Oligobenzamide analogs and their use in cancer treatment

Abstract

To provide an oligo-benzamide peptidonimetic compound for use in the treatment and / or prevention of cancer.SOLUTION: The present invention provides compounds of the formulae (I) and (II) as well as pharmaceutical compositions thereof.SELECTED DRAWING: None

Description

[Technical Field]

[0001] Priority claim This application claims the benefit of priority to U.S. Provisional Application No. 62 / 774,671, filed December 3, 2018, the entire contents of which are incorporated herein by reference.

[0002] Federal Funding Statement This invention was made with government support under Grant No. 1R01 CA223828-01 awarded by the National Institutes of Health. The government has certain rights in this invention.

[0003] I. FIELD OF THE INVENTION FIELD OF THE DISCLOSURE The present disclosure relates generally to the field of peptidomimetics, and specifically to compositions and methods of their use in medical indications such as cancer. [Background technology]

[0004] II. Description of Related Art Peptide mimetics (also known as peptidomimetics) are small organic molecules that do not have a peptide backbone structure but still retain the ability to interact with the same target protein by arranging essential functional groups (i.e., pharmacophores) in a required three-dimensional pattern that is complementary to the binding pocket in the protein. Because peptides and proteins adopt and utilize secondary structures (e.g., α-helices, β-sheets, and reverse turns) to create their globular shape and recognize their binding partners, the rational design of secondary structure mimetics is an important strategy for developing small molecule modulators of protein complex formation compared to traditional high-throughput screening of chemical libraries.

[0005] These compounds are known to bind to hormone receptors in cancer cells and are useful in treating these indications. Thus, there remains a need to develop new and useful compounds that are useful in treating cancer through modulation of hormone receptors. Summary of the Invention

[0006] overview The present disclosure provides oligobenzamide peptidomimetic compounds for use in the treatment and / or prevention of cancer. These small molecules contain α-helix mimetics that represent helical segments in target molecules. Oligobenzamide peptidomimetic compounds modulate protein-protein, protein-peptide, or protein-drug interactions to exert various physiological effects. Oligobenzamide peptidomimetic compounds can also cause significant endoplasmic reticulum stress in cancer cells, effectively halting de novo protein synthesis and leading to cell death.

[0007] In one aspect, the disclosure provides a compound of the following formula or a pharmaceutically acceptable salt of the following formula: TIFF0007770716000001.tif68128 formula: R1 is halo, -NO2, alkyl (C≦12) , substituted alkyl (C≦12) , amide (C≦12) , substituted amide (C≦12) , or -NHC(O)CH(R 1a )NH2, R 1a is aralkyl (C≦18) , substituted aralkyl (C≦18) , or the side chain of a standard amino acid; R2, R3, and R4 are each independently alkyl (C≦12) , substituted alkyl (C≦12) , aralkyl (C≦18) , or substituted aralkyl (C≦18) and R5 is -OR 5a or -NHR 5b and R 5a is an alkyl (C≦12) or substituted alkyl (C≦12) and R 5b is hydrogen, or cycloalkyl (C≦12), aryl (C≦12) , aralkyl (C≦18) , heteroaryl (C≦12) , heteroaralkyl (C≦18) or a substituted form of any of these groups, or Groups of the formula: TIFF0007770716000002.tif21128, L1 is -CO2- or -C(O)NR L1 - and R L1 is hydrogen, alkyl (C≦12) , or substituted alkyl (C≦12) and R 5b’ is an aryl (C≦12) , aralkyl (C≦18) , heteroaryl (C≦12) , heteroaralkyl (C≦18) or a substituted version of any of these groups; However, R 5b is hydrogen, then R is halo, and with the proviso that R 5a is methyl, R3 is alkyl (C≦12) isn't it; or TIFF0007770716000003.tif51128 formula: R6 is halo, -NO2, alkyl (C≦12) , substituted alkyl (C≦12) , amide (C≦12) , substituted amide (C≦12) , or -NHC(O)CH(R 6a )NH2, R 6a is aralkyl (C≦18) , substituted aralkyl (C≦18) , or the side chain of a standard amino acid; R7 and R8 are each independently alkyl (C≦12) , -alkanediyl (C≦12) -cycloalkyl (C≦12) , aralkyl (C≦18) or a substituted form of any of these groups; and R9 is cycloalkyl (C≦12) , aryl (C≦12), aralkyl (C≦18) , heteroaryl (C≦12) , heteroaralkyl (C≦18) or a substituted version of any of these groups; or Groups of the formula: TIFF0007770716000004.tif21128, L2 is -CO2- or -C(O)NR L2 - and R L2 is hydrogen, alkyl (C≦12) , or substituted alkyl (C≦12) and R 9a is an aryl (C≦12) , aralkyl (C≦18) , heteroaryl (C≦12) , heteroaralkyl (C≦18) or a substituted version of any of these groups.

[0008] In some embodiments, the compound is of formula (I). In further embodiments, the compound is TIFF0007770716000005.tif67128 or a pharmaceutically acceptable salt thereof; During the ceremony: R1 is halo, -NO2, alkyl (C≦12) , substituted alkyl (C≦12) , amide (C≦12) , substituted amide (C≦12) , or -NHC(O)CH(R 1a )NH2, R 1a is aralkyl (C≦18) , substituted aralkyl (C≦18) , or the side chain of a standard amino acid; R2, R3, and R4 are each independently alkyl (C≦12) , substituted alkyl (C≦12) , aralkyl (C≦18) , or substituted aralkyl (C≦18) and R5 is -OR 5a or -NHR 5b and R 5ais an alkyl (C≦12) or substituted alkyl (C≦12) and R 5b is a cycloalkyl (C≦12) , aryl (C≦12) , aralkyl (C≦18) , heteroaryl (C≦12) , heteroaralkyl (C≦18) or a substituted form of any of these groups, or Groups of the formula: TIFF0007770716000006.tif21128, L1 is -CO2- or -C(O)NR L1 - and R L1 is hydrogen, alkyl (C≦12) , or substituted alkyl (C≦12) and R 5b’ is an aryl (C≦12) , aralkyl (C≦18) , heteroaryl (C≦12) , heteroaralkyl (C≦18) or a substituted version of any of these groups.

[0009] In some embodiments, the compound is TIFF0007770716000007.tif68128 or a pharmaceutically acceptable salt thereof; During the ceremony: R1 is a halo; and R2, R3, and R4 are each independently alkyl (C≦12) , substituted alkyl (C≦12) , aralkyl (C≦18) , or substituted aralkyl (C≦18) is.

[0010] In some embodiments, the compound is TIFF0007770716000008.tif68128 or a pharmaceutically acceptable salt thereof; During the ceremony: R1 is halo, -NO2, alkyl (C≦12) , substituted alkyl (C≦12), amide (C≦12) , substituted amide (C≦12) , or -NHC(O)CH(R 1a )NH2, R 1a is aralkyl (C≦18) , substituted aralkyl (C≦18) , or the side chain of a standard amino acid; R2, R3, and R4 are each independently alkyl (C≦12) , substituted alkyl (C≦12) , aralkyl (C≦18) , or substituted aralkyl (C≦18) and R5 is -OR 5a or -NHR 5b and R 5a is an alkyl (C2-12) or substituted alkyl (C≦12) and R 5b is hydrogen, or cycloalkyl (C≦12) , aryl (C≦12) , aralkyl (C≦18) , heteroaryl (C≦12) , heteroaralkyl (C≦18) or a substituted form of any of these groups, or Groups of the formula: TIFF0007770716000009.tif21128, L1 is -CO2- or -C(O)NR L1 - and R L1 is hydrogen, alkyl (C≦12) , or substituted alkyl (C≦12) and R 5b’ is an aryl (C≦12) , aralkyl (C≦18) , heteroaryl (C≦12) , heteroaralkyl (C≦18) or a substituted version of any of these groups.

[0011] In some embodiments, the compound is TIFF0007770716000010.tif67128 or a pharmaceutically acceptable salt thereof; During the ceremony: R1 is halo, -NO2, alkyl (C≦12) , substituted alkyl (C≦12) , amide (C≦12) , substituted amide (C≦12) , or -NHC(O)CH(R 1a )NH2, R 1a is aralkyl (C≦18) , substituted aralkyl (C≦18) , or the side chain of a standard amino acid; R2 and R4 are each independently alkyl (C≦12) , substituted alkyl (C≦12) , aralkyl (C≦18) , or substituted aralkyl (C≦18) and R3 is a substituted alkyl (C≦12) , aralkyl (C≦18) , or substituted aralkyl (C≦18) is.

[0012] In some embodiments, R 5b is hydrogen. In some embodiments, R 5a is methyl.

[0013] In some embodiments, the compound is TIFF0007770716000011.tif68128 or a pharmaceutically acceptable salt thereof; During the ceremony: R1 is halo, -NO2, alkyl (C≦12) , substituted alkyl (C≦12) , amide (C≦12) , substituted amide (C≦12) , or -NHC(O)CH(R 1a )NH2, R 1a is aralkyl (C≦18) , substituted aralkyl (C≦18) , or the side chain of a standard amino acid; R2, R3, and R4 are each independently alkyl (C≦12), substituted alkyl (C≦12) , aralkyl (C≦18) , or substituted aralkyl (C≦18) and R5-NHR 5b and R 5b is a cycloalkyl (C≦12) , aryl (C≦12) , aralkyl (C≦18) , heteroaryl (C≦12) , heteroaralkyl (C≦18) or a substituted form of any of these groups, or Groups of the formula: TIFF0007770716000012.tif21128, L1 is -CO2- or -C(O)NR L1 - and R L1 is hydrogen, alkyl (C≦12) , or substituted alkyl (C≦12) and R 5b’ is an aryl (C≦12) , aralkyl (C≦18) , heteroaryl (C≦12) , heteroaralkyl (C≦18) or a substituted version of any of these groups.

[0014] In some embodiments, R2 is aralkyl (C≦18) or substituted aralkyl (C≦18) In a further embodiment, R2 is a substituted aralkyl (C≦18) In other embodiments, R2 is alkyl, for example, 4-hydroxyphenethyl. (C≦12) or substituted alkyl (C≦12) In a further embodiment, R2 is substituted alkyl (C≦12) In some embodiments, R4 is aralkyl, for example, 1-hydroxyethyl. (C≦18) or substituted aralkyl (C≦18) In a further embodiment, R4 is aralkyl (C≦18) In other embodiments, R4 is alkyl, for example, benzyl. (C≦12) or substituted alkyl(C≦12) In a further embodiment, R4 is alkyl (C≦12) In some embodiments, R is aralkyl, for example, n-butyl or i-butyl. (C≦18) or substituted aralkyl (C≦18) In a further embodiment, R3 is aralkyl (C≦18) In another embodiment, R3 is alkyl, for example, 2-(naphthalen-2-yl)ethyl. (C≦12) or substituted alkyl (C≦12) In a further embodiment, R3 is alkyl (C≦12) , for example, methyl or i-butyl.

[0015] In some embodiments, R 5b is aralkyl (C≦18) or substituted aralkyl (C≦18) In a further embodiment, R 5b is aralkyl (C≦18) , for example, (naphthalen-2-yl)methyl. In other embodiments, R 5b is heteroaryl (C≦12) or substituted heteroaryl (C≦12) In a further embodiment, R 5b is heteroaryl (C≦12) , for example, 1H-imidazol-2-yl. In still other embodiments, R 5b is a cycloalkyl (C≦12) or substituted cycloalkyl (C≦12) In a further embodiment, R 5b is a cycloalkyl (C≦12) In some embodiments, L is -C(O)NR L1 In some embodiments, R L1 is hydrogen. In some embodiments, R 5b’ is heteroaryl (C≦12) or substituted heteroaryl (C≦12) In a further embodiment, R 5b’ is heteroaryl (C≦12) , for example, quinolin-3-yl or 1H-indazol-7-yl.

[0016] In some embodiments, R1 is -NO2. In other embodiments, R1 is alkyl (C≦12) or substituted alkyl (C≦12) In a further embodiment, R1 is alkyl (C≦12) In yet another embodiment, R1 is halo, e.g., fluoro or iodo. In yet another embodiment, R1 is amide. (C≦12) or substituted amide (C≦12) In a further embodiment, R is a substituted amide (C≦12) , for example, 3-aminopropanamide. In some embodiments, R 1a is aralkyl (C≦18) or substituted aralkyl (C≦18) In a further embodiment, R 1a is aralkyl (C≦18) , for example, benzyl.

[0017] In other embodiments, the compound is of formula (II). In some embodiments, R7 is alkyl (C≦12) or substituted alkyl (C≦12) In a further embodiment, R7 is substituted alkyl (C≦12) In some embodiments, R8 is -alkanediyl, for example, 1-hydroxyethyl. (C≦12) -cycloalkyl (C≦12) or substituted alkanediyl (C≦12) -cycloalkyl (C≦12) In a further embodiment, R8 is -alkanediyl (C≦12) -cycloalkyl (C≦12) In some embodiments, R is aralkyl, for example, (cyclohexyl)methyl. (C≦18) or substituted aralkyl (C≦18) In a further embodiment, R9 is aralkyl (C≦18) In some embodiments, R6 is amide, for example, 2-(naphthalen-2-yl)ethyl. (C≦12) or substituted amide (C≦12) In a further embodiment, R6 is a substituted amide(C≦12) , for example, 3-aminopropanamide.

[0018] In some embodiments, the compound is further defined as the following or a pharmaceutically acceptable salt thereof: TIFF0007770716000013.tif177133TIFF0007770716000014.tif183128TIFF0007770716000015.tif125128

[0019] In some embodiments, the compound is further defined as the following or a pharmaceutically acceptable salt thereof: TIFF0007770716000016.tif177133TIFF0007770716000017.tif183128

[0020] In some embodiments, the compound is further defined as the following or a pharmaceutically acceptable salt thereof: TIFF0007770716000018.tif67128

[0021] In some embodiments, the compound is further defined as the following or a pharmaceutically acceptable salt thereof: TIFF0007770716000019.tif54128

[0022] In another aspect, the present disclosure provides a method for manufacturing a semiconductor device comprising: (a) a compound disclosed herein; and (b) excipients and / or pharmaceutically acceptable carriers The present invention provides a pharmaceutical composition comprising:

[0023] In some embodiments, the composition is formulated for administration orally, intraadiposely, intraarterially, intraarticularly, intracranially, intradermally, intralesionally, intramuscularly, intranasally, intraocularly, intrapericardially, intraperitoneally, intrapleurally, intraprostatically, intrarectally, intrathecally, intratumorally, intraumbilically, intravaginally, intravenously, intravesically, intravitreally, by liposome, topically, mucosally, parenterally, rectally, subconjunctivally, subcutaneously, sublingually, topically, transbuccally, transdermally, vaginally, by cream, lipid composition, by catheter, by irrigation, by continuous infusion, by injection, by inhalation, by injection, by local delivery or by local perfusion.In further embodiments, the composition is formulated for administration orally, intraarterially, intratumorally, intravenously, topically, subcutaneously, topically, intraperitoneally or by injection.

[0024] In yet another aspect, the present disclosure provides a method of treating a disease or disorder in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of a compound or composition disclosed herein. In some embodiments, the patient is a mammal, e.g., a human. In some embodiments, the disease or disorder is cancer. In some embodiments, the cancer is a treatment-resistant cancer. In some embodiments, the cancer is breast cancer, ovarian cancer, pancreatic cancer, or brain cancer. In further embodiments, the cancer is breast cancer, e.g., triple-negative breast cancer. In other embodiments, the cancer is ovarian cancer. In yet other embodiments, the cancer is pancreatic cancer. In yet other embodiments, the cancer is brain cancer, e.g., glioblastoma. In some embodiments, the cancer is an estrogen receptor-positive cancer. In other embodiments, the cancer is an estrogen receptor-negative cancer.

[0025] In some embodiments, the administering step comprises intravenous, intraarterial, intratumoral, subcutaneous, topical, or intraperitoneal administration. In some embodiments, the administering step comprises local, regional, systemic, or continuous administration. In some embodiments, the method further comprises providing a second anticancer therapy to the subject. In some embodiments, the second anticancer therapy is surgery, chemotherapy, radiation therapy, hormone therapy, toxin therapy, immunotherapy, and cryotherapy. In some embodiments, the second anticancer therapy is provided before the step of administering the compound. In other embodiments, the second anticancer therapy is provided after the step of administering the compound. In still other embodiments, the second anticancer therapy is provided simultaneously with the compound.

[0026] In some embodiments, the compound is administered daily. In some embodiments, the compound is administered daily for 7 days, 2 weeks, 3 weeks, 4 weeks, 1 month, 6 weeks, 8 weeks, 2 months, 12 weeks, or 3 months. In further embodiments, the compound is administered weekly. In some embodiments, the compound is administered weekly for 2 weeks, 3 weeks, 4 weeks, 6 weeks, 8 weeks, 10 weeks, or 12 weeks. In some embodiments, the compound or composition is administered in an amount sufficient to induce endoplasmic reticulum stress and / or stop protein synthesis. In some embodiments, the compound acts by inducing endoplasmic reticulum stress within a few hours of administration, followed by stopping protein synthesis. In some embodiments, the level of basal endoplasmic reticulum stress or compensatory unfolded protein response in cells determines the response to the drug.

[0027] The use of the words "a" or "an" when used in conjunction with the word "comprising" in the claims and / or specification may mean "one," but is also consistent with the meaning of "one or more," "at least one," and "one or more than one."

[0028] As used herein, the term "or combinations thereof" refers to all permutations and combinations of the listed items preceding the term. For example, "A, B, C, or combinations thereof" is intended to include at least one of A, B, C, AB, AC, BC, or ABC, and also BA, CA, CB, CBA, BCA, ACB, BAC, or CAB if order is important in the particular context. Those skilled in the art will understand that there is typically no limit to the number of items or entities in any combination unless otherwise clear from the context.

[0029] As used in the specification and claims, the terms "comprising" (and any form of comprising, e.g., "comprise" and "comprises"), "having" (and any form of having, e.g., "have" and "has"), "including" (and any form of including, e.g., "includes" and "include") or "containing" (and any form of containing, e.g., "contains" and "contain") are inclusive or open-ended and do not exclude further, unrecited elements or method steps.

[0030] [The present invention 1001] A compound of the following formula or a pharmaceutically acceptable salt of the following formula: TIFF0007770716000020.tif68128 formula: R1 is halo, -NO2, alkyl (C≦12) , substituted alkyl (C≦12) , amide (C≦12) , substituted amide (C≦12) , or -NHC(O)CH(R 1a )NH2, R 1a is aralkyl (C≦18) , substituted aralkyl (C≦18) , or the side chain of a standard amino acid; R2, R3, and R4 are each independently alkyl (C≦12) , substituted alkyl (C≦12) , aralkyl (C≦18) , or substituted aralkyl (C≦18) and R5 is -OR 5a or -NHR 5b and R 5a is an alkyl (C≦12) or substituted alkyl (C≦12) and R 5b is hydrogen, or cycloalkyl (C≦12) , aryl (C≦12) , aralkyl (C≦18) , heteroaryl (C≦12) , heteroaralkyl (C≦18) or a substituted form of any of these groups, or Groups of the formula: TIFF0007770716000021.tif21128, L1 is -CO2- or -C(O)NR L1 - and R L1 is hydrogen, alkyl (C≦12) , or substituted alkyl (C≦12) and R 5b’ is an aryl (C≦12) , aralkyl (C≦18) , heteroaryl (C≦12) , heteroaralkyl (C≦18) or a substituted version of any of these groups; However, R 5b is hydrogen, then R is halo, and with the proviso that R 5a is methyl, R3 is alkyl (C≦12) isn't it; or A compound of the following formula or a pharmaceutically acceptable salt of the following formula: TIFF0007770716000022.tif51128 formula: R6 is halo, -NO2, alkyl (C≦12) , substituted alkyl (C≦12) , amide(C≦12) , substituted amide (C≦12) , or -NHC(O)CH(R 6a )NH2, R 6a is aralkyl (C≦18) , substituted aralkyl (C≦18) , or the side chain of a standard amino acid; R7 and R8 are each independently alkyl (C≦12) , -alkanediyl (C≦12) -cycloalkyl (C≦12) , aralkyl (C≦18) or a substituted form of any of these groups; and R9 is cycloalkyl (C≦12) , aryl (C≦12) , aralkyl (C≦18) , heteroaryl (C≦12) , heteroaralkyl (C≦18) or a substituted form of any of these groups, or Groups of the formula: TIFF0007770716000023.tif21128, L2 is -CO2- or -C(O)NR L2 - and R L2 is hydrogen, alkyl (C≦12) , or substituted alkyl (C≦12) and R 9a is an aryl (C≦12) , aralkyl (C≦18) , heteroaryl (C≦12) , heteroaralkyl (C≦18) or a substituted version of any of these groups. [The present invention 1002] 1001. A compound of the present invention, wherein the compound is of formula (I): [The present invention 1003] The compound is TIFF0007770716000024.tif68128 or a pharmaceutically acceptable salt thereof; During the ceremony: R1 is halo, -NO2, alkyl (C≦12) , substituted alkyl (C≦12) , amide(C≦12) , substituted amide (C≦12) , or -NHC(O)CH(R 1a )NH2, R 1a is aralkyl (C≦18) , substituted aralkyl (C≦18) , or the side chain of a standard amino acid; R2, R3, and R4 are each independently alkyl (C≦12) , substituted alkyl (C≦12) , aralkyl (C≦18) , or substituted aralkyl (C≦18) and R5 is -OR 5a or -NHR 5b and R 5a is an alkyl (C≦12) or substituted alkyl (C≦12) and R 5b is a cycloalkyl (C≦12) , aryl (C≦12) , aralkyl (C≦18) , heteroaryl (C≦12) , heteroaralkyl (C≦18) or a substituted form of any of these groups, or Groups of the formula: TIFF0007770716000025.tif21128, L1 is -CO2- or -C(O)NR L1 - and R L1 is hydrogen, alkyl (C≦12) , or substituted alkyl (C≦12) and R 5b’ is an aryl (C≦12) , aralkyl (C≦18) , heteroaryl (C≦12) , heteroaralkyl (C≦18) or a substituted form of any of these groups, Compound 1001 or 1002 of the present invention. [The present invention 1004] The compound is TIFF0007770716000026.tif68128 or a pharmaceutically acceptable salt thereof; During the ceremony: R1 is a halo; and R2, R3, and R4 are each independently alkyl (C≦12) , substituted alkyl (C≦12) , aralkyl (C≦18) , or substituted aralkyl (C≦18) That is, Compound 1001 or 1002 of the present invention. [The present invention 1005] The compound is TIFF0007770716000027.tif68128 or a pharmaceutically acceptable salt thereof; During the ceremony: R1 is halo, -NO2, alkyl (C≦12) , substituted alkyl (C≦12) , amide (C≦12) , substituted amide (C≦12) , or -NHC(O)CH(R 1a )NH2, R 1a is aralkyl (C≦18) , substituted aralkyl (C≦18) , or the side chain of a standard amino acid; R2, R3, and R4 are each independently alkyl (C≦12) , substituted alkyl (C≦12) , aralkyl (C≦18) , or substituted aralkyl (C≦18) and R5 is -OR 5a or -NHR 5b and R 5a is an alkyl (C2-12) or substituted alkyl (C≦12) and R 5b is hydrogen, or cycloalkyl (C≦12) , aryl (C≦12) , aralkyl (C≦18) , heteroaryl (C≦12) , heteroaralkyl (C≦18)or a substituted form of any of these groups, or Groups of the formula: TIFF0007770716000028.tif21128, L1 is -CO2- or -C(O)NR L1 - and R L1 is hydrogen, alkyl (C≦12) , or substituted alkyl (C≦12) and R 5b’ is an aryl (C≦12) , aralkyl (C≦18) , heteroaryl (C≦12) , heteroaralkyl (C≦18) or a substituted form of any of these groups, Compound 1001 or 1002 of the present invention. [The present invention 1006] The compound is TIFF0007770716000029.tif67128 or a pharmaceutically acceptable salt thereof; During the ceremony: R1 is halo, -NO2, alkyl (C≦12) , substituted alkyl (C≦12) , amide (C≦12) , substituted amide (C≦12) , or -NHC(O)CH(R 1a )NH2, R 1a is aralkyl (C≦18) , substituted aralkyl (C≦18) , or the side chain of a standard amino acid; R2 and R4 are each independently alkyl (C≦12) , substituted alkyl (C≦12) , aralkyl (C≦18) , or substituted aralkyl (C≦18) and R3 is a substituted alkyl (C≦12) , aralkyl (C≦18) , or substituted aralkyl (C≦18) That is, Compound 1001 or 1002 of the present invention. [The present invention 1007] R 5bThe compound of the present invention 1001 or 1002, wherein is hydrogen. [The present invention 1008] R 5a The compound of the present invention 1001 or 1002, wherein is methyl. [The present invention 1009] The compound is TIFF0007770716000030.tif68128 or a pharmaceutically acceptable salt thereof; During the ceremony: R1 is halo, -NO2, alkyl (C≦12) , substituted alkyl (C≦12) , amide (C≦12) , substituted amide (C≦12) , or -NHC(O)CH(R 1a )NH2, R 1a is aralkyl (C≦18) , substituted aralkyl (C≦18) , or the side chain of a standard amino acid; R2, R3, and R4 are each independently alkyl (C≦12) , substituted alkyl (C≦12) , aralkyl (C≦18) , or substituted aralkyl (C≦18) and R5-NHR 5b and R 5b is a cycloalkyl (C≦12) , aryl (C≦12) , aralkyl (C≦18) , heteroaryl (C≦12) , heteroaralkyl (C≦18) or a substituted form of any of these groups, or Groups of the formula: TIFF0007770716000031.tif21128, L1 is -CO2- or -C(O)NR L1 - and R L1 is hydrogen, alkyl (C≦12) , or substituted alkyl (C≦12) and R 5b’ is an aryl (C≦12) , aralkyl(C≦18) , heteroaryl (C≦12) , heteroaralkyl (C≦18) or a substituted form of any of these groups, Any of compounds 1001 to 1003 of the present invention. [The present invention 1010] R2 is aralkyl (C≦18) or substituted aralkyl (C≦18) The compound of any one of 1001 to 1009 of the present invention, [The present invention 1011] R2 is a substituted aralkyl (C≦18) The compound of any one of 1001 to 1010 of the present invention, [The present invention 1012] The compound of any one of claims 1001 to 1011, wherein R2 is 4-hydroxyphenethyl. [The present invention 1013] R2 is alkyl (C≦12) or substituted alkyl (C≦12) The compound of any one of 1001 to 1009 of the present invention, [The present invention 1014] R2 is substituted alkyl (C≦12) The compound of any one of 1001 to 1009 and 1013 of the present invention, [The present invention 1015] Compounds of any one of 1001 to 1009, 1013, and 1014 of the present invention, wherein R2 is 1-hydroxyethyl. [The present invention 1016] R4 is aralkyl (C≦18) or substituted aralkyl (C≦18) The compound of any one of claims 1001 to 1015 of the present invention, [The present invention 1017] R4 is aralkyl (C≦18) The compound of any one of claims 1001 to 1016 of the present invention, [The present invention 1018] The compound of any one of claims 1001 to 1017, wherein R4 is benzyl. [The present invention 1019] R4 is alkyl (C≦12) or substituted alkyl (C≦12)The compound of any one of claims 1001 to 1015 of the present invention, [The present invention 1020] R4 is alkyl (C≦12) The compound of any one of 1001 to 1015 and 1019 of the present invention, [The present invention 1021] Compounds of any one of 1001 to 1015, 1019, and 1020 of the present invention, wherein R4 is n-butyl. [The present invention 1022] Compounds of any one of 1001 to 1015, 1019, and 1020 of the present invention, wherein R4 is i-butyl. [The present invention 1023] R3 is aralkyl (C≦18) or substituted aralkyl (C≦18) The compound of any one of the present inventions 1001 to 1022, [The present invention 1024] R3 is aralkyl (C≦18) The compound of any one of claims 1001 to 1023 of the present invention, [The present invention 1025] The compound of any one of claims 1001 to 1024, wherein R3 is 2-(naphthalen-2-yl)ethyl. [The present invention 1026] R3 is alkyl (C≦12) or substituted alkyl (C≦12) The compound of any one of 1001 to 1005, 1007, and 1009 to 1022 of the present invention, [The present invention 1027] R3 is alkyl (C≦12) Any of compounds 1001 to 1005, 1007, 1009 to 1022, and 1026 of the present invention, [The present invention 1028] Compounds of any one of 1001 to 1005, 1007, 1009 to 1022, 1026, and 1027 of the present invention, wherein R3 is methyl. [The present invention 1029] Compounds of any one of 1001 to 1005, 1007, 1009 to 1022, 1026, and 1027 of the present invention, wherein R3 is i-butyl. [The present invention 1030] R5b But aralkyl (C≦18) or substituted aralkyl (C≦18) Any of compounds 1001 to 1003, 1005, and 1008 to 1029 of the present invention, [The present invention 1031] R 5b is aralkyl (C≦18) The compound of any one of 1001 to 1003, 1005, and 1008 to 1030 of the present invention, [The present invention 1032] R 5b The compound of any one of claims 1001 to 1003, 1005, and 1008 to 1031 of the present invention, wherein is (naphthalen-2-yl)methyl. [The present invention 1033] R 5b But heteroaryl (C≦12) or substituted heteroaryl (C≦12) Any of compounds 1001 to 1003, 1005, and 1008 to 1029 of the present invention, [The present invention 1034] R 5b is heteroaryl (C≦12) The compound of any one of 1001 to 1003, 1005, 1008 to 1029, and 1033 of the present invention, [This invention 1035] R 5b The compound of any one of claims 1001 to 1003, 1005, 1008 to 1029, 1033, and 1034 of the present invention, wherein is 1H-imidazol-2-yl. [The present invention 1036] R 5b But cycloalkyl (C≦12) or substituted cycloalkyl (C≦12) Any of compounds 1001 to 1003, 1005, and 1008 to 1029 of the present invention, [This invention 1037] R 5b is cycloalkyl (C≦12) Any of compounds 1001 to 1003, 1005, 1008 to 1029, and 1036 of the present invention, [The present invention 1038] R5b The compound of any one of 1001 to 1003, 1005, 1008 to 1029, 1036, and 1037 of the present invention, wherein is 4-methylcyclohexyl. [This invention 1039] L1 is -C(O)NR L1 - Any of compounds 1001 to 1003, 1005, and 1008 to 1029 of the present invention, [The present invention 1040] R L1 The compound of any one of 1001 to 1003, 1005, 1008 to 1029, and 1039 of the present invention, wherein is hydrogen. [This invention 1041] R 5b’ But heteroaryl (C≦12) or substituted heteroaryl (C≦12) The compound of any one of 1001 to 1003, 1005, 1008 to 1029, 1039, and 1040 of the present invention, [The present invention 1042] R 5b’ is heteroaryl (C≦12) The compound of any one of 1001 to 1003, 1005, 1008 to 1029, and 1039 to 1041 of the present invention, [This invention 1043] R 5b’ is quinolin-3-yl. [This invention 1044] R 5b’ is 1H-indazol-7-yl. [This invention 1045] Compounds of any one of 1001 to 1003, 1005, 1006, and 1008 to 1044 of the present invention, wherein R1 is -NO2. [The present invention 1046] R1 is alkyl (C≦12) or substituted alkyl (C≦12)Any of compounds 1001 to 1003, 1005, 1006, and 1008 to 1044 of the present invention, [This invention 1047] R1 is alkyl (C≦12) Any of compounds 1001 to 1003, 1005, 1006, 1008 to 1044, and 1046 of the present invention, [This invention 1048] Compounds of any one of 1001 to 1003, 1005, 1006, 1008 to 1044, 1046, and 1047 of the present invention, wherein R1 is methyl. [This invention 1049] The compound of any one of claims 1001 to 1044, wherein R1 is halo. [The present invention 1050] Compounds of any of claims 1001 to 1044 and 1049, wherein R1 is fluoro. [This invention 1051] The compound of any one of claims 1001 to 1044 and 1049, wherein R1 is iodo. [This invention 1052] R1 is an amide (C≦12) or substituted amide (C≦12) Any of compounds 1001 to 1003, 1005, 1006, and 1008 to 1044 of the present invention, [This invention 1053] R1 is a substituted amide (C≦12) The compound of any one of 1001 to 1003, 1005, 1006, 1008 to 1044, and 1052 of the present invention, [This invention 1054] Compounds of any one of 1001 to 1003, 1005, 1006, 1008 to 1044, 1052, and 1053 of the present invention, wherein R1 is 3-aminopropanamide. [This invention 1055] R 1a But aralkyl (C≦18) or substituted aralkyl (C≦18) Any of compounds 1001 to 1003, 1005, 1006, and 1008 to 1044 of the present invention, [This invention 1056] R1a is aralkyl (C≦18) The compound of any one of 1001 to 1003, 1005, 1006, 1008 to 1044, and 1055 of the present invention, [This invention 1057] R 1a The compound of any one of 1001 to 1003, 1005, 1006, 1008 to 1044, 1055, and 1056 of the present invention, wherein is benzyl. [This invention 1058] 1001. A compound of the present invention, wherein the compound is of formula (II): [This invention 1059] R7 is alkyl (C≦12) or substituted alkyl (C≦12) The compound of the present invention 1001 or 1058, [The present invention 1060] R7 is substituted alkyl (C≦12) Any of compounds 1001, 1058, and 1059 of the present invention, [This invention 1061] The compound of any one of 1001 and 1058 to 1060 of the present invention, wherein R7 is 1-hydroxyethyl. [The present invention 1062] R8 is -alkanediyl (C≦12) -cycloalkyl (C≦12) or substituted alkanediyl (C≦12) -cycloalkyl (C≦12) The compound of any one of the present inventions 1001 and 1058 to 1061, [The present invention 1063] R8 - Alkanediyl (C≦12) -cycloalkyl (C≦12) The compound of any one of the present inventions 1001 and 1058 to 1062, [The present invention 1064] The compound of any one of claims 1001 and 1058 to 1063, wherein R8 is (cyclohexyl)methyl. [This invention 1065] R9 is aralkyl (C≦18) or substituted aralkyl (C≦18)The compound of any one of the present inventions 1001 and 1058 to 1064, [The present invention 1066] R9 is Arakyl (C≦18) The compound of any one of 1001 and 1058 to 1065 of the present invention, [This invention 1067] The compound of any one of Nos. 1001 and 1058 to 1066 of the present invention, wherein R9 is 2-(naphthalen-2-yl)ethyl. [The present invention 1068] R6 is an amide (C≦12) or substituted amide (C≦12) The compound of any one of the present inventions 1001 and 1058 to 1067, [This invention 1069] R6 is a substituted amide (C≦12) The compound of any one of 1001 and 1058 to 1068 of the present invention, [The present invention 1070] The compound of any one of claims 1001 and 1058 to 1069 of the present invention, wherein R6 is 3-aminopropanamide. [This invention 1071] The compound is TIFF0007770716000032.tif177133TIFF0007770716000033.tif183128TIFF0007770716000034.tif125128, or a pharmaceutically acceptable salt thereof. [This invention 1072] The compound is TIFF0007770716000035.tif177133TIFF0007770716000036.tif183128, or a pharmaceutically acceptable salt thereof. [This invention 1073] The compound is TIFF0007770716000037.tif67128, or a pharmaceutically acceptable salt thereof. [This invention 1074] The compound is Compounds of any of claims 1001 and 1058-1071, further defined as TIFF0007770716000038.tif54128 or a pharmaceutically acceptable salt thereof. [This invention 1075] (a) any one of compounds 1001 to 1074 of the present invention; and (b) excipients and / or pharmaceutically acceptable carriers 10. A pharmaceutical composition comprising: [This invention 1076] The pharmaceutical composition of the present invention 1075, formulated for administration orally, intraadiposely, intra-arterially, intra-articularly, intracranially, intradermally, intralesionally, intramuscularly, intranasally, intraocularly, intrapericardially, intraperitoneally, intrapleurally, intraprostatically, intrarectally, intrathecally, intratracheally, intratumorally, intraumbilically, intravaginally, intravenously, intravesicularly, intravitreally, via liposomes, topically, mucosally, parenterally, rectally, subconjunctivally, subcutaneously, sublingually, topically, transbuccally, transdermally, vaginally, in a cream, in a lipid composition, by catheter, by lavage, by continuous infusion, by injection, by inhalation, by injection, by local delivery, or by local perfusion. [This invention 1077] A pharmaceutical composition of 1075 or 1076 formulated for administration orally, intraarterially, intratumorally, intravenously, topically, subcutaneously, locally, intraperitoneally, or by injection. [This invention 1078] A method for treating a disease or disorder in a patient in need thereof, comprising the step of administering to the patient a therapeutically effective amount of any of the compounds or compositions of present inventions 1001-1077. [This invention 1079] The method of claim 1078, wherein the patient is a mammal. [The present invention 1080] The method of any one of claims 1078 to 1079, wherein the patient is a human. [This invention 1081] The method of any one of claims 1078 to 1080, wherein the disease or disorder is cancer. [This invention 1082] The method of claim 1081, wherein the cancer is a treatment-resistant cancer. [This invention 1083] The method of claim 1081 or 1082, wherein the cancer is breast cancer, ovarian cancer, pancreatic cancer, or brain cancer. [This invention 1084] The method of claim 1083, wherein the cancer is breast cancer. [This invention 1085] The method of claim 1084, wherein the breast cancer is triple-negative breast cancer. [This invention 1086] The method of claim 1083, wherein the cancer is ovarian cancer. [This invention 1087] The method of claim 1083, wherein the cancer is pancreatic cancer. [This invention 1088] The method of claim 1083, wherein the cancer is brain cancer. [This invention 1089] The method of claim 1088, wherein the brain cancer is glioblastoma. [The present invention 1090] The method of any one of claims 1081 to 1084, 1086, and 1087, wherein the cancer is an estrogen receptor-positive cancer. [This invention 1091] The method of any one of claims 1081 to 1087, wherein the cancer is an estrogen receptor-negative cancer. [This invention 1092] The method of claim 1078, wherein the administering step comprises intravenous, intraarterial, intratumoral, subcutaneous, topical, or intraperitoneal administration. [This invention 1093] The method of claim 1078, wherein the administering step comprises local, regional, systemic, or continuous administration. [This invention 1094] The method of claim 1078, further comprising providing a second anti-cancer therapy to the subject. [This invention 1095] The method of claim 1094, wherein the second anti-cancer therapy is surgery, chemotherapy, radiation therapy, hormone therapy, toxin therapy, immunotherapy, and cryotherapy. [This invention 1096] The method of claim 1094, wherein a second anti-cancer therapy is provided prior to the step of administering said compound. [This invention 1097] The method of claim 1094, wherein a second anti-cancer therapy is provided after the step of administering said compound. [This invention 1098] The method of claim 1094, wherein a second anti-cancer therapy is provided simultaneously with said compound. [This invention 1099] The method of claim 1078, wherein the compound is administered daily. [The present invention 1100] The method of claim 1099, wherein the compound is administered daily for 7 days, 2 weeks, 3 weeks, 4 weeks, 1 month, 6 weeks, 8 weeks, 2 months, 12 weeks, or 3 months. [The present invention 1101] The method of claim 1078, wherein the compound is administered weekly. [The present invention 1102] The method of claim 1078, wherein the compound is administered weekly for 2, 3, 4, 6, 8, 10, or 12 weeks. [The present invention 1103] The method of claim 1078, wherein said compound or said composition is administered in an amount sufficient to induce endoplasmic reticulum stress and / or arrest protein synthesis. Other objects, features, and advantages of the present disclosure will become apparent from the following detailed description. However, it should be understood that the detailed description and specific examples, while indicating specific embodiments of the present disclosure, are provided by way of illustration only, since various changes and modifications within the spirit and scope of the present disclosure will become apparent to those skilled in the art from this detailed description. It should be noted that the fact that a particular compound belongs to one particular general formula does not mean that the compound cannot also belong to another general formula. [Brief explanation of the drawings]

[0031] For a more complete understanding of the features and advantages of the present disclosure, reference is now made to the detailed description of the disclosure taken in conjunction with the accompanying drawings. [Figure 1] The primary TK41 (ie, ERX-41) structure and the low-energy helical structure are shown. [Figure 2] The potency of TK41 (IC50 of 50–500 nM) against estrogen receptor-positive (Figure 2A), estrogen receptor-negative (Figure 2B), and treatment-resistant ERMT (Figure 2C) cells, as determined by MTT assay, is shown. [Figure 3] TK41 (i.e., ERX-41) docked to TLX (MacroModel and AutoDock; Figure 3A) is shown. Avidin bead pull-down was used to analyze the interaction with purified TLX protein after incubation with biotinylated ERX-41 (Figure 3B). Figure 3C shows that GST-TLX was incubated with TNBC cell lysates in the presence or absence of TK41 (1 μM), and TLX interaction with PELP1 was analyzed by GST pull-down followed by Western blotting. [Figure 4] Figure 4 shows the effect of TK41 on estrogen receptor-positive (ER+ve) tumor growth. ZR75 (ER+ve; n = 18) xenografts were established in nude mice and treated with either vehicle (circle markers) or 10 mg / kg / day TK41 (square markers) administered by oral gavage in Captisol®. The effect on tumor volume is shown in Figure 4A. The effect on tumor weight is shown in Figure 4B. Comparison of mouse body weights is shown in a bar graph (Figure 4C). *p<0.05; ****p<0.001. [Figure 5] Figure 5 shows the effect of TK41 on triple-negative breast cancer xenograft tumors. MDA-MB-231 (TNBC; n = 10) xenografts were established in nude mice and treated with either vehicle (circle markers) or 10 mg / kg / day TK41 (square markers) administered by oral gavage in Captisol®. Comparison of mouse body weights is shown in a bar graph (Figure 5A). The effect on tumor weight is shown in Figure 5B. The effect on tumor volume is shown in Figure 5C. Photographs of individual tumors at necropsy support the effect of TK41 on TNBC. *p<0.05; ****p<0.001. [Figure 6] Figure 1 shows the effect of ERX-41 (TK41) on the proliferation of primary patient-derived TNBC ex vivo cultures as measured by ki67 staining. A cumulative series of n = 11 experiments is shown. [Figure 7] Figure 7 shows the effect of TK41 on triple-negative breast cancer in patient-derived xenografts. TNBC patient-derived xenografts (n = 6) were established in nude mice and treated with vehicle (circle markers) or 10 mg / kg / day / oral ERX-41 (i.e., TK41; square markers). Tumor volume (Figure 7A), distribution of tumor weight at necropsy (Figure 7B), and mouse body weight (bar graph; Figure 7C) support the activity of ERX-41 against TNBC PDX tumors. *p<0.05; ****p<0.001. [Figure 8] Figure 8 shows the effect of TK41 (i.e., ERX-41) on therapy-resistant cancer cells. ERMT (therapy-resistant) xenografts (n = 8) were established in nude mice and treated with vehicle (circle markers) or 10 mg / kg / day / oral ERX-41 (square markers). Tumor volume (Figure 8A) and mouse weight (bar graph; Figure 8B) support the activity of ERX-41 against ERMT tumors. *p<0.05; **p<0.01. [Figure 9] Figure 1 shows the structure-activity relationship between TK11 (i.e., ERX-11; Raj et al., 2017), TK41, TK207, TK203, TK208, and YL144. Replacement of the R5 amino group of TK11 with a substituted amino group significantly increased activity against estrogen receptor-positive and estrogen receptor-negative cell lines. [Figure 10] Figure 10 shows the effect of TK208 on cancer cells. Figure 10A shows the effect of TK208 on various TNBC cell lines. Figure 10B shows the effect of TK208 on various ovarian cancer cell lines. [Figure 11]Figure 11 shows a comparison of the cytotoxic effects of TK208 in BT549 NR1H4 knockout cells versus parental cells. Figure 11A shows the results of a cell viability assay. Figure 11B shows the results of a caspase assay demonstrating the effect of TK208 on apoptosis. [Figure 12] The effects of TK208 on the ovarian cancer cell lines ES2 (FIGS. 12A and 12B) and SKOV3 (FIGS. 12C and 12D) are shown. Figures 12A and 12C show that TK208 promotes apoptosis in both ovarian cancer cells. Figures 12B and 12D show that TK208 reduces cell viability in both cancer cell lines. [Figure 13] 1 shows that TK208 reduces colony formation in ES2 and SKOV3 ovarian cancer cells. [Figure 14] Figure 2 shows that TK208 reduces the invasion of ES2 and SKOV3 ovarian cancer cells. [Figure 15] We show that TK208 promotes growth arrest of ES2 and SKOV3 ovarian cancer cells in S phase. [Figure 16] 1 shows the effect of YL144 on breast cancer cells derived from various cell lines. [Figure 17] The effect of YL144 on BT549 / NR-targeted knockout cells is shown. [Figure 18] 1 shows the effect of YL144 on cell viability of VDR-CRISPR knockout cells. [Figure 19] The structure-activity relationships between TK11 ( Raj et al., 2017 ), TK41, TK208, TK231, YL144, TK227, YL1113, and TK245 are shown. [Figure 20] This shows that TK245 has high specificity for estrogen receptor-positive cells. [Figure 21] The effects of TK308 on various cancer cell lines are shown. [Figure 22] The effects of TK309 on various cancer cell lines are shown. [Figure 23]The effects of TK315 on various cancer cell lines are shown. [Figure 24] Figure 1 shows the effect of TK314 on various cancer cell lines. TK314 exhibits unique activity against ovarian cancer cells and significantly less activity against breast cancer cells. [Figure 25] Electron microscopy is used to demonstrate the ability of TK41 to induce ER stress in TNBC MD-MBA-231 cells. TK41 does not induce ER stress in HMEC cells (bottom panel). [Figure 26] Western blots are used to demonstrate the ability of TK41 to induce endoplasmic reticulum stress in MD-MBA-231 cells.TK41 does not induce endoplasmic reticulum stress in HMEC cells. [Figure 27] Figure 1 shows the ability of TK41 to stop de novo protein synthesis. TK-41 reduces global new protein synthesis at 4 and 16 hours in three TNBC cells, as shown by Western blot for puromycin-labeled nascent proteins. Total protein is shown on the right with Coomassie blue staining. [Figure 28] We show that basal levels of endoplasmic reticulum stress and unfolded protein response expression correlate with TK41 activity. [Figure 29] Using electron microscopy, we demonstrate the ability of TK41 to induce endoplasmic reticulum stress in pancreatic cancer MiaPaca cells, but not in HMEC cells. [Figure 30] A schematic diagram illustrating the mechanism of action of TK41 by targeting either the ER or TLX, inducing ER stress and subsequent apoptosis, and blocking autophagy fusion is shown. [Figure 31] Figure 31 shows that oral administration of TK315 (ERX-315) reduced the growth and tumor weight of BC xenografts engineered by CRISPR to express the Y537S ERa mutant in ZR75 (Figure 31A-B) and MCF7 cells (Figure 31C-D). No change in body weight was observed. [Figure 32] Established breast PDX tumors treated with either vehicle (circles) or ERX-41 (squares) are shown. Tumor volume (left) and distribution of tumor weight at necropsy (center panel) are graphed. *p<0.05; ****p<0.001. [Figure 33] Figures 33A-D show ovarian cancer xenografts (ES2) treated with vehicle or TK208 (ERX-208). Tumor volume (Figure 33A), body weight (Figure 33B), distribution of tumor weight at necropsy (Figure 33C), and nodules (Figure 33D) are graphed. Figures 33E-H show ovarian PDX tumors treated with vehicle or TK208 (ERX-208). Tumor volume (Figure 33E), distribution of tumor weight at necropsy (Figure 33F), and tumor images (Figure 33G) and body weight (Figure 33H) are graphed. DETAILED DESCRIPTION OF THE INVENTION

[0032] Detailed Description The present disclosure relates to oligobenzamides modified at the southern end of the compound with a cyclohexylamide group. These compounds have been shown to bind to hormone receptors in one or more cancer cells, such as breast cancer. These compounds may exhibit one or more preferential properties over those known in the art, such as improved efficacy. These and other details are described below.

[0033] I. Compounds of the Present Disclosure TIFF0007770716000039.tif173128TIFF0007770716000040.tif175128TIFF0007770716000041.tif181128 TIFF0007770716000042.tif157128TIFF0007770716000043.tif171128TIFF0007770716000044.tif213113

[0034] The compounds of the present disclosure are shown, for example, above, in the Summary section, and in the Claims section below. They may be made using the synthetic methods outlined in the Examples section. These methods can be further modified and optimized using the principles and techniques of organic chemistry applied by those skilled in the art. Such principles and techniques are taught, for example, in Smith, March's Advanced Organic Chemistry: Reactions, Mechanisms, and Structure, (2013), which is incorporated herein by reference. In addition, the synthetic methods can be further modified and optimized for preliminary, pilot, or large-scale production, whether batch or continuous, using the principles and techniques of process chemistry applied by those skilled in the art. Such principles and techniques are taught, for example, in Anderson, Practical Process Research & Development - A Guide for Organic Chemists (2012), which is incorporated herein by reference.

[0035] All of the compounds disclosed herein may, in some embodiments, be useful for the prevention and treatment of one or more diseases or disorders described herein or otherwise. In some embodiments, one or more compounds characterized or exemplified herein as intermediates, metabolites, and / or prodrugs may also be useful for the prevention and treatment of one or more diseases or disorders. Therefore, unless expressly stated otherwise, all of the compounds disclosed herein are considered "active compounds" and "therapeutic compounds" intended for use as active pharmaceutical ingredients (APIs). Actual suitability for human or animal use is typically determined using a combination of clinical trial protocols and regulatory procedures, such as those administered by the Food and Drug Administration (FDA). In the United States, the FDA is responsible for protecting public health by ensuring the safety, effectiveness, quality, and assurance of human and animal drugs, vaccines and other biological products, and medical devices.

[0036] In some embodiments, the compounds of the present disclosure have the advantage that they may be more effective, less toxic, longer acting, more potent, have fewer side effects, be more readily absorbed, metabolically stable, more lipophilic, more hydrophilic, and / or have better pharmacokinetic properties (e.g., higher oral bioavailability and / or lower clearance), and / or have other useful pharmacological, physical, or chemical properties than compounds known in the prior art, whether for use in the indications described herein or otherwise.

[0037] The compounds of the present disclosure may contain one or more asymmetrically substituted carbon or nitrogen atoms and may be isolated in optically active or racemic forms. Therefore, unless a specific stereochemistry or isomeric form is specifically indicated, all chiral, diastereomeric, racemic, epimeric, and all geometric isomeric forms of the chemical formula are intended. Compounds may appear as racemates and racemic mixtures, single enantiomers, diastereomeric mixtures, and individual diastereomers. In some embodiments, a single diastereomer is obtained. The chiral centers of the compounds of the present disclosure may have an S or R configuration. In some embodiments, the compounds may contain two or more atoms with a defined stereochemical orientation.

[0038] The chemical formulas used to represent the compounds of the present disclosure typically represent only one of several different possible tautomers. For example, many forms of ketone groups are known to exist in equilibrium with the corresponding enol groups. Similarly, many forms of imine groups exist in equilibrium with enamine groups. All tautomers of a given chemical formula are intended, regardless of which tautomer is represented for a given compound, or which one is most prevalent.

[0039] Additionally, atoms constituting the compounds of the present disclosure are intended to include all isotopic forms of such atoms. As used herein, isotopes include atoms having the same atomic number but different mass numbers. As general examples, isotopes of hydrogen include tritium and deuterium, and isotopes of fluorine include 18 It contains F, and the carbon isotopes are 13 C and 14 Includes, but is not limited to, C.

[0040] In some embodiments, the compounds of the present disclosure function as prodrugs or can be derivatized to function as prodrugs. Because prodrugs are known to enhance many desirable properties of drugs (e.g., solubility, bioavailability, manufacturing, etc.), compounds used in some methods of the present disclosure may be delivered in prodrug form, if necessary. Thus, the present disclosure contemplates prodrugs of the compounds of the present disclosure, as well as methods for delivering prodrugs. Prodrugs of the compounds used in the present disclosure may be prepared by modifying functional groups present in the compound in such a way that the modifications are cleaved to the parent compound, either by routine manipulation or in vivo. Thus, prodrugs include, for example, compounds described herein in which a hydroxyl, amino, or carboxyl group is bonded to any group that, when administered to a subject, is cleaved to generate a hydroxyl, amino, or carboxylic acid, respectively.

[0041] In some embodiments, the compounds of the present disclosure exist in salt or non-salt form.With respect to salt form(s), in some embodiments, the specific anion or cation forming part of any salt form of the compounds provided herein is not important, as long as the salt as a whole is pharmacologically acceptable.Further examples of pharmaceutically acceptable salts and their preparation and use are shown in Handbook of Pharmaceutical Salts: Properties, and Use (2002), which is incorporated herein by reference.

[0042] It will be understood that many organic compounds can form complexes with the solvent in which they react or from which they precipitate or crystallize. These complexes are known as "solvates." When the solvent is water, the complex is known as a "hydrate." It will also be understood that many organic compounds can exist in multiple solid forms, including crystalline and amorphous forms. All solid forms of the compounds provided herein, including any solvates thereof, are within the scope of this disclosure.

[0043] II.Chemical definition When used in the context of chemical groups, "hydrogen" means -H; "hydroxy" means -OH; "oxo" means =O; "carbonyl" means -C(=O)-; "carboxy" means -C(=O)OH (also written -COOH or -COH); "halo" means independently -F, -Cl, -Br, or -I; "amino" means -NH; "hydroxyamino" means -NHOH; "nitro" means -NO; and imino means =NH. "cyano" means -CN; "isocyanyl" means -N=C=O; "azido" means -N3; ​​in the monovalent context, "phosphate" means -OP(O)(OH)2 or its deprotonated form; in the divalent context, "phosphate" means -OP(O)(OH)O- or its deprotonated form; "mercapto" means -SH; and "thio" means =S; "sulfonyl" means -S(O)2-; and "sulfinyl" means -S(O)-.

[0044] In the context of chemical formulas, the symbol "-" denotes a single bond, "=" denotes a double bond, and "≡" denotes a triple bond. The symbol "----" denotes any bond, if present, which may be either single or double. The symbol TIFF0007770716000045.tif5128 means a single bond or a double bond. Therefore, the formula For example, TIFF0007770716000046.tif10128 contains TIFF0007770716000047.tif10128 is included. It is also understood that one such ring atom does not form part of multiple double bonds. It is further noted that the covalent bond symbol "-" does not indicate any preferred stereochemistry when connecting one or two stereogenic atoms. Instead, it includes all stereoisomers as well as mixtures thereof. The symbol TIFF0007770716000048.tif5128 shows that when a line is drawn perpendicularly across a bond (e.g., for methyl TIFF0007770716000049.tif6128), indicating the point of attachment of the group. It is noted that points of attachment are typically only identified in this fashion on larger groups to aid the reader in clearly identifying the point of attachment. TIFF0007770716000050.tif5128 indicates a single bond, with the group attached to the thick end of the wedge "off the page." TIFF0007770716000051.tif5129 represents a single bond, with the group attached to the thick end of the wedge "into the page." TIFF0007770716000052.tif5128 refers to a single bond where the geometry around the double bond is undefined (e.g., either E or Z). Thus, both options, as well as combinations, are contemplated. Any undefined valence on an atom of a structure shown in this application implicitly represents a hydrogen atom bonded to that atom. A bold dot on a carbon atom indicates that the hydrogen bonded to that carbon is pointing out of the plane of the paper.

[0045] The variable may be a "floating group" on a ring system, for example, in the formula: When depicted as a group "R" in TIFF0007770716000053.tif14128, the variable may replace any hydrogen atom attached to any ring atom, including drawn, implied, or explicitly defined hydrogens, so long as a stable structure is formed. When depicted as the group "R" in TIFF0007770716000054.tif16128, the variable may replace any hydrogen bonded to any ring atom of any of the fused rings, unless otherwise noted. Replaceable hydrogens include depicted hydrogens (e.g., the hydrogen bonded to the nitrogen in the formula above), implied hydrogens (e.g., hydrogens in the formula above that are not shown but whose presence is understood), explicitly defined hydrogens, and any hydrogens whose presence depends on the identity of the ring atom (e.g., the hydrogen bonded to group X when X is equal to -CH-), so long as a stable structure is formed. In the depicted example, R may be in either the 5-membered or 6-membered ring of the fused ring system. In the formula above, the subscript "y" immediately following the parenthesized R represents a numerical variable. Unless otherwise noted, this variable may be 0, 1, 2, or any integer greater than 2, limited only by the maximum number of replaceable hydrogen atoms in the ring or ring system.

[0046] For chemical groups and compound classes, the number of carbon atoms in the group or class is as follows: "Cn" or "C=n" defines the exact number (n) of carbon atoms in the group / class. "C≦n" defines the maximum number (n) of carbon atoms that can be in the group / class, with the minimum number being as small as possible for the group / class in question. For example, the group "alkyl (C≦8) ", "Cycloalkanediyl (C≦8) ", "heteroaryl (C≦8) ", and "Acyl (C≦8) The minimum number of carbon atoms in the group "alkenyl" is 1. (C≦8) ", "alkynyl (C≦8) ", and "heterocycloalkyl (C≦8) The minimum number of carbon atoms in the group "cycloalkyl" is two. (C≦8) The minimum number of carbon atoms in the group "aryl" is 3, and (C≦8) " and "Arrangeil (C≦8) It is understood that the minimum number of carbon atoms in an "alkyl" group is six. "Cn-n'" defines both the minimum (n) and maximum number (n') of carbon atoms in the group. (C2-10)" denotes an alkyl group having 2 to 10 carbon atoms. These carbon number digits may precede or follow the chemical group or class that they modify, and may or may not be in parentheses, without implying any change in meaning. Thus, "C5 olefin," "C5-olefin," "olefin" (C5) ", and "Olefins C5 " are all synonyms. Except as noted below, to determine whether a group or compound conforms to a specified number of carbon atoms, every carbon atom is counted. For example, the group dihexylamino is dialkylamino. (C=12) An example of a group is dialkylamino (C=6) Similarly, phenylethyl is not an example of an aralkyl group. (C=8) is an example of a group. When any chemical group or class of compounds defined herein is modified by the term "substituted," any carbon atoms in the moiety that replace a hydrogen atom are not counted. Thus, methoxyhexyl has a total of 7 carbon atoms, but is a substituted alkyl. (C1-6) Unless otherwise stated, any chemical group or class of compounds recited in a claim without a carbon atom limit has a carbon atom limit of 12 or less.

[0047] The term "saturated," when used to modify a compound or chemical group, means that the compound or chemical group has no carbon-carbon double bonds or carbon-carbon triple bonds, except as noted below. When the term is used to modify an atom, it means that the atom is not part of any double or triple bonds. In the case of substituted forms of saturated groups, one or more carbon-oxygen or carbon-nitrogen double bonds may be present. Furthermore, when such bonds are present, it does not exclude carbon-carbon double bonds that may occur as part of keto-enol tautomerism or imine / enamine tautomerism. When the term "saturated," when used to modify a solution of a substance, it means that the substance cannot be further dissolved in that solution.

[0048] The term "aliphatic" indicates that the compound or chemical group so modified is acyclic or cyclic, but non-aromatic. In an aliphatic compound / group, the carbon atoms can be linked together in a straight chain, branched chain, or non-aromatic ring (alicyclic). An aliphatic compound / group can be saturated (alkane / alkyl) linked by a single carbon-carbon bond, or unsaturated by one or more carbon-carbon double bonds (alkene / alkenyl) or one or more carbon-carbon triple bonds (alkyne / alkynyl).

[0049] The term "aromatic" indicates that the compound or chemical group so modified has a planar, unsaturated ring of atoms with 4n+2 electrons in a completely conjugated cyclic π-system. An aromatic compound or chemical group may be depicted as a single resonance structure, but depiction of one resonance structure is considered to refer to any other resonance structure. For example: TIFF0007770716000055.tif14128 is TIFF0007770716000056.tif14128. Aromatic compounds may also be depicted using circles to represent the electron delocalization character of fully conjugated cyclic π-systems, two non-limiting examples of which are shown below: TIFF0007770716000057.tif11128

[0050] The term "alkyl" refers to a monovalent saturated aliphatic group having a carbon atom as the point of attachment, a straight or branched acyclic structure, and no atoms other than carbon and hydrogen. Examples include the groups -CH3(Me), -CH2CH3(Et), -CH2CH2CH3(n-Pr or propyl), -CH(CH3)2(i-Pr, i Pr or isopropyl), -CH2CH2CH2CH3(n-Bu), -CH(CH3)CH2CH3(sec-butyl), -CH2CH(CH3)2(isobutyl), -C(CH3)3(tert-butyl, t-butyl, t-Bu or tBu), and -CHC(CH)(neo-pentyl) are non-limiting examples of alkyl groups. The term "alkanediyl" refers to a divalent saturated aliphatic group having one or two saturated carbon atoms as points of attachment, a straight or branched acyclic structure, no carbon-carbon double or triple bonds, and no atoms other than carbon and hydrogen. The groups -CH-(methylene), -CHCH-, -CHC(CH)CH-, and -CHCHCH- are non-limiting examples of alkanediyl groups. The term "alkylidene" refers to the divalent group =CRR', where R and R' are independently hydrogen or alkyl. Non-limiting examples of alkylidene groups include: =CH, =CH(CHCH), and =C(CH). "Alkane" refers to the class of compounds having the formula HR, where R is alkyl, as this term is defined above.

[0051] The term "cycloalkyl" refers to a monovalent saturated aliphatic group having a carbon atom as the point of attachment, the carbon atom forming part of one or more non-aromatic ring structures, no carbon-carbon double or triple bonds, and no atoms other than carbon and hydrogen. Non-limiting examples include: -CH(CH2)2 (cyclopropyl), cyclobutyl, cyclopentyl, or cyclohexyl (Cy). As used herein, this term does not exclude the presence of one or more alkyl groups (where the carbon number limit permits) attached to a carbon atom of a non-aromatic ring structure. The term "cycloalkanediyl" refers to a divalent saturated aliphatic group having two carbon atoms as points of attachment, no carbon-carbon double or triple bonds, and no atoms other than carbon and hydrogen. Group TIFF0007770716000058.tif8128 is a non-limiting example of a cycloalkanediyl group. "Cycloalkane" refers to the class of compounds having the formula H-R, where R is cycloalkyl, as that term is defined above.

[0052] The term "aryl" refers to a monovalent unsaturated aromatic group having an aromatic carbon atom as the point of attachment, the carbon atom forming part of one or more aromatic ring structures, each having six ring atoms, all of which are carbon atoms, and the group consisting solely of carbon and hydrogen. When multiple rings are present, the rings may be fused or non-fused. Non-fused rings are linked by covalent bonds. As used herein, the term aryl does not exclude the presence of one or more alkyl groups (carbon number limitations permitting) attached to the first aromatic ring or any additional aromatic rings present. Non-limiting examples of aryl groups include phenyl (Ph), methylphenyl, (dimethyl)phenyl, -CHCHCH (ethylphenyl), naphthyl, and the monovalent group derived from biphenyl (4-phenylphenyl). The term "arenadiyl" refers to a divalent aromatic group having two aromatic carbon atoms as points of attachment, the carbon atoms forming part of one or more six-membered aromatic ring structures, each having six ring atoms that are all carbon atoms, and the divalent group consisting solely of carbon and hydrogen. As used herein, the term arenadiyl does not exclude the presence of one or more alkyl groups (carbon number limitations permitting) attached to the first aromatic ring or any additional aromatic rings present. When multiple rings are present, the rings may be fused or non-fused. Non-fused rings are linked by covalent bonds. Non-limiting examples of arenadiyls include: TIFF0007770716000059.tif14150. "Allene" means the class of compounds having the formula H-R, where R is aryl, as that term is defined above. Benzene and toluene are non-limiting examples of allenes.

[0053] The term "aralkyl" refers to the monovalent group -alkanediyl-aryl, where the terms alkanediyl and aryl are each used in a manner consistent with the above definitions. Non-limiting examples are: phenylmethyl (benzyl, Bn) and 2-phenyl-ethyl.

[0054] The term "heteroaryl" refers to a monovalent aromatic group having an aromatic carbon or nitrogen atom as the point of attachment, the carbon or nitrogen atom being part of one or more aromatic ring structures, each having from 3 to 8 ring atoms, at least one of the ring atoms of the aromatic ring structure being nitrogen, oxygen, or sulfur, and the heteroaryl group consisting exclusively of carbon, hydrogen, aromatic nitrogen, aromatic oxygen, and aromatic sulfur. When multiple rings are present, the rings are fused; however, the term heteroaryl does not exclude the presence of one or more alkyl or aryl groups (carbon number limitations permitting) attached to one or more ring atoms. Non-limiting examples of heteroaryl groups include benzoxazolyl, benzimidazolyl, furanyl, imidazolyl (Im), indolyl, indazolyl (Im), isoxazolyl, methylpyridinyl, oxazolyl, oxadiazolyl, phenylpyridinyl, pyridinyl (pyridyl), pyrrolyl, pyrimidinyl, pyrazinyl, quinolyl, quinazolyl, quinoxalinyl, triazinyl, tetrazolyl, thiazolyl, thienyl, and triazolyl. The term "N-heteroaryl" refers to a heteroaryl group having a nitrogen atom as the point of attachment. "Heteroarene" refers to the class of compounds having the formula HR, where R is heteroaryl. Pyridine and quinoline are non-limiting examples of heteroarenes.

[0055] The term "heteroaralkyl" refers to the monovalent group -alkanediyl-heteroaryl, where the terms alkanediyl and heteroaryl are each used in a manner consistent with the definitions provided above. Non-limiting examples are pyridinylmethyl and 2-quinolinyl-ethyl.

[0056] The term "acyl" refers to the group -C(O)R, where R is hydrogen, alkyl, cycloalkyl, or aryl, as those terms are defined above. The groups -CHO, -C(O)CH3 (acetyl, Ac), -C(O)CH2CH3, -C(O)CH(CH3)2, -C(O)CH(CH2)2, -C(O)CH6H5, and -C(O)CH4CH3 are non-limiting examples of acyl groups. "Thioacyl" is defined in a similar manner, except that the oxygen atom of the group -C(O)R is replaced with a sulfur atom, -C(S)R. The term "aldehyde" corresponds to an alkyl group, as defined above, attached to a -CHO group.

[0057] The term "alkylamino" refers to the group -NHR, where R is alkyl, as that term is defined above. Non-limiting examples include: -NHCH and -NHCHCH. The term "dialkylamino" refers to the group -NRR', where R and R' can be the same or different alkyl groups. Non-limiting examples of dialkylamino groups include: -N(CH) and -N(CH)(CHCH). The terms "cycloalkylamino," "alkenylamino," "alkynylamino," "arylamino," "aralkylamino," "heteroarylamino," "heterocycloalkylamino," and "alkoxyamino," when used without the "substituted" modifier, refer to the group defined as -NHR, where R is cycloalkyl, alkenyl, alkynyl, aryl, aralkyl, heteroaryl, heterocycloalkyl, and alkoxy, respectively. A non-limiting example of an arylamino group is -NHCH. The terms "dicycloalkylamino," "dialkenylamino," "dialkynylamino," "diarylamino," "diaralkylamino," "diheteroarylamino," "diheterocycloalkylamino," and "dialkoxyamino" refer to the group defined as -NRR', where R and R' are both cycloalkyl, alkenyl, alkynyl, aryl, aralkyl, heteroaryl, heterocycloalkyl, and alkoxy, respectively. Similarly, the term alkyl(cycloalkyl)amino refers to the group defined as -NRR', where R is alkyl and R' is cycloalkyl. The term "amido" (acylamino), when used without the "substituted" modifier, refers to the group -NHR, where R is acyl, as that term is defined above. A non-limiting example of an amido group is -NHC(O)CH.

[0058] When a chemical group is used with the modifier "substituted," one or more hydrogen atoms are replaced, independently in each occurrence, with -OH, -F, -Cl, -Br, -I, -NH, -NO, -COH, -COCH, -CN, -SH, -OCH, -OCHCH, -C(O)CH, -NHCH, -NHCHCH, -N(CH), -C(O)NH, -C(O)NHCH, -C(O)N(CH), -OC(O)CH, -NHC(O)CH, -S(O)OH, or -S(O)NH. For example, the following groups are non-limiting examples of substituted alkyl groups: -CHOH, -CHCl, -CF, -CHCN, -CHC(O)OH, -CHC(O)OCH, -CHC(O)NH, -CHC(O)CH, -CHOCH, -CHOC(O)CH, -CHNH, -CHN(CH), and -CHCHCl. ​​The term "haloalkyl" is a subset of substituted alkyl, limited to the replacement of hydrogen atoms by halo (i.e., -F, -Cl, -Br, or -I), so that no other atoms other than carbon, hydrogen, and halogen are present. The group -CHCl is a non-limiting example of a haloalkyl. The term "fluoroalkyl" is a subset of substituted alkyl, limited to the replacement of hydrogen atoms by fluoro, so that no other atoms other than carbon, hydrogen, and fluorine are present. The groups -CHF, -CF, and -CHCF are non-limiting examples of fluoroalkyl groups. Non-limiting examples of substituted aralkyls are: (3-chlorophenyl)-methyl, and 2-chloro-2-phenyl-eth-1-yl. The groups -C(O)CHCF, -COH(carboxyl), -COCH(methylcarboxyl), -COCHCH, -C(O)NH(carbamoyl), and -CON(CH) are non-limiting examples of substituted acyl groups. The groups -NHC(O)OCH and -NHC(O)NHCH are non-limiting examples of substituted amido groups.

[0059] The use of the terms "a" or "an," when used in conjunction with the term "comprising" in the claims and / or specification, can mean "one," but is also consistent with the meanings of "one or more," "at least one," and "one or more than one."

[0060] Throughout this application, the term "about" is used to indicate that a value includes the inherent variation of error for the device, the method being employed to determine the value, or the variation that exists among test subjects or patients.

[0061] An "active ingredient" (AI) or pharmaceutically active ingredient (API) (also called an active compound, active substance, active agent, pharmaceutical agent, agent, biologically active molecule, or therapeutic compound) is the component in a pharmaceutical drug that is biologically active.

[0062] The terms "comprise," "having," and "include" are open-ended linking verbs. Any form or tense of one or more of these verbs, such as "comprises," "comprising," "has," "having," "includes," and "including," is also open-ended. For example, any method that "comprises," "has," or "includes" one or more steps is not limited to having only those one or more steps, but also covers other unlisted steps.

[0063] The term "effective," as used in this specification and / or claims, means sufficient to achieve a desired, expected, or intended result. An "effective amount," "therapeutically effective amount," or "pharmaceutically effective amount," as those terms are defined below, when used in the context of treating a patient or subject with a compound, means the amount of the compound that, when administered to a subject or patient, is sufficient to effect such treatment or prevention of disease.

[0064] An "excipient" is a pharmaceutically acceptable substance formulated with the active ingredient of a drug, pharmaceutical composition, formulation, or drug delivery system. Excipients may be used, for example, to stabilize the composition, bulk the composition (and thus, when used for this purpose, are often referred to as "fillers," "fillers," or "diluents"), or to provide therapeutic enhancements to the active ingredient in the final dosage form, such as facilitating drug absorption, reducing viscosity, or enhancing solubility. Excipients include pharmaceutically acceptable anti-adherents, binders, coatings, dyes, disintegrants, flavoring agents, glidants, preservatives, adsorbents, sweeteners, and vehicles. The primary excipient that serves as a vehicle for carrying the active ingredient is usually referred to as the vehicle. Excipients may be used in the manufacturing process to aid in handling of the active agent, for example, by promoting powder flowability or non-adhesiveness, as well as to aid in in vitro stability, such as preventing denaturation or aggregation during the expected shelf life. The suitability of an excipient will typically vary depending on the route of administration, dosage form, active ingredient, as well as other factors.

[0065] The term "hydrate," when used as a modifier to a compound, means that the compound has less than one (e.g., a hemihydrate), one (e.g., a monohydrate), or multiple (e.g., a dihydrate) water molecules bound to each compound molecule, such as a solid form of the compound.

[0066] As used herein, "IC 50 The term "inhibitory dose" refers to an inhibitory dose that is 50% of the maximum response obtained. This quantitative measure indicates how much of a particular drug or other substance (inhibitor) is needed to inhibit a given biological, biochemical, or chemical process (or component of the process, i.e., enzyme, cell, cell receptor, or microorganism) by half.

[0067] An "isomer" of a first compound is a distinct chemical compound whose each molecule contains the same constituent atoms as the first compound, but differs in the three-dimensional arrangement of those atoms.

[0068] As used herein, the term "patient" or "subject" refers to a living mammalian organism, such as a human, monkey, cow, sheep, goat, dog, cat, mouse, rat, guinea pig, or transgenic species thereof. In certain embodiments, the patient or subject is a primate. Non-limiting examples of human patients include adults, juveniles, infants, and fetuses.

[0069] As generally used herein, "pharmaceutically acceptable" means compounds, materials, compositions, and / or dosage forms that are, within the scope of sound medical judgment, suitable for use in contact with the tissues, organs, and / or body fluids of human beings and animals without undue toxicity, irritation, allergic response, or other problem or complication commensurate with a reasonable benefit / risk ratio.

[0070] "Pharmaceutically acceptable salts" refers to salts of the compounds disclosed herein that are pharmaceutically acceptable, as defined above, and have the desired pharmacological activity. Such salts include salts with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, and phosphoric acid; or salts with 1,2-ethanedisulfonic acid, 2-hydroxyethanesulfonic acid, 2-naphthalenesulfonic acid, 3-phenylpropionic acid, 4,4'-methylenebis(3-hydroxy-2-ene-1-carboxylic acid), 4-methylbicyclo[2.2.2]oct-2-ene-1-carboxylic acid, acetic acid, aliphatic mono- and dicarboxylic acids, aliphatic sulfuric acids, aromatic sulfuric acids, benzenesulfonic acid, benzoic acid, camphorsulfonic acid, carbonic acid, cinnamic acid, citric acid, cyclopentanepropionic acid, ethanesulfonic ... Pharmaceutically acceptable salts include acid addition salts formed with organic acids such as sulfonic acid, fumaric acid, glucoheptonic acid, gluconic acid, glutamic acid, glycolic acid, heptanoic acid, hexanoic acid, hydroxynaphthoic acid, lactic acid, lauryl sulfuric acid, maleic acid, malic acid, malonic acid, mandelic acid, methanesulfonic acid, muconic acid, o-(4-hydroxybenzoyl)benzoic acid, oxalic acid, p-chlorobenzenesulfonic acid, phenyl-substituted alkanoic acids, propionic acid, p-toluenesulfonic acid, pyruvic acid, salicylic acid, stearic acid, succinic acid, tartaric acid, tert-butylacetic acid, and trimethylacetic acid. Pharmaceutically acceptable salts also include base addition salts that can be formed when acidic protons present are capable of reacting with inorganic or organic bases. Acceptable inorganic bases include sodium hydroxide, sodium carbonate, potassium hydroxide, aluminum hydroxide, and calcium hydroxide. Acceptable organic bases include ethanolamine, diethanolamine, triethanolamine, tromethamine, N-methylglucamine, etc. It should be understood that the particular anion or cation forming a part of any salt of the present disclosure is not critical, so long as the salt, as a whole, is pharmacologically acceptable.Further examples of pharmaceutically acceptable salts and their methods of preparation and use are presented in Handbook of Pharmaceutical Salts: Properties, and Use (PH Stahl & CG Wermuth eds., Verlag Helvetica Chimica Acta, 2002).

[0071] A "pharmaceutically acceptable carrier," "drug carrier," or simply "carrier" is a pharmaceutically acceptable substance formulated with an active ingredient drug that is involved in carrying, delivering, and / or transporting a chemical compound. Drug carriers may be used to improve drug delivery and effectiveness, including, for example, controlled-release technologies to regulate drug bioavailability, decrease drug metabolism, and / or reduce drug toxicity. Some drug carriers may enhance the effectiveness of drug delivery to specific target sites. Examples of carriers include liposomes, microspheres (e.g., made of poly(lactic-co-glycolic acid)), albumin microspheres, synthetic polymers, nanofibers, protein-DNA complexes, protein conjugates, red blood cells, virosomes, and dendrimers.

[0072] A "pharmaceutical drug" (also called a drug, pharmaceutical preparation, pharmaceutical composition, pharmaceutical formulation, pharmaceutical product, medicinal product, medicament, pharmaceutical product, drug, or simply drug, agent, or preparation) is a composition that contains an active pharmaceutical ingredient (API) (defined above) and optionally contains one or more inactive ingredients, also called excipients (defined above), used to diagnose, cure, treat, or prevent disease.

[0073] "Prevention" or "preventing" includes: (1) inhibiting the onset of disease in a subject or patient who may be at risk and / or predisposed to the disease, but who has not yet experienced or displayed any or all of the symptoms or symptomatology of the disease, and / or (2) delaying the onset of symptoms or symptomatology of the disease in a subject or patient who may be at risk and / or predisposed to the disease, but who has not yet experienced or displayed any or all of the symptoms or symptomatology of the disease.

[0074] "Prodrug" refers to a compound that can be metabolically converted into an inhibitor of the present disclosure in vivo. The prodrug itself may or may not have activity with respect to a given target protein. For example, a compound containing a hydroxy group may be administered as an ester that is converted by hydrolysis to the hydroxy compound in vivo. Non-limiting examples of suitable esters that can be converted to the hydroxy compound in vivo include acetate, citrate, lactate, phosphate, tartrate, malonate, oxalate, salicylate, propionate, succinate, fumarate, maleate, methylene-bis-β-hydroxynaphthoate, gentisate, isethionate, di-p-toluoyltartrate, methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate, cyclohexylsulfamate, quinate, and esters of amino acids. Similarly, compounds containing an amine group may be administered as an amide that is hydrolytically converted in vivo to the amine compound.

[0075] "Stereoisomers" or "optical isomers" are isomers of a given compound that have the same atoms bonded to the same other atoms but differ in the three-dimensional arrangement of those atoms. "Enantiomers" are stereoisomers of a given compound that are mirror images of each other, like left and right hands. "Diastereomers" are stereoisomers of a given compound that are not enantiomers. Chiral molecules contain a chiral center, also called a stereogenic center or stereocenter, which is any point in a molecule bearing groups such that the interchange of any two groups leads to a stereoisomer, but not necessarily an atom. In organic compounds, chiral centers are typically carbon, phosphorus, or sulfur atoms, although other atoms can be stereocenters in organic and inorganic compounds. A molecule can also have multiple stereocenters, resulting in many stereoisomers. In a compound whose stereoisomerism is due to a tetrahedral stereogenic center (e.g., a tetrahedral carbon), the total number of hypothetical possible stereoisomers is 2. n where n is the number of tetrahedral stereocenters. Molecules with symmetry often have fewer than the maximum possible number of stereoisomers. A 50:50 mixture of enantiomers is called a racemic mixture. Alternatively, a mixture of enantiomers can be enantiomerically enriched, such that one enantiomer is present in an amount greater than 50%. Typically, enantiomers and / or diastereomers can be resolved or separated using techniques known in the art. For any stereocenter or axis of chirality with undefined stereochemistry, it is contemplated that the stereocenter or axis of chirality can exist as its R-form, S-form, or a mixture of R- and S-forms, including racemic and non-racemic mixtures. As used herein, the phrase "substantially free of other stereoisomers" means that the composition contains ≦15%, more preferably ≦10%, even more preferably ≦5%, or most preferably ≦1% of another stereoisomer.

[0076] "Treatment" or "treating" includes (1) inhibiting a disease (e.g., halting further development of the pathology and / or symptomatology) in a subject or patient experiencing or exhibiting the pathology or symptomatology of the disease, (2) ameliorating a disease (e.g., reversing the pathology and / or symptomatology) in a subject or patient experiencing or exhibiting the pathology or symptomatology of the disease, and / or (3) making any measurable reduction in the disease or its symptoms in a subject or patient experiencing or exhibiting the pathology or symptomatology of the disease.

[0077] The term "unit dose" refers to a formulation of a compound or composition such that the formulation is prepared in a manner sufficient to provide a patient with a single therapeutically effective dose of the active ingredient in a single administration. Such unit dose formulations that can be used include, but are not limited to, a single tablet, capsule, or other oral formulation, or a single vial containing a syringe-fillable liquid or other injectable formulation.

[0078] The foregoing definitions supersede any conflicting definitions in any reference incorporated herein by reference. However, the fact that certain terms are defined should not be considered to indicate that any undefined term is unclear. Rather, all terms used are considered to describe the present disclosure in terms such that one skilled in the art can understand the scope and practice the present disclosure.

[0079] III. Oligobenzamides and Methods of Synthesis The present disclosure provides synthetic molecules that display essential functional groups of corresponding protein ligands in the appropriate three-dimensional orientation that allows for specific protein interactions that lead to either stimulation or inhibition of protein-mediated functions.

[0080] Peptide mimetics (also known as peptidomimetics) are small molecule compounds that lack the peptide backbone of natural peptides. Despite this modification, they still retain the ability to interact with corresponding receptors or enzymes by displaying essential chemical functional groups (i.e., pharmacophores) in characteristic three-dimensional patterns complementary to the target protein (Marshall, 1993; Ahn et al., 2002). This allows peptidomimetics to potentially combine the advantages of peptides (e.g., high potency and selectivity, minimal side effects) with those of small organic molecules (e.g., high enzymatic stability and oral bioavailability).

[0081] To mimic an α-helix, the present disclosure provides an oligobenzamide scaffold that is structurally rigid and positions and orients substituents similarly to an α-helix. For example, substitutions on the rigid trisbenzamide include three functional groups (R 2-4 ) has been readily placed. Furthermore, the present inventors have developed a facile synthetic route to prepare several trisbenzamides that represent α-helical segments of target proteins. U.S. Patent Application Publication No. 2009 / 0012141, incorporated herein by reference, discloses various oligobenzamide compounds and methods for their synthesis.

[0082] More specifically, the present disclosure provides exemplary oligobenzamide peptidomimetic compounds containing two or three optionally substituted benzamides, so-called "bis" and "tris" benzamides. Furthermore, the bond between the optionally substituted benzamides can be varied as needed, including ester, thioester, thioamide, trans-ethylene, ethyl, methyloxy, methylamino, hydroxyethyl, carbamate, urea, imide, hydrazide, aminooxy, or other bonds known to those skilled in the art. Oligobenzamide peptidomimetic compounds can also be linked to amino acids, oligopeptides, optionally substituted alkyls, or other structures known to those skilled in the art.

[0083] Substitutions on substituted benzamides are generally on the benzene ring and may be on the 2-, 3-, 4-, 5-, or 6-positions of each benzene ring. The substitutions may be at the same position on each benzamide ring or at different positions on each benzene ring. For example, the substitutions are connected to the benzamide ring by chemical bonds including ether bonds, thioether bonds, amine bonds, amide bonds, carbamate bonds, urea bonds, and carbon-carbon (single, double, and triple) bonds, and the substitutions may be optionally substituted alkyl groups, lower alkyl groups, alkoxy groups, alkoxyalkyl groups, hydroxy groups, hydroxyalkyl groups, alkenyl groups, amino groups, imino groups, nitrate groups, alkylamino groups, nitroso groups, aryl groups, biaryl groups, bridged aryl groups, fused aryl groups, alkylaryl groups, arylalkyl groups, arylalkoxy groups, arylalkylamino groups, cycloalkyl groups, bridged ... The bridged cycloalkyl group, cycloalkoxy group, cycloalkyl-alkyl group, arylthio group, alkylthio group, alkylsulfinyl group, alkylsulfonyl group, arylsulfonyl group, arylsulfinyl group, carboxamide group, carbamoyl group, carboxyl group, carbonyl group, alkoxycarbonyl group, halogen group, haloalkyl group, haloalkoxy group, heteroaryl, heterocycle, arylheterocycle, heterocyclic compound, amide, imide, guanidino, hydrazide, aminooxy, alkoxyamino, alkylamide, carboxylic acid ester group, thioether group, carboxylic acid, phosphoryl group, or a combination thereof.

[0084] The present disclosure also provides oligobenzamide peptidomimetic compounds comprising at least two optionally substituted benzamides, each substituted benzamide having one substitution on the benzene ring, the substitutions being individually attached to the benzene ring of the oligobenzamide peptidomimetic compound by chemical bonds including ether, thioether, amine, amide, carbamate, urea, and carbon-carbon (single, double, and triple) bonds. Substitutions generally include optionally substituted alkyl groups, lower alkyl groups, alkoxy groups, alkoxyalkyl groups, hydroxy groups, hydroxyalkyl groups, alkenyl groups, amino groups, imino groups, nitrate groups, alkylamino groups, nitroso groups, aryl groups, biaryl groups, bridged aryl groups, fused aryl groups, alkylaryl groups, arylalkyl groups, arylalkoxy groups, arylalkylamino groups, cycloalkyl groups, bridged cycloalkyl groups, cycloalkoxy groups, cycloalkyl-alkyl groups, arylthio groups, alkylthio groups, alkylsulfinyl groups, alkylsulfonyl groups, arylsulfonyl groups, arylsulfinyl groups, carboxamide groups, carbamoyl groups, carboxyl groups, carbonyl groups, alkoxycarbonyl groups, halogen groups, haloalkyl groups, haloalkoxy groups, heteroaryl groups, heterocycles, arylheterocycles, heterocyclic compounds, amides, imides, guanidino groups, hydrazides, aminooxy groups, alkoxyamino groups, alkylamides, carboxylic acid ester groups, thioether groups, carboxylic acids, phosphoryl groups, or combinations thereof.

[0085] U.S. Patent Application Publication No. 2009 / 0012141 provides, for example, in Figure 2 therein, a synthetic scheme for preparing the α-helix mimetic compounds of the present disclosure. A specific example in that document shows 15 α-helix mimetic compounds made by starting with 4-amino-3-hydroxybenzoic acid compound 7 and converting it to N-Ac-protected methyl ester compound 8. Various alkyl groups were introduced to the hydroxyl group using various alkyl halides and bases (e.g., NaOH) known to those skilled in the art. After the alkylation reaction, methyl ester compound 9 was hydrolyzed using a base (such as LiOH), and methyl 4-amino-3-hydroxybenzoate compound 10 was coupled to the free benzoic acid using a coupling reagent (such as BOP) to give benzamide compound 11, which contains one alkyl group corresponding to the i-position of the helix. These steps were repeated to synthesize oligobenzamide compounds. Those skilled in the art will appreciate the even broader applicability of such methods in the synthesis of other compounds, such as those disclosed herein.

[0086] Additional peptidomimetics and methods for their preparation are disclosed in Raj et al., 2017, which is incorporated herein by reference. Those skilled in the art will recognize that the synthetic methods disclosed in Raj et al., 2017 can be used to construct the compounds of the present disclosure.

[0087] IV. Pharmaceutical Formulations and Methods of Treatment A. Formulation In another aspect, for administration to a patient in need of such treatment, a pharmaceutical formulation (also referred to as a pharmaceutical preparation, pharmaceutical composition, pharmaceutical product, medicinal product, drug, medicament, or medicine) comprises a therapeutically effective amount of a compound disclosed herein formulated with one or more excipients and / or drug carriers suitable for the indicated route of administration. In some embodiments, the compounds disclosed herein are formulated in a manner suitable for treating a human and / or animal patient. In some embodiments, the formulation comprises blending or mixing one or more of the compounds disclosed herein with one or more of the following excipients: lactose, sucrose, starch powder, cellulose esters of alkanoic acid, cellulose alkyl esters, talc, stearic acid, magnesium stearate, magnesium oxide, sodium and calcium salts of phosphate and sulfate, gelatin, acacia, sodium alginate, polyvinylpyrrolidone, and / or polyvinyl alcohol. In some embodiments, for example, for oral administration, the pharmaceutical formulation may be tableted or encapsulated. In some embodiments, the compounds may be dissolved or slurried in water, polyethylene glycol, propylene glycol, ethanol, corn oil, cottonseed oil, peanut oil, sesame oil, benzyl alcohol, sodium chloride, and / or various buffers. In some embodiments, the pharmaceutical formulations may be subjected to pharmaceutical operations such as sterilization and / or may contain drug carriers and / or excipients such as preservatives, stabilizers, wetting agents, emulsifiers, encapsulating agents, e.g., lipids, dendrimers, polymers, proteins such as albumin, nucleic acids, and buffers.

[0088] Pharmaceutical preparations can be administered in various ways, for example, orally or by injection (e.g., subcutaneously, intravenously, and intraperitoneally). Depending on the route of administration, the compounds disclosed herein can be coated in a material to protect the compound from the action of acid and other natural conditions that may inactivate the compound. To administer the active compound by other than parenteral administration, it may be necessary to coat the compound with or co-administer a material to prevent its inactivation. In some embodiments, the active compound can be administered to a patient in a suitable carrier, for example, liposomes, or a diluent. Pharmaceutically acceptable diluents include saline and aqueous buffer solutions. Liposomes include water-in-oil-in-water CGF emulsions and conventional liposomes.

[0089] The compound disclosed herein can be administered parenterally, intraperitoneally, intraspinally or intracerebrally.Dispersion can be prepared in glycerol, liquid polyethylene glycol and its mixture and oil.Under normal conditions of storage and use, these preparations can contain preservatives to prevent the growth of microorganisms.

[0090] Pharmaceutical compositions suitable for injectable use include sterile aqueous solutions (where water soluble) or dispersions and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersions. Carriers can be solvents or dispersion media containing, for example, water, ethanol, polyols (e.g., glycerol, propylene glycol, and liquid polyethylene glycol, etc.), suitable mixtures thereof, and vegetable oils. Proper fluidity can be maintained, for example, by the use of a coating such as lecithin, by the maintenance of the required particle size in the case of dispersions, and by the use of surfactants. Prevention of microbial action can be achieved by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, ascorbic acid, thimerosal, and the like. In many cases, it will be preferable to include isotonic agents, for example, sugars, sodium chloride, or polyalcohols such as mannitol and sorbitol, in the composition. Prolonged absorption of injectable compositions can be achieved by including in the composition an agent that delays absorption, for example, aluminum monostearate or gelatin.

[0091] The compound disclosed herein can be orally administered, for example, with inert diluent or absorbable edible carrier.The compound and other ingredients can be encapsulated in hard or soft gelatin capsules, compressed into tablets, or directly incorporated into patient's diet.For therapeutic oral administration, the compound disclosed herein can be incorporated with excipients and used in the form of ingestible tablets, buccal tablets, troches, capsules, elixirs, suspensions, syrups, wafers, etc.The percentage of therapeutic compound in compositions and preparations can, of course, vary.The amount of therapeutic compound in such pharmaceutical preparations is such that an appropriate dosage is obtained.

[0092] Therapeutic compounds may also be administered topically to the skin, eye, ear, or mucous membranes. Administration of therapeutic compounds may include formulation of the compound as a topical solution, lotion, cream, ointment, gel, foam, transdermal patch, or tincture. When a therapeutic compound is formulated for topical administration, the compound may be combined with one or more agents that increase the compound's permeability through the tissue to which it is administered. In other embodiments, topical administration to the eye is contemplated. Such administration may be applied to the surface of the cornea, conjunctiva, or sclera. While not wishing to be bound by any theory, it is believed that administration to the surface of the eye allows the therapeutic compound to reach the posterior part of the eye. Topical ocular administration may be formulated as a solution, suspension, ointment, gel, or emulsion. Finally, topical administration may also include administration to mucous membranes, such as the inside of the mouth. Such administration may be directly to specific locations within mucous membranes, such as teeth, sores, or ulcers. Alternatively, if local delivery to the lungs is desired, the therapeutic compound may be administered by inhalation in a dry powder or aerosol formulation.

[0093] In some embodiments, it may be advantageous to formulate parenteral compositions into unit dosage forms for ease of administration and uniformity of dosage.As used herein, unit dosage refers to a physically discrete unit suitable as a unitary dose for the patient to be treated; each unit contains a predetermined amount of therapeutic compound calculated to produce a desired therapeutic effect together with the required pharmaceutical carrier.In some embodiments, the specifications of the unit dosage form of the present disclosure are determined and directly depend on (a) the unique characteristics of the therapeutic compound and the specific therapeutic effect to be achieved, and (b) the limitations inherent in the art of compounding such therapeutic compounds for the treatment of selected conditions in patients.In some embodiments, the active compound is administered at a therapeutically effective dose sufficient to treat the condition related to the patient's condition.For example, the effectiveness of the compound can be evaluated in an animal model system that can predict the effectiveness of treating a disease in humans or another animal.

[0094] In some embodiments, the effective dose range of a therapeutic compound can be extrapolated from the effective dose determined in animal studies of a variety of different animals. In some embodiments, the human equivalent dose (HED) in mg / kg can be calculated using the following formula (see, for example, Reagan-Shaw et al., FASEB J., 22(3):659-661, 2008, which is incorporated herein by reference): HED (mg / kg) = Animal dose (mg / kg) × (Animal K m / Human K m )

[0095] K in transformation m The use of factors allows for HED values ​​to be based on body surface area (BSA) rather than just body weight. m The values ​​are well known. For example, for an average 60 kg human (1.6 m 2 (with BSA) m is 37, while a 20 kg child (BSA is 0.8 m 2 )K m is 25. K in some relevant animal models m is also well known and is as follows: m is 3 (assuming body weight of 0.02 kg and BSA of 0.007); K for hamsters m is 5 (assuming body weight 0.08 kg and BSA 0.02); K for rats m is 6 (assuming a body weight of 0.15 kg and a BSA of 0.025) and the K m is 12 (assuming a body weight of 3 kg and a BSA of 0.24).

[0096] The exact amount of therapeutic composition depends on the judgment of the practitioner and is specific to each individual. Nevertheless, the calculated HED dose provides a general guide. Other factors that affect the dose include the patient's physical and clinical condition, the route of administration, the intended goal of treatment, and the efficacy, stability and toxicity of the specific therapeutic formulation.

[0097] The actual dosage of the compound of the present disclosure or the composition containing the compound of the present disclosure administered to a patient may be determined by physical and physiological factors such as the type of animal being treated, age, sex, weight, severity of the condition, the type of disease being treated, previous or concurrent therapeutic interventions, the patient's underlying disease, and the route of administration. These factors may be determined by those skilled in the art. The physician responsible for administration will typically determine the concentration of the active ingredient in the composition and the appropriate dose for each individual patient. The dose may be adjusted by the individual physician if any complications occur.

[0098] In some embodiments, a therapeutically effective amount typically ranges from about 0.001 mg / kg to about 1000 mg / kg, about 0.01 mg / kg to about 750 mg / kg, about 100 mg / kg to about 500 mg / kg, about 1 mg / kg to about 250 mg / kg, or about 10 mg / kg to about 150 mg / kg (depending, of course, on the mode of administration and the factors mentioned above), in one or more doses administered daily for one or several days. Other suitable dose ranges include 1 mg to 10,000 mg per day, 100 mg to 10,000 mg per day, 500 mg to 10,000 mg per day, and 500 mg to 1,000 mg per day. In some specific embodiments, the amount is less than 10,000 mg per day and ranges from 750 mg to 9,000 mg per day.

[0099] In some embodiments, the amount of active compound in the pharmaceutical formulation is from about 2 to about 75% by weight. In some of these embodiments, the amount is from about 25 to about 60% by weight.

[0100] It is contemplated that the drug can be administered once or multiple times.The desired time interval for the delivery of multiple doses can be determined by those skilled in the art through routine experimentation only.As an example, the drug can be administered twice a day at intervals of about 12 hours to patients.In some embodiments, the drug is administered once a day.

[0101] The drug may be administered according to a daily schedule. As used herein, the term "daily schedule" refers to a predetermined, specified period. The daily schedule may include periods of the same length or different lengths, as long as the schedule is predetermined. For example, the daily schedule may include administration twice a day, daily, every two days, every three days, every four days, every five days, every six days, weekly, monthly, or any number of days or weeks in between. Alternatively, the predetermined daily schedule may include administration twice a day for the first week, followed by daily administration for several months. In other embodiments, the present disclosure provides that the drug may be taken orally, and the timing may be dependent or independent of food intake. Thus, for example, the drug may be taken every morning and / or every evening, regardless of whether the patient is taking the drug after or before meals.

[0102] B. Breast cancer Breast cancer refers to cancer that originates in breast tissue, most commonly in the lining of the milk ducts or the lobules that supply the ducts with milk. Cancer that originates in the milk ducts is known as ductal carcinoma, and cancer that originates in the lobules is known as lobular carcinoma. There are many different types of breast cancer with different stages (spread), aggressiveness, and genetic predisposition, and survival rates vary widely depending on these factors. Computerized models are available to predict survival. Depending on the best treatment and staging, 10-year disease-free survival rates vary from 98% to 10%. Treatments include surgery, drugs (hormonal therapy and chemotherapy), and radiation.

[0103] Worldwide, breast cancer constitutes 10.4% of all cancer cases in women, is the second most common type of non-skin cancer (after stomach cancer), and the fifth most common cause of cancer death. In 2004, breast cancer caused 519,000 deaths worldwide (7% of cancer deaths, about 1% of all deaths). Breast cancer is about 100 times more common in women than in men, but men tend to have a poorer prognosis due to delayed diagnosis.

[0104] Some breast cancers require the hormones estrogen and progesterone to grow and have receptors for these hormones. After surgery, these cancers are treated with drugs that interfere with these hormones, usually tamoxifen, and drugs that block estrogen production in the ovaries or elsewhere, which can damage the ovaries and terminate fertility. After surgery, low-risk hormone-sensitive breast cancers can be treated with hormone therapy and radiation alone. Breast cancers without hormone receptors, breast cancers that have spread to lymph nodes in the armpits, or breast cancers that express certain genetic traits are relatively high-risk and are treated more aggressively. One standard regimen commonly used in the United States is cyclophosphamide plus doxorubicin (adriamycin), known as CA. These drugs damage DNA in cancer cells but also in rapidly growing normal cells, causing serious side effects. Sometimes taxane drugs such as docetaxel are added, and this regimen is therefore known as CAT. Taxanes attack microtubules in cancer cells. A common equivalent treatment in Europe is cyclophosphamide, methotrexate, and fluorouracil (CMF). Monoclonal antibodies such as trastuzumab (Herceptin) are used to target cancer cells with HER2 mutations. Radiation is typically applied to the operating table to control cancer cells missed by surgery, which usually prolongs survival, but radiation exposure to the heart can cause damage and heart failure later in life.

[0105] Although screening techniques (discussed further below) are useful in determining the likelihood of cancer, further testing is required to confirm whether a mass detected by screening is cancerous as opposed to a benign surrogate such as a simple cyst.

[0106] In clinical settings, breast cancer is commonly diagnosed using the "triple test" of clinical breast exam (a breast examination by a trained physician), mammography, and fine-needle aspiration cytology. Both mammography and clinical breast exam, which are also used for screening, can indicate the approximate likelihood that a mass is cancerous and can also identify any other pathologies. Fine-needle aspiration cytology (FNAC), which may be performed in a doctor's office using local anesthesia if necessary, involves attempting to extract a small amount of fluid from the mass. Clear fluid makes the mass highly unlikely to be cancerous, while bloody fluid may be sent for examination under a microscope for cancer cells. These three tools, used together, can diagnose breast cancer with good accuracy.

[0107] Other options for biopsy include a core biopsy, in which part of the breast mass is removed, and an excision biopsy, in which the entire mass is removed.

[0108] Furthermore, vacuum-assisted breast biopsy (VAB) can be useful in diagnosing breast cancer in women with mammographically detected breast lesions according to a systematic review. In this study, the approximate estimates of VAB for diagnosing breast cancer were as follows: sensitivity was 98.1% (95% CI = 0.972-0.987), and specificity was 100% (95% CI = 0.997-0.999). However, the underdiagnosis rates for atypical ductal hyperplasia (ADH) and ductal carcinoma in situ (DCIS) were 20.9% (95% CI = 0.177-0.245) and 11.2% (95% CI = 0.098-0.128), respectively.

[0109] Breast cancer screening refers to the examination of otherwise healthy women for breast cancer with the goal of achieving a relatively early diagnosis. It is hypothesized that early detection improves prognosis. Several screening tests are used, including clinical breast examination and breast self-examination, mammography, genetic screening, ultrasound, and magnetic resonance imaging.

[0110] Clinical breast examinations, or breast self-examinations, involve palpating the breasts for lumps or other abnormalities. Research evidence does not support the effectiveness of any type of breast examination, as lumps likely have been growing for several years by the time they become large enough to be detected and would likely become large enough to be detected without immediate examination. Mammography screening for breast cancer uses X-rays to examine the breasts for any non-descript masses or lumps. For high-risk women, such as those with a strong family history of cancer, mammography screening is recommended at a relatively young age, and further testing may include genetic screening to test for BRCA genes and / or magnetic resonance imaging.

[0111] Breast cancer is sometimes treated first with surgery, followed by chemotherapy, radiation, or both. Treatments are increasingly aggressive according to prognosis and risk of recurrence. Stage 1 cancer (and DCIS) has an excellent prognosis and is commonly treated with lumpectomy with or without chemotherapy or radiation. However, aggressive HER2+ cancers should also be treated with a trastuzumab (Herceptin) regimen. Stage 2 and 3 cancers, which have a more advanced, poorer prognosis and a greater risk of recurrence, are commonly treated with surgery (lumpectomy or mastectomy with or without lymph node removal), radiation (sometimes), and chemotherapy (with the addition of trastuzumab for HER2+ cancers). Stage 4 metastatic cancer (i.e., spread to distant sites) is not curable and is managed with various combinations of all treatments, from surgery, radiation, chemotherapy, and targeted therapy. These treatments increase the median survival time for stage 4 breast cancer by approximately 6 months.

[0112] C. Ovarian cancer Ovarian cancers are cancerous growths that arise from different parts of the ovaries. Most (over 90%) ovarian cancers are classified as "epithelial" and are thought to arise from the surface (epithelium) of the ovaries. However, recent evidence suggests that the fallopian tubes may also be the source of some ovarian cancers. Because the ovaries and fallopian tubes are closely related to each other, it is hypothesized that these cells may mimic ovarian cancer. Other types arise from egg cells (germ cell tumors) or supporting cells (sex cords / stroma).

[0113] In 2004, 25,580 new cases were diagnosed in the United States, and 16,090 women died from ovarian cancer. Risk increases with age and decreases with pregnancy. The lifetime risk is approximately 1.6%, but women with an affected first-degree relative have a 5% risk. Women with a mutated BRCA1 or BRCA2 gene have a 25% to 60% risk, depending on the specific mutation. Ovarian cancer is the fifth leading cause of cancer death in women and the leading cause of death from gynecological cancers.

[0114] Ovarian cancer causes nonspecific symptoms. It is assumed (though this has not been proven) that stage I and II cancers progress to stage III and IV cancers, and early diagnosis is thought to result in better survival rates. Most women with ovarian cancer report one or more symptoms, such as abdominal pain or discomfort, abdominal mass, bloating, back pain, urinary urgency, constipation, fatigue, and a range of other nonspecific symptoms, as well as more specific symptoms such as pelvic pain, abnormal vaginal bleeding, or involuntary weight loss. Fluid accumulation within the abdominal cavity (ascites) may occur.

[0115] Diagnosis of ovarian cancer begins with a physical exam (including a pelvic exam), blood tests (for CA-125 and sometimes other markers), and a transvaginal ultrasound. The diagnosis must be confirmed by surgery to examine the abdominal cavity, take a biopsy (a tissue sample for microscopic analysis), and look for cancer cells in abdominal fluid. Treatment usually includes chemotherapy and surgery, and sometimes radiation therapy.

[0116] In most cases, the cause of ovarian cancer remains unknown. Older women and those with first- or second-degree relatives with the disease are at increased risk. Hereditary forms of ovarian cancer can be caused by mutations in certain genes (most notably BRCA1 and BRCA2, but also the genes for hereditary nonpolyposis colorectal cancer). Infertile women are at increased risk, as are women with a condition called endometriosis, women who have never been pregnant, and women using postmenopausal estrogen replacement therapy. Use of combined oral contraceptives is a protective factor. Risk is also relatively low in women whose fallopian tubes have been surgically blocked (tubal ligation).

[0117] Ovarian cancers are classified according to the tumor histology provided in the pathology report. Histology determines many aspects of clinical treatment, management, and prognosis. Superficial epithelial-stromal tumors, also known as ovarian epithelial cancers, are the most common type of ovarian cancer. They include serous tumors, endometriotic tumors, and mucinous cystadenocarcinomas. Sex cord-stromal tumors, including estrogen-producing granulosa cell tumors and virilizing Sertoli-Leydig cell tumors or virilomas, account for 8% of ovarian cancers. Germ cell tumors account for approximately 30% of ovarian tumors but only 5% of ovarian cancers. This is because most germ cell tumors are teratomas, and most teratomas are benign (see Teratoma). Germ cell tumors tend to occur in young women and girls. Prognosis depends on the specific histology of the germ cell tumor but is generally favorable. Mixed tumors contain elements of more than one of the above classes of tumor histology.

[0118] Ovarian cancer can also be a secondary cancer, the result of metastasis from a primary cancer elsewhere in the body. Seven percent of ovarian cancers are due to metastasis, while the remainder are primary cancers. Common primary cancers are breast cancer and gastrointestinal cancer (a common mistake is to label all peritoneal metastases from any gastrointestinal cancer as Krukenberg cancer, but this is only true when they originate from primary gastric cancer). Superficial epithelial-stromal tumors can originate in the peritoneum (the lining of the abdominal cavity); in this case, the ovarian cancer is secondary to a primary peritoneal cancer, but treatment is essentially the same as for primary superficial epithelial-stromal tumors involving the peritoneum.

[0119] Staging of ovarian cancer is according to the FIGO staging system and uses information obtained after surgery, which may include total abdominal hysterectomy, removal of (usually) both ovaries and fallopian tubes, (usually) the omentum, and pelvic (peritoneal) washings for cytopathology. AJCC stages are identical to FIGO stages. The AJCC staging system describes the extent of the primary tumor (T), the absence or presence of metastasis to nearby lymph nodes (N), and the absence or presence of distant metastasis (M).

[0120] The AJCC / TNM staging system includes three categories of ovarian cancer: T, N, and M. The T category includes three other subcategories, T1, T2, and T3, each classified according to where the tumor originates (one or both ovaries, inside or outside the ovaries). The T1 category of ovarian cancer describes ovarian tumors that are confined to one ovary and may affect one or both ovaries. The sub-subcategory T1a is used to stage cancers that are found in only one ovary, the capsule remains intact, and are not visible in fluids obtained from the pelvis. Cancers that do not affect the capsule, are confined to the inside of the ovary, and are not visible in fluids obtained from the pelvis but affect both ovaries are staged as T1b. The T1c category describes tumor types that can affect one or both ovaries and have grown through the ovarian capsule or are present in fluids obtained from the pelvis. T2 is a more advanced stage cancer. In this case, the tumor is growing in one or both ovaries and has spread to the uterus, fallopian tubes, or other pelvic tissues. Stage T2a is used to describe cancerous tumors that have spread to the uterus or fallopian tubes (or both) but are not present in fluids taken from the pelvis. Stages T2b and T2c refer to cancers that have spread to pelvic tissues other than the uterus and fallopian tubes and are not visible in fluids taken from the pelvis, and tumors that have spread to any of the pelvic tissues (including the uterus and fallopian tubes) but are also visible in fluids taken from the pelvis, respectively. T3 is a stage used to describe cancer that has spread to the peritoneum. This stage provides information about the size of metastatic tumors (tumors located in other areas of the body but caused by ovarian cancer). These tumors can be very small and only visible under a microscope (T3a), visible but not exceeding 2 centimeters in size (T3b), or larger than 2 centimeters (T3c).

[0121] The staging system also uses N categories to describe cancer that has or has not spread to nearby lymph nodes. There are only two N categories: N0, which indicates that the cancerous tumor has not affected the lymph nodes, and N1, which indicates involvement of lymph nodes close to the tumor. The M categories of the AJCC / TNM staging system provide information about whether ovarian cancer has metastasized to distant organs, such as the liver or lungs. M0 indicates that the cancer has not spread to distant organs, and the M1 category is used for cancer that has spread to other organs of the body. The AJCC / TNM staging system also includes Tx and Nx subcategories, which indicate that insufficient data cannot be used to describe the extent of the tumor and, for the same reason, to describe lymph node involvement, respectively.

[0122] Like any other type of cancer, ovarian cancer is graded in addition to being staged. A tumor's histological grade is a measure of how abnormal or malignant its cells appear under a microscope. There are four grades that indicate the cancer's potential to spread, with the higher the grade, the more likely this will occur. Grade 0 is used to describe a non-invasive tumor. Grade 0 cancers are also called borderline malignant tumors. Grade 1 tumors have cells that are well differentiated (looking very similar to normal tissue) and have the best prognosis. Grade 2 tumors, also called moderately differentiated, are made up of cells similar to normal tissue. Grade 3 tumors have the worst prognosis; their cells are abnormal and are called poorly differentiated.

[0123] Signs and symptoms of ovarian cancer are absent most of the time, but when they are present, they are nonspecific. In most cases, symptoms persist for several months before a patient receives a diagnosis.

[0124] A prospective case-control study of 1,709 women who visited a primary care clinic found that the combination of abdominal bloating, increased abdominal size, and urinary symptoms was present in 43% of women with ovarian cancer but only 8% of women who visited a primary care clinic.

[0125] The exact cause is usually unknown. The risk of developing ovarian cancer appears to be influenced by several factors. The more children a woman has, the lower her risk of ovarian cancer. Also, a young age at first pregnancy, an older age at last pregnancy, and the use of low-dose hormonal contraceptives have been found to be protective. Ovarian cancer is reduced in women after tubal ligation.

[0126] The relationship between oral contraceptive use and ovarian cancer was presented in a summary of the results of 45 case-control and prospective studies. Cumulatively, these studies demonstrate a protective effect against ovarian cancer. Women who used oral contraceptives for 10 years showed an approximately 60% reduction in the risk of ovarian cancer (a risk ratio of 0.42 with a statistically significant confidence interval, as expected given the large study size). This means that if 250 women take oral contraceptives for 10 years, one case of ovarian cancer will be prevented. This study is the largest epidemiological study to date on this subject (45 studies, over 20,000 women with ovarian cancer, and approximately 80,000 controls).

[0127] The association with the use of fertility drugs such as clomiphene citrate has been controversial. A 1991 analysis raised the possibility that drug use may increase the risk of ovarian cancer. Since then, several cohort and case-control studies have failed to provide conclusive evidence of such an association. It remains a complex research topic, as the reproductive history of infertile populations differs from that of "normal" populations.

[0128] There is strong evidence that genetic factors are important in some women. Carriers of certain mutations in the BRCA1 or BRCA2 genes are at particular risk. BRCA1 and BRCA2 genes account for 5% to 13% of ovarian cancers, and certain populations (e.g., Ashkenazi Jewish women) are at higher risk of both breast and ovarian cancer, often at an earlier age than the general population. Patients with a personal history of breast cancer or a family history of breast and / or ovarian cancer may be at higher risk, especially if diagnosed at a young age.

[0129] A strong family history of uterine, colon, or other gastrointestinal cancers may indicate the presence of a syndrome known as hereditary nonpolyposis colorectal cancer (HNPCC, also known as Lynch syndrome), which confers a relatively high risk of developing ovarian cancer. Patients with a strong genetic risk of ovarian cancer may consider the use of prophylactic, or preventative, oophorectomy after childbearing is complete. Australia, a member of the International Cancer Genome Consortium, is leading efforts to map the entire genome for ovarian cancer.

[0130] Early stage (I / II) ovarian cancer is difficult to diagnose until it has spread and progressed to later stages (III / IV), because most symptoms are nonspecific and therefore of little diagnostic value.

[0131] When ovarian malignancy is included in the list of possible diagnoses, a limited number of laboratory tests are indicated. A complete blood count (CBC) and serum electrolytes should be obtained in all patients.

[0132] Serum BHCG levels should be measured in all women of childbearing potential. In addition, serum alpha-fetoprotein (AFP) and lactate dehydrogenase (LDH) should be measured in girls and adolescent women with suspected ovarian tumors, because the younger the patient, the greater the likelihood of malignant germ cell tumors.

[0133] A blood test called CA-125 is useful for differential diagnosis and disease monitoring, but has not itself been shown to be an effective way to screen for early-stage ovarian cancer because of its unacceptably low sensitivity and specificity. However, it is the only widely used marker currently available.

[0134] Current research is exploring how to combine tumor marker proteomics with other indicators of disease (i.e., radiology and / or symptoms) to improve accuracy. The challenge with such an approach is that the very low population prevalence of ovarian cancer means that testing with very high sensitivity and specificity will still lead to some false-positive results (i.e., surgical procedures in which cancer is not found during surgery). However, the contribution of proteomics is still in its infancy and requires further refinement. Current research into proteomics represents the beginning of a paradigm shift toward personalized treatment.

[0135] Pelvic examination and imaging, including CT scan and transvaginal ultrasound, are mandatory. Physical examination may reveal increased abdominal circumference and / or ascites (fluid in the abdominal cavity). Pelvic examination may reveal an ovarian mass or abdominal mass. Pelvic examination may include a rectovaginal component for better palpation of the ovaries. In very young patients, magnetic resonance imaging may be preferred over a rectal and vaginal examination.

[0136] Definitively diagnosing ovarian cancer requires a surgical procedure to examine the inside of the abdomen. This can be an open procedure (laparotomy, an incision through the abdominal wall) or keyhole surgery (laparoscopy). During this procedure, suspicious areas are removed and sent for microscopic analysis. Fluid from the abdominal cavity may also be analyzed for cancer cells. If cancer is present, this procedure may also determine its spread (a form of tumor staging).

[0137] Women who have had children are less likely to develop ovarian cancer than women who have never had children, and breast-feeding may reduce the risk of certain types of ovarian cancer. Tubal ligation and hysterectomy reduce risk, and removal of both fallopian tubes and ovaries (bilateral salpingo-oophorectomy) dramatically reduces the risk of breast cancer as well as ovarian cancer. Use of oral contraceptives (birth control pills) for five or more years reduces the risk of ovarian cancer later in life by 50%.

[0138] Tubal ligation may reduce the chance of developing ovarian cancer by up to 67%, while a hysterectomy may reduce the risk of getting ovarian cancer by about one-third. Additionally, some studies have shown that painkillers such as acetaminophen and aspirin appear to reduce the risk of developing ovarian cancer. However, information is inconsistent, and more research is needed on this issue.

[0139] Routine screening of women for ovarian cancer is not recommended by any medical association, including the US Preventive Services Task Force, the American Cancer Society, the American College of Obstetricians and Gynecologists, and the National Comprehensive Cancer Network. This is because no studies have demonstrated improved survival rates for women who undergo screening. Screening for any type of cancer must be accurate and reliable, i.e., it must accurately detect the disease and not produce false-positive results in people without cancer. To date, no ovarian screening technology has been found to meet these criteria. However, in some countries, such as the UK, women who are likely to exhibit an increased risk of ovarian cancer (e.g., if they have a family history of the disease) may be offered personal screening through their physician, although this does not necessarily detect the disease early.

[0140] Researchers are evaluating different methods of screening for ovarian cancer. Screening tests that could potentially be used alone or in combination for routine screening include the CA-125 marker and transvaginal ultrasound. Doctors can measure the level of CA-125 protein in a woman's blood. While a high level can be a sign of ovarian cancer, this is not always the case. Also, not all women with ovarian cancer have high CA-125 levels. Transvaginal ultrasound involves using an ultrasound probe to scan the ovaries from inside the vagina, giving a clearer picture than scanning the abdomen. The UK Collaborative Trial of Ovarian Cancer Screening is testing a screening technique that combines the CA-125 blood test with transvaginal ultrasound.

[0141] The goal of screening is to diagnose ovarian cancer early, when it is more likely to be treated successfully. However, the development of the disease is not fully understood, and it has been argued that early-stage cancers do not necessarily develop into late-stage disease. As with any screening technique, there are risks and benefits that must be carefully considered, and health authorities should evaluate these before introducing any ovarian cancer screening program.

[0142] The goal of ovarian cancer screening is to detect the disease at stage I. Several large studies are underway, but none have identified an effective technique. However, in 2009, early results from the UK Collaborative Trial of Ovarian Cancer Screening (UKCTOCS) showed that a technique using annual CA-125 testing in conjunction with ultrasound imaging could help detect the disease early. However, it is not yet clear whether this approach will actually help save lives. Final results from this trial are expected to be published in 2015.

[0143] Surgery may be sufficient for malignant tumors that are well differentiated and confined to the ovary. More aggressive tumors confined to the ovary may require the addition of chemotherapy. For patients with advanced disease, surgical reduction combined with a combination chemotherapy regimen is standard. Borderline tumors, even after spread outside the ovary, are adequately managed with surgery, and chemotherapy is not considered useful.

[0144] Surgery is the preferred procedure and is often necessary to obtain tissue samples for differential diagnosis via histology. Surgery performed by a gynecologic oncologist usually results in improved outcomes. Improved survival rates are attributed to the accuracy of staging the disease by gynecologic oncologists compared with general gynecologists and general surgeons, and to the faster rate of invasive surgical resection of tumors within the abdomen.

[0145] The type of surgery depends on how far the cancer has spread when diagnosed (cancer stage) and the estimated type and grade of cancer. The surgeon may remove one ovary (unilateral oophorectomy) or both ovaries (bilateral oophorectomy), fallopian tubes (salpingectomy), and the uterus (hysterectomy). In some very early-stage tumors (stage 1, low-grade or low-risk disease), especially in young women who wish to preserve fertility, only the involved ovary and fallopian tube are removed (called a "unilateral salpingo-oophorectomy," USO).

[0146] In advanced malignancies where complete resection is not feasible, as much of the tumor as possible is removed (debulking surgery). When this type of surgery is successful (i.e., leaving a tumor less than 1 cm in diameter ["optimal debulking"]), the prognosis is improved compared with patients who are left with a large mass (greater than 1 cm in diameter). Minimally invasive surgical techniques can facilitate the safe removal of very large (greater than 10 cm) tumors with fewer surgical complications.

[0147] Chemotherapy has been the general standard of care for ovarian cancer for decades, but protocols are highly variable. If appropriate, chemotherapy is used after surgery to treat any remaining disease. This depends on the tumor histology, and some tumor types (particularly teratomas) are not sensitive to chemotherapy. In some cases, there may be reasons to administer chemotherapy first, followed by surgery.

[0148] For patients with stage IIIC epithelial ovarian adenocarcinoma who underwent successful optimal debulking, a recent clinical trial showed that median survival was significantly longer in patients who received intraperitoneal (IP) chemotherapy. Patients in this trial reported relatively low adherence to IP chemotherapy, with fewer than half of the patients receiving all six cycles of IP chemotherapy. Despite this high "dropout" rate, the entire group (including patients who did not complete IP chemotherapy treatment) survived, on average, longer than patients who received intravenous chemotherapy alone.

[0149] Some experts believe that the toxicity and other complications of IP chemotherapy may be obviated by improved IV chemotherapy drugs currently under development.

[0150] IP chemotherapy is recommended as the standard of care for first-line treatment of ovarian cancer, although the basis for this recommendation has been challenged.

[0151] Radiation therapy is not effective in advanced stages of disease because high doses cannot be safely delivered when vital organs are in the radiation field. Therefore, radiation therapy is generally avoided in such stages because the vital organs may not be able to tolerate the problems associated with these ovarian cancer treatments.

[0152] Ovarian cancer typically has a poor prognosis. Ovarian cancer is disproportionately fatal because there are no obvious early detection or screening tests for the disease, and therefore the majority of cases are not diagnosed until they reach an advanced stage. More than 60% of women who present with this cancer already have stage III or IV cancer that has spread beyond the ovaries. Ovarian cancer sheds cells into the natural fluids of the abdominal cavity. These cells can then implant on other abdominal (peritoneal) structures, including the uterus, bladder, intestine, and omental lining of the intestinal wall, forming new tumor growths even before cancer is suspected.

[0153] The 5-year survival rate for all stages of ovarian cancer is 45.5%. In cases where the disease is diagnosed early, when the cancer is still confined to the primary site, the 5-year survival rate is 92.7%.

[0154] D. Brain cancer Brain tumors are solid intracranial neoplasms, i.e., tumors (defined as abnormal growths of cells) within the brain or central spinal canal. Brain tumors include all tumors within the brain or central spinal canal. They are usually produced by abnormal and uncontrolled cell division in either the brain itself (neurons, glial cells (astrocytes, oligodendrocytes, ependymal cells, myelin-producing Schwann cells), lymphatic tissue, and blood vessels), cranial nerves, the outer membranes of the brain (meninges), skull, pituitary gland, and pineal gland, or have spread from a primarily located cancer to another organ (metastatic tumor).

[0155] Any brain tumor is inherently serious and life-threatening due to its invasive and infiltrative nature within the confined space of the intracranial cavity. However, brain tumors, even malignant ones, are not necessarily fatal. Brain tumors or intracranial neoplasms can be cancerous (malignant) or noncancerous (benign), but the definitions of malignant and benign neoplasms differ from those commonly used for other types of cancerous or noncancerous neoplasms in the body. Their threat level depends on a combination of factors such as the type of tumor, its location, its size, and its developmental state. Because the brain is well protected by the skull, early detection of brain tumors occurs only when diagnostic tools are directed into the cranial cavity. Detection usually occurs at an advanced stage, when the presence of the tumor causes unexplained symptoms.

[0156] Primary (true) brain tumors are commonly located in the posterior fossa in children and the anterior two-thirds of the cerebral hemispheres in adults, but can affect any part of the brain.

[0157] The prognosis for brain cancer varies based on the type of cancer. Medulloblastoma has a favorable prognosis with chemotherapy, radiation therapy, and surgical resection, whereas glioblastoma multiforme has a median survival of only 12 months even with aggressive chemoradiotherapy and surgery. Brainstem glioma has the poorest prognosis of any form of brain cancer, with most patients dying within one year despite treatment typically consisting of tumor radiation and corticosteroids. However, localized brainstem gliomas appear to have exceptional prognostic potential, with long-term survival frequently reported.

[0158] Glioblastoma multiforme is the most lethal and most common form of malignant brain tumor. Even with aggressive multimodality therapy consisting of radiation therapy, chemotherapy, and surgical resection, median survival is only 12 to 17 months. Standard treatment for glioblastoma multiforme consists of maximal surgical resection of the tumor, followed by radiation therapy to eliminate the cancer 2 to 4 weeks after the surgical procedure. This is followed by chemotherapy. Most patients with glioblastoma take corticosteroids, typically dexamethasone, to relieve symptoms during the disease. Experimental treatments include gamma knife radiosurgery, boron neutron capture therapy, and gene transfer.

[0159] Oligodendrogliomas are incurable but slowly progressing malignant brain tumors. They can be treated with surgical resection, chemotherapy, and / or radiation therapy. For suspected low-grade oligodendrogliomas in selected patients, some neuro-oncologists opt for a course of watchful waiting with supportive care only. Tumors with 1p / 19q codeletion have been found to be particularly chemosensitive, with one source reporting that oligodendrogliomas are among the most chemosensitive human solid malignancies. Median survival times of up to 16.7 years have been reported for low-grade oligodendrogliomas.

[0160] Although there is no specific or unique clinical symptom or sign for any brain tumor, the presence of a combination of symptoms and the absence of corresponding clinical signs of infection or other causes may be an indication to redirect the diagnostic investigation toward the possibility of an intracranial neoplasm.

[0161] Diagnosis often begins with a patient interview to obtain a clear overview of the patient's medical precursors and current symptoms. Clinical and laboratory investigations help to rule out infection as a cause of symptoms. Testing at this stage may include ophthalmologic, otolaryngological (or ENT) and / or electrophysiological testing. The use of electroencephalography (EEG) often plays a role in diagnosing brain tumors.

[0162] Swelling or obstruction of the passage of cerebrospinal fluid (CSF) from the brain can cause (early) signs of increased intracranial pressure, which translates clinically into headache, vomiting, or altered states of consciousness, as well as changes in skull diameter and bulging fontanelles in children. Relatively complex symptoms, such as endocrine dysfunction, should alert the physician not to exclude a brain tumor.

[0163] The likelihood of a brain tumor should be raised by the occurrence of either a slow progression or sudden onset of bitemporal visual field defects (due to compression of the optic chiasm) or dilated pupils, and focal neurological symptoms such as cognitive and behavioral disturbances (including impaired judgment, memory loss, cognitive deficits, and spatial disorientation), personality or emotional changes, hemiparesis, hypoesthesia, aphasia, ataxia, visual field defects, olfactory impairment, hearing impairment, facial paralysis, diplopia, or more severe symptoms such as tremors, hemiplegia (paralysis of one side of the body), or (epileptic) seizures in patients with a negative history of epilepsy.

[0164] Imaging plays a central role in diagnosing brain tumors. Recently, invasive and sometimes dangerous early imaging methods such as pneumocephalography and cerebral angiography have been abandoned and replaced by noninvasive high-resolution techniques such as computed tomography (CT) scans and especially magnetic resonance imaging (MRI). Neoplasms often appear as different-colored masses (also called protrusions) on CT or MRI results.

[0165] Benign brain tumors often appear as hypodense (darker than brain tissue) mass lesions on cranial CT scans. On MRI, they appear as either hypointense (darker than brain tissue) or isointense (same intensity as brain tissue) on T1-weighted scans, or hyperintense (brighter than brain tissue) on T2-weighted MRI, although this appearance is variable.

[0166] In most malignant primary and metastatic brain tumors, contrast uptake, sometimes in a characteristic pattern, can be demonstrated on either CT or MRI scans. Perilesional edema, or areas of compression, or areas where brain tissue has been compressed by an infiltrative process, also appear as hyperintense areas on T2-weighted MRI and may indicate the presence of a diffuse neoplasm (ill-defined). This is because these tumors disrupt the normal function of the blood-brain barrier, leading to increased permeability. However, it is not possible to diagnose high-grade versus low-grade gliomas based solely on the enhancement pattern.

[0167] Glioblastoma multiforme and anaplastic astrocytoma are associated with the genetic acute hepatic porphyrias (PCT, AIP, HCP, and VP), including positive test results associated with drug-resistant seizures. Unexplained complications associated with drug treatment of these tumors should alert physicians to the possibility of undiagnosed neuroporphyria.

[0168] A definitive diagnosis of brain tumor can only be confirmed by histological examination of tumor tissue samples obtained either by brain biopsy or open surgery. Histological examination is essential for determining appropriate treatment and an accurate prognosis. This examination, performed by a pathologist, typically involves three stages: intraoperative examination of fresh tissue, preliminary microscopic examination of prepared tissue, and follow-up examination of prepared tissue after immunohistochemical staining or genetic analysis.

[0169] When a brain tumor is diagnosed, a medical team is formed to evaluate the treatment options that the patient's doctor will present to the patient and their family. Given the location of primary solid neoplasms in the brain, "doing nothing" is not usually an option in the majority of cases. It takes time for the neurosurgeon to monitor the progression of the neoplasm before presenting a management plan to the patient and their relatives. A variety of these treatments are available depending on the type and location of the neoplasm and can be combined to maximize the chances of survival: surgery; complete or partial tumor resection with the goal of removing as many tumor cells as possible; radiation therapy; and chemotherapy with the goal of killing as many cancer cells as possible remaining after surgery and keeping any remaining tumor cells in a non-dividing, dormant state for as long as possible.

[0170] Survival rates for primary brain tumors depend on the type of tumor, the age and functional status of the patient, the extent of surgical tumor removal, and other factors specific to each case.

[0171] The primary and most preferred procedure described in the medical literature is surgical removal (resection) via craniotomy. Minimally invasive techniques are under investigation but have never become commonplace. The primary therapeutic goal of surgery is to remove as many tumor cells as possible, with complete removal being the best outcome, whereas tumor cytoresection ("debulking") is different. In some cases, access to the tumor is impossible, hindering or obstructing surgery.

[0172] Many meningiomas can be successfully removed surgically, except for some tumors located at the base of the skull. Most pituitary adenomas can be surgically removed, often using a minimally invasive approach through the nasal cavity and skull base (transsphenoidal approach). Removal of larger pituitary adenomas requires craniotomy (opening of the skull). Radiation therapy, including stereotactic approaches, is reserved for inoperable cases.

[0173] Some current research aims to improve the surgical removal of brain tumors by labeling tumor cells with a chemical (5-aminolevulinic acid) that causes them to fluoresce. Postoperative radiation therapy and chemotherapy are essential parts of the standard of care for malignant tumors. In the case of "low-grade" gliomas, radiation therapy may be performed when significant tumor burden reduction cannot be achieved surgically.

[0174] Any individual who has undergone brain surgery may suffer from epileptic seizures. Seizures can range from absent to severe tonic-clonic seizures. Medications are prescribed and administered to minimize or eliminate the occurrence of seizures.

[0175] Generally, multiple metastatic tumors are treated with radiation therapy and chemotherapy rather than surgery. The prognosis in such cases is determined by the primary tumor and is generally poor.

[0176] The goal of radiation therapy is to selectively kill tumor cells while leaving normal brain tissue intact. In standard external beam radiation therapy, multiple treatments with standard "fractionated" doses of radiation are administered to the brain. This process is repeated for a total of 10 to 30 treatments, depending on the type of tumor. These additional treatments provide an improved prognosis and increased survival rate for some patients.

[0177] Radiosurgery is a treatment method that uses computer calculations to focus radiation at the site of the tumor while minimizing radiation dose to the surrounding brain. Radiosurgery can be an adjunct to other treatments or represent the primary treatment technique for some tumors.

[0178] Radiation therapy may be used after tumor removal, or in some cases instead of tumor removal. Forms of radiation therapy used for brain cancer include external beam radiation therapy, brachytherapy, and, in more difficult cases, stereotactic radiosurgery such as Gamma Knife, CyberKnife, or Novalis Tx radiosurgery.

[0179] Radiation therapy is the most common treatment for secondary brain tumors. The amount of radiation therapy depends on the size of the area of ​​the brain affected by the cancer. Conventional extracorporeal "whole brain radiation therapy" (WBRT) or "whole brain irradiation" may be indicated at risk for the future development of other secondary tumors. In cases involving fewer than three small secondary brain tumors, stereotactic radiation therapy is usually recommended.

[0180] Patients undergoing chemotherapy are given drugs designed to kill tumor cells. Chemotherapy can improve overall survival in patients with the most aggressive primary brain tumors, but only in about 20 percent of patients. Because radiation can have adverse effects on the developing brain, chemotherapy is often used instead of radiation in young children. The decision to prescribe this treatment is based on the patient's overall health, the type of tumor, and the extent of the cancer. The toxicity and numerous side effects of the drugs, as well as the uncertain prognosis of chemotherapy for brain tumors, place this treatment further down the line of treatment options, with surgery and radiation therapy being preferred.

[0181] Shunts are not used as a cure, but to relieve symptoms by reducing hydrocephalus caused by blockage of cerebrospinal fluid.

[0182] Researchers are currently investigating several promising new treatments, including gene therapy, highly focused radiation therapy, immunotherapy, and novel chemotherapies. A variety of new treatments are available on an investigational basis at centers that specialize in the treatment of brain tumors. [Example]

[0183] V. Working Examples The following examples are included to demonstrate preferred embodiments of the present disclosure. Those of skill in the art should appreciate that the techniques disclosed in the examples which follow represent techniques discovered by the inventors to function well in the practice of the present disclosure, and as such can be considered to constitute preferred modes of practice thereof. However, those of skill in the art should, in light of the present disclosure, appreciate that many changes can be made in the specific embodiments which are disclosed and still obtain a like or similar result without departing from the spirit and scope of the present disclosure.

[0184] Example 1 - Results The oligobenzamide analogs of the present invention are highly potent and effective against a variety of cancer cells, including breast, ovarian, and pancreatic cancers. These compounds have a unique mode of action compared to existing therapeutic treatments for these diseases. The compounds exhibit IC values ​​of 10-50 nM for growth inhibition. 50 TK41 is a trisbenzamide analogue that exhibits high potency (IC 50 It inhibits nuclear receptor (NR) interactions with its coregulator proteins in cancer cells at approximately 100 nM (Figures 1-4). This compound was found to be highly effective against endocrine therapy-resistant breast cancer cells, which are difficult to treat with currently available endocrine and chemotherapeutic approaches (Figures 2 and 8).

[0185] Although TK41 was originally designed to target estrogen receptors, it was found to also exhibit activity in triple-negative breast cancer cells, which are estrogen receptor-negative (Figure 2 and Figures 5-7). This result was unexpected based on the performance of previous benzamide compounds (see Figure 9 for structure-activity table). Indeed, TK41 exhibited an IC<100 nM. 50TK41 shows very strong growth inhibition of triple-negative breast cancer cells (TNBC) at 400 mg / kg / day. TNBC is difficult to treat, and there are currently no effective drugs available on the market. Animal studies with TK41 not only showed significant tumor growth inhibition, but also no obvious side effects or toxicity. TK41 can be taken orally and is an excellent therapeutic candidate for a wide range of breast cancers.

[0186] Additionally, another trisbenzamide compound, TK208, was synthesized and tested against breast and ovarian cancer cell lines (Figures 10-15). TK208 exhibited IC values ​​of 10-100 nM. 50 Additional trisbenzamide analogs, TK314 (Figure 24) and TK315 (Figure 23), were further prepared and showed IC values ​​ranging from 10 to 50 nM. 50 These compounds (e.g., TK41, TK208, TK308 (Figure 21), TK309 (Figure 22), TK314, TK315) are highly potent compounds that inhibit tumor growth and kill breast and ovarian cancer cells, and therefore are excellent therapeutic candidates for such diseases.

[0187] We also synthesized the trisbenzamide YL144, which was found to inhibit the vitamin D receptor (VDR) with high potency and may be a useful therapeutic candidate for pancreatic cancer (Figures 16-18). The bisbenzamide TK245 is a unique compound that exhibits potent growth inhibition of estrogen receptor-positive breast cancer (Figures 19 and 20).

[0188] TK41 was also shown to induce ER stress in TNBC MD-MBA-231 cells, but not in HMEC cells (Figures 25 and 26). TK41 halts de novo protein synthesis in TNBC cells (Figure 27). The basal levels of ER stress and unfolded protein response protein expression correlate with TK41 activity (Figure 28). Modulation of these stress protein levels affects TK41 activity. Therefore, the basal levels of ER stress and unfolded protein response protein expression may serve as biomarkers for predicting response to TK41. ER stress was also induced in pancreatic cancer MiaPaca cells upon exposure to TK41, but did not induce ER stress in HMEC cells (Figure 29). Without wishing to be bound by any particular theory, the mechanism of action of TK41 may involve targeting either the ER or TLX, inducing endoplasmic reticulum stress and subsequent apoptosis, and blocking autophagic fusion (Figure 30).

[0189] In summary, we have developed a number of oligobenzamide analogs that have shown very strong therapeutic potential in treating breast, ovarian, and pancreatic cancer. Their mode of action and potency are unparalleled among currently available drugs, making them very promising therapeutic candidates.

[0190] Example 2 - Synthesis TIFF0007770716000060.tif94142

[0191] Scheme 1. Synthetic route to TK41. Reagents and conditions: (a) (COCl)2, cat. DMF, DCM, rt, 2 h; (b) DIEA, DCM, rt, 24 h; (c) SnCl2, DMF, rt, 12 h; (d) HATU, DIEA, DMF, rt, 24 h; (e) Pd(PPh3)4, PhSiH3, THF, rt, 1 h; (f) HATU, DIEA, DMF, rt, 24 h; (g) conc. HCl, rt, 24 h.

[0192] Compound 4: A 250 mL round-bottom flask was charged with compound 1 (5.45 g, 22.8 mmol), DCM (100 mL), oxalyl chloride (2.6 mL, 30.1 mmol), and two drops of DMF. The reaction mixture was stirred at room temperature for 2 hours and then concentrated under reduced pressure. The resulting compound 2 was dissolved in DCM (20 mL) and slowly added to a solution of compound 3 (3.8 g, 15.2 mmol), DIEA (5.3 mL, 30.4 mmol), and DCM (100 mL). The reaction mixture was stirred at room temperature for 24 hours and then washed with 1 N HCl (50 mL), saturated NaHCO (50 mL), and brine (50 mL). The organic layer was dried over Na SO , filtered, and concentrated under reduced pressure to give the crude product. Purification by crystallization from EtOAc / hexane (1:4) afforded compound 4 as a pale yellow solid (5.1 g, 71%).

[0193] Compound 5: A 250 mL round-bottom flask was charged with compound 4 (4.7 g, 10.0 mmol), DMF (100 mL), and SnCl₂·2H₂O (6.8 g, 30.0 mmol). The reaction mixture was stirred at room temperature for 12 h and then diluted with EtOAc (200 mL) and 1 N HCl (200 mL). The organic layer was separated and washed with 1 N HCl (100 mL) and brine (100 mL). The organic layer was dried over Na₂SO₄, filtered, and concentrated under reduced pressure to give the crude product. Purification by flash chromatography (hexane / EtOAc 4:1) afforded compound 5 as a pale yellow solid (3.6 g, 82%).

[0194] Compound 7: A 250 mL round-bottom flask was charged with compound 5 (3.6 g, 8.2 mmol), compound 6 (6.2 g, 13.2 mmol), HATU (6.7 g, 17.6 mmol), DMF (100 mL), and DIEA (4.6 mL, 26.4 mmol). The reaction mixture was stirred at room temperature for 24 hours and then diluted with EtOAc (300 mL) and 0.5 N HCl (200 mL). The organic layer was separated and washed with 0.5 N HCl (100 mL) and brine (100 mL). The organic layer was concentrated under reduced pressure to give the crude product. Purification by crystallization from EtOAc afforded compound 7 as a pale yellow solid (5.6 g, 77%).

[0195] Compound 8: A 250 mL round-bottom flask was charged with compound 7 (5.3 g, 5.9 mmol) and THF (100 mL). Pd(PPh3)4 (0.69 g, 0.60 mmol) and PhSiH3 (1.5 mL, 12.2 mmol) were then added to the reaction mixture. The reaction mixture was stirred at room temperature for 1 hour. The resulting solid was filtered, washed with ether, and dried in vacuo to give compound 8 as a white solid (4.9 g, 97%).

[0196] Compound 9: A 100 mL round-bottom flask was charged with compound 8 (2.7 g, 3.2 mmol), HATU (1.4 g, 3.7 mmol), DMF (30 mL), trans-4-methylcyclohexylamine (0.73 g, 6.4 mmol), and DIEA (1.2 mL, 6.9 mmol). The reaction mixture was stirred at room temperature for 24 hours and then diluted with EtOAc (100 mL) and 0.5 N HCl (50 mL). The organic layer was separated and washed with 0.5 N HCl (50 mL) and brine (50 mL). The resulting solid was filtered, washed with EtOAc, and dried in vacuo to give compound 9 as a white solid (1.75 g). The product was used in the next reaction without further purification.

[0197] TK41: A 500 mL round-bottom flask was charged with compound 9 (1.75 g), THF (300 mL), and conc. HCl (30 mL). The reaction mixture was stirred at room temperature for 24 hours and then concentrated under reduced pressure. The resulting solid was filtered, washed with MeOH, and dried in vacuo to give TK11-41 as a pale yellow solid (1.3 g, 57% over two reaction steps).

[0198] TIFF0007770716000061.tif96141

[0199] Scheme 2. Synthetic route to TK296. Reagents and conditions: (a) ), naphthalene-2-methanamine hydrochloride, NaBH3CN, 1% AcOH / DMF, rt, 24 h; (b) PyBroP, DIEA, DCM, rt, 24 h; (c) Na2S2O4, 1,1'-di-n-octyl-4,4'-bipyridinium dibromide, K2CO3, HO / THF, rt, 24 h; (d) Boc-β-Ala-OH, DIC, DMF / DCM, rt, 24 h; (e) TFA, rt, 1 h.

[0200] Compound 1: AM PS resin (0.42 mmol / g, 3.0 g, 1.26 mmol) was swollen in DMF for 12 h and washed with DMF (3 × 1 min). A solution of BAL linker (676 mg, 2.52 mmol), PyBOP (1.44 g, 2.77 mmol), and DIEA (0.97 mL, 5.6 mmol) in DMF (25 mL) was added to the resin, shaken at room temperature for 24 h, and washed with DMF (3 × 1 min). Completion of the coupling reaction was confirmed by a negative Kaiser ninhydrin test.

[0201] Compound 2: A mixture of compound 1 (0.25 g, 0.11 mmol), naphthalene-2-methanamine hydrochloride (85 mg, 0.44 mmol), and NaBHCN (29 mg, 0.44 mmol) in 1% AcOH / DMF (5 mL) was shaken at room temperature for 24 h and washed with DMF (3 × 1 min). The reaction was monitored using a positive chloranil test.

[0202] Compound 4: 1. Amide bond formation: A solution of compound 3 (90 mg, 0.33 mmol), PyBroP (154 mg, 0.33 mmol), and DIEA (0.11 mL, 0.66 mmol) in DCM (6 mL) was shaken at room temperature for 1 h and added to compound 2. The reaction mixture was shaken at room temperature for 24 h and washed with DMF (3 × 1 min). Completion of the reaction was confirmed by a negative chloranil test. 2. Reduction: A mixture of the resulting resin, NaSO (113 mg, 0.55 mmol), 1,1'-di-n-octyl-4,4'-bipyridinium dibromide (6 mg, 0.01 mmol), and KCO (30 mg, 0.22 mmol) in 20% HO / THF (8 mL) was shaken at room temperature for 24 h and washed with HO (3 × 1 min), 20% 1N HCl (aq) / THF (3 × 1 min), 20% HO / THF (3 × 1 min), and DMF (3 × 1 min) to give compound 4.

[0203] Compound 6: This compound was prepared from compound 5 by using the same procedure as for compound 4.

[0204] Compound 8: This compound was prepared from compound 7 by using the same procedure as for compound 4.

[0205] Compound 9: A solution of Boc-β-Ala-OH (378 mg, 2.0 mmol), DIC (0.15 mL, 1.0 mmol) in 20% DMF / DCM (6 mL) was shaken at room temperature for 1 h and added to compound 6. The reaction mixture was shaken at room temperature for 24 h and washed with DMF (3 × 1 min).

[0206] A mixture of TK296:Compound 9 in 5% HO / TFA (5 mL) was shaken at room temperature for 2 hours, then the TFA solution was filtered and the resin was washed with TFA (2 mL) and DCM (2 mL). The combined TFA solution was concentrated under a gentle stream of nitrogen, and a white solid was precipitated by adding cold diethyl ether (5 mL). The white solid was washed with ether and dried in vacuo to give TK296 (30 mg, 28%).

[0207] TIFF0007770716000062.tif128143

[0208] Scheme 3. Synthetic route to TK207. Reagents and conditions: (a) (COCl)2, cat. DMF, DCM, rt, 2 h; (b) DIEA, DCM, rt, 24 h; (c) Pd(PPh3)4, PhSiH3, THF, rt, 1 h; (d) PyBOP, DIEA, DMF, rt, 24 h; (e) Pd(PPh3)4, PhSiH3, THF, rt, 1 h; (f) 7-amino-1H-indazole, HATU, DIEA, DMF, rt, 24 h; (g) TFA, rt, 1 h.

[0209] Compound 4: A 250 mL round-bottom flask was charged with compound 1 (1.91 g, 6.75 mmol), DCM (50 mL), oxalyl chloride (1.2 mL, 13.5 mmol), and two drops of DMF. The reaction mixture was stirred at room temperature for 2 hours and then concentrated under reduced pressure. The resulting compound 2 was dissolved in DCM (20 mL) and slowly added to a solution of compound 3 (2.0 g, 4.5 mmol), DIEA (1.6 mL, 9.0 mmol), and DCM (50 mL). The reaction mixture was stirred at room temperature for 24 hours and then washed with 1 N HCl (50 mL), saturated NaHCO3 (50 mL), and brine (50 mL). The organic layer was concentrated under reduced pressure to give the crude product. Purification by crystallization from EtOAc / hexane (1:2) afforded compound 4 as a pale yellow solid (2.7 g, 85%).

[0210] Compound 5: A 250 mL round-bottom flask was charged with compound 4 (2.7 g, 3.83 mmol) and THF (100 mL). Pd(PPh3)4 (0.59 g, 0.51 mmol) and PhSiH3 (0.95 mL, 7.7 mmol) were then added to the reaction mixture. The reaction mixture was stirred at room temperature for 1 hour and then concentrated under reduced pressure. The resulting solid was washed with ether and dried in vacuo to give compound 5 as a pale yellow solid (2.5 g, 98%).

[0211] Compound 7: A 100 mL round-bottom flask was charged with compound 5 (0.60 g, 0.90 mmol), PyBOP (0.56 g, 1.1 mmol), DMF (30 mL), and DIEA (0.93 mL, 5.3 mmol), and the mixture was stirred at room temperature for 1 hour. Compound 6 (0.80 g, 2.70 mmol) was then added to the reaction mixture, and the resulting mixture was stirred at room temperature for 24 hours. The reaction mixture was diluted with EtOAc (100 mL) and 1 N HCl (50 mL). The organic layer was separated and washed with 1 N HCl (50 mL) and brine (50 mL). The organic layer was concentrated under reduced pressure to give the crude product. Purification by crystallization from EtOAc gave compound 7 as a pale yellow solid (0.51 g, 68%).

[0212] Compound 8: A 250 mL round-bottom flask was charged with compound 7 (0.49 g, 0.59 mmol) and THF (100 mL). Pd(PPh3)4 (0.14 g, 0.12 mmol) and PhSiH3 (0.30 mL, 0.24 mmol) were then added to the reaction mixture. The reaction mixture was stirred at room temperature for 1 hour and then concentrated under reduced pressure. The resulting solid was washed with ether and dried in vacuo to give compound 8 as a yellow solid (0.38 g, 81%).

[0213] TK207: A solution of compound 8 (40 mg, 0.051 mmol), HATU (25 mg, 0.066 mmol), and DIEA (27 μL, 0.16 mmol) in DMF (3 mL) was stirred at room temperature for 1 hour. 7-Amino-1H-indazole (20 mg, 0.15 mmol) was then added to the reaction mixture, and the resulting mixture was stirred at room temperature for 24 hours. The reaction mixture was diluted with EtOAc (30 mL) and 1 N HCl (20 mL). The organic layer was separated and washed with 1 N HCl (20 mL) and brine (20 mL). The organic layer was concentrated under reduced pressure to give the crude product. Purification by crystallization from EtOAc gave compound 9 as a yellow solid.

[0214] A solution of compound 9 in TFA (3 mL) was stirred at room temperature for 1 hour and then concentrated under reduced pressure. The resulting solid was washed with ether and dried in vacuo to give TK207 as a yellow solid (16 mg, 37% over two reaction steps).

[0215] TIFF0007770716000063.tif78128

[0216] Scheme 4. Synthetic route to TK208. Reagents and conditions: (a) 3-aminoquinoline, HATU, DIEA, DMF, rt, 24 h; (b) TFA, rt, 1 h.

[0217] Compound 2: A solution of compound 1 (2.6 g, 3.3 mmol), HATU (1.5 g, 3.9 mmol), and DIEA (1.1 mL, 6.3 mmol) in DMF (50 mL) was stirred at room temperature for 1 hour. 3-Aminoquinoline (1.4 g, 9.7 mmol) was then added to the reaction mixture, and the resulting mixture was stirred at room temperature for 24 hours. The reaction mixture was diluted with EtOAc (100 mL) and 1 N HCl (50 mL). The organic layer was separated and washed with 1 N HCl (50 mL) and brine (50 mL). The organic layer was concentrated under reduced pressure to give the crude product. Purification by crystallization from EtOAc gave compound 2 as a yellow solid (2.6 g, 86%).

[0218] TK208: A solution of compound 9 (1.2 g, 1.31 mmol) in TFA (30 mL) was stirred at room temperature for 1 hour and then concentrated under reduced pressure. The resulting solid was washed with ether and dried in vacuo to give TK208 as a yellow solid (0.67 g, 60%).

[0219] TIFF0007770716000064.tif130147

[0220] Scheme 5. Synthetic route to TK314. Reagents and conditions: (a) (COCl)2, cat. DMF, DCM, rt, 2 h; (b) DIEA, DCM, rt, 24 h; (c) Pd(PPh3)4, PhSiH3, THF, rt, 1 h; (d) trans-4-methylcyclohexylamine, HATU, DIEA, DMF, rt, 24 h; (e) TFA, rt, 1 h.

[0221] Compound 4: A solution of compound 1 (0.62 g, 2.4 mmol), oxalyl chloride (0.41 mL, 4.7 mmol), and 2 drops of DMF in DCM (30 mL) was stirred at room temperature for 2 hours and then concentrated under reduced pressure. The resulting compound 2 was dissolved in DCM (10 mL) and slowly added to a solution of compound 3 (0.70 g, 1.6 mmol), DIEA (0.55 mL, 3.2 mmol), and DCM (30 mL). The reaction mixture was stirred at room temperature for 24 hours and then washed with 1 N HCl (50 mL), saturated NaHCO3 (50 mL), and brine (50 mL). The organic layer was concentrated under reduced pressure to give the crude product. Purification by crystallization from EtOAc / hexane (1:2) gave compound 4 as a yellow solid (0.46 g, 42%).

[0222] Compound 5: A solution of compound 4 (0.40 g, 0.59 mmol), Pd(PPh3)4 (69 mg, 0.06 mmol), and PhSiH3 (0.15 mL, 1.2 mmol) in THF (30 mL) was stirred at room temperature for 2 h and then concentrated under reduced pressure. The resulting solid was washed with ether and dried in vacuo to give compound 5 as a yellow solid (0.37 g, 98%).

[0223] TK314: A solution of compound 5 (50 mg, 0.078 mmol), HATU (39 mg, 0.10 mmol), and DIEA (41 μL, 0.24 mmol) in DMF (4 mL) was stirred at room temperature for 1 hour, and then trans-4-methylcyclohexylamine (45 mg, 0.40 mmol) was added to the reaction mixture. The resulting mixture was stirred at room temperature for 24 hours and then diluted with EtOAc (20 mL) and 1 N HCl (10 mL). The organic layer was separated, washed with 1 N HCl (10 mL) and brine (10 mL), and concentrated under reduced pressure. The resulting solid was washed with EtOAc and dried in vacuo to give compound 6 as a yellow solid.

[0224] A solution of compound 6 in TFA (3 mL) was stirred at room temperature for 1 hour and then concentrated under reduced pressure. The resulting solid was washed with ether and dried in vacuo to give TK314 as a yellow solid (42 mg, 79% over two reaction steps).

[0225] TIFF0007770716000065.tif78128

[0226] Scheme 6. Synthetic route to TK315. Reagents and conditions: (a) HATU, DIEA, DMF, rt, 24 h; (b) TFA, rt, 1 h.

[0227] TK315: A solution of compound 1 (50 mg, 0.078 mmol), HATU (39 mg, 0.10 mmol), and DIEA (41 μL, 0.24 mmol) in DMF (4 mL) was stirred at room temperature for 1 hour, and then compound 2 (91 mg, 0.24 mmol) was added to the reaction mixture. The resulting mixture was stirred at room temperature for 24 hours and then diluted with EtOAc (20 mL) and 1 N HCl (10 mL). The organic layer was separated, washed with 1 N HCl (10 mL) and brine (10 mL), and concentrated under reduced pressure. The resulting solid was washed with EtOAc and dried in vacuo to give compound 3 as a yellow solid.

[0228] A solution of compound 3 in TFA (3 mL) was stirred at room temperature for 1 hour and then concentrated under reduced pressure. The resulting solid was washed with ether and dried in vacuo to give TK315 as a yellow solid (51 mg, 78% over two reaction steps).

[0229] TIFF0007770716000066.tif129147

[0230] Scheme 7. Synthetic route to TK308. Reagents and conditions: (a) (COCl)2, cat. DMF, DCM, rt, 2 h; (b) DIEA, DCM, rt, 24 h; (c) Pd(PPh3)4, PhSiH3, THF, rt, 1 h; (d) trans-4-methylcyclohexylamine, HATU, DIEA, DMF, rt, 24 h; (e) TFA, rt, 1 h.

[0231] Compound 4: A solution of compound 1 (1.1 g, 4.4 mmol), oxalyl chloride (0.78 mL, 9.0 mmol), and 2 drops of DMF in DCM (30 mL) was stirred at room temperature for 2 hours and then concentrated under reduced pressure. The resulting compound 2 was dissolved in DCM (10 mL) and slowly added to a solution of compound 3 (1.3 g, 3.0 mmol), DIEA (1.0 mL, 5.7 mmol), and DCM (30 mL). The reaction mixture was stirred at room temperature for 24 hours and then washed with 1 N HCl (50 mL), saturated NaHCO3 (50 mL), and brine (50 mL). The organic layer was concentrated under reduced pressure to give the crude product. Purification by crystallization from EtOAc / hexane (1:2) gave compound 4 as a yellow solid (0.74 g, 37%).

[0232] Compound 5: A solution of compound 4 (0.70 g, 1.04 mmol), Pd(PPh3)4 (0.12 g, 0.10 mmol), and PhSiH3 (0.26 mL, 2.1 mmol) in THF (30 mL) was stirred at room temperature for 2 h and then concentrated under reduced pressure. The resulting solid was washed with ether and dried in vacuo to give compound 5 as a yellow solid (0.57 g, 86%).

[0233] TK308: A solution of compound 5 (50 mg, 0.079 mmol), HATU (39 mg, 0.10 mmol), and DIEA (41 μL, 0.24 mmol) in DMF (4 mL) was stirred at room temperature for 1 hour, and then trans-4-methylcyclohexylamine (45 mg, 0.40 mmol) was added to the reaction mixture. The resulting mixture was stirred at room temperature for 24 hours and then diluted with EtOAc (20 mL) and 1 N HCl (10 mL). The organic layer was separated, washed with 1 N HCl (10 mL) and brine (10 mL), and concentrated under reduced pressure. The resulting solid was washed with EtOAc and dried in vacuo to give compound 6 as a yellow solid.

[0234] A solution of compound 6 in TFA (3 mL) was stirred at room temperature for 1 hour and then concentrated under reduced pressure. The resulting solid was washed with ether and dried in vacuo to give TK308 as a yellow solid (40 mg, 75% over two reaction steps).

[0235] TIFF0007770716000067.tif78128

[0236] Scheme 8. Synthetic Route to TK309. Reagents and conditions: (a) HATU, DIEA, DMF, rt, 24 h; (b) TFA, rt, 1 h.

[0237] TK309: A solution of compound 1 (50 mg, 0.079 mmol), HATU (39 mg, 0.10 mmol), and DIEA (41 μL, 0.24 mmol) in DMF (4 mL) was stirred at room temperature for 1 hour, and then compound 2 (91 mg, 0.24 mmol) was added to the reaction mixture. The resulting mixture was stirred at room temperature for 24 hours and then diluted with EtOAc (20 mL) and 1 N HCl (10 mL). The organic layer was separated, washed with 1 N HCl (10 mL) and brine (10 mL), and concentrated under reduced pressure. The resulting solid was washed with EtOAc and dried in vacuo to give compound 3 as a yellow solid.

[0238] A solution of compound 3 in TFA (3 mL) was stirred at room temperature for 1 hour and then concentrated under reduced pressure. The resulting solid was washed with ether and dried in vacuo to give TK309 as a yellow solid (55 mg, 84% over two reaction steps).

[0239] TIFF0007770716000068.tif58128

[0240] Scheme 9. Synthetic route to YL144. Reagents and conditions: (a) 2-aminoimidazole sulfate, HATU, DIEA, DMF, rt, 24 h; (b) TFA, rt, 1 h.

[0241] YL144: A mixture of compound 1 (0.20 g, 0.30 mmol), 2-aminoimidazole sulfate (79 mg, 0.60 mmol), and DIEA (0.42 mL, 2.4 mmol) in DMF (20 mL) was stirred at 60° C. for 1 hour. HATU (0.15 g, 0.39 mmol) was then added to the reaction mixture, and the resulting mixture was stirred at 60° C. for 24 hours. The reaction mixture was cooled to room temperature and diluted with EtOAc (50 mL) and 1 N HCl (30 mL). The organic layer was separated and washed with 1 N HCl (30 mL) and brine (30 mL). The organic layer was concentrated under reduced pressure to give the crude product. Purification by crystallization from EtOAc gave compound 2 as a yellow solid.

[0242] A solution of compound 2 in TFA (5 mL) was stirred at room temperature for 1 hour and then concentrated under reduced pressure. The resulting solid was washed with ether and dried in vacuo to give YL144 as a yellow solid (0.12 g, 52%).

[0243] Example 3 - Oligobenzamide Analogs and Their Use in Cancer Treatment - OTC Ref.: HSC-1542 We conducted several studies at UTHSCSA using preclinical mouse xenografts and patient-derived xenografts (PDX) to investigate the efficacy of the new compounds TK41 (ERX-41), TK208 (ERX-208), and TK315 (ERX-315). The results are presented below.

[0244] Oral administration of TK315 (ERX-315) in a Captisol formulation demonstrated potent activity against both MCF7-MT ESR1 ZR-75 and ZR75-MT Y537S ERα-expressing treatment-resistant BC xenograft models, but had no effect on mouse liver or body weight (Figure 31A-C). Histological evaluation of tumors demonstrated dramatically reduced Ki67 proliferation indices in these tumors. Importantly, the lack of immune antibody infiltrates in the spleen, lymph nodes, kidneys, or liver of syngeneic D2A1 tumors treated with ERX-315 suggested that ERX-315 is potent, not immunogenic, and can be safely administered orally.

[0245] PDX models recapitulate the structural complexity and individual heterogeneity of human BC (primary tumor samples), and therefore, studies in these models establish a clear basis for clinical translation. Three distinct TNBC PDX tumors were established in NSG mice by implanting PDX tumor fragments into the mammary fat pad using established protocols in our laboratory. Results showed that TK41 (ERX-41) treatment significantly reduced the growth of all three TNBC PDX tumors tested (Figures 32A-C).

[0246] We tested the in vivo activity of TK208 (ERX-208) using both ovarian xenograft and PDX models. The results showed that TK208 (ERX-208) had good efficacy in reducing ovarian tumor volume and had no effect on mouse body weight, suggesting a lack of toxicity (Figures 33A-H).

[0247] All compositions and / or methods disclosed and claimed herein can be made and executed without undue experimentation in light of the present disclosure. Although the compositions and methods of the present disclosure have been described with reference to preferred embodiments, it will be apparent to those skilled in the art that variations can be made to the compositions and / or methods, and to the steps or sequence of steps of the methods described herein, without departing from the concept, spirit and scope of the present disclosure. All such similar substitutes and modifications apparent to those skilled in the art are deemed to be within the spirit, scope and concept of the present disclosure as defined by the appended claims.

[0248] References The following references, to the extent that they provide exemplary procedural or other details supplementary to those set forth herein, are specifically incorporated herein by reference. TIFF0007770716000069.tif71146

Claims

1. A compound of the following formula: or a pharmaceutically acceptable salt thereof.

2. (a) a compound according to claim 1; and (b) excipients and / or pharmaceutically acceptable carriers 10. A pharmaceutical composition comprising:

3. 10. Use of the compound of claim 1 or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for treating a disease or disorder in a patient in need thereof, wherein the disease or disorder is cancer.

4. 4. The use of claim 3, wherein the cancer is breast cancer, ovarian cancer, pancreatic cancer, or brain cancer.

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