Carborane Compounds, Carborane Analogues, and Methods of Use Thereof

Abstract

Methods for treating fibrotic conditions using carboranes and carborane analogs are disclosed. Also disclosed are compounds comprising dicarba-closo-dodecaborane or dicarba-closo-dodecaborane analogs. The compounds can be, for example, estrogen receptor β (ERβ) agonists. In some examples, the compounds can be selective ERβ agonists. Also provided herein are methods for treating, preventing, or ameliorating cancer in a subject, inhibiting tumor growth in a subject, treating an inflammatory disease in a subject, treating a neurodegenerative disease in a subject, treating a psychotropic disorder in a subject, or a combination thereof, by administering to the subject a therapeutically effective amount of one or more of the compounds or compositions disclosed herein, or a pharmaceutically acceptable salt thereof.

Description

[Technical field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit of U.S. Provisional Patent Application No. 62 / 774,688, filed December 3, 2018, U.S. Provisional Patent Application No. 62 / 798,713, filed January 30, 2019, U.S. Provisional Patent Application No. 62 / 798,710, filed January 30, 2019, and U.S. Provisional Patent Application No. 62 / 798,711, filed January 30, 2019, which are incorporated by reference in their entireties. [Background technology]

[0002] Estrogen can affect the growth, differentiation and function of many cells.For example, estrogen plays an important role in female and male reproductive system, as well as in bone maintenance, central nervous system and cardiovascular system.Due to its excellent action in non-reproductive tissues, such as bone, brain and urogenital tract, estrogen is an ideal drug if it does not have serious side effects such as breast cancer, endometrial cancer, thromboembolism and stroke.

[0003] The physiological functions of estrogenic compounds are largely regulated by the estrogen receptor subtypes alpha (ERα) and beta (ERβ). The actions of the two ER subtypes are controlled by the binding of the endogenous hormone 17β-estradiol or synthetic non-hormonal compounds to their ligand-binding domains.

[0004] In humans, both receptor subtypes are expressed in many cells and tissues and can control physiological functions in various organ systems, such as the reproductive system, skeletal system, cardiovascular system, and central nervous system, as well as in specific tissues (breast and subcompartments of the ovary and prostate). ERα is primarily present in the mammary gland, uterus, ovary (thecal cells), bone, male reproductive organs (testis and epididymis), prostate (stroma), liver, and adipose tissue. In contrast, ERβ is primarily present in the prostate (epithelium), bladder, ovary (granulosa cells), colon, adipose tissue, and immune system. Both subtypes are significantly expressed in the cardiovascular system and central nervous system. There are some common physiological roles for both estrogen receptor subsystems, such as in ovarian development and function, and in protecting the cardiovascular system. The alpha subtype has a greater role in the mammary gland and uterus, as well as in maintaining skeletal homeostasis and metabolic regulation. The beta subtype has more profound effects on the central nervous and immune systems, and corrects ERα-driven cellular hyperproliferation in tissues such as the breast and uterus.

[0005] Compounds that induce or suppress cellular estrogen responses have potential value as biochemical tools and candidates for drug development. Most estrogen receptor modulators are non-selective for ER subtypes, but it has been proposed that compounds with ER subtype selectivity would be useful. However, the development of compounds that address ER subtype specificity remains a significant challenge, as the ligand-binding domains of the two subtypes are quite similar in structure and amino acid sequence. Summary of the Invention

[0006] Disclosed herein is a method for treating fibrotic conditions using carboranes or carborane analogs.The carboranes or carborane analogs function as ERβ agonists.In certain embodiments, the fibrotic conditions include fibrotic conditions of the liver, such as nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH).

[0007] Also disclosed are compounds comprising dicarba-closo-dodecaborane, for example, a compound defined by the formula: or a pharma-ceutically acceptable salt thereof: [ka] Q is a substituted or unsubstituted dicarba-closo-dodecaborane cluster, and A and R 1 is attached to Q in a para configuration, A is a substituted or unsubstituted heteroaryl ring, and R 1 is substituted or unsubstituted C2-C 20 Alkyl, substituted or unsubstituted C2-C 20 Alkenyl, substituted or unsubstituted C2-C 20 Alkynyl, substituted or unsubstituted C3-C 20 Alkylaryl, substituted or unsubstituted C3-C 20 Alkylheteroaryl, substituted or unsubstituted C4-C 20 Alkylcycloalkyl, substituted or unsubstituted C4-C 20 Alkylheterocycloalkyl, substituted or unsubstituted C1-C 20 Acyl, C1-C 20 Acyl, -C(O)NR 3 R 4 , -S(O)-R 3 , -S(O2)-R 3 , substituted or unsubstituted C2~C 20 Heteroalkyl, or NR 3 R 4 and R 3 and R 4 are independently substituted or unsubstituted C1-C 20 Alkyl, substituted or unsubstituted C2-C 20 Alkenyl, substituted or unsubstituted C2-C 20 Alkynyl, substituted or unsubstituted C2-C 20 Alkylaryl, substituted or unsubstituted C4-C 20 Alkylcycloaryl, and substituted or unsubstituted C2-C 20 heteroalkyl, or a pharma- ceutically acceptable salt thereof.

[0008] In some embodiments, Q is: [ka] In the formula, ● is a carbon atom or a boron atom; ○ is CH, C-halogen, C-alkyl, C-OH, C-NH2, BH, B-halogen, B-alkyl, B-OH, or B-NH2.

[0009] In some cases, the compound is defined by the formula: [ka] wherein ● is a carbon atom; ○ is BH, B-halogen, B-alkyl, B-OH, or B-NH; X is OH, NHR, SH, or S(O)(O)NHR; Z is, independently for each occurrence, N or CH, provided that at least one of Z is N; and R 1 is substituted or unsubstituted C2-C 20 Alkyl, substituted or unsubstituted C2-C 20 Alkenyl, substituted or unsubstituted C2-C 20 Alkynyl, substituted or unsubstituted C3-C 20 Alkylaryl, substituted or unsubstituted C4-C 20 Alkylcycloalkyl, substituted or unsubstituted C1-C 20 Acyl, C1-C 20 Acyl, -C(O)NR 3 R 4 , -S(O)-R 3 , -S(O2)-R 3 , substituted or unsubstituted C2~C 20 Heteroalkyl, or NR 3 R 4 and R 2 is H, OH, halogen, or substituted or unsubstituted C1-C4 alkyl; R 3 and R 4 are independently substituted or unsubstituted C1-C 20Alkyl, substituted or unsubstituted C2-C 20 Alkenyl, substituted or unsubstituted C2-C 20 Alkynyl, substituted or unsubstituted C2-C 20 Alkylaryl, substituted or unsubstituted C4-C 20 Alkylcycloalkyl, and substituted or unsubstituted C2-C 20 heteroalkyl.

[0010] In some cases, one of Z can be N. In some cases, two or more of Z can be N. In some cases, three of Z can be N.

[0011] In some cases, the compound is defined by the formula: [ka] In the formula, ● is a carbon atom, ○ is BH, B-halogen, B-alkyl, B-OH, or B-NH2, and X is OH, NHR 2 , SH, or S(O)(O)NHR 2 and R 1 is substituted or unsubstituted C2-C 20 Alkyl, substituted or unsubstituted C2-C 20 Alkenyl, substituted or unsubstituted C2-C 20 Alkynyl, substituted or unsubstituted C3-C 20 Alkylaryl, substituted or unsubstituted C4-C 20 Alkylcycloalkyl, substituted or unsubstituted C1-C 20 Acyl, C1-C 20 Acyl, -C(O)NR 3 R 4 , -S(O)-R 3 , -S(O2)-R 3 , substituted or unsubstituted C2~C 20 Heteroalkyl, or NR 3 R 4 and R 2 is H, OH, halogen, or substituted or unsubstituted C1-C4 alkyl; R3 and R 4 are independently substituted or unsubstituted C1-C 20 Alkyl, substituted or unsubstituted C2-C 20 Alkenyl, substituted or unsubstituted C2-C 20 Alkynyl, substituted or unsubstituted C2-C 20 Alkylaryl, substituted or unsubstituted C4-C 20 Alkylcycloalkyl, and substituted or unsubstituted C2-C 20 heteroalkyl.

[0012] In some cases, the compound is defined by one of the following formulas, or a pharma- ceutically acceptable salt thereof: [ka] In the formula, ● is a carbon atom, ○ is BH, B-halogen, B-alkyl, B-OH, or B-NH2, and R 1 is substituted or unsubstituted C2-C 20 Alkyl, substituted or unsubstituted C2-C 20 Alkenyl, substituted or unsubstituted C2-C 20 Alkynyl, substituted or unsubstituted C3-C 20 Alkylaryl, substituted or unsubstituted C4-C 20 Alkylcycloalkyl, substituted or unsubstituted C1-C 20 Acyl, C1-C 20 Acyl, -C(O)NR 3 R 4 , -S(O)-R 3 , -S(O2)-R 3 , substituted or unsubstituted C2~C 20 Heteroalkyl, or NR 3 R 4 and R 2 is H, OH, halogen, or substituted or unsubstituted C1-C4 alkyl; R 3 and R 4 are independently substituted or unsubstituted C1-C 20 Alkyl, substituted or unsubstituted C2-C 20 Alkenyl, substituted or unsubstituted C2-C20 Alkynyl, substituted or unsubstituted C2-C 20 Alkylaryl, substituted or unsubstituted C4-C 20 Alkylcycloaryl, and substituted or unsubstituted C2-C 20 heteroalkyl.

[0013] In some of the above embodiments, X can be OH.

[0014] In some of the above embodiments, R 1 is a substituted or unsubstituted C6-C 10 Alkyl (e.g., C6-C 10 hydroxyalkyl).

[0015] In some of the above embodiments, R 1 is a substituted or unsubstituted C3-C 16 Alkylaryl (e.g., C3-C 16 hydroxyalkylaryl).

[0016] In some of the above embodiments, R 1 is a substituted or unsubstituted C8-C 20 Alkylaryl (e.g., C8-C 20 hydroxyalkylaryl).

[0017] In some of the above embodiments, R 1 is a substituted or unsubstituted C5-C 10 It may be acyl.

[0018] In some of the above embodiments, R 1 is a substituted or unsubstituted branched C4-C 10 Alkyl (e.g., branched C4-C 10 hydroxyalkyl).

[0019] In some cases, the compound is defined by one of the following formulas, or a pharma- ceutically acceptable salt thereof: [ka] where ● is a carbon atom, ○ is BH, B-halogen, B-alkyl, B-OH, or B-NH2, the dotted line to Y indicates that the bond may be a single or double bond where valences permit, A is a substituted or unsubstituted heteroaryl ring, and Y, when present, is O, halogen, OR 2 ', N.H.R. 2 , SH, or S(O)(O)NHR 2 and R 6 is substituted or unsubstituted C1-C 19 Alkyl, substituted or unsubstituted C2-C 19 Alkenyl, substituted or unsubstituted C2-C 19 Alkynyl, substituted or unsubstituted C2-C 19 Alkylaryl, substituted or unsubstituted C4-C 19 Alkylcycloalkyl, substituted or unsubstituted C2-C 20 Heteroalkyl, or NR 3 R 4 and R 2 is H, OH, halogen, or substituted or unsubstituted C1-C4 alkyl; R 2 ' is H or a substituted or unsubstituted C1-C4 alkyl; R 3 and R 4 are independently substituted or unsubstituted C1-C 20 Alkyl, substituted or unsubstituted C2-C 20 Alkenyl, substituted or unsubstituted C2-C 20 Alkynyl, substituted or unsubstituted C2-C 20 Alkylaryl, substituted or unsubstituted C4-C 20 Alkylcycloaryl, and substituted or unsubstituted C2-C 20 heteroalkyl.

[0020] In some of these embodiments, Y is OH. In some of these embodiments, Y is F. In some of these embodiments, Y is O.

[0021] In some embodiments, R6 is a substituted or unsubstituted C3-C 10 It can be an alkyl, for example, a substituted or unsubstituted C6 to C9 alkyl.

[0022] In some embodiments, R 6 is substituted or unsubstituted C2-C 15 It may be alkylaryl.

[0023] In some embodiments, R 6 can be a substituted or unsubstituted branched C2-C9 alkylaryl.

[0024] In some embodiments, R 6 is C4~C 10 Substituted or unsubstituted C3-C 10 The heteroalkyl can be, for example, a substituted or unsubstituted C6-C9 heteroalkyl.

[0025] Also provided is a compound defined by the formula: [ka] where Q is a substituted or unsubstituted dicarba-closo-dodecaborane cluster, and A and R 1 is attached to Q in a para configuration, A is a substituted or unsubstituted aryl ring or a substituted or unsubstituted heteroaryl ring, R 1 is substituted or unsubstituted C2-C 20 Heteroalkyl, -C(O)NR 3 R 4 , -S(O)-R 3 , -S(O2)-R 3 , or N.R. 3 R 4 and R 3 and R 4 are independently, if present, R 3 and R 4 At least one of C2~C 20 Substituted or unsubstituted C1-C, provided that it is heteroalkyl. 20Alkyl, substituted or unsubstituted C2-C 20 Alkenyl, substituted or unsubstituted C2-C 20 Alkynyl, substituted or unsubstituted C2-C 20 Alkylaryl, substituted or unsubstituted C4-C 20 Alkylcycloalkyl, and substituted or unsubstituted C2-C 20 heteroalkyl.

[0026] In some embodiments, Q is: [ka] In the formula, ● is a carbon atom or a boron atom, and ○ is CH, C-halogen, C-alkyl, C-OH, C-NH2, BH, B-halogen, B-alkyl, B-OH, or B-NH2.

[0027] In some embodiments, the compound may be defined by the following formula: [ka] wherein ● is a carbon atom; ○ is BH, B-halogen, B-alkyl, B-OH, or B-NH; X is OH, NHR, SH, or S(O)(O)NHR; Z is, independently for each occurrence, N or CH, provided that at least one of Z is N; and R 1 is substituted or unsubstituted C2-C 20 Heteroalkyl, -C(O)NR 3 R 4 , -S(O)-R 3 , -S(O2)-R 3 , or N.R. 3 R 4 and R 3 and R 4 are independently, if present, R 3 and R 4 At least one of C2~C 20 Substituted or unsubstituted C1-C, provided that it is heteroalkyl.20 Alkyl, substituted or unsubstituted C2-C 20 Alkenyl, substituted or unsubstituted C2-C 20 Alkynyl, substituted or unsubstituted C2-C 20 Alkylaryl, substituted or unsubstituted C4-C 20 Alkylcycloalkyl, and substituted or unsubstituted C2-C 20 heteroalkyl.

[0028] In some of these embodiments, X can be OH.

[0029] Also provided is a compound defined by any of the following formulas, or a pharma- ceutically acceptable salt thereof: [ka] where ● is a carbon atom, ○ is BH, B-halogen, B-alkyl, B-OH, or B-NH2, the dotted line to Y indicates that the bond may be single or double, where valences permit, A is a substituted or unsubstituted aryl ring or a substituted or unsubstituted heteroaryl ring, and Y, when present, is O, halogen, OR, 2 ', N.H.R. 2 , SH, or S(O)(O)NHR 2 and R 6 is substituted or unsubstituted C1-C 19 Alkyl, substituted or unsubstituted C2-C 19 Alkenyl, substituted or unsubstituted C2-C 19 Alkynyl, substituted or unsubstituted C2-C 19 Alkylaryl, substituted or unsubstituted C4-C 19 Alkylcycloalkyl, substituted or unsubstituted C2-C 20 Heteroalkyl, or NR 3 R 4 and R 2 is H, OH, halogen, or substituted or unsubstituted C1-C4 alkyl; R 2 ' is H or a substituted or unsubstituted C1-C4 alkyl; R 3 and R 4are independently substituted or unsubstituted C1-C 20 Alkyl, substituted or unsubstituted C2-C 20 Alkenyl, substituted or unsubstituted C2-C 20 Alkynyl, substituted or unsubstituted C2-C 20 Alkylaryl, substituted or unsubstituted C4-C 20 Alkylcycloalkyl, and substituted or unsubstituted C2-C 20 heteroalkyl.

[0030] In some of these embodiments, Y is OH. In some of these embodiments, Y is F. In some of these embodiments, Y is O.

[0031] In some embodiments, R 6 is a substituted or unsubstituted C3-C 10 It can be an alkyl, for example, a substituted or unsubstituted C6 to C9 alkyl.

[0032] In some embodiments, R 6 is substituted or unsubstituted C2-C 15 It may be alkylaryl.

[0033] In some embodiments, R 6 can be a substituted or unsubstituted branched C2-C9 alkylaryl.

[0034] In some embodiments, R 6 is C4~C 10 Substituted or unsubstituted C3-C 10 The heteroalkyl can be, for example, a substituted or unsubstituted C6-C9 heteroalkyl.

[0035] In some embodiments, the carborane cluster can include a heteroatom. In some embodiments, the carborane cluster can include an isotopically labeled atom (i.e., a radiolabeled atom). In some embodiments, the carborane cluster can include an isotopically labeled atom (e.g., 10 B).

[0036] Also provided herein are dicarba-closo-dodecaborane analogs, for example compounds defined herein as follows, or a pharma- ceutically acceptable salt thereof: [ka] wherein A is a substituted or unsubstituted aryl ring or a substituted or unsubstituted heteroaryl ring; Q is a spacer group selected from one of the following: [ka] where m and n are each independently 0, 1, 2, or 3; R 1 is a substituted or unsubstituted C4-C 20 Alkyl, substituted or unsubstituted C4-C 20 Heteroalkyl, substituted or unsubstituted C2-C 20 Alkenyl, substituted or unsubstituted C2-C 20 Alkynyl, substituted or unsubstituted C3-C 20 Alkylaryl, substituted or unsubstituted C4-C 20 Alkylcycloalkyl, substituted or unsubstituted C1-C 20 Acyl, C1-C 20 Acyl, -C(O)NR 3 R 4 , or N.R. 3 R 4 and R 3 and R 4 are independently substituted or unsubstituted C1-C 20 Alkyl, substituted or unsubstituted C1-C 20 Heteroalkyl, substituted or unsubstituted C2-C 20 Alkenyl, substituted or unsubstituted C2-C 20 Alkynyl, substituted or unsubstituted C2-C 20 Alkylaryl, or substituted or unsubstituted C4-C 20 Disclosed are compounds in which the aryl group is selected from alkylcycloalkyl.

[0037] In certain embodiments, Q may be selected from one of the following formulas: [ka] In some embodiments, A is [ka] where X is OH, NHR 2 , SH, or S(O)(O)NHR 2 and R 2 is H, OH, halogen, or substituted or unsubstituted C1-C4 alkyl. In some of these embodiments, X is OH.

[0038] In some embodiments, A is [ka] where X is OH, NHR 2 , SH, or S(O)(O)NHR 2 and R 2 is H, OH, halogen, or substituted or unsubstituted C1-C4 alkyl. In some of these embodiments, X is OH.

[0039] In some embodiments, A is [ka] wherein Z is, independently for each occurrence, N or CH, with the proviso that at least one of the Z is N; and X is OH, NHR 2 , SH, or S(O)(O)NHR 2 and R 2 is H, OH, halogen, or substituted or unsubstituted C1-C4 alkyl. In some of these embodiments, A can be one of the following formulas: [ka] In some of these embodiments, X is OH.

[0040] In some embodiments, A is [ka] where Y is S or O and X is OH, NHR 2 , SH, or S(O)(O)NHR 2 and R 2 is H, OH, halogen, or substituted or unsubstituted C1-C4 alkyl. In some of these embodiments, X is OH.

[0041] In some embodiments, A is [ka] where Y is S or O and X is OH, NHR 2 , SH, or S(O)(O)NHR 2 and R 2 is H, OH, halogen, or substituted or unsubstituted C1-C4 alkyl. In some of these embodiments, X is OH.

[0042] In some embodiments, A is [ka] It is.

[0043] In some of the above embodiments, R 1 is a substituted or unsubstituted C6-C 10 Alkyl (e.g., substituted or unsubstituted C6-C 10 hydroxyalkyl).

[0044] In some of the above embodiments, R 1 is a substituted or unsubstituted C3-C 16 Alkylaryl (e.g., substituted or unsubstituted C3-C 16hydroxyalkylaryl).

[0045] In some of the above embodiments, R 1 is a substituted or unsubstituted C8-C 20 Alkylaryl (e.g., substituted or unsubstituted C to C 20 hydroxyalkylaryl).

[0046] In some of the above embodiments, R 1 is a substituted or unsubstituted C5-C 10 It may be acyl.

[0047] In some of the above embodiments, R 1 is a substituted or unsubstituted branched C4-C 10 Alkyl (e.g., branched C4-C 10 hydroxyalkyl).

[0048] In some embodiments, R 1 may have one of the following formulas: [ka] In the formula, the dotted line to Y indicates that the bond may be a single or double bond, if valence allows, and Y, when present, is O, halogen, OR 2 ', N.H.R. 2 , SH, or S(O)(O)NHR 2 and R 6 is substituted or unsubstituted C1-C 19 Alkyl, substituted or unsubstituted C2-C 19 Alkenyl, substituted or unsubstituted C2-C 19 Alkynyl, substituted or unsubstituted C2-C 19 Alkylaryl, substituted or unsubstituted C4-C 19 Alkylcycloalkyl, substituted or unsubstituted C2-C 20 Heteroalkyl, or NR 3 R 4 and R 2is H, OH, or substituted or unsubstituted C1-C4 alkyl, R 2 ' is H or a substituted or unsubstituted C1-C4 alkyl; R 3 and R 4 are independently substituted or unsubstituted C1-C 20 Alkyl, substituted or unsubstituted C2-C 20 Alkenyl, substituted or unsubstituted C2-C 20 Alkynyl, substituted or unsubstituted C2-C 20 Alkylaryl, substituted or unsubstituted C4-C 20 Alkylcycloalkyl, and substituted or unsubstituted C2-C 20 heteroalkyl.

[0049] In some of these embodiments, Y is OH. In some of these embodiments, Y is F. In some of these embodiments, Y is O.

[0050] In some embodiments, R 6 is a substituted or unsubstituted C3-C 10 It can be an alkyl, for example, a substituted or unsubstituted C6 to C9 alkyl.

[0051] In some embodiments, R 6 is substituted or unsubstituted C2-C 15 It may be alkylaryl.

[0052] In some embodiments, R 6 can be a substituted or unsubstituted branched C2-C9 alkylaryl.

[0053] In some embodiments, R 6 is C4~C 10 Substituted or unsubstituted C3-C 10 The heteroalkyl can be, for example, a substituted or unsubstituted C6-C9 heteroalkyl.

[0054] In some examples, the compounds disclosed herein have an EC50 of 800 nM or less at the estrogen receptor beta (ERβ). 50 In some examples, the compounds disclosed herein may have an EC 50 In some examples, the compounds disclosed herein may have an EC 50 (e.g., EC 50 , EC below 0.5 nM 50 , or an EC of 0.1 nM or less 50 ).

[0055] In some embodiments, the compounds disclosed herein may have an ERβ to ERα agonist ratio of greater than or equal to 8. In some embodiments, the compounds disclosed herein may have an ERβ to ERα agonist ratio of greater than or equal to 400.

[0056] Some compounds disclosed herein have selectivity for ERα and ERβ, so that they exert agonistic effects on ERβ without undesirable effects on ERα.Therefore, the compounds can be used in the treatment of various ERβ-related (ERβ-mediated) diseases, such as cancer, inflammatory diseases, neurodegenerative diseases, cardiovascular diseases, prostatic hyperplasia and osteoporosis.

[0057] Also provided herein is a method for treating, preventing, or ameliorating cancer in a subject. The method comprises administering to the subject a therapeutically effective amount of one or more of the compounds or compositions disclosed herein, or pharma-ceutically acceptable salts thereof. In some embodiments, the cancer may be selected from the group consisting of breast cancer, colorectal cancer, endometrial cancer, ovarian cancer, and prostate cancer. The method for treating or preventing cancer disclosed herein may further comprise treatment with one or more additional drugs (e.g., anticancer agents or ionizing radiation).

[0058] Also provided is a method of inhibiting a tumor in a subject, the method comprising contacting at least a portion of the tumor with a therapeutically effective amount of a compound or composition described herein, and optionally comprising irradiating at least a portion of the tumor with a therapeutically effective amount of ionizing radiation.

[0059] Also disclosed herein is a method for treating an inflammatory disease in a subject. The method may include administering to the subject a therapeutically effective amount of a compound or composition disclosed herein. In some embodiments, the inflammatory disease is selected from the group consisting of arthritis and inflammatory bowel disease. The method for treating an inflammatory disease described herein may further include treatment with one or more additional agents (e.g., anti-inflammatory agents).

[0060] Also disclosed herein is a method of treating a neurodegenerative disease in a subject, which can include administering to the subject a therapeutically effective amount of a compound or composition disclosed herein.

[0061] Also disclosed herein are methods of treating a psychotropic disorder in a subject, which may include administering to the subject a therapeutically effective amount of a compound or composition disclosed herein.

[0062] Also disclosed herein is a method of imaging a cell or population of cells expressing ERβ in or around a subject, comprising administering to the subject an amount of a compound or composition described herein and detecting the compound or composition.

[0063] The details of one or more embodiments of the invention are set forth in the drawings and description below. Other features, objects, and advantages of the invention will be apparent from the description and drawings, and from the claims. [Brief description of the drawings]

[0064] [Figure 1]The mean changes in body weight observed in the four study groups over the course of the treatment period are shown. [Figure 2A] 1 is a plot showing the body weight of the animals on the day of sacrifice. [Figure 2B] 1 is a plot showing the liver weight of animals on the day of sacrifice. [Figure 2C] 1 is a plot showing liver weight to body weight ratios of animals on the day of sacrifice. [Figure 3A] 1 is a plot showing plasma alanine aminotransferase (ALT) levels (U / L) on the day of sacrifice. [Figure 3B] FIG. 1 is a plot showing liver triglyceride levels (mg / g liver) on the day of sacrifice. [Figure 4] 1 is a plot showing non-alcoholic fatty liver disease (NAFLD) activity scores on the day of sacrifice. [Figure 5A] 1 is a plot showing fatty liver scores on the day of sacrifice. [Figure 5B] 1 is a plot showing inflammation scores on the day of sacrifice. [Figure 5C] 1 is a plot showing ballooning scores on the day of sacrifice. [Figure 6] Plot showing fibrotic area (Sirius Red positive area (%)) on the day of sacrifice. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0065] The compounds, compositions, and methods described herein can be readily understood by reference to the following detailed description of specific aspects and examples of the disclosed subject matter contained herein.

[0066] Before the present compounds, compositions, and methods are disclosed and described, it is to be understood that the embodiments described below are not limited to particular synthetic methods or to particular reagents, as such can, of course, vary. It is also understood that the terminology used herein is for the purpose of describing particular embodiments only, and is not intended to be limiting.

[0067] Also, throughout this specification, various publications are referenced. The disclosures of these publications in their entireties are incorporated by reference into this application in order to more fully describe the state of the art to which the disclosed subject matter pertains. These references are also individually and specifically incorporated by reference herein for the material contained in the references that is discussed in the language in which the reference is relied upon.

[0068] General definitions In this specification and in the claims that follow, reference will be made to a number of terms that shall be defined to have the following meanings.

[0069] Throughout the description and claims of this specification, the word "comprise" and other derivatives of this word, such as "comprising" and "comprises", means including, but is not limited to, and is not intended to exclude other addenda, components, integers, or steps.

[0070] As used in this specification and the appended claims, the singular forms "a," "an," and "the" include plural referents unless the context clearly dictates otherwise. Thus, for example, reference to "a composition" includes mixtures of two or more such compositions, reference to "an agent" includes mixtures of two or more such agents, reference to "the component" includes mixtures of two or more such agents, etc.

[0071] "Optionally" or "optionally" means that the subsequently described event or circumstance may or may not be present, and is meant to include instances in which the event or circumstance is present and instances in which it is not present.

[0072] Ranges can be expressed herein as from "about" one particular value and / or to "about" another particular value. "About" means within 5% of the value, for example, within 4, 3, 2, or 1% of the value. When such a range is expressed, another aspect includes from the one particular value and / or to the other particular value. Similarly, when values ​​are expressed as approximations, by using the antecedent "about," it will be understood that the particular value constitutes another aspect. It will be further understood that the endpoints of each range are significant both in relation to the other endpoint, and independently of the other endpoint.

[0073] It is understood that the identifiers "first" and "second" are used alone throughout this specification to distinguish various components and steps of the disclosed subject matter. The identifiers "first" and "second" are not intended to imply any particular order, quantity, priority, or importance to the components or steps modified by these terms.

[0074] As used herein, "subject" refers to an individual. Thus, "subject" can include domestic animals (e.g., cats, dogs, etc.), livestock (cows, horses, pigs, sheep, goats, etc.), laboratory animals (mouse, rabbits, rats, guinea pigs, etc.), and birds. "Subject" can also include mammals, such as primates or humans. Thus, a subject can be a human or veterinary patient. The term "patient" refers to a subject receiving treatment from a clinician, e.g., a physician.

[0075] As used herein, the term "fibrotic condition" refers to a disease or condition involving the formation and / or deposition of fibrous tissue, e.g., excess connective tissue accumulates in tissues and / or distributes among or replaces normal organ cells (reviewed, e.g., in Wynn, Nature Reviews 4:583-594 (2004) and Abdel-Wahab, O. et al (2009) Annu. Rev. Med. 60:233-45, incorporated herein by reference). In certain embodiments, the fibrotic condition involves excess collagen mRNA production and deposition. In certain embodiments, the fibrotic condition is caused, at least in part, by injury, e.g., chronic injury (e.g., insult, wound, toxin, disease). In certain embodiments, the fibrotic condition is associated with an inflammatory, autoimmune, or connective tissue disorder. For example, chronic inflammation in a tissue can result in fibrosis of that tissue. Exemplary fibrotic tissues include, but are not limited to, biliary tissue, liver tissue, lung tissue, cardiac tissue, kidney tissue, skin tissue, intestinal tissue, peritoneal tissue, bone marrow, etc. In certain embodiments, the tissue is an epithelial tissue.

[0076] The term "inhibit" refers to a decrease in activity, reactivity, condition, disease, or other biological parameter. This can include, but is not limited to, the complete elimination of activity, reactivity, condition, or disease. It can also include, for example, a 10% decrease in activity, reactivity, condition, or disease compared to native or control levels. Thus, the decrease can be 10, 20, 30, 40, 50, 60, 70, 80, 90, 100%, or any amount therebetween compared to native or control levels.

[0077] "Reduce" or other derivatives of this word, such as "reducing" or "reduction", refers to the decrease of an event or characteristic (e.g., tumor growth). This is typically understood to be relative to some standard or expected value, in other words, it is not necessarily relative to the standard or relative value being referred to. For example, the term "reducing tumor growth" refers to slowing the growth rate of a tumor compared to a standard or control value.

[0078] "Prevent" or other derivatives of this word, such as "preventing" or "prevention", mean to stop a particular event or characteristic, stabilize or delay the occurrence or progression of a particular event or characteristic, or minimize the chance of a particular event or characteristic occurring. Prevent does not require a comparison to a control, since it is usually more absolute than, for example, reduce. As used herein, something can be reduced and prevented, but something that is reduced can also be prevented. Similarly, something can be prevented and not reduced, but something that is prevented can also be reduced. When reduce or prevent is used, it is understood that the use of other words is also expressly disclosed unless otherwise specified. For example, the term "prevent" or "suppress" can refer to a treatment that forestalls or slows the onset of a disease or condition, or reduces the severity of a disease or condition. Thus, if a treatment can treat a disease in a subject who has symptoms of the disease, it can also prevent or suppress the disease in a subject who must still suffer some or all of the symptoms.

[0079] The term "treatment" refers to the medical management of a patient with the intent of curing, ameliorating, stabilizing, or preventing a disease, condition, or disorder. The term includes active treatment, i.e., treatment specifically directed toward the improvement of a disease, condition, or disorder, and also includes causal treatment, i.e., treatment directed toward the elimination of the cause of the associated disease, condition, or disorder. In addition, the term includes symptomatic treatment, i.e., treatment designed to alleviate symptoms rather than cure the disease, condition, or disorder, preventive treatment, i.e., treatment directed toward minimizing or partially or completely suppressing the occurrence of a disease, condition, or disorder, and adjunctive treatment, i.e., treatment employed to assist another specific therapy directed toward the improvement of a disease, condition, or disorder. By way of example, in the context of a fibrotic condition, "treating," "treat," and "treatment" as used herein refer to partially or completely suppressing or reducing the fibrotic condition suffered by the subject. In one embodiment, the term refers to the action of reducing the severity of, and slowing or retarding the development of, a fibrotic condition in which a patient is suffering from, or diagnosed with, a fibrotic condition while it is occurring. Treatment need not result in a complete cure of the condition; partial inhibition or reduction of the fibrotic condition is encompassed by the term.

[0080] "Therapeutically effective amount," as used herein, refers to the minimum amount or concentration of ERβ that, when administered alone or in combination, is sufficient to provide a therapeutic effect in the treatment of a condition or to delay or minimize one or more symptoms associated with the condition. The term "therapeutically effective amount" can encompass an amount that improves overall therapy, reduces or avoids symptoms, or improves the therapeutic efficacy of another therapeutic agent. A therapeutic amount need not result in a complete cure of a condition, and partial inhibition or reduction of a fibrotic condition is encompassed by this term.

[0081] As used herein, unless otherwise specified, the terms "prevent," "preventing," and "prevention" refer to an action that occurs before a subject begins to suffer from or experience a recurrence of a condition. Prevention need not result in complete prevention of a condition; partial prevention or reduction of a fibrotic condition is encompassed by the term.

[0082] As used herein, unless otherwise specified, a "pharmaceutical effective amount" of ERβ, when administered alone or in combination, prevents or prevents the recurrence of a condition or one or more symptoms associated with a condition. The term "pharmaceutical effective amount" encompasses an amount that improves overall disease prevention and improves the pharmaceutical efficacy of another disease prevention agent. A disease prevention amount need not result in complete prevention of a condition, and partial prevention or reduction of a fibrotic condition is encompassed by this term.

[0083] The term "anti-cancer" refers to the ability of any concentration to treat or control cell proliferation and / or tumor growth.

[0084] The term "pharmacologically acceptable" refers to compounds, materials, compositions, and / or dosage forms that are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication commensurate with a reasonable benefit / risk ratio.

[0085] Chemical Definition Terms used herein have their customary meaning in the art unless otherwise specified. Organic moieties shown when defining variable positions in the general formulas described herein (e.g., the term "halogen") are collective terms for the individual substituents encompassed by the organic moiety. The prefixes Cn-Cm in front of a group or moiety in each case represent the number of possible carbon atoms in the following group or moiety.

[0086] As used herein, the term "substituted" is intended to include all permissible substituents of organic compounds. In a broad aspect, the permissible substituents include acyclic and cyclic, branched and unbranched, carbocyclic and heterocyclic, and aromatic and nonaromatic substituents. Exemplary substituents include, for example, the substituents described below. The permissible substituents can be one or more and the same or different for appropriate organic compounds. For purposes of this disclosure, heteroatoms present in a compound or moiety, such as nitrogen, can have hydrogen substituents, and / or any of the permissible substituents of organic compounds described herein that satisfy the valence of the heteroatom. This disclosure is not intended to be limited in any manner by the permissible substituents of organic compounds. Also included in the terms "substituted" or "substituted" is the implicit proviso that such substitution is subject to the possible valences of the atom and substituent being substituted, and that the substitution results in a stable compound (e.g., a compound that does not spontaneously transform by rearrangement, cyclization, elimination, etc.).

[0087] "Z 1 ", "Z 2 ", "Z 3 " and "Z 4 " are used herein as generic symbols to represent various specific substituents. These symbols can be any substituent and are not limited to those disclosed herein, and when they are defined as certain substituents in one instance, they may be defined as certain other substituents in another instance.

[0088] As used herein, the term "alkyl" refers to a saturated straight chain or branched, saturated hydrocarbon moiety. Unless otherwise specified, C1-C 24 (For example, C1~C 22 , C1~C 20 , C1~C 18 , C1~C 16 , C1~C 14 , C1~C 12 , C1~C10 , C1-C8, C1-C6, or C1-C4) alkyl groups are contemplated. Examples of alkyl groups include methyl, ethyl, propyl, 1-methyl-ethyl, butyl, 1-methyl-propyl, 2-methyl-propyl, 1,1-dimethyl-ethyl, pentyl, 1-methyl-butyl, 2-methyl-butyl, 3-methyl-butyl, 2,2-dimethyl-propyl, 1-ethyl-propyl, hexyl, 1,1-dimethyl-propyl, 1,2-dimethyl-propyl, 1-methyl-pentyl, 2-methyl-pentyl, 3-methyl-pentyl, 4-methyl-pentyl, 1,1-dimethyl-butyl, 1,2-dimethyl-butyl, 1,3-dimethyl-butyl, 2,2-dimethyl-butyl, 2,3-dimethyl-butyl, 3,3-dimethyl-butyl, 1-ethyl-butyl, 2-ethyl-butyl, 1,1,2-trimethyl-propyl, 1,2,2-trimethyl-propyl, 1-ethyl-1-methyl-propyl, and 1-ethyl-2-methyl-propyl. Alkyl substituents may be unsubstituted or substituted with one or more chemical moieties. Alkyl groups can be substituted with one or more groups, including but not limited to, hydroxy, halogen, acyl, alkyl, alkoxy, alkenyl, alkynyl, aryl, heteroaryl, acyl, aldehyde, amino, carboxylic acid, ester, ether, ketone, nitro, silyl, sulfo-oxo, sulfonyl, sulfone, sulfoxide, or thiol, as described below, provided that the substituents are sterically compatible and chemical bond theory and strain energy are satisfied. Alkyl groups can also include one or more heteroatoms (e.g., 1 to 3 heteroatoms) incorporated within the hydrocarbon moiety. Examples of heteroatoms include, but are not limited to, nitrogen, oxygen, sulfur, and phosphorus.

[0089] Throughout this specification, "alkyl" generally refers to both unsubstituted and substituted alkyl groups, but also specifically refers to substituted alkyl groups by identifying certain substituents for the alkyl group. For example, the term "halogenated alkyl" specifically refers to an alkyl group substituted with one or more halides (halogens, e.g., fluorine, chlorine, bromine, or iodine). The term "alkoxyalkyl" specifically refers to an alkyl group substituted with one or more alkoxy groups, as described below. The term "alkylamino" specifically refers to an alkyl group substituted with one or more amino groups, as described below. When "alkyl" is used in one instance and a specific term, such as "alkylalcohol", is used in another instance, this is not meant to imply that the term "alkyl" also refers to a specific term, such as "alkylalcohol".

[0090] This practice is also used for other groups described herein. That is, a term such as "cycloalkyl" refers to both unsubstituted and substituted cycloalkyl moieties, while substituted moieties may additionally be specifically identified herein, e.g., a particular substituted cycloalkyl may be referred to, e.g., as an "alkylcycloalkyl." Similarly, a substituted alkoxy may be specifically referred to, e.g., as a "halogenated alkoxy," a particular substituted alkenyl may be referred to, e.g., as an "alkenylalcohol," and the like. Again, the practice of using a general term, e.g., "cycloalkyl," and a specific term, e.g., "alkylcycloalkyl," is not meant to imply that the general term also includes the specific term.

[0091] As used herein, the term "alkenyl" refers to an unsubstituted straight chain or branched hydrocarbon moiety containing a double bond. Unless otherwise specified, C-C 24 (For example, C2~C 22 , C2~C 20 , C2~C 18 , C2~C 16 , C2~C 14 , C2~C 12、C2~C 10, C2-C8, C2-C6, or C2-C4) alkenyl groups are contemplated. The alkenyl group may contain one or more unsubstituted bonds.Examples include ethenyl, 1-propenyl, 2-propenyl, 1-methylethenyl, 1-butenyl, 2-butenyl, 3-butenyl, 1-methyl-1-propenyl, 2-methyl-1-propenyl, 1-methyl-2-propenyl, 2-methyl-2-propenyl, 1-pentenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 1-methyl-1-butenyl, 2-methyl-1-butenyl, 3-methyl-1-butenyl, 1-methyl-2-butenyl, 2-methyl-2-butenyl, 3-methyl-2-butenyl, 1-methyl-3-butenyl, 2-methyl-3-butenyl. , 3-methyl-3-butenyl, 1,1-dimethyl-2-propenyl, 1,2-dimethyl-1-propenyl, 1,2-dimethyl-2-propenyl, 1-ethyl-1-propenyl, 1-ethyl-2-propenyl, 1-hexenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, 5-hexenyl, 1-methyl-1-pentenyl, 2-methyl-1-pentenyl, 3-methyl-1-pentenyl, 4-methyl-1-pentenyl, 1-methyl-2-pentenyl, 2-methyl-2-pentenyl, 3-methyl-2-pentenyl, 4-methyl-2-pentenyl, 1-methyl 1-methyl-3-pentenyl, 2-methyl-3-pentenyl, 3-methyl-3-pentenyl, 4-methyl-3-pentenyl, 1-methyl-4-pentenyl, 2-methyl-4-pentenyl, 3-methyl-4-pentenyl, 4-methyl-4-pentenyl, 1,1-dimethyl-2-butenyl, 1,1-dimethyl-3-butenyl, 1,2-dimethyl-1-butenyl, 1,2-dimethyl-2-butenyl, 1,2-dimethyl-3-butenyl, 1,3-dimethyl-1-butenyl, 1,3-dimethyl-2-butenyl, 1,3-dimethyl-3-butenyl, 2,2-dimethyl-3-butenyl dimethyl-1-butenyl, 2,3-dimethyl-2-butenyl, 2,3-dimethyl-3-butenyl, 3,3-dimethyl-1-butenyl, 3,3-dimethyl-2-butenyl, 1-ethyl-1-butenyl, 1-ethyl-2-butenyl, 1-ethyl-3-butenyl, 2-ethyl-1-butenyl, 2-ethyl-2-butenyl, 2-ethyl-3-butenyl, 1,1,2-trimethyl-2-propenyl, 1-ethyl-1-methyl-2-propenyl, 1-ethyl-2-methyl-1-propenyl, and 1-ethyl-2-methyl-2-propenyl.The term "vinyl" refers to a group having the structure -CH=CH2, 1-propenyl refers to a group having the structure -CH=CH-CH3, and 2-propenyl refers to a group having the structure -CH2-CH=CH2. (Z. 1 Z 2 )C=C(Z 3 Z 4 Asymmetric structures such as alkene, alkoxy ...

[0092] As used herein, the term "alkenyl" refers to a straight or branched chain hydrocarbon moiety containing a triple bond. Unless otherwise specified, C2-C 24 (For example, C2~C 22 , C2~C 20 , C2~C 18 , C2~C 16 , C2~C 14 , C2~C 12 , C2~C 10, C2-C8, C2-C6, or C2-C4) alkynyl groups are contemplated. The alkynyl group may contain one or more unsubstituted bonds. Examples include C2-C6-alkynyl, such as ethynyl, 1-propynyl, 2-propynyl (or propargyl), 1-butynyl, 2-butynyl, 3-butynyl, 1-methyl-2-propynyl, 1-pentynyl, 2-pentynyl, 3-pentynyl, 4-pentynyl, 3-methyl-1-butynyl, 1-methyl-2-butynyl, 1-methyl-3-butynyl, 2-methyl-3-butynyl, 1,1-dimethyl-2-propynyl, 1-ethyl-2-propynyl, 1-hexyl, 2-hexyl, 3-hexyl, 4-hexyl, 5-hexyl, 3-methyl-1-pentynyl, 4-methyl-1-pentynyl, 5 ... Alkynyl substituents include ethyl-1-pentynyl, 1-methyl-2-pentynyl, 4-methyl-2-pentynyl, 1-methyl-3-pentynyl, 2-methyl-3-pentynyl, 1-methyl-4-pentynyl, 2-methyl-4-pentynyl, 3-methyl-4-pentynyl, 1,1-dimethyl-2-butynyl, 1,1-dimethyl-3-butynyl, 1,2-dimethyl-3-butynyl, 2,2-dimethyl-3-butynyl, 3,3-dimethyl-1-butynyl, 1-ethyl-2-butynyl, 1-ethyl-3-butynyl, 2-ethyl-3-butynyl, and 1-ethyl-1-methyl-2-propynyl. Alkynyl substituents may be unsubstituted or substituted with one or more chemical moieties. Examples of suitable substituents include, for example, alkyl, alkyl halide, alkoxy, alkenyl, alkynyl, aryl, heteroaryl, acyl, aldehyde, amino, carboxylic acid, ester, ether, halide, hydroxy, ketone, nitro, silyl, sulfo-oxo, sulfonyl, sulfone, sulfoxide, or thiol, as described below.

[0093] As used herein, the term "aryl" and derived terms such as aryloxy refer to a monovalent aromatic heterocyclic group containing radicals of 3 to 20 carbon atoms. Aryl groups can contain a single ring or multiple fused rings. In some examples, aryl groups include C6 to C8 10The term "heteroaryl" is defined as a group that contains an aromatic group having at least one heteroatom incorporated within the ring of the aromatic group. Examples of heteroatoms include, but are not limited to, nitrogen, oxygen, sulfur, and phosphorus. The term "non-heteroaryl" is defined as a group that contains an aromatic group that is included in the term "aryl" and does not contain a heteroatom. The aryl and heteroaryl substituents may be unsubstituted or substituted with one or more chemical moieties. Examples of suitable substituents include, for example, alkyl, alkyl halide, alkoxy, alkenyl, alkynyl, aryl, heteroaryl, acyl, aldehyde, amino, carboxylic acid, cycloalkyl, ester, ether, halide, hydroxy, ketone, nitro, silyl, sulfo-oxo, sulfonyl, sulfone, sulfoxide, or thiol, as described herein. The term "biaryl" is a specific type of aryl group and is included in the definition of aryl. Biaryl refers to two aryl groups that are bonded together through a fused ring structure, as in naphthalene, or through one or more carbon-carbon bonds, as in biphenyl.

[0094] The term "cycloalkyl" as used herein is a non-aromatic carbon-based ring consisting of at least three carbon atoms. Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and the like. The term "heterocycloalkyl" is a cycloalkyl as defined above, in which at least one of the carbon atoms of the ring is replaced with a heteroatom, such as, but not limited to, nitrogen, oxygen, sulfur, or phosphorus. Cycloalkyl and heterocycloalkyl groups can be substituted or unsubstituted. Cycloalkyl and heterocycloalkyl groups can be substituted with one or more groups, including, but not limited to, alkyl, alkoxy, alkenyl, alkynyl, aryl, heteroaryl, acyl, aldehyde, amino, carboxylic acid, ester, ether, halide, hydroxy, ketone, nitro, silyl, sulfo-oxo, sulfonyl, sulfone, sulfoxide, or thiol, as described herein.

[0095] The term "cycloalkenyl" as used herein is a non-aromatic carbon-based ring consisting of at least three carbon atoms and containing at least one double bond, i.e., C=C. Examples of cycloalkenyl groups include, but are not limited to, cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclopentadienyl, cyclohexenyl, cyclohexadienyl, and the like. The term "heterocycloalkenyl" is a type of cycloalkenyl group as defined above and is included in the meaning of the term "cycloalkenyl", in which at least one of the carbon atoms of the ring is replaced with a heteroatom, such as, but not limited to, nitrogen, oxygen, sulfur, or phosphorus. Cycloalkenyl and heterocycloalkenyl groups can be substituted or unsubstituted. The cycloalkenyl and heterocycloalkenyl groups may be substituted with one or more groups including, but not limited to, alkyl, alkoxy, alkenyl, alkynyl, aryl, heteroaryl, acyl, aldehyde, amino, carboxylic acid, ester, ether, halide, hydroxy, ketone, nitro, silyl, sulfo-oxo, sulfonyl, sulfone, sulfoxide, or thiol, as described herein.

[0096] The term "cyclic group" is used herein to refer to either aryl groups, non-aryl groups (i.e., cycloalkyl, heterocycloalkyl, cycloalkenyl, and heterocycloalkenyl groups), or both. Cyclic groups have one or more ring systems that can be substituted or unsubstituted. Cyclic groups can contain one or more aryl groups, one or more non-aryl groups, or one or more aryl groups and one or more non-aryl groups.

[0097] As used herein, "heteroaryl" refers to a monocyclic or polycyclic aromatic heterocycle having at least one heteroatom ring member selected from sulfur, oxygen, and nitrogen. In some embodiments, the heteroaryl ring has 1, 2, 3, or 4 heteroatom ring members independently selected from nitrogen, sulfur, and oxygen. In some embodiments, any ring-forming N in the heteroaryl moiety can be an N-oxide. In some embodiments, the heteroaryl has 5-10 ring atoms and 1, 2, 3, or 4 heteroatom ring members independently selected from nitrogen, sulfur, and oxygen. In some embodiments, the heteroaryl has 5-6 ring atoms and 1 or 2 heteroatom ring members independently selected from nitrogen, sulfur, and oxygen. In some embodiments, the heteroaryl is a 5- or 6-membered heteroaryl ring. A 5-membered heteroaryl ring is a heteroaryl having a ring with 5 ring atoms, where one or more (e.g., 1, 2, or 3) ring atoms are independently selected from N, O, and S. Exemplary 5-membered heteroaryls are thienyl, furyl, pyrrolyl, imidazolyl, thiazolyl, oxazolyl, pyrazolyl, isothiazolyl, isoxazolyl, 1,2,3-triazolyl, tetrazolyl, 1,2,3-thiadiazolyl, 1,2,3-oxadiazolyl, 1,2,4-thiazolyl, 1,2,4-thiadiazolyl, 1,2,4-oxadiazolyl, 1,3,4-triazolyl, 1,3,4-thiadiazolyl, and 1,3,4-oxadiazolyl. A 6-membered heteroaryl ring is a heteroaryl having a ring with 6 ring atoms, where one or more (e.g., 1, 2, or 3) ring atoms are independently selected from N, O, and S. Exemplary 6-membered heteroaryls are pyridyl, pyrazinyl, pyrimidinyl, triazinyl, and pyridazinyl.

[0098] As used herein, "heterocycloalkyl" refers to a non-aromatic monocyclic or polycyclic heterocycle having one or more ring-forming heteroatoms selected from O, N, or S. Monocyclic 4-, 5-, 6-, and 7-membered heterocycloalkyl groups are included in heterocycloalkyl. Heterocycloalkyl groups can also include spirocycles. Exemplary heterocycloalkyl groups include pyrrolidin-2-one, 1,3-isoxazolidin-2-one, pyranyl, tetrahydrofuran, oxetanyl, azetidinyl, morpholino, thiomorpholino, piperazinyl, tetrahydrofuranyl, tetrahydrothienyl, piperidinyl, pyrrolidinyl, isoxazolidinyl, isothiazolidinyl, pyrazolidinyl, oxazolidinyl, thiazolidinyl, imidazolidinyl, azepanyl, benzazapene, and the like. Ring-forming carbon atoms and heteroatoms of heterocycloalkyl groups can be optionally substituted by oxo or sulfido (e.g., C(O), S(O), C(S), or S(O)2, etc.). Heterocycloalkyl groups can be bonded through ring-forming carbon atoms or ring-forming heteroatoms. In some embodiments, heterocycloalkyl groups contain 0-3 double bonds. In some embodiments, heterocycloalkyl groups contain 0-2 double bonds. Also included in the definition of heterocycloalkyl are moieties that have one or more aromatic rings fused to a cycloalkyl ring (i.e., having a common bond with the cycloalkyl ring), e.g., benzo or thienyl derivatives such as piperidine, morpholine, azepines, etc. Heterocycloalkyl groups that contain fused aromatic rings can be bonded through any ring-forming atom, including the ring-forming atoms of the fused aromatic rings. In some embodiments, heterocycloalkyls have 4-10, 4-7, or 4-6 ring atoms with 1 or 2 heteroatoms independently selected from nitrogen, oxygen, or sulfur and having one or more oxidized ring members.

[0099] In certain places, definitions or embodiments refer to certain rings (e.g., azetidine ring, pyridine ring, etc.). Unless otherwise specified, these rings can be bonded to any ring member, but not beyond the valence of the atom. For example, the azetidine ring can be bonded to any position of the ring, and the pyridin-3-yl ring is bonded to the 3-position.

[0100] As used herein, the term "acyl" refers to a group of the formula -C(O)Z 1 In the formula, Z 1 may be hydrogen, hydroxyl, alkoxy, alkyl, halogenated alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, or heterocycloalkenyl groups as described above. As used herein, the term "acyl" may be used interchangeably with "carbonyl". Throughout this specification, "C(O)" or "CO" is a shorthand notation for C=O.

[0101] As used herein, the term “alkoxy” refers to a group of the formula Z 1 refers to the group -O-, 1 is an unsubstituted or substituted alkyl group as defined above. Unless otherwise specified, an alkoxy group having a C1-C 24 (For example, C1~C 22 , C1~C 20 , C1~C 18 , C1~C 16 , C1~C 14 , C1~C 12 , C1~C 10, C1-C8, C1-C6, or C1-C4) alkyl groups are contemplated. Examples include methoxy, ethoxy, propoxy, 1-methyl-ethoxy, butoxy, 1-methyl-propoxy, 2-methyl-propoxy, 1,1-dimethyl-ethoxy, pentoxy, 1-methyl-butyloxy, 2-methyl-butoxy, 3-methyl-butoxy, 2,2-di-methyl-propoxy, 1-ethyl-propoxy, hexoxy, 1,1-dimethyl-propoxy, 1,2-dimethyl-propoxy, 1-methyl-pentoxy, 2-methyl-pentoxy, 3- Examples include methyl-pentoxy, 4-methyl-pentoxy, 1,1-dimethyl-butoxy, 1,2-dimethyl-butoxy, 1,3-dimethyl-butoxy, 2,2-dimethyl-butoxy, 2,3-dimethyl-butoxy, 3,3-dimethyl-butoxy, 1-ethyl-butoxy, 2-ethylbutoxy, 1,1,2-trimethyl-propoxy, 1,2,2-trimethyl-propoxy, 1-ethyl-1-methyl-propoxy, and 1-ethyl-2-methyl-propoxy.

[0102] The term "aldehyde" as used herein is represented by the formula --C(O)H.

[0103] As used herein, the term "amine" or "amino" refers to a group of the formula -NZ 1 Z 2 In the formula, Z 1 and Z 2 may each be a substituent as described herein, for example, hydrogen, alkyl, halogenated alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, or heterocycloalkenyl group as described above.

[0104] "Amide" is -C(O)NZ 1 Z 2 It is.

[0105] The term "carboxylic acid" as used herein is represented by the formula -C(O)OH. "Carboxylate" or "carboxyl" as used herein is represented by the formula -C(O)O-.

[0106] As used herein, the term "ester" refers to an ester of the formula -OC(O)Z 1 or -C(O)OZ 1 In the formula, Z 1 can be an alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, or heterocycloalkenyl group as described above.

[0107] As used herein, the term "ether" refers to a group of the formula Z 1 OZ 2 In the formula, Z 1 and Z 2 can be an alkyl, halogenated alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, or heterocycloalkenyl group as described above.

[0108] As used herein, the term "acyl" refers to a group of the formula Z 1 C(O)Z 2 In the formula, Z 1 and Z 2 can be an alkyl, halogenated alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, or heterocycloalkenyl group as described above.

[0109] As used herein, "halide" or "halogen" or "halo" refers to fluorine, chlorine, bromine, and iodine.

[0110] As used herein, "hydroxyl" is represented by the formula --OH.

[0111] As used herein, "nitro" appears in the formula --NO.

[0112] As used herein, the term "silyl" refers to a group of the formula -SiZ 1 Z 2 Z3 In the formula, Z 1 , Z 2 , and Z 3 can be hydrogen, alkyl, halogenated alkyl, alkoxy, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, or heterocycloalkenyl group as described above.

[0113] As used herein, the term "sulfonyl" refers to a group of the formula -S(O)Z 1 In the formula, Z 1 can be hydrogen, alkyl, halogenated alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, or heterocycloalkenyl group as described above.

[0114] The term "sulfonylamino" or "sulfonamide" as used herein is represented by the formula -S(O)2NH-.

[0115] As used herein, a "thiol" is represented by the formula --SH.

[0116] As used herein, a "thiol" is represented by the formula -S-.

[0117] As used herein, Me refers to a methyl group, OMe refers to a methoxy group, and i-Pr refers to an isopropyl group.

[0118] As used herein, "R" refers to a set of integers, n being an integer. 1 ", "R 2 ", "R 3 ", "R n " and the like have one or more of the groups listed above. For example, R 1When is a straight chain alkyl group, one of the hydrogen atoms of the alkyl group can be optionally replaced with a hydroxyl group, an alkoxy group, an amine group, an alkyl group, a halide, etc. Depending on the group selected, the first group can be incorporated into the second group, or alternatively, the first group can be a side chain to (i.e., attached to) the second group. For example, according to the expression "the alkyl group comprises an amino group", the amino group is incorporated into the backbone of the alkyl group. Alternatively, the amino group can be attached to the backbone of the alkyl group. The nature of the group selected will determine whether the first group is incorporated into or attached to the second group.

[0119] Unless otherwise indicated, stereoisomers or mixtures of stereoisomers (e.g., individual enantiomers, individual diastereomers, individual meso compounds, racemic mixtures, or scalemic mixtures) are intended by each formula shown as a solid line only and not as a wedge or dashed line.

[0120] Reference will now be made to certain embodiments of the disclosed materials, compounds, compositions, articles, and methods, examples of which are illustrated by the following examples and figures.

[0121] Carboranes and Carborane Analogues Dicarba-closo-dodecaborane (also referred to herein as "caborane") is an icosahedral cluster containing two carbon atoms and ten boron atoms, both of which are six-coordinated. Carboranes exist in three isomers, depending on the position of the carbon atoms in the cluster: 1,2-dicarba-closo-dodecaborane (ortho-caborane), 1,7-dicarba-closo-dodecaborane (meta-caborane), and 1,12-dicarba-closo-dodecaborane (para-caborane). These structures are unique among boron compounds because they may have high thermal stability and hydrophobicity, for example, compared to hydrocarbons.

[0122] Carboranes, for example, 10It can be used in boron neutron capture therapy (BNCT), which has been developed as a therapy for glioma and melanoma. 10 When boron is irradiated with thermal (slow) neutrons, alpha rays with an energy of 2.4 MeV are emitted and the atom breaks down into 7Li and 4He. The area of ​​the alpha rays is about 10 μm, which corresponds to the diameter of a cell. Therefore, 10 The expected effect is that only cells that take up B atoms will be destroyed, while other cells will not be damaged. To develop BNCT, it is necessary to develop a neutron irradiation concentration that can destroy cells. 10 It is important to have cancer cells that selectively take up B atoms. Therefore, it is important to have low toxicity and high 10 Other carborane scaffolds that have B content and are easy to synthesize have been utilized. Additionally, ortho-carboranes containing nucleic acid precursors, amino acids, and porphyrins have been synthesized and evaluated.

[0123] Carborane-based ERβ agonists are described, for example, in U.S. Pat. No. 6,838,574 by Endo and U.S. Patent Application No. 2018 / 0264017 by Tjarks et al., each of which is incorporated by reference in its entirety.

[0124] In some embodiments, the carborane is defined as follows: [ka] During the ceremony, R 1 may have one or more substituents selected from the group consisting of alkyl groups, alkenyl groups, carboxyl groups, alkoxycarbonyl groups, amino groups, hydroxyl groups, hydroxyalkyl groups, mono- or di-alkylcarbamoyl-substituted alkyl groups, alkanoyl groups, aryl groups, and aralkyl groups, each of which may be substituted or unsubstituted;

[0125] R 2represents a carboxyl group, an alkoxycarbonyl group, or a hydroxyl group; X represents a single bond or a linking group selected from the group consisting of groups represented by the following formulas: [ka] In the formula, Y 1 , Y 2 , Y 3 , Y 4 , Y 5 , Y 6 , and Y 7 are independently an oxygen atom or -N(R 3 )-, R 3 represents a hydrogen atom or an alkyl group, and Y 8 is an oxygen atom, -N(R 4 )-, R 4 represents a hydrogen atom, an alkyl group, -CO-, -CH2-, or -C(=CH2)-, and R 5 , R 6 , and R 7 each independently represents a hydrogen atom or one or more substituents on a phenyl group; R 8 represents an alkyl or aryl group which may be substituted; R 9 represents an alkyl group, R 10 represents a substituted or unsubstituted aryl group.

[0126] In some embodiments, the carborane can be defined as in Formula II, or a pharma- ceutically acceptable salt thereof: [ka] During the ceremony, Q is a substituted or unsubstituted dicarba-closo-dodecaborane cluster; [ka] and R 1 is attached to Q in a para configuration, X is OH, NHR 2 , SH, or S(O)(O)NHR 2 and R 1is a substituted or unsubstituted C4-C 20 Alkyl, substituted or unsubstituted C2-C 20 Alkenyl, substituted or unsubstituted C2-C 20 Alkynyl, substituted or unsubstituted C3-C 20 Alkylaryl, substituted or unsubstituted C3-C 20 Alkylheteroaryl, substituted or unsubstituted C4-C 20 Alkylcycloalkyl, substituted or unsubstituted C4-C 20 Alkylheterocycloalkyl, substituted or unsubstituted C1-C 20 Acyl, or NR 3 R 4 and R 2 is H, OH, halogen, or substituted or unsubstituted C1-C4 alkyl; R 3 and R 4 are independently substituted or unsubstituted C1-C 20 Alkyl, substituted or unsubstituted C2-C 20 Alkenyl, substituted or unsubstituted C2-C 20 Alkynyl, substituted or unsubstituted C2-C 20 Alkylaryl, substituted or unsubstituted C4-C 20 Alkylcycloaryl or substituted or unsubstituted C1-C 20 acyl, When X is OH, R 1 is not (CH2)5CH(CH3)2 or NH2.

[0127] In some embodiments of Formula II, the carborane cluster can include a heteroatom. In some embodiments of Formula II, the carborane cluster can include an isotopically labeled atom (i.e., a radiolabeled atom). In some embodiments of Formula II, the carborane cluster can include an isotopically labeled boron atom (e.g., 10 B).

[0128] In some embodiments of Formula II, Q can be: [ka] During the ceremony, ● is a carbon atom or a boron atom, ○ is CH, C-halogen, C-alkyl, C-OH, C-NH2, BH, B-halogen, B-alkyl, B-OH, or B-NH2.

[0129] In some embodiments of Formula II, X is OH.

[0130] In some embodiments of Formula II, R 1 is a substituted or unsubstituted C6-C 10 In some embodiments of Formula II, R 1 is C6~C 10 In some embodiments of Formula II, R 1 is a substituted or unsubstituted C3-C 16 In some embodiments of Formula II, R 1 is C3~C 16 In some embodiments of Formula II, R 1 is a substituted or unsubstituted C5-C 10 In some embodiments of Formula II, R 1 is a substituted or unsubstituted branched C4-C 10 In some embodiments of Formula II, R 1 is branch C4~C 10 It is a hydroxyalkyl.

[0131] In some embodiments of Formula II, the compound may be of Formula III, or a pharma- ceutically acceptable salt thereof: [ka] During the ceremony, ● is a carbon atom, ○ is BH, B-halogen, B-alkyl, B-OH, or B-NH2, X is OH, NHR2 , SH, or S(O)(O)NHR 2 and R 1 is a substituted or unsubstituted C4-C 20 Alkyl, substituted or unsubstituted C2-C 20 Alkenyl, substituted or unsubstituted C2-C 20 Alkynyl, substituted or unsubstituted C3-C 20 Alkylaryl, substituted or unsubstituted C3-C 20 Alkylheteroaryl, substituted or unsubstituted C4-C 20 Alkylcycloaryl, substituted or unsubstituted C4-C 20 Alkylheterocycloaryl, substituted or unsubstituted C1-C 20 Acyl, or NR 3 R 4 and R 2 is H, OH, halogen, or substituted or unsubstituted C1-C4 alkyl; R 3 and R 4 are independently substituted or unsubstituted C1-C 20 Alkyl, substituted or unsubstituted C2-C 20 Alkenyl, substituted or unsubstituted C2-C 20 Alkynyl, substituted or unsubstituted C2-C 20 Alkylaryl, substituted or unsubstituted C4-C 20 Alkylcycloaryl or substituted or unsubstituted C1-C 20 acyl, When X is OH, R 1 is not (CH2)5CH(CH3)2 or NH2.

[0132] In some embodiments of Formula III, the carborane cluster can include a heteroatom.

[0133] In some embodiments of Formula III, the carborane cluster can include an isotopically labeled atom (i.e., a radiolabeled atom). In some embodiments of Formula III, the carborane cluster can include an isotopically labeled boron atom (e.g., 10 B).

[0134] In some embodiments of Formula III, X is OH.

[0135] In some embodiments of Formula III, R 1 is a substituted or unsubstituted C6-C 10 In some embodiments of Formula III, R 1 is C6~C 10 In some embodiments of Formula III, R 1 is a substituted or unsubstituted C3-C 16 In some embodiments of formula III, R 1 is C3~C 16 In some embodiments of Formula III, R 1 is a substituted or unsubstituted C5-C 10 In some embodiments of formula III, R 1 is a substituted or unsubstituted branched C4-C 10 In some embodiments of Formula III, R 1 is branch C4~C 10 It is a hydroxyalkyl.

[0136] In some embodiments of Formula III, the compound may be of Formula IV, or a pharma- ceutically acceptable salt thereof: [ka] During the ceremony, ● is a carbon atom, ○ is BH, B-halogen, B-alkyl, B-OH, or B-NH2; X is OH, NHR 2 , SH, or S(O)(O)NHR2 and Y is O, OR 2 ', N.H.R. 2 , SH, or S(O)(O)NHR 2 and R 5 is substituted or unsubstituted C2-C 19 Alkyl, substituted or unsubstituted C2-C 19 Alkenyl, substituted or unsubstituted C2-C 19 Alkynyl, substituted or unsubstituted C2-C 19 Alkylaryl, substituted or unsubstituted C 2~ C 19 Alkylheteroaryl, substituted or unsubstituted C3-C 19 Alkylcycloalkyl, substituted or unsubstituted C3-C 19 Alkylheterocycloalkyl, or NR 3 R 4 and R 2 is H, OH, halogen, or substituted or unsubstituted C1-C4 alkyl; R 2 ' is H or substituted or unsubstituted C1-C4 alkyl; R 3 and R 4 are independently substituted or unsubstituted C1-C 20 Alkyl, substituted or unsubstituted C2-C 20 Alkenyl, substituted or unsubstituted C2-C 20 Alkynyl, substituted or unsubstituted C2-C 20 Alkylaryl, substituted or unsubstituted C4-C 20 Alkylcycloaryl or substituted or unsubstituted C1-C 20 acyl.

[0137] In some embodiments of Formula IV, the carborane cluster can include a heteroatom. In some embodiments of Formula IV, the carborane cluster can include an isotopically labeled atom (i.e., a radiolabeled atom). In some embodiments of Formula IV, the carborane cluster can include an isotopically labeled boron atom (e.g., 10B).

[0138] In some embodiments of Formula IV, X is OH.

[0139] In some embodiments of Formula IV, Y is OH. In some embodiments of Formula IV, Y is O.

[0140] In some embodiments of formula IV, R 5 is a substituted or unsubstituted C3-C9 alkyl. In some embodiments of formula IV, R 5 is a substituted or unsubstituted C6-C9 alkyl. In some embodiments of formula IV, R 5 is substituted or unsubstituted C2-C 15 In some embodiments of formula IV, R 5 is a substituted or unsubstituted branched C2-C9 alkyl.

[0141] Also disclosed is a compound of formula V, and pharma- ceutically acceptable salts thereof: [ka] During the ceremony, Q is a substituted or unsubstituted dicarba-closo-dodecaborane cluster; [ka] is attached to Q in a para configuration, The dotted line to Y indicates that the bond may be a single or double bond, if valences permit; X is OH, NHR 2 , SH, or S(O)(O)NHR 2 and Y is O, OR 2 ', N.H.R. 2 , SH, or S(O)(O)NHR 2 and R 6 is substituted or unsubstituted C1-C 20 Alkyl, substituted or unsubstituted C2-C 20Alkenyl, substituted or unsubstituted C2-C 20 Alkynyl, substituted or unsubstituted C2-C 20 Alkylaryl, substituted or unsubstituted C2-C 20 Alkylheteroaryl, substituted or unsubstituted C4-C 20 Alkylcycloalkyl, substituted or unsubstituted C4-C 20 Alkylheterocycloalkyl, or NR 3 R 4 and R 2 is H, OH, halogen, or substituted or unsubstituted C1-C4 alkyl; R 2 ' is H or substituted or unsubstituted C1-C4 alkyl; R 3 and R 4 are independently substituted or unsubstituted C1-C 20 Alkyl, substituted or unsubstituted C2-C 20 Alkenyl, substituted or unsubstituted C2-C 20 Alkynyl, substituted or unsubstituted C2-C 20 Alkylaryl, substituted or unsubstituted C4-C 20 Alkylcycloaryl or substituted or unsubstituted C1-C 20 acyl, When X is OH, R 6 is not CH2OH, CH(CH3)OH, CH2CH2OH, CH2CH2CH2OH, (CH2)5CH(CH3)2, or NH2.

[0142] In some embodiments of Formula V, the carborane cluster can include a heteroatom. In some embodiments of Formula V, the carborane cluster can include an isotopically labeled atom (i.e., a radiolabeled atom). In some embodiments of Formula V, the carborane cluster can include an isotopically labeled boron atom (e.g., 10 B). In some embodiments of Formula V, Q can be: [ka] During the ceremony, ● is a carbon atom or a boron atom, ○ is CH, C-halogen, C-alkyl, C-OH, C-NH2, BH, B-halogen, B-alkyl, B-OH, or B-NH2; In some embodiments of Formula V, X is OH.

[0143] In some embodiments of formula V, Y is OH. In some embodiments of formula V, Y is O.

[0144] In some embodiments of Formula V, R 6 is C6~C 10 In some embodiments of formula V, R 6 is substituted or unsubstituted C2-C 15 In some embodiments of formula V, R 6 is a substituted or unsubstituted branched C3-C 10 It is an alkyl.

[0145] In some embodiments of formula V, the compound may be of formula VI, or a pharma- ceutically acceptable salt thereof: [ka] During the ceremony, ● is a carbon atom, ○ is BH, B-halogen, B-alkyl, B-OH, or B-NH2; The dotted line to Y indicates that the bond may be a single or double bond, if valences permit; X is OH, NHR 2 , SH, or S(O)(O)NHR 2 and Y is O, OR 2 ', N.H.R. 2 , SH, or S(O)(O)NHR 2 and R 6 is substituted or unsubstituted C1-C 20Alkyl, substituted or unsubstituted C2-C 20 Alkenyl, substituted or unsubstituted C2-C 20 Alkynyl, substituted or unsubstituted C2-C 20 Alkylaryl, substituted or unsubstituted C2-C 20 Alkylheteroaryl, substituted or unsubstituted C4-C 20 Alkylcycloalkyl, substituted or unsubstituted C4-C 20 Alkylheterocycloalkyl, or NR 3 R 4 and R 2 is H, OH, halogen, or substituted or unsubstituted C1-C4 alkyl; R 2 ' is H or substituted or unsubstituted C1-C4 alkyl; R 3 and R 4 are independently substituted or unsubstituted C1-C 20 Alkyl, substituted or unsubstituted C2-C 20 Alkenyl, substituted or unsubstituted C2-C 20 Alkynyl, substituted or unsubstituted C2-C 20 Alkylaryl, substituted or unsubstituted C4-C 20 Alkylcycloalkyl, or substituted or unsubstituted C1-C 20 acyl, When X is OH, R 6 is not CH2OH, CH(CH3)OH, CH2CH2OH, CH2CH2CH2OH, (CH2)5CH(CH3)2, or NH2.

[0146] In some embodiments of Formula VI, the carborane cluster can include a heteroatom. In some embodiments of Formula VI, the carborane cluster can include an isotopically labeled atom (i.e., a radiolabeled atom). In some embodiments of Formula VI, the carborane cluster can include an isotopically labeled boron atom (e.g., 10 B).

[0147] In some embodiments of Formula VI, X is OH.

[0148] In some embodiments of formula VI, Y is OH. In some embodiments of formula VI, Y is O.

[0149] In some embodiments of formula VI, R 6 is C6~C 10 In some embodiments of formula VI, R 6 is substituted or unsubstituted C2-C 15 In some embodiments of formula VI, R 6 is a substituted or unsubstituted branched C3-C 10 It is an alkyl.

[0150] Also disclosed herein is a compound of formula VII, and pharma- ceutically acceptable salts thereof: [ka] During the ceremony, Q is a substituted or unsubstituted dicarba-closo-dodecaborane cluster; [ka] and R 7 is attached to Q in a para configuration, X is OH, NHR 2 , SH, or S(O)(O)NHR 2 and R 7 is substituted or unsubstituted C1-C 14 Alkyl, substituted or unsubstituted C2-C 14 Alkenyl, substituted or unsubstituted C2-C 14 Alkynyl, substituted or unsubstituted C1-C 14 Acyl, or NR 3 R 4 and R 8 , R 9 , R 10 , R 11 , and R 12are independently H, OH, halogen, substituted or unsubstituted C1-C 20 Alkyl, substituted or unsubstituted C2-C 20 Alkenyl, substituted or unsubstituted C2-C 20 Alkynyl, substituted or unsubstituted C2-C 20 Alkylaryl, substituted or unsubstituted C4-C 20 Alkylcycloalkyl, substituted or unsubstituted C1-C 20 Acyl, or NR 3 R 4 or, if valence permits, R 8 and R 9 , R 9 and R 10 , R 10 and R 11 , or R 11 and R 12 together with the atoms to which they are attached form a 3-10 membered substituted or unsubstituted cyclic moiety optionally containing 1-3 heteroatoms; R 2 is H, OH, halogen, or substituted or unsubstituted C1-C4 alkyl; R 3 and R 4 are independently substituted or unsubstituted C1-C 20 Alkyl, substituted or unsubstituted C2-C 20 Alkenyl, substituted or unsubstituted C2-C 20 Alkynyl, substituted or unsubstituted C2-C 20 Alkylaryl, substituted or unsubstituted C4-C 20 Alkylcycloalkyl, or substituted or unsubstituted C1-C 20 acyl.

[0151] In some embodiments of Formula VII, the carborane cluster can include a heteroatom. In some embodiments of Formula VII, the carborane cluster can include an isotopically labeled atom (i.e., a radiolabeled atom). In some embodiments of Formula VII, the carborane cluster can include an isotopically labeled boron atom (e.g., 10 B).

[0152] In some embodiments of Formula VII, Q can be: [ka] During the ceremony, ● is a carbon atom or a boron atom, ○ is CH, C-halogen, C-alkyl, C-OH, C-NH2, BH, B-halogen, B-alkyl, B-OH, or B-NH2; In some embodiments of Formula VII, X is OH. In some embodiments of Formula VII, R 7 is a substituted or unsubstituted C1-C7 alkyl. In some embodiments of Formula VII, R 7 is a C1-C7 heteroalkyl.

[0153] In some embodiments of Formula VII, R 8 ~R 12 are independently H, OH, halogen, or substituted or unsubstituted C1-C4 alkyl, or, where valences permit, R 8 and R 9 , R 9 and R 10 , R 10 and R 11 , or R 11 and R 12 together with the atoms to which they are attached form a 3-10 membered substituted or unsubstituted cyclic moiety optionally containing 1-3 heteroatoms. In some embodiments of Formula VII, R 8 ~R 12 Each is H. In some embodiments of Formula VII, R 8 , R 10 , and R 12 are H and R 9 and R 10 together with the atoms to which they are attached form a substituted or unsubstituted 5- to 7-membered ring moiety.

[0154] In some embodiments of formula VII, the compound may be of formula VIII, or a pharma- ceutically acceptable salt thereof: [ka] During the ceremony, ● is a carbon atom, ○ is BH, B-halogen, B-alkyl, B-OH, or B-NH2; X is OH, NHR 2 , SH, or S(O)(O)NHR 2 and R 7 is substituted or unsubstituted C1-C 14 Alkyl, substituted or unsubstituted C2-C 14 Alkenyl, substituted or unsubstituted C2-C 14 Alkynyl, substituted or unsubstituted C1-C 14 Acyl, or NR 3 R 4 and R 8 , R 9 , R 10 , R 11 , and R 12 are independently H, OH, halogen, substituted or unsubstituted C1-C 20 Alkyl, substituted or unsubstituted C2-C 20 Alkenyl, substituted or unsubstituted C2-C 20 Alkynyl, substituted or unsubstituted C2-C 20 Alkylaryl, substituted or unsubstituted C4-C 20 Alkylcycloalkyl, substituted or unsubstituted C1-C 20 Acyl, or NR 3 R 4 or, if valence permits, R 8 and R 9 , R 9 and R 10 , R 10 and R 11 , or R 11 and R 12 together with the atoms to which they are attached form a 3-10 membered substituted or unsubstituted cyclic moiety optionally containing 1-3 heteroatoms; R 2 is H, OH, halogen, or substituted or unsubstituted C1-C4 alkyl; R 3 and R 4 are independently substituted or unsubstituted C1-C 20 Alkyl, substituted or unsubstituted C2-C 20 Alkenyl, substituted or unsubstituted C2-C 20 Alkynyl, substituted or unsubstituted C2-C 20 Alkylaryl, substituted or unsubstituted C4-C 20 Alkylcycloalkyl, or substituted or unsubstituted C1-C 20 acyl.

[0155] In some embodiments of Formula VIII, the carborane cluster can include a heteroatom. In some embodiments of Formula VIII, the carborane cluster can include an isotopically labeled atom (i.e., a radiolabeled atom). In some embodiments of Formula VIII, the carborane cluster can include an isotopically labeled boron atom (e.g., 10 B).

[0156] In some embodiments of Formula VIII, X is OH.

[0157] In some embodiments of Formula VIII, R 7 is a substituted or unsubstituted C1-C7 alkyl. In some embodiments of Formula VIII, R 7 is a C1 to C7 hydroxyalkyl.

[0158] In some embodiments of Formula VIII, R 8 ~R 12 are independently H, OH, halogen, or substituted or unsubstituted C1-C4 alkyl, or, where valences permit, R 8 and R 9 , R 9 and R 10 , R 10 and R 11 , or R11 and R 12 together with the atoms to which they are attached form a 3-10 membered substituted or unsubstituted cyclic moiety optionally containing 1-3 heteroatoms. In some embodiments of Formula VIII, R 8 ~R 12 Each is H. In some embodiments of Formula VIII, R 8 , R 10 , and R 12 are H and R 9 and R 10 together with the atoms to which they are attached form a substituted or unsubstituted 5- to 7-membered ring moiety.

[0159] Also disclosed is a compound of formula IX, and pharma- ceutically acceptable salts thereof: [ka] During the ceremony, Q is a substituted or unsubstituted dicarba-closo-dodecaborane cluster; [ka] and R 13 is attached to Q in a para configuration, X is OH, NHR 2 , SH, or S(O)(O)NHR 2 and R 13 is substituted or unsubstituted C1-C 19 Alkyl, substituted or unsubstituted C2-C 19 Alkenyl, substituted or unsubstituted C2-C 19 Alkynyl, substituted or unsubstituted C1-C 20 It is acyl, R 14 , R 15 , and R 16 are independently hydrogen, halogen, hydroxyl, substituted or unsubstituted C1-C 18 Alkyl, substituted or unsubstituted C2-C 18 Alkenyl, substituted or unsubstituted C1-C 18 Alkynyl, substituted or unsubstituted C2-C 18Aryl, substituted or unsubstituted C3-C 18 Cycloalkyl, substituted or unsubstituted C1-C 20 Acyl, or NR 3 R 4 or, if valence permits, R 14 and R 15 , R 14 and R 16 , or R 15 and R 16 together with the atoms to which they are attached form a 3-10 membered substituted or unsubstituted cyclic moiety optionally containing 1-3 heteroatoms; R 14 , R 15 and R 16 provided that at least two of are not hydrogen, halogen, or hydroxyl; X is OH and R 13 is C5 alkyl, R 14 , R 15 and R 16 is not H, methyl, or methyl.

[0160] In some embodiments of Formula IX, the carborane cluster can include a heteroatom. In some embodiments of Formula IX, the carborane cluster can include an isotopically labeled atom (i.e., a radiolabeled atom). In some embodiments of Formula IX, the carborane cluster can include an isotopically labeled boron atom (e.g., 10 In some embodiments of formula IX, Q is: [ka] During the ceremony, ● is a carbon atom or a boron atom, ○ is CH, C-halogen, C-alkyl, C-OH, C-NH2, BH, B-halogen, B-alkyl, B-OH, or B-NH2.

[0161] In some embodiments of Formula IX, X is OH.

[0162] In some embodiments of Formula IX, R 13 is a substituted or unsubstituted C4-C8 alkyl. In some embodiments of Formula IX, R 13 is a C4 to C8 hydroxyalkyl.

[0163] In some embodiments of Formula IX, R 14 ~R 16 are independently hydrogen, halogen, hydroxyl, substituted or unsubstituted C1-C4 alkyl, and R 14 , R 15 and R 16 X is OH and R 13 is C5 alkyl, R 14 , R 15 and R 16 is not H, methyl, or methyl.

[0164] In some embodiments of formula IX, the compound may be of formula X, or a pharma- ceutically acceptable salt thereof: [ka] During the ceremony, ● is a carbon atom, ○ is BH, B-halogen, B-alkyl, B-OH, or B-NH2; X is OH, NHR 2 , SH, or S(O)(O)NHR 2 and R 13 is substituted or unsubstituted C1-C 19 Alkyl, substituted or unsubstituted C2-C 19 Alkenyl, substituted or unsubstituted C2-C 19 Alkynyl, substituted or unsubstituted C1-C 20 It is acyl, R 14 , R 15 , and R 16 are independently hydrogen, halogen, hydroxyl, substituted or unsubstituted C1-C18 Alkyl, substituted or unsubstituted C2-C 18 Alkenyl, substituted or unsubstituted C1-C 18 Alkynyl, substituted or unsubstituted C2-C 18 Aryl, substituted or unsubstituted C3-C 18 Cycloalkyl, substituted or unsubstituted C1-C 20 Acyl, or NR 3 R 4 or, if valence permits, R 14 and R 15 , R 14 and R 16 , or R 15 and R 16 optionally contains 1-3 heteroatoms together with the atom attached to the 3-10 membered substituted or unsubstituted cyclic portion; R 14 , R 15 and R 16 are not hydrogen, halogen, or hydroxyl; X is OH and R 13 is C5 alkyl, R 14 , R 15 , and R 16 is not H, methyl, or methyl.

[0165] In some embodiments of formula X, the carborane cluster can include a heteroatom. In some embodiments of formula X, the carborane cluster can include an isotopically labeled atom (i.e., a radiolabeled atom). In some embodiments of formula X, the carborane cluster can include an isotopically labeled boron atom (e.g., 10 B).

[0166] In some embodiments of formula X, X is OH.

[0167] In some embodiments of formula X, R 13 is a substituted or unsubstituted C4-C8 alkyl. In some embodiments of formula X, R 13is a C4 to C8 hydroxyalkyl.

[0168] In some embodiments of formula X, R 14 ~R 16 are independently hydrogen, halogen, hydroxyl, substituted or unsubstituted C1-C4 alkyl, and R 14 , R 15 and R 16 X is OH and R 13 is C5 alkyl, R 14 , R 15 and R 16 is not H, methyl, or methyl.

[0169] In some embodiments, the compound has the formula: [ka] [ka] [ka] and pharma- ceutically acceptable salts thereof. In some embodiments, the carborane cluster may include a heteroatom.

[0170] Also disclosed is a compound of formula XI, and pharma- ceutically acceptable salts thereof: [ka] During the ceremony, Q is a substituted or unsubstituted dicarba-closo-dodecaborane cluster; D is -S-, -S(O)-, -S(O)(O)-, -S(O)(NH)-, -P(O)(OH)O-, -P(O)(OH)NH-, or -O-; X is OH, NHR 2 , SH, or S(O)(O)NHR 2 and R 6 is substituted or unsubstituted C1-C 20 Alkyl, substituted or unsubstituted C2-C 20 Alkenyl, substituted or unsubstituted C2-C 20 Alkynyl, substituted or unsubstituted C2-C 20 Alkylaryl, substituted or unsubstituted C2-C 20 Alkylheteroaryl, substituted or unsubstituted C4-C 20 Alkylcycloalkyl, or substituted or unsubstituted C4-C 20 alkylheterocycloalkyl, R 2 is H, OH, halogen, or substituted or unsubstituted C1-C4 alkyl.

[0171] In some embodiments of Formula XI: [ka] is bonded to Q in a para configuration.

[0172] In some embodiments of formula XI, the carborane cluster can include a heteroatom. In some embodiments of formula XI, the carborane cluster can include an isotopically labeled atom (i.e., a radiolabeled atom). In some embodiments of formula XI, the carborane cluster can include an isotopically labeled boron atom (e.g., 10 B).

[0173] In some embodiments of formula XI, Q can be: [ka] During the ceremony, ● is a carbon atom or a boron atom, ○ is CH, C-halogen, C-alkyl, C-OH, C-NH2, BH, B-halogen, B-alkyl, B-OH, or B-NH2.

[0174] In some embodiments of formula XI, X is OH.

[0175] In some embodiments of formula XI, R 6 is a substituted or unsubstituted C6-C 10 In some embodiments of formula XI, R 6 is substituted or unsubstituted C2-C 15 In some embodiments of formula XI, R 6 is a substituted or unsubstituted branched C3-C 10 It is an alkyl.

[0176] In some embodiments, the compound of the formula: [ka] [ka] [ka] [ka] and pharma- ceutically acceptable salts thereof. In some embodiments, the carborane cluster may include a heteroatom.

[0177] In some embodiments, the carborane is defined as in Formula XII, or a pharma- ceutically acceptable salt thereof: [ka] where Q is a substituted or unsubstituted dicarba-closo-dodecaborane cluster, and A and R 1 is attached to Q in a para configuration, A is a substituted or unsubstituted heteroaryl ring, and R 1 is substituted or unsubstituted C2-C 20 Alkyl, substituted or unsubstituted C2-C 20 Alkenyl, substituted or unsubstituted C2-C 20 Alkynyl, substituted or unsubstituted C3-C 20Alkylaryl, substituted or unsubstituted C3-C 20 Alkylheteroaryl, substituted or unsubstituted C4-C 20 Alkylcycloalkyl, substituted or unsubstituted C4-C 20 Alkylheterocycloalkyl, substituted or unsubstituted C1-C 20 Acyl, C1-C 20 Acyl, -C(O)NR 3 R 4 , -S(O)-R 3 , -S(O2)-R 3 , substituted or unsubstituted C2~C 20 Heteroalkyl, or NR 3 R 4 and R 3 and R 4 are independently substituted or unsubstituted C1-C 20 Alkyl, substituted or unsubstituted C2-C 20 Alkenyl, substituted or unsubstituted C2-C 20 Alkynyl, substituted or unsubstituted C2-C 20 Alkylaryl, substituted or unsubstituted C4-C 20 Alkylcycloalkyl, and substituted or unsubstituted C2-C 20 heteroalkyl.

[0178] In some embodiments, Q is: [ka] In the formula, ● is a carbon atom or a boron atom, and ○ is CH, C-halogen, C-alkyl, C-OH, C-NH2, BH, B-halogen, B-alkyl, B-OH, or B-NH2.

[0179] In some embodiments, A can be a 5-membered substituted or unsubstituted heteroaryl ring. For example, A can include thienyl, furyl, pyrrolyl, imidazolyl, thiazolyl, oxazolyl, pyrazolyl, isothiazolyl, isoxazolyl, 1,2,3-triazolyl, tetrazolyl, 1,2,3-thiadiazolyl, 1,2,3-oxadiazolyl, 1,2,4-triazolyl, 1,2,4-thiadiazolyl, 1,2,4-oxadiazolyl, 1,3,4-triazolyl, 1,3,4-thiadiazolyl, or 1,3,4-oxadiazolyl ring. In some embodiments, A can be a 6-membered substituted or unsubstituted heteroaryl ring. For example, A can include pyridyl, pyrazinyl, pyrimidinyl, triazinyl, or pyridazinyl ring.

[0180] In some cases, the compound may be defined as formula XIIA, or a pharma- ceutically acceptable salt thereof: [ka] In the formula, ● is a carbon atom, ○ is BH, B-halogen, B-alkyl, B-OH, or B-NH2, and X is OH, NHR 2 , SH, or S(O)(O)NHR 2 Z is, independently for each occurrence, N or CH, with the proviso that at least one of the Z is N; 1 is substituted or unsubstituted C2-C 20 Alkyl, substituted or unsubstituted C2-C 20 Alkenyl, substituted or unsubstituted C2-C 20 Alkynyl, substituted or unsubstituted C3-C 20 Alkylaryl, substituted or unsubstituted C3-C 20 Alkylheteroaryl, substituted or unsubstituted C4-C 20 Alkylcycloalkyl, substituted or unsubstituted C4-C 20 Alkylheterocycloalkyl, substituted or unsubstituted C1-C 20 Acyl, C1-C 20 Acyl, -C(O)NR 3 R 4, -S(O)-R 3 , -S(O2)-R 3 , substituted or unsubstituted C2~C 20 Heteroalkyl, or NR 3 R 4 and R 2 is H, OH, halogen, or substituted or unsubstituted C1-C4 alkyl; R 3 and R 4 are independently substituted or unsubstituted C1-C 20 Alkyl, substituted or unsubstituted C2-C 20 Alkenyl, substituted or unsubstituted C2-C 20 Alkynyl, substituted or unsubstituted C2-C 20 Alkylaryl, substituted or unsubstituted C4-C 20 Alkylcycloalkyl, and substituted or unsubstituted C2-C 20 heteroalkyl.

[0181] In some cases, one of Z can be N. In some cases, two or more of Z can be N. In some cases, three of Z can be N.

[0182] In some cases, the compound is defined by one of the following formulas, or a pharma- ceutically acceptable salt thereof: [ka] In the formula, ● is a carbon atom, ○ is BH, B-halogen, B-alkyl, B-OH, or B-NH2, and X is OH, NHR 2 , SH, or S(O)(O)NHR 2 and R 1 is substituted or unsubstituted C2-C 20 Alkyl, substituted or unsubstituted C2-C 20 Alkenyl, substituted or unsubstituted C2-C 20 Alkynyl, substituted or unsubstituted C3-C 20 Alkylaryl, substituted or unsubstituted C3-C 20 Alkylheteroaryl, substituted or unsubstituted C4-C20 Alkylcycloalkyl, substituted or unsubstituted C4-C 20 Alkylheterocycloalkyl, substituted or unsubstituted C1-C 20 Acyl, C1-C 20 Acyl, -C(O)NR 3 R 4 , -S(O)-R 3 , -S(O2)-R 3 , substituted or unsubstituted C2~C 20 Heteroalkyl, or NR 3 R 4 and R 2 is H, OH, halogen, or substituted or unsubstituted C1-C4 alkyl; R 3 and R 4 are independently substituted or unsubstituted C1-C 20 Alkyl, substituted or unsubstituted C2-C 20 Alkenyl, substituted or unsubstituted C2-C 20 Alkynyl, substituted or unsubstituted C2-C 20 Alkylaryl, substituted or unsubstituted C4-C 20 Alkylcycloalkyl, and substituted or unsubstituted C2-C 20 heteroalkyl.

[0183] In some embodiments, the compound may be defined by one of formulas XIIB-XIIF, or a pharma-ceutically acceptable salt thereof: [ka] In the formula, ● is a carbon atom, ○ is BH, B-halogen, B-alkyl, B-OH, or B-NH2, and R 1 is substituted or unsubstituted C2-C 20 Alkyl, substituted or unsubstituted C2-C 20 Alkenyl, substituted or unsubstituted C2-C 20 Alkynyl, substituted or unsubstituted C3-C 20 Alkylaryl, substituted or unsubstituted C3-C 20 Alkylheteroaryl, substituted or unsubstituted C4-C 20Alkylcycloalkyl, substituted or unsubstituted C4-C 20 Alkylheterocycloalkyl, substituted or unsubstituted C1-C 20 Acyl, C1-C 20 Acyl, -C(O)NR 3 R 4 , -S(O)-R 3 , -S(O2)-R 3 , substituted or unsubstituted C2~C 20 Heteroalkyl, or NR 3 R 4 and R 2 is H, OH, halogen, or substituted or unsubstituted C1-C4 alkyl; R 3 and R 4 are independently substituted or unsubstituted C1-C 20 Alkyl, substituted or unsubstituted C2-C 20 Alkenyl, substituted or unsubstituted C2-C 20 Alkynyl, substituted or unsubstituted C2-C 20 Alkylaryl, substituted or unsubstituted C4-C 20 Alkylcycloalkyl, and substituted or unsubstituted C2-C 20 heteroalkyl.

[0184] In some of the above embodiments, X can be OH.

[0185] In some of the above embodiments, R 1 is a substituted or unsubstituted C6-C 10 Alkyl (e.g., C6-C 10 hydroxyalkyl).

[0186] In some of the above embodiments, R 1 is a substituted or unsubstituted C3-C 16 Alkylaryl (e.g., substituted or unsubstituted C3-C 16 hydroxyalkylaryl).

[0187] In some of the above embodiments, R1 is a substituted or unsubstituted C8-C 20Alkylaryl (e.g., substituted or unsubstituted C to C 20 hydroxyalkylaryl).

[0188] In some of the above embodiments, R 1 is a substituted or unsubstituted C5-C 10 It may be acyl.

[0189] In some of the above embodiments, R 1 is a substituted or unsubstituted branched C4-C 10 Alkyl (e.g., branched C4-C 10 hydroxyalkyl).

[0190] In some cases, the compound is defined by the formula: [ka] where ● is a carbon atom, ○ is BH, B-halogen, B-alkyl, B-OH, or B-NH2, the dotted line to Y indicates that the bond may be a single or double bond where valences permit, A is a substituted or unsubstituted heteroaryl ring, and Y, when present, is O, halogen, OR 2 ', N.H.R. 2 , SH, or S(O)(O)NHR 2 and R 6 is substituted or unsubstituted C1-C 19 Alkyl, substituted or unsubstituted C2-C 19 Alkenyl, substituted or unsubstituted C2-C 19 Alkynyl, substituted or unsubstituted C2-C 19 Alkylaryl, substituted or unsubstituted C2-C 19 Alkylheteroaryl, substituted or unsubstituted C4-C 19 Alkylcycloalkyl, substituted or unsubstituted C4-C 19 Alkylheterocycloalkyl, substituted or unsubstituted C2-C 20 Heteroalkyl, or NR 3 R 4 and R2 is H, OH, halogen, or substituted or unsubstituted C1-C4 alkyl; R 2 ' is H or a substituted or unsubstituted C1-C4 alkyl; R 3 and R 4 are independently substituted or unsubstituted C1-C 20 Alkyl, substituted or unsubstituted C2-C 20 Alkenyl, substituted or unsubstituted C2-C 20 Alkynyl, substituted or unsubstituted C2-C 20 Alkylaryl, substituted or unsubstituted C4-C 20 Alkylcycloalkyl, and substituted or unsubstituted C2-C 20 heteroalkyl.

[0191] In some embodiments, A can be a 5-membered substituted or unsubstituted heteroaryl ring. For example, A can include thienyl, furyl, pyrrolyl, imidazolyl, thiazolyl, oxazolyl, pyrazolyl, isothiazolyl, isoxazolyl, 1,2,3-triazolyl, tetrazolyl, 1,2,3-thiadiazolyl, 1,2,3-oxadiazolyl, 1,2,4-triazolyl, 1,2,4-thiadiazolyl, 1,2,4-oxadiazolyl, 1,3,4-triazolyl, 1,3,4-thiadiazolyl, or 1,3,4-oxadiazolyl ring. In some embodiments, A can be a 6-membered substituted or unsubstituted heteroaryl ring. For example, A can include pyridyl, pyrazinyl, pyrimidinyl, triazinyl, or pyridazinyl ring.

[0192] In some of these embodiments, Y is OH. In some of these embodiments, Y is F. In some of these embodiments, Y is O.

[0193] In some embodiments, R 6 is a substituted or unsubstituted C3-C 10 It can be an alkyl, for example, a substituted or unsubstituted C6 to C9 alkyl.

[0194] In some embodiments, R 6 is substituted or unsubstituted C2-C 15 It may be alkylaryl.

[0195] In some embodiments, R 6 can be a substituted or unsubstituted branched C2-C9 alkylaryl.

[0196] In some embodiments, R 6 is C4~C 10 Substituted or unsubstituted C3-C 10 The heteroalkyl can be, for example, a substituted or unsubstituted C6-C9 heteroalkyl.

[0197] Also provided is a compound defined by formula XIII, or a pharma- ceutically acceptable salt thereof: [ka] where Q is a substituted or unsubstituted dicarba-closo-dodecaborane cluster, and A and R 1 is attached to Q in a para configuration, A is a substituted or unsubstituted aryl ring or a substituted or unsubstituted heteroaryl ring, R 1 is substituted or unsubstituted C2-C 20 Heteroalkyl, -C(O)NR 3 R 4 , -S(O)-R 3 , -S(O2)-R 3 , or N.R. 3 R 4 and R 3 and R 4 are independently substituted or unsubstituted C1-C 20 Alkyl, substituted or unsubstituted C2-C 20 Alkenyl, substituted or unsubstituted C2-C 20 Alkynyl, substituted or unsubstituted C2-C 20 Alkylaryl, substituted or unsubstituted C2-C 20 Alkylheteroaryl, substituted or unsubstituted C4-C 20 Alkylcycloalkyl, substituted or unsubstituted C4-C 20Alkylheterocycloalkyl, and substituted or unsubstituted C-C 20 heteroalkyl, when present, R 3 and R 4 At least one of C2~C 20 Provided that it is heteroalkyl.

[0198] In some embodiments, A may include a substituted or unsubstituted aryl ring (e.g., a substituted or unsubstituted phenyl ring). In some embodiments, A may be a 5-membered substituted or unsubstituted heteroaryl ring. For example, A may include thienyl, furyl, pyrrolyl, imidazolyl, thiazolyl, oxazolyl, pyrazolyl, isothiazolyl, isoxazolyl, 1,2,3-triazolyl, tetrazolyl, 1,2,3-thiadiazolyl, 1,2,3-oxadiazolyl, 1,2,4-triazolyl, 1,2,4-thiadiazolyl, 1,2,4-oxadiazolyl, 1,3,4-triazolyl, 1,3,4-thiadiazolyl, or 1,3,4-oxadiazolyl ring. In some embodiments, A may be a 6-membered substituted or unsubstituted heteroaryl ring. For example, A may include a pyridyl, pyrazinyl, pyrimidinyl, triazinyl, or pyridazinyl ring.

[0199] In some embodiments, Q is: [ka] In the formula, ● is a carbon atom or a boron atom, and ○ is CH, C-halogen, C-alkyl, C-OH, C-NH2, BH, B-halogen, B-alkyl, B-OH, or B-NH2.

[0200] In some embodiments, the compound may be defined as formula XIIIA, or a pharma- ceutically acceptable salt thereof: [ka] In the formula, ● is a carbon atom, ○ is BH, B-halogen, B-alkyl, B-OH, or B-NH2, and X is OH, NHR 2 , SH, or S(O)(O)NHR 2 Z is, independently for each occurrence, N or CH, with the proviso that at least one of the Z is N; 1 is substituted or unsubstituted C2-C 20 Heteroalkyl, -C(O)NR 3 R 4 , -S(O)-R 3 , -S(O2)-R 3 , or N.R. 3 R 4 and R 3 and R 4 are independently substituted or unsubstituted C1-C 20 Alkyl, substituted or unsubstituted C2-C 20 Alkenyl, substituted or unsubstituted C2-C 20 Alkynyl, substituted or unsubstituted C2-C 20 Alkylaryl, substituted or unsubstituted C2-C 20 Alkylheteroaryl, substituted or unsubstituted C4-C 20 Alkylcycloalkyl, substituted or unsubstituted C4-C 20 Alkylheterocycloalkyl, and substituted or unsubstituted C-C 20 heteroalkyl, when present, R 3 and R 4 At least one of C2~C 20 Provided that it is heteroalkyl.

[0201] In some of these embodiments, X can be OH.

[0202] Also provided is a compound defined by any of the following formulas, or a pharma- ceutically acceptable salt thereof: [ka] where ● is a carbon atom, ○ is BH, B-halogen, B-alkyl, B-OH, or B-NH2, the dotted line to Y indicates that the bond may be a single or double bond where valences permit, A is a substituted or unsubstituted aryl ring or a substituted or unsubstituted heteroaryl ring, and Y, when present, is O, halogen, OR 2 ', N.H.R. 2 , SH, or S(O)(O)NHR 2 and R 6 is substituted or unsubstituted C1-C 19 Alkyl, substituted or unsubstituted C2-C 19 Alkenyl, substituted or unsubstituted C2-C 19 Alkynyl, substituted or unsubstituted C2-C 19 Alkylaryl, substituted or unsubstituted C2-C 19 Alkylheteroaryl, substituted or unsubstituted C4-C 19 Alkylcycloalkyl, substituted or unsubstituted C4-C 19 Alkylheterocycloalkyl, substituted or unsubstituted C2-C 20 Heteroalkyl, or NR 3 R 4 and R 2 is H, OH, halogen, or substituted or unsubstituted C1-C4 alkyl; R 2 ' is H or a substituted or unsubstituted C1-C4 alkyl; R 3 and R 4 are independently substituted or unsubstituted C1-C 20 Alkyl, substituted or unsubstituted C2-C 20 Alkenyl, substituted or unsubstituted C2-C 20 Alkynyl, substituted or unsubstituted C2-C 20 Alkylaryl, substituted or unsubstituted C4-C 20 Alkylcycloalkyl, and substituted or unsubstituted C2-C 20 heteroalkyl.

[0203] In some embodiments, A may include a substituted or unsubstituted aryl ring (e.g., a substituted or unsubstituted phenyl ring). In some embodiments, A may be a 5-membered substituted or unsubstituted heteroaryl ring. For example, A may include thienyl, furyl, pyrrolyl, imidazolyl, thiazolyl, oxazolyl, pyrazolyl, isothiazolyl, isoxazolyl, 1,2,3-triazolyl, tetrazolyl, 1,2,3-thiadiazolyl, 1,2,3-oxadiazolyl, 1,2,4-triazolyl, 1,2,4-thiadiazolyl, 1,2,4-oxadiazolyl, 1,3,4-triazolyl, 1,3,4-thiadiazolyl, or 1,3,4-oxadiazolyl ring. In some embodiments, A may be a 6-membered substituted or unsubstituted heteroaryl ring. For example, A may include a pyridyl, pyrazinyl, pyrimidinyl, triazinyl, or pyridazinyl ring.

[0204] In some of these embodiments, Y is OH. In some of these embodiments, Y is F. In some of these embodiments, Y is O.

[0205] In some embodiments, R 6 is a substituted or unsubstituted C3-C 10 It can be an alkyl, for example, a substituted or unsubstituted C6 to C9 alkyl.

[0206] In some embodiments, R 6 is substituted or unsubstituted C2-C 15 It may be alkylaryl.

[0207] In some embodiments, R 6 can be a substituted or unsubstituted branched C2-C9 alkylaryl.

[0208] In some embodiments, R 6 is C4~C 10 Substituted or unsubstituted C3-C 10 The heteroalkyl can be, for example, a substituted or unsubstituted C6-C9 heteroalkyl.

[0209] In some embodiments, the carborane has the formula: [ka] [ka] and pharma- ceutically acceptable salts thereof. In some embodiments, the carborane cluster may include a heteroatom.

[0210] In some embodiments, the compound may be a carborane analog, such as a dicarba-closo-dodecaborane analog of the compound described in WO2017 / 049307 by Tjarks et al. The compound includes a spacer group replacing the carborane moiety in the compound therein. The resulting compound may exhibit biological activity similar to the compounds described in WO2017 / 049307.

[0211] For example, provided herein is a compound defined as formula XIV, or a pharma- ceutically acceptable salt thereof: [ka] wherein A is a substituted or unsubstituted aryl ring or a substituted or unsubstituted heteroaryl ring, and Q is a spacer group selected from one of the following: [ka] where m and n are each independently 0, 1, 2, or 3; R 1 is a substituted or unsubstituted C4-C 20 Alkyl, substituted or unsubstituted C4-C 20 Heteroalkyl, substituted or unsubstituted C2-C 20 Alkenyl, substituted or unsubstituted C2-C 20 Alkynyl, substituted or unsubstituted C3-C 20 Alkylaryl, substituted or unsubstituted C3-C 20Alkylheteroaryl, substituted or unsubstituted C4-C 20 Alkylcycloalkyl, substituted or unsubstituted C4-C 20 Alkylheterocycloalkyl, substituted or unsubstituted C1-C 20 Acyl, C1-C 20 Acyl, -C(O)NR 3 R 4 , or N.R. 3 R 4 and R 3 and R 4 are independently substituted or unsubstituted C1-C 20 Alkyl, substituted or unsubstituted C1-C 20 Heteroalkyl, substituted or unsubstituted C2-C 20 Alkenyl, substituted or unsubstituted C2-C 20 Alkynyl, substituted or unsubstituted C2-C 20 Alkylaryl, or substituted or unsubstituted C4-C 20 alkylcycloalkyl.

[0212] In certain embodiments, Q may be selected from one of the following formulas: [ka] In some embodiments, A may include a substituted or unsubstituted aryl ring (e.g., a substituted or unsubstituted phenyl ring). In some embodiments, A may be a 5-membered substituted or unsubstituted heteroaryl ring. For example, A may include thienyl, furyl, pyrrolyl, imidazolyl, thiazolyl, oxazolyl, pyrazolyl, isothiazolyl, isoxazolyl, 1,2,3-triazolyl, tetrazolyl, 1,2,3-thiadiazolyl, 1,2,3-oxadiazolyl, 1,2,4-triazolyl, 1,2,4-thiadiazolyl, 1,2,4-oxadiazolyl, 1,3,4-triazolyl, 1,3,4-thiadiazolyl, or 1,3,4-oxadiazolyl ring. In some embodiments, A may be a 6-membered substituted or unsubstituted heteroaryl ring. For example, A may include a pyridyl, pyrazinyl, pyrimidinyl, triazinyl, or pyridazinyl ring.

[0213] In some embodiments, A is [ka] where X is OH, NHR 2 , SH, or S(O)(O)NHR 2 and R 2 is H, OH, halogen, or substituted or unsubstituted C1-C4 alkyl. In some of these embodiments, X is OH.

[0214] In some embodiments, A is [ka] where X is OH, NHR 2 , SH, or S(O)(O)NHR 2 and R 2 is H, OH, halogen, or substituted or unsubstituted C1-C4 alkyl. In some of these embodiments, X is OH.

[0215] In some embodiments, A is [ka] wherein Z is, independently for each occurrence, N or CH, with the proviso that at least one of the Z is N; and X is OH, NHR 2 , SH, or S(O)(O)NHR 2 and R 2 is H, OH, halogen, or substituted or unsubstituted C1-C4 alkyl. In some of these embodiments, A can be one of the following formulae: [ka] In some of these embodiments, X is OH.

[0216] In some embodiments, A is [ka] where Y is S or O and X is OH, NHR 2 , SH, or S(O)(O)NHR 2 and R 2 is H, OH, halogen, or substituted or unsubstituted C1-C4 alkyl. In some of these embodiments, X is OH.

[0217] In some embodiments, A is [ka] where Y is S or O and X is OH, NHR 2 , SH, or S(O)(O)NHR 2 and R 2 is H, OH, halogen, or substituted or unsubstituted C1-C4 alkyl. In some of these embodiments, X is OH.

[0218] In some embodiments, A is [ka] It is.

[0219] In some of the above embodiments, R 1 is a substituted or unsubstituted C6-C 10 Alkyl (e.g., substituted or unsubstituted C6-C 10 hydroxyalkyl).

[0220] In some of the above embodiments, R 1 is a substituted or unsubstituted C3-C 16 Alkylaryl (e.g., substituted or unsubstituted C3-C 16 hydroxyalkylaryl).

[0221] In some of the above embodiments, R 1is a substituted or unsubstituted C8-C 20 Alkylaryl (e.g., substituted or unsubstituted C to C 20 hydroxyalkylaryl).

[0222] In some of the above embodiments, R 1 is a substituted or unsubstituted C5-C 10 It may be acyl.

[0223] In some of the above embodiments, R 1 is a substituted or unsubstituted branched C4-C 10 Alkyl (e.g., branched C4-C 10 hydroxyalkyl).

[0224] In some embodiments, R 1 may have one of the following formulas: [ka] In the formula, the dotted line to Y indicates that the bond may be a single or double bond, if valence allows, and Y, when present, is O, halogen, OR 2 ', N.H.R. 2 , SH, or S(O)(O)NHR 2 and R 6 is substituted or unsubstituted C1-C 19 Alkyl, substituted or unsubstituted C2-C 19 Alkenyl, substituted or unsubstituted C2-C 19 Alkynyl, substituted or unsubstituted C2-C 19 Alkylaryl, substituted or unsubstituted C2-C 19 Alkylheteroaryl, substituted or unsubstituted C4-C 19 Alkylcycloalkyl, substituted or unsubstituted C4-C 19 Alkylheterocycloalkyl, substituted or unsubstituted C2-C 20 Heteroalkyl, or NR 3 R 4 and R 2 is H, OH, halogen, or substituted or unsubstituted C1-C4 alkyl; R2 ' is H or a substituted or unsubstituted C1-C4 alkyl; R 3 and R 4 are independently substituted or unsubstituted C1-C 20 Alkyl, substituted or unsubstituted C2-C 20 Alkenyl, substituted or unsubstituted C2-C 20 Alkynyl, substituted or unsubstituted C2-C 20 Alkylaryl, substituted or unsubstituted C4-C 20 Alkylcycloalkyl, and substituted or unsubstituted C2-C 20 heteroalkyl.

[0225] In some embodiments, A may include a substituted or unsubstituted aryl ring (e.g., a substituted or unsubstituted phenyl ring). In some embodiments, A may be a 5-membered substituted or unsubstituted heteroaryl ring. For example, A may include thienyl, furyl, pyrrolyl, imidazolyl, thiazolyl, oxazolyl, pyrazolyl, isothiazolyl, isoxazolyl, 1,2,3-triazolyl, tetrazolyl, 1,2,3-thiadiazolyl, 1,2,3-oxadiazolyl, 1,2,4-triazolyl, 1,2,4-thiadiazolyl, 1,2,4-oxadiazolyl, 1,3,4-triazolyl, 1,3,4-thiadiazolyl, or 1,3,4-oxadiazolyl ring. In some embodiments, A may be a 6-membered substituted or unsubstituted heteroaryl ring. For example, A may include a pyridyl, pyrazinyl, pyrimidinyl, triazinyl, or pyridazinyl ring.

[0226] In some of these embodiments, Y is OH. In some of these embodiments, Y is F. In some of these embodiments, Y is O.

[0227] In some embodiments, R 6 is a substituted or unsubstituted C3-C 10 It can be an alkyl, for example, a substituted or unsubstituted C6 to C9 alkyl.

[0228] In some embodiments, R 6 is substituted or unsubstituted C2-C 15 It may be alkylaryl.

[0229] In some embodiments, R 6 can be a substituted or unsubstituted branched C2-C9 alkylaryl.

[0230] In some embodiments, R 6 is C4~C 10 Substituted or unsubstituted C3-C 10 The heteroalkyl can be, for example, a substituted or unsubstituted C6-C9 heteroalkyl.

[0231] In some embodiments, the compound may include one of the following formulas: [ka] [ka] Also disclosed are pharma- ceutically acceptable salts and carborane and carborane analogs described herein. Pharmaceutically acceptable salts include salts of the disclosed carborane and carborane analogs prepared with acids or bases, depending on the particular substituents found on the compound. Under conditions where the carborane and carborane analogs disclosed herein are sufficiently basic or acidic to form stable non-toxic acid or base salts, administration of the compound as a salt may be appropriate. Examples of pharma- ceutical acceptable base addition salts include sodium, potassium, calcium, ammonium, or magnesium salts. Examples of pharma- ceutical acceptable acid addition salts include hydrochloric acid, hydrobromic acid, nitric acid, phosphoric acid, carbonic acid, sulfuric acid, organic acids (acetic acid, propionic acid, benzoic acid, succinic acid, fumaric acid, mandelic acid, oxalic acid, citric acid, tartaric acid, malonic acid, ascorbic acid, alpha-ketoglutaric acid, alpha-glycolic acid, maleic acid, tosylic acid, methanesulfonic acid), and the like. Thus, disclosed herein are hydrochloride, nitrate, phosphate, carbonate, bicarbonate, sulfate, acetate, propionate, benzoate, succinate, fumarate, mandelate, oxalate, citrate, tartrate, malonate, ascorbate, alpha-ketoglutarate, alpha-glycolate, maleate, tosylate, and methanesulfonate salts. Pharmaceutically acceptable salts of compounds can be obtained by standard procedures well known in the art, for example, by reacting a sufficiently basic compound, such as an amine, with a suitable acid to provide a physiologically acceptable anion. Alkali metal (e.g., sodium, potassium, or lithium) or alkaline earth metal (e.g., calcium) salts of carboxylic acids can also be prepared.

[0232] In some examples, the carboranes and carborane analogs disclosed herein have an EC50 of 800 nM or less at the estrogen receptor beta (ERβ). 50(e.g., 700 nM or less, 600 nM or less, 500 nM or less, 400 nM or less, 300 nM or less, 200 nM or less, 100 nM or less, 90 nM or less, 80 nM or less, 70 nM or less, 60 nM or less, 50 nM or less, 40 nM or less, 30 nM or less, 20 nM or less, 10 nM or less, 9 nM or less, 8 nM or less, 7 nM or less, 6 nM or less, 5 nM or less, 4.5 nM or less, 4 nM or less, 3.5 nM or less, 3 nM or less, 2.5 nM or less, 2 nM or less, 1.5 nM or less, 1 nM or less, 0.9 nM or less, 0.8 nM or less, 0.7 nM or less, 0.6 nM or less, 0.5 nM or less, 0.4 nM or less, 0.3 nM or less, 0.2 nM or less, or 0.1 nM or less).

[0233] In some examples, the carboranes and carborane analogs disclosed herein have an EC50 activity at ERβ of 1 pM or greater. 50 (e.g., 0.1 nM or more, 0.2 nM or more, 0.3 nM or more, 0.4 nM or more, 0.5 nM or more, 0.6 nM or more, 0.7 nM or more, 0.8 nM or more, 0.9 nM or more, 1 nM or more, 1.5 nM or more, 2 nM or more, 2.5 nM or more, 3 nM or more, 3.5 nM or more, 4 nM or more, 4.5 nM or more, 5 nM or more, 6 nM or more, 7 nM or more, 8 nM or more, 9 nM or more, 10 nM or more, 20 nM or more, 30 nM or more, 40 nM or more, 50 nM or more, 60 nM or more, 70 nM or more, 80 nM or more, 90 nM or more, 100 nM or more, 200 nM or more, 300 nM or more, 400 nM or more, 500 nM or more, 600 nM or more, or 700 nM or more).

[0234] EC of carboranes and carborane analogues on ERβ 50 can range from the minimum value described above to the maximum value described above. For example, the carboranes and carborane analogs disclosed herein have an EC 50(e.g., 1 pM to 400 nM, 400 nM to 800 nM, 1 pM to 300 nM, 1 pM to 200 nM, 1 pM to 100 nM, 1 pM to 50 nM, 1 pM to 20 nM, 1 pM to 10 nM, 1 pM to 6 nM, 1 pM to 5 nM, 1 pM to 2 nM, 1 pM to 1 nM, 1 pM to 0.7 nM, 1 pM to 0.5 nM, 1 pM to 0.2 nM, 1 pM to 0.1 nM).

[0235] In some embodiments, the carboranes and carborane analogs disclosed herein are selective ERβ agonists. In some embodiments, selective ERβ agonists have a lower EC50 activity at estrogen receptor alpha (ERα) than at ERβ. 50 The selectivity of the compound is, in some embodiments, determined by the EC 50 EC of compound at ERα divided by 50 In some embodiments, the compounds disclosed herein may have an agonistic ratio of ERβ to ERα of 8 or greater (e.g., 10 or greater, 20 or greater, 30 or greater, 40 or greater, 50 or greater, 60 or greater, 70 or greater, 80 or greater, 90 or greater, 100 or greater, 150 or greater, 200 or greater, 250 or greater, 300 or greater, 350 or greater, 400 or greater, 450 or greater, 500 or greater, 600 or greater, 700 or greater, 800 or greater, 900 or greater, 1000 or greater, 1100 or greater, 1200 or greater, 1300 or greater, 1400 or greater, 1500 or greater, 2000 or greater, 2500 or greater).

[0236] In some examples, carboranes and carborane analogs may have an ERβ to ERα agonist ratio of 3000 or less (e.g., 2500 or less, 2000 or less, 1500 or less, 1400 or less, 1300 or less, 1200 or less, 1100 or less, 1000 or less, 900 or less, 800 or less, 700 or less, 600 or less, 500 or less, 450 or less, 400 or less, 350 or less, 300 or less, 250 or less, 200 or less, 150 or less, 100 or less, 90 or less, 80 or less, 70 or less, 60 or less, 50 or less, 40 or less, 30 or less, 20 or less, or 10 or less).

[0237] The ERβ to ERα agonist ratio of carboranes and carborane analogs at ERβ can be within the range of any of the minimum values ​​described above to any of the maximum values ​​described above. For example, carboranes and carborane analogs can have an ERβ to ERα agonist ratio of 8 to 3000 (e.g., 8 to 1500, 1500 to 3000, 400 to 3000, 500 to 3000, 600 to 3000, 700 to 3000, 800 to 3000, 900 to 3000, 1000 to 3000, 2000 to 3000).

[0238] Method of preparation The compounds described herein can be prepared in various ways well known to those skilled in the art of organic synthesis, or in variations thereof, as will be appreciated by those skilled in the art.The compounds described herein can be prepared from readily available starting materials.Optimal reaction conditions may vary depending on the specific reactants or solvents used, but such conditions can be determined by those skilled in the art.

[0239] Variations of the compounds described herein include the addition, subtraction, or movement of various components as described for each compound. Similarly, if there is one or more chiral centers in the molecule, the chirality of the molecule can be altered. In addition, the synthesis of the compounds can include the protection and deprotection of various chemical groups. The use of protection and deprotection, and the selection of appropriate protecting groups can be determined by those skilled in the art. The chemistry of protecting groups can be found, for example, in Wuts and Greene, Protective Groups in Organic Synthesis, 4th Ed., Wiley & Sons, 2006, which is incorporated herein by reference in its entirety.

[0240] Starting materials and reagents used in preparing the disclosed compounds and compositions are available from commercial suppliers, such as Aldrich Chemical Co., (Milwaukee, WI), Acros Organics (Morris Plains, NJ), Fisher Scientific (Pittsburgh, PA), Sigma (St. Louis, MO), Pfizer (New York, NY), GlaxoSmithKline (Raleigh, NC), Merck (Whitehouse Station, NJ), Johnson & Johnson (New Brunswick, NJ), Aventis (Bridgewater, NJ), AstraZeneca (Wilmington, DE), Novartis (Basel, Switzerland), Wyeth (Madison, NJ), Bristol-Myers-Squibb (New York, NY), Roche (Basel, Switzerland), Lilly (Indianapolis, IN), Abbott (Abbott Park, IL), Schering Plough (Kenilworth, NJ), or Boehringer Ingelheim (Ingelheim, Germany), or according to procedures described in the following references: Fieser and Fieser's Reagents for Organic Synthesis, Volumes 1-17 (John Wiley and Sons, 1991); Rodd's Chemistry of Carbon Compounds, Volumes 1-5 and Supplementals (Elsevier Science Publishers, 1989); Organic Reactions, Volumes 1-40 (John Wiley and Sons, 1991); March's Advanced Organic Chemistry, (John Wiley and Sons, 4th Edition); and Larock's Comprehensive Organic Transformations (VCH Publishers Inc., 1989). Other materials, such as pharmaceutical excipients disclosed herein, can be obtained from commercial sources.

[0241] The reaction for producing the compounds described herein can be carried out in a solvent that can be selected by one skilled in the art of organic synthesis. The solvent can be substantially non-reactive with the starting materials (reactants), intermediates, or products under the conditions (i.e., temperature and pressure) in which the reaction is carried out. The reaction can be carried out in one solvent or a mixture of two or more solvents. The formation of the product or intermediate can be controlled by any suitable method known in the art. For example, the formation of the product can be controlled by spectroscopy, such as nuclear magnetic resonance spectroscopy (e.g., 1H or 13C), infrared spectroscopy, spectrophotometry (e.g., UV-visible), or mass spectrometry, or chromatography, such as high performance liquid chromatography (HPLC) or thin layer chromatography.

[0242] How to use Methods of using the compounds described herein are also provided herein. Also provided herein are methods for treating a disease or condition in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of any of the compounds or compositions described herein.

[0243] Methods are provided for treating, preventing, or ameliorating fibrotic conditions in a subject using the carboranes and carborane analogs described herein.Exemplary fibrotic conditions that can be treated or prevented using the carboranes and carborane analogs described herein (e.g., the ERβ agonists described herein) include, but are not limited to, fibrotic conditions of the lung, liver, heart, vasculature, kidney, skin, gastrointestinal tract, bone marrow, or combinations thereof.Each of these conditions is described in more detail herein.

[0244] Pulmonary fibrosis (also referred to herein as "pulmonary fibrosis") is characterized by the formation of scar tissue in the lungs, resulting in reduced function. Pulmonary fibrosis is associated with shortness of breath, progressive weakness and fatigue, and ultimately leads to loss of appetite and rapid weight loss. Half a million people in the United States and 5 million people worldwide suffer from pulmonary fibrosis, with 40,000 deaths from the disease in the United States each year. Pulmonary fibrosis has multiple causes, including radiation therapy, but may also be due to smoking or genetic factors (Meltzer, EB et al. (2008) Orphanet J. Rare Dis. 3:8).

[0245] Pulmonary fibrosis can occur as a side effect of disease processes such as asbestosis and silicosis and is known to be more common in certain occupations, such as coal miners, shipworkers and sandblasters, where exposure to environmental pollution is an occupational hazard (Green, FH et al. (2007) Toxicol Pathol. 35:136-47). Other factors that can cause pulmonary fibrosis include cigarette smoking, and autoimmune connective tissue diseases (rheumatoid arthritis, scleroderma, and systemic lupus erythematosus (SLE) (Leslie, KO et al. (2007) Semin Respir Crit. Care Med 28:369-78; Swigris, JJ et al. (2008) Chest. 133:271-80; and Antoniou, KM et al. (2008) Curr Opin Rheumatol. 20:686-91). Other connective tissue disorders such as sarcoidosis may include pulmonary fibrosis as part of the disease (Paramothayan, S et al. (2008) Respir Med. 102:1-9), lung infections may result from long-term effects of infection, especially fibrosis as chronic infections progress. Pulmonary fibrosis may also be a side effect of certain medical treatments, especially chest radiation therapy and certain medications (bleomycin, methotrexate, amiodarone, busulfan, nitrofurantoin, etc.) (Catane, R et al. (1979) Int J Radiat Oncol Biol Phys. 5:1513-8; Zisman, DA et al. (2001) Sarcoidosis Vasc Diffuse Lung Dis. 18:243-52; Rakita, L et al. (1983) Am Heart J. 106:906-16; Twohig, KJ et al. (1990) Clin Chest Med. 11:31-54; and Witten C M. (1989) Arch Phys Med. Rehabil. 70:55-7). In other embodiments, idiopathic pulmonary fibrosis may occur where no clear etiology or disease can be identified.Increasingly, it is believed that genetic factors may play an important role in these cases of pulmonary fibrosis (Steele, MP et al. (2007) Respiration 74:601-8; Brass, DM et al. (2007) Proc Am Thorac Soc. 4:92-100 and du Bois R M. (2006) Semin Respir Crit. Care Med. 27:581-8).

[0246] In some embodiments, the pulmonary fibrotic condition may be selected from one or more of pulmonary fibrosis, idiopathic pulmonary fibrosis (IPF), common interstitial pneumonia (UIP), interstitial lung disease, idiopathic fibrosing alveolitis (CFA), or bronchiectasis.

[0247] In other embodiments, pulmonary fibrosis includes, but is not limited to, chronic obstructive pulmonary disease (COPD), scleroderma, pleural fibrosis, chronic asthma, acute respiratory syndrome, amyloidosis, bronchopulmonary dysplasia, Kaplan's disease, Dressler's syndrome, histiocytosis X, idiopathic pulmonary hemosiderosis, lymphangioleiomyomatosis, mitral stenosis, polymyositis, pulmonary edema, pulmonary hypertension (e.g., idiopathic pulmonary hypertension (IPH)), pneumoconiosis, radiation therapy (radiation fibrosis), rheumatic diseases, Shaver's disease, systemic lupus erythematosus, systemic scleroderma, tropical pulmonary acidosis, and the like. Pulmonary fibrosis may include, but is not limited to, pulmonary fibrosis associated with pulmonary cytosis, tuberous sclerosis, Weber-Christian disease, Wegener's granulomatosis, Whipple's disease, or exposure to toxins or irritants (e.g., inhalation of medicines (amiodarone, bleomycin, carmustine, chloramphenicol, hexamethonium, methotrexate, mitomycin C, nitrofurantoin, penicillamine, peplomycin, practolol), talc, or dusts (e.g., carbon dust, silica)). In certain embodiments, the pulmonary fibrosis is associated with an inflammatory disease of the lungs, e.g., asthma, COPD.

[0248] In some embodiments, the fibrotic condition can be a fibrotic condition of the liver (also referred to herein as "liver fibrosis"), e.g., fatty liver disease, e.g., nonalcoholic steatohepatitis (NASH), bile duct fibrosis, cholestatic liver disease (e.g., primary biliary cirrhosis (PBC), and cholangiopathy (e.g., chronic cholangiopathy)).

[0249] In certain embodiments, the liver fibrosis or liver fibrosis may be selected from one or more of fatty liver disease, fatty liver (e.g., nonalcoholic steatohepatitis (NASH), cholestatic liver disease, primary biliary cirrhosis (PBC), biliary fibrosis, cirrhosis, alcoholic liver fibrosis, bile duct injury, infectious or viral liver fibrosis, congenital liver fibrosis, autoimmune hepatitis, or cholangiopathy (e.g., chronic cholangiopathy)).

[0250] In certain embodiments, hepatic or liver fibrosis includes, but is not limited to, alcoholism, viral infections, such as hepatitis (e.g., hepatitis C, B, D), autoimmune hepatitis, nonalcoholic fatty liver disease (NAFLD), progressive massive fibrosis, toxins or irritants (e.g., exposure to alcohol, pharmaceuticals, and environmental toxins, such as arsenic), alpha-1 antitrypsin deficiency, hemochromatosis, Wilson's disease, galactosemia, or glycogen storage disease.In certain embodiments, liver fibrosis is associated with inflammatory diseases of the liver.

[0251] In some embodiments, liver fibrosis can be a fibrotic condition of the heart or vasculature, such as myocardial fibrosis. Fibrotic conditions of the heart or vasculature include, but are not limited to, myocardial fibrosis (e.g., myocardial fibrosis associated with radiation myocarditis, surgical procedure complications (e.g., fibrosis after myocardial surgery), vascular restenosis, atherosclerosis, cerebral disease, peripheral vascular disease, infectious diseases (Chagas disease, bacterial, trichinellosis or fungal myocarditis)); granulomatous, metabolic storage disorders (e.g., cardiomyopathy, hemochromatosis); developmental disorders (e.g., endocardial fibroelastosis); arteriosclerosis, or exposure to toxins or irritants (e.g., drug-induced cardiomyopathy, drug-induced cardiotoxicity, alcoholic cardiomyopathy, cobalt poisoning or exposure). In certain embodiments, myocardial fibrosis is associated with inflammatory diseases of cardiac tissue (e.g., myocardial sarcoidosis).

[0252] In some embodiments, the fibrotic condition may be a renal fibrotic condition, such as renal fibrosis (e.g., chronic renal fibrosis). Renal fibrosis includes, but is not limited to, injury / fibrosis-related nephropathy (e.g., chronic nephropathy associated with diabetes (e.g., diabetic nephropathy)), lupus, renal scleroderma, glomerulonephritis, focal segmental glomerulosclerosis, IgA-associated fibrosis associated with human chronic kidney disease (CKD), chronic renal fibrosis, nephrogenic systemic fibrosis, chronic progressive nephropathy (CPN), tubulointerstitial fibrosis, ureteral obstruction (e.g., fetal partial ureteral obstruction), chronic uremia, chronic interstitial nephritis, radiation nephropathy, glomerulosclerosis (e.g., focal segmental glomerulosclerosis (FSGS)), progressive glomerulonephritis (PGN), endothelial / thrombotic microcirculatory disorder, renal scleroderma, HIV-associated nephropathy (HIVVAN), or exposure to toxins, irritants, and chemotherapeutic drugs. In one embodiment, renal fibrosis is mediated by bone morphogenetic proteins (BMPs). In certain embodiments, renal fibrosis is the result of inflammatory diseases of the kidney.

[0253] In some embodiments, the fibrotic condition can be a bone marrow fibrotic condition.In certain embodiments, the bone marrow fibrotic condition is myelofibrosis (e.g., primary myelofibrosis (PMF)), myeloid metaplasia, chronic idiopathic myelofibrosis, or primary myelofibrosis.In other embodiments, the myelofibrosis is associated with a blood disorder selected from one or more of hairy cell leukemia, lymphoma, or multiple myeloma.

[0254] In other embodiments, the myelofibrosis may be associated with one or more myeloproliferative neoplasms (MPNs) selected from essential thrombocythemia (ET), polycythemia vera (PV), mastocytosis, chronic eosinophilic leukemia, chronic neutrophilic leukemia, or other MPNs.

[0255] In some embodiments, the fibrotic condition may be primary myelofibrosis. Primary myelofibrosis (PMF) (also referred to herein as idiopathic myeloid metaplasia and myeloid metaplasia of unknown etiology) is a condition characterized by the development of multiple hematopoietic progenitor cells (Abdel-Wahab, O. et al. (2009) Annu. Rev. Med. 60:233-45; Varicchio, L. et al. (2009) Expert Rev. Hematol. 2(3):315-334; Agrawal, M. et al. (2010) Cancer 1-15). The disease is characterized by anemia, splenomegaly and extramedullary hematopoiesis, and is characterized by progressive myelofibrosis and atypical erythrohypertrophy. CD34+ stem / progenitor cells enter the peripheral blood abnormally, and multiorgan extramedullary hematopoiesis is characteristic of disease, particularly in the spleen and liver. Bone marrow architecture is altered due to progressive fibrosis, angiogenesis, and increased bone deposition. A significant proportion of patients with PMF have Janus kinase 2 (JAK2) (approximately 50%) (e.g., JAK2 V617F ) or thrombopoietin receptor (MPL) (5-10%), resulting in abnormal megakaryocytic proliferation. Studies have shown that chronic hematopoietic disorders lead to secondary proliferation of fibroblasts and excessive collagen deposition. Reduction of bone marrow fibrosis may improve clinical signs and symptoms, including anemia, abnormal white blood cell counts, and splenomegaly.

[0256] Myelofibrosis can be observed in several other blood disorders, including, but not limited to, hairy cell leukemia, lymphoma, and multiple myeloma. However, each of these conditions is characterized by clinical, pathological, and molecular findings that are not characteristic of PMF (see Abdel-Wahab, O. et al. (2009) (supra) p. 235).

[0257] In other embodiments, myelofibrosis may be secondary to solid tumor metastases to the bone marrow, autoimmune disorders (systemic lupus erythematosus, scleroderma, mixed connective tissue disease, polymyositis), and secondary hyperparathyroidism associated with vitamin D deficiency (see Abdel-Wahab, O. et al. (2009) supra, p. 235). In rare cases, the presence of JAK2V617F or MPLW515L / K mutations can be used to indicate the presence of clonal MPN and exclude the possibility of reactive fibrosis, but in most cases it is possible to distinguish PMF from the above disorders.

[0258] Optionally, monitoring clinical efficacy in a subject with myelofibrosis can be assessed by one or more of monitoring peripheral blood counts (e.g., red blood cells, white blood cells, platelets), with an increase in peripheral blood count indicating an improved prognosis. In other embodiments, clinical improvement in a subject with myelofibrosis can be assessed by monitoring one or more of spleen size, liver size, and extramedullary hematopoiesis, with a decrease in one or more of these parameters indicating an improved prognosis.

[0259] In other embodiments, the fibrotic condition may be a fibrotic condition of the skin. In certain embodiments, the fibrotic condition is selected from one or more of skin fibrosis and / or scarring, postoperative adhesions, scleroderma (systemic sclerosis), or skin lesions such as keloids.

[0260] In certain embodiments, the fibrotic condition can be the fibrotic condition of the digestive tract.Such fibrotic condition can be associated with inflammatory disease of the digestive tract, for example, the fibrosis associated with scleroderma; radiation-induced intestinal fibrosis; the fibrosis associated with anterior intestinal inflammatory disease, such as Barrett's esophagus and chronic gastritis, and / or the fibrosis associated with posterior intestinal inflammatory disease, such as inflammatory bowel disease (IBD), ulcerative colitis and Crohn's disease.In certain embodiments, the fibrotic condition can be generalized scleroderma.

[0261] Fibrotic conditions may further include diseases that have an manifest fibrotic disorder of the penis, including Peyronie's disease (fibrosis of the cavernous sheath leading to contracture of the covering fascia of the corpus cavernosum resulting in a deflected and painful penile erection).

[0262] In some cases, the fibrotic condition may include Dupuytren's contracture (palmar fibromatosis).

[0263] In some cases, the fibrotic condition can include fibrosis associated with rheumatoid arthritis.

[0264] In certain embodiments, the fibrotic condition may be selected from pulmonary fibrosis, bronchiectasis, interstitial lung disease; fatty liver disease; cholestatic liver disease, biliary fibrosis, hepatic fibrosis; myocardial fibrosis; renal fibrosis.

[0265] In certain embodiments, the fibrotic condition may be selected from biliary fibrosis, liver fibrosis, pulmonary fibrosis, myocardial fibrosis, and renal fibrosis.

[0266] In certain embodiments, the fibrotic condition may be selected from non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH).

[0267] Other fibrotic conditions that may be treated with the methods and compositions of the present invention include cystic fibrosis, endomyocardial fibrosis, mediastinal fibrosis, sarcoidosis, spinal cord injury / fibrosis.

[0268] A number of models are available in the art in which fibrosis is induced. Administration of carboranes and carborane analogs can be readily used to assess whether fibrosis is ameliorated in such models. Examples of such models include the unilateral ureteral ligation model of renal fibrosis (see Chevalier et al., “Ureteral Obstruction as a Model of Renal Interstitial Fibrosis and Obstructive Nephropathy” Kidney International (2009) 75:1145-1152), the bleomycin-induced model of pulmonary fibrosis (see Moore and Hogaboam “Murine Models of Pulmonary Fibrosis” Am. J. Physiol. Lung. Cell. Mol. Physiol. (2008) 294:L152-L160), various models of liver / biliary fibrosis (Chuang et al., “Animal Models of Primary Biliary Cirrhosis” Clin Liver Dis (2008) 12:333-347; Omenetti, A. et al. (2007) Laboratory Investigation 87:499-514), and the bleomycin-induced model of pulmonary fibrosis (see Moore and Hogaboam “Murine Models of Pulmonary Fibrosis” Am. J. Physiol. Lung. Cell. Mol. Physiol. (2008) 294:L152-L160). (see, e.g., the bile duct ligation model), or the numerous myelofibrosis mouse models described in Varicchio, L. (2009) (supra). Regardless of the model, carboranes and carborane analogs can be evaluated in essentially three paradigms: 1) to test whether they can suppress a fibrotic state, 2) to test whether they can halt the progression of fibrosis once it has been initiated, and / or 3) to test whether they can reverse a fibrotic state once it has been initiated.

[0269] In certain embodiments, a fibrotic condition is provided in a tissue (e.g., bile duct tissue, liver tissue, lung tissue, heart tissue, kidney tissue, skin tissue, intestinal tissue, or nervous tissue). In certain embodiments, the tissue is bile duct tissue. In certain embodiments, the tissue is liver tissue. In certain embodiments, the tissue is lung tissue. In certain embodiments, the tissue is cardiac tissue. In certain embodiments, the tissue is kidney tissue. In certain embodiments, the tissue is skin tissue. In certain embodiments, the tissue is intestinal tissue. In certain embodiments, the tissue is bone marrow tissue. In certain embodiments, the tissue is epithelial tissue. In certain embodiments, the tissue is nervous tissue.

[0270] Compositions for and uses of the carboranes and carborane analogs described herein are provided, alone or in combination with another agent, for use in reducing fibrosis or for the preparation of one or more medicaments for the treatment of a fibrotic condition.

[0271] The examples examine the in vivo efficacy of compound 25 for the treatment of NASH. [ka] Nonalcoholic steatohepatitis (NASH) is increasingly recognized as the most prevalent chronic liver disease worldwide and an important precursor condition to hepatocellular carcinoma (J.Gastroenterol.(2018)53:362-376). With effective hepatitis B and C treatment and vaccination programs, respectively, in place, it is hoped that NASH-mediated HCC will soon overcome all other known causes of HCC (Cell.Metab.2019 Jan 8;29(1):18-26). NASH prevalence is thought to be approaching 40% of obese adults, with overall incidence rising in tandem with the expanding obesity epidemic, representing one of the unmet medical needs in medicine. To date, there are no effective FDA-approved treatments that address hepatic steatosis, subsequent inflammation, and resultant liver fibrosis associated with NASH. However, anti-NASH therapy remains an intense focus for the pharmaceutical industry (J Gastroenterol (2018) 53: 362-376).

[0272] Like other liver pathologies, fatty liver disease shows a higher prevalence in men than women, even when controlled for known risk factors (Adv Ther. 2017 Jun;34(6):1291-1326.). This dimorphism suggests an important role for sex hormone signaling, such that male hormones may reasonably be hypothesized to support the development of NASH, whereas female hormones are expected to play a protective role. Several lines of evidence suggest that exogenous estrogen administration can attenuate fat accumulation and adverse metabolic changes associated with a high-fat diet (FASEB J. 2017 Jan;31(1):266-281.; Mol Cell Endocrinol. 2019 Jan 5;479:147-158.), reverse fatty liver disease associated with a high-fat diet (Exp Biol Med(Maywood). 2017 Mar;242(6):606-616, Mol Med Rep. 2016 Jul;14(1):425-31.), and prevent both high-fat diet-related fibrosis (Exp Biol Med(Maywood). 2017 Mar;242(6):606-616) or other liver injury (World J Gastroenterol. 2002 Oct;8(5):883-7.; J Gastroenterol Hepatol. 2018 Mar;33(3):747-755). Overall, these data highlight multiple potentially beneficial mechanisms of therapeutic estrogen administration in NASH. However, there are no limitations to the administration of pure, potent estrogens.

[0273] Therapeutic administration of steroidal endogenous estrogen is associated with, but not limited to, very low drug-like properties, metabolic interconversion with other undesirable hormones, and significant undesirable estrogenic side effects.For example, the recognized controversy in administering strong exogenous estrogen is accompanied by the fear of stimulating nascent breast cancer in postmenopausal women with NASH, which has been presented as a challenge by the Women's Health Initiative (J Steroid Biochem Mol Biol.2014 Jul;142:4-11.).Similarly, in female patients, exogenous estrogen administration is associated with the risk of serious deep vein thrombosis, which appears when DES is given as prostate cancer treatment (Urology.2001 Aug;58(2 Suppl 1):108-13.).

[0274] The early described selective estrogen receptor modulators (SERMS) revealed that the pharmacology of desirable estrogens can be separate from that of undesirable estrogens (Curr Clin Pharmacol. 2013 May; 8(2): 135-55.). Estrogen pharmacology was further advanced by the characterization of the ERβ isoform, the receptor originally described for endogenous estrogens, which exhibits additional and highly relevant differential tissue distribution and biology compared to ERα (Proc Natl Acad Sci USA 93: 5925-5930). As ERβ biology has become increasingly well characterized, there has been great interest in developing therapeutic estrogens that selectively target ERβ over ERα as well as other closely related nuclear hormone receptors to achieve this (Expert Opin Ther Pat. 2010 Apr; 20(4): 507-34.). One such ligand, compound 25, is a carborane-based highly ERβ selective SERM.

[0275] It was hypothesized that compound 25 may provide anti-NASH efficacy through its combined anti-metabolic, anti-steatotic, and anti-fibrotic effects. To test this hypothesis, compound 25 was administered once daily at two dose levels by oral gavage to male STAM model mice (Cell Metab. 2019 Jan 8;29(1):18-26,slide #2). STAM mice were given pharmacological beta cell dysfunction to mimic type 1 diabetes and then fed a 67% fat diet to recapitulate NASH progression. Mice treated for 7 weeks during the fatty liver phase tolerated both dose levels fairly well. Both the 10 and 100mpk dose levels of compound 25 were associated with prevention of plasma ALT and hepatic triglyceride levels suggestive of disease progression, suggesting that compound 25 may prevent hepatocyte necrosis and hepatic lipid accumulation. Notably, this efficacy is comparable to that of FGF21 mimetics currently being developed by Bristol Meyer Squibb (BMS). Critically, administration of 100 mpk of compound 25 was also associated with a significant reduction in liver fibrosis as measured by collagen staining (Sirius Red). The magnitude of this antifibrotic effect is similar to that reported in the same model for an FXR agonist in clinical development by Novartis (LJN452) and a BMS FGF21 mimetic.

[0276] Because this is the first demonstration of efficacy of an ERβ ligand in the STAM model, these findings hold considerable promise for combinations of compound 25 (or other carborane-based or carborane analog SERMS) with other anti-NASH agents, including, but not limited to, SGLT inhibitors, PPARα / γ / δ agonists, ACC inhibitors, FXR ligands, FGF-19 and FGF-21 or mimetics, GLP-1R inhibitors, LOXL-2 inhibitors, Galectin-3 inhibitors, HSP-47 inhibitors, ASK-1 inhibitors, VAP-1 inhibitors, SCD inhibitors, CCR2 / 5 antagonists, and caspase inhibitors (J Gastroenterol (2018) 53:362-376).

[0277] Similarly, because this is the first demonstration of an antifibrotic effect of a carborane-based SERM, these findings suggest that compound 25 (or other carborane-based or carborane analog SERMS) may be broadly effective in many fibrotic diseases, including but not limited to IPF, calcineurin-induced renal fibrosis, renal fibrotic NOS, myocardial fibrosis associated with chronic heart failure (CHF), fibrosis associated with post-MI cardiac remodeling, Dupuytren's contracture, fibrosis associated with RA, pulmonary fibrosis (viral, alcohol-dependent, unidentified cause), Peyronie's disease, keloid scars or other scars (post-surgical, etc.).

[0278] Also provided herein is a method for treating, preventing, or ameliorating cancer in a subject. The method comprises administering to the subject a therapeutically effective amount of one or more of the compounds or compositions disclosed herein, or pharma- ceutically acceptable salts thereof. The compounds and compositions described herein, or their pharma- ceutically acceptable salts, are useful for treating cancer in humans, e.g., pediatric and geriatric populations, and in animals, e.g., veterinary applications. The disclosed method can optionally include identifying a patient who is in need of or may be in need of cancer treatment. Examples of types of cancer that can be treated with the compounds and compositions described herein include bladder cancer, brain cancer, breast cancer, colon cancer, cervical cancer, gastrointestinal cancer, genitourinary cancer, head and neck cancer, lung cancer, ovarian cancer, pancreatic cancer, prostate cancer, kidney cancer, skin cancer, and testicular cancer. Further examples include cancers and / or tumors of the anus, bile duct, bone, bone marrow, intestine (including colon and rectum), eye, gallbladder, kidney, mouth, larynx, esophagus, stomach, testis, cervix, mesothelial, neuroendocrine, penis, skin, spinal cord, thyroid, vagina, vulva, uterus, liver, muscle, blood (including lymphocytes and immune system cells). Further examples of cancers treatable by the compounds and compositions described herein include cell carcinoma, Kaposi's sarcoma, melanoma, mesothelioma, soft tissue sarcoma, pancreatic cancer, lung cancer, leukemia (such as acute lymphocytic leukemia, acute myeloid leukemia, chronic lymphocytic leukemia, chronic myeloid leukemia), and lymphoma (Hodgkin's lymphoma and non-Hodgkin's lymphoma), and multiple myeloma. In some embodiments, the cancer may be selected from the group consisting of breast cancer, colon cancer, and prostate cancer.

[0279] The cancer treatment or prevention method disclosed herein may further include treatment with one or more additional drugs (e.g., anticancer drugs or ionizing radiation). One or more additional drugs and the compounds and compositions described herein or pharmaceutically acceptable salts thereof may be administered in any order, including simultaneous administration and time-spaced orders up to several days apart. The method may also include more than a single administration of one or more additional drugs and / or the compounds and compositions described herein or pharmaceutically acceptable salts thereof. The administration of one or more additional drugs and the compounds and compositions described herein or pharmaceutically acceptable salts thereof may be by the same or different routes. When treated with one or more additional drugs, the compounds and compositions described herein or pharmaceutically acceptable salts thereof may be combined into a pharmaceutical composition comprising one or more additional drugs.

[0280] For example, the compounds and compositions described herein, or pharma- ceutically acceptable salts thereof, can be used in combination with other agents, such as, for example, 13-cis-retinoic acid, 2-amino-6-mercaptopurine, 2-CdA, 2-chlorodeoxyadenosine, 5-fluorouracil, 6-thioguanine, 6-mercaptopurine, Accutane, actinomycin D, adriamycin, adrsil, Agrylin, Ala-Cort, aldesleukin, alemtuzumab, alitretinoin, Alkaban-AQ, Alkeran, all-trans retinoic acid, alpha interferon, Altretamine, Amethopterin, Amifostine, Aminoglutethimide, Anagrelide, Anandron, Anastrozole, Arabinosylcytosine, Aranesp, Aredia, Arimidex, Aromasin, Arsenic Trioxide, Asparaginase, ATRA, Avastin, BCG, BCNU, Bevacizumab, Bexarotene, Bicalutamide, BiCNU, Blenoxane, Bleomycin, Bortezomib, Busulfan, Busulfex, C225, Calcium Leucovorin, Campath, Camptosar, Camptothecin- 11, Capecitabine, Carac, Carboplatin, Carmustine, Carmustine Wafer, Casodex, CCNU, CDDP, CeeNU, Cervizin, Cetuximab, Chlorabcil, Cisplatin, Citrovorum Factor, Cladribine, Cortisone, Cosmegen, CPT-11, Cyclophosphamide, Cytadren, Cytarabine, Cytarabine Liposomal, Cytosal-U, Cytoxan, Dacarbazine, Dactinomycin, Darbepoetin alfa, Daunomycin, Daunorubicin, Daunorubicin Hydrochloride, Daunorubicin Liposomal, Daunoxome , Decadron, Delta-Cortef, Deltason, Denileukin diftitox, Depocyte, Dexamethasone, Dexamethasone acetate, Dexamethasone sodium phosphate, Dexasone, Dexrazoxane, DHAD, DIC, Geodex, Docetaxel, Doxy, Doxorubicin, Doxorubicin liposome, Droxy, DTIC, DTIC-Dome, Duralon, Efdex, Eligard, Elence, Eloxatin, Elspar, Emcyte, Epirubicin, Epoetin alfa, Erbitux, Erwinia L-asparaginase, Estramustine,Ethiol, Etopophos, Etoposide, Etoposide phosphate, Eurexin, Evista, Exemestane, Fareston, Faslodex, Femara, Filgrastim, Floxuridine, Fludara, Fludarabine, Fluoroplex, Fluorouracil, Fluorouracil (cream), Fluoxymesterone, Flutamide, Folinic acid, FUDR, Fluvestant, G-CSF, Gefitinib, Gemcitabine, Gemtuzumab-o Zogamicin, Gemzar, Gleevec, Lupron, Lupron Depot, Matulan, Maxidex, Mechlorethamine, -Mechlorethamine Hydrochloride, Medralon, Medrol, Megase, Megesterol, Megesterol Acetate, Melphalan, Mercaptopurine, Mesna, Methnex, Methotrexate, Methotrexate Sodium, Methylprenisolone, Milocel, Letrozole, Neosar, Neulasta, Neumega, Neupogen, Ni Landron, Nilutamide, Nitrogen Mustard, Novardex, Novantrone, Octreotide, Octreotide Acetate, Oncospar, Oncovin, Ontac, Onxal, Oplevukin, Orapred, Orason, Oxaliplatin, Paclitaxel, Pamidronate, Panretin, Paraplatin, Peziapred, PEG-Interferon, Pegaspargase, Pegfilgrastim, Peg-Intron, PEG-L-Asparaginase, Phenylalanine Mustard, Platinol, Platinol-AQ, Prenisolone, Prenison, Prelon, Procarbazine, PROCRIT, Proleukin, Prolife Prospan 20 with Camstin Implant, Prinetol, Raloxifene, Rheumatrex, Rituxan, Rituximab, Roveron-A (Interferon alpha-2a), Rubex, Rubidomycin Hydrochloride, Sandostatin, Sandostatin LAR, Sargramostim, Solu-Cortef, Solu-Medrol, STI-571, Streptozocin, Tamoxifen, Targretin, Taxol, Taxotere, Temodar, Temozolomide, Teniposide, TESPA, Thalidomide, Thalomid, TheraCys, Thioguanine, Thioguanine Tabloid, Thiophosphoamide, Thioplex, Thiotepa, TICE, Toposar, Topotecan, Toremifene,Trastuzumab, tretinoin, Trexal, Trisenox, TSPA, VCR, Velban, Velcade, Bepesid, Besanoid, Viadur, Vinblastine, Vinblastine sulfate, Vincersar Pfs, Vincristine, Vinorelbine, Vinorelbine tartrate, VLB, VP-16, Bumon, Xeloda, Zanosar, Zevalin, Zenecard, Zoladex, Zoledronic acid, Zometa, Gliadelwafer, Glivec, GM-CSF, Goserelin, Granulocyte colony-stimulating factor, Halotestin, Herceptin, Hexadrol, Hexalen, Hexamethylmelanin, HMM, Hycamtin, Hydrea, Hydrocort Acetate, Hydrocortisone, Hydrocortisone Sodium Phosphate, Hydrocortisone Sodium Succinate, Hydrocortisone Phosphatase, Hydroxyurea, Ibritumomab, Ibritumomab Tiuxetan, Idamycin, Idarubicin, Ifex, IFN-α, Ifosfamide, IL 2, IL-11, Imatinib Mesylate, Imidazole Carboxamide, Interferon α, Interferon α-2b (PEG conjugate), Interleukin 2, Interleukin-11, Intron A (Interferon α-2b), Leucovorin, Leukeran, Leukin, Leuprolide, Leulocristin, Leustatin, Liposomal Ara-C, Liquid Additional anti-cancer drugs may be combined in the pharmaceutical composition, such as Pred, lomustine, L-PAM, L-sarcolysin, methycortene, mitomycin, mitomycin-C, mitoxantrone, M-prenisol, MTC, MTX, mustalgen, mustine, mutamycin, myleran, Iressa, irinotecan, isotretinoin, quidrolase, lanacort, L-asparaginase, and LCR. Additional anti-cancer drugs also include biologics, such as, for example, antibodies.

[0281] Many tumors and cancers have viral genomes present in the tumor or cancer cells. For example, Epstein-Barr Virus (EBV) is associated with many mammalian malignancies. The compounds described herein can also be used alone or in anti-cancer or anti-viral agents, such as ganciclovir, azidothymidine (AZT), lamivudine (3TC), etc., to treat patients infected with viruses that can result in cell transformation and / or to treat patients with tumors or cancers associated with the presence of viral genomes in cells. The compounds described herein can also be used in virus-based treatments of oncological diseases.

[0282] Also provided is a method of suppressing tumors in a subject. The method includes contacting at least a portion of the tumor with a therapeutically effective amount of a compound or composition described herein, and optionally includes irradiating at least a portion of the tumor with a therapeutically effective amount of ionizing radiation. As used herein, the term ionizing radiation refers to radiation that includes particles or photons that have or can generate sufficient energy through nuclear interactions to generate ionization. One example of ionizing radiation is an x-ray. The term therapeutically effective amount of ionizing radiation refers to a dose of ionizing radiation that, when administered in combination with a compound described herein, results in increased cell damage or death. The ionizing radiation is delivered according to methods known in the art, including radiolabeled antibodies and radioisotopes.

[0283] Also disclosed herein is a method of treating an inflammatory disease in a subject. The method may comprise administering to the subject a therapeutically effective amount of a compound or composition disclosed herein. Inflammatory diseases include, but are not limited to, acne vulgaris, ankylosing spondylitis, asthma, autoimmune diseases, celiac disease, chronic prostatitis, Crohn's disease, glomerulonephritis, hidradenitis suppurativa, inflammatory bowel disease, pelvic inflammatory disease, psoriasis, reperfusion injury, rheumatoid arthritis, sarcoidosis, vasculitis, interstitial cystitis, type 1 hypersensitivity, systemic sclerosis, dermatomyositis, polymyositis, and inclusion body myositis. In some embodiments, the inflammatory disease is selected from the group consisting of arthritis and inflammatory bowel disease.

[0284] The method of treating inflammatory disease described herein may further include treatment with one or more additional agents (e.g., anti-inflammatory drugs). One or more additional agents and the compounds and compositions described herein or pharma- ceutically acceptable salts thereof may be administered in any order, including simultaneous administration and time-spaced orders up to several days apart. The method may also include more than a single administration of one or more additional agents and / or the compounds and compositions described herein or pharma- ceutically acceptable salts thereof. The administration of one or more additional agents and the compounds and compositions described herein or pharma- ceutically acceptable salts thereof may be by the same or different routes. When treated with one or more additional agents, the compounds and compositions described herein or pharma- ceutically acceptable salts thereof may be combined into a pharmaceutical composition comprising one or more additional agents.

[0285] Also disclosed herein is a method of treating a neurodegenerative disease in a subject. The method may include administering to the subject a therapeutically effective amount of a compound or composition disclosed herein. Neurodegenerative diseases include, but are not limited to, Alzheimer's disease, amyotrophic lateral sclerosis (ALS), Alper's disease, Batten disease, Benson syndrome, cerebro-oculo-facial-skeletal (COFS) syndrome, corticobasal degeneration, Creutzfeldt-Jakob disease, dementia, Friedreich ataxia, Gerstmann-Straussler-Scheinker syndrome, Huntington's disease, Lewy body syndrome, Leigh's disease, lumbar spondylolysis, motor neuron disease, multiple system atrophy, opsoclonus-myoclonus ataxia, progressive multifocal leukoencephalopathy, Parkinson's disease, prion disease, primary progressive aphasia, progressive supranuclear palsy, spinocerebellar ataxia, spinal muscular atrophy, kuru, and Shy-Drager syndrome.

[0286] Also disclosed herein is a method of treating a psychotropic disorder in a subject. The method may comprise administering to the subject a therapeutically effective amount of a compound or composition disclosed herein. Psychotropic disorders include, but are not limited to, attention deficit disorder (ADD), attention deficit hyperactivity disorder (ADHD), anorexia nervosa, anxiety, bipolar disorder, bulimia, depression, insomnia, neuropathic pain, mania, obsessive-compulsive disorder (OCD), panic disorder, premenstrual dysphoric disorder (PMDD), mood disorder, serotonin syndrome, schizophrenia, and seasonal affective disorder.

[0287] The compounds described herein may also be used to treat other ERβ-related (ERβ-mediated) diseases, including cardiovascular disease (e.g., heart attack, heart failure, ischemic stroke, arrhythmias), benign prostatic hyperplasia, and osteoporosis.

[0288] Also disclosed herein is a method of imaging a cell or population of cells expressing ERβ in or around a subject. The method includes administering to the subject an amount of a compound or composition described herein and detecting the compound or composition. The detecting can include methods well known in the art, such as positron emission tomography (PET), single photon emission computed tomography (SPECT), magnetic resonance imaging (MRI), x-ray, microscopy, computed tomography (CT). In some embodiments, the compound or composition can further include a detectable label, such as a radiolabel, a fluorescent label, an enzyme label, etc. In some embodiments, the detectable label can be: 10 The imaging method may include a radiolabel, such as B. Such imaging methods may be used, for example, to assess the extent of disease and / or the targeting of therapeutic agents.

[0289] The methods and compounds described herein are useful for both preventive and therapeutic treatments. As described herein, the term treating or treatment includes prevention, delay of onset, reduction, eradication, or delay of worsening of signs or symptoms after onset, and prevention of recurrence. For prophylactic use, a therapeutically effective amount of the compounds and compositions described herein or pharmaceutically acceptable salts thereof is administered to a subject before onset, during early onset (e.g., at the first signs and symptoms of a disease or disorder), or after established development of a disease or disorder. Prophylactic administration can occur days to years before the manifestation of symptoms of a disease or disorder. Therapeutic treatment includes administering to a subject a therapeutically effective amount of the compounds and compositions described herein or pharmaceutically acceptable salts thereof after a disease or disorder is diagnosed.

[0290] Compounds, Formulations and Methods of Administration The application of the disclosed compounds and compositions containing them to the living body can be achieved by any suitable method and technique known to those skilled in the art now or in the future.For example, the disclosed compounds can be formulated in a physiologically or pharmaceutically acceptable form and can be administered by any suitable route known in the art, including, for example, oral, nasal, rectal, topical and parenteral routes of administration.As used herein, the term parenteral includes, for example, subcutaneous, intradermal, intravenous, intramuscular, intraperitoneal and intrasternal administration by injection.The administration of the disclosed compounds or compositions can be a single administration, or continuous or at separate intervals, as can be easily determined by those skilled in the art.

[0291] The compounds disclosed herein and compositions containing them can also be administered using liposome technology, sustained release capsules, implantable pumps, and biodegradable containers.These delivery methods can advantageously provide a uniform dosage over a long period of time.The compounds can also be administered in their salt derivative form or crystalline form.

[0292] The compounds disclosed herein can be formulated by known methods for preparing pharma-ceutically acceptable compositions. Formulations are described in detail in many sources known and readily available to those skilled in the art. For example, Remington's Pharmaceutical Science by EW Martin (1995) describes formulations that can be used in the disclosed methods. In general, the compounds disclosed herein can be formulated so that an effective amount of the compound is combined with a suitable excipient to aid in the effective administration of the compound. The compositions used can also be in various forms. These include solid, semi-solid, and liquid dosage forms, such as tablets, pills, powders, liquid solutions or suspensions, suppositories, injectable and infusible solutions, and sprays. The preferred form depends on the intended method of administration and therapeutic application. The compositions also preferably include conventional pharma-ceutically acceptable carriers and diluents well known to those skilled in the art. Examples of carriers or diluents for use with the compounds include ethanol, dimethyl sulfoxide, glycerol, alumina, starch, saline, and equivalent carriers and diluents. To provide for administration of such dosages for the desired therapeutic treatment, the compositions disclosed herein may advantageously contain from about 0.1% to 100% by weight of the total of one or more subject compounds, based on the weight of the total composition including any carrier or diluent.

[0293] Preparations suitable for administration include, for example, aqueous sterile injection solutions, which may contain antioxidants, buffers, bacterial growth inhibitors, and solutes that render the preparation isotonic with the blood of the intended recipient; and aqueous and non-aqueous sterile suspensions, which include suspending agents and thickening agents. Preparations can be provided in unit-dose or multi-dose containers, for example sealed ampoules and vials, and can be stored in the form of a sterile liquid carrier, for example, lyophilized (freeze-dried) condition, requiring only water for injection before use. Extemporaneous injection solutions and suspensions can be prepared from sterile powders, granules, tablets, etc. In addition to the excipients that are partly mentioned above, it is understood that the compositions disclosed herein may contain other agents that are conventional in the art for the type of formulation discussed.

[0294] The compounds disclosed herein and compositions comprising them can be delivered to cells via direct contact with cells or via carrier means.Carrier means for delivering compounds and compositions to cells are well known in the art, including, for example, encapsulating the composition in liposome moieties.Other means for delivering the compounds and compositions disclosed herein to cells include attaching the compounds to proteins or nucleic acids that are targeted for delivery to the target cells.US Patent 6,960,648 and US Patent Publication Nos. 2003 / 0032594 and 2002 / 0120100 disclose amino acid sequences that can be linked to another composition and then allow the composition to move across biological membranes.US Patent Publication No. 20020035243 also describes compositions for transporting biological moieties across cell membranes for intracellular delivery. The compounds can also be incorporated into polymers, examples of which include poly(DL lactide-co-glycolide) polymers for intracranial tumors; poly[bis(p-carboxyphenoxy)propane:sebacic acid], molar ratio 20:80 (as used in GLIADEL); chondroitin; chitin; and chitosan.

[0295] For the treatment of oncological disorders, the compounds described herein can be administered to patients in need of treatment in combination with other antitumor or anticancer substances and / or radiation and / or photodynamic therapy and / or surgical treatment to remove tumors. These other substances or treatments can be given at the same or different times as the compounds disclosed herein. For example, the compounds disclosed herein can be used in combination with mitotic inhibitors such as taxol or vinblastine, alkylating agents such as cyclophosphamide or ifosfamide, metabolic antimetabolites such as 5-fluorouracil or hydroxyurea, DNA interveners such as adriamycin or bleomycin, topoisomerase inhibitors such as etoposide or camptothecin, antiangiogenic agents such as angiostatin, antiestrogens such as tamoxifen, other anticancer agents or antibodies such as GLEEVEC (Novartis Pharmaceuticals Corporation) and HERCEPTIN (Genentech, Inc.), respectively, or immunotherapies such as ipilimumab and bortezomib.

[0296] In certain examples, the compounds and compositions described herein may be administered locally to one or more anatomical sites, for example, at the site of unwanted cell proliferation (e.g., at the site of a tumor or benign skin tumor, injected or applied topically to a tumor or skin tumor, etc.), optionally in combination with a pharma- ceutically acceptable carrier, such as an inert diluent. The compounds and compositions disclosed herein may be administered systemically, for example, intravenously or orally, optionally in combination with a pharma- ceutically acceptable carrier, such as an inert diluent, an absorbable edible carrier for oral delivery. They may be enclosed in hard or soft shell gelatin capsules, compressed into tablets, or directly incorporated into the food of the patient's diet. For oral therapeutic administration, the active compounds may be combined with one or more excipients and used in the form of ingestible tablets, buccal tablets, troches, capsules, elixirs, suspensions, syrups, wafers, aerosol sprays, and the like.

[0297] Tablets, troches, pills, capsules, etc. may also contain binders such as gum tragacanth, acacia, corn starch, or gelatin; diluents such as dicalcium phosphate; lubricants such as magnesium stearate; and sweeteners such as sucrose, fructose, lactose, or aspartame, or flavorings such as peppermint, oil of wintergreen, or cherry flavoring may be added. When the unit dosage form is a capsule, it may contain a liquid carrier, such as vegetable oil or polyethylene glycol, in addition to the above-mentioned types of materials. Various other materials may be present as coatings or to otherwise modify the physical form of the solid unit dosage form. For example, tablets, pills, or capsules may be coated with gelatin, wax, shellac, sugar, etc. Syrup or elixir may contain the active compound, sucrose or fructose as a sweetener, methyl and propylparabens as preservatives, a dye and flavoring agent such as cherry or orange flavoring. Of course, any material used in any unit dosage form should be pharma- ceutically acceptable and substantially non-toxic in the amounts employed.In addition, the active compounds may be incorporated into sustained-release preparations and devices.

[0298] The compounds and compositions disclosed herein, including their pharmaceutically acceptable salts or prodrugs, can be administered intravenously, intramuscularly, or intraperitoneally by infusion or injection.The solution of the active agent or its salt can be prepared in water, optionally mixed with non-toxic surfactant.Dispersions can also be prepared in glycerol, liquid polyethylene glycol, triacetin, and mixtures thereof, and in oil.Under normal storage and use conditions, these preparations can contain preservatives to prevent the growth of microorganisms.

[0299] The dosage forms of the pharmaceutical suitable for injection or infusion include sterile aqueous solutions or dispersions or sterile powders containing the active ingredient, which are suitable for the extemporaneous preparation of sterile injectable or infusible solutions or dispersions, optionally encapsulated in liposomes. The final dosage form must be sterile, fluid, and stable under the conditions of manufacture and storage. The liquid carrier or vehicle can be, for example, a solvent or liquid dispersion medium, including water, ethanol, polyol (for example, glycerol, propylene glycol, liquid polyethylene glycol, etc.), vegetable oils, non-toxic glyceryl esters, and suitable mixtures thereof. The appropriate fluidity can be maintained, for example, by the formation of liposomes, by the maintenance of the required particle size in the case of dispersions, or by the use of surfactants. If necessary, the prevention of microbial activity can be brought about by various other antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, sorbic acid, thimerosal, etc. In many cases, it is preferable to include an isotonic agent, for example, sugar, buffer solution, or sodium chloride. Prolonged absorption of the injectable compositions can be brought about by the inclusion of agents which delay absorption, for example, aluminum monostearate and gelatin.

[0300] Sterile injectable solutions are prepared by incorporating the compounds and / or agents disclosed herein in the required amount in a suitable solvent with various other ingredients listed above, followed by filter sterilization as required. In the case of sterile powders for the preparation of sterile injectable solutions, the preferred preparation method is vacuum drying and freeze-drying technology, which yields a powder of the active ingredient and any additional desired ingredients present in the previously sterile-filtered solution.

[0301] For topical administration, the compounds and agents described herein may be applied as liquids or solids. However, it is generally desirable to combine them with a dermatologically acceptable carrier, which may be solid or liquid, and administer them locally to the skin as a composition. The compounds and agents and compositions disclosed herein may be applied locally to the skin of a subject to reduce the size (and may include complete removal) of malignant or benign growths and treat the site of infection. The compounds and agents disclosed herein may be applied directly to the site of growth or infection. Preferably, the compounds and agents are applied to the site of growth or infection in a formulation such as an ointment, cream, lotion, solution, tincture, etc.

[0302] Useful solid carriers include finely divided solids such as talc, clay, crystalline cellulose, silica, alumina, etc. Useful liquid carriers include water, alcohol or glycol or water-alcohol / glycol mixtures, in which the compound can be dissolved or dispersed at effective levels, optionally with the aid of non-toxic surfactants. Adjuvants such as fragrances and additional antibacterial agents can be added to optimize the properties for a given use. The resulting liquid composition can be applied from absorbent pads, used to impregnate bandages and other dressings, and sprayed onto the affected area using, for example, pump-type or aerosol sprays.

[0303] Thickening agents such as synthetic polymers, fatty acids, fatty acid salts and esters, fatty alcohols, modified cellulose, or modified mineral materials may also be used with liquid carriers to form spreadable pastes, gels, ointments, soaps, and the like, for application directly to the user's skin.

[0304] Useful dosages of the compounds and agents and pharmaceutical compositions disclosed herein can be determined by comparing their in vitro activity, and in vivo activity in animal models. Methods for the extrapolation of effective dosages in mice, and other animals, to humans are well known in the art.

[0305] The dosage range for administration of the composition is large enough to produce the desired effect that the symptom or disorder is affected. The dosage should not be so large as to cause adverse side effects, such as undesirable cross-reactions, anaphylactic reactions, etc. In general, the dosage varies according to the age, condition, sex and degree of disease of the patient, and can be determined by those skilled in the art. The dosage can be adjusted by the individual physician in the event of any contraindications. The dosage can vary and can be administered in one or multiple administrations daily, for one or several days.

[0306] Also disclosed are pharmaceutical compositions comprising the compounds disclosed herein in combination with pharma- ceutically acceptable excipients. Pharmaceutical compositions suitable for oral, topical or parenteral administration contain the amount of the compounds constituting preferred embodiments. The dose administered to a patient, particularly a human, must be sufficient to achieve a therapeutic effect in the patient over a reasonable time frame without lethal toxicity, and preferably without causing more than acceptable levels of side effects or morbidity. Those skilled in the art will recognize that the dose depends on a variety of factors, including the subject's condition (health), the subject's weight, the type of concomitant treatment, if any, frequency of treatment, therapeutic ratio, and the severity and stage of pathological symptoms.

[0307] Also disclosed are kits comprising the compounds disclosed herein in one or more containers. The disclosed kits may optionally comprise a pharma- ceutically acceptable carrier and / or diluent. In one embodiment, the kit comprises one or more other components, additives, or adjuvants as described herein. In another embodiment, the kit comprises one or more anti-cancer agents, e.g., agents described herein. In one embodiment, the kit comprises instructions or packaging materials that describe how to administer the compounds or compositions of the kit. The containers of the kit can be of any suitable material, e.g., glass, plastic, metal, etc., and of any suitable size, shape, or configuration. In one embodiment, the compounds and / or agents disclosed herein are provided in the kit as solids, e.g., tablets, pills, or powder forms. In another embodiment, the compounds and / or agents disclosed herein are provided in the kit as liquids or solutions. In one embodiment, the kit comprises an ampoule or syringe that comprises the compounds and / or agents disclosed herein in liquid or solution form.

[0308] Although several embodiments of the invention have been described, it will be understood that various modifications may be made without departing from the spirit and scope of the invention. Accordingly, other embodiments are within the scope of the following claims. EXAMPLES

[0309] The following examples are described to illustrate the methods and results according to the disclosed subject matter. These examples are not intended to be exhaustive of all aspects of the subject matter disclosed herein, but are instead intended to illustrate representative methods and results. These examples are not intended to exclude equivalents and variations that are obvious to those skilled in the art.

[0310] Efforts have been made to ensure accuracy with respect to numbers (e.g., amounts, temperatures, etc.), but some errors and deviations should be accounted for. Unless otherwise indicated, parts are parts by weight, temperature is °C or is ambient, and pressure is at or near atmospheric. There are many variations and combinations of reaction conditions, e.g., component concentrations, temperatures, pressures, and other reaction ranges and conditions, that can be used to optimize product purity and yields obtained from the described processes. Only reasonable and routine experimentation is required to optimize such process conditions.

[0311] 1 H- and 13 C-NMR spectra were recorded using a Bruker AVIII400HD NMR spectrometer or a Bruker DRX400 NMR spectrometer at The Ohio State University College of Pharmacy, or a Bruker Ascend 700 MHz NMR at The Ohio State University Campus Chemical Instrumentation Center. Chemical shifts (δ) are reported in ppm from internally deuterated chloroform and deuterated acetone. Coupling constants are reported in Hz. 13C NMR spectra are fully resolved. NMR spectra were analyzed on a Mnova Lite SE (Mestrelab Research, Bajo, Spain). Melting points were obtained on a Thomas Hoover "UNI-MELT" capillary melting point apparatus. Optical rotations were measured on a JASCO J-810 mass spectrometer. High-precision and high-resolution mass spectra were obtained by the Ohio State University Campus Chemical Instrumentation Center using a Waters Micromass LCT mass spectrometer or a Waters Micromass Q-TOF II mass spectrometer, by The Ohio State University College of Pharmacy using a Waters Micromass Q-TOF micro mass spectrometer or a Thermo LTQ Orbitrap mass spectrometer, or by The University of Illinois Urbana-Champaign Mass Spectrometry Laboratory using a Waters Micromass 70-VSE mass spectrometer. For all carborane-containing compounds, the determined mass corresponding to the most intense peak of the theoretical isotopic pattern was reported. The measured patterns were consistent with the calculated patterns.

[0312] Silica gel 60 (0.063-0.200 mm) was used for gravity column chromatography. Reagent solvents were used for silica gel column chromatography. Glass-backed TLC plates precoated with silica gel 60 F254 (0.25-mm layer thickness) from Dynamic Adsorbents (Norcross, GA) were used for TLC. Visualization of general compounds for TLC was achieved by UV light. Carborane-containing compounds were selectively visualized by spraying the plates with a PdCl2 (0.06%) / HCl (1%) solution and heating at 120 °C, which allowed the Pd 2+ From Pd 0Slow (15-45 s) formation of a gray spot occurred due to reduction to . Chiral analytical HPLC was performed using a Hitachi HPLC system (L-2130) with Windows-based data acquisition and a CHIRAL PAK® IB-3 column (250 x 4.6 mm, 3 μm particle size) from Chiral Technologies (PA USA) using a Hitachi Diode Array Detector (L-2455). HPLC grade solvents were used for HPLC.

[0313] Anhydrous solvents for reactions were purchased from Acros Organics (Morris Plains, NJ) or directly from Sigma Aldrich (Milwaukee, WI). Other solvents and chemicals were obtained from standard vendors. All reactions were carried out under an argon atmosphere unless otherwise stated.

[0314] Example 1 To a solution of 1-(4-methoxyphenyl)-1,12-dicarba-closo-dodecaborane (Endo Y et al. Chemistry & Biology, 2001, 8, 341-355) (500 mg, 2 mmol) in anhydrous dimethoxyethane (DME, 40 mL) was added n-butyllithium (1 mL, 2.5 mmol, 2.5 M solution in hexane) at 0°C. The reaction mixture was stirred at room temperature for 1.5 h. An amount of 0.49 mL (3.0 mmol) of 1-iodoheptane was added at 0°C. After stirring at room temperature for 4 h, the reaction mixture was carefully poured into 60 mL of HCl (1 M) and extracted with ethyl acetate. The organic phase was washed with 10% sodium thiosulfate solution and brine and dried over MgSO4. The solvent was evaporated and the residue was purified by silica gel column chromatography (hexane, Rf: 0.38) to give 550 mg (79%) of the product as a white solid having a melting point of 45-46°C. Scheme 1. Synthesis of 1-(4-methoxyphenyl)-12-heptyl-1,12-dicarba-closo-dodecaborane. [ka]

[0315] 1 H NMR(CDCl3):δ0.87(t,3H,CH3),1.08~1.28(m,10H,5×CH2),1.64(m,2H,C カルボラン -CH2),1.85~3.0(br.m,10H,BH),3.74(s,3H,OCH3),6.67(d,2H,aromatic,J=9.0Hz),7.11(d,2H,aromatic,J=9.0Hz). 13 C NMR(CDCl3):δ 14.21,22.73,29.02,29.24,29.67,31.82,38.05,55.39,80.92,113.36,128.49,128.97,159.61.Accurate mass HRMS(EI+):C 16 H 32 B 10 O(M) + Calculated m / z 348.3465, observed 348.3461.

[0316] Example 2 To a solution of 1-(4-methoxyphenyl)-1,12-dicarba-closo-dodecaborane (Endo Y et al. Chemistry & Biology, 2001, 8, 341-355) (500 mg, 10 mmol) in anhydrous dimethoxyethane DME (100 mL) was added n-butyllithium (4.8 mL, 12 mmol, 2.5 M solution in hexane) at 0°C. The reaction mixture was stirred at room temperature for 1.5 h. 1-heptanal in an amount of 1.83 mL (13 mmol) was added at 0°C. After stirring overnight at room temperature, the reaction mixture was carefully poured into 150 mL of HCl (1 M) and extracted with ethyl acetate. The organic phase was washed with brine and dried over MgSO4. The solvent was evaporated and the residue was purified by column chromatography (Hexane / EtOAc, 19 / 1, v / v, Rf: 0.43) to give 3.0 g (82%) of a white solid having a melting point of 45-46 °C. Scheme 2. Synthesis of (RS)-1-[1-(4-methoxyphenyl)-1,12-dicarba-closo-dodecaboran-12-yl]heptan-1-ol. [ka]

[0317] 1 H NMR(CDCl3):δ0.88(t,3H,CH3),1.15~1.30(m,8H,4×CH2),1.38~1.47(m,2H,CH2),1.59(br.s,1H,OH),1.85~3 .0(br.m,10H,BH),3.47(m,1H,CH),3.74(s,3H,OCH3),6.68(d,2H,aromatic,J=9.0Hz),7.12(d,2H,aromatic,J=9.0Hz). 13 C NMR(CDCl3): δ14.20,22.71,26.59,28.98,31.83,36.92,55.39,73.10,83.53,86.36,113.41,128.43,128.84,159.73.

[0318] Accurate mass HRMS(EI+):C 16 H 32 B 10 O2(M) + Calculated m / z 364.3414, observed 364.3423.

[0319] Example 3 For the synthesis of (RS)-1-[1-(4-methoxyphenyl)-1,12-dicarba-closo-dodecaborane-12-yl]butan-1-ol, the procedure and conditions described for the synthesis of (RS)-1-[1-(4-methoxyphenyl)-1,12-dicarba-closo-dodecaborane-12-yl]heptan-1-ol were applied using 500 mg (2 mmol) of 1-(4-methoxyphenyl)-1,12-dicarba-closo-dodecaborane (Endo Y et al. Chemistry & Biology, 2001, 8, 341-355) as starting material. Scheme 3. Synthesis of (RS)-1-[1-(4-methoxyphenyl)-1,12-dicarba-closo-dodecaboran-12-yl]butan-1-ol. [ka]

[0320] Yield: 500 mg (78%, white solid), R f : 0.33 (Hexane / EtOAc, 19 / 1, v / v), mp: 96-97°C. 1 H NMR(CDCl3):δ0.87(t,3H,CH3),1.16~1.27(m,4H,2 xCH2),1.35~1.39(m,2H,CH2),1.45~152(m,2H,CH2),1.59(br.s,1H,OH),1.85~3.0(br.m, 10H,BH),3.49(m,1H,CH),3.74(s,3H,OCH3),6.68(d,2H,aromatic,J=9.0Hz),7.12(d,2H,aromatic,J =9.0Hz). 13 C NMR(CDCl3):δ13.75,19.82,38.94,55.40,72.84,83.54,86.34,113.42,128.43,128.84,159.73.Accurate mass HRMS(EI+):C 13 H 26 B 10 O2(M) + Calculated m / z 322.2943, observed 322.2929.

[0321] Example 4 For the synthesis of (RS)-1-[1-(4-methoxyphenyl)-1,12-dicarba-closo-dodecaborane-12-yl]-6-methylheptan-1-ol, the procedure and conditions described for the synthesis of (RS)-1-[1-(4-methoxyphenyl)-1,12-dicarba-closo-dodecaborane-12-yl]heptan-1-ol were applied using 1 g (4 mmol) of 1-(4-methoxyphenyl)-1,12-dicarba-closo-dodecaborane (Endo Y et al. Chemistry & Biology, 2001, 8, 341-355) and 0.75 g (5.85 mmol) of 6-methylheptanal (Kuhnke J & Bohlman F., Tetrahedron Lett. 1985, 26, 3955-3958) as starting materials. Scheme 4: Synthesis of (RS)-1-[1-(4-methoxyphenyl)-1,12-dicarba-closo-dodecaboran-12-yl]-6-methylheptan-1-ol [ka]

[0322] Yield: 1.16 mg (77%, white solid), R f : 0.49 (Hexane / EtOAc, 19 / 1, v / v), mp: 95-96°C. 1 H NMR(CDCl3):δ0.85(s,3H,CH3),0.86(s,3H,CH3),1.11~1.28(m,6H,3xCH2),1.39~1.44(m,2H,CH2),1.47~1.53(m,1H,CH),1.45~152(m,2H,C H2),1.58(br.s,1H,OH),1.85~3.0(br.m,10H,BH),3.47(m,1H,CH),3.74(s,3H,OCH3),6.68(d,2H,aromatic,J=9.0Hz),7.12(d,2H,aromatic,J=9.0Hz). 13 C NMR (CDCl3): δ22.71,22.78,26.89,27.08,28.04,36.94,38.95,55.40,73.10,83.54,86.39,113.42,128.43,128.84,159.73. Accurate mass HRMS(EI+):C 17 H 34 B 10 O2(M) + Calculated m / z 378.3571, observed 378.3576.

[0323] Example 5 For the synthesis of (RS)-1-[1-(4-methoxyphenyl)-1,12-dicarba-closo-dodecaborane-12-yl]-3-phenylpropan-1-ol, the procedure and conditions described for the synthesis of (RS)-1-[1-(4-methoxyphenyl)-1,12-dicarba-closo-dodecaborane-12-yl]heptan-1-ol were applied using 250 mg (1 mmol) of 1-(4-methoxyphenyl)-1,12-dicarba-closo-dodecaborane (Endo Y et al. Chemistry & Biology, 2001, 8, 341-355) and 0.17 g (1.5 mmol) of 3-phenylheptanal as starting materials. Scheme 5: Synthesis of (RS)-1-[1-(4-methoxyphenyl)-1,12-dicarba-closo-dodecaboran-12-yl]-3-phenylpropan-1-ol [ka]

[0324] Yield: 344 mg (90%, white solid), R f : 0.27 (Hexane / EtOAc, 19 / 1, v / v), mp: 123-124°C. 1 H NMR(CDCl3):δ01.49~1.77(m,2H,CH2),1.69(br.s,1H,OH),1.85~3.0(br.m,10H,BH),2.51~2.83( m,2H,CH2),3.48(m,1H,CH),3.74(s,3H,OCH3),6.68(d,2H,aromatic,J=9.0Hz),7.11(d,2H,aromatic,J=9.0 Hz),7.14(d,2H,aromatic),7.20(t,1H,aromatic),7.28(t,2H,aromatic). 13 C NMR (CDCl3): δ32.69,38.29,55.39,72.31,83.64,86.02,113.42,126.19,128.41,128.52,128.61,128.77,141.15,159.74. Accurate mass HRMS(EI+):C 18 H 28 B 10 O2(M) +Calculated m / z 384.3102, observed 38.3101.

[0325] Example 6 For the synthesis of (RS)-(2,3-dihydro-1H-inden-5-yl)-[1-(4-methoxyphenyl)-1,12-dicarba-closo-dodecaborane-12-yl]methanol, the procedure and conditions described for the synthesis of (RS)-1-[1-(4-methoxyphenyl)-1,12-dicarba-closo-dodecaborane-12-yl]heptan-1-ol were applied using 450 mg (1.8 mmol) of 1-(4-methoxyphenyl)-1,12-dicarba-closo-dodecaborane (Endo Y et al. Chemistry & Biology, 2001, 8, 341-355) and 100 g (0.69 mmol) of 5-formylindane as starting materials. After the reaction, the excess 1-(4-methoxyphenyl)-1,12-dicarba-closo-dodecaborane was first recovered by column chromatography using only hexane. Scheme 6: Synthesis of (RS)-(2,3-dihydro-1H-inden-5-yl)-[1-(4-methoxyphenyl)-1,12-dicarba-closo-dodecaboran-12-yl]methanol [ka]

[0326] Yield: 240 mg (79%, white solid), Rf: 0.28 (Hexane / EtOAc, 19 / 1, v / v), mp: 123-124°C. 1 H NMR(CDCl3):δ1.85~3.0(br.m,10H,BH),2.06~2.10(m,3H,CH2,OH),2.89(m,4H,2xCH2),3.74(s,3H,OCH3),4.46(s, 1H,CH),6.66(d,2H,aromatic,J=9.0Hz),6.92(d,1H,aromatic),7.03(s,1H,aromatic),7.09(d,2H,aromatic,J=9.0Hz),7.15(d,2H,aromatic). 13C NMR(CDCl3):δ25.56,32.77,32.95,55.39,76.11,83.65,85.84,113.39,1 22.74,123.95,124.92,128.41,128.86,138.24,144.29,144.95,159.71. Accurate mass HRMS(EI+):C 19 H 28 B 10 O2(M) + Calculated m / z 396.3102, observed 396.3096.

[0327] Example 7 Pyridinium chlorochromate (PCC, 2.0 g, 9.34 mmol) was dispersed in anhydrous DCM (50 mL). (RS)-1-[1-(4-Methoxyphenyl)-1,12-dicarba-closo-dodecaboran-12-yl]heptan-1-ol (1.7 g, 4.67 mmol) solution in anhydrous DCM (15 mL) was then added to obtain a dark reaction mixture, which was stirred overnight at room temperature. Diethyl ether (60 mL) was added, followed by stirring for 1 h after molecular sieving. The supernatant was decanted and the insoluble residue was washed with dry ether (3x20 mL). The combined organic phase was passed through a short column of Florisil and then evaporated. The residue was purified by silica gel column chromatography (hexane, R f :0.13) to give 1.6 g (95%) of a white waxy solid which had a melting point of 36-37°C. Scheme 7. Synthesis of 1-[1-(4-methoxyphenyl)-1,12-dicarba-closo-dodecaboran-12-yl]heptan-1-one. [ka]

[0328] 11H NMR (CDCl3): δ 0.87 (t, 3H, CH3), 1.14~1.46 (m, 8H, 4×CH2), 1.85~3.0 (br.m, 10H, BH), 2.39 (m, 2H, C(O)-CH2), 3.74 (s, 3H, OCH3), 6.69 (d, 2H, aromatic, J = 9.0 Hz), 7.10 (d, 2H, aromatic, J = 8.9 Hz). 13 13C NMR (CDCl3): δ 14.14, 22.58, 23.60, 28.51, 31.60, 39.39, 55.41, 83.75, 85.64, 113.50, 128.28, 128.73, 159.92, 195.48. High resolution precision mass HRMS (EI+): C 16 H 30 B 10 O2 (M) + Calculated m / z 362.3257 for, measured value 362.3254.

[0329] Example 8 A solution of borane-tetrahydrofuran complex (16.5 mL, 16.5 mmol, 1.0 M) in THF was stabilized with 0.005 M N-isopropyl-N-methyl-tert-butylamine (NIMBA) followed by (S)-2-methyl-CBS-oxazaborolidine [(S)-MeCBS] (1.65 mL, 1.65 mmol, 1.0 M solution in toluene) and added to 15 mL of anhydrous THF. The reaction mixture was stirred at room temperature for 10 minutes and 1-[1-(4-methoxyphenyl)-1,12-dicarba-closo-dodecaboran-12-yl]heptan-1-one (600 mg, 1.65 mmol) in 15 mL of anhydrous THF was added slowly over a period of 2 hours at 25°C. The reaction mixture was stirred at room temperature for an additional 6 h and then carefully quenched by adding small amounts of 2.0 M HCl (30 mL) to control H2 evolution. Diethyl ether (50 mL) was added and the organic phase was washed with brine and saturated NaHCO3. The organic phase was dried over MgSO4, filtered and evaporated. The residue was purified by silica gel column chromatography (hexane / EtOAc, 19 / 1, v / v) to give a white solid. Chiral HPLC (CHIRALPAK IB-3 [Chiral Technologies, INC.], hexane / DCM [9 / 1], 1 mL flow rate) and the corresponding Mosher ester were purified. 1 Based on the analysis of the 1 H NMR spectrum, the enantiomeric excess (ee) was estimated to be >85%. The absolute configuration was confirmed to be that of the corresponding Mosher ester. 1 It was determined by analysis of the 1 H NMR spectrum. Scheme 8. Synthesis of (R)-1-[1-(4-hydroxyphenyl)-1,12-dicarba-closo-dodecaboran-12-yl]heptan-1-ol. [ka]

[0330] Yield: 440mg (73%), R f : 0.43 (Hexane / EtOAc, 19 / 1, v / v), mp: 95-96°C, [α] D 20℃= +27°(0.1, DCM). 1 1H NMR (CDCl3): δ 0.87 (t, 3H, CH3), 1.15~1.31 (m, 8H, 4xCH2), 1.38~1.48 (m, 2H, CH2), 1.58 (br.s, 1H, OH), 1.85 - 3.0 (br.m, 10H, BH), 3.47 (m, 1H, CH), 3.74 (s, 3H, OCH3), 6.68 (d, 2H, aromatic, J = 9.0 Hz), 7.12 (d, 2H, aromatic, J = 9.0 Hz). 13 13C NMR (CDCl3): δ 14.20, 22.72, 26.60, 28.98, 31.83, 36.92, 55.40, 73.10, 83.53, 86.39, 113.42, 128.43, 128.85, 159.73. High resolution mass HRMS (EI+): C 16 H 32 B 10 O2(M) + calculated m / z 364.3414 for, measured value 364.3417.

[0331] Example 9 The procedure and conditions described for the synthesis of (R)-1-[1-(4-methoxyphenyl)-1,12-dicarba-closo-dodecaboran-12-yl]heptan-1-ol are applied using 500 mg (1.38 mmol) of 1-[1-(4-methoxyphenyl)-1,12-dicarba-closo-dodecaboran-12-yl]heptan-1-one and 1.38 mL (1.38 mmol, 1.0 M solution in toluene) of (R)-MeCBS. The residue was purified by silica gel column chromatography (hexane / EtOAc, 19 / 1, v / v) to give a white solid. The enantiomeric excess (ee) was estimated to be >85% based on chiral HPLC (CHIRALPAK IB-3 [Chiral Technologies, INC.], hexane / DCM [9 / 1], 1 mL flow rate). The assignment of the absolute configuration was derived from the analysis of the 1H-NMR spectrum of the Mosher ester (S)-1-[1-(4-methoxyphenyl)-1,12-dicarba-closo-dodecaboran-12-yl]heptan-1-ol. Scheme 9: Synthesis of (R)-1-[1-(4-methoxyphenyl)-1,12-dicarba-closo-dodecaboran-12-yl]heptan-1-ol [ka]

[0332] Yield: 400mg (80%), R f : 0.43 (Hexane / EtOAc, 19 / 1, v / v), mp: 95-96°C, [α] D 20℃ =-24°(0.1,DCM). 1H NMR(CDCl3):δ0.87(t,3H,CH3),1.15~1.31(m,8H,4xCH2),1.38~1.47(m,2H,CH2),1.57(br.s,1H,OH),1.85~3 .0(br.m,10H,BH),3.47(m,1H,CH),3.74(s,3H,OCH3),6.68(d,2H,aromatic,J=9.0Hz),7.12(d,2H,aromatic,J=9.0Hz). 13 C NMR (CDCl3): δ14.20,22.72,26.60,28.99,31.83,36.92,55.40,73.10,83.54,86.39,113.42,128.43,128.85,159.73. Accurate mass HRMS(EI+):C 16 H 32 B 10 O2(M) + Calculated m / z 364.3414, observed 364.3406.

[0333] Example 10 To a solution of 1-(4-methoxyphenyl)-12-heptyl-1,12-dicarba-closo-dodecaborane (600 mg, 1.72 mmol) in anhydrous DCM (40 mL) was added boron tribromide (3.4 mL, 3.4 mmol), 1 M solution in DCM at 0° C. The reaction mixture was stirred overnight at room temperature, poured into ice-cold 1 M HCl (60 mL) and extracted with DCM. The organic phase was washed with 10% sodium thiosulfate solution and brine, and dried over MgSO4. The solvent was evaporated and the residue was purified by silica gel column chromatography (hexane / EtOAc, 9 / 1, v / v) to give a white solid. Further purification can be achieved with pentane or hexane (−20° C.). Scheme 10. Synthesis of 1-(4-hydroxyphenyl)-12-heptyl-1,12-dicarba-closo-dodecaborane. [ka]

[0334] Yield: 380mg (66%), R f: 0.36 (Hexane / EtOAc, 9 / 1, v / v), mp: 114-115°C. 1 H NMR(CDCl3):δ0.87(t,3H,CH3),1.08~1.29(m,10H,5×CH2),1.64(m,2H,C カルボラン -CH2),1.85~3.0(br.m,10H,BH),4.68(br.s,1H,OH),6.60(d,2H,aromatic,J=8.8Hz),7.07(d,2H,aromatic,J=8.8Hz).13C NMR (CDCl3): δ14.20,22.73,29.02,29.23,29.67,31.87,38.04,80.82,80.98,81.21,114.83,128.76,129.30,155.59. Accurate mass HRMS (ESI):C 15 H 29 B 10 O(M-1) - Calculated m / z 333.3216, observed 333.3213.

[0335] Example 11 To a solution of (RS)-1-[1-(4-methoxyphenyl)-1,12-dicarba-closo-dodecaboran-12-yl]heptan-1-ol (570 mg, 1.57 mmol) in anhydrous DCM (40 mL) was added boron tribromide (4.7 mL, 4.7 mmol, 1 M solution in DCM) at 0° C. The reaction mixture was stirred overnight at room temperature, poured into ice-cold 1 M HCl (60 mL) and extracted with DCM. The organic phase was washed with 10% sodium thiosulfate solution and brine, and dried over MgSO4. The solvent was evaporated and the residue was purified by silica gel column chromatography (hexane / EtOAc, 9 / 1, v / v) to give a white solid. Further purification can be achieved by recrystallization from hexane / i-propanol [24:1] and washing the resulting residue with ice-cold pentane. Scheme 11. Synthesis of (RS)-1-[1-(4-hydroxyphenyl)-1,12-dicarba-closo-dodecaboran-12-yl]heptan-1-ol. [ka]

[0336] Yield: 400mg (73%), R f : 0.23 (hexane / EtOAc, 9 / 1, v / v), mp: 129-130°C. 1 H NMR(CDCl3):δ0.87(t,3H,CH3),1.14~1.30(m,8H,4×CH2),1.38~1.45(m,2H,CH2),1.62~1.63(m,~2H,OH&H2O),1.8 5~3.0(br.m,10H,BH),3.46(m,1H,CH),4.96(br.s,1H,OH),6.61(d,2H,aromatic,J=8.8Hz),7.07(d,2H,aromatic,J=8.9Hz). 13 C NMR (CDCl3): δ14.19,22.71,26.58,28.97,31.82,36.91,73.14,83.57,86.37,114.90,128.68,129.06,155.82. Accurate mass HRMS (ESI):C 15 H 31 B 10 O2(M+1) - Calculated m / z 351.3329, observed 351.3322.

[0337] Example 12 The procedure and conditions described for the synthesis of (RS)-1-[1-(4-hydroxyphenyl)-1,12-dicarba-closo-dodecaboran-12-yl]heptan-1-ol are applied using 450 mg (1.4 mmol) of (RS)-1-[1-(4-methoxyphenyl)-1,12-dicarba-closo-dodecaboran-12-yl]butan-1-ol as starting material. Purification of the product was carried out by silica gel column chromatography (hexane / EtOAc, 9 / 1, v / v) to obtain a white solid. Further purification can be achieved by recrystallization from hexane / i-propanol [24:1] and washing of the resulting residue with ice-cold pentane. Scheme 12. Synthesis of (RS)-1-[1-(4-methoxyphenyl)-1,12-dicarba-closo-dodecaboran-12-yl]butan-1-ol. [ka]

[0338] Yield: 265 mg (62%), Rf: 0.22 (Hexane / EtOAc, 9 / 1, v / v), mp: 184-185°C. 1 H NMR(CDCl3):δ0.87(t,3H,CH3),1.15~1.26(m,2H,CH2),1.33~1.51(m,2H,CH2),1.55(br.s,~2H,OH&H2O),1.85~ 3.0(br.m,10H,BH),3.48(m,1H,CH),4.69(br.s,~1H,OH),6.61(d,2H,aromatic,J=8.8Hz),7.07(d,2H,aromatic,J=8.8Hz). 13 C NMR(CDCl3):δ13.75,19.82,38.95,72.86,83.41,86.39,114.90,128.71,129.15,155.75.Accurate mass HRMS(ESI):C 12 H 23 B 10 O2(M-1) - Calculated m / z 307.2701, observed 307.2700.

[0339] Example 13 The procedure and conditions described for the synthesis of (RS)-1-[1-(4-hydroxyphenyl)-1,12-dicarba-closo-dodecaboran-12-yl]heptan-1-ol were applied using 550 mg (1.46 mmol) of (RS)-1-[1-(4-methoxyphenyl)-1,12-dicarba-closo-dodecaboran-12-yl]-6-methylheptan-1-ol as the starting material. Purification of the product was carried out by silica gel column chromatography (hexane / EtOAc, 9 / 1, v / v) to obtain a white solid. Further purification can be achieved by recrystallization from hexane / i-propanol [24:1] and washing of the resulting residue with ice-cold pentane. Scheme 13. Synthesis of (RS)-1-[1-(4-hydroxyphenyl)-1,12-dicarba-closo-dodecaboran-12-yl]-6-methylheptan-1-ol. [ka]

[0340] Yield: 340mg (72%), R f : 0.23 (hexane / EtOAc, 9 / 1, v / v), mp: 120-121°C. 1 H NMR(CDCl3):δ0.84(s,3H,CH3),δ0.85(s,3H,CH3),1.10~1.28(m,6H,3xCH2),1.38~1.45(m,2H,CH2),1.46~1.52(m,1H,CH),1.61(br.s ,~2H,OH&H2O),1.85~3.0(br.m,10H,BH),3.47(m,1H,CH),4.88(br.s,~1H,OH),6.61(d,2H,aromatic,J=8.8Hz),7.07(d,2H,aromatic,J=8.8Hz). 13 C NMR(CDCl3):δ22.71,22.78,26.88,27.07,28.04,36.93,38.94,73.13,83.33,86.38,114.90,128.69,129.09,155.80.Accurate mass HRMS(ESI):C 16 H 31 B 10 O2(M-1) - Calculated m / z 363.3322, observed 363.3331.

[0341] Example 14 The procedure and conditions described for the synthesis of (RS)-1-[1-(4-hydroxyphenyl)-1,12-dicarba-closo-dodecaboran-12-yl]heptan-1-ol were applied using 250 mg (0.65 mmol) of (RS)-1-[1-(4-methoxyphenyl)-1,12-dicarba-closo-dodecaboran-12-yl]-3-phenylpropan-1-ol as starting material. Purification of the product was carried out by silica gel column chromatography (hexane / EtOAc, 9 / 1, v / v) to obtain a white solid. Further purification can be achieved by recrystallization from hexane / i-propanol [24:1] and washing of the resulting residue with ice-cold pentane. Scheme 14: Synthesis of (RS)-1-[1-(4-hydroxyphenyl)-1,12-dicarba-closo-dodecaboran-12-yl]-3-phenylpropan-1-ol [ka]

[0342] Yield: 200mg (83%), R f : 0.15 (Hexane / EtOAc, 9 / 1, v / v), mp: 135-136°C. 1 H NMR(CDCl3):δ01.49~1.77(m,2H,CH2),1.70(br.s,~1H,OH),1.85~3.0(br.m,10H,BH),2.50~2.78(m,2H,CH2),3.48(m,1H,CH), 4.81(br.s,1H,OH),6.60(d,2H,aromatic,J=8.8Hz),7.06(d,2H,aromatic,J=8.8Hz),7.14(d,2H,aromatic),7.19(t,1H,aromatic),7.28(t,2H,aromatic). 13 C NMR (CDCl3): δ32.68,38.29,72.35,83.56,86.01,126.20,128.52,128.61,128.68,129.04,141.12,155.78. Accurate mass HRMS (ESI):C 17 H 25 B 10 O2(M-1) -Calculated m / z 369.2852, observed 369.2851.

[0343] Example 15 The procedure and conditions described for the synthesis of (RS)-1-[1-(4-hydroxyphenyl)-1,12-dicarba-closo-dodecaboran-12-yl]heptan-1-ol were applied using 280 mg (0.63 mmol) of (RS)-(2,3-dihydro-1H-inden-5-yl)-[1-(4-methoxyphenyl)-1,12-dicarba-closo-dodecaboran-12-yl]methanol as starting material. Purification of the product was carried out by silica gel column chromatography (hexane / EtOAc, 9 / 1, v / v) to obtain a white solid. Further purification can be achieved by refluxing a suspension of the product in hexane / i-propanol [24:1] and washing the obtained residue with ice-cold pentane after cooling the suspension to 0° C. Scheme 15: Synthesis of (RS)-(2,3-dihydro-1H-inden-5-yl)-[1-(4-hydroxyphenyl)-1,12-dicarba-closo-dodecaboran-12-yl]methanol [ka]

[0344] Yield: 240mg (89%), R f : 0.19 (hexane / EtOAc, 9 / 1, v / v), mp: 231° C. (decomp.). 1 H NMR (acetone-d6): δ1.9~3.0(br.m,10H,BH),2.06(m,~2H,CH2),2.88(m,~4H,2xCH2),4.68(s,H,OH),4.99(m,1H,CH),6.66 (d,2H,aromatic, J=8.6Hz),6.97(d,1H,aromatic),7.05(d,2H,aromatic,J=8.9Hz),7.08(s,1H,aromatic),7.13(d,2H,aromatic),8.51(s,H,OH). 13C NMR (acetone-d6): δ26.41,33.09,33.31,75.96,84.58,88.01,115.65,123.59,124.21,125.86,128.30,129.09,140.63,144.24,144.71,158.58. Accurate mass HRMS (ESI):C 18 H 25 B 10 O2(M-1) - Calculated m / z 381.2852, observed 381.2855.

[0345] Example 16 To a solution of 1-[1-(4-methoxyphenyl)-1,12-dicarba-closo-dodecaboran-12-yl]heptan-1-one (630 mg, 1.74 mmol) in anhydrous DCM (40 mL) was added boron tribromide (5.2 mL, 5.2 mmol, 1 M solution in DCM) at 0° C. The reaction mixture was stirred overnight at room temperature, carefully poured into ice-cold 1 M HCl (60 mL) and extracted with DCM. The organic phase was washed with 10% sodium thiosulfate solution and brine, and dried over MgSO4. The solvent was evaporated and the residue was purified by silica gel column chromatography (hexane / EtOAc, 9 / 1, v / v) to give a white solid. Further purification can be achieved with pentane or hexane (−20° C.). Scheme 16. Synthesis of 1-[1-(4-hydroxyphenyl)-1,12-dicarba-closo-dodecaboran-12-yl]heptan-1-one. [ka]

[0346] Yield: 520mg (86%), R f : 0.31 (Hexane / EtOAc, 9 / 1, v / v), mp: 79-80°C. 1H NMR(CDCl3):δ0.86(t,3H,CH3),1.12~1.27(m,6H,3×CH2),1.39~1.46(m,2H,CH2),1.55~3.40(br.m,10H ,BH),2.39(t,2H,C(O)-CH2),5.11(br.s,1H,OH),6.62(d,2H,aromatic,J=8.7Hz),7.05(d,2H,aromatic,J=8.9Hz). 13 C NMR (CDCl3): δ14.09,22.52,23.53,28.44,31.54,39.40,83.61,85.83,114.95,128.49,128.87,155.99,195.87. Accurate mass HRMS (ESI):C 15 H 27 B 10 O2 (M-1) - Calculated m / z 347.3001, observed 347.3014.

[0347] Example 17 The procedure and conditions described for the synthesis of (RS)-1-[1-(4-hydroxyphenyl)-1,12-dicarba-closo-dodecaboran-12-yl]heptan-1-ol are applied using 300 mg (0.825 mmol) of (S)-1-[1-(4-methoxyphenyl)-1,12-dicarba-closo-dodecaboran-12-yl]heptan-1-ol as starting material. Purification of the product was carried out by silica gel column chromatography (hexane / EtOAc, 9 / 1, v / v) to obtain a white solid. Further purification can be achieved by refluxing a suspension of the product in hexane / i-propanol [24:1] and washing the obtained residue with ice-cold pentane after cooling the suspension to 0° C. The enantiomeric excess (ee) of the corresponding Mosher ester was calculated using the formula: 1 According to the analysis of H-NMR spectrum, it was estimated to be >85%. The absolute configuration was confirmed to be that of the corresponding Mosher ester. 1 It was determined by analysis of H-NMR spectrum. Scheme 17: Synthesis of (S)-1-[1-(4-hydroxyphenyl)-1,12-dicarba-closo-dodecaboran-12-yl]heptan-1-ol

Chem.

[0348] Yield: 220 mg (76%), R f : 0.23 (hexane / EtOAc, 9 / 1, v / v), m.p.: 120 - 121 °C, [α]D 20℃ = +23° (0.1, DCM). 1 1H NMR (CDCl3): δ 0.87 (t, 3H, CH3), 1.15 - 1.30 (m, 8H, 4xCH2), 1.39 - 1.45 (m, 2H, CH2), 1.66 - 1.71 (m, ~2H, OH&H2O), 1.85 - 3.0 (br.m, 10H, BH), 3.46 (m, 1H, CH), 5.08 (br.s, 1H, OH), 6.61 (d, 2H, aromatic, J = 8.8 Hz), 7.07 (d, 2H, aromatic, J = 8.9 Hz). 13 13C NMR (CDCl3): δ 14.19, 22.70, 26.58, 28.97, 31.81, 36.90, 73.16, 83.49, 86.33, 114.90, 128.67, 129.03, 155.84. High resolution accurate mass HRMS (ESI): C 15 H 29 B 10 O2 (M - 1) - Calculated m / z 349.3165 for, found 349.3162.

[0349] Example 18 The procedure and conditions described for the synthesis of (RS)-1-[1-(4-hydroxyphenyl)-1,12-dicarba-closo-dodecaboran-12-yl]heptan-1-ol were applied using 300 mg (0.825 mmol) of (R)-1-[1-(4-methoxyphenyl)-1,12-dicarba-closo-dodecaboran-12-yl]heptan-1-ol as starting material. Purification of the product was carried out by silica gel column chromatography (hexane / EtOAc, 9 / 1, v / v) to obtain a white solid. Further purification can be achieved by refluxing a suspension of the product in hexane / i-propanol [24:1] and washing the obtained residue with ice-cold pentane after cooling the suspension to 0° C. The enantiomeric excess (ee) of the corresponding Mosher ester was calculated using the formula: 1 According to the analysis of H-NMR spectrum, it was estimated to be >85%. The absolute configuration was confirmed to be that of the corresponding Mosher ester. 1 It was determined by analysis of H-NMR spectrum. Scheme 18: Synthesis of (R)-1-[1-(4-hydroxyphenyl)-1,12-dicarba-closo-dodecaboran-12-yl]heptan-1-ol [ka]

[0350] Yield: 180 mg (62%), Rf: 0.23 (Hexane / EtOAc, 9 / 1, v / v), mp: 120-121° C., [α]D20° C.=-28° (0.1, DCM). 1 H NMR(CDCl3):δ0.87(t,3H,CH3),1.15~1.30(m,8H,4xCH2),1.39~1.45(m,2H,CH2),1.68~1.76(m,~2H,OH&H2O),1. 9~3.0(br.m,10H,BH),3.47(m,1H,CH),5.17(br.s,1H,OH),6.61(d,2H,aromatic,J=8.8Hz),7.07(d,2H,aromatic,J=8.9Hz). 13C NMR(CDCl3):δ14.19,22.70,26.58,28.96,31.81,36.90,73.17,83.50,86.31,114.90,128.67,129.01,155.86.Accurate mass HRMS(ESI):C 15 H 29 B 10 O2(M-1) - Calculated m / z 349.3165, observed 349.3158.

[0351] Example 19 Estrogen receptor beta (ERβ) agonists have the potential to function as tumor suppressors in the treatment of cancers such as breast cancer, colon cancer, prostate cancer, etc. Such agents may also be used in the treatment of inflammatory diseases such as arthritis and inflammatory bowel disease, as well as neurodegenerative and psychotropic disorders.

[0352] A library of 22 compounds (Table 2) was synthesized (e.g., as described above or using methods derived therefrom) and biologically evaluated in vitro for estrogen receptor beta (ERβ) selective agonist activity. The library of 22 compounds was synthesized based on a reference compound (Table 1). Within the synthesized structure (Table 2), the B and C rings of the endogenous ligand E2 were replaced with a carborane cluster. The hydrophobicity and spherical shape of the carborane may play a role in increasing the binding affinity of the ligand to the estrogen receptor.

[0353] In addition to the three reference compounds (Table 1) and the library of 22 synthetic compounds (Table 2), three compounds described by Thirumamagal, BTS et al. (Bioconj. Chem. 2006, 17, 114-1150) were also included in the in vitro evaluation of ERβ selective agonist activity.

[0354] The selectivity and potency of various compounds were achieved by in vitro testing in ERα and ERβ cell-based reporter assays. The activity of selected compounds was determined in HEK293 cells in cell-based reporter assays. The HEK293 cell line was selected because it does not express endogenous ERα or ERβ at significant levels.

[0355] HEK293 cells were grown in monolayer in phenol red-free DMEM supplemented with 10% fetal bovine serum, 2 mM Glutamax and penicillin / streptomycin (Thermo Fisher Scientific, MA, USA) and incubated at 37°C in a 5% CO2 humidified atmosphere. Just before transfection, the growth medium was changed to phenol red-free DMEM supplemented with 4% HyClone Fetal Bovine Serum, Charcoal / Dextran Treated (GE Healthcare Life Sciences, USA) and 2 mM Glutamax (starvation medium). Cells were transfected with expression vectors encoding human full-length ERα or ERβ and with a reporter vector containing three repeats of the estrogen response element (ERE), followed by the herpes simplex virus-derived minimal thymidine kinase promoter in the pGL4 vector (Promega, USA). Luciferase served as the reporter gene. Transfections were performed in starvation medium in 10 cm dishes (Nunc). After 24 h, cells were trypsinized, counted, and seeded in cell culture-treated white solid 1536-well plates (Corning Inc., New York, USA) at 1500 cells / well in a total medium volume of 4 μl. Compounds to be tested were diluted in DMSO and transferred to the cells using an acoustic dispenser Echo 520 (Labcyte). Compounds were tested in triplicate at least 12 different concentration points ranging from 10 μM to 100 pM. Luciferase activity was measured after 24 h of incubation with compounds using Britelite plus luciferase reporter gene assay reagent (Perkin Elmer, USA) according to the manufacturer's protocol. Luciferase signal was measured in an Envison multimode plate reader (Perkin Elmer, USA).Data were collected and processed using an in-house built LIMS system ScreenX and GraphPad Prism software. EC. 50 Values ​​were calculated using a regression function (dose-response, variable slope). A description of the assay is summarized in Table 4.

[0356] The results of in vitro evaluation of compounds for estrogen receptor beta (ERβ) selective agonist activity are summarized in Table 5. Experiments with Compound 04 demonstrated an EC 50 with an EC of 46 nM for ERβ 50 Compound 05 was shown to have an EC of >5000 nM at ERα, demonstrating high ERβ selectivity. 50 with an EC of 64 nM for ERβ 50 It was shown that the compound had high ERβ selectivity.

[0357] The results (Table 5) showed that the active carboranyl compounds of the synthetic library were those that retained the para-hydrophenyl ring (A-ring) of E2 to allow hydrogen bond stacking and pi-stacking interactions with the receptor. The results further showed that the active compounds from the synthetic library were those in which the D-ring of E2, containing the 17β-hydroxyl group, was replaced with an alkyl-hydroxyalkyl group or a 1-hydroxyalkyl group. The latter structural element is believed to be related to the selectivity of ERβ.

[0358] One promising compound from this library was 1-(4-hydroxyphenyl)-12-(1-hydroxyheptyl)-1,12-dicarba-closo-dodecaborane (06). Evaluation of this compound in a luciferase reporter-based cellular assay in human embryonic kidney (HEK) cells (Sedlak, D. et al. Comb. Chem. High T. Scr. 2011, 14, 248-266) revealed an EC of 5 nM at ERβ. 50and an ERβ to ERα agonist ratio of 1,800. For comparison, the reference ERβ selective agonist diarylpropionitrile (DPN) had an EC50 of 6.3 nM and an ERβ to ERα agonist ratio of 358. [Table 1] [Table 2-1] [Table 2-2] [Table 3] [Table 4-1] [Table 4-2] [Table 5-1] [Table 5-2]

[0359] Example 20 The steroid receptor family consists of six highly evolutionarily conserved, but structurally related, receptors. The natural ligands for steroid receptors are much more structurally related and, despite the high similarity, are able to bind quite selectively to their specialized targets. For example, cortisol is a ligand for the glucocorticoid receptor and does not interact with the estrogen receptor.

[0360] As discussed above, a library of carborane derivatives showed preferential activation of ERβ relative to ERα based on profiling over a wide concentration range. However, it is possible that these carborane derivatives, being a new class of artificially prepared ERβ ligands and structurally unrelated to natural estrogen hormones, may have a different activity profile and may interact with the remaining members of the steroid receptor family, such as the androgen receptor. Such undesirable activity would have significant biological consequences.

[0361] To evaluate the off-target activity of carborane compounds on other steroid receptors, androgen receptor (AR) and glucocorticoid receptor (GR) cell-based luciferase reporter assays were performed in the same manner as the estrogen receptor (ER) reporter assay described above (Sedlak, D. et al. Comb. Chem. High T. Scr. 2011, 14, 248-266). Compounds tested were E2, DPN, PPT, 01, 02, 03, 04, 05, 06, 07, 08, 09, 10, 11, 12, 13, 20, 21, 22, 23, 24, and 25. Descriptions of the AR and GR assays are summarized in Table 4. The assays were performed using stable reporter cell lines expressing full-length AR or GR in the osteosarcoma U2OS cell line, which has no endogenous expression of these receptors. Experiments were performed in agonist and antagonist modes to detect all possible interactions of the compounds with the receptors. In antagonist mode, dihydrotestosterone (DHT) or dexamethasone was added to the cell cultures 1 h after compound addition to a final concentration of 2 nM or 10 nM for the AR and GR reporter assays, respectively. Within the tested concentration range (100 μM to 100 pM), no agonist or antagonist activity at AR or GR was detected for the tested compounds, suggesting that the activity of the carborane derivatives is restricted to ERβ only.

[0362] Example 21 The in vitro cytotoxicity of the compounds was evaluated by performing a viability assay in HEK293 cells in parallel with the ERα and ERβ reporter assays to ensure the comparability of the results obtained. Non-transfected HEK293 cells were seeded at 5000 cells / well in 384-well plates and compounds were added, but the timing of all subsequent steps was exactly the same as for the reporter assays. The compounds tested were E2, DPN, PPT, 01, 02, 03, 04, 05, 06, 07, 08, 09, 10, 11, 12, 13, 20, 21, 22, 23, 24, and 25. After 24 hours of compound incubation with the cells, cell viability was measured by determining ATP levels in the samples using a luciferase cell viability assay, ATPlite 1step (Perkin Elmer, USA). The results are summarized in Table 6 and show that the compounds are non-toxic or that they are toxic at the highest concentration tested (IC 50 >20 μM) showing slight cytotoxicity. [Table 6] Study 1, Study 2 = For compounds with multiple studies reported, the Study 2 data are considered more reliable, but all data are reported here for completeness. Low = activity was detected, but activity was so low that an exact value was not reported.

[0363] Example 22 A second library of compounds containing (i) carboranes substituted with heteroalkyl groups, (ii) carborane groups containing sulfide groups (thioethers), sulfoxide groups, and sulfone groups, and (iii) carborane analogs are synthesized and biologically evaluated in vitro for estrogen receptor beta (ERβ)-selective agonist activity. [Table 7-1] [Table 7-2] [Table 7-3]

[0364] The compounds in the second library were prepared as described below. [ka]

[0365] Synthesis of 1-(heptan-1-yl)-1,12-dicarba-closo-dodecaborane To a solution of 1,12-dicarba-closo-dodecaborane (1.44 g, 10 mmol) in 1,2 dimethoxyethane (50 ml) was added dropwise at 0° C. under argon atmosphere n-BuLi solution (2.5 M in hexane, 4.4 ml). The mixture was stirred at room temperature for 1 h, followed by addition of 1-heptane (1.55 ml, 11 mmol) at 0° C. The mixture was stirred overnight at room temperature, then poured into 1 M HCl solution (100 ml) and extracted with ethyl acetate (3×25 ml). The combined organic phase was washed with brine and dried over MgSO4. The solvent was evaporated and the residue was purified on a Teledyne Isco (RediSepRf column) to give a colorless oil. Yield 1.4 g low 1 H NMR(CDCl3)δ3.38~3.45(m,1H),3.35~1.14(m,22H),0.88(t,3H),MS258.291.

[0366] Synthesis of 1-(heptan-1-one)-1,12-dicarba-closo-dodecaborane Pyridinium chlorochromate (PCC, 1.7 g, 7.71 mmol) was suspended in anhydrous DCM (50 ml). A solution of 1-(heptan-1-yl)-1,12-dicarba-closo-dodecaborane (1.3 g, 5.04 mmol) in DCM (10 ml) was then added and the reaction mixture was stirred at room temperature overnight. Diethyl ether (50 ml) was added followed by molecular sieves and then stirred for 1 h. The supernatant was decanted and the undissolved residue was washed with dry ether (3x20 ml). The combined organic phase was passed through a short column of Celite followed by evaporation. The residue was purified on a Teledyne Isco (RediSepRf column) to give a colourless oil, yield 1.2 g. 1 H NMR(CDCl3)δ1.16(m,21H),0.88(t,3H),MS256.189.

[0367] Synthesis of (R)-1-(heptan-1-yl)-1,12-dicarba-closo-dodecaborane Borane-tetrahydrofuran complex (51 mL, 51 mmol, 1.0 M solution in THF, stabilized with 0.005 M N-isopropyl-N-methyl-tert-butylamine (NEVIBA)) was added to 50 mL of anhydrous THF, followed by (R)-2-methyl-CBS-oxazaborolidine [(2-MeCBS] (5.1 mL, 5.1 mmol, 1.0 M solution in toluene). The reaction mixture was stirred at room temperature for 15 min to give 1-(heptan-1-one)-1,12-dicarba Closo-dodecaborane (1.3 g, 5.08 mmol) in 25 mL anhydrous THF was added slowly over 2 h at 0° C. The reaction mixture was stirred at room temperature overnight and then carefully quenched by portionwise addition of 2.0 M HCl (80 mL) to control H2 evolution. Diethyl ether (100 mL) was added and the organic phase was washed with brine and saturated NaHC03. The organic phase was dried over MgSO4, filtered and evaporated. The residue was purified on a Teledyne Isco (RediSepRf column) to give a colorless oil in a yield of 1.1 g (81%). 1H NMR(CDCl3)δ3.38~3.45(m,1H),3.35~1.14(m,22H),0.88(t,3H),MS258.291.

[0368] Synthesis of (R)-1-(1-benzyloxy)heptyl)-1,12-dicarba-closo-dodecaborane To a solution of (R)-1-(heptan-1-yl)-1,12-dicarba-closo-dodecaborane (900 mg, 3.49 mmol) in anhydrous DMF (10 ml) was added NaH (60% in mineral, 175 mg, 4.36 mmol) in one portion at 0° C. and then stirred at the same temperature for 30 min. BnBr (746 mg, 4.36 mmol) was added and the reaction mixture was stirred at 55° C. for 3 h, cooled at room temperature, methanol (0.5 ml) was added slowly, diluted with ethyl acetate (50 ml), washed with water, brine and dried over Na2SO4. The solvent was evaporated and the residue was purified on a Teledyne Isco (RediSepRf column) to give a colorless oil in a yield of 1.1 g (93%). 1 H NMR(CDCl3)δ7.28(d,2H),7.73(d,2H),4.63(d,1H),3.76(s,3H),2.61~3.62(m,5H),2.53(s,3H),1.50~2.45(m,5H),MS Calculated value 329.200, actual value 329.189

[0369] Synthesis of (R)-1-(1-(6-methoxypyridazin-3-yl)-12-(1-benzyloxy)heptyl)1,12-dicarba-closo-dodecaborane To a solution of (R)-1-(1-benzyloxy)heptyl)-1,12-dicarba-closo-dodecaborane (106 mg, 0.19 mmol) in 1,2-dimethoxyethane (5 ml) was added dropwise at 0° C. under Ar atmosphere with n-BuLi solution (2.5 M in hexane 92 μl, 0.23 mmol). The mixture was stirred at room temperature for 1 h and CuCl (46 mg, 0.23 mmol) was added in one portion. Stirring was continued at room temperature for 1 h, then pyridine (218 μl) was added, 3-iodo-6-methoxypyridazine (35 mg, 0.23 mmol) was further added in one portion and the mixture was heated at 80° C. for 48 h. After cooling, the reaction mixture was diluted with Et2O and stirred at room temperature for 3 h. The undissolved material was filtered through Celite. The filtrate was washed with Na2S2O3, H2O and brine, dried over Na2SO4, then concentrated and the residue was purified by Teledyne Isco (RediSepRf column) to give the pure product.

[0370] Synthesis of (R)-1-(1-(6-hydroxypyridazin-3-yl)-12-(1-benzyloxy)heptyl)1,12-dicarba-closo-dodecaborane To a solution of (R)-1-(1-(6-methoxypyridazin-3-yl)-12-(1-benzyloxy)heptyl)-1,12-dicarba-closo-dodecaborane (35 mg, 0.08 mmol) in CHCl (1 ml) was added 1M BBr3 solution in CHCl (0.28 ml) dropwise at 0° C. The mixture was stirred at room temperature for 2 h, then poured into ice water and extracted with CHCl. ​​The organic layer was washed with brine, dried over NaSO and concentrated. Purification by Teledyne Isco (RediSepRf column) gave the pure product as a yellow solid. 1 H NMR (CDCl3) δ7.27(d,2H),6.82(d,2H),3.26(d,1H),1.50-3.1(m,22H)0.88(t,3H), MS calculated value 441.351, actual value 441.362.

[0371] Synthesis of (R)-1-[1-(6-hydroxypyridazin-3-yl)-1,12-dicarba-closo-dodecaboran-12-yl]heptan-1-ol A mixture of (R)-1-(1-(6-Hydroxypyridazin-3-yl)-12-(1-benzyloxy)heptyl)-1,12-dicarba-closo-dodecaborane (26 mg, 0.06 mmol), Pd / C on carbon (5 mg) in methanol (5 ml) was reacted with H2 in a Parr shaker at 55 psi for 48 h. After filtration and washing with methanol, the combined filtrate was concentrated and the residue was purified on a Teledyne Isco (RediSepRf column) to give the pure product as a brown solid. 1 H NMR (CDCl3) δ7.27(d,2H),6.82(d,2H),3.26(d,1H),1.50-3.1(m,22H)0.88(t,3H), MS calculated value 351.310, actual value 351.310. [ka]

[0372] Synthesis of 1-mercapto-12-(4-methoxyphenyl)-1,12-dicarbaclosododecaborane To a solution of 1-(4-methoxyphenyl)-1,12-dicarba-closo-dodecaborane (1.58 g, 6.3 mmol) in 1,2 dimethoxyethane (50 ml) was added dropwise n-BuLi solution (2.5 M in hexane 2.8 ml) at 0° C. under Ar atmosphere. The mixture was stirred at room temperature for 1 h, followed by the addition of elemental sulfur (250 mg, 7.8 mmol) at 0° C. The mixture was stirred at room temperature for 3 h and 50 ml of water was added. The organic layer was separated and then extracted with 50 ml of 10% aqueous NaOH solution. The aqueous layer was combined with the extract and the mixture was acidified with HCl to a pH of about 1. The product was extracted twice with 100 ml of diethyl ether and the organic phase was dried over Na2SO4. The solvent was evaporated and the residue was dissolved in 10 ml of water using a Teledyne Purification by Isco (RediSepRf column) gave 1.53 g of 1-mercapto-12-(4-methoxyphenyl)-1,12-dicarba-closododecaborane as a yellow solid as pure product.

[0373] Synthesis of 1-mercapto-12-(4-hydroxyphenyl)-1,12-dicarbaclosododecaborane To a solution of 1.5 g (5.3 mmol) of 1-mercapto-12-(4-methoxyphenyl)-1,12-dicarba-closododecaborane in CHCl (20 ml) was added 1 M solution of BBr3 in CHCl (20 ml) at 0° C. The mixture was stirred at room temperature for 16 h, then poured into ice water and extracted with CHCl. ​​The organic layer was washed with brine, dried over NaSO, and concentrated. Purification by Teledyne Isco (RediSepRf column) gave 1.17 g of 1-mercapto-12-(4-hydroxyphenyl)-1,12-dicarba-closododecaborane as a white solid as pure product.

[0374] Synthesis of 1-methylthio-12-(4-hydroxyphenyl)-1,12-dicarbacloso-dodecaborane To a solution of 1-mercapto-12-(4-hydroxyphenyl)-1,12-dicarba-closo-dodecaborane (112 mg, 0.42 mmol) in ethanol (10 ml), NaOH (34 mg, 0.84 mmol) was added and the reaction mixture was stirred at 55 °C for 15 min before iodomethane (60 mg, 0.42 mmol) was added. The final reaction mixture was stirred overnight at 55 °C, cooled to room temperature and adjusted to pH 1-3. The ethanol was removed, the residue was dissolved in ethyl acetate, washed with brine, the organic layer was dried over Na2SO4, concentrated in vacuum and the residue was purified by silica gel column. Pure product 1-methylthio-12-(4-hydroxyphenyl)-1,12-dicarba-closo-dodecaborane 100 mg (85% yield) was obtained as a yellow solid. 1 H NMR(CDCl3)δ7.04(d,2H),6.60(d,2H),2.15(s,3H),1.16~3.62(m,11H),MS(-ESI)calculated value 281.392(M-1),actual value 281.200

[0375] Alternative general S-alkylation procedure: To a suspension of sodium hydride (60% in mineral oil, 2.1 or 3.1 equiv.) in DMF at 0° C. was added a solution of 1-mercapto-12-(4-hydroxyphenyl)-1,12-dicarba-closododecaborane (1.0 equiv.) in DMF. The resulting mixture was stirred until bubbling ceased. A solution of alkyl halide (0.95 equiv.) in DMF was added dropwise to this mixture at 0° C. over several minutes. (In the case of alkyl chlorides, catalytic sodium iodide was added afterwards.) The final reaction mixture was stirred at room temperature for 1 h to overnight, quenched with H2O, and adjusted to pH 2 with 2N HCl. The aqueous layer was extracted three times with ether or ethyl acetate, and the organic layer was washed with H2O (four times) and brine (once), dried over Na2SO4, and concentrated in vacuo. The residue was purified by CombiFlash Teledyne Isco (RediSepRf column).

[0376] Synthesis of 1-methylsulfinyl-12-(4-hydroxyphenyl)-1,12-dicarbacloso-dodecaborane To a solution of 1-methylthio-12-(4-hydroxyphenyl)-1,12-dicarba-closo-dodecaborane (34 mg, 0.12 mmol) in EtOH (2 ml) was added hydrogen peroxide (33%, 90 μl) followed by oxalic acid (11.4 mg, 0.12 mmol). The final reaction mixture was stirred at room temperature for 48 h, diluted with ethyl acetate (20 ml), washed with water, NaHCO3, and brine, dried over Na2SO4, and concentrated in vacuo. The residue was purified by silica gel column to give 1-methylsulfinyl-12-(4-hydroxyphenyl)-1,12-dicarba-closo-dodecaborane 18 mg (50% yield) as an off-white solid. 1 H NMR(CDCl3)δ7.05(d,2H),6.64(d,2H),3.54(s,3H),2.55~3.62(m,5H),1.16~2.53(m,6H),MS(-ESI)calculated value 297.1948(M-1),actual value 297.1947

[0377] Alternative sulfoxide formation procedure: To a solution of the sulfide (1.0 equiv.) in dichloromethane (0.1 M) at 0° C. was added dropwise a solution of mCPBA (77%, 1.0 equiv.) in dichloromethane (0.1 M). Note: In branching, co-solvents such as AcOH, MeOH, or acetone may be used. The reaction mixture was stirred at 0° C. for 1 h. The reaction mixture was then diluted with dichloromethane, washed with NaSO, NaHCO, and brine, and concentrated in vacuo. Alternatively, the reaction was dried with a gentle stream of argon, and then the same work-up procedure was carried out instead with ethyl acetate. The residue was purified by CombiFlash Teledyne Isco (RediSepRf column).

[0378] Sulfone formation procedure: To a solution of the sulfoxide (1.0 equiv.) in dichloromethane (0.1M) was added mCPBA (77%, 1.0-2.0 equiv.). Note: In some cases, a cosolvent such as AcOH, MeOH, or acetone may be used. The reaction mixture was stirred for 1 h to overnight. The reaction mixture was then diluted with dichloromethane, washed with NaSO, NaHCO, and brine, dried over NaSO, and concentrated in vacuo. Alternatively, the reaction was dried with a gentle stream of argon, and then the same work-up procedure was carried out instead with ethyl acetate. The residue was purified by CombiFlash Teledyne Isco (RediSepRf column).

[0379] Synthesis of 1-methylsulfonyl-12-(4-hydroxyphenyl)-1,12-dicarba-closo-dodecaborane To a solution of 1-methylthio-12-(4-hydroxyphenyl)-1,12-dicarba-closo-dodecaborane (35 mg, 0.12 mmol) in DCM (2 ml) was added mCPBA (63 mg, 0.36 mmol). The reaction mixture was stirred at room temperature for 4 h, washed with Na2S2O3, NaHCO3 and brine, dried over Na2SO4, and concentrated in vacuo. The residue was purified by silica gel column to give 31 mg (80% yield) of 1-methylsulfonyl-12-(4-hydroxyphenyl)-1,12-dicarba-closo-dodecaborane as an off-white solid. 1 H NMR (CDCl3) δ7.02(d,2H),6.62(d,2H),2.93(s,3H),2.95~3.62(m,3H),1.16~2.92(m,8H), MS(-ESI) calculated value 313.1896(M-1), actual value 313.1896.

[0380] Synthesis of 1-propylthio-12-(4-hydroxyphenyl)-1,12-dicarba-closo-dodecaborane 1-Propylthio-12-(4-hydroxyphenyl)-1,12-dicarba-closo-dodecaborane was prepared by a similar procedure. 1H NMR (CDCl3) δ7.02(d,2H),6.58(d,2H),2.56(t,2H),1.45~1.53(m,2H),1.16~3.62(m,11H),0.91(t,3H),MS(-ESI) calculated value 309.448(M-1), actual value 309.233.

[0381] Synthesis of 1-propylsulfinyl-12-(4-hydroxyphenyl)-1,12-dicarba-closo-dodecaborane 1-Propylsulfinyl-12-(4-hydroxyphenyl)-1,12-dicarba-closo-dodecaborane was prepared by a similar procedure. 1 H NMR(CDCl3)δ7.03(d,2 H), 6.63 (d, 2H), 2.98 (t, 2H), 1.84~1.92 (m, 2H), 1.16 ~ 3.62 (m, 11H), 1.07 (t, 3H), MS (-ESI) calculated value 325.447 (M-1), actual value 325.228.

[0382] Synthesis of 1-propylsulfinyl-12-(4-hydroxyphenyl)-1,12-dicarba-closo-dodecaborane 1-Propylsulfinyl-12-(4-hydroxyphenyl)-1,12-dicarba-closo-dodecaborane was prepared by a similar procedure. 1 H NMR(CDCl3)δ7.05(d,2H),6.63(d,2H),2.98(t,2H),2.43~2.622(m,2H),1.60~1.85( m, 2H), 1.16~3.62 (m, 11H), 1.06 (t, 3H), MS (-ESI) calculated value 341.2185 (M-1), actual value 341.2217.

[0383] Synthesis of 1-pentylthio-12-(4-hydroxyphenyl)-1,12-dicarba-closo-dodecaborane 1-Pentylthio-12-(4-hydroxyphenyl)-1,12-dicarba-closo-dodecaborane was prepared by a similar procedure. 1H NMR(CDCl3)δ7.05(d,2H),6.63(d,2H),2.98(t,2H),2.43~2.622(m,2H),1.26~1.49 (m, 6H), 1.16~3.62 (m, 11H), 0.86 (t, 3H), MS (-ESI) calculated value 337.502 (M-1), actual value 337.328.

[0384] Synthesis of 1-propylsulfinyl-12-(4-hydroxyphenyl)-1,12-dicarba-closo-dodecaborane 1-Propylsulfinyl-12-(4-hydroxyphenyl)-1,12-dicarba-closo-dodecaborane was prepared by a similar procedure. 1 H NMR(CDCl3)δ7.03(d,2H),6.62(d,2H),2.45~2.61(m,2H),1.65~1.79(m,4H),1.27~1. 44 (m, 5H), 1.00~3.62 (m, 8H), 0.90 (t, 3H), MS (-ESI) calculated value 353.2573 (M-1), actual value 353.2585.

[0385] Synthesis of 1-propylsulfonyl-12-(4-hydroxyphenyl)-1,12-dicarba-closo-dodecaborane 1-Propylsulfonyl-12-(4-hydroxyphenyl)-1,12-dicarba-closo-dodecaborane was prepared by a similar procedure. 1 H NMR(CDCl3)δ7.02(d,2H),6.62(d,2H),2.96~3.02(m,2H),2.43~2.62(m,2H),1.79~1.84(m,2H), 1.33~1.41 (m, 4H), 1.00~3.62 (m, 11H), 0.91 (t, 3H), MS (-ESI) calculated value 369.2522 (M-1), actual value 369.2527.

[0386] Synthesis of 1-hexylthio-12-(4-hydroxyphenyl)-1,12-dicarba-closo-dodecaborane 1-Hexylthio-12-(4-hydroxyphenyl)-1,12-dicarba-closo-dodecaborane was prepared by a similar procedure. 1H NMR (CDCl3) δ7.04(d,2H),6.60(d,2H),2.59(t,2H),1.20~1.49(m,8H),1.16~3.62(m,11H),0.86(t,3H),MS(-ESI) calculated value 351.529(M-1), measured value 351.347.

[0387] Synthesis of 1-hexylsulfinyl-12-(4-hydroxyphenyl)-1,12-dicarba-closo-dodecaborane 1-Propylsulfonyl-12-(4-hydroxyphenyl)-1,12-dicarba-closo-dodecaborane was prepared by a similar procedure. 1 H NMR(CDCl3)δ7.06(d,2H),6.63(d,2H),2.47~2.62(m,2H),1.30~3.62(m,19H),0.90(t,3H), MS(-ESI) calculated value 368.2807(M), actual value 367.2737 M-1).

[0388] Synthesis of 1-hexylsulfonyl-12-(4-hydroxyphenyl)-1,12-dicarba-closo-dodecaborane 1-Hexylsulfonyl-12-(4-hydroxyphenyl)-1,12-dicarba-closo-dodecaborane was prepared by a similar procedure. 1 H NMR(CDCl3)δ7.04(d,2H),6.63(d,2H),4.93(bs,1H),2.97~3.01(m,2H),1.3 0~3.63 (m, 18H), 0.91 (t, 3H), MS (-ESI) calculated value 384.2756 (M), actual value 383.2687 (M-1).

[0389] Synthesis of 1-(5-methyl-hexyl)thio-12-(4-hydroxyphenyl)-1,12-dicarba-closo-dodecaborane 1-(5-Methyl-hexyl)thio-12-(4-hydroxyphenyl)-1,12-dicarba-closo-dodecaborane was prepared by a similar procedure. 1H NMR(CDCl3)δ7.05(d,2H),6.61(d,2H),2.59(t,2H),1.16~3.62(m,17H),0.88(d,6H), MS(-ESI) calculated value 333.3015(M), actual value 365.2944(M-1).

[0390] Synthesis of 1-(5-methyl-hexyl)sulfinyl-12-(4-hydroxyphenyl)-1,12-dicarba-closo-dodecaborane 1-(5-Methyl-hexyl)sulfinyl-12-(4-hydroxyphenyl)-1,12-dicarba-closo-dodecaborane was prepared by a similar procedure. 1 H NMR(CDCl3)δ7.06(d,2H),6.63(d,2H),4.94(bs,1H),2.50~2.59(m,2H),1.19~3.62(m,17H),0.88(d,6H),MS(-ESI) Calculated value 382.2964(M), Actual value 381.2900 M-1).

[0391] Synthesis of 1-(5-methyl-hexyl)sulfonyl-12-(4-hydroxyphenyl)-1,12-dicarba-closo-dodecaborane 1-(5-Methyl-hexyl)sulfonyl-12-(4-hydroxyphenyl)-1,12-dicarba-closo-dodecaborane was prepared by a similar procedure. 1 H NMR(CDCl3)δ7.03(d,2H),6.63(d,2H),5.00(bs,1H),2.97~3.02(m,2H),1.1 6~3.63 (m, 17H), 0.88 (d, 6H), MS (-ESI) calculated value 398.2913 (M), actual value 397.2851M-1). [ka]

[0392] Synthesis of 1-(4'-methoxy-[1,1'-biphenyl]-4-yl)heptan-1-ol To a solution of 4'-methoxy-[1,1'-biphenyl]-4-carbaldehyde (0.69 g, 3.25 mmol) in anhydrous diethyl ether (25 ml) was added hexylmagnesium bromide (2M in diethyl ether, 1.95 ml, 3.9 mmol) at 0°C. The reaction mixture was stirred for another hour after the addition, quenched by adding 0.1 N HCl (10 ml), the organic layer was separated and the aqueous layer was extracted with diethyl ether (2x20 ml). The combined organic layers were washed with water, NaHCO3, brine and dried over Na2SO4. The solvent was evaporated and the residue was purified by (RediSepRf column) to give a yellow solid. 0.85 g of pure product.

[0393] Synthesis of 1-(4'-methoxy-[1,1'-biphenyl]-4-yl)heptan-1-one Pyridinium chlorochromate (PCC, 0.9 g, 4.1 mmol) was suspended in anhydrous DCM (25 ml). A solution of 1-(4'-methoxy-[1,1'-biphenyl]-4-yl)heptan-1-ol (0.8 g, 2.68 mmol) in DCM (10 ml) was then added and the reaction mixture was stirred overnight at room temperature. Diethyl ether (25 ml) was added followed by molecular sieving and stirring for 1 h. The supernatant was decanted and the undissolved residue was washed with dry ether (3x20 ml). The combined organic phase was passed through a short column of Celite followed by evaporation. The residue was purified by Teledyne Isco (RediSepRf column) to give 0.64 g of pure product as a white waxy solid.

[0394] Synthesis of (S)-1-(4'-methoxy-[1,1'-biphenyl]-4-yl)heptan-1-ol Borane-tetrahydrofuran complex (10 mL, 10 mmol, 1.0 M solution in THF, (stabilized with 0.005 M N-isopropyl-N-methyl-tert-butylamine (NEVIBA)) was added to 10 mL of anhydrous THF followed by (R)-2-methyl-CBS-oxazaborolidine [(2-MeCBS] (1.0 mL, 1.0 mmol, 1.0 M solution in toluene). The reaction mixture was stirred at room temperature for 15 min and then diluted with 10 mL of anhydrous 1-(4'-methoxy-[1 ,1'-biphenyl]-4-yl)heptan-1-one (0.29 g, 1.0 mmol) was added slowly over a period of 2 h at 0°C. The reaction mixture was stirred at room temperature overnight and carefully quenched by portionwise addition of 2.0 M HCl (15 mL) to control H2 evolution. Diethyl ether (15 mL) was added and the organic phase was washed with brine and saturated NaHC03. The organic phase was dried over MgSO4, filtered and evaporated. The residue was purified by Teledyne Isco (RediSepRf column) to give a white waxy solid. Yield 0.21 g.

[0395] Synthesis of (S)-4'-(1-hydroxyheptyl)-[1,1'-biphenyl]-4-ol To a mixture of (S)-1-(4'-methoxy-[1,1'-biphenyl]-4-yl)heptan-1-ol (72 mg, 0.24 mmol), 1-dodecanethiol (75 mg, 89 μl, 0.37 mmol) in NMP (N-methylpyrrolidinone, 2 ml), NaOH (29 mg, 0.73 mmol) was added and the reaction mixture was heated at 100° C. overnight. It was cooled to room temperature, diluted with ethyl acetate (15 ml), washed with 1N HCl (10 ml), water, and brine, and dried over Na2SO4. The solvent was evaporated and the residue was purified by (RediSepRf column) to give 42 mg of pure product as a white solid. 1 H NMR(CDCl3)δ7.48~7.55(m,4H),7.42(d,2H)6.93(d,2H),4.74(brs,2H),1.30~1.81(m,11H),0.89(t,3H),HRMS Calculated value 283.17708 (M-1), actual value 283.17184. [ka]

[0396] Synthesis of 4-(4-methoxyphenyl)cyclohexan-1-one A reaction mixture of 4-(4-hydroxyphenyl)cyclohexan-1-one (2.4 g, 12.62 mmol), Cs2CO3 (6.16 g, 18.91 mmol) and iodomethane (6 ml, 18.91 mmol) in acetone (50 ml) was heated to reflux for 3 h, cooled to room temperature, filtered and washed with acetone (2x20 ml). The combined acetone filtrate was concentrated and the residue was purified by Teledyne Isco (RediSepRf column) to give 2.58 g of pure product as a white solid.

[0397] Synthesis of 4-(4-methoxyphenyl)cyclohexane-1-carbaldehyde To a solution of (methoxymethyl)triphosphonium chloride (3.8 g, 11 mmol) in anhydrous THF (950 ml) was added lithium bis(trimethylsilyl)amide (1.0 M in THF, 11 ml) dropwise at -78°C. The reaction mixture was stirred for 1 h and a solution of 4-(4-methoxyphenyl)cyclohexan-1-one (2.04 g, 10 mmol) was added dropwise. The reaction mixture was stirred for 30 min after addition, warmed to room temperature and stirred overnight. 2N HCl (50 ml) was added and stirred for 2 h. The reaction mixture was extracted with ethyl acetate (3x30 ml) and the combined organic layers were washed with water, NaHCO3 and brine and dried over Na2SO4. The solvent was evaporated and the residue was purified by (RediSepRf column) to give a yellow solid. 1.25 g of pure product.

[0398] Synthesis of 1-(4-(4-methoxyphenyl)cyclohexyl)heptan-1-ol To a solution of 4-(4-methoxyphenyl)cyclohexyl-1-carbaldehyde (0.86 g, 3.94 mmol) in anhydrous diethyl ether (50 ml) was added hexylmagnesium bromide (2M in diethyl ether, 2.46 ml, 4.52 mmol) dropwise at 0°C. The reaction mixture was stirred for another hour after the addition, quenched by adding 0.1 N HCl (20 ml), the organic layer was separated and the aqueous layer was extracted with diethyl ether (2x25 ml). The combined organic layers were washed with water, NaHCO3, brine and dried over Na2SO4. The solvent was evaporated and the residue was purified by (RediSepRf column) to give a yellow solid. 0.99 g of pure product.

[0399] Synthesis of 1-(4-(4-methoxyphenyl)cyclohexyl)heptan-1-one Pyridinium chlorochromate (PCC, 0.97 g, 4.42 mmol) was suspended in anhydrous DCM (25 ml). A solution of 1-(4-(4-methoxyphenyl)cyclohexyl)heptan-1-ol (0.88 g, 2.89 mmol) in DCM (10 ml) was then added and the reaction mixture was stirred at room temperature overnight. Diethyl ether (25 ml) was added followed by molecular sieves and then stirred for 1 h. The supernatant was decanted and the undissolved residue was washed with dry ether (3x20 ml). The combined organic phase was passed through a short column of Celite followed by evaporation. The residue was purified by Teledyne Isco (RediSepRf column) to give 0.72 g of pure product as a white waxy solid.

[0400] Synthesis of (S)-1-(4-(4-methoxyphenyl)cyclohexyl)heptan-1-ol Borane-tetrahydrofuran complex (21.5 mL, 21.5 mmol, 1.0 M solution in THF, stabilized with 0.005 M N-isopropyl-N-methyl-tert-butylamine (NEVIBA)) was added to 20 mL of anhydrous THF, followed by (R)-2-methyl-CBS-oxazaborolidine [(2-MeCBS] (2.15 mL, 2.15 mmol, 1.0 M solution in toluene). The reaction mixture was stirred at room temperature for 15 min and 1-(4-(4 (Methoxyphenyl)cyclohexyl)heptan-1-one (0.65 g, 2.15 mmol) was added slowly over a period of 2 h at 0° C. The reaction mixture was stirred overnight at room temperature and carefully quenched by portionwise addition of 2.0 M HCl (25 mL) to control H2 evolution. Diethyl ether (25 mL) was added and the organic phase was washed with brine and saturated NaHCO3. The organic phase was dried over MgSO4, filtered and evaporated. The residue was purified by Teledyne Isco (RediSepRf column) to give a white waxy solid. Yield 0.50 g.

[0401] Synthesis of (S)-4-(4-(1-hydroxyheptyl)cyclohexyl)phenol To a mixture of (S)-1-(4-(4-methoxyphenyl)cyclohexyl)heptan-1-ol (0.25 g, 0.82 mmol), 1-dodecanethiol (0.26 g, 0.3 ml, 1.26 mmol) in NMP (N-methylpyrrolidinone, 5 ml), NaOH (100 mg, 2.48 mmol) was added and the reaction mixture was heated at 100° C. overnight. It was cooled to room temperature, diluted with ethyl acetate (15 ml), washed with 1N HCl (10 ml), water, and brine, and dried over Na2SO4. The solvent was evaporated and the residue was purified by (RediSepRf column) to give 96 mg of pure product as a white solid.

[0402] 1H NMR(CDCl3)δ7.10(d,2H),6.79(d,2H),4.53(s,1H),3.45(m,1H),2.42(m,1H),1.96(m,3H),1.83(m,1H),1.31~1.56(m,18H),0.91(t,3H),HRMS Calculated value 289.21621(M-1), Actual value 289.21902 [ka]

[0403] Synthesis of methyl (1R,3S,5s,7s)-5-(4-methoxyphenyl)adamantane-2-carboxylate A mixture of (1R,3S,5s,7s)-5-(4-methoxyphenyl)adamantane-2-carboxylic acid (0.59 g, 2.06 mmol), concentrated H2SO4 (1 ml) in methanol (50 ml) was heated to reflux overnight. After cooling to room temperature, the methanol was evaporated and the residue was neutralized with saturated sodium bicarbonate solution and extracted with ethyl acetate (3x2 ml). The combined organic phase was washed with water and dip and dried over Na2SO4. The solvent was evaporated to give an off-white solid. 0.62 g crude product. Used directly in the next reaction without further purification.

[0404] Synthesis of ((1R,3S,5s,7s)-5-(4-methoxyphenyl)adamantan-2-yl)methanol Methyl (1R,3S,5s,7s)-5-(4-methoxyphenyl)adamantane-2-carboxylate (crude product from the last reaction 0.62 g, 2.06 mmol) was dissolved in anhydrous diethyl ether (50 ml) and treated with LAH (160 mg, 4.21 mmol) at 0° C. for 2 h. 2N NaOH was added dropwise until a white precipitate formed, filtered and washed with diethyl ether (3×30 ml). The combined organic layers were dried over Na2SO4. The solvent was evaporated and the residue was purified by (RediSepRf column) to give 498 mg of pure product as a white solid.

[0405] Synthesis of (1R,3S,5s,7s)-5-(4-methoxyphenyl)adamantane-2-carbaldehyde To a mixture of ((1R,3S,5s,7s)-5-(4-methoxyphenyl)adamantan-2-yl)methanol (0.46 g, 1.7 mmol), NaHCO3 (0.14 g, 1.7 mmol) in anhydrous DCM was added NaOAc (143 mg, 1.7 mmol), pyridinium chlorochromate (PCC, 0.37 g, 1.7 mmol). The reaction mixture was stirred at room temperature for 3 h. It was filtered and the filtrate was washed with 1N HCl, water, NaHCO3, and brine, and dried over Na2SO4. The solvent was evaporated and the residue was purified by (RediSepRf column) to give 290 mg of pure product as a white solid.

[0406] Synthesis of 1-((1R,3S,5s,7s)-5-(4-methoxyphenyl)adamantan-2-yl)heptan-1-ol To a solution of (1R,3S,5s,7s)-5-(4-methoxyphenyl)adamantane-2-carbaldehyde (0.26 g, 0.96 mmol) in anhydrous diethyl ether (20 ml) was added hexylmagnesium bromide (2M in diethyl ether, 0.6 ml, 1.2 mmol) dropwise at 0°C. The reaction mixture was stirred for another hour after the addition, quenched by adding 0.1 N HCl (10 ml), the organic layer was separated and the aqueous layer was extracted with diethyl ether (2x20 ml). The combined organic layers were washed with water, NaHCO3, brine and dried over Na2SO4. The solvent was evaporated and the residue was purified by (RediSepRf column) to give a yellow solid. 287 mg of pure product.

[0407] Synthesis of 1-((1R,3S,5s,7s)-5-(4-methoxyphenyl)adamantan-2-yl)heptan-1-one Pyridinium chlorochromate (PCC, 0.25 g, 1.16 mmol) was suspended in anhydrous DCM (25 ml). A solution of 1-((1R,3S,5s,7s)-5-(4-methoxyphenyl)adamantan-2-yl)heptan-1-ol (0.27 g, 0.76 mmol) in DCM (10 ml) was then added and the reaction mixture was stirred overnight at room temperature. Diethyl ether (25 ml) was added followed by molecular sieves and then stirred for 1 h. The supernatant was decanted and the undissolved residue was washed with dry ether (3x20 ml). The combined organic phase was passed through a short column of Celite followed by evaporation. The residue was purified by Teledyne Isco (RediSepRf column) to give 235 mg of pure product as a white waxy solid.

[0408] Synthesis of (1S)-1-((1R,3S,5R,7R)-5-(4-methoxyphenyl)adamantan-2-yl)heptan-1-ol Borane-tetrahydrofuran complex (5.9 mL, 21.5 mmol, 1.0 M solution in THF, stabilized with 0.005 M N-isopropyl-N-methyl-tert-butylamine (NEVIBA)) was added to 20 mL of anhydrous THF, followed by (R)-2-methyl-CBS-oxazaborolidine [(2-MeCBS] (0.59 mL, 0.59 mmol, 1.0 M solution in toluene). The reaction mixture was stirred at room temperature for 15 min and 1-((1R,3S,5s,7s)-5- (4-Methoxyphenyl)adamantan-2-yl)heptan-1-one (0.21 g, 0.59 mmol) was added slowly over a period of 2 h at 0° C. The reaction mixture was stirred overnight at room temperature and then carefully quenched by portionwise addition of 2.0 M HCl (25 mL) to control H2 evolution. Diethyl ether (25 mL) was added and the organic phase was washed with brine and saturated NaHC03. The organic phase was dried over MgS04, filtered and evaporated. The residue was purified by Teledyne Isco (RediSepRf column) to give a white waxy solid. Yield 158 mg.

[0409] Synthesis of 4-((1R,3R,5S,7R)-4-((S)-1-hydroxyheptyl)adamantan-1-yl)phenyl (1S)-1-((1R,3S,5R,7R)-5-(4-methoxyphenyl)adamantan-2-yl)heptan-1-ol

[0410] To a mixture of (132 mg, 0.37 mmol), NMP (N-methylpyrrolidinone, 5 ml), 1-dodecanethiol (0.21 g, 0.24 ml, 0.56 mmol), NaOH (67.2 mg, 1.68 mmol) was added and the reaction mixture was degassed and then heated at 130° C. overnight. It was cooled to room temperature, diluted with ethyl acetate (15 ml), washed with 1N HCl (10 ml), water, and brine, and dried over Na2SO4. The solvent was evaporated and the residue was purified by (RediSepRf column) to give 62 mg of pure product as a white solid. 1 H NMR(CDCl3)δ7.27(d,2H),6.81(d,2H),4.56(s,1H),3.12(brs,1H),2.22(brs,2H),1.55~1.85(m,24H),0.90(t,3H),HRMS Calculated value 341.2319 (M-1), actual value 315.2372. [ka]

[0411] Synthesis of methyl 4-bromobicyclo[2.2.2]octane-1-carboxylate A solution of bromine (3.3 g, 20.6 mmol) in dichloromethane (20 ml) is added dropwise over 10 min to a refluxing heterogeneous mixture of 4-(methoxycarbonyl)bicyclo[2.2.2]octane-1-carboxylic acid (3.0 g, 13.90 mmol) and mercuric oxide (5.12 g) in dichloromethane (60 ml) and heating is continued for 3.5 h. The reaction mixture is allowed to cool at room temperature before being filtered and the resulting pale orange filtrate is treated with MgSO4 and filtered again. Volatiles are removed and the residue is purified by Teledyne Isco (RediSepRf column) to give 1.93 g of pure product as a white waxy solid.

[0412] Synthesis of methyl 4-phenylbicyclo[2.2.2]octane-1-carboxylate A solution of methyl 4-bromobicyclo[2.2.2]octane-1-carboxylate (1.90 g, 7.7 mmol) in benzene (30 ml) was added dropwise over 15 min to a cooled (ca. -12°C) mixture of benzene (100 ml) and aluminium chloride (5.0 g, 35 mmol). The heterogeneous mixture was stirred for 1 h with gradual warming of the cooling bath to 3°C, then stirred at room temperature overnight. Diluted with diethyl ether (100 ml), washed with 1N HCl, and dried over Na2SO4. The solvent was evaporated and the residue was purified (RediSepRf column) to give 1.6 g of pure product as a white solid.

[0413] Synthesis of (4-phenylbicyclo[2.2.2]octan-1-yl)methanol Methyl 4-phenylbicyclo[2.2.2]octane-1-carboxylate (0.51 g, 2.1 mmol) was dissolved in anhydrous diethyl ether (25 ml) and treated with LAH (159 mg, 4.2 mmol) at 0° C. for 2 h. 2N NaOH was added dropwise until a white precipitate formed, filtered and washed with diethyl ether (3×30 ml). The combined organic layers were dried over Na2SO4. The solvent was evaporated and the residue was purified by (RediSepRf column) to give 0.45 g of pure product as a white solid.

[0414] Synthesis of 4-phenylbicyclo[2.2.2]octane-1-carbaldehyde To a mixture of (4-phenylbicyclo[2.2.2]octan-1-yl)methanol (0.43 g, 1.99 mmol), NaHCO3 (166 mg, 1.99 mmol), NaOAc (163 mg, 1.99 mmol) in water DCM, pyridinium chlorochromate (PCC, 0.43 g, 1.99 mmol) was added. The reaction mixture was stirred at room temperature for 3 h. Filtered, the filtrate was washed with 1N HCl, water, NaHCO3, and brine, and dried over Na2SO4. The solvent was evaporated, and the residue was purified by (RediSepRf column) to give 405 mg of pure product as a white solid.

[0415] Synthesis of 1-(4-phenylbicyclo[2.2.2]octan-1-yl)heptan-1-ol To a solution of 4-phenylbicyclo[2.2.2]octane-1-carbaldehyde (0.4 g, 1.87 mmol) in anhydrous diethyl ether (25 ml) was added hexylmagnesium bromide (2M in diethyl ether, 02.0 ml, 4.0 mmol) dropwise at 0° C. The reaction mixture was stirred for another hour after the addition, quenched by adding 0.1 N HCl (10 ml), the organic layer was separated, and the aqueous layer was extracted with diethyl ether (2×20 ml). The combined organic layers were washed with water, NaHCO3, brine, and dried over Na2SO4. The solvent was evaporated and the residue was purified by (RediSepRf column) to give a yellow solid. 0.48 g of pure product.

[0416] Synthesis of 1-(4-(4-bromophenyl)bicyclo[2.2.2]octan-1-yl)heptan-1-ol To a mixture of 1-(4-phenylbicyclo[2.2.2]octan-1-yl)heptan-1-ol (0.28, 0.94 mmol), silver acetate (0.24, 1.09 mmol) in chloroform (25 ml) was added dropwise a solution of bromine (0.16 g, 0.99 mmol) in chloroform (10 ml) at 0° and stirred for 3 h, then warmed to room temperature. Washed with NaHCO3, water, and brine, dried over Na2SO4. The solvent was evaporated and the residue was purified by (RediSepRf column) to give a yellow solid. 0.28 g of pure product.

[0417] Synthesis of 1-(4-(4-bromophenyl)bicyclo[2.2.2]octan-1-yl)heptan-1-one Pyridinium chlorochromate (PCC, 0.27 g, 1.27 mmol) was suspended in anhydrous DCM (25 ml). A solution of 1-(4-(4-bromophenyl)bicyclo[2.2.2]octan-1-yl)heptan-1-ol (0.16 g, 0.42 mmol) in DCM (10 ml) was then added and the reaction mixture was stirred overnight at room temperature. Diethyl ether (25 ml) was added followed by molecular sieves and then stirred for 1 h. The supernatant was decanted and the undissolved residue was washed with dry ether (3x20 ml). The combined organic phase was passed through a short column of Celite followed by evaporation. The residue was purified by Teledyne Isco (RediSepRf column) to give 135 mg of pure product as a white waxy solid.

[0418] Synthesis of (S)-1-(4-(4-bromophenyl)bicyclo[2.2.2]octan-1-yl)heptan-1-ol Borane-tetrahydrofuran complex (3.2 mL, 3.2 mmol, 1.0 M solution in THF, stabilized with 0.005 M N-isopropyl-N-methyl-tert-butylamine (NEVIBA)) was added to 20 mL of anhydrous THF, followed by (R)-2-methyl-CBS-oxazaborolidine [(2-MeCBS] (0.32 mL, 0.32 mmol, 1.0 M solution in toluene). The reaction mixture was stirred at room temperature for 15 min and diluted with 1-(4-(4-bromophenyl)-2-methyl-2-phenylpropanediol) in 10 mL of anhydrous THF. (2.2.2)octan-1-yl)bicyclo[2.2.2]octan-1-yl)heptan-1-one (0.12 g, 0.32 mmol) was added slowly over a period of 2 h at 0° C. The reaction mixture was stirred overnight at room temperature and carefully quenched by portionwise addition of 2.0 M HCl (25 mL) to control H2 evolution. Diethyl ether (25 mL) was added and the organic phase was washed with brine and saturated NaHCO3. The organic phase was dried over MgSO4, filtered and evaporated. The residue was purified by Teledyne Isco (RediSepRf column) to give a white waxy solid. Yield 98 mg.

[0419] Synthesis of (S)-4-(4-(1-hydroxyheptyl)bicyclo[2.2.2]octan-1-yl)phenyl A mixture of (S)-1-(4-(4-bromophenyl)bicyclo[2.2.2]octan-1-yl)heptan-1-ol (72 mg, 0.19 mmol), benzaldehyde oxime (30 mg, 0.25 mmol), Cs2CO3 (136.2 mg, 0.42 mmol), and RockPhos Pd G3 (8 mg) in DMF (1 ml) was degassed with Ar for 15 min. The mixture was then heated at 80° C. for 18 h. The mixture was then cooled to room temperature, diluted with ethyl acetate (10 ml), washed with 1N HCl (10 ml), water, and brine, dried over Na2SO4, filtered, and evaporated. The residue was purified by (RediSepRf column) to give 98 mg of a white solid. 1H NMR(CDCl3)δ7.21(d,2H),6.79(d,2H),3.22(d,1H),1.81(t,6H),1.28~1.61(m,18H),0.90(t,3H),HRMS calculated value 315.23186(M-1),actual value 315.23676

[0420] The selectivity and potency of various exemplary compounds in the second library was achieved by in vitro testing in ERα and ERβ cell-based reporter assays, and the results are included in Table 8 below. [Table 8]

[0421] Example 23 Evaluation of illustrative carboranes for the treatment of fibrotic conditions The in vivo efficacy of compound 25 (shown below) was evaluated in the STAM model of non-alcoholic steatohepatitis (NASH, a fibrotic condition). [ka]

[0422] Materials and Methods Compound 25 was prepared as described above. To prepare the dosing solution, Compound 25 was weighed and suspended in vehicle (5% DMSO, 5% Tween® 20, water). Compound 25 was administered orally in a volume of 10 mL / kg. Compound 25 was administered once a day at two dose levels, 10 and 100 mg / kg.

[0423] Pathogen-free, 14-day-old pregnant C57BU6 mice were obtained for use in this study. All animals used in this study were housed and cared for according to industry standards. NASH was established in male mice by a single subcutaneous injection of 200 μg of streptozotocin (STZ, Sigma Aldrich, USA) at 2 days of age and in male mice fed a high-fat diet (HFD, 57 kcal% lipids, Cat. No. HFD32, CLEA Japan Inc., Japan) ad libitum after 4 weeks of age (28 days). NASH mice were randomized into three groups of eight mice at 5 weeks of age (35 ± 2 days) on the day before the start of treatment based on body weight. Litter-mate control mice (n = 8) without STZ priming were set up for control purposes. Individual body weights were measured daily during the treatment period. Survival, clinical signs, and behavior of mice were also monitored.

[0424] Plasma biochemistry measurements To evaluate plasma biochemistry, nonfasting blood was collected in polypropylene tubes with anticoagulant (Novo-Heparin, Mochida Pharmaceutical Co. Ltd., Japan) and centrifuged at 1,000 × g for 15 min at 4 °C. Supernatants were collected and stored at -80 °C until use. Plasma ALT levels were measured by FUJI DRI-CHEM 7000 (Fujifilm, Japan).

[0425] Liver biochemistry measurements Liver total lipid extracts were obtained by the Folch method (Folch J. et al., J. Biol. Chem. 1957;226:497). Liver samples were homogenized in chloroform-methanol (2:1, v / v) and incubated overnight at room temperature. After washing with chloroform-methanol-water (8:4:3, v / v / v), the extracts were dried and dissolved in isopropanol. Liver triglyceride content was measured by Triglyceride E-Test (Wako Pure Chemical Industries, Ltd., Japan).

[0426] For histological analysis HE staining, sections were cut from paraffin blocks of liver tissue prefixed in Bouin's solution and stained with Lillie-Mayer's Hematoxylin (Muto Pure Chemicals Co., Ltd., Japan) and eosin solution (Wako Pure Chemical Industries). NAFLD Activity score (NAS) was calculated according to the Kleiner criteria (Kleiner DE. et al., Hepatology, 2005; 41: 1313). To visualize collagen deposition, Bouin's fixed liver sections were stained using picrosirius red solution (Waldeck, Germany). For quantitative analysis of fibrotic areas, bright-field images of Sirius red stained sections were captured around the central vein using a digital camera (DFC295; Leica, Germany) at 200x magnification, and the positive areas in five fields / section were measured using ImageJ software (National Institute of Health, USA).

[0427] Sample collection. For plasma samples, unfixed blood was collected in polypropylene tubes with anticoagulant (Novo-Heparin) and centrifuged at 1,000 x g for 15 min at 4 °C. Supernatants were collected and stored at -80 °C for biochemistry (20 μL) and transport (remainder).

[0428] For liver samples, the lateral left lobe was collected and cut into six pieces. Two parts of the lateral left lobe, the medial left lobe and the right lobe, and the caudate lobe were quickly frozen in liquid nitrogen and stored at -80°C for transport. The other two parts of the lateral left lobe were fixed in Bouin's solution and then embedded in paraffin. The paraffin blocks were stored at room temperature for histology. The remaining part of the lateral left lobe was embedded in OCT compound and quickly frozen in liquid nitrogen. The OCT blocks were stored at -80°C. The right lobe was quickly frozen in liquid nitrogen and stored at -80°C for liver biochemistry.

[0429] Statistical tests. Statistical analysis was performed using the Bonferroni Multiple Comparison Test on GraphPad Prism 6 (GraphPad Software Inc., USA). A P value < 0.05 was considered statistically significant. A trend or tendency was inferred if the one-tailed t-test returned P value < 0.1. The results obtained were expressed as the mean ± SD.

[0430] Experimental design and procedures Study Groups The mouse population was divided into four study groups. Group 1: normal. Eight normal mice were left without any treatment until sacrifice. Group 2: Vehicle. Eight NASH mice were orally administered vehicle (5% DMSO, 5% Tween® 20, water) at a volume of 10 mL / kg once daily at age 5-12 weeks. Group 3: Compound High. Eight NASH mice were orally administered vehicle supplemented with Compound 25 at a dose of 100 mL / kg once daily from 5 to 12 weeks of age. Group 4: Compound Low. Eight NASH mice were orally administered vehicle supplemented with Compound 25 at a dose of 10 mL / kg once daily from 5 to 12 weeks of age. The treatment schedule is summarized in the table below. [Table 9]

[0431] Animal monitoring and sacrifice. Viability, clinical signs and behavior were monitored daily. Body weights were recorded prior to treatment. Mice were observed approximately 60 minutes after each dose for clinical signs of toxicity, moribundity and mortality. Animals were sacrificed at 12 weeks of age under isoflurane anesthesia (Pfizer Inc.) and exsanguination via direct cardiac puncture.

[0432] result Body Weight and General Condition Figure 1 shows the average body weight changes observed in the four study groups over the course of the treatment period. The average body weight in all groups increased progressively during the treatment period. The average body weight of the vehicle group was significantly lower than that of the regular group from day 0 to day 49. There was no significant difference in average body weight between the vehicle and compound-treated groups on any day during the treatment period.

[0433] During the treatment period, mice died before reaching day 49 as follows: 3 out of 8 mice died in the vehicle group, and 2 out of 8 mice died in the compound high and compound low groups.

[0434] Body weight and liver weight on the day of sacrifice. Figure 2A is a plot showing the body weight of the animals on the day of sacrifice. The vehicle group showed a significant decrease in mean body weight on the day of sacrifice compared to the normal group. There was no significant difference in mean body weight on the day of sacrifice between the vehicle group and the compound-treated group.

[0435] Figure 2B is a plot showing the liver weight of animals on the day of sacrifice. The vehicle group showed a significant increase in mean liver weight compared to the normal group. There was no significant difference in mean liver weight between the vehicle group and the compound-treated group.

[0436] FIG. 2C is a plot showing the liver weight to body weight ratio of animals on the day of sacrifice. The vehicle group showed a significant increase in mean liver weight to body weight ratio compared to the normal group. The mean liver weight to body weight ratio in the compound (high) group tended to increase compared to the vehicle group. There was no significant difference in mean liver weight to body weight ratio between the vehicle group and the compound low treatment group.

[0437] The results of these studies are summarized in the table below. [Table 10]

[0438] Biochemistry. Figure 3A is a plot showing plasma alanine aminotransferase (ALT) levels on the day of sacrifice. The vehicle group showed a significant increase in plasma ALT levels compared to the normal group. The compound high and compound low groups showed a significant decrease in plasma ALT levels compared to the vehicle group.

[0439] FIG. 3B is a plot showing liver triglyceride levels (mg / g liver) on the day of sacrifice. The vehicle group showed a significant increase in liver triglyceride levels compared to the normal group. The compound high and compound low groups showed a significant decrease in liver triglycerides compared to the vehicle group.

[0440] These results are summarized in the table below. [Table 11]

[0441] Histological analysis Liver sections are stained with HE and imaged as described above. Fatty liver, lobule inflammation and hepatocyte ballooning are evaluated to calculate NAFLD activity score. The definition of NAS components is included in the table below. [Table 12]

[0442] Liver sections from the vehicle group showed microdroplet and macrodroplet fatty deposits, hepatocyte ballooning and inflammatory cell infiltration compared to the normal group. The vehicle group showed a significant increase in NAS levels compared to the normal group. NAS in the compound high and compound low groups tended to be lower than that in the vehicle group.

[0443] Figure 4 is a plot showing the non-alcoholic fatty liver disease (NAFLD) activity score on the day of sacrifice. Figure 5A is a plot showing the fatty liver score on the day of sacrifice. Figure 5B is a plot showing the inflammation score on the day of sacrifice. Figure 5C is a plot showing the ballooning score on the day of sacrifice. The results of these studies are summarized in the table below. [Table 13]

[0444] Sirius Red Staining and Fibrotic Area. Liver sections were stained with Sirius Red as shown, and positive areas were determined as described above. Liver sections from the vehicle group showed increased collagen deposition in the pericentral regions of the liver lobule compared to the normal group. The vehicle group showed a significant increase in fibrotic area (Sirius Red positive area) compared to the normal group. The compound high group showed a significant decrease in fibrotic area compared to the vehicle group.

[0445] Figure 6 is a plot showing the fibrotic area (Sirius Red positive area (%)) on the day of sacrifice. The results of these studies are summarized in the table below. [Table 14]

[0446] Summary and Conclusion Compound 25 treatment showed a significant decrease in plasma ALT level and liver triglyceride content compared with vehicle group.Compound 25 treatment showed a tendency to decrease NAFLD activity score (NAS) compared with vehicle group.Compound 25 treatment at high doses showed a significant decrease in fibrotic area compared with vehicle group in a dose-dependent manner.

[0447] In conclusion, compound 25 demonstrated hepatoprotective potential, anti-fatty liver and anti-fibrotic effects in this NASH model.

[0448] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which the disclosed invention belongs. Publications cited herein and the materials for which they are cited are specifically incorporated by reference.

[0449] Those skilled in the art will recognize, or be able to ascertain using no more than routine experimentation, many equivalents to the specific embodiments of the invention described herein which equivalents are intended to be encompassed by the following claims.

Claims

1. A pharmaceutical composition for reducing fibrosis of a cell or tissue or for treating a fibrotic condition, wherein treating a fibrotic condition comprises reducing fibrosis of a cell or tissue; wherein the pharmaceutical composition comprises a carborane and a pharma- ceutically acceptable excipient, the carborane comprising an ERβ agonist, and the carborane comprising a compound defined in formula XI, or a pharma- ceutically acceptable salt thereof: 【Chemistry 1】 During the ceremony, Q is a substituted or unsubstituted 1,12-dicarba-closo-dodecaborane cluster; D is -S-, -S(O)-, or -S(O)(O)-; X is OH; R ６ C may be unsubstituted or substituted by OH or an aryl group; ４ ~C ２０ is alkyl, The pharmaceutical composition.

2. The carborane is 【Chemistry 2】 (In the formula, ● is a carbon atom, ○ is B-H, B-halogen, B-alkyl, B-OH, or B-NH ２ (It is) and pharma- ceutically acceptable salts thereof.

3. The pharmaceutical composition of any one of claims 1 to 2, wherein the carborane comprises a selective ERβ agonist.

4. The carborane has an EC ５０ EC of 800 nM or less ５０ The pharmaceutical composition according to any one of claims 1 to 2, comprising:

5. 3. The pharmaceutical composition of any one of claims 1 to 2, wherein the carborane has an ERβ agonist to ERα agonist ratio of 8 or greater, such as an ERβ agonist to ERα agonist ratio of 400 or greater.

6. 3. The pharmaceutical composition of any one of claims 1-2, wherein treating the fibrotic condition comprises reducing or inhibiting one or more of the formation or deposition of tissue fibrosis, or reducing the size, cellularity, composition, cell or collagen content of a fibrotic lesion.

7. 3. The pharmaceutical composition according to any one of claims 1 to 2, wherein the fibrotic condition is a pulmonary fibrotic condition, a liver fibrotic condition, a heart or vasculature fibrotic condition, a kidney fibrotic condition, a skin fibrotic condition, a gastrointestinal fibrotic condition, a bone marrow or hematopoietic tissue fibrotic condition, a nervous system fibrotic condition, or a combination thereof.

8. 3. The pharmaceutical composition of any one of claims 1 to 2, wherein the fibrotic condition is secondary to an infectious disease, an inflammatory disease, an autoimmune disease, a connective tissue disease, a malignant or clonal proliferative disorder, a toxin, an environmental hazard, tobacco smoking, a wound, or a medical treatment selected from a surgical incision, chemotherapy or radiation.

9. The pharmaceutical composition according to any one of claims 1 to 2, wherein the fibrotic condition is a pulmonary fibrotic condition.

10. 10. The pharmaceutical composition of claim 9, wherein the fibrotic condition of the lung is selected from one or more of pulmonary fibrosis, idiopathic pulmonary fibrosis (IPF), usual interstitial pneumonia (UIP), interstitial lung disease, idiopathic fibrosing alveolitis (CFA), bronchiectasis.

11. The pharmaceutical composition according to any one of claims 1 to 2, wherein the fibrotic condition is a fibrotic condition of the liver.

12. 12. The pharmaceutical composition of claim 11, wherein the fibrotic condition of the liver is selected from fatty liver disease, steatosis, primary biliary cirrhosis (PBC), cirrhosis, alcohol-induced liver fibrosis, bile duct injury, bile duct fibrosis, liver fibrosis associated with hepatitis infection, autoimmune hepatitis, nonalcoholic fatty liver disease (NAFLD), nonalcoholic steatohepatitis (NASH), or progressive massive fibrosis.

13. 13. The pharmaceutical composition of claim 12, wherein the fibrotic condition of the liver is selected from non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH).

14. The pharmaceutical composition according to any one of claims 1 to 2, wherein the fibrotic condition is a fibrotic condition of the heart or vasculature.

15. 15. The pharmaceutical composition of claim 14, wherein the fibrotic condition of the heart or vasculature is myocardial fibrosis.

16. The pharmaceutical composition according to any one of claims 1 to 2, wherein the fibrotic condition is a fibrotic condition of the kidney.

17. 17. The pharmaceutical composition of claim 16, wherein the fibrotic condition of the kidney is chronic renal fibrosis, injury / fibrosis associated nephropathy, diabetic nephropathy, lupus, renal scleroderma, glomerulonephritis, focal segmental glomerulosclerosis, IgA nephropathy human chronic kidney disease (CKD) associated renal fibrosis, chronic progressive nephropathy (CPN), tubulointerstitial fibrosis, ureteral obstruction, chronic uremia, chronic interstitial nephritis, radiation nephropathy, glomerulosclerosis, progressive glomerulonephropathy (PGN), endothelial / thrombotic microangiopathy, or HIV-associated nephropathy.

18. The pharmaceutical composition according to any one of claims 1 to 2, wherein the fibrotic condition is a fibrotic condition of the skin.

19. 19. The pharmaceutical composition of claim 18, wherein the fibrotic condition of the skin is selected from dermal fibrosis, scleroderma, nephrogenic systemic fibrosis, and keloids.

20. The pharmaceutical composition according to any one of claims 1 to 2, wherein the fibrotic condition is a fibrotic condition of the gastrointestinal tract.

21. 21. The pharmaceutical composition of claim 20, wherein the fibrotic condition of the gastrointestinal tract is diffuse scleroderma of the gastrointestinal tract.

22. The pharmaceutical composition according to any one of claims 1 to 2, wherein the fibrotic condition is a fibrotic condition of the bone marrow.

23. 23. The pharmaceutical composition of claim 22, wherein the fibrotic condition of the bone marrow or hematopoietic tissue is selected from one or more of: primary myelofibrosis; fibrosis associated with a hematological disorder selected from polycythemia vera, essential thrombocythemia, myelodysplasia, hairy cell leukemia, lymphoma, or multiple myeloma; fibrosis secondary to a non-hematologic disorder selected from solid tumor metastasis to the bone marrow, an autoimmune disorder; infection; or secondary hyperparathyroidism.

24. A compound defined by formula XI, or a pharma- ceutically acceptable salt thereof: 【Chemistry 3】 During the ceremony, Q is a substituted or unsubstituted 1,12-dicarba-closo-dodecaborane cluster; D is -S-, -S(O)-, or -S(O)(O)-; X is OH; R ６ is a substituted or unsubstituted C ４ ~C ２０ alkyl, which may be unsubstituted or substituted by OH or an aryl group; The compound, or a pharma- ceutically acceptable salt thereof.

25. R ６ is a substituted or unsubstituted C ６ ~C ９ 25. The compound of claim 24, which is alkyl.

26. The compound has an EC ５０ EC of 800 nM or less, including ５０ The compound according to any one of claims 24 to 25, having the formula:

27. 26. The compound of any one of claims 24 to 25, wherein the compound has an ERβ agonist to ERα agonist ratio of 8 or greater, including an ERβ agonist to ERα agonist ratio of 400 or greater.

28. The compound of any one of claims 24 to 25, wherein the carborane cluster comprises a heteroatom.

29. The compound of any one of claims 24 to 25, wherein the carborane cluster comprises an isotopically labeled atom.

30. The isotopically labeled atom １０ 30. The compound of claim 29 comprising B.

31. 30. The compound of claim 29, wherein the isotopically labeled atom comprises a radioactive halogen bonded to the carborane cluster.

32. A pharmaceutical composition for treating cancer, comprising a compound according to any one of claims 24 to 25 and a pharma- ceutically acceptable excipient.

33. 33. The pharmaceutical composition of claim 32, wherein the cancer is selected from the group consisting of breast cancer, colon cancer, endometrial cancer, ovarian cancer, and prostate cancer.

34. 33. The pharmaceutical composition of claim 32, wherein the pharmaceutical composition further comprises an additional anti-cancer agent.

35. A pharmaceutical composition for inhibiting tumor growth, comprising a compound according to any one of claims 24 to 25 and a pharma- ceutically acceptable excipient.

36. A pharmaceutical composition for treating an inflammatory disease comprising a compound according to any one of claims 24 to 25 and a pharma- ceutically acceptable excipient.

37. 37. The pharmaceutical composition of claim 36, wherein the inflammatory disease is selected from the group consisting of arthritis and inflammatory bowel disease.

38. 37. The pharmaceutical composition of claim 36, wherein the pharmaceutical composition further comprises an anti-inflammatory agent.

39. A pharmaceutical composition for treating a neurodegenerative disease comprising a compound according to any one of claims 24 to 25 and a pharma- ceutically acceptable excipient.

40. A pharmaceutical composition for treating a psychotropic disorder comprising a compound according to any one of claims 24 to 25 and a pharma- ceutically acceptable excipient.

41. A method of imaging a cell or a population of cells expressing ERβ, comprising contacting said cell or population of cells removed from the body of a subject of interest with a compound according to any one of claims 24-25, or a pharmaceutical composition according to any one of claims 1-23, and detecting the compound according to any one of claims 24-25, or the pharmaceutical composition according to any one of claims 1-23.

42. 42. The method of claim 41, wherein the cell or population of cells is indicative of cancer, an inflammatory disease, a neurodegenerative disease, a psychotropic disorder, or a combination thereof.

43. 43. The method of claim 42, wherein the cancer is selected from the group consisting of breast cancer, colon cancer, and prostate cancer.

44. 43. The method of claim 42, wherein the inflammatory disease is selected from the group consisting of arthritis and inflammatory bowel disease.

45. A medicament for treating cancer comprising a combination of a compound according to any one of claims 24 to 25 and a further anti-cancer agent, wherein the compound according to any one of claims 24 to 25 is administered simultaneously with, before or after the further anti-cancer agent.

46. A medicament for treating an inflammatory disease comprising a combination of a compound according to any one of claims 24 to 25 and a further anti-inflammatory agent, wherein the compound according to any one of claims 24 to 25 is administered simultaneously with, before or after the further anti-inflammatory agent.

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