WO2023141262A1 - Bax activators and use thereof - Google Patents

Abstract

Disclosed herein are small molecule activators of the B-cell lymphoma-2-associated X protein (BAX). Also disclosed are compositions containing one or more BAX activators and uses thereof in the treatment of cancer, including leukemia and lymphoma. Also provided a method of inducing apoptosis in cancer cells in a subject, comprising administering to the subject an effective amount of a pharmaceutical composition disclosed herein.

Description

BAX ACTIVATORS AND USE THEREOF BACKGROUND Programmed cell death, or apoptosis, is a vital component for important processes such as normal cell turnover, the development and functioning of the immune system, hormone-dependent atrophy, and embryonic development (Elmore, Toxicol Pathol.2007; 35(4); 495-516). The commitment of a cell to apoptosis via the mitochondrial pathway is regulated by a complex interaction network of proteins of the B-cell lymphoma-2 (BCL-2), which include proteins that are pro-apoptosis (e.g., BCL-2-associated X-protein (BAX) and BCL-2 homologous Antagonist Killer (BAK)) and those that are anti-apoptosis (e.g., BCL-2, B-cell lymphoma-extra large protein (BCL-XL), B cell lymphoma 2-like protein (BCL-w), and myeloid cell leukemia 1 (MCL-1). Importantly, the dysregulation of apoptosis is implicated in a number of human pathologies, including cancer (Elmore, 2007). Cancer cells are known to reprogram the interaction between BCL-2 proteins to ensure their growth, maintenance, and resistance to cancer therapies (Hata et al., Cancer Discov.2015; 5(5) 475-87; Llambi et al., Curr Opin Genet Dev.2011; 21(1): 12-20). For example, cancer cells are frequently found to overexpress BCL-2, BCL-XL, and MCL-1, which bind to and neutralize the BH3 death domains of the activated pro-apoptotic BCL-2 members BAX, BAK and the BH3-only proteins such as BCL-2-like protein 11 (BIM) and BH3-interacting domain death agonist (BID) and therefore impede cell apoptosis (Letai, Nat Rev Cancer.2008; 8(2): 121-32; Youle et al., Nat Rev Mol Cell Biol.2008; 9(1): 47-59). It has also been found that the vast majority of cancer cells contain functional BAX in an inactive conformation or suppressed by anti-apoptotic proteins (Gao et al., Sci Signal.2013; 6(269): pl1). The direct activation of BAX with targeted therapeutics can therefore be used to counteract the effects of anti-apoptotic BCL-2 proteins or otherwise promote apoptosis in cancer cells. Thus, there is a need to provide BAX activators for the treatment of cancers, particularly apoptosis-resistant cancers. SUMMARY The present disclosure provides compounds (e.g., BAX activator compounds), compositions, and methods for treating cancer. In one aspect, the disclosure provides a compound of formula (I):

or a pharmaceutically acceptable salt thereof, in which A is N or CH; R^1a and R^1b are independently H; halo; C₁-C₆ alkyl optionally substituted with one or more groups independently selected from OH, halo, and COORa, wherein Ra is H or C₁-C₆ alkyl; or C₃-C₈ cycloalkyl,provided that at least one of R^1a and R^1b is not H; or R^1a and R^1b, together with the atoms to which each is attached, combine to form C₃-C₈ cycloalkyl or

, wherein R^b is H or C₁-C₆ alkyl; each of R^2a, R^2b, R^2c, R^2d, and R^2e is independently selected from H, halo, and OCH₃; each of R^3a, R^3b, R^3c, R^3d, and R^3e is independently selected from H, halo, OH, OCH₃, COOH, and CH₂COOH; and R⁴ is H or CH₃; provided that: (i) when R^1a and R^1b are both CH₃; each of R^2a, R^2b, R^2c, R^2d; R^2e is H; R⁴ is H; (a) A is N; and each of R^3a, R^3b, R^3d, and R^3e is H; R^3c is not H, F, or COOH; and (b) A is CH; and each of R^3a, R^3b, R^3d, and R^3e is H; R^3c is not F; (ii) when R^1a and R^1b are both CH₃; A is N; and each of R^2a, R^2b, R^2d, R^2e, R^3a, R^3b, R^3c, R^3d; R^3e is H; and R⁴ is H; R^2c is not H, halo, or OCH₃; (iii) when A is N; each of R^2a, R^2b, R^2c, R^2d, R^2e, R^3a, R^3b, R^3c, R^3d, and R^3e is H; R⁴ is H; and (a) R^1a is COOCH₃; R^1b is not H, CH(CH₃)₂, or (CH₂)2CH₃; (b) R^1a is H; R^1b is not F, Cl, CH₃, CH₂Cl, or COOH; (c) R^1a is CH₃; R^1b is not CH₃ or COOH; (d) R^1b is H; R^1a is not F, CH(CH₃)₂, C(CH₃)₃, COOH, cyclopropyl, or CH₂ , together with the atoms to which each is attached, do not form cyclohexyl

(vi) when A is N; each of R^2a, R^2b, R^2c, R^2e, R^3a, R^3b, R^3d, and R^3e is H; R^3c is COOH; R⁴ is H; (a) R^2d is OCH₃; and R^1a is H or CH₃; R^1b is not CH₃; (b) R^2d is OCH₃; and R^1b is H or CH₃, R^1a is not CH₃; (c) R^2d is H; and R^1a is H; R^1b is not CH₃; and (d) R^2d is H; and R^1a is CH₃; R^1b is not H; and (v) when A is N; each of R^2a, R^2b, R^2d, R^2e, R^3a, R^3b, R^3d, and R^3e is H; R^2c is OCH₃; R^3c is F; and R⁴ is H; R^1a and R^1b are not both CH₃. In some embodiments, A is N. In some embodiments, the compound is a compound of formula (IA):

or a pharmaceutically acceptable salt thereof. In some embodiments, R⁴ is H. In some embodiments, R⁴ is CH₃. In some embodiments, R^1a is halo; C₁-C₆ alkyl substituted with one or more groups independently selected from OH, halo, and COORa; unsubstituted C₂-C₆ alkyl; or C₃-C₈ cycloalkyl; and R^1b is halo; C₁-C₆ alkyl optionally substituted with one or more groups independently selected from OH, halo, and COORa; or C₃-C₈ cycloalkyl. In some embodiments, in which R^1a is halo; C₁-C₆ alkyl substituted with one or more groups independently selected from OH, halo, and COORa; unsubstituted C₂-C₆ alkyl; or C₃-C₈ cycloalkyl; R^1b is C₁-C₆ alkyl optionally substituted with one or more groups independently selected from OH, halo, and COORa, e.g., CH₃ or CH₂CH₃. In some embodiments, in which R^1a is halo; C₁-C₆ alkyl substituted with one or more groups independently selected from OH, halo, and COORa; unsubstituted C₂-C₆ alkyl; or C₃-C₈ cycloalkyl; R^1b is halo, e.g., Cl. In some embodiments, in which R^1a is halo; C₁-C₆ alkyl substituted with one or more groups independently selected from OH, halo, and COORa; unsubstituted C₂-C₆ alkyl; or C₃-C₈ cycloalkyl; R^1a is preferably unsubstituted C₂-C₆ alkyl, e.g., CH₂CH₃, CH(CH₃)₂, C(CH₃)₃, CH₂CH(CH₃)₂, or CH₂(CH₃)₃. In some embodiments, in which R^1a is halo; C₁-C₆ alkyl substituted with one or more groups independently selected from OH, halo, and COORa; unsubstituted C₂-C₆ alkyl; or C₃-C₈ cycloalkyl; R^1a is preferably C₁-C₆ alkyl substituted with one or more groups independently selected from OH, halo, and COORa, e.g., R^1a is CF₃, CH₂ CF₃, CH₂OH, (CH₂)2OH, CH( CH₃)CH₂OH, C(CH₃)₂CH₂OH, CH₂COOH, CH(CH₃)COOH, C(CH₃)₂COOH, or (CH₂)2COOH. In some embodiments, in which R^1a is halo; C₁-C₆ alkyl substituted with one or more groups independently selected from OH, halo, and COORa; unsubstituted C₂-C₆ alkyl; or C₃-C₈ cycloalkyl; R^1a is preferably halo, e.g., Cl. In some embodiments, in which R^1a is halo; C₁-C₆ alkyl substituted with one or more groups independently selected from OH, halo, and COORa; unsubstituted C₂-C₆ alkyl; or C₃-C₈ cycloalkyl; R^1a is preferably C₃-C₈ cycloalkyl, e.g., cyclopropyl. In some embodiments, R^1b is halo; C₁-C₆ alkyl substituted with one or more groups independently selected from OH, halo, and COORa; unsubstituted C₂-C₆ alkyl; or C₃-C₈ cycloalkyl; and R^1a is halo; C₁-C₆ alkyl optionally substituted with one or more groups independently selected from OH, halo, and COORa; or C₃-C₈ cycloalkyl. In some embodiments, in which R^1b is halo; C₁-C₆ alkyl substituted with one or more groups independently selected from OH, halo, and COORa; unsubstituted C₂-C₆ alkyl; or C₃-C₈ cycloalkyl; R^1a is C₁-C₆ alkyl optionally substituted with one or more groups independently selected from OH, halo, or COORa, e.g., CH₃ or CH₂CH₃. In some embodiments, in which R^1b is halo; C₁-C₆ alkyl substituted with one or more groups independently selected from OH, halo, and COORa; unsubstituted C₂-C₆ alkyl; or C₃-C₈ cycloalkyl; R^1a is halo, e.g., Cl. In some embodiments, in which R^1b is halo; C₁-C₆ alkyl substituted with one or more groups independently selected from OH, halo, or COORa; unsubstituted C₂-C₆ alkyl; or C₃-C₈ cycloalkyl; R^1b is preferably unsubstituted C₂-C₆ alkyl, e.g., CH₂CH₃, CH(CH₃)₂, C(CH₃)₃, CH₂CH(CH₃)₂, or CH₂(CH₃)₃. In some embodiments, in which R^1b is halo; C₁-C₆ alkyl substituted with one or more groups independently selected from OH, halo, and COORa; unsubstituted C₂-C₆ alkyl; or C₃-C₈ cycloalkyl; R^1b is preferably C₁-C₆ alkyl substituted with one or more groups independently selected from OH, halo, and COORa, e.g., CF₃, CH₂CF₃, CH₂OH, (CH₂)2OH, CH(CH₃)CH₂OH, C(CH₃)₂CH₂OH, CH₂COOH, CH(CH₃)COOH, C(CH₃)₂COOH, or (CH₂)2COOH. In some embodiments, in which R^1b is halo; C₁-C₆ alkyl substituted with one or more groups independently selected from OH, halo, and COORa; unsubstituted C₂-C₆ alkyl; or C₃-C₈ cycloalkyl; R^1b is preferably halo, e.g., Cl. In some embodiments, in which in which R^1b is halo; C₁-C₆ alkyl substituted with one or more groups independently selected from OH, halo, and COORa; unsubstituted C₂-C₆ alkyl; or C₃-C₈ cycloalkyl; R^1b is preferably C₃-C₈ cycloalkyl, e.g., cyclopropyl. In some embodiments, R^1a and R^1b, together with the atoms to which each is attached, form cyclopentyl. In some embodiments, R^1a and R^1b, together with the atoms to which each is attached, form

which R^b is methyl. In some embodiments, R^1a and R^1b are independently H or C₁-C₆ alkyl optionally substituted with one or more groups independently selected from OH, halo, and COORa, provided that at least one of R^1a and R^1b is not H. In some embodiments, R^1a and R^1b are both C₁-C₆ alkyl optionally substituted with one or more groups independently selected from OH, halo, and COORa. In some embodiments, in which R^1a and R^1b are both C₁-C₆ alkyl optionally substituted with one or more groups independently selected from OH, halo, and COORa; R^1a is preferably CH₃, and, in further embodiments, R^1b is preferably CH₂CH₃ or CF₃. In some embodiments, in which R^1a and R^1b are both C₁-C₆ alkyl optionally substituted with one or more groups independently selected from OH, halo, and COORa; R^1b is preferably CH₃, and, in further embodiments, R^1a is preferably CH₂CH₃. In some embodiments, in which R^1a and R^1b are both C₁-C₆ alkyl optionally substituted with one or more groups independently selected from OH, halo, and COORa; R^1a and R^1b are preferably both CH₂CH₃. In some embodiments, in which R^1a and R^1b are both C₁-C₆ alkyl optionally substituted with one or more groups independently selected from OH, halo, and COORa, and R^1a and R^1b are not bothCH₃; each of R^3a, R^3b, R^3d, and R^3e is H, and R^3c is COOH. In some embodiments, in which R^1a and R^1b are both C₁-C₆ alkyl optionally substituted with one or more groups independently selected from OH, halo, and COORa; R^1a and R^1b are preferably both CH₃. In some embodiments, in which R^1a and R^1b are both C₁-C₆ alkyl optionally substituted with one or more groups independently selected from OH, halo, and COORa; each of R^3a, R^3b, R^3d, and R^3e is H, and R^3c is CH₂COOH. In some embodiments, in which R^1a and R^1b are both C₁-C₆ alkyl optionally substituted with one or more groups independently selected from OH, halo, and COORa; each of R^3b, R^3c, R^3d, and R^3e is H, and R^3a is OH. In some embodiments, in which R^1a and R^1b are both C₁-C₆ alkyl optionally substituted with one or more groups independently selected from OH, halo, and COORa; each of R^3a and R^3e is Cl; and each of R^3b, R^3c, and R^3d is H. In some embodiments, in which R^1a and R^1b are both C₁-C₆ alkyl optionally substituted with one or more groups independently selected from OH, halo, and COOR_a; both R^3a and R^3e are Cl, both R^3b and R^3d are H, and R^3c is COOH. In some embodiments, in which R^1a and R^1b are both C₁-C₆ alkyl optionally substituted with one or more groups independently selected from OH, halo, and COORa; both R^3a and R^3e are Cl; and each of R^3b, R^3c, and R^3d is H. In some embodiments, in which R^1a and R^1b are both C₁-C₆ alkyl optionally substituted with one or more groups independently selected from OH, halo, and COORa; each of R^3a, R^3c, R^3d, and R^3e is H, and R^3b is COOH. In some embodiments, in which R^1a and R^1b are both C₁-C₆ alkyl optionally substituted with one or more groups independently selected from OH, halo, and COORa; each of R^2a, R^2b, R^2c, R^2d, and R^2e is H. In some embodiments, in which R^1a and R^1b are both C₁-C₆ alkyl optionally substituted with one or more groups independently selected from OH, halo, and COORa, and R^1a and R^1b are not both CH₃; each of R^2a, R^2b, R^2d, R^2e, R^3a, R^3b, R^3c, R^3d, and R^3e is H; and R^2c is OCH₃. In some embodiments, in which R^1a and R^1b are both C₁-C₆ alkyl optionally substituted with one or more groups independently selected from OH, halo, and COORa; each of R^2a, R^2b, R^2d, and R^2e, R^3a, R^3b, R^3d, and R^3e is H; R^2c is F; and R^3c is COOH. In some embodiments, in which R^1a and R^1b are both C₁-C₆ alkyl optionally substituted with one or more groups independently selected from OH, halo, and COORa; each of R^2a, R^2b, R^2d, and R^2e, R^3a, R^3b, R^3d, and R^3e is H; R^2c is OCH₃; and R^3c is COOH. In some embodiments, in which R^1a and R^1b are both C₁-C₆ alkyl optionally substituted with one or more groups independently selected from OH, halo, and COORa; each of R^2a, R^2b, R^2d, and R^2e, R^3a, R^3b, R^3d, and R^3e is H; and both R^2c and R^3c are F. In some embodiments, in which R^1a and R^1b are both C₁-C₆ alkyl optionally substituted with one or more groups independently selected from OH, halo, and COORa; each of R^2a, R^2b, R^2c, and R^2e, R^3a, R^3b, R^3d, and R^3e is H; and both R^2d and R^3c are OCH₃. In some embodiments, the compound is any one of the compounds of Table 1: Table 1

or a pharmaceutically acceptable salt thereof. In another aspect, the present disclosure provides a pharmaceutical composition containing one or more of the compounds disclosed herein (e.g., one or more of the formula (I), (IA), and the compounds of Table 1) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient. In another aspect, the present disclosure provides a method of treating cancer, the method including, comprising administering to a subject in need thereof an effective amount of a pharmaceutical composition described herein, e.g., a pharmaceutical composition containing one or more of the compounds disclosed herein (e.g., one or more of the formula (I), (IA), and the compounds of Table 1) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient. In some embodiments, the pharmaceutical composition is administered in combination with a second therapeutic agent, wherein the second therapeutic agent is an inhibitor of B cell lymphoma 2 (BCL-2), B-cell lymphoma-extra large protein (BCL-XL), B cell lymphoma 2-like protein (BCL-w), BCL-2- related protein A1 (BFL-1), myeloid cell leukemia 1 (MCL-1), or a combination thereof. In some embodiments, the cancer is a solid tumor. In some embodiments, the cancer is breast cancer, such as breast carcinoma; skin cancer, such as melanoma (e.g., malignant melanoma); central nervous system cancer, such as brain cancer (e.g., primary brain carcinoma, medulloblastoma, glioma, or glioblastoma) and spinal cord cancer; head and neck cancer, such as head and neck carcinoma; bladder cancer, such as bladder carcinoma; kidney cancer, such as renal cell carcinoma and Wilms’ tumor; cancer of the gastrointestinal tract, such as colon cancer (e.g., colon carcinoma), rectal cancer, liver cancer, stomach cancer (e.g., stomach carcinoma), esophageal cancer (e.g., esophageal carcinoma), and pancreatic cancer (e.g., pancreatic carcinoma); lung cancer, such as small cell lung cancer and non-small cell lung cancer (e.g., lung carcinoma); eye cancer, such as retinoblastoma; genitourinary cancer, such as urethra cancer, testicular cancer (e.g., testicular carcinoma), and prostate cancer (e.g., prostatic carcinoma); gynecologic cancer, such as placental cancer (e.g., choriocarcinoma), ovarian cancer (e.g., ovarian carcinoma), cervical cancer (e.g., cervical carcinoma), vulvar cancer, and uterine cancer (e.g., endometrial carcinoma); endocrine cancer, such as thyroid cancer (e.g., thyroid carcinoma) and adrenal cancer (e.g., adrenal carcinoma or adrenal cortex carcinoma); soft tissue sarcoma, such as rhabdomyosarcoma, Kaposi’s sarcoma, and osteosarcoma; hematopoietic cancer, such as myeloma (e.g., multiple myeloma), leukemia (e.g., acute lymphoblastic leukemia, chronic lymphocytic leukemia, chronic granulocytic leukemia, acute granulocytic leukemia, acute myeloid leukemia, chronic myeloid leukemia, hairy cell leukemia, polycythemia vera, or essential thrombocytosis), Hodgkin’s lymphoma, and non-Hodgkin’s lymphoma (e.g., primary macroglobulinemia or mycosis fungoides); or neuroendocrine cancer, such as neuroblastoma, malignant pancreatic insulinoma, and malignant carcinoid carcinoma. In some embodiments, the cancer is leukemia, e.g., acute lymphoblastic leukemia, acute myeloid leukemia, chronic lymphocytic leukemia, or chronic myeloid leukemia. In some embodiments, the cancer is lymphoma. In another aspect, the present disclosure provides a method of inducing apoptosis in cancer cells in a subject, comprising administering to the subject an effective amount of a pharmaceutical composition disclosed herein, e.g., a pharmaceutical composition containing one or more of the compounds disclosed herein (e.g., one or more of the compounds of formula (I), formula (IA), and Table 1) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient. In some embodiments, the cancer cells are leukemia cells, e.g., acute lymphoblastic leukemia cells, acute myeloid leukemia cells, chronic lymphocytic leukemia cells, or chronic myeloid leukemia cells. In some embodiments, the cancer cells are solid tumor cells. In another aspect, the present disclosure provides a method of inducing apoptosis in leukemic stem cells in a subject, comprising administering to the subject an effective amount of a pharmaceutical composition disclosed herein, e.g., a pharmaceutical composition containing one or more of the compounds disclosed herein (e.g., one or more of the formula (I), (IA), and the compounds of Table 1) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient. In some embodiments of any of the preceding methods, the method does not induce apoptosis in healthy tissue. In some embodiments of any of the preceding methods, the subject is a human. In another aspect, provides a method of treating a disorder associated with cancer, in which the disorder is malignant hypercalcemia or cervical hyperplasia. In another aspect, the present disclosure provides a compound disclosed herein (e.g., any one of the compounds of formula (I), formula (IA), or Table 1) or a composition disclosed herein (e.g., a composition including one or more of the compounds disclosed herein) for use in any of the preceding methods. In another aspect, the present disclosure provides a use of a compound disclosed herein (e.g., any one of the compounds of formula (I), formula (IA), or Table 1) or a composition disclosed herein (e.g., a composition including one or more of the compounds or pharmaceutically acceptable salts thereof disclosed herein) for the manufacture of a medicant for use in any of the preceding methods. Definitions To facilitate the understanding of this invention, a number of terms are defined below. Terms defined herein have meanings as commonly understood by a person of ordinary skill in the areas relevant to the invention. Terms such as “a”, “an,” and “the” are not intended to refer to only a singular entity, but include the general class of which a specific example may be used for illustration. The terminology herein is used to describe specific embodiments of the invention, but their usage does not limit the invention, except as outlined in the claims. As used herein, the term “about” refers to a value that is within 10% above or below the value being described. As used herein, any values provided in a range of values include both the upper and lower bounds, and any values contained within the upper and lower bounds. As used herein, the term “pharmaceutically acceptable salt” represents those salts of the compounds described that are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and animals without undue toxicity, irritation, allergic response and the like and are commensurate with a reasonable benefit/risk ratio. Pharmaceutically acceptable salts are well known in the art. For example, pharmaceutically acceptable salts are described in: Berge et al., J. Pharmaceutical Sciences 66:1-19, 1977 and in Handbook of Pharmaceutical Salts: Properties, Selection, and Use, (Eds. P.H. Stahl and C.G. Wermuth), Wiley-VCH, 2008. These salts may be acid addition salts involving inorganic or organic acids. The salts can be prepared in situ during the final isolation and purification of the compounds described herein or separately by reacting the free base group with a suitable acid. As used herein, the term “effective amount” refers to an amount sufficient to effect beneficial or desired results, such as clinical results, and, as such, a “therapeutically effective amount” depends upon the context in which it is being applied. For example, in the context of administering a compound disclosed herein (e.g., a compound of formula (I), formula (IA), or Table 1) to treat cancer, a therapeutically effective amount of a compound is, for example, an amount sufficient to induce apoptosis in cancer cells and/or leukemic stem cells. As used herein, and as well understood in the art, “to treat” a condition or “treatment” of various diseases and disorders is an approach for obtaining beneficial or desired results, such as clinical results. Beneficial or desired results can include, but are not limited to, alleviation of one or more symptoms or conditions; diminishment of extent of disease, disorder, or condition; stabilizing (i.e., not worsening) state of disease, disorder, or condition; delay or slowing the progress of the disease, disorder, or condition; amelioration or palliation of the disease, disorder, or condition; and remission (whether partial or total), whether detectable or undetectable. “Palliating” a disease, disorder, or condition means that the extent and/or undesirable clinical manifestations of the disease, disorder, or condition are lessened and/or time course of the progression is slowed or lengthened, as compared to the extent or time course in the absence of treatment. In the context of cancer, the term “treating” may refer to reducing the growth of the cancer in a subject, reducing the spread of cancer in the subject, or reducing the severity of a symptom of the cancer in the subject. In the context of a method of treating a tumor, “treating” may refer to reducing the size of the tumor, stabilizing the size of the tumor or otherwise reducing the further growth of the tumor. In some embodiments, “treating” may refer to inducing apoptosis in cancer cells and/or leukemic stem cells. The term “subject,” as used herein, can be a human, non-human primate, or other mammal, such as but not limited to dog, cat, horse, cow, pig, goat, monkey, rat, mouse, and sheep. In preferred embodiments, the subject is a human. As used herein, the term “pharmaceutical composition” refers to an active compound, formulated together with one or more pharmaceutically acceptable excipients. In some embodiments, a compound of the invention is present in unit dose amount appropriate for administration in a therapeutic regimen that shows a statistically significant probability of achieving a predetermined therapeutic effect when administered to a relevant population. In certain embodiments, pharmaceutical compositions may be specially formulated for administration in solid or liquid form, including those adapted for the following: oral administration, for example, drenches (aqueous or non-aqueous solutions or suspensions), tablets, or capsules; and parenteral administration, for example, by subcutaneous, intramuscular, or intravenous injection. The term “pharmaceutically acceptable excipient,” as used herein, refers to any inactive ingredient (for example, a vehicle capable of suspending or dissolving the active compound) that is biocompatible and suitable for administration to a subject. Typical excipients include, for example: antiadherents, antioxidants, binders, coatings, compression aids, disintegrants, dyes, emollients, emulsifiers, diluents, film formers or coatings, flavors, fragrances, glidants, lubricants, preservatives, printing inks, sorbents, suspending or dispersing agents, sweeteners, or waters of hydration. Excipients include, but are not limited to: butylated optionally substituted hydroxytoluene (e.g., BHT), calcium carbonate, calcium phosphate dibasic, calcium stearate, croscarmellose, crosslinked polyvinyl pyrrolidone, citric acid, crospovidone, cysteine, ethylcellulose, gelatin, optionally substituted hydroxypropyl cellulose, optionally substituted hydroxypropyl methylcellulose, lactose, magnesium stearate, maltitol, mannitol, methionine, methylcellulose, methyl paraben, microcrystalline cellulose, polyethylene glycol, polyvinyl pyrrolidone, povidone, pregelatinized starch, propyl paraben, retinyl palmitate, shellac, silicon dioxide, sodium carboxymethyl cellulose, sodium citrate, sodium starch glycolate, sorbitol, starch, stearic acid, stearic acid, sucrose, talc, titanium dioxide, vitamin A, vitamin E, vitamin C, and xylitol. Those of ordinary skill in the art are familiar with a variety of agents and materials useful as excipients. The term “alkyl,” as used herein, refers to a branched or straight-chain monovalent saturated aliphatic radical containing only C and H when unsubstituted. The monovalency of an alkyl group does not include the optional substituents on the alkyl group. For example, if an alkyl group is attached to a compound, monovalency of the alkyl group refers to its attachment to the compound and does not include any additional substituents that may be present on the alkyl group. In some embodiments, the alkyl group may contain, e.g., 1-8, 1-6, 1-4, or 1-2 carbon atoms (e.g., C1-C8, C₁-C₆, C1-C4, or C1-C2). Examples include, but are not limited to, methyl, ethyl, isobutyl, sec-butyl, tert-butyl, 2-methylpropyl, and 2,2-dimethylpropyl. The term “cycloalkyl,” as used herein, represents a monovalent, saturated cyclic group containing only C and H when unsubstituted. A cycloalkyl may have, e.g., three to eight carbons (e.g., a C3-C4, C3- C5, C3-C6, C3-C7, or C₃-C₈ cycloalkyl). Examples of cycloalkyls include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl. The term “cycloalkyl” also includes cyclic groups having a bridged multicyclic structure in which one or more carbons bridges two non-adjacent members of a monocyclic ring, e.g., bicyclo[2.2.1]heptyl. The term “halo,” as used herein, refers to a fluorine (fluoro), chlorine (chloro), bromine (bromo), or iodine (iodo) radical. DETAILED DESCRIPTION Disclosed herein are compounds, pharmaceutical compositions, and the use of the pharmaceutical compositions for the treatment of cancer in a subject. The disclosure is based, at least in part, on the realization that certain structural modifications to the BAX activator compounds provide advantageous properties (e.g., as compared to other BAX activator compounds such as Gav2-006 disclosed in PCT/US2018/034279), such as improved solubility in aqueous media, increased metabolic stability, improved pharmacokinetic properties (e.g., increased serum half-life), increased BAX activation, and/or increased BAX selectivity. Compounds The compounds for treating cancer herein include compounds of formula (I):

Or a pharmaceutically acceptable salt thereof, in which A is N or CH; R^1a and R^1b are independently H; halo; C₁-C₆ alkyl optionally substituted with one or more groups independently selected from OH, halo, and COORa, wherein Ra is H or C₁-C₆ alkyl; or C₃-C₈ cycloalkyl, provided that at least one of R^1a and R^1b is not H; or R^1a and R^1b, together with the atoms to which each is attached, combine to form C₃-C₈ cycloalkyl or

, wherein R^b is H or C₁-C₆ alkyl; each of R^2a, R^2b, R^2c, R^2d, and R^2e is independently selected from H, halo, and OCH₃; each of R^3a, R^3b, R^3c, R^3d, and R^3e is independently selected from H, halo, OH, OCH₃, COOH, and CH₃COOH; and R⁴ is H or CH₃; provided that: (i) when R^1a and R^1b are both CH₃; each of R^2a, R^2b, R^2c, R^2d; R^2e is H; R⁴ is H; (a) A is N; and each of R^3a, R^3b, R^3d, and R^3e is H; R^3c is not H, F, or COOH; and (b) A is CH; and each of R^3a, R^3b, R^3d, and R^3e is H; R^3c is not F; (ii) when R^1a and R^1b are both CH₃; A is N; and each of R^2a, R^2b, R^2d, R^2e, R^3a, R^3b, R^3c, R^3d; R^3e is H; and R⁴ is H; R^2c is not H, halo, or OCH₃; (iii) when A is N, each of R^2a, R^2b, R^2c, R^2d, R^2e, R^3a, R^3b, R^3c, R^3d, and R^3e is H; R⁴ is H; and (a) R^1a is COOCH₃, R^1b is not H, CH(CH₃)₂, or (CH₂)2CH₃; (b) R^1a is H, R^1b is not F, Cl, CH₃, CH₂Cl, or COOH; (c) R^1a is CH₃, R^1b is not CH₃ or COOH; (d) R^1b is H, R^1a is not F, CH(CH₃)₂, C(CH₃)₃, COOH, cyclopropyl, or CH₂OH; and (e) R^1a and R^1b, together with the atoms to which each is attached, do not form cyclohexyl or

; (iv) when A is N, each of R^2a, R^2b, R^2c, R^2e, R^3a, R^3b, R^3d, and R^3e is H; R^3c is COOH; R⁴ is H; (a) R^2d is OCH₃, and R^1a is H or CH₃, R^1b is not CH₃; (b) R^2d is OCH₃, and R^1b is H or CH₃, R^1a is not CH₃; (c) R^2d is H, and R^1a is H, R^1b is not CH₃; and (c) R^2d is H, and R^1a is CH₃, R^1b is not H; and (v) when A is N; each of R^2a, R^2b, R^2d, R^2e, R^3a, R^3b, R^3d, and R^3e is H; R^2c is OCH₃; R^3c is F; and R⁴ is H ; R^1a and R^1b are not both CH₃. or a pharmaceutically acceptable salt thereof. Exemplary compounds for the treatment of cancer are shown in Table 1. Pharmaceutical Compositions A pharmaceutical composition of the invention contains one or more of the compounds disclosed herein (e.g., one or more of the compounds of formula (I), formula (IA), and Table 1) as the therapeutic compound. In addition to a therapeutically effective amount of the compound, the pharmaceutical compositions also contain a pharmaceutically acceptable excipient, which can be formulated by methods known to those skilled in the art. In some embodiments, the pharmaceutical compositions for treating cancer contain one or more of the compounds disclosed herein (e.g., one or more of the compounds of formula (I), formula (IA), and Table 1) may be formulated and/or administered with or without other therapeutics for a particular condition. Examples of such therapeutics (second therapeutic agents) are described herein. The compounds disclosed herein (e.g., the compounds of formula (I), formula (IA), and Table 1) may be used in the form of free base, or in the form of salts, and as solvates. All forms are within the scope of the disclosure. Exemplary routes of administration of the pharmaceutical compositions (or the compounds of the composition) include oral, sublingual, buccal, transdermal, intradermal, intramuscular, parenteral, intravenous, intra-arterial, intracranial, subcutaneous, intraorbital, intraventricular, intraspinal, intraperitoneal, intranasal, inhalation, and topical administration. Formulations for Oral Administration The pharmaceutical compositions of the invention include those formulated for oral administration (“oral dosage forms”). Oral dosage forms can be, for example, in the form of tablets, capsules, a liquid solution or suspension, a powder, or liquid or solid crystals, which contain the active ingredient(s) in a mixture with non-toxic pharmaceutically acceptable excipients. These excipients may be, for example, inert diluents or fillers (e.g., sucrose, sorbitol, sugar, mannitol, microcrystalline cellulose, starches including potato starch, calcium carbonate, sodium chloride, lactose, calcium phosphate, calcium sulfate, or sodium phosphate); granulating and disintegrating agents (e.g., cellulose derivatives including microcrystalline cellulose, starches including potato starch, croscarmellose sodium, alginates, or alginic acid); binding agents (e.g., sucrose, glucose, sorbitol, acacia, alginic acid, sodium alginate, gelatin, starch, pregelatinized starch, microcrystalline cellulose, magnesium aluminum silicate, carboxymethylcellulose sodium, methylcellulose, hydroxypropyl methylcellulose, ethylcellulose, polyvinylpyrrolidone, or polyethylene glycol); and lubricating agents, glidants, and antiadhesives (e.g., magnesium stearate, zinc stearate, stearic acid, silicas, hydrogenated vegetable oils, or talc). Other pharmaceutically acceptable excipients can be colorants, flavoring agents, plasticizers, humectants, buffering agents, and the like. Pharmaceutical compositions for oral administration may also be presented as chewable tablets, as hard gelatin capsules where the active ingredient is mixed with an inert solid diluent (e.g., potato starch, lactose, microcrystalline cellulose, calcium carbonate, calcium phosphate or kaolin), or as soft gelatin capsules where the active ingredient is mixed with water or an oil medium, for example, peanut oil, liquid paraffin, or olive oil. Powders, granulates, and pellets may be prepared using the ingredients mentioned above under tablets and capsules in a conventional manner using, e.g., a mixer, a fluid bed apparatus or a spray drying equipment. The liquid forms in which the compounds and compositions of the present invention can be incorporated for administration orally include aqueous solutions, suitably flavored syrups, aqueous or oil suspensions, and flavored emulsions with edible oils, e.g., cottonseed oil, sesame oil, coconut oil, or peanut oil, as well as elixirs and similar pharmaceutical vehicles. Formulations for Parenteral Administration The pharmaceutical compositions of the invention can be administered in a pharmaceutically acceptable parenteral (e.g., intravenous, intramuscular, subcutaneous or the like) formulation as described herein. The pharmaceutical composition may also be administered parenterally in dosage forms or formulations containing conventional, non-toxic pharmaceutically acceptable carriers and adjuvants. In particular, formulations suitable for parenteral administration include aqueous and non- aqueous sterile injection solutions which may contain antioxidants, buffers, bacteriostats and solutes which render the formulation isotonic with the blood of the intended recipient; and aqueous and non- aqueous sterile suspensions which may include suspending agents and thickening agents. For example, to prepare such a composition, the compounds of the invention may be dissolved or suspended in a parenterally acceptable liquid vehicle. Among acceptable vehicles and solvents that may be employed are water; water adjusted to a suitable pH by addition of an appropriate amount of hydrochloric acid, sodium hydroxide, or a suitable buffer; 1,3-butanediol; Ringer’s solution; and isotonic sodium chloride solution. The aqueous formulation may also contain one or more preservatives, for example, methyl, ethyl, or n-propyl p-hydroxybenzoate. Additional information regarding parenteral formulations can be found, for example, in the United States Pharmacopeia-National Formulary (USP-NF), herein incorporated by reference in its entirety. The parenteral formulation can be any of the five general types of preparations identified by the USP-NF as suitable for parenteral administration: (1) “Drug Injection:” a liquid preparation that is a drug substance (e.g., a compound of the invention), or a solution thereof; (2) “Drug for Injection:” the drug substance (e.g., a compound of the invention) as a dry solid that will be combined with the appropriate sterile vehicle for parenteral administration as a drug injection; (3) “Drug Injectable Emulsion:” a liquid preparation of the drug substance (e.g., a compound of the invention) that is dissolved or dispersed in a suitable emulsion medium; (4) “Drug Injectable Suspension:” a liquid preparation of the drug substance (e.g., a compound of the invention) suspended in a suitable liquid medium; and (5) “Drug for Injectable Suspension:” the drug substance (e.g., a compound of the invention) as a dry solid that will be combined with the appropriate sterile vehicle for parenteral administration as a drug injectable suspension. Exemplary formulations for parenteral administration include solutions of the compound prepared in water suitably mixed with a surfactant, e.g., hydroxypropyl cellulose. Dispersions can also be prepared in glycerol, liquid polyethylene glycols, DMSO and mixtures thereof with or without alcohol, and in oils. Under ordinary conditions of storage and use, these preparations may contain a preservative to prevent the growth of microorganisms. Conventional procedures and ingredients for the selection and preparation of suitable formulations are described, for example, in Remington: The Science and Practice of Pharmacy, 23^rd Ed., Adejare, Ed., Academic Press (2020) and in The United States Pharmacopeia and National Formulary (USP-NF 2021 Issues 1-3), published in 2021. Formulations for parenteral administration may, for example, contain sterile water, saline, polyalkylene glycols (e.g., polyethylene glycol), oils of vegetable origin, or hydrogenated naphthalenes. Biocompatible, biodegradable lactide polymer, lactide/glycolide copolymer, or polyoxyethylene- polyoxypropylene copolymers may be used to control the release of the compounds. Other potentially useful parenteral delivery systems for compounds include ethylene-vinyl acetate copolymer particles, osmotic pumps, implantable infusion systems, and liposomes. Formulations for inhalation may contain, for example, lactose, or may be aqueous solutions containing, for example, polyoxyethylene-9-lauryl ether, glycocholate and deoxycholate, or may be oily solutions for administration in the form of nasal drops, or as a gel. Methods of Treatment The compounds disclosed herein (e.g., the compounds of formula (I), formula (IA), and Table 1) are, in general, suitable for any therapeutic use. In some embodiments, compounds disclosed herein (e.g., the compounds of formula (I), formula (IA), and Table 1) may be used to treat any disease or disorder that may benefit from BAX activation, e.g., cancer. In some embodiments, compounds disclosed herein (e.g., the compounds of formula (I), formula (IA), and Table 1) may be used to induce apoptosis in cancer cells and/or leukemic stem cells. The cancer may be a solid tumor or a “liquid tumor” (i.e., a cancer that is present in body fluids). Examples of cancers that can be treated with compounds of the disclosure include, but are not limited to, breast cancer, such as breast carcinoma; skin cancer, such as melanoma (e.g., malignant melanoma); central nervous system cancer, such as brain cancer (e.g., primary brain carcinoma, medulloblastoma, glioma, or glioblastoma) and spinal cord cancer; head and neck cancer, such as head and neck carcinoma; bladder cancer, such as bladder carcinoma; kidney cancer, such as renal cell carcinoma and Wilms' tumor; cancer of the gastrointestinal tract, such as colon cancer (e.g., colon carcinoma), rectal cancer, liver cancer, stomach cancer (e.g., stomach carcinoma), esophageal cancer (e.g., esophageal carcinoma), and pancreatic cancer (e.g., pancreatic carcinoma); lung cancer, such as small cell lung cancer and non-small cell lung cancer (e.g., lung carcinoma); eye cancer, such as retinoblastoma; genitourinary cancer, such as urethra cancer, testicular cancer (e.g., testicular carcinoma), and prostate cancer (e.g., prostatic carcinoma); gynecologic cancer, such as placental cancer (e.g., choriocarcinoma), ovarian cancer (e.g., ovarian carcinoma), cervical cancer (e.g., cervical carcinoma), vulvar cancer, and uterine cancer (e.g., endometrial carcinoma); endocrine cancer, such as thyroid cancer (e.g., thyroid carcinoma) and adrenal cancer (e.g., adrenal carcinoma or adrenal cortex carcinoma); soft tissue sarcoma, such as rhabdomyosarcoma, Kaposi's sarcoma, and osteosarcoma; hematopoietic cancer, such as myeloma (e.g., multiple myeloma), leukemia (e.g., acute lymphoblastic leukemia, chronic lymphocytic leukemia, chronic granulocytic leukemia, acute granulocytic leukemia, acute myeloid leukemia, chronic myeloid leukemia, hairy cell leukemia, polycythemia vera, or essential thrombocytosis), Hodgkin’s lymphoma, and non-Hodgkin’s lymphoma (e.g., primary macroglobulinemia or mycosis fungoides); or neuroendocrine cancer, such as neuroblastoma, malignant pancreatic insulinoma, and malignant carcinoid carcinoma. In some embodiments, the cancer is resistant to apoptosis. The dosage of the compound of the disclosure depends on factors including the route of administration, the disease to be treated, and physical characteristics, e.g., age, weight, and general health, of the subject. Typically, the amount of a compound disclosed herein (e.g., a compound of formula (I), formula (IA), or Table 1) contained within a single dose may be an amount that effectively treats the disease without inducing significant toxicity. A pharmaceutical composition of the disclosure for use in a method of treating a disease or disorder that may benefit from BAX activation, e.g., cancer, includes a dosage of a compound disclosed herein (e.g., a compound of formula (I), formula (IA), or Table 1) ranging from 0.001 to 500 mg/kg/day and, in a more specific embodiment, about 0.1 to about 100 mg/kg/day. The dosage may be adapted by the clinician in accordance with conventional factors such as the extent of the disease and different parameters of the subject. Typically, a pharmaceutical composition of the disclosure can be administered in an amount from about 0.001 mg up to about 500 mg/kg/day of a compound disclosed herein (e.g., a compound of formula (I), formula (IA), or Table 1). Pharmaceutical compositions of the disclosure that contain one or more of the compounds disclosed herein (e.g., one or more of the compounds of formula (I), formula (IA), and Table 1) may be administered to a subject in need thereof one or more times (e.g., 1-10 times or more) daily, or as medically necessary. Combination Therapy In some embodiments, a compound disclosed herein (e.g., any one of the compounds of formula (I), (IA), and Table 1) is administered in combination with one or more second therapeutic agents. The compound and the second therapeutic agent may be administered concurrently or sequentially (in any order), either through the same route or different routes of administration. In some embodiments, the second therapeutic agent is provided with a compound disclosed herein (e.g., any one of the compounds of formula (I), (IA), and Table 1) in a single formulation. In some embodiments, the one or more second therapeutic agents include an inhibitor of one or more anti-apoptotic proteins of the BCL-2 family, e.g., one or more of BCL-2, BCL-XL, BCL-w, BFL-1, and MCL-1. BCL-2, BCL-XL, BCL-w, BFL-1, and MCL-1 are proteins that inhibit cellular apoptosis through various mechanisms, such as the inhibition of BAX. Thus, in some embodiments, the second therapeutic agent (e.g., an inhibitor of one or more anti-apoptotic proteins) is administered in an amount sufficient to inhibit an anti-apoptotic activity of one or more anti-apoptotic proteins (e.g., one or more of BCL-2, BCL- XL, BCL-w, BFL-1, and MCL-1) in a subject. In some embodiments, the one or more second therapeutic agents include an inhibitor of BCL- XL. Examples of inhibitors of BCL-XL include, but are not limited to, Navitoclax (AbbVie), A-1331852 (AbbVie, Genentech), A-1155463 (AbbVie, Genentech), AZD-0466 (AstraZeneca), AZD-4320 (AstraZeneca), ABBV-155 (AbbVie), APG-1252 (Ascentage Pharma), and DT2216 (Dialectic Therapeutics). In some embodiments, the one or more second therapeutic agents include an inhibitor of MCL-1. Examples of inhibitors of MCL-1 include, but are not limited to, AMG-176 (Amgen), AZD5991 (AstraZeneca), MIK554 (Servier and Novartis), and VU661013 (Vanderbilt University). In some embodiments, the one or more second therapeutic agents include ABT-737 (AbbVie), ABT-199 (AbbVie), or AMG 397 (Amgen). In some embodiments, the one or more second therapeutic agents include an anti-cancer agent. Examples of anti-cancer agents include, but are not limited to, MEK (e.g., MEK1, MEK2, or MEK1 and MEK2) inhibitors (e.g., XL518, CI-1040, PD035901, selumetinib/AZD6244, GSK1120212/trametinib, GDC-0973, ARRY-162, ARRY-300, AZD8330, PD0325901, U0126, PD98059, TAK-733, PD318088, AS703026, BAY 869766, PD184352, SB239063, BAY 43-9006); alkylating agents such as nitrogen mustards (e.g., mechloroethamine, cyclophosphamide, uramustine, chlorambucil, melphalan, ifosfamide), ethylenimine and methylmelamines (e.g., hexamethlymelamine and thiotepa), alkyl sulfonates (e.g., busulfan and hepsulfam), nitrosoureas (e.g., carmustine, lomusitne, semustine, and streptozocin), and triazenes (e.g., decarbazine); anti-metabolites such as folic acid analogs (e.g., methotrexate, leucovorin, raltitrexed, and pemetrexed), pyrimidine analogs (e.g., fluorouracil, floxouridine, cytarabine, capecitabine, and gemcitabine), and purine analogs (e.g., mercaptopurine, thioguanine, pentostatin, fludarabine, and 5- azathioprine); plant alkaloids (e.g., vincristine, vinblastine, vinorelbine, vindesine, podophyllotoxin, paclitaxel, docetaxel, and homoharringtonine); topoisomerase inhibitors such as camptothecin derivatives (e.g., irinotecan and topotecan), amsacrine, and epipodophyllotoxins (e.g., etoposide (VP16), etoposide phosphate, and teniposide); antibiotics such as anthracenediones (e.g., mitoxantrone), anthracyclines (e.g., doxorubicin, daunorubicin, epirubicin, and fluorodaunorunicin hydrochloride), streptomyces-derived antibiotics or derivatives thereof (e.g., dactinomycin, bleomycin, mitomycin, geldanamycin, plicamycin, and 17-N-allylamino-17-demethoxygeldanamycin (17-AAG; tanespimycin), clofazimine, and beta lactam derivatives; platinum-based compounds (e.g., cisplatin, oxaliplatin, carboplatin); substituted ureas (e.g., hydroxyurea); methyl hydrazine derivatives (e.g., procarbazine), adrenocortical suppressants (e.g., mitotane and aminoglutethimide); angiogenesis-inhibiting enzymes (e.g., L-asparaginase and arginine deiminase); PI3K inhibitors (e.g., wortmannin and LY294002); mTOR inhibitors (e.g., sertraline); DNA methyltransferase inhibitors (e.g., 5-aza-2'-deoxycytidine); antisense oligonucleotides; apoptosis gene modulators; apoptosis regulators (e.g., deoxyadenosine and triptolide); BCR/ABL antagonists; bFGF inhibitor; casein kinase inhibitors (ICOS); gallium nitrate; gelatinase inhibitors; glutathione inhibitors (e.g., etanidazole); immunostimulant peptides; insulin-like growth factor-1 receptor inhibitors; leukemia inhibiting factor; matrilysin inhibitors; matrix metalloproteinase inhibitors; MIF inhibitors; mismatched double stranded RNA; mycobacterial cell wall extract; nitric oxide modulators; phosphatase inhibitors; plasminogen activator inhibitor; proteasome inhibitors (e.g., bortezomib); protein A-based immune modulators; protein kinase C inhibitors; protein tyrosine phosphatase inhibitors; purine nucleoside phosphorylase inhibitors; ras farnesyl protein transferase inhibitors; ras inhibitors; ras-GAP inhibitors; ribozymes; signal transduction inhibitors/modulators (e.g., itraconazole); single chain antigen-binding proteins; stem cell inhibitors; stem-cell division inhibitors; stromelysin inhibitors; synthetic glycosaminoglycans; telomerase inhibitors; thyroid stimulating hormones; translation inhibitors; urokinase receptor antagonists; gonadotropin-releasing hormone agonists (GnRH) such as goserelin and leuprolide (leuprorelin); steroids such as adrenocorticosteroids (e.g., prednisone and dexamethasone); progestins (e.g., hydroxyprogesterone caproate, megestrol acetate, medroxyprogesterone acetate); antiprogestrogens (e.g., mifepristone); estrogens (e.g., diethylstilbestrol and ethinylestradiol); antiestrogens such as aromatase inhibitors (e.g., exemestane, fadrozole, letrozole, pentrozole, and anastrozole), selective estrogen receptor modulators (e.g., tamoxifen, tamoxifen methiodide, panomifene, and clomifene analogues); androgens (e.g., testosterone propionate and fluoxymesterone); antiandrogens (e.g., flutamide, finasteride, and bicalutamide); immunostimulants such as levamisole, interleukins (e.g., interleukin-2) and interferons/interferon agonists (e.g., alpha-interferon); monoclonal antibodies such as anti-CD20 (e.g., rituximab), anti-HER2 (e.g., trastuzumab), anti-CD52, anti-CD25 (e.g., daclizumab, anti-HLA-DR, and anti-VEGF monoclonal antibodies); immunotoxins (e.g., anti-CD33 monoclonal antibody-calicheamicin conjugates and anti-CD22 monoclonal antibody-pseudomonas exotoxin conjugates); radioimmunotherapeutic agents (e.g., anti-CD20 monoclonal antibody conjugated to ¹¹¹In, ⁹⁰Y, or ¹³¹I, etc.); statins (e.g., cerivastatin and pitavastatin); 5-T1B receptor agonists (e.g., 5- nonyloxytryptamine); BRAF kinase inhibitors (e.g., vemurafenib and dabrafenib); tyrosine kinase inhibitors such as inhibitors of one or more of EGFR, HER2, KDR, FLT4, EphB4, and Src (e.g., gefitinib (Iressa™), erlotinib (Tarceva™), cetuximab (Erbitux™), lapatinib (Tykerb™), panitumumab (Vectibix™) vandetanib (Caprelsa™), afatinib/BIBW2992, CI-1033/canertinib, neratinib/HKI-272, CP-724714, TAK-285, AST- 1306, ARRY334543, AG-1478, dacomitinib/PF299804, OSI-420/desmethyl erlotinib, AZD8931, ARRY- 380, AEE788, pelitinib/EKB-569, CUDC-101, WZ8040, WZ4002, WZ3146, AG-490, XL647, PD153035, BMS-599626, sorafenib, imatinib (Gleevec®), sunitinib, and dasatinib; immune-checkpoint inhibitors (e.g., anti-CTLA-4, anti-PD1/L1 antibodies); PLK1 inhibitors (GSK461364, BI2536, Tak960, NMS-P937, BI6727), mitotic kinase inhibitors, or the like, or mixtures thereof (e.g., a combination of euprolide, estrogen, and progesterone). In some embodiments, a compound disclosed herein (e.g., any one of the compounds of formula (I), formula (IA), and Table 1) is administered in combination with radiation therapy and/or surgical intervention. EXAMPLES Example 1. Synthesis of 4-(2-(5-ethyl-4-methylthiazol-2-yl)hydrazineylidene)-5-phenyl-2-(4- phenylthiazol-2-yl)-2,4-dihydro-3H-pyrazol-3-one (Compound 1)

Synthesis of 2-Hydrazineyl-4-phenylthiazole (1.2) To a stirring solution of 2-bromo-1-phenylethan-1-one 1.1 (15 g, 75.36 mmol) in ethanol: H2O (1:1) (150 mL) were added KOAc (7.38 g, 75.19 mmol) and thiosemicarbazide (6.86 g, 75.27 mmol) at room temperature. The reaction mixture was stirred at room temperature for 4 h. The reaction mixture was filtered and the collected residue washed with water. The residue was dried under vacuum to afford compound 1.2 (10 g). Compound 1.2 was used in the next reaction step without purification.¹H NMR (400 MHz, DMSO-d6) δ = 8.54 (s, 1H), 7.84 - 7.73 (m, 2H), 7.41 - 7.31 (m, 2H), 7.28 - 7.20 (m, 1H), 7.09 (s, 1H), 4.85 (br s, 2H); LC-MS = 192.20 [M+H]⁺ at RT 1.484 min (column: X-bridge BEH C18(3.0*50mm,2.5um), Mobile Phase A: 0.025% FA in H2O, Mobile Phase B: ACN, Gradient % B:0/2,0.2/2,2.2/98,3.0/98,3.2/2,4/2, Flow Rate:1.2 mL/min). Synthesis of 3-Phenyl-1-(4-phenylthiazol-2-yl)-1H-pyrazol-5-ol (1.4) Ethyl 3-oxo-3-phenylpropanoate 1.3 (10 g, 0.52 mmol) was added at room temperature under an inert atmosphere to a solution of 2-hydrazineyl-4-phenylthiazole (1.2) (10 g, 52.35 mmol) in AcOH (100 mL). The reaction mixture was heated at 120 °C for 16 h, filtered and the collected residue washed with water. The residue was purified by chromatography, eluting with 20-25% EtOAc/ hexane to afford compound 1.4 (13 g, 77.92%) as a dark red solid. ¹H NMR (400 MHz, DMSO-d6) δ = 12.69 - 12.29 (m, 1H), 8.02 (br d, J = 7.4 Hz, 2H), 7.89 (br dd, J = 1.3, 8.0 Hz, 3H), 7.55 - 7.43 (m, 5H), 7.40 - 7.32 (m, 1H), 6.11 (s, 1H); LC-MS = 320.20 [M+H]⁺ at RT 2.313 min (column: X-bridge BEH C18(3.0*50mm,2.5um), Mobile Phase A: 0.025% FA in H2O+50ml ACN, Mobile Phase B: ACN, Gradient % B:0/2,0.2/2,2.2/98,3.0/98,3.2/2,4/2, Flow Rate:1.2 mL/min). Synthesis of (3-bromopentan-2-ylidene)oxonium (1.7) and 1-bromopentan-2-one (1.8) A solution of pentan-2-one 1.6 (1.0 g, 11.61 mmol) in AcOH (10 mL) was cooled to 0-5 °C and bromine (11.61 mmol) in AcOH (3 mL) was slowly added. The reaction mixture was stirred at room temperature for 16 h. The reaction mixture was quenched with ice water, followed by the addition of aqueous NaHCO3(50 mL), and then extracted with EtOAc (2 x 50 mL). The organic layer was collected, dried over Na2SO4, filtered, and the solvent removed under reduced pressure. The resulting crude mixture of 1.6 and 1.7 (1.1 g) was directly used for next step without any purification. LC-MS = 167.24 [M+2]⁺ at RT 1.33 min (Column: X-Select CSH-C18-50X3.0mm 2.5u, Mobile Phase A:0.05% FA in water B: ACN, Gradient: Time/ %B :0.0/0_1.5/100_2.2/100_2.6/0_3/0, Flow Rate:1.5 mL/min). Synthesis of 5-ethyl-4-methylthiazol-2-amine (1.10) Thiourea (0.46 g, 6.06 mmol) in water (10 mL) was added to a solution of compounds 1.7 and 1.8 (mixture; 1.0 g, 6.06 mmol) in EtOH (10 mL). The reaction mixture was heated to 75° C for 5 h. The reaction mixture solvent was removed under vacuum. Aqueous NaHCO3 (50 mL) was added to the residue and the reaction mixture extracted with CH₂Cl2 (2 x 50 mL). The organic layer was collected, dried over Na2SO4 and concentrated under reduced pressure. The resulting residue contained a mixture of 1.9 and 1.10 which was purified by chromatography to afford compound 1.10 (0.240 g, 27.90 %). ¹H NMR (400 MHz, CDCl3) δ = 4.96 - 4.57 (m, 2H), 2.56 (q, J = 7.4 Hz, 2H), 2.09 (s, 3H), 1.14 (t, J = 7.5 Hz, 3H); LC-MS = 143.20 [M+H]⁺ at RT 0.971 min (Column: X-Bridge BEH C18(3.0*50mm,2.5um), Mobile Phase A: 0.025% FA in H2O, Mobile Phase B: ACN, Gradient % B:0/2,0.2/2,2.2/98,3.0/98,3.2/2,4/2, Flow Rate:1.2ml/min,). Synthesis of 5-ethyl-4-methylthiazole-2-diazonium chloride (1.11) To a stirring solution of 5-ethyl-4-methylthiazol-2-amine 1.10 (0.25 g, 1.75 mmol) in 6N HCl (1.32 mL) at 0 ^oC was slowly added a solution of NaNO₂ (0.121 g, 1.75 mmol) in water (1.32 mL). The reaction mixture was stirred for 30 min. The resulting freshly prepared 1.11 was not isolated by used directly in the next reaction. Synthesis of 4-(2-(5-ethyl-4-methylthiazol-2-yl)hydrazineylidene)-5-phenyl-2-(4-phenylthiazol-2-yl)-2,4- dihydro-3H-pyrazol-3-one (Compound 1) A solution of a 3-phenyl-1-(4-phenylthiazol-2-yl)-1H-pyrazol-5-ol 1.2 (560 mg, 1.75 mmol) in ethanol (2 mL) was treated with NaOH (175 mg, 4.37 mmol) in H2O (1 mL) at 0 ^o C. The reaction mixture was stirred at room temperature for 30 min to afford sodium enolate 1.5 in situ. The solution of 1.5 was re-chilled to 0 °C and freshly prepared 5-ethyl-4-methylthiazole-2-diazonium chloride 1.10 (250 mg, 1.31 mmol) was added. The reaction mixture was stirred at room temperature for 6 h. The reaction mixture was filtered. The collected residue was washed with water and dried under vacuo. The residue was purified by chromatography to afford the Compound 1 as a brown solid (140 mg, 16.84%). ¹H NMR (400 MHz, DMSO-d6) δ = 8.15 (br d, J = 6.9 Hz, 2H), 8.03 - 7.95 (m, 2H), 7.80 (s, 1H), 7.57 - 7.52 (m, 3H), 7.49 - 7.43 (m, 2H), 7.39 - 7.30 (m, 1H), 2.70 (q, J = 7.4 Hz, 2H), 2.24 (s, 3H), 1.19 (t, J = 7.5 Hz, 3H); LC-MS = 473.2 [M+H] ⁺ at RT 2.479 min; (Column: X-Select CSH C18 (3.0*50) mm 2.5u Mobile Phase: A: 0.05% Formic acid in water: ACN (95:5) B: 0.05% Formic acid in ACN ; Gradient program: 0% B to 98 % B in 2.0 minute, hold till 3.0 min, at 3.2 min B conc. is 0 % up to 4.0 min; Flow Rate: 1.2. mL/minute); HPLC = 98.64% at RT 7.662 min (Column: X-Select Column : X-Select CSH C18 (4.6*150) mm 5u Mobile Phase: A - 0.1% TFA in water B - Acetonitrile ; Gradient program: Time(min)/ B Conc. : 0.01 Pumps Pump B Conc.501.00 Pumps Pump B Conc.504.00 Pumps Pump B Conc.10012.00 Pumps Pump B Conc.10016.00 Pumps Pump B Conc.5018.00 Pumps Pump B Conc.5018.00 Controller Stop; Flow Rate: 1.2 mL/minute). Example 2. 4-(2-(4-ethyl-5-methylthiazol-2-yl) hydrazineylidene)-5-phenyl-2-(4-phenylthiazol-2-yl)- 2,4-dihydro-3H-pyrazol-3-one (Compound 2)

To a stirring solution of 4-ethyl-5-methylthiazol-2-amine hydrobromic salt 2.1 (0.3 g, 1.34 mmol) in 6N HCl (1.2 mL) was added a solution of NaNO₂ (0.092 mg, 1.33 mmol) in water (1.2 mL) slowly at 0 ^oC. The reaction mixture was stirred for 30 min. The freshly prepared solution of diazonium salt 2.2 was reacted with intermediate 1.5 as described above in the procedure described in Example 1. The reaction mixture was filtered. The collected residue was washed with water and dried under vacuo. The reside was purified by chromatography eluting with 60-80% EtOAc/ heptane to afford Compound 2 (0.14 g, 33.2%) as brick red colored solid. ¹H NMR (400 MHz, DMSO-d6) δ = 8.16 (br d, J = 7.4 Hz, 2H), 8.05 - 7.95 (m, 2H), 7.74 (s, 1H), 7.57 - 7.41 (m, 5H), 7.38 - 7.29 (m, 1H), 2.60 (q, J = 7.4 Hz, 2H), 2.30 (s, 3H), 1.20 (t, J = 7.5 Hz, 3H); LC-MS = 473.2 [M+H]⁺ at RT 2.498 min; (Column: X-Select CSH (3.0*50) mm 2.5u Mobile Phase: A: 0.05% Formic acid in water: ACN (95:5) B: 0.05% Formic acid in ACN; Gradient program: 0% B to 98 % B in 2.0 min, hold till 3.0 min, at 3.2 min B conc. is 0 % up to 4.0 min; Flow Rate: 1.2 mL/minute); HPLC = 97.19% at RT 7.751 min; (Column: X-Select CSH C18 (4.6*150) mm 5u; Mobile Phase: A - 0.1% TFA in water B - Acetonitrile ; Gradient program: Time(min)/ B Conc. : 0.01 Pumps Pump B Conc.501.00 Pumps Pump B Conc.504.00 Pumps Pump B Conc.10012.00 Pumps Pump B Conc.10016.00 Pumps Pump B Conc.5018.00 Pumps Pump B Conc.5018.00 Controller Stop; Flow Rate: 1.2 mL/minute). Example 3. Synthesis of 4-(2-(5-isobutyl-4-methylthiazol-2-yl)hydrazineylidene)-5-phenyl-2-(4- phenylthiazol-2-yl)-2,4-dihydro-3H-pyrazol-3-one (Compound 3)

Synthesis of 3-bromo-5-methylhexan-2-one (3.2) Bromine in methanol (0.45 mL 8.76 mmol) was added slowly to a solution of 5-methylhexan-2- one 3.1 (1.0 g, 8.76 mmol) in methanol (10 mL) at 0-5 °C. The reaction mixture was stirred at room temperature for 16 h. The reaction mixture was quenched with aqueous NaHCO3 (5 mL) and extracted with DCM (2 x 20 mL). The organic layer collected, dried over Na2SO4 and concentrated under reduced pressure to afford mixture of bromides 3.2 and 3.3. This material was used in next step without any further purification. LC-MS = 193.0 M+H]⁺ at RT 1.831 min; (Column: X-Select CSH C18 (3.0*50) mm 2.5um Mobile Phase: A: 0.05% Formic acid in water:ACN(95:05) B: 0.05% Formic acid in ACN Gradient program: 0% B to 98 % B in 2.0 minute, Hold till 3.0 min, At 3.2 min B conc is 0 % up to 4.0 min. Flow Rate : 1.2. mL/minute). Synthesis of 5-isobutyl-4-methylthiazol-2-amine (3.4) Thiourea (0.591 g, 7.77 mmol) in water (15 mL) was added to a solution of 3-bromo-5- methylhexan-2-one 3.2 and 3.3 (1.5 g, 7.77 mmol) in EtOH at room temperature. The reaction mixture was heated to 75 °C for 5 h. The reaction mixture was quenched with aqueous NaHCO3 (5 mL) and extracted with DCM (2 x 40 mL). The organic layer was dried over Na2SO4 and concentrated under reduced pressure to afford compound. The resulting residue containing a mixture of 3.4 and 3.5 was purified by chromatography to afford 3.4 (300 mg, 20%) as brown solid. ¹H NMR (400 MHz, CDCl3) δ = 4.68 (br s, 2H), 2.42 (d, J = 7.1 Hz, 2H), 2.11 (s, 3H), 1.81 - 1.68 (m, 1H), 0.93 (d, J = 6.6 Hz, 6H); LC-MS = 171.5 [M+H]⁺ at RT 1.178 min; (Column: X-Select CSH C18 (3.0*50) mm 2.5um Mobile Phase: A: 0.05% Formic acid in water:ACN(95:05) B: 0.05% Formic acid in ACN Gradient program: 0% B to 98 % B in 2.0 minute, Hold till 3.0 min, At 3.2 min B conc is 0 % up to 4.0 min. Flow Rate : 1.2. mL/minute). Synthesis of 4-(2-(5-isobutyl-4-methylthiazol-2-yl)hydrazineylidene)-5-phenyl-2-(4-phenylthiazol-2-yl)-2,4- dihydro-3H-pyrazol-3-one (Compound 3) A solution of 5-isobutyl-4-methylthiazol-2-amine 3.4 (0.293g, 1.72 mmol) in water (3.0 mL) was treated with 6N HCl (0.817 mL, 22.40 mmol) and aqueous NaNO2 (0.178 g, 2.58) at 0-5 °C. The reaction mixture was stirred for 30 min at room temperature. The freshly prepared solution of diazonium salt so obtained 3.6 was reacted with intermediate 1.5 as described above in the procedure described in Example 1. The reaction mixture was diluted with water, filtered and the collected residue dried under vacuo. The residue was purified by chromatography to afford Compound 3 (116.0 mg, 14.8 %) as a brick red solid. ¹H NMR (400 MHz, DMSO-d6) δ = 8.14 (br d, J = 7.3 Hz, 2H), 7.99 (br d, J = 8.3 Hz, 2H), 7.81 (s, 1H), 7.60 - 7.41 (m, 5H), 7.39 - 7.30 (m, 1H), 2.56 (br d, J = 7.3 Hz, 2H), 2.23 (s, 3H), 1.83 (dt, J = 6.7, 13.6 Hz, 1H), 0.93 (d, J = 6.4 Hz, 6H); LC-MS = 501.2 [M+H]⁺ at RT 2.624 min; (Column: X-Select CSH C18 (3.0*50) mm 2.5um Mobile Phase: A: 0.05% Formic acid in water:ACN(95:05) B: 0.05% Formic acid in ACN Gradient program: 0% B to 98 % B in 2.0 minute, Hold till 3.0 min, At 3.2 min B conc is 0 % up to 4.0 min. Flow Rate : 1.2. mL/minute). HPLC = 99.63% at RT 8.049 min; (Column: X-Select CSH C18 (4.6*150) mm 5u Mobile Phase: A - 0.1% TFA in water B - Acetonitrile, Gradient program: Time(min)/ B Conc. : 0.01 Pumps Pump B Conc.501.00 Pumps Pump B Conc.504.00 Pumps Pump B Conc.100 12.00 Pumps Pump B Conc.10016.00 Pumps Pump B Conc.5018.00 Pumps Pump B Conc.5018.00 Controller Stop, Flow Rate: 1.2 mL/minute). Example 4. Synthesis of (4Z)-4-[(5-isopropyl-4-methyl-thiazol-2-yl)hydrazono]-5-phenyl-2-(4- phenylthiazol-2-yl)pyrazol-3-one (Compound 4)

Synthesis of 3-bromo-4-methyl-pentan-2-one (4.2) To the solution of 4-methylpentan-2-one 4.1 (3.00 g, 29.9 mmol, 1.00 eq) in CH₃CN (30.0 mL) was added TMSBr (5.04 g, 32.9 mmol, 4.27 mL, 1.10 eq) at 15~25 °C. DMSO (2.57 g, 32.9 mmol, 2.57 mL, 1.10 eq) was added dropwise to the reaction mixture at 0 °C. The reaction mixture was stirred for 2 h at 15-25 °C. The reaction mixture was quenched with water (50.0 mL) at 0 °C and extracted with MTBE (50.0 mL x 2). The combined organic layers were washed with saturated brine (50.0 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give 3-bromo-4-methyl-pentan- 2-one 4.2 (3.20 g, crude) as a light-yellow oil.¹H NMR (400 MHz, CDCl3) δ ppm 4.02 (d, J=8.3 Hz, 1H), 2.35 (s, 3H), 2.24 - 2.18 (m, 1H), 1.11 (d, J=6.5 Hz, 3H), 1.00 (d, J=6.8 Hz, 3H) Synthesis of 5-isopropyl-4-methyl-thiazol-2-amine (4.3) To a solution of 3-bromo-4-methyl-pentan-2-one 4.2 (3.20 g, 17.9 mmol, 1.00 eq) in EtOH (10.0 mL) was added thiourea (1.50 g, 19.7 mmol, 1.10 eq) at 15-25 ℃. The mixture was stirred at 80 ℃ for 1 h. The mixture was filtered and the wet cake was washed with MTBE (20 mL). The wet cake was dried under vacuum, purified by prep-HPLC (column: Phenomenex C1880*40mm*3um;mobile phase: [water(NH3H2O)-ACN];B%: 26%-56%, 8min) and concentrated under reduced pressure to give 5- isopropyl-4-methyl-thiazol-2-amine 4.3 (730 mg, 4.64 mmol, 26.0% yield, 99.3% purity) as a yellow solid. MS: product: m/z 156.8 (M+H) ^{+ 1}H NMR (400 MHz, CHLOROFORM-d) δ ppm 4.83 (br, 2H), 3.06 (m, 1H), 2.12 (s, 3H), 1.19 (d, J=6.8 Hz, 6H). Synthesis of (4Z)-4-[(5-isopropyl-4-methyl-thiazol-2-yl)hydrazono]-5-phenyl-2-(4-phenylthiazol-2- yl)pyrazol-3-one (Compound 4) The solution of 5-isopropyl-4-methyl-thiazol-2-amine 4.3 (170 mg, 1.09 mmol, 1.00 eq) in aqueous HCl (1.47 mL, 14.4 mmol, 35%) was cooled to -10-5°C. A solution of NaNO2 (75.1 mg, 1.09 mmol, 1.00 eq) in water (0.50 mL) was added dropwise to the above mixture at -10~-5°C. The reaction mixture was stirred for 0.5 h at -10-5°C to give diazonium salt 4.4. Separately, 5-phenyl-2-(4- phenylthiazol-2-yl)pyrazol-3-ol 1.4 (350 mg, 1.10 mmol, 1.00 eq) in EtOH (0.50 mL) was treated with aqueous NaOH (2.50 M, 1.10 mL, 2.50 eq) at 15-25°C. The reaction mixture was stirred for 0.5 h at 15~25°C to give a clear solution of [5-phenyl-2-(4-phenylthiazol-2-yl)pyrazol-3-yl]oxysodium 1.5 (0.374 g, 1.10 mmol, 1.01 eq). The clear solution of 1.5 was added dropwise to the freshly prepared solution of diazonium salt 4.4 (0.222 g, 1.09 mmol, 1.00 eq) in H2O at -10-5°C. After complete addition, the reaction mixture was stirred for 1 h at 15-25°C. The reaction mixture was filtered. The wet cake was slurried in MeOH (10.0 mL) and DCM (2.00 mL) for 1 h at 68 °C. The solid was collected by filtration, dried in vacuo to give Compound 4 (0.128 g, 255 umol, 23.5% yield, 96.6% purity) as a red solid. MS: product: m/z 487.1 (M+H)⁺. ¹H NMR (400 MHz, DMSO-d6) δ ppm 8.14 (d, J=6.5 Hz, 2H), 7.99 (d, J=7.5 Hz, 2H), 7.81 (s, 1H), 7.59 - 7.44 (m, 5H), 7.38 - 7.32 (m, 1H), 3.27 - 3.22 (m, 2H), 2.25 (s, 3H), 1.24 (d, J=7.0 Hz, 6H). Example 5. Synthesis of 4-(2-(4-(hydroxymethyl)-5-methylthiazol-2-yl)hydrazineylidene)-5-phenyl- 2-(4-phenylthiazol-2-yl)-2,4-dihydro-3H-pyrazol-3-one (Compound 31)

Synthesis of (2-amino-5-methylthiazol-4-yl)methanol (31.2) To a stirred solution of methyl 2-amino-5-methylthiazole-4-carboxylate 31.1 (0.5 g, 2.90 mmol), in THF (15 mL) at 0 °C was added lithium aluminum hydride (LAH; 0.22 g, 5.80 mmol). The reaction mixture was stirred for 16 h. The reaction mixture was quenched with aqueous NaHCO₃ solution (5 mL) and filtered. The aqueous layer was extracted with 10% MeOH in DCM. The organic extract were dried over anhydrous Na2SO4 and concentrated under reduced pressure. The residue was purified by chromatography eluting with 8 % MeOH in DCM to afford 31.2 (0.15 g, 35.81 %) as a brown solid. ¹H NMR (400 MHz, DMSO-d₆) δ = 6.54 (s, 2H), 4.70 (t, J = 5.5 Hz, 1H), 4.17 (d, J = 5.9 Hz, 2H), 2.16 (s, 3H); LC-MS = 144.85 [M+H]⁺ at RT 1.924 min; (Column: X-Select CSH C18 (3.0*50) mm 2.5um Mobile Phase: A: 0.05% Formic acid in water:ACN(95:05) B: 0.05% Formic acid in ACN Gradient program: 0% B to 98 % B in 2.0 minute, Hold till 3.0 min, At 3.2 min B conc is 0 % up to 4.0 min. Flow Rate : 1.2. mL/minute). Synthesis of 4-(2-(4-(hydroxymethyl)-5-methylthiazol-2-yl)hydrazineylidene)-5-phenyl-2-(4-phenylthiazol- 2-yl)-2,4-dihydro-3H-pyrazol-3-one (Compound 31) To a stirring solution of (2-amino-5-methylthiazol-4-yl)methanol 31.2 (0.25 g, 1.73 mmol) in 6N HCl (1.6 mL, 22.52 mmol) was added a solution of NaNO2 (0.11 g, 1.73 mmol) in water (1.6 mL) at 0-5 °C. The reaction mixture was stirred at 0-5 °C for 30 min. The resulting freshly prepared diazonium salt 31.3 was added directly to a solution of 1.5 (0.35 g, 1.097 mmol) in EtOH (3 mL) and water (3 mL) at 0 ^o C using the procedure described in Example 1. The reaction mixture was stirred at room temperature for 3 h, diluted with ice water, filtered, and the residue dried under vacuo. The crude solid was purified by chromatography eluting with 2-6% MeOH/ DCM. The final product was washed with diethyl ether/pentane dried under vacuum to afford Compound 31 (80 mg, 15.3%) as brown solid. ¹H NMR (400 MHz, DMSO- d6) δ = 8.14 (br d, J = 6.9 Hz, 2H), 7.99 (d, J = 7.3 Hz, 2H), 7.83 (s, 1H), 7.60 - 7.50 (m, 3H), 7.50 - 7.43 (m, 2H), 7.39 - 7.31 (m, 1H), 4.42 (s, 2H), 2.37 (s, 3H); LC-MS = 475.0 [M+H]⁺ at RT 2.176 min; (Column: X-Select CSH C18 (3.0*50) mm 2.5um Mobile Phase: A: 0.05% Formic acid in water:ACN (95:05) B: 0.05% Formic acid in ACN Gradient program: 0% B to 98 % B in 2.0 minute, Hold till 3.0 min, At 3.2 min B conc is 0 % up to 4.0 min. Flow Rate : 1.2. mL/minute); HPLC = 95.998 % at RT 7.923 min; (Column : X-Select CSH C18 (4.6*150) mm 5u Mobile Phase: A - 0.1% TFA in water B - Acetonitrile, Gradient program: Time(min)/ B Conc. : 0.01 Pumps Pump B Conc.501.00 Pumps Pump B Conc.504.00 Pumps Pump B Conc.10012.00 Pumps Pump B Conc.10016.00 Pumps Pump B Conc.5018.00 Pumps Pump B Conc.5018.00 Controller Stop, Flow Rate: 1.2. mL/minute). Example 6. Synthesis of 4-(2-(5-(hydroxymethyl)-4-methylthiazol-2-yl)hydrazineylidene)-5-phenyl- 2-(4-phenylthiazol-2-yl)-2,4-dihydro-3H-pyrazol-3-one (Compound 32)

Synthesis of (2-amino-4-methylthiazol-5-yl)methanol (32.2) To a stirred solution of methyl 2-amino-4-methylthiazole-5-carboxylate 32.1 (0.5 g, 2.90 mmol) in THF (25 mL) was added LAH (2 eq) at 0 °C. The reaction mixture was stirred at room temperature for 6 h. The reaction mixture was quenched with saturated NH₄Cl solution (5 mL), filtered and extracted with 10% DCM (5 mL). The aqueous layer was further extracted with 10% MeOH in DCM (2 x 10 mL). The combined organic extracts were dried over anhydrous Na2SO4 and concentrated under reduced pressure. The residue was purified by chromatography eluting with 2-5% MeOH in DCM to afford compound 32.2 (0.1 g, 5.98 %) as a brown solid. ¹H NMR (400 MHz, DMSO-d6) δ = 6.66 (s, 2H), 4.94 (t, J = 5.6 Hz, 1H), 4.35 (d, J = 5.5 Hz, 2H), 2.01 (s, 3H); LC-MS = 144.80 [M+H]⁺ at RT 1.707 min; (Column: X-Select CSH C18 (3.0*50) mm 2.5um Mobile Phase: A: 0.05% Formic acid in water:ACN (95:05) B: 0.05% Formic acid in ACN Gradient program: 0% B to 98 % B in 2.0 minute, Hold till 3.0 min, At 3.2 min B conc is 0 % up to 4.0 min. Flow Rate : 1.2. mL/minute). Synthesis of 4-(2-(5-(hydroxymethyl)-4-methylthiazol-2-yl)hydrazineylidene)-5-phenyl-2-(4-phenylthiazol- 2-yl)-2,4-dihydro-3H-pyrazol-3-one The conversion of 33.2 to diazonium salt 32.3 and its reaction with intermediate 1.5 was carried out as described in Example 5 to afford Compound 32 (8 mg, 3.58 %) as a brown solid. ¹H NMR (400 MHz, DMSO-d6) δ = 8.18 (br d, J = 5.4 Hz, 2H), 7.99 (br d, J = 7.3 Hz, 2H), 7.70 (s, 1H), 7.56 - 7.26 (m, 6H), 5.35 (br s, 1H), 4.52 (br s, 2H), 2.26 (s, 3H); LC-MS = 474.10 [M+H]⁺ at RT 2.545 min; (Column : X- Select CSH C18 (3.0*50)mm 2.5u Mobile Phase: A: 2.5 mM Ammonium Bicarbonate in water; B: Acetonitrile; Flow Rate: 1.2 mL/minute; Column oven temp.50°C; Gradient program: 0% B to 98 % B in 2.0 minute, hold till 3.0 min, at 3.2 min B conc is 0 % up to 4.0 min); HPLC = 99.07% at RT 5.197 min; (Column : X-Select CSH C18 (4.6*150) mm 5u Mobile Phase: A - 0.1% TFA in water B - Acetonitrile, Gradient program: Time(min)/ B Conc. : 0.01 Pumps Pump B Conc.501.00 Pumps Pump B Conc.50 4.00 Pumps Pump B Conc.10012.00 Pumps Pump B Conc.10016.00 Pumps Pump B Conc.5018.00 Pumps Pump B Conc.5018.00 Controller Stop, Flow Rate: 1.2. mL/minute). Example 7. Synthesis of (Z)-4-(2-(5,6-dihydro-4H-cyclopenta[d]thiazol-2-yl)hydrazono)-3-phenyl-1- (4-phenylthiazol-2-yl)-1H-pyrazol-5(4H)-one (Compound 35)

A solution of 5,6-dihydro-4H-cyclopenta[d]thiazol-2-amine 35.1 (90.0 mg, 641 µmol, 1.00 eq) in HCl (882 mg, 8.47 mmol, 865 uL, 35.0% purity) was cooled to -10-5°C. A solution of NaNO2 (44.3 mg, 641 umol, 1.00 eq) in water (0.60 mL) was added dropwise. The reaction mixture was stirred for 0.5 h at 50 °C to afford diazonium salt 35.2. Using the procedures described in Example 1, freshly prepared diazonium salt 35.2 was reacted with intermediate 1.5 affording the Compound 35 (19.1 mg, 38.6 µmol, 6.18% yield, 95.0% purity). MS: product: m/z 471.0 (M+H) ⁺.¹H NMR (400 MHz, DMSO-d) δ ppm 8.16 (d, J = 6.8 Hz, 2H), 8.02 - 7.98 (m, 2H), 7.82 (s, 1H), 7.57 - 7.51 (m, 3H), 7.47 (t, J = 7.6 Hz, 2H), 7.38 - 7.33 (m, 1H), 2.85 ( t, J = 6.8 Hz, 2H), 2.78 (t, J = 6.8 Hz, 2H), 2.45 - 2.39 (m, 2H). Example 8. 4-(2-(4,5-dimethylthiazol-2-yl)hydrazineylidene)-2-(5-methyl-4-phenylthiazol-2-yl)-5- pheny

Synthesis of 2-hydrazineyl-5-methyl-4-phenylthiazole (42.2) To a stirred solution of 2-bromo-1-phenylpropan-1-one 42.1 (5.0 g, 23.46 mmol) in 50% aqueous ethanol (25 mL) were added thiosemicarbazide (2.13 g, 23.37 mmol) and KOAc (2.53 g, 25.77 mmol) at 0-5 °C. The reaction mixture was stirred at room temperature for 3 h. The reaction mixture was filtered and the filter cake washed with hexane/diethyl ether. The residue was purified by medium pressure liquid column chromatography by eluting with 1% MeOH/ CH₂Cl2 to afford compound 41.2 (2.1g, 43%) as a pale-yellow solid. ¹H NMR (400 MHz, DMSO-d6) δ = 8.25 (s, 1H), 7.56 (d, J = 7.3 Hz, 2H), 7.38 (t, J = 7.8 Hz, 2H), 7.30 - 7.23 (m, 1H), 4.75 (s, 2H), 2.35 (s, 3H); LC-MS = 206.20 [M+H]⁺ at RT 1.577 min (Column: X-bridge BEH C18(3.0*50mm,2.5um), Mobile Phase A:0.025% FA in H2O, Mobile Phase B: ACN, Gradient % B:0/2,0.2/2,2.2/98,3.0/98,3.2/2,4/2, Flow Rate:1.2mL/min,); Synthesis of 1-(5-methyl-4-phenylthiazol-2-yl)-3-phenyl-1H-pyrazol-5-ol (42.3) To a stirred solution of 2-hydrazineyl-5-methyl-4-phenylthiazole 42.2 (2.1 g, 10.22 mmol) in AcOH (23 mL) was added ethyl 3-oxo-3-phenylpropanoate 1.3 (2.16 g, 11.25 mmol) at room temperature under inert atmosphere. The reaction mixture was heated at 120 °C and stirred for 16 h. the reaction mixture was cooled at room temperature, diluted with ice water (2 mL) and stirred for 30 min. The reaction mixture was filtered and the filter cake washed with diethyl ether (2 mL). The residue was dried under vacuum to afford compound 42.2 (2.7 g, 79 %) as a pale-yellow solid. Compound 42.2 was used directly without further purification. ¹H NMR (400 MHz, DMSO-d6) δ = 12.43 - 11.75 (br s, 1H), 7.86 (br d, J = 7.3 Hz, 2H), 7.73 (br d, J = 7.3 Hz, 2H), 7.55 - 7.43 (m, 5H), 7.42 - 7.35 (m, 1H), 6.08 (s, 1H), 2.54 (s, 3H). Synthesis of 4-(2-(4,5-dimethylthiazol-2-yl)hydrazineylidene)-2-(5-methyl-4-phenylthiazol-2-yl)-5-phenyl- 2,4-dihydro-3H-pyrazol-3-one (Compound 42) The conversion of amino thiazole 42.5 to diazonium salt 42.6 and condensation with freshly prepared 42.4 using carried out using the procedures described in Example 1 to afford Compound 42 (500 mg, 35.28 %) as a brick red solid. ¹H NMR (400 MHz, DMSO-d6) δ = 8.11 (br d, J = 6.9 Hz, 2H), 7.73 - 7.67 (m, 2H), 7.56 - 7.43 (m, 5H), 7.41 - 7.33 (m, 1H), 2.54 (s, 3H), 2.27 (s, 3H), 2.21 (s, 3H); LC- MS = 473.00 [M+H]⁺ at RT 2.638 min (Column: X-Select CSH C18 (3.0*50) mm 2.5um Mobile Phase: A: 0.05% Formic acid in water: ACN (95:05) B: ACN Gradient program: 0% B to 98 % B in 2.0 minute, Hold till 3.0 min, At 3.2 min B conc. is 0 % up to 4.0 min, Flow Rate: 1.2. mL/minute); HPLC = 95.10% at RT 6.78 min (Column: X-Select CSH C18 (4.6*150) mm 5u Mobile Phase: A - 0.1% TFA in water B - Acetonitrile Gradient program: Time(min)/ B Conc. : 0.01 Pumps Pump B Conc.501.00 Pumps Pump B Conc.504.00 Pumps Pump B Conc.10012.00 Pumps Pump B Conc.10016.00 Pumps Pump B Conc. 5018.00 Pumps Pump B Conc.5018.00 Controller Sto, Flow Rate: 1.2 mL/minute). Example 9. 4-(2-(4,5-dimethylthiazol-2-yl)hydrazineylidene)-5-(3-methoxyphenyl)-2-(4-(4- methoxyphenyl)thiazol-2-yl)-2,4-dihydro-3H-pyrazol-3-one (Compound 47)

Synthesis of 2-hydrazineyl-4-(4-methoxyphenyl) thiazole (47.2) Thiosemicarbazide (1.8 g, 19.74 mmol) and KOAc (2.14 g, 21.82 mmol) were added to solution of bromide 47.1 (5.0 g, 21.82 mmol) in 50% aqueous ethanol (25 mL) at room temperature. The reaction mixture was stirred at room temperature for 3 h. The reaction mixture was filtered and the filter cake washed with water. The residue was dried under vacuum to afford compound 47.2 (3.8 g, 79.16 %) as a cream white solid. Compound 47.2 was used in the next reaction step without further purification. ¹H NMR (400 MHz, DMSO-d₆) δ = 8.51 (br s, 1H), 7.74 (d, J = 8.8 Hz, 2H), 7.02 - 6.79 (m, 3H), 4.88 (br s, 2H), 3.78 (s, 3H); LC-MS = 222.20 [M+H]⁺ at RT 1.384 (Column: X-bridge BEH C18(3.0*50mm,2.5um), Mobile Phase A:0.025% FA in H2O, Mobile Phase B :ACN, Gradient % B:0/2,0.2/2,2.2/98,3.0/98,3.2/2,4/2,Flow Rate:1.2mL/min,); Synthesis of 3-(3-methoxyphenyl)-1-(4-(4-methoxyphenyl)thiazol-2-yl)-1H-pyrazol-5-ol (47.4) Ethyl 3-(3-methoxyphenyl)-3-oxopropanoate 47.3 (2.0 g, 9.02 mmol) was added to a solution of 2-hydrazineyl-4-(4-methoxyphenyl) thiazole (47.2) (2.0 g, 9.04 mmol) in AcOH (20 mL) at room temperature under inert atmosphere. The reaction mixture was heated to 120 °C and stirred for 16 h. The reaction mixture was cooled at room temperature, diluted with ice water (2 mL) and stirred for 10 min. The reaction mixture was filtered and the filter cake dried under vacuo. The reside was purified by medium pressure liquid column chromatography by eluting with 50% EtOAc/ heptane to afford compound 47.4 (2.0 g, 58.47%) as pale-brown solid. ¹H NMR (400 MHz, DMSO-d6) δ = 12.77 - 12.11 (m, 1H), 7.95 (d, J = 8.8 Hz, 2H), 7.70 (s, 1H), 7.50 - 7.37 (m, 3H), 7.12 - 6.95 (m, 3H), 6.11 (br s, 1H), 3.85 (s, 3H), 3.81 (s, 3H); LC-MS = 379.90 [M+H]⁺ at RT 2.097 min; (Column: X-Select CSH (3.0*50) mm 2.5u Mobile Phase: A: 0.05% Formic acid in water : ACN (95:5) B: 0.05% Formic acid in ACN; Gradient program: 0% B to 98 % B in 2.0 min, hold till 3.0 min, at 3.2 min B conc. is 0 % up to 4.0 min; Flow Rate: 1.2 mL/minute). Synthesis of 4-(2-(4,5-dimethylthiazol-2-yl)hydrazineylidene)-5-(3-methoxyphenyl)-2-(4-(4- methoxyphenyl)thiazol-2-yl)-2,4-dihydro-3H-pyrazol-3-one (Compound 47) The conversion of amino thiazole 47.6 (CAS 2289-75-0) to diazonium salt 47.7 and its condensation with a freshly prepared solution of 47.5 obtained from 47.4 were all carried out using the procedures described in Example 1 to afford Compound 47 (33% yield) as a pale-brown solid. ¹H NMR (400 MHz, DMSO-d6) δ = 7.92 (d, J = 8.8 Hz, 2H), 7.76 - 7.67 (m, 2H), 7.63 (s, 1H), 7.46 (t, J = 7.9 Hz, 1H), 7.08 (dd, J = 2.1, 8.3 Hz, 1H), 7.02 (d, J = 8.8 Hz, 2H), 3.88 (s, 3H), 3.81 (s, 3H), 2.28 (s, 3H), 2.22 (s, 3H); LC-MS = 519.10 [M+H] ⁺ at RT 2.504 min (Column: X- Select CSH C18 (3.0*50) mm 2.5um Mobile Phase: A: 0.05% Formic acid in water: ACN (95:05) B: ACN; Gradient program: 0% B to 98 % B in 2.0 minute, Hold till 3.0 min, At 3.2 min B conc. is 0 % up to 4.0 min; Flow Rate: 1.2. mL/minute); HPLC = 98.30% at RT = 6.455 min. (Column: X-Select CSH C18 (4.6*150) mm 5u Mobile Phase: A - 0.1% TFA in water B – Acetonitrile; Gradient program: Time (min)/ B Conc.: 0.01 Pumps Pump B Conc.501.00 Pumps Pump B Conc.504.00 Pumps Pump B Conc.10012.00 Pumps Pump B Conc.10016.00 Pumps Pump B Conc.5018.00 Pumps Pump B Conc.5018.00 Controller Stop; Flow Rate: 1.2. mL/minute). Example 10. (Z)-4-(2-(5-methyl-4,5,6,7-tetrahydrothiazolo[4,5-c]pyridin-2-yl)hydrazineylidene)-5- phenyl-2-(4-phenylthiazol-2-yl)-2,4-dihydro-3H-pyrazol-3-one (Compound 33)

To a solution of 5-methyl-4,5,6,7-tetrahydrothiazolopyridin-2-amine 33.1 (CAS 17899-48-8) (0.291 g, 1.72 mmol) in 6 N HCl (0.81 mL) was slowly added a solution of NaNO2 (118.8 mg, 1.72 mmol) in water (0.81 mL) at 0 ^oC. The reaction mixture was stirred for 30 min. Diazonium salt 33.2 so obtained was condensed with a freshly prepared solution of 1.5 using the procedures described in Example 1 to afford Compound 33 (22% yield) as a brick red solid. ¹H NMR (400 MHz, DMSO-d6) δ = 10.90 - 10.64 (br s, 1H), 8.15 (br d, J = 6.2 Hz, 2H), 7.99 (br d, J = 7.3 Hz, 2H), 7.78 (s, 1H), 7.60 - 7.41 (m, 5H), 7.39 - 7.31 (m, 1H), 4.64 - 4.13 (m, 4H), 3.02 (br s, 2H), 2.94 (s, 3H); LC-MS = 500.05 [M+H]⁺ at RT 1.735 min; (Column: X-Select CSH C18 (3.0*50) mm 2.5um Mobile Phase: A: 0.05% Formic acid in water: ACN (95:05) B: ACN ; Gradient program: 0% B to 98 % B in 2.0 minute, Hold till 3.0 min, At 3.2 min B conc. is 0 % up to 4.0 min; Flow Rate: 1.2. mL/minute); HPLC = 95.51% at RT 6.85 min (Column : X-Select CSH C18 (4.6*150) mm 5u; Mobile Phase: A - 0.1% TFA in water B – Acetonitrile; Gradient program: Time(min)/ B Conc. : 0.01/5, 1.0/5, 8.0/100, 12.0/100, 14.0/5, 18.0/5; Flow Rate: 1.0. mL/minute). Example 11. Synthesis of Compounds of the Disclosure Compounds 5, 7, 9-12, 14, 16, 34 and 50, shown in Table 2, were prepared from 3-phenyl-1-(4- phenylthiazol-2-yl)-1H-pyrazol-5-ol 1.4 or 3-(4-methoxy)phenyl-1-(4-phenylthiazol-2-yl)-1H-pyrazol-5-ol 55.1 (Sehindler, W. Azomethine dyes from 2-thiazolylpyrazolones, Mitteilungen aus den Forschungslaboratorien der AGFA-Gevaert AG Leverkusen-Muenchen (1961), 133-149) with commercially available amino thiazoles using the synthetic procedures using described in the preparation of Compound 1. The structures of the compounds were consistent with their proton NMR spectra. Table 2.

* Compounds 6, 8, 13, 15, 17-30, 36-41, 43-46, 48, and 49 are prepared from amino thiazoles and pyrazol-5-ols by the following schemes using procedures based on to those described herein. Table 3

Note 1. The condensation product of pyrazo-5-ols with the requisite thiazole diazonium salts is hydrolyzed with aqueous NaOH to liberate the carboxylic acid. Note 2. The condensation product of pyrazo-5-ols with the requisite thiazole diazonium salts is treated with tetrabutylammonium fluoride in DCM to remove the t-butyldiphenylsilyl protecting group to liberate the alcohol. Example 12. Preparation of Synthons Amino thiazoles and pyrazol-5-ols shown in Tables 3 are prepared by the following synthetic routes: Amino thiazole 13.4

Amino thiazole 15.3

Amino thiazole 18.2

Amino thiazole 19.2

Amino thiazole 21.3

Amino thiazole 22.2

Amino thiazole 23.1

Pyrazolo carboxylic acid 26.3

Pyrazolo carboxylic acid 27.2

Amino thiazole 36.1

Amino thiazole 37.3

Amino thiazole 38.4

Amino thiazole 39.2

Amino thiazole 40.2

Amino thiazole 41.4

Dichlorophenyl pyrazol 43.2

Dichlorophenyl pyrazol carboxylate 44.5

Hydroxyphenyl pyrazol 45.2

Phenyl pyrazolo acetate 46.2

Pyrazol-5-ol 48.3

Pyrazol-5-ol 49.3

Example 13. Binding of Compounds to BAX Protein Recombinant human BAX protein expression and purification The gene sequence encoding H. sapiens BAX was custom-synthesized and cloned into pTYB1 vector (New England Biolabs Inc.) using NdeI and SapI restriction sites to create plasmid pL-001 (reference 1). The final construct was confirmed by sequencing, and the protein matched that of human BAX protein (Uniprot accession number Q07812). The plasmid was transformed into E. coli BL21(DE3). A single colony of BL21(DE3)/pL-001 was inoculated into a 200 ml culture of Luria Broth (LB) containing 100 µg/mL ampicillin and grown overnight at 37 °C. The overnight culture was diluted to OD600=0.1 in 10 x 1-liter of LB containing 100 μg/mL ampicillin and grown at 30 °C with aeration to OD600 = 0.8. IPTG was then added to a final concentration of 1 mM. After 4 hours at 30 °C, the cells were harvested by centrifugation at 5,000 x g for 15 min at 25 °C. Cell pastes were stored at -20 °C. The frozen cell paste from 10 L of cell culture was suspended in 300 ml of Buffer A consisting of 20 mM Tris/HCl, pH 7.2, 250 mM NaCl, 5% (v/v) glycerol, supplemented with 6 EDTA-free protease inhibitor cocktail tablets (Roche Molecular Biochemical). Cells were disrupted by high pressure homogenizer at 4 ºC, and the crude extract was centrifuged at 16,000 rpm for 60 min at 4 ºC. The supernatant was applied to 5 ml chitin beads (New England Biolabs Inc.) pre-equilibrated with buffer A and then washed with buffer A, and BAX protein was cleaved by overnight incubation with 50 mM DTT in Buffer A. The cleaved BAX protein was concentrated by Amicon^® Ultracel-10K (Millipore) and loaded onto a Superdex 7510/300 GL column (Cytiva) pre-equilibrated with 20 mM HEPES, pH 7.2, 150 mM KCl, 1 mM TCEP, 10% glycerol. The fractions containing BAX protein were pooled and concentrated by Amicon^® Ultracel-10K (Millipore) to about 1 mg/ml. Fluorescence polarization assay A fluorescence polarization (FP) assay was used to assess the binding affinity of Compounds 1- 11, 14, 16, 31-35, 42, 47, and 50 to BAX protein. The competitive fluorescence polarization assay was developed based on the interaction between human recombinant BAX protein and fluorescein isothiocyanate (FITC) labelled at N-terminus of stabilized α-helix of BCL-2 domain (SAHB) as FITC-bAla- EIWIAQELRS5IGDS5FNAYYA-CONH2 (FITC-BIM SAHB), where S5 represents the non-natural amino acid inserted for olefin metathesis. The FITC-BIM SAHB peptide was synthesized and purified at >95% purity (CPC Scientific Inc.). The Kd value was determined by fluorescence polarization direct binding assay in a 96-well plate (Corning Cat# 3915). Reactions were performed in 150 µL at ~21 ºC in buffer consisting of 50 mM Tris/HCl, pH 7.5, 150 mM NaCl, 1 mM DTT. Assays contained 25 nM FITC-BIM SAHB and 2-fold serial dilution of full-length human BAX protein starting at 2 µM. The FP was measured on an Infinite M1000 (TECAN) plate reader. Excitation and emission wavelengths were 470 nm and 525 nm, respectively. Subsequently, the FP competitive assay was performed in 96-well plates (Corning Cat# 3915) and run in two sets of plates in the presence and absence of BAX protein. In the assay, 8-dose response with 3-fold serial dilution of small molecule compounds starting at 5 µM was incubated with 25 nM FITC- BIM SAHB and 150 nM BAX protein. Each assay consisted of two replicate wells at each of 8 test compound concentrations, and 8-dose response IC50 of Gav2-006 was included in every screening as a positive control. Reaction was incubated at room temperature for 15 to 20 minutes before reading on a plate reader Infinite M1000 (TECAN) with the MIN (5 µM Gav2-006 as the positive control) and the MAX (DMSO as the negative control) in each plate. IC50 values were calculated by nonlinear regression analysis of competitive binding curves using Graphpad Prism version 9.3.1software or CDD Vault. The percentage inhibition is based on the following calculation: % inhibition = [(MAX (DMSO) - Compound)/(Max (DMSO) - MIN (5 µM BTSA1.2))]*100 The IC50 values of the compounds tested were determined to be about 100 nM to about 10,000 nM. Other Embodiments Various modifications and variations of the described compositions, methods, and uses of the invention will be apparent to those skilled in the art without departing from the scope and spirit of the invention. Although the invention has been described in connection with specific embodiments, it should be understood that the invention as claimed should not be unduly limited to such specific embodiments. Indeed, various modifications of the described modes for carrying out the invention that are obvious to those skilled in the art are intended to be within the scope of the invention. Other embodiments are in the claims.

Claims

What is claimed is: CLAIMS 1. A compound of formula (I):

or a pharmaceutically acceptable salt thereof, wherein A is N or CH; R^1a and R^1b are independently H; halo; C₁-C₆ alkyl optionally substituted with one or more groups independently selected from OH, halo, and COORa, wherein Ra is H or C₁-C₆ alkyl; or C₃-C₈ cycloalkyl, provided that at least one of R^1a and R^1b is not H; or R^1a and R^1b, together with the atoms to which each is attached, combine to form C₃-C₈ cycloalkyl

, wherein R^b is H or C₁-C₆ alkyl; each of R^2a, R^2b, R^2c, R^2d, and R^2e is independently selected from H, halo, and OCH₃; each of R^3a, R^3b, R^3c, R^3d, and R^3e is independently selected from H, halo, OH, OCH₃, COOH, and CH₂COOH; and R⁴ is H or CH₃; provided that: (i) when R^1a and R^1b are both CH₃; each of R^2a, R^2b, R^2c, R^2d; R^2e is H; R⁴ is H; (a) A is N; and each of R^3a, R^3b, R^3d, and R^3e is H; R^3c is not H, F, or COOH; and (b) A is CH; and each of R^3a, R^3b, R^3d, and R^3e is H; R^3c is not F; (ii) when R^1a and R^1b are both CH₃; A is N; and each of R^2a, R^2b, R^2d, R^2e, R^3a, R^3b, R^3c, R^3d; R^3e is H; and R⁴ is H; R^2c is not H, halo, or OCH₃; (iii) when A is N, each of R^2a, R^2b, R^2c, R^2d, R^2e, R^3a, R^3b, R^3c, R^3d, and R^3e is H; R⁴ is H; and (a) R^1a is COOCH₃, R^1b is not H, CH(CH₃)₂, or (CH₂)2CH₃; (b) R^1a is H, R^1b is not F, Cl, CH₃, CH₂Cl, or COOH; (c) R^1a is CH₃, R^1b is not CH₃ or COOH; (d) R^1b is H, R^1a is not F, CH(CH₃)₂, C(CH₃)₃, COOH, cyclopropyl, or CH₂OH; and (e) R^1a and R^1b, together with the atoms to which each is attached, do not form cyclohexyl

(iv) when A is N, each of R^2a, R^2b, R^2c, R^2e, R^3a, R^3b, R^3d, and R^3e is H; R^3c is COOH; R⁴ is H; (a) R^2d is OCH₃, and R^1a is H or CH₃, R^1b is not CH₃; (b) R^2d is OCH₃, and R^1b is H or CH₃, R^1a is not CH₃; (c) R^2d is H, and R^1a is H, R^1b is not CH₃; and (d) R^2d is H, and R^1a is CH₃, R^1b is not H; and (v) when A is N; each of R^2a, R^2b, R^2d, R^2e, R^3a, R^3b, R^3d, and R^3e is H; R^2c is OCH₃; R^3c is F; and R⁴ is H ; R^1a and R^1b are not both CH₃.

2. The compound of claim 1, wherein A is N.

3. The compound of claim 2, wherein the compound is a compound of formula (IA):

or a pharmaceutically acceptable salt thereof.

4. The compound of any one of claims 1-3, wherein R⁴ is H.

5. The compound of any one of claims 1-3, wherein R⁴ is CH₃.

6. The compound of any one of claims 1-5, wherein R^1a is halo; C₁-C₆ alkyl substituted with one or more groups independently selected from OH, halo, and COORa; unsubstituted C₂-C₆ alkyl; or C3- C8 cycloalkyl; and R^1b is halo; C₁-C₆ alkyl optionally substituted with one or more groups independently selected from OH, halo, and COORa; or C₃-C₈ cycloalkyl.

7. The compound of any one of claims 1-6, wherein R^1b is C₁-C₆ alkyl optionally substituted with one or more groups independently selected from OH, halo, and COORa.

8. The compound of claim 7, wherein R^1b is CH₃.

9. The compound of claim 7, wherein R^1b is CH₂CH₃.

10. The compound of any one of claims 1-6, wherein R^1b is halo.

11. The compound of claim 10, wherein R^1b is Cl.

12. The compound of any one of claims 1-11, wherein R^1a is unsubstituted C₂-C₆ alkyl.

13. The compound of claim 12, wherein R^1a is CH₂CH₃, CH(CH₃)₂, C(CH₃)₃, CH₂CH(CH₃)₂, or CH₂(CH₃)₃.

14. The compound of any one of claims 1-11, wherein R^1a is C₁-C₆ alkyl substituted with one or more groups independently selected from OH, halo, and COORa.

15. The compound of claim 14, wherein R^1a is CF₃, CH₂CF₃, CH₂OH, (CH₂)2OH, CH(CH₃)CH₂OH, C(CH₃)₂CH₂OH, CH₂COOH, CH(CH₃)COOH, C(CH₃)₂COOH, or (CH₂)2COOH.

16. The compound of any one of claims 1-11, wherein R^1a is halo.

17. The compound of claim 16, wherein R^1a is Cl.

18. The compound of any one of claims 1-11, wherein R^1a is C₃-C₈ cycloalkyl.

19. The compound of claim 18, wherein R^1a is cyclopropyl.

20. The compound of any one of claims 1-5, wherein R^1b is halo; C₁-C₆ alkyl substituted with one or more groups independently selected from OH, halo, and COORa; unsubstituted C₂-C₆ alkyl; or C3- C8 cycloalkyl; and R^1a is halo; C₁-C₆ alkyl optionally substituted with one or more groups independently selected from OH, halo, and COORa; or C₃-C₈ cycloalkyl.

21. The compound of any one of claims 1-5 and 20, wherein R^1a is C₁-C₆ alkyl optionally substituted with one or more groups independently selected from OH, halo, and COORa.

22. The compound of claim 21, wherein R^1a is CH₃.

23. The compound of claim 21, wherein R^1a is CH₂CH₃.

24. The compound of any one of claims 1-5 and 20, wherein R^1a is halo.

25. The compound of claim 24, wherein R^1a is Cl.

26. The compound of any one of claims 1-5 and 20-25, wherein R^1b is unsubstituted C₂-C₆ alkyl.

27. The compound of claim 26, wherein R^1b is CH₂CH₃, CH(CH₃)₂, C(CH₃)₃, CH₂CH(CH₃)₂, or CH₂(CH₃)₃.

28. The compound of any one of claims 1-5 and 20-25, wherein R^1b is C₁-C₆ alkyl substituted with one or more groups independently selected from OH, halo, and COORa.

29. The compound of claim 28, wherein R^1b is CF₃, CH₂CF₃, CH₂OH, (CH₂)2OH, CH(CH₃)CH₂OH, C(CH₃)₂CH₂OH, CH₂COOH, CH(CH₃)COOH, C(CH₃)₂COOH, or (CH₂)2COOH.

30. The compound of any one of claims 1-5 and 20-25, wherein R^1b is halo.

31. The compound of claim 30, wherein R^1b is Cl.

32. The compound of any one of claims 1-5 and 20-25, wherein R^1b is C₃-C₈ cycloalkyl.

33. The compound of claim 32, wherein R^1b is cyclopropyl.

34. The compound of any one of claims 1-5, wherein R^1a and R^1b, together with the atoms to which each is attached, form cyclopentyl.

35. The compound of any one of claims 1-5, wherein R^1a and R^1b, together with the atoms to which each is attached, form , wherein R^b is methyl.

36. The compound of any one of claims 1-5, wherein R^1a and R^1b are independently H or C1- C6 alkyl optionally substituted with one or more groups independently selected from OH, halo, and COOR_a, provided that at least one of R^1a and R^1b is not H.

37. The compound of claim 36, wherein R^1a and R^1b are both C₁-C₆ alkyl optionally substituted with one or more groups independently selected from OH, halo, and COORa.

38. The compound of claim 36 or 37, wherein R^1a is CH₃.

39. The compound of claim 38, wherein R^1b is CH₂CH₃.

40. The compound of claim 38, wherein R^1b is CF₃.

41. The compound of claim 36 or 37, wherein R^1b is CH₃.

42. The compound of claim 41, wherein R^1a is CH₂CH₃.

43. The compound of claim 36 or 37, wherein R^1a and R^1b are both CH₂CH₃.

44. The compound of any one of claims 38-43, wherein each of R^3a, R^3b, R^3d, and R^3e is H, and R^3c is COOH.

45. The compound of claim 36 or 37, wherein R^1a and R^1b are both CH₃.

46. The compound of any one of claims 36-45, wherein each of R^3a, R^3b, R^3d, and R^3e is H, and R^3c is CH₂COOH.

47. The compound of any one of claims 36-45, wherein each of R^3b, R^3c, R^3d, and R^3e is H, and R^3a is OH.

48. The compound of any one of claims 36-45, wherein both R^3a and R^3e are Cl; and each of R^3b, R^3c, and R^3d is H.

49. The compound of any one of claims 36-45, wherein both R^3a and R^3e are Cl, both R^3b and R^3d are H, and R^3c is COOH.

50. The compound of any one of claims 36-45, wherein each of R^3a, R^3c, R^3d, and R^3e is H, and R^3b is COOH.

51. The compound of any one of claims 36-50, wherein each of R^2a, R^2b, R^2c, R^2d, and R^2e is H.

52. The compound of any one of claims 38-43, wherein each of R^2a, R^2b, R^2d, R^2e, R^3a, R^3b, R^3c, R^3d, and R^3e is H; and R^2c is OCH₃.

53. The compound of any one of claims 36-43 and 45, wherein each of R^2a, R^2b, R^2d, and R^2e, R^3a, R^3b, R^3d, and R^3e is H; R^2c is F; and R^3c is COOH.

54. The compound of any one of claims 36-43 and 45, wherein each of R^2a, R^2b, R^2d, and R^2e, R^3a, R^3b, R^3d, and R^3e is H; R^2c is OCH₃; and R^3c is COOH.

55. The compound of any one of claims 36-43 and 45, wherein each of R^2a, R^2b, R^2d, and R^2e, R^3a, R^3b, R^3d, and R^3e is H; and both R^2c and R^3c are F.

56. The compound of any one of claims 36-43 and 45, wherein each of R^2a, R^2b, R^2c, and R^2e, R^3a, R^3b, R^3d, and R^3e is H; and both R^2d and R^3c are OCH₃.

57. The compound of claim 1, wherein the compound is:

,

,

, or , or a pharmaceutically acceptable salt thereof.

58. A pharmaceutical composition comprising a compound of any one of claims 1-57 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient.

59. A method of treating cancer, comprising administering to a subject in need thereof an effective amount of a compound of any one of claims 1-57 or a pharmaceutically acceptable salt thereof.

60. The method of claim 59, wherein the pharmaceutical composition is administered in combination with is an inhibitor of B cell lymphoma 2 (BCL-2), B-cell lymphoma-extra large protein (BCL- XL), B cell lymphoma 2-like protein (BCL-w), BCL-2-related protein A1 (BFL-1), myeloid cell leukemia 1 (MCL-1), or a combination thereof.

61. The method of claim 59 or 60, wherein the cancer is a solid tumor.

62. The method of claim 59 or 60, wherein the cancer is breast cancer, skin cancer, central nervous system cancer, head and neck cancer, bladder cancer, kidney cancer, cancer of the gastrointestinal tract, lung cancer, eye cancer, genitourinary cancer, gynecologic cancer, endocrine cancer, soft tissue sarcoma, hematopoietic cancer, or neuroendocrine cancer.

63. The method of claim 62, wherein the cancer is hematopoietic cancer.

64. The method of claim 63, wherein the cancer is leukemia.

65. The method of claim 64, wherein the cancer is acute lymphoblastic leukemia, acute myeloid leukemia, chronic lymphocytic leukemia, or chronic myeloid leukemia.

66. The method of claim 65, wherein the cancer is lymphoma.

67. A method of treating a disorder associated with cancer, comprising administering to a subject in need thereof an effective amount of a compound of any one of claims 1-57 or a pharmaceutically acceptable salt thereof, wherein the disorder is malignant hypercalcemia or cervical hyperplasia.

68. A method of inducing apoptosis in cancer cells in a subject, comprising administering to the subject an effective amount of a compound of any one of claims 1-57 or a pharmaceutically acceptable salt thereof.

69. The method of claim 68, wherein the cancer cells are leukemia cells.

70. The method of claim 69, wherein the cancer cells are acute lymphoblastic leukemia cells, acute myeloid leukemia cells, chronic lymphocytic leukemia cells, or chronic myeloid leukemia cells.

71. The method of claim 68, wherein the cancer cells are solid tumor cells.

72. A method of inducing apoptosis in leukemic stem cells in a subject, comprising administering to the subject an effective amount of a compound of any one of claims 1-57 or a pharmaceutically acceptable salt thereof.

73. The method of any one of claims 59-72, wherein the method does not induce apoptosis in healthy tissue.

74. The method of any one of claims 59-73, wherein the subject is a human.