WO2022148331A1

WO2022148331A1 - Aminoheteroaryl compounds and uses thereof

Info

Publication number: WO2022148331A1
Application number: PCT/CN2022/070011
Authority: WO
Inventors: Wei Cheng; Donghai WU
Original assignee: Beijing Erai Therapeutics Co., Ltd.
Priority date: 2021-01-06
Filing date: 2022-01-04
Publication date: 2022-07-14
Also published as: WO2022147694A1

Abstract

Provided herein are novel compounds (e.g., Formula I, II, III, or IV), pharmaceutical compositions, and methods of using the same. The compounds herein can typically induce UCP-1 expression and/or browning of white adipose tissues. The compounds herein can also be used for treating a variety of diseases or disorders, such as a metabolic disease or disorder such as obesity and/or diabetes (e.g., Type 2 diabetes) and/or a liver disease or disorder such as NASH and/or non-alcoholic fatty liver disease.

Description

AMINOHETEROARYL COMPOUNDS AND USES THEREOF

In various embodiments, the present disclosure generally relates to novel aminoheteroaryl compounds, compositions comprising the same, methods of preparing and methods of using the same, e.g., for inducing uncoupling protein-1 (UCP-1) expression and/or for treating or preventing various diseases or disorders described herein.

BACKGROUND

Adipose tissues can be traditionally classified into white adipose tissue (WAT) and brown adipose tissue (BAT) . While WAT stores nutrients as lipids, BAT can dissipate lipids to provide heat in a process called thermogenesis. BAT thermogenesis is dependent on the activation of uncoupling protein-1 (UCP1) , which is located in the inner mitochondrial membrane of BAT. When activated, UCP1 uncouples oxidative phosphorylation in mitochondria to dissipate the electrochemical gradient as heat.

In addition to the “classical” and “developmentally programmed” brown adipocytes clustered in defined anatomical BAT depots, a “browning” process, which consists of the induced appearance of UCP1-expressing and multilocular brown adipocytes in WAT depots, often in response to specific stimuli such as prolonged cold exposure and chronic treatment with β3-adrenergic stimuli. These inducible brown adipocytes within classical WAT depots have been called “brite” (brown-in-white) or “beige” adipocytes. The important roles of brite/beige cells in thermoregulation and energy homeostasis are highlighted recently. In adult humans, the predominant form of brown adipocytes is brite/beige cells, which can be induced from WAT under proper stimulation. In light of the promising metabolic benefits of brown and beige adipocytes, intense research has been conducted in recent years to search for physiological, pharmacological and dietary agents that can enhance browning of WAT by induction of UCP1 expression or/and mitochondrial oxidative metabolism. So far, dozens of “browning” agents have been reported, including the sympathetic activators (such as the β3-adrenergic agonists BRL26830A and CL-316243) , prostaglandins, PPARα and PPARγ agonists, retinoids, activators of AMP-activated protein kinase, thyroid hormone, bone morphogenetic protein 7 (BMP7) , irisin and fibroblast growth factor (FGF) 21. While most of these agents exert dual effects on both activation of classical BAT and induction of WAT browning, and some of them (such as prostaglandin, irisin and FGF21) are specific to the browning of WAT. Although some drugs are found to induce browning, they may show strong side effect. Therefore, it is important to look for safer and more effective “browning” food supplements and/or drugs for healthy development and treatment of obesity as well as it associated metabolic disorders.

BRIEF SUMMARY

In various embodiments, the present disclosure provides novel compounds, pharmaceutical compositions, methods of preparing and using the same. Typically, the compounds herein can induce UCP1 expression or/and mitochondrial oxidative metabolism in white adipose tissues. The compounds and compositions herein have various utilities, such as for inducing browning of white adipose tissues, and/or for treating or preventing various diseases or disorders described herein, for example, metabolic diseases or disorders such as obesity or diabetes (e.g., Type 2 diabetes) , liver diseases or disorders such as non-alcoholic fatty liver disease or NASH, etc.

In various embodiments, the present disclosure provides a compound of Formula I, II, III, or IV, a pharmaceutically acceptable ester or amide thereof, as applicable, or a pharmaceutically acceptable salt thereof:

wherein the variables are defined herein. In some embodiments, the compound of Formula I can have a subformula of Formula I-1, I-2, I-3, or I-3A, as defined herein. In some embodiments, a pharmaceutically acceptable ester or amide of the compound of Formula I, or a pharmaceutically acceptable salt thereof, is provided. In some embodiments, the compound of Formula II can have a subformula of Formula II-1, II-2, II-3, II-4, II-5, II-6, II-7, II-8, II-7A, or II-8A, as defined herein. In some embodiments, the compound of Formula III can have a subformula of Formula III-1, as defined herein. In some embodiments, the present disclosure provides a compound selected from compound Nos. 1-21, a pharmaceutically acceptable ester or amide thereof, as applicable, or a pharmaceutically acceptable salt thereof.

Certain embodiments of the present disclosure are directed to a pharmaceutical composition comprising one or more of the compounds of the present disclosure (e.g., a compound of Formula I (e.g., I-1, I-2, I-3, or I-3A) , Formula II (e.g., II-1, II-2, II-3, II-4, II-5, II-6, II-7, II-8, II-7A, or II-8A) , Formula III (e.g., III-1) , Formula IV, or any of Compound Nos. 1-21, a pharmaceutically acceptable ester or amide thereof, as applicable, or a pharmaceutically acceptable salt thereof) and optionally a pharmaceutically acceptable excipient. The pharmaceutical composition described herein can be formulated for different routes of administration, such as oral administration, parenteral administration, or inhalation etc.

Certain embodiments of the present disclosure are directed to a method of inducing uncoupling protein-1 (UCP-1) expression and/or mitochondrial oxidative metabolism in a white adipose tissue, which comprises contacting the white adipose tissue with an effective amount of the compound of the present disclosure (e.g., a compound of Formula I (e.g., I-1, I-2, I-3, or I-3A) , Formula II (e.g., II-1, II-2, II-3, II-4, II-5, II-6, II-7, II-8, II-7A, or II-8A) , Formula III (e.g., III-1) , Formula IV, or any of Compound Nos. 1-21, a pharmaceutically acceptable ester or amide thereof, as applicable, or a pharmaceutically acceptable salt thereof) or a pharmaceutical composition described herein.

In some embodiments, the present disclosure also provides a method of inducing browning of a white adipose tissue, which comprises contacting the white adipose tissue with an effective amount of the compound of the present disclosure (e.g., a compound of Formula I (e.g., I-1, I-2, I-3, or I-3A) , Formula II (e.g., II-1, II-2, II-3, II-4, II-5, II-6, II-7, II-8, II-7A, or II-8A) , Formula III (e.g., III-1) , Formula IV, or any of Compound Nos. 1-21, a pharmaceutically acceptable ester or amide thereof, as applicable, or a pharmaceutically acceptable salt thereof) or a pharmaceutical composition described herein. In some embodiments, the contacting can be in vitro or in vivo.

In some embodiments, the present disclosure also provides a method of treating or preventing a metabolic disease or disorder in a subject in need thereof. In some embodiments, the metabolic disease or disorder is diabetes (e.g., Type 2 diabetes) and/or obesity. In some embodiments, the method comprises administering to the subject an effective amount of a compound of the present disclosure (e.g., a compound of Formula I (e.g., I-1, I-2, I-3, or I-3A) , Formula II (e.g., II-1, II-2, II-3, II-4, II-5, II-6, II-7, II-8, II-7A, or II-8A) , Formula III (e.g., III-1) , Formula IV, or any of Compound Nos. 1-21, a pharmaceutically acceptable ester or amide thereof, as applicable, or a pharmaceutically acceptable salt thereof) or an effective amount of a pharmaceutical composition described herein.

In some embodiments, the present disclosure also provides a method of treating or preventing a liver disease or disorder in a subject in need thereof. In some embodiments, the metabolic disease or disorder is non-alcoholic steatohepatitis (NASH) and/or non-alcoholic fatty liver disease (NAFLD) . In some embodiments, the method comprises administering to the subject an effective amount of a compound of the present disclosure (e.g., a compound of Formula I (e.g., I-1, I-2, I-3, or I-3A) , Formula II (e.g., II-1, II-2, II-3, II-4, II-5, II-6, II-7, II-8, II-7A, or II-8A) , Formula III (e.g., III-1) , Formula IV, or any of Compound Nos. 1-21, a pharmaceutically acceptable ester or amide thereof, as applicable, or a pharmaceutically acceptable salt thereof) or an effective amount of a pharmaceutical composition described herein.

In some embodiments, the present disclosure also provides a method of improving liver health (e.g., reducing AST/ALT ratio, lowering liver triglycerides, and/or lowering liver weight) in a subject in need thereof. In some embodiments, the method comprises administering to the subject an effective amount of a compound of the present disclosure (e.g., a compound of Formula I (e.g., I-1, I-2, I-3, or I-3A) , Formula II (e.g., II-1, II-2, II-3, II-4, II-5, II-6, II-7, II-8, II-7A, or II-8A) , Formula III (e.g., III-1) , Formula IV, or any of Compound Nos. 1-21, a pharmaceutically acceptable ester or amide thereof, as applicable, or a pharmaceutically acceptable salt thereof) or an effective amount of a pharmaceutical composition described herein.

The administering in the methods herein is not limited to any particular route of administration. For example, in some embodiments, the administering can be orally, nasally, transdermally, pulmonary, inhalationally, buccally, sublingually, intraperintoneally, subcutaneously, intramuscularly, intravenously, rectally, intrapleurally, intrathecally and parenterally. The compounds of the present disclosure can be used as a monotherapy or in a combination therapy. For example, the compounds of the present disclosure can be used in a combination therapy along with other useful agents for treating or preventing diabetes (e.g., Type 2 diabetes) , obesity, non-alcoholic steatohepatitis and/or non-alcoholic fatty liver disease, etc.

It is to be understood that both the foregoing summary and the following detailed description are exemplary and explanatory only, and are not restrictive of the invention herein.

BRIEF DESCRIPTION OF THE DRAWINGS/FIGURES

FIG. 1 is a graph showing the overall scheme of the high fat diet induced obesity mouse model.

DETAILED DESCRIPTION

In various embodiments, the present disclosure provides novel aminoheteroaryl such as aminothiozole compounds, which are useful in treating various diseases or disorders such as diabetes (e.g., Type 2 diabetes) , obesity, non-alcoholic steatohepatitis, non-alcoholic fatty liver disease, etc. Without wishing to be bound by theories, it is believed that the observed biological activity of the novel compounds herein is due in part to their ability to induce UCP-1 expression and/or mitochondrial oxidative metabolism, which can lead to browning of white adipose tissues.

Compounds

In some embodiments, the present disclosure provides a compound of Formula I, a pharmaceutically acceptable ester or amide thereof, or a pharmaceutically acceptable salt thereof:

wherein:

R ¹ is selected from halogen, optionally substituted C _1-6 alkyl, CN, or an optionally substituted C _3-12 carbocyclyl;

Ring A is a phenyl, 5 or 6 membered heteroaryl or a 8-10 membered bicyclic heteroaryl; each of R ¹⁰ and R ¹¹ at each occurrence is independently halogen, CN, optionally substituted C _1-6 alkyl, optionally substituted C _1-6 alkoxy, optionally substituted -OH, optionally substituted –NH ₂, optionally substituted C _1-6 heteroalkyl, optionally substituted C _3-6 cycloalkyl, optionally substituted C _3-6 cycloalkoxy, or optionally substituted 4-8 membered heterocyclyl,

wherein two R ¹⁰ groups or two R ¹¹ groups, together with the intervening atoms, can optionally form a 4-8 membered ring structure,

wherein m is an integer of 0, 1, 2, 3, or 4, as valency permits; and

n is an integer of 0, 1, 2, or 3.

For the avoidance of doubt, the pharmaceutically acceptable ester or amide of the compound of Formula I refers to an ester or amide that can be formed from reacting an alcohol or amine with the –COOH group shown in Formula I, which is pharmaceutically acceptable. As would be understood by those skilled in the art, an ester or amide of the compound of Formula I can be converted into the compound of Formula I in vitro or in vivo, and thus at least can be useful for treating or preventing the various diseases or disorders described herein through convertion into the corresponding acid. It would also be apparent to those skilled in the art that esters or amides of compounds of Formula I can be useful synthetic intermediates for the preparation of the acid of Formula I. Pharmaceutically acceptable esters or amides referred to herein in connection with other Formulae or specific compounds should be similarly understood as those esters or amides that can be formed from the corresponding acid, which can at least be useful for in vivo convertion into the corresponding acid or as synthetic intermediates for preparing the acid.

In some embodiments, the present disclosure provides a pharmaceutically acceptable ester or amide of the compound of Formula I, or a pharmaceutically acceptable salt thereof. In some embodiments, the pharmaceutically acceptable ester or amide can be converted into the compound of Formula I in vivo. The pharmaceutically acceptale ester or amide is not particularly limited to any types of esters or amides, so long as the amine or alcohol resulting from hydrolysis of the amide or ester, respectively, is pharmaceutically acceptable. For example, such amine or alcohol can include a lower alkyl (e.g., C ₁-C ₆) amine or alcohol, a naturally occuring amine or alcohol in a mammal, an amine or alcohol that has been shown to be safe for use in humans, etc.

Compounds of Formula I can also exist in the form of a pharmaceutically acceptable salt. Pharmaceutically acceptable salts are well known in the art and include acid addition salts and base addition salts.

As would be understood by those skilled in the art, in certain cases, compounds of Formula I may exist as a mixture of tautomers, such as those resulting from keto-to-enol, amide-to-imide, lactam-to-lactim, enamine-to-imine, and enamine-to- (a different enamine) tautomerizations. The present disclosure is not limited to any specific tautomer. Rather, the present disclosure encompasses any and all of such tautomers whether or not explicitly drawn or referred to.

In some embodiments, compounds of Formula I are characterized by the R ¹ group. As shown in the Examples section, it was found that representative compounds of Formula I, or an ester thereof, having an ortho-substituent (e.g., methyl) to the COOH group (or a corresponding ester group) in Formula I are much more effective in reducing body weight, improving liver function, and reducing the size of fat tissues, while being equally effective in reducing blood glucose levels and improve insulin sensitivity, when compared to similar compounds without the ortho-substituent. In some embodiments, R ¹ is a halogen, such as F or Cl. In some embodiments, R ¹ is an optionally substituted C _1-6 alkyl. In some embodiments, R ¹ is an unsubstituted C _1-6 alkyl (e.g., methyl, ethyl, n-propyl, isopropyl, etc. ) . In some embodiments, R ¹ is a C _1-6 alkyl optionally substituted with one or more substituents, such as 1, 2, or 3 substituents. Suitable substituents are not particularly limited and can include any of the permissible substituents described herein, such as the carbon atom substituents described herein. In some embodiments, the C _1-6 alkyl can be substituted with one or more (e.g., 1, 2, or 3) substituents each independently selected from oxo, F, optionally substituted -OH, optionally substituted C _1-4 heteroalkyl, optionally substituted –NH ₂, optionally substituted C _3-6 cycloalkyl, optionally substituted C _3-6 cycloalkoxy, optionally substituted 4-8 membered heterocyclyl, optionally substituted phenyl, and optionally substituted monocyclic or bicyclic heteroaryl. As used herein, optionally substituted –OH should be understood as –OH or –O-R, wherein R is an oxygen atom substituent described herein, such as an oxygen protecting group (e.g., described herein) . Similarly, optionally substituted –NH ₂ should be understood as -NH ₂, –NHR or –NRR', wherein R and R' are independently a nitrogen atom substituent described herein, such as a nitrogen protecting group as described herein, or R together with R' can be a nitrogen protecting group described herein.

In some preferred embodiments, R ¹ in Formula I can be a C _1-4 alkyl optionally substituted with 1-3 fluorine. For example, in some embodiments, Formula I can have a Formula I-1:

wherein R ¹⁰, R ¹¹, Ring A, m, and n include any of those described herein in any combination.

In some embodiments, R ¹ in Formula I can also be an optionally substituted C _3-12 carbocyclyl group, which can be saturated or partially unsaturated, monocyclic, bicyclic (such as fused, spiro, or bridged bicyclic) , or polycyclic. When substituted, the C _3-12 carbocyclyl group can be substituted by one or more (e.g., 1, 2, or 3) substituents, which include any of the permissible substituents described herein, such as the carbon atom substituents described herein. Non-limiting suitable substituents include oxo, F, optionally substituted -OH, optionally substituted C _1-4 heteroalkyl, optionally substituted –NH ₂, optionally substituted C _3-6 cycloalkyl, optionally substituted C _3-6 cycloalkoxy, optionally substituted 4-8 membered heterocyclyl, optionally substituted phenyl, and optionally substituted monocyclic or bicyclic heteroaryl.

Typically, the phenyl ring shown in Formula I (e.g., Formula I-1) can be unsubstituted or substituted with 1 or 2 R ¹⁰ groups, i.e., n is 0, 1, or 2. In some embodiments, n is 0. In some embodiments, n is 1. Various groups are suitable for R ¹⁰, which include without limitation F, Cl, Br, CN, C _1-6 alkyl optionally substituted with 1-3 fluorine, C _1-6 alkoxy optionally substituted with 1-3 fluorine, C _1-6 heteroalkyl optionally substituted with 1-3 substituents each independently selected from oxo, fluorine, C _1-4 alkyl and C _1-4 alkoxy, C _3-6 cycloalkyl optionally substituted with 1-3 substituents each independently selected from fluorine, C _1-4 alkyl and C _1-4 alkoxy, C _3-6 cycloalkoxy optionally substituted with 1-3 substituents each independently selected from fluorine, C _1-4 alkyl and C _1-4 alkoxy, and 4-8 membered heterocyclyl optionally substituted with 1-3 substituents each independently selected from oxo, fluorine, C _1-4 alkyl and C _1-4 alkoxy.

Ring A in Formula I (e.g., Formula I-1) is typically a 5 or 6 membered heteroaryl, e.g., as described herein. The 5 or 6-membered heteroaryl typically includes 1-4 ring heteroatoms independently selected from S, O, and N. In some embodiments, Ring A in Formula I (e.g., Formula I-1) is a 6-membered heteroaryl having 1 or 2 ring nitrogen atoms, such as pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, etc. In some preferred embodiments, Ring A can have a ring nitrogen ortho to the aminothiozole moiety, such that the compound of Formula I can be represented by the following formula I-2:

wherein Ring A is a 5 or 6-membered heteroaryl or a bicyclic heteroaryl, and R ¹, R ¹⁰, R ¹¹, m, and n include any of those described herein in any combination. To be clear, Ring A shown in Formula I-2 should be understood as connecting to the aminothiozole moiety through a ring carbon atom.

In some embodiments, Ring A is pyridyl. In some preferred embodiments, Ring A is 2-pyridyl, and the compound of Formula I can be represented by the following formula I-3:

wherein R ¹, R ¹⁰, R ¹¹, m, and n include any of those described herein in any combination.

Typically, Ring A in Formula I (e.g., Formula I-1, I-2, or I-3) can be unsubstituted or substituted with 1 or 2 R ¹¹ groups, i.e., m is 0, 1, or 2. For example, in some embodiments, m is 0. In some embodiments, m is 1. Various groups are suitable for R ¹¹, which include without limitation F, Cl, Br, CN, -OH, -NH ₂, -NH (C _1-6 alkyl) , -N (C _1-6 alkyl) (C _1-6 alkyl) , C _1-6 alkyl optionally substituted with 1-3 fluorine, C _1-6 alkoxy optionally substituted with 1-3 fluorine, C _1-6 heteroalkyl optionally substituted with 1-3 substituents each independently selected from oxo, fluorine, C _1-4 alkyl and C _1-4 alkoxy, C _3-6 cycloalkyl optionally substituted with 1-3 substituents each independently selected from fluorine, C _1-4 alkyl and C _1-4 alkoxy, C _3-6 cycloalkoxy optionally substituted with 1-3 substituents each independently selected from fluorine, C _1-4 alkyl and C _1-4 alkoxy, or 4-8 membered heterocyclyl optionally substituted with 1-3 substituents each independently selected from oxo, fluorine, C _1-4 alkyl and C _1-4 alkoxy. For example, in some embodiments, one or more instances of R ¹¹ can be selected from C _1-4 alkyl optionally substituted with 1-3 fluorine, such as CH ₃ or CF ₃. In some embodiments, one or more instances of R ¹¹ can be CN. In some embodiments, one or more instances of R ¹¹ can be -NH (C _1-6 alkyl) , such as –NHCH ₃. In some embodiments, one or more instances of R ¹¹ can be halogen, such as F or Cl. In some embodiments, one or more instances of R ¹¹ can be NH ₂. In some embodiments, one or more instances of R ¹¹ can be OH. In some preferred embodiments, m in Formula I (e.g., Formula I-1, I-2, or I-3) is 0, i.e., Ring A is not substituted. In some preferred embodiments, m in Formula I (e.g., Formula I-1, I-2, or I-3) is 1, and R ¹¹ is F, CH ₃, CN, CF ₃, NH ₂, or –NHCH ₃. In some preferred embodiments, at least one instance of R ¹¹ is in the meta-position to the aminothiozole moiety and ortho to a ring nitrogen. For example, in some embodiments, the compound of Formula I-3 can have a sub-formula of Formula I-3A:

wherein:

R ^11A is any of the R ¹¹ groups described herein for Formula I (e.g., Formula I-1, I-2, or I-3) ; q is 0, 1, or 2, preferably, 0 or 1, and

R ¹, R ¹⁰, R ¹¹, and n include any of those described herein in any combination. In some embodiments, q is 0. In some embodiments, q is 1. In some embodiments, R ^11A is F, CH ₃, CN, CF ₃, NH ₂, or –NHCH ₃.

In some embodiments, the present disclosure also provides a compound of Formula II, or a pharmaceutically acceptable salt thereof:

wherein:

J is O or NR ^A;

R ² is an optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted phenyl, or optionally substituted heteroaryl;

R ^A is hydrogen, an optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted phenyl, or optionally substituted heteroaryl;

or R ^A and R ² are joined to form an optionally substituted heterocyclyl or optionally substituted heteroaryl;

wherein m is an integer of 0, 1, 2, 3, or 4, as valency permits; and

n is an integer of 0, 1, 2, or 3.

Compounds of Formula II can also exist in the form of a pharmaceutically acceptable salt. Pharmaceutically acceptable salts are well known in the art and include acid addition salts and base addition salts.

As would be understood by those skilled in the art, in certain cases, compounds of Formula II may exist as a mixture of tautomers, such as those resulting from keto-to-enol, amide-to-imide, lactam-to-lactim, enamine-to-imine, and enamine-to- (a different enamine) tautomerizations. The present disclosure is not limited to any specific tautomer. Rather, the present disclosure encompasses any and all of such tautomers whether or not explicitly drawn or referred to.

In some embodiments, compounds of Formula II are characterized by the R ¹ group. In some embodiments, R ¹ is a halogen, such as F or Cl. In some embodiments, R ¹ is an optionally substituted C _1-6 alkyl. In some embodiments, R ¹ is an unsubstituted C _1-6 alkyl (e.g., methyl, ethyl, n-propyl, isopropyl, etc. ) . In some embodiments, R ¹ is a C _1-6 alkyl optionally substituted with one or more substituents, such as 1, 2, or 3 substituents. Suitable substituents are not particularly limited and can include any of those permissible substituents described herein, such as the carbon atom substituents described herein. In some embodiments, the C _1-6 alkyl can be substituted with one or more (e.g., 1, 2, or 3) substituents each independently selected from oxo, F, optionally substituted -OH, optionally substituted C _1-4 heteroalkyl, optionally substituted –NH ₂, optionally substituted C _3-6 cycloalkyl, optionally substituted C _3-6 cycloalkoxy, optionally substituted 4-8 membered heterocyclyl, optionally substituted phenyl, and optionally substituted monocyclic or bicyclic heteroaryl.

In some preferred embodiments, R ¹ in Formula II can be a C _1-4 alkyl optionally substituted with 1-3 fluorine. For example, in some embodiments, Formula II can have a Formula II-1 or II-2:

wherein R ², R ^A, R ¹⁰, R ¹¹, Ring A, m, and n include any of those described herein in any combinations.

In some embodiments, R ¹ in Formula II can also be an optionally substituted C _3-12 carbocyclyl group, which can be saturated or partially unsaturated, monocyclic, bicyclic (such as fused, spiro, or bridged bicyclic) , or polycyclic. When substituted, the C _3-12 carbocyclyl group can be substituted by one or more (e.g., 1, 2, or 3) substituents, which include any of the permissible substituents described herein, such as the carbon atom substituents described herein. Non-limiting suitable substituents include oxo, F, optionally substituted -OH, optionally substituted C _1-4 heteroalkyl, optionally substituted –NH ₂, optionally substituted C _3-6 cycloalkyl, optionally substituted C _3-6 cycloalkoxy, optionally substituted 4-8 membered heterocyclyl, optionally substituted phenyl, and optionally substituted monocyclic or bicyclic heteroaryl.

Typically, the phenyl ring shown in Formula II (e.g., Formula II-1 or II-2) can be unsubstituted or substituted with 1 or 2 R ¹⁰ groups, i.e., n is 0, 1, or 2. In some embodiments, n is 0. In some embodiments, n is 1. Various groups are suitable for R ¹⁰, which include without limitation F, Cl, Br, CN, C _1-6 alkyl optionally substituted with 1-3 fluorine, C _1-6 alkoxy optionally substituted with 1-3 fluorine, C _1-6 heteroalkyl optionally substituted with 1-3 substituents each independently selected from oxo, fluorine, C _1-4 alkyl and C _1-4 alkoxy, C _3-6 cycloalkyl optionally substituted with 1-3 substituents each independently selected from fluorine, C _1-4 alkyl and C _1-4 alkoxy, C _3-6 cycloalkoxy optionally substituted with 1-3 substituents each independently selected from fluorine, C _1-4 alkyl and C _1-4 alkoxy, and 4-8 membered heterocyclyl optionally substituted with 1-3 substituents each independently selected from oxo, fluorine, C _1-4 alkyl and C _1-4 alkoxy.

Various groups are suitable as R ² in Formula II (e.g., Formula II-1 or II-2) . For example, in some embodiments, R ² is a C _1-16 alkyl, C _2-16 alkenyl, C _2-16 alkynyl, C _3-12 carbocyclic ring, or 4-10 membered heterocyclic ring, each optionally substituted with one or more independently selected substituents, such as 1, 2, or 3 substituents. Suitable substituents are not particularly limited, which can include any of the permissible substituents described herein, such as the carbon or nitrogen atom substituents described herein, as applicable. For example, suitable substituents include but not limited to halogen, -OH, -NR ¹²R ¹³, - (NR ¹²R ¹³R ¹⁴) ⁺, -C (O) -NR ¹²R ¹³, -COOR ¹⁵, -N (R ¹⁶) -C (O) -R ¹⁷, -O-C (O) -R ¹⁸, -O-C (O) -NR ¹²R ¹³, -O-COOR ¹⁵, -N (R ¹⁶) -C (O) -O-R ¹⁵, -O-C (O) -O-R ¹⁵, -N (R ¹⁶) -C (O) -NR ¹²R ¹³, CN, optionally substituted C _1-6 heteroalkyl, optionally substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted phenyl, and optionally substituted monocyclic or bicyclic heteroaryl, wherein:

each of R ¹², R ¹³, R ¹⁴, and R ¹⁶ at each occurrence is independently hydrogen, a nitrogen protecting group, an optionally substituted C _1-6 alkyl, optionally substituted carbocyclic ring, or optionally substituted heterocyclic ring; or R ¹² and R ¹³ are joined to form an optionally substituted heterocyclic or heteroaryl ring,

wherein R ¹⁵ at each occurrence is independently hydrogen, an oxygen protecting group, an optionally substituted C _1-6 alkyl, optionally substituted carbocyclic ring, or optionally substituted heterocyclic ring;

each of R ¹⁷ and R ¹⁸ at each occurrence is independently hydrogen, an optionally substituted alkyl, optionally substituted carbocyclic ring, optionally substituted heterocyclic ring, optionally substituted phenyl, or optionally substituted monocyclic or bicyclic heteroaryl. Further, in some embodiments, two or more substituents can optionally form a ring structure. For example, two substituents on the same carbon or adjacent atoms (two carbons, two nitrogens, or one carbon and one nitrogen, etc. ) can form ring structure.

In some embodiments, R ² in Formula II (e.g., Formula II-1 or II-2) can be a group such that the compound of Formula II can be converted into the acid derivative thereof, in vitro and/or in vivo.

In some embodiments, R ² in Formula II (e.g., Formula II-1 or II-2) can be an optionally substituted C _1-16 alkyl. In some embodiments, R ² in Formula II (e.g., Formula II-1 or II-2) can be an unsubstituted C _1-16 alkyl, such as methyl, ethyl, n-propyl, isopropyl, etc. In some embodiments, R ² in Formula II (e.g., Formula II-1 or II-2) can be a substituted C _1-16 alkyl, for example, substituted with 1, 2, or 3 independently selected substituents. Suitable substituents are not particularly limited, which can include any of those permissible substituents described herein, such as the carbon atom substituents described herein. In some embodiments, R ² in Formula II (e.g., Formula II-1 or II-2) can be a C _1-16 alkyl substituted with 1, 2, or 3 independently selected substituents selected from halogen, -OH, -NR ¹²R ¹³, - (NR ¹²R ¹³R ¹⁴) ⁺, -C (O) -NR ¹²R ¹³, -COOR ¹⁵, -N (R ¹⁶) -C (O) -R ¹⁷, -O-C (O) -R ¹⁸, -O-C (O) -NR ¹²R ¹³, -O-COOR ¹⁵, -N (R ¹⁶) -C (O) -O-R ¹⁵, -O-C (O) -O-R ¹⁵, -N (R ¹⁶) -C (O) -NR ¹²R ¹³, CN, optionally substituted C _1-6 heteroalkyl, optionally substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted phenyl, and optionally substituted monocyclic or bicyclic heteroaryl, wherein R ¹², R ¹³, R ¹⁴, R ¹⁵, R ¹⁶, R ¹⁷, R ¹⁸ are defined herein. In some embodiments, two or more substituents, e.g., those on the same carbon or adjacent carbons, can optionally form a ring structure.

In some embodiments, R ² in Formula II (e.g., Formula II-1 or II-2) can be an optionally substituted C _2-16 alkenyl, such as those having 1-3 carbon-carbon double bounds. In some embodiments, R ² in Formula II (e.g., Formula II-1 or II-2) can be an unsubstituted C _2-16 alkenyl. In some embodiments, R ² in Formula II (e.g., Formula II-1 or II-2) can be a substituted C _2-16 alkenyl, for example, substituted with 1, 2, or 3 independently selected substituents. Suitable substituents are not particularly limited, which can include any of those permissible substituents described herein, such as the carbon atom substituents described herein. In some embodiments, R ² in Formula II (e.g., Formula II-1 or II-2) can be a C _2-16 alkenyl substituted with 1, 2, or 3 independently selected substituents selected from halogen, -OH, -NR ¹²R ¹³, - (NR ¹²R ¹³R ¹⁴) ⁺, -C (O) -NR ¹²R ¹³, -COOR ¹⁵, -N (R ¹⁶) -C (O) -R ¹⁷, -O-C (O) -R ¹⁸, -O-C (O) -NR ¹²R ¹³, -O-COOR ¹⁵, -N (R ¹⁶) -C (O) -O-R ¹⁵, -O-C (O) -O-R ¹⁵, -N (R ¹⁶) -C (O) -NR ¹²R ¹³, CN, optionally substituted C _1-6 heteroalkyl, optionally substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted phenyl, and optionally substituted monocyclic or bicyclic heteroaryl, wherein R ¹², R ¹³, R ¹⁴, R ¹⁵, R ¹⁶, R ¹⁷, R ¹⁸ are defined herein. In some embodiments, two or more substituents, e.g., those on the same carbon or adjacent carbons, can optionally form a ring structure.

In some embodiments, R ² in Formula II (e.g., Formula II-1 or II-2) can be an optionally substituted C _2-16 alkynyl, such as those having 1-3 carbon-carbon triple bonds. In some embodiments, R ² in Formula II (e.g., Formula II-1 or II-2) can be an unsubstituted C _2- ₁₆ alkynyl. In some embodiments, R ² in Formula II (e.g., Formula II-1 or II-2) can be a substituted C _2-16 alkynyl, for example, substituted with 1, 2, or 3 independently selected substituents. Suitable substituents are not particularly limited, which can include any of those permissible substituents described herein, such as the carbon atom substituents described herein. In some embodiments, R ² in Formula II (e.g., Formula II-1 or II-2) can be a C _2-16 alkynyl substituted with 1, 2, or 3 independently selected substituents selected from halogen, -OH, -NR ¹²R ¹³, - (NR ¹²R ¹³R ¹⁴) ⁺, -C (O) -NR ¹²R ¹³, -COOR ¹⁵, -N (R ¹⁶) -C (O) -R ¹⁷, -O-C (O) -R ¹⁸, -O-C (O) -NR ¹²R ¹³, -O-COOR ¹⁵, -N (R ¹⁶) -C (O) -O-R ¹⁵, -O-C (O) -O-R ¹⁵, -N (R ¹⁶) -C (O) -NR ¹²R ¹³, CN, optionally substituted C _1-6 heteroalkyl, optionally substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted phenyl, and optionally substituted monocyclic or bicyclic heteroaryl, wherein R ¹², R ¹³, R ¹⁴, R ¹⁵, R ¹⁶, R ¹⁷, R ¹⁸ are defined herein. In some embodiments, two or more substituents, e.g., those on the same carbon or adjacent carbons, can optionally form a ring structure.

In some embodiments, R ² in Formula II (e.g., Formula II-1 or II-2) can be an optionally substituted C _3-12 carbocyclic ring, such as a monocyclic C _3-8 carbocyclic or a C _5-12 bicyclic or polycyclic carbocyclic ring, which can be saturated or partially unsaturated. In some embodiments, R ² in Formula II (e.g., Formula II-1 or II-2) can be an unsubstituted C _3- ₁₂ carbocyclic ring. In some embodiments, R ² in Formula II (e.g., Formula II-1 or II-2) can be a substituted C _3-12 carbocyclic ring, for example, substituted with 1, 2, or 3 independently selected substituents. Suitable substituents are not particularly limited, which can include any of those permissible substituents described herein, such as the carbon atom substituents described herein. In some embodiments, R ² in Formula II (e.g., Formula II-1 or II-2) can be a C _3-12 carbocyclic ring substituted with 1, 2, or 3 independently selected substituents selected from halogen, -OH, -NR ¹²R ¹³, - (NR ¹²R ¹³R ¹⁴) ⁺, -C (O) -NR ¹²R ¹³, -COOR ¹⁵, -N (R ¹⁶) -C (O) -R ¹⁷, -O-C (O) -R ¹⁸, -O-C (O) -NR ¹²R ¹³, -O-COOR ¹⁵, -N (R ¹⁶) -C (O) -O-R ¹⁵, -O-C (O) -O-R ¹⁵, -N (R ¹⁶) -C (O) -NR ¹²R ¹³, CN, optionally substituted C _1-6 heteroalkyl, optionally substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted phenyl, and optionally substituted monocyclic or bicyclic heteroaryl, wherein R ¹², R ¹³, R ¹⁴, R ¹⁵, R ¹⁶, R ¹⁷, R ¹⁸ are defined herein. In some embodiments, two or more substituents, e.g., those on the same carbon or adjacent carbons, can optionally form a ring structure.

In some embodiments, R ² in Formula II (e.g., Formula II-1 or II-2) can be an optionally substituted 4-10 membered heterocyclic ring, such as a monocyclic 4-8 membered heterocyclic ring or a 5-10 membered bicyclic or polycyclic heterocyclic ring. The heterocyclic ring typically can have 1-4 ring heteroatoms independently selected from S, O, and N. The heterocyclic ring can be saturated or partially unsaturated. In some embodiments, R ² in Formula II (e.g., Formula II-1 or II-2) can be an unsubstituted 4-10 membered heterocyclic ring. In some embodiments, R ² in Formula II (e.g., Formula II-1 or II-2) can be a substituted 4-10 membered heterocyclic ring, for example, substituted with 1, 2, or 3 independently selected substituents. Suitable substituents are not particularly limited, which can include any of those permissible substituents described herein, such as the carbon or nitrogen atom substituents described herein as applicable. In some embodiments, R ² in Formula II (e.g., Formula II-1 or II-2) can be a 4-10 membered heterocyclic ring substituted with 1, 2, or 3 independently selected substituents selected from halogen, -OH, -NR ¹²R ¹³, -(NR ¹²R ¹³R ¹⁴) ⁺, -C (O) -NR ¹²R ¹³, -COOR ¹⁵, -N (R ¹⁶) -C (O) -R ¹⁷, -O-C (O) -R ¹⁸, -O-C (O) -NR ¹²R ¹³, -O-COOR ¹⁵, -N (R ¹⁶) -C (O) -O-R ¹⁵, -O-C (O) -O-R ¹⁵, -N (R ¹⁶) -C (O) -NR ¹²R ¹³, CN, optionally substituted C _1-6 heteroalkyl, optionally substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted phenyl, and optionally substituted monocyclic or bicyclic heteroaryl, wherein R ¹², R ¹³, R ¹⁴, R ¹⁵, R ¹⁶, R ¹⁷, R ¹⁸ are defined herein. In some embodiments, two or more substituents, e.g., those on the same carbon or adjacent atoms, can optionally form a ring structure.

In some preferred embodiments, J in Formula II can be O, and the compound of Formula II can have a Formula II-3:

wherein R ¹, R ², R ¹⁰, R ¹¹, Ring A, m, and n include any of those described herein in any combination.

In some preferred embodiments, J in Formula II can be NR ^A, and the compound of Formula II can have a Formula II-4:

wherein R ¹, R ², R ^A, R ¹⁰, R ¹¹, Ring A, m, and n include any of those described herein in any combination. R ^A in Formula II-4 is typically hydrogen or an optionally substituted C _1-6 alkyl. In some embodiments, R ^A in Formula II-4 is hydrogen or an unsubstituted C _1-6 alkyl. In some embodiments, R ^A in Formula II-4 can also be joined with R ² to form an optionally substituted 4-10 membered heterocyclic ring, which can have 1-4 ring heteroatoms independently selected from S, O, and N. For example, in some embodiments, R ^A in Formula II-4 can also be joined with R ² to form an optionally substituted monocyclic 4-10 membered heterocyclic ring such as morpholine ring.

Ring A in Formula II (e.g., Formula II-1, II-2, II-3, or II-4) is typically a 5 or 6 membered heteroaryl, e.g., as described herein. The 5 or 6-membered heteroaryl typically includes 1-4 ring heteroatoms independently selected from S, O, and N. In some embodiments, Ring A in Formula II (e.g., Formula II-1, II-2, II-3, or II-4) is a 6-membered heteroaryl having 1 or 2 ring nitrogen atoms, such as pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, etc. In some preferred embodiments, Ring A can have a ring nitrogen ortho to the aminothiozole moiety, such that the compound of Formula II can be represented by the following formula II-5 or II-6:

wherein Ring A is a 5 or 6-membered heteroaryl or a bicyclic heteroaryl, and R ¹, R ², R ^A, R ¹⁰, R ¹¹, m, and n include any of those described herein in any combination. To be clear, Ring A shown in Formula II-5 or II-6 should be understood as connecting to the aminothiozole moiety through a ring carbon atom.

In some embodiments, Ring A is pyridyl. In some preferred embodiments, Ring A is 2-pyridyl, and the compound of Formula II can be represented by the following formula II-7 or II-8:

wherein R ¹, R ², R ^A, R ¹⁰, R ¹¹, m, and n include any of those described herein in any combination.

Typically, Ring A in Formula II (e.g., Formula II-1, II-2, II-3, II-4, II-5, II-6, II-7, or II-8) can be unsubstituted or substituted with 1 or 2 R ¹¹ groups, i.e., m is 0, 1, or 2. For example, in some embodiments, m is 0. In some embodiments, m is 1. Various groups are suitable for R ¹¹, which include without limitation F, Cl, Br, CN, -OH, -NH ₂, -NH (C _1-6 alkyl) , -N (C _1-6 alkyl) (C _1-6 alkyl) , C _1-6 alkyl optionally substituted with 1-3 fluorine, C _1-6 alkoxy optionally substituted with 1-3 fluorine, C _1-6 heteroalkyl optionally substituted with 1-3 substituents each independently selected from oxo, fluorine, C _1-4 alkyl and C _1-4 alkoxy, C _3-6 cycloalkyl optionally substituted with 1-3 substituents each independently selected from fluorine, C _1-4 alkyl and C _1-4 alkoxy, C _3-6 cycloalkoxy optionally substituted with 1-3 substituents each independently selected from fluorine, C _1-4 alkyl and C _1-4 alkoxy, or 4-8 membered heterocyclyl optionally substituted with 1-3 substituents each independently selected from oxo, fluorine, C _1-4 alkyl and C _1-4 alkoxy. For example, in some embodiments, one or more instances of R ¹¹ can be selected from C _1-4 alkyl optionally substituted with 1-3 fluorine, such as CH ₃ or CF ₃. In some embodiments, one or more instances of R ¹¹ can be CN. In some embodiments, one or more instances of R ¹¹ can be -NH (C _1-6 alkyl) , such as –NHCH ₃. In some embodiments, one or more instances of R ¹¹ can be halogen, such as F or Cl. In some embodiments, one or more instances of R ¹¹ can be NH ₂. In some embodiments, one or more instances of R ¹¹ can be OH. In some preferred embodiments, m in Formula II (e.g., Formula II-1, II-2, II-3, II-4, II-5, II-6, II-7, or II-8) is 0, i.e., Ring A is not substituted. In some preferred embodiments, m in Formula II (e.g., Formula II-1, II-2, II-3, II-4, II-5, II-6, II-7, or II-8) is 1, and R ¹¹ is F, CH ₃, CN, CF ₃, NH ₂, or –NHCH ₃. In some preferred embodiments, at least one instance of R ¹¹ is in the meta-position to the aminothiozole moiety and ortho to a ring nitrogen. For example, in some embodiments, the compound of Formula II-7 or II-8 can have a sub-formula of Formula II-7A or II-8A:

wherein:

R ^11A is any of the R ¹¹ groups described herein for Formula II;

q is 0, 1, or 2, preferably, 0 or 1, and

R ¹, R ¹⁰, R ¹¹, R ^A, and n include any of those described herein in any combination. In some embodiments, q is 0. In some embodiments, q is 1. In some embodiments, R ^11A is F, CH ₃, CN, CF ₃, NH ₂, or –NHCH ₃.

In some embodiments, the present disclosure provides a compound of Formula III, a pharmaceutically acceptable ester or amide thereof, as applicable, or a pharmaceutically acceptable salt thereof:

wherein:

G is COOH, COOR ², or CON (R ^A) (R ²) ,

R ^A is hydrogen, an optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted phenyl, or optionally substituted heteroaryl; or R ^A and R ² are joined to form an optionally substituted heterocyclyl or optionally substituted heteroaryl;

Ring B is a phenyl, or 5 or 6 membered heteroaryl or 8-10 membered bicyclic heteroaryl;

R ^B is hydrogen, halogen, CN, optionally substituted C _1-6 alkyl, optionally substituted C _1-6 alkoxy, optionally substituted -OH, optionally substituted –NH ₂, optionally substituted C _1-6 heteroalkyl, optionally substituted C _3-6 cycloalkyl, optionally substituted C _3-6 cycloalkoxy, or optionally substituted 4-8 membered heterocyclyl, each of R ¹⁰ and R ¹¹ at each occurrence is independently halogen, CN, optionally substituted C _1-6 alkyl, optionally substituted C _1-6 alkoxy, optionally substituted -OH, optionally substituted –NH ₂, optionally substituted C _1-6 heteroalkyl, optionally substituted C _3-6 cycloalkyl, optionally substituted C _3-6 cycloalkoxy, or optionally substituted 4-8 membered heterocyclyl,

wherein two R ¹⁰ groups or two R ¹¹ groups, or R ¹¹ and R ^B, together with the intervening atoms, can optionally form a 4-8 membered ring structure,

wherein m is an integer of 0, 1, 2, or 3; and

n is an integer of 0, 1, 2, or 3.

Compounds of Formula III can also exist in the form of a pharmaceutically acceptable salt. Pharmaceutically acceptable salts are well known in the art and include acid addition salts and base addition salts.

As would be understood by those skilled in the art, in certain cases, compounds of Formula III may exist as a mixture of tautomers, such as those resulting from keto-to-enol, amide-to-imide, lactam-to-lactim, enamine-to-imine, and enamine-to- (a different enamine) tautomerizations. The present disclosure is not limited to any specific tautomer. Rather, the present disclosure encompasses any and all of such tautomers whether or not explicitly drawn or referred to.

In some embodiments, G in Formula III is COOH. In some embodiments, G in Formula III is COOR ². In some embodiments, G in Formula III is CON (R ^A) (R ²) . In some embodiments, Ring B is a monocyclic ring and the group G is positioned on Ring B para (for a 6-membered ring) or in a 1, 3-or 1, 4-relationship (for a 5-membered ring) to the thiazole ring. Suitable groups for R ² include any of those described herein in connection with Formula II. For example, in some embodiments, when present, R ² in Formula III can be a C _1-16 alkyl, C _2-16 alkenyl, C _2-16 alkynyl, C _3-12 carbocyclic ring, or 4-10 membered heterocyclic ring, each optionally substituted with one or more independently selected substituents, such as 1, 2, or 3 substituents. In some embodiments, R ² is an optionally substituted C _1-16 alkyl, such as methyl, ethyl, n-propyl, isopropyl, etc. In some embodiments, R ² is an optionally substituted C _3-12 carbocyclic ring. Suitable groups for R ^A include any of those described herein in connection with Formula II. For example, in some embodiments, when present, R ^A in Formula III can be hydrogen or an optionally substituted C _1-6 alkyl. In some embodiments, when present, R ^A in Formula III can also be joined with R ² to form an optionally substituted 4-10 membered heterocyclic ring, which can have 1-4 ring heteroatoms independently selected from S, O, and N, such as an optionally substituted monocyclic 4-10 membered heterocyclic ring, such as morpholine ring.

Ring B in Formula III is typically a phenyl ring. For example, the compound of Formula III can have a Formula III-1:

wherein R ^B, R ¹⁰, R ¹¹, G, m, and n include any of those described herein in any combinations.

In some embodiments, Ring B in Formula III can also be a 5 or 6-membered heteroaryl, such as those having 1-4 (e.g., 1 or 2) ring heteroatoms independently selected from S, O, and N. In some embodiments, Ring B in Formula III can also be a 5 or 6-membered heteroaryl, such as those having 1-4 (e.g., 1 or 2) ring heteroatoms independently selected from S, O, and N, with 1 or 2 ring nitrogens. In some embodiments, Ring B in Formula III can also be a bicyclic heteroaryl, such as those having 1-4 (e.g., 1, 2, or 3) ring heteroatoms independently selected from S, O, and N.

Typically, Ring B in Formula III can be unsubstituted or substituted with 1-3 R ¹⁰ groups, i.e., n is 0, 1, 2, or 3. In some embodiments, n is 0. In some embodiments, n is 1. In some embodiments, n is 2. Various groups are suitable for R ¹⁰, which include without limitation F, Cl, Br, CN, C _1-6 alkyl optionally substituted with 1-3 fluorine, C _1-6 alkoxy optionally substituted with 1-3 fluorine, C _1-6 heteroalkyl optionally substituted with 1-3 substituents each independently selected from oxo, fluorine, C _1-4 alkyl and C _1-4 alkoxy, C _3-6 cycloalkyl optionally substituted with 1-3 substituents each independently selected from fluorine, C _1-4 alkyl and C _1-4 alkoxy, C _3-6 cycloalkoxy optionally substituted with 1-3 substituents each independently selected from fluorine, C _1-4 alkyl and C _1-4 alkoxy, and 4-8 membered heterocyclyl optionally substituted with 1-3 substituents each independently selected from oxo, fluorine, C _1-4 alkyl and C _1-4 alkoxy.

In some embodiments, n is 1 or 2, and at least one instance of R ¹⁰ is substituted ortho to the G group on Ring B in Formula III (e.g., Formula III-1) . In some embodiments, such ortho substituent R ¹⁰ can be any of those R ¹ groups defined in connection with Formula I or II, for example, a halogen, such as F or Cl, or an optionally substituted C _1-6 alkyl such as an unsubstituted C _1-6 alkyl (e.g., methyl, ethyl, n-propyl, isopropyl, etc. ) , or a C _1-6 alkyl optionally substituted with one or more independently selected substituents, such as 1, 2, or 3 substituents, as described herein.

R ^B group in Formula III (e.g., III-1) is typically hydrogen, F, Cl, Br, CN, -OH, -NH ₂, -NH (C _1-6 alkyl) , -N (C _1-6 alkyl) (C _1-6 alkyl) , C _1-6 alkyl optionally substituted with 1-3 fluorine, C _1-6 alkoxy optionally substituted with 1-3 fluorine, C _1-6 heteroalkyl optionally substituted with 1-3 substituents each independently selected from oxo, fluorine, C _1-4 alkyl and C _1-4 alkoxy, C _3-6 cycloalkyl optionally substituted with 1-3 substituents each independently selected from fluorine, C _1-4 alkyl and C _1-4 alkoxy, C _3-6 cycloalkoxy optionally substituted with 1-3 substituents each independently selected from fluorine, C _1-4 alkyl and C _1-4 alkoxy, or 4-8 membered heterocyclyl optionally substituted with 1-3 substituents each independently selected from oxo, fluorine, C _1-4 alkyl and C _1-4 alkoxy. In some embodiments, R ^B group in Formula III is hydrogen. In some embodiments, R ^B group in Formula III is C _1-4 alkyl optionally substituted with 1-3 fluorine, such as CH ₃ or CF ₃. In some embodiments, R ^B group can be CN. In some embodiments, R ^B group can be -NH (C _1-6 alkyl) , such as –NHCH ₃. In some embodiments, R ^B group can be halogen, such as F or Cl. In some embodiments, R ^B group can be NH ₂. In some embodiments, R ^B group can be OH. It was discovered that substitution of the pyridine ring in Formula III at the R ^B position can improve the pharmacokinetic profile of the compounds. In some preferred embodiments, R ^B is F, CH ₃, CN, CF ₃, NH ₂, or –NHCH ₃.

The pyridine ring in Formula III can also be optionally substituted with one or more R ¹¹ groups. In some embodiments, the pyridine ring in Formula III is not substituted with R ¹¹, i.e., m is 0. In some embodiments, m is 1, and R ¹¹ can be, for example, F, Cl, Br, CN, -OH, -NH ₂, -NH (C _1-6 alkyl) , -N (C _1-6 alkyl) (C _1-6 alkyl) , C _1-6 alkyl optionally substituted with 1-3 fluorine, C _1-6 alkoxy optionally substituted with 1-3 fluorine, C _1-6 heteroalkyl optionally substituted with 1-3 substituents each independently selected from oxo, fluorine, C _1-4 alkyl and C _1-4 alkoxy, C _3-6 cycloalkyl optionally substituted with 1-3 substituents each independently selected from fluorine, C _1-4 alkyl and C _1-4 alkoxy, C _3-6 cycloalkoxy optionally substituted with 1-3 substituents each independently selected from fluorine, C _1-4 alkyl and C _1-4 alkoxy, or 4-8 membered heterocyclyl optionally substituted with 1-3 substituents each independently selected from oxo, fluorine, C _1-4 alkyl and C _1-4 alkoxy.

In some embodiments, the present disclosure provides a compound of Formula IV, a pharmaceutically acceptable ester or amide thereof, as applicable, or a pharmaceutically acceptable salt thereof:

wherein:

G is COOH, COOR ², or CON (R ^A) (R ²) ,

R ¹ is selected from hydrogen, halogen, optionally substituted C _1-6 alkyl, CN, or an optionally substituted C _3-12 carbocyclyl;

Ring C is an optionally substituted 5 or 6 membered heteroaryl or 8-10 membered bicyclic heteroaryl;

wherein m is an integer of 0, 1, 2, or 3; and

n is an integer of 0, 1, 2, or 3.

Compounds of Formula IV can also exist in the form of a pharmaceutically acceptable salt. Pharmaceutically acceptable salts are well known in the art and include acid addition salts and base addition salts.

As would be understood by those skilled in the art, in certain cases, compounds of Formula IV may exist as a mixture of tautomers, such as those resulting from keto-to-enol, amide-to-imide, lactam-to-lactim, enamine-to-imine, and enamine-to- (a different enamine) tautomerizations. The present disclosure is not limited to any specific tautomer. Rather, the present disclosure encompasses any and all of such tautomers whether or not explicitly drawn or referred to.

In some embodiments, G in Formula IV is COOH. In some embodiments, G in Formula IV is COOR ². In some embodiments, G in Formula IV is CON (R ^A) (R ²) . Suitable groups for R ² include any of those described herein in connection with Formula II. For example, in some embodiments, when present, R ² in Formula IV can be a C _1-16 alkyl, C _2-16 alkenyl, C _2-16 alkynyl, C _3-12 carbocyclic ring, or 4-10 membered heterocyclic ring, each optionally substituted with one or more independently selected substituents, such as 1, 2, or 3 substituents. In some embodiments, R ² is an optionally substituted C _1-16 alkyl, such as methyl, ethyl, n-propyl, isopropyl, etc. In some embodiments, R ² is an optionally substituted C _3-12 carbocyclic ring. Suitable groups for R ^A include any of those described herein in connection with Formula II. For example, in some embodiments, when present, R ^A in Formula IVcan be hydrogen or an optionally substituted C _1-6 alkyl. In some embodiments, when present, R ^A in Formula IV can also be joined with R ² to form an optionally substituted 4-10 membered heterocyclic ring, which can have 1-4 ring heteroatoms independently selected from S, O, and N, such as an optionally substituted monocyclic 4-10 membered heterocyclic ring, such as morpholine ring.

Ring C in Formula IV is typically a thiozole ring, which for example can connect to the remainder of the molecule similar to Formulae I-III. However, in some embodiments, Ring C in Formula IV can also be other 5 or 6-membered heteroaryls, such as those having 1-4 (e.g., 1 or 2) ring heteroatoms independently selected from S, O, and N. In some embodiments, Ring C in Formula IV can also be a 5 or 6-membered heteroaryl, such as those having 1-4 (e.g., 1 or 2) ring heteroatoms independently selected from S, O, and N, with 1 or 2 ring nitrogens. In some embodiments, Ring C in Formula IV can also be a bicyclic heteroaryl, such as those having 1-4 (e.g., 1, 2, or 3) ring heteroatoms independently selected from S, O, and N.

Typically, Ring C in Formula IV can be unsubstituted or substituted with 1-3 (such as 1) substituents, as valency permits. Suitable substituents are not particularly limited, which include without limitation the carbon or nitrogen atom substituents described herein as applicable. For example, in some embodiments, suitable substituents include but not limited to F, Cl, Br, CN, C _1-6 alkyl optionally substituted with 1-3 fluorine, C _1-6 alkoxy optionally substituted with 1-3 fluorine, C _1-6 heteroalkyl optionally substituted with 1-3 substituents each independently selected from oxo, fluorine, C _1-4 alkyl and C _1-4 alkoxy, C _3-6 cycloalkyl optionally substituted with 1-3 substituents each independently selected from fluorine, C _1-4 alkyl and C _1-4 alkoxy, C _3-6 cycloalkoxy optionally substituted with 1-3 substituents each independently selected from fluorine, C _1-4 alkyl and C _1-4 alkoxy, and 4-8 membered heterocyclyl optionally substituted with 1-3 substituents each independently selected from oxo, fluorine, C _1-4 alkyl and C _1-4 alkoxy.

In some embodiments, R ¹ in Formula IV is hydrogen. However, in some preferred embodiments, R ¹ in Formula IV can be any of those R ¹ groups defined in connection with Formula I or II, for example, a halogen, such as F or Cl, or an optionally substituted C _1-6 alkyl such as an unsubstituted C _1-6 alkyl (e.g., methyl, ethyl, n-propyl, isopropyl, etc. ) , or a C _1-6 alkyl optionally substituted with one or more independently selected substituents, such as 1, 2, or 3 substituents, as described herein.

Typically, the phenyl ring in Formula IV can be unsubstituted or substituted with 1 or 2 R ¹⁰ groups, i.e., n is 0, 1, or 2. In some embodiments, n is 0. In some embodiments, n is 1. Various groups are suitable for R ¹⁰, which include without limitation F, Cl, Br, CN, C _1- ₆ alkyl optionally substituted with 1-3 fluorine, C _1-6 alkoxy optionally substituted with 1-3 fluorine, C _1-6 heteroalkyl optionally substituted with 1-3 substituents each independently selected from oxo, fluorine, C _1-4 alkyl and C _1-4 alkoxy, C _3-6 cycloalkyl optionally substituted with 1-3 substituents each independently selected from fluorine, C _1-4 alkyl and C _1-4 alkoxy, C _3-6 cycloalkoxy optionally substituted with 1-3 substituents each independently selected from fluorine, C _1-4 alkyl and C _1-4 alkoxy, and 4-8 membered heterocyclyl optionally substituted with 1-3 substituents each independently selected from oxo, fluorine, C _1-4 alkyl and C _1-4 alkoxy.

R ^B group in Formula IV is typically hydrogen, F, Cl, Br, CN, -OH, -NH ₂, -NH (C _1- ₆ alkyl) , -N (C _1-6 alkyl) (C _1-6 alkyl) , C _1-6 alkyl optionally substituted with 1-3 fluorine, C _1-6 alkoxy optionally substituted with 1-3 fluorine, C _1-6 heteroalkyl optionally substituted with 1-3 substituents each independently selected from oxo, fluorine, C _1-4 alkyl and C _1-4 alkoxy, C _3-6 cycloalkyl optionally substituted with 1-3 substituents each independently selected from fluorine, C _1-4 alkyl and C _1-4 alkoxy, C _3-6 cycloalkoxy optionally substituted with 1-3 substituents each independently selected from fluorine, C _1-4 alkyl and C _1-4 alkoxy, or 4-8 membered heterocyclyl optionally substituted with 1-3 substituents each independently selected from oxo, fluorine, C _1-4 alkyl and C _1-4 alkoxy. In some embodiments, R ^B group in Formula IV is hydrogen. In some embodiments, R ^B group in Formula IV is C _1-4 alkyl optionally substituted with 1-3 fluorine, such as CH ₃ or CF ₃. In some embodiments, R ^B group can be CN. In some embodiments, R ^B group can be -NH (C _1-6 alkyl) , such as –NHCH ₃. In some embodiments, R ^B group can be halogen, such as F or Cl. In some embodiments, R ^B group can be NH ₂. In some embodiments, R ^B group can be OH. It was discovered that substitution of the pyridine ring in Formula IV at the R ^B position can improve the pharmacokinetic profile of the compounds. In some preferred embodiments, R ^B is F, CH ₃, CN, CF ₃, NH ₂, or –NHCH ₃.

The pyridine ring in Formula IV can also be optionally substituted with one or more R ¹¹ groups. In some embodiments, the pyridine ring in Formula IV is not substituted with R ¹¹, i.e., m is 0. In some embodiments, m is 1, and R ¹¹ can be, for example, F, Cl, Br, CN, -OH, -NH ₂, -NH (C _1-6 alkyl) , -N (C _1-6 alkyl) (C _1-6 alkyl) , C _1-6 alkyl optionally substituted with 1-3 fluorine, C _1-6 alkoxy optionally substituted with 1-3 fluorine, C _1-6 heteroalkyl optionally substituted with 1-3 substituents each independently selected from oxo, fluorine, C _1-4 alkyl and C _1-4 alkoxy, C _3-6 cycloalkyl optionally substituted with 1-3 substituents each independently selected from fluorine, C _1-4 alkyl and C _1-4 alkoxy, C _3-6 cycloalkoxy optionally substituted with 1-3 substituents each independently selected from fluorine, C _1-4 alkyl and C _1-4 alkoxy, or 4-8 membered heterocyclyl optionally substituted with 1-3 substituents each independently selected from oxo, fluorine, C _1-4 alkyl and C _1-4 alkoxy.

In some embodiments, the present disclosure also provide a compound selected from Compound Nos. 1-21, a pharmaceutically acceptale ester or amide thereof, or a pharmaceutically acceptable salt thereof:

In some embodiments, to the extent applicable, the genus of compounds described herein, such as Formula I, II, III, or IV, or any sub-formulae described herein, also excludes any specifically known single compounds prior to this disclosure. In some embodiments, to the extent applicable, any sub-genus of compounds prior to this disclosure that are entirely within a genus of compounds described herein can also be excluded from such genus herein.

Method of Synthesis

The compounds of the present disclosure can be readily synthesized by those skilled in the art in view of the present disclosure. Exemplified synthesis are also shown in the Examples section.

The following synthetic process of Formula I is illustrative, which can be applied similarly by those skilled in the art for the synthesis of compounds of Formula II, III, or IV. In some embodiments, the present disclosure also provides synthetic methods and synthetic intermediates for preparing the compounds of Formula I, II, III, or IV, as described herein.

As shown in Scheme 1, in some embodiments, compounds of Formula I can be prepared by reacting a compound of S-1 with S-2 under suitable conditions to provide intermediate S-3, wherein Lg ¹ is a leaving group such as a halide (e.g., F, Cl, Br, or I) or a sulfonate leaving group such as triflate (CF ₃SO ₃-) or tosylate etc. and Pg ¹ is a protecting group for a carboxylic acid, which can be an alkyl (e.g., a C _1-4 alkyl, such as methyl, ethyl, isopropyl, n-butyl, tert-Butyl, etc. ) , substituted alkyl, etc. This coupling can be typically a metal catalyzed coupling reaction, such as a palladium catalyzed amination reaction as exemplified herein. Useful reagents and reaction conditions for palladium catalyzed amination reactions are generally known. The compound of Formula I can then be prepared by deprotecting intermediate S-3. In some embodiments, the compound of Formula I is further converted into a pharmaceutically acceptable ester or amide through an ester or amide formation reaction, suitable conditions for ester or amide formations include those known in the art. The variables R ¹, R ¹⁰, R ¹¹, Ring A, m, and n in Scheme 1 include any of those defined herein in connection with Formula I in any combinations.

Alternatively, the compounds of the present disclosure can be prepared by following the general strategies shown in U.S. Patent No. 10,532,987, the content of which is herein incorporated by reference in its entirety.

As will be apparent to those skilled in the art, conventional protecting groups may be necessary to prevent certain functional groups from undergoing undesired reactions. Suitable protecting groups for various functional groups as well as suitable conditions for protecting and deprotecting particular functional groups are well known in the art. For example, numerous protecting groups are described in “Protective Groups in Organic Synthesis” , 4 ^th ed. P.G.M. Wuts; T.W. Greene, John Wiley, 2007, and references cited therein. The reagents for the reactions described herein are generally known compounds or can be prepared by known procedures or obvious modifications thereof. For example, many of the reagents are available from commercial suppliers such as Aldrich Chemical Co. (Milwaukee, Wisconsin, USA) , Sigma (St. Louis, Missouri, USA) . Others may be prepared by procedures, or obvious modifications thereof, described in standard reference texts such as Fieser and Fieser's Reagents for Organic Synthesis, Volumes 1-15 (John Wiley and Sons, 1991) , Rodd's Chemistry of Carbon Compounds, Volumes 1-5 and Supplemental (Elsevier Science Publishers, 1989) , Organic Reactions, Volumes 1-40 (John Wiley and Sons, 1991) , March's Advanced Organic Chemistry, (Wiley, 7 ^th Edition) , and Larock's Comprehensive Organic Transformations (Wiley-VCH, 1999) , and any of available updates as of this filing.

Pharmaceutical Compositions

Certain embodiments are directed to a pharmaceutical composition comprising one or more compounds of the present disclosure.

The pharmaceutical composition can optionally contain a pharmaceutically acceptable excipient. In some embodiments, the pharmaceutical composition comprises a compound of the present disclosure (e.g., a compound of Formula I (e.g., I-1, I-2, I-3, or I-3A) , Formula II (e.g., II-1, II-2, II-3, II-4, II-5, II-6, II-7, II-8, II-7A, or II-8A) , Formula III (e.g., III-1) , Formula IV, or any of Compound Nos. 1-21, a pharmaceutically acceptable ester or amide thereof, as applicable, or a pharmaceutically acceptable salt thereof) and a pharmaceutically acceptable excipient. Pharmaceutically acceptable excipients are known in the art. Non-limiting suitable excipients include, for example, encapsulating materials or additives such as antioxidants, binders, buffers, carriers, coating agents, coloring agents, diluents, disintegrating agents, emulsifiers, extenders, fillers, flavoring agents, humectants, lubricants, perfumes, preservatives, propellants, releasing agents, sterilizing agents, sweeteners, solubilizers, wetting agents and mixtures thereof. See also Remington's The Science and Practice of Pharmacy, 21st Edition, A. R. Gennaro (Lippincott, Williams &Wilkins, Baltimore, Md., 2005; incorporated herein by reference) , which discloses various excipients used in formulating pharmaceutical compositions and known techniques for the preparation thereof.

The pharmaceutical composition can include any one or more of the compounds of the present disclosure. For example, in some embodiments, the pharmaceutical composition comprises a compound of Formula I (e.g., I-1, I-2, I-3, or I-3A) , Formula II (e.g., II-1, II-2, II-3, II-4, II-5, II-6, II-7, II-8, II-7A, or II-8A) , Formula III (e.g., III-1) , Formula IV, or any of Compound Nos. 1-21, a pharmaceutically acceptable ester or amide thereof, as applicable, or a pharmaceutically acceptable salt thereof, e.g., in a therapeutically effective amount. In any of the embodiments described herein, the pharmaceutical composition can comprise a therapeutically effective amount of a compound selected from Compound Nos. 1-21, a pharmaceutically acceptable ester or amide thereof, as applicable, or a pharmaceutically acceptable salt thereof.

The pharmaceutical composition can be formulated for delivery via any of the known routes of delivery, which include but are not limited to oral, parenteral, inhalation, etc.

In some embodiments, the pharmaceutical composition can be formulated for oral administration. The oral formulations can be presented in discrete units, such as capsules, pills, cachets, lozenges, or tablets, each containing a predetermined amount of the active compound; as a powder or granules; as a solution or a suspension in an aqueous or non-aqueous liquid; or as an oil-in-water or water-in-oil emulsion. Excipients for the preparation of compositions for oral administration are known in the art. Non-limiting suitable excipients include, for example, agar, alginic acid, aluminum hydroxide, benzyl alcohol, benzyl benzoate, 1, 3-butylene glycol, carbomers, castor oil, cellulose, cellulose acetate, cocoa butter, corn starch, corn oil, cottonseed oil, cross-povidone, diglycerides, ethanol, ethyl cellulose, ethyl laureate, ethyl oleate, fatty acid esters, gelatin, germ oil, glucose, glycerol, groundnut oil, hydroxypropylmethyl cellulose, isopropanol, isotonic saline, lactose, magnesium hydroxide, magnesium stearate, malt, mannitol, monoglycerides, olive oil, peanut oil, potassium phosphate salts, potato starch, povidone, propylene glycol, Ringer's solution, safflower oil, sesame oil, sodium carboxymethyl cellulose, sodium phosphate salts, sodium lauryl sulfate, sodium sorbitol, soybean oil, stearic acids, stearyl fumarate, sucrose, surfactants, talc, tragacanth, tetrahydrofurfuryl alcohol, triglycerides, water, and mixtures thereof.

In some embodiments, the pharmaceutical composition is formulated for parenteral administration (such as intravenous injection or infusion,

ubcutaneous or intramuscular injection) . The parenteral formulations can be, for example, an aqueous solution, a suspension, or an emulsion. Excipients for the preparation of parenteral formulations are known in the art. Non-limiting suitable excipients include, for example, 1, 3-butanediol, castor oil, corn oil, cottonseed oil, dextrose, germ oil, groundnut oil, liposomes, oleic acid, olive oil, peanut oil, Ringer's solution, safflower oil, sesame oil, soybean oil, U.S.P. or isotonic sodium chloride solution, water and mixtures thereof.

In some embodiments, the pharmaceutical composition is formulated for inhalation. The inhalable formulations can be, for example, formulated as a nasal spray, dry powder, or an aerosol administrable through a metered-dose inhaler. Excipients for preparing formulations for inhalation are known in the art. Non-limiting suitable excipients include, for example, lactose, talc, silicic acid, aluminum hydroxide, calcium silicates and polyamide powder, and mixtures of these substances. Sprays can additionally contain propellants, such as chlorofluorohydrocarbons and volatile unsubstituted hydrocarbons, such as butane and propane.

Compounds of the present disclosure can be used alone, in combination with each other, or in combination with one or more additional therapeutic agents, e.g., an additional agent that is useful for treating or preventing a disease or disorder described herein (e.g., obesity, diabetes (e.g., Type 2 diabetes) , non-alcoholic steatohepatitis (NASH) , non-alcoholic fatty liver disease, etc. ) . For example, in some embodiments, compounds of the present disclosure can be used in combination with an additional agent useful for treating or preventing NASH, such as obeticholic acid. Obeticholic Acid (OCA) , a derivative of cholic acid, acts as a potent and selective FXR agonist and was used to treat NASH in clinical trials. Mice treated with OCA or compounds of the present disclosure respectively both attenuated liver fibrosis, but OCA had less effect on fatty acid accumumaltion in liver, while compounds of the present disclosure reduced fatty acid deposition in liver, which suggested that compounds of the present disclosure have more effects on fats with a different mechanism from OCA for NASH treatment. In some embodiments, compounds of the present disclosure can be used in combination with an anti-inflammatory or anti-fibrogenic compounds to further enhance the therapeutic efficacy for NASH.

When used in combination with one or more additional therapeutic agents, compounds of the present disclosure or pharmaceutical compositions herein can be administered to the subject either concurrently or sequentially in any order with such additional therapeutic agents. In some embodiments, the pharmaceutical composition can comprise one or more compounds of the present disclosure and the one or more additional therapeutic agents in a single composition. In some embodiments, the pharmaceutical composition comprising one or more compounds of the present disclosure can be included in a kit which also comprises a separate pharmaceutical composition comprising the one or more additional therapeutic agents.

The pharmaceutical composition can include various amounts of the compounds of the present disclosure, depending on various factors such as the intended use and potency and selectivity of the compounds. In some embodiments, the pharmaceutical composition comprises a therapeutically effective amount of a compound of the present disclosure. In some embodiments, the pharmaceutical composition comprises a therapeutically effective amount of the compound of the present disclosure and a pharmaceutically acceptable excipient. As used herein, a therapeutically effective amount of a compound of the present disclosure is an amount effective to treat a disease or disorder as described herein, such as obesity, diabetes (e.g., Type 2 diabetes) , NASH, non-alcoholic fatty liver disease, etc., which can depend on the recipient of the treatment, the disorder, condition or disease being treated and the severity thereof, the composition containing the compound, the time of administration, the route of administration, the duration of treatment, the compound potency, its rate of clearance and whether or not another drug is co-administered.

For veterinary use, a compound of the present disclosure can be administered as a suitably acceptable formulation in accordance with normal veterinary practice. The veterinarian can readily determine the dosing regimen and route of administration that is most appropriate for a particular animal.

Method of Treatment/Use

Compounds of the present disclosure have various utilities, such as inducing UCP-1 expression and/or mitochondrial oxidative metabolism in a white adipose tissue, and/or treating or preventing a disease or disorder for which such induction is beneficial. In some embodiments, compounds of the present disclosure can be used for inducing browning of white adipose tissues and/or treating or preventing a disease or disorder for which browning of white adipose tissues is beneficial. In some embodiments, compounds of the present disclosure can be used as therapeutic active substances for the treatment and/or prophylaxis of various diseases or disorders described herein, such as metabolic diseases or disorders such as obesity or diabetes (e.g., Type 2 diabetes) , liver diseases or disorders such as non-alcoholic fatty liver disease or NASH. In some embodiments, the liver diseases or disorders are characterized as having high AST/ALT ratio, high liver triglycerides, and/or high liver weight, for example, a human subject having such liver diseases or disorders can have an AST/ALT ratio, liver triglycerides content, and/or liver weight beyond those normal ranges for a healthy human subject. See e.g., Hall, P. and Cash, J. Ulster Med J. 2012 Jan; 81 (1) : 30–36. As would be understood by those skilled in the art in the context of liver function, "ALT" refers to alanine aminotransaminase and "AST" refers to aspartate transaminase.

In some embodiments, the present disclosure provides a method of inducing uncoupling protein-1 (UCP-1) expression and/or mitochondrial oxidative metabolism in a white adipose tissue, which comprises contacting the white adipose tissue with an effective amount of the compound of the present disclosure (e.g., a compound of Formula I (e.g., I-1, I-2, I-3, or I-3A) , Formula II (e.g., II-1, II-2, II-3, II-4, II-5, II-6, II-7, II-8, II-7A, or II-8A) , Formula III (e.g., III-1) , Formula IV, or any of Compound Nos. 1-21, a pharmaceutically acceptable ester or amide thereof, as applicable, or a pharmaceutically acceptable salt thereof) or a pharmaceutical composition described herein. In some embodiments, the contacting can be in vitro or in vivo.

In some embodiments, the present disclosure provides a method of treating or preventing a disease or disorder for which inducing uncoupling protein-1 (UCP-1) expression and/or mitochondrial oxidative metabolism in a white adipose tissue is beneficial, which comprises administering to a subject in need thereof an effective amount of the compound of the present disclosure (e.g., a compound of Formula I (e.g., I-1, I-2, I-3, or I-3A) , Formula II (e.g., II-1, II-2, II-3, II-4, II-5, II-6, II-7, II-8, II-7A, or II-8A) , Formula III (e.g., III-1) , Formula IV, or any of Compound Nos. 1-21, a pharmaceutically acceptable ester or amide thereof, as applicable, or a pharmaceutically acceptable salt thereof) or a pharmaceutical composition described herein. In some embodiments, the subject can be characterized as having a metabolic disease or disorder, such as obesity and/or diabetes (e.g., Type 2 diabetes) . In some embodiments, the subject can be characterized as having a liver disease or disorder, such as non-alcoholic fatty liver disease and/or NASH.

In some embodiments, the present disclosure provides a method of inducing browning of a white adipose tissue, which comprises contacting the white adipose tissue with an effective amount of the compound of the present disclosure (e.g., a compound of Formula I (e.g., I-1, I-2, I-3, or I-3A) , Formula II (e.g., II-1, II-2, II-3, II-4, II-5, II-6, II-7, II-8, II-7A, or II-8A) , Formula III (e.g., III-1) , Formula IV, or any of Compound Nos. 1-21, a pharmaceutically acceptable ester or amide thereof, as applicable, or a pharmaceutically acceptable salt thereof) or a pharmaceutical composition described herein. In some embodiments, the contacting can be in vitro or in vivo.

In some embodiments, the present disclosure provides a method of treating or preventing a disease or disorder for which inducing browning of a white adipose tissue is beneficial, which comprises administering to a subject in need thereof an effective amount of the compound of the present disclosure (e.g., a compound of Formula I (e.g., I-1, I-2, I-3, or I-3A) , Formula II (e.g., II-1, II-2, II-3, II-4, II-5, II-6, II-7, II-8, II-7A, or II-8A) , Formula III (e.g., III-1) , Formula IV, or any of Compound Nos. 1-21, a pharmaceutically acceptable ester or amide thereof, as applicable, or a pharmaceutically acceptable salt thereof) or a pharmaceutical composition described herein. In some embodiments, the subject can be characterized as having a metabolic disease or disorder, such as obesity and/or diabetes (e.g., Type 2 diabetes) . In some embodiments, the subject can be characterized as having a liver disease or disorder, such as non-alcoholic fatty liver disease and/or NASH.

In some embodiments, the present disclosure provides a method of treating or preventing one or more diseases or disorders described herein. Diseases or disorders suitable to be treated with the methods herein include but not limited to metabolic diseases or disorders, such as obesity, diabetes (e.g., Type 2 diabetes) , liver diseases or disorders, such as non-alcoholic fatty liver disease or NASH. In some embodiments, a method of of treating or preventing a metabolic disease or disorder is provided. In some embodiments, a method of treating or preventing a liver disease or disorder is provided. The method typically comprises administering to a subject in need thereof an effective amount of a compound of the present disclosure (e.g., a compound of Formula I (e.g., I-1, I-2, I-3, or I-3A) , Formula II (e.g., II-1, II-2, II-3, II-4, II-5, II-6, II-7, II-8, II-7A, or II-8A) , Formula III (e.g., III-1) , Formula IV, or any of Compound Nos. 1-21, a pharmaceutically acceptable ester or amide thereof, as applicable, or a pharmaceutically acceptable salt thereof) or an effective amount of a pharmaceutical composition described herein. In some embodiments, the administering reduces AST/ALT ratio, lowers liver triglycerides, and/or lowers liver weight in the subject. In some embodiments, the administering reduces blood glucose level. In some embodiments, the administering also lowers the body weight of the subject. In some embodiments, the administering also reduces the size of fat tissues.

For example, in some embodiments, the present disclosure provides a method of treating diabetes (e.g., Type 2 diabetes) in a subject in need thereof. In some embodiments, the method comprises administering to the subject an effective amount of a compound of the present disclosure (e.g., a compound of Formula I (e.g., I-1, I-2, I-3, or I-3A) , Formula II (e.g., II-1, II-2, II-3, II-4, II-5, II-6, II-7, II-8, II-7A, or II-8A) , Formula III (e.g., III-1) , Formula IV, or any of Compound Nos. 1-21, a pharmaceutically acceptable ester or amide thereof, as applicable, or a pharmaceutically acceptable salt thereof) or an effective amount of a pharmaceutical composition described herein. In some embodiments, the administering reduces blood glucose level.

In some embodiments, the present disclosure provides a method of treating obesity in a subject in need thereof, which comprises administering to the subject an effective amount of a compound of the present disclosure (e.g., a compound of Formula I (e.g., I-1, I-2, I-3, or I-3A) , Formula II (e.g., II-1, II-2, II-3, II-4, II-5, II-6, II-7, II-8, II-7A, or II-8A) , Formula III (e.g., III-1) , Formula IV, or any of Compound Nos. 1-21, a pharmaceutically acceptable ester or amide thereof, as applicable, or a pharmaceutically acceptable salt thereof) or an effective amount of a pharmaceutical composition described herein. In some embodiments, the administering lowers body weight of the subject.

In some embodiments, the present disclosure also provides a method of treating non-alcoholic steatohepatitis in a subject in need thereof, which comprises administering to the subject an effective amount of a compound of the present disclosure (e.g., a compound of Formula I (e.g., I-1, I-2, I-3, or I-3A) , Formula II (e.g., II-1, II-2, II-3, II-4, II-5, II-6, II-7, II-8, II-7A, or II-8A) , Formula III (e.g., III-1) , Formula IV, or any of Compound Nos. 1-21, a pharmaceutically acceptable ester or amide thereof, as applicable, or a pharmaceutically acceptable salt thereof) or an effective amount of a pharmaceutical composition described herein. In some embodiments, the administering reduces AST/ALT ratio, lowers liver triglycerides, and/or lowers liver weight in the subject. In some embodiments, the administering also reduces blood glucose level of the subject. In some embodiments, the administering also lowers body weight of the subject. In some embodiments, the administering also reduces the size of fat tissues.

In some embodiments, the present disclosure also provides a method of treating non-alcoholic fatty liver disease in a subject in need thereof, which comprises administering to the subject an effective amount of a compound of the present disclosure (e.g., a compound of Formula I (e.g., I-1, I-2, I-3, or I-3A) , Formula II (e.g., II-1, II-2, II-3, II-4, II-5, II-6, II-7, II-8, II-7A, or II-8A) , Formula III (e.g., III-1) , Formula IV, or any of Compound Nos. 1-21, a pharmaceutically acceptable ester or amide thereof, as applicable, or a pharmaceutically acceptable salt thereof) or an effective amount of a pharmaceutical composition described herein. In some embodiments, the administering reduces AST/ALT ratio, lowers liver triglycerides, and/or lowers liver weight in the subject. In some embodiments, the administering also reduces blood glucose level of the subject. In some embodiments, the administering also reduces body weight of the subject. In some embodiments, the administering also reduces the size of fat tissues.

In some embodiments, the present disclosure also provides a method of improving liver health (e.g., reducing AST/ALT ratio, lowering liver triglycerides, and/or lowering liver weight) in a subject in need thereof, which comprises administering to the subject an effective amount of a compound of the present disclosure (e.g., a compound of Formula I (e.g., I-1, I-2, I-3, or I-3A) , Formula II (e.g., II-1, II-2, II-3, II-4, II-5, II-6, II-7, II-8, II-7A, or II-8A) , Formula III (e.g., III-1) , Formula IV, or any of Compound Nos. 1-21, a pharmaceutically acceptable ester or amide thereof, as applicable, or a pharmaceutically acceptable salt thereof) or an effective amount of a pharmaceutical composition described herein. In some embodiments, the subject is characterized as having NASH and/or non-alcoholic fatty liver disease.

In some embodiments, the present disclosure also provides a method of lowering liver triglycerides in a subject in need thereof, which comprises administering to the subject an effective amount of a compound of the present disclosure (e.g., a compound of Formula I (e.g., I-1, I-2, I-3, or I-3A) , Formula II (e.g., II-1, II-2, II-3, II-4, II-5, II-6, II-7, II-8, II-7A, or II-8A) , Formula III (e.g., III-1) , Formula IV, or any of Compound Nos. 1-21, a pharmaceutically acceptable ester or amide thereof, as applicable, or a pharmaceutically acceptable salt thereof) or an effective amount of a pharmaceutical composition described herein. In some embodiments, the subject is characterized as having NASH and/or non-alcoholic fatty liver disease.

The administering in the methods herein is not limited. For example, in some embodiments, the administering can be orally, nasally, transdermally, pulmonary, inhalationally, buccally, sublingually, intraperintoneally, subcutaneously, intramuscularly, intravenously, rectally, intrapleurally, intrathecally and parenterally. In some embodiments, the administering is orally.

Compounds of the present disclosure can be used as a monotherapy or in a combination therapy. In some embodiments according to the methods described herein, compounds of the present disclosure can be administered as the only active ingredient (s) . In some embodiments according to the methods described herein, compounds of the present disclosure can also be co-administered with an additional therapeutic agent, either concurrently or sequentially in any order, to the subject in need thereof. Suitable additional therapeutica agents include any of those that are known, approved by a regulatory agency such as the U.S. Food and Drug Administration, in clinical studies, etc. for treating obesity, diabetes (e.g., Type 2 diabetes) , NASH, and/or non-alcholic fatty liver disease, or for treating a known risk factor for obesity, diabetes (e.g., Type 2 diabetes) , NASH, and/or non-alcholic fatty liver disease.

Dosing regimen including doses for the methods described herein can vary and be adjusted, which can depend on the recipient of the treatment, the disorder, condition or disease being treated and the severity thereof, the composition containing the compound, the time of administration, the route of administration, the duration of treatment, the compound potency, its rate of clearance and whether or not another drug is co-administered. Definitions

It is meant to be understood that proper valences are maintained for all moieties and combinations thereof.

It is also meant to be understood that a specific embodiment of a variable moiety herein can be the same or different as another specific embodiment having the same identifier.

Suitable groups for the variables in compounds of Formula I, II, III, or IV, or a subformula thereof, as applicable, are independently selected. Non-limiting useful groups for the variables in compounds of Formula I, II, III, or IV, or a subformula thereof, as applicable, include any of the respective groups, individually or in any combination, as shown in the specific examples 1-21. For example, in some embodiments, suitable groups as R ¹ in Formula I or II include any of the R ¹ groups shown in specific examples 1-21, without regard to the other variables shown in the specific examples. In some embodiments, suitable groups as R ¹ in Formula I or II include any of the R ¹ groups shown in specific examples 1-21 in combination with one or more other variables specified in the specific examples, either in the same example or a different example. Any of such combinations are contemplated and within the scope of the present disclosure.

The described embodiments of the present disclosure can be combined. Such combination is contemplated and within the scope of the present disclosure. For example, it is contemplated that the definition (s) of any one or more of R ¹, R ¹⁰, R ¹¹, Ring A, m and n of Formula I can be combined with the definition of any one or more of the other (s) of R ¹, R ¹⁰, R ¹¹, Ring A, m and n, as applicable, and the resulted compounds from the combination are within the scope of the present disclosure. Similar combinations of variables for other formulae described herein are also comtemplated and within the scope of the present disclosure.

The symbol,

whether utilized as a bond or displayed perpendicular to (or otherwise crossing) a bond, indicates the point at which the displayed moiety is attached to the remainder of the molecule. It should be noted that the immediately connected group or groups maybe shown beyond the symbol,

to indicate connectivity, as would be understood by those skilled in the art.

Definitions of specific functional groups and chemical terms are described in more detail below. The chemical elements are identified in accordance with the Periodic Table of the Elements, CAS version, Handbook of Chemistry and Physics, 75 ^th Ed., inside cover, and specific functional groups are generally defined as described therein. Additionally, general principles of organic chemistry, as well as specific functional moieties and reactivity, are described in Thomas Sorrell, Organic Chemistry, University Science Books, Sausalito, 1999; Smith and March, March’s Advanced Organic Chemistry, 5 ^th Edition, John Wiley &Sons, Inc., New York, 2001; Larock, Comprehensive Organic Transformations, VCH Publishers, Inc., New York, 1989; and Carruthers, Some Modern Methods of Organic Synthesis, 3 ^rd Edition, Cambridge University Press, Cambridge, 1987. The disclosure is not intended to be limited in any manner by the exemplary listing of substituents described herein.

Compounds described herein can comprise one or more asymmetric centers, and thus can exist in various stereoisomeric forms, e.g., enantiomers and/or diastereomers. For example, the compounds described herein can be in the form of an individual enantiomer, diastereomer or geometric isomer, or can be in the form of a mixture of stereoisomers, including racemic mixtures and mixtures enriched in one or more stereoisomer. Isomers can be isolated from mixtures by methods known to those skilled in the art, including chiral high performance liquid chromatography (HPLC) and the formation and crystallization of chiral salts; or preferred isomers can be prepared by asymmetric syntheses. See, for example, Jacques et al., Enantiomers, Racemates and Resolutions (Wiley Interscience, New York, 1981) ; Wilen et al., Tetrahedron 33: 2725 (1977) ; Eliel, Stereochemistry of Carbon Compounds (McGraw–Hill, NY, 1962) ; and Wilen, Tables of Resolving Agents and Optical Resolutions p. 268 (E.L. Eliel, Ed., Univ. of Notre Dame Press, Notre Dame, IN 1972) . The disclosure additionally encompasses compounds described herein as individual isomers substantially free of other isomers, and alternatively, as mixtures of various isomers including racemic mixtures. When a stereochemistry is specifically drawn, unless otherwise contradictory from context, it should be understood that with respect to that particular chiral center or axial chirality, the compound can exist predominantly as the as-drawn stereoisomer, such as with less than 20%, less than 10%, less than 5%, less than 1%, by weight, by HPLC area, or both, or with a non-detectable amount of the other stereoisomer (s) . The presence and/or amounts of stereoisomers can be determined by those skilled in the art in view of the present disclosure, including through the use of a chiral HPLC.

When a range of values is listed, it is intended to encompass each value and sub–range within the range. For example “C _1–6” is intended to encompass, C ₁, C ₂, C ₃, C ₄, C ₅, C ₆, C _1–6, C _1–5, C _1–4, C _1–3, C _1–2, C _2–6, C _2–5, C _2–4, C _2–3, C _3–6, C _3–5, C _3–4, C _4–6, C _4–5, and C _5–6.

As used herein, the term “compound (s) of the present disclosure” refers to any of the compounds described herein according to Formula I (e.g., I-1, I-2, I-3, or I-3A) , Formula II (e.g., II-1, II-2, II-3, II-4, II-5, II-6, II-7, II-8, II-7A, or II-8A) , Formula III (e.g., III-1) , Formula IV, or any of Compound Nos. 1-21, isotopically labeled compound (s) thereof (such as a deuterated analog wherein one or more of the hydrogen atoms is/are substituted with a deuterium atom with an abundance above its natural abundance, e.g., a CD ₃ analog when the compound has a CH ₃ group) , possible regioisomers, possible geometric isomers, possible stereoisomers thereof (including diastereoisomers, enantiomers, and racemic mixtures) , tautomers thereof, conformational isomers thereof, pharmaceutically acceptable esters or amides thereof, and/or possible pharmaceutically acceptable salts thereof (e.g., acid addition salt such as HCl salt or base addition salt such as Na salt) . For the avoidance of doubt, Compound Nos. 1-21 or Compounds 1-21 refer to the compounds described herein labeled as integers 1, 2, 3, …, 21, which are shown under the section Compounds. For convenience, the synthetic starting materials or intermedates leading to Compounds 1-21 may be labaled as the compound number followed by a dash "-" and then another integer, such as 1-1, 1-2, etc.; these starting materials or intermediates so labeled should not be confused with Compounds 1-21. Hydrates and solvates of the compounds of the present disclosure are considered compositions of the present disclosure, wherein the compound (s) is in association with water or solvent, respectively.

Compounds of the present disclosure can exist in isotope-labeled or -enriched form containing one or more atoms having an atomic mass or mass number different from the atomic mass or mass number most abundantly found in nature. Isotopes can be radioactive or non-radioactive isotopes. Isotopes of atoms such as hydrogen, carbon, phosphorous, sulfur, fluorine, chlorine, and iodine include, but are not limited to ²H, ³H, ¹³C, ¹⁴C, ¹⁵N, ¹⁸O, ³²P, ³⁵S, ¹⁸F, ³⁶Cl, and ¹²⁵I. Compounds that contain other isotopes of these and/or other atoms are within the scope of this invention.

As used herein, the phrase “administration” of a compound, “administering” a compound, or other variants thereof means providing the compound or a prodrug of the compound to the individual in need of treatment.

As used herein, the term "alkyl" as used by itself or as part of another group refers to a straight-or branched-chain aliphatic saturated hydrocarbon. In some embodiments, the alkyl can include one to twelve carbon atoms (i.e., C _1-12 alkyl) or the number of carbon atoms designated. In one embodiment, the alkyl group is a straight chain C _1-10 alkyl group. In another embodiment, the alkyl group is a branched chain C _3-10 alkyl group. In another embodiment, the alkyl group is a straight chain C _1-6 alkyl group. In another embodiment, the alkyl group is a branched chain C _3-6 alkyl group. In another embodiment, the alkyl group is a straight chain C _1-4 alkyl group. For example, a C _1-4 alkyl group includes methyl, ethyl, propyl (n-propyl) , isopropyl, butyl (n-butyl) , sec-butyl, tert-butyl, and iso-butyl. As used herein, the term "alkylene" as used by itself or as part of another group refers to a divalent radical derived from an alkyl group. For example, non-limiting straight chain alkylene groups include -CH ₂-CH ₂-CH ₂-CH ₂-, -CH ₂-CH ₂-CH ₂-, -CH ₂-CH ₂-, and the like.

As used herein, the term "alkenyl" as used by itself or as part of another group refers to a straight-or branched-chain aliphatic hydrocarbon containing one or more, for example, one, two or three carbon-to-carbon double bonds. In one embodiment, the alkenyl group is a C _2-6 alkenyl group. In another embodiment, the alkenyl group is a C _2-4 alkenyl group. Non-limiting exemplary alkenyl groups include ethenyl, propenyl, isopropenyl, butenyl, sec-butenyl, pentenyl, and hexenyl.

As used herein, the term "alkynyl" as used by itself or as part of another group refers to a straight-or branched-chain aliphatic hydrocarbon containing one or more, for example, one to three carbon-to-carbon triple bonds. In one embodiment, the alkynyl has one carbon-carbon triple bond. In one embodiment, the alkynyl group is a C _2-6 alkynyl group. In another embodiment, the alkynyl group is a C _2-4 alkynyl group. Non-limiting exemplary alkynyl groups include ethynyl, propynyl, butynyl, 2-butynyl, pentynyl, and hexynyl groups.

As used herein, the term "alkoxy" as used by itself or as part of another group refers to a radical of the formula OR ^a1, wherein R ^a1 is an alkyl.

As used herein, the term "cycloalkoxy" as used by itself or as part of another group refers to a radical of the formula OR ^a1, wherein R ^a1 is a cycloalkyl.

As used herein, the term "haloalkyl" as used by itself or as part of another group refers to an alkyl substituted with one or more fluorine, chlorine, bromine and/or iodine atoms. In preferred embodiments, the haloalkyl is an alkyl group substituted with one, two, or three fluorine atoms. In one embodiment, the haloalkyl group is a C _1-10 haloalkyl group. In one embodiment, the haloalkyl group is a C _1-6 haloalkyl group. In one embodiment, the haloalkyl group is a C _1-4 haloalkyl group.

As used herein, the term "heteroalkyl, " by itself or in combination with another term, means, unless otherwise stated, a stable straight or branched-chain alkyl group, e.g., having from 2 to 14 carbons, such as 2 to 10 carbons in the chain, one or more of the carbons has been replaced by a heteroatom selected from S, O, P and N, and wherein the nitrogen, phosphine, and sulfur atoms can optionally be oxidized and the nitrogen heteroatom can optionally be quaternized. The heteroatom (s) S, O, P and N may be placed at any interior position of the heteroalkyl group or at the position at which the alkyl group is attached to the remainder of the molecule. When the heteroalkyl is said to be substituted, the substituent (s) can replace one or more hydrogen atoms attached to the carbon atom (s) and/or the heteroatom (s) of the heteroalkyl. In some embodiments, the heteroalkyl is a C _1-4 heteroalkyl, which refers to the heteroalkyl defined herein having 1-4 carbon atoms. Examples of C _1-4 heteroalkyl include, but are not limited to, C ₄ heteroalkyl such as -CH ₂-CH ₂-N (CH ₃) -CH ₃, C ₃ heteroalkyl such as -CH ₂-CH ₂-O-CH ₃, -CH ₂-CH ₂-NH-CH ₃, -CH ₂-S-CH ₂-CH ₃, -CH ₂-CH ₂-S (O) -CH ₃, -CH ₂-CH ₂-S (O) ₂-CH ₃, C ₂ heteroalkyl such as -CH ₂-CH ₂-OH, -CH ₂-CH ₂-NH ₂, -CH ₂-NH (CH ₃) , -O-CH ₂-CH ₃ and C ₁ heteroalkyl such as, -CH ₂-OH, -CH ₂-NH ₂, -O-CH ₃. Similarly, the term "heteroalkylene" by itself or as part of another substituent means a divalent radical derived from heteroalkyl, as exemplified, but not limited by, -CH ₂-CH ₂-O-CH ₂-CH ₂-and –O-CH ₂-CH ₂-NH-CH ₂-. For heteroalkylene groups, heteroatoms can also occupy either or both of the chain termini (e.g., alkyleneoxy, alkylenedioxy, alkyleneamino, alkylenediamino, and the like) . Still further, for alkylene and heteroalkylene linking groups, no orientation of the linking group is implied by the direction in which the formula of the linking group is written. Where "heteroalkyl" is recited, followed by recitations of specific heteroalkyl groups, such as -NR'R” or the like, it will be understood that the terms heteroalkyl and -NR'R” are not redundant or mutually exclusive. Rather, the specific heteroalkyl groups are recited to add clarity. Thus, the term "heteroalkyl" should not be interpreted herein as excluding specific heteroalkyl groups, such as -NR'R” or the like.

“Carbocyclyl” or “carbocyclic” as used by itself or as part of another group refers to a radical of a non–aromatic cyclic hydrocarbon group having at least 3 carbon atoms, e.g., from 3 to 10 ring carbon atoms ( “C _3–10 carbocyclyl” ) , and zero heteroatoms in the non–aromatic ring system. The carbocyclyl group can be either monocyclic ( “monocyclic carbocyclyl” ) or contain a fused, bridged or spiro ring system such as a bicyclic system ( “bicyclic carbocyclyl” ) and can be saturated or can be partially unsaturated. Non-limiting exemplary carbocyclyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, norbornyl, decalin, adamantyl, cyclopentenyl, and cyclohexenyl. As used herein, the term "carbocyclylene" as used by itself or as part of another group refers to a divalent radical derived from the carbocyclyl group defined herein.

In some embodiments, “carbocyclyl” is fully saturated, which is also referred to as cycloalkyl. In some embodiments, the cycloalkyl can have from 3 to 10 ring carbon atoms ( “C _3–10 cycloalkyl” ) . In preferred embodiments, the cycloalkyl is a monocyclic ring. As used herein, the term "cycloalkylene" as used by itself or as part of another group refers to a divalent radical derived from a cycloalkyl group, for example,

etc.

“Heterocyclyl” or “heterocyclic” as used by itself or as part of another group refers to a radical of a 3-membered or larger, such as 3–to 14–membered, non–aromatic ring system having ring carbon atoms and at least one ring heteroatom, such as 1 to 4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, sulfur, boron, phosphorus, and silicon. In heterocyclyl groups that contain one or more nitrogen atoms, the point of attachment can be a carbon or nitrogen atom, as valency permits. A heterocyclyl group can either be monocyclic ( “monocyclic heterocyclyl” ) or a fused, bridged, or spiro ring system, such as a bicyclic system ( “bicyclic heterocyclyl” ) , and can be saturated or can be partially unsaturated. Heterocyclyl bicyclic ring systems can include one or more heteroatoms in one or both rings, wherein the attaching point can be on either ring. As used herein, the term "heterocyclylene" as used by itself or as part of another group refers to a divalent radical derived from the heterocyclyl group defined herein. The heterocyclyl or heterocylylene can be optionally linked to the rest of the molecule through a carbon or nitrogen atom.

Exemplary 3–membered heterocyclyl groups containing one heteroatom include, without limitation, azirdinyl, oxiranyl, thiiranyl. Exemplary 4–membered heterocyclyl groups containing one heteroatom include, without limitation, azetidinyl, oxetanyl and thietanyl. Exemplary 5–membered heterocyclyl groups containing one heteroatom include, without limitation, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothiophenyl, dihydrothiophenyl, pyrrolidinyl, dihydropyrrolyl, and pyrrolyl–2, 5–dione. Exemplary 5–membered heterocyclyl groups containing two heteroatoms include, without limitation, dioxolanyl, oxasulfuranyl, disulfuranyl, and oxazolidin-2-one. Exemplary 5–membered heterocyclyl groups containing three heteroatoms include, without limitation, triazolinyl, oxadiazolinyl, and thiadiazolinyl. Exemplary 6–membered heterocyclyl groups containing one heteroatom include, without limitation, piperidinyl, tetrahydropyranyl, dihydropyridinyl, and thianyl. Exemplary 6–membered heterocyclyl groups containing two heteroatoms include, without limitation, piperazinyl, morpholinyl, dithianyl, and dioxanyl. Exemplary 6–membered heterocyclyl groups containing two heteroatoms include, without limitation, triazinanyl. Exemplary 7–membered heterocyclyl groups containing one heteroatom include, without limitation, azepanyl, oxepanyl and thiepanyl. Exemplary 8–membered heterocyclyl groups containing one heteroatom include, without limitation, azocanyl, oxecanyl and thiocanyl. Exemplary 5-membered heterocyclyl groups fused to a C ₆ aryl ring (also referred to herein as a 5, 6-bicyclic heterocyclic ring) include, without limitation, indolinyl, isoindolinyl, dihydrobenzofuranyl, dihydrobenzothienyl, benzoxazolinonyl, and the like. Exemplary 6-membered heterocyclyl groups fused to an aryl ring (also referred to herein as a 6, 6-bicyclic heterocyclic ring) include, without limitation, tetrahydroquinolinyl, tetrahydroisoquinolinyl, and the like.

“Aryl” as used by itself or as part of another group refers to a radical of a monocyclic or polycyclic (e.g., bicyclic or tricyclic) 4n+2 aromatic ring system (e.g., having 6, 10, or 14 pi electrons shared in a cyclic array) having 6–14 ring carbon atoms and zero heteroatoms provided in the aromatic ring system ( “C _6–14 aryl” ) . In some embodiments, an aryl group has six ring carbon atoms ( “C ₆ aryl” ; e.g., phenyl) . In some embodiments, an aryl group has ten ring carbon atoms ( “C ₁₀ aryl” ; e.g., naphthyl such as 1–naphthyl and 2–naphthyl) . In some embodiments, an aryl group has fourteen ring carbon atoms ( “C ₁₄ aryl” ; e.g., anthracyl) . As used herein, the term "arylene" as used by itself or as part of another group refers to a divalent radical derived from the aryl group defined herein.

“Aralkyl” as used by itself or as part of another group refers to an alkyl substituted with one or more aryl groups, preferably, substituted with one aryl group. Examples of aralkyl include benzyl, phenethyl, etc. When an aralkyl is said to be optionally substituted, either the alkyl portion or the aryl portion of the aralkyl can be optionally substituted.

“Heteroaryl” as used by itself or as part of another group refers to a radical of a 5–14 membered monocyclic, bicyclic, or tricyclic 4n+2 aromatic ring system (e.g., having 6 or 10 pi electrons shared in a cyclic array) having ring carbon atoms and at least one, preferably, 1–4, ring heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen and sulfur ( “5–14 membered heteroaryl” ) . In heteroaryl groups that contain one or more nitrogen atoms, the point of attachment can be a carbon or nitrogen atom, as valency permits. Heteroaryl bicyclic ring systems can include one or more heteroatoms in one or both rings. In bicyclic heteroaryl groups wherein one ring does not contain a heteroatom (e.g., indolyl, quinolinyl, and the like) , the point of attachment can be on either ring, i.e., either the ring bearing a heteroatom (e.g., 2–indolyl) or the ring that does not contain a heteroatom (e.g., 5–indolyl) . As used herein, the term "heteroarylene" as used by itself or as part of another group refers to a divalent radical derived from the heteroaryl group defined herein.

Exemplary 5–membered heteroaryl groups containing one heteroatom include, without limitation, pyrrolyl, furanyl, and thiophenyl. Exemplary 5–membered heteroaryl groups containing two heteroatoms include, without limitation, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, and isothiazolyl. Exemplary 5–membered heteroaryl groups containing three heteroatoms include, without limitation, triazolyl, oxadiazolyl, and thiadiazolyl. Exemplary 5–membered heteroaryl groups containing four heteroatoms include, without limitation, tetrazolyl. Exemplary 6–membered heteroaryl groups containing one heteroatom include, without limitation, pyridinyl. Exemplary 6–membered heteroaryl groups containing two heteroatoms include, without limitation, pyridazinyl, pyrimidinyl, and pyrazinyl. Exemplary 6–membered heteroaryl groups containing three or four heteroatoms include, without limitation, triazinyl and tetrazinyl, respectively. Exemplary 7–membered heteroaryl groups containing one heteroatom include, without limitation, azepinyl, oxepinyl, and thiepinyl. Exemplary 5, 6–bicyclic heteroaryl groups include, without limitation, indolyl, isoindolyl, indazolyl, benzotriazolyl, benzothiophenyl, isobenzothiophenyl, benzofuranyl, benzoisofuranyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzoxadiazolyl, benzthiazolyl, benzisothiazolyl, benzthiadiazolyl, indolizinyl, and purinyl. Exemplary 6, 6–bicyclic heteroaryl groups include, without limitation, naphthyridinyl, pteridinyl, quinolinyl, isoquinolinyl, cinnolinyl, quinoxalinyl, phthalazinyl, and quinazolinyl.

“Heteroaralkyl” as used by itself or as part of another group refers to an alkyl substituted with one or more heteroaryl groups, preferably, substituted with one heteroaryl group. When a heteroaralkyl is said to be optionally substituted, either the alkyl portion or the heteroaryl portion of the heteroaralkyl can be optionally substituted.

An “optionally substituted” group, such as an optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl groups, refers to the respective group that is unsubstituted or substituted. In general, the term “substituted” , whether preceded by the term “optionally” or not, means that at least one hydrogen present on a group (e.g., a carbon or nitrogen atom) is replaced with a permissible substituent, e.g., a substituent which upon substitution results in a stable compound, e.g., a compound which does not spontaneously undergo transformation such as by rearrangement, cyclization, elimination, or other reaction. Unless otherwise indicated, a “substituted” group has a substituent at one or more substitutable positions of the group, and when more than one position in any given structure is substituted, the substituent can be the same or different at each position. Typically, when substituted, the optionally substituted groups herein can be substituted with 1-5 substituents. Substituents can be a carbon atom substituent, a nitrogen atom substituent, an oxygen atom substituent or a sulfur atom substituent, as applicable. Two of the optional substituents can join to form an optionally substituted cycloalkyl, heterocylyl, aryl, or heteroaryl ring. Substitution can occur on any available carbon, oxygen, or nitrogen atom, and can form a spirocycle. Typically, substitution herein does not result in an O-O, O-N, S-S, S-N (except SO ₂-N bond) , heteroatom-halogen, or -C (O) -S bond or three or more consecutive heteroatoms, with the exception of O-SO ₂-O, O-SO ₂-N, and N-SO ₂-N, except that some of such bonds or connections may be allowed if in a stable aromatic system.

In a broad aspect, the permissible substituents herein for use in connection with Formula I, II, III, or IV include acyclic and cyclic, branched and unbranched, carbocyclic and heterocyclic, aromatic and non-aromatic substituents of organic compounds. The permissible substituents for use in connection with Formula I, II, III, or IV can be one or more and the same or different for appropriate organic compounds. For purposes of this disclosure, the heteroatoms such as nitrogen may have hydrogen substituents and/or any permissible substituents of organic compounds described herein which satisfy the valences of the heteroatoms. Substituents can include any substituents described herein, for example, a halogen, a hydroxyl, a carbonyl (such as a carboxyl, an alkoxycarbonyl, a formyl, or an acyl) , a thiocarbonyl (such as a thioester, a thioacetate, or a thioformate) , an alkoxy, a cycloalkoxy, a phosphoryl, a phosphate, a phosphonate, a phosphinate, an amino, an amido, an amidine, an imine, a cyano, a nitro, an azido, a sulfhydryl, an alkylthio, a sulfate, a sulfonate, a sulfamoyl, a sulfonamido, a sulfonyl, a heterocyclyl, an aralkyl, an aryl, or a heteroaryl, each of which can be substituted, if appropriate.

Exemplary substituents suitable for use in connection with Formula I, II, III, or IV include, but not limited to, alkyl, alkenyl, alkynyl, aryl, heteroaryl, -alkylene-aryl, -arylene-alkyl, -alkylene-heteroaryl, -alkenylene-heteroaryl, -alkynylene-heteroaryl, -OH, hydroxyalkyl, haloalkyl, -O-alkyl, -O-haloalkyl, -alkylene-O-alkyl, -O-aryl, -O-alkylene-aryl, acyl, -C (O) -aryl, halo, -NO ₂, -CN, -SF ₅, -C (O) OH, -C (O) O-alkyl, -C (O) O-aryl, -C (O) O-alkylene-aryl, -S (O) -alkyl, -S (O) ₂-alkyl, -S (O) -aryl, -S (O) ₂-aryl, -S (O) -heteroaryl, -S (O) ₂-heteroaryl, -S-alkyl, -S-aryl, -S-heteroaryl, -S-alkylene-aryl, -S-alkylene-heteroaryl, -S (O) ₂-alkylene-aryl, -S (O) ₂-alkylene-heteroaryl, cycloalkyl, heterocycloalkyl, -O-C (O) -alkyl, -O-C (O) -aryl, -O-C (O) -cycloalkyl, -C (═N-CN) -NH ₂, -C (═NH) -NH ₂, -C (═NH) -NH (alkyl) , -N (Y ₁) (Y ₂) , -alkylene-N (Y ₁) (Y ₂) , -C (O) N (Y ₁) (Y ₂) and -S (O) ₂N (Y ₁) (Y ₂) , wherein Y ₁ and Y ₂ can be the same or different and are independently selected from the group consisting of hydrogen, alkyl, aryl, cycloalkyl, and -alkylene-aryl.

Some examples of suitable substituents for use in connection with Formula I, II, III, or IV include, but not limited to, (C ₁-C ₈) alkyl groups, (C ₂-C ₈) alkenyl groups, (C ₂-C ₈) alkynyl groups, (C ₃-C ₁₀) cycloalkyl groups, halogen (F, Cl, Br or I) , halogenated (C ₁-C ₈) alkyl groups (for example but not limited to -CF ₃) , -O- (C ₁-C ₈) alkyl groups, -OH, -S- (C ₁-C ₈) alkyl groups, -SH, -NH (C ₁-C ₈) alkyl groups, -N ( (C ₁-C ₈) alkyl) ₂ groups, -NH ₂, -C (O) NH ₂, -C (O) NH (C ₁-C ₈) alkyl groups, -C (O) N ( (C ₁-C ₈) alkyl) ₂, -NHC (O) H, -NHC (O) (C ₁-C ₈) alkyl groups, -NHC (O) (C ₃-C ₈) cycloalkyl groups, -N ( (C ₁-C ₈) alkyl) C (O) H, -N ( (C ₁-C ₈) alkyl) C (O) (C ₁-C ₈) alkyl groups, -NHC (O) NH ₂, -NHC (O) NH (C ₁-C ₈) alkyl groups, -N ( (C ₁-C ₈) alkyl) C (O) NH ₂ groups, -NHC (O) N ( (C ₁-C ₈) alkyl) ₂ groups, -N ( (C ₁-C ₈) alkyl) C (O) N ( (C ₁-C ₈) alkyl) ₂ groups, -N ( (C ₁-C ₈) alkyl) C (O) NH ( (C ₁-C ₈) alkyl) , -C (O) H, -C (O) (C ₁-C ₈) alkyl groups, -CN, -NO ₂, -S (O) (C ₁-C ₈) alkyl groups, -S (O) ₂ (C ₁-C ₈) alkyl groups, -S (O) ₂N ( (C ₁-C ₈) alkyl) ₂ groups, - S (O) ₂NH (C ₁-C ₈) alkyl groups, -S (O) ₂NH (C ₃-C ₈) cycloalkyl groups, -S (O) ₂NH ₂ groups, -NHS (O) ₂ (C ₁-C ₈) alkyl groups, -N ( (C ₁-C ₈) alkyl) S (O) ₂ (C ₁-C ₈) alkyl groups, - (C ₁-C ₈) alkyl-O- (C ₁-C ₈) alkyl groups, -O- (C ₁-C ₈) alkyl-O- (C ₁-C ₈) alkyl groups, -C (O) OH, -C (O) O (C ₁-C ₈) alkyl groups, NHOH, NHO (C ₁-C ₈) alkyl groups, -O-halogenated (C ₁-C ₈) alkyl groups (for example but not limited to -OCF ₃) , -S (O) ₂-halogenated (C ₁-C ₈) alkyl groups (for example but not limited to -S (O) ₂CF ₃) , -S-halogenated (C ₁-C ₈) alkyl groups (for example but not limited to -SCF ₃) , - (C ₁-C ₆) heterocycle (for example but not limited to pyrrolidine, tetrahydrofuran, pyran or morpholine) , - (C ₁-C ₆) heteroaryl (for example but not limited to tetrazole, imidazole, furan, pyrazine or pyrazole) , -phenyl, -NHC (O) O- (C ₁-C ₆) alkyl groups, -N ( (C ₁-C ₆) alkyl) C (O) O- (C ₁-C ₆) alkyl groups, -C (═NH) - (C ₁-C ₆) alkyl groups, -C (═NOH) - (C ₁-C ₆) alkyl groups, or -C (═N-O- (C ₁-C ₆) alkyl) - (C ₁-C ₆) alkyl groups.

Exemplary carbon atom substituents suitable for use in connection with Formula I, II, III, or IV include, but are not limited to, halogen, –CN, –NO ₂, –N ₃, hydroxyl, alkoxy, cycloalkoxy, aryloxy, amino, monoalkyl amino, dialkyl amino, amide, sulfonamide, thiol, acyl, carboxylic acid, ester, sulfone, sulfoxide, alkyl, haloalkyl, alkenyl, alkynyl, C _3–10 carbocyclyl, C _6–10 aryl, 3–10 membered heterocyclyl, 5–10 membered heteroaryl, etc. For example, exemplary carbon atom substituents can include F, Cl, -CN, –SO ₂H, –SO ₃H, –OH, –OC _1–6 alkyl, –NH ₂, –N (C _1–6 alkyl) ₂, –NH (C _1–6 alkyl) , –SH, –SC _1–6 alkyl, –C (=O) (C _1–6 alkyl) , –CO ₂H, –CO ₂ (C _1–6 alkyl) , –OC (=O) (C _1–6 alkyl) , –OCO ₂ (C _1–6 alkyl) , –C (=O) NH ₂, –C (=O) N (C _1–6 alkyl) ₂, –OC (=O) NH (C _1–6 alkyl) , –NHC (=O) (C _1–6 alkyl) , –N (C _1–6 alkyl) C (=O) (C _1–6 alkyl) , –NHCO ₂ (C _1–6 alkyl) , –NHC (=O) N (C _1–6 alkyl) ₂, –NHC (=O) NH (C _1–6 alkyl) , –NHC (=O) NH ₂, –NHSO ₂ (C _1–6 alkyl) , –SO ₂N (C _1–6 alkyl) ₂, –SO ₂NH (C _1–6 alkyl) , –SO ₂NH ₂, –SO ₂C _1–6 alkyl, –SO ₂OC _1–6 alkyl, –OSO ₂C _1–6 alkyl, –SOC _1–6 alkyl, C _1–6 alkyl, C _1–6 haloalkyl, C _2–6 alkenyl, C _2–6 alkynyl, C _3–10 carbocyclyl, C _6–10 aryl, 3–10 membered heterocyclyl, 5–10 membered heteroaryl; or two geminal substituents can be joined to form =O.

Nitrogen atoms can be substituted or unsubstituted as valency permits, and include primary, secondary, tertiary, and quaternary nitrogen atoms. Exemplary nitrogen atom substituents suitable for use in connection with Formula I, II, III, or IV include, but are not limited to, hydrogen, acyl groups, esters, sulfone, sulfoxide, C _1–10 alkyl, C _1–10 haloalkyl, C _2– ₁₀ alkenyl, C _2–10 alkynyl, C _3–10 carbocyclyl, 3–14 membered heterocyclyl, C _6–14 aryl, and 5– 14 membered heteroaryl, or two substituent groups attached to a nitrogen atom are joined to form a 3–14 membered heterocyclyl or 5–14 membered heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl can be further substituted as defined herein. In certain embodiments, the substituent present on a nitrogen atom is a nitrogen protecting group (also referred to as an amino protecting group) . Nitrogen protecting groups are well known in the art and include those described in detail in Protective Groups in Organic Synthesis, T.W. Greene and P.G.M. Wuts, 3 ^rd edition, John Wiley &Sons, 1999, incorporated by reference herein. Exemplary nitrogen protecting groups include, but not limited to, those forming carbamates, such as Carbobenzyloxy (Cbz) group, p-Methoxybenzyl carbonyl (Moz or MeOZ) group, tert-Butyloxycarbonyl (BOC) group, Troc, 9-Fluorenylmethyloxycarbonyl (Fmoc) group, etc., those forming an amide, such as acetyl, benzoyl, etc., those forming a benzylic amine, such as benzyl, p-methoxybenzyl, 3, 4-dimethoxybenzyl, etc., those forming a sulfonamide, such as tosyl, Nosyl, etc., and others such as p-methoxyphenyl.

Exemplary oxygen atom substituents suitable for use in connection with Formula I, II, III, or IV include, but are not limited to, acyl groups, esters, sulfonates, C _1–10 alkyl, C _1– ₁₀ haloalkyl, C _2–10 alkenyl, C _2–10 alkynyl, C _3–10 carbocyclyl, 3–14 membered heterocyclyl, C _6–14 aryl, and 5–14 membered heteroaryl, wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl can be further substituted as defined herein. In certain embodiments, the oxygen atom substituent present on an oxygen atom is an oxygen protecting group (also referred to as a hydroxyl protecting group) . Oxygen protecting groups are well known in the art and include those described in detail in Protective Groups in Organic Synthesis, T.W. Greene and P.G.M. Wuts, 3 ^rd edition, John Wiley &Sons, 1999, incorporated herein by reference. Exemplary oxygen protecting groups include, but are not limited to, those forming alkyl ethers or substituted alkyl ethers, such as methyl, allyl, benzyl, substituted benzyls such as 4-methoxybenzyl, methoxylmethyl (MOM) , benzyloxymethyl (BOM) , 2–methoxyethoxymethyl (MEM) , etc., those forming silyl ethers, such as trymethylsilyl (TMS) , triethylsilyl (TES) , triisopropylsilyl (TIPS) , t-butyldimethylsilyl (TBDMS) , etc., those forming acetals or ketals, such as tetrahydropyranyl (THP) , those forming esters such as formate, acetate, chloroacetate, dichloroacetate, trichloroacetate, trifluoroacetate, methoxyacetate, etc., those forming carbonates or sulfonates such as methanesulfonate (mesylate) , benzylsulfonate, and tosylate (Ts) , etc.

Unless expressly stated to the contrary, combinations of substituents and/or variables are allowable only if such combinations are chemically allowed and result in a stable compound. A “stable” compound is a compound that can be prepared and isolated and whose structure and properties remain or can be caused to remain essentially unchanged for a period of time sufficient to allow use of the compound for the purposes described herein (e.g., therapeutic administration to a subject) .

In some embodiments, the “optionally substituted” alkyl, heteroalkyl, alkenyl, alkynyl, carbocyclic, cycloalkyl, alkoxy, cycloalkoxy, or heterocyclyl herein, e.g., referred to in connection with Formula I, II, III, or IV, can each be independently unsubstituted or substituted with 1, 2, 3, or 4 substituents independently selected from F, Cl, -OH, protected hydroxyl, oxo (as applicable) , NH ₂, protected amino, NH (C _1-4 alkyl) or a protected derivative thereof, N (C _1-4 alkyl ( (C _1-4 alkyl) , C _1-4 alkyl, C _2-4 alkenyl, C _2-4 alkynyl, C _1-4 alkoxy, C _3-6 cycloalkyl, C _3-6 cycloalkoxy, phenyl, 5 or 6 membered heteroaryl containing 1, 2, or 3 ring heteroatoms independently selected from O, S, and N, 3-7 membered heterocyclyl containing 1 or 2 ring heteroatoms independently selected from O, S, and N, wherein each of the alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, cycloalkoxy phenyl, heteroaryl, and heterocyclyl, is optionally substituted with 1, 2, or 3 substituents independently selected from F, -OH, oxo (as applicable) , C _1-4 alkyl, fluoro-substituted C _1-4 alkyl (e.g., CF ₃) , C _1-4 alkoxy and fluoro-substituted C _1-4 alkoxy. In some embodiments, the “optionally substituted” aryl, heteroaryl group herein, e.g., referred to in connection with Formula I, II, III, or IV, can each be independently unsubstituted or substituted with 1, 2, 3, or 4 substituents independently selected from F, Cl, -OH, -CN, NH ₂, protected amino, NH (C _1-4 alkyl) or a protected derivative thereof, N (C _1-4 alkyl ( (C _1-4 alkyl) , –S (=O) (C _1-4 alkyl) , –SO ₂ (C _1-4 alkyl) , C _1-4 alkyl, C _2-4 alkenyl, C _2-4 alkynyl, C _1-4 alkoxy, C _3-6 cycloalkyl, C _3-6 cycloalkoxy, phenyl, 5 or 6 membered heteroaryl containing 1, 2 or 3 ring heteroatoms independently selected from O, S, and N, 3-7 membered heterocyclyl containing 1 or 2 ring heteroatoms independently selected from O, S, and N, wherein each of the alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, cycloalkoxy, phenyl, heteroaryl, and heterocyclyl, is optionally substituted with 1, 2, or 3 substituents independently selected from F, -OH, oxo (as applicable) , C _1-4 alkyl, fluoro-substituted C _1-4 alkyl, C _1-4 alkoxy and fluoro-substituted C _1-4 alkoxy.

“Halo” or “halogen” refers to fluorine (fluoro, –F) , chlorine (chloro, –Cl) , bromine (bromo, –Br) , or iodine (iodo, –I) .

The term “pharmaceutically acceptable salt” refers to those salts which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response, and the like, and are commensurate with a reasonable benefit/risk ratio. Pharmaceutically acceptable salts are well known in the art.

The term “pharmaceutically acceptable ester or amide” refers to those esters or amides that can be formed from the corresponding acid (COOH) , which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response, and the like, and are commensurate with a reasonable benefit/risk ratio.

The term “tautomers” or “tautomeric” refers to two or more interconvertible compounds resulting from tautomerization. The exact ratio of the tautomers depends on several factors, including for example temperature, solvent, and pH. Tautomerizations are known to those skilled in the art. Exemplary tautomerizations include keto-to-enol, amide-to-imide, lactam-to-lactim, enamine-to-imine, and enamine-to- (a different enamine) tautomerizations.

The term “subject” (alternatively referred to herein as “patient” ) as used herein, refers to an animal, preferably a mammal, most preferably a human, who has been the object of treatment, observation or experiment.

As used herein, the terms "treat, " "treating, " "treatment, " and the like refer to eliminating, reducing, or ameliorating a disease or condition, and/or symptoms associated therewith. Although not precluded, treating a disease or condition does not require that the disease, condition, or symptoms associated therewith be completely eliminated. As used herein, the terms "treat, " "treating, " "treatment, " and the like may include "prophylactic treatment, " which refers to reducing the probability of redeveloping a disease or condition, or of a recurrence of a previously-controlled disease or condition, in a subject who does not have, but is at risk of or is susceptible to, redeveloping a disease or condition or a recurrence of the disease or condition. The term "treat" and synonyms contemplate administering a therapeutically effective amount of a compound described herein to a subject in need of such treatment.

The term "effective amount" or "therapeutically effective amount" refers to that amount of a compound or combination of compounds as described herein that is sufficient to effect the intended application including, but not limited to, prophylaxis or treatment of diseases. A therapeutically effective amount may vary depending upon the intended application (in vitro or in vivo) , or the subject and disease condition being treated (e.g., the weight, age and gender of the subject) , the severity of the disease condition, the manner of administration, etc. which can readily be determined by one of ordinary skill in the art. The term also applies to a dose that will induce a particular response in target cells and/or tissues. The specific dose will vary depending on the particular compounds chosen, the dosing regimen to be followed, whether the compound is administered in combination with other compounds, timing of administration, the tissue to which it is administered, and the physical delivery system in which the compound is carried.

As used herein, the singular form “a” , “an” , and “the” , includes plural references unless it is expressly stated or is unambiguously clear from the context that such is not intended.

The term “and/or” as used in a phrase such as “A and/or B” herein is intended to include both A and B; A or B; A (alone) ; and B (alone) . Likewise, the term “and/or” as used in a phrase such as “A, B, and/or C” is intended to encompass each of the following embodiments: A, B, and C; A, B, or C; A or C; A or B; B or C; A and C; A and B; B and C; A (alone) ; B (alone) ; and C (alone) .

Headings and subheadings are used for convenience and/or formal compliance only, do not limit the subject technology, and are not referred to in connection with the interpretation of the description of the subject technology. Features described under one heading or one subheading of the subject disclosure may be combined, in various embodiments, with features described under other headings or subheadings. Further it is not necessarily the case that all features under a single heading or a single subheading are used together in embodiments.

Examples

The various starting materials, intermediates, and compounds of the preferred embodiments can be isolated and purified where appropriate using conventional techniques such as precipitation, filtration, crystallization, evaporation, distillation, and chromatography. Characterization of these compounds can be performed using conventional methods such as by melting point, mass spectrum, nuclear magnetic resonance, and various other spectroscopic analyses. Exemplary embodiments of steps for performing the synthesis of products described herein are described in greater detail infra.

Example 1. Synthesis of 2-methyl-4- (2- ( (6- (methylamino) pyridin-2-yl) amino) thiazol-4-yl) benzoic acid (Compound 1) and n-butyl 2-methyl-4- (2- ( (6- (methylamino) pyridin-2-yl) amino) thiazol-4-yl) benzoate (Compound 21) .

Step 1: To a solution of butyl 4-acetyl-2-methylbenzoate 1-1 (10 g, 42.7 mmol) was in CHCl ₃ 150 mL, was slowly added Br ₂ (6.8 g, 42.7mmol) in 50mL CHCl ₃ at 0℃. After the dropwise process was finished, the solution was allowed warm to room temperature stirred for another 2 hours. The reaction was monitored by the LCMS and TLC, after the reaction, the mixture was concentrated in vacuo, then added water100 mL, the pH was adjust with NaHCO ₃ to 7-8. Extracted with EtOAc (3 *150 mL) for 3 times. The combined organic phase was dried over by Na ₂SO ₄ and evaporated in vacuo to dryness. The crude product was purified by the column chromatography (EtOAc: PE=1: 20) and get the title compound 1-2 (12 g, 90%yield) as a yellow oil. MS (ESI) m/z: 313.0, 315.0 (M+H) ⁺.

Step 2: A solution of butyl 4- (2-bromoacetyl) -2-methylbenzoate 1-2 (12 g, 38.3 mmol) and 1- (pyridin-2-yl) thiourea (2.91 g, 38.3 mmol) in EtOH (100 mL) was stirred overnight at reflux. After the reaction, the mixture was cooled to room temperature and filtered to give 1-3 (10 g, 90.9%yield) as a yellow solid. MS (ESI) m/z: 291 (M+H) ⁺.

Step 3: To a solution of butyl 4- (2-aminothiazol-4-yl) -2-methylbenzoate 1-3 (4.0 g, 13.7 mmol) and 6-bromo-N-methylpyridin-2-amine (2.5 g, 13.7 mmol) in dioxane (100 mL) was added Cs ₂CO ₃ (13.3 g, 41.1 mmol) , Xantphos (100 mg, 0.16 mmol) and Pd ₂ (dba) ₃ (72 mg, 0.078 mmol) . The mixture was stirred at 90 ℃ for 8 h under Ar gas. When it completed by the LC-MS, the solution was diluted with EA (200 mL) , filtrated, the organic phase was washed with H ₂O (100 mL) and dried by Na ₂SO ₄. The combined organic phase was dried over Na ₂SO ₄, evaporated in vacuo to dryness. The mixture was purified by column chromatography (DCM: MeOH=20: 1) to give the title compound 21 (1.7 g, 31%yield) . MS (ESI) m/z: 397.1 (M+H) ⁺. ¹H NMR (400 MHz, DMSO) δ 11.16 (s, 1H) , 7.95 –7.74 (m, 3H) , 7.56 (s, 1H) , 7.32 (t, J = 7.4 Hz, 1H) , 6.17 (d, J = 7.6 Hz, 1H) , 6.02 (d, J = 8.0 Hz, 1H) , 4.62 (s, 1H) , 4.26 (t, J = 6.5 Hz, 2H) , 2.96 (s, 3H) , 2.58 (s, 3H) , 1.79 –1.60 (m, 2H) , 1.44 (dd, J = 15.0, 7.6 Hz, 2H) , 0.95 (t, J = 7.4 Hz, 3H) .

Step 4: To a solution of butyl 2-methyl-4- (2- ( (6- (methylamino) pyridin-2-yl) amino) thiazol-4-yl) benzoate, Compound 21 (1.7 g, 4.2 mmol) in THF/H ₂O (40 mL/10 mL) was added KOH (1.2 g, 21.4 mmol) . The mixture was stirred at 60℃ over night, When it completed by the LC-MS, the solution was concentrated in vacuo, then the pH was adjust with 6M HCl to 4-5 and filtration the solution, the filter cake was wash with water, and the filter cake was drying under reduced pressure to get product Compound 1 (370 mg, 57.74%yield) . MS (ESI) m/z: 341.2 (M+H) ⁺. ¹H NMR (400 MHz, DMSO) δ 11.17 (s, 1H) , 8.00 –7.76 (m, 3H) , 7.54 (s, 1H) , 7.32 (s, 1H) , 6.18 (d, J = 7.0 Hz, 1H) , 6.03 (s, 1H) , 2.96 (s, 3H) , 2.58 (s, 3H) .

Example 2. Synthesis of methyl 4- (2- (6- (methylamino) pyridin-2-ylamino) thiazol-4-yl) -2-methylbenzoate (Compound 2) .

To a solution of 2-methyl-4- (2- ( (6- (methylamino) pyridin-2-yl) amino) thiazol-4-yl) benzoic acid, Compound 1 (600 mg, 1.76 mmol) in MeOH (40 mL) was added SOCl ₂ (624 mg, 5.29 mmol) . The mixture was stirred at 50℃ overnight under N ₂. When it completed by the LC-MS, the solution was concentrated in vacuo, then the mixture was quenched with NaHCO ₃ (aq) to pH to 7-8 and filtration the solution, the filter cake was wash with water, and the filter cake was drying under reduced pressure to get product Compound 2 (410 mg, 65.8%yield) . MS (ESI) m/z: 355.1 (M+H) ⁺.

Example 3. Synthesis of methyl 2-methyl-4- (2- (pyridin-2-ylamino) thiazol-4-yl) benzoate (Compound 3) .

Step 1: To a solution of 4-bromothiazol-2-amine 3-1 (4.0 g, 22.35 mmol) was added in THF (100 mL) , Then added Boc ₂O (9.7 g, 44.69 mmol) , DMAP (1.3 g, 11.17 mmol) and dropwise DIEA (8.6 g, 67.05 mmol) . The mixture was stirred at 60℃ and overnight, When it completed by the LC-MS, then H ₂O 100mL was added and extracted with EtOAc (3 *150 mL) for 3 times. The combine organic phase was dried over Na ₂SO ₄, evaporated in vacuo to dryness. The purified by the column chromatography (PE: EtOAc=15: 1) and get the title compound 3-2 (3.3 g, 52.97%yield) as a white solid. MS (ESI) m/z: 281.0 (M+H) ⁺.

¹HNMR (400 MHz, DMSO) : δ 11.77 (s, 1H) , 7.24 (s, 1H) , 1.49 (s, 9H) .

Step 2: To a solution of tert-butyl (4-bromothiazol-2-yl) carbamate 3-2 (2.0 g, 7.17 mmol) and methyl 2-methyl-4- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) benzoate 3-3 (2.3 g, 8.60 mmol) were added in Dioxane/H ₂O (20/4 mL) , Then added CsF (2.1 g, 14.34 mmol) , A-TAPHOS (510 mg, 0.72 mmol) . The mixture was stirred at 100 ℃ of microwave and use Ar ₂ gas to protect for 3h, When it completed by the LC-MS, then H ₂O 150 mL was added and extracted with EtOAc (3 *150 mL) for 3 times. The combine organic phase was dried over Na ₂SO ₄, evaporated in vacuo to dryness. The purified by the column chromatography (PE: EtOAc=15: 1) and get the title compound 3-4 (2.0 g, 80.17%yield) as a Yellow solid. MS (ESI) m/z: 349.1 (M+H) ⁺.

¹HNMR (400 MHz, CDCl3) : δ 9.03 (s, 1H) , 7.96 (d, J=8.4Hz, 1H) , 7.71-7.68 (m, 2H) , 7.21 (s, 1H) , 3.90 (s, 3H) , 2.65 (s, 3H) , 1.47 (s, 9H) .

Step 3: To a solution of methyl 4- (2- ( (tert-butoxycarbonyl) amino) thiazol-4-yl) -2-methylbenzoate 3-4 (2.0 g, 5.75 mmol) was added in MeOH (10 mL) , Then added HCl/Dioxane 4 mol/L (10 mL) . The mixture was stirred at room temperature over night, When it completed by the LC-MS, the solution was concentrated in vacuo, then H ₂O 50 mL was added, the pH was adjust with NaHCO ₃ to 7-8 and extracted with CH ₂Cl ₂ (3 *100 mL) for 3 times. The combine organic phase was dried over Na ₂SO ₄, evaporated in vacuo to dryness and get crude the title compound 3-5 1.3 g as a Yellow solid. MS (ESI) m/z: 249.1 (M+H) ⁺.

¹HNMR (400 MHz, CDCl ₃) : δ 7.94 (d, J=8.0Hz, 1H) , 7.68 (s, 1H) , 7.62 (d, J=8.0Hz, 1H) , 6.85 (s, 1H) , 5.01 (s, 2H) , 3.89 (s, 3H) , 2.64 (s, 3H) .

Step 4: To a solution of methyl 4- (2-aminothiazol-4-yl) -2-methylbenzoate 3-5 (200 mg, 0.81 mmol) and 2-bromopyridine (128 mg, 0.81 mmol) were added in Dioxane (20 mL) , Then added Cs ₂CO ₃ (792 mg, 2.43 mmol) , Xantphos (140 mg, 0.24 mmol) and Pd ₂ (dba) ₃ (74 mg, 0.08 mmol) . The mixture was stirred at 110℃ and use Ar ₂ gas to protect for 5h, When it completed by the LC-MS, the solution was concentrated in vacuo, then H ₂O 50mL was added and extracted with CH ₂Cl ₂: MeOH=20: 1 (3 *100 mL) for 3 times. The combine organic phase was dried over Na ₂SO ₄, evaporated in vacuo to dryness. The purified by the column chromatography (CH ₂Cl ₂: MeOH=15: 1) and get the title compound 3 (118 mg, 45.0%yield) .

MS (ESI) m/z: 326.1 (M+H) ⁺

¹HNMR (400 MHz, DMSO) : δ 11.66 (s, 1H) , 8.36-8.35 (m, 1H) , 7.92-7.90 (m, 2H) , 8.87-7.85 (m, 1H) , 7.82-7.78 (m, 1H) , 7.66 (s, 1H) , 7.16 (d, J = 8.0 Hz, 1H) , 7.02-6.99 (m, 1H) , 3.86 (s, 3H) , 2.60 (s, 3H) .

Example 4. Synthesis of 2-methyl-4- (2- (pyridin-2-ylamino) thiazol-4-yl) benzoic acid (Compound 4) .

Step 1: To a solution of methyl 2-methyl-4- (2- (pyridin-2-ylamino) thiazol-4-yl) benzoate Compound 3 (23 g, 70.76 mmol) was added in THF 400 mL and water 100 mL, Then added LiOH. H ₂O (5.94 g, 141.54 mmol) and NaOH (5.66 g, 141.54 mmol) . The mixture was stirred at 55℃ over night, When it completed by the LC-MS, the solution was concentrated in vacuo, then the pH was adjust with 2mol/L HCl to 4-5 and filtration the solution , the filter cake was wash with water and EtOAc, and the filter cake was drying under reduced pressure to get product 4 (17 g, 77.27%yield) . MS (ESI) m/z: 312.1 (M+H) ⁺

¹HNMR (400 MHz, DMSO) : δ11.43 (s, 1H) , 8.31 (d, J=4.8Hz, 1H) , 7.72-7.68 (t, J=7.6Hz, 2H) , 7.64 (s, 2H) , 7.39 (s, 1H) , 7.09 (d, J=8.0Hz, 1H) , 6.94-6.91 (t, J=6.0Hz, 1H) , 2.51 (s, 3H) .

Example 5. Synthesis of 4- (2- ( (6-aminopyridin-2-yl) amino) thiazol-4-yl) -2-methylbenzoic acid (Compound 5) .

Compound 5 was prepared by following similar procedure described in Example 1. MS (ESI) m/z: 327.0 (M+H) ⁺. ¹HNMR (400 MHz, DMSO) : δ11.50 (s, 1H) , 7.91-7.83 (m, 3H) , 7.70 (s, 1H) , 7.63-7.60 (m, 1H) , 6.54 (d, J=5.6Hz, 1H) , 6.30 (d, J=7.2Hz, 1H) , 2.59 (s, 3H) .

Example 6. Synthesis of 4- (2- ( (6-cyanopyridin-2-yl) amino) thiazol-4-yl) -2-methylbenzoic acid (Compound 6) .

Compound 6 was prepared by following similar procedure described in Example 1.MS (ESI) m/z: 337.4 (M+H) ⁺. ¹H NMR (400 MHz, DMSO) δ 11.95 (s, 1H) , 7.96 –7.79 (m, 4H) , 7.72 (s, 1H) , 7.59 (dd, J = 7.2, 0.6 Hz, 1H) , 7.39 (d, J = 8.2 Hz, 1H) , 2.59 (s, 3H) .

Example 7. Synthesis of 2-methyl-4- (2- ( (6- (trifluoromethyl) pyridin-2-yl) amino) thiazol-4-yl) benzoic acid (Compound 7) .

Compound 7 was prepared by following similar procedure described in Example 1. MS (ESI) m/z: 380.0 (M+H) ⁺. ¹HNMR (400 MHz, DMSO) : δ12.78 (s, 1H) , 11.92 (s, 1H) , 7.99-7.80 (m, 4H) , 7.70 (s, 1H) , 7.42 (d, J=7.2Hz, 1H) , 7.35 (d, J=8.8Hz, 1H) , 2.59 (s, 3H) .

Example 8. Synthesis of 4- (2- ( (6-fluoropyridin-2-yl) amino) thiazol-4-yl) -2-methylbenzoic acid (Compound 8) .

Compound 8 was prepared by following similar procedure described in Example 1.MS (ESI) m/z: 330.0 (M+H) ⁺. ¹HNMR (400 MHz, DMSO) : δ12.76 (s, 1H) , 11.74 (s, 1H) , 7.91-7.80 (m, 4H) , 7.67 (s, 1H) , 7.02 (d, J=7.6Hz, 1H) , 6.65 (d, J=7.2Hz, 1H) , 2.59 (s, 3H) .

Example 9. Synthesis of 2-methyl-4- (2- (pyrazin-2-ylamino) thiazol-4-yl) benzoic acid (Compound 9) .

Compound 9 was prepared by following similar procedure described in Example 1. MS (ESI) m/z: 312.9 (M+H) ⁺. ¹HNMR (400 MHz, DMSO) : δ11.97 (s, 1H) , 8.52 (s, 1H) , 8.34 (s, 1H) , 8.15 (d, J=2.0Hz, 1H) , 7.92-7.82 (m, 3H) , 7.71 (s, 1H) , 2.60 (s, 3H) .

Example 10. Synthesis of 2-methyl-4- (2- (pyrimidin-4-ylamino) thiazol-4-yl) benzoic acid (Compound 10) .

Compound 10 was prepared by following similar procedure described in Example 1. MS (ESI) m/z: 313.1 (M+H) ⁺. ¹HNMR (400 MHz, DMSO) : δ11.97 (s, 1H) , 8.86 (s, 1H) , 8.47 (s, 1H) , 7.92-7.78 (m, 4H) , 7.10 (d, J=5.6Hz, 1H) , 2.59 (s, 3H) .

Example 11. Synthesis of 4- (2- ( (6- (methylamino) pyridin-2-yl) amino) thiazol-4-yl) benzoic acid (Compound 11) .

Step 1: To a solution of 6-bromopyridin-2-amine 11-1 (300 mg, 1.73 mmol) in DMF (5 mL) was added NaH (104 mg, 4.33 mmol) . The mixture was stirred at 0 ℃ for 30 minutes under the N ₂. Then was added CH3I (369 mg, 2.60 mmol) , the mixture was stirred at rt for 12 hours under the N2. LCMS showed completion of the reaction, then H2O (10 mL) was added and extracted with EtOAc (3 *50 mL) . The combined organic phase was dried over Na ₂SO ₄ and evaporated in vacuo to dryness. The crude was purified by the column chromatography (PE: EtOAc =5: 1) to give the title compound 11-2 (90 mg, 27.8%yield) as a brown solid. MS (ESI) m/z: 187.0, 189.0 (M+H) ⁺.

Step 2: To a solution of methyl 4- (2-aminothiazol-4-yl) benzoate 11-3 (91 mg, 0.39 mmol) and 6-bromo-N-methylpyridin-2-amine 11-2 (86 mg, 0.46 mmol) in dioxane (10 mL) was added Cs ₂CO ₃ (381 mg, 1.17 mmol) , Xantphos (45 mg, 0.078 mmol) and Pd ₂ (dba) ₃ (36 mg, 0.039 mmol) . The mixture was stirred at 90 ℃ for 2 h under Ar gas. When it completed by the LC-MS, the solution was concentrated in vacuo, diluted with H ₂O (30 mL) and extracted with CH ₂Cl ₂: MeOH=20: 1 (3 *50 mL) for 3 times. The combined organic phase was dried over Na ₂SO ₄, evaporated in vacuo to dryness. The mixture was purified by the pre-HPLC to give the compound 11-4 (120 mg, 73.3%yield) as a light yellow solid. MS (ESI) m/z: 341.0 (M+H) ⁺.

Step 3: To a solution of methyl 4- (2- ( (6- (methylamino) pyridin-2-yl) amino) thiazol-4-yl) benzoate 11-4 (163 mg, 0.48 mmol) in THF (12 mL) and H2O (4 mL) were added LiOH. H2O (200 mg, 4.76 mmol) . The mixture was stirred at 45℃ for 12 hours under the N2. LCMS showed completion of the reaction, the mixture was concentrated under reduced pressure to remove the THF, then was added H2O (5 mL) , and HCl (2 N, 2.5 mL) to adjust pH to 6-7, after filtration and dryness to give 11 (75 mg, 65.2%yield) . MS (ESI) m/z: 326.9 (M+H) ⁺. ¹HNMR (400 MHz, DMSO) : δ8.02-7.97 (m, 4H) , 7.59 (s, 1H) , 7.49 (s, 1H) , 7.35 (s, 1H) , 6.21 (t, J = 3.2 Hz, 1H) , 6.05 (t, J = 4.0 Hz, 1H) , 2.96 (s, 3H) .

Example 12. Synthesis of ethyl 2-methyl-4- (2- (pyridin-2-ylamino) thiazol-4-yl) benzoate (Compound 12) .

Compound 12 was prepared by following similar procedures herein.

Example 13. Synthesis of (2-methyl-4- (2- ( (6-methylpyridin-2-yl) amino) thiazol-4-yl) phenyl) (morpholino) methanone (Compound 13) .

Step 1: To a solution of 2-methyl-4- (2- ( (6-methylpyridin-2-yl) amino) thiazol-4-yl) benzoic acid 15 (105 mg, 0.32 mmol) and morpholine (35 mg, 0.38 mmol) were added in DMF (10 mL) , Then added HATU (188 mg, 0.48 mmol) and Et3N (81 mg, 0.80 mmol) . The mixture was stirred at 25℃ for 2h. When it completed by the LC-MS, the solution was concentrated in vacuo, then H ₂O (10 mL) was added and extracted with EtOAc (3 *30 mL) . The combine organic phase was dried over Na ₂SO ₄, evaporated in vacuo to dryness. The crude product was purified by the prep-HPLC and get product 13 (55 mg, 76.8%yield) .

MS (ESI) m/z: 395.1 (M+H) ⁺

¹HNMR (400 MHz, DMSO) : δ11.60 (s, 1H) , 7.83 (s, 1H) , 7.77 (d, J =7.6 Hz, 1H) , 7.66 (dd, J 1= 7.6 Hz, J 2= 8.0 Hz, 1H) , 7.50 (s, 1H) , 7.23 (d, J =7.6 Hz, 1H) , 6.95 (d, J =8.0 Hz, 1H) , 6.84 (d, J =7.2 Hz, 1H) , 3.66 (s, 4H) , 3.52 (s, 2H) , 3.18 (s, 2H) , 2.50 (s, 3H) , 2.28 (s, 3H)

Example 14. Synthesis of 4- (2- ( (6-methylpyridin-2-yl) amino) thiazol-4-yl) benzoic acid (Compound 14) .

Step 1: To a solution of methyl 4- (2-aminothiazol-4-yl) benzoate (150 mg, 0.64 mmol) and 2-bromo-6-methylpyridine (110mg, 0.64 mmol) in dioxane (10 mL) Then was added Cs ₂CO ₃ (417 mg, 1.28mmol) , Xantphos (111 mg, 0.192 mmol) and Pd ₂ (dba) ₃ (59 mg, 0.064 mmol) . The mixture was stirred at 95 ℃ under Ar ₂ gas for 7h. When it completed by the LC-MS, the solution was concentrated in vacuo, diluted with H ₂O 50 mL and extracted with EtOAc (3 *50 mL) for 3 times. The combined organic phase was dried over Na ₂SO ₄, evaporated in vacuo to dryness. The mixture was purified by the column chromatography (EtOAc: PE=1: 1) to give the title compound 14-1 (200mg, 96.01%yield) as a yellow solid. MS (ESI) m/z: 326.1 (M+H) ⁺.

Step 2: To a solution of methyl 4- (2- ( (6-methylpyridin-2-yl) amino) thiazol-4-yl) benzoate 14-1 (200 mg, 0.62 mmol) was added in THF (20 mL) and water (5 mL) . Then added LiOH. H ₂O (78 mg, 1.85 mmol) and NaOH (74 mg, 1.85 mmol) . The mixture was stirred at 60℃ over night, When it completed by the LC-MS, the solution was concentrated in vacuo , then the pH was adjust with 2mol/L HCl to 4-5 and filtration the solution , the filter cake was wash with water and EtOAc, and the filter cake was drying under reduced pressure to get product 14 (130 mg, 67.92%yield) . MS (ESI) m/z: 312.0 (M+H) ⁺.

¹HNMR (400 MHz, DMSO) : δ 11.48 (s, 1H) , 8.04-7.98 (m, 4H) , 7.64-7.60 (m, 2H) , 6.91 (d, J=4.4Hz, 1H) , 6.81 (d, J=7.6Hz, 1H) , 2.48 (s, 3H) .

Example 15. Synthesis of 2-methyl-4- (2- ( (6-methylpyridin-2-yl) amino) thiazol-4-yl) benzoic acid (Compound 15) and methyl 2-methyl-4- (2- ( (6-methylpyridin-2-yl) amino) thiazol-4-yl) benzoate (Compound 16) .

To a solution of methyl 4- (2-bromothiazol-4-yl) -2-methylbenzoate 15-1 (396mg, 1.27 mmol) and 6-methylpyridin-2-amine (45mg, 0.42mmol) were added in dioxane (10 mL) , Then was added Cs ₂CO ₃ (411 mg, 1.26mmol) , Xantphos (73 mg, 0.126 mmol) and Pd ₂ (dba) ₃ (38mg, 0.042 mmol) . The mixture was stirred at 95 ℃ for 4h under Ar ₂ gas protect. When it completed by the LC-MS, the solution was concentrated in vacuo, added H ₂O 50 mL and extracted with CH ₂Cl ₂: MeOH=20: 1 (3 *80 mL) for 3 times. The combined organic phase was dried over Na ₂SO ₄, evaporated in vacuo to dryness. The purified by column chromagraphy CH ₂Cl ₂: MeOH=15: 1 get the title compound 16 (110 mg) . MS (ESI) m/z: 340.2 (M+H) ⁺.

Step 2: To a solution of methyl 2-methyl-4- (2- ( (6-methylpyridin-2-yl) amino) thiazol-4-yl) benzoate 16 (110 mg, 0.32mmol) was added in THF 10 mL and water 3 mL, Then added LiOH. H ₂O (68 mg, 1.60 mmol) and NaOH (65 mg, 1.60 mmol) . The mixture was stirred at 60℃ over night, When it completed by the LC-MS, the solution was concentrated in vacuo, then the pH was adjust with 2mol/L HCl to 4-5 and filtration the solution , the filter cake was wash with water and EtOAc, and the filter cake was drying under reduced pressure to get product 15 (60 mg, 56.89%yield) . MS (ESI) m/z: 326.1 (M+H) ⁺, ¹HNMR (400 MHz, DMSO) : δ11.40 (s, 1H) , 7.89-7.79 (m, 3H) , 7.60-7.57 (m, 2H) , 6.88 (d, J=8.0Hz, 1H) , 6.80 (d, J=6.0Hz, 1H) , 2.58 (s, 3H) , 2.48 (s, 3H) .

Example 16. Synthesis of n-butyl 2-methyl-4- (2- ( (6-methylpyridin-2-yl) amino) thiazol-4-yl) benzoate (Compound 18) .

To a solution of 2-methyl-4- (2- ( (6-methylpyridin-2-yl) amino) thiazol-4-yl) benzoic acid (700 mg, 2.0 mmol) was added in butan-1-ol (10 mL) was added SOCl ₂ (2.0 mL) . The mixture was stirred at 100 ℃ under Ar ₂ protect for overnight. When it completed by the LC-MS, the solution was concentrated in vacuo, The mixture was purified by the pre-HPLC to give n-butyl 2-methyl-4- (2- ( (6-methylpyridin-2-yl) amino) thiazol-4-yl) benzoate (24 mg, 35.29%yield) . MS (ESI) m/z: 382.5 (M+H) ⁺. ¹H NMR (400 MHz, DMSO) δ 11.16 (s, 1H) , 7.95 –7.74 (m, 3H) , 7.56 (s, 1H) , 7.32 (t, J = 7.4 Hz, 1H) , 6.17 (d, J = 7.6 Hz, 1H) , 6.02 (d, J = 8.0 Hz, 1H) , 4.26 (t, J = 6.5 Hz, 2H) , 2.60 (s, 3H) , 2.58 (s, 3H) , 1.79 –1.60 (m, 2H) , 1.44 (dd, J = 15.0, 7.6 Hz, 2H) , 0.95 (t, J = 7.4 Hz, 3H) .

Example 17. Synthesis of isopropyl 2-methyl-4- (2- (pyridin-2-ylamino) thiazol-4-yl) benzoate (Compound 19) .

To a solution of 2-methyl-4- (2- (pyridin-2-ylamino) thiazol-4-yl) benzoic acid (80mg, 0.26mmol) was added in isopropanol (10 mL) Then was dropwise SOCl ₂and H ₂SO ₄ (0.2mL) . The mixture was stirred at 100 ℃ under Ar ₂ protect for overnight. When it completed by the LC-MS, the solution was concentrated in vacuo, The mixture was purified by the pre-HPLC to give isopropyl 2-methyl-4- (2- (pyridin-2-ylamino) thiazol-4-yl) benzoate (24 mg, 35.29%yield) . MS (ESI) m/z: 354.0 (M+H) ⁺. ¹HNMR (400 MHz, DMSO) : δ11.50 (s, 1H) , 8.32 (d, J=4.0Hz, 1H) , 7.87-7.82 (m, 3H) , 7.74-7.70 (m, 1H) , 7.61 (s, 1H) , 7.08 (d, J=8.0Hz, 1H) , 6.96-6.93 (m, 1H) , 5.16-5.10 (m, 1H) , 2.57 (s, 3H) , 1.33 (d, J=6.0Hz, 6H) .

Example 18. Synthesis of isopropyl 2-methyl-4- (2- (pyridin-2-ylamino) thiazol-4-yl) benzoate (Compound 20) .

To a solution of 2-methyl-4- (2- (pyridin-2-ylamino) thiazol-4-yl) benzoic acid (800 mg, 2.6 mmol) in DCM (30 mL) was added phenylboronic acid (320 mg, 2.6 mmol) CuOAc (320 mg, 2.6 mmol) and Prydine (616 mg, 7.8 mmol) at room temperature. Then the result reaction mixture was heated at 25 ℃ for 12 hours. After it completed monitored by the LC-MS, the solution was concentrated in vacuo. The residue was dissolved with EtOAc (30 mL) and washed with Sat. NaHCO ₃ solution. The combined organic phase was dried over Na ₂SO ₄, evaporated in vacuo to dryness. The mixture was purified by Prep-HPLC to give phenyl 2-methyl-4- (2- (pyridin-2-ylamino) thiazol-4-yl) benzoate hydrochloride (25 mg) . MS (ESI) m/z: 388.1 (M+H) ⁺. ¹HNMR (400 MHz, DMSO-D6) : δ8.46 (d, J=3.6 Hz, 1H) , 7.80-7.46 (m, 10 H) , 7.09 (m, 1H) , 6.57 (d, J=8.0Hz, 1H) , 2.54 (s, 3H) .

Biological Example 1. UCP1 Luciferase Assay: Evaluating compounds that induce Ucp1 up-regulation.

Ucp1-luciferase knock-in mice will be housed in cages and fed on standard chow diets (the detailed procedures please see reference 14) . The 8-week-old mice will be killed by the cervical dislocation and put into 75%alcohol for 5 minutes. The inguinal adipose tissue will be dissected out and transferred to the three 10-cm petri dishes and washed with PBS for three times. The adipose tissue will be dissected and minced on a 10-cm petri dish for several minutes and then pipetted into 20 ml 0.1%collagenase solution in 50ml conical tubes and digested at 37 ℃ for 1 hour. Next, 20 ml culture medium will be added to terminate the digestion and centrifuged for 10 minutes at 1000 rpm respectively. The supernatants will be removed and the pellets re-suspended in 10 mL culture medium and plated into 10-cm plates. The cells will be left to adhere to the plates overnight and the culture medium will be changed every other day. The confluent cells will be trypsinized, counted and plated to 24-well plate (5x10 ⁴cells/well) . The cells will be washed and re-fed the next day (as day -2) . Two days later (day 0) , the cells will usually become confluent and be induced to differentiate with MDIR medium. On day 2, the medium will be changed to IR medium and re-fed every 2 days. Complete differentiation is usually achieved by day 10. On day 10, the medium will be changed to the culture medium of 10%FBS/DMEM with indicated drugs along with the positive and negative controls for 2 days. The media will be removed and the cells washed with 1 ml PBS per well three times. Then 100μl lysis buffer will be used to lyse the cells at 4 ℃ for 1 hour. 30μl culture medium, 30μl cell lysates and 60μl

Reagent to a well of 96-well-plate and the luminescence will be measured using a luminometer. The protein concentration will be determined using 20μl cell lysates and specific activity of luciferase will be tabulated and data analyzed.

By following the above procedures, representative compounds were tested with the results shown in Table 1 below:

Table 1. Induction of UCP-1 Expression

Compound No.	Activation (fold)
1	5.5
2	6.1
3	7.5
4	7.2
5	4.6
6	3.4
7	5.8
8	6.1
9	2.9
10	3.1
11	7.0
12	5.2
13	2.4
14	5.7

Biological Example 2. High Fat Diet Induced Obesity Mouse Model

The overall scheme of the mouse model is shown in FIG. 1.

Mice: Eight-week-old male C57BL/6J mice were maintained on a 12-h light/12-h dark cycle at 23 ℃ and fed on a high-fat diet (D12492, Research Diet) for 8 weeks. Then these obese mice were gavaged daily with vehicle or compounds (25 mg/kg body weight) for 8 weeks. The high fat diet provides 21.9 kJ/g: 60%of energy from fat, 20%from protein, and 20%from carbohydrate. Food intake and mice were weighed weekly. Animal experiments were approved by the Animal Care and Use Committee of Guangzhou Institute of Biomedicine and Health (GIBH) , Chinese Academy of Sciences. All animal experiments were conducted in accordance with the GIBH Guide for the Care and Use of Laboratory Animals.

Glucose and Insulin Tolerance Tests: For the glucose-tolerance test, mice were fasted overnight and injected intraperitoneally (i.p. ) with 15%glucose (w/v) at a dose of 2 g/kg. For the insulin-tolerance test, mice were fasted for 6 h and injected with recombinant human insulin (Eli Lilly, 0.5 U/kg i.p. ) . Blood glucose was monitored in the tail vein blood with a glucometer (ACCU-CHEK Advantage; Roche Diagnostics) at various time points.

Histology: Liver, brown adipose tissue and inguinal and epididymal adipose tissues were fixed in 4%formaldehyde overnight at room temperature, embedded in paraffin, and cut into 5-μm section with a microtome. The slides were deparaffinized, rehydrated, and stained with hematoxylin and eosin (Sigma) by a standard protocol.

Analysis of plasma constituents: Blood samples were collected and centrifuged at 3000g for 30min, then the supernatant were harvested. Plasma triacylglycerol (E1025) , ALT (E2021) and AST (E2023) were measured using commercial Kit from Beijing applygen Technology Co., Ltd.

Quantification of TG contents in liver: The tissue was broken by electric high-speed homogenizer and stand for 10 minutes. Transfer an appropriate amount of supernatant to 1.5ml centrifuge tube and heated at 70 ℃ for 10 minutes. Centrifugation at 2000 rpm at room temperature for 5 minutes, the supernatant can be used for enzymatic determination by the same Triacylglycerol Kit mentioned above.

Several compounds were tested in this model and the results are shown in the

tables 2-5 below.

In particular, Table 2 shows the effect of the compounds on glucose reduction and insulin sensitivity. These tested compounds have similar efficacy.

Table 2. Effect on glucose and insulin sensitivity

Table 3 shows the effect of the compounds on body weight reduction.

Table 3. Effect on body weight reduction

^a.Compound 17 is 4- (2- (pyridin-2-ylamino) thiazol-4-yl) benzoic acid, which was prepared similarly according to the synthetic methods described herein.

Table 4 shows the effect of the compounds on liver functions, including ALT/AST ratio, liver triglycerides, and liver weight. In Table 4, "****" refers to higher efficacy compared to "*" .

Table 4. Effect on liver function

Table 5 shows the effect of compounds on fat tissue size. In Table 5, "****" refers to higher efficacy compared to "*" .

Table 5. Effect on fat tissue size

Compound No.

Fat tissue size

1	****
2	****
3	****
4	****
11	*
12	****
13	*
14	*

The Summary and Abstract sections may set forth one or more but not all exemplary embodiments of the present invention as contemplated by the inventor (s) , and thus, are not intended to limit the present invention and the appended claims in any way.

The present invention has been described above with the aid of functional building blocks illustrating the implementation of specified functions and relationships thereof. The boundaries of these functional building blocks have been arbitrarily defined herein for the convenience of the description. Alternate boundaries can be defined so long as the specified functions and relationships thereof are appropriately performed.

With respect to aspects of the invention described as a genus, all individual species are individually considered separate aspects of the invention. If aspects of the invention are described as "comprising" a feature, embodiments also are contemplated "consisting of” or "consisting essentially of” the feature.

The foregoing description of the specific embodiments will so fully reveal the general nature of the invention that others can, by applying knowledge within the skill of the art, readily modify and/or adapt for various applications such specific embodiments, without undue experimentation, without departing from the general concept of the present invention. Therefore, such adaptations and modifications are intended to be within the meaning and range of equivalents of the disclosed embodiments, based on the teaching and guidance presented herein. It is to be understood that the phraseology or terminology herein is for the purpose of description and not of limitation, such that the terminology or phraseology of the present specification is to be interpreted by the skilled artisan in light of the teachings and guidance.

The breadth and scope of the present invention should not be limited by any of the above-described exemplary embodiments.

All of the various aspects, embodiments, and options described herein can be combined in any and all variations.

All publications, patents, and patent applications mentioned in this specification are herein incorporated by reference to the same extent as if each individual publication, patent, or patent application was specifically and individually indicated to be incorporated by reference. To the extent that any meaning or definition of a term in this document conflicts with any meaning or definition of the same term in a document incorporated by reference, the meaning or definition assigned to that term in this document shall govern.

Claims

A compound of Formula I, a pharmaceutically acceptable ester or amide thereof, or a pharmaceutically acceptable salt thereof:

wherein:

R ¹ is selected from halogen, optionally substituted C _1-6 alkyl, CN, or an optionally substituted C _3-12 carbocyclyl;

Ring A is a phenyl, 5 or 6 membered heteroaryl or a 8-10 membered bicyclic heteroaryl;

each of R ¹⁰ and R ¹¹ at each occurrence is independently halogen, CN, optionally substituted C _1-6 alkyl, optionally substituted C _1-6 alkoxy, optionally substituted -OH, optionally substituted –NH ₂, optionally substituted C _1-6 heteroalkyl, optionally substituted C _3-6 cycloalkyl, optionally substituted C _3-6 cycloalkoxy, or optionally substituted 4-8 membered heterocyclyl,

wherein two R ¹⁰ groups or two R ¹¹ groups, together with the intervening atoms, can optionally form a 4-8 membered ring structure,

wherein m is an integer of 0, 1, 2, 3, or 4, as valency permits; and

n is an integer of 0, 1, 2, or 3.
The compound of claim 1, a pharmaceutically acceptable ester or amide thereof, or a pharmaceutically acceptable salt thereof, wherein R ¹ is a C _1-6 alkyl optionally substituted with one or more substituents, such as 1, 2, or 3 substituents, each independently selected from oxo, F, optionally substituted -OH, optionally substituted C _1-4 heteroalkyl, optionally substituted –NH ₂, optionally substituted C _3-6 cycloalkyl, optionally substituted C _3-6 cycloalkoxy, optionally substituted 4-8 membered heterocyclyl, optionally substituted phenyl, and optionally substituted monocyclic or bicyclic heteroaryl.
The compound of claim 1, a pharmaceutically acceptable ester or amide thereof, or a pharmaceutically acceptable salt thereof, wherein R ¹ is a C _1-4 alkyl optionally substituted with 1-3 fluorine.
The compound of claim 1, a pharmaceutically acceptable ester or amide thereof, or a pharmaceutically acceptable salt thereof, wherein R ¹ is methyl.
The compound of any one of claims 1-4, a pharmaceutically acceptable ester or amide thereof, or a pharmaceutically acceptable salt thereof, wherein n is 1.
The compound of any one of claims 1-5, a pharmaceutically acceptable ester or amide thereof, or a pharmaceutically acceptable salt thereof, wherein R ¹⁰ at each occurrence is independently F, Cl, Br, CN, C _1-6 alkyl optionally substituted with 1-3 fluorine, C _1-6 alkoxy optionally substituted with 1-3 fluorine, C _1-6 heteroalkyl optionally substituted with 1-3 substituents each independently selected from oxo, fluorine, C _1-4 alkyl and C _1-4 alkoxy, C _3-6 cycloalkyl optionally substituted with 1-3 substituents each independently selected from fluorine, C _1-4 alkyl and C _1-4 alkoxy, C _3-6 cycloalkoxy optionally substituted with 1-3 substituents each independently selected from fluorine, C _1-4 alkyl and C _1-4 alkoxy, or 4-8 membered heterocyclyl optionally substituted with 1-3 substituents each independently selected from oxo, fluorine, C _1-4 alkyl and C _1-4 alkoxy.
The compound of any one of claims 1-4, a pharmaceutically acceptable ester or amide thereof, or a pharmaceutically acceptable salt thereof, wherein n is 0.
The compound of any one of claims 1-7, a pharmaceutically acceptable ester or amide thereof, or a pharmaceutically acceptable salt thereof, wherein Ring A is a 5 or 6 membered heteroaryl.
The compound of any one of claims 1-7, a pharmaceutically acceptable ester or amide thereof, or a pharmaceutically acceptable salt thereof, wherein Ring A is pyridyl, such as 2-pyridyl.
The compound of any one of claims 1-9, a pharmaceutically acceptable ester or amide thereof, or a pharmaceutically acceptable salt thereof, wherein m is 1.
The compound of any one of claims 1-10, a pharmaceutically acceptable ester or amide thereof, or a pharmaceutically acceptable salt thereof, wherein R ¹¹ at each occurrence is independently F, Cl, Br, CN, -OH, -NH ₂, -NH (C _1-6 alkyl) , -N (C _1-6 alkyl) (C _1-6 alkyl) , C _1-6 alkyl optionally substituted with 1-3 fluorine, C _1-6 alkoxy optionally substituted with 1-3 fluorine, C _1-6 heteroalkyl optionally substituted with 1-3 substituents each independently selected from oxo, fluorine, C _1-4 alkyl and C _1-4 alkoxy, C _3-6 cycloalkyl optionally substituted with 1-3 substituents each independently selected from fluorine, C _1-4 alkyl and C _1-4 alkoxy, C _3-6 cycloalkoxy optionally substituted with 1-3 substituents each independently selected from fluorine, C _1-4 alkyl and C _1-4 alkoxy, or 4-8 membered heterocyclyl optionally substituted with 1-3 substituents each independently selected from oxo, fluorine, C _1-4 alkyl and C _1-4 alkoxy.
The compound of any one of claims 1-9, a pharmaceutically acceptable ester or amide thereof, or a pharmaceutically acceptable salt thereof, wherein m is 0.
A compound of Formula II, or a pharmaceutically acceptable salt thereof:

wherein:

R ¹ is selected from halogen, optionally substituted C _1-6 alkyl, CN, or an optionally substituted C _3-12 carbocyclyl;

J is O or NR ^A;

R ² is an optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted phenyl, or optionally substituted heteroaryl;

R ^A is hydrogen, an optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted phenyl, or optionally substituted heteroaryl;

or R ^A and R ² are joined to form an optionally substituted heterocyclyl or optionally substituted heteroaryl;

Ring A is a phenyl, 5 or 6 membered heteroaryl or a 8-10 membered bicyclic heteroaryl; each of R ¹⁰ and R ¹¹ at each occurrence is independently halogen, CN, optionally substituted C _1-6 alkyl, optionally substituted C _1-6 alkoxy, optionally substituted -OH, optionally substituted –NH ₂, optionally substituted C _1-6 heteroalkyl, optionally substituted C _3-6 cycloalkyl, optionally substituted C _3-6 cycloalkoxy, or optionally substituted 4-8 membered heterocyclyl,

wherein two R ¹⁰ groups or two R ¹¹ groups, together with the intervening atoms, can optionally form a 4-8 membered ring structure,

wherein m is an integer of 0, 1, 2, 3, or 4, as valency permits; and

n is an integer of 0, 1, 2, or 3.
The compound of claim 13, or a pharmaceutically acceptable salt thereof, wherein R ¹ is a C _1-6 alkyl optionally substituted with one or more substituents, such as 1, 2, or 3 substituents, each independently selected from oxo, F, optionally substituted -OH, optionally substituted C _1-4 heteroalkyl, optionally substituted –NH ₂, optionally substituted C _3-6 cycloalkyl, optionally substituted C _3-6 cycloalkoxy, optionally substituted 4-8 membered heterocyclyl, optionally substituted phenyl, and optionally substituted monocyclic or bicyclic heteroaryl.
The compound of claim 13, or a pharmaceutically acceptable salt thereof, wherein R ¹ is a C _1-4 alkyl optionally substituted with 1-3 fluorine.
The compound of claim 13, or a pharmaceutically acceptable salt thereof, wherein R ¹ is methyl.
The compound of any one of claims 13-16, or a pharmaceutically acceptable salt thereof, wherein n is 1.
The compound of any one of claims 13-17, or a pharmaceutically acceptable salt thereof, wherein R ¹⁰ at each occurrence is independently F, Cl, Br, CN, C _1-6 alkyl optionally substituted with 1-3 fluorine, C _1-6 alkoxy optionally substituted with 1-3 fluorine, C _1-6 heteroalkyl optionally substituted with 1-3 substituents each independently selected from oxo, fluorine, C _1-4 alkyl and C _1-4 alkoxy, C _3-6 cycloalkyl optionally substituted with 1-3 substituents each independently selected from fluorine, C _1-4 alkyl and C _1-4 alkoxy, C _3-6 cycloalkoxy optionally substituted with 1-3 substituents each independently selected from fluorine, C _1-4 alkyl and C _1-4 alkoxy, or 4-8 membered heterocyclyl optionally substituted with 1-3 substituents each independently selected from oxo, fluorine, C _1-4 alkyl and C _1-4 alkoxy.
The compound of any one of claims 13-16, or a pharmaceutically acceptable salt thereof, wherein n is 0.
The compound of any one of claims 13-19, or a pharmaceutically acceptable salt thereof, R ² is a C _1-16 alkyl, C _2-16 alkenyl, C _2-16 alkynyl, C _3-12 carbocyclic ring, or 4-10 membered heterocyclic ring, each optionally substituted with one or more substituents, such as 1, 2, or 3 substituents, each independently selected from halogen, -OH, -NR ¹²R ¹³, - (NR ¹²R ¹³R ¹⁴) ⁺, -C (O) -NR ¹²R ¹³, -COOR ¹⁵, -N (R ¹⁶) -C (O) -R ¹⁷, -O-C (O) -R ¹⁸, -O-C (O) -NR ¹²R ¹³, -O-COOR ¹⁵, -N (R ¹⁶) -C (O) -O-R ¹⁵, -O-C (O) -O-R ¹⁵, -N (R ¹⁶) -C (O) -NR ¹²R ¹³, CN, optionally substituted C _1-6 heteroalkyl, optionally substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted phenyl, and optionally substituted monocyclic or bicyclic heteroaryl, wherein:

each of R ¹², R ¹³, R ¹⁴, and R ¹⁶ at each occurrence is independently hydrogen, a nitrogen protecting group, an optionally substituted C _1-6 alkyl, optionally substituted carbocyclic ring, or optionally substituted heterocyclic ring; or R ¹² and R ¹³ are joined to form an optionally substituted heterocyclic or heteroaryl ring,

wherein R ¹⁵ at each occurrence is independently hydrogen, an oxygen protecting group, an optionally substituted C _1-6 alkyl, optionally substituted carbocyclic ring, or optionally substituted heterocyclic ring;

each of R ¹⁷ and R ¹⁸ at each occurrence is independently hydrogen, an optionally substituted alkyl, optionally substituted carbocyclic ring, optionally substituted heterocyclic ring, optionally substituted phenyl, or optionally substituted monocyclic or bicyclic heteroaryl.
The compound of any one of claims 13-20, or a pharmaceutically acceptable salt thereof, wherein J is O.
The compound of any one of claims 13-20, or a pharmaceutically acceptable salt thereof, wherein J is NR ^A, and R ^A is hydrogen or optionally substituted C _1-6 alkyl.
The compound of any one of claims 13-22, or a pharmaceutically acceptable salt thereof, wherein Ring A is a 5 or 6 membered heteroaryl.
The compound of any one of claims 13-23, or a pharmaceutically acceptable salt thereof, wherein Ring A is pyridyl, e.g., 2-pyridyl.
The compound of any one of claims 13-24, or a pharmaceutically acceptable salt thereof, wherein m is 1.
The compound of any one of claims 13-25, or a pharmaceutically acceptable salt thereof, wherein R ¹¹ at each occurrence is independently F, Cl, Br, CN, -OH, -NH ₂, -NH (C _1-6 alkyl) , -N (C _1-6 alkyl) (C _1-6 alkyl) , C _1-6 alkyl optionally substituted with 1-3 fluorine, C _1-6 alkoxy optionally substituted with 1-3 fluorine, C _1-6 heteroalkyl optionally substituted with 1-3 substituents each independently selected from oxo, fluorine, C _1-4 alkyl and C _1-4 alkoxy, C _3-6 cycloalkyl optionally substituted with 1-3 substituents each independently selected from fluorine, C _1-4 alkyl and C _1-4 alkoxy, C _3-6 cycloalkoxy optionally substituted with 1-3 substituents each independently selected from fluorine, C _1-4 alkyl and C _1-4 alkoxy, or 4-8 membered heterocyclyl optionally substituted with 1-3 substituents each independently selected from oxo, fluorine, C _1-4 alkyl and C _1-4 alkoxy.
The compound of any one of claims 13-24, or a pharmaceutically acceptable salt thereof, wherein m is 0.
A compound selected from Compound Nos. 1-21, or a pharmaceutically acceptable salt thereof.
A pharmaceutical composition comprising the compound or pharmaceutically acceptable ester or amide thereof according to any one of claims 1-12, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.
A pharmaceutical composition comprising the compound according to any one of claims 13-28, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.
A method of inducing uncoupling protein-1 (UCP-1) expression and/or mitochondrial oxidative metabolism in a white adipose tissue, the method comprising contacting the white adipose tissue with an effective amount of the compound or pharmaceutically acceptable ester or amide thereof according to any one of claims 1-12, the compound according to any one of claims 13-28, or a pharmaceutically acceptable salt thereof.
A method of inducing browning of a white adipose tissue, the method comprising contacting the white adipose tissue with an effective amount of the compound or pharmaceutically acceptable ester or amide thereof according to any one of claims 1-12, the compound according to any one of claims 13-28, or a pharmaceutically acceptable salt thereof.
A method of treating diabetes (e.g., Type 2 diabetes) in a subject in need thereof, the method comprising administering to the subject an effective amount of the compound or pharmaceutically acceptable ester or amide thereof according to any one of claims 1-12, the compound according to any one of claims 13-28, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of claim 29 or 30.
A method of treating obesity in a subject in need thereof, the method comprising administering to the subject an effective amount of the compound or pharmaceutically acceptable ester or amide thereof according to any one of claims 1-12, the compound according to any one of claims 13-28, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of claim 29 or 30.
A method of treating improving liver health in a subject in need thereof, the method comprising administering to the subject an effective amount of the compound or pharmaceutically acceptable ester or amide thereof according to any one of claims 1-12, the compound according to any one of claims 13-28, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of claim 29 or 30.
A method of lowering liver triglycerides in a subject in need thereof, the method comprising administering to the subject an effective amount of the compound or pharmaceutically acceptable ester or amide thereof according to any one of claims 1-12, the compound according to any one of claims 13-28, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of claim 29 or 30.
A method of treating non-alcoholic steatohepatitis in a subject in need thereof, the method comprising administering to the subject an effective amount of the compound or pharmaceutically acceptable ester or amide thereof according to any one of claims 1-12, the compound according to any one of claims 13-28, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of claim 29 or 30.
A method of treating non-alcoholic fatty liver disease in a subject in need thereof, the method comprising administering to the subject an effective amount of the compound or pharmaceutically acceptable ester or amide thereof according to any one of claims 1-12, the compound according to any one of claims 13-28, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of claim 29 or 30.