl-1H-pyrazole-5-carboxylic acid; 4-(3-fluorophenyl)-1-(5-(isopropylthio)-4-morpholinothiazol-2-yl)-3-methyl-1H-pyrazole-5-carboxylic acid; 1-(4-(4,4-difluoropiperidin-1-yl)-5-(isopropylthio)thiazol-2-yl)-4-(3-fluorophenyl)-3-methyl-1H-pyrazole-5-carboxylic acid; 4-(3-fluorophenyl)-3-methyl-1-(4-(4-(trifluoromethyl)cyclohexyl)thiazol-2-yl)-1H-pyrazole-5-carboxylic acid; 4-(3-fluorophenyl)-1-(5-isobutyl-4-(4-(trifluoromethyl)phenyl)thiazol-2-yl)-3-methyl-1H-pyrazole-5-carboxylic acid; 4-(3-fluorophenyl)-1-(5-(isopropylthio)-4-(4-(2,2,2-trifluoroethyl)piperazin-1-yl)thiazol-2-yl)-3-methyl-1H-pyrazole-5-carboxylic acid; 1-(4-(4-cyanopiperidin-1-yl)-5-(isopropylthio)thiazol-2-yl)-4-(3-fluorophenyl)-3-methyl-1H-pyrazole-5-carboxylic acid; 1-(4-(4-cyclopropylpiperazin-1-yl)-5-(isopropylthio)thiazol-2-yl)-4-(3-fluorophenyl)-3-methyl-1H-pyrazole-5-carboxylic acid; 1-(4-(4-ethylpiperazin-1-yl)-5-(isopropylthio)thiazol-2-yl)-4-(3-fluorophenyl)-3-methyl-1H-pyrazole-5-carboxylic acid; 1-(4-(4-acetylpiperazin-1-yl)-5-(isopropylthio)thiazol-2-yl)-4-(3-fluorophenyl)-3-methyl-1H-pyrazole-5-carboxylic acid; 4-(3-fluorophenyl)-1-(5-(isopropylthio)-4-(4-methylpiperidin-1-yl)thiazol-2-yl)-3-methyl-1H-pyrazole-5-carboxylic acid; 4-(3-fluorophenyl)-1-(5-(isopropylthio)-4-(4-methylpiperazin-1-yl)thiazol-2-yl)-3-methyl-1H-pyrazole-5-carboxylic acid; 1-(4-(4,4-dimethylpiperidin-1-yl)-5-(isopropylthio)thiazol-2-yl)-4-(3-fluorophenyl)-3-methyl-1H-pyrazole-5-carboxylic acid; 1-(4-(4-(tert-butoxycarbonyl)piperazin-1-yl)-5-(isopropylthio)thiazol-2-yl)-4-(3-fluorophenyl)-3-methyl-1H-pyrazole-5-carboxylic acid; 4-(3-fluorophenyl)-1-(5-(isopropylthio)-4-(3-(trifluoromethyl)pyrrolidin-1-yl)thiazol-2-yl)-3-methyl-1H-pyrazole-5-carboxylic acid; 4-(3-fluorophenyl)-1-(5-(isopropylthio)-4-(piperazin-1-yl)thiazol-2-yl)-3-methyl-1H-pyrazole-5-carboxylic acid; 1-(4,5-bis(4-(trifluoromethyl)phenyl)thiazol-2-yl)-4-(3-fluorophenyl)-3-methyl-1H-pyrazole-5-carboxylic acid; 1-(4-(4-(tert-butyl)piperidin-1-yl)-5-(isopropylthio)thiazol-2-yl)-4-(3-fluorophenyl)-3-methyl-1H-pyrazole-5-carboxylic acid; 4-(3-fluorophenyl)-1-(5-(isopropylthio)-4-(6-azaspiro[2.5]octan-6-yl)thiazol-2-yl)-3-methyl-1H-pyrazole-5-carboxylic acid; 4-(3-fluorophenyl)-1-(5-(isopropylthio)-4-(4-methoxy-4-(trifluoromethyl)piperidin-1-yl)thiazol-2-yl)-3-methyl-1H-pyrazole-5-carboxylic acid; 4-(3-fluorophenyl)-1-(4-(4-methoxyphenyl)-5-(4-(trifluoromethyl)phenyl)thiazol-2-yl)-3-methyl-1H-pyrazole-5-carboxylic acid; 1-(4,5-bis(4-methoxyphenyl)thiazol-2-yl)-4-(3-fluorophenyl)-3-methyl-1H-pyrazole-5-carboxylic acid; 4-(3-fluorophenyl)-1-(5-(4-methoxyphenyl)-4-(4-(trifluoromethyl)phenyl)thiazol-2-yl)-3-methyl-1H-pyrazole-5-carboxylic acid; 1-(4-(4-(tert-butyl)-3-oxopiperazin-1-yl)-5-(isopropylthio)thiazol-2-yl)-4-(3-fluorophenyl)-3-methyl-1H-pyrazole-5-carboxylic acid; 4-(3-fluorophenyl)-1-(5-(isopropylthio)-4-(4-(2-methoxyethoxy)-4-(trifluoromethyl)piperidin-1-yl)thiazol-2-yl)-3-methyl-1H-pyrazole-5-carboxylic acid; 4-(3-fluorophenyl)-1-(5-(4-((2-methoxyethyl)carbamoyl)phenyl)-4-(4-(trifluoromethyl)phenyl)thiazol-2-yl)-3-methyl-1H-pyrazole-5-carboxylic acid; 4-(3-fluorophenyl)-1-(5-(4-((2-methoxyethyl)(methyl)carbamoyl)phenyl)-4-(4-(trifluoromethyl)phenyl)thiazol-2-yl)-3-methyl-1H-pyrazole-5-carboxylic acid; 4-(3-fluorophenyl)-1-(5-(4-(2-methoxyacetamido)phenyl)-4-(4-(trifluoromethyl)phenyl)thiazol-2-yl)-3-methyl-1H-pyrazole-5-carboxylic acid; 4-(3-fluorophenyl)-1-(5-(4-(2-(2-methoxyethoxy)acetamido)phenyl)-4-(4-(trifluoromethyl)phenyl)thiazol-2-yl)-3-methyl-1H-pyrazole-5-carboxylic acid; 4-(3-fluorophenyl)-1-(5-(3-((2-methoxyethyl)(methyl)amino)-3-oxopropyl)-4-(4-(trifluoromethyl)phenyl)thiazol-2-yl)-3-methyl-1H-pyrazole-5-carboxylic acid; 4-(3-fluorophenyl)-1-(5-(4-(2-methoxy-N-methylacetamido)phenyl)-4-(4-(trifluoromethyl)phenyl)thiazol-2-yl)-3-methyl-1H-pyrazole-5-carboxylic acid; 4-(3-fluorophenyl)-1-(5-(4-(2-(2-methoxyethoxy)-N-methylacetamido)phenyl)-4-(4-(trifluoromethyl)phenyl)thiazol-2-yl)-3-methyl-1H-pyrazole-5-carboxylic acid; 4-(3-fluorophenyl)-1-(5-(methoxymethyl)-4-(4-(trifluoromethyl)phenyl)thiazol-2-yl)-3-methyl-1H-pyrazole-5-carboxylic acid; 1-(5-(4-(2-(2-ethoxyethoxy)ethoxy)phenyl)-4-(4-(trifluoromethyl)phenyl)thiazol-2-yl)-4-(3-fluorophenyl)-3-methyl-1H-pyrazole-5-carboxylic acid; 4-(3-fluorophenyl)-1-(5-(3-fluorophenyl)-4-(4-(trifluoromethyl)phenyl)thiazol-2-yl)-3-methyl-1H-pyrazole-5-carboxylic acid; 4-(3-fluorophenyl)-3-methyl-1-(5-(4-(trifluoromethyl)phenyl)-4-(4-(trifluoromethyl)piperidin-1-yl)thiazol-2-yl)-1H-pyrazole-5-carboxylic acid; 4-(3-fluorophenyl)-1-(4-(3-fluorophenyl)-5-(4-(trifluoromethyl)phenyl)thiazol-2-yl)-3-methyl-1H-pyrazole-5-carboxylic acid; 4-(3-fluorophenyl)-1-(5-(4-(2-methoxyethoxy)phenyl)-4-(4-(trifluoromethyl)phenyl)thiazol-2-yl)-3-methyl-1H-pyrazole-5-carboxylic acid; 4-(3-fluorophenyl)-1-(4-(4-isopropylpiperidin-1-yl)-5-(isopropylthio)thiazol-2-yl)-3-methyl-1H-pyrazole-5-carboxylic acid; and 4-(3-fluorophenyl)-1-(5-(isopropylthio)-4-(3-methoxy-3-(trifluoromethyl)-8-azabicyclo[3.2.1]octan-8-yl)thiazol-2-yl)-3-methyl-1H-pyrazole-5-carboxylic acid The pharmaceutical composition according to any one of claims 1 to 13, wherein the pharmaceutical composition is selected from the group consisting of

30. 5. The method of claim 1, wherein the solid tumor cancer is a compound represented by formula (IIa): 【Chemistry 3】 [In the formula, L １ -S-, -O-, -S(O)-, -S(O) ２ - or a bond, R １ is unsubstituted or fluorinated C １ -C ８ Alkyl, unsubstituted or fluorinated C １ -C ８ Alkenyl, unsubstituted or fluorinated C １ -C ８ Alkynyl, 1-5 R １Ｅ or phenyl substituted with 1-5 R １Ｅ is a monocyclic heteroaryl substituted with Where: Each R １Ｅ is oxo, optionally substituted C １ -C ４ Alkyl, C １ -C ４ Fluoroalkyl, halogen, -CN, SF ５ , -N ３ , -C(O)R １Ｆ , -SR １Ｆ , -S(O) １―２ R １Ｆ , -OR １Ｆ , -(OCH ２ CH ２ O) ｎ -R １Ｇ [wherein n is 1 to 4], -N(R １Ｇ )C(O)CH ２ -O-(CH ２ CH ２ O) ｎ R １Ｇ [wherein n is 0 to 3], -C(O)NR １Ｇ (CH ２ CH ２ O) ｎ R １Ｇ , -NR １Ｇ R １Ｆ and -C(O)R １Ｆ are independently selected from Each R １Ｆ is H, C １ -C ３ Alkyl, and C １ -C ３ fluoroalkyl; Each R １Ｇ is H and C １ -C ３ independently selected from alkyl, L ２ is a bond or -CH ２ - and Q is -COOH; L ３ is a bond, -C(O)-, -S-, -S(O) １―２ -, -O-, -NR ６ --, --CH ２ -, -CH(CH ３ )(OH)—, or —CH(OH)—, R ３ are (i)-L ３Ｃ - (1-5 R ３Ｄ phenyl, which may be substituted with -L ３Ｃ - (1-5 R ３Ｄ -L ３Ｃ - (1-5 R ３Ｅ (monocyclic C3-C6 cycloalkyl optionally substituted with), -L ３Ｃ - (1-5 R ３Ｅ (ii) 1 to 5 R ３Ｅ phenyl or monocyclic heteroaryl, optionally substituted with Where: Each L ３Ｃ is a bond, methylene, ethylene, -C(O)-, -S-, -S(O) １―２ -, -O-, or -NR ３Ｇ - and Each R ３Ｄ is optionally substituted C １ -C ４ Alkyl, C １ -C ４ Fluoroalkyl, halogen, -CN, SF ５ , -N ３ , -C(O)R ３Ｆ , -SR ３Ｆ , -S(O) １―２ R ３Ｆ , -OR ３Ｆ , -NR ３Ｇ R ３Ｆ , -C(O)R ３Ｆ , -C(O)NR ３Ｇ R ３Ｆ , -NR ３Ｇ C(O)R ３Ｆ , -C(S)NR ３Ｇ R ３Ｆ , -NR ３Ｇ C(S)R ３Ｆ , -C(O)OR ３Ｆ , -OC(O)R ３Ｆ , -C(O)SR ３Ｆ , -SC(O)R ３Ｆ , -C(S)OR ３Ｆ , -OC(S)R ３Ｆ , -C(S)SR ３Ｆ , -SC(S)R ３Ｆ , -S(O) １―２ OR ３Ｆ , -OS(O) １―２ R ３Ｆ , -S(O) １―２ N.R. ３Ｇ R ３Ｆ , and -NR ３Ｇ S (O) １―２ R ３Ｆ are independently selected from Each R ３Ｅ is oxo, optionally substituted C １ -C ４ Alkyl, C １ -C ４ Fluoroalkyl, halogen, -CN, SF ５ , -N ３ , -C(O)R ３Ｆ , -SR ３Ｆ , -S(O) １―２ R ３Ｆ , -OR ３Ｆ , -NR ３Ｇ R ３Ｆ , -C(O)R ３Ｆ , -C(O)NR ３Ｇ R ３Ｆ , -NR ３Ｇ C(O)R ３Ｆ , -C(S)NR ３Ｇ R ３Ｆ , -NR ３Ｇ C(S)R ３Ｆ , -C(O)OR ３Ｆ , -OC(O)R ３Ｆ , -C(O)SR ３Ｆ , -SC(O)R ３Ｆ , -C(S)OR ３Ｆ , -OC(S)R ３Ｆ , -C(S)SR ３Ｆ , -SC(S)R ３Ｆ , -S(O) １―２ OR ３Ｆ , -OS(O) １―２ R ３Ｆ , -S(O) １―２ N.R. ３Ｇ R ３Ｆ , and -NR ３Ｇ S (O) １―２ R ３Ｆ are independently selected from Each R ３Ｆ is H, C １ -C ３ Alkyl, and C １ -C ３ fluoroalkyl; Each R ３Ｇ is H, C １ -C ３ Alkyl, and C １ -C ３ fluoroalkyl; L ４ is a bond, -C(O)-, -S-, -S(O) １―２ -, -O-, and -NR ６ - selected from the group consisting of R ４ is unsubstituted, hydroxylated, C １ -C ４ Alkoxylated or Fluorinated C １ -C ８ Alkyl, unsubstituted or fluorinated C １ -C ８ Alkenyl, and unsubstituted or fluorinated C １ -C ８ alkynyl, L ５ is a bond, -C(O)-, -S-, -S(O) １―２ -, -O-, or -NR ６ - and R ５ Each has 1-5 R ５Ｅ phenyl, monocyclic heteroaryl, monocyclic heterocycloalkyl or monocyclic cycloalkyl, optionally substituted with Where: Each R ５Ｅ is oxo, optionally substituted C １ -C ４ Alkyl, C １ -C ４ Fluoroalkyl, halogen, -CN, -SF ５ , -N ３ , -C(O)R ５Ｆ , -SR ５Ｆ , -S(O) １－２ R ５Ｆ , -OR ５Ｆ , -NR ５Ｇ R ５Ｆ , -C(O)R ５Ｆ , -C(O)NR ５Ｇ R ５Ｆ , -NR ５Ｇ C(O)R ５Ｆ , -C(S)NR ５Ｇ R ５Ｆ , -NR １Ｇ C(S)R ５Ｆ , -C(O)OR ５Ｆ , -OC(O)R ５Ｆ , -C(O)SR ５Ｆ , -SC(O)R ５Ｆ , -C(S)OR ５Ｆ , -OC(S)R ５Ｆ , -C(S)SR ５Ｆ , -SC(S)R ５Ｆ , -S(O) １―２ OR ５Ｆ , -OS(O) １―２ R ５Ｆ , -S(O) １―２ N.R. ５Ｇ R ５Ｆ , and -NR ５Ｇ S (O) １―２ R ５Ｆ are independently selected from Each R ５Ｆ is H, C １ -C ３ Alkyl, and C １ -C ３ fluoroalkyl; Each R ５Ｇ is H and C １ -C ３ independently selected from alkyl, Each R ６ is hydrogen, C １ -C ３ Alkyl, and -C(O)(C １ -C ３ alkyl), Each optionally substituted alkyl, alkenyl and alkynyl is unsubstituted, fluorinated or substituted with one or two hydroxyl groups; each cycloalkyl has 3-7 ring carbons and is saturated or partially unsaturated; each heterocycloalkyl has 3-7 ring members, has 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and is saturated or partially unsaturated; Each monocyclic heteroaryl is a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

1. A method for determining whether a subject is responsive to a therapeutic compound comprising: (i) the method comprises the steps of: Measuring the expression level of FAM210B in a sample taken from the solid tumor cancer; determining the fold change in expression of FAM210B compared to the expression level of FAM210B in a reference cell; identifying the solid tumor cancer as likely to be responsive to the therapeutic compound if the fold change in expression of FAM210B is significant and if FAM210B expression in the solid tumor cancer is lower than FAM210B expression in the reference cell; Contains, or (ii) the method comprises the steps of: measuring the expression levels of a plurality of genes in a sample taken from the solid tumor cancer; measuring a fold change in gene expression compared to the expression level of one or more genes in a reference cell; identifying the solid tumor cancer as likely to be responsive to the therapeutic compound if the fold change in gene expression is greater for a first number of the plurality of genes, the first number being 5 or greater; wherein the solid tumor cancer exhibits a significant fold change in gene expression relative to a reference cell for a first number of a plurality of genes, the first number being at least five, selected from LAMC3, FAM210B, SENP8, ITGB3BP, NUDT2, HNRNPCL1, C20orf43, FRMD8, and STX16, and one of the first number of a plurality of genes is FAM210B.

31. 31. The method of claim 30, wherein the first number is six or greater.

32. 31. The method of claim 30, wherein the first number is seven or greater.

33. 33. The method of any one of claims 30 to 32, wherein the solid tumor cancer is adrenal gland cancer, bile duct cancer, bone cancer or muscle cancer, cervical cancer, colorectal cancer, esophageal cancer, eye cancer, head and neck cancer, kidney cancer, liver cancer, colon cancer, small cell lung cancer or non-small cell lung cancer, nervous system cancer, ovarian cancer, pancreatic cancer, placental cancer, prostate cancer, skin cancer, small intestine cancer, gastric cancer, or uterine cancer.

34. 4. The method of claim 1, wherein the hematopoietic cancer is a compound represented by formula (IIa): 【Chemistry 4】 [In the formula, L １ -S-, -O-, -S(O)-, -S(O) ２ - or a bond, R １ is unsubstituted or fluorinated C １ -C ８ Alkyl, unsubstituted or fluorinated C １ -C ８ Alkenyl, unsubstituted or fluorinated C １ -C ８ Alkynyl, 1-5 R １Ｅ or phenyl substituted with 1-5 R １Ｅ is a monocyclic heteroaryl substituted with Where: Each R １Ｅ is oxo, optionally substituted C １ -C ４ Alkyl, C １ -C ４ Fluoroalkyl, halogen, -CN, SF ５ , -N ３ , -C(O)R １Ｆ , -SR １Ｆ , -S(O) １―２ R １Ｆ , -OR １Ｆ , -(OCH ２ CH ２ O) ｎ -R １Ｇ [wherein n is 1 to 4], -N(R １Ｇ )C(O)CH ２ -O-(CH ２ CH ２ O) ｎ R １Ｇ [wherein n is 0 to 3], -C(O)NR １Ｇ (CH ２ CH ２ O) ｎ R １Ｇ , -NR １Ｇ R １Ｆ and -C(O)R １Ｆ are independently selected from Each R １Ｆ is H, C １ -C ３ Alkyl, and C １ -C ３ fluoroalkyl; Each R １Ｇ is H and C １ -C ３ independently selected from alkyl, L ２ is a bond or -CH ２ - and Q is -COOH; L ３ is a bond, -C(O)-, -S-, -S(O) １―２ -, -O-, -NR ６ --, --CH ２ -, -CH(CH ３ )(OH)—, or —CH(OH)—, R ３ are (i)-L ３Ｃ - (1-5 R ３Ｄ phenyl, which may be substituted with -L ３Ｃ - (1-5 R ３Ｄ -L ３Ｃ - (1-5 R ３Ｅ (monocyclic C3-C6 cycloalkyl optionally substituted with), -L ３Ｃ - (1-5 R ３Ｅ (ii) 1 to 5 R ３Ｅ phenyl or monocyclic heteroaryl, optionally substituted with Where: Each L ３Ｃ is a bond, methylene, ethylene, -C(O)-, -S-, -S(O) １―２ -, -O-, or -NR ３Ｇ - and Each R ３Ｄ is optionally substituted C １ -C ４ Alkyl, C １ -C ４ Fluoroalkyl, halogen, -CN, SF ５ , -N ３ , -C(O)R ３Ｆ , -SR ３Ｆ , -S(O) １―２ R ３Ｆ , -OR ３Ｆ , -NR ３Ｇ R ３Ｆ , -C(O)R ３Ｆ , -C(O)NR ３Ｇ R ３Ｆ , -NR ３Ｇ C(O)R ３Ｆ , -C(S)NR ３Ｇ R ３Ｆ , -NR ３Ｇ C(S)R ３Ｆ , -C(O)OR ３Ｆ , -OC(O)R ３Ｆ , -C(O)SR ３Ｆ , -SC(O)R ３Ｆ , -C(S)OR ３Ｆ , -OC(S)R ３Ｆ , -C(S)SR ３Ｆ , -SC(S)R ３Ｆ , -S(O) １―２ OR ３Ｆ , -OS(O) １―２ R ３Ｆ , -S(O) １―２ N.R. ３Ｇ R ３Ｆ , and -NR ３Ｇ S (O) １―２ R ３Ｆ are independently selected from Each R ３Ｅ is oxo, optionally substituted C １ -C ４ Alkyl, C １ -C ４ Fluoroalkyl, halogen, -CN, SF ５ , -N ３ , -C(O)R ３Ｆ , -SR ３Ｆ , -S(O) １―２ R ３Ｆ , -OR ３Ｆ , -NR ３Ｇ R ３Ｆ , -C(O)R ３Ｆ , -C(O)NR ３Ｇ R ３Ｆ , -NR ３Ｇ C(O)R ３Ｆ , -C(S)NR ３Ｇ R ３Ｆ , -NR ３Ｇ C(S)R ３Ｆ , -C(O)OR ３Ｆ , -OC(O)R ３Ｆ , -C(O)SR ３Ｆ , -SC(O)R ３Ｆ , -C(S)OR ３Ｆ , -OC(S)R ３Ｆ , -C(S)SR ３Ｆ , -SC(S)R ３Ｆ , -S(O) １―２ OR ３Ｆ , -OS(O) １―２ R ３Ｆ , -S(O) １―２ N.R. ３Ｇ R ３Ｆ , and -NR ３Ｇ S (O) １―２ R ３Ｆ are independently selected from Each R ３Ｆ is H, C １ -C ３ Alkyl, and C １ -C ３ fluoroalkyl; Each R ３Ｇ is H, C １ -C ３ Alkyl, and C １ -C ３ fluoroalkyl; L ４ is a bond, -C(O)-, -S-, -S(O) １―２ -, -O-, and -NR ６ - selected from the group consisting of R ４ is unsubstituted, hydroxylated, C １ -C ４ Alkoxylated or Fluorinated C １ -C ８ Alkyl, unsubstituted or fluorinated C １ -C ８ Alkenyl, and unsubstituted or fluorinated C １ -C ８ alkynyl, L ５ is a bond, -C(O)-, -S-, -S(O) １―２ -, -O-, or -NR ６ - and R ５ Each has 1-5 R ５Ｅ phenyl, monocyclic heteroaryl, monocyclic heterocycloalkyl or monocyclic cycloalkyl, optionally substituted with Where: Each R ５Ｅ is oxo, optionally substituted C １ -C ４ Alkyl, C １ -C ４ Fluoroalkyl, halogen, -CN, -SF ５ , -N ３ , -C(O)R ５Ｆ , -SR ５Ｆ , -S(O) １－２ R ５Ｆ , -OR ５Ｆ , -NR ５Ｇ R ５Ｆ , -C(O)R ５Ｆ , -C(O)NR ５Ｇ R ５Ｆ , -NR ５Ｇ C(O)R ５Ｆ , -C(S)NR ５Ｇ R ５Ｆ , -NR １Ｇ C(S)R ５Ｆ , -C(O)OR ５Ｆ , -OC(O)R ５Ｆ , -C(O)SR ５Ｆ , -SC(O)R ５Ｆ , -C(S)OR ５Ｆ , -OC(S)R ５Ｆ , -C(S)SR ５Ｆ , -SC(S)R ５Ｆ , -S(O) １―２ OR ５Ｆ , -OS(O) １―２ R ５Ｆ , -S(O) １―２ N.R. ５Ｇ R ５Ｆ , and -NR ５Ｇ S (O) １―２ R ５Ｆ are independently selected from Each R ５Ｆ is H, C １ -C ３ Alkyl, and C １ -C ３ fluoroalkyl; Each R ５Ｇ is H and C １ -C ３ independently selected from alkyl, Each R ６ is hydrogen, C １ -C ３ Alkyl, and -C(O)(C １ -C ３ alkyl), Each optionally substituted alkyl, alkenyl and alkynyl is unsubstituted, fluorinated or substituted with one or two hydroxyl groups; each cycloalkyl has 3-7 ring carbons and is saturated or partially unsaturated; each heterocycloalkyl has 3-7 ring members, has 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and is saturated or partially unsaturated; Each monocyclic heteroaryl is a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

1. A method for determining whether a subject is responsive to a therapeutic compound comprising: The method comprises the steps of: Measuring the expression levels of a plurality of genes in a sample taken from the hematopoietic cancer; measuring a fold change in gene expression compared to the expression level of one or more genes in a reference cell; identifying the hematopoietic cancer as likely to be responsive to the therapeutic compound if the fold change in gene expression is greater for a first number of the plurality of genes, the first number being 5 or greater; Including, the hematopoietic cancer exhibits a significant fold change in gene expression relative to a reference cell for a first number of a plurality of genes, the first number being at least five, selected from CASP10, TMED1, PPP1CC, TMEM59, BRD7, CYB561, FAM210B, NDRG1, CTSB, MMAB, SETDB2, VPS37B, ELL3, and KIF13B; The method of claim 1, wherein one of the first number of genes is FAM210B.

35. 35. The method of claim 34, wherein the first number is seven or greater.

36. 35. The method of claim 34, wherein the first number is 11 or greater.

37. The method of any one of claims 34 to 36, wherein the hematopoietic cancer is a chronic myeloproliferative neoplasm, lymphoma, leukemia, or plasma cell neoplasm.

38. The hematopoietic cancer is Burkitt's lymphoma, Hodgkin's lymphoma, non-Hodgkin's lymphoma, hairy cell lymphoma, mantle cell lymphoma, T cell lymphoma, cutaneous T cell lymphoma, B cell lymphoma, diffuse large B cell lymphoma, double hit lymphoma, Waldenstrom's macroglobulinemia, primary central nervous system (CNS) lymphoma, intravascular large B cell lymphoma (ILBCL), acute lymphocytic leukemia (ALL), acute myeloid leukemia (AML). , acute myeloblastic leukemia, chronic lymphocytic leukemia (CLL), chronic myelogenous leukemia (CML), chronic neutrophilic leukemia (CNL), chronic myelomonocytic leukemia (CMML), aggressive NK cell leukemia, acute pleoplasmic leukemia, polycythemia vera, or acute and chronic T-cell and B-cell leukemia, multiple myeloma, chronic myeloproliferative neoplasms, myelodysplastic syndromes, myelodysplastic / myeloproliferative neoplasms, or chronic myeloproliferative neoplasms.

39. The method of any one of claims 30 to 38, wherein a fold change in gene expression of at least 1.5 is a significant change in gene expression.

40. The method of any one of claims 30 to 38, wherein a fold change in gene expression of at least 2 is a significant change in gene expression.

41. The method of any one of claims 30 to 38, wherein a fold change in gene expression of at least 3 is a significant change in gene expression.

42. The reference cell is a non-cancerous cell of the human individual, a non-cancerous cell of a different human, a non-cancerous cell from a cell line, or a cell that has an IC of at least 30 μM for the therapeutic compound. ５０ The method according to any one of claims 30 to 41, wherein the cell is derived from a cancer cell line having the following structure:

43. 43. The method of any one of claims 30 to 42, wherein the therapeutic compound is 4-(3-fluorophenyl)-1-(5-(isopropylthio)-4-(4-(trifluoromethyl)phenyl)thiazol-2-yl)-3-methyl-1H-pyrazole-5-carboxylic acid or 4-(3-fluorophenyl)-1-(5-(isopropylthio)-4-(4-(trifluoromethyl)cyclohexen-1-en-1-yl)thiazol-2-yl)-3-methyl-1H-pyrazole-5-carboxylic acid, optionally in enantiopure form.

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