Inhibitors of human epididymis protein 4

Abstract

The present disclosure provides compounds for use in the treatment of medical disorders through the inhibition of human epididymis protein 4 (HE4).

Description

[Technical Field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit of priority to U.S. Provisional Application No. 63 / 013,227, filed April 21, 2020, the disclosure of which is incorporated herein by reference in its entirety.

[0002] The present disclosure relates to compounds for the treatment of medical disorders, and more particularly to compounds that inhibit human epididymis protein 4 (HE4). [Background technology]

[0003] Human epididymis protein 4 (HE4) was identified in the epithelium of the distal epididymis using Northern blot analysis and in situ transcript hybridization (Kirchhoff et al., 1991 Biol Reprod, 45:350-357). Subsequent studies using RNA dot blot, reverse transcription-polymerase chain reaction (RT-PCR), and Northern blot analysis suggested that HE4 RNA expression is widespread (Clauss et al., 2002 Biochem J, 368:233-242). Previous studies using comparative genomic hybridization and in silico chromosome clustering reported that human chromosome 20ql2-13.2 is consistently amplified in ovarian cancer and harbors genes that may play a causal role in disease pathogenesis. This region contains a cluster of 14 genes homologous to whey acidic protein (WAP). Among these genes, HE4 is overexpressed in ovarian and endometrial cancers and certain forms of breast cancer. HE4 protein expression is highly restricted in normal human tissues, being limited to the epithelium of the reproductive tract and the respiratory epithelium of the proximal airway. In malignant neoplasms, gene expression profiling has consistently identified HE4 upregulation in ovarian cancer (Wang et al., 1999 Gene, 229:101-108; Hough CD et al., 2000 Cancer Res, 60:6281-6287; Gilks ​​CB et al., 2005 Gynecol Oncol, 96:684-694).

[0004] In malignant tumor tissues, HE4 has been considered a biomarker for epithelial ovarian cancer (WO2007 / 081768, WO2007 / 081767, Moore RG et al., 2008 Gynecologic Oncology, 1 10:196-201, Moore RG et al., 2009 Gynecologic Oncology, 1 12:40-46). Similarly, malignant tumors of the uterine corpus are also positive for HE4 (Drapkin R et al., 2005 Cancer Res, 65:2162-2169). HE4 is also a marker for other Müllerian tumors. In cell line studies, secreted HE4 was found in ovarian or endometrial cancer cell lines (e.g., CaOV-3, ECC-1, OVCAR-3, and OVCAR5) that express endogenous HE4 RNA. Intracellular immunofluorescence studies revealed that HE4 is distributed on the cell surface and in regions of the cytoplasm, such as the endoplasmic reticulum or Golgi apparatus organelles (Drapkin R et al., 2005 Cancer Res, 65:2162-2169).

[0005] Excluding cases of carcinoma in situ and basal and squamous cell skin cancer, which are not reportable, more than 1.5 million new cases of cancer were diagnosed in 2012. There is a clear need to develop new treatments for cancer and other medical disorders. Summary of the Invention

[0006] In accordance with the objectives of the disclosed materials and methods, as embodied and generally described herein, the disclosed subject matter relates, in one aspect, to compounds that are inhibitors of human epididymis protein 4 (HE4) and their use in the treatment of medical disorders such as cancer, inflammatory disorders, or organ fibrosis.

[0007] Thus, in one aspect, a compound of formula I: [ka] or a pharmaceutically acceptable salt or derivative thereof, wherein all variables are as defined herein.

[0008] Also provided is a pharmaceutical composition comprising a compound of Formula I, or a pharmaceutically acceptable salt or derivative thereof, in a pharmaceutically acceptable carrier.

[0009] Also provided are methods for the treatment of a medical disorder, such as, for example, cancer or an inflammatory disorder, comprising administering a compound of Formula I, or a pharmaceutically acceptable salt or derivative thereof. In some embodiments, the medical disorder is one that can be treated by inhibition of HE4.

[0010] The details of one or more embodiments of the disclosure are set forth in the accompanying and following description. Other features, objects, and advantages of the disclosure will be apparent from the description and drawings, and from the claims. [Brief explanation of the drawings]

[0011] [Figure 1] 1 shows HE4 expression levels in SKOV-3 ovarian cancer cells treated with DMSO or UR238 (0.5 or 2 μM). UR238 inhibited HE4 expression in SKOV-3 cells. [Figure 2] 1 shows the levels of HE4 secreted in the medium of ECC-1 endometrial cancer cells treated with DMSO or UR238 (0.1, 1.0, or 10 μM). UR238 inhibited HE4 secretion from ECC-1 cells. [Figure 3] Figure 1 shows the tumor volume (mm3) of SKOV-3SH1 ovarian cancer cell-derived xenografts in NSG mice treated with vehicle or UR238 over the indicated monitoring days. UR238 inhibited the growth of ovarian cancer cell-derived xenografts. [Figure 4] Figure 1 shows tumor volume (mm3) of AN3CA endometrial cancer cell-derived xenografts in NSG mice treated with vehicle or UR238 over the indicated monitoring days. Ur238 inhibited the growth of endometrial cancer cell-derived xenografts. [Figure 5] 1 shows images of xenograft tumors derived from AN3CA cells in mice treated with vehicle or UR238. DETAILED DESCRIPTION OF THE INVENTION

[0012] Like reference symbols in the various drawings indicate like elements.

[0013] The following description of the present disclosure is provided as an enabling teaching of the disclosure in its best currently known embodiment. To this end, those skilled in the relevant art will recognize and understand that many changes can be made to the various embodiments of the present invention described herein while still obtaining the beneficial results of the present disclosure. It will also be apparent that some of the desired benefits of the present disclosure can be obtained by selecting some of the features of the present disclosure without utilizing other features. Accordingly, many modifications and adaptations to the present disclosure will be possible for those working in the art and may even be desirable in certain circumstances, and are a part of this disclosure. Accordingly, the following description is provided as an illustration of the principles of the present disclosure, and not as a limitation thereof.

[0014] definition Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. The following definitions are provided to provide a full understanding of terms used herein.

[0015] As used in this specification and the claims, the singular forms "a," "an," and "the" include plural references unless the context clearly indicates otherwise. For example, the term "an agent" includes a plurality of agents, including mixtures thereof.

[0016] As used herein, the terms "may," "optionally," and "optionally" are used interchangeably and are intended to encompass not only cases in which the condition does not occur, but also cases in which the condition does occur. Thus, for example, a statement that a formulation "may include an excipient" encompasses not only cases in which the formulation does not include an excipient, but also cases in which the formulation includes an excipient.

[0017] "Administration" to a subject includes any route of introducing or delivering an agent to a subject. Administration can be by any suitable route, including oral, topical, intravenous, subcutaneous, transcutaneous, transdermal, intramuscular, intraarticular, parenteral, intraarteriolar, intradermal, intraventricular, intracranial, intraperitoneal, intralesional, intranasal, rectal, vaginal, by inhalation, via an implanted reservoir, parenteral (e.g., subcutaneous, intravenous, intramuscular, intraarticular, intrasynovial, intrasternal, intrathecal, intraperitoneal, intrahepatic, intralesional, and intracranial injection or infusion techniques), and the like. As used herein, "co-administration," "administration in combination," "co-administration," or "administered simultaneously" means that compounds are administered at the same time or essentially immediately after each other. In the latter case, the two compounds are administered sufficiently close in time that the results achieved and observed are indistinguishable from those that would be achieved if the compounds were administered at the same time. "Systemic administration" refers to the introduction or delivery of an agent to a subject via a route that introduces or delivers the agent to a wide area of ​​the subject's body (e.g., more than 50% of the body), for example, through an entry point into the circulatory or lymphatic system. In contrast, "local administration" refers to the introduction or delivery of an agent to a subject via a route that introduces or delivers the agent to an area at or immediately adjacent to the point of administration, but does not introduce the agent systemically in therapeutically significant amounts. For example, a locally administered agent is readily detectable in the local vicinity of the point of administration, but is undetectable or detectable in negligible amounts in distal portions of the subject's body. Administration includes self-administration and administration by another.

[0018] As used herein, the terms "beneficial agent" and "active agent" are used interchangeably to refer to chemical compounds or compositions that have a beneficial biological effect. Beneficial biological effects include both therapeutic effects, i.e., the treatment of a disorder or other undesirable physiological condition, and prophylactic effects, i.e., the prevention of a disorder or other undesirable physiological condition. These terms also encompass pharmaceutically acceptable, pharmacologically active derivatives of the beneficial agents specifically named herein, including, but not limited to, salts, esters, amides, prodrugs, active metabolites, isomers, fragments, analogs, and the like. When the term "beneficial agent" or "active agent" is used, or when a particular agent is specifically identified, it is understood that the term includes the agent itself as well as pharmaceutically acceptable, pharmacologically active salts, esters, amides, prodrugs, conjugates, active metabolites, isomers, fragments, analogs, and the like.

[0019] As used herein, the term "treating" or "treatment" of a subject includes the administration of a drug to a subject with the intent to cure, heal, alleviate, relieve, alter, repair, ameliorate, improve, stabilize, or affect a disease or disorder, or the symptoms of a disease or disorder. The terms "treating" and "treatment" also refer to the reduction in severity and / or frequency of symptoms, elimination of symptoms and / or underlying causes, and amelioration or repair of damage.

[0020] As used herein, the term "preventing" a disorder or unwanted physiological event in a subject specifically refers to preventing the occurrence of symptoms and / or underlying causes, and the subject may or may not exhibit an increased susceptibility to the disease or event.

[0021] The term "effective amount" of a therapeutic agent refers to a non-toxic but sufficient amount of a beneficial agent to provide a desired effect. The amount of a beneficial agent that is "effective" will vary from subject to subject, depending on the subject's age and general condition, as well as the particular beneficial agent or agents. Therefore, it is not always possible to specify an exact "effective amount." However, an appropriate "effective amount" for any given subject may be determined by one of ordinary skill in the art using routine experimentation. Furthermore, as used herein, unless otherwise specifically stated, the "effective amount" of a beneficial agent can also refer to an amount that covers both a therapeutically effective amount and a prophylactically effective amount.

[0022] The "effective amount" of a drug required to achieve a therapeutic effect may vary depending on factors such as the age, sex, and weight of the subject. Dosage regimens may be adjusted to provide the optimal therapeutic response. For example, several divided doses may be administered daily or the dose may be proportionally reduced as indicated by the exigencies of the therapeutic situation.

[0023] As used herein, a "therapeutically effective amount" of a therapeutic agent refers to an amount effective to achieve a desired therapeutic result, and a "prophylactically effective amount" of a therapeutic agent refers to an amount effective to prevent an undesirable physiological condition. The therapeutically and prophylactically effective amounts of a given therapeutic agent will typically vary with respect to factors such as the type and severity of the disorder or disease being treated, as well as the age, sex, and weight of the subject. The term "therapeutically effective amount" can also refer to the amount of therapeutic agent or the rate of release of therapeutic agent (e.g., amount over time) effective to promote a desired therapeutic effect. The exact desired therapeutic effect will vary depending on the condition to be treated, the subject's tolerance, the drug and / or drug formulation to be administered (e.g., potency of the therapeutic agent (drug), concentration of the drug in the formulation, etc.), and various other factors recognized by those skilled in the art.

[0024] As used herein, with respect to the term "pharmaceutically acceptable," a "pharmaceutically acceptable" component can refer to a component that is not biologically or otherwise undesirable. That is, the component can be included in the pharmaceutical formulations of the present invention and administered to a subject as described herein without causing any significant undesirable biological effects and without adversely interacting with any other components in the formulation in which it is included. When the term "pharmaceutically acceptable" is used to refer to an excipient, it generally implies that the component has met the required standards in toxicological and manufacturing testing or that the component is listed in the Inactive Ingredients Guide prepared by the U.S. Food and Drug Administration.

[0025] A "pharmaceutically acceptable carrier" (sometimes referred to as a "carrier") refers to a carrier or excipient that is generally safe and non-toxic and useful in preparing pharmaceutical or therapeutic compositions, and includes carriers that are acceptable for veterinary and / or human pharmaceutical or therapeutic use. The term "carrier" or "pharmaceutically acceptable carrier" can include, but is not limited to, phosphate buffered saline, water, emulsions (such as oil / water emulsions or water / oil emulsions), and / or various types of wetting agents. As used herein, the term "carrier" encompasses, but is not limited to, any excipient, diluent, filler, salt, buffer, stabilizer, solubilizer, lipid, stabilizer, or other material that is well known in the art for use in pharmaceutical formulations and as further described herein.

[0026] As used herein, "pharmaceutically acceptable salts" refer to derivatives of the disclosed compounds in which the parent compound is modified by making its inorganic and organic non-toxic acid or base addition salts. Salts of the present compounds can be synthesized from parent compounds containing a basic or acidic moiety by conventional chemical methods. Generally, such salts can be prepared by reacting the free acid forms of these compounds with a stoichiometric amount of an appropriate base (e.g., hydroxide, carbonate, bicarbonate, etc. of Na, Ca, Mg, or K), or by reacting the free base forms of these compounds with a stoichiometric amount of an appropriate acid. Such reactions are typically carried out in water or an organic solvent, or a mixture of the two. Generally, non-aqueous media such as ether, ethyl acetate, ethanol, isopropanol, or acetonitrile are typical, where feasible. Salts of the present compounds also include solvates of the compounds and salts of the compounds.

[0027] Examples of pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic residues such as amines; alkali or organic salts of acidic residues such as carboxylic acids; etc. Pharmaceutically acceptable salts include the conventional non-toxic salts and the quaternary ammonium salts of the parent compound formed, for example, from non-toxic inorganic or organic acids. For example, salts of conventional non-toxic acids include salts derived from inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, sulfamic acid, phosphoric acid, and nitric acid, as well as salts derived from acetic acid, propionic acid, succinic acid, glycolic acid, stearic acid, lactic acid, malic acid, tartaric acid, citric acid, ascorbic acid, pamoic acid, maleic acid, hydroxymaleic acid, phenylacetic acid, glutamic acid, benzoic acid, salicylic acid, mesylic acid, esylic acid, besylic acid, sulfanilic acid, 2-acetoxybenzoic acid, fumaric acid, toluenesulfonic acid, methanesulfonic acid, ethanedisulfonic acid, oxalic acid, isethionic acid, HOOC-(CH2) nIncluded are salts prepared from organic acids such as —COOH, where n is 0 to 4, or salts using a different acid that produces the same counterion. Additional suitable salts can be found, for example, in Remington's Pharmaceutical Sciences, 17th ed., Mack Publishing Company, Easton, Pa., p. 1418 (1985).

[0028] Also, as used herein, the term "pharmacologically active" (or simply "active"), as in the expression "pharmacologically active" derivative or analog, can refer to a derivative or analog (e.g., a salt, ester, amide, conjugate, metabolite, isomer, fragment, etc.) that has the same type of pharmacological activity as the parent compound and is approximately equivalent in extent to that activity.

[0029] As used herein, the term "subject" or "host" refers to an organism such as a mammal, including, but not limited to, humans, livestock, dogs, cats, and other mammals. Therapeutic agents can be administered at dosages and for periods of time effective to treat the subject. In some embodiments, the subject is a human.

[0030] chemical definition As used herein, the term "composition" is intended to encompass a product containing the specified ingredients in the specified amounts, as well as any product resulting directly or indirectly from combining the specified ingredients in the specified amounts.

[0031] References in this specification and the concluding claims to parts by weight of a particular element or component in a composition indicate the weight relationship between the element or component and any other element or component in the composition or article to which the parts by weight are expressed. Thus, in a mixture containing 2 parts by weight of component X and 5 parts by weight of component Y, X and Y are present in a weight ratio of 2:5, and are present in such ratio regardless of whether additional components are included in the mixture.

[0032] Weight percent (wt %) of a component is based on the total weight of the formulation or composition in which the component is included, unless specifically stated to the contrary.

[0033] As used herein, the term "substituted" is intended to include all permissible substituents of organic compounds. In a broad aspect, the permissible substituents include acyclic and cyclic, branched and unbranched, carbocyclic and heterocyclic, and aromatic and nonaromatic substituents of organic compounds. Illustrative substituents include, for example, those described below. The permissible substituents can be one or more and the same or different for appropriate organic compounds. For purposes of this disclosure, heteroatoms such as nitrogen can have hydrogen substituents and / or any permissible substituents for organic compounds described herein that satisfy the valences of the heteroatoms. The present invention is not limited in any manner by the permissible substituents of organic compounds. Additionally, the terms "substituted" or "substituted with" include the implicit proviso that such substitution is subject to the permissible valences of the substituted atom and substituent, and that substitution results in a stable compound, e.g., a compound that does not undergo spontaneous transformation by rearrangement, cyclization, elimination, and the like.

[0034] The term "aliphatic," as used herein, refers to a non-aromatic hydrocarbon group, and includes branched and unbranched alkyl, alkenyl, or alkynyl groups.

[0035] The term "alkyl" as used herein refers to a branched or unbranched saturated hydrocarbon group of 1 to 24 carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, t-butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, dodecyl, tetradecyl, hexadecyl, eicosyl, tetracosyl, etc. Alkyl groups can also be substituted or unsubstituted. Alkyl groups can be substituted with one or more groups, including, but not limited to, alkyl, alkyl halide, alkoxy, alkenyl, alkynyl, aryl, heteroaryl aldehyde, amino, carboxylic acid, ester, ether, halide, hydroxy, ketone, nitro, silyl, sulfo-oxo, sulfonyl, sulfone, sulfoxide, or thiol, as described below. As used herein, "perfluoroalkyl" refers to an alkyl group, as described herein, in which each hydrogen substituent on the group is replaced with a fluorine atom. Representative, but non-limiting, examples of "perfluoroalkyl" groups include trifluoromethyl, pentafluoroethyl, or heptadecafluorooctyl.

[0036] Symbol A n is used herein merely as a generic substituent in the definitions below.

[0037] The term "alkoxy" as used herein refers to an alkyl group attached through a single, terminal ether linkage, i.e., an "alkoxy" group is -OA 1 (In the formula, A 1 is as defined above).

[0038] The term "alkenyl," as used herein, refers to a hydrocarbon group of 2 to 24 carbon atoms with a structural formula containing at least one carbon-carbon double bond. 1 A 2 )C=C(A 3 A 4Asymmetric structures, such as alkene, are intended to include both the E and Z isomers. This can be inferred in structural formulas herein where an asymmetric alkene is present, or can be explicitly indicated by the bond symbol C=C. The alkenyl group can be substituted with one or more groups, including, but not limited to, alkyl, alkyl halide, alkoxy, alkenyl, alkynyl, aryl, heteroaryl aldehyde, amino, carboxylic acid, ester, ether, halide, hydroxy, ketone, nitro, silyl, sulfo-oxo, sulfonyl, sulfone, sulfoxide, or thiol, as described below.

[0039] The term "alkynyl," as used herein, refers to a hydrocarbon group of 2 to 24 carbon atoms with a structural formula containing at least one carbon-carbon triple bond. The alkynyl group can be substituted with one or more groups, including, but not limited to, alkyl, alkyl halide, alkoxy, alkenyl, alkynyl, aryl, heteroaryl, aldehyde, amino, carboxylic acid, ester, ether, halide, hydroxy, ketone, nitro, silyl, sulfo-oxo, sulfonyl, sulfone, sulfoxide, or thiol, as described below.

[0040] The term "aryl," as used herein, refers to a group containing any carbon-based aromatic group, including, but not limited to, benzene, naphthalene, phenyl, biphenyl, phenoxybenzene, and the like. The term "heteroaryl" is defined as a group containing an aromatic group with at least one heteroatom incorporated within the ring of the aromatic group. Examples of heteroatoms include, but are not limited to, nitrogen, oxygen, sulfur, and phosphorus. The term "non-heteroaryl," included within the term "aryl," defines a group containing an aromatic group that does not contain a heteroatom. Aryl and heteroaryl groups can be substituted or unsubstituted. Aryl and heteroaryl groups can be substituted with one or more groups, including, but not limited to, alkyl, alkyl halide, alkoxy, alkenyl, alkynyl, aryl, heteroaryl aldehyde, amino, carboxylic acid, ester, ether, halide, hydroxy, ketone, nitro, silyl, sulfo-oxo, sulfonyl, sulfone, sulfoxide, or thiol, as described below. The term "biaryl" is a specific type of aryl group and is included in the definition of aryl. Biaryl refers to two aryl groups that are bonded together through a fused ring structure, as in naphthalene, or linked through one or more carbon-carbon bonds, as in biphenyl.

[0041] The term "cycloalkyl" as used herein refers to a non-aromatic carbon-based ring composed of at least three carbon atoms. Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, etc. The term "heterocycloalkyl" refers to a cycloalkyl group as defined above in which at least one of the ring carbon atoms is replaced with a heteroatom, including, but not limited to, nitrogen, oxygen, sulfur, or phosphorus. Cycloalkyl and heterocycloalkyl groups can be substituted or unsubstituted. Cycloalkyl and heterocycloalkyl groups can be substituted with one or more groups, including, but not limited to, alkyl, alkoxy, alkenyl, alkynyl, aryl, heteroaryl aldehyde, amino, carboxylic acid, ester, ether, halide, hydroxy, ketone, nitro, silyl, sulfo-oxo, sulfonyl, sulfone, sulfoxide, or thiol, as described below.

[0042] The term "cycloalkenyl," as used herein, refers to a non-aromatic carbon-based ring composed of at least three carbon atoms and containing at least one double bond, i.e., C=C. Examples of cycloalkenyl groups include, but are not limited to, cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclopentadienyl, cyclohexenyl, cyclohexadienyl, and the like. The term "heterocycloalkenyl" refers to certain cycloalkyl groups, as defined above, in which at least one of the ring carbon atoms is replaced with a heteroatom, including, but not limited to, nitrogen, oxygen, sulfur, or phosphorus. Cycloalkenyl and heterocycloalkenyl groups can be substituted or unsubstituted. The cycloalkenyl and heterocycloalkenyl groups may be substituted with one or more groups, including, but not limited to, alkyl, alkoxy, alkenyl, alkynyl, aryl, heteroaryl aldehyde, amino, carboxylic acid, ester, ether, halide, hydroxy, ketone, nitro, silyl, sulfo-oxo, sulfonyl, sulfone, sulfoxide, or thiol, as described below.

[0043] The term "cyclic group" is used herein to refer to either aryl groups, non-aryl groups (i.e., cycloalkyl, heterocycloalkyl, cycloalkenyl, and heterocycloalkenyl groups), or both. Cyclic groups have one or more ring systems that can be substituted or unsubstituted. A cyclic group can contain one or more aryl groups, one or more non-aryl groups, or one or more aryl groups and one or more non-aryl groups.

[0044] The term "aldehyde" as used herein is represented by the formula -C(O)H. Throughout this specification, "C(O)" is a shorthand notation for C=O.

[0045] As used herein, the term "amine" or "amino" refers to a group of the formula NA 1 A 2 A 3 wherein A 1 , A2 , and A 3 can independently be an alkyl, halogenated alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, or heterocycloalkenyl group as described above.

[0046] The term "carboxylic acid" as used herein is represented by the formula -C(O)OH. The term "carboxylate" as used herein is represented by the formula -C(O)O - is expressed by

[0047] As used herein, the term "ester" refers to an ester of the formula -OC(O)A 1 or -C(O)OA 1 wherein A 1 can be an alkyl, halogenated alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, or heterocycloalkenyl group as described above.

[0048] As used herein, the term "ether" refers to a group of the formula A 1 Office Automation 2 wherein A 1 and A 2 can independently be an alkyl, halogenated alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, or heterocycloalkenyl group as described above.

[0049] As used herein, the term "ketone" refers to a compound of formula A 1 C(O)A 2 wherein A 1 and A 2 can independently be an alkyl, halogenated alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, or heterocycloalkenyl group as described above.

[0050] As used herein, the term "halide" refers to the halogens fluorine, chlorine, bromine, and iodine.

[0051] The term "hydroxyl" as used herein is represented by the formula --OH.

[0052] The term "nitro" as used herein is represented by the formula --NO.sub.2.

[0053] The term "cyano" as used herein is represented by the formula --CN.

[0054] The term "azide" as used herein is represented by the formula --N3.

[0055] The term "sulfonyl" refers to a group of the formula -S(O)A 1 wherein A 1 can be hydrogen, an alkyl, halogenated alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, or heterocycloalkenyl group as described above.

[0056] The term "sulfonylamino" or "sulfonylamido" as used herein is represented by the formula --S(O)2NH2.

[0057] The term "thiol" as used herein is represented by the formula --SH.

[0058] It should be understood that the compounds provided herein may contain chiral centers. Such chiral centers may be of either the (R-) or (S-) configuration. The compounds provided herein may be enantiomerically pure or may be either diastereomeric or enantiomeric mixtures. It should be understood that the chiral centers of the compounds provided herein may undergo epimerization in vivo. Thus, one skilled in the art will recognize that administration of a compound in its (R-) form is equivalent to administration of a compound in its (S-) form, for compounds that undergo epimerization in vivo.

[0059] As used herein, substantially pure means sufficiently homogeneous to appear free of readily detectable impurities as determined by standard methods such as thin layer chromatography (TLC), nuclear magnetic resonance (NMR), gel electrophoresis, high performance liquid chromatography (HPLC) and mass spectrometry (MS), gas chromatography-mass spectrometry (GC-MS), and the like used by those skilled in the art to assess such purity, or sufficiently pure that further purification does not detectably alter the physical and chemical properties, such as enzymatic and biological activity, of the substance. Both traditional and modern methods of purifying compounds to produce substantially chemically pure compounds are known to those skilled in the art. However, a substantially chemically pure compound may be a mixture of stereoisomers.

[0060] Unless otherwise specified, formulas having chemical bonds shown only with solid lines, and not as wedges or dotted lines, contemplate each possible isomer, e.g., each enantiomer, diastereomer, and meso compound, as well as mixtures of isomers, such as racemic or scalemic mixtures.

[0061] compound In one embodiment, a compound of formula I [ka] or a pharmaceutically acceptable salt or derivative thereof, During the ceremony, X is O, -CH2-, N(R 6 ), and S; Y is selected from S, S(=Z), and S(=Z)2; Z is O, S, and NR 7 is selected from m, n, and o are independently 0 or 1; R 1 is H or C1-C6 alkyl, R 2 , R 3 , R 4 , and R 5 is independently, at each occurrence, selected from H, C-C alkyl, aryl(C-C alkyl), and heteroaryl(C-C alkyl), 2 , R 3 , R 4 , and R 5 each of which may be optionally substituted with one or more substituents as defined herein; R 6 is selected from H or C1-C6 alkyl; R 7 is H, optionally substituted C1-C6 alkyl, optionally substituted aryl, optionally substituted heteroaryl, -OR 8 and -NR 9 R 10 is selected from R 8 is selected from H, optionally substituted C1-C6 alkyl, optionally substituted aryl, and optionally substituted heteroaryl; R 9 and R 10 are each independently at each occurrence selected from H, optionally substituted C1-C6 alkyl, optionally substituted aryl, and optionally substituted heteroaryl.

[0062] In some embodiments of Formula I, X is O. In some embodiments of Formula I, X is -CH-. In some embodiments of Formula I, X is N(R 6 ), for example, NH or N(CH). In some embodiments of Formula I, X is S.

[0063] In some embodiments of Formula I, Y is S. In some embodiments of Formula I, Y is S(=Z), e.g., S(=O) or S(=NR 7 In some embodiments of Formula I, Y is S(=Z)2, e.g., S(=O)2 or S(=NR 7 )2.

[0064] In some embodiments of Formula I, m, n, and o are each 0. In some embodiments of Formula I, m and o are each 0 and n is 1. In some embodiments of Formula I, m is 0 and n and o are each 1. In some embodiments of Formula I, m is 1 and n and o are each 0. In some embodiments of Formula I, m and o are each 1 and n is 0. In some embodiments of Formula I, m and n are each 1 and o is 0. In some embodiments of Formula I, m, n, and o are each 1.

[0065] In some embodiments of Formula I, R 1 is hydrogen. In some embodiments of Formula I, R 1 is C1-C6 alkyl, for example, methyl, ethyl, n-propyl, or isopropyl. 1 is methyl.

[0066] In some embodiments of Formula I, R 2 is hydrogen. In some embodiments of Formula I, R 2 is C1-C6 alkyl, for example, methyl, ethyl, n-propyl, isobutyl, n-butyl, sec-butyl, or isobutyl. In some embodiments of Formula I, R 2 is isobutyl. In some embodiments of Formula I, R 2is aryl(C0-C6 alkyl), for example, phenyl, benzyl, or 2-phenylethyl. In some embodiments of Formula I, R 2 is benzyl. In some embodiments of Formula I, R 2 is 2-phenylethyl. In some embodiments of Formula I, R 2 is heteroaryl(C0-C6 alkyl).

[0067] In some embodiments of Formula I, R 3 is hydrogen. In some embodiments of Formula I, R 3 is C1-C6 alkyl, for example, methyl, ethyl, n-propyl, isobutyl, n-butyl, sec-butyl, or isobutyl. In some embodiments of Formula I, R 3 is isobutyl. In some embodiments of Formula I, R 2 is aryl(C0-C6 alkyl), for example, phenyl, benzyl, or 2-phenylethyl. In some embodiments of Formula I, R 3 is benzyl. In some embodiments of Formula I, R 3 is 2-phenylethyl. In some embodiments of Formula I, R 3 is heteroaryl(C0-C6 alkyl).

[0068] In some embodiments of Formula I, R 4 is hydrogen. In some embodiments of Formula I, R 4 is C1-C6 alkyl, for example, methyl, ethyl, n-propyl, isobutyl, n-butyl, sec-butyl, or isobutyl. In some embodiments of Formula I, R 4 is isobutyl. In some embodiments of Formula I, R 4 is aryl(C0-C6 alkyl), for example, phenyl, benzyl, or 2-phenylethyl. In some embodiments of Formula I, R 4 is benzyl. In some embodiments of Formula I, R 4 is 2-phenylethyl. In some embodiments of Formula I, R 4is heteroaryl(C0-C6 alkyl).

[0069] In some embodiments of Formula I, R 5 is hydrogen. In some embodiments of Formula I, R 5 is C1-C6 alkyl, for example, methyl, ethyl, n-propyl, isobutyl, n-butyl, sec-butyl, or isobutyl. In some embodiments of Formula I, R 5 is isobutyl. In some embodiments of Formula I, R 5 is aryl(C0-C6 alkyl), for example, phenyl, benzyl, or 2-phenylethyl. In some embodiments of Formula I, R 5 is benzyl. In some embodiments of Formula I, R 5 is 2-phenylethyl. In some embodiments of Formula I, R 5 is heteroaryl(C0-C6 alkyl).

[0070] In some embodiments, the compound of formula I is a compound of formula II [ka] or a pharmaceutically acceptable salt or derivative thereof, wherein all variables are as defined herein.

[0071] In some embodiments, the compound of formula I is a compound of formula III [ka] or a pharmaceutically acceptable salt or derivative thereof, wherein all variables are as defined herein.

[0072] In some embodiments, the compound of Formula I is a compound of Formula Ia, Formula Ib, Formula Ic, or Formula Id: [ka] or a pharmaceutically acceptable salt or derivative thereof, wherein all variables are as defined herein.

[0073] In some embodiments, the compound of Formula I is a compound of Formula IIa, Formula IIb, Formula IIc, or Formula IId: [ka] or a pharmaceutically acceptable salt or derivative thereof, wherein all variables are as defined herein.

[0074] In some embodiments, the compound of Formula I is a compound of Formula IIIa, Formula IIIb, Formula IIIc, or Formula IIId: [ka] or a pharmaceutically acceptable salt or derivative thereof, wherein all variables are as defined herein.

[0075] Representative examples of compounds of formula I include: [ka] [ka]

[0076] Treatment method Ongoing research suggests that overexpression of HE4 leads to increased surface expression of PD-L1 on tumor cells and macrophages, which, together with other immunosuppressive factors, creates an immunosuppressive environment that allows tumors to evade the immune system. Further studies have shown that in ovarian tumors, increased HE4 expression correlates with decreased numbers of CD8+ T-cell lymphocytes, and that targeting HE4 reduces PD-L1 expression on tumor cells both in vitro and in vivo. T-cell lymphocyte infiltration has been shown to be an indicator of the host's immune response to tumors and often correlates with a favorable prognosis (Clemente et al., 1996 Cancer, 77:1303-10; Schumacher et al., 2001 Cancer Res, 61:3932-6). In ovarian cancer, infiltration of CD3+ T lymphocytes correlates with prolonged progression-free survival and overall survival (Zhang et al., N Eng J Med 2003, 348:203-13). Further studies confirmed these findings, and in particular, that CD8+ tumor-infiltrating lymphocytes correlate with better prognosis and prolonged survival (Sato et al., Proc Natl Acad Sci USA 2005, 102:18538-43; Clarke et al., Mod Pathol 2009, 22:393-402; Hwang et al., Gyncol Oncol 2012, 124:192-8). The immune checkpoint inhibitor programmed cell death 1 ligand 1 (PD-L1; GenBank: NP_001254635) has also been shown to have a prognostic impact in ovarian cancer (Hamanishi et al., Proc Natl Acad Sci USA 2007, 104:3360-5). It is expressed on various adaptive immune effectors in the ovarian tumor microenvironment, including CD8 and CD4 cells, and it negatively regulates cell activation.Local immunosuppression is mediated by myeloid-derived dendritic cells via PD-1 / PD-L1 and by the production of immunosuppressive mediators such as arginase, indoleamine 2,3-dioxygenase, nitric oxide, and reactive oxygen species (Charbonneau et al., Crit Rev Immunol. 2013;33(2):137-164). In ovarian cancer, PD-1 / PD-L1 is the dominant immunosuppressive mechanism by inhibiting the antitumor activity of T cells. However, PD-1 blockade only results in a partial antitumor effect due to the release of immunoregulatory cytokines such as IL-10, IL-6, and G-CSF (Kirchhoff et al., Biol Reprod 1991,45:350-357). Understanding the mechanisms of immunosuppression may provide clues for improving ovarian cancer treatment. Targeting HE4 results in a reduction of the immunosuppressive tumor microenvironment and restores the host's anti-tumor immune response, and thus targeting HE4 may result in eradication of established tumors by reactivating the host's immune system and / or removing the immune system breach imposed by upregulation of PD-L1.

[0077] Thus, in one aspect, there is provided a method for treating cancer in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound described herein, or a pharmaceutically acceptable salt or derivative thereof.

[0078] Exemplary cancers that can be treated using the compounds of the present disclosure include "Müllerian cancer." As used herein, "Müllerian cancer" or "Müllerian-derived tumor" refers to any cancer arising from any part of the female reproductive system, including, but not limited to, the uterus, fallopian tubes, ovaries, and / or other malignant tumors of the female reproductive system. In some embodiments, the term Müllerian cancer refers to ovarian cancer, fallopian tube cancer, primary peritoneal cancer, endometrial cancer, and uterine cancer, including all of their associated histological subtypes, including, but not limited to, serous carcinoma, endometrioid carcinoma, clear cell carcinoma, undifferentiated carcinoma, poorly differentiated carcinosarcoma (MMMT), sarcoma germ cell tumor, and sex cord-stromal tumor.

[0079] Carcinomas are cancers of epithelial origin. Carcinomas contemplated for treatment by the methods of the present invention include acinar carcinoma, lobular carcinoma, follicular adenocarcinoma, carcinoma adenomatous, adenocarcinoma, adrenocortical carcinoma, alveolar carcinoma, alveolar cell carcinoma, basal cell carcinoma, carcinoma basocellular, basoid carcinoma, basosquamous cell carcinoma, breast carcinoma, bronchioloalveolar carcinoma, bronchiolar carcinoma, cerebriform carcinoma, cholangiocarcinoma, choriocarcinoma, mucinous carcinoma, colloid carcinoma, comedocarcinoma, corpus carcinoma, cribriform carcinoma, armored carcinoma, skin carcinoma, cylindrical carcinoma, columnar cell carcinoma, ductal carcinoma, carcinoma durum, embryonal carcinoma, medullary carcinoma, supraocular carcinoma, epidermoid carcinoma, epithelial adenocarcinoma epitheliate adenoids, ulcer carcinoma, carcinoma fibrosum, gelatinous carcinoma, colloid carcinoma, giant cell carcinoma, giant cell carcinoma, adenocarcinoma, granulosa cell carcinoma, pilomatrix carcinoma, hematoid carcinoma, hepatocellular carcinoma, Hürthle cell carcinoma, hyaline carcinoma, hypernephroid carcinoma, infantile embryonal carcinoma, carcinoma in situ, carcinoma in epidermis, intraepithelial carcinoma, Krompecher's carcinoma, Kulchitzky-cell carcinoma, lentivular carcinoma, carcinoma lenticulare, lipomatous carcinoma, lymphoepithelial carcinoma, carcinoma mastotoids, medullary carcinoma medullary carcinoma, medullary carcinoma, melanoma melanodes, melanotonic carcinomacarcinoma, mucinous carcinoma, carcinoma muciparum, carcinoma mucocullare, mucosal carcinoma, myxomatous carcinoma, nasopharyngeal carcinoma, carcinoma nigrum, oat cell carcinoma, carcinoma ossificans, osteoid carcinoma, ovarian cancer, papillary carcinoma, periportal carcinoma, preinvasive carcinoma, prostate cancer, renal cell carcinoma of the kidney, renal cell carcinoma, sarcomatoid carcinoma, Schneiderian carcinoma, scirrhous carcinoma, scrotal carcinoma, signet ring cell carcinoma, simplex carcinoma, small cell carcinoma, solandoid carcinoma These include, but are not limited to, spheroid cell carcinoma, spindle cell carcinoma, cavernous carcinoma, squamous cell carcinoma, squamous cell carcinoma, string carcinoma, carcinoma telangiectaticum, carcinoma telangiectodes, transitional cell carcinoma, carcinoma tuberrosum, tuberous carcinoma, verrucous carcinoma, and choriocarcinoma.

[0080] The present invention also provides methods and agents for treating sarcoma. Sarcoma is a rare mesenchymal neoplasm that occurs in bone and soft tissue. Different types of sarcoma are recognized, including liposarcoma (including myxoid liposarcoma and pleomorphic liposarcoma), leiomyosarcoma, rhabdomyosarcoma, neurofibrosarcoma, malignant peripheral nerve sheath tumor, Ewing's sarcoma (including skeletal, extraskeletal, or non-skeletal Ewing's sarcoma), primitive neuroectodermal tumor (PNET), synovial sarcoma, hemangioendothelioma, fibrosarcoma, desmoid tumor, dermatofibrosarcoma protuberans (DFSP), malignant fibrous histiocytoma (MFH), hemangiopericytoma, malignant mesenchymoma, alveolar soft part sarcoma, epithelioid sarcoma, clear cell sarcoma, desmoplastic small cell tumor, gastrointestinal stromal tumor (GIST), osteosarcoma (also known as osteogenic sarcoma) (skeletal and extraskeletal), and chondrosarcoma.

[0081] Optionally, the cancer being treated is a refractory or responsive cancer. As used herein, a refractory cancer is a cancer that is resistant to the usual standard of care prescribed. These cancers may initially respond to treatment but recur and / or fail to respond to treatment at all. The present invention can also be used to treat immunogenic cancers. Exemplary immunogenic cancers include melanoma and renal cell carcinoma, mantle cell lymphoma, follicular lymphoma, diffuse large B-cell lymphoma, T-cell acute lymphoblastic leukemia, Burkitt's lymphoma, myeloma, immunocytoma, acute promyelocytic leukemia, chronic myeloid / acute lymphoblastic leukemia, acute leukemia, B-cell acute lymphoblastic leukemia, anaplastic large cell leukemia, myelodysplastic syndrome / acute myeloid leukemia, non-Hodgkin's lymphoma, chronic lymphocytic leukemia, acute myeloid leukemia (AML), common (pre-B) acute lymphoblastic leukemia, melanoma, T-cell lymphoma, leukemia, B-cell lymphoma, carcinomas, lymphoid malignancies, gynecological cancers, biliary adenocarcinoma, and ductal adenocarcinoma.

[0082] The present disclosure also provides a method for inhibiting angiogenesis in a subject, comprising administering a therapeutically effective amount of a compound described herein, or a pharmaceutically acceptable salt or derivative thereof. Angiogenesis, the rapid proliferation of epithelial cells that leads to the formation of new blood vessels, supports tumor progression and survival. As a secondary effect, angiogenesis can damage various organs and tissues, including the eyes, skin, heart, blood vessels, lungs, gastrointestinal tract, and genitourinary tract. Methods and techniques for assessing angiogenesis are known to those skilled in the art.

[0083] Also provided are methods for inhibiting tumor cell growth in a subject in need thereof, comprising administering a therapeutically effective amount of a compound described herein, or a pharmaceutically acceptable salt thereof. In some embodiments, tumor cell growth is suppressed or inhibited by inhibiting the activity of HE4 levels in tumor cells.

[0084] Also provided is a method for sensitizing tumor cells to treatment with an additional therapeutic agent, comprising administering a therapeutically effective amount of a compound described herein, or a pharmaceutically acceptable salt thereof.

[0085] In another aspect, there is also provided a method for treating an inflammatory disorder in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound described herein, or a pharmaceutically acceptable salt or derivative thereof. Representative examples of inflammatory disorders include peritonitis, osteoarthritis, acute pancreatitis, chronic pancreatitis, asthma, adult respiratory distress syndrome, glomerulonephritis, rheumatoid arthritis, systemic lupus erythematosus, scleroderma, chronic thyroiditis, Graves' secundum, autoimmune gastritis, insulin-dependent diabetes mellitus (type 1), autoimmune hemolytic anemia, autoimmune neutropenia, thrombocytopenia, chronic active hepatitis, myasthenia gravis, inflammatory bowel disease, Crohn's disease, psoriasis, atopic dermatitis, graft-versus-host disease, osteoporosis, multiple myeloma-related bone disorder, leukemia and related disorders, myelodysplastic syndrome, acute myeloid leukemia, chronic myeloid leukemia, metastatic melanoma, Kaposi's sarcoma, multiple sclerosis, sepsis, septic shock, dysentery, Alzheimer's disease, Parkinson's disease, cerebral ischemia, myocardial ischemia, spinal muscular atrophy, multiple sclerosis, and AIDS. S-related encephalitis, HIV-related encephalitis, aging, alopecia, nerve damage from stroke, ulcerative colitis, infectious hepatitis, juvenile diabetes, lichen planus, acute dermatomyositis, eczema, primary liver cirrhosis, uveitis, Behcet's disease, atopic dermatitis, pure red cell aplasia, aplastic anemia, amyotrophic lateral sclerosis, nephrotic syndrome, burns, bronchitis, tendonitis, bursitis, polyarteritis nodosa, thyroiditis, Hodgkin's disease These include rheumatic fever, sarcoidosis, polymyositis, gingivitis, hypersensitivity, conjunctivitis, swelling following injury, allergic rhinitis, endotoxin shock syndrome, and atherosclerosis, psoriatic arthritis, vasculitis, polymyalgia rheumatica, Wegener's granulomatosis, temporal arteritis, chronic obstructive pulmonary disease, cryoglobulinemia, transplant rejection, and ataxia-telangiectasia.

[0086] In another aspect, there is provided a method for treating organ fibrosis in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound described herein, or a pharmaceutically acceptable salt or derivative thereof. Representative examples of organ fibrosis that may be treated include renal fibrosis, pulmonary fibrosis, liver cirrhosis, endomyocardial fibrosis, Crohn's disease, liver fibrosis, cardiac fibrosis, scleroderma, or progressive massive fibrosis.

[0087] In another aspect, there is provided a method for treating infertility in a subject in need thereof, comprising administering a therapeutically effective amount of a compound described herein, or a pharmaceutically acceptable salt or derivative thereof.

[0088] Combination therapy The compounds described herein can be administered in combination with other therapies, such as, for example, radiation therapy, surgery, conventional chemotherapy, one or more checkpoint inhibitors, or in combination with one or more additional therapies. The methods and agents derived from the present invention can be administered alone as a pharmaceutical composition or in combination with one or more other active ingredients or agents in a therapeutically effective and physiologically acceptable amount. Such other active ingredients include, but are not limited to, glutathione antagonists, angiogenesis inhibitors, chemotherapeutic agents, and antibodies (e.g., cancer antibodies). The agents described in the present invention can be administered simultaneously or sequentially. The time separation between administrations can be minutes, hours, days, or even longer.

[0089] For example, the compounds described herein can be used to treat or prevent the progression of various cancers, including but not limited to, alkylating agents (e.g., chlorambucil, cyclophosphamide, ccnu, melphalan, procarbazine, thiotepa, bcnu, and busulfan), antimetabolites (e.g., 6-mercaptopurine and 5-fluorouracil), anthracyclines (e.g., daunorubicin, doxorubicin, idarubicin, epirubicin, and mitoxantrone), antitumor antibiotics (e.g., bleomycin), monoclonal antibodies (e.g., alemtuzumab, bevacizumab, cetuximab, gemtuzumab, ibritumomab, panitumumab), and the like. tumumab, rituximab, tositumomab, and trastuzumab), platinum (e.g., cisplatin, oxaliplatin, and carboplatin), plant alkaloids (e.g., vincristine), topoisomerase I or II inhibitors (e.g., irinotecan, topotecan, amsacrine, etoposide, etoposide phosphate, and teniposide), vinca alkaloids (e.g., vincristine), They may be administered before, after, or simultaneously with chemotherapeutic and / or cytotoxic agents such as cyclosporine (e.g., vinblastine, vinorelbine, and vindesine), taxanes (e.g., paclitaxel and docetaxel), epipodophyllotoxins (e.g., etoposide and teniposide), nucleoside analogs, and angiogenesis inhibitors (e.g., Avastin (beracizumab), a humanized monoclonal antibody specific for VEGF-A). Examples of glutathione antagonists include, but are not limited to, buthionine sulfoximine, cyclophosphamide, ifosfamide, actinomycin d, and N-(4-hydroxyphenyl)retinamide (4-HPR).Examples of angiogenesis inhibitors include 2-methoxyestradiol (2-ME), AG3340, angiostatin, antithrombin III, anti-VEGF antibodies, batimastat, bevacizumab (avastatin), BMS-275291, CA1, canstatin, combretastatin, combretastatin-A4 phosphate, CC-5013, captopril, celecoxib, dalteparin, EMD121974, endostatin, erlotinib, gefitinib, genistein, halofuginone, ID1, ID3, IM862, imatinib mesylate, inducible protein 10, interferon-alpha, interleukin 12, lavendustin-a, LY317615 or AE-941, marimastat, maspin, medroxyprogesterone, and the like. Examples of angiogenesis inhibitors include, but are not limited to, medroxyprogesterone acetate, Meth-1, Meth-2, Neovastat, osteopontin cleavage products, PEX, pigment epithelial growth factor (PEGF), platelet factor 4, prolactin fragments, proliferin-related protein (PRP), PTK787 / ZK222584, recombinant human platelet factor 4 (rPF4), restin, squalamine, SU5416, SU6668, suramin, taxol, tecogalan, thalidomide, tetrathiomolybdate (TM), thrombospondin, TNP-470, troponin I, vasostatin, VEGF1, VEGF-TPvAP, and ZD6474. In some embodiments, the angiogenesis inhibitor is a VRGF antagonist. The VEGF antagonist may be a VEGF-binding molecule. VEGF binding molecules include VEGF antibodies, or antigen-binding fragments thereof. An example of a VEGF antagonist is NeXstar.

[0090] Chemotherapeutic agents that can be combined with the compounds disclosed herein include DNA damaging agents, including topoisomerase inhibitors (e.g., etoposide, camptothecin, topotecan, irinotecan, teniposide, mitoxantrone), anti-microtubule agents (e.g., vincristine, vinblastine), antimetabolites (e.g., cytarabine, methotrexate, hydroxyurea, 5-fluorouracil, fluoridine, 6-thioguanine, 6-mercaptompurine, fludarabine, pentostatin, chlorodeoxyadenosine), DNA alkylating agents (e.g., cisplatin, mecholorethamine, cyclophosphamide, ifosphamide, melphalan, chlorambucil, busulfan, thiotepa), carmustine, lomustine, carboplatin, dacarbazine, procarbazine), and DNA strand break inducers (e.g., bleomycin, doxorubicin, daunorubicin, idarubicin, mitomycin C).

[0091] Other chemotherapeutic agents that can be combined with the compounds described herein include synthetic, semi-synthetic, and naturally occurring agents. Important chemotherapeutic agents include avicin, aclarubicin, acodazole, acronin, adzelesin, adriamycin, aldesleukin, alitretinoin, allopurinol sodium (allopurinol sodium), altretamine, ambomycin, amethanthrone acetate, aminoglutethimide, amsacrine, anastrazole, annonaceous acetogenins, anthramycin, asimycin, asparaginase, asperlin, azacytidine, azetepa, azotomycin, batimastat, benzodepa, bexarotene, bicalutamide, bisantrene, visnafide, bizelesin, bleomycin, brequinar, bropirimine, bullatacin, busulfan, cabergoline, cactinomycin, calusterone, caracemide, carbetimer, carboplatin, carmustine, carubicin, carzelesin, cedefingol, chlorambucil, Celecoxib, ciloremycin, cisplatin, cladribine, crisnatol, cyclophosphamide, cytarabine, dacarbazine, DACA, dactinomycin, daunorubicin, daunomycin, decitabine, denileukin, dexorumaplatin, dezaguanine, diaziclone, docetaxel, doxorubicin, droloxifene, duazomycin, edatrexate, eflornithine, elsamitrucin, estra Mustine, Etanidazole, Etoposide, Etoprine, Fadrozole, Fazarabine, Fenretinide, Floxuridine, Fludarabine, Fluorouracil, Flurocitabine, 5-FdUMP, Foskidone, Fosteuecine, FK-317, FK-973, FR-66979, FR-900482, Gemcitabine, Gemtuzumab, Ozogamicin, Gold Aul98, goserelin, guanaconazole, hydroxyurea, idarubicin, irmofosine, interferon alpha and analogs, iproplatin, irinotecan, lanreotide, letrozole, leuprolide, liarozole, lometrexol, lomustine, losoxantrone, masoprocol, maytansine, mechlorethamine, megastrol, melengestrol, melphalan, menogaril,Metoprine, maturedepa, mitindomide, mitocalcin, mitogillin, mitomalacin, mitomycin, mitomycin C, mitospel, mitotane, mitoxantrone, mycophenolic acid, nocodazole, nogalamycin, oprelvekin, ormaplatin, oxisuran, paclitaxel, pamidronate, pegaspargase, periomycin, pentamstine, peplomycin, perfosfamide, pipobroman, piposulfan, piroxantrone, plicamycin, promestane, porfimer , porfiromycin, prednimustine, procarbazine, puromycin, pyrazofurin, ribopurine, rituximab, rogletimide, rolliniastatin, safingol, samarium, semustine, cinthrazene, sfarfosate, sparsomycin, spirogermanium, spiromustine, spiroplatin, squamocin, squamotacin, streptonigrin, streptozocin, SrC12, sulfofenur, tallysomycin taxane, toxoid, tecogran, tegafur, Teloxantrone, temoporfin, teniposide, teroxylon, testolactone, thiamiprine, thiotepa, Thymitaq, tiazofurin, tirapazamine, tomudex, Top-53, topotecan, toremixifme, trastuzumab, trestron, triciribine, trimetrexate, trimetrexate glucuronate, triptorelin, tuburosol, uracil mustard, uredepa, valur Bicine, vapreotide, vinblastine, vincristine, vindesine, vinepidine, vinglisinate, vinleurosine, vinorelbine, vinrocidine, vinzolidine, vorozole, zeniplatin, zinostatin, zorubicin, 2-chlorodeoxyrubicin, 2'-deoxyformycin, 9-aminocamptothecin, raltitrexed, N-propargyl-5,8-didezafolic acid, 2-chloro-2'arabinofluoro-2'deoxyadenosine, 2-chloro-2'-deoxyadenosine, anisomycin, trichostatin, hPRL-G129R,CEP-751, linomide, sulfur mustard, nitrogen mustard, N-methyl-N-nitrosourea, fotemustine, streptozotocin, decarbazine, mitozolomide, temozolomide, AZQ, ormaplatin, CI-973, DWA21 These include, but are not limited to, 14R, JM216, JM335, bisplatinum, tomudex, azecitidine, cytravincin, gemcitabine, 6-mercaptopurine, hypoxanthine, temiposide, CPT-11, doxorubicin, daunorubicin, epirubicin, darubicin, losoxantrone, amsacrine, pyrazoloacridine, all-trans-retinol, 14-hydroxy-retro-retinol, all-trans-retinoic acid, N-(4-hydroxyphenyl)retinamide, 13-cis-retinoic acid, 3-methyl-TTNEB, 9-cis-retinoic acid, fludarabine, and 2-Cda.

[0092] Other chemotherapeutic agents that can be combined with the compounds described herein include 20-epi, 1,25-dihydroxyvitamin-D3, 5-ethynyluracil, abiraterone, aclarubicin, acylfulvene, adecipenol, adzelesin, aldesleukin, ALL-TK antagonists, altretamine, ambamustine, amidox, amifostine, aminolevulinic acid, anagrelide, anastrozole, andrographolide, angiogenesis inhibitors, antagonist D, antagonists D, antarelix, anti-dorsal morphogenetic protein-1, anti-androgen, anti-estrogen, anti Neoplastron, antisense oligonucleotide, aphidicolin, apoptosis gene modulator, apoptosis regulator, apurinic acid, ara-cdp-dl-PTBA, arginine aminase, asulaculin, atamestane, atlimustine, axinamastine 1 and axinamastine 2, axinamastine 3, azasetron, azatoxin, azatyrosine, baccatin III derivative, balanol, BCR / ABL antagonist, benzochlorin, benzoylsaurosporine, beta-lactam derivative, beta-arretin. Perillyl alcohol, phenozenomyein, phenyl acetate, phosphatase inhibitors, picibanil, pilocarbine and its salts or analogues, pirarbucin, piritrexim, prasetin A, plasminogen activator inhibitors, platinum complexes, phenylethyl isothiocyanate and its analogues, platinum compounds, platinum triamine complexes, podophylotoxin, porfimer sodiumsodium), porphyromycin, propyl bisacridone, prostaglandin J2, proteasome inhibitors, protein A-based immunomodulators, PKC inhibitors, microalgal, protein tyrosine phosphatase inhibitors, purine nucleoside phosphorylase inhibitors, purpurins, pyrazoloacridine, pyridoxylated hemoglobin polyoxyethylene conjugates, raf antagonists, raltitrexed, ramosetron, ras farnesyl protein tranaferase inhibitors, ras inhibitors; ras-GAP inhibitors, demethylated reterliptin, rhenium Re186 etidronate etidronate, rhizoxine, ribozyme, RII retinamide, rogletimide, rosagliatazone and its analogs and derivatives, rohitukine, romurtide, roquinimex, rubiginone B1, ruboxyl, safingol, saintopin, SarCNU, sarcophytol A, sargrmostim, sdi1 mimetics, semustine, senescence derived inhibitor 1 inhibitor 1), sense oligonucleotide, signal transduction inhibitor, signal transduction modulator, single-chain antigen binding protein, sizofiran, sobuzoxane, borocaptan sodium, sodium phenylacetate, sorberol, somatomedin binding protein, sonermin, sparfosic acidacid, spicamycin D, spiromustine, splenopentin, spongistatin 1, squalamine, stem cell inhibitors, stem cell cell division inhibitors, stipiamide, stromelysin, sulfinosine, superactive vasoactive intestinal peptide antagonists, suradista, suramin, swainsonine, synthetic glycosaminoglycans, tallimustine, tamoxifen methiodide methiodide), tauromustine, tazarotene, tecogalan sodium, tegafur, tellurapyrilium, telomerase inhibitors, temoporfin, temozolomide, teniposide, tetrachlorodecaoxide, tetrazomine, thaliblastine, thalidomide, thiocoraline, thrombopoietin and its mimetics, thymalfasin, thymopoietin receptor agonists, thymotrin, thyroid-stimulating hormone, tin ethyl etiopurin etiopurpin, tirapazamine, titanocene and its salts, topotecan, topsentin, toremifene, totipotent stem cell factor, translation inhibitors, tretinoin, triacetyluridine, tricribine, trimetrexate, triptorelin, tropisetron, turosteride, tyrosine kinase inhibitors, tyrphostins, UBC inhibitors, ubenimex, urogenital sinus-derived growth inhibitory factor, urokinase receptor antagonists, vapreotide, variolin B, vector systems, red blood cell gene therapy, velaresol, veramine, verdin, verteporfin, vinorelbine, vinxartin, vitaxin, vorozole, zanoteron, zeniplatin, zilascorub, and zinostatin.

[0093] Additional chemotherapeutic agents that can be combined with the compounds described herein include antiproliferative agents (e.g., piritrexim isothiocyanate), antiprostatic hyperplasia agents (cytoglucide), benign prostatic hyperplasia treatments (e.g., tomsulosin, RBX2258), prostatic growth inhibitors (pentomone), and radioactive agents: fibrinogen 1125, fludeoxyglucose F18, fluorodopa F18, insulin 1125, iobenguane 1123, iodipamide sodium 1131 (lodipamide Iodoantipyrine 1131, Iodocholesterol 1131, Iodopyracet 1125, Iofetamine HCl 1123, Iomethin 1131, Iomethin 1131, Iothalamate sodium 1125, Iothalamate sodium 1131, Iothyrosine 1131, Liothyronine 1125, Merisoprolol Hgl97 Hgl97), iodobenzoguanine methyl (MIBG-I131 or MIBGI123), selenomethionine Se75, technetium Tc99m furifosmin, technetium Tc99m gluceptategluceptate, Tc-99m biscisate, Tc-99m disofenin, Tc-99m gluceptate, Tc-99m lidofenin, Tc-99m mebrofenin, Tc-99m medronate and its sodium salt, Tc-99m mertiatide, Tc-99m oxidronate, Tc-99m pentetate and its salt, Tc-99 m sestambi, Tc99m siboroxime, Tc99m succimer, Tc99m sulfur colloid, Tc99m teboroxime, Tc99m tetrofosmin, Tc99m tiatide, thyroxine 1125, thyroxine 1131, tolpovidone 1131, triolein 1125 and threolin 1125, and threolin 131, MIBG-I123 and MIBG1131.

[0094] In some embodiments, the compounds described herein are administered in combination with one or more immune checkpoint inhibitors, kinase inhibitors, tubulin inhibitors, or topoisomerase inhibitors.

[0095] In some embodiments, the compounds described herein are administered in combination with one or more immune checkpoint inhibitors. Immune checkpoint inhibitors include any agent that blocks or inhibits an inhibitory pathway of the immune system in a statistically significant manner. Exemplary immune checkpoint targets for blockage or inhibition include, but are not limited to, CTLA-4, PDL1, PDL2, PD1, B7-H3, B7-H4, BTLA, HVEM, GAL9, LAG3, TIM3, VISTA, KIR, 2B4 (a member of the CD2 family of molecules expressed on all NK, gamma delta, and memory CD8+ (alpha beta) T cells), CD160 (also known as BY55), CGEN-15049, CHK1 and CHK2 kinases, A2aR, and various B-7 family ligands. B7 family ligands include, but are not limited to, B7-1, B7-2, B7-DC, B7-H1, B7-H2, B7-H3, B7-H4, B7-H5, B7-H6, and B7-H7. Immune checkpoint inhibitors include antibodies, or antigen-binding fragments thereof, other binding proteins, biotherapeutics, or small molecules that bind to and block or inhibit the activity of one or more of CTLA-4, PDL1, PDL2, PD1, BTLA, HVEM, TIM3, GAL9, LAG3, VISTA, KIR, 2B4, CD160, and CGEN-15049. Exemplary immune checkpoint inhibitors include tremelimumab (a CTLA-4 blocking antibody), anti-OX40, PD-L1 monoclonal antibody (anti-B7-H1; MEDI4736), MK-3475 (a PD-1 blocker), nivolumab (an anti-PD1 antibody), CT-011 (an anti-PD1 antibody), BY55 monoclonal antibody, AMP224 (an anti-PDL1 antibody), BMS-936559 (an anti-PDL1 antibody), MPLDL3280A (an anti-PDL1 antibody), MSB0010718C (an anti-PDL1 antibody), and yervoy / ipilimumab (an anti-CTLA-4 checkpoint inhibitor). Checkpoint protein ligands include, but are not limited to, PD-L1, PD-L2, B7-H3, B7-H4, CD28, CD86, and TIM-3.

[0096] In one embodiment, the present invention covers the use of compounds of the present invention with one or more additional therapeutic agents that block the interaction between the immune checkpoint receptor programmed cell death protein 1 (PD-1) and its ligand, PD-L1. See, for example, A. Mullard, "New checkpoint inhibitors ride the immunotherapy tsunami," Nature Reviews: Drug Discovery (2013), 12:489-492. PD-1 is expressed on T cells and regulates T cell activity. Specifically, when PD-1 is not bound to PDL-1, T cells can engage and kill target cells. However, when PD-1 is bound to PDL-1, it stops T cells from engaging and killing target cells. Furthermore, unlike other checkpoints, PD-1 acts in close proximity to such PDL-1 and is directly overexpressed on cancer cells, which leads to increased binding to PD-1-expressing T cells.

[0097] In another aspect, the compounds of the present disclosure can be used in combination with antibodies that can act as PD-1 agonists, thereby modulating immune responses controlled by PD-1. In one embodiment, the anti-PD-1 antibody can be an antigen-binding fragment. The anti-PD-1 antibodies disclosed herein can bind to human PD-1 and stimulate the activity of PD-1, thereby inhibiting the function of immune cells that express PD-1. In some embodiments, compounds of the present disclosure may be used in combination with one or more PD-1 inhibitors selected from pembrolizumab, nivolumab, cemiplimab, spartalizumab, camrelizumab, sintilimab, tislelizumab, toripalimab, nivolumab, AMP-224, or AMP-514. In some embodiments, compounds of the present disclosure may be used in combination with one or more PD-L1 inhibitors selected from atezolizumab, avelumab, durvalumab, KN035, CK-301, AUNP12, CA-170, or BMS-986189.

[0098] In some embodiments, compounds of the present disclosure may be used in combination with one or more therapeutic agents that inhibit CTLA-4. Suitable anti-CTLA4 antagonist agents for use herein include anti-CTLA4 antibodies, human anti-CTLA4 antibodies, murine anti-CTLA4 antibodies, mammalian anti-CTLA4 antibodies, humanized anti-CTLA4 antibodies, monoclonal anti-CTLA4 antibodies, polyclonal anti-CTLA4 antibodies, chimeric anti-CTLA4 antibodies, MDX-010 (ipilimumab), tremelimumab, anti-CD28 antibodies, anti-CTLA4 adnectins, anti-C These include, but are not limited to, TLA4 domain antibodies, single chain anti-CTLA4 fragments, heavy chain anti-CTLA4 fragments, light chain anti-CTLA4 fragments, inhibitors of CTLA4 that stimulate the costimulatory pathway, antibodies disclosed in PCT Publication No. 2001 / 014424, antibodies disclosed in PCT Publication No. 2004 / 035607, antibodies disclosed in U.S. Patent Publication No. 2005 / 0201994, and antibodies disclosed in granted European Patent No. 1212422B1. Additional CTLA-4 antibodies are described in U.S. Patent Nos. 5,811,097, 5,855,887, 6,051,227, and 6,984,720; PCT Publication Nos. 01 / 14424 and 00 / 37504; and U.S. Patent Publication Nos. 2002 / 0039581 and 2002 / 086014. Other anti-CTLA-4 antibodies that can be used in the methods of the invention include those disclosed in WO 98 / 42752; U.S. Patent Nos. 6,682,736 and 6,207,156; Hurwitz et al., Proc. Natl. Acad. Sci. USA, 95(17):10067-10071 (1998); Camacho et al., J. Clin. Oncology, 22(145):Abstract No. 2505 (2004) (antibody CP-675206); Mokyr et al., Cancer Res., 58:5301-5304 (1998), and U.S. Patent Nos. 5,977,318, 6,682,736, 7,109,003, and 7,132,281.Additional anti-CTLA4 antagonists include those that disrupt the ability of the CD28 antigen to bind to its cognate ligand, inhibit the ability of CTLA4 to bind to its cognate ligand and enhance T cell responses via the costimulatory pathway, disrupt the ability of B7 to bind to CD28 and / or CTLA4, disrupt the ability of B7 to activate the costimulatory pathway, disrupt the ability of CD80 to bind to CD28 and / or CTLA4, disrupt the ability of CD80 to activate the costimulatory pathway, and disrupt the ability of CD86 to bind to CD28 and / or CTLA4. These include, but are not limited to, any inhibitors that disrupt the ability to bind to CTLA4, disrupt the ability of CD86 to activate the costimulatory pathway, and generally disrupt the costimulatory pathway from an activated state, including small molecule inhibitors of CD28, CD80, CD86, CTLA4, among other members of the costimulatory pathway; antibodies against CD28, CD80, CD86, CTLA4, among other members of the costimulatory pathway; antisense molecules against CD28, CD80, CD86, CTLA4, among other members of the costimulatory pathway; adnectins against CD28, CD80, CD86, CTLA4, among other members of the costimulatory pathway, among other members of the costimulatory pathway, among other anti-CTLA4 antagonists. It is necessary to include RNAi inhibitors (both single-stranded and double-stranded) of CD28, CD80, CD86, CTLA4, among other members of the costimulatory pathway.

[0099] In some embodiments, the compounds of the present disclosure can be used in combination with one or more therapeutic agents that inhibit TIM-3. Blocking TIM-3 activation by its ligand results in increased Th1 cell activation. Furthermore, TIM-3 has been identified as an important inhibitory receptor expressed by exhausted CD8+ T cells. TIM-3 has also been reported as a key regulator of nucleic acid-mediated antitumor immunity. In one example, TIM-3 has been shown to be upregulated on tumor-associated dendritic cells (TADCs).

[0100] Method of administration The compounds used in the methods described herein can be administered by any suitable method and technique currently known or expected to become known to those skilled in the art. For example, the active ingredients described herein can be formulated in a physiologically acceptable or pharmaceutically acceptable form and administered by any suitable route known in the art, including, for example, oral and parenteral routes of administration. As used herein, the term "parenteral" includes subcutaneous, intradermal, intravenous, intramuscular, intraperitoneal, and intrasternal administration, such as by injection. The administration of the active ingredients of these compositions can be a single administration or can be continuous and at distinct intervals that can be easily determined by those skilled in the art.

[0101] The compositions described herein that include active compounds and certain excipients may be useful for a variety of medical and non-medical applications. For example, pharmaceutical compositions that include active compounds and excipients may be useful for treating and preventing mycobacterial infections.

[0102] "Excipients" include any and all solvents, diluents or other liquid vehicles, dispersing or suspending aids, surfactants, isotonic agents, thickening or emulsifying agents, preservatives, solid binders, lubricants, etc., appropriate for the particular dosage form desired. General considerations in formulation and / or manufacturing can be found, for example, in Remington's Pharmaceutical Sciences, Sixteenth Edition, E. W. Martin (Mack Publishing Co., Easton, Pa., 1980), and Remington: The Science and Practice of Pharmacy, 21st Edition (Lippincott Williams & Wilkins, 2005).

[0103] Exemplary excipients include, but are not limited to, any non-toxic, inert solid, semi-solid, or liquid filler, diluent, encapsulating material, or formulation auxiliary of any kind. Some examples of materials which may function as excipients include, but are not limited to, sugars such as lactose, glucose, sucrose, and the like; starches such as corn starch and potato starch; cellulose and its derivatives such as sodium carboxymethylcellulose, ethyl cellulose, and cellulose acetate; powdered tragacanth; malt; gelatin; talc; excipients such as cocoa butter and suppository waxes; oils such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil, and soybean oil; glycols such as propylene glycol; esters such as ethyl oleate and ethyl laurate; agar; detergents such as Tween 80; buffers such as magnesium hydroxide and aluminum hydroxide; alginic acid; isotonic saline; Ringer's solution; ethyl alcohol; and phosphate buffers, as well as other non-toxic compatible lubricants such as sodium lauryl sulfate and magnesium stearate, as well as coloring agents, releasing agents, coating agents, sweetening agents, flavoring agents, and perfuming agents; preservatives and antioxidants can also be present in the compositions, according to the judgment of the formulator. As will be appreciated by those skilled in the art, excipients may be selected based on what the composition is useful for. For example, in pharmaceutical or cosmetic compositions, the choice of excipients will depend on the route of administration, the agent being delivered, the time course of delivery of the agent, etc., and may be administered to humans and / or animals orally, rectally, parenterally, intracisternally, intravaginally, intranasally, intraperitoneally, topically (such as by powder, cream, ointment, or drops), bucally, or as an oral or nasal spray. In some embodiments, the active compounds disclosed herein are administered topically.

[0104] Exemplary diluents include calcium carbonate, sodium carbonate, calcium phosphate, dicalcium phosphate, calcium sulfate, calcium hydrogen phosphate, sodium phosphate, lactose, sucrose, cellulose, microcrystalline cellulose, kaolin, mannitol, sorbitol, inositol, sodium chloride, dry starch, corn starch, powdered sugar, and the like, and combinations thereof.

[0105] Exemplary granulating and / or dispersing agents include potato starch, corn starch, tapioca starch, sodium starch glycolate, clays, alginic acid, guar gum, citrus juice pomace, agar, bentonite, cellulose and wood products, sponge, cation exchange resins, calcium carbonate, silicates, sodium carbonate, cross-linked poly(vinyl-pyrrolidone) (croscarmellose), sodium carboxymethyl starch (sodium starch glycolate), carboxymethylcellulose, cross-linked sodium carboxymethylcellulose (croscarmellose), methylcellulose, pregelatinized starch (starch 1500), microcrystalline starch, water insoluble starch, calcium carboxymethylcellulose, magnesium aluminum silicate (Veegum), sodium lauryl sulfate, quaternary ammonium compounds, and the like, and combinations thereof.

[0106] Exemplary surfactants and / or emulsifiers include natural emulsifiers (e.g., acacia, agar, alginic acid, sodium alginate, tragacanth, chondrux, cholesterol, xanthan, pectin, gelatin, egg yolk, casein, wool fat, cholesterol, wax, and lecithin), colloidal clays (e.g., bentonite [aluminum silicate] and veegum [magnesium aluminum silicate]), long-chain amino acid derivatives, high molecular weight alcohols (e.g., stearyl alcohol, cetyl alcohol, oleyl alcohol, triacetin monostearate, ethylene glycol distearate, glyceryl monostearate, and propylene glycol monostearate, polyvinyl alcohol), carbomers (e.g., carboxypolymethylene, polyacrylic acid, acrylic acid polymers, and carboxyvinyl polymers), carrageenan, cellulose derivatives (e.g., sodium carboxymethylcellulose, powdered cellulose, hydroxymethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, methylcellulose), sorbitan fatty acid esters, and the like. oleates (e.g., polyoxyethylene sorbitan monolaurate [Tween 20], polyoxyethylene sorbitan [Tween 60], polyoxyethylene sorbitan monooleate [Tween 80], sorbitan monopalmitate [Span 40], sorbitan monostearate [Span 60], sorbitan tristearate [Span 65], glyceryl monooleate, sorbitan monooleate [Span 80]), polyoxyethylene esters (e.g., polyoxyethylene monostearate [Myrj45], polyoxyethylene hydrogenated Castor oil, polyethoxylated castor oil, polyoxyethylene stearate, and Solutol), sucrose fatty acid esters, polyethylene glycol fatty acid esters (e.g., Cremophor), polyoxyethylene ethers (e.g., polyoxyethylene lauryl ether [Brij30]), poly(vinyl-pyrrolidone), diethylene glycol monolaurate, triethanolamine oleate, sodium oleate, potassium oleate, ethyl oleate, oleic acid, ethyl laurate, sodium lauryl sulfate, PluronicF68, Poloxamer 188, cetrimonium bromide, cetylpyridinium chloride, benzalkonium chloride, docusate sodium, and the like, and / or combinations thereof. Exemplary binders include starches (e.g., corn starch and starch paste), gelatin, sugars (e.g., sucrose, glucose, dextrose, dextrin, molasses, lactose, lactitol, mannitol, etc.), natural and synthetic gums (e.g., acacia, sodium alginate, Irish moss extract, panwar gum, ghatti gum, mucilage of isapol husks, carboxymethylcellulose, methylcellulose, ethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, microcrystalline cellulose, cellulose acetate, poly(vinyl-pyrrolidone), magnesium aluminum silicate (veegum), and larch arabogalactan), alginates, polyethylene oxide, polyethylene glycol, inorganic calcium salts, silicic acid, polymethacrylates, waxes, water, alcohol, and the like, and / or combinations thereof.

[0107] Exemplary preservatives include antioxidants, chelating agents, antibacterial preservatives, antifungal preservatives, alcohol preservatives, acidic preservatives, and other preservatives.

[0108] Exemplary antioxidants include alpha tocopherol, ascorbic acid, ascorbyl palmitate, butylated hydroxyanisole, butylated hydroxytoluene, monothioglycerol, potassium metabisulfite, propionic acid, propyl gallate, sodium ascorbate, sodium bisulfite, sodium metabisulfite, and sodium sulfite.

[0109] Exemplary chelating agents include ethylenediaminetetraacetic acid (EDTA) and its salts and hydrates (e.g., sodium edetate, disodium edetate, trisodium edetate, calcium disodium edetate, dipotassium edetate, etc.), citric acid and its salts and hydrates (e.g., citric acid monohydrate), fumaric acid and its salts and hydrates, malic acid and its salts and hydrates, phosphoric acid and its salts and hydrates, and tartaric acid and its salts and hydrates. Exemplary antimicrobial preservatives include benzalkonium chloride, benzethonium chloride, benzyl alcohol, bronopol, cetrimide, cetylpyridinium chloride, chlorhexidine, chlorobutanol, chlorocresol, chloroxylenol, cresol, ethyl alcohol, glycerin, hexetidine, imidurea, phenol, phenoxyethanol, phenylethyl alcohol, phenylmercuric nitrate, propylene glycol, and thimerosal.

[0110] Exemplary fungal preservatives include butylparaben, methylparaben, ethylparaben, propylparaben, benzoic acid, hydroxybenzoic acid, potassium benzoate, potassium sorbate, sodium benzoate, sodium propionate, and sorbic acid.

[0111] Exemplary alcohol preservatives include ethanol, polyethylene glycol, phenol, phenolic compounds, bisphenol, chlorobutanol, hydroxybenzoates, and phenylethyl alcohol.

[0112] Exemplary acidic preservatives include vitamin A, vitamin C, vitamin E, beta-carotene, citric acid, acetic acid, dehydroacetic acid, ascorbic acid, sorbic acid, and phytic acid. Other preservatives include tocopherol, tocopherol acetate, deteroxime mesylate, cetrimide, butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), ethylenediamine, sodium lauryl sulfate (SLS), sodium lauryl ether sulfate (SLES), sodium bisulfite, sodium metabisulfite, potassium sulfite, potassium metabisulfite, Glydant Plus, Phenonip, methylparaben, Germall 115, Germaben II, Neolone, Kathon, and Euxyl. In certain embodiments, the preservative is an antioxidant. In other embodiments, the preservative is a chelating agent.

[0113] Exemplary buffering agents include citrate buffer, acetate buffer, phosphate buffer, ammonium chloride, calcium carbonate, calcium chloride, calcium citrate, calcium glubionate, calcium gluceptate, calcium gluconate, D-gluconic acid, calcium glycerophosphate, calcium lactate, propanoic acid, calcium levulinate, pentanoic acid, dibasic calcium phosphate, phosphoric acid, tricalcium phosphate, calcium phosphate hydroxide, potassium acetate, potassium chloride, potassium gluconate, potassium mixtures, dipotassium hydrogen phosphate, potassium dihydrogen phosphate, potassium phosphate mixtures, sodium acetate, sodium bicarbonate, sodium chloride, sodium citrate, sodium lactate, disodium hydrogen phosphate, sodium dihydrogen phosphate, sodium phosphate mixtures, tromethamine, magnesium hydroxide, aluminum hydroxide, alginic acid, pyrogen-free water, isotonic saline, Ringer's solution, ethyl alcohol, and the like, and combinations thereof.

[0114] Exemplary lubricants include magnesium stearate, calcium stearate, stearic acid, silica, talc, malt, glyceryl behenate, hydrogenated vegetable oils, polyethylene glycol, sodium benzoate, sodium acetate, sodium chloride, leucine, magnesium lauryl sulfate, sodium lauryl sulfate, and the like, and combinations thereof.

[0115] Exemplary natural oils include almond, apricot kernel, avocado, babassu, bergamot, blackcurrant seed, borage, cade, chamomile, canola, caraway, carnauba, castor, cinnamon, cocoa butter, coconut, cod liver, coffee, corn, cottonseed, emu, eucalyptus, evening primrose, fish, linseed, geraniol, loofah, grape seed, hazelnut, hyssop, isopropyl myristate, jojoba, kukui nut, lavandin, lavender, lemon, litsea cucumber, macadamia. Exemplary synthetic oils include macadamia nut, mallow, mango seed, meadowfoam seed, mink, nutmeg, olive, orange, orange roughy, palm, palm kernel, peach kernel, peanut, poppy seed, pumpkin seed, rapeseed, rice bran, rosemary, safflower, sandalwood, sasquana, savory, sea buckthorn, sesame, shea butter, silicone, soybean, sunflower, tea tree, thistle, camellia, vetiver, walnut, and wheat germ oil. Exemplary synthetic oils include, but are not limited to, butyl stearate, caprylic triglyceride, capric triglyceride, cyclomethicone, diethyl sebacate, dimethicone 360, isopropyl myristate, mineral oil, octyldodecanol, oleyl alcohol, silicone oil, and combinations thereof.

[0116] Furthermore, the composition may further comprise a polymer. Exemplary polymers contemplated herein include cellulose polymers and copolymers, such as cellulose ethers such as methylcellulose (MC), hydroxyethylcellulose (HEC), hydroxypropylcellulose (HPC), hydroxypropylmethylcellulose (HPMC), methylhydroxyethylcellulose (MHEC), methylhydroxypropylcellulose (MHPC), carboxymethylcellulose (CMC) and various salts thereof, including, for example, sodium salts, hydroxyethylcarboxymethylcellulose (HECMC) and various salts thereof, carboxymethylhydroxyethylcellulose (CMHEC) and various salts thereof, starch, dextran, dextran derivatives, chitosan, and other polysaccharides and polysaccharide derivatives, such as alginic acid and various salts thereof, various gums, including carrageenan, xanthan gum, guar gum, gum arabic, karaya gum, ghatti gum, konjac, and tragacanth gum, glycosaminoglycans and proteoglycans, such as hyaluronic acid and salts thereof, proteins, such as gelatin, collagen, albumin, and fibrin, Other polymers, such as polyhydroxy acids such as polylactide, polyglycolide, poly(lactide-co-glycolide) and poly(epsilon-caprolactone-co-glycolide), carboxyvinyl polymers and their salts (e.g., carbomer), polyvinylpyrrolidone (PVP), polyacrylic acid and its salts, polyacrylamide, polyacrylic acid / acrylamide copolymers, polyalkylene oxides such as polyethylene oxide, polypropylene oxide, poly(ethylene oxide-propylene oxide), and Pluronics. (Pluronic) polymers, polyethylene glycol (PEG) polymers such as polyoxyethylene (polyethylene glycol), polyanhydrides, polyvinyl alcohol, polyethyleneamines and polypyridines, and PEGylated lipids (e.g., PEG-stearate, l,2-distearoyl-sn-glycero-3-phosphoethanolamine-N-[methoxy(polyethylene glycol)-1000], l,2-distearoyl-sn-glycero-3-phosphoethanolamine-N-[methoxy(polyethylene glycol)-2000], and l,2-distearoyl-sn-glycero-3-phosphoethanolamine-N-[methoxy(polyethylene glycol)-5000]), copolymers and salts thereof, but are not limited to these.

[0117] In addition, the composition may further comprise an emulsifier. Exemplary emulsifiers include polyethylene glycol (PEG), polypropylene glycol, polyvinyl alcohol, poly-N-vinylpyrrolidone and its copolymers, poloxamer nonionic surfactants, natural water-soluble polysaccharides (e.g., dextran, ficoll, cellulose), non-cationic poly(meth)acrylates, non-cationic polysaccharides such as poly(meth)acrylic acid and its ester amides and hydroxyalkyl amides, natural emulsifiers (e.g., acacia, agar, alginic acid, sodium alginate, tragacanth, chondroitin, sorbitan, sorbitol ... chondrux, cholesterol, xanthan, pectin, gelatin, egg yolk, casein, wool fat, cholesterol, wax, and lecithin), colloidal clays (e.g., bentonite [aluminum silicate] and veegum [magnesium aluminum silicate]), long-chain amino acid derivatives, high molecular weight alcohols (e.g., stearyl alcohol, cetyl alcohol, oleyl alcohol, triacetin monostearate, ethylene glycol distearate, glyceryl monostearate, and propylene glycol monostearate, polyvinyl alcohol), carbomers (e.g., carboxypolymethylene, polyacrylic acid, acrylic acid polymers, and carboxyvinyl polymers), carrageenan, cellulose derivatives (e.g., sodium carboxymethylcellulose, powdered cellulose, hydroxymethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, methylcellulose), sorbitan fatty acid esters (e.g., polyoxyethylene sorbitan monolaurate [Tween 20], polyoxyethylene sorbitan [Tween 60]). , polyoxyethylene sorbitan monooleate [Tween 80], sorbitan monopalmitate [Span 40], sorbitan monostearate [Span 60], sorbitan tristearate [Span 65], glyceryl monooleate, sorbitan monooleate [Span 80]), polyoxyethylene esters (e.g., polyoxyethylene monostearate [Myrj 45], polyoxyethylene hydrogenated castor oil, polyethoxylated castor oil, polyoxyethylene stearate, and Solutol), sucrose fatty acid esters,Examples of emulsifiers include, but are not limited to, polyethylene glycol fatty acid esters (e.g., Cremophor), polyoxyethylene ethers (e.g., polyoxyethylene lauryl ether [Brij30]), poly(vinyl-pyrrolidone), diethylene glycol monolaurate, triethanolamine oleate, sodium oleate, potassium oleate, ethyl oleate, oleic acid, ethyl laurate, sodium lauryl sulfate, Pluronic F68, Poloxamer 188, cetrimonium bromide, cetylpyridinium chloride, benzalkonium chloride, docusate sodium, and / or combinations thereof. In certain embodiments, the emulsifier is cholesterol.

[0118] Liquid compositions include emulsions, microemulsions, solutions, suspensions, syrups, and elixirs. In addition to the active compound, the liquid composition may contain inert diluents commonly used in the art, such as water or other solvents, solubilizers and emulsifiers, such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, oils (especially cottonseed, peanut, corn, germ, olive, castor, and sesame oils), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycol, and fatty acid esters of sorbitan, and mixtures thereof. In addition to inert diluents, oral compositions may also contain adjuvants such as wetting agents, emulsifiers and suspending agents, sweeteners, flavoring agents, and flavoring agents.

[0119] Injectable compositions, for example, injectable aqueous or oily suspensions, can be formulated according to known methods using suitable dispersing or wetting agents and suspending agents. Sterile injectable preparations can also be injectable solutions, suspensions, or emulsions in non-toxic, parenterally acceptable diluents or solvents, such as solutions in 1,3-butanediol. Acceptable vehicles and solvents for pharmaceutical or cosmetic compositions that can be used include water, Ringer's solution, and USP saline. In addition, sterile, solidified oils are conventionally used as solvents or suspending media. Any brand of solidified oil, including synthetic mono- or diglycerides, can be used. In addition, fatty acids such as oleic acid are used in injectable formulations. In certain embodiments, particles are suspended in a carrier fluid containing 1% (w / v) sodium carboxymethylcellulose and 0.1% (v / v) Tween 80. Injectable compositions can be sterilized, for example, by filtration through a bacterial-retaining filter, or by incorporating sterilizing agents in the form of sterile solid compositions which can be dissolved or dispersed in sterile water or other sterile injectable medium prior to use.

[0120] Compositions for rectal or vaginal administration may be in the form of suppositories, which can be prepared by mixing the particles with a suitable non-irritating excipient or carrier such as cocoa butter, polyethylene glycol, or a suppository wax which is solid at ambient temperature but liquid at body temperature and therefore will melt in the rectum or vaginal cavity and release the particles.

[0121] Solid compositions include capsules, tablets, pills, powders, and granules. In such solid compositions, particles are mixed with at least one excipient and / or a) filler such as starch, lactose, sucrose, glucose, mannitol, and silicic acid; b) binder such as carboxymethylcellulose, alginate, gelatin, polyvinylpyrrolidone, sucrose, and acacia; c) wetting agent such as glycerol; d) disintegrating agent such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate; e) solution retardant such as paraffin; f) absorption accelerator such as quaternary ammonium compound; g) wetting agent such as cetyl alcohol and glycerol monostearate; h) absorbent such as kaolin and bentonite clay; i) lubricant such as talc, calcium stearate, solid polyethylene glycol, sodium lauryl sulfate, and mixtures thereof. In the case of capsules, tablets, and pills, the dosage forms may also comprise buffering materials. Solid compositions of a similar type may also be employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polyethylene glycols and the like.

[0122] Tablets, capsules, pills, and granules can be prepared with coatings such as enteric coatings, as well as shells and other coatings well known in the pharmaceutical formulation art. They may optionally contain opacifying agents and can be of a composition that releases the active ingredient only, or preferentially, in a certain part of the intestinal tract, optionally in a delayed manner. Examples of embedding compositions that can be used include polymeric substances and waxes. Solid compositions of a similar type may also be used as fillers in soft and hard-filled gelatin capsules using excipients such as lactose or milk sugar and high molecular weight polyethylene glycols.

[0123] Compositions for topical or transdermal administration include ointments, pastes, creams, lotions, gels, powders, solutions, sprays, inhalants, or patches. The active compound is mixed with an excipient and any needed preservatives or buffers as required.

[0124] The ointments, pastes, creams, and gels may contain, in addition to the active compound, excipients such as animal and vegetable fats, oils, waxes, paraffin, starch, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonite, silicic acid, talc, and zinc oxide, or mixtures thereof.

[0125] Powders and sprays can contain, in addition to the active compound, excipients such as lactose, talc, silicic acid, aluminum hydroxide, calcium silicates and polyamide powder, or mixtures of these substances. Sprays can also contain conventional propellants such as chlorofluorohydrocarbons.

[0126] Transdermal patches have the added advantage of providing controlled delivery of compounds to the body. Such dosage forms can be made by dissolving or dispersing nanoparticles in a suitable medium. Absorption enhancers can also be used to increase the flux of the compound through the skin. The rate can be controlled by either providing a rate-controlling membrane or by dispersing the particles in a polymer matrix or gel.

[0127] The active ingredient may be administered in such amounts, for such times, and by such routes as are deemed necessary to achieve the desired results. The precise amount of the active ingredient will vary from subject to subject, depending on the species, age, and general condition of the subject, the severity of the infection, the particular active ingredient, its mode of administration, its mode of activity, and the like. The active ingredient, whether it is the active compound itself or the active compound is combined with a drug, is preferably formulated in unit dosage form for ease of administration and uniformity of dosage. However, it will be understood that the total daily amount of the active ingredient will be determined by the attending physician within the scope of sound medical judgment. A certain therapeutically effective dose level for any particular subject will depend on a variety of factors, including the disorder being treated and the severity of the disorder; the activity of the active ingredient used; the particular composition used; the patient's age, weight, general health, sex, and diet; the time, route of administration, and excretion rate of the particular active ingredient used; the duration of treatment; drugs used in combination or concurrently with the particular active ingredient used; and similar factors well known in the medical field.

[0128] The active ingredient may be administered by any route. In some embodiments, the active ingredient is administered via various routes, including oral, intravenous, intramuscular, intraarterial, intraspinal, intrathecal, subcutaneous, intraventricular, transdermal, intradermal, rectal, vaginal, intraperitoneal, topical (as powder, ointment, cream, and / or liquid drops), mucosal, intranasal, buccal, enteral, sublingual; by intratracheal instillation, bronchial instillation, and / or inhalation; and / or as oral spray, nasal spray, and / or aerosol. Generally, the most appropriate route of administration will depend on various factors, including the properties of the active ingredient (e.g., its stability in the gastrointestinal environment), the condition of the subject (e.g., whether the subject can tolerate oral administration), etc.

[0129] The exact amount of active ingredient required to obtain a therapeutically or prophylactically effective amount will vary from subject to subject, depending on the species, age, and general health of the subject, the severity of the side effect or disorder, the identity of the particular compound, the mode of administration, etc. For example, the amount to be administered to a child or adolescent can be determined by a medical professional or skilled artisan, or may be lower than or similar to the amount administered to an adult.

[0130] Useful dosages of the active agents and pharmaceutical compositions disclosed herein can be determined by comparing their in vitro activity, and in vivo activity in animal models. Methods for the extrapolation of effective dosages in mice, and other animals, to humans are known in the art.

[0131] The dosage range for administering the compositions is a dosage large enough to produce the desired effect in which the symptom or disorder is affected, based on their in vitro activity and in vivo activity range. The dosage should not be so large as to cause side effects such as undesirable cross-reactions, anaphylactic-type reactions, etc. Generally, the dosage will vary depending on the patient's age, condition, sex, and degree of disease, and can be determined by one skilled in the art. The dosage can be adjusted by an individual physician in the event of any contraindications. The dosage can be varied and can be administered in one or more doses daily for one or several days.

[0132] Although several embodiments of the present disclosure have been described, it will be understood that various modifications can be made without departing from the spirit and scope of the invention. Accordingly, other embodiments are within the scope of the following claims. [Example]

[0133] The following examples are presented below to illustrate methods and results according to the disclosed subject matter. These examples are not intended to be inclusive of all aspects of the subject matter disclosed herein, but rather to illustrate representative methods, compositions, and results. These examples are not intended to exclude equivalents and variations of the present invention that would be apparent to one skilled in the art.

[0134] Efforts have been made to ensure accuracy with respect to numbers (e.g., amounts, temperatures, etc.), but some errors and deviations should be accounted for. Unless otherwise indicated, parts are parts by weight, temperature is in °C or is ambient, and pressure is at or near atmospheric. There are numerous variations and combinations of reaction conditions, e.g., component concentrations, temperatures, pressures, and other reaction ranges and conditions, which can be used to optimize product purity and yields obtained from the described processes. Only reasonable and routine experimentation is required to optimize such process conditions.

[0135] Representative compounds of the present disclosure can be prepared using the process provided in the following scheme showing the synthesis of UR238. [ka]

[0136] UR238 inhibited HE4 expression in SKOV-3 ovarian cancer cells HE4 expression in SKOV-3 ovarian cancer cells was analyzed after treatment with DMSO or UR238 (0.5 or 2 μM). GAPDH expression was analyzed as a control. The results are shown in Figure 1. HE4 expression was found to be inhibited in UR238-treated cells compared to DMSO-treated cells.

[0137] UR238 inhibited HE4 secretion from ECC-1 endometrial cancer cells HE4 secretion from ECC-1 endometrial cancer cells was analyzed. Cells were treated with either DMSO or UR238 at concentrations of 0.1, 1.0, or 10 μM. The results are shown in Figure 2. Secreted HE4 levels were found to be decreased in cells treated with UR238 compared to DMSO-treated cells.

[0138] UR238 inhibited the growth of ovarian cancer cell-derived xenografts in NSG mice The effect of UR238 treatment on SKV-3 SH1 ovarian cancer cell-derived xenografts in NSG mice was analyzed. Treatment with vehicle or UR238 was initiated on day 9 after implantation, and tumor size was measured on days 9, 13, 15, 18, and 21 after implantation. The results are shown in Figure 3. UR238 treatment inhibited the growth of SKOV-3 cancer cell-derived xenografts.

[0139] UR238 inhibited the growth of endometrial cancer cell-derived xenografts in NSF mice The effect of UR238 treatment on AN3CA endometrial cancer cell-derived xenografts in NSG mice was analyzed. Treatment with vehicle or UR238 was initiated on day 9 after implantation, and tumor size was measured on days 10, 14, 18, and 21 after implantation. The results are shown in Figure 4, and images of excised tumors are shown in Figure 5. UR238 treatment inhibited the growth of AN3CA cancer cell-derived xenografts.

[0140] The compositions and methods of the appended claims are not limited in scope by the specific compositions and methods described herein; they are intended as illustrations of some aspects of the claims; any compositions and methods that are functionally equivalent are intended to be within the scope of the claims. Various modifications of the compositions and methods in addition to those shown and described herein are intended to be within the scope of the appended claims. Furthermore, while only certain representative compositions and method steps disclosed herein are specifically recited, other combinations of compositions and method steps, even if not specifically recited, are also intended to be within the scope of the appended claims. Thus, although combinations of steps, elements, components, or ingredients may be explicitly referred to herein or hereinafter, other combinations of steps, elements, components, or ingredients are included, even if not explicitly recited.

[0141] As used herein, the term "comprising" and variations thereof are used synonymously with the term "including" and variations thereof and are open, non-limiting terms. Although the terms "comprising" and "including" have been used herein to describe various embodiments, the terms "consisting essentially of" and "consisting of" can be used in place of "comprising" and "including" to provide more specific embodiments of the present invention, and are also disclosed. Except in the examples, or unless otherwise specified, it should be understood that all numbers expressing quantities of ingredients, reaction conditions, and the like used in the specification and claims are to be construed in light of the number of significant digits and ordinary rounding approaches, at least not as an attempt to limit the application of the doctrine of equivalents to the scope of the claims. The inventions described in the original claims of this application are listed below. [Invention 1] Compounds of Formula I [ka] or a pharmaceutically acceptable salt or derivative thereof, During the ceremony, X is O, -CH 2 -, N(R 6 ), and S; Y is S, S(=Z), and S(=Z) 2 is selected from Z is O, S, and NR 7 is selected from m, n, and o are independently 0 or 1; R 1 is hydrogen or C 1 ~C 6 is alkyl, R 2 、R 3 、R 4 , and R 5 But independently, in each occurrence, H, C 1 ~C 6 Alkyl, aryl (C 0 ~C 6 alkyl), and heteroaryl (C 0 ~C 6 alkyl), wherein R 2 、R 3 、R 4 , and R 5 each of which may be optionally substituted with one or more substituents selected from alkyl, alkoxy, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, cycloalkenyl, heterocycloalkenyl, aldehyde, amino, carboxylic acid, ester, ether, halide, hydroxy, ketone, nitro, cyano, azide, silyl, sulfo-oxo, sulfonyl, sulfonylamino, sulfone, sulfoxide, and thiol; R 6 But H or C 1 ~C 6 alkyl, R 7 is H, optionally substituted C 1 ~C 6 alkyl, optionally substituted aryl, optionally substituted heteroaryl, -OR 8 and -NR 9 R 10 is selected from R 8 is H, optionally substituted C 1 ~C 6 selected from alkyl, optionally substituted aryl, and optionally substituted heteroaryl; R 9 and R 10 is independently at each occurrence H, optionally substituted C1 ~C 6 A compound, or a pharmaceutically acceptable salt or derivative thereof, selected from alkyl, optionally substituted aryl, and optionally substituted heteroaryl. [Invention 2] The compound is of formula II:

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Claims

1. The following compounds 【Chemistry 1】 or a pharmaceutically acceptable salt thereof.

2. A pharmaceutical composition comprising the compound of claim 1, or a pharmaceutically acceptable salt thereof, in a pharmaceutically acceptable carrier.

3. 10. A composition for treating cancer in a subject, comprising the compound of claim 1, or a pharmaceutically acceptable salt thereof.

4. The composition of claim 3 , wherein the cancer is selected from carcinoma or sarcoma.

5. The composition of claim 3 , wherein the cancer is selected from ovarian cancer, endometrial cancer, breast cancer, lung cancer, or testicular cancer.

6. The composition of claim 3 , wherein the cancer is a refractory cancer.

7. The composition of claim 3 , wherein the cancer is an immunogenic cancer.

8. 8. The composition of claim 7, wherein the immunogenic cancer is selected from malignant melanoma and renal cell carcinoma, mantle cell lymphoma, follicular lymphoma, diffuse large B-cell lymphoma, T-cell acute lymphoblastic leukemia, Burkitt's lymphoma, myeloma, immunocytoma, acute promyelocytic leukemia, chronic myeloid / acute lymphoblastic leukemia, acute leukemia, B-cell acute lymphoblastic leukemia, anaplastic large cell leukemia, myelodysplastic syndrome / acute myeloid leukemia, non-Hodgkin's lymphoma, chronic lymphocytic leukemia, acute myeloid leukemia (AML), common (pre-B) acute lymphoblastic leukemia, malignant melanoma, T-cell lymphoma, leukemia, B-cell lymphoma, epithelial malignancies, lymphoid malignancies, gynecological cancers, biliary adenocarcinoma, and ductal adenocarcinoma.

9. 10. A composition for treating an inflammatory disorder in a subject, comprising the compound of claim 1, or a pharmaceutically acceptable salt thereof.

10. 10. A composition for treating organ fibrosis in a subject, comprising the compound of claim 1, or a pharmaceutically acceptable salt thereof.

11. 11. The composition of claim 10, wherein the organ fibrosis is selected from renal fibrosis, pulmonary fibrosis, liver cirrhosis, endomyocardial fibrosis, Crohn's disease, liver fibrosis, cardiac fibrosis, scleroderma, or progressive massive fibrosis.

12. 10. A composition for treating infertility in a subject, comprising the compound of claim 1, or a pharmaceutically acceptable salt thereof.

13. The composition according to any one of claims 3 to 12, wherein the compound according to claim 1 is administered in combination with one or more additional therapies.

14. 14. The composition of claim 13, wherein the one or more additional therapies are selected from radiation therapy, surgery, chemotherapy, or administration of one or more checkpoint inhibitors.

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