ERR regulator

Abstract

On the one hand, this disclosure describes compounds that can be used to modulate the activity of estrogen receptor-associated orphan receptors (EERs). Pharmaceutical formulations, methods of synthesis, and uses thereof are also described.

Description

[0001] Cross-references to related applications

[0002] This application claims the benefit of priority to U.S. Provisional Patent Application No. 63 / 546,458, filed October 30, 2023, the entire contents of which are incorporated herein by reference.

[0003] Federally funded research

[0004] This work was conducted by the National Institute on Aging, National Institutes of Health, with government funding under grant numbers R21AG065657 and RAG077160A. The U.S. government holds certain rights to this invention. Technical Field

[0005] This disclosure relates to the fields of medicine, pharmacology, chemistry, and metabolism. Specifically, it discloses novel compounds, compositions, and treatment methods related to orphan receptors associated with estrogen receptors. Background Technology

[0006] The nuclear receptor (NR) superfamily comprises a group of 48 transcription factors in humans, including receptors for steroid hormones, thyroid hormones, lipophilic vitamins, and cholesterol metabolites (Manglesdorf et al., 1995; Evans, RM, 1988). Approximately half of the NRs are classified as orphan receptors because they lack well-characterized ligands (Kliewer et al., 1999; Giguere, V., 1999; Manglesdorf & Evans, 1995; Omalley & Conneely, 1992). In fact, almost all NRs with identified ligands are well-characterized targets for developing drugs to treat a wide range of diseases, including diabetes, atherosclerosis, inflammation, and endocrine / reproductive disorders. NRs are proteins composed of multiple domains that provide a variety of functions, including DNA binding, small molecule ligand binding, and transcriptional regulatory activity (Manglesdorf et al., 1995; Evans, RM, 1988). NR functions as a transcription factor and typically regulates the transcription of target genes in a ligand-dependent manner. NR recognizes specific DNA response elements in the promoters / enhancers of their homologous target genes, where they respond to ligands by altering their ability to recruit a variety of other transcriptional proteins that change gene expression rates. Much of the known information about the ligand-dependent transcriptional regulation mechanism of NR has been revealed through structure-function studies of the carboxyl-terminal ligand-binding domain (LBD). The LBD is a globular domain composed almost entirely of α-helices arranged in a three-layer “sandwich” configuration. NR ligands bind to the ligand-binding pocket (LBP) within this globular domain, consistent with the typical hydrophobic properties of NR ligands.

[0007] Estrogen receptor-associated orphan receptors (ERRs) were the first orphan NRs to be identified. As their names suggest, they are very similar to estrogen receptors (ERα and ERβ) but do not bind to endogenous ER ligands. ER functions as a obligate homodimer, while ERRs (ERRα, ERRβ, and ERRγ) function as monomers and bind to a DNA reactive element distinct from ER (Giguere, V., 2008). ERRα is widely expressed, as is ERRγ, but is most highly expressed in high-energy-demand tissues such as skeletal muscle, heart, adipose tissue, liver, and kidney (Giguere et al., 1988; Chen et al., 1999; Sladek et al., 1997). ERRβ is considerably restricted in its expression pattern, with low levels found in the liver, stomach, skeletal muscle, heart, and kidney (Giguere et al., 1988; Chen et al., 1999). Unlike ERs, which require ligand binding to exhibit transcriptional activity, all three ERs exhibit constitutive transcriptional activity in the absence of any ligand (Giguere, V., 2008). Given the lack of ligands that bind to these receptors, there remains a need to develop new compounds that bind to these ligands. Summary of the Invention

[0008] On the one hand, compounds of the following formula, or pharmaceutically acceptable salts thereof, are disclosed:

[0009] (II-A)

[0010] Wherein: A is phenyl, pyridyl, thiophenyl, or naphthyl; B is phenyl, imidazolyl, or naphthyl; each R1 is independently H, OH, halogen, or C. 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy or C 1-6 Haloalkoxy groups; each R2 is independently H, OH, halogen, N(R4)2, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy or C 1-6 Haloalkoxy; each R3 is independently H or -C(O)-phenyl-tert-butyl; each R4 is independently H or C 1-6 Alkyl; n is 0, 1, 2, 3, 4, 5, 6 or 7; and m is 0, 1, 2, 3, 4, 5, 6 or 7.

[0011] In some embodiments, A is phenyl. In some embodiments, B is phenyl. In some embodiments, B is naphthyl. In some embodiments, at least one R1 is a halogen. In some embodiments, at least one R1 is C. 1-6Alkyl halide. In some embodiments, at least one R1 is CF3. In some embodiments, n is 1. In some embodiments, at least one R2 is OH. In some embodiments, at least one R2 is a halogen and one R2 is OH. In some embodiments, m is 1 or 2.

[0012] In some embodiments, the compound has the following formula

[0013] Where B is phenyl, imidazolyl, or naphthyl; each R1 is independently H, OH, halogen, or C. 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy or C 1-6 Haloalkoxy groups; each R2 is independently H, OH, halogen, N(R4)2, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy or C 1-6 Halogenated alkoxy group; R4 is H or C 1-6 Alkyl group; n is 0, 1 or 2; and m is 0, 1 or 2; or a pharmaceutically acceptable salt thereof.

[0014] In some embodiments, the compound has the following formula

[0015] Each R1 is independently H, OH, halogen, or C. 1-6 Alkyl group; each R2 is independently H, OH, halogen, or C. 1-6 Alkyl group; n is 1 or 2; and m is 0, 1 or 2; or a pharmaceutically acceptable salt thereof.

[0016] In some embodiments, the compound is selected from Table A, or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is in a non-salt form.

[0017] On the other hand, a pharmaceutical composition comprises a compound and one or more pharmaceutically acceptable carriers or solvents.

[0018] In another aspect, a method for modulating the activity of estrogen-related receptors is disclosed, the method comprising contacting the estrogen-related receptors with a compound.

[0019] In another aspect, a method for modulating the activity of estrogen-related receptors is disclosed, the method comprising contacting the estrogen-related receptors with a compound.

[0020] In some implementations, the estrogen-related receptor is selected from the group consisting of estrogen-related receptor α, estrogen-related receptor β, and estrogen-related receptor γ.

[0021] On the other hand, one method of inhibiting the activity of estrogen-related receptors includes administering the compounds disclosed herein to a subject.

[0022] In another aspect, a method of treating a disease or disorder of a subject or alleviating the severity of said disease or disorder includes administering the compounds disclosed herein to the subject. In some embodiments, the disease or disorder is selected from the group consisting of: diabetes, breast cancer, bone disease, bone resorption, heart failure, obesity, metabolic diseases, muscle wasting and other muscle function disorders, mitochondrial dysfunction, kidney disease and dysfunction, and neurodegenerative diseases including AD, PD, and ALS. Detailed Implementation

[0023] As provided herein, this disclosure relates to compounds that modulate the activity of estrogen receptor-associated orphan receptors. In some embodiments, this disclosure provides compounds of the following formula, or pharmaceutically acceptable salts thereof:

[0024] (I)

[0025] in:

[0026] R1 is an alkyl group. (C≤12) cycloalkyl (C≤12) aryl (C≤12) Aryl alkyl (C≤12) heteroaryl (C≤12) , heteroaryl (C≤12) heterocyclic alkyl (C≤12) heterocyclic alkyl (C≤12) Or any substituted form of these groups; and

[0027] R2 is an alkyl group. (C≤12) cycloalkyl (C≤12) aryl (C≤12) Aryl alkyl (C≤12) heteroaryl (C≤12) , heteroaryl (C≤12) heterocyclic alkyl (C≤12) heterocyclic alkyl (C≤12) Or any substitution of these groups;

[0028] R3 is hydrogen or alkyl. (C≤12) acyl group (C≤12) sulfonyl (C≤12) Or any substituted form of these groups.

[0029] In some aspects, this disclosure provides a method for modulating the activity of estrogen-related receptors, the method comprising contacting the estrogen-related receptors with a compound of the following formula or a pharmaceutically acceptable salt thereof:

[0030] (I)

[0031] in:

[0032] R1 is an alkyl group. (C≤12) cycloalkyl (C≤12) aryl (C≤12) Aryl alkyl (C≤12) heteroaryl (C≤12) , heteroaryl (C≤12) heterocyclic alkyl (C≤12) heterocyclic alkyl (C≤12) Or any substituted form of these groups; and

[0033] R2 is an alkyl group. (C≤12) cycloalkyl (C≤12) aryl (C≤12) Aryl alkyl (C≤12) heteroaryl (C≤12) , heteroaryl (C≤12) heterocyclic alkyl (C≤12) heterocyclic alkyl (C≤12) Or any substitution of these groups;

[0034] R3 is hydrogen or alkyl. (C≤12) acyl group (C≤12) sulfonyl (C≤12) Or any substituted form of these groups.

[0035] In some implementations, R1 and R2 are the same. In other implementations, R1 and R2 are different.

[0036] In some embodiments, R3 is an acyl group. In some embodiments, R3 is a substituted benzoyl group. In some embodiments, the benzoyl group is substituted with a tert-butyl group.

[0037] In some implementations, R1 is a cycloalkyl group. (C≤12) or substituted cycloalkyl (C≤12) In some embodiments, R1 is a cycloalkyl group. (C≤12) For example, cyclohexyl or adamantyl. In other embodiments, R1 is an aralkyl group. (C≤12) or substituted aralkyl (C≤12) In some embodiments, R1 is a substituted aralkyl group. (C≤12) For example, 2-nitrobenzyl. In other embodiments, R1 is aryl. (C≤12) Or substituted aryl (C≤12) In some implementations, R1 is an aryl group. (C≤12) For example, phenyl or 4-methylphenyl. In other embodiments, R1 is a substituted aryl group. (C≤12)Examples include 4-bromophenyl, 4-chlorophenyl, 2-nitrophenyl, 3-nitrophenyl, 4-nitrophenyl, 4-methoxyphenyl, 3-trifluoromethylphenyl, 4-trifluoromethylphenyl, 2-aminophenyl, 3-aminophenyl, 4-aminophenyl, 2-amino-4-methoxyphenyl, 2-amino-4-bromophenyl, 2-amino-5-bromophenyl, 2-amino-5-methoxyphenyl, 2-amino-3-methoxyphenyl, 2-amino-3-chlorophenyl, 2-nitro-5-bromophenyl, 2-nitro-4-bromophenyl, 2-nitro-4-methoxyphenyl, 2-nitro-5-methoxyphenyl, 2-nitro-3-methoxyphenyl, or 2-nitro-3-chlorophenyl.

[0038] In some embodiments, R1 is an optionally substituted phenyl, optionally substituted pyridyl, optionally substituted naphthyl, or optionally substituted thiophene. In some embodiments, R1 is a benzene ring substituted with one to three substituents. In some embodiments, R1 is an unsubstituted benzene ring. In some embodiments, the benzene ring is substituted with one substituent. In some embodiments, the benzene ring is substituted with two substituents. In some embodiments, the benzene ring is substituted with three substituents. In some embodiments, R1 is an optionally substituted 2-pyridyl. In some embodiments, R1 is an optionally substituted 4-pyridyl. In some embodiments, R1 is an optionally substituted naphthyl. In some embodiments, R1 is an optionally substituted 2-thiophene.

[0039] In some implementations, R2 is an alkyl group. (C≤12) or substituted alkyl (C≤12) In some embodiments, R2 is an alkyl group. (C≤12) For example, ethyl. In other embodiments, R2 is aryl. (C≤12) Or substituted aryl (C≤12) In some implementations, R2 is an aryl group. (C≤12) For example, phenyl, 2-methylphenyl, 4-methylphenyl, or 4-tert-butylphenyl. In other embodiments, R2 is a substituted aryl group. (C≤12) Examples include 2-nitrophenyl, 2-chlorophenyl, 4-chlorophenyl, 4-methoxyphenyl, 3-methoxyphenyl, 3-nitrophenyl, 4-dimethylaminophenyl, 4-trifluorophenyl, 4-bromophenyl, or 4-chlorophenyl. In other embodiments, R2 is a heteroaryl group. (C≤12) Or substituted heteroaryl (C≤12) In some implementations, R2 is a heteroaryl group. (C≤12) For example, 2-pyridyl, 2-quinolinyl, 4-quinolinyl, furanyl, thiophenyl or 5-methylfuranyl.

[0040] In some embodiments, R2 is an optionally substituted phenyl, optionally substituted pyridyl, optionally substituted naphthyl, or optionally substituted thiophene. In some embodiments, R2 is a benzene ring substituted with one to three substituents. In some embodiments, R2 is an unsubstituted benzene ring. In some embodiments, the benzene ring is substituted with one substituent. In some embodiments, the benzene ring is substituted with two substituents. In some embodiments, the benzene ring is substituted with three substituents. In some embodiments, R2 is an optionally substituted 2-pyridyl. In some embodiments, R2 is an optionally substituted 4-pyridyl. In some embodiments, R2 is an optionally substituted naphthyl. In some embodiments, R2 is an optionally substituted 2-thiophene.

[0041] In some embodiments, the method is performed in vivo. In other embodiments, the method is performed in vitro. In other embodiments, the method is performed ex vivo. In some embodiments, the method results in modulation of estrogen-related receptors, said modulation being sufficient to treat a disease or disorder. In some embodiments, the disease or disorder is associated with estrogen-related receptor α. In some embodiments, the disease or disorder is associated with estrogen-related receptor β. In other embodiments, the disease or disorder is associated with estrogen-related receptor γ. In some embodiments, the disease or disorder is associated with cellular energy metabolism. In some embodiments, the disease or disorder is associated with glucose metabolism, such as diabetes. In other embodiments, the disease or disorder is associated with lipid metabolism. In other embodiments, the disease or disorder is cancer, such as breast cancer. In other embodiments, the disease or disorder is a bone disease or bone disorder. In some embodiments, the disease or disorder is associated with bone resorption.

[0042] In another aspect, this disclosure provides a method for treating a disease or disorder in a patient with this need, the method comprising administering to the patient a therapeutically effective amount of a compound of the following formula or a pharmaceutically acceptable salt thereof:

[0043] (I)

[0044] in:

[0045] R1 is an alkyl group. (C≤12) cycloalkyl (C≤12) aryl (C≤12) Aryl groups (C≤12) heteroaryl (C≤12) , heteroaryl (C≤12) heterocyclic alkyl (C≤12) Heterocyclic alkyl (C≤12) Or any substituted form of these groups; and

[0046] R2 is an alkyl group. (C≤12) cycloalkyl (C≤12) aryl (C≤12)Aryl alkyl (C≤12) heteroaryl (C≤12) , heteroaryl (C≤12) heterocyclic alkyl (C≤12) heterocyclic alkyl (C≤12) Or any substitution of these groups;

[0047] R3 is hydrogen or alkyl. (C≤12) acyl group (C≤12) sulfonyl (C≤12) Or any substituted form of these groups.

[0048] In some implementations, R1 and R2 are the same. In other implementations, R1 and R2 are different.

[0049] In some embodiments, R3 is an acyl group. In some embodiments, R3 is a substituted benzoyl group. In some embodiments, the benzoyl group is substituted with a tert-butyl group.

[0050] In some implementations, R1 is a cycloalkyl group. (C≤12) or substituted cycloalkyl (C≤12) In some embodiments, R1 is a cycloalkyl group. (C≤12) For example, cyclohexyl or adamantyl. In other embodiments, R1 is an aralkyl group. (C≤12) or substituted aralkyl (C≤12) In some embodiments, R1 is a substituted aralkyl group. (C≤12) For example, 2-nitrobenzyl. In other embodiments, R1 is aryl. (C≤12) Or substituted aryl (C≤12) In some implementations, R1 is an aryl group. (C≤12) For example, phenyl or 4-methylphenyl. In other embodiments, R1 is a substituted aryl group. (C≤12) Examples include 4-bromophenyl, 4-chlorophenyl, 2-nitrophenyl, 3-nitrophenyl, 4-nitrophenyl, 4-methoxyphenyl, 3-trifluoromethylphenyl, 4-trifluoromethylphenyl, 2-aminophenyl, 3-aminophenyl, 4-aminophenyl, 2-amino-4-methoxyphenyl, 2-amino-4-bromophenyl, 2-amino-5-bromophenyl, 2-amino-5-methoxyphenyl, 2-amino-3-methoxyphenyl, 2-amino-3-chlorophenyl, 2-nitro-5-bromophenyl, 2-nitro-4-bromophenyl, 2-nitro-4-methoxyphenyl, 2-nitro-5-methoxyphenyl, 2-nitro-3-methoxyphenyl, or 2-nitro-3-chlorophenyl.

[0051] In some embodiments, R1 is an optionally substituted phenyl, optionally substituted pyridyl, optionally substituted naphthyl, or optionally substituted thiophene. In some embodiments, R1 is a benzene ring substituted with one to three substituents. In some embodiments, R1 is an unsubstituted benzene ring. In some embodiments, the benzene ring is substituted with one substituent. In some embodiments, the benzene ring is substituted with two substituents. In some embodiments, the benzene ring is substituted with three substituents. In some embodiments, R1 is an optionally substituted 2-pyridyl. In some embodiments, R1 is an optionally substituted 4-pyridyl. In some embodiments, R1 is an optionally substituted naphthyl. In some embodiments, R1 is an optionally substituted 2-thiophene.

[0052] In some implementations, R2 is an alkyl group. (C≤12) or substituted alkyl (C≤12) In some embodiments, R2 is an alkyl group. (C≤12) For example, ethyl. In other embodiments, R2 is aryl. (C≤12) Or substituted aryl (C≤12) In some implementations, R2 is an aryl group. (C≤12) For example, phenyl, 2-methylphenyl, 4-methylphenyl, or 4-tert-butylphenyl. In other embodiments, R2 is a substituted aryl group. (C≤12) Examples include 2-nitrophenyl, 2-chlorophenyl, 4-chlorophenyl, 4-methoxyphenyl, 3-methoxyphenyl, 3-nitrophenyl, 4-dimethylaminophenyl, 4-trifluorophenyl, 4-bromophenyl, or 4-chlorophenyl. In other embodiments, R2 is a heteroaryl group. (C≤12) Or substituted heteroaryl (C≤12) In some implementations, R2 is a heteroaryl group. (C≤12) For example, 2-pyridyl, 2-quinolinyl, 4-quinolinyl, furanyl, thiophenyl or 5-methylfuranyl.

[0053] In some embodiments, R2 is an optionally substituted phenyl, optionally substituted pyridyl, optionally substituted naphthyl, or optionally substituted thiophene. In some embodiments, R2 is a benzene ring substituted with one to three substituents. In some embodiments, R2 is an unsubstituted benzene ring. In some embodiments, the benzene ring is substituted with one substituent. In some embodiments, the benzene ring is substituted with two substituents. In some embodiments, the benzene ring is substituted with three substituents. In some embodiments, R2 is an optionally substituted 2-pyridyl. In some embodiments, R2 is an optionally substituted 4-pyridyl. In some embodiments, R2 is an optionally substituted naphthyl. In some embodiments, R2 is an optionally substituted 2-thiophene.

[0054] In some embodiments, the disease or disorder is associated with estrogen-related receptor α. In other embodiments, the disease or disorder is associated with estrogen-related receptor β. In other embodiments, the disease or disorder is associated with estrogen-related receptor γ. In some embodiments, the disease or disorder is associated with cellular energy metabolism. In some embodiments, the disease or disorder is associated with glucose metabolism, such as diabetes. In other embodiments, the disease or disorder is associated with lipid metabolism. In other embodiments, the disease or disorder is cancer, such as breast cancer. In other embodiments, the disease or disorder is a bone disease or bone disorder. In some embodiments, the disease or disorder is associated with bone resorption.

[0055] In some embodiments, the method further includes administering a second therapeutic agent. In some embodiments, the compound is formulated as a pharmaceutical composition. In some embodiments, the pharmaceutical composition further comprises excipients. In some embodiments, the pharmaceutical composition is formulated for oral, topical, intravenous, or injection administration. In some embodiments, the pharmaceutical composition is formulated as a unit dose. In some embodiments, the patient is a mammal. In some embodiments, the mammal is a human. In some embodiments, the compound is administered once. In other embodiments, the compound is administered two or more times. In some embodiments, the compound is administered daily, weekly, or monthly.

[0056] It is anticipated that any method or composition described herein can be practiced in relation to any other method or composition described herein. For example, a compound synthesized by one method can be used to prepare the final compound according to different methods.

[0057] When used in conjunction with the term "comprising" in the claims and / or description, the word "a" or "an" may mean "an," but it is also consistent with the meanings of "one or more," "at least one," and "one or more." The word "about" means ±5% of the stated figure.

[0058] Other objects, features, and advantages of this disclosure will become apparent from the following detailed description. However, it should be understood that while the detailed description and specific examples indicate particular embodiments of this disclosure, they are given by way of illustration only, and various changes and modifications within the spirit and scope of this disclosure will become apparent to those skilled in the art based on this detailed description.

[0059] Example

[0060] This article provides synthetic ligands for modulating ERR activity. Some of these compounds have shown activity against both ERRα and ERRγ. These compounds can be used to exhibit micromolar or lower activity in one or more ERRs. These compounds can be used to treat one or more conditions for which modulating the activity of one or more ERRs can be useful. Some of these conditions include bone diseases or disorders, cancer, or metabolic disorders such as diabetes, obesity, lipid metabolism disorders, or muscle wasting disorders. Furthermore, these compounds may represent improvements over those known in the art because they may be more effective, less toxic, have a longer duration of action, be more potent, produce fewer side effects, be more readily absorbed, and / or have better pharmacokinetic characteristics (e.g., higher oral bioavailability and / or lower clearance), and / or possess other useful pharmacological, physical, or chemical properties. These and more details will be discussed in more detail below.

[0061] Compounds and their preparations

[0062] compound

[0063] The compounds disclosed herein can be prepared using the synthetic methods outlined in the Examples section. These methods can be further modified and optimized using principles and techniques of organic chemistry applied by those skilled in the art. Such principles and techniques are taught, for example, in Smith's March's Advanced Organic Chemistry: Reactions, Mechanisms, and Structure, (2013), which is incorporated herein by reference. Furthermore, the synthetic methods can be further modified and optimized using principles and techniques of process chemistry applied by those skilled in the art for preparation, pilot-scale, or large-scale production (batch or continuous). Such principles and techniques are taught, for example, in Anderson's Practical Process Research & Development – ​​A Guide for Organic Chemists (2012), which is incorporated herein by reference.

[0064] In some embodiments, this disclosure relates to compounds of formula (II), or pharmaceutically acceptable salts thereof:

[0065] (II)

[0066] in:

[0067] A is phenyl, pyridyl, thiophenyl, or naphthyl;

[0068] B is phenyl, imidazolyl, or naphthyl;

[0069] Each R1 is independently H, OH, halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy or C 1-6 Halogenated alkoxy groups;

[0070] Each R2 is independently H, OH, halogen, N(R4)2, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy or C 1-6 Halogenated alkoxy groups;

[0071] Each R3 is independently H, -C(O)-C 1-6 Alkyl or -C(O)-phenyl-tert-butyl;

[0072] Each R4 is independently H or C. 1-6 alkyl;

[0073] n is 0, 1, 2, 3, 4, 5, 6, or 7; and

[0074] m can be 0, 1, 2, 3, 4, 5, 6, or 7.

[0075] In some embodiments, this disclosure relates to compounds of formula (II), wherein A is selected from the group consisting of phenyl, pyridyl, thiophene, and naphthyl. In some embodiments, A is phenyl. In some embodiments, A is pyridyl. In some embodiments, A is thiophene. In some embodiments, A is naphthyl. In some embodiments, A is selected from optionally substituted compounds:

[0076] , , , , and A group that is formed.

[0077] In some embodiments, this disclosure relates to compounds of formula (II), wherein B is selected from the group consisting of phenyl, imidazolyl, and naphthyl. In some embodiments, B is phenyl. In some embodiments, B is imidazolyl. In some embodiments, B is naphthyl. In some embodiments, B is selected from optionally substituted compounds: , , , and A group that is formed.

[0078] In some embodiments, this disclosure relates to compounds of formula (II), wherein each R1 is independently selected from the group consisting of: H, OH, halogen, C1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy and C 1-6 Haloalkoxy group. In some embodiments, one or more R1s are H. In some embodiments, one or more R1s are OH. In some embodiments, one or more R1s are halogens. In some embodiments, one or more R1s are C. 1-6 Alkyl group. In some embodiments, one or more R1s are C1. 1-6 Halogenated alkyl group. In some embodiments, one or more R1s are C1. 1-6 Alkyl group. In some embodiments, one or more R1s are C1. 1-6 Halogenated alkoxy groups.

[0079] In some implementations, at least one R1 is C 1-6 Alkyl group. In some embodiments, at least one R1 is OCH3. In some embodiments, at least one R1 is C. 1-6 The alkoxy group is present and at least one R1 is OH. In some embodiments, at least one R1 is OCH3 and wherein at least one R1 is OH.

[0080] In some embodiments, this disclosure relates to compounds of formula (II), wherein at least one R1 is C 1-6 Halogenated alkoxy groups. In some embodiments, this disclosure relates to compounds of formula (II), wherein at least one R1 is OCF3.

[0081] In some embodiments, this disclosure relates to compounds of formula (II), wherein each R2 is independently selected from the group consisting of: H, OH, halogen, N(R4)2, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy and C 1-6 Haloalkoxy group. In some embodiments, R2 is H. In some embodiments, R2 is OH. In some embodiments, R2 is a halogen. In some embodiments, R2 is N(R4)2. In some embodiments, R2 is C. 1-6 Alkyl group. In some embodiments, R2 is C2. 1-6 Haloalkyl. In some embodiments, R2 is C10. 1-6 Alkyl group. In some embodiments, R2 is C 1-6 Halogenated alkoxy groups.

[0082] In some embodiments, this disclosure relates to compounds of formula (II), wherein each R2 is independently selected from the group consisting of: H, OH, halogen, N(R4)2, C 1-6 Alkyl, C1-6 Haloalkyl, C 1-6 Alkoxy or C 1-6 Haloalkoxy group. In some embodiments, one or more R2s are H. In some embodiments, one or more R2s are OH. In some embodiments, one or more R2s are halogens. In some embodiments, one or more R2s are N(R4)2. In some embodiments, one or more R2s are C. 1-6 Alkyl group. In some embodiments, one or more R2 groups are C2. 1-6 Halogenated alkyl group. In some embodiments, one or more R2 groups are C2. 1-6 Alkyl group. In some embodiments, one or more R2 are C 1-6 Halogenated alkoxy groups.

[0083] In some implementations, at least one R2 is OH.

[0084] In some embodiments, at least one R2 is a halogen. In some embodiments, at least one R2 is Br. In some embodiments, at least one R2 is Cl. In some embodiments, at least one R2 is F.

[0085] In some embodiments, at least one R2 is a halogen and one R2 is OH. In some embodiments, at least one R2 is Br and one R2 is OH. In some embodiments, at least one R2 is Cl and one R2 is OH. In some embodiments, at least one R2 is F and one R2 is OH.

[0086] In some embodiments, at least two R2s are halogens. In some embodiments, at least two R2s are Br. In some embodiments, at least two R2s are Br and one R2 is OH. In some embodiments, at least two R2s are Cl.

[0087] In some embodiments, at least one R2 is N(R4)2. In some embodiments, at least one R2 is N(R4)2 and R4 is H. In some embodiments, at least one R2 is N(R4)2 and one R4 is H and one R4 is C. 1-6 Alkyl group. In some embodiments, at least one R2 is N(R4)2 and one R4 is H and one R4 is CH3. In some embodiments, at least one R2 is N(R4)2 and one R4 is CH3.

[0088] In some implementations, at least one R2 is C 1-6Alkyl group. In some embodiments, at least one R2 is CH3. In some embodiments, at least one R2 is CH2CH3. In some embodiments, at least one R2 is CH2CH2CH3. In some embodiments, at least one R2 is CH(CH3)2. In some embodiments, at least one R2 is C(CH3)3. In some embodiments, at least two R2s are CH(CH3)2.

[0089] In some implementations, at least one R2 is C 1-6 The alkyl group is used, and one of the R2 groups is OH. In some embodiments, at least one R2 group is CH3 and one R2 group is OH. In some embodiments, at least two R2 groups are CH3 and one R2 group is OH.

[0090] In some embodiments, this disclosure relates to compounds of formula (II), wherein at least one R2 is C 1-6 Halogenated alkyl groups. In some embodiments, this disclosure relates to compounds of formula (II), wherein at least one R2 is CF3.

[0091] In some implementations, at least one R2 is C 1-6 Alkyl group. In some embodiments, at least one R2 is OCH3.

[0092] In some implementations, at least one R2 is C 1-6 The alkoxy group is present and at least one R1 is OH. In some embodiments, at least one R1 is OCH3 and at least one R2 is OH.

[0093] In some implementations, at least one R2 is C 1-6 Halogenated alkoxy group. In some embodiments, at least one R2 is OCF3.

[0094] In some embodiments, at least one R1 is a halogen and one R2 is OH. In some embodiments, at least one R1 is Cl and one R2 is OH. In some embodiments, at least one R1 is F and one R2 is OH. In some embodiments, at least one R1 is Br and one R2 is OH. In some embodiments, this disclosure relates to compounds of formula (II), wherein at least one R1 and at least one R2 are halogens.

[0095] In some implementations, at least one R1 is C 1-6 The alkyl group and one of R2 is OH. In some embodiments, at least one R1 is C. 1-6 The alkyl group and one of R2 is a halogen. In some embodiments, at least one R1 is C. 1-6The alkoxy group is present and one of the R2 groups is OH. In some embodiments, at least one R1 group is C. 1-6 alkoxy group and one R2 is C 1-6 Alkyl group. In some embodiments, this disclosure relates to compounds of formula (II), wherein at least one R1 is C. 1-6 The alkyl group is haloalkyl and one of the R2 groups is OH. In some embodiments, at least one R1 group is C. 1-6 The alkyl group is haloalkyl and one of R2 is a halogen. In some embodiments, at least one R1 is C. 1-6 Haloalkyl and one R2 is C 1-6 Alkyl group. In some embodiments, at least one R1 is C1. 1-6 The alkyl group is haloalkyl and one of R2 is N(R4)2. In some embodiments, at least one R1 is C 1-6 The alkoxy group is a haloalkoxy group, and one of the R2 groups is OH. In some embodiments, at least one R1 group is C. 1-6 The alkoxy group is a haloalkoxy group, and one of the R2 groups is a halogen. In some embodiments, at least one R1 group is OH and one of the R2 groups is halogen. In some embodiments, at least one R1 group is OH and one of the R2 groups is C. 1-6 Alkyl group. In some embodiments, at least one R1 and at least one R2 are OH.

[0096] In some embodiments, this disclosure relates to compounds of formula (II), wherein R3 is selected from the group consisting of: H, -C(O)-C 1-6 Alkyl and -C(O)-phenyl-tert-butyl. In some embodiments, R3 is H. In some embodiments, R3 is -C(O)-C 1-6 Alkyl group. In some embodiments, R3 is -C(O)-phenyl-tert-butyl.

[0097] In some embodiments, this disclosure relates to compounds of formula (II), wherein n is selected from the group consisting of 0, 1, 2, 3, 4, 5, 6, and 7. In some embodiments, n is 0. In some embodiments, n is 1. In some embodiments, n is 2. In some embodiments, n is 3. In some embodiments, n is 4. In some embodiments, n is 0. In some embodiments, n is 5. In some embodiments, n is 6. In some embodiments, n is 7.

[0098] In some embodiments, this disclosure relates to compounds of formula (II), wherein m is selected from the group consisting of 0, 1, 2, 3, 4, 5, 6, and 7. In some embodiments, m is 0. In some embodiments, m is 1. In some embodiments, m is 2. In some embodiments, m is 3. In some embodiments, m is 4. In some embodiments, m is 5. In some embodiments, m is 6. In some embodiments, m is 7.

[0099] In some embodiments, this disclosure relates to compounds of formula (II-A):

[0100] (II-A)

[0101] in:

[0102] A is phenyl, pyridyl, thiophenyl, or naphthyl;

[0103] B is phenyl, imidazolyl, or naphthyl;

[0104] Each R1 is independently H, OH, halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy or C 1-6 Halogenated alkoxy groups;

[0105] Each R2 is independently H, OH, halogen, N(R4)2, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy or C 1-6 Halogenated alkoxy groups;

[0106] Each R3 is independently H or -C(O)-phenyl-tert-butyl;

[0107] Each R4 is independently H or C. 1-6 alkyl;

[0108] n is 0, 1, 2, 3, 4, 5, 6, or 7; and

[0109] m is 0, 1, 2, 3, 4, 5, 6 or 7;

[0110] Or its pharmaceutically acceptable salt.

[0111] In some embodiments, this disclosure relates to compounds of formula (II-A), wherein A is selected from the group consisting of phenyl, pyridyl, thiophene, and naphthyl. In some embodiments, A is phenyl. In some embodiments, A is pyridyl. In some embodiments, A is thiophene. In some embodiments, A is naphthyl. In some embodiments, A is selected from optionally substituted:

[0112] , , , , and A group that is formed.

[0113] In some embodiments, this disclosure relates to compounds of formula (II-A), wherein B is selected from the group consisting of phenyl, imidazolyl, and naphthyl. In some embodiments, B is phenyl. In some embodiments, B is imidazolyl. In some embodiments, B is naphthyl. In some embodiments, B is selected from optionally substituted compounds: , , , and A group that is formed.

[0114] In some embodiments, this disclosure relates to compounds of formula (II-A), wherein each R1 is independently selected from the group consisting of: H, OH, halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy and C 1-6 Haloalkoxy group. In some embodiments, R1 is H. In some embodiments, R1 is OH. In some embodiments, R1 is a halogen. In some embodiments, R1 is C. 1-6 Alkyl group. In some embodiments, R1 is C1. 1-6 Haloalkyl. In some embodiments, R1 is C1. 1-6 Alkyl group. In some embodiments, R1 is C 1-6 Halogenated alkoxy groups.

[0115] In some implementations, at least one of R1 is OH.

[0116] In some embodiments, at least one R1 is a halogen. In some embodiments, at least one R1 is Br. In some embodiments, at least one R1 is Cl. In some embodiments, at least one R1 is F.

[0117] In some embodiments, at least two R1s are halogens. In some embodiments, at least two R1s are Br. In some embodiments, at least two R1s are Cl.

[0118] In some implementations, at least one R1 is C 1-6 Alkyl group. In some embodiments, at least one R1 is CH3.

[0119] In some implementations, at least one R1 is C 1-6Halogenated alkyl group. In some embodiments, at least one R1 is CF3.

[0120] In some implementations, at least two R1s are C 1-6 Halogenated alkyl group. In some embodiments, at least two R1s are CF3.

[0121] In some implementations, at least one R1 is C 1-6 Alkyl group. In some embodiments, at least one R1 is OCH3. In some embodiments, at least one R1 is C. 1-6 The alkoxy group is present and at least one R1 is OH. In some embodiments, at least one R1 is OCH3 and wherein at least one R1 is OH.

[0122] In some embodiments, this disclosure relates to compounds of formula (II-A), wherein at least one R1 is C 1-6 Halogenated alkoxy groups. In some embodiments, this disclosure relates to compounds of formula (II-A), wherein at least one R1 is OCF3.

[0123] In some embodiments, this disclosure relates to compounds of formula (II-A), wherein each R2 is independently selected from the group consisting of: H, OH, halogen, N(R4)2, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy and C 1-6 Haloalkoxy group. In some embodiments, R2 is H. In some embodiments, R2 is OH. In some embodiments, R2 is a halogen. In some embodiments, R2 is N(R4)2. In some embodiments, R2 is C. 1-6 Alkyl group. In some embodiments, R2 is C2. 1-6 Haloalkyl. In some embodiments, R2 is C10. 1-6 Alkyl group. In some embodiments, R2 is C 1-6 Halogenated alkoxy groups.

[0124] In some implementations, at least one R2 is OH.

[0125] In some embodiments, at least one R2 is a halogen. In some embodiments, at least one R2 is Br. In some embodiments, at least one R2 is Cl. In some embodiments, at least one R2 is F.

[0126] In some embodiments, at least one R2 is a halogen and one R2 is OH. In some embodiments, at least one R2 is Br and one R2 is OH. In some embodiments, at least one R2 is Cl and one R2 is OH. In some embodiments, at least one R2 is F and one R2 is OH.

[0127] In some embodiments, at least two R2s are halogens. In some embodiments, at least two R2s are Br. In some embodiments, at least two R2s are Br and one R2 is OH. In some embodiments, at least two R2s are Cl.

[0128] In some embodiments, at least one R2 is N(R4)2. In some embodiments, at least one R2 is N(R4)2 and R4 is H. In some embodiments, at least one R2 is N(R4)2 and one R4 is H and one R4 is C. 1-6 Alkyl group. In some embodiments, at least one R2 is N(R4)2 and one R4 is H and one R4 is CH3. In some embodiments, at least one R2 is N(R4)2 and one R4 is CH3.

[0129] In some implementations, at least one R2 is C 1-6 Alkyl group. In some embodiments, at least one R2 is CH3. In some embodiments, at least one R2 is CH2CH3. In some embodiments, at least one R2 is CH2CH2CH3. In some embodiments, at least one R2 is CH(CH3)2. In some embodiments, at least one R2 is C(CH3)3. In some embodiments, at least two R2s are CH(CH3)2.

[0130] In some implementations, at least one R2 is C 1-6 The alkyl group is used, and one of the R2 groups is OH. In some embodiments, at least one R2 group is CH3 and one R2 group is OH. In some embodiments, at least two R2 groups are CH3 and one R2 group is OH.

[0131] In some embodiments, this disclosure relates to compounds of formula (II-A), wherein at least one R2 is C 1-6 Halogenated alkyl groups. In some embodiments, this disclosure relates to compounds of formula (II-A), wherein at least one R2 is CF3.

[0132] In some implementations, at least one R2 is C 1-6 Alkyl group. In some embodiments, at least one R2 is OCH3.

[0133] In some implementations, at least one R2 is C1-6 The alkoxy group is present and at least one R1 is OH. In some embodiments, at least one R1 is OCH3 and at least one R2 is OH.

[0134] In some implementations, at least one R2 is C 1-6 Halogenated alkoxy group. In some embodiments, at least one R2 is OCF3.

[0135] In some embodiments, at least one R1 is a halogen and one R2 is OH. In some embodiments, at least one R1 is Cl and one R2 is OH. In some embodiments, at least one R1 is F and one R2 is OH. In some embodiments, at least one R1 is Br and one R2 is OH. In some embodiments, this disclosure relates to compounds of formula (II-A), wherein at least one R1 and at least one R2 are halogens.

[0136] In some implementations, at least one R1 is C 1-6 The alkyl group and one of R2 is OH. In some embodiments, at least one R1 is C. 1-6 The alkyl group and one of R2 is a halogen. In some embodiments, at least one R1 is C. 1-6 The alkoxy group is present and one of the R2 groups is OH. In some embodiments, at least one R1 group is C. 1-6 alkoxy group and one R2 is C 1-6 Alkyl group. In some embodiments, this disclosure relates to compounds of formula (II-A), wherein at least one R1 is C. 1-6 The alkyl group is haloalkyl and one of the R2 groups is OH. In some embodiments, at least one R1 group is C. 1-6 The alkyl group is haloalkyl and one of R2 is a halogen. In some embodiments, at least one R1 is C. 1-6 Haloalkyl and one R2 is C 1-6 Alkyl group. In some embodiments, at least one R1 is C1. 1-6 The alkyl group is haloalkyl and one of R2 is N(R4)2. In some embodiments, at least one R1 is C 1-6 The alkoxy group is a haloalkoxy group, and one of the R2 groups is OH. In some embodiments, at least one R1 group is C. 1-6 The alkoxy group is a haloalkoxy group, and one of the R2 groups is a halogen. In some embodiments, at least one R1 group is OH and one of the R2 groups is halogen. In some embodiments, at least one R1 group is OH and one of the R2 groups is C. 1-6 Alkyl group. In some embodiments, at least one R1 and at least one R2 are OH.

[0137] In some embodiments, this disclosure relates to compounds of formula (II-A), wherein R3 is selected from the group consisting of H and -C(O)-phenyl-tert-butyl. In some embodiments, R3 is H. In some embodiments, R3 is -C(O)-phenyl-tert-butyl.

[0138] In some embodiments, this disclosure relates to compounds of formula (II-A), wherein n is selected from the group consisting of 0, 1, 2, 3, 4, 5, 6, and 7. In some embodiments, n is 0. In some embodiments, n is 1. In some embodiments, n is 2. In some embodiments, n is 3. In some embodiments, n is 4. In some embodiments, n is 0. In some embodiments, n is 5. In some embodiments, n is 6. In some embodiments, n is 7.

[0139] In some embodiments, this disclosure relates to compounds of formula (II-A), wherein m is selected from the group consisting of 0, 1, 2, 3, 4, 5, 6, and 7. In some embodiments, m is 0. In some embodiments, m is 1. In some embodiments, m is 2. In some embodiments, m is 3. In some embodiments, m is 4. In some embodiments, m is 5. In some embodiments, m is 6. In some embodiments, m is 7.

[0140] In some embodiments, this disclosure relates to compounds of formula (II) or (II-A) or any embodiment thereof, i.e., compounds in non-salt form.

[0141] In some embodiments, this disclosure relates to compounds of formulas (I), (II), and (II-A), wherein R2 is not N(R4)2. In some embodiments, when m is 2, R2 is not OCH3. In some embodiments, when m is 2, R2 is not OH.

[0142] In some embodiments, this disclosure relates to compounds of formulas (I), (II), and (II-A), wherein R1 is not N(R4)2. In some embodiments, when m is 2, R1 is not OCH3.

[0143] In some embodiments, this disclosure relates to compounds selected from Table 1 or pharmaceutically acceptable salts thereof. In other embodiments, this disclosure relates to compounds selected from Table 1, i.e., compounds in non-salt form.

[0144] Table 1. Compounds

[0145]

[0146]

[0147]

[0148]

[0149]

[0150]

[0151]

[0152]

[0153]

[0154]

[0155]

[0156] In some embodiments, all ERR-modifying compounds of this disclosure may be used to prevent and treat one or more of the diseases or disorders discussed herein or otherwise. In some embodiments, one or more of the compounds characterized or exemplified herein as intermediates, metabolites, and / or prodrugs may also be used to prevent and treat one or more diseases or disorders. Therefore, unless expressly stated to the contrary, all ERR-modifying compounds of this disclosure are considered “active compounds” and “therapeutic compounds” intended for use as active pharmaceutical ingredients (APIs). Actual suitability for human or veterinary use is typically determined using a combination of clinical trial protocols and regulatory procedures, such as those administered by the U.S. Food and Drug Administration (FDA). In the United States, the FDA is responsible for protecting public health by ensuring the safety, efficacy, quality, and safety of human and veterinary medicines, vaccines and other biological products, and medical devices.

[0157] In some embodiments, the ERR-regulating compounds of this disclosure have the advantages of being more effective, less toxic, having a longer duration of action, greater potency, producing fewer side effects, being more easily absorbed, more metabolically stable, more lipophilic, more hydrophilic, and / or having better pharmacokinetic characteristics (e.g., higher oral bioavailability and / or lower clearance), and / or having other useful pharmacological, physical, or chemical properties, whether for the indications stated herein or otherwise.

[0158] The ERR-regulating compounds of this disclosure may contain one or more asymmetrically substituted carbon or nitrogen atoms and may be separated in optically active or racemic form. Therefore, all chiral, diastereomer, racemic, epimeric, and geometrical isomer forms of the chemical formula are covered unless a specific stereochemical or isomeric form is specifically indicated. The compounds may exist as racemic mixtures and mixtures of racemates, as single enantiomers, mixtures of diastereomers, and single diastereomers. In some embodiments, a single diastereomer is obtained. The chiral center of the ERR-regulating compounds of this disclosure may have an S-configuration or an R-configuration. In some embodiments, the compounds of this disclosure may contain two or more atoms having a defined stereochemical orientation.

[0159] The chemical formulas used to represent the ERR-regulating compounds of this disclosure typically show only one of several possible different tautomers. For example, many types of ketone groups are known to exist in equilibrium with their corresponding enol groups. Similarly, many types of imine groups exist in equilibrium with enamine groups. Regardless of which tautomer is described for a given compound, and whichever is the most common, all tautomers of a given chemical formula are contemplated.

[0160] Furthermore, the atoms constituting the ERR-regulating compounds of this disclosure are intended to include all isotopic forms of these atoms. Isotopes as used herein include atoms having the same atomic number but different mass numbers. By way of general example and not limitation, isotopes of hydrogen include tritium and deuterium, and isotopes of carbon include... 13 C and 14 C.

[0161] In some embodiments, the ERR-regulating compounds of this disclosure are used as prodrugs or can be derivatized for use as prodrugs. Since prodrugs are known to enhance many desired properties of a drug (e.g., solubility, bioavailability, manufacturability, etc.), compounds used in some methods of this invention can be delivered in prodrug form, if desired. Therefore, this disclosure contemplates prodrugs of the ERR-regulating compounds of this disclosure and methods for delivering prodrugs. Prodrugs of the compounds used in this disclosure can be prepared by modifying functional groups present in the compound such that the modification is cleaved into the parent compound under normal operating conditions or in vivo. Thus, prodrugs include, for example, compounds described herein, wherein a hydroxyl, amino, or carboxyl group is bonded to any group that, when the prodrug is administered to a patient, cleaves to form a hydroxyl, amino, or carboxylic acid group, respectively.

[0162] In some embodiments, the ERR-regulating compounds of this disclosure are present in salt or non-salt forms. Regarding salt forms (one or more), in some embodiments, the specific anion or cation forming part of any salt form of the compounds provided herein is not critical, provided that the salt as a whole is pharmacologically acceptable. Additional examples of pharmaceutically acceptable salts and their preparation and use are presented in the Handbook of Pharmaceutical Salts: Properties, and Use (2002), which is incorporated herein by reference.

[0163] It should be understood that many organic compounds can form complexes with solvents, in which they react or precipitate or crystallize. These complexes are called "solvents." When the solvent is water, the complex is called a "hydrate." It should also be understood that many organic compounds can exist in more than one solid form, including crystalline and amorphous forms. All ERR-regulating compounds in solid forms provided herein, including any of their solvates, are within the scope of this invention.

[0164] preparation

[0165] In some embodiments of this disclosure, the ERR-modifying compounds of this disclosure are included in pharmaceutical formulations. Materials used to prepare microspheres and / or microcapsules are, for example, biodegradable / bioergogradable polymers, such as polygalactin, poly(isobutyl cyanoacrylate), poly(2-hydroxyethyl-L-glutamine), and polylactic acid. Biocompatible carriers that can be used when formulating controlled-release parenteral formulations are carbohydrates (e.g., dextran), proteins (e.g., albumin), lipoproteins, or antibodies. Materials used for implants can be non-biodegradable (e.g., polydimethylsiloxane) or biodegradable (e.g., polycaprolactone, polylactic acid, polyglycolic acid, or polyorthoesters or combinations thereof).

[0166] Oral formulations include tablets containing a mixture of an active ingredient (one or more) (e.g., a compound described herein) and a non-toxic, pharmaceutically acceptable excipient. Such formulations are well known to those skilled in the art. Excipients may be, for example, inert diluents or fillers (e.g., sucrose, sorbitol, sugar, mannitol, microcrystalline cellulose, starch including potato starch, calcium carbonate, sodium chloride, lactose, calcium phosphate, calcium sulfate, or sodium phosphate); granulating and disintegrants (e.g., cellulose derivatives including microcrystalline cellulose, starch including potato starch, croscarmellose sodium, alginate, or alginic acid); binders (e.g., sucrose, glucose, sorbitol, gum arabic, alginic acid, sodium alginate, gelatin, starch, pregelatinized starch, microcrystalline cellulose, magnesium aluminum silicate, sodium carboxymethyl cellulose, methylcellulose, hydroxypropyl methylcellulose, ethylcellulose, polyvinylpyrrolidone, or polyethylene glycol); and lubricants, flow aids, and anti-adhesion agents (e.g., magnesium stearate, zinc stearate, stearic acid, silica, hydrogenated vegetable oil, or talc). Other pharmaceutically acceptable excipients may be colorants, flavoring agents, plasticizers, humectants, buffers, etc.

[0167] Tablets may be uncoated or coated using known techniques to optionally delay disintegration and absorption in the gastrointestinal tract, thereby providing sustained action over a longer period. The coating may be adapted to release the active drug in a predetermined manner (e.g., to obtain a controlled-release formulation), or it may be adapted to release the active drug only after it has passed through the stomach (enteric coating). The coating may be a sugar coating, a film coating (e.g., based on hydroxypropyl methylcellulose, methylcellulose, methyl hydroxyethyl cellulose, hydroxypropyl cellulose, carboxymethyl cellulose, acrylate copolymers, polyethylene glycol, and / or polyvinylpyrrolidone), or an enteric coating (e.g., based on methacrylic acid copolymers, cellulose acetate phthalate, hydroxypropyl methylcellulose phthalate, hydroxypropyl methylcellulose succinate, polyvinyl acetate phthalate, shellac, and / or ethyl cellulose). Furthermore, delay-release materials such as glyceryl monostearate or glyceryl distearate may be used.

[0168] Metabolic diseases

[0169] Metabolic diseases encompass conditions caused by a variety of metabolic defects and present with diverse symptoms. For example, obesity and diabetes are metabolic disorders that can be associated or discovered separately. Muscle-wasting diseases, including various forms of muscular dystrophy, are also considered disorders with a metabolic basis. Some of these conditions are described below.

[0170] In some implementation schemes, the condition is selected from the group consisting of non-alcoholic fatty liver disease, non-alcoholic steatohepatitis (NASH), hypothyroidism, obesity, monogenic obesity, type I diabetes, type II diabetes, and lipodystrophy.

[0171] In some implementations, one or more symptoms of a disease or condition associated with metabolic dysfunction are selected from the group consisting of excessive fat, obesity, hyperappetite, hyperglycemia, hypoleptinemia, hypertriglyceridemia, hypercholesterolemia, insulin resistance, dyslipidemia, growth retardation, delayed pubertal growth spurt, abnormal growth hormone secretion, elevated HbA1c, low bone mineral density (or low bone mass), low bone mineral content, and low lean body mass. Upon administration of a compound or composition of this disclosure in combination with a human ERR, the severity and / or duration of symptoms of a disease or condition associated with metabolic dysfunction may be prevented, improved, or reduced, or their severity and / or duration may be alleviated.

[0172] diabetes

[0173] Diabetes mellitus, often simply called diabetes, is a group of metabolic diseases in which patients have high blood sugar, either because their bodies cannot produce enough insulin or because their cells do not respond to the insulin produced. This high blood sugar produces typical symptoms such as polyuria (frequent urination), polydipsia (increased thirst), and polyphagia (increased hunger).

[0174] obesity

[0175] Another aspect of this disclosure relates to novel methods and compounds for the treatment and prevention of obesity. Obesity is a medical condition in which excess body fat accumulates to a level that can adversely affect health. It is typically defined by body mass index (BMI) and can be further assessed by waist-to-hip ratio and total cardiovascular risk factors. BMI is related to both body fat percentage and total body fat, and is calculated by dividing the subject's weight by their height (metric units: kg / m²). 2 The square of ( ) is used for calculation. Obesity increases the risk of many physical and mental illnesses. These comorbidities are most common in metabolic syndrome, a combination of medical disorders including: type 2 diabetes, high blood pressure, high cholesterol, and high triglyceride levels.

[0176] In some embodiments, this disclosure includes a method of treating a disease or disorder of a subject or reducing the severity of said disease or disorder, the method comprising administering to the subject a compound or pharmaceutical composition of the disclosure, wherein the disease or disorder is obesity.

[0177] In some implementations, the treatment reverses or alleviates one or more of the following symptoms in the subject: hyperappetite, obesity, hyperinsulinemia, dyslipidemia, and hepatic steatosis. In some implementations, the subject experiences a decrease in blood glucose, a decrease in body weight, a reduction in food intake, a decrease in body fat mass, an increase in lean body mass, and / or an increase in bone mass.

[0178] In other respects, this article provides therapeutic methods for treating obesity or losing weight. In some respects, this article provides therapeutic methods for reducing fat mass. In some respects, this article provides therapeutic methods for increasing lean body mass.

[0179] Muscular dystrophy

[0180] Muscular dystrophy (MD) is a group of muscle diseases that cause skeletal muscle to weaken and break down over time. These diseases differ in the primary muscles affected, the degree of weakness, the rate of deterioration, and when symptoms begin. Many people eventually become unable to walk. Some types are also associated with problems in other organs.

[0181] Nonalcoholic fatty liver disease

[0182] Nonalcoholic fatty liver disease (NAFLD) is a type of fatty liver that occurs when fat deposits (steatohepatitis) in the liver due to causes other than excessive alcohol consumption. Nonalcoholic steatohepatitis (NASH) is the most extreme form of NAFLD. NAFLD is the most common liver disease in developed countries.

[0183] Other uses and indications

[0184] In some embodiments, the compounds of Formula I can be used to treat one or more of the following: heart failure (including, but not limited to, heart failure with reduced ejection fraction and heart failure with preserved ejection fraction), cardiac fibrosis, cardiac hypertrophy, cardiomyopathy, dilated cardiomyopathy, heart failure, obesity, metabolic diseases, muscle wasting and other muscle dysfunction, mitochondrial dysfunction, kidney disease and dysfunction, chronic kidney disease, and neurodegenerative diseases including AD, PD and ALS.

[0185] In some embodiments, based on various types of assays, compounds of Formula I can be used to treat one or more of the following: heart failure (including, but not limited to, heart failure with reduced ejection fraction and heart failure with preserved ejection fraction), cardiac fibrosis, cardiac hypertrophy, myopathy, dilated cardiomyopathy, obesity, metabolic diseases, muscle wasting and other muscle dysfunction disorders, mitochondrial dysfunction, kidney disease and dysfunction, chronic kidney disease, and neurodegenerative diseases including AD, PD, and ALS. In one aspect, the assay can measure an increase in mitochondrial biogenesis. In another aspect, the assay can measure an increase in oxidative metabolism. In another aspect, the assay can measure an increase in fatty acid oxidation. In yet another aspect, the assay can also measure an increase in the expression of genes that guide the biochemical pathways responsible for oxidative metabolism and fatty acid metabolism.

[0186] therapy

[0187] Drug formulation and route of administration

[0188] On the other hand, for administration to patients requiring such treatment, pharmaceutical formulations (also referred to as pharmaceutical preparations, pharmaceutical compositions, pharmaceutical products, medical products, drugs, medicines, or pharmaceutical agents) comprise a therapeutically effective amount of the ERR-regulating compound of this disclosure, formulated together with one or more excipients and / or pharmaceutical carriers suitable for indicating the route of administration. In some embodiments, the ERR-regulating compounds disclosed herein are formulated in a manner suitable for treating human and / or veterinary patients. In some embodiments, the formulation comprises mixing or combining one or more of the ERR-regulating compounds disclosed herein with one or more of the following excipients: lactose, sucrose, starch powder, cellulose esters of alkanonic acids, alkyl cellulose, talc, stearic acid, magnesium stearate, magnesium oxide, sodium and calcium salts of phosphoric acid and sulfuric acid, gelatin, gum arabic, sodium alginate, polyvinylpyrrolidone, and / or polyvinyl alcohol. In some embodiments, for example for oral administration, the pharmaceutical preparation may be formulated as tablets or capsules. In some embodiments, the ERR-regulating compound may be dissolved or slurried in water, polyethylene glycol, propylene glycol, ethanol, corn oil, cottonseed oil, peanut oil, sesame oil, benzyl alcohol, sodium chloride, and / or various buffer solutions. In some embodiments, the pharmaceutical formulation may undergo pharmaceutical processing, such as sterilization, and / or may contain a pharmaceutical carrier and / or excipients, such as preservatives, stabilizers, humectants, emulsifiers, encapsulating agents (e.g., lipids, dendritic polymers, polymers, proteins such as albumin, nucleic acids), and buffers.

[0189] Pharmaceutical formulations can be administered via various methods, such as oral or injectable (e.g., subcutaneous, intravenous, and intraperitoneal). Depending on the route of administration, the ERR-regulating compounds disclosed herein may be coated with a material to protect them from acids and other natural conditions that could inactivate them. For administration of the active compound via routes other than parenteral administration, it may be necessary to coat it with a substance that prevents inactivation of the ERR-regulating compound, or to administer the ERR-regulating compound co-administered with such a substance. In some embodiments, the active ERR-regulating compound may be administered to the patient in a suitable carrier, such as a liposome or diluent. Pharmaceutically acceptable diluents include saline and buffered aqueous solutions. Liposomes include water-in-oil-in-water CGF emulsions and conventional liposomes.

[0190] The ERR-regulating compounds disclosed herein can also be administered parenterally, intraperitoneally, intraspinally, or intracerebrally. Dispersions can be prepared in glycerol, liquid polyethylene glycol, mixtures thereof, and oils. Under normal storage and use conditions, these formulations may contain preservatives to prevent microbial growth.

[0191] Pharmaceutical compositions suitable for injection include sterile aqueous solutions (water-soluble) or dispersions, as well as sterile powders for reconstitution into sterile injectable solutions or dispersions immediately before use. The carrier can be a solvent or dispersion medium containing, for example, water, ethanol, polyols (e.g., glycerol, propylene glycol, and liquid polyethylene glycol), suitable mixtures thereof, and vegetable oils. Appropriate flowability can be maintained, for example, by using a coating such as lecithin, in the case of dispersions by maintaining the desired particle size, and by using surfactants. Antimicrobial activity can be achieved by various antibacterial and antifungal agents, such as parabens, chlorobutanol, phenol, ascorbic acid, thimerosal, etc. In many cases, it is preferable to include isotonic agents in the composition, such as sugars, sodium chloride, or polyols such as mannitol and sorbitol. The absorption of injectable compositions can be prolonged by adding a delaying absorption agent (e.g., aluminum monostearate or gelatin).

[0192] The ERR-regulating compounds disclosed herein can be administered orally, for example, with an inert diluent or an assimilateable edible carrier. The ERR-regulating compounds and other ingredients can also be encapsulated in hard or soft gelatin capsules, compressed into tablets, or directly incorporated into the patient's diet. For oral therapeutic administration, the compounds disclosed herein can be incorporated with excipients and used in the form of ingestible tablets, buccal lozenges, tablets, capsules, elixirs, suspensions, syrups, rice paper capsules, etc. The percentage of the therapeutic ERR-regulating compound in the composition and formulation can, of course, vary. The amount of the therapeutic ERR-regulating compound in such pharmaceutical formulations should ensure an appropriate dosage.

[0193] Therapeutic ERR-modifying compounds can also be applied topically to the skin, eyes, ears, or mucous membranes. Topical application of therapeutic ERR-modifying compounds may include formulating the ERR-modifying compound as a topical solution, lotion, cream, ointment, gel, foam, transdermal patch, or tincture. When a therapeutic ERR-modifying compound is formulated for topical application, the ERR-modifying compound may be combined with one or more agents that increase the permeability of the ERR-modifying compound through the tissue to which it is applied. In other embodiments, topical application to the eye is contemplated. Such application may be applied to the surface of the cornea, conjunctiva, or sclera. Without being bound by any theory, it is believed that application to the surface of the eye allows the therapeutic ERR-modifying compound to reach the posterior segment of the eye. Ophthalmic topical applications may be formulated as solutions, suspensions, ointments, gels, or emulsions. Finally, topical application may also include application to mucous membranes, such as the interior of the mouth. Such applications may be applied directly to specific locations within the mucous membrane, such as teeth, sores, or ulcers. Alternatively, if local delivery to the lungs is desired, the therapeutic ERR-modifying compound may be administered by inhalation in the form of a dry powder or aerosol.

[0194] In some embodiments, it may be advantageous to formulate the parenteral composition into unit dosage forms to facilitate administration and uniformity of dosage. As used herein, a unit dosage form refers to a physically discrete unit suitable as a unit dose for a patient to be treated; each unit contains a predetermined amount of a therapeutic ERR-modifying compound that, together with a desired drug carrier, produces the desired therapeutic effect. In some embodiments, the specifications of the unit dosage forms of this disclosure are determined by and directly depend on: (a) the unique characteristics of the therapeutic ERR-modifying compound and the specific therapeutic effect to be achieved, and (b) the inherent limitations in the art of formulating such therapeutic ERR-modifying compounds for treating selected conditions in patients. In some embodiments, the active ERR-modifying compound is administered at a therapeutically effective dose sufficient to treat the disease associated with the patient's condition. For example, the efficacy of the ERR-modifying compound can be evaluated in an animal model system that can predict the efficacy of treating the disease in humans or another animal.

[0195] In some embodiments, the effective dose range of the therapeutic ERR-regulating compound can be extrapolated from the effective doses determined in a variety of different animals in animal studies. In some embodiments, the human equivalent dose (HED) in mg / kg can be calculated according to the following formula (see, for example, Reagan-Shaw et al., FASEB J., 22(3):659-661,2008, which is incorporated herein by reference):

[0196] HED (mg / kg) = Animal dose (mg / kg) × (Animal K) m / personK m )

[0197] Using K in the transformation m The factor yields HED values ​​based on body surface area (BSA) rather than just body weight. K in humans and various animals... m The value is well-known. For example, the K value for a person with an average weight of 60 kg (BSA of 1.6 m²) is... m The value was 37, while the K value for a 20kg child (BSA 0.8m²) was... m The value is 25. K in some relevant animal models... m Also well known, including: mouse K m The value is 3 (assuming a weight of 0.02 kg and a BSA of 0.007); Hamster K m The value was 5 (assuming a body weight of 0.08 kg and a BSA of 0.02); rat K m The value is 6 (assuming a body weight of 0.15 kg and a BSA of 0.025); and monkey K m The value is 12 (assuming a weight of 3 kg and a BSA of 0.24).

[0198] The precise amount of a therapeutic composition depends on the practitioner's judgment and is specific to each individual. Nevertheless, the calculated HED dosage provides a general guideline. Other factors influencing dosage include the patient's physical and clinical condition, route of administration, intended therapeutic goals, and the potency, stability, and toxicity of the specific therapeutic agent.

[0199] The actual dose of the ERR-regulating compound of this disclosure or a composition containing an ERR-regulating compound of this disclosure administered to a patient may be determined by physical and physiological factors, such as the type of animal being treated, its age, sex, weight, severity of the condition, type of disease being treated, prior or concurrent therapeutic interventions, patient idiopathicity, and route of administration. These factors may be determined by a technician. The physician responsible for administration will typically determine the concentration of one or more active ingredients in the composition and the appropriate dose (one or more) for the individual patient. In the event of any complications, the dose may be adjusted by the individual physician.

[0200] In some embodiments, the therapeutically effective dose typically varies from about 0.001 mg / kg to about 1000 mg / kg, about 0.01 mg / kg to about 750 mg / kg, about 100 mg / kg to about 500 mg / kg, about 1 mg / kg to about 250 mg / kg, and about 10 mg / kg to about 150 mg / kg, when administered once or multiple times daily for one or more days (depending on the course of administration and the factors discussed above). Other suitable dose ranges include 1 mg to 10,000 mg daily, 100 mg to 10,000 mg daily, 500 mg to 10,000 mg daily, and 500 mg to 1,000 mg daily. In some embodiments, the dose is less than 10,000 mg daily, ranging from 750 mg to 9,000 mg daily.

[0201] In some embodiments, the amount of the active ERR-regulating compound in the pharmaceutical formulation is from about 2% by weight to about 75% by weight. In some of these embodiments, the amount is from about 25% by weight to about 60% by weight.

[0202] The intended dosage may be a single or multiple dose. Those skilled in the art can determine the desired time intervals for delivering multiple doses using only routine experiments. As an example, a patient may be given two doses daily at approximately 12-hour intervals. In some embodiments, the dosage is administered once daily.

[0203] The medication (one or more) may be administered according to a regular schedule. As used herein, a regular schedule refers to a predetermined, specified period of time. As long as the schedule is predetermined, a regular schedule may include periods of time with the same or different durations. For example, a regular schedule may involve administration twice daily, once daily, once every two days, once every three days, once every four days, once every five days, once every six days, once a week, once a month, or any set number of days or weeks in between. Alternatively, a predetermined regular schedule may involve administration twice daily for the first week, followed by administration once daily for several months, and so on. In other embodiments, this disclosure provides that the medication (one or more) can be taken orally, and the timing of its administration may depend on or not depend on food intake. Thus, for example, the medication may be taken every morning and / or evening, regardless of when the patient eats or is about to eat.

[0204] Another embodiment of this disclosure features a pharmaceutical composition comprising a compound of the present disclosure or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

[0205] Another embodiment of this disclosure features a pharmaceutical composition comprising a therapeutically effective amount of a compound or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers or solvents.

[0206] Treatment

[0207] Specifically, this document discloses compositions for use in treating metabolic disorders in subjects (e.g., human subjects). These compositions are preferably administered to mammals (e.g., rodents, humans, non-human primates, dogs, cattle, sheep, horses, cats, etc.) in an effective amount that produces the desired outcome in the treated subject (e.g., alleviating, stopping, reducing, or eliminating one or more symptoms or underlying causes of the disease). The toxicity and therapeutic efficacy of the compositions used in the methods disclosed herein can be determined using standard pharmaceutical procedures. It is well known in the medical and veterinary fields that the dosage for any animal depends on many factors, including the size of the subject, body surface area, weight, age, the specific composition administered, the time and route of administration, general health status, clinical symptoms, and other concurrently administered drugs. In some embodiments, the amount of the ERR-regulating compound used is calculated to be from about 0.01 mg / day to about 10,000 mg / day. In some embodiments, the amount is from about 1 mg / day to about 1,000 mg / day. In some implementations, this dosage can be reduced or increased based on specific patient biological factors, such as increased or decreased drug metabolism or reduced uptake via the digestive tract when administered orally. Furthermore, compounds that modulate the ERR can be more effective, thus requiring smaller doses to achieve similar effects. These doses are typically administered once daily for several weeks or until sufficient clinical benefit is achieved.

[0208] The therapeutic methods (including preventative treatments) disclosed herein generally involve administering a therapeutically effective amount of the composition described herein to a subject (including mammals, particularly humans) in need. Such treatments will be appropriately administered to subjects, particularly humans, who have, are susceptible to, or are at risk of a disease, disorder, or its symptoms. Those subjects “at risk” can be determined by any objective or subjective determination, such as diagnostic testing or the opinion of the subject or a healthcare provider (e.g., genetic testing, enzyme or protein markers, family history, etc.).

[0209] Use of compounds and pharmaceutically acceptable salts and compositions

[0210] In another embodiment, this disclosure features a method for modulating the activity of estrogen-related receptors, the method comprising administering to a subject a compound of the disclosure or a pharmaceutically acceptable salt thereof or a pharmaceutical composition thereof. In some embodiments, the estrogen-related receptor is selected from the group consisting of estrogen-related receptor α, estrogen-related receptor β, and estrogen-related receptor γ. In some embodiments, the estrogen-related receptor is estrogen-related receptor α. In some embodiments, the estrogen-related receptor is estrogen-related receptor β. In some embodiments, the estrogen-related receptor is estrogen-related receptor γ.

[0211] In another embodiment, this disclosure features a method for inhibiting the activity of estrogen-related receptors, the method comprising administering to a subject a compound of the disclosure or a pharmaceutically acceptable salt thereof or a pharmaceutical composition thereof. In some embodiments, the estrogen-related receptor is selected from the group consisting of estrogen-related receptor α, estrogen-related receptor β, and estrogen-related receptor γ. In some embodiments, the estrogen-related receptor is estrogen-related receptor α. In some embodiments, the estrogen-related receptor is estrogen-related receptor β. In some embodiments, the estrogen-related receptor is estrogen-related receptor γ.

[0212] In yet another embodiment, the present disclosure is characterized by a method for treating a disease or disorder of a subject or for alleviating the severity of said disease or disorder, the method comprising administering to the subject an effective amount of a compound of the present disclosure, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.

[0213] In some embodiments, the compounds of this disclosure can be used to treat one or more of the following: diabetes, breast cancer, bone disease, bone resorption, heart failure, obesity, metabolic diseases, muscle wasting and other muscle function disorders, mitochondrial dysfunction diseases, kidney disease and dysfunction, and neurodegenerative diseases including AD, PD, and ALS. In some embodiments, the disease or disorder is diabetes. In some embodiments, the disease or disorder is breast cancer. In some embodiments, the disease or disorder is bone disease. In some embodiments, the disease or disorder is bone resorption. In some embodiments, the disease or disorder is heart failure. In some embodiments, the disease or disorder is obesity. In some embodiments, the disease or disorder is a metabolic disease. In some embodiments, the disease or disorder is a muscle wasting disease. In some embodiments, the disease or disorder is other muscle function disorders. In some embodiments, the disease or disorder is a mitochondrial dysfunction disease. In some embodiments, the disease or disorder is kidney disease and dysfunction. In some embodiments, the disease or disorder is a neurodegenerative disease including AD, PD, and ALS.

[0214] In another aspect, this disclosure is characterized by a method in which the subject is treated with one or more additional therapeutic agents, which are administered simultaneously, before, or after an effective amount of the compound, a pharmaceutically acceptable salt, or a pharmaceutical composition.

[0215] Compounds, pharmaceutically acceptable salts, and the compositions used

[0216] In another embodiment, the present disclosure is characterized by the use of the disclosed compound or a pharmaceutically acceptable salt or pharmaceutical composition thereof as a medicament.

[0217] In another embodiment, the present disclosure is characterized by a compound of the present disclosure or a pharmaceutically acceptable salt or pharmaceutical composition thereof for modulating estrogen-related receptors. In another embodiment, the present disclosure is characterized by a compound of the present disclosure or a pharmaceutically acceptable salt or pharmaceutical composition thereof for inhibiting the activity of estrogen-related receptors. In some embodiments, the estrogen-related receptor is selected from the group consisting of estrogen-related receptor α, estrogen-related receptor β, and estrogen-related receptor γ. In some embodiments, the estrogen-related receptor is estrogen-related receptor α. In some embodiments, the estrogen-related receptor is estrogen-related receptor β. In some embodiments, the estrogen-related receptor is estrogen-related receptor γ.

[0218] In another embodiment, the present disclosure is characterized by the use of the compounds of the present disclosure or pharmaceutically acceptable salts or pharmaceutical compositions thereof for the treatment of one or more of the following: diabetes, breast cancer, bone diseases, bone resorption, heart failure, obesity, metabolic diseases, muscle wasting and other muscle dysfunction diseases, mitochondrial dysfunction diseases, kidney diseases and dysfunctions, and neurodegenerative diseases including AD, PD and ALS.

[0219] In some embodiments, the disease or disorder is diabetes. In some embodiments, the disease or disorder is breast cancer. In some embodiments, the disease or disorder is a bone disease. In some embodiments, the disease or disorder is bone resorption. In some embodiments, the disease or disorder is heart failure. In some embodiments, the disease or disorder is obesity. In some embodiments, the disease or disorder is a metabolic disease. In some embodiments, the disease or disorder is a muscle wasting disease. In some embodiments, the disease or disorder is other muscle function disorders. In some embodiments, the disease or disorder is a mitochondrial dysfunction disease. In some embodiments, the disease or disorder is kidney disease and dysfunction. In some embodiments, the disease or disorder is a neurodegenerative disease including AD, PD, and ALS.

[0220] In another embodiment, the present disclosure is characterized by the use of the disclosed compound or a pharmaceutically acceptable salt or pharmaceutical composition thereof in a method in which the subject is treated with one or more additional therapeutic agents, which are administered simultaneously with, before or after treatment with the compound, pharmaceutically acceptable salt or pharmaceutical composition in an effective amount.

[0221] Drug preparation

[0222] In another embodiment, this disclosure provides the use of the compounds of this disclosure or pharmaceutically acceptable salts or pharmaceutical compositions thereof in the preparation of a medicament.

[0223] In another embodiment, this disclosure provides the use of the compounds of this disclosure, pharmaceutically acceptable salts thereof, or pharmaceutical compositions thereof in the preparation of a medicament for modulating estrogen-related receptors. In another embodiment, this disclosure provides the use of the compounds of this disclosure, pharmaceutically acceptable salts thereof, or pharmaceutical compositions thereof in the preparation of a medicament for inhibiting the activity of estrogen-related receptors. In some embodiments, the estrogen-related receptor is selected from the group consisting of estrogen-related receptor α, estrogen-related receptor β, and estrogen-related receptor γ. In some embodiments, the estrogen-related receptor is estrogen-related receptor α. In some embodiments, the estrogen-related receptor is estrogen-related receptor β. In some embodiments, the estrogen-related receptor is estrogen-related receptor γ.

[0224] In yet another embodiment, this disclosure provides the use of the compounds of this disclosure, their pharmaceutically acceptable salts, or pharmaceutical compositions thereof in the preparation of a medicament for treating one or more of the following: diabetes, breast cancer, bone disease, bone resorption, heart failure, obesity, metabolic disease, muscle wasting and other muscle dysfunction, mitochondrial dysfunction, kidney disease and dysfunction, and neurodegenerative diseases including AD, PD, and ALS.

[0225] In some embodiments, the disease or disorder is diabetes. In some embodiments, the disease or disorder is breast cancer. In some embodiments, the disease or disorder is a bone disease. In some embodiments, the disease or disorder is bone resorption. In some embodiments, the disease or disorder is heart failure. In some embodiments, the disease or disorder is obesity. In some embodiments, the disease or disorder is a metabolic disease. In some embodiments, the disease or disorder is a muscle wasting disease. In some embodiments, the disease or disorder is other muscle function disorders. In some embodiments, the disease or disorder is a mitochondrial dysfunction disease. In some embodiments, the disease or disorder is kidney disease and dysfunction. In some embodiments, the disease or disorder is a neurodegenerative disease including AD, PD, and ALS.

[0226] In yet another embodiment, this disclosure provides the use of the compounds of this disclosure, pharmaceutically acceptable salts thereof, or pharmaceutical compositions thereof in the preparation of a medicament for use in combination with one or more adjunct therapeutic agents, which are administered concurrently with, before, or after treatment with the compound or pharmaceutical composition.

[0227] combination therapy

[0228] It is envisioned that the ERR-regulating compounds described herein can be used in combination therapy with one or more adjunctive therapies or compounds that alleviate one or more side effects experienced by a patient. Combining multiple treatment methods is common in the medical field. The following is a general discussion of therapies that can be used in conjunction with the therapies disclosed herein.

[0229] To treat a disease or disorder using the methods and compositions of this disclosure, cells or a subject are generally exposed to an ERR-regulating compound and at least one other therapy. These therapies are delivered in a combined effective amount to achieve a reduction in one or more disease parameters. The process may involve simultaneously exposing cells / subjects to two agents / therapies, such as using a single composition or pharmacological preparation containing two drugs, or by simultaneously exposing cells / subjects to two different compositions or preparations, one containing a compound and the other containing another drug.

[0230] Alternatively, the compounds described herein may be administered at intervals ranging from minutes to weeks before or after other treatments. Generally, it is ensured that there is no significant time gap between each delivery so that these therapies can still exert a beneficial combined effect on the cells / subject. In such cases, it is expected that the cells will be contacted in two forms within a delay of approximately 12 to 24 hours, approximately 6 to 12 hours, or only approximately 1 to 2 hours. In some cases, significantly longer treatment durations may be necessary; however, this is also true where intervals between administrations range from several days (2, 3, 4, 5, 6, or 7 days) to several weeks (1, 2, 3, 4, 5, 6, 7, or 8 weeks).

[0231] It is also conceivable that more than one administration of the compound or other therapy may be required. Various combinations may be employed, wherein the compound disclosed herein is "A" and another therapy is "B," as exemplified below:

[0232] A / B / AB / A / BB / B / AA / A / BB / A / AA / B / BB / B / B / AB / B / A / B

[0233] A / A / B / BA / B / A / BA / B / B / AB / B / A / AB / A / B / AB / A / A / BB / B / B / A

[0234] A / A / A / BB / A / A / AA / B / A / AA / A / B / AA / B / B / BB / A / B / BB / B / A / B

[0235] Other combinations are also anticipated. Discussions of other potential therapies that may be used in combination with the compounds disclosed herein are given elsewhere herein.

[0236] Another embodiment of this disclosure relates to modulating the activity of estrogen-related receptors in a biological sample or subject, the method comprising administering to the subject a compound of the present disclosure, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, or contacting the biological sample with a compound of the present disclosure, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof. Another embodiment of this disclosure relates to inhibiting the activity of estrogen-related receptors in a biological sample or subject, the method comprising administering to the subject a compound of the present disclosure, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, or contacting the biological sample with a compound of the present disclosure, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.

[0237] As used herein, the term "biological sample" includes, but is not limited to, cell cultures or extracts thereof; biopsy material or extracts thereof obtained from mammals; and blood, saliva, urine, feces, semen, tears or other bodily fluids or extracts thereof.

[0238] Modulating the activity of estrogen-related receptors in biological samples can be used for a variety of purposes known to those skilled in the art. Examples of such purposes include, but are not limited to, studying the role of estrogen-related receptors in biological and pathological phenomena, and comparative evaluation of novel estrogen-related receptor modulators.

[0239] Inhibition of the activity of estrogen-related receptors in biological samples can be used for a variety of purposes known to those skilled in the art. Examples of such purposes include, but are not limited to, studying the role of estrogen-related receptors in biological and pathological phenomena, and comparative evaluation of novel estrogen-related receptor inhibitors.

[0240] In some implementations, the additional therapeutic agent is a hyperglycemic or diabetes medication. Hyperglycemic or diabetes medications include, but are not limited to: insulin and insulin mimics; PPAR (peroxisome proliferator-activated receptor) γ-agonists, such as pioglitazone, troglitazone, ciglitazone, rivoglitazone, rosiglitazone, and other 2,4-thiazolidinedione derivatives; and DPP-4 inhibitors, such as sitagliptin (JANUVIA) ​​and vildagliptin (VILD). saxagliptin, linagliptin (TRADJENTA), dutogliptin, gemigliptin, and alogliptin (NESINA); GLP-1 analogs, such as exenatide, liraglutide, taspoglutide, albiglutide, and lixisenatide; biguanide derivatives, such as metformin (GLU-METZA). GLUCOPHAGE, methylphenidate, and phenformin; ATP-sensitive potassium channel regulators, such as mitiglinide, repaglinide, and nateglinide; sulfonylurea derivatives, such as tolbutamide, chlorpropamide, tolazamide, acetohexamide, glipizide, gliclazide, and glimepiride. Medicinal herbs include: gliquidone, glibomuride, glisoxepid, glibenclamide, glisen-tide, glisolamide, glybuzole, and glyclopyramide; α-glucosidase inhibitors, such as miglitol (GLYSET), acarbose (PRECOSE), and voglibose.And SGLT2 inhibitors, such as canagliflozin (INVOKANA), dapagliflozin (FARXIGA), and empagliflozin (JARDIANCE).

[0241] In some implementations, the additional treatment is an obesity medication. Obesity medications include, but are not limited to, orlistat (XENICAL), phentermine / topiramate (QSYMIA), lorcaserin (BELVIQ), naltrexone / bupropion (CONTRAVE), and liraglutide (SAXENDA).

[0242] In some implementations, the additional therapeutic agent is a lipid-lowering or cholesterol-lowering drug. Lipid-lowering drugs include, but are not limited to, fibrates, statins, omega-3 fatty acids, and niacin. In some implementations, the additional therapeutic agent is a fibrate. Fibrates are a class of amphiphilic carboxylic acids, including, but not limited to: aluminum clofibrate, bezafibrate, ciprofibrate, choline fenofibrate, clinofibrate, clofibrate (e.g., ATROMID-S), clofibride, fenofibrate (e.g., FIBRICOR, LOFIBRA, TRICOR), gemfibrozil (e.g., LOPID), ronifibrate, simfibrate, and fenofibric acid. In some embodiments, the additional therapeutic agent is a statin. Statins are HMG-CoA reductase inhibitors, including but not limited to atorvastatin (LIPITOR), fluvastatin (LESCOL), lovastatin (MEVACOR), pravastatin (PRAVACHOL), rosuvastatin (ZOCOR), and pitavastatin (LIVALO). In some embodiments, the additional therapeutic agent is niacin (vitamin B3). In some embodiments, the additional therapeutic agent is an omega-3 fatty acid.

[0243] In some implementations, the additional therapeutic agents are selected from, but are not limited to, the group consisting of: glucagon receptor antagonists; GLP-1, GLP-1 mimics, and GLP-1 receptor agonists; GIP, GIP mimics, and GIP receptor agonists; PACAP, PACAP mimics, and PACAP receptor 3 agonists; cholesterol-lowering agents, such as HMG-CoA reductase inhibitors, chelators, nicotinic acid, nicotinic acid and its salts, PPARα agonists, PPARα / γ dual agonists, cholesterol absorption inhibitors, acyl-CoA:cholesterol acyltransferase inhibitors, antioxidants, and LXR modulators; PPARδ agonists; anti-obesity compounds; ileal bile acid transporter inhibitors; anti-inflammatory agents excluding glucocorticoids; protein tyrosine phosphatase-IB (PTP-IB) inhibitors, and CB1 antagonists / inverse agonists.

[0244] Chemical background

[0245] In some respects, the ERR-regulating compounds of this disclosure can be synthesized using the organic chemical methods described in this application. These methods can be further modified and optimized using principles and techniques of organic chemistry applied by those skilled in the art. Such principles and techniques are taught, for example, in March's Advanced Organic Chemistry: Reactions, Mechanisms, and Structure (2007), which is incorporated herein by reference.

[0246] Process Scale-up

[0247] The synthetic methods described herein can be further modified and optimized using principles and techniques of process chemistry applied by those skilled in the art for preparative, pilot-scale, or large-scale production (batch or continuous). Such principles and techniques are taught, for example, in Practical Process Research & Development (2000), which is incorporated herein by reference. The synthetic methods described herein can be used to produce preparative-scale quantities of the compounds described herein.

[0248] Chemical definition

[0249] When used in the context of chemical groups: "hydrogen" means -H; "hydroxyl" means -OH; "oxo" means =O; "carbonyl" means -C(=O)−; "carboxyl" means -C(=O)OH (also written as -COOH or -CO2H); "halogen" independently means -F, -Cl, -Br or -I; "amino" means -NH2; "hydroxyamino" means -NHOH; "nitro" means -NO2; "imino" means =NH; "cyano" means... -CN; "isocyanate" means -N=C=O; "azide" means -N3; ​​in a monovalent context, "phosphate" means -OP(O)(OH)2 or its deprotonated form; in a divalent context, "phosphate" means -OP(O)(OH)O- or its deprotonated form; "mercapto" means -SH; "thio" means =S; "thiocarbonyl" means -C(=S)−; "sulfonyl" means -S(O)2−; "sulfinyl" means -S(O)−.

[0250] In the context of chemical formulas, the symbol "−" indicates a single bond, "=" indicates a double bond, and "≡" indicates a triple bond. "Indicates an optional key, either a single or double key if present. The symbol " "" indicates a single bond or a double bond. For example, this formula Including, for example , , , and Furthermore, it should be understood that no single ring atom constitutes part of more than one double bond. Additionally, it should be noted that the covalent bond symbol "−" does not indicate any preferred stereochemistry when connecting one or two stereo atoms. Instead, it encompasses all stereoisomers and mixtures thereof. When drawing perpendicularly through the key (e.g., The symbol "" indicates the methyl group and the junction of the group. It should be noted that junctions are typically identified only for large groups in this way to help readers clearly identify the junction. "" indicates a single bond, where the group attached to the thick end of the wedge is "outside the paper". The symbol " The symbol “” indicates a single bond, where the group attached to the thick end of the wedge is “in the plane of the paper.” "" indicates a single bond, where the geometry around a double bond (e.g., E or Z) is undefined. Therefore, both options and combinations thereof are covered. Any undefined valence on an atom in the structure shown in this application implicitly represents a hydrogen atom bonded to that atom. Bold dots on carbon atoms indicate that the hydrogen atoms bonded to that carbon are oriented outside the plane of the paper.

[0251] When the variable is described as a “floating group” on a ring system, such as group “R” in the formula:

[0252] ,

[0253] This variable can replace any hydrogen atom attached to any ring atom, including depicted, implicit, or explicitly defined hydrogens, as long as a stable structure is formed. When a variable is described as a "floating group" on a fused ring system, such as group "R" in the formula:

[0254] ,

[0255] Unless otherwise specified, this variable can substitute for any hydrogen atom attached to any ring atom of any fused ring. Substitutable hydrogens include depicted hydrogens (e.g., hydrogen attached to nitrogen in the above formula), implicit hydrogens (e.g., hydrogens not shown in the above formula but understood to be present), explicitly defined hydrogens, and optional hydrogens whose presence depends on the identity of the ring atom (e.g., hydrogen attached to group X when X equals −CH−), provided a stable structure is formed. In the depicted example, R can be located on a 5-membered or 6-membered ring of the fused ring system. In the above formula, the subscript letter “y” immediately following R in parentheses indicates a numerical variable. Unless otherwise specified, this variable can be 0, 1, 2, or any integer greater than 2, limited only by the maximum number of substitutable hydrogen atoms in the ring or ring system.

[0256] For chemical groups and compound categories, the number of carbon atoms in that group or category is as follows: "Cn" or "C=n" defines the exact number (n) of carbon atoms in that group / category. "C≤n" defines the maximum number (n) of carbon atoms in that group / category, and the minimum number should be as small as possible for the group / category discussed. For example, it should be understood that the group "alkyl" (C≤8) "alkyldiyl" (C≤8) "Miscellaneous aromatic compounds" (C≤8) "and "acyl" (C≤8) The minimum number of carbon atoms in "" is 1; the group "alkene" (C≤8) "Alkyne" (C≤8) "and heterocyclic alkyl" (C≤8) The minimum number of carbon atoms in "" is 2; the group "cycloalkyl" (C≤8) The minimum number of carbon atoms in “” is 3; and the group “aryl” (C≤8) "and "Arandib" (C≤8) The minimum number of carbon atoms in “Cn-n′” is 6. “Cn-n′” defines the minimum (n) and maximum (n′) carbon atoms in the group. Therefore, “alkyl (C2-10)” specifies those alkyl groups having 2 to 10 carbon atoms. These carbon number indicators can precede or follow the chemical group or class they modify, and they can or cannot be enclosed in parentheses without changing their meaning. Therefore, the term “Cn-n′” is used in conjunction with the standard term “Cn-n′”. 1-4 -alkyl", C1-4 -alkyl", "alkyl" (C1-4) "and "alkyl (C≤4) "All are synonyms. Except as indicated below, each carbon atom is counted to determine whether the group or compound belongs to the specified number of carbon atoms. For example, dihexylamino is a dialkylamino group." (C12) Examples of functional groups; however, it is not a dialkylamino group. (C6) Examples of functional groups. Similarly, phenethyl is an aralkyl group. (C=8) Examples of functional groups. When any chemical group or class of compounds as defined herein is modified by the term "substituted," any carbon atoms in the portion that substituted hydrogen atoms are not counted. Thus, the methoxyhexyl group, with a total of 7 carbon atoms, is a substituted alkyl group. ( C 1-6) Examples. Unless otherwise stated, any chemical group or compound class listed in the claims set that does not have a carbon atom limit has a carbon atom limit of 12 or less.

[0257] The term "saturated" when used to modify a compound or chemical group means that the compound or chemical group does not contain carbon-carbon double bonds or carbon-carbon triple bonds, unless otherwise stated below. When the term is used to modify an atom, it means that the atom is not part of any double or triple bond. In the case of substituted forms of saturated groups, one or more carbon-oxygen double bonds or carbon-nitrogen double bonds may be present. And when such bonds are present, carbon-carbon double bonds that may appear as part of keto-enol tautomerism or imine / enamine tautomerism are not excluded. When the term "saturated" is used to modify a solution of a substance, it means that the substance is no longer soluble in the solution.

[0258] The term "aliphatic" indicates that the modified compound or chemical group is acyclic or cyclic but non-aromatic. In aliphatic compounds / groups, carbon atoms can be linked together in the form of straight chains, branched chains, or non-aromatic rings (alicyclic rings). Aliphatic compounds / groups can be saturated, i.e., linked by a single carbon-carbon bond (alkane / alkyl), or unsaturated, having one or more carbon-carbon double bonds (alkene / alkenyl) or one or more carbon-carbon triple bonds (alkynyl / alkynyl).

[0259] The term "aromatic" refers to a compound or chemical group modified in this way to have a planar unsaturated atomic ring containing 4n+2 electrons in a fully conjugated cyclic π-system. Aromatic compounds or chemical groups can be described as a single resonance structure; however, a description of one resonance structure is also considered to refer to any other resonance structure. For example:

[0260] Also considered to refer to .

[0261] Aromatic compounds can also be depicted using circles to represent the delocalization of electrons in fully conjugated π-ring systems. Two non-limiting examples are shown below:

[0262] and .

[0263] The term "alkyl" refers to a monovalent saturated aliphatic group with a carbon atom as the link, having a straight-chain or branched acyclic structure, and containing no atoms other than carbon and hydrogen. Examples of alkyl groups include −CH3 (Me), −CH2CH3 (Et), −CH2CH2CH3 (n-Pr or propyl), and −CH(CH3)2 (i-Pr). i Pr or isopropyl), −CH2CH2CH2CH3(n-Bu), −CH(CH3)CH2CH3(sec-butyl), −CH2CH(CH3)2(isobutyl), −C(CH3)3(tert-butyl, t-butyl, t-Bu or t Bu) and -CH2C(CH3)3 (neopentyl) are non-limiting examples of alkyl groups. The term "alkanediyl" refers to a divalent saturated aliphatic group with one or more saturated carbon atoms as connecting points, having a straight or branched acyclic structure, without carbon-carbon double or triple bonds, and containing no atoms other than carbon and hydrogen. The groups -CH2− (methylene), -CH2CH2−, -CH2C(CH3)2CH2−, and -CH2CH2CH2− are non-limiting examples of alkanediyl groups. The term "alkoxylide" refers to a divalent group =CRR′, where R and R′ are independently hydrogen or alkyl. Non-limiting examples of alkoxylides include: =CH2, =CH(CH2CH3), and =C(CH3)2. "Alkane" refers to the class of compounds having the formula HR, where R is the term alkyl as defined above.

[0264] The term "cycloalkyl" refers to a monovalent saturated aliphatic group with a carbon atom as the connecting point, said carbon atom forming part of one or more non-aromatic ring structures, without carbon-carbon double or triple bonds, and containing no atoms other than carbon and hydrogen. Non-limiting examples include: −CH(CH2)2 (cyclopropyl), cyclobutyl, cyclopentyl, or cyclohexyl (Cy). As used herein, this term does not exclude the presence of one or more alkyl groups (where the carbon number limit allows) attached to a carbon atom of a non-aromatic ring structure. The term "cycloalkyldiyl" refers to a divalent saturated aliphatic group with two carbon atoms as the connecting points, without carbon-carbon double or triple bonds, and containing no atoms other than carbon and hydrogen. These are non-limiting examples of cycloalkanediyl compounds. "Cycloalkanes" refers to a class of compounds having the formula HR, where R is the term cycloalkyl as defined above.

[0265] The term "alkenyl" refers to a monovalent unsaturated aliphatic group with carbon atoms as the connecting points, having a straight-chain or branched acyclic structure, at least one non-aromatic carbon-carbon double bond, no carbon-carbon triple bonds, and containing no atoms other than carbon and hydrogen. Non-limiting examples include: −CH=CH2 (vinyl), −CH=CHCH3, −CH=CHCH2CH3, −CH2CH=CH2 (allyl), −CH2CH=CHCH3, and −CH=CHCH=CH2. The term "alkendiyl" refers to a divalent unsaturated aliphatic group with two carbon atoms as the connecting points, having a straight-chain or branched acyclic structure, at least one non-aromatic carbon-carbon double bond, no carbon-carbon triple bonds, and containing no atoms other than carbon and hydrogen. The groups −CH=CH−, −CH=C(CH3)CH2−, −CH=CHCH2−, and −CH2CH=CHCH2− are non-limiting examples of alkendiyl groups. It should be noted that although the alkenyl group is aliphatic, once the two ends are connected, the group does not preclude the formation of part of an aromatic structure. The terms "alkene" and "olefin" are synonymous, referring to a class of compounds having the formula HR, where R is the term alkenyl group as defined above. Similarly, the terms "terminal olefin" and "α-olefin" are synonymous, referring to an olefin having only one carbon-carbon double bond, where that bond is part of a terminal vinyl group.

[0266] The term "alkynyl" refers to a monovalent unsaturated aliphatic group with a carbon atom as the linking point, having a straight-chain or branched acyclic structure, at least one carbon-carbon triple bond, and containing no atoms other than carbon and hydrogen. As used herein, the term alkynyl does not exclude the presence of one or more non-aromatic carbon-carbon double bonds. The groups −C≡CH, −C≡CCH3, and −CH2C≡CCH3 are non-limiting examples of alkynyl groups. "Alkyne" refers to a class of compounds having the formula HR, where R is an alkynyl group.

[0267] The term "aryl" refers to a monovalent unsaturated aromatic group with an aromatic carbon atom as a connecting point, said carbon atom forming part of one or more aromatic ring structures, each aromatic ring structure having six ring atoms, all of which are carbon, and wherein the group consists of no atoms other than carbon and hydrogen. If more than one ring is present, these rings can be fused or unfused. Unfused rings are connected by covalent bonds. As used herein, the term aryl does not exclude the presence of one or more alkyl groups (where the carbon number limit allows) attached to the first aromatic ring or any additional aromatic ring present. Non-limiting examples of aryl include phenyl (Ph), methylphenyl, (dimethyl)phenyl, −C6H4CH2CH3 (ethylphenyl), naphthyl, and monovalent groups derived from biphenyl (e.g., 4-phenylphenyl). The term "aryl diaryl" refers to a divalent aromatic group with two aromatic carbon atoms as connecting points, said carbon atoms forming part of one or more six-membered aromatic ring structures, each six-membered aromatic ring structure having six ring atoms, and wherein the divalent group consists of no atoms other than carbon and hydrogen. As used herein, the term aryldiyl does not exclude the presence of one or more alkyl groups (as permitted by carbon number restrictions) attached to the first aromatic ring or any additional aromatic ring present. If more than one ring is present, these rings may be fused or unfused. Unfused rings are connected by covalent bonds. Non-limiting examples of aryldiyl groups include:

[0268] , , , , and .

[0269] "Aromatic hydrocarbons" refers to a class of compounds having the formula HR, where R is the term aryl as defined above. Benzene and toluene are non-limiting examples of aromatic hydrocarbons.

[0270] The term "aralkyl" refers to a monovalent group -alkyldiyl-aryl, wherein the terms alkyldiyl and aryl are used in a manner consistent with the definitions provided above. Non-limiting examples are: phenylmethyl (benzyl, Bn) and 2-phenyl-ethyl.

[0271] The term "heteroaryl" refers to a monovalent aromatic group with an aromatic carbon or nitrogen atom as a connecting point, said carbon or nitrogen atom forming part of one or more aromatic ring structures, each aromatic ring structure having 3 to 8 ring atoms, wherein at least one of the ring atoms of the aromatic ring structure (one or more) is nitrogen, oxygen, or sulfur, and wherein the heteroaryl group consists of atoms other than carbon, hydrogen, aromatic nitrogen, aromatic oxygen, and aromatic sulfur. If more than one ring is present, these rings are fused; however, the term heteroaryl does not preclude the presence of one or more alkyl or aryl groups (where the number of carbon atoms allows) attached to one or more ring atoms. Non-limiting examples of heteroaryl groups include benzoxazolyl, benzimidazolyl, furanyl, imidazolyl (Im), indolyl, indazole, isoxazolyl, methylpyridyl, oxazolyl, oxadiazolyl, phenylpyridyl, pyridyl (pyridyl), pyrroleyl, pyrimidinyl, pyrazinyl, quinolinyl, quinazolinyl, quinoxalolinyl, triazinyl, tetrazolyl, thiazolyl, thiopheneyl, and triazolyl. The term "N-heteroaryl" refers to a heteroaryl group with a nitrogen atom as the connecting point. "Heteroary hydrocarbon" refers to a class of compounds having the formula HR, where R is a heteroaryl group. Pyridine and quinoline are non-limiting examples of heteroary hydrocarbons.

[0272] The term "heteroaryl" refers to a monovalent group -alkyldiyl-heteroaryl, wherein the terms alkyldiyl and heteroaryl are used in a manner consistent with the definitions provided above. Non-limiting examples are: pyridylmethyl and 2-quinolinyl-ethyl.

[0273] The term "heterocyclic alkyl" refers to a monovalent non-aromatic group with a carbon or nitrogen atom as a linking point, said carbon or nitrogen atom forming part of one or more non-aromatic ring structures, each non-aromatic ring structure having 3 to 8 ring atoms, wherein at least one of the ring atoms of the non-aromatic ring structure (one or more) is nitrogen, oxygen, or sulfur, and wherein the heterocyclic alkyl group consists of atoms other than carbon, hydrogen, nitrogen, oxygen, and sulfur. If more than one ring is present, these rings are fused. As used herein, the term does not exclude the presence of one or more alkyl groups (within the limits of carbon number) attached to one or more ring atoms. Furthermore, the term does not exclude the presence of one or more double bonds in the ring or ring system, provided that the resulting group remains non-aromatic. Non-limiting examples of heterocyclic alkyl groups include aziridinyl, azirrobutyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, tetrahydrofuranyl, tetrahydrothiophenyl, tetrahydropyranyl, pyranyl, ethylene oxide, and oxacyclobutyl. The term "N-heterocyclic alkyl" refers to a heterocyclic alkyl group with a nitrogen atom as the connecting point. N-pyrrolidinyl is an example of this type of group.

[0274] The term "heterocyclic alkyl" refers to a monovalent group -alkyldiyl-heterocyclic alkyl, wherein the terms alkyldiyl and heterocyclic alkyl are used in a manner consistent with the definitions provided above. Non-limiting examples are: morpholinylmethyl and piperidinylethyl.

[0275] The term "acyl" refers to the group −C(O)R, where R is hydrogen, alkyl, cycloalkyl, or aryl, as defined above. The groups −CHO, −C(O)CH3 (acetyl, Ac), −C(O)CH2CH3, −C(O)CH(CH3)2, −C(O)CH(CH2)2, −C(O)C6H5, and −C(O)C6H4CH3 are non-limiting examples of acyl groups. "Thioacyl" is defined similarly, except that the oxygen atom in the group −C(O)R has been replaced by a sulfur atom, i.e., −C(S)R. The term "aldehyde" corresponds to an alkyl group attached to the −CHO group as defined above.

[0276] The term "alkoxy" refers to the group −OR, where R is an alkyl group, as defined above. Non-limiting examples include −OCH3 (methoxy), −OCH2CH3 (ethoxy), −OCH2CH2CH3, −OCH(CH3)2 (isopropoxy), or −OC(CH3)3 (tert-butoxy). The terms "cycloalkoxy," "alkenoxy," "alkynoxy," "aryloxy," "araneoxy," "heteroaryloxy," "heterocycloalkoxy," and "acyloxy," when used without the modifier "substituted," refer to a group defined as −OR, where R is cycloalkyl, alkenyl, alkynyl, aryl, aralkyl, heteroaryl, heterocycloalkyl, and acyl, respectively. The terms "alkathioyl" and "acylthioyl" refer to the group −SR, where R is alkyl and acyl, respectively. The term "alcohol" corresponds to an alkane as defined above, where at least one hydrogen atom is substituted with a hydroxyl group. The term "ether" corresponds to an alkane as defined above, where at least one hydrogen atom is substituted with an alkoxy group.

[0277] The term "alkylamino" refers to the group −NHR, where R is an alkyl group, as defined above. Non-limiting examples include −NHCH3 and −NHCH2CH3. The term "dialkylamino" refers to the group −NRR′, where R and R′ can be the same or different alkyl groups. Non-limiting examples of dialkylamino include −N(CH3)2 and −N(CH3)(CH2CH3). The term "acylamino," when used without the "substituted" modifier, refers to the group −NHR, where R is an acyl group, as defined above. A non-limiting example of acylamino is −NHC(O)CH3.

[0278] When a chemical group is used with the modifier “substituted”, one or more hydrogen atoms have been independently replaced each time they appear by −OH, −F, −Cl, −Br, −I, −NH2, −NO2, −CO2H, −CO2CH3, −CO2CH2CH3, −CN, −SH, −OCH3, −OCH2CH3, −C(O)CH3, −NHCH3, −NHCH2CH3, −N(CH3)2, −C(O)NH2, −C(O)NHCH3, −C(O)N(CH3)2, −OC(O)CH3, −NHC(O)CH3, −S(O)2OH or −S(O)2NH2. For example, the following groups are non-limiting examples of substituted alkyl groups: −CH2OH, −CH2Cl, −CF3, −CH2CN, −CH2C(O)OH, −CH2C(O)OCH3, −CH2C(O)NH2, −CH2C(O)CH3, −CH2OCH3, −CH2OC(O)CH3, −CH2NH2, −CH2N(CH3)2, and −CH2CH2Cl. The term “haloalkyl” is a subset of substituted alkyl groups in which the substitution of hydrogen atoms is limited to halogens (i.e., −F, −Cl, −Br, or −I), such that no other atoms exist besides carbon, hydrogen, and halogens. The group −CH2Cl is a non-limiting example of a haloalkyl group. The term “fluoroalkyl” is a subset of substituted alkyl groups in which the substitution of hydrogen atoms is limited to fluorine, such that no other atoms exist besides carbon, hydrogen, and fluorine. The groups −CH2F, −CF3, and −CH2CF3 are non-limiting examples of fluoroalkyl groups. Non-limiting examples of substituted aralkyl groups are (3-chlorophenyl)-methyl and 2-chloro-2-phenyl-ethyl-1-yl. Non-limiting examples of substituted acyl groups are −C(O)CH2CF3, −CO2H (carboxyl), −CO2CH3 (methoxycarbonyl), −CO2CH2CH3, −C(O)NH2 (carbamoyl), and −CON(CH3)2. Non-limiting examples of substituted amide groups are −NHC(O)OCH3 and −NHC(O)NHCH3.

[0279] When used in conjunction with the term "comprising" in the claims and / or specification, the word "a" or "an" may mean "an," but it is also consistent with the meanings of "one or more," "at least one," and "one or more."

[0280] In this application, the term "about" is used to indicate that a value includes inherent error variations of the device, inherent error variations of the method used to determine the value, or variations that exist between study subjects or patients. Unless otherwise stated, the term "about" is used to indicate ±10% of a reported value, preferably ±5% of a reported value. It should be understood that whenever the term "about" is used, the precise numerical value indicated is also specifically referred to.

[0281] An "active ingredient" (AI) or active pharmaceutical ingredient (API) (also known as an active compound, active substance, active agent, pharmaceutical preparation, drug, bioactive molecule, or therapeutic compound) is a biologically active component of a drug.

[0282] The terms “contains,” “has,” and “includes” are open-ended connecting verbs. Any form or tense of one or more of these verbs, such as “contains,” “includes,” “has,” “includes,” and “includes,” is also open-ended. For example, any method of “contains,” “has,” or “includes” one or more steps is not limited to having only those one or more steps, but also covers other steps not listed.

[0283] The term “effective” as used in the specification and / or claims means sufficient to achieve the desired, anticipated, or intended result. “Effective amount,” “therapeutic effective amount,” or “pharmaceutical effective amount,” when used in the context of treating a patient or object with the compound, means an amount of the compound, when administered to the patient or object, sufficient to affect the disease as defined below for such treatment or prevention.

[0284] "Excipients" are pharmaceutically acceptable substances formulated with one or more active ingredients in a drug, pharmaceutical composition, formulation, or drug delivery system. Excipients can be used, for example, to stabilize a composition, increase the volume of the composition (and are therefore often referred to as "fillers," "compatibilizers," or "diluents" when used for this purpose), or to impart therapeutic enhancements to the active ingredient in the final dosage form, such as promoting drug absorption, reducing viscosity, or enhancing solubility. Excipients include pharmaceutically acceptable anti-adhesion agents, binders, coating agents, colorants, disintegrants, flavoring agents, flow aids, lubricants, preservatives, adsorbents, sweeteners, and solvents. The primary excipient used as a medium for delivering the active ingredient is often referred to as a solvent. Excipients can also be used in manufacturing processes, for example, to aid in handling the active substance, such as by promoting powder flowability or non-stickiness, and also to aid in in vitro stability, such as preventing denaturation or aggregation during the expected shelf life. The suitability of excipients typically depends on the route of administration, dosage form, active ingredient, and other factors.

[0285] When used as a modifier for a compound, the term "hydrate" means that each molecule of the compound is associated with fewer than one (e.g., hemihydrate), one (e.g., monohydrate), or more than one (e.g., dihydrate) water molecules, for example, in the solid form of the compound.

[0286] As used in this article, the term "IC" 50"EC" refers to the amount of inhibitor that achieves 50% of the maximum response. This quantitative measurement indicates how much of a specific drug or other substance (inhibitor) is needed to inhibit a given biological, biochemical, or chemical process (or a component of the process, i.e., an enzyme, cell, cell receptor, or microorganism) by half. 50 "" refers to the amount of effective concentration that produces the half-maximum reaction.

[0287] An "isomer" of the first compound is a separate compound in which each molecule contains the same constituent atoms as the first compound, but these atoms have different configurations in three-dimensional space.

[0288] As used herein, the terms "patient" or "object" refer to a living mammalian organism, such as a human, monkey, cow, sheep, goat, dog, cat, mouse, rat, guinea pig, or a transgenic species thereof. In some embodiments, the patient or object is a primate. Non-limiting examples of human patients are adults, adolescents, infants, and fetuses.

[0289] As used in this article, "pharmaceutically acceptable" generally refers to compounds, materials, compositions, and / or dosage forms that, within a reasonable medical judgment, are suitable for contact with human and animal tissues, organs, and / or body fluids without excessive toxicity, irritation, allergic reactions, or other problems or complications, and have a reasonable benefit / risk ratio.

[0290] "Pharmaceutically acceptable salt" means a salt of the compounds disclosed herein that is pharmaceutically acceptable as defined above and possesses the desired pharmacological activity. Such salts include acid addition salts formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, etc.; or with organic acids such as 1,2-ethanedisulfonic acid, 2-hydroxyethanesulfonic acid, 2-naphthalenesulfonic acid, 3-phenylpropionic acid, 4,4′-methylenebis(3-hydroxy-2-en-1-carboxylic acid), 4-methylbicyclo[2.2.2]oct-2-en-1-carboxylic acid, acetic acid, aliphatic monocarboxylic and dicarboxylic acids, aliphatic sulfuric acid, aromatic sulfuric acid, benzenesulfonic acid, benzoic acid, camphorsulfonic acid, carbonic acid, cinnamon, etc. Salts formed from acids such as citric acid, cyclopentanepropionic acid, ethanesulfonic acid, fumaric acid, glucoheponic acid, gluconic acid, glutamic acid, glycolic acid, heptanoic acid, hexanoic acid, hydroxynaphthoic acid, lactic acid, lauryl sulfate, maleic acid, malic acid, malonic acid, mandelic acid, methanesulfonic acid, mucoconic acid, o-(4-hydroxybenzoyl)benzoic acid, oxalic acid, p-chlorobenzenesulfonic acid, phenyl-substituted alkanic acids, propionic acid, p-toluenesulfonic acid, pyruvic acid, salicylic acid, stearic acid, succinic acid, tartaric acid, tert-butylacetic acid, and trimethylacetic acid. Pharmaceutically acceptable salts also include base addition salts formed when the present acidic protons can react with inorganic or organic bases. Acceptable inorganic bases include sodium hydroxide, sodium carbonate, potassium hydroxide, aluminum hydroxide, and calcium hydroxide. Acceptable organic bases include ethanolamine, diethanolamine, triethanolamine, tromethamine, and N-methylglucosamine. It should be understood that the specific anion or cation constituting any salt of the present invention is not critical, as long as the salt as a whole is pharmacologically acceptable. Additional examples of pharmaceutically acceptable salts and their preparation and use are presented in Handbook of Pharmaceutical Salts: Properties, and Use (PH Stahl & CG Wermuth eds., Verlag Helvetica Chimica Acta, 2002).

[0291] A pharmaceutically acceptable carrier, a drug carrier, or simply a carrier, is a pharmaceutically acceptable substance formulated with an active pharmaceutical ingredient (API) that involves carrying, delivering, and / or transporting a chemical reagent. Drug carriers can be used to improve drug delivery and efficacy, including controlled-release techniques such as modulating drug bioavailability, reducing drug metabolism, and / or reducing drug toxicity. Some drug carriers can increase the effectiveness of drug delivery to specific target sites. Examples of carriers include liposomes, microspheres (e.g., made from poly(lactic-co-glycolic acid) copolymers), albumin microspheres, synthetic polymers, nanofibers, protein-DNA complexes, protein conjugates, erythrocytes, virions, and dendritic polymers.

[0292] A “medicine” (also known as a pharmaceutical preparation, pharmaceutical composition, pharmaceutical product, medical product, drug, medicine, pharmaceutical agent or simply a drug, reagent or preparation) is a composition intended to diagnose, cure, treat or prevent a disease, comprising an active pharmaceutical ingredient (API) (as defined above) and optionally comprising one or more inactive ingredients, also known as excipients (as defined above).

[0293] "Prevention" or "avoidance" includes: (1) suppressing the onset of disease in subjects or patients who may be at risk of disease and / or susceptible to disease but have not yet experienced or shown any of the pathology or symptoms of the disease, and / or (2) slowing the onset of the pathology or symptoms of the disease in subjects or patients who may be at risk of disease and / or susceptible to disease but have not yet experienced or shown any of the pathology or symptoms of the disease.

[0294] "Prodrug" refers to a compound that can be metabolized in vivo into the active pharmaceutical ingredient of the present invention. A prodrug may or may not be active in its prodrug form. For example, compounds containing a hydroxyl group can be administered as an ester, which is converted to a hydroxyl compound in vivo via hydrolysis. Non-limiting examples of suitable esters that can be converted to a hydroxyl compound in vivo include acetates, citrates, lactates, phosphates, tartrates, malonates, oxalates, salicylates, propionates, succinates, fumarates, maleates, methylene bis-β-hydroxynaphthyl esters, gentianates, hydroxyethyl sulfonates, ditolyl tartrates, methanesulfonates, ethanesulfonates, benzenesulfonates, p-toluenesulfonates, cyclohexylaminosulfonates, quinic acid esters, and esters of amino acids. Similarly, compounds containing an amino group can be administered as an amide, which is converted to an amine compound in vivo via hydrolysis.

[0295] Stereoisomers, or optical isomers, are isomers of a given compound in which the same atoms are bonded to the same other atoms, but these atoms have different configurations in three-dimensional space. Enantiomers are stereoisomers of a given compound; they are mirror images of each other, like the left and right hands. Diastereomers are stereoisomers of diastereomers of a given compound. Chiral molecules contain a chiral center, also called a stereocenter or stereocenter, which is any point in the molecule (not necessarily an atom) that has a group attached, such that the interchange of any two groups results in stereoisomers. In organic compounds, the chiral center is typically a carbon, phosphorus, or sulfur atom, although other atoms can also be stereocenters in both organic and inorganic compounds. A molecule can have multiple stereocenters, resulting in many stereoisomers. In compounds where stereoisomerism arises due to a tetrahedral stereocenter (e.g., tetrahedral carbon), the total number of hypothetical stereoisomers does not exceed 2. n, where n is the number of tetrahedral stereocenters. A symmetric molecule often has fewer stereoisomers than the maximum possible number. A 50:50 mixture of enantiomers is referred to as a racemic mixture. Alternatively, the enantiomer mixture may be enantiomer-enriched, such that one enantiomer is present in an amount greater than 50%. Typically, enantiomers and / or diastereomers can be resolved or separated using techniques known in the art. It is anticipated that for any stereocenter or chiral axis for which stereochemistry is not yet defined, it may exist in its R form, S form, or mixture of R and S forms (including racemic and non-racemic mixtures). The phrase “substantially free of other stereoisomers” as used herein means that the composition contains ≤15%, more preferably ≤10%, even more preferably ≤5%, or most preferably ≤1% of another stereoisomer (one or more).

[0296] Unless otherwise stated, the compounds of this invention, whether identified by chemical name or chemical structure, include all stereoisomers (e.g., enantiomers and diastereomers), double bond isomers (e.g., (Z) and (E)), conformational isomers, and tautomers of the compounds identified by the chemical names and chemical structures provided herein. Furthermore, single stereoisomers, double bond isomers, conformational isomers, and tautomers, as well as mixtures of stereoisomers, double bond isomers, conformational isomers, and tautomers, are all within the scope of this invention.

[0297] "Treatment" or "treating" includes (1) suppressing disease in a subject or patient who is experiencing or exhibiting disease pathology or symptoms (e.g., preventing further development of pathology and / or symptoms), (2) improving disease in a subject or patient who is experiencing or exhibiting disease pathology or symptoms (e.g., reversing pathology and / or symptoms), and / or (3) achieving any measurable reduction of disease or its symptoms in a subject or patient who is experiencing or exhibiting disease pathology or symptoms.

[0298] The term "unit dose" refers to a formulation of a compound or composition such that the formulation is prepared in a manner sufficient to provide a single therapeutic dose of the active ingredient to a patient in a single administration. Such unit dose formulations may include, but are not limited to, single tablets, capsules, or other oral formulations, or single vials containing injectable liquids or other injectable formulations.

[0299] The foregoing definitions supersede any conflicting definitions cited in any references incorporated herein by reference. However, the fact that some terms are defined should not be construed as indicating that any undefined term is indeterminate. Rather, all terminology used is believed to describe the invention in a manner that would allow those skilled in the art to understand its scope and practice.

[0300] Example

[0301] The following embodiments are included to illustrate preferred embodiments of this disclosure. Those skilled in the art will understand that the techniques disclosed in the following embodiments represent techniques that the discloser has found to be effective in the practice of this disclosure, and therefore can be considered as constituting a preferred mode of practice. However, based on this disclosure, those skilled in the art will understand that many changes can be made to the specific embodiments disclosed without departing from the spirit and scope of this disclosure, and the same or similar results can still be obtained.

[0302] Abbreviations

[0303] Unless otherwise stated or provided by context, the following abbreviations shall be understood to have the following meanings:

[0304]

[0305] Example 1 – Synthesis of ERR-Regulating Compounds

[0306]

[0307] Scheme 1. Synthesis of 3,5-disubstituted-4,5-dihydro-1H-pyrazole

[0308] General Procedure for Synthesizing 3,5-Disubstituted-4,5-dihydro-1H-pyrazole

[0309] To a 100 mL round-bottom flask, add compound A (10 mmol) dissolved in 30 mL of ethanol, followed by dropwise addition of hydrazine monohydrate (50 mmol). Heat the reaction mixture under reflux for 4 hours. Then quench the reaction mixture with crushed ice, filter the resulting solid, and dry it under vacuum. Purify the product by recrystallization, rapid column chromatography, or both.

[0310] Table 2. Characterization of the compounds

[0311]

[0312]

[0313]

[0314]

[0315]

[0316]

[0317]

[0318]

[0319]

[0320]

[0321]

[0322]

[0323]

[0324]

[0325]

[0326]

[0327]

[0328]

[0329]

[0330]

[0331]

[0332]

[0333]

[0334]

[0335]

[0336] Example 2 - In vitro bioactivity of ERR-regulating compounds

[0337] HEK293 cells were maintained in Dulbecco's modified Eagles medium (DMEM) supplemented with 10% fetal bovine serum and cultured at 37°C and 5% CO2. Cells were sputtered at 2.5 × 10⁻⁶ cells / year. 4Cells were seeded at a density of 100 cells / well in 96-well plates and transiently transfected using Lipofectamine 2000 (Invitrogen) according to the manufacturer's instructions. Cells were transfected with the ERRE reporter gene construct and pcDNA3.1 ERRα or ERRγ. 24 hours post-transfection, cells were treated with solvent or compound (various concentrations) for 24 hours (4 wells per dose). Luciferase activity was measured using the One-Glo Tox Luciferase Reporter Assay System (Promega), and EC50 was calculated using GraphPad Prism software. 50 The results are shown in Table 3.

[0338] Test compounds that were active within the tested concentration range were reported: *** <1µM, **1-5µM, * >5µM, and ia (inactive).

[0339] Table 3. Bioactivity of the compounds

[0340]

[0341]

[0342]

[0343]

[0344]

[0345]

[0346]

[0347]

[0348]

[0349]

[0350]

[0351]

[0352]

[0353]

[0354]

[0355]

[0356]

[0357]

[0358]

[0359]

[0360]

[0361] Example 3 - In vivo biological activity of ERR-regulated compounds

[0362] Neonatal rat ventricular myocytes (NRVMs) were prepared according to the method previously described in Xu et al., Circulation (2024), 149(3):227 (PMID: 37961903), which is incorporated herein by reference, and were treated with a putative ERR agonist at concentrations ranging from 5 µM to 10 µM. After 72 hours of treatment, cells were harvested and RNA was prepared according to the method previously described in Xu et al. (PMID: 37961903), and RNA sequencing analysis was performed. 332 = SLU-PP-332; 915 = SLU-PP-915; GSK = GSK716.

[0363] Neonatal rat ventricular myocytes (NRVMs) were prepared according to the method previously described in Xu et al. (PMID: 37961903) and treated with putative ERR agonists for 24 to 72 hours. Cellular respiration was then assessed using a Seahorse instrument (Agilent Technologies) according to the method previously described in Billon et al. ACS Chem. Biol. (2023), 18(4):756 (PMID: 36988910), which is incorporated herein by reference. Oxygen consumption rate (OCR) was calculated using the instrument, with only the solvent used as a control, to compare the ability of compounds to induce an increase in OCR. *, P>0.05 vs. control; **, P<0.01 vs. control; ***, P<0.001 vs. control. 332 = SLU-PP-332; 915 = SLU-PP-915.

[0364] statement

[0365] 1. A compound of the following formula, or a pharmaceutically acceptable salt thereof:

[0366] (II-A)

[0367] in:

[0368] A is phenyl, pyridyl, thiophenyl, or naphthyl;

[0369] B is phenyl, imidazolyl, or naphthyl;

[0370] Each R1 is independently H, OH, halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy or C 1-6 Halogenated alkoxy groups;

[0371] Each R2 is independently H, OH, halogen, N(R4)2, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy or C 1-6 Halogenated alkoxy groups;

[0372] Each R3 is independently H or -C(O)-phenyl-tert-butyl;

[0373] Each R4 is independently H or C. 1-6 alkyl;

[0374] n is 0, 1, 2, 3, 4, 5, 6, or 7; and

[0375] m can be 0, 1, 2, 3, 4, 5, 6, or 7.

[0376] 2. The compound according to statement 1, wherein A is a phenyl group.

[0377] 3. The compound according to any one of statements 1 and 2, wherein B is phenyl.

[0378] 4. The compound according to any one of statements 1 and 2, wherein B is a naphthyl group.

[0379] 5. The compound according to any one of statements 1 to 4, wherein at least one R1 is a halogen.

[0380] 6. The compound according to any one of statements 1 to 4, wherein at least one R1 is C 1-6 Halogenated alkyl groups.

[0381] 7. The compound according to any one of statements 1 to 4 and 6, wherein at least one R1 is CF3.

[0382] 8. The compound according to any one of statements 1 to 7, wherein n is 1.

[0383] 9. The compound according to any one of statements 1 to 8, wherein at least one R2 is OH.

[0384] 10. The compound according to any one of statements 1 to 9, wherein at least one R2 is a halogen and one R2 is OH.

[0385] 11. The compound according to any one of statements 1 to 10, wherein m is 1 or 2.

[0386] 12. The compound according to statement 1, wherein

[0387]

[0388] B is phenyl, imidazolyl, or naphthyl;

[0389] Each R1 is independently H, OH, halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy or C 1-6 Halogenated alkoxy groups;

[0390] Each R2 is independently H, OH, halogen, N(R4)2, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy or C 1-6 Halogenated alkoxy groups;

[0391] R4 is H or C. 1-6 alkyl;

[0392] n is 0, 1, or 2; and

[0393] m is 0, 1, or 2;

[0394] Or its pharmaceutically acceptable salt.

[0395] 13. The compound according to statement 1, wherein

[0396]

[0397] Each R1 is independently H, OH, halogen, or C. 1-6 Alkoxy;

[0398] Each R2 is independently H, OH, halogen, or C. 1-6 Alkoxy;

[0399] n is 1 or 2; and

[0400] m is 0, 1, or 2;

[0401] Or its pharmaceutically acceptable salt.

[0402] 14. A compound selected from Table A or a pharmaceutically acceptable salt thereof.

[0403] 15. The compound according to any one of statements 1 to 14, wherein the compound is in a non-salt form.

[0404] 16. A pharmaceutical composition comprising a compound of any one of statements 1 to 14 or a pharmaceutically acceptable salt thereof or a compound of statement 15 and one or more pharmaceutically acceptable carriers or solvents.

[0405] 17. A method for modulating the activity of an estrogen-related receptor, the method comprising contacting the estrogen-related receptor with a compound of any one of statements 1 to 15.

[0406] 18. A method for modulating the activity of an estrogen-related receptor, the method comprising contacting the estrogen-related receptor with a compound of any one of statements 1 to 14 or a pharmaceutically acceptable salt thereof, a compound of statement 15 or a pharmaceutical composition of statement 16.

[0407] 19. The method according to statement 17, wherein the estrogen-related receptor is selected from the group consisting of estrogen-related receptor α, estrogen-related receptor β and estrogen-related receptor γ.

[0408] 20. A method for inhibiting the activity of estrogen-related receptors, the method comprising administering to a subject a compound of any one of statements 1 to 14 or a pharmaceutically acceptable salt thereof, a compound of statement 15 or a pharmaceutical composition of statement 16.

[0409] 21. A method for treating a disease or disorder of a subject or for reducing the severity of said disease or disorder, the method comprising administering to the subject a compound of any one of statements 1 to 14 or a pharmaceutically acceptable salt thereof, a compound of statement 15 or a pharmaceutical composition of statement 16.

[0410] 22. The method according to statement 19, wherein the disease or disorder is selected from the group consisting of: diabetes, breast cancer, bone disease, bone resorption, heart failure, obesity, metabolic disease, muscle wasting and other muscle function disorders, mitochondrial dysfunction, kidney disease and dysfunction, and neurodegenerative diseases including AD, PD and ALS.

[0411] 23. Use as a medicament by any one of statements 1 to 14, a pharmaceutically acceptable salt thereof, a compound of statement 15, or a pharmaceutical composition of statement 16.

[0412] 24. Use of the compound of any one of statements 1 to 14 or a pharmaceutically acceptable salt thereof, the compound of statement 15, or the pharmaceutical composition of claim 16 in the preparation of a medicament.

[0413] Although the compositions and methods of this disclosure have been described in accordance with embodiments, it will be apparent to those skilled in the art that changes may be made to the compositions and / or methods described herein, as well as the steps or sequence of steps thereof, without departing from the concept, spirit, and scope of this disclosure. More specifically, it will be apparent that certain chemically and physiologically relevant reagents may be substituted for the reagents described herein while obtaining the same or similar results. All such similar substitutions and modifications that will be apparent to those skilled in the art are considered to be within the spirit, scope, and concept of this disclosure as defined by the appended claims.

Claims

1. A compound of the following formula, or a pharmaceutically acceptable salt thereof: (II-A) in: A is phenyl, pyridyl, thiophenyl, or naphthyl; B is phenyl, imidazolyl, or naphthyl; Each R1 is independently H, OH, halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy or C 1-6 Halogenated alkoxy groups; Each R2 is independently H, OH, halogen, N(R4)2, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy or C 1-6 Halogenated alkoxy groups; Each R3 is independently H or -C(O)-phenyl-tert-butyl; Each R4 is independently H or C. 1-6 alkyl; n is 0, 1, 2, 3, 4, 5, 6, or 7; and m can be 0, 1, 2, 3, 4, 5, 6, or 7.

2. The compound according to claim 1, wherein A is a phenyl group.

3. The compound according to claim 1, wherein B is a phenyl group.

4. The compound according to claim 22, wherein B is a naphthyl group.

5. The compound according to claim 1, wherein at least one R1 is a halogen.

6. The compound according to claim 1, wherein at least one R1 is C 1-6 Halogenated alkyl groups.

7. The compound according to claim 1, wherein at least one R1 is CF3.

8. The compound according to claim 1, wherein n is 1.

9. The compound according to claim 1, wherein at least one R2 is OH.

10. The compound according to claim 1, wherein at least one R2 is a halogen and one R2 is OH.

11. The compound according to claim 1, wherein m is 1 or 2.

12. The compound according to claim 1, wherein the compound has the following formula: B is phenyl, imidazolyl, or naphthyl; Each R1 is independently H, OH, halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy or C 1-6 Halogenated alkoxy groups; Each R2 is independently H, OH, halogen, N(R4)2, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy or C 1-6 Halogenated alkoxy groups; R4 is H or C. 1-6 alkyl; n is 0, 1, or 2; and m is 0, 1, or 2; Or its pharmaceutically acceptable salt.

13. The compound according to claim 1, wherein the compound has the following formula: Each R1 is independently H, OH, halogen, or C. 1-6 Alkoxy; Each R2 is independently H, OH, halogen, or C. 1-6 Alkoxy; n is 1 or 2; and m is 0, 1, or 2; Or its pharmaceutically acceptable salt.

14. A compound selected from Table A, or a pharmaceutically acceptable salt thereof.

15. The compound according to claim 1, wherein the compound is in a non-salt form.

16. A pharmaceutical composition comprising the compound of claim 1 and one or more pharmaceutically acceptable carriers or solvents.

17. A method for modulating the activity of an estrogen-related receptor, the method comprising contacting the estrogen-related receptor with a compound according to claim 1.

18. A method for modulating the activity of an estrogen-related receptor, the method comprising contacting the estrogen-related receptor with a compound according to claim 1.

19. The method of claim 18, wherein the estrogen-related receptor is selected from the group consisting of estrogen-related receptor α, estrogen-related receptor β and estrogen-related receptor γ.

20. A method for inhibiting the activity of estrogen-related receptors, the method comprising administering to a subject the compound according to claim 1.

21. A method for treating a disease or disorder of a subject or for reducing the severity of said disease or disorder, the method comprising administering to the subject the compound according to claim 1.

22. The method of claim 21, wherein the disease or disorder is selected from the group consisting of: diabetes, breast cancer, bone disease, bone resorption, heart failure, obesity, metabolic disease, muscle wasting and other muscle function disorders, mitochondrial dysfunction, kidney disease and dysfunction, and neurodegenerative diseases including AD, PD and ALS.

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